Palladium-catalyzed method for the synthesis of carbazoles via tandem C-H functionalization and C-N bond formation

Article abstract of DOI:10.1021/jo801273q

(Chemical Equation Presented) The development of a new method for the assembly of unsymmetrical carbazoles is reported. The strategy involves the selective intramolecular functionalization of an arene C-H bond and the formation of a new arene C-N bond. The substitution pattern of the carbazole product can be controlled by the design of the biaryl amide substrate, and the method is compatible with a variety of functional groups. The utility of the new protocol was demonstrated by the concise synthesis of three natural products from commercially available materials.

Full text of DOI:10.1021/jo801273q

Palladium-Catalyzed Method for the Synthesis of Carbazoles via
Tandem C-H Functionalization and C-N Bond Formation
W. C. Peter Tsang, Rachel H. Munday, Gordon Brasche, Nan Zheng, and
Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology Cambridge, Massachusetts 02139
sbuchwal@mit.edu
ReceiVed June 13, 2008
The development of a new method for the assembly of unsymmetrical carbazoles is reported. The strategy
involves the selective intramolecular functionalization of an arene C-H bond and the formation of a
new arene C-N bond. The substitution pattern of the carbazole product can be controlled by the design
of the biaryl amide substrate, and the method is compatible with a variety of functional groups. The
utility of the new protocol was demonstrated by the concise synthesis of three natural products from
commercially available materials.
Introduction
Carbazole alkaloids manifest a variety of biological activities
and, hence, they are attractive synthetic targets.1,2 The indig-
enous application of the stem bark of the curry-leaf tree as folk
medicine2 led to the discovery of the antibacterial, antifungal,
and antiviral properties of this class of natural products.1-4 The
anti-inflammatory properties of carbazomycin B4,5 and the anti-
tumor properties of ellipticine derivatives6 encouraged the
development of synthetic methods for the preparation of
carbazoles (Figure 1). Carvedilol7 and carazolol8 were identified
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FIGURE 1. Therapeutically valuable carbazole alkaloids.
for their potential as multiple-action antihypertensive drugs. It
was later realized that their therapeutic value might derive from
the properties of the 4-alkoxycarbazole cores that act as potent
antioxidants against radical-induced lipid oxidation. Subse-
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10.1021/jo801273q CCC: $40.75
Published on Web 08/29/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7603–7610 7603

Tsang et al.
quently, new molecules with a 4-alkoxycarbazole core have been
developed for the treatment of obesity and type II diabetes.9
to our investigations, Du Bois, Che, and their respective co-
workers had demonstrated that a metal-catalyzed sequence
converting an alkyl C-H bond to a C-N bond can be quite
efficient.15-18 On the basis of successful applications of direct
arylation of arene C-H bonds in recent years19 and our long-
standing interest in the formation of aromatic C-N bonds,20
we felt that it should be possible to realize an overall substitution
reaction where an arene C-H bond is replaced with a C-N
bond. In late 2005,21 our laboratory reported a new strategy for
assembling simple unsymmetrical carbazoles by combining
sequential palladium-catalyzed C-H functionalization and C-N
bond-forming reactions, although the substrate scope was limited
to molecules containing functional groups that were compatible
with the co-oxidant Cu(OAc)2. This method was recently
adopted by Shi as a part of an elegant sequence for the synthesis
of unsymmetrical carbazoles such as 4-deoxycarbazomycin B.22
To address the shortcomings of our earlier work, we decided
to expand our research to address the issue of the functional
group compatibility, to study the reaction mechanism, and to
apply the method to the synthesis of naturally occurring
carbazoles. Herein we report our progress toward achieving these
goals.
In addition to their use in medicinal chemistry, carbazoles
have attracted increasing attention from the community of
material scientists owing to their potential in photophysical and
optoelectronic applications. Polyvinylcarbazole (PVK) has been
extensively investigated for its use in photorefractive materials
and xerography, while N-ethylcarbazole (ECz) was recognized
as an effective charge-transporting functional plasticizer for PVK
and other doped polymers.10 In the past decade, carbazole
compounds were intensively investigated for the development
of optoelectronic applications such as polymeric light-emitting
diodes (PLED)10a,c,11 and organic light-emitting devices
(OLED).12-14 In particular, it was found that certain carbazole
oligomers led to a family of host materials that were suitable
for the electrophosphorescence of blue lights,12,13 a critical
component for the fabrication of commercial OLED displays.
