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-2-ones 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 1H and 13C 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, C24H21NO4, (Ic), and (RS)-1-benzyl-3-{2-[4-(dimethylamino)phenyl]-2-oxoethyl}-3-hydroxyindolin-2-one, C25H24N2O3, (Id), inversion-related pairs of molecules are linked by O-H...O hydrogen bonds to form R22(10) rings, which are further linked into chains of rings by a combination of C-H...O and C-H...π(arene) hydrogen bonds in (Ic) and by C-H...π(arene) hydrogen bonds in (Id). The molecules of (RS)-1-benzyl-3-hydroxy-3-[2-oxo-2-(pyridin-4-yl)ethyl]indolin-2-one, C22H18N2O3, (Ie), are linked into a three-dimensional framework structure by a combination of O-H...N, C-H...O and C-H...π(arene) hydrogen bonds. (RS)-3-[2-(Benzo[d][1,3]dioxol-5-yl)-2-oxoethyl]-1-benzyl-3-hydroxyindolin-2-one, C24H19NO5, (If), crystallizes with Z' = 2 in the space group P-1 and the molecules are linked into complex sheets by a combination of O-H...O, C-H...O and C-H...π(arene) hydrogen bonds. In each of (E)-1-benzyl-3-[2-(4-fluorophenyl)-2-oxoethylidene]indolin-2-one, C23H16FNO2, (IIa), and (E)-1-benzyl-3-[2-oxo-2-(thiophen-2-yl)ethylidene]indolin-2-one, C21H15NO2S, (IIg), the molecules are linked into simple chains by a single C-H...O hydrogen bond, while those of (E)-1-benzyl-3-[2-oxo-2-(pyridin-4-yl)ethylidene]indolin-2-one, C22H16N2O2, (IIe), are linked by three C-H...O hydrogen bonds to form sheets which are further linked into a three-dimensional structure by C-H...π(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, C24H19NO3, (IIc), or (E)-1-benzyl-5-chloro-3-[2-(4-chlorophenyl)-2-oxoethylidene]indolin-2-one, C23H15Cl2NO2, (IIh), but the molecules of (IIh) are linked into chains of π-stacked dimers by a combination of C-Cl...π(arene) and aromatic π-π stacking interactions.
Highlights
We reported the synthesis and structures of a range of 3-alkyl-3-hydroxyindolin-2-ones by reaction of isatin itself with a variety of methyl ketones in the presence of piperidine
Focusing primarily on the N-benzyl intermediate of type (B), the subsequent reactions with aryl methyl ketones in the presence of piperidine did 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, Figure 1 The molecular structure of the R enantiomer of compound (Ic), showing the atom-labelling scheme
Which is consistent with the idea of partial proton transfer from the N-unsubstituted isatin to piperidine
Summary
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)
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