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Synlett 2009(5): 838-842  
DOI: 10.1055/s-0028-1087947
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Regioselective Sonogashira Reactions of N-Methyltetrabromopyrrole: First Synthesis of Tri- and Tetra(1-alkynyl)pyrroles

Farman Ullaha, Tung T. Dangb, Joachim Heinickea, Alexander Villingerb, Peter Langer*b,c
a Institut für Biochemie, Universität Greifswald, Felix-Hausdorff-Str. 4, 17487 Greifswald, Germany
b Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Fax: +49(381)4986412; e-Mail: peter.langer@uni-rostock.de;
c Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
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Publication History

Received 11 November 2008
Publication Date:
24 February 2009 (online)

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Abstract

N-Methyl-2,3,4,5-tetrabromopyrrole is transformed into a variety of alkynyl-substituted pyrroles by regioselective Sonogashira cross-coupling reactions. In this context, the synthesis of the first tri- and tetra(1-alkynyl)pyrroles is reported.

Key words

catalysis - palladium - carbon-carbon bond formation - regioselectivity - pyrroles

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General Procedure for Sonogashira Reactions
Tetrabromo-N-methylpyrrole (1, 750 mg, 1.87 mmol), Ph3P (98 mg, 20 mol%), PdCl2 (MeCN)2 (49 mg, 10 mol%), and CuI (36 mg, 10 mol%) were added to an oven-dried Schlenk flask, evacuated for 10 min, and then flushed with argon. To the mixture was added thoroughly dried, freshly distilled and oxygen-free diisopropylamine (20 mL). The clear yellow solution was stirred for 15 min at 20 ˚C for the generation of the catalyst. The solution was subsequently cooled to 0 ˚C, and the alkyne was dropwise added by syringe. The solution was stirred for 1 h at 0 ˚C and for 3 h at 20 ˚C. The dark brown mixture was heated at 90 ˚C. The solution was allowed to cool to ambient temperature, filtered, and the filtrate was concentrated in vacuo. To the residue was added CH2Cl2, and the solution was extracted with H2O. The combined organic layers were dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (neutral silica gel, n-hexane). For the synthesis of products 3, the two alkynes were added at the same time.

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Synthesis of 2a
Starting with 1 (500 mg, 1.25 mmol) and 2-pentyne (1.3 mmol), 2a was isolated (134 mg, 30%) as a brownish highly viscous oil. ¹H NMR (250 MHz, CDCl3): δ = 1.06 (t, ³ J = 7.5 Hz, 3 H, Me), 1.64 (sext, ³ J = 7.2 Hz, 2 H, CH2), 2.47 (t, ³ J = 7.0 Hz, 2 H, CH2), 3.64 (s, 3 H, NCH3). ¹³C NMR (62.8 MHz, CDCl3): δ = 13.5 (CH3), 21.6, 22.0 (CH2), 35.6 (NCH3), 70.1, 98.8 (CºC), 100.4, 102.93, 104.19, 118.34 (C, pyrrole). IR (KBr): 3436 (br, s), 2958 (s), 2932 (m), 2872 (m), 2228 (w), 1717 (m), 1529 (m), 1456 (s), 1431 (m), 1378 (m), 1330 (s), 1092 (m) cm-¹. MS (EI, 70 eV, 85 ˚C): m/z (%) = 381 (19) [M+, 79Br, 79Br, 79Br], 356 (67), 354 (58), 275 (14), 224 (54), 194 (60), 115 (100). HRMS: m/z calcd for C10H10Br3N [M+, 79Br, 79Br, 79Br]: 380.83579; found: 380.83501.

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Synthesis of 3c
Starting with 1 (500 mg, 1.25 mmol), 2-methyl-3-pentyne-2-ol (1.3 mmol), and p-tolylacetylene (1.3 mmol), 3c was isolated (238 mg, 44%) as a red to brown solid. ¹H NMR (250 MHz, CDCl3): δ = 1.65 (s, 6 H, CH3), 2.36 (s, 3 H, Me-tolyl), 3.72 (s, 3 H, CH3), 7.16 (d, ³ J = 8.1 Hz, 2 H, tolyl), 7.43 (d, ³ J = 8.1 Hz, 2 H, tolyl). ¹³C NMR (62.8 MHz, CDCl3): δ = 21.6 (CH3, tolyl), 31.3 (CH3), 34.4 (NCH3), 65.9 (C, CMe2OH), 71.7, 71,6 (CºC), 97.5, 97.7 (C, pyrrole), 102.2, 103.9 (CºC), 116.9, 117.9 (C, pyrrole), 119.1, 131.4 (CH, p-tolyl), 139.2 (C, p-tolyl). IR (KBr): 3324 (br, s), 2983 (s), 2929 (s), 2865 (w), 2249 (m), 1906 (w), 1728 (s), 1534 (m), 1509 (m), 1440 (s), 1232 (s), 1160 (br, s), 910 (s), 815 (s), 730 (br, s) cm-¹. MS (EI, 70 eV, 110 ˚C): m/z (%) = 433 (49) [M+, 79Br, 79Br], 418 (40) [M+ - CH3, 79Br, 79Br], 417 (11), 405 (17), 377 (18), 356 (15)
[M+ - 79Br].

