# Hydrolysis and Hydrazinolysis of Isatin-Based Ald- and Ketazines

Authors: Hany S. Ibrahim; Soha R. Abdelhadi; Hatem A. Abdel-Aziz
Journal: Journal of Chemistry
 (2015)

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## Abstract

The hydrolysis of isatin aldazine4a–d afforded the unexpected 3,3′-(hydrazine-1,2-diylidene)bis(indolin-2-one) (5) and 1,2-di(arylidene)hydrazines 6a–d through dual hydrolysis of  4a–d. A mechanism to explain the formation of 5 and 6a–d was proposed. In addition, the hydrazinolysis of 4a–d yielded 3-hydrazonoindolin-2-one (2) and 1,2-di(arylidene)hydrazines 6a–d instead of hydrazones 17a–d, while hydrazinolysis of isatin ketazine 5 gave the expected 3-hydrazonoindolin-2-one (2). These results indicated the ability of the title compounds for unusual hydrolysis and hydrazinolysis reactions.


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## Body

## 1. Introduction

Isatin imines including Schiff bases1b and isatin hydrazones2, which are the product of condensation of amines or hydrazines with isatins1a, respectively, are considered as a pharmacophore for diverse spectrum of biological activities [1–5] (Figure 1). They have been reported as anticancer agents where they were found to be inhibitors of tyrosine phosphatase Shp2 [6]. Furthermore, they have been identified as kinase inhibitors and they also have been reported as cytotoxic agents towards U937 lymphoma cells [7]. In addition, hydrazones2 (R = –COAr) revealed a good cytotoxic activity against K562, MDA-MB-468, and HT-29 cell lines [8].Figure 1
General structure of1–5.Isatin-based azines4 are usually prepared by the condensation of isatin hydrazones2 (R1 = H) with aldehydes or ketones3 to construct the connectivity >C=N–N=CR2R3 and then the formation of isatin aldazines (4, R2 or R3 = H) or isatin ketazines (4, R2 and R3 ≠ H), respectively (Figure 1). Isatin aldazines4 showed a significant anticancer activity against human breast cell line MCF-7 [9], whereas a series of symmetrical and asymmetrical isatin ketazines5 showed a selective activity against multidrug-resistant cancer cells [10]. Moreover, bis-Schiff bases of isatins4 represent significant antiglycation activity [11].On the other hand, azines undergo hydrolysis to regenerate the hydrazine and aldehydes or ketones. However, ketazines are important intermediates in the production of hydrazine hydrate when subjected to hydrolysis processes [12]. In addition, the reaction of azines with hydrazine (hydrazinolysis) regenerates the hydrazones [13]. In light of the latter results and in continuation of our interest in the chemistry of isatin-based azines4 and5, we hope to report herein the unexpected results of hydrolysis and hydrazinolysis of isatin aldazines4a–d and isatin ketazines5.


## 2. Experimental

### 2.1. General

Melting points were measured with a Stuart melting point apparatus and were uncorrected. IR spectra (KBr disks) were recorded with a Pye Unicam SP 1000 IR spectrophotometer. The NMR spectra were recorded by Varian Gemini-300BB 300 MHz FT-NMR spectrometers (Varian Inc., Palo Alto, CA).1H and 13C spectra were run at 300 and 75 MHz, respectively, in deuterated dimethyl sulfoxide (DMSO-d6). Chemical shifts (δH) are reported relative to TMS as internal standard. All coupling constant (J) values are given in Hertz. Chemical shifts (δC) are reported relative to DMSO-d6 as internal standards. The abbreviations used are as follows: s: singlet; d: doublet; and m: multiplet. Mass spectra were recorded on Helwett Packard 5988 spectrometer at 70 eV. Reaction courses and product mixtures were routinely monitored by thin layer chromatography (TLC) on silica gel precoated F254 Merck plates. Unless otherwise noted, all solvents and reagents were commercially available and were used without further purification.


### 2.2. Synthesis of Isatin Aldazines4a–d

A mixture of 3-hydrazonoindolin-2-one (2) (0.161 g, 1 mmol) and aldehyde from3a–c (1 mmol) in acetic acid (25 mL) was stirred at room temperature for 12 h. The resulted precipitate was filtered, dried, and finally crystallized from EtOH/DMF to afford hydrazones4a–c, respectively. Aldazines4a–d were also prepared by the reaction of2 with3a–d in refluxing ethanol, in the presence of catalytic amount of glacial acetic acid for 6 h [10].


#### 2.2.1. 3-((Benzylidene)hydrazono)indolin-2-one (4a)

Yield (62%), mp > 300°C (lit. mp 300°C [14]); IR (KBr)v 3280 (NH), 1722 (C=O), 1614 (C=N) cm−1; 1H NMR (DMSO-d6) δ 6.90 (d, 1H,J = 7.8 Hz, H4 of isatin), 7.04 (t, 1H,J = 7.5 Hz, H5 of isatin), 7.42 (t, 1H,J = 7.5 Hz, H6 of isatin), 7.51 (d, 1H,J = 7.8 Hz, H7 of isatin), 7.57–7.99 (m, 5H, Ar–H), 8.61 (s, 1H, N=CH), 10.97 (s, D2O exchangeable, 1H, NH); 13C NMR (DMSO-d6) δ 110.95, 111.19, 115.73, 122.39, 122.63, 128.03, 128.25, 134.26, 134.47, 144.70, 145.16, 163.36 (C=O); MSm/z (%) 249 (M+, 30.02), 221 (17.03), 145 (35.41).


