Reformatsky Route

The first step is considered to involve the condensation of the Reformatsky reagent with benzonitrile to yield the Zn salt 3B. C-alkylation by bromoacetate, followed by ring closure, is believed to lead to the hitherto elusive key intermediate 6A, a pyrrolinone ester. Condensation with a second molecule of benzonitrile and subsequent cyclization of intermediate 7, which could be isolated and was also mentioned by Farnum, finally affords the DPP 2. 

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Acid (23) could be made by dehydration of alcohol (24), but this 1,5-difunctionalised compound cannot be made by a Michael reaction because the alcohol is tertiary. Instead a malonate disconnection on (23) gives an alkyl halide which comes from (25) by FGI. The Reformatsky route gives (25). 

In 1988, new investigations on the Reformatsky route were published. Synthesis of cTudal intermediates and crossing experiments using two different benzo-nitriles strongly indicated that the reaction did not proceed via an oxidative dimerization mechanism and the intermediate 4. Instead, it could be shown, that the lactam S is formed during the reaction, and a new mechanism was postulated involving a sequential build up of the DPP via the pyrrolinone ester 6A as the crucial intermediate (Scheme 11-3). 

Shamekhi investigated a pathway for the synthesis of high performance diketopyrrolopyrrole pigments (DPPs) 27 using diethyl succinate xmder microwave irradiation in tire presence of IL [BMIM][Bp4] as reaction medium. The author also compared the obtained results with those of conventional metiiod as well as Reformatsky route under microwave irradiation (Scheme 2) [79]. 

Ethyl chlorodifluoroacetate has been used in a silicon-induced Reformatsky-Claisen reaction of allyl chlorodifluoroacetates in the presence ot zinc as a route to 2,2-difluoro unsaturated acids [( S] (equahon 58) When this methodology is applied to chlorodifluoropropargylic esters, the corresponding allenic esters are formed [SS]... 

The intramolecular cyclization route to p-lactams still provides interest. P-Amino esters (obtained by a Reformatsky-type reaction of an imine and bromoacetates derived from chiral alcohols) are cyclized by the action Grignard reagents to 4-substituted P-lactams with impressive e.e. <96TL4095>. A similar approach through a Reformatsky-type reaction uses tricarbonyl(Ti -benzaldimine)chromium complexes and ultrasound <96T4849>. 3-Methyl-azetidin-2-ones (obtained from 3-amino-2-methylpropionates) have been resolved and their... 

Alternatively, a macrolactonization route can be followed, where formation of the C6-C7 aldol by chromium-Reformatsky and esterification are interchanged. However, this route is longer and less selective in formation of the C6 and C7 stereocenters, giving both syn products [50, 86-88]. 

In order to overcome the problem, the inverse strategy was followed. Chromium-Reformatsky reaction between 76-derived C8 aldehyde and a 68-derived ester afforded all four possible C6,C7-diastereomers, which can be independently processed to epothilone D5 diastereomers (including the natural one) by the macrolactonization route. 

Three approaches to zinc enolates are commonly adopted the process associated to the classical Reformatsky reaction is based on the insertion of Zn(0) into the carbon—halogen bond of an a-haloester. Two additional routes involve (i) transmetallation of a lithium enolate with a Zn(II) salt (Section V.A) and (ii) the transition-metal-catalysed conjugate addition of diethylzinc to Michael acceptors (Section V.B). 

Electrochemistry offers alternative routes to the preparation of active zinc for the Reformatsky reactions, for instance exploiting the cathodic reduction (—0.8 V v.v SCE) of ZnBr2 in acetonitrile containing Bu4N+BF4 as supporting electrolyte53. 

Even more interesting turned out to be the Sml2 -promoted intramolecular Reformatsky reaction. It opens a route to medium and large ring systems, as shown by the examples reported in Table l79a e. 

A nickel-catalysed electro-Reformatsky reaction has been previously presented (Section . . , Figure 5)57. Based on a formally related catalytic cycle, a nickel-catalysed 3-component route to /J-arnino esters and amides has been proposed (equation 41). To a CH2CI2 solution of an aldehyde and an aromatic amine are successively added dimethylz-inc, methyl bromoacetate (la) and bistriphenylphosphine nickel dichloride. After 1-3 h at rt, products were isolated in very high yield, and this procedure was exploited for the preparation of a chemical library of 64 members, using 4 aldehydes, 4 cr-haloesters and 4 substituted anilines58. 

En route to 1 -/J-methyl carbapenem antibiotics, the reaction of 31 with Reformatsky reagents 78 has been explored it likely involves preliminary formation of the intermediate 79, which then undergoes nucleophilic addition to give 2-(4-oxoazetidin-2-yl)-propanoic acid derivatives 80 (equation 48). 

