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Synlett 2011(19): 2795-2798  
DOI: 10.1055/s-0031-1289563
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Transition Metals in Organic Synthesis, Part 97: [¹] Silver-Catalyzed Synthesis of Hexahalogenated 2,2′-Bipyrroles

René Martin, Anne Jäger, Hans-Joachim Knölker*
Department Chemie, Technische Universität Dresden, Bergstr. 66, 01069 Dresden, Germany
Fax: +49(351)46337030; e-Mail: hans-joachim.knoelker@tu-dresden.de;
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Publication History

Received 12 September 2011
Publication Date:
31 October 2011 (online)

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Abstract

We describe the synthesis of three hexahalogenated 1,1′-dimethyl-2,2′-bipyrroles using an efficient silver(I)-catalyzed cyclization as key step.

Key words

alkaloids - catalysis - cyclization - halogenation - pyrroles

    References and Notes

  • 1 For Part 96, see: Thomas C. Kataeva O. Knölker H.-J. Synlett  2011,  2663
  • See for example:
  • 2a Fan H. Peng J. Hamann MT. Hu J.-F. Chem. Rev.  2008,  108:  264 
    Search in Google Scholar
  • 2b Fukuda T. Ishibashi F. Iwao M. Heterocycles  2011,  83:  491 
    Search in Google Scholar
  • 3 Gribble GW. In Comprehensive Heterocyclic Chemistry II   Vol. 2:  Katritzky AR. Rees CW. Scriven EFV. Elsevier; Oxford: 1996.  p.207 
    Search in Google Scholar
  • For recent work, see:
  • 4a Bellur E. Langer P. Tetrahedron Lett.  2006,  47:  2151 
    Search in Google Scholar
  • 4b Morita N. Krause N. Eur. J. Org. Chem.  2006,  4634 
  • 4c Knight DW. Rost HC. Sharland CM. Singkhonrat J. Tetrahedron Lett.  2007,  48:  7906 
    Search in Google Scholar
  • 4d Bergner I. Opatz T. J. Org. Chem.  2007,  72:  7083 
    Search in Google Scholar
  • 4e Liu W. Jiang H. Huang L. Org. Lett.  2010,  12:  312 ; and references cited therein
    Search in Google Scholar
  • 5a Agarwal S. Knölker H.-J. Org. Biomol. Chem.  2004,  2:  3060 
    Search in Google Scholar
  • 5b For a review, see: Agarwal S. Cämmerer S. Filali S. Fröhner W. Knöll J. Krahl MP. Reddy KR. Knölker H.-J. Curr. Org. Chem.  2005,  9:  1601 
    Search in Google Scholar
  • 6 Knölker H.-J. Agarwal S. Synlett  2004,  1767 
  • 7 Knölker H.-J. Agarwal S. Tetrahedron Lett.  2005,  46:  1173 
    Search in Google Scholar
  • 8a Martin R. Jäger A. Böhl M. Richter S. Fedorov R. Manstein DJ. Gutzeit HO. Knölker H.-J. Angew. Chem. Int. Ed.  2009,  48:  8042 ; Angew. Chem. 2009, 121, 8186
    Search in Google Scholar
  • 8b For a review, see: Forke R. Gruner KK. Knott KE. Auschill S. Agarwal S. Martin R. Böhl M. Richter S. Tsiavaliaris G. Fedorov R. Manstein DJ. Gutzeit HO. Knölker H.-J. Pure Appl. Chem.  2010,  82:  1975 
    Search in Google Scholar
  • 9a Fedorov R. Böhl M. Tsiavaliaris G. Hartmann FK. Taft MH. Baruch P. Brenner B. Martin R. Knölker H.-J. Gutzeit HO. Manstein DJ. Nat. Struct. Mol. Biol.  2009,  16:  80 
    Search in Google Scholar
  • 9b Martin R. Kirst J. Weidlich S. Schieb H. Schlechtingen G. Jäger A. Rajendran L. Böhl M. Richter S. Fedorov R. Manstein DJ. Gutzeit HO. Klafki H. Wiltfang J. Simons K. Knölker H.-J. Med. Chem. Res.  2010,  19:  S23 
