Intramolecular oxidative C-N bond formation for the synthesis of carbazoles: Comparison of reactivity between the copper-catalyzed and metal-free conditions

Article abstract of DOI:10.1021/ja111652v

New synthetic procedures for intramolecular oxidative C-N bond formation have been developed for the preparation of carbazoles starting from N-substituted amidobiphenyls under either Cu-catalyzed or metal-free conditions using hypervalent iodine(III) as an oxidant. Whereas iodobenzene diacetate or bis(trifluoroacetoxy)iodobenzene alone undergoes the reaction to provide carbazole products in moderate to low yields, combined use of copper(II) triflate and the iodine(III) species significantly improves the reaction efficiency, giving a more diverse range of products in good to excellent yields. On the basis of mechanistic studies including kinetic profile, isotope effects, and radical inhibition experiments, the copper species is proposed to catalytically activate the hypervalent iodine(III) oxidants. The synthetic utility of the present approach was nicely demonstrated in a direct synthesis of indolo[3,2-b]carbazole utilizing a double C-N bond formation.

Full text of DOI:10.1021/ja111652v

ARTICLE
pubs.acs.org/JACS
Intramolecular Oxidative CꢀN Bond Formation for the Synthesis of
Carbazoles: Comparison of Reactivity between the Copper-Catalyzed
and Metal-Free Conditions
Seung Hwan Cho, Jungho Yoon, and Sukbok Chang*
Department of Chemistry and Molecular-Level Interface Research Center, Korea Advanced Institute of Science of Technology (KAIST),
Daejeon 305-701, Republic of Korea
S Supporting Information
b
ABSTRACT: New synthetic procedures for intramolecular oxida-
tive CꢀN bond formation have been developed for the prepara-
tion of carbazoles starting from N-substituted amidobiphenyls
under either Cu-catalyzed or metal-free conditions using hyperva-
lent iodine(III) as an oxidant. Whereas iodobenzene diacetate or
bis(trifluoroacetoxy)iodobenzene alone undergoes the reaction to
provide carbazole products in moderate to low yields, combined
use of copper(II) triflate and the iodine(III) species significantly
improves the reaction efficiency, giving a more diverse range of
products in good to excellent yields. On the basis of mechanistic studies including kinetic profile, isotope effects, and radical
inhibition experiments, the copper species is proposed to catalytically activate the hypervalent iodine(III) oxidants. The synthetic
utility of the present approach was nicely demonstrated in a direct synthesis of indolo[3,2-b]carbazole utilizing a double CꢀN bond
formation.
’ INTRODUCTION
proper combination of copper species and oxidants would promote an
intramolecular oxidative CꢀN bond formation of N-substituted
amidobiphenyls to give carbazoles by taking advantage of the high
electrophilicity of presumed Cu(III) intermediates.12 We herein
describe our new finding that carbazole synthesis can indeed be facilitated
by the action of a copper catalyst under oxidative conditions, revealing that
the copper species works as an activator of the iodine(III) oxidants
employed. In addition, we also discovered that oxidative CꢀN bond
formation is possible even in the absence of copper species, although the
reaction efficiency is lower under metal-free conditions.13 Since carbazole is
an important structural motif having a diverse range of applications,
such as bioactive alkaloids (Figure 1)14,15 and electronic materials,16
new practical synthetic methods for the preparation of carbazoles are
highly desired.
