Facile and efficient aromatization of 1,4-dihydropyridines with M(NO 3)2·XH2O, TNCB, TBAP and HMTAI and preparation of deuterium labeled dehydronifedipine from nifedipine-d3

Article abstract of DOI:10.1016/j.bmcl.2010.04.096

The easy and efficient aromatization of various 1,4-dihydropyridines was investigated using various metal nitrates, trinitratocerium(IV) bromate (TNCB), and tetrabutyl ammonium periodate (TBAP) as oxidant in acetic acid at 100 °C, as well as hexamethylenetetramine-iodine (HMTAI) reflux in methanol. The efficient conversion of nifedipine-d₃ to dehydronifedipine-d ₃ as an internal standard can be used in the measurement of nifedipine concentration in a body.

Full text of DOI:10.1016/j.bmcl.2010.04.096

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3664–3668
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Facile and efficient aromatization of 1,4-dihydropyridines with M(NO3)2ꢀXH2O,
TNCB, TBAP and HMTAI and preparation of deuterium labeled
dehydronifedipine from nifedipine-d3
*
Ajam C. Shaikh, Chinpiao Chen
Department of Chemistry, National Dong Hwa University, Soufeng, Hualien 97401, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
The easy and efficient aromatization of various 1,4-dihydropyridines was investigated using various
metal nitrates, trinitratocerium(IV) bromate (TNCB), and tetrabutyl ammonium periodate (TBAP) as oxi-
dant in acetic acid at 100 °C, as well as hexamethylenetetramine-iodine (HMTAI) reflux in methanol. The
efficient conversion of nifedipine-d3 to dehydronifedipine-d3 as an internal standard can be used in the
measurement of nifedipine concentration in a body.
Received 18 February 2010
Revised 17 April 2010
Accepted 21 April 2010
Available online 24 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Hantzsch’s 1,4-dihydropyridines
Aromatization
Tetra-n-butylammonium periodate
Hexamethylenetetramine-iodine
Trinitratocerium bromate
The oxidation of Hantzsch’s 1,4-dihydropyridines (1,4-DHPs) to
the corresponding pyridines has been extensively studied.1 The rel-
evance of this reaction to the metabolism of Hantzsch’s esters as
calcium channel blocking drugs is exploited to treat various cardio-
vascular disorders.2 For example, 1,4-DHP-derived drugs such as
nifedipine, nitrendipine, and nimodipine are frequently used as
cardiovascular agents (Ca2+ channel blockers) in the treatment of
hypertension and angina pectoris diseases.3 The metabolism of
these drugs involves the oxidative aromatization of 1,4-DHP nu-
cleus to the corresponding pyridine derivatives, which are cata-
lyzed in the liver by cytochrome P-450.4 Therefore, numerous
studies have been performed on the mimicking of this enzyme.5,6
To investigate the mode of action, pharmacokinetics and drug
metabolism of dihyropyridine drugs derived from it, such as nifed-
ipine, nilvadipine and amlodipine, the stable isotope-labeled drugs
are necessary.7 In particular, tritium, carbon-14, iodine-125 and la-
beled dihydropyridine drugs have been used in metabolic investi-
gations, and to determine the affinity as well as binding to
receptors in various tissues.8 However, standard samples for ana-
lyzing drugs are very difficult to obtain, and many researchers
are interested in the preparation of labeled drugs as internal stan-
dards for GC–MS analysis. To fulfill the demand for highly pure
standards, including isotope-labeled dihydropyridines, the authors
initiated a study of the synthesis of such standards. However, our
expertise in the synthesis of internal standards for various con-
trolled drugs motivated us to synthesize nifedipine-d3.9
Numerous reagents have been recommended for the oxidative
aromatization of 1,4-DHPs to the pyridines, such as I2,10 KMnO4,11
SeO2,12 KBrO3/SnCl4ꢀ5H2O,13 magtrieve,14 Pb(OAc)4,15 chloranil,16
H2O2/Co(OAc)2,17 Co-naphthenate/O2,18 nicotinium dichromate,19
clay or wet-SiO2 supported oxidants,20 S-nitrosoglutathione,21
NO,22 palladium catalyst,23 peroxydisulfate–cobalt(II),24 hyperva-
lent iodine reagents,25 inorganic acidic salts, and sodium nitrite
or nitrate,26 solid acids,27 sodium periodate catalyzed by manga-
nese(III) Schiff’s base,28 N,N0-ethylene-bis(benzoylacetoniminato)
copper(II),29 cytochrome P-450,30 electrochemical methods,31
K2FeO4 by microwave promoted32 and photooxidation.33 Although
some of these reactions are performed under mild conditions, most
of them require a long period for completion, strong oxidants,
freshly prepared reagents, tedious work-up, dealkylation, the for-
mation of side products and only modest yields of the products
(Table 1). Therefore, a convenient, rapid and efficient method for
oxidizing 1,4-DHPs is still sought.
