A metal-free catalytic aerobic aromatization of Hantzsch 1,4-dihydropyridines by N-hydroxyphthalimide

Article abstract of DOI:10.1055/s-2005-872267

4-Alkyl- and 4-aryl-Hantzsch 1,4-dihydropyridines were oxidized to the corresponding pyridine derivatives in excellent yields by molecular oxygen using N-hydroxyphthalimide (NHPI) as the catalyst. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872267

LETTER
2333
A Metal-Free Catalytic Aerobic Aromatization of Hantzsch 1,4-Dihydro-
pyridines by N-Hydroxyphthalimide
A
romatization of
i
H
antzs
n
c
h
1,4-Dihy
g
N-H
ade n, Qiang Liu, Zhengang Liu, Ruizhu Mu, Wei Zhang, 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 12 June 2005
pyridine derivative 2 in excellent yield (Scheme 1). The
product 2 was easily separated by flash chromatography
(silica gel, PE–EtOAc, 6:1 v/v) after removal of the sol-
vent under reduced pressure. The results are summarized
in Table 1.
Abstract: 4-Alkyl- and 4-aryl-Hantzsch 1,4-dihydropyridines were
oxidized to the corresponding pyridine derivatives in excellent
yields by molecular oxygen using N-hydroxyphthalimide (NHPI) as
the catalyst.
Key words: Hantzsch 1,4-dihydropiridines, aromatization, N-hy-
droxyphthalimide, molecular oxygen
H
R
R
EtO2C
Me
CO2Et
Me
EtO2C
Me
CO2Et
Me
NHPI (20 mol%), O2
MeCN, reflux
Hantzsch 1,4-dihydropyridines (DHPs), a class of model
compounds of NADH coenzyme,1 have been extensively
studied in view of the biological pertinence of these com-
pounds to the NADH redox process,2 and their therapeutic
functions for treatment of a variety of deseases,3 such as
cardiovascular disorders,3a anticancer3b and anti-HIV.3c
The oxidation of DHPs to the corresponding pyridine
derivatives is the principal metabolic route in biological
systems,1,2 as well as a facile access to the corresponding
pyridine derivatives from the easy available DHPs by
Hantzsch reaction or its modifications.4 Therefore, oxida-
tive aromatization of DHPs has attracted continuing inter-
ests of organic and medicinal chemists and a plethora of
protocols has been developed.5–8 Early works mostly used
strong oxidants, such as HNO3,5b KMnO4,5c or CAN.5d
Recently, attention has been paid to more efficient and
environmentally benign methods, such as electrochemical
oxidation6 and catalytic aerobic oxidation by using
N
N
H
1
2
Scheme 1
It is seen from Table 1 that excellent yields were obtained
with most substrates except 1c and 1j. In the case of 1c, in
addition to the normal dehydrogenation product 2c, 4-
dealkylation product 2a was also obtained in 26% yield
(entry 3). Similar dealkylation has also been observed pre-
viously in the photochemically induced aromatization of
DHPs,8 as well as in the aromatization of DHPs by urea
nitrate and peroxydisulfate-cobalt (II),5i and by nitric ox-
ide.5j In the case of 1j (entry 10), no appreciable reaction
took place even after prolonged refluxing, demonstrating
Table 1 Catalytic Aerobic Aromatization of Hantzsch 1,4-Dihydro-
pyridines (1) by NHPIa
7d
RuCl3,7a Pd/C,7b activated carbon7c or Fe(ClO4)3 as the
catalyst. We have also reported a photochemically in-
duced aromatization of DHPs.8 Herein we wish to report
a convenient metal-free catalytic aerobic oxidation of
DHPs by using an organic catalyst N-hydroxyphthalimide
(NHPI). Ishii has developed a series of NHPI-based cata-
lytic systems for the functionalization of hydrocarbons
under O2, NO, or NO2 atmosphere to give oxygen-con-
taining compounds, such as alcohols, ketones, carboxylic
acids and nitroalkanes.9 It is of interest to observe that this
Ishii catalysis can also be used for the aromatization of
DHPs.
