From halo ketones

Ketones can be reduced by LiAlH4 in the same way as aldehydes and provide a particular large number of examples for this method. Halohydrins are obtained from halo ketones. 1,3-Dichloroacetone is reduced by LiAlH4 in good yield, whereas only 20-25% of l,3-dichloro-2-propanol is obtained by use of aluminum alkoxides.351 Even sterically hindered ketones such as 1,1-diphenylacetone... 

The P-halo ketone intermediates formed in the foregoing reactions arise from the capture of carbocationic intermediates by halide of the gegenions. In some cases, solvents such as acetonitrile can act as the competing nucleophilic species. For example, P-amido ketones could be obtained by the acylation of alkenes in acetonitrile (172). 

The optical rotatory dispersion curves of steroidal ketones permit a distinction to be made between the conformations, and assignment of configuration is possible without resorting to chemical methods (see, e.g. ref. 36) which are often tedious. The axial halo ketone rule and, in the more general form, the octant rule summarize this principle and have revealed examples inconsistent with the theory of invariable axial attack in ketone bromination. 2-Methyl-3-ketones have been subjected to a particularly detailed analysis. There are a considerable number of examples where the products isolated from kinetically controlled brominations have the equatorial orientation. These results have been interpreted in terms of direct equatorial attack rather than initial formation of the axial boat form. 

In the absence of steric factors e.g. 5 ), the attack is antiparallel (A) (to the adjacent axial bond) and gives the axially substituted chair form (12). In the presence of steric hindrance to attack in the preferred fashion, approach is parallel (P), from the opposite side, and the true kinetic product is the axially substituted boat form (13). This normally undergoes an immediate conformational flip to the equatorial chair form (14) which is isolated as the kinetic product. The effect of such factors is exemplified in the behavior of 3-ketones. Thus, kinetically controlled bromination of 5a-cholestan-3-one (enol acetate) yields the 2a-epimer, (15), which is also the stable form. The presence of a 5a-substituent counteracts the steric effect of the 10-methyl group and results in the formation of the unstable 2l5-(axial)halo ketone... 

Until recently, pyridine-type bases have been commonly used to produce conjugated enones from 2-halo ketones yields are usually poor °° and these reactions are frequently accompanied by rearrangement, reduction and salt formation. Thus, Warnhoff found that dehydrobromination of (28) with 2,4-lutidine gave a mixture of (29), (30) and (31) in the ratio 55 25 20. Collidine gave a ratio of 38 25 37, whereas pyridine gave mainly the salt (32). 

Mattox and Kendall have suggested that loss of bromide from the initially formed hydrazone of the a-halo ketone is facilitated by participation of the electron pair on the amine nitrogen atom. The same group has shown that semicarbazones are often superior to 2,4-dinitro-phenylhydra-zones since they can be obtained in higher yields and undergo cleavage more... 

Tosylates also undergo elimination upon treatment with lithium salts in amide solvents. The a,/ -unsaturated ketone (106) is formed from the a-hy-droxy ketone tosylate in a fashion analogous to a-halo ketone eliminations. 

Whereas simple olefins are not usually made by elimination from halides, conjugated systems are frequently obtained in this way. The cases of a- and j5-halo ketones and their vinylogues have already been covered. Allylic halides may also be eliminated to form dienes, for example, the 2,4-diene (109)... 

The reductive elimination of halohydrins provides a means of introduction of double bonds in specific locations, particularly as the halohydrin may be obtained from the corresponding a-halo ketone. This route is one way of converting a ketone into an olefin. (The elimination of alcohols obtainable by reduction has been covered above, and other routes will be discussed in sections IX and X.) An advantage of this method is that it is unnecessary to separate the epimeric alcohols obtained on reduction of the a-bromo ketone, since both cis- and tran -bromohydrins give olefins (ref. 185, p. 251, 271 cf. ref. 272). Many examples of this approach have been recorded. (For recent examples, see ref. 176, 227, 228, 242, 273.) The preparation of an-drost-16-ene (123) is illustrative, although there are better routes to this compound. 

The rearrangement with ring contraction probably is the most important synthetic application of the Favorskii reaction it is for example used in the synthesis of steroids. Yields can vary from good to moderate. As solvents diethyl ether or alcohols are often used. With acyclic a-halo ketones bearing voluminous substituents in a -position, yields can be low a tcrt-butyl substituent will prevent the rearrangement. 

The imidazole nucleus is often found in biologically active molecules,3 and a large variety of methods have been employed for their synthesis.4 We recently needed to develop a more viable process for the preparation of kilogram quantities of 2,4-disubstituted imidazoles. The condensation of amidines, which are readily accessible from nitriles,5 with a-halo ketones has become a widely used method for the synthesis of 2,4-disubstituted imidazoles. A literature survey indicated that chloroform was the most commonly used solvent for this reaction.6 In addition to the use of a toxic solvent, yields of the reaction varied from poor to moderate, and column chromatography was often required for product isolation. Use of other solvents such as alcohols,7 DMF,8 and acetonitrile9 have also been utilized in this reaction, but yields are also frequently been reported as poor. 

In conclusion, a scaleable process for the preparation of 2,4-subsituted imidazole from amidines and a-halo ketones is described. This method avoids the use of chloroform as solvent and affords the desired products in consistently good to excellent yields. 

Primary amines can be prepared from alkyl halides by the use of hexamethylenetetramine followed by cleavage of the resulting salt with ethanolic HCl. The method, called the Delepine reaction, is most successful for active halides such as allylic and benzylic halides and a-halo ketones, and for primary... 

Trialkylboranes react rapidly and in high yields with a-halo ketones,a-halo esters, a-halo nitriles, and a-halo sulfonyl derivatives (sulfones, sulfonic esters, sulfonamides) in the presence of a base to give, respectively, alkylated ketones, esters, nitriles, and sulfonyl derivatives. Potassium tert-butoxide is often a suitable base, but potassium 2,6-di-tert-butylphenoxide at 0°C in THF gives better results in most cases, possibly because the large bulk of the two tert-buXy groups prevents the base from coordinating with the R3B. The trialkylboranes are prepared by treatment of 3 mol of an alkene with 1 mol of BH3 (15-16). With appropriate boranes, the R group transferred to a-halo ketones, nitriles, and esters can be vinylic, or (for a-halo ketones and esters) aryl. " °... 

Although superficially this reaction resembles 10-94 it is likely that the mechanism is quite different, involving migration of an R group from boron to carbon (see also 18-23-18-26). The mechanism is not known with certainty, it may be tentatively shown as (illustrated for an a-halo ketone) ... 

---