Direct installation of nitrogen groups into hydrocarbons,
without relying on prefunctionalization of the simple compounds
to the corresponding organic (pseudo)halides, is a highly attrac-
tive synthetic strategy as an atom-economic and environmentally
benign method for CꢀN bond formation. While an approach
based on nitrenoid transfer to CꢀH bonds was extensively
investigated by using Rh, Ru, or Pd catalysts,1 oxidative amina-
tion of alkenes or (hetero)arenes has been scrutinized only in
recent years.2,3 In this context, Buchwald disclosed an efficient
route to carbazoles starting from 2-acetamidobiphenyl under Pd-
catalyzed oxidative conditions.4 In addition, Gaunt elegantly
utilized a postulated Pd(II)/Pd(IV) catalytic cycle for the pre-
paration of carbazoles under mild oxidative conditions,5 and its
success was attributed to the facile reductive elimination of
aminoaryl palladium(IV) intermediates, leading to CꢀN bond
formation (Scheme 1).6ꢀ8 In this regard, while much effort has
been devoted to the development of Pd-catalyzed oxidative
CꢀH/NꢀH couplings, alternative and/or complementary meth-
ods using more practical metal catalysts such as Cu species or metal-
free conditions are less investigated.
’ RESULTS AND DISCUSSION
To test our initial hypothesis of the Cu-catalyzed intramole-
cular CꢀN bond formation, N-substituted amidobiphenyl deri-
vatives 1aꢀc were subjected to various reaction conditions
(Table 1). When 2-acetamidobiphenyl (1a) was used as a
substrate, no conversion was observed under the conventional
oxidative conditions using O2 or peroxides in the presence of
copper(II) triflate species (entries 1 and 2). In a sharp contrast,
the use of PhI(OAc)2 as an oxidant significantly improved the
In recent years, copper catalysts have come to be regarded as a
promising alternative in metal-catalyzed oxidative coupling reac-
tions to replace costly metal species such as Pd and Rh.9,10
A
postulated organocopper(III) intermediate in the catalytic cycle
of copper species enabled numerous important organic transfor-
mations such as arylation, alkenylation, and alkynylation reac-
tions.11 Based on these observations, we initially envisaged that a
Received: December 27, 2010
Published: March 29, 2011
r
2011 American Chemical Society
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Scheme 1. Oxidative Carbazole Synthesis via CꢀH/NꢀH Couplings
Table 1. Optimization of Oxidant and Additivesa
entry
R1
catalyst
oxidant
additive
yield (%)b
1c
2c
3
Ac (1a)
1a
Cu(OTf)2 O2 (1 atm)
Cu(OTf)2 t-BuOOBz
Cu(OTf)2 PhI(OAc)2
ꢀ
ꢀ
ꢀ
ꢀ
<1
<1
63
74
1a
4
SO2Ph (1b) Cu(OTf)2 PhI(OAc)2
5
1b
Cu(OTf)2 PhI(OAc)2
Cu(OTf)2 PhI(OAc)2
Cu(OTf)2 PhI(OAc)2
Cu(OAc)2 PhI(OAc)2
Cu(OTf)2 PhI(OAc)2
CH3COOH 84
CF3COOH 93 (90)d
CF3COOH 75
CF3COOH 20
CF3COOH <1
CF3COOH 40
6
7e
1b
Figure 1. Biologically active alkaloids bearing a carbazole motif.
1b
8
1b
reaction efficiency to provide N-acetylcarbazole in 63% yield
within 10 min at 50 °C (entry 3).
9
Me (1c)
10f 1b
11f 1b
12f 1a
13f 1a
ꢀ
ꢀ
ꢀ
ꢀ
PhI(OAc)2
Changing the N-substituent from an acetyl to a sulfonyl group
(1b) further increased the product yield (entry 4). In particular,
the addition of an acid additive such as acetic acid also enhanced
the reaction efficiency (entry 5). When trifluoroacetic acid was
employed as an additive, 9-benzenesulfonyl carbazole was iso-
lated in excellent yield within 10 min at 50 °C (entry 6). Impor-
tantly, the reaction proceeded smoothly even at room temperature,
albeit with a slight decrease of the product yield (entry 7).
Cu(OTf)2 was proved to be the choice of catalyst since other
copper sources showed lower efficiency (entry 8). On the other
hand, introducing an electron-donating N-substituent in the
substrate (e.g., 1c) deteriorated the reaction progress (entry 9).
