Construction of Druglike 2-Amido Benzo[ d]imidazole Analogues via Desulfurative Cyclization of Thiourea Intermediate Resin on Solid-Phase

Article abstract of DOI:10.1021/acscombsci.8b00004

A 2-amido benzo[d]imidazole library has been constructed by solid-phase synthesis. The key step of this solid-phase synthesis involves the preparation of polymer-bound 2-amino benzo[d]imidazole resin through desulfurative cyclization of thiourea resin using 2-chloro-1,3-dimethylimidazolinium chloride and N,N-diisopropylethylamine in dichloromethane (DCM), and the resin is then functionalized by acylation at the 2-amine position to afford 2-amidobenzo[d]imidazole resin. In the case of 2-amidobenzo[d]imidazole resin having a p-I or m-NO₂, the resin was further functionalized by Suzuki/Sonogashira-coupling (p-I) and reduction to the primary amine (m-NO₂) followed by acylation. Finally, the functionalized 2-amido-benzo[d]imidazole resin was cleaved from the polymer support by treatment with a cocktail of trifluoroacetic acid and DCM. As a result, we obtained 2-amidobenzo[d]imidazole analogues in high yield and good purities.

Full text of DOI:10.1021/acscombsci.8b00004

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Construction of Drug-like 2-Amido Benzo[d]imidazole Analogues via
Desulfurative Cyclization of Thiourea Intermediate Resin on Solid-phase
Hyun-Jeong Ryu, Seung-Ju Yang, Gee-Hyung Lee, and Young-Dae Gong
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.8b00004 • Publication Date (Web): 20 Mar 2018
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Graphical Abstract
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Construction of Drug-like 2-Amido Benzo[d]imidazole Analogues
via Desulfurative Cyclization of Thiourea Intermediate Resin
on Solid-phase
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Hyun-Jeong Ryu, Seung-Ju Yang, Gee-Hyung Lee, 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. : +82-2-2260-3206, Fax : +82-2-2290-1349 ; e-mail: ydgong@dongguk.edu
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Construction of Drugꢀlike 2ꢀAmido Benzo[d]imidazole Analogues
via Desulfurative Cyclization of Thiourea Intermediate Resin
on Solidꢀphase
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HyunꢀJeong Ryu, SeungꢀJu Yang, GeeꢀHyung Lee, YoungꢀDae 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.
Abstract: A 2ꢀamido benzo[d]imidazole library has been constructed by solidꢀphase synthesis. The
key step of this solidꢀphase synthesis involves the preparation of polymerꢀbound 2ꢀamino
benzo[d]imidazole resin through desulfurative cyclization of thiourea resin using DMC and DIPEA
in DCM, and the resin is then functionalized by acylation at the 2ꢀamine position to afford 2ꢀ
amidobenzo[d]imidazole resin. In the case of 2ꢀamidobenzo[d]imidazole resin having a pꢀI or mꢀ
NO2, the resin was further functionalized by Suzuki/Sonogashiraꢀcoupling (pꢀI) and reduction to the
primary amine (mꢀNO2) followed by acylation. Finally, the functionalized 2ꢀamidoꢀ
benzo[d]imidazole resin was cleaved from the polymer support by treatment with cocktail of TFA
and DCM. As a result, we obtained 2ꢀamidobenzo[d]imidazole analogues in high yield and good
purities.
KEYWORDS: Benzo[d]imidazole, Solidꢀphase, Desulfurative cyclization, Combinatorial synthesis
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Introduction
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Solidꢀphase organic synthesis (SPOS) is routinely used to prepare drugꢀlike, small organic molecules
in medicinal chemistry programs. This procedure enables the generation of massive numbers of
small molecules.1 Among these small molecules, heterocyclic compounds have played a vital role in
the development of therapeutic agents.2 Furthermore, to advance High Throughput Screening (HTS),
the demand for construction of a large number of members of a heterocyclic compound library has
increased. In this context, we have previously constructed a heterocyclic small molecule library on
solidꢀphase using a carbon disulfide linker3 and a Backꢀbonded Amide Linker (BAL).4 As a
continuation of our previous work, we now focus on the synthesis of 2ꢀamidobenzo[d]imidazole,
since benzo[d]imidazole is a well known biologically active structure in medicinal chemistry.5
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Figure 1. Representative biologically active compounds containing 2ꢀamidoꢀbenzo[d]imidazole
motif
Figure 1 shows that in particular, 2ꢀamidobenzo[d]imidazoles exhibit interesting biological activities,
such as opioid type drug,6 inhibitor of Epidermal Growth Factor Receptor (EGFR),7 Interleukinꢀ1
receptor associated kinaseꢀ4,8 Inducible Tꢀcell kinase (ITK),9 and histone demethylase JMJD2A.10
For this reason, benzo[d]imidazole core skeleton has been targeted for synthesis by many organic
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and medicinal chemists.11 However, although there are several synthetic methods in the literature to
afford 2ꢀamidobenzo[d]imidazole,12 it is difficult to introduce diverse amide group at the 2ꢀposition
of benzo[d]imidazole with the precedent methods, and the solidꢀphase synthesis of 2ꢀ
amidobenzo[d]imidazole analogues is rare.13 Thus, as a continuation of our ongoing project to
construct small molecule libraries, we have tried to develop an expedient method to make a 2ꢀ
amidobenzo[d]imidazole library on solidꢀphase in a combinatorial way. Herein, we report our recent
progress on this project.