#### 2.2.2. 3-((4-Nitrobenzylidene)hydrazono)indolin-2-one (4b) [11]

Yield (66%), mp 254–256°C; IR (KBr)v 3161 (NH), 1734 (C=O), 1616 (C=N) cm−1; 1H NMR (DMSO-d6) δ 6.90 (d, 1H,J = 7.8 Hz, H4 of isatin), 7.01 (t, 1H,J = 7.5 Hz, H5 of isatin), 7.41 (t, 1H,J = 7.5 Hz, H6 of isatin), 7.73 (d, 1H,J = 7.8 Hz, H7 of isatin), 8.20 (d, 2H,J = 8.7 Hz, Ar–H), 8.37 (d, 2H,J = 8.7, Ar–H), 8.66 (s, 1H, N=CH), 10.86 (s, D2O exchangeable, 1H, NH); 13C NMR (DMSO-d6) δ 110.85, 111.08, 116.01, 122.29, 122.53, 124.23, 128.59, 128.78, 129.64, 133.98, 134.19, 139.06, 145.27, 148.97, 149.67, 156.21, 156.35, 164.10 (C=O); MSm/z (%) 294 (M+, 10.49), 266 (100).


#### 2.2.3. 3-((4-Chlorobenzylidene)hydrazono)indolin-2-one (4c)

Yield (78%), mp = 270–272°C (lit. mp = 200°C [14]); IR (KBr)v 3248 (NH), 1734 (C=O), 1604 (C=N) cm−1; 1H NMR (DMSO-d6) δ 6.90 (d, 1H,J = 7.5 Hz, H4 of isatin), 7.02 (t, 1H,J = 7.8 Hz, H5 of isatin), 7.41 (t, 1H,J = 7.8 Hz, H6 of isatin), 7.63 (d, 2H,J = 8.4 Hz, Ar–H), 7.85 (d, 1H,J = 7.5 Hz, H7 of isatin), 7.98 (d, 2H,J = 8.4, Ar–H), 8.61 (s, 1H, N=CH), 10.86 (s, D2O exchangeable, 1H, NH); 13C NMR (DMSO-d6) δ 110.73, 110.98, 116.26, 128.82, 129.23, 130.37, 130.45, 132.24, 133.92, 136.65, 141.72, 145.07, 150.29, 158.75, 164.35 (C=O); MSm/z (%) 285 (M+ + 2, 6.78), 283 (M+, 20.10), 255 (89.86), 145 (16.96), 138 (54.66), 111 (95.01).


#### 2.2.4. 3-((4-Methoxybenzylidene)hydrazono)indolin-2-one (4d)

Yield (69%), mp = 182-183°C (lit. mp = 182°C [14]); IR (KBr)v 3194 (NH), 1732 (C=O), 1606 (C=N) cm−1; 1H NMR (DMSO-d6) δ 3.87 (s, 6H, 2OCH3), 6.89 (d, 1H,J = 7.5 Hz, H4 of isatin), 7.04 (t, 1H,J = 7.8 Hz, H5 of isatin), 7.12 (d, 2H,J = 8.4, Ar–H), 7.39 (t, 1H,J = 7.5 Hz, H6 of isatin), 7.94 (d, 2H,J = 8.4 Hz, Ar–H), 8.02 (d, 1H,J = 7.8 Hz, H7 of isatin), 8.61 (s, 1H, N=CH), 10.76 (s, D2O exchangeable, 1H, NH); 13C NMR (DMSO-d6) δ 55.55 (OCH3), 110.58, 110.81, 114.62, 114.87, 116.59, 122.13, 122.36, 126.32, 128.79, 128.86, 130.91, 131.03, 133.29, 133.52, 144.80, 145.15, 150.65, 161.81, 161.93, 162.58, 163.36, 164.69 (C=O); MSm/z (%) 279 (M+, 30.31), 251 (100), 134 (17.79).


### 2.3. Hydrolysis of Isatin Aldazines4a–d

Method A. A solution of isatin aldazines4a–d (1 mmol) in H2O/AcOH (1 : 3, v : v, 25 mL) was refluxed for 4 h. The given 3,3′-(hydrazine-1,2-diylidene)bis(indolin-2-one) (5) was filtered while hot and crystallized from EtOH/DMF. The filtrate of the latter reaction was concentrated. The solid formed was washed with 50% ethanol, dried, and crystallized from EtOH to give 1,2-di(arylidene)hydrazines6a–d. The physical constants of5 and6a–d were identical with that reported.Method B. A mixture of 3-hydrazonoindolin-2-one (2) (0.161 g, 1 mmol) and the appropriate aldehyde from3a–c (1 mmol) in H2O/AcOH (1 : 3, v : v, 25 mL) was refluxed for 4 h. Ketazine5 was filtered while hot and crystallized from EtOH/DMF while aldazines6a–d were isolated from the filtrate after evaporation of the solvent.


