Highly efficient one-pot synthesis of 2-aminobenzoxazoles using triflic acid as a cyclodesulfurizing reagent

Article abstract of DOI:10.1080/00397911.2010.515337

An efficient one-pot synthetic strategy for 2-aminobenzoxazoles was developed from isothiocyanates and 2-aminophenol using triflic acid as a cyclodesulfurizing reagent. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.515337

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Highly Efficient One-Pot Synthesis of 2-
Aminobenzoxazoles Using Triflic Acid as
a Cyclodesulfurizing Reagent
Gopal L. Khatik a , Namita Dube a , Anang Pal a & Vipin A. Nair a
a Department of Medicinal Chemistry , National Institute of
Pharmaceutical Education and Research , Mohali , Punjab , India
Published online: 29 Jun 2011.
To cite this article: Gopal L. Khatik , Namita Dube , Anang Pal & Vipin A. Nair (2011) Highly Efficient
One-Pot Synthesis of 2-Aminobenzoxazoles Using Triflic Acid as a Cyclodesulfurizing Reagent,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:17, 2631-2639, DOI: 10.1080/00397911.2010.515337
To link to this article: http://dx.doi.org/10.1080/00397911.2010.515337
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Synthetic Communications1, 41: 2631–2639, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515337
HIGHLY EFFICIENT ONE-POT SYNTHESIS OF
2-AMINOBENZOXAZOLES USING TRIFLIC ACID
AS A CYCLODESULFURIZING REAGENT
Gopal L. Khatik, Namita Dube, Anang Pal, and Vipin A. Nair
Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research, Mohali, Punjab, India
GRAPHICAL ABSTRACT
Abstract An efficient one-pot synthetic strategy for 2-aminobenzoxazoles was developed
from isothiocyanates and 2-aminophenol using triflic acid as a cyclodesulfurizing reagent.
Keywords 2-Aminobenzoxazole; cyclodesulfurization; one-pot synthesis; triflic acid
INTRODUCTION
The 2-aminobenzoxazole moiety has been well explored as potential drug can-
didates for HIV, neurodegeneration, and inflammatory diseases.[1] There are various
methods available for the synthesis of 2-aminobenzoxazoles, which suffer from one
or more limitations because the reaction of an appropriately substituted 2-chloro-
benzoxazole with an amine in the presence of base may require a multistep pro-
cedure.[2] A more general method for the synthesis of 2-aminobenzoxazole is
through the cyclodesulfurization of N-substituted-2-hydroxy-phenylthioureas
(Fig. 1). These thiourea intermediates can be prepared by the condensation of 2-ami-
nophenol and isothiocyanates.[3,4] Various metallic reagents such as HgO,[5] NiO2,[4]
[6]
and AgNO3 have been reported but are unsatisfactory for large-scale preparation
because of the use of toxic heavy metals in excess amounts and longer reaction times.
Oxidative cyclodesulfurization of thiourea in the presence of KO2 is exemp-
lary;[7] however, this reagent has substrate limitation. Various salts of transition
metals were also employed for this transformation,[8] but cyclodesulfurization
required several days and removal of toxic metals from the product involved difficult
procedures. Peptide coupling reagents were also employed[9] but are uneconomical,
Received April 20, 2010.
Address correspondence to Vipin A. Nair, Department of Medicinal Chemistry, National Institute
of Pharmaceutical Education and Research, Sector 67, Mohali, Punjab 160 062, India. E-mail: vnair@
niper.ac.in
2631

