A practical green chemistry approach to synthesize fused bicyclic 4H-pyranes via an amine catalysed 1,4-addition and cyclization cascade

Abstract

A newly developed synthetic approach to densely functionalized 4H-pyrane derivatives via an amine catalysed cascade reaction is presented. This protocol is relatively environmentally benign because it proceeds smoothly in water or ethanol at ambient temperature with low catalyst loading; more importantly, the products are easily purified, and some show promising antibacterial activity.

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Synthetic chemistry has made incredible advances in the past decades, yet achieving “ideal syntheses” still remains a challenging and urgent task.¹ Of particular interest is the development of useful synthetic procedures in an economical, energy-saving, easy to handle and environmentally sound way. An attractive new transformation is expected to show not only high efficiency and good selectivity but also a reasonable E factor.² By far, the reaction component most responsible for the elevated E factor is organic solvents,^3a many of which are considered to have negative impact on ecological systems. One elegant solution is to develop reactions under solvent-free conditions⁴ or to use “greener” solvents³ such as water, supercritical CO₂, ionic liquid or ethanol. While the introduction of green reaction media has reduced the overall consumption of toxic solvents, most such syntheses still require substantial amounts of environmentally harmful solvents for subsequent workup and product purification. Thus, the development of practical synthetic methodologies involving exclusively green solvents is undoubtedly in high demand.

Functionalized 4H-pyranes, especially novel bicyclic molecules incorporating a 4H-pyrane moiety, have received much attention from both synthetic and medicinal chemists because of their huge potential in drug discovery.⁵ Such compounds have already been demonstrated to have antiviral, antifungal, antibacterial, and anticonvulsant activity, as well as activity against the excitatory amino acid transporter 1 (EAAT1), linked to episodic ataxia (Fig. 1). The diverse bioactivity of these molecules appears to depend mainly on the fused ring system, since bioactive 4H-pyranes have quite similar substituents at the 2-, 3- and 4-positions. This suggests that assembling new polycyclic framework based on this core structure, especially involving pharmacologically relevant heterocycles,⁶ may provide additional leads for drug discovery.

Fig. 1 Selected bioactive molecules incorporating a 4H-pyrane core structure.⁵

A typical strategy for constructing such hetero bi- and tri-cycles is via an elegant formal [3 + 3] cyclization reaction of benzylidenemalononitriles and carbonyl nucleophiles (Scheme 1). This strategy has led to remarkable advances in medicinal chemistry,⁵ but the resulting 4H-pyrane fused ring systems have still been limited to ketone and (hetero-)aromatics. Herein, we report an amine catalysed formal [4 + 2] reaction via a 1,4-conjugate addition and cyclization cascade⁷ that generates novel fused bicyclic 4H-pyranes with a γ-lactam functionality.⁸ Notably, this transformation is characterized by its high efficiency, exclusive 1,4-regioselectivity, environmental friendliness and operational simplicity.

Scheme 1 Assembly of fused bicyclic 4H-pyranes with a γ-lactam moiety via formal [4 + 2] cyclization.

Initially, we chose readily available 1-benzyl-4-benzylidene-pyrrolidine-2,3-dione⁹ 1a and malononitrile 2 as model substrates to test the feasibility of this approach. To our satisfaction, the reaction proceeded smoothly in water at ambient temperature in the presence of piperidine 3a (10 mol% catalyst loading). Simple filtration and washing with warm water gave the desired racemic product 4a in good yield (Table 1, entry 1). Other amine catalysts such as pyrrolidine 3b, benzyl amine 3c and n,n-diethylamine 3d led to inferior results (Table 1, entries 2–4). Organic solvents were also screened in an attempt to increase yield, but pure products could not be directly obtained without using flash chromatography, and yields were much lower (Table 1, entries 5–10). The exception was ethanol, which gave the product in nearly quantitative yield (Table 1, entry 11).

Table 1 Screening studies of the formal [4 + 2] cyclization^a

Entry	3	Solvent	Purification^b	Yield^c (%)
a Unless otherwise noted, reactions were performed with 0.1 mmol of 1a, 0.11 mmol of 2a, and 10 mol% of 3 in 1 mL solvent at rt for 5–30 min.b F&W: filtration and washing; FC: flash chromatography; for details, see ESI.c Isolated yield.d In the presence of 1 mol% 3a at rt for 15 min.
1	3a	H2O	F&W	84
2	3b	H2O	F&W	75
3	3c	H2O	F&W	78
4	3d	H2O	F&W	55
5	3a	Toluene	FC	76
6	3a	THF	FC	62
7	3a	DCM	FC	66
8	3a	MeOH	FC	78
9	3a	MeCN	FC	74
10	3a	EtOAc	FC	80
11	3a	EtOH	F&W	98
12^d	3a^d	EtOH	F&W	96
13^d	3a^d	H2O	F&W	82

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Furthermore, based on the promising results (Table 1, entries 1 and 11), we tried to reduce the catalyst loading to 1 mol%, and the yield was only slightly affected (Table 1, entries 12 and 13). These results identify water and ethanol, both practical and environmentally benign, as effective media for this reaction at ambient temperature in the presence of 1 mol% of piperidine as catalyst.

With the optimal reaction conditions in hand, we investigated the generality of the formal [4 + 2] reactions, starting with ethanol as a higher-yield solvent. To our gratification, a broad range of cyclic α,β-enones with diverse steric and electronic properties could readily participate in this reaction. As summarized in Table 2, the N-protecting groups on the amide in the enone substrate negligibly influenced the results (Table 2, 4a, 4b). Various α,β-enones with electron-donating or – withdrawing substituents at para-, meta-, or ortho-positions of the aromatic rings were well tolerated, affording the expected hetero bicycles 4c–4m in good to excellent yield.

