Allyl Metals. oxidative addition. transmet. + M(n) η 1 -allyl. n = 0, 1. base. X η 3 -allyl. Nuc. insertion. insertion. M(n+2)X MgX + MX2 MX 2

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1 Allyl tals Virtually all transition metals can form η 3 -allyl complexes, but few are synthetically useful. Pd is most widely studied and has broad utility. Allyl complexes of h, Ir, u and Mo are becoming more important and display reactivity differences that are complimentary to Pd. These are usually quite stable (but still reactive), and their formation is typically preferred over other posibilities. X + M(n) oxidative addition transmet. M(n+2)X MgX + MX2 n = 0, 1 η 1 -allyl base MX MX 2 X η 3 -allyl / M + insertion / M //uc MX uc M / M + C insertion / / MX M

2 Allyl tals nce formed the allyl palladium intermediate is available for a wide range of subsequent transformations. X phosphine ligands are normally used uc (net retention) LPd(0) (S 2 or S 2') oxidative addition (inversion) Pd(II) L X X Pd(II) L BE uc Pd(II)X + Pd(0)L 2 Pd X uc "reductive elimination" (inversion) insertion X LPd(0) X Pd(II) Pd(II)L 2 L, + +L X (retention) (net inversion) Pd(II) L M transmetallation + Pd(0)L

3 The electrophile Pd Catalyzed Allylic Alkylation A wide range of leaving groups have been used all with varying rates of reaction and synthetic utility/ease of installation. X Pd(0) Pd + X X = Br, Cl, Ac, C, P(Et) 2, S,,, 3 +, 2, S 2, C most commonly used selective reactions possible: Cl > C 2 > Ac >> Pd basic Pd basic + C 2 Pd not basic

4 The electrophile regioselectivity Pd Catalyzed Allylic Alkylation Because Pd proceeds through η 3 -allyl intermediate, it does not matter which isomer is used as the starting material. ther metals may behave differently. X Pd(0) Pd(0) PdX X With Pd nucleophiles usually attack at less-substituted end. Can vary with ligands and other metals. PdX uc major uc uc minor Stereoselectivity With chiral substrates high levels of stereoselectivity are observed. verall retention of configuration is the result of a "double inversion". 1 X 2 Pd(0) (inversion) 1 PdX 2 uc 1 (inversion) uc or uc

5 The nucleophile Pd Catalyzed Allylic Alkylation Typical carbon nucleophiles are relatively soft, stabilized carbanions. The anion can be pregenerated, or made in situ in the presence of an added base. Some of the leaving groups can serve as this base. Z Y Z, Y = C 2, C, S 2, C, 2 PdX Z Y Z Y Intramolecular examples are kown and work well. Can be used to make rings from members. Silyl enol ethers can also be used. TMS 2 2 PdX

6 Pd Catalyzed Allylic Alkylation 2 C cat. Pd(P 3 ) 2 C C 2 4 C 2 ( )C(C 2 ) 2 TF, 95% J. Am. Chem. Soc. 1981, 103, complete chirality transfer 2 S Pd(Ac) 2 P(i-Pr) 3 2 S S 2 S 2 TBS 26-membered ring TBS Tetrahedron Lett. 1986, 27, C 5 11 C C Ac 2 C 5 11 C 5% Pd(P 3 ) 4 TF, rt Ac 2 C C 2 C C 5 11 C 67% C Tetrahedron Lett. 1981, 22, EWG controls regioselectivity

7 Allylic Alkylation Stereoselectivity Acyclic allyl Pd intermediates are dynamic. This has important consequences with regard to regio- and stereoselectivity. uc Ac racemic Pd(0)L* (S 2) PdL* σ-allyl diastereomeric, different rxn rates PdL* π-allyl fast rxn (S 2) PdL* uc high ee σ-allyl PdL* σ-allyl PdL* π-allyl uc slow rxn PdL* σ-allyl π σ π isomerization results in "enantioface exchange" disubtituted acyclic both enantiomers give same intermediate 1 1 Pd(0)L* 1 1 uc 1 1 Ac racemic PdL* one isomer (enantiotopic ends) uc high ee

