LETTER
A Practical Synthesis of 2-Aryl-Indole-6-carboxylic Acids
885
2 H), 8.54–8.52 (m, 2 H), 8.19 (s, 1 H), 7.74–7.71 (m, 1 H), 7.66–
7.63 (m, 2 H). 13C NMR (100 MHz, DMSO-d6): d = 167.8, 145.1,
143.4, 138.0, 135.5, 130.9, 126.4, 121.3, 121.2, 120.9, 114.2, 105.9.
HRMS: calcd 238.0742; found: 238.0748.
Use of 1-chloro-2,4-dinitrobenzene for this reaction se-
quence provided an entry into 2-aryl-6-aminoindole (en-
try 7). Excellent reactivity was observed in the SNAr
reaction and the following reductive cyclization steps
(85% yield by NMR). However the subsequent decarbox-
ylation was found to proceed in only ca. 60% yield, the
overall isolated yield for the sequence was 38%.
2-(2,2-Dimethylethyl)-indole-6-carboxylic Acid (1e): (0.54 g,
25% yield). 1H NMR (400 MHz, DMSO-d6): d = 7.96 (s, 1 H), 7.61
(d, J = 8.8 Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 1.39 (s, 9 H). 13C
NMR (100 MHz, DMSO-d6): d = 159.8, 136.9, 135.3, 128.9, 128.1,
120.7, 120.0, 112.9, 99.0, 30.0, 23.1. HRMS: calcd 217.1103;
found: 217.1100.
2-Phenyl-6-aminoindole (1f): (0.79 g, 38% yield). 1H NMR (400
MHz, DMSO-d6): d = 12.35 (s, 1 H), 8.30 (s, 1 H), 7.97–7.90 (m, 2
H), 7.73 (d, m, 1 H), 7.57–7.53 (m, 2 H), 7.46–7.44 (m, 1 H), 7.16
(s, 1 H). 13C NMR (100 MHz, DMSO-d6): d = 143.9, 141.2, 135.2,
133.6, 130.6, 129.6, 128.9, 125.7, 120.1, 114.8, 107.7, 99.8. HRMS:
calcd 208.1000; found: 208.1003.
In conclusion, the above protocol discloses the first suc-
cessful and practical use of b-keto esters in SNAr reac-
tions. The method allows for a highly efficient access to
2-aryl-indole-6-carboxylic acid systems via a sequence
consisting in SNAr reaction, reductive cyclization, and de-
carboxylation. Considering its operational simplicity and
cost effectiveness, this protocol will be useful in the large
scale synthesis of this class of compounds.
References
(1) Kamijo, S.; Yamamoto, Y. J. Org. Chem. 2003, 68, 4764.
(2) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
(3) Gribble, G. W. Contemp. Org. Synth. 1994, 1, 145.
(4) (a) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 10251. (b) Rutherford, J. L.; Rainka, M. P.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 15168.
(c) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem.
1998, 63, 7652. (d) Kawatsura, M.; Hartwig, J. F. J. Am.
Chem. Soc. 1999, 121, 1473.
General Procedure: 2-(2-Pyridyl)-indole-6-carboxylic Acid (1a)
To a solution of ethyl picolinoylacetate (3) (3.86 g, 20 mmol) in N-
methylpyrrolidinone/dioxane (1:1, 12 mL) at r.t. was added t-BuOK
portionwise (2.24 g, 20 mmol) over 10 min. The suspension was
heated to 70 °C and 4-chloro-3-nitrobenzonitrile (2) (1.83 g, 10
mmol) in dioxane (5 mL) was added at such a rate to keep the inter-
nal temperature below 80 °C. After the reaction was complete, the
mixture was cooled to r.t. and added to a solution of 4 N HCl in di-
oxane (5 mL, 20 mmol) by cannula. To the resulting mixture was
added HOAc (5 mL) and Fe (2.24 g, 40 mmol). The thick slurry was
heated to 85 °C and stirred for 3 h. The resulting mixture was fil-
tered hot through a pad of celite, which was washed with EtOAc (20
mL). The organic solvents were removed by distillation under vac-
uum. The thick oil obtained was suspended in methyl-tert-butyl-
methylether [MTBE] (20 mL) and the slurry was washed with 2 M
NaOH solution until pH 8. The organic layer was concentrated and
the residue was dissolved in MeOH (50 mL). A 10 M NaOH solu-
tion (50 mL) was added and the resulting mixture was heated at re-
flux for 6 h and cooled to r.t. The reaction mixture was extracted
with 10% MeOH in CH2Cl2 and acidified with a 6 M HCl solution
to pH 1–2. Concentration of the organic layer afforded the desired
2-(2-pyridyl)-indole-6-carboxylic acid (1a) (1.72 g, overall 72%
yield), which could be further recrystallized from EtOH.
(5) Vazquez, E.; Davies, I. W.; Payack, J. F. J. Org. Chem.
2002, 67, 7551; and references therein.
(6) (a) Fairley, T. A.; Tidwell, R. R.; Donkor, I.; Naiman, N. A.;
Ohemeng, K. A.; Lombardy, R. J.; Bentley, J. A.; Cory, M.
J. Med. Chem. 1993, 36, 1746. (b) Izumi, T.; Sugano, M.;
Konno, T. J. Heterocycl. Chem. 1992, 29, 899. (c) Clark, C.
