Facile synthesis of benzoxazoles from 1,1-dibromoethenes

Article abstract of DOI:10.1016/j.tetlet.2010.04.071

Direct coupling of 1,1-dibromoethenes with 2-aminophenols had been achieved to form the corresponding benzoxazoles under mildly basic reaction conditions. A variety of substituted 2-aminophenols provided the desired products in moderate to good yields. Even though 1,1-dibromoethenes have to be derived from arylcarboxaldehydes or glyoxalate for the reactions, this method still provides a new route to the preparation of benzoxazoles, complementing to existing synthetic strategies.

Full text of DOI:10.1016/j.tetlet.2010.04.071

Tetrahedron Letters 51 (2010) 3246–3249
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of benzoxazoles from 1,1-dibromoethenes
a,b,
Kemei Tao a, Jianlong Zheng a, Zhaogui Liu a, Wang Shen c, , Jiancun Zhang
*
*
a Guangzhou Institute of Biomedicine and Health, CAS, 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China
b State Key Laboratory of Respiratory Diseases, Guangzhou Medical College, Guangzhou 510120, PR China
c Kanion USA Inc., 3916 Trust Way, Hayward, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Direct coupling of 1,1-dibromoethenes with 2-aminophenols had been achieved to form the correspond-
ing benzoxazoles under mildly basic reaction conditions. A variety of substituted 2-aminophenols pro-
vided the desired products in moderate to good yields. Even though 1,1-dibromoethenes have to be
derived from arylcarboxaldehydes or glyoxalate for the reactions, this method still provides a new route
to the preparation of benzoxazoles, complementing to existing synthetic strategies.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 5 April 2010
Revised 15 April 2010
Accepted 16 April 2010
Available online 20 April 2010
Benzoxazoles are an important class of heterocyclic compounds
due to their wide spectrum of biological and photochromatic activ-
ities. Previous reports revealed that benzoxazoles possess diverse
chemotherapeutic activities including anticancer agent1 NSC-
693638, L-697,661, antiviral,2 and antibacterials3 UK-1, AJI9561.
Recent studies showed substituted 2-benzylbenzoxazoles have
antibacterial, antifungal,4 antimicrobial,5 and anti-measles virus
activities6 (Scheme 1). Benzoxazoles also find applications in mate-
rial sciences as photochromatic agents7 and laser dyes.8
the desired benzoxazole (3a) in a moderate yield (Scheme 3). Un-
der the same conditions, we expanded substrates to a variety of
1,1-dibromoalkenes and 2-aminophenols to investigate the scope
of the reaction. The results are described herein.
O
X
N
N
O
To date, a variety of methods were reported for the preparation
of benzoxazoles. The most notable ones include the condensation
of o-aminophenols with benzoic acids9,10 or acid derivatives in
strong acidic condition such as in polyphosphoric acid (PPA)
(Scheme 2);11 and with aldehydes under strong oxidative condi-
tions using oxidants such as DDQ,12 PhI(OAc)2,13 ThClO4,14 and
PCC.15 Other reported methods are copper-catalyzed intramolecu-
lar ortho arylation of o-haloanilides and intermolecular annula-
tions of o-arylhalides with acylamides.16
O
O
N
O
HO
F
R1
Y
R1=Me; UK-1; R1=H; AJI9561
2-Benzylbenzoxazoles
O
Cl
NH
HN
Me
O
N
N
O
NH
Et
N
These methods17 have the limitations when acid sensitive moi-
eties are present, or when molecules are sensitive to strong oxida-
tive conditions. Therefore, there is a need to develop an effective
alternative method to produce benzoxazoles under milder condi-
tions, especially without the presence of acid.
N
Me
Cl
L-697,661
NSC 693638
Scheme 1. Various bioactive molecules containing benzoxazoles.
As part of a program to extend the recently developed method
for an efficient synthesis of benzimidazole from 1,1-dibromoeth-
enes,18 we further investigated the direct coupling of 1,1-dibromo-
ethenes with 2-aminophenols. Like the o-diaminobenzenes, the
electrophilic 2-aminophenols were expected to couple with 1,1-
dibromoethenes leading to the formation of benzoxazoles.
In line with our expectation, under the mildly basic condi-
tions,18a,b 1,1-dibromoalkene (1a) and 2-aminophenol (2a) gave
OH
OH
NH2
HO
O
- H2O
- H2O
O
+
Ar(R)
Ar(R)
N
H
Ar(R)
O
OH
Ar(R)
O
N
N
H
* Corresponding author.
E-mail address: wshen@kanionusa.com (W. Shen).
Scheme 2. The classical method for the preparation of benzoxazoles.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.071