#### 2.3.1. 3,3′-(Hydrazine-1,2-diylidene)diindolin-2-one (5) [8]

Yield (46%), mp > 300°C; IR (KBr)v 3276 (2NH), 1722 (2C=O), 1615 (2C=N) cm−1; 1H NMR (DMSO-d6) δ 6.82 (d, 2H, J=7.8 Hz, H5 of isatin), 6.96 (t, 2H, J=7.5 Hz, H6 of isatin), 7.14 (t, 2H, J=7.5 Hz, H7 of isatin), 7.34 (d, 2H, J=7.8 Hz, H4 of isatin), 10.55 (s, D2O exchangeable, 2H, 2NH); 13C NMR (DMSO-d6) δ 111.59, 116.26, 123.03, 128.66, 134.89, 145.22, 145.68, 163.89 (2C=O).


#### 2.3.2. 1,2-Di(benzylidene)hydrazine (6a)

Yield (70%), mp = 95–97°C (Lit. mp = 92–93°C [15]). IR 1615–1620 (2C=N) cm−1; 1H NMR (DMSO-d6) δ 7.57–7.99 (m, 10H, Ar–H), 8.61 (s, 2H, N=CH); MSm/z (%) 209 (M+ + 1, 11.68), 208 (M+, 79.43), 207 (100), 138 (100).


#### 2.3.3. 1,2-Bis(-4-chlorobenzylidene)hydrazine (6b)

Yield (82%), mp = 211–213°C (Lit. mp = 207-208°C [15]) IR 1617–1625 (2C=N) cm−1; 1H NMR (DMSO-d6) δ 7.56 (d, 4H,J = 8.4 Hz, Ar–H), 7.88 (d, 4H,J = 8.4 Hz, Ar–H), 8.61 (s, 2H, N=CH); 13C NMR (DMSO-d6) δ 128.93, 129.89, 132.56, 135.791, 160.44 (2C=N); MSm/z (%) 279 (M+ + 2, 9.68), 277 (M+, 31.14), 165 (100), 138 (23.01), 111 (34.85).


#### 2.3.4. 1,2-Bis(4-methoxybenzylidene)hydrazine (6c)

Yield (77%), mp = 170–172°C (Lit. mp = 175°C [15]) IR 1615–1622 (2C=N) cm−1; 1H NMR (DMSO-d6) δ 3.83 (s, 6H, OCH3), 7.04 (d, 4H,J = 8.4 Hz, Ar–H), 7.79 (d, 4H,J = 8.4 Hz, Ar–H), 8.61 (s, 2H, N=CH); 13C NMR (DMSO-d6) δ 55.27 (2OCH3), 114.23, 126.53, 129.83, 160.35, 161.62 (2C=N); MSm/z (%) 268 (M+, 18.37), 161 (31.72), 134 (26.80), 107 (16.07).


#### 2.3.5. 1,2-Bis(4-nitrobenzylidene)hydrazine (6d)

Yield (74%), mp = 223–225°C (Lit. mp = 223.3-223.4°C [16]) IR 1610–1617 (2C=N) cm−1; 1H NMR (DMSO-d6) δ 7.55 (d, 4H, J=8.4 Hz, Ar–H), 7.88 (d, 4H, J=8.4 Hz, Ar–H), 8.60 (s, 2H, N=CH); MSm/z 272 (%) 298 (M+, 10.03), 252 (100), 176 (50.55).


### 2.4. Hydrazinolysis of4a–d

To a solution of hydrazones4a–d (1 mmol) in ethanol (25 mL), hydrazine hydrate (0.06 g 0.12 mmol) was added. The reaction was refluxed for 5 h. The formed precipitate was filtered, washed with ethanol, dried, and finally crystallized from EtOH/DMF to give 3-hydrazonoindolin-2-one (2) with mp = 217–219°C (Lit. mp = 219–220°C [16]); IR (KBr) v 3361–3215 (NH, NH2), 1687 (C=O), 1608 (C=N) cm−1; 1H NMR (DMSO-d6) δ 6.87 (d, 1H,J = 7.5; Hz, H5 of isatin), 6.97 (t, 1H,J = 7.8 Hz, H6 of isatin), 7.15 (t, 1H,J = 7.8 Hz, H7 of isatin), 7.37 (d, 1H,J = 7.5 Hz, H4 isatin), 9.55 (d, 1H,J = 14.0 Hz, D2O exch., amino H), 10.56 (d, 1H,J = 14.0 Hz, D2O exch., amino H), 10.72 (s, D2O exch., 1H, NH isatin); MSm/z (%) 161.1 (M+). The filtrate was evaporated under vacuum. The obtained residue was filtered, washed with 50% ethanol, dried, and crystallized from EtOH to yield 1,2-di(arylidene)hydrazines6a–d.


### 2.5. Hydrazinolysis of5

To a solution of5 (0.29 g, 1 mmol) in ethanol (25 mL), hydrazine hydrate (0.06 g 0.12 mmol) was added. The reaction was refluxed for 5 h. The formed precipitate was filtered, washed with ethanol, dried, and finally crystallized from EtOH/DMF to give hydrazonoindolin-2-one (2).


