Synthesis of 2-Alkoxy/Thioalkoxy Benzo[d]imidazoles and 2-Thione Benzo[d]imidazoles via a Phase-Based, Chemoselective Reaction

Article abstract of DOI:10.1021/acscombsci.7b00106

2-Alkoxy/thioalkoxy benzo-[d]-imidazole and 2-thione benzo-[d]-imidazole libraries were constructed in solution phase and on solid phase, respectively. The key step in this work is the phase-based chemoselective reaction of the 2-mercaptobenzo-[d]-imidazole intermediate with benzyl chloride (solution phase) and Merrifield resin (solid phase). In the solution-phase case, benzyl chloride reacted with the thiol group of 2-mercaptobenzo-[d]-imidazole, whereas in the solid-phase case, Merrifield resin was introduced at an internal amine group of benzo-[d]-imidazole. To afford the desired 2-alkoxy/thioalkoxy benzo-[d]-imidazole analogues, we used various alkyl halides, alcohols, and thiols in solution phase, and to obtain 2-thione benzo-[d]-imidazole derivatives on solid phase, we used diverse alkyl halides and boronic acids. Finally, to measure the drug potential to be orally active and the molecular diversity in three-dimensional (3D) space, we calculated physicochemical properties and displayed energy-minimized 3D structures. As a result, the libraries from solution phase and solid phase show distinct features in physicochemical properties and skeletal diversities in 3D space.

Full text of DOI:10.1021/acscombsci.7b00106

Subscriber access provided by UNIVERSITY OF MICHIGAN LIBRARY
Article
Synthesis of 2-Alkoxy/thioalkoxy Benzo[d]imidazoles and 2-Thione
Benzo[d]imidazoles via phase-based Chemo-Selective reaction
Hyo-Jeong Yoon, Seung-Ju Yang, and Young-Dae Gong
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.7b00106 • Publication Date (Web): 02 Nov 2017
Downloaded from http://pubs.acs.org on November 7, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
ACS Combinatorial Science is published by the American Chemical Society. 1155
Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 26
ACS Combinatorial Science
Graphical Abstract
1
2
3
4
5
6
7
8
Synthesis of 2-Alkoxy/thioalkoxy Benzo[d]imidazoles and 2-Thione
Benzo[d]imidazoles via a phase-based, Chemo-Selective reaction
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hyo-Jeong Yoon, Seung-Ju Yang, Young-Dae Gong*
Innovative Drug Library Research Center, Department of Chemistry, College of Science,
Dongguk University, 26, 3-ga, Pil-dong Jung-gu, Seoul 100-715, Korea
R3
Boc
N
Boc
N
R1
Chemo-selectivity
to Thiol
R1
R2
R1
R2
4 Steps
R4,5
N
X
S
SH
R2
X
N
N
N
Solution-phase
=
=
15
15
O,
S,
Samples
Samples
R3
Boc
N
R1
R2
Chemo-selectivity
to Amine
Boc
N
R1
R2
3 Steps
N
R1
R2
S
S
N
H
S
Solid-phase
N
N
H
34
Samples
* Corresponding author Tel.
ydgong@dongguk.edu
:
+82-2-2290-3206, Fax
:
+82-2-2260-1349
;
e-mail:
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 2 of 26
1
2
3
4
Synthesis of 2-Alkoxy/thioalkoxy Benzo[d]imidazoles and 2-Thione
Benzo[d]imidazoles via a phase-based, Chemo-Selective reaction
5
6
7
8
9
Hyo-Jeong Yoon, Seung-Ju Yang, Young-Dae Gong*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Innovative Drug Library Research Center, Department of Chemistry, College of Science,
Dongguk University, 26, 3-ga, Pil-dong Jung-gu, Seoul 100-715, Korea
Abstract : 2-Alkoxy/thioalkoxy benzo[d]imidazole and 2-thione benzo[d]imidazole library were
constructed in solution-phase and on solid-phase, respectively. The key step in this work is reaction
phase-based chemo-selective reaction of 2-mercapto benzo[d]imidazole intermediate with benzyl
chloride (solution-phase) and Merrifield resin (solid-phase). In the case of solution-phase, benzyl
chloride reacted with thiol group of 2-mercapto benzo[d]imidazole whereas, in the case of solid-phase,
Merrifield resin was introduced at internal amine group of benzo[d]imidazole. To afford desired 2-
alkoxy/thioalkoxy benzo[d]imidazole analogues, we used various alkyl halides, alcohols, and thiols in
solution-phase, and, to obtain 2-thione benzo[d]imidazole derivatives on solid-phase, we used diverse
alkyl halides, boronic acids. Finally, to measure drug potential to be orally active and molecular
diversity in 3D space, we calculated physicochemical properties and displayed energy minimized 3D
structure. As a result, both libraries from solution-phase and solid-phase show distinct features in
physicochemical properties and skeletal diversities in 3D space.
KEYWORDS : Benzo[d]imidazole, Solution-phase, Solid-phase,
ACS Paragon Plus Environment

Page 3 of 26
ACS Combinatorial Science
1
2
Introduction
3
4
5
6
7
8
9
A library of drug-like small molecules has been used in medicinal chemistry area to extract promising
biologically active molecule.1 Among drug-like small molecules, heterocyclic compounds have played
pivotal role due to its various biological potencies.2 In this respect, to construct a library of
heterocyclic compounds, combinatorial chemistry has been used as an efficient tool to generate
massive numbers of heterocyclic compounds with high level of diversity.3 In this context, we have
focused on the synthesis of benzo[d]imidazole analogues based on combinatorial chemistry since it
has been shown wide range of biological activities such as anti-cancer activity,4 anti-schizophrenia,5
anti-asthma6, anti-parasitic7 and anti-microbial8 (Figure 1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
N
S
N
HN
N
N
O
S
N
N
HN
O
D
O
O
N
H
OH
O
O
6
Inhibitor of Aurora Kinase4
4 receptor agonist5
CRTh2
receptor
antagonist
Dopamine
Ph
O
O
N
N
N
N
Ph
O
N
N
F
O
N
N
S
SH
F
Anti-parasitic7
Anti-microbial8
Figure 1. Representative biologically active compounds containing Benzo[d]imidazole core skeleton
Synthesis of Benzo[d]imidazole has been well studied in the literature.9 Sun and co-worker reported
microwave-assisted synthesis of Benzo[d]imidazole by using ionic liquid support.10 Gangi Reddy and
co-worker used indion 190 resin as a heterogeneous recyclable catalyst to afford2-aryl-1-arylmethyl-
1H-benzo[d]imidazoles.11 Recently, Bardajee and co-worker reported efficient protocol for the
synthesis of benzoimidazole analogues by using Fe(lll)-Schiffbase/SBA-15 as a nanocatalyst.12
Nevertheless, to our knowledge, combinatorial synthetic route for synthesis of benzo[d]imidazole is
rare.13 Thus, there are still challenges in developing useful method for synthesis of Benzo[d]imidazoles
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 4 of 26
in time- and cost-efficient manner. For this reason, as a part of our ongoing project aimed at a
construction of small molecule library,14 we aimed to develop an expedient, synthetic pathway to
construct a library of 2-alkoxy/thioalkoxy-Benzo[d]imidazole and 2-Thione-Benzo[d]imidazole from
one versatile intermediate via phase-based, chemo-selective reaction. Herein, we report our recent
progress on this project.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Results and Discussion
Scheme 1.a
Boc
Boc
N
Boc
N
Cl
R1
R2
R1
R2
NH2
NH2
R1
R2
NH
SH
S
a
c
N
N
b
NH2
4
2
3
1
Cl
d
h
R3
Boc
N
H
N
H
N
R1
R2
R1
R2
R1
R2
N
S
S
S
S
N
N
N
N
j
i
10
5
12
11
1
2
e
=
=
H)
l
Br, R
k,
(R
R3
R3
R3
R3
R1
R2
N
R4,5
N
N
N
S
S
X
S
O
N
N
N
N
O
g
f
H
13
=
or
S(9)
6
X
7
O(8)
o
a Reaction condition : (a)Boc2O, NaHCO3, MeCN, room temperature, 2 h. (b) CS2, Et3N, THF, 40 C, 2 h. (c) benzyl
o
chloride, K2CO3, DMF, 40 C, 3 h. (d) 20% TFA in DCM (v/v), room temperature, 0.5 h (e) Alkyl halide, NaH, THF,
room temperature 2 h. (f) mCPBA, DCM, room temperature, 4 h. (g) Nucleophiles, tBuOK, DMF, room temperature, 1 h.
o
(h) Merrifield resin (loading capacity : 2.2 mmol/g), Cs2CO3, DMF, 60 C, 8 h (i) 20% TFA in DCM (v/v), room
temperature, 4 h. (j) Alkyl halides, NaH, THF, 60 oC, 6 h. (k) Benzyl thiol, tBuOK, DMF, 60 oC, 4 h. (l) Pd2(dBa)3, xphos,
BaOH, 1,4-dioxane:H2O=9:1, 110 oC, 30 h. and then Benzyl thiol, tBuOK, DMF, 60 oC, 4 h.
The sequence used to prepare the versatile intermediate 3 uses the 1,2-phenylenediamine 1 as a starting
material. 1,2-Phenylenediamine 1 was mono-protected with a Boc group in the presence of NaHCO3
in ACN at room temperature for 0.5 h followed by desulfurative cyclization reaction with CS2 and
o
Et3N in THF at 40 C for 2 h to afford N-Boc protected benzo[d]imidazole-2-thiol 3. From the
intermediate 3, the reaction scheme was diverged into solution-phase synthesis and solid-phase
synthesis. (The yields for N-Boc protected 1,2-phenylenediamine 2 and N-Boc protected
ACS Paragon Plus Environment

