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

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.


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.ese interesting properties have prompted many efforts toward the synthesis and pharmacological screening of isatin derivatives.e 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], Al 2 O 3 [7], N(CH 2 CH 2 OH) 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 workup, and use of environmentally toxic or expensive reagents or media.us, 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][12][13][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 iodinecatalyzed 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).

Experimental
1 H NMR and 13 C NMR spectra were determined on Bruker AV-400 spectrometer (100 MHz for 13 C NMR) at room temperature using tetramethylsilane (TMS) as an internal standard (DMSO- 6 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 puri�cation unless otherwise stated.

General Procedure for the Preparation of 3.
A mixture of isatins (1 mmol), malononitrile (1 mmol), and I 2 (0.1 mmol) in EtOH (10 mL) was heated at 60 ∘ C for the appropriate time.e reaction was monitored by TLC.Aer completion, the mixture was treated with aqueous Na 2 S 2 O 3 solution extracted with ethyl acetate (2 × 10 mL).e extract was dried over sodium sulfate, �ltered and solvent was evaporated in vacuo.Products 3 were puri�ed by recrystallizing from ethanol.

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 puri�cation or drying.We found that a remarkable solvent effect existed in 10 mol% iodinecatalyzed reaction at 60 ∘ C. ese results showed that EtOH was the most suitable solvent for this transformation among others, such as acetonitrile, toluene, THF, CHCl 3 , 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 e 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 I 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 signi�cant 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.

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.e 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.
T 1: Optimization studies of the condensation of isatin with malononitrile a .