Synthesis of N-substituted 3-(2-aryl-2-oxoethyl)-3-hydroxyindolin-2-ones and their conversion to N-substituted (E)-3-(2-aryl-2-oxoethylidene)indolin-2-ones: synthetic sequence, spectroscopic characterization and structures of four 3-hydroxy compounds and five oxoethylidene products

Abstract

An operationally simple and time-efficient approach has been developed for the synthesis of racemic N-substituted 3-(2-aryl-2-oxoethyl)-3-hydroxyindolin-2ones by a piperidine-catalysed aldol reaction between aryl methyl ketones and N-alkylisatins. These aldol products were used successfully as strategic intermediates for the preparation of N-substituted (E)-3-(2-hetaryl-2-oxoethylidene)indolin-2-ones by a stereoselective dehydration reaction under acidic conditions. The products have all been fully characterized by 1 H and 13 C NMR spectroscopy, by mass spectrometry and, for a representative selection, by crystal structure analysis. In each of (RS)-1-benzyl-3-hydroxy-3-[2-(4-methoxyphenyl)-2-oxoethyl]indolin-2-one, C 24 H 21 NO 4 , (Ic), and (RS)-1-benzyl-3-{2-[4-(dimethylamino)phenyl]-2-oxoethyl}-3-hydroxyindolin-2-one, C 25 H 24 N 2 O 3 , (Id), inversion-related pairs of molecules are linked by O-HÁ Á ÁO hydrogen bonds to form R 2 2 (10) rings, which are further linked into chains of rings by a combination of C-HÁ Á ÁO and C-HÁ Á Á(arene) hydrogen bonds in (Ic) and by C-HÁ Á Á (arene) hydrogen bonds in (Id). The molecules of (RS)-1-benzyl-3-hydroxy-3-[2-oxo-2-(pyridin-4-yl)ethyl]indolin-2-one, C 22 H 18 N 2 O 3 , (Ie), are linked into a three-dimensional framework structure by a combination of O-HÁ Á ÁN, C-HÁ Á ÁO and C-HÁ Á Á(arene) hydrogen bonds. (RS)-3-[2-(Benzo[d][1,3]dioxol-5yl)-2-oxoethyl]-1-benzyl-3-hydroxyindolin-2-one, C 24 H 19 NO 5 , (If), crystallizes with Z 0 = 2 in the space group P1 and the molecules are linked into complex sheets by a combination of O-HÁ Á ÁO, C-HÁ Á ÁO and C-HÁ Á Á(arene) hydrogen bonds. In each of (E)-1-benzyl-3-[2-(4-fluorophenyl)-2-oxoethylidene]indolin-2one, C 23 H 16 FNO 2 , (IIa), and (E)-1-benzyl-3-[2-oxo-2-(thiophen-2-yl)ethylidene]indolin-2-one, C 21 H 15 NO 2 S, (IIg), the molecules are linked into simple chains by a single C-HÁ Á ÁO hydrogen bond, while those of (E)-1-benzyl-3-[2-oxo-2-(pyridin-4-yl)ethylidene]indolin-2-one, C 22 H 16 N 2 O 2 , (IIe), are linked by three C-HÁ Á ÁO hydrogen bonds to form sheets which are further linked into a three-dimensional structure by C-HÁ Á Á(arene) hydrogen bonds. There are no hydrogen bonds in the structures of either (E)-1-benzyl-3-[2-(4-methoxyphenyl)-2-oxoethylidene]indolin-2-one, C 24 H 19 NO 3 , (IIc), or (E)-1-benzyl-5-chloro-3-[2-(4-chlorophenyl)-2oxoethylidene]indolin-2-one, C 23 H 15 Cl 2 NO 2 , (IIh), but the molecules of (IIh) are linked into chains of -stacked dimers by a combination of C-ClÁ Á Á(arene) and aromaticstacking interactions.

Synthesis and Biological Studies of Benzo[b]furan Derivatives: A Review from 2011 to 2022

“…Isatin, also known as 1 H -indole-2,3-dione, is an important N -heterocycle in medicinal chemistry and drug discovery [ 55 ]. In their study, Mohammed et al synthesized an isatin–benzofuran hybrid 126 and investigated its antiproliferative activity against HT29 and SW620 cancer cell lines, along with its impact on tumor and metastatic development involved in primary cellular processes [ 56 ].…”

“…Notably, the phenyl and heterocyclic rings of 120d engaged in π-sigma interactions with Leu1256 and Val1130, while the NH group formed hydrogen bonds with Gly1201 and π-anion bonds with Glu1210. Isatin, also known as 1H-indole-2,3-dione, is an important N-heterocycle in medicinal chemistry and drug discovery [55]. In their study, Mohammed et al synthesized an isatinbenzofuran hybrid 126 and investigated its antiproliferative activity against HT29 and SW620 cancer cell lines, along with its impact on tumor and metastatic development involved in primary cellular processes [56].…”

Synthesis, Characterization, and DFT Studies of N-(3,5-Bis(trifluoromethyl)benzyl)stearamide

“…Importantly, the metal-and catalyst-free direct amidation of carboxylic acids with amines has been neglected for many years owing to its high temperatures and long reaction times; nonetheless, this thermal approach can eliminate some of the previously reported synthetic drawbacks. In connection with the ongoing development of efficient and simple protocols for the construction of carbon-nitrogen bonds [27][28][29][30][31] and our current studies on the synthetic utility of benzylamine derivatives [32,33], we describe a solventless synthesis of N-(3,5bis(trifluoromethyl)benzyl)stearamide 3 through an uncatalyzed process under normal atmospheric conditions. Moreover, molecular electrostatic potential studies, determination of quantum descriptors, fundamental vibrational frequencies, and intensity of vibrational bands were computed by the B3LYP method using 6-311+G(d,p) basis set in gas phase.…”