Page 5 of 26
ACS Combinatorial Science
benzo[d]imidazole-2-thiol 3 in Table S1 and Table S2).
1
2
3
4
5
6
1. Solution-phase synthesis of 2-Alkoxy/thioalkoxy Benzo[d]imidazole derivatives
7
8
9
Scheme 2a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R3
Boc
N
1. Benzyl chloride, NaH
H
N
1. Alkyl halide, NaH
THF, rt, 2 h
THF, 40 o 3 h
N
C,
SH
S
S
O
rt
2.
mCPBA, DCM,
4 h
N
N
N
2. 20% TFA in
DCM
O
rt,
h
0.5
5
3
7
R3 Benzyl, 79%
=
83%
R3
R3
62%
=
=
4-Methoxybenzyl,
76%
4-methylbenzyl,
R3 4-benzonitrile, 54%
=
R3
48%
=
cyclopropyl,
R3 methyl, 41%
=
a
are overall
two steps
Yields
yield
The intermediate 3 reacted with benzyl chloride in the presence of NaH in THF at 40 oC for 3 h and
benzyl group was chemo-selectively introduced at thiol position followed by deprotection of Boc
group with 20% TFA in DCM to afford 2-(benzylthio)-1H-benzo[d]imidazole 5 in good yield (83%
for 2 steps). Next, various alkyl halides were introduced at amine group and then sulfide at 2-position
of benzo[d]imidazole was oxidized by using mCPBA to sulfone as a good leaving group for
nucleophilic aromatic substitution reaction. The yields for compounds 7 are ranged from moderate to
good yields (41~79% for 2 steps).
Table 1. Yields of 2-Alkoxy Benzo[d]imidazoles 8 and 2-thioalkoxy Benzo[d]imidazoles 9
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 6 of 26
1
2
3
4
5
6
R3
R3
R4,5
N
N
R4,5 XH
tBuOK
S
X
=
or
S)
O
(X
O
DMF, rt, 1 h
N
N
O
=
X
O(8), X(9)
7
7
8
9
Yield
(%)a
Yield
(%)a
X
O
O
O
O
O
O
O
O
O
O
O
R3
R4
X
R3
R5
No
8a
8b
8c
8d
8e
8f
No
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
Bn
Bn
Bn
Bn
Bn
Bn
N
86
80
88
78
69
75
54
88
80
88
87
S
9a
9b
9c
9d
9e
9f
49
35
74
65
70
73
41
53
93
66
O
O
O
O
O
S
S
S
S
S
S
S
S
S
O
N
N
O
O
O
O
O
O
8g
8h
8i
9g
9h
9i
O
N
N
N
N
8j
9j
N
8k
N
a is an obtained yield.
For the nucleophilic, aromatic substitution reaction with alcohols, we screened several reaction
conditions with NaH, K2CO3, and tBuOK, in THF, and DMF. Among these conditions, tBuOK in DMF
afforded the best results. The yields are summarized in Table 1 (8a ~ 8k). To increase molecular
diversity, we also used thiols as a nucleophile and the reaction smoothly proceeded under the same
conditions in moderate to good yields (Table 1, 9a ~ 9j).
2. Solid-phase synthesis of 2-Thione Benzo[d]imidazole derivatives
Scheme 3.
ACS Paragon Plus Environment

Page 7 of 26
ACS Combinatorial Science
R3
Boc
N
1
2
3
4
5
6
H
R1
Benzyl chloride, NaH
R1
R2
R1
R2
1.
resin,
CS2CO3
Merrifield
N
N
DMF, 60 o 8 h
C,
THF, 60 o 6 h
S
S
C,
S
R2
N
N
N
2. 20% TFA in
rt, 4 h
DCM
H
3
12
11
7
8
9
In the case of solid-phase, the intermediate 3 reacted with Merrifield resin at internal amine group,
chemo-selectively, in the presence of Cs2CO3 in DMF at 60 oC for 8 h (The study for optimization of
synthesis of 2-Thione-Benzo[d]imidazole 13aa in Table S3).15 After that, Boc group was deprotected
by 20% TFA in DCM to afford benzo[d]imidazole-2-thione terminated resin 11. As can be seen in
Figure 2a and 2b, we checked appearance and disappearance of the peak of the carbamate group at
1746, 1446 cm-1 by using ATR-FTIR. Next, for high molecular diversity in combinatorial manner, we
introduced numerous alkyl halides in the presence of NaH in DMF at 60 oC for 6 h to obtain N-alkyl
substituted benzo[d]imidazole-2-thione terminated resin 12.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. ATR-FTIR spectrum of representative resin 10, 11
Table 2. Yields and purities of the 2-Thione Benzo[d]imidazole derivatives 13
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 8 of 26
1
2
3
4
5
6
R3
R3
R1
R2
R1
Benzyl thiol,
tBuOK
N
N
S
S
DMF, 60 o 4 h
R2
C,
N
N
H
13
12
7
8
9
Yield Purity
Yield
(%)a
Purity
(%)b
R1
H
R2
H
R3
R1
H
R2
R3
No
No
(%)a
(%)b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13aa
13ab
13ac
57
100
nitro
nitro
nitro
13ar
13as
13at
51
54
33
96
89
H
H
53
47
95
89
H
N
H
H
H
100
F
13ad
13ae
13af
13ag
13ah
H
H
H
H
H
H
H
H
H
H
F3C
33
28
44
49
58
100 13au
H
nitro
Me
Me
Me
Me
12
30
15
19
16
97
99
100 13av Me
F3C
N
100 13aw Me
100
100
100
O
91
85
13ax Me
13ay Me
O
N
O
13ai
13aj
H
H
H
H
39
30
100 13az Me
100 13ba Me
Me
Me
43
30
100
100
Cl
O
13ak
H
H
30
100 13bb Cl
Cl
32
100
F3C
13al
H
H
H
H
16
25
100 13bc Cl
100 13bd Cl
Cl
Cl
51
48
100
100
O
H
3C
13am
13an
13ao
13ap
13aq
H
H
H
H
H
17
31
17
21
100 13be Cl
Cl
Cl
Cl
44
17
55
100
100
100
N
H
100
13bf Cl
nitro
nitro
100 13bg Cl
F3C
95
O
a is a yield for four steps. (Loading capacity of Merrifield resin is 2.2 mmol/g)
b is checked by LC-MS.
ACS Paragon Plus Environment

