A new [4 + 1]/[4 + 2]bicycliaztion strategy for accessing functionalized indeno[1,2-b]pyran-2-ones

Abstract

A new base-promoted bicyclization strategy for the synthesis of functionalized indeno[1,2-b]pyran-2-ones has been established from readily accessible o-phthalaldehydes (OPA) and the preformed 1-arylethylidenemalononitriles. The reaction pathway involves an aldol addition, 5-exo-trig carbocyclization and 6-exo-dig oxo-cyclization sequence, resulting in continuous multiple C–C and C–O bond formation.

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Indeno-fused heterocycles are important motifs, found in many natural and pharmaceutically interesting compounds.¹ The pyran-2-ones are widely present in many pharmacological substances, and have been found to display a broad range of biological activities, such as anticancer,² antiviral,³ cytotoxicity,⁴ and neurotoxicity.⁵ Merging the aforementioned two rings into a single framework, indeno[1,2-b]pyran-2-one (Fig. 1, type I) possesses potent cytotoxicity^1a and has also acted as a topoisomerase I inhibitor,⁶ while indeno[1,2-b]pyran-2-ones (Fig. 1, type II) have been reported to be one of the metabolites of β-lapachone, a new anti-cancer drug.⁷ Therefore, the design and synthesis of new compounds incorporating both indene and pyran-2-one units would be an interesting target for chemists.

Fig. 1 Bioactive indeno[1,2-b]pyran-2(3H)-ones.

Owing to their biological significance, these derivatives attract the attention of synthetic chemists. Over the years, several synthetic methods are dedicated to construct these frameworks. Cushman and co-workers reported the synthesis of indeno[1,2-b]pyrans from the preformed 3-hydroxyisobenzofuran-1(3H)-one and isobenzofuran-1(3H)-one through two-step strategy (Scheme 1a).⁸ Takahashi et al. presented rhodium-catalyzed bicyclization of ethyl 2-phenylethynylbenzoate under water-gas shift reaction conditions, resulting in the formation of fused indeno[1,2-b]pyrans (Scheme 1b).⁹ However, the above methods suffer from multiple steps, metal catalysts, or narrow substrate scope. Therefore, the development of a new and general protocol toward indeno[1,2-b]pyrans is still highly desired.

Scheme 1 Synthesis of indeno[1,2-b]pyran-2-one derivatives.

Bicyclization reactions enable rapid access to structural variation and complexity within single-step conversions for the collection of functional polycyclic structures of chemical and pharmaceutical interest.¹⁰ Specifically, o-phthalaldehydes behaved the exceptional reactivity, allowing their direct transformations toward complex and diverse drug-like small molecules.¹¹ Recently, we have achieved bicyclization reactions of o-phthalaldehyde with 3-amino-5H-furan-2-ones, leading to the construction of ([3,4]furanoimino)benzo[e]pyrano[4,3-b]oxepine framework.¹² To continue this project, herein, we would like to report a novel and challenging base-promoted bicyclization between o-phthalaldehydes and 1-arylethylidenemalononitriles under mild conditions, providing a straightforward domino access to indeno[1,2-b]pyran-2-ones (Scheme 1c). The reaction enabled continuous multiple bond-forming events including C–C and C–O bonds, resulting in the simultaneous formation of two new rings including cyclopentadiene and pyran-2-one rings. Note that the utilization of bicyclization reaction of o-phthalaldehydes provides a special protocol toward indeno[1,2-b]pyran-2-ones.

Our initial efforts focused on this bicyclization using phthalaldehyde (1a, 1.0 equiv.) with 2-(1-phenylethylidene) malononitrile (2a, 1.0 equiv.) as model substrates to search the optimal conditions. The reaction was first carried out by using K₂CO₃ as a base promoter in DMF at room temperature, but without observation of desired product 3a (Table 1, entry1). The similar outcomes were observed using either piperidine or 4-dimethylaminopyridine (DMAP) as a base promoter (entries 2–3). To our delight, the use of Et₃N facilitated this transformation and confirmed the reaction efficiency, giving access to an 84% yield of product 3a (entry 4), while other bases such as NaOEt and NaOH completely suppressed the reaction process (entries 5–6). Next, different solvents, such as tetrahydrofuran (THF), dichloromethane (DCM) and toluene, were examined under these identical reactions. Experimental results showed that all these attempted solvents were inferior to DMF in view of the reaction yields (entries 7–9 vs. 4). Increasing the reaction temperatures is harmful to this transformation. When the temperature was elevated to 50 °C, no desired product was obtained in the reaction system (entry 11).

