One pot synthesis of 2-phenylbenzoxazoles by potassium cyanide assisted reaction of o-aminophenols and benzaldehydes

Article abstract of DOI:10.1016/j.tetlet.2010.11.038

The 2-phenylbenzoxazoles were obtained in moderate to good yields by reaction of the substituted o-aminophenols with benzaldehydes in the presence of one equivalent of potassium cyanide as an equimolecular catalyst in N,N-dimethylformamide at room temperature.

Full text of DOI:10.1016/j.tetlet.2010.11.038

Tetrahedron Letters 52 (2011) 308–310
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Tetrahedron Letters
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One pot synthesis of 2-phenylbenzoxazoles by potassium cyanide assisted
reaction of o-aminophenols and benzaldehydes
⇑
Horacio Reyes , Hiram I. Beltran, Ernesto Rivera-Becerril
Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana Unidad Cuajimalpa, Avenida Pedro Antonio de los Santos 84, 11850 México D. F., México
a r t i c l e i n f o
a b s t r a c t
Article history:
The 2-phenylbenzoxazoles were obtained in moderate to good yields by reaction of the substituted
o-aminophenols with benzaldehydes in the presence of one equivalent of potassium cyanide as an equi-
molecular catalyst in N,N-dimethylformamide at room temperature.
Received 1 October 2010
Revised 4 November 2010
Accepted 8 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Potassium cyanide
2-Phenylbenzoxazoles
Heterocycles
Synthetic methods
The benzoxazole derivatives are a well-known kind of heterocy-
cles that have considerable importance in the field of materials
chemistry, in particular due to their fluorescence properties. These
electronic states and behavior are mainly attributed to the reached
planarity and rigidity of the delocalized electronic system. Taking
advantage of this distinctive attribute, several groups have used
these type of compounds in a number of different applications,
such as electronic devices,1 sensors for metals,2 as well as their
use as photoluminescent dyes.3 Moreover, the family of benzoxaz-
oles is a frequent motif in nature and have potential uses in medic-
inal chemistry as anticancer,4 antimicrobial,5 and antiinflamatory
agents.6
On the other hand, potassium cyanide has been used to catalyze
diverse organic reactions, for example, the benzoin condensation,15
and the synthesis of diverse heterocycles.16 In particular the trans-
formation of [4.3.0] boron heterocycles to the corresponding 2-
arylbenzoxazoles promoted by non equimolecular amounts of
KCN, has been reported recently (Scheme 1).17 This protocol is very
attractive because the reaction proceeds under very mild condi-
tions and in good yields. Nevertheless, the reaction has the disad-
vantage to require the preparation of the corresponding boron
heterocycle as an intermediate step during the linear synthesis.
The closer analyses of the reaction suggest that perhaps the
intermediate boron heterocycle is not a necessary molecule for
the preparation of the final benzoxazoles. To test this hypothesis
we performed the reaction of the phenolic Schiff base obtained
by reaction of o-aminophenol with benzaldehyde under the re-
ported conditions, obtaining the corresponding 2-phenylbenzoxaz-
ole in a 60% yield. Using this reaction as a model we tried different
conditions to improve the yield. The increase of the time or the
temperature did not give better yields, nevertheless, when we
changed the solvent to N,N-dimethylformamide (DMF) and used
The most traditional method for the synthesis of the benzoxaz-
ole moiety is the reaction of o-aminophenols with carboxylic acid
derivatives in the presence of strong acids at high temperature.7
Nevertheless, these harsh conditions do not allow the presence of
several acid sensitive groups such as nitro or tert-butyl, further-
more the yields are low due to the side reactions. The other most
often used methodology is the oxidative cyclization of the phenolic
Schiff bases obtained from the condensation of aldehydes and 2-
aminophenols, using different oxidant agents, including DDQ,8
11
O2/TEMPO,9 O2/Pd(II),10 PhI(OAc)2 and Dess–Martin reagent.12
Some other synthetic protocols have been reported, for example,
the reaction of o-aminophenol with 1,1-dibromoethenes,13 or the
reaction of 2-nitrophenols with orthoesters in the presence of
In(III) as catalyst.14
N
N
B
3 eq. KCN
O
O
O
MeOH, 4 h.
OH
⇑
Corresponding author. Tel.: +52 5526363800x3818; fax: +52 5526363800x3847.
E-mail address: hreyes@correo.cua.uam.mx (H. Reyes).
Scheme 1. Preparation of 2-phenylbenzoxazoles from boron heterocycles.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.038

