Palladium-catalyzed direct synthesis of carbazoles via one-pot N-arylation and oxidative biaryl coupling: Synthesis and mechanistic study

Article abstract of DOI:10.1021/jo9003376

(Chemical Equation Presented) An efficient catalytic system has been developed for the synthesis of carbazoles by one-pot N-arylation and oxidative biaryl coupling. A significant substituent effect of the diarylamine intermediate on oxidative coupling was observed. Mechanistic studies of oxidative coupling, including trapping of reaction intermediates and kinetic isotope effect experiments, are also presented.

Full text of DOI:10.1021/jo9003376

Palladium-Catalyzed Direct Synthesis of Carbazoles via One-Pot
N-Arylation and Oxidative Biaryl Coupling: Synthesis and
Mechanistic Study
Toshiaki Watanabe, Shinya Oishi, Nobutaka Fujii,* and Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Sakyo-ku, Kyoto 606-8501, Japan
hohno@pharm.kyoto-u.ac.jp; nfujii@pharm.kyoto-u.ac.jp
ReceiVed February 18, 2009
An efficient catalytic system has been developed for the synthesis of carbazoles by one-pot N-arylation
and oxidative biaryl coupling. A significant substituent effect of the diarylamine intermediate on oxidative
coupling was observed. Mechanistic studies of oxidative coupling, including trapping of reaction
intermediates and kinetic isotope effect experiments, are also presented.
SCHEME 1. Synthesis of Carbazole by
Palladium-Catalyzed C-H Activation
Introduction
Nitrogen heterocycles are found in many biologically active
compounds and also useful as drug-like templates. Carbazoles
have various biological activities (e.g., antibacterial, anti-
inflammatory, antitumor).1 They also exhibit useful properties
as organic materials, such as hole-transporting, photoconductive
effects, and photorefractive effects.2 Developing a reliable
methodology to obtain carbazoles with multiple functionalities
in a single step is desirable because most methods of synthesiz-
ing carbazoles require several steps.3 In view of synthesizing
carbazoles in an atom-economical manner, we focused on one-
pot synthesis of carbazoles through a palladium-catalyzed C-H
arylation reaction.4-6
of carbazoles (eq 1, Scheme 1).7 The oxidative biaryl coupling
reaction, originally reported by Yoshimoto8 and Åkemark9a
using palladium(II) (eq 2, Scheme 1), can be an atom-
economical approach to carbazoles, particularly if the reaction
proceeds catalytically.10-12 As related reactions to eq 1, Scheme
Palladium-catalyzed intramolecular C-H arylation of N-phenyl-
2-haloaniline derivatives is a useful method for the synthesis
(5) For some recent examples, see: (a) Grigg, R.; Savic, V.; Tambyrajah, V.
Tetrahedron Lett. 2000, 41, 3003–3006. (b) Terao, Y.; Wakui, H.; Satoh, T.; Miura,
M.; Nomura, M. J. Am. Chem. Soc. 2001, 123, 10407–10408. (c) Hughes, C. C.;
Trauner, D. Angew. Chem., Int. Ed. 2002, 41, 1569–1572. (d) Campo, M. A.; Larock,
R. C. J. Am. Chem. Soc. 2002, 124, 14326–14327. (e) Hennessy, E. J.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 12084–12085. (f) Campeau, L.-C.; Parisien,
M.; Leblanc, M.; Fagnou, K. J. Am. Chem. Soc. 2004, 126, 9186–9187. (g) Cuny,
G.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2004, 126, 14475–14484. (h)
Ferraccioli, R.; Carenzi, D.; Rombola`, O.; Catellani, M. Org. Lett. 2004, 6, 4759–
4762. (i) Abe, H.; Nishioka, K.; Takeda, S.; Arai, M.; Takeuchi, Y.; Harayama, T.
Tetrahedron Lett. 2005, 46, 3197–3200. (j) Lafrance, M.; Rowley, C. N.; Woo,
T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754–8756.