I.; White, J. M.; Kelly, D. P.; Martin, R. F.; Lobachevsky, P.
Aust. J. Chem. 1998, 51, 243.
(7) Selvakumar, N.; Reddy, B. Y.; Kumar, G. S.; Iqbal, J.
Tetrahedron Lett. 2001, 42, 8395.
(8) Quallich, G. J.; Morrissey, P. M. Synthesis 1993, 51.
(9) Augustine, R. L.; Gustavsen, A. J.; Wanat, S. F.; Pattison, I.
C.; Houghton, K. S.; Koletar, G. J. Org. Chem. 1973, 38,
3004.
(10) (a) Loudon, J. D.; Tennant, G. Quart. Rev., Chem. Soc. 1964,
18, 389. (b) Ruhland, B.; Leclerc, G. J. Heterocycl. Chem.
1989, 26, 469.
2-(2-Pyridyl)-indole-6-carboxylic Acid (1a): (1.72 g, 72% yield).
1H NMR (400 MHz, DMSO-d6): d = 11.95 (s, 1 H), 8.66 (s, 1 H),
8.11 (s, 1 H), 8.05–8.02 (m, 1 H), 7.89–7.88 (m, 1 H), 7.61–7.60 (m,
1 H), 7.58–7.57 (m, 1 H), 7.35–7.33 (m, 1 H), 7.20 (s, 1 H). 13C
NMR (100 MHz, DMSO-d6): d = 169.2, 149.9, 149.6, 140.2, 137.5,
136.6, 123.1, 120.7, 120.6, 120.3, 114.3, 100.9. HRMS: calcd
238.0742; found: 238.0742.
(11) The spectral data of compounds 4 and 5 were obtained from
the NMR of the mixture. Not all the coupling constants could
be calculated due to overlapping signals. Compound 4: 1H
NMR (400 MHz, DMSO-d6): d = 8.59 (d, J = 1.3 Hz, 1 H),
8.28 (d, J = 1.3 Hz, 1 H), 8.06 (d, J = 4.5 Hz, 1 H), 7.88 (m,
1 H), 7.86 (m, 1 H), 7.69 (dd, J = 1.3, 4.5 Hz, 1 H), 7.67 (dd,
J = 1.3, 7.8 Hz, 1 H), 6.83 (s, 1 H), 4.27 (q, 2 H), 1.25 (t, 3
H). Compound 5: 1H NMR (400 MHz, DMSO-d6): d = 8.50–
7.20 (m, 3 H), 4.09 (s, 2 H), 4.17 (q, 2 H), 1.25 (t, 3 H).
Compound 6: MS: calcd 267.24; found: (M + 1) 268.27.
(12) The use of fluoride as a better leaving group for the SNAr
reaction was evaluated but showed little improvement. The
less expensive and commercially available aryl chloride was
preferred in this study.
1
2-Phenyl-indole-6-carboxylic Acid (1b): (1.71 g, 79% yield). H
NMR (400 MHz, DMSO-d6): d = 11.88 (s, 1 H), 8.07 (s, 1 H), 7.91–
7.88 (m, 2 H), 7.65–7.62 (m, 2 H), 7.51–7.48 (m, 2 H), 7.36–7.34
(m, 1 H), 6.98 (s, 1 H), 3.35 (br s, 1 H). 13C NMR (100 MHz,
DMSO-d6,): d = 168.3, 141.0, 136.4, 132.0, 131.6, 129.0, 128.1,
125.4, 123.6, 120.4, 119.5, 113.2, 99.1. HRMS: calcd 237.0790;
found: 237.0788.
2-(4-Methoxyphenyl)-indole-6-carboxylic Acid (1c): (2.11 g,
72% yield). 1H NMR (400 MHz, DMSO-d6): d = 12.46 (br s, 1 H),
11.75 (s, 1 H), 8.00 (s, 1 H), 7.85–7.82 (m, 2 H), 7.61–7.58 (m, 1
H), 7.55–7.53 (m, 1 H), 7.08–7.05 (m, 2 H), 6.87 (s, 1 H), 4.02 (s, 3
H). 13C NMR (100 MHz, DMSO-d6): d = 168.3, 159.4, 140.5, 135.5,
132.1, 126.8, 124.7, 122.8, 120.4, 119.1, 114.5, 112.9, 97.8, 55.3.
HRMS: calcd 267.0895; found: 267.0895.
(13) (a) Krapcho, A. P. Synthesis 1982, 805. (b) Gurjar, M.;
Reddy, D. S.; Murugaiah, A.; Murugaiah, S. Synthesis 2000,
1659.
(14) Challis, B. C.; Rzepa, H. S. J. Chem. Soc., Perkin Trans. 2
1977, 281.
(15) Krolski, M. E.; Renaldo, A. F.; Rudisill, D. E.; Stille, J. K. J.
Org. Chem. 1988, 53, 1170.
2-(4-Pyridyl)-indole-6-carboxylic Acid (1d): (1.52 g, 64% yield).
1H NMR (400 MHz, DMSO-d6): d = 13.39 (s, 1 H), 8.88–8.86 (m,
Synlett 2004, No. 5, 883–885 © Thieme Stuttgart · New York