H. Reyes et al. / Tetrahedron Letters 52 (2011) 308–310
309
O
NH2
OH
H
N
O
1 eq. KCN
+
DMF/ r. t.
1
2
3
Scheme 2. One pot protocol for the preparation of 2-phenylbenzoxazoles.
Table 1
Synthesis of 2-phenylbenzoxazoles18
O
R1
NH2
R1
H
N
O
1 eq. KCN
DMF/ r. t.
+
R2
R2
OH
1
2
3
Product
R1
R2
H
t-Bu
Br
O-Bu
H
t-Bu
Br
Time (h)
Yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
CH3
CH3
CH3
CH3
Cl
5
5
6
8
4
4
6
7
8
85
76
80
70
85
87
80
65
O-Bu
H
70
3j
3k
3l
3m
3n
Cl
Cl
Cl
NO2
NO2
t-Bu
Br
O-Bu
H
8
74
71
60
N. R.
N. R.
12
24
48
48
t-Bu
only one equivalent of potassium cyanide, the yield increased to
85%. In order to shorten the whole synthetic procedure we ex-
plored the same reaction conditions but without the preformation
of the Schiff base. The treatment of o-aminophenol (1) with benz-
aldehyde (2), in the presence of one equivalent of potassium
cyanide and using small amounts of DMF as solvent, afforded the
2-phenylbenzoxazole (3) in 87% yield in five hours carrying the
reaction at room temperature (Scheme 2).
Different 5-substituted o-aminophenols were coupled with 4-
substituted benzaldehydes (Table 1). As is shown in Table 1, the
reaction proceeds smoothly at room temperature in moderate to
good yields. An analysis of the effect of the substituent in the reac-
tion time and yields showed that as the electro-withdrawing
power of the substituent in the aminophenol increases, the reac-
tion time was longer and the yield diminished. Contrary, in the
case of benzaldehyde this effect is caused by the electro-donating
power of the groups at position 4 of benzaldehyde. As it is shown
for the case of 3l, a good electro-withdrawing group in the amino-
phenol combined with a good electro-donating group in the benz-
aldehyde, gave the longest reaction time and also the lowest yield.
There are two possible reaction mechanisms to account for this
transformation, either the typical benzoin kind condensation,15 or
the almidine coupling.16 The need for a stoichiometric amount of
KCN for a successful reaction suggests that the most plausible
mechanism is the benzoin kind condensation.
applicability of this protocol a greener alternative to potassium
cyanide is required, which is currently under investigation in our
group by using thiamine catalyzed reactions and will be reported
in due course.
Acknowledgments
The financial support from CONACyT, project number
47310097, is acknowledged.
References and notes
1. Ko, C. W.; Tao, Y. T. Chem. Mater. 2001, 13, 2441.
2. Tian, Y.; Chen, C. Y.; Yang, C. C.; Young, A. C.; Jang, S. H.; Chen, W. C.; Jen, A. K. Y.
Chem. Mater. 2008, 20, 1977.
3. Kocher, C.; Smith, P.; Weder, C. J. Mater. Chem. 2002, 12, 2620.
4. Mckee, M. L.; Kerwin, S. M. Bioorg. Med. Chem. 2008, 16, 1775.
5. Ertan, T.; Yildiz, I.; Tekiner-Gulbas, B.; Bolelli, K.; Temiz-Arpaci, O.; Ozcan, S.;
Kaynak, F.; Yalcin, I.; Aki, E. Eur. J. Med. Chem. 2009, 44, 501.
6. Srinivas, A.; Sagar, J. V.; Srangapani, M. J. Chem. Pharm. Res. 2010, 2, 319.
7. Chen, T. R. J. Organomet. Chem. 2008, 693, 3117.
8. Chang, J.; Zhao, K.; Pan, S. Tetrahedron Lett. 2002, 43, 951.
9. Chen, Y. C.; Qian, L. F.; Zhang, W.; Han, B. Angew. Chem., Int. Ed. 2008, 47, 9330.
10. Pang, Y.; Chen, W. Tetrahedron Lett. 2009, 50, 6680.
11. Varma, R. S.; Saini, R. K.; Prakash, O. Tetrahedron Lett. 1997, 15, 2621.
12. Bose, D. S.; Idrees, M. Synthesis 2010, 3, 398.
13. Tao, K.; Zheng, J.; Liu, Z.; Shen, W.; Zhang, J. Tetrahedron Lett. 2010, 51, 3246.
14. Lee, J. J.; Kim, J.; Jun, Y. M.; Lee, B. M.; Kim, B. H. Tetrahedron 2009, 65, 8821.
15. Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326.
In summary, the preparation of 2-phenylbenzoxazoles by a one
pot synthesis, involving the reaction of o-aminophenols with benz-
aldehydes, assisted by potassium cyanide has been achieved under
mild conditions. This reaction scheme represents a broad scope of
application, with the limitation in the case of the o-aminophenols
with potent electro-withdrawing groups. In order to increase the
16. Reich, B. J. E.; Justice, A. K.; Beckstead, B. T.; Reibenspiens, J. H.; Miller, S. A. J.
Org. Chem. 2004, 69, 1357.
17. López-Ruiz, H.; Briseño-Ortega, H.; Rojas-Lima, S.; Santillan, R.; Farfán, N.
Tetrahedron Lett. 2010, 51, 2633.
18. Typical reaction procedure.
A mixture of o-aminophenol (1, 2 mmol),
benzaldehyde (2, 2 mmol) and KCN (2 mmol) in DMF (5 mL) was stirred at
room temperature, the progress of the reaction was monitored using thin layer