## 2.1. General

Melting points were measured with a Stuart melting point apparatus and were uncorrected. IR spectra (KBr disks) were recorded with a Pye Unicam SP 1000 IR spectrophotometer. The NMR spectra were recorded by Varian Gemini-300BB 300 MHz FT-NMR spectrometers (Varian Inc., Palo Alto, CA).1H and 13C spectra were run at 300 and 75 MHz, respectively, in deuterated dimethyl sulfoxide (DMSO-d6). Chemical shifts (δH) are reported relative to TMS as internal standard. All coupling constant (J) values are given in Hertz. Chemical shifts (δC) are reported relative to DMSO-d6 as internal standards. The abbreviations used are as follows: s: singlet; d: doublet; and m: multiplet. Mass spectra were recorded on Helwett Packard 5988 spectrometer at 70 eV. Reaction courses and product mixtures were routinely monitored by thin layer chromatography (TLC) on silica gel precoated F254 Merck plates. Unless otherwise noted, all solvents and reagents were commercially available and were used without further purification.


## 2.2. Synthesis of Isatin Aldazines4a–d

A mixture of 3-hydrazonoindolin-2-one (2) (0.161 g, 1 mmol) and aldehyde from3a–c (1 mmol) in acetic acid (25 mL) was stirred at room temperature for 12 h. The resulted precipitate was filtered, dried, and finally crystallized from EtOH/DMF to afford hydrazones4a–c, respectively. Aldazines4a–d were also prepared by the reaction of2 with3a–d in refluxing ethanol, in the presence of catalytic amount of glacial acetic acid for 6 h [10].


### 2.2.1. 3-((Benzylidene)hydrazono)indolin-2-one (4a)

Yield (62%), mp > 300°C (lit. mp 300°C [14]); IR (KBr)v 3280 (NH), 1722 (C=O), 1614 (C=N) cm−1; 1H NMR (DMSO-d6) δ 6.90 (d, 1H,J = 7.8 Hz, H4 of isatin), 7.04 (t, 1H,J = 7.5 Hz, H5 of isatin), 7.42 (t, 1H,J = 7.5 Hz, H6 of isatin), 7.51 (d, 1H,J = 7.8 Hz, H7 of isatin), 7.57–7.99 (m, 5H, Ar–H), 8.61 (s, 1H, N=CH), 10.97 (s, D2O exchangeable, 1H, NH); 13C NMR (DMSO-d6) δ 110.95, 111.19, 115.73, 122.39, 122.63, 128.03, 128.25, 134.26, 134.47, 144.70, 145.16, 163.36 (C=O); MSm/z (%) 249 (M+, 30.02), 221 (17.03), 145 (35.41).


### 2.2.2. 3-((4-Nitrobenzylidene)hydrazono)indolin-2-one (4b) [11]

Yield (66%), mp 254–256°C; IR (KBr)v 3161 (NH), 1734 (C=O), 1616 (C=N) cm−1; 1H NMR (DMSO-d6) δ 6.90 (d, 1H,J = 7.8 Hz, H4 of isatin), 7.01 (t, 1H,J = 7.5 Hz, H5 of isatin), 7.41 (t, 1H,J = 7.5 Hz, H6 of isatin), 7.73 (d, 1H,J = 7.8 Hz, H7 of isatin), 8.20 (d, 2H,J = 8.7 Hz, Ar–H), 8.37 (d, 2H,J = 8.7, Ar–H), 8.66 (s, 1H, N=CH), 10.86 (s, D2O exchangeable, 1H, NH); 13C NMR (DMSO-d6) δ 110.85, 111.08, 116.01, 122.29, 122.53, 124.23, 128.59, 128.78, 129.64, 133.98, 134.19, 139.06, 145.27, 148.97, 149.67, 156.21, 156.35, 164.10 (C=O); MSm/z (%) 294 (M+, 10.49), 266 (100).


### 2.2.3. 3-((4-Chlorobenzylidene)hydrazono)indolin-2-one (4c)

Yield (78%), mp = 270–272°C (lit. mp = 200°C [14]); IR (KBr)v 3248 (NH), 1734 (C=O), 1604 (C=N) cm−1; 1H NMR (DMSO-d6) δ 6.90 (d, 1H,J = 7.5 Hz, H4 of isatin), 7.02 (t, 1H,J = 7.8 Hz, H5 of isatin), 7.41 (t, 1H,J = 7.8 Hz, H6 of isatin), 7.63 (d, 2H,J = 8.4 Hz, Ar–H), 7.85 (d, 1H,J = 7.5 Hz, H7 of isatin), 7.98 (d, 2H,J = 8.4, Ar–H), 8.61 (s, 1H, N=CH), 10.86 (s, D2O exchangeable, 1H, NH); 13C NMR (DMSO-d6) δ 110.73, 110.98, 116.26, 128.82, 129.23, 130.37, 130.45, 132.24, 133.92, 136.65, 141.72, 145.07, 150.29, 158.75, 164.35 (C=O); MSm/z (%) 285 (M+ + 2, 6.78), 283 (M+, 20.10), 255 (89.86), 145 (16.96), 138 (54.66), 111 (95.01).