    Search in Google Scholar
  • 9c Martin R. Agarwal S. Jäger A. Böhl M. Richter S. Tsiavaliaris G. Fedorov R. Manstein DJ. Gutzeit HO. Knölker H.-J. In The Chemistry and Biological Activity of Synthetic and Natural Compounds, Modern Aspects of Chemistry of Heterocycles   Kartsev VG. ICSPF Press; Moscow: 2010.  p.110 
  • 9d Preller M. Chinthalapudi K. Martin R. Knölker H.-J. Manstein DJ. J. Med. Chem.  2011,  54:  3675 
    Search in Google Scholar
  • 9e Chintalapudi K. Taft MH. Martin R. Heissler SM. Preller M. Hartmann FK. Brandstaetter H. Kendrick-Jones J. Tsiavaliaris G. Gutzeit HO. Fedorov R. Buss F. Knölker H.-J. Coluccio LM. Manstein DJ. J. Biol. Chem.  2011,  286:  29700 
    Search in Google Scholar
  • 10a Andersen RJ. Wolfe MS. Faulkner DJ. Mar. Biol.  1974,  27:  281 
    Search in Google Scholar
  • 10b Tittlemier SA. Simon M. Jarman WM. Elliott JE. Norstrom RJ. Environ. Sci. Technol.  1999,  33:  26 
    Search in Google Scholar
  • 11a Gribble GW. Blank DH. Jasinski JP. Chem. Commun.  1999,  2195 
  • 11b Blank DH. Gribble GW. Schneekloth JS. Jasinski JP. J. Chem. Cryst.  2002,  32:  541 
    Search in Google Scholar
  • 11c Fu L. Gribble GW. Tetrahedron Lett.  2008,  49:  7352 
    Search in Google Scholar
  • 12a Bennett JW. Bentley R. Adv. App. Microbiol.  2000,  47:  1 
    Search in Google Scholar
  • 12b Fürstner A. Angew. Chem. Int. Ed.  2003,  42:  3582 ; Angew. Chem. 2003, 115, 3706
    Search in Google Scholar
  • 13 Laatsch H. Kellner M. Weyland H. J. Antibiot.  1991,  44:  187 
    Search in Google Scholar
  • 14a Carté B. Faulkner DJ. J. Org. Chem.  1983,  48:  2314 
    Search in Google Scholar
  • 14b Lindquist N. Fenical W. Experientia  1991,  47:  504 
    Search in Google Scholar
  • 14c Blackman AJ. Li C. Aust. J. Chem.  1994,  47:  1625 
    Search in Google Scholar
  • 15a Flögel O. Reissig H.-U. Synlett  2004,  895 
  • 15b Matsumoto S. Kobayashi T. Ogura K. Heterocycles  2005,  66:  319 
    Search in Google Scholar
  • 15c Dohi T. Morimoto K. Maruyama A. Kita Y. Org. Lett.  2006,  8:  2007 
    Search in Google Scholar
  • 15d Jolicoeur B. Lubell WD. Org. Lett.  2006,  8:  6107 
    Search in Google Scholar
  • 15e Jiao L. Hao E. Vicente GH. Smith KM. J. Org. Chem.  2007,  72:  8119 ; and references cited therein
    Search in Google Scholar
  • 16 Love BE. Raje PS. Williams II TC. Synlett  1994,  493 
  • 17 Kawate T. Nakagawa M. Yamazaki H. Hirayama M. Hino T. Chem. Pharm. Bull.  1993,  41:  287 
    Search in Google Scholar
  • 18 Sisko J. Weinreb SM. J. Org. Chem.  1990,  55:  393 
    Search in Google Scholar
  • 22a Kauffmann T. Lexy H. Chem. Ber.  1981,  114:  3674 
    Search in Google Scholar
  • 22b Dohi T. Morimoto K. Ito M. Kita Y. Synthesis  2007,  2913 
  • 22c Sánchez-García D. Borrell JI. Nonell S. Org. Lett.  2009,  11:  77 
    Search in Google Scholar
  • 24 Rosenfelder N. Ostrowicz P. Fu L. Gribble GW. Tittlemier SA. Fey W. Vetter W. J. Chromatogr. A  2010,  1217:  2050 
    Search in Google Scholar
19