Entry Substrate
R
Product Time (h) Yield (%)b
1
2
1a
1b
1c
1d
1e
1f
H
2a
0.5
3
99
98
72, 26
99
96
96
98
95
93
0
Me
2b
3
n-Propyl
Ph
2c, 2a
2d
3
4
4
5
4-ClC6H4
4-MeC6H4
2e
5
6
2f
3
7
1g
1h
1i
4-MeOC6H4 2g
Ph-CH=CH 2h
1.5
4.5
7
In a typical experiment a MeCN solution (3 mL) of
Hantzsch 1,4-dihydropyridine (1, 1 mmol) and NHPI (0.2
mmol) was refluxed under stirring and oxygen atmo-
sphere (1 atm). The reaction completed in a couple of
hours as monitored by TLC, giving the corresponding
8
9
2-Furyl
2i
10
1j
4-NO2C6H4
–
10
a For reaction conditions see text.
b Isolated yields. The products were identified by comparing their 1H
NMR and EI-MS spectral data and melting points with those reported
in the literature.5i
SYNLETT 2005, No. 15, pp 2333–2334
Advanced online publication: 03.08.2005
DOI: 10.1055/s-2005-872267; Art ID: U18305ST
© Georg Thieme Verlag Stuttgart · New York
1
9
.0
9
.2
0
0
5

2334
B. Han et al.
LETTER
that the strong electron-withdrawing nitro substituent oxidant and NHPI as an organic catalyst. Extension of this
remarkably retarded the reaction. On the other hand, method to other potential substrates is underway in this
electron-donating methoxy substituent significantly laboratory.
facilitated the reaction (entry 7).
It was found that the turnover number (TON) of the cata-
lyst depended on the concentrations of the catalyst and the
substrate, as well as the reaction scale, because NHPI was
found to partly decompose under the reaction condition,
as having been reported previously.10 At least 0.5 mmol (5
mol%) of NHPI must be used for the total conversion of
1d on 10 mmol scale, corresponding to TON of 20. How-
ever, prolonged time (45 h) must be used to complete the
reaction. Therefore, 20 mol% of NHPI was used for the
best performance of the reaction.
Acknowledgment
We thank the National Natural Science Foundation of China (grant
20372030) for financial support.
References
(1) (a) Eisner, U.; Kuthan, J. Chem. Rev. 1972, 72, 1. (b) Stout,
D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223.
(2) (a) Kill, R. J.; Widdowson, D. A. In Bioorganic Chemistry,
Vol. 4; van Tamelen, E. E., Ed.; Academic Press: New York,
1978, 239–275. (b) Böcker, R. H.; Guengerich, F. P. J. Med.
Chem. 1986, 29, 1596.
(3) (a) Triggle, D. J.; Langs, D. D.; Janis, R. A. Med. Res. Rev.
1989, 9, 123. (b) Kawase, M.; Shah, A.; Gaveriya, H.;
Motohashi, N.; Sakagami, H.; Varga, A.; Molnar, J. Bioorg.
Med. Chem. 2002, 10, 1051. (c) Hilgeroth, A. Mini-Rev.
Med. Chem. 2002, 2, 235. (d) Max, I. T.; Zhang, J.;
Weglicki, W. B. Pharmacol. Res. 2002, 45, 27. (e) Suarez,
M.; Verdecia, Y.; Illescas, B.; Matinenz-Alvarez, R.;
Alvarez, A.; Ochoa, E.; Seoane, C.; Kayali, N.; Martin, N.
Tetrahedron 2003, 59, 9179.
The mechanism of the reduction of organic substrates by
DHPs has been intensively investigated, which indicated
that the reaction might proceed via either direct hydride
transfer or electron transfer followed by proton transfer
and second electron transfer, depending on the substrate
and reaction conditions.11 In the present case, however, no
reaction occurred between excessive amount of NHPI and
DHPs under argon atmosphere, demonstrating that NHPI
could not directly oxidize DHPs. The reaction did not take
place under oxygen atmosphere in the absence of NHPI,
too. Therefore, this reaction is obviously an NHPI-cata-
lyzed free radical oxidation (Scheme 2), similar to that
proposed previously by Ishii.9a In the scheme the reaction
is initiated by the reaction of NHPI with O2 to generate ph-
thalimide-N-oxyl radical (PINO) which has been detected
by ESR.9a,b PINO abstracts hydrogen from DHP to pro-
duce alkyl radical 3. Generally, alkyl radicals would react
with oxygen to form alkyl peroxyl radical, which in turn,
would produce oxygenated products.9 In the present case,
however, the strong driving force of aromatization makes
the second hydrogen abstraction by PINO and/or O2 very
effective. Therefore, the pyridine derivative is formed
exclusively rather than the oxygenated products.
