Copper-promoted one-pot approach: Synthesis of benzimidazoles

Article abstract of DOI:10.3390/molecules25081788

A facile, one-pot, and proficient method was developed for the production of various 2-arylaminobenzimidazoles. This methodology is based for the first time on a copper catalyst promoted domino C-N cross-coupling reaction for the generation of 2-arylaminobenzimidazoles. Mechanistic investigations revealed that the synthetic pathway involves a copper-based desulphurization/nucleophilic substitution and a subsequent domino intra and intermolecular C-N cross-coupling reactions. Some of the issues typically encountered during the synthesis of 2-arylaminobezimidazoles, including the use of expensive catalytic systems and the low reactivity of bromo precursors, were addressed using this newly developed copper-catalyzed method. The reaction procedure is simple, generally with excellent substrate tolerance, and provides good to high yields of the desired products.

Full text of DOI:10.3390/molecules25081788

molecules
Article
Copper-Promoted One-Pot Approach:
Synthesis of Benzimidazoles
S. N. Murthy Boddapati 1,2 , Ramana Tamminana 3, Ravi Kumar Gollapudi 1,
Sharmila Nurbasha 1, Mohamed E. Assal 4, Osamah Alduhaish 4,
* ,
Mohammed Rafiq H. Siddiqui 4 , Hari Babu Bollikolla 1,* and Syed Farooq Adil 4,
*
1
Department of Chemistry, Acharya Nagarjuna University, Guntur, Andhar Pradesh 522510, India;
snmurthyboddapati@gmail.com (S.N.M.B.); ravig333@gmail.com (R.K.G.); nurbasha@gmail.com (S.N.)
Department of Chemistry, Sir C. R. Reddy College, PG Courses, Eluru, Andhra Pradesh 534002, India
Department of Chemistry, GITAM Deemed to Be University, Bengaluru Campus, Karnataka 562163, India;
rtamminana17@gmail.com
2
3
4
Department of Chemistry, College of Science, King Saud University, P.O. 2455, Riyadh 11451, Saudi Arabia;
masl@ksu.edu.sa (M.E.A.); rafiqs@ksu.edu.sa (M.R.H.S.)
*
Correspondence: oalduhaish@ksu.edu.sa (O.A.); dr.b.haribabu@gmail.com (H.B.B.);
sfadil@ksu.edu.sa (S.F.A.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Narciso M. Garrido
Received: 11 March 2020; Accepted: 9 April 2020; Published: 14 April 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: A facile, one-pot, and proficient method was developed for the production of various
2-arylaminobenzimidazoles. This methodology is based for the first time on a copper catalyst
promoted domino C–N cross-coupling reaction for the generation of 2-arylaminobenzimidazoles.
Mechanistic investigations revealed that the synthetic pathway involves a copper-based
desulphurization/nucleophilic substitution and a subsequent domino intra and intermolecular
C–N cross-coupling reactions. Some of the issues typically encountered during the synthesis of
2-arylaminobezimidazoles, including the use of expensive catalytic systems and the low reactivity of
bromo precursors, were addressed using this newly developed copper-catalyzed method. The reaction
procedure is simple, generally with excellent substrate tolerance, and provides good to high yields of
the desired products.
Keywords: copper catalyst; desulfurization; domino C–Ncross-coupling; 2-aminoaryl benzimidazole;
homogeneous catalysis
1. Introduction
Heterocyclic compounds like benzimidazoles are very important molecules that can be
found in a number of natural and synthetically prepared biologically active compounds such
as 3-chloro-1-5-(2-methyl-1H-bezimidazol-2-yl)-4-(substituted) phenylazetidin-2-one (an antimicrobial
compound [
thio-methyl-benzimidazole(an antiulcer molecule [
(an antiasthmatic compound [ ]), and 1-butyl-2-(3,4-dihydro-4,4-dimethyl-2H-thiochromyl)phenyl-1H-
benzo[d]imidazole (an anti-diabetic molecule [ ]), shown in Figure 1. Furthermore, these compounds have
been identified in N-methyl-d-aspartate (NMDA) antagonists [5], in analgesic [6], anti-inflammatory [7],
anti-cancer [ ] drugs, in factor Xa(FXa) inhibitors [ ], in poly(ADP-ribose)polymerase (PARP) inhibitors [10
1]), 5, 6-dichloro-1-(β-d-ribofuranosyl)benzimidazoles(an antiviral agent [2]), pyrimidyl-
3]), 1-ethyl-2-(4-phenyl)phenyl-1H-benzo[d]imidazole
4
4
8
9
]
and in non-peptide thrombin inhibitordrugs [11].
