Parallel synthesis of benzoxazoles via microwave-assisted dielectric heating

Article abstract of DOI:10.1016/S0040-4039(02)02495-4

A facile route to benzoxazoles has been developed using microwave-assisted dielectric heating. The ease of synthesis and workup allowed the parallel synthesis of a 48-membered library of benzoxazoles quickly and efficiently.

Full text of DOI:10.1016/S0040-4039(02)02495-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 175–178
Parallel synthesis of benzoxazoles via microwave-assisted
dielectric heating
Richard S. Pottorf,a Naresh K. Chadha,a Martins Katkevics,b Vita Ozola,b Edgars Suna,b
Hadi Ghane,c Tor Regbergc and Mark R. Playera,*
a3-Dimensional Pharmaceuticals, Inc., 8 Clarke Drive, Cranbury, NJ 08512, USA
bLatvian Institute of Organic Synthesis, Aizkraukles 21, Riga LV-1006, Latvia
cPersonal Chemistry, Hamnesplanaden 5, 753 19 Uppsala, Sweden
Received 11 June 2002; revised 23 October 2002; accepted 25 October 2002
Abstract—A facile route to benzoxazoles has been developed using microwave-assisted dielectric heating. The ease of synthesis
and workup allowed the parallel synthesis of a 48-membered library of benzoxazoles quickly and efficiently. © 2002 Elsevier
Science Ltd. All rights reserved.
The parallel synthesis of small focused libraries has
become an important strategy for the follow-up of
screening hits. The benzoxazole scaffold 1 is found in
many biologically active compounds, such as elastase
inhibitors1 and H2-antagonists.2 There are several
reports3 for the synthesis of benzoxazoles including one
which uses solid-phase support.4 Although the latter
method does allow the parallel synthesis of libraries,
product diversity is limited since one monomer must
contain a functional group which can be tethered to the
2-aminophenols.6 Unfortunately, this particular reac-
tion was promoted with mineral supports such as
MnO2 or SiO2 which prevents facile isolation of the
products. An additional method for the microwave-
assisted synthesis of benzoxazoles using S-methylisoth-
ioamides has been reported.7 Disadvantages of this
method are that the S-methyl isothioamides must be
synthesized prior to use and that toxic methanethiol is
produced during the reaction. Microwave-assisted reac-
tions in a common solvent using readily available
reagents would be a desirable approach to enhance
synthetic throughput for benzoxazoles 1.
solid support.
A solution-phase parallel synthetic
approach would be more flexible with respect to usable
reagents and would yield more diverse products. There-
fore, we desired a solution-phase route to libraries of
the scaffold 1.
Previous thermal cyclizations3b were reported to go
through the preformed diacylated aminophenol
(Scheme 1a). Since acylations are also promoted by
microwave energy,5 we thought a one-pot (acylation/
cyclization) strategy (Scheme 1b) would be amenable
for a solution-phase library approach. The effect of
base, solvent, concentration, time and temperature on
the reaction was systematically explored using the
model reaction between 2a and 3,4,5-trimethoxybenzoyl
chloride 3h to give the desired product 1h. Product
formation from these reactions was followed by gas
chromatography.
The reported standard thermal cyclization routes to 1
are not amenable for a parallel approach due to long
reaction times and difficult product isolation.3 The use
of microwave-assisted dielectric heating to accelerate
reactions has been reported for a number of reactions5
including benzoxazole formation from aldehydes and
Additives such as base to facilitate the acylation and
Lewis acids to aid dehydration are thought to be neces-
sary to promote high conversion to 1.3b,c Several addi-
tives including triethylamine and pyridinium tosylate,3c
toluenesulfonic acid,3b and triflic acid were explored.
The control reaction in Scheme 1b (without additives)
Keywords: benzoxazole; microwave; parallel synthesis.
* Corresponding author. Tel.: 609-655-6950; fax: 609-655-6930;
e-mail: mark.player@3dp.com
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02495-4

