Enaminonitriles synthesis

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

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 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... 

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). 

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

The photolysis of enaminonitriles provides a convenient and direct one-step synthesis of imidazoles. l,6-Dihydroimidazo[4,5-d]imidazole was prepared by the photochemical rearrangement of 3-aminopyrazole-4-carbonitrile (76JOC19) and by photolysis of 4-aminoimidazole-5-carbonitrile (74JA2014) (equation 71). The precise nature of the reaction intermediates (if any) formed on irradiation of enaminonitriles remains to be determined. However, the direct photochemical inversion of the nitrile to isocyanide is a possibility. 

A variation of the Hantzsch synthesis uses enaminones instead of / -dicarbonyl derivatives (for another variant, see Section II.A.l.e). Here the method consists of a condensation of two enaminone molecules and one molecule of aromatic or aliphatic aldehyde to give 1,4-dihydropyridines (equation 14). Various dihydropyridines have been synthesized by this method20-22. Enaminonitriles can be cyclocondensed in the same manner23 (equation 15). 

A similar intramolecular nucleophilic aromatic substitution has been used for the synthesis of pyrrolo[l,2-a] indoles in astonishing high yield from Z-enaminonitriles (equation 108)160. 

The photochemical behavior of enamines and their derivatives has been the subject of extensive mechanistic and synthetic investigations. The goal of this chapter is to summarize the photochemistry of enamines as well as enamides, enaminones, en-amidones and enaminonitriles, with particular emphasis on the application of the photochemistry of these chromophores in the synthesis of natural products. 

There are a number of examples of photochemical transformations of DAMN which may have some synthetic applications. At first, irradiation isomerizes the cir-dinitrile to the rrani -dinitrile, which then forms 5-amino-4-cyanoimidazole (18). Both azctidine or azirine intermediates have been postulated for these cyclizations [54, 55]. Although yields are good the photolytic conditions require dilute solutions ( lO moll solutions of the enaminonitriles) and may not prove practicable for the synthesis of larger quantities of imidazoles. On a small scale, however, the method merits consideration particularly since the process works for a wide variety of enaminonitriles (Scheme 2.1.9) [56-58]. 

In the Nenitzescu synthesis of 5-hydroxyindoles, an A-aryl substituted amino-propenoic ester may be used, albeit with a low yield of product [2343]. Better yields may be obtained by reacting the quinone at ambient temperature with an enaminonitrile [3246]. The methylthio group may be removed by heating with Raney nickel. Magnesium methyl carbonate is sometimes used to carboxylate a methyl ketone but when it is warmed with the methyl ketone (35.3), it causes cyclization of the keto side-chain [2747]. A dioxopyrimidine aldehyde (35.4) is cyclized in moderate yield by heating with carbonate in DMF [2668]. 

A reaction of the dinitrile (83) with hydrogen chloride in ether yielded the enaminonitrile (84). From the unsaturated (85), a dark blue immonium salt (86) was obtained <80JCR(S)233>. A new metabolite from Streptomyces olivaceus has been shown to be (25)-l-oxo-2,3-dihydropyrrolizin-3-carboxylic acid (88b) by total synthesis. Compound (87) was cyclized stereoselectively with phosphorus pentoxide in toluene. Partial racemization occurred during the hydrolysis of (88a) <81TL3293>. 

The Thorpe-Ziegler cyclization has found substantial utility in synthetic endeavors. Specifically, it has found broad scope for a variety of heterocyclic compounds. As demonstrated in the work of Salaheldin and coworkers, a one-pot alkylation/Thorpe-Ziegler sequence resulted in the synthesis of 3-aminopyrroles. Treatment of p,p-enaminonitrile 9 with chloroacetonitrile under basic conditions results in alkylation to produce intermediate 10, which undergoes a spontaneous Thorpe-Ziegler cyclization to create the 3-aminopyrrole 11. Notably, the use of EtsN as base resulted in a substantial improvment compared to the use of K2CO3 in DMF. 

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