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Results and Discussion
Scheme 1a
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a
Reaction condition: (a) CS2, Triethylamine, pꢀTsCl, THF, rt, 19 h (b) In the case of alkylamine(R2): K2CO3, DMF,
50 °C, 4 h; In the case of aniline(R2) KF, K2CO3, 170 °C, 9 h; In the case of pyrazineꢀ2ꢀamine(R2): KOH, DMSO, rt, 1.5
h (c) SnCl2 and E.A, 80 °C, 2 h; In the case of the reduction of pyrazineꢀ2ꢀamine: NH4Cl, Fe, THF/ D.W, 60 °C, 24 h; (d)
Triethylamine, THF, 50 °C, 12 h; (e) DMC, DIPEA, MC, rt, 6 h; (f) acid chlorides, pyridine, 60 °C, 12 h; (g) TFA, MC,
rt, 4 h; (h) SnCl2, DMF, rt, 12 h; (i) acid chlorides, pyridine, 60 °C, 12 h; (j) In the case of R2=benzyl: arylacetylenes,
Pd(PPh3)2Cl2, CuI, diethylamine, 60 °C, 12 h; In the case of R2=phenyl: arylacetylenes, Pd(PPh3)2Cl2, CuI, diethylamine,
rt, 24 h; (k) boronic acids, Ph2(dba)3, Xphos, CS2CO3, 1,4ꢀDioxane/ D.W, 110 °C, 12 h.
On the basis of solidꢀphase parallel synthesis, Scheme 1 shows the synthetic route to afford 2ꢀ
amidobenzo[d]imidazole analogues 9, 12, 14, and 16. To obtain thiourea resin 6, we used 4ꢀ
benzyloxyꢀ2ꢀmethoxybenzylamine (BOMBA) resin 1 as the starting material. BOMBA resin 1
reacted with CS2 and pꢀTsCl in the presence of Et3N in THF at room temperature for 18 h. The
formation of isothiocyanate terminated resin 2 was checked by its attenuated total reflection (ATR)
single bead Fourier transform infrared (FTIR) spectrum, which showed the presence of a typical
isothiocyanate peak at 2,071 cmꢀ1 (Fig. S1). Resin 2 was reacted with 1,2ꢀphenylenediamineꢀderived
from orthoꢀfluoro nitro benzene via nucleophilic aromatic substitution and reductionꢀto afford
thiourea resin 6 (yields for the nucleophilic aromatic substitution and the reduction reactions are
summarized in Table S1 and Table S2). The formation of thiourea resin 6 was signaled by the
disappearance of the isothiocyanate peak at 2,071 cmꢀ1 (Fig. S1). To obtain benzo[d]imidazole resin
7, we screened several solutionꢀphase reaction conditions for desulfurative cyclization (Table S3ꢀ5).
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As a result, we used 2ꢀchloroꢀ1,3ꢀdimethylimidazolinium chloride (DMC) for desulfurative
cyclization of the resin 6 and obtained benzo[d]imidazole resin 7 as signaled by an imine peak at
1,659 cmꢀ1 (Fig. S1). With resin 7 in hand, we introduced various acid chlorides at the 2ꢀamine
position to afford 2ꢀamidobenzo[d]imidazole resin 8. The reaction proceeded in pyridine at 60 °C for
12 h and we monitored by an amide peak at 1,670 cmꢀ1 (Fig. S1). To obtain our desired 2ꢀ
amidobenzo[d]imidazole derivative 9, resin 8 was treated with a cocktail of TFA and DCM (1:9, v/v)
at room temperature for 4 h (Table 1).
