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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

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ACS Combinatorial Science

Graphical Abstract

Synthesis of 2-Alkoxy/thioalkoxy Benzo[d]imidazoles and 2-Thione Benzo[d]imidazoles via a 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

R1 R2

Boc N SH N

Chemo-selectivity R1 to Thiol Solution-phase

R2

Boc N S N

4 Steps

R1

R3 N

R2

N

R4,5 X

X = O, 15 Samples = S, 15 Samples

R1 R2

*

Corresponding

author

Boc N S N H

Tel.

Chemo-selectivity R1 to Amine Solid-phase

R2

Boc N S N

3 Steps

R1

R3 N

R2

N H

S

34 Samples

:

+82-2-2290-3206,

Fax

[email protected]

ACS Paragon Plus Environment

:

+82-2-2260-1349

;

e-mail:


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Synthesis of 2-Alkoxy/thioalkoxy Benzo[d]imidazoles and 2-Thione Benzo[d]imidazoles via a phase-based, Chemo-Selective reaction


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 2alkoxy/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,


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Introduction 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). O

O

N

S

HN O

N N

S N

N HN O

O

O

O

N

N H

OH

O

Inhibitor of Aurora Kinase4

Dopamine D4 receptor agonist

CRTh2 receptor antagonist6

5

Ph N N

N N O

N N

O F

Anti-parasitic

O

Ph F

S

O

7

N SH N 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-arylmethyl1H-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


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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.

Results and Discussion Scheme 1.a R1

NH2

R2

NH2

R1

Boc NH

R2

NH2

R1

Boc N

R2

N

b

2

R2

N

S

R1

H N

R2

N

12

N 4

h

d

R1

Boc N

H N

R2

N

S

S j

c

3 Cl

R3 N

Boc N

SH

a

1

R1

Cl

S

S i

N

10

11

5 e

k, l (R1 = Br, R2 = H)

R1

R3 N

R2

N H

R3 N S

13

R3 N

R4,5

S O O

X N

g

X = O(8) or S(9)

R3 N

N 7

S N

f 6

a Reaction condition : (a)Boc2O, NaHCO3, MeCN, room temperature, 2 h. (b) CS2, Et3N, THF, 40 oC, 2 h. (c) benzyl chloride, K2CO3, DMF, 40 oC, 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. (h) Merrifield resin (loading capacity : 2.2 mmol/g), Cs2CO3, DMF, 60 oC, 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 Et3N in THF at 40 oC 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

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benzo[d]imidazole-2-thiol 3 in Table S1 and Table S2).

1. Solution-phase synthesis of 2-Alkoxy/thioalkoxy Benzo[d]imidazole derivatives Scheme 2a Boc N SH N 3

1. Benzyl chloride, NaH THF, 40 oC, 3 h

H N

2. 20% TFA in DCM rt, 0.5 h

N

S 5

1. Alkyl halide, NaH THF, rt, 2 h

R3 N

2. mCPBA, DCM, rt 4h

N

S O O 7

R3 = Benzyl, 79% R3 = 4-Methoxybenzyl, 62% R3 = 4-methylbenzyl, 76% R3 = 4-benzonitrile, 54% R3 = cyclopropyl, 48% R3 = methyl, 41%

83%

a

Yields are two steps overall 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


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R3 N N

R3 N

tBuOK

R4,5 XH

S O O

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(X = O or S)

DMF, rt, 1 h

N X = O(8), X(9)

7

No

X

8a

O

8b

O

8c

O

R3

O

R4

Yield (%)a

No

X

Bn

86

9a

S

Bn

80

9b

S

Bn

88

9c

S

R4,5 X

R3

Yield (%)a

R5 O

O

O

O

49 35 74

N

8d

O

Bn

78

9d

S

O

65

N

8e

O

Bn

69

9e

S

8f

O

Bn

75

9f

S

8g

O

54

9g

S

8h

O

88

9h

S

O N

O O N

O

O

70 73 41 53

N

8i

O

O

N

80

9i

S

93

88

9j

S

66

N

a

O

8j

O

N

8k

O

N

O

87

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

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R1

Boc N

R2

N H

S 3

1. Merrifield resin, CS2CO3 DMF, 60 oC, 8 h

R1

H N

2. 20% TFA in DCM rt, 4 h

R2

N

S

Benzyl chloride, NaH THF, 60 oC, 6 h

11

R1

R3 N

R2

N

S 12

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.

