Solid supported synthesis of structurally diverse dihydropyrido[2,3-d] pyrimidines using microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2004.12.109

We have synthesized a library of 16 dihydropyrido[2,3-d]pyrimidines in high yields (82-92%) on solid support using microwave irradiation.

Full text of DOI:10.1016/j.tetlet.2004.12.109

Tetrahedron
Letters
Tetrahedron Letters46 (2005) 1345–1348
Solid supported synthesis of structurally diverse
dihydropyrido[2,3-d]pyrimidines using microwave irradiation
Anu Agarwal and Prem M. S. Chauhan*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 27 October 2004; revised 14 December 2004; accepted 21 December 2004
Available online 11 January 2005
Abstract—We have synthesized a library of 16 dihydropyrido[2,3-d]pyrimidines in high yields (82–92%) on solid support using
microwave irradiation.
ꢀ
2004 Elsevier Ltd. All rights reserved.
The versatility of uracil derivatives for the synthesis of
nitrogen-containing heteroaromatic species of biological
longer reaction times required in spite of using excess
reactants(2–3 time )s , often taking 2–3 timeslonger to
reach completion in comparison to solution phase reac-
tions. This disadvantage can be overcome by using
microwave irradiation instead of traditional heating.
For example, reactionswhich require 8–10 h of heating
by conventional methodsand take 24–30 h heating in
solid supported reactions, can occur within 3–5 min
using microwave irradiation. Due to this advantage
and parallel to the developmentsin combinatorial and
solid phase organic synthesis, microwave enhanced syn-
thesis has attracted a great deal of attention in recent
1
importance hasbeen well documented. Pyrazolopyr-
2
idines, pyrimidopyrimidines, pyridopurines, pyrazolo-
3
4
5
6
pyrimidines and xanthine derivatives have all been
prepared by functionalization of these important hetero-
cyclic building blocks, the structures of which are inter-
e ts ing in their own right, aswell asbeing biologically
7
active pyrimidine nucleosides. The diverse range of bio-
logical activities(antitumour, anticancer, anti-inflamma-
tory and CNS depressant activities) have stimulated
considerable interest in the synthesis of dihydropyr-
ido[2,3-d]pyrimidinesvia new and efficient route .s To
accelerate a drug discovery program, combinatorial
chemistry is recognized as a very powerful tool. The
main attraction of combinatorial chemistry is the rapid
synthesis of libraries of structurally related compounds,
which isof great value for the identification, develop-
ment and optimization of lead compounds. Solid sup-
ported ys nthe is sisthe core technology for generating
combinatorial librariesof compoundsdue to the advan-
tagesof thistechnique over traditional o sl ution
8
years. During the past decade a number of reports have
been published that advocate the advantages and uses of
microwave irradiation in organic synthesis. Dramatic
increases in rates, yields and purities of products have
frequently been observed with this nonconventional
and energy efficient heating method. It istherefore su r-
prising that the combination of solid phase synthesis
9
and microwave heating has os far not received much
attention.
approaches. For example, solid supported reactions
are easier to work-up and as these reactions proceed
to completion (by using high quantities of the other
reactants), purification of the products are easy. The
main disadvantage of solid supported reactions is the
O
(
a)
CHO
OH
Cl
O
CHO
(
b)
Keywords: Dihydropyrido[2,3-d]pyrimidines; Solid support; Micro-
wave irradiation.
O
*
Corresponding author. Tel.: +91 522 2212411x4332; fax: +91 522
623405; e-mail addresses: prem_chauhan_2000@yahoo.com;
premsc58@hotmail.com
Scheme 1. Reagentsand condition s: (a) 4-carboxybenzaldehyde, DIC,
DMAP, NMP, MW, 15 min; (b) 4-hydroxybenzaldehyde, NaH, NMP,
MW, 15 min.
