Chan-Lam cross-coupling reaction based on the Cu2S/TMEDA system

Article abstract of DOI:10.1016/j.tet.2017.12.042

A catalyst based on the readily available Cu₂S/TMEDA system using a stable copper(I) source was developed for the Chan-Lam cross-coupling reaction. The capability of the catalyst was demonstrated with 1H-benzo[d]imidazol-2(3H)-one, 1H-benzo[d]imidazole, and 1H-imidazole together with electron-deficient, electron-rich, and sterically demanding boronic acids at room temperature in the presence of atmospheric oxygen to give the cross-coupling products in moderate to excellent yields. In addition, the coupling reaction of 1H-benzo[d]imidazole with several pinacol or neopentylglycol boronates indicated further potential of the catalyst. The reaction conditions tolerate the hydroxyl and bromo functional groups. The catalytic system also enables to synthesize the mono-N-substituted anilines from primary aliphatic amines. However, the two model compounds for the secondary and aromatic amines, piperidine and aniline, do not react. Two sterically demanding products with the restricted C–N bond rotation, synthesized by the N-arylation of 1H-benzo[d]imidazol-2(3H)-one with o-tolylboronic acid, enabled to confirm the atropisomers prepared by the Chan-Lam cross-coupling reaction. Furthermore, an example of one-pot Chan-Lam and Suzuki-Miyaura reaction has been reported.

Full text of DOI:10.1016/j.tet.2017.12.042

Accepted Manuscript
Chan-Lam cross-coupling reaction based on the Cu S/TMEDA system
2
Kateřina Janíková, Lukáš Jedinák, Tereza Volná, Petr Cankař
PII:
S0040-4020(17)31316-9
10.1016/j.tet.2017.12.042
TET 29198
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 November 2017
Revised Date: 18 December 2017
Accepted Date: 20 December 2017
Please cite this article as: Janíková Kateř, Jedinák Lukáš, Volná T, Cankař P, Chan-Lam cross-coupling
reaction based on the Cu S/TMEDA system, Tetrahedron (2018), doi: 10.1016/j.tet.2017.12.042.
2
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ACCEPTED MANUSCRIPT
Chan-Lam Cross-Coupling Reaction Based on the Cu2S/TMEDA
System
Kateřina Janíková,a Lukáš Jedinák,a Tereza Volná,b and Petr Cankařa*
a Department of Organic Chemistry, Palacký University, 17. listopadu 1192/12, 77146,
Olomouc, Czech Republic.
b Institute of Molecular and Translation Medicine, Faculty of Medicine, Palacký University,
Hněvotínská 5, 77900 Olomouc, Czech Republic.
E-mail: petr.cankar@upol.cz
Abstract
A catalyst based on the readily available Cu2S/TMEDA system using a stable copper(I) source was
developed for the Chan-Lam cross-coupling reaction. The capability of the catalyst was demonstrated
with 1H-benzo[d]imidazol-2(3H)-one, 1H-benzo[d]imidazole, and 1H-imidazole together with
electron-deficient, electron-rich, and sterically demanding boronic acids at room temperature in the
presence of atmospheric oxygen to give the cross-coupling products in moderate to excellent yields.
In addition, the coupling reaction of 1H-benzo[d]imidazole with several pinacol or neopentylglycol
boronates indicated further potential of the catalyst. The reaction conditions tolerate the hydroxyl
and bromo functional groups. The catalytic system also enables to synthesize the mono-N-
substituted anilines from primary aliphatic amines. However, the two model compounds for the
secondary and aromatic amines, piperidine and aniline, do not react. Two sterically demanding
products with the restricted C-N bond rotation, synthesized by the N-arylation of 1H-
benzo[d]imidazol-2(3H)-one with o-tolylboronic acid, enabled to confirm the atropisomers prepared
by the Chan-Lam cross-coupling reaction. Furthermore, an example of one-pot Chan-Lam and Suzuki-
Miyaura reaction has been reported.
Introduction
1

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The N-arylazole structural motif is common in numerous biologically active compounds.1 Therefore,
procedures allowing simple and efficient construction of such patterns would represent a significant
contribution to the field of medicinal chemistry.2 Apart from less universal and time consuming de
novo synthetic methods,3 there are several reactions enabling direct arylation of heterocycles.
Presumably, the oldest method is classical nucleophilic aromatic substitution utilizing aryl halides,4
which, however, suffers from the poor substrate scope, as only electron deficient aryl halides offer
reasonable reactivity.5 The activation of C-halogen bonds via oxidative addition by transitional metals
significantly improved the reactivity, and also extended the substrate scope. Nevertheless, the
requirement of high reaction temperature and/or strong base limits such C-N couplings, typically
referred as Ullman-Goldberg6 or Buchwald-Hartwig reactions.7
Copper mediated coupling of arylboronic acids with various types of nucleophiles, known as the
Chan-Lam reaction, represents an experimentally simple procedure that forms C(sp2)-heteroatom
bond under mild reaction conditions, thus allowing incorporation of otherwise sensitive substrates.8
Moreover, the reaction tolerates various functionalities including halogens; therefore it offers
compatibility with subsequent transformations of C-halogen bonds, such as Suzuki-Miyaura
reaction.9
Synthetically relevant N-arylations (or alkenylations) of heterocycles via Chan-Lam reaction have
been reported with various copper salts or complexes, ligands or bases, and solvents.10 Despite
significant progress being made with copper catalysts since seminal reports by Chan, Lam, and Evans
(1999), there still remains space for the development. The goal would be stable, inexpensive, and
easily available copper catalyst, which enables arylation of N-heterocycles at room temperature,
especially with electron-poor or sterically demanding boronic acids. Ideally, the reaction should be
performed under ambient atmosphere without a need for additional oxidant or oxygen
atmosphere.11
Herein, we present a novel Cu2S/TMEDA system as a readily available catalyst for the Chan-Lam
reaction using just 5 mol% of Cu2S (10 mol% of [Cu]) at room temperature and under ambient
atmosphere. The Cu2S/TMEDA system originally came out from the optimization of N-arylation
involving benzimidazolone 1 as a model substrate. The fact that benzimidazolone 1 possess two
reactive sites brought a question, if this compound can be substituted selectively to form monoaryl
derivatives, or diarylated compounds will be unavoidable (side)products of the reaction.
Furthermore, this method was extended to the N-arylation of 1H-benzo[d]imidazole, 1H-imidazole,
and primary aliphatic amines.
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Results and Discussion
Our experiments started with a mixture of benzimidazolone 1, p-tolylboronic acid 2a (2 equiv.),
copper acetate (0.5 equiv.), and TMEDA (1 equiv.) in CH2Cl2 under ambient atmosphere (Table 1,
entry 1). The reaction produced only 13% of mono-arylated compound 3a together with 6% of di-
arylated compound 4a after 24 hours, while 77% of starting material 1 remained unchanged. From
CH2Cl2, MeOH, MeCN, and DMF tested in the combination with Cu(OAc)2/TMEDA (entries 1-4), DMF
performed best, yet it led to compound 3a in only 27% after 24 hours.
Substitution of Cu(OAc)2 with CuCl significantly improved the rate of the Chan-Lam reaction (entry 5),
thus 45% of mono-arylated product 3a was formed after 3 hours, together with 5% of di-arylated
derivative 4a. Prolonging the reaction time to 24 hours revealed 47 % of 3a, 15 % of 4a, and 36% of
starting material 1. Slightly lower reactivity was observed with CuI and Cu2O (entries 6 and 7), while
25 mol% of Cu2S (entry 8) displayed the most promising catalytic activity from all tested copper
compounds, giving 50% of mono-arylated derivative 3a, 8% of di-arylated derivative 4a, and 39% of
starting material 1 after 3 hours. Increasing TMEDA to two equivalents did not have any significant
effect on the reaction (entry 9). Examination of pyridine and Et3N as plausible ligands for Cu2S
brought inferior yields in comparison to the Cu2S/TMEDA system (entries 10 and 11). The Chan-Lam
coupling reaction using Cu2S without any ligand was very sluggish (entry 12).
Table 1. Optimization of the Chan-Lam reaction
H
N
H
O
N
B(OH)2
N
N
N
+
+
O
O
N
H
2a
1
4a
3a
Entry
1
2
3
4
5
6
7
8
[Cu]
Ligand
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDAb
Pyridine
Et3N
Solvent
CH2Cl2
MeOH
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Time [h]
24
24
24
24
3 (24)
3 (24)
3 (24)
3 (24)
3 (24)
3 (24)
3 (24)
3 (24)
1 (%) a
77
73
78
3a (%) a
13
19
17
4a (%) a
6
3
3
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl
CuI
Cu2O
Cu2S
Cu2S
60
27
5
46 (36)
58 (44)
53 (5)
39 (7)
35 (4)
44 (25)
58 (42)
95 (94)
45 (47)
32 (43)
34 (26)
50 (33)
49 (31)
37 (43)
30 (40)
2 (2)
5 (15)
3 (9)
3 (49)
8 (55)
11 (56)
4 (16)
2 (9)
< 1 (< 1)
9
10
11
12
Cu2S
Cu2S
Cu2S
none
General conditions: Benzimidazolone 1 (0.5 mmol), boronic acid 2a (1.0 mmol), ligand (0.5 mmol), copper salt (0.25 mmol
for Cu(OAc)2, CuCl and CuI; or 0.125 mmol for Cu2O and Cu2S), solvent (2 mL), rt, air. a HPLC yield determined from LCMS
after 3 or 24 hours using N-Fmoc-L-alanine as an internal standard. b 1.0 mmol (2 equiv.) of TMEDA were used.
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HPLC analyses after 3 and 24 hours demonstrated that mono-aryl derivative 3a was a major product
after 3 hours and its concentration decreased after 24 hours as a consequence of formation of di-
arylated derivative 4a (Table 1, entry 8). This observation prompted us to explore the reaction
progress with the Cu2S/TMEDA using various amounts (25%, 10%, 5% and 2.5%) of Cu2S, one
equivalent of TMEDA, and two equivalents of boronic acid 2a in DMF (Figures 1A-D). Use of Cu2S at
25% molar ratio (50% of [Cu]) showed that the amount of product 3a was increasing up to 3 hours,
when it reached its maximum at 49% (Figure 1A). Then it began to decrease, while the percentage of
4a was constantly increasing. After approximately 5 hours, the amount of both arylated products 3a
100
100
80
60
40
20
0
A (25 mol % of Cu2S)
B (10 mol % of Cu2S)
80
60
40
20
0
0
1
2
3
4
5
6
7
8
24
0
1
2
3
4
5
6
7
9
24
100
80
60
40
20
0
100
80
60
40
20
0
C (5 mol % of Cu2S)
D (2.5 mol % of Cu2S)
0
1
2
3
4
5
6
7
8
24
0
1
2
3
4
5
6
7
8
24
Figure 1. Reaction progress was monitored with HPLC using N-Fmoc-L-alanine as an
internal standard after 1 – 8 and 24 hours. Starting material 1 is depicted as a blue line,
mono-arylated compound 3a as a red line, and di-arylated compound 4a as a green line.
and 4a was equal. Around 6 hours 4a became the major compound in the reaction mixture and after
24 hours it reached 60%, while 3a was formed in 29% and 4% of staring material 1 remained.
Almost identical results were obtained with 10% of Cu2S (Figure 1B). The same trend, but lower
reaction rate was observed with molar ratio at 5% and 2.5% of Cu2S (Figure 1C and 1D). It seems that
the reaction has an induction period at the 2.5% catalyst loading (Figure 1D), which was not observed
at the higher loadings. Then, it was obvious from all diagrams that both benzimidazolones 1a and 3a
underwent N-arylation at similar rate. While the amount of 3a increased in time, it became more
available for subsequent N-arylation to yield 4a. Therefore no more than approximately 50% of 3a
can be obtained from this reaction. However, the limit 50% can be potentially exceeded in case of a
significantly slower rate of second N-arylation caused by stereo-electronic effects (vide infra).
Reducing the ratio of benzimidazolone 1/boronic acid 2a to 1:1 did not avoid the formation of 4a,
only led to a higher content of unreacted starting material 1.
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Despite 10% of Cu2S was optimal for the model Chan-Lam reaction in study, molar ratio at 5% also
offered acceptable reaction rate and product conversion; therefore 5% of Cu2S (10% of [Cu]), 1
equivalent of TMEDA, and two equivalents of boronic acid 2a-n were used in subsequent
experiments. Boronic acids 2a-n with various stereo-electronic substitution patterns were employed
in the Chan-Lam reaction using benzimidazolone 1 as a substrate (Table 2).
Table 2. Scope of the Chan-Lam reaction with benzimidazolone 1
Compound 3
Compound 4
Compound 3
Compound 4
3a (40%)
4a (17%)
3h (34%)
4h (NI)a
3b (40%)
4b (6%)
3i (60%)
4i (ND)c
3c (41%)
3d (NI)a
4c (39%)
4d (NI)a
3j (NI)a
4j (ND)c
3k (44%)
4k (22%)
3e (48%)b
4e (ND)b,c
4f (ND)b,c
4g (20%)
3l (40%)
3m (37%)
3n (42%)
4l (NI)c
4m (14%)
4n (39%)
3f (41%)b
O
HN
N
3g (42%)
a Compounds were formed, but not isolated in acceptable purity. b Reaction time 24 hours. c Not detected.
When the Chan-Lam reaction between benzimidazolone 1 and p-tolylboronic acid 2a was quenched
after 8 hours, mono-arylated product 3a was isolated in 40% yield and di-arylated product 4a in 17%
yield. In general, the separation of 1, 3, and 4 by column chromatography was facile due to distinct
5

