Tetrabutylammonium hydrogen sulfate catalyzed eco-friendly and efficient synthesis of glycosyl 1,4-dihydropyridines

Article abstract of DOI:10.1016/j.tetlet.2004.10.057

An efficient and eco-friendly synthesis of glycosyl 1,4-dihydropyridines has been achieved by a three-component reaction of β-keto esters or ketones, enamines and glycosyl aldehydes in the presence of tetrabutylammonium hydrogen sulfate as catalyst in diethylene glycol.

Full text of DOI:10.1016/j.tetlet.2004.10.057

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9011–9014
Tetrabutylammonium hydrogen sulfate catalyzed eco-friendly
and efficient synthesis of glycosyl 1,4-dihydropyridines
Neetu Tewari, Namrata Dwivedi and Rama P. Tripathi*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow-226001, India
Received 29 July 2004; revised 27September 2004; accepted 8 October 2004
Abstract—An efficient and eco-friendly synthesis of glycosyl 1,4-dihydropyridines has been achieved by a three-component reaction
of b-keto esters or ketones, enamines and glycosyl aldehydes in the presence of tetrabutylammonium hydrogen sulfate as catalyst in
diethylene glycol.
ꢀ 2004 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 Ca++ channel blockers and their role as drugs for
the treatment of cardiovascular diseases and hyperten-
sion.3 The dihydropyridine skeleton is common in many
vasodialator, bronchiodialator, anti-atherosclerotic,
antitumor, hepatoprotective and anti-diabetic agents.4,5
They are also known as neuroprotectants, anti-platelet
treatment of aggregators and are important in Alzhei-
merꢀs disease as antiischemic agents.6 Interest in 1,4-
dihydropyridines also relates to nicotinamide dinucleo-
tide (NADH), a co-enzyme, and its unique ability to
reduce many functional groups in biological systems.
Alternative strategies for their synthesis involving differ-
ent catalysts and conditions have been developed but all
suffer from one or more drawbacks including low yields,
use of costly reagents and drastic reaction conditions. In
continuation of our effort to develop new anti-tubercu-
losis agents6,7 from sugars and the report of reversal
of drug resistance8,9 and anti-tubercular activity8,10 in
this class of molecule, we were prompted to synthesize
several glycosylated dihydropyridines.
and pharmacodynamic properties and the role of sugars
in molecular recognition whereby they can influence
drug receptor interaction in a beneficial manner.11
Dondoni et al.12 have synthesized glycosyl dihydropyri-
dines using two- or three-component Hantzsch reactions
with C-glycosylated reagents. Their novel method
requires a very high temperature and DMF as solvent
with 48h reflux and the yields are not high in every
reaction. Very recently we encountered a solventless
approach for the synthesis of 1,4-dihydropyridines pub-
lished in Synlett13 Encouraged by this report we carried
R
COR1
O
COR1
CH3
R
R1OC
H3C
NH4OAc/30-60 οC
+
O
H
H3C
N
H
1a and 1d
R1
a CH3
b OC2H5
3a and 3b
Scheme 1.
R
R
COR2
O
R1OC
H
COR2
COR1
1a-e
a. (CH2CH2OH)2O,
TBAHS, 80oC
+
The synthesis of sugar-substituted dihydropyridines is of
great significance because of their good pharmacokinetic
H3C
CH3
N
H
b. (CH2CH2OH)2O,
30-60oC
O
H3C
CH3
NH2
2a-c
3a-l
R1
R2
a CH3,
b OC2H5
c OCH3
a CH3
b OC2H5
c OCH3
Keywords: Glycosyl dihydropyridines; Tetrabutylammonium hydrogen
sulfate; 1,4-dihydropyridines; Enamines; Ammonium acetate.
