Reaction With a-Halocarbonyls

Chapter 8. Nucleophilic Species That Form Carbon-Carbon Bonds 

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Thiosemicarbazides (141), Ri = H, yield the 2-hydrazinothiazoles (Scheme 68). Compound 142, Rj = H, on reaction with a-halocarbonyl... 

Diazomethane alkylation of A-4-thiazoline-2-ones (36, 214) or the Williamson reaction of 2-halogenothiazoles (6. 287-300) provide good yields of 2-alkoxythiazole otherwise obtained by reaction between O-esters of monothiocarbamic acid with a-halocarbonyl compounds (see Chapter II). 

The reaction of a thioamide with a-halocarbonyl compounds has been applied extensively, and many thiazoles (10) with alkyl, aryl, aralkyl, or heteroaryl functional groups at the three 2-, 4-, or 5-positions have been reported (Scheme 6). 

Initiated by Miolati in 1893 (27), taken up later by Levi (82), and successively by many other authors, the reaction of ammonium dithiocar-bamate (162) with a-halocarbonyl compounds gives 2-mercaptothiazole derivatives with yields varying greatly according to experimental conditions (Table 11-25). 

Several modifications of the Feist-Benary furan synthesis have been reported and fall into two general classes 1) reactions that yield furan products 2) reactions that yield dihydrofuran products. One variant that furnishes dihydrofiirans uses substrates identical to the traditional Feist-Benary furan synthesis with a slight modification of the reaction conditions. The other transformations covered in this section involve the combination of P-dicarbonyls with reagents that are not simple a-halocarbonyls. Several reactions incorporate a-halocarbonyl derivatives while others rely on completely different compounds. 

Sekine, M., Okimoto, K., Yamada, K., and Hata, T., Silyl phosphites. 15. Reactions of silyl phosphites with a-halocarbonyl compounds. Elucidation of the mechanism of the Perkow reaction and related reactions with confirmed experiments, /. Org. Chem., 46, 2097, 1981. 

Homologation via a-Haloenolates. Organoboranes can also be used to construct carbon-carbon bonds by several other types of reactions that involve migration of a boron substituent to carbon. One such reaction involves a-halocarbonyl compounds.19 For example, ethyl bromoacetate reacts with trialkylboranes in the presence of base to give alkylated acetic acid derivatives in excellent yield. The reaction is most efficiently carried out with a 9-BBN derivative. These reactions can also be effected with B-alkenyl derivatives of 9-BBN to give /i,y-unsaturatcd esters.20... 

Olefinic azo compounds, in which the double bond is conjugated with the azo group, have been prepared from a-halocarbonyl compounds by reaction with a substituted hydrazine to form a hydrazone which, on treatment with a base, is dehydrohalogenated and isomerized to an olefinic azo compound. The reaction may be represented by Eqs. (19) and (20). 

Reaction of an alkylborane with a-halocarbonyl compounds in the presence of a base leads to the replacement of the halogen atom in the carbonyl compound with an alkyl group from the borane. The reaction is most commonly applied to a-bromoesters (Equation B3.18). 

First discovered by Miolati in 1893 (1893G(23)437), the reaction of ammonium dithiocarba-mate with a-halocarbonyl compounds gives 2-mercaptothiazole derivatives, usually in good yields. These compounds have found wide use as accelerators in the vulcanization of rubber (Scheme 178). 

Cyclizations involving reactions of a-amino N-heterocycles with a-halocarbonyl compounds leading to similar ring systems by forming two new C—N bonds will be discussed in more detail in Section 4.36.4.2.3. 

Orsini reported the use of a 10 mol % Sml2-Mg reagent system in the Reformatsky reactions of a-halocarbonyl compounds, nitriles and phospho-nates with ketones, aldehydes and imines.29... 

In addition to alkylation of enamines with a-halocarbonyl compounds66,75,76 (Scheme 10), 1,4-dicarbonyl compounds and derivatives may also be prepared by propenylation of enamines followed by ozonolysis77, propynylation followed by hydration54d,7S and reaction with ketone thioacetal monoxide79, diethyl 3-bromopropene phosphonate80 and dichloroacetaldehyde oxime81 (Scheme 21). 

The range of suitable participants in the Michaelis-Becker reaction is essentially the same as for the Michaelis-Arbuzov reaction. Halo-aldehyde and -ketone substrates suffer the competing reaction of direct attack at the carbonyl group leading to Perkow reaction products (with a-halocarbonyl compounds) or Pudovik reaction products, which often cyclize (cf. Sections 4 and 6). 

Although very common with a-halocarbonyl compounds, cleavage of a-oxygenated substances by nu> cleophiles is almost unknown. A mixture of phenyl trimethylsilyl selenide (38) and MgBr2 dehalogenates substituted benzoin acetates under mild conditions. The reaction probably proceeds by the HSAB path (equation 11) the precise function of MgBr is unclear. 

Of the different thiadiazines, the 1,3,4-thiadiazines have been most extensively studied. They are best prepared by condensation of thiohydrazides with a-halocarbonyl compounds. This ring system was first reported from the reaction of phenacyl bromide with thiosemicarbazide or its 4-substituted derivatives.26 Similar reactions were later investigated,27 29 and important details about the synthesis and reactivity of 1,3,4-thiadiazines were reported in the following years by Beyer etal., Sandstrom, and Bulka et al.7,8... 

A generalized reaction scheme has been developed for the reactions of thiosemicarbazides with a-halocarbonyl compounds. Depending on whether condensation occurs at the N1, N2, or N4 atom, three different sulfur-containing heterocyclic rings may be expected after ring closure 1,3,4-thiadiazines, 2-alkyl(aryl)imino-2,3-dihydrothiazol-3-amines, and 3-alkyl(aryl)-2-hydra-zono-2,3-dihydrothiazoles as well as, with R3 = H, thiazole-2-hydrazines (see p 494). 

Reference standards were synthesized by procedures described in the literature or by some modifications thereof. The method mostly applicable to the synthesis of alkylthiazoles involves the reaction of a-halocarbonyls with thioamides. Dubs and Stiissi (1976b) described a simple new synthesis of 2,4-disubstituted and 2,4,5-trisubstituted 1,3-thiazoles. 

The Feist-Benary synthesis requires the presence of a base, e.g. aqueous Na2C03. It proceeds as a multistep reaction involving at least two intermediates (16/17) of which 3-hydroxy-2,3-dihydrofurans 17 can be isolated in some cases. The formation of 16 results from an aldol addition, that of 17 from an intramolecular nucleophilic substitution. Cyclic 1,3-diketones also react with a-halocarbonyl compounds according to the Feist-Benary synthesis to produce flirans, e.g. ... 

Thiadiadiazines are prepared best by condensation of thiohydrazides with a-halocarbonyl compounds. As thiohydrazide components, most substituted thiosemicarbazides, aryl and alkyl thiocarbonylhydrazides, or 0-alkyl dithiocarbazates can be used. The cyclocondensation with thiosemicarbazides and a-halocarbonyl compounds can provide three isomeric compounds, 2-amino-l,3,4-thiadiazines A, 2-hydrazino-l,3-thiazoles or 2-hydrazono-2,3-dihy-dro-l,3-thiazoles B, and 2-alkyl(aryl)imino-3-amino-2,3-dihydro-l,3-thiazoles C (Scheme 31). The course of the cyclization of thiosemicarbazides with a-halocarbonyl compounds depends on the acidity of the reaction medium and the substituents R, R, and R. The reaction of aromatic a-halo ketones with thiosemicarbazides leads under neutral... 

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