Site-Selective N-Arylation of Carbazoles with Halogenated Fluorobenzenes

Article abstract of DOI:10.1055/s-0035-1560386

A method for the highly site-selective C-N bond-formation reaction of halogenated fluorobenzenes with carbazoles is described. The selectivity of iodine and fluorine atoms on the aromatic ring of fluorinated iodobenzenes was initially determined with a copper-N,N-diisopropylethylamine catalytic system. By changing the position of the iodine atom on the aromatic ring from the 3- or 4-position to the 2-position, the preferred coupling site was switched from the iodine atom to the fluorine atom. Steric hindrance of the fluorinated iodobenzenes is responsible for the selectivity switch. After elucidating the reaction mechanisms of these reaction processes, a metal-free method for the highly site-selective C-N bond-formation reaction of halogenated fluorobenzenes with carbazoles was revealed through C-F bond activation. The metal-free system is able to handle a range of halogenated groups. Thus, a broad range of chlorinated, brominated, and iodinated N-arylated carbazoles were generated, which are widely useful in organic chemistry.

Full text of DOI:10.1055/s-0035-1560386

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, 737–750
paper
737
L. Wang et al.
Paper
Synthesis
Site-Selective N-Arylation of Carbazoles with Halogenated Fluoro-
benzenes
R1
R1
Lei Wang
Enhui Ji
R1
I
2-I
Cu
F
Ning Liu*
Bin Dai*
4-I or 3-I
Cu
N
+
HN
N
I
School of Chemistry and Chemical Engineering, Key
Laboratory for Green Processing of Chemical Engineering
of Xinjiang Bingtuan, Shihezi University, North 4th Road,
Shihezi, Xinjiang 832003, P. R. of China
ninglau@163.com
F
R2
R2
R2
R1, R2 = H, Br, t-Bu, OH, NO2
4 examples
yields 26–49%
13 examples
yields 24–95%
dbinly@126.com
Received: 26.09.2015
Accepted after revision: 11.11.2015
Published online: 28.12.2015
drawbacks of this process are the harsh reaction conditions
and limited substrate scope. These limitations were over-
come by the development of a method to synthesise fluori-
nated N-arylated carbazoles through palladium-catalysed
double N-arylation by using primary amines and 2,2′-di-
halobiphenyls (Scheme 1, route A).6 Recently, cyclic dia-
ryliodonium salts have been studied as arylation agents for
use in C–N bond-formation reactions. Riedmüller and
Nachtsheim reported a palladium-catalysed N-arylation of
cyclic diaryliodonium salts with anilines to synthesise fluo-
rinated N-arylated carbazoles (Scheme 1, route B).7 Wen
and co-workers have found a low-cost and environment-
friendly copper catalyst, and have developed a copper-cata-
lysed method to synthesise the same compounds by using
cyclic diaryliodonium salts and amines (Scheme 1, route
B).8 Metal-free methods are an alternative synthetic strate-
gy. Thus, Wang and co-workers have developed a metal-
free method to prepare fluorinated N-arylated carbazoles
(Scheme 1, route C).9
The limitations of Ullmann-type reactions have been re-
duced through the pioneering work of the Buchwald10 and
Hartwig groups.11 Several high-performance ligands have
been developed for the copper-catalysed N-arylation of car-
bazole (Scheme 1, route D).12
Carbazoles are derived from non-petroleum resources.
The availability of carbazoles prompted us to develop an ef-
ficient ligand to prepare fluorinated N-arylated carbazoles
via a copper-catalysed method. Diamine derivatives are
commercially available, and Buchwald and co-workers have
reported that these derivatives are efficient ligands for cop-
per-catalysed N-arylation.13 In this paper, the copper–
amine-catalysed N-arylation of carbazole with fluorinated
iodobenzenes is developed. Interestingly, the reactivity of
the C–X bond can be tuned by adjusting the position of the
iodo substituent on the aromatic ring. The preferred cou-
pling site of the fluorinated iodobenzenes was switched
DOI: 10.1055/s-0035-1560386; Art ID: ss-2015-h0563-op
Abstract A method for the highly site-selective C–N bond-formation
reaction of halogenated fluorobenzenes with carbazoles is described.
The selectivity of iodine and fluorine atoms on the aromatic ring of flu-
orinated iodobenzenes was initially determined with a copper–N,N-di-
isopropylethylamine catalytic system. By changing the position of the
iodine atom on the aromatic ring from the 3- or 4-position to the 2-
position, the preferred coupling site was switched from the iodine atom
to the fluorine atom. Steric hindrance of the fluorinated iodobenzenes
is responsible for the selectivity switch. After elucidating the reaction
mechanisms of these reaction processes, a metal-free method for the
highly site-selective C–N bond-formation reaction of halogenated fluo-
robenzenes with carbazoles was revealed through C–F bond activation.
The metal-free system is able to handle a range of halogenated groups.
Thus, a broad range of chlorinated, brominated, and iodinated N-arylat-
ed carbazoles were generated, which are widely useful in organic chem-
istry.
Key words N-arylation, site selectivity, halobenzenes, N-arylated car-
bazoles
Carbazole structural units have numerous applications
in medicine as synthetic intermediates,1 and in advanced
materials as building blocks.2 Introduction of an oganofluo-
rine into a carbazole can efficiently tune the absorption,
light-emitting, and electronic properties of materials,3 as
well as affect physical, adsorption, distribution, and metab-
olism properties of medicines.4 However, naturally occur-
ring fluorinated compounds are virtually absent from the
natural world. Given the importance and rarity of this class
of compounds, the search for an efficient synthetic protocol
for their preparation remains an urgent priority.
Various methods to construct fluorinated N-arylated
carbazoles have been described.
A copper-catalysed
Ullmann-type reaction was initially applied in the synthe-
sis of fluorinated N-arylated carbazoles.5 However, the main
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738
L. Wang et al.
Paper
Synthesis
F
Y
Y
H2N
+
X = Cl, Br, I
Pd-catalysed double N-arylation (ref. 6)
route A
F
F
X
H2N
X = Br, I
+
+
F
N
OTf
I
H
N
Pd or Cu catalysis (refs. 7 and 8)
our work
Cu-catalyzed method (ref. 10–12)
route B
route D
F
ArI
NH
+
OTf
metal-free method (ref. 9)
route C
Scheme 1 Different methods towards fluorinated N-arylated carbazoles
from the iodine atom to the fluorine atom when the posi-
tion of the iodine atom on the aromatic ring was changed
from the 3- or 4-position to the 2-position. The main fac-
tors responsible for the selectivity of halides attached to an
aromatic ring are investigated in this paper.
The N-arylation of carbazole with 1-fluoro-4-iodoben-
zene was also used as the model reaction to further opti-
mise the reaction conditions, in which a range of tempera-
tures, solvents, and bases was investigated (Table 1).
The effect of reaction temperature on this cross-cou-
pling was evaluated, and the results show that the reaction
temperature plays an important role in the reaction. The
coupling reaction was slow at 90 °C, with a mere 54% isolat-
ed yield obtained (Table 1, entry 1). The cross-coupling was
remarkably accelerated when the temperature was raised
to 110 °C, with an increased yield of 76% (Table 1, entry 2).
Upon further increase of the reaction temperature to
130 °C, the isolated yield reached 82% (Table 1, entry 3).
However, NMR analysis showed that the higher reaction
temperature led to low selectivity of the C–X bond and re-
sulted in the formation of a mixture of products, namely 9-
(4-fluorophenyl)-9H-carbazole and 9-(4-iodophenyl)-9H-
carbazole, from which the desired product is often difficult
to isolate.
The coupling reaction of 1-fluoro-4-iodobenzene and
carbazole was selected as the model reaction to optimise
the reaction conditions. First, the efficiency of different li-
gands on the coupling reaction was evaluated (Scheme 2).
Ligand efficiency was verified by designing control ex-
periments in the absence of a ligand. Results show that the
reaction had difficulty proceeding with copper(I) iodide in
the absence of a ligand, with a 14% product yield. A number
of diamine ligands were initially evaluated, and N1,N1,N2,N2-
tetramethylethane-1,2-diamine (L7) was more catalytically
efficient than other ethanediamine derivatives. Encouraged
by these results, the catalytic efficiency of another four ter-
tiary amine derivatives (L8–L11) was subsequently tested in
the coupling of 1-fluoro-4-iodobenzene and carbazole,
with the commercially available N,N-diisopropylethylamine
(L9) proving the most efficient (Scheme 2).
