Copper catalyzed room temperature lactonization of aromatic C–H bond: a novel and efficient approach for the synthesis of dibenzopyranones

Abstract

We have developed a novel and efficient methodology for the intramolecular aryl C–H oxidative lactonization of 2-arylbenzaldehyde using a low-cost CuCl catalyst and TBHP as the oxidant at room temperature. We applied the methodology to the synthesis of a series of dibenzopyranones.

---

Transition metal catalyzed un-activated aromatic C–H bond functionalization is a very powerful synthetic strategy for the synthesis of complex molecules from simple precursors.¹ Of these reactions, the oxidative lactonization of an aromatic C–H bond gives access for the synthesis of important lactone containing molecules. Recently, a number of methods have been reported in the literature for the sp²C–H lactonization with a carboxylic acid group in the presence of expensive transition metal catalysts along with various oxidants and additives at elevated temperature.² Therefore, the development of a newer methodology for oxidative C–H bond lactonization using a cheaper catalyst and under mild reaction conditions, especially at room temperature, is highly desirable.

Herein, we are reporting a methodology for the synthesis of dibenzopyranones through copper-catalyzed intra-molecular aryl C–H oxidative lactonization of 2-arylbenzaldehydes at room temperature (Scheme 1).

Scheme 1 Literature reports and present work.

Dibenzopyranone is an interesting class of lactones found as the core structure of many natural products, such as autumnariol (Fig. 1, 1), alternariol, altenuisol, and graphislactones (Fig. 1, 2) and bioactive compounds.³ Dibenzopyranone scaffolds have been used as intermediates for the synthesis of many pharmaceutically interesting compounds, such as progesterone,⁴ androgen receptor ligands,⁵ glucocorticoids,⁶ and endothelial cell proliferation inhibitors.⁷ Dibenzopyranones are also found in various naturally occurring food sources, such as citrus fruits, herbs and vegetables.⁸ Furthermore, such lactones are also present in human metabolites, such as urolithins. Urolithins A–C (Fig. 1, 3a–c) are produced by the in vitro fermentation of punicalagins.⁹

Fig. 1 Structure of some natural products and bioactive compounds.

In the literature, several methods are available for the synthesis of dibenzopyranones. Most of the popular methods involve (1) Baeyer–Villiger oxidation of fluorenone (Scheme 2, path a),¹⁰ (2) Lewis acid or metal mediated lactonization of the ester and methoxy groups (path b),¹¹ (3) lactonization of 2-halobiarylcarboxylic acid derivative (Scheme 2, path c),¹² (4) cross coupling of 2-halobenzaldehyde and o-hydroxyarylboronic acid and followed by lactonization (path d),¹³ (5) cross coupling of aryl o-halobenzoate (path e),¹⁴ and (6) C–H activation/carbonylation of 2-arylphenol (path f).¹⁵ All the present methods, despite their individual advantages, suffer from some drawbacks, such as (a) multistep procedures, (b) extremely low (−78 °C) or high temperature reaction conditions, (c) use of readily unavailable starting materials, (d) requirement of pre-functionalization of the starting materials, and (e) the use of poisonous CO gas. To overcome all of the above drawbacks, a mild, efficient and room temperature reaction procedure starting from readily synthesizable starting materials is highly desirable. Herein we report a CuCl catalyzed reaction for the synthesis of dibenzopyranones at room temperature.

Scheme 2 Literature reports and present work.

Our investigation was started by the reaction 2-phenylbenzaldehyde in the presence of a CuBr catalyst and TBHP (2 equiv.) as an oxidant in an acetonitrile solvent at room temperature, which gave the desired product dibenzopyranone in 33% yield along with the unconsumed substrate. The amounts of TBHP, catalyst and solvent were varied to determine optimized reaction condition, and the results are listed in Table 1.

Table 1 Screening of the reaction conditions

Entry	Solvent	Catalyst	TBHP (equiv.)	Time (h)	Yield^a
a Isolated yield.b About 6% of fluorenone was formed along with the normal product.c About 27% of 2-phenylbenzoic acid was isolated.d Optimized reaction condition: the substrate 4a (0.25 mmol), CuCl (5 mol%), DMSO (2 mL), TBHP (6 equiv.) stirred at room temperature for 4 h.e The catalyst, 2 mol% of CuCl, was used.
1	CH3CN	CuBr	2	24	33
2	CH3CN	CuBr	4	24	54
3	CH3CN	CuBr	6	8	68
4	DMF	CuBr	6	24	0
5	DMA	CuBr	6	24	Trace
6	DMSO	CuBr	6	4	74^b
7	DCM	CuBr	6	4	66
8	H2O	CuBr	6	24	19^c
9	DMSO	CuI	6	24	Trace
10	DMSO	CuCl	6	4	78^d
11	DMSO	CuCl	6	24	70^e
12	DMSO	Cu(OAc)2·2H2O	6	24	38
13	DMSO	CuCl	0	24	0
14	DMSO	—	6	24	Trace

