Green synthesis of novel isatin thioketal derivatives under solvent-free conditions

ABSTRACT A new series of spiro[[1,3]dithiolane-2,3′-indolines]-2′-one derivatives was synthesized using Michael addition reaction of spiro[[1,3]dithiolane-2,3′-indolin]-2′-one to various α,β-unsaturated esters as well as direct alkylation of this compound with alkyl dihalides. Michael reaction of spiro[[1,3]dithiolane-2,3′-indolin]-2′-one and α,β-unsaturated esters produced related Michael adduct in the presence of tetrabutylammonium bromide and base 1,4-diazabicyclo[2.2.2]octane in good to excellent yields at 80°C under solvent-free conditions. Also, direct alkylation of spiro[[1,3]dithiolane-2,3′-indolin]-2′-one by dihaloalkanes in the presence of base K2CO3 afforded the corresponding products in good yields under the same conditions.

In contrast to the many examples of the synthesis of different isatin derivative systems, there are only a few reports with regard to the synthesis of isatin thioketal systems. It is surprising that there are no reports on the alkylation of spiro[ [1,3]dithiolane-2,3 ′ -indolin]-2 ′ -one 1 to α,β-unsaturated esters by Michael addition reaction or direct alkylation to dihaloalkanes. Herein, in continuation of our interest in the design and discovery of new aza-Michael addition of amides and imides to α,βunsaturated esters (11)(12)(13), we report the aza-Michael addition of spiro[ [1,3]dithiolane-2,3 ′ -indolin]-2 ′ -one to α,β-unsaturated esters and also direct alkylation of this compound by dihaloalkanes under solvent-free conditions (Scheme 1).

Experimental section
Spiro[ [1,3]dithiolane-2,3 ′ -indolin]-2 ′ -one and α,β-unsaturated esters were synthesized in our laboratory according to the literature procedures (10,14). Dihaloalkanes were purchased from Merck and used without further purification. Esters were transferred via syringe. Organic solvents were removed by a rotary evaporator. Structure of the compounds were confirmed by IR, 1 H NMR and 13 C NMR spectroscopies. The progress of the reactions was followed by TLC using silica-gel SILIG/UV 254 plates. 1 H NMR (400 MHz) and 13 C NMR (100 MHz) spectra were recorded on a Bruker 400 MHz instrument. FT-IR spectra were recorded on a Perkin-Elmer RX-1 instrument. Elemental analysis for C, H, and N were performed using a Heraeus CHN-O-Rapid analyzer. The melting points were determined in open capillaries with a Stuart Melting Point Apparatus and are uncorrected.
Physical and spectroscopic data of isolated products

Results and discussion
In line with our interest in the aza-Michael addition reaction of isatin ketal derivatives to α,β-unsaturated esters (13), in this project we decided to synthesize some novel isatin thioketal derivatives by applying solventfree conditions. Therefore, the aza-Michael addition of spiro[ [1,3]dithiolane-2,3 ′ -indolin]-2 ′ -one 1 to n-butyl acrylate 2c in the presence of organic salt TBAB and different bases such as pyridine, K 2 CO 3 , Na 2 CO 3 , KOH, NaOH, and DABCO was investigated as a model reaction to evaluate their capabilities for access to the best base (Scheme 2).
This investigation showed that DABCO is a suitable base for this reaction and the best results were obtained when DABCO was applied as a base at 80°C. To select the best solvent for the model reaction in the absence of TBAB and in the presence of base DABCO, next we tested various solvents in the reaction media. This study showed that in the presence of a variety of solvents such as CH 2 Cl 2 , CHCl 3 , DMSO, CH 3 OH, EtOH, CH 3-CO 2 Et, n-hexane, and water, no considerable progress was observed for the model reaction and we obtained the best yields in the presence of TBAB. In interpretation of this successfully, we can think that, in our reaction, organic salt TBAB plays the role of a high polar solvent and accelerates the reaction by dissolving all the organic (thioketal, ester, dihaloalkane, and DABCO) and inorganic (K 2 CO 3 ) reactants. Also, we optimized the amounts of TBAB and DABCO. Herein, the best conditions were obtained as spiro[ [1,3]dithiolane-2,3 ′indolin]-2 ′ -one (1 mmol), α,β-unsaturated esters (1.2 mmol), TBAB (0.5 mmol), and DABCO (1 mmol). Therefore, with this established optimum conditions, we were keen to explore the scope of the reaction with respect to various α,β-unsaturated esters and spiro[ [1,3] dithiolane-2,3 ′ -indolin]-2 ′ -one, the results of which are depicted in Table 1.
It is seen from results of Table 1 that the reactions proceeded smoothly and afforded the corresponding products with isolated yields ranging from 50% to 90% in 120-150 min. It has been observed that the bulkiness of the alkoxy group (-OR) of acrylic esters did not affect significantly the yields and reaction times under model reaction conditions (Table 1, entries 1-4). It is important to note that when fumaric esters were used as the Michael acceptor, the reaction proceeded slowly ( Table 1, entries 7-10). Surprisingly, we observed that the best results were achieved by carrying out the reaction with acrylic esters, despite containing only one carbonyl electron-withdrawing group, as the Michael acceptor. The results in Table 1 show that the steric effects of substitutes on β-carbon atom are more important than their electronic effects. These effects showed that fumaric esters were more sensitive to the size of alkoxy groups than acrylic esters (Table 1, entries 9 and 10). Also, when methyl and butyl methacrylate were used as Michael acceptors, the yields were lower than that obtained using acrylic esters (Table 1, entries 5 and 6). It can be attributed to the steric hindrance of methyl at the α-position of these esters.
In the presence of TBAB and different organic and inorganic bases, the results for the model reaction indicated that K 2 CO 3 was the best choice. Also, we proceeded this reaction in the absence of TBAB and in different solvents. The reaction failed in most of conventional organic solvents such as CH 2 Cl 2 , CHCl 3 , DMSO, CH 3 OH, EtOH, CH 3 CO 2 Et, n-hexane as well as water, even upon prolonged heating at the boiling point. Therefore, with the best reaction conditions in hand (K 2 CO 3 (1 mmol), TBAB (0.5 mmol), spiro[ [1,3]dithiolane-2,3 ′ -indolin]-2 ′ -one (1 mmol), and dihaloalkane (1 mmol)), we next considered the scope of the reaction by employing various dihaloalkanes with isatin thioketal 1 ( Table 2).
From Table 2, it is clear that, generally, the reactions produced the corresponding products in good yields and change in the length of chain (CH 2 )n did not have a considerable effect on the reaction yields.
We suggested two suitable mechanisms for the production of compounds 3 and 5. These mechanisms explain the role of TBAB and bases DABCO and K 2 CO 3 in these reactions (Scheme 4).

Conclusions
In summary, we synthesized novel derivatives of isatin thioketal using a new, facile, and efficient method under solvent-free conditions. The reaction between spiro[ [1,3]dithiolane-2,3 ′ -indolin]-2 ′ -one and α,β-unsaturated esters was successful in the presence of organic salt TBAB and basic catalyst DABCO at 80°C. Also, spiro [ [1,3]dithiolane-2,3 ′ -indolin]-2 ′ -one and alkyl dihalides reacted successfully in the presence of TBAB and inorganic base K 2 CO 3 at 80°C. We also observed that in the first reaction, lower yields of products and longer reaction time were obtained when fumaric esters were used as the Michael acceptor. It is considerable that both the bases used in the reactions are readily available, and also facile procedures would make the method practical and useful to synthetic chemists.