Regio- and Stereoselective Catalytic Addition of Amides to Alkynes

Transcription

1 egio- ad Stereoselective Catalytic Additio of Amides to Alkyes Dissertatio geehmigt vom Fachbereich Chemie der Uiversität Kaiserslauter zur Verleihug des akademische Grades Doktor der aturwisseschafte D Vorgelegt vo Dipl. Chem. Mathieu Blachot gebore i Autu (Frakreich) Betreuer: Prof. Dr. Lukas J. Gooße Kaiserslauter, 009

2 Die vorliegede Arbeit wurde i der Zeit vo September 00 bis Februar 009 i der Arbeitsgruppe vo Prof. Dr. L. J. Gooße a der Techische Uiversität Kaiserslauter agefertigt. Prüfugskommissio Vorsitzeder Prof. Dr. S. Erst. Gutachter Prof. Dr. S. Kubik. Gutachter Prof. Dr. L. Gooße Tag der müdliche Prüfug:

3 Eidesstattliche Erklärug iermit versichere ich, dass ich die vorliegede Arbeit eigestädig verfasst ud keie adere als die agegebee Quelle ud ilfsmittel verwedet, sowie Literaturzitate ketlich gemacht habe. Ich erkläre außerdem, dass diese Arbeit weder i gleicher och i ählicher Form bereits i eiem adere Prüfugsverfahre vorgelege hat. Kaiserslauter, de (Mathieu Blachot)

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5 Abbreviatios Abbreviatios -Fur ortho-furyl Ac acetyl acac acetylacetoate Ar aryl biol, -bi--aphthol B bezyl Cat. catalyst cod/cd,-cyclooctadiee cot/ct,,,-cyclooctatetraee Cp cyclopetadieyl Cy cyclohexyl dcpe bis(dipheylphosphio)ethae dcypb bis(dicyclohexylphosphio)butae dcypm bis(dicyclohexylphosphio)methae DMA,-dimethylacetamide DMAP dimethylamiopyridie DMF dimethylformamide dmfm dimethyl fumarate DMS dimethylsulfoxide dppb bis(dipheylphosphio)butae Eq. equivalet Et ethyl GC gas chromatography PLC high pressure liquid chromatography i Pr/i-Pr iso-propyl L ligad M metal Me methyl met methallyl MS mass spectroscopy MW microwave heatig ormal-butyl /- -i-

6 Abbreviatios ex/-ex ormal-hexyl MP -methylpyrrolidioe M uclear magetique resoace Pet/-Pet ormal-petyl Pr/-Pr ormal-propyl u ucleophile ormal-udecae Ud/-Ud pheyl ppm parts per millio temp. temperature Tf trifluoromethae sulfoyl TF tetrahydrofurae Tp tris(pyrazolyl)borate Ts -tolueesulfoyl X halide or pseudohalide - ii -

7 Table of cotets Table of cotets Abbreviatios... i Table of cotets... iii Product umberig... iv Publicatios... iv Geeral part.... Itroductio.... Eamides.... Additio of hydroge boded ucleophiles to alkyes.... Project aim... esults ad discussio.... Additio of imides to alkyes.... Additio of primary amides to alkyes.... Secod geeratio catalyst for the additio of secodary amides to alkyes.... Mechaistic studies of the hydroamidatio of alkyes Additio of thioamides to alkyes Markovikov additio of secodary amides to alkyes... Summary ad future aspects... Ackowledgemets... Experimetal part.... Geeral iformatio.... Additio of imides to alkyes.... Additio of primary amides to alkyes.... Secod geeratio catalyst for the additio of secodary amides to alkyes..... Additio of thioamides to alkyes.... Markovikov additio of secodary amides to alkyes Procedure for the mechaistic studies... 9 Literature iii -

8 ote Product umberig For practicality reasos, the umberig of some compouds is differet throughout the dissertatio. For example, -hexye appears with the umber a i chapter., but also with the umbers a, a ad a i chapters.,. ad. respectively. Publicatios The results of this work were published i the followig publicatios: Lukas J. Goosse, Mathieu Blachot, Claus Brikma, Käthe Goosse, alf Karch, ad Adreas ivas-ass, J. rg. Chem. 00,, , u-catalyzed Stereoselective Additio of Imides to Alkyes. Lukas J. Gooße, Kifah S. M. Salih, Mathieu Blachot Agew. Chem. It. Ed. 00,, 9-9; Agew. Chem. 00, 0, 0-, Sythesis of Secodary Eamides by utheium-catalyzed Selective Additio of Amides to Termial Alkyes. Lukas J. Goosse, Mathieu Blachot, Kifah S. M. Salih, alf Karch, Adreas ivas-ass rg. Lett. 00, 0, 9-99, utheium-catalyzed Stereoselective ati-markovikov Additio of Thioamides to Alkyes. Lukas J. Gooße, Matthias Ardt, Mathieu Blachot, Felix udolphi, Fabia Meges, Gereo ieder-schatteburg Adv. Syth. Catal. 00, 0, 0-0, A Practical ad Effective utheium Trichloride-Based Protocol for the egio- ad Stereoselective Catalytic ydroamidatio of Termial Alkyes. Lukas J. Goosse, Mathieu Blachot, Kifah S. M. Salih, alf. Karch, Adreas. ivas-ass Syfacts 00,, Stereodiverget Sythesis of (Z)- ad (E)-Thioeamides. - iv -

9 Itroductio. Geeral part Itroductio Developmet that meets the eeds of the preset without compromisig the ability of future geeratios to meet their ow eeds. This is the defiitio for Sustaiable Developmet, a sciece i which Gree Chemistry represets a major compoet. The term Gree Chemistry was coied by Aastas of the US Evirometal Protectio Agecy (EPA) i 99. This does ot mea that research o gree chemistry did ot exist before the early 990s, merely that it did ot have the ame. t what does Gree Chemistry mea? owadays, chemistry is a sciece so far developed that it is possible to prepare ay desired orgaic compoud as log as it is sufficietly stable ad its structure ca be draw. Utilizatio of this capability is most ofte foud i agrochemical, fie chemical or pharmaceutical idustries. For istace, certai pharmaceuticals have aual sales exceedig oe billio US dollars per years (blockbusters). It is therefore essetial to strive for the ideal reactio which produces oly the desired compoud ad miimizes the formatio of waste i a simple, safe ad evirometally acceptable process. Based o this fact a ew chemical philosophy called Gree Chemistry has emerged almost twety years ago. I order to explai what this ew philosophy meas, Paul Aastas came out with the twelve priciples of Gree Chemistry. ) It is better to prevet waste tha to treat or clea up waste after it is formed. ) Sythetic methods should be desiged to maximize the icorporatio of all materials used i the process ito the fial product. ) Wherever practicable, sythetic methodologies should be desiged to use ad geerate substaces that possess little or o toxicity to huma health ad the eviromet. ) Chemical products should be desiged to preserve efficacy of fuctio while reducig toxicity. ) The use of auxiliary substaces (e.g. solvets, separatio agets, ad so forth) should be made uecessary wherever possible ad iocuous whe used. ) Eergy requiremets should be recogized for their evirometal ad ecoomic impacts ad should be miimized. Sythetic methods should be coducted at ambiet temperature ad pressure. --

10 Itroductio ) A raw material or feedstock should be reewable rather tha depletig wherever techically ad ecoomically practicable. ) Uecessary derivatizatio (blockig group, protectio/deprotectio, temporary modificatio of physical/chemical processes) should be avoided wheever possible. 9) Catalytic reagets (as selective as possible) are superior to stoichiometric reagets. 0) Chemical products should be desiged so that at the ed of their fuctio they do ot persist i the eviromet ad break dow ito iocuous degradatio products. ) Aalytical methodologies eed to be developed further to allow for real-time iprocess moitorig ad cotrol before the formatio of hazardous substaces. ) Substaces ad the form of a substace used i a chemical process should be chose so as to miimize the potetial for chemical accidets, icludig releases, explosios, ad fires. Uder ideal reactio coditios, substace A reacts with substace B to produce the desired product (C) (equatio ). ) AB C t i reality, chemical reactios produce waste (W), eed temperature ( ) or pressure (P) ad use orgaic solvets (S), which could be flammable, volatile, ad toxic, with resultat potetial threat to both the eviromet ad huma health (equatio ). ) AB, S, P CW owadays, the use of catalysts represets probably the best way to get close to this utopia ideal reactio. It results i remarkable acceleratio of some reactios ad ca also allow selective actio. A ideal catalyst alters the speed of a chemical reactio by its presece while ot beig cosumed itself. I moder chemistry, approximately 0% of all chemicals are produced while i cotact with a catalyst i oe or more process steps. A good example to illustrate this idea is the sythesis of hydroquioe (Scheme ). It was traditioally produced by oxidatio of ailie with stoichiometric amouts of magaese dioxide to give bezoquioe. eductio of the latter by iro ad hydrochloric acid gave access to the desired hydroquioe (Béchamp reductio). Ailie was previously derived --

11 Itroductio from bezee via itratio ad Béchamp reductio. The overall process geerated more tha 0 kg of iorgaic salts per kg of hydroquioe. A more moder route that has ow replaced this old process ivolves autoxidatio of p-di-isopropylbezee (produced by Friedel-Crafts alkylatio of bezee), followed by acid-catalyzed rearragemet of the bis-hydroperoxide, producig less tha kg of iorgaic salts per kg of hydroquioe. M Fe Cl Classical S Fe Cl Catalytic - MeC Scheme : two routes for the sythesis of hydroquioe. Aother example of a atom-ecoomic reactio is the catalytic additio of hydroge boded ucleophiles to alkyes (Scheme ). Because of the high importace of the products resultig from this kid of trasformatios, the catalytic additios of u- substrates across C-C multiple bods have bee the focus of may studies both from the academic ad idustrial world. owever, oe particular class of ucleophiles has ot bee yet studied for this trasformatio, amely the amides. This remarkable eglect is really very surprisig cosiderig the eormous potetial of this reactio from a sythetic poit of view. Scheme : additio of amides to alkyes. -- [cat.]

12 Itroductio Thus, it appeared essetial for us to develop a catalyst system which would allow the direct sythesis of the eamide moiety by additio of a amide to a alkye. The aim of this thesis was to achieve the sythesis of the eamide substructure i the most atom-ecoomic ad evirometally friedly way. owever, as ca bee see i the figure below, may challeges have to be surmouted before a reactio of this type ca have broad idustrial sythetic applicatios. chemoselectivity stereoselectivity FG regioselectivity Figure : chemo-, stereo- ad regiocotrol of the additio of ucleophile across C-C multiple bod. Sice amides are weak ucleophiles, a o-catalytic direct additio of amides to the triple bod of a alkye is ot favored, thus the catalyst system has to overcome first the problem of chemoselectivity so that oly attacks o the triple bod will take place ad ot o the possible fuctioal groups. The, the regioselectivity of the reactio has to be cotrolled i such a way that the product resultig from either a Markovikov or a ati-markovikov attack will be formed selectively. Fially, if the ati-markovikov product is desired, a catalytic system able to favor oly oe of the stereoisomers has to be foud. Thus, a perfectly optimized catalytic system must be desiged, which should be able to cotrol all these parameters, so that oly oe product will be formed selectively. This catalytic system should also be highly efficiet i terms of turover umber so that the amout of waste products could be reduced to a miimum, accordig to the atom-ecoomy priciples. --

13 Eamides... Eamides Eamides as substructure i atural products The eamide or -viylamide fuctioal group is a substructure ofte ecoutered i the literature. The eamide likage represets a fragile structural elemet that is promietly featured i a wide rage of atural products with promisig biological activities. Several fugicides, metabolic drugs, ad fuctioal materials cotai eamides as key structural elemets (Scheme ). Lasiumamid A Lasiumamid B Lasamid-I (/-) Salicylihalamid A: (E) (/-) Salicylihalamid B: (Z) Apiculare A S S S Fugicide Semicoductor for photoelectric coverters Scheme : eamides i bioactive or fuctioal molecule. For example, the leaves ad fruits of Clausea lasium have bee used as folk medicie i Souther Chia to treat a rage of ailmets icludig asthma ad viral hepatitis. Amog other cyclic amides, three major compouds have bee isolated from the leaves of Clausea lasium: Lasiumamid A, B ad Lasamid-I. the other had, Apiculare A isolated from a myxobacteria ad salicylihalamide A ad B preset i the marie spoge alicoa show high activity agaist huma tumor cells. --

14 Eamides.. Eamides as substrates Eamides are also versatile sythetic itermediates that ca serve as substrates for polymerizatios, []-cycloadditios, cross-couplig reactios, eck olefiatios,9 0 eatioselective additios or asymmetric hydrogeatios. Poly(-viyl--pyrrolidioe) (PVP) for example is probably the best characterized ad most widely studied -viyl polymer. Some of the umerous applicatios of the eamide moiety i orgaic sythesis are depicted i scheme below. eatioselective hydrogeatio [] cycloadditio Ac Cl Pet eatioselective additio B [] hetero-cycloadditio Ar MeC Ac Ac Me CMe eck olefiatio Suzuki Cross-couplig Scheme : applicatio of the eamide moiety i orgaic sythesis. umerous heterocycles ca be sythesized by []-cycloadditios usig eamides ad aromatic imies (Scheme )a or Michael-Acceptors (Scheme )b as startig materials. --

15 Eamides Pet Y(Tf) Pet CC, C % yield Scheme : regioselective Lewis acid catalyzed []-cycloadditio by Povarov. Me Eu(fod) [ ] Me Me,, =, Alkyl, eyl up to 9% yield Scheme : sythesis of --deoxyglycoside by [ ]-heterocycloadditio. Eamides ca also serve as substrates for Suzuki couplig, for example i the sythesis of βbrached α-amio acids (Scheme ) or for eck olefiatio reactios for the sythesis of eatiopure substituted pheylalaies (Scheme ).9 I Me Ac ) ArB(), Pd(Ac) CMe ) ac, Et Suzuki couplig Ar Me Ar Me Ar Me or Ac CMe C up to % yield (last step) >99% ee C up to 9% yield (last step) >99% ee Scheme : Suzuki cross-couplig i the sythesis of β-brached α-amio acids. MeC Ac Br Pd(Ac) CCEtBr eck lefiatio MeC Ac MeC up to % yield Scheme : eck olefiatio reactio i the sythesis of eatiopure substituted pheylalaies. -- * Ac

16 Eamides The copper(ii)-catalyzed eatioselective additio of eamides to imies also represets a sigificat use of the eamide moiety i asymmetric catalysis (Scheme 9).0 Et 0 mol% Cu(Tf) 0 mol% L* B CCl Ud Ud * Et 9% yield B 9% ee L*= = -aphthyl Scheme 9: copper-catalyzed eatioselective additio of eamides to imies. The eatioselective hydrogeatio of eamides catalyzed by chiral rhodium moodetate phosphite complexes delivers chiral amies i high eatioselectivities (Scheme 0). Ac Cl - mol% [h(cod)] [BF] mol% ligad * Ac ligad: bar, CCl, T, h P Cl 00% cov 9% ee () Scheme 0: eatioselective hydrogeatio of eamides. -- = ()-C()(C)(S-biol)

17 Eamides.. The traditioal sytheses of eamides The regio- ad stereoselective costructio of eamide substructures represets a major challege a major challege for orgaic chemists ad due the high importace of this substructure, there have bee umerous attempts to fid a way to prepare eamides regio- ad stereoselectively. A o-exhaustive list of sythetic ways to prepare eamides is depicted i scheme below. i) ) Peterso elimiatio ) codesatio CCl SiMe ) isomerizatio of -allylamides ) oxidative amidatio of alkees = EWG ) cross-couplig reactio ) Curtis rearragemet of acyl azide X X= Tf,Br,I,BF-K Ar ) co-dimerizatio reactio ) eck reactio Br EtC Scheme : traditioal sythetic pathways for eamides. Codesatio reactio (Scheme, equatio ) permits the sythesis of eamides startig from aldehydes ad alkyes. This reactio mostly delivers the E-isomer or a mixture of the E/Z-isomers ad ofte requires the use of strog bases or high temperatures. For example, Zezza ad Smith used a codesatio reactio for the sythesis of -alkeyl lactams (Scheme ).f -9-

18 Eamides eq. p-ts toluee, reflux 90% yield >99/ E/Z Scheme : codesatio reactio from Zezza ad Smith. The palladium-catalyzed amidatio of alkees (Scheme, equatio ) allows the costructio of the eamide motif uder mild coditios. Startig from alkees bearig electro withdrawig groups ad amides this reactio allows the sythesis of umerous eamides. evertheless, the E/Z cofiguratio is highly depedat o the amide employed, ad this reactio is strictly limited to a specific class of alkees. Below, the palladium(ii)catalyzed amidatio of alkees from Murahashi et al. for the sythesis of (E)--carbamates (Scheme ).a mol% PdCl(MeC) mol% CuCl Me DME,, 0 C % yield Me Scheme : palladium catalyzed amidatio of alkees from Murahashi. Palladium or copper catalyzed cross-couplig betwee amides ad viyl halide, -triflate, -ether or trifluoroborate salts (Scheme, equatio ) allows the stereoselective sythesis of the E- or Z-isomer i good yields. The geometry of the product is directed by the geometry of the substituted alkee. The major drawback of this reactio is the low availability of the viyl compouds ad/or the ligads employed. A good example for this reactio is the copper catalyzed couplig of viyl halides with amides promoted by,-dimethylglycie developed by Ma et al (Scheme ).b 0 mol% CuI 0 mol%,-dimethylglycie Cl salt eq. CsC Br dioxae, 0 C, h Z/E = / % yield Z/E = / Scheme : couplig reactio of viyl halides with amides uder catalysis of CuI ad,-dimethylglycie

19 Eamides A eck reactio usig viyl amides ad usaturated halides (Scheme, equatio ), such as the reactio developed by sacca et al. (Scheme )b allows the sythesis of eamides. evertheless, sice oe of the startig materials is already a eamide, sythesis of the latter is ecessary, moreover, the reactio is limited to usaturated halides such as aryl halides i most of the cases. 0. mol% Pd(Ac) eq. -Cl. eq. ac I DMF, 90 C, h % yield Scheme : eck reactio by sacca. After treatmet of the α-tms-β-amio alcohol with the correspodig carboxylic acid chloride, the desired eamide could be obtaied by a Peterso elimiatio i moderate yields. I this case agai, the selectivity issue is trasferred to the preparatio of the α-tms-βamio alcohol (Scheme, equatio ). evertheless, the multistep sythesis of the latter represets the major drawback of this reactio. Fürster et al. coverted viylsilaes ito eamides by a multistep sythesis with a Peterso elimiatio as a key step reactio (Scheme ). i) epoxidatio ii) ucleophilic rig opeig with a iii) reductio of the azide SiMe SiMe eq. Et eq. CyCCl TF, T, h oe-pot -acylatio/peterso elimiatio % yield Scheme : Peterso elimiatio as a key step reactio i the sythesis of eamides. - -

20 Eamides Double bod migratio of -allylamides catalyzed by rutheium or rhodium (Scheme, equatio ) is also a coveiet method to produce eamides. Drawbacks of the reactio are a poor scope of the reactio limited to -allylamides ad o direct availability of the startig materials. A example of this reactio is the rutheium catalyzed isomerizatio of allylamides to correspodig -(-propeyl)amides from Pigulla et al (Scheme ). mol% ucl(c)(p) 00% yield 9/ E/Z bezee, 0 C, h Scheme : sythesis of -(-propeyl)ethaamide by Pigulla et al. eactio ivolvig orgaometallic additio of viyl Grigards to viyl isocyaates (Scheme, equatio ), which are readily obtaied usig the Curtius rearragemet of acyl azides, is also a suitable method for preparig eamides. The E/Z geometry of the product is directed by the geometry of the viyl isocyaate, evertheless, if the Z-isomer is the desired product oly the reactio carried out at very low temperatures will preserve the Z-geometry, otherwise, the E-isomer predomiate. A iterestig applicatio of this method is the sythesis of the atural product Lasamide I developed by Taylor et al. (Scheme ). toluee,, h C BrMg % overall yield a, MeI 90 % yield Lasamide-I Scheme : sythesis of Lasamide-I by Tailor et al. ecetly, Kodo et al. have developed the rutheium-catalyzed co-oligomerizatio of -viylamides with alkees (Scheme, equatio )9 which provides E-eamides i good yields (Scheme 9). owever, the preparatio of the -viylamides is ot trivial at all, ad represets the same major disadvatage of the reactio. - -

21 Eamides CEt mol% u(cot)(dmfm) DMA, 0 C, h CEt % yield Scheme 9: co-oligomerizatio of -viylamides with alkees. evertheless, oe of these methods allows a cocise ad evirometally beig approach for the sythesis of eamides. Isufficiet availability of the startig materials, poor selectivity of the reactio or harsh reactio coditios are the mai drawbacks. A catalytic additio of amides to alkyes would be a ideal sythetic etry to eamides, sice it would use readily available startig materials ad be iheretly atom-ecoomic. Moreover, similar reactios, e.g. additio of hydroge-boded ucleophiles such as carboxylates, water, ad amies are well established ad represeted a great source of ispiratio for our work. - -

22 Additio of hydroge boded ucleophiles to alkyes. Additio of hydroge boded ucleophiles to alkyes The additio of hydroge boded ucleophiles (u-) across the carbo-carbo triple bod, catalyzed by trasitio-metal complexes, is oe of the most iterestig ad itriguig subjects i orgaic chemistry. ly four types of ucleophiles (carboxylates, water, amies ad amides) will be covered i the followig chapter; but this kid of chemistry also icludes other differet types of bods, such as S-, Se-, ad P-. The atom ecoomy of this process, coupled with miimized amouts of produced waste, make this chemistry far more evirometally friedly tha substitutio reactios leadig to the same products, ad explai the kee iterest i ad the importace of these trasformatios. esultig from this reactio, very useful alkeyl orgaic compouds, such as itroge- ad oxyge- cotaiig products, ca be obtaied. Moreover, the itramolecular versio of this reactio represets a straightforward way to obtai heterocycles. These trasformatios allow very mild reactio coditios whe catalyzed by trasitio metals, ad proceed with good yields ad selectivities if the appropriate catalyst system is employed. It is likely that the major challege ecoutered while performig this kid of trasformatio is the cotrol of the regio- ad stereoselectivity. Ideed, if termial alkyes are employed, three differet products could be obtaied. e product as a result of a Markovikov additio, ofte described as Markovikov product (Scheme 0, equatio ), ad two other products resultig from a ati-markovikov additio, which differ i their stereochemistry Z or E (Scheme 0, equatio ). ) u ) Markovikov pathway u u ) u ) ati-markovikov pathway or u Z E Scheme 0: regio- ad stereoselectivity of the additio of u- to termial alkyes. The type of trasitio-metal complex used, the ature of the hydroge boded to the ucleophile which ca be totally differet depedig o the electroegativity of the - -

23 Additio of hydroge boded ucleophiles to alkyes heteroatom, ad the electroic effect of the alkyes are parameters that strogly affect the selectivity of those reactios. Attempts were made to uderstad the reasos for a reactio to proceed either via a Markovikov or a ati-markovikov pathway. As depicted below, the types of activatio ca be divided ito categories. M M u u u M M or M u M u u ) u ) Markovikov selectivity ati-markovikov selectivity M C C, -shift M u u M - u ) Scheme : differet modes of activatio for the additio of ucleophile to alkyes. Activatio of the carbo-carbo triple bod toward ucleophilic attack ca be performed by metals with high Lewis acidity; this alkye activatio type should lead, after additio of the ucleophile, to a product with Markovikov selectivity (Scheme, equatio ). the other had, the same selectivity is described if the reactio proceeds via isertio of the alkye moiety ito the M- or M-u bod of a activated ucleophile (typically, complex of the type -M-u, Scheme, equatio ). To explai the ati-markovikov selectivity, Dixeuf et al. metioed the possibility of formatio of a rutheium viylidee species with a electro-deficiet u=c carbo site (Scheme, equatio ). There is o doubt that such a approach to the sythesis of may atural products or buildig blocks represets great advatages, particularly because of the relative readily availability ad low costs of the startig materials. The mai problem that chemists have to face i these reactios is to fid the particular catalytic system which would allow the reactio to proceed regio- ad stereoselectively, ad also be relatively cheap ad stable at the same time. The aim of the followig chapter is to summarize some of the most importat results i this area. - -

24 Additio of hydroge boded ucleophiles to alkyes.. Additio of water to alkyes A paitig by M. Kucherov of the Chemical Laboratory at the Imperial Forestry Istitute i St. Petersburg, ussia at the ed of 9th cetury.0 I orgaic molecules, carboyl groups are amog the most commo fuctioalities. A large umber of differet product classes have become accessible from this sigle fuctioality alog with multiple faceted reactio pathways. A relevat example is the idustrial productio of acetaldehyde sythesized by acid catalyzed hydratio of acetylee usig mercury salts. The developmet of this trasformatio was a great revelatio at that momet but was far from complete. owever, this process has bee itesively used for the idustrial productio of acetoe for the explosives maufacture durig the First World War i Germay. After the coflict ad based o the hydratio of acetylee, a variety of idustrial chemicals have bee produced o large scale over may years (Scheme ). - -

25 Additio of hydroge boded ucleophiles to alkyes i ii Me iii Me Me i = hydratio of acetylee usig mercury (II) salts. ii = oxydatio of acetic acid usig oxyge ad magaese acetate. iii = CaC CC Ca(CC) C Ca(CC) Δ Ca C(C)C C Scheme : chemicals accessible from acetaldehyde. Acid-catalyzed hydratio of alkyes has bee kow for a log time. Marcelli Berthelot, durig his work o acetylee (0), described its hydratio i sulfuric acid ad believed he had obtaied viyl alcohol, but it tured out that the product sythesized was a mixture of acetaldehyde ad crotoaldehyde. Twety years later, Kucherov described the mercury salt catalyzed hydratio of acetylees ad alkyes ad first itroduced the cocept of hydratio. A process developed by Kucherov ad usig mercury (II) sulfate is owadays still i use ad was employed all over the years i may applicatios (Scheme ). owever, pollutio by toxic mercurial waste had always bee a problem of the process, ad research aimig to reduce the toxicity of the reactio by replacig mercury by less toxic metals has cotiued over the years sice the additio to C-C triple bod is desirable i terms of atom-ecoomy i formig C- double bod compouds. The acid-catalyzed hydratio of alkyes proceeds by protoatio of the carbo carbo triple bod, followed by fast additio of water to geerate a eol which leads to the correspodig ketoe sice the reactio is directed by the Markovikov rule. owever, oly electro-rich alkyes such as pheyl acetylee react satisfactorily by this method. The reactio of simple - -

26 Additio of hydroge boded ucleophiles to alkyes alkyes is usually sluggish ad eeds co-catalysts, typically mercury (II) salts such as mercury (II) chloride, mercury (II) bromide, mercury (II) acetate or mercury (II) sulfate to ehace the reactivity. The role of the catalyst is to polarize the alkye i order to facilitate the attack of water. Kucherov discovered the activity of mercury(ii) bromide catalyst i the hydratio of alkyes ad later, succeeded i hydratig propye to acetoe ad acetylee to acetaldehyde uder mild coditios by the use of dilute sulfuric acid ad mercuric salts as catalysts (Scheme, equatio ). Carter ad Coaway successfully applied the same method to the sythesis of methyl viyl ketoe from viylacetylee (Scheme, equatio ). Fially, eio et al. exteded the reactio to higher alkyes (Scheme, equatio ). Scheme depicts some examples for this trasformatio. 9 The regiochemistry is idicative of a mercuriium io itermediate which is i tur opeed by ucleophilic attack at the more positively charged carbo; that is, the additio follows the Markovikov rule. Termial ad disubstituted alkyes could also be coverted ito ketoes with very good results. ) g/s = or Me S, gs ) ), C S, gs Me, 0 C 0% yield S, gs ) -% yield, 0 C Scheme : typical mercury catalyzed hydratio of alkyes. Further studies showed that other metal species such as Ag (I), Pd (II), h (III), Pt (II) are also useful for this coversio. oteworthy are platium(ii)-salts such as Zeise s dimer [{PtCl(C)}], that show promisig activities for the hydratio of o-activated alkyes.0 The mechaisms of these reactios are idetical for all of these metals with subtle differeces due to the relative stabilities of the itermediates. Meawhile several aspects of the reactio - -

27 Additio of hydroge boded ucleophiles to alkyes are still uclear ad oly simple mechaisms such as the oe depicted i scheme below are described i the literature. M M M M [M] = g (II), Ag (I), Pd (II), h (III), Pt (II) Scheme : proposed mechaism for the mercury catalyzed hydratio reactio. The alkye uses a pair of electros to attack the electrophilic metal io, yieldig a metal-cotaiig viylic carbocatio itermediate (). ucleophilic attack of water o the carbocatio forms a C- bod ad yields a protoated metal-cotaiig eol (). Abstractio of from the protoated eol by water gives the orgaometallic compoud. eplacemet of M by occurs to give a eutral eol (), which udergoes tautomerizatio to give the fial ketoe product (). Gold has traditioally bee regarded as iactive for catalysis, but it has gaied iterest i the last decades. Whe applied to the hydratio of alkyes, it is able to covert termial ad iteral alkyes ito the correspodig ketoes. The first gold-catalyzed hydratio was observed i 9 usig AuCl but it suffered from low yields.a breakthrough i the field was made by usig catalysts of the type [L-Au] reported by Teles, highly active for the additios of alcohols to alkyes, while they also appear to be very active for the hydratio of alkyes simply by usig methaol as solvet. Gold ios with a d0 electroic cofiguratio, such as [(P)AuMe], have to be combied with a strog acid such as S i order to - 9 -

28 Additio of hydroge boded ucleophiles to alkyes geerate the catioic active species that is able to catalyze the hydratio of alkyes. Activated ad o-activated termial alkyes as well as iteral alkyes are coverted to the correspodig ketoes i very good yields ad selectivities. Although the mechaism of the reactio is ot perfectly uderstood; it could be assimilated to the oe described for the gold catalyzed additio of alcohols to alkyes (Scheme ). Me P Au Me Me Me Me Me P Au P Au Me P Au Me Me P Au Me Me Me Scheme : proposed mechaism for the gold catalyzed additio of alcohols to alkyes. Ufortuately, all of these reactios reported so far follow the Markovikov rule ad exclusively lead to ketoe products i the case of termial alkyes. utheium is oe of the promiet metals i alkye chemistry, however whe applied to the hydratio of alkyes it first appears to oly suffer from i situ deactivatio due to C-C bod cleavage of the termial alkyes by water assisted by rutheium with release of alkaes. The mechaism of this reactio described by Biachii at al. (Scheme ) highlights the possibility of the formatio of a viylidee complex resposible for this deactivatio. owever, other catalysts such as [ucl(c)(p)] are able to covert aryl or alkyl alkyes to the correspodig ketoes as well as aldehydes as side products. As described above, the ability of rutheium to form viylidee itermediates with alkyes leads to a deactivatio of the catalyst, but it appears that this peculiarity represeted a way to - 0 -

29 Additio of hydroge boded ucleophiles to alkyes reverse the selectivity of the reactio. I 99, more tha 00 years after the first catalyzed hydratio of alkyes, Tokuaga ad Wakatsuki developed the first aldehyde sythesis based o catalytic ati-markovikov hydratio of termial alkyes. This ovel hydratio of termial alkyes catalyzed by rutheium(ii) complexes combied with a excess of the appropriate phosphie ligads leads to predomiatly ati-markovikov additio of water ad yields aldehydes with oly a small amout of ketoes (Scheme ). 0 mol% [ucl(c){p(cf)}] 0 mol% P(CF) ipr /, - 00 C up to % yield ad 9% selectivity = -C9, -C, -C0, t-c9,, C,(C)Cl, (C)C Scheme : first catalytic ati-markovikov hydratio of termial alkyes. The mechaism of the reactio is still uder ivestigatio but could be summarized as follows (Scheme ). It is likely that the rutheium catalyzed ati-markovikov hydratio of alkyes ivolves a tautomerizatio of the -alkye complex to the viylidee complex, geeratig a metal-acyl species (0) after attack of the water oxyge atom. This acyl itermediate would udergo the protoolysis of a carbo-metal bod with release of a aldehyde (). The C-C bod cleavage or decarboylatio reactio ( to ) is expected to occur together with the mai reactio, formatio of aldehyde, sice it is a highly favored reactio pathway i the stoichiometric systems reported by Biachii et al. the other had, the formatio of the ketoe 9 ivolves a ucleophilic attack of water o a coordiated alkye () with Markovikov selectivity; this mechaism is similar to the oe ivolvig mercury (II). - -

30 Additio of hydroge boded ucleophiles to alkyes eductive elimiatio or protoolysis u u elimiatio u C u u C-C bod cleavage u 0 ati-markovikov pathway Scheme : mechaism of the rutheium catalyzed hydratio of alkyes. Depedig o the type ad amout of phosphie used, both ati-markovikov ad Markovikov products ca be accessed regioselectively (Scheme ). The role of the phosphie is probably to shift the equilibrium betwee ad (Scheme ). [u-cat.] = -C catalytic system [ucl (C)(P)] 9 Markovikov pathway or - u b yield (%)a of yield (%)a of selectivity / / [ucl (C)(P)] P 9 / [ucl(c){p(cf)}] P(CF)c. / [ucl(c)] P(-CSa) / [ucl(c)] P(-CSa) d eactio coditios: 0 mol % of the u-source ad 0 mol % phosphie whe eeded i -propaol at 00 C for 0 h. a) GLC yields. b) h. c) h ad C. d) i -methoxyethaol. Scheme : differet phosphie ad catalyst combiatios for the hydratio of -octye. - -

31 Additio of hydroge boded ucleophiles to alkyes At preset, rutheium remais the oly metal able to catalyze this reactio ad the oly major improvemet was made by Wakatsuki et al. by usig a cyclopetadieyl ligad. Complexes of the type [Cpu(P) Cl ] remarkably icrease the rate ad the selectivity of the reactio. Catalytic ati-markovikov hydratio of termial alkyes is a ew reactio with great potetial i orgaic sythesis. Its study has just begu ad there is o doubt that fasciatig applicatios will result from this type of chemistry. Moreover, sice the riddle of its mechaism is ot yet solved, it will be iterestig to see whether metals other tha rutheium ca catalyze the reactio. - -