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polarity of most compounds. Using unsubstituted phenylboronic acid 2b, phenyl derivative 3b was
obtained together with di-substituted derivative 4b in 40% and 6% yield, respectively. Electron-
donating p-methoxy group possessed positive effect on the reactivity, which resulted in the isolation
of compounds 3c and 4c in 41% and 39% yield, respectively. Hydroxyphenylboronic acid 2d also
displayed favorable reactivity in the N-arylation of 1, while the competitive O-arylation of phenolic
hydroxyl was negligible. The respective products 3d and 4d were formed in approximately 1:1 ratio
after 8 hours as major compounds together with small amount of residual starting material 1.
However, we failed to separate 3d from 4d, which were obtained as a 1:1 mixture after column
chromatography.
The reactivity of phenylboronic acids 2e (p-NO2) and 2f (p-CF3) was lower in the Chan-Lam arylation,
therefore the reaction time was prolonged to 24 hours in order to obtain mono-arylated compounds
3e and 3f in 48% and 41% yield, respectively. Di-arylated compounds 4e and 4f were not formed
during the reaction of benzimidazolone 1 with boronic acids bearing electron-withdrawing
substituents.
Next, sterically hindered boronic acids 2g-j were employed in the Chan-Lam reaction. One methyl
substituent in the ortho position of boronic acid 2g was compatible with the reaction, leading to
benzimidazoles 3g and 4g in 42% and 20% yield, respectively. 2-Methoxyphenylboronic acid 2h
partially decomposed under the reaction conditions, therefore mono-aryl product 3h was obtained in
only 34% yield. Di-arylated derivative 4h was detected in the crude mixture in approximately 5% and
all attempts to isolate 4h in acceptable purity failed. To our delight, mono-arylated derivative 3i,
bearing two ortho methyl substituents, was isolated in 60% yield. Two ortho methyl substituents
precluded the formation of di-arylated compound 4i, which was not detected in the crude reaction
mixture. 2,6-Dimethoxyphenylboronic acid 2j possessed, similarly to 2-methoxyphenylboronic acid
2h, lower stability under the reaction conditions, therefore mono-aryl product 3j was detected in less
than 5% in the crude mixture and its isolation failed. Di-aryl product 4j was not detected.
Compounds 3k and 4k, bearing large naphthyl substituent, were obtained in the reaction with
boronic acid 2k in 44% and 22% yield, respectively. Alkenyl substituent was introduced into the
benzimidazole core via styrylboronic acid 2l, yielding compound 3l in 40% yield. Small amount of di-
substituted derivative 4l was detected in the crude mixture; however, its isolation failed.
Thienylboronic acid 2m showed moderate reactivity, providing mono-aryl product 3m and di-aryl
product 4m in 37 and 14% yield, respectively. As expected, bromo-substituent in the structures 3n
and 4n was preserved during the Chan-Lam reaction.
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1
Both H and 13C NMR spectra of di-arylated benzimidazolone 4g showed two sets of peaks at the
ratio of 3:2. The ratio was independent on the solvent (CDCl3 or DMSO-d6) and temperature (20 – 120
°C in DMSO-d6), suggesting the occurrence of stable isomers. Further analysis using chiral HPLC
revealed three peaks at the ratio of 1:3:1. Chiral detector revealed that two minor peaks belong to
the optically active compounds, while the major compound was inactive. These data clearly indicated
the presence of atropisomers 4gx, 4gy, and optically inactive mesoform 4gz (Figure 2). To the best of
our knowledge, this is the first example of atropisomers being formed by the Chan-Lam reaction,
although not in the stereoselective fashion.12 Moreover, chiral HPLC allowed observation of
atropisomers in mono-aryl derivative 3g (ortho-Me), while no isomers were separated in compound
3h bearing ortho methoxy group.
Figure 2. Atropisomers
The scope of the Chan-Lam reaction using 5 mol% of Cu2S and one equivalent of TMEDA as a ligand
was further explored on the N-arylation of benzimidazole 5. The reaction of p-tolylboronic acid 2a
with benzimidazole 5 took 24 hours to consume all starting material. Inspired by the work of
Sreedhar,10c we switched to MeOH as a solvent, which resulted in the complete conversion of
benzimidazole 5 in 8 hours and respective product 6a was isolated in 90% yield. Therefore, we
employed MeOH instead of DMF for the N-arylation of benzimidazole 5 (Table 3) using boronic acids
2a-n.
Unsubstituted 2b, electron-rich 2c and 2d, and bulky boronic acid 2k completely arylated
benzimidazole 5 within 8 hours, providing desired products 6b, 6c, and 6k in high yields (88 – 91%),
except for 6d, which was obtained in 73% yield, as a result of losses during purification. The reaction
with electron-poor boronic acids 2e and 2f proceeded slowly (48 hours), but still provided high yield
of desired products 6e (84%) and 6f (89%). Methyl or methoxy substituent in ortho position did not
decrease the yield, albeit the reaction required longer time (24 hours) for compounds 6g and 6h.
Methyl groups in both ortho positions retarded the formation of product 6i, which was found in a
trace amount in the crude reaction mixture after 72 hours together with unreacted benzimidazole 5
and boronic acid 2i. Compound 2j bearing two ortho methoxy groups proved to be a suitable
coupling partner, giving product 6j in 70% yield after 72 hours. N-Styryl and N-thienyl derivatives 6l
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and 6m were obtained in good yields (both 73%). Boronic acid 2n containing bromo-substituent gave
desired product 6n in 85% yield, preserving bromo-substituent for further possible transformations.
N-arylated benzimidazoles 6a, 6f, and 6m were also obtained in the high yields with the respective
pinacol esters, although it was necessary to increase the reaction time to 72 hours. Neopentylglycol
ester of 3-pyridylboronic acid gave benzimidazole 6o in 90% under the same conditions.
Furthermore, the reaction of benzimidazole 5 and boronic acid 2a was performed at a gram scale (20
mmol of benzimidazole 5) yielding 93% of product 6a in 8 hours.
Table 3. Scope of the Chan-Lam reaction with benzimidazole 5
6a (90%)a/ (93%)a,b/(89%)c, d
6b (88%)a
6c (91%)a
6d (73%)a
N
N
CF3
6e (84%)e
6f (89%)e/(88%)c,d
6g (88%)f
6h (92%)f
N
N
O
6i (NI)d,g
6j (72%)d
6k (90%)a
6l (73%)f
6m (73%)f/(77%)c,d
6n (85%)f
6o (90)d,h
a Reaction time 8 hours. b 20 mmol scale of benzimidazole 5. c Pinacol ester of the respective boronic acid was
used. d Reaction time 72 hours. e Reaction time 48 hours. f Reaction time 24 hours. g Not isolated. h
Neopentylglycol ester of 3-pyridineboronic acid was used.
As in the case of benzimidazole 5, the N-arylation of imidazole 7 with p-tolylboronic acid 2a was
sluggish in DMF, leaving unreacted starting material 7 after 24 hours. As previously shown, switching
solvent to MeOH allowed full conversion in a shorter time. In general, the N-arylation of imidazole 7
was slower compared to benzimidazole 5. For instance, full consumption of the imidazole 7 was
achieved after 24 hours (versus 8 hours for benzimidazole 5) on the reaction with p-tolylboronic acid
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2a in MeOH, providing product 8a in 89% yield. Results summarizing C-N coupling of imidazole 7 and
boronic acids 2a-n are depicted in Table 4.
The N-arylation proceeded smoothly and in high isolated yields with phenylboronic acid 2b, electron-
rich 2c, naphtyl 2k, and sterically hindered boronic acids 2g and 2h. Unprotected phenolic OH was
compatible with the reaction. Compound 8d was isolated in 60% yield, while the side product
resulting from the competitive O-arylation was formed in a negligible amount (approximately 5%
according to LCMS). More sterically demanding boronic acid 2i gave only a trace amount of the
product 8i, which precluded its isolation, while 2,6-dimethoxyphenyl boronic acid 2j gave the desired
product in 79% yield after 48 hours. Styryl derivative 8l was obtained in 74% yield on the prolonged
reaction time, 48 hours, as well as thiophene substituted derivative 8m (60% yield), which required
one additional equivalent of boronic acid 2m. Imidazoles bearing electron-withdrawing substituents
(8e and 8f) were obtained in the high yields, although they required 48 hours and one additional
equivalent of boronic acid. Furthermore, brominated derivative 8n was obtained in high yield of 90%.
Table 4. Scope of the Chan-Lam reaction with imidazole 7
8a (87%)
8b (85%)
8c (90%)
8d (60%)
8e (76%)a,b
8f (79%)a,b
8g (85%)
8h (86%)
8i (NI)
8j (79%)a
8k (88%)
8l (74%)a
8m (60%)a,b
8n (90%)a
a Reaction time 48 hours. b Additional one equivalent of boronic acid was added after 24h.
The Cu2S/TMEDA proved to be efficient catalyst system for the N-arylation of primary aliphatic
amines 9a-d (Table 5), although it was necessary to adjust amine/boronic acid ratio to 1.5:1. The
respective mono-substituted anilines 10a-d were obtained in 78 – 85% yields. The formation of di-
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substituted anilines from primary amines was not observed. Unfortunately, secondary amine 9e and
aromatic amine 9f were formed in trace amount under the standard reaction conditions.
Table 5. N-arylation of amines
Amine
Product Yield
9a
9b
10a (81%)
10b (85%)
10c (79%)
9c
9d
10d (78%)
10e (NI)a
10f (NI)a
9e
9f
General conditions: amine (1.5 mmol), boronic acid 2a
(1.0 mmol), Cu2S (0.05 mmol), TMEDA (1.0 mmol), MeOH
(4 mL), rt, air, 24h. a Not isolated.
Finally, we explored whether two seemingly incompatible reactions, the Chan-Lam and Suzuki-
Miyaura coupling, can be performed in a one-pot fashion (Scheme 1). Benzimidazole 5 reacted with a
slight excess of (4-bromophenyl)boronic acid 2n under our Chan-Lam conditions providing
intermediate 6n in 24 hours. Then, the mixture was flushed with nitrogen, diluted with water, and
treated with boronic acid 2a, K2CO3 (3 equivalents), and XPhos Pd G2 (1 mol%) at 70 °C (external
temperature). After 24 hours, the HPLC/MS showed approximately 1:1 ratio of the desired product
11 and intermediate 6n. We envisioned that the higher reaction temperature in the second step can
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improve the rate of C-C coupling; therefore we switched a solvent from MeOH to EtOH. Performing
the Chan-Lam arylation in EtOH with 5 and 2n gave almost exclusively brominated intermediate 6n,
which upon heating with boronic acid 2a and XPhos Pd G2 in EtOH/H2O gave almost exclusively
desired product 11.13 Practically the same results were obtained when the Suzuki-Miyaura reaction
was performed in an oil bath (80 °C, 24 hours), or in a microwave reactor (120 °C, 30 minutes).
Column chromatography over silica gel gave compound 11 in 93% yield, which was contaminated
with 2% of 6n and two unknown impurities (both approximately 1%). Subsequent crystallization from
MeOH provided analytically pure 11 in 68% yield.
Scheme 1. One-pot Chan-Lam and Suzuki-Miyaura reaction
Conclusion
In Summary, we developed the Cu2S/TMEDA system for the Chan-Lam C-N coupling of several
imidazole-based heterocycles with boronic acids. Two reactive sites of benzimidazolone 1 underwent
the first and second N-arylation at similar rates, leading to mono- and di-arylated benzimidazolones 3
and 4. Benzimidazole and imidazole gave the high yields of the N-aryl products 6 and 8 with a range
of diversely substituted arylboronic acids or esters. It was demonstrated, that the Chan-Lam coupling
with Cu2S/TMEDA can be reliably reproduced at the 20 mmol scale and performed in a one-pot
fashion with the Suzuki-Miyaura coupling, when the brominated boronic acid 2n was used.
Furthermore, the Cu2S/TMEDA catalyst enabled the preparation of mono-N-substituted anilines 10
from boronic acid 2a and primary aliphatic amines in the high yields. Benzimidazolones 3g and 4g
with the restricted C-N bond rotation allowed to confirm the atropisomers synthesized by the Chan-
Lam coupling.
Experimental Section
General procedure for compounds 3 and 4 (Table 2): A 10 mL round bottom flask was charged with
a magnetic stirring bar, benzimidazolone 1 (67 mg, 0.5 mmol), boronic acid 2 (1.0 mmol), Cu2S (4 mg,
0.025 mmol), and DMF (2 mL), then followed by the addition of TMEDA (0.075 mL, 0.5 mmol). The
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flask was sealed with a septum, through which was inserted 18-gauche needle. This setup allowed
access of air and avoided contamination. The reaction mixture was stirred from 400 to 600 rpm for 8
hours and extracted with EtOAc (2x 15 mL). Combined organic layers were washed with a saturated
aqueous solution of ethylenediaminetetraacetic acid disodium salt (15 mL), then with water (2x 15
mL), and dried over anhydrous Na2SO4. Volatiles were removed under reduced pressure and the
residue was purified by column chromatography (silica gel, hexanes – EtOAc) to yield the title
product, which was characterized by 1H NMR, 13C NMR, HRMS, and melting point (if solid).
1-(p-Tolyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (3a):14 Prepared according to general procedure
1
using boronic acid 2a. Title product was obtained as a white solid (45 mg, 40%), mp 221 °C. H NMR
(400 MHz, DMSO-d6): δ = 11.09 (s, 1 H), 7.39 (d, J = 8.6 Hz, 2 H), 7.35 (d, J = 8.6 Hz, 2 H), 7.08 - 7.02
(m, 2 H), 7.01 – 6.96 (m, 1 H), 6.95 - 6.91 (m, 1 H), 2.38 (s, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ
= 153.3, 136.8, 132.0, 130.2, 129.8, 128.4, 125.8, 121.7, 120.8, 109.1, 108.0, 20.7 ppm. HRMS (ESI-
Orbitrap): calcd for C14H12N2O [M + H]+ 225.1022; found 225.1023.
1-Phenyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (3b):15 Prepared according to general procedure
1
using boronic acid 2b. Title product was obtained as a white solid (42 mg, 40%), mp 201-202 °C. H
NMR (400 MHz, DMSO-d6): δ = 11.13 (s, 1 H), 7.58 – 7.51 (m, 4 H), 7.45 – 7.40 (m, 1 H), 7.09 – 7.03
(m, 2 H), 7.02 – 6.97 (m, 2 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 153.2, 134.6, 130.0, 129.4,
128.4, 127.3, 125.9, 121.8, 120.9, 109.2, 108.1 ppm. HRMS (ESI-Orbitrap): calcd for C13H10N2O [M +
H]+ 211.0866; found 211.0870.
1-(4-Methoxyphenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (3c):14 Prepared according to general
procedure using boronic acid 2c. Title product was obtained as a pale yellow solid (49 mg, 41%), mp
238-240 °C. 1H NMR (400 MHz, DMSO-d6): δ = 11.05 (s, 1 H), 7.41 (ddd, J = 8.9, 3.4, 2.2 Hz, 2 H), 7.10
(ddd, J = 8.9, 3.4, 2.2 Hz, 2 H), 7.07 – 7.01 (m, 2 H), 7.00 – 6.96 (m, 1 H), 6.89 – 6.86 (m, 1 H), 3.82 (s, 3
H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 158.3, 153.5, 130.6, 128.3, 127.5, 127.1, 121.5, 120.8,
114.6, 109.0, 107.8, 55.4 ppm. HRMS (ESI-Orbitrap): calcd for C14H12N2O [M + H]+ 241.0972; found
241.0971.
1-(4-Nitrophenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (3e):16 Prepared according to general
procedure (reaction time 24 hours) using boronic acid 2e. Title product was obtained as a yellow
1
solid (61 mg, 48%), mp 306-308 °C. H NMR (400 MHz, DMSO-d6): δ = 11.39 (s, 1 H), 8.40 (d, J = 9.1
Hz, 2 H), 7.91 (d, J = 9.1 Hz, 2 H), 7.22 (d, J = 7.8 Hz, 1 H), 7.16 – 7.09 (m, 2 H), 7.06 (ddd, J = 8.0, 6.4,
2.5 Hz, 1 H) ppm. 13C NMR (100 MHz, DMSO-d6 ): δ = 152.7, 145.2, 140.7, 128.7, 128.7, 125.7, 124.8,
122.7, 121.2, 109.6, 108.8 ppm. HRMS (ESI-Orbitrap): calcd for C13H9N3O3 [M - H]- 254.0571; found
254.0564.
12

