Enamines with isocyanates

The addition of phenylisocyanate to aldehyde-derived enamines resulted in the formation of aminobutyrolactams (438,439). As aminal derivatives these produets can be hydrolyzed to the linear aldehyde amides and thus furnish a route to derivatives of the synthetically valuable malonaldehyde-acid system. With this class of reactions, a second acylation on nitrogen becomes possible and the six-membered cyclization products have been reported (440). Closely related to the reactions of enamines with isocyanates is the condensation of cyclohexanone with urea in base (441). 

Reactions of enamines with isocyanates (568) and isothiocyanates (569) in the presence of sulfur gave l,3-thiazolidine-2-ones and l,3-thiazolidine-2-thiones. 

Schiff s bases also underwent C or N acylation with isocyanates (698) and isothiocyanates (698,701). Further studies provided 2 1 and 2 2 reaction products of arylisothiocyanates and enamines (702) and polymers derived from enamines and bisisocyanates (703). 

In contrast to 4-alkyl-5-sulfonylimino-A -l,2,3,4-thiatriazolines (58) (Section 4.19.5.1.2), 4-alkyl-5-alkylimino-A -l,2,3,4-thiatriazolines (50) react with immediate nitrogen evolution when added to electron-rich alkenes or to heterocumulenes such as enamines, carbodiimides, isocyanates, isothiocyanates, or styrene. Reaction kinetics for certain of this type of system show that they undergo bimolecular processes as described below. 

Substituted 2-pyridones were obtained from enamines with appropriate functional groups. Phenyl isocyanates and phenyl isothiocyanates... 

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... 

An interesting variant of the annulation of enamine substrates with acrylic acid derivatives was the thermal reaction of enamines with vinyl isocyanates (eq. 17).31 Treatment of 68 with DPPA produced the intermediate vinyl isocyanate, which underwent cycloaddition with the enamine followed by elimination of the pyrrolidine to give pyridone 70. Pyridone 70 was efficiently converted to the corresponding highly substituted pyridine. 

The interaction of enamines with sulphur in conjunction with carbon disulphide, isocyanates, or isothiocyanates results in the production of sulphur-containing heterocyclics. Cyanamide has now been shown to participate in this reaction. Treatment of enamines of type (24) with sulphur and cyanamide at room temperature in ethanol produces a range of 2-aminothiazoles (27) in 30—70% yield no catalyst is required. Initial formation of the thiolated intermediate (25) is probably followed by addition of cyanamide, yielding (26) elimination of amine finally produces the observed thiazoles (27). Since AW-dialkylcyanamides do not undergo this reaction, cyanamide may react as the tautomeric carbodi-imide. An actual example of the reaction employing the enamine derived from cyclohexanone and morpholine is also shown [(28) - (29)]. ... 

Metal carbonyl catalysis improves the yields in the condensation of aldehydes with isocyanates to give imines. The utility of molecular sieves in the preparation of aldehyde and ketone di-s-alkyl acetals, enamines and ketimines has been noted. 

The reactivity of isocyanates in [2+2] cycloaddition reactions is as follows alkyl < aryl < nitroaryl << arenesulfonyl < halosulfonyl. Also, the reactivity of the substrate is determined by the substituents. For example, vinyl ethers and enamines are more reactive than olefins. Often the formation of the [2+2] cycloadducts involves polar linear intermediates, which can be intercepted by the isocyanate or the substrate to form six-membered ring [2+2+2] cycloadducts (see Section 3.3.1.4). Also, diynes react with isocyanates to give six-membered ring [2+2+2] cycloadducts. In the latter reactions catalysts play an important role. From Q, ty-diynes macrocyclic adducts are obtained. 

Some imines behave like enamines in their reactions with isocyanates. For example, the reaction of the cyclopentanone anil 117 with phenyl isocyanate gives 1-anilinocyclopentene-2-carboxanilide 118. ... 

Enamines and enolate anions react with benzofuroxan to give quinoxaline di-A -oxides (Scheme 38) (69AHC(10)1). Sydnones (274) with phenyl isocyanate give 1,2,4-triazoles (275) (76AHC(19)l), and from (276) the intermediate adduct (277) can be isolated (73JA8452). This is one of the few instances in which such primary cycloadducts have been isolated in the oxazole series of mesoionic compounds. 

Other isocyanates undergo [2 + 2] cycloaddition, but only with very electron rich alkenes. Thus phenyl isocyanate gives /3-lactams with ketene acetals and tetramethoxyethylene. With enamines, unstable /3-lactams are formed if the enamine has a /3-H atom, ring opened amides are produced 2 1 adducts are also found. Photochemical addition of cis- and traH5-stilbene to phenyl isocyanate has also been reported (72CC362). 

The reaction of morpholine enamine of cyclohexanone with 1 mole of phenyl isocyanate has been reported (30,31) to give the monoadduet (49), consisting largely of the trisubstituted isomer, and with 2 moles of phenyl isocyanate, the bis adduct (50). That the bis adduct is a dicarboxyanilide rather than a urea derivative (32) such as 51 was shown by its mild hydrolysis to the ketone (52). Reaction of the morpholine enamine of 2-methylcyclo-... 

The reaction of isocyanates with enamines disubstituted at the -carbon gives -amino- -lactams (107,108). Thus the enamine (16) reacted exothermally with phenylisocyanate to give (33) dimethyl-l-phenyl-4-dimethylamino-2-acetidinone (157), which was converted by acid hydrolysis to 2-formyl-2-methyl propionanilide (158). 

When the reaction is carried out at 120-140°, 2 moles of phenyl isocyanate react with one of the enamine (16) to give l,3-diphenyl-5,5-dimethyl-6-dimethylamino hydrouracil (159) (109). 

Enamines of cyclic ketones do not form cycloaddition products, but give the mono- or dicarboxanilides (110,111). Thus the enamine (113) on reaction with 1 equivalent of phenyl isocyanate gave 160. Treatment of 113 with 2 equivalents, or 160 with 1 equivalent, of phenyl isocyanate gave the 2,6-disubstituted product (161). Mild acid hydrolysis of 160 and 161 produced the corresponding cyclohexanone(2-mono- and 2,5-di)carbox-anilides (110). 

Proof that the second mole of phenyl isocyanate did not react at the nitrogen of 160 was provided by the reaction of the enamine from 2-methylcyclo-hexanone, which gave only the monocarboxanilide on reaction with excess phenyl isocyanate. 

The reaction of the enamines of cyclic ketones with alkyl isocyanates, acyl isocyanates, phenyl isothiocyanates, and acyl isothiocyanates has also been reported 112). The products are the corresponding carboxamides. The products from the isothiocyanates have been utilized as intermediates in the preparation of various heterocyclic compounds 113). 

The rate of addition of isocyanates to enamines increases with decreasing basicity of the isocyanate nitrogen and with increasing basicity of the enamine nitrogen 112). 

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