1,2-enaminonitriles

R] Taylor, E. C. McKillop, A. The Chemistry of Cyclic Enaminonitriles and a-Aminonitriles, Interseience New York, 1970. 

Enaminonitriles are useful intermediates in the synthesis of a wide variety of heterocyclic systems. The microwave-enhanced reaction of a cyano-... 

Reaction of 1,3-dicarbonyl compounds with IVJV-dimethylformamide dimethyl acetal followed by malonamide in the presence of sodium hydride gives 5,6-disubstituted 1,2-dihydro-2-oxopyridine-3-carboxamides, whereas reaction of the intermediate enamines with cyanothioacetamide or cyanoacetamide in the presence of piperidine provides 2-thioxopyridine-3-carboxamides and 4,5-disubstituted l,2-dihydro-2-oxopyridine-3-carboxamides, respectively <95S923>. P-Enaminonitriles 14 react with p-ketoesters and alkyl malonates, in the presence of stoichiometric amounts of tin(IV) chloride, to afford 4-aminopyiidines 15 and 4-amino-2-pyridones 16 <95T(51)12277>. 

The photocyclization of cis-diaminomaleonitrile (372) to 4-amino-5-cyanoimidazole (373) has been shown to proceed via the trans isomer 374.308 4-Amino-3-cyanopyrazole does not seem to be an intermediate in this transformation.309 Analogous cyclizations have been reported in the imidazole 373 which undergoes further photoreaction to yield the bicycle 375, and in o-aminobenzonitrile which is converted into indazole.310 This photocyclization has been extended to include enaminonitriles 376 spectroscopic evidence for the intermediacy of iminoketenimes 377 in this311 and other similar transformations312 have been reported. 

An efficient one-pot synthesis of some novel azolo[l,5-a]pyrimidines, via enaminonitriles, has been described <00SC1985>. The utility of 3-aminocinnamonitrile in the synthesis of new pyrazolo[l,5-a]pyrimidines has been reported <00ZN(B)321>. The synthesis of novel arylaminopyrazolo[3,4-d]pyrimidin-4-ones has been described <99IJC(B)1075>. The synthesis and properties of a-Thiagra, a substituted 5-(2-thienyl)pyrazolo[4,3-d]pyrimidin-7-one bioisostere of Viagra, have been described <00H(53)2643>. Imidazo[4,5-b]pyrazines are obtained by the reaction of 4-amino- 5-imino-imidazole derivatives with acetophenone dimethylacetal . 

The reaction of o-nitrobenzaldehydes with some benzene derivatives in the presence of strong acid (H2S04, PPA) is a classical synthesis of acridinol N-oxides (373) (37BSF240) The synthesis works for benzyl alcohol, benzene, toluene and halobenzenes, but not for benzoic acid, benzonitrile, dimethylaniline, or nitrobenzene. Isoquinoline N-oxides (374) have been obtained from o-bromobenzaldoxime or the acetophenone derivative, and active methylene compounds with copper bromide and sodium hydride (77S760). The azobenzene cobalt tricarbonyl (375) reacts with hexafluorobut-2-yne to give a quinol-2-one (72CC1228), and the 3,4,5-tricyanopyridine (376) is formed when tetracyanoethylene reacts with an enaminonitrile (80S471). 

The enaminonitriles 55a and c react with 12 in refluxing pyridine to give 59a and b. In contrast, 12 and 55b react in acetic acid to give the oxa-zinopyrazolo[l,5-a]pyrimidines 60. It is assumed that the amino function in 12 adds to the activated double bond in 55 to yield the intermediate adduct 56, which loses chloroform to yield 57. This cyclizes under basic conditions to yield 59a and b. In acetic acid, the 58 that is formed is converted under the reaction conditions to the oxazino[4,5 5,6 ]pyrazolo[I,5-a]pyrimidine derivative 60 (77ZN(B)I478). 

Enaminonitriles and cycloalkylidenemalonodinitriles gave spiro cyclic compounds (132) containing a 1,4-dihydropyridine moiety (90MI1). A number of N-substituted Hantzsch 1,4-dihydropyridines (134) were obtained under mild and neutral conditions from N-substituted enaminocar-bonyl compounds and aldehydes, activated by interaction with thionyl chloride and pyridines (92SC3291,92T1263). 

