Efficient method for the synthesis of fused benzimidazole-imidazoles via deprotection and cyclization reactions

Article abstract of DOI:10.1016/j.tet.2015.09.008

A fused benzimidazole-imidazole scaffold was designed and synthesized using a facile procedure involving deprotection and cyclization reactions. The acidic conditions and high yields for the benzimidazole ring closure allow potential application of this e

Full text of DOI:10.1016/j.tet.2015.09.008

Tetrahedron xxx (2015) 1e4
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient method for the synthesis of fused
benzimidazoleeimidazoles via deprotection and cyclization
reactions
Zhong-Zhu Chen, Shi-Qiang Li, Wen-Li Liao, Zhi-Gang Xie, Ming-Shu Wang, Yun Cao,
*
*
Jin Zhang , Zhi-Gang Xu
International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing,
402160, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2015
Received in revised form 1 September 2015
Accepted 3 September 2015
Available online xxx
A fused benzimidazoleeimidazole scaffold was designed and synthesized using a facile procedure in-
volving deprotection and cyclization reactions. The acidic conditions and high yields for the benzimid-
azole ring closure allow potential application of this efficient methodology for the design and synthesis
of a range of bioactive compounds.
Ó 2015 Published by Elsevier Ltd.
Keywords:
Benzimidazoles
Imidazoles
Imidazole-4,5-dicarboxamide
Deprotection
Cyclization
1. Introduction
Benzimidazoles are important heterocycles and structurally
related to purine bases. They were found in a variety of natural and
synthetic products, with numerous biological activities and func-
tions such as antibacterial,1 anticancer,2 antihelminthic,3 antifun-
gal,4 antiallergic,5 antimicrobial,6 antiviral,7 and antineoplastic
activities.8 The ring system of benzimidazole can be considered as
a new device for the target-specific transcription aspect at binding
sites related to biological systems. Some representative benzimi-
dazoleeimidazole conjugates are shown in Fig. 1.
Compounds 1 and 2, with modifications to the imidazole ring,
have functions as mitochondrial apoptosis inducers and inhibitors
of both tubulin polymerization and the PI3K/Akt pathway, respec-
tively.2c,9 Modification of the benzimidazole group in compounds 4
and 5 gives rise to nitric oxide synthase (NOS) inhibitors and an-
tibacterial agents.10 Compounds 1e5 can be synthesized by the
reaction of phenylene-1,2-diamine 3 with aldehydes,11 and com-
Fig. 1. Bioactive fused benzimidazoleeimidazole compounds.
pound
condensation of
6
can be obtained from
a
three-component cyclo-
-hydroxyketone or a-
a
1,2-diketone, an
a
ketomonoxime with an aldehyde and ammonium acetate, under
microwave irradiation.12 In our previous reports,13 N-Boc-phenyl-
ene-1,2-diamine could effect closure of the benzimidazole ring in
acidic solvents. The design and synthesis of second-generation
oligomeric imidazole-4,5-dicarboxamide (I45DCs) for the
* Corresponding authors. Tel.: þ86 023 61162838; fax: þ86 023 61162836; e-mail
addresses: hxxzj2282@163.com (J. Zhang), xuzhigangyours@yahoo.com (Z.-G. Xu).
http://dx.doi.org/10.1016/j.tet.2015.09.008
0040-4020/Ó 2015 Published by Elsevier Ltd.
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2
Z.-Z. Chen et al. / Tetrahedron xxx (2015) 1e4
inhibition of proteineprotein interactions (PPI) was reported by Dr.
Baures.14 Herein, we describe our most recent work towards the
development of a novel strategy for the construction of fused
benzimidazoleeimidazoles using oligomeric imidazole-4,5-
dicarboxamide (I45DCs) as one of the starting materials.
2. Discussion
Acid chloride 7 was treated with Boc-diamine 8 at ꢀ78 ꢁC to
afford compound 9 in 89% yield (Scheme 1). Compound 9 was then
reacted with a range of amines in DCM at room temperature. The
solvent was then removed and crude compound 10 was used for
the next reaction without further purification. The residue was
diluted with 10% TFA/DCE and heated at 120 ꢁC for 10 min under
microwave irradiation to afford compound 11 in good yield. Com-
pound 12 contains two imidazole positions (A and B) that could be
modified. Position A could also be modified in structure of com-
pound 10, so these two positions could be selectively functionalized
in different steps. A range of amines, including an amino acid ester,
was reacted, and gave products 12aeg in 56e69% yield. This facile
procedure would be suitable for the synthesis of a range of com-
pounds for use in high-throughput screening.