8 Allylic Alkylation Stereoselectivity The π σ π isomerization pathway is not available to cyclic systems, but asymmetric induction has been acheived. Erosion of enantioenrichment is observed with chiral substrates and achiral catalysts at high metal loadings. PdL * PdL * PdL * L n Pd "diastereoface exchange" Pd(II)L is leaving group for Pd(0)L attack PdL *

9 Allylic Alkylation Stereoselectivity Desymmetrization of meso substrates is quite common. In these cases, the chiral catalyst can choose between the enantiotopic leaving groups. Z () (S) Ac Pd(0)L* Ac Ac Pd(0)L* Ac () (S) Z Y Z Y (achiral) Z Y Y The remaining allylic leaving group is available for a second reaction with an achiral catalyst. Ac Z Y Pd(0)L uc uc Z Y uc uc Ac Z Y Pd(0)L uc Z Y otice the tether alters the regioselectivity

10 Enantioselective Allylic Alkylation Several different ligands have been used to impart asymmetry. The Trost ligands have demonstrated the widest utility. P 2 2 P (S,S)-Trost Ligand eviews: Chem. ev. 1996, 96, 395. Acc. Chem. es. 2006, 39, 747.

11 I Enantioselective Allylic Alkylation C 2 (±) C a. 10% PdCl 2 (C 3 C) 2 C 2, PMP, DMF, 50 ºC b. Ac 2, Et 3, DMAP, C 2 Cl 2 81% yield, 87% ee J. Am. Chem. Soc. 2002, 124, % Pd 2 (dba) 3, 2.7% (,)-Trost C 2 Cl 2, rt, 97%, dr 92/8 C Ac C I Bz Bz 2 S 2 (η 3 -allyl-pdcl) 2 (S,S)-Trost ac 3, TF 87%, >99% ee S 2 J. Am. Chem. Soc. 1998, 120, 1732

12 Enantioselective Allylic Alkylation 2.5% Pd 2 (dba) 3 7.5% Trost Cs 2 C 3, TF, rt 87%, 82% ee th J. Am. Chem. Soc. 1996, 118, Cl 0.026% [(allyl)pdcl] % Ligand ac(c 2 ) 2, TF 93% yield, 95% ee 2 C C 2 1. a, Δ 2. KI, I 2, ac 3 recrystallization 3. DBU, TF Mn(C) 3 Angew. Chem. Int. Ed. 2002, 41, >99.9% ee P 2-Biph ligand t-bu Pd 2 (dba) 3 BIAP C 2 Tsallyl TF, rt 80%, 86% ee Ts J. rg. Chem. 1997, 62, 3263.

13 Allylic Alkylation via Transmetallation Used less frequently than other nucleophiles. Allylic acetates are not great substrates, but can work. Transmetallation is slowed due to tight coordination of acetate, and reductive elimination is slower with allyl groups than other alkyl/aryl groups. eactivity acheived with polar solvents (DMF), "ligandless" Pd [Pd 2 (dba) 3, PdCl 2 (C) 2 ], and excess LiCl (facilitate transmetallation). rganostannanes work well (transmetallation facile relative to B() 2 ). eaction occurs on less substituted end, with net inversion of configuration (.E. occurs with renention). TES TES TES Sn 3 + Ac Pd 2 (dba) 3 LiCl, DIEA MP, 40 ºC 86% TES TES TES configuration maintained J. Am. Chem. Soc. 2003, 125, skipped diene

