A-Chloro nitriles

Cross coupling between an aryl halide and an activated alkyl halide, catalysed by the nickel system, is achieved by controlling the rate of addition of the alkyl halide to the reaction mixture. When the aryl halide is present in excess, it reacts preferentially with the Ni(o) intermediate whereas the Ni(l) intermediate reacts more rapidly with an activated alkyl halide. Thus continuous slow addition of the alkyl halide to the electrochemical cell already charged with the aryl halide ensures that the alkyl-aryl coupled compound becomes the major product. Activated alkyl halides include benzyl chloride, a-chloroketones, a-chloroesters and amides, a-chloro-nitriles and vinyl chlorides [202, 203, 204], Asymmetric induction during the coupling step occurs with over 90 % distereomeric excess from reactions with amides such as 62, derived from enantiomerically pure (-)-ephedrine, even when 62 is a mixture of diastereoisomcrs prepared from a racemic a-chloroacid. Metiha-nolysis of the amide product affords the chiral ester 63 and chiral ephedrine is recoverable [205]. 

On heating in ethyl acetate, 2-aminopyridine and the fluorinated a-chloro nitriles 245 gave the fluorinated tricyclic compounds 246. ... 

Shiner, C. S. Fisher, A. M. Yacoby, F. Intermediacy of a-Chloro Amides in the Basic Hydrolysis of a-Chloro nitriles to Ketones Tetrahedron Lett. 1983, 24, 5687-5690. 

The comparatively ready accessibility of selenocarboxamides has encouraged the use of this procedure for the synthesis of selenazoles (1889LA(250)294). Reaction of the a-chloro-carbonyl compound (73) with the selenocarboxamide (74) provided a ready synthesis of a variety of substituted selenazoles (75). Useful variations of this general procedure are described in detail in Chapter 4.20, and particularly attractive is the reaction of hydrogen selenide with a mixture of a nitrile and the a-halogenoketone to afford the selenazole (48YZ191, 79S66). 

The intermediate Michael adducts have been isolated from the reaction of a-chloro-a-nitroalkanes with a, 3-unsaturated aldehydes, ketones, nitriles and esters... 

Method A (liquid liquid conditions) The a,p-unsaturated ketone, ester, or nitrile (5 mmol) and the a-chloro ester (or nitrile) (5 mmol) in CH2Cl2 (25 ml) are stirred with TBA-Br or TEBA-Cl (5 mmol) in aqueous NaOH (50%, 10 ml) for 1-2 h at room temperature. The organic phase is separated, washed well with H20, dried (Na2S04) and evaporated. The residue is triturated with Et20 (50 ml) and the filtered solution is evaporated to yield the cyclopropane. 

Amination. A continuous process in which aliphatic and aromatic amines are produced by (1) high pressure, catalytic hydrogenation of nitro compounds (-NO2 or nitriles (-CN)) and (2) action of ammonia on a chloro- or hydroxy-compound. 

The oxidation of hydrazones 143 provides, in principle, a very convenient route to nitrile imines from easily accessible starting materials. However, the earliest reagent used, lead tetraacetate, was of limited effectiveness as yields were low and the reaction often gave high yields of diacyUiydrazides as byproducts. Work has been done on the apphcation of several other oxidants to this process to produce a more effective general route. The one that has proved most popular is chloramine T (A(-chloro-A(-sodio-p-toluenesulfonamide, CAT) which is used under mild conditions and has been shown to work well for both cycloaddition (79) (e.g., in the preparation of 146 from 145) and electrocychzation (80) reactions. 

Preparation of the prototype drug departs from the phenylenediamine strategy used in all of the previous examples. Condensation of thiazolo nitrile (53-2) with aniline catalyzed by aluminum chloride affords the amidine addition product (53-3). This is then converted to its reactive A -chloro derivative (53-4) by reaction with sodium hypochlorite. Treatment of that intermediate with a base such as potassium hydroxide leads directly to the cyclization product and thus the benzimidazole thiabendazole (53-6) [56]. The reaction can be rationalized by invoking as the first step the abstraction of chloride to leave behind a nitrene species such as (53-5) this would then readily insert in the CH bond at the ortho position. 