Page 9 of 26
ACS Combinatorial Science
1
2
3
4
5
6
7
8
9
To cleave our desired 2-Thione benzo[d]imidazoles 13 from the polymer support, we used benzyl thiol
in the presence of tBuOK in DMF at 60 oC for 4 h. To purify the crude product mixture of 13, we used
a short plug of silica with hexane / ethyl acetate. As a result, we could obtain diverse 2-thione
benzo[d]imidazole 13 analogues in good yields and high purities as shown in Table 2. In the case of
the nitro-substituted 2-thione benzo[d]imidazole 13 (13ap ~ 13au), the study for regio-selectivity is
described in Scheme S1, and the plausible mechanism for this cleavage reaction is depicted in the
scheme 4. First, deprotonated benzyl thiol attacks to methylene moiety, adjacent to nitrogen atom of
benzo[d]imidazole and there are two possibilities, Path A, and Path B (Scheme 4). In the reaction, the
methylene moieties are quite electrophilic due to the electronic withdrawing effect of thiourea group.16
To clarify the reaction mechanism, we checked LC-MS of crude product mixture (Figure S1).
According to the LC-MS result, Path B is favored rather than Path A and, it is probably due to the
steric hindrance of benzyl group (Path A) caused by single bond rotation between carbon and nitrogen
whereas, in the case of Path B, single bond rotation between carbon and nitrogen is inhibited by rigidity
of the backbone of Merrifield resin, which means that the methylene moiety is exposed to the
nucleophile.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Plausible mechanism for cleavage reaction
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 10 of 26
1
2
Path A
S
N
3
4
5
6
NH
S
N
N
Byproduct
S
S
7
8
9
N
S
Path B
12a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
S
N
H
13a
Table 3. Yields and purities of the Suzuki coupled 2-Thione Benzo[d]imidazole derivatives 13’
Pd
2(dBa)3
,
xphos
BaOH
N
N
N
Benzyl thiol, tBuOK
N
N
S
S
S
DMF, 60 o 4 h
C,
O=9:1
1,4-dioxane:H2
R2
R2
N
H
Br
110 o 30 h
C
,
12e
12'e
13'
Purity
(%)b
Purity
(%)b
No
R2
Yield (%)a
No
R2
Yield (%)a
N
13’a
13’d
39
22
100
100
-
33
24
21
100
100
100
13’b
13’c
13’e
13’f
O
S
O
O2N
NR
a is a yield for 5 steps. b is checked by LC-MS. NR : No reaction
To maximize skeletal diversity, we conducted Suzuki-coupling reaction with the bromo-substituted
benzo[d]imidazole 12e. Various alkyl groups derived from boronic acids were introduced at the
bromo-position in the presence of Pd2(dBa)3, XPhos, and BaOH in 1,4-dioxane and H2O (9:1, v/v),
and then desired Suzuki coupled 2-Thione benzo[d]imidazoles 13’were obtained through the cleavage
conditions in high yields and good purities (Table 3). However, in case of 4-nitrobenzeneboronic acid,
Suzuki coupling reaction is not going well (No 13’c in Table 3).
3. Calculation and alignment of Physicochemical Properties of Benzo[d]imidazole derivatives 8,
ACS Paragon Plus Environment

Page 11 of 26
ACS Combinatorial Science
9, and 13.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Calculation and comparison of physicochemical property of constructed library
In drug discovery process, one of the challenging goals is to develop orally available drug and
Lipinski’s Rule17 and some physicochemical parameters could be used as a guideline to measure the
possibility to be orally active. In this respect, physicochemical and biological parameters such as
molecular weight, ALogP, number of rotatable bonds, polar surface area, and number of hydrogen
bond acceptors and donors are displayed and we compared these parameters for the solution-phase
library and the solid-phase library (Figure 3). As can be seen in the Figure 3, in the case of ALogP,
molecular weight, and number of hydrogen bonding acceptors, both libraries show similar distribution
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 12 of 26
within a range of those predicted for reasonable oral bioavailable drugs whereas both libraries display
distinct properties in the number of hydrogen bonding donors, polar surface area, and number of
rotatable bonds. In medicinal chemistry, number of hydrogen bonding donor and polar surface area
are considered as key factors to interact with target protein through hydrogen bonding and non-
covalent interaction, respectively. In addition, rotatable bond affects flexibility of a compound, which
influences a level of drug metabolism. For these reasons, both libraries are expected to show different
biological and physicochemical properties.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. Alignment of energy minimized 3D structure of benzo[d]imidazole 8 (a), 9 (b), and 13 (c).
Lastly, 3D structural diversity of benzo[d]imidazole 8, 9, and 13 is displayed in Figure 4. As shown in
Figure 4, each energy minimized 3D structure is aligned with benzo[d]imidazole core skeleton and
the structures are diverged widely by various building blocks in 3D space. In the case of 2-
alkoxy/thioalkoxy benzo[d]imidazole 8 (Figure 4a), and 9 (Figure 4b) afforded from solution-phase,
each compound occupies 3D space in similar pattern whereas, 2-Thione benzo[d]imidazole 13
(Figure 4c) afforded from solid-phase shows different arrangement in 3D space.
In conclusion, we have developed expedient solution- and solid-phase synthetic route to generate
benzo[d]imidazole library in combinatorial manner. From the versatile intermediate 3, we could
generate 2-alkoxy/thioalkoxy-benzo[d]imidazole 8 / 9 and 2-Thione benzo[d]imidazole 13 via chemo-
selective reaction in solution-phase and solid-phase, respectively. To maximize molecular diversity,
we used various 1,2-phenylene diamines, alkyl halides, boronic acids, alcohols, and thiols as building
blocks. Finally, we calculated physicochemical properties of solution-phase library and solid-phase
ACS Paragon Plus Environment

