An efficient synthesis of novel hexahydropyrido[2,3-d]pyrimidine derivatives from (arylmethylidene)pyruvic acids =(3E)-4-aryl-2-oxobut-3-enoic acids in aqueous media

Article abstract of DOI:10.1002/hlca.200800318

A series of new hexahydropyrido[2,3-d]pyrimidine derivatives 3 were synthesized by the cyclo-condensation reaction of (arylmethylidene)pyruvic acids (=(3E)-4-aryl-2-oxobut-3-enoic acids) 1 and 6-aminouracils (=6-aminopyrimidine- 2,4(1H,3H)-diones) 2 in H<

Full text of DOI:10.1002/hlca.200800318

932
Helvetica Chimica Acta – Vol. 92 (2009)
An Efficient Synthesis of Novel Hexahydropyrido[2,3-d]pyrimidine
Derivatives from (Arylmethylidene)pyruvic Acids (¼(3E)-4-Aryl-2-oxobut-
3-enoic Acids in Aqueous Media
by Saeed Balalaie*a), Shahrzad Abdolmohammadib), and Bita Soleimanifarda)
a) Peptide Chemistry Research Group, K. N. Toosi University of Technology, P. O. Box 15875-4416,
Tehran, Iran
(phone: þ 98-21-2288 6575; fax: þ 98-21-2285 3650; e-mail: balalaie@kntu.ac.ir)
b) School of Chemistry, College of Science, University of Tehran, P. O. Box 14155-6455, Tehran, Iran
A series of new hexahydropyrido[2,3-d]pyrimidine derivatives 3 were synthesized by the cyclo-
condensation reaction of (arylmethylidene)pyruvic acids (¼(3E)-4-aryl-2-oxobut-3-enoic acids) 1 and 6-
aminouracils (¼6-aminopyrimidine-2,4(1H,3H)-diones) 2 in H2O under reflux conditions (Scheme 1,
Table). This novel protocol has the advantages of facility, of easy workup, of high yields, and of an
environmentally benign procedure. The structures of compounds 3a – 3f were corroborated spectroscopi-
cally (IR, 1H- and 13C-NMR, and EI-MS). A plausible mechanism for the reaction is proposed
(Scheme 2).
Introduction. – The compounds which possess a dihydropyridopyridine framework
in their structure have been recognized both in medicinal [1] and in synthetic chemistry
[2 – 4] due to their unique properties. Syntheses of pyridopyrimidine derivatives are of
considerable interest as they have a wide range of biological properties such as
antibacterial [5], antiasthmatic, antiallergic [6], antifolate [7], tyrosine-kinase [8],
antimicrobial [9], calcium-channel-antagonist [10], anti-inflammatory and analgesic
[11], antihypertensive [12], antileishmanial [13], tuberculostatic [14], anticonvulsant
[15], diuretic and potassium-sparing [16], and antiaggressive [17] activities.
With the aim of developing more efficient synthetic methods, improving the bond-
forming efficiency (BFE), and in continuation of our previous work on the cyclo-
condensation reactions, which were performed in H2O successfully [18], we now report
our study about the reaction of (arylimethylidene)pyruvic acids (¼(3E)-4-aryl-2-
oxobut-3-enoic acids) 1 with 6-aminouracils (¼6-aminopyrimidine-2,4(1H,3H)-dio-
nes) 2 as highly reactive heterocyclic C-nucleophiles. This approach allowed us to
prepare the previously unknown hexahydropyrido[2,3-d]pyrimidine derivatives 3
(Scheme 1). Besides their potential biologic activities, the produced target compounds
3, as heterocyclic a-amino-a,b-unsaturated carboxylic acids, can be of interest for the
synthesis of novel peptides containing a heterocyclic moiety in their skeleton, which
could lead to some biologically active compounds. On the other hand, compounds 3 can
be used as efficient starting materials for further multicomponent reactions due to the
presence of both an amine and a carboxylic acid functional group.
Because of the toxic and volatile nature of many organic solvents, the use of H2O as
a solvent medium is of interest. Compared with organic solvents, H2O has advantages
ꢀ 2009 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 92 (2009)
933
Scheme 1
such as safety, low cost, and environmentally friendly processes [19]. These facts
prompted us to use H2O as solvent in the synthesis of 3 from 1 and 2.