Metal nitrates are widely known inorganic salts, and have been
used in various organic transformations, such as the tetrahydro-
pyranylation of alcohols and phenols,34 selective and solvent-free
oxidation using microwave,35 the nitration of thiophene deriva-
tives, the highly regioselective conversion of epoxides to bromohy-
drins,36 aldol condensation,37 Fischer–Tropsch synthesis,38
the preparation of vitamin B12,39 and the chemoselective and
regioselective reduction of nitroarenes, carbonyls and azo dyes.40
* Corresponding author. Tel.: +886 3 863 3597; fax: +886 3 863 0475.
E-mail address: chinpiao@mail.ndhu.edu.tw (C. Chen).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.096

A. C. Shaikh, C. Chen / Bioorg. Med. Chem. Lett. 20 (2010) 3664–3668
3665
Table 1
oxidant in the oxidative transformation to the corresponding sub-
strate was studied. 0.5 equiv of the oxidant gave a very poor yield
with a longer reaction time, but increasing the loading of the oxi-
dant not only increased the yield of the reaction but also consider-
ably reduced the reaction time. Two equivalents of the oxidant
were sufficient for the complete conversion of 1,4-DHP to pyridine
in a short reaction time at 100 °C (Table 3). Temperature is crucial
to efficient conversion. Therefore, the model reaction was per-
formed at an elevated temperature, and reveled that 100 °C is opti-
mal. Because of these results, several 1,4-DHPs were oxidized to
corresponding pyridines in high yields and short reaction times
using various metal nitrates, and TNCB, under the aforementioned
conditions, as indicated in Table 4.
Various reagents for the oxidative aromatization of 1,4-DHP (1b) to the pyridine (2b)
Oxidant
Temp (°C) Solvent
Time (min) Yield (%)
PhCH2Ph3PHSO5/BiCl3
KBrO3/SnCl4
Cu(C22H22N2O2)
PhI(OAc)2
DMP/I2
DMP/KBr
rt
CH3CN
CH3CN
AcOH
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CCl4
120
40
60
60
25
8924a
9013
82
118
rt
rt
rt
9029
8725b
8925d
8225d
9127
180
75
Oxone/NaNO2, wet-SiO2
rt
rt
h
m
180
105
210
30
10033b
9420h
9020h
9424b
Ag2CO3/SiO2
Ag2CO3/Celite
Mn(III)–Salophen/Oxone rt
82
82
CH3CN
CH3CN
Aq CH3CN
The oxidation of 1,4-DHPs using metal nitrates in acetic acid at
100 °C is usually a very clean and efficient method. Alkyl groups
are incompatible at 4-position of 1,4-DHP under various oxidizing
conditions, and readily undergo dealkylation. However, the pro-
posed protocol leaves intact numerous substituents at the 4-posi-
tion, such as alkyl, aryl and heterocyclic groups.
Aromatization by TNCB in acetic acid at 100 °C had a very short
reaction time with moderate to good yield of the corresponding
pyridines. The observed oxidation of 1,4-dihydropyridines with
an alkyl group or a phenyl at the 4-position gave the usual product
with retention of the group at 4-position but trace amount of deal-
kylated pyridine derivative was also observed. This is a general
trend in the oxidation of 1,4-dihydropyridines. However, com-
pounds 1g, 1h, 1j and 1k were subjected to the same reaction con-
ditions to obtain corresponding pyridines with the retention of the
substitution at the 4-position. Metal nitrates were found to be
more effective than TNCB in aromatization.
In the light of the aforementioned conditions, several 1,4-DHPs
were oxidized to corresponding pyridines using TBAP in acetic acid
at 100 °C is very clean and efficient. Surprisingly, this method tol-
erates several substituents, such as alkyl, aryl and heterocyclic
groups at the 4-position of 1,4-DHPs. One of the salient features
of this protocol is the short reaction time. It is one of the best meth-
ods known for the oxidation of 1,4-DHPs to corresponding
pyridines.
Cerium(IV) compounds are the most important oxidants among
lanthanide reagents; specifically, ceric ammonium nitrate (CAN)
is the most versatile oxidizing lanthanide reagents. Sodium bro-
mate is also well documented as an oxidizing agent in various or-
ganic transformations, but both have their limits. A synergistic
effect between CAN and sodium bromate in trinitratocerium(IV)
bromate, (NO3)3CeBrO3 (TNCB), which is quite stable and capable
of the oxidation of benzyl alcohols and acyloins,41 the solvent-free
oxidation of alcohols and deprotection, the oxidative deprotection
of trimethylsilyl ethers,42 and the coupling of thiols,43 makes CAN
and sodium bromate synthetically valuable reagents.
Tetra-n-butylammoinum periodate was reported to be used in
the oxidation of sulfides to sulfoxides, the decarboxylation of a-hy-
droxy carboxylic acids, the transformation of phenyl bromides to
benzoic acids,44 the oxidation of olefins to oxiranes,45 the decar-
boxylation of arylacetic acids,46 and oxidative cleavage of covalent
stannylene derivatives.47 Along with these reports, it was also been
documented that the oxidation of 1,4-DHP’s was performed with
tetra-n-butylammonium periodate in the presence of catalytic
amount of tetraphenylporphyrinatomanganese(III) chloride
[Mn(TPP)Cl] and imidazole as a co-catalyst.286 Hexamethylenetet-
raamine bromide has been well documented for various transfor-
mations,48 but it is congener hexamethylenetetramine iodide is
some what ignored by scientific fraternity. So we decided to ex-
plore its utility in organic transformations.