Scheme 2. Synthesis of compounds 15aec.
From Scheme 2, the use of Boc-diamine allows the formation of
two benzimidazole groups in one step. Based on this idea, diamine
16 was used to link two I45DC functional groups together to afford
17 (Scheme 3). The imidazole group in compound 17 could still be
modified in this step. The next deprotection and cyclization steps
were carried out under microwave irradiation at 120 ꢁC for 10 min
to give 18aef in 42e65% yield over two steps in a one-pot pro-
cedure. These compounds containing four imidazole groups were
very polar and purified by recrystallization from ethyl acetate.
3. Discussion
In summary, we have demonstrated a facile and efficient pro-
cedure for the synthesis of fused benzimidazoleeimidazoles. This
procedure provides opportunities for the selective modification of
the imidazole groups in two different steps as marked in positions
A and B in compound 11. Biological screening results will provide
insights into which way the structures should be modified to im-
prove the bioactivity.
4. Experimental section
4.1. General procedures for compound 12
To a suspension of acid chloride 7 (1.56 g, 5.0 mmol) and N,N-
diethylaniline (1.60 mL, 10 mmol) in DCM (40 mL), N-Boc-1,2-
phenylenediamine 8 (1.04 g, 5.0 mmol) was added at ꢀ78 ꢁC. The
reaction was kept for 1 h at this temperature and then warmed to
room temperature. After stirring 5 h, the yellow solid was pre-
cipitated from the solvent and filtered to give compound 9 in 92%
yield.
To a suspension of compound 9 (66 mg, 0.1 mmol) in DCM
(3 mL), amine (0.21 mmol) was added and stirred at room tem-
perature overnight. Then, the solvent was removed and 10% TFA/
DCE (3 mL) was added to the residue. The mixture was treated with
microwave at 120 ꢁC for 10 min. After the microwave vial was
cooled to room temperature, the solvent was removed under re-
duced pressure and then diluted with EtOAc (15 mL) and washed
with satd Na2CO3 and brine. The organic layer was dried over
MgSO4 and concentrated. The residue was purified by silica gel
column chromatography using a gradient of ethyl acetate/hexane
(20e100%) to afford the relative targeted product 12.
Scheme 1. Synthesis of fused benzimidazoleeimidazoles 12aeg.
Compound 9 was also treated with Boc-diamine 8 in DCM to
afford compound 13 (Scheme 2). Following the same procedure as
compound 12, compound 13 was not purified and the solvent was
removed to give a residue. The residue was then treated with 10%
TFA/DCE to afford intermediate 14. Following the arrows in struc-
ture 14, two new benzimidazole groups would be formed at the
same time to afford compounds 15aec in over 50% yield for the two
steps. This route was designed so that two benzimidazoles could be
formed in the same step, and the three imidazole groups present
could be modified with different functional groups in different
steps.
4.1.1. Methyl (4-(1H-benzo[d]imidazol-2-yl)-1H-imidazole-5-
carbonyl)-
-alaninate (Compound 12a). White solid, yield 67%. 1H
D
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Z.-Z. Chen et al. / Tetrahedron xxx (2015) 1e4
3
135.8, 135.5, 129.2, 128.8, 127.4, 125.9, 120.6, 116.1, 113.2, 53.8, 52.7,
38.1. LC/MS calculated for C21H20N5O3 [MþH]þ, 390; found 390.
4.1.3. 4-(1H-Benzo[d]imidazol-2-yl)-N-phenyl-1H-imidazole-5-
carboxamide (Compound 12c). White solid, yield 69%. 1H NMR
(400 MHz, DMSO-d6) d 14.65 (s, 1H), 13.45 (s, 1H), 13.22 (s, 1H), 8.08
(s, 1H), 7.98 (d, J¼7.6 Hz, 2H), 7.86 (s, 1H), 7.60 (s, 1H), 7.48 (t,
J¼7.1 Hz, 2H), 7.32 (s, 2H), 7.17 (t, J¼7.0 Hz, 1H). 13C NMR (100 MHz,
DMSO-d6) d 157.2,148.3,142.1, 139.9,138.6,134.1,130.6,129.7, 126.8,
124.1, 123.8, 123.0, 119.8, 118.5, 112.6. LC/MS calculated for
C
17H14N5O [MþH]þ, 304; found 304.
