Ultrasound-assisted synthesis of substituted 2-aminobenzimidazoles, 2-aminobenzoxazoles, and related heterocycles

Article abstract of DOI:10.1016/j.tetlet.2016.10.060

A sonochemical method for the synthesis of 2-aminobenzimidazoles and 2-aminobenzoxazoles, as well as chiral aminooxazolines and a chiral substituted quinazolin-5-one is reported. Using the Ph₃P–I₂system in the presence of triethylami

Full text of DOI:10.1016/j.tetlet.2016.10.060

Accepted Manuscript
Ultrasound-assisted synthesis of substituted 2-aminobenzimidazoles, 2-amino-
benzoxazoles, and related heterocycles
Wong Phakhodee, Chuthamat Duangkamol, Nittaya Wiriya, Mookda
Pattarawarapan
PII:
S0040-4039(16)31374-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.060
TETL 48230
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 August 2016
11 October 2016
17 October 2016
Please cite this article as: Phakhodee, W., Duangkamol, C., Wiriya, N., Pattarawarapan, M., Ultrasound-assisted
synthesis of substituted 2-aminobenzimidazoles, 2-aminobenzoxazoles, and related heterocycles, Tetrahedron
Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.10.060
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Ultrasound-assisted synthesis of substituted 2-aminobenzimidazoles, 2-aminobenzoxazoles,
and related heterocycles
Wong Phakhodee,* Chuthamat Duangkamol, Nittaya Wiriya, and Mookda Pattarawarapan
Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200,
Thailand
To whom correspondence should be addressed.
Department of Chemistry,
Faculty of Science,
Chiang Mai University,
Chiang Mai
50200
Thailand
Tel. +66 5394 3341
Fax. +66 5389 2277
e-mail: wongp2577@gmail.com

Ultrasound-assisted synthesis of substituted 2-aminobenzimidazoles, 2-aminobenzoxazoles,
and related heterocycles
Wong Phakhodee,* Chuthamat Duangkamol, Nittaya Wiriya, and Mookda Pattarawarapan
Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200,
Thailand
Abstract
A sonochemical method for the synthesis of 2-aminobenzimidazoles and 2-aminobenzoxazoles,
as well as chiral aminooxazolines and a chiral substituted quinazolin-5-one is reported. Using the
Ph3P-I2 system in the presence of triethylamine as a desulfurization agent, monothioureas
prepared in-situ from the reaction of bis-nucleophiles with isothiocyanates underwent rapid
cyclization to afford a variety of N-heterocyclic compounds in good to excellent yields under
mild conditions.
Keywords 2-Aminobenzimidazole; 2-Aminobenzoxazole; Aminooxazoline; Quinazolin-5-one;
Triphenylphosphine; Iodine

Introduction
2-Aminobenzimidazoles and 2-aminobenzoxazoles are important pharmacophores in
medicinal chemistry. Both natural products and synthetic molecules possessing these
heterocyclic scaffolds have been shown to exhibit useful pharmacological and biological
properties such as antimicrobial, antiallergic, immunosuppressive, and antiviral activities.1-4 For
example, algeladine A (I), a marine natural product, was reported as a promising antimetastatic
agent.5,6 Compound II was identified as a novel class of orally active antimalarial agent,7 while
compound III is a potent p38α MAP kinase inhibitor for the treatment of inflammatory disease.8
Compound IV acts as a potent A2B adenosine receptor antagonist which may be useful for the
treatment of diabetes, asthma and chronic obstructive pulmonary disease.9 Finally, suvorexant
(V) has recently been approved as a therapeutic drug for insomnia.10,11
Figure 1. Representative examples of bioactive molecules containing the 2-aminobenzimidazole
and 2-aminobenzoxazole moieties.
Currently, there are several approaches for the synthesis of these heterocyclic systems.
One of the most convenient routes involves the cyclodesulfurization of the preformed
monothioureas, derived from bis-nucleophiles such as o-phenylenediamine or aminophenol