Molecules 2020, 25, 1788; doi:10.3390/molecules25081788
www.mdpi.com/journal/molecules

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Figure 1. Examples of some biologically active benzimidazoles.
Thus, enormous efforts have been focused on the preparation of benzimidazole structural
frameworks. Classical methods may involve (i) the inter cyclocondensation of 2-aminophenylaniline
precursors with either carboxylic acids or aldehydes followed by oxidation [12], (ii) the diazotization
on 1-benzimidazolylidenehydrazine [13], (iii) the cyclocondensation of esters with diaminobenzene
under microwave irradiation [14], (iv) the reductive cyclization of o-nitroaniline with aldehyde using
sodium dithionite [15] and (v) a solid-phase route [16]. However, most of these protocols suffer
from major shortcomings such as limited suitable substituents for diverse synthesis, strong alkaline
conditions, troublesome management of the chemical process, and elevated temperature. Therefore,
we reasoned that a catalytic approach involving C–N bond formation would overcome the
abovementioned disadvantages.
In the past decade, efficient methods have been described for the synthesis of heterocyclic
compounds by aryl halides with copper catalysts [17,18]. Buchwald and co-authors developed the
preparation of indulines [19], 2-aryl-4-quinolones [20] and N-alkylbenzimidazoles [21]. The group of Ma
described a cascade approach for the production of benzofurans [22], dihydrobenzimidazole-2-ones [23],
benzimidazoles [24], isoquinolines [25], pyrrolo [1,2-a]quinoxaline [26], and indoles [27]. Intramolecular
C–X bond formation has been established by Batey’s group to synthesize benzoxazoles [28],
benzothiazoles [29] and aminobenzimidazoles [30]. In addition, C–N bond formation has been
well explored using various transition metals such as copper [31,32], palladium [33], cobalt [34],
zinc [35], ruthenium [36] for the production of various heterocycles, but, to the best of our knowledge,
no report is available on the synthesis of substituted 2-aminophenylbenzimidazoles employing a copper
catalyst through the reporting strategy.
Very recently, 2-phenylaminobenzimidazoles have been reported from thiourea using cobalt
catalysis [37]; however, they have failed to develop from bromo precursors. Therefore, in continuation of
our research towards the development of efficient methodologies for the synthesis of heterocycles [38,39],
herein, we developed a methodology for the synthesis of 2-phenylamino benzimidazoles from molecules
having a bromo moiety, under moderate reaction conditions using copper catalysis. Another advantage
of our method is the use of copper, which is cheaper, more air-stable and more easily available
than cobalt.
2. Results and Discussion
In this context, 2-phenylaminobenzimidazoles were prepared from thiourea through an approach
consisting of consecutive desulphurization/nucleophilic substitution and C–N cross-coupling.
Thiourea reacted with 2-bromoaniline at room temperature using copper salt as a catalyst to give

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N-(2-bromophenyl)-guanidine, which further underwent a domino intra and intermolecular C–N
cross-coupling reaction with aryliodide to yield the desired product 2-phenylaminobenzimidazole 1a
(Scheme 1). Optimization was achieved by taking thiourea and bromoaniline as model substrates and
using various solvents, bases, ligands, and copper salts at different temperatures. We were pleased to
observe that thiourea gave 2-bromoguanidine in quantitative conversion using NaOAc as a base and
both copper (I) and copper (II) salts in the presence of DMSO/DMF at room temperature. The reaction
was further continued at room temperature using K2CO3 (2 equiv) as a base, Cu salt (20 mol%),
ligand L4 (20 mol%) for 18 h. Unfortunately, no target product was observed (Table 1, entry 1). Later,
the reaction was performed at 50 ◦C, however, no product formed (Table 1, entry 2). In contrast, target
product 1a was observed in 15% yield when the reaction was carried out at 80 ◦C (Table 1, entry 3).
The yield of the product increased to 52% when the reaction was conducted at 100 ◦C (Tabl◦e 1, entry 4).
Very interestingly, the reaction provided the desired product 1a quantitatively at 120 C (Table 1,
entry 5).
Scheme 1. Synthetic route for the synthesis of N-phenyl-1H-benzo[d]imidazol-2-amine.
Bases like K2CO3 and Cs2CO3 were found to be effective for the reaction (Table 1, entries 5
and 7), whereas KOH was less effective (Table 1, entry 6). All the tested copper salts, i.e., CuI, CuBr,
CuCl, CuSO4
·
5H2O, Cu(OAc)2 H2O, exhibited similar catalytic activity (Table 1, entries 5 and 8–11).