*
Corresponding author. Tel.: +91 522 212411 18; fax: +91 522 223405/
22393; e-mail: rpt_56@yahoo.com
Scheme 2.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.057

9012
N. Tewari et al. / Tetrahedron Letters 45 (2004) 9011–9014
out the reaction of glycosyl aldehyde 1a,14 acetyl acetone
and ammonium acetate under similar conditions to
those of Zolfigol and Safaiee,13 however, a mixture of
three products was obtained and completion of the
reaction required a long time (Scheme 1). Even using
the same substrate, 3-nitrobenzaldehyde 1d and similar
reaction conditions to those reported13 did not give
the same result in our hands. The intermediate enamine
2a was a major product (Scheme 2). Hence, we decided
to use the enamine of the b-keto compound 2a (obtained
by reaction of acetylacetone and ammonium acetate in
the presence of IR-120 resin in refluxing toluene15) and
1equiv of the above keto-ester or diketone, instead of
using 2equiv of the keto compound and 1equiv of
Table 1. Synthesized glycosyl-, aryl- and heteroaryl-1,4-dihydropyridines
Entry
Product
R
R1
R2
Time
1.5h
Isolated yield (%)
98a
O
O
1
3a
CH3
CH3
H
1a
O
OCH3
1d
NO2
O
2
3
3b
3c
OCH2CH3
OCH2CH3
30mina, 1hb, 2minc
93a, 60b, <50c
O
O
95a
H
CH3
CH3
2h
1b
OCH2Ph
O
1c
90a
98a
97a
O
O
4
5
6
3d
3e
3f
CH3
CH3
2.5h
1.5h
1h
O
O
O
O
H
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
1a
O
OCH3
O
O
H
1b
O
OCH2Ph
O
O
O
1c
O
O
7
3g
OCH2CH3
OCH2CH3
1.5h
90a
O
O
O
O
O
O
H
8
3h
3i
CH3
CH3
CH3
CH3
OCH3
OCH3
CH3
2h
95a
95a
95a
95a
1a
OCH3
H
9
2h
1b
OCH2Ph
1d
10
11
3j
1.5h
30min
NO2
3k
CH3
1e
N
12
3l
OCH2CH3
OCH2CH3
35min
90a
1e
N
a Present method in the presence of catalyst.
b Present method without catalyst.
c As reported earlier.13

N. Tewari et al. / Tetrahedron Letters 45 (2004) 9011–9014
9013
ammonium acetate. Although the formation of side
products was reduced, the yield of the reaction was
not very encouraging. This led us to think of using some
sort of catalyst in a suitable eco-friendly solvent.
respectively. Financial Assistance from ICMR New
Delhi in the form of a Project grant BMS-II 58/6/2000
is also acknowledged.
Based on our earlier observation that phase transfer cata-
lysts work well in such cyclization reactions,16 we chose
tetrabutylammonium hydrogen sulfate (TBAHS) as the
phase transfer catalyst, being acidic in nature, to help in
the dehydration and cyclization steps. To our pleasant
surprise the desired product 3a was obtained rapidly in
almost quantitative yield (98%) in the reaction of alde-
hyde 1a, enamine 2a and acetylacetone in the presence
of TBAHS in diethylene glycol at 80ꢁC (Scheme 2).
The structure of compound 3a was established on the
basis of spectroscopic data and elemental analysis. In
References and notes
1. (a) Eisner, U.; Kuthan, J. Chem. Rev. 1972, 72, 1–42; (b)
Kill, R. J.; Widdowson, D. A. In Bioorg. Chem.; Van
Tamelen, E. E., Ed.; Academic: New York, 1978; Series 4,
pp 239–275; (c) Kutney, J. P. Heterocycles 1977, 7, 593–
614.
2. Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223–
243.
3. (a) Bossert, F.; Meyer, H.; Wehinger, E. Angew Chem.,
Int. Ed. Engl. 1981, 20, 762–769; (b) Nakayama, H.;
Kasoka, Y. Heterocycles 1996, 42, 901–909.
1
the H NMR spectrum, H-4 appeared as a doublet at
4. (a) Saushins, A.; Duburs, G. Heterocycles 1988, 27, 269–
289; (b) Mager, P. P.; Coburn, R. A.; Solo, A. J.; Triggle,
D. J.; Rothe, H. Drug Des. Discov. 1992, 8, 273–289.
5. Manhold, R.; Jablonka, B.; Voigdt, W.; Schoenfinger, K.
F.; Schravan, K. Eur. J. Med. Chem. 1992, 27, 229–235.
