Sodium dichloroiodate promoted C-C bond cleavage: An efficient synthesis of 1,3-Benzazoles via condensation of o -amino/mercaptan/hydroxyanilines with β -diketones

Article abstract of DOI:10.1007/s12039-017-1414-z

An efficient aqueous sodium dichloroiodate (NaICl ₂) mediated protocol is developed for the synthesis of benzofused azoles by the cyclization of 2-amino anilines/thiophenols/phenols with β-diketone compounds. The reactions gave moderate to good yield of the corresponding 2-substituted benzimidazoles/benzothiazoles/benzoxazoles under mild conditions. This tandem process involved a C-C bond cleavage and C-N bond formation. Graphical Abstract?: SYNOPSIS A facile and single protocol for the synthesis of three versatile 1,3-benzazoles viz 2-substituted 1H-benzimidazoles, benzoxazoles and benzothiazoles from readily available starting materials, 1,3-diketones and corresponding o-amino anilines/thiophenols/phenols, by aqueous sodium dichloroiodate (NaICl ₂) mediated C—C bond cleavage has been developed. The reaction provides a rapid access to these 1, 3-benzazoles in good yields, thus speeding up the drug discovery process.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s12039-017-1414-z

J. Chem. Sci. (2018) 130:10
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-017-1414-z
REGULAR ARTICLE
Sodium dichloroiodate promoted C-C bond cleavage: An efficient
synthesis of 1,3-Benzazoles via condensation of
o-amino/mercaptan/hydroxyanilines with β-diketones
SAKET B BHAGAT , SHRIKANT M GHODSE and VIKAS N TELVEKAR∗
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai,
Maharashtra 400 019, India
E-mail: vikastelvekar@gmail.com
MS received 4 August 2017; revised 29 November 2017; accepted 1 December 2017
Abstract. An efficient aqueous sodium dichloroiodate (NaICl2) mediated protocol is developed for
the synthesis of benzofused azoles by the cyclization of 2-amino anilines/thiophenols/phenols with β-
diketone compounds. The reactions gave moderate to good yield of the corresponding 2-substituted
benzimidazoles/benzothiazoles/benzoxazoles under mild conditions. This tandem process involved a C-C bond
cleavage and C-N bond formation.
Keywords. Benzimidazole/benzothiazole/benzoxazole; β-diketones; NaICl2; C-C bond cleavage.
1. Introduction
2-haloanilides analogues.26–30 Despite many method-
ologies for the synthesis of benzofused azoles, some
of them suffer from one or more shortcomings, such
as complicated catalyst, long reaction time, expen-
sive and/or non-commercially available starting mate-
rials, transition metal catalyst, use of oxidant, and/or
harsh conditions. Therefore, the development of novel
and more effective synthetic strategies is undoubtedly
attractive and desirable. Recently, p-toluene sulfonic
acid (TsOH · H2O) has been utilized for the synthe-
sis of benzothiazoles/benzimidazoles from β-diketones
and 2-aminothiophenols/2-aminoanilines respectively,
Nitrogen-containing five-member heterocyclic rings,
such as benzoxazoles, benzthiazoles and benzimida-
zoles, are widely distributed in nature and are important
fragments in medicinal chemistry because of their wide
range of biological activities, for example anticancer,
anti-inflammatory, antimicrobial, and antiviral.1–6 They
are also found in number of commercially available
drugs (albendazole, omeprazole, pimobendan, meben-
dazoleand phortress).7 Moreover, benzofused azoles are
also widely used in dyes, agrochemicals, chemosensing,
andfluorescence.8–10 Therefore, thedevelopmentofeffi-
cient methods for the synthesis of benzofused azoles has
been receiving considerable attention in recent years.
