A Novel Method for the Synthesis of 2(3H)-Benzimidazolones, 2(3H)-Benzoxazolone, and 2(3H)-Benzothiazolone via in Situ Generated Ortho Substituted Benzoic Acid Azides: Application of Ammonium Azide and Vilsmeier Complex for Acid Azide Generation

Article abstract of DOI:10.1081/SCC-120027722

An easy and generalized route to 2(3H)-benzimidazolones, 2(3H)-benzoxazolone and 2(3H)-benzothiazolone is attempted. A novel one-pot method for the in situ generation and cyclisation of ortho substituted benzoic acid azides is reported via the application of ammonium azide and Vilsmeier complex.

Full text of DOI:10.1081/SCC-120027722

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A Novel Method for the Synthesis of
2(3H)‐Benzimidazolones, 2(3H)‐Benzoxazolone,
and 2(3H)‐Benzothiazolone via In Situ Generated
Ortho Substituted Benzoic Acid Azides: Application
of Ammonium Azide and Vilsmeier Complex for Acid
Azide Generation
Radhakrishnan Sridhar a & Paramasivan T. Perumal a
a Organic Chemistry Division , Central Leather Research Institute , Chennai, 600 020,
India
Published online: 16 Aug 2006.
To cite this article: Radhakrishnan Sridhar & Paramasivan T. Perumal (2004) A Novel Method for the Synthesis of
2(3H)‐Benzimidazolones, 2(3H)‐Benzoxazolone, and 2(3H)‐Benzothiazolone via In Situ Generated Ortho Substituted
Benzoic Acid Azides: Application of Ammonium Azide and Vilsmeier Complex for Acid Azide Generation, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:4, 735-742, DOI:
10.1081/SCC-120027722
To link to this article: http://dx.doi.org/10.1081/SCC-120027722
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 4, pp. 735–742, 2004
A Novel Method for the Synthesis of 2(3H)-
Benzimidazolones, 2(3H)-Benzoxazolone,
and 2(3H)-Benzothiazolone via In Situ
Generated Ortho Substituted Benzoic
Acid Azides: Application of Ammonium
Azide and Vilsmeier Complex for Acid
Azide Generation
*
Radhakrishnan Sridhar and Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute,
Chennai, India
ABSTRACT
An easy and generalized route to 2(3H)-benzimidazolones, 2(3H)-
benzoxazolone and 2(3H)-benzothiazolone is attempted. A novel one-pot
method for the in situ generation and cyclisation of ortho substituted
benzoic acid azides is reported via the application of ammonium azide
and Vilsmeier complex.
*
Correspondence: Paramasivan T. Perumal, Organic Chemistry Division, Central
Leather Research Institute, Chennai 600 020, India; Fax: 91-044-2491 1589; E-mail:
ptperumal@hotmail.com.
735
DOI: 10.1081/SCC-120027722
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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736
Sridhar and Perumal
Key Words: Vilsmeier complex; Acid azide; Curtius rearrangement;
2(3H)-benzimidazolone; 2(3H)-benzoxazolone; 2(3H)-benzothiazolone.
Acyl azides serve as valuable synthetic intermediates in organic chem-
istry.[1] They undergo Curtius rearrangement[2] to isocyanates and thereby
leading to a variety of products.[1] In our recent communication we have
reported the synthesis of acyl azides using Vilsmeier complex starting from
the respective acids in one-pot.[3] In continuation of our research interests on
the synthesis of heterocyclic compounds[4] using the Vilsmeier complex, we
aimed to synthesize these title compounds from in situ formed ortho
substituted benzoic acid azides after Curtius rearrangement at room tempera-
ture (Sch. 1). Benzimidazole derivatives possess a variety of biological
activities.[5] A large number of derivatives of benzimidazole found to show
trypanosomicidal and spirocheticidal action and are active against diseases
caused by protozoa.[6] Most of them are derivatives of 2(3H)-benzimidazol-
ethione or 2(3H)-benzimidazolone.
Since the first report on the hypnotic properties of 2-benzoxazolinone[7a]
a
number of derivatives have been tested for various activities including
anticonvulsant, antipyretic, analgesic, cardiotonic, antiulcer, antineoplastic or
antibacterial, antimicrobial and antifungal effects.[7b] 2(3H)-benzothiazolone
and its derivatives possess excellent biological activities.[8] There are several
synthetic routes to 2(3H)-benzimidazolones,[9] 2(3H)-benzoxazolones[10] and
2(3H)-benzothiazolones.[11] But most of the synthetic routes[12] to 2(3H)-
benzimidazolone involve o-phenylenediamine as the starting material, which
is a suspected carcinogen and is costlier. And there is no generalized strategy
available for the synthesis of these title compounds in one pot. Hence we
aimed at a generalized procedure, which is simpler for the preparation of
2(3H)-benzimidazolones, 2(3H)-benzoxazolone and 2(3H)-benzothiazolone.
The novelty in the synthesis of these heterocycles is achieved here not only
through the in situ formation of acyl azides but also by the employment of
Scheme 1. Synthesis of 2(3H)-benzimidazolones, 2(3H)-benzoxazolone and 2(3H)-
benzothiazolone.