2632
G. L. KHATIK ET AL.
Figure 1. Synthetic strategy for the formation of 2-aminobenzoxazoles.
create difficult product isolation, and have poor yields. Cyclodesulfurization with
TsCl=NaOH also has limitations because of the poor yield and undesired side
products.[10] Recent reports have shown that LiOH in the presence of H2O2 in an
excess amount can be used for the heterocyclization, though it is not tolerated by
several functional groups.[11] There is an unmet need to develop a better method-
ology for the synthesis of 2-aminobenzoxazoles.
RESULTS AND DISCUSSION
For the synthesis of 2-aminobenzoxazoles, we assumed that a one-pot reaction
involving 2-aminophenol and isothiocyanate followed by the addition of a desulfur-
izing agent to the reaction mixture would be a viable strategy to the desired com-
pound and will circumvent the additional steps of isolation of the intermediate
thiourea and its cyclization. To this end, a model reaction of 4-chlorophenyl isothio-
cyanate (1b) with 2-aminophenol (2) using various protic acids as given in Table 1
was tested to obtain N-4-chlorophenyl-2-aminobenzoxazoles (3b) (Scheme 1).
We observed that trifluoromethanesulfonic acid (triflic acid) has shown the best
results among the various protic acid employed (entry 3, Table 1). The superiority of trif-
lic acid over other protic acids may be due to its high proton-donor ability. Triflic acid is
widely used as a catalyst and a precursor in organic chemistry.[12–14] To ascertain the
concentration of the desulfurizing agent required, reactions were carried out by employ-
ing 0.2, 0.6, and 1.2 equivalents of triflic acid, and it was observed that 1.2 equivalent of
protic acid afforded good yield of the product in short reaction time (entry 4, Table 1).
Table 1. Synthesis of N-4-chlorophenyl-2-aminobenzoxazole employing various regentsa
Entry
Reagent
Time (h)
Isolated yield of 3b (%)b
1
2
—
12
12
4
0
35
CF3SO3H (0.2 equiv.)
CF3SO3H (0.6 equiv.)
CF3SO3H (1.2 equiv.)
CH3SO3H (1.2 equiv.)
CH3CO2H (1.2 equiv.)
CF3CO2H (1.2 equiv.)
p-TsOH (1.2 equiv.)
HClO4 (1.2 equiv.)
3
62
85
4
2
5
6
Trace
Trace
50
6
6
7
6
8
6
25
36
9
12
12
12
10
11
Conc. H2SO4 (1.2 equiv.)
Conc. HCl (1.2 equiv.)
20
30
aThe reaction was carried out by stirring a mixture of 4-chlorophenyl isothiocyanate (1.83 mmol, 1.0
equiv) and 2-aminophenol (1.83 mmol, 1.0 equiv) in THF (10 mL) for 0.5 h for intermediate thiourea
formation followed by the addition of the reagent and refluxing for the time indicated.
bThe product was characterized by NMR and mass spectroscopic methods.

SYNTHESIS OF 2-AMINOBENZOXAZOLES
2633
Scheme 1. One-pot synthesis of 2-aminobenzoxazoles.
Table 2. Effect of solvent for the synthesis of N-4-chlorophenyl-2-aminobenzoxazole using triflic acida
Entry
Solvent
Time (h)
Isolated yield of 3 (%)b
1
2
3
4
5
6
7
8
9
Toluene
Benzene
6
6
2
6
6
6
6
6
6
20
24
85
42
32
35
28
0
Tetrahydrofuran
1,2-Dichloroethane
1,4-Dioxan
Acetonitrile
N,N-Dimethylformamide
Ethanol
Methanol
0
aThe reaction was carried out by stirring a mixture of 4-chlorophenyl isothiocyanate (1.83 mmol, 1.0
equiv) and 2-aminophenol (1.83 mmol, 1.0 equiv) in solvent (10 mL) for 2 h for intermediate thiourea
formation followed by the addition of the triflic acid (2.2 mmol, 1.2 equiv) and refluxing for the time
indicated.
bThe product was characterized by NMR and mass spectroscopic methods.
From a solvent study carried out, we found that nonpolar solvents as well as
protic polar solvents were ineffective for the heterocyclization (entries 1, 2, 8, and
9; Table 2), while aprotic polar solvents such as tetrahydrofuran (THF) has indicated
the best results for the reaction (entries 3 and 4–7; Table 2).
A plausible mechanism for the formation of the product is illustrated in Fig. 2.
The reaction is expected to involve an initial reversible cyclization of the thiourea(III)
to a tetrahedral thiol intermediate (IV) under the influence of triflic acid, which is
finally desulfurized[15] to give the 2-aminobenzoxazole.
To investigate the scope of the reaction, the standardized condition was
employed on 2-aminophenol (2) and various isothiocyanates (1a–k).[16] All the reac-
tions afforded the respective 2-aminobenzoxazoles (3a–k) in good yields; the results
Figure 2. Plausible mechanism for the formation of 2-aminobenzoxazoles.

2634
Entry
1
G. L. KHATIK ET AL.
Table 3. Synthesis of various 2-aminobenzoxazolesa
Isothiocyanate
Reaction time (h)
Product
Isolated yield (%)b
2
80
2
2
85
3
4
5
6
3
3
4
3
86
83
77
82
7
8
9
2
2
3
79
74
76
(Continued )

