Room temperature catalytic aromatization of Hantzsch 1,4-dihydropyridines by sodium nitrite in the presence of acidic silica gel

Article abstract of DOI:10.1007/s00706-005-0425-5

Various alkyl, aryl, and heterocyclic Hantzsch 1,4-dihydropyridines were converted to the corresponding pyridines in excellent yields and short times using sodium nitrite in the presence of a catalytic amount of acidic silica gel at room temperature. Spri

Full text of DOI:10.1007/s00706-005-0425-5

Monatshefte f€ur Chemie 137, 197–200 (2006)
DOI 10.1007/s00706-005-0425-5
Room Temperature Catalytic Aromatization
of Hantzsch 1,4-Dihydropyridines by Sodium
Nitrite in the Presence of Acidic Silica Gel
ꢀ
Mohammed M. Hashemi , Hossein Ghafuri, and Zahed Karimi-Jaberi
Department of Chemistry, Sharif University of Technology, P.O. Box 11365-9516, Tehran, Iran
Received October 26, 2005; accepted October 31, 2005
Published online January 20, 2006 # Springer-Verlag 2006
Summary. Various alkyl, aryl, and heterocyclic Hantzsch 1,4-dihydropyridines were converted to the
corresponding pyridines in excellent yields and short times using sodium nitrite in the presence of a
catalytic amount of acidic silica gel at room temperature.
Keywords. Hantzsch 1,4-dihydropyridines; Aromatization; Sodium nitrite; Silica gel.
Introduction
Hantzsch 1,4-dihydropyridines (DHPs) and their derivatives are an important class
of bioactive molecules in the field of drugs and pharmaceuticals, and have been
extensively studied in view of the biological pertinence of these compounds to the
NADH redox process [1]. Aromatization of Hantzsch DHPs has attracted consider-
able attention due to the fact that DHPs based antihypertensive drugs (Ca2þ chan-
nel blockers) are oxidatively converted to pyridine derivatives by cytochrome
P-450 in the liver [2]. Furthermore, the oxidation of DHPs provides an easy access
to pyridine derivatives. Therefore, oxidative aromatization of DHPs has attracted
continuing interest of organic and medicinal chemists and a plethora of protocols
has been developed [2–11]. Early works mostly used strong oxidants, such as
HNO3 [2], KMnO4 [3], or CAN [4]. Recently, attention has been paid to more
efficient and environmentally benign methods, such as electrochemical oxidation
[5] and catalytic aerobic oxidation using RuCl3 [6], Pd=C [7], activated carbon [8],
Fe(ClO4)3 [9], or N-hydroxyphthalimide [10] as the catalyst. We have also re-
ported aromatization of DHPs with hydrogen peroxide in the presence of cobalt(II)
acetate [11].
Recently, the use of solid supported reagents has received considerable impor-
tance in organic synthesis because of their ease of handling, enhanced reaction
ꢀ
Corresponding author. E-mail: mhashemi@sharif.edu

198
M. M. Hashemi et al.
Scheme 1
times, greater selectivity, simple workup, and recoverability of catalysts [12].
Among the various heterogeneous catalysts silica gel, particularly, impregnated
with hydrochloric acid has advantages of low cost and ease of preparation.
Sodium nitrite generates HNO2 when used under acidic condition and is been
known as oxidant [13]. Recently, sodium nitrite in the presence of silica sulfuric
acid [14] and trifluoroacetic acid [15] has been reported for the oxidation of
alcohols.
Results and Discussions
As part of our studies on the development of supported reagents and catalysts for
the oxidation of organic compounds [11, 16], we describe here a simple, cheap,
and convenient method for the effective aromatization of DHPs with NaNO2
under mild and heterogeneous condition using acidic silica gel (HCl=SiO2) at room
temperature (Scheme 1).
The catalyst (acidic silica gel) is stable and can be easily prepared by addition
of silica gel to aqueous hydrochloric acid, followed by evaporation of the solvent.
Different types of DHPs were subjected to the aromatization at room temperature
with sodium nitrite using acidic silica gel as catalyst. The aromatization of DHPs is
carried out in dichloromethane as solvent and workup is a simple extraction and
separation of the heterogeneous catalyst by filtration. Removal of solvent followed
by purification of products gives pyridines in high yields.
Table 1. Aromatization of Hantzsch 1,4-dihydropyridines by sodium nitrite in the presence of acidic
silica gel
Entry
R
Time=min
Yield=%
1
2
H
5
10
10
10
10
40
30
30
15
15
50
35
10
10
95
90
91
92
92
85
90
75
92
85
84
90
92
91
CH3
3
CH3CH2
CH3CH2CH2
C6H5
4
5
6
3-NO2C6H4
2-thienyl
C6H5–CH¼CH
4-ClC6H4
2-ClC6H4
2-NO2C6H4
2-OHC6H4
4-BrC6H4
4-MeC6H4
7
8
9
10
11
12
13
14

Aromatization of Hantzsch 1,4-Dihydropyridines
199
To establish the generality of this catalytic method, various alkyl, aryl, and
heterocyclic DHPs were converted to the corresponding pyridines. Representative
reaction times and yields are given in Table 1.
Some experiments were performed in order to show the utility of the metho-
dology. When this reaction was done without catalyst after 10 h only starting
materials were observed on the TLC plate.
In conclusion, we have extended successfully the application of sodium nitrite
and acidic silica gel for the aromatization of DHPs at room temperature. This
method offers advantages in terms of simplicity of performance, room temperature
condition, no side product formation, very low reaction times, and a wide range of
DHPs can be converted to their corresponding pyridines. In addition, the silica gel
can be recycled after activation.
Experimental
Products were characterized by comparison of their physical and spectral data with those of authentic
samples. All yields refer to isolated products. IR and NMR spectra were recorded on Perkin Elmer 781
and Bruker DPX500. The progress of reactions was monitored by TLC. DHPs were synthesized
according to the Hantzsch procedure [17].
Preparation of the Catalyst: Acidic Silica Gel
Silica gel (1g) was added to 1 cm3 conc HCL and stirred at room temperature for 10 min. The mixture
was evaporated and dried in vacuum.
Typical Experimental Procedure
To a solution of 1 mmol DHP in 2 cm3 CH2Cl2, 2 mmol NaNO2 and 0.1 g acidic silica gel were added.
The resulting mixture was stirred at room temperature for the time indicated in Table 1. After
completion of the reaction (TLC), the heterogeneous mixture was filtered and thoroughly washed with
the solvent. Rotatory evaporation of the combined filtrate gave the corresponding pyridines. The crude
1
product was pure based on H NMR analysis and could be further purified by crystallization.
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