Alkyl cyanates

Alkyl Thio-cyanates Alkyl Iso-thio-cyanates.—In the alkyl derivatives of thio-cyanic acid we again have isomerism exactly analogous to that in the unknown cyanates and the known iso-cyanates. 

In contrast to alkyl cyanates, alkyl thiocyanates trimerize to provide the 2,4,6-tris(alkylsul-fanyl)-l,3,5-triazines 21 without notable formation of the corresponding isothiocyanu-rates.265 -267,481 In general, the reaction is acid catalyzed to prevent isomerization of the starting alkyl thiocyanate to the corresponding alkyl iso thiocyanate. 

Alkylation. Ben2otrifluoride can also be alkylated, eg, chloromethyl methyl ether—chlorosulfonic acid forms 3-(trifluoromethyl)ben2yl chloride [705-29-3] (303,304), which can also be made from / -xylene by a chlorination—fluorination sequence (305). Exchange cyanation of this product in the presence of phase-transfer catalysts gives 3-(trifluoromethylphenyl)acetonitrile [2338-76-3] (304,305), a key intermediate to the herbicides flurtamone... 

Isocyanates are derivatives of isocyanic acid, HN=C=0, ia which alkyl or aryl groups, as weU as a host of other substrates, are direcdy linked to the NCO moiety via the nitrogen atom. StmcturaHy, isocyanates (imides of carbonic acid) are isomeric to cyanates, ROCMSI (nitriles of carbonic acid), and nitrile oxides, RCMSI—>0 (derivatives of carboxyUc acid). 

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). 

Alkyl halides or sulfuric or sulfonic esters can be heated with sodium or potassium thiocyanate to give alkyl thiocyanates, though the attack by the analogous cyanate ion (10-66) gives exclusive N-alkylation. Primary amines can be converted to thiocyanates by the Katritzky pyrylium-pyridinium method (pp. 447, 489). "... 

When the reagent is the thiocyanate ion, S-alkylation is an important side reaction (10-43), but the cyanate ion practically always gives exclusive N-alkylation. ° Primary alkyl halides have been converted to isocyanates by treatment with sodium nitrocyanamide (NaNCNN02) and m-chloroperoxybenzoic acid, followed by heating of the initially produced RN(N02)CN. ° When alkyl halides are treated with NCO in the presence of ethanol, carbamates can be prepared directly (see 16-7). ° Acyl halides give the corresponding acyl isocyanates and isothiocyanates. For the formation of isocyanides, see 10-111. 

For a monograph, see Reutov, O.A. Beletskaya, I.P. Kurts, A.L. Ambident Anions Plenum NY, 1983. For a review, see Black, T.H. Org. Prep. Proced. Int., 1989, 21, 179. Both cyanates and isocyanates have been isolated in treatment of secondary alkyl iodides with NCO Holm, A. Wentrup, C. Acta Chem. Scand., 1966, 20, 2123. 

Vinylic copper reagents react with CICN to give vinyl cyanides, though BrCN and ICN give the vinylic halide instead." Vinylic cyanides have also been prepared by the reaction between vinylic lithium compounds and phenyl cyanate PhOCN." Alkyl cyanides (RCN) have been prepared, in varying yields, by treatment of sodium trialkylcyanoborates with NaCN and lead tetraacetate." Vinyl bromides reacted with KCN, in the presence of a nickel complex and zinc metal to give the vinyl nitrile. Vinyl triflates react with LiCN, in the presence of a palladium catalyst, to give the vinyl nitrile." ... 

In an analogous reaction, urea substrates having alkyl substituents at only one of the N atoms undergo alkylamine elimination to form a dinickel cyanate complex.2081 In contrast, no reaction was observed for A ,A7-dialkylated substrates. 