Further investigation of the reaction conditions revealed that
the CꢀN bond formation took place even in the absence of copper
catalysts to some extent (entry 10). Moreover, when N-sulfonyla-
midobiphenyl (1b) was used as a substrate, the reaction effi-
ciency was greatly increased up to 75% NMR yield in the
presence of an acid additive when PhI(OTFA)2 was employed
instead of PhI(OAc)2 (entry 11).17,18 This observation that a
significant amount of background reaction is operative under
metal-free conditions is highly noteworthy, considering the
previous reports that the oxidative cyclization of N-substituted
amidobiphenyls required a palladium catalyst in combination
with certain external oxidants such as Cu(II)/O2 or PhI(OAc)2,
revealed by Buchwald4b and Gaunt,5 respectively (Scheme 1).
In order to elucidate how the copper species is involved in our
cyclization procedures, we first carried out a comparison experiment
PhI(OTFA)2 CF3COOH 75 (75)d
PhI(OTFA)2
PhI(OTFA)2 CF3COOH 38
ꢀ
9
a Reaction conditions: substrate (1, 0.2 mmol), Cu catalyst (5 mol %),
oxidant (1.5 equiv), and additive (3.0 equiv) in 1,2-dichloroethane for 10
min at 50 °C. b NMR yield of 2 (internal standard: 1,1,2,2-tetra-
chloroethane). c Carried out for 12 h. d Isolated yield in parentheses.
e Carried out at 25 °C for 30 min. f Conditions: substrate (1, 0.2 mmol),
oxidant (1.5 equiv), and additive (3.0 equiv) in 1,2-dichloroethane for 10
min at 50 °C.
to see the initial rate difference (within 1 min) between the Cu-
catalyzed and metal-free conditions (Scheme 2). It was observed
that copper species (5 mol %) significantly accelerated the
reaction rate compared to the metal-free conditions using PhI-
(OAc)2 oxidant alone. On the other hand, the use of PhI-
(OTFA)2 instead of PhI(OAc)2 improved the reaction
efficiency, but it was still significantly lower than under the Cu-
catalyzed conditions. Therefore, it is evident that the copper
species plays a pivotal role in facilitating the CꢀN bond
formation under the employed catalytic conditions.
The above result that significant conversion took place even
under metal-free conditions left us with an important question
about the exact role of copper catalyst in combination with the
hyperiodine(III) oxidant, especially with regard to our initial
postulation of the Cu(I)/Cu(III) catalytic cycle.19 In order to
gain mechanistic insights to answer this question, we undertook
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Scheme 2. Initial Rates in the Cu-Catalyzed and Metal-Free
Reaction Conditions
detailed studies of (i) kinetic isotope effects, (ii) kinetic profile of
each reactant under either Cu-catalyzed or metal-free conditions,
and (iii) effects of radical scavengers.
Intra- and intermolecular kinetic isotope effects (KIE, kH/kD)
were readily obtained using deuterium-labeled substrates (eqs 1
and 2). No significant intramolecular isotopic effect was ob-
served, and kH/kD values were similar under either Cu-catalyzed
(1.21) or metal-free conditions (1.37). Likewise, negligible KIE
values were determined in the case of intermolecular experiments
(1.17 and 1.08, respectively). These negligible KIE values
indicate that CꢀH bond cleavage of a phenyl moiety for the
CꢀN bond formation may not be involved in the rate-determin-
ing step during the course of carbazole synthesis. Interestingly,
our observation is distinct from the recently developed Cu-
catalyzed intramolecular CꢀH amination of N-aryl-2-aminopyr-
idines in the synthesis of pyrido[1,2-a]benzimidazoles, in which
the intramolecular KIE was measured to be 2.4.10f
Figure 2. Plot of initial rates versus concentration of (a) oxidant
PhI(OTFA)2 and (b) substrate 1a under metal-free conditions.
Figure 3. Plot of initial rates of copper species.
We next carried out kinetic profile studies to determine the
order of reaction components in the present carbazole synthesis.
