Microwave-assisted synthesis of benzoxazole-7-carboxylate esters using trifluoroacetic acid and acetic acid

Article abstract of DOI:10.1055/s-2006-951489

Existing routes to benzoxazole-7-carboxylates are low-yielding. The following letter describes a new methodology for the synthesis of benzoxazole-7-carboxylates in much improved yield using trifluoroacetic acid-acetic acid and microwave irradiation. Georg

Full text of DOI:10.1055/s-2006-951489

2658
LETTER
Microwave-Assisted Synthesis of Benzoxazole-7-carboxylate Esters Using
Trifluoroacetic Acid and Acetic Acid
M
icrowave-Assist
n
e
d
Synthesis
t
of
B
en
h
zoxazole-7-c
o
arboxylate
E
n
sters
U
sing
T
y
FA and AcO
H
Huxley*
Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex,
CM19 5AW, UK
Fax +44(1279)627896; E-mail: Anthony.2.Huxley@gsk.com
Received 4 July 2006
acid chloride used, and was difficult to remove from the
Abstract: Existing routes to benzoxazole-7-carboxylates are low-
monoacylated product. A study of cyclisation conditions
yielding. The following letter describes a new methodology for the
was then undertaken for the direct ring synthesis from
synthesis of benzoxazole-7-carboxylates in much improved yield
using trifluoroacetic acid–acetic acid and microwave irradiation.
amino phenol 2b utilising the BiotageTM InitiatorTM
microwave to rapidly screen a range of acid catalysts and
Key words: benzoxazoles, heterocycles, cyclisations, acylations,
temperatures. The key challenge was to find suitable acid
conditions that would facilitate the dehydration of the
amide intermediate and give the desired product
(Scheme 2).
microwave-assisted synthesis, trifluoroacetic acid
The benzoxazole ring system is a feature of several drug
molecules e.g. Benoxaprofen (antiinflammatory) and
Zoxazolamine (antirheumatic). A one-step synthesis of
4-carboxy-2-substituted benzoxazoles is described in the
literature.1 The synthesis of 5-carboxy-2 and 6-carboxy-3
2-substituted benzoxazoles has been described utilising a
two-step procedure starting from the relevant amino
phenol.
Initial reactions using acetic acid as solvent at 200 °C for
15 minutes, gave an indication of product and increasing
the temperature to 230 °C for 30 minutes increased the
yield to 30%. As this temperature represented the upper
limit of what could be achieved with acetic acid, N-meth-
yl-2-pyrrolidinone was added as co-solvent and the reac-
tion was heated to 250 °C for 45 minutes. LCMS revealed
only trace quantities of starting material remaining, but as
well the benzoxazole product, three significant impurity
peaks had formed. Ionic liquid (1,3-dibutyl-1H-imidazol-
3-ium tetrafluoroborate) was also used to increase the
temperature of the acetic acid to 250 °C but, again, this
gave a number of unidentified products. Cyclisation using
acetic acid with two equivalents of 4-toluenesulfonic acid
at 225 °C was also attempted. Only trace quantities of the
desired product were observed.
Our interest was concentrated on the synthesis of the
7-carboxy system 1 (Figure 1). Although a route to these
systems has been published4 utilising an initial coupling
of the relevant 2-amino phenol with an acid chloride fol-
lowed by cyclisation using 4-toluenesulfonic acid in
xylene under reflux, the reported yields were poor (11–
27%).
4
N
5
R'
6
O
NH2
OH
NHC(O)Ph
NHC(O)Ph
OC(O)Ph
7
i) or ii)
O
OR
OH
OR'
+
1
O
OR'
O
O
OR'
Figure 1 Structure of the benzoxazole-7-carboxylate ester system
3
4
4a: R = Et
4b: R = Me
3a: R = Et, 81%
3b: R = Me, 75%
2a: R = Et
2b: R = Me
Initial efforts to synthesise the 2-phenylbenzoxazole-7-
carboxylate system from 2a and benzoyl chloride using a
one-step procedure with pyridinium 4-toluenesulfonate,
