Chemo- and Regioselective 4CR Synthesis of Oxathiaaza[3.3.3]propellanes via Sequential C–S, C–N and C–O Bond Formation in a Single Pot

Abstract

Oxathiaaza[3.3.3]propellane derivatives were prepared by reaction of in situ generated asymmetric thioureas with inter­mediate Knoevenagel adducts resulting from ninhydrin and malononitrile. This four-component sequential transformation performed in one reaction flask represents a general route to this unexplored valuable class of sulfur–nitrogen heterocycles. The chemoselectivity and regiochemistry of the products were established by IR, NMR and single crystal X-ray analysis.

Key words

chemoselectivity - regioselectivity - oxathiaaza[3.3.3]-propellanes - four-component reaction (4CR)

• References

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• 21 General Procedure: To a solution of ninhydrin (1 mmol) and malononitrile (1 mmol) in EtOH (4 mL) was added Et₃N (0.1 mmol), and the solution was stirred for 1 h at r.t. Then, aryl isothiocyanate 1 (1 mmol) and primary amine 2 (1 mmol) were added at once and dropwise over 15 min, respectively. Upon completion (7 h), monitored by TLC, the mixture was filtered and the precipitate was washed with EtOH (4 mL) to afford the pure product 3. 8c-Amino-8-oxo-2-phenylimino-3-propyl-2,3-dihydro-8H-8d-oxa-1-thia-3-azapentaleno[3a,6a-a]inden-8-yl Cyanide (3a): white powder; yield: 0.37 g (93%); mp 188–190 °C. IR (KBr): 3338, 3274 (NH₂), 2195 (CN), 1733 (C=O), 1666 (C=N), 1618 (NC=C) cm^–1. ¹H NMR (500 MHz, DMSO): δ = 0.88 (t, J = 7.0 Hz, 3 H, Me), 1.51 (br, 1 H, CH₂), 1.76 (br, 1 H, CH₂), 3.71 (br, 1 H, CH₂), 3.81 (br, 1 H, CH₂), 6.83 (d, J = 7.3 Hz, 2 H, 2 × CH of Ph), 7.96 (t, J = 6.9 Hz, 1 H, CH of Ph), 7.28 (t, J = 7.2 Hz, 2 H, 2 × CH of Ph), 7.83 (t, J = 7.3 Hz, 1 H, CH of Ar), 7.94 (d, J = 7.3 Hz, 1 H, CH of Ar), 8.01–8.04 (m, 3 H, CH of Ar, NH₂), 8.18 (d, J = 7.5 Hz, 1 H, CH of Ar). ¹³C NMR (125 MHz, DMSO): δ = 11.42 (Me), 21.23 (CH₂), 45.93 (CH₂N), 53.02 (CS), 71.26 (CCN), 107.80 (CN), 116.48 (OCN), 121.67 (2 × CH of Ph), 124.23 (CH of Ar), 125.75 (CH of Ar), 126.07 (CH of Ar), 129.53 (2 × CH of Ph), 132.90 (CH of Ph), 132.96 (CH of Ar), 137.73 (C _ipso of Ar), 144.74 (C _ipso of Ar), 150.30 (C_ipso of Ph), 154.72 (SCN), 166.49 (CNH₂), 193.25 (CO). MS: m/z = 402 [M⁺], 359, 317, 289, 241, 192, 163, 135, 77. Anal. Calcd for C₂₂H₁₈N₄O₂S: C, 65.66; H, 13.92; N, 7.75. Found: C, 65.57; H, 13.97; N, 7.80. 