Intramolecular Pd(II)-catalyzed oxidative biaryl synthesis under air: Reaction development and scope

Article abstract of DOI:10.1021/jo800596m

(Figure Presented) New reaction conditions for intramolecular palladium(II)-catalyzed oxidative carbon-carbon bond formation under air are described. The use of pivalic acid as the reaction solvent, instead of acetic acid, results in greater reproducibility, higher yields, and broader scope. This includes the use of electron-rich diarylamines as illustrated in the synthesis of three naturally occurring carbazole products: Murrayafoline A, Mukonine, and Clausenine. A variety of side products have also been isolated, casting light on competing reaction pathways and revealing new reactivity with palladium(II) catalysis.

Full text of DOI:10.1021/jo800596m

Intramolecular Pd(II)-Catalyzed Oxidative Biaryl Synthesis Under
Air: Reaction Development and Scope
Benoît Lie´gault, Doris Lee, Malcolm P. Huestis, David R. Stuart, and Keith Fagnou*
Center for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of Ottawa, 10 Marie
Curie, Ottawa, ON, K1N 6J7, Canada
keith.fagnou@uottawa.ca
ReceiVed March 16, 2008
New reaction conditions for intramolecular palladium(II)-catalyzed oxidative carbon-carbon bond
formation under air are described. The use of pivalic acid as the reaction solvent, instead of acetic acid,
results in greater reproducibility, higher yields, and broader scope. This includes the use of electron-rich
diarylamines as illustrated in the synthesis of three naturally occurring carbazole products: Murrayafoline
A, Mukonine, and Clausenine. A variety of side products have also been isolated, casting light on competing
reaction pathways and revealing new reactivity with palladium(II) catalysis.
Introduction
catalytic processes7 is only quite recent. Furthermore, the scope
of these transformations remains limited; electron-rich arenes,
for example, remain problematic in carbazole synthesis and are
Chemists continue to develop increasingly efficient methods
for the construction of biaryl molecules. Emerging alternatives
to the frontline of palladium-catalyzed cross-coupling reactions1
include direct arylation and related processes in which one of
the preactivated arenes is replaced by a simple arene.2,3 Recently,
methods that avoid arene preactivation have appeared, enabling
the coupling of two unactivated aromatic compounds directly.4
As part of our work in this area, we conducted studies in the
area of intramolecular oxidative biaryl coupling reactions
(Scheme 1).5–8 These processes have recognized value in
synthesis, particularly in the preparation of the carbazole
motif.9,10 Despite their potential, the evolution of these reactions
from stoichiometric processes, described over 30 years ago5 to
(5) For the use of stoichiometric palladium in carbazole synthesis, see: (a)
Åkermark, B.; Eberson, L.; Jonsson, E.; Pettersson, E. J. Org. Chem. 1975, 40,
1365. (b) Miller, R. B.; Moock, T. Tetrahedron Lett. 1980, 21, 3319. (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. 1992, 1, 3439. (d) Kno¨lker, H.-J.;
O’Sullivan, N. Tetrahedron Lett. 1994, 35, 1695. (e) Ferreira, I. C. F. R.; Queiroz,
M.-J. R. P.; Kirsch, G. Tetrahedron 2002, 58, 7943. (f) Kno¨lker, H.-J.; Kno¨ll,
J. Chem. Commun. 2003, 1170. (g) Benavides, A.; Peralta, J.; Delgado, F.;
Tamariz, J. Synthesis 2004, 2499. (h) Kno¨ll, J.; Kno¨lker, H.-J. Synlett 2006,
651. (i) Sridharan, V.; Mart´ın, M. A.; Mene´ndez, J. C. Synlett 2006, 2375. (j)
Bernal, P.; Benavides, A.; Bautista, R.; Tamariz, J. Synthesis 2007, 1943.
(6) For the use of stoichiometric palladium in various intramolecular biaryl
coupling, see: (a) Yoshimoto, H.; Itatani, H. Bull. Chem. Soc. Jpn. 1973, 46,
2490. (b) Shiotani, A.; Itatani, H. Angew. Chem., Int. Ed. Engl. 1974, 13, 471.
(c) Itahara, T. Synthesis 1979, 151. (d) Itahara, T. Heterocycles 1986, 24, 2557.
(e) Harris, W.; Hill, C. H.; Keech, E.; Malsher, P. Tetrahedron Lett. 1993, 34,
8361. (f) Merlic, C. A.; You, Y.; McInnes, D. M.; Zechman, A. L.; Miller, M. M.;
Deng, Q. Tetrahedron 2001, 57, 5199. (g) Ryu, C.-K.; Choi, I. H.; Park, R. E.
Synth. Commun. 2006, 36, 3319. (h) Wada, Y.; Nagasaki, H.; Tokuda, M.; Orito,
K. J. Org. Chem. 2007, 72, 2008. See also ref 5a.
(1) For recent reviews on this topic, see: (a) Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 2004. (b)
Hassan, J.; Gvignon, M. S.; Gozzi, C.; Shulz, E.; Lemaire, M. Chem. ReV. 2002,
102, 1359.
(2) For recent reviews on this topic, see: (a) Zeni, G.; Larock, R. C. Chem.
ReV. 2006, 106, 4644. (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV.
2007, 107, 174. (c) Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36,
1173.
