Domino Knoevenagel condensation–Michael addition–cyclization for the diastereoselective synthesis of dihydrofuropyrido[2,3-d]pyrimidines via pyridinium ylides in water

Somayeh Ahadia, Telma Kamranifarda, Mahsa Armaghanb, Hamid Reza Khavasia and Ayoob Bazgir*a
aDepartment of Chemistry, Shahid Beheshti University, General Campus, Tehran 1983963113, Iran. E-mail: a_bazgir@sbu.ac.ir; Fax: +98 21-22431661; Tel: +98 21-29903104
bInstitute of Materials Research and Engineering, Agency for Science Technology and Research, 3 Research Link, S117602, Singapore. E-mail: stu-armaghanm@imre.a-star.edu.sg; Fax: +65 68720785; Tel: +65 68748111

Received 13th October 2013 , Accepted 25th November 2013

First published on 25th November 2013


Abstract

A green method for the diastereoselective synthesis of dihydrofuropyrido[2,3-d]pyrimidines via the reaction of 6-amino-1,3-dimethyl pyrimidine-2,4(1H,3H)-dione, aldehydes and 1-(2-oxo-2-phenylethyl)pyridin-1-ium bromides as a pyridinium ylide base on an organocatalyst assisted domino Knoevenagel condensation–Michael addition–cyclization is investigated. To the best our knowledge, employing 6-amino-1,3-dimethyl pyrimidine-2,4(1H,3H)-dione for the synthesis of dihydrofuropyrido[2,3-d]pyrimidines has not been report yet. This synthesis serves as a nice addition to group-assistant-purification (GAP) chemistry in which purification via chromatography and recrystallization can be avoided, and the pure products were obtained simply by washing the crude products with ethanol.


Introduction

The concept of green chemistry now goes further than chemistry and touches on topics ranging from energy to societal sustainability. The key idea of green chemistry is efficiency, including material, energy, man-power and property efficiency.1 Selectivity, atom economy,2–4 time saving, environmental friendliness, cost effectiveness and the reconciliation of molecular complexity with experimental simplicity are some of the pieces of the puzzle needing to be assembled by modern academic and industrial synthetic chemists to reach maximum efficiency.5 As part of green chemistry efforts, a variety of cleaner solvents have been evaluated as replacements.6 However, an ideal and universal green solvent for all situations does not exist. Green solvents such as ionic liquids,7 supercritical CO2,8 and water9 complement each other nicely both in properties and applications.

Notably the use of water as a solvent has attracted much interest in recent years.10–18 Indeed; water has many advantages because it is a cheap, readily available, non-toxic and non-flammable solvent, thus being very attractive from both an economical and an environmental point of view. But it is now well established that the unique structure and physicochemical properties of water lead to particular interactions like polarity, hydrogen bonding, hydrophobic effect and trans-phase interactions that might greatly influence the reaction course.19

Fused pyrimidine chemistry began in 1776, when Scheele isolated uric acid.20 Hetero-fused pyrimidines exhibit favorable antiviral,21 antibacterial,22 anti-AIDS,23 antitumor,24 antialergic,25 antimalarial,26 antifungal27 and antinociceptive28 activities. They are greatly used in neurology, particularly in the treatment of neurodegenerative disorders such as Parkinson's disease,29 antianxiety disorders,30 and depression.31 Pyrido[2,3-d]pyrimidines, one of the important fused pyrimidine families, display several potential biological activities, such as tyrosine kinase inhibition,32 dihydrofolate reductase inhibition,33 STa-induced cGMP synthesis inhibition,34 anti-bacterial,35 anti-inflammatory36 and in vitro cytotoxic activities.37 Functionalized pyrido[2,3-d]pyrimidines have various types of bioactivity.38 For example compounds I, II, III and IV are known as inhibitors of dihydrofolate reductases, an anti-diarrhoea compound, a CDK-4 inhibitor and an anti-leukaemic coumpounds, respectively (Fig. 1).


image file: c3ra45795h-f1.tif
Fig. 1 Biologically active pyrido[2,3-d]pyrimidine frameworks.

