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DOI: 10.1055/s-0029-1217357
Synthesis of Carbazoles and 1,2-Dihydrocarbazoles by Domino ‘Twofold Heck-6π-Electrocyclization’ Reactions of Di- and Tribromo-N-methylindoles
Publication History
Publication Date:
12 June 2009 (online)
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Abstract
The palladium(0)-catalyzed Heck cross-coupling reaction of 2,3-dibromo- and 2,3,6-tribromo-N-methylindole, using Pd(OAc)2 as the catalyst and a novel biaryl monophosphine ligand developed by Buchwald and co-workers, afforded the corresponding di- and trialkenylindoles in high yields. The formation of 1,2-dihydrocarbazoles by a domino ‘twofold Heck-6π-electrocyclization’ was observed when the reaction was carried out at 120 ˚C rather than 90 ˚C.
Key Words
cross-coupling - electrocyclic reactions - nitrogen heterocycles - Heck reaction - palladium
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References and Notes
Synthesis of 2,3-Dibromo- N -methylindole (2a) To a THF solution (20 mL) of N-methylindole (1, 1.0 mL, 8.0 mmol) was added portionwise NBS (3.30 g, 18.4 mmol) at -78 ˚C, and the soln was stirred at this temperature for 4 h. To the soln was added water (25 mL). The organic and the aqueous layer were separated and the latter was extracted with CH2Cl2 (3 × 25 mL). The combined organic layers were washed with a saturated aqueous soln of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica column chromatography (pure heptanes) to yield 2a as a colorless solid (1.83 g, 90%).
18
General procedure
for Heck cross-coupling reactions. In a pressure tube (glass
bomb) a suspension of Pd(OAc)2 (12 mg, 0.05 mmol, 1.25
mol% per Br) and dicyclohexyl (2",6"-dimethoxybiphenyl-2-yl)
phosphine (L) (41 mg, 0.10 mmol) in DMF
(5 mL) was purged with argon and stirred at 20 ˚C to
get a yellowish or brownish transparent soln. To the stirred soln
were added the brominated indole 2a,b (1.0 mmol),
Et3N (1.1 mL, 8.0 mmol) and the acrylate (1.25 equiv.
per Br). The reaction mixture was stirred at 120 ˚C for 48
h. The soln was cooled to 20 ˚C, poured into H2O,
and CH2Cl2 (25 mL each), and the organic and
the aqueous layer 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, heptanes-EtOAc).
Diethyl 9-Methyl-2,9-dihydro-1
H
-carbazole-2,3-dicarboxylate (5b)
Product 5b was
prepared starting with 2a (367 mg, 1.0 mmol)
as a yellow solid (297 mg, 93%), mp 100-103 ˚C. ¹H NMR
(250 MHz, CDCl3): δ = 1.10
(s, 3 H, CH3), 1.30 (s, 3 H,CH3), 2.90 (dd,
1 Hα, J = 8.8,
17.1 Hz, H-1), 3.50 (dd, 1 Hβ, J = 2.6,
17.2 Hz, H-1), 3.60 (s, 3 H, NCH3), 3.90-4.10 (m,
3 H, Hα and CH2O), 4.20 (q, J = 7.1, 13.5
Hz, 2 H, CH2O), 7.10-7.20 (m, 3 H, ArH), 7.50-7.60
(m, 1 H, ArH), 7.90 (s, 1 H, H-4). ¹³C
NMR (75 MHz, CDCl3): δ = 13.0 (CH3),
13.5 (CH3), 22.8 (CH2), 28.7 (CH, C-4), 37.7 (NCH3),
59.3 (CH2O), 60.1 (CH2O), 108.3 (C), 108.6
(CH), 115.4 (C), 116.9, 120.0, 120.8 (CH), 124.1(C), 131.2 (CH), 137.0,
138.6 (C), 166.3, 172.3 (CO). IR (KBr): ν = 2981, 2928,
2854(w), 1725(s), 1629, 1599(w), 1470 1454(m), 1372, 1261, 1238(s),
1109, 1079, 147(m), 787, 747, 723, 608, 561(w)cm-¹.
GC-MS (EI, 70 eV): m/z (%) = 325(89) [M - 2]+(carbazole),
280(13), 252(100), 208(07), 179(13). HRMS (ESI+): m/z calcd for C19H19NO4 [M - 2]+(carbazole): 325.13141;
found: 325.13161.
Dibutyl 9-Methyl-9
H
-carbazole-2,3-dicarboxylate (6)
To xylene (5 mL) were added 5c (100 mg, 0.26 mmol) and Pd/C
(10 mg, 10 mol%). The soln was stirred under reflux for
48 h under argon atmosphere. The reaction mixture was filtered,
and the filtrate was concentrated in vacuo to give 6 as
a light yellow solid (99 mg, 100%). ¹H
NMR (250 MHz, CDCl3): δ = 0.90
(t, 3 H, J = 7.4
Hz, CH3), 0.90 (t, 3 H, J = 7.3
Hz, CH3), 1.30-1.50 (m, 4 H, 2 CH2),
1.60-1.80 (m, 4 H, 2 CH2), 3.80 (s, 3 H, NCH3),
4.30 (t, 2 H, J = 6.8
Hz, CH2O), 4.30 (t, 2 H, J = 6.7
Hz, CH2O), 7.20-7.30 (m, 1 H, ArH), 7.30-7.40
(m, 1 H, ArH), 7.40-7.50 (m, 1 H, ArH), 7.60 (s, 1 H, H-1),
8.00-8.10 (m, 1 H, ArH), 8.40 (s, 1 H,
H-4). ¹³C
NMR (62 MHz, CDCl3): δ = 13.7,
13.8 (CH3), 19.2, 19.3 (CH2), 29.4 (NCH3),
30.6, 30.8 (CH2), 65.3, 65.7 (CH2O), 109.0,
109.1, 120.2, 121.0 (CH), 121.7, 122.2 (C), 122.4 (CH), 123.6 (C),
127.1 (CH), 131.1, 141.5, 142,1 (C), 167.9, 169.4 (CO). IR (KBr): ν = 2956,
2931, 2871(w), 1709(s), 1464, 1387, 1362, 1340, 1325(m)1255, 1221(s), 1131,
1106, 1077, 1045(m), 950, 902, 843, 829(w), 784, 743, 721(m), 632,
608, 561(w)cm-¹. GC-MS (EI, 70 eV):
m/z (%) = 381(56) [M+],
308(15), 280(100), 224(87), 212(27), 206(77), 180(10), 152(11).
HRMS (EI, 70 eV):
m/z calcd
for C23H27NO4 [M+]:
381.19401; found: 381.19422.