Hydrogen chloride with nitriles

Huisgen and his co-workers190 have recently reported that the addition of aromatic nitrile ylides to carbonyl compounds results in the formation of A3-oxazolines, which are easily oxidizable to oxazoles. Typically, benzonitrile 4-nitrobenzylide (131, Ar = p-OsNC6H4), generated from the imidoyl chloride (130) by 1,3-elimination of hydrogen chloride with triethylamine, reacts smoothly with benzaldehyde to give a pair of... 

From nitriles by treatment with anhydrous Stannous chloride dissolved in ether saturated with hydrogen chloride the resulting crystaUine aldimine stannichloride, [(RCH=NHj)2] SnCl, or (RCH=NH,HCl)2SnCl4, is hydrolysed by warm water, and the aldehyde is isolated by distillation with steam or by extraction with a solvent (Stephen reaction), for example, for R = CH3(CH2)4, i.e., n-amyl ... 

By the condensation of a nitrile with a phenol or phenol ether in the presence of zinc chloride and hydrogen chloride a hydroxyaryl- or alkoxyaryl-ketone is produced. The procedure is termed the Hoesch reaction and is clearly an extension of the Gattermann aldehyde reaction (Section IV,121). The reaction gives the best results with polyhydric phenols and their ethers with simple monohydric phenols the imino ester hydrochloride is frequently the sole product for example ... 

Miyatake and Yashikawa have prepared several 2,4-disubstituted thiazoies in fairly low yield (16 to 40%) by the action of a-mercaptoketones (226) on nitriles (227) (Scheme 118 and Table IT38). The reaction was carried out in benzene solution at 0 C by passing a current of dry hydrogen chloride through the mixture. After 3 hr the mixture was filtered and washed with benzene. When the resins had been removed and the remaining solution alkalinized, the product was extracted. 

The pharmacological versatility of this general substitution strategy is further illustrated by diazonium coupling of 14 with 2-nitrobenzenediazonium chloride to produce biarylal-dehyde 18. Formation of the oxime with hydroxylamine is followed by dehydration to the nitrile. Reaction with anhydrous methanolic hydrogen chloride leads to imino ether and addition-elimination of ammonia leads to the antidepressant amid-ine, nitrafudam (20). ... 

In marked contrast to the above results, double nitrile insertion into both the titanium-alkyl and titanium—vinyl bonds occurs to form the diazatitanacycles 74. Treatment of these titanacycles with dry hydrogen chloride affords the tetrasubstituted pyridine derivatives 75 (Scheme 14.32) [74], On the other hand, 2,3-diphenyltitanacyclobutene reacts with various nitriles to afford the products of mono-insertion, which afford the corresponding unsaturated ketones upon hydrolysis [73,74]. 

The complex hydride reductions of nitriles to aldehydes compare favorably with the classical Stephen reduction which consists of treatment of a nitrile with anhydrous stannous chloride and gaseous hydrogen chloride in ether or diethylene glycol and applies to both aliphatic and aromatic nitriles [183,285, 1152]. An advantage of the Stephen method is its applicability to polyfunctional compounds containing reducible groups such as carbonyl that is reduced by hydrides but not by stannous chloride [1153]. 

The A-methyl-A -arylazoaminoacetonitriles (194) and hydrogen chloride in ether yield the 1,2,3-triazolium chlorides (195). These salts (195) and base did not give the corresponding meso-ionic compounds (193, R = Me, R == Ar, R = R = H), but the corresponding J acetyl derivatives (193, R = Me, R = Ar, R = H, R = Ac) were produced either from the nitriles (194) and acetyl chloride or from the 1,2,3-triazolium chlorides (195) and acetic aidiydride, followed by treatment with ammonium hydroxide. ... 

Chloramine-T has also been employed, both as a halogenating reagent and base the reaction proceeds in good yield with aromatic as well as with aliphatic aldoximes (81). The role of chloramine-T probably involves an initial chlorination of the aldoxime to give the hydroximoyl chloride, followed by base-catalyzed hydrogen chloride elimination to afford the nitrile oxide (81). 

An unusual reaction leading to the formation of 4-thioxopyrazolo[3,4-d]-pyrimidines has been reported. 1-Substituted 4-cyano-5-aminopyrazoles (103, R = H) react with phenyl isothiocyanate in dimethylformamide (DMF) saturated with hydrogen chloride to yield 1-substituted 4(5//)-pyrazolo[3,4-d]-pyrimidinethione (110). A proposed reaction sequence involved an initial nucleophilic addition of phenyl isothiocyanate to the protonated o-amino-nitrile to give an o-aminothioamide (108), followed by formylation by the dimethylformamide-hydrogen chloride mixture affording 109, which then cyclizes to the final product 110 (70MI1). 

A rather simpler compound includes both a benzodioxan nucleus and the imidazoline function associated with a-adrenergic agonists such as clonidine. As in the standard approach for preparing imidazolines, the treatment of nitrile (60-1) with alcoholic hydrogen chloride leads to the iminoether (60-2). Reaction of that intermediate with ethylenediamine then affords idazoxin (60-3) [70], a compound that interacts with a-adrenergic receptors. 

Treatment of the dichloromethyl derivative 472 with sodium cyanide gave290 an almost quantitative yield of the epimeric nitriles (480, 481). The mixture could not he separated by chromatographic methods, but differences in reactivity of the stereoisomers towards methanolic hydrogen chloride allowed isolation of only one ester, namely, 482 the trails cyanide underwent ready conversion into the methyl ester, whereas the cis compound gave a rather complicated mixture of products, with amide 483 being identified as the major component. Reduction of the ester group in 482, followed hydrolysis of the dichloromethyl group, afforded DL-t/ireo-DL- Y/o-octose, characterized as the heptaacetate, and identified as threo-ido-octito by comparison with an authentic sample. 

Analogous ring closures are to be found in the cyclizations of cinnamonitriles (191 R1 = C1, R2 = H and R OH, R2 = Ar) to 2-benzazepin-l-ones (192) and (193 R = aryl) with hydrogen chloride and polyphosphoric acid respectively (74AHC(17)45>. Polyphosphoric acid has also been used to effect cyclization of the mono- or di-nitriles (191 R1 = OH,... 

To an ice-cooled solution of the nitrile, in absolute alcohol (see Table II above) is added dry hydrogen chloride until 1.1 moles has been taken up. The resulting solution is allowed to stand at 0°C for the times shown in Table II, column 2. After this time, ether is added in the amounts shown in column 3 for the purpose of preventing the formation of a hard cake of the salt. In the case of very reactive nitriles such as acetonitrile and chloroacetonitrile it is advisable to have the ether present before the hydrogen chloride is added in order to prevent solidification of the reaction mixture. After allowing the reaction mixture to stand for 15-20 hr in a refrigerator, it is cooled to —30°C to hasten crystallization. The product salt is filtered, washed with cold (—40°C) ether, and dried... 

Phenols are also known to be able to condense with nitriles to give phenolic ketimines as shown in Eq. (2) [17]. The reaction between the phenol and nitrile is carried out in ether solution when hydrogen chloride gas is added to the saturation point. Less reactive phenols also require the presence of zinc chloride. 

Nitriles also can be reduced to imines with stannous chloride in ethyl acetate containing hydrogen chloride [26]. The imines are isolated as the stannous chloride salt. 

---