---

At first, we increased the amount of oxidant TBHP to 4 equivalents and the yield was increased to 54% along with the unconsumed substrate. The yield was improved to 68% after further increasing the amount of TBHP to 6 equivalents and the substrate also vanished within 8 h. After varying the nature of the solvent (Table 1, entries 3–8), DMSO was found to be as the best. Different copper catalysts were assessed and the CuCl catalyst gave the highest yield of 78% (Table 1, entry 10). Cu(II) acetate also promoted the reaction but gave a lower yield. The reaction did not occur in the absence of either the catalyst or TBHP (entries 13 and 14).

Therefore the optimized reaction conditions are the substrate (0.25 mmol), CuCl catalyst (5 mol%), DMSO solvent (2 mL), TBHP (6 equiv.) stirred at room temperature for 4 h. After obtaining the optimized reaction conditions, they were applied to different substrates to examine the scope of this methodology, and the results are summarized in Table 2. The substrate 2-arylbenzaldehydes (4) were synthesized by the Suzuki–Miyaura cross coupling of 2-bromobenzaldehydes and arylboronic acid derivatives. We applied the optimized reaction condition on the substrates (4) bearing a range of electron withdrawing and donating group on both of the aryl rings and the corresponding dibenzopyranones were obtained in good to excellent yield (Table 2, entries 5a–5p). In presence of the electron withdrawing group on either of the aryl rings, biaryl substrates gave a lower yield (Table 2, entries 5c, 5i–k) while the electron donating groups on aryl rings gave a higher yield (Table 2, entries 5d–e, 5l, 5p–r). The yield was lower for entries 5f and 5g due to steric repulsion between the methoxy group and peri hydrogen of the adjacent phenyl ring. The substrate, 2-(m-tolyl)benzaldehyde, gave two possible pyranone derivatives in a 3 : 2 ratio (entry 2n). The substituents at the ortho-position of the Ar₂ ring were unfavourable for product formation (entry 5m, 5o). Finally the methyl ethers of the natural product urolithins A–C were obtained from the corresponding suitably substituted starting materials in excellent yield due to the presence of an electron donating methoxy group (Table 2, entries 5p–r).

Table 2 Investigation of the scope of the substrates^a,b,c

a Reaction conditions: 2-arylbenzaldehyde (0.25 mmol), CuCl (5 mol%), DMSO (2 mL), TBHP (6 equiv.) stirred at room temperature for 4 h.b Isolated yield.c 5n isomers as an NMR ratio.

---

After achieving success in the synthesis of a series of dibenzopyranones, the methodology was applied to fused o-phenylnaphthaldehydes and the results are listed in Table 3. Under the optimized reaction conditions, the substrate o-phenylnaphthaldehydes took a longer reaction time to complete the reaction and the product naphthochromens were formed along with a significant amount of fluorenone derivatives. Finally, the yield of the reaction was lower compared to the benzochromen systems.

Table 3 Extension of the reaction scope for the synthesis of naphthochromens^a,b

a Reaction conditions: 2-arylbenzaldehyde (0.25 mmol), CuCl (5 mol%), DMSO (2 mL), TBHP (6 equiv.) stirred at room temperature for 12 h.b Isolated yield.

---

After the successful application of this methodology to different o-arylbenzaldehyde derivatives, we examined whether the methodology could also be applicable to 2-arylbenzylalcohol or benzoic acid derivatives. Therefore, we applied the methodology to 2-phenylbenzyl alcohol and 2-phenylbenzoic acid. The substrate 2-phenylbenzyl alcohol promoted the reaction successfully and gave the product dibenzopyranone along with the unreacted intermediate 2-phenylbenzaldehyde under the optimized reaction conditions (Table 4). On the other hand, the 2-phenylbenzoic acid gave the product dibenzopyranone in trace amounts even after 48 h.

Table 4 Investigation on the scope of the reaction^a

a Reaction conditions: 2-arylbenzaldehyde (0.25 mmol), CuCl (5 mol%), DMSO (2 mL), TBHP (6 equiv.) stirred at room temperature for the required time.

