Synthesis of structurally diverse benzimidazolyl benzimidazolones by application of soluble polymer support

Article abstract of DOI:10.1016/j.tet.2008.04.081

Chemical stability and reactivity of a bifunctional polymer conjugate containing an ortho-amino arylamide linkage have been successfully exploited to achieve a parallel synthesis of methoxycarbonylated head-tail bis-benzimidazoles. Regioselective alkylation of the two nitrogens in the benzimidazolone moiety has been carried out by ipso-fluoro displacement, and N-alkylation to generate two diversities. Cleavage of the polymer support has resulted in two libraries of di- and tri-substituted benzimidazolyl benzimidazolones in high purity and high yield. All reaction steps have been monitored by ¹H NMR on the support directly.

Full text of DOI:10.1016/j.tet.2008.04.081

Tetrahedron 64 (2008) 6387–6394
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of structurally diverse benzimidazolyl benzimidazolones
by application of soluble polymer support
*
Hsia-Yuan Chen, Manohar V. Kulkarni, Chih-Hau Chen, Chung-Ming Sun
Laboratory of Combinatorial Drug Discovery, Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan 300-10, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 March 2008
Received in revised form 18 April 2008
Accepted 22 April 2008
Available online 25 April 2008
Chemical stability and reactivity of a bifunctional polymer conjugate containing an ortho-amino
arylamide linkage have been successfully exploited to achieve a parallel synthesis of methoxycarbonyl-
ated head–tail bis-benzimidazoles. Regioselective alkylation of the two nitrogens in the benzimidazolone
moiety has been carried out by ipso-fluoro displacement, and N-alkylation to generate two diversities.
Cleavage of the polymer support has resulted in two libraries of di- and tri-substituted benzimidazolyl
benzimidazolones in high purity and high yield. All reaction steps have been monitored by 1H NMR on
the support directly.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
alkylation of benzimidazolin-2-ones, which was circumvented by
protection–deprotection strategy via N-carboxyalkoxylation, under
The main purpose of combinatorial chemistry is to create wider
structural diversity in small molecules, which has been realized in
practice by the application of both solid1,2 and liquid phase3,4
synthetic strategies. Molecular libraries of biologically active
nitrogen heterocycles like quinoxalines,5 piperazinones,6 fused
imidazoles,7 hydantoins,8 benzimidazoles,9 and pyrimidinones10
have been successfully generated by our group applying the in-
creasingly useful soluble polymer supports under microwave
conditions.
Benzimidazolin-2-ones have been found to exhibit a wide range
of biological activities.11–18 Interestingly, benzimidazolin-2-one
skeleton has been a subject of crystal engineering,19 based on which
several benzimidazolin-2-ones with improved binding affinity
have been designed for p-38 MAP kinase inhibiting activity.20
In view of their multi-dimensional activities (Fig. 1), these mo-
lecular motifs have been the targets for both solid21,22 and liquid
phase23 synthetic methods. A survey of literature indicates that
the benzimidazolyl benzimidazolone skeleton has received little
attention. The 6–20 and the 1–20 isomers have been obtained as the
photolysis products of benzimidazoles.24,25 The recently reported
bromo ter-benzimidazole possessing this skeleton was found to be
an effective topoisomerase-I inhibitor.26 A series of 6-anilino-N-
heterocyclic benzimidazolones have been patented for their pro-
nounced cytokinase inhibiting activity related to the inflammation
process.27 One of the reasons for the paucity of literatures also lies
in the formation of mixture of regioisomers during the N,N-
harsh reaction conditions.28,29 Construction of bis-benzimidazole
skeleton without the use of support requires use of dinitro alde-
hydes and 5-formyl benzimidazole,26 and involves the use of
a number of ortho-phenylene diamines, which again are required to
be synthesized by at least a three-step sequence. Hence it is quite
apparent that a systematic synthetic strategy without the need of
all the above cited starting materials is required for the construc-
tion of functionalized benzimidazolyl benzimidazolones and an
unambiguous method for introducing alkyl groups on the two
nitrogens of the cyclic ureide moiety.
2. Results and discussion
In the present paper we have demonstrated the application of
soluble polymer supports to generate a wide range of bis-benz-
imidazolin-2-ones and successfully addressed the issue of N-alkyl-
ation, which is in agreement with our earlier work.9d It can be seen
that the present methodology does not make use of dinitro alde-
hydes and ortho-phenylene diamines, which are usually employed
in conventional methods. Our strategy has resulted in the title
compounds with two and three points of structural diversity,
without any ambiguity. Various steps involved in the synthesis of
benzimidazolyl benzimidazolones are shown in Scheme 1.
The starting polymer organic conjugate 1 required for the
present synthetic sequence was obtained by our own established
four-step procedures.6 Initial ring closure was brought about by an
acid catalyzed (5% TFA) room temperature reaction in 1,2-di-
chloroethane. It was found that use of anhydrous MgSO4 can reduce
the reaction time to 12 h from 24 h and can enhance the yields of
* Corresponding author.
E-mail address: cmsun@mail.nctu.edu.tw (C.-M. Sun).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.081

6388
H.-Y. Chen et al. / Tetrahedron 64 (2008) 6387–6394
Br
N
Het
N
N
H
N
NH
NH
N
H
H
N
N
H
O
N
O
N
H
N
H
O
N
H
Photolysis product
Topoisomerase I inhibitor
Cytokinase inhibitor
Figure 1. Structurally related benzimidazolinones.
F
O
NO2
O
O
PEG
NO2
N
N
TFA, MgSO4
ClCH2CH2Cl, r.t., 12 h
O
PEG
NH
F
O
R1
NH
R1
2
1
O
NO2
PEG
N
R2NH2, CH2Cl2
r.t., 12 h
Zn, ammonium formate
CH3OH, r.t., 30 min
O
NH
R2
N
R1
3
O
H
N
O
NH2
O
PEG
PEG
N
N
triphosgene
ClCH2H2Cl, r.t., 12 h
O
O
N
NH
R2
R2
N
R1
N
R1
4
5
R3
N
KCN, CH3OH
O
O
PEG
N
N
R3X, NaH
CH2Cl2, r.t., 12 h
O
H
N
N
O
O
R2
N
N
O
R1
N
R2
6
R1
KCN, CH3OH
7
R3
N
O
O
N
N
O
N
R2
R1
8
Scheme 1. Synthetic route toward the benzimidazolyl benzimidazolones 7 and 8.
the cyclized, polymer-supported product 2, probably by removing
the eliminated water in the reaction. MgSO4 was removed by
passing through a thin layer of Celite before precipitation. After the
reactions were completed, the reaction mixtures were sub-
sequently purified by simple precipitation, filtration, and ether
washing to remove unreacted reagents and byproducts.
