Copper-catalyzed decarboxylative intramolecular C–O coupling: synthesis of 2-arylbenzofuran from 3-arylcoumarin

Abstract

A copper-catalyzed decarboxylative intramolecular C–O coupling reaction was established. Under aerobic conditions in the presence of cupric chloride/1,10-phenathroline, a variety of 2-arylbenzofurans were prepared from 3-arylcoumarins in one-pot with yields from 26% to 84%.

---

The transition metal catalyzed decarboxylative cross-coupling is one of the most attractive methodologies in organic synthesis. Starting from low-cost, conveniently available and structurally diverse carboxylic acids (and their derivatives), transition metal catalyzed decarboxylative C–H, C–C, C–N, C–P, C–S and C–halogen bond formation was achieved in the past few decades.¹ Recently, decarboxylative intermolecular C–O cross-coupling utilizing catalytic amounts of copper salts was developed by Gooßen et al.^2a Han et al. reported Ir(I)-catalyzed decarboxylative intramolecular allylic etherification from aryl allyl carbonates.^2b We are interested in the development of new methods for the construction of heterocyclic compounds from easily available starting materials. We rationalized that oxygen-containing heterocycles could be accomplished from corresponding lactones with a formal extrusion of a carbonyl group, via a three-step transformation involving (1) ring-opening, (2) decarboxylation and (3) intramolecular Chan–Evans–Lam type C–O cross-coupling (Scheme 1). In our preliminary study, benzofuran was successfully prepared from coumarin via decarboxylative intramolecular C–O coupling in the presence of copper powder.³ To the best of our knowledge, this is the first example of direct decarboxylative intramolecular C–O coupling without converting the nucleophile into borate or silicate ester^2a or aryl allyl carbonates.^2b

Scheme 1 Three-step transformation.

2-Arylbenzofurans and their analogues, involving both natural and synthetic origins, are of particular interest because of their broad range of biological activities and significant pharmacological potentials.⁴ Several synthetic approaches to 2-arylbenzofuran skeleton were reported.⁵ However, these approaches suffer from some fundamental drawbacks. For instance, it is hard to purify cross-coupling intermediate in o-hydroxylstilbene approach,^5b and, in o-hydroxylphenylacetylene approach,^5a great difficulty existed in phenylacetylene preparation. The conversion of 3-arylcoumarin to 2-arylbenzofuran was previously reported by Kinoshita,^5d,e in which a reductive ring-opening and an oxidative elimination of formaldehyde were involved. The use of strong reducing reagent (AlH₃) and oxidant (DDQ) limited the substrate scope and yields. There is still a demand for new synthetic methods to obtain versatile 2-arylbenzofurans. Herein, we report a decarboxylative intramolecular C–O cross-coupling in the presence of copper and base, and the application of this coupling for the preparation of 2-arylbenzofuran from 3-arylcoumarin in a one-pot manner. Coumarins are abundant in nature and can be easily synthesized. Thus, this method provides a novel and easy access to a variety of 2-arylbenzofurans.

Our initial work focused on the conversion of coumarin 1bb into benzofuran 2bb under air at 190 °C in the presence of copper powder, quinoline and sodium hydroxide. The model reaction was proved to be successful with 26% isolated yield. After adding some grinded molecular sieve and maintaining the temperature at 110 °C for an hour before raising to 190 °C, the yield was improved to 41% (Scheme 2).

Scheme 2 Synthesis of 2-arylbenzofuran from 3-arylcoumarin.

We also noticed that air was necessary for the above transformation. Thus, copper(0) was unlike the active catalytic species, though copper powder was added in the above catalytic process. To find optimal catalytic conditions for the transformation, copper(0), copper(I) and copper(II), ligands and bases were screened. As shown in Table 1, cupric chloride (15 mol%), 1,10-phenathroline (15 mol%), sodium hydroxide (3 eq.) and DMSO at 150 °C for 24 hours (ref. 6) came out to be the favorable conditions (entry 17). Air seemed to have significant impact on the yields (entries 3–6, 9, 10, 17, 19, 24 and 25).