176
R. S. Pottorf et al. / Tetrahedron Letters 44 (2003) 175–178
Clearly, the combination of high heat and pressure
produced in the microwave-assisted reaction is the pre-
ferred methodology for the rapid synthesis of a focused
library.
resulted in a 30% yield of 1h, while basic or acidic
additives resulted in yields varying from 8 to 60%.
Ultimately, these additives were found to be unneces-
sary as other parameters resulted in a much higher yield
of product. Presumably, as HCl is produced as a by-
product during the acylation, it catalyzes the subse-
quent cyclization reaction.
To demonstrate the advantages of the currently devel-
oped procedure for the parallel synthesis of benzoxa-
zoles, a 48-compound library was synthesized (Table 1).
Method 1 was chosen due the simple work-up and
isolation of the products. An aqueous quench and
filtration of the precipitate afforded the product. All
entries of the library were synthesized by this method.
For comparison, several examples were generated using
Method 2. All benzoxazoles were obtained in good to
excellent yields (46–98% pure). Method 1 resulted in a
6–25% increase in yield over Method 2. However, in a
few cases, Method 2 resulted in a better yield compared
to that obtained via Method 1. For example, 1b was
obtained in a 71% yield using Method 2 compared to
66% using Method 1. This may be due to the increased
temperature used in Method 2 with this hindered acid
chloride 3b. Moreover, with Method 1 this ortho-substi-
tuted acid chloride 3b gave lower yields (49–92%) com-
pared to the para-substituted analog 3d (75–98%)
suggesting that steric constraints may limit the scope of
this reaction. Electron-withdrawing substituents on the
acid chlorides 3d, 3e facilitated benzoxazole formation
with yields ranging from 75 to 98%.
Conventionally, benzoxazoles have been synthesized in
non-polar high boiling solvents such as toluene and
xylene.3b In the model reaction, other solvents such as
dichloroethane, dichlorobenzene and 1,4-dioxane were
equally efficient. In addition, aminophenols are
markedly more soluble in dioxane. Polar solvents with
high boiling points e.g. sulfolane, did not give satisfac-
tory results.
Higher reactant concentrations improved the product
yield considerably. A 30% yield was obtained when the
aminophenol concentration was 0.9 mM, compared to
76% at 2.7 mM.
The exploration of temperature and reaction time with
dioxane and xylene determined that temperatures of at
least 200°C resulted in a high yield of the desired
product in 10–15 min. Longer reaction times (20–30
min) resulted in partial decomposition of the product.
Optimization of the various parameters resulted in two
preferred methods. Both of these methods in the model
reaction shown in Scheme 1b resulted in yields of 92
and 81%, respectively.
The six aminophenols 2 gave high yields with the
simple acid chloride 3a with the exception of 2d (52%).
This reagent tended to work less well in all the exam-
ples using Method 1. However, significant improvement
in the yield with this reagent was observed using
Method 2 as shown for product 1y (54% versus 73%).
Reagent solubility may play a role in this observation
as this method uses xylene and 2d is a naphthalene
derivative.
Method 1: 2.5 mL dioxane, 1.8 mM of 2-aminophenol,
2.0 mM of acid chloride for 15 min at 210°C.
Method 2: 2.5 mL xylene, 2.7 mM of 2-aminophenol,
3.0 mM of acid chloride for 10 min at 250°C.
In conclusion, two efficient methods for the solution-
phase synthesis of benzoxazoles have been developed.
The fact that readily available reagents are used along
with the short reaction time, no additives, and simple
work-up and isolation of the product make the current
approach a feasible and attractive protocol for genera-
tion of benzoxazole libraries as demonstrated in Table
1.
Control experiments were run with the model reaction
between 2a and 3h. Conventional dioxane reflux at
ambient pressure required 24 h to give an 85% product
yield. Further heating resulted in decomposition and
lower product purity. This reaction was also run in a
sealed tube with refluxing dioxane. In this case, a 15
min reaction time resulted in only a 2% product yield.
Scheme 1. (a) Conventional synthesis of benzoxazoles through diacylated intermediate.3b (b) Microwave-assisted synthesis of
benzoxazoles in a one-pot acylation/cyclization step. Example shown is model reaction for optimization of reaction conditions.