The second point of structural diversity was introduced by an
ipso-fluoro displacement, by an SNAr reaction using various primary
amines leading to the ortho-nitro anilines 3. Reduction of the nitro
group was achieved in half an hour under neutral conditions using
zinc dust and ammonium formate in methanol at room tempera-
ture. This led to the diamine 4 leaving the polymer unaffected. The
one carbon homologation to construct the benzimidazolone moiety
was completed by N,N-carbonylation using triphosgene in 1,2-di-
chloroethane at room temperature. The time required of the cy-
clization was 12 h and the yields were in the range of 72–85% with
excellent crude purities (80–96%). When dichloromethane was
used as a reaction medium in this step, compound 10 was obtained
in 40–50% after cleavage along with expected product 7. It is clear
that solvent was involved during the cyclization. However, this side
reaction can be avoided by switching the solvent from dichloro-
methane to dichloroethane and maintained the good solubility of
polymer immobilized intermediates (Scheme 2).
This key intermediate 5 has given rise to benzimidazolones 7
with two points of molecular diversity, after the cleavage of the
polymer support by treatment with methanolic KCN at room
temperature in 72 h. This led to the mono-alkylation in one of the
nitrogens in the benzimidazolone part, which is the second di-
versity introduced after ipso-fluoro displacement by various
amines. The HPLC purities of the crude products were analyzed by
normal phase silica column with 5% methanol in dichloroethane as
the eluent. For all the crude products, more than 80% purity was
observed (Table 1).
Structural ambiguity and formation of mixtures of isomers have
been avoided by introduction of the N-alkyl group by ipso-fluoro
displacement. Furthermore, N-alkylation of 5 was affected by
deprotonation of the cyclic ureide using sodium hydride in meth-
ylene chloride at room temperature. An interesting feature of this

H.-Y. Chen et al. / Tetrahedron 64 (2008) 6387–6394
6389
O
O
H
N
NH2
PEG
PEG
N
N
N
N
O
triphosgene
CH2Cl2, r.t., 12 h
+
5
O
N
NH
R2
R2
R1
R1
9
4
O
H
N
N
O
KCN, CH3OH
N
+
8
R2
N
R1
10
Scheme 2. Formation of side product 9 during the cyclization in CH2Cl2.
Table 1
Bis-benzimidazolones with two points of structural diversity
Table 2
Bis-benzimidazolones with three points of structural diversity
Isolated LRMSb
yielda (%)
Entry
R1NH2
R2NH2
Isolated yielda (%) LRMSb HPLCc
Entry
R1NH2
R2NH2
R3–X
7a
72
74
418
422
83
86
NH2
NH2
NH2
NH2
NH2
NH2
NH2
8a
8b
CH3I
70
66
422
448
O
O
O
NH2
7b
O
O
Br
NH2
NH2
7c
84
80
406
420
84
92
Br
NH2
NH2
NH2
NH2
8c
8d
8e
8f
68
65
71
73
528
446
434
460
H3CO
7d
CH3I
CH3I
NH2
NH2
NH2
NH2
7e
83
408
95
NH2
NH2
NH2
NH2
NH2
7f
Ph
80
79
482
444
80
96
NH2
NH2
O
O
Br
NH2
NH2
7g
Br
8g
68
540
7h
7i
83
78
432
430
78
82
NH2
NH2
NH2
NH2
NH2
H3CO
Ph
Br
Br
8h
8i
78
70
488
536
NH2
NH2
NH2
NH2
NH2
7j
72
484
96
O
NH2
a
8j
CH3I
72
64
420
446
Yields were based on loading of soluble support.
LRMS were detected with EI ionization source.
Crude products were analyzed by normal phase HPLC (column: silica,
NH2
NH2
NH2
b
c
Br
8k
250ꢀ4.6 mm, 5 mm; eluent: 5% MeOH in CH2Cl2).
NH2
NH2
Br
8l
73
526
NH2
H3CO
selective deprotonation was that the hydride ion did not attack the
ester carbonyl to induce the cleavage of the polymer. Secondly, the
ambident nucleophilicity of the cyclic ureide moiety was also
controlled as no O-alkylated product was obtained. The reaction of
this sodium salt with various alkyl halides lead exclusively to N-
alkylation and cleavage of the polymer support using KCN in
methanol led to the final bis-benzimidazolones 8 with three points
of structural diversity (Table 2). The final compounds 7 and 8 were
clearly distinguishable by TLC (CH2Cl2/CH3OH¼50:1). For bis-
alkylated compounds, for example, 8a (Rf¼0.3) had higher Rf values
than mono-alkylated compounds 7a (Rf¼0.2).
Br
8m
8n
70
70
474
436
NH2
NH2
NH2
CH3I
O
O
NH2
NH2
NH2
Br
8o
8p
70
70
462
542
NH2
NH2
Br
O
H3CO
Conventional proton NMR (Fig. 2) was effectively used to
monitor the sequence of steps in this synthetic route. The initial
polymer conjugate 1h (8a, Table 2) exhibited a slightly broad low
field NH singlet around 9.2 (Spectrum A) and the aromatic protons
Ha and Hc also displayed characteristic variations. The first ring
closure leading to the benzimidazole polymer conjugate 2h was
characterized by the absence of the NH proton with the simulta-
neous deshielding of Ha, which has now appeared at 8.7 ppm due to
the anisotropic effects of the ring nitrogen and the ester carbonyl
group (Spectrum B).
8q
68
554
NH2
NH2
Br
a
Yields were based on loading of soluble support.
LRMS were detected with EI ionization source.
b
The ipso-fluoro displacement resulted in 3h with the appear-
ance of a D2O exchangeable NH proton at 8.3 ppm (Spectrum C). He
is moving to the upfield from 7.47 to 7.0 ppm because the weak
electron withdrawing fluoride was replaced by electron donating
amine. Reduction of the nitro group led to the diamine 4h in which

6390
H.-Y. Chen et al. / Tetrahedron 64 (2008) 6387–6394
He
(a)
PEG
Hf
F
O
O
Ha
NO2
PEG
NH Hd
NH
O
Hb
Ha
Hb
Hc
Hc
NH
Hd
He
Hf
O
1h
ppm
10
10
10
9
8
7
6
6
6
5
5
5
4
3
3
3
2
2
2
1
1
1
O
Ha
Hc
PEG
Hd
Hf
NO2
F
(b)
PEG
N
N
O
Hb
He
O
Hc
He
2h
HaHb
Hd
Hf
ppm
9
8
7
4
(c)
O
Ha
PEG
Hd
NO2
NH
PEG
N
O
N
Hb
Hf
He
Hc
O
Hb
Hf
3h
Hd
Hc
Ha
He
NH
9
8
7
4
ppm
(d)
PEG
O
Ha
Hd
NH2
NH
PEG
N
N
O
R2
Hb
Hf
He
Hc
Hd
Hf
O
Ha
Hc
4h
He
Hb
10
9
7
6
5
4
3
2
1
ppm
8
H3C
(e)
O
Ha
Hc
Hd
Hf
O
N
N
N
O
N
Hb
He
O
8a
10
9
8
7
6
5
4
3
2
1
ppm
Figure 2. Formation of compound 8a monitored by 1H NMR.
the Hd observed earlier as a low field singlet around 8.9 ppm
exhibited an upfield shift and was observed at 7.3 ppm (Spectrum
D). Hf is also moving to upfield from 8.04 to 7.25 ppm because the
nitro group was reduced to amine functionality. Formation of the
benzimidazolone conjugate 5 was indicated by the low field NH
proton around 10.2 ppm (not shown in Fig. 2).