4.1.4. 4-(1H-Benzo[d]imidazol-2-yl)-N-benzyl-1H-imidazole-5-
carboxamide (Compound 12d). White solid, yield 58%. 1H NMR
(400 MHz, DMSO-d6)
(s, 1H), 7.51 (s, 3H), 7.40 (s, 4H), 7.22 (s, 2H), 4.67 (s, 2H). 13C NMR
(100 MHz, DMSO-d6) 158.8, 148.2, 142.2, 139.1, 138.0, 134.1, 130.5,
d 13.30 (s, 1H), 13.04 (s, 1H), 12.70 (s, 1H), 7.99
d
128.9, 128.3, 127.5, 126.3, 123.5, 122.6, 118.4, 112.3, 43.6. LC/MS
calculated for C18H16N5O [MþH]þ, 318; found 318.
4.1.5. 4-(1H-Benzo[d]imidazol-2-yl)-N-(4-methoxybenzyl)-1H-imid-
azole-5-carboxamide (Compound 12e). White solid, yield 65%. 1H
NMR (400 MHz, DMSO-d6)
7.78e7.35 (m, 4H), 7.23 (s, 2H), 6.95 (d, J¼7.4 Hz, 2H), 4.57 (s, 2H),
3.75 (s, 3H). 13C NMR (100 MHz, DMSO-d6)
158.9, 137.9, 131.2,
d 13.69e11.93 (m, 3H), 7.98 (s, 1H),
d
129.6, 123.0, 114.4, 55.6, 42.9. LC/MS calculated for C19H18N5O2
[MþH]þ, 348; found 348.
4.1.6. 4-(1H-Benzo[d]imidazol-2-yl)-N-(2-bromophenyl)-1H-imidaz-
ole-5-carboxamide (Compound 12f). White solid, yield 56%. 1H NMR
(400 MHz, DMSO-d6)
d 13.43 (s, broad, 1H), 11.76 (s, broad, 2H),
8.14e8.12 (m, 1H), 7.99 (d, J¼7.8 Hz, 1H), 7.84e7.74 (m, 1H), 7.67 (d,
J¼2.9 Hz, 2H), 7.47 (t, J¼7.7 Hz, 1H), 7.30e7.28 (m, 2H), 7.20 (t,
J¼7.7 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
d 158.5, 146.6, 138.9,
136.8, 133.4, 130.1, 128.5, 127.2, 126.9, 123.5, 117.0, 115.5, 114.3. 1H
NMR (400 MHz, DMSO-d6þD2O)
d 8.16 (s, 1H), 7.97 (s, 1H), 7.79 (d,
J¼7.8 Hz, 1H), 7.73 (s, 2H), 7.50 (t, J¼7.5 Hz, 1H), 7.36 (dd, J¼5.8,
2.9 Hz, 2H), 7.24 (t, J¼7.5 Hz, 1H). 13C NMR (100 MHz, DMSO-
d6þD2O)
d 158.4, 145.8, 138.9, 136.8, 136.2, 133.4, 129.4, 128.6, 127.7,
127.4, 127.0, 124.1, 117.6, 117.2, 115.6, 114.7. LC/MS calculated for
C
17H13BrN5O [MþH]þ, 382; found 382.
4.1.7. 4-(1H-Benzo[d]imidazol-2-yl)-N-phenethyl-1H-imidazole-5-
carboxamide (Compound 12g). White solid, yield 65%. 1H NMR
(400 MHz, DMSO-d6)
d 13.18e12.22 (m, 3H), 7.97 (s, 1H), 7.60 (s,
2H), 7.43e7.12 (m, 7H), 3.71 (d, J¼4.7 Hz, 2H), 3.01 (s, 2H). 13C NMR
(100 MHz, DMSO-d6)
d 139.9, 137.8, 129.1, 128.8, 126.6, 123.1, 35.5.
LC/MS calculated for C19H18N5O [MþH]þ, 332; found 332.
4.2. General procedures for compound 15
With the same procedure for compound 12.
Scheme 3. Synthesis of compounds 18aef.