A range of methods are available for synthesis
of these heterocycles, including condensation of o-
phenylenediamine, o-aminophenol, or o-aminobenzen-
ethiol, with aldehydes/carboxylic acids or their
equivalents including acid chlorides, amides, nitriles,
orthoesters, and β-ketoesters.11–25 All these methods
involve the use of strong oxidative conditions, high
temperature, strongprotonacids, and/ormicrowaveirra-
diation for high yields. Another method involves the
transition-metal-catalyzed intramolecular cyclization of
31
however, this method is not useful for the synthe-
sis of benzoxazoles, the same authors later reported the
synthesis of benzoxazoles from 2-aminophenol and β-
diketones using a combination of p-toluene sulfonic
acid (TsOH·H2O) and copper iodide (CuI).32 This result
motivated us to explore a single metal free protocol
for the synthesis of these 1,3-benzazoles, benzimida-
zoles/benzothiazoles/benzoxazoles, using β-diketones
and o-amino anilines/thiophenols/phenols.
Carbon–carbon bonds are ubiquitous in organic com-
pounds. Compared to the highly developed C-C bond
forming reactions, the cleavage of C-C single bonds
is the most challenging issue in organic chemistry
due to their inert nature, thermodynamic stability and
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-017-1414-z) contains
supplementary material, which is available to authorized users.

10 Page 2 of 10
J. Chem. Sci. (2018) 130:10
Scheme 1. Single protocol for the synthesis of 2-substituted 1,3-benzazoles from β-diketones.
uncontrollable selectivity. Thus the cleavage of 2.2 General procedure for the synthesis of
C-C bond has emerged as a challenging and attractive 2-substituted 1,3-Benzazoles 3, 5 and 7
area which provides new modes of chemical reactiv-
To a mixture of o-substituted (–NH2 or –SH or –OH) anilines
ity to synthetic organic chemistry. To cleave unstrained
inert C-C bonds, harsh conditions with stoichiometric
(1.0 mmol) and appropriate 1,3-diketones (1.1 mmol) in THF
(5 mL) was added 30%w/w aqueous NaICl2 (0.2 mmol, 20
oxidants, such as peroxides and toxic metal salts includ-
mol%). The reaction was allowed to remain stirred at reflux
ing transition metals are frequently employed.33–36
temperature for 2–3 h. After the reaction was complete, as
Sodium dichloroiodate is a commercially available
indicated by TLC, the mixture was cooled to room temper-
iodine reagent previously investigated in our labora-
ature. The volatiles were removed under reduced pressure
tory for a number of varied organic transformations.37–39
and treated successively with aqueous sodium thiosulphate
This prompted us to explore the feasibility of this
versatile reagent for C-C bond cleavage. Herein, in con-
tinuation of our ongoing research on the synthesis of were washed with brine and dried over Na2SO4 and evapo-
solution and saturated solution of NaHCO3, and extracted
by ethylacetate (2×10 mL). The combined organic phases
rated under vacuum. The crude reaction mixture was purified
by column chromatography on silica gel using petroleum
ether/ethyl acetate as eluents.
N-heterocycles, we report an efficient method for the
synthesis of benzofused azoles via NaICl2 catalyzed C-
C bond cleavage of β-diketones (Scheme 1).
2.2a 2-Methyl-1H-benzimidazole 3a40: Yield 90%,
White solid, M.p. 173–175 ◦C (Lit. 174–176 ◦C); FT-IR
(KBr): v 3420, 3110, 2985, 1630, 1560, 1450, 1370, 1275,
2. Experimental
1
1215, 1047, 846, 753 cm−1; H NMR (400 MHz, CDCl3) δ
2.1 Materials and methods
12.21 (brs, 1H, NH), 7.52–7.48 (m, 2H, ArH), 7.22–7.19 (m,
2H, ArH), 2.59 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ
151.7, 138.6, 122.1, 114.6, 14.9. HRMS: calcd for C8H8N2:
132.0687, found 132.0687.
