Passarini Reaction Passerini reaction three-component coupling reaction

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Garry Ellis
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1 Passarini eaction The Passerini reaction is a convenient route to amide esters and is considered to be a three-component coupling reaction. When propionic acid was heated with acetone and tert- butylisonitrile,, the product was α-propanoyloxy amide 11. A useful modification of the Passerini reaction used trifluoroacetic acid. Hydrolysis of the trifluoroacetyl ester with aqueous sodium carbonate led to isolation of the α-hydroxyamide (14) in 69% yield. 1 H N t-bu H t-bu N!C 11 H Ph CH t-bu N!C F 3 C aq Na 2 C 3 Ph CF 3 C 2 H, 50 C Ph NHt-Bu CHCl NHt-Bu

2 Alkyne Anions 2 3 fundamental reaction types C!C: H H C Br H H C C!C- S N 2 (alkylation) C!C: C!C- 1 acyl addition C!C- acyl substitution C!C: Plus acid/base; carbon dioxide; epoxides

3 Alkyne Anions 3 Acetylene and other terminal alkynes have an acidic hydrogen atom (C C-H), and they are weak acids, pk a about The conjugate base of an alkyne is an alkyne anion (a carbanion. older literature, acetylide), and it is generated by reaction with a strong base. A carbon nucleophile that reacts with alkyl halides or sulfonate esters via an S N 2 sequence to give disubstituted alkynes such as 36. C C H BASE C C: M 1 X C C 1 Tf TBS PMB, BuLi, THF PMB DMPU, 65 C 37 Tf = triflate = S 2 S 2 CF 3 38 TBS

4 Acidity of Alkynes 4 Acid Conjugate Base pk a C!CH C!C: 25 2 C=CH 2 2 CH=CH: 36 H 3 C CH 3 H 3 C CH 2 H C!C H Ph- H- n-bu- Cl(CH 2 ) 4 - HC!C(CH 2 ) NEt 3, DMF D 2 C!C D 39 elative Acidity

5 Acyl Addition: Alkynyl Alcohols 5 1. CH 3 C!C: Na +, DMF 2. aq. H + H Do not see many acyl substitution reactions with alkyne anions

6 Grignard eagents 6 3 fundamental reaction types MgX H H C Br H H C S N 2 (alkylation) MgX acyl addition acyl substitution MgX Plus acid/base; carbon dioxide; epoxides

7 Preparation of Grignard eagents The so-called Grignard reagent (MgX) is formed by the reaction of magnesium (Mg(0)) with an alkyl or aryl halide, usually in an ether solvent. A simple example is the reaction of bromoethane with magnesium in ether to give 51. The C-Mg bond in the Grignard reagent generates a negative dipole on carbon, so it is a nucleophilic carbon. 7!+ C Br!" CH 3 CH 2 Br + Mg ether CH 3 CH 2 MgBr!" C Mg!+ Br 51

8 Barbier eaction 8 The reaction was first discovered in 1899 by Barbier, who was Grignard's mentor, although its nature was not well understood at the time. A ketone, Mg and halide were all mixed together in what is now known as the Barbier reaction or Barbier coupling. In subsequent work, Grignard took the reaction much further. He premixed magnesium metal and the halide, characterized the resulting product as MgX, and showed how MgX reacted with many functional groups (particularly with ketones and aldehydes). 1. Mg, ether, I 2. H H

9 Schlenk Equilibrium 9 In solution, a Grignard reagent (see 56) is not the monomeric MgX. The MgX structure (56) usually drawn for a Grignard reagent is in equilibrium with dimethylmagnesium (57) and MgBr 2 as well as 58, in what is called the Schlenk equilibrium. The Grignard reagent equilibrium is more complex in ether than it is in THF. The equilibrium favored MgBr in ether, although there is a mixture. X Mg Mg 2 MgX 2 Mg + MgX 2 X X 2 Mg 2 X 2 Mg X Mg

10 Aggregation State 10 In ether, the monomeric species is largely of MgX with lesser amounts of 2 Mg and MgX 2. In other work, it was concluded that the Grignard reagent exists primarily as the MgX species in ether, THF or triethylamine but the composition varies in each solvent. Ether solutions of Grignard reagents are stable if protected from moisture and air. A 2 N solution of CH 3 MgI in ether was stored in a sealed tube for 20 years, and shown to have virtually the same concentration of Grignard reagent as when originally sealed. X X Mg Mg Mg Mg X X Mg X Mg X Mg X Et 2 61 Et 2 Et 2