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Table 1. Yields and purities of the 2ꢀamidoꢀbenzo[d]imidazole derivatives 9
Yield Purity
Yield Purity
No
R1
R2
R3
No
R1
R2
R3
(%)a
(%)b
(%)a
(%)b
H
29
100
Cl
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100
9{1,1,1}
9{2,3,3}
H
H
H
H
H
H
41
27
22
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29
48
100
100
100
100
100
100
Cl
Cl
Cl
Cl
Cl
Cl
29
48
54
48
41
17
100
98.15
100
9{1,1,2}
9{1,1,3}
9{1,1,4}
9{1,2,1}
9{1,2,2}
9{1,2,3}
9{2,3,4}
9{2,4,1}
9{2,4,2}
9{2,4,3}
9{2,4,4}
9{2,5,1}
95.26
100
98.34
9{1,2,4}
H
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97.33
9{2,5,2}
Cl
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100
H
H
H
H
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28
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100
100
100
Cl
Cl
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Trace
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100
ꢀ
9{1,3,1}
9{1,3,2}
9{1,3,3}
9{1,3,4}
9{2,5,3}
9{2,5,4}
9{3,1,1}
9{3,1,2}
CH3
CH3
100
100
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H
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98.96
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94.24
ꢀ
CH3
CH3
CH3
CH3
CH3
CH3
CH3
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100
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9{1,4,1}
9{1,4,2}
9{1,4,3}
9{1,4,4}
9{1,5,1}
9{1,5,2}
9{1,5,3}
9{1,5,4}
9{2,1,1}
9{2,1,2}
9{2,1,3}
9{2,1,4}
9{2,2,1}
9{2,2,2}
9{2,2,3}
9{2,2,4}
9{2,3,1}
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H
48
25
100
H
34
14
100
H
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Trace
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ꢀ
H
40
92.98
98.65
94.43
100
H
Trace
30
9{3,3,2} CH3
37
Cl
Cl
Cl
Cl
Cl
Cl
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Cl
Cl
Cl
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98.54
94.19
ꢀ
CH3
CH3
CH3
CH3
CH3
CH3
CH3
29
9{3,3,3}
9{3,3,4}
9{3,4,1}
9{3,4,2}
9{3,4,3}
9{3,4,4}
9{3,5,1}
42
63
51
50
100
Trace
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48
100
98.28
100
100
100
100
97.68
49
100
31
28
100
21
12
94.03
100
30
9{3,5,2} CH3
42
20
CH3
26
97.33
100
9{3,5,3}
9{3,5,4}
29
CH3
29
a
b
is for fiveꢀstep overall yields (loading capacity of the resin 1 is 1.02 mmol/g). All of the purified products were
checked by LC/MS.
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As can be seen in Table 1, most of the 2ꢀamidobenzo[d]imidazole derivatives 9 were obtained in
good yields and high purities, 2ꢀamidobenzo[d]imidazole derivatives 9{1,5,4}, 9{2,1,4}, 9{2,5,4},
and 9{3,2,4} having a cyclopropane group at R3 were only obtained in a trace. Next, in the case of 2ꢀ
amidoꢀbenzo[d]imidazole resin 8’ equipped with a mꢀnitro group, the nitro group was reduced using
Tin(ll) chloride in DMF at room temperature for 12 h to generate 2ꢀamidobenzo[d]imidazole 10
having a primary amine at the meta position. The reaction was monitored by the disappearance of
nitro group peaks at 1,347 and 1,531 cmꢀ1 and the appearance of a broad amine peak at 3,330 cmꢀ1
(Fig. S1). Resin 10 was next reacted with various acid chlorides in pyridine (neat) at 60 °C. As a
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result, we obtained 2ꢀamidobenzo[d]imidazole resin 11, which was signaled by the disappearance of
the broad amine peak at 3,330 cmꢀ1 and the appearance of an amide peak at 1,680 cmꢀ1 (Fig. S1). To
afford the desired 2ꢀamidobenzo[d]imidazole 12, resin 11 was treated with a cocktail of TFA and
DCM (1:9, v/v) at room temperature for 4 h. Table 2 summarizes the yields and purities of 2ꢀ
amidobenzo[d]imidazole 12.
Table 2. Yields and purities of the 2ꢀamido benzo[d]imidazole derivatives 12
Yield
(%)a
Purity
(%)b
No
R1
R2
R4
H
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37
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100
100
100
100
100
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12{1,3,2}
12{1,3,3}
12{1,3,4}
12{1,3,5}
H
H
H
H
11
a
b
is for sevenꢀstep overall yields (loading capacity of the resin 1 is 1.02 mmol/g). All of the purified products were
checked by LC/MS.
Next, 2ꢀamidobenzo[d]imidazole 8’ having a pꢀiodo group was diversified by a Suzukiꢀcoupling
or Sonogashiraꢀcoupling reactions. First, we used diverse arylacetylenes to yield Sonogashiraꢀ
coupled 2ꢀamidobenzo[d]imidazole resin 13 in the presence of Pd(PPh3)2Cl2, CuI,
and
diethylamine at 60 °C for 12 h followed by treatment with cocktail of TFA and DCM (1:9, v/v) at
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room temperature for 4 h. As a result, we obtained Sonogashiraꢀcoupled 2ꢀamidobenzo[d]imidazole
14 in high yields and purities (Table 3). Finally, for more diversity on the 2ꢀamidobenzo[d]imidazole
core, we conducted Suzikiꢀcoupling reaction with a 2ꢀamidobenzo[d]imidazole 8’ having a pꢀiodo
group. The Suzikiꢀcoupling reaction proceeded well with boronic acids, Ph2(dba)3, Xphos, and
CS2CO3 in 1,4ꢀDioxane/ D.W (9:1, v/v) at 110 °C for 12 h. The Suzukiꢀcoupled 2ꢀ
amidobenzo[d]imidazole resin 15 was treated with a cocktail of TFA and DCM (1:9, v/v) at room
temperature for 4 h to yield Suzukiꢀcoupled 2ꢀamidobenzo[d]imidazole analogues 16. Table 3
summarizes the yields and purities.
