N-Nitroso-2-aryl-1,3-oxazolidines catalyzed aromatization of Hantzsch 1,4-dihydropyridines

Article abstract of DOI:10.1016/j.tetlet.2008.01.043

A catalytic amount of N-nitroso-2-aryl-1,3-oxazolidines leading to the aromatization of Hantzsch 1,4-dihydropyridines (DHPs) was successfully achieved. A catalytic mechanism for the reaction is proposed.

Full text of DOI:10.1016/j.tetlet.2008.01.043

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Tetrahedron Letters 49 (2008) 1586–1588
N-Nitroso-2-aryl-1,3-oxazolidines catalyzed aromatization
of Hantzsch 1,4-dihydropyridines
Li-jun Peng a, Jian-tao Wang a, Zhou Lu a, Zhong-quan Liu b, Long-min Wu a,*
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
b Institute of Organic Chemistry, Gannan Normal University, Ganzhou 341000, PR China
Received 6 December 2007; revised 27 December 2007; accepted 10 January 2008
Available online 15 January 2008
Abstract
A catalytic amount of N-nitroso-2-aryl-1,3-oxazolidines leading to the aromatization of Hantzsch 1,4-dihydropyridines (DHPs) was
successfully achieved. A catalytic mechanism for the reaction is proposed.
Ó 2008 Elsevier Ltd. All rights reserved.
Two lines of thought motivated the present study (a)
Hantzsch 1,4-dihydropyridines (DHPs) are model com-
pounds of NADH1 and an important class of drug, which
act as potent blockers of calcium (Ca2+) currents.2 The
metabolism of DHPs involves an oxidation step catalyzed
by cytochrome P-450 in the liver;3 and (b) N-nitrosamines
contained in the human diet are naturally occurring carcino-
gens. They undergo a cytochrome P-450-mediated a-oxi-
dation that converts them into active carcinogens.4
Hence, an investigation of the reaction of DHPs with N-
nitrosamines will be of interest in this particular biochem-
ical context.
Oxidation of DHPs has been carried out using various
oxidants.5 Reactions of DHPs with nitric oxide (NO),6 nitro-
sonium (NO+),7 S-nitrosoglutathione,8 and nitroxide9 are
especially relevant to the present study because N-nitros-
amines are potential NOÅ/NO+ donors through homolytic
and heterolytic cleavage of the N–NO bond.10 Based on
these previous results, we examined the oxidation of DHPs
with N-nitrosamines.
estimated to be À1.2 V versus Fc+/Fc.12 In a typical exper-
iment, treatment of 1 mmol of 1a with 0.1 mmol of N-
nitroso-2-phenyl-1,3-oxazolidine 2a in 20 mL of anhydrous
CH2Cl2 at room temperature gave corresponding pyridine
3a in 96% yield13 in 6 h (Scheme 1). The reaction occurred
efficiently. Side products were small amounts of benzalde-
hyde and 2-aminoethanol, which were produced from the
decomposition of 2a. Pyridine 3a was characterized by
1H NMR and mass spectroscopy. The reaction conditions
were well optimized using 1a as a substrate in several
organic solvents and with various amounts of 2a, respec-
tively (Tables 1 and 2). They suggest that the oxidation
of 1a very favorably proceeds in CH2Cl2 and with 0.1 equiv
of 2a. Extension to other DHPs with different R-substitu-
ents also gave encouraging results (Table 3). Dealkylation
inclusively occurred only when R is isopropyl group
(entries 7 and 8).5e,6,7,14
We carried out the oxidation of DHPs (1) with N-
nitroso-2-aryl-1,3-oxazolidines (2). Oxazolidine 2 is a weak
oxidant easily obtained from the reaction of (E)-2-(benzyl-
idene-amino)ethanol with NO.11 Its reduction potential is
O
R(H)
N
R
H
N
ON
EtO2C
CO2Et
EtO2C
CO2Et
(0.1 equiv.)
+
CH Cl , r.t.
X
2
2
N
H
Yield up to 96%
R = H, alkyl, Ar
X = H, p-Cl
1
2
3
*
Corresponding author. Tel.: +86 931 891 2500; fax: +86 931 891 5557.
