Selective reduction exocyclic double bond of isoxazolones and pyrazolones by hantzsch 1,4-dihydropyridine

Article abstract of DOI:10.1055/s-2005-869860

Hantzsch 1,4-dihydropyridine (HEH) was used to realize the selective reduction of the exocyclic double bond of 4-arylmethylene- and 4-alkylidene-4H-isoxazol-5-ones and 4-arylraethylene-4H-pyrazol-5-ones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869860

LETTER
1579
Selective Reduction of the Exocyclic Double Bond of Isoxazolones and
Pyrazolones by Hantzsch 1,4-Dihydropyridine
S
elective Reduc
h
tion by
H
an
e
tzsc
h
E
sterngang Liu, Bing Han, Qiang Liu, Wei Zhang, Li Yang, Zhong-Li Liu, Wei Yu*
National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, P. R. China
Fax +86(931)8625657; E-mail: yuwei@lzu.edu.cn
Received 29 March 2005
Table 1 Reduction of the 4H-Isoxazol-5-ones (1) by HEH
Abstract: Hantzsch 1,4-dihydropyridine (HEH) was used to realize
the selective reduction of the exocyclic double bond of 4-arylmeth-
ylene- and 4-alkylidene-4H-isoxazol-5-ones and 4-arylmethylene-
4H-pyrazol-5-ones.
Substrate R1
R2
R3
Product Yield (%)a
1a
1b
1c
1d
1e
1f
CH3
H
Ph
2a
2b
2c
2d
2e
2f
94
93
95
93
94
93
96
98
92
95
90
94
Key words: Hantzsch 1,4-dihydropyridine, reduction, isoxazol-5-
one, pyrazol-5-one
CH3
CH3
CH3
CH3
CH3
Ph
H
4-CH3-C6H4
4-CH3O-C6H4
4-Cl-C6H4
4-HO-C6H4
Ph-CH=CH
Ph
H
H
Hantzsch 1,4-dihydropyridine (HEH), a well-known
model compound of co-enzyme nicotinamide adenine di-
nucleotide (NADH), has been extensively studied from
both mechanistic and synthetic points of view.1 Recent at-
tention has been focused on using this compound as an at-
tractive biomimetic reducing agent for synthetically
useful organic transformations,2–6 such as organocatalytic
and enantioselective conjugated reduction of a,b-unsatur-
ated aldehydes,2 reduction of conjugated olefins,3 reduc-
tive amination of carbonyl compounds4 and reductive
cyclization of electron deficient double bonds.5 We found
previously that photoexcited HEH could reduce carbon
tetrachloride,7 and selectively break the Ca–O bond of
a,b-epoxy ketones to give the corresponding b-hydroxy
ketones.8 Herein we wish to report that HEH could selec-
tively reduce the exocyclic double bond of 4-arylmethyl-
ene- and 4-alkylidene-4H-isoxazol-5-ones (1) to the
corresponding 3,4-disubstituted 2H-isoxazol-5-ones (2)
with high efficiency (Scheme 1 and Table 1).
H
H
1g
1h
1i
H
2g
2hb
2i
Ph
H
4-NO2-C6H4
4-NMe2-C6H4
2-Furyl
Ph
H
1j
Ph
H
2j
1k
1l
Ph
H
Ph-CH=CH
2k
Ph
-(CH2)4-
2l
a Isolated yields. All the products, except 2h, were identified by com-
paring their mp, 1H NMR and MS spectral data with those reported in
the literature.9c,d
b A new compound characterized by 1H- and 13C NMR, EI- and
HR-MS.10
An ethanolic solution (3 mL) of the 4H-isoxazol-5-one (1,
1 mmol) and HEH (1 mmol) was refluxed under argon at-
mosphere. The reaction was completed within 20–30 min-
utes as monitored by thin layer chromatography. After
removal of the solvent under reduced pressure, the prod-
ucts were isolated by flash chromatography on silica gel,
purified by recrystallization from chloroform–hexane,
and identified by 1H NMR and mass spectroscopy as the
3,4-disubstituted 2H-isoxazol-5-one (2) and the pyridine
derivative 3. The results are listed in Table 1.