8c-Amino-2-(4-methylphenylimino)-8-oxo-3-propyl-2,3-dihydro-8H-8d-oxa-1-thia-3-azapentaleno[3a,6a-a]inden-8-yl Cyanide (3b): white powder; yield: 0.37 g (90%); mp 191–193 °C. IR (KBr): 3320, 3296 (NH₂), 2190 (CN), 1739 (C=O), 1664 (C=N), 1593 (NC=C) cm^–1. ¹H NMR (500 MHz, DMSO): δ = 0.86 (s, 3 H, Me), 1.51 (s, 1 H, CH₂), 1.75 (s, 1 H, CH₂), 2.23 (s, 3 H, Me), 3.38 (s, 1 H, CH₂), 3.69 (s, 1 H, CH₂), 6.72 (s, 2 H, 2 × CH of Ar), 7.07 (s, 2 H, 2 × CH of Ar), 7.81–7.82 (m, 1 H, CH of Ar), 7.94–8.16 (m, 5 H, 3 × CH of Ar, NH₂). ¹³C NMR (125 MHz, DMSO): δ = 10.95 (Me), 20.41 (Me), 20.77 (CH₂), 45.45 (CH), 53.27 (CS), 70.74 (CCN), 91.81, 107.35 (CN), 116.09 (OCN), 121.03 (2 × CH of Ph), 123.69 (CH of Ar), 125.28 (CH of Ar), 125.58 (CH of Ar), 127.93 (C _ipso of Ar), 129.53 (2 × CH of Ar), 130.01 (C _ipso of Ar), 132.44 (CH of Ar), 132.67 (CH of Ar), 137.23 (CH of Ar), 144.32 (C_ipso of Ar), 147.35 (C _ipso of Ar), 154.12 (SCN), 166.04 (CNH₂), 192.86 (CO). MS: m/z = 416 [M⁺], 373, 344, 331, 271, 257, 236, 210, 174, 146, 127, 104, 91, 76, 57. Anal. Calcd for C₂₃H₂₀N₄O₂S: C, 66.33; H, 4.84; N, 13.45. Found: C, 66.28; H, 13.4.86; N, 13.88. Crystal data (CCDC 869053) for 3b: C₂₃H₂₀N₄O₂S, M_W = 416.50, monoclinic, space group Pbcn, a = 14.0889(5) Å, b = 16.4966(7) Å, c = 18.9450(6) Å, V = 4403.2(3) ų, Z = 8, Dc = 1.257 mg/m³, F(000) = 1744, crystal dimension 0.32 × 0.26 × 0.22 mm, radiation, Mo–K_α (λ = 0.71073 Å), 2.89≤ 2θ ≤25.19, intensity data were collected at 295(2) K with a Bruker APEX area-detector diffractometer, and employing α/2θ scanning technique, in the range of –16 ≤ h ≤ 16, –16 ≤ k ≤ 19, –18 ≤ l ≤ 22; the structure was solved by a direct method, all non-hydrogen atoms were positioned and anisotropic thermal parameters refined from 2686 observed reflections with R (into) = 0.0538 by a full-matrix least-squares technique converged to R = 0.0390 and Raw = 0.1029 [I > 2σ(I)]. 8c-Amino-2-(4-chlorophenylimino)-8-oxo-3-propyl-2,3-dihydro-8H-8d-oxa-1-thia-3-azapentaleno[3a,6a-a]inden-8-yl Cyanide (3c): white powder; yield: 0.38 g (87%); mp 184–186 °C. IR (KBr): 3310, 3296 (NH₂), 2195 (CN), 1746 (C=O), 1666 (C=N), 1616 (NC=C) cm^–1. ¹H NMR (500 MHz, DMSO): δ = 0.87 (t, J = 6.6 Hz, 3 H, Me), 1.51 (br, 1 H, CH₂), 1.76 (br, 1 H, CH₂), 3.69 (br, 1 H, CH₂), 3.82 (br, 