14 Allylic Alkylation via Transmetallation Works better with allylic chlorides/carbonates and vinyl epoxides. Chlorides reactive enough that phosphines can be used. Pd cat 1: PdCl 2 (C) 2, Pd(cod)Cl 2, Pd 2 (dba) 3, Pd(bpy)Cl 2 2 C 2 C SnBu 3 + Pd cat 1 2, DMF, rt Pd cat 2 2 C 2 C 2 C 2 C SnBu 3 up to 93% Pd cat 2: Pd(P 3 ) 4, Pd(dba)(dppf), Pd(dba)(P 3 ) 2, Pd(dba)(As 3 ) 2 Tetrahedron Lett. 1996, 37, , DMF, rt (with a salt of malonate) up to 92% Bn S SnBu 3 Pd 2 (dba) 3, P(2-furyl) 3 Bn S Cl TF, 65 ºC C 2 C 2 Tetrahedron Lett. 1988, 29, C 2 C 2

15 eactions With oncarbon ucleophiles The nucleophile does not have to be carbon-based. eteroatom nucleophiles also work. itrogen nucleophiles: 1º, 2º amines (not 3 ), amides, imides, sulfonamides, and azide (as TMS 3 ) all work. Stereo- and regioselectivity parallels malonates. Almost invariably ends up on less-substituted end. + Cl Pd(P 3 ) 4 DMS/TF 53% Cl J. Chem. Soc., Perkin Trans , 391 C 2 + Ts Pd 2 (dna) 3 (S)-binbpo TF 80% yield, 86% ee Ts J. rg. Chem. 1997, 62, 3263.

16 Intramolecular aminations possible as well. eactions With oncarbon ucleophiles Pd(P 3 ) 4 TMG Br C, 45 ºC 88% Br J. Am. Chem. Soc. 1999, 121, Ac ote: reaction in the prsence of aryl bromide Ac Pd(P 3 ) 4 dppb 2 TF, 70 ºC 89% Ac J. Am. Chem. Soc. 1982, 104, Ac

17 eactions With oncarbon ucleophiles ot as many examples with oxygen nucleophiles. enols work well. Glycosylations at the anomeric postions are known. Cyclizations with aliphatic alcohols work. Water and hydroxide are unknown, but 3 Si can serve as an alternative. Bz TBDPS rg. Lett. 1999, 1, a, 3 SnCl 20% Pd(Ac) 2 /P 3 TF, 60 ºC, 77% TBDPS 8:1 dr ote: in this case the nucleophile attacks at more hindered position. 2% Pd 2 (dba) 3 4% dppb, 8% P 3 3 Si 3 Si C 2 TF, rt, 64% Tetrahedron Lett. 1993, 34, C 2

18 eactions With oncarbon ucleophiles Formate salts: eductions can be carried out by using ammonium formates or allyl formates. The hydride is delivered from same side as Pd (net inversion). Appears to prefer delivery of hydride to more substituted side. Pd 2 (dba) 3 chiral lig. Ac Et 3, C 2 Bn PMB Pd 2 (dba) 3 PBu 3 C 2, Et 3 dioxane, rt 96% C 2 Et Bn PMB C 2 Et Tetrahedron Lett. 1996, 37, Ar (±) TF/dioxane 86%, 90% ee Tetrahedron 2000, 56, Ar TBS TBS Pd(acac) 2, PBu 3 Pd(acac) 2, PBu 3 C 2 TF, rt, 82% TBS C 2 TF, rt, 57% TBS J. rg. Chem. 1992, 57, 1326.

19 Insertion eactions with Allyl Pd nce formed, allylpalladium intermediates can also undergo insertion reactions with alkenes, alkynes and carbon monoxide much like we discussed in the previous section. Computational experiments have shown that the insertion occurs on the η 3 -allyl complex, but the η 1 -allyl complex coudl also be invoked. Intramolecular reactions are quite common direct insertion cannot do insertion on olefin Pd(0) π σ B..E. Ac Pd Ac Pd Ac alkene/alkyne insertion C PdAc transmetallation C 2 C 2 10% Pd 2 (dba) 3 P 3 C (1 atm) C 2 C 2 Ac, 45 ºC 81% elv. Chim. Acta 1991, 74, 465.

