One-pot transition-metal-free cascade synthesis of thieno[2,3-c]coumarins from chromones

Abstract

A one-pot transition-metal-free, base-mediated synthesis of a novel series of functionalized thieno[2,3-c]coumarins via a cascade reaction from chromones has been developed. This cascade reaction involves a Michael addition–Knoevenagel condensation–intramolecular cyclization. This transformation proceeds under mild conditions and gives various thieno[2,3-c]coumarins in good-to-excellent yields. The methodology is tolerant of a wide range of functional groups and applicable to library synthesis.

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Introduction

Coumarin derivatives containing fused benzene and α-pyrone rings originate from natural plants. A number of coumarins have been identified as secondary metabolites from plants, bacteria and fungi.¹ There are many bioactive products bearing coumarin moiety, such as 7-diethylamino-3-(2′-benzoxazolyl)-coumarin (DBC),² warfarin,³ coumestrol,⁴ lamellarins⁵ (Fig. 1). These compounds are used for preliminary studies including anti-virus,⁶ anticancer,⁷ anti-inflammatory,⁸ anticoagulant,⁹ etc. They also have been discovered to possess remarkable fluorescence due to their high fluorescence quantum yield.¹⁰ Furthermore, the thiophene moiety is also widely used as an essential motif in pharmaceutical chemistry owing to its promising biological activity.¹¹ Therefore, molecular scaffolds including both coumarins and thiophene moieties are of great interest from biological and molecular diversity viewpoint.

Fig. 1 Some bioactive coumarin-based derivatives.

Usually coumarins can be synthesised by classical methods such as Claisen rearrangement, Perkin reaction and Pechmann reaction as well as Knoevenagel condensation, but these traditional methods were hampered by the scope of substrates¹² or conducted under harsh reaction conditions.¹³ Over the last few decades, many alternative elegant modern syntheses of coumarins were developed under mild conditions, while transition metals were usually employed.¹⁴ Thieno-coumarins, a class of thieno-fused coumarin derivatives, have attracted great interest from researchers due to their bioactivities.¹⁵ Thus, more efforts have been made to establish new synthetic methods toward thieno[3,2-c]coumarins.¹⁶ However, works for systematic synthesis of thieno[2,3-c]coumarins are quite rare, and these methods were hampered by limited availability of starting materials and/or multisteps.¹⁷ Therefore, development of a convenient, metal-free catalyzed and one-pot approach to synthesize thieno[2,3-c]coumarins from simple and readily available starting materials is still in high demand.

Chromones are greatly useful starting materials for constructing various bioactive heterocycles. In our previous work, we have developed novel approaches for the preparation of bioactive heterocycles for drug discovery.¹⁸ In the light of preceding works,^18c,d we predicted that the chromone could react with ethyl mercaptoacetate to form ethyl-3-(2-hydroxyphen-yl)thiophene-2-carboxylate M in the presence of base, which was proceeding intramolecular cyclization to prepare structurally diverse thieno[2,3-c]coumarin 3a (Scheme 1). This could be a useful pot, atom and step economic reaction to synthesize drug-like compounds.¹⁹

Scheme 1 Outline of the synthesis of thieno[2,3-c]coumarins.

In our initial studies, we screened parameters to find optimal conditions (Table 1). We started our studies by treating chromone 1a with ethyl mercaptoacetate 2a in the presence of DBU (2 equiv.) in DMF at 60 °C for 12 h. Gratifyingly, the reaction occurred smoothly leading to 3a in a good yield (Table 1, entry 1). Afterwards, we investigated the solvent, including NMP, DMSO, 1,4-dioxane, and THF. The results revealed that 1,4-dioxane was the best solvent and the yield of 3a was further improved to 95% (Table 1, entries 1–5). Moreover, the effect of bases was also investigated. The screened results led to the identification of DBU as the optimal base (Table 1, entry 4, entries 6–10). However, further changes of the amount of DBU or reaction temperature did not provide better results (Table 1, entries 11–14, entries 15–18). In summary, the optimal reaction conditions were determined, including DBU (2.0 equiv.) in 1,4-dioxane (3.0 mL) at 60 °C for 12 h under nitrogen atmosphere. Additionally, the structure of 3a was unambiguously established by X-ray crystal structure analysis (Fig. 2).