### 2.2.4. 3-((4-Methoxybenzylidene)hydrazono)indolin-2-one (4d)

Yield (69%), mp = 182-183°C (lit. mp = 182°C [14]); IR (KBr)v 3194 (NH), 1732 (C=O), 1606 (C=N) cm−1; 1H NMR (DMSO-d6) δ 3.87 (s, 6H, 2OCH3), 6.89 (d, 1H,J = 7.5 Hz, H4 of isatin), 7.04 (t, 1H,J = 7.8 Hz, H5 of isatin), 7.12 (d, 2H,J = 8.4, Ar–H), 7.39 (t, 1H,J = 7.5 Hz, H6 of isatin), 7.94 (d, 2H,J = 8.4 Hz, Ar–H), 8.02 (d, 1H,J = 7.8 Hz, H7 of isatin), 8.61 (s, 1H, N=CH), 10.76 (s, D2O exchangeable, 1H, NH); 13C NMR (DMSO-d6) δ 55.55 (OCH3), 110.58, 110.81, 114.62, 114.87, 116.59, 122.13, 122.36, 126.32, 128.79, 128.86, 130.91, 131.03, 133.29, 133.52, 144.80, 145.15, 150.65, 161.81, 161.93, 162.58, 163.36, 164.69 (C=O); MSm/z (%) 279 (M+, 30.31), 251 (100), 134 (17.79).


## 2.2.1. 3-((Benzylidene)hydrazono)indolin-2-one (4a)

Yield (62%), mp > 300°C (lit. mp 300°C [14]); IR (KBr)v 3280 (NH), 1722 (C=O), 1614 (C=N) cm−1; 1H NMR (DMSO-d6) δ 6.90 (d, 1H,J = 7.8 Hz, H4 of isatin), 7.04 (t, 1H,J = 7.5 Hz, H5 of isatin), 7.42 (t, 1H,J = 7.5 Hz, H6 of isatin), 7.51 (d, 1H,J = 7.8 Hz, H7 of isatin), 7.57–7.99 (m, 5H, Ar–H), 8.61 (s, 1H, N=CH), 10.97 (s, D2O exchangeable, 1H, NH); 13C NMR (DMSO-d6) δ 110.95, 111.19, 115.73, 122.39, 122.63, 128.03, 128.25, 134.26, 134.47, 144.70, 145.16, 163.36 (C=O); MSm/z (%) 249 (M+, 30.02), 221 (17.03), 145 (35.41).


## 2.2.2. 3-((4-Nitrobenzylidene)hydrazono)indolin-2-one (4b) [11]

Yield (66%), mp 254–256°C; IR (KBr)v 3161 (NH), 1734 (C=O), 1616 (C=N) cm−1; 1H NMR (DMSO-d6) δ 6.90 (d, 1H,J = 7.8 Hz, H4 of isatin), 7.01 (t, 1H,J = 7.5 Hz, H5 of isatin), 7.41 (t, 1H,J = 7.5 Hz, H6 of isatin), 7.73 (d, 1H,J = 7.8 Hz, H7 of isatin), 8.20 (d, 2H,J = 8.7 Hz, Ar–H), 8.37 (d, 2H,J = 8.7, Ar–H), 8.66 (s, 1H, N=CH), 10.86 (s, D2O exchangeable, 1H, NH); 13C NMR (DMSO-d6) δ 110.85, 111.08, 116.01, 122.29, 122.53, 124.23, 128.59, 128.78, 129.64, 133.98, 134.19, 139.06, 145.27, 148.97, 149.67, 156.21, 156.35, 164.10 (C=O); MSm/z (%) 294 (M+, 10.49), 266 (100).


## 2.2.3. 3-((4-Chlorobenzylidene)hydrazono)indolin-2-one (4c)

Yield (78%), mp = 270–272°C (lit. mp = 200°C [14]); IR (KBr)v 3248 (NH), 1734 (C=O), 1604 (C=N) cm−1; 1H NMR (DMSO-d6) δ 6.90 (d, 1H,J = 7.5 Hz, H4 of isatin), 7.02 (t, 1H,J = 7.8 Hz, H5 of isatin), 7.41 (t, 1H,J = 7.8 Hz, H6 of isatin), 7.63 (d, 2H,J = 8.4 Hz, Ar–H), 7.85 (d, 1H,J = 7.5 Hz, H7 of isatin), 7.98 (d, 2H,J = 8.4, Ar–H), 8.61 (s, 1H, N=CH), 10.86 (s, D2O exchangeable, 1H, NH); 13C NMR (DMSO-d6) δ 110.73, 110.98, 116.26, 128.82, 129.23, 130.37, 130.45, 132.24, 133.92, 136.65, 141.72, 145.07, 150.29, 158.75, 164.35 (C=O); MSm/z (%) 285 (M+ + 2, 6.78), 283 (M+, 20.10), 255 (89.86), 145 (16.96), 138 (54.66), 111 (95.01).