The ease of handling, environmental friendliness, and extensive
availability of these reagents motivated the development of an effi-
cient and mild protocol for the aromatization of 1,4-DHPs to corre-
sponding pyridines using metal nitrates, TNCB, TBAP and HMTAI
(Scheme 1).
To determine the optimal reaction conditions and the efficiency
of various solvents for the oxidation of 1,4-DHP (1b), the represen-
tative of reactions were studied using Ni(NO3)ꢀ6H2O, and TNCB as
oxidants. In the initial experiment, 1b was subjected to oxidize to
study the effect of solvent on the reaction. Solvents from benzene
to the polar acetonitrile were used,49 and poor to moderate yields
were obtained at room temperature. The results obtained using
acetic acid50 as a solvent in the effective aromatization of 1,4-DHPs
motivated its use in the following reactions. Surprisingly, the oxi-
dative transformation of 1b to 2b was completed in a short time
with good yield (Table 2). The dependence of molar ratio on the
Table 2
Screening of solvent for converting 1b to 2b with 1 equiv of Ni(NO3)2ꢀ6H2O and TNCB
at rt
O
R
O
O
R
O
EtO
H3C
OEt
EtO
OEt
Ni(NO3)2.6H2O or
TNCB, solvent, 100 o
C
N
CH3
H3C
N
CH3
H
2b
TNCB
1b
Solvent
Ni(NO3)2ꢀ6H2O
Time (h)
Yield (%)
Time (h)
Yield (%)
C6H6
CH2Cl2
CH3CN
AcOH/H2O (1:1)
AcOH
12
—
—
10
52
63
12
12
12
6
—
—
8
41
48
12
12
6
1
1
Table 3
O
R
O
O
R
O
Screening of the amount of Ni(NO3)2ꢀ6H2O and TNCB in acetic acid at 100 °C for
M(NO3)2.XH2O or
TNCB or TBAP
converting 1b to 2b
R'O
H3C
OR'
R'O
H3C
OR'
CH3
AcOH, 100 oC or
HMTAI, MeOH, reflux
Equiv
Ni(NO3)3ꢀ6H2O
Time (h) Yield (%)
TNCB
N
H
1
CH3
N
Time (h)
Yield (%)
2
0.5
1
1.5
2
12
1
48
70
84
95
12
2
2
37
55
60
75
Scheme 1. General scheme for the oxidation of 1,4-dihydropyridines using
M(NO3)2ꢀXH2O or TNCB or TBAP in acetic acid at 100 °C or HMTAI reflux in
methanol.
0.5
0.16
0.083

3666
A. C. Shaikh, C. Chen / Bioorg. Med. Chem. Lett. 20 (2010) 3664–3668
Table 4
Oxidation of 1,4-DHP’s by different metal nitrates TNCB and TBAP in acetic acid at 100 °C, and HMTAI in methanol55
1,4-DHP
R
R0
Product
Time [min] (Yield)[%]
Mp (°C)
Literature
A
B
C
D
E
F
G
Found
1a
1b
1c
1d
1e
1f
1g
1h
1i
–H
–C6H5
–CH3
–C2H5
–C2H5
–C2H5
–C2H5
–C2H5
–C2H5
–C2H5
–C2H5
–C2H5
–C2H5
–C2H5
–CH3
2a
2b
2c
2d
2e
2f
2g
2h
2i
5 (97)
5 (93)
5 (91)
10 (92)
10 (95)
5 (94)
5 (95)
5 (90)
5 (92)
5 (94)
5 (90)
10 (91)
10 (88)
10 (94)
5 (94)
10 (85)
5 (75)
5 (65)
10 (70)
10 (68)
5 (72)
5 (71)
5 (76)
5 (69)
5 (63)
10 (68)
5 (70)
5 (94)
5 (93)
5 (95)
5 (92)
5 (92)
10 (93)
5 (91)
10 (90)
10 (90)
5 (92)
10 (93)
10 (92)
5 (93)
10 (94)
5 (90)
5 (89)
5 (91)
5 (92)
5 (94)
10 (92)
5 (92)
5 (90)
70–7138
63–649,51
Oil52
70–71
62–63
Oil
Oil
Oil
74–75
97–98
52–53
162–163
43–44
115–116
Oil
5 (90)
10 (91)
5 (90)
10 (93)
10 (90)
5 (95)
10 (96)
5 (90)
10 (89)
15 (90)
10 (96)
10 (95)
5 (90)
10 (89)
10 (88)
5 (93)
5 (90)
5 (90)
5 (92)
5 (94)
10 (90)
5 (93)
5 (98)
5 (92)
5 (90)
5 (87)
10 (94)
5 (95)
10 (89)
10 (88)
5 (92)
5 (91)
5 (92)
–(CH2)2CH3
–(CH2)8CH3
-4-CH3C6H4
-4-(CH3)3CC6H4
-4-CH3OC6H4
–CH@CHC6H5
-3-ClC6H4
-4-NO2C6H4
-2-Furyl
Oil52
Oil9,51
72–739,51
—
51–539,51
162–1659,51
41–447
114–1159,51
Oil16,51
1j
1k
1l
2j
2k
2l
10 (93)
5 (91)
A—Cu(NO3)2ꢀ3H2O in acetic acid at 100 °C; B—Ni(NO3)2ꢀ6H2O in acetic acid at 100 °C; C—Co(NO3)2ꢀ6H2O in acetic acid at 100 °C; D—Mg(NO3)2ꢀ6H2O in acetic acid at 100 °C;
E—TNCB in acetic acid at 100 °C; F—TBAP in acetic acid at 100 C; G—HMTAI in methanol, reflux.