Results and Discussion. – In the cyclocondensation reaction of Scheme 1,
(arylmethylidene)pyruvic acid 1 plays an important role as an attractive starting
material for the following reasons: a) it has a higher reactivity in comparison to usual
a,b-unsaturated ketones, b) it contains active functional groups which can be used for
further synthesis, and c) its preparation is easy, i.e., the acids 1 were synthesized
according to the known procedure [20] by reaction of aromatic aldehydes and pyruvic
acid in an aqueous MeOH solution of KOH (Scheme 1). The subsequent cyclo-
condensation of 1 with the uracils 2 to give the 5-aryl-1,2,3,4,5,8-hexahydro-2,4-
dioxopyrido[2,3-d]pyrimidine-7-carboxylic acids 3a – 3f in high yields (89 – 95%) was
carried out in aqueous medium under reflux conditions for 4 h (Table).
Table. Synthesis of Hexahydropyrido[2,3-d]pyrimidines 3a – 3f in Aqueous Medium
Product
X
R
M.p. [8]
Yield [%]a) Product
X
R
M.p. [8]
Yield [%]a)
3a
3b
3c
Cl
MeO
Me
H
H
H
319 – 320 95
315 – 316 90
298 – 299 93
3d
3e
3f
Cl
Me 236 – 238 91
MeO Me 228 – 229 89
Me Me 248 – 249 94
a) Yields refer to pure isolated products characterized by IR, 1H- and 13C-NMR spectroscopy, and mass
spectrometry.
Although several approaches have been developed for the synthesis of the
pyridopyrimidines, e.g., a) the reaction of benzylidene derivatives of malononitrile with
3,4-dihydropyrimidin-6-amine in boiling EtOH [2], b) the three-component reaction of
aldehydes, alkyl nitriles, and pyrimidinamines in H2O and in the presence of KF/Al2O3
as catalyst [3][21], or c) the similar three-component reaction catalyzed by TEBAC

934
Helvetica Chimica Acta – Vol. 92 (2009)
(¼ PhCH2NEt3 · Cl) [4], our new procedure is simple and occurs under milder reaction
conditions.
Considering the model of similar reactions for the synthesis of pyridopyrimidines,
including nucleophilic attack of a nucleophilic C-atom of the pyrimidine rings to the
a,b-unsaturated system [2 – 4], a plausible mechanism is proposed in Scheme 2. Due to
the C-nucleophilic character of 6-aminouracils, it is reasonable to assume that 3 can be
formed via the initial Michael addition of 6-aminouracil 2 to (arylmethylidene)pyruvic
acid 1 to generate the Michael adduct 4, which is isomerized under the reaction
conditions to yield 5. Intramolecular cyclization of 5 gives 3 after dehydration of
intermediate 6 (Scheme 2).
Scheme 2. Possible Mechanism for the Formation of Hexahydropyrido[2,3-d]pyrimidine Derivatives
1
The structures of compounds 3a – 3f were deduced from their H- and 13C-NMR,
IR, and MS data (see Exper. Part) and the NMR spectra. All products 3a – 3f, showed a
characteristic s for HꢀC(5) at d(H) 4.51 – 4.69 and a peak for C(5) at d(C) 36.4 – 37.7.
The MS displayed corresponding molecular-ion peaks.
In summary, we introduced an efficient method for the preparation of new
hexahydropyrido[2,3-d]pyrimidine derivatives. Besides the simplicity of the method,
our synthesized heterocyclic molecules have the potential to be biologically active or to
be used as precursors to produce other biologically active compounds. Further
investigations about the use of these product for the synthesis of novel compounds is
going on in our laboratory.

Helvetica Chimica Acta – Vol. 92 (2009)
935
Saeed Balalaie is grateful to the National Research Institute for Science Policy (NRISP; Iran) for the
financial support. We are thankful to Prof. Rolf Gleiter for his useful discussions and review of the article.
Experimental Part
General. All chemical materials used in this work were purchased from Merck and Fluka and used
without further purification. M.p.: Electrothermal-9100 apparatus; uncorrected. IR Spectra: ABB-FT-IR
(FTLA 2000) spectrometer; ˜n in cm1ꢀ. 1H- and 13C-NMR Spectra: Bruker-DRX-300 Avance at 300 and
75 MHz, resp.; in (D6)DMSO, d in ppm rel. to Me4Si, as internal standard, J in Hz. MS: GC-MS-Hewlett-
Packard (EI, 70 eV) instrument.
