Reformatsky type reaction

The reaction of an a-halo carbonyl compound with zinc, tin, or indium together with an aldehyde in water gave a direct cross-aldol reaction product (Eq. 8.90). A direct Reformatsky-type reaction occurred when an aromatic aldehyde reacted with an a-bromo ester in water mediated by zinc in low yields. Recently, it was found that such a reaction mediated by indium was successful and was promoted by son-ication (Eq. 8.91). The combination of BiCT-Al, CdCl2-Sm, and Zn-Et3B-Et20 is also an effective mediator. Bismuth metal, upon activation by zinc fluoride, effected the crossed aldol reaction between a-bromo carbonyl compounds and aldehydes in aqueous media. The reaction was found to be regiospeciflc and yn-diastereoselective (Eq. 8.92).232 

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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... 

Asymmetric intramolecular Reformatsky reactions/ The bromoacetates (1) of (3-hydroxy ketones undergo a Reformatsky-type reaction when treated with Sml2 to give (3-hydroxy-8-valerolactones (2). These products are useful in their own... 

Activation. Erdik1 has reviewed the methods used since 1970 for activation of zinc and of organozinc reagents. Although chemical activation is still useful, ultrasound activation is being used increasingly. Thus sonic activation allows use of ordinary zinc for cyclopropanation of alkenes with CH2I2 in 67-97% yield and for Reformatsky-type reactions at room temperatures. 

The application of lithiumtrimethylsilyl acetate for the C-l elongation of aldonolactones has been examined (73). Although the reagent had been successfully used for the alkenation of lactone carbonyl groups (74), in the case of aldonolactones 10b or 25b only insignificant yields of the alkenes, but 30 - 40% of the lactols 49a or 50a, were obtained (73). However, these lactols, alternatively prepared in good yields by a Reformatsky-type reaction (53,54), were readily eliminated to the desired alkenes by simple treatment with methanesulfonyl chloride-triethylamine at 0°. Thus, from 49a or 50a separable E,Z mixtures (76a and 76b, or 77a and 77b, respectively) were obtained in good yields (73). 

The previously described diisobutyl telluride/titanium(IV) system (see Section 4.1.1.3) also promotes similar Reformatsky-type reactions. In this case, however, the products are... 

Reduction of a range of allyl and benzyl chlorides at a stainless steel cathode in dimethylformamide in the presence of carbonyl compounds and using a sacrificial anode of aluminium or zinc, leads to a Reformatsky-type reaction in 40-80 % yields. Allyl halide give products by reaction at both the a- and y-positions. Tetra-chioromethane and bromotrifluoromethane take part in similar reactions provided a... 

As an example of the solid-state C-C bond forming reaction with a nucleophile, a Reformatsky-type reaction was conducted with Cgo- Thus, a mixture of Csoj ethyl bromoacetate, and zinc powder in a molar ratio of 1 5 20 was vigorously milled under the HSVM conditions for 20 min. After the mixture was treated with trifluoroacetic acid, the expected adduct 38 was obtained in 17%... 

A number of low-valent or zero-valent metals are able to promote Reformatsky-type reactions of a-bromoesters with carbonyl compounds and related electrophiles60. Starting with calcium and moving rightward along the fourth row of the periodic table, the following metal species have been reported to promote Reformatsky-type reactions ... 

Among fifth-row metals, a Reformatsky-type reaction of trichloronitromethane with aldehydes has been documented to be promoted by SnCl222. Furthermore, indium thrived... 

TABLE 1. Examples of medium/Large ring construction via the Sml2-promoted intramolecular Reformatsky-type reaction (the new —C bond is highlighted by the disconnection curve)... 

R. Csuk, A. Fiirstner, H. Sterk, and H. Weidmann, Synthesis of carbohydrate derived ot-methylene-y-lactones by diastereoselective, low temperature Reformatsky-type reactions, J Carbohydr. Chem. 5 459 (1986). 

Reformatsky-type reactions. This Ni(0) can effect selective addition of halo-acetonitriles to aldehydes. 

For an iron catalyzed Reformatsky-type reaction, see M. Durandetti, J. Perichon, Synthesis 2006, 1542-1548. 

In addition to aldehydes and ketones, a variety of other functional groups can be used as electrophiles in Reformatsky-type reactions.1-3 Among them, nitriles play a prominent role since they lead to p-oxoesters after hydrolytic work-up (the primary enamines initially formed can only be isolated when stabilized by extended conjugation or by conformational means, cf. Table 14.1, entry 4). 

Finally, the use of ultrasound to entrain Reformatsky reactions deserves mentioning.37 Since a conventional laboratory cleaning bath is usually sufficiently effective, this easily adaptable method should find wider use in particular for large scale preparations. The same may hold true for the use of sacrificial anodes and/or for Reformatsky-type reactions triggered by electrochemical means.38... 

Particularly challenging is the use of chiral ligands in order to impose enan-tiocontrol on a Reformatsky reaction. Although preparatively useful levels of asymmetric induction have been described in the recent literature by using enantiomerically pure amino alcohol ligands43 this reaction has not yet reached a similar level of perfection as the enantioselective addition of other organozinc reagents to aldehydes in the presence of the same type of additives. Some selected examples of stereoselective Reformatsky type reactions which delineate the present state of the art are summarized in Scheme 14.6. 

A number of azetidinones have been prepared, with ferrocene attached to carbon (56) and to nitrogen (57).51 These azetidinones were prepared by a Reformatsky-type reaction of aldimines with zinc and ethyl bromoacetate. 

P-Hydroxy ketones. a-Bromo ketones undergo a Reformatsky-type reaction with aldehydes which is promoted by R3Sb but which is only possible with iodine as catalyst. The function of I2 is probably for a Br/I exchange, since I2 is not required in reactions with a-iodo ketones. 

Highly ry//-selective aldol synthesis from cr-iodo ketones is promoted under aqueous conditions by a distannane system, (BujSnb, Bu2SnF2, and HMPA. Aqueous solutions of acetaldehyde or formaldehyde provide /3-hydroxy ketones.272 The ate complex Li+[//-Bu2Snl ( generated from Lil and -Bu2SnI2 leads to the highest class of syn-diastereoselectivity in the Reformatsky-type reaction (Equation (106)).273... 

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... 

In 1993, Corey reported the first synthesis of paeoniflorin.56 The core of paeoniflorin was constructed using a Sml2-mediated Reformatsky-type reaction (Scheme 7.16). Treatment of a-chloronitrile 31 with Sml2 gave cyclobutanol 32 in excellent yield. The sensitivity of cyclobutanol 32 to base precluded the use of more conventional aldol-type cyclisations.56... 

A SmI2-promoted intramolecular Reformatsky-type reaction was used for the cyclization of 5-(bromoacetoxy)alde-hyde 96 (Scheme 17) <1998SL735>. This reaction provided a 2 1 epimeric mixture of the oxocan-2-ones 97 and 98 in 63% yield. The isomer 97 could be converted almost quantitatively into 98 (a precursor of (—)-octalactin A) by sequential Dess-Martin oxidation and NaBH4 reduction. 

Reformatsky-type reaction. Reaction of an a-bromo aldehyde, ketone, or ester with the reagent (I) formed from Bu3SnLi and (CiHjj.AlCl provides an aluminum enolate... 

Lactams. Son le time ago, Gilman and Specter reported that a-bromo esters and Sehiff bases undergo a Reformatsky-type reaction in the presence of zinc activated by a trace of iodine to form -lactams in moderate yield. This reaction is markedly improved... 

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