Oxime-mediated facile access to 5-methylisoxazoles and applications in the synthesis of valdecoxib and oxacillin

Article abstract of DOI:10.1021/ol502246t

A palladium-catalyzed efficient synthesis of 5-methylisoxazoles via oxime-mediated functionalization of unactivated olefins is described. The reaction affords a variety of 5-methylisoxazoles in moderate to good yields. To further demonstrate the utility of the method, the rapid synthesis of valdecoxib and oxacillin is reported. (Chemical Equation Presented).

Full text of DOI:10.1021/ol502246t

Letter
pubs.acs.org/OrgLett
Oxime-Mediated Facile Access to 5‑Methylisoxazoles and
Applications in the Synthesis of Valdecoxib and Oxacillin
Kui-Yong Dong,† Hai-Tao Qin,† Xing-Xing Bao,† Feng Liu,*,† and Chen Zhu*,‡,§
†Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences,
Soochow University, 199 Ren-Ai Road, Suzhou, Jiangsu 215123, People’s Republic of China
‡Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, 199 Ren-Ai Road, Suzhou, Jiangsu 215123, People’s Republic of China
§Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed efficient synthesis of 5-
methylisoxazoles via oxime-mediated functionalization of
unactivated olefins is described. The reaction affords a variety
of 5-methylisoxazoles in moderate to good yields. To further
demonstrate the utility of the method, the rapid synthesis of
valdecoxib and oxacillin is reported.
to treat the infections caused by penicillin-resistant Staph-
soxazole motifs are extensively found in natural products,
Isuch as muscimol and ibotenic acid. They also constitute ylococcus aureus.3 Consequently, the divergent synthesis of
1
isoxazoles is of great importance and interest to organic and
medicinal chemists.4 For the sake of the studies in medicinal
chemistry, we need to establish an efficient route to access a
variety of functionalized 5-methylisoxazoles.
We have a long-term interest in the directed functionalization
of unactivated olefins, which provides a potent tool for the
construction of heterocycles.5 We recently reported the
palladium-catalyzed synthesis of tetrahydrofurans via hydrox-
yl-directed oxyarylation of olefins.5a Alcohol therein served as
both the heteroatom source and the directing group for gaining
precise regioselectivity. We consider if a similar strategy of
combining palladium catalysis and a directing group can be
applied to the synthesis of isoxazoles.
the basis for a number of molecules with biological activities. As
a specifically outstanding subunit of isoxazole, 5-methylisox-
azole exists in many marketed drugs. As depicted in Figure 1,
valdecoxib and its prodrug parecoxib are nonsteroidal anti-
inflammatory drugs for the treatment of osteoarthritis,
rheumatoid arthritis, and menstrual symptoms;2 oxacillin,
cloxacillin, flucloxacillin, and dicloxacillin are a group of β-
lactamase-resistant antibiotics which are widely used clinically
Oxime is a versatile building block in organic synthesis.6
Owing to its excellent coordinating ability and the unique
feature of the CN−O moiety, oxime is realized to be an apt
directing group for our hypothesis. Recently, Chen and co-
workers reported the palladium-catalyzed carboetherification of
β,γ-unsaturated oximes to generate isoxazolines;7 Loh and co-
workers developed the palladium-catalyzed oxime-assisted
intramolecular dioxygenation of alkenes.8 Mechanistically, in
both reports the carbopalladium intermediate generated by
oxypalladation uniformly undergoes reductive elimination to
give isoxazoline derivatives (Scheme 1, path A). However, an
alternate pathway is possible: the intermediate undergoes β-
Received: July 30, 2014
Published: September 25, 2014
Figure 1. Marketed drugs based on 5-methylisoxazole.
© 2014 American Chemical Society
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Organic Letters
Letter
Scheme 1. Mechanistic Consideration
hydride elimination, leading to 5-methylisoxazoles after
subsequent isomerization (Scheme 1, path B). Herein, we
report a palladium-catalyzed oxime-directed efficient synthesis
of 5-methylisoxazoles. The utility of the method is demon-
strated in the synthesis of valdecoxib and oxacillin.