6. (a) Klusa, V. Drugs Future 1995, 20, 135–138; (b) Bretzel,
R. G.; Bollen, C. C.; Maeser, E.; Federlin, K. F. Am. J.
Kidney Dis. 1993, 21, 53–64; (c) Boer, R.; Gekker, V.
Drugs Future 1995, 20, 499–509; (d) Bretzel, R. G.; Bollen,
C. C.; Maeser, E.; Fedrlin, K. F. Am. J. Kidney Dis. 1992,
17, 465–468.
7. (a) Tripathi, R. P.; Tripathi, R.; Tiwari, V. K.; Bala, L.;
Sinha, S.; Srivastava, A.; Srivastava, R.; Srivastava, B. S.
Eur. J. Med. Chem. 2002, 37, 773–781; (b) Tewari, N.;
Tiwari, V. K.; Mishra, R. C.; Tripathi, R. P.; Srivastava,
A. K.; Ahmad, R.; Srivastava, R.; Srivastava, B. S.
Bioorg. Med. Chem. 2003, 11, 2911–2923.
8. Shah, A.; Gaveriya, H.; Motohashi, N.; Kawase, S. M.;
Saito, S.; Sakagami, H.; Satoh, Y.; Solymosi, A.; Walfard,
K.; Molnar, J. Anticanc. Res. 2000, 20, 373–377.
9. Kharkar, P. S.; Desai, B.; Gaveria, H.; Varu, B.; Loria, R.;
Maliapara, Y.; Shah, A.; Kulkarni, V. M. J. Med. Chem.
2002, 45, 4858–4867.
10. Shah, A.; Gaveriya, H.; Motohashi, N.; Kawase, S.;
Farkas, S.; Gyorgyi, G.; Molnar, J. Int. J. Antimicrob.
Agents 2002, 20, 227–235.
d 4.27having a J value of 9.6Hz. The product 3b
obtained by the method of Zolfigol and Safaiee13 could
be obtained in quantitative yield by our method. To the
best of our knowledge this is the first report of glycosyl
1,4-dihydropyridines being synthesized simply by stir-
ring and pouring the reaction mixture into ice-water
followed by filtration and subsequent purification of
the products.
Similarly, tetrasubstituted 4-glycosyl-1,4-dihydropyri-
dines 3c and 3d were synthesized by the reaction of
glycosyl aldehydes 1b17 and 1c18 with enamine 2a in
quantitative yields. Glycosyl aldehydes 1a, 1b and 1c,
on similar reaction with enamine 2b and ethyl acetoace-
tate resulted in the 1,4-dihydropyridines 3e–g, respec-
tively, with carbethoxy substituents at C-3 and C-5 in
very good yields (Table 1).
The reaction was also carried out with glycosyl alde-
hydes 1a and 1b, enamine 2c and acetylacetone resulting
in the formation of 4-glycosyl-1,4-dihydropyridines 3h
and 3i (with different substituents at the 3- and 5-posi-
tions), respectively.
11. Shah, A.; Vora, V.; Desai, B.; Gaveriya, H. Heterocycl.
Commun. 2001, 7, 481–486.
12. Dondoni, A.; Massi, A.; Minghini, E. Synlett 2002, 89–92.
13. Zolfigol, M. A.; Safaiee, M. Synlett 2004, 827–830.
14. Freudberg, K.; Dum, W.; Hochstetter Von, H. Ber. Dtsch.
Chem. Ges. 1928, 61, 1732–1734.
15. Tewari, N.; Katiyar, D.; Tiwari, V. K.; Tripathi, R. P.
Tetrahedron Lett. 2003, 44, 6639–6642.
16. Tewari, N.; Mishra, R. C.; Tiwari, V. K.; Tripathi, R. P.
Synlett 2002, 1779–1782.