K. Tao et al. / Tetrahedron Letters 51 (2010) 3246–3249
3247
N
Br
H2N
HO
DABCO/NMP
100 ºC, 10 hr
+
O
Br
MeO2C
MeO2C
1a
2a
3a
Scheme 3. The new route for the preparation of benzoxazoles.
Table 1
Coupling of 1,1-dibromoalkenes with 2-aminophenol19
N
H2N
HO
Br
R
DABCO
NMP
R
+
O
Br
1
2a
3
Entry
1
1,1-Dibromoalkene 1
2-Aminophenol 2
Temp, time
Benzoxazole 3
Yielda (%)
O
Br
O
N
O
100 °C
10 h
2a
84
O
Br
Br
O
O
1b
3b
Br
N
100 °C
10 h
2
3
4
2a
2a
2a
80
72
62
F3C
F3C
1c
Br
3c
N
100 °C
10 h
O
Br
MeO2C
MeO2C
1a
Br
Br
N
N
100 °C
10 h
O
Br
Br
Cl
Cl
Br
1d
1e
3d
100 °C
10 h
5
6
7
8
2a
2a
2a
2a
2a
59
65
61
62
54
O
Br
3e
Br
N
100 °C
10 h
O
Br
Cl
Cl
Br
1f
3f
Br
N
100 °C
10 h
O
Br
Br
Br
1g
3g
N
100 °C
10 h
O
Br
1h
Br
3h
N
100 °C
10 h
9
O
Br
MeO
MeO
1i
3i
a
Isolated yield.
2-Aminophenol was coupled with substituted 1,1-dibromoalk-
point’ phenomenon in the 2-aminophenols containing basic
NH2-group and acidic OH-group at the same time, when elec-
tron-donating groups were substituted in 2-aminophenols, the
nucleophilicity of NH2 group was enhanced, meanwhile, the
nucleophilic reactivity of OH group was weakened. Similarly,
electron-withdrawing groups in 2-aminophenols would weaken
the nucleophilicity of the ‘NH2’ and enhance the nucleophilicity
of the ‘OH’ group.
A plausible mechanism is proposed in Scheme 4. It is believed
that alkynyl bromides were generated upon treatment of dibro-
mide with a suitable base.18 Alkynylamines are then formed and
followed by an intramolecular cyclization to give the benzoxazole
products.
enes successfully (Table 1). Interestingly, higher yields were ob-
tained when 1,1-dibromoalkenes was substituted with electron-
withdrawing groups, so the readily prepared electron-deficient
methyl 4-(2,2-dibromovinyl)benzoate was chosen to couple with
various 2-aminophenols.
Different substituted 2-aminophenols were coupled with
methyl 4-(2,2-dibromovinyl)benzoate to provide the desired
products in moderate to good yields (Table 2, entries 1–7). How-
ever, regardless of the difference of electron-donating or electron-
withdrawing nature in the 2-aminophenols, no clear trend was
found to influence the yield among these derivates. The interest-
ing observation could be rationalized that a similar ‘isoelectric