·
Among the tested ligands, L4 was efficient (Table 1, entry 5), while the other ligands L1–L3 and L5
provided the target product in lower yields (Table 1, entries 13–16). In contrast, the reaction didnot
proceed in the absence of ligand (Table 1, entry 12).
By lowering the quantity of the copper source (10 mol%) or of the base (1.0 equiv), the reaction
led to N-arylation, affording a lower amount of the target product (Table 1, entries 17–18). Control
experiments also confirmed that the reaction could not yield the target product in the absence of
a catalyst, and the intermediate 2-bromophenylguanidine was recovered intact (Table 1, entry 19).
This control experiments demonstrated that the reaction requires a catalyst. Despite the similar catalytic
activity of all the copper salts tested, considering the cost effectiveness of CuSO4
·
5H2O over the other
examined catalysts, the authors chosen CuSO4 5H2O as a reasonable copper source for both step 1
·
and step 2 in Scheme 1. Finally, the total outcome of the above optimization studies is presented in
Scheme 2.

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Table 1. Optimization of the reaction for the synthesis of 2-aminophenyl benzoimidazole a.
Entry
Copper Salt
Base
Temp ◦C
Ligand
Conversion e 1a
Yield (%) g
f
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
CuI
CuI
CuI
CuI
CuI
CuI
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOH
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
RT
50
80
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
-
L1
L2
L3
L5
L4
L4
L4
-
-
n.d.
n.d.
20
55
100
71
100
100
100
100
100
10
30
50
15
55
f
15
52
96
66
96
94
96
95
96
6
24
56
11
48
36
52
-
100
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
b
CuBr
CuCl
CuSO4·5H2O
Cu(OAc)2 H2O
·
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4
CuSO4·5H2O
·
5H2O c
K2CO3d
K2CO3
K2CO3
40
55
n.d.
f
-
a
Reaction conditions: Step-1: Thiourea (1 mmol); DMSO/DMF (2 mL); NaOAc (1 equiv); copper salt (50 mol%), 1 h,
room temperature; 2-bromo aniline (2 mmol), room temperature, 4 h; Step-2: iodo benzene (1 mmol); copper salt
(20 mol%); ligand (20 mol%); base (2 mmol) 18 h,temp; b Cs2CO3 (2.0 equiv); c copper salt (10 mol.%); d K2CO3
(1.0 equiv); e conversion based on diagnostic peaks integration in 1HNMR of crude reaction mixture; f n.d. = not
detected; gisolated yield.
Step-1
H
N
S
DMSO/DMF NaOAc (1 eq), RT,
CuSO4.5H2O (50 mol %), 1 h
NH
NH2
H2N
NH2
NH2
Br
RT, 4 h
Br
Step-2
PhI (1 eq), CuSO4.5H2O (20 mol %),
1,10-Phenanthroline (20 mol %)
DMSO, K2CO3/Cs2CO3 (2 eq),
120 °C, 18 h
N
NH
N
H
1a (96%)
Scheme 2. Optimized synthetic pathway for the synthesis of 2-phenylaminobenzimidazole
from thiourea.
The compound 1a was further confirmed based on spectral data, for example, the appearance of
characteristic peaks at 1542(m), 1478(s), 1413(s) cm−1, clearlyshowing Ar–C=C stretching, a peak at
3098(w) cm−1 showing aromatic =CH stretching, and peak at 3294(s) cm−1 indicating –N–H stretching.
In the 1H NMR spectrum of compound 1a, adoublet at
assigned to aromatic protons, and a broad singlet at
data allowed determining the structure of compound 1a as N-Phenyl-1H-benzo[d]imidazol-2-amine,
which was further confirmed by its 13C NMR spectrum which exposed 11 signals between
139.2 and
δ
7.78 ppm and amultiplet at
δ 7.26–7.11 ppm were
δ
6.12 ppm (br s, 1H) to a –N–H proton. This spectral
δ
110.8 ppm, indicates the existence of 11 different carbons in the compound. Further, the formation of
compound 1a was supported by the molecular ion peak at 210.10[M + H]+ in its mass spectrum (EI).