All the chemicals and reagents were purchased from Sigma
Aldrich, SD fine, Avra Synthesis or Spectrochem companies
and were used without further purification. Solvents were
distilled from an appropriate drying agent. The purity deter-
mination of the starting materials and reaction monitoring was
accomplished by thin-layer chromatography (TLC) on Merck
silica gel 60 F254 plates. Silica gel 60–120 mess was used for
column chromatography. Melting points of all the compounds
wererecordedonThermomikCampbellmeltingpointappara-
tus having an oil bath system and are uncorrected. The FT-IR
spectra (KBr) were recorded on Shimadzu FTIR Affinity-
2.2b 2-Ethyl-1H-benzimidazole 3b31: Yield 95%,
White solid, M.p. 171–173 ◦C (Lit. 171–173 ◦C); FT-IR
(KBr): v 3417, 2996, 1614, 1540, 1430, 1365, 1274, 1224,
1
1045, 887, 746 cm−1; H NMR (400 MHz, CDCl3) δ 10.3
(brs, 1H, NH), 7.58–7.55 (m, 2H, ArH), 7.26–7.20 (m, 2H,
ArH), 2.99(q, J = 7.6 Hz, 2H, CH2), 1.47(t, J = 7.6 Hz, 3H,
CH3); 13C NMR (100 MHz, CDCl3) δ 156.8, 138.7, 122.1,
114.6, 22.9, 12.4. HRMS: calcd for C9H10N2: 146.0844,
found 146.0845.
1
1 Fourier Transform Infrared spectrophotometer. H NMR
spectra were recorded on MR400 Agilent Technology NMR
spectrometer (400 MHz) using tetramethylsilane (TMS) as
internal standard and DMSO-d6/CDCl3 as solvent. Chemi- 2.2c 2-Isopropyl-1H-benzoimidazole 3c31:
Yield
cal shifts are reported in parts per million (ppm, δ) downfield 55%, White solid, M.p. 235–237 ◦C (Lit. 234–236 ◦C); FT-
from residual solvent peaks and coupling constants (J) are IR (KBr): v 3410, 2996, 1620, 1510, 1415, 1365, 1286, 1224,
1
reported as Hertz (Hz). Splitting patterns are designated as 1088 cm−1; H NMR (400 MHz, CDCl3) δ 9.97 (brs, 1H,
singlet (s), doublet (d), triplet (t). Splitting patterns that could NH), 7.58-7.56 (m, 2H, ArH), 7.23–7.16 (m, 2H, ArH), 3.30–
not be interpreted is designated as multiplet (m). All the prod- 3.22 (m, 1H, CH), 1.49 (t, 6H, CH3); 13C NMR (100 MHz,
ucts are known compounds and were identified by 1H NMR CDCl3) δ 160.8, 138.9, 122.1, 115.4, 30.3, 22.1. HRMS:calcd
spectroscopy.
for C10H12N2: 160.1000, found 160.1000.

J. Chem. Sci. (2018) 130:10
Page 3 of 10 10
Table 1. Screening of Reaction Conditionsa.
2.2g 5-Chloro-2-ethyl-1H-benzimidazole 3g31:
Yield 95%, Brown solid, M.p. 170–171 ◦C (Lit. 169–171 ◦C);
FT-IR (KBr): v 3420, 3130, 3003, 1670, 1572, 1391, 1265,
Entry NaICl2 (mol%) Temperature Time (h) Yield(%)b
1
1100, 921, 804 cm−1; H NMR (400 MHz, CDCl3) δ 12.47
1
2
3
4
5
6
None
100
100
50
20
10
rt
rt
24
5
2
2
2
NRc
60
88
93
90
(brs, 1H, NH), 7.62 (s, 1H, ArH), 7.51 (d, J = 8.2 Hz, 1H,
ArH), 7.18 (d, J = 8.2 Hz, 1H, ArH), 2.91 (q, J = 7.6 Hz,
2H, CH2), 1.37 (t, J = 7.6 Hz, 3H, CH3); 13C NMR (100
MHz, CDCl3) δ 158.3, 126.1, 121.8, 119.6, 117.7, 112.4,
111.2, 22.3, 12.7. HRMS: calcd for C9H9ClN2: 180.0454,
found 180.0454.
