Direct synthesis of N -H carbazoles via iridium(III)-catalyzed intramolecular C-H amination

Article abstract of DOI:10.1021/acs.orglett.5b00502

The iridium-catalyzed dehydrogenative cyclization of 2-aminobiphenyls proceeds smoothly in the presence of a copper cocatalyst under air as a terminal oxidant through intramolecular direct C-H amination to produce N-H carbazoles. A similar iridium/copper system can also catalyze the unprecedented dimerization reaction of 2-aminobiphenyl involving 2-fold C-H/N-H couplings.

Full text of DOI:10.1021/acs.orglett.5b00502

Letter
pubs.acs.org/OrgLett
Direct Synthesis of N‑H Carbazoles via Iridium(III)-Catalyzed
Intramolecular C−H Amination
Chiharu Suzuki,† Koji Hirano,† Tetsuya Satoh,*,†,‡ and Masahiro Miura*,†
†Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
‡JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
S
* Supporting Information
ABSTRACT: The iridium-catalyzed dehydrogenative cyclization of
2-aminobiphenyls proceeds smoothly in the presence of a copper
cocatalyst under air as a terminal oxidant through intramolecular
direct C−H amination to produce N-H carbazoles. A similar
iridium/copper system can also catalyze the unprecedented
dimerization reaction of 2-aminobiphenyl involving 2-fold C−H/
N−H couplings.
N-H carbazole derivatives have been recognized as important
building blocks for constructing organic materials.1 Moreover,
such motifs can be seen in naturally occurring as well as
synthesized bioactive compounds.2 Among general methods for
constructing carbazole frameworks is the intramolecular C−N
coupling of 2-amino-2′-halo-1,1′-biphenyls.3 However, such
substrates need to be prepared via complicated multistep routes.
One of the simplest, most straightforward approaches to the
structure is the dehydrogenative C−H/N−H coupling of 2′-
unsubstituted 2-amino-1,1′-biphenyls.4−6 Carbonyl-, sulfonyl-,
alkyl-, and heteroaryl-substituted amino groups have been shown
to act as good directing groups for C−H bond cleavage at the 2′-
position under palladium or copper catalysis to form N-
substituted carbazoles as dehydrogenative cyclization products
(Scheme 1, previous work).4 Compared to these protected
dimerization of 2-aminobiphenyl took place predominantly.
These new findings are described herein.
The reaction of 2-amino-1,1′-biphenyl (1a) was explored to
optimize the reaction conditions, as shown in the Supporting
Information (Table S1). The dehydrogenative cyclization
product, N-H carbazole (2a), was formed in 74% isolated yield
upon treatment of 1a (0.5 mmol) in the presence of catalytic
amounts of [Cp*IrCl2]2 (0.01 mmol, 2 mol %) and Cu(OAc)2
(0.1 mmol, 20 mol %) as well as PivOH (pivalic acid, 1 mmol)
under air in NMP at 120 °C for 3 h,11 along with a small amount
(4%) of dehydrogenative dimerization product 3a (eq 1 and
Table 1, entry 1).
Scheme 1. Carbazole Synthesis via C−H/N−H Coupling
The cyclization of 4′-substituted 2-amino-1,1′-biphenyls 1b−j
was next examined (Table 1, entries 2−10). While 2-
methylcarbazole (2b) was obtained in 67% yield upon treatment
of 4′-methyl substrate 1b under standard conditions (conditions
A), the reactions of other substrates 1c−j needed a higher
loading of [Cp*IrCl2]2 (4 mol %, conditions B) to produce 2c−j
in reasonable yields. Only in the case with 1f did the product yield
remain moderate even under conditions B due to unidentified
side reactions (entry 6). The cyclization of 3′-substituted
substrates 1k−m took place regioselectively, involving C−H
cleavage at the sterically less hindered 6′-position to afford 3-
substituted carbazoles 2k−m (entries 11−13). Expectedly, the
reactions of 2′-substituted 1n−p gave exclusively 4-substituted
carbazoles 2n−p in good yields (entries 14−16). It should be
noted that N-H 4-alkoxycarbazoles, including carvedilol and
amino functions, a free amino group has been less frequently
utilized as a directing group because of its tight coordination to
transition metals to suppress catalytic processes.7 Actually, the
dehydrogenative cyclization of N-free 2-aminobiphenyls forming
N-H carbazoles could be conducted only under harsh conditions
(>250 °C) using a Pt/C catalyst.8 In the context of our studies of
free amino group directed C−H functionalization,9 we
succeeded in finding that the step- and atom-economical
synthesis of N-H carbazoles can be achieved by the iridium-
catalyzed dehydrogenative C−H/N−H coupling10 of 2-amino-
biphenyls through free amino-directed C−H bond cleavage
(Scheme 1, this work). In the presence of a copper cocatalyst, the
reaction can be carried out smoothly even using air as a terminal
oxidant. Under modified conditions, a unique dehydrogenative
Received: February 17, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00502