32 Additio of hydroge boded ucleophiles to alkyes.. Additio of carboxylic acids to alkyes Eol esters have bee used i two major areas, polymerizatio ad acylatio. The simplest eol ester is the key moomer for access to polyviyl acetate (Scheme 9, equatio ), while eol esters are activated esters ad ca be used as mild ad efficiet acylatig reagets i orgaic sythesis: o acylatio, they release a eutral ad stable ketoe (Scheme 9, equatio ). ) C C free radical viyl polymerisatio ) C C u u Scheme 9: polymerizatio ad acylatio usig eol esters. Treatmet of aldehydes or ketoes uder either acidic or basic coditios with the appropriate acid ahydride or chloride or acetoxylatio of olefis promoted by palladium acetate are major methods to obtai eol carboxylates. Amog these methods, the additio of carboxylic acids to alkyes, i which mercury catalysts are very useful catalysts, is probably the most elegat way to sythesize eol esters. I 9, Béhal ad Desgrez reported a reactio betwee -heptye ad acetic acid, whe these were heated at 0 C for twety-four hours i a sealed tube.9 The oly product idetified after completio of the reactio was the -methylhexyl acetate 9 which they assumed was formed by the degradatio of the α-viyl acetate 0, which they did ot isolate (Scheme 0). I 9, ieuwlad et al. cofirmed these observatios.9 Performig the additio of acetic acid to -heptye, they obtaied % of the correspodig α-viyl acetate 0 ad the methyl ketoe 9 as a side product of the reactio (%). The use of mercury (II) oxide i combiatio with boro fluoride catalyzes the reactio ad permits the use of a lower temperature (0 C) which probably slows dow the degradatio of compoud 0 to

33 Additio of hydroge boded ucleophiles to alkyes 0 C Pet Pet 9 Pet g, BF, Et 0 C Pet 0 Scheme 0: reactio of -heptye with acetic acid. Sice viyl acetate is a importat raw material for sythetic resis, additio of acetic acid to acetylee has received the major share of attetio. Util 90, additio of acetic acid to acetylee i the presece of mercury or zic acetate o activated charcoal was oe of the major idustrial processes to produce viyl acetate. Eve if the reactio coditios are harsh, it is possible to prepare viyl stearate ad higher viyl esters, or hidered esters by this method (Scheme ).0 [cat.] 0-0 C up to 9 % yields [cat.] = Z(Ac) / charcoal g(ac) / charcoal Scheme : idustrial preparatio of viyl acetate. evertheless, the scope of the reactio is very limited because of the high temperatures used. Moreover, sice the mercury salts are very toxic, developmet of safer catalysts was required. Besides, similarly to the hydratio of alkyes, the mercury catalyzed additio of carboxylic acids to alkyes leads to the Markovikov product ad itesive studies were made to develop suitable methods to obtai the ati-markovikov product. o major improvemet was made i this area util otem ad Shvo i 9 described the first rutheium catalyzed additio of carboxylic acids to alkyes. They showed that u(c) is able to promote the additio of carboxylic acids to dipheylacetylee at C i toluee. Subsequetly Wataabe et al. foud ad reported a catalyst formed i situ from bis(cod)rutheium, a trialkyl phosphie (-P or PCy) ad maleic ahydride, able to - -

34 Additio of hydroge boded ucleophiles to alkyes catalyze the Markovikov additio of carboxylic acids to termial alkyes i high yields ad selectivities (Scheme ). 0-0 mol% [u(cod)] 0-0 mol% -P or PCy 0 mol% maleic ahydride toluee, 0 C, h up to 99% yield up to 99% selectivity % yield, 9% sel. % yield, 9% sel. 99% yield, 99% sel. % yield, % sel. Me 0% yield, % sel. % yield, 00% sel. Scheme : rutheium-catalyzed Markovikov additio of carboxylic acids to alkyes. Almost at the same time, Dixeuf et al. made a importat cotributio to this field by describig [ucl(p-cymee)(p)] ad [{u(c)(c)(p)}] as similarly widely applicable ad highly Markovikov-selective catalysts. Eve -protected amio acids ad peptides ca be coverted smoothly ito viyl esters with these catalysts. The authors also developed a complemetary system from bis(methallyl)rutheium ad the chelatig phosphie,-bis(dipheylphosphio)butae (dppb), with which the (Z)-ati-Markovikov products are selectively accessible for the first time. Furthermore, based o the previous kietic ivestigatios made by the group of Wataabe who showed that the additio of carboxylic acid is rate determiig i the Markoikovselective protocol, Gooße et al. developed a simple catalyst system i which catalytic amouts of base are used to accelerate the reactio ad to cotrol its selectivity. Based o [{ucl(p-cymee)}], the choice of the ligad ad the added base determie the regioselectivity of the reactio. If trifurylphosphie i combiatio with sodium carboate is used, the Markovikov product is formed exclusively. the other had, if tri-pchloropheylphosphie ad -dimethylamiopyridie are employed, the formatio of the Z-ati-Markovikov product is observed (Scheme ). - -

35 Additio of hydroge boded ucleophiles to alkyes 0. mol% [{ucl(p-cymee)}] 0. mol% P(-Fur). mol% ac, toluee, 0 C, h up to 99% yield up to 9% sel. mol% [{ucl(p-cymee)}] mol% P(p-ClC) mol % DMAP, toluee, 0 C, h up to 99% yield up to 9% sel. = -,, Me, t-,... =, p-mec, p-cfc, p-cc, -thieyl,... Scheme : additio of carboxylic acids to termial alkyes. The use of -heterocyclic carbees as ligads for the ati-markovikov additio described by Verpoort et al. represets a alterative to the phosphie system ad also allows the cotrol of the stereoselectivity of the rutheium catalyzed additio of carboxylic acids to alkyes (Scheme ). [cat.] toluee, 0 C, - h Cl Cl u Cl u t- t- -ex -ex C C C C C C [cat.] yield (E/Z) (0/0) 00 (/) 9 (/) 9 (/) (9/9) 9 (/9) (/) (/9) [cat.] = Scheme : ati-markovikov additio of carboxylic acids to alkyes reported by Verpoort. Mechaistically speakig, the formatio of the Markovikov product durig the rutheium catalyzed additio of carboxylic acids to alkyes is due to a ucleophilic attack of the carboxylic acid o a coordiated alkye () with Markovikov selectivity; o the other had, Dixeuf et al. explai that the formatio of the ati-markovikov product ivolves a viylidee itermediate () (Scheme ). - -

36 Additio of hydroge boded ucleophiles to alkyes Lu Lu C Lu - Lu 9 Lu - LuII ul C ati-markovikov pathway Markovikov pathway Scheme : proposed mechaism for the Markovikov ad ati-markovikov additio of carboxylic acids to alkyes. After coordiatio of the alkye to the rutheium ceter () the itermediate could either rearrage to a alkylidee complex () or to a cyclopropee rutheium (). As viylidees are electro-withdrawig ligads, electro rich ligads at the rutheium ceter such as electro rich phosphies or DMAP should stabilize the viylidee itermediates formed from the alkye ad favor the ucleophilic attack o the α-positio of the rutheium ceter to form the itermediate 9. After reductive elimiatio, the ati-markovikov product is obtaied ad the rutheium(ii) species is released. the other had, if the formatio of the viylidee does ot occur, formatio of the itermediate takes place. Sice the additio of carboxylic acid is rate determiig i the Markovikov pathway, presece of a base would accelerate the formatio of the viylcomplex which after reductive elimiatio will give rise to the Markovikov product ad regeerate the rutheium(ii) species. I additio to rutheium, a variety of other catalytic systems have bee employed for the additio of carboxylic acids to alkyes, icludig rhodium or iridium, from which the Markovikov products are formed i good or moderate selectivities. I cotrast, ua et al. reported a system composed oly from the air stable petacarboylrheium(i) bromide which allows the exclusive formatio of the ati-markovikov product (Scheme ).9 Eve if the stereoselectivity outcome of the reactio is still largely depedat o the substrate, this reactio represets a o-egligible alterative to the rutheium system ad the selectivity could presumably be cotrolled better by the use of directig ligads. - -

37 Additio of hydroge boded ucleophiles to alkyes mol% [ebr(c)] 0% yield % sel. toluee, 0 C, h mol% [ebr(c)] toluee, 0 C, h % yield 9% sel. Scheme : e-catalyzed additio of carboxylic acids to alkyes. I summary, the additio of carboxylic acids to alkyes is a well established reactio. The drawback of the high toxicity bearig by mercury complexes has bee overcome by usig rutheium catalysts ad recet breakthroughs made the cotrol of the regio- ad stereoselectivity possible. A better uderstadig of the reactio mechaism could be the key for optimizig the catalyst system ad icreasig the selectivity ad the scope of the reactio. Particularly for the ati-markovikov additio of carboxylic acids to alkyes, for which the cotrol of the stereoselectivity is still largely depedat o the substrates used, well tued catalytic systems or the use of ew metals such as rheium could overcome this key limitatio

38 Additio of hydroge boded ucleophiles to alkyes.. Additio of amies to alkyes Sice ammoia ad amies are much weaker acids tha water or carboxylic acids, ad sice acids could hardly catalyze the reactio (because they would protoate ito ), this reactio does ot occur by a electrophilic mechaism ad so it gives low yields uless extreme coditios are used (e.g., >00 C). Also, the direct additio of ammoia, primary or secodary amies to C-C multiple bods represets the most efficiet, simple ad atom ecoomic process for the formatio of amies, eamies or imies (Scheme ), which are importat buildig blocks for orgaic products, e.g., pharmaceuticals, detergets, techical additives ad dyes. The reactio offers a atomefficiet pathway startig from readily accessible alkees ad alkyes. * eductio if = * eductio Scheme : additio of amies to alkees ad alkyes. Eve if the products resultig from the additio of amies to alkees are more valuable because of their stability, the hydroamiatio of alkyes was for us more iterestig to study because of its direct correlatio with our reactio. Thermal processes ivolvig acetylee ad ammoia usually give complex mixtures of pyridie bases. owever, by cotrollig the speed of the gases evolved ad by usig supported zic compouds as catalysts, pyridie bases are obtaied oly i small amouts ad acetoitrile ad other itriles are formed (Scheme ).0-0 -

39 Additio of hydroge boded ucleophiles to alkyes Z()-SCl-Si-C o celite, 0 C C Et Et Et CC pyridie bases % 0% C 9% Scheme : reactio of acetylee ad ammoia ad possible itermediates. Kozlov was probably the first who observed homogeeous catalyzed hydroamiatio of alkyes. Durig his work o the codesatio of acetylee with ailie (9) he provided experimetal evidece that -pheylethylideeamie is a itermediate which evolves to a aldol-type codesatio product (Scheme 9). gcl eat Scheme 9: hydroamiatio product as itermediate i the reactio of acetylee with ailie. I 99, based o the work of Kozlov, Loritsch et al. described the hydroamiatio of heptye with ailie ad ethylailie catalyzed by mercury oxide ad boro trifluoride. This additio gave the correspodig eamie i low yields (-%). Later o (90), Barluega et al. foud that primary ad secodary aromatic amies ca perform the hydroamiatio of termial alkyl- ad arylalkyes by usig catalytic gcl. I additio, they reported that replacig the mercury catalyst by Tl(Ac) improved the reactio if pheylacetylee is the alkye employed (Scheme 0). - -

40 Additio of hydroge boded ucleophiles to alkyes = 9% yield T, TF C C C gcl, mol % = Me 0 C, amie as solvet Me = % yield 0 C, amie as solvet % yield E/Z mixture Me Tl(Ac), mol% = Me 0 C, amie as solvet % yield Scheme 0: Barluega hydroamiatio. Barluega et al. preseted this reactio as a amiomercuratio-demercuratio of alkyes which ca be described as follows (Scheme ): Ar = Ar Ar gcl Ar Cl Protoolysis = Tautomerism gcl = C Isomerizatio Ar Scheme : amiomercuratio-demercuratio of termial alkyes. - - Ar

41 Additio of hydroge boded ucleophiles to alkyes I geeral, the mai drawback of such protocols is the high toxicity of the catalysts employed ad such reactios could ot be cosidered practical. evertheless, they revealed the possibility of activatio of C-C triple bods agaist ucleophilic attack by amies. The developmets i this area were flourishig ad a plethora of methods were described durig the last decades for itra- or itermolecular hydroamiatio of iteral or termial alkyes. A abudace of differet methodologies usig base or metals such as lathaides (d), actiides (U, Th), earlier trasitio metals (Ti, Zr) ad late trasitio metals (Au, u, Pd, h) have bee used to catalyze these reactios. 9 evertheless, there is still o geeral method to apply this trasformatio to all kids of amies ad alkyes. Amog them, catalysis based o titaium complexes has sigificat advatages compared to that based o some toxic (g, Tl) or more expesive metals (u, h, Pd, U, Th) ad is ofte described i the literature for the hydroamiatio of alkyes. Livighouse described i 99 a itramolecular hydroamiatio of amio alkyes efficietly catalyzed by CpTiCl ad CpTi(Et)Cl (Scheme, equatio ).0 Eve if these catalysts are ot efficiet for the itermolecular hydroamiatio of alkyes, several five- ad sixmembered cyclic imies ca be sythesized. The reactio is performed uder mild coditios usig 0 mol% of the catalyst ad the developmet of a process for the total sythesis of the idolizidie alkaloid (±) moomorie with CpTiCl-catalyzed cyclizatio of amio alkyes as key-step demostrates the efficiecy of this trasformatio (Scheme, equatio ). 0 mol% CpTiCl 0 mol% i-pret ) ) TF, C, h TF, 0 C, h 0 mol% CpTiCl 0 mol% Et TF, C h 9% yield 0 mol% CpTiCl 0 mol% Me ) 9% yield Me (±)-moomorie 9% yield Scheme : itramolecular hydroamiatio of Livighouse. - -

42 Additio of hydroge boded ucleophiles to alkyes I 999, based o the work of Livighouse, Doye et al. disclosed the itermolecular hydroamiatio of iteral alkyes. The procedure developed with CpTiMe as a catalyst eables primary arylamies, as well as tert- ad sec-alkylamies, to be coupled with several disubstituted alkyes i good yields, although primary -alkylamies ad termial alkyes ca oly be coupled i poor yields. I geeral, the more favored product bears the smaller alkye substituet located α to the itroge atom. The iitially formed imies are usually hydrolyzed to ketoes or reduced to secodary amies (Scheme ). Si, CCl ) mol% [CpTiMe] toluee, 00 C, h ) * =, t-, Cy, -ex... LiAl, TF Scheme : Doyle s itermolecular hydroamiatio. A iterestig applicatio for this reactio is the hydroamiatio of iteral alkyes usig α amiodipheylmethae as a ammoia equivalet. This trasformatio, eve if its ot atom ecoomic i view of the amouts of waste produced durig the process, represets a alterative to the tricky direct additio of ammoia to the triple bod ad allows the sythesis of primary amies. The primary imies formed ca be hydrogeated ad cleaved directly to the correspodig primary amies by catalytic hydrogeatio usig Pd/C as catalyst (Scheme ). mol% [CpTiMe] bar mol% Pd/C * 0% overall yield Scheme : ammoia equivalet hydroamiatio of iteral alkyes. - -

43 Additio of hydroge boded ucleophiles to alkyes evertheless, the mai drawbacks of this trasformatio are the elevated temperatures (000 C) ad the log reactio times (up to h) that are usually required for the reactio to proceed. This issue could be overcome by usig microwaves which reduces the reactio time by a factor of 0. Surprisigly, the use of microwave irradiatio ehaced the poor yieldig hydroamiatio of termial alkyes, brigig the trasformatio to almost full coversio (Scheme ). Moreover, these ew coditios eabled the first ati-markovikov hydroamiatio of alkyes. Ideed, while the use of log-chai alkyes such as -dodecye yields predomiatly a Markovikov product, the use of pheylacetylee leads to the formatio of the ati-markovikov product. The resposible factors for this switch i regioselectivity are ot yet determied. ) mol % [CpTiMe] MW, 0 W, h ) abc, p-ts % yield : Dec Dec Me ) mol% [CpTiMe] MW, 0 W, h ) abc, p-ts 0% yield Me : Me Dec Scheme : microwave assisted hydroamiatio of termial alkyes. From a mechaistic poit of view, Bergma s ivestigatios show that the catalytically active species of the described reactio is a cyclopetadieyl(amido)titaium complex. Kietic ivestigatio performed by Doyle et al. i combiatio with the mechaistic studies of Bergma allowed them to suggest a catalytic cycle which correctly described the hydroamiatio of alkyes (Scheme ). - -

44 Additio of hydroge boded ucleophiles to alkyes L L Ti CpTiMe TiL L LLTi() -Me K K - [LLTi=] 0 Me Me Me Me L L Ti L L Ti Me = -MeC LL = Cp, Scheme : catalytic cycle for the titaium catalyzed hydroamiatio of alkyes. The ufavorable equilibriums (K, K) betwee the imido complexes (9), the imido complex dimers () ad bisamides () explai the fact that sterically demadig amies are better substrates tha the less hidered amies for the CpTiMe-catalyzed hydroamiatio of alkyes. Kietic studies suggest that bigger ligads at the titaium ceter should ifluece these equilibriums ad favor the reactio of less hidered amies. The proof of cocept was made by usig Cp*TiMe which catalyzed the reactio betwee -propylamie ad dipheylacetylee leadig after subsequet reductio to the correspodig secodary amie i % yield, while the use of CpTiMe for the same reactio oly gives 0% of the desired product (Scheme ). - -

45 Additio of hydroge boded ucleophiles to alkyes i i Pr ) mol% [Cat.] ) abc ZCl * Pr catalyst Cp*TiMe CpTiMe reactio time h h yield % 0% Scheme : compariso betwee CpTiMe ad Cp*TiMe for the hydroamiatio of alkyes by -propylamie. the other had, the use of late trasitio metals for the hydroamiatio represets a great advatage because of their lower affiity to oxyge. utheium catalysts seem to represet the best compromise i terms of fuctioal group compatibility, toxicity ad costs. I 999, Uchimaru et al. disclosed the first rutheium-catalyzed hydroamiatio of alkyes. I the presece of u(c), pheylacetylee ad its derivatives udergo the regioselective Markovikov isertio of - bod of -methylailie to afford -methyl--(αstyryl)ailies i good yields (Scheme ). Me Me mol % u(c) 0 C, h amie as solvet p-mec p-fc Cyclohex--eyl Me yield % % % % % Scheme : rutheium catalyzed hydroamiatio of alkyes. A plausible mechaism for this trasformatio is the oe proposed by Uchimaru, based o the (amido)rutheium hydride as itermediate () (Scheme 9). - -

46 Additio of hydroge boded ucleophiles to alkyes Me Me [u] i iv Me Me [u] [u] ii iii Me [u] Scheme 9: plausible mechaism for the rutheium catalyzed hydroamiatio of alkyes. This mechaism ivolves (i) oxidative additio of the - bod of amie to the rutheium ceter givig the (amido)rutheium hydride. Coordiatio of the alkye to the rutheium ceter leads to the complex, which udergoes isertio of the coordiated carbo-carbo triple bod ito the u- bod. Fially, the reductive elimiatio of the eamie from the viyl rutheium species regeerates the coordiatively usatured rutheium(0) ceter. It is worth metioig that the reactio proceeds regioselectively to give the Markovikov additio product. The oly drawback of this process is the ecessity to use a te-fold excess of the amie derivative to esure high yields. Usig oly a five-fold excess of the amie resulted i a dramatic reductio of the yields, typically lower tha %. Isomers of the eamie ad trimers of the employed pheylacetylees are detected as side products. A rutheium/acid catalyst system was itroduced early at the same time by Wakatsuki et al. allowig the reactio of ailie derivatives with termial alkyes with formatio of the correspodig imies. The use of the strog acids PF ad BF ad their ammoium salts as additives dramatically ehaces the rate ad the yield of the reactio. For example, the reactio betwee ailie ad pheylacetylee was completed i h at 00 C with oly 0. mol% [u(c)] ad 0. mol % PF ad gave a % yield (GC) of the correspodig product, while oly a.% yield of the product was obtaied uder the same coditios but without the additive (Scheme 0). The effect of the acid remais to be clarified, but it has bee reported by Lavige et al. that halides ad related salts ca promote substitutio reactios of [u(c)].9 - -

47 Additio of hydroge boded ucleophiles to alkyes 0. mol% u(c) 0. mol% PF 00 C, h o solvet % (GC yield) 9% isolated yield Scheme 0: additio of ailie to pheylacetylee. Based o this reactio Wakatsuki ad Tokuaga et al. developed a ew Bischler-type idole sythesis.0 This rutheium-catalyzed oe-pot reactio allows the sythesis of -substituated-methyl idols i good yields ad selectivities startig from commercially available propargylic alcohols ad ailie (Scheme ). Et Et i 0. mol % u(c).0 mol %.Cl 0 C, -9 h, ope air, o solvet 9% yield Et : iv 9. Et Et Et ii iii Scheme : Bischler-type idole sythesis by Wakatsuki ad Tokuaga. The reactio sequece cosists of three steps: hydroamiatio of C-C triple bod of the propargylic alcohol (i), hydroge migratio of the resultig imioalcohol to the amioketoe (ii) ad cyclizatio givig rise to the idole scaffold (iv). Moreover, it is kow that there is apparetly a fast itercoversio of the regioisomers of amioketoes i the presece of ailie hydrochloride so that differet amioketoes ofte give the same idole (iii). Fially, oe example for the rutheium-catalyzed ati-markovikov hydroamiatio of alkyes is the reactio of,-dimethylhydrazies with termial alkyes. This trasformatio - 9 -

48 Additio of hydroge boded ucleophiles to alkyes developed by Fukumoto et al. is catalyzed by TpuCl(P) ad yields itriles as products. Mechaistically speakig, a viylidee species is proposed as the key itermediate for this reactio. The additio of the hydrazie to the viylidee ligad geerates a hydrazie carbee, which loses dimethylamie ad provides the itrile (Scheme ). Me Me [ucl(tp)(p)],-dioxae, reflux C up to % yield [Lu] [ucl(tp)(p)] Me Lu C C Me Me C Lu C Lu C Me C - Me Scheme : rutheium catalyzed additio of dimethylhydrazie to alkyes. I summary, great success has bee made for the hydroamiatio of alkyes sice Kozlov s work. Titaium complexes bearig two labile ligads seem to be the catalysts of choice for this reactio, but the fuctioal group tolerace is supposed to be low because of the high oxophilicity of this metal. Late trasitio metal based complexes, ad particularly rutheium catalysts, offer theoretically a better group tolerace. evertheless, the scope of such processes is still ofte limited to specific substrates. owever, this chemistry is uder itesive studies ad there is o doubt that this drawback will be overcome thus makig late trasitio metals as importat as titaium for the hydroamiatio of alkyes

49 Additio of hydroge boded ucleophiles to alkyes.. Additio of amides to alkyes As show before, the eamide group is a importat substructure. evertheless i compariso with eamie s chemistry, the chemistry of eamides has ot bee well developed, ad sythetic methods for them are rather limited. Although, the product resultig from the additio of amides to alkyes are much stable ad ofte lead to more importat products. A catalytic additio of amides to alkyes (or hydroamidatio of alkyes) would be a ideal sythetic etry to eamides, sice it would use readily available startig materials ad be iheretly atom-ecoomic. Similarly to additio of water, carboxylic acids ad amies to alkyes, the amides ca add to alkyes regioselectively to provide Markovikov ad ati-markovikov products (Scheme ). Markovikov product Z or E ati-markovikov product Scheme : additio of amides to alkyes. This chemistry does ot have a log history like the additio of water to alkyes, ad o catalysis based o mercury has bee developed. The first example of trasitio metal complex-catalyzed additio of amides to alkyes was described i 99. Based o previous work o the additio of carboxylic acids to alkyes, Wataabe et al. developed a system capable of catalyzig the additio of amides to alkyes. The authors chose a system based o the low valet rutheium dodecacarboyl complex [u(c)] to perform the reactio. The catalyst system formed i situ from [u(c)] associated to tricyclohexylphosphie (PCy) eables the direct ati-markovikov additio of -aryl substituted amides to termial alkyes ad provides the correspodig E-isomers predomiatly i fair yields (Scheme ). - -

50 Additio of hydroge boded ucleophiles to alkyes [u(c)] PCy ex toluee, 0 C, h Me Cl Me ex yield (E/Z) % (9/) % (9/) 9 % (/) % (00/0) Scheme : rutheium catalyzed additio of amides to alkyes. Isertio of a triple bod ito a u- bod resultig from a - activatio was proposed as the preferred mechaism (Scheme ). Ar ' [u] [u] [u] Ar Ar Ar or [u] ' ' Ar 9 ' ' [u] 0 Ar Scheme : proposed mechaism for the hydroamidatio of alkyes from Wataabe. The authors explai the regioselectivity of the reactio by proposig the complex 9 resultig from the amide coordiatio to the rutheium complex through its carboyl oxyge atom as a key itermediate. This complex leads to a itermediate 0 i which the - bod would be activated. The the alkye coordiatio ad the cocomitat oxidative additio of the - - -

51 Additio of hydroge boded ucleophiles to alkyes bod followed by a alkye isertio gives a itermediate or. A subsequet reductive elimiatio gives the eamide, regeeratig the rutheium species. evertheless, oly a very limited rage of -aryl substituted amides ca be added to -octye usig this trasformatio, albeit at extremely high temperatures (0 C). Clearly, much more effective catalyst systems are required to allow a applicatio of this reactio i orgaic sythesis. A major breakthrough was made recetly i this area by Gooße et al. Ideed, they fially overcame the problem of the low scope by usig aother source of rutheium. With a system based o the commercially available rutheium dimethallyl cyclooctadiee [u(cod)(met)], tributylphosphie (-P) ad DMAP, E-eamides were formed regio- ad stereoselectively (Scheme ). -P, DMAP [u(met)(cod)] toluee, 00 C, h up to 99 % yields up to 9 % sel. PCyCPCy, up to 99 % yields up to % sel. Scheme : hydroamidatio of alkyes from Gooße et al. Compared to the method of Wataabe, umerous alkyes were successfully coverted ito eamides usig this protocol. Amog them pheylacetylee, acetyleecarboxylic esters, trimethylsilylacetylee, ad eve cojugated eyes. Besides lactams, various secodary amides, ailides, ureas, bislactams, carbamates ca be used as the --couplig parter. Uder similar coditios, but i the presece of bisdicyclohexylphosphiomethae (CyPCPCy) ad water as additive, the catalytic ati-markovikov additio selectively provides the Z isomers. It is oteworthy that this reactio allows the use of much lower temperatures tha the previous, better results i yields ad selectivity were obtaied by oly heatig the reactio at 00 C. A alterative mechaism to the oe proposed by Wataabe was postulated by Dixeuf et al. for this trasformatio. I his review article about metal viylidees i catalysis, he applied the same mechaism as for the additio of carboxylic acids to alkyes to this reactio. This - -

52 Additio of hydroge boded ucleophiles to alkyes way he explaied that this trasformatio probably ivolves formatio of a alkylidee itermediate (Scheme ). (II) * Lu * u * C L u(iv) * u- (II) Lu u Scheme : Dixeuf s proposed mechaism for the hydroamidatio of alkyes. A activated catioic rutheium species bids to the alkye through a,-proto shift to form a alkylidee itermediate. A ucleophilic attack i α-positio of the rutheium ceter of the alkylidee itermediate forms the itermediate. Protoolysis of the latter releases the eamide ad regeerates the rutheium active species. evertheless, this mechaism is still uclear ad itesive studies are required to uderstad the multiple steps of this catalytic process. Moreover, at this poit the reactio is still exclusively limited to secodary amides. ther classes of amides such as primary amides, imides or thioamides are iactive with the proposed system or were ot yet tested. For primary amide substrates, which would give access to the sythetically far more valuable secodary eamides, either o coversio at all was observed, or mostly double viylatio products i traces ad as mixtures of (E/Z)-isomers were reported. the other had, protocols for the Markovikov hydroamidatio of alkyes are barely foud i the literature. A iterestig method for the sythesis of dehydroamio acids has bee described by Trost i 99, who added ucleophiles to alkyoates uder formatio of - substituted acrylates. osphie as a catalyst iduces isomerizatio of the alkyoates to,-dieoates, which the udergo additio of proucleophiles to the -positio (Scheme - -

53 Additio of hydroge boded ucleophiles to alkyes ). Trost optimized a system capable of addig imides to some termial alkyes to give the Markovikov product, by oly usig tripheylphosphie, sodium acetate ad acetic acid. P P u P uc uc Scheme : Alkyoates-ucleophilic additios at the α-positio. Ufortuately, oly specific classes of substrates could be coverted by usig this reactio. ly succiimides ad phtalimides add to Michael acceptor type termial alkyes such as methyl- or ethylpropiolate, ad progress also eeds to be made i this area. - -

54 Project aim. Project aim A thorough survey of the specialty literature provided represeted a great source of ispiratio for our work ad a efficiet catalyst was developed i our group for the additio of secodary amides to alkyes. owever, this trasformatio is strictly limited to this specific class of substrates ad oly the product resultig from a ati-markovikov additio could be obtaied. Great applicatios could be evisioed, particularly i atural product sytheses, if we overcome these key limitatios. The aims of the preset study were: To develop a ew catalytic system for the additio of ew classes of amides to alkyes: o Sice we already observed activity i the case of the imides, the optimizatio of the reactio for this substrate class was the startig poit of our studies. o Particularly iterestig substrate cadidates are the primary amides. owever, it is possible to evisage the complexity of this reactio where we had to overcome the low ucleophilicity of the primary amides, while avoidig the additio of the mooviylated product to a secod equivalet of alkyes. o Fially we cocetrated our efforts i fidig a catalytic system active for the additio of thioamides to alkyes. Thioamides have a more ambidet ucleophilic character tha amides do, ad thus ca react at the sulfur termius rather tha the itroge oe. Therefore, it will be crucial to have a perfect cotrol o the chemo-, regio- ad stereoselectivity of the reactio. To have a better uderstadig of the reactio. Thus mechaistic studies were performed by usig i situ M ad ESI-MS i order to idetify the active species formed durig the reactio. To fid a ew catalytic system based o a less expesive rutheium sources i order to replace the [u(cod)(met)] used i our previous protocol for the additio of secodary amides to alkyes. To reverse the regioselectivity of the reactio i favor of the Markovikov product. utheium is a very low oxophilic metal ad displays the widest scope of oxidatio states (from valet i u(c) to octavalet i u) ad therefore has great potetial for the exploitatio of ovel catalytic reactios ad sythetic methods. utheium also presets very - -

55 Project aim low toxicity compared to mercury-based catalysts; actually, its potetial for the medical field is ow beig recogized (rutheium aticacer agets). As show previously rutheium based catalysts could act either as Lewis acids ad thus promote Markovikov additio of hydroge-boded ucleophiles to alkyes or be ivolved i viylidee itermediates ad lead to ati-markovikov products. This importat feature i additio to the low prices of rutheium complexes compared to other metals made us choose rutheium complexes for our further ivestigatios. - -

56 Additio of imides to alkyes esults ad discussio. Additio of imides to alkyes.. Strategy for the developmet of catalyst system for the additio of imides to alkyes The catalyst system previously developed for the additio of secodary amides to alkyes is ot extedable to the imides substrates. Differet reasos could explai this lack of reactivity; amog them the acidity of the imide proto (situated o the itroge) which is much more acidic tha i the case of the secodary amides (Table ) ad thus makes imides less ucleophilic tha secodary amides. Table : pka of some compouds i DMS. compoud pka bezoic acid. acetic acid. succiimide. -methylhydatoi.0 pyrrolidioe. -piperidoe. The aim of this project is to fid a catalyst system able to promote the additio of a wide rage of imides to alkyes. This well tued catalyst system, while showig high activity with regard to the imides, should also be iheretly atom-ecoomic ad easy to hadle. As a startig poit for catalyst developmet, we used the reactio of succiimide (a) with hexye (a) to ivestigate the catalytic activity of several rutheium complexes uder various coditios (Scheme 9). a a aa Scheme 9: additio of succiimide to -hexye. - - aa aa

57 Additio of imides to alkyes I theory, three differet products could be obtaied by additio of succiimide (a) to alkyes (a): two products resultig from a ati-markovikov additio (aa ad aa) ad oe resultig from a Markovikov additio (aa). evertheless, oly the ati-markovikov products were observed durig this project. This project was first carried out i collaboratio ad the take over from Dipl.-Chem. Claus Brikma. e had developed the first effective catalyst withi his diploma work ad cocluded from spectroscopic data that the products that he isolated had E-cofiguratio. After successful isolatio of both isomers, I performed additioal M experimets, which led to the coclusio that the products isolated by Claus Brikma were i fact the Z-isomers. I thus repeated the decisive screeig experimet ad isolated the products oce agai to cofirm their stereochemistry as detailed below... Developmet of a ew catalyst system The first test we did by usig the exact same system as for the additio of secodary amides to alkyes developed by Gooße et al. showed, as expected, very low activity (Scheme 0). mol% [u(cod)(met)] mol% -P mol% DMAP toluee, 00 C, h a % yield : aa : aa a aa : aa Scheme 0: additio of succiimide to -hexye with the coditios of the additio of secodary amides to alkyes. evertheless, we made a critical observatio durig the reactio cocerig the low solubility of succiimide i toluee. We first tested the reactio i differet solvets ad foud out that dimethylformamide (DMF), while preservig the yields ad ratio of the reactio, was also able to dissolve the startig materials. We the decided to opt for DMF as a solvet for the further developmet of the reactio

58 Additio of imides to alkyes Variatio of the rutheium sources We chose rutheium as a metal ceter for the developmet of a ew catalytic system, because of its high activity i alkye chemistry ad particularly i the additio of amides to alkyes. For the ligad, tri--butylphosphie (-P), which was decisive for the additio of secodary amides to alkyes, was also used as a startig poit for the developmet of the ew catalytic system. Differet rutheium sources were the tested i DMF as depicted i the table below. Table : test of differet rutheium sources. [u-cat.] -P DMF, 00 C, h a a aa aa etry [u-cat.] yield (%)a ratio (aa:aa)b [u(cod)(met)] : [u(c)] 0 - [u(acac)] 0 - [ucl(c)] 0 - [ucl(c)] : [(p-cymee)ucl] : eactio coditios: mmol succiimide, mmol -hexye, mol% u-source, mol% -P, DMF, 00 C, h. a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by GC. As show i the table above, [u(cod)(met)] (etry ) ad [(p-cymee)ucl] (etry ) previously used for the additio of secodary amides to alkyes ad the additio of carboxylic acids to alkyes, respectively, showed promisig results. While [u(met)(cod)] already showed better selectivity, [(p-cymee)ucl] was able to promote the reactio i a better yield. Sice the selectivity of the catalyst is as much importat as its activity, we decided to ru the ext set of experimets usig i parallel [u(met)(cod)] ad [(p-cymee)ucl]