triethylamine in xylene at reflux (Scheme 1), as described
in the literature1 for 4-carboxy derivatives, failed to give
any benzoxazole product. Instead, this method gave the
amide product 3a in 81% yield.5 Use of triethylamine in
dichloromethane and benzoyl chloride on 2b also gave the
amide 3b in good yield (75%). A by-product that was
observed during the initial acylation of the amino phenol
was the N,O-diacylated material 4b. The diacylated
material was formed in varying yield, depending on the
Conditions:
i) R' = Et: PhC(O)Cl, pyridinium 4-toluenesulfonate,
Et3N, xylene, reflux
ii) R' = Me: PhC(O)Cl, Et3N, CH2Cl2, r.t.
Scheme 1 Synthesis of mono- and diacylated amino phenols 3 and 4
It was reasoned that a stronger acid was required as sol-
vent to enable the dehydration to take place rapidly, and
avoid side-products created by elevated temperatures and
prolonged reaction times. Trifluoroacetic acid was there-
fore chosen as co-solvent with acetic acid in a 1:1 ratio
and the reaction mixture was heated to 200 °C for 20
minutes.6 LCMS showed only the desired product peak
present and the yield of methyl 2-phenylbenzoxazole-7-
SYNLETT 2006, No. 16, pp 2658–2660
0
4
.1
0
.2
0
0
6
Advanced online publication: 22.09.2006
DOI: 10.1055/s-2006-951489; Art ID: D19406ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Microwave-Assisted Synthesis of Benzoxazole-7-carboxylate Esters Using TFA and AcOH
2659
carboxylate (5), after evaporation and chromatography the desired benzoxazoles 5–10 in excellent yield after
was 88%.
evaporation, workup and chromatography, if required.
This methodology proved to be generally applicable to the
synthesis of derivatives, incorporating a variety of sub-
stituents, including electron-donating and electron-with-
drawing groups (Table 1).
NHC(O)R
(i)
NHC(O)R
OC(O)R
N
O
R
(i)
OH
In conclusion, a novel method has been developed for the
synthesis of 2-arylbenzoxazole-7-carboxylic acid deriva-
tives in excellent yields. The procedure is simple and
allows reactions to be performed rapidly in trifluoroacetic
acid–acetic acid solvent, utilising microwave heating.
Moreover, this approach can be applied to both mono- and
diacylated amino phenol precursors.
O
OMe
3b–g
O
OMe
O
OMe
4b–g
5–10
(i) TFA –AcOH (1:1), 200 °C, 20 min, microwave
Scheme 2 Synthesis of 2-arylbenzoxazole-7-carboxylates
Table 1 Synthesis of Benzoxazoles 5–10 from Mono- (3) and
Diacyl (4) Amino Phenolsa,b (Scheme 2)
Acknowledgment
Product
R
3
Yield
4
Yield
from 3
from 4
Many thanks to Dr Barry Orlek for his help and guidance through-
out the duration of this work.
5
6
Ph
3b
3c
3d
3e
3f
88%
88%
84%
85%
37%
95%
4b
4c
4d
4e
4f
84%
95%
92%
92%
100%
93%
3,5-diClC6H3
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
References and Notes
7
(1) Goldstein, S. W.; Dambeck, P. J. J. Heterocycl. Chem. 1990,
27, 335.
(2) Kosoka, T.; Wakabuyashi, T. Heterocycles 1995, 41, 477.
(3) Meyer, V. J. Prakt. Chem. 1915, 92, 265.
(4) Razavi, H.; Palaninathan, S. K.; Powers, E. T.; Wiseman, R.
L.; Purkey, H. E.; Mohamedmohaideen, N. N.; Deechongkit,
S.; Chiang, K. P.; Dendle, M. T. A.; Sacchettini, J. C.; Kelly,
J. W. Angew. Chem. Int. Ed. 2003, 42, 2758.
8
9
10
3g
4g
a Reactions were carried out using the BiotageTM InitiatorTM micro-
wave, TFA–AcOH (1:1), 200 °C, 20 min.
(5) General Procedure for Mono-N-acyl Compounds 3:
Amino phenol (1.0 equiv), benzoyl chloride (1.1 equiv),
pyridinium 4-toluenesulfonate (0.26 equiv) and Et3N (1.1
equiv) were stirred in xylene (10 mL) and heated at reflux
overnight. The reaction mixture was evaporated and purified
by chromatography (silica gel; 0–30% EtOAc–pentane).
Combined fractions were evaporated and redissolved in