In view of these important applications, we set out to develop
a metal-catalyzed synthesis of unsymmetrical carbazoles. Prior
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Synthesis of Carbazoles
TABLE 1. Investigation of Palladium Precatalysts and Reoxidants
TABLE 2. Evaluation of Reoxidants in the Synthesis of
Carbazoles
reoxidant/
equiv
gas time yield
entry
Pd source
Pd(OAc)2
solvent atm (h) (%)a
1
2
3
4
5
6
7
8
Cu(OAc)2/1
toluene O2
toluene O2
toluene O2
toluene O2
toluene O2
toluene O2
toluene O2
toluene O2
toluene O2
12
12
12
24
24
24
24
12
12
12
12
12
92
5
0
70
21
27
67b
5
entry
R
reoxidant/equiv solvent gas atm time (h) yield (%)a
Pd(OAc)2
Cu(OAc)2/1
Cu(OAc)2/1
Cu(OAc)2/1
1
2
3
4
5
6
7
H
H
H
Cu(OAc)2/1
Cu(OAc)2/1
Cu(OAc)2/0.2 toluene
toluene
toluene
air
O2
O2
O2
O2
O2
O2
24
12
12
12
12
12
12
94
92b
90
Pd(O2CCF3)2
PdCl2
PdCl2(CH3CN)2 Cu(OAc)2/1
OMe Cu(OAc)2/0.2 toluene
CF3
H
88
PdCl2(PPh3)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cu(OAc)2/1
PPh3/0.2
pyridine/0.2
Phl(OAc)2/0.2
K2S2O8/5
Cu(OAc)2/0.2 toluene
76
DMSO
DMF
92b
11b
9
1
H
10
11
12
DCEc
DCEd
air
air
25
2
a Isolated yield after silica gel chromatography. b GC yield was
determined with respect to a calibrated internal standard.
benzoquinone/1 toluene air
4
a GC yield was determined with respect to a calibrated internal standard.
b About 5-10% diacetylated amide of 2-aminobiphenyl was observed.
c Slightly higher yield was obtained in dichloroethane than in methylene
chloride. d The reaction was performed at 80 °C in dichloroethane; the same
low yield was observed with or without bases.
TABLE 3. Effect of Nitrogen Protecting Groups
Results and Discussion
entry
R
reoxidant/equiv
Cu(OAc)2/1
solvent
yield (%)a
Catalyst and Oxidation Systems for the Synthesis of
Carbazoles. We initiated our investigation by studying the
conversion of 2-acetaminobiphenyl (1) to N-acetylcarbazole (2).
Substrate 1 was quantitatively converted to 2 in the presence
of a stoichiometric amount of Pd(OAc)2 in toluene at 120 °C
after 24 h. As shown in Table 1 (entry 1), a near-quantitative
yield of 2 can also be obtained with a combination of 5%
Pd(OAc)2 and 1 equiv of Cu(OAc)2 in an atmosphere of oxygen.
No product was observed in the absence of Pd(OAc)2, suggest-
ing that the role of Cu(OAc)2 was primarily to mediate the
reoxidation of the reduced palladium species. Other commercially
available palladium precatalysts (entries 4-7) were less efficient
than Pd(OAc)2 in affecting the transformation. Attempts to use other
reoxidants (entries 8-12), which have been reported to be effective
in mediating other palladium-catalyzed oxidative coupling reac-
tions,23 were largely unsuccessful.
Air could be used in the place of oxygen in the synthesis of
2 (Table 2, entry 1), although the reaction was significantly
slower compared to that using oxygen (entry 2). We subse-
quently found that in the presence of oxygen, a catalytic amount
of Cu(OAc)2 was sufficient to effect the synthesis of carbazoles.