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Acyl Azides
737
ammonium azide for the generation of acyl azides. Since efficient application
of sodium azide in the introduction of azide moiety involves trituration and its
storage under nitrogen atmosphere,[13] ammonium azide[14] was employed
instead of sodium azide. And it was found that in situ formed ammonium azide
is more reactive and more advantageous.[15] Hence ammonium azide was
generated in situ under reaction conditions using powdered sodium azide,
ammonium chloride and DMF. The acyl azides thus formed being highly
reactive, undergo Curtius rearrangement leading to unstable isocyanates. The
amino group of anthranilic acid and substituted anthranilic acids which is
viable to the attack of the Vilsmeier reagent takes up one mole of the same and
cyclises with the neighbouring isocyanate moiety to form 2(3H)-benzimidazo-
lones upon careful hydrolysis with 1N NaOH. N-Formyl benzimidazolones
are also formed upon hydrolysis with H2O along with 2(3H)-benzimidazo-
lones. This rationalises the reaction path (Sch. 2).
In the case of 4-nitroanthranilic acid the dimerised product (95% yield)
was obtained even at room temperature.[16] Salicylic acid and thiosalicylic
acid yield 2(3H)-benzoxazolone and 2(3H)-benzothiazolone respectively in
Scheme 2. Mechanism involved in the synthesis of 2(3H)-benzimidazolones.

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Sridhar and Perumal
Table 1. Synthesis of 2(3H)-benzimidazolones, 2(3H)-benzoxazolone and 2(3H)-
benzothiazolone.
Entry
X
R1
R2
R3
% Yielda
Time (hrs)
Mp (8C)b
2a
2b
2c
2d
2e
2f
NH
NH
NH
NH
NH
NH
H
Cl
H
H
H
H
H
H
H
H
80
8
8
.300[17a]
.300
88
70
Cl
H
H
8
324–328[18]
324–328[18]
308[19]
Cl
H
15
75
10
8
NO2
H
NO2
dimerised
product16
82
6
.250
2g
2h
O
S
H
H
H
H
H
H
8
8
137[17b]
138[17c]
70
aIsolated yields after column chromatography.
bAll the products were characterised by 1H and 13C NMR, mass spectral and elemental
analysis data.
good yields upon treatment with ammonium azide and three equivalents of
DMF-POCl3 complex (Table 1).
Excess POCl3 (Sch. 3) replaces –OH group with –Cl yielding 94% of
2-chlorobenzothiazole. Stirring the reaction mixture at room temperature for
about 6–10 h effected both rearrangement and cyclization. The versatility of
our method involves a novel in situ generation and cyclisation of the ortho
substituted benzoic acid azide obtained from the action of Vilsmeier complex,
ortho substituted benzoic acid and in situ generated ammonium azide.
Scheme 3. Synthesis of 2(3H)-benzothiazolone and 2-chlorobenzothiazole.

