Expansive Rearrangement of N-Vinylthiazolidines to 2,3,4,7-Tetrahydro-1,4-thiazepines and their Transformation in 3-Thia-6-azabicyclo[3.2.1]oct-6-enes

Abstract

3-(2-Cyano-1-methylvinyl)-N-methoxy-N-methylthiazolidine-4-carboxamide was transformed in 1H,3H-pyrrolo[1,2-c]thiazoles by means of a modified Knorr synthesis or in 6-cyano-N-methoxy-N,5-dimethyl-2,3,4,7-tetrahydro-1,4-thiazepine-3-carboxamide by simple thermal treatment. The latter led to 8-hydroxy-3-thia-6-azabicyclo[3.2.1]oct-6-ene-1-carbonitrile derivatives when it reacted with Grignard or organolithium compounds.

thiazepine - rearrangement - N-vinylthiazolidine - Weinreb amide - 3-thia-6-azabicyclo[3.2.1]oct-6-ene-1-carbonitrile

References

1 Venuti MC. Comprehensive Medicinal Chemistry   Vol. 3:  Emmett JC. Pergamon Press; New York: 1990.  p.749-750  

2 Kulikov VI. Muzya GI. Biochemistry  1998,  63:  47 

3 Calvo L. González Ortega A. Sañudo MC. Synthesis  2002,  2450 

4

Synthesis of 5,7-Dimethyl-1 H ,3 H -pyrrolo[1,2- c ]thiazole-6-carbonitrile ( 5). To a magnetically stirred solution of 3 (1.08 g, 4.48 mmol) in anhyd THF (50 mL) was added dropwise MeLi (4.48 mL 1.5 M, 6.72 mmol) under nitrogen at -40 °C. At the end of the reaction, monitored by TLC, the mixture was hydrolyzed. The organic layer was decanted, washed with H₂O, dried (MgSO₄) and evaporated. The carbonyl intermediate 4 was not isolated and the concentrate underwent cyclization treatment. The previously mentioned intermediate (ca. 4.00 mmol) and silica gel (5 × w/w) in CHCl₃ (50 mL) was heated in a rotatory evaporator, slowly distilling the solvent. The silica gel was filtered off and washed thoroughly with hot acetone. The solvent was removed in vacuo, and the concentrate was chromatographed (silica gel; CH₂Cl₂, R _f = 0.53; 80%). Colorless solid, mp 150 °C. IR (KBr): 3436, 2920, 2214, 1596, 1527, 1420, 1384, 1276, 1181, 922, 898 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 4.83 (s, 2 H, N-CH₂-S), 3.91 (s, 2 H, S-CH₂), 2.30 (s, 3 H, -C=C-CH₃), 2.03 [s, 3 H, =C(CH₃)-N]. ¹³C NMR (75 MHz, CDCl₃): δ = 132.25 [=C(CH₃)-N], 130.21 (-C=C-CH₃), 116.41 (N≡C), 112.34 (NC-C), 95.97 (-C=C-CH₃), 46.91 (S-CH₂-N), 27.34 (S-CH₂), 11.33 (-C=C-CH₃), 10.00 [=C(CH₃)-N]. MS (EI): m/z (%) = 178 (85) [M⁺], 133 (100). Anal. Calcd for C₉H₁₀N₂S: C, 60.64; H, 5.65; N, 15.72. Found: C, 60.77;
H, 5.67; N, 15.69.

5

Preparation of Intermediate ( R )-3-(2-Cyano-1-methylvinyl)- N -methoxy- N -methylthiazolidine-4-carboxamide ( 3) . A mixture of enaminonitrile 1 (0.32 g, 3.89 mmol) and (R)-N-methoxy-N-methylthiazolidine-4-carboxamide (hydrobromide derivative) (2.00 g, 7.78 mmol) in MeOH (10 mL) was stirred at r.t. for 3 h. At the end of the reaction, monitored by TLC, the solution was concentrated in vacuo, and the residue was dissolved in CH₂Cl₂-H₂O (1:1, 25 mL). The aqueous layer was extracted with CH₂Cl₂ (2 × 20 mL) and the combined organic layers were dried (MgSO₄) and evaporated to dryness. The residue was chromatographed (silica gel, CH₂Cl₂-Et₂O, 20:1, R_f = 0.30; 62%). Colorless solid, mp 87 °C. IR (KBr): 3312, 3135, 3076, 2937, 2195, 1669, 1583, 1514, 1417, 1386, 1283, 1090, 889 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 4.88 (dd, J = 7.4 and 3.5 Hz, 1 H, CH-CO), 4.48 (s, 2 H, N-CH₂-S), 3.79 (s, 1 H, HC=), 3.77 (s, 3 H, N-OCH₃), 3.45 (dd, J = 11.8 and 7.4 Hz, 1 H, S-CHH), 3.22 (s, 3 H, N-CH₃), 3.14 (dd, J = 11.8 and 3.5 Hz, 1 H, S-CHH), 2.21 (s, 3 H, =C-CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 169.66 (C=O), 158.03 (=C), 120.81 (C≡N), 65.16 (=CH), 61.31 (N-OCH₃), 60.98 (CH-CO) 51.09 (N-CH₂-S), 33.38 (S-CH₂), 32.20 (N-CH₃), 19.20 (CH₃). MS (EI): m/z (%) = 241 (26) [M⁺], 116 (100). [α]_D ²⁰ -79.8 (c 0.29, CHCl₃). Anal. Calcd for C₁₀H₁₅N₃O₂S: C, 49.77; H, 6.27; N, 17.41. Found: C, 49.68; H, 6.28; N, 17.43.