That the reaction is equally good with aromatic 1d and
heteroaromatic aldehydes 1e was evidenced by reaction
of enamines 2a and 2b with acetylacetone and ethyl
acetoacetate separately resulting in very good yields of
the 1,4-dihydropyridines 3j, 3k and 3l, respectively. A
general method for the synthesis and physical data of
prototype compounds are given.19 A comparative study
of the solventless conditions is also given in Table 1.
17. Wolform, M. L.; Hanessian, S. J. Org. Chem. 1962, 27,
1800–1804.
18. Katiyar, D.; Mishra, R. C.; Tripathi, R. P. J. Carbohydr.
Chem. 2004, 23, 49–70.
19. General Procedure: A mixture of glycosyl aldehyde 1a
(1.0g, 4.95mmol), enamine 2a (0.49mL, 4.95mmol),
acetylacetone (0.49mL, 4.95mmol) and TBAHS (0.2g)
was magnetically stirred at 80ꢁC in diethylene glycol
(2mL) for 1.5h. After cooling the reaction mixture it was
poured onto crushed ice. The crude product, thus
obtained, was purified by column chromatography on
silica gel using chloroform:methanol (98:2) as eluent to
In conclusion we have developed a novel method using
tetrabutylammonium hydrogen sulfate, a cheap and eas-
ily available phase transfer catalyst, and diethylene gly-
col as an eco-friendly solvent for the synthesis of several
4-substituted dihydropyridines having the same or dif-
ferent substitutents at the 3- and 5- positions.
Acknowledgements
This paper is CDRI Communication 6604. N.T. and
N.D. are thankful to CSIR New Delhi for a Senior Re-
search Fellowship and a Junior Research Fellowship,
afford the desired product 3a. Physical data 3a: Colourless
20
D
foam, yield 98%, ½aŠ À120 (c = 0.25, CHCl3), ESMS:
m/z = 366 [M+H]+, IR (KBr) 3430, 2827, 1596, 1465,

9014
N. Tewari et al. / Tetrahedron Letters 45 (2004) 9011–9014
1353cmÀ1. H NMR (200MHz, CDCl3) d = 6.52 (s, 1H,
NH), 5.83 (d, J = 3.9Hz, 1H, H-10), 4.49 (d, J = 3.9Hz,
1H, H-20), 4.27(d, J = 9.6Hz, 1H, H-4), 3.80 (dd, J = 3.1,
9.6Hz, 1H, H-40), 3.41 (d, J = 3.1Hz, 1H, H-30), 3.26 (s,
3H, OCH3), 2.38 and 2.36 (each s, 6H, 2 · COCH3), 2.30,
2.19 (each s, 6H, 2 · C=CCH3), 1.35, 1.26 (each s, 6H,
(CH3)2C). 13C NMR (50MHz, CDCl3) d = 200.7, 199.2
(C OCH3), 145.2, 141.6 (N–C@C), 111.5 (N–C@C), 110.0,
109.2 (C(CH3)2), 105.0 (C-10), 83.4 (C-20), 82.4 (C-40), 80.9
(C-30), 56.4 (OCH3), 36.1 (C-4), 30.0, 28.6 (COCH3), 26.9,
26.4 (C(CH3)2), 20.5, 18.4 (C@CCH3); Anal. Calcd for
C19H27NO6 ÆH2O (383): calcd C, 59.53; H, 7.62; N, 3.65.
1H, H-4), 4.46 (d, J = 3.9Hz, 1H, H-20), 4.15 (q,
J = 6.9Hz, 4H, 2 · OCH2CH3), 3.89 (dd, J = 3.1, 7.6Hz,
1H, H-40), 3.49 (d, J = 3.0Hz, 1H, H-30), 3.27(s, 3H,
OCH3), 2.31, 2.25 (each s, 6H, 2 · C@CCH3), 1.77 (s, 1H,
NH), 1.41, 1.33 (each s, 6H, (CH3)2C), 1.30 (t, J = 7.3Hz,
6H, 2 · OCH2CH3). 13C NMR (50MHz, CDCl3) =
168.7, 168.4, (CO), 145.1, 144.9 (N–C@C), 111.3
(C(CH3)2), 105.0 (C-10), 101.1, 100.0 (N–C@C), 84.4
(C-20), 82.5 (C-40), 81.3(C-30), 61.7, 60.13 (OCH2CH3),
57.2 (OCH3); 33.7(C-4); 27.0, 26.5 (C( CH3)2), 19.6, 19.1
(C@CCH3), 14.7(OCH 2CH3). Anal. Calcd. for
C21H31NO8ꢀH2O (443): C, 56.87; H, 7.50; N, 3.16.
