Molecular Iodine: A Powerful Catalyst for the Knoevenagel Condensation of Isatins with Malononitrile

Abstract

Molecular iodine has been used as an efficient catalyst for an improved and rapid condensation of isatins with malononitrile in excellent yields. The significant features of the iodine-catalyzed Knoevenagel condensation are operational simplicity, inexpensive reagents, high yield of products, and the use of nontoxic reagents.

1. Introduction

Isatin is a privileged lead molecule for designing potential bioactive agents, and its derivatives have been shown to possess a broad spectrum of bioactivity, as many of which have been assessed as anti-HIV [1], antiviral [2], antitumor [3], and anticonvulsants [4] agents. These interesting properties have prompted many efforts toward the synthesis and pharmacological screening of isatin derivatives. The most common methods for the synthesis of 2-(2-oxoindolin-3-ylidene)malononitriles are the condensation of isatins with malononitrile in the presence of a catalyst, such as piperidine acetate [5], DBU [6], Al₂O₃ [7], N(CH₂CH₂OH)₃ [8], chitosan [9]. Recently, MW irradiation [10] has also been applied to the condensation. However, most of these procedures have signicant drawbacks such as long reaction times, low yields, harsh reaction conditions, difficult work-up, and use of environmentally toxic or expensive reagents or media. Thus, there is still a need for a simple and general protocol for the condensation of isatins with malononitrile.

Over the past few years, molecular iodine has emerged as powerful catalyst in various organic transformations [11–14]. Owing to several advantages such as being inexpensive, nontoxic, and nature friendly, iodine affords the desired product in good to excellent range yields with high selectivity. As a part of our studies to explore the utility of iodine-catalyzed reactions [15, 16], we have described a novel and an efficient protocol for the Knoevenagel condensation of isatins with malononitrile using molecular iodine as the catalyst (Scheme 1).

Scheme 1 

2. Experimental

¹H NMR and ¹³C NMR spectra were determined on Bruker AV-400 spectrometer (100 MHz for ¹³C NMR) at room temperature using tetramethylsilane (TMS) as an internal standard (DMSO- solution); coupling constants (J) were measured in Hz; elemental analysis was performed by a Vario-III elemental analyzer; melting points were determined on a XT-4 binocular microscope and were uncorrected; commercially available reagents were used throughout without further purification unless otherwise stated.

2.1. General Procedure for the Preparation of 3

A mixture of isatins (1 mmol), malononitrile (1 mmol), and I₂ (0.1 mmol) in EtOH (10 mL) was heated at 60°C for the appropriate time. The reaction was monitored by TLC. After completion, the mixture was treated with aqueous Na₂S₂O₃ solution extracted with ethyl acetate (2 × 10 mL). The extract was dried over sodium sulfate, filtered and solvent was evaporated in vacuo. Products 3 were purified by recrystallizing from ethanol.

2-(2-Oxoindolin-3-ylidene)malononitrile (3a):¹H NMR (DMSO-, 400 MHz) δ: 11.19 (s, 1H), 7.87 (d, 1H, J = 7.6 Hz), 7.56 (t, 1H, J = 7.6 Hz), 7.12 (t, 1H, J = 7.6 Hz), 6.93 (d, 1H, J = 8.0 Hz) ¹³C NMR (DMSO-, 100 MHz) δ: 164.1, 151.0, 146.9, 126.2, 123.3, 119.0, 113.4, 112.1, 111.9, 81.0; Anal. calcd for C₁₁H₅N₃O: C 67.69, H 2.58, N 21.53; found: C 67.52, H 2.66, N 21.58.

2-(5-Chloro-2-oxoindolin-3-ylidene)malononitrile (3b):¹H NMR (DMSO-, 400 MHz) δ: 11.35 (s, 1H), 7.75 (s, 1H), 7.62 (d, 1H, J = 8.4 Hz), 6.96 (d, 1H, J = 7.6 Hz); ¹³C NMR (DMSO-, 100 MHz) δ: 163.8, 150.0, 145.6, 137.4, 126.9, 125.2, 120.3, 113.7, 113.1, 111.5, 82.7; Anal. calcd for C₁₁H₄ClN₃O: C 57.54, H 1.76, N 18.30; found: C 57.46, H 1.78, N 18.42.

2-(5-Bromo-2-oxoindolin-3-ylidene)malononitrile (3c):¹H NMR (DMSO-, 400 MHz) δ: 11.35 (s, 1H), 7.90 (s, 1H), 7.74 (d, 1H, J = 8.4 Hz), 6.91 (d, 1H, J = 7.6 Hz); ¹³C NMR (DMSO-, 100 MHz) δ: 163.7, 149.9, 145.9, 140.1, 128.0, 120.9, 114.4, 114.1, 113.1, 111.6, 82.6; Anal. calcd for C₁₁H₄BrN₃O: C 48.21, H 1.47, N 15.33; found: C 48.13, H 1.51, N 15.42.