Reflux
Reflux
Reflux
Reflux
5
58
aReaction conditions: o-phenylenediamine (1a, 1.0 mmol),
2,4-pentanedione (2a, 1.1 mmol), 30% aqueous NaICl2 cata-
lyst in tetrahydrofuran (5.0 mL). bIsolated yield. cNo reaction
2.2h 2-Phenyl-1H-benzim◦idazole 3h43: Yield 20%,
◦
Yellow solid, M.p. 290–293 C (Lit. 292–294 C); FT-IR
(KBr): v 3450, 3045, 1620, 1580, 1458 cm−1; 1H NMR (400
MHz, CDCl3) δ 12.80 (s, 1H, NH), 7.56–7.50 (m, 4H, ArH),
7.21–7.15 (m, 5H, ArH); 13C NMR (100 MHz, CDCl3) δ
151.9, 144.5, 135.2, 130.6, 130.3, 129.5, 126.9, 123.1, 122.2,
119.5, 111.7. HRMS: calcd for C13H10N2: 194.0844, found
194.0846.
2.2d 2,5-Dimethyl-1H-benzimidazole 3d41:
Yield
84%, White solid, M.p. 200–202 ◦C (Lit. 202–203 ◦C); FT-
IR (KBr): v 3420, 3040, 2915, 2765, 1620, 1550, 1480, 1281,
1
1034, 877, 791 cm−1; H NMR (400 MHz, CDCl3) δ 12.04
(brs, 1H, NH), 7.43 (d, J = 7.9 Hz, 1H, ArH), 7.33 (s, 1H,
ArH), 7.02 (d, J = 7.9 Hz, 1H, ArH), 2.62 (s, 3H, CH3), 2.41
(s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 151.7, 138.3,
136.7, 132.6, 124.4, 114.5, 114.3, 22.1, 14.9. HRMS: calcd
for C9H10N2: 146.0844, found 146.0847.
2.2i 2-Methylbenzothiazole 5a44: Yield 90%, Pale yel-
low liquid; FT-IR (KBr): v 1554, 1521, 1450, 1310, 1232
1
cm−1; H NMR (400 MHz, CDCl3)δ 7.97 (d, J = 7.9 Hz,
1H, ArH), 7.81 (d, J = 7.9 Hz, 1H, ArH), 7.44−7.41 (m, 1H,
ArH), 7.32−7.28 (m, 1H, ArH), 2.80 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3) δ 164.9, 151.2, 133.4, 124.0, 122.7, 119.3,
18.1. HRMS: calcd for C8H7NS: 149.0299, found 149.0301.
2.2e 2-Ethyl-5-methyl-1H-benzimidazole 3e31:
Yield 93%, White solid, M.p. 160–163 ◦C (Lit. 160–162 ◦C);
FT-IR (KBr): v 3421, 3010, 2985, 2740, 1630, 1554, 1421,
1320, 1277, 1138, 1070, 970, 873, 801 cm−1; 1H NMR (400
MHz, CDCl3) δ 11.26 (brs, 1H, NH), 7.45 (d, J = 8.4 Hz, 1H,
ArH), 7.34 (s, 1H, ArH), 7.06 (d, J = 8.4 Hz, 1H, ArH), 2.99
(q, J = 7.6 Hz, 2H, CH2), 2.43 (s, 3H, CH3), 1.42 (t, J = 7.6
Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 155.1, 137.4,
135.9, 130.8, 113.3, 113.0, 122.5, 21.6, 20.4, 11.4. HRMS:
calcd for C10H12N2: 160.1000, found 160.1001.
2.2j 2-Ethylbenzothiazole 5b40: Yield 85%, Yellow
liquid; FT-IR (KBr): v 1565, 1534, 1455, 1320, 1240 cm−1
;
1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 1H,
ArH), 7.78 (d, J = 8.0, 1H, ArH), 7.39 (m, 1H, ArH),
7.29 (m, 1H, ArH), 3.11 (q, J = 7.1 Hz, 2H, CH2), 1.43
(t, J = 7.1 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ
173.2, 153.0, 135.2, 125.9, 124.7, 122.6, 121.4, 28.1, 13.8.
HRMS: calcd for C9H9NS: 163.0456, found 163.0455.