A series of potent, linear C2-symmetric HIV-1 protease inhibitors with K, values in the nanomolar range was prepared from a diaryl bromide precursor emanating from a carbohydrate scaffold, by application of Heck, Suzuki, Stille, and cyanation reactions. Included in this series was the first reported microwave-promoted Suzuki coupling with an alkyl borane [41]. A very high-yielding Suzuki coupling is presented... 

A typical phase transfer catalytic reaction of the liquid/liquid type is the cyanation of an alkyl halide in an organic phase using sodium or potassium cyanide in an aqueous phase. When these phases are stirred and heated together very little reaction occurs. However, addition of a small amount of crown ether (or cryptand) results in the reaction occurring to yield the required nitrile. The crown serves to transport the cyanide ion, as its ion pair with the complexed potassium cation, into the organic phase allowing the reaction to proceed. 

Cyanates contain the OCN group. Inorganic cyanates that are formed industrially by the oxidation of cyanide salts hydrolyze in water to form ammonia and bicarbonate ion. Alkyl cyanates are insoluble in water and form cyanurates. Alkyl isocyanates contain the OCN radical, are formed from cyanates, and, like cyanates, are readily hydrolyzed. Thiocyanates (SCN group) are formed from cyanides and sulfur-containing materials and are relatively stable. 

The first reported synthesis of hydroxyurea (24) consists of the condensation of hy-droxylamine with potassium cyanate (Scheme 7.14) [87]. Condensation of hydroxy-lamine with ethyl carbamate also gives pure hydroxyurea in good yield after recrystallization (Scheme 7.14) [88]. Nitrogen-15 labeled hydroxyurea provides a useful tool for studying the NO-producing reactions of hydroxyurea and can be prepared by the condensation of N-15 labeled hydroxylamine with either potassium cyanate or trimethylsilyl isocyanate followed by silyl group removal (Scheme 7.14) [89, 90]. Addition of hydroxylamine to alkyl or aryl isocyanates yields alkyl or aryl N-hydroxyureas (Scheme 7.14) [91, 92]. The condensation of amines with aromatic N-hydroxy carbamates also produces N-substituted N-hydroxyureas (Scheme 7.14) [93]. 

Autoxidation of secondary acetonitriles under phase-transfer catalytic conditions [2] avoids the use of hazardous and/or expensive materials required for the classical conversion of the nitriles into ketones. In the course of C-alkylation of secondary acetonitriles (see Chapter 6), it had been noted that oxidative cleavage of the nitrile group frequently occurred (Scheme 10.7) [3]. In both cases, oxidation of the anionic intermediate presumably proceeds via the peroxy derivative with the extrusion of the cyanate ion [2], Advantage of the direct oxidation reaction has been made in the synthesis of aryl ketones [3], particularly of benzoylheteroarenes. The cyanomethylheteroarenes, obtained by a photochemically induced reaction of halo-heteroarenes with phenylacetonitrile, are oxidized by air under the basic conditions. Oxidative coupling of bromoacetonitriles under basic catalytic conditions has been also observed (see Chapter 6). 

The anodic cyanation of A-alkyl tertiary cyclic amines can give a mixture of regioisomers as observed in Scheme 109. 

For synthetic purposes the cyanate ion is a promising reagent leading to amines in water and to carbamates in dcohol (Hartsuiker et al., 1971). Alkyl-lithium reagents may also function in nucleophilic photosubstitutions with aromatic partners containing suitable leaving groups (Shapiro and Tomer, 1968). 

In addition, stereoselective synthesis of solenopsin A has been reported by four research groups. An approach utilizing the stereoselective reductive de-cyanation (596) starts with aminonitrile 229, prepared from 2-picoline. It was selectively hydrogenated in the presence of Pd-C, followed by alkylation with undecyl bromide, affording 231. Reductive decyanation of 231 with NaBH4 in MeOH led to predominant (8 2) formation of the trans isomer (232) which was then debenzylated to ( )-solenopsin A (Id). The cis product (Ic) was in turn prepared by treatment of 231 with sodium in liquid ammonia followed by de-benzylation (Scheme 10). 

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