Diphosphorus tetraiodide (P2I4): An efficient catalyst for synthesis of 2-Aryl-1,3-benzazoles via cyclocondensation of o-Amino/Mercaptan/Hydroxy anilines with aryl acids

Article abstract of DOI:10.14233/ajchem.2018.21001

An efficient and versatile approach for the synthesis of 2-substituted 1,3-benzazoles has been developed via diphosphorus tetraiodide (P2I4) catalyzed condensation reaction of ortho-substituted anilines (–NH2, –SH and –OH) with various aromatic acids to give benzimidazoles, benzothiazoles and benzoxazoles in excellent yields. Additionally, the synthetic approach reported herein has advantages such as mild reaction conditions, broad substrate scopes as well as simple one-pot operation, common for all the three 1,3-benzazoles, which makes this strategy highly attractive.

Full text of DOI:10.14233/ajchem.2018.21001

Asian Journal of Chemistry; Vol. 30, No. 2 (2018), 376-380
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2018.21001
Diphosphorus Tetraiodide (P I ): An Efficient Catalyst for Synthesis of 2-Aryl-1,3-benzazoles
2
4
via Cyclocondensation of o-Amino/Mercaptan/Hydroxy Anilines with Aryl Acids
*
SAKET B. BHAGAT, YOGESH B. SUTAR, YOGESH MANOHAR and VIKAS N. TELVEKAR
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai-400 019, India
*
Corresponding author: E-mail: vikastelvekar@gmail.com
Received: 24 August 2017; Accepted: 26 October 2017;
Published online: 31 December 2017;
AJC-18709
An efficient and versatile approach for the synthesis of 2-substituted 1,3-benzazoles has been developed via diphosphorus tetraiodide
) catalyzed condensation reaction of ortho-substituted anilines (–NH , –SH and –OH) with various aromatic acids to give benzimidazoles,
(P I
2 4
2
benzothiazoles and benzoxazoles in excellent yields. Additionally, the synthetic approach reported herein has advantages such as mild
reaction conditions, broad substrate scopes as well as simple one-pot operation, common for all the three 1,3-benzazoles, which makes
this strategy highly attractive.
Keywords: Aryl/heteroaryl acids, Heterocycles, Benzimidazole, Benzothiazole, Benzoxazole, Diphosphorus tetraiodide.
reactions (which leads to poor yield and difficulty in isolation),
low reaction rate, additional oxidation step, tedious work-up
procedure and lack of selectivity.
INTRODUCTION
1
,3-Benzazoles, which include three scaffolds i.e., benzimi-
dazole, benzothiazole and benzoxazole, are an important class
of compounds that provide a common scaffold to various deriva-
tives exhibiting exciting and diverse biological and pharma-
ceutical properties and are therefore considered privileged
structures in the design and discovery of new drugs. The 2-substi-
tuted benzofused azoles have gained importance in medicinal
chemistry owing to their use as anti-inflammatory, antimicro-
bial, antidiabetic, antiulcer, antihelmentic, antihypertensive,
antiviral and anticancer agents [1-8].
In the course of our research on the development of efficient
methods to access these bioactive 1,3-benzazoles, we decided
to explore a single versatile synthetic protocol by condensing
carboxylic acids with o-phenylenediamines, o-aminobenzene-
thiol and o-aminophenols respectively, utilizing an iodine
reagent under mild reaction conditions. The ready availability
of diverse set of carboxylic acids and their higher stability
compared to aldehydes and alcohols, prompted us to focus on
carboxylic acids as reagents for this isohypsic heterocycliza-
tion. However, these types of organic transformations, invol-
ving loss of water, require the use of strong dehydrating agents.
The ideal features in a dehydrating agent include easy prepa-
ration, selectivity for oxygen, minimum unwanted by-product
formation, enough reactivity for rapid reaction at moderate
temperatures, utility in a range of common solvents. This
encouraged us to explore various iodine reagents including
There are several classical methods in the literature to obtain
,3-benzazoles which involves the condensation reactions of
1
either o-phenylenediamine, o-aminobenzenethiol, or o-amino-
phenol with substituted carboxylic acids, aldehydes, acyl
chlorides, or nitriles [9-15].Alternatively, benzimidazoles have
also been synthesized using transition-metal catalyzed amina-
tion followed by condensation [16] and cyclization of o-nitro-
aniline derivatives with aryl isothiocyanates [17]. Recently,
substituted alcohols have been used for the synthesis of benzi-
midazoles and benzothiazoles, however, the use of oxidative
steps in case of aldehydes or alcohols affect the overall economy
of the reaction [18]. Also, benzoxazoles have been obtained
diphosphorus tetraiodide (P
for such conversion.