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Synthesis
Table 1 Optimisation of the Reaction Conditionsa
H
N
CuI (10 mol%)
ligand (10 or 20 mol%)
F
+
F
I
N
F
KOH (2 equiv)
DMF, 90 °C
H
N
[Cu], L9
2.0 mmol
0.5 mmol
+
F
I
N
base, solvent
H
N
NH2
COOH
ligand-free
Yield 14%
N
H
NH2
N
H
Entry Solvent Copper source
Base
KOH
Temp (°C) Yield (%)
L1 Yield 27%
L2 Yield 38%
L3 Yield 41%
1
2
DMF
DMF
DMF
DMA
NMP
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CuI
90
110
130
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
54
76
82
37
26
23
72
64
59
57
49
14
42
55
33
57
65
16
24
45
51
CuI
KOH
H
NH2
N
N
N
H2N
3
CuI
KOH
N
H
N
H2N
4
CuI
KOH
L4 Yield 23%
L7 Yield 45%
L6 Yield 36%
L5 Yield 28%
5
CuI
KOH
6
CuI
KOH
N
N
N
N
7
Cu2O
KOH
N
N
8
CuCl
KOH
L8 Yield 24%
L9 Yield 54%
L11 Yield 34%
L10 Yield 52%
9
CuSO4·5H2O
KOH
10
11
12
13
14
15
16
17
18
19
20
21
Cu(OAc)2·H2O
KOH
Scheme 2 Ligands for the copper-catalysed cross-coupling of 1-fluoro-
4-iodobenzene with carbazole
Cu(NO3)2
CuO
Cu
KOH
KOH
KOH
The effect of different solvents was also determined.
The reaction carried out in N,N-dimethylformamide (DMF)
gave a good yield (Table 1, entry 2), while the yields were
decreased when N,N-dimethylacetamide (DMA), N-methyl-
2-pyrrolidinone (NMP), or dimethyl sulfoxide (DMSO) was
employed (Table 1, entries 4–6).
Copper-catalysed cross-coupling is often affected by the
oxidation state of the copper source. Therefore, different
copper sources [Cu(I), Cu(II), and Cu(0)] were evaluated for
the N-arylation of carbazole with 1-fluoro-4-iodobenzene
when using N,N-dimethylformamide as the solvent. The
copper(I) catalysts were more catalytically active than the
other copper sources. Thus, the copper(I) states showed
moderate to good catalytic activity, with copper(I) iodide
providing the best results (Table 1, entry 2 vs entries 7 and
8). Among the copper(II) sources, copper(II) sulfate, cop-
per(II) acetate, and copper(II) nitrate showed relatively
higher catalytic activity than copper(II) oxide (Table 1, en-
tries 9–11 vs entry 12). The use of copper powder resulted
in a moderate conversion (Table 1, entry 13).
CuI
K2CO3
K3PO4·3H2O
t-BuOK
NaOH
Na2CO3
NaHCO3
t-BuONa
Cs2CO3
CuI
CuI
CuI
CuI
CuI
CuI
CuI
a Reaction conditions: 1-fluoro-4-iodobenzene (2.0 mmol), carbazole (0.5
mmol), copper source (10 mol%), L9 (20 mol%), base (1.0 mmol), solvent (2
mL), 12 h, under N2; isolated yields are given.
Soulé, Doucet, and co-workers14 have described a palla-
dium-catalysed methodology for the synthesis of fluorinat-
ed biphenyls through C–H bond activation of halogenated
fluorobenzenes. However, no biaryl product generated from
C–H bond activation of halogenated fluorobenzene was ob-
served in the developed copper-catalysed system.
A series of bases was also evaluated. Strong bases
showed higher catalytic activity than weak bases. The ac-
tivity of potassium hydroxide was superior to other potas-
sium bases, with potassium phosphate giving lowest con-
version (Table 1, entry 2 vs entries 14–16). The activity of
sodium hydroxide was superior to a range of other sodium
bases (Table 1, entry 17 vs entries 18–20). By contrast, cesi-
um carbonate showed moderate catalytic activity (Table 1,
entry 21).
The scope and limitations for the cross-coupling of io-
dinated fluorobenzenes with a range of carbazoles was ex-
amined using the optimised reaction conditions, namely
copper(I) iodide as catalyst, N,N-diisopropylethylamine (L9)
as ligand, potassium hydroxide as base, and N,N-dimethyl-
formamide as solvent at 110 °C (Scheme 3).
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L. Wang et al.
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Synthesis
The effect of a fluoro substituent at the different posi-
tions of iodobenzene on the copper-catalysed coupling re-
action with carbazole was initially examined. N-Arylation
was not affected by the electronic effect of an aromatic
fluoro substituent; thus, 4-fluoro- or 3-fluoro-substituted
iodobenzene smoothly underwent coupling to give corre-
sponding products in good yields (Scheme 3, 1a and 1b).
However, steric hindrance of fluorinated iodobenzene was
evident; the 2-fluoro-substituted iodobenzene resulted in
low conversion, and gave 57% yield (Scheme 3, 1c). Subse-
quently, the electronic nature of substituents on carbazole
was also investigated, and an electronic effect of substitu-
ents attached to the aromatic rings of carbazole was ob-
served. Thus, carbazoles bearing the electron-donating tert-
butyl group reacted with 4-fluoro- or 3-fluoro-substituted
iodobenzene to produce high yields (Scheme 3, 1h and 1l).
However, carbazoles bearing electron-withdrawing substit-
uents such as 3-bromo, 3,6-dibromo, 2,7-dibromo, and 3-
nitro groups, showed relatively lower reactivity in the de-
veloped catalytic system (Scheme 3, 1d–f and 1i–k). The
coupling with 4-hydroxycarbazole failed to furnish the de-
sired product (Scheme 3, 1g).
X
H
N
F
CuI, L9, KOH
N
I
+
DMF, 110 o
C
C−I bond activation
F
F
F
N
N
N
1b, 78%
1c, 57%
1a, 87%
F
F
F
N
N
N
Br
Br
Br
NO2
1d, 71%
1f, 24%
1e, 64%
F
F
F
Steric hindrance effects of the fluorinated iodobenzenes
significantly influenced the selectivity of the reaction. 1-
Fluoro-2-iodobenzene was selected as the model substrate
to explore the selectivity of the reaction under the opti-
mised conditions. Carbazole itself, bearing the electron-
neutral hydrogen group, preferentially reacted with the C–I
bond (Scheme 3, 1c). Carbazoles bearing electron-donating
groups, such as 3,6-di-tert-butyl groups, showed poor se-
lectivity and reacted with the C–I and C–F bonds to yield a
mixture of products (Scheme 3, 1m and 1n). Finally, carba-
zoles bearing electron-withdrawing groups, such as 3-bro-
mo, 3,6-dibromo, and 2,7-dibromo groups, preferentially
reacted with the C–F bond (Scheme 3, 1o–q).
N
N
N
Br
t-Bu
t-Bu
HO
1g, trace
1i, 69%
1h, 95%
F
F
F
N
N
N
Br
Br
Br
Br
t-Bu
t-Bu
1j, 61%
1l, 84%
1k, 53%
Scheme 4 summarises the reaction rules for the cou-
pling of fluorinated iodobenzenes with carbazoles. The po-
sition effect of the iodine atom is crucial to the selectivity of
this coupling. Fluorobenzenes with the iodo substituent at
the para or meta position to the fluorine atom show higher
reactivity with the C–I bond of the benzene ring than with
the C–F bond in the presence of a copper catalyst. Steric
hindrance significantly affects the copper-catalysed N-ary-
lation of carbazoles and inhibits the reaction. Carbazole
bearing the electron-neutral hydrogen group showed rela-
tively high reactivity and selectivity, and reacted with the
C–I bond of the benzene ring to provide the desired prod-
ucts. However, carbazoles bearing electron-donating
groups, such as 3,6-di-tert-butyl groups, exhibited low se-
lectivity with 1-fluoro-2-iodobenzene, to give a mixture of
C–F and C–I bond activation. In the case of the ortho-iodin-
ated fluorobenzene, the preferred coupling site switched
from the iodine atom to the fluorine atom with carbazoles
bearing electron-withdrawing groups, such as 3-bromo,
3,6-dibromo, and 2,7-dibromo groups.
F
I
N
N
+
t-Bu
t-Bu
t-Bu
t-Bu
1m, 48%a
1n, 26%a
C−F bond activation
I
I
I
N
N
N
Br
Br
Br
Br
Br
1p, 37%
1q, 32%
1o, 49%
Scheme 3 Copper-catalysed cross-coupling of iodinated fluoroben-
zenes with carbazoles. Reagents and conditions: fluorinated iodoben-
zene (2.0 mmol), carbazole (0.5 mmol), CuI (10 mol%), L9 (20 mol%),
KOH (1.0 mmol), DMF (2 mL), under N2, 110 °C, 24 h; isolated yields are
given, except where otherwise indicated. a NMR yield.