OCH3 protons of the methyl ester (not shown in Fig. 2). The signal at
10.2 ppm disappeared upon alkylation and removal of the polymer
resulted in bis-alkylated benzimidazoles 8 (Spectrum F).
3. Conclusion
Cleavage of the polymer at this stage led to benzimidazoles 7.
This was indicated by an upfield singlet at 3.9–4.00 ppm due to
This paper shows the first systematic approach for the benzi-
midazolyl benzimidazolones with a methoxycarbonyl function in

H.-Y. Chen et al. / Tetrahedron 64 (2008) 6387–6394
6391
the aromatic ring. The selective N,N-bisalkylation of benzimid-
4.1.2. 10-Isobutyl-1-(2-methoxy-ethyl)-20-oxo-20,30-dihydro-
1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl
ester (7b)
azolinone has been achieved by employing various substituted
amines in an ipso-fluoro displacement and the second alkylation
has been brought about using sodium hydride with different alkyl
halides. All the transformations on the PEG–organic conjugates
have been carried out at ambient temperature. With two stages
being available for the cleavage of the polymer, the present
synthetic route has facilitated the generation of two libraries
of benzimidazolones with two or three points of structural
diversity.
1H NMR (300 MHz, CDCl3)
d 10.57 (s, 1H), 8.52 (s, 1H), 8.04 (d,
J¼8.5 Hz, 1H), 7.65 (s, 1H), 7.53 (d, J¼8.1 Hz, 1H), 7.49 (d, J¼8.5 Hz,
1H), 7.09 (d, J¼8.1 Hz,1H), 4.46 (t, J¼5.4 Hz, 2H), 3.96 (s, 3H), 3.78 (t,
J¼5.3 Hz, 2H), 3.72 (d, J¼7.4 Hz, 2H), 3.27 (s, 3H), 2.30–2.18 (m, 1H),
1.00 (d, J¼6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 168.0, 156.5,
156.3,142.6,139.4,132.7, 128.8,125.1,124.7,123.3,122.8,122.1,111.5,
110.5, 108.3, 71.0, 59.5, 52.5, 48.8, 45.5, 28.4, 20.5; IR (KBr) 2925,
1708, 1486, 1302 cmꢁ1; EIMS m/z 422 (Mþ); HRMS m/z calcd for
4. Experimental section
C24H26N4O3 422.1954, found 422.1940.
4.1. General procedures for the synthesis of benzimidazolyl
benzimidazolones (7 and 8)
4.1.3. 1-Isobutyl-10-isopropyl-20-oxo-20,30-dihydro-1H,10H-[2,50]
bisbenzoimidazolyl-5-carboxylic acid methyl ester (7c)
1H NMR (300 MHz, CDCl3)
d 10.84 (s, 1H), 8.51 (s, 1H), 8.01 (d,
To a solution of 1 (0.33 mmol, 1.0 equiv) in dichloroethane,
0.5 mL trifluoroacetic acid and 0.5 g MgSO4 were added. The re-
action mixture was refluxed for 12 h and after completion, the
reaction mixture was passed through a thin layer of Celite to
remove MgSO4. The solution was concentrated by rotary evapo-
ration and diluted with slow addition of excess of cold ether. The
precipitated benzoimidazole conjugate was filtered through a frit-
ted funnel and washed with ether to obtain polymer immobilized
J¼8.4 Hz, 1H), 7.51 (s, 1H), 7.40 (d, J¼8.4 Hz, 1H), 7.35 (d, J¼8.4 Hz,
1H), 7.26–7.21 (m, 1H), 4.75 (septet, J¼6.9 Hz, 1H), 4.13 (d, J¼7.5 Hz,
2H), 3.93 (s, 3H), 2.15–2.06 (m, 1H), 1.57 (d, J¼6.9 Hz, 6H), 0.73 (d,
J¼6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 168.0, 156.4, 155.7, 142.7,
139.4, 130.9, 129.2, 124.8, 124.5, 123.3, 122.5, 122.3, 111.2, 110.6,
109.3, 52.5, 52.4, 45.3, 29.1, 20.7, 20.3; IR (KBr) 2925, 1712, 1481,
1286 cmꢁ1; EIMS m/z 406 (Mþ); HRMS m/z calcd for C23H26N4O3
406.2005, found 406.2023.
2. Compound
2 was further reacted with different amines
(2.31 mmol, 7.0 equiv) in dichloroethane at ambient temperature
for 12 h. After completion, the reaction mixture was washed with
ether and dried to obtain compound 3. To a solution of 3 in
methanol, zinc (3.3 mmol, 30.0 equiv) and ammonium formate
(3.75 mmol, 15.0 equiv) were added. The reaction mixture was
allowed to stir for 30 min at room temperature. The mixture was
centrifuged to remove zinc and concentrated by rotary evapora-
tion to remove methanol. Then dichloromethane was added to salt
out ammonium formate. The mixture was passed through a thin
layer of Celite to remove ammonium formate and amine 4 was
obtained. The polymer conjugate 4 (0.33 mmol, 1.0 equiv) and
triphosgene (0.73 mmol, 2.2 equiv) were dissolved in 1,2-di-
chloroethane (dichloromethane for 9) and the reaction mixtures
were stirred for 12 h at room temperature. The cyclized product 5
was isolated by similar precipitation and washed with excess of
ether. Compound 5 (0.33 mmol, 1.0 equiv) and sodium hydride
(0.72 mmol, 2.2 equiv) were put in a 100 mL flask under nitrogen
at room temperature and dry dichloromethane was added. After
the reaction mixtures stirred for 10 min, appropriate halides
(1.0 mmol, 3 equiv) were added and continuously stirred for 12 h.
After completion, wet acetone was added to quench the excess
sodium hydride. The reaction mixture was precipitated and
washed several times with ether. To a solution of compound 7 in
methanol, KCN (0.1 g) was added and stirred for 3 days. After the
quenching procedure, the crude products 8 and 10 were obtained.
The crude product was purified by column chromatography
(CH2Cl2/MeOH¼30:1) and final products were obtained in high
total yields.