CO2R'
O
The aforementioned conditions for the oxidation of 1,4-DHP by
hexamethylenetetramine-iodine (HMTAI), were performed, but
gave some dealkylated product. The alternative condition was
2 equiv of HMTAI in methanol at reflux temperature effectively
converted 1b to the corresponding pyridine 2b within 5 min. To
establish the generality of this protocol, various 1,4-DHPs were
subjected to the same conditions and the outcomes presented in
Table 4. All substituents at the 4-position, such as alkyl, aryl and
heterocyclic groups, were found to be intact, and the reaction time
was short.
R
R'O2C
R
H
R'O2C
CO2R'
TBAP
H
N
-O
I
O
N
H
H
1
O
R
R'O2C
CO2R'
-
H O +
2
IO3
+
N
2
Figure 1 presents the mechanism of oxidation with tetrabutyl
ammonium periodate (TBAP). The periodate ion removed a proton
and a hydride from 1,4-DHP, and formed the corresponding pyri-
dine, iodate ion and one H2O. Little is known about the mechanism
and structure of the HMTAI, but we strongly believe that active
species must be formed between nitrogen and the I2 molecule as
a transition state.53 Therefore, hydride transfer from the 1,4-DHP
moiety to the active species may drive equilibrium to the right-
side, causing aromatization of the 1,4-DHP.
Figure 2 proposes a mechanism. The electron-rich iodine may
remove a proton from the amino group of 1,4-DHP to form an HI,
and the bonding electron pair conjugates to eject a hydride from
the 4-position of 1,4-DHP. The ejected hydride reacts with the
other iodine to form HI. Two molecules of HI are neutralized by
HMTAI to form an ammonium salt. This neutralization drives the
reaction to the products.
Figure 1. Mechanism of oxidation of 1,4-DHPs by TBAP.
CO2R'
R
R'O2C
R
H
R'O2C
CO2R'
HMTAI
H
N
I
δ
H
N
−
I
H
1
N
δ+
I
I
N
N
N
N
R
R'O2C
CO2R'
N
N
+
I
I
N
+ 2HI
N
2
Preparation of nifedipine-d3 began with the synthesis of methyl
Figure 2. Mechanism of oxidation of 1,4-DHPs by HMTAI.
acetoacetate-d3 by Meldrum’s acid (Scheme 2).54 Acetylation of
O
O
O
O
O
CD3OD
(38%)
O
HO
OH
O
O
AcCl
pyridine
(78%)
Ac2O, acetone
conc. H2SO4
(55%)
OCD3
NO2
O
O
O
O
O
5
3
4
O
O
NO2
O
OCH3
AcOH, piperidine
benzene, Dean-Stark
5
NO2
H3CO2C
CO2CD3
H
MeOH, NH3(I)
(46%, 2 steps)
H3CO2C
N
H
7
O
6
NO2
Ni(NO3)2.6H2O
AcOH, 100 oC
(90%)
H3CO2C
CO2CD3
N
8
Scheme 2. Synthesis of nifedipine-d3 and dehydronifedepine-d3.

A. C. Shaikh, C. Chen / Bioorg. Med. Chem. Lett. 20 (2010) 3664–3668
3667
12. (a) Phanchgalle, S. P.; Choudhary, S. M.; Chavan, S. P.; Kalkote, U. R. J. Chem. Res.
2004, 550; (b) Cai, X.; Yang, H.; Zhang, G. Can. J. Chem. 2005, 83, 273.
13. Zeynizadeh, B.; Dilmaghani, K. A.; Roozijoy, A. Synth. Commun. 2005, 35, 557.
14. Ko, K.-Y.; Kim, J.-Y. Tetrahedron Lett. 1999, 40, 3207.
15. (a) Litvic, M.; Cepanec, I.; Filipan, M.; Kos, K.; Bartolincic, A.; Druskovic, V.; Tibi,
M. M.; Vinkovic, V. Heterocycles 2005, 65, 23; (b) Varma, R. S.; Kumar, D.
Tetrahedron Lett. 1999, 40, 21.
