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.

KEYWORDS:

• Green synthesis
• tetrabutylammonium bromide
• spiro[[1,3]dithiolane-2,3′-indolines]-2′-one
• α,β-unsaturated esters
• dihaloalkanes

Introduction

Isatin (1-H indole 2–3 dione) is synthetically a versatile molecule that is employed for the synthesis of a large variety of heterocyclic compounds ( 1). Isatin and its derivatives have diversified biological activities, for example, antibacterial ( 2), anticonvulsant ( 3), antiviral ( 4), and antitubercular ( 5) activities. Some of the spiro derivatives of isatin are important pharmacophores and exhibit promising biological activities, such as analgesic, fungicidal, and anti-inflammatory activities ( 6). Isatin ketals have anxiolytic ( 7), psychotropic ( 8), and anticonvulsant activities ( 9). For instance, spiro[1,3-dioxolane-2,3′-indol]-2′(1′H)-one (I) has sedative, hypnotic, and anesthetic properties ( 10).

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,β-unsaturated esters ( 11–13), 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).

Scheme 1. Alkylation of isatin thioketal by Michael reaction and direct method.

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, ¹H NMR and ¹³C NMR spectroscopies. The progress of the reactions was followed by TLC using silica-gel SILIG/UV 254 plates. ¹H NMR (400 MHz) and ¹³C 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.

General procedure for the addition of spiro[[1,3]dithiolane-2,3′-indolin]-2′-one to α,β-unsaturated esters and dihaloalkanes

To a well-ground mixture of spiro[[1,3]dithiolane-2,3′-indolin]-2′-one 1 (1.0 mmol), tetrabutylammonium bromide (TBAB) (0.5 mmol), base (1.0 mmol, 1,4-diazabicyclo[2.2.2]octane (DABCO) for Michael addition, and K₂CO₃ for N-alkylation), and α,β-unsaturated esters or dihaloalkanes (1.2 mmol) were added and mixed thoroughly with a glass rod. The resulting mixture was kept in an oil bath at 80°C for the stipulated time (Tables 1 and 2). The progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was cooled to room temperature and dissolved in chloroform (20 mL). TBAB was recovered by the addition of water (20 mL × 3), then collected, and dried under vacuum. The chloroform layer was washed with water (15 mL × 3). The organic layer was dried over anhydrous Na₂SO₄. The solvent was removed under reduced pressure and the resulting crude material was purified on a short silica-gel column with ethyl acetate:n-hexane (1:9) as the eluent.

Table 1. Aza-Michael addition of spiro[[1,3]dithiolane-2,3′-indolin]-2′-one 1 to α,β-unsaturated esters 2 under solvent-free conditions.

Entry	Ester 2	Product 3	Time (min)	Yield (%)^a
1			120	90
2			120	85
3			120	90
4			120	80
5			120	75
6			120	65
7			150	70
8			150	65
9			150	63
10			150	50

^aIsolated yields.

Table 2. N-alkylation of spiro[[1,3]dithiolane-2,3′-indolin]-2′-one 1 by dihaloalkanes 4 under solvent-free conditions.

Entry	dihaloalkane 4	Product 5	Time (min)	Yield (%)^a
1			120	80
2			120	85
3			120	80
4			120	85
5			120	75

^aIsolated yields.