Page 13 of 26
ACS Combinatorial Science
library, and displayed chemical structures in 3D space. As a result, both libraries have distinct
physicochemical properties and occupation in 3D space. We believe that these molecules would serve
valuable library for medicinal chemistry area and we will explore biological evaluation with the
libraries in hand.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental section
General procedure for synthesis : All chemicals were reagent grade and used as purchased.
Reactions were monitored by ATR-FTIR. Flash column chromatography was carried out on silica
1
13
gel(230-400 mesh). H NMR and C NMR spectra were recorded in δ units relative to deuterated
solvent as an internal reference using a 500 MHz NMR instrument. Liquid chromatography tandem
mass spectrometry analysis was performed on an electro spray ionization (ESI) mass spectrometer
with photodiode-array detector (PDA) detection.
Representative Procedure for the preparation of the 1-Boc protected phenylenediamine 2
NaHCO3 (12 mmol, 1.2 eq) was added to a stirred solution of benzene-1,2-diamine 1a (10 mmol, 1.0
eq) in ACN (10 mL), and then the mixture was stirred for 15 min at room temperature. Di-tertbutyl
di-carbonate (10 mmol, 1.0 eq) was added to the mixture, and stirred for 2 h. The ACN was evaporated
under reduced pressure, and the crude mixture was extracted by ethyl acetate, and distilled water. The
aqueous layer was back extracted by ethyl acetate. The combined organic layer was dried over by
MgSO4 and was filtered in accordance with the suction filtration procedure. The filtrate was
evaporated under reduced pressure, and was purified by using column chromatography (Hexane /
1
Ethyl Acetate) to afford tert-butyl (2-aminophenyl)carbamate 2a. : 69% yield; H NMR (500 MHz,
CDCl3) δ 7.31 (s, 3H), 7.02 (t, J = 7.1 Hz, 3H), 6.82 (t, 5H), 6.24 (s, 3H), 3.76 (s, 7H), 1.54 (s, 32H13C
NMR (126 MHz, DMSO) δ 153.64, 141.21, 124.92, 124.51, 123.75, 116.29, 115.71, 78.62, 28.19,
28.06. LC-MS/MS (ESI) : m/z = 209 [M + H]+, HRMS (ESI) m/z: [M + H]+ Calcd for 209.1285 ;
found 209.1282
Representative Procedure for the preparation of the 2-mercapto Benzo[d]imidazole 3
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 14 of 26
Et3N (10 mmol, 2.0 eq) was added to a stirred solution of tert-butyl (2-aminophenyl)carbamate 2a (5
mmol, 1.0 eq) in THF (16.7 mL), and then the mixture was stirred for 15 min at room temperature.
The reaction mixture was cooled down to 0 oC in ice-bath. CS2 (7.5 mmol, 1.5 eq) was added to the
mixture drop by drop, and then the mixture was heated up to 60 oC followed by stirring for 3 h. The
reaction mixture was cooled down to room temperature, and extracted by ethyl acetate and distilled
water. The aqueous layer was back extracted by ethyl acetate. The combined organic layer added
anhydrous MgSO4 to be dried and was filtered in accordance with the suction filtration procedure. The
filtrate was evaporated under reduced pressure, and purified by using column chromatography
(Hexane / Ethyl Acetate) to afford tert-butyl 2-mercapto-1H-benzo[d]imidazole-1-carboxylate 3a : 80%
yield; 1H NMR (500 MHz, CDCl3) δ 12.29 (s, 11H), 7.79 (d, J = 7.8 Hz, 11H), 7.27 (s, 10H), 7.25 ?
7.23 (m, 8H), 7.22 (d, J = 4.2 Hz, 3H), 1.75 (s, 110H). 13C NMR (126 MHz, CDCl3) δ 169.80, 148.49,
130.80, 130.46, 125.20, 123.74, 114.80, 109.95, 86.65, 28.19. LC-MS/MS (ESI) : m/z = 251.14[M +
H]+, HRMS (ESI) m/z: [M + H]+ Calcd for 251.0849 ; found 102.1266,151.0314
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Representative Procedure for the preparation of the tert-butyl 2-(benzylthio)-1H-benzo[d]-
imidazole-1-carboxylate 4
NaH (2.0 mmol, 2.0 eq) was added to a stirred solution of tert-butyl 2-mercapto-1H-
benzo[d]imidazole-1-carboxylate 3a (1 mmol, 1.0 eq) in THF (3.33 mL), and then the mixture was
stirred for 15 min. A benzyl chloride (1.3 mmol, 1.3 eq) was added to the mixture drop by drop, and
o
heated to 40 C followed by stirring for 2 h. The reaction mixture was cooled down to room
temperature, and was extracted by ethyl acetate and distilled water. The aqueous layer was back
extracted by ethyl acetate. The combined organic layer added anhydrous MgSO4 to be dried and was
filtered in accordance with the suction filtration procedure. The mixture was evaporated under reduced
pressure, and was purified by using column chromatography (Hexane / Ethyl Acetate) to afford tert-
butyl 2-(benzylthio)-1H-benzo[d]imidazole-1-carboxylate 4. : 89% yield; 1H NMR (500 MHz, DMSO)
δ 7.83 (d, J = 7.1 Hz, 1H), 7.68 – 7.60 (m, 1H), 7.52 (d, J = 7.4 Hz, 2H), 7.35 (t, 3H), 7.30 (t, 2H),
13
4.54 (s, 2H), 1.65 (s, 8H). C NMR (126 MHz, DMSO) δ 153.69, 148.18, 142.84, 136.85, 133.08,
ACS Paragon Plus Environment