(7) For the use of catalytic palladium in carbazole synthesis, see: (a) Kno¨lker,
H.-J.; O’Sullivan, N. Tetrahedron 1994, 50, 10893. (b) Åkermark, B.; Oslob,
J. D.; Heuschert, U. Tetrahedron Lett. 1995, 36, 1325. (c) Kno¨lker, H.-J.; Fro¨hner,
W. J. Chem. Soc., Perkin Trans 1 1998, 173. (d) Kno¨lker, H.-J.; Reddy, K. R.;
Wagner, A. Tetrahedron Lett. 1998, 39, 8267. (e) Hagelin, H.; Oslob, J. D.;
Åkermark, B. Chem. Eur. J. 1999, 5, 2413. (f) Kno¨lker, H.-J.; Fro¨hner, W.
Synthesis 2002, 557. (g) Matsubara, S.; Asano, K.; Kajita, Y.; Yamamoto, M.
Synthesis 2007, 2055. (h) Watanabe, T.; Ueda, S.; Inuki, S.; Oishi, S.; Fujii, N.;
Ohno, H. Chem. Commun. 2007, 4516.
(3) For our own work on Pd(0)-catalyzed intramolecular direct arylation,
see: (a) Campeau, L.-C.; Parisien, M.; Leblanc, M.; Fagnou, K. J. Am. Chem.
Soc. 2004, 126, 9186. (b) Campeau, L.-C.; Thansandote, P.; Fagnou, K. Org.
Lett. 2005, 7, 1857. (c) Parisien, M.; Valette, D.; Fagnou, K. J. Org. Chem.
2005, 70, 7578. (d) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 581.
(4) (a) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904. (b)
Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett.
2007, 9, 3137. (c) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (d) Stuart,
D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072. (e) Rong,
Y.; Li, R.; Lu, W. Organometallics 2007, 26, 4376. (f) Xia, J.-B.; You, S.-L.
Organometallics 2007, 26, 4869. (g) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2008, 47, 1115.
(8) For the use of catalytic palladium in various intramolecular biaryl
coupling, see: Wang, J.; Rosingana, M.; Watson, D. J.; Dowdy, E. D.; Discordia,
R. P.; Soundarajan, N.; Li, W.-S. Tetrahedron Lett. 2001, 42, 8935. See also
refs 6h and 7e.
(9) For recent reviews on carbazoles, see: (a) Kno¨lker, H.-J.; Reddy, K. R.
Chem. ReV. 2002, 102, 4303. (b) Kno¨lker, H.-J. Curr. Org. Synth. 2004, 1, 309.
(c) Kno¨lker, H.-J. Top. Curr. Chem. 2005, 244, 115.
5022 J. Org. Chem. 2008, 73, 5022–5028
10.1021/jo800596m CCC: $40.75 2008 American Chemical Society
Published on Web 06/11/2008

OxidatiVe Biaryl Synthesis Under Air
SCHEME 1. Palladium(II)-Catalyzed Oxidative Biaryl
Synthesis
employing an air atmosphere at ambient pressure as the terminal
oxidant were considered. From these studies, we were pleased
to find that substituting the use of acetic acid with 2,2-
dimethylpropionic acid (pivalic acid, PivOH) not only increases
the reactivity but drastically improves the selectivity for the
formation of the carbazole products. For example, when mono-
and disubstituted electron-rich diphenylamines 3-6 are reacted
in the presence of palladium acetate (3-5 mol %) and potassium
carbonate (10 mol %) in pivalic acid (1 M), good isolated yields
(up to 78%) are obtained for the preparation of carbazole
products 7-10 (Table 1, entries 2, 4, 6, and 8). Previous work
in our group has shown that pivalic acid can play an important
role as a cocatalyst in Pd(0)-catalyzed benzene arylation.11
Sigman and co-workers have also demonstrated the efficiency
of the pivaloyl moiety for palladium-catalyzed aerobic oxidation
of alcohols.12 In both of these cases, the pivalate ligand is
proposed to play a key role in a C-H bond cleaving event.
While it is speculative, a similar effect may be operating here.
In contrast to many reactions performed in AcOH, very little
secondary oxidative byproduct is detected in the crude reaction
mixtures with PivOH; only the carbazole products and unreacted
starting materials are observed by 1H NMR analysis of the crude
reaction mixtures (Figure 1). To elucidate the mechanism of
this oxidative byproduct formation, major side products were
isolated whenever possible. These efforts led to the discovery
not only of known reactions accounting for lost mass balance,
but also to the discovery of new reactivity as well.
Since byproduct formation may occur from both the starting
material and the products, both were subjected to the reaction
conditions to determine if unwanted processes might occur. It
is important to note that several competing processes may be
at play in each case, and that the isolated compounds likely
comprise only one of the possible undesired outcomes. Informa-
tive results dealing with competitive diarylamine side reactions
are illustrated in eqs 2-4 and Figure 1.
While submission of 11 to conditions employing acetic acid
as the solvent leads to extensive decomposition, the use of
pivalic acid results in the formation of the desired product in
91% yield (Scheme 2). Potentially problematic reactivity was
revealed by the isolation of a major side product 12 involving
the catalytic formation of a new carbon-oxygen bond (eq 2).
