Synthesis of the Carbazole Scaffold Directly from 2-Aminobiphenyl by Means of Tandem C–H Activation and C–N Bond Formation

Article abstract of DOI:10.1002/ejoc.201601191

An efficient method for the synthesis of the carbazole scaffold was designed and investigated. The method was developed to produce substituted carbazoles by an intramolecular combination of a free amine group and an arene. The steps of the method involved tandem Pd-catalyzed C–H activation and intramolecular C–N bond formation. The method showed good functional group tolerance, and substituent(s) could be on either of the two rings or on both of the two rings of the 2-aminobiphenyl substrate. After ring closure, the reduced Pd catalyst was oxidized to Pd^IIby hydrogen peroxide. The novel method was also demonstrated to operate excellently with the corresponding 2-N-acetylaminobiphenyls.

Full text of DOI:10.1002/ejoc.201601191

A Journal of
Accepted Article
Title: Synthesis of the carbazole scaffold directly from 2-amino-biphenyl by means
of a concurrent C-H activation and C-N bond formation
Authors: Hans-Rene Bjørsvik; Vijayaragavan Elumalai
This manuscript has been accepted after peer review and the authors have elected
to post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Digital
Object Identifier (DOI) given below. The VoR will be published online in Early View as
soon as possible and may be different to this Accepted Article as a result of editing.
Readers should obtain the VoR from the journal website shown below when it is pu-
blished to ensure accuracy of information. The authors are responsible for the content
of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601191
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601191
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201601191
COMMUNICATION
Synthesis of the carbazole scaffold directly from 2-amino-
biphenyl by means of a concurrent C–H activation and C–N
bond formation
Hans-René Bjørsvika* and Vijayaragavan Elumalaia
a
Department of Chemistry, University of Bergen, Allégaten 41, N-5007 Bergen, Norway
phone +47 55 58 34 52, fax +47 55 58 94 90, and e-mail hans.bjorsvik@kj.uib.no, web: http://folk.uib.no/nkjhn/
Supporting information for this article is available on the WWW under http://dx.doi.org/###########
Abstract. An efficient synthetic method for the synthesis
of the carbazole scaffold was designed and investigated.
The method was developed to produce substituted
carbazoles by an intramolecular combination of a free
amine group and an arene. The steps of the method
involves a concurrent Pd catalysed C−H activation and
intramolecular C-N bond formation. The method shows
good functional group tolerance, where the substituent(s)
might be installed on either of the two rings or on both of
the two rings of the 2-amino biphenyl substrate. After the
ring closure, the reduced Pd catalyst is oxidized to Pd(II)
by means of hydrogenperoxide. The novel method was
demonstrated to operate excellently with the corresponding
2-N-acetylamino biphenyls as well.
Scheme 1. Intramolecular C-H activation and C-N bond
formation that results in the carbazole framework.
Keywords: C-H activation; C-N bond formation;
carbazole; palladium; hydrogen peroxide
Gaunt and collaborators[3 ] disclosed a process that
also involves Pd(OAc)2 as the catalyst, but with the
hypervalent iodine compound phenyliodosyl diacetate
in DMF as the re-oxidant for the palladium catalyst,
Scheme 1 path (b). An important improvement
offered by this method is the low reaction temperature
Introduction
The carbazole framework constitutes an essential
kernel of numerous indispensable applications in the
society and the industry. Therefore, a considerable
effort has been devoted to the development of
efficient methods exploitable for the synthesis of such
molecular motifs.[ 1 ] A decade ago, Buchwald and
o
(20 C), although the method is still saddled with
drawbacks, namely the need of a protective or
auxilliary group and the production of stoichiometric
quantities of the reduced oxidant as a by-product.