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Table 3. Yields and purities of the 2ꢀamido benzo[d]imidazole derivatives 14 and 16
Yield Purity
Yield Purity
No
R1
R2
R6
No
R1
R2
R6
(%)a
(%)b
(%)a
(%)b
H
28
100
H
21
100
14{1,1,1}
16{1,1,1}
H
H
14
33
100
100
H
H
21
8
98.99
98.96
14{1,1,2}
14{1,1,3}
16{1,1,2}
16{1,1,3}
H
34
100
H
30
98.06
14{1,3,1}
16{1,3,1}
H
H
37
35
100
H
H
33
21
100
14{1,3,2}
14{1,3,3}
16{1,3,2}
16{1,3,3}
95.42
98.87
a is for sevenꢀstep overall yields (loading capacity of resin 1 is 1.02 mmol/g). b All of the purified products were checked
by LC/MS.
In the drug discovery process, the ultimate goal is often to develop orally available drugs. To
achieve this, Lipinski’s rule and related parameters are used to measure a drug’s potential to be used
as an orally available drug. In this context, we calculated the physicochemical properties of our 2ꢀ
amidobenzo[d]imidazole derivatives 9, 12, 14, and 16. Figure 2 shows that most of the key
parameters are within the range of those predicted to afford orally availability
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Figure 2. Physicochemical properties of 2ꢀamidobenzo[d]imidazole analogues.
In conclusion, we developed a robust solidꢀphase synthetic route to construct the 2ꢀamidoꢀ
benzo[d]imidazole libraries. Unlike the precedent methods,12 we first synthesized 2ꢀ
aminobenzo[d]imidazole core skeleton of resin 7, and then introduced numerous acid chlorides at the
2ꢀamine position to afford 2ꢀamidobenzo[d]imidazole resin 8. Resin 8 was treated with a cocktail of
TFA and DCM (1:9, v/v) to cleave our desired 2ꢀamidobenzo[d]imidazole analogues 9 in high yields
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and purities. In the case of mꢀnitro or pꢀiodo substituted 2ꢀamidobenzo[d]imidazole resin 8’, we
carried out further diversifications, such as amide formation or Suzuki and Sonogashiraꢀcouplings,
followed by cleavage by treatment with a cocktail of TFA and DCM (1:9, v/v), to yield numerous 2ꢀ
amidobenzo[d]imidazole derivatives 12, 14, and 16. Finally, to measure the potential of our
constructed libraries to afford orally available compounds, we calculated physicochemical
parameters such as ALogP, molecular weight, hydrogen bonding acceptor, and donor, rotatable bond,
and polar surface area. Indeed, most of the key parameters fall within the acceptable range for an
oral drug.
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Experimental section
General Procedure for Synthesis
All the chemicals were of reagent grade, and were used as purchased. Reactions were monitored by
TLC analysis using Merck silica gel 60 Fꢀ254 thin layer plates (for solutionꢀphase synthesis), and by
ATRꢀFTIR spectrometry (for solidꢀphase synthesis). The crude product mixtures were purified by
flash chromatography using CombiFlash® Rf+ (Teledyne ISCO). Flash column chromatography
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was carried out on Merck silica gel 60 (230−400 mesh). H NMR and 13C NMR spectra were
recorded in δ units relative to deuterated solvent as an internal reference using 500 MHz NMR
spectrometry (Bruker). For liquid chromatography tandem mass spectrometry (ESI, PDA detection),
a 6460 Triple Quad LC/MS (Agilent) was used. Highꢀresolution mass spectrometry was performed
using a 6550 iFunnel QꢀTOF LC/MS system (Agilent).
Representative Procedure for the Preparation of 2ꢀnitroanilines (4{1,1}−4{3,5})
In the case of alkyl amine : 1ꢀfluoroꢀ2ꢀnitrobenzene (1.47 ml, 14 mmol) was added to a stirred
solution of benzylamine (1.68 ml, 15.4 mmol) and K2CO3 (1.94 g, 14 mmol) in DMF (5 ml) at room
temperature. The reaction mixture was heated to 40 °C, and was stirred for 4 h. After 4 h, the
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reaction mixture was cooled to room temperature and extracted with ethyl acetate and distilled water.
The aqueous layer was backꢀextracted with ethyl acetate. The combined organic layers were dried
over MgSO4 and evaporated to afford the crude product, which was purified by column
chromatography on silica gel (hexane/E.A), to afford 3.297 g (94 %, orange solid) of the desired Nꢀ
benzylꢀ2ꢀnitroaniline 4{1,1}. 1H NMR (500 MHz, DMSO) δ 8.67 (t, J = 5.7 Hz, 1H), 8.08 (d, J = 8.6
Hz, 1H), 7.45 (dd, J = 8.3, 7.3 Hz, 1H), 7.35 (dt, J = 15.2, 7.8 Hz, 4H), 7.25 (t, J = 7.0 Hz, 1H), 6.91
(d, J = 8.7 Hz, 1H), 6.67 (dd, J = 8.4, 7.1 Hz, 1H), 4.63 (d, J = 6.1 Hz, 2H). LCꢀMS (ESI): m/z =
229.1 [M+H]+.