Such a C-O bond-forming process may also occur with acetic
acid as the solvent; however, the arylacetoxy products may be
unstable under the reaction conditions, undergoing acetate
deprotection. The resulting aryloxyphenylamines would be
highly sensitive to further oxidative degradation and lead to
complex mixtures and further loss of material. While palladium-
catalyzed carbon-oxygen bond-forming reactions have been
recently described at aromatic C-H bonds, all have required
the use of stoichiometric iodine(III) oxidants.13 The fact that
this side process can occur with air as an oxidant is interesting
from a reaction development perspective.
associated with extensive substrate and/or product decomposition
reducing the yield and utility.5i With these limitations in mind,
and with the desire to learn more about the challenges associated
with palladium-catalyzed oxidative arene cross-coupling, we
initiated studies aimed at elucidating competing and deleterious
side reactions and at minimizing their occurrence.
Herein, we describe our findings in this area by defining
several competing palladium-catalyzed oxidative reaction path-
ways as well as the development of new reaction conditions
that minimize their formation. These conditions permit the use
of otherwise problematic electron-rich substrates and have been
appliedtothesynthesisofseveralnaturallyoccurringcarbazoles.9,15
Importantly, these reactions employ an air atmosphere at ambient
pressure as the terminal oxidant, obviating the need for
stoichiometric metal oxidants as is frequently the case. In
addition to explaining the low mass balance in challenging
reactions, the isolation and structural characterization of oxida-
tive byproducts also sheds light on new catalytic possibilities
for palladium complexes and should serve as a source of
inspiration in the development of other novel palladium-
catalyzed transformations.
Results and Discussion
Initial investigations were performed with diphenylamine 1
and catalytic Pd(OAc)2 in acetic acid at 110 °C under an air
atmosphere. During early reaction development efforts, it was
discovered that the addition of small amounts of potassium
carbonate resulted in enhanced yields; consequently, its use was
applied in these studies. Despite the widespread use of condi-
tions very similar to these, they were found to provide
inconsistent yields of the carbazole 2 ranging from 8% to 82%
(eq 1).
Even more problematic were reactions with electron-rich
diarylamines that are known to be challenging substrates for
these transformations.5i When acetic acid was employed as the
solvent with diarylamines 3-6, complete consumption of the
starting materials was observed, but with very low yields of
the desired carbazole products 7-10 (Table 1, entries 1, 3, 5,
and 7). To improve the yield of the desired carbazole products,
a variety of solvents, solvent mixtures, catalyst precursors, and
additives were evaluated. To maximize the ultimate efficiency
and technical simplicity of the overall reaction, only conditions
Another interesting side reaction is observed with diarylamine
4 (eq 3). Instead of undergoing the desired oxidative biaryl
(12) Schultz, M. J.; Hamilton, S. S.; Jensen, D. R.; Sigman, M. S. J. Org.
Chem. 2005, 70, 3343.
(13) (a) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005,
127, 7690. (b) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179. (c)
Desai, L. V.; Sanford, M. S. Angew. Chem., Int. Ed. 2007, 46, 5737. (d) Li, Y.;
Song, D.; Dong, V. M. J. Am. Chem. Soc. 2008, 130, 2962.
(10) For the use of carbazoles in material chemistry, see :(a) Morin, J.-F.;
Leclerc, M.; Ade`s, D.; Siove, A. Macromol. Rapid Commun. 2005, 26, 761. (b)
Vecchi, P. A.; Padmaperuma, A. B.; Qiao, H.; Sapochak, L. S.; Barrows, P. E.
Org. Lett. 2006, 8, 4211.
(14) (a) Mun˜iz, K. J. Am. Chem. Soc. 2007, 129, 14542. (b) Dick, A. R.;
Remy, M. S.; Kampf, J. W.; Sanford, M. S. Organometallics 2007, 26, 1365.
(c) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932. (d)
Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 130, 3316.
(11) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
J. Org. Chem. Vol. 73, No. 13, 2008 5023

Lie´gault et al.
TABLE 1. Effect of Solvent on the Palladium(II)-Catalyzed Oxidative Ring Closure of Electron-Rich Diarylaminesa
a Conditions: Diarylamine (0.5 mmol), Pd(OAc)2 (3-5 mol %), K2CO3 (10 mol %), solvent (0.5 mL), 110 °C, 14 h under air at ambient pressure; see
the Supporting Information for details; b Isolated yield. c See also Figure 1 for crude 1H NMR spectra. d Only one isomer detected by GC-MS and 1H
NMR. e Isolated yields of the major and the minor regioisomers, respectively.
1
FIGURE 1. Crude H NMR spectra (in DMSO-d6) of the intramolecular coupling of diarylamine 3: (a) reaction conducted in AcOH and (b)
reaction conducted in PivOH.
coupling, as is observed in pivalic acid, carbazole 13 is formed
in 27% yield when performed in acetic acid. This could arise
from the fragmentation of a molecule of 4 and subsequent
recombination with a second starting diarylamine 4. While the
mechanism has not yet been elucidated, the relatively high yield
of this interesting process may warrant further attention and
reaction development.
We have also found that the carbazole products may
undergo further oxidative transformations under the reaction
conditions, and that the presence of these secondary oxidation
events is highly solvent dependent. For example, treatment
of diarylamine 3 under the standard conditions with acetic
acid provides a mixture of products and very low yield of 7
(Table 1, entry 1; Figure 1). We have determined that a major
side reaction is the formation of dimer 14, which could be
isolated in 14% yield when the product carbazole 7 is
subjected to the acetic acid reaction conditions. Dimer 14 is
not observed in reactions employing pivalic acid. In fact,
even when isolated carbazole 7 is placed under standard
conditions in pivalic acid, no reaction is observed, underlining
the low propensity for unwanted byproduct formation in this
solvent.