EtOAc and washed with aq 2 M aq HCl solution, sat. aq
NaHCO3 and brine. The organic solution was dried (MgSO4)
and evaporated to give the desired mono-N-acylated product
3b–g.
(6) Representative Cyclisation Procedure for Mono-N-
acylated Precursors; Methyl 2-Phenylbenzoxazole-7-
carboxylate (5): Methyl-2-hydroxy-3-(phenylamido)-
benzoate (0.15 g) was dissolved in TFA–AcOH (1:1, 3 mL),
in a 5-mL microwave vial, sealed and irradiated to 200 °C
for 20 min in a BiotageTM InitiatorTM microwave. The
reaction mixture was evaporated to a minimum (co-evapo-
rated with toluene thrice) and purified by flash chromatog-
raphy [silica gel, 0–30% Et2O–PE (40:60)] and evaporated
to give the title compound as a white powder (0.12 g; 88%
conversion). 1H NMR (400 MHz, CDCl3): d = 8.34 (m, 2 H),
7.99 (m, 2 H), 7.57 (m, 3 H), 7.43 (t, J = 7.8 Hz, 1 H), 4.06
(s, 3 H). MS: [ES (Waters Alliance HT LCMS system)
(+ve ion)]: m/z = 254 [MH+].
b Non-optimised yields based on isolated products.
To demonstrate the utility of the trifluoroacetic acid–ace-
tic acid conditions, a number of mono-acylated amino
phenols, 3b–g, were synthesised (by reacting the amino
phenol with a range of acid chlorides using standard
conditions5) and cyclised to give the desired benzoxazoles
in good to excellent yield (Scheme 2, Table 1, 5–10) and
high purity.
Previous work7 had shown that it was possible to obtain
benzoxazoles by heating amino phenols with excess acid
chloride in dioxane at 210 °C and proposed that the reac-
tion proceeded via the diacylated amino phenol.8 It was
reasoned that treatment of the diacyl products with tri-
fluoroacetic acid–acetic acid mixture at 200 °C in the
microwave could give the desired benzoxazole products.
The required diacylated compounds, 4b–g, were readily
obtained9 by treatment of the amino phenol 2b with 2.1
equivalents of acid chloride in the presence of triethyl-
amine in dichloromethane at room temperature followed
by aqueous sodium bicarbonate workup, or filtration in
cases where the diacyl compound precipitated from the
reaction mixture. Subsequent treatment of the diacyl
material with trifluoroacetic acid–acetic acid10 (1:1) at
200 °C for 20 minutes in the microwave (Scheme 2) gave
(7) Pottorf, R. S.; Chadha, N. K.; Katkevics, M.; Ozola, V.;
Suna, E.; Ghane, H.; Regberg, T.; Player, M. R. Tetrahedron
Lett. 2003, 44, 175.
(8) Attempted cyclisation using one-pot conditions described by
Pottorf did not give any desired product when applied to the
synthesis 7-carboxy benzoxazole system.
Synlett 2006, No. 16, 2658–2660 © Thieme Stuttgart · New York

2660
A. Huxley
LETTER
(9) General Procedure for Diacylation of Amino Phenol 4:
Amino phenol (1 equiv), aroyl chloride (2.1 equiv), and Et3N
(2.1 equiv) were stirred in CH2Cl2 for 1–4 d. For 4c–g, diacyl
material can be filtered off from reaction mixture as a white
precipitate. For phenyl diacyl compound 4b, the reaction
mixture was then diluted with CH2Cl2 and washed with sat.
aq NaHCO3 solution. The organic layer was dried (MgSO4)
and evaporated to give the desired material as a white solid.
(10) General Procedure for Cyclisation of Diacyl Compounds
5–10: The diacylated amino phenol was suspended in TFA–
AcOH in a microwave vial, sealed and irradiated to 200 °C
for 20 min in BiotageTM InitiatorTM microwave. The reaction
mixture was evaporated to a minimum (co-evaporated with
toluene thrice), redissolved in CH2Cl2 and washed with sat.
NaHCO3 solution. The organic layer was dried (MgSO4),
evaporated and purified by chromatography (if required) to
give the desired benzoxazole product. 1H NMR and MS (ES)
data were consistent with those previously described.
Synlett 2006, No. 16, 2658–2660 © Thieme Stuttgart · New York