4.1.4. 10-Butyl-1-isobutyl-20-oxo-20,30-dihydro-1H,10H-[2,50]
bisbenzoimidazolyl-5-carboxylic acid methyl ester (7d)
1H NMR (300 MHz, CDCl3)
d 10.58 (s, 1H), 8.53 (s, 1H), 8.03 (d,
J¼8.5 Hz, 1H), 7.51 (s, 1H), 7.44–7.38 (m, 2H), 7.11 (d, J¼8.1 Hz, 1H),
4.15 (d, J¼7.5 Hz, 2H), 3.96–3.90 (m, 5H), 2.14–2.10 (m, 1H), 1.80
(quint, J¼7.4 Hz, 2H), 1.45 (sextet, J¼7.7 Hz, 2H), 0.99 (t, J¼7.2 Hz,
3H), 0.75 (d, J¼6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 168.0, 156.4,
156.1, 142.6, 139.3, 132.2, 128.9, 124.9, 124.5, 123.5, 122.9, 122.3,
111.2,110.6,108.1, 52.6, 52.5, 41.2, 30.8, 29.2, 20.5, 20.3,14.1; IR (KBr)
2959, 1714, 1487, 1301 cmꢁ1; EIMS m/z 420 (Mþ); HRMS m/z calcd
for C24H28N4O3 420.2161, found 420.2163.
4.1.5. 10-Isopropyl-1-(2-methoxy-ethyl)-20-oxo-20,30-dihydro-
1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl ester (7e)
1H NMR (300 MHz, CDCl3)
d 10.45 (s, 1H), 8.53 (s, 1H), 8.04 (d,
J¼8.5 Hz, 1H), 7.67 (s, 1H), 7.54–7.48 (m, 2H), 7.25 (d, J¼8.3 Hz, 1H),
4.77 (septet, J¼7.0 Hz,1H), 4.47 (t, J¼5.3 Hz, 2H), 3.96 (s, 3H), 3.79 (t,
J¼5.3 Hz, 2H), 3.28 (s, 3H), 1.59 (d, J¼6.9 Hz, 6H); 13C NMR (75 MHz,
CDCl3)
d 168.0, 156.5, 155.5, 142.4, 139.4, 131.2, 129.1, 125.1, 124.7,
123.0, 122.4, 122.1, 111.6, 110.5, 109.3, 71.0, 59.5, 52.5, 45.5, 45.3,
20.7; IR (KBr) 2935, 1711, 1482, 1301 cmꢁ1; EIMS m/z 408 (Mþ);
HRMS m/z calcd for C22H24N4O4 408.1798, found 408.1796.
4.1.6. 1-Butyl-20-oxo-10-(3-phenyl-propyl)-20,30-dihydro-1H,10H-
[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl ester (7f)
1H NMR (300 MHz, CDCl3)
d 11.28 (s, 1H), 8.54 (s, 1H), 8.02 (d,
J¼8.4 Hz, 1H), 7.52 (s, 1H), 7.39 (d, J¼8.5 Hz, 1H), 7.35 (d, J¼8.2 Hz,
1H), 7.29–7.18 (m, 5H), 6.97 (d, J¼8.1 Hz, 1H), 4.24 (t, J¼7.2 Hz, 2H),
3.93–3.90 (m, 5H), 2.72 (t, J¼7.4 Hz, 2H), 2.12 (quint, J¼7.1 Hz, 2H),
1.74 (quint, J¼7.0 Hz, 2H), 1.24 (sextet, J¼7.6 Hz, 2H), 0.84 (t,
4.1.1. 1-Cyclopentyl-10-isopropyl-20-oxo-20,30-dihydro-1H,10H-[2,50]
bisbenzimidazolyl-5-carboxylic acid methyl ester (7a)
J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 168.0, 156.1, 142.7, 141.3,
1H NMR (300 MHz, CDCl3)
d
10.68 (s, 1H), 8.53 (s, 1H), 7.99 (d,
139.2, 132.2, 129.2, 128.8, 128.7, 126.5, 124.9, 124.6, 123.2, 122.5,
122.2, 111.2, 110.2, 108.0, 52.5, 45.2, 41.0, 33.4, 32.1, 30.1, 20.3, 13.9;
IR (KBr) 2953, 1712, 1486, 1301 cmꢁ1; EIMS m/z 482 (Mþ); HRMS
m/z calcd for C29H30N4O3 482.2318, found 482.2312.
J¼8.5 Hz, 1H), 7.53 (d, J¼8.4 Hz, 1H), 7.53 (s, 1H), 7.32 (d, J¼8.2 Hz,
1H), 7.28–7.25 (m, 1H), 5.02 (quint, J¼8.7 Hz, 1H), 4.78 (septet,
J¼6.9 Hz, 1H), 3.95 (s, 3H), 2.35–2.28 (m, 2H), 2.13–2.05 (m, 4H),
1.79–1.67 (m, 2H), 1.59 (d, J¼6.9 Hz, 6H), 0.78 (d, J¼6.6 Hz, 6H); 13
C
NMR (75 MHz, CDCl3)
d
168.0, 156.6, 155.5, 143.3, 136.7, 131.1,
4.1.7. 1-Butyl-10-furan-2-ylmethyl-20-oxo-20,30-dihydro-1H,10H-
129.3, 124.7, 124.0, 122.7, 122.5, 111.9, 111.3, 109.3, 58.1, 52.5, 45.3,
30.8, 25.6, 20.7; IR (KBr) 2951, 1714, 1482, 1302 cmꢁ1; EIMS m/z
418 (Mþ); HRMS m/z calcd for C23H26N4O4 418.2005, found
418.2007.
[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl ester (7g)
1H NMR (300 MHz, CDCl3)
d 11.02 (s, 1H), 8.52 (s, 1H), 8.03 (d,
J¼8.1 Hz, 1H), 7.54 (s, 1H), 7.42–7.34 (m, 3H), 7.20 (d, J¼8.1 Hz, 1H),
6.33 (m, 1H), 5.07 (s, 2H), 4.25 (t, J¼7.4 Hz, 2H), 3.94 (s, 3H), 1.76

6392
H.-Y. Chen et al. / Tetrahedron 64 (2008) 6387–6394
(quint, J¼7.0 Hz, 2H), 1.25 (sextet, J¼7.0 Hz, 2H), 0.85 (t, J¼7.2 Hz,
3H); 13C NMR (75 MHz, CDCl3)
168.0, 156.0, 155.6, 149.6, 143.1,
142.5, 139.1, 132.0, 129.1, 125.0, 124.6,123.1, 122.6, 122.1, 110.8, 110.9,
110.3, 109.2, 108.7, 52.5, 45.2, 37.9, 32.1, 20.3, 13.9; IR (KBr) 2955,
1712, 1484, 1301 cmꢁ1; EIMS m/z 444 (Mþ); HRMS m/z calcd for
59.6, 52.5, 40.9, 40.7, 44.9, 20.8; IR (KBr) 2981, 1713, 1699, 1488,
1302 cmꢁ1; EIMS m/z 448 (Mþ); HRMS m/z calcd for C25H28N4O4
448.2111, found 448.2112.
d
4.1.13. 10-Isopropyl-30-(3-methoxy-benzyl)-1-(2-methoxy-ethyl)-
20-oxo-20,30-dihydro-1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic
acid methyl ester (8c)
C
25H24N4O4 444.1798, found 444.1800.