2
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.109

1346
A. Agarwal, P. M. S. Chauhan / Tetrahedron Letters 46 (2005) 1345–1348
Table 1. Structuresof the active methylene compoundsand reaction
products
In thiscommunication, we de sc ribe the combination of
solid support and microwave techniques to synthesize
structurally diverse dihydropyrido[2,3-d]pyrimidinesin
high yields(82–92%). The ysnth ei sof dihydropyr-
ido[2,3-d]pyrimidinesui sn g 6-amino-1,3-dimethyluracil
Active methylene compoundsProducts
O
Y
1
0
Me
COCH3
CH3
wasreported by Kajino and Meguro,
but asa one-
O
O
N
(a)
pot, three-component cyclocondensation reaction, suf-
fering from very poor yields and limited substrate toler-
ance. We had earlier synthesized dihydropyrido[2,3-d]-
pyrimidinesin high yieldsand in one pot u si ng conven-
O
N
Me
N
H
1
1
tional methods.
O
Y
Me
COOCH3
CH3
As part of our ongoing program devoted to the synthesis
12
of diverse heterocycles of biological interest, we con-
O
O
O
O
N
(
(
b)
O
O
centrated our investigations on dihydropyrido[2,3-d]pyr-
imidinesdue to their broad range of biological activities.
Previously we have reported solid supported synthesis of
O
N
Me
N
H
1
3
14
O
Y
quinolones, substituted pyrimidines and pyrimido-
1
[4,5-d]pyrimidines.
5
Me
COOCH CH3
2
N
c)
The resin-bound aldehydes were attached to Wang and
Merrifield resins by condensing with 4-carboxybenzalde-
hyde and 4-hydroxybenzaldehyde, respectively (Scheme
O
N
Me
N
H
CH3
1
). 4-Carboxybenzaldehyde wasloaded on Wang re is n
in the presence of DIC (1,3-diisopropylcarbodiimide)
and DMAP (4-dimethylaminopyridine) in NMP (1-
methyl-2-pyrrolidinone) according to a reported meth-
O
Y
Me
COOCH CH3
O
2
N
(
(
(
(
(
d)
NC
16
od. The resin was heated in a domestic microwave
O
N
Me
O
N
H
NH2
oven at 180 W for 60 · 15 swith manual agitation dur-
ing the intervals. 4-Hydroxybenzaldehyde was loaded
on Merrifield resin by irradiation in a similar manner
in the presence of NaH and NMP.
O
Y
Me
CN
N
The resin-bound aldehydes were irradiated in the pres-
ence of 6-amino-1,3-dimethyluracil and compounds
having an active methylene group (Table 1) in acetic
acid for 60 · 4 swith manual agitation between each
irradiation. The resin was then filtered off and
washed thoroughly with DMF (3 · 10 mL), MeOH
(3 · 10 mL) and CH Cl (3 · 10 mL), dried under
e) NC
CN
O
N
Me
N
H
NH2
O
Y
O
O
O
O
2
2
Me
N
reduced pressure and used directly for the next step.
The productswere cleaved from the re si n in high yields
(82–92%) with 50% TFA and CH Cl . The solvent was
f)
O
N
Me
N
H
O
2
2
evaporated and the productswere recry ts allized either
from methanol or from chloroform and hexane. The
structures were confirmed from IR, mass and NMR
O
Y
17
spectroscopic data. The structures of the active meth-
ylene compoundsand their corre sp onding productsare
shown in Table 1 (Scheme 2).
O
O
Me
N
g)
O
N
Me
N
H
O
In conclusion, we have synthesized structurally
diverse dihydropyrido[2,3-d]pyrimidinesby three-com-
ponent reactionsin high yields(82–92%) on oslid
support using microwave irradiation. The use of micro-
wave irradiation greatly reduced the time of reaction on
solid support leading to rapid access to heterocyclic
compounds.