2
I ) as a suitable dehydrating reagent
4
EXPERIMENTAL
by reacting o-hydroxyphenyl ketoximes with PCl
reaction of 2-aminophenols with allenic and acetylenic nitriles
19,20]. However, the above mentioned methods suffer from
several disadvantages like harsh reaction conditions (strong
acid, high temperature), high catalyst cost, occurrence of side
5
or P
2
O
5
and
Chemicals and solvents used were of LR grade and pur-
chased from SD fine,Avra Synthesis or Spectrochem and used
without purification. The purity determination of the starting
materials and reaction monitoring was accomplished by thin-
layer chromatography (TLC) on Merck silica gel G F254 plates.
[

Vol. 30, No. 2 (2018)
Diphosphorus Tetraiodide (P
2
I
4
): An Efficient Catalyst for Synthesis of 2-Aryl-1,3-benzazoles 377
1
Silica gel 60-120 mess was used for column chromatography.
Melting points of all the compounds were recorded onThermomik
Campbell melting point apparatus having an oil bath system
and are uncorrected. The FTIR spectra (KBr) were recorded on
Shimadzu FTIRAffinity-1 Fourier transform infrared spectro-
1660, 1445; H NMR (400 MHz, DMSO-d
6
1
): δ 7.19 (m, 1H),
3
7.27-7.31 (m, 4H), 7.73 (d, 1H), 7.93 (m, 3H); C NMR (DMSO-
d , TMS): δ 121.5, 122.1, 123.6, 125.5, 126.7, 129.1, 132.4,
135.3, 151.2, 154.3, 166.4; MS (ESI) m/z: [M+H] 212.05.
6
+
1
RESULTS AND DISCUSSION
photometer. H NMR spectra were recorded on MR400Agilent
Technology NMR spectrometer using tetramethylsilane (TMS)
In an initial attempt, we selected o-phenylenediamine (1a)
and benzoic acid (2a) as the model substrates to probe the
optimal reaction conditions (Scheme-I).
as an internal standard and DMSO-d
6
/CDCl as a solvent. All
3
1
the products are known compounds and were identified by H
NMR spectroscopy.
General procedure for synthesis of 2-aryl-benzimi-
dazoles/2-aryl-benzoxazoles/2-aryl-benzothiazoles: To a
NH2
NH2
COOH
N
Iodine reagent
acetonitrile, 80 0C
sealed tube
mixture of ortho-substituted (–NH
2
or –SH or –OH) anilines
N
H
1
a
2a
3a
(
1 mmol) and aryl acids (1 mmol) in acetonitrile (2 mL) in a
Scheme-I: Reaction between o-phenylenediamine and benzoic acid in
sealed tube (10 mL) was added diphosphorus tetraiodide (0.2
mmol) under nitrogen atmosphere. Then, the tube was capped
and the mixture heated in an oil bath at 80 °C with stirring
until the reaction was complete as monitored by TLC. After
being cooled to room temperature, the reaction was quenched
presence of iodine reagents
The desired product 2-phenyl-1H-benzimidazole (3a) was
not obtained in absence of the catalyst upon reacting 1a and
a in stoichiometric amounts using acetonitrile as a solvent in a
2
with aqueous NaHCO
three times. The combined organic layer was washed with
water and brine and then dried over anhydrous Na SO . The
3
solution and extracted with ethyl acetate
sealed tube [15] at 80 °C (Table-1, entry 1); Next, various iodine
reagents like iodine, sodium iodide/o-phosphoric acid, aqueous
hydroiodic acid (56 %), red phosphorus/aq. hydroiodic acid/
iodine were used as a catalyst in the reaction, however, either
the reaction did not afford the desired product or the yield was
very low (Table-1, entry 2-5). We next attempted the reaction
using 1 equivalent P
product 3a was obtained in 92 % yield after 3 h (Table-1,
entry 6). Further, reducing the amount of P to 0.7, 0.5 and
.2 equivalents had no significant impact on the yield of the
product 3a (Table-1, entry 7-9). However, a further decrease
in the amount of P to 0.1 equivalents affected the yield
adversely (Table-1, entry 10).
