Bismuth nitrate pentahydrate: A convenient reagent for the oxidation of Hantzsch 1,4-dihydropyridines

Article abstract of DOI:10.1055/s-1998-4516

Bi(NO₃)₃·5 H₂O (1), an inexpensive crystalline solid readily oxidises several 4-substituted Hantzsch 1,4-dihydropyridines in acetic acid medium at room temperature. The reaction conditions are mild, easy to execute and the

Full text of DOI:10.1055/s-1998-4516

May 1998
SYNTHESIS
713
Bismuth Nitrate Pentahydrate: A Convenient Reagent for the Oxidation
of Hantzsch 1,4-Dihydropyridines
Sabir H. Mashraqui,* Madhavi A. Karnik
Department of Chemistry, University of Mumbai, Vidyanagari, Santacruz (East), Mumbai 400098, India
Fax +91(22)6145722; E-mail shm@chbu.ernet.in
Received 3 June 1997; revised 29 July 1997
Abstract: Bi(NO3)3·5 H2O (1), an inexpensive crystalline solid
readily oxidises several 4-substituted Hantzsch 1,4-dihydropyridi-
nes in acetic acid medium at room temperature. The reaction con-
ditions are mild, easy to execute and the isolated yields of the
oxidised products are fair to excellent. However, oxidation of 4-
isopropyl-1,4 DHP 16 with 1 afforded the dealkylated pyridine 9,
whereas the oxidation of 4-(4-hydroxyphenyl) Hantzsch ester 17
products are fair to excellent (50–90%). The unique role
of acetic acid in promoting these oxidations may be tenta-
tively attributed to, i) appreciable solubility of 1 in this
solvent, and ii) generation of the active oxidant, HNO3 by
equilibrium exchange between NO3 and CH3CO2 ligands.
All the starting Hantzsch esters 2–8 and the oxidised py-
was accompanied by the nitration at the phenolic ring to form 18 ridines 9–15 are known compounds which have been fully
in good yield.
characterised by their analysis, mps and/or spectral data.
Hantzsch 1,4-dihydropyridines (Hantzsch 1,4-DHP) have
been extensively utilised as the analogs of NAD(P)H co-
enzymes to study the mechanism and synthetic potential
of various redox processes.1,2 In addition, several 1,4-
DHP based drugs, such as Nifedipine and Niguldipine
have been recognised as calcium entry blockers for the
treatment of cardiovascular diseases.3–5 Both during the
Scheme 1
redox processes2 and in the course of drug metabolism,3
However, oxidation of diethyl 4-isopropyl-2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylate (16)18 (Scheme 2)
with 1 proceeded exceptionally rapidly and gave, after
workup, the dealkylated pyridine 17 in 75% yield. Ace-
tone was detected in the reaction mixture (IR 1710 cm-1;
1H NMR, sharp singlet at d = 2.1) as a byproduct. The for-
mation of acetone can be tentatively explained by assum-
ing heterolysis of the C–C bond to generate an isopropyl
cation which undergoes oxidation with 1 to form acetone.
The dealkylation noted above has ample precedence in
1,4-DHP systems are oxidatively transformed into the
corresponding pyridine derivatives. Furthermore, the oxi-