ACCEPTED MANUSCRIPT
1-(4-(Trifluoromethyl)phenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (3f):14 Prepared according to
general procedure (reaction time 24 hours) using boronic acid 2f. Title product was obtained as a
white solid (57 mg, 41%), mp 260-261 °C. 1H NMR (400 MHz, DMSO-d6): δ = 11.29 (s, 1 H), 7.93 (d, J =
8.8 Hz, 2 H), 7.83 (d, J = 8.8 Hz, 2 H), 7.17 - 7.13 (m, 1 H), 7.12 - 7.08 (m, 2 H), 7.04 (qd, J = 8.0, 4.3 Hz,
1 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 152.9, 138.4, 129.1, 128.6, 127.1 (q, J = 32 Hz), 126.5 (q,
J = 4 Hz), 126.0, 122.4, 121.1, 124.1 (q, J = 272 Hz), 109.4, 108.5 ppm. HRMS (ESI-Orbitrap): calcd for
C14H9F3N2O [M - H]- 277.0594; found 277.0586.
1-(o-Tolyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (3g): Prepared according to general procedure
1
using boronic acid 2g. Title product was obtained as a white solid (47 mg), mp 170-173 °C. H NMR
(400 MHz, DMSO-d6): δ = 11.07 (s, 1 H), 7.47 – 7.43 (m, 1 H), 7.41 (td, J = 7.4, 1.7 Hz, 1 H), 7.37 (td, J =
7.4, 2.0 Hz, 1 H), 7.32 (dd, J = 7.6, 1.5 Hz, 1 H), 7.08 (dd, J = 7.7, 1.1 Hz, 1 H), 7.04 (td, J = 7.5, 1.1 Hz, 1
H), 6.95 (td, J = 7.5, 1.5 Hz, 1 H), 6.55 (d, J = 7.7 Hz, 1 H), 2.07 (s, 3 H) ppm. 13C NMR (100 MHz, DMSO-
d6): δ = 153.2, 136.3, 133.1, 131.2, 130.8, 128.8, 128.6, 128.5, 127.1, 121.5, 120.8, 109.1, 107.8, 17.3
ppm. HRMS (ESI-Orbitrap): calcd for C14H12N2O [M + H]+ 225.1022; found 225.1023.
1-(2-Methoxyphenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (3h):14 Prepared according to general
procedure using boronic acid 2h. Title product was obtained as a pale yellow solid (41 mg, 34%), mp
1
173-176 °C. H NMR (400 MHz, DMSO-d6): δ = 10.98 (s, 1 H), 7.52 – 7.45 (m, 1 H), 7.37 (dd, J = 7.7,
1.7 Hz, 1 H), 7.25 (dd, J = 8.4, 1.0 Hz, 1 H), 7.10 (td, J = 7.6, 1.2 Hz, 1 H), 7.04 (dd, J = 7.8, 1.6 Hz, 1 H),
7.00 (td, J = 7.6, 1.0 Hz, 1 H), 6.93 (td, J = 7.4, 1.6 Hz, 1 H), 6.54 (d, J = 7.7 Hz, 1 H), 3.73 (s, 3 H) ppm.
13C NMR (100 MHz, DMSO-d6): δ = 155.3, 153.4, 131.0, 130.1, 129.9, 128.5, 122.5, 121.2, 120.8,
120.6, 112.7, 108.8, 108.2, 55.6 ppm. HRMS (ESI-Orbitrap): calcd for C14H12N2O2 [M + H]+ 241.0972;
found 241.0973.
1-(2,6-Dimethylphenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (3i): Prepared according to general
procedure using boronic acid 2i. Title product was obtained as a white solid (71 mg, 60%), 246-249
°C. 1H NMR (400 MHz, DMSO-d6): δ = 11.10 (s, 1 H), 7.33 (dd, J = 8.5, 6.5 Hz, 1 H), 7.29 – 7.23 (m, 2 H),
7.09 (d, J = 7.7 Hz, 1 H), 7.04 (td, J = 7.6, 1.0 Hz, 1 H), 6.95 (td, J = 7.6, 1.2 Hz, 1 H), 6.42 (d, J = 7.7 Hz,
1 H), 1.98 (s, 6 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 152.9, 136.9, 131.9, 129.9, 128.9, 128.7,
128.5, 121.5, 121.0, 109.2, 107.5, 17.4 ppm. HRMS (ESI-Orbitrap): calcd for C15H14N2O [M + H]+
239.1179; found 239.1180.
1-(6-Methoxynaphthalen-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (3k): Prepared according to
general procedure using boronic acid 2k. Title product was obtained as a white solid (64 mg, 44%),
mp 256-258 °C. 1H NMR (400 MHz, DMSO-d6): δ = 11.16 (s, 1 H), 8.01 (d, J = 1.7 Hz, 1 H), 7.98 (d, J =
8.8 Hz, 1 H), 7.92 (d, J = 9.0 Hz, 1 H), 7.60 (dd, J = 8.7, 2.1 Hz, 1 H), 7.43 (d, J = 2.4 Hz, 1 H), 7.24 (dd, J
13

