N,N-Dialkyl-N′-Chlorosulfonyl Chloroformamidines in Heterocyclic Synthesis. Part XII. Synthesis and Reactivity of the Pyrazolo[3,4-e][1,2,4]thiadiazine Ring System

Abstract

N,N-Dialkyl-N 0 -chlorosulfonyl chloroformamidines 1 reacted regioselectively with 1-substituted 5-aminopyrazoles 2 via a 1,3-CCN dinucleophilic substitution to afford pyrazolo[3,4-e][1,2,4]thiadiazines 3 as the sole isolated products. Compounds 3, representatives of a very rare ring system, were shown to possess three nucleophilic sites at N2, N4, and N6. Methylation occurred at all three sites. Alkylation with benzylic halides occurred preferentially at N2, but some also occurred at N4, and at C7a. Alkylation with ethyl bromoacetate occurred at both N4 and N6, but the latter derivatives underwent a pyrazole ring expansion to afford pyrimido[4,5-e][1,2,4]thiadiazine derivatives. Compounds 3 were unreactive towards various acylating agents.

New heteroatom-rich ring systems from N,N-dialkyl-N’-chlorosulfonyl chloroformamidines

“…67 The regiochemical outcome of these reactions is in accord with our other studies with dichlorides 1, where carbon nucleophiles typically reacted at the sulfamoyl group (see previous section 3.2.4).…”

“…50 Treatment of pure samples of 40e with TFAA in acetonitrile or pyridine afforded the C5 trifluoroacetylated product 59. No NH acylated products were isolated, confirming the significant nucleophilicity of C5 in this ring system.…”

“…74 It is apparent that this methodology can be extended to reactions with other 1,3-dicarbonyl systems to produce related Table 21) were isolated. 67 Compounds 81 are derivatives of a very rare ring system.…”

“…Methylation of 81b and 81h was not very selective and a mixture of products was obtained in each case; however, methylation of substrate 81b, with a (relatively small) methyl substituent at C7, resulted in a higher yield of N6 methylated product 85a (65%) than with substrate 81h, with a 7-(thien-2-yl) substituent (85b; 21%). 67 NOe data could not be used to effectively elucidate regioisomers of the methylated compounds owing to the methyl groups in N-methylated products 83a-85b not being in sufficiently close proximity to the other substituents; therefore, an X-ray crystal structure of an example of each of 83, 84, and 85 was solved. 67 Alkylation of 81b and 81h with 4-chlorobenzyl bromide occurred at N2 and N4; preferentially at N2, providing products 83, and to a lesser extent at N4, giving 84.…”

“…67 NOe data could not be used to effectively elucidate regioisomers of the methylated compounds owing to the methyl groups in N-methylated products 83a-85b not being in sufficiently close proximity to the other substituents; therefore, an X-ray crystal structure of an example of each of 83, 84, and 85 was solved. 67 Alkylation of 81b and 81h with 4-chlorobenzyl bromide occurred at N2 and N4; preferentially at N2, providing products 83, and to a lesser extent at N4, giving 84. The structural assignments of these products were based on key nOe interactions shown in Scheme 49.…”