derivatives. Some examples of desulfurization agents include HgO,12 polymer-supported
carbodiimide,13 TsCl/NaOH,14 LiOH/H2O2,15 hypervalent iodine(III),16 1,1′-(ethane-1,2-
diyl)dipyridinium bistribromide (EDPBT),17 and BOP reagent.18 However, these methods are
associated with one or more limitations such as being expensive or using highly toxic reagents,
requiring long reaction times or harsh reaction conditions, and having low chemoselectivity and
yields.
Ultrasound has proven to be a powerful process intensification tool for organic synthesis,
presumably due to the acoustic cavitation phenomenon.19 Compared to conventional stirring,
reactions under ultrasonic irradiation have been reported to proceed with shortened times,
improved yields, and selectivity.20-22 Although
a
number of ultrasound-promoted
heterocyclization reactions toward five- or six-membered rings have been developed,23-26
surprisingly, the synthesis of 2-aminobenzimidazoles and related heterocycles has not been
reported under ultrasonic irradiation.
Triphenylphosphine (Ph3P) is a readily available and inexpensive reagent which has been
used in combination with several halogenated additives as effective dehydrating agents.27
Recently, we reported that the combination of Ph3P and I2 could be used to promote the
guanylation of thioureas, presumably through the formation of a carbodiimide intermediate.28 To
the best of our knowledge, this reagent system has never been used in cyclodesulfurization
reactions where all reactive species are presented in one-pot. Herein, we report a facile and
effective sonochemical method for the synthesis of substituted 2-aminobenzimidazoles and 2-
aminobenzoxazoles, as well as other related heterocyclics through the Ph3P-I2 reagent system
promoted cyclodesulfurization of monothiourea intermediates.

Results and Discussion
Our investigation began with the ultrasonic-assisted cyclodesulfurization of
monothiourea VI, generated in-situ from the reaction of o-phenylenediamine with
phenylisothiocyanate. The effect of both the halogen additive and type of base were evaluated.
Typically, the reaction was carried out by mixing Ph3P (1.5 equiv.) and the additive (1.5 equiv.)
o
in dichloromethane at 0 C. The preformed thiourea (1.0 equiv.) was then added, followed by
base (3.0 equiv.). The reaction mixture was then sonicated in an ultrasonic bath at ambient
temperature for a further 10 min before product isolation.
According to Table 1, using I2 as the additive in the presence of triethylamine gave the
best result compared to those using N-bromosuccinimide (NBS) or bromine (Br2) (Entries 1-3).
Changing the base to imidazole led to lower product yield due to incomplete conversion of the
formed carbodiimide intermediate (Entry 4). The reaction in the presence of N,N’-
dimethylaminopyridine (DMAP) and 1,8-diazabicycloundec-7-ene (DBU) only gave the product
in trace amount (Entries 5-6). In these reactions, most of the starting thiourea was unreacted,
indicating that these bases were ineffective or led to decomposition of the formed reactive
species. The benefit of ultrasound was further confirmed by the low conversion of the reaction
mediated by the Ph3P-I2/Et3N system under traditional stirring where the formed thiourea and
corresponding carbodiimide intermediate still remained (Entry 7).

Table 1. Optimization of the reaction conditionsa
Entry Additive
Base
Method
Yield (%)
53
1
2
3
4
5
6
7
NBS
Br2
I2
Et3N
))), 10 min
))), 10 min
))), 10 min
))), 10 min
))), 10 min
))), 10 min
stirring, 10 min
Et3N
48
Et3N
90
I2
imidazole
DMAP
DBU
75
I2
trace
trace
trace
I2
I2
Et3N
aReaction conditions: o-phenylenediamine (0.41 mmol), phenylisothiocyanate
(0.41 mmol), Ph3P (0.62 mmol), additive (0.62 mmol), base (1.23 mmol),
CH2Cl2 (2 mL), 0 oC-RT.
With the optimized reaction conditions in hand, a series of substituted 2-
aminobenzimidazoles were synthesized from phenylenediamines and isothiocyanates (Table 2).
The reaction of o-phenylenediamine with aryl isothiocyanates proceeded rapidly, especially
when the isothiocyanates contained an electron withdrawing group (Entries 1–4). Slightly longer
reaction times were required when an electron donating group was presented at the para-position
of the phenyl isothiocyanate (Entry 6) or when using the relatively sterically hindered 1-
napthylisothiocyanate (Entry 7). Apart from aryl isothiocyanates, the reaction conditions were
also applicable to alkyl isothiocyanates where benzyl isothiocyanate reacted smoothly to afford
the corresponding product in good yield (Entry 8). Other diamine derivatives were also viable

substrates under the applied conditions (Entries 9-14), although the electron-deficient dibromo-
substituted substrate (Entry 14) reacted less favorably, providing lower yields of the
corresponding aminobenzimidazole.
The chemistry could be extended to other related bis-nucleophiles such as the reaction of
2-aminophenol with isothiocyanates which produced substituted 2-aminobenzoxazole derivatives
in reasonable yields (Entries 15-18). Due to the lower nucleophilicity of the OH group compared
to the –NH2 group, extended reaction times were required for reaction completion. Nevertheless,
it is noteworthy that, under our developed conditions, the reaction between 2-aminophenol and
1-napthylisothiocyanate proceeded with high chemoselectivity to provide the expected N-
(naphthalen-1-yl)benzo[d]oxazol-2-amine in good yield, whereas the reaction mediated by 1,1′-
(ethane-1,2-diyl)dipyridinium bistribromide gave the 2-(naphtho[1,2-d]thiazol-2-ylamino)phenol
as the major product.17

