LETTER
Synthesis of 2,5,6-Trisubstituted N-Methylindoles
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(12) (a) Dang, T. T.; Dang, T. T.; Rasool, N.; Villinger, A.;
In conclusion, we have reported an efficient synthesis of
2,5,6-trisubstituted indoles based on Suzuki and Heck
reactions of 2,4,5-tribromo-N-methylpyrrole and subse-
quent 6p-electrocyclization–dehydrogenation reactions.
This methodology provides a convenient access to various
indoles which are not readily available by other methods.
Langer, P. Adv. Synth. Catal. 2009, 351, 1595. (b) Dang,
T. T.; Villinger, A.; Langer, P. Adv. Synth. Catal. 2008, 350,
2109. (c) Ehlers, P.; Reimann, S.; Erfle, S.; Villinger, A.;
Langer, P. Synlett 2009, 1528. (d) Toguem, S.-M. T.;
Villinger, A.; Langer, P. Synlett 2010, 909. (e) Dang, T. T.;
Dang, T. T.; Ahmad, R.; Reinke, H.; Langer, P. Tetrahedron
Lett. 2008, 49, 1698.
(13) Gilow, H. M.; Burton, D. E. J. Org. Chem. 1981, 46, 2221.
(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-d6): d = 1.34 (s, 9 H, 3 × Me), 3.61 (s, 3 H,
NMe), 6.29 (s, 1 H, CHpyrrole), 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-
d6): d = 31.6 (3 × Me), 35.2 (C), 35.4 (NMe), 98.5, 105.5
(CBr), 111.3 (CHpyrrole), 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) (2E,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): d = 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, CHpyrrole), 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,
Acknowledgment
Financial support by the DAAD (scholarship for S.-M.T.T.) is gra-
tefully acknowledged.
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Synlett 2011, No. 4, 513–516 © Thieme Stuttgart · New York