Three 2-substituted carbazoles (Note: the numbering of the rings
changes from the starting biarylamides to the carbazole products)
were obtained in >75% yield using only 20% Cu(OAc)2 for
reactions carried out in toluene as the solvent (entries 3-5).
Studies of these three cyclizations also revealed the trend:
Cu(OAc)2 as low as 10% could be used in the cases where the
“bottom” aryl ring is neutral or electron-rich; on the other hand,
it appears that a minimum of 20% Cu(OAc)2 is necessary in
the cases where the bottom ring bears an electron-withdrawing
group. Because of the functional group compatibility, the need
1
2
3
4
5
6
7
8
9
10
Ac
Ac
toluene
DMSO
toluene
DMSO
toluene
DMSO
toluene
DMSO
toluene
DMSO
92
92
SO2Ph
SO2Ph
BOC
BOC
COPh
COPh
COCF2CF3
COCF2CF3
Cu(OAc)2/1
Cu(OAc)2/1
Cu(OAc)2/1
Cu(OAc)2/1
81b
99
34
30
<10c
<10c
0
0
a Isolated yield after silica gel chromatography, average of two runs.
b 10% Pd(OAc)2 was used. c Yield estimated from GC analysis.
to use Cu(OAc)2 as a cocatalyst is a limitation of the method.
In our search for improved reaction conditions, we found that
when dimethyl sulfoxide (DMSO) was used as the solvent under
an atmosphere of oxygen, no Cu(OAc)2 was necessary and a
comparable yield of 2 was obtained (entry 6). Presumably in
this case, DMSO is acting as a ligand to support the direct
oxidation of Pd(0) to Pd(II) with oxygen.24 Protocols that
employed other polar solvents such as N,N-dimethylformamide
(DMF) gave poor yields of 2 (entry 7).
Having established that acetamide-based biaryl amides were
efficiently transformed to the carbazoles in the presence of
oxygen with either Cu(OAc)2 or when carried out in DMSO
(Table 3, entries 1 and 2), we turned our attention to substrates
containing other amine protecting groups. Sulfonamide-based
biaryl amides underwent the cyclization just as efficiently as
the corresponding acetamide (entries 3 and 4). In contrast,
2-aminobiphenyl protected as other amides such as benzamide,
tert-butylcarboxycarbonylamide (BOC-amide), and pentafluo-
ropropionamide provided much lower yields of the desired
products (entries 5-10). It appeared that part of the reason for
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J. Org. Chem. Vol. 73, No. 19, 2008 7605

Tsang et al.
SCHEME 1. Synthesis of Biaryl Acetamides by Suzuki-Miyaura Coupling
TABLE 4. Synthesis of Substituted Carbazoles by Cyclization of
Biaryl Amides
the lower yields in these cases was the cleavage of the amide
under the reaction conditions prior to complete conversion to
the carbazole. This was clearly observed in the case of the N-Boc
substrate when the reaction was attempted in DMSO. In this
case, both the 2-aminobiphenyl and free carbazole generated
appeared to inhibit the palladium-catalyzed transformation. Since
the acetamide group is generally easier to remove than the
sulfonamide group, we focused on the formation of N-
acetylcarbazoles in subsequent studies of the substrate scope.
The free carbazoles can be librated in almost quantitative yield
(97%) by treatment with either acid (1:5 H2SO4:MeOH) or base
(DBU) at 60-80 °C (see the Supporting Information).
Synthesis of Substituted Biaryl Amides and 9-Acetylcar-
bazoles. A variety of substituted biaryl acetamide compounds
were prepared in near-quantitative yield from commercially
available 2′-bromoacetanilide and appropriate boronic acids
(Scheme 1, eq 1). The Suzuki-Miyaura coupling reaction was
carried out in the presence of a bulky biaryl phosphine,
2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (SPhos),
following a procedure recently developed in our laboratory.25
The reaction can be extended to chloroacetanilide substrates in
cases where the substituted bromoacetanilide is inaccessible or
costly (Scheme 1, eq 2).