Table 2. Synthesis of substituted 2-aminobenzimidazoles and 2-aminobenzoxazolesa
Entry
1
R1
H
H
H
H
H
H
H
H
H
H
H
H
Br
Br
H
H
H
H
R2
H
R3
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
H
H
H
H
X
Ar
Time (min)
Yield (%)
1a, 94
1b, 91
1c, 92
1d, 91
1e, 90
1f, 89
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
O
4-NO2C6H4
4-CF3C6H4
4-FC6H4
4-ClC6H4
C6H5
10
10
10
10
15
20
20
20
10
15
20
20
20
25
45
45
45
60
2
H
3
H
4
H
5
H
6
H
4-CH3C6H4
1-naphthyl
Bn
7
H
1g, 86
1h, 87
1i, 88
8
H
9
CH3
CH3
CH3
CH3
H
4-FC6H4
C6H5
10
11
12
13
14
15
16
17
18
1j, 87
4-CH3C6H4
1-naphthyl
C6H5
1k, 87
1l, 85
1m, 90
1n, 76
2a, 76
2b, 74
2c, 70
2d, 56
H
4-NO2C6H4
4-NO2C6H4
C6H5
H
H
O
H
O
1-naphthyl
Bn
H
O
aReaction conditions: diamine derivative or 2-aminophenol (0.41 mmol), isothiocyanate (0.41 mmol), Ph3P (0.62 mmol), I2
(0.62 mmol), Et3N (1.23 mmol), CH2Cl2 (2 mL).

Encouraged by these results, the scope of the reaction was further extended to chiral bis-
nucleophiles. Using (1S,2R)-1-amino-2-indanol as the nucleophilic substrate, the reaction with
aryl isothiocyanates proceeded rapidly to provide a series of chiral aminooxazoline derivatives in
good to excellent yields (Scheme 1). Notably, no side-products such as those derived from
activation of the hydroxyl group were observed. The substituted aminooxazolines are potentially
useful as chiral auxiliary ligands for asymmetric processes.29-32
Scheme 1. Synthesis of substituted aminooxazolines 3
1
It should be noted that, based on H-NMR spectroscopic analysis of compound 3b as a
representative molecule, the product was obtained as a single diastereomer with retention of
configuration of the chiral centers. The signal of H-8a (Fig. 2) appears as a triplet of doublets at
δH 5.39 ppm with coupling constants J = 7.2 and 1.6 Hz. The large coupling constant is
consistent with coupling between this proton and the vicinal proton, H-3a, having an
approximate 40o dihedral angle according to the Karplus equation. The small coupling constant
(1.6 Hz) is presumably due to coupling between H-8a and Hb-8, suggesting a perpendicular
dihedral angle between these nuclei.
Figure 2. Structure of compound 3b

It is also noteworthy that unlike previously reported procedures for the synthesis of
quinazolin-5-one derivatives which required multistep synthesis,33-36 our protocol allows
convenient access to chiral fused pentacyclic quinazolin-5-ones such as 4 in excellent yields over
one-step using readily available precursors, inexpensive reagents, and mild reaction conditions
(Scheme 2).
Scheme 2. Synthesis of fused pentacyclic quinazolin-5-one 4
Conclusion
In summary, we have developed a simple one-pot sonochemical method for the
preparation of 2-aminobenzimidazoles, 2-aminobenzoxazoles, and related systems mediated by
the Ph3P/I2-Et3N system. The procedure is compatible with a range of structurally diverse bis-
nucleophiles and isothiocyanates with various N-heterocycles prepared in short reaction times
under mild conditions. High chemoselectivity and stereoselectivity as well as the use of low-cost,
easy to handle, and readily available reagents are additional benefits of the method.
Acknowledgements
Financial support from The Thailand Research Fund through the Royal Golden Jubilee Ph.D.
Program (Grant No. PHD/0086/2557) to C.D. and the National Research University Project
under Thailand’s Office of the Higher Education Commission are gratefully acknowledged.
Supplementary Data

1H NMR spectra for all compounds and 13C NMR spectra for the representative products are
available. Supplementary data related to this article can be found at http://xxx.
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Graphical Abstract
Leave this area blank for abstract info.
Ultrasound-assisted synthesis of substituted 2-amino-
benzimidazoles, 2-aminobenzoxazoles, and related
heterocycles
Wong Phakhodee,* Chuthamat Duangkamol, Nittaya Wiriya, and Mookda Pattarawarapan

Highlights
 Synthesis of 2-aminobenzimidazoles and related systems is reported.
 Cyclization of monothioureas using PPh3/I2 proceeded rapidly under sonication.
 N-heterocycles were obtained in high yields under mild conditions.