2
4
solvent was removed under reduced pressure and the residue
was purified by chromatography on silica gel, eluting with
petroleum ether/ethyl acetate, to afford the corresponding
product. The products obtained were known compounds and
2
I in a sealed tube at 80 °C, the desired
4
1
were identified by melting point and H NMR spectroscopy.
The spectral data were compared with the literature values.
2 4
I
2
-Phenyl-1H-benzimidazole (Table-2, entry 1): m.p.:
0
–1
2
3
7
1
1
90-293 °C (Lit. [21] 292-294 °C); IR (KBr, νmax, cm ): 3450,
045, 1620, 1580, 1458; H NMR (400 MHz, DMSO-d
1
6
): δ
I
2 4
.08–7.14 (m, 2H), 7.31–7.5 (m, 5H), 7.96 (d, 2H), 12.80 (s,
13
H); C NMR (DMSO-d
29.5, 130.7, 139.0, 152.7; MS (ESI) m/z: [M+H] 195.1.
-(4-Chlorophenyl)-1H-benzimidazole (Table-2, entry
): m.p.: 290–292 °C (Lit. [21] 289–291 °C); IR (KBr, νmax
6
, TMS): δ 116.5, 123.1, 127.4, 128.6,
+
TABLE-1
SCREENING OF IODINE REAGENTS IN
THE SYNTHESIS OF BENZIMIDAZOLES
2
a
2
,
–1
1
cm ): 3448, 3050, 1640, 1580, 1480, 745; H NMR (400 MHz,
c
Entry
1
2
3
4
5
6
7
8
9
10
11
12
Catalyst
Equivalents
–
Time (h)
Yield (%)
DMSO-d ): δ 7.22 (d, 2H), 7.46–7.62 (m, 4H), 8.25 (d, 2H),
6
–
I2
24
24
24
24
24
3
3
3
3
6
NR
NR
NR
5-10
30
92
91
94
95
1
3
1
1
2.91 (s, 1H); C NMR (DMSO-d
6
, TMS): δ 150.5, 143.8,
1.0
0.3/1.1
1.0
5/1/2
1.0
0.7
0.5
0.2
0.1
0.2
35.1, 134.7, 129.2, 129.0, 127.5, 122.4, 121.8, 117.5, 111.4;
MS (ESI) m/z: [M+H] 229.01.
-(2-Thiophen)-1H-benzimidazole (Table-2, entry 6):
m.p.: 341-343 °C (Lit. [21] 342–343 °C). IR (KBr, νmax, cm ):
380, 3040, 1635, 1569, 1451, 1420, 1310, 1255. H NMR
NaI/H
PO
3
4
+
Aq. HI
Red P/aq. HI/I2
P I
2
–1
2
4
4
4
4
4
4
4
P I
2
1
3
P I
2
(
7
400 MHz, DMSO-d ): 7.1 (m, 1H), 7.25–7.52 (m, 3H), 7.75–
.90 (m, 2H), 8.2–8.22 (m, 1H), 12.49 (bs, 1H), C NMR
6
P I
2
13
P I
60
30
35
2
b
(
1
2
DMSO-d
6
, TMS): δ 111.1, 118.4, 121.6, 122.5, 126.6, 128.0,
P
I
2
24
24
b
+
P I
2
1.0
28.6, 133.6, 134.5, 143.6, 146.4. MS (ESI) m/z: [M+H]
01.05.
a
Reaction conditions: o-phenylenediamine (1a, 1 mmol), benzoic acid
(
2a, 1 mmol) and catalyst were reacted in acetonitrile in a sealed tube
2
-Phenylbenzoxazole (Table-3, entry 1): m.p.: 99–101
b
at 80 °C. Reaction carried out in acetonitrile at 80 °C under reflux.
