Silica gel-supported bis(trimethylsilyl) chromate: Oxidation of 1,4-dihydropyridines to pyridines

Article abstract of DOI:10.1080/00397910500330189

An efficient and convenient method for the oxidation of 1,4-dihydropyridines mediated by silica gel-supported bis(trimethylsilyl) chromate in refluxing CH₂Cl₂ is reported. Copyright Taylor & Francis LLC.

Full text of DOI:10.1080/00397910500330189

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Silica Gel–Supported bis(Trimethylsilyl)
Chromate: Oxidation of 1,4‐Dihydropyridines
to Pyridines
Majid M. Heravi a , Fatemeh Derikvand a , Hossein A. Oskooie a & Rahim
Hekmat Shoar a
a Department of Chemistry, School of Science, Azzahra University, Vanak,
Tehran, Iran
Version of record first published: 21 Aug 2006.
To cite this article: Majid M. Heravi , Fatemeh Derikvand , Hossein A. Oskooie & Rahim Hekmat Shoar (2006):
Silica Gel–Supported bis(Trimethylsilyl) Chromate: Oxidation of 1,4‐Dihydropyridines to Pyridines, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:1,
77-82
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Synthetic Communicationsw, 36: 77–82, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500330189
Silica Gel–Supported bis(Trimethylsilyl)
Chromate: Oxidation of
1,4-Dihydropyridines to Pyridines
Majid M. Heravi, Fatemeh Derikvand, Hossein A. Oskooie,
and Rahim Hekmat Shoar
Department of Chemistry, School of Science, Azzahra University, Vanak,
Tehran, Iran
Abstract: An efficient and convenient method for the oxidation of 1,4-dihydropyri-
dines mediated by silica gel–supported bis(trimethylsilyl) chromate in refluxing
CH2Cl2 is reported.
Keywords: Oxidation, DHP, Hantzsch, Bistrimethylsilyl chromate, Supported silica gel
Several 1,4-dihydropyridines (DHPs) are important cardiovascular drugs
because of their calcium antagonistic effect.[1] In the human body, these
compounds are oxidized. They serve as effective redox catalysts under mild
conditions, modeling the NAD(P)H coenzyme to allow study of its
oxidation mechanism in a living system[2,3] in the search for new drugs for
heart vascular disease.[4,5] In addition, recent studies have suggested that
1,4-DHP derivatives also provide an antioxidant protective effect that may
contribute to their pharmacological activity.[6] This effect is not due to the
Ca2þ antagonist effect but is related to the reactivity of these compounds
toward radical species.[7] The oxidation of the dihydropyridine ring is the
main metabolic route for these compounds.
Received in the UK April 18, 2005
Address correspondence to Majid M. Heravi, Department of Chemistry, School of
Science, Azzahra University, Vanak, Tehran, Iran. Fax: 00982/8047861; E-mail:
mmh1331@yahoo.com
77

78
M. M. Heravi et al.
The oxidation of 1,4-DHPs is an important problem in organic chemistry,
and several groups have reported oxidation methods including chemical
oxidation with ferric or cupperic nitrate on a solid support,[8] ceric
ammonium nitrate,[9] ultrasound-promoted oxidation by clay-supported
cupric nitrate,[10] oxidation with PPC,[11] nitric acid,[12] aromatization
with Magtrone TM,[13] oxidation with manganese triacetate,[14] catalytic
oxidation by RuCl3 under oxygen atmosphere,[15] bismuth nitrate penta-
hydrate,[16] pyridinum dichromate,[17] nitric oxide,[18] urea nitrate, and
peroxydisulfide-cobalt(II).[19] More recently the detailed mechanism for the
oxidation of 1,4-DHP derivatives has attracted more attention from
chemists.[20] However, oxidation with most of these reagents leads to
dealkylation at the 4-position or formation of side products.
We have recently used bis(trimethylsilyl) chromate as a versatile
oxidizing agent;[21] herein we report experimentation for the oxidation of
Hantzsch 1,4-dihydropyridines to the corresponding pyridines using bis(tri-
methylsilyl) chromate in refluxing CH2Cl2. In the preliminary examination
we found that reaction is very slow, the yield is low, and the isolation of
products from the ensuing residues is difficult.
The use of a supported regent[22] has attracted interest because of
improved selectivity, reactivity, and associated ease of manipulation.
In view of ongoing research using solid supports in our laboratory,[23] we
used silica gel–supported bis(trimethylsilyl) chromate as an efficient
oxidizing agent to effect the 1,4-dihydropyridines to pyridines conversions.
We examined various supports such as clay, alumina, and montmorilonite
K-10 and found that silica gel provides the best result in terms of formation
of pure products. Dichloromethane is the solvent of choice in this conversion
for the optimum yield. The general applicability, versatility, and scope of this
supported reagent is proved by using a variety of 1,4-DHPs including
1,4-DHPs with H, alkyl, benzyl, and heterocycle at the 4-position (Table 1).
The salient feature of this reaction is the stability of the substituents at the
4-position, confirmed by spectroscopic and physical data. Substituents at the
4-position are normally dealkylated during aromatization by some existing
methods.[24] The other advantages of this method over the existing methods
are milder reaction conditions, excellent yields, availability of reagent,
and easy workup procedure. The procedure involves simple mixing of
1,4-DHPs, silica gel, and bis(trimethylsilyl) chromate and refluxing them in
CH2Cl2.
In summary, the present methodology offers an attractive, efficient,
and high-yielding method for the aromatization of 1,4-dihydropyridines
with keeping the substitutents at 4-position. To show the merit of
the present work in comparison with recently reported protocols, we
compared the results of the oxidation of entry 3 (Table 1) in the
.
presence of NO, PDC, Bi(NO3)3 5H2O, RuCl2–O2, and BTSC–silica
gel with respect to reaction times, yields, and the obtained products
(Table 2).