## 2.2.4. 3-((4-Methoxybenzylidene)hydrazono)indolin-2-one (4d)

Yield (69%), mp = 182-183°C (lit. mp = 182°C [14]); IR (KBr)v 3194 (NH), 1732 (C=O), 1606 (C=N) cm−1; 1H NMR (DMSO-d6) δ 3.87 (s, 6H, 2OCH3), 6.89 (d, 1H,J = 7.5 Hz, H4 of isatin), 7.04 (t, 1H,J = 7.8 Hz, H5 of isatin), 7.12 (d, 2H,J = 8.4, Ar–H), 7.39 (t, 1H,J = 7.5 Hz, H6 of isatin), 7.94 (d, 2H,J = 8.4 Hz, Ar–H), 8.02 (d, 1H,J = 7.8 Hz, H7 of isatin), 8.61 (s, 1H, N=CH), 10.76 (s, D2O exchangeable, 1H, NH); 13C NMR (DMSO-d6) δ 55.55 (OCH3), 110.58, 110.81, 114.62, 114.87, 116.59, 122.13, 122.36, 126.32, 128.79, 128.86, 130.91, 131.03, 133.29, 133.52, 144.80, 145.15, 150.65, 161.81, 161.93, 162.58, 163.36, 164.69 (C=O); MSm/z (%) 279 (M+, 30.31), 251 (100), 134 (17.79).


## 2.3. Hydrolysis of Isatin Aldazines4a–d

Method A. A solution of isatin aldazines4a–d (1 mmol) in H2O/AcOH (1 : 3, v : v, 25 mL) was refluxed for 4 h. The given 3,3′-(hydrazine-1,2-diylidene)bis(indolin-2-one) (5) was filtered while hot and crystallized from EtOH/DMF. The filtrate of the latter reaction was concentrated. The solid formed was washed with 50% ethanol, dried, and crystallized from EtOH to give 1,2-di(arylidene)hydrazines6a–d. The physical constants of5 and6a–d were identical with that reported.Method B. A mixture of 3-hydrazonoindolin-2-one (2) (0.161 g, 1 mmol) and the appropriate aldehyde from3a–c (1 mmol) in H2O/AcOH (1 : 3, v : v, 25 mL) was refluxed for 4 h. Ketazine5 was filtered while hot and crystallized from EtOH/DMF while aldazines6a–d were isolated from the filtrate after evaporation of the solvent.


### 2.3.1. 3,3′-(Hydrazine-1,2-diylidene)diindolin-2-one (5) [8]

Yield (46%), mp > 300°C; IR (KBr)v 3276 (2NH), 1722 (2C=O), 1615 (2C=N) cm−1; 1H NMR (DMSO-d6) δ 6.82 (d, 2H, J=7.8 Hz, H5 of isatin), 6.96 (t, 2H, J=7.5 Hz, H6 of isatin), 7.14 (t, 2H, J=7.5 Hz, H7 of isatin), 7.34 (d, 2H, J=7.8 Hz, H4 of isatin), 10.55 (s, D2O exchangeable, 2H, 2NH); 13C NMR (DMSO-d6) δ 111.59, 116.26, 123.03, 128.66, 134.89, 145.22, 145.68, 163.89 (2C=O).


### 2.3.2. 1,2-Di(benzylidene)hydrazine (6a)

Yield (70%), mp = 95–97°C (Lit. mp = 92–93°C [15]). IR 1615–1620 (2C=N) cm−1; 1H NMR (DMSO-d6) δ 7.57–7.99 (m, 10H, Ar–H), 8.61 (s, 2H, N=CH); MSm/z (%) 209 (M+ + 1, 11.68), 208 (M+, 79.43), 207 (100), 138 (100).


### 2.3.3. 1,2-Bis(-4-chlorobenzylidene)hydrazine (6b)

Yield (82%), mp = 211–213°C (Lit. mp = 207-208°C [15]) IR 1617–1625 (2C=N) cm−1; 1H NMR (DMSO-d6) δ 7.56 (d, 4H,J = 8.4 Hz, Ar–H), 7.88 (d, 4H,J = 8.4 Hz, Ar–H), 8.61 (s, 2H, N=CH); 13C NMR (DMSO-d6) δ 128.93, 129.89, 132.56, 135.791, 160.44 (2C=N); MSm/z (%) 279 (M+ + 2, 9.68), 277 (M+, 31.14), 165 (100), 138 (23.01), 111 (34.85).


### 2.3.4. 1,2-Bis(4-methoxybenzylidene)hydrazine (6c)

Yield (77%), mp = 170–172°C (Lit. mp = 175°C [15]) IR 1615–1622 (2C=N) cm−1; 1H NMR (DMSO-d6) δ 3.83 (s, 6H, OCH3), 7.04 (d, 4H,J = 8.4 Hz, Ar–H), 7.79 (d, 4H,J = 8.4 Hz, Ar–H), 8.61 (s, 2H, N=CH); 13C NMR (DMSO-d6) δ 55.27 (2OCH3), 114.23, 126.53, 129.83, 160.35, 161.62 (2C=N); MSm/z (%) 268 (M+, 18.37), 161 (31.72), 134 (26.80), 107 (16.07).


### 2.3.5. 1,2-Bis(4-nitrobenzylidene)hydrazine (6d)

Yield (74%), mp = 223–225°C (Lit. mp = 223.3-223.4°C [16]) IR 1610–1617 (2C=N) cm−1; 1H NMR (DMSO-d6) δ 7.55 (d, 4H, J=8.4 Hz, Ar–H), 7.88 (d, 4H, J=8.4 Hz, Ar–H), 8.60 (s, 2H, N=CH); MSm/z 272 (%) 298 (M+, 10.03), 252 (100), 176 (50.55).