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In the case of aniline: aniline (2.05 ml, 22.5 mmol) was stirred with 1ꢀfluoroꢀ2ꢀnitrobenzene (1.58
ml, 15 mmol), K2CO3 (3.11 g, 22.5 mmol), and KF (0.8715 g, 15 mmol) at 170 °C for 9 h. The
reaction mixture was cooled to room temperature and extracted with ethyl acetate and distilled water.
The aqueous layer was backꢀextracted with ethyl acetate. The combined organic layers were dried
over MgSO4 and evaporated to afford the crude product, which was purified by column
chromatography on silica gel (hexane/E.A) to afford 2.919 g (91 %, redꢀorange solid) of the desired
2ꢀnitroꢀNꢀphenylaniline 4{1,3}. 1H NMR (500 MHz, DMSO) δ 9.37 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H),
7.51 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.4 Hz, 2H), 7.33 (d, J = 7.6 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H),
6.88 (t, J = 7.6 Hz, 1H). LCꢀMS (ESI): m/z = 215.1 [M+H]+.
In the case of 2ꢀaminopyrazine: 1ꢀfluoroꢀ2ꢀnitrobenzene (1.58 ml, 15 mmol) was added to a
stirred solution of 2ꢀaminopyrazine (2.1 ml, 22.5 mmol) and KOH (4.951 g, 75 mmol) in DMSO (18
ml) at room temperature. The reaction mixture was stirred for 1.5 h and extracted with ethyl acetate
and cold distilled water, after which the aqueous layer was removed. The aqueous layer was backꢀ
extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated to
afford the crude product, which was purified by column chromatography on silica gel (hexane/E.A),
1
to afford 2.3583 g (73 %, orange solid) of the desired Nꢀ(2ꢀnitrophenyl)pyrazinꢀ2ꢀamine 4{1,5}. H
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NMR (500 MHz, DMSO) δ 9.91 (s, 1H), 8.43 (s, 1H), 8.09 (d, J = 13.6 Hz, 2H), 8.05 (d, J = 8.3 Hz,
1H), 8.00 (d, J = 8.3 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H). LCꢀMS (ESI): m/z =
217.1 [M+H]+.
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Representative Procedure for the Preparation of 1,2ꢀdiamines (5{1,1}−5{3,5})
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In the case of alkyl amine and aniline: SnCl2 (11.2815 g, 50 mmol) was added to a stirred
solution of Nꢀbenzylꢀ2ꢀnitroaniline 4{1,1} (2.4 g, 10 mmol) in ethyl acetate. (20 ml). The reaction
mixture was stirred at 80 °C for 2 h, and the mixture was neutralized with saturated aqueous
NaHCO3 solution, undissolved material was removed by filtration with celite. The filtrate was
extracted with ethyl acetate and distilled water, after which the aqueous layer was removed. The
aqueous layer was backꢀextracted with ethyl acetate. The combined organic layers were dried over
MgSO4 and evaporated to afford the crude product, which was purified by column chromatography
on silica gel (hexane/E.A), to afford 1.919 g (90 %, dark red oil) of the desired N1ꢀbenzylbenzeneꢀ
1,2ꢀdiamine 5{1,1}. 1H NMR (500 MHz, DMSO) δ 7.37 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H),
7.22 (d, J = 7.3 Hz, 1H), 6.57 – 6.51 (m, 1H), 6.41 – 6.36 (m, 2H), 6.35 – 6.30 (m, 1H), 5.09 (t, J =
5.3 Hz, 1H), 4.55 (s, 2H), 4.28 (d, J = 5.4 Hz, 2H). LCꢀMS (ESI): m/z = 199.1 [M+H]+.
In the case of 2ꢀaminopyrazine: A solution of Nꢀ(2ꢀnitrophenyl)pyrazinꢀ2ꢀamine 4{1,5} (1.081 g,
5 mmol) in THF (26.25 ml) was followed by the addition of a solution of NH4Cl (1.3373 g, 25 mmol)
in H2O (8.75 ml). To the above was added Fe (1.3963 g, 25 mmol) in several batches, while
warming to a temperature of 60 °C, followed by shaking for 24 h. The reaction mixture was cooled
to room temperature and undissolved material was removed by filtration. The filtrate was dried over
MgSO4 and evaporated to afford the crude product, which was purified by column chromatography
on silica gel (hexane/THF), to afford 405.1 mg (44 %, orange solid) of the desired N1ꢀ(pyrazinꢀ2ꢀ
yl)benzeneꢀ1,2ꢀdiamine 5{1,5}. 1H NMR (500 MHz, DMSO) δ 8.32 (s, 1H), 8.00 (d, J = 1.4 Hz, 1H),
7.98 (dd, J = 2.7, 1.5 Hz, 1H), 7.80 (d, J = 2.7 Hz, 1H), 7.27 (dd, J = 7.8, 1.2 Hz, 1H), 6.90 (td, J =
7.9, 1.4 Hz, 1H), 6.75 (dd, J = 8.0, 1.4 Hz, 1H), 6.56 (td, J = 7.6, 1.4 Hz, 1H), 5.76 (s, 1H), 4.88 (s,
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2H). LCꢀMS (ESI): m/z = 187.2 [M+H]+.