Table 1 Optimization of the reaction conditions^a

Entry	Base	Base equiv.	Solvent	Temp (°C)	Yield (%)
a Reaction conditions: 1a (0.5 mmol), 2a (0.55 mmol) and solvent (3.0 mL), all reagents were mixed and stirred under nitrogen atmosphere at room temperature for 5 minutes, then were heated at 60 °C for 12 h.b NR = no reaction.c The reaction was carried out without base.
1	DBU	2	DMF	60	80
2	DBU	2	NMP	60	67
3	DBU	2	THF	60	70
4	DBU	2	1,4-Dioxane	60	95
5	DBU	2	DMSO	60	67
6	K2CO3	2	1,4-Dioxane	60	61
7	KOAc	2	1,4-Dioxane	60	5
8	Cs2CO3	2	1,4-Dioxane	60	36
9	DIPEA	2	1,4-Dioxane	60	NR^b
10	Et3N	2	1,4-Dioxane	60	NR^b
11	DBU	2	1,4-Dioxane	RT	10
12	DBU	2	1,4-Dioxane	40	88
13	DBU	2	1,4-Dioxane	80	92
14	DBU	2	1,4-Dioxane	100	70
15	DBU	1.5	1,4-Dioxane	60	88
16	DBU	1	1,4-Dioxane	60	80
17	DBU	0.5	1,4-Dioxane	60	60
18^c	—	—	1,4-Dioxane	60	NR^b

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Fig. 2 X-ray crystal structure of 3a.

Under optimized reaction conditions, we then examined the scope of the method with various chromones (Table 2). Generally, both electron-donating and -withdrawing substitutents chromones are well tolerated in the formation of the thieno[2,3-c]coumarins (Table 2, 3a–3w). Electronic effects had no significant influence on the sequential reactions with ethyl mercaptoacetate. Electron-donating substituents including alkyl, methoxy (Table 2, 3b–i, 3n–o, 3q) or electron-withdrawing groups (Table 2, 3u, 3v, 3w) on the chromone rings all gave the corresponding coumarins in good to excellent yields. The position of substituent groups on compounds 1a did not influence the synthesis of thienocoumarins (Table 2, 3b, 3f, 3g).

Table 2 The synthesis of various thieno[2,3-c]coumarins^a,b

a Reagents and reaction conditions: chromone derivatives 1 (0.5 mmol), ethyl mercaptoacetate 2a (0.55 mmol), and DBU (1.0 mmol) in 1,4-dioxane (3.0 mL), heated at 60 °C for 12 h under N₂ atmosphere.b Isolated yields.c The procedure was scaled up to 6.25 mmol.d R = F, 2a is 2.2 equiv.

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Sensitive halogens such as bromo- and chloro-substitutions on the chromone rings were tolerated and afforded lower yields owing to the side reactions (Table 2, 3j–3m). Surprisingly, when ethyl mercaptoacetate was 1.1 equiv. and substrate was 6-fluoro- or 7-fluoro-chromones, reactions lead to generate corresponding ethyl-2-((4-oxo-4H-chromen-6-yl)thio)acetate or ethyl-2-((4-oxo-4H-chromen-7-yl)thio)acetate respectively. However, when ethyl mercaptoacetate was raised to 2.2 equiv., reactions lead to produce corresponding ethyl-2-((4-oxo-4H-thieno[2,3-c]chromen-8-yl)thio)acetate or ethyl-2-((4-oxo-4H-thieno[2,3-c]chromen-7-yl)thio)acetate (Table 2, 3s–3t). Furthermore, chromones with two electron-donating substituents were also compatible with the reaction processes and produced substituted-thieno[2,3-c]coumarins with excellent yields (Table 2, 3n–3p). However the substrate with methyl and chloro-substitution delivered the corresponding product in diminished yield (Table 2, 3q vs. 3n). The benzo[h]chromen-4-one 1r also afforded tetracyclic compound with an excellent yield (Table 2, 3r). Moreover, aryl-substituted compounds were proved to be suitable substrates (Table 2, 3u–3w). To demonstrate the synthetic utility of the reaction, we successfully scaled up the procedure to 6.25 mmol and obtained 1.19 g of 3b after 12 h in 88% isolated yield (Table 2, 3b).

Conclusions

In summary, we have developed an efficient and useful synthetic method via a three-step one-pot transition-metal-free reaction to construct various thieno[2,3-c]coumarins that drastically enrich molecular diversity. The substrate scope was wide and good-to-excellent yields were obtained even on gram scale. Due to the efficiency to form the thienocoumarin skeleton and the potential utilization of thieno[2,3-c]coumarins, this methodology may be of great interest to organic and medicinal chemists.

Acknowledgements

This study was supported by the National Natural Science Foundation of China (Grant Number 81321092) and SKLDR/SIMM (SIMM1601ZZ-03).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1498043. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra21776a

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