ACCEPTED MANUSCRIPT
= 9.0, 2.5 Hz, 1 H), 7.12 – 7.07 (m, 2 H), 7.04 – 7.00 (m, 2 H), 3.91 (s, 3 H) ppm. 13C NMR (100 MHz,
DMSO-d6): δ = 157.7, 153.5, 133.2, 130.3, 129.9, 129.4, 128.5, 128.5, 127.8, 124.7, 124.2, 121.7,
120.9, 119.3, 109.1, 108.2, 106.0, 55.3 ppm. HRMS (ESI-Orbitrap): calcd for C18H14N2O2 [M + H]+
291.1128; found 291.1125.
(E)-1-Styryl-1,3-dihydro-2H-benzo[d]imidazol-2-one (3l): Prepared according to general procedure
1
using boronic acid 2l. Title product was obtained as a white solid (47 mg, 40%), mp 188-190 °C. H
NMR (400 MHz, DMSO-d6): δ = 11.25 (s, 1 H), 7.70 – 7.65 (m, 1 H), 7.61 – 7.55 (m, 3 H), 7.40 – 7.33
(m, 2 H), 7.28 (d, J = 14.8 Hz, 1 H), 7.26 – 7.22 (m, 1 H), 7.13 – 7.04 (m, 3 H) ppm. 13C NMR (100 MHz,
DMSO-d6): δ = 152.9, 136.2, 128.7, 128.3, 128.1, 126.9, 125.8, 122.3, 121.3, 121.1, 116.2, 109.7,
109.2 ppm. HRMS (ESI-Orbitrap): calcd for C15H12N2O [M + H]+ 237.1022; found 237.1023.
1-(Thiophen-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (3m):17 Prepared according to general
procedure using boronic acid 2m. Title product was obtained as a white solid (40 mg, 37%), mp 181-
184 °C. 1H NMR (400 MHz, DMSO-d6): δ = 11.15 (s, 1 H), 7.74 (dd, J = 3.1, 1.5 Hz, 1 H), 7.71 (d, J = 5.1,
3.2 Hz, 1 H), 7.40 (dd, J = 5.1, 1.5 Hz, 1 H), 7.12 (dt, J = 7.2, 1.2 Hz, 1 H), 7.08 – 7.00 (m, 3 H) ppm. 13
C
NMR (100 MHz, DMSO-d6): δ = 152.9, 132.5, 129.7, 128.3, 126.2, 124.3, 121.9, 121.0, 118.2, 109.1,
108.5 ppm. HRMS (ESI-Orbitrap): calcd for C11H8N2OS [M + H]+ 217.0430; found 217.0431.
1-(4-Bromophenyl)- 1,3-dihydro-2H-benzo[d]imidazol-2-one (3n):18 Prepared according to general
procedure using boronic acid 2n. Title product was obtained as a white solid (66 mg, 42%), mp 241-
1
242 °C. H NMR (400 MHz, DMSO-d6): δ = 11.18 (s, 1 H), 7.76 – 7.72 (m, 2 H), 7.54 – 7.50 (m, 2 H),
7.09 – 7.04 (m, 2 H), 7.04 – 6.99 (m, 2 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 153.0, 133.9, 132.3,
129.6, 128.5, 127.9, 122.0, 121.0, 119.8, 109.3, 108.2 ppm. HRMS (ESI-Orbitrap): calcd for
C13H9BrN2O [M + H]+ 288.9971 and 290.9951; found 288.9974 and 290.9947.
1,3-Di-p-tolyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4a): Prepared according to general
procedure using boronic acid 2a. Title product was obtained as a white solid (27 mg, 17%), mp 157 -
160 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.48 (d, J = 8.3 Hz, 4 H), 7.39 (d, J = 8.3 Hz, 4 H), 7.13 – 7.08
(m, 2 H), 7.06 – 7.02 (m, 2 H), 2.40 (s, 6 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 151.8, 137.3,
131.7, 130.0, 129.3, 126.2, 122.0, 108.5, 20.8 ppm. HRMS (ESI-Orbitrap): calcd for C21H18N2O [M + H]+
315.1492; found 315.1491.
1,3-Diphenyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4b):19 Prepared according to general
procedure using boronic acid 2b. Title product was obtained as a pale yellow solid (9 mg, 6%), mp 99-
101 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.66 – 7.57 (m, 8 H), 7.52 – 7.45 (m, 2 H), 7.16 – 7.06 (m, 4
14

