1,2,3 triazole enamine intermediates

The reaction is surmised to occur via the formation of an enamine intermediate, followed by azide addition to generate a zwitterionic intermediate primed for the 1,3-dipolar-cycloaddition event (Scheme 5.46). Syn-elimination regenerates the catalyst, where proline s carhojg late group plays an important role in the elimination step, driven hy rearomatisation of the triazole product. 

The general plausible mechanism proposed for this enamine-based triazole synthesis is shown in Scheme 4.38. The first step is most likely the condensation of the organocatalyst with the carbonyl compound 22 to generate the enamine intermediate A, which acts as the electron-rich olefinic partner and reacts with the aryl azide 2 to form the intermediate B. The cycloaddition adduct, intermediate B undergoes a 1,3-hydride shift to generate the triazoline intermediate C. The zwit-terion D formed from the triazoline then eliminates the organocatalyst to furnish the 1,2,3-triazole 64. 

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. 

The reactions of enamines as 1,3-dipolarophiles provide the most extensive examples of applications to heterocyclic syntheses. Thus the addition of aryl azides to a large number of cyclic (596-598) and acyclic (599-602) enamines has led to aminotriazolines which could be converted to triazoles with acid. Particular attention has been given to the direction of azide addition (601,603). While the observed products suggest a transition state in which the development of charges gives greater directional control than steric factors, kinetic data and solvent effects (604-606) speak against zwitterionic intermediates and support the usual 1,3-dipolar addition mechanism. 

On the other hand, Lipson and co-authors in their pubhcations described numerous MCRs of cyclic (3-dicarbonyl compounds and aldehydes with 5-amino-3-methylpy-razole [84], 3-amino-1,2,4-triazole [90], 3-amino-5-methyltio-l,2,4-triazole [91], 2-aminobenimidazole [92], and 2,5-diamino-l,2,4-triazole [93]. It was shown that multicomponent treatments studied in the case of these aminoazoles should proceed via preliminary formation of corresponding enamines, which were isolated and subsequently transformed into target heterocycles (Scheme 28). Intermediates... 

Junjappa and co-workers (9) reported the cycloaddition of sodium azide to the polarized ketene-(5,5)-acetal 33 to give the tiiazole 35 they also reported an intermolecular cycloaddition of tosyl azide 37 with the enamine 36 to give an unstable triazoline intermediate 38. Ring opening 38 followed by a Dimroth rearrangement afforded the triazole 41 (Scheme 9.9). 

However, this approach required additional functional group manipulation steps since the chiral P-amino ester intermediate had to be hydrolyzed and activated to be converted to the desired amide. These steps could potentially be dirni-nated by introducing the triazole fragment much earlier in the synthesis and then introducing the chiral center on an enamine-amide instead of an enamine-ester (Route B on Scheme 5.8). 

Sulfonyl azides react rapidly (at room temperature) with enamines, and here, too, no triazolines are isolated. The reaction products nevertheless can be easily explained when an intermediate triazoline is postulated. The hypothetic triazoline can then decompose in three different ways leading either to amidines and nitrogen, or to amidines and diazoketones, or to triazoles and sulfonamines.226-241-270-272 A typical example of each mode of decomposition is given in Scheme IX. 

The 1,3-dipolar cycloaddition of azidoalkylphosphonates to enamines afforded A2-1,2,3-triazoles which are further converted to the 1,2,3-triazoles [95H(40)543] fused triazoles are similarly obtained when a cyclic enamine was employed. Fused 1,2,3-triazole (88), a xanthine oxidase inhibitor, was prepared by the reaction of an alkyl azide with cyanoacetamide with further elaboration of intermediate (87) by treatment with HMDS in xylene [95FES257]. The fused 4H-l,2,3-triazolo[l,5- ][l,4]benzodiazepin-6(5H)-one (90) was obtained from propargylamide (89) via an intermediate azide [95S647]. 

Triazolines which are formed as intermediates after the 1,3-dipolar cycloaddition of azides to enamines cannot be isolated but directly undergo elimination to give triazoles. 

The yields of nitro-1,2,3-triazoles are not usually high, but such products are useful intermediates in the preparation of many of the compounds previously discussed. For example, /3-nitrostyrenes or enamines provide routes to the 4-amino compounds that are difficult to obtain by other methods (Eqs. 10 to 12).When R = H, the yields are vastly superior. A still more promising route involves -bromo-/3-nitrostyrenes (Eq. 13). ... 

In 1986, Gelmi et al. converted a mixture of stereoisomers of the aldehyde 46 exo-endo in the ratio 95 5 into the corresponding enamines by treatment with secondary amines, which underwent quick cycloaddition with 4-nitrophenylazide to furnish the triazole 48 via the triazoline intermediate 47 by a rearrangement at room temperature (Scheme 4.16) [19]. 

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