16. Gelbard, G.; Lin, J.; Roques, N. J. Org. Chem. 1992, 57, 1789.
17. (a) Hashemi, M. M.; Ahmadibeni, Y.; Ghafuri, H. Monatsh. Chem. 2003, 134, 107;
(b) Karami, B.; Montazerozohori, M.; Nasr-Esfahani, M. Heterocycles 2005, 65,
2181.
18. (a) Chavan, S. P.; Kalkote, U. R.; Shivakumar, I.; Kharul, R. K. Synth. Commun.
2003, 33, 1333; (b) Mashraqui, S. H.; Kamik, M. A. Tetrahedron Lett. 1998, 39,
4895.
Meldurm’s acid (3), followed by refluxing with methanol-d4, and
yielded methyl acetoacetate-d3 (5). Methyl acetoacetate was con-
densed with 2-nitrobenzaldehyde and then with methyl acetoace-
tate-d3 (5) to yield nifedipine-d3 (7). Efficient oxidation with
Ni(NO3)2ꢀ6H2O under the specified conditions gave the corre-
sponding dehydronifedipine-d3 (8) in quantitative yield.
In conclusion, metal nitrates, TNCB, TBAP and HMTAI are valu-
able for use with the methods currently available for the oxidation
of Hantzsch’s 1,4-DHPs. These reagents are very stable and can be
taken in carrying out their reactions in general conditions. A short
reaction time, easy work-up55 and good to excellent yields of cor-
responding pyridines are obtained. Additionally, this protocol pro-
vides transformation to corresponding pyridines without any
external activation such as microwave or ultrasound. Nifedipine-
d3 is easily and elegantly synthesized and ultimately converted
to the corresponding dehydronifedipine-d3, which can be exploited
as an internal standard for the quantitative measurement of the
consumption of nifedipine in the body. This synthesis may be use-
ful in studying metabolic activity and pharmacokinetics and in the
quantitative analysis of nifedipine.
19. (a) Eynde, J.-J. V.; Mayence, A.; Maquestiau, A. Tetrahedron 1992, 48, 463; (b)
Sadeghi, M. M.; Baltork, I. M.; Memarian, H. R.; Sobhani, S. Synth. Commun.
2000, 30, 1661.
20. (a) Maquestiau, A.; Mayence, A.; Eynde, J.-J. V. Tetrahedron Lett. 1991, 32, 3839;
(b) Zeynizadeh, B.; Dilmaghani, K. A.; Roozijoy, A. J. Chin. Chem. Soc. 2005, 52,
1001; (c) Niknam, K.; Zolfigol, M. A.; Razavian, S. M.; Baltork, I. M. Heterocycles
2005, 65, 657; (d) Zolfigol, M. A.; Sadeghi, M. M.; Baltork, I. M.; Choghamarani,
A. G.; Taqian-Nasab, A. Asian J. Chem. 2001, 13, 887; (e) Heravi, M. M.;
Derikvand, F.; Oskooie, H. A.; Shoar, R. H. Synth. Commun. 2006, 36, 77; (f)
Zolfigol, M. A.; Ghorbani Choghamarani, A.; Dialameh, S.; Sadeghi, M. M.;
Mohammadpoor-Baltork, I.; Memarian, H. R. J. Chem. Res. (S) 2003, 19; (g)
Zolfigol, M. A.; Shirin, F.; Choghamarani, A. G.; Baltork, I. M. Phosphorus, Sulfur
Silicon Relat. Elem. 2003, 178, 1709; (h) Momeni, A. R.; Sameh, T.;
Golmohammadi, H.; Naghash, H. J.; Aliyan, H.; Massah, A. R.; Solati, S. Bull.
Korean Chem. Soc. 2006, 27, 355.
Acknowledgment
21. (a) Mao, Y. Z.; Jin, M. Z.; Liu, Z. L.; Wu, L. M. Org. Lett. 2000, 2, 741; (b) Zolfigol,
M. A.; Choghamarani, A. G.; Shahamirian, M.; Safaiee, M.; Baltork, I. M.;
Mallakpour, S.; Alibeik, M. A. Tetrahedron Lett. 2005, 46, 5581.
22. (a) Itoh, T.; Nagata, K.; Okada, M.; Ohsawa, A. Tetrahedron Lett. 1995, 36, 2269;
(b) Itoh, T.; Nagata, K.; Matsuya, Y.; Miyazaki, M.; Ohsawa, A. J. Org. Chem. 1997,
62, 3582; (c) Zolfigol, M. A.; Zebarjadian, M. H.; Sadeghi, M. M.;
Mohammadpoor-Baltork, I.; Memarian, H. R.; Shamsipur, M. Synth. Commun.
2001, 31, 929.
This research was supported by the National Science Council of
the Republic of China under grant of NSC 97-2113-M-259-002-
MY3.
Supplementary data
23. (a) Dzhemilev, U. M.; Yakupova, A. Z.; Minsker, S. K.; Tolstikov, G. A. Bull. Acad.