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Representative Procedure for the Preparation of the Isothiocyanate Terminated Resin 2
To a mixture of BOMBA resin 1 (8 g, 8.24 mmol) in THF (65 mL), Et3N (11.48 ml, 82.4 mmol) and
CS2 (2.98 ml, 49.44 mmol) were added at 0 °C, resulting in a suspension. After shaking the
suspension for 3 h at room temperature, pꢀTsCl (9.43 g, 49.44 mmol) was added slowly at 0 °C, and
the suspension was shaken for 12 h at room temperature. Isothiocyanate terminated resin 2 was
filtered, washed successively with THF (60 mL), MeOH (100 mL), H2O (100 mL), MeOH (×2) (150
mL), and DCM (×2) (150 mL), and dried under high vacuum.
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Representative Procedure for the Preparation of the Thiourea Resin 6 (6{1,1}ꢀ6{3,5})
To a mixture of isothiocyanate terminated resin 2 (1.55 g, 1.52 mmol) in THF (10 ml), Et3N (0.646
ml, 4.64 mmol) and N1ꢀbenzylbenzeneꢀ1,2ꢀdiamine 5{1,1} (0.92 g, 4.64 mmol) were added at room
temperature. The mixture was heated at 50 °C, followed by shaking for 12 h, filtered, washed
successively with DCM, MeOH, H2O, MeOH (×2), and DCM (×2), and dried under high vacuum.
Representative Procedure for the Preparation of the cyclized Resin 7
Preparation of 1ꢀ(2ꢀ(benzylamino)phenyl)thiourea Resin 6{1,1}. To a suspension of thiourea resin
6{1,1} (1.55 g, 1.52 mmol) in DCM (10 ml), DIPEA (0.809 ml, 4.64 mmol) and 2ꢀchloroꢀ1 3ꢀ
dimethylimidazolium chloride (0.786 g, 4.64 mmol) were added, successively. The reaction mixture
was shaken for 6 h at room temperature. 1ꢀBenzylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀamine resin 7{1,1} was
filtered, washed successively with DCM, MeOH, H2O, MeOH (×2), and DCM (×2), and dried under
high vacuum.
Representative Procedure for the Acylation Reaction (8{1,1,1}ꢀ8{3,5,4})
In the case of benzoyl chloride: Preparation of 1ꢀbenzylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀamine Resin 7{1,1}.
To a suspension of cyclized resin 7{1,1} (0.23 g, 0.204 mmol) in pyridine (2 ml), benzoyl chloride
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(0.119 ml, 1.02 mmol) and DMAP (cat. amount, 2ꢀ3 particles) were added successively. The reaction
mixture was shaken for 12 h at 60 °C. Nꢀ(1ꢀBenzylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀyl)benzamide resin
8{1,1,1} was filtered, washed successively with DCM, MeOH, H2O, MeOH (×2), and DCM (×2),
and dried under high vacuum.
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Representative Procedure for the Reduction Reaction
Preparation of 3ꢀnitroꢀNꢀ(1ꢀphenylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀyl)benzamide Resin 8’{1,3,5}. To a
suspension of acylated resin 8’{1,3,5} (1.0 g, 1.02 mmol) in DMF (5 ml), SnCl2 (1.15 g, 5.1 mmol)
was added successively. The reaction mixture was shaken for 12 h at room temperature. 3ꢀAminoꢀNꢀ
(1ꢀphenylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀyl)benzamide resin 10{1,3} was filtered, washed successively
with DCM, MeOH (×2), and DCM (×2), and dried under high vacuum.
Representative Procedure for the amide bond Reaction (11{1,3,1}ꢀ11{1,3,5})
Preparation of 3ꢀaminoꢀNꢀ(1ꢀphenylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀyl)benzamide Resin 10{1,3}. To a
suspension of reduced resin 10{1,3} (0.23 g, 0.204 mmol) in pyridine (2 ml), benzoyl chloride (0.119
ml, 1.02 mmol) and DMAP (cat. amount, 2ꢀ3 particles) were added successively. The reaction
mixture was shaken for 12 h at 60 °C. 3ꢀBenzamidoꢀNꢀ(1ꢀphenylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀ
yl)benzamide resin 11{1,3,1} was filtered, washed successively with DCM, MeOH (×2), and DCM
(×2), and dried under high vacuum.