Table 1 Optimization of reaction conditions^a

Entry	[Cu]	Ligand^d	Base	Solvent	Air	Yield^b (%)
a Reaction condition: [Cu] (15 mol %), ligand (15 mol %), base (3 eq.) and MS 4 Å were used under heating (in quinoline at 190 °C or in DMSO at 150 °C) for 24 h.b Isolated yield. HPLC yield given in parentheses.c 50 mol% Cu powder was used.d Phen = phenathroline, DMEDA = N,N′-dimethylethylenediamine, PPh3 = triphenylphosphine, Q = quinolone. MS = molecular sieve. n.d. = not detectable.
1	Cu	None	NaOH	Q	Y	9
2	Cu	None	NaOH	Q	N	Trace
3	Cu^c	None	NaOH	Q	Y	41
4	Cu^c	None	NaOH	Q	N	2
5	Cu^c	Phen	NaOH	DMSO	Y	34
6	Cu^c	Phen	NaOH	DMSO	N	2
7	Cu^c	Phen	KOH	DMSO	Y	38
8	CuI	None	NaOH	Q	Y	43
9	CuI	Phen	NaOH	DMSO	Y	41(52)
10	CuI	Phen	NaOH	DMSO	N	16(18)
11	CuI	Phen	KOH	DMSO	Y	47(53)
12	CuI	DMEDA	NaOH	DMSO	Y	12(15)
13	CuI	PPh3	NaOH	DMSO	Y	22(26)
14	Cu2O	None	NaOH	Q	Y	Trace
15	Cu2O	Phen	NaOH	DMSO	Y	5
16	CuCl2	None	NaOH	Q	Y	43(49)
17	CuCl2	Phen	NaOH	DMSO	Y	72(79)
18	CuCl2	Phen	None	DMSO	Y	n.d.(3)
19	CuCl2	Phen	NaOH	DMSO	N	13(17)
20	CuCl2	Phen	KOH	DMSO	Y	67(75)
21	CuCl2	DMEDA	NaOH	DMSO	Y	43(45)
22	CuCl2	PPh3	NaOH	DMSO	Y	38(42)
23	Cu(OH)2	Phen	None	DMSO	Y	Trace(2)
24	Cu(OH)2	Phen	NaOH	DMSO	Y	64(70)
25	Cu(OH)2	Phen	NaOH	DMSO	N	16(17)

---

With the conditions in hand, we further explored the scope of the methodology. A series of 3-arylcoumarins were synthesized through classical Perkin condensation, which was perhaps the most practical route among the plethora of methods available for coumarin motif.⁷ As shown in Table 2, most of the 3-arylcoumarins were successfully converted to corresponding 2-arylbenzofurans with yields between 26% and 84%. 6-Chloro-3-arylcoumarins were easier to be converted to corresponding benzofurans (entries 9–19). Transformations were hampered by 4′-hydroxyl and 4′-acetoxyl substituents on coumarins (entries 30 and 31). 8-Methoxyl substituents (entries 1–8, 25–29) were less favoured than 8-chloride ones (entries 15–19). 2′-Methoxyl (entries 11 and 18) or successive three methoxyls at C-3′, 4′ and 5′ (entries 4 and 12) were unfavored. 3′,4′-Dimethoxyl, 4′-methoxyl, 3′-methoxyl, 4′-chloro or 4′-fluoro substitutions had relatively slight impact on the yields.

Table 2 Scope of 3-arylcoumarins^a

Entry	R^1	R^2	Phenyl	Product	Yield^b (%)
a Reactions were carried out in DMSO under air for 24 h in the presence of cupric chloride (15 mol%), 1,10-phenathroline (15 mol%), sodium hydroxide (3 eq.) and MS 4 Å.b Isolated yield.c No substitution. n.d. = not detectable.
1	H	OCH3	3′,4′-Dimethoxyl	2aa	36
2	H	OCH3	4′-Methoxyl	2ab	34
3	H	OCH3	3′-Methoxyl	2ac	41
4	H	OCH3	3′,4′,5′-Trimethoxyl		n.d.
5	H	OCH3	—^c	2af	30
6	H	OCH3	4′-Chloro	2ag	42
7	H	OCH3	4′-Fluoro	2ah	36
8	H	OCH3	4′-Nitro	2an	45
9	Cl	H	3′,4′-Dimethoxyl	2ba	76
10	Cl	H	4′-Methoxyl	2bb	72
11	Cl	H	2′-Methoxyl	2bd	63
12	Cl	H	3′,4′,5′-Trimethoxyl	2be	52
13	Cl	H	4′-Chloro	2bg	71
14	Cl	H	4′-Nitro	2bn	74
15	Cl	Cl	3′,4′-Dimethoxyl	2ca	82
16	Cl	Cl	4′-Methoxyl	2cb	73
17	Cl	Cl	3′-Methoxyl	2cc	67
18	Cl	Cl	2′-Methoxyl	2cd	60
19	Cl	Cl	—^c	2cf	84
20	H	H	3′,4′-Dimethoxyl	2da	47
21	H	H	4′-Methoxyl	2db	52
22	H	H	3′-Methoxyl	2dc	56
23	H	H	—^c	2df	61
24	H	H	4′-Fluoro	2dh	69
25	Br	OCH3	3′,4′-Dimethoxyl	2ea	26
26	Br	OCH3	—^c		n.d.
27	Br	OCH3	4′-Chloro		n.d.
28	Br	OCH3	4′-Fluoro		n.d.
29	Br	OCH3	2′,5′-Dimethoxyl		n.d.
30	Cl	H	4′-Hydroxyl		n.d.
31	Cl	H	4′-Acetoxyl		n.d.