Scheme 1.
E-mail addresses: penglj04@lzu.cn, nlaoc@lzu.edu.cn (L. Wu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.043

L. Peng et al. / Tetrahedron Letters 49 (2008) 1586–1588
1587
Table 1
EtO2C
H
R
O
N
N
Solvent effects on the aromatization of 1a with 2a
.
NO+ catalytic amount O2
.
N
H
O
Entry Solvent Amount of 2a
Conver.a
(%)
Time
(h)
Yield of 3ab
(%)
EtO2C
X
(mol %)
2
1
1
2
3
4
5
6
7
CH3CN 10
CH2Cl2 10
Toluene 10
88
100
100
78
85
100
50
12
6
6
12
12
12
12
78
96
90
70
76
88
20
substitution
R
H
H
R(H)
O
CHO
N
EtO2C
CO2Et
+
EtO2C
CO2Et
EtOH
MeOH
THF
10
10
10
10
+
H2N
OH
X
N
X
N
3
NO
4
5
H2O
H2O quench
homolysis
proton transfer
a
Determined by GC.
Isolated yield.
b
OH
N
R
H
R
H
O
HN
X
EtO2C
CO2Et
EtO2C
homolysis
CO2Et
+
N
N
NO
X
NO
Table 2
ring-7
8
6
chain-7
Optimization of the amount of 2a
Entry Amount of 2a
Conver.a
Time
Yield of 3ab
Scheme 2.
(mol %)
(%)
(h)
(%)
1
2
3
4
5
6
1
5
10
10
15
20
88
90
100
100
100
100
12
12
6
12
12
12
78
85
96
96
95
96
the nitrogen atom of 1 at the nitrogen atom of the N-nitroso
of 2 most likely undergoes a transnitrosation7b,15 to give a
nitronium ion 4 and an oxazolidine anion 5.7b Followed
by a proton transfer, N-nitrosodihydropyridine 6 and
oxazolidine ring-7 with its acyclic tautomer chain-7 are
formed.11 Oxazolidine ring-7 and chain-7 react with NO
released from 6 in the presence of catalytic O2 to regenerate
2. The homolysis of 6 gives an aminyl radical 8 and
NO.7b,c,15 Followed by a homolysis, radical 8 then converts
to pyridine 3. Aldehyde and 2-aminoethanol are produced
from the decomposition of ring-7 and chain-7.
a
Determined by GC.
Isolated yield.
b
Table 3
Oxidation of DHPs with N-nitroso-2-aryl-1,3-oxazolidines
Entry
Substrate
R
Oxazolidinea
Product
R
Yield of
In conclusion, this work demonstrates a N-nitroso-2-aryl-
1,3-oxazolidine catalyzed pathway for the aromatization of
DHPs to pyridines. It will be of interest to both biochemistry
and organic chemistry.
3b (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
a
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
H
H
Me
Me
Et
Et
(CH3)2CH
(CH3)2CH
Ph
2a
2b
2a
2b
2a
2b
2a
2b
2a
2b
3a
3a
H
H
96
90
90
77
88
84
92
89
90
88
3b Me
3b Me
3c Et
3c Et
3dc
3d
Acknowledgment
Project No. 20572040 was supported by National Natural
Science Foundation of China.
H
H
3e Ph
3e Ph
Ph
References and notes
p-CH3O–Ph 2a
p-CH3O–Ph 2b
p-Cl–Ph
p-Cl–Ph
p-O2N–Ph
p-O2N–Ph
3f
p-CH3O–Ph 95
p-CH3O–Ph 95
1f
3f
1. (a) Mauzeral, D.; Westheimer, F. H. J. Am. Chem. Soc. 1955, 77,
2261; (b) Abeles, R. J.; Hutton, R. F.; Westheimer, F. H. J. Am.
Chem. Soc. 1957, 79, 712.
1g
1g
1h
1h
2a
2b
2a
2b
3g p-Cl–Ph
3g p-Cl–Ph
3h p-O2N–Ph
3h p-O2N–Ph
96
95
94
93
2. Triggle, D. J.; Langs, D. A.; Janis, R. A. Med. Res. Rev. 1989, 9, 123.
3. (a) Bossert, V. F.; Meyer, H.; Wehinger, E. Angew. Chem., Int. Ed.