5024 J. Org. Chem. Vol. 73, No. 13, 2008

OxidatiVe Biaryl Synthesis Under Air
Murrayafoline A (17), Clausenine (18) and Mukonine (19).9,15,16
All three syntheses commenced with arene 20, which was either
reduced to the corresponding aniline 21 in near quantitative
yield17 or first oxidized to the benzoic acid 22, esterified to 23,
and reduced to give aniline 24 in a three-step sequence.18 These
compounds were then subjected to Buchwald-Hartwig amina-
tion19 to furnish the key diarylamines 11, 25, and 26. The
coupling of 21 with bromobenzene was found to best proceed
when reacted in the presence of Pd2(dba)3, DavePhos (27),20
and sodium tert-butoxide in dioxane at 80 °C,21 giving diarylamine
25 in 96% yield. These same conditions were employed to
couple 21 with 4-bromoanisole to provide 26 in 89% yield. On
the other hand, the optimal conditions for the coupling of the
more electron-deficient aniline 24 with bromobenzene required
the use of the more sterically encumbered X-Phos ligand 2822
instead of DavePhos. Under these conditions, diarylamine 11
could be generated in 76% isolated yield. With the three
diarylamine precursors 11, 25, and 26 in hand, we were pleased
to find that the intramolecular Pd(II)-catalyzed oxidative
coupling reaction under the standard conditions in pivalic acid
provided the three target molecules 17, 18, and 19 in 50%, 79%,
and 91% yields, respectively. In each case, when pivalic acid
was substituted with acetic acid, significantly lower yields (12%,
8%, and 19%, respectively) and complex product mixtures were
produced, again illustrating the benefits associated with the use
of pivalic acid.
Also noteworthy is the outcome with carbazole 15 that does
not undergo further reaction when subjected to the standard
reaction conditions in pivalic acid. In contrast, when reacted in
acetic acid, 39% consumption of 15 is observed and product
16 arising from oxidative C-N bond formation is isolated in
7% yield (eq 4). Given the importance of nitrogen-containing
compounds in medicinal chemistry, and the potential efficiency
that an oxidative C-N bond-forming process could provide,14
this reaction may also warrant further investigation.
In addition to electron-rich diarylamines, the new reaction
conditions are compatible with a wide range of other substrates,
including those bearing electron-withdrawing groups (Table 2,
entries 2-4 and 7). 2-Anilinonaphthoquinone (35) is also a good
substrate for the reaction, providing 36 in 77% isolated yield
(entry 5), as are diaryl ethers as exemplified by the formation
of dibenzofurans 38 and 40 in good yields (entries 6 and 7).23
To further evaluate the improved reactivity and yields that
can be achieved with pivalic acid as the reaction solvent, a
concise approach to the synthesis of three naturally occurring
electron-rich tricyclic carbazoles was undertaken including
SCHEME 2. Synthesis of Naturally Occurring Carbazoles 17, 18, and 19
J. Org. Chem. Vol. 73, No. 13, 2008 5025

Lie´gault et al.
TABLE 2. Scope of the Palladium-Catalyzed Oxidative Ring Closure Reactiona
a Conditions: starting material (0.5 mmol), Pd(OAc)2 (3-10 mol %), K2CO3 (10 mol %), PivOH (0.5 mL), air at ambient pressure; see the Supporting
c
Information for details; b Isolated yield. Only one isomer detected by GC-MS and H NMR.
1
by silica gel column chromatography to afford the corresponding
coupling product.
N-Benzoylindoles 41 and 43 are also good substrates, giving
rise to the corresponding cyclized products 42 and 44 (entries
8 and 9). As noticed by DeBoef and co-workers,4b compound
43, with a methoxy group on the benzoyl moiety, proved to be
more reactive than compound 41, which required a higher
temperature and a longer reaction time (120 °C vs 110 °C, 24 h
vs 14 h).
3,5-Dimethoxydiphenylamine, 3. Synthesized according to a
literature procedure.21 Light brown solid; mp 72-73 °C; Rf 0.4
(petroleum ether/ethyl acetate 90/10); 1H NMR (400 MHz, CDCl3)
δ 7.26 (dd, J ) 8.5 and 7.3 Hz, 2H), 7.09 (dd, J ) 8.5 and 1.1 Hz,
2H), 6.94 (t, J ) 7.3 Hz, 1H), 6.23 (d, J ) 2.1 Hz, 2H), 6.06 (t, J
) 2.1 Hz, 1H), 5.72 (br s, NH), 3.74 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 161.6, 145.2, 142.5, 129.3, 121.5, 118.8, 95.8, 93.0, 55.3;
IR (νmax) 3387, 2941, 2842, 1593, 1495, 1256, 1203, 1151, 1065,
815, 754, 687 cm-1; HRMS calcd for C14H15NO2 (M+) 229.1103,
found 229.1090.
Conclusion
In summary, these studies should not only enable a broaden-
ing of the applicability of the palladium-catalyzed oxidative
biaryl coupling in intramolecular processes, but also should cast
light on the challenges associated with achieving more chal-
lenging intermolecular processes. Furthermore, the isolation and
characterization of several oxidative byproducts not only begins
to account for the poor mass balance associated with the use of
challenging substrates, but also hints at new reaction develop-
ment opportunities.