O
Y
Me
N
h)
O
N
Me
N
H
O
Acknowledgements
COOH and
OH
Y
A.A. thanksthe Council of Scientific and Indu tsr ial
Research (India) for the award of fellowship. We are

A. Agarwal, P. M. S. Chauhan / Tetrahedron Letters 46 (2005) 1345–1348
1347
O
O
X
O
Y
Me
Me
R''
R'
Me
R''
R'
(
b)
N
R
R'
(a)
N
N
X
C
H
CHO
+
+ O
N
Me
NH2
2
O
N
Me
N
H
O
N
Me
N
H
O
X =
O
Y =
COOH
OH
and
and
O
2 2
Scheme 2. Reagentsand condition s: (a) acetic acid, MW, 60 · 4 s; (b) TFA–CH Cl 1:1, 30 min, rt.
also thankful to S.A.I.F., CDRI, Lucknow for provid-
ing spectroscopic data. C.D.R.I. communication no.
Agarwal, S. K.; Bhaduri, A. P.; Singh, S. N.; Fatima, N.;
Chatterjee, R. K. Bioorg. Med. Chem. 1999, 7, 1223–1236;
(
d) Srivastava, S. K.; Chauhan, P. M. S.; Bhaduri, A. P.;
Fatima, N.; Chatterjee, R. K. J. Med. Chem. 2000, 43,
275–2279; (e) Tiwari, S.; Chauhan, P. M. S.; Bhaduri, A.
6
683.
2
P.; Fatima, N.; Chatterjee, R. K. Bioorg. Med. Chem. Lett.
2000, 10, 1409–1412.
3. Srivastava, S. K.; Haq, W.; Murthy, P. K.; Chauhan, P.
M. S.; Murthy, P. K. Bioorg. Med. Chem. Lett. 1999, 9,
1885–1888.
14. (a) Chauhan, P. M. S.; Kumar, A. Comb. Chem.
Highthroughput Screening 2002, 5, 93–95; (b) Kumar, A.;
Sinha, S.; Chauhan, P. M. S. Bioorg. Med. Chem. Lett.
2002, 12, 667–669; (c) Srivastava, S. K.; Haq, W.;
Chauhan, P. M. S. Comb. Chem. Highthroughput Screen-
ing 1999, 2, 33–37.
References and notes
. (a) Lunt, E.; Newton, C. C. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Boulton, A. J.,
McKillop, A., Eds.; Pergamon: Oxford, 1984; Vol. 3,
p 199, 232, 260–261; (b) Bradskaw, T. K.; Hutchinson,
D. W. Chem. Soc. Rev. 1977, 6, 43–62.
. Quiroga, J.; Cruz, S.; Insuasty, B.; Abonia, R. J. Hetero-
cycl. Chem. 2001, 38, 53–60.
. Thakur, A. J.; Saikia, P.; Prajapati, D.; Sandhu, J. S.
Synlett 2001, 1299–1301.
1
1
2
3
4
5
6
15. Srivastava, S. K.; Haq, W.; Chauhan, P. M. S. Bioorg.
Med. Chem. Lett. 1999, 9, 965–966.
16. Stadler, A.; Kappe, C. O. Tetrahedron 2001, 57, 3915–
3920.
. Perez-Perez, M.-J.; Pretago, E.-M.; Jimeno, M.-L.; Cam-
arasa, M.-J. Synlett 2002, 155–157.
. Bhuyan, P.; Boruah, R. C.; Sandhu, J. S. J. Org. Chem.
1
990, 55, 568–571.
17. Y = 4OHC H (a) MS 342 (M+1); mp 180–182 ꢁC; IR
6
4
À1
1
(KBr) 3420, 2953, 1709, 1682, 1502, 1388 cm ; H NMR
. Muller, C. E.; Geis, U.; Hipp, J.; Schobert, U.; Frobenius,
W.; Pawlowski, M.; Suzuki, F.; Sandoval-Ramirez, J. J.
Med. Chem. 1997, 40, 4396–4405.
(CDCl
(d, 2H, J = 8.5 Hz), 5.00 (s, 1H), 3.48 (s, 3H), 3.21 (s, 3H),
3
, 200 MHz) d (ppm) 7.19 (d, 2H, J = 8.5 Hz), 6.74
1
3
7
. Kumar, R.; Tyrrell, D. L. J. Bioorg. Med. Chem. Lett.
