2418
Z. Zhang et al. / Tetrahedron Letters 48 (2007) 2415–2419
Pd-Ar
Ar
electrophilic
substitution
H
reductive
elimination
Pd
Pd-Ar
Ar-PdX
base
Ar
N
N
N
H
N
N
H
H
H
H
Scheme 3.
Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127,
13148–13149; (c) Lane, B. S.; Sames, D. Org. Lett. 2004, 6,
2897–2900; (d) Toure, B. B.; Lane, B. S.; Sames, D. Org.
Lett. 2006, 8, 1979–1982; (e) Lane, B. S.; Brown, M. A.;
Sames, D. J. Am. Chem. Soc. 2005, 127, 8050–8057.
The reactions of various substituted indoles with substi-
tuted bromobenzenes were also explored and the results
are shown in Table 3.10 It was found that either electron-
withdrawing substituted bromobenzenes (entries 2 and
3) or electron-donating substituted bromobenzenes
(entry 4) depressed the arylation. When methoxyl group
was introduced at 5-position of indole, the reaction
occurred in good yield (entry 5), while cyano and nitro
group were introduced at the same position, the reaction
was seriously retarded (entries 6 and 7). When 2-acetyl-
indole reacted with bromobenzene, no arylated product
was found possibly due to the steric effect (entry 8).
According to our findings, we proposed a possible
reaction mechanism in the C-3 arylation of indoles
(Scheme 3).
4. (a) Watanabe, M.; Yamamoto, T.; Nishiyama, M. Angew.
Chem., Int. Ed. 2000, 39, 2501–2504; (b) Lebedev, A. Y.;
Izmer, V. V.; Kazyul, D. N.; Beletskaya, I. P.; Vosko-
boynikov, A. Z. Org. Lett. 2002, 4, 623–626; (c) Wata-
nabe, M.; Nishiyama, M.; Yamamoto, T.; Koie, Y.
Tetrahedron Lett. 2000, 41, 481–483; (d) Old, D. W.;
Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 1403–
1406; (e) Kamikawa, K.; Kinoshita, S.; Matsuzaka, H.;
Uemura, M. Org. Lett. 2006, 8, 1097–1100.
5. Hoppe, H. H.; Kerkenaar, A.; Kaars Sijpesteijn, A.
Pesticide Biochem. Physiol. 1976, 6, 422–429.
6. (a) Verkade, P. E. Rec. Trav. Chim. 1946, 65, 921; (b)
Junjappa, H. Synthesis 1975, 798–800; (c) Penoni, A.;
Volkmann, J.; Nicholas, K. M. Org. Lett. 2002, 4, 699–
701.
7. (a) Uchiyama, M.; Koike, M.; Kameda, M.; Kondo, Y.;
Sakamoto, T. J. Am. Chem. Soc. 1996, 118, 8733–8734; (b)
Kawasaki, I.; Katsuma, H.; Nakayama, Y.; Yamashita,
M.; Ohta, S. Heterocycles 1998, 48, 1887–1901; (c) Akita,
Y.; Itagaki, Y.; Takizawa, S.; Ohta, A. Chem. Pharm. Bull.
1989, 37, 1477–1480; (d) Lane, B. S.; Brown, M. A.;
Sames, D. J. Am. Chem. Soc. 2005, 127, 8050–8057.
8. POPd catalysts are commercially available from Combi-
Phos Catalysts, Inc., Princeton, NJ 08542.
9. (a) Li, G. Y. J. Org. Chem. 2002, 67, 3643–3650; (b) Li, G.
Y. Angew. Chem., Int. Ed. 2001, 40, 1513–1516; (c)
Khanapure, S. P.; Garvey, D. S. Tetrahedron Lett. 2004,
45, 5283–5286; (d) Wolf, C.; Lerebours, R. J. Org. Chem.
