New synthetic strategies using alkynes and propargylic amines for the preparation of azaheterocyclic and non-cyclic compounds

Abstract

Combining simple organic substrates through single step multicomponent reactions to build up complex compounds with potential therapeutic and synthetic applications has enormously been evolved in the previous decades. Adopting this strategy, a library of trisubstituted propargylamines was synthesized by the condensation of aldehydes, amines and terminal alkynes. Zn(II) triflate was found to be the catalyst of choice amongst a number of many Lewis acids tested during optimization. Toluene was proved to be best solvent to carry out this reaction. After finding best reaction conditions a variety of aldehydes, amines and alkynes were utilized to furnish the tri-substituted propargylamines. In case of aldehydes; tert-butyraldehyde, iso-butyraldehyde, nbutyraldehyde and benzaldehydes were successfully incorporated while in case of amines, not only primary but also secondary and tertiary amines even t-butyl amine were well tolerated under developed conditions. Variety of alkynes both aromatic (with electron withdrawing such as Cl, Br, and F, as well as electron donating groups such as CH3 and OCH3) and aliphatic worked well to deliver expected products in good yields. In continuation of broadening the scope of this methodology and as an application of aldehyde, amine and alkyne condensation, incorporation of carbazole-3-formaldehyde was carried out. After optimization of various catalysts, reaction conditions and solvents it was found that CuBr is the most efficient catalyst for condensation of Nalkylcarbazole- 3-carbaldehyde, amines and alkynes in acetonitrile or under solvent free conditions. Under the optimized conditions N-octyl, N-butyl and N-ethyl carbazole-3-carbaldehyde were condensed with a variety of amines and alkynes to deliver a range of carbazolyl decorated propargylamines. Regarding primary aliphatic amines; n-propalamine, npentylamine and benzalamine were successfully incorporated. In case of anilines both bearing electron withdrawing as well as electron donating groups such as 3-Me, 4-Me, 4- Et, 4-Cl, 4-Br, 4-OMe and 4-OH were utilized. Only in case of 4-methoxyaniline instead of expected product, a side product was obtained with elimination of aniline group. Similarly a range of pheneylacetylenes both with electron withdrawing as well as electron iii donating groups were well tolerated. The structures of all new compounds were determined and confirmed by spectroscopic methods. Further, one-pot reaction of N-alkylcarbazole-3-carbaldehydes with amines and thioglycolic acid (TGA) was carried out, which resulted in the formation of selectively 2- carbazolyl-1,3-thiazolidin-5-ones. The scope of reaction was tested by utilizing various N-substituted carbazolaldehyde, primary and secondary amines which were successfully condensed with TGA to deliver expected carbazolylthiazolidinones in good to moderate yield. Finally, one-pot three-component reaction involving aldimines, alkynes and thiocyanates to densely-functionalized 5-benzylidene thiazolidin-2-imines was also discovered. Although reaction could not beoptimized starting from aldehydes, amines and alkynes but starting from preformed imines, alkynes and thioisocyanates, the expected thiazolidins could be achieved under optimized conditions. For this reaction zinc chloride proved to be catalyst of choice from all other metal salts which were tested. Dimethylformamide was best solvent and under optimized conditions a variety of Schiff bases and terminal alkynes were successfully reacted with various phenyl isothiocyanates to furnish corresponding thiazolidin-2-imines in excellent yields. The possibility of formation of 4-benzylidine imidazolidine-2-thiones in this reaction was ruled out by 13C-NMR spectroscopy and finally by single crystal analysis. While exploring the substrate scope with respect to N-substituents of Schiff bases, it was realized that primary amines such as n-propyl, n-pentyl and N-benzyl group were well tolerated while N-ter-butyl group did not afford the expected product. In case of alkynes both with electron donating as well as electron withdrawing groups such as 2-methyl, 4- methyl, 4-ethyl, 4-methoxy, 4-chloro, 4-bromo and 4-fluoro-2-methyl showed good reactivity. In case of isothiocyanates it was observed that those with electron withdrawing groups, for instance 4-chloro and 4-fluoro furnished corresponding thiazolidin-2-imines with high yield as compare to those bearing mild electron donating groups such as 2-Me, 4-Me, 4-Et and strong electron donating group such as 4-methoxy isothiocyanate. The structures of all new compounds were determined and confirmed by spectroscopic methods.