Initial rates were monitored upon changing the concentration of
each reactant using 2-acetamidobiphenyl (1a) and hypervalent
iodine(III) as substrate and oxidant, respectively (see Supporting
Information for experimental details). NMR analysis was carried
out by taking aliquots from the reaction mixture at regular
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intervals. As shown in Figure 2, the reaction exhibited approxi-
mately first-order dependence on both PhI(OTFA)2 and sub-
strate 1a under metal-free conditions.
Table 2. Effects of Radical Inhibitor on the Reaction
Efficiencya
Kinetic profiles of the copper species were also obtained to
show that the cyclization proceeded almost independently with
regard to the concentration of Cu(OTf)2 in the range of 2ꢀ6 mol
% at room temperature, suggesting that the copper species are
not involved in the rate-limiting step (Figure 3).
It was initially envisaged that the cyclization could be pro-
moted by generating plausible Cu(III) intermediates under
oxidative conditions since those higher oxidation states of
copper species were known to be highly electrophilic,11aꢀd,19
facilitating the subsequent aromatic attack on the metal center.
However, the observed kinetic insensitivity to the copper
species led us to challenge our initial postulation. Instead, we
now propose that the copper species works as a Lewis acid to
activate hypervalent iodine(III) oxidants.20 In fact, very recently,
Gaunt et al. reported that a meta-selective arylation of R-aryl
carbonyl compounds proceeds even in the absence of copper
catalysts, albeit at higher temperatures compared to Cu-cata-
lyzed conditions.21 This result is especially noteworthy in that
the reaction was originally proposed to be catalyzed at ambient
temperature by a copper(III) species.11e
a Reaction conditions: 1b (0.2 mmol), Cu(OTf)2 (5 mol %, if
necessary), oxidant (1.5 equiv), CF3COOH (3 equiv), and radical
scavanger (1.0 equiv) in 1,2-dichloroethane for 10 min at 50 °C. b NMR
yield of 2b (internal standard: 1,1,2,2-tetrachloroethane). c Carried out
for 24 h.
The kinetic order of oxidant PhI(OAc)2 was next measured to be
first-order under the Cu-catalyzed conditions (Figure 4a), indicating
that the oxidant participates most likely in the rate-limiting step, as
already seen in the metal-free conditions (Figure 2a). On the other
hand, it was highly intriguing to observe that the initial reaction was
inhibited upon increasing the substrate concentration (Figure 4b).
This inverse order dependence of substrate implies that a complex,
presumably in a resting stage, may form by the interaction of copper
species with substrate, and its formation suppresses the Lewis acidic
behavior of the copper employed. A similar inverse order on a
substrate was previously found in the metal-catalyzed hydroamina-
tion of alkenes and alkynes, in which a slimier type of resting state of
substrate-bound complex was assumed to form, thus slowing down
the reaction progress.22
A radical inhibition test was next carried out in order to get
insight into whether the reaction proceeds via radical intermedi-
ates. When 1,1-diphenylethylene or 2,6-di-tert-butyl-4-methyl-
phenol (BHT), which are both known to be effective radical
scavengers, was added to the reaction mixture, the reaction
progress was significantly decreased under either the Cu-cata-
lyzed or metal-free conditions, and only poor product yields were
obtained, even after longer reaction times, suggesting that our
present oxidative CꢀN bond-forming reaction involves radical
intermediates (Table 2).
Based on the above experimental mechanistic data, a plausible
pathway for the oxidative carbazole synthesis is proposed in
Scheme 3, although more comprehensive experiments are re-
quired in order to describe exact mechanistic details. Initially, 2
equiv of the biphenylamido substrate is presumed to bind
reversibly to a metal center to form a tetradentate copper species
(3), and the subsequent step is proposed to form an N-
iodoamido species (4) upon release of acetic acid and Cu(OTf)2
which is ready to participate in the next cycles.17b,c,f In fact, it was
previously reported that certain Lewis acids facilitate the conver-
sion of hypervalent iodine(III) reagents in a number of reactions.18
In accordance with the above radical inhibition experiments, the
following electrophilic aromatic attack of the ortho-phenyl group
onto an amido moiety of 4 is presumed to occur via a radical
Figure 4. Plot of initial rates versus concentration of (a) oxidant and (b)
substrate 1a under Cu-catalyzed conditions.