2.2f 5-Chloro-2-methyl-1H-benzimidazole 3f42:
Yield 91%, Off white solid, M.p. 202–203 ◦C (Lit. 200–201
◦C); FT-IR (KBr): v 3414, 3122, 2971, 1634, 1552, 1401,
2.2k 5-Chloro-2-methylbenz◦othiazole 5c31:
Yield
◦
70%, White solid, M.p. 67–69 C (Lit. 68–69 C); FT-IR
(KBr): v 1550, 1521, 1440, 1307, 1275, 757 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.81 (m, 1H, ArH), 7.77 (s, 1H, ArH),
7.39 − 7.36 (m, 1H, ArH), 2.79 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3) δ 169.6, 154.7, 134.1, 132.3, 125.5, 122.6,
122.1, 20.3. HRMS: calcd for C8H6ClNS: 182.9909, found
182.9907.
1
1279, 1057, 923, 797 cm−1; H NMR (400 MHz, CDCl3) δ
12.29 (brs, 1H, NH), 7.51 (s, 1H, ArH), 7.45 (d, J = 8.4 Hz,
1H, ArH), 7.12 (d, J = 8.3 Hz, 1H, ArH), 2.51 (s, 3H,
CH3); 13C NMR (100 MHz, CDCl3) δ 152.7, 140.1, 137.1,
126.1, 121.8, 115.4, 114.3, 15.1. HRMS:calcdforC8H7ClN2:
166.0298, found 166.0300.
Scheme 2. Reaction between o-phenylenediamines and β–diketones in presence of aq. NaICl2.

10 Page 4 of 10
Table 2. Synthesis of 2-substituted benzimidazolea.
J. Chem. Sci. (2018) 130:10
Entry
No.
Substituted 1,2-
diamines
1,3-diketones
2
Product
Yield (%)b
3
1
NH2
N
O
O
1
2
3
4
5
90
95
55
84
93
N
H
NH2
2a
2b
1a
3a
NH2
N
O
O
N
H
NH2
3b
1a
NH2
N
O
O
N
H
NH2
2c
2a
1a
3c
NH2
N
O
O
O
O
N
H
NH2
1b
3d
3e
NH2
N
O
N
H
NH2
2b
1b
NH2
Cl
Cl
Cl
N
O
6
7
8
9
91
95
70
74
N
H
NH2
NH2
2a
2b
1c
1c
1a
1b
3f
Cl
N
O
O
N
H
NH2
3g
3a
3d
NH2
N
O
O
N
H
P
P
P
h
h
h
NH2
2d
2d
NH2
N
O
O
O
N
H
NH2
NH2
Cl
Cl
N
O
O
10
11
70
N
H
NH2
2d
2e
3f
1c
1a
O
NH2
N
20/60c
P
h
P
h
N
NH2
H3h
aReaction conditions: 1.0 mmol of o-phenylenediamine, 1.1 mmol of β–diketone and 20 mol% aqueous
b
NaICl2 in tetrahydronfuran at reflux. Isolated yields after column chromatography and structures were
confirmed by comparison of IR, 1H NMR and M.P. with literature reports. cReaction carried in a sealed tube
for 10 h.

J. Chem. Sci. (2018) 130:10
Page 5 of 10 10
Scheme 3. Reaction between o-amino phenols/thiophenols and β–diketones in presence of aq. NaICl2.
2.2l 5-Chloro-2-ethylbenzothiazole 5d31: Yield 65%, The desired product, 2-methyl-1H-benzimidazole 3a
Yellow liquid; FT-IR (KBr): v 1560, 1527, 1445, 1310, 1280,
754 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H, ArH),
7.72 (d, J = 8.1 Hz, 1H, ArH), 7.30 (d, J = 8.1 Hz, 1H,
ArH), 3.13(q, J = 7.5 Hz, 2H, CH2), 1.46(t, J = 7.5 Hz, 3H,
CH3); 13C NMR (100 MHz, CDCl3) δ 175.9, 154.4, 133.7,
132.3, 125.4, 122.8, 122.6, 28.4, 13.7. HRMS: calcd for
C9H8ClNS: 197.0066, found 197.0067.