Page 15 of 26
ACS Combinatorial Science
129.23, 128.49, 127.35, 124.26, 123.54, 118.07, 114.24, 86.42, 35.64, 27.53. LC-MS/MS (ESI) : m/z
= 341 [M + H]+, HRMS (ESI) m/z: [M + H]+ Calcd for 341.1318; found 341.1319
1
2
3
4
5
6
7
8
9
Representative Procedure for the preparation of the 2-(bezylthio)-1H-benzo[d]imidazole 5
tert-butyl 2-(benzylthio)-1H-benzo[d]imidazole-1-carboxylate 4a (1 mmol, 1.0 eq) was dissolved in
20% TFA of DCM (2 mL, v/v) at room temperature followed by stirring for 0.5 h. The mixture was
neutralized by sat’d NaHCO3 solution (aq), and was extracted by DCM. The aqueous layer was back
extracted by ethyl acetate. The combined organic layer added anhydrous MgSO4 to be dried and was
filtered in accordance with the suction filtration procedure. The mixture was evaporated under reduced
pressure, and was purified by using column chromatography (Hexane / Ethyl Acetate) to afford 2-
(benzylthio)-1H-benzo[d]imidazole 5. : 93% yield; 1H NMR (500 MHz, DMSO) δ 7.41 (d, J = 22.9
Hz, 8H), 7.26 (d, J = 29.3 Hz, 6H), 7.00 (s, 4H), 6.46 (s, 3H), 4.54 (s, 4H). 13C NMR 13C NMR (126
MHz, DMSO) δ 150.19, 140.09, 138.15, 132.73, 129.33, 128.96, 127.80, 122.78, 121.92, 114.30,
109.95, 35.63. LC-MS/MS (ESI) : m/z = 241 [M + H]+, HRMS (ESI) m/z: [M + H]+ Calcd for
241.0794; found 241.0798
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Representative Procedure for the preparation of the N-alkyl benzo[d]imidazole 6
NaH (1.0 mmol, 2.0 eq) was added to a stirred solution of 2-(benzylthio)-1H-benzo[d]imidazole 5 (0.5
mmol, 1.0 eq) in THF 1.67 mL at 0 oC, and then the mixture was stirred for 15 min. Benzyl chloride
(0.65 mmol, 1.3 eq) was added to the mixture drop by drop. The reaction mixture was heated to 40 oC
followed by stirring for 2 h. The reaction mixture was cooled down to room temperature, and was
extracted by ethyl acetate and distilled water. The aqueous layer was back extracted by ethyl acetate.
The combined organic layer added anhydrous MgSO4 to be dried and was filtered in accordance with
the suction filtration procedure. The filtrate was evaporated under reduced pressure, and was purified
by using column chromatography (Hexane / Ethyl acetate) to afford 1-benzyl-2-(benzylthio)-1H-
benzo[d]imidazole 6a : 94% yield, 1H NMR (500 MHz, DMSO) δ 7.65 (d, J = 7.6 Hz, 7H), 7.50 (d, J
= 7.3 Hz, 8H), 7.45 (d, J = 7.1 Hz, 14H), 7.30 (t, 20H), 7.26 (t, J = 8.4 Hz, 24H), 7.21 (t, J = 7.2 Hz,
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 16 of 26
12H), 7.13 (d, J = 6.9 Hz, 14H), 5.38 (s, 14H), 4.66 (s, 14H). 13C NMR (126 MHz, DMSO) δ 151.05,
142.04, 137.13, 136.07, 135.83, 128.97, 128.68, 128.52, 127.70, 127.51, 126.98, 122.21, 122.11,
117.46, 110.13, 46.81, 36.03. LC-MS/MS (ESI) : m/z = 331 [M + H]+, HRMS (ESI) m/z: [M + H]+
Calcd for 331.1263; found 331.1270
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Representative Procedure for the preparation of the N-alkyl-2-solfone benzo[d]imidazole 7
mCPBA (1.5 mmol, 3.0 eq) in DCM (5 mL) was added to a stirred solution of 1-benzyl-2-(benzylthio)-
1H-benzo[d]imidazole 6a (0.5 mmol, 1.0 eq) in DCM (5 mL) at 0 oC followed by stirring for 4 h at
o
room temperature. The mixture was neutralized by Sat’d NaCO3 aqueous solution at 0 C, and was
extracted by DCM. The aqueous layer was back extracted by DCM. The combined organic layer added
anhydrous MgSO4 to be dried and was filtered in accordance with the suction filtration procedure. The
filtrate was evaporated under reduced pressure, and was purified by using column chromatography
(Hexane / Ethyl acetate) to afford 1-benzyl-2-(benzylsulfonyl)-1H-benzo[d]imidazole 7a. : 84% yield,
1H NMR (500 MHz, DMSO) δ 7.65 (d, J = 7.6 Hz, 7H), 7.50 (d, J = 7.3 Hz, 8H), 7.45 (d, J = 7.1 Hz,
14H), 7.30 (t, 20H), 7.26 (t, J = 8.4 Hz, 24H), 7.21 (t, J = 7.2 Hz, 12H), 7.13 (d, J = 6.9 Hz, 14H),
5.38 (s, 14H), 4.66 (s, 14H). 13C NMR (126 MHz, CDCl3) δ 146.55, 141.18, 135.27, 133.22, 131.42,
130.08, 129.78, 129.30, 128.87, 128.16, 126.96, 126.26, 124.34, 121.86, 111.62, 61.67, 48.48. LC-
MS/MS (ESI) : m/z = 363.44 [M + H]+, HRMS (ESI) m/z: [M + H]+ Calcd for 363.1162; found
363.1164
1
2-(benzylsulfonyl)-1-(4-methoxybenzyl)-1H-benzo[d]imidazole 7b : 86% yield, H NMR (500
MHz, CDCl3) δ 8.11 (s, 5H), 8.01 (d, J = 7.8 Hz, 5H), 7.94 (dd, J = 6.1, 2.6 Hz, 4H), 7.59 (d, J = 7.8
Hz, 6H), 7.49 – 7.33 (m, 20H), 7.29 (dd, J = 13.7, 6.2 Hz, 12H), 7.23 (d, J = 7.4 Hz, 7H), 5.32 (s, 7H),
4.78 (s, 7H), 3.74 (s, 11H). 13C NMR (126 MHz, CDCl3) δ 159.41, 146.61, 141.34, 135.55, 131.52,
129.35, 128.96, 128.62, 127.40, 126.50, 126.21, 124.30, 121.98, 114.25, 111.72, 61.68, 55.34, 48.13.
LC-MS/MS (ESI) : m/z = 393 [M + H]+, HRMS (ESI) m/z: [M + H]+ Calcd for 393.1267; found
393.1255
ACS Paragon Plus Environment