At the outset, the reaction parameters were surveyed (Table
1). Organic solvents were first assessed, showing that
a
Table 1. Reaction Parameters Survey
b
c
entry
Pd cat.
oxidant
solvent
time (h)
yield (%)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOAc
CuCl2
toluene
DCE
THF
DMF
DMSO
PhF
2.5
8
38
82
30
34
50
47
82
33
61
79
54
30
38
37
68
2
3
18
1.5
1
4
5
6
4
7
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
3
8
5
9
4
10
11
12
13
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
4
12
12
12
8
BQ
air
d
14
Ag2CO3
Ag2CO3
e
15
16
a
1a (0.15 mmol), oxidant (Ag2CO3 0.22 mmol; AgOAc 0.45 mmol;
CuCl2 0.45 mmol; BQ 0.22 mmol; air balloon) in 5 mL of solvent.
Based on entire conversion. Isolated yield. 5 mol % Pd catalyst. 50
Figure 2. Scope of 5-methylisoxazoles.
b
c
d
e
good yields; the former generally resulted in completion in a
shorter time. The steric hindrance seemed to have little impact
on the reactions. The example of bromide (2i) was noteworthy,
since the surviving bromo atom reserved the options for further
cross-coupling. Polyaryl (2m) and heteroaryl (2n−o) oximes
were compatible with the reaction conditions; the latter
furnished diheteroarenes in useful yields. Not only aryl but
also alkyl substrates were apt (2p−2t). In the examples of 2r
and 2s, the other olefinic unit did not impede the Wacker-type
oxypalladation of the allyl group. Substrate 2t derived from the
natural product Myrtenal also gave a satisfactory yield. The
chemical yield was not compromised when alkyl/aryl
substitution occurred on the allyl group, giving fully function-
alized 5-methylisoxazoles 2u/2v. However, using crotyl oxime
instead of allyl oxime, which was supposed to give 5-
ethylisoxazole, only furnished trace amounts of the expected
°C.
chlorobenzene was the best one in terms of chemical yield
and reaction rate (entries 1−7). Palladium acetate displayed
better catalytic ability than the trifluoroacetate and chloride
salts (entries 8−9). Silver carbonate was more efficient for the
redox cycle compared to other oxidants (entries 10−13).
Reducing either the amount of the catalyst or the reaction
temperature resulted in lower yields (entries 14−15).
With the optimized reaction conditions in hand, we applied it
to a wide range of β,γ-unsaturated oximes. The process readily
provided 5-methylisoxazoles regardless of the electronic
properties of the substituents on arenes (Figure 2). Substrates
with both electron-rich (2b−f) and -deficient (2g−l)
substituents gave the corresponding products in moderate to
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Organic Letters
Letter
product.9 It was reasoned that upon β-H elimination the
external rather than internal olefin was generated that impeded
the subsequent isomerization.
To demonstrate the utility of this method, we applied it in
the synthesis of valdecoxib and oxacillin (Scheme 2). First,
ACKNOWLEDGMENTS
■
F.L. is grateful for the financial support from the National
Natural Science Foundation of China (Grant No. 21302134),
the Natural Science Foundation of Jiangsu (Grant No.
BK20130338), and the Priority Academic Program Develop-
ment of Jiangsu Higher Education Institutions (PAPD). C.Z. is
grateful for the financial support from Soochow University, the
National Natural Science Foundation of China (Grant No.
21402134), the Natural Science Foundation of Jiangsu (Grant
No. BK20140306), the Project of Scientific and Technologic
Infrastructure of Suzhou (SZS201207), and the Priority
Academic Program Development of Jiangsu Higher Education
Institutions (PAPD).
Scheme 2. Synthesis of Valdecoxib and Oxacillin
REFERENCES
■
(1) (a) Bowden, K.; Drysdale, A. C. Tetrahedron Lett. 1965, 6, 727−
728. (b) Oster, T. A.; Harris, T. M. J. Org. Chem. 1983, 48, 4307−
4311. (c) Gagneux, A. R.; Hafliger, F.; Meier, R.; Eugster, C. H.
Tetrahedron Lett. 1965, 6, 2081−2084. (d) Filer, C. N.; Lacy, J. M.;
Peng, C. T. Synth. Commun. 2005, 35, 967−970.
̈
(2) (a) Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.;
Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer,
A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. J. Med. Chem. 2000, 43,
775−777. (b) Talley, J. J.; Bertenshaw, S. R.; Brown, D. L.; Carter, J.
S.; Graneto, M. J.; Kellogg, M. S.; Koboldt, C. M.; Yuan, J.; Zhang, Y.
Y.; Seibert, K. J. Med. Chem. 2000, 43, 1661−1663.