2
]
collaborators[
disclosed a seminal work that
describes an attractive strategy and methodology that
permit the synthesis of the carbazole framework
through a concurrent C–H activation and C–N bond
formation, Scheme 1 path (a). This strategy involves
2-N-acetylamino biphenyl 2 as the substrate, which
was exposed for C–H activation at the 2’-position
assisted by a Pd(II) moiety coordinated to the 2-N-
acetylamino group. The subsequent step results in C–
N bond formation that affords the carbazole scaffold
concomitant with release of Pd(0). Pd(0) was oxidized
to Pd(II) by O2, which allowed a recycling of Pd as a
catalyst, Scheme 2. The major drawbacks of this
method[2] comprises; a rather long reaction time and
the need of a protective or auxiliary group attached to
the 2-amino group, which is provoked by the fact that
the oxidative conditions can also support the parasite
oxidation reaction, 15.
O
NO2
HN
[O]
CH3
+
when R=H
5
2
R
R
R
N
H
N
H
N
H
O
O
H
H
Pd
O
Pd
O
Pd(OAc)2
[O]
Pd(0)
O
O
O
CH3
CH3
H
# R
1 H
2 COCH3
O
CH COOH
3
+
CH3
H
CH3
CH3COOH
R
N
O
N
Pd
O
CH3
# R
R
3 COCH3
4 H
Scheme 2. Reaction mechanism proposal for the con-
current Pd – catalysed C–H activation and C–N bond
formation resulting in the carbazole scaffold using 2-amino
biphenyl as the substrate.
During the last decade, a few more methods based on
concurrent C–H activation and C–N bond formation
have been revealed.
1
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601191
Satho, Miura and collaborators[4] communicated lately Table 1. Screening experiments for the ring closing of 2-
a method that encompassing an Ir(III) / Cu based amino biphenyl to achieve the carbazole scaffold[a]
catalytic system with air as the terminal oxidant,
O
Scheme 1 path (e). This method is until now the only
NH2
NO2
N
H
CH3
[a]
+
NH
intramolecular amination method allowing the
preparation of the carbazole scaffold from
unprotected 2-amino biphenyl, but this protocol
requires an expensive Ir based catalyst along with
several other additives to operate the ring closing
reaction. Two various methods involving copper as
catalyst were disclosed by Chang and collaborators[5a]
and Hirano, Miura and collaborators[5b] shown in
paths (c) and (d), respectively. Both of these methods
also request supporting / auxiliary groups installed on
the amino group and stoichiometric quantities of
oxidants, PhI(OAc)2 and MnO2, respectively.
+
1
4
5
2
Measured response[b]
t
#
Catalyst/Ligand
[min]
Conv. y4 y5 y2
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
90
60
20
93
86
67
84
77
83
97
39 26 20
48 30 nd
30 10 24
45 18 15
2
3
4
5
6
Pd(OAc)2 /IMes·HCl 20
Pd(TFA)2 20
Pd(TFA)2 /IMes·HCl 20
49
43 15 21
67 28
9
16
Results and Discussion
7 [c] Pd(OAc)2 /IMes·HCl 10
2
For a project in progress in our group dedicated to a
novel total synthesis of the natural products
carbazomycin G and H,[6] several new methods were
needed: preparation of the functionalized benzene
moieties[7] needed for the 2-amino biphenyl precursor,
Suzuki cross-coupling methods suitable for the
preparation of the 2-nitro biphenyls,[8] and an efficient
method for nitro-group reduction.[ 9 ] Moreover, we
aimed to utilize the C–H activation and intra-
molecular C–N formation strategy disclosed by
Buchwald and collaborators.[2] Thus, we initiated to
use the Buchwald protocol in attempts to accomplish
the intramolecular amidation with the biphenyl 2a,
Scheme 3.
[a]Reaction conditions: A solution of 2-aminobiphenyl 1
(84.5 mg, 0. 5 mmol) in glacial acetic acid (5 mL),
Pd(OAc)2 (5.6 mg, 0.025 mmol or Pd(TFA)2 (8.3 mg, 0.025
mmol)]) (5 mol-%), IMes·HCl (8.5 mg, 0.025 mmol) when
specified, and H2O2 (35%, 0.128 mL, 1.45 mmol) were
placed in a reactor tube and immersed into the cavity of the
o
microwave oven for t min. at T=90 C. [b]The reaction was
monitored by means of GC-MS; Conv. = conversion of 1.
