Mild and efficient synthesis of benzoxazoles, benzothiazoles, benzimidazoles, and oxazolo[4,5-b]pyridines catalyzed by Bi(III) salts under solvent-free conditions

Article abstract of DOI:10.1007/s00706-007-0655-9

A series of benzoxazoles, benzothiazoles, benzimidazoles, and oxazolo[4,5-b]pyridines was efficiently synthesized from the reactions of o-aminophenols, o-aminothiophenol, o-phenylenediamines, and 2-amino-3- hydroxypyridine with orthoesters in the presence of catalytic amounts of Bi(III) salts, such as Bi(TFA)₃, Bi(OTf)₃, and BiOClO₄ ? xH₂O under solvent-free conditions. The remarkable features of this new protocol are high conversion, very short reaction times, cleaner reaction profiles under solvent-free conditions, straightforward procedure, and use of relatively non-toxic catalysts. Springer-Verlag 2007.

Full text of DOI:10.1007/s00706-007-0655-9

Monatshefte fu¨r Chemie 138, 663–667 (2007)
DOI 10.1007/s00706-007-0655-9
Printed in The Netherlands
Mild and Efficient Synthesis of Benzoxazoles, Benzothiazoles,
Benzimidazoles, and Oxazolo[4,5-b]pyridines Catalyzed by Bi(III)
Salts Under Solvent-Free Conditions
ꢀ
Iraj Mohammadpoor-Baltork , Ahmad R. Khosropour, and Seyedeh F. Hojati
Department of Chemistry, Isfahan University, Isfahan, Iran
Received December 22, 2006; accepted January 22, 2007; published online May 11, 2007
# Springer-Verlag 2007
Summary. A series of benzoxazoles, benzothiazoles, benz-
densation of carboxylic acids [11], acid chlorides
imidazoles, and oxazolo[4,5-b]pyridines was efficiently
synthesized from the reactions of o-aminophenols, o-ami-
nothiophenol, o-phenylenediamines, and 2-amino-3-hydroxy-
pyridine with orthoesters in the presence of catalytic amounts
of Bi(III) salts, such as Bi(TFA)3, Bi(OTf)3, and BiOClO4 ꢁ
xH2O under solvent-free conditions. The remarkable features
of this new protocol are high conversion, very short reac-
tion times, cleaner reaction profiles under solvent-free con-
ditions, straightforward procedure, and use of relatively
non-toxic catalysts.
[12], nitriles [13], orthoesters [14], amides [15],
esters [16], and aldehydes [17] with o-aminophenols,
o-aminothiophenols, and o-phenylenediamines, de-
hydration of o-acylaminophenols [18], the reaction
of o-quinones with amines [19], Beckmann rearran-
gement of o-acylphenol oximes [20], and photo-
cyclization of phenolic Schiff bases [21]. However,
all of these procedures suffer from one or more of
the following disadvantages such as long reaction
times, low yields of the products, harsh reaction
conditions, the use of excess amounts of reagents,
tedious workup procedures, and co-occurrence of
several side reactions. In addition, some of the cat-
alysts and reagents are expensive, toxic, and air sen-
sitive. Therefore, there is still a need to search for
better catalysts that could be superior to the existing
ones with regards to toxicity, handling, and opera-
tional simplicity.
Keywords. Benzoxazoles; Benzothiazoles; Benzimidazoles;
Oxazolo[4,5-b]pyridines; Bi(III) salts.
Introduction
Benzoxazole, benzothiazole, benzimidazole, and
oxazolo[4,5-b]pyridine moieties have attracted a great
deal of interest in diverse fields of chemistry [1].
Some of these nuclei are found in various naturally
occurring compounds [2]. These heterocycles have
achieved significance in pharmacology as antibacter-
ial [3], antiviral [4], antifungal [5], anticancer [6],
antibiotic [7], anticonsulvant [8], and immunosup-
pressant [9] agents. They have also been used as li-
gands in asymmetric syntheses [10].
