Synthesis of N-substituted indole-3-carboxylic acid derivatives via Cu(I)-catalyzed intramolecular amination of aryl bromides

Article abstract of DOI:10.1021/jo800630v

(Chemical Equation Presented) A variety of N-alkylated and N-arylated derivatives of methyl 1H-indole-3-carboxylate were synthesized efficiently via Ullmann-type intramolecular arylamination, using the CuI-K₃PO ₄-DMF system. This cat

Full text of DOI:10.1021/jo800630v

convenient routes to indole derivatives.5 In the past decade, copper-
catalyzed C-N bond formation via coupling between amines or
amides with aryl halides has received significant attention and
provided a versatile method for the synthesis of a wide range of
arylamines.6 A number of useful synthetic protocols utilizing
various combinations of a copper source, a ligand, a base, and a
solvent have been developed to achieve a high efficiency of the
Ullmann-type amination reaction of various substrates under mild
conditions.7 On the other hand, intramolecular Ullmann coupling
reactions have remained less explored. To the best of our
knowledge, only a few examples of intramolecular copper-catalyzed
amination of aryl (or vinyl) halides have been reported, which led
to the formation of nitrogen heterocyclic compounds.8 Application
of the copper-catalyzed amination methodology for the construction
of the indole ring via a key N(1)-C(7a) bond formation9 has been
demonstrated by the synthesis of pyrazolo[1,5-a]indoles5b and
indole- and 6-azaindole-2-carboxylates.5f
Synthesis of N-Substituted Indole-3-carboxylic
Acid Derivatives via Cu(I)-Catalyzed
Intramolecular Amination of Aryl Bromides
Ferdinand S. Melkonyan, Alexander V. Karchava,* and
Marina A. Yurovskaya
Department of Chemistry, M.V. LomonosoV Moscow State
UniVersity, Moscow 119992, Russia
karchaVa@org.chem.msu.ru
ReceiVed March 19, 2008
Indole-3-carboxylic acids and the corresponding esters have
found significant use as building blocks for the synthesis of
pharmaceutically important molecules.10 A number of effective
means for the assembly of indole-3-carboxylic acid derivatives
have been developed, which include either the formation of the
A variety of N-alkylated and N-arylated derivatives of methyl
1H-indole-3-carboxylate were synthesized efficiently via
Ullmann-type intramolecular arylamination, using the
CuI-K3PO4-DMF system. This catalytic amination proce-
dure can be performed with good to high yields under mild
conditions under an air atmosphere.
(5) For recent reports, see: (a) Chen, Y.; Wang, Y.; Sun, Z.; Ma, D. Org.
Lett. 2008, 10, 625-628. (b) Zhu, Y.-M.; Qin, L.-N.; Liu, R.; Ji, S.-J.; Katayama,
H. Tetrahedron Lett. 2007, 48, 6262–6266. (c) Tanimori, S.; Ura, H.; Kirihata,
M. Eur. J. Org. Chem. 2007, 3977–3980. (d) van den Hoogenband, A.; Lange,
J. H. M.; den Hartog, J. A.; Henzen, R.; Terpstra, J. W. Tetrahedron Lett. 2007,
48, 4461–4465. (e) Ohno, H.; Ohta, Y.; Oishi, S.; Fudjii, N. Angew. Chem., Int.
Ed. 2007, 46, 2295–2298. (f) Barberris, C.; Gordon, D.; Thomas, C.; Zhang,
X.; Cusack, K. P. Tetrahedron Lett. 2005, 46, 8877–8880.
(6) For reviews, see: (a) Kienle, M.; Dubbaka, S. R.; Brade, K.; Knochel, P. Eur.
J. Org. Chem. 2007, 4166–4176. (b) Beletskaya, I. P.; Cheprakov, A. V. Coord.
Chem. ReV. 2004, 248, 2337–2364. (c) Ley, S. V.; Thomas, A. W. Angew. Chem.,
Int. Ed. 2003, 42, 5400–5449. (d) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003,
2428–2439. (e) Corbert, J.-P.; Mignani, G. Chem. ReV. 2006, 106, 2651–2710.
