Synthesis of benzoxazolones from nitroarenes or aryl halides

Article abstract of DOI:10.1021/ol902885j

Chemical equation presented A simple and effective method for the preparation of benzoxazolones from nitroarenes or aryl halides is described. Partial reduction of a nitro group in the presence of a chloroformate followed by a microwave-assisted rearrangement/ring closure sequence provides a convenient and practical procedure to prepare this important pharmacophore. Rearrangement precursors were also accessed from aryl halides through transitionmetal-catalyzed coupling.

Full text of DOI:10.1021/ol902885j

ORGANIC
LETTERS
2010
Vol. 12, No. 4
812-815
Synthesis of Benzoxazolones from
Nitroarenes or Aryl Halides
Achim Porzelle,† Michael D. Woodrow,‡ and Nicholas C. O. Tomkinson*,†
School of Chemistry, Main Building, Cardiff UniVersity, Park Place, Cardiff,
CF10 3AT, U.K., and ImmunoInflammation Centre of Excellence for Drug DiscoVery,
GlaxoSmithKline Medicines Research Centre, SteVenage, Hertfordshire,
SG1 2NY, U.K.
tomkinsonnc@cardiff.ac.uk
Received December 15, 2009
ABSTRACT
A simple and effective method for the preparation of benzoxazolones from nitroarenes or aryl halides is described. Partial reduction of a nitro
group in the presence of a chloroformate followed by a microwave-assisted rearrangement/ring closure sequence provides a convenient and
practical procedure to prepare this important pharmacophore. Rearrangement precursors were also accessed from aryl halides through transition-
metal-catalyzed coupling.
The benzoxazolone nucleus represents an important phar-
macophore present in both pharmaceutical and agrochemical
products.1 Due to the ability of the benzoxazolone core to
act as a metabolically stable mimic of phenol, catechol,
coumarin, and phenylurethane groups, compounds possessing
this structure have a broad spectrum of biological activities.
For example, the analgesic Paraflex (1),2 the insecticide and
acaricide Phosalone (2),3 and the OP2 agonist 34 all possess
a benzoxazolone scaffold (Figure 1).
Methods for the preparation of benzoxazolones generally
involve reaction of a 2-aminophenol (e.g., 5) with a phosgene
† Cardiff University.
‡ GlaxoSmithKline, Stevenage.
Figure 1. Drug molecules containing a benzoxazolone.
(1) Poupaert, J.; Carato, P.; Colacino, E.; Yous, S. Curr. Med. Chem.
2005, 12, 877.
(2) Conney, A. H.; Burns, J. J. J. Pharmacol. Exp. Ther. 1960, 128,
340.
equivalent. Methods for this transformation are well devel-
oped.5 Therefore, the challenge in their preparation resides
in the synthesis of the 2-aminophenol. Synthetic routes to
2-aminophenols are often plagued by multistep, nonselective
transformations, and the scaffold is generally purchased
(3) (a) Venugopal, V.; Naidu, V. G.; Prasad, P. R. Pestology 2003, 27,
29. (b) Ahmad, R.; Kookana, R. S.; Alston, A. M.; Skjemstad, J. O. EnViron.
Sci. Technol. 2001, 35, 878. (c) Sanusi, A.; Millet, M.; Mirabel, P.;
Wortham, H. Sci. Total EnViron. 2000, 263, 263.
(4) Barber, A.; Bender, H. M.; Gottschlich, R.; Greiner, H. E.; Harting,
J.; Mauler, F.; Seyfried, C. A. Methods Find. Exp. Clin. Pharmacol. 1999,
21, 105.
10.1021/ol902885j  2010 American Chemical Society
Published on Web 01/21/2010

