N-Aryl-2-nitrosoanilines as intermediates in the two-step synthesis of substituted 1,2-diarylbenzimidazoles from simple nitroarenes

Article abstract of DOI:10.1055/s-0030-1260764

N-Aryl-2-nitrosoanilines, easily available from reaction of nitroarenes with anilide anions, undergo base-promoted condensation reaction with substituted benzyl aryl sulfones, furnishing 1,2-diaryl-1H-benzimidazoles. Georg Thieme Verlag Stuttgart - New Yo

Full text of DOI:10.1055/s-0030-1260764

LETTER
1439
N-Aryl-2-nitrosoanilines as Intermediates in the Two-Step Synthesis of
Substituted 1,2-Diarylbenzimidazoles from Simple Nitroarenes
S
ynthesis of Su
b
bstitute
d
1,2
i
g
benzimidazo
n
les from
S
im
i
ple Nit
e
roarenes w Wróbel,*a Karolina Stachowska,a Krzysztof Grudzień,b Andrzej Kwasta
a
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44, 01-224 Warszawa 42, POB 58, Poland
Fax +48(22)6326681; E-mail: wrobel@icho.edu.pl
b
Faculty of Chemistry, University of Warsaw, ul. Pasteura 1, 02-093 Warszawa, Poland
Received 17 January 2011
amines and nitroarenes bearing fluorine or other good
leaving group in the ortho position, followed by the reduc-
tion of the nitro group. In addition, properly substituted
ortho-halonitroarenes may be not easily available, and nu-
cleophilic substitution of ortho-halogens with arylamines
can be difficult, in certain cases.9
Abstract: N-Aryl-2-nitrosoanilines, easily available from reaction
of nitroarenes with anilide anions, undergo base-promoted conden-
sation reaction with substituted benzyl aryl sulfones, furnishing 1,2-
diaryl-1H-benzimidazoles.
Key words: heterocycles, nitroso group, carbanions, condensation,
sulfones, cyclization
In recent times, alternative strategies for the synthesis of
benzimidazoles have been revealed, which involve an N–
C cross-coupling process leading to the formation of the
fused imidazole ring. An intramolecular amination of o-
halo-phenylamidines catalyzed by CuO or cobalt(II) com-
plexes,10 a CuI/L-proline-catalyzed coupling reaction of
primary amines with 2-haloacetanilides,11 and a tandem
amination reaction between 1,2-differentiated dihalo-
arenes and N-substituted amidines12 have been applied
also for the synthesis of 1,2-diaryl derivatives.
Benzimidazoles are heterocyclic compounds of signifi-
cant importance to medicinal chemistry.1 Although those
1,2-disubstituted with aryl groups have been relatively
less frequently reported, there is noticeable interest in
their synthesis due to their potential biological activity
and pharmacological applications. For example, they
have been included in certain drug discovery programs,
such as screening for anti-inflammatory activity2 or selec-
tive ligands for ER-b.3
In our studies on the synthesis of polycyclic nitrogen het-
erocycles from nitroarenes, we explore reactions which
involve intermediate formation of sH adducts of anionic
nucleophiles to the aromatic nitro compounds. Recently,
we have described a reaction of nucleophilic substitution
of hydrogen in nitroarenes with anilines, in which in-
tramolecular oxidation of sH adducts occurs in expense of
the nitro group, which in turn is transformed into a nitroso
group.13 The reaction readily takes place ortho to the nitro
group, leading to variously substituted N-aryl-2-nitroso-
anilines – stable, easy-to-handle compounds, which are
potentially useful intermediates in the synthesis of poly-
cyclic nitrogen heterocycles.
The chemistry of benzimidazoles is covered in several
comprehensive reviews.4 A number of methods reported
for the general synthesis of benzimidazoles have been ap-
plied to obtain those at 1- and 2-positions disubstituted
benzimidazoles, although examples of the synthesis of
1,2-diarylbenzimidazoles are less common. ortho-Phe-
nylenediamine derivatives remain the most popular sub-
strates, and two general methods leading to the
benzimidazole system have been used. One of them in-
volves the condensation of N-arylphenylenediamines with
carboxylic acids, or their equivalents, followed by cy-
clization–dehydratation of the amides formed,3,5 carried
out as a two-step sequence3,5a–5c or in a one-pot process
with the amide generated in situ.5d,e The cyclization step
usually occurs under acidic conditions at elevated temper-
ature.
The value of N-aryl-2-nitrosoanilines in heterocyclic syn-
thesis consists in their structure, containing two nitrogen
functions of opposite reactivity, that is, the nucleophilic
aniline group and the electrophilic nitroso group, located
in proximity. Furthermore, positions of these groups in the
benzene ring are defined towards other substituents,
which is essential for regioselectivity of the formation of
the new heterocyclic ring.
