Convenient synthesis of N-1-alkyl benzimidazoles via Pd catalyzed C–N bond formation and cyclization

Article abstract of DOI:10.1080/00397911.2021.1939056

N-1-Alkyl-2-unsubstituted benzimidazoles were directly synthesized by intermolecular coupling of formimidamides with benzylamines; the syntheses were catalyzed by Pd(OAc)₂ in one pot, giving rise to moderate to good yields. Aromatic formamidine

Full text of DOI:10.1080/00397911.2021.1939056

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Convenient synthesis of N-1-alkyl benzimidazoles
via Pd catalyzed C–N bond formation and
cyclization
Fusheng Bie, Yongfeng Yao, Han Cao, Yijun Shi, Peng Yan, Jie Ma, Ying Han &
Xuejing Liu
To cite this article: Fusheng Bie, Yongfeng Yao, Han Cao, Yijun Shi, Peng Yan, Jie Ma, Ying
Han & Xuejing Liu (2021) Convenient synthesis of N-1-alkyl benzimidazoles via Pd catalyzed
C–N bond formation and cyclization, Synthetic Communications, 51:15, 2387-2396, DOI:
10.1080/00397911.2021.1939056
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2021, VOL. 51, NO. 15, 2387–2396
https://doi.org/10.1080/00397911.2021.1939056
Convenient synthesis of N-1-alkyl benzimidazoles via Pd
catalyzed C–N bond formation and cyclization
Fusheng Biea, Yongfeng Yaob, Han Caoa , Yijun Shia, Peng Yana, Jie Maa,
Ying Hana, and Xuejing Liua
aEngineering and Technology Institute of LuNan Coal Chemical Engineering, ZaoZhuang University,
b
Zaozhuang, P. R. China; Zaozhuang Ecological Environment Monitoring Center, Zaozhuang, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 27 February 2021
N-1-Alkyl-2-unsubstituted benzimidazoles were directly synthesized
by intermolecular coupling of formimidamides with benzylamines;
the syntheses were catalyzed by Pd(OAc)2 in one pot, giving rise to
moderate to good yields. Aromatic formamidines with various sub-
stituents as starting materials could be readily prepared from the
reactions of the corresponding anilines and N,N-dimethylformamide
dimethyl acetal in high yields.
KEYWORDS
Aromatic formamidine;
benzimidazole; catalysis;
cyclization; palladium
GRAPHICAL ABSTRACT
Introduction
Benzimidazole scaffolds have played important roles in bioactive natural products, syn-
thetic drugs, and agricultural chemicals after being discovered as the integral part of the
structure of vitamin B12 in the 1950s.[1–3] A recent analysis found that benzimidazole
scaffolds are the top five most commonly used five-membered heterocycle in the
FDA-approved drugs.[4,5] Drugs consisting of such skeletons are widely applied to the
treatment of many kinds of diseases, such as antihypertension,[6] anti-HIV,[7] anti-
cancer,[8–11] anti-viral,[12,13] and anti-bacterial.[14,15] Additionally, the derivatives derived
from substitutions at N-1-position occupy 46% of FDA-approved pharmaceuticals bear-
ing a benzimidazole core, forming a vital branch due to their broad-spectral activ-
ities.[16–18] Numerous synthetic strategies have been introduced based on these
important scaffolds to build an efficient route for the construction of benzimida-
zoles.[19–27] Generally, the benzimidazoles are cyclocondensed from suitably substituted
1,2-diaminoarenes with carboxylic acids or equivalents under harsh dehydrating
conditions or oxidative coupling reactions with benzaldehydes.[28] The following-up
CONTACT Fusheng Bie
fsbie@uzz.edu.cn
Engineering and Technology Institute of LuNan Coal Chemical
Engineering, ZaoZhuang University, Zaozhuang, P. R. China.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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Scheme 1. Some typical methods for the synthesis of N-1-aryl-benzimidazoles.
N-alkylation of the benzimidazole ring generally shows many critical weaknesses, such
as low regioselectivity, sensitive to steric hindrance and laborious procedures. It is still a
challenge to acquire conveniently N-alkyl-substituted benzimidazoles during this
whole process.[29–33] Therefore, the development of an effective method for synthesis of
N-1-aryl-substituted benzimidazoles will gain a considerable interest.
Other synthetic methodologies for N-1-aryl-benzimidazoles include Cu- and Pd-cata-
lyzed intramolecular cyclization reactions (as illustrated in Scheme 1, methods A and
B).[34–37] Buchwald et al. have developed a strategy which relies on the intermolecular
formation of benzimidazoles by coupling 2-bromoacetanilides with anilines (cf. Scheme
1, method C)[38,39]; the strategy has involved various pre-prepared alkyl-amides ortho to
a halide and gave both 2- and N-substituted benzimidazoles. Clearly, most of the above
synthetic routes required elaborately synthesized starting materials. Recently, we
reported an intermolecular cyclization method for synthesis of N-1-alkyl benzimidazoles
from formamidines and primary amines (Scheme 1, method D).[40] This method only
worked efficiently with the formamidine ring which has a strong electron with-drawing
group (such as -NO2). Since formamidines can be prepared relatively easily, we envi-
sioned that they can be coupled intermolecularly with various commercial amines, thus
broadening the potential application of this method. Herein, we report a convenient
synthetic strategy of constructing N-1-alkyl-2-unsubstituted benzimidazoles by intermo-
lecular coupling of aryl formamidines with benzylamine in the presence of Pd catalyst.
Results and discussion
First, we commenced the synthesis of N-1-alkyl-2-unsubstituted benzimidazole from
N0-(2-bromophenyl)-N,N-dimethylformimidamide (1), 4-methoxybenzylamine (2a),
Pd(OAc)2, sodium t-butoxide (t-BuONa) and ( )-2,20-bis(diphenylphosphino)-1,10-
binaphthalene (( )-BINAP) at 110 ꢀC under argon (Table 1, entry 1). The desired prod-
uct (3a) was isolated in a good yield (64%).