dation of readily accessible Hantzsch 1,4-DHP constitutes
by far the easiest method to obtain pyridine derivatives.
As a consequence, newer and improved methods to effect
the oxidation of 1,4-DHP systems continued to be inves-
tigated.6–14 However, many of the reported oxidation pro-
cedures either suffer from the use of strong oxidants
7
(HNO3,5 CrO3,6 KMnO4 ), require severe conditions (S8,
and Pd/C dehydrogenations9) or need excess of the oxi-
dants (CAN,10 PCC11). In connection with our interest in
the chemistry of dihydropyridines and related sys-
tems,15,16 we became interested in developing a milder
and convenient method to effect 1,4-DHP to pyridine con-
version. We now report that Bi(NO3)3 · 5 H2O (1), a com-
mercially available, inexpensive, crystalline solid, serves
as an excellent oxidant for a variety of 4-substituted
Hantzsch 1,4-DHP systems as shown in the generalised
Scheme 1. Our results are collected in the Table.
Table. Oxidation of Hantzsch 1,4-Dihydropyridines by Bi(NO3)3
·5 H2Oa
Hantzsch Oxidised R
1,4-DHPb Products
Time Yieldc mp
Lit. mp
(°C)
2–8
9–15
(h) (%) (°C)
2
3
4
5
6
7
8
920
1018
1118
1222
1323
1424
1518
H
CH3
C6H5
4-(NO2)C6H4
4-(OCH3)C6H4
CH3CH=CH–
14 75
70–71 72–72.521
5
7
2
8
1
68
90
84
82
60
liquidd
–
62–64 63–6418
113–115 11522
Our initial attempts to effect the oxidation of the simple
Hantzsch 1,4-DHP 220 (R = H, Table) as a test case with 1
in CH3OH, CH3CN, or CH3COCH3 solvents at ambient or
thermal conditions produced none or insignificant amount
of the corresponding pyridine (9, entry 1). However, to
our delight, the oxidation of 2 with a stoichiometric
amount of 1 in acetic acid occurred smoothly at room tem-
perature to afford the expected pyridine 9 in 75% isolated
yield (quantitative conversion by TLC). The success of
50
5023
–
liquide
C6H5CH=CH– 1 50
162–163 162–16518
a All reactions conducted at r.t. in glacial AcOH using 5 mmol each of
the Hantzsch 1,4-DHP and Bi(NO3)3· 5 H2O.
b Hantzsch esters 2–8 are fully characterised by their mps and spectral
data.
c Yields are for isolated products and are unoptimised.
this reaction prompted us to study the oxidation of several d Lit.18 1H NMR (CDCl3): d = 1.1 (6 H, t,–COOCH2CH3), 2.0 (3 H, s,
–CH3), 2.2 (6 H, s, –CH3), 4.05 (4 H, t, –COOCH2CH3). Anal. calcd
4-alkyl, aryl and alkenyl Hantzsch 1,4-DHP under the
above conditions. All reactions were stirred at room tem-
for C14H19NO4: C, 63.40; H, 7.71; N, 5.28. Found: C, 63.71; H, 7.57;
N, 5.54%.
perature until the substrates were completely consumed.
e Lit.24 1H NMR (CDCl3): d = 1.3 (6 H, t, –COOCH2CH3), 1.8 (3 H,
The crude products obtained upon extractive workup are
purified by short silica gel column chromatography or
crystallisation, and the isolated yields of the oxidised
d, –CH=CH–CH3), 2.5 (3 H, s, –CH3), 4.3 (4 H, q, –COOCH2CH3),
6.0–6.4 (2 H, m, CH=CH–). Anal. calcd for C16H21NO4: C, 65.98; H,
7.22; N, 4.81. Found: C, 66.2l; H, 7.12, N, 4.7l%.

