Isocyanates heterocycle synthesis

An interesting new approach to l,3-diazepin-2-ones 61 via a palladium-catalysed highly regioselective, cyclisation of 2-vinylpyrrolidines 59 with aryl isocyanates 60 has been developed by Zhou and Alper <03JOC3439>. This reaction has considerable potential for further applications in heterocyclic synthesis. 

The Wittig-type reactions of iminophosphoranes with isocyanates and related compounds have also been extensively used in heterocyclic synthesis. Examples include the preparations of the mesoionic [l,3,4]thiadiazolo[2,3-c][l,2,4]triazines (210) from (209), 0 bicyclic guanidines, e.g. (212), from (211), naphthypyridines (215), (216), and (217) from (213) and (214), 2 pyrido[l,2-f]pyrimido-[4,5-d)pyrimidines (218), 7H-pyrido-[4,3-c]- (219) and 10H-pyrido[3,4-b]- (220) carbazoles, tricyclic fused 2,4-diimino-l,3-diazetidines (222) from the bisiminophosphorane (221), benzotriazepines (225) from (223) and (224), 6 and mesoionic thiazolo-[2,3-b]-1,3,4-thiadiazoles (227) and N,N-bisheteroarylamines from the iminophosphorane (226), derived from 3-amino-4-phenylthiazole-2(3H)-thione. The carbodiimides (229), prepared from the iminophosphorane (228), can be converted into quinolines or a-carboline derivatives depending on the nature of the isocyanate used in the reaction with (228) and the reactions of iminophosphoranes (230) and (231) with aryl and styryl isocyanates provide one-pot syntheses of quinoline, a-carboline, and quinindoline derivatives. 9... 

Synthesis.—From Thid)carbamoyl Isothiocyanates. Carbamoyl isothiocyanates and thiocarbamoyl isocyanates are thermally interconvertible X-CS NCO X CO NCS.i2 In an extensive study of the preparation and chemical behaviour of these reagents, their use in heterocyclic synthesis was evaluated. 2 ... 

Ring expansion of 1,3,2-diazaboracycloalkanes with phenyl isocyanate and isothiocyanate has resulted via insertion of two atoms of the double bond system into the ring. Similarly, three new heterocyclic organoboranes have been produced from heterocyclic aminoboranes and organic isocyanates. The synthesis and thermal rearrangement of boron carbamoylaminopyridin-ates of the type (30) and (31) have been discussed. ... 

As already described for the all-carbon-Diels-Alder reaction, a hetero-Diels-Alder reaction can also be followed by a retro-hetero-Diels-Alder reaction. This type of process, which has long been known, is especially useful for the synthesis of heterocyclic compounds. Sanchez and coworkers described the synthesis of 2-aminopyridines [48] and 2-glycosylaminopyridines 4-144 [49] by a hetero-Diels-Alder reaction of pyrimidines as 4-143 with dimethyl acetylenedicarboxylate followed by extrusion of methyl isocyanate to give the desired compounds (Scheme 4.30). This approach represents a new method for the synthesis of 2-aminopyridine nucleoside analogues. In addition to the pyridines 4-144, small amounts of pyrimidine derivatives are formed by a Michael-type addition. 

A recent review on four-membered heterocycles formed from imino-phosphoranes concentrates on the preparation and the reactivity of 2,4-diimino-l,3-diazetidine and related compounds (93JPR305). As an example, the synthesis via bisiminophosphorane 85 is described in Scheme 42. The bisiminophosphorane has both a heteroaryl and a styryl site. From a mechanistic view, the reaction of the bisiminophosphorane proceeds with aryl isocyanate formation via an aza-Wittig mechanism. Intermediate car-bodiimide formation (86) occurs directly on the iminophosphorane moiety... 

Due to their high electrophihcity, isocyanates are useful starting materials for the synthesis of heterocycles and C-C bond formation using carbon nucleophiles. A key feature of these reactions is the requirement for more than one equivalent of base. Additionally, a few examples of transition metal-catalyzed homologation of the central carbon of the heterocumulene moiety have been reported. 

In a related type of reaction, the styryl isocyanates, readily available by Curtius rearrangement of cinnamoyl azides, undergo thermal cyclization to l-isoquinolones in good yield (equation 34) the reaction can also be carrried out using Friedel-Crafts catalysts. 2,3-Dihydro-4( 1//)- isoquinolones are obtained by Dieckmann cyclization of N- (o- carbalkoxy-benzyl)glycine ester derivatives (equation 35). The same reaction has been used for the synthesis of a range of non-aromatic heterocycles (equations 36 and 37). 

Examples of synthesis of five-membered heterocycles following this strategy are limited in number. An approach to 1,3,4-triazoles involves bonding of C-l and C-3 of vinyl isocyanate 150 to both nitrogen atoms of aromatic hydrazines (78JOC402) (Scheme 37). The reaction was run at room temperature and gave quantitatively regioisomer 151 or a mixture of 151 and 152 when p-nitrophenyl and phenylhydrazine, respectively, were employed. 

The synthesis of the pyrimidine ring represents a well-studied group of heterocyclization reactions based on enamines. One of the important approaches involves the reaction of enamines with assorted isocyanates and isothiocyanates. Thus, a reaction of enaminonitriles with benzyl isocyanate or phenyl isocyanate gives C- and N-adducts (190a and 190b, respectively) or their mixtures, which are transformed in a single step into 4-pyrimidinone (191) and 2-pyrimidinone (192) derivatives (94JHC329). The... 

Cycloaddition Reactions. Isocyanates undergo cycloadditions across the carbon—nitrogen double bond with a variety of unsaturated substrates. Addition across the C=0 bond is less common. The propensity of isocyanates to undergo cydization reactions has been widely explored for the synthesis of heterocyclic systems. Substrates with C=0, C=N, C=S, and C=C bonds have been found to yield either 2 + 2, 2 + 2 + 2, or 2 + 4 cycloadducts or a variety of secondary reaction products (2). 

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