---

Except 2ea, which was obtained with 26% yield (entry 25), the other 5-bromo-2-arylbenzofurans were not obtained from corresponding 6-bromo coumarins (entries 26–29). Instead, 5-hydrogen, 5-chloro and 5-methylthio 2-arylbenzofurans, were found from the reactions of 1ef, 1eg and 1eh. Only 5-chloro-2-arybenzofuran 2ek was isolated from the reaction of 1ek (Scheme 3). These phenomena might be due to the activation of C–Br bond on the aromatic ring by copper during the transformation.⁸ To explain the formation of 5-chloro-2-arylbenzofuran, we replaced cupric chloride with cupric hydroxide. However, even no chlorines were added in the catalytic processes, the chlorinated by-products still existed. Thus, the chlorine might come from hydrochloric acid in the quenching step. The methanthiol by-products might be derived from DMSO. To overcome the difficulty of the transformation of hydroxyl or acetoxyl bearing 3-arylcoumarins (entries 30 and 31), the hydroxyl group was protected by benzyl. As depicted in Scheme 4, 1bjdb was successfully converted to corresponding 2-arylbenzofuran 2bjdb with 69% yield.

Scheme 3 By-products via C–Br activation.

Scheme 4 Strategy for hydroxyl or acetoxyl 3-arylcoumarins.

We subsequently tested the impact of water (generated from base hydrolysis of coumarin), sodium hydroxide and molecular sieve on the yield. To avoid the generation of water in situ, 1bbs was used as starting material for the reaction. Comparing with Table 1 entry 17 (water was generated in situ) and Scheme 5(3) (no water generated in situ), there is a negligible difference of the yields (79% vs. 78%). This indicated water generated from base hydrolysis of coumarin did not significantly influence the reaction. Sodium hydroxide was needed for the base hydrolysis of coumarin. However, the presence of sodium hydroxide after ring opening of coumarin resulted in a reduced yield from 85% (Scheme 5(1)) to 78% (Scheme 5(3)), implying sodium hydroxide was unfavourable for the decarboxylative C–O coupling reaction. Finally, the addition of molecular sieves improved the yield from 64% (Scheme 5(2)) to 85% (Scheme 5(1)), revealing that molecular sieves had significant influence on the yield. The role of molecular sieves in the reaction was not clear but not likely acting as water absorbent.

Scheme 5 The influences of water, sodium hydroxide and molecular sieve on the yields.

Scheme 6 Transformation of coumarin.

A proposed mechanism is outlined in Fig. 1. The metal–carboxylate and phenoxide intermediate A is formed in situ by base hydrolysis of coumarin. This intermediate is favored for the decarboxylative C–O coupling because protonolysis by hydroxyl group is avoided, which would cease the C–O coupling.^1,9 The vinylmetal intermediate B is then resulted from Cu(II)-catalyzed decarboxylation. Based on previous reports and our experimental data, a copper(III)-mediated C–O coupling pathway is proposed in the following Chan–Evans–Lam type coupling.¹⁰ Copper(III) intermediate C could be generated from oxidation of copper(II) intermediate B by oxygen¹¹ or another equivalent of copper(II) species.¹² 2-Arylbenzofuran was finished by reductive elimination of intermediate D.

Fig. 1 Proposed mechanism.

In summary, a decarboxylative intramolecular C–O cross-coupling reaction capable of forming oxygen-containing heterocyclic compounds from lactones was developed. This reaction was successfully applied for the conversion of 3-arylcoumarins to 2-arylbenzofurans.

Acknowledgements

This work was financially supported by National Natural Science Foundation of China (Grants 20932007 and 21372213).