## 2.3.1. 3,3′-(Hydrazine-1,2-diylidene)diindolin-2-one (5) [8]

Yield (46%), mp > 300°C; IR (KBr)v 3276 (2NH), 1722 (2C=O), 1615 (2C=N) cm−1; 1H NMR (DMSO-d6) δ 6.82 (d, 2H, J=7.8 Hz, H5 of isatin), 6.96 (t, 2H, J=7.5 Hz, H6 of isatin), 7.14 (t, 2H, J=7.5 Hz, H7 of isatin), 7.34 (d, 2H, J=7.8 Hz, H4 of isatin), 10.55 (s, D2O exchangeable, 2H, 2NH); 13C NMR (DMSO-d6) δ 111.59, 116.26, 123.03, 128.66, 134.89, 145.22, 145.68, 163.89 (2C=O).


## 2.3.2. 1,2-Di(benzylidene)hydrazine (6a)

Yield (70%), mp = 95–97°C (Lit. mp = 92–93°C [15]). IR 1615–1620 (2C=N) cm−1; 1H NMR (DMSO-d6) δ 7.57–7.99 (m, 10H, Ar–H), 8.61 (s, 2H, N=CH); MSm/z (%) 209 (M+ + 1, 11.68), 208 (M+, 79.43), 207 (100), 138 (100).


## 2.3.3. 1,2-Bis(-4-chlorobenzylidene)hydrazine (6b)

Yield (82%), mp = 211–213°C (Lit. mp = 207-208°C [15]) IR 1617–1625 (2C=N) cm−1; 1H NMR (DMSO-d6) δ 7.56 (d, 4H,J = 8.4 Hz, Ar–H), 7.88 (d, 4H,J = 8.4 Hz, Ar–H), 8.61 (s, 2H, N=CH); 13C NMR (DMSO-d6) δ 128.93, 129.89, 132.56, 135.791, 160.44 (2C=N); MSm/z (%) 279 (M+ + 2, 9.68), 277 (M+, 31.14), 165 (100), 138 (23.01), 111 (34.85).


## 2.3.4. 1,2-Bis(4-methoxybenzylidene)hydrazine (6c)

Yield (77%), mp = 170–172°C (Lit. mp = 175°C [15]) IR 1615–1622 (2C=N) cm−1; 1H NMR (DMSO-d6) δ 3.83 (s, 6H, OCH3), 7.04 (d, 4H,J = 8.4 Hz, Ar–H), 7.79 (d, 4H,J = 8.4 Hz, Ar–H), 8.61 (s, 2H, N=CH); 13C NMR (DMSO-d6) δ 55.27 (2OCH3), 114.23, 126.53, 129.83, 160.35, 161.62 (2C=N); MSm/z (%) 268 (M+, 18.37), 161 (31.72), 134 (26.80), 107 (16.07).


## 2.3.5. 1,2-Bis(4-nitrobenzylidene)hydrazine (6d)

Yield (74%), mp = 223–225°C (Lit. mp = 223.3-223.4°C [16]) IR 1610–1617 (2C=N) cm−1; 1H NMR (DMSO-d6) δ 7.55 (d, 4H, J=8.4 Hz, Ar–H), 7.88 (d, 4H, J=8.4 Hz, Ar–H), 8.60 (s, 2H, N=CH); MSm/z 272 (%) 298 (M+, 10.03), 252 (100), 176 (50.55).


## 2.4. Hydrazinolysis of4a–d

To a solution of hydrazones4a–d (1 mmol) in ethanol (25 mL), hydrazine hydrate (0.06 g 0.12 mmol) was added. The reaction was refluxed for 5 h. The formed precipitate was filtered, washed with ethanol, dried, and finally crystallized from EtOH/DMF to give 3-hydrazonoindolin-2-one (2) with mp = 217–219°C (Lit. mp = 219–220°C [16]); IR (KBr) v 3361–3215 (NH, NH2), 1687 (C=O), 1608 (C=N) cm−1; 1H NMR (DMSO-d6) δ 6.87 (d, 1H,J = 7.5; Hz, H5 of isatin), 6.97 (t, 1H,J = 7.8 Hz, H6 of isatin), 7.15 (t, 1H,J = 7.8 Hz, H7 of isatin), 7.37 (d, 1H,J = 7.5 Hz, H4 isatin), 9.55 (d, 1H,J = 14.0 Hz, D2O exch., amino H), 10.56 (d, 1H,J = 14.0 Hz, D2O exch., amino H), 10.72 (s, D2O exch., 1H, NH isatin); MSm/z (%) 161.1 (M+). The filtrate was evaporated under vacuum. The obtained residue was filtered, washed with 50% ethanol, dried, and crystallized from EtOH to yield 1,2-di(arylidene)hydrazines6a–d.


## 2.5. Hydrazinolysis of5

To a solution of5 (0.29 g, 1 mmol) in ethanol (25 mL), hydrazine hydrate (0.06 g 0.12 mmol) was added. The reaction was refluxed for 5 h. The formed precipitate was filtered, washed with ethanol, dried, and finally crystallized from EtOH/DMF to give hydrazonoindolin-2-one (2).