was obtained when reaction of 1a with 2a was per-
formed in tetrahydrofuran (THF) using 1 equivalents of
NaICl2 at room temperature in good yield (60%) after
5 hrs stirring (Table 1, entry 2). It was observed that
raising the reaction temperature from room temperature
to reflux brought about a considerable increase in yield
of 3a (88%) simultaneously reducing the reaction time
(Table 1, entry 3). Further, decreasing the quantity of the
NaICl2 to 50 mol% or 20 mol% did not affect the product
2.2m 2-Methylbenzoxazole 7a45: Yield 80%, Yellow
liquid; FT-IR (KBr): v 3050, 2995, 2930, 2851, 1435, 1270, yield and reaction time considerably (Table 1, entry 4–
710 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.61–7.58 (m, 1H,
5). A further decrease in the NaICl2 quantity to 10 mol%,
however, resulted in relatively low yield (Table 1, entry
6). After testing other solvents, such as acetonitrile, 1,4-
dioxane, dichloromethane, methanol, andethanol, itwas
ArH), 7.42–7.40 (m, 1H, ArH), 7.24-7.21 (m, 2H, ArH), 2.59
(s, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ 163.6, 150.8,
141.4, 124.5, 124.0, 119.3, 110.2, 14.5. HRMS: calcd for
C8H7NO: 133.0528, found 133.0525.
found that THF is most suitable solvent for this reaction
(Scheme 2).
2.2n 2,5-Dimethylbenzoxazole 7b32:
Yield 67%,
With the optimum reaction conditions in hand, an
explorationofsubstratescopewasperformedwithstruc-
tural varied β-diketones 2 and o-phenylenediamines
1 and the results are summarized in Table 2. The
reactions proceeded smoothly affording the expected 2-
substituted-1H-benzimidazoles 3 in moderate to good
yields, regardless of the steric hindrance and elec-
tronic effect of the substituents. The reactions of o-
phenylenediamine 1a with β-diketones 2a, 2b, and 2c
bearing aliphatic groups on their 1,3-positions, under
optimised reaction conditions, proceeded smoothly to
afford the desired 2-substituted-1H-benzimidazoles 3
in good yields (Table 2, entry 1-3). The lower yield of
the product 3c, obtained by reacting 1a with 2c, may be
due to steric hindrance of the bulky iso-propyl group of
the diketone.
The presence of electron donating group and elec-
tron withdrawing group on 2-aminoaniline had an
insignificant effect on the reaction yields (Table 2,
entry 4–7). Next, the reaction of o-phenylenediamine
1a with unsymmetrical β-diketone, 1-methyl-3-phenyl-
1,3-dione 2d, gave the corresponding 2-methyl-1H-
benzimidazole 3a as the major product (Table 2, entry
8), thus indicating the higher reactivity of acetyl group
as compared to benzoyl group under the present reaction
conditions. The same was ascertained by the reaction of
Colourless liquid; FT-IR (KBr): v 3030, 2975, 2856, 1484,
1256, 722 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H,
ArH), 7.32 (d, J = 8.1 Hz, 1H, ArH), 7.04 (d, J = 8.1 Hz,
1H, ArH), 2.57 (s, 3H, CH3), 2.38 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3) δ 161.8, 147.3, 140.2, 130.1, 122.5, 117.6,
107.1, 19.4, 13.3. HRMS: calcd for C9H9NO: 147.0684,
found 147.0683.
2.2o 2-Methyl-5-chlorobenzoxazole 7c46: Yield 71%,
◦
◦
White solid, M.p. 55–57 C (Lit. 53–55 C); FT-IR (KBr):
1
v 3110, 3093, 2994, 1495, 1260, 747 cm−1; H NMR (400
MHz, CDCl3) δ 7.59 (s, 1H, ArH), 7.34 (d, J = 8.3 Hz, 1H,
ArH), 7.23 (d, J = 8.3 Hz, 1H, ArH), 2.61 (s, 3H, CH3);
13C NMR (100 MHz, CDCl3) δ 165.6, 149.4, 142.6, 129.3,
124.7, 119.3, 111.2, 14.8. HRMS: calcd for C8H6ClNO:
167.0138, found 167.0141.
3. Results and Discussion
To optimize the reaction conditions, including catalyst
loading, temperature, and solvent, the condensation of
o-phenylenediamine 1a and 2,4-pentanedione 2a was
used as the model reaction and results are summarized
in Table 1.

