Convenient One-Pot Synthesis of Spirooxindole Derivatives Containing a 1,3,4-Thiadiazine Scaffold

Abstract

A useful strategy for the construction of spirocyclic oxindoles bearing a 1,3,4-thiadiazine skeleton is reported. The desired products were obtained in high yields under mild conditions.

Key words

spiro compounds - heterocycles - indoles - thiadiazines - cyclizations

• References

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• 22 Spiro Compounds 4a–g; General Procedure A mixture of the appropriate isatin derivative 1 (1 mmol), 2-aryl-2-oxoethyl thiocyanate 2 (1 mmol), and Et₃N (1 mmol) in EtOAc (3 mL) was stirred at r.t. for 7 h. Hydrazonoyl chloride 3 (1 mmol) was then added, and the mixture was stirred at reflux for 10 min. When the reaction was complete, the mixture was filtered and concentrated, and the residue was purified by crystallization (EtOH). The two diastereoisomers of products 4a–c were separated by washing the precipitate with hexane–EtOAc (10:1). 6′-Benzoyl-2′,4′-diphenyl-4′H-spiro[indole-3,5′-[1,3,4]thiadiazin]-2(1H)-one (4a; Major Diastereoisomer) Yellow powder; yield: 0.23 g (49%); mp 162–164 °C. IR (KBr): 3420 (NH), 1713 (C=O, NCO), 1597 and 1490 (Ar) cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 5.65 (s, 1 H, CH), 6.79 (d, ³ J _HH = 7.1 Hz, 2 H, 2 × CH _ortho of Ph), 6.93 (t, ³ J _HH = 6.7 Hz, 1 H, CH _para of Ph), 7.11 (t, ³ J _HH = 7.4 Hz, 1 H, CH of Ar), 7.26–7.48 (m, 13 H, 13 × CH), 7.79 (d, ³ J _HH = 7.5 Hz, 2 H, 2 × CH of Ph), 10.70 (s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 52.8 (CH), 87.5 (C _spiro ), 109.4 (CH of Ar), 115.7 (2 × CH _ortho of Ph), 121.5 (CH of Ar), 121.9 (CH _para of Ph), 124.0 (CH of Ar), 125.7 (CH of Ar), 126.2 (2 × CH _ortho of Ph), 128.3 (2 × CH _meta of Ph), 128.6 (2 × CH _meta of Ph), 128.7 (C _ipso –C _spiro ), 129.0 (2 × CH _ortho of Ph), 129.2 (CH _para of Ph), 129.6 (2 × CH _meta of Ph), 130.2 (CH _para of Ph), 133.3 (C _ipso –C=N), 134.1 (C _ipso –C=O), 141.1 (C _ipso –NHCO), 142.7 (C=N), 143.7 (C _ipso –N), 175.1 (NCO), 190.7 (C=O). Anal. Calcd for C₂₉H₂₁N₃O₂S (475.56): C, 73.24; H, 4.45; N, 8.84. Found: C, 73.19; H, 4.52; N, 8.90. 6′-Benzoyl-2′,4′-diphenyl-4′H-spiro[indole-3,5′-[1,3,4]thiadiazin]-2(1H)-one (4a; Minor Diastereoisomer) Yellow powder; yield: 0.19 g (40%); mp 163–165 °C. IR (KBr): 3241 (NH), 1709 (C=O, NCO), 1595 and 1486 (Ar) cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 5.06 (s, 1 H, CH), 6.78 (d, ³ J _HH = 7.5 Hz, 2 H, 2 × CH _ortho of Ph), 6.96 (t, ³ J _HH = 6.7 Hz, 1 H, CH _para of Ph), 7.20 (t, ³ J _HH = 7.2 Hz, 1 H, CH of Ar), 7.36–7.54 (m, 13 H, 13 × CH), 7.95 (d, ³ J _HH = 7.7 Hz, 2 H, 2 × CH of Ph), 10.55 (s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 52.8 (CH), 90.2 (C _spiro ), 109.4 (CH of Ar), 115.8 (2 × CH _ortho of Ph), 121.4 (CH of Ar), 121.9 (CH _para of Ph), 124.0 (CH of Ar), 125.6 (CH of Ar), 126.3 (2 × CH _ortho of Ph), 128.3 (2 × CH _meta of Ph), 128.6 (2 × CH _meta of Ph), 128.7 (C _ipso –C _spiro ), 129.0 (2 × CH _ortho of Ph), 129.2 (CH _para of Ph), 129.6 (2 × CH _meta of Ph), 130.0 (CH _para of Ph), 133.4 (C _ipso –C=N), 134.1 (C _ipso –C=O), 141.1 (C _ipso –NHCO), 142.7 (C=N), 143.7 (C _ipso –N), 175.0 (NCO), 190.9 (C=O). Anal. Calcd for C₂₉H₂₁N₃O₂S (475.56): C, 73.24; H, 4.45; N, 8.84. Found: C, 73.28; H, 4.53; N, 8.80. 6′-Benzoyl-2′-(4-chlorophenyl)-4′-phenyl-4′H-spiro[indole-3,5′-[1,3,4]thiadiazin]-2(1H)-one (4b; Major Diastereoisomer) Orange powder; yield: 0.24 g (48%); mp 163–165 °C. IR (KBr): 3241 (NH), 1709 (C=O, NCO), 1595 and 1486 (Ar) cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 5.07 (s, 1 H, CH), 6.79 (d, ³ J _HH = 7.5 Hz, 2 H, 2 × CH _ortho of Ph), 6.96 (t, ³ J _HH = 7.1 Hz, 1 H, CH _para of Ph), 7.17–7.26 (m, 3 H, 3 × CH), 7.36–7.43 (m, 5 H, 5 × CH), 7.47–7.54 (m, 4 H, 4 × CH), 7.96 (d, ³ J _HH = 7.7 Hz, 2 H, 2 × CH _ortho of Ph), 10.56 (s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 52.8 (CH), 90.4 (C _spiro ), 109.2 (CH of Ar), 115.8 (2 × CH _ortho of Ph), 121.4 (CH of Ar), 121.5 (CH _para of Ph), 124.0 (CH of Ar), 125.6 (CH of Ar), 126.2 (2 × CH _meta of Ph), 128.3 (2 × CH of Ar), 128.6 (2 × CH of Ar), 128.9 (C _ipso –C _spiro ), 129.1 (2 × CH _meta of Ph), 129.6 (2 × CH _ortho of Ph), 130.0 (CH _para of Ph), 133.4 (C _ipso –C=N), 133.7 (C _ipso –Cl), 134.1 (C _ipso –C=O), 141.1 (C _ipso –NHCO), 142.7 (C=N), 143.7 (C _ipso –N), 175.1 (NCO), 190.6 (C=O). Anal. Calcd for C₂₉H₂₀ClN₃O₂S (510.01): C, 68.30; H, 3.95; N, 8.24. Found: C, 68.35; H, 4.01; N, 8.20. 6′-Benzoyl-2′-(4-chlorophenyl)-4′-phenyl-4′H-spiro[indole-3,5′-[1,3,4]thiadiazin]-2(1H)-one (4b; Minor Diastereoisomer) Orange powder; yield: 0.20 g (39%); mp 161–163 °C. IR (KBr): 3241 (NH), 1709 (C=O, NCO), 1595 and 1486 (Ar) cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 5.64 (s, 1 H, CH), 6.78 (d, ³ J _HH = 7.5 Hz, 2 H, 2 × CH _ortho of Ph), 6.95 (t, ³ J _HH = 7.1 Hz, 1 H, CH _para of Ph), 7.11 (t, ³ J _HH = 7.5 Hz, 1 H, CH of Ar), 7.25–7.32 (m, 5 H, 5 × CH), 7.39–7.44 (m, 4 H, 4 × CH), 7.49–7.54 (m, 3 H, 3 × CH), 7.77 (d, ³ J _HH = 8.0 Hz, 2 H, 2 × CH _ortho of Ph), 10.69 (s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 51.7 (CH), 87.5 (C _spiro ), 109.4 (CH of Ar), 115.9 (2 × CH _ortho of Ph), 121.3 (CH of Ar), 121.9 (CH _para of Ph), 124.1 (CH of Ar), 125.7 (CH of Ar), 126.1 (2 × CH _meta of Ph), 128.3 (2 × CH of Ar), 128.6 (2 × CH of Ar), 128.9 (C _ipso –C _spiro ), 129.0 (2 × CH _meta of Ph), 129.5 (2 × CH _ortho of Ph), 130.2 (CH _para of Ph), 133.4 (C _ipso –C=N), 133.9 (C _ipso –Cl), 134.1 (C _ipso –C=O), 138.4 (C _ipso –NHCO), 143.2 (C=N), 143.5 (C _ipso –N), 174.9 (NCO), 194.0 (C=O). Anal. Calcd for C₂₉H₂₀ClN₃O₂S (510.01): C, 68.30; H, 3.95; N, 8.24. Found: C, 68.23; H, 4.02; N, 8.29.