A facile access to cis-dihydrofurobenzofuran from 2-(2,5-dihydro-furan-2-yl)-phenol

Abstract

A facile access to cis-dihydrofurobenzofuran from a Pd-catalyzed intramolecular oxidative C–O bond formation of 2-(2,5-dihydro-furan-2-yl)-phenol is reported. The combined use of Pd(OAc)₂ as catalyst, acetonitrile as solvent and AgOAc or air as oxidant affords cis-dihydrofurobenzofurans in good (up to 83%) yields.

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cis-Fused dihydrofurobenzofurans with a main tricyclic core exist in many natural products and synthetic compounds with good biological activities (Fig. 1).¹ For example, panacene, isolated in 1977 from the marine plant Aplysia brasiliana, is a feeding deterrent to sharks and other predatory fishes. As a valuable natural bioactive molecule, the Feldman, Canesi and Boukouvalas groups have pioneered seminal pieces of work on total synthesis of panacene with different strategies.² Psorofebrin, another classical example with a cis-fused dihydrofurobenzofuran scaffold, was isolated from Psorospermum and reported to have anti-leukemic activity.³ Meanwhile, the alkaloid Rutagravine⁴ and a decomposition product of coumarin micromelin⁵ have also been found to contain this tricyclic skeleton.

Fig. 1 Naturally occurring cis-fused-dihydrofurobenzofurans or their derivatives.

Several synthetic methods of benzofuran have been reported in the literature.⁶ A pioneering and elegant work on the synthesis of dihydrofurobenzofuran derivatives via hypervalent iodine reagent promoted formal [3 + 2] cycloaddition of phenol with furan was developed by Canesi and coworkers.^7a,b In that report, 2-TMS-protected-phenol was utilized to achieve a multi-step conversion for controlling regioselectivity ((1) in Scheme 1).^7c Recently, we have developed a one-pot amine-promoted Petasis reaction for the synthesis of 2-(2,5-dihydro-furan-2-yl)-phenols,⁸ which has been highlighted as a short, simple and cheap strategy for the construction of bioactive natural compounds.^9,10 Thus, we were encouraged to broaden the application of this strategy¹¹ ((2) in Scheme 1). In our investigation towards the complexation of 3a with metal salt, serendipitously, tricyclic product 4a was produced in acetonitrile at room temperature in 78% yield in the presence of one equivalent of Pd(OAc)₂ ((3) in Scheme 1), therefore, we sought to explore this process to establish a convenient protocol for the synthesis of these compounds.

Scheme 1 Strategies for the construction of cis-fused-dihydrofurobenzofurans.

With 2-(4-phenyl-2,5-dihydrofuran-2-yl)-phenol 3a as the model substrate, we began with the optimization of reaction conditions. With 10 mol% Pd(OAc)₂ as catalyst, a number of solvents was screened with the reaction mixture exposed to air. The results indicated that the reaction was sensitive to solvents. In methanol, acetone, 1,2-dichloroethane, chloroform, dichloro-methane and ethyl acetate, 4a was produced in 20–41% yields (entries 2, 6, 7, 9, 10, 11 in Table 1), while in toluene, xylene, DMF, DMSO, 1,4-dioxane and hexane, no product was produced with a large amount of starting material 3a remaining (entries 3, 4, 5, 8, 12, 13 in Table 1). CH₃CN was found to be the best solvent giving a 53% yield (entry 1 in Table 1). When the temperature was elevated from room temperature to 80 °C, less reaction time was needed to complete the conversion of 3a, though the yield of 4a failed to be improved (entries 1 and 14 in Table 1). Subsequently, at 80 °C the reaction gave 4a in the presence of 5% and 20% Pd(OAc)₂ in 42% and 60% yield, respectively.

Table 1 Solvents screening

Entry^a	Solvent	Temp (°C)	Pd(OAc)2 (mol%)	Time (h)	Yield^b (%)
a The reaction was performed with 3a (0.1 mmol), Pd(OAc)2 (10 mol%) in solvents (2 mL).b Isolated yields.c Not detected.
1	CH3CN	rt	10	24	53
2	CH3OH	rt	10	24	41
3	Toluene	rt	10	24	n.d^c
4	DMF	rt	10	24	n.d
5	Xylene	rt	10	24	n.d
6	(CH3)2CO	rt	10	24	32
7	ClCH2CH2Cl	rt	10	24	20
8	DMSO	rt	10	24	n.d
9	CHCl3	rt	10	24	28
10	CH2Cl2	rt	10	24	34
11	EA	rt	10	24	30
12	1,4-Dioxane	rt	10	24	n.d
13	Hexane	rt	10	24	n.d
14	CH3CN	80	10	12	58
15	CH3CN	80	5	12	42
16	CH3CN	80	20	6	60

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Then, with 10 mol% Pd(OAc)₂ and CH₃CN as solvent at 80 °C, a variety of oxidants were surveyed to improve the reaction. Pure oxygen instead of air did not change the reactivity (entry 1 Table 2). In the presence of Cs₂CO₃ or KOtBu as base, no product was given as determined by TLC (entries 4 and 5 in Table 2). To our delight, with AgOAc (2 equiv.) and Cu(OAc)₂ (2 equiv.) as oxidant, the yield was increased to 72% and 68%, respectively (entries 6 and 7 in Table 2). Other oxidants such as DDQ, Selectfluor, PhI(OAc)₂ and chloranil failed to give the desired product (entries 8–11 in Table 2). Accordingly, Pd(OAc)₂ (10 mol%)/AgOAc (2 equiv.)/80 °C/CH₃CN was chosen as the optimal reaction condition for further study.