4.1.8. 1-Butyl-10-cyclopentyl-20-oxo-20,30-dihydro-1H,10H-[2,50]
1H NMR (300 MHz, CDCl3)
d
8.51 (s, 1H), 8.02 (d, J¼8.5 Hz, 1H),
bisbenzoimidazolyl-5-carboxylic acid methyl ester (7h)
7.55 (d, J¼8.2 Hz, 1H), 7.46 (d, J¼8.5 Hz, 1H), 7.46 (s, 1H), 7.29–7.19
(m, 2H), 6.92–6.88 (m, 2H), 6.78 (d, J¼8.1 Hz, 1H), 5.10 (s, 2H), 4.83
(septet, J¼6.9 Hz, 1H), 4.32 (t, J¼5.2 Hz, 2H), 3.95 (s, 3H), 3.75 (s,
3H), 3.70 (t, J¼5.2 Hz, 2H), 3.22 (s, 3H), 1.61 (d, J¼6.9 Hz, 6H); 13C
1H NMR (300 MHz, CDCl3)
d 10.32 (s, 1H), 8.51 (s, 1H), 8.02 (d,
J¼8.5 Hz, 1H), 7.52 (s, 1H), 7.41–7.34 (m, 2H), 7.15 (d, J¼8.2 Hz, 1H),
4.87 (quint, J¼8.8 Hz, 1H), 4.26 (t, J¼8.4 Hz, 2H), 3.94 (s, 3H), 2.17–
1.75 (m, 8H), 1.28–1.22 (m, 4H), 0.86 (t, J¼7.2 Hz, 3H); 13C NMR
NMR (75 MHz, CDCl3) d 167.9, 160.3, 156.4, 142.7, 139.4, 138.0, 130.2,
(75 MHz, CDCl3)
d
167.7, 155.7, 155.5, 142.5, 138.9, 130.6, 129.0,
129.9, 125.0, 124.6, 123.6, 122.5, 122.2, 120.0, 113.8, 11.3.1, 110.5,
110.1,109.3, 70.9, 59.5, 55.5, 52.4, 45.9, 45.5, 45.1, 30.0, 20.7; IR (KBr)
2935, 1711, 1489, 1303 cmꢁ1; EIMS m/z 528 (Mþ); HRMS m/z calcd
for C30H32N4O5 528.2373, found 528.2374.
124.6, 124.2, 122.8, 121.9, 110.8, 109.8, 108.8, 53.4, 52.1, 45.1, 44.8,
31.8, 28.9, 25.0, 19.9, 13.5; IR (KBr) 2957, 1714, 1482, 1301 cmꢁ1
;
EIMS m/z 432 (Mþ); HRMS m/z calcd for C25H28N4O3 432.2161,
found 432.2167.
4.1.14. 10-Cyclopentyl-1-isobutyl-30-methyl-20-oxo-20,30-dihydro-
1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl
ester (8d)
4.1.9. 10-Furan-2-ylmethyl-1-isopropyl-20-oxo-20,30-dihydro-
1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl ester (7i)
1H NMR (300 MHz, CDCl3)
d
10.89 (s, 1H), 8.49 (s, 1H), 7.97 (d,
1H NMR (300 MHz, CDCl3)
d
8.53 (s, 1H), 8.03 (d, J¼8.5 Hz, 1H),
J¼8.6 Hz, 1H), 7.62 (d, J¼8.6 Hz, 1H), 7.47 (s, 1H), 7.35 (s, 1H), 7.28–
7.26 (m, 1H), 7.20–7.17 (m, 1H), 6.38 (d, J¼3.1 Hz, 1H), 6.32–6.30 (m,
1H), 5.05 (s, 1H), 4.92–4.83 (m, 1H), 3.93 (s, 1H), 1.62 (d, J¼6.9 Hz,
7.44 (d, J¼8.5 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J¼8.1 Hz, 1H), 7.18 (d,
J¼8.1 Hz, 1H), 4.93 (quint, J¼8.8 Hz, 1H), 4.17 (d, J¼7.6 Hz, 2H), 3.97
(s, 3H), 3.48 (s, 3H), 2.23–1.95 (m, 5H), 1.84–1.70 (m, 4H), 0.78 (d,
6H); 13C NMR (75 MHz, CDCl3)
d
167.9, 155.9, 155.5, 149.5, 143.1,
J¼6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 168.0, 156.4, 154.7, 142.9,
137.0, 131.9, 129.0, 124.7, 124.2,123.5,122.9,122.3,112.3, 111.4, 110.9,
109.2, 108.7, 52.5, 49.5, 37.9, 21.7; IR (KBr) 2981, 1714, 1484,
1304 cmꢁ1; EIMS m/z 430 (Mþ); HRMS m/z calcd for C24H22N4O4
430.1641, found 430.1646.
139.5, 131.1, 129.8, 124.9, 124.5, 123.4, 122.4, 122.3, 110.5, 109.2,
108.8, 54.1, 52.6, 52.5, 29.3, 29.2, 27.6, 25.4, 20.4; IR (KBr) 2956,
1710, 1493, 1302 cmꢁ1; EIMS m/z 446 (Mþ); HRMS m/z calcd for
C26H30N4O3 446.2318, found 446.2315.
4.1.10. 1-Isopropyl-10-(4-methoxy-benzyl)-20-oxo-20,30-dihydro-
4.1.15. 10-Butyl-1-isobutyl-30-methyl-20-oxo-20,30-dihydro-1H,10H-
1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl ester (7j)
[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl ester (8e)
1H NMR (300 MHz, CDCl3)
d
10.28 (s, 1H), 8.51 (s, 1H), 7.99 (d,
1H NMR (300 MHz, CDCl3)
d
8.42 (s, 1H), 7.93 (d, J¼8.5 Hz, 1H),
J¼8.6 Hz, 1H), 7.63 (d, J¼8.6 Hz, 1H), 7.47 (s, 1H), 7.32 (d, J¼8.6 Hz,
2H), 7.23 (d, J¼8.1 Hz, 1H), 6.99 (d, J¼8.1 Hz, 1H), 6.88 (d, J¼8.6 Hz,
2H), 5.05 (s, 2H), 4.94–4.82 (m,1H), 3.95 (s, 3H), 3.79 (s, 3H),1.64 (d,
7.35–7.27 (m, 3H), 7.01 (d, J¼8.4 Hz, 1H), 4.07 (d, J¼7.5 Hz, 2H),
3.86–3.81 (m, 5H), 3.38 (s, 3H), 1.93 (m, 1H), 1.68 (quint, J¼7.5 Hz,
2H), 1.33 (sextet, J¼7.8 Hz, 2H), 0.88 (t, J¼7.2 Hz, 3H), 0.67 (d,
J¼6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d
168.0, 159.5, 156.1, 156.0,
J¼6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 167.9, 156.3, 154.9, 142.6,
143.4, 137.1, 132.0, 129.3, 129.2, 128.4, 124.5, 124.1, 123.5, 122.7,
122.4, 114.5, 112.3, 111.4, 108.6, 55.6, 52.5, 49.4, 44.5, 21.7; IR (KBr)
2951, 1713, 1484, 1303 cmꢁ1; EIMS m/z 470 (Mþ); HRMS m/z calcd
for C27H26N4O4 470.1954, found 470.1941.