Preparation of Compounds 3a – 3f: General Procedure. A mixture of the appropriate (arylmethy-
lidene)pyruvic acid 1 (1 mmol) and 6-aminouracil or 6-amino-1,3-dimethyluracil 2 (1 mmol) in H2O
(15 ml) was heated to reflux for 4 h. After cooling, the formed precipitate was isolated by filtration and
purified by washing with cold 50% aq. EtOH to afford the corresponding products in high yields.
5-(4-Chlorophenyl)-1,2,3,4,5,8-hexahydro-2,4-dioxopyrido[2,3-d]pyrimidine-7-carboxylic Acid (3a):
Yield 303 mg (95%). White powder. M.p. 319 – 3208. IR (KBr): 3344 (NH), 3242 (COOH), 1733
(COOH), 1659 (NCO), 1621 (NCON), 1544 (arom.). 1H-NMR: 4.60 (d, J ¼ 5.3, HꢀC(5)); 5.86 (dd, J ¼
5.3, 1.2, HꢀC(6)); 7.24 (d, J ¼ 8.5, 2 arom. H); 7.32 (d, J ¼ 8.5, 2 arom. H); 8.15 (s, NH); 9.91 (s, NH);
10.47 (s, NH); 13.43 (br. s, COOH). 13C-NMR: 36.9; 83.7; 113.7; 126.4; 128.2; 129.3; 131.0; 144.8; 145.9;
149.7; 162.9; 163.2. EI-MS (70 eV): 319 (3, Mþ), 264 (28), 238 (28), 97 (57), 83 (68), 77 (16), 69 (80), 57
(100), 43 (94). Anal. calc. for C14H10ClN3O4 (319.75): C 52.60, H 3.15, N 13.14; found: C 52.50, H 3.10, N
13.08.
1,2,3,4,5,8-Hexahydro-5-(4-methoxyphenyl)-2,4-dioxopyrido[2,3-d]pyrimidine-7-carboxylic Acid
(3b): Yield 284 mg (90%). White powder. M.p. 315 – 3168. IR (KBr): 3344 (NH), 3242 (COOH),
1
1730 (COOH), 1658 (NCO), 1617 (NCON), 1544 (arom.). H-NMR: 3.70 (s, MeO); 4.51 (d, J ¼ 5.4,
HꢀC(5)); 5.87 (dd, J ¼ 5.4, 1.0, HꢀC(6)); 6.83 (d, J ¼ 8.6, 2 arom. H); 7.12 (d, J ¼ 8.6, 2 arom. H); 8.10 (s,
NH); 9.90 (s, NH); 10.43 (s, NH); 13.40 (br. s, COOH). 13C-NMR: 36.4; 55.1; 84.2; 113.8; 114.7; 125.7;
128.5; 138.2; 145.7; 149.8; 157.9; 163.0; 163.5. EI-MS (70 eV): 315 (5, Mþ), 313 (49), 297 (9), 269 (100),
207 (41), 163 (82), 108 (92), 77 (25), 43 (16). Anal. calc. for C15H13N3O5 (315.28): C 57.14, H 4.16, N
13.33; found: C, 57.09; H, 4.13; N, 13.30.
1,2,3,4,5,8-Hexahydro-5-(4-methylphenyl)-2,4-dioxopyrido[2,3-d]pyrimidine-7-carboxylic Acid (3c):
Yield 278 mg (93%). White powder. M.p. 298 – 2998. IR (KBr): 3344 (NH), 3245 (COOH), 1729
(COOH), 1659 (NCO), 1621 (NCON), 1545 (arom.). 1H-NMR: 2.24 (s, Me); 4.52 (d, J ¼ 5.4, HꢀC(5));
5.85 (d, J ¼ 5.4, HꢀC(6)); 7.08 (br. s, 4 arom. H); 8.09 (s, NH); 9.88 (s, NH); 10.41 (s, NH); 14.35 (br. s,
COOH). 13C-NMR: 20.5; 36.8; 83.9; 114.5; 125.8; 127.2; 128.9; 135.3; 142.9; 145.7; 149.7; 162.9; 163.3. EI-
MS (70 eV): 299 (14, Mþ), 297 (56), 252 (100), 208 (21), 164 (22), 91 (15), 77 (9), 43 (6). Anal. calc. for
C15H13N3O4 (299.28): C 60.20, H 4.38, N 14.04; found: C 60.12, H 4.30, N 14.00.
