Cascade synthesis of novel functionalized pyridine-fused coumarins in aqueous medium

Abstract

A simple, convenient and efficient catalyst-free approach for synthesis of a novel series of functionalized pyridine-fused coumarins via a cascade reaction from chromone derivatives in an environmentally friendly aqueous medium has been developed. This cascade reaction involves a chemoselective Michael addition–heterocyclization-intramolecular cyclization sequence.

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Coumarins belong to a common and important class of heterocyclic compounds which are ubiquitous in numerous natural products, pharmaceuticals, dyes, agrochemicals and materials science.¹ Particularly, large numbers of coumarins and their derivatives as privileged scaffolds with low toxicity have been reported to exhibit various bioactivities, such as selective carbonic anhydrase IX inhibitors,² anti-tumour activities,³ potential multireceptor atypical antipsychotics⁴ and selective MAO-B inhibitors,⁵ etc. and have also been discovered to possess remarkable fluorescence due to their high fluorescence quantum yield.^1g,6 In addition, pyridine ring is also widely used as an important motif in pharmaceutical chemistry owing to their potential biological activity.⁷ Thus a molecular scaffold containing both coumarin and pyridine unit may be of great interest from biological and molecular diversity viewpoint.

Traditionally, a number of methods such as the Perkin,⁸ Knoevenagel⁹ and Pechmann¹⁰ reactions have been applied to synthesize kinds of courmarins, which were usually conducted under harsh reaction conditions. Despite many alternative modern syntheses of coumarins were carried out under mild conditions, but using environmentally harmful transition metals.¹¹ Moreover, the work for systematic synthesis of pyridine-fused coumarins is quite rare, and these methods hampered by limited availability of the starting materials and/or needed multisteps.¹² Therefore, the development of a one-pot protocol to functionalized pyridine-fused coumarins under green reaction conditions without any catalysts is of great interest.

3-Cyanochromones as highly reactive compounds have been widely used to construct lots of bioactive compounds due to its three strong electrophilic centres which could react with various nucleophilic reagents, but controlling their chemoselectivity is challenging.¹³ Among many nucleophilic reagents, carbamimidoyl-acetic acid ethyl ester as C,N-bis-nucleophiles was applied in drug discovery to construct many bioactive heterocycles.¹⁴ In our previous work,¹⁵ we found that carbamimidoyl-acetic acid ethyl ester could react with chromone to give a 2-(pyridin-2-yl)phenol ring. Inspired by these works, we envisaged that if the phenolic hydroxyl group could undergo further intramolecular cyclizaiton reaction with cyano group of 1a to construct a tricyclic heterocycle via an intermediate A (Scheme 1). To our delight, consistent with our hypothesis, a tricyclic imine B was obtained in a moderate yield without the use of a catalyst at room temperature. Then, we discovered that imine B could be hydrolysed to fused coumarin 3a in one pot in an aqueous medium just like our expect (Scheme 1) and the structure of 3a was further confirmed by X-ray crystallography (Fig. 1). To the best of our knowledge, these compounds could be synthesized through the method developed by Simeonov and co-workers in 1992.^12b They afforded a powerful synthesis of 3,4-pyridyl-fused coumarins from 4-aminocoumarins followed by Vilsmeier formylation, then Knoevenagel reaction and finally cyclization. However this approach exploited a multi-step strategy and its starting materials were not commercial available. Compared to Simeonov's approach, we herein described a facile synthesis of 3,4-pyridyl-fused coumarins from commercial available starting materials 3-cyanochromones and carbamimidoyl-acetic acid ethyl ester in one-pot. The reaction could occur in aqueous medium or even in water without any catalyst and one equiv. of ammonia was formed as the only by-product, which was very eco-friendly and atom/step economic. This reaction involves a chemoselective Michael addition–heterocyclization-intramolecular cyclization sequence and ortho-amino carboxylate group was introduced meanwhile in one pot, which could further to construct structurally diverse and complicated molecules.

Scheme 1 Established methods for synthesis of novel 3,4-pyridyl-fused coumarins.

Fig. 1 X-ray crystal structure of compound 3a.

Our present study commenced with the treatment of 3-cyanochromone 1a and carbamimidoyl-acetic acid ethyl ester 2a with 4 equiv. NaOAc as the base in DMSO or DMF as the solvents (Table 1, entry1, 2). Delightfully, the reaction occurred smoothly leading to intermediate B detected by LC-MS. However, it should be noted that segmental intermediate B could directly be converted to product 3a during the chromatographically purified procedure. Other solvents as AcOH and H₂O were investigated and there was no reaction at room temperature with 1a being recovered (Table 1, entry 3, 4). After that, we raised the temperature to 100 °C using water as the solvent and a delighted result was found that product 3a was obtained in 70% yield (Table 1, entry 5). Subsequently, a range of bases were examined, and the results indicated that the bases of this reaction had a great effect on the isolated yields of the product 3a. When we changed NaOAc to other inorganic bases as Na₂CO₃ or NaHCO₃, the reaction was kept at the intermediate B stage with little or no product 3a detected by LC-MS (Table 1, entry 5 vs. 6, 7). We supposed that an equivalent AcOH formed in situ might be essential for catalysing the intermediate B to convert to the desired product. To our surprise, neither intermediate B nor product 3a was detected by LC-MS in the presence of organic base DBU (Table 1, entry 8). Considering the solubility of both the starting materials and product in water was not very well, we employed mixed solvents. Among the various mixed solvents screened, the mixed solvents DMSO–H₂O or EtOH–H₂O resulted in a higher yields (entry 5 vs. 9, 10), whereas the reaction carried out in other mixed solvents such as MeCN–H₂O and acetone–H₂O resulted in inferior yields (Table 1, entry 5 vs. 11, 12). Finally, the investigation of the temperature indicated that the reaction worked best at 80 °C with an 85% yield (Table 1, entry 13). Lowering the temperature to 60 °C decreased the yield and extended the reaction time from 12 hours to 24 hours (Table 1, entry 14).

