l-Ascorbic acid in organic synthesis: a facile synthesis of 4-(butenolide-5-methylidenyl)-1,4-dihydropyridines

Article abstract of DOI:10.1016/j.tetlet.2006.12.067

An efficient synthesis of 4-(butenolide-5-methylidenyl)-1,4-dihydropyridines has been achieved via a three-component reaction of β-keto esters or ketones, ammonium acetate and vinylic aldehydes from ascorbic acid in the presence of tetrabutylammonium hydr

Full text of DOI:10.1016/j.tetlet.2006.12.067

Tetrahedron Letters 48 (2007) 1187–1189
L-Ascorbic acid in organic synthesis: a facile synthesis of
4-(butenolide-5-methylidenyl)-1,4-dihydropyridinesI
Surendra S. Bisht, Namrata Dwivedi and Rama P. Tripathi*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 19 September 2006; revised 5 December 2006; accepted 13 December 2006
Available online 8 January 2007
Abstract—An efficient synthesis of 4-(butenolide-5-methylidenyl)-1,4-dihydropyridines has been achieved via a three-component
reaction of b-keto esters or ketones, ammonium acetate and vinylic aldehydes from ascorbic acid in the presence of tetrabutyl-
ammonium hydrogen sulfate in ethylene glycol.
Ó 2007 Elsevier Ltd. All rights reserved.
Since the first report of the Hantzsch synthesis of 1,4-
dihydropyridines, a number of strategies have been
developed for their synthesis1,2 due to their important
biochemistry and biological activities. The prominent
biological activities associated with 1,4-dihydropyridines
are as Ca2+ channel blockers and as drugs for the treat-
ment of cardiovascular diseases and hypertension.3 The
dihydropyridine skeleton is common in many vasodila-
tor, bronchiodilator, anti-atherosclerotic, anti-tumour,
hepatoprotective and anti-diabetic agents.4,5 They are
also known as neuroprotectants, as anti-platelet treat-
ment of aggregators and are important in Alzheimer’s
disease as anti-ischaemic agents.6 Interest in 1,4-dihy-
dropyridines also relates to nicotinamide dinucleotide
(NADH), a co-enzyme, and its unique ability to reduce
many functional groups in biological systems. Although
1,4-dihydropyridines with various aromatic, heteroaro-
matic, aliphatic and sugar substituents at C-4 have been
reported,1,7,8 there is no report of 1,4-dihydropyridines
bearing a (5-ethylidene tetranolactonyl) substituent at
C-4. In continuation of our studies towards the develop-
ment of new anti-tuberculosis agents8 from sugars and
prompted by the reports on the wide range of biological
activities, particularly anti-microbial (anti-tubercular),
in butenolides9,10 as well as drug resistance reversal11
and anti-tubercular activity12 in dihydropyridines, we
investigated the synthesis of butenolide derivatives of
1,4-dihydropyridines. To the best of our knowledge
there is no report where an aldehyde (butenolidyl alde-
hyde) possessing a number of potentially reactive func-
tional groups has been used as a substrate in the
Hantzsch synthesis.
To start, we prepared the butenolidyl aldehydes (2a and
2b) by the oxidation of allyl alcohols (1a and1b),13
obtained from L-ascorbic acid, with pyridinium
chlorochromate (PCC) in anhydrous dichloromethane.
The reaction of (3,4-dimethoxy-5-oxo-5H–furan-2-yl-
idene)acetaldehyde 2a with acetylacetone in the presence
of ammonium acetate and tetrabutylammonium
hydrogensulfate (TBAHS) in ethylene glycol as in our
earlier method2d gave 4-(butenolide-5-methylidenyl)-
1,4-dihydropyridine 3 in a good yield along with several
unisolated minor products as observed on TLC after
work-up of the reaction. The structure of compound 3
was established on the basis of spectroscopic data and
elemental analysis. The MS data and NMR spectra
(1H and 13C) were consistent with structure 3. In the
1H NMR spectrum of 3, H-4 appeared as a doublet at
d 4.90 having a J value of 10.3 Hz while the olefinic pro-
ton of the ethylidene moiety appeared as a doublet at d
5.12 with a J value of 10.4 Hz. The six protons corre-
sponding to the two methoxy groups in the tetranolac-
tone moiety appeared as two singlets at d 4.10 and d
3.91 and two singlets at d 2.32 and d 2.29 (each six pro-
tons) accounted for the six acetyl and six methyl group
protons. The exchangeable NH appeared as a broad
singlet at d 5.90.
Keywords: L-Ascorbic acid; 1,4-Dihydropyridines; 4-(Butenolide-5-
methylidenyl)-1,4-dihydropyridines; Tetrabutylammonium hydrogen
sulfate; Ammonium acetate.
q CDRI Communication No. 7074.
*
Corresponding author. Tel.: +91 522 2612412; fax: +91 522 2623405/
2624305; e-mail: rpt_56@yahoo.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.067