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Table 1. Reaction of 2′-, 3′-, and 4′-Substituted 2-
Table 2. Reaction of 3-, 4′-, and 5-Substituted 2-
a
a
Aminobiphenyls 1
Aminobiphenyls 1
a
Reaction conditions: 1 (0.25 mmol), [Cp*IrCl2]2 (0.01 mmol),
Cu(OAc)2 (0.05 mmol), PivOH (0.5 mmol) in NMP (3 mL) under
air at 120 °C. Isolated yield.
b
Scheme 2. Plausible Mechanism for the Reaction of 1a
a
Reaction conditions: (A) 1 (0.5 mmol), [Cp*IrCl2]2 (0.01 mmol),
amino-directed C−H bond cleavage takes place at the 2′ position
to form an iridacycle intermediate B,13 which undergoes C−N
reductive elimination to afford 2a. The Cp*Ir(I) species
generated in the last step may be reoxidized by a copper(II)
cocatalyst to regenerate the iridium(III) species along with
copper(I).14 The latter may be reoxidized under air in the
reaction system.
To obtain further mechanistic insight, the reaction of
deuterated 2-aminobiphenyl [2-(NH2)C6H4−C6D5, 1a-d5] was
examined. In the early stage (15 min), no significant D/H
exchange at the 2′-position of recovered 1a-d5 as well as the 4-
position of produced 2a-d4 was observed (Scheme S1,
Supporting Information). Comparison of the reaction rates of
1a-d5 and nondeuterated 1a-d0 (∼20 min) gave a very small KIE
value (Scheme S2 and Figure S1, Supporting Information, kH/kD
= 1.1). These results suggest that the amino-directed C−H bond
cleavage step may be irreversible and may not be involved in the
rate-determining step.
Cu(OAc)2 (0.1 mmol), PivOH (1 mmol) in NMP (3 mL) under air at
120 °C; (B) 1 (0.25 mmol), [Cp*IrCl2]2 (0.01 mmol), Cu(OAc)2
(0.05 mmol), PivOH (0.5 mmol) in NMP (3 mL) under air at 120 °C.
b
c
Isolated yield. A small amount (4%) of 3a was also formed.
carazolol, are of interest because of their biological activities.12
Similarly, 2-(naphthalen-1-yl)aniline (1q) underwent cyclization
to form benzo[c]carbazole 2q in 90% yield (entry 17).
Treatment of 2-(naphthalen-2-yl)aniline (1r) gave a separable
mixture of benzo[b]carbazole 2r and benzo[a]carbazole 2r′ in 79
and 10% yields, respectively (entry 18).
Under conditions B, the cyclization of 5-substituted 2-
aminobiphenyls 1s−u proceeded efficiently to give the
corresponding 3-substituted carbazoles 2k, 2s, and 2m in 81−
90% yields (Table 2, entries 1−3). The syntheses of 1,3- and 2,6-
disubstituted carbazoles 2t−v were also achieved by the reactions
of 3,5- (1v,w) and 4′,5- (1x) disubstituted 2-amino-1,1′-
biphenyls (entries 4−6).
A plausible pathway for the transformation of 1a to 2a is
illustrated in Scheme 2. Coordination of the nitrogen atom of 1a
to a Cp*-iridium(III) species gives an intermediate A. Then,
Next, we examined the dehydrogenative dimerization of 1a to
form 3a, which was formed as a minor product in eq 1 along with
2a. During preliminary trials, we obtained 3a predominantly in
47% isolated yield by treatment of 1a (0.5 mmol) in the presence
B
DOI: 10.1021/acs.orglett.5b00502
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a b
,
of [Cp*IrCl2]2 (0.01 mmol), AgSbF6 (0.04 mmol), and
Cu(OAc)2 (1 mmol) in DMF at 80 °C under N2 (Scheme 3).
Scheme 5. Cross-Dehydrogenative Coupling of 1a with 4
a
Scheme 3. Dehydrogenative Dimerization of 1a
a
GC yield based on the amount of 1a used. Value in parentheses
indicates isolated yield.
a
b
GC yield based on the amount of 1a used. Value in parentheses
At the present stage, the reaction mechanism for the formation
of 3a is obscure. Recently, Patureau and co-workers reported an
interesting dehydrogenative coupling of N-H carbazoles with
secondary anilines under ruthenium catalysis to produce N-(2-
aminophenyl)carbazoles.15 In the present reaction, it would be
possible for 3a to form via a similar dehydrogenative coupling of
1a with once formed 2a. However, this pathway could be
excluded by crossover experiments with the addition of
substituted carbazoles. Thus, treatment of 1a (0.25 mmol)
with 3,6-di-tert-butyl- (2w) and 3,6-dichlorocarbazoles (2x)
(0.25 mmol) in the presence of [Cp*IrCl2]2 (0.01 mmol),
AgSbF6 (0.04 mool), and Cu(OAc)2 (1 mmol) in DMF at 80 °C
under N2 for 24 h gave only 3a and 2a with almost complete
recovery of 2w and 2x, with no crossover products 3b and 3c
being detected (Scheme 4).
indicates isolated yield.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, additional results, and characterization
data of products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: satoh@chem.eng.osaka-u.ac.jp.
*E-mail: miura@chem.eng.osaka-u.ac.jp.
Notes
The authors declare no competing financial interest.
a b
,
Scheme 4. Crossover Experiments with 1a and 2
ACKNOWLEDGMENTS
This work was partly supported by Grants-in-Aid from MEXT,
JSPS, and JST, Japan.
■
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DOI: 10.1021/acs.orglett.5b00502
Org. Lett. XXXX, XXX, XXX−XXX