Another common approach involves the condensation of
N-aryl-o-phenylenediamines with aldehydes, followed by
oxidative cyclization of the so-formed imines.6,7 On the
other hand, under reductive conditions, o-nitroanilines
have been used as substrates in direct cyclization reactions
with aldehydes.8
In this paper, we present the synthesis of 1,2-diaryl-1H-
benzimidazoles, which takes advantage of the above fea-
tures
of
N-aryl-2-nitrosoanilines
(Scheme 1,
In most cases, however, the use of N-substituted ortho-
Table 1).Together with the one-step method of prepara-
tion of the latter,13 this provides a new way to 1,2-diaryl-
1H-benzimidazoles, which is one of the shortest, and
starts from simple nitroarenes with no leaving group at
ortho position, required in the majority of other methods.
arylenediamines requires their earlier synthesis from aryl-
SYNLETT 2011, No. 10, pp 1439–1443
x
x
.x
x
.2
0
1
1
Advanced online publication: 26.05.2011
DOI: 10.1055/s-0030-1260764; Art ID: B01811ST
© Georg Thieme Verlag Stuttgart · New York

1440
Z. Wróbel et al.
LETTER
SO2Ar
O
N
N
N
NO2
NH2
R1
H
N
R3
R3
2
ref. 13b
+
base
R2
R1
R1
R2
1
R2
3
Scheme 1
Table 1 Synthesis of 1,2-Diaryl-1H-benzimidazoles 3
Nitrosoaniline 1a
Entry R1 R2
Sulfone 2
Reaction conditionsb
Time (h)c
Benzimidazole 316
1
Ar
R3
2
Base/solvent
DBU/DMFe
DBU/DMFe
DBU/MeCN
DBU/DMF
DBU/DMF
DBU/DMF
DBU/DMF
DBU/DMF
DBU/DMF
DBU/DMF
DBU/DMF
Et3N/DMF
3
Yield (%)d
1
2
4-Cl-2-MeO
4-Cl-2-MeO
4-Cl-2-MeO
4-Cl-2-MeO
4-Cl-2-MeO
4-Cl-2-MeO
4-MeO
4-EtO
4-EtO
4-EtO
4-EtO
4-EtO
4-EtO
4-Me
4-Me
4-Me
4-Me
4-Cl
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1b
Ph
4-O2N
2a
24
1
3a
3b
3b
3c
3d
3e
3f
42
72
31
38
35
51
81
87
76
72
20
60
13
81
46
Tol
Tol
Tol
Ph
2-O2N-5-Cl
2-O2N-5-Cl
2b
2b
3
1
4
2-O2N-4-Me-5-MeO 2c
2
5
2-O2N-4-t-Bu
8-O2N-quinoline-7
3,4-Cl2
2d
2e
2f
2
6
Tol
Ph
2
7
96
2
8
4-MeO
Tol
Tol
Ph
2-O2N-5-Cl
2b
3g
3h
3i
9
4-MeO
2-O2N-4-Me-5-MeO 2c
24
24
1
10
11
12
13
14
15
4-MeO
2-O2N-4-t-Bu
3,4-Cl2
2d
2f
4-Cl
Ph
3j
4-Cl
4-Cl
Tol
Tol
Ph
2-O2N-5-Cl
2-O2N-5-Cl
4-O2N
2b
2b
2a
2g
72
21
6
3k
3k
3l
4-Cl
4-Cl
DBU/DMF
K2CO3/MeCN
NaOHaq/PhMef
4-Cl
4-Cl
4-MeO
4-Me
Tol
H
1.5
3m
a Substituents numbered as in the starting nitroarene and aniline respectively, see Scheme 1.
b Except entry 15, procedure A was used.14,
c Reactions were carried out up to complete conversion of 1 or 2.
d Isolated yields.
e No reaction was observed when Et3N was used instead of DBU.
f Two-phase reaction, procedure B.15
Most likely, and according to the intended strategy, the re- the aniline nucleophile (Scheme 2). Thus, the arylsulfonyl
action of carbanions, generated from substituted benzyl group plays the role of both an elctron-withdrawing group
sulfones, with N-aryl-2-nitrosoanilines 1 consists of the stabilizing the benzylic carbanion and a leaving group in
Ehrlich–Sachs condensation17 with the nitroso group, fol- the addition–elimination step constituting the five-mem-
lowed by a vinylic substitution of the sulfonyl entity with bered ring.
