Efficient Synthesis of Functionalized 2,3-Di(alkenyl)benzothiophenes and Dibenzothiophenes Based on the First Heck Reactions of 2,3-Di- and 2,3,6-Tribromobenzothiophene

Abstract

Alkenyl-substituted benzothiophenes were prepared by the first Heck reactions of 2,3-di- and 2,3,6-tribromobenzo­thiophene. Functionalized dibenzothiophenes were prepared based on domino ‘twofold Heck-6π-electrocyclization’ reactions.

Key words

catalysis - palladium - Heck reaction - electrocyclization - benzothiophene

References and Notes

• 1a Jeong S.-J. Higuchi R. Miyamoto T. Ono M. Kuwano M. Mawatari SF. J. Nat. Prod.  2002,  65:  1344 
• 1b Kelly TR. Fu Y. Sieglen JT. De Silva H. Org. Lett.  2000,  2:  2351 
• 2 El-Naggar AM. Ahmed FSM. Donia SG. J. Indian Chem. Soc.  1983,  60:  479 
• 3 Brendle JJ. Outlaw A. Kumar A. Boykin DW. Patrick DA. Tidwell RR. Werbovetz KA. Antimicrob. Agents Chemother.  2002,  46:  797 
• 4 Patrick DA. Hall JE. Bender BC. McCurdy DR. Wilson WD. Tanious FA. Saha S. Tidwell RR. Eur. J. Med. Chem.  1999,  575 
• 5 Wrobel J. Sredy J. Moxham C. Dietrich A. Li Z. Sawicki DR. Seestaller L. Wu L. Katz A. Sullivan D. Tio C. Zhang Z.-Y. J. Med. Chem.  1999,  42:  3199 
• 6a Saulnier MG. Balasubramanian BN. Long BH. Frennesson DB. Ruediger E. Zimmermann K. Eummer JT. Laurent DRS. Stoffan KM. Naidu BN. Mahler M. J. Med. Chem.  2005,  48:  2258 
• 6b Li Z. Yang Q. Qian X. Tetrahedron  2005,  61:  8711 
• 6c Durant JL. Busby WF. Lafleur AL. Penman BW. Crespi CL. Mutat. Res.  1996,  371:  123 
• 6d King LC. Kohan MJ. Brooks L. Nelson GB. Ross JA. Allison J. Adams L. Desai D. Amin S. Padgett W. Lambert GR. Chem. Res. Toxicol.  2001,  14:  661 
• 7 Xu Y. Qian X. Yao W. Mao P. Cui J. Bioorg. Med. Chem.  2003,  11:  5427 
• 8a Ellefson CR. Prodan KA. J. Med. Chem.  1981,  24:  1107 
• 8b Arlt M. Boettcher H. Riethmueller A. Schneider G. Bartoszyk GD. Bioorg. Med. Chem. Lett.  1998,  8:  2033 
• 9a Mori Y. Taneda S. Hayashi H. Sakushima A. Kamata K. Suzuki AK. Yoshino S. Sakata M. Sagai M. Seki K.-i. Biol. Pharm. Bull.  2002,  25:  145 
• 9b Wallace OB. Bryant HU. Shetler PK. Adrian MD. Geiser AG. Bioorg. Med. Chem. Lett.  2004,  14:  5103 
• 10 Clark RD. Jahangir A. Severance D. Salazar R. Chang T. Chang D. Jett MF. Smith S. Bley K. Bioorg. Med. Chem. Lett.  2004,  14:  1053 
• 11 Shim YS. Kim KC. Lee KA. Shrestha S. Lee K.-H. Kim CK. Cho H. Bioorg. Med. Chem.  2005,  13:  1325 
• 12 Harfenist M. Joyner CT. Mize PD. White HL.
  J. Med. Chem.  1994,  37:  2085 
• 13 Review: Schröter S. Stock C. Bach T. Tetrahedron  2005,  61:  2245 
• 14a Dang TT. Dang TT. Ahmad R. Reinke H. Langer P. Tetrahedron Lett.  2008,  49:  1698 
• 14b Dang TT. Villinger A. Langer P. Adv. Synth. Catal.  2008,  350:  2109 
• 14c Hussain M. Nguyen TH. Langer P. Tetrahedron Lett.  2009,  50:  3929 
• 14d Tengho Toguem S.-M. Hussain M. Malik I. Villinger A. Langer P. Tetrahedron Lett.  2009,  50:  4962 
• 14e Dang TT. Dang TT. Rasool N. Villinger A. Langer P. Adv. Synth. Catal.  2009,  351:  1595 
• 15 Bussenius J. Laber N. Müller T. Eberbach W. Chem. Ber.  1994,  127:  247 
• 16 Heynderickx A. Samat A. Gugliemetti R. Synthesis  2002,  213 
• 17 Yamamura K. Houda Y. Hashimoto M. Kimura T. Kamezawa M. Otani T. Org. Biomol. Chem.  2004,  2:  1413 
• 18 De Meijere and co-workers reported twofold Heck reactions of 1,2-dibromocycloalk-1-enes and related substrates and subsequent 6π-electrocyclization: Voigt K. von Zezschwitz P. Rosauer K. Lansky A. Adams A. Reiser O. de Meijere A. Eur. J. Org. Chem.  1998,  1521 ; and references cited therein
• 21 Billingsley K. Buchwald SL. J. Am. Chem. Soc.  2007,  129:  3358 ; and references cited therein