Table 2 Oxidants screening

Entry^a	Oxidant (2 equiv.)	Base (2 equiv.)	Time (h)	Yield of 4a^b (%)
a All the reactions were performed with 3a (0.1 mmol), Pd(OAc)2 (10 mol%) in MeCN (2 mL) with oxidants (2 equiv.), and if needed, base (2 equiv.) was added.b Isolated yields.c Not detected.
1	O2	—	12	56
2	Air	K2CO3	12	53
3	Air	Na2CO3	12	50
4	Air	Cs2CO3	12	n.d^c
5	Air	KO^tBu	12	n.d
6	Cu(OAc)2	—	12	68
7	AgOAc	—	6	72
8	DDQ	—	12	n.d
9	Selectfluor	—	12	n.d
10	PhI(OAc)2	—	12	n.d
11	Chloranil	—	12	n.d

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With the optimized reaction conditions in hand, a diverse range of substrates were examined to broaden the substrate scope (Scheme 2). Substrates with electron withdrawing groups (R²) on aryl afforded 4 in higher yields than those with electron donating groups, and a substitution of R² on aryls also had significantly impact on the reactivity. Higher yields (68–83%) were obtained for meta-R² substitution on aryls (Scheme 2, 4b, 4e, 4h and 4l), while para- and ortho-R² substitution gave 57–70% (Scheme 2, 4c, 4g, 4j and 4m) and 0–67% yields (Scheme 2, 4d, 4f and 4i), respectively. For the OMe-substituted substrates, no desired product was obtained for ortho OMe, while compound 4b with meta-OMe and compound 4c with para-OMe substitution were afforded in 81% and 57% yields, respectively. Similar results were obtained for fluoro-substituted substrates (R² = F) (meta-F (4e, 76%), ortho-F (4f, 67%) and para-F (4g, 68%)). For meta and para-substituted products, these results were in agreement with the electronic effect of substituents i.e. the electron withdrawing induced effect: meta-OMe > para-OMe; meta-F > para-F; the electron donating conjugated effect: para-OMe > meta-OMe; para-F > meta-F. However, ortho-substituted products were hardly produced possibly due to more complicated electronic and steric effects.

Scheme 2 Substrate scopes. ^aAll reactions were carried out with 3 (0.2 mmol), Pd(OAc)₂ (10 mol%), and AgOAc (2 equiv.) in CH₃CN (4 mL) at 80 °C, the reaction was stirred until 3 was disappeared by TLC. ^bIsolated yields for all the examples. ^cCu(OAc)₂ as an oxidizing agent. ^dNo reaction occurred with raw material retaining.

While 4c was afforded with Cu(OAc)₂ as an oxidant, no desired compound was detected when AgOAc was used as an oxidant. When R¹ was para-methyl phenyl instead of phenyl, no change in reactivity was observed (Scheme 2, 4k and 4l). However, when R¹ was 2-phenylethyl, no desired compound was obtained, which might be attributed to the structural instability of the corresponding tricycle compound 4 as a result of a loss of the conjugation between C=C double bond and phenylethyl group. The structure of products 4 were further confirmed by the X-ray single crystal diffraction of 4j (Fig. 2). In this intramolecular cyclization, a strong steric strain needs to be overcome, and Pd(II) acted as a template to connect between C=C and OH groups in the oxidative cyclization process. This could be demonstrated by its easy ring-opening isomerization under acid catalysis at room temperature (Scheme 3).

Fig. 2 X-ray crystal structure of 4j (CCDC 1447730†).

Scheme 3 The isomerization of 4 for the formation of 5.

A plausible mechanism for this reaction was proposed as shown in Scheme 4. Initial coordination and ligand exchange of Pd(OAc)₂ with substrate 3 give intermediate I and II. Then intramolecular oxo-palladation with C=C double bond gives intermediate III, followed by Pd(II) and β-hydrogen elimination to form the desired product 4 and Pd(0) species. Finally, Pd(II) was regenerated by the oxidation of Pd(0) with AgOAc, achieving the catalytic cycle.^12,13

Scheme 4 Proposed mechanism.

Conclusions

In conclusion, we have developed a novel approach for the construction of cis-dihydrofurobenzofuran from 2-dihydrofuranyl-phenol, a valuable class of bioactive compounds which are difficult to obtain by conventional methods. This reaction features a Pd(II)-catalyzed direct intramolecular C–O bond formation, which could be completed with inexpensive air as an oxidant. The optimal results were obtained with AgOAc as oxidant. The reaction conditions are mild, and the products were obtained with acceptable yields. Further studies on the extension of the application of this methodology are underway.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (NSFC) (grant number 21372077) for financial support and Dr XIAO-PENG He for his contribution in the revision of this manuscript.

