Synthesis of 2-(2-, 3-, and 4-pyridyl)benzoxazoles by the reaction of phenolic schiff bases with thianthrene cation radical

Article abstract of DOI:10.1002/jhet.5570390625

2-(2-, 3-, and 4-Pyridyl)benzoxazole derivatives were prepared in excellent yields by the oxidative cyclization of phenolic Schiff bases with thianthrene cation radical perchlorate in the presence of 2,6-di-tert-butyl-4-methylpyridine.

Full text of DOI:10.1002/jhet.5570390625

Nov-Dec 2002
Synthesis of 2-(2-, 3-, and 4-Pyridyl)benzoxazoles by the Reaction of
Phenolic Schiff Bases with Thianthrene Cation Radical
1279
Myeong Soon Park*, Kun Jun, Seung Rim Shin, Sea Wha Oh, and Koon Ha Park*
*Department of Chemistry, Chungnam National University, 220 Kung Dong, Yusung Ku,
Taejon305-764,Korea
Korea Research Institute of Chemical Technology, P.O. Box 107, Yusung Ku, Taejon 305-606, Korea
Received July 5, 2001
2-(2-, 3-, and 4-Pyridyl)benzoxazole derivatives were prepared in excellent yields by the oxidative cyclization of phe-
nolic Schiff bases with thianthrene cation radical perchlorate in the presence of 2,6-di-tert-butyl-4-methylpyridine.
J. Heterocyclic Chem., 39, 1279(2002).
Benzoxazole derivatives, especially 2-(pyridyl)benzoxa-
zoles, have attracted particular interests for their biological
and analytical significance [1]. For an example, 5-substi-
tuted 2-(3-pyridyl)benzoxazoles were reported to show
significant activity against microorganisms [2]. Due to
their applications in industry and argriculture, a variety of
methods have been developed for the synthesis of benzox-
azoles using benign oxidizing agents [3]. Generally, 2-(2-
pyridyl)benzoxazoles are made by the condensation of a
pyridinecarboxylic acids with o-aminophenols [4]. Also,
2-(3-pyridyl)benzoxazoles were obtained from 3-
pyridinecarbaldehyde (nicotinaldehyde) and o-aminophe-
nols in the presence of iodobenzene diacetate [5].
Recently, we have also prepared various benzoxazole
derivatives [6] from phenolic Schiff bases and thianthrene
+.
-
cation radical (Th ClO ). In the present study, we report
4
the preparation and mechanism of 2-(2-, 3-, and
4-pyridyl)benzoxazoles as shown in Scheme 1 and 2
respectively.
1-3, 5-tert-butyl-2-(2-, 3-, and 4-pyridyl)benzoxazoles (2c,
4c, and 6c) are new compounds. In all of the reactions, for-
mation of thianthrene oxide is not related to the main reac-
tion but stems from the hydrolysis of thianthrene cation
radical due to either adventitious water or water added in
the work-up procedure.
In conclusion, oxidative cyclization of phenolic Schiff
bases to 2-(2-, 3-, and 4-pyridyl)benzoxazoles was
achieved in excellent yields by thianthrene cation radical
under mild conditions. It was also observed that Schiff
bases with electron donating group were cyclized to give
products in higher yields.
The reaction of phenolic Schiff base with 2 equivalents
of thianthrene cation radical perchlorate at room tempera-
ture in acetonitrile containing 2,6-di-tert-butyl-4-
methylpyridine (DTBMP) afforded 2-(2-, 3-, and 4-
pyridyl)benzoxazoles in excellent yields as shown in
Tables 1-3.
In this reaction, Schiff bases treated with thianthrene
cation radical participated in oxidative cyclization at room
temperature. Among the nine products shown in Tables