SYNTHESIS OF 2-AMINOBENZOXAZOLES
2635
Table 3. Continued
Entry
10
Isothiocyanate
Reaction time (h)
Product
Isolated yield (%)b
4c
74
73
11
4c
aThe reaction was carried out by stirring a mixture of isothiocyanate (1.83 mmol, 1.0 equiv) and 2-ami-
nophenol (1.83 mmol, 1.0 equiv) in THF (10 mL) for 0.5 h for intermediate thiourea formation followed by
the addition of the triflic acid (2.2 mmol, 1.2 equiv) and refluxing for the time indicated.
bThe product was characterized by NMR and mass spectroscopic methods.
cThe reaction mixture was refluxed for 1 h for intermediate thiourea formation followed by the addition
of the triflic acid (2.2 mmol, 1.2 equiv) and refluxing for the time indicated.
are summarized in Table 3. The yield of the product was influenced by the substitu-
ent on the aromatic ring (Table 3). Electron-withdrawing functional groups, which
generally increase the electrophilicity of aryl isothiocyanate, provided better yields
(entries 2–7; Table 3), whereas electron-donating groups led to longer reaction time
with lesser yields (entries 8, and 9; Table 3). The reaction conditions were also com-
patible with disubstituted aryl isothiocyanates (entries 6–9; Table 3) and benzyl
isothiocyanates (entries 10 and 11; Table 3).
CONCLUSION
In conclusion, an efficient and viable one-pot synthetic strategy for 2-amino-
benzoxazoles has been demonstrated.
EXPERIMENTAL
The 1H and 13C NMR spectra were recorded at 400 MHz and 100 MHz,
respectively on a Bruker Avance DPX 400 (400-MHz) spectrometer in CDCl3=
(CD3)2SO using tetramethylsilane (TMS) as an internal standard. The chemical
shifts (d) for 1H and 13C are given in parts per million (ppm) relative to residual sig-
nals of the solvent. Coupling constants are given in hertz. The following abbrevia-
tions are used to indicate the multiplicity: s, singlet; d, doublet; t, triplet; m,
multiplet; and bs, broad signal. Mass spectra were recorded on Finnigan LCQ
LCMS instrument, and the elemental analyses were done on a Vario-EL elemental
analyzer. The reactions were monitored by thin-layer chromatography (TLC;
Merck). Evaporation of solvents was performed under reduced pressure using a
Buchi rotary evaporator. Melting points are uncorrected.