Sci. USSR Div. Chem. Sci. (Engl. Transl.) 1978, 27, 585; (b) Nakamichi, N.;
Kawashita, Y.; Hayashi, M. Org. Lett. 2002, 4, 3955.
24. (a) Anniyappan, M.; Muralidharan, D.; Perumal, P. T. Tetrahedron 2002, 58,
5069; (b) Nasr-Esfahani, M.; Moghadam, M.; Valipour, G. J. Iran. Chem. Soc.
2008, 5, 244; (c) Adibi, H.; Hajipour, A. R. Bioorg. Med. Chem. Lett. 2007, 17,
1008.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.04.096.
References and notes
25. (a) Varma, R. S.; Kumar, D. J. Chem. Soc., Perkin Trans. 1 1999, 1755; (b) Cheng,
D. P.; Chen, Z. C. Synth. Commun. 2002, 32, 793; (c) Lee, J. W.; Ko, K. Y. Bull.
Korean Chem. Soc. 2004, 25, 19; (d) Karade, N. N.; Gampawar, S. V.; Kondre, J.
M.; Shinde, S. V. ARKIVOC 2008, xii, 9; (e) Lee, K.-H.; Ko, K.-Y. Bull. Korean Chem.
Soc. 2002, 23, 1505; (f) Chai, L.; Zhao, Y.; Sheng, Q.; Liu, Z. Q. Tetrahedron Lett.
2006, 47, 9283.
1. (a) Eisner, U.; Kuthan, J. Chem. Rev. 1972, 72, 1; (b) Stout, D. M. Chem. Rev. 1982,
82, 223. and references cited therein.
2. (a) Janis, R. A.; Triggle, D. J. J. Med. Chem. 1983, 26, 775; (b) Gordeev, M. F.; Patel,
D. V.; Gordon, E. M. J. Org. Chem. 1996, 61, 924; (c) Bossert, F.; Vater, W. Med.
Res. Rev. 1989, 9, 291.
3. (a) Flaim, S. F.; Zelis, R. Fed. Proc. 1981, 40, 2877; (b) Reid, J. L.; Meredith, P. A.;
Pasanisi, F. J. Cardiovasc. Pharmacol. 1985, 7, S18; (c) Buhler, F. R.; Kiowski, W. J.
Hypertens. 1987, 5, S3; (d) Triggle, D. J.; Lango, D. D.; Janis, R. A. Med. Res. Rev.
1989, 9, 123; (e) Baranda, A. B.; Alonso, R. M.; Jiménez, R. M.; Weinmann, W.
Forensic Sci. Int. 2006, 156, 23.
4. (a) Böcker, R.; Guengerich, F. P. J. Med. Chem. 1986, 29, 1596; (b) Guengerich, F.
P.; Brian, W. R.; Iwasaki, M.; Sari, M. A.; Baarnhielm, C.; Berntsson, P. J. Med.
Chem. 1991, 34, 1838.
26. (a). Org. Synth. 1943, Coll. 2, 214; (b) Tsuda, K.; Satch, Y.; Ikekawa, N.; Mishima,
H. J. Org. Chem. 1956, 21, 800; (c) Kuno, A.; Sugiyama, Y.; Katsuta, K.; Takenaka,
T.; Murakami, M. Chem. Pharm. Bull. 1992, 40, 1452; (d) Loev, B.; Snader, K. M. J.
Org. Chem. 1965, 30, 1914; (e) Zolfigol, M. A.; Kiany-Borazjani, M.; Sadeghi, M.
M.; Memarian, H. R.; Mohammadpoor-Baltork, I. J. Chem. Res. (S) 2000, 167; (f)
Zolfigol, M. A.; Kiany-Borazjani, M.; Sadeghi, M. M.; Memarian, H. R.;
Mohammadpoor-Baltork, I. Synth. Commun. 2000, 30, 2945; (g) Zolfigol, M.
A.; Kiany-Borazjani, M.; Sadeghi, M. M.; Mohammadpoor-Baltork, I.;
Memarian, H. R. Synth. Commun. 2000, 30, 3919; (h) Zolfigol, M. A.; Shirin, F.;
Ghorbani Choghamarani, A.; Mohammadpoor-Baltork, I. Green Chem. 2002, 4,
562; (i) Zolfigol, M. A.; Kiany-Borazjani, M.; Sadeghi, M. M.; Mohammadpoor-
Baltork, I.; Memarian, H. R. Synth. Commun. 2000, 30, 551; (j) Heravi, M. M.;
Bakhtiari, K.; Oskooie, H. A.; Hekmatshoar, R. Russ. J. Org. Chem. 2007, 43, 1408;
(k) Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Fatima, N.; Yadav, J. S. Synthesis
2003, 1267; (l) Balogh, M.; Hermecz, I.; Meszaros, Z.; Laszlo, P. Helv. Chim. Acta
1984, 67, 2270.
27. Zolfigol, M. A.; Bagherzadeh, M.; Niknam, K.; Shirind, F.; Mohammadpoor-
Baltore, I.; Choghamarana, A. G.; Baghbanzadeh, M. J. Iran. Chem. Soc. 2006, 3,
73.