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Synthesis of 2,3-Dibromobenzothiophene (2a) To a CH₂Cl₂ solution (50 mL) of benzo[b]thiophene (1, 5.00 g, 37.3 mmol) and KOAc (7.30 g, 74.6 mmol) was added Br₂ (3.8 mL, 74.6 mmol) at 20 ˚C, and the solution was heated under reflux for 24 h. To the solution was added a sat. solution of Na₂S₂O₃ and NaHCO₃. The organic and the aqueous layer were separated, and the latter was extracted with CH₂Cl₂ (3 × 30 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by flash silica column chromatography (pure heptanes) to yield 2a as a white solid (8.30 g, 76%). Depending on the scale of the reaction, inseparable mixtures of bromo- and 2,3-dibromobenzothiophene were formed. In this case, the mixture was reacted again with 1.0 equiv each of Br₂ and KOAc to give pure 2a.

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Synthesis of 2,3,6-Tribromobenzothiophene (2b) To a CH₂Cl₂ solution (50 mL) of benzo[b]thiophene (1, 5.00 g, 37.3 mmol) and KOAc (16.5 g, 167.9 mmol) was added Br₂ (8.6 mL, 167.9 mmol) at 20 ˚C, and the solution was heated under reflux for 24 h. To the solution was added a sat. solution of Na₂S₂O₃ and NaHCO₃. The organic and the aqueous layer were separated, and the latter was extracted with CH₂Cl₂ (3 × 30 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by flash silica column chromatography (pure heptanes) to yield 2b as a white solid (9.7 g, 70%).