Table 2 Substrate scope of the formal [4 + 2] cyclization in ethanol^a

a Unless otherwise noted, reactions were performed with 0.2 mmol of 1, 0.22 mmol of 2, and 1 mol% of 3a in 2 mL solvent at rt for about 15 min; chromatography-free work up; data for isolated yield; for details, see ESI.b The correct structure of product 4l was further confirmed by X-ray diffraction analysis.

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Substrates with strong electron-donating groups or sensitive functionalities such as free hydroxyls also reacted smoothly under standard reaction conditions, albeit with slightly lower yield (Table 2, 4n, 4o). An enone bearing ortho- and para-dichlorobenzene group could also be efficiently cyclized (Table 2, 4p). Furthermore, polycyclic- and heterocyclic-aromatic moieties were investigated because of their biological importance, which led to the corresponding 4q and 4r in satisfactory yield.

The development of catalytic reactions in water,¹⁰ as the ultimate environmentally neutral solvent, is arguably one of the most interesting topics in current organic chemistry. Therefore, we reinvestigated the generality of the above reactions using water as the medium. Some representative substrates were examined, which included substituents with different electronic properties as well as hetero-aromatics. The results compared favorably to those obtained with ethanol (Table 3). In fact, using water in some cases led to even higher yield (e.g. Table 3, entry 2 vs. Table 2, 4c).

Table 3 Study of the formal [4 + 2] cyclization in water^a

Entry	1	4	Yield^b (%)
a Unless otherwise noted, reactions were performed with 0.2 mmol of 1a, 0.22 mmol of 2a, and 1 mol% of 3a in 2 mL water at rt for 30 min.b Isolated yield for dry product.
1	1a	4a	82
2	1c	4c	92
3	1d	4d	88
4	1f	4f	77
5	1g	4g	82
6	1i	4i	78
7	1j	4j	83
8	1k	4k	90
9	1q	4q	75
10	1r	4r	84

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To further illustrate the practicality of this methodology, the reaction with 1a was scaled up to 10 mmol under optimal conditions in ethanol. The desired product 4a was obtained in excellent yield (Scheme 2). The correct structures of this new collection of compounds were further confirmed by X-ray diffraction analysis of the representative product 4l (Fig. 2).¹¹

Scheme 2 Gram-scale synthesis of fused bicyclic 4H-pyrane 4a via formal [4 + 2] cyclization under optimal reaction conditions.

Fig. 2 Single crystal X-ray diffraction analysis of product 4l.¹¹

The new compound library of 4a–4r was screened for preliminary in vitro antibacterial activity against three ATCC-bacterial strains: Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853) and Enterococcus faecalis (ATCC 29212).¹² Antibacterial activity was assessed using the broth dilution method.¹³ The novel bicyclic 4H-pyranes exhibited promising antibacterial activity, with minimum inhibitory concentrations (MICs) ranging from 16 to 128 μg mL⁻¹ (Table 4). In the case of E. coli, most of the compounds did not show antibacterial activity except for 4k, 4m, 4q and 4r. On the other hand, the activity against P. aeruginosa and E. faecalis was generally quite good. In particular, compounds with meta-chlorobenzene, naphthalene or thiophene moieties showed promising antibacterial activity at relatively lower concentrations (Table 4, entries 11, 17 and 18).

Table 4 Preliminary study of antibacterial activity of the fused bicyclic 4H-pyranes^a

Entry	Compound	MIC^a (μg mL^−1)
		E. coli^b	P. aeruginosa^c	E. faecalis^d
a MIC: minimum inhibitory concentration (μg mL^−1).b E. coli: Gram-negative, MIC of cefotaxime: 1 μg mL^−1 (positive control).c P. aeruginosa: Gram-negative, MIC of cefotaxime: 16 μg mL^−1 (positive control).d E. faecalis: Gram-positive, MIC of benzylpenicillin: 4 μg mL^−1 (positive control).
1	4a	>128	64	64
2	4b	>128	128	64
3	4c	>128	64	128
4	4d	>128	128	>128
5	4e	>128	128	128
6	4f	>128	64	64
7	4g	>128	64	64
8	4h	>128	128	128
9	4i	>128	64	32
10	4j	>128	128	128
11	4k	64	16	32
12	4l	>128	64	64
13	4m	128	32	32
14	4n	>128	128	128
15	4o	>128	64	64
16	4p	>128	128	128
17	4q	128	32	16
18	4r	128	32	16

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Conclusions

In summary, we have developed an amine catalysed formal [4 + 2] cycloaddition in green solvent that generates novel bicyclic 4H-pyranes with γ-lactam functionalities. The advantages of this protocol include highly efficient bond formation, mild reaction conditions, simple work-up, environmentally benign solvents and reasonable isolated yield. Preliminary biological study of the synthesized compounds showed promising in vitro antibacterial activity against P. aeruginosa and E. faecalis. Investigation of medicinal applications of these fused bicyclic 4H-pyranes and of chiral amine catalysed asymmetric synthesis are currently underway in our laboratory.

Acknowledgements

Financial support from National Natural Science Foundation of China (no. 21502009, 81573588 and 81573589), Scientific Research Fund of Sichuan Provincial Education Department (no. 16ZB0430), the Open Research Fund of State Key Laboratory Breeding Base of Systematic research, development and Utilization of Chinese Medicine Resources, and the Start-up Fund of Chengdu University （no. 2081915026 and 2080515047）is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data for new compounds. CCDC 1439424. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra06441h

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