Notes and references

1. (a) M. Jevric, D. K. Taylor, B. W. Greatrex and E. R. T. Tiekink, Tetrahedron, 2005, 61, 1885; (b) M. A. Brimble and M. Y. H. Lai, Org. Biomol. Chem., 2003, 1, 4227; (c) S. Boutefnouchet, N. Gaboriaud-Kolar, N. T. Minh, S. Depauw, M. H. David-Cordonnier, B. Pfeiffer, S. Leonce, A. Pierre, F. Tillequin, M. C. Lallemand and S. Michel, J. Med. Chem., 2008, 51, 7287; (d) S. K. Manna, S. L. K. Manda and G. Panda, Tetrahedron Lett., 2014, 55, 5759.
2. (a) K. S. Feldman, C. C. Mechem and L. Nader, J. Am. Chem. Soc., 1982, 104, 4011; (b) J. Boukouvalas, M. Pouliot, J. Robichaud, S. MacNeil and V. Snieckus, Org. Lett., 2006, 8, 3597; (c) C. Sabot, D. Bérard and S. Canesi, Org. Lett., 2008, 10, 4629.
3. R. A. Heald, T. S. Dexheimer, H. Vankayalapati, A. Siddiqui-Jain, L. Z. Szabo, M. C. Gleason-Guzman and L. H. Hurley, J. Med. Chem., 2005, 48, 2993.
4. (a) M. A. Brimble, M. T. Brimble and J. J. Gibson, J. Chem. Soc., Perkin Trans. 1, 1989, 179; (b) A. Nahrstedt, V. Wray, B. Engel and R. Reinhard, Planta Med., 1985, 44, 517.
5. S. K. Talapatra, N. C. Ganguly, S. Goswami and B. Talapatra, J. Nat. Prod., 1983, 46, 401.
6. (a) Z.-J. Xin, Y. Zhang, H. Tao, J.-J. Xue and Y. Li, Synlett, 2011, 11, 1579; (b) A. Kuramochi, H. Usuda, K. Yamatsugu, M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2005, 127, 14200; (c) V. N. Korotchenko and M. R. Gagné, J. Org. Chem., 2007, 72, 4877; (d) T. Hosokawa, T. Uno, S. Inui and S. I. Murahashi, J. Am. Chem. Soc., 1981, 103, 2318; (e) Y. Uozumi, K. Kato and T. Hayashi, J. Am. Chem. Soc., 1976, 119, 5063; (f) L. F. Tietze, F. Stecker, J. Zinngrebe and K. M. Sommer, Chem.–Eur. J., 2006, 12, 8770.
7. (a) D. Bérard, J. Alexandre and S. Canesi, Tetrahedron Lett., 2007, 48, 8238; (b) D. Bérard, M. A. Giroux, L. Racicot, C. Sabot and S. Canesi, Tetrahedron, 2008, 64, 7537; (c) K. C. Guérard, C. Sabot, M. A. Beaulieu, M. A. Giroux and S. Canesi, Tetrahedron, 2010, 66, 5893.
8. C.-X. Cui, H. Li, X.-J. Yang, J. Yang and X.-Q. Li, Org. Lett., 2013, 15, 5944.
9. H.-M. Li, Y.-L. Tang, Z.-H. Zhang, C.-J. Liu, H.-Z. Li, R.-T. Li and X.-S. Xia, Planta Med., 2012, 78, 39.
10. L.-J. Yang, K. Jiang, J.-J. Tang, S.-J. Qu, H.-F. Luo, C.-H. Tan and D.-Y. Zhu, Helv. Chim. Acta, 2013, 96, 119.
11. V. Snieckus and Y.-G. Zhao, Synfacts, 2014, 10, 134.
12. (a) Y. Uozumi, K. Kato and T. Hayashi, J. Am. Chem. Soc., 1997, 119, 5063; (b) Y. Uozumi, H. Kyota, K. Kato, M. Ogasawara and T. Hayashi, J. Org. Chem., 1999, 64, 1620; (c) R. M. Trend, Y. K. Ramtohul, E. M. Ferreira and B. M. Stoltz, Angew. Chem., Int. Ed., 2003, 42, 2892; (d) K. Muñiz, Adv. Synth. Catal., 2004, 346, 1425; (e) S. W. Youn and J. I. Eom, Org. Lett., 2005, 7, 3355; (f) R. M. Trend, Y. K. Ramtohul and B. M. Stoltz, J. Am. Chem. Soc., 2005, 127, 17778; (g) R. I. McDonald, G. Liu and S. S. Stahl, Chem. Rev., 2011, 111, 2981.
13. (a) T. Hayashi, K. Yamasaki, M. Mimura and Y. Uozumi, J. Am. Chem. Soc., 2004, 126, 3036; (b) B. Xiao, T.-J. Gong, Z.-J. Liu, J.-H. Liu, D.-F. Luo, J. Xu and L. Liu, J. Am. Chem. Soc., 2011, 133, 9250.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1447730. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra06840e

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