Page 17 of 26
ACS Combinatorial Science
2-(benzylsulfonyl)-1-(4-methylbenzyl)-1H-benzo[d]imidazole 7c : 98% yield, 1H NMR (500 MHz,
CDCl3) δ 7.93 (d, J = 7.5 Hz, 1H), 7.38 (dt, J = 10.4, 7.1 Hz, 3H), 7.29 (t, J = 7.3 Hz, 3H), 7.23 (d, J
= 7.5 Hz, 2H), 7.03 (d, J = 7.8 Hz, 2H), 6.93 (d, J = 7.9 Hz, 2H), 5.36 (s, 2H), 4.75 (s, 2H), 2.27 (s,
3H). 13C NMR (126 MHz, CDCl3) δ 146.67, 141.34, 137.97, 135.62, 132.33, 131.52, 129.59, 129.35,
128.96, 127.08, 126.50, 126.23, 124.31, 121.99, 111.72, 61.70, 48.41, 21.20. LC-MS/MS (ESI) : m/z
= 377 [M + H]+, HRMS (ESI) m/z: [M + H]+ Calcd for 377.1318; found 377.1318
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
4-((2-(benzylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile 7d : 64% yield, H NMR
(500 MHz, CDCl3) δ 7.97 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.43 (t, 1H), 7.40 (t, 1H), 7.36
(d, J = 7.4 Hz, 1H), 7.27 (t, J = 7.4 Hz, 3H), 7.22 (d, J = 7.4 Hz, 2H), 7.17 (d, J = 8.0 Hz, 1H), 6.98 (d,
13
J = 8.0 Hz, 2H), 5.40 (s, 2H), 4.86 (s, 2H). C NMR (126 MHz, CDCl3) δ 146.46, 141.31, 140.53,
135.17, 132.73, 131.52, 129.46, 129.02, 127.40, 126.71, 126.49, 124.79, 122.28, 118.41, 112.06,
111.02, 61.65, 48.01. LC-MS/MS (ESI) : m/z = 388 [M + H]+, HRMS (ESI) m/z: [M + H]+ Calcd for
388.1114; found 388.1113
1
2-(benzylsulfonyl)-1-(cyclopropylmethyl)-1H-benzo[d]imidazole 7e : 72% yield, H NMR (500
MHz, CDCl3) δ 7.94 (d, J = 7.8 Hz, 2H), 7.45 (t, J = 4.9 Hz, 1H), 7.43 (d, J = 4.6 Hz, 2H), 7.41 (d, J
= 6.9 Hz, 3H), 7.32 (t, J = 7.2 Hz, 2H), 7.25 (d, J = 7.4 Hz, 3H), 7.21 (d, J = 7.6 Hz, 4H), 4.85 (s, 4H),
4.04 (d, J = 7.1 Hz, 4H), 1.15 (ddd, J = 12.3, 7.5, 5.0 Hz, 2H), 0.42 (d, J = 7.7 Hz, 3H), 0.36 (d, 3H).
13C NMR (126 MHz, CDCl3) δ 146.49, 141.32, 135.51, 131.41, 129.26, 128.88, 126.61, 125.95,
124.13, 121.95, 111.35, 61.75, 49.44, 11.61, 4.22. LC-MS/MS (ESI) : m/z = 327.11 [M + H]+,
HRMS (ESI) m/z: [M + H]+ Calcd for 327.1162; found 327.1162
2-(benzylsulfonyl)-1-methyl-1H-benzo[d]imidazole 7f : 75% yield, 1H NMR (500 MHz, CDCl3) δ
8.11 (d, 5H), 8.01 (d, J = 7.8 Hz, 5H), 7.94 (d, J = 8.2 Hz, 13H), 7.46 (t, 16H), 7.42 (dd, J = 10.0, 5.0
Hz, 19H), 7.33 (t, 27H), 7.27 (d, J = 3.4 Hz, 2H), 7.25 (d, J = 7.7 Hz, 21H), 7.16 (d, J = 7.8 Hz, 28H),
4.79 (s, 27H), 3.54 (s, 39H). 13C NMR (126 MHz, CDCl3) δ 146.45, 141.11, 135.96, 131.32, 129.39,
128.90, 126.66, 126.13, 124.26, 121.98, 110.66, 61.99, 31.12. LC-MS/MS (ESI) : m/z = 287.35 [M +
H]+, HRMS (ESI) m/z: [M + H]+ Calcd for 287.0849; found 287.0851
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 18 of 26
Representative Procedure for the preparation of 2-alkoxy benzo[d]imidazole 8
1
2
3
4
5
6
7
8
9
The tBuOK (0.75 mmol, 1.5 eq) was added to a stirred solution of benzyl alcohol (0.6 mmol, 1.2 eq)
in DMF (1.67 mL) at room temperature followed by stirring for 15 min. The 1-benzyl-2-
(benzylsulfonyl)-1H-benzo[d]imidazole 7a (0.5 mmol, 1.0 eq) was added to the mixture, and the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
mixture was heated to 40 C followed by stirring for 3 h. The reaction mixture was cooled down to
room temperature, and then extracted by ethyl acetate and distilled water. The aqueous layer was back
extracted by ethyl acetate. The combined organic layer was added anhydrous MgSO4 to be dried and
was filtered in accordance with the suction filtration procedure. The filtrate was evaporated under
reduced pressure, and was purified by column chromatography (Hexane / Ethyl acetate) to afford 1-
benzyl-2-(benzyloxy)-1H-benzo[d]imidazole 8a. : 86% yield, , 1H NMR (500 MHz, CDCl3) δ 7.59 (d,
J = 7.9 Hz, 2H), 7.43 (d, J = 6.3 Hz, 4H), 7.37 (d, J = 7.8 Hz, 6H), 7.27 (t, J = 7.8 Hz, 6H), 7.18 (dd,
J = 5.4, 2.8 Hz, 5H), 7.10 (d, J = 3.1 Hz, 4H), 5.62 (s, 4H), 5.17 (s, 4H). 13C NMR (126 MHz, CDCl3)
δ 157.19, 140.10, 136.12, 135.65, 133.70, 128.77, 128.59, 128.46, 128.07, 127.77, 127.13, 121.70,
121.13, 117.83, 108.70, 71.84, 45.75. LC-MS/MS (ESI) : m/z = 315.38 [M + H]+, HRMS (ESI) m/z:
[M + H]+ Calcd for 315.1492; found 315.1489
Representative Procedure for the preparation of 2-thioalkoxy benzo[d]imidazole 9
The tBuOK (0.75 mmol, 1.5 eq) was added to a stirred solution of furan-2-ylmethanethiol (0.6 mmol,
1.2 eq) in DMF (1.67 mL) at room temperature followed by stirring for 10 min. The 1-benzyl-2-
(benzylsulfonyl)-1H-benzo[d]imidazole 7a (0.5 mmol, 1.0 eq) was added to the mixture, and the
o
mixture was heated to 40 C followed by stirring for 3 h. The reaction mixture was cooled down to
room temperature, and then extracted by ethyl acetate and distilled water. The aqueous layer was back
extracted by ethyl acetate. The combined organic layer was added anhydrous MgSO4 to be dried and
was filtered in accordance with the suction filtration procedure. The filtrate was evaporated under
reduced pressure, and was purified by column chromatography (Hexane / Ethyl acetate) to afford 2-
((furan-2-ylmethyl)thio)-1-(4-methoxybenzyl)-1H-benzo[d]imidazole 9a. : 49% yield, 1H NMR (500
MHz, CDCl3) δ 7.73 (d, J = 7.9 Hz, 1H), 7.35 (s, 1H), 7.25 – 7.14 (m, 3H), 7.07 (d, J = 8.6 Hz, 2H),
ACS Paragon Plus Environment

Page 19 of 26
ACS Combinatorial Science
6.80 (d, J = 8.6 Hz, 2H), 6.28 (s, 2H), 5.19 (s, 2H), 4.67 (s, 2H), 3.75 (s, 3H). 13C NMR (126 MHz,
CDCl3) δ 159.22, 150.88, 149.89, 143.61, 142.46, 136.13, 128.29, 127.63, 122.19, 122.03, 118.47,
114.17, 110.68, 109.37, 108.79, 55.23, 47.11, 29.86. LC-MS/MS (ESI) : m/z = 351.43 [M + H]+,
HRMS (ESI) m/z: [M + H]+ Calcd for 351.1162; found 351.1147
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Representative Procedure for the preparation of 1-Boc protected benzo[d]imidazole resin 10
Cs2CO3 (11 mmol, 5.0 eq) was added to a stirred solution of tert-butyl 2-mercapto-1H-
benzo[d]imidazole-1-carboxylate 3a (11 mmol, 5.0 eq) in DMF (10 mL) at room temperature, and
the mixture was stirred for 15 min. The Merrifield resin (2.2 mmol, 1.0 eq, Loading capacity : 2.2
mmol/g) was added to the mixture, and the mixture was heated at 60 oC followed by shaking for 8 h.
The mixture was cooled down to room temperature, and was filtered followed by washing with DCM,
MeOH, H2O, MeOH (×2) and DCM (×2). The washed resin was dried under reduced pressure to afford
1-Boc protected benzo[d]imidazole resin 10.
Representative Procedure for the preparation of deprotected benzo[d]imidazole resin 11
1-Boc protected benzo[d]imidazole resin 10 (2.2 mmol) in 20% TFA of DCM was shaken at room
temperature for 4 h. The resin was filtered, and washed successively with sat’d NaHCO3 aqueous
solution, DCM, MeOH, H2O, MeOH (×2) and DCM (×2), and dried under reduced pressure to afford
deprotected benzo[d]imidazole resin 11.
Representative Procedure for the preparation of N-alkylated benzo[d]imidazole resin 12
The resin 11 (2.2 mmol, 1.0 eq) and NaH (11 mmol, 5.0 eq) in THF (12 mL) ) were shaken at room
temperature for 1 h. The benzyl chloride (11 mmol, 5.0 eq) was added to the mixture and, the mixture
was heated to 60 oC followed by shaking for 8 h. The mixture was filtered, and washed successively
with DCM, MeOH, H2O, MeOH (×2) and DCM (×2). The washed resin was dried under reduced
pressure to afford N-alkylated benzo[d]imidazole resin 12.
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 20 of 26
Representative Procedure for the preparation of 2-Thione benzo[d]imidazole 13
1
2
3
4
5
6
To obtain 2-mercapto benzo[d]imidazole 13, phenylmethanethiol (2.2 mmol, 5.0 eq) was stirred in
DMF with tBuOK (2.2 mmol, 5.0 eq) at room temperature. After 15 min, N-alkylated
7
8
9
o
benzo[d]imidazole resin 12 (0.44 mmol, 1.0 eq) was added to the mixture, and heated to 60 C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
followed by shaking for 5 h. The mixture was filtered, and washed successively with DCM, MeOH,
H2O, MeOH (×2) and DCM (×2). Washed solvent was evaporated and extracted with ethyl acetate
and distilled water. The aqueous layer was back extracted by ethyl acetate. The combined organic
layer was added anhydrous MgSO4 to be dried and was filtered in accordance with the suction filtration
procedure. The filtrate was evaporated under reduced pressure, and was purified by using column
chromatography to afford desired 1-benzyl-1,3-dihydro-2H-benzo[d]imidazole-2-thione 13aa : 57%
(4 step overall yield), 1H NMR (500 MHz, DMSO) δ 12.92 (s, 1H), 7.37 (d, J = 7.5 Hz, 2H), 7.32 (t,
J = 7.4 Hz, 2H), 7.26 (t, J = 7.4 Hz, 2H), 7.21 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.12 (t, J
= 7.5 Hz, 1H), 5.51s (s, 2H). 13C NMR (126 MHz, DMSO) δ 168.81, 136.37, 132.25, 130.82, 128.55,
127.52, 127.48, 123.05, 122.31, 109.85, 109.79, 46.07. LC-MS/MS (ESI) : m/z = 241.32 [M + H]+,
HRMS (ESI) m/z: [M + H]+ Calcd for 241.0794; found 241.0798
Representative Procedure for the preparation of Suzuki cross-coupled benzo[d]imidazole resin
12’ea
To obtain Suzuki cross-coupled benzo[d]imidazole resin 12’ea, Pd2(dba)3 (0.088 mmol, 0.2 eq),
XPhos (0.176 mmol, 0.4 eq), alkylboronic acid (1.32 mmol, 3.0 eq), and Cs2CO3 (1.32 mmol, 3.0 eq)
were added to the mixture of bromo substituted benzo[d]imidazole resin 12e (0.44 mmol, 1.0 eq) at
o
room temperature. The reaction mixture was heated to 110 C, and then was stirred for 30 h. The
mixture was cooled down to room temperature. The resin was filtered and washed successively with
DCM, MeOH, H2O, MeOH (×2), and DCM (×2), and dried under reduced pressure to afford Suzuki
cross-coupled resin 12’ea.
ACS Paragon Plus Environment