R3
R3
R3
O
N
H
SO2Ar
N–
SO2Ar
–O
SO2Ar
N
[H+]
base
N
N
N
base
+
2
H
N
H
N
3
– H2O
– SO2Ar–
R2
R1
R1
R1
R1
R2
R2
R2
1
Scheme 2
Synlett 2011, No. 10, 1439–1443 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted 1,2-Diarylbenzimidazoles from Simple Nitroarenes
1441
Although nitrosoanilines 1 are powerful electrophiles, The observations, based on the limited number of results
they are also strong NH acids, which under basic condi- in Table 1, seem to roughly support the predicted relation-
tions form anions, lacking their electrophilic activity. The ship between the acidity of both reagents and the observed
positive result of the reaction could be expected when efficiency of the reactions. However, since the reaction is
acidity of both reagents is balanced, and the base used is multistage, also other aspects may have important influ-
appropriate to acquire sufficient concentration of the car- ence on its course. For example, the rate of the elimination
banion of 2 and, at the same time, to retain no less than a of water molecule from the initial adduct (Scheme 2), sup-
fraction of the nitrosoaniline 1 neutral. Therefore, only posedly strongly depended on structural factors and reac-
acidic enough benzylic sulfones 2 and rather weak bases tion conditions, may govern the whole process
could be used in the reaction.
considerably. Moreover, since more acidic sulfones are
precursors of less reactive carbanions, and less acidic ni-
trosoanilines are believed to be also less electrophilic, the
acid/base do not sufficiently explain the actual reaction
course, and the results of any particular reaction may be
difficult to predict. Apparently, also some side reactions
play an important role and could be responsible for the ob-
served low yield of the product despite of fast conversion
of 1 (entry 11).
Following the above considerations, a choice of benzylic
sulfones substituted with the nitro group in the aromatic
ring (2a–e), and two other, much less acidic (2f and 2g)
were subjected to the reaction with a few, differently sub-
stituted nitrosoanilines (1a–c). After a very brief search-
ing, DBU in DMF was chosen as a base/solvent system
for most of the experiments.14 While these reaction condi-
tions were not optimized for individual pairs of reactants,
selected reactions were attempted to proceed under differ- The starting nitrosoarenes 1 as well as benzylic sulfones 2
ent conditions. All reactions were performed at room tem- are easily available. Those of the latter, which are substi-
perature, up to complete conversion of the starting tuted with a nitro group, can be obtained by vicarious nu-
nitrosoaniline. Although, for that reason, particular reac- cleophilic substitution of hydrogen (VNS) in appropriate
tion times combined with their yields do not reflect direct- nitroarenes with chloromethyl aryl sulfones.18 By using
ly rates of these reactions, a comparison of the results the method described here, one can obtain highly substi-
allows for cautious formulating of some comments.
tuted 1,2-diaryl-1H-benzimidazoles, suitable for further
transformations and functionalization.
For nitrosoaniline 1b, which is the less acidic substrate
among being examined, satisfactory results were obtained The presented synthesis of 1,2-diarylbenzimidazoles ex-
in the reactions carried out in the DBU/DMF system (en- hibits several features making it fairly distinctive among
tries 7–10), with the rates of the overall reactions follow- the others. The reaction occurs under very mild basic con-
ing roughly the anticipated acidity of the benzylic ditions, which may be suitable for reagents with labile,
sulfones (2b > 2c = ca. 2d > 2f). On the other hand, for ni- acid-sensitive substituents. Although sometimes pro-
trosoaniline 1c, assumed as the most acidic one, such rel- longed, the reaction is carried out at room temperature.
atively strong basic system did not work well (entries 11 Further advantages of the reaction are clear, when it is
and 13). The reactions produced complex mixtures, and considered as a part of the entire two-step synthetic route
low yields of the desired benzimidazoles. A weaker base, starting from simple nitroarenes (Scheme 1). Thus, the
such as triethylamine or potassium carbonate in acetoni- starting nitroarenes do not need to bear any leaving group,
trile, yielded better results (entries 12 and 14). Apparent- such as halogens, at ortho position, so they are much more
ly, such bases provided low concentration of carbanions easily available. Furthermore, there are no reducing or
of 2, at the same time as 1c was not completely deproto- oxidazing agents involved in the synthesis, therefore it is
nated, thus, suitable for nucleophilic addition.
presumably compatible with substrates sensitive to those
processes.
Intermediate, as to acidity, 1a reacted easily in the DBU/
DMF system, but the yields of the reactions were rather The communication is a preliminary account of the new
moderate and seem to depend on the acidity of the benzyl- strategy of synthesis of 1,2-disubstituted benzimidazoles.
ic sulfones (2b, 2e > 2c, 2d). Noteworthy, triethylamine in This approach is presently a subject of our effort directed
DMF did not work properly in attempted reactions of 1a to extend its scope regarding nitrosoarenes and carbanion-
with sulfones 2a and 2b, giving not more than traces of the ic reactants of general formula RCH2Y which could be
products after 24 hours of the reaction. This suggests that used as more versatile reagents for the synthesis of 2-sub-
for the reaction of nitrosoaniline 1b considerably higher stituted derivatives of N-arylbenzimidazoles.
concentration of the carbanion than in the case of 1c is re-
quired.