Results and Discussion
Recently there has been growing interest in the use
of Bi(III) salts as catalysts in various organic reac-
tions due to their low toxicity, ease of handling, and
relative insensitivity to air and moisture [22]. Bis-
muth has been heralded as a green element, and the
low toxicity of many bismuth compounds is evident
from their LD50 (rat, oral LD50 ¼ 2–22 g=kg [23]).
In continuation of our research on the use of Bi(III)
Several methods have been developed for the
preparation of these heterocycles including the con-
ꢀ
Corresponding author. E-mail: imbaltork@sci.ui.ac.ir

664
I. Mohammadpoor-Baltork et al.
Scheme 1
salts in organic transformations [24], we now report
a simple and environmentally benign methodology
for the synthesis of benzoxazole, benzothiazole, benz-
imidazole, and oxazolo[4,5-b]pyridine derivatives
from orthoesters under solvent-free conditions using
Bi(III) salts as catalysts.
At first, the solvent effect was examined by the
reaction of 1 equiv. o-aminophenol (1a) with 1.1
equiv. triethyl orthoacetate (2b) in the presence of
0.015 equiv. Bi(TFA)3 (Scheme 1) in different sol-
vents, such as ClCH2CH2Cl, CHCl3, CH3OH, CH3CN,
and also under solvent-free conditions at room tem-
perature (Table 1). The best result was obtained
under solvent-free conditions, which is also econom-
ically and environmentally favourable (Table 1,
entry 5). On the other hand, further examination illus-
trated that Bi(TFA)3 is essential for this transforma-
tion whereas in the absence of the catalyst, only 5%
of the product was obtained from the reaction mix-
ture (Table 1, entry 6).
The applicability of this method was then exam-
ined for the preparation of benzoxazole, benzothia-
zole, benzimidazole, and oxazolo[4,5-b]pyridine
derivatives from various orthoesters under solvent-
free conditions. To this aim, different orthoesters were
reacted with 2-substituted anilines and 2-amino-3-
hydroxypyridine in the presence of catalytic amounts
of Bi(TFA)3, Bi(OTf)3, or BiOClO4 ꢁ xH2O (Scheme 2)
and the corresponding products were obtained in
high to excellent yields (Table 2).
Table 1. Investigation of solvent and catalyst effects on the
synthesis of 2-methylbenzoxazole (3d)
Entry
Catalyst
Solvent
Time=min Yield=%
The results showed that 2-substituted benzoxa-
zoles were efficiently and rapidly formed under mild
reaction conditions at room temperature in the pres-
ence of the above mentioned catalysts in excellent
yields (Table 2, entries 1–6), whereas synthesis of
benzoxazoles unsubstituted at 2-position needs heat-
ing at 85ꢂC (Table 2, entries 7–9). 2-Aminothiophe-
1
2
3
4
5
6
Bi(TFA)3 ClCH2CH2Cl
15
10
20
10
2
83
87
50
85
96
5
Bi(TFA)3
Bi(TFA)3
Bi(TFA)3
Bi(TFA)3
–
CHCl3
CH3OH
CH3CN
–
–
20
Scheme 2

Mild and Efficient Synthesis of Benzoxazoles
665
Table 2. Synthesis of benzoxazoles, benzothiazoles, benzimidazoles, and oxazolo[4,5-b]pyridines catalyzed by Bi(III) salts
under solvent-free conditions
M:P:
ꢂC
Entry
1
2
3
Catalyst (eq.)
Time=min (Yield=%a,b
)
Ref.