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Scheme 3. Proposed Mechanistic Pathway
Table 3. Screening of Various Additives
that, while the most frequently used Lewis acid BF3ꢀEt2O displayed
little effects (entry 3), some Lewis acids retarded the conversion
(entries 4 and 5). Interestingly, certain metal Lewis acids containing
trifluoromethanesufonate as a ligand increased the reaction efficiency
(entries 6ꢀ8), albeit to a lower extent compared to the presently
employed copper triflate (entry 2). Although we cannot rule out the
possibility of ligand exchange between Cu(OTf)2 and PhI(OAc)2 to
generate an active iodine species,23 a moderate product yield (entries
9 and 10) was obtained when trifluoromethanesulfonic acid was
employed as an additive. This result indicates that Cu(OTf)2 itself
plays a role to activate the PhI(OAc)2 oxidant for the facile oxidative
transformation.
However, other mechanistic possibilities can also be conceived
(e.g., Scheme 4), in which an aromatic cation radical (7) is generated
by a single electron transfer, presumably through a charge-transfer
π-complex (6), as proposed by Kita et al.18 In fact, it was demon-
strated that aromatic cation radicals can be induced when hyperva-
lent iodine(III) reagents react with electron-rich arenes such
as para-substituted phenol ethers,18a thiophenes,18c or naphthalene
derivatives.18f In those cases, it was shown that subsequent trapping
of the aromatic cation radicals by certain nucleophiles such as
TMSN3 or mesitylene provided the corresponding coupled adducts
with high efficiency.
entry
additive (equiv)
yield (%)b
1
ꢀ
40
93
47
25
15
55
59
68
44
30
2
3
Cu(OTf)2 (0.05)
BF3 Et2O (1.0)
3
4
TMSOTf (1.0)
Zn(OAc)2 (0.05)
Zn(OTf)2 (0.05)
Fe(OTf)2 (0.05)
Sc(OTf)3 (0.05)
CF3SO3H (0.1)
CF3SO3H (1.0)
5
6
7
8
9
10
a Reaction conditions: 1b (0.2 mmol), additive (indicated equiv), PhI-
(OAc)2 (1.5 equiv) and trifluoroacetic acid (3.0 equiv) in 1,2-dichlor-
oethane for 10 min at 50 °C. b NMR yield of 2b (internal standard:
1,1,2,2-tetrachloroethane).
Substrate Scope and Reactivity Pattern. In the present
oxidative CꢀN bond formation, the combined use of Cu(OTf)2
catalyst and PhI(OAc)2 oxidant showed much improved
reaction efficiency compared to the corresponding metal-free
conditions, in which employment of PhI(OTFA)2 gave higher
product yields than PhI(OAc)2. Therefore, we set up two
experimental procedures to apply for a wide range of substrates:
(i) the use of PhI(OAc)2 oxidant in the presence of Cu(OTf)2
catalyst for 10 min at 50 °C, and (ii) employment of
PhI(OTFA)2 alone in the absence of copper species for 10
min at the same temperature.
In general, the catalytic carbazole synthesis proceeded smoothly
with substrates bearing electron-donating substituents (R2) at the
“right” side nucleophilic phenyl part (Table 4, entries 2ꢀ5 and 7). In
those cases, the cyclization was quite facile, even at room temperature
(entries 2ꢀ5). It is especially noteworthy that not only N-sulfonyl but
also N-acetyl groups can be readily utilized in the reaction, both giving
reasonable product yield at ambient temperature (entry 3), thus
pathway to generate a radical species (5). The final step of the
carbazole synthesis would most likely be H-abstraction from 5 by
an in situ-generated acetoxy radical.17c
Since the oxidative cyclization exhibits a first-order rate depen-
dence on the employed oxidant irrespective of the presence of
copper species, it is reasonable to assume that the formation of a key
intermediate (4) is involved in the rate-determining step. On the
other hand, under the metal-free conditions, the N-iodo intermediate
4 is expected to form in one step directly from a bimolecular reaction
between substrate 1 and iodine(IIII) species, and the rate of its
formation in the absence of copper species is lower compared to that
of the Cu-mediated reaction, as shown in Scheme 2.