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L. Wang et al.
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Synthesis
mixture
F
I
+
N
N
t-Bu
t-Bu
t-Bu
t-Bu
2-I
R
1 and R2 = electron-donating group
F
F
3-I or 4-I, R is unlimited
2-I
I
I
+
N
N
R1 and/or R2 = electron-withdrawing
group
2-I, R1 and R2 = H
H
N
R2
Br
R1
Br
R2
R1
CuI/L9, KOH in DMF, 110 °C
Scheme 4 Selective synthesis of N-arylated carbazoles
Control experiments in the absence of a copper source
and ligand were designed to probe the main reason for the
selectivity of the aromatic halide group (Scheme 5). Such a
control experiment showed that 3,6-dibromocarbazole
preferentially reacted with the fluoro group of 1-fluoro-2-
iodobenzene to generate the monosubstituted product
through a nucleophilic substitution reaction (Scheme 5,
equation 1). The selectivity of aromatic polyhalides was ex-
plored in the presence and absence of a copper source. The
results revealed that the C–I and C–F bonds of 1-bromo-2-
fluoro-4-iodobenzene exhibited similar reactivity in the
presence of copper and were simultaneously activated to
give the disubstituted product 2a. However, in the absence
of copper, 1-bromo-2-fluoro-4-iodobenzene underwent
highly selective coupling at the fluorine group with carba-
zole through a nucleophilic substitution reaction (Scheme
5, equation 2). The results indicate that nucleophilic attack
is likely to occur at the fluoro-substituted carbon atom of
the aromatic ring. The metal-free method shows excellent
selectivity for the halogen atoms of the aromatic ring, lead-
ing to the creation of the desired product with a minimal
amount of byproducts.
acted at the fluorine group of the aromatic ring with carba-
zole, both in the presence and absence of a copper catalyst.
In summary, copper-catalysed coupling of halogenated
benzenes with carbazole is significantly affected by steric
hindrance; however, steric hindrance has a slight effect on
the nucleophilic substitution reaction.
Halogens including chlorine, bromine, and iodine on the
aromatic ring are well-tolerated in metal-free N-arylation,
thus providing an opportunity to functionalise the result-
ing halogenated N-arylated carbazoles and to convert them
into useful pharmaceuticals, dye-sensitised solar cells, and
advanced materials intermediates. We chose 9-(4-iodophe-
nyl)-9H-carbazole (4r, see Scheme 7) as a model substrate
to explore its reactivity in a series of transition-metal-cata-
lysed cross-coupling reactions. As illustrated in Scheme 6,
iodo derivative 4r could be successfully converted into valu-
able intermediates through classical transition-metal-cata-
lysed Suzuki coupling, Ullmann-type reaction, and Sono-
gashira coupling.
The N-arylation of carbazole with 1-fluoro-4-iodoben-
zene was also selected as the model reaction to optimise
the metal-free reaction conditions (Table 2).
Our results indicated that copper-catalysed C–I bond ac-
tivation is significantly affected by steric hindrance. Howev-
er, steric hindrance only slightly affects the metal-free nuc-
leophilic substitution reaction. This hypothesis was tested
by selecting 2-bromo-4-fluoro-1-iodobenzene, containing
steric hindrance at the ortho position of the iodine atom, to
elucidate the reaction process (Scheme 5, equation 3). As
shown, 2-bromo-4-fluoro-1-iodobenzene preferentially re-
The amount of base, crucial for the nucleophilic substi-
tution reaction to activate the N–H bond of carbazole, was
investigated under metal-free conditions. The amount of
base had an effect on the product yield (Table 2, entry 1 vs
entry 2); thus, considering efficiency, four equivalents of
base was selected as the optimised mole ratio.
The effect of reaction temperature on the cross-cou-
pling was evaluated. The results show that the reaction
temperature plays an important role in metal-free N-aryla-
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L. Wang et al.
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Synthesis
and potassium carbonate were superior to other potassium
bases, with potassium tert-butoxide giving lower conver-
sion and potassium phosphate yielding a trace of product
(Table 2, entries 4 and 6 vs entries 7 and 8). Sodium tert-
butoxide was superior to a range of other sodium bases, but
promoted byproduct formation (Table 2, entry 9 vs entries
10–12). Cesium carbonate was the most efficient base of all
tested bases (Table 2, entry 13).
1p, 37%
I
CuI, L9, KOH
DMF, 110 °C
F
2 mmol
+
I
N
H
N
KOH, DMF
110 °C
Br
Br
1p
1p, 39%
Br
Br
The reaction was promoted with an increased amount
of 1-fluoro-4-iodobenzene, but the increasing rate slowed
down when the concentration was 6 equivalents (Table 2,
entries 13–15); 4 equivalents of 1-fluoro-4-iodobenzene
was the best compromise between cost and product yield
(Table 2, entry 13).
The effect of various solvents was also determined. The
reaction carried out in N,N-dimethylformamide, dimethyl
sulfoxide, or N,N-dimethylacetamide produced good to ex-
equation 1
0.5 mmol
Br
N
Br
F
CuI, L9, KOH
DMF, 130 °C
N
2a, 53%
I
2 mmol
+
I
H
N
Table 2 Optimisation of the Metal-Free Reaction Conditionsa
KOH, DMF
130 °C
Br
N
equation 2
base
0.5 mmol
HN
I
F
I
N
+
solvent
2b, 68%
I
Br
Entry
Solvent
Base
KOH
Temp (°C) Yield (%)
2c, 37%
27b
35
I
1
2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMA
NMP
toluene
110
110
130
150
170
150
150
150
150
150
150
150
150
150
150
150
150
150
150
CuI, L9, KOH
DMF, 130 °C
Br
KOH
F
2 mmol
+
3
KOH
43
N
4
KOH
48
H
N
KOH, DMF
130 °C
5
KOH
52
2c, 41%
6
K2CO3
t-BuOK
36
2c
equation 3
0.5 mmol
7
13
Scheme 5 Control experiments to probe the coupling selectivity
8
K3PO4·3H2O
t-BuONa
NaOH
trace
36
9
10
11
12
13
14
15
16
17
18
19
28
tion. The N-arylation of carbazole with 1-fluoro-4-iodoben-
zene was slow at 110 °C, with merely 35% isolated yield (Ta-
ble 2, entry 2). The cross-coupling was remarkably acceler-
ated when the temperature was increased to 150 °C, with
48% yield (Table 2, entry 4). Upon further increase of the re-
action temperarure to 170 °C, the isolated yield reached
52% (Table 2, entry 5). However, HPLC–MS analysis showed
that the higher reaction temperature was likely to result in
disubstituted and dehalogenated side products. In view of
this, 150 °C was selected as the optimised reaction tem-
perature for use in subsequent studies.
Na2CO3
NaHCO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
trace
trace
92
74c
94d
85
71
54
trace
The nature of the base is crucial to the efficiency of met-
al-free N-arylation. Therefore, various bases were evaluated
for the cross-coupling of carbazole with 1-fluoro-4-iodo-
benzene when using N,N-dimethylformamide as the sol-
vent. Among the potassium bases, potassium hydroxide
a Reaction conditions: 1-fluoro-4-iodobenzene (2.0 mmol), carbazole (0.5
mmol), base (2.0 mmol), solvent (2 mL), 24 h; isolated yields are given.
b Base (1.0 mmol).
c 1-Fluoro-4-iodobenzene (1.0 mmol).
d 1-Fluoro-4-iodobenzene (3.0 mmol).
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Synthesis
N
86%
3a
Pd(OAc)2 (5 mol%)
Ph3P (15 mol%)
Cs2CO3 (2.0 equiv)
PhB(OH)2 (1.5 equiv)
DMA
130 °C, 24 h
F
I
pyrazole
(2.0 equiv)
(4.0 equiv)
N
N
N
I
NH
CuI (20 mol%)
DMA
160 °C
Cs2CO3 (2.0 equiv)
N
Cs2CO3, DMF
150 °C, 24 h
4r
83%
3b
PdCl2 (5 mol%)
CuI (2,5 mol%)
Ph3P (15 mol%)
Et3N (2.0 equiv)
Ph
(2 equiv)
DMA
130 °C
N
72%
3c
Scheme 6 Functionalisation of 9-(4-iodophenyl)-9H-carbazole (4r)
cellent yields (Table 2; entries 13, 16, and 17). The yield de-
creased upon switching to N-methyl-2-pyrrolidinone as the
solvent (Table 2, entry 18), while the nonpolar solvent tolu-
ene gave a poor result (Table 2, entry 19).
cessfully converting various carbazoles into the corre-
sponding N-arylated products in moderate to excellent
yields (Scheme 7; 4l–w, 1p, and 1q).