4.2.1. 2,20-(1H-Imidazole-4,5-diyl)bis(1H-benzo[d]imidazole) (Com-
NMR (400 MHz, CDCl3)
d
14.70 (s, 1H), 8.17 (s, 1H), 7.78e7.67 (m,
pound 15a). White solid, yield 53%. 1H NMR (400 MHz, DMSO-d6)
3H), 7.40 (s, 2H), 4.95e4.71 (m, 1H), 3.83 (s, 3H), 1.62 (d, J¼6.2 Hz,
d
13.84 (s, 3H), 8.12 (s, 1H), 7.83 (s, 4H), 7.32 (d, J¼2.3 Hz, 4H). 13
C
3H). 13C NMR (100 MHz, CDCl3)
d
172.5, 163.3, 142.1, 137.8, 134.6,
NMR (100 MHz, DMSO-d6) d
138.9, 123.0, 115.8. 1H NMR (400 MHz,
124.6, 122.7, 118.1, 117.0, 112.9, 52.7, 48.4, 18.2. LC/MS calculated for
C
DMSO-d6þCD3OD)
d 8.09e8.05 (m, 1H), 7.80 (s, 4H), 7.40e7.22 (m,
15H16N5O3 [MþH]þ, 314; found 314.
4H). 13C NMR (100 MHz, DMSO-d6þCD3OD)
d 138.6, 122.9, 115.1. LC/
MS calculated for C17H13N6 [MþH]þ, 301; found 301.
4.1.2. Methyl (4-(1H-benzo[d]imidazol-2-yl)-1H-imidazole-5-
carbonyl)- -phenylalaninate (Compound 12b). White solid, yield
61%. 1H NMR (400 MHz, CDCl3)
D
4.2.2. 2-(4-(1H-Benzo[d]imidazol-2-yl)-1H-imidazol-5-yl)-5,6-
d
15.22 (s,1H), 8.20 (d, J¼6.6 Hz,1H),
dimethyl-1H-benzo[d]imidazole (Compound 15b). White solid, yield
7.85 (s, 2H), 7.67 (s, 1H), 7.47 (s, 2H), 7.31 (d, J¼6.4 Hz, 2H), 7.22 (d,
55%. 1H NMR (400 MHz, DMSO-d6)
d
8.30 (s, 1H), 7.88 (dd, J¼5.6,
J¼6.2 Hz, 2H), 5.05 (d, J¼6.2 Hz, 1H), 3.78 (s, 3H), 3.29 (dt, J¼20.0,
2.9 Hz, 2H), 7.62 (s, 2H), 7.41 (dd, J¼5.9, 3.0 Hz, 2H), 2.37 (s, 6H). 13
C
11.5 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d
171.0, 163.2, 140.9, 138.8,
NMR (100 MHz, DMSO-d6) d 144.5, 140.0, 136.6, 133.8, 125.8, 124.3,
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4
Z.-Z. Chen et al. / Tetrahedron xxx (2015) 1e4
115.6, 115.1, 20.4. 1H NMR (400 MHz, DMSO-d6þCD3OD)
d
8.30 (d,
solid, yield 42%. 1H NMR (400 MHz, DMSO-d6)
(s, 2H), 7.67 (s, 2H), 7.39 (s, 4H), 7.05 (s, 4H), 2.33 (s, 6H). 13C NMR
d 13.39 (s, 2H), 7.85
J¼7.2 Hz, 1H), 7.89 (dd, J¼6.0, 3.1 Hz, 2H), 7.63 (s, 2H), 7.43 (dd,
J¼6.0, 3.1 Hz, 2H), 2.38 (s, 6H). 13C NMR (100 MHz, DMSO-
(100 MHz, DMSO-d6)
d 158.4, 146.6, 138.1, 133.8, 129.7, 128.8, 127.6,
d6þCD3OD)
d
139.8, 136.2, 134.2, 133.1, 125.5, 124.4, 115.4, 114.8,
126.8, 123.1, 115.0, 19.7. LC/MS calculated for C30H25N10O2 [MþH]þ,
20.1. LC/MS calculated for C19H17N6 [MþH]þ, 329; found 329.
557; found 557.