rather than constructed.6 This significantly restricts the
diversity accessible when introducing this group in medicinal
chemistry.
Preparation of the rearrangement substrates used in reac-
tion development involved partial reduction of nitroarenes
in the presence of chloroformates, trapping out the interme-
diate hydroxylamine (Scheme 1).9 The reactions were
A convenient and controlled strategy to access the 2-ami-
nophenol architecture is by [3,3]-sigmatropic rearrangement
of O-acyl-N-aryl hydroxylamines 6 (R2 ) aryl).7 If the
O-substituent on this rearrangement precursor included a
leaving group (e.g., R2 ) OMe), it could be possible to access
benzoxazolones directly by intramolecular cyclization after
rearrangement. Although the rearrangement of N-aryl-O-acyl
hydroxylamines has been well studied,7 only a single
example of the rearrangement of an O-carbonate has been
described.8 This showed that rearrangement of 7 in refluxing
xylene gave the protected 2-aminophenol 8 (65%) (Figure
2) where it was suggested this class of substrate should be
Scheme 1. Preparation of Protected N-Aryl Hydroxylamines
generally efficient (68-94% yield) allowing access to a range
of stable rearrangement precursors 7 and 9-19 that were
used throughout this study.
In the development of the thermal rearrangement of these
hydroxylamines (9-19), we modified the conditions previ-
ously reported for the rearrangement of 7 (Table 1).8
Figure 2. Synthetic strategy for accessing benzoxazolones.
avoided due to sluggish reactivity and reduced yields. Due
to the potential of the product from this rearrangement (7f8)
in heterocycle synthesis, we sought to investigate this
transformation further. Within this paper we describe a
simple synthetic method to access benzoxazolones from
nitroarenes or aryl halides through a rearrangement/cycliza-
tion strategy.
Table 1. Thermal Rearrangement of N-Aryl Hydroxylaminesa
(5) These methods include the use of dimethyl carbonate: Fu, Y.; Baba,
T.; Ono, Y. J. Catal. 2001, 197, 91. Carbonyl diimidazole: Nachman, R. J.
J. Heterocycl. Chem. 1982, 19, 1545. Urea: (a) Li, F.; Xia, C. Tetrahedron
Lett. 2007, 48, 4845. (b) Bhanage, B. M.; Fujita, S.-I.; Ikushima, Y.; Arai,
M. Green Chem. 2004, 6, 78. (c) Kim, Y. J.; Varma, R. S. Tetrahedron
Lett. 2004, 45, 7205. Carbon Monoxide: (aa) Li, F.; Xia, C. J. Catal. 2004,
227, 542. (bb) Gabriele, B.; Mancuso, R.; Salerno, G.; Costa, M. J. Org.
Chem. 2003, 68, 601. Chloroformadinium salts: El-Faham, A.; Chebbo,
M.; Abdul-Ghani, M.; Younes, G. J. Herocycl. Chem. 2006, 43, 599.
(6) For selected examples of the synthesis of 2-aminophenols and their
derivatives see: (a) Koley, D.; Colo´n, O. C.; Savinov, S. N. Org. Lett. 2009,
11, 4172. (b) Palmisano, G.; Addamo, M.; Augugliaro, V.; Caronna, T.;
Garc´ıa-Lo´pez, E.; Loddo, V.; Palmisano, L. Chem. Commun. 2006, 1012.
(c) Selvam, J. J. P.; Rajesh, S. K.; Reddy, S. R.; Venkateswarlu, Y.
Tetrahedron Lett. 2006, 47, 2507. (d) Khenkin, A. M.; Weiner, L.; Neumann,
R. J. Am. Chem. Soc. 2005, 127, 9988. (e) Sun, H.-B.; Hua, R.; Yin, Y. J.
Org. Chem. 2005, 70, 9071. (f) Kikugawa, Y.; Tsuji, C.; Miyazawa, E.;
Sakamoto, T. Tetrahedron Lett. 2001, 42, 2337, and references therein.
(7) For selected examples on this class of rearrangement, see: (a) Horner,
L.; Steppan, H. Liebigs Ann. Chem. 1957, 606, 24. (b) Oae, S.; Sakurai,
T.; Kimura, H.; Kozuka, S. Chem. Lett. 1974, 671. (c) Oae, S.; Sakurai, T.
Tetrahedron 1976, 32, 2289. (d) Gutschke, D.; Heesing, A.; Heuschkel, U.
Tetrahedron Lett. 1979, 20, 1363. (e) Bassoli, A.; Di Gregorio, G.; Galliani,
G.; Riboldi, M.; Rindone, B.; Tollari, S.; Chioccara, F. Bull. Chem. Soc.
Fr. 1988, 293.
entry
substrate
R1
R2
product
% yieldb
1
2
3
4
5
9
10
11
12
13
Me
Me
Me
Me
Bn
4-Me
3-Me
4-Br
4-I
20
21
22
23
24
88
75c
76
72
83
4-Me
a All reactions conducted on a 1 mmol scale in 5 mL of p-xylene.
b Isolated yield. c Product isolated as a 1:1 mixture of regioisomers.
p-Xylene emerged as the optimal solvent, performing the
reactions at higher concentration providing consistently
higher yields than that previously reported. Reactions were
amenable to scale-up and allowed convenient access to a
series of protected 2-aminophenols 20-24 (entries 1-5;
72-88%).
(8) Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Eur. J. Org.
Chem. 2008, 5135.
(9) Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Synlett 2009,
798.
Org. Lett., Vol. 12, No. 4, 2010
813

