Benzyl cyanide, reaction with base

Phenylethylamine has been made by a number of reactions, many of which are unsuitable for preparative purposes. Only the most important methods, from a preparative point of view, are given here. The present method is adapted from that of Adkins,1 which in turn was based upon those of Mignonac,2 von Braun and coworkers,3 and Mailhe.4 Benzyl cyanide has been converted to the amine by catalytic reduction with palladium on charcoal,5 with palladium on barium sulfate,6 and with Adams catalyst 7 by chemical reduction with sodium and alcohol,8 and with zinc dust and mineral acids.9 Hydrocinnamic acid has been converted to the azide and thence by the Curtius rearrangement to /3-phenyl-ethylamine 10 also the Hofmann degradation of hydrocinnamide has been used successfully.11 /3-Nitrostyrene,12 phenylthioaceta-mide,13 and the benzoyl derivative of mandelonitrile 14 all yield /3-phenylethylamine upon reduction. The amine has also been prepared by cleavage of N- (/3-phenylethyl) -phthalimide 15 with hydrazine by the Delepine synthesis from /3-phenylethyl iodide and hexamethylenetetramine 16 by the hydrolysis of the corre-... 

The base-catalyzed reaction of benzyl cyanides with p-chloronitro-benzenes is widely used as a preparative route to 3-arylanthranils (Eq. 8), and hence, by reductive ring opening, o-aminobenzophenones, the valuable precursors of the pharmacologically important benzodiazepinones. By this method 3-phenylanthranils bearing trifluoromethoxy,173 (trifluoromethyl)-thio,173 sulfonamido,174 methoxy- and ethoxycarbonyl,175,176 cyano,175 methylsulfonyl,175 halo,176 difluoromethoxy,177 and acetyl (protected as the... 

Occasionally, the reaction is complex and affords a multitude of products. For example, 2,4-dichloronitrobenzene and benzyl cyanide produce a mixture containing bis(4-chloro-2-benzoyl)azoxybenzene, 2-benzoyl-4-chlo-ronitrobenzene, 5,7-dichloroanthranil, and a-(5-chloro-2-nitrophenyl) benzyl cyanide.180 Using sodium hydride in dimethylsulfoxide as the base, the substituted benzyl cyanide, formed by direct nucleophilic displacement of chloride, becomes the major product (48%), whereas with sodium hydroxide and benzyltriethylammonium chloride the dichloroanthranil (33%) predominates. 

The reaction between a mole each of benzyl cyanide and ethylene diamine in the presence of carbon disulphide as a medium gives rise to the formation of the desired tolazoline (base) through cyclization and subsequent elimination of a mole each of hydrogen sulphide and ammonia that are liberated from the reaction mixture. The base thus obtained is treated with a HCl in molar concentration to obtain the corresponding salt. 

Another type of o-aminobenzyl synthon is based on o-(bis-trimethylsilylaminobenzyl)copper-zinc reagents <89TL4795>. These are prepared from the corresponding benzylic bromides by reaction with zinc, followed by addition of cuprous cyanide. These reagents react with acid chlorides to give 2-substituted indoles. Since the reactions proceed by C-acylation rather than iV-acylation, the conditions required for cyclization are mild and typically the C-acylated intermediates are not isolated. 

The direct synthesis of a, unsaturated nitriles occurs in high yields at 40 to 50 °C from aldehydes and acetonitrile or benzyl cyanide in the presence of catalytic amounts of lb or 9b [125]. These reactions take place in both polar protic and non-polar aprotic solvents. Pro-azaphosphatrane 9b, which is a stronger base than lb, effidently catalyzes the condensation/dehydration of aromatic aldehydes and tertiary aliphatic aldehydes. The use of 9b in these reactions gave rise to products with imusuahy high E/Z ratios. With either lb or 9b, ahphatic aldehydes gave aldol products, and secondary aldehydes led to novel Michael addition products which are described in the next section. Ketones do not condense wiA either benzyl cyanide or acetonitrile under our conditions. 

The mechanism of the reaction was supposed to be similar to that of the allylation process. Deprotonation of benzyl cyanides requires very strong bases (pfC = 21.9) [44]. However, coordination of the CN group to the palladium atom of la allows easy deprotonation even with very weak bases, such as NaHCOj. The next step is a nucleophilic attack of the carbon atom of the imine group, which leads to C-C bond formation. This step determines the stereoselectivity of the process [43]. 

In the reaction of ethyl cyanoacetate with sulphur and base, 2,4-diamino-3,S-di(ethoxycarbonyl)thiophen was only the minor product (20%). The major products were pyrrole derivatives. From cyanoacetamide and benzyl cyanide no thiophen derivatives were obtained. The reaction of (9a) with (10) in the presence of triethylamine yields the aminothiophen (11), while (9b) gives the hydroxy thiophen (12). If the salt of ethyl (thiobenzoyl)... 

This procedure is representative of a new general method for the preparation of noncyclic acyloins by thiazol ium-catalyzed dimerization of aldehydes in the presence of weak bases (Table I). The advantages of this method over the classical reductive coupling of esters or the modern variation in which the intermediate enediolate is trapped by silylation, are the simplicity of the procedure, the inexpensive materials used, and the purity of the products obtained. For volatile aldehydes such as acetaldehyde and propionaldehyde the reaction Is conducted without solvent in a small, heated autoclave. With the exception of furoin the preparation of benzoins from aromatic aldehydes is best carried out with a different thiazolium catalyst bearing an N-methyl or N-ethyl substituent, instead of the N-benzyl group. Benzoins have usually been prepared by cyanide-catalyzed condensation of aromatic and heterocyclic aldehydes.Unsymnetrical acyloins may be obtained by thiazol1um-catalyzed cross-condensation of two different aldehydes. -1 The thiazolium ion-catalyzed cyclization of 1,5-dialdehydes to cyclic acyloins has been reported. 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

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