4.2.3. 2,20-(1H-Imidazole-4,5-diyl)bis(5,6-dimethyl-1H-benzo[d] im-
4.3.6. N,N0-(4,5-Dimethyl-1,2-phenylene)bis(4-(5,6-dimethyl-1H-
benzo [d]imidazol-2-yl)-1H-imidazole-5-carboxamide) (Compound
idazole) (Compound 15c). White solid, yield 58%. 1H NMR
(400 MHz, DMSO-d6)
NMR (100 MHz, DMSO-d6)
d
8.25 (s, 1H), 7.52 (s, 4H), 2.34 (s, 12H). 13
C
18f). White solid, yield 50%. 1H NMR (400 MHz, DMSO-d6)
d
13.07
(s, 1H), 7.87 (s, 2H), 7.68 (s, 2H), 7.12 (s, 4H), 2.31 (s, 6H), 2.13 (s,
12H). 13C NMR (100 MHz, DMSO-d6)
158.3, 145.2, 138.1, 133.6,
d
143.5, 139.9, 133.6, 115.3, 20.5. 1H NMR
(400 MHz, DMSO-d6þCD3OD)
d
8.31 (d, J¼6.4 Hz, 1H), 7.68 (d,
d
J¼8.0 Hz, 4H), 2.42 (s, 12H). 13C NMR (100 MHz, DMSO-d6þCD3OD)
132.3, 129.7, 128.6, 127.3, 126.7, 114.8, 21.1, 19.7. LC/MS calculated for
d
139.7, 134.2, 114.9, 20.0. LC/MS calculated for C21H21N6 [MþH]þ,
C
34H23N10O2 [MþH]þ, 613; found 613.
357; found 357.
Acknowledgements
4.3. General procedures for compound 18
The authors thank the Scientific Research Foundation of
Chongqing University of Arts and Sciences (Grant Nos. R2013XY01
and R2013XY02) and SRF for ROCS, SEM for funding this research.
We would also like to thank Ms H.Z. Liu for obtaining the LC/MS and
NMR data.
To a suspension of compound 9 (66 mg, 0.1 mmol) in DCM (3 mL),
diamine 16 (0.1 mmol) was added and stirred at room temperature
overnight. Then, the solvent was removed and 10% TFA/DCE (3 mL)
was added to the residue. The mixture was treated in microwave at
120 ꢁC for 10 min. After the microwave vial was cooled to room
temperature, the solvent was removed under reduced pressure and
then diluted with EtOAc (15 mL) and washed with satd Na2CO3 and
brine. The organic layer was dried over MgSO4 and concentrated.
The products were purified by recrystallization from ethyl acetate to
afford compound 18 with white solid.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.09.008.
4.3.1. N,N0-(Ethane-1,2-diyl)bis(4-(1H-benzo[d]imidazol-2-yl)-1H-
imidazole-5-carboxamide) (Compound 18a). White solid, yield 45%.
References and notes
1H NMR (400 MHz, DMSO-d6)
d
13.34 (s, 2H), 11.45 (s, 2H), 7.95 (s,
2H), 7.51 (s, 4H), 7.19 (s, 4H), 3.77 (s, 4H). 13C NMR (100 MHz, DMSO-
1. (a) Gadad, A. K.; Mahajanshetti, C. S.; Nimbalkar, S.; Raichurkar, A. Eur. J. Med.
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Mane, R. B. Eur. J. Med. Chem. 2006, 41, 599; (c) Guven, O. O.; Erdogan, T.; Goker,
d6)
d 160.8, 146.9, 138.0, 128.6, 123.3, 115.7, 46.1. LC/MS calculated
for C24H21N10O2 [MþH]þ, 481; found 481.
€
H.; Yildiz, S. Bioorg. Med. Chem. Lett. 2007, 17, 2233.
2. (a) Noolvi, M. N.; Patel, H. M.; Singh, N.; Gadad, A. K.; Cameotra, S. S.; Badiger, A.
Eur. J. Med. Chem. 2011, 46, 4411; (b) Karki, S. S.; Panjamurthy, K.; Kumar, S.;
Nambiar, M.; Ramareddy, S. A.; Chiruvella, K. K.; Raghavan, S. C. Eur. J. Med.
Chem. 2011, 46, 2109; (c) Kamal, A.; Ponnampalli, S.; Vishnuvardhan, M. V. P. S.;
Narasimha Rao, M. P.; Mullagiri, K.; Lakshma Nayak, V.; Chandrakant, B. Med.
Chem. Commun. 2014, 5, 1644.
4.3.2. N,N0-(Ethane-1,2-diyl)bis(4-(5,6-dimethyl-1H-benzo[d]imida-
zol-2-yl)-1H-imidazole-5-carboxamide) (Compound 18b). White
solid, yield 48%. 1H NMR (400 MHz, DMSO-d6)
d
11.08 (s, 3H), 7.98
(s, 2H), 7.26 (s, 4H), 3.73 (s, 4H), 2.26 (s, 12H). 13C NMR (100 MHz,
3. Mavrova, A. Ts.; Anichina, K. K.; Vuchev, D. I.; Tsenov, J. A.; Kondeva, M. S.;
DMSO-d6) d 160.6, 145.2, 138.2, 132.7, 127.8, 115.0, 46.0, 20.3. LC/MS
calculated for C28H29N10O2 [MþH]þ, 537; found 537.