(6) For our related work, see: (a) Ohno, H.; Miyamura, K.; Takeoka, Y.;
Tanaka, T. Angew. Chem., Int. Ed. 2003, 42, 2647–2650. (b) Ohno, H.;
Yamamoto, M.; Iuchi, M.; Tanaka, T. Angew. Chem., Int. Ed. 2005, 44, 5103–
5106. (c) Ohno, H.; Miyamura, K.; Mizutani, T.; Kadoh, Y.; Takeoka, Y.;
Hamaguchi, H.; Tanaka, T. Chem.sEur. J. 2005, 11, 3728–3741. (d) Watanabe,
T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2007, 9, 4821–4824. (e) Ohno, H.;
Iuchi, M.; Fujii, N.; Tanaka, T. Org. Lett. 2007, 9, 4813–4815. (f) Watanabe,
T.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 1759–1762.
(1) (a) Chakraborty, D. P. Alkaloids 1993, 44, 257–364. (b) Chakraborty,
¨
D. P.; Roy, R. S. Prog. Chem. Org. Nat. Prod. 1991, 57, 71–152. (c) Stolc, S.
Life Sci. 1999, 65, 1943–1950. (d) Tachibana, Y.; Kikuzaki, H.; Lajis, N. H.;
Nakatani, N. J. Agric. Food Chem. 2001, 49, 5589–5594.
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(b) D´ıaz, J. L.; Dobarro, A.; Villacampa, B.; Velasco, D. Chem. Mater. 2001,
13, 2528–2536. (c) Thomas, K. R. J.; Lin, J. T.; Tao, Y.-T.; Ko, C.-W. J. Am.
Chem. Soc. 2001, 123, 9404–9411. (d) Grazulevicius, J. V.; Strohriegl, P.;
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(4) For pioneering works, see: (a) Ames, D. E.; Bull, D. Tetrahedron 1982,
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4720 J. Org. Chem. 2009, 74, 4720–4726
10.1021/jo9003376 CCC: $40.75  2009 American Chemical Society
Published on Web 06/02/2009

Palladium-Catalyzed Direct Synthesis of Carbazoles
SCHEME 2. One-Pot Synthesis of Carbazoles by
N-Arylation and Oxidative Biaryl Coupling
1, direct syntheses of carbazoles by cascade Buchwald-Hartwig
N-arylation-C-H arylation using o-haloanilines/halobenzenes13
and anilines/o-dihalobenzenes14 were recently reported. These
contributions prompted us to develop a more atom-economical,
direct synthetic method of carbazoles. We present the full
account of our palladium-catalyzed carbazole synthesis by direct
coupling of aryl triflates and anilines through one-pot N-
arylation15 and oxidative biaryl coupling reaction in the presence
of a common palladium catalyst and molecular oxygen or air
(Scheme 2).16 Some mechanistic considerations regarding the
oxidative coupling shown in eq 2, Scheme 1, are also discussed.
Results and Discussion
reaction, whereas the commonly used solvents for the N-
arylation reaction (toluene, dioxane, DMF) were ineffective.16,17
Carbazole formation was therefore carried out in a mixed solvent
containing acetic acid, which was added after N-arylation in
toluene. We chose the triflate as a leaving group for N-arylation
because a halide anion in the reaction vessel poisons the
palladium catalyst in the oxidative coupling reaction.10b,18,19
Results of the direct synthesis of carbazoles with phenyl triflates
and anilines are summarized in Table 1.
Synthesis of Various Carbazoles by One-Pot N-Arylation
and Oxidative Biaryl Coupling. Our preliminary investigation
revealed that acetic acid or a mixed solvent containing acetic
acid were the solvents of choice for the oxidative biaryl coupling
(7) (a) Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans.
1 1999, 1505–1510. (b) Campeau, L.-C.; Thansandote, P.; Fagnou, K. Org. Lett.
2005, 7, 1857–1860. (c) Parisien, M.; Valette, D.; Fagnou, K. J. Org. Chem.
2005, 70, 7578–7584. (d) Leclerc, J.-P.; Andre´, M.; Fagnou, K. J. Org. Chem.
2006, 71, 1711–1714. (e) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K.
J. Am. Chem. Soc. 2006, 128, 581–590. (f) Liu, Z.; Larock, R. C. Tetrahedron
2007, 63, 347–355.
After the N-arylation of aniline 2a with phenyl triflate 1a
under the Buchwald-Hartwig conditions was completed (moni-
tored by TLC), acetic acid was added and the reaction mixture
subjected to an oxygen atmosphere to afford the desired
carbazole 5aa in 69% yield (Table 1, entry 1).20 Air proved to
be a good co-oxidant and 5aa was obtained in 67% yield,
although a slightly longer reaction time was required (entry 2).
