A facile aromatisation of 1,4-dihydropyridines by ammonium nitrate in acetic acid

Article abstract of DOI:10.3184/030823407X200010

The oxidation of 1,4-dihydropyridines to pyridines with ammonium nitrate as an oxidant in the presence of acetic acid proceeds in excellent yield.

Full text of DOI:10.3184/030823407X200010

JOURNAL OF CHEMICAL RESEARCH 2007
APRIL, 193–194
RESEARCH PAPER 193
A facile aromatisation of 1,4-dihydropyridines by ammonium nitrate in
acetic acid
a
a
a
b
Moreshwar M. Awachat , Ajam C. Shaikh , Nitin V. Ganjave , Subhash P. Chavan ,
b
b*
I. Shivakumar and Uttam R Kalkote
Department of Chemistry, S.P. College, Pune-411030, India
a
bDivision of Organic Chemistry: Technology, Pune-411008, India
The oxidation of 1,4-dihydropyridines to pyridines with ammonium nitrate as an oxidant in the presence of acetic
acid proceeds in excellent yield.
Keywords: 1,4-dihydropyridines, ammonium nitrate, acetic acid, aromatisation
The chemistry of dihydropyridines was reviewed in 1972
Our initial attempts to effect the oxidation of the
simple 4-phenyl-1,4-dihydropyridine as a test case with
a stoichiometric amount of ammonium nitrate in various
solvents, such as CHCl , CH COCH , CCl at room as well
1
2
by Kuthan and in 1988 by Stout. These compounds have
medicinal interest.3 Current studies in dihyropyridine
chemistry involve synthesising NADH mimics, and utilising
them in a variety of synthetic reactions.
3
3
3
4
as at elevated temperature showed an insignificant formation
of the corresponding pyridines. However, oxidation of
4-phenyl-1,4-dihydropyridine was observed when the reaction
was performed with a stoichiometric amount of ammonium
nitrate in acetic acid at reflux temperature, affording the
corresponding pyridine in 45% yield. After increasing the
oxidant to two equivalents, quantitative formation of the
product was observed. The combination of ammonium nitrate
and acetic acid is critical for the success of the reaction as no
reaction was observed with only ammonium nitrate or acetic
acid separately (Table 1).
This success led us to study a variety of 1,4-dihydropyridines
having various substituents at 4-position. A series of 1,
4-dihydropyridines were subjected to the oxidation reaction
in the presence of ammonium nitrate in acetic acid at reflux
temperature to furnish corresponding pyridines in excellent
yields (Table 2).
Substituted 1,4-DHP's are analogues of NADH-coenzymes
and are an important class of drugs.4 These substituted
5
,6
pyridines are useful as anti-hypoxics and anti-ischaemics and
some compounds have acaricidal, insecticidal, bactericidal,
and herbicidal activity.7,8 Oxidation of a 1,4-DHP to a pyridine
is important in the synthesis of the respective radiolabelled
compounds. 1,4-Dihydropyridine based drugs are oxidatively
converted to the corresponding pyridine derivatives by the
action of cytochrome P-450 or other related enzymes in
the liver.9
1
0-12
1
,4-DHPs have a wide range of biological activity
and
13
find use as calcium channel blockers as exemplified by
nifedipine, nitrendipine, nimodipine and amlodipine.
The oxidation of 1,4-DHPs to the corresponding pyridine
derivatives is well documented but many of the reported
1
4
15
procedures either use strong oxidants like HNO
CrO3,
3,
16
KMnO , under severe conditions or need excess reagent like
In the oxidative reactions of the 1,4-dihydropyridines to
4
CAN,17 PCC or expensive Pd/C catalyst, bismuth nitrate,
18
3
19
pyridines it was previously observed that dealkylated
16,24
or cumbersome workup procedures.1
8
products were obtained with oxidants such as KMnO and
4
In view of the above limitations and in continuation of our
Clay MnO . One of the salient feature of our reaction is the
2
interest2
0-22
in developing mild and efficient protocols for
the oxidation of dihydropyridines to pyridine, we thought
that NH NO could serve as an efficient reagent for this
retention of alkyl substituent at 4-position (Table 2, entry
7, 8). This result is in stark contrast to most of the reported
reagents which lead to dealkylation.
4
3
transformation (Scheme 1).
In summary, we have described a practical, efficient and
inexpensive pathway for the oxidation of 1,4-dihydropyridines
in excellent yields using ammonium nitrate as an oxidant in
presence of acetic acid. The availability of ammonium nitrate
and the ease of the reaction should find a widespread use as
the method of choice to effect such transformation.
We now report an efficient oxidation of 1,4-dihydropyridines
to pyridines with inexpensive and readily available ammonium
nitrate in acetic acid at reflux temperature.
1
,4-Dihydropyridines were synthesised according to the
23
reported procedure.
O
R
O
O
R
O
R'
R'
R'
R' Ammonium nitrate
acetic acid
O
O
O
O
N
N
H
Scheme 1
Table 1 Oxidation of 4-phenyl-1,4-dihydropyridine with ammonium nitrate in different solvent at reflux temperature
No.
DHP mmol
Ammonium nitrate/equiv
Solvent
Reaction time/h
Yield/%
1
2
3
4
1
1
1
1
0.0
1.0
2.0
1.0
Acetic acid
Acetic acid
Acetic acid
Water
2
2
2
2
00
45
97
00
*
Correspondent. E-mail: ur.kalkote@ncl.res.in
PAPER: 07/4532