Engl. 1981, 20, 762; (b) de Matteis, F.; Hollands, C.; Gibbs, A. H.; de
Sa, N.; Rizzardini, M. FEBS Lett. 1982, 145, 87; (c) Boecker, R. H.;
Guengerich, F. P. J. Med. Chem. 1986, 29, 1596; (d) McCluskey, S.
A.; Riddick, D. S.; Mackie, J. E.; Kimmet, S. M.; Whitney, R. A.;
Marks, G. S. Can. J. Physiol. Pharmcol. 1992, 70, 1069; (e)
Guengerich, F. P.; Brian, W. R.; Iwasaki, M.; Sari, M. A.; Baarhielm,
C.; Berntsson, P. J. Med. Chem. 1991, 34, 1838.
4. (a) Yang, C. S.; Smith, T. J. Adv. Exp. Med. Biol. 1996, 387, 385; (b)
Yang, C. S.; Tu, Y. Y.; Koop, D. R.; Coon, M. J. Cancer Res. 1985,
45, 1140; (c) Chemical Carcinogens; Preusmann, R., Stewart, B. W.,
Searle, C. E., Eds.; ACS Monograph; American Chemical Society:
Washington, DC, 1984; p 643; (d) Mochizuki, M.; Anjo, T.; Okada,
M. Tetrahedron Lett. 1980, 21, 3693.
2a: X = H; 2b: X = p-Cl.
Isolated yield.
3d is identical to 3a.
b
c
A catalytic mechanism in the aromatization of 1 with 2 is
depicted in Scheme 2. Although the oxidation of 1 with 2 is
unfavorable in thermodynamics, yet, N-nitroso compounds
are well-known nitrosotransfer agents,7b which have been
widely used to nitrosate many compounds containing NH
group to form the corresponding N-nitroso compounds
via a nucleophilic substitution. A nucleophilic attack of

1588
L. Peng et al. / Tetrahedron Letters 49 (2008) 1586–1588
5. (a) Sausins, A.; Duburs, G. Heterocycles 1988, 27, 291; (b) Chennot,
T.; Eisner, U. J. Chem. Soc., Perkin Trans. 1 1975, 926; (c) Eynde, J. J.
V.; D’Orazio, R.; van Haverbeke, Y. Tetrahedron 1994, 50, 2479; (d)
Pfister, J. R. Synthesis 1990, 689; (e) Chai, L. Z.; Zhao, Y. K.; Sheng,
Q. J.; Liu, Z. Q. Tetrahedron Lett. 2006, 47, 9283; (f) Yadav, J. S.;
Reddy, B. V. S.; Sabitha, G.; Reddy, G. S. K. K. Synthesis 2000, 11,
1532; (g) Zhang, D.; Wu, L. Z.; Zhou, L.; Han, X.; Yang, Q. Z.;
Zhang, L. P.; Tung, C. H. J. Am. Chem. Soc. 2004, 126, 3440; (h)
Nakamichi, N.; Kawashita, L.; Hayashi, M. Org. Lett. 2002, 4, 3955.
6. Itoh, T.; Nagata, K.; Matsuya, Y.; Miyazaki, M.; Ohsawa, A. J. Org.
Chem. 1997, 62, 3582.
7. (a) Chen, W.; Jin, M. Z.; Liu, Z. L.; Wu, L. M. Chin. Chem. Lett.
1999, 10, 991; (b) Zhu, X. Q.; Zhao, B. J.; Cheng, J. P. J. Org. Chem.
2000, 65, 8158; (c) Wu, L. M.; Chen, W.; Liu, Z. L. Res. Chem.
Intermed. 2001, 27, 219.
8. Mao, Y. Z.; Jin, M. Z.; Liu, Z. L.; Wu, L. M. Org. Lett. 2000, 2, 741.
9. Lu, M.; Gang, J. G.; Liu, Z. L.; Wu, L. M. Chin. Chem. Lett. 2002,
13, 923.