1 H, CH₂), 6.86 (d, J = 7.7 Hz, 2 H, 2 × CH of Ar), 7.31 (d, J = 7.7 Hz, 2 H, 2 × CH of Ar), 7.83 (t, J = 7.0 Hz, 1 H, CH of Ar), 7.95 (d, J = 7.3 Hz, 1 H, CH of Ar), 8.02 (t, J = 7.0 Hz, 1 H, CH of Ar), 8.09 (s, 2 H, NH₂), 8.18 (d, J = 7.3 Hz, 1 H, CH of Ar). ¹³C NMR (125 MHz, DMSO): δ = 10.95 (Me), 20.74 (CH₂), 45.52 (CH₂), 53.10 (CS), 70.95 (CCN), 107.36 (CN), 116.0 (OCN), 123.12 (2 × CH of Ar), 125.32 (CH of Ar), 125.64 (CH of Ar), 127.80 (CH of Ar), 128.99 (2 × CH of Ar), 132.42 (CH of Ar), 132.55 (C _ipso of Ar), 137.32 (C _ipso of Ar), 144.18 (C _ipso of Ar), 148.73 (C _ipso of Ar), 154.92 (SCN), 166.04 (CNH₂), 192.63 (CO). MS: m/z = 436 [M⁺], 411, 393, 368, 351, 315, 241, 210, 194, 169, 152, 111, 83, 57. Anal. Calcd for C₂₂H₁₇ClN₄O₂S: C, 60.48; H, 3.92; N, 8.11. Found: C, 60.53; H, 3.88; N, 8.06. 8c-Amino-3-ethyl-8-oxo-2-phenylimino-2,3-dihydro-8H-8d-oxa-1-thia-3-azapentaleno[3a,6a-a]inden-8-yl Cyanide (3d): white powder; yield: 0.35 g (91%); mp 187–189 °C. IR (KBr): 3310, 3285 (NH₂), 2193 (CN), 1731 (C=O), 1666 (C=N), 1619 (NC=C) cm^–1. ¹H NMR (300 MHz, DMSO): δ = 1.16 (s, 3 H, Me), 3.89 (q, J = 6.8 Hz, 2 H, CH₂), 6.83 (d, J = 7.1 Hz, 2 H, CH of Ph), 7.05 (t, J = 6.5 Hz, 1 H, CH of Ph), 7.26 (t, J = 6.5 Hz, 2 H, 2 × CH of Ph), 7.84 (t, J = 6.5 Hz, 1 H, CH of Ar), 7.94 (d, J = 7.4 Hz, 1 H, CH of Ar), 7.98–8.06 (m, 3 H, 2 × CH of Ar, NH₂), 8.19 (d, J = 7.1 Hz, 1 H, CH of Ar). ¹³C NMR (75 MHz, DMSO): δ = 13.66 (Me), 53.63 (CH₂), 56.97 (CS), 71.23 (CCN), 107.80 (CN), 116.56 (OCN), 121.75 (2 × CH of Ph), 124.28 (CH of Ar), 125.73 (CH of Ar), 126.13 (CH of Ar), 129.58 (2 × CH of Ph), 132.87 (CH of Ar), 133.0 (CH of Ph), 137.84, (C _ipso of Ar), 144.80 (C_ipso of Ar), 150.33 (C _ipso of Ph), 154.36 (SCN), 166.52 (CNH₂), 193.29 (CO). MS: m/z = 388 [M⁺], 368, 354, 317, 285, 257, 241, 210, 181, 152, 135, 105, 77, 57. Anal. Calcd for C₂₁H₁₆N₄O₂S: C, 64.93; H, 4.15; N, 14.42. Found: C, 64.86; H, 4.19; N, 14.45. 8c-Amino-3-ethyl-8-oxo-2-(4-methylphenylimino)-2,3-dihydro-8H-8d-oxa-1-thia-3-azapentaleno[3a,6a-a]inden-8-yl Cyanide (3e): white powder; yield: 0.34 g (85%); mp 199–201 °C. IR (KBr): 3377, 3282 (NH₂), 2192 (CN), 1733 (C=O), 1661 (C=N), 1594 (NC=C) cm^–1. ¹H NMR (300 MHz, DMSO): δ = 1.15 (s, 3 H, Me), 2.22 (s, 3 H, Me), 3.87 (q, J = 6.5 Hz, 2 H, CH₂), 6.72 (d, J = 7.4 Hz, 2 H, 2 × CH of Ar), 7.06 (t, J = 7.1 Hz, 2 H, 