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General Procedure A for the Synthesis of Dibenzo[ b , d ]thiophenes 6
In a pressure tube (glass bomb) a suspension of Pd(OAc)₂ (12 mg, 0.05 mmol, 2.5 mol% per Br atom) and dicyclo-hexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (L ₁ , 41 mg, 0.10 mmol) in DMF (5 mL) was flushed with Ar and stirred at 20 ˚C to give a yellowish or brownish transparent solution. To the stirred solution were added the 2,3-dibromo-benzothiophene (2a, 292 mg, 1.0 mmol), Et₃N (1.1 mL, 8.0 mmol), and the acrylate (1.25 equiv per Br). The reaction mixture was stirred at 130 ˚C for 48 h. The solution was cooled to 20 ˚C, poured into H₂O and CH₂Cl₂ (25 mL each), and the organic and the aqueous layer were separated. The latter was extracted with CH₂Cl₂ (3 × 25 mL). The combined organic layers were washed with H₂O (3 × 20 mL), dried (Na₂SO₄), concentrated in vacuo, and passed through a column (silica gel). To a xylene solution (3 mL) of the crude product was added Pd/C (30 mg, 10 mol%). The solution was stirred under reflux for 48 h under argon atmosphere. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (flash silica gel, heptanes-EtOAc) to yield the product. Analytical Data of Diethyl Dibenzo[ b , d ]thiophene-2,3-dicarboxylate (6a)
Compound 6a was prepared starting with 2a (292 mg, 1.0 mmol) as an amorphous white solid (249 mg, 76%); mp 118-119 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.33 (t, 3 H, J = 7.76 Hz, CH₃), 1.35 (t, 6 H, J = 7.76 Hz, CH₃), 4.31-4.40 (m, 4 H, 2 CH₂O), 7.41-7.48 (m, 2 H, ArH), 7.79-7.82 (m, 2 H, ArH), 8.12 (s, 1 H, ArH), 8.13-8.15 (m, 1 H, ArH), 8.43 (s, 1 H, ArH). ^¹³C NMR (62 MHz, CDCl₃): δ = 14.2 (2 CH₃), 61.7, 61.8 (CH₂O), 122.3, 122.4, 123.0, 123.6, 125.1, 128.0 (CH), 128.5, 130.4, 134.4, 137.1, 140.7, 141.9 (C), 167.5, 167.7 (CO). IR (KBr): ν = 3053, 2975, 2931, 2896, 2867 (w), 1706 (s), 1632, 1603, 1540, 1483, 1469 (w), 1440, 1366, 1314 (m), 1247, 1229, 1098, 1021 (s), 913, 885, 873, 853 (w), 765, 757, 708 (s), 642, 583, 552 (w) cm^-¹. MS (EI, 70 eV): m/z (%) = 330 (17) [M]⁺, 284 (06), 257 (54), 229 (19), 211 (58), 185 (100). HRMS (EI, 70 eV): m/z calcd for C₁₈H₁₈NO₄S [M]⁺: 330.09203; found: 330.091818.

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General Procedure B for the Synthesis of 7
In a pressure tube (glass bomb) a suspension of Pd(OAc)₂ (06 mg, 0.025 mmol) and dicyclohexyl(2′,6′-dimethoxy-biphenyl-2-yl)phosphine (L ₁ , 21 mg, 0.05 mmol) in DMF
(5 mL) was flushed with Ar and stirred at 20 ˚C to give a yellowish or brownish transparent solution. To the stirred solution were added the 2,3-dibromobenzothiophene (2a, 292 mg, 1.0 mmol), Et₃N (1.1 mL, 8.0 mmol), and the acrylate (1.25 mmol). The reaction mixture was stirred at 130 ˚C for 24 h. The solution was cooled to 20 ˚C, poured into H₂O and CH₂Cl₂ (25 mL each), and the organic and the aqueous layer were separated. The latter was extracted with CH₂Cl₂ (3 × 25 mL). The combined organic layers were washed with H₂O (3 × 20 mL), dried (Na₂SO₄), concentrated in vacuo, and passed through a column (flash silica gel, heptanes-EtOAc) to yield the product. Analytical Data of ( E )-3-Styrylbenzo[ b ]thiophene (7d)
Compound 7d was prepared starting with 2a (292 mg, 1.0 mmol) as a colorless crystalline solid (174 mg, 76%); mp 93-95 ˚C (CH₂Cl₂-EtOH). ^¹H NMR (300 MHz, CDCl₃): δ = 7.12-7.23 (m, 2 H), 7.28-7.36 (m, 5 H), 7.46 (s, 1 H, ArH), 7.46-7.49 (m, 2 H, ArH), 7.77-7.83 (m, 1 H, ArH), 7.91-7.94 (m, 1 H, ArH). ^¹³C NMR (62 MHz, CDCl₃): δ = 120.7, 121.8, 122.0, 123.0, 124.33, 124.6, 126.4, 127.7, 128.8, 130.3 (CH), 134.2, 137.4, 137.8, 140.5 (C). IR (KBr): ν = 2921, 2851 (s), 1667, 1598, 1492, 1454, 1446, 1434 (m), 1377, 1365, 1346, 1260, 1243, 1204, 1176, 1156, 1029, 1019, 948, 907, 887, 864 (w), 757, 748, 730, 696 (s), 623, 591, 555, 538 (w) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 236 (100) [M]⁺, 221 (18), 202 (16), 189 (05), 117 (08). HRMS (EI, 70 eV): m/z calcd for C₁₆H₁₂S [M]⁺: 236.06542; found: 236.064490.