1280
M. S. Park, K. Jun, S. R. Shin, S. W. Oh, and K. H. Park
Vol. 39
sulfate. After filtration, the solvent was evaporated at room tem-
perature. The solid residue was dissolved in methylene chloride
(50 mL) and used for identification of products by GC and GC-
MS and for quantitative analysis by GC. The products were iden-
tified by GC, GC-MS and by comparison with authentic samples
[8]. Yields of the products were determined by GC with biphenyl,
as an internal standard, and predetermined response factors. The
benzoxazoles were purified by chromatography on silica gel
(methylene chloride:methanol = 15:1) and identified by 1H
NMR, GC-MS and elemental analysis. Each reaction was carried
out twice.
Preparation of Thianthrene Cation Radical Perchlorate.
To a solution of perchloric acid (70%, 0.60 mL) in acetic anhy-
dride (33 mL) was added a solution of thianthrene (1.0 g, 4.6
mmoles) in carbon tetrachloride (66 mL). The reaction mixture
was then allowed to stand for 24 hours in the dark at room tem-
perature. Dark purple colored crystals were formed and were col-
lected by filtration and washed with carbon tetrachloride until the
filtrate was colorless. The crystals were then dried in a flask
under vacuum. The product (1.2 g, 3.9 mmoles, 84%) was dried
under vacuum for short periods before use.
4-tert-Butyl-2-[(2-pyridylmethylene)amino]phenol (1c).
To a stirred solution of 2-amino-4-tert-butylphenol (3.34 g, 20
mmoles) in ethanol (20 mL) was added dropwise a solution of 2-
pyridinecarbaldehyde (2 mL, 21 mmoles) in ethanol (20 mL) at
room temperature. After stirring for 2 hours, the solvent was
evaporated and the residue was crystallized from ethanol to give
yellow crystals (3.04 g, 60%), mp 134-136°; 1H nmr (300 MHz,
deuterioacetone): d 8.84 (s. 1H, methylene), 8.70 (dt, 1H, C6'-H,
J=4.8), 8.41 (dt, 1H, C3'-H, J=7.9), 8.04 (s. 1H, OH), 7.92 (td,
1H, C4'-H, J=7.7, 1.7), 7.51-7.44 (m, 2H, C3-H, C5'-H), 7.28
(dd, 1H, C6-H, J=8.5, 2.3), 6.88 (d, 1H, C5-H, J=8.5), 1.30 (s,
9H, t-butyl).
Anal. Calcd. for C16H18N2O: C, 75.59; H, 7.08; N, 11.02.
Found: C, 75.53; H, 7.20; N, 11.13.
4-tert-Butyl-2-[(3-pyridylmethylene)amino]phenol (3c).
Compound 3c was prepared from 2-amino-4-tert-butylphenol
and 3-pyridinecarbaldehyde by the above procedure and the
residue was crystallized from ethanol to give yellow crystals
(4.16 g, 82%), mp 100-102°; 1H nmr (300 MHz, deuterioace-
tone): d 9.15 (s, 1H, C2'-H), 8.98 (s. 1H, methylene), 8.67 (dd,
1H, C6'-H, J=4.8, 1.6), 8.46 (dt, 1H, C4'-H, J=7.9, 2.0), 8.01 (s.
1H, OH), 7.50 (td, s, 2H, C5'-H, J=6.9, C3-H), 7.25 (dd, 1H, C6-
H, J=8.5, 2.3), 6.87 (d, 1H, C5-H, J=8.5), 1.32 (s, 9H, t-butyl).
Anal. Calcd. for C16H18N2O: C, 75.59; H, 7.08; N, 11.02.
Found: C, 75.81; H, 7.37; N, 10.92.
EXPERIMENTAL
Acetonitrile was purified by distillation over phosphorus pen-
toxide under argon prior to use. Thianthrene (Aldrich) was
recrystallized twice from acetone. Aldehydes and aminophenols
were used without further purification. Thianthrene cation radical
perchlorate and Schiff bases were prepared according to the
known procedure [5,7].
General Procedure.
4-tert-Butyl-2-[(4-pyridylmethylene)amino]phenol (5c).
The phenolic Schiff base, thianthrene cation radical perchlo-
rate, and 2,6-di-tert-butyl-4-methylpyridine were placed in a sep-
tum-capped flask, which was evacuated and then filled with
argon. Acetonitrile (20 mL) was added to the flask with a syringe.
The reaction mixture was stirred at room temperature, during
which time the cation radical color disappeared completely
within 5-10 minutes. After stirring was continued overnight,
water (10 mL) was added and the reaction mixture was neutral-
ized with dilute aqueous sodium bicarbonate. The resultant mix-
ture was extracted with methylene chloride (5x30 mL) and the
combined organic layers were dried over anhydrous sodium
Compound 5c was prepared from 2-amino-4-tert-butylphenol
and 4-pyridinecarbaldehyde by the above procedure and the
residue was crystallized from ethanol to give yellow crystals
(4.77 g, 94%), mp 150-152°; 1H nmr (300 MHz, deuterioace-
tone): d 8.95 (s. 1H, methylene), 8.71 (dd, 2H, C2'-H, J=4.4, 1.6),
8.06 (s. 1H, OH), 7.96 (dd, 2H, C3'-H, J=4.4, 1.6), 7.50 (d, 1H,
C3-H, J=2.3), 7.28 (dd, 1H, C6-H, J=8.5, 2.3), 6.90 (d, 1H, C5-
H, J=8.5), 1.31 (s, 9H, t-butyl).
Anal. Calcd. for C16H18N2O: C, 75.59; H, 7.08; N, 11.02.
Found: C, 75.40; H, 7.20; N, 10.95.