Representative Procedure for the Sonogashira Coupling Reaction (13{1,1,1}ꢀ13{1,3,3})
In the case of R2 = benzyl: Preparation of Nꢀ(1ꢀbenzylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀyl)ꢀ4ꢀ
iodobenzamide resin 8’{1,1,6}. To a suspension of Nꢀ(1ꢀbenzylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀyl)ꢀ4ꢀ
iodobenzamide resin 8’{1,1,6} (0.25 g, 0.204 mmol) in DMF (1 ml), Pd(PPh3)2Cl2 (28.6 mg, 0.0408
mmol), CuI (7.8 mg, 0.0408 mmol), phenylacetylene (0.0672 ml, 0.612 mmol), and diethylamine
(0.1266 ml, 1.224 mmol) were added. The reaction mixture was shaken for 12 h at 60 °C. The resin
was filtered, washed successively with DCM, MeOH, H2O, MeOH (×2), and DCM (×2), and dried
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under high vacuum.
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In the case of R2 = phenyl: Preparation of 4ꢀiodoꢀNꢀ(1ꢀphenylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀ
yl)benzamide resin 8’{1,3,6}. To a suspension of 4ꢀiodoꢀNꢀ(1ꢀphenylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀ
yl)benzamide resin 8’{1,3,6} (0.25 g, 0.204 mmol) in DMF (1 ml), Pd(PPh3)2Cl2 (28.6 mg, 0.0408
mmol), CuI (7.8 mg, 0.0408 mmol), phenylacetylene (0.0672 ml, 0.612 mmol), and diethylamine
(0.1266 ml, 1.224 mmol) were added. The reaction mixture was shaken for 24 h at room temperature.
The resin was filtered, washed successively with DCM, MeOH, H2O, MeOH (×2), and DCM (×2),
and dried under high vacuum.
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Representative Procedure for the Suzuki Coupling Reaction (15{1,1,1}–15{1,3,3})
Preparation of Nꢀ(1ꢀbenzylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀyl)ꢀ4ꢀiodobenzamide resin 8’{1,1,6}. To a
suspension of Nꢀ(1ꢀbenzylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀyl)ꢀ4ꢀiodobenzamide resin 8’{1,1,6} (0.25 g,
0.204 mmol) in 1,4ꢀdioxane (1.8 ml), Pd2(dba)3 (37.4 mg, 0.0408 mmol), XPhos (39 mg, 0.0816
mmol), phenylboronic acid (74.6 mg, 0.612 mmol), and Cs2CO3 (332.2 mg, 1.02 mmol) dissolved in
H2O (0.2 ml) were added. The reaction mixture was shaken for 12 h at 110 °C, and cooled to room
temperature. The resin was filtered, washed successively with DCM, MeOH, H2O, MeOH (×2), and
DCM (×2), and dried under high vacuum.
Representative Procedure for the Cleavage Reaction
In the case of acylated resins : Acylated resin 8{1,1,1} (0.25 g, 0.204 mmol) was treated with a
mixture of TFA and DCM (1:9, v/v, 2 mL), and shaken for 4 h at room temperature. The resin was
filtered, washed with DCM and MeOH (×2), and the organic filtrate was collected and evaporated to
remove TFA. The residue was dissolved in DCM, purified by column chromatography on silica gel,
and triturated with hexane and ethyl acetate (9:1, v/v) to afford the desired product Nꢀ(1ꢀbenzylꢀ1Hꢀ
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benzo[d]imidazolꢀ2ꢀyl)benzamide 9{1,1,1} (29 %, fiveꢀsteps overall yield). H NMR (500 MHz,
CDCl3) δ 12.48 (s, 1H), 8.38 (d, J = 7.2 Hz, 2H), 7.52 – 7.40 (m, 5H), 7.38 – 7.26 (m, 4H), 7.18 (dd,
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J = 14.0, 6.7 Hz, 3H), 5.48 (s, 2H). C NMR (126 MHz, CDCl3) δ 176.74, 154.24, 137.95, 135.81,
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131.31, 129.43, 129.30, 128.90, 128.37, 128.03, 127.96, 127.74, 123.15, 123.12, 111.18, 109.82,
45.76. LCꢀMS (ESI): m/z = 328.3 [M+H]+. HRMS (ESI) m/z: [M+H]+ Calcd for C21H17N3O
328.1444; found 328.1463.
