2,5,6-Trisubstituted N-Methylindoles from Site-Selective Suzuki-Miyaura Cross-Coupling, Twofold Heck and 6π-Electrocyclization-Dehydrogenation Reactions of 2,3,5-Tribromo-N-methylpyrrole

Abstract

Site-selective Suzuki-Miyaura reactions of 2,3,5-tribromo-N-methylpyrrole afforded 5-aryl-2,3-dibromo-N-methylpyrroles. These products were transformed into 2,5,6-trisubstituted N-methylindoles by twofold Heck reactions and subsequent 6π-electrocyclization-dehydrogenation reactions.

Key words

catalysis - palladium - Heck reaction - electrocyclization - indoles

References and Notes

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14

Synthesis of 5-Aryl-2,3-dibromo- N -methylpyrroles 3a-d: To a mixture of 2(0.159 g, 0.5 mmol), aryl boronic acid (0.55 mmol), and Pd(PPh₃)₄ (5 mol%) was added a mixture of 1,4-dioxane and toluene (1:1; 5 mL) and K₃PO₄ (4.0 equiv, 424 mg) under an argon atmosphere. The reaction mixture was stirred at 100 ˚C for 12 h and was subsequently allowed to cool to 20 ˚C. The solution was poured into H₂O and EtOAc (25 mL each) and the organic and the aqueous layers were separated. The latter was extracted with EtOAc (3 × 25mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (flash silica gel, eluent: n-heptane).

15

Synthesis of 2,3-Dibromo-5-(4- tert -butylphenyl)- N -methylpyrrole (3c): Starting with 2 (0.318 g, 1.0 mmol) and 4-tert-butylphenylboronic acid (0.178 g, 1.1 mmol), 3c was isolated (237 mg, 64%) as a colorless oil. ^¹H NMR (300 MHz, acetone-d ₆): δ = 1.34 (s, 9 H, 3 × Me), 3.61 (s, 3 H, NMe), 6.29 (s, 1 H, CH_pyrrole), 7.34 (d, 2 H, J = 8.6 Hz, ArH), 7.59 (d, 2 H, J = 8.6 Hz, ArH). ^¹³C NMR (62 MHz, acetone-d ₆): δ = 31.6 (3 × Me), 35.2 (C), 35.4 (NMe), 98.5, 105.5 (CBr), 111.3 (CH_pyrrole), 126.4 (2 × CH), 129.4 (2 × CH), 130.2, 137.4, 151.7 (C). IR (KBr): 2959 (m), 2903, 2866, 1783, 1697, 1650, 1606, 1537 (w), 1499, 1456, 1362, 1318, 1265 (m), 1216, 1201 (w), 1109, 1086, 1017, 946 (m), 837 (s), 821, 779 (m), 741, 668, 595 (w), 574 (m), 532 (w) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 373 (36) [M⁺ (^8¹Br, ^8¹Br)], 371 (73) [M⁺ (⁷⁹Br, ^8¹Br)], 369 (36) [M⁺, (⁷⁹Br, ⁷⁹Br)], 358 (50), 357 (16), 356 (100) [M⁺], 354 (53), 164 (15). HRMS (EI, 70 eV): m/z [M⁺ (Br, ^8¹Br)] calcd for C₁₅H₁₇NBr₂: 370.97018; found: 370.97046.

16

Synthesis of 2,3-Di(alkenyl)pyrroles 5a-n: In a pressure tube (glass bomb) a suspension of Pd(OAc)₂ (12 mg, 0.05 mmol, 5 mol%) and TCHP (28.04 mg, 0.10 mmol, 10 mol%) in DMF (5 mL) was purged with Ar and stirred at 20 ˚C to give a yellowish or brownish clear solution. To the stirred solution were added 3a-d (1.0 mmol), Et₃N (1.1 mL, 8.0 mmol) and the acrylate (5.0 equiv). The reaction mixture was stirred at 100 ˚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 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), and concentrated in vacuo. The residue was purified by chromatography (flash silica gel, eluent: heptanes-EtOAc).