ACCEPTED MANUSCRIPT
H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 151.6, 134.2, 129.6, 129.1, 127.8, 126.3, 122.2, 108.6
ppm. HRMS (ESI-Orbitrap): calcd for C19H14N2O [M + H]+ 287.1179; found 287.1180.
1,3-Bis(4-methoxyphenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (4c):6c Prepared according to
general procedure using boronic acid 2c. Title product was obtained as a white solid (68 mg, 39%),
mp 178-179 °C. 1H NMR (400 MHz, CDCl3): δ = 7.52 (d, J = 8.9 Hz, 4 H), 7.13 – 7.06 (m, 8 H), 3.90 (s, 6
H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 159.1, 153.0, 130.1, 127.8, 127.3, 122.0, 114.9, 108.8,
55.7 ppm. HRMS (ESI-Orbitrap): calcd for C21H18N2O3 [M + H]+ 347.1390; found 347.1390.
1,3-Di-o-tolyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (4g): Prepared according to general
procedure using boronic acid 2g. Title product was obtained as a white solid (32 mg, 20%), mp 187-
189 °C. 1H NMR (400 MHz, CDCl3): δ = 7.46 – 7.33 (m, 8 H), 7.09 – 7.05 (m, 2 H), 6.81 – 6.75 (m, 2 H),
2.27 and 2.26 (s, 6 H, 2:3 ratio) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.2, 152.1, 137.1, 137.0, 133.2,
133.1, 131.7, 131.6, 130.6, 130.50, 129.3, 129.2, 128.8, 128.7, 127.3, 127.2, 122.0, 108.9, 108.8, 18.1,
18.0 ppm. HRMS (ESI-Orbitrap): calcd for C21H18N2O [M + H]+ 315.1492; found 315.1490.
1,3-Bis(6-methoxynaphthalen-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one
(4k):
Prepared
according to general procedure using boronic acid 2k. Title product was obtained as a yellow solid
(49 mg, 22%), mp 247-249 °C. 1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 2.0 Hz, 2 H), 7.92 (d, J = 8.7
Hz, 2 H), 7.81 (dd, J = 6.2, 3.4 Hz, 2 H), 7.70 (dd, J = 8.7, 2.1 Hz, 2 H), 7.25 – 7.17 (m, 6 H), 7.16 – 7.11
(m, 2 H), 3.97 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.4, 153.1, 134.0, 130.1, 129.6, 129.2,
128.4, 125.0, 124.8, 122.3, 119.8, 109.1, 106.0, 105.9, 55.5 ppm. HRMS (ESI-Orbitrap): calcd for
C29H22N2O3 [M + H]+ 447.1703; found 447.1703.
1,3-Di(thiophen-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (4m): Prepared according to general
procedure using boronic acid 2m. Title product was obtained as a white solid (21 mg, 14%), mp 106-
107 °C. 1H NMR (400 MHz, DMSO-d6): δ = 7.86 – 7.83 (m, 2 H), 7.78 – 7.75 (m, 2 H), 7.44 (ddd, J = 5.2,
1.3, 0.8 Hz, 2 H), 7.23 – 7.14 (m, 4 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 151.1, 131.9, 128.7,
126.6, 124.5, 122.4, 119.6, 108.9 ppm. HRMS (ESI-Orbitrap): calcd for C15H10N2OS2 [M + H]+ 299.0307;
found 299.0306.
1,3-Bis(4-bromophenyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (4n):20 Prepared according to
general procedure using boronic acid 2n. Title product was obtained as a white solid (85 mg, 39%),
mp 219-220 °C. 1H NMR (400 MHz, CDCl3): δ = 7.70 – 7.67 (m, 4 H), 7.51 – 7.48 (m, 4 H), 7.16 – 7.10
(m, 4 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 152.1, 133.6, 132.9, 129.3, 127.8, 122.7, 121.6, 109.1
ppm. HRMS (ESI-Orbitrap): calcd for C19H12Br2N2O [M + H]+ 442.9377, 444.9369 and 446.9348; found
442.9389, 444.9371 and 446.9346.
15

ACCEPTED MANUSCRIPT
General procedure for compounds 6a-o (Table 3): A 10 mL round bottom flask was charged with a
magnetic stirring bar, benzimidazole 1 (59 mg, 0.5 mmol), boronic acid 2 (1.0 mmol), Cu2S (4 mg,
0.025 mmol), and MeOH (2 mL), followed with the addition of TMEDA (0.075 mL, 0.5 mmol). The
flask was sealed with a septum, through which was inserted 18-gauche needle. This setup allowed air
to go into the reaction and avoid contamination of a mixture. The reaction mixture was stirred from
400 to 600 rpm for appropriate time and extracted with EtOAc (2x 15 mL).. Combined organic layers
were washed with saturated aqueous solution of ethylenediaminetetraacetic acid disodium salt (15
mL), and then dried over anhydrous Na2SO4. Volatiles were removed under reduced pressure and the
residue was purified by column chromatography (silica gel, hexanes – EtOAc) to yield the title
product, which was characterized by 1H NMR, 13C NMR, HRMS, and melting point (if solid).
1-(p-Tolyl)-1H-benzo[d]imidazole (6a):11a Prepared from boronic acid 2a (reaction time 8 hours or 72
hours with the pinacol ester). Title product was obtained as a white solid (94 mg, 90%; 92 mg, 89%
with the pinacol ester; 3.87 g, 93% at the 20 mmol scale), mp 50-52 °C. 1H NMR (400 MHz, DMSO-d6):
δ = 8.51 (s, 1 H), 7.81 – 7.72 (m, 1 H), 7.59 – 7.52 (m, 3 H), 7.43 (d, J = 8.1 Hz, 2 H), 7.35 – 7.26 (m, 2
H), 2.41 (s, J = 9.7 Hz, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 143.8, 143.3, 137.3, 133.5, 133.2,
130.4, 123.6, 123.4, 122.3, 119.9, 110.6, 20.6 ppm. HRMS (ESI-Orbitrap): calcd for C14H12N2 [M + H]+
209.1073; found 209.1074.
1-Phenyl-1H-benzo[d]imidazole (6b):21 Prepared from boronic acid 2b (reaction time 8 hours). Title
product was obtained as a pale yellow oil (86 mg, 88%). 1H NMR (400 MHz, DMSO-d6): δ = 8.56 (s, 1
H), 7.80 – 7.76 (m, 1 H), 7.71 – 7.60 (m, 5 H), 7.53 – 7.47 (m, 1 H), 7.36 – 7.29 (m, 2 H) ppm. 13C NMR
(100 MHz, DMSO-d6): δ = 144.4, 143.8, 136.5, 133.6, 130.6, 128.3, 124.2, 124.0, 123.0, 120.5, 111.2
ppm. HRMS (ESI-Orbitrap): calcd for C13H10N2 [M + H]+ 195.0917; found 195.0917.
1-(4-Methoxyphenyl)-1H-benzo[d]imidazole (6c):22 Prepared from boronic acid 2c (reaction time 8
1
hours). Title product was obtained as a white solid (102 mg, 91%), mp 89-92 °C. H NMR (400 MHz,
DMSO-d6): δ = 8.47 (s, 1 H), 7.80 – 7.71 (m, 1 H), 7.58 (d, J = 8.9 Hz, 2 H), 7.53 – 7.48 (m, 1 H), 7.34 –
7.26 (m, 2 H), 7.17 (d, J = 8.9 Hz, 2 H), 3.85 (s, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 158.7,
143.4, 143.4, 133.6, 128.8, 125.4, 123.3, 122.2, 119.8, 115.1, 110.4, 55.5 ppm. HRMS (ESI-Orbitrap):
calcd for C14H12N2O [M + H]+ 225.1022; found 225.1023.
4-(1H-Benzo[d]imidazol-1-yl)phenol (6d):23 Prepared from boronic acid 2d (reaction time 8 hours).
1
Title product was obtained as an orange solid (77 mg, 73%), mp 188-190 °C. H NMR (400 MHz,
DMSO-d6): δ = 9.87 (s, 1 H), 8.41 (s, 1 H), 7.78 – 7.71 (m, 1 H), 7.51 – 7.46 (m, 1 H), 7.44 (d, J = 8.8 Hz,
2 H), 7.32 – 7.24 (m, 2 H), 6.98 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 157.1,
16