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Synthesis of 5b
Procedure A ¹6
Starting with 1 (750 mg, 1.87 mmol) and p-tolylacetylene (0.6 mL, 4.67 mmol), 5b (620 mg, 71%) was isolated as a white solid. ¹H NMR (250 MHz, CDCl3): δ = 2.36 (s, 6 H, CH3, p-tolyl), 3.77 (s, 3 H, NCH3), 7.14 (d, ³ J = 8.1 Hz, 4 H, p-tolyl), 7.56 (d, ³ J = 8.1 Hz, 4 H, p-tolyl). ¹³C NMR (62.8 MHz, CDCl3): δ = 21.6 (CH3, p-tolyl), 34.6 (NCH3), 77.9 (CºC), 97.7 (C, pyrrole), 104.1 (CºC), 117.9 (C, pyrrole), 119.1 (C, p-tolyl), 129.2 (CH, p-tolyl), 131.3 (CH, p-tolyl), 139.1 (C, p-tolyl). IR (KBr): 3435 (br, m), 3023 (m), 2717 (s), 2206 (w), 1537 (s), 1441 (s), 1377 (s), 1345 (s), 817 (s), 809 (8 s), 535 (s), 520 (s) cm-¹. MS (EI, 70 eV, 320 ˚C):
m/z (%) = 465.6 (51) [M+, 79Br, 79Br], 403 (16), 306.5 (10), 292.5 (14), 277 (42). HRMS: m/z calcd for C23H17Br2N: 464.97223; found: 464.97163.

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CCDC-689251 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: +44 (1223)336033; or deposit@ccdc.cam.ac.uk.

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Synthesis of 8c
Starting with 1 (500 mg, 1.25 mmol) and 2-methyl-3-pentyne-2-ol (0.4 mL, 4.12 mmol), 8c was isolated (198 mg, 40%) as a brownish solid. ¹H NMR (250 MHz, DMSO-d 6): δ = 1.45, (s, 12 H, 4 CH3), 1.48 (s, 6 H, 2 CH3), 3.60 (s, 3 H, NCH3), 5.42, 5.60, 5.61 (3 s, 3 OH). ¹³C NMR (62.8 MHz, DMSO-d 6): δ = 31.35, 31.38, 31.8, (6 CH3), 33.8 (NCH3), 63.8, 63.9, (C, CMe2OH), 69.8, 70.0, 72.4, (CºC), 100.1, 102.6, 103.7 (C, pyrrole), 104.1, 110.0 (CºC), 116.8 (C, pyrrole), 119.9 (C, pyrrole). IR (KBr): 3435 (br, s), 2980 (s), 2933 (s), 2226 (w), 1634 (m), 1452 (m), 1374 (s), 1374 (s), 1238 (s), 1164 (s), 1137 (s), 989 (w), 938 (s), 939 (m), 892 (w), 841 (m) cm-¹. MS (EI, 70 eV, 130 ˚C): m/z (%) = 405 (99) [M+, 79Br], 403 (16), 390 (14), 388 (28), 374 (65), 372 (71), 278 (40), 235 (23). HRMS: m/z calcd for C20H24BrNO3 [M+, 79Br]: 405.09341; found: 405.09328.

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Synthesis of 9a.
Starting with 1 (500 mg, 1.25 mmol) and phenylacetylene (0.82 mL, 7.5 mmol), 9a was isolated (150 mg, 25%) as an orange-red oil. ¹H NMR (250 MHz, CDCl3): δ = 3.81 (s, 3 H, NCH3), 7.32 (br s, 4 H, Ph), 7.35 (m, 8 H, Ph), 7.56 (m, 8 H, Ph). ¹³C NMR (62.8 MHz, CDCl3): δ = 33.8 (NCH3), 79.2, 82.3, 94.3 (CºC), 112.7 (C, pyrrole), 120.6 (C, pyrrole), 122.5 (C, Ph), 123.9 (C, Ph), 127.9, 128.3, 128.46, 128.7, 131.46, 131.52 (CH, Ph). IR (KBr): 3435 (m), 3058 (w), 2959 (s), 2927 (s), 2871 (m), 2204 (s), 1728 (s), 1597 (s), 1478 (s), 1454 (s), 1376 (m), 1255 (m), 1067 (m), 910 (m), 754 (s), 688 (s) cm-¹. MS (EI, 70 eV, 85 ˚C): m/z (%) = 482 (10), 481 (39) [M+], 480 (100), 476 (6), 401 (4), 338 (6), 239 (22), 230 (2). HRMS: m/z calcd for C37H23N; 481.18301; found: 481.18276.