Yields (y) of compound 4 and 5 were corrected using the
response factors; 2-aminobiphenyl 1, rf1=1.00; carbazole,
rf4=1.00, and 2-nitrobiphenyl, rf5=1.29. The selectivity and
yield of compound 2 and 5 are uncorrected with response
factor. [c]20 mol-% (22.4 mg, 0.100 mmol) of Pd(OAc)2
was used.
O
O
O
H3CO
H3C
H3CO
O
CH3
CH3
Pd(OAc)2 (5 mol%) H3CO
Cu(OAc)2 (1 equiv)
A
B
O2 (1atm), PhCH3
H3C
Although, alterations of the reaction time, reaction
temperature, and the compositions of the catalytic
system were revealed to affect not only the yield of
the target carbazole 4, but also the distribution of the
side-products 2 and 5. Evidently, the NHC ligand
IMes with Pd(OAc)2 operated reasonable well as a
catalyst for the ring closing. Moreover, the reaction
time appeared also to be of paramount importance,
Table 1. The reaction trial of entry 7 was used as a
basis in an attempt to discover a higher yielding
protocol. A series of experiments with various Pd
loading (5-20 mol%) was conducted and monitored
over a period of 20 min. The alterations of the Pd
loading revealed a great effect on the outcome of the
reaction, Figure 1a. Moreover, after a reaction time of
10-15 min. the target molecule started to depredate
concomitantly as two parasite products 2 and 5 were
produced.
120oC, 2-24 h
N
N
H
3a
2a
H3CO
29%
O
O
CH3
O
CH3
R
OCH3
R
H
OCH3
Carbazomycin
G
CH3
CH3
H
N
H
HO
Scheme 3. Intramolecular C–H activation and C–N
formation leading to the carbazole precursor 3a (29%) for
carbazomycin G (R=H) and H (R=OCH3).
However, probably due to the highly congested
substitution pattern of the A-ring combined with the
acetyl group attached to the 2-amino group, the ring
closing reaction afforded a yield of only 29% of target
carbazole 3a. This somewhat disappointing result
spurred us to undertake further investigations of the
ring closing protocol. Even thought the amino group
can be oxidized to the nitro group under various
conditions,[ 10 ] we wanted to investigate the ring
closure using the non-protected 2-amino biphenyl
framework. 2-Nitro biphenyl 5 might be a parasite
reaction product under the oxidative conditions used
in a Pd catalysed intramolecular amination. Indeed,
we observed this oxidation product as soon as
unprotected 2-amino biphenyl 1 was tried as the
substrate, Table 1.
Further optimisation of the method was conducted by
means of a systematic variation (in a grid pattern) of
the reaction temperature and time, Figure 1b.
2
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601191
Figure 1. (a) Reaction profile showing the outcome of 4, 5, and 2 at various Pd loading. To a solution of 2-aminobiphenyl
(84.5 mg, 0.5 mmol) in glacial acetic acid (5 mL), Pd(OAc)2 (5-20 mol%), IMes  HCl (8.5 mg, 0.025 mmol) and H2O2
(35%, 0.128 mL, 1.45 mmol) were added to perform the above reactions under microwave irradiation (W) for 15-20 min.
o
at 90 C. (b) Screening of the reaction time (5-20 min.) versus reaction temperature (90-130 oC) reveals optimized
conditions at the higher temperature and longer reaction time. (c) Variation (5-20%) of the catalyst loading (using 20 min.
and 120oC) afforded a high conversion (97%) of the 2-amino-biphenyl 1 with 4 and 5 as reaction products.