139.4, 131.2, 130.9, 124.9, 124.5, 123.3, 122.7, 122.3, 110.6, 109, 107.7,
52.6, 52.5, 41.5, 30.9, 29.2, 27.7, 20.4, 20.4, 14.1; IR (KBr) 2958, 1711,
1496, 1302 cmꢁ1; EIMS m/z 434 (Mþ); HRMS m/z calcd for
C25H30N4O3 434.2318, found 434.2307.
4.1.11. 10-Isopropyl-1-(2-methoxy-ethyl)-30-methyl-20-oxo-20,30-
dihydro-1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl
ester (8a)
4.1.16. Methyl-30-allyl-10-butyl-1-isobutyl-20-oxo-2,50-bi-
(1H-benzo[d]imidazole)-5-carboxylate (8f)
1H NMR (300 MHz, CDCl3)
d
8.51 (s, 1H), 8.02 (d, J¼8.5 Hz, 1H),
1H NMR (300 MHz, CDCl3)
d
8.53 (s, 1H), 8.05 (d, J¼8.5 Hz, 1H),
7.43–7.33 (m, 2H), 7.33 (s, 1H), 7.12 (d, J¼8.1 Hz, 1H), 5.92 (tdd,
J¼11.1, 10.4, 5.3 Hz), 5.29–5.17 (m, 2H), 4.57 (d, J¼5.3 Hz, 2H), 4.11
(d, J¼7.6 Hz, 2H), 3.93–3.92 (m, 5H), 2.12 (m, 1H), 1.79 (quint,
J¼7.3 Hz, 2H), 1.43 (sextet, J¼7.6 Hz, 2H), 0.98 (t, J¼7.2 Hz, 3H), 0.75
7.59 (s, 1H), 7.54 (d, J¼8.1 Hz, 1H), 7.49 (d, J¼8.6 Hz, 1H), 7.27 (m,
1H), 4.79 (septet, J¼7.0 Hz, 1H), 4.47 (t, J¼5.4 Hz, 2H), 3.97 (s, 3H),
3.84 (t, J¼5.3 Hz, 2H), 3.46 (s, 3H), 3.32 (s, 3H), 1.58 (d, J¼6.9 Hz,
6H); 13C NMR (75 MHz, CDCl3)
d
168.0, 156.6, 154.4, 143.0, 139.6,
(d, J¼6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 167.9, 156.3, 154.4,
131.0, 130.0, 125.0, 124.6, 123.0, 122.6, 122.4, 110.3, 109.6, 108.9, 71.1,
59.6, 52.4, 45.7, 45.6, 27.5, 20.7; IR (KBr) 2925, 1709, 1493,
1302 cmꢁ1; EIMS m/z 422 (Mþ); HRMS m/z calcd for C23H26N4O4
422.1954, found 422.1953.
142.7,139.4,132.1,131.3,129.9,124.9,124.5,123.4,123.1,122.4,118.0,
110.5, 109.7, 108.0, 52.6, 52.4, 43.9, 41.6, 30.8, 29.2, 20.4, 20.3, 14.1;
IR (KBr) 2957, 1710,1492,1301 cmꢁ1; EIMS m/z 460 (Mþ); HRMS m/z
calcd for C27H32N4O3 460.2474, found 460.2429.
4.1.12. 30-Allyl-10-isopropyl-1-(2-methoxy-ethyl)-20-oxo-20,30-
dihydro-1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl
ester (8b)
4.1.17. 10-Butyl-1-isobutyl-30-(3-methoxy-benzyl)-20-oxo-20,30-
dihydro-1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl
ester (8g)
1H NMR (300 MHz, CDCl3)
d
8.53 (s, 1H), 8.05 (d, J¼8.5 Hz, 1H),
1H NMR (300 MHz, CDCl3)
d
8.49 (s, 1H), 8.01 (d, J¼8.5 Hz, 1H),
7.57–7.54 (m, 2H), 7.49 (d, J¼8.4 Hz, 1H), 7.29–7.26 (m, 1H), 5.93
(tdd, J¼11.2, 10.2, 5.4 Hz, 1H), 5.27–5.20 (m, 2H), 4.80 (septet,
J¼7.0 Hz, 1H), 4.56 (d, J¼5.3 Hz, 2H), 4.44 (t, J¼5.4 Hz, 2H), 3.96 (s,
3H), 3.82 (t, J¼5.3 Hz, 2H), 3.31 (s, 3H), 1.59 (d, J¼6.9 Hz, 6H); 13C
7.43–7.37 (m, 2H), 7.28–7.11 (m, 3H), 6.88 (d, J¼7.6 Hz, 1H), 6.84 (s,
1H), 6.78 (d, J¼8.1 Hz, 1H), 5.10 (s, 2H), 4.01–3.93 (m, 7H), 3.74 (s,
3H), 1.99 (m, 1H), 1.82 (quint, J¼7.4 Hz, 2H), 1.45 (sextet, J¼7.7 Hz,
2H), 1.00 (t, J¼7.2 Hz, 3H), 0.63 (d, J¼6.6 Hz, 6H); 13C NMR (75 MHz,
NMR (75 MHz, CDCl3)
d
168.0, 156.5, 154.0, 142.8, 139.7, 132.2, 130.3,
CDCl3) d 167.9, 160.3, 156.2, 154.8, 142.5, 139.3, 137.9, 131.3, 130.2,
130.2, 125.1, 124.8, 123.3, 122.7, 122.4, 118.1, 110.4, 110.2, 109.2, 71.1,
129.7, 124.9, 124.5, 123.4, 123.3, 122.3, 120.0, 113.5, 113.4, 110.5,

H.-Y. Chen et al. / Tetrahedron 64 (2008) 6387–6394
6393
109.7, 108.1, 55.5, 52.4, 52.4, 45.2, 41.7, 30.8, 29.0, 20.4, 20.2, 14.1; IR
(KBr) 2958, 1712, 1492, 1302 cmꢁ1; EIMS m/z 540 (Mþ); HRMS m/z
calcd for C32H36N4O4 540.2737, found 540.2713.
113.3, 110.5, 109.7, 109.3, 55.5, 52.4, 45.9, 45.2, 30.0, 29.1, 20.7, 20.2;
IR (KBr) 2957, 1708, 1489, 1301 cmꢁ1; EIMS m/z 526 (Mþ); HRMS m/
z calcd for C31H34N4O4 526.2580, found 526.2582.