We next examined the reaction of various triflates and anilines
under oxygen conditions. The reaction of phenyl triflates 1b-d
bearing an electron-donating group at the para position resulted
in low yields of the carbazoles 5ba-da due to their instability
under the reaction conditions (entries 3-5).21 The reaction of
triflates 1e-i with an electron-withdrawing group at the para
position resulted in better yields of carbazoles (50-74%, entries
6-10) than those of the electron-rich triflates 1b-d. When using
meta-substituted phenyl triflates 1j-m, the biaryl coupling
reaction selectively proceeded at the less hindered position of
the triflates, leading to 2-substituted carbazoles 5ja-ma (entries
11-15). The electron-deficient triflate 1m gave poor results
(34%, entry 15) in contrast with the reaction of the para-
substituted electron-deficient triflates 1e-i (entries 6-10). By
using air in place of oxygen as the co-oxidant, the desired
carbazole 5ja was obtained in 82% yield (entry 12). The reaction
of the ortho-substituted triflates 1n and 1o led to the desired
carbazoles 5na and 5oa in only 20% and 27% yields, presum-
ably due to steric hindrance as well as fewer reactive carbons
in the cyclization step (entries 16 and 17).12c Introduction of a
substituent to aniline such as the trifluoromethyl group, the
methoxycarbonyl group, and the phenyl group was tolerated
(entries 18-20). Regioisomeric trifluoromethylated diphenyl-
(8) For pioneering work for oxidative biaryl coupling mediated by palladium,
see: Yoshimoto, H.; Itatani, H. Bull. Chem. Soc. Jpn. 1973, 46, 2490–2492.
(9) For stoichiometric reactions, see: (a) Åkermark, B.; Eberson, L.; Jonsson,
E.; Pettersson, E. J. Org. Chem. 1975, 40, 1365–1367. (b) Miller, R. B.; Moock,
T. Tetrahedron Lett. 1980, 21, 3319–3322. (c) Hall, R. J.; Marchant, J.; Oliveira-
Campos, A. M. F.; Queiroz, M.-J. R. P.; Shannon, P. V. R. J. Chem. Soc., Perkin
Trans. 1 1992, 3439–3450. (d) Kno¨lker, H.-J.; O’Sullivan, N. Tetrahedron Lett.
1994, 35, 1695–1698. (e) Ferreira, I. C. F. R.; Queiroz, M.-J. R. P.; Kirsch, G.
Tetrahedron 2002, 58, 7943–7949. (f) Kno¨lker, H.-J.; Kno¨ll, J. Chem. Commun.
2003, 1170–1171. (g) Kno¨ll, J.; Kno¨lker, H.-J. Synlett 2006, 651–653. (h)
Sridharan, V.; Mart´ın, M. A.; Mene´ndez, J. C. Synlett 2006, 2375–2378. (i)
Bernal, P.; Benavides, A.; Bautista, R.; Tamariz, J. Synthesis 2007, 1943–1948.
(10) For catalytic synthesis, see: (a) Åkermark, B.; Oslob, J. D.; Heuschert,
U. Tetrahedron Lett. 1995, 36, 1325–1326. (b) Hagelin, H.; Oslob, J. D.;
Åkermark, B. Chem.sEur. J. 1999, 5, 2413–2416. (c) Lie´gault, B.; Lee, D.;
Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org. Chem. 2008, 73, 5022–5028.
(11) For catalytic synthesis of carbazolequinone derivatives, see: (a) Kno¨lker,
H.-J.; O’Sullivan, N. Tetrahedron 1994, 50, 10893–10908. (b) Kno¨lker, H.-J.;
Fro¨hner, W. J. Chem. Soc., Perkin Trans. 1998, 1, 173–175. (c) Kno¨lker, H.-J.;
Reddy, K. R.; Wagner, A. Tetrahedron Lett. 1998, 39, 8267–8270. For related
oxidative carbazole syntheses, see: (d) Matsubara, S.; Asano, K.; Kajita, Y.;
Yamamoto, M. Synthesis 2007, 2055–2059. (e) Tsang, W. C. P.; Munday, R. H.;
Brasche, G.; Zheng, N.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7603–7610.
For a related carbazole synthesis, see: (f) Jordan-Hore, J. A.; Johansson, C. C. C.;
Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184–
16186.