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Table 1. Optimization of the reaction conditions for the synthesis of 1-benzylbenzimidazole.a
Entry
Catalyst
Ligand
Base
t-BuONa
t-BuONa
t-BuONa
t-BuONa
KOH
t-BuOK
NaH (60%)
EtONa
DBU
DABCO
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
Solvent
Toluene
Temp. (oC)
Yield (%)b
1
2
3
4
5
6
7
8
Pd(OAc)2
PdCl2
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
PPh3
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
90
64
37
46
5
84
68
56
43
4
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
NMP
DMF
DMSO
Xylenes
CH3CN
Dioxane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Pd2(dba)3
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
3
33
42
40
37
26
45
42
8
77
48
19
56
69
57
66c
87d
90e
N.D.f
N.D.
DPPF
DPPP
PCy3ꢁHBF4
TFP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
( )-BINAP
–
100
140
110
110
110
110
110
Pd(OAc)2
a1 (0.1 mmol), 2a (0.1 mmol), solvent (0.5 mL), catalyst (5 mol%), ligand (10 mol%), base (2.2 equiv) in a sealed tube,
argon protected, 18 h.
bIsolated yields.
cReaction time: 6 h.
dReaction time: 24 h.
eCatalyst: 10 mol%, ligand (20 mol%).
fNot detected.
Then we screened several common palladium catalysts and found that Pd(OAc)2 was
the most effective one in 5 mol% (Table 1, entries 1–4). Different kinds of bases were
also employed and KOH gave the highest yield (Table 1, entries 5–10). On the other
hand, the strong organic bases, such as 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) and
1,4-diazabicyclo[2.2.2]octane (DABCO), did not work well due probably to the big steric
hindrance of the organic bases. When the maneuverability and the product yield are
compared, toluene was superior to other solvents such as N-methyl pyrrolidone (NMP),
N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), xylenes, acetonitrile and
dioxane (Table 1, entries 5 and 16–21). Moreover, 110 ꢀC was proved to be the most
suitable temperature (Table 1, entries 5 and 22–24), and ( )-BINAP served as the best

