Amide Reformatsky reagents

Most recently, Bentz and co-workers established that the Pd-catalyzed a-arylation of esters and amides, using Reformatsky reagents and the corresponding aryl bromides, can be successfully performed under microwave conditions.417 The reported yields are somewhat lower than those reported by Hartwig 414 however, this approach does not require the use of Q-phos and can be considered as valuable alternative for a-arylation. 

As a part of ongoing efforts to synthesize a potent, orally active anti-platelet agent, xemilofiban 1 [1], development of an efficient chemoenzymatic process for 2, the chiral yS-amino acid ester synthon (Fig. 1) was proposed. The scheme emphasized the creation of the stereogenic center as the key step. In parallel with the enzymatic approach, chemical synthesis of the / -amino acid ester synthon emphasized formation of a chiral imine, nucleophilic addition of the Reformatsky reagent, and oxidative removal of the chiral auxiliary. This chapter describes a selective amida-tion/amide hydrolysis using the enzyme Penicillin G amidohydrolase from E. coli to synthesize (R)- and (S)-enantiomers of ethyl 3-amino-5-(trimethylsilyl)-4-pen-tynoate in an optically pure form. The design of the experimental approach was applied in order to optimize the critical reaction parameters to control the stereoselectivity of the enzyme Penicillin G amidohydrolase. 

Functionalization of pyridines from the corresponding bromo substrates has been achieved by use of Reformatsky reagents and a microwave-accelerated reaction procedure [65]. This approach utilizes Pd(0)-catalyzed a-arylation of esters and amides (Scheme 10.29). The Reformatsky reagent was prepared by microwave irradiation of tert-butyl bromoacetate or dibenzyl bromoacetamide with Zn in THF for 5 min at 100 °C. 

The modifications of the Gilman-Speeter reaction include the activation of zinc by tri-methylsilyl chloride (TMSCl) and the application of lithium ester enolate" or lithium thioester enolate as the substitute for the traditional Reformatsky reagent. In these modifications, it was found that TMSCl-activated zinc is much more effective in promoting the reaction between ethyl bromoacetate and Schiff bases. In addition, in the presence of a chiral ether ligand, the reaction between lithium ester enolate and imines affords 0-lactams of high enantiomeric excess, probably due to the formation of a ternary complex reagent. " The enantioselectivity and reactivity of the ternary complex depend on the size and nature of the lithium amide used. For example, the lithium amide from 2,2,6,6-tetramethylpiperidine (LTMP) is unfavorable for this reaction." ... 

Palladium complexes derived from stericaUy encumbered electron-rich phosphines such as QPhos (362) are well-suited catalysts for the reaction of aryl bromides with zinc enolates of esters [259] or amides [260] and also of aryl chlorides with the Reformatsky reagents [261]. As exemplified with the efficient formation of 361 (Scheme 4.82), only mono-arylation is observed, and the... 

O-Alkyl lactic acid esters are useful reagents for the stereoselective construction of erythro- and t/ireo-a-methyl-a,/3-dihydroxy-esters (Scheme 37). " In the case of (47), R = R = Me, the major product is erythro- (48), but when in (47), R = CH2Ph and R = 2,6-t-butyl-4-methyl, the main product is threo-(49). Yields are excellent, and the stereoselectivity is greater than 97%. Reasonable enantiomeric excesses have been achieved during a study of the Reformatsky and amide base-mediated condensations of chiral acetates with ketones. ... 

---