Oxidative aromatization of hantzsch 1,4-dihydropyridines by H 2O2/V2o5 at room temperature

Article abstract of DOI:10.1080/00397910903007087

A mild and highly efficient synthetic method was developed for the aromatization of 1,4-dihydropyridines employing H₂O₂ and 5mol% of V₂O₅. The reactions were carried out in CH ₃CN to give pyridine compounds in excellent yields. Copyright Taylor & Francis Group, LLC.

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Oxidative Aromatization of Hantzsch
1,4-Dihydropyridines by H2O2/V2O5 at
Room Temperature
Jinlong Su a , Cai Zhang a , Dan Lin a , Yiqin Duan a , Xiangkai Fu a &
Ruizhu Mu a
a College of Chemistry and Chemical Engineering, Southwest
University , Chongqing, China
Published online: 03 Feb 2010.
To cite this article: Jinlong Su , Cai Zhang , Dan Lin , Yiqin Duan , Xiangkai Fu & Ruizhu Mu (2010)
Oxidative Aromatization of Hantzsch 1,4-Dihydropyridines by H2O2/V2O5 at Room Temperature,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 40:4, 595-600, DOI: 10.1080/00397910903007087
To link to this article: http://dx.doi.org/10.1080/00397910903007087
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Synthetic Communications1, 40: 595–600, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903007087
OXIDATIVE AROMATIZATION OF HANTZSCH
1,4-DIHYDROPYRIDINES BY H2O2/V2O5 AT
ROOM TEMPERATURE
Jinlong Su, Cai Zhang, Dan Lin, Yiqin Duan,
Xiangkai Fu, and Ruizhu Mu
College of Chemistry and Chemical Engineering, Southwest University,
Chongqing, China
A mild and highly efficient synthetic method was developed for the aromatization of
1,4-dihydropyridines employing H2O2 and 5 mol% of V2O5. The reactions were carried
out in CH3CN to give pyridine compounds in excellent yields.
Keywords: Aromatization; H2O2; Hantzsch 1,4-dihydropyridines; V2O5
Hantzsch 1,4-dihydropyridine derivatives are usually regarded as a model of the
natural reduced nicotinamine adenine dinucleotide (NADH) coenzyme, which plays
a vital role in many bioreductions by transferring a hydride ion or an electron to
ambient substrates. These compounds possess high pharmacological activity as a
class of useful drugs and antioxidants. Therefore, the aromatization of Hantzsch
1,4-dihydropyridines has recently attracted considerable attention from synthetic
chemists.
In this context, a wide variety of oxidants have been reported for the aromati-
zation of Hantzsch 1,4-dihydropyridines such as ferric chloride hexahydrate,[1]
manganese dioxde,[2] I2=MeOH,[3] nitrosoglutathione (GSNO),[4] silica chromate,[5]
Zr(NO3)4,[6] CO(NH2)2 ꢀ H2O2=I2,[7] IBX,[8] ferric perchlorate,[9] oxone,[10] Pt (II)
complex=hn,[11] 9-phenyl-10-methylacridinium=O2=hn,[12] NHPI=O2,[13] KBrO3=
SnCl4 ꢀ 5H2O,[14] vanadium(V) salts under microwave irradiation,[15] Pd=C=acetic
acid,[16] and 2,6-dicarboxypyridinum.[17] However, most of these reactions require
extended reaction time for completion and give poor yields of the products.
The literature review shows that the combination system of H2O2 and V2O5
has been used for the oxidation alcohols to their correspanding carbonyl com-
pounds.[18–20] In continuation of these works, we decided to examine the capability
of the H2O2=V2O5 system for aromatization of Hantzsch 1,4-dihydropyridines.
Reaction conditions were optimized, and the usefulness of this synthetic
method was studied by subjecting a variety of Hantzsch 1,4-dihydropyridines to
Received December 22, 2008.
Address correspondence to Ruizhu Mu, College of Chemistry and Chemical Engineering,
Southwest University, Chongqing, China. E-mail: muruizhu2008@163.com
595