2 × CH of Ar), 7.82 (t, J = 6.8 Hz, 1 H, CH of Ar), 7.93 (t, J = 7.4 Hz, 1 H, CH of Ar), 7.98–8.04 (m, 3 H, CH of Ar, NH₂), 8.19 (d, J = 7.4 Hz, 1 H, CH of Ar). ¹³C NMR (75 MHz, DMSO): δ = 13.68 (Me), 20.91 (Me), 53.68 (CH₂), 63.0 (CS), 71.18 (CCN), 107.79 (CN), 116.58 (OCN), 121.56 (2 × CH of Ar), 125.72 (CH of Ar), 126.11 (CH of Ar), 130.04 (C _ipso of Ar), 132.97 (2 × CH of Ar), 133.17 (CH of Ar), 137.82 (CH of Ar), 144.84 (C _ipso of Ar), 147.83 (C _ipso of Ar), 153.76 (C _ipso of Ar), 154.20 (SCN), 166.51 (CNH₂), 193.35 (CO). MS: m/z = 402 [M⁺], 359, 331, 271, 241, 210, 149, 119, 83, 57. Anal. Calcd for C₂₂H₁₈N₄O₂S: C, 65.66; H, 4.51; N, 13.92. Found: C, 65.61; H, 4.53; N, 13.95. 8c-Amino-2-(4-chlorophenylimino)-3-ethyl-8-oxo-2,3-dihydro-8H-8d-oxa-1-thia-3-azapentaleno[3a,6a-a]inden-8-yl Cyanide (3f): white powder; yield: 0.35 g (88%); mp 178–180 °C. IR (KBr): 3330, 3257 (NH₂), 2197 (CN), 1710 (C=O), 1637 (C=N), 1588 (NC=C) cm^–1. ¹H NMR (300 MHz, DMSO): δ = 1.15 (t, J = 7.1 Hz, 3 H, Me), 3.87 (m, 2 H, CH₂), 6.87 (d, J = 8.6 Hz, 2 H, 2 × CH of Ar), 7.31 (d, J = 8.3 Hz, 2 H, 2 × CH of Ar), 7.82 (t, J = 7.4 Hz, 1 H, CH of Ar), 7.94 (d, J = 7.4 Hz, 1 H, CH of Ar), 8.01 (t, J = 7.4 Hz, 1 H, CH of Ar), 8.08 (s, 2 H, NH₂), 8.20 (d, J = 7.7 Hz, 1 H, CH of Ar). ¹³C NMR (75 MHz, DMSO): δ = 13.63 (Me), 53.54 (Me), 64.0 (CS), 71.40 (CCN), 107.80 (CN), 116.49 (OCN), 123.65 (2 × CH of Ar), 125.75 (CH of Ar), 126.15 (CH of Ar), 128.28 (CH of Ar), 129.49 (2 × CH of Ar), 132.87 (CH of Ar), 133.06 (C _ipso of Ar), 137.88 (C _ipso of Ar), 144.70 (C _ipso of Ar), 149.22 (C _ipso of Ar), 155.01 (SCN), 166.52 (CNH₂), 193.12 (CO). MS: m/z = 423 [M⁺], 368, 313, 257, 236, 152, 127, 111, 83, 57. Anal. Calcd for C₂₁H₁₅ClN₄O₂S: C, 59.64; H, 3.58; N, 8.38. Found: C, 59.72; H, 3.53; N, 8.35. 8c-Amino-3-methyl-8-oxo-2-phenylimino-2,3-dihydro-8H-8d-oxa-1-thia-3-azapentaleno[3a,6a-a]inden-8-yl Cyanide (3g): white powder; yield: 0.34 g (92%); mp 181–183 °C. IR (KBr): 3380, 3271 (NH₂), 2194 (CN), 1732 (C=O), 1666 (C=N), 1620, 1591, 1433 cm^–1. ¹H NMR (300 MHz, DMSO): δ = 3.33 (s, 3 H, Me), 6.82 (d, J = 7.7 Hz, 2 H, 2 × CH of Ph), 7.05 (t, J = 6.8 Hz, 1 H, CH of Ph), 7.26 (t, J = 6.8 Hz, 2 H, 2 × CH of Ph), 7.82 (t, J = 7.4 Hz, 1 H, CH of Ar), 7.95 (d, J = 7.4 Hz, 1 H, CH of Ar), 7.98 (d, J = 7.4 Hz, 1 H, CH of Ar), 8.09 (s, 2 H, NH₂), 8.17 (d, J = 