A divergent and selective synthesis of isomeric benzoxazoles from a single N-Cl imine

Article abstract of DOI:10.1021/ol202844c

A divergent and regioselective synthesis of either 3-substituted benzisoxazoles or 2-substituted benzoxazoles from readily accessible ortho-hydroxyaryl N-H ketimines is described. The reaction proceeds in two distinct pathways through a common N-Cl imine intermediate: (a) N-O bond formation to form benzisoxazole under anhydrous conditions and (b) NaOCl mediated Beckmann-type rearrangement to form benzoxazole, respectively. The reaction path also depends on the electronic nature of the aromatic ring, with the electron-rich aromatic rings favoring the rearrangement and the electron-deficient rings favoring the N-O bond formation. A Beckmann-type rearrangement mechanism via net [1,2]-aryl migration for the formation of 2-substituted benzoxazole is proposed.

Full text of DOI:10.1021/ol202844c

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6300–6303
A Divergent and Selective Synthesis
of Isomeric Benzoxazoles from a
Single NꢀCl Imine
Cheng-yi Chen,* Teresa Andreani, and Hongmei Li
Process Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway,
New Jersey 07065, United States
cheng_chen@merck.com
Received October 21, 2011
ABSTRACT
A divergent and regioselective synthesis of either 3-substituted benzisoxazoles or 2-substituted benzoxazoles from readily accessible ortho-
hydroxyaryl NꢀH ketimines is described. The reaction proceeds in two distinct pathways through a common NꢀCl imine intermediate: (a) NꢀO
bond formation to form benzisoxazole under anhydrous conditions and (b) NaOCl mediated Beckmann-type rearrangement to form benzoxazole,
respectively. The reaction path also depends on the electronic nature of the aromatic ring, with the electron-rich aromatic rings favoring the
rearrangement and the electron-deficient rings favoring the NꢀO bond formation. A Beckmann-type rearrangement mechanism via net [1,2]-aryl
migration for the formation of 2-substituted benzoxazole is proposed.
The isomeric benzisoxazole and benzoxazole hetero-
cycles are ubiquitous in the realms of pharmacologically
active agents and natural products (Figure 1). For exam-
ple, benzisoxazole serves as a starting material for the
synthesis of more elaborate structures with bioactive proper-
ties. Three important pharmaceutical drugs (the antipsycho-
tic risperidone1 and its hydroxyl analogue, paliperidone,2
and the anticonvulsant zonisamide) were discovered based
on the benzisoxazole core.3 Benoxaprofen and flunoxapro-
fen, both containing benzoxazole cores, are chiral nonsteroi-
dal anti-inflammatory drugs once approved for improving
the symptoms of osteoarthritis and rheumatoid arthritis.4
Additionally, the benzoxazole ring occurs in a number of
natural products such as salvianen and its regioisomer,
pseudosalvianen.5 Given the importance of this class of
heterocycles, the pursuit of a general and efficient synthesis
of both benzisoxazole and benzoxazole that controls the
formation of heterocycles in a regioselective fashion is of
great importance. Many existing approaches to either
benzisoxazole6 or benzoxazole7 have been reported. The
efficient synthesis of either benzisoxazoles or benzoxazoles
from the same substrate, however, remains elusive and
would have great advantages over existing protocols. Here-
in, we report a divergent and regioselective synthesis of either
(1) Risperidone was approved by the United States Food and Drug
Administration (FDA) in 1993 for the treatment of schizophrenia. For
reviews on risperidone, see: (a) Swainston, H. T.; Goa, K. L. CNS Drugs
2004, 18, 113. (b) Deeks, E. D. Drugs 2010, 70, 1001 and references cited
therein.
(2) Paliperidone was commercialized recently as an improved drug
compared to its parent, risperidone; see: (a) Yang, L. P. H.; Plosker,
G. L. CNS Drugs 2007, 21, 417. (b) Ivo, C. L.; Joris, B. In Bipolar
Psychopharmacotherapy: Caring for the Patient, 2nd ed.; Akiskal, H.,
Mauricio, T., Eds.; Wiley: 2011, p 153.
(3) Zonisamide, widely prescribed as an antiepileptic drug, was
developed by Dianippon of Japan. For reviews on zonisamide in the
treatment of epilepsy, see: (a) Andreas, S.-B. Expert Opin. Pharmaco.
2010, 11, 115. (b) Wroe, S. J. Zonisamide. Treatment of Epilepsy, 3rd ed.;
Wiley: 2009; p 713.
(4) (a) Dunwell, D. W.; Evans, D. J. Med. Chem. 1977, 20, 791.
(b) Hopkins, S. J. Drugs Today 1980, 16, 281. (c) Dong, J. Q.; Liu, J.;
Smith, P. C. Biochem. Pharmacol. 2005, 70, 937.
(5) (a) Don, M.-J.; Shen, C.-C.; Lin, Y.-L.; Syu, W., Jr.; Ding, Y.-H.;
Sun, C.-M. J. Nat. Prod. 2005, 68, 1066. (b) Viirre, R. D.; Evindar, G.;
Batey, R. A. J. Org. Chem. 2008, 73, 3452.
(6) For recent reviews of the synthesis of benzisoxazoles, see:
(a) Hartinger, S. Sci. Syn., Knowl. Upd. 2010, 1, 133. (b) Smalley,
R. K. Sci. Syn., Schaumann, E., Ed.; Thieme: Stuttgart, 2002, 11, 289.
(7) For recent reviews of the synthesis of benzoxazoles, see:
€
€
(a) Schnurch, M.; Hammerle, J.; Stanetty, P. Sci. Syn., Knowl. Upd.
2010, 1, 153. (b) Boyd, G. V. Sci. Syn. 2002, 11, 481.
r
10.1021/ol202844c
Published on Web 11/08/2011
2011 American Chemical Society

