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-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.

Keywords: 3-hydroxyindolinone; crystal structure; heterocyclic compounds; hydrogen bonding; isatin; molecular structure; supramolecular assembly; synthesis.

Figure 1

The mol­ecular structure of the R enanti­omer of com­pound (Ic), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 2

The mol­ecular structure of the R enanti­omer of com­pound (Id), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 3

The mol­ecular structure of the R enanti­omer of com­pound (Ie), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 4

The R enanti­omers of the two independent mol­ecules of com­pound (If), showing the atom-labelling schemes for (a) mol­ecule 1 and (b) mol­ecule 2. Displacement ellipsoids are drawn at the 30% probability level.

Figure 5

The mol­ecular structure of com­pound (IIa), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 6

The mol­ecular structure of com­pound (IIc), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 7

The mol­ecular structure of com­pound (IIe), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 8

The mol­ecular structure of com­pound (IIg), showing the atom-labelling scheme and the disorder of the thio­phene unit. The major-disorder com­ponent is drawn using full lines and the minor-disorder com­ponent has been drawn using broken lines. Displacement ellipsoids are drawn at the 30% probability level.

Figure 9

The mol­ecular structure of com­pound (IIh), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 10

Part of the crystal structure of com­pound (Ic), showing the formation of a chain of rings built from O—H⋯O, C—H⋯O and C—H⋯π(arene) hydrogen bonds. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motifs shown have been omitted.

Figure 11

Part of the crystal structure of com­pound (Id), showing the formation of a chain of rings built from O—H⋯O and C—H⋯O hydrogen bonds. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motifs shown have been omitted.

Figure 12

Part of the crystal structure of com­pound (Ie), showing the formation of a chain of rings running parallel to the [010] direction and built from O—H⋯N and C—H⋯π(arene) hydrogen bonds. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motifs shown have been omitted.

Figure 13

Part of the crystal structure of com­pound (Ie), showing the formation of a chain of rings running parallel to the [001] direction and built from two types of C—H⋯O hydrogen bonds. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motifs shown have been omitted.

Figure 14

Part of the crystal structure of com­pound (Ie), showing the formation of a chain of rings running parallel to the [100] direction and built from two types of C—H⋯O hydrogen bonds. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motifs shown have been omitted.

Figure 15

Part of the crystal structure of com­pound (If), showing the linking of the two independent mol­ecules by two independent O—H⋯O hydrogen bonds. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motifs shown have been omitted.

Figure 16

Part of the crystal structure of com­pound (If), showing the formation of a chain of rings running parallel to the [100] direction and built from O—H⋯O and C—H⋯O hydrogen bonds. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motifs shown have been omitted.

Figure 17

Part of the crystal structure of com­pound (If), showing the formation of a chain of rings running parallel to the [010] direction and built from O—H⋯O, C—H⋯O and C—H⋯π(arene) hydrogen bonds. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motifs shown have been omitted.

Figure 18

Part of the crystal structure of com­pound (IIa), showing the formation of a hydrogen-bonded chain running parallel to [010]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motif shown have been omitted.

Figure 19

Part of the crystal structure of com­pound (IIg), showing the formation of a hydrogen-bonded chain running parallel to [100]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the minor-disorder com­ponent and H atoms not involved in the motif shown have been omitted.

Figure 20

Part of the crystal structure of com­pound (IIe), showing the formation of a sheet built from three C—H⋯O hydrogen bonds and lying parallel to (010). Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, H atoms not involved in the motifs shown have been omitted.

Figure 21

Part of the crystal structure of com­pound (IIh), showing the formation of a chain of π-stacked dimers running parallel to the [100] direction. The Cl⋯(ring centroid) contacts are shown as tapered lines and, for the sake of clarity, H atoms have all been omitted.