As a privileged scaffold, dihydrofuran is a ubiquitous subunit in many natural products with remarkable biological activities and are widely applied in the pharmaceutical industry.39 Therefore, many methodologies reported for the synthesis of dihydrofurans, including non-ionic and ionic procedures. Radical40 or carbenoid41 additions to olefins have been utilized as non-ionic procedures. Dihydrofuran syntheses via tandem nucleophilic reaction of 1,3-dicarbonyl compounds42 or ylides43 with enones have been reported as ionic procedures. Pyridinium salts derived from α-halogenocarbonyl compounds are easily deprotonated to give pyridinium ylide, which has found wide application in the synthesis of dihydrofurans.44

According to the above reports, we herein report the green synthesis of dihydrofuro[2′,3′:4,5]pyrido[2,3-d]pyrimidine-trione derivatives employing an organocatalyst domino Knoevenagel condensation–Michael addition–cyclization of 5-hydroxy-1,3-dimethylpyrido[2,3-d]pyrimidine-trione 1, aromatic aldehydes 2 and 1-(2-oxo-2-phenylethyl)pyridin-1-ium bromides 3 as pyridinium ylide in water in the presence of a catalytic amount of triethylamine (Scheme 1). To our surprise, expected product dihydrofuro[2′,3′:4,5]pyrido[2,3-d]pyrimidine-trione, 5, was not obtained and only dihydrofuro[3′,2′:5,6]pyrido[2,3-d]pyrimidine-dione 4, was isolated in good yield (Scheme 1). The synthesis of new heterocycles containing both pyrido[2,3-d]pyrimidine and dihydrofuran moieties may result new drug candidates.


image file: c3ra45795h-s1.tif
Scheme 1 Synthesis of dihydrofuropyrido[2,3-d]pyrimidine-dione.

Results and discussion

First, we have synthesized pyrido[2,3-d]pyrimidine-trione 1 as a new heterocyclic active methylene compound via the reaction of 6-amino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 6 and diethyl malonate 7 at 220 °C under solvent-free conditions (Scheme 2).
image file: c3ra45795h-s2.tif
Scheme 2 Synthesis of pyrido[2,3-d]pyrimidine-trione 1.

Then, the three-component reaction of pyrido[2,3-d]pyrimidine-trione 1 (1 mmol), 4-nitrobenzaldehyde 2a (1 mmol) and 1-(2-oxo-2-phenylethyl)pyridin-1-ium bromide 3 (1 mmol) in the presence of various bases and solvents was investigated (Table 1). The screening of the solvent reveals that water is the solvent of choice for this transformation and provides 7-benzoyl-5-hydroxy-1,3-dimethyl-6-(4-nitrophenyl)-6,7-dihydrofuro[3′,2′:5, 6]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 4a in 97% isolated yield in the presence of 30 mol% Et3N (entry 3). It was found that when increasing the amount of the NEt3 from 10 to 20, and 30 mol%, the isolated yield increases from 80 to 85 and 97%, respectively, and more of the NEt3 did not improve the yield (entry 6). It should be mentioned when the reaction was carried out in the absence of NEt3 the yield of the product was low (entry 7). When this reaction was carried out with other bases, such as DBU, Cs2CO3, K2CO3 and NH4OAc, the yield of the expected product was lower. Also, it was observed that a lower reaction temperature leads to a lower yield (entry 8).

Table 1 Optimisation of reaction conditions

image file: c3ra45795h-u1.tif

Entry Solvent Base (mol%) Yielda (%)
a Isolated yield. Reaction time = 48 h.
1 CH3CN (reflux) Et3N (30) 20
2 EtOH (reflux) Et3N (30) 55
3 H2O (reflux) Et3N (30) 97
4 H2O (reflux) Et3N (10) 80
5 H2O (reflux) Et3N (20) 85
6 H2O (reflux) Et3N (40) 97
7 H2O (reflux) Et3N (30) 43
4 DMF (100 °C) Et3N (30) 58
6 H2O (reflux) DBU (30) 65
7 H2O (reflux) K2CO3 (30) 51
8 H2O (reflux) Cs2CO3 (30) 70
9 H2O (reflux) NH4OAc (10) 35


With this protocol in hand, we extended the reaction to various aromatic aldehydes 2a–f and 1-(2-oxo-2-phenylethyl)pyridin-1-ium bromides 3a–c, and trans-dihydrofuro[2′,3′:4,5]pyrido[2,3-d]pyrimidine-4,7,9(2H,5H,8H)-trione 4a–k were isolated in good yields (Table 2).