4.1.18. 10-Butyl-1-isobutyl-30-(3-methyl-but-2-enyl)-20-oxo-20,30-
dihydro-1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl
ester (8h)
4.1.23. 1-Isobutyl-10-isopropyl-30-(3-methyl-but-2-enyl)-20-oxo-
20,30-dihydro-1,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid
methyl ester (8m)
1H NMR (300 MHz, CDCl3)
d
8.54 (s, 1H), 8.05 (d, J¼8.5 Hz, 1H),
1H NMR (300 MHz, CDCl3)
d
8.53 (s, 1H), 8.04 (d, J¼8.5 Hz, 1H),
7.46–7.40 (m, 2H), 7.31 (s, 1H), 7.12 (d, J¼8.1 Hz, 1H), 5.29 (t,
J¼6.6 Hz, 1H), 4.55 (d, J¼6.6 Hz, 2H), 4.14 (d, J¼7.5 Hz, 2H), 3.99–
3.92 (m, 5H), 2.02–1.97 (m, 1H), 1.84 (s, 3H), 1.84–1.72 (m, 2H), 1.72
(s, 3H), 1.44 (sextet, J¼7.6 Hz, 2H), 0.99 (t, J¼7.4 Hz, 3H), 0.77 (d,
7.44 (d, J¼8.5 Hz, 1H), 7.39 (d, J¼8.1 Hz, 1H), 7.30–7.24 (m, 2H), 5.29
(t, J¼6.6 Hz, 1H), 4.80 (septet, J¼6.9 Hz, 1H), 4.54 (d, J¼6.6 Hz, 1H),
4.13 (d, J¼7.6 Hz, 2H), 3.97 (s, 3H), 2.04 (m, 1H), 1.84 (s, 3H), 1.73 (s,
3H),1.59 (d, J¼6.9 Hz, 6H), 0.78 (d, J¼6.6 Hz, 6H); 13C NMR (75 MHz,
J¼6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d
167.9, 156.4, 154.5, 139.3,
CDCl3) d 168.0, 156.4, 153.9, 142.7, 139.4, 137.2, 130.1, 125.0, 124.6,
137.3, 131.4, 130.0, 125.0, 124.6, 123.0, 122.3, 118.9, 110.6, 109.4,
107.9, 52.6, 52.5, 41.6, 39.6, 30.9, 29.2, 26.0, 20.5, 20.3, 18.5, 14.1; IR
(KBr) 2958, 1712, 1492, 1301 cmꢁ1; EIMS m/z 488 (Mþ); HRMS m/z
calcd for C29H36N4O3 488.2787, found 488.2759.
122.7, 122.4, 118.9, 110.6, 109.4, 109.1, 52.6, 52.5, 45.7, 39.6, 29.2,
26.0, 20.7, 20.3,18.5; IR (KBr) 2927,1709,1488,1301 cmꢁ1; EIMS m/z
474 (Mþ); HRMS m/z calcd for C28H34N4O3 474.2631, found
474.2637.
4.1.19. 10-Butyl-1-isobutyl-20-oxo-30-(3-phenyl-allyl)-20,30-dihydro-
4.1.24. 10-Isobutyl-1-(2-methoxy-ethyl)-30-methyl-20-oxo-20,30-
dihydro-1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl
ester (8n)
1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl ester (8i)
1H NMR (300 MHz, CDCl3)
d
8.51 (s, 1H), 8.01 (d, J¼8.5 Hz, 1H),
7.44–7.21 (m, 8H), 7.14 (d, J¼8.0 Hz, 1H), 6.63 (d, J¼15.9 Hz, 1H),
6.28 (dt, J¼15.9, 5.9 Hz, 1H), 4.74 (d, J¼5.9 Hz, 2H), 4.03 (d, J¼7.5 Hz,
2H), 4.00–3.95 (m, 5H), 1.99 (m, 1H), 1.81 (quint, J¼7.3 Hz, 2H), 1.45
(sextet, J¼7.6 Hz, 2H), 1.00 (t, J¼7.2 Hz, 3H), 0.62 (d, J¼6.6 Hz, 6H);
1H NMR (300 MHz, CDCl3)
d
8.52 (s, 1H), 8.04 (d, J¼8.5 Hz, 1H),
7.59 (s, 1H), 7.55 (d, J¼8.1 Hz, 1H), 7.48 (d, J¼8.5 Hz, 1H), 7.11 (d,
J¼8.0 Hz, 1H), 4.47 (t, J¼5.3 Hz, 2H), 3.96 (s, 3H), 3.83 (t, J¼5.3 Hz,
2H), 3.73 (d, J¼7.4 Hz, 2H), 3.48 (s, 3H), 3.31 (s, 3H), 2.22 (m, 1H),
13C NMR (75 MHz, CDCl3)
d
167.9, 156.3, 154.4, 142.7, 139.4, 136.3,
0.99 (d, J¼6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 167.9, 156.5,
133.7, 131.3, 129.8, 128.9, 128.3, 126.8, 124.9, 124.5, 123.4, 123.4,
123.2, 122.3, 110.6, 109.6, 108.1, 52.5, 52.4, 43.6, 41.6, 30.9, 29.1, 20.5,
20.2; IR (KBr) 2958, 1711, 1492, 1301 cmꢁ1; EIMS m/z 536 (Mþ);
HRMS m/z calcd for C33H36N4O3 536.2787, found 536.2832.
155.2, 142.7, 139.4, 131.7, 130.7, 125.1, 124.7, 123.3, 122.7, 122.2, 110.4,
109.6, 108.0, 71.0, 59.5, 52.5, 49.2, 45.6, 28.4, 27.7, 20.5; IR (KBr)
2956, 1712, 1496, 1302 cmꢁ1; EIMS m/z 436 (Mþ); HRMS m/z calcd
for C24H28N4O4 436.2111, found 436.2121.