10. (a) Loeppky, R. N.; Outram, J. R. N-Nitroso Compounds: Occurrence
and Biological Effects; IARC Scientific: Lion, 1982; (b) Wang, P. G.;
Xian, M.; Tang, X.; Wu, X.; Wen, Z.; Cai, T.; Janczuk, J. Chem. Rev.
2002, 102, 1091.
11. Peng, L. J.; Liu, Z. Q.; Wang, J. T.; Wu, L. M. Tetrahedron Lett.
2007, 48, 7418.
12. The redox potentials of 2a and DHP were measured at ambient
temperature using cyclic voltammetry performed on an electrochem-
ical analyzer (model CHI 760B), which was connected to a PC with
Origin 6.0 software. Au flag was used as the working electrode, Pt flag
as the auxiliary electrode, and HgCl2/Hg as the reference electrode.
(C2H5)4NBr was applied to a background electrolyte. The reduction
potential of 2a is À1.2 V versus Fc+/Fc and the oxidation potential of
DHP is 0.5 V versus Fc+/Fc.
13. Typical procedure: A solution of 1 mmol 1a and 0.1 mmol 2a in 20 mL
of anhydrous CH2Cl2 was stirred at room temperature. After
completion of the reaction, as indicated by TLC, the reaction mixture
was quenched with water. Extracted with 20 mL of CH2Cl2 and dried
over Na2SO4. After removal of the solvent under reduced pressure,
the products were isolated by flash chromatography on silica gel,
purified by recrystallization from chloroform–hexane. Data for
diethyl 2,6-dimethyl-3,5-pyridinedicarboxylate (3a): white solid; mp
70–71 °C; IR (KBr) mmax 2986, 2978, 2930, 2912, 1718, 1591, 1555,
1548, 1444, 1380, 1368, 1297 cmÀ1 1H NMR (300 MHz, CDCl3) d
;
1.41 (6H, t, J = 7.2 Hz), 2.84 (6H, s), 4.40 (4H, q, J = 7.2 Hz), 8.67
(1H, s); 13C NMR (75 MHz, CDCl3) d 14.2, 25.0, 61.4, 123.0, 140.9,
162.2, 165.9; MS m/z (relative intensity): 251 (M+, 39.8), 206, 195,
178, 150, 106.
14. (a) Itoh, T.; Nagata, K.; Okada, M.; Ohsawa, A. Tetrahedron Lett.
1995, 13, 2269; (b) Eynde, J. J. V.; Delfosse, F.; Mayence, A.;
Haverbeke, Y. V. Tetrahedron 1995, 51, 6511; (c) Eynde, J. J. V.;
Mayence, A.; Maquestiau, A. Tetrahedron 1992, 48, 463; (d) Maques-
tiau, A.; Mayence, A.; Eynde, J. J. V. Tetrahedron Lett. 1991, 32,
3839; (e) Jin, M. Z.; Yang, L.; Wu, L. M.; Liu, Y. C.; Liu, Z. L.
Chem. Commun. 1998, 2451; (f) Delgado, F.; Alvarez, C.; Garcia, O.;
Medina, S.; Marquez, C. Synth. Commun. 1991, 619; (g) Love, B.;
Snader, K. M. J. Org. Chem. 1965, 30, 1914; (h) Bacon, R. G. R.;
Osuntogun, B. A. J. Chem. Soc., Chem. Commun. 1979, 1159; (i) Kurz,
J. L.; Hutton, R.; Westheimer, F. H. J. Am. Chem. Soc. 1961, 83,
584.
15. (a) Yanagimoto, T.; Toyota, T.; Matsuki, N.; Makino, Y.; Uchiyama,
S.; Ohwada, T. J. Am. Chem. Soc. 2007, 129, 736; (b) Ohwada, T.;
Miura, M.; Tanaka, H.; Sakamoto, S.; Yamaguchi, K.; Ikeda, H.;
Inagaki, S. J. Am. Chem. Soc. 2001, 123, 10164; (c) Zhu, X. Q.; Hao,
W. F.; Tang, H.; Wang, C. H.; Cheng, J. P. J. Am. Chem. Soc. 2005,
127, 2696.