R. S. Pottorf et al. / Tetrahedron Letters 44 (2003) 175–178
Table 1. A 48-membered library of benzoxazoles synthesized via method 1a
177
References
Experimental
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P. A.; Andisik, D. A.; Gomes, B.; Strimpler, A. J. Am.
Chem. Soc. 1992, 114, 1854–1863.
All reactions were performed on a SmithSynthesizer™
from Personal Chemistry, Uppsala, Sweden. This
instrument typically initiates microwave irradiation at
300 W to raise the temperature to the desired endpoint
and then monitors the temperature and reduces the
microwave power to 50–100 W to maintain this temper-
ature. Since the reactions are run in a closed vessel,
typical pressures observed during reaction were approx-
imately 6 atm. Acyl chlorides and 2-aminophenols were
purchased from Aldrich and were of the highest purity
available. 1,4-Dioxane and toluene were distilled from
2. Katsura, Y.; Inoue, Y.; Tomishi, T.; Itoh, H.; Ishikawa,
H.; Takasugi, H. Chem. Pharm. Bull. 1992, 40, 2432–2441.
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1
sodium prior to use. H NMR spectra8 were recorded
on a Varian 200 MHz spectrometer. Low-resolution
mass spectral analyses were performed on an HP-6890
mass spectrometer. TLC analysis was performed using
silica gel 60 F254 plates purchased from Merck.
7. Rostamizadeh, S.; Derafshian, E. J. Chem. Res. (S) 2001,
1, 227–228.
Typical reaction conditions: A mixture of 1.8 mmol of
2-aminophenol, 2.0 mmol of acyl chloride in 2.5 mL of
1,4-dioxane (or xylene) was treated with microwave in a
sealed reaction vessel for 15 min at 210°C (or 250°C).
After cooling, the reaction mixture was slowly trans-
ferred to a stirred solution of 1N NaOH (50 mL). The
precipitated product was filtered, washed with water
and dried in vacuo.
1
8. All compounds in Table 1 were fully characterized by H
NMR, mass spec and TLC. Representative examples
NMR data for compounds in Table 1: 2-(4-Bro-
1
mophenyl)benzoxazole (1d) H NMR (CDCl3) l 8.17–8.09
(m, 2H), 7.81–7.30 (m, 1H), 7.72–7.63 (m, 2H), 7.62–7.54
(m, 1H), 7.43–7.32 (m, 2H). 2-(3,4,5-Trimethoxyphenyl)
1
benzoxazole (1h) H NMR (CDCl3) l 7.82–7.72 (m, 1H),
7.64–7.53 (m, 1H), 7.50 (s, 2H), 7.41–7.30 (m, 2H), 3.99 (s,

178
R. S. Pottorf et al. / Tetrahedron Letters 44 (2003) 175–178
1
6H), 3.94 (s, 3H). 6-(1,1-Dimethylpropyl)-2-(4-nitrophenyl)
benzoxazole (1m) H NMR (CDCl3) l 8.46–8.34 (m, 4H),
Biphenyl-4-yl-4-methylbenzoxazole (1ai) H NMR (CDCl3)
l 7.71–7.64 (m, 2H0, 7.54–7.38 (m, 4H), 7.25 (dd, J=8.0,
7.4 Hz, 1H), 7.19–7.12 (m, 1H), 2.70 (s, 3H). 2-(2-Bro-
mophenyl)-5-nitrobenzoxazole (1ap) 1H NMR (CDCl3) l
8.55 (dd, J=2.2, 0.7 Hz, 1H), 8.37 (dd, J=8.8, 2.2 Hz,
1H), 8.16 (dd, J=7.6 2.0 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H),
7.83 (dd, J=7.6, 1.6 Hz, 1H), 7.53 (ddd, J=7.6, 7.6, 1.6
Hz, 1H), 7.44 (ddd, J=7.6, 7.6, 2.0 Hz, 1H).
1
7.79 (dd, J=1.8, 0.7 Hz, 1H), 7.56 (dd, J=8.8, 0.7 Hz,
1H), 7.43 (dd, J=8.8, 1.8 Hz, 1H), 1.72 (q, J=7.4 Hz,
2H), 2.37, (s, 6H), 0.69 (t, J=7.4 Hz, 3H). 2-Thiophen-2-
1
ylnaphtho[2,3-d]oxazole (1ad) H NMR (CDCl3) l 8.15(s,
1H), 8.04–7.90 (m, 4H), 7.63 (dd, J=5.1, 1.1 Hz, 1H),
7.54–7.43 (m, 2H), 7.23 (dd, J=5.1, 3.6 Hz, 1H). 2-