Figure 2. ATR-FTIR spectrum of representative resin 10, 11

Table 2. Yields and purities of the 2-Thione Benzo[d]imidazole derivatives 13



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R3 N

R1

Benzyl thiol, tBuOK S

N

R2

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R1

R3 N

R2

N H

S

DMF, 60 oC, 4 h

13

12

Yield (%)a

Purity (%)b

No

R1

R2

H

57

100

13ar

H

nitro

H

H

53

95

13as

H

nitro

H

H

47

89

13at

H

33

100

13au

28

100

No

R1

R2

13aa

H

13ab 13ac

R3

Yield (%)a

Purity (%)b

51

96

54

89

nitro

33

100

H

nitro

12

97

13av

Me

Me

30

99

15

100

19

100

16

100

R3

N

F

13ad

H

H

13ae

H

H

13af

H

H

44

100

13aw

Me

Me

13ag

H

H

49

91

13ax

Me

Me

58

85

13ay

Me

Me

39

100

13az

Me

Me

43

100

30

100

13ba

Me

Me

30

100

30

100

13bb

Cl

Cl

32

100

51

100

48

100

44

100

F3C

N

F3C

O

O

13ah

H

H

N

O

13ai

H

H Cl

13aj

H

H

13ak

H

H

O

F3C

13al

H

H

16

100

13bc

Cl

Cl O

13am

H

H

13an

H

13ao

13ap

H3C

25

100

13bd

Cl

Cl

H

17

100

13be

Cl

Cl

H

H

31

100

13bf

Cl

Cl

17

100

H

nitro

17

100

13bg

Cl

Cl

55

100

21

95

F3C

13aq

H

nitro O

a b

is a yield for four steps. (Loading capacity of Merrifield resin is 2.2 mmol/g) is checked by LC-MS. ACS Paragon Plus Environment

N

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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.

Scheme 4. Plausible mechanism for cleavage reaction



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Path A

S

N S

N S

Byproduct

NH

S N N

Path B

12a

S

S N H 13a

Table 3. Yields and purities of the Suzuki coupled 2-Thione Benzo[d]imidazole derivatives 13’

Pd2(dBa)3, xphos BaOH

N S

1,4-dioxane:H2O=9:1 110 oC, 30 h

N

Br

N R2

N

Benzyl thiol, tBuOK S

N

DMF, 60 oC, 4 h

S

12'e

12e

R2

No

N H

R2 13'

Yield (%)a

Purity (%)b

No

39

100

13’d

22

100

13’e

NR

-

13’f

R2

Yield (%)a

Purity (%)b

33

100

24

100

21

100

N

13’a 13’b

O

13’c

O2N

S O

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,


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9, and 13.

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


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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 noncovalent 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.

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 2alkoxy/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 chemoselective 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

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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.

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 gel(230-400 mesh). 1H NMR and

13

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 / Ethyl Acetate) to afford tert-butyl (2-aminophenyl)carbamate 2a. : 69% yield; 1H 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


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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

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-1Hbenzo[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 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 mixture was evaporated under reduced pressure, and was purified by using column chromatography (Hexane / Ethyl Acetate) to afford tertbutyl 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), 4.54 (s, 2H), 1.65 (s, 8H). 13C NMR (126 MHz, DMSO) δ 153.69, 148.18, 142.84, 136.85, 133.08, ACS Paragon Plus Environment

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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

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

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)-1Hbenzo[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


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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

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 room temperature. The mixture was neutralized by Sat’d NaCO3 aqueous solution at 0 oC, 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, 1

H 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. LCMS/MS (ESI) : m/z = 363.44 [M + H]+, HRMS (ESI) m/z: [M + H]+ Calcd for 363.1162; found 363.1164 2-(benzylsulfonyl)-1-(4-methoxybenzyl)-1H-benzo[d]imidazole 7b : 86% yield, 1H 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


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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 4-((2-(benzylsulfonyl)-1H-benzo[d]imidazol-1-yl)methyl)benzonitrile 7d : 64% yield, 1H 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, J = 8.0 Hz, 2H), 5.40 (s, 2H), 4.86 (s, 2H). 13C 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 2-(benzylsulfonyl)-1-(cyclopropylmethyl)-1H-benzo[d]imidazole 7e : 72% yield, 1H 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). C NMR (126 MHz, CDCl3) δ 146.49, 141.32, 135.51, 131.41, 129.26, 128.88, 126.61, 125.95,

13

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



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Representative Procedure for the preparation of 2-alkoxy benzo[d]imidazole 8 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 mixture was heated to 40 oC 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 1benzyl-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 mixture was heated to 40 oC 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

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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

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-1Hbenzo[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.



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Representative Procedure for the preparation of 2-Thione benzo[d]imidazole 13 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 benzo[d]imidazole resin 12 (0.44 mmol, 1.0 eq) was added to the mixture, and heated to 60 oC 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 room temperature. The reaction mixture was heated to 110 oC, 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.


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Representative

Procedure

for

the

preparation

of

Suzuki

cross-coupled

2-thione

benzo[d]imidazole 13’ 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 1benzyl-5-phenyl-1,3-dihydro-2H-benzo[d]imidazole-2-thione 13’a. : 25% (5 step overall yield), 1H 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 (s, 10H).

13

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


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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.

References 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; WileyVCH: 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

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acids:

Discovery

and

hit-to-lead

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broad range of functionalized 2-aryl benzimidazoles can be prepared by a solvent-free cobaltor 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. 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 2mercaptobenzoimidazoles. 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 N

Cl

SH

Cs2CO3

S DMF, 60 oC, 8 h 97%

N 3

Boc N N 4

16. In our previous study, we experienced thiourea group plays as a leaving group due to its electronic withdrawing effect. ACS Paragon Plus Environment

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Si

N

O

O

S N

N N H H

Me

O Si

Me

O

O

Me N N

S

NEt3

N O

N

HNEt3

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. 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.



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Graphical Abstract

Synthesis of 2-Alkoxy/thioalkoxy Benzo[d]imidazoles and 2-Thione Benzo[d]imidazoles via Reaction phase-based Chemo-Selective reaction


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Thioalkoxy Benzo[d ... - ACS Publications

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