Acetylcarbazoles with various substitution patterns can be
obtained in excellent yields via the palladium-catalyzed cy-
clization reaction (Table 4). In particular, the presence of a
substituent (C3′) adjacent to the acetamide moiety in the “upper”
ring did not affect the efficiency of the cyclization reaction
(entries 1 and 2). This observation is significant as it allows us
to conveniently assemble carbazoles in excellent yields with
substitution at both positions meta to the biaryl axis, which is
the substitution pattern observed in Mukonine and a number of
related natural products.1,2 Furthermore, the presence of sub-
stituents at positions ortho or para to the biaryl axis did not
affect the formation of the carbazole (entries 6-9). Carbazoles
with substitution on both rings were also assembled in good
yield (entry 10). The 2-methoxy-6-methylcarbazole core is a
synthetically useful building block and has recently been
elaborated to form Siamenol,26 a 3,6-disubstituted 2-hydroxy-
carbazole with anti-HIV activity.27
While all the examples in Table 4 were performed on a 0.2
mmol scale in our initial investigation, both steps in our method
a Isolated yield after silica gel chromatography, average of two runs.
(25) (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685–4696. (b) Walker, S. D.; Barder, T. E.; Martinelli,
J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871–1876.
(26) Krahl, M. P.; Ja¨ger, A.; Krause, T.; Kno¨lker, H.-J. Org. Biomol. Chem.
2006, 4, 3215–3219.
(27) Meragelman, K. M.; McKee, T. C.; Boyd, M. R. J. Nat. Prod. 2000,
63, 427–428.
can be scaled up with no loss in yield, allowing efficient access
to the target carbazoles in sufficient quantity from commercial
reagents. For example, the biaryl amide 2-acetamino-2′-meth-
7606 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of Carbazoles
TABLE 5. Investigation of Functional Group Compatibility
TABLE 6. Regioselective Synthesis of 3-substituted Carbazoles
yield (%)a
entry
R
reoxidant/equiv
solvent
yield (%)a
entry
R
reoxidant/equiv
solvent
1
2
3
4
5
6
7
8
9
F
Me
Cu(OAc)2/1
Cu(OAc)2/1
Cu(OAc)2/1
Cu(OAc)2/1
Cu(OAc)2/1
Cu(OAc)2/1
toluene
toluene
toluene
toluene
toluene
toluene
DMSO
DMSO
DMSO
87
98
97
94
86
96
82
72b
84b
1
2
3
4
5
6
7
Me
Cu(OAc)2/1
Cu(OAc)2/1
toluene
toluene
DMSO
toluene
toluene
toluene
toluene
82b
41c
59
86
99
OMe
OMe
CF3
CO2Me
OTIPS
TBS
OMe
CF3
COMe
CO2Me
SMe
NO2
Cu(OAc)2/1
Cu(OAc)2/1
Cu(OAc)2/1
Cu(OAc)2/1
81
98
a Isolated yield after silica gel chromatography, average of two runs.
Unless otherwise stated, the regioisomeric ratio is >25:1 (GC); only the
major product is shown. b Selectivity ) 18:1 (GC). c Selectivity ) 16:1
(GC).
CN
a Isolated yield after silica gel chromatography, average of two runs.
b 10% Pd(OAc)2 was used.
SCHEME 2. Our Initial Proposed Pathway for Carbazole
Synthesis
oxybiphenyl (entry 6) could be obtained in 97% yield on a 15
mmol scale from 2′-bromoacetanilide and 2-methoxyphenyl-
boronic acid with 1% Pd(OAc)2, 2% SPhos, and K3PO4 in
toluene in 30 min at 90 °C. That product was cyclized in the
presence of Pd(OAc)2, DMSO, and oxygen and subsequently
hydrolyzed to give 9H-4-methoxycarbazole in 86% yield in 2
steps on a 5 mmol scale. This gram-scale experiment demon-
strated the practicality of our method to access carbazoles such
as 9H-4-hydroxycarbazole, a major building block for a variety
of therapeutically valuable candidates.7-9
The cyclization process of the biaryl amide was compatible
with a variety of functional groups. Ketone- and methyl ester-
containing substrates can be used in the Cu(OAc)2 protocol
(Table 5). On the other hand, biaryl amides with nitro, cyano,
and even thioether groups were more efficiently cyclized in
DMSO (entries 7-9). Unfortunately, attempts to extend this
cyclization strategy to substrates with heteroaromatic groups
in place of either aryl rings have been unsuccessful.