2636
G. L. KHATIK ET AL.
Commercial-grade reagents and solvents were used without further purification:
hydrochloric acid (Renkem); a-methyl benzylamine, 4-aminobenzonitrile, 4-chloro-3-
trifluoromethylaniline (Aldrich); perchloric acid, aniline, bromoaniline, 4-fluoro-
aniline, triflic acid, methane sulfonic acid, p-toluene sulfonic acid (p-TsOH), 4-methyl-
aniline, 3,4-dimethylaniline, thiophosgene, 1,4-dioxan, THF (Spectrochem); sulfuric
acid, 4-chloroaniline, methanol, toluene (Merck); sodium hydrogen carbonate, acet-
onitrile, ethanol, benzene (CDH); trifluoroacetic acid, DCE (Loba Chemie); DMF
(SISCO); and 4-nitroaniline and benzylamine (SD Fine Chemical).
General Procedure for the Synthesis of 2-Aminobenzoxazole
To a solution of 4-chlorophenyl isothiocyanate (0.25 g, 1.83 mmol, 1.0 equiv) in
THF (10 mL) was added 2-aminophenol (0.2 g, 1.83 mmol, 1.0 equiv), the and the
mixture was stirred at room temperature for 30 min. Triflic acid (0.19 mL, 2.2 mmol,
1.2 equiv) was then added to it and refluxed for 2 h. The reaction mixture was cooled,
extracted with ethyl acetate, and washed with aqueous NaHCO3 solution; the organic
layer was dried over anhydrous Na2SO4 and concentrated to afford the crude pro-
duct. It was dissolved in a minimum amount of dichloromethane, precipitated with
excess of hexane, filtered, and dried to get the desired product as a white solid
(0.26 g, 85%). The compound was identified by spectral and analytical methods.
N-Phenyl-2-aminobenzoxazole (3a). Yield: 80%, white solid; mp
1
119–121 ꢀC; H NMR [400 MHz, (CD3)2SO] d 7.01–7.05 (m, 1H), 7.11–7.15 (m,
1H), 7.20–7.24 (m, 1H), 7.32–7.39 (m, 2H), 7.44–7.49 (m, 2H), 7.76 (d, 2H), 10.61
(s, 1H, NH); 13C NMR [100 MHz, (CD3)2SO] d 109.40, 117.05, 118.01, 122.12,
122.57, 124.85, 129.43, 139.17, 142.87, 147.44, 158.42; MS (m=z): 211.53 (Mþ1).
C13H10N2O calcd. C, 74.27; H, 4.79; N, 13.33. Found: C, 74.29; H, 4.84; N, 13.37.
N-(4-Chlorophenyl)benzoxazol-2-amine (3b). Yield: 85%, white solid; mp
216–219 ꢀC; 1H NMR [400 MHz, (CD3)2SO] d 7.15–7.19 (m, 1H), 7.32–7.35 (m, 1H),
7.41 (d, 2H), 7.61 (d, 1H), 7.82 (d, 3H), 10.60 (s, 1H, NH); 13C NMR [100 MHz,
(CD3)2SO]: d 119.65, 119.82, 121.58, 122.96, 125.87, 126.41, 129.29, 130.44,
139.98, 152.37, 161.76; MS (m=z): 245.27 (Mþ1). C13H9ClN2O calcd. C, 63.81; H,
3.71; N, 11.45. Found: C, 63.80; H, 3.72; N, 11.48.
N-(4-Fluorophenyl)benzoxazol-2-amine (3c). Yield: 86%, white solid; mp
1
167–169 ꢀC; H NMR [400 MHz, (CD3)2SO] d 7.11–7.14 (m, 1H), 7.19–7.23 (m,
3H), 7.42–7.44 (m, 1H), 7.46–7.48 (m, 1H), 7.72–7.75 (m, 2H), 10.63 (s, 1H, NH);
13C NMR [100 MHz, (CD3)2SO]: d 109.42, 115.91, 116.14, 117.03, 119.67, 122.16,
124.49, 135.60, 142.75, 147.46, 158.47; MS (m=z): 229.33 (Mþ1). C13H9FN2O calcd.
C, 68.42; H, 3.97; N, 12.27. Found: C, 68.45; H, 3.99; N, 12.30.
N-(4-Bromophenyl)benzoxazol-2-amine (3d). Yield: 83%, white solid; mp
217–219 ꢀC; 1H NMR [400 MHz, (CD3)2SO] d 7.13–7.15 (m, 1H), 7.20–7.24 (m, 1H),
7.44–7.49 (m, 2H), 7.54 (d, J ¼ 8.6 Hz, 2H), 7.72 (d, J ¼ 8.6 Hz, 2H), 10.79 (s, 1H,
NH); 13C NMR [100 MHz, (CD3)2SO]: d 109.51, 114.02, 117.20, 119.91, 122.37,
124.54, 132.19, 138.59, 142.64, 147.42, 158.08; MS (m=z): 289.33 (Mþ1), 291.33
(Mþ2). C13H9BrN2O calcd. C, 54.00; H, 3.14; N, 9.69. Found: C, 54.04; H, 3.16;
N, 9.71.

