Synthesis of Tris-Heterocycles via a Cascade IMCR/Aza Diels-Alder + CuAAC Strategy

Abstract

6-Triazolylmethyl-pyrrolo[3,4- b ]pyridin-5-one tris-heterocycles were synthesized in 43–57% overall yields. The two-stage synthesis involved a cascade process (Ugi-3CR/aza Diels-Alder/ N -acylation/aromatization) followed by a copper-assisted alkyne-azide [3+2] cycloaddition (CuAAC). This efficient and convergent strategy proceeded via complex terminal alkynes functionalized with a fused bis-heterocycle at the α-position. The final products are ideal candidates for SAR studies as they possess two privileged scaffolds in medicinal chemistry: 4-substituted or 1,4-substituted 1 H -1,2,3-triazoles and pyrrolo[3,4- b ]pyridin-5-ones.

Synthesis of Polyheterocyclic Dimers Containing Restricted and Constrained Peptidomimetics via IMCR-Based Domino/Double CuAAC Click Strategy

“…Thus, with the optimized conditions, the desired propane-linked bis-triazolyl-pyrrolo[3,4- b ]pyridin-5-ones 13a – j were prepared in 44–80% yields from pyrrolo[3,4- b ]pyridin-5-ones 11a – j ( Table 1 ). Contrary to our previous report, MW irradiation at 100 °C allowed generation of the products in short reaction times of 5 min [ 32 ]. All the synthesized products were characterized by 1 H and 13 C-NMR and HRMS ( compounds 13a – j are shown in the Supplementary Material ).…”

“…(Table 1). Contrary to our previous report, MW irradiation at 100 °C allowed generation of the products in short reaction times of 5 min [32]. All the synthesized products were characterized by 1 H and 13 C-NMR and HRMS (compounds 13a-j are shown in the Supplementary Material).…”

“…The use of Lewis acids to activate imines has proven useful in Ugi-3CR with α-isocyano acetamides as reported by Zhu and co-workers [ 54 ], as the resulting iminium ions are more reactive than imines in the Ugi-3CR. Thus, after some reactions and with previously optimized reaction conditions [ 32 , 33 , 34 ], propargyl amine 6 was combined with aldehyde 7 to give the imine. Heating this imine at 50 °C for 30 min in microwave (MW) with 3 mol% Sc(OTf) 3 resulted in iminium ion, which was then reacted with the α-isocyanoacetamide 8 at 80 °C for 15 min to give key 5-aminooxazole 9 via chain-ring tautomerization.…”

“…Our ongoing research program focuses on the design of new or novel, rapid, convergent, ecofriendly, and efficient post-IMCR/transformation strategies in consecutive [ 32 , 33 , 34 , 35 , 36 , 37 , 38 ] or domino manner [ 39 , 40 , 41 ] toward the synthesis of novel molecules containing conformationally restricted and/or constrained peptidomimetics. Recently, we reported the first ultrasound-assisted green one-pot synthesis of molecules containing privileged restricted peptidomimetics via this strategy: post-IMCR transformation/ Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction employing a green alternative energy source [ 42 ].…”

“…Recently, we reported the first ultrasound-assisted green one-pot synthesis of molecules containing privileged restricted peptidomimetics via this strategy: post-IMCR transformation/ Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction employing a green alternative energy source [ 42 ]. In addition, the synthesis of molecules containing restricted and constrained PHPs via IMCR, followed by a domino process and subsequent CuAAC to incorporate 1,2,3-triazoles moiety ( Scheme 1 b) [ 32 ]. Surprisingly, the synthesis of PHPs via the post-MCR transformation click strategy has rarely been reported [ 43 , 44 ].…”