20 Insertion eactions with Allyl Pd Ac S 2 S 2 + Cl 5% Pd 2 (dba) 3 20% P 3 a, TF, 25 ºC 68% Ac S 2 S 2 5% Pd 2 (dba) 3 20% P 3 Ac, 80 ºC 81% elv. Chim. Acta 1991, 74, 465. S 2 S 2 2 C 2 C C 2 C 2 10% Pd 2 (dba) 3 50% P(2-furyl) 3 Ac, 110 ºC 2 C 2 C C 2 C 2 Ac J. rg. Chem. 1991, 56, Ac 10% Pd(Ac) 2 20% P 3 2 S ab 4 anisole, 60 ºC 80% 2 S Tetrahedron Lett. 1991, 32, 2545.

21 Decarboxylative Allylation A unique way to generate ketone enolates (and other anions) in a regiospecific manner and with no base. Chiral lignads allow enantioselective reactions to occur even with racemic starting materials. Allyl Enol Carbonates Silyl Enol Ethers Pd 2 (dba) 3, P 3 TMS Pd 2 (dba) 3 CCl 3 dppe dioxane, rt diallyl carbonate TF, 82% yield 76% yield Tetrahedron Lett. 1983, 24, Chem. Lett. 1983, Allyl b-ketoesters Enol Acetates Pd(P 3 ) 4 DMF, rt 67% yield J. Am. Chem. Soc. 1980, 102, Pd 2 (dba) 3 CCl 3 dppe, SnBu 3 dioxane, Tetrahedron Lett. 1983, 24, % yield

22 Decarboxylative Allylation The allylation occurs on the same side the enolate forms on. Scrambling of enolate position does not occur. Pd 2 (dba) 3, P 3 dioxane, rt Pd 2 (dba) 3, P 3 dioxane, rt Tetrahedron Lett. 1983, 24, only product only product Pd(0)L n PdL n + C 2 eview: Chem. ev. 2011, 111, "tight ion pair"? reacts to quickly to isomerize or protonate

23 Decarboxylative Allylation This approach has also been extended to other substrates I rg. Lett. 2008, 10, a. Pd(P 3 ) 4, Ag 2 S 4 DMF, 20 ºC, 5 min b. Et 3, µw, 150 ºC 91% yield I intermediate 2 C 2 allyl Bn Pd(P 3 ) 4 2 Bn C 2 Cl 2, 23 ºC 92%, dr 6.5:1 rg. Lett. 2010, 12, C 2 Et Pd 2 (dba) 3 rac-biap toluene, 110 ºC Pd(P 3 ) 4 toluene, 75 ºC 80% J. Am. Chem. Soc. 2005, 127, C 2 Et J. Am. Chem. Soc. 2007, 129,

24 Enantioselective reactions with ketones. Decarboxylative Allylation Pd 2 (dba) 3 (2.5 mol%) (S)-t-BuPX (6.25 mol%) TF, 25 C racemic 80-99% yield, 81-91% ee 2 P (S)-t-BuPX Angew. Chem., Int. Ed. 2005, 44, Pd 2 (dba) 3 (2.5 mol%) ligand (5.5 mol%) dioxane, 23 C 93% yield, 99% ee J. Am. Chem. Soc. 2005, 127, P 2 2 P ligand

25 Allylations With ther tals Pd is not the only metal to perform synthetically useful allyl complexes. thers include: Mo, Ir, h, u. While these have been investigated, their develpment is not nearly as extensive as Pd. While the overall transformations and mechanisms are quite similar, these alternate metals often behave much differently with respect to regioselectivity and stereoselectivity. Mo(0) The regioselectivity of nucleophile attack is quite dependent on catalyst structure/ligands, but reaction at more-substituted end is common. h(i), u(0 & II), Ir(I) Alkylation of allylic acetates and carbonates occur at more-substituted position. Alkoxides and enolates can be used if Cu salt if formed. Bn + 2 C (S) hcl(p 3 ) 3, P() 3 LiMDS, CuI, 90%, dr 37:1 J. Am. Chem. Soc. 2004, 126, Bn C 2 t-bu + 1. BuLi, CuI 2. [Ir(cod)Cl] 2. L* 87%, >98% ee Chem. Commun. 2006, 1968.