(7) Several supporting ligands have been introduced to achieve a high
efficiency of Ullmann coupling under mild reaction conditions, among them: (a)
N,N-Diethylsalicylamide: Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5,
793–796. (b) ꢀ-Diketone: Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006,
128, 8742–8743. (c) ꢀ-Keto ester: Lv, X.; Bao, W. J. Org. Chem. 2007, 72,
3863–3867. (d) 2-Hydroxybenzaldehyde N-phenylhydrazone: Jiang, Q.; Jiang,
D.; Jiang, Y.; Zhao, Y. Synlett 2007, 1836–1842. (e) N-Hydroxyimide: Ma, H.-
C.; Jiang, X.-Z. J. Org. Chem. 2007, 72, 8943–8946. (f) Hyppuric acid : Mao,
J.; Guo, J.; Song, H.; Ji, S.-J. Tetrahedron 2008, 64, 1383–1387. (g) Glyoxale
bis hydrazone: Mino, T.; Harada, Y.; Shindo, H.; Sakamoto, M.; Fujita, T. Synlett
2008, 614–620. (h) Amino acids: Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003,
5, 2453–2455. (i) Amino acids: Cai, Q.; Zhu, W.; Zhang, H.; Zhang, Y. D.; Ma,
D. W. Synthesis 2005, 496–499. (j) N,N-Dimethylaminoethanol: Twieg, H., Jr.;
R., J.; Lu, Z. K.; Huang, S. P. D. Tetrahedron Lett. 2003, 2453–2455. (k) Ethylene
glycol: Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581–
584. (l) 1,10-Phenantroline: Gujadhur, R. K.; Bates, C. G.; Venkataraman, D.
Org. Lett. 2001, 3, 4315–4317. (m) 8-Hydroxyquinoline : Liu, L.; Frohn, M.;
Domingueez, C.; Hungate, R.; Reider, P. J. J. Org. Chem. 2005, 70, 10135–
10138. (n) 1,2-Diamines : Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 7421–7428. (o) rac-1,1′-Binaphthol : Jiang, D.; Fu, H.; Jiang,
Y.; Zhao, Y. J. Org. Chem. 2007, 72, 672–674.
The indole nucleus is one of the most widely distributed
heterocyclic ring systems in nature.1 Also, the indole ring system
has become an important structural component in many synthetic
pharmaceuticals.2 As a result, a great number of various methods
for the preparation of indoles have been developed with use of
intermolecular and intramolecular approaches.3
Recent advances of transition metal chemistry in organic
synthesis have provided new versatile catalytic methodologies for
the synthesis of indoles from various arene derivatives via different
bond formation. Among transition metals, the most extensively
investigated and employed metal for the construction of the indole
ring system was palladium.4 However, recent considerable progress
in copper-catalyzed organic reactions has provided several new
(1) For selected recent reviews on indole-containing natural products, see:
(a) Huguchi, K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24, 843-868. (b) O’Connor,
S. E.; Maresh, J. Nat. Prod. Rep. 2006, 23, 532–547. (c) Kawasaki, T.; Huguchi,
K. Nat. Prod. Rep. 2005, 22, 761–793. (d) Gul, W.; Hamann, M. T. Life Sci.
2005, 78, 442–453. (e) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278–
311. (f) Lounasmaa, M.; Tolvanen, N. Nat. Prod. Rep. 2000, 17, 175–191.
(2) For selected recent reports, see: (a) Suzen, S. Top. Heterocycl. Chem.
(8) (a) Pyrroles: Pan, Y.; Lu, H.; Fang, Y.; Chen, L.; Qian, J.; Wang, J.; Li,
C. Synthesis 2007, 1242–1246. (b) Pyrrolo[2,3-c]pyridine, see ref 5f. (c) 1-Aryl-
1H-indazoles : Liu, R.; Zhu, Y.; Qin, L.; Ji, S. Synth. Commun. 2008, 38, 249–
254. (d) 2-Aryl-2H-indazoles : Liu, R.; Zhu, Y.; Qin, L.; Ji, S.; Katayama, H.