High yielding conditions were located at a reaction means of standard protection (t-butyldimethylsilyl
time of 15-20 min. with a temperature of 120-130 oC. chloride) of the hydroxyl group, a high yield of target
The so far optimized protocol (Figure 1a,b) was then carbazole was obtained (entry 15, Table 2).
repeated, although under various Pd loadings (5- The method was also explored with 2-N-acetyl-amino
20%), Figure 1c. A high conversion (97%) of the 2- biphenyls as substrates, Table 3. In this context,
amino-biphenyl 1 substrate was achieved for all of minor alterations of the experimental conditions were
these experiments. When a Pd loading of <20% was found to be beneficial, namely a lowered Pd loading
used, an oxidation of the amino group into the nitro (5 mol%) and an extended reaction time (3 h). Using
group occurred. In fact, as much as 23% of 2-nitro these conditions with 3'-methoxy- and 4'-methoxy-2-
biphenyl 5 was formed using 5% Pd and only ≈2% of N-acetyl-amino biphenyls, the corresponding
5 was formed with a Pd loading of 15%. With a Pd carbazoles were achieved in high yields (entries 7 and
loading of 20%, the carbazole scaffold was obtained 8 of Table 3). Although the 2´-methoxy- substituted
in 97% yield.
substrate provided a low yield (25%) only. The 3'-
A scope and limitation study of our new method was methoxy- substituted substrate (entry 7) provided two
then undertaken by means of a series of substituted 2- regioisomers, viz. 1-(3-methoxy-9H-carbazol-9-yl)
amino biphenyls, Table 2. Overall, the method ethan-1-one 3g (major) and 1-(2-methoxy-9H-
tolerates both electron-withdrawing and -donating carbazol-9-yl)ethan-1-one (minor). The methylated
groups to afford moderate to excellent yields of target substrates (entries 3 and 4) provided low to moderate
carbazole scaffold. However, some few exceptions yields, this applied also for a substrate with a strong
were observed; 2'-methoxy and 3'-methoxy-2-amino electron-withdrawing group (entry 2). The observed
biphenyls afforded yields of ≈10% only (entries 6 and results were consistent with previous observations.[2]
7) and 4'-methoxy-2-amino biphenyl provided a Electrophilic substitution on carbazole scaffold
moderate yield (entry 8). These observations might be favours normally the position 3 and 6. However, our
due to the inductive effect of the methoxy substituent new method allows functionalization in the positions
that would disrupt the intermediate, but the oxidative 2 and 4, which might be valuable for the synthesis of
condition present for the catalytic cycle might as well natural products that contain the carbazole scaffold.
give rise to oxidation of the aromatic kernel into a de- As an ultimate test of the new protocol we attempted
methoxylated quinoid framework[ 11 ] followed by to perform the transformation 2a  3a previously
additional degradation reactions. Moreover, as performed with the Buckwald method,2 Scheme 2.
expected, the method did not operate with substrates Only a minor alteration of the conditions of our new
that contained a free hydroxy group; nevertheless by method was needed; while 3h afforded 37% yield, a
3
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601191
reaction time of 5h provided an excellent yield of Table 2. Scope of reaction using 2-amino biphenyls 1 as
94%. The conditions and results are summarized in substrate.
Scheme 4.
Pd(OAc)2 (20 mol%)
Imes HCl (5 mol%)
O
O
H2O2 (35%), AcOH
O
N
N
H3CO
H3C
H3CO
O
Pd(OAc)2 (5 mol%)
IMes (5 mol%)
CH3
CH3
120oC, 20 min. mW
H
H3CO
H3C
1
4
H2N
Responsesa)
y[%] yi[%]
H2O2 (35%, 0.05 mL)
AcOH (5 mL)
mW at 120 oC
#
1
2-Amino- biphenyls
Carbazole
N
H
3a
2a
H3CO
92
84
O
3 h (37% GC)
5 h (94% GC)
O
CH3
CH3
N
4
CF3
1
H2N
CF3
H
Scheme 4. Intramolecular C–H activation and C–N
formation leading to the carbazole 3a (94%) as a precursor
for carbazomycin G.
2
na
60
N
1b
4b
H2N
CH3
H
CH3
3
4
>99
82
71
70
Conclusion
N
H
1c
1d
1e
4c
4d
4e
H2N
H2N
In summary, we have developed a new highly efficient
and high rate method for the synthesis of the carbazole
framework by means of a Pd catalysed concurrent C–H
activation and intramolecular C–N bond formation using
the 2-amino biphenyl scaffold as the substrate. In
general, the method tolerates both electron withdrawing
and donating groups on one or both of the two aromatic
rings of the substrate. Even substrates labile for
oxidation such as aromatics that contain the hydroxyl
and/or the methoxy groups can be converted into their
corresponding carbazoles. However, if the 2-amino
biphenyl scaffold is substituted with the methoxy group,
an acetyl group should be introduced on the 2-amino
group as an auxiliary group. Free hydroxyl groups
should be protected.