3,4-Dimethoxydiphenylamine, 4. Synthesized according to a
literature procedure.21 Light brown solid; mp 102-103 °C; Rf 0.2
(petroleum ether/ethyl acetate 90/10); 1H NMR (400 MHz, CDCl3)
δ 7.23 (dd, J ) 8.5 and 7.4 Hz, 2H), 6.95 (d, J ) 7.6 Hz, 2H),
6.85 (t, J ) 7.3 Hz, 1H), 6.81 (d, J ) 8.5 Hz, 1H), 6.72 (d, J ) 2.4
Hz, 1H), 6.67 (dd, J ) 8.4 and 2.1 Hz, 1H), 5.63 (br s, NH), 3.86
(s, 3H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.6, 144.8,
144.7, 136.2, 129.3, 119.9, 116.1, 112.2, 112.2, 105.3, 56.3, 55.9;
IR (νmax) 3370, 2935, 2837, 1598, 1513, 1495, 1230, 1025, 691
cm-1; HRMS calcd for C14H15NO2 (M+) 229.1103, found 229.1108.
3-Methyldiphenylamine, 6. Synthesized according to a literature
procedure.21 Black oil; Rf 0.5 (petroleum ether/ethyl acetate 90/
10); 1H NMR (400 MHz, CDCl3) δ 7.24 (t, J ) 7.4 Hz, 2H), 7.14
(t, J ) 8.1 Hz, 1H), 7.04 (t, J ) 8.5 Hz, 2H), 6.90 (td, J ) 7.4 and
1.1 Hz, 1H), 6.88-6.85 (m, 2H), 6.74 (d, J ) 7.4 Hz, 1H), 5.61
(br s, NH), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.2,
143.0, 139.2, 129.3, 129.1, 121.8, 120.8, 118.5, 117.8, 114.9, 21.5;
Experimental Section
General Procedure of the Intramolecular Pd(II)-Catalyzed
Biaryl Coupling Reaction. Biaryl compound (0.5 mmol), Pd(OAc)2
(2-10 mol %), K2CO3 (10 mol %), and pivalic acid (450 mg) are
weighed to air and transferred into a test tube (1.2 × 10 cm2). The
uncapped test tube is placed in an oil bath and the mixture is stirred
under air at the indicated temperature and time. The solution is
then cooled to rt, diluted with CH2Cl2, washed with a saturated
aqueous solution of Na2CO3, dried over MgSO4, filtered, and
evaporated under reduced pressure. The crude product is purified
IR (νmax) 3393, 3036, 2919, 1590, 1495, 1316, 1166, 744, 690 cm-1
;
HRMS calcd for C13H13N (M+) 183.1048, found 183.1035.
5026 J. Org. Chem. Vol. 73, No. 13, 2008

OxidatiVe Biaryl Synthesis Under Air
2,4-Dimethoxycarbazole, 7. Synthesized according to the
general procedure. Light brown solid; mp 114-115 °C; Rf 0.3
(petroleum ether/ethyl acetate 80/20); 1H NMR (400 MHz, DMSO-
d6) δ 11.13 (s, NH), 7.99 (d, J ) 7.7 Hz, 1H), 7.39 (d, J ) 8.0 Hz,
1H), 7.23 (ddd, J ) 8.1, 7.1, and 1.1 Hz, 1H), 7.08 (ddd, J ) 7.8
, 7.1, and 0.6 Hz, 1H), 6.59 (d, J ) 1.8 Hz, 1H), 6.32 (d, J ) 1.8
Hz, 1H), 3.97 (s, 3H), 3.84 (s, 3H); 13C NMR (100 MHz, DMSO-
d6) δ 159.6, 155.9, 141.6, 138.7, 123.1, 121.9, 120.9, 118.5, 110.0,
105.4, 90.4, 86.9, 55.3, 55.3; IR (νmax) 3407, 2940, 2840, 1632,
1610, 1457, 1323, 1209, 1150, 1123, 750, 727 cm-1; HRMS calcd
for C14H13NO2 (M+) 227.0946, found 227.0939.
2,3-Dimethoxycarbazole, 8. Synthesized according to the
general procedure. Mauve solid; mp 184-186 °C; Rf 0.15 (petro-
leum ether/ethyl acetate 80/20); 1H NMR (400 MHz, DMSO-d6) δ
10.94 (s, NH), 7.98 (d, J ) 7.6 Hz, 1H), 7.65 (s, 1H), 7.41 (d, J )
8.0 Hz, 1H), 7.25 (t, J ) 7.4 Hz, 1H), 7.07 (d, J ) 7.4 Hz, 1H),
7.02 (s, H), 3.85 (s, 3H), 3.84 (s, 3H); 13C NMR (100 MHz, DMSO-
d6) δ 149.0, 143.6, 139.4, 134.5, 123.5, 122.8, 119.1, 117.9, 114.2,
110.5, 103.3, 94.5, 56.1, 55.5; IR (νmax) 3396, 3022, 1497, 1455,
1312, 1204, 1148, 1027, 747 cm-1; HRMS calcd for C17H13NO2
(M+) 227.0946, found 227.0924.