Heterocycles 2007, 71, 1755–1763. (e) Oxindoles: ref 5d. (f) ꢀ-Lactams: Lu,
H.; Li, C. Org. Lett. 2006, 8, 5365–5367. (g) Other lactams: Hu, T.; Li, C. Org.
Lett. 2005, 7, 2035–2038. (h) Indolines: Yamada, K.; Kubo, T.; Tokuyama, H.;
Fukuyama, T. Synlett 2002, 231–234. (i) 2-Aminobenzimidazoles: Evindar, G.;
Batey, R. A. Org. Lett. 2003, 5, 133–136.
¨
2007, 11, 145–178. (b) Olgen, S.; Kaessler, K.; Nebiog˘lu, D.; Joachim, J. Chem.
Biol. Drug Des. 2007, 70, 547–551. (c) Smart, B. P.; Oslund, R. S.; Walsh,
L. A.; Gelb, M. N. J. Med. Chem. 2006, 49, 2858–2860. (d) Dandia, A.; Singh,
N.; Khaturia, S.; Merienne, C.; Morgant, G.; Loupy, A. Bioorg. Med. Chem.
2006, 14, 2409–2417.
(3) For recent reviews on indole synthesis, see: (a) Gribble, G. W. J. Chem.
Soc., Perkin Trans. 1 2000, 1045–1075. (b) Hamphrey, G. R.; Kuethe, J. T.
Chem. ReV. 2006, 106, 2875–2911. (c) Gilchrist, T. L. J. Chem. Soc., Perkin
Trans. 1 2001, 2491–2515.
(9) For examples of related Pd-catalyzed N-anulation routes to indoles, see:
(a) Fletcher, A. J.; Bax, M. N.; Willis, M. C. Chem. Commun. 2007, 4764–
4766. (b) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem., Int. Ed.
2005, 44, 403–406. (c) Watanabe, M.; Yamamoto, T.; Nishiyama, M. A Angew.
Chem., Int. Ed. 2000, 39, 2501–2504.
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Chem. ReV. 2005, 105, 2873–2920. (b) Patil, S.; Buolamwini, J. K. Curr. Org.
Synth. 2006, 3, 477–498.
10.1021/jo800630v CCC: $40.75
Published on Web 05/10/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4275–4278 4275

SCHEME 1. Synthesis of N-Substituted Methyl
Indole-3-carboxylates via Cu(I)-Catalyzed Intramolecular
Amination of Aryl Bromides
indoles 2 in moderate to good yields. High yields with
quantitative conversion of starting materials were achieved with
unhindered amines (entries 2, 4, 13, 18, and 21). The reaction
seemed to be sensitive to the steric hindrance. R-Branched
alkylamines (entries 6, 10, and 14) and ortho-substituted anilines
(entries 17 and 19) required longer reaction times (9 h); however,
yields of 2 were moderate due to the transesterification with
ethylene glycol (entry 7). Applying the ligandless conditions C
resulted in the product formation in comparable yields for
slightly longer reaction times (entries 2 vs 3, 4 vs 5, 6 vs 8 and
21vs 22).
The formation of N-tert-butyl indole 2d under the C condi-
tions was found to be very problematic. After long reaction time
(20 h) the reaction of 1d was only 46% complete (determined
by 1HNMR) with the formation of the corresponding indole 2d
in 32% yield (entry 12). The cyclization of 1d was much slower
than the reaction of all other enamines 1.14 Another hindered
amine such as cyclohexylamine gave a similar result and the
corresponding indole was prepared by using the C conditions
in only 57% yield (entry 16). On the other hand, ortho-
substituted anilines such as o-toluidine and even more sterically
hindered 2,4,6-trimethylaniline under the ligandless conditions
gave the corresponding indoles in good yields (entries 17 and
19). It should be noted that the reaction of 2,4,6-trimethylaniline
with methyl 2-(2-bromophenyl)-2-formylacetate was much
slower (48 h) than the reaction of all over amines including
tert-butylamine (6 h). Moreover, the reaction of methyl 2-(2-
bromophenyl)-2-formylacetate with weakly nucleophilic anilines
such as 4-nitro- and 2-trifluoromethylanilines failed to give the
desired enamines 1, only starting materials were detected even
after refluxing a toluene solution for several hours. Thus, this
protocol seemed to be unsuitable for the preparation of 1-aryl-
1H-indole-3-carboxylic acid derivatives containing strong electron-
withdrawing substituents in ortho and para positions of the
phenyl ring.