28. (a) Nasr-Esfahani, M.; Moghadam, M.; Tangestaninejad, S.; Mirkhanib, V.;
Momenic, A. R. Bioorg. Med. Chem. 2006, 14, 2720; (b) Nasr-Esfahani, M.;
Moghadam, M.; Tangestaninejad, S.; Mirkhani, V. Bioorg. Med. Chem. Lett. 2005,
15, 3276; (c) Heravi, M. M.; Behbahani, F. K.; Oskooie, H. A.; Shoar, R. H.
Tetrahedron Lett. 2005, 46, 2775.
29. Dehghanpour, S.; Heravi, M. M.; Derikvand, F. Molecules 2007, 12, 433.
30. Guengrich, F. P.; Bocker, R. H. J. Biol. Chem. 1998, 263, 8168.
31. (a) Pragst, F.; Kaltofen, B.; Volke, J.; Kuthan, J. J. Electroanal. Chem. 1981, 119,
301; (b) López-Alarcón, C.; Núñez-Vergara, L. J.; Squella, J. A. Electrochim. Acta
2003, 48, 2505.
32. Khalilzadeh, M. A.; Hosseini, A.; Sadeghifar, H.; Valipour, P. Acta Chim. Slov.
2007, 54, 900.
33. (a) Mitsunobu, O.; Matsumoto, S.; Wada, M.; Masuda, H. Bull. Chem. Soc. Jpn.
1972, 45, 1453; (b) Jin, M. Z.; Yang, L.; Wu, L. M.; Liu, Y. C.; Liu, Z. L. Chem.
Commun. 1998, 2451.
5. Meunier, B. Chem. Rev. 1992, 92, 1411.
6. Sono, M.; Roach, M. P. Chem. Rev. 1992, 96, 2841.
7. (a) Rampe, D.; Hake, P. W.; Borretzen, B.; Holm, K. H.; Skattebol, L. Eur. J. Med.
Chem. 1993, 28, 259; (b) Satoh, Y.; Okumura, K.; Shiokawa, Y. Chem. Pharm. Bull.
1994, 42, 950; (c) Ohtaka, K.; Kajiwara, M. J. Labelled Compd. Radiopharm. 2003,
46, 1177; (d) Pleiss, U. J. Labelled Compd. Radiopharm. 2007, 50, 818.
8. (a) Soldatov, N. M. Bioorg. Chem. 1989, 17, 141; (b) Demmer, A.; Andreae, S.;
Thole, H.; Tümmler, B. Eur. J. Biochem. 1999, 264, 800; (c) Shevchenko, V. P.;
Myasoedov, N. F.; Soldatov, N. M.; Duburs, G. J.; Kastron, V. V.; Skrastins, I. P. J.
Labelled Compd. Radiopharm. 1989, 27, 721; (d) Taki, M.; Kuniyasu, A.;
Nakayama, H.; Kanaoka, Y. Chem. Pharm. Bull. 1991, 39, 1860; (e) Iwanami,
M.; Shibanuma, T.; Fujimoto, M.; Kawai, R.; Tamazawa, K.; Takenaka, T.;
Takahashi, K.; Murakami, M. Chem. Pharm. Bull. 1979, 27, 1426; (f) Arima, H.;
Tamazawa, K.; Takeuchi, M. J. Labelled Compd. Radiopharm. 1987, 25, 161.
9. (a) Xu, Y.-Z.; Chen, C. J. Labelled Compd. Radiopharm. 2006, 49, 897; (b) Xu, Y.-Z.;
Chen, C. J. Labelled Compd. Radiopharm. 2006, 49, 1187; (c) Xu, Y.-Z.; Lin, H.-R.;
Lua, C.-A.; Chen, C. J. Chin. Chem. Soc. 2007, 54, 493; (d) Shaikh, A. C.; Wang, Y.-
Y.; Chen, C. J. Labelled Compd. Radiopharm. 2007, 50, 660; (e) Chen, Y.-J.; Chen, C.
J. Labelled Compd. Radiopharm. 2007, 50, 1143; (f) Wang, Y.-Y.; Chen, C. J. Chin.
Chem. Soc. 2007, 54, 1363; (g) Wang, Y.-Y.; Chen, C. J. Labelled Compd.
Radiopharm. 2007, 50, 1262; (h) Shaikh, A. C.; Chen, C. J. Labelled. Comp.
Radiopharm. 2008, 51, 72; (i) You, Z.-Y.; Chen, Y.-J.; Wang, Y.-Y.; Chen, C. J. Chin.
Chem. Soc. 2008, 55, 663; (j) Xu, Y.-Z.; Lin, H.-R.; Lua, A.-C.; Chen, C. J. Serb.
Chem. Soc. 2008, 73, 1223; (k) Srimurugan, S.; Murugan, K.; Chen, C. Chem.
Pharm. Bull. 2009, 57, 1421.
10. Yadav, J. S.; Reddy, B. V. S.; Sabitha, G.; Reddy, G. S. K. K. Synthesis 2000, 11,
1532.