(s, NH), 8.13 (d, J ) 7.8 Hz, 1H), 7.95 (dd, J ) 9.4 and 2.6 Hz,
1H), 7.51-7.47 (m, 2H), 7.41 (ddd, J ) 8.2, 7.0, and 1.2 Hz, 1H),
7.23 (td, J ) 9.2 and 2.4 Hz, 1H), 7.15 (dd, J ) 7.9, 7.0, and 1.0
Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 156.3 (d, 1JCF ) 232
Hz), 140.7, 136.1, 126.0, 122.7 (d, 3JCF ) 10 Hz), 122.0 (d, 4JCF
)
2
3
4 Hz), 120.5, 118.3, 113.0 (d, JCF ) 25 Hz), 111.6, (d, JCF ) 9
2
Hz), 111.1, 105.6 (d, JCF ) 24 Hz); IR (νmax) 3420, 1585, 1456,
1167, 865, 807, 746, 724, 598, 570 cm-1; HRMS calcd for C12H8NF
(M+) 185.0641, found 185.0648.
3-Acetylcarbazole, 32. Synthesized according to the general
procedure. Light brown solid; mp 165-167 °C; Rf 0.45 (petroleum
ether/ethyl acetate 70/30); 1H NMR (400 MHz, DMSO-d6) δ 11.71
(s, NH), 8.85 (d, J ) 1.6 Hz, 1H), 8.27 (d, J ) 7.8 Hz, 1H), 8.04
(dd, J ) 8.6 and 1.7 Hz, 1H), 7.56 (br d, J ) 8.6 Hz, 2H), 7.46
(ddd, J ) 8.2, 7.1, and 1.1 Hz, 1H), 7.25 (ddd, J ) 7.9, 7.0, and
0.9 Hz, 1H), 2.58 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 196.9,
142.5, 140.3, 128.2, 126.2, 125.8, 122.6, 122.0, 122.0, 120.5, 119.4,
111.3, 110.6, 26.5; IR (νmax) 3405, 3283, 1658, 1601, 1331, 1247,
737 cm-1; HRMS calcd for C14H11NO (M+) 209.0841, found
209.0870.
3-Nitrocarbazole, 34. Synthesized according to the general
procedure. Dark yellow solid; mp 212-213 °C; Rf 0.2 (petroleum
ether/ethyl acetate 80/20); 1H NMR (400 MHz, DMSO-d6) δ 12.08
(s, NH), 9.17 (d, J ) 2.2 Hz, 1H), 8.38 (br d, J ) 7.8 Hz, 1H),
8.31 (dd, J ) 9.0 and 2.3 Hz, 1H), 7.65 (d, J ) 9.1 Hz, 1H), 7.61
(d, J ) 8.1 Hz, 1H), 7.53 (ddd, J ) 8.2, 7.1, and 1.1 Hz, 1H), 7.30
(ddd, J ) 8.0, 7.0, and 1.0 Hz, 1H); 13C NMR (100 MHz, DMSO-
d6) δ 143.2, 140.9, 139.7, 127.2, 122.4, 122.1, 121.2, 121.1, 120.2,
117.3, 111.8, 111.0; IR (νmax) 3414, 3332, 3236, 3067, 1643, 1459,
1311, 1084, 814, 751, 724 cm-1; HRMS calcd for C12H8N2O2 (M+)
212.0586, found 212.0605.
Methyl 1-Methoxy-8-(pivaloyloxy)carbazole-3-carboxylate,
12. Synthesized according to the general procedure. Colorless oil;
1
Rf 0.4 (petroleum ether/ethyl acetate 80/20); H NMR (400 MHz,
CDCl3) δ 8.45 (dd, J ) 1.2 and 0.6 Hz, 1H), 8.23 (br s, 1H), 7.95
(ddd, J ) 7.3, 1.3, and 0.6 Hz, 1H), 7.61 (d, J ) 1.2 Hz, 1H),
7.28-7.21 (m, 2H), 4.07 (s, 3H), 3.98 (s, 3H), 1.49 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 176.7, 167.9, 145.4, 136.6, 133.1, 131.9,
126.7, 124.0, 122.7, 120.7, 118.6, 118.3, 116.4, 107.3, 55.9, 52.2,
39.7, 27.5; IR (νmax) 3325, 2962, 2932, 1749, 1709, 1346, 1242,
1215, 1118, 758 cm-1; HRMS calcd for C20H21NO5 (M+) 355.1420,
found 355.1416.
2-Anilinonaphthoquinone, 35. To a solution of naphthaquinone
(10 mmol, 1.58 g) in H2O/AcOH 1:1 (10 mL) at 0 °C is added
aniline (10 mmol, 0.91 mL) dropwise. The mixture is stirred under
reflux over 3 h, cooled, and allowed to reach pH ∼ 7 by adding
saturated aqueous solution of Na2CO3. CH2Cl2 is then added and
the organic phase is dried over MgSO4, filtered on silica, and
evaporated under reduced pressure. The residue is washed with
diethyl ether and dried under vacuum to afford 198 mg of 35 as a
dark red solid in 32% yield. Mp 198-199 °C; Rf 0.35 (CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 8.13-8.10 (m, 2H), 7.76 (td, J )
7.6 and 1.2 Hz, 1H), 7.66 (td, J ) 7.6 and 1.2 Hz, 1H), 7.58 (br s,
NH), 7.42 (t, J ) 7.9 Hz, 2H), 7.28 (d, J ) 7.7 Hz, 2H), 7.22 (t,
J ) 7.4 Hz, 1H), 6.42 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
183.9, 182.0, 144.7, 137.4, 134.9, 133.2, 132.3, 130.4, 129.7, 126.5,
126.2, 125.6, 122.6, 103.4; IR (νmax) 3317, 1667, 1638, 1608, 1595,
1571, 1527, 1447, 1294, 775, 723 cm-1; HRMS calcd for
C16H11NO2 (M+) 249.0790, found 249.0800.