Encouraged by the success of monohalogenated fluoro-
benzenes, fluorobenzenes bearing an additional two differ-
ent halogen groups were also investigated for reactivity and
selectivity with the metal-free catalytic system. Four diha-
logenated fluorobenzenes were examined under the opti-
mised conditions. Remarkably, there was full conversion of
all four dihalogenated fluorobenzenes, resulting in excel-
lent product yields (Scheme 7; 4x, 4y, 2b, and 2c). Con-
trolling the selectivity of multiple halogens on an aromatic
ring to avoid the formation of various byproducts has been
a challenge in previous studies. Interestingly, this metal-
free method showed excellent selectivity of the aromatic
halogen atoms, yielding the desired products with minimal
amounts of byproducts. The results indicate that nucleop-
hilic attack is likely to occur at the fluoro-substituted car-
bon atom of the halogenated aromatic ring.
The reaction is scalable, and could be scaled up to a
gram scale without any setbacks (Scheme 7; 4aa, 4oa, and
4ra).
In summary, the catalytic system generated in situ from
an inexpensive copper salt, the commercially available li-
gand N,N-diisopropylethylamine, and a simple inorganic
base is able to perform the C–N bond-formation reaction of
halogenated fluorobenzenes with carbazoles with high se-
lectivity. The selectivity of iodine and fluorine atoms on the
aromatic ring was evaluated in the developed catalytic sys-
The scope for the N-arylation of a range of carbazoles
with halogenated fluorobenzenes was explored under the
optimised metal-free reaction conditions (Scheme 7).
The electronic and steric hindrance effects of brominat-
ed fluorobenzenes in reactions with carbazoles were first
studied. Electronic and steric hindrance effects were not
apparent in the metal-free catalytic system. Thus, 4-bromo-,
3-bromo-, and the sterically hindered 2-bromo-substituted
fluorobenzene smoothly reacted with carbazole to give the
corresponding products in good to excellent yields (Scheme
7, 4a–c). The nature of substituents on carbazole was then
investigated. The results show an evident electronic effect
of substituents attached to the aromatic rings of carbazole.
1-Bromo-4-fluorobenzene smoothly reacted with carba-
zoles bearing electron-neutral or electron-donating 3,6-di-
tert-butyl groups to produce excellent yields (Scheme 7, 4a
and 4k). However, carbazoles bearing electron-withdraw-
ing substituents such as 3-bromo, 3,6-dibromo, 2,7-dibro-
mo, 3-nitro, and 4-hydroxy groups, showed relatively lower
reactivity (Scheme 7, 4d and 4g–j).
Brominated fluorobenzenes were replaced by a series of
other halogenated fluorobenzenes to extend the scope of
N-arylation. As listed in Scheme 7, chlorinated and iodinat-
ed fluorobenzenes showed similar reactivities as the bro-
minated fluorobenzenes upon metal-free N-arylation, suc-
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744
L. Wang et al.
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Synthesis
Xn
H
Xn
N
Cs2CO3
DMF
F
+
N
R2
R1
R2
R1
X = Br, Cl, I
Br
N
Br
N
Br
Br
Br
Br
N
N
N
N
Br
Br
Br
4a, 95% (91%b)
4d, 73%
4f, 84%
4c, 87%
4e, 94%
4b, 73%
Br
Br
Br
Br
Br
N
Cl
N
N
N
N
N
Br
Br
Br
Br
OH
t-Bu
t-Bu
O2N
4l, 92%
4i, 77%
4j, trace
4g, 66%
4h, 78%
4k, 96%
Cl
N
Cl
Cl
I
Cl
Cl
N
N
N
N
N
Br
Br
Br
Br
Br
4n, 84%
4q, 87%
4r, 97% (94%a)
4o, 68% (63%a)
4m, 96%
4p, 76%
I
I
I
I
I
I
N
N
N
N
N
N
Br
Br
Br
Br
Br
Br
Br
1p, 61%
4w, 82%
4t, 86%
4u, 74%
4v, 81%
4s, 90%
Br
I
Br
Cl
Br
I
I
Cl
Br
N
N
N
N
N
Br
Br
4y, 98%
4x, 95%
2c, 85%
1q, 62%
2b, 83%
Scheme 7 Metal-free N-arylation of carbazoles with halogenated fluorobenzenes. Reagents and conditions: fluorinated halobenzene (2.0 mmol), carba-
zole (0.5 mmol), Cs2CO3 (2.0 mmol), DMF (2 mL), under air, 150 °C, 24 h; isolated yields are given. a The reaction was performed with a 10-fold amount
of the reactants in DMF (20 mL) at 150 °C for 24 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 737–750

745
L. Wang et al.
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Synthesis
tem. The selectivity of fluorinated iodobenzenes can be
tuned by adjusting the position of the iodine atom on the
aromatic ring. The preferred coupling site of the fluorinated
iodobenzenes was switched from the iodine atom to the
fluorine atom when the position of the iodine atom on the
aromatic ring was changed from the 3- or 4-position to the
2-position. The main factor that affects the selectivity of
halides attached to aromatic rings is steric hindrance. These
reaction processes are composed of two competing reac-
tions: a metal-free nucleophilic substitution reaction and a
copper-catalysed C–N bond formation. Control experi-
ments showed that the copper-catalysed coupling of halo-
genated benzenes with carbazole was significantly affected
by steric hindrance; however, steric hindrance has only a
slight effect on the nucleophilic substitution reaction.
Therefore, fluorinated iodobenzenes containing a sterically
demanding group preferentially react at the C–F bond rath-
er than the C–I bond. The major advantage of the metal-free
process is that the selectivity of halogen atoms on the aro-
matic ring can be completely controlled, giving a range of
N-arylated carbazoles bearing chlorine, bromine, and io-
dine groups. The resulting halogenated N-arylated carba-
zoles are synthetically useful intermediates for the pharma-
ceutical, agrochemical, and materials science fields.
9-(4-Fluorophenyl)-9H-carbazole (1a)6d
Purification by flash chromatography [petroleum ether (PE)]; white
solid; yield: 114 mg (87%); mp 113–115 °C.
1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 7.6 Hz, 2 H), 7.56–7.53 (m, 2
H), 7.44 (t, J = 7.6 Hz, 2 H), 7.37–7.30 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 161.60 (d, JC–F = 246.0 Hz), 141.01,
133.60 (d, JC–F = 3.1 Hz), 129.00 (d, JC–F = 8.5 Hz), 125.99, 123.26,
120.33, 119.98, 116.82 (d, JC–F = 22.6 Hz), 109.49.
19F NMR (376 MHz, CDCl3): δ = –35.9 to –35.98 (m).
9-(3-Fluorophenyl)-9H-carbazole (1b)
Purification by flash chromatography (PE); white solid; yield: 102 mg
(78%); mp 78–79 °C.
1H NMR (400 MHz, CDCl3): δ = 8.18 (dt, J = 7.6, 0.8 Hz, 2 H), 7.63–7.58
(m, 1 H), 7.50–7.41 (m, 5 H), 7.38–7.32 (m, 3 H), 7.21 (ddd, J = 8.4, 2.8,
1.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 163.47 (d, JC–F = 246.6 Hz), 140.56,
139.34 (d, JC–F = 9.8 Hz), 131.08 (d, JC–F = 9.2 Hz), 126.16, 123.59,
122.73 (d, JC–F = 3.2 Hz), 120.44, 120.36, 114.52 (d, JC–F = 7.1 Hz),
114.30 (d, JC–F = 8.8 Hz), 109.73.
19F NMR (376 MHz, CDCl3): δ = –110.46.
HRMS (MALDI): m/z [M]+ calcd for C18H12FN: 261.0948; found:
261.0947.
9-(2-Fluorophenyl)-9H-carbazole (1c)
Purification by flash chromatography (PE); yellow oil; yield: 74 mg
(57%).
1H NMR (400 MHz, CDCl3): δ = 8.18 (dt, J = 8.0, 0.8 Hz, 2 H), 7.60 (td,
J = 8.0, 1.6 Hz, 1 H), 7.55–7.50 (m, 1 H), 7.47–7.37 (m, 4 H), 7.35–7.31
(m, 2 H), 7.27 (dt, J = 8.0, 0.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 158.36 (d, JC–F = 251.4 Hz), 140.85,
129.88 (d, JC–F = 1.2 Hz), 129.61 (d, JC–F = 7.6 Hz), 126.05, 125.10 (d,
JC–F = 3.9 Hz), 123.55, 120.33, 120.18, 117.39 (d, JC–F = 19.6 Hz), 109.89
(d, JC–F = 1.5 Hz).