596
J. SU ET AL.
Scheme 1.
the H2O2=V2O5 system as shown in Scheme 1. The results of this investigation are
summarized in Table 1. As shown, all reactions were carried out within 1 h, and
the pyridine products were obtained in good to excellent yields. The exact mech-
anism of this protocol is not clear; however, we think that the aromatization of
1,4-dihydropyridines follows a redox cycle depicted in Scheme 2.
In conclusion, this article described a novel and mild method for the aromati-
zation of Hantzsch 1,4-dihydropyridines using the H2O2=V2O5 system at room tem-
perature. The cheapness, easy availability of the reagents, mild reaction conditions,
and excellent yield of the products are the advantages that make this protocol a
useful addition to the existing methodologies.
EXPERIMENTAL
General
All reagents and solvents were purchased from commercial sources and used as
received. Hantzsch 1,4-dihydropyridines were synthesized from a combination of
ethyl acetoacetate, aldehyde, and ammonium acetate under mild and solvent-free
conditions (Hantzsch reaction).[21] Silica gel (200–300 mesh) for column chromato-
graphy was purchased from the Qingdao Marine Chemical Factory in China, and
the distillation range of petroleum ether is 60–90ꢁC. Melting points were determined
1
on a Xianke melting-point apparatus and are uncorrected. H NMR spectra were
a
Table 1. Aromatization of Hantzsch 1,4-dihydropyridines by H2O2=V2O5
Hantzsch
1,4-DHPs
Oxidized
products
Reaction
time (h)
Yieldb
(%)
R
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
H
1
1
1
1
1
1
1
1
1
98
94
96
98
95
94
96
96
98
Me
C6H5
4-Br-C6H4
4-Cl-C6H4
4-(MeO)-C6H4
3-(NO2)-C6H4
=
PhCH CH2
2-Furyl
1g
1h
1i
2g
2h
2i
aAll reactions were carried out at room temperature in CH3CN.
bIsolated yields.

H2O2 OXIDIZES 1,4-DIHYDROPYRIDINES
597
Scheme 2.
recorded on Bruker AV-300 or Varian Mercury Plus 300 spectrometer in CDCl3, and
spectral data are reported in parts per million (ppm) relative to tetramethylsilane
(TMS) as internal standard. Mass spectra (MS) were determined on a HP 5988A spec-
trometer by direct inlet at 70 eV. All products were identified by comparison of their
1H NMR, MS spectra, and=or melting point with those of the authentic samples.
General Procedure for the Aromatization of Hantzsch
1,4-Dihydropyridines with H2O2/V2O5 System
In a typical reation, a mixture of V2O5 (5 mg, 0.027 mmol) and aq. 30% H2O2
(2.16 mmol) was prepared. The mixture was stirred at room temperature for 10 min,
and then a solution of 1,4-dihydropyridine (0.54 mmol) in CH3CN (5 mL) was
added. The resulting mixture was stirred for 1 h at room temperature. After com-
pletion of the reaction (monitored by thin-layer chromatography), the mixture was
poured into H2O (10 mL) and extracted with Et2O (3 ꢂ 10 mL). The combined
extracts were dried over anhydrous Na2SO4. Evaporation of the solvent under
reduced pressure followed by short-column chromatography (silica gel, PE–EtOAc,
6:1 v=v) afforded the pure pyridine product.
Representative Spectral Data
1
Compound 2a. Colorless solid, mp 69–70ꢁC (lit.[16] mp 71–72ꢁC); H NMR
(300 MHz, CDCl3): d 1.42 (t, 6H, J ¼ 7.2 Hz), 2.86 (s, 6H), 4.40 (q, 4H, J ¼ 7.2 Hz),
8.68 (s, 1H); MS (EI, 70 ev): m=z (%) 251 (39.8, [M]þ), 206 (100), 195 (19.6), 178
(53.8), 150 (29.0), 106 (21.6).
Compound 2b. Pale yellow oil (lit.[22] oil); 1H NMR (300 MHz, CDCl3): d 1.27
(t, 6H, J ¼ 6.9 Hz), 2.16 (s, 3H), 2.40 (s, 6H), 4.30 (q, 4H, J ¼ 6.9 Hz); MS (EI, 70 ev):
m=z (%) 265 (31.4, [M]þ), 236 (45.9), 220 (100), 208 (43.2), 192 (25.9), 77 (34.5).
1
Compound 2c. Colorless solid, mp 60–62ꢁC (lit.[23] mp 62–63ꢁC); H NMR
(300 MHz, CDCl3): d 0.85 (t, 6H, J ¼ 7.2 Hz), 2.57 (s, 6H), 3.96 (q, 4H, J ¼ 7.2 Hz),
7.21 (d, 2H), 7.32 (t, 3H); MS (EI, 70 ev): m=z (%) 327 (71.2, [M]þ), 282 (48.1), 254
(42.4), 236 (100), 209 (29.4), 139 (33.8).