(12) For related palladium-catalyzed or -mediated oxidative C-H function-
alization, see: (a) Fujiwara, Y.; Asano, R.; Moritani, I.; Teranishi, S. J. Org.
Chem. 1976, 41, 1681–1683. (b) Iida, H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem.
1980, 45, 2938–2942. (c) Jia, C.; Lu, W.; Kitamura, T.; Fujiwara, Y. Org. Lett.
1999, 1, 2097–2100. (d) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries,
A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am.
Chem. Soc. 2002, 124, 1586–1587. (e) Hull, K. L.; Lanni, E. L.; Sanford, M. S.
J. Am. Chem. Soc. 2006, 128, 14047–14049. (f) Ferreira, E. M.; Zhang, H.;
Stoltz, B. M. Tetrahedron 2008, 64, 5987–6001. For a review, see: (g) Beccalli,
E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. ReV. 2007, 107,
5318–5365.
(13) (a) Bedford, R. B.; Cazin, C. S. J. Chem. Commun. 2002, 2310–2311.
(b) Bedford, R. B.; Betham, M. J. Org. Chem. 2006, 71, 9403–9410. (c) Bedford,
R. B.; Betham, M.; Charmant, J. P. H.; Weeks, A. L. Tetrahedron 2008, 64,
6038–6050. (d) Della Ca’, N.; Sassi, G.; Catellani, M. AdV. Synth. Catal. 2008,
350, 2179–2182.
(14) Ackermann, L.; Althammer, A. Angew. Chem., Int. Ed. 2007, 46, 1627–
1629.
(17) Quite recently, it has been reported that pivalic acid works well as the
reaction solvent for oxidative biaryl coupling, see ref 10c.
(18) Indeed, the treatment of diphenylamine in AcOH under oxygen
atomosphere with palladium dichloride or palladium acetate/tetrabutylammonium
bromide led to recovery of the starting material.
(19) Ligand screening for N-arylation is given in the Supporting Information.
(20) When N-methyl anisidine was used, the corresponding N-methyl
carbazole was obtained in ca. 7% yield. In this case, demethylated carbazole
was formed in ca. 3% yield as a byproduct under the oxidative coupling process.
Use of N-phenylaniline (diphenylamine) in place of aniline was ineffective in
the oxidative coupling step after N-arylation.
(15) (a) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116, 5969–
5970. (b) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 7901–
7902. (c) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046–2067. (d) Hartwig,
J. F. Pure Appl. Chem. 1999, 71, 1417–1423. (e) Yang, B. H.; Buchwald, S. L.
J. Organomet. Chem. 1999, 576, 125–146. (f) Wolfe, J. P.; Tomori, H.; Sadighi,
J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158–1174.
(16) A portion of this study was already reported in
a preliminary
communication: Watanabe, T.; Ueda, S.; Inuki, S.; Oishi, S.; Fujii, N.; Ohno,
H. Chem. Commun. 2007, 4516–4518.
(21) High reactivity of electron-rich carbazoles was described in ref 10c.
J. Org. Chem. Vol. 74, No. 13, 2009 4721

Watanabe et al.
TABLE 1. Synthesis of Monosubstituted Carbazolesa
FIGURE 1. Electronic state in the C-H activation site.
of type A (Figure 1), having an electron-withdrawing group at
the meta position, to palladium(II) was remarkably low (entry
15), whereas diarylamines having an electron-withdrawing group
at the para position gave moderate-to-good results (50-74%,
entries 6-8).23 These results can be attributed to the electron
density of the C-H activation site; more direct influence of
the electron-withdrawing group at the meta position would
reduce the electron density of the reaction site as shown in A,
thereby lowering the reactivity of A toward the electron-deficient
palladium(II). The higher reactivity of diarylamine of type B
bearing an electron-donating group at the meta position can be
explained by the higher electron density at the C-H activation
site compared with the ortho- or para-substituted ones (entries
3, 11, and 16).