Table 2 Synthesis of dihydrofuro pyrido[2,3-d]pyrimidine-triones 4

image file: c3ra45795h-u2.tif

Compound Ar Ar′ Yield (%)
4a 4-O2NC6H4 C6H5 97
4b 4-HO2CC6H4 C6H5 78
4c 4-H3COC6H4 C6H5 84
4d 3-O2NC6H4 C6H5 81
4e 2-Thienyl C6H5 95
4f C6H5 4-H3COC6H4 69
4g 4-O2NC6H4 4-H3COC6H4 70
4h 4-H3COC6H4 4-H3COC6H4 94
4i C6H5 4-BrC6H4 60
4j 4-O2NC6H4 4-BrC6H4 80
4k 4-HOC6H4 4-BrC6H4 70


The structures of the products 4a–k were fully characterized by 1H and 13C NMR, MS, and IR spectra and elemental analysis. For example, in the 1H NMR spectra of 4a, the two methine hydrogens of the dihydrofuran ring display two doublets at 5.04 and 5.99 ppm with the vicinal coupling constant J = 4.5 Hz. It has been established that in cis-2,3-dihydrofuran the vicinal coupling constant of the two methine protons J = 7–10 Hz, while in trans-2,3-dihydrofuran the vicinal coupling constant J = 4–7 Hz (Fig. 2).45 According to the careful analysis of 1H NMR data and single crystal X-ray analysis (Fig. 3), we could experimentally conclude that dihydrofuro[2′,3′:4,5]pyrido[2,3-d]pyrimidine-4,7,9(2H,5H,8H)-triones 4a–l were the thermodynamically stable trans isomers.


image file: c3ra45795h-f2.tif
Fig. 2 Determination of stereochemistry of products.45

image file: c3ra45795h-f3.tif
Fig. 3 X-ray crystal structure of 4c.

The chromone scaffold forms the nucleus of flavanoids that are found naturally in fruits, vegetables, nuts, seeds, flowers, and barks.46 Chromone is also part of pharmacophores of a large number of molecules of medicinal significance47 including anticancer agents such as psorospermin and pluramycin A.48 According to the very important biologically activities of the molecules containing chromone scaffold, we presume that the integration of a chromone moiety with a dihydrofuropyrido[2,3-d]pyrimidine may result in the discovery of novel drug candidates with unknown biologically activities. With this in mind, we investigated the reaction of 5-hydroxy-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione 1 with 4-oxo-4H-chromene-3-carbaldehydes 8 and 1-(2-oxo-2-phenylethyl)pyridin-1-ium bromides 3 under the same reaction conditions and obtained desired dihydrofuropyrido[2,3-d]pyrimidine-triones 9 containing chromone moiety in good yields (Table 3).

Table 3 Synthesis of dihydrofuropyrido[2,3-d]pyrimidine-triones containing a chromone moiety

image file: c3ra45795h-u3.tif

Compound X Y Yielda (%)
a Isolated yield.
9a H H 70
9b Cl H 60
9c Me H 94
9d H OMe 85
9e Cl OMe 90
9f H Br 60
9g Me Br 65


The final products could be isolated readily by simple filtration, because of their low solubility in water, and the pure products were obtained simply by washing the crude products with ethanol.

A plausible mechanism for the formation of dihydrofuro[3′,2′:5,6]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 4 is shown in Scheme 3. First, triethyl amine catalyzed the Knoevenagel condensation reaction of pyrido[2,3-d]pyrimidine-trione 1 and aromatic aldehyde 2 to obtain 2-arylidene-pyrido[2,3-d]pyrimidine-trione 10. Then, a Michael addition reaction of pyridinium ylide 11 (formed in situ by the deprotonation of 1-(2-oxo-2-phenylethyl)pyridin-1-ium bromide 3) to 10 produces zwitterion intermediate 12. Finally, an intramolecular nucleophilic reaction followed by a [1,5] H-shift leads to the product 4.


image file: c3ra45795h-s3.tif
Scheme 3 Plausible mechanism.

Conclusions

The diastereoselective and high-yielding synthesis of dihydrofuropyrido[2,3-d]pyrimidine derivatives via a domino Knoevenagel condensation–Michael addition–cyclization reaction of readily available starting materials under environmentally friendly conditions is reported. The regioselectivity of the reaction is extremely high and only a product, dihydrofuro[3′,2′:5,6]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, was isolated in good yield.

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Footnote

Electronic supplementary information (ESI) available: Experimental procedures, 1H NMR and 13C NMR spectra for products and X-ray crystal structure of 4c. CCDC 955501. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra45795h

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