59 Additio of imides to alkyes The effect of the additives As experieced durig the previous work dealig with the additio of secodary amides to alkyes, the presece of a additive is crucial. We therefore studied the effect of differet additives (e.g. bases, acids, salts) o the reactio. Table : test of differet additives. [u-cat.] -P additive DMF, 00 C, h a a aa aa etry [u-cat.] additive yield (%)a ratio (aa:aa)b [u(cod)(met)] CC 0 - [(p-cymee)ucl] " 0-9 [u(cod)(met)] DMAP : 0 [(p-cymee)ucl] " : [u(cod)(met)] Et : [(p-cymee)ucl] " : [u(cod)(met)] MgC 0 : [(p-cymee)ucl] " 9 : [u(cod)(met)] KBr : [(p-cymee)ucl] " : [u(cod)(met)] Mg(Tf) : [(p-cymee)ucl] " : eactio coditios: mmol succiimide, mmol -hexye, mol% u-source, mol% -P, mol% additive, DMF, 00 C, h. a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by GC. As expected, the use of acid totally stops the reactio (etries, ). Coversely, the use of base (e.g. DMAP) ehaces the rate of the reactio, particularly if [u(cod)(met)] is employed (etry 9). A iterestig result was obtaied by usig MgC; i combiatio with [u(cod)(met)] (etry ), a sigificat 0% yield was obtaied while retaiig the selectivity previously observed. Iterestigly, the use of Mg(Tf) shows better selectivity (etry ). Sice both catalysts showed almost the same activity, but with a sigificat - -

60 Additio of imides to alkyes ifluece o the selectivity if [u(met)(cod)] is employed, we decided to oly employ the latter for further optimizatios. Suspectig that the Lewis acidic magesium io might have a share i the beeficial effect of this additive, we exteded our search to other Lewis acids (Table ). Table : test of differet Lewis acids. [u-cat.] -P additive DMF, 00 C, h a a aa aa etry additive yield (%)a ratio (aa:aa)b Mg(Tf) : 9 Z(Tf). 0 Al(Tf) 9 : Yb(Tf) 9 : Sc(Tf) 90 : Yb() 0 : eactio coditios: mmol succiimide, mmol -hexye, mol% u-source, mol% -P, mol% additive, DMF, 00 C, h. a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by GC. We were pleased to fid that they caused a dramatic icrease i catalyst productivity. Scadium ad ytterbium triflates were particularly effective, leadig to complete coversio of the startig imide ad the formatio of the desired product i good selectivities (etries, ). This is probably due to a coordiatio of the Lewis acid to the oxyge atom of the amide thus ehacig its ucleophilicity. - -

61 Additio of imides to alkyes The effect of the ligads Sice the choice of the ligad could have sigificat ifluece o the selectivity of a metalcatalyzed reactio, we ext set up a rage of experimets to determie if it is possible to either icrease the selectivity for the Z-eimide or totally reverse the selectivity i favor of the E-eimide. Table : test of differet ligads. [u(cod)(met)] ligad Yb(Tf) DMF, 00 C, h a a aa aa etry ligad yield (%)a ratio (aa:aa)b -P 9 : P(-pyridyl) 9 : PCy(C)PCy : P(-furyl) :,'-bis-(p)-ferrocee Imes(-) Cl -c P : i-prp : 9 PCy : eactio coditios: mmol succiimide, mmol -hexye, mol% [u(cod)(met)], mol% ligad, mol% Yb(Tf), DMF, 00 C, h. a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by GC. c),-dibutylimidazolium chloride. Ufortuately, o icrease of the Z-selectivity was observed ad -P remais the best ligad for this protocol (etries -). owever, we discovered that with triisopropylphosphie (i-prp), the E-isomer became the major product (etry ). This chage i selectivity was also observed if tripheylphosphie or tricyclohexylphosphie are employed (etries ad 9, respectively) ad it is probably due to the steric hidrace of these ligads. - -

62 Additio of imides to alkyes ptimizatio of the reactio coditios Fially a rage of experimets was set up to fid out the ideal coditios for this reactio. It was importat to determie whether or ot humidity or air ca ifluece the activity of the catalyst, if a less toxic solvet tha DMF could be used ad if the temperature ad the time of the reactio could be reduced. Table : optimizatio of the reactio coditios. [u(cod)(met)] -P Yb(Tf) solvet temperature, h a a etry solvet temperature ( C) yield (%)a ratio (aa:aa)b DMF 00 9 : 0 toluee " : acetoitrile " 0 - TF " 0 - MP " : c DMF " 9 : d DMF " 0 - " 0 9 : " 0 9 : " 0: e " 0 9 : 9 aa aa eactio coditios: mmol succiimide, mmol -hexye, mol% [u(cod)(met)], mol% -P, mol% Yb(Tf), h. a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by GC. c) mmol of water are added. d) air was itroduced ito the vessel durig the reactio. e) the reactio was stopped after h. I compariso to DMF, other solvets were less effective: low polarity solvets were uable to dissolve the polar reagets ad catalyst, while sufficietly strog coordiatig solvets, e.g. acetoitrile, appeared to slow dow the reactio (etries 0-). The additio of water does ot affect the reactio (etry ) but if air is itroduced i the vessel, the reactio stops immediately (etry ), probably because of the high sesitivity of tri--butylphosphie. A reactio temperature of 0 C tured out to be sufficiet (etry ), ad a further decrease to - -

63 Additio of imides to alkyes C led to a icrease i Z-selectivity, though with a lower yield (etry ). Fially after oly h, the reactio appeared to be complete (etry 9)... Scope of the reactio After optimizig the catalyst system, we tested the geerality of the reactio protocols with regard to both couplig parters. A excess of the alkye was used to make up for losses due to evaporatio or oligomerizatio reactios. Sice scadium(iii)trifluoromethaesulfoate (Sc(Tf)) shows almost the same activity as ytterbium(iii)trifluoromethaesulfoate (Yb(Tf)) while havig a higher tolerace i regard to fuctioal groups, we preferred to choose Sc(Tf) to perform the reactios. As show i table below, several imides were added smoothly to -hexye i high yields ad selectivities. Table : additio of differet imides to -hexye. a imide product yield (%)a ratio (:)b 9 : ()c : ()c 9: a aa b ba c ca - -

64 Additio of imides to alkyes a imide product yield (%)a ratio (:)b : : d : d da e ea f fa eactio coditios: mmol imide, mmol -hexye, mol% u(met)(cod), mol% -P, mol% Sc(Tf), DMF ( ml), 0 C, h. a) isolated yield. b) ratio determied by GC. c) after days reactio time. d) GC-yield with -tetradecae as iteral stadard. Cyclic imides such as succiimide (a), glutarimide (b) or,-dimethylglutarimide (c) reacted with -hexye i high selectivities ad the correspodig products were isolated i good yields. We obtaied also very good results with the aromatic phthalimide (d), although i the case of the much more electro-rich,-pyrididicarboximide (e), oly low yields were observed. o-cyclic imides such as diacetamide (f) also reacted with -hexye but oly i very low yields so that the isolatio of the product was ot possible. - -

65 Additio of imides to alkyes Table : further additio of differet imides to -hexye. a imide product yield (%)a ratio (:)b 90 : d : d : d,e : g ga h ha S S i ia j ja eactio coditios: mmol imide, mmol -hexye, mol% [u(cod)(met)], mol% -P, mol% Sc(Tf), DMF ( ml), 0 C, h. a) isolated yield. b) ratio determied by GC. c) after days reactio time. d) GC-yield with -tetradecae as iteral stadard. e) reactio carried out at C. The same good results as with succiimide were obtaied with,,-trimethylhydatoie (g), ad surprisigly the less sterically demadig -methylhydatoie (h) oly gives very poor yields, thus probably its sesibility leadig to its degradatio. Two other examples of cyclic imides bearig aother heteroatom, reacted with -hexie,,-thiazolididioe (i) ad -methyluracil (j), although with very poor yields. - -

66 Additio of imides to alkyes Table 9: additio of succiimide to differet alkyes. a alkye product yield (%)a ratio (:)b 0: 99 0: ()c 9: : d : b ab c ac ex d ex ad Cl Cl e ae - -

67 Additio of imides to alkyes a alkye product f af yield (%)a ratio (:)b d : d : d : g ag t h ah i ai eactio coditios: mmol succiimide, mmol alkye, mol% [u(cod)(met)], mol% -P, mol% Sc(Tf), DMF ( ml), 0 C, h. a) isolated yield. b) ratio determied by GC. c) after days reactio time. d) GC yield with -tetradecae as iteral stadard. As show i the table above, imide a was added smoothly to differet alkyes. Aliphatic (b) ad aromatic (d) alkyes were coverted ito the correspodig eimides i very good yields ad selectivities. alogeides (e) are also tolerated by the catalytic system. Sterically demadig alkyes such as,-dimethyl--butie (g) ad olefiic alkyes (h) oly react i very low yields. I this case, we observed predomiatly formatio of a side product due to the dimerizatio of the alkye. Alkyes bearig a oxyge cotaiig fuctioal group, such as ether (i) ad ester (f) reacted with difficulties, probably because of a coordiatio of the - 9 -

68 Additio of imides to alkyes oxyge atom to the metal istead of the triple bod. owever, o protected alcohols (e.g. as -propyol) do ot react at all. We ext exteded the scope of the reactio by testig differet imides with pheylacetylee (b) ad -pheyl--butie (c). Table 0: additio of differet imides to pheylacetylee ad -pheyl--butie. alkye imide product yield (%)a ratio (:)b >0: : 0 >0: 0 >0: d b db g b gb c b cb b b bb - 0 -

69 Additio of imides to alkyes imide product alkye yield (%)a ratio (:)b 9 >0: 9 >0: >0: g c gc c c cc b c bc eactio coditios: mmol imide, mmol alkye, mol% [u(cod)(met)], mol% -P, mol% Sc(Tf), DMF ( ml), 0 C, h. a) isolated yield. b) ratio determied by GC. As depicted i the table above, the ew catalyst system allows the additio of cyclic ad aromatic imides as well as heterocyclic imides to aliphatic or aromatic alkyes i good yields. - -

70 Additio of imides to alkyes.. eversal of the selectivity To complete the scope of the reactio, we developed the E-protocol of the reactio. Startig with the coditios of the etry of the table we used Sc(Tf) istead of Yb(Tf) which permitted us to ehace the activity of the catalyst (etry ). Fially, after risig the catalyst loadig to mol %, the E-eimide was obtaied i high yield ad excellet selectivity (etry ). Table : optmizatio of the E-protocol. [u(cod)(met)] ligad Yb(Tf) DMF, 00 C, h a a aa aa etry additives ligad yield (%)a ratio (aa:aa)b Yb(Tf) i-prp : Sc(Tf) i-prp : c Sc(Tf) i-prp : eactio coditios: mmol succiimide, mmol -hexye, mol% [u(cod)(met)], mol% ligad, mol% Yb(Tf) or Sc(Tf), DMF, 00 C, h. a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by GC. c) reactio performed with mol% [u(cod)(met)] ad mol% i-prp. The scope of the E-selective protocol was ivestigated usig a more limited umber of substrates, but always gave similarly high yields ad selectivities as for the Z-protocol (Table ). - -

71 Additio of imides to alkyes Table : scope of the E-protocol. imide alkye yield (%)a ratio (:)b product : 0 : : 9 : :0 a a aa b a ba c a ca a b ab a c ac eactio coditios: mmol imide, mmol alkye, mol% [u(cod)(met)], mol% i-prp, mol% Sc(Tf), DMF, 00 C, h. a) isolated yield. b) ratio determied by GC. I summary, two complemetary catalyst systems have bee developed that efficietly mediate the additio of imides to termial alkyes, givig rise to either the E- or the Z-atiMarkovikov products. The mechaistic aspect of the reactio will be discussed i a ext chapter. - -

72 Additio of primary amides to alkyes. Additio of primary amides to alkyes.. Strategy for the developmet of a ew catalyst system for the additio of primary amides to alkyes Primary amides are aother particularly attractive class of ucleophiles that we have ot bee able yet to add to alkyes usig our iitial catalyst system. The additio of primary amides bears additioal challeges whe compared to the aalogous additio of secodary amides ad imides. Besides the kow problems of regio- ad stereoselectivity (Scheme : 9, 0, ), the product obtaied from the iitial additio of a primary amide to a alkye ca react with aother equivalet of the alkye to give the double additio product (Scheme :,,, ). Depedig o the regio- ad stereoselectivity of the catalyst, a mixture of up to seve differet products could result from a sigle trasformatio. Therefore, it is clearly a great challege to fid a catalytic system that selectively facilitates the formatio of a sigle moo-additio product with complete cotrol of regio- ad stereoselectivity. 0 Scheme : possible products durig the additio reactio of primary amides to alkyes

73 Additio of primary amides to alkyes Moreover, a perfect cotrol of the rate ad the selectivity of the first additio could allow us to perform selectively a secod additio, usig a secod equivalet of alkyes, similar or differet from the first oe, givig us access to bis-eamides (Scheme ). // 9/0 Scheme : selective sigle ad double additio of amides to alkyes. The iferior reactivity of primary compared to secodary amides is easily explaied by their lower ucleophilicity ad uderlies the magitude of the challege posed by this substrate class: a highly developed catalyst system is required that reaches a ew level of activity ad stereoselectivity for the ati-markovikov additio of primary amides to alkyes but is uable to mediate the coversio of the more ucleophilic ad sterically oly slightly more demadig mooviylated products 9 or 0 (Scheme ). Iitially, I was the oly studet o this project. For a short time, the postdoctoral researcher Iyad Karame joied i but moved to aother project after his attempts to cotrol the stereochemistry of this trasformatio remaied usuccessful. After my discovery that the reactio turover ca be improved by usig Lewis acids, Kifah S. M. Salih joied the project ad successfully developed a PLC method which for the first time allowed the precise determiatio of stereoselectivities thus layig the foudatio for the developmet of a stereoselective method. All further screeig experimets, e. g. those reported i Table,,, ad, were carried out together, ad the scope of the reactio (Table ad Table 9) was also ivestigated i close collaboratio. These results thus appear i both our D theses... Developmet of a ew catalyst system I order to idetify a catalyst system with such a uique profile, we selected the reactio of bezamide with -hexye as the model system to examie the catalytic activity of various rutheium sources i combiatio with differet ligads, solvets ad additives (Scheme ). a a 9aa Scheme : additio of bezamide to -hexye aa

74 Additio of primary amides to alkyes Test of differet rutheium sources As expected, a combiatio of [u(cod)(met)] with -P ad -(dimethylamio)pyridie (DMAP), the most effective system for the aalogous reactio of secodary amides, gave oly margial coversio ad displayed o selectivity for the mooadditio products (Table, etry ). We first set up a rage of experimets aimig to fid a more active rutheium source (Table ). Table : test of differet rutheium sources. [cat.] -P DMAP toluee, 00 C, h a a 9aa a 0aa ratio (9aa:0aa)b etry [cat.] yield (%) [u(cod)(met)] < - [u(c)] 0 - [u(acac)] 0 - [ucl(c)] 0 - [ucl(c)] 0 - [(p-cymee)ucl] - [AuCl] 0 - eactio coditios: mmol bezamide, mmol -hexye, mol% u-source or AuCl, mol% -P, mol% DMAP, toluee, 00 C, h. a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by PLC. ther rutheium precursors were foud to be eve less efficiet (etries -), ad eve gold catalysts which are very useful catalyst i alkye chemistry did ot show ay reactivity (etry ). - -

75 Additio of primary amides to alkyes The ifluece of the solvet As the choice of the solvet appears to be fudametal i the additio of imides to alkyes we the decided to perform the reactio i differet solvets (Table ). Table : test of differet solvets. [u(cod)(met)] -P DMAP solvet, 00 C, h a a 0aa 9aa a ratio (9aa:0aa)b etry solvet yield (%) toluee < - TF - 9 acetoitrile - 0 ethaol 0 - DMF : eactio coditios: mmol bezamide, mmol -hexye, mol% u(met)(cod), mol% P, mol% DMAP, solvet, 00 C, h. a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by PLC. Protic solvets such as ethaol (etry 0) appear to be totally iefficiet. Acetoitrile, probably because of coordiatio to the rutheium ceter slowed dow the reactio (etry 9). DMF was uiquely effective as for the additio of imides to alkyes, resultig i the first icrease i yield (etry ). - -

76 Additio of primary amides to alkyes The ifluece of the additives As experieced durig our work o the additio of secodary amides ad imides to alkyes, the reactivity of amides i regards to alkyes seems to be very depedet o the additive used. We the ext tested differet additives. Table : test of differet additives. [u(cod)(met)] -P additive DMF, 00 C, h a a 9aa 0aa etry additive yield (%)a ratio (9aa:0aa)b DMAP : ac : KI : LiTf < - Mg(Tf) : Cu(Tf) 0 - Z(Tf) 0 - Bi(Tf) < - 9 Sc(Tf) : 0 Yb(Tf) 9 : eactio coditios: mmol bezamide, mmol -hexye, mol% [u(cod)(met)], mol% P, mol% additive, DMF, 00 C, h. a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by PLC. The use of iorgaic bases such as sodium carboate (etry ) did ot lead to ay improvemet. Based o the reasoig that the coordiatio of a Lewis acid to the carboyl oxyge would acidify the amide protos ad therefore serve the same purpose as a added base, we replaced DMAP, which we had foud to aid the deprotoatio of the amide substrate ad facilitate its coordiatio to the u-ceter, by a Lewis acid (etries -0). This ideed led to a dramatic icrease i catalyst activity, ad 9% yield was achieved with Yb(Tf) (etry 0). The other triflates we tested (etries -0) ever reached this activity. - -

77 Additio of primary amides to alkyes The ifluece of the ligads To achieve the completio of the reactio ad push the selectivity i favor of oe of the stereoisomers, we decided to test some ligads. Table : test of differet ligads. [u(cod)(met)] ligad Yb(Tf) DMF, 00 C, h a a 9aa a 0aa ratio (9aa:0aa)b etry ligad yield (%) -P 9 : (-) 0 - pheathrolie 0 - P 0 : P(i-Pr) : PCy 0 - i-prp 0 - dcypb : eactio coditios: mmol bezamide, mmol -hexye, mol% [u(cod)(met)], mol% moodedate ligad or mol% bidetate ligad, mol% Yb(Tf), DMF, 00 C, h. a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by PLC. The use of itroge ligads such as tri--butylamie or pheathrolie, resulted i o yields (etries, ). Electro poor phosphies, such as tri-pheylphosphie, appear to slow dow the reactio (etries, ). Surprisigly, tri-cyclohexyl phosphie ad tri-isopropyl phosphie did ot show ay activity (etries, ), probably because of their too low stability. Fially, we foud that sterically demadig, electro-rich chelatig phosphies resulted i a major ehacemet of the Z/E-ratio. Usig,-bis-(dicyclohexylphosphio)butae (dcypb), the selectivity for the Z-product 9aa was icreased to a : ratio (etry )

78 Additio of primary amides to alkyes ptimizatio of the reactio coditios Due to the high activity of the catalyst system, the reactio temperature could be reduced to 0 C (Table, etry 9). This resulted i sigificatly better yields of the mooadditio products because the mai side reactio, the hydrolysis of the eamide products by traces of water, o loger played a importat role. At this moderate temperature, the presece of water was eve foud to ehace the catalyst performace (etry ), so that fially early complete coversio ad a impressive : selectivity for the thermodyamically disfavored ad thus more iterestig Z-eamide 9aa was reached withi six-hour reactio time (etry ). Table : optimizatio of the reactio coditios. [u(cod)(met)] dcypm Yb(Tf) a solvet temperature, h a 0aa 9aa etry solvet temperature ( C) yield (%)a ratio (9aa:0aa)b DMF 00 : " 0 : 9 " 0 9 : 0 " < - DMF/waterc 0 9 : d " " 9 : eactio coditios: mmol bezamide, mmol -hexye, mol% u(met)(cod), mol% dcypb, mol% Yb(Tf), DMF, h. a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by PLC. c) water as co-solvet (0 L). d) h reactio time... Scope of the reactio To ivestigate the scope of this ew hydroamidatio protocol, we applied it to the additio of a broad variety of itroge ucleophiles to several termial alkyes

79 Additio of primary amides to alkyes Table : additio of bezamide to differet alkyes. a alkye 0 9 product yield (%)a ratio (9:0)b 9 : 9 : 9 >0: 9 : : a 9aa b 9ab c 9ac d 9ad e 9ae - -

80 Additio of primary amides to alkyes a alkye 0 9 product yield (%)a ratio (9:0)b 9 : 99 0: 9: Cl Cl f 9af F F g 9ag Me Me h 9ah eactio coditios: mmol bezamide, mmol alkye, mol% [u(cod)(met)], mol% dcypb, mol% Yb(Tf), DMF ( ml), 0 C, h. a) isolated yield. b) ratio determied by PLC. As show i the table above, bezamide reacted with a wide rage of alkyes, icludig the stadard -hexye (a), haloalkyl (f), alicyclic (e) or -pheyl--butye (d), but also with sterically hidered alkyes such as pheylacetylee (b), pheylacetylee aalogous (g, h) or tert-butylacetylee (c) yieldig the correspodig products i high yields ad excellet selectivities. Furthermore, a rage of primary amides, amog them sesitive ad highly fuctioalized derivatives, were smoothly added to pheylacetylee. - -

81 Additio of primary amides to alkyes Table 9: additio of differet primary amides to pheylacetylee. b 9 amide product 0 yield (%)a ratio (9:0)b 0: 0: 90 9: 9 : : b 9bb c 9cb d 9db e 9eb f 9fb - -

82 Additio of primary amides to alkyes b 9 amide product 0 yield (%)a ratio (9:0)b 0 0: 9 9: 9. c : >0: g 9gb F F h 9hb Me Me i 9ib Et Et j 9jb k 9kb - -

83 Additio of primary amides to alkyes b product Et 9 amide Et 0 yield (%)a ratio (9:0)b c 9: l 9lb eactio coditios: mmol amide, mmol pheylacetylee, mol% [u(cod)(met)], mol% dcypb, mol% Yb(Tf), DMF ( ml), 0 C, h. a) isolated yield. b) ratio determied by PLC. c) the reactio was performed without water to avoid hydrolysis of the sesitive products. Commo fuctioal groups such as dialkylamie (b), tert-butyl (c), alkee (d), acetyl (c), alkae (f), itro (g), ad halide groups (h) were tolerated, ad eve fragile oxalic (j), maloic (l) or α-cyaoacetic (k) amides were smoothly coverted. Arguably the most spectacular result was obtaied i the sythesis of eamide 9eb, where a primary amide fuctioality was selectively viylated i the presece of a secodary amide group... eversal of the selectivity We ext tried to ivert the selectivity of the reactio i favor of the E-eamide 9 by modifyig the catalyst system, ad thus to further improve the sythetic utility of the hydroamidatio protocol. Disappoitigly, the best result, obtaied with -P as the ligad ad Å molecular sieves as additives, was a.: ratio of E- to Z-isomer. A superior strategy proved to be isomerizig the double bod isomers i situ after the hydroamidatio reactio was complete, by addig triethylamie ad heatig the reactio mixture to 0 C while usig molecular sieves to reduce the hydrolytic cleavage to a miimum (Scheme ). - -

84 Additio of primary amides to alkyes a a ot isolated 9aa Et MS Å toluee, 0 C, h same pot 0aa 9% overall yield 0% E-selectivity Scheme : oe pot Z-hydroamidatio of -hexye followed by isomerizatio. This way, a E/Z-ratio of : was achieved for the model system, ad as ca be see from the table below, E-selectivities of up to 0: were reached for other substrates. Table 0: scope for the E-protocol of the additio of primary amides to alkyes. ) Z-protocol reactio ) isomerisatio reactio amide 0 9 alkye yield (%)a ratio (9:0)b product a a 9 : 9 : 9 :0 0aa a b 0ab - -

85 Additio of primary amides to alkyes ) Z-protocol reactio ) isomerisatio reactio 0 9 amide alkye product a c 0ac yield (%)a ratio (9:0)b a d a e : : :0 : 0ae d b 0db e b 0eb Et f Et : 0ad b 0fb eactio coditios: mmol amide, mmol alkye, mol% [u(cod)(met)], mol% dcypb, mol% Yb(Tf), DMF ( ml), 0 C, h. After complete reactio, 00 mg of Å molecular sieves ad 00 L triethylamie were added, ad the mixture was heated to 0 C for h. a) isolated yield. b) ratio determied by PLC. - -

86 Additio of primary amides to alkyes Eamides thus accessible i oly oe step from easily available materials iclude the atural products lasiumamide A (9mb) ad alatamide (0ah) (Scheme ), whose previously published sytheses ivolved three to four steps ad gave iferior yields, ad compoud 9h, which is a key itermediate i Castedo s total sythesis of aristolactam (Scheme ). m b 9% yield 9% Z-selectivity 9mb (lasiumamide A) 9ah isomerizatio reactio Me Me Me Me Br Me 9% overall yield 9% E-selectivity 0ah (alatamide) Me Me h Br 9h Me Me Me,,-trimethoxyaristolactam Scheme : sythesis of some atural products % yield >9% Z-selectivity Me

87 Additio of primary amides to alkyes.. Mechaistic hypothesis ur mechaistic proposal for such hydroamidatios is that the alkye first coordiates to a uii-amide complex geerated from the catalyst precursor, the a amide aio adds to the C-C-triple bod givig rise to a -u-viyl complexes (c, d). Depedig o whether the attack occurs from iside (c) or outside (d) the coordiatio sphere of the rutheium, the metal will ed up Z- or E- to the amide group. The product is liberated by protoolysis, regeeratig the iitial uii-species (a) ad completig the catalytic cycle (Scheme )., [u] [u] [u] b a 0 d 9 [u] c Yb _ Yb [u] [u] = Lu Scheme : mechaistic hypothesis for the additio of primary amides to alkyes. Mechaistic studies accordig to this trasformatio ad based o observatios made durig our work o the additio of secodary amides ad imides to alkyes will be describe i a ext chapter... Secod additio As metioed earlier, after additio of a amide to a first equivalet of alkye, the product formed ca react with a secod equivalet of alkye. owever, the activity ad selectivity obtaied with our system permits us to stop the reactio after the first additio. We the tried, after isolatio of this first additio product, to put the secodary eamide with a secod - 9 -

88 Additio of primary amides to alkyes equivalet of alkye uder coditios similar to those used for the additio of secodary additio to alkyes developed by Gooße ad auhaus (Scheme ). a a 9aa [u(cod)(met)] -P DMAP toluee, 00 C, h a b aaa Cl f aab aaf Cl % % % : GC yields of the secod additio Scheme : first ad secod selective additio of amides to alkyes. We were pleased to fid that these first tests already gave fair isolated yields; ideed, after the first additio of bezamide to -hexye we were able to add selectively aother equivalet of -hexye, but also pheylacetylee ad -chloropetye to the secodary eamide formed. This ew reactio ot yet well optimized is still very promisig, ad ew compouds ad a completely ew family of compouds could be sythesized usig this methodology. Amog them, cyclizatio product, by usig diyes could lead to very iterestig products (Scheme ) - 0 -

89 Additio of primary amides to alkyes (C) Scheme : possible sythesis usig the double additio of amides to alkyes... Coclusio verall, a ew catalyst system has bee developed that allows the chemo-, regio-, ad stereoselective sythesis of secodary Z-eamides from easily available primary amides ad termial alkyes. I combiatio with a optioal i situ isomerizatio to the E-eamides, this represets a expediet sythetic etry to this structural motif, which is featured i may atural products ad is hard to access by other meas. The mechaism of the reactio ad particularly the role of the triflate salts is ot yet well uderstood, but the mechaistic studies curretly i progress may clarify this aspect. - -

90 Secod geeratio catalyst for the additio of secodary amides to alkyes. Secod geeratio catalyst for the additio of secodary amides to alkyes.. Mechaistic studies As show i the two last chapters, the u-catalyzed additio of amides to alkyes is a very powerful reactio. It allows the sythesis of umerous eamides i high yields ad selectivities. owever, practical applicatios of this rutheium-catalyzed additios have so far bee hampered by the prohibitive price of rutheium(ii) complexes stabilized with labile ligads, e.g. [u(cod)(met)] ( /mmol)9, that is required for geeratig the catalytically active species ad by the use of highly air sesitive ad pyrophoric -P. The replacemet of this catalytic system by a easier to hadle phosphie ad a readily available rutheium source such as ucl ( /mmol)9 could vastly improve the sythetic utility of this trasformatio. Eve if such a replacemet could be difficult, cosiderig the ecessity of selectively reducig rutheium(iii) to rutheium(ii) durig the reactio, it should still be feasible sice ucl is the startig material of a wide scope of rutheium complexes, icludig [u(cod)(met)] (Scheme 9).0 u u [ucp(c)] LiAl C [u] [uclcp*] uc ai CMe [ucl(p-cymee)] C, Z p-meccme ucl CD [u(cod)cl] MgCl P Me,-C Z [u(cod)(met)] [u(cod)(cot)] [ucl(p)] C Cl Cl P u P Scheme 9: differet sytheses of complexes startig from ucl. - -

91 Secod geeratio catalyst for the additio of secodary amides to alkyes This project was carried out i collaboratio with Matthias Ardt ad Felix udolphi, who both focused o the sythesis of ew rutheium precusors ad o the i situ geeratio of active catalysts. My share was the developmet of the hydroamidatio coditios suitable for the ew systems. ur combied efforts led to the discovery of the ew reactio protocol detailed below. We joitly isolated the compouds Table i order to demostrate the scope of this protocol. The results were published i Advaced Sythesis ad Catalysis. Because of the wide scope of the reactio ad the relative simplicity of the catalytic system, we chose the additio of secodary amides to alkyes as a startig poit for our ivestigatios. ur first objective was to pipoit the active species egaged i the catalyzed reactio betwee pyrrolidi--oe ad -hexye (Scheme 0). (II) u -P DMAP a? a toluee, 00 C active species aa/aa Scheme 0: formatio of a active species durig the reactio betwee pyrrolidi--oe ad -hexye. - -

92 Secod geeratio catalyst for the additio of secodary amides to alkyes ESI-MS (Electrospray Ioisatio-Mass Spectroscopy) of a sample take directly from the reactio solutio durig the catalyst preformatio displayed two predomiat sigals (Scheme ). e sigal at m/z =. which correspods to [(-P)u(C)(C0)] ad aother sigal at m/z = 9. which could be assiged to [(-P)u(C)]. Additioally, stadard GC-MS of this sample also shows sigals for free CD ad isobutee. Ites. MS, 0.-.9mi #(-) x m/z [(-P) P)u(C u(c)(c )(C00)])] [(- [(-P) P) u(c ) [(- u(c )] Scheme : ESI-MS of the catalyst systems based o [u(cod)(met)]. - - m/z

93 Secod geeratio catalyst for the additio of secodary amides to alkyes The i situ formatio of the catalyst from [u(cod)(met)] was ivestigated by a series of ad P-M experimets (Scheme ad Scheme ) a) Toluol-d Toluol-d..9 b) d) Toluol-d Toluol-d. c) Scheme : -M of the catalyst preformatio. A mm M tube was charged with [u(cod)(met)] (. mg, 0.0 mmol). The tube was sealed with a rubber septum ad purged with alteratig vacuum ad itroge cycles. Tri-butylphosphie (0 µl, 0.0 mmol) ad toluee-d ( ml) were added via syrige. For clearess reasos, the sectio δ <.0 ppm of the -M spectra (i which the alkyl sigals correspodig to the excess of phosphie appears) was bleded. The -M spectrum take at this poit ( C), prior to catalyst preformatio (a), shows clear siglets at. (),.0 - -

94 Secod geeratio catalyst for the additio of secodary amides to alkyes (),.9 (),. (), ad 0. () ppm for two rutheium-boud methallyl ligads, ad multiplets at.-.9,.-.9,.-.,.-.9 ppm ( each),.-. ad.09-. ppm ( each, overlappig with sigals of the phosphie ligads) for the rutheium-boud CD ligad. A secod sample was prepared uder the same coditios but with a two-fold excess of DMAP. A first -M take at this poit at C (b) displayed the same sigals as before plus the sigals of DMAP at. (),.0 () ad. (). After heatig the reactio mixture to 00 C for mi, aother -M was take (c). CD ligad had completely bee displaced. I the -M spectrum, the sigals for coordiated CD ligads have disappeared, ad sigals at.-. () ad.-. () ppm idicate free,cyclooctadiee. Due to the ligad exchage, the sigals for the methallyl ligads are shifted to higher field, makig a assigmet difficult. Sigals for isobutee which would idicate protoolysis or decompositio of the rutheium complex caot be observed. After the additio of pyrrolidi--oe (. µl, 0.0 mmol) via syrige, the methyl ligads were protoated off by the amide, ad sigals at.0-. ad. ppm i the -M spectrum (d) gave evidece of the formatio of isobutee. The -protos of the amide were foud at.-.0 ppm, whereas the other rig protos are cocealed amog the overlappig alkyl sigals of tri--butylphosphie i the rage of ppm. - -

95 Secod geeratio catalyst for the additio of secodary amides to alkyes The P-M (Scheme ) spectrum at C shows a mior sigal at 0. ppm for metal- coordiated tri--butylphosphie ad a strog sigal at. ppm for ucoordiated phosphie (b). After heatig the above solutio to 00 C for mi (c), a strog sigal for coordiatig phosphie appeared at 0. ppm, meaig that most of the phosphie was bod to the rutheium ceter at this poit of the reactio. Fially, after additio of the pyrrolidi-oe, oly a sigal correspodig to the coordiated phosphie was displayed (d). b) a) d) c).0-0. [u(cod)(met)] -P toluee-d 00 C [u(cod)(met)] -P DMAP toluee-d C 0. [u(cod)(met)] -P DMAP pyrrolidioe toluee-d 00 C [u(cod)(met)] -P DMAP toluee-d 00 C ? (ppm) ? (ppm) 0 0? (ppm) ? (ppm) Scheme : P-M of the catalyst preformatio. To summarize (Scheme ), durig the preformatio steps, the,-cyclooctadiee (CD) ligad is displaced by the phosphie ad/or DMAP ligads givig rise to itermediate b, as idicated by the characteristic sigals for free, ualtered CD ad u-coordiated -P i GC-MS / M spectra. Moreover, the detectio of isobutee suggests that the methallyl ligads are protoated off by the acidic of the amides, thus leadig to a u(ii) amide complex c. - -