2,2′,4,4′-Tetramethoxy-1,1′-bicarbazole, 14. Synthesized ac-
cording to the general procedure. Mauve solid; mp 206-209 °C;
1
Rf 0.2 (petroleum ether/ethyl acetate 80/20); H NMR (400 MHz,
CDCl3) δ 8.24 (dd, J ) 7.7 and 0.5 Hz, 2H), 7.71 (br s, 2H),
7.29-7.25 (m, 2H), 7.22-7.18 (m, 4H), 6.56 (s, 2H), 4.16 (s, 6H),
3.84 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 157.2, 156.3, 141.0,
138.9, 123.9, 123.2, 122.2, 119.6, 109.8, 107.2, 97.9, 88.8, 57.1,
55.6; IR (νmax) 3422, 2937, 2835, 1608, 1452, 1322, 1197, 1127,
982, 745 cm-1; HRMS calcd for C28H24N2O4 (M+) 452.1736, found
452.1755.
3-Methoxycarbazole, 15. Synthesized according to the general
procedure. Light brown solid; mp 152-153 °C; Rf 0.2 (petroleum
ether/ethyl acetate 90/10); 1H NMR (400 MHz, DMSO-d6) δ 11.03
(s, NH), 8.09 (d, J ) 7.8 Hz, 1H), 7.67 (d, J ) 2.5 Hz, 1H), 7.44
(br d, J ) 8.1 Hz, 1H), 7.39 (br d, J ) 8.7 Hz, 1H), 7.34 (ddd, J
) 8.2, 7.0, and 1.1 Hz, 1H), 7.11 (ddd, J ) 7.9, 7.0, and 1.0 Hz,
1H), 7.02 (dd, J ) 8.7 and 2.5 Hz, 1H), 3.84 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 152.8, 140.2, 134.4, 125.2, 122.6, 122.3,
120.1, 117.8, 114.6, 111.5, 110.8, 102.8, 55.5; IR (νmax) 3404, 1460,
1170, 1132, 817, 748 cm-1; HRMS calcd for C13H11NO (M+)
197.0841, found 197.0834.
3,3′-Dimethoxy-1,9′-bicarbazole, 16. Synthesized according to
the general procedure. Brown oil; Rf 0.45 (petroleum ether/ethyl
acetate 80/20); 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J ) 7.4 Hz,
1H), 8.11 (d, J ) 7.8 Hz, 1H), 7.70 (d, J ) 2.3 Hz, 1H), 7.68 (d,
J ) 2.4 Hz, 1H), 7.61 (br s, 1H), 7.41-7.37 (m, 2H), 7.30 (ddd, J
) 8.0 , 7.0, and 1.0 Hz, 1H), 7.28-7.22 (m, 4H), 7.16 (d, J ) 8.8
Hz, 1H), 7.03 (dd, J ) 8.8 and 2.5 Hz, 1H), 3.98 (s, 3H), 3.96 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 154.5, 154.2, 141.0, 140.0,
135.5, 130.8, 126.5, 126.2, 125.8, 124.0, 123.4, 123.3, 121.2, 120.5,
120.4, 119.8, 119.5, 115.1, 113.3, 111.1, 110.9, 110.2, 103.5, 103.5,
56.3, 56.2; IR (νmax) 3406, 3323, 3005, 2933, 2854, 1594, 1490,
1461, 1432, 1321, 1286, 1203, 1035, 745 cm-1; HRMS calcd for
C26H20N2O2 (M+) 392.1525, found 392.1549.
Benzo[b]carbazole-6,11-dione, 36. Synthesized according to the
general procedure. Bright orange solid, mp 312-314 °C; Rf 0.3
1
(CH2Cl2); H NMR (400 MHz, DMSO-d6) δ 13.08 (s, NH), 8.21
(d, J ) 7.9 Hz, 1H), 8.13-8.09 (m, 2H), 7.86 (td, J ) 7.4 and 1.6
Hz, 1H), 7.81 (td, J ) 7.4 and 1.6 Hz, 1H), 7.6 (d, J ) 8.3 Hz,
1H), 7.45 (ddd, J ) 8.3, 7.0, and 1.2 Hz, 1H), 7.37 (ddd, J ) 8.0,
7.0, and 1.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 180.3,
177.5, 138.1, 137.1, 134.1, 134.0, 133.1, 132.5, 126.9, 126.0, 125.9,
123.9, 123.8, 122.3, 117.3, 113.8; IR (νmax) 3255, 2920, 2852, 1643,
1008, 753, 708, 659 cm-1; HRMS calcd for C16H9NO2 (M+)
247.0633, found 247.0619.