The above mechanistic consideration, especially with respect to
the role of copper species working as a Lewis acid to activate
hypervalent iodine(III) oxidants, is further examined by performing
additional experiment on the effects of other Lewis acids under
otherwise the same reaction conditions (Table 3). It was observed
Scheme 4. Alternative Mechanistic Route
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Table 4. Scope of the “Right” Side (R2) Aromatic Ring
a Conditions: 1 (0.2 mmol), Cu(OTf)2 (5 mol %), and PhI(OAc)2 (1.5 equiv) in 1,2-dichloroethane for 10 min at 50 °C. b Conditions: 1 (0.2 mmol) and
PhI(OTFA)2 (1.5 equiv) in 1,2-dichloroethane for 10 min at 50 °C. c Yields in parentheses were determined using PhI(OAc)2 (1.5 equiv) as oxidant.
d Isolated yield. e 3 equiv of CF3COOH was used. f Carried out at 25 °C.
demonstrating that the reaction is highly flexible with respect to the
substrate type. In contrast, electron-withdrawing substituents at the
same “right” side exhibited lower reactivity, giving satisfactory
product yields only in the presence of trifluoroacetic acid additive
(e.g., entries 6 and 8). Interestingly, single regioisomers were exclusively
generated from substrates having substituents at the 5-position, and this
selectivity was maintained regardless of electronic properties of those
substituents (entries 7 and 8).
In comparison, product yields are generally lower under the
employed metal-free conditions. The difference is more significant
in the reaction of 2-acetamido-40-methoxybiphenyl (1d, entry 3) or
substrates bearing substituents at the 5-position (entries 7 and 8). It
should also be pointed out that the PhI(OTFA)2 oxidant gave
significantly higher product yields than PhI(OAc)2 in many cases,
but still lower than that those obtained under Cu-catalyzed condi-
tions in all cases investigated.
It was observed that the reactivity pattern of the “left”
amido-containing aryl part was opposite to that of the the “right”
phenyl side, and electron-withdrawing substituents on that
portion facilitate the cyclization (Table 5, entries 1ꢀ6). The
metal-free conditions using PhI(OTFA)2 alone offered product
yields comparable to those obtained under Cu-catalyzed
conditions, especially in the cyclization of substrates bearing
electron-withdrawing substituents on the “left” side (entries 2, 3,
5, and 6).
However, reaction of N-acetylamido substrates was rather
sluggish under metal-free conditions (entry 4). Disubstituted
carbazoles could be readily obtained in good yields (entries
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Table 5. Scope of the “Left” Side (R3) Amidoaryl Ring
a Conditions: 1 (0.2 mmol), Cu(OTf)2 (5 mol %), PhI(OAc)2 (1.5 equiv) in 1,2-dichloroethane for 10 min at 50 °C. b Conditions: 1 (0.2 mmol),
PhI(OTFA)2 (1.5 equiv) in 1,2-dichloroethane for 10 min at 50 °C. c Yield in parentheses was determined using PhI(OAc)2 (1.5 equiv) as an oxidant.
d Isolated yield. e 3 Equiv of CF3COOH was used. f Carried out at 25 °C. g Carried out at 0 °C.
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Scheme 5. Generalized Reactivity Pattern
9ꢀ11). A benzocarbazole derivative was obtained in moderate
yield upon the reaction of 1-phenyl-2-naphthalenyl-sulfonamide
(entry 12). It is noteworthy that the reaction proceeded
smoothly at room temperature (entries 5, 6, and 10) or even at
0 °C (entry 11) for certain substrates under Cu-catalyzed
conditions, while lower conversion was observed under metal-
free conditions at the same temperatures.
merit to the present methodology, allowing a broad range of
applications in organic synthesis and medicinal chemistry.15
On the basis of the above observations, a reactivity pattern of
amidobiphenyl substrates can be depicted as shown in Scheme 5.