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F. BIE ET AL.
Table 2. The scope of different aromatic amines for the synthesis of benzimidazoles.a
Entry
Amine (2)
Product (3)
Yield (%)b
1
2
3
4
5
6
7
8
2b, R ¼ benzyl
3b
3c
3d
3e
3f
3g
–
–
–
–
–
70
79
55
37
20
2c, R ¼ 4-methylbenzyl
2d, R ¼ 1-phenylethyl
2e, R ¼ 4-(methoxycarbonyl)benzyl
2f, R ¼ 4-fluorobenzyl
2g, R ¼ 4-chlorobenzyl
2h, R ¼ 4-methoxyphenyl
2i, R ¼ 3,4-dimethoxyphenyl
2j, R ¼ 3,4,5-trimethoxyphenyl
2k, R ¼ 4-methylphenyl
2l, R ¼ n-butyl
36
N.D.c
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
9
10
11
12
13
14
2m, R ¼ t-butyl
–
–
–
2n, R ¼ cyclohexyl
2o, R ¼ octadecyl
a1 (0.1 mmol), 2b–k (0.1 mmol), toluene (0.5 mL), Pd(OAc)2 (5 mol%), ( )-BINAP (10 mol%), KOH (2.2 equiv) in a sealed
tube, argon protected.
bIsolated yields.
cNot detected.
ligand for the palladium catalyst among commercially available ligands trialed (Table 1,
entries 5 and 11–15). Furthermore, we also investigated the effect of reaction time on
the product yield and found that 18-h reaction time gave essentially the best results.
When the reaction time was less than 18 h, the yield of the product deceased remark-
ably (Table 1, entry 25). However, when the reaction time was extended to 24 h, the
yield of the product was not increased much (Table 1, entry 26). Obviously, 10 mol%
catalyst gave a slightly better yield than 5 mol% catalyst (Table 1, entry 27); however,
when the cost of the catalyst was taken into account, a 5 mol% catalyst was chosen. In
fact, no desired product was observed when neither catalyst nor the ligand was added
(Table 1, entries 28 and 29). After optimization of the reaction conditions, we chose
Pd(OAc)2 (5 mol%) and ( )-BINAP as the catalyst system, KOH as the base and toluene
the solvent, widening our synthetic scope (Table 1, entry 5). These results were sum-
marized in Table 2.
Generally, the electronic effect of the substituted groups played important roles in
terms of the yields. The benzylamines with electron-donating groups gave rise to much
better yields than electron-withdrawing groups (Table 1, entry 5; Table 2, entries 1–6).
Product 3d was obtained in a much lower yield due to the steric hindrance of methyl-
group (Table 2, entries 1 and 3), indicating the importance played by the steric hin-
drance. Unfortunately, both phenylamines and aliphatic amines did not work in this
catalyzed reaction system, even if they were substituted with strong electron-donating
groups (Table 2, entries 7–14). In addition, we got the single crystal structure of 3b
(CCDC 1944526) which was shown in Figure S1 and Table S1 in Supporting
Information.

