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Synlett 2005(2): 239-242  
DOI: 10.1055/s-2004-836069
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Luis Calvo, Alfonso González-Ortega*, Mónica Pérez, María Carmen Sañudo
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Dr Mergelina s/n, 47002 Valladolid, Spain
Fax: +34(983)423013; e-Mail: algon@qo.uva.es;
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Publication History

Received 27 October 2004
Publication Date:
10 December 2004 (online)

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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.

Key words

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

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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, Rf = 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, Rf = 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.

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).