2.43 (s, 3H), 2.15 (s, 3H); C (50 MHz) 199.5, 161.5,
158.5, 150.8, 142.0, 141.8, 137.1, 128.6, 128.2, 113.7, 91.5,
37.4, 29.8, 28.7, 28.2, 19.8. (b) MS 358 (M+1); mp 244–
2
. (a) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199–
001, 11, 2917–2920.
8
À1
9
223; (b) Larhed, M.; Hallberg, A. Drug Discovery Today
001, 6, 406–416.
. (a) Stadler, A.; Kappe, C. O. Eur. J. Org. Chem. 2001, 31,
246 ꢁC; IR (KBr) 3424, 2958, 1735, 1654, 1514, 1384 cm
;
1
2
H NMR (CDCl
2H, J = 8.4 Hz), 6.68 (d, 2H, J = 8.4 Hz), 5.04 (s, 1H), 3.62
3 6
+ DMSO-d , 200 MHz) d (ppm) 7.15 (d,
9
1
3
9
2
19–925; (b) Alterman, M.; Hallberg, A. J. J. Org. Chem.
000, 65, 7984–7989; (c) Combs, A. P.; Saubern, S.;
(s, 3H), 3.47 (s, 3H), 3.25 (s, 3H), 2.42 (s, 3H);
C
(50 MHz) 171.9, 165.8, 159.9, 155.4, 48.6, 147.6, 141.8,
132.8, 119.3, 110.1, 95.3, 55.2, 40.6, 34.1, 32.2, 21.9. (c)
MS 372 (M+1); mp 240–242 ꢁC; IR (KBr) 3450, 2932,
Rafalski, M.; Lam, P. Y. Tetrahedron Lett. 1999, 40,
597–1599; (d) Chandrashekhar, S.; Padmaja, M. B.;
1
À1
1
Raja, A. Synlett 1999, 1597–1599; (e) Hoel, A. M. L.;
Nielsen, J. Tetrahedron Lett. 1999, 40, 3941–3944; (f)
Kuster, G.; Scheeren, H. W. Tetrahedron Lett. 2000, 41,
1732, 1648, 1512, 1378 cm ; H NMR (CDCl + DMSO-
3
d6, 200 MHz) d (ppm) 7.20 (d, 2H, J = 8.4 Hz), 6.68 (d,
2H, J = 8.4 Hz), 5.06 (s, 1H), 4.08 (q, 2H, J = 7.0 Hz), 3.49
(s, 3H), 3.27 (s, 3H), 2.46 (s, 3H), 1.21 (t, 3H, J = 5.95 Hz);
5
15–519; (g) Larshed, M.; Lindeberg, G.; Hallberg, A.
Tetrahedron Lett. 1996, 37, 8219–8222.
0. Kajino, M.; Meguro, K. Heterocycles 1990, 31, 2153–
161.
1. Agarwal, A.; Chauhan, P. M. S. Synth. Commun. 2004,
4.
1
3
C (50 MHz) 172.3, 166.7, 160.7, 156.4, 149.1, 148.6,
142.9, 133.9, 120.1, 111.3, 96.2, 64.9, 41.7, 34.9, 33.1, 23.8,
1
1
1
2
19.3. (d) MS 373 (M+1); mp 230–232 ꢁC; IR (KBr) 3426,
À1
1
3340, 2952, 1740, 1686, 1522, 1396 cm
;
H NMR
3
(CDCl + DMSO-d , 200 MHz) d (ppm) 7.16 (d, 2H,
3 6
2. (a) Srivastava, S. K.; Chauhan, P. M. S.; Agarwal, S. K.;
Bhaduri, A. P.; Singh, S. N.; Fatima, N.; Chatterjee, R.