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Next, to validate the efficiency of the protocol, we investigated the substrate scope towards
the production of 15 more 2-arylaminobenzimidazoles 1b–1p under optimized conditions, and the
results are indicated in Figure 2. N-(2-bromophenyl)-guanidine was reacted with various derivatives
of aryl iodide having 2-CH3, 3-CH3, 4-CH3, 4-OCH3, 4-COOCH3, 4-Cl, 2,4-DiCH3, 2,6-DiCH3 and
naphthyl to obtain the final products 1b
holding substituents such as 2-Me, 3-Me, 4-Me, 4-CN readily provided the desired products 1k
–
1j in 62–97% yields. Similarly, the reaction of 2-bromoaniline
1n in
–
56–96% yields. In addition, several substrates were tested to understand the reactivity of aryl halides.
For example, thiourea reacted with 4-chloro-2-bromoaniline to provide guanidine which consecutively
underwent a C–N cross-coupling reaction with 4-methyliodobenzene and 4-nitroiodobenzene to afford
the target products 1o and 1p in 79% and 62% yields respectively. The above mentioned results
clearly confirmed that the substrates having electron-donating and electron-withdrawing groups are
compatible with this process, affording the substituted 2-aminobenzimidazoles in moderate to excellent
yield. All the spectroscopic and analytical data of the synthesized compounds were in full agreement
with the anticipated structures.
Figure 2. Substrate scope evaluation; Reaction conditions: thiourea (1 mmol); DMSO (2 mL); NaOAc
(1 equiv); CuSO4 5H2O (50 mol%), 1 h, room temperature; 2-bromo aniline/substituted 2-bromo aniline
·
(2 mmol), room temperature, 4 h; Next, ArI (1 mmol); CuSO4
(20 mol%); K2CO3 (2 mmol); 18 h; 120 ◦C; a Isolated yield.
·5H2O (20 mol%); 1,10-Phenanthroline

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The reaction of aryl halides was next examined under optimized reaction conditions. Iodobenzene
afforded the target product 1a in 96% yield (Equation (1)). On the other hand, bromobenzene
led to the target product 1a in 12% yield and to the product 2-aminobenzimidazole
yield (Equation (2)). However, no target product could be obtained when using chlorobenzene,
which provided 2-aminobenzimidazole in 97% yield (Equation (3)). In addition, we also examined
the activity of different haloanilines. It was observed that 2-iodoaniline readily reacted with thiourea
to give iodoguanidine , which required a shorter reaction time than bromoguanidine to undergo
a domino C–N cross-coupling reaction with iodobenzene, affording the desired product 1a in 96%
yield (Equation (4)). However, 2-chloroaniline gave the intermediate chloroguanidine in complete
B in 81%
B
C
D
conversion, but no domin O C–N cross-coupled product was observed with iodobenzene under
optimized reaction conditions (Equation (5)).
(1)
(2)
(3)
(4)

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(5)
To reveal the mechanism, control experiments were conducted. The reaction was performed in the
absence of aryl iodide and resulted inthe intramolecular C–N cyclized product 2-aminobenzimidazole
B
in 97% yield (Equation (6)) under optimized reaction conditions. Furthermore, 2-aminobenzimidazole
readily reacted with iodobenzene under optimized conditions to afford the target product 1a in 96%
yield (Equation (7)).
(6)
(7)
The above results clearly suggested that thiourea treated with 2-bromoaniline to provide
N-(2-bromophenyl)-guanidine
A gave first the intramolecular C–N cyclised product 2-amino
benzimidazole , which reacted with iodobenzene to providethe final product 1a by an intermolecular
B
C–N cross-coupling reaction.
Moreover, the formation of the key intermediate
B was confirmed based on its spectral data.
In fact, in the IR spectrum of compound
N–H stretching, the peak at 3063(w) cm−1 represents –C=C–H stretching, the peaks at 1626(s), 1530(s),
1444(s) cm−1 correspond to Ar–C=C stretching; 1H-NMR analysis showed a broad signal at
5.62(2H)
ppm, indicating amino protons and signals between 7.58 and 7.09 ppm representing aromatic protons.
Moreover, in the 13C NMR spectrum, seven signals between
167.0 and 118.2 ppm also confirmed
that compound is 1H-benzo[d]imidazol-2-amine. Finally, the structure of was confirmed by the
appearanceof a peak at m/z 134.07 [M + H]+ in its mass spectrum (EI).
Based on these experimental investigations and the available literature [37
B
, thepeaks at 3421(w) and 3396(w) cm−1 corresponds to
δ
δ
δ
B
B
,
40–50], the mechanism
for the formation of the final product 2-phenylaminobenzimidazole is very much similar to the
mechanism reported for cobalt catalysis [37] (see supporting information Scheme S1).
