Synthesis of 1,2-disubstituted benzimidazoles using an aza-Wittig-equivalent process

Article abstract of DOI:10.1039/c7ra09010b

A synthetic approach for 1,2-disubstituted benzimidazoles has been successfully designed based on effective C-N bond construction, which demonstrated mild reaction conditions and excellent yields. The method involves treating derivatives of o-phenylenediamine with tert-butanesulfoxide and NBS under acidic conditions, which undergoes an aza-Wittig-equivalent process to afford the desired products. Using this method, a series of benzimidazoles containing multiple functional groups with varying electronic effects have been successfully constructed.

Full text of DOI:10.1039/c7ra09010b

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Synthesis of 1,2-disubstituted benzimidazoles
using an aza-Wittig-equivalent process†
Cite this: RSC Adv., 2017, 7, 44421
*
Yuan Chen, Fanghui Xu and Zhihua Sun
A synthetic approach for 1,2-disubstituted benzimidazoles has been successfully designed based on
effective C–N bond construction, which demonstrated mild reaction conditions and excellent yields. The
method involves treating derivatives of o-phenylenediamine with tert-butanesulfoxide and NBS under
acidic conditions, which undergoes an aza-Wittig-equivalent process to afford the desired products.
Using this method, a series of benzimidazoles containing multiple functional groups with varying
electronic effects have been successfully constructed.
Received 15th August 2017
Accepted 9th September 2017
DOI: 10.1039/c7ra09010b
rsc.li/rsc-advances
Introduction
In recent years, molecules based on 1,2-disubstituted benzimid-
azole have attracted extensive attention due to their wide appli-
cations in new drugs, including antihypertensive drugs, GABAA
receptor agonists and the hepatitis C virus (HCV) NS5B poly-
merase inhibitors.1–3 We have witnessed great progress in the
development of benzimidazole derivatives in recent decades. One
of the key improvements is the effective synthesis of these
functional benzimidazole compounds. The reported methods for
the synthesis of 1,2-disubstituted benzimidazoles mostly include
condensation of anilines with aldehydes under relatively harsh
conditions (Scheme 1a),4 direct oxidative coupling of amines to
imines (Scheme 1b)5 and transition metal-catalyzed intra-
molecular cyclization (Scheme 1c).6 However, the reported
methods mostly employ harsh and strict conditions or expensive
catalysts. Considering that harsh conditions could possibly cause
decomposition of substrates or products, it is signicant to
explore milder conditions for the synthesis of 1,2-disubstituted
benzimidazoles.
Scheme
benzimidazoles.
1
The
synthetic
methods
of
1,2-disubstituted
The synthesis of benzimidazoles involves the construction of
C–N bond, an important class of transformation in organic
synthesis.7,8 Of all C–N bond forming reactions, Schiff base
represents an attractive and robust approach to the synthesis of
nitrogen-containing compounds.9,10 However, in some cases,
the activity of Schiff base reactions is not high enough. In this
regard, assistant groups are introduced to enhance the activity.
Our group recently successfully established an effective C–S
functionalization strategy, and various useful Wittig-like processes
have been developed based on these investigations. For example,
the synthesis of 3-substituted aryl4,5 isothiazoles through an all-
heteroatom Wittig-equivalent process offers a novel approach for
isothiazoles.11 Based on this discovery, we were interested in
investigating the possibility to construct C–N bond in order to
synthesize substituted benzimidazoles with the help of an aza-
Wittig-equivalent process.12 In this respect, the reaction presents
extremely mild conditions compared with the reported methods.
In this work, we use derivatives of o-phenylenediamine with the
help of tert-butanesulfoxide and NBS in acid conditions to
synthesize 1,2-disubstituted benzimidazoles, which demonstrates
a novel synthetic route for functional benzimidazoles.
Results and discussion
College of Chemistry and Chemical Engineering, Shanghai University of Engineering
Science, 333 Longteng Road, Shanghai 201620, China. E-mail: sungaris@gmail.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra09010b
The reaction details are outlined in Table 1. Our research
initially began with the reaction of o-phenylenediamine
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Table
1 Exploration of optimal conditions for synthesizing 1,2-
disubstituted benzimidazoles
N-Halogen
Entry
Acid
Solvent
succinamide
Yield 5a (%)
1
2
3
4
5
6
7
8
TFA
TFA
TFA
TFA
CH2Cl2
THF
Tol
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NCS
NIS
84
52
34
60
25
64
43
48
72
66
75
36
50
68
Scheme 2 The possible mechanism of forming benzimidazole.