310
H. Reyes et al. / Tetrahedron Letters 52 (2011) 308–310
chromatography. Once the reaction was complete, the reaction mixture was
(15%). Compound 3h: light brown solid, mp 84.2–86.1. IR (KBr) tmax 2955,
2871, 1609, 1581, 1500, 1471, 1253, 1170, 1040, 835, 802; 1H NMR (500 MHz,
CDCl3) 8.1 (d, J = 9.1 Hz, 2H), 7.5 (s, 1H), 7.4 (d, J = 8 Hz, 1H), 7.1 (d, J = 8 Hz, 1H),
6.9 (d, J = 9.1 Hz, 1H), 4.0 (t, J = 5.2 Hz, 2H), 2.4 (s, 3H), 1.8 (quin, J = 6.5 Hz, 2H),
1.5 (sx, J = 6.5 Hz, 2H), 0.9 (t, J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) 163.3,
161.8, 148.8, 142.4, 134.1, 129.2, 125.5, 119.5, 119.4, 114.7, 109.6, 67.8, 31.1,
21.49, 19.2, 13.8; MS (m/z) 281 (MI, 55%), 225 (100). Compound 3l: light brown
diluted with 30 mL of water and extracted twice with ethyl acetate (30 mL),
the solvent was removed under reduced pressure. The obtained solid was then
recrystalized from a boiling mixture of ethanol/water 50–50, giving the pure
compound. Compound 3d: light brown solid, mp 86.2–87.5. IR (KBr) tmax 2955,
2871, 1616, 1498, 1468, 1422, 1243, 1173, 842, 747; 1H NMR (500 MHz, CDCl3)
8.1 (d, J = 9.0 Hz, 2H), 7.7 (m, 1H), 7.5 (m, 1H), 7.3 (m, 1H), 7.0 (d, J = 9.0, 2H),
4.0 (t, J = 5.2 Hz, 2H), 1.7 (quin, J = 6.5 Hz, 2H), 1.5 (sx, J = 6.5 Hz, 2H), 0.9 (t,
J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) 150.6, 142.2, 129.3, 124.5, 124.3,
119.5, 119.3, 114.8, 110.3, 67.8, 31.1, 19.1, 13.8; MS (m/z) 267 (MI, 50%), 211
(100%). Compound 3f: yellow solid, mp 77.5–79.5. IR (KBr) tmax 2965, 1619,
1577, 1555, 1286, 1266, 1058, 804; 1H NMR (500 MHz, CDCl3) 8.1 (d, J = 9.1 Hz,
2H), 7.5 (m, 3H), 7.4 (d, J = 8.0, 1H), 7.1 (m, 1H), 2.47 (s, 3H), 1.3 (s, 9H); 13C
NMR (125 MHz, CDCl3) 163.2, 154.9, 148.9, 142.3, 134.2, 127.3, 125.9, 125.8,
124.4, 119.7, 109.8, 35.0, 31.1, 21.5; MS (m/z) 265 (MI, 75), 250 (100%), 222
solid, mp 106.0–107.6. IR (KBr) tmax 2963, 2872, 1613, 1556, 1499, 1424, 1257,
1173, 1055, 841, 803; 1H NMR (400 MHz, DMSO-d6) 8.1 (d, J = 9.1 Hz, 2H), 7.8
(dd, J = 0.5, J = 2.0 Hz, 1H), 7.7 (dd, J = 0.5, J = 8.5 Hz, 1H), 7.4 (dd, J = 2.0,
J = 8.5 Hz, 1H), 7.1 (d, J = 9.1 Hz, 2H), 4.1 (t, J = 5.2 Hz, 2H), 2.5 (s, 3H), 1.8 (quin,
J = 6.5 Hz, 2H), 1.5 (sx, J = 6.5 Hz, 2H), 0.9 (t, J = 6.5 Hz, 3H); 13C NMR (100 MHz,
DMSO-d6) 163.9, 161.9, 138.9, 143.03, 129.3, 128.8, 124.8, 119.0, 118.0, 115.2,
111.9, 67.6, 30.5, 18.6, 13.6; MS (m/z) 301, 303 (MI, 30, 10%), 245, 247 (100,
33%).