H3C
na
H3C
N
H
5
>99
H3C
N
H
OCH3
H3C
H2N
OCH3
6b)
na
9
1f
4f
N
H
H2N
H2N
H3CO
H3CO
7
na
10
1g
1h
1i
4g
4h
4i
N
H
8
9
H3CO
Cl
na
90
41
70
H3CO
Cl
N
H
H2N
H2N
N
H
COOH
na
94
75
73
COOH
N
1j
4j
H2N
H
O
O
11
Cl
Cl
CH3
N
CH3
1k
4k
H2N
CH3
H
CH3
O
O
12
13
98
91
85
77
CH3
N
H
1l
4l
CH3
H2N
CH3
Cl
Cl
CH3
N
1m
4m
H2N
Cl
H
Cl
14
>99
82
81
61
CH3
CH3
CH3
CH3
N
H
1n
1o
4n
4o
H2N
H2N
15c)TBSO
TBSO
N
H
a) y = conversion yield based on GC, yi =isolated yield after column
chromatography (silica gel), na=not analyzed on GC.
b) An additional experiment using 20 mol% IMes was also conducted. The
outcome was similar to the experiment where 5 mol% IMes was used.
c) An experiment without the TBS protective group installed did not afford
the target carbazole.
4
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601191
flame ionization detector. Mass spectra were obtained with
a GC–MS instrument, with a gas chromatograph equipped
with a fused silica column (l30 m, 0.25 mm i.d., 0.25 mm
film thickness) and helium as the carrier gas. DARTmass
spectra were obtained by using PEG as an internal standard
in positive ionization mode with a TOF mass analyzer. 1H
and 13CNMR spectra were recorded at ambient temperature
at a frequency of 400, 500 MHz and 100, 125 MHz
respectively. The chemical shifts are reported in ppm
relative to residual CDCl3 for proton (δ = 7.26 ppm) and
CDCl3 for carbon (δ = 77.0 ppm) and DMSO-d6 for proton
(δ = 2.50 ppm) and carbon (δ = 39 ppm) with
tetramethylsilane as an external reference. Flash
chromatography was performed by using the indicated
solvent system and silica gel (230–400 mesh). All reagents
used were commercially available from Aldrich Chemical
Co. For new compounds HRMS data were also recorded.
Table 3. Scope of reaction using using 2-N-acetylamino
biphenyl 2 as substrate.
Pd(OAc)2 (5 mol%)
Imes HCl (5 mol%)
H2O2 (35%), AcOH
120oC, 3 h, mW
N
HN
2
3
CH3
H3C
O
O
Responsesa)
y[%] yi[%]
#
2-Amino- biphenyls
Carbazole
1
91
85
N
HN
2
3
CH3
H3C
CF3
O
O
CF3
2
20
ni
The microwave-assisted experiments were performed by
means of a Biotage Initiator Sixty EXP Microwave System,
that operates at 0–400 W at 2.45 GHz, in the temperature
range of 40–250 °C, a pressure range of 0–20 bar (2 MPa,
290 psi), and with reactor vial volumes of 0.2–20 mL.