Synthesis of 2,3-Dihydro-1′-methyl-1-tosyl-2,2′-bipyrrole (10) by Silver(I)-Catalyzed Cyclization of the N -Tosylhomopropargylamine 9: Silver(I) acetate (6 mg, 35.9 µmol) was added to a stirred solution of compound 9 (105 mg, 347 µmol) in anhyd acetone (12 mL) and the resulting mixture was heated at reflux for 3 d. After cooling to r.t., the solvent was removed in vacuum. Purification of the crude product by flash chromatography (light petroleum ether-Et2O, 5:1) on silica gel provided the 2,3-dihydro-2,2′-bipyrrole 10; yield: 100 mg (95%); yellow crystals; mp 125 ˚C. UV (MeOH): λ = 221, 252, 277 nm. IR (ATR): 3099, 2925, 2857, 1619, 1597, 1494, 1451, 1344, 1295, 1160, 1089, 1049, 957, 911, 814, 706, 664 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 2.41 (s, 3 H), 2.60 (ddt, J = 16.7, 7.6, 2.4 Hz, 1 H), 2.84 (ddt, J = 16.7, 11.2, 2.4 Hz, 1 H), 3.54 (s, 3 H), 4.86 (dd, J = 11.2, 7.6 Hz, 1 H), 5.14 (m, 1 H), 6.00 (m, 2 H), 6.47 (m, 1 H), 6.50 (t, J = 2.2 Hz, 1 H), 7.24 (m, 2 H), 7.51 (d, J = 8.3 Hz, 2 H). ¹³C NMR (DEPT; 125 MHz, CDCl3): δ = 21.55 (Me), 34.47 (Me), 38.43 (CH2), 56.76 (CH), 106.87 (CH), 108.74 (CH), 109.35 (CH), 123.51 (CH), 127.44 (2 × CH), 129.44 (2 × CH), 130.61 (CH), 130.92 (C), 134.30 (C), 143.49 (C). MS (EI): m/z (%) = 302 (33) [M+], 147 (100), 107 (11). HRMS: m/z [M+] calcd for C16H18N2O2S: 302.1089; found: 302.1078. Anal. Calcd for C16H18N2O2S: C, 63.55; H, 6.00; N, 9.26; S, 10.60. Found: C, 63.72; H, 5.97; N, 9.15; S, 10.49.

20

Crystallographic Data for the 2,3-Dihydro-2,2′-bipyrrole 10: C16H18N2O2S, M = 302.38 g mol-¹, crystal size: 0.70 ¥ 0.55 ¥ 0.30 mm³, monoclinic, space group P21/n, a = 13.286 (1), b = 8.603 (1), c = 13.580 (1) Å, V = 1494.6 (2) ų, Z = 4, ρ calcd = 1.344 g cm-³, µ = 0.223 mm-¹, λ = 0.71073 Å, T = 198 (2) K, θ range = 3.04-30.00˚, reflections collected: 73987, independent: 4349 (R int = 0.0256), 192 parameters. The structure was solved by direct methods and refined by full-matrix least-squares on F ²; final R indices [I > 2σ(I)]: R 1 = 0.0353; wR 2 = 0.1005; maximal residual electron density: 0.302 e Å-³. CCDC 829173 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

21

Synthesis of 1,1′-Dimethyl-2,2′-bipyrrole (11) by Aromatization and Alkylation of 10:
A solution of potassium tert-butoxide (926 mg, 8.25 mmol) and the 2,3-dihydro-2,2′-bipyrrole 10 (500 mg, 1.65 mmol) in dimethyl sulfoxide (35 mL) was stirred at 50 ˚C for 3 h. The solution was cooled to 0 ˚C, MeI (1.0 mL, 2.28 g, 16.1 mmol) was added and the reaction mixture was stirred at r.t. overnight. After addition of H2O (50 mL), the reaction mixture was extracted with Et2O (3 × 25 mL). The combined organic layers were washed with H2O (2 × 25 mL) and dried over MgSO4. Removal of the solvent and purification of the crude product by flash chromatography (light petroleum ether-Et2O, 10:1) on silica gel afforded 1,1′-dimethyl-2,2′-bipyrrole (11) as a yellow oil; yield: 200 mg (76%). IR (ATR): 3101, 2926, 1514, 1484, 1447, 1410, 1359, 1312, 1282, 1234, 1203, 1088, 1062, 968, 781, 706 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 3.52 (s, 6 H), 6.16-6.17 (m, 2 H), 6.19-6.21 (m, 2 H), 6.73 (m, 2 H). ¹³C NMR (DEPT; 125 MHz, CDCl3): δ = 34.38 (2 × Me), 107.30 (2 × CH), 110.44 (2 × CH), 122.58 (2 × CH), 125.05 (2 × C). MS (EI): m/z (%) = 160 (100) [M+], 159 (38), 145 (16), 118 (21), 117 (16). HRMS: m/z [M+] calcd for C10H12N2: 160.1000; found: 160.0995.