17

(2 E ,2′ E )-Isobutyl 3,3′-[5-(4-Ethylphenyl)- N -methyl-pyrrole-2,3-diyl]diacrylate (5c): Compound 5c was prepared starting with 3b (343 mg, 1.0 mmol) as a brown highly viscous oil (301 mg, 69%). ^¹H NMR (300 MHz, CDCl₃): δ = 0.90 (d, 6 H, J = 6.7 Hz, 2 × Me), 0.91 (d, 6 H, J = 6.7 Hz, 2 × Me), 1.20 (t, 3 H, J = 7.6 Hz, Me), 1.87-1.99 (m, 2 H, 2 × CH), 2.62 (q, 2 H, J = 7.6 Hz, CH₂), 3.57 (s, 3 H, NMe), 3.90 (d, 2 H, J = 6.8 Hz, CH₂O), 3.92 (d, 2 H, J = 6.8 Hz, CH₂O), 6.10 (d, 1 H, J = 16.0 Hz, CH), 6.18 (d, 1 H, J = 15.6 Hz, CH), 6.42 (s, 1 H, CH_pyrrole), 7.20-7.25 (m, 4 H, Ar), 7.71 (d, 1 H, J = 16.0 Hz, ArH), 7.78 (d, 1 H, J = 15.7 Hz, ArH). ^¹³C NMR (75 MHz, CDCl₃): d = 15.4 (Me), 19.2 (4 × Me), 27.8, 27.9 (CH), 28.6 (CH₂), 33.9 (NMe), 70.4, 70.8 (CH₂O), 107.7, 116.5, 117.5 (CH), 123.7 (C), 128.2 (2 × CH), 129.0 (C), 129.1 (2 × CH), 130.9 (C), 131.1, 136.3 (CH), 140.7, 144.6 (C), 167.2, 167.5 (CO). IR (KBr): 2959 (m), 2932, 2872 (w), 1699, 1615 (s), 1548, 1504 (w), 1468, 1453 (m), 1424, 1392 (w), 1368, 1284, 1260, 1241, 1220 (m), 1148 (s), 1015, 966, 839, 799 (m), 773, 723, 703, 672, 610, 533 (w) cm^-¹. EI⁺ (70 eV): m/z (%) = 437 (7) [M]⁺, 280 (14), 236 (11), 66 (13), 44 (16), 43 (100), 42 (30), 41 (55). HRMS (EI, 70 eV): m/z [M]⁺ calcd for C₂₇H₃₅O₄N: 437.25606; found: 437.25529.

18

Synthesis of Indoles 6a-n: A diphenyl ether solution (3 mL) of 5a-n was stirred at 200 ˚C for 24 h in a pressure tube. The solution was allowed to cool to 20 ˚C and Pd/C (30 mg, 10 mol%) was added. The solution was stirred at 200 ˚C for 48 h under an argon atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (flash silica gel, eluent: heptanes-EtOAc).

19

Dibutyl 2-(4- tert -Butylphenyl)- N -methylindole-5,6-dicarboxylate Diacrylate ( 6j): Compound 6j was prepared starting with 5j (465 mg, 1.0 mmol) as a brown highly viscous oil (412 mg, 89%). ^¹H NMR (250 MHz, CDCl₃): δ = 0.89 (t, 6 H, J = 8.7 Hz, 2 × Me), 1.29 (s, 9 H, 3 × Me), 1.33-1.42 (m, 4 H, 2 × CH₂), 1.61-1.72 (m, 4 H, 2 × CH₂), 3.71 (s, 3 H, NMe), 4.23 (t, 2 H, J = 6.7 Hz, CH₂O), 4.25 (t, 2 H, J = 6.7 Hz, CH₂O), 6.52 (s, 1 H, CH_pyrrole), 7.36 (d, 2 H, J = 8.4 Hz, ArH), 7.43 (d, 2 H, J = 8.5 Hz, ArH), 7.65 (s, 1 H, ArH), 7.92 (s, 1 H, ArH). ^¹³C NMR (75 MHz, CDCl₃): δ = 12.8 (2 × Me), 18.2 (2 × CH₂), 29.6, 29.7 (CH₂), 30.3 (3 × Me), 30.5 (NMe), 33.7 (C), 64.1, 64.3 (CH₂O), 101.5, 110.1, 121.1 (CH), 123.2, 124.5 (C), 124.6 (2 × CH), 127.8 (C), 128.0 (2 × CH), 128.0, 137.2, 144.1, 150.7 (C), 167.8, 168.0 (CO). IR (KBr): 2956 (m), 2870 (w), 1711 (s), 1611, 1562, 1494 (w), 1475, 1461 (m), 1430, 1390 (w), 1360, 1339 (m), 1256, 1243 (s), 1209, 1157 (m), 1103 (s), 1060, 1036, 1004 (m), 962, 944, 896 (w), 839, 783, 736 (m), 672, 625, 602, 565 (w) cm^-¹. GC-MS (EI, 70 eV): m/z (%) = 463 (100) [M]⁺, 448 (13), 407 (10), 355 (14), 334 (54), 318 (13), 290 (11). HRMS (EI, 70 eV): m/z [M]⁺ calcd for C₂₉H₃₇O₄N: 463.27171; found: 463.27286.