The 2H- and 4H-isoxazol-5-ones are versatile organic in-
termediates because the existence of three different tau-
tomers that leads to a variety of interesting chemistry.11 A
practical way for the preparation of 4-arylmethyl isox-
azol-5-ones is the reduction of the exocyclic double bond
of the readily available 4-arylmethylene isoxazol-5-ones.9
R2
R2
O
O
O
O
R1
R1
R3
EtOH, reflux
R3
EtO
Me
EtO
Me
OEt
Me
OEt
Me
+
+
HN
N
N
N
H
O
O
O
O
3
2
HEH
1
Scheme 1
SYNLETT 2005, No. 10, pp 1579–1580
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6
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Advanced online publication: 07.06.2005
DOI: 10.1055/s-2005-869860; Art ID: U09105ST
© Georg Thieme Verlag Stuttgart · New York

1580
Z. Liu et al.
LETTER
R2
R2
O
O
O
O
R1
R1
N
R3
R3
EtO
Me
EtO
Me
OEt
Me
OEt
Me
EtOH, reflux
+
+
HN
N
N
H
O
O
N
H
N
H
HEH
4
5
3
Scheme 2
Palladium-catalyzed hydrogenation,9a in situ generated
benzimidazolines,9b,c and sodium borohydride9d have
been used for such reduction. However, the yield was gen-
erally not satisfactory due to the cleavage of the isox-
azolone ring9a and/or the formation of dimers9c and other
by-products.9b
References
(1) (a) Marukami, Y.; Kikuchi, J.; Hisaida, Y.; Hayashida, O.
Chem. Rev. 1996, 96, 721. (b) Yasui, S.; Ohno, A. Bioorg.
Chem. 1986, 14, 70. (c) Fukuzumi, S.; Tanaka, T. In Photo-
induced Electron Transfer, Part C; Fox, M. A.; Chanon, M.,
Eds.; Elsevier: Amsterdam, 1988, 578. (d) Fukuzumi, S.;
Suenobu, T.; Kawamura, S.; Ishida, A.; Mikami, K. Chem.
Commun. 1997, 291. (e) Fujii, M.; Yasui, S.; Nakamura, K.
In Reviews on Heteroatom Chemistry, Oae S., Vol. 20;
MYU: Tokyo, 1999, 167.
(2) (a) Yang, J. W.; Hechavarria Fonseca, M. T.; List, B. Angew.
Chem. Int. Ed. 2004, 43, 2. (b) Yang, J. W.; Hechavarria
Fonseca, M. T.; Vignola, N.; List, B. Angew. Chem. Int. Ed.
2005, 44, 108. (c) Ouellet, S. G.; Tuttle, J. B.; Macmillan, D.
W. C. J. Am. Chem. Soc. 2005, 127, 32.
(3) Garden, S. J.; Guimarães, C. R. W.; Corréa, B.; Oliveira, C.
A. F.; Pinto, A. C.; Alencastro, R. B. J. Org. Chem. 2003, 68,
8815.
(4) (a) Itoh, T.; Nagata, A.; Kurihara, A.; Miyazaki, M.;
Ohsawa, A. Tetrahedron Lett. 2002, 43, 3105. (b) Takashi,
I.; Kazuhiro, N.; Michiko, M.; Hiroyuki, I.; Ayako, K.; Akio,
O. Tetrahedron 2004, 60, 6785.
It is seen from Table 1 that the present procedure affords
a very clean, mild and efficient approach for the selective
reduction of the exocyclic double bond of 4-arylmethyl-
ene- and 4-alkylidene-4H-isoxazol-5-ones. The corre-
sponding 2H-isoxazol-5-ones were obtained as a single
reduction product with excellent yield. HEH was trans-
formed in a quantitative way to its pyridine derivative,
which could easily be removed by chromatography. The
approach is applicable to substrates with either electron-
donating or electron-withdrawing substituents, and is tol-
erant to carbonyl and nitro functionalities.