Physical and spectroscopic data of isolated products

Methyl 3-(2′-oxospiro[[1,3]dithiolane-2,3′-indolin]-1′-yl) propanoate (3a): Green viscous oil, yield 90%. IR (KBr, cm⁻¹): 3056, 2980, 1735, 1609, 1466, 1187, 1064, 852, 750, 658, 567, 489. ¹H NMR (400 MHz, CDCl₃): δ ppm 2.63 (t, 2H, J = 7.25 Hz), 3.55–3.61 (m, 5H), 3.77–3.83 (2H, m), 3.91 (t, 2H, J = 7.25 Hz), 6.81 (d, 1H, J = 7.85 Hz), 7.01 (1H, t, J = 7.50 Hz), 7.23 (t, 1H, J = 7.00 Hz), 7.45 (d, 1H, J = 7.45 Hz). ¹³C NMR (100 MHz, CDCl₃): 30.7, 35.2, 39.3, 39.3, 50.8, 107.4, 122.1, 124.5, 125.1, 128.8, 140.6, 170.3, 176.57. Anal. Calcd. For C₁₄H₁₅NO₃S₂: C, 54.35; H, 4.89; N, 4.53. Found: C, 54.49; H, 5.05; N, 4.72.

Ethyl 3-(2′-oxospiro[[1,3]dithiolane-2,3′-indolin]-1′-yl) propanoate (3b): Green viscous oil, yield 85%. IR (KBr, cm⁻¹): 2963, 2873, 1734, 1612, 1464, 1351, 1262, 1097, 804, 686, 476. ¹H NMR (400 MHz, CDCl₃): δ ppm 1.13–1.20 (m, 3H), 2.66–2.70 (t, 2H, J = 7.50 Hz), 3.58–3.66 (m, 2H), 3.82–3.85 (m, 2H), 3.87–3.88 (m, 2H), 3.94–3.96 (m, 2H), 6.87 (d, 1H, J = 8.00 Hz), 7.05 (t, 1H, J = 5.20 Hz), 7.25(t, 1H, J = 3.60 Hz) 7.50 (d, 1H, 7.20 Hz). ¹³C NMR (100 MHz, CDCl₃): 15.2, 33.2, 37.5, 41.5, 61.4, 63.2, 109.8, 124.3, 126.7 127.3, 131.0, 143.3, 166.4, 171.8. Anal. Calcd. For C₁₅H₁₇NO₃S₂: C, 55.70; H, 5.30; N, 4.33. Found: C, 55.78; H, 5.20; N, 4.19.

Butyl 3-(2′-oxospiro[[1,3]dithiolane-2,3′-indolin]-1′-yl) propanoate (3c): Orang viscous oil, yield 90%. IR (KBr, cm⁻¹): 3080, 2949, 1717, 1608, 1486, 1467, 1353, 1165, 752, 686, 442. ¹H NMR (400 MHz, CDCl₃): δ ppm 0.78 (m, 3H), 1.11–1.24 (m, 2H), 1.39–1.45 (t, 2H, J = 6.80 Hz), 2.60 (t, 2H, J = 4.80 Hz), 3.52–3.57 (m, 2H), 3.76–3.81 (m, 2H), 3.88 (t, 2H, J = 4.80 Hz), 3.92 (t, 2H, J = 2.00 Hz), 6.80 (d, 1H, J = 7.60 Hz), 6.96 (t, 2H, J = 4.80 Hz), 7.18 (t, 1H, J = 7.6 Hz), 7.42 (d, 1H, J = 7.2 Hz). ¹³C NMR (100 MHz, CDCl₃): 14.8, 20.1, 31.5, 33.2, 37.5, 41.2, 63.2, 65.7, 109.8, 124.2, 126.7, 127.2, 131.0, 143.3, 166.4, 171.0. Anal. Calcd. For C₁₇H₂₁NO₃S₂: C, 58.09; H, 6.02; N, 3.99. Found: C, 58.26; H, 5.91; N, 4.15.