A closely related reaction between 1 -arylpyrrolidine-2-thiones 96 and diethyl bromoma-lonate97 under Reformatsky conditions afforded l-arylpyrrolidin-2-ylidenemalonates 98, which, upon polyphosphoric acid (PPA) induced cyclization, opened a route to pyrrolo[l, 2-a] quinolones 99145, tricyclic analogues of quinolone antibiotics (equation 58). 

This material is available commercially, or can be prepared by palladium(O)-catalysed carbonylation [281] of bromotrifluoropropene. Carbonylation routes to (trifluoromethyl)propanals were described in the same paper. A route to higher 2-trifluoromethyl 2-alkenoates was described by the Ciba-Geigy group [282] Reformatsky reaction of methyl 2,2-dichloro-3,3,3-trifluoropropionate with aldehydes in the presence of acetic or trifluoroacetic anhydride resulted in elimination forming the alkenoate in situ (Eq. 99). 

Several older syntheses are based on o-hydroxyacetophenones but these routes generally offer little or no advantage over other methods. The Reformatsky reaction has been used to prepare 3- and 3,4-substituted coumarins (44JIC109) and the Kostanecki-Robinson reaction may yield coumarins instead of or as well as the chromone (see Section 2.24.3.4.1 for further discussion). 

This strategy did not appeal to Ruppert and White9 who preferred to make 36 by a chain extension route. A Reformatsky reagent gave 39 and dehydration and alkylation of malonate gave 36. Treatment with oxalyl chloride (COCl)2 followed by reaction with diazomethane gave... 

This template removal was encountered during studies to prepare the avP3 integrin antagonist (16). The route that emerged used phenylglycinol as a template in a Reformatsky approach (Scheme 2.25). Unfortunately, lead tetraacetate had to be used to remove this template, so there are still problems to be overcome in this area.93... 

The Reformatsky reactions of methyl or ethyl bromoacetate with 4-acetoxy-,2,24 4-benzyloxy-,2 4-tetrahydropyranyloxy-,2 4-chloro-,8 and 4,4-dimethoxy-2-butanone1418 have been carried out. The adducts were converted to mevalonolactone by hydrolysis and, in the case of the acetal reactant, by appropriate reduction and oxidation procedures. The same Reformatsky-type syntheses of mevalonolactone have also been performed using the lithium and magnesium carbanions of acetate esters5,19 25 26 and the dianion of acetic acid28,27 instead of the usual zinc reagent. The intramolecular Reformatsky reaction of 4-(bromoacetoxy)-2-butanone gives mevalonolactone directly.28 A related route to mevalonolactone involves boron trifluoride-catalyzed cycloaddition of ketene to 4-acetoxy-2-butanone followed by hydrolysis.183... 

Like /3-hydroxyaldehydes and -ketones, jS-hydroxyesters and -acids are readily dehydrated. The unsaturated compounds thus obtained (chiefly a,]3-unsaturated) can be hydrogenated to saturated carboxylic acids. Extended in this way, the Reformatsky reaction is a useful general method for preparing carboxylic acids, paralleling the aldol route to alcohols. 

Using this way to protect the carboxyl group, A. I. Meyers (Colorado State University) has recently opened an elegant route to alkylated acetic acids—or, by modification along Reformatsky lines, to j3-hydroxy esters. 

An important application of the Reformatsky reaction is the conversion of P-hydroxy esters to a, P-unsaturated esters. Acid-catalyzed dehydration usually leads to a mixture of a, P- and P, y-unsaturated esters. However, conversion of the initially formed p-hydroxy esters to their corresponding acetates by treatment with acetyl chloride, followed by base-catalyzed dehydration with NaOEt, produces conjugated esters in high purity. This sequence of reactions provides an alternative route to the Homer-Wads worth-Emmons olefmation of ketones (see Chapter 8). 

Nitriles and esters are also unreactive in Smh-promoted Barbier reactions. A very useful procedure for lactone synthesis has been developed making use of this fact. Treatment of 7-bromobutyrates or 8-bro-movalerates with Smh in THF/HMPA in the presence of aldehydes or ketones results in generation of lactones through a Barbier-type process (equations 25 and 26). This nicely complements the -metaUo ester or homoenolate chemistry of organosamarium(III) reagents described above (Section 1.9.2.1), and also the Reformatsky-type chemistry promoted by Sml2 (Section 1.9.2.3.2). Further, it provides perhaps the most convenient route to 7- and 8-carbanionic ester equivalents yet devised. 

Interest in the synthesis of compounds containing the P(CHaC02R) grouping continues, and routes involving the reactions of chlorophosphines with sodium enolates of acetate esters and Reformatsky reagents have been reported. A range... 

A Reformatsky type of reaction has been utilized in a novel route to /3-lactams, by allowing carbodi-imides and a-bromo-esters to react in the presence of zinc metal.Cyanuric chloride has been shown to activate the... 

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