We next examined the one-pot reaction using a combination
of substituted triflates and anilines (Table 2). Among the triflates
1b, 1j, and 1n bearing a methyl group at the para, meta, and
ortho position, respectively (entries 1, 2, and 4), m-methylated
triflate 1j gave the carbazole in the highest yield (>99%, entry
2) by the reaction with aniline 2c having a p-methoxycarbonyl
group under an oxygen atmosphere. A comparable result with
entry 2 was obtained by using air as the co-oxidant (93%, entry
3). Combination of phenyl triflates 1k, 1l, 1m, and 1j bearing
an electron-donating group at the meta position and anilines
2c-g bearing an electron-withdrawing group at the para position
gave good results to afford the corresponding carbazoles in
yields of 71-95% (entries 5-9). Substitution of aniline by the
o-methoxycarbonyl group lowered the yield to 52% (entry 10).
A trace amount of carbazole 5ec was obtained by combination
of 1e and 2c both having an electron-withdrawing group at the
para position. The reaction of triflate and aniline both having a
m-methyl group led to the desired carbazole 5ji in 43% yield,
along with 30% of diarylamine after 30.5 h at 100 °C (entry
12).
We next explored the one-pot reaction triflate 1j with aniline
2j, both having a meta substituent (Scheme 3). In contrast with
the reaction using other meta-substituted components such as
1j-m, 2d, and 2i leading to single carbazoles by the oxidative
coupling at the less hindered position (Tables 1 and 2),
a Reaction conditions: triflate 1 (1.0 equiv), aniline 2 (1.1 equiv),
Pd(OAc)2 (10 mol %), 3 (15 mol %), Cs2CO3 (1.2 equiv), toluene (0.5
M), 100 °C, 1-2 h, then O2 (1 atm), AcOH (0.125 M). b Conditions for
oxidative coupling. c Isolated yield. d When N-arylation was conducted
for 24 h, a similar result (62% yield) was obtained. e Air was used in
place of O2. f N-Arylation product was obtained in 28% yield.
g N-Arylation product was obtained in 49% yield. h N-Arylation product
was obtained in 68% yield. i N-Arylation product was obtained in 23%
yield.
(22) Almost the same results were obtained when the one-pot N-arylation-
oxidative coupling was performed separately. For example, the stepwise reactions
of 1a and 2c gave 70% yield of 5ea in 2 steps (compare with entry 19: 66%).
The stepwise and one-pot reaction of 1e and 2a also gave comparable results
(69% and 64%, respectively, see entry 6).
amine intermediates should be formed in entries 15 and 18, but
a remarkable difference in the yield of carbazoles was observed
(34% for 5ma and 72% for 5ab).
The results shown in Table 1 indicate that the reactivity in
the oxidative biaryl coupling step is strongly influenced by the
substitution pattern of diarylamine intermediates because N-
arylation proceeded almost quantitatively in many cases.22
Furthermore, the product yields are not dependent on the
reaction time of N-arylation (for example, 69% of 5aa with 1 h;
62% of 5aa with 24 h, entry 1). The reactivity of diarylamines
(23) Although the exact reason for the positive effect of an electron-
withdrawing group at the para position on the carbazole formation is unclear,
the increased acidity of the releasing proton may be one possible explanation.
4722 J. Org. Chem. Vol. 74, No. 13, 2009

Palladium-Catalyzed Direct Synthesis of Carbazoles
TABLE 2. Synthesis of Disubstituted Carbazolesa
TABLE 3. Synthesis of Multisubstituted Carbazolesa
a Reaction conditions: triflate 1 (1.0 equiv), aniline 2 (1.1 equiv),
Pd(OAc)2 (10 mol %), 3 (15 mol %), Cs2CO3 (1.2 equiv), toluene (0.5
M), 100 °C, 1-2 h, then O2 (1 atm), AcOH (0.125 M). b Conditions for
oxidative coupling. c Isolated yield.
SCHEME 4. One-Pot Synthesis of Clausine L 5ak
rationalized by the coordinating effect of the carbonyl oxygen
to palladium(II)24,25 and/or the electronic effect of the ester
group, which promotes proton abstraction on the C-H activation
step.7e,5j,26,27
We next investigated the reaction of disubstituted triflates/
anilines to synthesize multisubstituted carbazoles (Table 3). The
reaction of the disubstituted triflate 1p having an o-methoxy
group gave a 2,5-disubstituted carbazole 5pa in only 19% yield
(entry 1), which was in good agreement with the result obtained
with the o-methylated triflate 1n (20%; Table 1, entry 16).