26 Allylations With ther tals With some catalyst systems the nucelophile adds to the carbon bearing the leaving group, regardless of the substitution "memory effect" likely due to an η 1 -allyl intermediate and not a η 3 -allyl intermediate. C 2 hcl(p 3 ) 3 P() 3 C 2 C ac(c 2 ) 2 i-pr i-pr a 1 =, 2 = i-pr b 1 = i-pr, 2 = J. Am. Chem. Soc. 1998, 120, from a: 97 : 3, 83% from b: 3 : 97, 87% 5% [ucl 2 (p-cymene)] 2 10% P 3 C 2 (C 2 2 ), LMDS Ac toluene 5% [ucl 2 (p-cymene)] 2 10% P 3 C 2 (C 2 2 ), LMDS ul n η 1 -allyl? 2 C 99:1 C 2 Ac toluene Chem. Commun. 2007, ul n η 1 -allyl? 2 C 99:1 C 2

27 Trimethylenemethane Intermediates Pd(0) complexes react with bifunctional allylic groups to form unstable (and uncharacterized) trimethylenemethane intermediates. Similar complexes have been formed and characterized with other metals, but they are too stable to be synthetically useful. nucleophilic Ac TMS Pd(0)L n L n Pd elecrophilic trimethylenemethane intermediate zwitterionic undergoes [3+2] reactions with electrophiles Unknown if cycloaddition is concerted. If stepwise, then ring closure is faster than bond rotation (stereochemistry in reaction partner conserved). 2 C Ac TMS 2% Pd(P 3 ), 80 ºC 78% yield, 3:1 dr C 2 trans product Tetrahedron Lett. 1986, 27, C 2 Ac TMS 2% Pd(P 3 ), 80 ºC 69% yield, >50:1 dr C 2 cis product

28 Trimethylenemethane Intermediates Substituted precursors also react well and give highly regioselective reactions, regardless of the starting postion of the acetate and TMS groups. Ac TMS Pd(0)L n L n Pd L n Pd J. Am. Chem. Soc. 1985, 107, 721. appears to react through this isomer irregardless of group identity Intramolecular reactions and enantioselective reactions possible TMS Ac S 2 C 2 Pd(Ac) 2 P(-i-Pr) 3 3 SnAc C 3, 110 ºC 83% yield C 2 S 2 DBU C 2 S 2 J. Am. Chem. Soc. 1996, 118, :1 dr

29 Trimethylenemethane Intermediates Aldehydes and ketones also react. Unsymmetrical interedmaites can be poorly regioselective. Lewis acid additive can improve reactivity and regioselectivity. TMS Ac 5% Pd(Ac) 2 -DIBAL 40% P(2-C 6 4 ) 3 10% In(acac) 4 C 3, 110 ºC 70% yield Ac TMS 5% Pd(Ac) 2 -DIBAL 40% P 3 10% In(acac) 4 C 3, 110 ºC 81% yield sterically crowded, electron-rich catalyst J. Am. Chem. Soc. 1992, 114, action with aziridines gives piperidines Ts Ac TMS 10% Pd(Ac) 2 60% P(-i-Pr) 3 20% BuLi TF, 65 ºC Ts 44-82% yield J. rg. Chem. 2003, 68, 4286.

30 Trimethylenemethane Intermediates Trimethylenemethane intermediates are also thought to be generated from methylenecyclopropanes and have similar reactivity. TMS + M(0) TMS Intramolecular ractions also work well. 2 C J. Am. Chem. Soc. 1996, 118, C 6 11 Pd 2 (dba) 3 P(i-Pr) 3, 110 ºC 75% yield 2 C C 6 11