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

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.

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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).

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.

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).

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

Entry	Solvent	Base (mol%)	Yield^a (%)
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

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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

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

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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.

Fig. 2 Determination of stereochemistry of products.⁴⁵

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

Compound	X	Y	Yield^a (%)
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

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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.

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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