2-Ethylhexyl 3-(2′-oxospiro[[1,3]dithiolane-2,3′-indolin]-1′-yl) propanoate (3d): Red viscous oil, yield 80%. IR (KBr, cm⁻¹): 3056, 2930, 1722, 1609, 1467, 1350, 1185, 1062, 749, 685, 490. ¹H NMR (400 MHz, CDCl₃): δ ppm 0.81–0.87 (m, 6H), 1.23–1.30 (m, 8H), 1.49–1.50 (m, 1H), 2.72 (t, 2H, J = 7.05 Hz), 3.63–3.69 (m, 2H), 3.85–4.01 (m, 6H), 6.90 (d, 1H, J = 7.80 Hz), 7.07 (t, 1H, J = 7.40 Hz), 7.29 (t, 1H, J = 7.60 Hz), 7.52 (1H, d, J = 7.32 Hz). ¹³C NMR (100 MHz, CDCl₃): 9.7, 12.8, 21.7, 22.4, 27.6, 29.0, 30.9, 35.2, 37.3, 37.5, 39.2, 65.7, 66.1, 107.4, 122.0, 124.4, 125.0, 128.7, 140.9, 170.1, 176.6. Anal. Calcd. For C₂₁H₂₉NO₃S₂: C, 61.88; H, 7.17; N, 3.44. Found: C, 62.08; H, 7.25; N, 3.66.

Methyl 2-methyl-3-(2′-oxospiro[[1,3]dithiolane-2,3′-indolin]-1′-yl) propanoate (3e): Green viscous oil, yield 78%. IR (KBr, cm⁻¹): 3010, 2936, 1724, 1610, 1468, 1353, 1203, 1092, 752, 687, 490. ¹H NMR (400 MHz, CDCl₃): δ ppm 1.21–12.4 (m, 3H), 2.97–3.02 (m, 1H), 3.62 (s, 2H), 3.63–3.65 (m, 3H), 3.65–3.70 (m, 1H), 3.85–3.90 (m, 3H), 6.86 (d, 1H, J = 7.60 Hz), 7.08 (t, 1H, J = 7.60 Hz), 7.28 (t, 1H, J = 6.80 Hz), 7.53 (d, 1H, J = 7.60 Hz). ¹³C NMR (100 MHz, CDCl₃): 15.8, 38.7, 41.5, 44.3, 53.2, 63.2, 109.8, 124.4, 126.8, 127.2, 131.1, 143.5, 166.4, 173.0. Anal. Calcd. For C₁₅H₁₇NO₃S₂: C, 55.70; H, 5.30; N, 4.33. Found: C, 55.92; H, 5.18; N, 4.51.

Butyl 2-methyl-3-(2′-oxospiro[[1,3]dithiolane-2,3′-indolin]-1′-yl) propanoate (3f): Orange viscous oil, yield 65%. IR (KBr, cm⁻¹): 3057, 2959, 1724, 1609, 1467, 1352, 1193, 1091, 750, 686, 490. ¹H NMR (400 MHz, CDCl₃): δ ppm 0.86 (t, 3H, J = 7.3 Hz), 1.22 (d, 3H, J = 7.02 Hz), 1.26 (t, 2H, J = 3.50), 1.45–1.52 (m, 1H), 3.97–3.02 (m, 1H), 3.62–3.68 (m, 2H), 3.84–3.87 (dd, 2H, J₁ = 2.30 Hz, J₂ = 7.40 Hz), 3.89–3.93 (m, 3H), 3.95–3.98(m, 1H), 6.86 (d, 1H, J = 7.85 Hz), 7.08 (t, 1H, J = 7.50 Hz), 7.29 (t, 1H, J = 7.65 Hz), 7.35(d, 1H, J = 35 Hz). ¹³C NMR (100 MHz, CDCl₃): 12.6, 13.8, 17.9, 28.6, 29.4, 36.9, 39.3, 39.4, 42.2, 63.8, 107.7, 122.2, 124.6, 127.0, 128.8, 141.4, 173.4, 177.2. Anal. Calcd. For C₁₈H₂₃NO₃S₂: C, 59.15; H, 6.34; N, 3.83. Found: C, 58.99; H, 6 .52; N, 4.02.