All copper-catalysed reactions were performed in Schlenk tubes un-
der nitrogen atmosphere. DMF, DMSO, DMA, and NMP were distilled
from 4-Å molecular sieves. All reagents were purchased from com-
mercial sources and used without additional purification. NMR spec-
tra were recorded on a Varian Inova 400 or a Bruker Avance III HD 400
spectrometer using TMS as internal standard (400 MHz for 1H NMR,
100 MHz for 13C NMR, and 376 MHz for 19F NMR). Mass data of the
compounds were collected on a Bruker ultrafleXtreme mass spec-
trometer. All products were isolated by short chromatography on a
silica gel (200–300 mesh) column.
19F NMR (376 MHz, CDCl3): δ = –118.46.
HRMS (MALDI): m/z [M]+ calcd for C18H12FN: 261.0948; found:
261.0954.
Copper-Catalysed N-Arylation of Carbazoles; General Procedure
A mixture of a fluorinated aryl iodide (2.0 mmol), a carbazole (0.5
mmol), a copper source (0.05 mmol), a ligand (0.05 or 0.1 mmol), and
a base (1.0 mmol) in solvent (2 mL) was allowed to react under nitro-
gen atmosphere. The reaction mixture was heated to the specified
temperature for 24 h. After reaction completion, the mixture was
added to brine (15 mL) and extracted with CH2Cl2 (3 × 15 mL). The
combined extract was concentrated under reduced pressure and the
product was isolated by short chromatography on a silica gel (200–
300 mesh) column.
3-Bromo-9-(4-fluorophenyl)-9H-carbazole (1d)
Purification by flash chromatography (PE); yellow oil; yield: 121 mg
(71%).
1H NMR (400 MHz, CDCl3): δ = 8.29 (d, J = 1.6 Hz, 1 H), 8.12 (d, J = 7.2
Hz, 1 H), 7.54–7.46 (m, 4 H), 7.37–7.31 (m, 4 H), 7.22 (d, J = 8.4 Hz, 1
H).
13C NMR (100 MHz, CDCl3): δ = 161.81 (d, JC–F = 246.4 Hz), 141.38,
139.71, 133.18 (d, JC–F = 3.0 Hz), 129.02, 128.83 (d, JC–F = 20.4 Hz),
126.81, 125.06, 123.13, 122.25, 120.58, 120.47, 117.03 (d, JC–F = 22.6
Hz), 112.83, 111.03, 109.79.
19F NMR (376 MHz, CDCl3): δ = –112.99 to –113.01 (m).
HRMS (MALDI): m/z [M]+ calcd for C18H11BrFN: 339.0053; found:
Metal-Free N-Arylation of Carbazoles; General Procedure
A mixture of a fluorinated aryl halide (2.0 mmol), a carbazole (0.5
mmol), and a base (2.0 mmol) in solvent (2 mL) was allowed to react
under air atmosphere. The reaction mixture was heated to the speci-
fied temperature for 24 h. After reaction completion, the mixture was
added to brine (15 mL) and extracted with CH2Cl2 (3 × 15 mL). The
combined extract was concentrated under reduced pressure and the
product was isolated by short chromatography on a silica gel (200–
300 mesh) column.
339.0053.
3,6-Dibromo-9-(4-fluorophenyl)-9H-carbazole (1e)
Purification by flash chromatography (PE); white solid; yield: 134 mg
(64%); mp 164–166 °C.
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746
L. Wang et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.19 (dd, J = 2.0, 0.4 Hz, 2 H), 7.51 (dd,
J = 8.8, 2.0 Hz, 2 H), 7.48–7.45 (m, 2 H), 7.33–7.29 (m, 2 H), 7.17 (dd,
J = 8.4, 0.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 163.19, 160.71, 140.01, 132.69,
132.66, 129.46, 128.95, 128.87, 123.86, 123.25, 117.25, 117.03,
113.16, 111.24.
13C NMR (100 MHz, CDCl3): δ = 163.44 (d, JC–F = 247.6 Hz), 139.49,
138.31 (d, JC–F = 9.8 Hz), 131.38 (d, JC–F = 9.1 Hz), 129.58, 124.10,
123.32, 122.53 (d, JC–F = 3.3 Hz), 115.16 (d, JC–F = 20.9 Hz), 114.26 (d,
JC–F = 22.7 Hz), 113.47, 111.39.
19F NMR (376 MHz, CDCl3): δ = –109.75 to –109.77 (m).
HRMS (MALDI): m/z [M]+ calcd for C18H10Br2FN: 416.9159; found:
19F NMR (376 MHz, CDCl3): δ = –34.72 to –34.79 (m).
416.9159.
HRMS (MALDI): m/z [M]+ calcd for C18H10Br2FN: 416.9159; found:
416.9159.
2,7-Dibromo-9-(3-fluorophenyl)-9H-carbazole (1k)
Purification by flash chromatography (PE); white solid; yield: 111 mg
(53%); mp 149 °C.
9-(4-Fluorophenyl)-3-nitro-9H-carbazole (1f)15
Purification by flash chromatography (PE–EtOAc, 10:1); yellow solid;
yield: 37 mg (24%); mp 145 °C.
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.0 Hz, 2 H), 7.62 (q, J = 8.0
Hz, 1 H), 7.54 (s, 2 H), 7.41 (dd, J = 8.0, 1.6 Hz, 2 H), 7.30–7.22 (m, 3 H).
1H NMR (400 MHz, CDCl3): δ = 9.07 (d, J = 2.0 Hz, 1 H), 8.33 (dd,
J = 8.8, 2.0 Hz, 1 H), 8.22 (d, J = 7.6 Hz, 1 H), 7.56–7.53 (m, 3 H), 7.45–
7.32 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 162.29 (d, JC–F = 247.9 Hz), 144.06,
142.46, 141.51, 132.25 (d, JC–F = 3.3 Hz), 129.13 (d, JC–F = 8.6 Hz),
127.76, 123.08, 122.94, 121.89, 121.70, 120.98, 117.40 (d, JC–F = 16.9
Hz), 117.25, 110.46, 109.31.
13C NMR (100 MHz, CDCl3): δ = 163.50 (d, JC–F = 248.0 Hz), 141.46,
137.93 (d, JC–F = 9.7 Hz), 131.58 (d, JC–F = 9.2 Hz), 124.02, 122.70 (d, JC–
F = 3.3 Hz), 121.83, 121.55, 120.20, 115.49 (d, JC–F = 20.8 Hz), 114.39
(d, JC–F = 22.8 Hz), 112.94.
19F NMR (376 MHz, CDCl3): δ = –109.17 to –109.22 (m).
HRMS (MALDI): m/z [M]+ calcd for C18H10Br2FN: 416.9159; found:
416.9159.
19F NMR (376 MHz, CDCl3): δ = –111.63.
3,6-Di-tert-butyl-9-(3-fluorophenyl)-9H-carbazole (1l)
3,6-Di-tert-butyl-9-(4-fluorophenyl)-9H-carbazole (1h)
Purification by flash chromatography (PE); white solid; yield: 156 mg
(84%); mp 143–145 °C.
1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 2.0 Hz, 2 H), 7.59–7.53 (m, 1
H), 7.50 (dd, J = 4.8, 2.0 Hz, 2 H), 7.42–7.38 (m, 3 H), 7.35–7.31 (m, 1
H), 7.18–7.13 (m, 1 H), 1.50 (s, 18 H).
Purification by flash chromatography (PE); pale yellow solid; yield:
176 mg (95%); mp 192–193 °C.
1H NMR (400 MHz, CDCl3): δ = 8.15 (dd, J = 1.6, 0.4 Hz, 2 H), 7.53–7.49
(m, 2 H), 7.47 (dd, J = 8.4, 2.0 Hz, 2 H), 7.30–7.25 (m, 4 H), 1.47 (s, 18
H).
13C NMR (100 MHz, CDCl3): δ = 164.60, 162.13, 143.22, 139.80,
139.71, 138.81, 130.89, 130.80, 123.72, 123.50, 122.19, 122.16,
116.27, 113.91, 113.70, 113.68, 109.10, 34.71, 31.96.
19F NMR (376 MHz, CDCl3): δ = –33.09 to –33.15 (m).
HRMS (MALDI): m/z [M]+ calcd for C26H28FN: 373.2200; found:
13C NMR (100 MHz, CDCl3): δ = 162.52, 160.06, 142.86, 139.36,
134.07, 134.04, 128.61, 128.52, 123.60, 123.20, 116.76, 116.53,
116.22, 108.86, 34.69, 31.96.
