Cascade imination, Buchwald–Hartwig cross coupling and cycloaddition reaction: synthesis of pyrido[2,3-d]pyrimidines

Abstract

A novel and efficient palladium catalyzed method was developed for the synthesis of wide range of pyrido[2,3-d]pyrimidines, using readily available β-bromovinyl/aryl aldehydes and 6-amino-1,3-dialkyluracils as the starting materials with good yields. This reaction proceeds via cascade imination/Buchwald–Hartwig cross coupling/cycloaddition reactions under microwave irradiation and solvent free conditions.

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Pyrido[2,3-d]pyrimidine heterocycles are of tremendous biological importance due to their wide range of biological properties such as anti-inflammatory, analgesic, antihypertensive, antiviral, antimicrobial, antiasthmatic and anticancer activities.¹ Some of the biologically active pyrido[2,3-d]pyrimidine derivatives are shown in Fig. 1. In view of their very high biological and pharmaceutical importances, synthesis of these pyrido[2,3-d]pyrimidine derivatives have received considerable attentions in the literature. Typically, these heterocycles were synthesized by the reaction of 6-aminouracils with α,β-unsaturated carbonyl compounds,² Meldrum's acid derivatives³ 3-chloro-2-propeniminium salts⁴ and electron-rich enamines.⁵ Moreover, multi-component reactions were used to obtain these heterocycles.⁶ Recently, Kolos and coworkers reported an elegant synthetic method for pyrido[2,3-d]pyrimidines by the reaction of 3-(hetero)aroylacrylic acids or their methyl esters with 6-amino-1,3-dimethyluracil.⁷ In spite of various reports for the synthesis of pyrido[2,3-d]pyrimidines, there is still lack of a facile and environmentally benign general strategy for the synthesis of these important fused heterocycles.

Fig. 1 Examples of bioactive pyrido[2,3-d]pyrimidines.

Chemical reactions performed under microwave heating have couple of advantages such as decreased reaction time, high yield of products and enhancement of the chemo-, regio- and stereoselectivity of the reactions. Several novel transition-metal catalyzed reactions are known in the literature which have been performed under microwave heating.⁸ As a part of our ongoing research interests in the synthesis of biologically important N-containing heterocycles, utilizing β-bromovinyl/aryl aldehydes as the versatile synthons,⁹ herein, we wish to report an efficient Pd catalyzed synthesis of pyrido[2,3-d]pyrimidines using β-halovinyl/aryl aldehydes and 6-amino-1,3-dialkyluracils as the starting materials in solvent-free conditions under microwave irradiation.

We started our studies by examining the reaction of β-bromovinyl aldehyde 1a (1.0 mmol), with equimolar amount of 6-amino-1,3-dimethyluracil (2a, 1.0 mmol). To our delight, heating the reaction mixture at 120 °C for 12 hours in presence of PdCl₂ (2.5 mol%), K₂CO₃ (1.1 mmol) and PPh₃ (5.0 mol%), afforded pyrido[2,3-d]pyrimidine derivative 3a in 54% yield (Table 1, entry 1), which was fully characterized by ¹H NMR, ¹³C NMR and mass spectroscopy. Screening of other palladium catalysts, such as PdCl₂(PPh₃)₂, Pd(dppf)Cl₂, Pd(OAc)₂ and Pd(TFA)₂, revealed Pd(OAc)₂ as the most effective catalyst to synthesize 3a (Table 1, entries 2–5). Then we studied the effect of ligand on this cascade reaction. The ligand xantphos turned out to be the best ligand amongst the screened ligands (dppf, 1,10-phen) to carry out this reaction under thermal conditions (Table 1, entries 6–8). This reaction provided inferior results when the base K₂CO₃ was replaced with base Na₂CO₃ or Cs₂CO₃ or NaO^tBu (Table 1, entries 9–11). Moreover, screening of solvents such as DMSO and CH₃CN provided lower yield of 3a (Table 1, entries 12–13). In order to curtail the reaction time when we studied the influence of microwave (MW) irradiation (700 W, 120 °C, 14 bar), we observed a significant reduction in reaction time from 12 hours to 5 minutes to perform this reaction in DMF (Table 1, entry 14). Subsequently, because of the various advantages of solvent-free reactions,¹⁰ we performed the reaction under solvent free condition. Gratifyingly, under this condition we obtained slight increase of 3a to 91% in 5 minutes of reaction time under microwave irradiation (Table 1, entry 15). Our attempt to perform the reaction without catalyst could not provide 3a under the solvent free condition (Table 1, entry 16).