96 Secod geeratio catalyst for the additio of secodary amides to alkyes, -P DMAP (II) u LXu Lu(met) a b c L= -P ad/or DMAP X = C or Cl,... Scheme : suggested catalyst preformatio. This results show that oe of the origial ligads remaied actually boud to rutheium ceter, suggestig that simple rutheium salts such as ucl could also be utilized. By searchig for a method to reduce ucl to u(ii) while at the same time removig the chloride ios, which ca be expected to compete with the substrate for coordiatio to the rutheium ceter, we came across a publicatio by Kölle et al. They described the sythesis of di-µ-methoxo-bis[( -petamethylcyclopetadieyl) dirutheium(ii) [(Cp*uMe)] from di-µ-chloro-bis[( -petamethylcyclopetadieyl)chlororutheium(iii)] [(Cp*uCl)] usig Me as a reductat ad the mild base KC for the geeratio of the methoxide ligads as well as for precipitatio of the chloride as KCl. The first test usig these coditios o our test reactio was very successful (Scheme ad Table, etry ). Ideed, the desired E--(hex--eyl)pyrrolidi--oe product had formed i high (E/Z)-selectivity ad reasoable but varyig yields. mol% ucl 9 mol% -P/DMAP mol% KC 0 eq. Me a toluee, 00 C, h a 0-99% yield -: E:Z aa/aa Scheme : first attempt usig ucl as catalyst for our test reactio. evertheless, i our search for a better protocol, we made a iterestig observatio. To facilitate our task, we prepared a stock solutio of the catalyst. I.e. if the catalyst is soluble i the reactio solvet, we dissolved it ad thus it became easier to always add the same amout - -

97 Secod geeratio catalyst for the additio of secodary amides to alkyes of catalyst to the reactio vessel. owever, the commercial ucl was ot soluble i toluee, so we decided to first dissolve it i acetoe, ad after evaporatio of the latter from the reactio vessel, addig the remaiig compouds icludig the solvet. The catalyst became the totally soluble i toluee. We do ot fully uderstad the reaso for this behavior. To the best of our kowledge, two modificatios of ucl have bee reported: -uc which is characterized chemically by strog hygroscopic properties ad good solubility i water ad polar orgaic solvets, ad α-ucl, which is highly iert ad oly soluble i hot aqua regia.] Ayway, this peculiar behavior we observed ot oly ehaces the solubility of ucl i toluee, but also makes the reactio reproducible (Table, etry )... Developmet of a ew catalyst system We were ow able to begi our ivestigatio. The yields of the reactio already beig high, we focused our efforts to make this reactio easier to hadle ad less expesive. Test of differet ligads e of the primary objectives of this work was to fid a less air sesitive phosphie (Table ). Table : test of differet ligads. ucl ligad / DMAP KC/ Me toluee, 00 C, h a a aa aa etry ligad yield (%)a ratio (aa:aa)b c -P : -P >99 : -ctp >99 9: i-prp.: t-p : P : P(o-Tol).: P(p-CMe).: - 9 -

98 Secod geeratio catalyst for the additio of secodary amides to alkyes ucl ligad / DMAP KC/ Me toluee, 00 C, h a a aa aa etry ligad yield (%)a ratio (aa:aa)b 9 P(-Fur) : 0 dcypb : CyP(C)PCy : [P(-)][BF]- >99 : eactio coditios:.00 mmol pyrrolidi--oe,.00 mmol -hexye, mol% ucl *, mol% ligad ( mol% for chelatig ligads), mol% DMAP, 0.0 mmol Me, 0 mol% KC, ml toluee, 00 C, h; a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by GC. c) o previous dissolutio i acetoe was performed for this reactio. * The catalyst was ijected as a stock solutio of ucl (0.0 mmol) i acetoe ( ml) via syrige. The solvet was removed uder vacuum before ay liquid compouds were added. Best results were obtaied with -P ad -ctp (etries, ). I cotrast, other alkylphosphies such as i-prp or t-p did ot show comparable activities, probably because of their high steric hidrace (etries, ). Moderate results were observed with arylphosphies such as P, (o-tol)p ad P(p-CMe) (etries,, respectively) which is iterestig because of the very low price of P ad its high stability. Fially, chelatig phosphies did ot show ay activity (etries 0, ). Full coversio with high stereoselectivity was also obtaied with the tetrafluoroborate salt of -P (etry ), which is air- ad water-stable, ad advatageous especially for large-scale applicatios

99 Secod geeratio catalyst for the additio of secodary amides to alkyes Test of differet additives Systematic ivestigatios revealed that a base, for example potassium carboate or hydroxide, is essetial, whereas the alcohol ca be replaced by water (Table, etries -). This goes alog with reports i the literature that phosphies themselves ca act as reducig agets for trasitio metals, a process assisted by water. Table : variatio of additives ad bases. ucl -P additive/base toluee, 00 C, h a a aa aa etry additive base yield (%)a ratio (aa:aa)b c Me KC >99 : Me - : - KC 9 : Et KC >99 : KC >99 : eactio coditios:.00 mmol pyrrolidi--oe,.00 mmol -hexye, mol% ucl *, mol% -P, mol% DMAP, 0.0 mmol additive, 0 mol% base, ml toluee, 00 C, h; a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by GC. * The catalyst was ijected as a stock solutio of ucl (0.0 mmol) i acetoe ( ml) via syrige. The solvet was removed uder vacuum before ay liquid compoud was added

100 Secod geeratio catalyst for the additio of secodary amides to alkyes ptimizatio of the reactio coditios Fially a rage of experimets was set up to fid out what are the ideal coditios for this reactio. It was importat to observe if toluee could be replaced by a differet solvet ad if the temperature of the reactio could be lowered (Table ). Table : optimizatio of the reactio coditios. ucl -P KC/ a solvet temperature, h a aa aa etry solvet temperature ( C) yield (%)a ratio (aa:aa)b toluee 00 >99 >0: Cl '' 9 9: chiolie '' >99 : 9 -octae '' 9 >0: 0 Et '' : acetoitrile ''.: DMF '' 0 : toluee 0 >99 >0: '' 0 9 >0: '' 0 >0: '' 0 9 >0: eactio coditios:.00 mmol pyrrolidi--oe,.00 mmol -hexye, mol% ucl *, mol% -P, mol% DMAP, 0.0 mmol, 0 mol% KC, ml solvet, h; a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by GC. * The catalyst was ijected as a stock solutio of ucl (0.0 mmol) i acetoe ( ml) via syrige. The solvet was removed uder vacuum before ay liquid compoud was added. ther aromatic solvets such as chlorobezee ad quiolie also led to total coversios (etries, ) but with lower selectivities. -ctae o the other had shows very good results with high yields ad selectivities ad therefore represets the best alterative to toluee (etry 9). Dipolar protic or aprotic solvets appear to slow dow the reactio (etries 0-). This could be explaied by two effects, first, the solubility of the released KCl i - 9 -

101 Secod geeratio catalyst for the additio of secodary amides to alkyes polar solvets, which could affect the efficiecy of the reactio, ad secod, solvets with Lewis-basicity could coordiate to the rutheium ceter ad deactivate the active species. Fially we foud out that a temperature of 0 C appears to be sufficiet (etry ), but a decrease i temperature uder 0 C led to low coversios (etries -). The performace of this simple system i the model reactio matches that of the expesive [u(cod)(met)]-derived catalyst, Moreover, ESI-MS measuremets of a sample take from a toluee solutio of ucl, -P, DMAP, KC, water, ad pyrrolidi--oe displayed agai the distict sigals correspodig to [(-P)u(C)(C0)] ad [(-P)u(C)] fragmets (Scheme )

102 Secod geeratio catalyst for the additio of secodary amides to alkyes Ites. MS, 0.-.9mi #(-) x0..0 a) Ites. MS, 0.-.mi #(-0) x b) m/z u-dimers m/z. c) m/z [(- P) u(c )(C 00 )] [(- P) u(c )(C )] [(- [(-P) P)u(C u(c)] ) Scheme : ESI-MS of the catalyst systems based o a) ucl ad b) [u(cod)(met)]. These results support our hypothesis that the same type of catalytically active rutheium(ii) species is geerated with either method (Scheme )

103 Secod geeratio catalyst for the additio of secodary amides to alkyes, -P / DMAP (II) u LXu -P / DMAP KC, P(-) KCl, KC ucl L= -P ad/or DMAP X = C or Cl,... Scheme : catalyst preformatio with [u(cod)(met)] ad ucl... Scope of the reactio usig the secod geeratio catalyst We ext tested the geerality of the ew protocol by applyig it to the sythesis of eamide derivatives from various -ucleophiles ad alkyes (Table ). Table : scope of the reactio. ucl -P/DMAP KC / a-p toluee, 00 C, h a-j yield product yield (ratio :)a 99 (:) (9 (:))b 9 (:) (99 0:)b (C) 9 (:) (9 (0:))b aa ab t 99 (0:) (99 (0:))b ac ad Me 9 (0:) (99 (0:))b 9 (:) (9 (:))b ae af (C)Cl 99 (:) ( (0:))b product (ratio :)a (C)Me 99 (:) (9 (:))b

104 Secod geeratio catalyst for the additio of secodary amides to alkyes ucl -P/DMAP KC / a-p toluee, 00 C, h a-j yield product ag yield (ratio :)a ah 90 (:) (9 (:))b SiMe (9:) (99 (0:))b ai aj (:) (0 (:))b ba 9 (0:) (9 (0:))b ca 99 (0:) (9 (0:))b da 0 (0:) ( (0:))b ea (0:) (99 (0:))b 0 (0:) ( (0:))b fa ga 9 (0:) (99 (0:))b 0 (0:) Et ha ia (.:) ( (0:))b ja 0 (.:) ( (0:))b ka 9 (0:) ( (0:))b la ma product (ratio :)a (0:) (90 (0:))b

105 Secod geeratio catalyst for the additio of secodary amides to alkyes ucl -P/DMAP KC / a-p toluee, 00 C, h yield (ratio :)a yield product (ratio :)a a-j product 9 (:) (9 (0:))b 9 (:) ( (:))b a oa (:) ( (:))b pa eactio coditios:.00 mmol -ucleophile,,.00 mmol alkye, mol% ucl *, 9 mol% -P, 9 mol% DMAP, 0.0 mmol, mol% KC, ml toluee, 00 C, h; a) isolated yield, ratio determied by GC. b) isolated yields ad selectivity of the [u(cod)(met)] based hydroamidatio. * The catalyst was ijected as a stock solutio of ucl (0.0 mmol) i acetoe ( ml) via syrige. The solvet was removed uder vacuum before ay liquid compoud was added. As ca be see from above, liear ad brached aliphatic as well as aromatic termial alkyes bearig a rage of fuctioal groups were smoothly ad selectively coverted with pyrrolidi-oe (aa-aj) i yields that were sometimes eve i excess of those obtaied with the first geeratio catalyst. Moreover, various -ucleophiles could be added to -hexye (ba-pa), icludig amides, lactams, bislactams ad oxazolidioes. For the products ba ad ea, lower yields were observed. This could be explaied by the competitio betwee the substrates ad the chloride ios still i solutio. This effect becomes more proouced if the -ucleophile has difficulties to coordiate to the rutheium ceter. These difficulties could be due to the rig-tesio after the deprotoatio of the four-membered lactam or to the importat steric hidrace of the ie-membered lactam. A similar competitio was also observed for the products ia, ja, ka. It is likely that these particular substrates already have difficulties to coordiate to the rutheium-ceter, ad the are too slow to compete with the chloride ios. To summarize, a practical protocol for hydroamidatio reactios has bee discovered i which the catalyst is geerated i situ from iexpesive rutheium(iii) chloride hydrate, tri-- 9 -

106 Secod geeratio catalyst for the additio of secodary amides to alkyes butylphosphie or its BF adduct, -(dimethylamio)pyridie ad potassium carboate. The catalyst allows the additio of secodary amides to termial alkyes, ad yields the correspodig E-ati-Markovikov eamides. The coversios observed ofte match or eve exceed those of the costly first-geeratio catalyst. Moreover, the protocol could easily be scaled up to gram quatities without ay losses i yield, selectivity or moey

107 Mechaistic studies of the hydroamidatio of alkyes. Mechaistic studies of the hydroamidatio of alkyes To summarize, the hydroamidatio of alkyes is o loger limited to the secodary amides, major chages i the protocol allow us ow to add primary amides ad imides to termial alkyes i very good yields ad selectivities. Moreover, great achievemets were made by replacig the expesive [u(cod)(met)] catalyst by the more cheaper ucl. for the secodary amides protocol. owever, the mechaism of this reactio is still uclear. A possible route to obtai this kid of regioselectivity would be the oe supported by Dixeuf et al. for the additio of carboxylic acid to alkyes ivolvig a u-alkylidee complexe (Scheme ). * * [u] [u] - [u] or * 0 * [u] 9 [u] C * * [u] - * Scheme : mechaism ivolvig a u-alkylidee. The catalytic cycle begis by coordiatio of the alkye to the metal ceter (). Tautomerizatio of the complex ivolvig [, ] proto shift leads to the itermediate. The latter udergoes a ucleophilic attack of the amide o the positio of the rutheium

108 Mechaistic studies of the hydroamidatio of alkyes cetre to give itermediate. Protoatio of followed by a reductive elimiatio delivers the desired product ad recreates the origial rutheium ceter. Aother plausible mechaism would be the oe developed by Wakatsuki et al. for the additio of water to alkyes. Scheme 9 depicts this mechaism adapted to our reactio. * * [u] [u] * [u] * [u] [u] C * * Scheme 9: mechaism accordig to Wakatsuki et al. This mechaism begis agai with coordiatio of the alkye to the metal ceter to form the itermediate. Exteral attack of the latter by leads to a viylic rutheium species, which is stabilized by a [, ]-shift of hydroge to the metal. Attack of a deprotoated amide to the viylidee-rutheium complex leads to the itermediate, which reductively elimiates the eamide with release of the origial rutheium complex. Fially, we also developed a mechaism based o our observatios. ur approach differs from the previous oes with regards to the coordiatio step. From our poit of view, the rutheium ceter first coordiates to the amide moiety (Scheme 0)

109 Mechaistic studies of the hydroamidatio of alkyes * * [u] [u] * [u] * Scheme 0: mechaism ivolvig activatio of the amide. ur proposed catalytic cycle starts from a rutheium-amide complex (). Iitially, the alkye adds to the u-ceter, possibly displacig oe of the ligads uder formatio of complex. The amide aio the attacks the coordiated alkye, ad the eamide product is fially released from the itermediate by protoatio, thus regeeratig the origial catalytic active species. I order to pipoit which of these mechaisms could be best applied to our reactio, we decided to perform the reactio with deuterated alkyes, so that we could observe whether or ot the termial proto is shifted. We performed the additio of pyrrolidi--oe, bezamide, ad succiimide to deuterated hexye (Scheme, respectively equatio, ad ) with the best coditios developed for each of the substrates

110 Mechaistic studies of the hydroamidatio of alkyes ) mol% [u(cod)(met)] mol% -P mol% DMAP D 9% DG 9% yield 90% DG D D DMF, 0 C, h mol% [u(cod)(met)] mol% -P mol% Sc(Tf) D % yield 9% DG 9aa* toluee, 00 C, h mol% [u(cod)(met)] mol% dcypb mol% Yb(Tf) 9% DG ) aa* D ) D DMF, 0 C, h aa* 9% DG % yield 9% DG DG = deuteratio grade Scheme : deuteratio experimets. As we solely detected the formatio of products with the deuterium remaiig i the positio for all of these reactios, reactio pathways via, proto shift have to be excluded for these particular trasformatios. ly the two other reactio mechaisms remai plausible, the oe proposed by Wakatsuki et al. ad the oe that we proposed. Ufortuately, at this stage of the mechaistic studies, it is ot possible to decide if oe of these mechaisms is the right oe or ot. A decisive poit would be the isolatio of reactio itermediates, however this was ot possible so far. ur attempts to preform the supposedly active catalytic species ad to isolate it failed because of the too high sesitivity of rutheium complexes. t i view of the results obtaied with the ESI-MS experimets (see previous chapter), we are able to propose a hypothetic mechaism, which from our poit of view describes best what happes i the reactio vessels (Scheme ). This mechaism is the oe we propose for the additio of primary amides to alkyes

111 Mechaistic studies of the hydroamidatio of alkyes L DMAP [u(cod)(met)] Lu(met) CD 9 E-product * LXu 0 * X Lu Lu Z-product X * * * LXu a b * X X L = phosphie ad/or co-ligad (i.e. DMAP) X = C() (or Tf i the case of the primary amide protocol) Scheme : proposed catalytic cycle for the additio of secodary amides to alkyes. Supported by the ESI-MS experimets, we are sure that oe of the origial ligads of the elaborate u-precursor actually remais boud to the metal ceter, so that our catalytic cycle starts from LXu-amide complex 0. Coordiatio of the alkye to the rutheium ceter leads to the complex. Attack of the amide aio to the coordiated alkye forms the rutheium complexes a ad b. Depedig o whether the coordiated amides attacks the alkye ad is replaced by a exteral amide aio or whether the latter directly attacks the coordiated alkye, the (Z)-cofigured (a) or (E)-cofigured (b) rutheium amide complex forms. Protoolysis of the itermediate would probably proceed with preservatio of the stereochemistry, regeeratig the iitial rutheium species (0) ad completig the catalytic cycle. To coclude, we were able to propose a mechaism supported by our experimetal observatios. owever, it is strictly hypothetic ad the reactio pathway postulated by Wakatsuki et al. could ot be excluded

112 Additio of thioamides to alkyes... Additio of thioamides to alkyes Problem statemet The particular reliability of the methodology developed for the additio of amides to alkyes ecouraged us to exted this strategy to the rapid sythesis of thioeamides. As see before, eamides are well described i the literature, however, their sulfurated aalogues which could be of cosiderable iterest as a structural variat of the eamide subuit are oly scarcely represeted. At preset, treatmet of the aalogous eamides by Lawesso s reaget or other similarly aggressive sulfurizig9 agets is the oly possibility to obtai the thioeamide structure. t it is evidet that the most sesitive fuctioal groups would ot be tolerated by such processes. Thus, a easy ad cocise method for the sythesis of thioeamides is probably the key to the developmet of its chemistry. As for the sythesis of eamides, a expediet method for the preparatio of thioeamides would be the catalytic additio of thioamides to alkyes (Scheme ).90 S S [cat.] / Scheme : additio of thioamides to alkyes. owever, i compariso to amides, thioamides preset a more proouced ambidet ucleophilic ature due to the softess of the sulfur ad itroge atoms, ad thus ca react o the itroge or sulfur termius depedig o the electrophile used, followig the SAB priciple (Scheme ).9 S S E E = electrophile Scheme : additio of thioamides to a electrophile E S or E

113 Additio of thioamides to alkyes This additioal chemoselectivity issue, i additio to the regio- ad stereocotrol, also had to be cotrolled i our plaed trasitio metal-catalyzed reactio, alog with the fact that sulfur-cotaiig compouds are kow catalyst poisos due to their strog iteractio with late trasitio metals. This project was pursued together with Dipl.-Chem. Kifah M. Salih ad is part of both our.d. theses... Developmet of a ew catalyst system We chose thiopyrolidioe ad -hexye as test substrates for our studies because of their good availability (Table ). Table : test of differet additives. S a [u(cod)(met)] -P additive toluee, 00 C S S a aa aa etry additive yield (%)a ratio (aa:aa)b DMAP 0 : KC : ac : LiCl : CsCl 9 : Å MS 9 : eactio coditios: 0.0 mmol thiopyrolidioe,.00 mmol -hexye, mol% [u(cod)(met)], mol% -P, mol% additive or 0 mg Å molecular sieves, toluee (. ml), 00 C, h. a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by GC. ur first attempt usig the catalytic system developed for the additio of secodary amides to alkyes did ot reach the expected level of activity ad -((E)-hex--eyl)pyrrolidie-thioe was obtaied rather i low yields ad usatisfactory selectivity (etry ). This may be attributed to the substatially higher acidity of thioamides compared to amides (pka of pyrrolidoe,.; pyrrolidie--thioe,.).9 The idetity of the product obtaied was cofirmed by compariso to a sample that was prepared via a literature procedure usig the aalogous eamides as startig material.9b - 0 -

114 Additio of thioamides to alkyes igher yields were obtaied by substitutig DMAP with iorgaic bases, although without improvemet i terms of selectivity. This ehacemet i yield is probably caused by the effect of the couter ios of the iorgaic base (etries, ). Mild Lewis acids (etries -) such as lithium chloride, cesium chloride or molecular sieves improved both yield ad selectivity, with the added beeficial effect of the latter beig capable to remove the moisture cotaied i the reactio mixture, thus preservig the product from a hydrolysis. Test of differet rutheium sources Amog all the rutheium sources tested, oly [u(cod)(met)] was particularly effective. ther rutheium catalysts were also active but they ever reached its level of activity ad selectivity. (Table ) Table : test of differet rutheium sources. [u-cat.] -P Å MS S S S toluee, 00 C a a aa aa etry [u-cat.] yield (%)a ratio (aa:aa)b [u(cod)(met)] 9 : [(p-cymee)ucl] 0: [u(cod)cl] 0 9: 9 [u(c)] 0 d 0 [ucl] : eactio coditios: 0.0 mmol thiopyrrolidioe,.00 mmol -hexye, mol% [u-cat.], mol% -P, 0 mg Å molecular sieves, toluee (. ml), 00 C, h. a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by GC

115 Additio of thioamides to alkyes Test of differet ligads To achieve the completio of the reactio ad make the reactio more selective, we the tested some other ligads. Table : test of differet ligads. [u(cod)(met)] ligad Å MS toluee, 00 C S a a S S aa aa etry ligad yield (%)a ratio (aa:aa)b -P 9 : P(-Fur) >0: P : t-p 0 d -ctp 9 : dppm 0 : dcypm : eactio coditios: 0.0 mmol thiopyrrolidioe,.00 mmol -hexye, mol% [u(cod)(met)], mol% ligad (or. mol% for chelatig ligad), 0 mg Å molecular sieves, toluee (. ml), 00 C, h. a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by GC. As experieced durig our previous reactio optimizatios, electro-poor ad sterically hidered phosphies slow dow the reactio (etries -). Chelatig phosphies did ot lead to ay improvemet, probably because of their too strog coordiatio to the metal ceter, ad i the case of bis(dicyclohexyl-phosphio)methae, the yield of the reactio dramatically dropped to % (etries, ). As i the additio of secodary amides to alkyes, oly tri-alkyl phosphies led to the desired product with high yields ad selectivities. A small improvemet compared to the previous protocol was made by usig tri(octyl)phosphie (etry ), istead of tri(-butyl)phosphie. It is likely that the stroger steric effect of the former is resposible for this ehacemet of the selectivity

116 Additio of thioamides to alkyes ptimizatio of the reactio coditios We fially tested the reactio i other solvets i order to fid out if toluee could be substituted by aother solvet with positive effect o the selectivity of the trasformatio. Importat was also to observe if the reactio temperature could be reduced without loss of activity (Table ). Table : optimizatio of the reactio coditios. S a [u(cod)(met)] -P Å MS solvet, temperature a S S aa aa etry solvet temp. ( C) yield (%)a ratio (aa:aa)b toluee 00 9 : glyme '' : Et '' 0: 9 DMF '' 9 : 0 mesitylee '' 9 : '' 0 : '' 0 : eactio coditios: 0.0 mmol thiopyrrolidioe,.00 mmol -hexye, mol% u-source, mol% -P, 0 mg Å molecular sieves, solvet (. ml), h. a) corrected GC yields with -tetradecae as iteral stadard. b) ratio determied by GC. opolar solvets were most effective, as expected reactio performed i mesitylee leads to almost the same results as i toluee. owever, other solvets ca also be used, although with either lower yields i the case of ethaol, or loss of selectivity if DMF is used (etry 9). Fially mesitylee was used for testig differet temperatures because of its higher boilig poit. It appears that 00 C represets the best compromise betwee turover rate ad stereoselectivity. Performig the reactio at lower or higher temperature slowed dow the reactio (etries 0-)

117 Additio of thioamides to alkyes Uder these optimized coditios (etry ), we exclusively observed the formatio of the (E)-ati-Markovikov product, ad the hypothetic additio occurrig from the S-rather tha the -termius of the thioamide could ever be detected... Scope of the reactio To ivestigate the scope of this ew hydroamidatio protocol, we applied it to the additio of a broad variety of itroge ucleophiles to several termial alkyes. Table 9: scope of the reactio. [u(cod)(met)] -ctp Å MS S toluee, 00 C, h S S yield (%)a product S yield (%)a product (ratio :)b (ratio :) S t 9 (:) aa 9 (:) ab S S 9 (:) Cl ac 9 (:)c ad S S (:) ae Me (:)c SiMe (:)c af S S SiMe (9:) ag ah

118 Additio of thioamides to alkyes [u(cod)(met)] -ctp Å MS S toluee, 00 C, h S S yield (%)a product yield (%)a product (ratio :)b S (ratio :) S (:)c ai 9 (:) aj S S 9 (:)c, d bj (0:)c cj S S 9 (0:)c dj 9 (0:) (:)c ej S S 9 (:)c fj gj eactio coditios:.00 mmol -ucleophile,.00 mmol alkye, mol% [u(cod)(met)], mol% -ctp, 00 mg Å molecular sieves, toluee ( ml), h. a) isolated yield. b) ratio determied by GC. c) mol% [u(cod)(met)], mol% -ctp. d) ratio determied by M. the oe had, pyrrolidie--thioe added smoothly to various alkyes, amog them alkylad aryl-substituted alkyes, trimethylsilylacetylee, ad cojugated eyes. Surprisigly, low yields were observed i the case of trimethyl-prop--yyloxy-silae (ag). Sice o dimerizatio products were observed with this alkye, we assumed that it decomposed durig the reactio because of its sesitivity. the other had, pheylacetylee reacted with a rage of secodary thioamides bearig aromatic or aliphatic substitutets, as well as with a thiocarbamate. I most cases, the products were obtaied i good yields ad high selectivities for the (E)-cofigured ati- 0 -

119 Additio of thioamides to alkyes Markovikov-thioeamides. We still faced a problem by usig [,]oxaziae--thioe as it seems that the dimerizatio reactio of pheylacetylee is faster tha the additio reactio, thus leadig to low yields (gj)... eversal of the selectivity I a attempt to ivert the stereoselectivity of the additio, we combied the ligad with the lowest E-selectivity, bis(dicyclohexylphosphio)methae (dcypm), with various additives, ad foud that the Z-isomer ca ideed be obtaied as the major product with % yield ad : selectivity i the presece of potassium tert-butoxide. Table 0: scope of the Z-selective protocol. [u(cod)(met)] dcypm Kt S toluee, 00 C, h S S yield (%)a product (ratio :)b product yield (%)a (ratio :) S S (:) 0 (:) t aa ab S (:) ac eactio coditios:.00 mmol -ucleophile,.00 mmol alkye, mol% u(cod)(met), mol% dcypm, mol% Kt, toluee ( ml), h. a) isolated yield. b) ratio determied by GC. The scope of the complemetary (Z)-selective hydrothioamidatio was also tested o a umber of examples. This protocol appears to be as high-yieldig, although the level of stereoselectivity ever exceeded a moderate : ratio. Further work is aimed at extedig the sythetic utility of this complemetary protocol by improvig the (Z)-selectivity with the help of customized ligads. - -

120 Markovikov additio of secodary amides to alkyes. Markovikov additio of secodary amides to alkyes Fially, we cocetrated our efforts i fidig a protocol for the Markovikov additio of amides to alkyes. Products resultig from such a trasformatio are of particular importace from a sythetic poit of view (i.e. eatioselective hydrogeatio, etc ), they are also ofte represeted i the sythesis of atural products. Followig the methodology developed for the sythesis of the ati-markovikov eamides, we tried to idetify a catalytic system active oly for the Markovikov additio of amides to alkyes. The experimetal results obtaied so far show the complexity of our u-catalyzed reactio protocols. It was very disappoitig that o Markovikov product had formed uder ay set of coditios, ad solely from the proposed catalytic cycle, it is hard to ratioalize this decisive differece of reactivity betwee amides ad carboxylic acids. This is why we decided to seek ispiratio from related literature procedures o the hydroamiatio of alkyes ad hydroamidatio of alkees... Based o the Markovikov selective hydroamiatio of alkyes of Uchimaru Uchimaru preseted a iterestig method for the additio of secodary amies to termial alkyes catalyzed by [uc] i the absece of solvet (Scheme ). uc 9% yield 0 C, h amie as solvet Scheme : additio of secodary amies to termial alkyes accordig to the method of Uchimaru. The proposed mechaism of the reactio cosists of a oxidative additio of the amie bod to a rutheium ceter givig the amidorutheium hydride, a coordiatio of the alkye to the metal, followed by a itramolecular attack of the itroge to the C C triple bod ad a reductive elimiatio of the eamie. The yields were moderate ad the scope limited to very few combiatios of startig materials, but we still decided to ivestigate whether this reactio might serve as a startig poit for further ivestigatios. - -

121 Markovikov additio of secodary amides to alkyes Table : screeig table for the hydroamiatio of alkyes. [cat.] ligad additive solvet, 0 C, h -ucleophile etry 9 [cat.] / ligad solvet yield (%)a [uc] eat " " toluee " " DMF " [u(cod)(met)] / -P eat 0 uc eat 0 eat 0 " " " DMF 0 " " toluee 0 " eat " " DMF 0 " " toluee 0 eactio coditios:.00 mmol of amie / amide,.00 mmol of pheylacetylee, mol% u precursor, mol% ligad, mol% additive, ml solvet, 0 C, h. a) corrected GC yields with -tetradecae as iteral stadard. - -

122 Markovikov additio of secodary amides to alkyes Ufortuately, our ow experiece with this reactio was ot at all ecouragig. All of our attempts to reproduce the results of Uchimaru failed, ad % was the best yield obtaied, istead of the 9% reported. ther catalyst systems also gave low yields (Etries -). Applyig this system to secodary amides ad imides did ot result i ay coversio, so that we abadoed this approach... Based o the hydroamidatio of alkyl propiolates from Trost A iterestig method for the sythesis of dehydroamio acids has bee described by Trost, who added ucleophiles to alkyoates uder formatio of - substituted acrylates. osphies as catalysts iduce isomerizatio of the alkyoates to,-dieoates, which the udergo additio of proucleophiles to the -positio (Scheme ). e optimized a system capable of addig imides to some termial alkyes to give the Markovikov product, just by usig tripheylphosphie, sodium acetate ad acetic acid. P P u- P - uc uc Scheme : Alkyoates-ucleophilic additio at the -positio. We chose the reactio of phthalimide with ethyl propiolate as a model system to verify these results, ad were pleased to fid that we could reproduce the 9% yield described i the literature (Table, etry ). - -

123 Markovikov additio of secodary amides to alkyes Table : additio of phthalimide to alkyes. [cat.] ligad additive toluee, 0 C, h 0 etry alkye [cat.] ligad additive yield (%)a - P aac, Ac 9 - " " 9 " " " - 0 " " - 0 " " t-p " - PCy - " - -P - 9 " [u(cod)(met)] P - " " eactio coditios:.00 mmol phthalimide,.00 mmol of alkye, mol% [cat.], mol% ligad, mol% additive, ml solvet, 0 C, h. a) corrected GC yields with -tetradecae as iteral stadard. - -

124 Markovikov additio of secodary amides to alkyes This system is also efficiet for the additio of other imides, e.g. glutarimide, phthalimide ad succiimide to propiolates, although with very low yields. owever, it was ot possible to exted this method to other alkyes. Ideed, the alkyes described i the publicatio were the oly oes able to react with the imides (etries -). We performed a series of experimets i order to further optimize the catalyst system (etries -9), ad possibly exted its scope with regard to the alkyes. owever, it tured out that eve small chage i the phosphie or additives, or the use of a coordiatig metal all slowed dow the reactio. As expected from the mechaism, we ever observed ay coversio of imides with o-activated alkyes such as -hexye; the reactio is strictly limited to cojugated alkyes... Followig up o a ukow compoud observed i our hydroamidatios We moitored all of our reactios by GC ad GC/MS usig -tetradecae as the iteral stadard. Usually, we observed a maximum of two peaks with the mass of the desired product, which always tured out to be the two possible ati-markovikov stereoisomers. Due to their similar polarity, the separatio of such a pair of isomers by colum chromatography was usually quite challegig, especially whe oe of them was formed i small amouts. We were very excited to see that i some samples, a third peak with the mass of the desired product was observed, leadig us to coclude that this must be the log awaited Markovikov product (Figure ) owever, because it was formed i rather low yields ad had almost the same polarity as oe of the other isomers, its isolatio proved to be extremely difficult ad time-cosumig. Figure : GC cotrol spectra of the reactio. - -

125 Markovikov additio of secodary amides to alkyes We thus decided to optimize the reactio parameters to icrease the selectivity for what we believed to be the Markovikov product. We chose the reactio of pyrrolidioe with hexye as a model system ad ivestigated the activity of several rutheium catalysts uder differet coditios (Table ). Table : additio of pyrrolidioe to -hexye. [cat.] ligad additive a? solvet temperature, h aa a -aa yields (%)a etry [cat.] T C ligad additive [u(cod)(met)] 00 -ctp Sc(Tf) (:) AuI " " " (>:0) [Ir(coe)Cl)] " " " 0 (d) [h(cod)(acac)] " " " (:) [Ir(cod)(acac)] " " " 0 (:) AuCl " " " 0 (d) h(bd) BF " " " (:.) - " " " 0 (d) 9 [u(cod)(met)] 0 " " (>:0) 0 " 0 " " 9 (:) " 00 " " 0 (d) " 0 -ctp Z(Tf) (:) " " " Li(Tf) (>:0) " " " Al(Tf) 9 (:) " 0 P Z(Tf) 0 (>:0) " " i-prp " (:) " " P(-Fur) " 0 " 0 dcpe Z(Tf) 0 (:) (aa:-aa) eactio coditios:.00 mmol of pyrrolidioe,.00 mmol of -hexye, mol% of [cat.], mol% ligad, mol% additive, h; a) corrected GC yields with -tetradecae as iteral stadard ad ratio determied by GC. - -

