Solid state photochemistry of 1,4-dihydropyridines

Article abstract of DOI:10.1016/j.bmcl.2005.05.026

Photochemical behavior of some 1,4-dihydropyridines has been investigated in the solid state. Whereas upon irradiation of 1,4-dihydropyridines in solution phase, their photo-oxidation and formation of pyridine derivatives have been observed, irradiation o

Full text of DOI:10.1016/j.bmcl.2005.05.026

Bioorganic & Medicinal Chemistry Letters 15 (2005) 3423–3425
Solid state photochemistry of 1,4-dihydropyridines
Hamid R. Memarian* and Arsalan Mirjafari
Department of Chemistry, Faculty of Science, University of Isfahan, 81746-73441 Isfahan, Iran
Received 28 February 2005; revised 27 April 2005; accepted 6 May 2005
Available online 9 June 2005
Abstract—Photochemical behavior of some 1,4-dihydropyridines has been investigated in the solid state. Whereas upon irradiation
of 1,4-dihydropyridines in solution phase, their photo-oxidation and formation of pyridine derivatives have been observed, irradi-
ation of these compounds in the solid state decreases their light sensitivity. In many cases photo-oxidation has been observed only in
very low yields.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
tzsch-type dihydropyridines without any substituents at
2- and 6-positions takes place through two regioselective
and consecutive [2+2]-cycloaddition and affords the for-
mation of cage dimer.16–18 Recently, solid state photo-
chemistry of only one 2,6-dimethyl-1,4-dihydropyridine
and formation of head to tail cage dimer have been
reported.19 Most of the 1,4-dihydropyridines exhibit
pharmaceutical activity and this property is due to the
presence of dihydropyridine ring; therefore, because of
their light sensitivity especially in the solution phase,
protection from light during their preparation has been
recommended12,20 to prevent photo-oxidation to the
pyridine ring. In the course of our studies on the chem-
istry of 1,4-dihydropyridines, we investigated solid state
photochemistry of various dihydropyridines to elucidate
their light sensitivity in the solid state versus the solution
phase.
1,4-Dihydropyridines are interesting compounds and
play an important role in synthetic, therapeutic and
bioorganic chemistry.1–4 The most interesting aspect
of dihydropyridines can be attributed to the coenzyme
reduced nicotinamide adenine dinucleotide (NADH)
and the unique ability of these compounds in biological
systems to reduce unsaturated functionalities and also
strained ring systems (carbonyls, conjugated olefins,
epoxides, etc.).5–8 Phototoxicity of nifedipine, one of
the 1,4-dihydropyridine classes, has also been re-
ported.9 Oxidation of 1,4-dihydropyridine compounds
with various oxidizing agents has been extensively stud-
ied.10,11 Photo-oxidation of 1,4-dihydropyridines is also
of great interest and is still under intensive investiga-
tion. Recently, we have reported on the photochemical
behavior of these compounds and investigated the
effect of the type and the nature of the 4-substituent
and also the presence or absence of oxygen on the rate
of photo-oxidation.12,13 Since the presence of the acetyl
groups instead of the ester groups on 3- and 5-posi-
tions could also affect the rate of photo-oxidation, we
have synthesized some novel keto-dihydropyridines
and studied their photochemical reactions.14,15
2. Results and discussion
Direct irradiation (k P 280 nm) of 0.03 mol of each of
the powdered 1,4-dihydropyridine-3,5-diesters (1a–1p)
or 3,5-diacetyl-1,4-dihydropyridines (4a–4n) in the solid
state was carried out on a water cooled plate with admis-
sion of air for 50 h and the progress of the reaction was
followed by thin layer chromatography (TLC). Since the
aim of this work was to compare the photochemical
behavior of 1,4-dihydropyridines in the solution phase
and solid state, the same amount of 1a–1p and 4a–4n
was dissolved in 3 ml CHCl3 and exposed to UV-light
simultaneously with the powdered dihydropyridine until
total disappearance of the dissolved dihydropyridine
was observed.21 The results are summarized in Tables
1 and 2.
Solid state photochemistry of 1,4-dihydropyridines is
not widely investigated. Solid state and solution photo-
dimerization of N-substituted and non-substituted Han-
Keywords: 1,4-Dihydropyridines; Photodehydrogenation; Photo-oxi-
dation; Solid state photochemistry.
*
Corresponding author. Tel.: +98 311 793 2707; fax: +98 311 668
9732; e-mail: memarian@sci.ui.ac.ir
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.05.026