1
94 JOURNAL OF CHEMICAL RESEARCH 2007
Table 2 Oxidation of 1,4-dihydropyridines with ammonium nitrate in acetic acid at reflux temperature
O
R
O
O
R
O
R'
R'
R'
O
R'
O
O
O
N
H
N
Entry no.
R
R'
R
R'
Yield/%
M.p./°C (litref
)
5
1
2
3
4
5
6
7
8
9
0
1
2
3
4
C H
–C H
2
C H
–C H
2
97
90
92
89
91
91
86
88
90
95
90
92
88
90
642
6
H
5
2
5
5
5
5
5
5
5
5
6
H
5
2
5
5
5
5
5
5
5
5
2
2
2
2
2
2
2
2
6
7
5
8
9
0
7
0
0
0
0
0
0
–C H
–C H
70
58
72
62
61
Oil
Oil
1362
1553
100
4–OCH –C H
–C H
4–OCH –C H
–C H
3
6
4
2
3
6
4
2
4–CH –C H
–C H
4–CH –C H
–C H
3
6
4
2
3
6
4
2
2–Cl–C H
–C H
2–Cl–C H5
–C H
6
5
2
6
2
3–NO –C H
–C H
3–NO –C H
–C H
2
6
5
2
2
6
5
2
–(CH ) CH
–C H
–(CH ) CH3
–C H
2
3
3
2
2 3
2
–CH3
–C H
–C H
–CH3
–C H
5
–C H
2
2
–CH3
–CH3
CH3
–CH3
–CH3
CH3
6
5
6
1
1
1
1
1
4–OCH –C H
–H–
4–CH –C H –
3–NO –C H
2–Cl–C H –
4–OCH –C H
–H–
4–CH –C H –
3–NO –C H
2–Cl–C H –
3
6
5
3 6 5
3
CH3
–CH3
CH3
CH3
–CH3
CH3
91
1212
3
6
5
3
6
5
3
2
6
5
2
6
5
71
6
5
6
5
9
0
R.H. Bocker and F.P. Guengerich, J. Med. Chem., 1986, 29, 12.
M. Schramm; G. Thomas; R. Towart and G. Franckowiak, Nature, 1983,
03, 535.
Experimental
1
Typical procedure for oxidation of dihydropyridines with ammonium
nitrate
3
11 A.M. Brown; D.H. Kunze and A. Yatani, Nature, 1984, 311, 570.
12 R.W. Chapman; G. Danko and M.I. Siegel, Pharmacology, 1984, 29,
1
,4-Dihydropyridine (1 mmol), ammonium nitrate (2 mmol) and
2
82.
V.H. Meyer; F. Bossert; W. Vater and K. Stoepel, US. Patent, 1974, 3,
99, 934.
acetic acid (2 ml), were refluxed for 2 h. After completion of the
reaction, it was neutralised with aq.10% NaHCO3 and extracted
with ethyl acetate, dried (anhydrous sodium sulfate) and filtered.
Evaporation of solvent yielded the pyridines in 86–95% yield
1
3
7
1
4
A. Kuno; Y. Sugiyama; K. Katsuta, T. Takenaka and M. Murakami, Chem.
Pharm. Bull., 1992, 40, 1452.
(
Table 2, Entry 1–14). All the products were identical in melting
15 E. Grinsteins; E. Stankevics and G. Duburs, Khim. Geterotsikl. Soedin.,
1967, 1118; Chem. Abstr., 1967, 69, 77095.
1
20,25-30
