A-chloromethyl ketones

The addition of halomethyl metal reagents provides another Darzens-like route to aziridines <06JOC9373>. Reaction of ICH2C1 with MeLi generates a chloromethyllithium reagent, which then adds to the inline 74. A subsequent intramolecular /V-alkylation provides the aziridine 75. The isolation of a chloromethyl ketone byproduct demonstrated that the chloromethyllithium reagent is operative as opposed to a carbene. 

Reaction of a-chloromethyl ketones with (3-ketoesters and ammonia to assemble pyrroles. 

Hamada, T., Torii, T, Onishi, T, Izawa, K. and Ikariya, T. Asymmetric Transfer Hydrogenation of a-Aminoalkyl-a -Chloromethyl Ketones with Chiral Rh Complexes. J. Org. Chem. 2004, 69, 7391-7394. 

Triazoles and tetrazoles can be alkylated on nitrogen under basic conditions, as in the synthesis of the clinically-used antifungal drug 8.35 in which 11,2,4-triazole is alkylated by a chloromethyl ketone and an epoxide, both good alkylating agents. What is the mechanism of formation of epoxide 8.34 Of compounds 8.34 and 8.35, which is achiral and which is racemic ... 

Peptide Chloromethyl Ketones. Peptide chloromethyl ketone inhibitors have been studied extensively and a fairly detailed picture of the inhibition reaction (see Figure 3) has emerged from numerous chemical and crystallographic studies (30,31). The inhibitor resembles a serine protease substrate with the exception that the scissile peptide bond of the substrate is replaced with a chloromethyl ketone functional group in the inhibitor. The inhibitor binds to the serine protease in the extended substrate binding site and the reactive chloromethyl ketone functional group is placed then in the proper position to alkylate the active-site histidine residue. In addition, the serine OH reacts with the inhibitor carbonyl group to form a hemiketal. 

Enol adenosine 5 -phosphate derivatives (28, 29, 30) are formed by the Perkow reaction of a-chloromethyl ketone with an in situ-generated adenosine-5 -yl bis(trimethylsilyl)phosphite (27). Among these reactions, the use of a-chloro-2, 4 -difluoroacetophenone gave predominantly the enol phosphate derivative over the Arbuzov reaction product and the carbonyl adduct, which were formed as by-products.25... 

Ketones. Rieke zinc produced by the reduction of Zn(CN)j with Li naphthalenide reacts with alkyl halides, and the organozinc halides can be used to form ketones on treatment with CuCN and acid chlorides. Secondary and tertiary alkylzinc bromides are readily prepared in this direct manner." a-Chloromethyl ketones have been prepared by this method using chloroacetyl chloride in the coupling reaction. ... 

Chloromethyl ketones. The ketones can be prepared by reaction of an aldehyde wilh lilhio chloromethylphenyl sulfoxide in THF at —78° to form a -hy-droxy- t-chloro sulfoxide. Pyrolysis of the product in xylene (160°) leads to a chloromethyl ketone.-... 

This reaction was first reported by Staudinger in 1914, subsequently by Clibbens and Nierenstein in 1915, and extensively studied by Nierenstein. It is the synthesis of a -chloromethyl ketone by treatment of an aliphatic or aromatic acyl chloride with diazomethane. Therefore, it is generally known as the Nierenstein reaction." Occasionally, it is also referred to as the Clibbens-Nierenstein reaction or Nierenstein chloromethylation. ... 

Short peptide chains in which one of the amino acid residues is replaced by a moiety related (or sometimes unrelated) to it appear with increased frequency in the literature. In the center of interest are enzyme inhibitors. Synthesis of these compounds is obviously determined by the reactivity of the unusual constituent and therefore it is hardly possible to set rules for such endeavours. We must confine the discussions therefore to generalities. For example chloromethylketones derived from certain amino acids are irreversible inhibitors which not merely interact but indeed react with the active site of an enzyme with the formation of a covalent bond. Chloromethyl ketones are synthesized by activation of the blocked amino acid followed by reaction with diazomethane to yield a diazoketone. This is transformed to the corresponding chloromethyl ketone by HCl in an organic solvent. From p-toluenesulfonyl-L-phenylalanine a chloromethyl ketone is obtained... 

Cinchonidine (99) has extended the substrate scope of the ketone conjugate additions to P-substituted methylidene malononitriles. In particular, the reaction of a-chloromethyl ketones, under very low loading conditions, affords tetrasubstituted cyclopropanes in moderate to good enantioselectivities after intramolecular cycliza-tion (Scheme 2.45) [142], A similar strategy has been followed to synthesize, with moderate to good enantioselectivities (56-90% ee) optically active naphlhopyran derivatives by a conjugate addition/cyclization sequence between 2-naphthol and a,a-dicyanoolefins [ 143 ]. 

Formation of pyrrole derivatives from a-chloromethyl ketones, (3-keto esters and ammonia or amines ... 

Preparation of Functionalized a-Chloromethyl Ketones 107 Table 3.46 Reaction of organozinc reagent mediated by copper with chloroacetyl chloride. 

Photochemical decarboxylation in the presence of diacetoxyiodobenzenc and the appropriate heterocycle has been used to make some compounds related to C-nucleosides, such as 167.192 The preparation of a chloromethyl ketone related to 2,5-anhydro-D-allonic acid, and of potential use in C-nucleoside synthesis, is discussed in Chapter 3. 

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