bis(Trimethylsilyl) Chromate
79
Table 1. Oxidation of 1,4-DHPs using BTSC–silica gel
Time
(min)
Yield
(%)b
Observed
mp (8C)a
Entry
R
Reported
1
2
3
H–
H3C–
Et–
20
30
30
100
100
96
70
69–70[26]
Liq.[5]
Liq.[5]
Liq.
Liq.
4
5
20
40
97
61
61–62[5]
100
60–62
61–63[26]
50[27]
6
7
120
120
100
50
38–41[26]
95.2
Liq.
aProducts exhibited physical properties in accordance with the assigned structures.
bYields refer to the isolated pure products.
EXPERIMENTAL
All the dihydropyridines were prepared according to the literature procedure,
using the appropriate aldehydes, ammonia, and ethyl acetoacetate.[25] Silica
gel 60 for column chromatography was purchased from Merck. All products
Table 2. Results of the oxidation of entry 3 (Table 1) in the
presence of BTSC–silica gel and some of other reagents
Yield of
dehydrogenated
product (%)
Time
(h)
Entry
Oxidant
Ref.
1
2
3
4
5
NO
PDC
.
Bi(NO3)3 5H2O
4
1
91
77
18
17
16
15
—
5
68
45
RuCl2–O2
BTSC–silica gel
60
0.5
100

80
M. M. Heravi et al.
were known; their physical and spectroscopic data were compared with those
of authentic samples and found to be identical.
Preparation of bis(Trimethylsilyl) Chromate, Supported on Silica
Gel, BTSC–Silica Gel
CrO3 (3 g, 0.03 mol) was added to a solution of hexamethyldisiloxane (6.4 mL,
0.03 mol) in dichloromethane (40 mL). The reaction mixture was stirred in a
508C bath for 5 h. Solid CrO3 dissolved, and the dark red mixture became
homogeneous. Silica gel (13 g) was added to the warm reaction mixture and
the resulting mixture was stirred for another 5 h. The solvent and other
volatile components were removed under reduced pressure to afford 19.3 g
of supported reagent.
Oxidation of Hantzsch 1,4-Dihydropyridines: General Procedure
BTSC–silica gel (1.5 g, 2.2 mmol) was added to a solution of 1,4-dihydro-
pyridine (1 mmol) in CH2Cl2 (10 mL). The reaction mixture was refluxed
for the indicated time (Table 1). The progress of reaction was monitored
by TLC using (98 : 2 dichloromethane–ethylacetate) as eluent. After com-
pletion of the reaction, the reaction mixture was filtered on a silica-gel
pad. The filtrate was evaporated to dryness to afford the corresponding
pyridine.
Data
Selected data for 1: Yield: 100%; mp: 70 (lit.[26] 69–70); IR n (KBr): 755,
¯
1553, 1600, 1730, 2923, 2965 cm21
2CH3); 3.0 (s, 6H, 2CH3); 4.2 (q, 4H, 2CH2); 8.6 (s, 1H).
;
1H NMR d (CDCl3): 1.1 (t, 6H,
Selected data for 2: Yield: 100%, liq. (lit.[5] liq.); IR n (film): 1064, 1560,
¯
1730, 2930, 2984 cm21; H NMR d (CDCl3): 1.1 (t, 6H, 2CH3); 2.3 (s, 3H),
2.4 (s, 6H, 2CH3); 4.2 (q, 4H, 2CH2).
1
Selected data for 3: Yield: 96%, liq. (lit.[5] liq.); IR n (film): 1238, 1453,
¯
1569, 1730, 2976 cm21; H NMR d (CDCl3): 0.8–1.2 (t, 3H); 1.1 (t, 6H,
2CH3); 2.4 (s, 6H, 2CH3); 2.8 (q, 2H); 4.2 (q, 4H, 2CH2).
1
Selected data for 4: Yield: 97%, mp: 61 (lit.[5] 61–62); IR n (KBr): 1107,
¯
1561, 1730, 2976, 3015 cm21; H NMR d (CDCl3): 1.1 (t, 6H, 2CH3); 2.4
(s, 6H, 2CH3); 4.2 (q, 4H, 2CH2); 7.3 (s, 5H).
1
Selected data for 5: Yield: 100%, mp: 61–62, (lit.[26] 61–63); IR n
¯
(KBr): 1535–1538, 1560, 1623, 1730, 2965, 3050 cm21
;
1H NMR d
(CDCl3): 1.1 (t, 6H, 2CH3); 2.4 (s, 6H, 2CH3); 4.2 (q, 4H, 2CH2); 7.7
(d, 2H); 8.2 (s, 1H); 8.3 (m, 2H).

bis(Trimethylsilyl) Chromate
81
Selected data for 6: Yield: 100%, mp: 50 (lit.[27] 50); IR n (KBr): 1115,
¯
1292, 1515, 1615, 1730, 2970 cm21; 1H NMR d (CDCl3): 1.1 (t, 6H, 2CH3);
2.4 (s, 6H, 2CH3); 3.8 (s, 3H, CH3); 4.2 (q, 4H, 2CH2); 6.7 (d, 2H); 7.2 (d, 2H).
Selected data for 7: Yield: 95.2%, liq. (lit.[26] 38–41); IR n (KBr): 1046,
¯
1
1107, 1561, 1575, 1730, 2984, 3075 cm21; H NMR d (CDCl3): 1.1 (t, 6H,
2CH3); 2.4 (s, 6H, 2CH3); 4.2 (q, 4H, 2CH2); 6.2–6.5 (c, 2H); 7.4 (c, 1H).
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