2-(5-Fluoro-2-oxoindolin-3-ylidene)malononitrile (3d):¹H NMR (DMSO-, 400 MHz) δ: 11.20 (s, 1H), 7.55 (d, 1H, J = 6.0 Hz), 7.47 (t, 1H, J = 8.8 Hz), 6.97–6.91 (dd, 1H, J = 4.0, 8.4 Hz); ¹³C NMR (DMSO-, 100 MHz) δ: 164.1, 159.1, 156.7, 150.6, 143.4, 125.0, 119.6, 113.4, 112.5, 111.6, 82.7; Anal. calcd for C₁₁H₄FN₃O: C 61.98, H 1.89, N 19.71; found: C 62.08, H 1.94, N 19.82.

2-(5-Nitro-2-oxoindolin-3-ylidene)malononitrile (3e):¹H NMR (DMSO-, 400 MHz) δ: 11.91 (s, 1H), 8.65 (s, 1H), 8.44 (d, 1H, J = 8.0 Hz), 7.14 (d, 1H, J = 4.0, 8.8 Hz); ¹³C NMR (DMSO-, 100 MHz) δ: 164.4, 151.6, 149.7, 142.8, 133.1, 121.1, 119.2, 112.9, 112.3, 111.3, 83.9; Anal. calcd for C₁₁H₄N₄O: C 55.01, H 1.68, N 23.33; found: C 55.10, H 1.75, N 23.19.

2-(1-Methyl-2-oxoindolin-3-ylidene)malononitrile (3f):¹H NMR (DMSO-, 400 MHz) δ: 7.90 (d, 1H, J = 7.6 Hz), 7.65 (t, 1H, J = 7.6 Hz), 7.21–7.14 (m, 2H), 3.14 (m, 3H); ¹³C NMR (DMSO-, 100 MHz) δ: 162.8, 150.2, 147.6, 138.1, 125.9, 123.9, 118.4, 113.3, 111.8, 111.0, 81.6, 26.7; Anal. calcd for C₁₂H₇N₃O: C 68.89, H 3.37, N 20.09; found: C 68.92, H 3.29, N 20.15.

3. Results and Discussion

Exhaustive studies of the reaction conditions for the condensation of isatin with malononitrile in the presence of molecular iodine were conducted (Table 1). We examined several organic solvents, which are commercially available and used without further purification or drying. We found that a remarkable solvent effect existed in 10 mol% iodine-catalyzed reaction at 60°C. These results showed that EtOH was the most suitable solvent for this transformation among others, such as acetonitrile, toluene, THF, CHCl₃, and MeOH (Table 1, entries 1–6). When the model reaction was carried out under room temperature, reduced yield was observed (Table 1, entry 7). Furthermore, the reaction was accelerated when the amount of catalyst was increased to 15 mol%, but the yield was not improved (Table 1, entry 8). When the reaction was catalyzed by 5 mol% iodine, the reaction time was prolonged to 10 min and the desired product 3a was obtained with only 76% (Table 1, entry 9). While a small number of product 3a was obtained in the absence of molecular iodine (Table 1, entry 10). Thus, the most suitable reaction conditions for the formation of 3a were established (Table 1, entry 6).

Table 1 

Optimization studies of the condensation of isatin with malononitrile^a.

Based on the above experimental results, different isatins are employed in the condensation of malononitrile. Both electron-rich (Table 2, entries 1–5) and electron-poor isatins (Table 3, entries 6) could react with malononitrile smoothly to afford the corresponding 2-(2-oxoindolin-3-ylidene)malononitriles in high yields.

Table 2 

The Knoevenagel condensation of isatins with malononitrile catalyzed by .

Table 3 

Comparison of the effect of catalysts in synthesis of 3a.

The formation of products 3a–3f can be rationalized by standard Knoevenagel condensation of malononitrile 2 and isatins 1 in the presence of a catalytic amount of  I₂ (Scheme 2).

Scheme 2 

To illustrate the efficiency of the proposed method, Table 3 compares some of our results with some of those reported for relevant reagents in the literature, which demonstrates its significant superiority. Compared with some of the reported methods in Table 3, the present method has a short reaction time and good yield. In addition, molecular iodine is a stable, cost effective, and noncorrosive catalyst with high efficiency.

4. Conclusion

In summary, we have described a novel and an efficient protocol for the knoevenagel condensation of isatins with malononitrile using molecular iodine as the catalyst. The shorter reaction times, product yields, the easy procedure to carry out the reaction, and utilization of an inexpensive and readily available catalyst are the advantages of the present method.

Acknowledgment

The authors are pleased to acknowledge the financial support from Xinxiang University.