3. Experimental
3.1. Material and Methods
General information: 2-bromoaniline, iodobenzene, CuSO4
·
5H2O (98%), CuI (98%), CuBr (98%),
Cu2O (97%), CuCl (99%), Cu(OAc)2 H2O (98%), sodium acetate, KOH, K2CO3, and Cs2CO3 were
·

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purchased from Sigma-Aldrich (St. Luis, MO, USA) and were used without further purification.
The solvents were purchased and dried according to standard procedures prior to use. The reactions
were monitored by using pre-coated Merck60 F254 (Merck, Darmstadt, Germany) TLC silica gel plates
with 0.25 mm thickness. Column chromatography was performed for purification, utilizing silica gel
(60–120 mesh, Merck, Darmsadt, Germany). A Cintex melting point apparatus (Cintex, Mumbai, India)
was used to determine the melting points. Infrared (IR) spectra were recorded on a Perkin Elmer
Spectrum one FT-IR spectrometer (Perkin Elmer, Waltham, Massachusetts, USA). A Varian 400 MHz
spectrometer (Varian, Palo Alto, CA, USA) was utilized to record the 1H NMR and 13C-NMR spectra
in CDCl3/DMSO-d6. Chemical shifts are presented in
δ ppm, employing TMS as internal reference.
A Jeol SX-102 spectrometer (JEOL Ltd., Akishima, Tokyo, Japan) was used to record the Mass spectra.
3.2. General Procedure for the Synthesis of 2-(N-arylamino)Benzimidazole
To a stirred solution of DMSO (2–3 mL), thiourea (1 mmol, 76 mg) was added slowly, followed
by the addition of NaOAc (1 mmol, 82 mg) and a copper source (50 mol%) at room temperature.
The whole reaction mixture was stirred for 1 h (until a black-colored solution was obtained) at room
temperature. To this, 2-bromoaniline (2 mmol, 344 mg) was added. After completion of the reaction
(monitored by TLC), the reaction mixture was transferred into tubes and the mixture was centrifuged
for 10 min. A black solid was then recovered from the tubes, and to this a clear solution of iodobenzene
(1 mmol, 204 mg), K2CO3 (2 mmol, 277 mg), Cu(SO)4.5H2O (20 mol%, 50 mg), and 1,10-phenanthroline
(20 mol%, 36 mg) was◦added slowly in several minutes, and the reaction mixture was then allowed
to stir for 18 h at 120 C. Progress of the reaction was monitored by TLC, using ethyl acetate and
hexane (1:4). After completion of the reaction, the reaction mixture was cooled to room temperature.
Then, the solution was washed with ethyl acetate (7 mL) and water (3 mL) for 5 times. The organic layer
was evaporated, and the crude reaction mixture was purified on asilica gel (60–120 mesh) column by
chromatography to obtain the final product 2-(N-arylamino)benzimidazole, which was characterized
by NMR (1H and 13C), IR, and mass spectral data.
N-Phenyl-1H-benzo[d]imidazol-2-amine (1a): White solid; yield 96%; mp 97–99 ◦C; 1H NMR (400 MHz,
CDCl3)
δ δ 139.2,
7.78 (d,J = 6.8 Hz, 2H), 7.26–7.11 (m, 7H), 6.12 (br s, 1H); 13C NMR (100 MHz, CDCl3)
137.2, 134.2, 132.6, 130.5, 129.9, 129.7, 127.3, 115.0, 114.7, 110.8; FT-IR (KBr) 3294, 3098, 1676, 1618, 1597,
1542, 1478, 1413, 1253, 1076 cm−1. m/z (ESI–MS) 210.10 [M + H]+.
N-O-Tolyl-1H-benzo[d]imidazol-2-amine (1b): White solid; yield 87%; mp 151–152 ◦C; 1H NMR (400 MHz,
DMSO)
δ
7.35 (d, J = 12 Hz, 1H), 7.25–7.19 (m, 2H), 7.00 (d,J = 7.4 Hz, 2H), 6.88–6.77 (m, 3H), 2.18
138.2, 137.5, 137.1, 135.7, 133.9, 132.2, 131.6, 130.9, 129.0, 125.3,
(s, 3H); 13C NMR (100 MHz, CDCl3)
δ
123.2, 118.2, 115.2, 20.7; FT-IR (KBr) 3314, 2924, 2859, 3109, 2115, 1619, 1509, 1330, 1250, 1112, 1088,
1025 cm−1. m/z (ESI–MS) 224.11 [M + H]+.