–1
c
°
2
C (Lit. [22] 101–102 °C); IR (KBr, νmax, cm ): 3458, 3060,
951, 1640, 1460,1340, 1240, 1050, 1022; H NMR (400
Isolated yield.
1
MHz, DMSO-d ): δ 7.16 (m, 2H), 7.26-7.41 (m, 3H), 7.58
6
We also carried out the reaction using P
condition using acetonitrile as a solvent, however, the desired
product 3a was obtained in a very low yield even with up to 1
2
I under reflux
4
13
(
m, 2H), 8.01 (m, 2H); C NMR (DMSO-d , TMS): δ 121.5,
6
1
1
22.4, 123.5, 124.7, 125.6, 129.6, 132.2, 138.7, 150.5, 154.2,
62.3; MS (ESI) m/z: [M+H] 196.1.
+
equivalents of P
2
I (Table-1, entry 11-12). Reaction at a tempe-
4
2
-Phenylbenzothiazole (Table-3, entry 6): m.p.: 111–
rature lower than 80 °C resulted in poor conversion, while no
obvious improvement was achieved when the temperature was
–1
1
14 °C (Lit. [23] 110–112 °C); IR (KBr, νmax, cm ): 3430,

378 Bhagat et al.
Asian J. Chem.
TABLE-2
a
SYNTHESIS OF VARIOUS SUBSTITUTED 2-ARYL-BENZIMIDAZOLES
H
NH2
NH2
COOH
Acid
N
N
P I
2
4
0
acetonitrile, 80 C
sealed tube
R
b
Entry
1
Amine (R)
H
Product
N
Yield (%)
COOH
95
93
92
94
91
N
H
COOH
N
Cl
NO2
2
3
4
5
H
H
H
H
N
Cl
H
COOH
COOH
N
N
H
N
O N
2
OCH3
CH3
N
H
N
H CO
3
COOH
N
H3C
H
N
S
6
H
88
COOH
COOH
N
H
S
N
7
8
9
H
91
94
93
94
N
H
COOH
N
4-CH3
4-Cl
4-Cl
H C
N
H
N
3
COOH
Cl
N
H
COOH
N
CH3
10
Cl
N
H
H3C
a
Reaction conditions: substituted 1,2-diamines (1 mmol), aryl acid (1 mmol) and P I (0.2 equivalent) in acetonitrile were reacted in a sealed tube at
0 °C for 3-5 h. Isolated yields after column chromatography and structures were confirmed by comparison of IR, H NMR and melting point with
2
4
b
1
8
literature reports.
increased to 120 °C. The use of other solvents such as ethanol,
,4-dioxane, tetrahydrofuran, DMSO and toluene were also
examined, although most of the solvents promoted the reaction,
acetonitrile was found the most suitable media for this cycliza-
tion reaction.
With the optimized conditions in hand (Table-1, entry 9),
to study the generality and scope of this cyclization protocol,
a variety of aryl/heteroaryl acids were reacted with o-phenylene-
diamine and its derivatives (Table-2). The reaction proceeded
well in all the cases to give the corresponding benzimidazoles
in excellent yields. Aromatic acids containing various substi-
tuents, such as electron-withdrawing (Table-2, entries 2-3) and
electron-donating (Table-2, entries 4-5), were well tolerated
and did not affect the product yields. This methodology also
worked well with heteroaromatic acid (Table-2, entry 6) as
well as α,β-unsaturated carboxylic acids like cinnamic acid
(Table-2, entry 7). Significantly, good yields of the correspon-
ding benzimidazoles were obtained upon reaction of various
o-phenylenediamine derivatives with different aromatic acids
(Table-2, entries 8-10).
Gratifyingly, when the similar reaction conditions were
expanded to the synthesis of benzoxazoles and benzothiazoles
from o-aminophenol and o-aminobenzenethiol respectively,
using various aromatic acids, all the reactions proceeded effi-
ciently and the products were obtained in good to excellent
yields (Table-3, entries 1-8).