Studies of reactions of 3-chloro-2-propenyliminium salts (141) with enaminonitriles and enaminoesters (59CCC2385 72ZC417 76JPR705) established that the cationic center in 141 attacks the /3-position of enam-ines, and this is followed by a cyclization to 1,4-dihydropyridines (142) with... 

JOC2691). Analogously, in the reaction of chalcone (145) with the enaminonitrile 146, the intermediate dihydropyridine (147) can be detected only in trace amounts because it undergoes disproportionation with the formation of tetrahydropyridine (148) and pyridine derivatives (149) (92JOC7352). Fused 5,6-dihydropyridines (150) were obtained from cyclic... 

Enaminonitriles (154) easily react with esters of acetylenedicarboxylic acid or propiolic acid. The first step is an electrophilic attack of the reactant on the /3-position of the enamine, and this is followed by cyclization with... 

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... 

Enaminoamides with phosphorus trichloride yielded diazaphosphorins (92JPR711) (Scheme 48). Diazaphosphorins were also obtained by treatment of enaminonitriles, enaminoamides, and enaminothioamides with phosphorus pentasulfide in pyridine (96MC191) (Scheme 49). Fused 3-cyano-2-pyridones react with the Lawesson reagent giving phosphorus-containing heterocycles (95MC191) (Scheme 50). 

Condensation of cyclic enaminoamides (246) with dimethyl acetylene-dicarboxylate gives 2-azepinone derivatives (247) (85AJC1847). Similarly, immonium salts (248) when treated with bases give enamines, which subsequently react with dimethyl acetylenedicarboxylate or unsaturated ketones and give azepines (81AP787). The reaction of primary enaminonitriles with dimethyl acetylenedicarboxylate proceeds in a similar fashion (84CPB2596). Another route to azepines has been described (95JHC57) (Scheme 51). 

Condensation of the pyrrolidine enamine of cyclohexanone with l,l-dicyano-2,2-dimethylcyclopropane proceeds smoothly in refluxing dry xylene and gives the expected adduct in 76% yield. Recrystallisation of the adduct from 95% ethanol, however, gave a 91% yield of a product which no longer contained the pyrrolidine group but whose spectral data clearly showed the presence of a ketone group and an enaminonitrile function. Hydrolysis of this latter product with phosphoric acid/acetic acid gave 5-(2-oxo-4,4-dimethylcyclopentyl)pentanoic acid in 83% yield. 

There are several examples of similar reactions of enaminonitriles [9,10,11, 12, 13, 14]. Katsuyama et al. [9] determined that refluxing 3-aminobut-2-enenitrile 16 with fluorinated unsaturated ketone 17 in ethanol leads to high yields of dihydropyridines 18 (Scheme 3.6). The reaction of 16 with fluorinated cyclic ketone 19 leading to heterocycle 20 can be carried out in glacial acetic acid and does not need any additional catalyst or reagent [14] (Scheme 3.6). On the other hand, treatment of aminobutenenitrile 16 with ketones without strong... 

The enaminonitrile (3) proved to be a useful key intermediate in the synthesis of a variety of new pyranopyrimidine, pyranotriazolopyrimdine and pyranopyrimidotriazine derivatives. Thus, treatment of 3 with tri-ethylorthoformate - AC2O - gave the corresponding ethoxymethyleneamino derivatives (7). Hydrazinolysis of 7 in ethanol at room temperature yielded 9-amino-8,9-dihydro-8-imino-7-methyl-6H,7H-[l]benzopyrano[3/,4/ 5,6]-[3, 2-d]pyrimidie-6-one (8a). 

The photo Diels-Alder reaction of a-acetylnaphthalene 82 with the chiral oc-enaminonitril 83 yielded the cycloadduct 84 with excellent diastereoselec-tivity (Sch. 16) [57]. The intermediary formed biradical Y is particular stable due to delocalization of the radical on the aromatic moiety and to a captodative effect on the enamine part. The chiral induction occurred in two steps [58]. In the first step, a stereogenic center is created in the a-position of the acyl group. In the second step of the diastereoselection, one of the two diasteromeric intermediates undergoes preferentially cyclization to yield the final product 84, while the other one is more readily decomposed to form the starting material. For a more detailed discussion of the mechanism see Ref. [59]. 

Enaminonitriles as versatile reagents in synthesis of heterocycles 93CRV1991... 

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