benzisoxazoles or benzoxazoles from a single, readily acces-
sible substrate, ortho-hydroxyaryl NꢀH ketimines.
(Table 1, entries 2ꢀ9). Furthermore, it was not necessary
to form the NꢀCl imine first prior to the introduction of
the base. The activation and ring closure can be run in one
pot by mixing an NꢀH ketimine, base, and NCS in a
solvent at ambient temperature. Alternative chlorinating
agents such as tert-BuOCl and trichloroisocyanic acid were
less effective than NCS, generating a messy reaction profile.
Table 1. Survey on the Basesa
Figure 1. Benzisoxazoles and benzoxazoles as medicinal agents
and natural products.
entry
base
solvent
CH2Cl2
2b
3b
4b
The ortho-hydroxyaryl NꢀH ketimines readily prepared
from the ortho-hydroxyaryl ketones have surprisingly
found limited application in organic synthesis.8 These
unsubstituted imines are stable species largely due to a
strong intramolecular H-bond between the OH and imino
nitrogen. In an effort to explore the utilization of these
ketimines in the synthesis of heterocycles, we envisioned
that an activation of the imino nitrogen followed by
intramolecular NꢀO bond formation would lead to effec-
tiveconstruction ofbenzisoxazolerings. Weweredelighted
to find that this conceptually simple approach worked well
when NꢀH ketimine 1 was treated with NCS in the
presence of DABCO to afford benzisoxazole 3 in 89%
yield (Table 1, entry 1). We subsequently found that
treatment of NꢀH ketimines in various organic solvents
with 10% aqueous NaOCl led to smooth formation of
benzoxazoles (Figure 3, vide infra). This preliminary lead
prompted us to develop a versatile method for direct access
to both isomeric heterocycles, benzisoxazole, and benzox-
azole, under different reaction conditions.
We further explored the generality of the controlled
synthesis of 3-substituted benzisoxazoles by using NCS
as a chlorinating agent to activate NꢀH ketimine. Treat-
ment of NꢀH ketimine with NCS in several solvents
afforded a new species NꢀCl imine (2).9 The NꢀCl imine
was not isolated, but rather it was treated with bases to
facilitate the NꢀO bond formation. As shown in Table 1, a
brief survey of bases for effective NꢀO formation indicates
that an inexpensive inorganic base such as K2CO3 is
superior to others, though potassium tert-butoxide and
DABCO also gave satisfactory results for this substrate.
Other bases were ineffective for the NꢀO bond formation
1
DABCO
Et3N
0
92
38
0
8
10
0
2
CH3CN
CH2Cl2
CH3CN
CH3CN
CH2Cl2
CH3CN
THFꢀH2Oc
THF
52
100
45
35
45
52
30
61
0
3
pyridine
i-PrNEt2
DBU
4
39
48
42
28
50
32
93
94
16
17
13
20
20
7
5
6
DBU
7
DIPA
8
K2CO3
NaOAc
K2CO3
KOt-Bu
9
10
11
THF
7
THF
0
6
a NꢀH ketimine (0.50 mmol), NCS (0.75 mol), and base (1.0 mmol)
were mixed in solvent (1.0 mL) at room temperature for 12 h. b Regioi-
someric ratio was determined by reverse HPLC and reported as area
percentage. c THF/H2O = 1:1.
A variety of ortho-hydroxyaryl NꢀH ketimines were
subjected to the previously identified conditions (Table 1,
entry 10) for the NꢀO bond formation. As shown in
Figure 2, the reaction is quite general for various substrates
(ketimines 5aꢀo). A wide variety of 3-substituted benzi-
soxazoles (6aꢀo) were readily prepared in good to excel-
lent yields (76ꢀ99% yield) under these milder conditions.
The NꢀO bond formation is independent of the substitu-
ents (R) attached to the hydroxy aromatic ketone, as
substrates with R = Me, Et, PhCH2CH2, and aryl all gave
benzisoxazoles. Moreover, it was noted that the NꢀO
bond formation of the substrates bearing electron-deficient
groups was extremely facile compared to the others as
shown in examples 6j and 6k; both were formed quantita-
tively. The NꢀO bond formation can be readily applied to
the preparation of 3-aryl benzisoxazoles 6lꢀn in good
yields and 3-(40-pyridinyl)-benzisoxazole(6o) in97%yield.
Having successfully prepared a range of 3-substituted
benzoisoxazoles 6aꢀo from ortho-hydroxyaryl NꢀH keti-
mines 5aꢀo employing NCS as an activating agent, we
next decided to explore the NaOCl mediated rearrange-
ment of ketimines for the preparation of 2-substituted
benzoxazoles. Delightfully, this reaction is also general as
a wide array of 2-substituted benzoxazoles can be readily
(8) (a) Korotaev, V. Y.; Sosnovskikh, V. Y.; Kutyashev, I. B.;
Barkov, A. Y.; Matochkina, E. G.; Kodess, M. Tetrahedron 2008, 64,
5055. (b) Enantioselective reduction of ortho-hydroxyaryl alkyl N-H
ketimines was reported; see: Nguyen, T. B.; Bousserouel, H.; Wang, Q.;
ꢀ
Gueritte, F. Org. Lett. 2010, 12, 4705. (c) Crecente-Campo, J.; Pilar
Vazquez-Tato, M.; Seijas, J. A. Eur. J. Org. Chem. 2010, 21, 4130.
(9) The structure elucidation of NꢀCl imine 2 was carried out
by NMR spectroscopic techniques. For details, see Supporting
Information.
Org. Lett., Vol. 13, No. 23, 2011
6301