N-m-Tolyl-1H-benzo[d]imidazol-2-amine (1c): White solid; yield 91%; mp 148–149 ◦C; 1H NMR (400 MHz,
CDCl3)
(100 MHz, CDCl3)
δ
7.55 (s, 1H), 7.43–7.34 (m, 3H), 7.31–7.25 (m, 3H), 6.70 (br s, 1H), 2.36 (s, 3H); 13C NMR
δ
149.0, 139.4, 137.4, 134.9, 134.7, 133.6, 133.1, 130.5, 124.0, 122.0, 115.5, 113.1, 110.4,
20.6; FT-IR (KBr) 3257, 3191, 2958, 1501, 1495, 1403, 1386, 1341, 1286, 1061 cm−1. m/z (ESI–MS) 224.11
[M + H]+.
N-p-Tolyl-1H-benzo[d]imidazol-2-amine (1d): White solid; yield 95%; mp 145–147 ◦C; 1H NMR (400 MHz,
CDCl3)
+ DMSO-d6)
δ
7.45–7.32 (m, 6H), 7.12 (d,J = 8 Hz, 2H), 5.98 (br s, 1H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3
δ
152.3, 142.2, 135.9, 133.0, 130.8, 129.8, 128.7, 128.5, 123.2, 120.6, 117.8, 20.0; FT-IR (KBr)
3256, 3121, 2963, 1643, 1586, 1514, 1367, 1234, 1136, 1094, 1017 cm−1. m/z (ESI–MS) 224.11 [M + H]+.
N-(4-Methoxyphenyl)-1H-benzo[d]imidazol-2-amine (1e): White solid; yield 97%; mp 153–154 ◦C; 1H NMR
(400 MHz, CDCl3)
δ
7.47–7.42 (m, 3H), 7.30–7.16 (m, 2H), 7.14–7.08 (m, 3H), 7.00 (br s, 1H), 3.87 (s, 3H);
154.7, 153.1, 142.9, 133.7, 132.6, 129.7, 129.5, 129.3, 126.1,
13C NMR (100 MHz, CDCl3 + DMSO-d6)
δ

Molecules 2020, 25, 1788
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121.3, 114.9, 55.02; FT-IR (KBr) 3345, 2958, 2857, 1567, 1535, 1506, 1321, 1271, 1235, 1182, 1123, 1074,
1033 cm−1. m/z (ESI–MS) 240.11 [M + H]+.
Methyl 4-(1H-benzo[d]imidazol-2-ylamino)benzoate (1f): White solid; yield 62%; mp 207–209 ◦C; 1H NMR
(300 MHz, d6-DMSO, ppm) δ
7.64–7.51 (m, 3H), 6.83–6.61 (m, 5H), 5.83 (br s, 1H), 3.83 (s, 3H);13C NMR
(75 MHz, d6-DMSO) d = 166.3, 152.7, 145.7, 144.2, 141.3, 132.3, 131.2, 128.1, 119.8, 119.1, 106.6, 106.3,
45.3; FT-IR (KBr) 3234, 3157, 2853, 1658, 1599, 1516, 1428, 1411, 1242, 1197, 1121, 1087, 1065, 1022 cm−1
m/z (ESI-MS) 268.10 [M + H]+.
.
N-(4-Chlorophenyl)-1H-benzo[d]imidazol-2-amine (1g): White solid; yield 77%; mp 158–159 ◦C; 1H NMR
(400 MHz, CDCl3) 7.77–7.50 (m, 4H), 7.26 (d, J = 7.6 Hz, 2H), 7.16 (d, J= 8.8 Hz, 2H), 4.66 (br s, 1H);
13C NMR (100 MHz, CDCl3 + DMSO-d6)
δ
δ
151.1, 141.7, 136.9, 132.3, 128.3, 128.1, 127.7, 127.0, 124.7,
120.0, 118.1; FT-IR (KBr) 3076, 2958, 2150, 1637, 1504, 1421, 1374, 1330, 1256, 1207, 1030 cm−1. m/z
(ESI–MS) 245.05 [M + H]+.
N-(2,4-Dimethylphenyl)-1H-benzo[d]imidazol-2-amine (1h): White solid; yield 90%; mp 143–144
◦C;1H NMR (400 MHz, CDCl3)
δ
7.65 (s, 1H), 7.38–7.33 (m, 3H), 7.27–7.09 (m, 3H), 6.74 (br s,
1H), 2.28 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ
141.3, 138.3, 137.2, 136.9, 132.9, 132.4, 130.6,
127.2, 117.7, 115.1, 111.2, 21.4, 20.4; FT-IR (KBr) 3278, 3201, 2922, 2858, 1607, 1581, 1453, 1410, 1389, 1268,
1155, 1018 cm−1. m/z (ESI–MS) 238.13 [M + H]+.