1
Found: C, 59.33; H, 7.23; N, 3.60%. 3c: Colourless foam,
À7 8 c(= 0.15, CHCl3); FAB MS:
Found: C, 57.41; H, 7.10; N, 3.15%. 3f: Colourless foam,
20
D
20
D
yield 95%, ½aŠ
yield 97%, ½aŠ +14 (c = 0.13, CHCl3); ESMS: m/z = 524
m/z = 442 [M+H]+, IR (KBr) 3295, 3034, 2946, 1592,
1473, 1353cmÀ1 1H NMR (200MHz, CDCl3) d = 7.34
[M+Na]+, IR (KBr) = 3342, 1596, 1480, 1380cmÀ1
.
1H
.
NMR (200MHz, CDCl3) d = 5.82 (d, J = 3.8Hz, 1H, H-
10), 4.72 (d, J = 7.9Hz, 1H, H-4), 4.59 (d, J = 11.9Hz, 1H,
OCHAPh), 4.53 (d, J = 13.0Hz, 1H, OCHBPh), 4.45
(d, J = 3.8Hz, 1H, H-20), 4.12 (q, J = 7.0Hz, 4H,
2 · OCH2CH3); 4.00 (dd, J = 3.0, 8.0Hz, 1H, H-40), 3.78
(d, J = 3.0Hz, 1H, H-30), 2.29, 2.17(each s, 6H, 2 · C@C–
CH3), 1.54, 1.42 (each s, 6H, (CH3)2C), 1.13 (t,
J = 7.08Hz, 6H, 2 · OCH2CH3). 13C NMR (50MHz,
CDCl3) d = 168.7, 168.4 (COO); 145.1, 144.8 (N–C@C);
138.7 (Ar-C); 128.5, 127.7, 127.2 (ArCH); 111.4 ((CH3)2
C); 105.0 (C-10); 100.94, 100.67(N–C @C); 82.7(C-2 0);
82.5 (C-40); 82.0 (C-30); 71.4 (OCH2Ph); 60.1, 59.9
(OCH2CH3); 33.4 (C-4); 27.1, 26.6 (C(CH3)2), 19.8, 19.2
(C@CCH3); 14.7, 14.6 (OCH2CH3). Anal. Calcd. for
C27H35NO8 (501): C, 64.65; H, 7.03; N, 2.79. Found: C,
(m, 5H, ArH), 5.85 (d, J = 3.9Hz, 1H, H-10), 4.57(m, 2H,
H-4, OCHAPh), 4.35 (d, J = 3.9Hz, 1H, H-20), 4.38 (d,
J = 11.5Hz, 1H, OCHBPh), 3.87(dd, J = 3.1, 9.5Hz, 1H,
H-40), 3.69 (d, J = 3.1Hz, 1H, H-30), 2.37, 2.35 (each s,
6H, 2 · COCH3), 2.17, 2.09 (each s, 6H, 2 · C@CCH3),
1.39, 1.32 (each s, 6H, (CH3)2C), 13C NMR (50
MHz, CDCl3) d = 201.0, 199.2 (COCH3), 145.0, 141.4
(N–C@C), 137.9 (ArC), 128.7, 128.1, 127.9 (ArCH),
111.6(N–C@C), 110.3, 109.3 (C(CH3)2), 104.9 (C-10),
82.3 (C-20), 82.2 (C-40), 81.7(C-3 ), 71.3 (OCH2Ph), 35.9
(C-4), 30.0, 29.1 (COCH3), 27.0, 26.4 (C(CH3)2), 20.6, 18.5
(C@CCH3). C25H31NO6CH2CH2OH (486): Anal. Calcd
for C, 61.72; H, 7.40; N, 2.88. Found: C, 61.42; H, 7.08; N,
0
20
D
2.79%. 3d: Colourless foam, yield 90%, ½aŠ À59 (c = 0.11,
CHCl3), FABMS: m/z = 422 (M + H)+; IR (Neat)
64.43; H, 7.03; N, 2.44%. 3h: Colourless foam, yield 95%,
20
D
3284, 2934, 1586, 1466, 1363cmÀ1
.
