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

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 
• 2b Fukuda T. Ishibashi F. Iwao M. Heterocycles  2011,  83:  491 
• 3 Gribble GW. In Comprehensive Heterocyclic Chemistry II   Vol. 2:  Katritzky AR. Rees CW. Scriven EFV. Elsevier; Oxford: 1996.  p.207 
• For recent work, see:
• 4a Bellur E. Langer P. Tetrahedron Lett.  2006,  47:  2151 
• 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 
• 4d Bergner I. Opatz T. J. Org. Chem.  2007,  72:  7083 
• 4e Liu W. Jiang H. Huang L. Org. Lett.  2010,  12:  312 ; and references cited therein
• 5a Agarwal S. Knölker H.-J. Org. Biomol. Chem.  2004,  2:  3060 
• 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 
• 6 Knölker H.-J. Agarwal S. Synlett  2004,  1767 
• 7 Knölker H.-J. Agarwal S. Tetrahedron Lett.  2005,  46:  1173 
• 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
• 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 
• 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 
• 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 
• 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 
• 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 
• 10a Andersen RJ. Wolfe MS. Faulkner DJ. Mar. Biol.  1974,  27:  281 
• 10b Tittlemier SA. Simon M. Jarman WM. Elliott JE. Norstrom RJ. Environ. Sci. Technol.  1999,  33:  26 
• 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 
• 11c Fu L. Gribble GW. Tetrahedron Lett.  2008,  49:  7352 
• 12a Bennett JW. Bentley R. Adv. App. Microbiol.  2000,  47:  1 
• 12b Fürstner A. Angew. Chem. Int. Ed.  2003,  42:  3582 ; Angew. Chem. 2003, 115, 3706
• 13 Laatsch H. Kellner M. Weyland H. J. Antibiot.  1991,  44:  187 
• 14a Carté B. Faulkner DJ. J. Org. Chem.  1983,  48:  2314 
• 14b Lindquist N. Fenical W. Experientia  1991,  47:  504 
• 14c Blackman AJ. Li C. Aust. J. Chem.  1994,  47:  1625 
• 15a Flögel O. Reissig H.-U. Synlett  2004,  895 
• 15b Matsumoto S. Kobayashi T. Ogura K. Heterocycles  2005,  66:  319 
• 15c Dohi T. Morimoto K. Maruyama A. Kita Y. Org. Lett.  2006,  8:  2007 
• 15d Jolicoeur B. Lubell WD. Org. Lett.  2006,  8:  6107 
• 15e Jiao L. Hao E. Vicente GH. Smith KM. J. Org. Chem.  2007,  72:  8119 ; and references cited therein
• 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 
• 18 Sisko J. Weinreb SM. J. Org. Chem.  1990,  55:  393 
• 22a Kauffmann T. Lexy H. Chem. Ber.  1981,  114:  3674 
• 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 
• 24 Rosenfelder N. Ostrowicz P. Fu L. Gribble GW. Tittlemier SA. Fey W. Vetter W. J. Chromatogr. A  2010,  1217:  2050 

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 mm^³, monoclinic, space group P2₁/n, a = 13.286 (1), b = 8.603 (1), c = 13.580 (1) Å, V = 1494.6 (2) Å^³, 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.