Bi(TFA)3
Bi(OTf)3
BiOClO4 ꢁ xH2O
1
2
3
4
5
1a
1b
1c
1a
1b
1c
1a
1b
1c
1d
1d
1d
1e
1f
1e
1f
1e
1f
1g
1g
1g
2a
2a
2a
2b
2b
2b
2c
2c
2c
2a
2b
2c
2a
2a
2b
2b
2c
2c
2a
2b
2c
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
0.01
0.005
0.01
0.015
0.01
0.02
0.005
0.005
0.005
0.01
0.01
0.01
0.03
0.04
0.03
0.04
0.015
0.04
0.01
0.01
0.03
4 (97)
0.5 (98)
2.5 (95)
2 (96)
0.5 (95)
5 (95)
12 (88)
8 (88)
15 (87)
2 (86)
3 (81)
5 (93)
1 (95)
4 (93)
3 (93)
1 (90)
10 (90)
10 (93)
7 (92)
10 (90)
4 (81)
5 (80)
5 (81)
9 (93)
6 (91)
4 (90)
4 (85)
7 (85)
8 (83)
6 (85)
8 (85)
10 (55)
10 (92)
2 (95)
10 (90)
10 (85)
5 (90)
15 (85)
10 (90)
8 (90)
15 (88)
4 (80)
5 (80)
7 (83)
8 (88)
5 (88)
4 (82)
4 (85)
6 (80)
10 (80)
8 (83)
10 (83)
12 (53)
Oil
59–61
29–31
Oil
53–55
Oil
Oil
36–38
42–44
Oil
Oil
Oil
163–165
160–163
172–174
198–200
170–172
112–114
51–53
70–72
69–72
[14c]
[20]
[20]
[14c]
[20]
[20]
6
7c
[14c]
[25a]
[25b]
[14c]
[14a]
[14a]
[25c]
[25d]
[25e]
[25d]
[14a]
[25f]
[14b]
[25g]
[14b]
8c
9c
10
11
12
13c
14c
15c
16c
17c
18c
19c
20c
21c
5 (83)
11 (87)
5 (84)
5 (82)
5 (90)
9 (92)
8 (85)
10 (83)
12 (82)
12 (52)
3t
3u
a
Products were identified by comparison of their physical and spectral data with those of authentic samples. b Isolated yields.
The reaction was performed at 85ꢂC
c
nol was also rapidly reacted with orthoesters at
yields of the products, and easy workup make this
methodology a valid contribution to the existing pro-
cesses in the field of these heterocycle syntheses.
room temperature to afford the corresponding ben-
zothiazoles in high yields (Table 2, entries 10–12).
The reactions of o-phenylenediamines with orthoe-
sters were also investigated. We found that o-phen-
ylenediamines reacted rapidly with orthoesters in
the presence of Bi(III) salts at 85ꢂC and the corre-
sponding benzimidazoles were isolated in high
yields (Table 2, entries 13–18). 2-Amino-3-hydro-
xypyridine was also reacted with orthoesters at 85ꢂC
and the corresponding oxazolo[4,5-b]pyridines were
isolated in good to high yields (Table 2, entries
19–21).
Experimental
Chemicals were purchased from Merck or Aldrich chemical
companies. Melting points were determined using a Stuart
scientific apparatus, the accuracy of which was checked
using standard compounds of known melting points. IR
spectra were recorded on a Shimadzu IR-435 spectrophot-
1
ometer. H NMR spectra were recorded in CDCl3 solvent
on a Bruker 500 MHz.
In conclusion, a very simple and convenient pro-
tocol for the synthesis of 2-substituted benzoxazoles,
benzothiazoles, benzimidazoles, and oxazolo[4,5-
b]pyridines using catalytic amounts of Bi(III) salts
under solvent-free conditions was demonstrated. Fur-
thermore, availability, stability, and non-toxicity of
the catalysts are other noteworthy advantages which
make this method eco-friendly and environmental-
ly benign. In addition, mild reaction conditions, ab-
sence of solvent, very short reaction times, high
General Procedure for the Synthesis of Benzoxazoles,
Benzothiazoles, Benzimidazoles and Oxazolo[4,5-b]-
pyridines Under Solvent-Free Conditions
To a mixture of orthoester (1.1mmol) and o-aminophenol, o-
aminothiophenol, o-phenylenediamine, or 2-amino-3-hydro-
xypyridine (1mmol) was added the catalyst (0.005–0.04 mmol
Bi(TFA)3, Bi(OTf )3, or BiOClO4 ꢁ xH2O). The mixture was
stirred at room temperature or at 85ꢂC for the appropriate
time according to Table 2. The progress of the reaction was
monitored by TLC (n-hexane:EtOAc, 2:1). After comple-
tion of the reaction, the crude product was purified by col-