It can be generalized that the electronic influences of substituents
on the “right” and “left” aryl sides are complementary to each
other under both Cu-catalyzed and metal-free conditions. High
product yield is attained with substrates bearing electron-donat-
ing groups (R2) at the “right” phenyl part and/or electron-
withdrawing substituents (R3) at the amido-containing “left” aryl
side. In contrast, poor reactivity was found with substrates having
electron-withdrawing groups (R2) at the “right” phenyl side and/
or electron-donating substituents (R3) at the “left” amidoaryl
position. Importantly, this electronic propensity can be reflected
in a flexible synthesis of substituted carbazoles. For instance,
3-trifluoromethyl N-sulfonylcarbazole can be envisioned to be
prepared via two routes, depending on the position of the CF3
substituent. Whereas the reaction of 2-benzensulfonylami-
do40-(trifluoromethyl)biphenyl (1w) resulted in poor conver-
sion as predicted by the above reactivity pattern, the use of
2-benzenesulfonylamido-4-(trifluoromethyl)biphenyl (1v) dra-
matically improved the cyclization efficiency in accordance with
the general reactivity pattern, thus providing the desired product
2v in high yield under either Cu-catalyzed or metal-free
conditions.
In addition, the present protocol could be applied to the one-step
synthesis of N-protectedindolo[3,2-b]carbazole, which is known to be
an active component in a number of electronic devices such as light
emitting diodes (LEDs),24a field effect transistors (FETs),24b and or-
ganic thin-film transistors (OTFTs).24c When 2,200-bis(sulfonamide)-
p-terphenyl (9) was subjected to the developed Cu-catalyzed condi-
tions using 4 equiv of PhI(OAc)2, the anticipated double cyclization
took place to afford 5,11-dibenzenesulfonyl-5,11-dihydroindolo[3,2-
b]carbazole (10) as a single isomer in moderate yield (eq 4).
The present oxidative cyclization procedure for the prepara-
tion of carbazoles could readily be scaled up to gram quantity
without difficulty (eq 3). When 2-benezenesulfonylamido-40-
methylbiphenyl (1z) was employed as a test substrate, the
cyclization took place smoothly under either Cu-catalyzed
(at room temperature) or metal-free conditions (at 50 °C)
to provide the desired carbazole in good yields. N-Desulfony-
lation of the obtained carbazole 2p was successfully achieved
under the conventional basic conditions, leading to 2-methyl-
carbazole (8) in high yield. This easy removal of N-protect-
ing groups such as sulfonyl as well as acetyl moieties gives further
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’ ASSOCIATED CONTENT
’ CONCLUSION
In summary, we have developed an intramolecular oxidative
CꢀN bond-forming reaction of N-substituted 2-amidobiphenyls
for the synthesis of carbazoles under mild conditions. Surpris-
ingly, it was observed that the cyclization took place readily under
both Cu-catalyzed and metal-free conditions, although product
yields were generally lower in the latter case. While bis-
(trifluoroacetoxy)iodobenzene alone can be used as an oxidant
for the corresponding carbazole synthesis, a combined use of
copper(II) triflate and phenyliodonium diacetate offered a more
diverse range of products with higher efficiency. A series of
mechanistic studies including kinetic isotope effects, reaction rate
profile, and radical inhibition experiments led us to propose that
the employed copper species catalyzes the activation of hyperva-
lent iodine(III) oxidants, leading to more facile CꢀN bond
formation. Considering its excellent reaction efficiency, wide
substrate scope, and very mild reaction conditions, the present
intramolecular oxidative CꢀN bond formation will be an attrac-
tive route to the practical synthesis of carbazoles and other
related nitrogen-containing heterocycles. Detailed mechanistic
studies as well as extension of the present protocol to an
intermolecular version are now underway.