Micheva, M. K. Bioorg. Med. Chem. 2005, 13, 5550.
€
4. Goker, H.; Kus, C.; Boykin, D. W.; Yildiz, S.; Altanlar, N. Bioorg. Med. Chem. 2002,
10, 2589.
4.3.3. N,N0-(1,2-Phenylene)bis(4-(1H-benzo[d]imidazol-2-yl)-1H-im-
5. Goker, H.; Ozden, S.; Yıldız, S.; Boykin, D. W. Eur. J. Med. Chem. 2005, 40, 1062.
€
€
€
idazole-5-carboxamide) (Compound 18c). White solid, yield 53%. 1H
€
6. Ozden, S.; Atabey, D.; Yıldız, S.; Goker, H. Bioorg. Med. Chem. 2005, 13, 1587.
7. Ramla, M. M.; Omar, M. A.; El-Khamry, A.-M. M.; El-Diwani, H. I. Bioorg. Med.
Chem. 2006, 14, 7324.
NMR (400 MHz, DMSO-d6)
d
13.83 (s, 1H), 7.93 (s, 1H), 7.80 (s, 1H),
158.3,
7.34 (s, 3H), 7.01 (s, 2H). 13C NMR (100 MHz, DMSO-d6)
d
8. Boiani, M.; Gonzalez, M. Mini-Rev. Med. Chem. 2005, 5, 409.
9. Kamal, A.; Subba Rao, A. V.; Lakshma Nayak, V.; Subba Reddy, N. V.; Swapna, K.;
Ramakrishna, G.; Alvala, M. Org. Biomol. Chem. 2014, 12, 9864.
10. Payne, J. E.; Bonnefous, C.; Symons, K. T.; Nguyen, P. M.; Sablad, M.; Ro-
zenkrants, N.; Zhang, Y.; Wang, L.; Yazdani, N.; Shiau, A. K.; Noble, S. A.; Rix, P.;
Rao, T. S.; Hassig, C. A.; Smith, N. D. J. Med. Chem. 2010, 53, 7739.
146.9, 138.1, 131.3, 130.2, 127.2, 125.9, 125.5, 122.9, 115.1. LC/MS
calculated for C28H21N10O2 [MþH]þ, 529; found 529.
4.3.4. N,N0-(1,2-Phenylene)bis(4-(5,6-dimethyl-1H-benzo[d]imida-
ꢀ
ꢁ
ꢁ
11. (a) Starcevic, K.; Kralj, M.; Ester, K.; Sabol, I.; Grce, M.; Pavelic, K.; Karminski-
Zamola, G. Bioorg. Med. Chem. 2007, 15, 4419; (b) Lam, T.; Hilgers, M. T.; Cun-
ningham, M. L.; Kwan, B. P.; Nelson, K. J.; Brown-Driver, V.; Ong, V.; Trzoss, M.;
Hough, G.; Joy Shaw, K.; Finn, J. J. Med. Chem. 2014, 57, 651.
zol-2-yl)-1H-imidazole-5-carboxamide) (Compound 18d). White
solid, yield 46%. 1H NMR (400 MHz, DMSO-d6)
d
13.99 (s, 4H), 7.95
(dd, J¼5.9, 3.6 Hz, 2H), 7.79 (s, 2H), 7.32 (dd, J¼6.0, 3.5 Hz, 2H), 7.02
(s, 4H), 2.13 (s, 12H). 13C NMR (100 MHz, DMSO-d6)
158.2, 145.9,
12. Mamedov, V. A.; Zhukova, N. A.; Beschastnova, T. N.; Gubaidullin, A. T.; Rakov,
d
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137.8, 131.5, 131.1, 130.5, 126.7, 125.7, 125.3, 114.5, 20.4. LC/MS cal-
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4.3.5. N,N0-(4,5-Dimethyl-1,2-phenylene)bis(4-(1H-benzo[d]imida-
zol-2-yl)-1H-imidazole-5-carboxamide) (Compound 18e). White
Please cite this article in press as: Chen, Z.-Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.008