6

Synthesis of ( R )-6-Cyano- N -methoxy- N ,5-dimethyl-2,3,4,7-tetrahydro-1,4-thiazepine-3-carboxamide ( 6). By a procedure analogous to the previous one starting from 1 (0.16 g, 1.94 mmol) and 2 (1 g, 3.89 mmol), in 25 mL of MeCN (reflux for 2.5 h), compound 6 was obtained (51%). Oil, R_f = 0.48 [CH₂Cl₂-Et₂O (20:1)]. IR (film): 3343, 2937, 2361, 2183, 1667, 1604, 1430, 1392, 1178, 1000 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 5.23 (d, J = 3.8 Hz, 1 H, NH), 4.88 (ddd, J = 11.0, 3.8 and 2.8 Hz, 1 H, CH-CO), 4.16 (d, J = 16.3 Hz, 1 H, =C-CHH), 3.77 (s, 3 H, N-OCH₃), 3.27 (dd, J = 12.4 and 2.8 Hz, 1 H, S-CHH), 3.26 (s, 3 H, N-CH₃), 2.93 (d, J = 16.3 Hz, 1 H, =C-CHH), 2.85 (dd, J = 12.4 and 11.0 Hz, 1 H, S-CHH), 2.08 (s, 3 H, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 169.41 (C=O), 158.33 (=C), 122.62 (C≡N), 77.21 (NC-C=), 61.65 (N-OCH₃), 55.43 (CH-CO), 33.41 (S-CH₂-CH), 32.48 (N-CH₃), 27.88 (S-CH₂-C=), 22.17 (CH₃). MS (EI): m/z (%) = 241 (3) [M⁺], 42 (100). [α]_D ²⁰ +72.7 (c 0.98, CHCl₃). Anal. Calcd for C₁₀H₁₅N₃O₂S: C, 49.77; H, 6.27; N, 17.41. Found: C, 49.92; H, 6.26; N, 17.38.