(3) (a) Sidell, S.; Bulger, R. J.; Brodie, J. L.; Kirby, W. M. Clin.
Pharmacol. Ther. 1964, 5, 26−34. (b) Turck, M.; Ronald, A.;
Petersdorf, R. G. JAMA 1965, 192, 961−963. (c) Shaw, R. F.; Riley,
H. D., Jr.; Bracken, E. C. Clin. Pharmacol. Ther. 1965, 6, 492−497.
(d) Micetich, R. G.; Raap, R. J. Med. Chem. 1968, 18, 159−160.
(e) Severin, A.; Tabei, K.; Tenover, F.; Chung, M.; Clarke, N.;
Tomasz, A. J. Biol. Chem. 2004, 279, 3398−3407.
(4) For selected reviews, see: (a) Sutharchanadevi, M.; Murugan, R.
In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C.
W., Scriven, E. F. V., Eds.; Elsevier B.V.: Amsterdam, The Netherlands,
1996; Vol. 3, pp 221−260. (b) Vitale, P.; Scilimati, A. Curr. Org. Chem.
2013, 17, 1986−2000. (c) Heasley, B. Angew. Chem., Int. Ed. 2011, 50,
8474−8477. (d) M.V.D., T.; Melo, P. e. Curr. Org. Chem. 2005, 9,
925−958.
bromination of isoxazole 2a using NBS gave rise to 3, which
was the common precursor for both valdecoxib and oxacillin.
Suzuki coupling of 3 with 4-sulfamoylbenzeneboronic acid
readily furnished valdecoxib in 73% yield. On the other hand,
methoxycarbonylation of 3 led to ester-substituted isoxazole 4
in good yield. After demethylation and the subsequent
treatment with thionyl chloride, 4 was coupled with 6-
aminopenicillanic acid (6-APA) to give oxacillin in an overall
67% yield for three steps. Significantly, both valdecoxib and
oxacillin were synthesized in a few steps starting from 5-
methylisoxazole. It can be anticipated that a series of valdecoxib
and oxacillin analogues can be readily accessed after gaining
various 5-methylisoxazoles from the current method.
In conclusion, we have developed a palladium-catalyzed
synthesis of 5-methylisoxazoles via oxime-directed functional-
ization of unactivated olefins. The reaction affords a variety of
5-methylisoxazoles in moderate to good yields. The value of the
method has been clearly demonstrated in the rapid synthesis of
valdecoxib and oxacillin. The oxime-directed functionalization
of olefins paved the way for a straightforward approach to the
construction of vicinal N,O-containing heterocycles.
(5) (a) Zhu, C.; Falck, J. R. Angew. Chem., Int. Ed. 2011, 50, 6626−
6629. (b) Zhu, C.; Falck, J. R. Org. Lett. 2011, 13, 1214−1217.
(6) For selected examples, see: (a) He, Y.-T.; Li, L.-H.; Yang, Y.-F.;
Wang, Y.-Q.; Luo, J.-Y.; Liu, X.-Y.; Liang, Y.-M. Chem. Commun. 2013,
49, 5687−5689. (b) Tripathi, C. B.; Mukherjee, S. Angew. Chem., Int.
Ed. 2013, 52, 8450−8453. (c) Han, B.; Yang, X.-L.; Fang, R.; Yu, W.;
Wang, C.; Duan, X.-Y.; Liu, S. Angew. Chem., Int. Ed. 2012, 51, 8816−
8820. (d) Mosher, M. D.; Norman, A. L.; Shurrush, K. A. Tetrahedron
Lett. 2009, 50, 5647−5648. (e) Norman, A. L.; Mosher, M. D.
Tetrahedron Lett. 2008, 49, 4153−4155. (f) Li, W.; Jia, P.; Han, B.; Li,
D.; Yu, W. Tetrahedron 2013, 69, 3274−3280.
(7) Jiang, D.; Peng, J.; Chen, Y. Org. Lett. 2008, 10, 1695−1698.
(8) Zhu, M.-K.; Zhao, J.-F.; Loh, T.-P. J. Am. Chem. Soc. 2010, 132,
6284−6285.
ASSOCIATED CONTENT
* Supporting Information
■
(9) See Supporting Information.
S
Detailed experimental procedures, characterizations, and copies
of 1H and 13C NMR spectra of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chzhu@suda.edu.cn.
*E-mail: fliu2@suda.edu.cn.
Notes
The authors declare no competing financial interest.
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