5-(4-Chlorophenyl)-1,2,3,4,5,8-hexahydro-1,3-dimethyl-2,4-dioxopyrido[2,3-d]pyrimidine-7-carbox-
ylic Acids (3d): Yield 316 mg (91%). White powder. M.p. 236 – 2388. IR (KBr): 3358 (NH), 3426
(COOH), 1701 (COOH), 1677 (NCO), 1620 (NCON), 1598 (arom.). 1H-NMR: 3.07 (s, MeN); 3.44 (s,
MeN); 4.69 (d, J ¼ 5.4, HꢀC(5)); 6.00 (d, J ¼ 5.4, HꢀC(6)); 7.25 (d, J ¼ 8.5, 2 arom. H); 7.33 (d, J ¼ 8.5, 2
arom. H); 7.63 (s, NH); 13.57 (br. s, COOH). 13C-NMR: 27.5; 29.1; 37.7; 85.1; 115.1; 126.7; 128.3; 129.3;
131.1; 144.7; 145.7; 150.7; 160.8; 163.4. EI-MS (70 eV): 349 (7, [M þ 2]þ), 347 (22, Mþ), 301 (31), 236
(100), 218 (63), 190 (91), 133 (28), 77 (4), 57 (4). Anal. calc. for C16H14ClN3O4 (347.80): C 55.26, H 4.06,
N 12.08; found: C 55.18, H 4.00, N 12.02.
1,2,3,4,5,8-Hexahydro-5-(4-methoxyphenyl)-1,3-dimethyl-2,4-dioxopyrido[2,3-d]pyrimidine-7-car-
boxylic Acids (3e): Yield 305 mg (89%). White powder. M.p. 228 – 2298. IR (KBr): 3411 (NH), 3366
(COOH), 1701 (COOH), 1669 (NCO), 1627 (NCON), 1598 (arom.). 1H-NMR: 3.07 (s, MeN); 3.44 (s,
MeN); 3.69 (s, MeO); 4.60 (d, J ¼ 5.5, HꢀC(5)); 5.99 (d, J ¼ 5.5, HꢀC(6)); 6.82 (d, J ¼ 8.6, 2 arom. H);
7.12 (d, J ¼ 8.6, 2 arom. H); 7.58 (s, NH); 13.50 (br. s, COOH). 13C-NMR: 27.5; 29.0; 37.2; 55.0; 85.7; 113.7;
116.0; 126.2; 128.4; 138.0; 145.4; 150.7; 157.9; 160.8; 163.5. EI-MS (70 eV): 343 (50, Mþ), 297 (100), 236
(83), 218 (70), 190 (99), 133 (32), 77 (12), 57 (6). Anal. calc. for C17H17N3O5 (343.34): C 59.47, H 4.99, N
12.24; found: C 59.40, H 4.93, N 12.18.

936
Helvetica Chimica Acta – Vol. 92 (2009)
1,2,3,4,5,8-Hexahydro-1,3-dimethyl-5-(4-methylphenyl)-2,4-dioxopyrido[2,3-d]pyrimidine-7-carbox-
ylic acids (3f): Yield 307 mg (94%). White powder. M.p. 248 – 2498. IR (KBr): 3423 (NH), 3358
1
(COOH), 1701 (COOH), 1669 (NCO), 1618 (NCON), 1596 (arom.). H-NMR: 2.23 (s, Me); 3.07 (s,
MeN); 3.44 (s, MeN); 4.62 (d, J ¼ 5.5, HꢀC(5)); 5.99 (d, J ¼ 5.5, HꢀC(6)); 7.06 (d, J ¼ 8.3, 2 arom. H);
7.11 (d, J ¼ 8.3, 2 arom. H); 7.58 (s, NH); 13.50 (br. s, COOH). 13C-NMR: 20.6; 27.5; 29.1; 37.7; 85.6; 116.0;
126.3; 127.3; 128.9; 135.5; 142.9; 145.5; 150.7; 160.8; 163.5. EI-MS (70 eV): 327 (35, Mþ), 281 (42), 236
(100), 218 (72), 190 (90), 133 (29), 77 (5), 57 (3). Anal. calc. for C17H17N3O4 (327.34): C 62.38, H 5.23, N
12.84; found: C 62.30, H 5.20, N 12.79.
REFERENCES
[1] R. E. Lyle, in ꢂPyridine and its Derivativesꢃ, Supplement, Ed. R. A. Abramovich, Wiley, New York,
1974, Vol. 1, p. 137.