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Table 3. The scope of different aromatic formamidines for the synthesis of benzimidazoles.a
Entry
Formamidine (4)
Amine (2)
Product (5)
Yield (%)b
1
2
3
4
5
6
7
8
4a, R1 ¼ 5-F
2a, R2 ¼ 4-methoxybenzyl
2a, R2 ¼ 4-methoxybenzyl
2a, R2 ¼ 4-methoxybenzyl
2a, R2 ¼ 4-methoxybenzyl
2a, R2 ¼ 4-methoxybenzyl
2a, R2 ¼ 4-methoxybenzyl
2a, R2 ¼ 4-methoxybenzyl
2a, R2 ¼ 4-methoxybenzyl
2a, R2 ¼ 4-methoxybenzyl
2a, R2 ¼ 4-methoxybenzyl
2a, R2 ¼ 4-methoxybenzyl
2a, R2 ¼ 4-methoxybenzyl
2a, R2 ¼ 4-methoxybenzyl
2c, R2 ¼ 4-methylbenzyl
2b, R2 ¼ 4-benzyl
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
–
75
63
60
72
57
52
81
78
45
52
59
80
91
87
80
N.D.c
4b, R1 ¼ 5-Cl
4c, R1 ¼ 5-Br
4d, R1 ¼ 5-COOMe
4e, R1 ¼ 5-Me
4f, R1 ¼ 5-OMe
4g, R1 ¼ 4-OMe
4h, R1 ¼ 4-Me
4i, R1 ¼ 4-COOMe
4j, R1 ¼ 4-CF3
4k, R1 ¼ 6-Me
4l, R1 ¼ 3-Me
9
10
11
12
13
14
15
16
4m, R1 ¼ 3-CF3
4m, R1 ¼ 3-CF3
4m, R1 ¼ 3-CF3
4m, R1 ¼ 3-CF3
2d, R2 ¼ 1-phenylethyl
a4a–m (0.1 mmol), 2a–d (0.1 mmol), toluene (0.5 mL), Pd(OAc)2 (5 mol%), ( )-BINAP (10 mol%), KOH (2.2 equiv) in a
sealed tube, argon protected.
bIsolated yields.
cNot detected.
To further expand the application scope, aromatic formamidines with various sub-
stituents were also investigated and the results are given in Table 3. Undoubtedly, both
the position of substituents and the electronic effect are important factors influencing
the product yields. Aromatic formamidines having 5-F, 5-Cl, 5-Br, and 5-COOMe sub-
stituents underwent reactions with yields ranging from 60 to 75% (Table 3, entries 1–4).
On the other hand, formamidines possessing electron-donating substituents the 5-Me
and 5-OMe leaded to a drop in the yield (Table 3, entries 5 and 6). These results indi-
cated that the electron-withdrawing substituents on the 5-position of the formamidines
were favorable for the reaction. But the opposite tendency was occurred when the sub-
stituents on the 4-positon of the formamidines. Under the same conditions, aromatic
formamidines bearing electron-donating groups, such as 4-OMe and 4-Me, gave yields
from 78% to 81% (Table 3, entries 7 and 8). Conversely, the electron-withdrawing
groups, such as 4-COOMe and 4-CF3, only gave yields from 45% to 52% (Table 3,
entries 9 and 10). Aromatic formimidamide with 6-Me substituent gave a yield of 59%
(Table 3, entry 11). Reactions of 4l and 4m, which contained steric groups on 3-positon
of the aromatic formamidines, proved to be much more efficient; the corresponding
products 5l and 5m are in good yields (80 and 91% yield, respectively, Table 3, entries
12 and 13).
The same observation was also reported by Brain and coworkers.[35,36] The steric hin-
drance from 3-CF3 group could be responsible for the relatively high yield. Finally, we
chose the best aromatic formimidamide (4m) to react with different benzylamines. As
expected, the yield of the product increased with the electron-donating capability of the