Reactions using the disubstituted triflate 1q (entry 2) or
a Reaction conditions: triflate 1 (1.0 equiv), aniline 2 (1.1 equiv),
Pd(OAc)2 (10 mol %), 3 (15 mol %), Cs2CO3 (1.2 equiv), toluene (0.5
M), 100 °C, 1-2 h, then O2 (1 atm), AcOH (0.125 M). b Conditions for
oxidative coupling. c Isolated yield. d Air was used in place of O2.
e N-Arylation product was obtained in 33% yield. f N-Arylation product
was obtained in 89% yield. g N-Arylation product was obtained in 30%
yield.
SCHEME 3. Regioselectivity on the Reaction of 1j with 2j
(24) Related coordination effects were also reported in palladium-catalyzed
intramolecular C-H activation: (a) Teijido, B.; Ferna´ndez, A.; Lo´pez-Torres,
M.; Castro-Juiz, S.; Sua´rez, A.; Ortigueira, J. M.; Vila, J. M.; Ferna´ndez, J. J. J.
Organomet. Chem. 2000, 598, 71–79. (b) Harayama, T.; Kawata, Y.; Nagura,
C.; Sato, T.; Miyagoe, T.; Abe, H.; Takeuchi, Y. Tetrahedron Lett. 2005, 46,
6091–6094. (c) Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411–
6413.
(25) In the coupling reaction with 1j, 3-aminoacetophenone 2l and 3-fluo-
roaniline 2m showed similar regioselectivity to 2j, although the product yields
were lower.
regioisomeric two products 5jj-1 and 5jj-2 (86:14) were
obtained in 60% yield. Oxidative coupling proceeded predomi-
nantly at the more hindered ortho position of the ester group,
whereas at the methylbenzene moiety the less hindered para
position of the methyl group reacted exclusively. This can be
J. Org. Chem. Vol. 74, No. 13, 2009 4723

Watanabe et al.
SCHEME 5. Possible Catalytic Cycle in Oxidative Coupling
disubstituted aniline 2k (entry 3) proceeded to afford substituted
carbazoles 5qa and 5jk in acceptable yields (42% and 71%,
respectively). The anti-platelet natural carbazole Clausine L
5ak28 was obtained in 74% yield by direct coupling of triflate
1a and aniline 2k (Scheme 4).
A catalytic cycle of the oxidative biaryl coupling is shown
in Scheme 5. The first C-H activation of diarylamine 4aa,
generated by N-arylation of the aniline 1a with the phenyl triflate
2a, with palladium(II) would give the o-palladation intermediate
A. The second C-H activation releasing acetic acid gives
palladacycle B, reductive elimination of which would produce
carbazole 5aa and palladium(0). Aerobic reoxidation of pal-
ladium(0) has been reported,29 with formation a η2-peroxido
palladium(II) species C,30 protonolysis with acetic acid affording
palladium(II) hydroperoxide D,31 and ligand exchange with
acetate liberating H2O2 regenerating catalytically active palla-
dium(II) species.32-34
Mechanism of the Oxidative Coupling Step. As shown in
Scheme 6, C-H activation in the first step would produce the
o-palladation intermediate E and/or F through electrophilic
substitution (path A), σ-bond metathesis (path B), or oxidative
addition (path C).5,6,35 The carbopalladation pathway (path G)
can also be involved in the second C-H activation,36 besides
paths D-F as presented in o-palladation (paths A-C).37 Two
C-H activation steps can proceed in different reaction mech-
anisms because the electronic and steric nature of palladium(II)
in the first and second C-H activation is considerably different.
We conducted trapping and deuterium experiments to obtain
some mechanistic information of the two palladation steps.
It is known that the reaction of electron-rich arenes with
alkenes in the presence of palladium(II) affords vinylarenes
through palladation of arenes followed by a Heck-type
reaction.9b,f Using this chemistry, we expected that the first
palladation intermediate of type E and/or F (Scheme 6) could
be trapped by an appropriate alkene to give the Heck-type
product bearing the alkenyl group on the more reactive
benzene ring. This would help to determine the mechanism
of the first palladation. The reaction of diarylamine 4b with
methyl (Z)-3-phenylacrylate in the presence of a stoichio-
metric amount of palladium acetate in acetic acid at 100 °C
(26) Garc´ıa-Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.; Maseras, F.;
Echavarren, A. M. J. Am. Chem. Soc. 2007, 129, 6880–6886.