## 3. Results and Discussion

In the reaction of 3-hydrazonoindolin-2-one (2) (R = H) with aldehydes3a–d in glacial acetic acid for 12 h, at ambient temperature, isatin aldazines4a–d were isolated extensively. The targeted aldazines4a–d were also prepared by the reaction of 3-hydrazonoindolin-2-one (2) with aldehydes3a–d in refluxing ethanol, in the presence of catalytic amount of glacial acetic acid for 6 h (Scheme 1) [9].Scheme 1
The reaction of 3-hydrazonoindolin-2-one (2) with aldehydes3a–d.Hydrolysis of hydrazones4a–d by their refluxing in H2O/AcOH afforded reddish precipitates during reflux in each case. These precipitates showed identical physical and chemical properties and they are not matched with the expected hydrazone2 (R = H) (Scheme 1).The1H NMR spectrum of the isolated precipitate did not show the characteristic signal of NH2 of2 and its mass spectrum exhibited molecular ion peak atm/z = 290. The latter data proposed the assigned structure 3,3′-(hydrazine-1,2-diylidene)bis(indolin-2-one) (5) for the isolated compound. An authentic sample of compound5 is prepared [10] and it was identical in all respects with the isolated compound in our hands.After evaporation of the filtrates of the latter reactions, they gave in each case a compound with melting points 97°C (Ar = Ph), 213°C (Ar = 4-Cl-C6H4), 172°C (Ar = 4-MeO-C6H4), and 225°C (Ar = 4-NO2-C6H4), respectively. These values do not match this reported for2, 217–219°C. Our attempts to explore these unknown compounds guided us to assign structure 1,2-di(arylidene)hydrazines6a–d for the isolated compounds. We found that the analytical data of authentic samples of isolated compounds is identical with those of6a–d [17–20]. Interestingly, refluxing2 with aldehydes3a–d in H2O/AcOH, 3,3′-(hydrazine-1,2-diylidene)bis(indolin-2-one) (5) and aldazines6a–d were also isolated.Keeping in mind the reported data about the mechanism of hydrolysis of –C=N– imines [21], we are interested in proposing a mechanism to explain the formation of 3,3′-(hydrazine-1,2-diylidene)bis(indolin-2-one) (5) and 1,2-di(arylidene)hydrazines6a–d. In this mechanism, dual acidic hydrolysis of aldazines4a–d took place in their two nucleophilic centers which are accessible to attack by two protons from the acidic medium (Figure 2). The first pathway, in which acidic proton attack took place by the nitrogen of –N=C–Ar followed by hydrolysis to give intermediates7(a–d)–10(a–d), respectively, yielded aldehydes3a–d and 3-hydrazonoindolin-2-ones (2) which would not undergo further hydrolysis. The second pathway, in which the other nitrogen of hydrazone function attacked the acidic proton followed by hydrolysis to give intermediates12(a–d)–15(a–d), respectively, yielded indoline-2,3-dione (1) and the corresponding hydrazones17a–d without further hydrolysis. Finally, the reaction of1a with2(R=H) and3a–d with17a–d led to the formation of final products 3,3′-(hydrazine-1,2-diylidene)bis(indolin-2-one) (5) and aldazines6a–d, respectively. The expected last step is hydrolysis of2(R=H) and/or17a–d.Figure 2
The proposed mechanism for the hydrolysis of isatin aldazines4a–d in refluxing H2O/AcOH.According to the previous results and in light of behavior of hydrazine hydrate towards certain –N=N– containing compounds [12], we stimulated to explore the reactivity of hydrazine hydrate towards –N=C– function in aldazines4a–d. Thus, the reaction of4a–d with hydrazine hydrate in refluxing ethanol afforded 3-hydrazonoindolin-2-one (2) and 1,2-di(arylidene)hydrazines6a–d, respectively, instead of2 and17a–d (Scheme 2).Scheme 2
Hydrazinolysis of aldazines4a–d.Hydrazine, as a nucleophile, attacked the carbon of –N=C– function of two molecules of hydrazones4a–d to form the nonisolable intermediates18a–d and19a–d, respectively (Scheme 3). Finally, the nonisolable intermediate19a–d afforded 3-hydrazonoindolin-2-one (2) and 1,2-di(arylidene)hydrazines6a–d as final isolated compounds.Scheme 3
Hydrazinolysis of 3,3′-(hydrazine-1,2-diylidene)bis(indolin-2-one) (5).Consequently, the reaction of hydrazine hydrate with C-3 of 3,3′-(hydrazine-1,2-diylidene)bis(indolin-2-one) (5) yielded the corresponding 3-hydrazonoindolin-2-one (2) as hydrazinolysis product (Scheme 3). The previous reaction proceeded through the attack of nucleophilic nitrogen of hydrazine on ketazine5 to form the nonisolable intermediate21 and then the formation of 3-hydrazonoindolin-2-one (2).


## 4. Conclusion

In conclusion, we reported herein the hydrolysis of isatin aldazines4a–d which gave unusual product 3,3′-(hydrazine-1,2-diylidene)bis(indolin-2-one) (5) and aldazines6a–d were formed through dual acidic hydrolysis. The hydrazinolysis of isatin aldazines4a–d yielded 3-hydrazonoindolin-2-one (2) and6a–d instead of17a–d. These results established the ability of the title compounds for unusual hydrolysis and hydrazinolysis reactions.



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*Source: 826489-2015-04-28.xml*