ACCEPTED MANUSCRIPT
143.5, 143.5, 133.7, 127.3, 125.6, 123.2, 122.1, 119.8, 116.3, 110.5 ppm. HRMS (ESI-Orbitrap): calcd
for C13H10N2O [M + H]+ 211.0866; found 211.0867.
1-(4-Nitrophenyl)-1H-benzo[d]imidazole (6e):24 Prepared from boronic acid 2e (reaction time 48
1
hours). Title product was obtained as a yellow solid (101 mg, 88%), mp 180-182 °C. H NMR (400
MHz, DMSO-d6): δ = 8.74 (s, 1 H), 8.46 (d, J = 9.1 Hz, 2 H), 8.03 (d, J = 9.0 Hz, 2 H), 7.84 – 7.74 (m, 2
H), 7.43 – 7.33 (m, 2 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 145.7, 144.1, 143.3, 141.4, 132.3,
125.6, 124.1, 123.78, 123.2, 120.3, 111.0 ppm. HRMS (ESI-Orbitrap): calcd for C13H9N3O2 [M + H]+
240.0768; found 240.0768.
1-(4-(Trifluoromethyl)phenyl)-1H-benzo[d]imidazole (6f):25 Prepared from boronic acid 2f (reaction
time 48 hours or 72 hours with the pinacol ester). Title product was obtained as a white solid (117
mg, 89%; 115 mg, 88% with the pinacol ester), mp 149-151 °C. 1H NMR (400 MHz, DMSO-d6): δ = 8.68
(s, 1 H), 8.00 (d, J = 8.7 Hz, 2 H), 7.96 (d, J = 8.6 Hz, 2 H), 7.81 (ddd, J = 7.8, 3.8, 3.1 Hz, 1 H), 7.75 –
7.69 (m, 1 H), 7.40 – 7.30 (m, 2 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 144.0, 143.3, 139.3, 132.6,
127.7 (q, J = 32 Hz), 127.2 (q, J = 4 Hz), 124.0 (q, J = 272 Hz), 123.8, 122.9, 120.1, 125.6, 110.8 ppm.
HRMS (ESI-Orbitrap): calcd for C14H9F3N2 [M + H]+ 263.0791; found 263.0793.
1-(o-Tolyl)-1H-benzo[d]imidazole (6g):10b Prepared from boronic acid 2g (reaction time 24 hours).
Title product was obtained as a pale yellow oil (92 mg, 88%). 1H NMR (400 MHz, DMSO-d6): δ = 8.38
(s, 1 H), 7.81 – 7.73 (m, 1 H), 7.55 – 7.47 (m, 2 H), 7.46 – 7.39 (m, 2 H), 7.31 – 7.24 (m, 2 H), 7.16 –
7.09 (m, 1 H), 2.04 (s, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 144.6, 143.6, 135.2, 135.1, 134.9,
132.0, 129.7, 128.1, 127.8, 123.8, 122.6, 120.3, 110.9, 17.7 ppm. HRMS (ESI-Orbitrap): calcd for
C14H12N2 [M + H]+ 209.1073; found 209.1074.
1-(2-Methoxyphenyl)-1H-benzo[d]imidazole (6h):10b Prepared from boronic acid 2h (reaction time
24 hours). Title product was obtained as a colorless oil (103 mg, 92%). 1H NMR (400 MHz, DMSO-d6):
δ = 8.33 (s, 1 H), 7.77 – 7.71 (m, 1 H), 7.56 – 7.48 (m, 2 H), 7.34 (dd, J = 8.3, 1.0 Hz, 1 H), 7.29 – 7.20
(m, 3 H), 7.16 (td, J = 7.5, 0.9 Hz, 1 H), 3.78 (s, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 154.3,
144.9, 143.6, 134.8, 130.6, 128.1, 124.6, 123.6, 122.5, 121.5, 120.1, 113.5, 111.4, 56.3 ppm. HRMS
(ESI-Orbitrap): calcd for C14H12N2O [M + H]+ 225.1022; found 225.1023.
1-(2,6-Dimethoxyphenyl)-1H-benzo[d]imidazole (6j): Prepared from boronic acid 2j (reaction time
1
72 hours). Title product was obtained as a pale yellow oil (91 mg, 72%). H NMR (400 MHz, DMSO-
d6): δ = 8.17 (s, 1 H), 7.76 – 7.66 (m, 1 H), 7.50 (t, J = 8.5 Hz, 1H), 7.27 – 7.16 (m, 2 H), 7.07 – 6.99 (m,
1 H), 6.92 (d, J = 8.5 Hz, 2 H), 3.71 (s, 6 H) ppm. 13C NMR (100 MHz, DMSO-d6):δ = 155.8, 145.2,
17

ACCEPTED MANUSCRIPT
142.9, 134.5, 130.6, 122.7, 121.6, 119.4, 112.3, 110.7, 104.9, 56.0.ppm. HTMS (ESI-Orbitrap): calcd
for C15H14N2O2 [M + H]+ 255.1128; found 255.1127.
1-(6-Methoxynaphthalen-2-yl)-1H-benzo[d]imidazole (6k): Prepared from boronic acid 2k (reaction
1
time 8 hours). Title product was obtained as a white solid (123 mg, 90%), mp 144-146 °C. H NMR
(400 MHz, DMSO-d6): δ = 8.63 (s, 1 H), 8.16 (d, J = 2.1 Hz, 1 H), 8.07 (d, J = 8.8 Hz, 1 H), 7.97 (d, J = 9.0
Hz, 1 H), 7.83 – 7.79 (m, 1 H), 7.76 (dd, J = 8.7, 2.2 Hz, 1 H), 7.70 – 7.65 (m, 1 H), 7.47 (d, J = 2.5 Hz, 1
H), 7.37 – 7.31 (m, 2 H), 7.29 (dd, J = 9.0, 2.6 Hz, 1 H), 3.92 (s, 3 H) ppm. 13C NMR (100 MHz, DMSO-
d6): δ = 158.3, 144.3, 144.1, 133.9, 133.9, 132.0, 130.0, 129.2, 129.2, 124.0, 123.3, 122.9, 122.2,
120.5, 120.4, 111.3, 106.6, 55.9 ppm. HRMS (ESI-Orbitrap): calcd for C18H14N2O [M + H]+ 275.1179;
found 275.1181.
(E)-1-Styryl-1H-benzo[d]imidazole (6l):26 Prepared from boronic acid 2l (reaction time 24 hours).
1
Title product was obtained as a pale yellow solid (80 mg, 73%), mp 88-91 °C. H NMR (400 MHz,
DMSO-d6): δ = 8.76 (s, 1 H), 8.07 (d, J = 14.8 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 1 H),
7.69 – 7.63 (m, 2 H), 7.44 – 7.35 (m, 3 H), 7.33 – 7.28 (m, 2 H), 7.26 (d, J = 14.7 Hz, 1 H) ppm. 13C NMR
(100 MHz, DMSO-d6): δ = 143.6, 141.7, 135.3, 132.4, 128.7, 127.5, 126.2, 123.5, 122.7, 122.2, 119.8,
117.7, 111.4 ppm. HRMS (ESI-Orbitrap): calcd for C15H12N2 [M + H]+ 221.1073; found 221.1073.
1-(Thiophen-3-yl)-1H-benzo[d]imidazole (6m):10d Prepared from boronic acid 2m (reaction time 24
hours or 72 hours with the pinacol ester). Title product was obtained as pale yellow oil (73 mg, 73%;
77 mg, 77% with the pinacol ester). 1H NMR (400 MHz, DMSO-d6): δ = 8.59 (s, 1 H), 7.93 (dd, J = 3.1,
1.5 Hz, 1 H), 7.84 (dd, J = 5.2, 3.1 Hz, 1 H), 7.78 – 7.75 (m, 1 H), 7.70 (ddd, J = 8.0, 1.4, 0.7 Hz, 1 H),
7.58 (dd, J = 5.2, 1.5 Hz, 1 H), 7.38 – 7.33 (m, 1 H), 7.33 – 7.28 (m, 1 H) ppm. 13C NMR (100 MHz,
DMSO-d6): δ = 143.5, 143.3, 134.3, 132.9, 127.8, 123.6, 123.0, 122.5, 119.9, 116.0, 111.0 ppm. HRMS
(ESI-Orbitrap): calcd for C11H8N2S [M + H]+ 201.0481; found 201.0481.
1-(4-Bromophenyl)-1H-benzo[d]imidazole (6n):5 Prepared from boronic acid 2n (reaction time 24
hours). Title product was obtained as a white solid (116 mg, 85%), mp 109-112 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.08 (s, 1 H), 7.90 – 7.86 (m, 1 H), 7.72 – 7.69 (m, 2 H), 7.52 – 7.47 (m, 1 H), 7.42 – 7.39 (m,
2 H), 7.37 – 7.32 (m, 2 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 144.2, 142.1, 135.5, 133.6, 133.4,
125.7, 124.1, 123.2, 121.8, 120.9, 110.3 ppm. HRMS (ESI-Orbitrap): calcd for C13H9BrN2 [M + H]+
273.0022 and 275.0001; found 273.0027 and 274.9999.
1-(Pyridin-3-yl)-1H-benzo[d]imidazole (6o):27 Prepared from pyridin-3-ylboronic acid neopentylglycol
ester 2o (reaction time 72 hours). Title product was obtained as a white solid (88 mg, 90%), mp 88-90
°C. 1H NMR (400 MHz, CDCl3): δ = 8.86 (s, 1 H), 8.73 (d, J = 4.0 Hz, 1 H), 8.16 (s, 1 H), 7.91 – 7.86 (m, 2
18