(27) It is likely that this biaryl coupling reaction needs to keep a balance
between both electron-donating and -withdrawing groups. Thus, electron-
withdrawing groups can (1) facilitate path E (σ-bond methathesis) by increasing
the acidity of aromatic C-H protons, (2) decrease nucleophilicity of the aromatic
carbon (when meta-substituted ones), and (3) stabilize the arylpalladium complex
B (Scheme 5) by coordination (when there is an o-methoxycarbonyl group),
and (4) stabilize the carbazoles. On the other hand, electron-donating groups
can (1) decrease the acidity of the aromatic proton to suppress path E (σ-bond
methathesis), (2) increase the nucleophilicity of the aromatic carbon, and (3)
destabilize the carbazoles. We would like to express our sincere appreciation to
the reviewer.
(32) Palladium(II) hydride pathway cannot be ruled out (insertion of O2 into
H-Pd-X followed by protonation of the resulting HOO-Pd-X with acetic acid
releasing H2O2), see: (a) Takehira, K.; Hayakawa, T.; Orita, H.; Shimizu, M. J.
Mol. Catal. 1989, 53, 15–21. (b) Hosokawa, T.; Murahashi, S. Acc. Chem. Res.
1990, 23, 49–54. (c) Hosokawa, T.; Nakahira, T.; Takano, M.; Murahashi, S. J.
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S. J. Org. Chem. 1999, 64, 6750–6755. See also, refs 29h and 29i.
(33) For related palladium-catalyzed aerobic oxidation, see: (a) Dams, M.;
De Vos, D. E.; Celen, S.; Jacobs, P. A. Angew. Chem., Int. Ed. 2003, 42, 3512–
3515. (b) Stoltz, B. M. Chem. Lett. 2004, 33, 362–367.
(34) Alternative Pd(II)/Pd(IV) catalytic cycle requires stronger oxidants than
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Chem., Int. Ed 2007, 46, 5737–5740. See also, refs 11f and 12e.
(35) Ryabov, A. D. Chem. ReV. 1990, 90, 403–424, See also, refs
5a, 5c, 5e, and 6b.
(36) The carbopalladation intermediate would have the wrong stereochemistry
for the well-accepted syn-elimination of H-Pd-OAc. However, a stereomutation
of the benzylic proton or anti-elimination cannot be completely ruled out, see:
(a) Grigg, R.; Sridharan, V.; Stevenson, P.; Sukirthalingam, S.; Worakun, T.
Tetrahedron 1990, 46, 4003–4018. (b) McClure, M. S.; Glover, B.; McSorley,
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Echavarren, A. M. Tetrahedron 2008, 64, 6021–6029.
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Teng, C.-M.; Ko, F.-N.; Kuoh, C.-S. Phytochemistry 1993, 32, 449–451. For
synthesis of clausine L, see: (b) Forke, R.; Ja¨ger, A.; Kno¨lker, H.-J. Org. Biomol.
Chem. 2008, 6, 2481–2483.
(29) (a) Stahl, S. S.; Thorman, J. L.; Nelson, R. C.; Kozee, M. A. J. Am.
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4724 J. Org. Chem. Vol. 74, No. 13, 2009

Palladium-Catalyzed Direct Synthesis of Carbazoles
SCHEME 6. Possible Reaction Mechanism of Oxidative Coupling
SCHEME 7. Scavenging of Intermediate by the Oxidative Heck Reaction
SCHEME 8. Investigation of KIE
provided the lactam 7 in 36% yield, formed by o-alkenylation
at the arene bearing a tert-butyl group followed by lactam
formation (Scheme 7).38 The regioisomeric lactam 8 (o-
alkenylation product at the fluorobenzene) as well as the
carbazole were not observed. The yield of the lactam 7 was
insufficient, but this result suggests that the first C-H
activation predominantly proceeds at the electron-rich arene
rather than electron-deficient fluorobenzene moiety.39,40
Because the electron-rich aromatic carbon readily undergoes
carbazole formation (Figure 1), the first C-H activation
would probably proceed by the electrophilic mechanism
(Scheme 6, path A). This is in good agreement with the
electronic state of palladium species: palladium(II) acetate
is electronically more deficient than the arylpalladium acetate
A that would be the active species in the second C-H
activation (Scheme 5).