´
[2] J. Quiroga, M. Alvarado, B. Insuasty, M. Nogueras, A. Sanchez, J. Cobo, J. Heterocycl. Chem. 1998,
35, 1309.
[3] X.-S. Wang, Z.-S. Zeng, D.-Q. Shi, S.-J. Tu, X.-Y. Wei, Z.-M. Zong, Synth. Commun. 2005, 35, 1921.
[4] D. Shi, S. Ji, L. Niu, J. Shi, X. Wang, J. Heterocycl. Chem. 2007, 44, 1083.
[5] L. V. G. Nargund, Y. S. R. Reddy, R. Jose, Indian Drugs. 1991, 29, 45.
[6] K. Furukawa, T. Hasegawa, Can. Pat. CA2151971 (Chem. Abstr. 1996, 124, 289568c).
[7] A. Rosowsky, C. E. Mota, S. F. Queener, J. Heterocycl. Chem. 1995, 32, 335.
[8] A. M. Thompson, A. J. Bridges, D. W. Fry, A. J. Kraker, W. A. Denny, J. Med. Chem. 1995, 38, 3780.
[9] I. O. Donkor, C. L. Klein, L. Liang, N. Zhu, E. Bradley, A. M. Clark, J. Pharm. Sci. 1995, 84, 661.
[10] A. Pastor, R. Alajarin, J. J. Vaquero, J. Alvarez-Builla, M. Fau de Casa-Juana, C. Sunkel, J. G. Priego,
I. Fonseca, J. Sanz-Aparicio, Tetrahedron 1994, 50, 8085.
´
[11] V. E. Kolla, A. B. Deyanov, F. Y. Nazmetdinov, Z. N. Kashina, L. P. Drovosekova, Khim-Farm. Zh.
´
1993, 27, 29; V. E. Kolla, A. B. Deyanov, F. Y. Nazmetdinov, Z. N. Kashina, L. P. Drovosekova,
Pharm. Chem. J. 1993, 27, 635.
[12] J. W. Ellingboe, US Pat. 5,466,692 (Chem. Abstr. 1996, 124, 176134q).
[13] N. K. Satti, K. A. Suri, O. P. Sun, A. Kapil, Indian J. Chem., Sect. B 1993, 32, 978.
[14] I. D. Bystryakova, I. A. Burova, G. M. Chelysheva, S. V. Zhilinkova, N. M. Smirnova, T. S. Safonova,
Khim-Farm. Zh. 1991, 25, 31; I. D. Bystryakova, I. A. Burova, G. M. Chelysheva, S. V. Zhilinkova,
N. M. Smirnova, T. S. Safonova, Pharm. Chem. J. 1991, 25, 874.
´
[15] A. B. Deyanov, R. K. Niyazov, F. Y. Nazmetdivov, B. Y. Syropyatov, V. E. Kolla, M. E. Konshin,
Khim-Farm. Zh. 1991, 25, 26; A. B. Deyanov, R. K. Niyazov, F. Y. Nazmetdivov, B. Y. Syropyatov,
´
V. E. Kolla, M. E. Konshin, Pharm. Chem. J. 1991, 25, 248.
[16] A. Monge, V. Martinez-Merino, C. Sanmartin, F. J. Fernandez, M. C. Ochoa, C. Bellver, P. Artigas,
E. Fernandez-Alvarez, J. Med. Chem. 1989, 24, 209.
[17] H. Saladowska, A. Bartoszko-Malik, T. Zawisza, Farmaco 1990, 45, 101.
[18] F. Darviche, S. Balalaie, F. Chadegani, P. Salehi, Synth. Commun. 2007, 37, 1059; S. Balalaie, M.
Bararjanian, M. Sheikh-Ahmadi, S. Hekmat, P. Salehi, Synth. Commun. 2007, 37, 1097; S.
Abdolmohammadi, S. Balalaie, Tetrahedron Lett. 2007, 48, 3299.
[19] C.-J. Li, Chem. Rev. 2005, 105, 3095.
[20] N. Anna, R. Paris, F. Jordan, J. Am. Chem. Soc. 1999, 111, 8895.
[21] X.-S. Wang, Z.-S. Zeng, D.-Q. Shi, X.-Y. Wei, Z.-M. Zong, Synth. Commun. 2004, 34, 4331.
Received August 13, 2008