The present method is a convenient alternative to the most
widely used polyphosphoric acid catalyzed synthesis of 1,3-
benzazoles, overcoming the major drawbacks of polyphos-
phoric acid like its physical attributes including hygroscopic
nature and extremely high viscosity which makes it virtually
impossible to stir effectively or manipulate conveniently at
1

Vol. 30, No. 2 (2018)
Diphosphorus Tetraiodide (P I ): An Efficient Catalyst for Synthesis of 2-Aryl-1,3-benzazoles 379
2
4
TABLE-3
SYNTHESIS OF VARIOUS SUBSTITUTED 2-ARYL-BENZOXAZOLES AND 2-ARYL-BENZOTHIAZOLES
a
NH2
COOH
N
R
P I (0.2 equiv.)
2
4
R
0
acetonitrile, 80 C
sealed tube
X
XH
X= S, O
X= S, O
b
Entry
1
Amine
Acid (R)
Product
Yield (%)
NH2
N
H
90
O
OH
NH2
N
O
2
3
4
5
4-Cl
4-CH3
H
Cl
88
89
89
87
OH
NH2
N
CH3
O
OH
NH2
N
O
H3C
H3 C
OH
H3C
NH 2
N
Cl
4-Cl
O
H C
OH
3
NH 2
N
6
H
90
S
SH
NH 2
N
7
8
4-OCH3
4-CH3
OCH3
88
87
S
SH
NH 2
N
S
CH3
SH
a
Reaction conditions: o-substituted aniline derivative (1 mmol), aryl acid (1 mmol) and P I (0.2 equivalent) in acetonitrile were reacted in a sealed
2
4
b
1
tube at 80 °C for 3-4 h. Isolated yields after column chromatography and structures were confirmed by comparison of IR, H NMR and melting
point with literature reports.
temperatures below 60-90 °C. It is difficult to handle on a
large scale, even at elevated temperature, over 200 °C, which
is required for this condensation reaction. Some organics are
only sparingly soluble in polyphosphoric acid and, in any case,
rates of dissolution are low. The hydrolysis of polyphosphoric
acid in work-up procedures is always tedious.
suitable in medicinal chemistry and drug discovery for a rapid
access to the library of novel small molecules based on diverse
1,3-benzazole framework for biological evaluation.
ACKNOWLEDGEMENTS
Two of the authors (S.B.B. & Y.B.S.) are thankful to the
University Grants Commission (New Delhi, India) and another
authorV.N.T. is thankful to Sciences and Engineering Research
Board (SERB), New Delhi, India for providing financial support.
Conclusion
In conclusion, an effective and quick method, providing
a single protocol for the synthesis of all the three 1,3-benzazoles,
by condensation between o-phenylenediamines, o-amino-
benzenethiol and o-aminophenols, with various aryl acids
REFERENCES
1
.
M. Mader, A. de Dios, C. Shih, R. Bonjouklian, T. Li, W. White, B.L. de
Uralde, C. Sánchez-Martinez, M. del Prado, C. Jaramillo, E. de Diego,
L.M. Martín Cabrejas, C. Dominguez, C. Montero, T. Shepherd, R. Dally,
J.E. Toth,A. Chatterjee, S. Pleite, J. Blanco-Urgoiti, L. Perez, M. Barberis,
M.J. Lorite, E. Jambrina, C.R. Nevill Jr., P.A. Lee, R.C. Schultz, J.A.Wolos,
L.C. Li, R.M. Campbell and B.D. Anderson, Bioorg. Med. Chem. Lett.,
18, 179 (2008);
using diphosphorus tetraiodide (P I ) as a catalyst has been
2
4
reported. The use of commercially available starting materials,
low catalyst loading, no isolation of intermediates, short reaction
times, easy work-up procedure and purification by simple
column chromatography, excellent yields of product, safe and
mild reaction conditions and applicability with a broad range
of substrate are noteworthy advantages of this method over the
existing process. Overall, the present methodology is especially
https://doi.org/10.1016/j.bmcl.2007.10.106.
2
.
F. Arjmand, B. Mohani and S. Ahmad, Eur. J. Med. Chem., 40, 1103
(
2005);
https://doi.org/10.1016/j.ejmech.2005.05.005.

380 Bhagat et al.
Asian J. Chem.
3
4
5
6
.
A.T. Mavrova, K.K. Anichina, D.I. Vuchev, J.A. Tsenov, P.S. Denkova,
M.S. Kondeva and M.K. Micheva, Eur. J. Med. Chem., 41, 1412 (2006);
https://doi.org/10.1016/j.ejmech.2006.07.005.