K.; Bose, C. Bioorg. Med. Chem. Lett. 1996, 6, 2623–2628;
J = 8.4 Hz), 6.70 (d, 2H, J = 8.4 Hz), 5.01 (s, 1H), 4.06 (q,
2H, J = 6.9 Hz), 3.48 (s, 3H), 3.21 (s, 3H), 1.26 (t, 3H,
1
3
J = 4.5 Hz); C (50 MHz) 172.1, 166.5, 160.5, 156.3,
154.7, 149.2, 148.6, 133.8, 120.1, 111.3, 96.2, 64.9, 41.7,
34.9, 33.2, 23.8. (e) MS 326 (M+1); mp 210–212 ꢁC; IR
(KBr) 3426, 3342, 2952, 2195, 1712, 1678, 1554,
(
b) Srivastava, S. K.; Agarwal, A.; Chauhan, P. M. S.;
Agarwal, S. K.; Bhaduri, A. P.; Singh, S. N.; Fatima, N.;
Chatterjee, R. K. J. Med. Chem. 1999, 42, 1667–1672; (c)
Srivastava, S. K.; Agarwal, A.; Chauhan, P. M. S.;
À1
1
1374 cm
; H NMR (CDCl + DMSO-d , 200 MHz) d
3 6

1348
A. Agarwal, P. M. S. Chauhan / Tetrahedron Letters 46 (2005) 1345–1348
ppm) 7.17 (d, 2H, J = 8.5 Hz), 6.68 (d, 2H, J = 8.5 Hz), 200 MHz) d (ppm) 7.17 (d, 2H, J = 8.2 Hz), 6.69 (d, 2H,
(
5
.03 (s, 1H), 4.8 (s, 2H, NH
C (50 MHz) 161.5, 160.8, 158.5, 150.8, 142.0, 137.1,
28.6, 128.2, 118.4, 113.7, 71.5, 37.4, 29.8, 28.7. (f) MS 354
2
), 3.48 (s, 3H), 3.24 (s, 3H);
J = 8.2 Hz), 5.08 (s, 1H), 3.47 (s, 3H), 3.24 (s, 3H), 2.57 (s,
2H), 2.48 (s, 2H), 1.06 (s, 3H), 0.94 (s, 3H). C (50 MHz)
1
3
13
1
200.7, 166.6, 160.7, 156.3, 154.7, 148.9, 142.5, 133.9, 120.0,
118.1. 96.9, 55.8, 45.5, 38.5, 35.5, 34.6, 33.2, 32.2, 18.4. (h)
MS 388 (M+1); mp >250 ꢁC; IR (KBr) 3442, 2942, 1708,
(
1
M+1); mp decomposes at 250 ꢁC; IR (KBr) 3425, 2912,
À1
3 6
; H NMR (CDCl + DMSO-d ,
1
706, 1682, 1512 cm
00 MHz) d (ppm) 7.11 (d, 2H,J = 8.5 Hz), 6.69 (d, 2H,
À1
1
2
J = 8.5 Hz), 4.95 (s, 1H), 3.48 (s, 3H), 3.25 (s, 3H), 2.63 (t,
1658, 1568 cm
;
H
NMR (CDCl + DMSO-d ,
3 6
200 MHz) d (ppm) 7.88 (d, 1H, J = 8.2 Hz), 7.50–7.60
(m, 3H), 7.18 (d, 2H, J = 8.2 Hz), 6.76 (d, 2H, J = 8.2 Hz),
1
3
2
(
1
H, J = 4.8 Hz), 2.37 (t, 2H, J = 4.8 Hz), 2.03 (m, 2H).
50 MHz) 199.9, 166.5, 161.7, 154.3, 153.9, 148.7, 142.6,
33.4, 120.3, 118.4. 96.6, 55.4, 45.5, 38.5, 35.5, 33.2, 19.2.
C
1
3
5.00 (s, 1H), 3.46 (s, 3H), 3.24 (s, 3H). C (50 MHz) 189.4,
161.5, 158.5, 150.8, 142.0, 141.8, 137.1, 136.3, 134.6, 132.4,
128.6, 127.8, 126.6, 126.2, 113.7, 61.5, 50.6, 37.4, 29.8,
28.7.
(
1
g) MS 382 (M+1); mp 238–240 ꢁC; IR (KBr) 3430, 2924,
À1
1
712, 1668, 1540 cm ; H NMR (CDCl + DMSO-d ,
3 6