10 Page 6 of 10
Table 3. Synthesis of 2-substituted benzothiazole and benzoxazolea.
J. Chem. Sci. (2018) 130:10
Entry
No.
Substituted
X
1,3-diketones
2
Product
Yield
o-amino derivative
(%)b
4/6
NH2
N
S
O
O
1
2
3
S
S
S
90
H
S
2a
2b
5a
4a
4a
4b
NH2
N
O
O
85
70
S
H
S
5b
NH2
Cl
Cl
Cl
N
O
O
H
S
S
2a
2b
5c
NH2
Cl
N
S
O
O
4
5
6
7
8
S
S
65
57
80
67
71
H
S
4b
4a
6a
6b
6c
5d
5a
NH2
N
S
O
O
P
h
H
S
2d
2a
2a
2a
NH2
N
O
O
O
O
O
O
O
O
H
O
7a
7b
NH2
N
O
O
O
H
O
NH2
Cl
Cl
N
H
O
O
7c
aReaction conditions: 1.0 mmol of o-amino thiophenol/phenol, 1.1 mmol of β–diketone and 20 mol% aque-
ous NaICl2 in tetrahydronfuran at reflux. bIsolated yields after column chromatography and structures were
confirmed by comparison of IR, 1H NMR and M.p. with literature reports.
substituted o-phenylenediamines with unsymmetrical The present method was successfully extended for
β-diketone (Table 2, entry 9–10). Further, the low yield the synthesis of 2-substituted benzothiazoles 5 and
of the desired product, 2-phenyl-1H-benzimidazole, 2-substituted benzoxazoles 7 from the reaction of 2-
obtained by treating o-phenylenediamine with 1,3- aminothiphenols 4 and 2-aminophenols 6, respectively,
diphenylpropane-1,3-dione, emphasize our claim of with various β-diketones 2 (Scheme 3).
low reactivity of the benzoyl group over acetyl group
The reaction of 2-aminothiophenol 4a with
(Table 2, entry 11). However, the yield of the desired 2,4-pentanedione 2a and 3,5-heptanedione 2b gave
product increased when the same reaction was con- the corresponding 2-methybenzothiazole 5a and 2-
ducted in a sealed tube, though the time required for ethylbezothiazole 5b in excellent yield respectively
the completion of the reaction increased to 10 h.
(Table3, entry1–2). Also, thereactionof2-aminophenol

J. Chem. Sci. (2018) 130:10
Page 7 of 10 10
(a)
(b)
(c)
Scheme 4. Control experiments.
6a with 2,4-pentanedione 2a gave the corresponding refluxed in THF in absence of NaICl2 the corresponding
2-methybenzoxazole 7a in good yield (Table 3, entry 2-methy-1H-benzimidazole product 3 was not observed
6). Next, the reactions of 4-chloro-2-aminothiphenol 4b, [Scheme4, (b)]. However, theimineA, uponrefluxingin
4-methyl-2-aminophenol 6b, 4-chloro-2-aminophenol THF in the presence of NaICl2, gave the desired cyclised
6c with β-diketones 2a and 2b smoothly proceeded product 2-methy-1H-benzimidazole 3 [Scheme 4, (c)].
to give corresponding benzothiazole and benzoxazole This finding supports the role of NaICl2 in this cycliza-
products in good to moderate yields (Table 3, entries tion and C-C bond cleavage reaction. However, the exact
3, 4, 7, 8). From these results, it can be concluded that role of NaICl2 in the pathway could not be determined
different substituent (either electron-donating group or as no other intermediates could be isolated in the reac-
electron-withdrawing group) on 2-aminothiophenol and tion and very few literature reports are available to get
2-aminophenol had no significant impact on the reaction a better insight into the mechanisti−c role of NaICl2 as
yield. Finally, the method was also successfully applied catalyst. Though, we suppose that ICl2 forms a com-
to the reaction of 2-aminothiophenol with unsymmet- plex with the N of intermediates A and B, thus affording
rical β-diketone, 1-methyl-3-phenyl-1,3-dione 2d, the the intramolecular nucleophilic cyclization and subse-
product 2-methylbenzothiazole was obtained in 57% quent C-C bond cleavage. Moreover, under the present
yield (Table 3, entry 5). The reactions in which the yields reaction conditions, NaICl2 did not cause iodination of
were moderate, a polar side product was observed on o-phenylenediamine.