Nov-Dec 2002
Synthesis of 2-(2-, 3-, and 4-Pyridyl)benzoxazoles
1281
5-tert-Butyl-2-(2-pyridyl)benzoxazole (2c).
acetonitrile to yield compound 6c (117 mg, 93%), mp 120-122°;
1H nmr (300 MHz, deuteriochloroform): d 8.76 (dd, 2H, C2'-H,
J=4.4, 1.6), 8.01 (dd, 2H, C3'-H, J=4.4, 1.6), 7.92 (s, 1H, C4-
H), 7.50-7.42 (m, 2H, C6-H, C7-H), 1.36 (s, 9H, t-butyl).
Anal. Calcd. for C16H16N2O: C, 76.19; H, 6.34; N, 11.11.
Found: C, 76.17; H, 6.45; N, 11.26.
The reaction was carried out with thianthrene cation radical
perchlorate (315 mg, 1.0 mmol), 1c (127 mg, 0.5 mmol) and 2,6-
di-tert-butyl-4-methylpyridine (308 mg, 1.50 mmol) in acetoni-
trile to yield compound 2c (125 mg, 99%), mp 116-117°; 1H nmr
(300 MHz, deuteriochloroform): d 8.75 (dq, 1H, C6'-H, J=4.8),
8.30 (dt, 1H, C3'-H, J=7.9, 0.9), 7.85-7.79 (m, 2H, C4'-H, C4-H),
7.53 (d, 1H, C7-H, J=8.6), 7.44-7.36 (m, 2H, C6-H, C5'-H), 1.35
(s, 9H, t-butyl).
REFERENCES AND NOTES
Anal. Calcd. for C16H16N2O: C, 76.19; H, 6.34; N, 11.11.
Found: C, 76.41; H, 6.66; N, 11.10.
[1] M. R. Grimmett, in Comprehensive Organic Chemistry,
Vol 4, D. Barton and W. D. Ollis eds, Pergamon Press, Oxford, 1979,
pp 357-410.
[2] E. Sener, H. Turgut, I. Yalcin, I. Oren, L. Turker, N.
Celebi, and A. Akin, Int. J. Pharm., 110, 109-115 (1994).
[3] R. S. Varma, D. Kumar, J. Heterocyclic Chem., 35, 1539
(1998).
[4] E. Barni and P. Savarino, J. Heterocyclic Chem., 14, 937
(1977).
[5] M. H. Jung, J. G. Park, B. S. Ryu and K. W. Cho, J.
Heterocyclic Chem., 36, 429 (1999).
5-tert-Butyl-2-(3-pyridyl)benzoxazole (4c).
The reaction was carried out with thianthrene cation radical
perchlorate(315 mg, 1.0 mmol), 3c (127 mg, 0.5 mmol) and 2,6-
di-tert-butyl-4-methylpyridine (308 mg, 1.50 mmol) in acetoni-
trile to yield compound 4c (118 mg, 93%), mp 109-111°; 1H nmr
(300 MHz, deuterioacetone): d 9.37 (dd, 1H, C2'-H, J=2.1, 0.7),
8.76 (dd, 1H, C6'-H, J=4.8, 1.6), 8.50 (dt, 1H, C4'-H, J=7.9, 2.0),
7.77 (s, 1H, C4-H), 7.61-7.50 (m, 3H, C6-H, C7-H, C5'-H), 1.38
(s, 9H, t-butyl).
[6] K. H. Park, K. Jun, S. R. Shin, and S. W. Oh, Tetrahedron
Lett., 37, 8869 (1996).
[7] H. J. Shine and Y. Murata, J. Am. Chem. Soc., 91, 1872
(1969).
Anal. Calcd. for C16H16N2O: C, 76.19; H, 6.34; N, 11.11.
Found: C, 76.22; H, 6.48; N, 11.24.
[8] H. J. Shine and A. K. M. M. Hoque, J. Org. Chem., 53,
4349 (1988).
5-tert-Butyl-2-(4-pyridyl)benzoxazole (6c).
The reaction was carried out with thianthrene cation radical
perchlorate (315 mg, 1.0 mmol), 5c (127 mg, 0.5 mmol) and
2,6-di-tert-butyl-4-methylpyridine (308 mg, 1.50 mmol) in
[9] R. D. Haugwitz, R. G. Angel, G. A. Jacobs, B. V. Maurer,
V. L. Narayanan, L. R. Cruthers and J. Szanto, J. Med. Chem., 25,
969 (1982).