◦
N-(2,6-Dimethylphenyl)-1H-benzo[d]imidazol-2-amine (1i): White solid; yield 82%; mp 148–149 C;
1H NMR (400 MHz, CDCl3)
δ
7.22–7.17 (m, 2H), 7.13 (d,J = 8.4 Hz, 2H), 7.06–6.97 (m, 3H), 6.35 (br s,
1H), 2.43 (s, 6H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ
142.8, 135.2, 134.4, 134.3, 130.5, 130.1, 129.5,
128.7, 118.4, 115.5, 111.2, 24.5, 20.7; FT-IR (KBr) 3094, 2921, 2867, 2222, 1574, 1486, 1456, 1374, 1241, 1208,
1027 cm−1. m/z (ESI–MS) 238.13 [M + H]+.
N-(Naphthalen-3-yl)-1H-benzo[d]imidazol-2-amine (1j): White solid; yield 78%; mp 168–169 ◦C; 1H NMR
(400 MHz, CDCl3)
δ 8.02–7.63 (m, 5H), 7.51–7.47 (m, 3H), 7.35 (d, J = 8 Hz, 1H), 7.26 (d, J = 5.2 Hz, 2H),
6.60 (br s, 1H); 13C NMR (100 MHz, CDCl3 + DMSO-d6)
δ
154.6, 142.6, 134.2, 133.8, 133.6, 131.2, 129.4,
129.1, 128.8, 128.3, 127.8, 127.2, 125.8, 125.4, 122.4, 121.1, 120.8. m/z (ESI–MS) 260.11 [M + H]+.
4-Methyl-N-phenyl-1H-benzo[d]imidazol-2-amine (1k): White solid; yield 90%; mp 151–153 ◦C;1H NMR
(400 MHz, CDCl3)
δ
7.47-7.25 (m, 4H), 7.07 (d, J = 7.6 Hz, 2H), 6.94 (d, J = 8 Hz, 1H), 6.74 (br s, 1H),
146.7, 139.5, 135.5, 134.4, 132.8, 129.7, 128.7,
6.54 (s, 1H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ
126.4, 124.5, 117.9, 110.0, 21.8; FT-IR (KBr) 3290, 3144, 2984, 2917, 2859, 1604, 1584, 1498, 1449, 1413,
1391, 1289, 1270, 1213, 1153, 1057, 934 cm−1. m/z (ESI–MS) 224.11 [M + H]+.
5-Methyl-N-phenyl-1H-benzo[d]imidazol-2-amine (1l): White solid; yield 93%; mp 151–153 ◦C; 1H NMR
(400 MHz, CDCl3)
DMSO-d6)
δ
7.76–7.49 (m, 4H), 7.25–6.85 (m, 4H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3 +
151.6, 141.5, 135.7, 134.8, 132.2, 128.3, 128.0, 127.8, 119.9, 118.0, 114.3, 19.1; FT-IR (KBr)
3306, 2920, 2847, 1603, 1515, 1444, 1302, 1236, 1302, 1236, 1191, 1115, 1095, 1020 cm−1. m/z (ESI–MS)
224.11 [M + H]+.
δ
6-Methyl-N-phenyl-1H-benzo[d]imidazol-2-amine (1m): White solid; yield 96%; mp 146–147 ◦C; 1H NMR
(400 MHz, CDCl3)
NMR (100 MHz, CDCl3)
δ C
7.40 (s, 1H), 7.30–7.19 (m, 5H), 7.04–7.01 (m, 2H), 6.81 (br s, 1H), 2.32 (s, 3H); 13
δ
138.0, 137.4, 135.3, 134.1, 132.7, 129.6, 127.0, 126.7, 115.3, 110.0, 20.3; FT-IR
(KBr) 3285, 3056, 2854, 1603, 1574, 1534, 1497, 1456, 1321, 1234, 1121, 1085 cm−1. m/z (ESI–MS) 224.11
[M + H]+.