11. Eynde, J.-J. V.; D’Orazio, R.; Van Haverbeke, Y. Tetrahedron 1994, 50, 2479.
34. Wang, M.; Song, Z.-G.; Gong, H.; Jiang, H. Monatsh. Chem. 2009, 140, 177.
35. Varma, R. S.; Dahiya, R. Tetrahedron Lett. 1998, 39, 1307.

3668
A. C. Shaikh, C. Chen / Bioorg. Med. Chem. Lett. 20 (2010) 3664–3668
36. Suh, Y.-G.; Koo, B.-A.; Ko, J.-A.; Cho, Y.-S. Chem. Lett. 1993, 22, 1907.
37. Choudary, B. M.; Kantam, M. L.; Kavita, B.; Reddy, C. V.; Rao, K. K.; Figueras, F.
Tetrahedron Lett. 1998, 39, 3555.
51. Sausins, A.; Duburs, G. Heterocycles 1988, 27, 291.
52. Eynde, J.-J. V.; Delfosse, F.; Mayence, A.; Haverbeke, Y. V. Tetrahedron 1995, 51,
6511.
38. Sun, S.; Tsubaki, N.; Fujimoto, K. Appl. Catal., A 2000, 202, 121.
39. http://en.wikipedia.org/wiki/Vitamin_B12.
40. Selvam, P.; Mohapatra, S. K.; Sonavane, S. U.; Jayaram, R. V. Tetrahedron Lett.
2004, 45, 2003.
41. (a) Firouzabadi, H.; Iranpoor, N. Synth. Commun. 1983, 13, 1143; (b) Shirini, F.;
Tajik, H.; Aliakbar, A.; Akbar, A. Synth. Commun. 2001, 31, 767. and references
cited therein.
42. Shirini, F.; Esm-Hosseini, M.; Hejazi, Z. Synth. Commun. 2005, 35, 2913.
43. Tajik, H.; Shirini, F.; Farahkah, O. R.; Lakouraj, M. M.; Baltork, I. M. Russ. J. Org.
Chem. 2002, 38, 1384.
44. Santaiello, R.; Manzocchi, A.; Farachi, C. Synthesis 1980, 563.
45. Comer, W.; Lane, R. U.S. Patent 4120,877, 1979; Chem. Abstr. 90, 54802q.
46. Santaniello, R.; Ponti, F.; Manzocchi, A. Tetrahedron Lett. 1980, 21, 2655.
47. David, S.; Thiéffry, A. Tetrahedron Lett. 1981, 22, 2885.
48. (a) Heravi, M. M.; Sabaghiani, A. J.; Bakavoli, M.; Ghassemzadeh, M.; Bakhtiari,
K. J. Chin. Chem. Soc. 2007, 54, 123; (b) Heravi, M. M.; Abdolhosseini, N.;
Oskooie, H. A. Tetrahedron Lett. 2005, 46, 8959; (c) Bandgar, B. P.; Admane, S. B.;
Jare, S. S. J. Chem. Res. (S) 1998, 154; (d) Gangwani, H.; Sharma, P. K.; Banerji, K.
K. J. Chem. Res. (S) 1999, 180.
53. Pritzkow, H. Acta Crystallogr., Sect. B 1975, 31, 1589.
54. Maquestiau, A.; Mayence, A.; Vanden Eynde, J. J. Tetrahedron Lett. 1991, 32,
3839.
55. General procedure of oxidation of Hantzsch’s 1,4-dihydropyridines using
Cu(NO3)2ꢀ3H2O, Ni(NO3)2ꢀ6H2O, Co(NO3)2ꢀ6H2O, Mg(NO3)2ꢀ6H2O, TNCB and TBAP
in acetic acid at 100 °C: Metal nitrate or TNCB (2 equiv) was added to the
solution of 1,4-DHP (1 equiv) in acetic acid (3.0 mL) and it was heated at 100 °C
for a given time. After completion of reaction, reaction mixture was cooled
down to rt and acetic acid was neutralized by 2 M NaOH. Aqueous layer was
extracted by dichloromethane, combined organic layers were dried over
anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude
product which was further purified by silica gel column chromatography using
ethyl acetate–hexanes as mobile phase yielded corresponding pyridine.
General procedure for oxidation of Hantzsch’s 1,4-DHPs (1g) by HMTAI in
methanol: An HMTAI (167 mg, 0.26 mmol) was added to the solution of 1,4-
DHP (1g) (50 mg, 0.13 mmol) in 7.0 mL methanol and it was heated at reflux
for given time. After completion of reaction, reaction mixture was cooled down
to rt and filtered through short Celite pad. Methanol was removed under
reduced pressure to obtain crude product which was further purified by silica
gel column using ethyl acetate–hexane as mobile phase yielded corresponding
pyridine.
49. We have tested number of solvents such as benzene, dichloromethane,
acetonitrile and acetic acid/water.
50. Awachat, M. M.; Shaikh, A. C.; Ganjave, N. V.; Chavan, S. P.; Shivakumar, I.;
Kalkote, U. R. J. Chem. Res. 2007, 193.