7 Van den Hoven BG. Alper H. J. Am. Chem. Soc.  2001,  123:  1017 

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16

Reaction of ( R )-6-Cyano- N -methoxy- N ,5-dimethyl-2,3,4,7-tetrahydro-1,4-thiazepine-3-carboxamide ( 6) with Organometallic Compounds. Synthesis of 8-Hydroxy-7-methyl-3-thia-6-azabicyclo[3.2.1]oct-6-ene-1-carbonitriles 12, General Procedure:
To a magnetically stirred solution of amide 6 (0.54 g, 2.22 mmol) in dry THF (35 mL) the organometallic compound was added dropwise under nitrogen (see Table [1] ). At the end of the reaction, the mixture was hydrolyzed. The organic layer was decanted, washed with H₂O, dried (MgSO₄) and evaporated. The concentrate and silica gel (5 × w/w) in 50 mL of CHCl₃ were heated in a rotary evaporator, slowly distilling the solvent. The silica gel was filtered off and washed thoroughly with hot acetone. The solvent was removed in vacuo, and the concentrate was chromato-graphed on silica gel using CH₂Cl₂-THF (10:1) as eluent (compounds 12a,b) or recrystallized from EtOH (compounds 12c,d). Representative compounds:
8-Hydroxy-7-methyl-3-thia-6-azabicyclo[3.2.1]oct-6-ene-1-carbonitrile ( 12a): Yield 39%. R _f = 0.23 [CH₂Cl₂-THF (10:1)]. Colorless solid, mp 178 °C. IR (KBr): 3435, 3082, 2944, 2864, 2232, 1647, 1434, 1382, 1244, 1161, 1096, 979 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 6.51 (br s, 1 H, OH), 4.28 (d, J = 5.9 Hz, 1 H, CH-OH), 4.07-4.04 (m, 1 H, =N-CH), 3.02 (d, J = 12.2 Hz, 1 H, CN-C-CHH), 2.94 (d, J = 12.7 Hz, 1 H, S-CHH), 2.53 (d, J = 12.2 Hz, 1 H, CN-C-CHH), 2.17 (s, 3 H, CH₃), 2.10 (dd, J = 12.7 and 4.2 Hz, 1 H, S-CHH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 168.64 (CH₃-C=N), 119.71 (C≡N), 73.44 (CH-OH), 64.55 (N-CH), 49.66 (CN-C), 20.00 (S-CH₂-), 19.72 (NC-C- CH₂-), 17.84 (CH₃). Anal. Calcd for C₈H₁₀N₂OS: C, 52.72; H, 5.53; N, 15.37. Found: C, 52.54; H, 5.52; N, 15.42.
8-Ethyl-8-hydroxy-7-methyl-3-thia-6-aza-bicyclo[3.2.1]oct-6-ene-1-carbonitrile ( 12c): Yield 63%. Colorless solid, mp 161 °C. IR (KBr): 3408, 3095, 2942, 2852, 2236, 1638, 1428, 1385, 1283, 1167, 1015, 928 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 4.20 (d, J = 3.2 Hz, 1 H, CH), 3.39 (d, J = 12.4 Hz, 1 H, CN-C-CHH), 3.23 (d, J = 12.5 Hz, 1 H, S-CHH), 2.40 (br s, 1 H, OH), 2.37 (d, J = 12.4 Hz, 1 H, CN-C-CHH), 2.35 (dd, J = 12.5 and 3.2 Hz, 1 H, S-CHH), 2.29 (s, 3 H, =C-CH₃), 1.76 (m, J = 7.4 Hz, 2 H, CH ₂-CH₃), 0.98 (t, J = 7.4 Hz, 3 H, CH₂-CH ₃). ¹³C NMR (75 MHz, CDCl₃): δ = 170.73 (CH₃-C=N), 117.28 (C≡N), 80.78 (C-OH), 66.40 (CH), 55.97 (CN-C), 29.68 (CH₂-CH₃), 24.20 (S-CH₂-), 23.07 (NC-C-CH₂-), 18.25 (=C-CH₃), 7.54 (CH₂-CH₃). Anal. Calcd for C₁₀H₁₄N₂OS: C, 57.11; H, 6.71; N, 13.32. Found: C, 57.28; H, 6.70; N, 13.29.
5-Methyl-3-(thiophene-2-carbonyl)-2,3,4,7-tetrahydro-1,4-thiazepine-6-carbonitrile ( 11e): Yield 58%. Colorless solid, mp 138 °C. IR (KBr): 3344, 2185, 1652, 1602, 1481, 1408, 1260, 1061, 859, 839, 734 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.85-7.80 (m, 2 H, =CH-CH=), 7.27-7.22 (m, 1 H, S-CH=), 5.46-5.41 (m, 1 H, CH), 5.30 (br s, 1 H, NH), 4.31 (d, J = 15.7 Hz, 1 H, CN-C-CHH), 3.36 (dd, J = 13.5 and 2.4 Hz, 1 H, S-CHH), 3.08 (dd, J = 13.5 and 3.2 Hz, 1 H, S-CHH), 3.05 (d, J = 15.7 Hz, 1 H, CN-C-CHH), 2.16 (s, 3 H, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 187.95 (C=O), 158.08 (=C-NH), 139.35 (=C-S), 136.02 (S-CH=), 133.23 (CO-C=CH), 128.77 (-CH=CH-S), 122.20 (C≡N), 78.67 (=C-CN), 61.27 (NH-CH-CO), 36.15 (-CH₂-S), 28.52 (S-CH₂-C=), 22.42 (CH₃). Anal. Calcd for C₁₂H₁₂N₂OS₂: C, 54.52; H, 4.58; N, 10.60. Found: C, 54.69; H, 4.57; N, 10.57.

17

Deposition number CCDC 253714.

18

As an example, the specific rotation of 12c varied from [α]_D ²⁰ -131 (c 0.62, CHCl₃) to [α]_D ²⁰ 0 (c 0.44, CHCl₃).