7.7 Hz, 1 H, CH of Ar). ¹³C NMR (75 MHz, DMSO): δ = 30.81 (Me), 53.57 (CS), 70.75 (CCN), 107.51 (CN), 116.55 (OCN), 121.75 (2 × CH of Ph), 124.32 (CH of Ar), 125.92 (CH of Ar), 126.19 (CH of Ar), 129.60 (2 × CH of Ph), 132.86 (C _ipso of Ph), 133.01 (CH of Ph), 137.82 (CH of Ar), 144.34 (C _ipso of Ar), 150.24 (C _ipso of Ar), 154.99 (SCN), 166.41 (CNH₂), 193.32 (CO). MS: m/z = 374 [M⁺], 331, 299, 236, 185, 149, 123, 97, 69. Anal. Calcd for C₂₀H₁₄N₄O₂S: C, 64.16; H, 3.77; N, 14.96. Found: C, 64.23; H, 3.73; N, 14.93. 8c-Amino-3-methyl-2-(4-methylphenylimino)-8-oxo-2,3-dihydro-8H-8d-oxa-1-thia-3-azapentaleno[3a,6a-a]inden-8-yl Cyanide (3h): white powder; yield: 0.32 g (84%); mp 189–191 °C. IR (KBr): 3460, 3337 (NH₂), 2190 (CN), 1714 (C=O), 1639 (C=N), 1612 (NC=C) cm^–1. ¹H NMR (300 MHz, DMSO): δ = 2.21 (s, 3 H, Me), 3.28 (s, 3 H, Me), 6.69 (s, 2 H, 2 × CH of Ar), 7.04 (s, 2 H, 2 × CH of Ar), 7.80–8.07 (m, 6 H, 4 × CH of Ar, NH₂). ¹³C NMR (75 MHz, DMSO): δ = 20.82 (Me), 32.71 (Me), 53.55 (CS), 75.17 (CCN), 107.50 (CN), 116.53 (OCN), 121.43 (2 × CH of Ar), 125.99 (CH of Ar), 126.0 (CH of Ar), 129.94 (2 × CH of Ar), 132.74 (C _ipso of Ar), 132.78 (CH of Ar), 137.57 (CH of Ar), 144.28 (C _ipso of Ar), 147.28 (C _ipso of Ar), 147.57 (C _ipso of Ar), 154.75 (SCN), 166.36 (CNH₂), 193.34 (CO). MS: m/z = 388 [M⁺], 368, 353, 236, 219, 137, 111, 97, 83, 69, 55. Anal. Calcd for C₂₁H₁₆N₄O₂S: C, 64.93; H, 4.15; N, 14.42. Found: C, 64.86; H, 4.20; N, 14.44. 8c-Amino-3-isobutyl-8-oxo-2-phenylimino-2,3-dihydro-8H-8d-oxa-1-thia-3-azapentaleno[3a,6a-a]inden-8-yl Cyanide (3i): white powder; yield: 0.37 g (89%); mp 200–202 °C. IR (KBr): 3326, 3280 (NH₂), 2196 (CN), 1732 (C=O), 1660 (C=N), 1618 (NC=C) cm^–1. ¹H NMR (500 MHz, DMSO): δ = 0.81 (t, J = 5.4 Hz, 3 H, Me), 0.94 (t, J = 5.3 Hz, 3 H, Me), 2.29 (br, 1 H, CH), 3.52 (d, J = 8.6 Hz, 1 H, CH₂), 3.73 (d, J = 7.9 Hz, 1 H, CH₂), 6.80 (d, J = 6.6 Hz, 2 H, 2 × CH of Ph), 7.05 (br, 1 H, CH of Ph), 7.27 (br, 2 H, 2 × CH of Ph), 7.82 (br, 1 H, CH of Ar), 7.95 (t, J = 7.0 Hz, 1 H, CH of Ar), 8.01–8.04 (m, 3 H, CH of Ar, NH₂), 8.09 (br, 1 H, CH of Ar). ¹³C NMR (125 MHz, DMSO): δ = 19.64 (Me), 19.98 (Me), 26.97 (CH), 50.64 (CH₂), 53.33 (CS), 70.90 (CCN), 107.58 (CN), 116.06 (OCN), 121.10 (2 × CH of Ph), 123.77 (CH of Ar), 125.56 (CH of Ar), 125.65 (CH of Ar), 129.08 (2 × CH of Ph), 132.48 (CH of Ar), 132.55 (C _ipso of Ph), 137.07 (CH of Ph), 144.15 (C _ipso of Ar), 149.79 (C _ipso of Ar), 154.94 (SCN), 168.07 (CNH₂), 192.85 (CO). MS: m/z = 416 [M⁺], 368, 317, 257, 236, 194, 135, 118, 83, 57. Anal. Calcd for C₂₃H₂₀N₄O₂S: C, 66.33; H, 4.84; N, 13.45. Found: C, 66.26; H, 4.88; N, 13.49. 