3248
K. Tao et al. / Tetrahedron Letters 51 (2010) 3246–3249
Table 2
Coupling of different 2-aminophenols with methyl 4-(2,2-dibromovinyl)benzoate19
N
Br
H2N
HO
DABCO
NMP
R2
+
O
Br
MeO2C
MeO2C
R2
1a
2
3
Entry
1
1,1-Dibromoalkene 1
2-Aminophenol 2
Temp, time
Benzoxazole 3
Yielda (%)
61
H2N
OMe
N
100 °C
10 h
1a
1a
1a
1a
1a
O
OMe
MeO2C
MeO2C
MeO2C
MeO2C
MeO2C
MeO2C
HO
2b
3j
H2N
N
100 °C
10 h
2
3
4
5
58
72
57
66
O
O
O
O
O
HO
2c
3k
H2N
N
100 °C
10 h
HO
2a
Cl
3a
H2N
N
N
N
100 °C
10 h
Cl
HO
2d
NO2
3l
H2N
100 °C
10 h
NO2
3m
HO
2e
H2N
100 °C
10 h
6
1a
1a
76
56
Cl
HO
2f
Cl
3n
H2N
HO
N
O
100 °C
10 h
7
MeO2C
NO2
2g
NO2
3o
a
Isolated yield.
Acknowledgment
HO
Base
-HBr
Br
Ar
Ar
+
This work was in part supported by the Grant-in-Aid for Scien-
tific Research from the Chinese Academy of Science Innovation
Grant (KSCX1-YW-10).
Br
Br
H2N
HO
O
References and notes
Ar
N
Ar
1. McKee, M. L.; Kerwin, S. M. Bioorg. Med. Chem. 2008, 16, 1775; Oksuzoglu, E.;
Temiz-Arpaci, O.; Tekiner-Gulbas, B.; Eroglu, H.; Sen, G.; Alper, S.; Yildiz, I.;
Diril, N.; Aki-Sener, E.; Yalcin, I. Med. Chem. Res. 2008, 16, 1.
2. Gong, B.; Hong, F.; Kohm, C.; Bonham, L.; Klein, P. Bioorg. Med. Chem. Lett. 2004,
14, 1455.
N
H
Scheme 4. A proposed mechanism for the formation of benzoxazoles.
3. Sun, L.-Q.; Chen, J.; Bruce, M.; Deskus, J. A.; Epperson, J. R.; Takaki, K.; Johnson,
G.; Iben, L.; Mahle, C. D.; Ryan, E.; Xu, C. Bioorg. Med. Chem. Lett. 2004, 14, 3799.
and references cited therein.
4. Ertan, T.; Yildiz, I.; Tekiner-Gulbas, B.; Bolelli, K.; Temiz-Arpaci, O.; Yalcin, I.;
Aki, E.; Ozkan, S.; Kaynak, F. Eur. J. Med. Chem. 2009, 44, 501.
5. (a) Alper-Hayta, S.; Arisoy, M.; Temiz-Arpaci, O.; Yildiz, I.; Aki, E.; Oezkan, S.;
Kaynak, F. Eur. J. Med. Chem. 2008, 43, 2568; (b) Tekiner-Gulbas, B.; Temiz-
Arpaci, O.; Yildiz, I.; Altanlar, N. Eur. J. Med. Chem. 2007, 42, 1293; (c) Yildiz-
Oren, I.; Tekiner-Gulbas, B.; Yalcin, I.; Temiz-Arpaci, O.; Aki-Sener, E.; Altanlar,
N. Arch. Pharm. 2004, 337, 402.
6. Sun, A.; Prussia, A.; Zhan, W.; Murray, E. E.; Doyle, J.; Cheng, L.-T.; Yoon, J. J.;
Radchenko, E. V.; Palyulin, V. A.; Compans, R. W.; Liotta, D. C.; Plemper, R. K.;
Snyder, J. A. J. Med. Chem. 2006, 49, 5080.
7. Varga, A.; Aki-Sxener, E.; Yalcin, I.; Temiz-Arpaci, O.; Tekiner-Gulbasx, B.;
Cherepnev, G.; Molnar, J. In Vivo 2005, 19, 1087.
In summary, the synthesis of benzoxazoles with direct coupling
of 1,1-dibromoethenes with 2-aminophenols has been achieved
under mildly basic conditions. This new method is restricted to
1,1-dibromoethenes derived from arylaldehydes and glyoxalate
or similar aldehydes, therefore limiting its scope. However, the
wide spread application of benzoxazoles could render this method
a useful addition to the existing methods, especially with the
milder conditions employed. A further investigation of the scope
and limitation of this novel preparative method and detailed
mechanism of these types of reactions is on-going and will be re-
ported in due course.
8. Heathcock, C. H.. In Comprehensive Organic Synthesis; Trost, B. M., Flemming, I.,
Eds.; Pergamon Press: New York, 1991; Vol. 2.