N
HN
2b
3b
CH3
H3C
O
O
CH3
CH3
3
17
51
ni
HN
O
N
2c
2d
2e
3c
General procedure for 2-aminobiphenyl derivatives (1-
1o). 2-Nitrobiphenyl (1 mmol, 0.2 g) was dissolved in
EtOH (4 mL) and transferred to a tube reactor. Then, a
mixture of NH4Cl (2 mmol, 0.107 g) in H2O (1.2 mL) and
indium powder (3 mmol, 0.344 g, 99.99% 100 mesh, use
preferably a freshly opened bottle or stored under Ar) were
added whereupon a magnetic stirrer bar was transferred to
the tube. The tube was then sealed and the reaction mixture
was stirred and heated at 120 °C for 3 h. The reaction
mixture was cooled to room temperature and diluted with
ethyl acetate (30 mL). The resulting mixture was filtered
through a pad of celite to remove the catalyst. Another
portion (20 mL) of ethyl acetate was used to wash through
the filter pad. The resulting transparent organic phase was
dried over Na2SO4, filtered and the solvent was removed
under reduced pressure using a rotary evaporator to obtain
the 2- aminobiphenyl compound.
CH3
CH3
CH3
H3C
O
46
H3C
4
5
H3C
HN
O
N
N
3d
H3C
H3C
O
100
25
81
ni
H3C
HN
H3C
3e
O
O
OCH3
OCH3
6
HN
O
N
2f
3f
CH3
H3C
O
H3CO
7b)
75
82
61
70
2'-methyl-[1, 1’-biphenyl]-2-amine (1c). 2'-methyl-2-
nitro-1, 1’-biphenyl (0.324 g, 1.52 mmol), NH4Cl (0.161 g,
3.04 mmol) and indium powder (0.523 g, 4.56 mmol). The
title compound was obtained as a yellow liquid (0.259 g,
93%): Rf = 0.66 [(Hx:EtOAc, 80:20)]; 1H-NMR (500 MHz,
CDCl3): 훿= 7.17-7.22 (m, 3H), 7.12-7.14(m, 1H), 7.08-
7.11 (td, J= 1.5 Hz, 7.5 Hz, 1H), 6.93-6.95 (dd, J= 1 Hz, 7
Hz, 1H), 6.72-6.75 (td, J= 1 Hz, 7 Hz, 1H), 6.68-6.70 (dd,
J= 1 Hz, 8 Hz, 1H), 2.10 (s, 3H),; 13C-NMR (125 MHz,
CDCl3): 훿= 143.6, 138.6, 137.0, 130.3, 130.1, 130.0, 128.4,
127.7, 127.5, 126.2, 118.3, 115.1, 19.7; HR-MS (DART):
(M+H)+: Calcd for C13H13N 184.1126; Found 184.1127);
IR (cm-1): 3465, 3375, 3018, 2921, 1612, 1480, 1447, 1296.
H3CO
HN
N
N
2g
3g
O
H3C
H3C
O
H3C
8
H3CO
H3CO
2h HN
3h
O
O
H3C
a) y = conversion yield based on GC, yi =isolated yield after column
chromatography (silica gel), ni=not isolated.
b) In addition to the major product 3g, a minor quantity (12%) of the
5'-methoxy derivative was obtained.
General procedure for 2-acetaminobiphenyl derivatives
(2-2h). To a solution of 2-aminobiphenyl (0.1 g, 0.59
mmol) and triethylamine (0.09 mL, 0.65 mmol) in 10 mL
anhydrous of dichloromethane at 0°C, acetyl chloride (0.04
mL, 0.62 mmol) was added dropwise. The mixture was
stirred at room temperature for 1 h. After the reaction time,
the solvent was evaporated under reduced pressure. The
residue was dissolved in ether (20 ml) washed with water
(20 ml). The organic phase was dried over Na2SO4, filtered
and the solvent was removed under reduced pressure using
a rotary evaporator to obtain the N-acetylated compound.
Experimental Section
All reagents and solvents were purchased from commercial
sources and used as received. Melting points were
determined in open capillaries. Reagent grade chemicals
were purchased from commercial sources and used without
further purification. All reaction mixtures and column
eluents were monitored by TLC (TLC plates Merck
Kieselgel 60 F254). The TLC plates were observed under
UV light at λ = 254 nm and λ = 365 nm. IR spectra were
recorded as KBr discs with a Shimadzu FTIR-8300
spectrophotometer, and 1H and 13C NMR spectra were
recorded with Bruker AV 400 MHz and 500 MHz
instruments. High- resolution mass spectra (HRMS) were
performed with a Q-TOF Micro YA263 instrument.