point and H NMR with the reported in literature
.
1
6
J.–J.V. Eynde; R. D'Orazio and Y. Van Haverbeke, Tetrahedron, 1994, 50,
479.
17 J.R. Pfister, Synthesis, 1990, 689.
2
The support of the Department of Chemistry, S. P. College,
Pune-411 030, Maharashtra, India, is gratefully acknowledged.
1
8
J.-J.V. Eynde; A. Mayence and A. Maquestiau, Tetrahedron, 1992, 48,
63.
4
1
2
9
0
S.H. Mashraqui and M.A. Karnik, Synthesis, 1998, 713.
S.P. Phanchgalle; S.M. Choudhary; S.P. Chavan and U.R. Kalkote,
J. Chem. Res., 2004, 550.
S.P. Chavan; S.W. Dantale; U.R. Kalkote; R.K. Kharul and V.S. Jyotirmai,
Synth. Commun., 1998, 28, 2789.
Received 12 March 2007; accepted 30 March 2007
Paper 07/4532 doi: 10.3184/030823407X200010
2
1
References
22 S.P. Chavan; U.R. Kalkote; I. Shivakumar and R.K. Kharul, Synth.
Commun., 2003, 33, 1333.
2
1
2
3
4
5
U. Eisner and J. Kuthan, Chem. Rev., 1972, 72, 1.
3
4
A. Hantzsch, Liebigs Ann. Chem., 1882, 1, 215.
F. Delgado; C. Abvarez; O. Garcia; G. Perucia and C. Marquez, Synth.
Commun., 1991, 21, 2137.
B. Love and R.M. Sander, J. Org. Chem., 1965, 30, 1914.
F. Engelman, Ann., 1885, 231, 37.
M. David; A. Stout and I. Maeyers, Chem. Rev., 1982, 82, 223.
N. Nakamichi; Y. Kawashita and M. Hayashi, Org. Letter 2002, 4, 3955.
D. Mauzerall and F.H. Westheimer, J. Am. Chem. Soc., 1955, 77, 2261.
E. Wehinger and H. Meyer, Benz, Ger. Offen DE.3.209.276, Chem. Abstr.,
2
2
2
2
5
6
7
1
984, 100, 22580.
E. Wehinger and H. Meyer, Benz, Ger. Offen DE.3.209.276, Chem. Abstr.,
984, 100, 51454.
M. Anniyappan; D. Murlidharan and P.T. Perumal, Tetrahedron, 2002, 58,
6
5
069.
1
2
8
A. Kamal; M. Ahmad; N. Mohd and A.M. Hamid, Bull. Chem. Soc. Jpn.,
1964, 37, 610.
7
8
Ciba Ltd, Neth.Appl. 6.414.307; Chem. Abstr., 1966, 64, 714.
M. Bologh; I. Hermecz; G. Kulcsar; Z. Mészáros; S. Virág; T. Szutz and
G. Sebestyén, Belg. Patent., 889, 340; Chem. Abstr., 1982, 96, 85541.
29 K.Y. Ko and J.Y. Park, Bull. Korean Soc., 1995, 16,200.
30 R.H. Bocker and F.P. Guengerich, J. Med. Chem., 1986, 29, 1596.
PAPER: 07/4532