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Synlett 2003(14): 2231-2233  
DOI: 10.1055/s-2003-42078
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 3,1-Benzothiazines by Cyclisation of 2-Thioformylamino­diphenylacetylenes

Manuel A. Fernandes, David H. Reid*
School of Chemistry, University of the Witwatersrand, Private Bag 3, Wits 2050, Johannesburg, South Africa
Fax: +27(11)7176749; e-Mail: dhreid@aurum.wits.ac.za;
Further Information

Publication History

Received 30 July 2003
Publication Date:
15 October 2003 (online)

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Abstract

2-Formylaminodiphenylacetylenes, obtained in excellent yield by Sonogashira coupling of (2-iodoaryl)formamides with phenylacetylene, were thionated with P4S10 in boiling THF to give 2-thioformylaminodiphenylacetylenes. These acetylenes were cyclised by DBU at ambient temperature to give (4Z)-4-benzylidene-4H-3,1-benzothiazines and small amounts of 2-phenylindoles. The structures of (4Z)-4-benzylidene-6,8-dichloro-4H-3,1-benzothiazine and 3,5-dichloro-2-thioformylaminodiphenylacetylene were established by single crystal X-ray analysis.

Key words

Sonogashira coupling - thionation - cyclisation - 3,1-benzothiazines - X-ray crystal structure

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Typical Experimental Procedure for the Preparation of 3. A solution of phenylacetylene (5.5 mL, 50 mmol) in Et3N (50 mL) was added over 10 min to a stirred mixture of (4-chloro-2-iodophenyl)formamide (14.1 g, 50 mmol), (Ph3P)2PdCl2 (702 mg, 1 mmol) and Cu2I2 (190 mg, 0.5 mmol) in Et3N (250 mL) under nitrogen and the resulting mixture was stirred at ambient temperature for 4 h. Diethyl ether (200 mL) was added, the resulting mixture was filtered through a bed of Celite (5 × 0.5 cm), and the solid was washed repeatedly with benzene (5 × 80 mL). Solvents and Et3N were removed at reduced pressure from the filtrates. The residual oil, which solidified rapidly, was dissolved in benzene (200 mL) and chromatographed on silica (12 × 3.2 cm) with benzene for elution. The eluates (800 mL) were concentrated to ca. 75 mL, hexane (200 mL) was added gradually, and the resulting voluminous precipitate was filtered off and washed with hexane to give the formamide 3b (12.5 g, 98% yield) as pale beige crystals, mp 117-118 °C (cyclohexane-acetone). Also obtained: compound 3a, 96% yield, mp 99-100 °C (benzene-hexane); compound 3c, 97% yield, mp 98-100 °C(cyclohexane); compound 3d, 96% yield, mp 180-182 °C (EtOH).

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Typical Experimental Procedure for the Preparation of 4: Celite (2 g) was added to a solution of the formamide 3b (5.11 g, 20 mmol) in THF (50 mL) and the mixture was stirred while P4S10 (6.67 g, 15 mmol) was added portionwise over 1 min. The resulting mixture was boiled with stirring for 20 min. Diethyl ether (100 mL) and then benzene (50 mL) were added and the solid was filtered off and washed with diethyl ether (300 mL) and benzene (50 mL). The combined filtrates were washed with sat. aq NaCl solution (400 mL), dried, and the solvent was removed. The residue was extracted with boiling benzene (200 mL) and the cooled extract was chromatographed on silica (25 × 2.4 cm) with benzene for elution. The residue from the evaporated eluates (500 mL) was dissolved in acetone (40 mL) and cyclohexane (120 mL). The solution was concentrated to ca. 40 mL, cooled, and hexane (120 mL) was added, giving the thioformamide 4b (2.94 g, 54%) as very pale yellow crystals, mp 163-165 °C. Also obtained: compound 4a, 48% yield, mp 102-103 °C (MeOH); compound 4c, 55% yield, mp 102-105 °C (cyclohexane-hexane); compound 4d, 80% yield, mp 156-159 °C(cyclohexane).

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Typical Experimental for the Preparation of 5. DBU (4 mL, 27 mmol) was added to a solution of the thioformamide 4b (1.40 g, 5 mmol) in THF (5 mL) and the resulting solution was kept at r.t. for 24 h, then dissolved in benzene (200 mL). The solution was washed with sat. aq NaCl solution (200 mL) and the aqueous extract was extracted with more benzene (100 mL). The benzene extracts were washed with more sat. aq NaCl solution (200 mL × 2), dried, and solvent was removed. The residual oil was extracted with boiling benzene (40 mL) and the cooled extract was chromatographed on silica (25 × 2.4 cm). Elution with benzene gave (i)very pale yellow eluates (150 mL),(ii) lemon-yellow eluates (300 mL) and left an intractable slow-moving (Et2O-benzene) orange-red band on the column. Fraction (i) yielded 5-chloro-2-phenylindole(6b) (52 mg, 5.7%), mp 185-190 °C (cyclohexane-hexane) (lit. [19] mp 191 °C). Fraction(ii) gave (4Z)-4-benzylidene-6-chloro-4H-3,1-benzothiazine(5b) (1.2 g, 75%) as yellow crystals, mp 82-84 °C (MeOH). Also obtained: compound 5a, 80% yield, orange oil; compound 5c, 82% yield, mp 63-65 °C (MeOH); compound 6c, 3.7% yield, mp 182-184 °C (cyclohexane); compound 5d, 69% yield, mp 140-142 °C (cyclohexane).

