Coupling Reformatsky reagent

A palladium catalyst can also be used to couple Reformatsky reagents... 

Several techniques have been used to activate the zinc metal and improve yields. For example, pretreatment of zinc dust with a solution of copper acetate gives a more reactive zinc-copper couple.168 Exposure to trimethylsilyl chloride also activates the zinc.169 Wilkinson s catalyst, RhCl(PPh3)3 catalyzes formation of Reformatsky reagents from diethylzinc, and reaction occurs under very mild conditions.170... 

At the other extreme of reactivity, 2-bromopyridine had to be transformed into the corresponding iodide to achieve good efficiency for the coupling reaction [14], For example, D-altro-2-(2,4 3,5-di-0-benzylidenepentitol-l-yl)-6-bromopyridine (17) was first converted to the corresponding iodide 18, which was then allowed to react with the Reformatsky reagent to give adduct 19. 

Improvement to the Reformatsky reactions was achieved (53) by the use of a highly activated zinc - silver couple dispersed on the surface of graphite. T reatment of protected aldono-1,4-lactones 10b or 25b and 1,5-lactones 51a or 51b with a Reformatsky reagent prepared from a-haloesters or alkyl 2-(bromomethyl)acrylates resulted in the formation of the corresponding 3-or 4-glyculofuranos (or pyranos)onates 49a,b-50a,b, or 52a,b, respectively, under mild conditions (— 40 ° to 00) and in very good yields. Ethyl 2-deoxy-2-fluoro (and 2-bromo)-a-D-wa o-3,6-furanos-3-octulosonate derivatives were also obtained. 

Organozinc reagents, including the Reformatsky reagents, are extensively used in transition metal catalysed coupling reactions with aryl halides or triflates, vinyl halides, and allylic halides or acetates, as reviewed by Erdik156. Nickel and palladium complexes are... 

A synthesis of the monomeric unit 128 of a peptide nucleic acid analog (PNA) offers an example of stereospecific cross-coupling of a Reformatsky reagent with (Z)-vinylic iodide 126. The coupling reaction of the preformed Reformatsky reagent prepared in dimethoxymethane (methylal) with 126 is carried out using 8% of Pd(PPh3)4 in DMPU as the solvent at 65 °C to afford 127 (equation 70)161. 

Reactions of different organometallic species with thiocarbonyi compounds have been extensively investigated and been shown to proceed both in a carbophilic and a thiophilic fashion. However, other reactions can be observed simultaneously such as reduction, double addition, coupling, deprotonation and formation of enesulfides1,226,423. A complex pattern appears in the reactions of thioketones with lithium or Grignard reagents424. The first application of Reformatsky reagents in C—C bond formation by reaction with... 

The reaction of aryl and alkenyl halides with the Reformatsky reagent 237 in polar solvents affords a-arylacetates [105], Iodides of heterocyclic compounds such as pyridine, quinoline and pyrimidine react smoothly with Reformatsky reagents. The cross-coupling of 237 with 4-iodo-2,6-dimethyl- and 2-iodo-4,6-dimethylpyrimidine (236) occurs smoothly to form 238. But no reaction of 5-iodo-2,4-dimethylpyrimidine (239) takes place [106],... 

The Reformatsky reagents, i.e. zinc enolates of esters, undergo Ni catalysed cross-coupling with aryl halides.53 The Ni catalysed reaction of arylzincs with a-bromoacetates also permits a-arylation of esters54 (Scheme 11.13). However, a-alkenylation of enolates of ketones, aldehydes, and esters has been less satisfactory. Its further development is clearly desirable. Alternatively, a-alkenylation of a-iodoenones in conjunction with conjugate reduction discussed earlier should be considered. 

The insight that zinc ester enolates can be prepared prior to the addition of the electrophile has largely expanded the scope of the Reformatsky reaction.1-3 Substrates such as azomethines that quaternize in the presence of a-halo-esters do react without incident under these two-step conditions.23 The same holds true for acyl halides which readily decompose on exposure to zinc dust, but react properly with preformed zinc ester enolates in the presence of catalytic amounts of Pd(0) complexes.24 Alkylations of Reformatsky reagents are usually difficult to achieve and proceed only with the most reactive agents such as methyl iodide or benzyl halides.25 However, zinc ester enolates can be cross-coupled with aryl- and alkenyl halides or -triflates, respectively, in the presence of transition metal catalysts in a Negishi-type reaction.26 Table 14.2 compiles a few selected examples of Reformatsky reactions with electrophiles other than aldehydes or ketones.27... 

An indium Reformatsky reagent has been prepared from 2-(chlorodifluoroacetyl)furan, which couples with aldehydes (Equation (84)).334 A similar Reformatsky-type reaction between some /3-aminovinyl chlorodifluoromethyl... 

Coupling reaction of Reformatsky reagent with allyl halide was reported (73, 526). 

Couplings between Reformatsky reagents and aromatic halides are catalyzed by Ni(PPh3)4 " or Pd(PPh3)4, " " with DMF, NMP or HMPA being used as the essential cosolvents. While the Ni-cata-lyzed reaction can be applied to aromatic chlorides, bromides and iodides, the Pd-catalyzed reaction is useful only for iodides. Compatibility of the free carboxylic acid may especially be noted (equation 109). 

P-Amino esters. Substitution of Al-protected benzenesulfonylamines by Reformatsky reagents that are generated by treating a-bromoesters with a Zn-Cu couple in dichloromethane represents a new entry to the p-amino esters. A second route involves addition of the Reformatsky reagents to aldimines derived from o-anisidine. No P-lactams are formed due to steric hindrance. 

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