Acyl derivatives cyanides

Another class of problematic amines are a-amino nitriles, which are readily accessible from ketones, amines, and cyanide. Like a-amino acids, these amines are electronically deactivated and less basic and nucleophilic than purely aliphatic amines, and are therefore difficult to acylate. Some a-amino nitriles or the corresponding acylated derivatives can, furthermore, decompose into imines and cyanide if reaction temperatures are too high or if the bases used are too strong (Scheme 7.11). 

Dihydrooxazoles are readily prepared from (V-acyl derivatives of /3-hydroxylamines by heating or by the action of thionyl chloride, sulfuric acid or phosphorus pentoxide (equation 167) (79JCS(P1)539>. The direct condensation of carboxylic acids with 13-hydroxylamines succeeds best with substituted compounds, such as norephedrine (equation 168). There are many variations of this general method, such as the use of imino ether hydrochlorides (equation 169) (78ACR375) and of cyanides (equation 170) (74LA996). 

The thenyl cyanides are of great importance for the preparation of thiophene derivatives. Because of the acidifying effects of both the thienyl and of the cyano groups, carbanions are easily obtained through the reaction with sodamide or sodium ethoxide, which can be alkylated with halides, carbethoxylated with ethyl carbonate, or acylated by Claisen condensation with ethyl... 

The preparation of a formyl-substituted aromatic derivative 3 from an aromatic substrate 1 by reaction with hydrogen cyanide and gaseous hydrogen chloride in the presence of a catalyst is called the Gattermann synthesis This reaction can be viewed as a special variant of the Friedel-Crafts acylation reaction. 

A series of complexes in which the cyanide ligands are modified or replaced arises from the decomposition of methyl and pyridiomethylcobalt(111) pentacyanide derivatives in acid solution. The reactions include protonation of a cyanide ligand, insertion of a cyanide ligand between the organic group and the cobalt atom to produce an imine (see Section VI,D), decomposition of this imine to an acyl product, and replacement of a cyanide ligand by water 100, 101). The products are listed in Table III, 29. 

Reissert compounds (>70%), derived from benzimidazole, phthalazine, quinoline and isoquinoline, have been prepared by a simple catalysed one-pot N-acylation of the appropriate heterocycle, followed by reaction with cyanide ion [e.g. 101-103],... 

Halide 32 was used first, in nitromethane-benzene solution in the presence of an equimolar proportion of mercuric cyanide. It was found83 that 32 gave a disaccharide at 0-6 of a protected derivative of 2-acetamido-2-deoxy-D-glucose in good yield, with a certain degree of stereoselectivity (a /3 ratio 7 3). Complete stereospecificity was attained, leading to the desired a-linked disaccharides, when the partially acylated bromide 33 was condensed with a number of different nucleophiles.66,83,84,93-95 A mechanism was postulated83 to explain the... 

Stoichiometry (28) is followed under neutral or in alkaline aqueous conditions and (29) in concentrated mineral acids. In acid solution reaction (28) is powerfully inhibited and in the absence of general acids or bases the rate of hydrolysis is a function of pH. At pH >5.0 the reaction is first-order in OH but below this value there is a region where the rate of hydrolysis is largely independent of pH followed by a region where the rate falls as [H30+] increases. The kinetic data at various temperatures both with pure water and buffer solutions, the solvent isotope effect and the rate increase of the 4-chloro derivative ( 2-fold) are compatible with the interpretation of the hydrolysis in terms of two mechanisms. These are a dominant bimolecular reaction between hydroxide ion and acyl cyanide at pH >5.0 and a dominant water reaction at lower pH, the latter susceptible to general base catalysis and inhibition by acids. The data at pH <5.0 can be rationalised by a carbonyl addition intermediate and are compatible with a two-step, but not one-step, cyclic mechanism for hydration. Benzoyl cyanide is more reactive towards water than benzoyl fluoride, but less reactive than benzoyl chloride and anhydride, an unexpected result since HCN has a smaller dissociation constant than HF or RC02H. There are no grounds, however, to suspect that an ionisation mechanism is involved. 

Treatment of 2,3,4,6,7,11 h-hexahydro[l,3]oxazino[2,3-a]isoquinolines with hydrogen bromide, benzylmagnesium chloride, acyl chloride, or hydrogen cyanide afforded ring-opened 1,2,3,4-tetrahydroisoquinoline derivatives (66AP817). 

The versatility of 5-nitrosopyrimidines in pteridine syntheses was noticed by Pachter (64MI21603) during modification of the Timmis condensation between (262) and benzyl methyl ketone simple condensation leads to 4-amino-7-methyl-2,6-diphenylpteridine (264) but in the presence of cyanide ion 4,7-diamino-2,6-diphenylpteridine (265) is formed (equation 90). The mechanism of this reaction is still uncertain (63JOC1187) it may involve an oxidation of an intermediate hydroxylamine derivative, nitrone formation similar to the Krohnke reaction, or nucleophilic addition of the cyanide ion to the Schiff s base function (266) followed by cyclization to a 7-amino-5,6-dihydropteridine derivative (267), oxidation to a quinonoid-type product (268) and loss of the acyl group (equation 91). Extension of these principles to a-aryl- and a-alkyl-acetoacetonitriles omits the oxidation step and gives higher yields, and forms 6-alkyl-7-aminopteridines, which cannot be obtained directly from simple aliphatic ketones. 

The reaction of tnfluoromethyl-substituted N-acyl umnes toward nucleophiles in many aspects parallels that of the parent polyfluoro ketones Heteronucleophiles and carbon nucleophiles, such as enamines [37, 38], enol ethers [38, 39, 40], hydrogen cyanide [34], tnmethylsilylcarbomtnle [2,41], alkynes [42], electron-nch heterocycles [43], 1,3-dicarbonyl compounds [44], organolithium compounds [45, 46, 47, 48], and Gngnard compounds [49,50], readily undergo hydroxyalkylation with hexafluoroace-tone and amidoalkylation with acyl imines derived from hexafluoroacetone... 

Cyanohydrin derivatives have also been widely used as acyl anion synthons. They are prepared from carbonyl compounds by addition of hydrogen cyanide. A very useful variant is to use trimethylsilyl cyanide with an aldehyde to produce a trimethylsilyloxy cyanide. The cyano group acidifies the a position (pKA 25) and the a proton can be removed by a strong base. Alkylation of the anion and unmasking of the hydroxy group cause elimination of cyanide and re-formation of the carbonyl group. 

A Japanese group have been investigating the use of readily accessible dihydrocinnoline derivatives of the type 1 (R = alkyl, aryl, styryl, ethoxy X = H or methoxy) as novel precursors for the synthesis of other types of heterocycles. The following synthesis of 2-acetyl-3-cyanoindole is representative of a new general method (22-88% for 10 examples) for the preparation of 2-acyl- and 2-ethoxycarbonyl-3-cyanoindoles from 1 a mixture of 1 (R = Me, X = H 1 eq.) and powdered potassium cyanide (2 eq.) was stirred overnight in aqueous DMF at room temperature. Addition of water to the reaction mixture precipitated 2-acetyl-3-cyanoindoIe, which was obtained in 54% yield after recrystallisation. 

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