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CCDC-746828 contains all crystallographic details of
this publication and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be ordered from the following address: Cambridge Crystallographic Data Centre, 12 Union Road, GB-Cambridge CB21EZ; fax: [phone]; or [e-mail].

25

General Procedure C for the Synthesis of Dibenzo[ b , d ]thiophenes 10 In a pressure tube (glass bomb) a suspension of Pd(OAc)₂ (12 mg, 0.05 mmol, 1.7 mol% per Br atom) and dicyclo-hexyl-(2′,6′-dimethoxybiphenyl-2-yl)phosphine (L ₁ , 41 mg, 0.10 mmol) in DMF (5 mL) was flushed with Ar and stirred at 20 ˚C to give a yellowish or brownish transparent solution. To the stirred solution were added the 2,3,6-tribromobenzothiophene (2b, 371 mg, 1.0 mmol), Et₃N (1.1 mL, 8.0 mmol), and the acrylate (1.25 equiv per Br). The reaction mixture was stirred at 130 ˚C for 48 h. The solution was cooled to 20 ˚C, poured into H₂O and CH₂Cl₂ (25 mL each), and the organic and the aqueous layers were separated. The latter was extracted with CH₂Cl₂ (3 × 25 mL). The combined organic layers were washed with H₂O (3 × 20 mL), dried (Na₂SO₄), concentrated in vacuo, and passed through a column (silica gel). To a xylene solution (3 mL) of the crude product was added Pd/C (30 mg, 10 mol%). The solution was stirred under reflux for 48 h under argon atmosphere. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography (flash silica gel, heptanes-EtOAc) to yield the product.
Analytical Data of ( E )-2,3-Diphenyl-7-styryldi-benzo[ b , d ]thiophene (10b) Compound 10b was prepared starting with 2b (371 mg, 1.0 mmol) as a brownish semisolid (319 mg, 73%). ^¹H NMR (300 MHz, CDCl₃): δ = 7.01-7.20 (m, 7 H), 7.24-7.34 (m, 7 H), 7.40-7.47 (m, 6 H), 7.75-7.86 (m, 2 H, ArH). ^¹³C NMR (62 MHz, CDCl₃): δ = 120.7, 121.3, 122.1, 122.3, 122.9, 125.6, 126.5, 126.6, 127.5, 128.6, 128.7, 128.8 (CH), 129.7, 130.3 (C), 130.4 (CH), 137.3, 137.4, 137.4, 137.5, 139.9, 140.5, 141.2, 142.1 (C). IR (KBr): ν = 3054, 3023, 291 (w), 1681, 1596, 1493, 1445 (m), 1178, 1155, 1072, 1026 (w), 956 (s), 908, 876, 812 (w), 747, 733, 688 (s) cm^-¹. MS (EI, 70 eV): m/z (%) = 438 (19) [M]⁺, 368 (31), 338 (100), 259 (20), 234 (16), 202 (10), 105 (15). HRMS (EI, 70 eV): m/z calcd for C₃₂H₂₂S [M]⁺: 438.14422; found: 438.144012.