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In the case of acylated resins : Acylated resin 11{1,3,1} (0.25 g, 0.204 mmol) was treated with a
mixture of TFA and DCM (1:9, v/v, 2 mL), and shaken for 4 h at room temperature. The resin was
filtered, washed with DCM and MeOH (×2), and organic filtrate was collected and evaporated to
remove TFA. The residue was dissolved in DCM, purified by column chromatography on silica gel,
and triturated with hexane and ethyl acetate (9:1, v/v), to afford the desired product (3ꢀbenzamidoꢀNꢀ
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(1ꢀphenylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀyl)benzamide) 12{1,3,1} (24 %, sevenꢀsteps overall yield). H
NMR (500 MHz, DMSO) δ 13.02 (s, 1H), 10.38 (s, 1H), 8.46 (s, 1H), 7.98 (d, J = 7.2 Hz, 2H), 7.89
(d, J = 6.3 Hz, 1H), 7.74 (d, J = 18.5 Hz, 3H), 7.67 (dd, J = 17.5, 7.8 Hz, 3H), 7.64 – 7.57 (m, 2H),
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7.54 (t, J = 7.4 Hz, 3H), 7.36 (s, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.27 – 7.17 (m, 2H). C NMR (126
MHz, CDCl3) δ 168.87, 167.66, 143.50, 137.58, 132.98, 132.84, 132.16, 131.30, 130.85, 130.34,
129.96, 129.90, 128.98, 127.68, 127.40, 127.26, 127.18, 127.05, 126.91, 125.60, 121.31, 114.00,
111.90. LCꢀMS (ESI): m/z = 433.3 [M+H]+. HRMS (ESI) m/z: [M+H]+ Calcd for C27H20N4O2
433.1659; found 433.1676.
In the case of Sonogashira coupled resins : Sonogashira coupled resin 13{1,1,1} (0.25 g, 0.204
mmol) was treated with a mixture of TFA and DCM (1:9, v/v, 2 mL), and shaken for 4 h at room
temperature. The resin was filtered, washed with DCM and MeOH (×2), and organic filtrate was
collected and evaporated to remove TFA. The residue was dissolved in DCM, purified by column
chromatography on silica gel, and triturated with hexane and ethyl acetate (9:1, v/v), to afford the
desired product Nꢀ(1ꢀbenzylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀyl)ꢀ4ꢀ(phenylethynyl)benzamide 14{1,1,1
}
(28 %, sixꢀsteps overall yield). 1H NMR (500 MHz, CDCl3) δ 12.46 (s, 1H), 8.35 (d, J = 8.0 Hz, 2H),
7.60 (d, J = 8.0 Hz, 2H), 7.56 (dd, J = 7.3, 2.0 Hz, 2H), 7.43 (d, J = 7.2 Hz, 2H), 7.39 – 7.27 (m, 7H),
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7.24 – 7.15 (m, 3H), 5.49 (s, 2H). C NMR (126 MHz, CDCl3) δ 176.01, 154.16, 137.58, 135.73,
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131.69, 131.24, 129.42, 129.24, 128.93, 128.44, 128.38, 128.30, 128.08, 127.71, 126.08, 123.26,
123.23, 123.12, 111.22, 109.90, 91.25, 89.50, 45.81. LCꢀMS (ESI): m/z = 428.3 [M+H]+. HRMS
(ESI) m/z: [M+H]+ Calcd for C29H21N3O 428.1757; found 428.1776.
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In the case of Suzuki coupled resins : Suzuki coupled resin 15{1,1,1} (0.25 g, 0.204 mmol) was
treated with a mixture of TFA and DCM (1:9, v/v, 2 mL), and shaken for 4 h at room temperature.
The resin was filtered, washed with DCM and MeOH (×2), and organic filtrate was collected and
evaporated to remove TFA. The residue was dissolved in DCM, purified by column chromatography
on silica gel, and triturated with hexane and ethyl acetate (9:1, v/v) to afford the desired product (Nꢀ
(1ꢀbenzylꢀ1Hꢀbenzo[d]imidazolꢀ2ꢀyl)ꢀ[1,1'ꢀbiphenyl]ꢀ4ꢀcarboxamide) 16{1,1,1} (21 %, sixꢀsteps
overall yield). 1H NMR (500 MHz, CDCl3) δ 12.48 (s, 1H), 8.44 (d, J = 8.3 Hz, 2H), 7.67 (t, J = 8.2
Hz, 4H), 7.50 – 7.42 (m, 4H), 7.34 (ddd, J = 25.2, 16.6, 8.4 Hz, 5H), 7.23 – 7.15 (m, 3H), 5.50 (s,
2H). 13C NMR (126 MHz, CDCl3) δ 176.53, 154.21, 143.96, 140.73, 136.86, 135.82, 129.82, 129.45,
128.92, 128.81, 128.36, 128.05, 127.76, 127.66, 127.27, 126.72, 123.17, 123.14, 111.17, 109.83,
45.79. LCꢀMS (ESI): m/z = 404.3 [M+H]+. HRMS (ESI) m/z: [M+H]+ Calcd for C27H21N3O
404.1757; found 404.1778.
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Acknowledgment
All authors were supported by the Basic Science Research Program through the National Research
Foundation of Korea (NRF), funded by the Ministry of Education (No. 2016R1D1A1B04932654);
and 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.
Supporting Information Available: Full analytical data of compounds, along with copies of the 1H
NMR, 13C NMR, LC/MS, and HRMS spectra of all synthesized compounds, are available in the
Supporting Information.
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