Synthesis of Novel N-Heterocyclic Compounds Containing 1,2,3-Triazole Ring System via Domino, "Click" and RDA Reactions

Abstract

An uncomplicated, high-yielding synthetic route has been developed to constitute complicated heterocycles, applying domino, click and retro-Diels⁻Alder (RDA) reaction sequences. Starting from 2-aminocarboxamides, a new set of isoindolo[2,1-a]quinazolinones was synthesized with domino ring closure. A click reaction was performed to create the 1,2,3-triazole heterocyclic ring, followed by an RDA reaction resulting in dihydropyrimido[2,1-a]isoindole-2,6-diones. The absolute configuration, concluded by the norbornene structure that served as a chiral source, remained constant throughout the transformations. The structure of the synthesized compounds was examined by ¹H and ¹³C Nuclear Magnetic Resonance (NMR) methods.

Keywords: RDA reaction; click reaction; domino ring closure; regioselectivity; stereoselectivity; traceless chirality transfer.

Scheme 1

Reagents and conditions: (i) H₂O, MW 100 °C, 30 min, 300 W, 90%; (ii) Boc₂O, NaOH, dioxane/H₂O, 0 °C, 30 min, r.t., 4 h, 87%; (iii) DIC, HOBt, propargylamine, THF, r.t., 24 h, 75%; (iv) 1. HCl/H₂O 10%, r.t., 4 h 2. NaOH, H₂O/CHCl₃; (v) 2-formylbenzoic acid, pTSA, EtOH, MW, 100 °C, 30 min; 71%; (vi) 1. 2-methylbenzyl chloride, NaN₃, Et₃N, H₂O/tBuOH, r.t., 1 h, 2. sodium ascorbate, (−)-6 or (−)-8, CuSO₄, r.t. 8 h, 70–72%; (vii) MW, DCB, 220 °C, 60 min, 300 W, 70–72%.

Scheme 2

Reagents and conditions, see in Scheme 1, yields: (i) 85%; (ii) 85%; (iii) 72%; (iv-v) 70% (vi) 70–72%; (vii) 70–72%.