K. Tao et al. / Tetrahedron Letters 51 (2010) 3246–3249
3249
9. Kumar, R.; Selvam, C.; Kaur, G.; Chakraborti, A. K. Synlett 2005, 1401.
10. Seijas, J. A.; Vazquez-Tato, M. P.; Carballido-Reboredo, M. R.; Crecente-Campo,
J.; Romar-Lopez, L. Synlett 2007, 313.
11. Terashima, M.; Ishii, M.; Kanaoka, Y. Synthesis 1982, 6, 484.
12. Chang, J.; Zhao, K.; Pan, S. Tetrahedron Lett. 2002, 43, 951.
13. Varma, R. S.; Saini, R. K.; Prakash, O. Tetrahedron Lett. 1997, 38, 2621.
14. Praveen, C.; Kumar, K. H.; Muralidharan, D.; Perumal, P. T. Tetrahedron 2008,
64, 2369.
18. There is a single prior example for the formation of benzoxazole from 1,1-
dibromoethenes: (a) Bozhenkov, G. V.; Frolov, Y. L.; Toryashinova, D. S.-D.;
Levkovskaya, G. G.; Mirskova, A. N. Russ. J. Org. Chem. 2003, 39, 807; (b) Shen,
W.; Kohn, T.; Fu, Z.; Jiao, X.; Lai, S.; Schmitt, M. Tetrahedron Lett. 2008, 49, 7284;
Shen, W.; Kunzer, A. Org. Lett. 2002, 4, 1315; (c) Huh, D. H.; Jeong, J. S.; Lee, H.
B.; Ryn, H.; Kim, Y. G. Tetrahedron 2002, 58, 9925; (d) Huh, D. H.; Ryu, H.; Kim,
Y. G. Tetrahedron 2004, 60, 9857; (e) Zhang, A.; Zheng, X.; Fan, J.; Shen, W.
Tetrahedron Lett. 2010, 51, 828.
15. Park, K. H.; Jun, K.; Shin, S. R.; Oh, S. W. Tetrahedron Lett. 1996, 37, 8869.
16. (a) Viirre, R. D.; Evindar, G.; Batey, R. A. J. Org. Chem. 2008, 73, 3452; (b)
Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802; (c) Altenhoff, G.; Glorius, F.
Adv. Synth. Catal. 2004, 346, 1661.
17. (a) Chen, C.; Chen, Y.-J. Tetrahedron Lett. 2004, 45, 113; (b) Nadaf, R. N.; Siddiqui, S.
A.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. J. Mol. Catal. A: Chem. 2004, 214, 155; (c)
Pottorf, R. S.; Chadha, N. K.; Katevics, M.; Ozola, V.; Suna, E.; Ghane, H.; Regberg,
T.; Player, M. R. Tetrahedron Lett. 2003, 44, 175; (d) Kawashita, Y.; Nakamichi, N.;
Kawabata, H.; Hayashi, M. Org. Lett. 2003, 5, 3713. and references therein; (e)
Wilfred, C. D.; Taylor, R. K. J. Synlett 2004, 1628.
19. A typical reaction procedure: A mixture of methyl 4-(2,2-dibromovinyl)-
benzoate (1a, 640 mg, 2.0 mmol), 5-chloro-2-aminophenol (2f, 430 mg,
3.0 mmol), and DABCO (494 mg, 4.4 mmol) in NMP (8 mL) was heated at
100 °C for 10 h. Then the reaction mixture was cooled to room temperature,
diluted with ethyl acetate (60 mL), washed with water (2 Â 20 mL) and brine
(10 mL), dried over anhydrous Na2SO4, and concentrated. The residue was
subjected to silica gel chromatography using ethyl acetate to petro ether as 1–6
to give 3n (435 mg, 72%). 1H NMR (CDCl3, 400 MHz) d 8.03 (d, J = 8.4 Hz, 2 H),
7.67 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.28 (dd,
J = 6.4, 2.0 Hz, 1H), 4.32 (s, 2H), 3.91 (s, 3H). MS (ESI+) m/z: 302.0 (M+H).