S
Supporting Information. Detailed experimental proce-
b
dures and characterization of new compounds, including 1H and
13C NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
sbchang@kaist.ac.kr
’ ACKNOWLEDGMENT
This research was supported by the Korea Research Founda-
tion (KRF-2008-C00024, Star Faculty Program) and MIRC
(NRF-2010-0001957).
’ REFERENCES
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’ EXPERIMENTAL SECTION
Representative Procedure for the Copper-Catalyzed Car-
bazole Synthesis (Table 4, Entry 1, Compound 2b). To an
oven-dried 10 mL round-bottom flask, equipped with a magnetic stir bar,
were added 2-benzenesulfonamidobiphenyl (61.9 mg, 0.2 mmol), Cu-
(OTf)2 (3.6 mg, 5 mol %), and CF3COOH (46 μL, 0.6 mmol, 3.0 equiv)
in 1,2-dichloroethane (1.0 mL). A solution of PhI(OAc)2 (96.6 mg, 0.3
mmol) in 1,2-dichloroethane (1.0 mL) was slowly added over 5 min.
After the reaction mixture was stirred for 10 min at 50 °C, the crude
mixture was filtered through a plug of Celite and then washed with
EtOAc (20 mL). The crude residue was purified by flash column
chromatography on silica gel to afford 9-benzenesulfonylcarbazole in
90% yield (55.3 mg): mp 121ꢀ123 °C; 1H NMR (400 MHz, CDCl3) δ
8.32 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 7.8 Hz, 2H), 7.80 (m, 2H), 7.47 (m,
2H), 7.40 (m, 1H), 7.34 (t, J = 7.4 Hz, 2H), 7.27 (t, J = 8.1 Hz, 2H); 13
C
NMR (100 MHz, CDCl3) δ 138.3, 137.9, 133.7, 129.0, 127.4, 126.42,
126.39, 123.9, 120.0, 115.1; IR (film) 3060, 1600, 1443, 1370, 1175, 978,
752 cmꢀ1; HRMS (EIþ) m/z calcd for C18H13NO2S [M]þ 307.0667,
found 307.0667.
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Representative Procedure for the Metal-Free Carbazole
Synthesis (Table 5, Entry 3, Compound 2i). To an oven-dried
10 mL round-bottom flask, equipped with a magnetic stir bar, were
added 2-benzenesulfonylamido-5-chlorobiphenyl (68.5 mg, 0.2 mmol)
and CF3COOH (46 μL, 0.6 mmol, 3.0 equiv) in 1,2-dichloroethane
(1.0 mL). A solution of PhI(OTFA)2 (129 mg, 0.3 mmol) in 1,2-
dichloroethane (1.0 mL) was slowly added over 5 min. After the reaction
mixture was stirred for 10 min at 50 °C, the crude mixture was filtered
through a plug of Celite and then washed with EtOAc (20 mL). The
crude residue was purified by flash column chromatography on silica gel
to afford the 9-benzenesulfonyl-3-chlorocarbazole in 87% yield (59.5
mg): mp 146ꢀ148 °C; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.5
Hz, 1H), 8.26 (d, J = 8.6 Hz, 1H), 7.85ꢀ7.83 (m, 2H), 7.80ꢀ7.77 (m,
2H), 7.54ꢀ7.42 (m, 3H), 7.38ꢀ7.30 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 138.8, 137.5, 136.6, 134.0, 129.8, 129.1, 128.1, 127.8, 127.4,
126.4, 125.3, 124.2, 120.2, 119.9, 116.2, 115.2; IR (film) 2919, 1599,
1443, 1410, 1372, 1177, 1091, 925, 730 cmꢀ1; HRMS (EIþ) m/z calcd
for C18H12ClNO2S [M]þ 341.0277, found 341.0277.
6004
dx.doi.org/10.1021/ja111652v |J. Am. Chem. Soc. 2011, 133, 5996–6005

Journal of the American Chemical Society
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6005
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