3424
H. R. Memarian, A. Mirjafari / Bioorg. Med. Chem. Lett. 15 (2005) 3423–3425
Table 1. Solid state and competitive solution photochemistry of 1,4-dihydropiridine-3,5-diesters (1a–1p) at k P 280 nm
Compound
R
Solid photochemistrya
Solution photochemistry
Product
Time (h)b
Product Yield (%)
1a
1b
1c
1d
1e
1f
H
CH3
2
95c
—
2
8
16
12
7
—
2
3b
2
i-Pr
PhCH2
Ph
63c
2
7d
2
—
3f
3g
—
3i
3j
—
3l
3m
2
—
3e
3f
3g
2
15
12
14
15
8
2-CH3OC6H4
2,5-(CH3O)2C6H3
4-HO-3-H3COC6H3
2-NO2C6H4
3-NO2C6H4
4-(CH3)2NC6H4
4-ClC6H4
1-Naphthyl
2-Furyl
Tracee
Tracee
—
1g
1h
1if
1j
30c
Tracee
3i
3j
3k
3l
3m
2
13
11
12
21
10
10
11
1k
1l
—
Tracee
Tracee
16d
1m
1n
1o
1p
5-Methyl-2-furyl
2-Thienyl
2
7d
Tracee
2
2
2
a Irradiation of powdered 1,4-dihydropyridines was carried out for 50 h.
b Irradiation was continued until total disappearance of 1,4-dihydropyridines was observed.
c Isolated yield.
d The yield was determined by the comparison of the integral ratios of the characteristic 1H NMR peaks in the starting materials and products.
e Formation of trace amount of products was detected on the TLC.
f 1i was converted to brownish oil after 15 min irradiation and the reaction was stopped.
Table 2. Solid state and competitive solution photochemistry of 3,5-diacetyl-1,4-dihydropyridines (4a–4n) at k P 28 nm
Compound
R
Solid photochemistry
Product
Yield (%)a
Solution photochemistry
Product
Time (h)b
4a
4b
4c
4d
4e
4f
CH3
Ph
—
—
—
—
—
—
—
6h
6i
—
—
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
5
15
15
13
12
13
22
21
21
20
13
18
18
19
13
2-CH3OC6H4
3-CH3OC6H4
4-CH3OC6H4
2,5-(CH3O)2C6H3
3,4-(CH3O)2C6H3
3-NO2C6H4
4-NO2C6H4
4-ClC6H4
—
—
—
—
4g
4h
4i
—
Tracec
Tracec
Tracec
8d
4j
6j
4k
4l
2-Furyl
5
5-Methyl-2-furyl
2-Thienyl
2-Pyridinyl
5
7d
Tracec
Tracec
5
4m
4n
5
6n
5
6n
a Irradiation of powdered 1,4-dihydropyridines was carried out for 50 h.
b Irradiation was continued until total disappearance of 1,4-dihydropyridines was observed.
c Formation of trace amount of products was detected on the TLC.
d The yield was determined by the comparison of the integral ratios of the characteristic 1H NMR peaks in the starting materials and products.

H. R. Memarian, A. Mirjafari / Bioorg. Med. Chem. Lett. 15 (2005) 3423–3425
3425
UV light simultaneously with the powdered
dihydropyridines.
The results presented in Tables 1 and 2 show that the
light sensitivity of many of the 1,4-dihydropyridines
investigated in this work in the solid state is very low
and these compounds are resistant to the UV-light. In
comparison, their photo-oxidations have been observed
successfully in the solution. The loss of the substituent in
position 4 has been observed earlier in photochemical
reactions of Hantzsch esters only in the cases of carboxy
group,22 some heterocyclic groups12 and secondary alkyl
and benzyl groups.12 The possible argument for the
expulsion of these substituents as in 1c, 1d, 1n and 1o
is the higher stability of these groups with radical or car-
bocation character compared with the other groups. The
interesting point in our reactions is the expulsion of
these groups even in the solid state, which we do not
have the effect of solvation due to the absence of a sol-
vent. This reflects only the higher light sensitivity of
dihydropyridines with these groups in position 4 com-
pared to the other groups listed in Tables 1 and 2.
References and notes
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3. Conclusion
In conclusion, we have found that the light sensitivity of
1,4-dihydropyridines in the solid state is decreased dras-
tically in comparison to that in their solution state and
that they have a good resistance to UV-light. Therefore,
due to their pharmaceutical activity, protection
from light of the reaction mixture during their
preparation is necessary; however, protection
during packing as a tablet or capsule is not important,
which is important for drug designers and
manufacturers.
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21. All photoproducts are known compounds and have been
identified by comparison of their physical and spectral
data with those of authentic samples.
Dihydropyridine crystals (3 mol) were ground in a mor-
tar and strewn on the glass surface (15 cm · 15 cm),
which was laid on the water cooled plate and exposed
to the 400 W high pressure mercury light source of a
reflector at a distance of 40 cm from the glass surface.
The light of the reflector was passed through a Pyrex
glass. The same amount of dihydropyridines was dis-
solved in 3 ml CHCl3, put in a vial and exposed to the
22. Biellmann, J. F.; Callot, H. J.; Pilgrim, W. R. Tetrahedron
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