Dipentyl 2-(2′-oxo-1′,2′-dihydrospiro[[1,3]dithiolane-2,3′-inden]-1′-yl) succinate (3g): Red viscous oil, yield 70%. IR (KBr, cm⁻¹): 3055, 2929, 1717, 1608, 1458, 1467, 1350, 1145, 1096, 750, 687, 490. ¹H NMR (400 MHz, CDCl₃): δ ppm 0.78 (t, 3H, J = 7.20 Hz), 0.85 (t, 3H, J = 6.90 Hz), 1.08–1.22 (m, 4H), 1.24–1.35 (m, 4H), 1.49–1.63 (m, 4H), 2.93–3.02 (dd, 1H, J₁ = 9.70 Hz, J₂ = 20.18 Hz), 3.36–3.42 (dd, 1H, J₁ = 6.65 Hz, J₂ = 16.75 Hz), 3.62–3.70 (m, 2H), 3.85–3.93 (m, 2H), 4.07 (m, 3H), 4.11–4.21 (m, 1H), 5.31 (t, 1H, J = 7.00 Hz), 6.86 (d, 1H, J = 7.90 Hz), 7.09 (t, 1H, J = 8.20 Hz), 7.29 (t, 1H, J = 7.55 Hz), 7.55 (d, 1H, J = 7.20 Hz). ¹³C NMR (100 MHz, CDCl₃): 12.8, 21.1, 21.2, 26.9, 27.0, 28.6, 32.6, 39.3, 39.4, 49.7, 64.3, 65.3, 107.9, 122.4, 124.7, 124.9, 128.8, 140.5, 167.5, 169.3, 176.5. Anal. Calcd. For C₂₄H₃₃NO₅S₂: C, 60.10; H, 6.93; N, 2.92. Found: C, 60.02; H, 7.11; N, 2.79.

Dihexyl 2-(2′-oxo-1′,2′-dihydrospiro[[1,3]dithiolane-2,3′-inden]-1′-yl) succinate (3h): Red viscous oil, yield 65%. IR (KBr, cm⁻¹): 3057, 2931, 1734, 1610, 1467, 1354, 1174, 1066, 994, 749, 686, 498. ¹H NMR (400 MHz, CDCl₃): δ ppm 0.80 (m, 3H, J = 7.00 Hz), 0.85–0.89 (m, 3H), 1.15–1.21 (m, 4H), 1.25–1.37 (m, 8H), 1.53–1.58 (m, 2H), 1.63–1.71 (m, 2H), 2.96–3.02 (dd, 1H, J₁ = 8.80 Hz, J₂ = 16.75 Hz), 3.36–3.42 (dd, 1H, J₁ = 6.60 Hz, J₂ = 16.80 Hz), 3.64–3.70 (m, 2H), 3.87–3.92 (m, 2H), 4.07 (t, 2H, J = 11.60 Hz), 4.17 (t, 2H, J = 9.75 Hz), 5.30 (t, 1H, J = 6.90 Hz), 6.86 (d, 1H, J = 8.15 Hz), 7.10 (t, 1H, J = 7.55 Hz), 7.28 (t, 1H, J = 7.80 Hz), 7.55 (d, 1H, J = 7.45 Hz). ¹³C NMR (100 MHz, CDCl₃): 12.8, 21.3, 21.4, 24.3, 24.4, 27.3, 27.4, 30.2, 30.4, 32.6, 39.2, 39.3, 49.6, 64.3, 64.5, 74.3, 107.8, 122.3, 124.7, 128.8, 132.4, 140.4, 167.41, 169.2, 176.4. Anal. Calcd. For C₂₆H₃₇NO₅S₂: C, 61.51; H, 7.35; N, 2.76. Found: C, 61.23; H, 7.21; N, 2.90.