19F NMR (376 MHz, CDCl3): δ = –36.65 to –36.72 (m).
HRMS (MALDI): m/z [M]+ calcd for C26H28FN: 373.2200; found:
373.2198.
373.2199.
3,6-Di-tert-butyl-9-(2-fluorophenyl)-9H-carbazole (1m) and 3,6-
Di-tert-butyl-9-(2-iodophenyl)-9H-carbazole (1n)
3-Bromo-9-(3-fluorophenyl)-9H-carbazole (1i)
Purification by flash chromatography (PE); colourless oil; yield: 117
mg (69%).
Compounds 1m and 1n are difficult to isolate by chromatography.
The molar ratio 1m/1n was 2:1, as determined by NMR spectroscopy.
1H NMR (400 MHz, CDCl3): δ = 8.28 (m, 1 H), 8.11 (d, J = 8.0 Hz, 1 H),
7.63–7.58 (m, 1 H), 7.55–7.45 (m, 3 H), 7.37–7.29 (m, 4 H), 7.26–7.21
(m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 163.45 (d, JC–F = 247.2 Hz), 140.86,
139.20, 138.82 (d, JC–F = 9.7 Hz), 131.23 (d, JC–F = 9.2 Hz), 128.81,
126.90, 125.32, 123.18, 122.62 (d, JC–F = 3.3 Hz), 122.47, 120.75,
120.61, 114.80 (d, JC–F = 20.9 Hz), 114.30 (d, JC–F = 22.7 Hz), 113.13,
111.19, 109.93.
3-Bromo-9-(2-iodophenyl)-9H-carbazole (1o)
Purification by flash chromatography (PE); yellow oil; yield: 110 mg
(49%).
1H NMR (400 MHz, CDCl3): δ = 8.30 (d, J = 2.0 Hz, 1 H), 8.14 (d, J = 8.0
Hz, 2 H), 7.60 (dd, J = 8.0, 1.2 Hz, 1 H), 7.51 (dd, J = 8.4, 2.0 Hz, 1 H),
7.48–7.43 (m, 2 H), 7.36–7.29 (m, 2 H), 7.06 (d, J = 8.0 Hz, 1 H), 6.94
(d, J = 8.8 Hz, 1 H).
19F NMR (376 MHz, CDCl3): δ = –110.04 (m).
HRMS (MALDI): m/z [M]+ calcd for C18H11BrFN: 339.0053; found:
13C NMR (100 MHz, CDCl3): δ = 141.05, 140.61, 139.87, 139.33,
130.66, 130.54, 129.88, 128.68, 126.74, 125.01, 123.20, 122.20,
120.60, 120.43, 112.89, 111.69, 110.37, 99.04.
339.0053.
HRMS (MALDI): m/z [M]+ calcd for C18H11BrIN: 446.9114; found:
446.9112.
3,6-Dibromo-9-(3-fluorophenyl)-9H-carbazole (1j)
Purification by flash chromatography (PE); white solid; yield: 128 mg
(61%); mp 154–155 °C.
3,6-Dibromo-9-(2-iodophenyl)-9H-carbazole (1p)
1H NMR (400 MHz, CDCl3): δ = 8.20 (s, 2 H), 7.61 (q, J = 8.0 Hz, 1 H),
7.55–7.52 (m, 2 H), 7.34–7.22 (m, 5 H).
Purification by flash chromatography (PE); white solid; yield: 97 mg
(37%); mp 162–164 °C.
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L. Wang et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.24 (dd, J = 1.6, 0.4 Hz, 2 H), 8.12 (dd,
J = 8.0, 1.6 Hz, 1 H), 7.60 (td, J = 7.6, 1.6 Hz, 1 H), 7.53 (d, J = 2.0 Hz, 1
H), 7.51 (d, J = 2.0 Hz, 1 H), 7.42 (dd, J = 7.6, 1.6 Hz, 1 H), 7.34–7.29 (m,
1 H), 6.92 (dd, J = 8.4, 0.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 140.69, 139.64, 139.36, 130.91,
130.40, 129.96, 129.48, 123.85, 123.37, 113.27, 111.86, 98.81.
9-(1,1′-Biphenyl-4-yl)-9H-carbazole (3a)16
Purification by flash chromatography (PE); white solid; yield: 138 mg
(86%); mp 218–219 °C.
1H NMR (400 MHz, CDCl3): δ = 8.19 (dd, J = 1.2, 0.8 Hz, 1 H), 8.17 (dd,
J = 1.2, 0.8 Hz, 1 H), 7.86–7.83 (m, 2 H), 7.73–7.70 (m, 2 H), 7.68–7.65
(m, 2 H), 7.55–7.41 (m, 7 H), 7.35–7.31 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 140.81, 140.26, 140.23, 136.82,
128.91, 128.46, 127.60, 127.28, 127.10, 125.91, 123.38, 120.28,
119.92, 109.79.
HRMS (MALDI): m/z [M]+ calcd for C18H10Br2IN: 526.8200; found:
526.8211.
2,7-Dibromo-9-(2-iodophenyl)-9H-carbazole (1q)
Purification by flash chromatography (PE); white solid; yield: 84 mg
(32%); mp 162–163 °C.
1H NMR (400 MHz, CDCl3): δ = 8.13 (dd, J = 8.0, 1.6 Hz, 1 H), 7.96 (d,
J = 8.4 Hz, 2 H), 7.61 (td, J = 7.6, 1.2 Hz, 1 H), 7.43–7.40 (m, 3 H), 7.32
(td, J = 7.6, 1.6 Hz, 1 H), 7.15 (d, J = 1.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 141.51, 140.71, 138.97, 131.02,
130.39, 130.02, 123.71, 121.57, 121.53, 119.98, 113.32, 98.80.
9-(4-(1H-Pyrazol-1-yl)phenyl)-9H-carbazole (3b)
Purification by flash chromatography (PE–EtOAc, 40:1); white solid;
yield: 128 mg (83%); mp 185–186 °C.
1H NMR (400 MHz, CDCl3): δ = 8.19 (dd, J = 8.0, 0.8 Hz, 2 H), 8.05 (d,
J = 2.0 Hz, 1 H), 7.98–7.94 (m, 2 H), 7.81 (d, J = 1.2 Hz, 1 H), 7.70–7.66
(m, 2 H), 7.47–7.42 (m, 4 H), 7.34–7.30 (m, 2 H), 6.56 (dd, J = 2.4, 2.0
Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 141.47, 140.78, 139.07, 135.79,
128.12, 126.79, 126.01, 123.38, 120.47, 120.33, 120.06, 109.57,
108.02.
HRMS (MALDI): m/z [M]+ calcd for C18H10Br2IN: 526.8200; found:
526.8211.
9,9′-(4-Bromo-1,3-phenylene)bis(9H-carbazole) (2a)
HRMS (MALDI): m/z [M]+ calcd for C21H15N3: 309.1260; found:
309.1260.
Purification by flash chromatography (PE); white solid; yield: 65 mg
(53%); mp 226 °C.
9-(4-(Phenylethynyl)phenyl)-9H-carbazole (3c)2h
1H NMR (400 MHz, CDCl3): δ = 8.21–8.12 (m, 5 H), 7.79 (d, J = 2.4 Hz, 1
H), 7.73 (dd, J = 8.4, 2.3 Hz, 1 H), 7.55–7.45 (m, 6 H), 7.35 (q, J = 8.0 Hz,
4 H), 7.27 (d, J = 8.0 Hz, 2 H).
Purification by flash chromatography (PE); white solid; yield: 124 mg
(72%); mp 144–146 °C.
1H NMR (400 MHz, CDCl3): δ = 8.17 (t, J = 1.2 Hz, 1 H), 8.15 (dd, J = 1.2,
0.8 Hz, 1 H), 7.79 (t, J = 2.0 Hz, 1 H), 7.77 (t, J = 2.0 Hz, 1 H), 7.62–7.58
(m, 4 H), 7.46–7.38 (m, 7 H), 7.34–7.30 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 140.66, 140.23, 138.51, 138.38,
135.50, 129.17, 128.32, 126.33, 126.19, 123.76, 123.50, 121.89,
120.69, 120.56, 120.54, 120.37, 110.00, 109.48.
13C NMR (100 MHz, CDCl3): δ = 140.51, 137.50, 133.06, 131.63,
128.45, 128.38, 126.80, 126.00, 123.49, 122.98, 122.23, 120.31,
120.15, 109.69, 90.26, 88.60.
HRMS (MALDI): m/z [M]+ calcd for C30H19BrN2: 486.0726; found:
486.0726.