126 Markovikov additio of secodary amides to alkyes The first time we observed the formatio of a ew product (aa) was whe usig [u(cod)(met)] / -ctp i DMF at 00 C i the presece of scadium triflate (etry ). Differet combiatios of u-sources with -ctp used istead of h(bd)bf ad [u(cod)(met)] (Etries, ) did ot give ay coversio to aa (Etries -). Based o the assumptio that the Markovikov product is a thermodyamic product, we also tested the reactio at differet temperatures. At low temperatures, -aa was obtaied as the major product i moderate yield (Etry 9). ly whe we performed the reactio at higher temperatures, we observed a improvemet of the selectivity to the desired ew product (Etry 0). evertheless, the temperature was limited to a maximum of 00 C due to a thermal degradatio of the startig materials (Etry ). The test of some additives revealed that orgaic bases such as DMAP were agai ieffective, ad oly specific triflates were able to give aa albeit i very low yields (Etries -). The use of electro-poor phosphies (Etry ) did ot give ay product, ad oly ligads such as -ctp ad dcpe (Etry ) allowed us to obtai eough of aa to permit us the isolatio of the desired compoud. Ufortuately, M spectroscopy revealed uambiguously that this compoud was ot the desired Markovikov, but rather a double-bod isomer of the ati-markovikov product (Figure ), which may have formed via a allyl-rutheium itermediate. aa Figure : product resultig from a isomerisatio of the double bod. - -

127 Markovikov additio of secodary amides to alkyes.. Usig a phosphie as catalyst ur last attempt to reverse the regioselectivity i favor of the Markovikov product cosisted i followig a protocol described by Iaaga et al. where they described the ati-markoikov additio of alcohol to methyl propiolate catalyzed by -P (Scheme ).9 -P CCl CMe -P P -P - P C a P - CMe b - Me c Scheme : additio of alcohol to alkyes by Iaaga et al. They assumed that -P attacks the -carbo of methyl propiolate leadig to the phosphoium eolate a. It the abstract protos from alcohol to give the itermediate b. Cosecutive additio of the alkoxy aio to the -trialkylphosphoium catio ad elimiatio of the phosphie geerates the desired product. By reproducig the same experimet usig toluee as solvet for the additio of pyrrolidioe to pheylacetylee, we were pleased to fid out that oly oe product resultig from the Markovikov additio was obtaied (Scheme ). The idetity of the product isolated was cofirmed by compariso of its -M spectra with a literature spectrum

128 Markovikov additio of secodary amides to alkyes -P toluee, 00 C, h aa % isol. ab % GC yield F ac % GC yield Et t ad % GC yield ae % GC yield Scheme : Markovikov additio of amides to alkyes. owever, this methodology oly allows the additio of pyrrolidioe to pheylacetylee derivatives. Attempts to reproduce this reactio usig other amides or alkyes oly led to the recovery of the startig materials. t to the best of our kowledge it represets the first ad oly Markovikov additio of amides to alkyes, ad this reactio is uder itesive studies i our group. The mechaism of the reactio is also uclear ad mechaistic ivestigatios are curretly ogoig

129 Summary ad future aspects Summary ad future aspects Progress has bee made i the search for ideal hydroamidatio of alkyes. I summary, the mai achievemets iclude: The developmet of a ew catalytic system for the additio of imides to alkyes. The use of Yb(Tf) as a additive ehaced the ucleophilicity of the imides, thus allowig us the selective Z-ati-Markovikov hydroamidatio of termial alkyes. Moreover, the stereoselectivity of the reactio could be cotrolled by chagig the ligad employed, ad a protocol was also developed for the exclusive sytheses of E-eimides. The developmet of a protocol for the additio of the primary amides to alkyes. We were able to cotrol the rate of the reactio so that oly the product resultig from the additio of amide to a sigle equivalet of alkye was obtaied. The reactio proceeded smoothly deliverig the thermodyamically ufavored Z-eamide i high yields ad with high selectivities. The E-isomer was obtaied by a simple isomerizatio reactio. The replacemet of the expesive [u(cod)(met)] by the more readily available [ucl ], which proves to be as effective for this reactio. Moreover, the use of the air stable [-P] [BF] as a ligad was foud to be also effective makig this reactio advatageous, especially for large-scale applicatios. The developmet of a methodology for the additio of a ew class of -ucleophiles to alkyes, amely the thioamides. o additio occurrig through the sulphur atom was oticed ad oly thioeamide products were observed with high E-selectivities. - -

130 Summary ad future aspects -P [u(cod)(met)] Sc(Tf) eimide X= up to 9% yield, 0/ Z/E i-prp up to % yield, / E/Z [u(cod)(met)] Yb(Tf) dcypb sec. eamide X= Et X up to 99% yield,0/ Z/E eamide X= [u(cod)(met)] thioeamide X=S [ucl ] -P/DMAP KC, up to 9% yield, 0/ E/Z S -ctp Å mol. sieves up to 99% yield, 0/ E/Z up to 9% yield, 0/ E/Z S dcypm Kt up to % yield, / Z/E Scheme 9: additio of amides to alkyes. I our ogoig research, we pla to exted the scope of this reactio by usig ew substrates. e directio is to use other -ucleophiles such as sulfoamides, or more complex ad sesitive amides. Aother research aveue will focus o usig other alkyes, for example, the selective additio of amides to disubstituted alkyes. We also pla to apply this methodology to the sythesis of some atural product (Scheme 90). - -

131 Summary ad future aspects Br Cosciamide A Chodriamide C Chodriamide A Br Cosciamide B Igzamide Scheme 90: possible atural products accessible via hydroamidatio of alkyes. Mechaistic studies icludig i situ ESI-MS ad M showed the formatio of a rutheium(ii)phosphiamide-complex for the additio of secodary amides to alkyes. Based o these results ad the experimets performed usig deuterated startig materials, we were able to propose a ew reactio pathway for the hydroamidatio. evertheless, oly the isolatio ad characterizatio of the itermediates will permit us to fully uderstad this reactio, but so far the isolatio of these highly sesitive complexes failed. Fially we disclosed a first protocol for the Markovikov additio of amides to alkyes. Eve if this reactio oly allows the additio of pyrrolidioe to pheylacetylee aalogous alkyes, for the momet it represets the proof that such a reactio is possible ad also a very excitig startig poit for further optimizatios. We are persuaded that the catalytic system ca be optimized fully ad fially employed to a broad rage of substrates. ther phosphies have to be tried, with maybe less steric hidrace, or free carbees could also be used to activate the triple bod of the alkye. Fially, a catalyst - -

132 Summary ad future aspects based o a metal such as gold or platium could be the solutio of this challege sice the Markovikov additio of other hydroge boded ucleophiles (i.e. water, amies, carboxylic acids) was ofte foud to be catalyzed by complexes cotaiig these metals. - -

133 Ackowledgemets Ackowledgemets This work was carried out i the Departmet of rgaic Chemistry of the Techische Uiversität Kaiserslauter, Germay. I would like to express my sicere gratitude ad thaks to all colleagues, past ad preset, i the departmet for makig the time I spet at the TU KL very ejoyable ad uforgettable. I particularly would like to express my special gratitude to Prof. Dr. Lukas J. Gooße, for beig a superb supervisor ad for his ispirig guidace, ever failig ethusiasm throughout this study, for sharig his wisdom i sciece ad life ad for providig excellet workig facilities. Also for itroducig me to the world of catalysis ad rutheium chemistry. I would like to thak all members of the AK Gooße: My co-authors: Claus Brikma, Kifah M. Salih, Matthias Ardt for fruitful collaboratio i the eamide project. Paul Lage, eiko Bauer, Marcus Fischer, Patrizia Mamoe for their fie cotributios to the projects durig their traiig stages. My co-workers ad room mates: Thomas Kauber (Der Kauber), Dr. Coreliu Staciu (thak you for the brilliat liguistic revisio of my thesis) ad oma Bauer (flash-games Meister) for valuable discussios ad very pleasat times i the lab. My proofreaders: Dr uria odríguez Garrido, Domiik hlma (thak you for your help o documet formattig), Bettia Zimmerma ée Melzer (Schatzelei) for costructive criticism ad liguistic revisio of the thesis. Felix udolphi ad Adreas Fromm, for excellet assistace i computer matters. Filipe Costa, Bilal Ahmad Kha, Christoph ppel ad fially Christophe Lider (my colleague, flat mate ad fried) for a good time both withi ad outside the lab. I also would like to thak all the persoel of the Uiversity of Kaiserslauter, Dr. arald Kelm ad Christiae Müller for their expertise with the M-machies ad i theoretical - -

134 Ackowledgemets M problems. Ludvik apast, Jürge ahm, Frak Schröer Csaba Tömör ad Carme Eggert for always beig there whe I eeded help. I would like to thak my family (thak you for forgivig me for movig to Germay), my sister, my frieds (for always beig supportive) ad my girlfried Iria who had to support me durig all this log ad stressful writig period. Fially I also would like to thak the Gesellschaft Deutscher Chemiker (GDCh) for makig it possible for me to atted several meetigs ad courses. Fiacial support was obtaied from Deutsche Forschugsgemeischaft (DFG) ad Umicore AG. - -

135 Experimetal part Experimetal part... Geeral iformatio Solvets ad chemicals All used solvets were purified by geeral described procedures.9 All commercially available reagets were distilled either from Ca or molecular sieves uder a iert atmosphere before use. All commercially available imides were used as received. All commercially available thioamides were used a received, while all others were obtaied by covertig the correspodig amides ito thioamides usig the method of Lawesso et al.c All commercial primary amides were used as obtaied without further purificatio, while the other were sythesized by treatig the commercially correspodig carboxylic acid with oxalyl chloride ad ammoia solutio i dry methylee chloride. All commercial amides were used as obtaied without further purificatio. [u(cod)(met)] was supplied by Umicore AG... Aalytical methods uclear Magetic esoace Proto- ad decoupled carbo-m spectra were recorded with a Bruker FT-M DPX 00, DPX 00 ad a Bruker Avace 00. The frequecy ad solvet used is described separately for each substace. Chemical shifts are give i uits of the δ-scale i ppm. Shifts for spectra are give respectively to the proto sigal of the solvet used (chloroform:. ppm, dimethyl sulfoxide:.0 ppm, methaol:. ppm, water:. ppm), for C-spectra respectively to the deuterated solvet (chloroform:.0 ppm, dimethyl sulfoxide:. ppm, methaol: 9. ppm). The atom umberig withi products is ot accordig to the IUPAC rules. The multiplicity of the sigals is abbreviated by the followig letters: Couplig costats are give i ertz (z). Processig ad iterpretatio was performed with ACD-Labs.0 (Advaced Chemistry Developmet Ic.) - -

136 Experimetal part abbreviatio sigal s siglet d doublet dd doublet of doublet ddd doublet of doublet of doublet td triplet of doublet q quartet Gaschromatography For GC-aalysis a ewlett Packard 90 chromatograph was used. The gas carrier was itroge with a flow rate of 9mL/mi (0. bar pressure). The temperature of the ijector was 0 C. The split-ratio was :00. For separatio a Agilet P--colum with % pheyl-methyl-siloxae (0 x 0 μm x.0 μm, 00/.-0-00/ ) was used. The followig temperature program was implemeted: startig temperature 0 C (mi), liear temperature icrease (0 C mi-) to 00 C, ed temperature 00 C (mi). igh-performace-liquid-chromatography A Shimadzu igh Performace Liquid Chromatograph with a Merck eversed ase LiChroCat PA C colum with a particle diameter of μm was used at a costat ove temperature of 0 C ad a colum pressure of bar. The eluets used were acetoitrile ad water with a flow rate of ml/mi. Gradiet: % acetoitrile for mi, liear icrease to % acetoitrile durig the course of mi, costat gradiet for.mi, decrease to % withi 0.mi ad costat for mi. The stadard cofiguratio ijected 0 μl of the sample. This amout could be maually chaged with the cotrol ad iterpretatio program Shimadzu Class-VP. Mass Spectrometry Mass spectrometry was performed with a GC-MS Varia Satur 00 T. The ioizatio was doe by EI AGC. The itesities of the sigals are relative to the highest peak. For fragmets with isotopomers oly the more itesive peak of the isotopomer is give. - -

137 Experimetal part Ifrared Spectroscopy Ifrared spectra were recorded with a Perki-Elmer Fourier Trasform Ifrared Spectrometer FT/I. Solids were thoroughly groud ad mixed with potassium bromide ad pressed ito a pellet. Liquids were measured as a thi film i betwee sodium chloride plates. Absorbacebads are show i wave umbers (cm-). Itesities are abbreviated: s (strog), m (medium) ad b (broad). Elemetal Aalysis C-elemetal aalysis was performed with a Perki-Elmer Elemetal Aalyzer EA 00 C... igh-throughput experimets I order to perform a vast umber of experimets a specially maufactured setup was used. All reactios were carried out i 0 ml headspace vials that were closed ad clamped shut with alumium caps fitted with a Teflo-coated butyl rubber septum (both commercially available at Macherey & agel). I cm high roud alumium cases, which fit the hot plate of a regular laboratory heater i diameter, 0 of the thus equipped 0 ml headspace vials ca be tempered betwee C ad 0 C. A th smaller hole drilled i the middle of the case creates room to hold the thermometer of the heater (Figure left). To correctly evacuate ad refill 0 reactio vessels with iert gas at the same time, special vacuum distributors were maufactured to be coected to the Schleck-lie (Figure right). A steel tubig is liked to te mm Teflo tubes, which are equipped o the opposite ed with adaptors for Luer-Lock syrige eedles. The steel tubig ca be coected to the Schleck-lie just like ay other laboratory equipmet by a steel olive ad vacuum tubig. To perform 0 or more reactios parallel the followig protocol was used. All solid substaces were weighed i the reactio vessels, a ove-dried, hot 0 mm stir bar added ad each vessel closed with a separate cap usig flagig pliars. All 0 vessels were trasferred to oe of the aforemetioed alumium cases ad evacuated usig syrige eedles coected to the vacuum steel tubig

138 Experimetal part Figure : 0-vessel alumiium case with heater (left) reactio setup ad vacuum distributor (right). The reactio vessels were evacuated ad refilled with itroge. A oil bubblig valve at the top of the steel tubig was used to guaratee a pressure release. Usig stadard sterile ad amilto syriges all liquid reagets, stock solutios of reagets, solvets ad the stadard (-tetradecae) were added ad the vessels were evacuated ad refilled with itroge times. After removal of the eedles, the alumium case was tempered to the desired temperature. Every temperature descriptio is the case temperature, which oly differs by maximum C from the actual reactio media temperature. At the ed of the reactio time ad after coolig to room temperature, the reactio vials were opeed carefully. ml of ethyl acetate were added to dilute the reactio mixture ad with a disposable pipette mixed thoroughly to esure a homogeous mixture. A 0. ml sample was withdraw ad extracted with ml of ethyl acetate ad ml of brie-solutio or ml of saturated potassium carboate solutio. The orgaic layer was filtered through a pipette filled with a cotto plug ad magesium sulfate ito a GC-vial

139 Experimetal part After evaluatig the cotets o the GC ad if ecessary GC-MS, the cotets of all work-up ad aalysis vials were recombied ad the product isolated usig stadard procedures, deposed o silica-gel ad purified by flash chromatography usig a Combi Flash Compaio-Chromatography apparatus from Ico-Systems (Figure ). Figure : Combi Flash Compaio-Chromatography. The developed experimetal setups ad a electroic laboratory joural allowed a substatial amout of reactios to be performed durig the course of this work. Approximately 00 reactios would have cosumed a much loger time usig stadard laboratory techiques. Preparative reactios were performed mostly i stadard laboratory ove-dried glass ware. The followig experimetal sectio describes all reactios performed, that are metioed i the theoretical sectio above. Yields are isolated yields if othig else is metioed. All kow compouds were aalyzed by proto ad carbo M, as well as GC-MS whe possible ad elemetal aalysis. - -

140 Experimetal part... Additio of imides to alkyes Geeral method Method A: A ove-dried flask was charged with the -ucleophile (.00 mmol), bis(methallyl)-cycloocta-,-diee-rutheium(ii) (. mg, 0.0 mmol) ad scadium triflate (9. mg, 0.0 mmol) ad flushed with itroge. Subsequetly, dry DMF (.0 ml), tri-butyl phosphie ( μl, 0.0 mmol) ad alkye (.00 mmol) were added via syrige. The resultig solutio was stirred for h at 0 C, ad the poured ito a aqueous sodium bicarboate solutio (0 ml). The resultig mixture was extracted repeatedly with 0 ml portios of ethyl acetate, the combied orgaic layers were washed with water ad brie, dried with magesium sulfate, filtered, ad the volatiles were removed i vacuo. The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae) to yield the Zeimide. The idetity ad purity of the products were cofirmed by ad C M spectroscopy, mass spectroscopy ad elemetal aalysis. Method B: A ove-dried flask was charged with the -ucleophile (.00 mmol), bis(methallyl)-cycloocta-,-diee-rutheium(ii) ( mg, 0.0 mmol) ad scadium triflate (9. mg, 0.0 mmol) ad flushed with itroge. Subsequetly, dry DMF (.0 ml), triisopropylphosphie (9 μl, 0. mmol) ad alkye (.00 mmol) were added via syrige. The resultig solutio was stirred for h at 0 C, ad the poured ito a aqueous sodium bicarboate solutio (0 ml). The resultig mixture was extracted repeatedly with 0 ml portios of ethyl acetate, the combied orgaic layers were washed with water ad brie, dried with magesium sulfate, filtered, ad the volatiles were removed i vacuo. The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae) to yield the Eeimide. The idetity ad purity of the products were cofirmed by ad spectroscopy, mass spectroscopy ad elemetal aalysis. - - C M

141 Experimetal part.. Sythesis of the eimides Sythesis of -[(Z)-hex--eyl]succiimide (aa) aa was sythesized followig method A usig succiimide (99. mg,.00 mmol) ad -hexye (9 L,.0 mmol) ad purified by colum chromatography (: ethyl acetate/hexae), yieldig the product as a 9 0 yellowish oil (. mg, 9%). -M (00 Mz, CDCl, C): =. (d, J =. z,, -),. (dt, J =.0 z,. z,, -),. (s,, -, -),.9 (dt, J =.,.,. z,, -),.. (m,, -, -9), 0. (t, J =. z,, -0) ppm. C-M (0 Mz, CDCl, C): =. (C-, C-),. (C-),. (C-), 0. C-),. (C-, C-),. (C-),. (C-9),. (C-0) ppm. EA Calcd: C,.;,.;,.. Foud: C,.;,.;,.. MS (Io trap, EI): m/z (%) = (, [M]), (), 00 (), (00), (). Sythesis of -[(Z)-hex--e--yl]glutarimide (ba) ba was sythesized followig method A usig glutarimide (. mg,.00 mmol) ad -hexye (9 L,.0 mmol) ad purified by colum chromatography (: ethyl acetate/hexae), yieldig the product as a 9 0 colorless oil (. mg, %). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),.0 (dt, J(,)=.0 z,. z,, -),. (t, J(,)=. z,, -, -),.9 (t, J(,)=. z,, -),. (dt, J(,)=.,.,. z,, ).. (m,, -9, -0), 0. (t, J(,)=. z,, -) ppm. C-M (0 Mz, CDCl, C): =. (C-, C-),.9 (C-), 0.0 (C-),.9 (C-, C-), 0. (C-),.9 (C-9),. (C-0),. (C-),. (C-) ppm. EA Calcd: C,.;,.;,.. Foud: C,.9;,.;,.0. MS (Io trap, EI): m/z (%) = 9 (00, [M]), (), (9), (0), (0). - -

142 Experimetal part Sythesis of -[(Z)-hex--e--yl]-,-dimethylglutarimide (ca) ca was sythesized followig method A usig,- 9 dimethylglutarimide (. mg,.00 mmol) ad -hexye (9 L, 0.0 mmol) ad purified by colum chromatography (: ethyl acetate/hexae), yieldig the product as a yellowish oil (. mg, %). -M (00 Mz, CDCl, C): =.90 (d, J(,)=. z,, -),. (dt, J(,)=.0 z,. z, -),. (s,, -, -),. (dt, J(,)=.,.9,. z,, -),..9 (m,, -9, -0),. (s,, -, -), 0. (t, J(,)=. z,, -) ppm. C-M (0 Mz, CDCl, C): =.0 (C-, C-),. (C-), 9. (C-),. (C-, C-), 0. (C-), 9. (C-),. (C-9),. (C-, C-),. (C-0),. (C-) ppm. EA Calcd: C, 9.9;, 9.;,.. Foud: C, 9.;, 9.;,.. MS (Io trap, EI): m/z (%) = (00, [M]), 0 (), (), (), (). Sythesis of -[(Z)-hex--e--yl]phthalimide (da) da was sythesized followig method A usig phtalimide (. mg, 0 chromatography (: ethyl acetate/hexae), yieldig the product as a 9.00 mmol) ad -hexye (9 L,.0 mmol) ad purified by colum white solid (0. mg, %). -M (00 Mz, CDCl, C): =.9. (m,, arom),.. (m,, arom),.0 (dt, J(,)=.,. z,, -),.0. (m,, -),.0 (dt, J(,)=.,.,. z,, -),.. (m,, -, ), 0. (t, J(,)=. z,, -) ppm. C-M (0 Mz, CDCl, C): =. (C-9, C-0),. (Carom),. (Carom),. (C-),. (Carom),. (C-), 0. (C-),.0 (C-),. (C),.9 (C-) ppm. EA Calcd: C,.;,.;,.. Foud: C,.;,.;,.. MS (Io trap, EI): m/z (%) = 9 (, [M]), (00), (0), (), (). - -

143 Experimetal part Sythesis of -[(E)-hex--eyl]-,-pyrididicarboximid (ea) 9 ea was sythesized followig method A usig,- L,.0 mmol) ad purified by colum chromatography (: ethyl pyridiedicarboximide (. mg,.00 mmol) ad -hexye (9 0 acetate/hexae), yieldig the product as a yellowish oil (. mg, %). -M (00 Mz, CDCl, C): =9. (s,, arom), 9.0 (d, J(,)=. z,, arom),. (d, J(,)=. z,, arom),.09 (d, J(,)=. z,, -9),. (m,, -0),.0 (dt, J(,)=.,.,. z,, -),.. (m,, -, -), 0. (t, J(,)=. z,, -) ppm. C-M (0 Mz, CDCl, C): =. (C-),. (C-),. (Carom),. (Carom), 9. (Carom),. (C-9),. (Carom),.9 (C-0),. (Carom), 0. (C-),.0 (C-),. (C-),. (C-) ppm. EA Calcd: C,.;,.;,.. Foud: C,.;,.;,.0. MS (Io trap, EI): m/z (%) = 0 (, [M]), (00), 0 (), (), 0 (). Sythesis of -acetyl--hex--eyl-acetamide (fa) fa was sythesized followig method A usig diacetamide (0. mg,.00 mmol) ad -hexye (9 L,.0 mmol) ad yield was determied by GC usig -tetradecae as iteral stadard (%). MS (Io trap, EI): m/z (%) = (9, [M]), 9 (00), (), (), (). - -

144 Experimetal part Sythesis of -[(Z)-hex--eyl]-,,-trimethylhydatoi (ga) ga was sythesized followig method A usig,,- trimethylhydatoi (. mg,.00 mmol) ad -hexye (9 L,.0 mmol) ad purified by colum chromatography (: ethyl 0 9 acetate/hexae), yieldig the product as a yellowish oil (0.9 mg, 90 %). -M (00 Mz, CDCl, C): =.9 (d, J(,)=. z,, -),. (dt, J(,)=. z,. z,, -),.0 (s,, -),. (dt, J(,)=.,.,. z,, -9),. (s,, -, -),.. (m,, -0, ), 0. (t, J(,)=. z,, -) ppm. C-M (0 Mz, CDCl, C): =. (C-),. (C-),. (C-),. (C),. (C-), 0. (C-9),.9 (C-0),. (C-),. (C-),. (C-, C),. (C-) ppm. EA Calcd: C,.;,.9;,.. Foud: C,.0;,.;,.. MS (Io trap, EI): m/z (%) = (00, [M]), 9 (), (), (), (). Sythesis of -hex--eyl--methyl-imidazolidie-,-dioe (ha) ha was sythesized followig method A usig -methylhydatoie (. mg,.00 mmol) ad -hexye (9 L,.0 mmol) ad yield was determied by GC usig -tetradecae as iteral stadard (%). MS (Io trap, EI): m/z (%) = 9 (, [M]), (), (), (), (). Sythesis of -hex--eyl-thiazolidie-,-dioe (ia) ia was sythesized followig method A usig thiazolidie-,-dioe (. mg,.00 mmol) ad -hexye (9 L,.0 mmol) ad yield S was determied by GC usig -tetradecae as iteral stadard (%). MS (Io trap, EI): m/z (%) = 00 (, [M]), (), (), (), 0 (). - -

145 Experimetal part Sythesis of -((E)-hex--eyl)--methyluracile (ja) ja was sythesized followig method A usig -methyluracile (. mg,.00 mmol) ad -hexye (9 L,.0 mmol) ad yield was determied by GC usig -tetradecae as iteral stadard (%). MS (Io trap, EI): m/z (%) = 0 (, [M]), 9 (), (9), (), (00). Sythesis of -[(Z)--pheylviyl]succiimide (ab) ab was sythesized followig method A usig succiimide (99. mg,.00 mmol) ad pheylacetylee (0 L,.0 mmol) ad purified by 9 colum chromatography (: ethyl acetate/hexae), yieldig the product 0 as a white solid (. mg, %). -M (00 Mz, CDCl, C): =.9.9 (m,, arom),. (d, J(,)=. z,, arom),. (d, J(,)=9. z,, -),.0 (d, J(,)=9. z,, -),. (s,, -, -) ppm. C-M (0 Mz, CDCl, C): =. (C-, C-),. (C-),.0 (Carom),. (Carom),. (Carom),.0 (Carom),. (C-),. (C-, C-) ppm. EA Calcd: C,.;,.;,.. Foud: C,.;,.;,.0. MS (Io trap, EI): m/z (%) = 9 (, [M]), (00), 0 (), (), (). Sythesis of -[(Z)--pheylbut--e--yl]succiimide (ac) (CAS-0: ) ac was sythesized followig method A usig succiimide (99. mg,.00 mmol) ad -pheyl--butye ( L,.0 mmol) ad yieldig the product as a white solid (. mg, 99 %). -M purified by colum chromatography (: ethyl acetate/hexae), 9 0 (00 Mz, CDCl, C): =.. (m,, arom),.. (m,, arom),. (d, J(,)=. z,, -),.0 (d, J(,)=. z,, - - -

146 Experimetal part ),.0 (t, J(,)=. z,, -),. (s,, -, -),. (dt, C-M J(,)=.,.,. z,, -) ppm. (0 Mz, CDCl, C): =. (C-, C-),. (Carom),. (C-),. (Carom),.0 (Carom),. (C-),. (C-), 0.0 (C-),. (C-, C) ppm. EA Calcd: C,.;,.;,.0. Foud: C,.;,.;,.. MS (Io trap, EI): m/z (%) = 0 (00, [M]), (), (), 9 (), (). The data correspod to those reported i the literature: T. gawa, T. Kiji, K. ayami,. Suzuki, Chem. Lett. 99, 0,. Sythesis of -[(Z)-oct--e--yl]succiimide (ad) ad was sythesized followig method A usig succiimide (99. mg,.00 mmol) ad -octye (9 L,.0 mmol) ad 0 purified by colum chromatography (: ethyl acetate/hexae), 9 yieldig the product as a yellowish oil (. mg, %). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),. (dt, J(,)=. z,. z,, -),. (s,, -, -),. (qd, J(,)=.,. z,, -),.9. (m,, -, -),.. (m,, -9, -0, -), 0. (t, J(,)=. z,, -) ppm. C-M (0 Mz, CDCl, C): =. (C-, C-),. (C-),. (C-),. (C-),. (C-),. (C-, C-),. (C-9),. (C-0),. (C-),.0 (C-) ppm. EA Calcd: C,.9;, 9.;,.. Foud: C,.;, 9.;,.. MS (Io trap, EI): m/z (%) = 0 (0, [M]), (0), 0 (00), (), (0). Sythesis of -[(Z)--chloropet--e--yl]succiimide (ae) ae was sythesized followig method A usig succiimide (99. mg,.00 mmol) ad -chloro--petye ( L,.0 mmol) ad purified Cl

147 Experimetal part by colum chromatography (: ethyl acetate/hexae), yieldig the product as a yellowish oil (. mg, %). -M (00 Mz, CDCl, C): =.9 (d, J(,)=. z,, -),. (m,, -),. (t, J(,)=.,, -9),. (s,, -, -),.09 (m,, -),. (m,, -) ppm. C-M (0 Mz, CDCl, C): =. (C-, C-),. (C-),. (C-),. (C-9),. (C-),. (C-, C-),. (C-) ppm. EA Calcd: C,.;,.0;,.9. Foud: C,.;,.;,.. MS (Io trap, EI): m/z (%) = 0 (0, [M]), (), (00), (), (). Sythesis of -(-oxo-but--eyl)-pyrrolidie-,-dioe (af) af was sythesized followig method A usig succiimide (99. mg,.00 mmol) ad but--y--oe (9 L,.0 mmol) ad yield was determied by GC usig -tetradecae as iteral stadard (%). MS Me (Io trap, EI): m/z (%) = (0, [M]), (), (00), 9 (), 0 (9), (). Sythesis of -(-methyl-buta-,-dieyl)-pyrrolidie-,-dioe (ag) ag was sythesized followig method A usig succiimide (99. mg,.00 mmol) ad -methyl-but--e--ye (9 L,.0 mmol) ad yield was determied by GC usig -tetradecae as iteral stadard (%). MS (Io trap, EI): m/z (%) = (, [M]), (), (00), 9 (), (), (0)

148 Experimetal part Sythesis of -(,-dimethyl-but--eyl)-pyrrolidie-,-dioe (ah) ah was sythesized followig method A usig succiimide (99. mg,.00 mmol) ad,-dimethyl-but--ye (9 L,.0 mmol) ad yield was t determied by GC usig -tetradecae as iteral stadard (%). MS (Io trap, EI): m/z (%) = (, [M]), (00), (), (), 0 (9). Sythesis of -(-methoxy-propeyl)-pyrrolidie-,-dioe (ai) ai was sythesized followig method A usig succiimide (99. mg,.00 mmol) ad -methoxypropye (9 L,.0 mmol) ad yield was determied by GC usig -tetradecae as iteral stadard (%). MS (Io trap, EI): m/z (%) = 0 (, [M]), (), (00), (), (). Sythesis of -[(Z)--pheylviyl]phthalimide (db) (CAS-0: --) db was sythesized followig method A usig phtalimide (. mg,.00 mmol) ad pheylacetylee (0 L,.0 mmol) ad purified by 0 9 -M product as a white solid (, mg, %). colum chromatography (: ethyl acetate/hexae), yieldig the (00 Mz, CDCl, C): =. (dd, J(,)=.,. z,, arom),. (dd, J(,)=.,. z,, arom),.9. (m,, arom),.0 (d, J(,)=9.9 z,, -),. (d, J(,)=9.9 z,, -) ppm. C-M (0 Mz, CDCl, C): =. (Carom),. (Carom),. (C-),. (Carom), 0. (Carom),. (Carom),. (Carom),.0 (Carom),. (Carom),. (C-) ppm. EA Calcd: C,.;,.;,.. Foud: C,.;,.;,.. MS (Io trap, EI): m/z (%) = 9 (00, [M]), 0 (), 0 (), (), 0 (). The data correspod to those reported i the literature: T. gawa, T. Kiji, K. ayami,. Suzuki Chem. Lett. 99, 0,

149 Experimetal part Sythesis of -[(Z)--pheylviyl]-,,-trimethylhydatoie (gb) gb was sythesized followig method A usig,,- L,.0 mmol) ad purified by colum chromatography (: ethyl 0 9 trimethylhydatoi (. mg,.00 mmol) ad pheylacetylee (0 acetate/hexae), yieldig the product as a yellowish oil (0. mg, %). -M (00 Mz, CDCl, C): =.0 (d, J(,)=. z,, arom),. (t, J(,)=. z,, arom),. (d, J(,)=. z,, arom),. (d, J(,)=. z,, -),.9 (d, J(,)=9.0 z,, -),.9 (s,, - ),. (s,, -, -) ppm. C-M (0 Mz, CDCl, C): =. (C-),.0 (C-),.0 (C-), 0. (Carom),. (Carom),. (Carom),.0 (Carom),.9 (C-),. (C-),. (C-),.0 (C-, C-) ppm. EA Calcd: C,.9;,.;,.. Foud: C,.;,.;,.. (Io trap, EI): m/z (%) = (00, [M]), (), (), 9 (), (). MS Sythesis of -[(Z)--pheylviyl]-,-dimethylglutarimide (cb) cb was sythesized,-dimethylglutarimide followig (. method mg,.00 A mmol) usig ad pheylacetylee (0 L,.0 mmol) ad purified by colum 9 0 chromatography (: ethyl acetate/hexae), yieldig the product as a yellowish oil (. mg, 0 %). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, arom),. (t, J(,)=. z,, arom),. (d, J(,)=. z,, arom),. (d, J(,)=. z,, -),. (d, J(,)= 9.0 z,, -),.0 (s,, -, -),.0 (s,, -, -) ppm. C-M (0 Mz, CDCl, C): =. (C-, C-),. (C-),. (Carom),. (Carom),.0 (Carom),. (Carom), 0.9 (C-),. (C-, C-), 9. (C-),.9 (C-, C-) ppm. - -

150 Experimetal part EA Calcd: C,.0;,.0;,.. Foud: C,.9;,.;,.. (Io trap, EI): m/z (%) = (00, [M]), 00 (0), 9 (), (), (). MS Sythesis of -[(Z)--pheylviyl]glutarimide (bb) bb was sythesized followig method A usig glutarimide (. mg, 9.00 mmol) ad pheylacetylee (0 L,.0 mmol) ad purified by 0 colum chromatography (: ethyl acetate/hexae), yieldig the product as a white solid (9. mg, 0%). -M C-M (00 Mz, CDCl, C): =. (t, J(,)=. z,, arom),. (t, J(,)=. z,, arom),. (d, J(,)=. z,, arom),. (d, J(,)=9.0 z,, -),. (d, J(,)=. z,, -),. (t, J(,)=. z,, -, -),.9.9 (m,, -) ppm. (0 Mz, CDCl, C): =. (C-, C-),. (C-),. (Carom),. (Carom),. (Carom),. (Carom),.0 (C-),.0 (C-, C-),.0 ( C-) ppm. EA Calcd: C,.;,.0;,.. Foud: C,.;,.;,.. (Io trap, EI): m/z (%) = 9 (00, [M]), (), (), (0), (0). MS Sythesis of -[(Z)--pheylbut--e--yl]-,,-trimethylhydatoie (gc) gc was sythesized followig method A usig,,-trimethylhydatoi (. mg,.00 mmol) ad -pheyl-butye ( L,.0 mmol) ad purified by colum chromatography 0 9 (: ethyl acetate/hexae), yieldig the product as a yellowish oil (. mg, 9 %). -M (00 Mz, CDCl, C): =. (t, J(,)=. z,, arom),.9 (t, J(,)=. z,, arom),.9 (d, J(,)=. z,, -),. (d, - -