Dioctyl 2-(2′-oxospiro[[1,3]dithiolane-2,3′-indolin]-1′-yl) succinate (3i): Red viscous oil, yield 63%. IR (KBr, cm⁻¹): 3057, 2928, 1734, 1610, 1467, 1353, 1175, 1099, 748, 686, 496. ¹H NMR (400 MHz, CDCl₃): δ ppm 0.84 (m, 6H), 1.15 (s, 4H), 1.24 (s, 16H), 1.53–1.58 (m, 3H), 1.64–1.69 (m, 1H), 2.96–3.02 (dd, 1H, J₁ = 7.65 Hz, J₂ = 16.57 Hz), 3.36–3.40 (dd, 1H, J₁ = 6.65 Hz, J₂ = 11.10 Hz), 3.62–3.69 (m, 2H), 3.86–3.92 (m, 2H), 4.03–4.09 (m, 2H), 4.15–4.21 (m, 2H), 5.30 (t, 1H, J = 6.90 Hz), 6.86 (d, 1H, J = 11.20 Hz), 7.09 (t, 1H, J = 7.40 Hz), 7.28 (t, 1H, J = 6.95 Hz), 7.55 (d, 1H, J = 7.45 Hz). ¹³C NMR (100 MHz, CDCl₃): 13.0, 21.5, 24.6, 24.7, 27.2, 27.4, 28.0, 28.6, 30.6, 30.7, 32.6, 39.3, 39.4, 49.7, 64.3, 65.3, 107.6, 122.4, 124.7, 128.8, 132.5, 140.5, 167.5, 169.3, 176.5. Anal. Calcd. For C₃₀H₄₅NO₅S₂: C, 63.91; H, 8.04; N, 2.48. Found: C, 63.77; H, 7.53; N, 2.71.

Didecyl 2-(2′-oxospiro[[1,3]dithiolane-2,3′-indolin]-1′-yl)succinate (3j): Red viscous oil, yield 65%. IR (KBr, cm⁻¹): 3050, 2854, 1734, 1610, 1467, 1260, 1173, 1058, 748, 685, 496. ¹H NMR (400 MHz, CDCl₃): δ ppm 0.80 (m, 6H), 1.05 (s, 8H), 1.19 (s, 16H), 1.45–1.50 (m, 8H), 2.90–2.95 (dd, 1H, J₁ = 4.90 Hz, J₂ = 11.80 Hz), 3.28–3.35 (dd, 1H, J₁ = 8.45 Hz, J₂ = 14.75 Hz), 3.55 (t, 4H, J = 6.65 Hz), 3.95–4.03 (m, 4H), 5.23 (t, 1H, J = 6.75 Hz), 6.79 (d, 1H, J = 9.45 Hz), 7.05 (t, 1H, J = 7.55 Hz), 7.21 (t, 1H, J = 6.80 Hz), 7.48 (d, 1H, J = 7.35 Hz). ¹³C NMR (100 MHz, CDCl₃): 13.1, 21.6, 24.7, 24.8, 27.3, 27.4, 28.3, 28.4, 28.5, 28.6, 30.8, 31.7, 32.7, 39.3, 39.4, 49.7, 61.9, 64.3, 65.3, 107.9, 122.4, 124.8, 128.9, 132.5, 140.5, 167.5, 169.4, 176.6. Anal. Calcd. For C₃₄H₅₃NO₅S₂: C, 65.87; H, 8.62; N, 2.26. Found: C, 65.59; H, 8.78; N, 2.60.

1′-(2-Bromoethyl)spiro[[1,3]dithiolane-2,3′-indolin]-2′-one (5a): White solid, yield 70%, m.p. 55°C. IR (KBr, cm⁻¹): 3057, 2915, 1717, 1609, 1464, 1357, 1157, 1083, 747, 539, 440. ¹H NMR (400 MHz, CDCl₃): δ ppm 3.57 (t, 2H, J = 7.05 Hz), 3.63–3.71 (m, 2H), 3.86–3.94 (m, 2H), 4.09 (t, 2H, J = 7.05 Hz), 6.88 (d, 1H, J = 7.85 Hz), 7.11 (t, 1H, J = 7.40 Hz), 7.31 (t, 1H, J = 7.80 Hz), 7.55 (1H, d, J = 7.35 Hz). ¹³C NMR (100 MHz, CDCl₃): 26.1, 39.4, 40.9, 61.0, 107.4, 122.4, 124.7, 125.0, 128.9, 140.9, 176.8. Anal. Calcd. For C₁₂H₁₂BrNOS₂: C, 43.64; H, 3.66; N, 4.24. Found: C, 43.85; H, 3.72; N, 4.60.