598
J. SU ET AL.
Compound 2d. Pale yellow solid, mp 53–54ꢁC (lit.[24] mp 52–54ꢁC); 1H NMR
(300 MHz, CDCl3): d 0.95 (t, 6H, J ¼ 7.2 Hz), 2.57 (s, 6H), 4.01 (q, 4H, J ¼ 7.2 Hz),
7.16 (d, 2H, J ¼ 8.4 Hz), 7.35 (d, 2H, J ¼ 8.4 Hz); MS (EI, 70 ev): m=z (%) 407 (31.3,
[M]þ), 362 (100), 334 (72), 289 (49), 77 (13).
1
Compund 2e. Pale yellow solid, mp 66–67ꢁC (lit.[22] mp 65–67ꢁC); H NMR
(300 MHz, CDCl3): d 0.93 (t, 6H, J ¼ 7.2 Hz), 2.57 (s, 6H), 4.00 (q, 4H, J ¼ 7.2 Hz),
7.16 (d, 2H, J ¼ 8.4 Hz), 7.35 (d, 2H, J ¼ 8.4 Hz); MS (EI, 70 ev): m=z (%) 361 (100,
[M]þ), 316 (74), 288 (50), 270 (66), 139 (72), 84 (59), 77 (7).
Compound 2f. Colorless solid, mp 50–52ꢁC (lit.[1] mp 50ꢁC); 1H NMR
(300 MHz, CDCl3): d 0.95 (t, 6H, J ¼ 7.2 Hz), 2.55 (s, 6H), 3.78 (q, 3H), 4.01 (d,
4H, J ¼ 7.2 Hz), 6.86 (d, 2H, J ¼ 9.0 Hz), 7.10 (d, 2H, J ¼ 9.0 Hz); MS (EI, 70 ev):
m=z (%) 357 (100, [M]þ), 312 (21), 282 (20), 266 (11), 255 (9), 135 (18), 105 (14), 77 (27).
Compound 2g. Pale yellow solid, mp 61–63ꢁC (lit.[23] mp 61–63ꢁC); 1H NMR
(300 MHz, CDCl3): d 0.98 (t, 6H, J ¼ 7.2 Hz), 2.62 (s, 6H), 4.04 (q, 4H, J ¼ 7.2 Hz),
7.57–7.59 (m, 2H), 8.18–8.27 (m, 2H); MS (EI, 70 ev): m=z (%) 372 (48.8, [M]þ), 355
(29.5), 327 (100), 299 (39.5), 281 (32.5), 139 (23.2).
1
Compund 2h. Pale yellow solid, mp 163–164ꢁC (lit.[25] mp 162–163ꢁC); H
NMR (300 MHz, CDCl3): d 1.27 (t, 6H, J ¼ 7.2 Hz), 2.56 (s, 6H), 4.32 (q, 4H,
J ¼ 7.2 Hz), 6.79 (d, 1H, J ¼ 16.5 Hz), 7.10 (d, 2H, J ¼ 16.5 Hz), 7.26–7.42 (m, 5H);
MS (EI, 70 ev): m=z (%) 353 (78, [M]þ), 308 (26), 278 (100), 263 (17), 250 (21),
234 (41), 165 (44), 152 (24), 105 (19), 77 (19).
1
Compund 2i. Yellow oil (lit.[1] oil); H NMR (300 MHz, CDCl3): d 1.15 (t,
6H, J ¼ 7.2 Hz), 2.51 (s, 6H), 4.21 (q, 4H, J ¼ 7.2 Hz), 6.42 (d, 1H, J ¼ 3.3 Hz),
6.54 (d, 1H, J ¼ 3.3 Hz), 7.42 (s, 1H); MS (EI, 70 ev): m=z (%) 317 (71.5, [M]þ),
272 (52.3), 243 (38.1), 214 (100), 95 (45.3).
ACKNOWLEDGMENT
The authors are grateful to Southwest University of China for financial support.
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