prepared in quantitative yields from the corresponding
electronic-rich aromatic NꢀH ketimines. Treatment of
ketimine 7j (X = 4-F) with NaOCl afforded benzoxazole
8j in 88% yield. Finally, a new heterocycle, quinoline fused
oxazole 8k, was obtained uneventfully in 91% yield.
Figure 2. Synthesis of 3-substituted benzoisoxazole 6 from
ortho-hydroxyaryl NꢀH ketimines. All the reactions were car-
ried out in THF at ambient temperature for 12 h employing
1.0 equiv of ortho-hydroxyaryl NꢀH ketimine, 1.5 equiv of
NCS, and 2 equiv of K2CO3. Yields refer to isolated material
based on ketimines 5. For 6g, MeꢀTHF was used and the yield
was based on NMR spectra. For 6m, the regiosiomer, 2-phenyl
benzoxazole, was isolated in 19% yield.
Figure 3. Synthesis of 2-substituted benzoxazole 8 from ortho-
hydroxyaryl NꢀH ketimines. All the reactions were carried out
in IPA at ambient temperature for 10ꢀ30 min employing 1.0
equiv of ortho-hydroxyaryl NꢀH ketimines and 3.0 equiv of
10% aq NaOCl. Yields refer to isolated material based on NꢀH
ketimines 5 and 7. Benzisoxazole regioisomers of 8d, 8e, and 8f
were obtained in 19%, 12%, and 11% yield, respectively.
prepared from the ortho-hydroxyaryl ketimines as sum-
marized in Figure 3. The same substrates used in the NCS-
mediated NꢀO bond formation (Figure 2, 6aꢀg) were
subjected to the NaOCl-mediated rearrangement, afford-
ing products 8aꢀg in good to excellent yields. Experimen-
tally, the NaOCl-mediated rearrangement of NꢀH
ketimine to benzoxazole was carried out by adding 3 equiv
of 10% aqueous NaOCl to NꢀH ketimine in IPA at
ambient temperature. The reaction is almost instantaneous
as indicated by the fading of the yellow color of NꢀH
ketimine in IPA upon addition of the NaOCl. The simplicity
and high efficiency of this protocol render it attractive when
compared to the others reported in the literature.7 Further
examination of a few more substrates (5j, 5k, 5l, and 5o)
revealed that substrates bearing electron-donating groups in
the hydroxy aromatic ring are more prone to the rearrange-
ment whereas those with electron-withdrawing groups
failed. For example, NꢀH ketimines 5j (X = NO2) and
5k (X = dichloro) afforded benzisoxazole (6j and 6k)
quantitatively upon treatment with NaOCl. Ketimines bear-
ing aromatic substituents (R = Ar, 5l, 5o) formed corre-
sponding benzisoxazoles in good yields, rather than their
regioisomers, benzoxazoles, upon treatment with NaOCl.
On the other hand, benzoxazoles (8h and 8i) can be readily
We propose that the formation of benzoxazole pro-
ceeds with a Beckmann-type rearrangement10 via a spiro
enone intermediate (12, Scheme 1).11 The generation of a
phenoxide intermediate (10) using NaOCl and an electron-
rich aromatic ring appears to facilitate the rearrangement.
We speculate that the hydrogen bond to the phenoxide in
aqueous media weakens the nucleophilicity of the phen-
oxides, and hence the species favors the rearrangement via
net [1,2]-aryl migration instead of the NꢀO bond
formation.12,13 It should be noted that the conventional
Beckmann rearrangement generally proceeds under
strongly acidic and dehydrating media at high reaction
temperature.14 The current anionic protocol for the ben-
zoxazole formation, however, is a very mild yet rapid
process run at ambient temperature.
(10) For reviews on Beckmann rearrangement, see: (a) Gawley, R. E.
Org. React. 1988, 35, 1 and references cited therein. (b) Smith, M. B.;
March, J. Advanced Organic Chemistry, 5th ed.; John Wiley & Sons: New
York, 2001; p 1415 and references cited therein.
(11) A spiro enone intermediate was proposed in the pyrolysis of
3-phenyl benzisoxazole to 2-phenyl benzoxazole; see: (a) Aldous, G. L.;
Bowie, J. H.; Thompson, M. J. J. Chem. Soc., Perkin Trans. 1 1976, 16.
(b) Davies, K.; Storr, R. C.; Whittle, P. J. J. Chem. Soc., Chem. Commun.
1978, 9.
6302
Org. Lett., Vol. 13, No. 23, 2011