9-(2-Bromo-5-iodophenyl)-9H-carbazole (2b)
9-(4-Bromophenyl)-9H-carbazole (4a)17
Purification by flash chromatography (PE); white solid; yield: 152 mg
(68%); mp 138 °C.
1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 7.6 Hz, 2 H), 7.85 (d, J = 2.0
Hz, 1 H), 7.75 (dd, J = 8.4, 2.4 Hz, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.48–
7.44 (m, 2 H), 7.37–7.33 (m, 2 H), 7.12 (d, J = 8.0 Hz, 2 H).
Purification by flash chromatography (PE); pale yellow solid; yield:
153 mg (95%); mp 143–146 °C.
1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 8.0 Hz, 2 H), 7.69 (d, J = 8.0
Hz, 2 H), 7.42–7.34 (m, 6 H), 7.29–7.26 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 139.57, 135.76, 132.07, 127.68,
13C NMR (100 MHz, CDCl3): δ = 140.59, 139.90, 139.14, 138.23,
125.04, 122.44, 119.85, 119.35, 119.17, 108.51.
135.54, 126.13, 123.95, 123.42, 120.47, 120.38, 110.00, 92.40.
HRMS (MALDI): m/z [M]+ calcd for C18H11BrIN: 446.9114; found:
446.9119.
9-(3-Bromophenyl)-9H-carbazole (4b)18
Purification by flash chromatography (PE); colourless oil; yield: 118
mg (73%).
9-(3-Bromo-4-iodophenyl)-9H-carbazole (2c)
1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 7.6 Hz, 2 H), 7.70 (s, 1 H),
7.54 (d, J = 8.0 Hz, 1 H), 7.46 (d, J = 7.6 Hz, 1 H), 7.41–7.37 (m, 5 H),
7.28–7.25 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 140.59, 139.17, 131.16, 130.54,
130.17, 126.19, 125.75, 123.60, 123.28, 120.46, 120.41, 109.67.
Purification by flash chromatography (PE); pale yellow solid; yield:
83 mg (37%); mp 168–170 °C.
1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 8.0 Hz, 2 H), 8.02 (d, J = 8.4
Hz, 1 H), 7.83 (d, J = 2.4 Hz, 1 H), 7.41–7.35 (m, 4 H), 7.28 (t, J = 8.0 Hz,
2 H), 7.20 (dd, J = 8.0, 2.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 141.32, 140.24, 138.89, 130.99,
130.89, 127.00, 126.28, 123.67, 120.62, 120.51, 109.52, 99.15.
9-(2-Bromophenyl)-9H-carbazole (4c)19
Purification by flash chromatography (PE); white solid; yield: 140 mg
(87%); mp 95–96 °C.
1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 8.0 Hz, 2 H), 7.84 (dd,
J = 8.0, 1.2 Hz, 1 H), 7.52–7.43 (m, 2 H), 7.39 (t, J = 8.0 Hz, 3 H), 7.28 (t,
J = 8.0 Hz, 2 H), 7.06 (d, J = 8.0 Hz, 2 H).
HRMS (MALDI): m/z [M]+ calcd for C18H11BrIN: 446.9114; found:
446.9113.
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13C NMR (100 MHz, CDCl3): δ = 140.79, 136.69, 134.18, 131.09,
130.10, 128.77, 125.89, 123.79, 123.20, 120.31, 119.94, 109.98.
13C NMR (100 MHz, CDCl3): δ = 143.67, 142.07, 141.63, 135.39,
133.57, 128.75, 127.82, 123.27, 123.08, 122.40, 121.94, 121.85,
121.03, 117.32, 110.46, 109.35.
3-Bromo-9-(4-bromophenyl)-9H-carbazole (4d)19
HRMS (MALDI): m/z [M]+ calcd for C18H11BrN2O2: 365.9998; found:
365.9993.
Purification by flash chromatography (PE); white solid; yield: 146 mg
(73%); mp 138–139 °C.
9-(4-Bromophenyl)-3,6-di-tert-butyl-9H-carbazole (4k)21
1H NMR (400 MHz, CDCl3): δ = 8.24 (s, 1 H), 8.08 (d, J = 8.0 Hz, 1 H),
7.74 (d, J = 8.0 Hz, 2 H), 7.50–7.40 (m, 4 H), 7.36–7.29 (m, 2 H), 7.23
(d, J = 8.0 Hz, 1 H).
Purification by flash chromatography (PE); white solid; yield: 208 mg
(96%); mp 158–159 °C.
13C NMR (100 MHz, CDCl3): δ = 140.95, 139.30, 136.32, 133.25,
128.76, 128.64, 126.83, 125.23, 123.15, 122.40, 121.31, 120.62,
120.57, 112.98, 111.03, 109.78.
1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 2.0 Hz, 2 H), 7.71 (dt, J = 8.8,
2.8 Hz, 2 H), 7.48–7.42 (m, 4 H), 7.32 (dt, J = 8.4, 0.4 Hz, 2 H), 1.47 (s,
18 H).
13C NMR (100 MHz, CDCl3): δ = 143.15, 138.93, 137.27, 132.95,
128.28, 123.71, 123.46, 120.24, 116.30, 108.96, 34.73, 31.98.
3-Bromo-9-(3-bromophenyl)-9H-carbazole (4e)19
Purification by flash chromatography (PE–EtOAc, 40:1); white solid;
yield: 188 mg (94%); mp 80–82 °C.
9-(4-Chlorophenyl)-9H-carbazole (4l)22
1H NMR (400 MHz, CDCl3): δ = 8.24 (s, 1 H), 8.07 (d, J = 8.0 Hz, 1 H),
7.70 (s, 1 H), 7.63–7.59 (m, 1 H), 7.50–7.25 (m, 7 H).
Purification by flash chromatography (PE); white solid; yield: 129 mg
(92%); mp 144–147 °C.
13C NMR (100 MHz, CDCl3): δ = 140.87, 139.22, 138.61, 131.22,
130.86, 130.07, 128.78, 126.85, 125.64, 125.25, 123.32, 123.13,
122.41, 120.71, 120.55, 113.08, 111.09, 109.82.
1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 8.0 Hz, 2 H), 7.56 (d, J = 8.0
Hz, 2 H), 7.49 (d, J = 8.0 Hz, 2 H), 7.43–7.35 (m, 4 H), 7.31–7.23 (m, 2
H).
13C NMR (100 MHz, CDCl3): δ = 140.68, 136.25, 133.01, 130.10,
128.39, 126.05, 123.44, 120.37, 120.17, 109.53.
3-Bromo-9-(2-bromophenyl)-9H-carbazole (4f)19
Purification by flash chromatography (PE); colourless oil; yield: 168
mg (84%).
9-(3-Chlorophenyl)-9H-carbazole (4m)6d
1H NMR (400 MHz, CDCl3): δ = 8.31 (dd, J = 2.0, 0.4 Hz, 1 H), 8.15–8.12
(m, 1 H), 7.89 (dd, J = 8.0, 1.6 Hz, 1 H), 7.57–7.51 (m, 2 H), 7.49–7.42
(m, 3 H), 7.37–7.33 (m, 1 H), 7.11 (dt, J = 8.4, 0.8 Hz, 1 H), 6.98 (dd,
J = 8.4, 0.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 141.19, 139.47, 136.22, 134.32,
130.99, 130.46, 128.94, 128.67, 126.76, 125.02, 123.69, 123.16,
122.20, 120.56, 120.46, 112.92, 111.57, 110.26.
Purification by flash chromatography (PE); pale yellow oil; yield: 133
mg (96%).
1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 7.6 Hz, 2 H), 7.54 (t, J = 1.6
Hz, 1 H), 7.47–7.36 (m, 7 H), 7.29–7.22 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 140.43, 138.88, 135.29, 130.75,
127.46, 127.12, 126.04, 125.10, 123.45, 120.31, 120.25, 109.54.
9-(2-Chlorophenyl)-9H-carbazole (4n)23
3,6-Dibromo-9-(4-bromophenyl)-9H-carbazole (4g)20
Purification by flash chromatography (PE); pale yellow solid; yield:
117 mg (84%); mp 98–99 °C.
1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 7.6 Hz, 2 H), 7.66–7.64 (m, 1
H), 7.49–7.42 (m, 3 H), 7.38 (t, J = 8.0 Hz, 2 H), 7.27 (t, J = 8.0 Hz, 2 H),
7.08 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 139.80, 133.98, 132.67, 129.96,
129.79, 128.71, 127.01, 124.87, 122.24, 119.26, 118.94, 108.90.
Purification by flash chromatography (PE); white solid; yield: 158 mg
(66%); mp 217–218 °C.