23

Synthesis of 3,3′,4,4′,5,5′-Hexabromo-1,1′-dimethyl-2,2′-bipyrrole (1) by Bromination of 11:
A solution of N-bromosuccinimide (449 mg, 2.52 mmol) in anhyd MeCN (10 mL) was added at -40 ˚C to a solution of 1,1′-dimethyl-2,2′-bipyrrole (11) (57.5 mg, 0.36 mmol) in MeCN (15 mL). The resulting green solution was warmed slowly to r.t. and stirred for 15 h. Removal of the solvent in vacuum and purification by flash chromatography (light petroleum ether-Et2O, 7:1) on silica gel provided compound 1; yield: 208 mg (91%).
Spectroscopic data for the 3,3′,4,4′,5,5′-Hexahalo-1,1′-dimethyl-2,2′-bipyrroles 1-3:
3,3′,4,4′,5,5′-Hexabromo-1,1′-dimethyl-2,2′-bipyrrole (1): pale yellow solid; mp 237-238 ˚C. UV (MeOH): λ = 256 nm. IR (ATR): 2923, 2853, 1478, 1462, 1436, 1402, 1384, 1364, 1321, 1228, 1187, 1087, 1042, 971, 753, 733, 677, 613 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 3.46 (s, 6 H). ¹³C NMR (DEPT; 125 MHz, CDCl3): δ = 35.37 (2 × Me), 101.21 (2 × C), 103.31 (2 × C), 106.77 (2 × C), 122.17 (2 × C). MS (EI): m/z (%) = 640 (7), 638 (44), 636 (81), 634 (100), 632 (84), 630 (47), 628 (7) [M+], 516 (10), 514 (23), 512 (24), 510 (11), 476 (29), 474 (46), 472 (31), 395 (15), 393 (15). HRMS: m/z [M+] calcd for C10H6Br6N2: 627.5631; found: 627.5619.
3,3′,4,4′,5,5′-Hexachloro-1,1′-dimethyl-2,2′-bipyrrole (2): colorless crystals; mp 208-209 ˚C (dec.). UV (MeOH): λ = 230, 260 nm. IR (ATR): 2951, 2920, 2846, 1509, 1446, 1382, 1348, 1333, 1259, 1198, 1112, 1055, 1015, 981, 909, 794, 734, 708, 690, 627 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 3.41 (s, 6 H). ¹³C NMR (DEPT; 125 MHz, CDCl3): δ = 32.79 (2 × Me), 108.38 (2 × C), 113.52 (2 × C), 116.39 (2 × C), 116.51 (2 × C). MS (EI): m/z (%) = 370 (30), 368 (78), 366 (100), 364 (47) [M+], 331 (11), 296 (16), 294 (17),
292 (16), 290 (26), 288 (16). HRMS: m/z [M+] calcd for C10H6Cl6N2: 363.8662; found: 363.8658. Anal. Calcd for C10H6Cl6N2: C, 32.74; H, 1.65; N, 7.64. Found: C, 32.76; H, 1.75; N, 7.44.
3,3′,4,4′-Tetrabromo-5,5′-dichloro-1,1′-dimethyl-2,2′-bipyrrole (3): yellow solid; mp 220 ˚C (dec.). UV (MeOH): λ = 232, 253 nm. IR (ATR): 2943, 2923, 2851, 1726, 1491, 1476, 1440, 1408, 1375, 1323, 1190, 1105, 1049, 978, 764, 681, 665, 620 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 3.43 (s, 6 H). ¹³C NMR (DEPT; 125 MHz, CDCl3): δ = 33.50 (2 × Me), 97.37 (2 × C), 102.89 (2 × C), 118.81 (2 × C), 120.25 (2 × C). MS (EI): m/z (%) = 550 (11), 548 (46), 546 (94), 544 (100), 542 (55), 540 (13) [M+], 428 (12), 426 (38), 424 (57), 422 (43), 420 (12), 388 (19), 386 (56), 384 (63), 382 (25). Anal. Calcd for C10H6Br4Cl2N2: C, 22.05; H, 1.11; N, 5.14. Found: C, 22.32; H, 1.21; N, 4.96.