SYNTHESIS OF 2-AMINOBENZOXAZOLES
2637
N-(4-Nitrophenyl)benzoxazol-2-amine (3e). Yield: 77%, yellow solid; mp
1
168–170 ꢀC; H NMR [400 MHz, (CD3)2SO] d 7.10–7.22 (m, 3H), 7.25–7.36 (m,
2H), 7.60–7.63 (m, 1H), 8.07 (d, J ¼ 9.2 Hz, 1H), 8.35 (d, J ¼ 9.2 Hz, 1H), 11.75 (s,
1H, NH); 13C NMR [100 MHz, (CD3)2SO]: d 109.92, 110.23, 117.72, 122.27,
124.22, 125.78, 130.76, 141.72, 143.75, 154.83, 157.35; MS (m=z): 256.60 (Mþ1).
C13H9N3O3 calcd. C, 61.18; H, 3.55; N, 16.46. Found: C, 61.21; H, 3.57; N, 16.49.
N-(3-Chloro-4-fluorophenyl)benzoxazol-2-amine (3f). Yield: 82%, white
solid; mp 201–203 ꢀC; 1H NMR [400 MHz, (CD3)2SO] d 7.14–7.16 (m, 1H),
7.21–7.23 (m, 1H), 7.43 (t, J ¼ 9.0 Hz, 1H), 7.48–7.51 (m, 2H), 7.60–7.64 (m, 1H),
8.06–8.08 (m, 1H), 10.85 (s, 1H, NH);13C NMR [100 MHz, (CD3)2SO]: d 109.57,
117.33, 117.57, 117.79, 118.24, 119.04, 119.82, 120.00, 122.49, 124.61, 142.44,
147.42, 158.01; MS (m=z): 263.27 (Mþ1). C13H8ClFN2O calcd. C, 59.44; H, 3.07;
N, 10.66. Found: C, 59.47; H, 3.09; N, 10.69.
N-(4-Chloro-3-trifluoromethylphenyl)benzoxazol-2-amine (3g). Yield:
1
79%, white solid; mp 199–200 ꢀC; H NMR [400 MHz, (CD3)2SO] d 7.15–7.19 (m,
1H), 7.23–7.27 (m, 1H), 7.49–7.53 (m, 2H), 7.72 (d, 1H), 8.03–8.06 (m, 1H),
8.27–8.28 (m, 1H), 11.11 (s, 1H, NH); 13C NMR [100 MHz, (CD3)2SO]: d 109.71,
116.59, 116.65, 117.52, 122.70, 122.77, 123.02, 124.71, 127.57, 132.80, 138.74,
142.27, 147.41, 157.70; MS (m=z): 313.27 (Mþ1). C14H8ClF3N2O calcd. C, 53.78;
H, 2.58; N, 8.96. Found: C, 53.80; H, 2.61; N, 8.99.
N-(4-Methylphenyl)benzoxazol-2-amine (3 h). Yield: 74%, white solid; mp
180–181 ꢀC; 1H NMR [400 MHz, (CD3)2SO] d 2.26 (s, 3H), 7.10–7.12 (m, 1H),
7.15–7.17 (m, 2H), 7.19–7.21 (m, 1H), 7.41–7.46 (m, 2H), 7.61–7.63 (m, 2H), 10.47
(s, 1H, NH); 13C NMR [100 MHz, (CD3)2SO]: d 20.82, 109.32, 116.92, 118.05,
121.95, 124.39, 129.81, 131.45, 136.66, 142.98, 147.45, 158.55; MS (m=z): 225.47
(Mþ1). C14H12N2O calcd. C, 74.98; H, 5.39; N, 12.49; Found: C, 75.01; H, 5.40;
N, 12.48.
N-(3,4-Dimethyl phenyl)benzoxazol-2-amine (3i). Yield: 76%, white solid;
1
mp 150–151 ꢀC; H NMR [400 MHz, (CD3)2SO] d 2.08 (s, 6H), 7.06–7.13 (m, 2H),
7.19–7.24 (m, 1H), 7.43–7.52 (m, 4H), 10.40 (s, 1H, NH); 13C NMR [100 MHz,
(CD3)2SO]: d 19.15, 20.18, 109.27, 115.60, 116.91, 119.26, 121.88, 124.36, 125.61,
130.29, 137.04, 136.89, 143.05, 147.46, 158.58; MS (m=z): 239.33 (Mþ1).
C15H14N2O calcd. C, 75.61; H, 5.92; N, 11.76. Found: C, 75.63; H, 5.95; N, 11.77.
N-Benzyl-2-aminobenzoxazole (3j). Yield: 74%, white solid; mp
1
104–106 ꢀC; H NMR [400 MHz, (CD3)2SO] d 4.50 (d, J ¼ 6.0 Hz, 2H), 6.94–6.98
(m, 1H), 7.07–7.11 (m, 1H), 7.21–7.25 (m, 2H), 7.30–7.37 (m, 5H), 8.48 (t, J ¼ 6.0 Hz,
1H, NH); 13C NMR [100 MHz, (CD3)2SO]: d 46.10, 109.04, 115.97, 119.97, 120.74,
124.12, 127.62, 128.84, 139.45, 143.48, 148.52, 162.88; MS (m=z): 225.20 (Mþ1).
C14H12N2O calcd. C, 74.98; H, 5.39; N, 12.49. Found: C, 75.02; H, 5.43; N, 12.51.
N-(1-Phenylethyl)benzoxazol-2-amine (3k). Yield: 73%, white solid; mp
1
49–52 ꢀC; H NMR [400 MHz, (CD3)2SO] d 1.49 (d, J ¼ 6.8 Hz, 3H), 4.89–4.97 (m,
1H), 6.96 (t, J ¼ 7.6 Hz, 1H), 7.08 (t, J ¼ 7.8 Hz, 1H), 7.19–7.25 (m, 2H), 7.33 (t,
J ¼ 7.8 Hz, 3H), 7.42 (d, J ¼ 7.6 Hz, 2H), 8.50 (d, 1H, NH); 13C NMR [100 MHz,
(CD3)2SO]: d 23.48, 52.69, 108.97, 115.93, 120.70, 124.05, 126.04, 127.33, 128.81,

2638
G. L. KHATIK ET AL.
143.45, 144.93, 148.34, 161.98; MS (m=z): 239.07 (Mþ1). C15H14N2O calcd. C, 75.61;
H, 5.92; N, 11.76. Found: C, 75.65; H, 5.95; N, 11.79.
ACKNOWLEDGMENT
We are thankful to the Department of Science and Technology, government of
India, for the research funding.
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