References and Notes
When the less acidic benzyl tolyl sulfone (2g) was sub-
jected to the reaction with 1b, after several attempts with
other base/solvent couples, the best yield was obtained in
the catalytic two-phase system 50% NaOH/toluene/
tetrabutylammonium bromide, according to procedure B
(entry 15).15
(1) (a) Spasov, A. A.; Yozhitsa, I. N.; Bugaeva, L. I.;
Anisimova, V. A. Pharm. Chem. J. 1999, 33, 232.
(b) Preston, P. N. Chem. Heterocycl. Compd. 1980, 40, 531.
(2) Evans, D.; Hicks, T. A.; Williamson, W. R. N.; Dawson, W.;
Meacock, S. C. R.; Kitchen, E. A. Eur. J. Med. Chem. 1996,
31, 635.
(3) Chesworth, R.; Wessel, M. D.; Heyden, L.; Mangano, F. M.;
Zawistoski, M.; Gegnas, L.; Galluzzo, D.; Lefker, B.;
Synlett 2011, No. 10, 1439–1443 © Thieme Stuttgart · New York

1442
Z. Wróbel et al.
LETTER
evaporated. The mixture was subjected to column
chromatography (SiO2, hexane–EtOAc), and the crude 3m
was recrystallized from EtOAc.
Cameron, K. O.; Tickner, J.; Lu, B.; Castleberry, T. A.;
Petersen, D. N.; Brault, A.; Perry, P.; Ng, O.; Owen, T. A.;
Pan, L.; Ke, H. Z.; Brown, T. A.; Brown, T. A.; Thompson,
D. D.; DaSilva-Jardine, P. Bioorg. Med. Chem. Lett. 2005,
15, 5562.
(16) Analytical Data for the Products 3a–m
6-Chloro-1-(4-ethoxyphenyl)-4-methoxy-2-(4-
(4) (a) Grimmett, M. R. Product Class 4: Benzimidazoles, In
Science of Synthesis; Neier, R., Ed.; Springer: New York,
2002, 529. (b) Preston, P. N. Chem. Rev. 1974, 74, 279.
(5) (a) Yun, Y. K.; Porco, J. A.; Labadie, J. Synlett 2002, 739.
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Wyatt, A. R. II.; Stockett, A. S.; Ritschdorff, E. T.; Shear,
J. B.; Bielawski, C. W. J. Am. Chem. Soc. 2008, 130, 3143.
(c) Lin, S.-Y.; Isome, Y.; Stewart, E.; Liu, J.-F.; Yohannes,
D.; Yu, L. Tetrahedron Lett. 2006, 47, 2883. (d) Wang, Y.;
Sarris, K.; Sauer, D. R.; Djuric, S. W. Tetrahedron Lett.
2006, 47, 4823. (e) Hendrickson, B. J.; Hussoin, M. S.
J. Org. Chem. 1989, 54, 1144.
(6) (a) Beaulieu, P. L.; Hache, B.; von Moos, E. Synthesis 2003,
1683. (b) Chakrabatry, M.; Karmakar, S.; Mukherjee, R.;
Arima, S.; Harigaya, Y. Monatsh. Chem. 2009, 140, 375.
(c) Goeker, H.; Alp, M.; Yildiz, S. Molecules 2005, 10,
1377. (d) Bressi, J. C.; Jong, R. de; Wu, Y.; Jennings, A. J.;
Brown, J. W.; O’Connell, S.; Tari, L. W.; Skene, R. J.; Vu,
Ph.; Navre, M.; Cao, X.; Gangloff, A. R. Bioorg. Med.
Chem. Lett. 2010, 20, 3138. (e) Lai, M.-Y.; Chen, C.-H.;
Huang, W.-S.; Lin, J. T.; Ke, T.-H.; Chen, L.-Y.; Tsai,
M.-H.; Wu, C.-C. Angew. Chem. Int. Ed. 2008, 47, 581.
(f) Liu, K.; Yin, D. Org. Lett. 2009, 11, 637.
nitrophenyl)-1H-benzimidazole (3a)
Yellow crystals, mp 211–212 °C. 1H NMR (400 MHz,
CDCl3): d = 1.37 (t, J = 7.0 Hz, 3 H), 4.03 (s, 3 H), 4.10 (q,
J = 7.0 Hz, 2 H), 6.74 (d, J = 1.8 Hz, 1 H), 6.92 (d, J = 1.8
Hz, 1 H), 7.09–7.13 (m, 2 H), 7.38–7.43 (m, 2 H), 7.75–7.79
(m, 2 H), 8.21–8.25 (m, 2 H). 13C NMR (100 MHz, CDCl3):
d = 14.6, 56.3, 63.5, 103.2, 105.4, 115.8, 123.6, 127.9,
128.7, 129.2, 130.0, 131.6, 135.6, 139.2, 147.6, 149.0,
151.8, 159.0. MS (EI): m/z (%) = 423 (95) [M+], 422 (100),
394 (43), 376 (9), 348 (13). Anal. Calcd for C22H18O4N3Cl:
C, 62.3; H, 4.3; N, 9.9. Found: C, 62.3; H, 4.3; N, 9.8.