2003, 68, 7077–7084; (e) Poondra, R. R.; Fischer, P. M.;
Turner, N. J. J. Org. Chem. 2004, 69, 6920–6922; (f) Miao,
G.; Ye, P.; Yu, L.; Baldino, C. M. J. Org. Chem. 2005, 70,
2332–2334; (g) Lerebours, R.; Camacho-Soto, A.; Wolf,
C. J. Org. Chem. 2005, 70, 8601–8604.
In conclusion, we have demonstrated that cross-cou-
pling of indoles with various aryl bromides proceeded
in moderate to good yields when the palladium–phosph-
inous acid complex POPd was used as the catalyst. The
direct arylation of an indole core would eliminate the
need to protect indole nitrogen atom or establish a reac-
tive functionality (cf., halogenation or stoichiometric
metalation) prior to C–C coupling, and would enable
the direct elaboration and expansion of the core motif.
The further application of this catalyst for the synthesis
of substituted indoles, mechanism study and scope and
limitation of this kind of reaction are currently under
investigation in our group.
Acknowledgements
This project was supported by the Natural Science
Foundation of Liaoning Education Department (Grant
No. 202193399). We would like to thank Dr. George Li,
at CombiPhos Catalysts, Inc., Princeton, NJ, for helpful
discussions regarding the use of POPd catalyst and Dr.
Jingbo Yan at AstraZeneca Pharmaceuticals, Wilming-
ton, DE for valuable suggestions.
10. Representative experimental procedure:
A mixture of
indole (58.6 mg, 0.500 mmol, 1.0 equiv), bromobenzene
(94.2 mg, 0.600 mmol, 1.2 equiv), potassium carbonate
(207.3 mg, 1.500 mmol, 3.0 equiv) and POPd (12.5 mg,
0.025 mmol, 5 mol %) was stirred and re-fluxed in 2 mL of
dioxane for 24 h. The reaction mixture was allowed to cool
to room temperature, quenched with water and extracted
with EtOAc. The combined organic layers were washed
with brine and dried over MgSO4, and the solvent was
removed under vacuum. The residue was purified by
chromatography on silica gel eluting with hexane/EtOAc
(15:1, v:v) to give white crystals 3a (69.1 mg, 71.5%). Mp
86.0–87.0 °C. (hexane) (lit.11 85.5–86 °C). 1H NMR
(500 MHz, CDCl3) d 8.24 (s, 1H), 7.97 (d, 1H, J =
8.1 Hz), 7.70 (d, 2H, J = 7.8 Hz), 7.47 (q, 3H), 7.40 (d, 1H,
J = 2.4 Hz), 7.32 (t, 1H, J = 7.6 Hz), 7.28 (t, 1H, J =
7.7 Hz), 7.22 (t, 1H, J = 7.5 Hz); 13C NMR (125 MHz,
CDCl3) d 136.7, 135.6, 128.8, 127.5, 126.0, 125.8, 122.5,
121.8, 120.4, 119.9, 118.4, 111.4; MS (m/z) 193.9 [M+H+].
Compound 3b: Light brown solid (48.0%), mp 142.5–
144.2 °C. 1H NMR (500 MHz, CDCl3) d 8.52 (s, 1H), 8.31
(d, 2H, J = 8.9 Hz), 7.97 (d, 1H, J = 8.0 Hz), 7.84 (d, 2H,
J = 8.8 Hz), 7.55 (s, 1H), 7.50 (d, 1H, J = 8.1 Hz), 7.31 (m,
References and notes
1. (a) Sundberg, R. J. Indoles (Best Synthetic Methods);
Academic: London, 1996; pp 1–6; (b) Katritzky, A. R.;
Pozharskii, A. F. Handbook of Heterocyclic Chemistry;
Pergamon: Oxford, 2000; Chapter 4.
2. (a) The Alkaloids Specialist Periodical Reports; The
Chemical Society: London, 1971; pp 150–200; (b) Saxton,
J. E. Nat. Prod. Rep. 1989, 6, 1–54; (c) Cordell, G. A.
Introduction to Alkaloids: A Biogenetic Approach; Wiley:
New York, 1981; pp 761–1055; (d) Pindur, U.; Adam, R.
J. Heterocycl. Chem. 1988, 25, 1–8.
3. (a) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S.
J. Am. Chem. Soc. 2006, 128, 4972–4973; (b) Bressy, C.;