indole ring system11 or the introduction of a substituent to the
nitrogen atom.12 All of these approaches cannot be regarded as
a general approach to both N-alkyl and N-aryl derivatives of
indole-3-carboxylic acid.
Herein, we wish to describe an efficient method for the
synthesis of N-substituted indole-3-carboxylic acid derivatives
via the copper(I)-catalyzed cyclization of N-substituted methyl
3-amino-2-(2-bromophenyl)acrylates 1. Substrates 1 are readily
achieved in nearly quantitative yields by the reaction of methyl
2-(2-bromophenyl)-2-formylacetate13 with various primary amines.
We first utilized N-benzyl derivative 1a (Scheme 1, R )
CH2Ph), as a mixture of cis and trans isomers, to examine the
possibility of indole ring formation via the Cu(I)-catalyzed
intramolecular amination reaction. In 2002, Buchwald and co-
workers reported an operationally simple CuI (5 mol %)-eth-
ylene glycol (2 equiv)-catalyzed amination of aryl iodides and
bromides.7k This amination protocol can be successfully per-
formed in unpurified 2-propanol as a solvent and K3PO4 (2
equiv) as a base even without protection from air or moisture.
These attractive reaction conditions (Table 1, A conditions) were
used to carry out the intramolecular amination reaction of
substrate 1a. It was found that the ring closure reaction
proceeded smoothly and gave a mixture of methyl 1-benzyl-
1H-indole-3-carboxylate (2a, R ) CH2Ph, Scheme 1) and
corresponding isopropyl ester 2a′ in 1:3 ratio and in 86% total
yield after 6 h at 75 °C (bath temperature). To avoid the
transesterification product we decided to investigate alternative
solvents. Only a trace amount, if any, of the product was
detected when the reaction was performed in dioxane, aceto-
nitrile, and tert-butyl alcohol. The best yield and a significant
rate enhancement were observed, however, if DMF was used
as the solvent (B conditions, 91% after 4 h at 75 °C).
In summary, we have shown a new efficient method to
produce N-substituted 1H-indole-3-carboxylic acid derivatives
via copper(I)-catalyzed intramolecular C-N bond formation.
Nonhindered primary alkyl and aryl amines can be involved in
the reaction under mild conditions. This protocol is simple and
avoids the use of an inert atmosphere without loss of yields.
This method is complementary to existing methods for the
construction of the indole ring.
Using the optimal reaction protocol we applied this meth-
odology to the synthesis of methyl 1H-indole-3-carboxylate with
various substituents at the nitrogen atom. As shown in Table 1,
both aliphatic and aromatic amines can be utilized in the
Cu(I)-ethylene glycol-catalyzed synthesis of a number of
Experimental Section
General Procedure. To a solution of methyl 2-(2-bromophenyl)-
2-formylacetate13 (500 mg, 1.94 mmol) in methanol (5 mL) was
added a corresponding amine (1.94 mmol) at room temperature.
After being stirred for 6 h at the same temperature solvent was
evaporated to dryness under reduced pressure. A crude product was
diluted with 8 mL of 2-propanol (Conditions A) or DMF
(Conditions B). CuI (19 mg, 0,194 mmol), anhydrous K3PO4 (0.826
g, 3.9 mmol), and ethylene glycol (241 µl, 3.9 mmol) were added.