6-Chloro-2-(5-chloro-2-nitrophenyl)-1-(4-
ethoxyphenyl)-4-methoxy-1H-benzimidazole (3b)
Yellow solid, mp 145–148 °C. 1H NMR (400 MHz, DMSO-
d6): d = 1.33 (t, J = 7.0 Hz, 3 H), 4.00 (s, 3 H), 4.04 (q,
J = 7.0 Hz, 2 H), 6.84 (d, J = 1.8 Hz, 1 H), 6.93 (d, J = 1.8
Hz, 1 H), 6.99–7.04 (m, 2 H), 7.23–7.28 (m, 2 H), 7.83 (dd,
J = 8.7, 2.3 Hz, 1 H), 7.89 (d, J = 2.3 Hz, 1 H), 8.09 (d,
J = 8.7 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6): d = 14.5,
56.3, 63.4, 103.02, 105.3, 115.5, 126.4, 126.5, 126.6, 128.2,
129.0, 131.3, 131.5, 132.7, 137.7, 138.2, 146.9, 147.1,
151.7, 158.7. MS (EI): m/z (%) = 459 (70), 457 (100) [M+],
428 (23), 409 (13), 289 (34), 261 (45). HRMS (EI): m/z calcd
for C22H17O4N335Cl2 [M]+: 457.0596; found: 457.0611.
6-Chloro-2-(5-methoxy-4-methyl-2-nitrophenyl)-1-(4-
ethoxyphenyl)-4-methoxy-1H-benzimidazole (3c)
Creamy powder, mp 175–176 °C (hexane–EtOAc). 1H NMR
(600 MHz, DMSO-d6): d = 1.32 (t, J = 7.0 Hz, 3 H), 2.23 (s,
3 H), 3.87 (s, 3 H), 4.00 (s, 3 H), 4.02 (q, J = 7.0 Hz, 2 H),
6.81 (d, J = 1.7 Hz, 1 H), 6.92 (d, J = 1.7 Hz, 1 H), 6.96–6.99
(7) Benzylic alcohols have been used instead of aldehydes, with
MnO2 as a double oxidant. See: Wilfred, C. D.; Taylor, R. J.
K. Synlett 2004, 1628.
(8) Yang, D.; Fokas, D.; Li, J.; Yu, L.; Baldino, C. M. Synthesis
2005, 47.
(9) Hornberger, K. R.; Badiang, J. G.; Salovich, J. M.; Kuntz, K.
W.; Emmitte, K. A.; Cheung, M. Tetrahedron Lett. 2008, 44,
6348.
(m, 2 H), 7.20–7.24 (m, 2 H), 7.31 (s, 1 H), 7.94 (s, 1 H). 13
C
(10) (a) Saha, P.; RamanaT, ; Purkait, N.; Ali, Md.. A.; Paul, R.;
Punniyamurthy, T. J. Org. Chem. 2009, 74, 8719. (b) Saha,
P.; Ali, Md.. A.; Ghosh, P.; Punniyamurthy, T. Org. Biomol.
Chem. 2010, 8, 5692.
(11) (a) Zheng, N.; Anderson, K. W.; Huang, X.; Nguyen, H. N.;
Buchwald, S. L. Angew. Chem. Int. Ed. 2007, 46, 7509.
(b) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem. Int. Ed. 2007,
46, 2598. (c) Diao, X.; Wang, Y.; Jiang, Y.; Ma, D. J. Org.
Chem. 2009, 74, 7974.
NMR (125 MHz, CDCl3): d = 14.7, 16.1, 56.1, 56.3, 63.7,
103.5, 104.9, 113.7, 115.2, 125.7, 127.1, 127.2, 128.0,
129.5, 129.9, 131.7, 137.9, 140.7, 149.4, 151.7, 158.9,
161.2. MS (EI): m/z (%) = 467 (100) [M+], 438 (14), 289
(68), 178 (21). HRMS (EI): m/z calcd for C24H22O5N335Cl
[M]+: 467.1248; found: 467.1256.