An entirely different synthesis, due to Meyers and Libano, involves the acid-catalyzed condensation of a ditertiary glycol with an w-chloro-nitrile. The resulting w-chloroalkylpyrroline is reduced with aqueous sodium borohydride and cyclized by steam distillation under basic conditions.234 An example of this route is given in Scheme 24. 

C—C—O+N—C. a-Hydroxy ketones react with monosubstituted cyanamides under the influence of sodium hydroxide to yield derivatives of 2-aminooxazole (equation 125) (76S591). Oxazoles are obtained by the action of nitriles on a-diazo carbonyl compounds in the presence of Lewis acids, such as aluminum chloride or boron trifluoride, and the reaction is thought to involve the intermediacy of nitrilium salts (equation 126). Nitrilium salts are also the effective agents in the formation of oxazoles from a-chloro ketones and nitriles in the presence of tin(IV) chloride (equation 127). 

Dipolar cycloadditions have been used successfully in assembling a number of these ring systems. Nitrile oxides, generated from a-chloro oximes and base, add to a wide range of aliphatic and aromatic aldehydes and ketones, but not to esters (Scheme 42), yielding... 

Certain olefinic nitriles ate readily available from a-chloro-/S ylpro-pionitriles obtained by the addition of diazonium salts to acrylonitrile. Dehydrohalogenation is effected by boiling with diethylaniline. ... 

RC = CCH,X — RCX = C==CH,. /S.y- and 7,S-Acetylenic alcohols can be transformed to the halides in better yields by an alternative procedure, which consists in their esterification with p-toluenesulfonyl chloride and subsequent cleavage of the ester by the action of sodium iodide, lithium chloride, or calcium bromide in an appropriate solvent (60-90%). Halo ethers are prepared by the action of phosphorus tribromide on hydroxy ethers, as in the preparation of /3-ethoxyethyl bromide (66%). In a similar manner, /3-halo esters have been prepared without appreciable dehydration of the /3-hydroxy ester (40-60%). The reaction of cyanohydrins leads to a-halo nitriles. Treatment of 2-nitro-l-propanol with phosphorus pentachloride gives l-chloro-2-nitropropane (47%). ... 

The formation of cyano ketones by this method is illustrated by the conversion of phenacyl halides to the corresponding nitriles. Ring closure to cyclopropane derivatives is a side reaction which has been encountered with y-halo ketones. Benzalacetophenone dibromide is converted by alcoholic potassium cyanide to the fi-cyaao ketone, the a-halogen atom being reduced. Several a-chloro ketones have been found to yield a-cyano epoxides. ... 

Aral, S., Suzuki, Y., Tokumaru, K., Shioiri, T. Diastereoselective Darzens reactions of a-chloro esters, amides and nitriles with aromatic aldehydes under phase-transfer catalyzed conditions. Tetrahedron Lett. 2002, 43, 833-836. 

Acyclic phosphoranes bearing a fluoroalkyl side chain (75), undergo intramolecular Wittig reactions when heated, producing cyclic benzoates. Shen and Gao have reported a stereoselective synthesis of trifluoromethylated a-chloro-a,P-unsaturated esters and nitriles by employing trifluoromethylated phosphoranes (scheme 13). 

The reaction of diethyl alkylphosphonates with phenylsulfonyl chloride in the presence of n-BuLi (2 eq) in THF at low temperature followed by the addition of carbonyl compounds produces diethyl l-alkyl-l,2-epoxyalkylphosphonates in 30-80% yields, whereas under the same conditions, diethyl benzylphosphonates give comparable quantities of 1-phenyl-1-chloroalkenes (35-55%, Scheme 3.28). Similarly, p-iminophosphonate carbanions, obtained from diethyl 1-lithiomethylphosphonate and nitriles, react with phenylsulfonyl chloride in THF at -78°C. Hydrolysis (3 M H2SO4) of the resulting a-chloro-p-enaminophosphonates produces diethyl a-chloro-P-ketoalkylphosphonates in satisfactory yields (53-67%). ... 

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