4.1.20. 1-Isobutyl-10-isopropyl-30-methyl-20-oxo-20,30-dihydro-
4.1.25. 30-Allyl-10-isobutyl-1-(2-methoxy-ethyl)-20-oxo-20,30-
dihydro-1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl
ester (8o)
1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl ester (8j)
1H NMR (300 MHz, CDCl3)
d
8.51 (s, 1H), 8.02 (d, J¼8.5 Hz, 1H),
7.42 (d, J¼8.6 Hz, 1H), 7.38 (s, 1H), 7.35 (d, J¼8.1 Hz, 1H), 7.23 (d,
J¼8.6 Hz, 1H), 4.76 (septet, J¼6.9 Hz, 1H), 4.15 (d, J¼7.5 Hz, 2H), 3.94
(s, 3H), 3.45 (s, 3H), 2.11 (m, 1H), 1.57 (d, J¼6.9 Hz, 6H), 0.76 (d,
1H NMR (300 MHz, CDCl3)
d
8.52 (s, 1H), 8.04 (d, J¼8.5 Hz, 1H),
7.58–7.55 (m, 2H), 7.49 (d, J¼8.5 Hz, 1H), 7.13 (d, J¼8.5 Hz, 1H), 5.93
(tdd, J¼11.0, 10.7, 5.3 Hz, 1H), 5.24–5.18 (m, 2H), 4.58 (d, J¼5.2 Hz,
2H), 4.44 (t, J¼5.3 Hz, 2H), 3.96 (s, 3H), 3.82 (t, J¼5.3 Hz, 2H), 3.75
(d, J¼7.4 Hz, 2H), 3.30 (s, 3H), 2.24 (septet, J¼6.8 Hz, 1H), 1.00 (d,
J¼6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 168.0, 156.3, 154.3, 142.7,
139.5, 131.0, 130.0, 124.9, 124.5, 123.2, 122.4, 122.3, 110.6, 109.1,
108.9, 52.6, 52.4, 45.7, 29.2, 27.6, 20.7, 20.3; IR (KBr) 2959, 1711,
1493, 1302 cmꢁ1; EIMS m/z 420 (Mþ); HRMS m/z calcd for
J¼6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 168.0, 156.5, 154.7, 142.8,
139.4,132.1,131.7, 129.8,125.1,124.6, 123.6,122.8,122.3,118.0, 110.4,
110.1, 108.2, 71.0, 59.5, 52.5, 49.2, 45.6, 43.9, 28.3, 20.5; IR (KBr)
2956, 1711, 1493, 1302 cmꢁ1; EIMS m/z 462 (Mþ); HRMS m/z calcd
for C26H30N4O4 462.2267, found 462.2277.
C
24H28N4O3 420.2161, found 420.2144.
4.1.21. 30-Allyl-1-isobutyl-10-isopropyl-20-oxo-20,30-dihydro-
1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl
ester (8k)
4.1.26. 10-Isobutyl-30-(3-methoxy-benzyl)-1-(2-methoxy-ethyl)-20-
oxo-20,30-dihydro-1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic
acid methyl ester (8p)
1H NMR (300 MHz, CDCl3)
d
8.51 (s, 1H), 8.02 (d, J¼8.5 Hz, 1H),
7.43–7.37 (m, 2H), 7.33 (s, 1H), 7.26 (d, J¼8.2 Hz, 1H), 5.92 (tdd,
J¼11.1, 10.4, 5.3 Hz, 1H), 5.24–5.17 (m, 2H), 4.79 (septet, J¼6.9 Hz,
1H), 4.55 (d, J¼5.3 Hz, 2H), 4.12 (d, J¼7.6 Hz, 2H), 3.95 (s, 3H), 2.08
(m, 1H), 1.59 (d, J¼6.9 Hz, 6H), 0.76 (d, J¼6.6 Hz, 6H); 13C NMR
1H NMR (300 MHz, CDCl3)
d
8.50 (s, 1H), 8.02 (d, J¼8.5 Hz, 1H),
7.56 (d, J¼8.1 Hz, 1H), 7.47–7.44 (m, 2H), 7.28–7.19 (m, 1H), 7.13 (d,
J¼8.1 Hz, 1H), 6.92–6.87 (m, 2H), 6.78 (d, J¼8.1 Hz, 1H), 5.12 (s, 2H),
4.31 (t, J¼5.2 Hz, 2H), 3.95 (s, 3H), 3.79 (d, J¼7.4 Hz, 2H), 3.74 (s, 3H),
3.70 (t, J¼5.2 Hz, 2H), 3.22 (s, 3H), 2.28 (septet, J¼6.7 Hz, 1H), 1.02
(75 MHz, CDCl3) d 168.0, 156.3, 153.9, 142.7, 139.4, 132.1, 130.1, 130.1,
124.9, 124.5, 123.1, 122.8, 122.4, 118.0, 110.5, 109.6, 109.2, 52.6, 52.4,
45.8, 43.8, 29.2, 20.7, 20.3; IR (KBr) 2960, 1712, 1489, 1302 cmꢁ1
;
(d, J¼6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 168.0, 160.3, 156.4,
EIMS m/z 446 (Mþ); HRMS m/z calcd for C26H30N4O3 446.2318,
155.1, 142.7, 139.4, 138.0, 131.7, 130.2, 129.6, 125.0, 124.6, 123.9,
122.8, 122.2, 120.0, 113.6, 113.3, 110.4, 110.1, 108.4, 70.9, 59.5, 55.5,
52.4, 49.2, 45.5, 45.1, 28.3, 20.5; IR (KBr) 2957, 1710, 1491,
1302 cmꢁ1; EIMS m/z 542 (Mþ); HRMS m/z calcd for C31H34N4O5
542.2529, found 542.2523.
found 446.2339.
4.1.22. 1-Isobutyl-10-isopropyl-30-(3-methoxy-benzyl)-20-oxo-20,30-
dihydro-1H,10H-[2,50] bisbenzoimidazolyl-5-carboxylic acid methyl
ester (8l)
1H NMR (300 MHz, CDCl3)
d
8.50 (s, 1H), 8.02 (d, J¼8.4 Hz, 1H),
4.1.27. (E)-Methyl-1-cyclopentyl-30-(3,7-dimethylocta-2,6-dienyl)-
10-isopropyl-20-oxo-2,50-bi(1H-benzo[d]imidazole)-5-
carboxylate (8q)
7.40 (d, J¼8.3 Hz, 1H), 7.29–7.17 (m, 3H), 6.91–6.78 (m, 3H), 5.10 (s,
1H), 4.84 (septet, J¼6.8 Hz, 1H), 3.96–3.94 (m, 2H), 3.76 (s, 3H),
2.07–1.96 (m, 1H), 1.63 (d, J¼6.9 Hz, 6H), 0.65 (d, J¼6.6 Hz, 6H); 13
C
1H NMR (300 MHz, CDCl3)
7.51 (d, J¼8.6 Hz, 1H), 7.34–7.24 (m, 3H), 5.30–5.26 (m, 1H), 5.04–
4.93 (m, 2H), 4.78 (quint, J¼6.9 Hz, 1H), 4.54 (d, J¼6.3 Hz, 2H), 3.94
d
8.51 (s, 1H), 7.98 (d, J¼8.5 Hz, 1H),
NMR (75 MHz, CDCl3)
d
168.0, 160.3, 156.2, 154.3, 142.7, 139.4, 137.9,
130.2, 130.2, 129.9, 124.9, 124.5, 123.1, 123.0, 122.4, 120.0, 113.6,

6394
H.-Y. Chen et al. / Tetrahedron 64 (2008) 6387–6394
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Acknowledgements
The authors thank the National Science Council of Taiwan for the
financial assistance and the authorities of the National Chiao Tung
University for providing the laboratory facilities.
Supplementary data
Representative 1H NMR and 13C NMR spectrum of compounds 7
and 8. This information is available free of charge via the internet at
<http://pubs.acs.org>. Supplementary data associated with this
article can be found in the online version, at doi:10.1016/
j.tet.2008.04.081.
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