1′-(2-Chloroethyl)spiro[[1,3]dithiolane-2,3′-indolin]-2′-one (5b): White solid, yield 82%, m.p. 55°C. IR (KBr, cm⁻¹): 3059, 2918, 1717, 1608, 1487, 1359, 1164, 1082, 667, 747, 444. ¹H NMR (400 MHz, CDCl₃): δ ppm 3.63–3.71 (m, 2H), 3.75 (t, 2H, J = 6.60 Hz), 3.86–3.92 (m, 2H), 4.03 (t, 2H, J = 6.55 Hz), 6.89 (d, 1H, J = 7.80 Hz), 7.11 (t, 1H, J = 7.55 Hz), 7.31 (t, 1H, J = 7.70 Hz), 7.55 (d, 1H, J = 7.45 Hz). ¹³C NMR (100 MHz, CDCl₃): 39.2, 39.4, 41.1, 61.0, 107.5, 122.4, 124.7, 125.0, 128.9, 141.2, 177.0. Anal. Calcd. For C₁₂H₁₂ClNOS₂: C, 50.43; H, 4.23; N, 4.90. Found: C, 50.66; H, 3.97; N, 4.73.

1′-(5-Bromopentyl)spiro[[1,3]dithiolane-2,3′-indolin]-2′-one (5c): Orange solid, yield 87% m.p. 64°C. IR (KBr, cm⁻¹): 3056, 2951, 1733, 1606, 1469, 1359, 1201, 1070 753, 601, 454. ¹H NMR (400 MHz, CDCl₃): δ ppm 1.25–1.54 (m, 4H), 1.76–1.90 (m, 2H), 3.45 (t, 2H, J = 5.40 Hz), 3.64–3.70 (m, 2H), 3.73 (t, 2H, J = 6.45 Hz) 3.86–3.93 (m, 2H), 6.86 (d, 1H, J = 7.75 Hz), 7.09 (t, 1H, J = 7.50 Hz), 7.26–7.32 (m, 1H), 7.54 (d, 1H, J = 7.30 Hz). ¹³C NMR (100 MHz, CDCl₃): 24.7, 28.4, 30.3, 32.0, 38.2, 39.4, 61.1, 107.5, 122.1, 124.6, 125.2, 129.8, 141.3, 177.0. Anal. Calcd. For C₁₅H₁₈BrNOS₂: C, 48.39; H, 4.87; N, 3.76. Found: C, 48.12; H, 4.76; N, 3.67.

1′-(6-Bromohexyl)spiro[[1,3]dithiolane-2,3′-indolin]-2′-one (5d): Red solid, yield 95%, m.p. 66°C. IR (KBr, cm⁻¹): 3027, 2930, 1705, 1609, 1465, 1353, 1144, 1090, 747, 552, 441. ¹H NMR (400 MHz, CDCl₃): δ ppm 1.34–1.50 (m, 4H), 1.66–1.73 (qui, 2H, J = 7.25 Hz), 1.80–1.87 (qui, 2H, J = 7.50 Hz), 3.38 (t, 2H, J = 6.70 Hz), 3.62–3.71 (m, 4H), 3.86–3.94 (m, 2H), 6.81 (d, 1H, J = 7.80 Hz), 7.08 (t, 1H, J = 7.55 Hz), 7.29 (t, 1H, J = 7.05 Hz), 7.35 (d, 1H, J = 7.40 Hz). ¹³C NMR (100 MHz, CDCl₃): 24.7, 25.9, 26.5, 31.3, 32.7, 38.9, 39.3, 61.0, 107.4, 121.9, 124.4, 125.1, 128.7, 141.4, 176.8. Anal. Calcd. For C₁₆H₂₀BrNOS₂: C, 49.74; H, 5.22; N, 3.63. Found C 49.93, H 5.35, N 3.50.