As shown in Table 4, we have been successful in obtaining
3-substituted carbazoles by derivatizing the “upper” ring (C5′)
in the biaryl amide substrates (entries 3-5). Alternatively, this
class of cabazoles could be obtained by derivatizing the
“bottom” ring (C3). Following this approach, 3-substituted
carbazoles were formed regioselectively in good to excellent
yields as steric factors probably govern the regiochemical nature
of the process (Table 6). The cyclization process was generally
efficient using Cu(OAc)2 as the reoxidant with one exception
(entries 1 and 4-7). In the case of 3-methoxycarbazole, the
cyclization process appeared to be more efficient when
Cu(OAc)2was replaced with DMSO (entries 2 and 3). When
the “bottom” ring is substituted at both C3 and C5, the
cyclization process was too slow to be synthetically useful.
Mechanism. We previously proposed a tandem electrophilic
palladation and C-N bond formation sequence to account for
the intramolecular addition of the amide group to the aryl ring
(Scheme 2).21,28 In such a pathway, complexation of Pd(OAc)2
to the amide moiety of the substrate (1) could form a palladium
amide (3) with concomitant release of one molecule of acetic
acid. Palladium amide 3 would then undergo electrophilic
palladation to provide a six-membered cyclic palladium amide
4. Reductive elimination produces the carbazole product (2) and
a Pd(0) species, which would be reoxidized to Pd(II) in the
presence of Cu(OAc)2 or DMSO and oxygen to complete the
catalytic cycle.
However, this proposed catalytic cycle appears to be incon-
sistent with two experimental observations. First, based on the
catalytic cycle, the cyclization of 2′-acetamino-3-methoxybi-
phenyl was expected to be more facile than those of 2′-
acetamino-3-(trifluoromethyl)biphenyl and 2′-acetamino-3-
(methoxycarbonyl)biphenyl. However, the experimental data did
not support this prediction (Table 6, entries 2, 4, and 5). Second,
during our initial optimization studies, attempts to effect the
cyclization of biaryl amide 1 at temperatures below 120 °C were
met with low yields. For example, only 10% of product 2 was
observed at 90 °C after 24 h, and no product was observed at
60 °C. In subsequent studies of substituent effects on the
cyclization at 90 °C, we were surprised to see that among all
the substrates with substituents at C4 examined, only 2′-
acetamino-4-methoxybiphenyl cyclized to the carbazole in
satisfactory yield, although this substrate would be expected to
destabilize the proposed intermediate due to the inductive effect
of the methoxy group in the mechanism suggested in Scheme
2 (Table 7, entry 5). This substituent effect became much less
(28) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org.
Lett. 2007, 9, 2931–2934.
J. Org. Chem. Vol. 73, No. 19, 2008 7607

Tsang et al.
TABLE 7. Reactivity Studies at 90 °C
conditions by the addition of acids or bases slowed down the
cyclization. Despite all our efforts, however, no clear picture
of the reaction mechanism emerged from these studies.
Target-Oriented Synthesis. To demonstrate the efficiency
and applicability of this method, we prepared three naturally
occurring carbazoles (mukonine,30 mukonidine, and glycosinine)
as shown in Scheme 4. Mukonidine and glycosinine were
synthesized from a common acetylcarbazole intermediate 6a
that was formed in 94% yield from biarylamide 5a using this
method. Biarylamide 5a was obtained in 98% yield using a
Suzuki-Miyaura cross-coupling protocol recently developed in
this laboratory.25 Demethylation of 6a followed by acid hy-
drolysis afforded mukonidine in 85% yield. Separately, reduction
of the methyl ester and cleavage of the amide group of 6a
followed by reoxidation of the resulting benzyl alcohol to an
aldehyde provided glycosinine in 74% yield. The synthesis of
mukonine followed a sequence similar to those of mukonidine
and glycosinine. Biarylamide 5b was obtained in 95% yield
using our protocol for a Suzuki-Miyaura cross coupling
between phenylboronic acid and aryl iodide 7 (obtained in 3
steps from commercially available 4-amino-3-methoxybenzoic
acid following published procedures31). Treatment of 5b with
Pd(OAc)2, Cu(OAc)2, and oxygen in toluene followed by acid
hydrolysis afford mukonine in 99% yield in two steps. In short,
mukonidine and glycosinine were synthesized in 79% and 68%
overall yield respectively in 4 steps from commercially available
reagents, while mukonine was synthesized in 74% overall yield
in 6 steps from commercially available reagents.