2-Nitrodibenzofuran, 40. Synthesized according to the general
procedure. Light brown solid; mp 151-152 °C; Rf 0.3 (petroleum
ether/diethyl ether 98/2); 1H NMR (400 MHz, CDCl3) δ 8.88 (dd,
J ) 2.4 and 0.4 Hz, 1H), 8.40 (dd, J ) 9.0 and 2.4 Hz, 1H), 8.04
(ddd, J ) 7.7, 1.3, and 0.7 Hz, 1H), 7.66 (dd, J ) 9.0 and 0.5 Hz,
1H), 7.65 (ddd, J ) 8.3, 1.0, and 0.7 Hz, 1H), 7.58 (ddd, J ) 8.5,
3-Fluorocarbazole, 30. Synthesized according to the general
procedure. Light brown solid; mp 209-211 °C; Rf 0.45 (petroleum
ether/ethyl acetate 80/20); 1H NMR (400 MHz, DMSO-d6) δ 11.30
7.1, and 1.3 Hz, 1H), 7.45 (ddd, J ) 7.7, 7.2, and 1.1 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 159.2, 157.5, 128.9, 125.0, 123.9, 123.1,
J. Org. Chem. Vol. 73, No. 13, 2008 5027

Lie´gault et al.
123.0, 121.3, 117.1, 112.3, 112.0; IR (νmax) 2916, 2847, 1525, 1339,
1182, 745 cm-1; HRMS calcd for C12H7NO3 (M+) 213.0426, found
213.0434.
argon, then DMF (20 mL) is added. The solution is cooled to 0
°C, and indole (10 mmol, 1.17 g) is added portionwise. After 15
min at 0 °C, 3-methoxybenzoyl chloride (12 mmol, 1.6 mL) is added
dropwise. The solution is then stirred at room temperature overnight,
quenched carefully by addition of water, diluted with CH2Cl2,
washed with H2O (3 times), dried over MgSO4, filtered, and
evaporated under reduced pressure. The crude product is purified
by silica gel column chromatography with petroleum ether/AcOEt,
and by Kugelrohr distillation, to afford 1.99 g of 43 as a light pink
oil in 79% yield, which exhibited identical spectral data to that
previously reported.4b Rf 0.2 (petroleum ether/ethyl acetate 95/5);
1H NMR (400 MHz, CDCl3) δ 8.40 (dd, J ) 8.3 and 0.8 Hz, 1H),
7.60 (d, J ) 7.5 Hz, 1H), 7.44-7.36 (m, 2H), 7.33-7.26 (m, 4H),
7.13 (ddd, J ) 8.3, 2.6, and 1.0 Hz, 1H), 6.60 (dd, J ) 3.8 and 0.6
Hz, 1H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.5, 159.6,
136.0, 135.8, 130.8, 129.6, 127.6, 124.9, 124.0, 121.4, 120.9, 118.0,
116.4, 114.1, 108.6, 55.5.
N-Benzoylindole, 41. Indole (16.9 mmol, 1.98 g) and DMAP
(2.3 mmol, 279 mg) are weighed to air and transferred to a round-
bottomed flask. The flask is then capped with a rubber septum and
purged with argon, then CH2Cl2 (36 mL) is added. The solution is
cooled to 0 °C, and triethylamine (25.6 mmol, 3.6 mL) and benzoyl
chloride (17 mmol, 2.0 mL) are successively added dropwise. The
solution is then stirred at room temperature overnight, diluted with
CH2Cl2, washed with a saturated aqueous solution of Na2CO3, dried
over MgSO4, filtered, and evaporated under reduced pressure. The
crude product is purified by silica gel column chromatography with
petroleum ether/Et2O to afford 2.72 g of 41 as a light pink solid in
73% yield, which exhibited identical spectral data to that previously
reported.24 Rf 0.5 (petroleum ether/ethyl acetate 90/10); H NMR
1
(400 MHz, CDCl3) δ 8.41 (d, J ) 8.3 Hz, 1H), 7.74-7.72 (m,
2H), 7.62-7.57 (m, 2H), 7.52 (t, J ) 7.4 Hz, 2H), 7.38 (m, 1H),
7.33-7.28 (m, 2H), 6.61 (dd, J ) 3.8 and 0.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 168.7, 136.0, 134.6, 131.9, 130.8, 129.1,
128.6, 127.6, 124.9, 123.9, 120.9, 116.4, 108.5.
N-(3-Methoxybenzoyl)indole, 43. NaH (60%, 15 mmol, 600
mg) is weighed to air and transferred to a round-bottomed flask.
The flask is then capped with a rubber septum and purged with
Acknowledgment. We thank NSERC, CFI, OIT, the Uni-
versity of Ottawa, the Research Corporation, Merck Frosst
Canada, Boehringer Ingelheim (Laval), and AstraZeneca for
financial support of this work.
Supporting Information Available: Copies of NMR spectra
for intramolecular coupling products and all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) For Clausenine, see: Chakraborty, A.; Chowdhury, B. K.; Bhattacharyya,
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(16) Tamariz and co-workers recently reported the palladium-mediated
synthesis of Murrayafoline A 17 and Clausenine 18 in 71% and 72% yield,
respectively, using a stoichiometric amount of Pd(OAc)2.5g,j
(17) Kno¨lker, H.-J.; Bauermeister, M. J. Chem. Soc., Chem. Commun. 1990,
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(23) Due to difficulties in the separation of dibenzofurans from diaryl ethers
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(19) (a) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046–2067. (b)
Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125.
(20) Harris, M. C.; Huang, X.; Buchwald, S. L. Org. Lett. 2002, 4, 2885.
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5028 J. Org. Chem. Vol. 73, No. 13, 2008