Notes and references

1. For recent reviews on transition metal catalyzed decarboxylative coupling, see: (a) N. Rodríguez and L. J. Gooßen, Chem. Soc. Rev., 2011, 40, 5030; (b) J. Cornella and I. Larrosa, Synthesis, 2012, 44, 653; (c) W. I. Dzik, P. P. Lange and L. J. Gooßen, Chem. Sci., 2012, 3, 2671.
2. (a) S. Bhadra, W. I. Dzik and L. J. Gooßen, J. Am. Chem. Soc., 2012, 134, 9938; (b) D. Kim, S. Reddy, O. V. Singh, J. S. Lee, S. B. Kong and H. Han, Org. Lett., 2013, 15, 512.
3. To test our hypothesis, a non-substituted lactone, coumarin, was chosen to conduct intramolecular decarboxylative C–O cross-coupling. Based on copper powder/quinolone promoted conditions,¹³ excessive sodium hydroxide was further added to generate carboxylate from lactone motif. When reaction temperature is up to 180 °C, target benzofuran was detected by TLC. Benzofuran was obtained with 39% isolated yield (Scheme 6).
4. W.-C. Pu, F. Wang and C. Wang, Chin. J. Org. Chem., 2011, 31, 155.
5. For approaches from o-ynylphenol, see: (a) S. A. Bakunov, S. M. Bakunova, T. Wenzler, K. A. Werbovetz, R. Brun and R. R. Tidwell, J. Med. Chem., 2008, 51, 6927, For approaches from o-hydroxyl stilbene, see: (b) X.-F. Duan, J. Zeng, Z.-B. Zhang and G.-F. Zi, J. Org. Chem., 2007, 72, 10283, For approaches from o-benzyloxybenzaldehyde, see: (c) M. One, Y. Cheng, H. Kimura, M.-C. Cui, S. Kagawa, R. Nishii and H. Saji, J. Med. Chem., 2011, 54, 2971, For approaches from 3-arylcoumarin, see: (d) T. Kinoshita, Tetrahedron Lett., 1997, 38, 259; (e) T. Kinoshita and K. Ichinose, Heterocycles, 2005, 65, 1641.
6. See ESI for time profile.†.
7. For the synthesis of 3-arylcoumarin, see: (a) S. H. Mashraqui, D. Vashi and H. D. Mistry, Synth. Commun., 2004, 34, 3129; (b) C.-F. Xiao, L.-Y. Tao, H.-Y. Sun, W. Wei, Y. Chen, L.-W. Fu and Y. Zou, Chin. Chem. Lett., 2010, 21, 1295; (c) D. Viña, M. J. Matos, G. Ferino, E. Cadoni, R. Laguna, F. Borges, E. Uriarte and L. Santana, ChemMedChem, 2012, 7, 464; (d) R. S. Mali and P. P. Joshi, Synth. Commun., 2001, 31, 2753; (e) S. Vilar, E. Quezada, L. Santana, E. Uriarte, M. Yanez, N. Fraiz, C. Alcaide, E. Cano and F. Orallo, Bioorg. Med. Chem. Lett., 2006, 16, 257; (f) M. J. Matos, S. Vazquez-Rodriguez, F. Borges, L. Santana and E. Uriarte, Tetrahedron Lett., 2011, 52, 1225.
8. (a) S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed., 2003, 42, 5400; (b) C. J. Ball and M. C. Wills, Eur. J. Org. Chem., 2013, 425.
9. (a) S. Matsubara, Y. Yokota and K. Oshima, Org. Lett., 2004, 6, 2071; (b) L. J. Gooßen, W. R. Thiel, N. Rodríguez, C. Linder and B. Melzer, Adv. Synth. Catal., 2007, 349, 2241; (c) L. J. Gooßen, F. Manjolinho, B. A. Khan and N. Rodríguez, J. Org. Chem., 2009, 74, 2620; (d) R. Grainger, A. Nikamal, J. Cornella and I. Larrosa, Org. Biomol. Chem., 2012, 10, 3172.
10. (a) D. M. T. Chan, K. L. Monaco, R. P. Wang and M. P. Winteres, Tetrahedron Lett., 1998, 39, 2933; (b) D. A. Evans, J. L. Katz and T. R. West, Tetrahedron Lett., 1998, 39, 2937; (c) P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T. Chan and A. Combs, Tetrahedron Lett., 1998, 39, 2941; (d) K. S. Rao and T. S. Wu, Tetrahedron, 2012, 68, 7735.
11. (a) Y. Zhang, S. Patel and N. Mainolfi, Chem. Sci., 2012, 3, 3196; (b) J. P. Collman and M. Zhang, Org. Lett., 2000, 2, 1233.
12. A. E. King, T. C. Brunold and S. S. Stahl, J. Am. Chem. Soc., 2009, 131, 5044.
13. K. Gaukroger, J. A. Hadfield, L. A. Hepworth, N. J. Lawrence and A. T. McGown, J. Org. Chem., 2001, 66, 8135.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra46414h

---