---

The substrate 4a under the optimized reaction conditions gave the product 5a in 22% yield only in presence of the radical scavenger TEMPO (2.0 equiv.).

Based on the experimental results and literature reports,¹⁶ the tentative mechanism of the reaction is described in Scheme 3. At first, in the presence of a CuCl catalyst, the TBHP decomposes to generate tert-butoxyl and tert-butylperoxy radicals. The tert-butoxyl radical abstracts the aldehyde proton from 4a and gives the radical intermediate A. The intermediate A either combines with the tert-butylperoxy radical to give the perester intermediate B or combines with the adjacent phenyl ring to form the fluorenone (C), which is isolated as a by-product in trace amounts. In presence of the Cu(I) catalyst, the intermediate B decomposes to form the intermediate D and tert-butoxyl radical. The intermediate D then combines with the adjacent phenyl ring to give the radical intermediate E, which forms the product 5a after the abstraction of a proton by the tert-butoxyl radical. The intermediate D gave 2-phenylbenzoic acid when the reaction was performed in water (Table 1, entry 8).

Scheme 3 Plausible reaction mechanism.

In conclusion, we have developed a novel and efficient methodology for the synthesis of dibenzopyranones involving the CuCl catalyzed intramolecular oxidative lactonization of aromatic C–H bond with an aldehyde group in 2-arylbenzaldehyde derivatives. We successfully applied our methodology to the synthesis of methyl ether of natural product urolithins A–C. Finally, we believe that the methodology will be widely exploited by synthetic organic chemists because of the low-cost CuCl catalyst, ambient reaction temperature, easily synthesizable starting materials, scalable¹⁷ and finally good to excellent yields of the reaction. The mechanistic details and the application of this methodology for the synthesis other benzochromen containing natural products are under progress in our laboratory.

Acknowledgements

We gratefully acknowledge DST for providing funds and R.S. thanks CSIR New Delhi for the fellowship.