Table 1 Optimization of reaction conditions^a

Entry	Base (eq.)	Solvent	T/°C	Yield^b/%
a Reaction conditions: OPA (1a, 1.0 mmol), 2-(1-phenylethylidene) malononitrile (2a, 1.0 mmol), solvent (8.0 mL) for 12 hours.b Isolated yield based on substrate 2a.
1	K2CO3 (1.0)	DMF	rt	None
2	Piperidine (1.0)	DMF	rt	Trace
3	DMAP (1.0)	DMF	rt	Trace
4	Et3N (1.0)	DMF	rt	84
5	NaOEt (1.0)	DMF	rt	None
6	NaOH (1.0)	DMF	rt	None
7	Et3N (1.0)	THF	rt	52
8	Et3N (1.0)	DCM	rt	40
9	Et3N (1.0)	Toluene	rt	25
10	Et3N (1.0)	DMF	35	64
11	Et3N (1.0)	DMF	50	Trace

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With the optimized reaction conditions in hand, the substrate scope of the transformation was then explored. Results in Scheme 2 clearly revealed that all reactions proceeded smoothly to offer the expected products 3 with good yields. At first, the use of various 1-arylethylidenemalononitriles was investigated in the reaction with 1a. The 1-arylethylidenemalononitriles 2 bearing both electron-withdrawing and electron-donating groups at the different positions of the arene ring (Ar) all participated in this bicyclization reaction, delivering the corresponding indeno[1,2-b]pyran-2-one products 3b–j with yields ranging from 65% to 84%. A variety of functional groups, like fluoro (2a), chloro (2c and 2d), bromo (2e), cyano (2f), methyl (2g), methoxy (2h), t-butyl (2i), and hydroxyl (2j), were well tolerated under this system. Among them, a sterically demanding 2,4-dichlorophenyl analogue (2d) showed a relatively weak reactivity and seemed slightly reluctant to undergo the reaction process, in which 3d was obtained in 65% yield, whereas 2-thienyl-substituted counterpart (2k) would be accommodated, confirming the reaction efficiency, as 3k was furnished in 78% yield. Alternatively, naphthalene-2,3-dicarbaldehyde 1b was proven to be a suitable substrate, which underwent a similar bicyclization process toward tetracyclic indeno[1,2-b]pyran-2-ones 3l–s with 72–84% yields by lowering reaction temperatures (0 °C) and prolonging reaction times (24 h). The presence of substituents with different electronic nature such as electronically neutral, poor and rich residing in the different positions of phenyl ring was compatible in this bicyclization system. Obviously, the present bicyclizations can tolerate structurally diverse substrates with steric bulk and a different electronic nature, which renders a direct and practical entry toward richly decorated indeno[1,2-b]pyran-2-ones. Note that this is the first reported procedure for the domino synthesis of these new indeno[1,2-b]pyrans through a base-promoted metal-free bicyclization cascade.

Scheme 2 Scope of the bicyclization reaction. Yields of isolated products based on substrates 2 after column chromatography on silica gel are given. 1 (1.0 mmol), 2 (1.0 mmol), and Et₃N (1.0 mmol), DMF (8.0 mL), at 0–25 °C.

The structures of the resulting indeno[1,2-b]pyran-2-ones 3 were characterized using NMR spectroscopy and HRMS. Furthermore, in the case of compound 3g, its structure was unambiguously determined by X-ray diffraction (Fig. 2).

Fig. 2 X-Ray structure of 3g.

Based on the above experiments and literature reports,¹¹ a plausible mechanism is proposed in Scheme 3. Firstly, in the presence of bases, 2-arylethylidenemalononitriles 2 are converted into intermediates A via deprotonation, followed by an aldol addition with OPA and proton transfer to yield intermediates C. Next, an intramolecular aldol addition (5-exo-trig carbocyclization) of C occurs to furnish intermediates D, which undergo 6-exo-dig oxo-cyclization, dehydration and 1,3-H transfer to provide G. Finally, intermediates G are transformed into indeno[1,2-b]pyrans 3 through nucleophilic substitution (G to H) and deamination (H to 3) with presence of bases.

Scheme 3 Plausible mechanism.

In conclusion, a reliable and mild base-promoted bicyclization reaction has been established using readily available o-phthalaldehydes and the preformed 1-arylethylidenemalononitriles, by which indeno[1,2-b]pyran-2-ones with a wide diversity in substituents are synthesized in a convergent fashion. This straightforward and operationally simple method allows to install two new rings and four σ-bonds in one pot, providing a new protocol to the collection of significant indenopyranone skeleton with potential applications in organic and medicinal chemistry.

Acknowledgements

We are grateful for financial support from the NSFC (No. 21232004, 21272095, and 21472071), PAPD of Jiangsu Higher Education Institutions, the Outstanding Youth Fund of JSNU (YQ2015003), NSF of Jiangsu Province (BK20151163), and the Qing Lan Project of Jiangsu Education Committee.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1487667. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra16462e

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