(4) (a) Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav, J.
S. Tetrahedron Lett. 2003, 44, 4129. (b) Zolfigol, M. A.;
Safaiee, M. Synlett 2004, 827.
(5) (a) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 291.
(b) Chennot, T.; Eisner, U. J. Chem. Soc., Perkin Trans. 1
1975, 926. (c) Vanden Eynde, J.-J.; D’Orazio, R.;
Havebeke, Y. V. Tetrahedron 1994, 50, 2479. (d) Pfister, J.
R. Synthesis 1990, 689. (e) Itoh, T.; Nagata, K.; Matsuya,
Y.; Miyazaki, M.; Ohsawa, A. J. Org. Chem. 1997, 62,
3582. (f) Mashraqui, S. H.; Karnik, M. A. Synthesis 1998,
713. (g) Varma, R. S.; Kumar, D. Tetrahedron Lett. 1999,
40, 21. (h) Ko, K.-Y.; Kim, J.-Y. Tetrahedron Lett. 1999,
40, 3207. (i) Anniyappan, M.; Muralidharan, D.; Perumal, P.
T. Tetrahedron 2002, 58, 5069. (j) Zhu, X.-Q.; Zhao, B.-J.;
Cheng, J.-P. J. Org. Chem. 2000, 65, 8158.
(6) (a) Lopez-Alarcon, C.; Nunez-Vergara, L. J.; Sturm, J. C.;
Squella, J. A. Electrochim. Acta 2003, 48, 505.
In conclusion, this work provides a simple metal-free cat-
alytic approach for the aromatization of Hantzsch 1,4-di-
hydropyridines with molecular oxygen as the terminal
(b) Arguello, J.; Nunez-Vergara, L. J.; Sturm, J. C.; Squella,
J. A. Electrochim. Acta 2004, 49, 4849.
(7) (a) Mashraqui, S. H.; Karnik, M. A. Tetrahedron Lett. 1998,
39, 4895. (b) Nakamichi, N.; Kawashita, Y.; Hayashi, M.
Org. Lett. 2002, 4, 3955. (c) Nakamichi, N.; Kawashita, Y.;
Hayashi, M. Synthesis 2004, 1015. (d) Heravi, M. M.;
Behbahani, F. K.; Oskooie, H. A.; Shoar, R. H. Tetrahedron
Lett. 2005, 46, 2775.
H
O
R
EtO2C
CO2Et
NO
N
H
O
PINO
(8) Jin, M.-Z.; Yang, L.; Wu, L.-M.; Liu, Y.-C.; Liu, Z.-L.
Chem. Commun. 1998, 2451.
1
O
R
(9) (a) For a review, see: Ishii, Y.; Sakaguchi, S.; Iwahama, T.
Adv. Synth. Catal. 2001, 343, 393. (b) Ishii, Y.; Iwahama,
T.; Sakaguchi, S.; Nakayama, K.; Nishiyama, Y. J. Org.
Chem. 1996, 61, 4520. (c) Iwahama, T.; Sakaguchi, S.; Ishii,
Y. Org. Process Res. Dev. 2000, 4, 94. (d) Sakaguchi, S.;
Nishiwaki, Y.; Kitamura, T.; Ishii, Y. Angew. Chem. Int. Ed.
2001, 40, 222. (e) Hirabayashi, T.; Sakaguchi, S.; Ishii, Y.
Angew. Chem. Int. Ed. 2004, 43, 1120.
CO2Et
EtO2C
NOH
O2
N
H
O
NHPI
3
O2
O
R
EtO2C
CO2Et
NO
(10) Cai, Y.; Koshino, N.; Saha, B.; Espenson, J. H. J. Org.
Chem. 2005, 70, 238.
N
O
(11) Zhu, X.-Q.; Li, H.-R.; Li, Q.; Ai, T.; Lu, J.-Y.; Yang, Y.;
Cheng, J.-P. Chem.–Eur. J. 2003, 9, 871; and references
cited therein.
PINO
NHPI
2
Scheme 2
Synlett 2005, No. 15, 2333–2334 © Thieme Stuttgart · New York