DMF
TFA
DMSO
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PTSA
AcOH
PhCOOH
CCl3COOH
TFA
TFA
TFA
TFA
TFA
process. In the beginning, tert-butanesulfoxide reacted with
NBS to afford tert-butanesulnic bromine (3). Subsequently,
tert-butanesulnic bromine reacted with the substrate (1) to
form tert-butanesulnamide (4). Then the sulnyl amide
attacks the carbonyl group to form the intermediate (5). In the
end, by intramolecular rearrangements and charge transfer,
accompanied by the elimination of tert-butanesulnic acid, 1,2-
disubstituted benzimidazole (2) can be formed. Consistent with
this mechanism, the intermediate (4) could be detected by NMR
and HRMS (see ESI†). From the mechanism, we can clearly see
that one of the key steps is the formation and stability of
intermediate (5). When the substrate is less reactive to form 5 or
5 is more inclined to decomposition rather than rearrange-
ments, the product (2) could not be successfully synthesized. It
is worth to note that by treating intermediate (4) in the opti-
mized condition, the yield of benzimidazole could be effectively
enhanced.
With the optimized reaction conditions in hand, a collection
of starting materials (1) bearing various functional or electronic
effecting groups were subjected to the NBS/TFA/CH2Cl2 protocol
to produce 2. As shown in Scheme 3, as expected, when R1 and
R2 are alky or alkoxy groups (2a–2d), the reactions proceed
smoothly and the yields are satisfying (73–80%). It is worthy to
note that for 2a, we obtained the dibromo substituted product,
which is possibly related to the high activity of 1a.
9
10
11
12a
13b
14c
NBS
NBS
NBS
a
The reaction was treated at ꢀ20 ꢁC. b The reaction was treated at 0 ꢁC.
c
The reaction was treated at 40 ꢁC.
derivatives 1 using tert-butanesulfoxide and NBS with the
catalysis of TFA in CH2Cl2. Aer 1 h, the conversion of the
starting material (1) was up to 95% and the product 1,2-disub-
stituted benzimidazole (2) was obtained in a 84% yield (entry 1).
By prolonging the reaction time to 4 h, the conversion would be
close to 100%, and the yield could slightly increase. To optimize
the reaction conditions, we rstly screened the solvents (entry
1–5). The results demonstrated that CH2Cl2 is the best solvent.
As shown in Table 1, other polar or non-polar solvents are not
optimal for this reaction. When THF, toluene and DMF were
introduced as the reaction media, the yields dramatically
decreased, reagent ratio (1/addition/acid ¼ 1/2/1.5).
To further improve the reaction efficiency, we examined the
inuences of the acids in this reaction (entry 6–9). The results
indicated that TFA with the appropriate acidity shows the best
catalysis, while stronger acid or weaker acid would decrease the
yields. It is possible that weaker acids are not suitable to form
the sulnyl halide, while stronger acids would decompose the
intermediates. Furthermore, the N-halogen succinamide in this
reaction could be NBS, NCS or NIS (entry 10–11), which helps to
convert tert-butanesulfoxide to sulnyl halogen. The results
indicated that NBS is the best reagent while NCS and NIS could
also play a similar role with the slightly decreased yields.
Moreover, when the reaction was carried out at ꢀ20 ꢁC, 0 ꢁC or
40 ꢁC,ꢁrespectively, all yields would decrease compared with that
at 25 C (entry 12–14).
Furthermore, substrates with substituent (R1), regardless of
an electron-withdrawing or electron-donating group, could
react smoothly to afford the desired product in high yields
(75–81%) (2e–2g). This reaction also tolerated a range of elec-
tronic effect groups in the substituent (R2) (80–87%), which
enabled potential applications of the nal products in further
functionalization (2h–2j). The substituents (R3) on aromatic
ring present few inuence with the reaction (2k, 2l), and the
yields are excellent. On the other hand, apart from introducing
benzene units to benzimidazoles, we have successfully synthe-
sized heterocycle fused products (2m–2o). However, the yields
are slightly lower than the benzo analogues. Interestingly, the
fused ring product was also obtained in a good yield (2p), which
affords a new route to synthesize novel benzimidazoles. In
comparison, 2k, 2l and 2n could also be obtained without using
According to our previous works, as shown in Scheme 2,
a possible mechanism is based on the aza-Wittig-equivalent
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General procedure for 2a–2o
In a 25 mL vial along with a stirring bar, to a mixture of tert-
butanesulfoxide (1.0 mmol), TFA (0.75 mmol) and NBS
(1.0 mmol) in CH2Cl2 (5 mL) under N2. A CH2Cl2 (5 mL) solution
of 1 (0.5 mmol) was added to the mixture and the reaction was
stirred at RT for additional 1 h. The reaction mixture was
washed with water; dried over anhydrous Na2SO4 and evapo-
rated in vacuo. The residue was puried by silica-gel column
chromatography with CH2Cl2/PE as an eluent. Recrystallization
from CH2Cl2/hexane gave the white solid 2.