Table 1 Optimization of reaction conditions^a

Entry	Solvent	Temp. (°C)	Base	Yield^b (100%)	Time
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), base (2 mmol), solvent (5 mL).b Isolated yield.c Only imine B was detected by LC-MS or little imine B was converted to the desired product.
1^c	DMSO	RT	NaOAc	—	12
2^c	DMF	RT	NaOAc	—	12
3	AcOH	RT	NaOAc	NR	12
4	H2O	RT	NaOAc	NR	12
5	H2O	100	NaOAc	70	12
6^c	H2O	100	Na2CO3	—	12
7^c	H2O	100	NaHCO3	—	12
8	H2O	100	DBU	0	12
9	H2O–DMSO (1 : 4)	100	NaOAc	77	12
10	H2O–EtOH (1 : 4)	Reflux	NaOAc	75	12
11	H2O–MeCN (1 : 4)	Reflux	NaOAc	41	12
12	H2O–acetone (1 : 4)	Reflux	NaOAc	68	12
13	H2O–DMSO (1 : 4)	80	NaOAc	85	12
14	H2O–DMSO (1 : 4)	60	NaOAc	61	24

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With the optimized reaction conditions in hand, we then examined the scope of this cascade reaction and the results are summarized in Table 2. Generally speaking, a variety of electron-donating and electron-withdrawing groups on chromone rings are well tolerated leading to formation of the 3,4-pyridyl-fused coumarins 3. Alkyl groups on the chromone rings all gave the corresponding coumarins in good yields (3b–3d). Additionally, stronger electron-donating substituents such as methoxyl and hydroxyl group on the chromone rings of compounds 3 also furnished moderate to good yields of the desired compounds (3e–3j). It was found that the position of the substituents on compounds 1 had some effects on the yield of the products. Compared with the MeO- or OH-groups substituted at 6-position of chromones 1, the 7-position substituted chromone gave a higher yields (3e vs. 3f, 3i vs. 3j). Gratifyingly, electron-withdrawing groups such as bromo, chloro and fluoro groups on the aromatic rings of compounds 1 all provided the corresponding products in good yields (3k–3o). Moreover, the desired Cl or Br (3m–3o) substituted products could be further expanded to a wider variety of functionalized coumarins by undergoing subsequent cross-coupling reactions. In contrast with electron-donating groups, fluoro-substituent at 7-position of chromone gave a lower yield than at 6-position (3k vs. 3l). Finally, replacing benzene moieties by naphthalene moieties of chromones 1 also afforded tetracyclic compounds in moderate yields (3p–3q).

Table 2 The synthesis of various fused coumarins 3^a

a General reaction conditions: 1 (X = CN) (0.5 mmol), 2a (0.5 mmol), NaOAc (2.0 mmol), DMSO–H₂O: 4/1 (5 mL), 80 °C.b Using cyclopropane-1-carboximidamide hydrochloride instead of 2a under standard reaction conditions.c Using DMSO as reaction solvent, 1 hour.

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It may be noted that when we changed the cyano group to ester group at 3-position on compound 1a, the reaction performed smoothly as well leading to desired product in a lower yield (78% vs. 85%), but in a shorter reaction time. Furthermore, another amidine cyclopropane-1-carboximidamide hydrochloride was used to expand the reaction scope in order to obtain 3,4-pyrimidinyl-fused coumarins. Surprisingly, no desired product was detected under standard conditions. However, cyclopropane-1-carboximidamide hydrochloride could react with methyl 4-oxo-4H-chromene-3-carboxylate to give 3,4-pyrimidinyl-fused coumarins 3r, but in a low yield due to partial hydrolysis of ethyl 4-oxo-4H-chromene-3-carboxylate in aqueous medium. Thus, only DMSO was used as the reaction solvent, and the target product 3r was isolated is an excellent yield after reacting in 1 hour.

In summary, we have developed a facile, catalyst-free and green method for synthesis of 3,4-pyridyl-fused coumarins that are ubiquitous structural units in a number of biologically active compounds from commercial available starting materials. Moreover, using aqueous medium as green solvent without any hazardous catalysts, operationally simple, broad substrate scope and a good functional group tolerance are the notable features of the present reaction. What's more, ortho-amino carboxylate group and halo groups could be introduced in the target products, which is very useful for constructing more structurally complicated molecules for drug discovery and material science by undergoing subsequent reactions. In addition, further study showed that both 3,4-pyridyl-fused coumarin and 3,4-pyrimidinyl-fused coumarins could be formed using 3-carboxylate chromone as starting material.

Acknowledgements

This work was financially supported by the Ministry of Science and Technology of China (“Key New Drug Creation and Manufacturing Program” 2012ZX09301001-001), the Chinese Academy of Sciences (“Interdisciplinary Cooperation Team” Program for Science and Technology Innovation), and SKLDR/SIMM(SIMM1105KF-02).

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra01848f

‡ These authors contributed equally to this work.

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