The reaction mixture was heated at 75-80 °C (bath temperature)
for the time specified. The reaction mixture was allowed to cool to
room temperature. Solvent was evaporated to dryness under reduced
pressure. Water (8 mL) was added to the residue and the mixture
was extracted (3 × 4 mL) with ethyl acetate. The combined organic
layers were washed with brine and dried over sodium sulfate. The
solvent was removed in vacuo to yield the crude product that was
purified by column chromatography on silica gel, using a mixture
hexane/ethyl acetate (20/1) as eluent.
(10) For examples, see: (a) Reference 2b. (b) Hopkins, C. R.; Czekaj, M.;
Kaye, S. S.; Gao, Z.; Pribish, J.; Pauls, H.; Liang, G.; Sides, K.; Cramer, D.;
Cairns, J.; Luo, Y.; Lim, H.-K.; Vaz, R.; Rebello, S.; Maignan, S.; Dupuy, A.;
Mathieu, M.; Levell, J. Bioorg. Med. Chem. Lett. 2005, 15, 2734–2737. (c)
So¨derberg, B. C. G.; Banini, S. R.; Turner, M. R.; Minter, A. R.; Arrington,
A. K. Synthesis 2008, 903–912, and references therein.
(11) For recent reports on the synthesis of indole-3-carboxylic acid deriva-
tives, see: (a) Reference 10c. (b) Sole, D.; Serrano, O. J. Org. Chem. 2008, 73,
2476–2479.
(12) For an example of copper-catalyzed N-arylation of methyl indole-3-
carboxylate, see: Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 11684–11688.
(13) Beautement, K.; Clough, J. M.; Godfrey, C. R. A. EP. Patent 0307101.
1989. Chem. Abstr. 1989, 111. 114868.
(14) This result is consistent with the literature report on the preparation of
N-tert-butyloxindole derivatives via Cu(I)-catalyzed intramolecular amidation,
see ref 5d.
4276 J. Org. Chem. Vol. 73, No. 11, 2008

TABLE 1. Synthesis of N-Substituted Methyl Indole-3-carboxylates via Cu(I)-Catalyzed Intramolecular Amination of Aryl Bromides
a Conditions: (A) 5 mol % CuI, 2 equiv K3PO4, 2 equiv ethylene glycol, 2-propanol, 75 °C. (B) 5 mol % CuI, 2 equiv K3PO4, 2 equiv ethylene
glycol, DMF, 75 °C. (C) 5 mol % CuI, 2 equiv K3PO4, DMF, 75 °C. b All yields refer to isolated products. c Corresponding isopropyl ester was also
obtained in 64% yield. d Performed under argon. e Corresponding ester of ethylene glycol was obtained in 45% yield (determined by 1HNMR). f Yield
1
was determined by H NMR.
Conditions C. ethylene glycol was not used.
The general procedure was followed to afford the following
compounds:
121.7, 122.1, 122.8, 125.9, 126.9, 127.9, 129.0, 131.7, 136.7, 141.3,
165.6. MS, m/z (%) 279 (M+, 33), 175 (27), 144 (22), 105 (100),
77 (18), 51 (8). Anal. Calcd for C18H17NO2: C, 77.40; H, 6.13.
Found: C, 77.44; H, 6.15.
Methyl 1-tert-Butyl-1H-indole-3-carboxylate (2d). Yield 0.114
g (32%, conditions C), pale-yellow oil. 1H NMR (400 MHz, CDCl3)
δ 1.76 (s, 9H), 3.92 (s, 3H), 7.22-7.31 (m, 2H), 7.68 (dd, J ) 6.1,
2.6 Hz, 1H), 8.03 (s, 1H), 8.26 (dd, J ) 5.5, 3.08 Hz, 1H).13C
NMR (100 MHz, CDCl3) δ 29.6, 50.9, 57.0, 105.8, 113.9, 121.4,
121.9, 122.0, 129.1, 132.3, 133.0, 165.7. MS, m/z (%) 231 (M+,
45), 175 (66), 144 (100), 130 (5), 116 (22), 103 (7), 89 (27), 84
(8), 75 (11), 63 (16), 57 (66), 41 (75). Anal. Calcd for C14H17NO2:
C, 72.70; H, 7.41. Found: C, 72.71; H, 7.38.