1
2a. H NMR (400 MHz, MeOD) d 8.19 (m, 1H), 7.99 (m, 1H),
4.00 (s, 3H), 2.91 (s, 3H). 13C NMR (100 MHz, MeOD) d 154.1,
134.3, 131.4, 129.5, 118.7, 115.0, 106.4, 62.8, 31.0, 10.5. HRMS
[M + H+] m/z ¼ 302.9126, calcd for C9H9N2Br2 ¼ 302.9127.
2b. 1H NMR (400 MHz, DMSO) d 8.12–7.95 (m, 1H), 7.85–7.71
(m, 1H), 7.57–7.39 (m, 2H), 4.95 (s, 1H), 2.82 (s, 3H), 1.64 (d, J ¼
6.9 Hz, 6H). 13C NMR (101 MHz, DMSO) d 125.2, 124.9, 115.3,
114.2, 49.9, 20.8, 13.1.
2c. 1H NMR (400 MHz, DMSO) d 7.51 (d, J ¼ 8.8 Hz, 2H),
7.23–7.08 (m, 2H), 3.35–3.23 (m, 1H), 2.58 (s, 3H), 1.18 (dd, J ¼
6.8, 2.0 Hz, 2H), 1.07–0.95 (m, 2H). 13C NMR (100 MHz, DMSO)
d 154.0, 142.4, 136.5, 121.9, 121.6, 118.7, 110.6, 40.4, 24.8, 14.8.
HRMS [M + H+] m/z ¼ 173.1075, calcd for C11H13N2 ¼ 173.1073.
1
2d. H NMR (400 MHz, MeOD) d 7.62–7.50 (m, 2H), 7.49 (d,
J ¼ 2.8 Hz, 2H), 3.85 (s, 3H), 3.38–3.30 (m, 3H). 13C NMR (100
MHz, MeOD) d 129.7, 128.3, 123.6, 52.8, 36.7.
2e. 1H NMR (400 MHz, CDCl3) d 7.75 (d, J ¼ 7.8 Hz, 1H), 7.58–
7.41 (m, 3H), 7.31 (d, J ¼ 7.4 Hz, 2H), 7.23 (t, J ¼ 7.4 Hz, 1H), 7.15
(t, J ¼ 7.4 Hz, 1H), 7.09 (d, J ¼ 7.8 Hz, 1H), 2.49 (s, 3H). 13C NMR
(100 MHz, CDCl3) d 129.9, 128.8, 127.0, 122.6, 122.4, 118.9,
109.9, 14.3.
Scheme 3 Additional examples of 1,2-disubstituted benzimidazoles
synthesis. Reaction conditions: a mixture of 1 (0.5 mmol), NBS (1.0
mmol), TFA (0.75 mmol), and CH2Cl2 (5 mL) was stirred at room
temperature for 2 h under a nitrogen atmosphere.
2f. 1H NMR (400 MHz, CDCl3) d 7.77 (d, J ¼ 6.2 Hz, 1H), 7.27
(t, J ¼ 7.8 Hz, 3H), 7.20 (s, 1H), 7.09 (t, J ¼ 7.8 Hz, 3H), 3.91 (s,
3H), 2.51 (s, 3H). 13C NMR (100 MHz, CDCl3) d 160.1, 128.3,
122.6, 118.8, 115.1, 110.0, 29.8.
the aza-Wittig process, but the yields were dramatically
decreased (see ESI†), indicating that our new aza-Wittig
protocol may be a very useful complement to the existing
methods of benzimidazole synthesis. However, N-mono-
substituted amide could not be transformed to corresponding
benzimidazole (2q).