To improve the transformation further, we examined
the effect of microwave heating on rearrangement (Table
2). Heating at high temperatures (>170 °C) resulted in
(R1 ) Me, R2 ) 4-Me) under microwave irradiation at
temperatures between 150 and 200 °C in an attempt to bring
about cyclization. The desired cyclization (to give 32)
occurred at temperatures in excess of 160 °C. Unfortunately,
at these temperatures 9 partially decomposed prior to
rearrangement. We therefore developed a two-stage process
to access the target heterocycle from the rearrangement
precursor (Table 3). Heating a solution of 9 in toluene (0.33
Table 2. Microwave-Assisted Rearrangement of N-Aryl
Hydroxylaminesa
Table 3. Microwave-Assisted Benzoxazolone Synthesisa
entry
substrate
R1
R2
product
% yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Me
Me
Me
Me
Bn
Me
Me
Me
Me
Me
Bn
4-Me
3-Me
4-Br
4-I
4-Me
3-CF3
4-CCH
4-Cl
3-Ph
3-Br
H
20
21
22
23
24
25
26
27
28
29
30
88
75c
89
72
entry substrate R1
R2
t1 (°C) t2 (°C) product % yieldb
90d
0e
1
2
3
4
5
6
7
8
7
9
Me
H
150
150
150
150
160
160
160
185
185
185
160
185
185
31
32
33
34
35
36
37
38
82
86
82
87
85
75c
81
76
82
91
Me 4-Me
Me 4-Br
Me 4-I
Bn 4-Me
Me 4-CCH 140
11
12
13
15
16
19
9
10
11
67c
76c
94d
a All reactions conducted on 0.5 mmol scale in 1.5 mL of toluene at
150 °C for 3 h. b Isolated yield. c Product isolated as a 1:1 mixture of
regioisomers. d Reaction conducted at 160 °C for 3 h. e Reaction conducted
up to 185 °C.
Me 4-Cl
Bn
150
160
H
a All reactions conducted on a 0.5 mmol scale in 1.5 mL of toluene at
t1 for 4 h then t2 for 3 h. b Isolated yield. c Carbonate group removed during
cyclization.
partial decomposition of the protected N-aryl hydroxy-
lamine substrate (e.g., 9) prior to rearrangement. However,
reducing the temperature to 150 °C smoothly brought
about rearrangement of 9 (entry 1; 88%). Application of
this protocol to a series of precursors consistently gave
the products in equal or higher yield than conductive
heating (entries 1-5; 72-90%). Benzyl carbonates re-
quired slightly higher temperatures (160 °C) for the
reaction to reach completion inside 3 h (entry 5, 90%;
entry 11, 94%). This method offers distinct advantages
over conductive heating including: the use of toluene as
solvent provides practical advantages over p-xylene in
isolation and purification; in addition, the reactions were
significantly quicker under microwave irradiation (3 vs
24 h). A limitation came from the attempted rearrangement
of electron-deficient substrates. Heating a toluene solution
of precursor 14 at 150 °C (up to 8 h) led to recovery of
starting material (>80%). Attempts to induce rearrange-
ment by heating at higher temperatures (up to 185 °C)
were equally unsuccessful (entry 6). At these elevated
temperatures, cleavage of the hydroxylamine bond oc-
curred prior to rearrangement. This electronic restriction
to rearrangement is consistent with the findings of others7,8
and provides an interesting opportunity for further investiga-
tion.
M) at 150 °C for 4 h followed by heating at 165 °C for 3 h
led to the benoxazolone 32 in a pleasing 86% isolated yield
(entry 2). Use of a similar two-stage protocol proved effective
for a series of substrates (entries 1-8) providing access to
benzoxazolones 31-38 in high chemical yield (75-87%)
in a simple and convenient manner. Reaction of the hy-
droxylamine 12 (entry 4; 87%) proceeded more efficiently
in this two-step protocol than observed in Table 2 (entry 4;
72%) due to incomplete rearrangement of 12 after 3 h at
150 °C.
To further develop the potential of the overall transforma-
tion, we examined the conversion of nitroarenes to the
corresponding benzoxazolones without purification of the
intermediate protected N-aryl hydroxylamine. This involved
partial reduction of nitrobenzene or 4-nitrotoluene with zinc
in the presence of methylchloroformate followed by aqueous
workup and heating of the crude product in toluene (150
°C, 4 h, then 160 °C, 3 h). On cooling, the benzoxazolones
31 (65%) and 32 (75%) crystallized directly from the reaction
mixture and could be isolated by filtration (see Supporting
Information for full details). The simplicity of this procedure
and number of commercially available nitroarenes suggest
the method should prove amenable to the preparation of
arrays of benzoxazolones in high chemical purity.
In each of the transformations above (Table 2), no
indication of a benzoxazolone was observed by 400 MHz
1H NMR spectroscopy of the crude reaction mixture in
CDCl3. We therefore heated the rearrangement product 20
An alternative and equally convenient method for the
preparation of the rearrangement precursors involves either
palladium10 or copper11 catalyzed coupling of protected
hydroxylamines with aryl halides. To expand the number
814
Org. Lett., Vol. 12, No. 4, 2010