666
I. Mohammadpoor-Baltork et al.
umn chromatography or recrystallization to afford the pure
product (Table 2).
Chemistry II, vol. 3, Elsevier Science Ltd, Oxford;
b) Grimmett MR (1997) Imidazole and Benzimidazole
Synthesis, Academic Press, San Diego
[10] Figge A, Altenbach HJ, Brauer DJ, Tielmann P (2002)
Tetrahedron: Asymmetry 13: 137
Acknowledgements
´
´
´
[11] a) Alcalde E, Dinares I, Perez-Garcıa L, Roca T (1992)
Synthesis 395; b) So Y-H, Heeschen JP (1997) J Org
Chem 62: 3552; c) Heuser S, Keenan M, Weichert AG
(2005) Tetrahedron Lett 46: 9001
We are grateful to the center of excellence (Chemistry) and
Office of Graduate Studies of Isfahan University for their
financial support.
[12] a) Pottorf RS, Chadha NK, Katkevics M, Ozola V, Suna
E, Ghane H, Regberg T, Player MR (2003) Tetrahedron
Lett 44: 175; b) Nadaf RN, Siddiqui SA, Daniel T,
Lahoti RJ, Srinivasan KV (2004) J Mol Catal A: Chem
214: 155
References
[1] a) Denny WA, Rewcastle GW, Baguley B (1990) J Med
Chem 33: 814; b) Kondo J, Suzuki N, Imaoka T,
Kawasaki T, Nakanishi A, Kawahara Y (1994) Anal
Sci 10: 17; c) Zhao M, Samoc M, Prasad PN, Reinhardt
BA, Sinky M (1992) Chem Mater 2: 670; d) Cassidy PE
(1980) Thermally Stable Polymers, Marcel Dekker,
New York; e) Lin S, Yang L (2005) Tetrahedron Lett
46: 4315; f) Mortimer CG, Wells G, Crochard J-P,
Stone EL, Bradshaw TD, Stevens MFG, Westwell
AD (2006) J Med Chem 49: 179; g) Chen C, Chen
Y-J (2004) Tetrahedron Lett 45: 113; h) Frachy G;
Crestini C, Berini R, Salidino R, Micione E (1994)
Heterocycles 38: 2621
[13] Hein DW, Alheim RJ, Leavitt JJ (1957) J Am Chem Soc
79: 427
[14] a) Villemin D, Hammadi M, Martin B (1996) Synth
Commun 26: 2895; b) Doise M, Dennin F, Blondeau D,
Sliwa H (1990) Tetrahedron Lett 31: 1155; c) Jenkins
GL, Knevel AM, Davis CS (1961) J Org Chem 26:
274
[15] Terashima M, Ishii M (1982) Synthesis 484
[16] a) Chakraborti AK, Rudrawar S, Kaur G, Sharma L
(2004) Synlett 1533; b) Dolbier Jr WR, Burkholder CR,
´
Medebielle M (1999) J Fluorine Chem 95: 127
[17] a) Hari A, Karan C, Rodrigues WC, Miller BL (2001) J
´
Org Chem 66: 991; b) Beaulieu PL, Hache B, Von Moos
[2] a) Kobayashi J, Madono T, Shigemori H (1995) Tetra-
hedron Lett 36: 5589; b) Rodriguez AD, Ramirez C,
Rodriguez II, Gonzales E (1999) Org Lett 1: 527; c)
Rodriguez II, Rodriguez AD (2003) J Nat Prod 66: 855;
d) Ueki M, Ueno K, Miyadoh S, Abe K, Shibata K,
