Au-catalyzed cascade addition/cyclization/H-transfer reactions of 3-(1-alkynyl)chromones to construct 4H-Furo[3,2-c]pyrans scaffold

Abstract

Using Au catalyst and ethyl Hantzsch ester as a hydrogen source, 3-(1-alkynyl)chromones were directly transformed to 4H-benzofuro[3,2-c]pyrans in good to excellent yields through a cascade process by addition, cyclization and hydrogen transfer under mild conditions.

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Introduction

Nicotinamide adenine dinucleotide (NADH) is an important hydride source with the catalysis of glutamate dehydrogenase in nature. Hantzsch ester (HEH) as a synthetic analog of NADH in combination with the different Lewis acids and Brønsted acids have been broadly reported to play as an efficient reagent for hydrogen transfer.¹ Au catalysis is a powerful tool in the synthesis of natural products.² The character of Au complexes as a strong Lewis acid has been utilized in the direct reductive amination of aromatic aldehydes.³ On the other hand, π-acidity is another unique character of Au complex and used to activate the multiple bonds. Continuing our interests to develop various cascade processes to construct diversified natural product-like scaffolds from 3-(1-alkynyl)chromones,⁴ we envisioned that 1a could be transformed to intermediate M, which was hydrogenated to form 4H-furo[3,2-c]chromene 2a by the Hantzsch ester 3 (Scheme 1).

Scheme 1 The envisioned cascade reaction.

The 4H-Furo[3,2-c]chromene skeleton can be found in many natural products and exhibits potent biological activity (Scheme 2).⁵ Most synthetic methods have focused on the construction of pterocarpan system which is the combination of benzofuran and chromene scaffold.⁶ Currently, the synthesis of substituted 4H-furo[3,2-c]chromene has been rarely investigated.⁷ As an important bioactive natural product-like template, developing an efficient synthetic method for the library construction to this scaffold could be beneficial for the discovery of lead compounds.

Scheme 2 Erypoegin H (1), Lespedezol A₁ (2) and their congeners (3 and 4).

Results and discussion

In the initial phase of an effort to explore this proposal, we started our examination of the H-transfer reaction by the following conditions (Table 1). The substrate 1a (0.3 mmol) was reacted with hydrogen source 3 (1.2 equiv.) and (PPh₃)AuOTf (0.01 equiv.) in DCM (3 mL) at room temperature under a N₂ atmosphere to give the expected product 2a in 90% yield (Table 1, entry 1). When the catalyst was changed from (Ph₃P)AuOTf to (PPh₃)AuCl (Table 1, entry 2), the yield of the reaction was decreased after completing the reaction in 12 h by checking TLC. Also, AuCl₃ could promote the reaction efficiently to afford 2a in 61% yield (Table 1, entry 3). Among other transition metal catalysts, AgOTf (0.015 equiv.) could cause the transformation to generate 3a in 56% yield (Table 1, entry 4). However, Cu(OTf)₂ could not proceed the reaction (Table 1, entry 5). After screening commonly used solvents, DCM was superior to MeCN, THF, MeOH and DMF (Table 1, entries 6–9). The reaction was performed in the presence of MeSO₃H, a Brønsted acid, the product 2a can not be obtained (Table 1, entry 10).

Table 1 Catalyst-dependent reactions of 1^a

Entry	Catalyst	Solvent	Time (h)	Yield of 2a (%)^b
a Reaction conditions: 1a (0.3 mmol), (PPh3)AuCl (0.003 mmol), AgOTf (0.003 mmol) and hydrogen source 3 (0.36 mmol, 1.2 equiv.) in the solvent (3 mL) under a N2 atmosphere at room temperature. b Isolated yield. c AgOTf (0.05 equiv.) was used.
1	(PPh3)AuOTf	DCM	3	90
2	(PPh3)AuCl	DCM	12	40
3	AuCl3	DCM	3	61
4^c	AgOTf	DCM	24	56
5	Cu(OTf)2	DCM	12	0
6	(PPh3)AuOTf	MeCN	3	34
7	(PPh3)AuOTf	THF	3	52
8	(PPh3)AuOTf	MeOH	12	<10
9	(PPh3)AuOTf	DMF	3	trace
10	MeSO3H	DCM	12	0

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Using the optimal reaction conditions (Table 1, entry 1), we examined the scope of this cascade reaction (Table 2). Obviously, R¹ with electronic and steric variation on acetylene moiety afforded the corresponding products in good to moderate yields. Comparing with electronic effects on aromatic substitution of chromone, R² with electron-donating group (such as OMe) at 6-position of chromone gave the desired product 2g in high yield, which may be stabilized the carbocation of the intermediate. Also, the effect of R³ group was investigated. The results showed the steric effect on the reaction obviously. When R³ was methyl or ethyl group, the reaction was given as reasonable yield (such as 2h, 2i and etc.). The sterically hindered group decreased the yield and prolonged the reaction time (completed after 12 h) without the significant electronic effect (2j and 2k). Due to the slight steric effects of R¹ and R³, 2o was obtained in 68% yield. Significantly, the cascade reaction is compatible with various functional groups (such as hydroxy, ester, heteroaryl and halogen) to give good yields.

Table 2 Scope of substrates 1^ab

a Reaction conditions: 1 (0.3 mmol), (PPh3)AuCl (0.003 mmol), AgOTf (0.003 mmol) and hydrogen source 3 (0.36 mmol, 1.2 equiv.) in DCM (3 mL) under a N2 atmosphere for 3 h. b The reaction was carried out for 12 h.

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When compound 1u was used as a expanded substrate in this reaction with 5% of catalyst, the corresponding product 2s was afforded in 61% yield after 24 h (eqn 1). It was interesting that the dehydroxylated product 2v was obtained in 82% yield when 1v was employed (eqn 2, Scheme 3). We speculated that the 1v was easily changed to the allene cation under the conditions of Au catalysis,⁸ and then followed the H-transfer cyclization to give 2v (Scheme 3).

Scheme 3 Proposed generation of allene.

In addition, pyridine 1-oxide could be employed as an oxygen source for oxygen transfer with substrate 1a to generate the product 2w in 72% yield after 6 h (Scheme 4).

Scheme 4 Oxygen-transfer reaction.

Conclusion

In summary, HEH as an analog of biological hydride source, in combination with Au catalysis, exhibits an efficient cyclization/hydrogen transfer access to directly assemble a natural product-like 4H-furo[3,2-c]pyrans scaffold from readily accessible starting material 3-(1-alkynyl)chromones. It is noteworthy that this reaction can be extended with broad substrates tolerating the various substitution under the mild conditions to give excellent yields.

Acknowledgements

We gratefully acknowledge the National Natural Science Foundation of China (21172232) and Ministry of Science and Technology of China (2009CB940903).

References

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data for new compounds. See DOI: 10.1039/c2ra22268j

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