714
Short Papers
SYNTHESIS
The crude product obtained on extractive work-up was crystallised
from aq EtOH to give the product 18 as yellow crystals in 70% yield
(1.35g); mp 72–74°C.
other oxidative processes also, especially when 4-isopro-
pyl- or 4-benzyl-substituted Hantzsch esters are used for
oxidations.10,17,18 Interestingly, oxidation of diethyl 4-(4-
hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (17)23 with 1 was accompanied by the nitra-
tion of the phenolic ring to give product 18 (Scheme 2).
The nitration of 17 at the phenolic ring is not totally unex-
pected since Laszlo19 has recently described the use of 1
as a nitrating agent for reactive arenes.
IR (KBr): n = 3300, 1740, 1720, 1540, 1230, 1100, 1030, 850 cm–1.
1H NMR (CDCl3): d = 1.0 (6H, t, –COOCH2CH3), 2.43 (6H, s, –CH3–
Ar), 3.95 (4H, q, COOCH2CH3), 6.8–8.0 (3H, m, ArH), 10.3 (1H, s,
–OH).
Anal. calcd for C19H20N2O7: C, 58.76; H, 5.15; N, 7.22. Found: C,
58.91; H, 5.29; N, 7.11.
(1) Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223.
(2) Kill, R. J.; Widdowson, D. A. In Bioorganic Chemistry; van Ta-
melen, E. E. Ed. Academic Press: New York, 1978; p 239.
(3) Janis, R. A.; Triggle, D. J. J. Med. Chem. 1983, 25, 775.
(4) Wei, X. Y.; Rutledge, A.; Triggle, D. J. J. Mol. Pharmacol.
1989, 35, 541.
(5) Bocker, R. H.; Guengerich, F. P. J. Med. Chem. 1986, 28, 1596.
(6) Grinsteins, E.; Stankevics, B.; Duburs, G. Khim. Geterotsikl.
Soedin. 1967, 1118; Chem. Abstr. 1967, 69, 77095.
(7) Vanden Eynde, J.-J.; D’orazio, R.; Yves Van, H. Tetrahedron
1994, 50, 2479.
Scheme 2
(8) Brignell, P. J.; Bullock, E.; Eisner, U.; Gregory, B.; Johnson, A.
W.; Williams, H. J. Chem. Soc. 1963, 4819.
(9) Kamal, A.; Ahmad, M.; Mohd. N.; Hamid, A. M. Bull. Chem.
Soc. Jpn. 1964, 37, 610.
(10) Pfister, J. R. Synthesis 1990, 689.
(11) Maquestiau, A.; Mayence, A.; Vanden Eynde, J.-J. Tetrahedron
1992, 48, 463.
(12) Chennat, T.; Eisner, U. J. Chem. Soc., Perkin Trans. 1 1975,
926.
In summary, we have found Bi(NO3)3 · 5 H2O to be a valu-
able new addition to the existing methods available for the
oxidation of Hantzsch 1,4-DHP with added advantages of
economy and convenient reaction conditions and good
yields.
Melting points (uncorrected) were determined on a Gallenkamp melt-
ing point apparatus. IR spectra were recorded on a Shimadzu FTIR-
4200 spectrophotometer either as oil film or KBr discs. 1H NMR
spectra were recorded on a Varian EM-360L (60 MHz) spectrometer
with TMS as internal standard.
(13) Balogh, M.; Hermecz, I.; Meszaros, Z.; Laszlo, P. Helv. Chim.
Acta. 1984, 67, 2270.
(14) Van Bergen, T. J.; Kellogg, R. M. J. Chem. Soc., Chem. Com-
mun. 1976, 964.
(15) Kellogg, R. M.; Mashraqui, S. H. J. Am. Chem. Soc. 1983, 105,
7792.
Diethyl 2,6-Dimethylpyridine-3,5-dicarboxylate (9) Typical Pro-
cedure:
(16) Mashraqui, S. H.; Kalgutkar, A. S. J. Chem. Res.(S) 1991, 96.
(17) Delgado, F.; Alvarez, C.; Garcia, O.; Penieres, G.; Marquez, C.
Synth. Commun. 1991, 21, 2137.
(18) Loev, B.; Snader, K. M. J. Org. Chem. 1965, 30, 1914.
(19) Laszlo, P.; Cornelis, A.; Delaude, L.; Gerstmans, A. Tetra-
hedron Lett. 1988, 29, 5909.
(20) Hantzsch, A. Liebigs Ann. Chem. 1882, 251, 1.
(21) Engelman, F. Liebigs Ann. Chem. 1885, 231, 37.
(22) Cook, A. H.; Heilboon, I. M.; Steger, L. J. Chem. Soc. 1943,
413.
(23) Emmert, B.; Diefenbach, E.; Eck, R.; Chem. Ber. 1927, 60,
2216.
The Hantzsch 1,4-DHP 220 (1.265 g, 5 mmol) was dissolved in glacial
AcOH (15 mL) and Bi(NO3)3·5 H2O (2.425 g, 5 mmol) was added in
portions over 15 min. at r.t. The reaction was stirred for 14 h, diluted
with water and neutralised with aq NaHCO3. It was then extracted
with CHCl3, dried (anhyd Na2SO4) and solvent removed. Crystallisa-
tion of the residue from aq EtOH gave colourless crystals of the prod-
uct 9 in 75% yield (950 mg); mp 70–71 °C (lit.21 mp 72–72.5 °C).
The structure of the spent Bi(NO3)3 reagent after the completion of
1,4-DHP oxidations, but prior to neutralisation was found by qualita-
tive and IR spectral analysis to consist of Bi+3 species mainly in the
form of Bi(O)NO3.
(24) Ayling, E. E. J. Chem. Soc. 1938, 1014.
Diethyl 4-(4-Hydroxy-5-nitrophenyl)-2,6-dimethylpyridine-3,5-
dicarboxylate (18):
The oxidation of 4-(4-hydroxyphenyl) Hantzsch ester 1723 with 1 was
carried out on 5 mmol scale for a period of 2 h as described above.