Page 21 of 26
ACS Combinatorial Science
Representative Procedure for the preparation of Suzuki cross-coupled 2-thione
benzo[d]imidazole 13’
1
2
3
4
5
6
7
8
To obtain Suzuki cross-coupled 2-thione benzo[d]imidazole 13’a, benzyl thiol (2.2 mmol, 5.0 eq) was
dissolved in DMF with tBuOK (2.2 mmol, 5.0 eq), and the mixture was stirred for 15 min at room
temperature. After 15 min, resin 12’ea was added to the mixture and stirred for 5 h at 60 oC, and then,
the resin was filtered, and washed successively with DCM, MeOH, H2O, MeOH (×2) and DCM (×2).
Washed solvent was evaporated to remove organic solvent, and the mixture was extracted by ethyl
acetate. The aqueous layer was back extracted by ethyl acetate. The combined organic layer was
washed by brine in three times, and was added anhydrous MgSO4 to be dried. The mixture was filtered
in accordance with the suction filtration procedure. The filtrate was evaporated under reduced pressure,
and was purified by column chromatography (Hexane / Ethyl acetate) to afford desired product 1-
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
benzyl-5-phenyl-1,3-dihydro-2H-benzo[d]imidazole-2-thione 13’a. : 25% (5 step overall yield), H
NMR (500 MHz, DMSO) δ 12.93 (s, 5H), 7.37 (d, J = 7.2 Hz, 13H), 7.32 (t, J = 7.1 Hz, 11H), 7.29 –
7.23 (m, 12H), 7.21 (d, J = 7.5 Hz, 5H), 7.17 (d, J = 7.1 Hz, 4H), 7.13 (dd, J = 14.1, 6.6 Hz, 6H), 5.51
13
(s, 10H). C NMR (126 MHz, DMSO) δ 169.80, 148.76, 140.56, 136.84, 136.19, 132.35, 129.44,
129.08, 128.04, 127.96, 127.72, 127.31, 121.94, 110.67, 108.21, 46.65. LC-MS/MS (ESI) : m/z =
318.41 [M + H]+, HRMS (ESI) m/z: [M + H]+ Calcd for 317.1107; found 317.1104
Supporting Information
Full analytical data of compounds, along with the copies of 1H NMR, 13C NMR, LC-MS, and HRMS
spectra of all the synthesized compounds, and complete description of the studies for the reactions;
this material is available free of charge via the Internet at http://pubs.acs.org
Acknowledgements
All authors were supported from the Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Education (No. 2016R1D1A1B04932654) and
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 22 of 26
by the Bio & Medical Technology Development Program of the National Research Foundation funded
by the Ministry of Science, ICT & Future Planning (No. 2014M3A9A9073847) in Korea.
1
2
3
4
5
6
7
8
9
References
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1. Swinney, D. C.; Anthony, J. How were new medicines discovered? Nat. Rev. Drug Discov.
2011, 10, 507–519.
2. (a) Krchnˇa´k, V.; Holladay, M. W. Solid Phase Heterocyclic Chemistry. Chem. Rev. 2002,
102, 61-92. (b) Nfzi, A.; Ostresh, J. M.; Houghten, R. A. The Current Status of Heterocyclic
Combinatorial Libraries. Chem. Rev. 1997, 97, 449-472. (c) Thompson, L. A.; Ellman, J. A.
Synthesis and Applications of Small Molecule Libraries. Chem. Rev. 1996, 96, 555-600. (d)
Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Combinatorial
synthesis — the design of compound libraries and their application to drug discovery.
Tetrahedron. 1995, 51, 8135-8173.
3. (a) Nicolaou, K. C.; Hanko, R.; Hatwig, W. Handbook of Combinatorial Chemistry; Wiley-
VCH: Washington, DC, 2002. (b) Wilson, S. R.; Czarnik, A. W. Combinatorial Chemistry,
Synthesis and Application; Wiley: New York, 1997. (c) Kennedy, J. P.; Williams, L.; Bridges,
T. M.; Daniels, R. N.; Weaver, D.; Lindsley, C. W. Application of Combinatorial Chemistry
Science on Modern Drug Discovery. J. Comb. Chem. 2008, 10, 345-354. (d) Dolle, R. E.; Le
Bourdonnec, B.; Goodman, A . J.; Morales, G. A.; Salvino, J. M.; Zhang, W. Comprehensive
Survey of Chemical Libraries for Drug Discovery and Chemical Biology: 2006. J. Comb.
Chem. 2007, 9, 855-902. (e) Dolle, R. E.; Le Bourdonnec, B.; Morales, G. A.; Moriarty, K. J.;
Salvino, J. M. Comprehensive Survey of Combinatorial Library Synthesis: 2005. J. Comb.
Chem. 2006, 8, 597-635.
4. Carry, J. C.; Clerc, F.; Minoux, H.; Schio, L.; Mauger, J.; Nair, A.; Parmantier, E.; Moigne,
R. L.; Delorme, C.; Nicolas, J. P.; Krick, A.; Abecassis, P. Y.; Crocq-Stuerga, V.; Pouzieux,
S.; Delarbre, L.; Maignan, S.; Bertrand, T.; Bjergarde, K.; Ma, N.; Lachaud, S.; Guizani, H.;
Lebel, R.; Doerflinger, G.; Monget, S.; Perron, S.; Gasse, F.; Angouillant-Boniface, O.;
ACS Paragon Plus Environment