ACCEPTED MANUSCRIPT
H), 7.56 – 7.49 (m, 2 H), 7.38 – 7.36 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 149.4, 145.4, 144.0,
141.9, 133.5, 133.2, 131.5, 124.6, 124.4, 123.5, 120.9, 110.1 ppm. HRMS (ESI-Orbitrap): calcd for
C12H9N3 [M + H]+ 196.0869; found 196.0871.
General method for compounds 8-n (Table 4): The same procedure as for compounds 6a-n was
employed, except imidazole 7 (34 mg, 0.5 mmol) was used as a starting material.
1-(p-Tolyl)-1H-imidazole (8a):11a Prepared from boronic acid 2a (reaction time 24 hours). Title
product was obtained as a white solid (69 mg, 87%), mp 39-41 °C. 1H NMR (400 MHz, DMSO-d6): δ =
8.20 – 8.18 (m, 1 H), 7.69 (t, J = 1.3 Hz, 1 H), 7.52 (d, J = 8.5 Hz, 2 H), 7.33 – 7.28 (m, 2 H), 7.09 – 7.08
(m, 1 H), 2.34 (s, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 136.2, 135.4, 134.6, 130.2, 129.7,
120.2, 118.0, 20.4 ppm. HRMS (ESI-Orbitrap): calcd for C10H10N2 [M + H]+ 159.0917; found 159.0917.
1-Phenyl-1H-imidazole (8b):10c Prepared from boronic acid 2b (reaction time 24 hours). Title product
was obtained as pale yellow oil (61 mg, 85%). 1H NMR (400 MHz, DMSO-d6): δ = 8.26 (s, 1 H), 7.75 (s,
1 H), 7.65 (dd, J = 7.3, 1.6 Hz, 2 H), 7.52 (t, J = 8.0 Hz, 2 H), 7.36 (t, J = 7.3 Hz, 1 H), 7.11 (s, 1 H) ppm.
13C NMR (101 MHz, DMSO-d6): δ = 136.9, 135.5, 129.9, 129.8, 126.8, 120.3, 118.0 ppm. HRMS (ESI-
Orbitrap): calcd for C9H8N2 [M + H]+ 145.0760; found 145.0761.
1-(4-Methoxyphenyl)-1H-imidazole (8c):11a Prepared from boronic acid 2c (reaction time 24 hours).
Title product was obtained as a white solid (78 mg, 90%), mp 60-62 °C. 1H NMR (400 MHz, DMSO-d6):
δ = 8.12 (t, J = 1.3 Hz, 1 H), 7.63 (t, J = 1.3 Hz, 1 H), 7.54 (d, J = 9.0 Hz, 2 H), 7.07 (t, J = 1.3 Hz, 1 H),
7.06 (d, J = 9.0 Hz, 2 H), 3.80 (s, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 158.0, 135.5, 130.3,
129.5, 122.0, 118.3, 114.9, 55.5 ppm. HRMS (ESI-Orbitrap): calcd for C10H10N2O [M + H]+ 175.0866;
found 175.0867.
4-(1H-Imidazol-1-yl)phenol (8d):28 Prepared from boronic acid 2d (reaction time 24 hours). Title
product was obtained as a reddish solid (48 mg, 60%), mp 189-190 °C. 1H NMR (400 MHz, DMSO-d6):
δ = 9.75 (s, 1 H), 8.09 (br. s, 1 H), 7.61 (br. s, 1 H), 7.40 (d, J = 8.4 Hz, 2 H), 7.10 (br. s, 1 H), 6.87 (d, J =
8.4 Hz, 2 H) ppm. 13C NMR (101 MHz, DMSO-d6): δ = 156.4, 129.7, 129.1, 122.3, 119.3, 116.1 ppm.
HRMS (ESI-Orbitrap): calcd for C9H8N2O [M + H]+ 161.0709; found 161.0710.
1-(4-Nitrophenyl)-1H-imidazole (8e):29 Prepared from boronic acid 2e (additional 0.5 mmol of
boronic acid 2e was added after 24 hours, total reaction time 48 hours). Title product was obtained
as a yellow solid (72 mg, 76%), mp 196-198 °C. 1H NMR (400 MHz, DMSO-d6): δ = 8.51 – 8.47 (m, 1 H),
8.36 (d, J = 9.0 Hz, 2 H), 8.00 – 7.96 (m, 2 H), 7.95 – 7.94 (m, 1 H), 7.19 – 7.17 (m, 1 H) ppm. 13C NMR
19

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(100 MHz, DMSO-d6): δ = 145.3, 141.7, 136.0, 130.8, 125.5, 120.4, 117.9 ppm. HRMS (ESI-Orbitrap):
calcd for C9H7N3O2 [M + H]+ 190.0611; found 190.0611.
1-(4-(Trifluoromethyl)phenyl)-1H-imidazole (8f):30 Prepared from boronic acid 2f (additional 0.5
mmol of boronic acid 2f was added after 24 hours, total reaction time 48 hours). Title product was
obtained as a white solid (84 mg, 79%), mp 65-67 °C. 1H NMR (400 MHz, DMSO-d6): δ = 8.42 (br.s, 1
H), 7.92 (d, J = 8.9 Hz, 2 H), 7.90 – 7.85 (m, 3 H), 7.16 (br.s, 1 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ
= 139.9, 135.8, 130.4, 127.1 (q, J = 4 Hz), 126.6 (q, J = 32 Hz), 120.6, 124.0 (q, J = 272 Hz), 117.9 ppm.
HRMS (ESI-Orbitrap): calcd for C10H7F3N3 [M + H]+ 213.0634; found 213.0634.
1-(o-Tolyl)-1H-imidazole (8g):11a Prepared from boronic acid 2g (reaction time 24 hours). Title
product was obtained as pale yellow oil (67 mg, 85%). 1H NMR (400 MHz, CDCl3): δ = 7.57 (br. s, 1 H),
7.36 – 7.32 (m, 2 H), 7.30 – 7.25 (m, 1 H), 7.21 – 7.19 (m, 2 H), 7.05 (br. s, 1 H), 2.17 (s, 3 H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 137.6, 136.7, 134.0, 131.4, 129.4, 128.9, 127.0, 126.6, 120.6, 17.7 ppm.
HRMS (ESI-Orbitrap): calcd for C10H10N2 [M + H]+ 159.0917; found 159.0916.
1-(2-Methoxyphenyl)-1H-imidazole (8h):11a Prepared from boronic acid 2h (reaction time 24 hours).
Title product was obtained as a white solid (75 mg, 86%), mp 53-54 °C. 1H NMR (400 MHz, DMSO-d6):
δ = 7.88 (s, 1 H), 7.47 – 7.34 (m, 3 H), 7.25 (d, J = 8.2 Hz, 1 H), 7.12 – 6.99 (m, 2 H), 3.82 (s, 3 H) ppm.
13C NMR (100 MHz, DMSO-d6): δ = 152.1, 137.6, 128.9, 128.3, 126.0, 125.5, 120.9, 120.5, 112.9, 55.9
ppm. HRMS (ESI-Orbitrap): calcd for C10H10N2O [M + H]+ 175.0866; found 175.0868.
1-(2,6-Dimethoxyphenyl)-1H-benzo[d]imidazole (8j):31 Prepared from boronic acid 2j (reaction time
1
48 hours). Title product was obtained as a white solid (81 mg, 79%), mp 145-147 °C. H NMR (400
MHz, DMSO-d6): δ = 7.56 (s, 1 H), 7.39 (t, J = 8.5 Hz, 1 H), 7.11 (d, J = 0.9 Hz, 1 H), 6.99 (d, J = 0.9 Hz, 1
H), 6.83 (d, J = 8.5 Hz, 2 H), 3.73 (s, 6 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 155.0, 138.6, 129.8,
127.5, 121.5, 114.8, 104.8, 56.1 ppm. HRMS (ESI-Orbitrap): calcd for C11H12N2O2 [M + H]+ 205.0972;
found 205.0974.
1-(6-Methoxynaphthalen-2-yl)-1H-imidazole (8k):32 Prepared from boronic acid 2k (reaction time 24
hours). Title product was obtained as pale yellow solid (99 mg, 88%), mp 76-78 °C. 1H NMR (400 MHz,
DMSO-d6): δ = 8.34 (br.s, 1 H), 8.11 (d, J = 2.3 Hz, 1 H), 7.97 (d, J = 8.8 Hz, 1 H), 7.87 (d, J = 9.0 Hz, 1
H), 7.83 (t, J = 1.3 Hz, 1 H), 7.78 (dd, J = 8.8, 2.3 Hz, 1 H), 7.40 (d, J = 2.5 Hz, 1 H), 7.25 (dd, J = 9.0, 2.6
Hz, 1 H), 7.15 (br.s, 1 H), 3.89 (s, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 157.5, 135.7, 132.9,
132.6, 129.9, 129.3, 128.5, 128.5, 120.1, 119.9, 118.2, 117.7, 106.0, 55.3 ppm. HRMS (ESI-Orbitrap):
calcd for C14H12N2O [M + H]+ 225.1022; found 225.1023.
20

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(E)-1-Styryl-1H-imidazole (8l):26 Prepared from boronic acid 2l (reaction time 48 hours). Title product
was obtained as pale yellow solid (63 mg, 74%), mp 78-79 °C. 1H NMR (400 MHz, DMSO-d6): δ = 8.02
(br.s, 1 H), 7.85 (d, J = 14.8 Hz, 1 H), 7.71 (br.s, 1 H), 7.50 (d, J = 7.3 Hz, 2 H), 7.38 (t, J = 7.6 Hz, 2 H),
7.26 (t, J = 7.3 Hz, 1 H), 7.06 (br.s, 1 H), 7.03 (d, J = 14.8 Hz, 1 H) ppm. 13C NMR (100 MHz, DMSO-d6):
δ = 137.0, 135.1, 129.8, 128.8, 127.4, 126.0, 123.8, 116.9, 116.6 ppm. HRMS (ESI-Orbitrap): calcd for
C11H10N2 [M + H]+ 171.0917; found 171.0918.
1-(Thiophen-3-yl)-1H-imidazole (8m):10d Prepared from boronic acid 2m (additional 0.5 mmol of
boronic acid 2m was added after 24 hours, total reaction time 48 hours). Title product was obtained
1
as a white solid (45 mg, 60%), mp 82-83 °C. H NMR (400 MHz, DMSO-d6): δ = 8.25 – 8.20 (m, 1 H),
7.75 (dd, J = 3.2, 1.6 Hz, 1 H), 7.73 – 7.69 (m, 2 H), 7.53 (dd, J = 5.1, 1.6 Hz, 1 H), 7.07 – 7.05 (m, 1 H)
ppm. 13C NMR (100 MHz, DMSO-d6): δ = 136.0, 135.8, 129.4, 127.8, 121.0, 118.3, 111.9 ppm. HRMS
(ESI-Orbitrap): calcd for C7H6N2S [M + H]+ 151.0324; found 151.0326.
1-(4-Bromophenyl)-1H-imidazole (8n):10c Prepared from boronic acid 2n (reaction time 24 hours).
Title product was obtained as a white solid (100 mg, 90%), mp 109-111 °C. 1H NMR (400 MHz, CDCl3):
1
δ = 7.82 (s, 1 H), 7.62 – 7.58 (m, 2 H), 7.28 – 7.25 (m, 2 H), 7.24 (s, 1 H), 7.21 (s, 1 H). H NMR (400
MHz, CDCl3): δ = 136.5, 135.6, 133.2, 130.9, 123.1, 121.1, 118.3 ppm. HRMS calcd for C9H7BrN2 [M +
H]+ 222.9873 and 224.9845; found 222.9865 and 224.9845.
General procedure for compounds 10 (Table 5): A 25 mL round bottom flask was charged with a
magnetic stirring bar, amine 9 (1.5 mmol), p-tolylboronic acid 2a (1.0 mmol), Cu2S (8 mg, 0.05 mmol),
and MeOH (4 mL), followed with the addition of TMEDA (0.15 mL, 1.0 mmol). The flask was sealed
with a septum, through which was inserted 18-gauche needle. This setup allowed air to go into the
reaction and avoid contamination of a mixture. The reaction mixture was stirred from 400 to 600
rpm for 24 hours, and then extracted with dichloromethane (2x 15 mL). Combined organic layers
were washed with saturated aqueous solution of ethylenediaminetetraacetic acid disodium salt (15
mL), and then dried over anhydrous Na2SO4. Volatiles were removed under reduced pressure and the
residue was purified by column chromatography (silica gel, hexanes – EtOAc) to yield the title
product, which was characterized by 1H NMR, 13C NMR, HRMS, and melting point (if solid).
N-butyl-4-methylaniline (10a):33 Title product was prepared from butylamine 9a and obtained as a
1
pale yellow oil (116 mg, 81%). H NMR (400 MHz, CDCl3): δ = 7.03 – 6.99 (m, 2 H), 6.58 – 6.55 (m, 2
H), 3.11 (t, J = 7.2 Hz, 2 H), 2.26 (s, 3 H), 1.65 – 1.58 (m, 2 H), 1.45 (sextet, J = 7.2 Hz, 2 H), 0.98 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 146.4, 129.8, 126.5, 113.1, 44.2, 31.8, 20.5, 20.4,
14.1 ppm. HRMS (ESI-Orbitrap): calcd for C11H17N [M + H]+ 164.1434; found 164.1435.
21