N-([1, 1’-biphenyl]-2-yl) acetamide.ꢀ 2'-amino-[1, 1'-
biphenyl] (1a) (0.10 g, 0.59 mmol), Acetyl chloride (0.04
mL, 0.62 mmol) and Triethylamine (0.09 mL, 0.65 mmol).
The title compound was obtained as a pale- white solid
o
(0.115 g,1 93%). mp 119.8-120 C; Rf = 0.24 [(Hx:EtOAc,
80:20)]; H-NMR (500 MHz, CDCl3): 훿 = 8.26 (d, J= 8.5
Hz, 1H), 7.49 (t, J= 7 Hz, 2H), 7.38(m, 3H), 7.24 (d, J= 7
Hz, 1H), 7.18 (d, J= 7.5 Hz, 1H), 2.02 (s, 3H); 13C-NMR
(125 MHz, CDCl3); 훿 = 168.3, 138.2, 134.7, 132.2, 130.1
129.2, 129.1, 128.4, 128.0, 124.4, 121.7, 24.6; HR-MS
General methods. GC analyses were performed with a
capillary gas chromatograph equipped with a fused silica
column (l25 m, 0.20 mm i.d., 0.33 mm film thickness) at a
helium pressure of 200 kPa, split less/split injector and
5
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601191
(ESI): (M+Na)+: Calcd for C14H13NNaO 234.0895; Found
234.0896); IR (cm-1): 3286, 3027, 1658, 1531, 1433, 1301.
General procedure for carbazole derivatives (4-4o). In a
microwave tube, 2-aminobiphenyl (84.5 mg, 0.5 mmol)
was dissolved in glacial acetic acid (5mL), Pd(OAc)2 (22.5
mg, 0.1 mmol), IMes.HCl (8.5 mg, 0.025 mmol) and H2O2
(35%, 0.128 mL, 1.45 mmol) were added. The vial was
sealed whereupon a magnetic stirrer bar was transferred to
the tube. The tube was submerged in the microwave cavity
for 20 min at 120oC. After the reaction time, the solvent
acetic acid was removed under reduced pressure. The crude
product was dissolved in EtOAc (25 mL) and washed with
water (20 mL). The aqueous phase was extracted with
EtOAc (2×20 mL). The combined organic layer was
washed with aqueous NaHCO3 (20 mL). The organic layer
was filtered off via pad of celite and dried over Na2SO4.
The solvent was evaporated under reduced pressure. The
crude product was purified by silica gel column
chromatography using hexanes (mixture of isomers) and
ethyl acetate (gradient; 90:10 to 50:50) to obtain the target
compound.
9H-carbazole (4). 2-amino-1, 1’-biphenyl (1a) (0.085 g,
0.50 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), IMes.HCl (8.5
mg, 0.05 mmol) and H2O2 (35%, 0.128 mL, 1.45 mmol).
The title compound was obtained as a pale- brown solid
o
(0.070 g, 84 %). mp 242-243 C ;Rf = 0.49 [(Hx:EtOAc,
80:20)]; 1H-NMR (400 MHz, CDCl3): 훿 = 8.09 (d, J= 8 Hz,
2H), 7.42-7.47 (m, 4H), 7.22-7.26 (m, 2H); 13C-NMR (100
MHz, CDCl3); 훿 = 139.5, 125.8, 123.4, 120.3, 119.4,
110.6; HR-MS (DART): (M+H)+: Calcd for C12H10N
168.0813; Found 168.0814; IR (cm-1): 3415, 3050, 1599,
1449, 1325, 722.
Acknowledgements
V.E. gratefully acknowledges the Department of Chemistry at
University of Bergen – Norway for funding his research
fellowships. Dr. Bjarte Holmelid is acknowledged for excellent
technical support with the HRMS analyses.
6
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601191
References
[1] a) A. W. Schmidt, K. R. Reddy, H. J. Knölker, Chem. Rev. 2012, 112, 3193; b) Hartwig, J. F. Angew.
Chem. Int. Ed. 1998, 37, 2046; c) Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 13848; d) L.