8c-Amino-3-isobutyl-8-oxo-2-(4-methylphenylimino)-2,3-dihydro-8H-8d-oxa-1-thia-3-azapentaleno[3a,6a-a]inden-8-yl Cyanide (3j): white powder; yield: 0.38 g (90%); mp 202–204 °C. IR (KBr): 3350, 3199 (NH₂), 2924 (CN), 2357, 2227, 1717 (C=O), 1649 (C=N), 1593 (NC=C) cm^–1. ¹H NMR (300 MHz, DMSO): δ = 0.78 (d, J = 6.5 Hz, 3 H, Me), 0.91 (d, J = 6.2 Hz, 3 H, Me), 2.23 (s, 3 H, Me), 2.24–2.47 (m, 1 H, CH), 3.44–3.75 (m, 2 H, CH₂), 6.68 (d, J = 7.4 Hz, 2 H, 2 × CH of Ar), 7.06 (d, J = 7.7 Hz, 2 H, 2 × CH of Ar), 7.83 (d, J = 6.5 Hz, 1 H, CH of Ar), 7.92–8.10 (m, 4 H, CH of Ar, NH₂), 8.31 (t, J = 6.2 Hz, 1 H, CH of Ar). ¹³C NMR (75 MHz, DMSO): δ = 20.12 (Me), 20.46 (Me), 20.92 (Me), 27.44 (CH), 51.20 (CH₂), 58.0 (CS), 75.10 (CCN), 108.50 (CN), 115.93 (OCN), 121.41 (2 × CH of Ar), 124.14 (CH of Ar), 128.40 (CH of Ar), 130.05 (CH of Ar), 130.54 (2 × CH of Ar), 133.0 (CH of Ar), 137.59 (C _ipso of Ar), 137.59 (C _ipso of Ar), 147.80 (C _ipso of Ar), 153.73 (C _ipso of Ar), 155.28 (SCN), 166.53 (CNH₂), 193.20 (CO). MS: m/z = 430 [M⁺], 374, 331, 242, 210, 155, 127, 91, 57. Anal. Calcd for C₂₄H₂₂N₄O₂S: C, 66.33; H, 4.84; N, 13.45. Found: C, 66.26; H, 4.88; N, 13.49. 8c-Amino-2-(4-chlorophenylimino)-3-isobutyl-8-oxo-2-(4-methylphenylimino)-2,3-dihydro-8H-8d-oxa-1-thia-3-azapentaleno[3a,6a-a]inden-8-yl Cyanide (3k): white powder; yield: 0.37 g (83%); mp 197–199 °C. IR (KBr): 3334, 3275 (NH₂), 2199 (CN), 1732 (C=O), 1653 (C=N), 1587 (NC=C) cm^–1. ¹H NMR (300 MHz, DMSO): δ = 0.70 (s, 6 H, 2 × Me), 2.76–2.90 (m, 1 H, CH), 3.32 (s, 2 H, CH₂), 6.62 (s, 2 H, 2 × CH of Ar), 7.22 (s, 2 H, 2 × CH of Ar), 7.52–7.80 (m, 3 H, CH of Ar), 8.11 (s, 2 H, NH₂), 8.29 (s, 1 H, CH of Ar). ¹³C NMR (75 MHz, DMSO): δ = 20.82 (Me), 29.82 (CH), 54.5 (CH₂), 62.01 (CS), 92.2 (CCN), 115.93 (CN), 116.60 (OCN), 124.18, 125.13, 125.94, 128.40, 130.53, 132.77, 133.47, 136.54, 137.06, 144.55, 153.74 (SCN), 166.41 (CNH₂), 193.0 (CO). MS: m/z = 448 [M⁺ – 2], 364, 291, 257, 210, 152, 127, 104, 76, 57. Anal. Calcd for C₂₃H₁₉ClN₄O₂S: C, 66.33; H, 4.25; N, 7.76. Found: C, 66.25; H, 4.29; N, 7.80.