entry
R
temp (°C)
yield (%)a
1
2
3
4
5
6
7
8
H
120
90
90
90
90
90
90
90
92
3
10
37
73
7
2-CF3
H
2-Me
2-OMe
3-CF3
3-Me
3-OMe
14
8
a GC yield was determined relative to an internal standard.
SCHEME 3. Two Alternative Pathways for Carbazole
Synthesis
Conclusion
The results presented in this paper describe the first applica-
tions of intramolecular conversion of an arene C-H bond to a
C-N bond in the elaboration of synthetically useful molecules
from commercially available and user-friendly reagents. This
C-H functionalization strategy allows the assembly of carba-
zoles with a variety of substitution patterns and functional groups
under relatively mild conditions. The utility of this method has
been unambiguously demonstrated by the high efficiency
displayed in the syntheses of mukonidine, glycosinine, and
mukonine. The observation that DMSO could be used in place
of Cu(OAc)2 broadens the substrate scope of this reaction by
increasing the number of compatible functional groups. For
example, both electron-donating and electron-withdrawing
groups are generally tolerated in the synthesis of these carbazoles
at 120 °C. Even strong electron-withdrawing groups such as
keto, ester, nitro, and cyano groups can all be incorporated into
the carbazoles. Additionally, this method proves particularly
effective for the synthesis of unsymmetrical carbazoles and is
complementary to other syntheses of carbazole alkaloids. This
feature differentiates it from known methods for the synthesis
of carbazoles.19,32-34 For example, the introduction of substit-
uents by traditional electrophilic aromatic substitution of 9H-
carbazole is normally limited to 3 and 6 positions that are para
to the NH moiety.12d,35 Our method allows efficient installation
of substituents at positions ortho and para to the biaryl axis of
pronounced at 120 °C, although 2′-acetamino-4-methoxybiphe-
nyl remained the most reactive substrate. When the biarylamide
is substituted at C3, regardless of the electronic character of
the C3 substituent, the carbazole was formed in about 10% yield
over a 24 h period when the reaction was conducted at 90 °C
(Table 7, entries 6-8).
Concerned by the discrepancy between our initial model and
the data discussed above, we proposed two related catalytic
pathways that could better explain the data (Scheme 3).
Beginning with the formation of palladium amide 3, intramo-
lecular cyclization could take place by different mechanisms
to form two diastereomeric Pd species (5a and 5b). An insertion
into the arene via a Heck-like process would form 5a, which
could undergo a trans ꢀ-hydrogen elimination to provide
carbazole 2.29 Alternatively, 3 could add to the arene via a
Wacker-like process to provide 5b, which would then undergo
a ꢀ-hydrogen elimination to provide carbazole 2. The reoxidation
of the Pd(0) species to Pd(II) in the presence of Cu(OAc)2 or
DMSO and oxygen would complete the catalytic cycle. To
further probe these three possible pathways for the cyclization
process, we undertook NMR studies of stoichiometric reactions,
measurement of inter- and intramolecular kinetic isotope effects,
and the examination of substituent effects on the rate of the
reaction. We also note that attempts to modify the reaction
(30) Lie´gault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org.
Chem. 2008, 73, 5022–5028.
(31) Ezquerra, J.; Pedregal, C.; Lamas, C. J. Org. Chem. 1996, 61, 5804–
5812.
(32) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc.
2006, 128, 581–590.
(33) Liu, Z.; Larock, R. C. Tetrahedron 2007, 63, 347–355.