151 Experimetal part J(,)=. z,, -),. (s,, -),. (t, J(,)=. z,, - 0),. (m,, -9),.9 (s,, -, -) ppm. C-M (0 Mz, CDCl, C): =. (C-),. (C-),. (Carom), 0. (C-),. (Carom),. (Carom),.9 (Carom),. (C-),. (C-),. (C-0), 9.9 (C-9),. (C-),. (C-, C-) ppm. EA Calcd: C, 0.;, 9.;, 0.. Foud: C, 0.;, 9.;, 0.. (Io trap, EI): m/z (%) = (, [M]), (00), (), (), (). MS Sythesis of,-dimethyl--(-pheyl-but--eyl)-piperidie-,-dioe (cc) cc was sythesized followig method A usig,-dimethylglutarimide (. mg,.00 mmol) ad -pheyl-- butye L, (.0 mmol) ad purified by 9 0 colum chromatography (: ethyl acetate/hexae), yieldig the product as a colorless oil (. mg, %). -M (00 Mz, CDCl, C): =. (t, J(,)=. z,, arom),. (t, J(,)=. z,, arom),.9 (d, J(,)=. z,, -),. (d, J(,)=. z,, -),. (t, J(,)=. z,, -9),. (s,, -, ),. (m,, -),.0 (s,, -, ) ppm. C-M (0 Mz, CDCl, C): =.0 (C-, ),. (Carom),. (C-),. (Carom),.0 (Carom), 0. (C-),. (C-, ),. (C-9), 9. (C-), 9. (C-),. (C-, ) ppm. EA Calcd: C,.;,.;,.. Foud: C,.;,.;,.0. MS (Io trap, EI): m/z (%) = (, [M]), 0 (00), 0 (), 9 (), (), (). - -

152 Experimetal part Sythesis of -[(Z)--pheylbut--e--yl]glutarimide (bc) bc was sythesized followig method A usig glutarimide (. mg,.00 mmol) ad -pheyl--butye ( L,.0 mmol) ad purified by colum chromatography (: ethyl acetate/hexae), 9 0 yieldig the product as a colorless oil (. mg, %). -M C-M (00 Mz, CDCl, C): =. (t, J(,)=. z,, arom),. (t, J(,)=. z,, arom),.9 (d, J(,)=. z,, -),. (d, J(,)=. z,, -),.0 (t, J(,)=. z,, -9),. (t, J(,)=. z,, -, -),.0 (m,, -),.9 (m,, -) ppm. (0 Mz, CDCl, C): =. (C-, C-),. (Carom),. (C-),. (Carom),.0 (Carom), 0. (C-),. (C-9),.9 (C-), 9. (C-, C),. (C-9) ppm. EA Calcd: C,.;,.0;,.. Foud: C,.;,.;,.. MS (Io trap, EI): m/z (%) = (0, [M]), (00), 0 (), 9 (), (). Sythesis of -[(E)-hex--eyl]succiimide (aa) aa was sythesized followig method B usig succiimide (99. mg,.00 mmol) ad -hexye (9 L,.0 mmol) ad purified by colum chromatography (: ethyl acetate/hexae), yieldig the 9 0 product as a yellowish oil (.9 mg, %). -M C-M (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),. (dt, J(,)=.0 z,. z,, -),. (s,, -, -),.0 (dt, J(,)=.,.,, -),.. (m,, -, -9), 0. (t, J(,)=. z,, -0) ppm. (0 Mz, CDCl, C): =. (C-, C-),. (C-),. (C-),. (C-), 0. (C-),. (C-, C-),.0 (C-9),. (C-0) ppm. EA Calcd: C,.;,.;,.. Foud: C,.;,.;,.9. MS (Io trap, EI): m/z (%) = (0, [M]), (00), 00 (), (9), (). - -

153 Experimetal part Sythesis of -[(E)-hex--e--yl]glutarimide (ba) ba was sythesized followig method B usig glutarimide (. colum chromatography (: ethyl acetate/hexae), yieldig the 0 mg,.00 mmol) ad -hexye (9 L,.0 mmol) ad purified by 9 product as a colorless oil (. mg, 0%). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),.9 (dt, J(,)=. z,, -),. (t, J(,)=. z,, -, -),. (dd, J(,)=. z,, -),.9.9 (m,, -).. (m,, -9, -0), 0. (t, J(,)=. z,, -) ppm. C-M (0 Mz, CDCl, C): = (C-, C-),. (C-), 9. (C-),. (C-, C-),. (C-), 0. (C-9),. (C-0),.9 (C-),. (C-) ppm. EA Calcd: C,.;,.;,.. Foud: C,.;,.;,.. MS (Io trap, EI): m/z (%) = 9 (, [M]), (), (00), (), (0). Sythesis of -[(E)-hex--e--yl]-,-dimethylglutarimide (ca) ca was sythesized followig method B usig,- L,.0 mmol) ad purified by colum chromatography (: 0 dimethylglutarimide (. mg,.00 mmol) ad -hexye (9 9 ethyl acetate/hexae), yieldig the product as a yellowish oil (. mg, %). -M (00 Mz, CDCl, C): =.0 (d, J(,)=. z,, -),.9 (dt, J(,)=. z, -),. (s,, -, -),..(m,, -).. (m,, -9),.0. (m,, -0),.0 (s,, -, -), 0. (t, J(,)=. z,, -) ppm. C-M (0 Mz, CDCl, C): =. (C-, C-),. (C-), 9. (C-),. (C-, C-),. (C-), 0. (C-9), 9.0 (C-),. (C-, C-),. (C-0),. (C-) ppm. EA Calcd: C, 9.9;, 9.;,.. Foud: C, 9.;, 9.;,.. MS (Io trap, EI): m/z (%) = (, [M]), 0 (), (00), (), (). - -

154 Experimetal part Sythesis of -[(E)--pheylviyl]succiimide (ab) (CAS-0: 0-0-) ab was sythesized followig method B usig succiimide (99. mg,.00 mmol) ad pheylacetylee (0 L,.0 mmol) ad purified by 9 colum chromatography (: ethyl acetate/hexae), yieldig the product as a white solid (9. mg, 9 %). -M (00 Mz, CDCl, C): =.9 (d, J(,)=.9 z,, -),. (m,, arom),. (m,, arom),. (m,, arom),.0 (d, J(,)=.9 z,, -),. (s,, -, -) ppm. C-M (0 Mz, CDCl, C): =. (C-, C-),. (C-),. (Carom),.9 (Carom),. (Carom),.9 (Carom),. (C-),. (C-, C-) ppm. EA Calcd: C,.;,.;,.0. Foud: C,.9;,.;,.9. MS (Io trap, EI): m/z (%) = 0 (00, [M]), (), 9 (0), 9 (), (). The data correspod to those reported i the literature: T. gawa, T. Kiji, K. ayami,. Suzuki Chem. Lett. 99, 0,. Sythesis of -[(E)--pheylbut--e--yl]succiimide (ac) ac was sythesized followig method B usig succiimide (99. mg,.00 mmol) ad -pheyl--butye ( L,.0 mmol) ad purified by colum chromatography (: ethyl 9 0 acetate/hexae), yieldig the product as a white solid (. mg, %). -M (00 Mz, CDCl, C): =.. (m,, arom),. (m, arom),.9 (dt, J(,)=. z,, -),.9 (d, J(,)=.9 z,, -),.. (m,, -9),. (s,, -, -),.. (m,, -) ppm. C-M (0 Mz, CDCl, C): =. (C-, C-),. (Carom),. (Carom),. (Carom),.9 (Carom),. (C-),. (C-),. (C-9),. (C-),. (C-, C-) ppm. EA Calcd: C,.;,.;,.. Foud: C,.;,.;,.. MS (Io trap, EI): m/z (%) = 9 (, [M]), (00), 0 (), (), (). - -

155 Experimetal part. Additio of primary amides to alkyes.. Geeral procedure for the hydroamidatio of termial alkyes Method A: A ove-dried flask was charged with the -ucleophile (.00 mmol), bis(methallyl)-cycloocta-,-diee-rutheium(ii) (.0 mg, 0.0 mmol),,-bis(di- cyclohexylphosphio)butae (.0 mg, 0.0 mmol) ad ytterbium triflate (. mg, 0.0 mmol) ad flushed with itroge. Subsequetly, dry DMF (.0 ml), alkye (.00 mmol) ad water (0 L,.00 mmol) were added via syrige. The resultig solutio was stirred for h at 0 C, the poured ito a aqueous sodium bicarboate solutio (0 ml). The resultig mixture was extracted repeatedly with 0 ml portios of ethyl acetate, the combied orgaic layers were washed with water ad brie, dried with magesium sulfate, filtered, ad the volatiles were removed i vacuo. The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae) to yield the Z-secodary eamide. The idetity ad purity of the products were cofirmed by ad C M spectroscopy, mass spectroscopy ad elemetal aalysis. Method B: After the completio of the reactio followig method A, 00 mg of Å molecular sieves ad 00 L triethylamie were added ito the reactio flask, ad the reactio mixture was stirred for h at 0 C, the poured ito a aqueous sodium bicarboate solutio (0 ml). The resultig mixture was extracted repeatedly with 0 ml portios of ethyl acetate, the combied orgaic layers were washed with water ad brie, dried with magesium sulfate, filtered, ad the volatiles were removed i vacuo. The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae) to yield the E-secodary eamide. The idetity ad purity of the products were cofirmed by ad C M spectroscopy, mass spectroscopy ad elemetal aalysis. - -

156 Experimetal part.. Sythesis of the secodary eamides Sythesis of -((Z)-hex--e--yl)bezamide (9aa) 9aa was sythesized followig method A usig bezamide (. mg,.00 mmol) ad -hexye (9 L,.00 mmol) ad 0 purified by colum chromatography (:9 ethyl acetate/hexae), 9 yieldig the product as a yellowish oil (9. mg, 9%). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, arom),. (d, J(,)=. z,, -),. (t, J(,)=. z,, arom),. (t, J(,)=. z,, arom),.90 (dd, J(,)=0., 9. z,, -),.-. (m,, -),.0 (qd, J(,)=.,. z,, -),.0-. (m,, -9),.-.9 (m,, -0), 0.9 (t, J(,)=. z,, -) ppm. C-M ( Mz, CDCl, C): =. (C-),.0 (Carom),.9 (Carom),. (Carom),.0 (Carom),. (C-),. (C-),. (C-),. (C-9),. (C0),.0 (C-) ppm. EA Calcd: C,.;,.;,.9. Foud: C,.;,.9;,.. MS (Io trap, EI): m/z (%) = 0 (, [M]), 0 (0), (), 0 (00), (9), (). Sythesis of -[(Z)--pheyl-viyl]bezamide (9ab) (CAS-0: 0--) 9ab was sythesized followig method A usig bezamide (. mg,.00 mmol) ad -hexye pheylacetylee (0 L,.00 mmol) ad purified by colum chromatography (:9 ethyl 0 9 acetate/hexae), yieldig the product as a white solid (. mg, 9%). -M (00 Mz, CDCl, C): =. (d, J(,)=9. z,, -),. (d, J(,)=. z,, arom),. (t, J(,)=. z,, arom),. (dt, J(,)=.9,. z,, arom),. (d, J(,)=. z,, arom),. (t, J(,)=. z,, arom),.0 (dd, J(,)=0., 9. z,, -),.9 (d, J(,)=9. z,, -) ppm. - -

157 Experimetal part C-M ( Mz, CDCl, C): =. (C-),. (Carom),. (Carom ),. (Carom), 9. (Carom),. (Carom),. (Carom),.0 (Carom),. (C-), 0.9 (C-) ppm. EA Calcd: C, 0.9;,.;,.. Foud: C, 0.;,.;,.0. MS (Io trap, EI): m/z (%) = (, [M]), (), 0 (00), 9 (), (), (). Sythesis of -[(Z)-,-dimethyl-but--e--yl]bezamide (9ac) 9ac was sythesized followig method A usig bezamide (. mg,.00 mmol) ad,-dimethyl--butye ( L,.00 mmol) ad purified by colum chromatography (:9 ethyl acetate/hexae), yieldig the product as a white solid (.0 mg, 9%). -M (00 Mz, CDCl, C): =.0 (d, J(,)=9. z,, -),. (d, J(,)=. z,, arom),. (t, J(,)=. z,, arom),. (t, J(,)=. z,, arom),.0-. (m,, -),.0 (d, J(,)=0.0 z,, -),. (s, 9, -9) ppm. C-M ( Mz, CDCl, C): =. (C-),. (Carom),.9 (Carom),. (Carom),. (Carom),. (C-),. (C-),. (C-), 0.9 (C-9) ppm. EA Calcd C,.;,.;,.9. Foud: C,.9;,.;,.. MS (Io trap, EI): m/z (%) = 0 (, [M]), (9), (), 0 (00), (0), ()

158 Experimetal part Sythesis of -[(Z)--pheyl-but--e--yl]bezamide (9ad) (CAS-0: 90--) 9ad was sythesized followig method A usig bezamide (. mg,.00 mmol) ad -pheyl--butye ( L,.00 mmol) ad purified by colum chromatography (:9 ethyl 0 9 acetate/hexae), yieldig the product as a white solid (. mg, 9%) -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, arom),. (t, J(,)=. z,, arom),. (t, J(,)=. z,, arom),.-.0 (m,, -, -),.-. (m,, arom),. (t, J(,)=. z,, arom),.9 (dd, J(,)=0., 9. z,, -),.9 (q, J(,)=.9 z,, -),. (t, J(,)=. z,, -9),.9-. (m,, -) ppm. C-M ( Mz, CDCl, C): =. (C-),. (Carom),. (Carom),. (Carom),. (Carom),.0 (Carom),. (Carom),.0 (Carom),. (Carom),. (C-), 0.9 (C-),. (C-9),. (C-) ppm. EA Calcd: C,.;,.;,.. Foud: C,.;,.;,.9. MS (Io trap, EI): m/z (%) = (, [M]), 0 (), 0 (00), 9 (), (), (). Sythesis of -[(Z)--cyclohexyl-prop--e--yl]bezamide (9ae) 9ae was sythesized followig method A usig bezamide (. mg,.00 mmol) ad -cyclohexyl--propye (9 L,.00 mmol) ad purified by colum chromatography (:9 ethyl acetate/hexae), yieldig the product as a white solid (09. mg, 9 0 %). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, arom),. (d, J(,)=9. z,, -),. (t, J(,)=. z,, arom),. (t, J(,)=. z,, arom),.9 (dd, J(,)=0., 9.0 z,, -),. (q, J(,)=. z,, -),.9-.9 (m,, -),.-. (m,, Cy),.0 (dt, J(,)=.0,. z,, Cy),.-. (m,, Cy),. (td, - 0 -

159 Experimetal part J(,)=.,. z,, Cy),.-. (m,, Cy),.0-. (m,, Cy), (m,, Cy) ppm. C-M ( Mz, CDCl, C): =. (C-),.9 (Carom),. (Carom),. (Carom),.0 (Carom),. (C-), 0. (C-),. (C-),. (CCy),. (CCy),. (CCy),. (CCy) ppm. EA Calcd: C,.9;,.0;,.. Foud: C,.9;,.;,.. MS (Io trap, EI): m/z (%) = (, [M]), 0 (), (), 0 (00), (), (). Sythesis of -[(Z)--chloro-pet--e--yl]bezamide (9af) 9af was sythesized followig method A usig bezamide (. mg,.00 mmol) ad -chloro--petye (0 L, 0.00 mmol) ad purified by colum chromatography (:9 ethyl 9 Cl acetate/hexae), yieldig the product as a white solid (0. mg, 9%). -M (00 Mz, CDCl, C): =.9 (d, J(,)=9.0 z,, -),.0-. (m,, arom),. (t, J(,)=. z,, arom),. (t, J(,)=. z,, arom),.0 (dd, J(,)=0., 9. z,, -),. (q, J(,)=. z,, -),.-. (m,, -0),.9-. (m,, -9),.9 (dq, C-M J(,)=.,. z,, -) ppm. ( Mz, CDCl, C): =. (C-),. (Carom),.9 (Carom),. (Carom),. (Carom),. (C-), 09. (C-),. (C-0),. (C-9),. (C-) ppm. EA Calcd: C,.;,.;,.. Foud: C,.0;,.;,.9. MS (Io trap, EI): m/z (%) = (, [M]), (), 0 (), 0 (00), (9), (0). - -

160 Experimetal part Sythesis of -[(Z)--(-fluoro-pheyl)-viyl]bezamide (9ag) 9ag was sythesized followig method A usig bezamide (. mg,.00 mmol) ad -ethyyl--fluorobezee (9 L,.00 mmol) ad purified by colum chromatography (:9 ethyl F 0 9 acetate/hexae), yieldig the product as a white solid (.9 mg, 99%). -M (00 Mz, CDCl, C): =. (d, J(,)=0.0 z,, -),.-. (m,, arom),.-. (m,, arom),. (t, J(,)=. z,, arom),.9-. (m,, arom),. (dd, J(,)=.0, 9. z,, -),.09-. (m,, arom),. (d, J(,)=9. z,, -) ppm. C-M ( Mz, CDCl, C): =. (d, J=0 z, C-F), 0. (C-),. (C-),. (C-),. (d, J=. z, C-), 9. (d, J=. z, C-9),. (C-),.0 (C-),. (C-),. (d, J=. z, C-0), 09.9 (C-) ppm. EA Calcd: C,.;,.0;,.. Foud: C,.;,.9;,.. MS (Io trap, EI): m/z (%) = (, [M]), (), 09 (), 0 (00), (), (). Sythesis of -[(Z)--(-methoxypheyl)viyl]bezamide (9ah) (CAS-0: --) 9ah was sythesized followig method A usig bezamide (. mg,.00 mmol) ad -methoxy-pheylacetylee (9 L,.00 mmol) ad purified by colum chromatography 0 9 (: ethyl acetate/hexae), yieldig the product as a white solid (0. mg, %). -M C-M (00 Mz, CDCl, C): =.0 (d, J(,)=0. z,, -),. (d, J(,)=. z,, arom),. (t, J(,)=. z,, arom),. (t, J(,)=. z,, arom),. (d, J(,)=. z,, arom),. (t, J(,)=0. z,, -),.9 (d, J(,)=. z,, arom),. (d, J(,)=9. z,, -),. (s,, -) ppm. ( Mz, CDCl, C): =. (C-),. (Carom),. (Carom),.0 (Carom), 9.0 (Carom),. (Carom),.0 (Carom),.0 (Carom),. (C-),., 0. (C-),. (C-) ppm. - -

161 Experimetal part EA Calcd: C,.;,.9;,.. Foud: C,.9;,.;,.. MS (Io trap, EI): m/z (%) = (, [M]), 0 (), (), 0 (00), (), (). Sythesis of,-dimethyl--[(z)--pheylviyl]urea (9bb) 9bb was sythesized followig method A usig,-dimethylurea (. mg,.00 mmol) ad pheylacetylee (0 L,.00 mmol) ad purified by colum chromatography (:9 ethyl acetate/hexae), yieldig the product as a white solid (. mg, %). -M (00 Mz, CDCl, C): =. (t, J(,)=. z,, arom),.9 (d, J(,)=.9 z,, arom),. (s,, -),.0 (s,, -),.9 (d, J(,)=9. z,, -),. (d, J(,)= 9. z,, -),.9 (s,, - ) ppm. C-M ( Mz, CDCl, C): =. (C-),. (Carom), 9. (Carom),. (Carom),. (Carom),. (C-), 0.0 (C-),. (C-) ppm. EA Calcd: C, 9.;,.;,.. Foud: C, 9.;,.;,.. MS (Io trap, EI): m/z (%) = 90 (, [M]), (), (0), 9 (0), (00), (). Sythesis of,-dimethyl--[(z)--pheylviyl]propaamide (9cb) (CAS-0: 909--) 9cb was sythesized followig method A usig,-dimethyl- propioamide (0. mg,.00 mmol) ad pheylacetylee (0 L,.00 mmol) ad purified by colum chromatography (:9 ethyl acetate/hexae), yieldig the product as a white solid (.9 mg, %)

162 Experimetal part -M (00 Mz, CDCl, C): =.9 (s,, -),.-. (m,, arom),.-. (m,, arom),.99 (dd, J(,, -)=0.9, 9. z, ),. (d, J(,)=9. z,, -),. (s, 9, -) ppm. C-M (0 Mz, CDCl, C): =. (C-),. (Carom), 9. (Carom),. (Carom),. (Carom),. (C-), 09. (C-),. (C-),. (C-) ppm. EA Calcd: C,.;,.;,.9. Foud: C,.;,.9;,.. MS (Io trap, EI): m/z (%) = 0 (00, [M]), 0 (), 9 (), 9 (), (), (9). Sythesis of -methyl--[(z)--pheylviyl]acrylamide (9db) 9db was sythesized followig method A usig -methyl-acrylamide (. mg,.00 mmol) ad pheylacetylee (0 L,.00 mmol) ad purified by colum chromatography (:9 ethyl acetate/hexae), yieldig 0 9 the product as a yellowish oil (. mg, 90%). -M (00 Mz, CDCl, C): =.0 (d, J(,)=. z,, -),.9 (t, J(,)=. z,, arom),. (d, J(,),=. z,, arom),. (t, J(,)=. z,, arom),.0 (dd, J(,)=., 9. z,, -),.0 (d, J(,)=9. z,, -),. (s,, -),. (d, J(,)=.0 z,, - ),.9 (s,, -) ppm. C-M ( Mz, CDCl, C): =. (C-), 9. (C-),. (Carom), 9. (Carom),. (Carom),.9 (Carom),. (C-),.0 (C-), 0. (C-),. (C-) ppm. EA Calcd: C,.9;,.00;,.. Foud: C,.;,.0;,.. MS (Io trap, EI): m/z (%) = (00, [M]), 9 (), (), (), 9 (), (). - -

163 Experimetal part Sythesis of -acetamido--[(z)--pheylviyl]acetamide (9eb) 9eb was sythesized followig method A usig -acetamidoacetamide (. mg,.00 mmol) ad pheylacetylee (0 L,.00 mmol) ad purified by colum chromatography (:9 ethyl 0 9 acetate/hexae), yieldig the product as a white solid (09. mg, 9%). -M (00 Mz, CDCl, C): =.9 (d, J(,)=0. z,, -),. (t, J(,)=.z,, arom),.-. (m,, arom),. (dd, J(,)=., 9. z,, -),. (s,, -),. (d, J(,)=9.9 z,, -),.9 (s,, -),.9 (s,, -) ppm. C-M (0 Mz, CDCl, C): =0.9 (C-),.9 (C-),. (Carom),.9 (Carom),.0 (Carom),. (Carom),.0 (C-),. (C-),. (C-),. (C-) ppm. EA Calcd: C,.0;,.;,.. Foud: C,.;,.;,.. MS (Io trap, EI): m/z (%) = (9, [M]), 9 (00), 0 (), 9 (0), (), (). Sythesis of -[(Z)--pheylviyl]butyramide (9fb) 9fb was sythesized followig method A usig butyramide (. mg,.00 mmol) ad pheylacetylee (0 L,.00 mmol) ad 0 purified by colum chromatography (:9 ethyl acetate/hexae), 9 yieldig the product as a yellowish oil (0.9 mg, %). -M (00 Mz, CDCl, C): =. (d, J(,)=.9 z,, -),.9 (t, J(,)=. z,, arom),.-. (m,, arom),.9 (dd, J(,)=.0, 9. z,, -),. (d, J(,)=9. z,, -),. (t, J(,)=. z,, -),.-. (m,, -), 0.9 (t, J(,)=. z,, -) ppm. C-M ( Mz, CDCl, C): =0. (C-),. (Carom), 9.0 (Carom),. (Carom),. (Carom),.0 (C-), 09. (C-),. (C-),. (C-),. (C-) ppm. - -

164 Experimetal part EA Calcd: C,.;,.99;,.0. Foud: C,.;,.9;,.9. MS (Io trap, EI): m/z (%) = 9 (0, [M]), 9 (00), 0 (), (), (), (). Sythesis of -itro--[(z)--pheylviyl]bezamide (9gb) (CAS-0: 9--) 9gb was sythesized followig method A usig -itrobezamide (. mg,.00 mmol) ad pheylacetylee (0 L,.00 mmol) ad purified by colum chromatography 0 9 (:9 ethyl acetate/hexae), yieldig the product as a white solid (. mg, 0%). -M (00 Mz, CDCl, C): =. (d, J(,)=0. z,, -),. (s,, arom),.0 (d, J(,)=. z,, arom),.0 (d, J(,)=.9 z,, arom),. (t, J(,)=.9 z,, arom),. (t, J(,)=.9 z,, arom),. (d, J(,)=. z,, arom),. (t, J(,)=. z,, arom),.0 (t, J(,)=0. z,, -),.9 (d, J(,)=9. z,, 9) ppm. C-M ( Mz, CDCl, C): =. (C-),.0 (Carom),. (Carom),. (Carom),. (Carom), 9. (Carom), 9. (Carom),. (Carom),. (Carom),. (Carom),. (Carom),. (C-),. (C-9) ppm. EA Calcd: C,.;,.;, 0.. Foud: C,.;,.;, 0.. MS (Io trap, EI): m/z (%) = (, [M]), 0 (00), 0 (0), 0 (), (), 0 (). Sythesis of -fluoro--[(z)--pheylviyl]bezamide (9hb) 9hb was sythesized followig method A usig -fluoro- bezamide (9. mg,.00 mmol) ad pheylacetylee (0 L,.00 mmol) ad purified by colum chromatography (:9 ethyl F acetate/hexae), yieldig the product as a white solid (. mg, 9%)

165 Experimetal part -M (00 Mz, CDCl, C): =. (d, J(,)=0. z,, -),.-.9 (m,, arom),. (t, J(,)=. z,, arom),.-. (m,, arom),. (t, J(,)=. z,, -), (m, ),.9 (d, J(,)=9. z,, -) ppm. C-M (0 Mz, CDCl, C): =.0 (d, J=. z, C-),. (C-),. (Carom), 9. (d, J=. z, C-), 9. (d, J=9. z, C-), 9. (Carom),. (Carom),. (Carom),. (C-),. (d, J=. z, C-),.0 (C) ppm. EA Calcd: C,.;,.0;,.. Foud: C,.;,.;,.. MS (Io trap, EI): m/z (%) = (00, [M ]), (, [M]), (00), 9 (), (), 0 (). Sythesis of -methoxy--[(z)--pheylviyl]bezamide (9ib) (CAS-0: 9--) 9ib was sythesized followig method A usig -methoxybezamide (. mg,.00 mmol) ad pheylacetylee (0 L,.00 mmol) ad purified by colum chromatography 9 0 (: ethyl acetate/hexae), yieldig the product as a white solid (. mg, 9%). -M (00 Mz, CDCl, C): =. (d, J(,)=0. z,, -),.0-. (m,, arom),. (t, J(,)=. z,, arom),. (d, J(,)=. z,, arom),. (t, J(,)=. z,, arom),.-. (m,, -),.9.9 (m,, arom),. (d, J(,)=9. z,, -),. (s,, -) ppm. C-M ( Mz, CDCl, C): =. (C-),. (Carom),.9 (Carom), 9. (Carom), 9.0 (Carom),. (Carom),.9 (Carom),. (Carom),. (C-),.0 (Carom), 0. (C-),. (C-) ppm. EA Calcd: C,.;,.9;,.. Foud: C,.9;,.;,.. MS (Io trap, EI): m/z (%) = (, [M]), (00), 0 (9), 9 (), (), (). - -

166 Experimetal part Sythesis of ethyl oxo{[(z)--pheylviyl]amio}acetate (9jb) 9jb was sythesized followig method A usig oxalamic acid ethyl ester (. mg,.00 mmol) ad pheylacetylee (0 L,.00 mmol) but owig to the high hydrolytic istability of the 0 9 product, o water was added. Purificatio by colum chromatography (: ethyl acetate/hexae), yielded the product as a white solid (.0 mg, %). -M (00 Mz, CDCl, C): =9. (d, J(,)=9. z,, -),. (t, J(,)=. z,, arom),.-. (m,, arom),.9 (dd, J(,)=., 9. z,, -),.9 (d, J(,)=9. z,, -),. (q, J(,)=. z,, -),. (t, J(,)=. z,, -) ppm. C-M ( Mz, CDCl, C): =0. (C-),. (C-),. (Carom), 9. (Carom),.9 (Carom),. (Carom), 0. (C-),. (C-),. (C-),.9 (C-) ppm. EA Calcd: C,.;,.9;,.9. Foud: C,.00;,.99;,.. MS (Io trap, EI): m/z (%) = 9 (00, [M]), (), (0), (), 9 (), 9 (). Sythesis of -cyao--[(z)--pheylviyl]acetamide (9kb) 9kb was sythesized followig method A usig -cyao-acetamide (. mg,.00 mmol) ad pheylacetylee (0 L,.00 mmol) ad purified by colum chromatography (: ethyl acetate/hexae), 9 yieldig the product as a white solid (. mg, %). -M (00 Mz, CDCl, C): =. (s,, -),. (t, J(,)=. z,, arom),.9 (s,, arom),. (d, J(,)=. z,, arom),.-.90 (m,, -),.9 (d, J(,)=9. z,, -),.0 (s,, -) ppm. C-M ( Mz, CDCl, C): =. (C-),. (Carom), 9. (Carom),. (Carom),. (Carom), 0. (C-),.9 (C-),. (C-),.9 (C-) ppm. EA Calcd: C, 0.9;,.;,

167 Experimetal part Foud: C,.0;,.;,.0. MS (Io trap, EI): m/z (%) = (00, [M]), (), (), 9 (), (), (). Sythesis of ethyl -oxo-{[(z)--pheylviyl]amio}propaoate (9lb) 9lb was sythesized followig method A usig maloamic acid ethyl ester (. mg,.00 mmol) ad pheylacetylee (0 L,.00 mmol) but owig to the high hydrolytic 0 9 istability of the product, o water was added. Purificatio by colum chromatography (: ethyl acetate/hexae), yielded the product as a white solid (. mg, %). -M (00 Mz, CDCl, C): =. (t, J(,)=. z,, arom),.-. (m,, arom),. (t, J(,)=.9 z,, arom),. (d, J(,)=. z,, -),.0 (s,, -),. (s,, -),.9 (t, J(,)=0.9 z,, -),. (d, J(,)=0. z,, -),.-. (m,, -),.-. (m,, -) ppm. C-M ( Mz, CDCl, C): =9. (C-), 9. (C-),. (C-),. (Carom),. (Carom),. (Carom),. (Carom),. (C-),.9 (C-),. (C-),.9 (C-) ppm. EA Calcd: C,.9;,.;,.00. Foud: C,.;,.;,.. MS (Io trap, EI): m/z (%) = (, [M]), 0 (00), 0 (), 0 (), (), 0 (). Sythesis of (E)--pheyl--[(Z)--pheylviyl]acrylamide (Lasiumamide A) (9mb) (CAS-0: --) 9mb was sythesized followig method A usig -pheyl- acrylamide (. mg,.00 mmol) ad pheylacetylee (0 L,.00 mmol) ad purified by colum chromatography 0 9 (: ethyl acetate/hexae), yieldig the product as a white solid (. mg, 9%). -M (00 Mz, CDCl, C): =. (d, J(,)=.0 z,, -),. (d, J(,)=. z,, -),.0 (dd, J(,)=.,. z,,arom),. (t, - 9 -

168 Experimetal part J(,)=. z,,arom),.-. (m,,arom),. (t, J(,)=. z,,arom),. (dd, J(,)=., 9. z,, -),.0 (d, J(,)=. z,, -),. (d, J(,)=9. z,, -9) ppm. C-M ( Mz, CDCl, C): =. (C-),.0 (C-),. (Carom),. (Carom), 0. (Carom), 9. (Carom),. (Carom),.0 (Carom),.9 (Carom),.0 (Carom),. (C-), 9. (C-), 0. (C-9) ppm. EA Aal. Calcd for C: C,.90;,.0;,.. Foud: C,.0;,.0;,.0. MS (Io trap, EI): m/z (%) = 9 (, [M]), (00), 9 () 0 (0), (), (0). Sythesis of -bromo-,-dimethoxy--[(z)--(-methoxy-pheyl)viyl]bezamide (9h) (CAS-0: 0-9-0) 9h was sythesized followig method A usig -bromo,-dimethoxy-bezamide (0. mg,.00 mmol) ad methoxy-pheylacetylee (9 L, 9.00 mmol) ad 0 Br purified by colum chromatography (: ethyl acetate/hexae), yieldig the product as a white solid (. mg, 0%). -M (00 Mz, CDCl, C): =. (d, J(,)=0.9 z,, -),. (s,, arom),.-. (m,, arom),.0 (dd, J(,)=., 9. z,, -0),.9 (s,, arom),.-.9 (m,, arom),. (d, J(,)=9. z,, ),. ( sigals, sigulets, each, - ad -),.0 (s,, ) ppm. C-M (0 Mz, CDCl, C): =. (C-9),. (Carom),. (Carom),. (Carom), 9. (Carom),. (Carom),. (Carom),.0 (C-0),.0 (Carom),. (Carom),.9 (Carom),. (Carom), 09. (C-),. ad. (C- ad C-),. (C-) ppm. MS (Io trap, EI): m/z (%) = 9 (9, [M]), 9 (, [M]), (00), (), 0 (), ()

