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

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

References and Notes

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16

General Procedure for Sonogashira Reactions
Tetrabromo-N-methylpyrrole (1, 750 mg, 1.87 mmol), Ph₃P (98 mg, 20 mol%), PdCl_{2 (}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.

17

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.

18

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].

19

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.

21

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: [phone]; or [e-mail].

22

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.

23

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.