(34) Bedford, R. B.; Betham, M. J. Org. Chem. 2006, 71, 9403–9410.
(29) For one selected example of intramolecular Heck reaction via a trans
ꢀ-hydrogen elimination, see: Lautens, M.; Fang, Y.-Q. Org. Lett. 2003, 5, 3679–
3682.
7608 J. Org. Chem. Vol. 73, No. 19, 2008

Synthesis of Carbazoles
SCHEME 4. Synthesis of Three Naturally Occurring Carbazolesa
a Reagents and conditions: (a) 1 mol % Pd(OAc)2, 2 mol % SPhos, K3O4, THF:H2O (20:1), PhB(OH)2, 70 °C, 3 h; (b) 5 mol % Pd(OAc)2, Cu(OAc)2,
O2, 120 °C, 12 h; (c) BBr3, CH2Cl2, 0 °C, 30 min; (d) H2SO4:MeOH (1:5), 80 °C, 15 min; (e) LiAlH4, Et2O, rt, 2 h; (f) MnO2, acetone, rt, 3 d; (g) SOCl2,
MeOH, rt, 17 h; (h) Py2IBF4, CF3SO3H, CH2Cl2, rt, 18 h; (i) Ac2O, H2SO4:CH2Cl2 (1:18), 0 °C to rt, 21 h; (j) H2SO4:MeOH (1:5), 80 °C, 10 min.
9-Acetyl-2-acetylcarbazole. Following Protocol A (12 h), an
off-white powder was obtained after silica gel chromatography
(gradient; hexanes:EtOAc, 95:5 to 60:40), yielding 44 mg (87%,
mp 110 °C). 1H NMR (500 MHz, CDCl3) δ 8.91 (s, 1H), 8.22 (d,
J ) 8.4 Hz, 1H), 8.12-7.98 (m, 3H), 7.57 (t, J ) 7.9 Hz, 1H),
7.44 (t, J ) 7.5 Hz, 1H), 2.95 (s, 3H), 2.74 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 198.04, 170.31, 140.08, 138.70, 136.22, 130.46,
128.96, 125.61, 124.24, 124.19, 121.01, 119.84, 116.92, 116.50,
28.07, 27.19. IR (KBr plate, CDCl3) ν 3004, 1693, 1678, 1418,
1368, 1326, 1304, 1229, 1020, 749. Anal. Calcd for C16H13NO2:
C, 76.48; H, 5.21. Found: C, 76.30; H, 5.25.
the amide substrate and leads to carbazoles that are substituted
at 2 and/or 4 positions. While the Pd-catalyzed cyclization of
o-halo diarylamines to carbazoles generally favors 2-substituted
carbazoles over 4-substituted ones,33,34 our method permits
extremely efficient synthesis of 4-substituted carbazoles. Using
this method, the carbazole cores substituted from C1 to C8 can
be prepared. Although we have undergone a number of studies
to probe the mechanism for the cyclization process, no clear
picture about its detailed course has emerged from these
studies.
General Procedure for the Synthesis of Carbazoles in
Dimethyl Sulfoxide (DMSO) (Protocol C). An oven-dried Schlenk
tube (15 mL in volume) was cooled under vacuum or Ar.
Biarylamide (0.2 mmol), Pd(OAc)2 (2.3 to 4.6 mg, 0.01 to 0.02
mmol, 5 to 10%), and powdered molecular sieves (40 mg, activated
3Å) were added under air. The tube was evacuated and refilled
with Ar. Under a positive Ar pressure, DMSO (2 mL) was added
via syringe. The reaction mixture was sonicated and degassed under
a weak vacuum and refilled with O2 from the double manifold (this
sequence was carried out three times). The sealed Schlenk tube
was lowered into an oil bath at 120 °C and stirred for 24 h. After
cooling to room temperature, distilled water (5 mL) and EtOAc (3
mL) were added to the reaction mixture. The organic phase was
separated, and the aqueous phase was further extracted with EtOAc
(3 × 3 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered through Celite, and concentrated. The
residue was purified by silica gel chromatography using a mixture
of hexanes and EtOAc to provide the desired carbazole. A
representative example is as follows.