Y. Kohara, K. Kubo, E. Imamiya, T. Wada, Y. Inada and T. Naka, J.
Med. Chem., 39, 5228 (1996);
13. J.A. Seijas, M.P. Vazquez-Tato, M.R. Carballido-Reboredo, J. Crecente-
Campo and L. Romar-Lopez, Synlett, 2007, 313 (2007);
https://doi.org/10.1055/s-2007-967994.
14. X. Wen, J.E. Bakali, R. Deprez-Poulain and B. Deprez, Tetrahedron
Lett., 53, 2440 (2012);
https://doi.org/10.1016/j.tetlet.2012.03.007.
15. D.W. Hein, R.J.Alheim and J.J. Leavitt, J. Am. Chem. Soc., 79, 427 (1957);
https://doi.org/10.1021/ja01559a053.
.
.
.
https://doi.org/10.1021/jm960547h.
F. Gualtieri, G. Brody,A.H. Fieldsteel and W.A. Skinner, J. Med. Chem.,
1
5, 420 (1972);
https://doi.org/10.1021/jm00274a026.
W.A. Denny, G.W. Rewcastle and B.C. Baguley, J. Med. Chem., 33,
16. C.T. Brain and J.T. Steer, J. Org. Chem., 68, 6814 (2003);
https://doi.org/10.1021/jo034824l.
8
14 (1990);
17. Y.S. Su and C.M. Sun, Synlett, 1243 (2005);
https://doi.org/10.1055/s-2005-865240.
https://doi.org/10.1021/jm00164a054.
7
8
.
.
G. Yadav and S. Ganguly, Eur. J. Med. Chem., 97, 419 (2015);
https://doi.org/10.1016/j.ejmech.2014.11.053.
R.S. Keri, M.R. Patil, S.A. Patil and S. Budagumpi, Eur. J. Med. Chem.,
18. A.J. Blacker, M.M. Farah, M.I. Hall, S.P. Marsden, O. Saidi and J.M.J.
Williams, Org. Lett., 11, 2039 (2009);
https://doi.org/10.1021/ol900557u.
8
9, 207 (2015);
19. Y.H. So and J.P. Heeschen, J. Org. Chem., 62, 3552 (1997);
https://doi.org/10.1021/jo960441u.
20. Z.T. Fomum, P.D. Landor, S.R. Landor and G.B. Mpango, Tetrahedron
Lett., 16, 1101 (1975);
https://doi.org/10.1016/j.ejmech.2014.10.059.
J.B. Wright, Chem. Rev., 48, 397 (1951);
https://doi.org/10.1021/cr60151a002.
9
1
.
0. Y. Riadi, R. Mamouni, R.Azzalou, M.E. Haddad, S. Routier, G. Guillaumet
and S. Lazar, Tetrahedron Lett., 52, 3492 (2011);
https://doi.org/10.1016/S0040-4039(00)72068-5.
21. Y. Kim, M.R. Kumar, N. Park, Y. Heo and S. Lee, J. Org. Chem., 76,
9577 (2011);
https://doi.org/10.1016/j.tetlet.2011.04.121.
1
1
1. H.M. Bachhav, S.B. Bhagat and V.N. Telvekar, Tetrahedron Lett., 52, 5697
https://doi.org/10.1021/jo2019416.
22. J. Peng, C. Zong, M. Ye, T. Chen, D. Gao, Y. Wang and C. Chen, Org.
Biomol. Chem., 9, 1225 (2011);
https://doi.org/10.1039/C0OB00454E.
23. A. Teimouri, A.N. Chermahini, H. Salavati and L. Ghorbanian, J. Mol.
Catal. Chem., 373, 38 (2013);
(
2011);
https://doi.org/10.1016/j.tetlet.2011.08.105.
2. D.F. Shi, T.D. Bradshaw, S. Wrigley, C.J. McCall, P. Lelieveld, I. Fichtner
and M.F.G. Stevens, J. Med. Chem., 39, 3375 (1996);
https://doi.org/10.1021/jm9600959.
https://doi.org/10.1016/j.molcata.2013.02.030.