ORDER
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Acyl Azides
739
In summary a convenient one-pot conversion of ortho substituted benzoic
acids into benzimidazolones, benzoxazolone and benzothiazolone at room
temperature is reported.
EXPERIMENTAL
All the reagents were distilled prior to use from an appropriate drying
agent. Infrared spectra were recorded as KBr pellets for all the samples except
for 2-chlorobenzothiazole, which is a liquid and was recorded as a film on a
Perkin Elmer FT-IR instrument. Nuclear Magnetic Resonance spectra
recorded on a Jeol Spectrometer, at 500 MHz (PMR) and at 125 MHz
(13C NMR). Mass spectra were obtained on Perkin Elmer Mass Spectrometer.
General Procedure for the in situ Generation and Cyclization
of the ortho Substituted Benzoic Acid Azide
To a stirred solution of the substituted benzoic acid (0.686 g, 5 mmol) and
sodium azide (0.358 g, 5.5 mmol, 1.1 equiv.) in 20 ml dry DMF, ammonium
chloride (0.03 g, 10 mol%) was added upon cooling to 08C. Then POCl3
(1.4 mL, 3 equiv.) was added drop wise to the solution. After the addition was
over the reaction mixture was allowed to attain room temperature gradually.
The solution after stirring for 8 h was neutralised with 1 N NaOH and extracted
with chloroform. The solvent was then evaporated off under reduced pressure
and the crude material was purified by column chromatography on silica gel
(s.d.fine, 100–200 mesh, hexane/ethyl acetate, 5 : 1) to afford the pure
1
product, which was characterised by H NMR, 13C NMR, mass spectral and
elemental analysis data.
Spectral analysis of 4-chloro-2(3H)-benzimidazolone (Compound
2b). IR (KBr) 3119 1745, 1665 cm21; 1H NMR (500 MHz, DMSO-d, ppm): d
11.14 (s, 1H), 10.9 (s, 1H), 6.99–6.97 (dd, J ¼ 1.145, 8.018 Hz, 1H), 6.95–
6.92 (t, J ¼ 7.447, 8.018 Hz, 1H), 6.90–6.89 (dd, J ¼ 1.145, 7.447 Hz, 1H).
13C NMR (125 MHz, DMSO-d, ppm): d 155.57, 131.46, 127.96, 122.17,
120.83, 113.35, 170.89; EI MS 168 (M þ ), 140, 105, 78. Anal. calcd for
C7H5ClN2O: C, 49.87; H, 2.99; N, 16.62. Found: C, 49.77; H, 3.02; N, 16.78.
5-Chloro-2(3H)-benzimidazolone (Compound 2c). IR (KBr) 3174,
1
1752 cm21; H NMR (500 MHz, DMSO-d, ppm): d 11.45 (s, 1H), 11.29
(s, 1H), 7.820–7.816 (d, J ¼ 2.291 Hz, 1H), 7.702–7.681 (dd, J ¼ 2.291,
8.588 Hz, 1H), 7.20–7.18 (d, J ¼ 8.593 Hz, 1H). 13C NMR (125 MHz,
DMSO-d, ppm): d 154.03, 131.87, 131.43, 130.97, 128.40, 118.96, 114.89; EI

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740
Sridhar and Perumal
MS 168 (M þ ), 140, 105, 78. Anal. calcd for C7H5ClN2O: C, 49.87; H, 2.99;
N, 16.62. Found: C, 50.02; H, 3.06; N, 16.54.
5-Nitro-2(3H)-benzimidazolone (Compound 2e). IR (KBr) 3188,
1
1758 cm21; H NMR (400 MHz, DMSO-d, ppm): d 11.40 (s, 1H), 11.17
(s, 1H), 7.94–7.91 (dd, J ¼ 2.17, 8.68 Hz, 1H), 7.81–7.80 (d, J ¼ 2.11 Hz,
1H), 7.13–7.11 (d, J ¼ 8.68 Hz, 1H). 13C NMR (100 MHz, DMSO-d, ppm): d
155.97, 141.47, 135.07, 129.13, 118.06, 108.58, 104.35; EI MS 179 (M þ ),
178, 148, 133, 105, 78. Anal. calcd for C7H5N3O3: C, 46.92; H, 2.81; N, 23.46.
Found: C,46.87; H, 2.85; N, 23.55.
4-Nitro-2-[7-nitro-3,4-dihydro-4-oxo-3-quinazolinyl]-N,N-dimethyl-
;
1H NMR
benzamide (Compound 2f). IR (KBr) 1691, 1637 cm21
(500 MHz, CDCl3, ppm): d 8.72–8.71 (d, J ¼ 2.291 Hz, 1H), 8.49–8.47
(m, 3H), 8.42–8.40 (d, J ¼ 8.593 Hz, 1H), 8.34–8.32 (dd, J ¼ 2.291,
8.588 Hz, 1H), 7.92–7.90 (d, J ¼ 8.593 Hz, 1H), 2.90 (s, 3H), 2,82 (s, 3H).
13C NMR (125 MHz, CDCl3, ppm): d 165.76, 159.76, 152.06, 149.54, 148.65,
148.54, 141.84, 135.87, 129.42, 129.29, 126.45, 125.69, 125.21, 123.06,
121.95, 39.21, 34.98; EI MS 383, 182, 164, 146, 117, 101, 91, 75. Anal. calcd
for C17H13N5O6: C, 53.27; H, 3.42; N, 18.27. Found: C, 53.19; H, 3.43;
N, 18.34.
2-Chlorobenzothiazole. IR (KBr) 3070, 1710, 1483, 1009 cm21 1H
;
NMR (500 MHz, CDCl3, ppm): d 7.94–7.93 (d, J ¼ 8.588 Hz, 1H), 7.76–7.74
(d, J ¼ 8.018 Hz, 1H), 7.48–7.45 (t, J ¼ 8. 593, 8.018 Hz, 1H), 7.41–7.37
(t, J ¼ 8.593, 8.018 Hz, 1H). 13C NMR (125 MHz, CDCl3, ppm): d 153.40,
151.09, 136.19, 126.81, 125.88, 123.00, 121.21; EI MS 169 (M þ ), 134, 108,
82, 69.
ACKNOWLEDGMENT
One of the authors R. S. is thankful to CSIR, New Delhi for the award of
Fellowship.
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741
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Received in India August 28, 2003

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