Experimental Section
General Procedure for the Synthesis of Carbazoles in the
Presence of Anhydrous Cu(OAc)2 (Protocol A). An oven-dried
Schlenk tube (15 mL in volume) was cooled under vacuum and
Ar. Biarylamide (0.2 mmol), Pd(OAc)2 (2.3 mg, 0.01 mmol, 5%),
and powdered molecular sieves (40 mg, activated 3Å) were added
under air. The tube was evacuated and refilled with Ar. Anhydrous
Cu(OAc)2 (36.3 mg, 0.2 mmol) was loaded into the Schlenk tube
in a nitrogen-filled glovebox. Under a positive Ar pressure, toluene
(2 mL) was added via syringe. The reaction mixture was sonicated
and degassed under a weak vacuum and refilled with O2 from the
double manifold (this sequence was carried out three times). The
sealed Schlenk tube was lowered into an oil bath at 120 °C and
stirred for 12-24 h. After cooling to room temperature, distilled
water (1 mL), ammonium hydroxide solution (3 mL, 30%), and
EtOAc (2 mL) were added to the reaction mixture. The organic
phase was separated, and the aqueous phase was further extracted
with EtOAc (3 × 2 mL). The combined organic layers were dried
over anhydrous Na2SO4 and filtered through Celite, and concen-
trated. The residue was purified by silica gel chromatography using
a mixture of hexanes and EtOAc to provide the desired carbazole.
A representative example is as follows.
9-Acetyl-2-methylthiocarbazole. Following Protocol C (5%
Pd(OAc)2, 24 h), a white powder was obtained after silica gel
chromatography (gradient; hexanes:EtOAc, 95:5 to 90:10), yielding
43.0 mg (84%, mp 79 °C). 1H NMR (500 MHz, CDCl3) δ 8.27 (s,
1H), 8.09 (d, J ) 8.4 Hz, 1H), 7.95 (d, J ) 7.7 Hz, 1H), 7.89 (d,
J ) 8.2 Hz, 1H), 7.47 (t, J ) 7.8 Hz, 1H), 7.39 (t, J ) 7.5 Hz,
(35) (a) Zhu, Z.; Moore, J. S. J. Org. Chem. 2000, 65, 116–123. (b) Zhu, Z.;
Moore, J. S. Macromolecules 2000, 33, 801–807. (c) Buu-Ho¨ı, N. P.; Hoa´n, N.
J. Org. Chem. 1951, 16, 1327–1332. (d) Buu-Ho¨ı, N. P.; Royer, R. J. Org. Chem.
1951, 16, 1198–1205. (e) Tucker, S. H. J. Chem. Soc. 1926, 546–553.
1H), 7.32 (dd, J ) 8.1, 1.5 Hz, 1H), 2.89 (s, 3H), 2.61 (s, 3H). 13
C
NMR (125 MHz, CDCl3) δ 170.31, 139.57, 138.59, 138.34, 127.20,
126.53, 124.05, 123.97, 122.94, 120.03, 119.90, 116.11, 114.73,
J. Org. Chem. Vol. 73, No. 19, 2008 7609

Tsang et al.
28.02, 16.75. IR (KBr plate, CDCl3) ν 2919, 1693, 1596, 1435,
1411, 1367, 1325, 1303, 1272, 1213, 1189, 1020, 765, 747. Anal.
Calcd for C15H13NOS: C, 70.56; H, 5.13. Found: C, 70.40; H, 5.17.
through a postdoctoral fellowship. N.Z. thanks the National
Institutes of Health for a postdoctoral fellowship (F32-
GM074407).
Acknowledgment. We thank Johnson & Johnson (Focused
Giving Grant), the National Institutes of Health (GM58160),
and the National Cancer Institute (Cancer Training Grant CA
09112) for supporting this research. G.B. thanks the Deut-
scher Akademischer Austauschdienst (DAAD) for support
Supporting Information Available: Experimental proce-
dures and spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO801273Q
7610 J. Org. Chem. Vol. 73, No. 19, 2008