of commercially available building blocks that could be
used within this chemistry, we prepared the rearrangement
precursors 39-41 (see Supporting Information for full
details). Within these substrates, the Boc protecting group
was incorporated to further expand the scope of this
transformation. Microwave irradiation of the phenyl
carbonates 39-41 in toluene at 150 °C for 4 h provided
two important alternatives to the overall synthetic proce-
dure (Scheme 2). First, incorporation of a better leaving
prepared by either partial reduction of nitroarenes in the
presence of a chloroformate or from a palladium-catalyzed
coupling of protected hydroxylamines. Heating these
products in xylene for 24 h leads to protected 2-amino
phenols. Using microwave irradiation, the rearrangement
proceeds more efficiently providing the products in good
chemical yield. Further heating of the rearranged products
provides access to the benzoxazolone nucleus. The overall
reaction sequence can be carried out without purification
of intermediates and the products purified by simple
filtration. The importance of the benzoxazolone pharma-
cophore together with the robust nature of the synthetic
chemistry described suggest this overall strategy will have
broad applicability in the preparation of biologically
significant molecules based around this central core.
Scheme 2. Rearrangement/Cyclization/Deprotection Sequence
Acknowledgment. The authors thank the EPSRC and
GlaxoSmithKline for financial support and the Mass Spec-
trometry Service, Swansea, for high-resolution spectra.
Supporting Information Available: Analytical data,
experimental procedures, and NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
group on the carbonate meant that intramolecular cycliza-
tion occurred at this lower reaction temperature negating
the need for a two-stage rearrangement/cyclization process
(cf. Table 3). Second, the Boc protecting group was
removed thermally12 under the reaction conditions provid-
ing an advanced building block for further manipulation.13
In summary, we have developed an efficient procedure
for the preparation of benzoxazolones from nitroarenes
or aryl halides. The substrates for rearrangement are easily
OL902885J
(10) Porzelle, A.; Woodrow, M. D.; Tomkinson, N. C. O. Org. Lett.
2009, 11, 233.
(11) Jones, K. L.; Porzelle, A.; Hall, A.; Woodrow, M. D.; Tomkinson,
N. C. O. Org. Lett. 2008, 10, 797.
(12) Rawal, V. H.; Jones, R. J.; Cava, M. P. J. Org. Chem. 1987, 52,
19.
(13) We believe cyclization occurs prior to Boc removal. See:
Dandepally, S. R.; Williams, A. L. Tetrahedron Lett. 2009, 50, 1071.
Org. Lett., Vol. 12, No. 4, 2010
815