1188
S. S. Bisht et al. / Tetrahedron Letters 48 (2007) 1187–1189
In the 13C NMR spectrum of 3, the two acetyl carbonyls
of the dihydropyridine ring appeared at d 196.4 and the
lactone carbonyl carbon occurred at d 164.5, while C-4
and the olefinic carbon appeared at d 108.6 and d
110.0, respectively. It was interesting to note that func-
tionalities other than aldehyde present in the butenolidyl
aldehyde were unaffected during the reaction. Similarly,
the reaction of 2a with other b-keto compounds includ-
ing methyl acetoacetate, ethyl acetoacetate, ethyl
butyrylacetate and cyclohexanone gave the correspond-
ing dihydropyridines in moderate to good yields (Table
1).
We have also demonstrated that 4-(butenolide-5-methyl-
idenyl)-1,4-dihydropyrdines with unsymmetrical sub-
stituents (13 and 14) at the 2,6- and 3,5-positions of
the dihydropyridine ring could also be prepared using
this method. For this purpose, we used two b-keto com-
pounds in this reaction. The enamine of one of the b-
keto compounds, acetylacetone prepared by our earlier
method14 was reacted with vinylic aldehyde and ethyl
acetoacetate and 1,3-cyclohexanedione, separately, in
the presence of TBAHS in ethylene glycol at 90 °C.
In conclusion we have synthesized a new class of di-
hydropyridines bearing a 4-(butenolide-5-methylidenyl)
moiety at C-4 having the same or different substituents
at the 3- and 5-positions using tetrabutylammonium
hydrogensulfate (a cheap and easily available phase
transfer catalyst) and ethylene glycol as an eco-friendly
solvent.
In order to determine the steric effects of substituents on
the tetranolactone moiety the reaction of (3,4-di-O-benz-
yl-5-oxo-5H-furan-2-ylidene)-acetaldehyde 2b with
b-keto compounds and ammonium acetate under the
above mentioned reaction conditions afforded the
respective products in similar yields (Table 1) indicating
that the change in the substituent on the tetranolactone
moiety did not affect the rate of reaction (Scheme 1).
Typical experimental procedure for the synthesis of dihy-
dropyridines: Compound 3: A mixture of vinylic alde-
Table 1. Synthesis of 4-(butenolide-5-methylidenyl)-1,4-dihydropyridines 3–14
Product
R
R1
R2
R3
R4
Time (h)
Yielda (%)
3
4
CH3
CH3
CH3
CH2Ph
CH2Ph
CH3
CH2Ph
CH2Ph
CH2Ph
CH3
CH3
CH3
CH2CH2CH3
CH2CH2CH3
COCH3
COCH3
CH3
CH3
CH2CH2CH3
CH2CH2CH3
1.0
1.5
2.0
2.0
1.0
2.0
1.0
1.3
2.0
1.5
1.0
1.0
70
60
60
75
70
70
75
55
45
50
60
60
COOCH3
COOC2H5
COOCH2CH3
COOCH3
COOC2H5
COOCH2CH3
5
6
7
–CH2CH2CH2CO–
–OCH2CH2CH2–
8
CH3
CH3
CH3
CH3
COOC2H5
COCH3
COOCH3
COOC2H5
COOC2H5
COCH3
COOCH3
COOC2H5
CH3
CH3
CH3
CH3
9
10
11
12
13
14
–CH2CH2CH2CO–
–OCH2CH2CH2–
CH3
–OCH2CH2CH2–
CH3
CH3
CH3
CH3
COCH3
COCH3
COOC2H5
a Isolated yield.
HO
HO
O
O
O
O
Ref.13
HO
RO
OR
1a, R=CH3
1b, R=CH2Ph
HO
OH
L-ascorbic acid
PCC, 4Å MS,
H
N
CH2Cl2, 0-30 °C,1 h
R1
R2
R4
R3
CHO
H
O
O
NH4OAc, TBAHS
O
O
H
β−keto-compound,
ethylene glycol, 90 °C
RO
OR
RO
OR
2a, R=CH3
2b, R=CH2Ph
3-14
Scheme 1. Synthesis of 4-(butenolide-5-methylidenyl)-1,4-dihydropyridines.

S. S. Bisht et al. / Tetrahedron Letters 48 (2007) 1187–1189
1189
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1
IR (neat): mmax 3309 cmÀ1 (OH stretching); H NMR
(200 MHz, CDCl3) d 5.90 (br s, 1H, NH), 5.12 (d, 1H,
J = 10.4 Hz, CH@CO), 4.90 (d, 1H, J = 10.3 Hz, CH),
4.10 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 2.32 (s, 6H,
COCH3), 2.29 (s, 6H, CH3), 13C NMR (50 MHz,
CDCl3) d 196.4 (2C), 164.5, 150.0 (2C), 146.4 (2C),
124.1, 110.0, 108.6 (2C), 60.9, 59.5, 31.8, 19.2 (2C).
Anal. Calcd for C18H21NO6: C, 62.24; H, 6.09; N,
4.03. Found: C, 62.21; H, 6.07; N, 4.01. Compound 4:
Light yellow foam, yield (0.58 g, 60%), Rf = 0.4 (ethyl
acetate/hexane, 4:6); MS (FAB): m/z 380 (M+H)+; IR
(neat): mmax 3433 cmÀ1 (OH stretching); 1H NMR
(200 MHz, CDCl3) d 7.30 (br s, 1H, NH), 5.15 (d, 1H,
J = 9.5 Hz, CH@CO), 4.88 (d, 1H, J = 9.6 Hz, CH),
4.09 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.66 (s, 6H,
OCH3), 2.37 (s, 6H, CH3); 13C NMR (50 MHz, CDCl3):
171.0 (2C), 155.0, 148.0 (2C), 144.0 (2C), 116.6, 104.0
(2C), 65.5, 64.2 (2C), 55.9 (2C), 36.1, 23.6 (2C). Anal.
Calcd for C18H21NO8: C, 56.99; H, 5.58; N, 3.69.
Found: C, 56.97; H, 5.56; N, 3.66. Experimental details
and full characterization data of other compounds is
available in Supplementary data.
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S.S.B. and N.D. are thankful to the CSIR, New Delhi,
for Junior and Senior Research Fellowships. Financial
assistance from the DRDO (Project No. ERIP/ER/
0502127/M/011857), New Delhi, is gratefully acknowl-
edged. The authors thank the staff of RSIC, CDRI for
providing spectral data and analysis.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2006.
12.067.
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