Methyl 1-(2-phenylethyl)-1H-indole-3-carboxylate (2b). Yield
0.434 g (80%, conditions B), pale-yellow amorphous solid. 1H NMR
(400 MHz, CDCl3) δ 3.13 (t, J ) 7.5 Hz, 2H), 3.88 (s, 3H), 4.36
(t, J ) 7.5 Hz, 2H), 7.05-7.07 (m, 2H), 7.22-7.39 (m, 8H), 7.65
(s, 1H), 8.17 (dd, J ) 6.0, 3.3 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 36.4, 48.7, 51.0, 106.9, 109.9, 121.8, 121.9, 122.8, 126.7,
127.0, 128.7, 128.8, 134.3, 136.3, 137.7, 165.5. MS, m/z (%) 279
(M+, 26), 188 (100), 174 (9), 135 (15), 128 (16), 104 (24), 91 (38),
77 (21), 65 (14), 59 (8), 51 (15), 43 (39). Anal. Calcd for
C18H17NO2: C, 77.40; H, 6.13. Found: C, 77.38; H, 6.09.
(S)-Methyl 1-(1-Phenylethyl)-1H-indole-3-carboxylate (2c).
Yield 0.367 g (68%, conditions C), pale-yellow amorphous solid.
Methyl 1-Cyclopropyl-1H-indole-3-carboxylate (2e). Yield
1
0.328 g (78%, conditions B), tan amorphous solid. H NMR (400
(S)-(-)-1-Phenylethylamine ([R]20 -31.8 (neat), 80% ee) was
MHz, CDCl3) δ 1.02-1.21 (m, 4H), 3.39-3.47 (m, 1H), 3.92 (s,
3H), 7.25-7.36 (m, 2H), 7.61 (dd, J ) 6.5, 3.3 Hz, 1H), 7.87 (s,
1H), 8.17 (dd, J ) 6.4, 1.9 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ 6.2, 27.6, 51.0, 107.0, 110.8, 121.7, 122.2, 122.8, 126.7, 134.5,
137.9, 165.5. MS, m/z (%) 215 (M+, 60), 200 (29), 184 (70), 156
D
used. [R]23 +120.63 (c 11.06, EtOAc). 1H NMR (400 MHz,
D
CDCl3) δ 1.93 (d, J ) 7.5 Hz, 3H), 3.92 (s, 3H), 5.66 (q, J ) 7.5
Hz, 1H), 7.10-7.33 (m, 8H), 8.03 (s, 1H), 8.18 (d, J ) 8.2 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ 21.8, 51.0, 55.7, 107.4, 110.7,
J. Org. Chem. Vol. 73, No. 11, 2008 4277

(100), 143 (17), 128 (45), 115 (40), 101 (31), 89 (27), 75 (45), 63
(35), 59 (10), 51 (39), 39 (85). Anal. Calcd for C13H13NO2: C, 72.54;
H, 6.09. Found: C, 72.57; H, 6.12.
8.01 (s, 1H), 8.25 (d, J ) 7.5 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ 51.2, 110.1, 110.6, 121.6 (q, JC-F ) 3.7), 122.1, 122.9, 123.5 (q,