6-Chloro-2-(4-tert-butyl-2-nitrophenyl)-1-(4-
ethoxyphenyl)-4-methoxy-1H-benzimidazole (3d)
Yellow powder, mp 162–163 °C. 1H NMR (500 MHz,
DMSO-d6): d = 1.18 (t, J = 7.1 Hz, 3 H), 1.31 (s, 9 H), 3.99
(s, 3 H), 4.03 (q, J = 7.1 Hz, 2 H), 6.81 (d, J = 1.8 Hz, 1 H),
6.91 (d, J = 1.8 Hz, 1 H), 6.99–7.03 (m, 2 H), 7.25–7.28 (m,
2 H), 7.60 (d, J = 8.1 Hz, 1 H), 7.81 (dd, J = 8.1, 1.9 Hz, 1
H), 7.98 (d, J = 1.9 Hz, 1 H). 13C NMR (100 MHz, DMSO-
d6): d = 14.0, 30.5, 35.0, 56.2, 63.4, 103.0, 105.2, 115.4,
121.1, 122.0, 126.9, 128.2, 128.7, 130.3, 131.5, 132.5,
137.9, 148.1, 148.9, 151.5, 154.5, 158.6. MS (EI): m/z
(%) = 479 (100) [M+], 450 (19), 289 (59) 260 (53). HRMS
(EI): m/z calcd for C26H26O4N335Cl [M]+: 479.1612; found:
479.1606.
(12) Deng, X.; Mani, N. S. Eur. J. Org. Chem. 2010, 680.
(13) (a) Wróbel, Z.; Kwast, A. Synlett 2007, 1525. (b) Wróbel,
Z.; Kwast, A. Synthesis 2010, 3865.
(14) Procedure A
To a solution of the nitrosoaniline 1 (0.5 mmol) and the
sulfone (0.6 mmol) in a specified solvent (3 mL or 6 mL in
the case of K2CO3 used as base) DBU (0.3 mL), Et3N (0.3
mL), or K2CO3 (700 mg) was added, according to Table 1,
and the mixture was stirred at r.t. for the time specified in
Table 1. In the case when K2CO3 was used, it was then
filtered off. The mixture was poured into 10% HCl aq (ca. 50
mL) and extracted with EtOAc. The extract was washed with
H2O and brine and dried with Na2SO4. After evaporation, the
crude product mixture was subjected to column
7-[6-Chloro-4-methoxy-1-(4-ethoxyphenyl)-1H-
benzimidazol-2-yl]-8-nitroquinoline (3e)
Pale yellow crystals, mp 127–130 °C (hexane–EtOAc). 1H
NMR (500 MHz, DMSO-d6): d = 1.31 (t, J = 7.0 Hz, 3 H),
4.02 (q, J = 7.0 Hz, 2 H), 4.04 (s, 3 H), 6.88 (d, J = 1.7 Hz,
1 H), 6.95 (d, J = 1.7 Hz, 1 H), 7.02–7.05 (m, 2 H), 7.33–
7.36 (m, 2 H), 7.52 (d, J = 8.6 Hz, 1 H), 7.80 (dd, J = 8.4, 4.1
Hz, 1 H), 8.15 (d, J = 8.6 Hz, 1 H), 8.55 (dd, J = 8.4, 1.5 Hz,
1 H), 9.09 (dd, J = 4.1, 1.5 Hz, 1 H). 13C NMR (125 MHz,
DMSO-d6): d = 14.9, 56.8, 63.9, 103.6, 106.1, 116.0, 123.0,
124.7, 127.3, 127.4, 128.7, 129.2, 130.0, 130.8, 132.1,
chromatography (SiO2, hexane–EtOAc).
(15) Procedure B
A solution of nitrosoaniline 1b (163 mg, 0.614 mmol) and
benzyl tolyl sulfone (184 mg, 0.75 mmol) in toluene (3 mL)
was vigorously stirred with 50% NaOH (1 mL) and TBAB
(30 mg) at r.t. for 1.5 h. The mixture was then diluted with
H2O (100 mL) and extracted with EtOAc. The extracts were
washed with H2O three times, dried with Na2SO4, and
Synlett 2011, No. 10, 1439–1443 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted 1,2-Diarylbenzimidazoles from Simple Nitroarenes
72.3; H, 6.1; N, 10.1. Found: C, 72.1; H, 6.2; N, 9.9.
1443
137.0, 138.6, 138.7, 146.2, 148.1, 152.2, 154.0, 159.3. MS
(EI): m/z (%) = 474 (100) [M+], 429 (31), 289 (59), 261 (66),
6-Chloro-1-(4-chlorophenyl)-2-(3,4-dichlorophenyl)-1H-
benzimidazole (3j)
155 (25). HRMS (EI): m/z calcd for C25H19O4N435Cl [M]+:
474.1095; found: 474.1089.
Yellow solid, mp 176–178 °C. 1H NMR (400 MHz, DMSO-
d6): d = 7.29 (d, J = 2.2 Hz, 1 H), 7.37 (dd, J = 8.4, 2.2 Hz, 1
H), 7.38 (dd, J = 8.8, 2.2 Hz, 1 H), 7.54–7.58 (m, 2 H), 7.66–
7.70 (m, 3 H), 7.79 (d, J = 2.2 Hz, 1 H), 7.84 (d, J = 8.8 Hz,
1 H). 13C NMR (100 MHz, DMSO-d6): d = 111.0, 121.5,
124.0, 128.9, 129.5, 129.9, 130.2, 130.7, 131.2, 131.5,
131.8, 133.2, 134.4, 134.8, 138.1, 141.6, 151.0. MS (EI):
m/z (%) = 408 (100), 407 (89), 406 (76) [M+], 372 (20), 370
(20), 336 (7). Anal. Calcd for C19H10N2Cl4: C, 55.9; H, 2.5;
N, 6.9. Found: C, 55.9; H, 2.7; N, 6.8.
