Research Article: 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

Date Published: May 01, 2020

Publisher: International Union of Crystallography

Author(s): Diana Becerra, Juan Castillo, Braulio Insuasty, Justo Cobo, Christopher Glidewell.


Ten novel 3-(2-aryl-2-oxoeth­yl)-3-hy­droxy­indolin-2-ones have been synthesized, mostly in excellent yield, and characterized spectroscopically, and nine of these have been dehydrated to the corresponding (E)-3-(2-aryl-2-oxo­ethyl­idene)indolin-2-ones, also in excellent yield, and again characterized spectroscopically. The structures of four of the former and five of the latter are reported, and all show different patterns of supra­molecular assembly.

Partial Text

Almost 60% of drugs based on small organic mol­ecules which are in use for medicinal purposes contain at least one N-heterocyclic ring (Vitaku et al., 2014 ▸). Amongst these, isatin (1H-indole-2,3-dione) and its derivatives have attracted particular inter­est because of their broad range of biological and pharmacological activities (Singh & Desta, 2012 ▸; Pakravan et al., 2013 ▸). Isatin derivatives have also been found to be useful synthetic inter­mediates for the production of both dyestuffs and organic electronic materials (Stalder et al., 2014 ▸; Deng & Zhang, 2014 ▸). These wide-ranging applications have prompted the development of a large range of synthetic approaches to functionalized isatin derivatives (Moradi et al., 2017 ▸; Bogdanov & Mironov, 2018 ▸; Varun et al., 2019 ▸). Amongst these, the addition of nucleophilic units to the pro­chiral carbonyl group at atom C3 permits the construction of chiral 3-substituted-3-hy­droxy­indolin-2-ones containing a stereo­genic centre at the 3-position (Peddibhotla, 2009 ▸; Mohammadi et al., 2013 ▸). Such species are desirable targets, because many related structural motifs are found in natural products and pharmaceutically active com­pounds; for example, convolutamydine A is a bioactive alkaloid with significant activity against HL-60 human plomyelocytic leukemia cells (Kamano et al., 1995 ▸), SM-130686 is a novel orally active growth hormone secretagogue (Nagamine et al., 2001 ▸), donaxaridine has shown effective anti­cancer properties (Kimura et al., 2016 ▸) and maremycins A and B exhibit anti­bacterial, anti­fungal and anti­tumour properties (Duan et al., 2018 ▸).

The title com­pounds were synthesized starting from the readily available isatins (A), (see Scheme 1, where X = H or Cl; Figs. 1–9 ▸ ▸ ▸ ▸ ▸ ▸ ▸ ▸ ▸). The N-alkyl­ation of the starting isatins was explored using both benzyl bromide and 1-hexyl bromide in the presence of caesium carbonate as a weak non-nucleophilic base, giving isolated yields of the N-alkyl inter­mediates (B) consistently in excess of 90%. Focusing primarily on the N-benzyl inter­mediate of type (B), the subsequent reactions with aryl methyl ketones in the presence of piperidine did indeed provide generally much higher yields of the products of type (I), usually well above 80%, than had previously been achieved using isatin carrying no substituent at the N atom, which is consistent with the idea of partial proton transfer from the N-unsubstituted isatin to piperidine. The yields in both steps appear to be much the same regardless of whether the substituent at the N atom is benzyl or 1-hexyl, or whether the substituent at C5 is H or Cl. The only exception was found for com­pound (Id), where the yield was quite low, 36%, even after a much longer reaction time than that required for all the other type (I) products; this may be associated with the strongly electron-donating nature of the di­methyl­amino group. Acid-catalysed dehydration of nine of products (I) gave the N-substituted (E)-3-(2-aryl-2-oxo­ethyl­idene)indolin-2-ones (II), again with yields well above 80%, although, because of the slow formation and poor yields of (Id) in the first step, the dehydration of this inter­mediate was not pursued.




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