We investigated the kinetic isotope effect (KIE) of the
oxidative biaryl coupling using diarylamine 4b-d41 having a
deuterium at the ortho position of the amino group in each
arene (Scheme 8). In the oxidative coupling of the diary-
lamine 4b-d, values of KH/KD ) 0.16 (tert-butylbenzene side)
and KH/KD ) 1.1 (fluorobenzene side) were observed. These
results indicate that the deuterium atom on the fluorobenzene
would not be involved in the rate-determining step. Because
the fluorobenzene would participate in the second C-H
activation step as described above (Scheme 7), σ-bond
metathesis (path E) and oxidative addition (path F), which
both require participation of the o-deuterium/hydrogen in the
transition state, would be less important pathways in the
second C-H activation. Considering that diarylamine derived
from the 3-methyphenyl triflate 1j and 3-methylaniline 2i
showed low reactivity toward oxidative coupling to give the
carbazole 5ji (43%) and the diarylamine (30%) (Table 2,
entry 12), involvement of electrophilic substitution (Path D)
in the second C-H activation is unlikely. The results
presented here can be explained by path A (electrophilic
substitution) in the first palladation and path G (carbopalla-
dation) in the second palladation, but participation of other
pathways cannot be completely excluded.
Conclusions
We developed an efficient method for construction of various
functionalized carbazoles by one-pot N-arylation-oxidative
biaryl coupling from readily available anilines and phenyl
triflates. Oxidative C-H activation is remarkably influenced by
substituents on the aromatic rings. Important information for
understanding the mechanism of palladium(II)-catalyzed oxida-
tive biaryl coupling was provided by conducting o-olefination
and deuterium experiments.
(38) The structure of 7 was confirmed by comparison of its spectral data
with the authentic sample prepared by a separete route, see the Supporting
Information.
(39) The possibility that 3-phenylacrylate present in the reaction mixture
might affect the reactivity of the palladium catalyst cannot be ruled out.
(40) The first palladation at the fluorobenzene moiety followed by 1,4-
palladium shift might be possible. However, the palladium shift process would
produce a regioisomeric mixture, see: (a) Campo, M. A.; Zhang, H.; Yao, T.;
Ibdah, A.; McCulla, R. D.; Huang, Q.; Zhao, J.; Jenks, W. S.; Larock, R. C.
J. Am. Chem. Soc. 2007, 129, 6298–6307. See also: (b) Mota, A. J.; Dedieu, A.;
Bour, C.; Suffert, J. J. Am. Chem. Soc. 2005, 127, 7171–7182.
(41) For synthesis of 4b-d, see the Supporting Information.
J. Org. Chem. Vol. 74, No. 13, 2009 4725

Watanabe et al.
Experimental Section
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Encouragement of Young Scientists (A) from
the Ministry of Education, Culture, Sports, Science and Tech-
nology of Japan; a Research Fellowship for Young Scientists
from the Japan Society for the Promotion of Science (JPS);
Targeted Proteins Research Program; and the Program for
Promotion of Fundamental Studies in Health Sciences of the
National Institute of Biomedical Innovation (NIBIO).
General Procedure for the Synthesis of Carbazoles (Table
2, Entry 1). Toluene (0.4 mL) was added to a flask containing
4-methylphenyl triflate (1b) (48.0 mg, 0.20 mmol), 4-(methoxy-
carbonyl)aniline (2c) (33.3 mg, 0.22 mmol), Pd(OAc)2 (4.49 mg,
10 mol %), ligand 3 (14.3 mg, 15 mol %), and Cs2CO3 (84.7 mg,
0.24 mmol) under an argon atmosphere. The mixture was stirred
at 100 °C for 1.5 h, then stirred at room temperature for 5 min.
AcOH (1.6 mL) was added to the mixture and an oxygen balloon
connected to the reaction vessel. The reaction mixture was stirred
at 80 °C for 22.5 h. After cooling, the reaction mixture was diluted
with ethyl acetate, washed with saturated NaHCO3, dried over
MgSO4, and concentrated in vacuo. Crude material was purified
by flash chromatography with hexane/ethyl acetate (15:1) to afford
the desired carbazole 5bc (37.4 mg, 78% yield).
Supporting Information Available: Characterization data
for all novel compounds, as well as NMR spectra for all the
carbazoles synthesized. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO9003376
4726 J. Org. Chem. Vol. 74, No. 13, 2009