JC-F ) 273.2 Hz) 123.9, 124.4 (q, JC-F ) 3.7 Hz), 127.0 (br),
127.9, 130.6, 132.5 (q, JC-F ) 33.1 Hz), 133.6, 136.4, 139.1 (br),
165.1. MS, m/z (%) 319 (M+, 69), 288 (100), 233 (12), 191 (22),
145 (20), 125 (6), 115 (11), 95 (14), 89 (22), 75 (26), 69 (16), 63
(27), 50 (17), 39 (16). Anal. Calcd for C17H12F3NO2: C, 63.95; H,
3.79. Found: C, 63.91; H, 3.82.
Methyl 1-Cyclohexyl-1H-indole-3-carboxylate (2f). Yield 0.284
g (57%, conditions C), pale-yellow oil. 1H NMR (CDCl3) δ
1.16-1.34 (m, 2H), 1.39-1.55 (m, 2H), 1.59-1,75 (m, 2H),
1.85-1.97 (m, 2H), 2.08-2.19 (m, 2H), 3,95 (s, 3H), 4.14-4.26
(m, 1H), 7.25-7.34 (m, 2H), 7.59 (d, J ) 8.0 Hz, 1H), 7.94 (s,
1H), 8.18 (dd, J ) 6, 3.2 Hz, 1H). 13C NMR (CDCl3) δ 25.5, 25.8,
33.4, 50.9, 52,2, 106.9, 110.1, 121.8, 121.9, 122.5, 125.0, 132.8,
134.2, 165.7. MS, m/z (%) 257 (M+, 64), 226 (10), 175 (46), 170
(15), 154 (15), 149 (21), 144 (100), 130 (11), 115 (30), 103 (7), 89
(35), 83 (19), 75 (12), 63 (20), 59 (17), 55 (70), 51 (15), 41 (75).
Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44. Found: C, 74.71;
H, 7.47.
Methyl 1-(2-Methylphenyl)-1H-indole-3-carboxylate (2g).
Yield 0.336 g (65%, conditions C), pale-yellow amorphous solid.
1H NMR (400 MHz, CDCl3) δ 2.03 (s, 3H), 3.92 (s, 3H), 7.00 (d,
J ) 8.2 Hz, 1H), 7.17-7.44 (m, 6H), 7.86 (s, 1H), 8.24 (d, J )
7.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 17.5, 51.1, 108.4,
111.1, 121.6, 122.2, 123.3, 126.1, 127.1, 127.9, 129.2, 131.4, 134.8,
135.6, 137.0, 137.7, 165.6. MS, m/z (%) 265 (M+, 66), 234 (70),
204 (45), 191 (8), 178 (16), 143 (8), 133 (7), 115 (32), 106 (7),
102 (42), 95 (9), 91 (67), 77 (40), 65 (100), 51 (77), 39 (97). Anal.
Calcd for C17H15NO2: C, 76.96; H, 5.70. Found: C, 77.01; H, 5.67.
Methyl 1-(3-(Trifluoromethyl)phenyl)-1H-indole-3-carboxy-
late (2h). Yield 0.460 g (74%, conditions B), tan solid. Mp
129-131 °C (hexane). 1H NMR (400 MHz, CDCl3) δ 3.94 (s, 3H),
7.22-7.37 (m, 2H), 7.46 (d, J ) 8.2 Hz, 1H), 7.65-7.80 (m, 4H),
Methyl 1-(2,4,6-Trimethylphenyl)-1H-indole-3-carboxylate
(2i). Yield 0.438 g (77%, conditions B), tan solid. Mp 113-115
°C (hexane). 1H NMR (400 MHz, CDCl3) δ 1.92 (s, 6H), 2.41 (s,
3H), 3,98 (s, 3H), 6.93 (d, J ) 7.7 Hz, 1H), 7.05 (s, 1H), 7.24 (t,
J ) 7.9 Hz, 1H), 7.33 (t, J ) 7.9 Hz, 1H), 7.81 (s, 1H), 8.29 (d,
J ) 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 17.3, 21.1, 51.1,
108.4, 110.7, 121.6, 122,2, 123.3, 126.1, 129.2, 133.4. 134.7, 136.4,
137.1, 139.0, 165.7. MS, m/z (%) 293 (M+, 44), 262 (36), 234 (34),
218 (46), 204 (23), 143 (24), 130 (14), 124 (35), 115 (74), 109
(40), 102 (34), 95 (23), 91 (80), 77 (84), 63 (55), 51 (67), 45 (7),
39 (100). Anal. Calcd for C19H19NO2: C, 77.79; H, 6.53. Found:
C, 77.75; H, 6.52.
Supporting Information Available: Experimental proce-
dures for starting materials, full characterization data for
previously known compounds, and copies of 1H, 13C, and mass
spectra for all compounds prepared. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO800630V
4278 J. Org. Chem. Vol. 73, No. 11, 2008