2-(3,4-Dichlorophenyl)-6-methoxy-1-(4-methylphenyl)-
1H-benzimidazole (3f)
Yellow crystals, mp 173–177 °C (hexane–EtOAc). 1H NMR
(400 MHz, DMSO-d6): d = 2.42 (s, 3 H), 3.73 (s, 3 H), 6.61
(d, J = 2.3 Hz, 1 H), 6.95 (dd, J = 8.8, 2.3 Hz, 1 H), 7.32–
7.36 (m, 3 H), 7.39–7.46 (m, 2 H), 7.62 (d, J = 8.4 Hz, 1 H),
7.68 (d, J = 8.8 Hz, 1 H), 7.74 (d, J = 2.0 Hz, 1 H). 13C NMR
(100 MHz, DMSO-d6): d = 20.8, 55.5, 93.3, 112.7, 120.2,
127.2, 128.5, 130.4, 130.5, 130.6, 130.7, 131.1, 131.9,
133.4, 136.7, 137.9, 138.7, 148.4, 157.0. MS (EI): m/z
(%) = 384 (71), 382 (100) [M+], 367 (64), 159 (41). Anal.
Calcd for C21H16ON2Cl2: C, 65.8; H, 4.2; N, 7.3. Found: C,
65.6; H, 4.2; N, 7.3.
6-Chloro-1-(4-chlorophenyl)-2-(5-chloro-2-
nitrophenyl)-1H-benzimidazole (3k)
Pale yellow crystals, mp 148–149 °C (hexane–EtOAc). 1H
NMR (400 MHz, CDCl3): d = 7.15–7.18 (m, 2 H), 7.27 (d,
J = 1.9 Hz, 1 H), 7.35 (dd, J = 8.6, 1.9 Hz, 1 H), 7.40–7.43
(m, 2 H), 7.58 (dd, J = 2.3, 8.8 Hz, 1 H), 7.68 (d, J = 2.3 Hz,
2-(5-Chloro-2-nitrophenyl)-6-methoxy-1-(4-
methylphenyl)-1H-benzimidazole (3g)
Yellow crystals, mp 155–158 °C (hexane–EtOAc). 1H NMR
(400 MHz, DMSO-d6): d = 2.34 (s, 3 H), 3.75 (s, 3 H), 6.73
(d, J = 2.2 Hz, 1 H), 6.96 (dd, J = 8.8, 2.2 Hz, 1 H), 7.22–
7.26 (m, 2 H), 7.28–7.34 (m, 2 H), 7.68 (d, J = 8.8 Hz, 1 H),
7.80 (dd, J = 8.8, 2.3 Hz, 1 H), 7.84 (d, J = 2.3 Hz, 1 H), 8.06
(d, J = 8.8 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6):
d = 20.6, 55.6, 93.3, 112.7, 120.4, 126.4, 126.6, 127.1,
130.4, 131.0, 132.1, 132.5, 136.6, 136.9, 137.9, 138.4,
146.2, 147.2, 157.1. MS (EI): m/z (%) = 393 (38) [M+], 348
(9), 225 (100), 182 (20). Anal. Calcd for C21H16N3O3Cl: C,
64.0; H, 4.1; N, 10.7. Found: C, 63.8; H, 4.2; N, 10.6.
6-Methoxy-2-(5-methoxy-4-methyl-2-nitrophenyl)-1-(4-
methylphenyl)-1H-benzimidazole (3h)
1 H), 8.62 (d, J = 8.6 Hz, 1 H), 7.99 (d, J = 8.8 Hz, 1 H). 13
NMR (100 MHz, CDCl3): d = 110.5, 121.5, 124.3, 126.2,
127.2, 128.1, 130.3, 130.4, 131.1, 132.9, 133.0, 135.3,
C
136.6, 140.1, 141.5, 146.7, 148.4. MS (EI): m/z (%) = 419
(24), 417 (25) [M+], 372 (27), 249 (100), 214 (22), 169 (16),
138 (18), 111 (28). HRMS (EI): m/z calcd for
C19H10O2N335Cl3 [M]+: 416.9839; found: 416.9842.