1′-(6-Chlorohexyl)spiro[[1,3]dithiolane-2,3′-indolin]-2′-one (5e): Red solid, yield 88%, m.p. 66°C. IR (KBr, cm⁻¹): 3058, 2934, 1714, 1609, 1467, 1351, 1153, 899, 748. ¹H NMR (400 MHz, CDCl₃): δ ppm 1.23–1.28 (m, 2H), 1.46–1.54 (m, 2H), 1.70 (qui, 2H, J = 7.50 Hz), 1.88 (qui, 2H, J = 6.40 Hz), 3.38 (t, 2H, J = 6.70 Hz), 3.61–3.71 (m, 4H), 3.86–3.94 (m, 2H), 6.81 (d, 1H, J = 7.80 Hz), 7.08 (t, 1H, J = 7.50 Hz), 7.29 (t, 1H, J = 8.00 Hz), 7.54 (d, 1H, J = 7.30 Hz). ¹³C NMR (100 MHz, CDCl₃): 24.2, 25.3, 28.6, 30.4, 32.4, 38.9, 39.4, 61.1, 107.5, 122.0, 124.6, 125.3, 128.9, 141.4, 176.9. Anal. Calcd. For C₁₆H₂₀ClNOS₂: C, 56.20; H, 5.90; N, 4.10. Found: C, 55.93; H, 5.80; N, 4.28.

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 solvent-free 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, K₂CO₃, Na₂CO₃, KOH, NaOH, and DABCO was investigated as a model reaction to evaluate their capabilities for access to the best base (Scheme 2).

Scheme 2. Aza-Michael addition of spiro[[1,3]dithiolane-2,3′-indolin]-2′-one 1 to n-butyl acrylate 2c as model reaction.

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 CH₂Cl₂, CHCl₃, DMSO, CH₃OH, EtOH, CH₃CO₂Et, 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 (K₂CO₃) 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.

With these precedents and with the aim of preparing other new derivatives of spiro[[1,3]dithiolane-2,3′-indolin]-2′-one, we decided to carry out N-alkylation of this compound by dihalogenoalkyl groups (Scheme 1). Therefore, the alkylation of isatin thioketal 1 to 1,6-dibromohexane 4d was tried as a model reaction (Scheme 3).

Scheme 3. Direct N-alkylation reaction of spiro[[1,3]dithiolane-2,3′-indolin]-2′-one 1 with 1,6-dibromohexane 4d (as a model reaction).

In the presence of TBAB and different organic and inorganic bases, the results for the model reaction indicated that K₂CO₃ 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 CH₂Cl₂, CHCl₃, DMSO, CH₃OH, EtOH, CH₃CO₂Et, n-hexane as well as water, even upon prolonged heating at the boiling point. Therefore, with the best reaction conditions in hand (K₂CO₃ (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 (CH₂)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 K₂CO₃ in these reactions (Scheme 4).

Scheme 4. Proposed mechanism for the formation of 3 and 5.

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 K₂CO₃ 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.

Acknowledgments

The authors are grateful to the laboratories of Tehran and Tabriz University as well as the University of Mohaghegh Ardabili for the product analysis.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes on contributors

Dr Imanzadeh is professor in University of Mohaghegh Ardabili.

Dr Banaei is Assistant Professor in Payame Noor University.

Mr Fathi is M.Sc. student in Payame Noor University.

Ms Soltanzadeh is Ph.D. student in University of Mohaghegh Ardabili.