2g. 1H NMR (400 MHz, CDCl3) d 7.77 (d, J ¼ 7.8 Hz, 1H), 7.41–
7.34 (m, 2H), 7.29 (dd, J ¼ 10.2, 6.2 Hz, 3H), 7.23 (t, J ¼ 7.4 Hz,
1H), 7.10 (d, J ¼ 7.8 Hz, 1H), 2.52 (s, 4H). 13C NMR (100 MHz,
CDCl3) d 162.4, 152.8, 150.0, 141.3, 135.3, 131.6, 129.0, 128.9,
126.2, 122.8, 120.5, 119.0, 117.1, 111.9, 109.7, 30.4, 24.5.
1
Experimental
Materials and instrumentation
2h. H NMR (400 MHz, DMSO) d 8.07 (dd, J ¼ 6.2, 2.8 Hz,
1H), 8.02 (d, J ¼ 6.8 Hz, 2H), 7.93–7.87 (m, 1H), 7.78 (dq, J ¼
14.4, 7.2 Hz, 3H), 7.69–7.62 (m, 2H), 4.06 (s, 3H). 13C NMR (100
MHz, DMSO) d 150.3, 133.8, 133.1, 131.5, 130.8, 129.7, 126.7,
126.2, 123.3, 114.9, 113.6, 33.2.
All the reactions were performed in oven-dried reaction vessels
under N2. Commercially available solvents and reagents were
used without further purication unless otherwise mentioned.
CH2Cl2, THF, toluene, DMF, DMSO were dried before using.
Thin-layer chromatography (TLC) was carried out on aluminum
sheets coated with silica gel 60 F254 (MERCK). 1H NMR spectra
were obtained using a Bruker AM 400 spectrometer, and
chemical shis were reported relative to DMSO-d6 (d ¼ 2.52),
MeOD (d ¼ 3.34) and CDCl3 (d ¼ 7.26) in ppm. 13C NMR spectra
were recorded at 100 MHz (Bruker AM 400) and chemical shis
were reported relative to DMSO-d6 (d ¼ 40.4), MeOD (d ¼ 49.8)
and CDCl3 (d ¼ 77.00) in ppm. The characterization data of 2b,
2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2m, 2n, 2p could be found in the
previous literature.13
2i. 1H NMR (400 MHz, DMSO) d 7.81 (d, J ¼ 8.8 Hz, 2H), 7.67
(d, J ¼ 7.4 Hz, 1H), 7.58 (d, J ¼ 7.8 Hz, 1H), 7.26 (dd, J ¼ 9.4,
7.8 Hz, 2H), 7.13 (d, J ¼ 8.4 Hz, 2H), 3.86 (d, J ¼ 1.8 Hz, 6H). 13
C
NMR (100 MHz, DMSO) d 160.8, 153.4, 142.9, 137.0, 131.2,
122.9, 122.4, 122.2, 119.2, 114.5, 110.8, 55.8, 32.1.
2j. 1H NMR (400 MHz, DMSO) d 8.07 (d, J ¼ 7.4 Hz, 1H), 7.97–
7.85 (m, 3H), 7.80 (dd, J ¼ 13.8, 7.6 Hz, 1H), 7.66 (dd, J ¼ 9.2,
6.8 Hz, 3H), 4.06 (s, 3H). 13C NMR (101 MHz, DMSO) d 163.4,
161.0, 149.0, 133.9, 132.0, 127.2, 126.7, 126.3, 120.1, 119.9,
118.0, 117.7, 115.2, 113.5, 33.1.
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2k. 1H NMR (400 MHz, DMSO) d 7.83 (dd, J ¼ 7.8, 1.6 Hz, 2H),
7.59–7.49 (m, 4H), 7.18 (d, J ¼ 2.2 Hz, 1H), 6.87 (dd, J ¼ 8.8,
2.4 Hz, 1H), 3.86 (s, 6H). 13C NMR (100 MHz, DMSO) d 156.6,
152.6, 137.7, 137.3, 130.8, 129.7, 129.5, 129.0, 119.9, 94.4, 32.1.
conditions and the yields are excellent. Furthermore, a series of
substituted benzimidazoles containing diverse electronic effect
groups have been successfully obtained based on this method.
Further work towards expanding the use of photoredox catalysis
in the construction of heterocyclic products is underway.