Notes and references

1. (a) X. Chen, K. M. Engle, D. H. Wang and J. Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094; (b) L. M. Xu, B. J. Li, Z. Yang and Z. J. Shi, Chem. Soc. Rev., 2010, 39, 712; (c) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147; (d) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215; (e) J. W. Delord, T. Droge, F. Liu and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740.
2. (a) Y. Wang, A. V. Gulevich and V. Gevorgyan, Chem.–Eur. J., 2013, 19, 15836; (b) J. G. Donaire and R. Martin, J. Am. Chem. Soc., 2013, 135, 9350; (c) Y. Li, Y. J. Ding, J. Y. Wang, Y. M. Su and X. S. Wang, Org. Lett., 2013, 15, 2574.
3. (a) K. Koch, J. Podlech, E. Pfeiffer and M. Metzler, J. Org. Chem., 2005, 70, 3275; (b) H. Abe, K. Nishioka, S. Takeda, M. Arai, Y. Takeuchi and T. Harayama, Tetrahedron Lett., 2005, 46, 3197; (c) C. Garino, F. Bihel, N. Pietrancosta, Y. Laras, G. Quelever, I. Woo, P. Klein, J. Bain, J. L. Boucher and J. L. Kraus, Bioorg. Med. Chem. Lett., 2005, 15, 135; (d) W. Sun, L. D. Cama, E. T. Birzin, S. Warrier, L. Locco, R. Mosley, M. L. Hammond and S. P. Rohrer, Bioorg. Med. Chem. Lett., 2006, 16, 1468; (e) R. W. Pero and D. Harvan, Tetrahedron Lett., 1973, 14, 945; (f) W. T. L. Sidwell, H. Fritz and C. Tamm, Helv. Chim. Acta, 1971, 54, 207; (g) H. Raistrick, C. E. Stilkings and R. Thomas, Biochemistry, 1953, 55, 421.
4. (a) J. P. Edwards, S. J. West, K. B. Marschke, D. E. Mais, M. M. Gottardis and T. K. Jones, J. Med. Chem., 1998, 41, 303; (b) L. Zhi, C. M. Tegly, K. B. Marschke, D. E. Mais and T. K. Jones, J. Med. Chem., 1999, 42, 1466.
5. L. G. Hamann, R. I. Higuchi, L. Zhi, J. P. Edwards, X. N. Wang, K. B. Marchke, J. W. Kong, L. J. Farmer and T. K. Jones, J. Med. Chem., 1998, 41, 623.
6. (a) M. J. Coghlan, P. R. Kym, S. W. Elmore, A. X. Wang, J. R. Luly, D. Wilcox, M. Stshko, C. W. Lin, J. Miner, C. Tyree, M. Nakane, P. Jacobsen and B. C. Lane, J. Med. Chem., 2001, 44, 2879; (b) Y. Y. Ku, T. Grieme, P. Raje, P. Sharma, S. A. King and H. E. Morton, J. Am. Chem. Soc., 2002, 124, 4282.
7. J. M. Schmidt, G. B. Tremblay, M. Page, J. Mercure, M. Feher, R. Dunn-Dufault, M. G. Peter and P. R. Redden, J. Med. Chem., 2003, 46, 1289.
8. R. Myrray, J. Mendez and S. Brown, The Natural Coumarins: Occurrence, Chemistry and Biochemistry, John Wiley & Sons, New York, 1982, pp. 97–111.
9. P. Nealmongkol, K. Tangdenpaisal, S. Sitthimonchai, S. Ruchirawat and N. Thasana, Tetrahedron, 2013, 69, 9277.
10. (a) G. Mehta and P. N. Pandey, Synthesis, 1975, 404; (b) K. Ruhland, A. Bruck and E. Herdtweck, Eur. J. Inorg. Chem., 2007, 944.
11. (a) Q. J. Zhou, K. Worm and R. E. Dolle, J. Org. Chem., 2004, 69, 5147; (b) G. J. Kemperman, B. T. Horst, D. Van de Goor, T. Roeters, J. Bergwerff, R. van der Eem and J. Basten, Eur. J. Org. Chem., 2006, 14, 3169; (c) I. Hussain, V. T. H. Nguyen, T. T. Yawer, C. Fiscer, H. Reinke and P. Langer, J. Org. Chem., 2007, 72, 6255; (d) B. I. Alo, P. A. Patil, M. J. Sharp, M. A. Siddiqui and V. Snieckus, J. Org. Chem., 1991, 56, 3763; (e) N. Thasana, R. Worayuthakarn, P. Kradanrat, E. Hohn, L. Young and S. Ruchirawat, J. Org. Chem., 2007, 72, 9379.
12. (a) N. Thasana, R. Worayuthakarn, P. Kradanrat, E. Hohn, L. Young and S. Ruchirawat, J. Org. Chem., 2007, 72, 9379; (b) S. Furuyama and H. Togo, Synlett, 2010, 2325; (c) Y. Li, Y. J. Ding, J. Y. Wang, Y. M. Su and X. S. Wang, Org. Lett., 2013, 15, 2574.
13. (a) D. H. Hey, J. A. Leonard and C. W. Ress, J. Chem. Soc., 1962, 4579; (b) Q. J. Zhou, K. Worm and R. E. Dolle, J. Org. Chem., 2004, 69, 5147; (c) G. J. Kemperman, B. Ter Horst, D. van de Goor, T. Roeters, J. Bergwerff, R. van der Eem and J. Basten, Eur. J. Org. Chem., 2006, 3169; (d) I. Hussain, V. T. H. Nguyen, M. A. Yawer, T. T. Dang, C. Fischer, H. Reinke and P. Langer, J. Org. Chem., 2007, 72, 6255; (e) W. Zhang, B. I. Wilke, J. Zhan, K. Watanabe, C. N. Boddy and Y. J. Tang, J. Am. Chem. Soc., 2007, 129, 9304; (f) J. Luo, Y. Lu, S. Liu, J. Liu and G. J. Deng, Adv. Synth. Catal., 2011, 353, 2604; (g) E. J. Carlson, A. M. S. Riel and B. J. Dahl, Tetrahedron Lett., 2012, 53, 6245; (h) R. Singha, S. Roy, S. Nandi, P. Ray and J. K. Ray, Tetrahedron Lett., 2013, 54, 657.
14. T. Harayama and H. Yasuda, Heterocycles, 1997, 46, 61.
15. CO insertion: (a) S. Luo, F. X. Luo, X. S. Zhang and Z. J. Shi, Angew. Chem., Int. Ed., 2013, 52, 10598; (b) T. H. Lee, J. Jayakumar, C. H. Cheng and S. C. Chuang, Chem. Commun., 2013, 49, 11797; (c) K. Inamoto, J. Kadokawa and Y. Kondo, Org. Lett., 2013, 15, 3962.
16. (a) H. Minto, H. Matsuzuki and K. Miwa, Bull. Chem. Soc. Jpn., 1968, 41, 249; (b) Y. Wang, A. V. Gulevich and V. Gevorgyan, Chem.–Eur. J., 2013, 19, 15836.
17. A 10 mmol biphenyl-2-carbaldehyde under the optimized reaction conditions afforded 71% yield.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra13665a

---