11 Solvent Stabilization 11 To form a Grignard reagent, an ether solvent stabilizes the Grignard reagent by forming a Lewis acid-lewis base chargetransfer complex such as 62. Coordination with ether assists in the initial magnesium insertion reaction, and minimizes decomposition of the Grignard reagent via disproportionation. For vinyl and aryl halides stronger Lewis base is required, both to assist the insertion and to stabilize the organometallic and, the more basic solvent THF is used when aryl or vinyl Grignard reagents must be prepared. C Mg X C Mg X

12 Grignards are BASES Grignard reagents are strong bases - the conjugate acid is an alkane MgX H Grignard reagents react with weak acids such as water, alcohols, amines, terminal alkynes. Grignard reagents react with oxygen. 12 MgX + HH H + HMgX MgX MgX + 2 MgX 2 MgX 2 H 64 65

13 Grignards with Alkyl Halides 13 For Grignard reagents derived from simple aliphatic, aryl, or vinyl halides that react with aliphatic alkyl halides, the yield of coupling product (- 1 ) is usually poor. nly reactive Grignard reagents such as allylmagnesium halides react with alkyl halides that are also highly reactive (io( iodomethane,, allyl bromide, benzyl bromide) to give good yields of a coupling product. MgCl Cl THF-HMPA Disproportionation is common. 71 MgBr EtMgBr CH 2 CH 3 ether CH 2 CH 3 52% 48% 44% 31% 5% MnCl %

14 Kharasch eaction 14 Kharasch showed the effectiveness of several transition metals that promoted the coupling reaction of phenylmagnesium bromide and chlorodiphenylmethane (68). Transition metal catalyzed coupling reaction is known as the Kharasch reaction. Ferric chloride is a very effective catalyst for the cross coupling of alkyl halides with aryl Grignard reagents, when tetramethylethylenediamine (TMEDA) is used as a stoichiometric additive. PhMgBr M + Ph 2 CH Cl Ph 2 CH Ph + Ph 2 CH CHPh 2 M 68 No catalyst 0 CoCl 2 82 FeCl 3 63 Cu 2 Cl 2 30 MnCl % 69 % 70 [eprinted with permission from Sayles, D.C.; Kharasch, M.S. J. rg. Chem. 1961, 26, Copyright 1961 American Chemical Society

15 Grignard eagents + Cuprous Salts Cuprous [ Cu(I) ] salts are readily available, and when mixed with Grignard reagents give excellent yields of cross-coupled products with very little disproportionation. 15 MgBr + Cu I Br Cu + MgBr 2 Cu + 1 slow Br Cu I Br MgBr I, THF, CuI 30 C 97% (Z/E = 90:10) (Z/E = 88:12)

16 Grignard Cuprates Li 2 CuCl 4 is prepared by reaction of LiCl and CuCl 2 in THF) to catalyze the coupling of Grignard reagents and alkyl halides. Note that the coupling occurred with the unprotected hydroxyl group in Br H MgBr Li 2 CuCl 4, THF 95% 77 (CH 2 ) 9 H

17 Ketones & Aldehdyes: Acyl Addition 17 + Mg-X Mg X Mg X Mg X Mg 81 + MgX 2 Mg MgX H 3 + H Mg X X HC 82 + MgBr Ar Mg X H 83 Ar = 4-methoxyphenyl H Ac Cl MgCl, THF 78 C! 0 C H H Ac Cl

18 Acid Derivatives: Acyl Substitution Acyl addition gives a tetrahedral intermediate, and loss of the leaving group (X) gives a ketone to complete the acyl substitution. 18 The ketone product competes with the acid derivative for MgX. X 1 MgX MgX 1 X 1 1 MgX Cl + BrMg MgX % H 3 + H 1 1

19 Acid Derivatives: Acyl Substitution 19 If the intermediate ketone is unreactive to nucleophilic substitution due steric hindrance or peculiar electronic factors (diisopropyl( ketone and phenyl-tert- tert-butyl ketone are both sterically hindered), the ketone can usually be isolated. An excellent method for converting an acid chloride to a ketone employs transition metal catalysts such as ferric chloride, in conjunction with low reaction temperatures. n-c 6 H 13 H 1. n-c 4 H 9 MgBr, cat + Cl n-c 6 H 13 n-c 4 H n-c 9 6 H 13 n-c 4 H H 3 + n-c 4 H n-c 9 6 H 13 catalyst = NNE, 60 C catalyst = 2% FeCl 3, 60 C % 76% 4% 3% 60% 15% H

20 Acid Derivatives: Excess Grignard 20 Addition of excess MgX forces the reaction towards the alcohol product. Note that Ac also reacts to release alcohol Ac 6 MgBr, ether, 0 C Bn 80% H H

Carboxylic Acid Derivatives and Nitriles

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