Intramolecular Cyclization of 3,3‐Diarylpropenylamides of Electron‐Deficient Alkenes: Stereoselective Synthesis of Functionalized Hexahydrobenzo[f]isoindoles

Abstract

Intramolecular Diels–Alder reactions of various 3,3‐diarylpropenylamides of electron‐deficient alkenes to give hexahydrobenzo[f]isoindoles were investigated. Reaction of 1,1,2‐ethenetricarboxylic acid 1,1‐diethyl ester with 3,3‐diaryl‐2‐propen‐1‐amines under the amide formation conditions gave the tricyclic compounds in sequential processes involving intramolecular Diels–Alder reaction. The reaction gave cis‐ and trans‐fused tricyclic compounds selectively, depending on the substituents on the benzene ring, reaction temperature and solvent. In the reaction with dissymmetrically substituted 3,3‐diaryl‐2‐propen‐1‐amines, trans‐substituted aryl group reacted mainly as a styrene component. Amides of electron‐deficient alkenic carboxylic acids such as fumarate do not undergo cyclization at room temperature sequentially and the reaction on heating gave trans‐fused hexahydrobenzo[f]isoindoles. The origin of the observed stereoselectivity has been examined by the DFT calculations.

Sequential Intramolecular Diels–Alder Reaction of 3‐Heteroaryl‐2‐propenylamides of Ethenetricarboxylate

“…Although the initial cycloadducts 3 and 6 are unstable, they were isolated as crude forms. On the other hand, the corresponding initial cycloadducts for styrenes were not detected under the reaction conditions . This is probably because the aromaticity strength of heteroarenes is lower than that of benzene.…”

“…Determination of the detailed reaction mechanism of the cycloadditions finds the factor to control the selectivity. In order to rationalize the observed cis ‐fused and trans ‐fused selectivities and examine the applicability of the reaction models on the selectivity to heteroaryl ring systems, the reaction mechanism was investigated using B3LYP/6‐31G* , ωB97X‐D , and M06‐2X calculations including the polarizable continuum model (PCM) solvent effect (solvent = THF). The transition state (TS) geometry was characterized by vibrational analysis, which checked whether the obtained geometry has single imaginary frequencies (ν ‡ ).…”

“…Recently, we have reported intramolecular [4 + 2] cycloaddition reactions of a highly electron‐deficient alkenic carboxylic acid, 1,1,2‐ethenetricarboxylic acid 1,1‐diethyl ester 1 with E , Z ‐cinnamylamines and 3,3‐diaryl‐2‐propenylamines under the amide condensation conditions in sequential processes involving amide formation, intramolecular Diels–Alder reaction, and rearomatization (Scheme ) . The reaction of 1 with E ‐cinnamylamines bearing electron‐withdrawing groups under the amide condensation conditions afforded trans ‐fused tetrahydrobenz[ f ]isoindolines.…”

IntraMolecular Diels–Alder Reactions of Vinylarenes and Alkynyl Arenes (the IMDAV Reaction)

“…addition, although a temperature of at least 80 °C is required (Scheme 91). 55 In this case, cis-fused tricyclic compounds 300 were obtained as the major products (compare with the trans-fused isomers 295, 296 and 298 formed in Schemes 89 and 90). The previously described reaction conditions for the domino N-acylation/cycloaddition sequence were assayed for the cyclization of 3,3-diphenyl allylamines 301 using the EDCI/HOBt/Et 3 N system.…”

“…The reaction proceeds through the same intermediates (55,56), and regardless of the substituents R 1 -R 4 , the chemo-and diastereoselectivity of the cycloaddition is maintained at a high level even at 140 °C, whilst the yields of products 57 range from low to moderate (Table 2).…”