Table 1 Optimization of the reaction conditions for the synthesis of 3a^a

Entry	Pd catalyst	Solvent	Ligand	Thermal/MW	3a^b (%)
a All reactions were performed in presence of K2CO3 (1.1 equiv.) for 12 hours (thermal) or for 5 minutes (microwave) unless otherwise mentioned.b Isolated yield.c Na2CO3 (1.1 equiv.) was used.d Cs2CO3 (1.1 equiv.) was used.e NaO^tBu (1.1 equiv.) was used.
1	PdCl2	DMF	PPh3	120 °C	54
2	PdCl2(PPh3)2	DMF	PPh3	120 °C	47
3	Pd(dppf)Cl2	DMF	PPh3	120 °C	50
4	Pd(OAc)2	DMF	PPh3	120 °C	72
5	Pd(TFA)2	DMF	PPh3	120 °C	61
6	Pd(OAc)2	DMF	dppf	120 °C	64
7	Pd(OAc)2	DMF	Xantphos	120 °C	84
8	Pd(OAc)2	DMF	1,10-Phen	120 °C	69
9^c	Pd(OAc)2	DMF	Xantphos	120 °C	77
10^d	Pd(OAc)2	DMF	Xantphos	120 °C	72
11^e	Pd(OAc)2	DMF	Xantphos	120 °C	63
12	Pd(OAc)2	DMSO	Xantphos	120 °C	71
13	Pd(OAc)2	CH3CN	Xantphos	120 °C	49
14	Pd(OAc)2	DMF	Xantphos	MW	87
15	Pd(OAc)2	Neat	Xantphos	MW	91
16	—	Neat	—	MW	0

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With the optimized reaction conditions in hand (Table 1, entry 11), we then explored the feasibility of the reaction by selecting some representative β-halovinyl/aryl aldehydes 1a–m and 6-amino-1,3-dialkyluracils 2a, b (Table 2). The β-aryl substituted β-bromovinyl aldehydes (1b–d) with electron donating and electron-withdrawing groups such as methyl, chloro and nitro present in the aromatic ring reacted smoothly with 6-amino-1,3-dimethyluracil 2a to afford pyrido[2,3-d]pyrimidines 3b–d¹¹ in 77–93% yields. Thus, this reaction indicated diversity in functional group tolerance. Similarly, the heterocycle substituted β-bromovinyl aldehyde 1e reacted with 2a under the optimized reaction conditions to afford 7-furyl substituted pyrido[2,3-d]pyrimidine 3e in 84% yield. The cyclic β-bromovinyl aldehydes 1f–h were also converted to pyrido[2,3-d]pyrimidines 3f–h¹² in good yields (85–90%). Because of the importance of steroids fused with heterocycles,¹³ we attempted to extend the scope of this reaction with steroidal β-bromovinyl aldehydes. As shown in Table 2, the cascade reactions of steroidal β-bromovinyl aldehydes 1i, j with 2a were tested under the above reaction conditions to afford corresponding steroidal pyrido[2,3-d]pyrimidines 3i, j in 73–78% yields. In addition, the reactions of β-bromovinyl aldehydes 1a and 1e with 6-amino-1,3-dipropyluracil 2b proceeded smoothly to provide pyrido[2,3-d]pyrimidines 3k, l in 74–86% yields. Next, we carried out the reaction of ortho-bromobenzaldehydes 1k–m with 2a under the optimized reaction condition to provide the aryl fused pyrido[2,3-d]pyrimidines 3m–o in 72–79% yields. The formation of isomer 3 was proved by comparison of new spectral and physical data with those reported in the literature for compound 3b.^11b

Table 2 Synthesis of pyrido[2,3-d]pyrimidine derivatives^a

a Reaction conditions: a grinded mixture of β-bromovinyl/aryl aldehydes (1.0 mmol), 6-amino-1,3-dialkyluracils (1.0 mmol), Pd(OAc)₂ (2.5 mol%), xantphos (5.0 mol%) and K₂CO₃ (1.1 mmol) was irradiated in a closed vessel in a Synthos 3000 microwave reactor at 700 Watt (120 °C and 14 bar) for 5 minutes; isolated yields.

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The formation of pyrido[2,3-d]pyrimidine 3 is envisaged to occur via a mechanism which is shown in Scheme 1. First, the aldehyde 1 reacts with 6-amino-1,3-dialkyluracil 2 to produce imine 4a, which on subsequent Buchwald–Hartwig cross coupling reaction with another molecule of 2 affords intermediate 4b. Then, rearrangement of electron generates probably azadiene intermediate 4c, which on six-electron cyclization and subsequent elimination of one molecule of 2 affords the final compound 3. To the best of our knowledge, this is the first example of C-5 alkylation of 6-amino-1,3-dialkyluracils via cascade imination/coupling/cycloaddition reaction which finally leads to the formation of pyrido[2,3-d]pyrimidines.

Scheme 1 Proposed mechanism for the formation of 3.

Conclusions

In conclusion, we have developed a novel environmentally benign procedure for the efficient synthesis of biologically important pyrido[2,3-d]pyrimidines. A variety of β-halovinyl/aryl aldehydes undergo this reaction with 6-amino-1,3-dialkyluracils in presence of palladium catalyst under microwave irradiation via cascade imination/coupling/cycloaddition. Several features such as solvent-free synthesis, energy efficiency, less catalyst loading and operation simplicity make this procedure greener.

Acknowledgements

Pallabi Saikia thanks UGC, New Delhi for the award of Senior Research Fellowship (CSIR-SRF). We are grateful to Director, CSIR-NEIST for his keen interests. We gratefully acknowledge financial support from CSIR-ORIGIN (CSC0108), CSIR-ACT (CSC0301) and CSIR-INSPIRE (CSC0107) projects.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H NMR, ¹³C NMR spectra of compounds 3a–o. See DOI: 10.1039/c5ra00725a

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