of either 3-substituted benzisoxazoles or 2-substituted
benzoxazoles from a single ortho-hydroxyaryl NꢀH keti-
mine starting material. The reaction proceeds via a facile
NꢀO bond formation from an NꢀCl imine intermediate
to form benzisoxazoles under anhydrous conditions. The
reaction mediated by NaOCl, on the other hand, likely
goes through an alkoxide intermediate via net [1,2]-aryl
rearrangement to form the corresponding 2-substituted
benzoxazoles. The methods demonstrated here allow easy
access to a wide array of two isomeric heterocycles tolerant
of various substitution patterns. They provide rapid access
to a variety of structurally useful benzoxazoles and, hence,
could serve as a versatile tool for the modular synthesis of
benzoxazole containing medicinal agents. We also hope
this work will prompt others to explore application of
ortho-hydroxyaryl NꢀH ketimines in organic synthesis.
Scheme 1. Proposed Rearrangement Mechanism via
Net [1,2]-Aryl Migration for the Formation of Benzoxazole
In summary, we have discovered and developed a ver-
satile method for the divergent and regioselective synthesis
(12) For our work on the syntheses of benzofuran and indole via net
[1,2]-aryl migration, see: (a) Pei, T.; Chen, C.-y.; Dimichele, L.; Davies,
I. W. Org. Lett. 2010, 12, 4972. (b) Pei, T.; Tellers, D. M.; Streckfuss,
E. C.; Chen, C.-y.; Davies, I. W. Tetrahedron 2009, 65, 3285. (c) Pei, T.;
Chen, C.-y.; Dormer, P. G.; Davies, I. W. Angew. Chem., Int. Ed. 2008,
47, 4231.
(13) Formation of amides via the migration of the R group was not
observed for all the runs in Figure 3. Furthermore, we proved that the
formation of benzoxazole 4 was not derived from the initially formed
benzisoxazole 3 as 3 remains intact upon treatment with 10% NaOCl.
(14) For selected examples on the syntheses of benzoxazoles from
ortho-hydroxylaryl oximes via Beckmann rearrangement at elevated
temperature, see: (a) Gadakh, A. V.; Pandit, C.; Rindhe, S. S.; Karale,
B.; K. Bioorg. Med. Chem. Lett. 2010, 20, 5572. (b) Sardarian, A. R.;
Shahsavari-Fard, Z. Synlett 2008, 9, 1391.
Acknowledgment. The authors would like to thank
our colleagues at Merck Research Laboratories, NJ, USA,
Dr. Charles W. Ross for the HRMS work as well as Dr.
Robert T. Williamson and Lisa Dimichele for the structural
elucidation work using NMR.
Supporting Information Available. Experimental pro-
cedure, spectroscopic and analytical data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 23, 2011
6303