Ackermann, A. Althammer, Angew. Chem. Int. Ed. 2007, 46, 1627; e) T. Tsuchimoto, H. Matsubayashi,
M. Kaneko, Y. Nagase, T. Miyamura, E. Shirakawa, J. Am. Chem. Soc. 2008, 130, 15823; f) Z. Shi, S.
Ding, Y. Cui, N. Jiao, Angew. Chem. 2009, 121, 8035; Angew. Chem. Int. Ed. 2009, 48, 7895; g) A. P.
Antonchick, R. Samanta, K. Kulikov, J. Lategahn, Angew. Chem. 2011, 123, 8764; Angew. Chem. Int.
Ed. 2011, 50, 8605; h) S. V. Ley, A. W. Thomas, Angew. Chem. Int. Ed. 2003, 42, 5400. ꢀ
[2] a) W. C. P. Tsang, N. Zheng, S. L. Buchwald. J. Am Chem. Soc. 2005, 127, 14560; b) W. C. P. Tsang, R.
H. Munday, G. Brasche, N. Zheng, S. L. Buchwald. J. Org. Chem. 2008, 73, 7603.
[3] J. A. Jordan-Hore, C. C. C. Johansson, M. Gulias, E. M. Beck, M. J. Gaunt. J. Am. Chem. Soc. 2008, 130,
16184.
[4] C. Suzuki, K. Hirano, T. Satoh, and M. Miura. Org. Lett. 2015, 17, 1597.
[5] a) S. H. Cho, J. Yoon, S. Chang, J. Am. Chem. Soc. 2011, 133, 5996–6005; b) K. Takamatsu, K. Hirano,
T. Satoh, M. Miura, Org. Lett. 2014, 16, 2892−2895.
[6] a H - n l er, r hner J. Chem. Soc. Perkin. Trans. 1 1998, 173; b) H. Hagiwara, T. Choshi, H.
Fujimoto, E. Sugino, S. HibinoTetrahedron 2000, 56, 580 c H - n l er, r hner, eddy
Eur. J. Org. Chem. 2003, 740.
[7] H.-R. Bjørsvik, G. Occhipinti, C. Gambarotti, L. Cerasino, V. R. Jensen. J. Org. Chem. 2005, 70, 7290.
[8] a) R. Rodríguez González, L. Liguori, A. Martinez Carrillo, H.-R. Bjørsvik. J. Org. Chem. 2005, 70,
9591; b) V. Elumalai, H.-R. Bjørsvik. Eur. J. Org. Chem. 2016, 1344.
[9] V. Elumalai, H.-R. Bjørsvik. Tetrahedron Lett. 2016, 57, 1224.
[10] a) G. A. Russell, E. G. Janzen, J. Am. Chem. Soc. 1962, 84, 4153. b) P. B. Ayscough, F.P. Sargent, R.
Wilson, R. J. Chem. Soc. 1963, 5418; c) H.-R. Bjørsvik, L. Liguori, J. A. Vedia Merinero, J. Org. Chem.
2002, 67, 7493.
[11] R. R. González, C. Gambarotti, L. Liguori, H.-R. Bjørsvik J. Org. Chem. 2006, 71, 1703.
COMMUNICATION
Synthesis of the carbazole scaffold directly from 2-
amino-biphenyl by means of concurrent C–H
activation and C–N bond formation
Pd(OAc)2, IMes
R1
R2
R1
R2
H2O2, AcOH
Hans-René Bjørsvik* and Vijayaragavan Elumalai
120 oC, mW
R
H
t [min]
20
An efficient Pd-catalyzed synthetic method for the
preparation of the carbazole scaffold was designed
and investigated. Non-symmetrical substituted
carbazoles can be synthesised by an intramolecular
combination of a free amine group and an arene via
a concurrent Pd catalysed C−H activation and
intramolecular C-N bond formation.
N
R
NHR H
C(=O)CH3 180
sealed tube
Isolated yield-%
41-85
R
H
Examples
15
8
46-85
C(=O)CH3
Key Topic: C−H activation
7
This article is protected by copyright. All rights reserved