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F. BIE ET AL.
Scheme 2. The proposed reaction mechanism for the synthesis of N-substituted benzimidazoles.
para-position on benzylamines (Table 3, entries 13–15). Surprisingly, when a methyl-
group on a-position of benzylamine was used, no reaction took place (Table 3, entry
16). This is ascribed probably to the steric interaction between 3-CF3 and a-CH3 in the
cyclization step.
A plausible mechanism for the synthesis of N-1-alkyl-2-unsubstituted benzimidazoles
is proposed. First, the Pd-catalyzed Buchwald-Hartwig coupling reaction occurs between
bromide and amine.[27,41] Then the thermal cyclization proceeds, giving the correspond-
ing benzimidazoles as products (Scheme 2).[42]
Conclusion
In summary, we have demonstrated a novel synthetic methodology involving Pd-cata-
lyzed reactions; the methodology is an efficient way for the synthesis of N-substituted
benzimidazoles. Aromatic formamidines as the starting materials can be simply obtained
in high yields. The products benzimidazoles with various substituents are obtainable in
moderate to good yields. The 2-unsubstituted position of acquired benzimidazoles could
be further elaborated by attaching various substituents.[43–45] This synthetic strategy
may show potential applications in the synthesis of biological and medical compounds.
Experimental
Unless otherwise noted, the chemical materials were purchased from commercial suppli-
ers and used without further purification. The solvents were degassed by burbling with
Argon before use. TLC analysis was performed on precoated plates (silica gel 60 F254)
and visualized by UV light. Flash chromatography was performed with silica gel (mesh
1
200–300) in glass columns. H-NMR, 13C-NMR, and 19F-NMR spectra were obtained
on a Bruker AVANCE NEO 400 MHz spectrometer at ambient temperature. Chemical
shifts were reported in parts per million (d) relative to residual solvent protons as
internal standards. (1H: CDCl3: d ¼ 7.26 ppm; acetone-d6: d ¼ 2.05 ppm. 13C: CDCl3:
d ¼ 77.16 ppm; acetone-d6: d ¼ 29.84 ppm and 206.26 ppm. Multiplicity: s ¼ singlet; d ¼
doublet; t ¼ triplet; q ¼ quartet; br ¼ broad; m ¼ multiplet). All the melting points
were recorded on INESA (SGWX-4B) equipment without corrected. HRMS data were
recorded on Agilent 6530 Accurate-Mass Q-TOF LCMS spectrometer by ESI in positive
mode. X-ray data were obtained on an Agilent SuperNova CCD-based diffractometer
(Cu Ka radiation, k ¼ 1.54184 Å).

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General procedures for synthesis of aromatic formamidines
The raw materials were synthesized according to the literature.[46] The reactions were
performed with different substituted 2-bromoanilines (typically, 0.01 mol) and N,N-
dimethylformamide dimethyl acetal (DMFꢁDMA, 0.02 mol, 2.0 equiv) at 80 ꢀC without
solvent for about 6 h. The reactions were checked by TLC on silica gel plates using a
mixture of petroleum and ethyl acetate as eluent. Then DMFꢁDMA was removed by
high vacuum to generate the product which was used without further purification.
General procedures for synthesis of benzimidazoles
An oven-dried vial (20 mL) equipped with a stir bar was quickly added aromatic formi-
midamide (typically, 0.1 mmol), benzylamine (0.1 mmol, 1.0 equiv), catalyst
(0.005 mmol, 0.05 equiv), ligand (0.01 mmol, 0.1 equiv) and base (0.22 mmol, 2.2 equiv),
placed under a positive pressure of argon, and subjected to three evacuation/backfilling
cycles under high vacuum. The pre-degassed solvent was added, and the reaction mix-
ture was heated at 110 ꢀC for 18 h. The reaction was monitored by TLC using a mixture
of petroleum and ethyl acetate as eluent. After the reaction was completed, the mixture
was cooled to room temperature, added 15 ml H2O, and then extracted with ethyl acet-
ate (3 ꢂ 10 ml). The organic layers were combined and dried over anhydrous Na2SO4.
1
After filtered, ethyl acetate was removed by vacuum. A sample was analyzed by H-
NMR (CDCl3, 400 MHz) and gas chromatography-mass spectrometry (GC-MS) to
obtain yield using internal standard and comparison with authentic samples. The crude
mixture was purified by flash column chromatography with a gradient of petroleum
ether and ethyl acetate to give the pure product.
1
Full experimental detail, H and 13C NMR spectra, Single crystal structure and data
of 3b. This material can be found via the “Supplementary Content” section of this
article’s webpage.
Acknowledgments
The authors are very grateful to Professor Dr. Tiesheng Shi for helping us to polish our manuscript.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
This work was supported by Zaozhuang University and Lunan Institute of Coal Chemical-
engineering Technology Research.
ORCID
Han Cao
http://orcid.org/0000-0001-7470-9213

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F. BIE ET AL.
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