169 Experimetal part Sythesis of -((E)-hex--e--yl)bezamide (0aa) (CAS-0: --) 0aa was sythesized followig method B usig bezamide (. mg,.00 mmol) ad -hexye (9 L,.00 mmol) ad purified by colum chromatography (:9 ethyl acetate/hexae), 0 9 yieldig the product as a white solid (0.9 mg, 9%). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, arom),.9 (d, J(,)=. z,, -),.0 (t, J(,)=. z,, arom),. (t, J(,)=. z,, arom),.9 (dd, J(,)=.0, 0. z,, -),.0 (dt, J(,)=.,. z,, -),.0 (q, J(,)=. z,, -),.0. (m,, -9, 0), 0.9 (t, J(,)=. z,, -) ppm. C-M ( Mz, CDCl, C): =. (C-),.9 (Carom),.9 (Carom),. (Carom),.0 (Carom),. (C-),. (C-),. (C-),. (C-9),. (C0),.9 (C-) ppm. (Io trap, EI): m/z (%) = 0 (, [M]), (), 0 (00), (), (), MS (). Sythesis of -[(E)--pheyl-viyl]bezamide (0ab) (CAS-0: 00--) 0ab was sythesized followig method B usig bezamide (. mg,.00 mmol) ad pheylacetylee (0 L,.00 mmol) ad purified by colum chromatography (: ethyl 0 9 acetate/hexae), yieldig the product as a white solid (0. mg, 9%). -M (00 Mz, CDCl, C): =.0 (d, J(,)=0.0 z,, -),.-. (m,, arom),. (dd, J(,)=., 0. z,, -),.-. (m,, arom),. (t, J(,)=. z,, arom),.-. (m,, arom),.9 (t, C-M J(,)=. z,, arom),.9 (t, J(,)=. z,, arom),. (d, J(,)=. z,, -) ppm. ( Mz, CDCl, C): =. (C-),.9 (Carom),. (Carom),. (Carom),. (Carom),. (Carom),. (Carom),. (Carom),. (Carom),.0 (C-),. (C-) ppm. - -

170 Experimetal part MS (Io trap, EI): m/z (%) = (9, [M]), 0 (00), 9 (), (), (), (). Sythesis of -[(E)-,-dimethyl-but--e--yl]bezamide (0ac) 0ac was sythesized followig method B usig bezamide (. mg,.00 mmol) ad,-dimethyl--butye 9 9 ( L,.00 mmol) ad purified by colum chromatography (:9 ethyl 9 acetate/hexae), yieldig the product as a white solid (. mg, 9%). -M (00 Mz, CDCl, C): =. (d, J(,)=0.0 z,, -),.-. (m,, arom),. (t, J(,)=. z,, arom),. (t, J(,)=. z,, arom),. (dd, C-M J(,)=., 0. z,, -),.0 (d, J(,)=. z,, ),.0 (s, 9, -9) ppm. ( Mz, CDCl, C): =. (C-),. (Carom),. (Carom),. (Carom),.0 (Carom),.9 (C-), 9. (C-),.9 (C-), 9. (C-9) ppm. EA Calcd: C,.;,.;,.9. Foud: C,.;,.;,.. MS (Io trap, EI): m/z (%) = 0 (0, [M]), (), 9 (), 0 (), (), (00). Sythesis of -[(E)--pheyl-but--e--yl]bezamide (0ad) 0ad was sythesized followig method B usig bezamide (. mg,.00 mmol) ad -pheyl--butye ( L,.00 mmol) ad purified by colum chromatography (: 0 9 ethyl acetate/hexae), yieldig the product as a white solid (. mg, %). -M (00 Mz, CDCl, C): =.0 (d, J(,)=0. z,, -),.-. (m,, arom),.-. (m,, arom),.0 (t, J(,)=. z,, arom),. (t, J(,)=. z,, arom),.-. (m,, arom),.00 (dd, J(,)=., 0. z,, -),. (dt, J(,)=.,. z,, -),.-. (m,, -),.9 (t, J(,)=. z,, -9) ppm. - -

171 Experimetal part C-M (0 Mz, CDCl, C): =. (C-),. (Carom),. (Carom),. (Carom),. (Carom),. (Carom),. (Carom),.0 (Carom),.9 (Carom),. (C-),. (C-),. (C-),. (C-9) ppm. EA Calcd: C,.;,.;,.. Foud: C, 0.;,.;,.. MS (Io trap, EI): m/z (%) = (, [M]), (), 0 (), 0 (), 0 (00), (). Sythesis of -[(E)--cyclohexyl-prop--e--yl]bezamide (0ae) 0ae was sythesized followig method B usig bezamide (. mg,.00 mmol) ad -cyclohexyl--propye (9 L,.00 mmol) ad purified by colum chromatography (:9 ethyl 9 0 acetate/hexae), yieldig the product as a white solid (0. mg, %). -M (00 Mz, CDCl, C): =. (d, J(,)=9.9 z,, -),.-.0 (m,, arom),.-. (m,, arom),. (t, J(,)=. z,, arom),.9 (dd, J(,)=., 0. z,, -),.9 (dt, J(,)=.,. z,, -),.9 (dd, J(,)=.,. z,, -),.-. (m,, Cy),.. (m,, Cy), (m,, Cy) ppm. C-M (0 Mz, CDCl, C): =. (C-),.9 (Carom),. (Carom),. (Carom),.0 (Carom),. (C-),. (C-),. (CCy),. (CCy),.0 (CCy),. (CCy),. (CCy) ppm. EA Calcd: C,.9;,.0;,.. Foud: C,.9;,.;,.. MS (Io trap, EI): m/z (%) = (, [M]), 0 (), (), 0 (00), (), (9). - -

172 Experimetal part Sythesis of -methyl--[(e)--pheylviyl]acrylamide (0db) 0db was sythesized followig method B usig -methyl- 0 acrylamide (. mg,.00 mmol) ad pheylacetylee (0 L,.00 mmol) ad purified by colum chromatography (:9 ethyl 9 acetate/hexae), yieldig the product as a white solid (. mg, %). -M (00 Mz, CDCl, C): =. (d, J(,)=0. z,, -),.0 (dd, J(,)=., 0.9 z, arom),.9-. (m, arom),. (d, J(,)=.0 z, arom),. (t, J(,)=. z,, -),. (d, J(,)=. z,, -),. (s,, -),. (s,, -),.0 (s,, -) ppm. C-M (0 Mz, CDCl, C): =. (C-), 9. (C-),. (Carom),. (Carom),. (Carom),. (Carom),.9 (C-), 0. (C-),. (C-),. (C-) ppm. EA Calcd: C,.9;,.00;,.. Foud: C,.;,.9;,.. MS (Io trap, EI): m/z (%) = (00, [M]), 9 (), (), (), 9 (0), (0). Sythesis of -acetamido--[(e)--pheylviyl]acetamide (0eb) 0eb was sythesized followig method B usig acetylamido-acetamide (. mg,.00 mmol) ad pheylacetylee (0 L,.00 mmol) ad purified by colum 0 9 chromatography (: ethyl acetate/hexae), yieldig the product as a white solid ( mg, %). -M (00 Mz, CDCl, C): =. (s,, -),. (dd, J(,)=., 0. z,, -),.-.0 (m,, arom),. (t, J(,)=.0 z,, arom),. (s,, -),.0 (d, J(,)=. z,, -),.0 (d, J(,)=.9 z,, -),.0 (s,, -) ppm. - -

173 Experimetal part C-M ( Mz, DMS-d, C): =9. (C-),. (C-),. (Carom),. (Carom),. (Carom),. (Carom),. (C-),. (C-),. (C-),. (C-) ppm. EA Calcd: C,.0;,.;,.. Foud: C,.9;,.;,.. MS (Io trap, EI): m/z (%) = (, [M]), 9 (00), 9 (), (), (), (). Sythesis of ethyl oxo{[(e)--pheylviyl]amio}acetate (0fb) 0fb was sythesized followig method B usig oxalamic acid ethyl ester (. mg,.00 mmol) ad pheylacetylee 0 (0 L,.00 mmol) ad purified by colum chromatography 9 (: ethyl acetate/hexae), yieldig the product as a white solid (9. mg, %). -M (00 Mz, CDCl, C): =9.00 (s,, -),. (dd, J(,)=., 0.9 z,, -),.-.9 (m,, arom),. (t, J(,)=. z,, arom),. (t, J(,)=. z,, arom),. (d, J(,)=. z,, ),. (q, J(,)=. z,, -),. (t, J(,)=. z,, -) ppm. C-M (0 Mz, CDCl, C): =0. (C-),. (C-),. (Carom),. (Carom),. (Carom),.9 (Carom),.0 (C-),.9 (C-),. (C-),.9 (C-) ppm. EA Calcd: C,.;,.9;,.9. Foud: C,.0;,.9;,.. MS (Io trap, EI): m/z (%) = 9 (00, [M]), (9), (), 9 (), (), (). Sythesis of -[(E)--(-methoxypheyl)viyl]bezamide (Alatamide) (0ah) (CAS-0: 9--) 0ah was sythesized followig method B bezamide.00 mmol) ad purified by colum - - (. mg,.00 mmol) ad -methoxy-pheylacetylee (9 L, 0 9

174 Experimetal part chromatography (: ethyl acetate/hexae), yieldig the product as a white solid (00 mg, 9%). -M (00 Mz, DMS-d, C): =0. (d, J(,)=9. z,, -),.9.9 (m,, arom),.-. (m,, -),.-. (m,, arom),. (d, C-M J(,)=. z, J(,)=.0 z,, -),. (s,, -) ppm., arom),.-.9 (m,, arom),. (d, ( Mz, DMS-d, C): =. (C-),.0 (Carom),. (Carom),. (Carom), 9.0 (Carom),. (Carom),. (Carom),. (Carom),. (C-),. (C-),. (Carom),. (C-) ppm. MS (Io trap, EI): m/z (%) = (, [M]), 0 (), (), 0 (00), (9), (). - -

175 Experimetal part. Secod geeratio catalyst for the additio of secodary amides to alkyes... Geeral method A ove-dried flask was charged with potassium carboate (0. mg, 0. mmol), ad a stock solutio cotaiig rutheium(iii) chloride hydrate (. mg, 0.0 mmol), - dimethylamiopyridie (.0 mg, 0.09 mmol) i acetoe (.0 ml). The acetoe was removed i vacuo ad the flask was flushed with itroge. Subsequetly, dry toluee (.0 ml), water ( μl, 0.0 mmol), -ucleophile (.00 mmol), tri--butylphosphie ( μl, 0.09 mmol) ad alkye (.00 mmol) were added via syrige. The resultig solutio was stirred for h at 00 C, the poured ito a aqueous sodium bicarboate solutio (0 ml). The resultig mixture was extracted repeatedly with 0 ml portios of ethyl acetate, the combied orgaic layers were washed with water ad brie, dried with magesium sulfate, filtered, ad the volatiles were removed i vacuo. The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae) to yield the E-secodary eamide. The idetity ad purity of the products were cofirmed by ad C M spectroscopy, mass spectroscopy ad elemetal aalysis. - -

176 Experimetal part.. Sythesis of the eamides Sythesis of -((E)-hex--eyl)pyrrolidi--oe (aa) [CAS: ] 0 aa was prepared from -hexye (9 μl,.00 mmol) followig the 9 geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a : mixture of a ad aa as a colorless solid (. mg, 99%). -M (00 Mz, CDCl, C): =.0 (d, J(,)=. z,, -),.9 (dt, J(,)=. z,. z,, -),. (t, J(,)=. z,, -),. (t, J(,)=. z,, -),.-.99 (m,, -, ),.-. (m,, -, 9), 0. (t, J(,)=. z,, -0) ppm. C-M (0 Mz, CDCl, C): =. (C-),. (C-),. (C-),.9 (C-),.9 (C-), 0.9 (C-), 9. (C-),. (C-9),. (C-),. (C-0) ppm. MS (Io trap, EI): m/z (%) = (), (00), 9 (), (), 9 (), (). Sythesis of -((E)--pheyl-viyl)pyrrolidi--oe (ab) [CAS: --9] 9 ab was prepared from pheylacetylee (0 μl,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a : 0 mixture of ab ad ab as a greyish solid (.. mg, 9%). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),.0-.9 (m, ; arom),.9 (t, J(,)=. z,, arom),. (d, J(,)=.0 z,, -),. (t, J(,)=. z,, -),.0 (t, J(,)=. z,, -),.0-. (m,, -) ppm. C-M (0 Mz, CDCl, C): =.0 (C-),. (Carom),. (Carom),. (Carom),. (Carom),. (C-),. (C-),.9 (C-), 0.9 (C-),. (C-) ppm. MS (Io trap, EI): m/z (%) = (00), 9 (), (), (), (), (). - -

177 Experimetal part Sythesis of -((E)-,-dimethyl-but--eyl)pyrrolidi--oe (ac) [CAS: 09--] ac was prepared from,-dimethylbut--ye ( μl,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a 0: mixture of ac ad ac as a colorless solid (.0 mg, 99%). -M C-M (00 Mz, CDCl, C): =. (d, J(,)=.0 z,, -),. (d, J(,)=. z, ; -),. (t, J(,)=. z,, -),. (t, J(,)=. z,, -),.9-.9 (m,, -), 0.9 (s, 9, -) ppm. (0 Mz, CDCl, C): =. (C-),. (C-), 0. (C-),.0 (C-),. (C-),. (C-), 0.0 (C-),. (C-) ppm. MS (Io trap, EI): m/z (%) = (9), (00), (), (), (9). Sythesis of -((E)--pheyl-but--eyl)pyrrolidi--oe (ad) [CAS: 09--] 0 ad was prepared from (but--yyl)bezee ( μl,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a : mixture of ad ad ad as a colorless oil 9 (0. mg, 9%). -M (00 Mz, CDCl, C): =.-. (m,, arom),.09-. (m,, arom),. (d, J(,)=. z,, -),.9 (dt, J(,)=. z,. z,, -),. (t, J(,)=. z,, -),.0-. (m,, -),.0-.9 (m,, -, ), (m,, -) ppm. C-M (0 Mz, CDCl, C): =. (C-),. (C-9),.0 (Carom),.9 (Carom),. (Carom),. (C-), 0. (C-),. (C-),. (C),. (C-), 0. (C-),.0 (C-). MS (Io trap, EI): m/z (%) = (), (00), 9 (), 9 (), ()

178 Experimetal part Sythesis of methyl-(e)--(-oxopyrrolidi--yl) acrylate (ae) [CAS: 9--] ae was prepared from methyl propargylate (9 μl,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a 0: mixture of ae ad ae as a colorless solid (. mg, 9%). -M (00 Mz, CDCl, C): =.9 (d, J(,)=. z,, -),.0 (d, J(,)=. z, ; -),.9 (s,, -),. (t, J(,)=. z,, -),.. (m,, -), (m,, -) ppm. C-M (0 Mz, CDCl, C): =.0 (C-),. (C-),. (C-), 99. (C-),.0 (C-),. (C-), 0. (C-),. (C-) ppm. MS (Io trap, EI): m/z (%) = 9 (), (), 0 (00), (), 0 (), (), (). Sythesis of -((E)--methyl-,-butadie--yl)pyrrolidi--oe (af) 9 [CAS: --] af was prepared from -methylbut--e--ye (9 μl,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a : mixture of af ad af as a colorless solid (. mg, 9%). -M (00 Mz, CDCl, C): =.9 (d, J(,)=. z,, -),. (d, J(,)=. z, ; -),.9(s,, -9),. (s,, -9),.-. (m,, -),.0 (t, J(,)=. z,, -), (m,, -),. (s,, -) ppm. C-M (0 Mz, CDCl, C): =. (C-), 0. (C-),. (C-),.9 (C-9),. (C-),.0 (C-),.0 (C-),. (C-),. (C-) ppm. MS (Io trap, EI): m/z (%) = (), (), 0 (00), (), 9 (), (0)

179 Experimetal part Sythesis of -((E)--chloro-pet--eyl)pyrrolidi--oe (ag) [CAS: 09--] Cl ag was prepared from -chloropet--ye ( μl,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a : mixture of ag ad ag as a colorless oil (.0 mg, 99%). -M 9 (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),. (dt, J(,)=. z,. z,, -),.-.9 (m,, -, 9),. (t, J(,)=. z,, -),.0-. (m,, -), (m,, -),.-.(m,, -) ppm. C-M (0 Mz, CDCl, C): =. (C-),. (C-), 09. (C-),.9 (C-),. (C-9),. (C-), 0.9 (C-),.9 (C-),.0 (C-) ppm. MS (Io trap, EI): m/z (%) = (), (00), 9 (), 9 (0), (). Sythesis of -((E)--methoxy-prop--eyl)pyrrolidi--oe (ah) [CAS: 09--] ah was prepared from -methoxypropye (9 μl,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a : mixture of ah ad ah as a colorless oil (. mg, 99%). -M (00 Mz, CDCl, C): =.9 (d, J(,)=.z,, -),.9 (dt, J(,)=. z,. z, ; -),.-. (m,, -),.-.0 (m,, -),. (s,, -),. (t, J(,)=. z,, -), (m,, -) ppm. C-M (0 Mz, CDCl, C): =.0 (C-),.9 (C-), 0. (C-), 0.9 (C-),.0 (C-),. (C-), 0. (C-),.0 (C-) ppm. MS (Io trap, EI): m/z (%) = (), 0 (), (00), (), 9 (), 9 (), (9), (). - -

180 Experimetal part Sythesis of -((E)--trimethylsilyl-viyl)pyrrolidi--o (ai) [CAS: --9] ai was prepared from trimethylsilylacetylee (i, μl,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a : Si mixture of ai ad ai as a colorless oil (. mg, 90%). -M C-M (00 Mz, CDCl, C): =.0 (d, J(,)=. z,, -),.(d, J(,)=. z, ; -),. (t, J(,)=. z,, -),.0 (t, J(,)=. z,, -),.9-.0 (m,, -), 0.90 (s, 9, -) ppm. (0 Mz, CDCl, C): =. (C-),. (C-), 0.9 (C-),. (C-),. (C-),. (C-), -.0 (C-) ppm. MS (Io trap, EI): m/z (%) = (), (00), (), 00 (), (), 9 (). Sythesis of -((E)-dodeca-,-dieyl)pyrrolidi--oe (aj) aj was prepared from dodec--e--ye ( L,. mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl 0 acetate/hexae :) yieldig a 9: mixture of aj ad aj -M 9 as a yellowish oil (. mg,.%). (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),. (qd, J(,)=.0 z, 0. z,. z,, -),.-. (m,, -),.-.90 (m,, -),. (t, J(,)=. z,, -),.-. (m,, -),..0 (m,, -,, ),.0-. (m,, -, 9, 0,,, ) ppm. C-M (0 Mz, CDCl, C): =. (C-),. (C-),. (C-),. (C),. (C-),.0 (C-),.,.0, 9., 9., 9.,.,. (C-,,, 9, 0,,,, ),. (C-) ppm. MS (Io trap, EI): m/z (%) = 9 (), (), (00), 9 (), (), 9 (), (). - -

181 Experimetal part Sythesis of -((E)-hex--eyl)azetidi--oe (ba) [CAS: 09--0] ba was prepared from azetidi--oe (. mg,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a : 9 mixture of ba ad ab as a yellowish oil (. mg, %). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),.9 (dt, J(,)=. z,. z,, -),. (t, J(,)=. z,, -),.9 (t, J(,)=. z,, -),.9 (q, J(,)=. z,, -),.-. (m,,, ), (m,, 9) ppm. C-M (0 Mz, CDCl, C): =. (C-),. (C-),. (C-),.0 (C-),. (C-),. (C-), 9.0 (C-),.9 (C-),. (C-9) ppm. MS (Io trap, EI): m/z (%) = (0), (), 0 (0), (9), (00), (), (). Sythesis of -((E)-hex--eyl)piperidi--oe (ca) [CAS: 09--9] ca was prepared from piperidi--oe (99. mg,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) 0 9 yieldig a 0: mixture of ca ad ca as a yellowish oil (. mg, 9%). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),.9 (dt, J(,)=. z,. z,, -),. (t, J(,)=. z,, -),. (t, J(,)=. z, -),.9.09 (m,, -),.-. (m,, -, ),.. (m,, -9, 0), 0.9 (t, J(,)=. z,, -) ppm. C-M (0 Mz, CDCl, C): =. (C-),. (C),. (C-),. (C-),. (C-),. (C-), 9. (C-9),. (C-0),. (C-), 0. (C-),. (C-) ppm. MS (Io trap, EI): m/z (%) = (), (0), (00), (), 0 (9), 00 (), (), (9), (). - -

182 Experimetal part Sythesis of -((E)-hex--eyl)azepa--oe (da) da was prepared from azepa--oe (. mg,.00 mmol) followig the geeral procedure. The product was purified by 9 0 colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a 0: mixture of da ad da as a yellowish oil (9. mg, 99%). -M (00 Mz, CDCl, C): =.9 (d, J(,)=. z,, -),. (dt, J(,)=. z,. z,, -),.-. (m,, -),.-.9 (m,, -),.9-.9 (m,, -9),.-. (m,, -,, ),.-. (m,, -0, ), 0. (t, J(,)=. z,, -) ppm. C-M (0 Mz, CDCl, C): =. (C-),. (C-), 0. (C-),. (C-),. (C-),. (C-9), 9. (C-0), 9. (C-),.0 (C-),. (C-),. (C-),. (C-) ppm. EA Calcd: C,.;, 0.;,.. Foud: C,.9;,.0;,.. MS (Io trap, EI): m/z (%) = 9 (), (), (), (00), (), (), 0 (0), 9 (0), (), 9 (0), (). Sythesis of -((E)-hex--eyl)azoa--oe (ea) [CAS: 09--] ea was prepared from azoa--oe (. mg,.00 mmol) followig the geeral procedure. The product was purified by 9 yieldig a 0: mixture of ea ad ea as a yellowish oil 0 colum chromatography (silica gel, ethyl acetate/hexae :) (. mg, 0%). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, -9),.9 (dt, J(,)=. z,. z,, -0),. (t, J(,)=. z,, -),.-. (m,, -), (m,, -),.-. (m,, -),.-.0 (m,, -),.-. (m,, -,, ),.-. (m,, -, ), 0. (t, J(,)=. z,, -) ppm. - -

183 Experimetal part C-M (0 Mz, CDCl, C): =. (C-),.0 (C-9),. (C-0),. (C-),. (C-),. (C-), 0. (C-),. (C-),. (C-),. (C-),. (C-),. (C-),.0 (C-),. (C-) ppm. MS (Io trap, EI): m/z (%) = (), 0 (00), (00), (), (9), (). Sythesis of,-di-((e)-hex--eyl)piperazi-,-dioe (fa) [CAS: 09--] fa was prepared from piperazi-,-dioe (. mg,.00 mmol) ad -hexye (a, μl,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a 0: mixture of fa ad fa as a colorless solid (9. mg, %). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),.0 (dt, J(,)=. z,. z,, -),. (s,, -),.09 (q, J(,)=.9 z,, -),.-.0 (m,, -, ), 0. (t, J(,)=. z,, -) ppm. C-M (0 Mz, CDCl, C): =0. (C-),. (C-),. (C-),. (C),.9 (C-), 9. (C-),.0 (C-),. (C-) ppm. MS (Io trap, EI): m/z (%) = (), (), 0 (00), (9), (), (). Sythesis of -(-acetyl-pheyl)--((e)-hex--eyl)acetamide (ga) [CAS: ] ga was prepared from -(-acetyl-pheyl)acetamide (. mg,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a 0: mixture of ga ad ga as a colorless solid 9 0 (0. mg, 0%). -M (00 Mz, CDCl, C): =.0 (d, J(,)=. z,, arom),. (d, J(,)=. z,, arom),. (d, J(,)=. z,, -9),.9 (dt, - -

184 Experimetal part J(,)=.9 z,. z,, -0),. (s,, -),.9-.9 (m,, -),. (s,, -),.-. (m,, -,), 0. (m,, -) ppm. C-M (0 Mz, CDCl, C): 9. (C-),. (C-),.9 (Carom),. (Carom), 9.9 (Carom), 9. (Carom),. (C-9),. (C-0),. (C-), 9. (C-),. (C-),.0 (C-),. (C-),. (C-) ppm. MS (Io trap, EI): m/z (%) = 9 (), (), 0 (9), (00), (), (), (9). Sythesis of -(-ethoxy-pheyl)--((e)-hex--eyl)acetamide (ha) [CAS: 09--] ha was prepared from -(-ethoxy-pheyl)acetamide (9. mg, 9.00 mmol) followig the geeral procedure. The product was 0 purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a 0: mixture of ha ad ha as a colorless solid -M (. mg, 9%). (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),.9 (d, J(,)=. z,, arom),. (d, J(,)=. z,, arom),.9 (dt, J(,)=. z,, z,, -0),.9 (q, J(,)=.9 z,, -),. (q, J(,)=. z,, -),. (s,, -),. (t, J(,)=.9 z,, -),.0-.9 (m,, -, ), 0. (t, J(,)=.0 z,, -) ppm. C-M (0 Mz, CDCl, C):. (C-),. (Carom),. (Carom), 9. (Carom),. (C-9),. (Carom),.0 (C-0),. (C-),. (C-), 9. (C-),. (C-),. (C-),. (C-),. (C-) ppm. MS (Io trap, EI): m/z (%) = (), (0), 0 (), (00), (), 0 (), (), (). - -

185 Experimetal part Sythesis of -pheyl--((e)-hex--eyl)bezamide (ia) ia was prepared from bezailide (9. mg,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) 0 yieldig a 0: mixture of ia ad ia as a colorless solid 9 (. mg, 0%). -M (00 Mz, CDCl, C): =. (d, J(,)=0.0 z,, -0),.-. (m,, arom),.-. (m,, arom),.09 (d, J =. z,, arom),. (dt, J(,)=. z,, z,, -),.0 (q, J(,)=.0 z,, -),.9-. (m,, -, ), 0. (t, J(,)=. z,, -) ppm. C-M (0 Mz, CDCl, C):. (C-), 0. (Carom),. (Carom), 9. (Carom), 9. (Carom), 9. (Carom), 9. (Carom),. (C-0),, (Carom),. (Carom),. (C-),.9 (C-), 9. (C-),. (C-),.9 (C-) ppm. EA Calcd: C,.;,.;,.0. Foud: C,.;,.;,.9. MS (Io trap, EI): m/z (%) = 9 (), (), 9 (), (0), 0 (00), (9), (). Sythesis of -((E)-hex--eyl)--(methyl)formamide (ja) [CAS: 09--] ja was prepared from -methylformamide (9. mg,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a : mixture of ja ad ja as a yellowish oil (. mg, %). -M (00 Mz, CDCl, C): =. (s,, -),. (d, J(,)=.0 z,, -),.0-. (m,, -),.9 (s,, -), (m,, -),.0-. (m,, -, ), (m,, -) ppm. C-M (0 Mz, CDCl, C):.0 (C-),. (C-),. (C-),. (C-), 9. (C-),. (C-),.0 (C-),. (C-) ppm. MS (Io trap, EI): m/z (%) = (), 9 (00), (), 0 (), 0 (), (). - -

186 Experimetal part Sythesis of -((E)-hex--eyl)--(methyl)acetamide (ka) [CAS: 09--0] ka was prepared from -methylacetamide (. mg,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a : 9 mixture of ka ad ka as a yellowish oil (. mg, 0%). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),.9-.0 (m,, -),.0 (s,, -),. (s,, -), (m,, -),.-.9 (m,, -, ), 0.9 (t, J(,)=. z,, -9) ppm. C-M (0 Mz, CDCl, C):.9 (C-),. (C-),. (C-),. (C-), 0. (C-), 9. (C-),. (C-),.0 (C-),.9 (C-9) ppm. MS (Io trap, EI): m/z (%) = (), (), 9 (0), 0 (00), (). Sythesis of -((E)-hex--eyl)--(isopropyl)acrylamide (la) [CAS: 09--] la was prepared from -isopropylacrylamide (. mg,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a 0: 9 mixture of la ad la as a colorless oil (9. mg, 9%). -M (00 Mz, CDCl, C): =. (dd, J tras(,)=.9 z,. (dd, J tras(,)=.9 z, J (,)=0. cis z, J gem(,)=. z,, -),.9 (d, J(,)=. z,, -),. (dd, J (,)=0. cis z, Jgem(,)=. z, -9),. (dt, J(,)=. z,, -9),.0 z,, -),.0-. (m,, -),. (q, J(,)=. z,, -),.-. (m,, -9, 0),.0 (d, J(,)=. z,, -), 0.90 (t, J(,)=. C-M z,, -) ppm. (0 Mz, CDCl, C):. (C-),. (C-), 0.0 (C-),. (C-),. (C-),. (C-),. (C-), 9. (C-9),. (C-0), 0.0 (C-),. (C-) ppm. MS (Io trap, EI): m/z (%) = 9 (), 0 (), (), (9), 0 (), 9 (00), (0)

187 Experimetal part Sythesis of -((E)-hex--eyl)oxazolidi--oe (ma) [CAS: 9--] ma was prepared from oxazolidi--oe (. mg,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) 9 yieldig a 0: mixture of ma ad ma as a colorless oil (. mg, %). -M (00 Mz, CDCl, C): =.0 (d, J(,)=. z, ; -),. (dt, J(,)=. J(,)=. z,. z,, -),. (t, J(,)=. z,, -),.9 (t, z,, -),.9 (dt, J(,)=. z,. z,, -),.-.0 (m,, -, ), 0.9 (t, J(,)=. z,, -9) ppm. C-M (0 Mz, CDCl, C):. (C-),. (C-),. (C-),.9 (C-),. (C-),. (C-), 9. (C-),. (C-),. (C-9) ppm. MS (Io trap, EI): m/z (%) = 0 (9), (00), (), (), (). Sythesis of ()--((E)-hex--eyl)--(isopropyl)-oxazolidi--oe (a) a was prepared from ()-isopropyl-oxazolidi--oe (9. mg,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl 0 9 acetate/hexae :) yieldig a : mixture of ma ad ma as a colorless oil (9. mg, 9.%). -M (00 Mz, CDCl, C): =. (d, J(,)=. z, ; -),. (dt, J(,)=. J(,)=. z,. z,, -),.0-. (m,, -),.9 (dt, z,. z, -),.-. (m,, -),.-.99 (m,, -),..9 (m,, -9, 0), (m,, -, ), 0.0 (d, J(,)=. C-M z,, -) ppm. (0 Mz, CDCl, C):. (C-),. (C-),.9 (C-),. (C-),. (C-),. (C-), 9. (C-9),. (C-),. (C-0),. (C-),. (C),. (C-) ppm. MS (Io trap, EI): m/z (%) = (00), (), (), (), ()

188 Experimetal part Sythesis of (S,)--((E)-hex--eyl)--methyl--pheyloxazolidi--oe (oa) [CAS: 09-9-] oa was prepared from (S,)--methyl--pheyloxazolidi-- oe (. mg,.00 mmol) followig the geeral procedure. The -M colorless solid (. mg, 9%). 0 product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) yieldig a : mixture of oa ad oa as a 9 (00 Mz, CDCl, C): =.-. (m,, arom),. (d, J(,)=. z, ; -9),. (d, J(,)=. z,, -),. (dt, J(,)=. z,. z,, -0),. (dt, J(,)=. z,. z,, -),.9 (q, J(,)=. z,, -),.-. (m,, -, ), 0. (t, C-M J(,)=. z,, -), 0. (d, J(,)=. z,, -) ppm. (0 Mz, CDCl, C):. (C-),.0 (Carom),. (Carom),. (C-),. (Carom),. (C-9),.0 (C-0),. (C-),.9 (C-),. (C-), 9. (C-),. (C-),. (C-),. (C-) ppm. MS (Io trap, EI): m/z (%) = 9 (), (), (00), (), 9 (), (), (). Sythesis of -[(E)-hex--eyl]succiimide (pa (aa)) pa was prepared from succiimide (99. mg,.00 mmol) followig the geeral procedure. The product was purified by colum chromatography (silica gel, ethyl acetate/hexae :) 9 0 yieldig a : mixture of pa ad pa as a colorless solid (. mg, 9%). -M C-M (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),. (dt, J(,)=.0 z,. z,, -),. (s,, -, -),.0 (dt, J(,)=.,.,, -),.. (m,, -, -9), 0. (t, J(,)=. z,, -0) ppm. (0 Mz, CDCl, C): =. (C-, C-),. (C-),. (C-),. (C-), 0. (C-),. (C-, C-),.0 (C-9),. (C-0) ppm. MS (Io trap, EI): m/z (%) = (0, [M]), (00), 00 (), (9), ()

189 Experimetal part... Additio of thioamides to alkyes Geeral method Method A: A ove-dried flask was charged with the -ucleophile (.00 mmol), bis(methallyl)-cycloocta-,-diee-rutheium(ii) (. mg, 0.0 mmol) ad molecular sieves (00 mg) ad flushed with itroge. Subsequetly, dry toluee (.0 ml), tri--octylphosphie ( L, 0.0 mmol), alkye (.00 mmol) ad water (0 L,.00 mmol) were added via syrige. The resultig solutio was stirred for h at 0 C, the poured ito a aqueous sodium bicarboate solutio (0 ml). The resultig mixture was extracted repeatedly with 0 ml portios of ethyl acetate, the combied orgaic layers were washed with water ad brie, dried with magesium sulfate, filtered, ad the volatiles were removed i vacuo. The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae) to yield the Z-secodary eamide. The idetity ad purity of the products were cofirmed by ad C M spectroscopy, mass spectroscopy ad elemetal aalysis. Method B: A ove-dried flask was charged with the -ucleophile (.00 mmol), bis(methallyl)-cycloocta-,-diee-rutheium(ii) (. mg, 0.0 mmol), Kt (. mg, 0.0 mmol) ad bis(dicyclohexylphosphio)methae (. mg, 0.0 mmol) ad flushed with itroge. Subsequetly, dry toluee (.0 ml) ad alkye (.00 mmol) were added via syrige. The resultig solutio was stirred for h at 0 C, the poured ito a aqueous sodium bicarboate solutio (0 ml). The resultig mixture was extracted repeatedly with 0 ml portios of ethyl acetate, the combied orgaic layers were washed with water ad brie, dried with magesium sulfate, filtered, ad the volatiles were removed i vacuo. The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae) to yield the Zsecodary eamide. The idetity ad purity of the products were cofirmed by ad M spectroscopy, mass spectroscopy ad elemetal aalysis. - - C