1H NMR (200MHz,
½aŠ À121 (c = 0.18, CHCl3); ESMS m/z = 382 [M+H]+,
CDCl3): d = 6.10 (br s, 1H, exchangeable NH), 5.40 (d,
J = 5.0Hz, 1H, H-10), 4.48 (dd, J = 8.0, 2.2Hz, 1H, H-30),
4.23 (d, J = 9.8Hz, 1H, H-4), 4.18 (d, 1H, J = 5.0Hz, H-
20), 3.96 (dd, J = 6.6, 1.0Hz, 1H, H-40), 3.22 (dd, J = 9.7,
1.0Hz, 1H, H-5ꢀ), 2.19, 2.16 (each s, each 6H, 2 · COCH3
IR (KBr) 3319, 1677, 1610, 1482, 1379cmÀ1
.
1H NMR
(200MHz, CDCl3) d = 5.85 (d, J = 3.9Hz, 1H, H-10), 4.47
(d, J = 3.9Hz, 1H, H-20), 4.42 (d, J = 9.5Hz, 1H, H-4),
3.81 (dd, J = 3.1, 9.5Hz, 1H, H-40), 3.72 (s, 3H,
COOCH3), 3.40 (d, J = 3.3Hz, 1H, H-30), 3.24 (s, 3H,
OCH3), 2.38, 2.36 (each s, 6H, C@CCH3), 2.18 (s,
3H, COCH3), 1.62 (s, 1H, NH), 1.39, 1.26 (each s, 6H,
(CH3)2C). 13C NMR (50MHz, CDCl3) d = 200.8 (CO),
168.1 (COO), 145.1 (NC@COCH3), 144.3 (N–
C@COOCH3), 110.8 (C(CH3)2), 109.5, 109.0 (NC@CH3),
104.6 (C-10), 100.2 (NC@C), 83.5, 83.1 (C-20), 81.9, 81.6
(C-40), 80.5, 80.2 (C-30), 56.8, 55.9 (COOCH3), 51.1
(OCH3), 35.5, 34.5 (C-4), 30.8, 29.6 (COCH3), 26.4, 25.8
(C(CH3)2), 19.3, 18.4 (C@CCH3). Anal. Calcd. for
C19H27NO7 (381): C, 59.83; H, 7.14; N, 3.67. Found: C,
59.96; H, 7.24; N, 3.62%.
and 2 · C@CCH3), 1.46, 1.32 (each s, 12H, (CH3)2C). 13
C
NMR (50MHz, CDCl3); d = 200.9, 199.7( COCH3), 143.8,
143.6 (N–C@C), 110.0 (N–C@C), 109.5, 109.3, 108.7
((CH3)2C), 96.8 (C-10), 71.3 (C-30), 71.2 (C-20), 70.6 (C-40),
69.4 (C-50), 36.9 (C-4), 29.8, 29.1 (COCH3), 29.4, 26.1,
25.4, 24.8 (C(CH3)2), 19.9, 19.2 (C@CCH3). Anal. Calcd
for C22H31NO7ÆH2O (439): C, 60.13; H, 7.57; N, 3.18.
Found: C, 60.00; H, 7.20; N, 3.00%. 3e: Colourless foam,
yield 98%, ESMS: m/z = 448 [M+Na]+, IR (KBr) 3351,
1669, 1489, 1380cmÀ1
d = 5.81 (d, J = 3.5Hz, 1H, H-10), 4.55 (d, J = 7.7Hz,
.
1H NMR (200MHz, CDCl3)