Preparation of a-halo ketones

Preparation of enamines, 409 Preparation of enol acetates, 411 Preparation of enol ethers, 409 Preparation of a-halo ketones, 267 Preparation of 3/3-hydroxyandrosta-5,15-dien-17-one, 302... 

Joly s method (or modifications) is the best procedure for preparing A " -3-ketones and can be extended to the elimination of hydrogen bromide from a-bromo ketones of all types. Rearrangement is sometimes observed but is not often serious. Selectivity can be improved in some instances by lowering the reaction temperature. The method has been found useful for the preparation of A" -3-ketones from 6-halo-A" -3-ketones ... 

Among other methods for the preparation of alkylated ketones are (1) the Stork enamine reaction (12-18), (2) the acetoacetic ester synthesis (10-104), (3) alkylation of p-keto sulfones or sulfoxides (10-104), (4) acylation of CH3SOCH2 followed by reductive cleavage (10-119), (5) treatment of a-halo ketones with lithium dialkyl-copper reagents (10-94), and (6) treatment of a-halo ketones with trialkylboranes (10-109). 

Various approaches have been used to prepare pyrroles on insoluble supports (Figure 15.1). These include the condensation of a-halo ketones or nitroalkenes with enamines (Hantzsch pyrrole synthesis) and the decarboxylative condensation of N-acyl a-amino acids with alkynes (Table 15.3). The enamines required for the Hanztsch pyrrole synthesis are obtained by treating support-bound acetoacetamides with primary aliphatic amines. Unfortunately, 3-keto amides other than acetoacetamides are not readily accessible this imposes some limitations on the range of substituents that may be incorporated into the products. Pyrroles have also been prepared by the treatment of polystyrene-bound vinylsulfones with isonitriles such as Tosmic [28] and by the reaction of resin-bound sulfonic esters of a-hydroxy ketones with enamines [29]. 

Table 1. Preparation of Cyclopropylamines by Reaction of a-Halo Ketones with Nucleophiles...

Rearrangement of the a-silyl ketone (35) has been used to prepare the halo-substituted enol silyl ether (36 Scheme 12). Normal enolization of a-halo ketones would have given the other regioisomers. 

The synthesis of Bliimlein82 and Lewy,83 which affords moderate yields of 2,4-disubstituted oxazoles (29) (having at least one aryl group) by the condensation of a-halo ketones with amides (other than formamide) is even at present a method of choice because of the ready availability of the starting materials. It has been extensively applied to the preparation of many 2,4-disubstituted oxazoles20 21 40 84-86 and is equally applicable... 

A variety of approaches have been employed to effect the preparation of a-alkenyl ketones and carblnols, including reactions of metallo alkenes with epoxides, a-halo ketones, or enolonium ion equivalents and the reactions of... 

Asymmetric synthesis of 8-functionalized optically active secondary alcohols was realized hy TarB-N02-catalyzed enantios-elective reduction of a-halo ketones to an intermediate terminal epoxide and sequential ring opening with various nucleophiles. Optically active st)Tene oxide was prepared from a-bromoacetophenone with NaBH4 and TarB-N02 in high yield and with high enantioselectivity (98% 3ueld and 94% ee). fi-Functionalized secondary alcohols could be obtained from the epoxides by nucleophilic attack under appropriate conditions (eq41). 

Some halides of sp carbons can be carbonylated. Carbonylation of a-halo ketones and esters is a known reaction [68,69]. jS-Keto esters are prepared by the carbonylation of halomethyl ketones [70,71]. Methyl benzoylacetate (160) was obtained in 86 % yield by the carbonylation of 2-chloroacetophenone (159) in MeOH using PdCl2(PPh3)2 as a catalyst at 110°C and 10 atm in the presence of n-BusN [71]. 

This reaction has applications in the preparation of )0-halo ketones and a,fi- or p,y-unsaturated ketones. 

Sodium dithionite in water or aqueous dimethylformamide is an economic, efficient system for the dehalogenation of a-halo-ketones. Other reagents that have been described recently for dehalogenation include iron-graphite (prepared by reduction of ferric chloride with potassium-graphite), sodium 0,0-diethyl phosphorotelluroate, and sodium borohydride in the presence of a catalytic amount of bis(2-thienyl) ditelluride. ... 

Dehalogenation of oi,a dihaloalkenes and Ketones. The preparation (eq 24) of the iron carbonyl complex of trimethylen-emethane (42) and some Fc2(CO)9-mediated rearrangements of dibromo ketones constitute the pioneering work in this area. Noyori has extended the dehalogenation reaction of a-halo ketones to a,a -dibromo ketones and o,a,a, a -tetrabromo ketones which can be dehalogenated with Fe(CO)5 or Fe2(CO)9. ... 

Among compounds other than simple alkyl halides a halo ketones and a halo esters have been employed as substrates m the Gabriel synthesis Alkyl p toluenesul fonate esters have also been used Because phthalimide can undergo only a single alkyl ation the formation of secondary and tertiary amines does not occur and the Gabriel synthesis is a valuable procedure for the laboratory preparation of primary amines... 

Various alkylating agents are used for the preparation of pyridazinyl alkyl sulfides. Methyl and ethyl iodides, dimethyl and diethyl sulfate, a-halo acids and esters, /3-halo acids and their derivatives, a-halo ketones, benzyl halides and substituted benzyl halides and other alkyl and heteroarylmethyl halides are most commonly used for this purpose. Another method is the addition of pyridazinethiones and pyridazinethiols to unsaturated compounds, such as 2,3(4//)-dihydropyran or 2,3(4//)-dihydrothiopyran, and to compounds with activated double bonds, such as acrylonitrile, acrylates and quinones. 

This approach has been most useful for the preparation of vinylogous a-halo ketones (see section II-H). 

Halogenation of the double bond usually prevents the satisfactory preparation of vinylogous a-halo ketones by direct reaction of unsaturated ketones with... 

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 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... 

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