Page 23 of 26
ACS Combinatorial Science
Filoche-Romme, B.; Murer, M.; Gontier, S.; Prevost, C.; Monteiro, M. L.; Combeau, C.
SAR156497, an Exquisitely Selective Inhibitor of Aurora Kinases. J. Med. Chem. 2015, 58,
362-375.
1
2
3
4
5
6
7
8
9
5. Wang, X.; Bhatia, P. A.; Daanen, J. F.; Latsaw, S. P.; Rohde, J.; Kolasa, T.; Hakeem, A. A.;
Matulenko, M. A.; Nakane, M.; Uchic, M. E.; Miller, L. N.; Chang, R.; Moreland, R. B.; Brioni,
J. D.; Stewart, A. O. Synthesis and evaluation of 3-aryl piperidine analogs as potent and
efficacious dopamine D4 receptor agonists. Bioorg. Med. Chem. 2005, 13, 4667-4678.
6. Pothier, J.; Riederer, M. A.; Peter, O.; Leroy, X.; Valdenaire, A.; Gnerre, C.; Fretz, H. Novel
2-(2-(benzylthio)-1H-benzo[d]imidazole-1-yl)acetic acids: Discovery and hit-to-lead
evolution of a selective CRTh2 receptor antagonist chemotype. Bioorg. Med. Chem. Lett. 2012,
22, 4660-4664.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7. Pérez-Villanueva, J.; Hernández-Campos, A.; Yépez-Mulia, L.; Méndez-Cuesta, C.; Méndez-
Lucio, O.; Hernández-Luis, F.; Castillo, R. Synthesis and antiprotozoal activity of novel 2-
{[2-(1H-imidazol- 1-yl)ethyl]sulfanyl}-1H-benzimidazole derivatives. Bioorg. Med. Chem.
Lett. 2013, 23, 4221-4224.
8. Doddaramappa, S. D.; Lokanatha Rai, K. M.; Srikantamurthy, N.; Chandra.; Chethan, J. Novel
5-functionalized-pyrazoles: Synthesis, characterization and pharmacological screening.
Bioorg. Med. Chem. Lett. 2015, 25, 3671-3675.
9. (a) Nale, D. B.; Bhanage, B. M. The use of various o-phenylenediamines and N-substituted
formamides as C1 sources in a zinc-catalyzed cyclization in the presence of
poly(methylhydrosiloxane) provides benzimidazoles in good yields. Benzoxazole and
benzothiazole derivates can also be synthesized. Synlett. 2015, 26, 2831-2834. (b) Mahesh, D.;
Sadhu, P.; Punniyamurthy, T. A one-pot, multicomponent reaction enables the transformation
of commercial aryl amines, aldehydes, and azides into valuable benzimidazole structural units
with wide substrate scope and diversity via an efficient copper-catalyzed amination of N-aryl
imines, in which imine acts as a directing group by chelating to the metal center. J. Org.
Chem. 2015, 80, 1644-1650. (c) Nguyen, T. B.; Le, J.; Ermolenko, L.; Al-Mourabit, A. A
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 24 of 26
broad range of functionalized 2-aryl benzimidazoles can be prepared by a solvent-free cobalt-
or iron-catalyzed redox condensation of 2-nitroanilines and benzylamines via benzylamine
oxidation, nitro reduction, condensation, and aromatization without any reducing or oxidizing
agent. The method can be extended to afford various other diazaheterocycles. Org.
Lett. 2013, 15, 6218-6221. (d) Baars, H.; Beyer, A.; Kohlhepp, S. V.; Bolm,
C. Intramolecular N-arylations of amidines mediated by potassium hydroxide in DMSO at
120°C enable the preparation of diversely substituted benzimidazoles in good yields. Org.
Lett. 2014, 16, 536-539.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10. Chanda, K.; Maiti, B.; Tseng, C. C.; Sun, C. M. Microwave-Assisted Linear Approach Toward
Highly Substituted Benzo[d]oxazol-5-yl-1H-benzo[d]imidazole on Ionic Liquid Support. ACS.
Comb. Sci. 2012, 14, 115-123.
11. Srinivasula Reddy, L.; Gangi Reddy, N. C.; Ram Reddy, T.; Lingappa, Y.; Mohan, R. B.
Chemoselective Synthesis of 2-Aryl-1-arylmethyl-1H-benzo[d]imidazoles Using Indion 190
Resin as a Heterogeneous Recyclable Catalyst. J. Korean Chem. Soc. 2011, 55, 304-307.
12. Bardajee, G. R.; Mohammadi, M.; Yari, H.; Ghaedi, A. Simple and efficient protocol for the
synthesis of benzoxazole, benzoimidazole and benzothiazole heterocycles using Fe(III)–
Schiff base/SBA-15 as a nanocatalyst. Chin. Chem. Lett. 2016, 27, 265-270.
13. Susanto, S.; Jung, N.; Brase, S. Solid phase syntheses of S,N-substituted 2-
mercaptobenzoimidazoles. RSC Adv. 2016, 6, 39573-39576.
14. Gong, Y. D.; Lee, T. Combinatorial Syntheses of Five-Membered Ring Heterocycles Using
Carbon Disulfide and a Solid Support. J. Comb. Chem. 2010, 12, 393-409.
15. We used the same condition in solution-phase and intermediate 3 reacted with benzyl chloride
at thiol group.
Boc
Boc
N
N
Cs2CO3
Cl
SH
S
DMF, 60 o 8 h
C,
N
N
4
3
97%
16. In our previous study, we experienced thiourea group plays as a leaving group due to its
electronic withdrawing effect.
ACS Paragon Plus Environment

Page 25 of 26
ACS Combinatorial Science
Si
1
2
3
4
5
6
O
O
S
O
N
N
N
H
Me
Me
O
N
H
Si
N
N
Me
O
S
NEt3
N
N
HNEt3
7
O
8
9
Yang, S. J.; Lee, J. M.; Lee, G. H.; Kim, N. Y.; Kim, Y. S.; Gong, Y. D. Microwave Assisted
Synthesis of 1,3,4-Oxadiazole/Thiohydantoin Hybrid Derivatives via Dehydrative Cycliztion of
Semicarbazide. Bull. Korean Chem. Soc. 2014, 35, 3609-3617.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
17. Lipinski, C. A.; Lombardo, F.; Doming, B. W.; Feeney, P. Experimental and computational
approaches to estimate solubility and permeability in drug discovery and development settings.
Adv. Drug Deliv Rev. 1997, 23, 3-25.
ACS Paragon Plus Environment

ACS Combinatorial Science
Page 26 of 26
1
2
3
4
5
Graphical Abstract
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of 2-Alkoxy/thioalkoxy Benzo[d]imidazoles and 2-Thione
Benzo[d]imidazoles via Reaction phase-based Chemo-Selective reaction
Hyo-Jeong Yoon, Seung-Ju Yang, Young-Dae Gong*
Innovative Drug Library Research Center, Department of Chemistry, College of Science,
Dongguk University, 26, 3-ga, Pil-dong Jung-gu, Seoul 100-715, Korea
* Corresponding author Tel. : +82-2-2290-3206, Fax : +82-2-2260-1349 ; e-mail:
ydgong@dongguk.edu
ACS Paragon Plus Environment