Similarly, the exocyclic double bond of 4-arylmethylene-
4H-pyrazol-5-ones (4) could also be selectively reduced
by HEH under the same conditions to give the corre-
sponding 2H-pyrazol-5-ones (5) in excellent yield
(Scheme 2, Table 2).
(5) Zhu, X.-Q.; Wang, H.-Y.; Wang, J.-S.; Liu, Y.-C. J. Org.
Chem. 2001, 66, 344.
(6) (a) Lee, H. W.; Kim, B. Y.; Ahn, J. B.; Son, H. J.; Lee, J. W.;
Ahn, S. K.; Hong, C. I. Heterocycles 2002, 57, 2163.
(b) Torchy, S.; Cordonnier, G.; Barbry, D.; Eynde, J. J. V.
Molecules 2002, 7, 528.
(7) Jin, M.-Z.; Yang, L.; Wu, L.-M.; Liu, Y.-C.; Liu, Z.-L.
Chem. Commun. 1998, 2415.
Table 2 Reduction of Pyrazol-5-ones (4) by HEH
Substrate R1
R2
H
H
H
H
R3
Product Yield (%)a
4a
4b
4c
4d
CH3
Ph
5a
5b
5c
5d
94
96
95
98
(8) Zhang, J.; Jin, M.-Z.; Zhang, W.; Yang, L.; Liu, Z.-L.
Tetrahedron Lett. 2002, 43, 9687.
Ph
Ph
Ph
Ph
(9) (a) Shaw, G. J. Chem. Soc. 1950, 720. (b) Risitano, F.;
Grassi, G.; Foti, F. Tetrahedron Lett. 1983, 24, 5893.
(c) Risitano, F.; Grassi, G.; Caruso, F.; Foti, F. Tetrahedron
1996, 52, 1443. (d) Beccalli, E. M.; Benincori, T.;
Marchesini, A. Synthesis 1988, 886.
(10) 3-Phenyl-4-(4-nitrophenylmethyl)-2H-isoxazol-5-one (2h):
colorless needles; mp 169–171 °C. 1H NMR (300 MHz,
DMSO-d6): d = 3.42 (1 H, br), 3.82 (2 H, s), 7.43 (2 H, d,
J = 8.2 Hz), 7.53 (5 H, s), 8.12 (2 H, d, J = 8.2 Hz). 13C NMR
(75.43 MHz, DMSO-d6): d = 27.4, 94.7, 123.7 × 2 C, 127.5
× 2 C, 127.4, 129.1 × 2 C, 129.3 × 2 C, 131.2, 146.1, 147.8,
162.0, 172.4. MS (EI): m/z (%) = 296 (2) [M+], 136 (100), 77
(5). ESI-HRMS: m/z calcd for C16H12N2O4 + H+: 297.0870;
found: 297.0870.
(11) (a) Batra, S.; Akhatar, M. S.; Seth, M.; Bhaduri, A. P. J.
Heterocycl. Chem. 1990, 27, 337. (b) Beccalli, E. M.;
Gelmi, M. L.; Marchesini, A. Tetrahedron 1998, 54, 14401.
(c) Beccalli, E. M.; Marchesini, A.; Pilati, T. Synthesis 1991,
127. (d) Beccalli, E. M.; Marchesini, A.; Pilati, T. Synth.
Commun. 1993, 23, 685.
4-CH3O-C6H4
4-CH3-C6H4
a Isolated yields. All the products were identified by comparing their
mp, 1H NMR and MS spectral data with those reported in the
literature.9c
In conclusion, the selective reduction of the exocyclic
double bond of the 4-arylmethylene- and 4-alkylidene-
4H-isoxazol-5-ones and 4-arylmethylene-4H-pyrazol-5-
ones can be effectively achieved by using Hantzsch 1,4-
dihydropyridine as the reducing agent. This method is
clean, mild and efficient, and is expecting to be useful for
other selective conjugate reductions.
Acknowledgment
We thank the National Natural Science Foundation of China
(20372030) for financial support.
Synlett 2005, No. 10, 1579–1580 © Thieme Stuttgart · New York