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N-hexyl-4-methylaniline (10b):34 Title product was prepared from hexylamine 9b and obtained as a
1
white solid (162 mg, 85%), mp 35-36 °C. H NMR (400 MHz, CDCl3): δ = 7.01 – 6.98 (m, 2 H), 6.58 –
6.54 (m, 2 H), 3.09 (t, J = 7.3 Hz, 2 H), 2.25 (s, 3 H), 1.62 (quintet, J = 7.3 Hz, 2 H), 1.44 – 1.28 (m, 6 H),
0.9 0.89 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 146.3, 129.8, 126.6, 113.2, 44.6, 31.8, 29.7,
27.0, 22.8, 20.5, 14.2 ppm. HRMS (ESI-Orbitrap): calcd for C13H21N [M + H]+ 192.1747; found
192.1745.
N-cyclopentyl-4-methylaniline (10c):35 Title product was prepared from cyclopentyl 9c and obtained
as a colorless oil (138 mg, 79%). 1H NMR (400 MHz, CDCl3): δ = 7.01 – 6.98 (m, 2 H), 6.58 – 6.55 (m, 2
H), 3.81 – 3.75 (m, 1 H), 2.25 (s, 3 H), 2.05 – 1.98 (m, 2 H), 1.75 – 1.68 (m, 2 H), 1.65 – 1.59 (m, 2 H),
1.51 – 1.43 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.8, 129.8, 126.4, 113.6, 55.2, 33.5, 24.2,
20.5 ppm. HRMS (ESI-Orbitrap): calcd for C12H17N [M + H]+ 176.1434; found 176.1434.
N-cyclohexyl-4-methylaniline (10d):36 Title product was prepared from cyclohexylamine 9d and
obtained as a white solid (147 mg, 78%), mp 39-41 °C. 1H NMR (400 MHz, CDCl3): δ = 6.99 (d, J = 7.9
Hz, 2 H), 6.57 – 6.54 (m, 2 H), 3.27 – 3.20 (m, 1 H), 2.25 (s, 3 H), 2.10 – 2.05 (m, 2 H), 1.80 – 1.75 (m, 2
H), 1.69 – 1.64 (m, 1 H), 1.43 – 1.33 (m, 2 H), 1.30 – 1.10 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
145.1, 129.9, 126.3, 113.7, 52.2, 33.6, 26.1, 25.2, 20.5 ppm. HRMS (ESI-Orbitrap): calcd for C13H19N
[M + H]+ 190.1590; found 190.1591.
One-pot Suzuki-Miyaura and Chan-Lam reaction
1-(4'-Methyl-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole (11): A microwave vial was charged with a
magnetic stirring bar, benzimidazole 5 (118 mg, 1.0 mmol), boronic acid 2n (220 mg, 1.1 mmol), Cu2S
(8 mg, 0.05 mmol), and EtOH (4 mL), then followed with the addition of TMEDA (0.15 mL, 1.0 mmol).
The flask was sealed with a septum, through which was inserted 18-gauche needle. This setup
allowed access of air and avoided contamination. The reaction mixture was stirred from 400 to 600
rpm for 24 hours. Then the mixture was flushed with nitrogen. To the flask was subsequently added
water (1.0 mL), K2CO3 (417 mg, 3.0 mmol), boronic acid (272 mg, 2.0 mmol), and XPhos Pd G2 (8 mg,
0.01 mmol). The vial was sealed and inserted into a microwave reactor, where it was irradiated at
variable power, so the temperature was maintained at 120 °C for 30 minutes. Then the mixture was
partitioned between dichloromethane (20 mL) and water (20 mL). The organic layer was separated
and aqueous layer extracted twice with dichloromethane (2x 20 mL). Combined organic layers were
dried over anhydrous Na2SO4. Volatiles were removed under reduced pressure and the residue was
purified by column chromatography (silica gel, hexanes – EtOAc) to yield the title compound 11 as a
white solid (264 mg, 93% yield, 96% HPLC purity). This material contained 2% of compound 6n, and
two unknown impurities (both 1% HPLC area). Crystallization from boiling MeOH (4 mL) gave
22

ACCEPTED MANUSCRIPT
compound 11 as a white crystalline solid (193 mg, 68%), mp 154 – 156 °C. 1H NMR (500 MHz, CDCl3):
δ = 8.16 (s, 1 H), 7.92 – 7.89 (m, 1 H), 7.77 (d, J = 8.6 Hz, 2 H), 7.61 – 7.59 (m, 1 H), 7.58 (d, J = 8.6 Hz,
2 H), 7.55 (d, J = 8.2 Hz, 2 H), 7.38 – 7.34 (m, 2 H), 7.31 (d, J = 8.2 Hz, 2 H), 2.43 (s, 3 H) ppm. 13C NMR
(500 MHz, CDCl3): δ = 142.4, 141.2, 138.0, 137.0, 135.3, 129.9, 128.6, 127.1, 124.4, 123.9, 122.9,
120.8, 110.7, 21.3 ppm. HRMS calcd for C20H16N2 [M + H]+ 285.1386, found 285.1395.
Acknowledgements
This work was supported by the Czech National Program for Sustainability (project LO1304), the
Operational Programme Enterprise and Innovations for Competitiveness (project
CZ.01.1.02/0.0/0.0/15_019/0004431), and the internal Palacky University IGA projects
(IGA_PrF_2017_009 and IGA_LF_2017_028).
Supporting Information
1
Copies of H NMR and 13C NMR spectra for all prepared compounds, HPLC for one-pot Chan-
Lam/Suzuki-Miyaura reactions, chiral HPLC for compounds 3g and 4g are included.
References and Notes
(1) Examples of N-arylazoles with biological activities: (a) Cozzi, P.; Carganico, G.; Fusar, D.; Grossoni,
M.; Menichincheri, M.; Pinciroli, V.; Tonani, R.; Vaghi, F.; Salvati, P. J. Med. Chem. 1993, 36, 2964-
2972. (b) Lange, J. H. M.; van Stuivenberg, H. H.; Coolen, H. K. A. C.; Adolfs, T. J. P.; McCreary, A. C.;
Keizer, H. G.; Wals, H. C.; Veerman, W.; Borst, A. J. M.; de Looff, W.; Verveer, P. C.; Kruse, C. G. J.
Med. Chem. 2005, 48, 1823-1838. (c) Quan, M.L.; Lam, P. Y. S.; Han, Q.; Pinto, D. J. P.; He, M. Y.; Li, R.;
Ellis, C. D.; Clark, C. G.; Teleha, C. A.; Sun, J.-H.; Alexander, R. S.; Bai, S.; Luettgen, J. M.; Knabb, R. M.;
Wong, P. C.; Wexler, R. R. J. Med. Chem. 2005, 48, 1729-1744.
(2) Gaba, M.; Mohan, C. Med. Chem. Res. 2016, 25, 173-210.
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S. H. J. Org. Chem. 2014, 79, 9231-9545. (b) Tang, D.; Wu, P.; Liu, X.; Chen, Y.-X.; Guo, S.-B.; Chen, W.-
L.; Li, J.-G.; Chen, B.-H. J. Org. Chem. 2013, 78, 2746-2750. (c) Caron, S.; Jones, B. P.; Wei, L. Synthesis,
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(4) Gungor, T.; Fouquet, A.; Teulon, J. M.; Prevost, D.; Cazes, M.; Cloarec, A. J. Med. Chem. 1992, 35,
4455-4463.
(5) Catalyst-free N-arylation using unactivated fluorobenzenes was reported, but it requires harsh
reaction conditions: Diness, F.; Fairlie, D. P. Angew. Chem. Int. Ed. 2012, 51, 8012-8016.
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(6) Ullman-type N-arylation of heterocycles: (a) Chen, H.; Wang, D.; Wang, X.; Huang, W.; Cai, Q.;
Ding, K. Synthesis 2010, 1505-1511. (b) Altman, R. A.; Buchwald, S. L. Org. Let. 2006, 8, 2779-2782. (c)
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