The tert-amino effect in heterocyclic chemistry: Synthesis of new fused pyrazolinoquinolizine and 1,4-oxazinopyrazoline derivatives

Abstract

The synthesis of novel fused heterocycles is based on reactions proceeding by the mechanism of the tert-amino effect, which generalizes cyclization of certain derivatives of 3-methyl-1-phenyl-2-pyrazolin-5-ones. Using this strategy a variety of fused heterocycles is obtained by the Knoevenagel condensation of 5-tert-amino-3-methyl-1-phenylpyrazolone-4-carboxal-dehyde 3 with active methylene compounds such as malononitrile and cyanoacetamide followed by cyclisation using anhydrous zinc chloride.

tert-Amino effect: the Meth-Cohn and Reinhoudt reactions (Review)

“…The Reinhoudt reaction is also characteristic of five-membered heterocycles [6,26,28,30] and their fused analogs [53,54]. Thus, in 5-chloro-3-methyl-1-phenylpyrazole-4-carbaldehyde [26,28] the chlorine atom was easily substituted by secondary amines.…”

“…It should be noted that all the above-mentioned reactions took place without a catalyst. However, the use of Lewis acids considerably accelerated [26,[58][59][60][61] cyclization by the tert-amino effect mechanism and made it possible to extend the applicability of the reaction [26,61]. It was also shown that using such acids as trifluoroacetic, HCl, HBr or (-)-camphorsulfonic acid allowed to cyclize the vinyl derivatives 72 containing only one withdrawing group at the double bond [57,62].…”

“…Thus, in 5-chloro-3-methyl-1-phenylpyrazole-4-carbaldehyde [26,28] the chlorine atom was easily substituted by secondary amines. The tertiary amines 66 thus obtained condensed with acyclic [30,53] or cyclic [6] For benzene and pyridazine substrates, ring closure was an exothermic reaction requiring high temperatures.…”

“…It should be noted that the reaction of the benzaldehyde 4n with cyanothioacetamide in butanol occurred in one stage, forming the tricyclic compound 32b. The cyclization of the amides 31a required a Lewis acid catalyst (ZnCl 2 ) [26]. …”

Thiourea: An Efficient and Inexpensive Catalyst for the Knoevenagel Condensation of Pyrazole Derivates

“…Recently, the Knoevenagel condesation about the pyrazole aldehyde as starting materials were reported. But these reactions are usually catalyzed by sodium acetate or piperidine in ethanol, [11][12][13] and the yield is low. Herein, we reported a genuienly green and mild Knoevenagel condensation containing pyrazole ring catalyzed by thiourea under microwave-assisted solvent-free conditions (Scheme I and Table 1).…”