A catalyst free, multicomponent-tandem, facile synthesis of pyrido[2,3-d]pyrimidines using glycerol as a recyclable promoting medium

Abstract

A clean and efficient, multicomponent-tandem strategy for the synthesis of pyrido[2,3-d]pyrimidines is reported in glycerol, a biodegradable and reusable promoting medium. The advantages of the present methodology includes a one-pot catalyst free environmentally friendly approach, 100% atom economy, cost effectiveness, broad substrate scope, operational simplicity, short reaction times, easy workup procedure and high yields.

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Multicomponent reactions have recently been recognized as a major new expansion in synthetic organic chemistry. They allow the assembly of complex molecules in one pot, thus maximizing synthetic efficiency and reducing costs. In the last few decades there has been a growing emphasis on sustainable chemistry due to the global push to improve green credentials.¹ Utilization of multicomponent reactions for sustainable synthesis holds great promise in organic synthesis; however, this area still remains under-utilised. One major thrust area in green chemistry is the replacement of toxic organic solvents with sustainable and green solvents.²

In this context perfluorinated solvents,³ water,⁴ ionic liquids,⁵ polyethylene glycol,⁶ supercritical fluids (particularly supercritical carbon dioxide – scCO₂)⁷etc. have been used as potential substitutes to conventional organic solvents. But their use involves many limitations, forcing the scientific community to look for better alternatives. In this backdrop glycerol has emerged as an attractive solvent. It possesses the benefits of both water and ionic liquids like low toxicity, relatively low vapour pressure, easy availability, reusability, inexpensiveness, renewability, a high boiling point and the ability to dissolve a wide range of organic and inorganic compounds.^8,9 Development of catalyst free reactions is another area that has attracted much attention in green chemistry due to the inherent advantages involved in terms of cost and the environment.^10,11

Pyrimidines represent one of the most biologically, and pharmaceutically active class of compounds.¹² When this pyrimidine moiety is fused with different heterocycles, it results in hybrid scaffolds with improved activity. Pyrido[2,3-d]pyrimidine is one such pyrimidine based hybrid scaffold, which has attracted considerable attention due to its broad biological and medicinal applications¹³ (Fig. 1).^14–19

Fig. 1 Some examples of biologically relevant compounds having a pyridopyrimidine and pyridopyrimidine type skeleton.

A large number of methods for the synthesis of pyrido[2,3-d]pyrimidines have already been reported in the literature^20–22 such as by using nanocrystalline MgO^22b sulfonic acid functionalized SBA-15,^20a HAp-encapsulated-γ-Fe₂O₃ supported sulfonic acid nanocatalyst,^22a vitamin B₁^20b in ionic liquid,^22c ZrO₂ nanoparticles,^20d diammonium hydrogen phosphate (DAHP),^20c TBAB (tetra-butyl ammonium bromide),^20f TEBAC (triethylbenzylammonium chloride),^20e KF–alumina,^21d and palladium.^21e However, in spite of their potential benefits, many of these reported methods suffer from drawbacks such as the use of environmentally harmful organic solvents, expensive catalysts, harsh reaction conditions, difficult work-up, non-recyclability of solvents, commercial unavailability and low yields.²² Therefore, the development of newer more efficient and greener methods for the synthesis of pyrido[2,3-d]pyrimidines remains a highly active research field, as evidenced by the increasing number of reports on the synthesis of pyridopyrimidines in the last ten years.^13a–m,20

To the best of our knowledge, a catalyst free synthesis of pyrido[2,3-d]pyrimidine has still not been reported. Consequently, in continuation of our ongoing research program on the development of green synthetic routes to important heterocyclic molecules,²³ we herein report a new, catalyst free, clean and efficient one-pot synthesis of pyrido[2,3-d]pyrimidines using glycerol as a promoting medium (Scheme 1).

Scheme 1 General synthetic strategy.

In our initial endeavour we conducted a model reaction using benzaldehyde (1, 1 mmol) and malononitrile (2, 1 mmol) in water at room temperature (RT). A white solution was obtained after 30 minutes with the disappearance of the starting material spots and formation of a new spot on TLC, indicating the formation of the cyano-olefin intermediate. To the reaction mixture containing the cyano-olefin was added 6-amino-1-methyl uracil (3, 1 mmol). However no further reaction was observed even after 12 h of stirring (Table 1). We further performed the same experiment at 60 °C and then under reflux, but in both cases the product was formed only in traces (Table 1). The experiment was also performed in the presence of CTAB and SDS respectively at RT as well as under reflux but with little success and the product was formed only in a trace amount even after 12 h of stirring. Now in order to improve the yield we decided to screen different solvents. The reaction was first performed in ethanol at 60 °C without using any catalyst. To our delight the reaction occurred in this case leading to the formation of a solid product in moderate yield (60%), which was identified as product 4, after about 6 h of addition of the third compound (6-amino-1-methyluracil, 3) to the reaction mixture. The reaction was now re-conducted at reflux but no improvement in yield was observed though reaction time was marginally reduced (5 h). In our effort to further improve the yield, the experiment was carried out using PEG-400 at 80 °C but with little success as there was only a marginal increase in yield in this case (63%). However the use of glycerol in place of PEG, led to a remarkable enhancement in yield (94%) and considerable reduction in reaction time (Table 1, entry 10). The experiment was now repeated at lower temperatures, viz. 60 °C, 40 °C and RT (Table 1) wherein it was noticed that there was a decrease in yield and an increase in reaction time with decreasing temperature.