Taniguchi M, Oi S (1993) J Antibiot 46: 1089; e)
Paramashivappa R, Kumar PP, Subba Rao PV, Srinivasa
E (2003) Synthesis 1683; c) Curini M, Epifano F,
Montanari F, Rosati O, Taccone S (2004) Synlett
1832; d) Gogoi P, Konwar D (2006) Tetrahedron Lett
47: 79; e) Trivedi R, De SK, Gibbs RA (2006) J Mol
´
Catal A: Chem 245: 8; f) Navarrete-Vazquez G,
Moreno-Diaz H, Aguirre-Crespo F, Leon-Rivera I,
´
Villalobos-Molina R, Mun˜oz-Mun˜iz O, Estrada-Soto
S (2006) Bioorg Med Chem Lett 16: 4169; g) Lee
CL, Lam Y, Lee S-Y (2001) Tetrahedron Lett 42: 109
[18] Boyd GV (1984) In: Katritzky AR, Rees CW, Potts
KT (eds) Comprehensive Heterocyclic Chemistry,
Pergamon Press, New York, pp 177
[19] Bu X-Z, Huang Z-S, Zhang M, Ma L, Xiao G-W, Gu
L-Q (2001) Tetrahedron Lett 42: 5737
[20] Bhawal BM, Mayabhate SP, Likhite AP, Deshmukh
ARAS (1995) Synth Commun 25: 3315
[21] Chen Y, Zeng DX (2004) J Org Chem 69: 5037
[22] a) Suzuki H, Ikegami T, Matano Y (1997) Synthesis 249;
b) Reglinski J (1998) In: Norman NC (ed) Chemistry of
Arsenic, Antimony and Bismuth, Balackie Academic
and Professional, New York; c) Anderson AM, Blazek
JM, Garg P, Payne BJ, Mohan RS (2000) Tetrahedron
Lett 41: 1527; d) Leonard NM, Wieland LC, Mohan RS
(2002) Tetrahedron 58: 8373; e) Chakraborti AK,
Shivani GR (2003) Synlett 1805; f) Sabitha G, Venkata
Reddy E, Swapna R, Mallikarjun Reddy N, Yadav JS
(2004) Synlett 1276; g) Yadav JS, Reddy BVS,
Premalatha K (2004) Synlett 963; h) Gosh R, Maiti S,
Chakraborty A (2005) Synlett 115; i) Sreedhar B,
Swapna V, Sridhar C (2005) Catal Commun 6: 293;
j) Ollevier T, Mwene-Mbeja TM (2006) Tetrahedron
Lett 47: 4051; k) Fu H, Zhang L, Yao W, Zhu Y (2006)
ꢀ
Rao A (2003) Bioorg Med Chem Lett 13: 657; f) Koci J,
Klimesova V, Waisser K, Kaustova J, Dahse H-M,
´
´
ꢀ
¨
Mollmann U (2002) Bioorg Med Chem Lett 12:
3275; g) Mann J, Baron A, Opoku-Boahen Y, Johansson
E, Parkinson G, Kelland LR, Neidle S (2001) J Med
Chem 44: 138; h) Craigo WA, LeSueur BW, Skibo EB
(1999) J Med Chem 42: 3324
[3] Yildiz-Oren I, Yalcin I, Aki-Sener E, Ucarturk N (2004)
Eur J Med Chem 39: 291
[4] Song X, Vig BS, Lorenzi PL, Drach JC, Townsend LB,
Amidon GL (2005) J Med Chem 48: 1274
[5] Yamato M (1992) J Pharm Soc Jpn 112: 81
[6] a) Kumar D, Jacob MR, Reynolds MB, Kerwin SM
(2002) Bioorg Med Chem 10: 3997; b) DeLuca MR,
Kerwin SM (1997) Tetrahedron Lett 38: 199; c) Sato S,
Kajiura T, Noguchi M, Takehana K, Kobayasho T, Tsuji