1H NMR (400 MHz, CDCl3): δ = 8.19 (s, 2 H), 7.74 (d, J = 8.0 Hz, 2 H),
7.51 (d, J = 8.0 Hz, 2 H), 7.38 (d, J = 8.0 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2
H).
13C NMR (100 MHz, CDCl3): δ = 139.62, 135.85, 133.39, 129.56,
128.56, 124.06, 123.33, 121.72, 113.37, 111.28.
3-Bromo-9-(4-chlorophenyl)-9H-carbazole (4o)
2,7-Dibromo-9-(4-bromophenyl)-9H-carbazole (4h)20
Purification by flash chromatography (PE); white solid; yield: 121 mg
(68%); mp 131–133 °C.
1H NMR (400 MHz, CDCl3): δ = 8.22 (s, 1 H), 8.05 (d, J = 8.0 Hz, 1 H),
7.55 (d, J = 8.0 Hz, 2 H), 7.47–7.40 (m, 4 H), 7.33–7.27 (m, 2 H), 7.19
(d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 139.95, 138.29, 134.71, 132.34,
129.18, 127.68, 127.24, 125.75, 124.13, 122.07, 121.30, 119.53,
119.51, 111.90, 109.95, 108.71.
Purification by flash chromatography (PE); white solid; yield: 186 mg
(78%); mp 190–192 °C.
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.0 Hz, 2 H), 7.77 (d, J = 8.0
Hz, 2 H), 7.46–7.38 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 141.63, 135.48, 133.55, 128.72,
123.92, 122.07, 121.80, 121.55, 120.13, 112.87.
9-(4-Bromophenyl)-3-nitro-9H-carbazole (4i)
HRMS (MALDI): m/z [M]+ calcd for C18H11BrClN: 354.9758; found:
354.9751.
Purification by flash chromatography (PE–EtOAc, 10:1); yellow solid;
yield: 141 mg (77%); mp 192 °C.
1H NMR (400 MHz, CDCl3): δ = 9.07 (d, J = 2.0 Hz, 1 H), 8.34 (dd,
J = 8.8, 2.0 Hz, 1 H), 8.22 (d, J = 8.0 Hz, 1 H), 7.82 (d, J = 8.8 Hz, 2 H),
7.57–7.52 (m, 1 H), 7.47–7.36 (m, 5 H).
2,7-Dibromo-9-(4-chlorophenyl)-9H-carbazole (4p)
Purification by flash chromatography (PE); white solid; yield: 165 mg
(76%); mp 166–168 °C.
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1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.0 Hz, 2 H), 7.62 (d, J = 8.0
3,6-Dibromo-9-(4-iodophenyl)-9H-carbazole (4v)25
Hz, 2 H), 7.46–7.40 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 141.71, 134.94, 134.18, 130.56,
Purification by flash chromatography (PE); pale yellow solid; yield:
212 mg (81%); mp 188–190 °C.
1H NMR (400 MHz, CDCl3): δ = 8.19 (s, 2 H), 7.94 (d, J = 8.0 Hz, 2 H),
7.51 (d, J = 8.0 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 4 H).
128.43, 123.89, 121.77, 121.55, 120.11, 112.87.
HRMS (MALDI): m/z [M]+ calcd for C18H10Br2ClN: 432.8863; found:
13C NMR (100 MHz, CDCl3): δ = 139.53, 139.36, 136.56, 129.55,
432.8859.
128.74, 124.09, 123.32, 113.38, 111.29, 92.93.
3,6-Dibromo-9-(4-chlorophenyl)-9H-carbazole (4q)24
Purification by flash chromatography (PE); white solid; yield: 189 mg
(87%); mp 214–216 °C.
1H NMR (400 MHz, CDCl3): δ = 8.19 (s, 2 H), 7.59 (d, J = 8.0 Hz, 2 H),
2,7-Dibromo-9-(4-iodophenyl)-9H-carbazole (4w)27
Purification by flash chromatography (PE); white solid; yield: 216 mg
(82%); mp 207–208 °C.
1H NMR (400 MHz, CDCl3): δ = 7.98–7.92 (m, 4 H), 7.46 (s, 2 H), 7.41
(d, J = 8.0 Hz, 2 H), 7.26 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 141.54, 139.52, 136.19, 128.89,
7.51 (d, J = 8.0 Hz, 2 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2
H).
13C NMR (100 MHz, CDCl3): δ = 139.71, 135.32, 133.85, 130.40,
129.54, 128.26, 124.03, 123.32, 113.34, 111.28.
123.93, 121.83, 121.55, 120.13, 112.88, 93.32.
9-(4-Iodophenyl)-9H-carbazole (4r)25
9-(4-Bromo-2-chlorophenyl)-9H-carbazole (4x)
Purification by flash chromatography (PE); white solid; yield: 179 mg
(97%); mp 133–135 °C.
1H NMR (400 MHz, CDCl3): δ = 8.13 (dt, J = 8.0, 1.2 Hz, 2 H), 7.95–7.91
(m, 2 H), 7.44–7.37 (m, 4 H), 7.35–7.28 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 140.50, 139.07, 137.50, 128.92,
Purification by flash chromatography (PE); pale yellow solid; yield:
170 mg (95%); mp 145–146 °C.
1H NMR (400 MHz, CDCl3): δ = 8.17 (t, J = 0.8 Hz, 1 H), 8.15 (t, J = 0.8
Hz, 1 H), 7.87 (d, J = 2.4 Hz, 1 H), 7.63 (dd, J = 8.4, 2.4 Hz, 1 H), 7.45–
7.38 (m, 3 H), 7.34–7.30 (m, 2 H), 7.09 (dt, J = 8.4, 0.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 140.59, 134.83, 134.31, 133.75,
126.06, 123.50, 120.37, 120.21, 109.55, 92.02.
131.91, 131.43, 126.04, 123.41, 122.62, 120.39, 120.25, 109.80.
HRMS (MALDI): m/z [M]+ calcd for C18H11BrClN: 354.9758; found:
9-(3-Iodophenyl)-9H-carbazole (4s)26
Purification by flash chromatography (PE); white solid; yield: 166 mg
(90%); mp 111–112 °C.
354.9752.
1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 7.6 Hz, 2 H), 7.93 (s, 1 H),
7.79 (d, J = 8.0 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 7.40 (q, J = 8.0 Hz, 4
H), 7.30 (q, J = 8.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 140.57, 138.98, 136.46, 136.00,
131.25, 126.44, 126.11, 123.51, 120.38, 120.31, 109.61, 94.58.
9-(3-Bromo-5-chlorophenyl)-9H-carbazole (4y)
Purification by flash chromatography (PE); white solid; yield: 177 mg
(98%); mp 147–148 °C.
1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 7.6 Hz, 2 H), 7.62 (s, 1 H),
7.59 (s, 1 H), 7.52 (s, 1 H), 7.43–7.40 (m, 4 H), 7.30 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 140.13, 139.86, 136.17, 130.20,
128.25, 126.26, 125.88, 123.66, 123.47, 120.69, 120.44, 109.46.
9-(2-Iodophenyl)-9H-carbazole (4t)
Purification by flash chromatography (PE); pale yellow solid; yield:
159 mg (86%); mp 130–131 °C.
1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 8.0 Hz, 2 H), 8.09 (d, J = 8.0
Hz, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.41–7.37 (m, 3 H), 7.30–7.21 (m, 3
H), 7.02 (d, J = 8.0 Hz, 2 H).
HRMS (MALDI): m/z [M]+ calcd for C18H11BrClN: 354.9758; found:
354.9755.
Acknowledgment
13C NMR (100 MHz, CDCl3): δ = 140.65, 140.44, 140.33, 130.59,
The authors are thankful for financial support from the National Nat-
ural Science Foundation of China (grant number 21466033).
130.30, 129.71, 125.89, 123.19, 120.33, 119.92, 110.09, 99.19.
HRMS (MALDI): m/z [M]+ calcd for C18H12IN: 369.0014; found:
369.0015.
Supporting Information
3-Bromo-9-(4-iodophenyl)-9H-carbazole (4u)
Supporting information for this article is available online at
Purification by flash chromatography (PE); pale yellow solid; yield:
166 mg (74%); mp 171–172 °C.
http://dx.doi.org/10.1055/s-0035-1560386.
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1H NMR (400 MHz, CDCl3): δ = 8.23 (s, 1 H), 8.07 (d, J = 8.0 Hz, 1 H),
7.92 (d, J = 8.0 Hz, 2 H), 7.49–7.41 (m, 2 H), 7.36–7.22 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 140.84, 139.20, 137.01, 128.81,
128.74, 126.81, 125.24, 123.13, 122.41, 120.62, 120.56, 112.99,
111.03, 109.78, 92.47.
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