Table 1 Effect of solvent and temp. on yield of pyrido[2,3-d]pyrimidine 4^a

Entry	Solvent	Additive	Temperature	Time (h)	Yield^b^,^c (%)
a All reactions were carried out with 1 (1 mmol), 2 (1 mmol), 3 (1 mmol) in 5 mL of solvent in air. b Isolated yields. c M.P. of compound 4 was found to be 303–306 °C (reported >300 °C).^20b
1	Water	None	RT	12	NR
2	Water	None	Reflux	12	NR
3	Water	CTAB	RT	12	Trace
3	Water	CTAB	Reflux	12	Trace
4	Water	SDS	RT	12	Trace
5	Water	SDS	Reflux	12	Trace
6	Ethanol	None	Reflux	5	60
7	Ethanol	None	60 °C	6	60
9	PEG-400	None	80 °C	4	63
10	Glycerol	None	80 °C	1.5	94
11	Glycerol	None	60 °C	3	86
12	Glycerol	None	40 °C	4	80
13	Glycerol	None	RT	6	76
14	Glycerol	None	100 °C	1.5	94

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We now also carried out the same reaction at a higher temperature (100 °C), but no increase in yield or reduction in reaction time was observed. From the above experiments it was inferred that the use of glycerol at 80 °C gave the best result. An improvement in yield and shortening of reaction time were observed upon increasing the reaction temperature, but increasing the reaction temperature beyond 80 °C did not lead to any further increase in yield or the rate of reaction.

Once ideal conditions for conducting the reaction had been identified, the scope and limitations of the developed synthetic protocol were explored under the optimized reaction conditions with aldehydes having different substituents (Table 2). In all the cases the desired product was obtained in high yield and short reaction times (Table 2). It was observed that when an electron withdrawing group was present on the aldehyde, the reaction proceeded faster and the product was formed in higher yield, while the presence of an electron donating group slowed down the reaction and led to reduced yield of the product (Table 2).

Table 2 Substrate scope^a

Entry	Aromatic aldehydes	Pyrido[2,3-d]pyrimidines	Tim (min)	Yield^b (%)	M.P. (°C)
a All reactions were carried out using benzaldehydes 6–16 (1 mmol), 2 (1 mmol), 3 or 5 (1 mmol) in 5 mL of glycerol in air. b Isolated yields.
1			60	94	300–302 (>300)^20b
2			70	94	298–300 (>300)^20b
3			90	90	300–303 (>300)^20d
4			90	90	295–298 (>300)^20b
5			80	93	298–300 (>300)^20b
6			80	93	300–304 (>300)^21b
7			70	94	300–302 (>300)^21b
8			90	90	297–300 (>300)^20b
9			90	86	303–305 (>300)^20a
10			80	93	303–306 (>300)^20a
11			80	93	300–302 (>300)^20b
12			80	94	>300

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The formation of the desired compound seemed to be initiated by Knoevenagel condensation of the aldehyde and malononitrile to give cyano-olefin I followed by Michael type addition between uracil 3 and cyano-olefin I to give the unstable intermediate II which undergoes concomitant cyclization affording the subsequent dihydropyridine type intermediate III which undergoes air oxidation to finally give the pyrido[2,3-d]pyrimidine 4 (Scheme 2).

Scheme 2 Plausible mechanism.

Once the methodology for the synthesis of pyrido[2,3-d]pyrimidine had been perfected and its generality had been amply demonstrated, we turned our attention towards examining the reusability of glycerol. Glycerol was dissolved in hot water while the product remained insoluble in water. The crude product was obtained by simple filtration and the filtrate containing glycerol was used again for the next reaction. The findings of this study are shown in Fig. 2. It was observed that the products were obtained in excellent to good yield even after reusing the glycerol four times, amply demonstrating the recyclability of glycerol.

Fig. 2 Recyclability of glycerol.

In conclusion we have disclosed a rapid and efficient one pot synthesis of pyrido[2,3-d]pyrimidine – a biologically significant hybrid scaffold in compliance with green chemistry principles. Highlights of the present methodology are the use of non-hazardous reaction conditions, the use of cheap starting materials, isolation of pure products through simple filtration thereby avoiding the need for column chromatography, very high yields and 100% atom economy. A key feature of the present work is the use of glycerol as a recyclable promoting medium amply highlighting the growing potential of glycerol in organic synthesis.

Experimental

To a round bottom flask containing 5 mL glycerol were added the respective benzaldehyde (1 mmol) and malononitrile (1 mmol) under stirring and the temperature of the reaction was set at 80 °C. After the formation of the cyano-olefin, the respective 6-amino-1-methyluracil (1 mmol) was added to the reaction mixture and it was allowed to stir until completion (TLC). Warm water was now added to the reaction mixture, glycerol was dissolved and the insoluble solid crude product was separated by simple filtration, which was as good as the pure compound (¹H NMR). The filtrate containing glycerol was extracted with methyl t-butyl ether (4 × 25 mL) to remove any organic compounds dissolved in the aqueous phase. The aqueous layer was separated and evaporated in vacuo to give pure glycerol, which was used for the next cycle.

Acknowledgements

The authors are thankful to SAIF, PU, Chandigarh and SAIF, CDRI, Lucknow, for spectral data. The authors also acknowledge financial support from UGC, New Delhi in the form of fellowships for SS, FT, MS and a major research project (Project No. 42-263/2013 (SR)). Dr Saquib specifically thanks UGC, New Delhi for the Dr D.S. Kothari Postdoctoral Fellowship (Award No. F.4-2/2006 (BSR)/13-1030/2013(BSR)) while JT thanks CSIR, New Delhi for a Junior Research Fellowship.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure, spectral data and ¹H and ¹³C spectra for pyrido[2,3-d]pyrimidine 28. See DOI: 10.1039/c5nj01938a

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