TLC. This side product was isolated by column chro-
matography but could not be identified.
On the basis of the above experimental results as well
as the literature reports, a plausible mechanism is pro-
To gain insight into the mechanism, several control posed in Scheme 5. Initially, condensation reaction of
experiments were performed as depicted in Scheme 4. o-phenylenediamine 1 with acetyl acetone 2 generates
Initially, when o-phenylenediamine 1 was reacted with a ketimine intermediate A. The ketimine intermediate
acetyl acetone 2 in presence of NaICl2, the imine A undergoes an intramolecular nucleophilic addition
intermediate A (ketimine-enaminone tautomer) was to produce adduct B. The C-C bond cleavage reaction
observed [Scheme 4, (a)]. Further, when this imine was finally occurs to generate product 3.

10 Page 8 of 10
J. Chem. Sci. (2018) 130:10
Scheme 5. Plausible Mechanism.
4. Conclusion
3. Tong Y S, Bouska J J, Ellis P A, Johnson E F, Leverson J,
Liu X S, Marcotte P A, Olson A M, Osterling D J, Przy-
tulinskaM, RodriguezLE, ShiY, SoniN, StavropoulosJ,
Thomas S, Donawho C K, Frost D J, Luo Y, Giranda V L
and Penning T D 2009 Synthesis and evaluation of a new
generation of orally efficacious benzimidazole-based
poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors as
anticancer agents J. Med. Chem. 52 6803
4. Achar K C S, Hosamani K M and Seetharamareddy H R
2010 In-vivo analgesic and anti-inflammatory activities
of newly synthesized benzimidazole derivatives Eur. J.
Med. Chem. 45 2048
5. Ertan T, Yildiz I, Tekiner-Gulbas B, Bolelli K, Temiz-
Arpaci O, Yalcin I, Aki E, Ozkan S and Kaynak F 2009
Synthesis, biological evaluation and 2D-QSAR analy-
sis of benzoxazoles as antimicrobial agents Eur. J. Med.
Chem. 44 501
6. Ansari K F and Lal C 2009 Synthesis, physicochemical
properties and antimicrobial activity of some new benz-
imidazole derivatives Eur. J. Med. Chem. 44 4028
7. Refaat H M 2010 Synthesis and anticancer activity of
some novel 2-substituted benzimidazole derivatives Eur.
J. Med. Chem. 45 2949
In conclusion, we have developed a general and facile
route for the sodium dichloroiodate (NaICl2) pro-
moted synthesis of benzazoles by the condensation of
o-amino anilines/thiophenols/phenols with β-diketone
compounds through the C—C bond cleavage. The reac-
tion can be performed with readily available starting
materialundermildconditions(withouttheuseofstrong
oxidants, metal catalyst or Bronsted acid catalyst, and
high temperature), and gives product with moderate to
good yields and high purity.
Supplementary Information (SI)
General Information, Experimental details and H and 13C
NMR spectra of selected synthesized compounds are accessi-
ble in Supplementary Information at www.ias.ac.in/chemsci.
1
Acknowledgements
8. Zhao J, Sun B, Qiu L, Caocen H, Li Q, Chen X and Yan F
2012 Efficient light-scattering functionalized TiO2 pho-
toanodes modified with cyanobiphenyl-based benzimi-
dazole for dye-sensitized solar cells with additive-free
electrolytes J. Mater. Chem. 22 18380
S.B.B. and S.M.G are thankful to the University Grants Com-
mission (UGC, New Delhi, India), and V.N.T. is thankful to
the Sciences and Engineering Research Board (SERB), New
Delhi, India for providing financial support.
9. Saluja P, Sharma H, Kaur N, Singh N and Jang D O
2012 Benzimidazole-based+imine-linked chemosensor:
chromogenic sensor for Mg2 and fluorescent sensor for
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