6-Chloro-1-(4-chlorophenyl)-2-(2-nitrophenyl)-1H-
benzimidazole (3l)
Yellow crystals, mp 274–275 °C (MeOH). 1H NMR (400
MHz, CDCl3): d = 7.23 (d, J = 2.0 Hz, 1 H), 7.25–7.29 (m, 2
H), 7.36 (dd, J = 8.8, 2.0 Hz, 1 H), 7.53–7.58 (m, 2 H), 7.72–
7.76 (m, 2 H), 7.81 (d, J = 8.8 Hz, 1 H), 8.18–8.22 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 110.6, 121.3, 123.7,
124.6, 128.4, 130.1, 130.5, 130.8, 134.3, 135.2, 135.7,
137.7, 141.4, 148.2, 150.3. MS (EI): m/z (%) = 383 (100)
[M+], 336 (39), 302 (15), 266 (12). HRMS (EI): m/z calcd for
C19H11O2N335Cl2 [M]+: 383.0228; found: 383.0216.
6-Methoxy-1-(4-methylphenyl)-2-phenyl-1H-
Yellow crystals, mp 200–201 °C (EtOH). 1H NMR (500
MHz, CDCl3): d = 2.26 (s, 3 H), 2.37 (s, 3 H), 3.80 (s, 3 H),
3.91 (s, 3 H), 6.73 (d, J = 2.3 Hz, 1 H), 6.99 (dd, J = 8.8, 2.3
Hz, 1 H), 7.04–7.08 (m, 3 H), 7.17 (m, 2 H), 7.76 (d, J = 8.8
Hz, 1 H), 7.80 (d, J = 0.8 Hz, 1 H). 13C NMR (125 MHz,
CDCl3): d = 16.1, 21.2, 55.9, 56.2, 93.8, 112.5, 113.5, 120.5,
126.0, 126.5, 127.1, 129.4, 130.2, 132.6, 136.9, 137.1,
138.5, 140.8, 148.9, 157.4, 161.2. MS (EI): m/z (%) = 403
(50) [M+], 361 (16), 225 (100), 182 (15). Anal. Calcd for
C23H21N3O4: C, 68.5; H, 5.2; N, 10.4. Found: C, 68.4; H, 5.2;
N, 10.4.
benzimidazole (3m)
Solid, mp 166–167 °C (EtOAc). 1H NMR (500 MHz,
DMSO-d6): d = 2.40 (s, 3 H), 3.72 (s, 3 H), 6.61 (d, J = 2.4
Hz, 1 H), 6.93 (dd, J = 8.8, 2.4 Hz, 1 H), 7.28–7.39 (m, 7 H),
7.47–7.50 (m, 2 H), 7.67 (d, J = 8.8 Hz, 1 H). 13C NMR (125
MHz, DMSO-d6): d = 20.7, 55.5, 93.4, 112.1, 119.9, 127.2,
128.3, 128.8, 129.1, 130.1,130.5, 133.9, 136.9, 137.8, 138.3,
150.9, 156.6. MS (EI): m/z (%) = 314 (100) [M+], 299 (50).
Anal. Calcd for C21H18ON2: C, 80.2; H, 5.8; N, 8.9. Found:
C, 79.9; H, 5.7; N, 8.9.
2-(4-tert-Butyl-2-nitrophenyl)-6-methoxy-1-(4-
methylphenyl)-1H-benzimidazole (3i)
Yellow crystals, mp 184–188 °C (hexane–EtOAc). 1H NMR
(400 MHz, DMSO-d6): d = 1.31 (s, 9 H), 2.34 (s, 3 H), 3.75
(s, 3 H), 6.70 (d, J = 2.3 Hz, 1 H), 6.94 (dd, J = 8.8, 2.3 Hz,
1 H), 7.24–7.33 (m, 4 H), 7.54 (d, J = 8.1 Hz, 1 H), 7.65 (d,
J = 8.8 Hz, 1 H), 7.77 (dd, J = 8.1, 1.9 Hz, 1 H), 7.96 (d,
J = 1.9 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6): d = 20.7,
30.5, 35.0, 55.6, 93.4, 112.4, 120.2, 121.0, 122.5, 126.6,
130.1, 130.4, 132.3, 132.5, 136.6, 137.0, 138.2, 147.4,
149.1, 154.2, 156.8. MS (EI): m/z (%) = 415 (53) [M+], 370
(17), 225 (100), 182 (13). Anal. Calcd for C25H25N3O4: C,
(17) Feuer, H. In The Chemistry of the Nitro and Nitroso Groups,
Part 1; Patai, S., Ed.; Wiley: New York, 1969, 278.
(18) (a) Mąkosza, M.; Winiarski, J. Acc. Chem. Res. 1987, 20,
282. (b) Mąkosza, M.; Goliński, J.; Baran, J. J. Org. Chem.
1984, 49, 1488. (c) Mąkosza, M.; Kinowski, A.;
Danikiewicz, W.; Mudryk, B. Liebigs Ann. Chem. 1986, 69.
Synlett 2011, No. 10, 1439–1443 © Thieme Stuttgart · New York