◦
2-(Phenylamino)-3H-benzo[d]imidazole-5-carbonitrile (1n): White solid: yield 56%; mp 169–170 C;
1H NMR (400 MHz, CDCl3)
δ 7.53 (s, 1H), 7.29–7.22 (m, 3H), 7.16 (d, J = 6.8 Hz, 2H), 6.97 (d, J = 7.2 Hz,
2H), 6.84 (br s, 1H); 13C NMR (100 MHz, CDCl3)
δ 139.2, 137.3, 134.2, 132.6, 130.5, 130.0, 129.7, 127.3,
115.0, 114.8, 111.0, 110.9; FT-IR (KBr) 3253, 3198, 1654, 1588, 1488, 1407, 1317, 1287, 1164, 1019, 927 cm−1
.
m/z (ESI–MS) 235.09 [M + H]+.

Molecules 2020, 25, 1788
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6-Chloro-N-p-tolyl-1H-benzo[d]imidazol-2-amine (1o): White solid: yield 79%; mp 151–152 ◦C; 1H NMR
(400 MHz, CDCl3) 7.77 (s, 1H), 7.50 (t, J = 9.2 Hz, 2H), 7.26 (d, J = 7.6 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H),
4.66 (br s, 1H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3 + DMSO-d6)
151.1, 141.7, 136.9, 132.3, 128.3,
δ
δ
128.1, 127.7, 127.0, 124.7, 120.0, 118.1, 19.2; FT-IR (KBr) 3076, 2958, 2150, 1637, 1504, 1421, 1374, 1330,
1256, 1207, 1030 cm−1. m/z (ESI–MS) 259.12 [M + H]+.
6-Chloro-N-(4-nitrophenyl)-1H-benzo[d]imidazol-2-amine(1p): White solid: yield 62%; mp 178–180 ◦C;
1H NMR (400 MHz, CDCl3)
δ
7.74 (d, J = 2.0 Hz, 1H), 7.47–7.37 (m, 3H), 7.10 (d, J = 9.2 Hz, 1H), 6.94
(br s, 1H), 6.81 (dd, J = 7.2, 2.4 Hz, 2H); 13C NMR (100 MHz, CDCl3 + DMSO-d6)
δ
153.9, 152.1, 135.8,
131.9, 131.2, 130.1, 129.9, 127.9, 121.8, 119.2, 112.7; FT-IR (KBr) 3275, 3085, 2834, 1607, 1579, 1486, 1302,
1233, 1179, 1085, 1036 cm−1. m/z (ESI–MS) 290.04 [M + H]+.
1H-benzo[d]imidazol-2-amine(
(td, J = 8.0, 0.4 Hz, 1H), 7.53–7.50 (dd, J = 8.0, 0.8 Hz, 1H), 7.31–7.27 (m, 1H), 7.13–7.09 (d, J = 7.6, 1.2 Hz,
B δ 7.58–7.56
): White solid; mp 129–130 ◦C; 1H NMR (400 MHz, CDCl3)
1H), 5.62 (br s, 2H); 13C NMR (100 MHz, CDCl3)
δ 167.0, 151.9, 131.0, 125.5, 121.4, 120.6, 118.2; FT-IR
(KBr) 3421, 3396, 3063, 1626, 1530, 1444, 1309, 1105 cm−1. m/z (ESI–MS) 134.07 [M + H]+.
4. Conclusions
In conclusion, we have developed a methodology for the synthesis of substituted 2-aminophenyl
benzimidazoles from thiourea through a multistep reaction. This methodology involves consecutive
a desulphurization/nucleophilic substitution and domino intra and inter molecular C–N cross-coupling
reaction. Control experiments were performed to understand themechanism. Many researchers
have reported reactions for the generationof benzimidazoles; however, the simplicity, environmental
acceptability, and cost effectiveness of copper makes this method more practical. Although the single
yields look moderate, considering that the reaction consists of multiple processes, the yields are in fact
good to high.
Supplementary Materials: The following are available online. Scheme S1. Proposed mechanism.
Author Contributions: S.N.M.B., R.T. and H.B.B. designed the project; S.F.A., R.K.G. and S.N. helped in the
preparation of the manuscript; R.T., R.K.G. and H.B.B. performed the experimental section, while S.F.A., M.E.A.
and H.B.B. contributed to the characterization; along with H.B.B. who provided scientific guidance and helped to
draft the manuscript. O.A. and M.R.H.S. helped procure the funding for the successful completion of the project.
All authors have read and agreed to the published version of the manuscript.
Funding: Research group project No. RG-1440-068.
Acknowledgments: The authors are grateful to the Deanship of Scientific Research at King Saud University for
funding this work through the research group project No. RG-1440-068.
Conflicts of Interest: The authors declare there are no conflicts to declare.
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