Cyanamide, acylation

The nitrogen of aHphatic and aromatic amines is alkylated rapidly by alkyl sulfates yielding the usual mixtures. Most tertiary amines and nitrogen heterocycles are converted to quaternary ammonium salts, unless the nitrogen is of very low basicity, eg, ia tn phenylamine. The position of dimethyl sulfate-produced methylation of several heterocycles with more than one heteroatom has been examined (22). Acyl cyanamides can be methylated (23). Metal cyanates are converted to methyl isocyanate or ethyl isocyanate ia high yields by heating the mixtures (24,25). 

Substitutions. The cyanamide anion is strongly nucleophilic and reacts with most alkylating or acylating reagents (4) addition to a variety of unsaturated systems occurs readily (4). In some cases, a cyanamide salt is used in others, base catalysis suffices. Ethyl iodide reacts with sodium hydrogen cyanamide [17292-62-5] to form a trisubstituted isomelamine. 

The acylation of enamines derived from cyclic ketones, which can lead to the acyl ketone or ring expansion (692-694), was studied by NMR and mass spectroscopic analysis of the products (695,696). In a comparative study of the rates of diphenylketene addition to olefins, a pronounced activation was observed in enamines (697). Enamine N- and C-acylation products were obtained from reactions of Schiff s bases (698), vinylogous urethanes (699), cyanamides (699), amides (670,700), and 2-benzylidene-3-methylbenzothiazoline (672) with acid chlorides, anhydrides, and dithio-esters (699). 

C Kwon, HT Nagasawa, EG DeMastr, FN Shirota. Acyl, N-protected alpha-aminoacyl, and peptidyl derivatives as prodrug forms of the alcohol deterrent agent cyanamide. J Med Chem 29 1922-1929, 1986. 

Amino-substituted naphthoquinones and heterocyclic variants have been disclosed in the patent literature as 5-LO inhibitors. Compounds represented by (80) (X = C, N) from Lilly inhibited SRS-A release from sensitized guinea-pig lung tissue [218]. Similar compounds such as (81) (R = carboxylic ester, acyl, or aryl) and related naphthalene derivatives, from American Cyanamid, gave good inhibition in guinea-pig ISN (at 10 //g/ml) and in passive cutaneous anaphylaxis in mice (25-60 /zM i.p.) [219,220]. 

Phenyloxadiazole and other homologues have now been prepared (44c, 55c). These compounds are stable at room temperature for a while, but on standing isomerize into acyl cyanamides. The transformation is faster in alcaline solution. 

Acyl and aroylcyanamides NCNC(0)R are also quite strong donors (Pi = —1.19 V) [40], similar to Cl , whereas organocyanamides NCNR2 are much weaker electron-donors [35, 36], being comparable to cyanamide itself. 

The active hydrogens of pseudoureas react with various reagents, such as sodium hypochlorite [72], acyl halides [73], sulfonyl halides [19], isocyanates [26], isothiocyanates [26, 74] cyanamide, [75] and esters [76], to give linear or cyclic derivatives as shown in Scheme 2. 

Synthesis Fenbufen is prepared by the Friedel-Crafts (aluminum chloride-nitrobenzene) acylation of biphenyl with succinic anhydride (Tomcufcik et al. (American Cyanamid Co.), 1972). 

An interesting variation on the above conversion of pyrylium into pyridinum salts is the reaction of the former with cyanamide in which a 3-acyl-2-aminopyridine (61) is formed in 75% yield, probably by the mechanism shown (71JCS(C)3873). 

As an extension of the known radical additions to isonitriles [87], aryl radical cyclizations to /V-acyl cyanamides provide new access to pyrrolo-quinazolines (Scheme 16) [88]. In a tandem process, the iminyl radical 41 resulting from the 5-exo cyclization onto the nitrile was used for a second cyclization step. In this way, the alkaloid luotonin A (42) was synthesized from cyanamide 43 in a single reaction. 

In 1982 Foley and Btichi (182a) described a biomimetic synthesis of racemic dibromophakellin (137) via an oxidative cyclization of dihydroor-oidih (138). The ethyl ester of (+)-citrulline (139) was reduced with sodium amalgam and the crude aldehyde obtained was condensed with cyanamid and cyclized with hydrochloric acid, respectively, to give 140. Compound 140 was hydrolyzed to the amine 141. Acylation with 2,3-dibromo-5-tri-chloroacetylpyrrole yielded dihydrooroidin (138). Exposure of the hydrochloride of 138 to bromine in acetic acid and addition of methanol, followed by treatment with potassium /eri-butanolate gave racemic 137, identical to... 

Carbodiimides are a unique class of reactive organic compounds having the heterocumu-lene structure R—N=C=N—R. They can be formally considered to be the diimides of carbon dioxide or the anhydrides of 1,3-substituted ureas, and they are closely related to the monoimides of carbon dioxide, the isocyanates. The substituent R can be alkyl, aryl, acyl, aroyl, imidoyl or sulfonyl, but nitrogen, silicon, phosphorous and metal substituted carbodiimides are also known. The unsubstituted carbodiimide HN=C=NH is isomeric with cyanamide, H2NCN. Mono substituted carbodiimides, generated in the thermolysis of 1-substituted tetrazoles, can be isolated at liquid nitrogen temperature but isomerize to the cyanamides at higher temperatures. ... 

Cyanamides, alcoholysis, 648 hydrolysis, 647, 680 Cyanides, acylation, 348 addition, of alcohols to, 634 of ammonia or amines to, 635 of olefins to, 571 alcoholysis, 485, 542 alkylation, 599 amination, 636 carbethoxylation, 489 condensation to /3-iminonitriles, 730 hydrolysis, to acids, 412 to amides, 570 preparation, 590... 

The alternative 5-amino-1-substituted imidazoles are usually made by reactions between primary amines and alkyl 7/-cyanoalkylimidates (see Section 3.2). Other possibilities include ring closure of formylglycineamidines by heating them alone or with phosphoryl chloride (yields are usually low) (see Section 2.1.1), cyclization of or-cyanoalkylcyanamides (to form 5-amino-2-bromoimidazoles) (see Section 2.2), alkylation of arylamino-methylene cyanamides or cyanoimidothiocarbanates with or-halogenocarbonyl compounds (gives 4-acyl-5-aminoimidazoles) (see Section 2.3), and cycliza-tions of DAMN with amidrazones (to 1,5-diaminoimidazoles) (see Section 2.2.1). 

H Acyl-cyanamides Mainly academic interest von Kohler et at. Kwon et al7 ... 

Amino derivatives of selenazoles are generally prepared from the haloketone or aldehyde and selenoureas. The latter can easily be obtained by either passing HjSe through a solution of cyanamide or a carbodiimide or from acyl selenoureas, which are obtained from the corresponding acyl halide and potassium selenocyanate. ... 

Lewis acid-catalyzed condensation of an aryl carbonitrile (2 equivs.) with an acyl halide (1 equiv.) is a well-established and popular route to 1,3,5-oxadiazinium salts (see Section 6.18.10.3.l.i). The carbonitrile can be replaced successfully by aryl cyanates, cyanamides, and alkylthiocyanates, and examples using carbamoyl chlorides rather than the acyl halide have also been reported. The 1,3,5-oxadiazinium salts are also accessible by cyclocondensation of A-acylchloroformamidines with cyanamides in the presence of stannic chloride (see Section 6.18.10.2.2.l.i) and by condensation of A A -disubstituted-ALacylthioureas (2 equivs.) with thionyl chloride or phosphorus pentachloride (see Section 6.18.10.2.2.i). 

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