T (2001) J Antibiot 54: 102; d) Ueki M, Shibata K,
Taniguchi M (1998) J Antibiot 51: 883
[7] Evans DA, Sacks CE, Kleschick WA, Taber TR (1979)
J Am Chem Soc 101: 6789
[8] a) Bywater WG, Coleman WR, Kamm O, Merritt HH
(1945) J Am Chem Soc 67: 905; b) Benazzouz A,
´
Boraud T, Dubedat P, Boireau A, Stutzmann J-M, Gross
C (1995) Eur J Pharmacol 284: 299
[9] a) Grimmett MR (1996) In: Katritzky AR, Rees
CW, Scriven EFV (eds) Comprehensive Heterocyclic

Mild and Efficient Synthesis of Benzoxazoles
667
Appl Catal B: Env 66: 100; l) Van Well WJM, Le MT,
Schiødt NC, Hoste S, Stoltze P (2006) J Mol Catal A:
Chem 256: 1; m) Sparks DE, Patterson PM, Jacobs G,
Dogimont N, Tackett A, Crocker M (2006) Appl Catal
B: Env 65: 44
Mohammadpoor-Baltork I, Kharamesh B, Kolagar S
(2002) Synth Commun 32: 1633; h) Mohammadpoor-
Baltork I, Khodaei MM, Nikoofar K (2003) Tetrahe-
dron Lett 44: 591; i) Mohammadpoor-Baltork I,
Khosropour AR, Hojati SF (2005) Synlett 2747;
j) Khosropour AR, Mohammadpoor-Baltork I,
Ghorbankhani H (2006) Catal Commun 7: 713;
k) Khosropour AR, Mohammadpoor-Baltork I,
Ghorbankhani H (2006) Tetrahedron Lett 47: 3561;
l) Mohammadpoor-Baltork I, Memarian HR, Khosropour
AR, Nikoofar K (2006) Heterocycles 68: 1837
[23] a) Irving Sax N, Lewis RJ (1988) Dangerous Properties
of Industrial Materials, Van Nostrand Reinhold, New
York, p 522; b) Wormser U, Nir I (1994) In: Patai S
(ed) The Chemistry of Organic Arsenic, Antimony and
Bismuth Compounds, Wiley, New York, p 715
[24] a) Firouzabadi H, Mohammadpoor-Baltork I,
Kolagar S (2001) Synth Commun 31: 905; b)
Mohammadpoor-Baltork I, Khosropour AR (2001)
Molecules996;c)Mohammadpoor-BaltorkI,Khosropour
AR, Aliyan H (2001) Synth Commun 31: 3411; d)
Mohammadpoor-Baltork I, Khosropour AR, Aliyan
H (2001) J Chem Res (S) 280; e) Mohammadpoor-
Baltork I, Aliyan H, Khosropour AR (2001) Tetra-
hedron 57: 5851; f) Mohammadpoor-Baltork I,
Khosropour AR (2002) Monatsh Chem 133: 189; g)
[25] a) Sam J, Plampin JN (1964) J Pharm Sci 53: 538; b)
Roussos M, Lecomte J (1962) Ger 1 124: 499, (1963)
Chem Abstr 57: 9858g; c) Raban M, Chang H, Craine L,
Hortelano E (1985) J Org Chem 50: 2205; d) Wang H,
Partch RE, Li Y (1997) J Org Chem 62: 5222; e) Aldrich
Catalogue Handbook of Fine Chemicals (2000–2001); f)
Kato H, Shiba T, Kitajima E, Kiyosawa T (1976) J Chem
Soc Perkin Trans I 863; g) Takahashi T, Yoneda F (1957)
Pharm Bull 5: 350