190 Experimetal part.. Sythesis of the thioeamides Sythesis of -[(E)-hex--eyl]pyrrolidie--thioe (aa). aa was prepared accordig to method A, usig the followig amouts: u(cod)[met] (. mg, 0.0 mmol), molecular sieves (00 mg), pyrrolidie--thioe (0. mg,.00 mmol), tri-- S 9 0 octylphosphie ( L, 0.0 mmol) ad -hexye (9 L,.0 mmol). The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford the title product as a yellowish oil (: mixture with the Z-isomer 9. mg, 9%). -M (00 Mz, CDCl, C): =.0 (d, J(,)=. z,, -),. (dt, J(,)=.,. z,, -),. (t, J(,)=. z,, -),.9 (t, J(,)=.9 z,, -),.0 (m,, -, -),.-.0 (m,, -, - 9), 0.9 (t, J(,)=. z,, -0) ppm. C-M (0 Mz, CDCl, C): =99.0 (C-),. (C-), 9. (C-),. (C),. (C-),. (C-), 9. (C-),. (C-9), 9. (C-),.9 (C-0) ppm. EA Calcd: C,.;, 9.;,.. Foud: C,.09;, 9.;,.. MS (Io trap, EI): m/z (%) = (, [M]), (00), 9 (), (), (). Authetic sample of -[(E)-hex--eyl]pyrrolidie--thioe (aa). A ove-dried flask was charged with Lawesso s reaget (0. mg,.00 mmol) ad flushed with itroge. Dry toluee (.0 ml) ad a solutio of -[(E)-hex--eyl]pyrrolidie (. mg,.0 mmol) i toluee (.0 ml) were added via syrige. The resultig solutio was stirred for h at 0 C, the the solvet was removed i vacuo ad the residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford product aa as a yellowish oil (. mg, 9%). The -, C-M, ad MS were correspodet to those above. Sythesis of -[(E)-,-dimethyl-but--eyl]pyrrolidie--thioe (ab) (CAS-r: 99--) ab was prepared accordig to method A, usig the followig amouts: u(cod)[met] (. mg, 0.0 mmol), molecular sieves (00 mg), S - -

191 Experimetal part pyrrolidie--thioe (0. mg,.00 mmol), tri--octylphosphie ( L, 0.0 mmol) ad,-dimethyl--butye ( L,.0 mmol). The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford the product as a yellowish oil (: mixture with the Z-isomer. mg, 9%). -M (00 Mz, CDCl, C): =.0 (d, J(,)=. z,, -),. (d, J(,)=. z,, -),. (t, J(,)=. z,, -),.9 (t, J(,)=. z,, -),.0 (tt, J(,)=.,. z,, -),.0 (s, 9, -) ppm. C-M (0 Mz, CDCl, C): =99. (C-), 0. (C-),. (C-),. (C),. (C-),. (C-), 9.9 (C-), 9. (C-) ppm. EA Calcd: C,.;, 9.;,.. Foud: C,.;, 9.;,.0. MS (Io trap, EI): m/z (%) = (, [M]), (), (), (), (00). The data correspod to those reported i the literature: E. Vedejs,. G. Wilde, J. rg. Chem. 9,,. Sythesis of -[(E)--pheylbut--e--yl]pyrrolidie--thioe (ac). ac was prepared accordig to method A, usig the followig amouts: u(cod)[met] (. mg, 0.0 mmol), molecular sieves (00 mg), pyrrolidie--thioe (0. mg,.00 mmol), tri-- S 0 9 octylphosphie ( L, 0.0 mmol) ad -pheyl--butye ( L,.0 mmol). The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford the product as a yellowish oil (: mixture with the Z-isomer, 9. mg, 9%). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),. (m,, arom),.-. (m,, arom),. (dt, J(,)=.,. z,, -),.9 (t, J(,)=. z,, -),.0 (t, J(,)=. z,, -),.9 (t, J(,)=. z,, -),.0-. (m,, -),.0-. (m,, -) ppm. - -

192 Experimetal part C-M (0 Mz, CDCl, C): =99.0 (C-), 0. (C-),.0 (Carom, double peak),. (Carom),. (Carom),. (C-),.0 (C-),.9 (C-),. (C-),. (C-),.9 (C-) ppm. EA Calcd: C,.;,.;,.0. Foud: C,.;,.0;,.90. MS (Io trap, EI): m/z (%) = (, [M]), (00), 9 (0), (), (). Sythesis of -[(E)--chloro-pet--eyl]pyrrolidie--thioe (ad) ad was prepared accordig to method A, usig the followig amouts: u(cod)[met] ( mg, 0.0 mmol), molecular sieves (00 mg) ad pyrrolidie--thioe (0. mg,.00 mmol), tri-- S 9 Cl octylphosphie ( L, 0. mmol) ad -chloro--petye (0 L,.0 mmol). The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford the product as a yellowish oil (: mixture with the Z-isomer,, mg, %). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),. (dt, J(,)=.,. z,, -),.-.9 (m,, -),.-. (m,, - 9),.0 (t, J(,)=.9 z,, -),.-.0 (m,, -),.0-. (m,, -),.-. (m,, -) ppm. C-M (0 Mz, CDCl, C): =99. (C-),. (C-),. (C-),. (C),. (C-),.0 (C-9),. (C-),. (C-), 9. (C-) ppm. EA Calcd: C,.0;,.9;,.. Foud: C,.;,.0;,.09. MS (Io trap, EI): m/z (%) = 0 (, [M]), (9), (00), 9 (), (). - -

193 Experimetal part Sythesis of -[(E)-hept--e--yyl]pyrrolidie--thioe (ae) ae was prepared accordig to method A, usig the followig amouts: u(cod)[met] (. mg, 0.0 mmol), molecular sieves (00 mg), pyrrolidie--thioe (0. mg,.00 mmol), tri-- S 9 0 octylphosphie ( L, 0.0 mmol) ad,-heptadiye (9 L,.0 mmol). The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford the product as a yellowish oil (: mixture with the Z-isomer,.9 mg, %). -M C-M (00 Mz, CDCl, C): =.0 (d, J(,)=. z,, -),.0 (dt, J(,)=.,. z,, -),. (t, J(,)=. z,, -),.0 (t, J(,)=.0 z,, -), (m,, -, -, -9),.9 (t, J(,)=. z,, -),.-. (m,, -) ppm. (0 Mz, CDCl, C): =99. (C-),. (C-),. (C-),. (C0),. (C-),. (C-),. (C-),.9 (C-),. (C-9), 9. (C-),. (C-) ppm. EA Calcd: C,.;,.;,.. Foud: C,.;,.9;,.. MS (Io trap, EI): m/z (%) = 9 (00, [M]), (0), (), 0 (), (). Sythesis of -[(E)--methoxy-propeyl]pyrrolidie--thioe (af) S af was prepared accordig to method A, usig the followig amouts: u(cod)[met] ( mg, 0.0 mmol), molecular sieves (00 mg), pyrrolidie--thioe (0. mg,.00 mmol), tri-- octylphosphie ( L, 0. mmol), -methoxy--propye (9 L,.0 mmol). The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford the product as a yellowish oil (: mixture with the Z-isomer, 0. mg, %). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),. (dt, J(,)=.,. z,, -),.9 (d, J(,)=. z,, -),.9 (t, J(,)=. z,, -),.9 (s,, -),.0 (t, J(,)=. z,, - ),.0-. (m,, -) ppm. - -

194 Experimetal part C-M (0 Mz, CDCl, C): =0. (C-), 9. (C-),. (C-), 0.9 (C),.9 (C-),. (C-),. (C-), 9. (C-) ppm. EA Calcd: C,.;,.;,.. Foud: C,.9;,.9;,.. MS (Io trap, EI): m/z (%) = (, [M]), 0 (0), (00), (), (). Sythesis of -[(E)--trimethylsilayloxypropeyl]pyrrolidie--thioe (ag) S ag was prepared accordig to method A, usig the followig amouts: u(cod)[met] (. mg, 0.0 mmol), molecular sieves Si (00 mg), pyrrolidie--thioe (0. mg,.00 mmol), tri-- octylphosphie ( L, 0.0 mmol) ad trimethyl(propargyloxy)silae (0 L,.0 mmol). The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford the title product as a yellow solid (9: mixture with the Z-isomer, 0. mg, %). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),. (dt, J(,)=.,. z,, -),. (d, J(,)=. z,, -),.9 (t, J(,)=. z,, -),.0 (t, J(,)=. z,, -),.0-. (m,, -), 0.0 (s, 9, -) ppm. C-M (0 Mz, CDCl, C): =0. (C-),. (C-),. (C-),. (C),. (C-),. (C-), 9. (C-), 0. (C-) ppm. EA Calcd: C,.;,.;,.. Foud: C,.9;,.;,.0. MS (Io trap, EI): m/z (%) = 9 (, [M]), (0), 0 (0), (00), (9). Sythesis of -[(E)-trimethylsilayl-viyl]pyrrolidie--thioe (ah) ah was prepared accordig to method A, usig the followig amouts: S u(cod)[met] ( mg, 0.0 mmol), molecular sieves (00 mg) ad Si pyrrolidie--thioe (0. mg,.00 mmol), tri--octylphosphie ( L, 0. mmol) ad trimethylsilylacetylee ( L,.0 mmol). The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford the title product as a white solid (: mixture with the Z-isomer,. mg, %). - -

195 Experimetal part (00 Mz, CDCl, C): =. (d, J(,)=. z,, -),.0 (d, -M J(,)=. z,, -),. (t, J(,)=. z,, -),.0 (t, J(,)=. z,, -),.0 (m,, -), 0. (s, 9, -) ppm. (0 Mz, CDCl, C): =0. (C-),.9 (C-),. (C-),. (C- C-M ),.0 (C-), 9. (C-), 0.9 (C-) ppm. EA Calcd: C,.;,.9;,.0. Foud: C,.;,.0;,.9. (Io trap, EI): m/z (%) = 99 (, [M]), (), (), (00), 9 (). MS Sythesis of -[(E)--methyl-buta-,-dieyl]pyrrolidie--thioe (ai) S ai was prepared accordig to method A, usig the followig amouts: u(cod)[met] ( mg, 0.0 mmol), molecular sieves (00 mg), pyrrolidie--thioe (0. mg,.00 mmol), tri--octylphosphie ( L, 0. mmol), -methyl--bute--ye (9 L,.0 mmol). The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford the product as a yellow solid (: mixture with the Z-isomer,. mg, %). -M (00 Mz, CDCl, C): =.0 (d, J(,)=. z,, -),.0 (d, J(,)=. z,, -),.0 (d,, -),. (m,, -),. (m,, -),. (m,, -),.9 (s,, -) ppm. C-M (0 Mz, CDCl, C): =00. (C-), 0. (C-),. (C-), 0.9 (C),. (C-),. (C-),. (C-), 9. (C-),. (C-) ppm. EA Calcd: C,.;,.;,.. Foud: C,.;,.;,.. MS (Io trap, EI): m/z (%) = (, [M]), (00), (9), 9 (), (). Sythesis of -[(E)--pheylviyl]pyrrolidie--thioe (aj) S aj was prepared accordig to method A, usig the followig amouts: u(cod)[met] (. mg, 0.0 mmol), molecular sieves 9 (00 mg), pyrrolidie--thioe (0. mg,.00 mmol), tri-- 0 octylphosphie ( L, 0.0 mmol) ad pheylacetylee (0 L,.0 mmol). The residue - -

196 Experimetal part was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford the product as a yellow solid (: mixture with the Z-isomer, 9.9 mg, 9%). -M (00 Mz, CDCl, C): =. (d, J(,)=.9 z,, -),. (m,, arom),.0 (m,, arom),. (m,, arom),. (d, J(,)=.9 z,, -),.9 (m,, -),.09 (m,, -),. (m,, -) ppm. C-M (0 Mz, CDCl, C): =00. (C-),. (C-),. (Carom),. (Carom),. (Carom),.9 (Carom),. (C-),. (C-),. (C-), 9. (C-) ppm. EA Calcd: C, 0.9;,.;,.9. Foud: C,.0;,.;,.. MS (Io trap, EI): m/z (%) = 0 (, [M]), (), (00), (), (). Sythesis of -[(E)--pheylviyl]piperidie--thioe (bj) 0 bj was prepared accordig to method A, usig the followig amouts: u(cod)[met] ( mg, 0.0 mmol), molecular sieves (00 mg), piperidie--thioe (. mg,.00 mmol), tri-- octylphosphie ( L, 0. mmol) ad pheylacetylee (0 L, 9 S.0 mmol). The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :9) to afford the product as a yellow solid (: mixture with the Z-isomer, 9. mg, 9%). -M (00 Mz, CDCl, C): =. (d, J(,)=.9 z,, -),. (d,, arom),. (t,, arom),. (d,, arom),. (d, J(,)=.9 z,, -),. (m,, -),. (m,, -), (m,, -),.-.0 (m,, -) ppm. C-M (0 Mz, CDCl, C): =0. (C-),.9 (C-),. (Carom),. (Carom),. (Carom),. (Carom),. (C-),. (C-),.9 (C-),. (C-), 0. (C-) ppm. EA Calcd: C,.;,.9;,.. Foud: C,.9;,.;,.. MS (Io trap, EI): m/z (%) = (, [M]), (), 0 (00), 9 (), (). - -

197 Experimetal part Sythesis of -[(E)--pheylviyl]azepae--thioe (cj) cj was prepared accordig to method A, usig the followig amouts: u(cod)[met] ( mg, 0.0 mmol), molecular sieves (00 mg), -azepie--thioe (9. mg,.00 mmol), S tri-- octylphosphie ( L, 0. mmol) ad pheylacetylee (0 L, 9.0 mmol). The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford the product as a yellow solid (0: mixture with the Z-isomer, 9. mg, %). -M (00 Mz, CDCl, C): =.9 (d, J(,)=. z,, -),.0 (d,, arom),. (t,, arom),. (t,, arom),. (d, J(,)=. z,, -),.0 (m,, -),. (m,, -),. (m,, -,, ) ppm. C-M (0 Mz, CDCl, C): =0. (C-),. (C-),. (Carom),. (Carom),. (Carom),. (Carom),. (C-), 0. (C-),. (C-),. (C-),. (C-),.0 (C-) ppm. EA Calcd: C,.;,.;,.0. Foud: C,.0;,.;,.0. MS (Io trap, EI): m/z (%) = (, [M]), (00), 9 (), 9 (), (9). Sythesis of -pheyl--[(e)--pheylviyl]thioacetamide (dj) dj was prepared accordig to method A, usig the followig S amouts: u(cod)[met] ( mg, 0.0 mmol), molecular sieves (00 mg), -pheyl-thioacetamide (. mg,.00 mmol), tri octylphosphie ( L, 0. mmol) ad pheylacetylee (0 L,.0 mmol). The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford the product as a yellow solid (0: mixture with the Z-isomer,. mg, 9%). -M (00 Mz, CDCl, C): =9.0 (d, J(,)=. z,, -),.0-. (m,, arom),.-.9 (m,, arom),. (d, J(,)=. z,, -),.9 (s,, -) ppm

198 Experimetal part C-M (0 Mz, CDCl, C): =00. (C-),. (Carom),. (C-),. (Carom), 0. (Carom), 9. (Carom),. (Carom),. (Carom),. (Carom),. (Carom), 0. (C-),.0 (C-) ppm. EA Calcd: C,.;,.9;,.. Foud: C,.0;,.;,.. MS (Io trap, EI): m/z (%) = (, [M]), (), (00), (), 9 (0). Sythesis of -pheyl--[(e)--pheylviyl]thiobezamide (ej) ej was prepared accordig to method A, usig the followig S amouts: u(cod)[met] (. mg, 0.0 mmol), molecular sieves 0 (00 mg), -pheyl-thiobezamide (. mg,.00 mmol), tri- -octylphosphie ( L, 0.0 mmol) ad pheylacetylee (0 L,.0 mmol). The residue was purified by colum 9 chromatography (silica gel, ethyl acetate/hexae :) to afford the product as a yellowsolid (0: mixture with the Z-isomer, 0.0 mg, 9%). -M (00 Mz, CDCl, C): =.-. (m,, arom),. (d,, -) ppm. C-M (0 Mz, CDCl, C): =0. (C-),. (Carom),. (Carom),. (C-0),. (Carom), 9. (Carom),. (Carom),. (Carom),. (Carom),. (Carom),.9 (Carom),. (Carom),. (Carom),. (C-) ppm. EA Calcd: C, 9.9;,.;,.. Foud: C, 9.;,.;,.. MS (Io trap, EI): m/z (%) = (0, [M]), 0 (00), (9), (), (). Sythesis of -methyl--[(e)--pheylviyl]thiobezamide (fj) fj was prepared accordig to method A, usig the followig amouts: u(cod)[met] ( mg, 0.0 mmol), molecular sieves (00 mg), -methyl-thiobezamide (. mg,.00 mmol), tri -octylphosphie ( L, 0. mmol) ad pheylacetylee S 9

199 Experimetal part (0 L,.0 mmol). The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford the product as a yellow solid (: mixture with the Z-isomer, 0. mg, 9%). -M (00 Mz, CDCl, C): =.-. (m,, arom),. (d,, -),.9 (s,, -), ppm. C-M (0 Mz, CDCl, C): =0. (C-),.9 (Carom),. (C-),. (Carom), 9. (Carom),. (Carom),. (Carom),. (Carom),.0 (Carom),. (Carom),. (C-),. (C-) ppm. EA Calcd: C,.;,.9;,.. Foud: C,.;,.9;,.. MS (Io trap, EI): m/z (%) = (9, [M]), (0), (), (00), (). Sythesis of -[(E)--pheylviyl]-,-oxaziae--thioe (gj) gj was prepared accordig to method A, usig the followig 9 S amouts: u(cod)[met] ( mg, 0.0 mmol), molecular sieves (00 mg),,-oxaziae--thioe (. mg,.00 mmol), tri-- octylphosphie ( L, 0. mmol) ad pheylacetylee (0 L, 0.0 mmol). The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford the product as a yellow solid (: mixture with the Z-isomer, 9. mg, %). -M (00 Mz, CDCl, C): =.0 (d, J(,)=.0 z,, -),.-. (m,, arom),. (t,, arom),.9 (d, J(,)=.0 z,, -),. (t,, -),.0 (t,, -),. (tt,, -) ppm. C-M (0 Mz, CDCl, C): =. (C-),. (C-),. (Carom),. (Carom),. (Carom),.9 (Carom), 0. (C-),. (C-),. (C-),. (C-) ppm. EA Calcd: C,.;,.9;,.9. Foud: C,.0;,.;,.. MS (Io trap, EI): m/z (%) = 9 (00, [M]), 9 (), 0 (), 0 (9), ()

200 Experimetal part Sythesis of -[(Z)-hex--eyl]pyrrolidie--thioe (aa) aa was prepared accordig to method B, usig the followig amouts: u(cod)[met] (. g, 0.0 mmol), pyrrolidie--thioe t K (0. mg, (. mg, 0.0 mmol), S.00 mmol), bis(dicyclohexylphosphio)methae (. mg, 0.0 mmol) ad -hexye 9 (9 L,.0 mmol). The residue was purified by colum chromatography 0 (silica gel, ethyl acetate/hexae :) to afford the product as a yellowish oil (: mixture with the E-isomer, mg, %). -M (00 Mz, CDCl, C): =. (d, J(,)=9. z,, -),.0-. (dt, J(,)=9. z,, -),.9 (t,, -),.00 (t,, -),.0-. (m,, -, ),.-. (m,, -, 9), 0. (t,, -0) ppm. C-M (0 Mz, CDCl, C): =0. (C-),.,.,. (C-),. (C-),. (C-),. (C-),. (C-9),. (C-),. (C-0) ppm. EA Calcd: C,.;, 9.;,.. Foud: C,.9;, 9.;,.. MS (Io trap, EI): m/z (%) = (, [M]), (00), 9 (), (), (0). Sythesis of -[(Z)-,-dimethyl-but--eyl]pyrrolidie--thioe (ab) ab was prepared accordig to method B, usig the followig amouts: S t u(cod)[met] (. g, 0.0 mmol), K (. mg, 0.0 mmol), pyrrolidie-thioe (0. mg,.00 mmol), bis(dicyclohexylphosphio)methae (. mg, 0.0 mmol) ad,-dimethyl--butye ( L,.0 mmol). The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae :) to afford the product as a yellowish oil (: mixture with the E-isomer,. mg, 0%). -M (00 Mz, CDCl, C): =. (d, J(,)=9. z,, -),. (d, J(,)=9. z,, -),. (t,, -),.9 (t,, -),.0-. (m,, -),.0 (s, 9, -) ppm. C-M (0 Mz, CDCl, C): =0. (C-),. (C-),. (C-),. (C),. (C-),. (C-), 9. (C-), 0. (C-) ppm. EA Calcd: C,.;, 9.;,.. Foud: C,.;, 9.;,

201 Experimetal part MS (Io trap, EI): m/z (%) = (, [M]), (), (), (), (00). Sythesis of -[(Z)--pheylbut--e--yl]pyrrolidie--thioe (ac) ac was prepared accordig to method B, usig the followig amouts: u(cod)[met] (. mg, pyrrolidie--thioe 0.0 mmol), t K (0. mg, (. mg, 0.0 mmol),.00 mmol), S bis(dicyclohexylphosphio)methae (. mg, 0.0 mmol) ad -pheyl-- 9 butye ( L,.0 mmol). The residue was purified by colum 0 chromatography (silica gel, ethyl acetate/hexae :) to afford the product as a yellowish oil (: mixture with the E-isomer,. mg, %). -M (00 Mz, CDCl, C): =. (d, J(,)=. z,, arom),.-. (m,, arom),. (d, J(,)=9. z,, -),.-. (dt, J(,)=9. z,, -),. (t,, -),.0 (t,, -),.-. (m,, -, ),. (m,, -) ppm. C-M (0 Mz, CDCl, C): =99. (C-),. (C-),. (Carom),.0 (Carom),. (Carom),. (Carom),.9 (C-),. (C-),. (C-),. (C-),. (C-),. (C-) ppm. EA Calcd: C,.;,.;,.0. Foud: C,.;,.;,.9. MS (Io trap, EI): m/z (%) = (, [M]), (00), 9 (), (), (0)

202 Experimetal part. Markovikov additio of secodary amides to alkyes Sythesis of -(-pheyl-viyl)-pyrrolidi--oe (aa) A ove-dried flask was charged flushed with itroge. Subsequetly, dry toluee (.0 ml), tri--butyl phosphie ( μl, 0.09 mmol), pyrolidioe ( mmol) ad -hexye (.00 mmol) were added via 9 0 syrige. The resultig solutio was stirred for h at 00 C, ad the poured ito a aqueous sodium bicarboate solutio (0 ml). The resultig mixture was extracted repeatedly with 0 ml portios of ethyl acetate, the combied orgaic layers were washed with water ad brie, dried with magesium sulfate, filtered, ad the volatiles were removed i vacuo. The residue was purified by colum chromatography (silica gel, ethyl acetate/hexae) to yield the eamide aa (9.0 mg, %). The idetity ad purity of the products were cofirmed by ad C M spectroscopy, ad mass. -M (00 Mz, CDCl, C): =.-.9 (m,, arom),. (s,, -),. (s,, -),. (t, J(,)=.0 z,, -),.9 (t, J(,)=. z,, -),.0 (dt, J(,)=.,.9, -) ppm. C-M (0 Mz, CDCl, C): =. (C-),. (C-),.9 (Carom),.0 (Carom),.0 (Carom),.0 (Carom), 0.9 (C-), 9. (C-),. (C-),. (C-) ppm. MS (Io trap, EI): m/z (%) = (00, [M]), 9 (), (9), (9), ()

203 Experimetal part... Procedure for the mechaistic studies ESI-MS experimets Experimets with [u(cod)(met)]: A ove-dried flask was charged with [u(cod)(met)] (. mg, 0.0 mmol) ad -dimethylamiopyridie (.9 mg, 0.0 mmol) ad the flask was flushed with itroge. Subsequetly, dry toluee (.0 ml), pyrrolidi--oe (a, μl,.00 mmol) ad tri--butylphosphie ( μl, 0.0 mmol) were added via syrige. The resultig solutio was stirred for h at 00 C. A sample of the reactio mixture was take for ESI-MS experimet (Figure, Figure ad Figure ). Ites. x0 MS, 0.-.9mi #(-) Ites. x0 00 m/z MS, 0.-.9mi #(-) Figure : ESI-MS experimet with [u(cod)(met)] u(pc)(c)(c0), M, m/z

204 Experimetal part Ites. x0 00 m/z MS, 0.-.9mi #(-) u(pc)(c)(c0), M, m/z m/z (% relative to peak at.) = 0. (), 0. (), 0. (), 09. (), 0. (),. (),. (00),. (),. (),. (),. (), Calc.: 0. (), 0. (), 0. (), 09. (), 0. (),. (9),. (00),. (),. (),. (0),. (). Figure : amplified area of the sigal at m/z =. ad simulated spectra of [(-P)u(C)(C0)]

205 Experimetal part Ites. x m/z MS, 0.-.9mi #(-) u(pc)(c), M, m/z m/z (% relative to peak at 9.) =. (),. (),. (), 9. (), 90. (), 9. (), 9. (00), 9. (0), 9. (), 9. (), 9. (), Calc.:. (),. (),. (), 9. (), 90. (), 9. (9), 9. (00), 9. (9), 9. (), 9. (), 9. (). Figure : amplified area of the sigal at m/z = 9. ad simulated spectra of [(-P)u(C)]

206 Experimetal part Experimets with ucl : A ove-dried flask was charged with potassium carboate (. mg, 0.0 mmol), ad a stock solutio cotaiig rutheium(iii) chloride hydrate (. mg, 0.0 mmol), -dimethylamiopyridie (.9 mg, 0.0 mmol) ad acetoe (.0 ml). The acetoe was removed i vacuo ad the flask was flushed with itroge. Subsequetly, dry toluee (.0 ml), water ( μl, 0.0 mmol), pyrrolidi--oe (a, μl,.00 mmol) ad tri-butylphosphie ( μl, 0.0 mmol) were added via syrige. The resultig solutio was stirred for h at 00 C. A sample of the reactio mixture was take for ESI-MS experimet. Ites. x0 MS, 0.-.mi #(-0) Ites. x0 00 m/z MS, 0.-.mi #(-0) Figure 9: ESI-MS experimet with ucl u(pc)(c)(c0)0, M, m/z

207 Experimetal part Ites. 00 m/z MS, 0.-.mi #(-0) u(pc)(c)(c0), M, m/z m/z (% relative to peak at.) = 0. (), 0. (), 0. (), 09. (0), 0. (),. (),. (00),. (),. (),. (),. (0), Calc.: 0. (), 0. (), 0. (), 09. (), 0. (),. (9),. (00),. (),. (),. (0),. (). Figure 0: amplified area of the sigal at m/z =. ad simulated spectra of [(-P)u(C)(C0)]

208 Experimetal part Ites. x0 00 m/z MS, 0.-.mi #(-0) u(pc)(c)(c0)0, M, m/z m/z (% relative to peak at 9.) =. (),. (),. (), 9. (9), 90. (), 9. (), 9. (00), 9. (), 9. (), 9. (), 9. (), Calc.:. (),. (),. (), 9. (), 90. (), 9. (9), 9. (00), 9. (9), 9. (), 9. (), 9. (). Figure : amplified area of the sigal at m/z = 9. ad simulated spectra of [(-P)u(C)]

209 Experimetal part.. Procedure for the i situ M A mm M tube was charged with [u(cod)(met)] (. mg, 0.0 mmol) ad DMAP (9. mg, 0.0 mmol). The tube was sealed with a rubber septum ad purged with alteratig vacuum ad itroge cycles. Tri--butylphosphie (0 µl, 0.0 mmol) ad toluee-d ( ml) were added via syrige ad placed i a ultrasoic bath for mi to give a clear yellow solutio. Spectra h/p (Figure ad Figure ) were recorded at C. The sample was heated to 00 C for mi. At C, spectra h/p (Figure ad Figure ) were recorded. Pyrrolidi--oe (. µl, 0.0 mmol) was added via syrige, the mixture was shake ad spectra h/p (Figure ad Figure ) were recorded at 00 C. Spectra h/p (Figure ad Figure 9) are the referece spectra ([u(cod)(met)] (. mg, 0.0 mmol) ad tri--butylphosphie (0 µl, 0.0 mmol) i toluee-d ( ml)) at C Toluol-d Chemical Shift (ppm) Figure : spectrum h: -M (00. Mz, toluee-d)

210 Experimetal part 0-0 Chemical Shift (ppm) Figure : spectrum p: P-M (.0 Mz, toluee-d) Toluol-d Chemical Shift (ppm) Figure : spectrum h: -M (00. Mz, toluee-d)

211 Experimetal part Chemical Shift (ppm) Figure : spectrum h: -M (00. Mz, toluee-d) Chemical Shift (ppm) Toluol-d Figure : spectrum p: P-M (.0 Mz, toluee-d)

212 . 0.0 Experimetal part Chemical Shift (ppm) Figure : spectrum p: P-M (.0 Mz, toluee-d) Chemical Shift (ppm) Figure : spectrum h: -M (00. Mz, toluee-d) Toluee d 0

213 Experimetal part Chemical Shift (ppm) Figure 9: spectrum p: P-M (.0 Mz, toluee-d)

214 Experimetal part.. Procedure for the D-experimets Sythesis of -deutero--hexye I a flame-dried, itroge-flushed flask, a small amout of sodium hydride D (0% i mieral oil) ( mg, 0 mmol) was added while stirrig to 99% D0 (0 ml, mol). -exye ( mmol, 9. ml) was added, ad the two-phase mixture was stirred for h. The operatio was repetead. The layers were separated uder a itroge atmosphere. The orgaic layer was dried over molecular sieves, filtered, ad distilled to afford -deutero--hexye (9%). -M (00 Mz, CDCl, C): =. (t, J(,)=.0 z,, ),.-. (m,, ), 0. (t, J(,)=.0 z,, ) ppm. C-M (0 Mz, CDCl, C): =.0 (t, J(C,D)=.0 z, ). (t, J(C,D)= z, ), 0.,.,.0,. ppm. Sytheses of -[ -deutero-(z)-hex--e--yl]succiimide (aa*) A ove-dried flask was charged with [u(cod)(met)] (. mg, 0.0 mmol), scadium triflate (9. mg, 0.0 mmol) ad succiimide (99. mg,.00 mmol) ad flushed with argo. Subsequetly, tri--butylphosphie ( μl, 0.0 mmol), -deutero--hexye (9 μl,.0 mmol), ad dry DMF D 9 (.0 ml) were added via syrige. The resultig colorless solutio was 0 stirred for h at 0 C, the volatiles were removed i vacuo. The residue was purified by colum chromatography (silica gel, ethyl acetate/hexaes :) to afford the title product (. mg, %) as yellowish oil. -M (00 Mz, CDCl, C): =. (t, J(,)=. z,, -),. (s,, -, ),. (dt, J(,)=.,,. z,, -),.-.0 (m,, -, 9), 0. (t, J(,)=. z,, -0) ppm. C-M (0 Mz, CDCl, C): =. (C-, ),. (C-),. (t, J(C,D)= z, C-), 0. (C-),. (C-, ),. (C-),. (C-9),. (C-0) ppm. D-M ( Mz, CCl ud CDCl): =,9 (s, D) ppm

215 Experimetal part Sytheses of -[ -deutero-(z)-hex--e--yl]pyrrolidioe (aa*) 0 A ove-dried flask was charged with [u(cod)(met)] (. mg, mmol) ad DMAP (,90 mg, 0,0 mmol) ad flushed with argo. Subsequetly, tri--butylphosphie ( μl, 0.0 mmol), -deutero-- hexye (9 μl,.0 mmol), ad dry toluee (.0 ml) were added via D syrige. The resultig colorless solutio was stirred for h at 00 C, the volatiles were removed i vacuo. The residue was purified by colum chromatography (silica gel, ethyl acetate/hexaes :) to afford the title product (9. mg, %) as yellowish oil. -M (00 Mz, CDCl, C): =. (m,, -),. (m,, -),. (m,, -),.0 (m,, -, ),. (m,, -, 9), 0. (m,, -0) ppm. C-M (0 Mz, CDCl, C): =. (C-),. (t, J(C,D)= z, C-),. (C-),. (C-),. (C-),. (C-), 0. (C-),.9 (C-9),. (C),. (C-0) ppm. D-M ( Mz, CCl ud CDCl): =. (s, D) ppm. Sytheses of -[ -deutero-(z)-hex--e--yl]bezamide (9aa*) A ove-dried flask was charged with [u(cod)(met)] (. mg, 0.0 mmol) ad dcypb (, mg, 0, mmol), Yb(Tf) 0 (, mg, 0,0 mmol) ad beazamide (. mg, mmol) ad D 9 flushed with argo. Subsequetly, -deutero--hexye (9 μl,.0 mmol), ad dry DMF (.0 ml) were added via syrige. The resultig colorless solutio was stirred for h at 0 C, the volatiles were removed i vacuo. The residue was purified by colum chromatography (silica gel, ethyl acetate/hexaes :) to afford the title product (. mg, 9 %) as yellowish oil. -M (00 Mz, CDCl, C): =.90 (s,, -),. (d, J(,)=. z,, arom),. (t, J(,)=. z,, arom),. (m,, arom),.0 (t, J(,)=. z,, -),.0 (q, J(,)=. z,, -),. (m,, -9),. (m,, -0), 0. (m,, -) ppm

216 Experimetal part C-M (0 Mz, CDCl, C): =. (Carom),. (Carom),. (Carom),. (Carom),.9 (Carom), 0. (t, J(C,D)=9 z, C-),, (C-),. (C-),. (C-9),. (C-0),. (C-) ppm. D-M ( Mz, CCl ud CDCl): =,00 (s, D) ppm

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224 Curriculum Vitae Sept. 00 Feb D. work at the Techische Uiversität Kaiserslauter (sice st of September 00) uder the supervisio of Prof. Lukas J. Gooße. Ja Jue 00 Diploma work uder the supervisio of Prof. Geeviève Balme (Lyo, Frace): Sythesis of -aalogous Pteruloe (a atural fugicide). Sept Dec 00 Master (Diploma) i Lyo (Frace): rgaic Sythesis ad chemistry of bioactive molecules. April 00 - Jue 00 Traiig period at the Johaes Guteberg Uiversität Maiz (Germay). Sept April 00 Maîtrise de Chemie at the Uiversité de Bourgoge i Dijo (Frace). Sept Jue 00 Licece de Chemie at the Uiversité de Bourgoge i Dijo (Frace). Sept Jue 00 DEUG de Chemie at the Uiversité de Bourgoge i Dijo (Frace). Sept. 000 Immatriculatio at the Uiversité de Bourgoge i Dijo (Frace) for a Chemistry degree. Sept Jue 000 Secodary School i Lycée Clos-Maire de Beaue (Beaue, Frace). Sept. 9 - Jue 99 Primary School i Ecole Sait-Yves (Autu, Frace), ad Collège Moge (Beaue, Frace). Jue 9 Bor i Autu (Frace) - -