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Detailed crystallographic data for 4d and 5d (excluding structure factors) were deposited at the Cambridge Crystallographic Database (deposition number CCDC-205334 and CCDC-205335 respectively). Copies of this information can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK; fax: +44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk.

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Reaction of 3d with DBU. A solution of the amide 3d (580 mg, 2 mmol) and DBU (1.5 mL, 10 mmol) in THF (2 mL) was kept at r.t. for 72 h. TLC then showed no starting material to be present. The solution was taken up in benzene (200 mL) and the resulting solution was washed with sat. aq NaCl solution (100 mL) and dried. Chromatography of the solid residue from the evaporated extracts on silica (10 × 2.0 cm) with benzene as eluent gave pale orange eluates. Recrystallisation of the residue from the evaporated eluates from benzene-acetone-hexane afforded 6d (314 mg, 57%) as colourless needles, mp 139-140 °C (lit. [20] mp 142 °C); 1H NMR (400 MHz, DMSO-d 6): δ = 6.97 (d, 1 H, J 3,NH = 2.1 Hz, 3-H), 7.25 (d, 1 H, J 6,4 = 1.8 Hz, 6-H), 7.39 (tt, 1 H, 4′-H), 7.49 (t, 2 H, 3′- + 5′-H), 7.58 (d, 1 H, J 4,6 = 1.8 Hz, 4-H), 8.00 (dt, 2 H, 2′- + 6′-H), 11.00 (1 H, NH). 13C NMR (75 MHz, DMSO-d 6): δ = 100.0 (C-3), 116.4 (C-5 or C-7), 118.2, 120.6, 123.9 (C-7 or C-5), 126.0 (C-3′ + C-5′), 128.2 (C-4′), 128.7 (C-2′ + C-6′), 130.9, 131.0, 132.7, 141.0 (C-7a).

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NMR data for compounds 5a-d (CDCl3), 1H NMR at 400 MHz, 13C NMR at 75 MHz, and 19F NMR at 282.4 MHz (CFCl3 as external 19F reference).
Compound 5a: 1H NMR: δ = 6.98 (d, J 2, α = 0.5 Hz, 1 H, α-H), 7.26-7.40 (m, 8 H, Ph + 6-H + 7-H + 8-H), 7.58, (dt,
J 5,6 = 7.8 Hz, 1 H, 5-H), 8.19 (d, J 2, α = 1.0 Hz, 1 H, 2-H).
13C NMR: δ = 122.8 (C-4 or C-α), 123.8 (C-α or C-4), 124.1, 125.2, 127.5, 128.2 (C-3′ + C-5′ or C-2′ +C-6′), 128.9 (C-2′ + C-6′ or C-3′ + C-5′), 129.1, 129.3, 129.8, 135.4 (C-4a or C-8a), 141.3 (C-8a or C-4a), 149 (C-2).
Compound 5b: 1H NMR: δ = 6.97 (s, 1 H, α-H), 7.31-7.41 (m, 7 H, Ph + 7-H + 8-H), 7.57 (d, J 5,7 = 1.84 Hz, 1 H, 5-H), 8.20 (s, 1 H, 2-H). 13C NMR: δ = 122.6 (C-6 or C-4), 124.0 (C-α), 124.3 (C-4 or C-6), 126.3, 127.9, 128.4 (C-3′ + C-5′ or C-2′ + C-6′), 129.0 (C-2′ + C-6′ or C-3′ + C-5′), 129.7, 130.7, 134.4 (C-1′ or C-4a), 135.1 (C-4a or C-1′), 139.9 (C-8a), 149.8 (C-2).
Compound 5c: 1H NMR δ = 6.93 (s, 1 H, α-H), 7.05-7.10 (m, 1 H), 7.23-7.39 (m, 7 H), 8.13 (s, 1 H, 2-H). 13C NMR: δ = 110.4 (d, J F,C = 24.4 Hz, C-7 or C-5), 116.7 (d, J F,C = 22.5 Hz, C-5 or C-7), 123.1 (d, J F,C = 2.5 Hz, C-8a), 124.4 (d, J F,C = 8.3 Hz, C-4a), 125.6 (C-α), 127.8 (C-4′), 128.3 (C-3′ + C-5′ or C-2′ + C-6′), 129.0 (C-2′ + C-6′ or C-3′ + C-5′), 131.4 (d, J F,C = 8.7 Hz, C-8), 135.1 (C-1′), 137.7 (d, J F,C = 2.7 Hz, C-4), 148.3 (d, J F,C = 2.2 Hz, C-2), 162.4 (d, J F,C-6 = 248.5 Hz, C-6). 19F NMR: δ = -111.7.
Compound 5d: 1H NMR: δ = 6.99 (s, 1 H, α-H), 7.30-7.45 (m, 5 H, Ph), 7.46 (d, 1 H, J 5,7 = 2.3 Hz, 5- or 7-H), 7.51 (d, J 7,5 = 2.3 Hz, 1 H, 7- or 5-H), 8.36 (d, J 2, α = 1.1 Hz, 1 H, 2-H). 13C NMR: δ = 121.8, 123.2, 126.1, 128.3 (C-5 or C-7), 128.4 (C-3′ + C-5′), 128.6 (C-4′), 129.2 (C-2′ + C-6′), 130.2 (C-7 or C-5), 134.1, 134.3, 134.7, 137.0, (C-8a), 151.8 (C-2).