1
2l. H NMR (400 MHz, DMSO) d 7.84 (s, 2H), 7.75–7.66 (m,
1H), 7.59–7.33 (m, 4H), 7.10 (s, 1H), 3.85 (s, 3H). 13C NMR (100
MHz, DMSO) d 160.5, 158.1, 154.4, 139.5, 137.3, 130.4, 129.67
(s), 129.1, 120.4, 110.5, 97.9, 32.3. HRMS [M + H+] m/z ¼
227.0981, calcd for C14H12N2F ¼ 227.0979.
Conflicts of interest
The authors declare no competing nancial interest.
2m. 1H NMR (400 MHz, DMSO) d 8.12 (d, J ¼ 4.7 Hz, 2H), 7.90
(d, J ¼ 7.6 Hz, 1H), 7.78 (d, J ¼ 7.2 Hz, 1H), 7.56–7.35 (m, 3H),
4.12 (s, 3H). 13C NMR (100 MHz, DMSO) d 132.8, 129.1, 125.0,
116.4, 112.4, 32.8.
Acknowledgements
The authors are grateful for nancial support from the Science
and Technology Commission of Shanghai Municipality
(17ZR1412000).
2n. 1H NMR (400 MHz, CDCl3) d 8.62 (d, J ¼ 4.0 Hz, 1H), 7.84
(dd, J ¼ 6.8, 2.8 Hz, 2H), 7.74 (d, J ¼ 7.8 Hz, 1H), 7.59–7.53 (m,
3H), 7.27 (dd, J ¼ 7.2, 4.0 Hz, 1H), 3.92 (s, 3H). 13C NMR (100
MHz, CDCl3) d 155.9, 151.9, 135.4, 130.2, 130.0, 129.7, 129.2,
128.7, 127.3, 117.9, 31.6, 27.0.
Notes and references
2o. 1H NMR (400 MHz, DMSO) d 7.58 (d, J ¼ 7.2 Hz, 1H), 7.52
(d, J ¼ 7.8 Hz, 1H), 7.19 (dd, J ¼ 13.4, 7.2 Hz, 2H), 5.24–4.92 (m,
1H), 3.82 (d, J ¼ 18.8 Hz, 3H), 3.58 (d, J ¼ 6.0 Hz, 1H), 3.45 (d, J ¼
7.2 Hz, 1H), 2.43–2.04 (m, 2H), 2.05–1.83 (m, 2H), 1.36 (s, 4H),
1.01 (s, 5H). 13C NMR (100 MHz, DMSO) d 156.9, 156.3, 153.4,
142.5, 135.9, 122.0, 121.8, 118.9, 110.2, 78.6, 32.9, 28.61, 28.1,
24.2, 23.5. HRMS [M + H+] m/z ¼ 302.1863, calcd for C17H24N3O2
¼ 302.1869.
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(d, J ¼ 1.6 Hz, 1H), 4.13 (t, J ¼ 7.2 Hz, 2H), 3.12 (t, J ¼ 7.8 Hz,
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Synthesis of intermediate 4
In a 25 mL vial along with a stirring bar, to a mixture of tert-
butanesulfoxide (1.0 mmol), TFA (0.75 mmol) and NBS (1.0
mmol) in CH2Cl2 (5 mL) under N2. A CH2Cl2 (5 mL) solution of
1h (0.5 mmol) was added to the mixture and the reaction was
stirred at RT for additional 10 min. The reaction mixture was
washed with water; dried over anhydrous Na2SO4 and evapo-
rated in vacuo. The residue was puried by silica-gel column
chromatography with CH2Cl2/PE as an eluent. Recrystallization
from CH2Cl2/hexane gave the white solid 4.
4. 1H NMR (400 MHz, CDCl3) d 7.32 (t, J ¼ 11.6 Hz, 2H), 7.21–
7.00 (m, 2H), 5.54 (m, 1H), 3.20 (m, 3H), 1.86 (s, 3H), 1.33 (s,
9H). 13C NMR (100 MHz, CDCl3) d 171.9, 171.5, 138.8, 133.6,
133.2, 129.6, 128.5, 123.9, 123.5, 118.9, 118.1, 36.0, 31.9, 29.8,
29.3, 22.6, 22.3, 14.0.
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Conclusions
In summary, by treating the derivatives of o-phenylenediamine
with the help of tert-butanesulfoxide and NBS in the acid
condition, we have demonstrated an effectively intramolecular
cyclization sequence to construct substituted benzimidazoles
containing various alky or aromatic groups, which reveals a new
approach for aza-Wittig-equivalent process. This synthetic
method involves mild conditions instead of reported harsh
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