One-Pot Synthesis of r-Carbolines via Sequential
Palladium-Catalyzed Aryl Amination and
Intramolecular Arylation
Joydev K. Laha, Philip Petrou, and Gregory D. Cuny*
Laboratory for Drug DiscoVery in Neurodegeneration,
HarVard NeuroDiscoVery Center, Brigham & Women’s
Hospital and HarVard Medical School, 65 Landsdowne
Street, Cambridge, Massachusetts 02139
FIGURE 1. Natural products that contain an R-carboline core.
The modified Graebe-Ullmann reaction of triazoles,5 in-
tramolecular Diels-Alder reactions,6 and cyclizations of aza-
indoles7 have been utilized to synthesize R-carbolines (1a). In
many cases, these multistep processes result in poor overall
yields of the R-carbolines and often suffer from limited
accessibility of starting materials. In addition, many of these
methods are capable of yielding products with only limited
substitution patterns. Other methods that involve either annu-
lation of the pyridine ring onto indole derivatives8 or by
formation of the pyrrole ring via intramolecular cyclization of
appropriately substituted N-phenyl-2-pyridinamines or 3-phe-
nylpyridines have also been reported.9
ReceiVed December 19, 2008
More recently, palladium-catalyzed one-pot syntheses of
N-substituted carbazoles (1b) have been described that utilize
either a domino Suzuki cross-coupling/SNAr reaction of aniline-
derived boronic esters with electron-deficient 2-fluoro-3-ha-
lobenzene10 or reaction between N-phenylanilines and 2,3-
dichlorobenzene (Scheme 1, Route A, Y ) CH).11 However,
only two examples of N-substituted R-carbolines and no
(5) (a) Lawson, W.; Perkin, W. H.; Robinson, R. J. Chem. Soc. 1924, 125,
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Chermann, J.-C. Tetrahedron 1981, 37, 2097–2103. (c) Kaczmarek, L.; Balicki,
R.; Nantka-Namirski, P.; Peczynska-Czoch, W.; Mordarski, M. Arch. Pharm.
1988, 321, 463–467. (d) Mehta, L. K.; Parrick, J.; Payne, F. J. Chem. Soc.,
Perkin Trans. 1 1993, 1261–1267. (e) Peczyn´ska-Czoch, W.; Pognan, F.;
Kaczmarek, L.; Boratyn´ski, J. J. Med. Chem. 1994, 37, 3503–3510. (f)
Kaczmarek, L.; Peczynka-Czoch, W.; Osiadacz, J.; Mordarski, M.; Sokalski,
W. A.; Boratynski, J.; Marcinkovska, E.; Glazman-Kusnierczyk, H.; Radzikowski,
C. Bioorg. Med. Chem. 1999, 7, 2457–2464. (g) Vera-Luque, P.; Alajar´ın, R.;
Alvarez-Builla, J.; Vaquero, J. J. Org. Lett. 2006, 8, 415–418. (h) Schneider,
C.; Gueyrard, D.; Popowycz, F.; Joseph, B.; Goekjian, P. G. Synlett 2007, 2237–
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(6) (a) Tahri, A.; Buysens, K. J.; Van der Eycken, E. V.; Vandenberghe,
D. M.; Hoonaert, G. J. Tetrahedron 1998, 54, 13211–13226. (b) Molina, P.;
Alajar´ın, M.; Vidal, A.; Sa´nchez-Andranda, P. J. Org. Chem. 1992, 57, 929–
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B. Bioorg. Med. Chem. 2007, 15, 5615–5619.
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(b) Yamazaki, T.; Matoba, K.; Imoto, S.; Terashima, M. Chem. Pharm. Bull.
1976, 24, 3011–3018. (c) Molina, P.; Fresneda, P. M. Synthesis 1989, 878–880.
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1 1992, 275–281. (e) Erba, E.; Gelmi, M. L.; Pocar, D. Tetrahedron 2000, 56,
9991–9997. (f) Beccalli, E. M.; Clerici, F.; Marchesini, A. Tetrahedron 2001,
57, 4787–4792. (g) Ono, A.; Narasaka, K. Chem. Lett. 2001, 146–147. (h) Tanaka,
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2127–2130. (c) Iwaki, T.; Yashuara, A.; Sakamoto, T. J. Chem. Soc., Perkin
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A one-pot synthesis of R-carbolines via a palladium-catalyzed
aryl amination followed by intramolecular arylation is
described. 2,3-Dichloro- and 2,3-dibromopyridines have been
shown to react with readily available anilines to obtain
various substituted R-carbolines in moderate to excellent
yields.
Several natural products have been isolated that contain a
pyrido[2,3-b]indole (R-carboline, 1a) including mescengricin
(2),1 an inhibitor of L-glutamate excitotoxicity in neurons, and
the marine cytotoxic agents grossularine-1 (3a) and grossu-
larine-2 (3b) (Figure 1).2 Interestingly, R-carboline byproduct
has also been detected from the combustion of protein-
containing foods and tobacco.3 Furthermore, synthetic R-car-
bolines have demonstrated an array of biological properties,
including anxiolytic, anti-inflammatory, and central nervous
system stimulating activities.4
(1) Kim, J.-S.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. Tetrahedron
Lett. 1997, 38, 3431–3434.
(2) Moquin-Patey, C.; Guyot, M. Tetrahedron 1989, 45, 3445–3450.
(3) (a) Ioshida, D.; Matsumoto, T.; Yoshimura, R.; Matsuzaki, T. Biochem.
Biophys. Res. Commun. 1978, 83, 915–920. (b) Ioshida, D.; Matsumoto, T.
Cancer Lett. 1980, 10, 141–149.
(4) (a) Paolini, L. Sci. Rep. Ist. Super. Sanita 1961, 1, 86. (b) Okamoto, T.;
Akase, T.; Izumi, S.; Inaba, S.; Yamamoto, H. Japanese Patent 7220196, 1972;
Chem. Abstr. 1972, 77, 152142. (c) Winters, J.; Di Mola, N. West German Patent
2442513, 1975; Chem. Abstr. 1975, 82, 156255.
3152 J. Org. Chem. 2009, 74, 3152–3155
10.1021/jo802776m CCC: $40.75 2009 American Chemical Society
Published on Web 03/26/2009