Regioselective palladium(II)-catalyzed aerobic oxidative Heck-type C3 alkenylation of sulfocoumarins

Abstract

An efficient method for the direct C–H olefination of sulfocoumarins with a wide range of alkenes is developed. Moreover, O₂ was successfully utilized as the sole oxidant for the oxidative Heck reaction. This approach enables the rapid generation of various 3-alkenylated sulfocoumarins.

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Sungwoo Hong

Sungwoo Hong is an Associate Professor at the Department of Chemistry at Korea Advanced Institute of Science and Technology (KAIST) and a Group Leader of Center for Catalytic Hydrocarbon Functionalizations at the Institute for Basic Science. He graduated from Seoul National University, where he received his B.S and M.S degrees. He then went to Pennsylvania State University for his Ph.D program. After he had finished his Postdoc course at Harvard University, he joined GlaxoSmithKline in USA as a Principal Scientist. In 2009, he started independent work at KAIST. His research interests are in the field of development of new reaction & synthesis, and advanced medicinal chemistry.

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Sulfocoumarins (1,2-benzoxathiine 2,2-dioxides) are bioisosteres of coumarins, where the carbonyl group in the coumarin ring is replaced by a sulfonyl group. Sulfocoumarin has been reported to be an important structural motif that inhibits the metalloenzyme, carbonic anhydrase.¹ Consequently, the development of efficient methods for the rapid derivatization of sulfocoumarin has been the subject of intensive research.² Despite significant synthetic efforts, an approach to functionalize this scaffold via C–H bond activation has not yet been reported.

Since Fujiwara's discovery of the direct olefination of benzene,³ substantial progress has been achieved in the field of oxidative Heck reactions.⁴ Our group and Lee's group recently developed Pd(II)-catalyzed oxidative Heck reactions of coumarins and phosphacoumarins, respectively.⁵ These studies prompted us to explore the feasibility of an expeditious synthetic approach to install an olefin into sulfocoumarins. We speculated that the C3-palladated species could be accessed in a catalytic fashion because of the inherent nucleophilic characteristics of the 3-position of sulfocoumarins. Herein, we describe a regioselective Pd(II)-catalyzed C–H olefination of sulfocoumarins using 1 atm O₂ as the only oxidant,⁶ which enables the construction of various 3-vinyl and 3-styryl sulfocoumarins (Scheme 1).

Scheme 1 Regioselective oxidative Heck reactions of sulfocoumarins.

We studied the feasibility of the proposed strategy by investigating the possibility of C–H activation/olefination of sulfocoumarin (1a) with n-butyl acrylate (2a): the representative catalyst screening data for the conversion are listed in Table 1. The reaction utilized a Pd(OPiv)₂ catalyst combined with Ag₂CO₃ to exclusively afford the C3-alkenylated product, presumably via an electrophilic palladation pathway (entry 1, 33%). Among the Pd species screened, Pd(OPiv)₂ displayed the best catalytic efficiency. Both the base and the solvent were found to fundamentally affect the reaction efficiency; K₂CO₃ and pivalic acid were the optimal base and solvent, respectively. The properties of the oxidant were also critical for the reaction efficiency, and the use of Cu(OAc)₂ dramatically improved the catalytic reactivity (entry 3). Based on the recent advances in palladium-catalyzed aerobic oxidation reactions, an intensive screen was conducted to promote the reactions using environmentally benign and economical oxidants.⁷ We therefore surveyed the capabilities of air and O₂ as oxidizing agents. Indeed, we were pleased to observe that the C3-alkenylation process proceeded in air (entry 6, 76%) and the yields were higher than those obtained using the Pd(II)/Cu(II) catalytic system. When the reaction was subjected to treatment with 1 atm O₂ as the only oxidant, an excellent product yield was obtained. Thus, this method presents an efficient and sustainable approach to the synthesis of various 3-vinylsulfocoumarin derivatives. Under the optimized reaction conditions, the C3 alkenylation of 1a in the presence of Pd(OPiv)₂ (0.1 equiv.) and K₂CO₃ (3 equiv.) in pivalic acid at 80 °C afforded the product 3a in the highest yield (93%).

Table 1 Optimization of alkenylation conditions^a

Entry	Oxidant (equiv.)	Base (equiv.)	Yield^c (%)
a Reactions were conducted with sulfocoumarin, butyl acrylate (2.0 equiv.), Pd(OPiv)2 (0.2 equiv.), and base (3 equiv.) in PivOH at 80 °C for 8 h. b Butyl acrylate (1.1 equiv.), Pd(OPiv)2 (0.1 equiv.), and base (3 equiv.). c Yields were determined using ^1H NMR analysis of the crude reaction mixture. d Isolation yield. Piv = pivaloyl, DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
1	Ag2CO3 (3)	—	33
2	Oxone (1.2)	K2CO3	34
3	Cu(OAc)2 (3)	K2CO3	61
4	AgNO3 (3)	K2CO3	75
5	DDQ (1)	K2CO3	14
6	Air (1 atm)	K2CO3	76
7	O2 (1 atm)	K2CO3	94
8	N2	K2CO3	15
9^b	O2 (1 atm)	K2CO3	95 (93^d)

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To gain some insight into the present alkenylation, a mechanistic analysis of the initial interaction of a Pd catalyst with sulfocoumarin 1b was performed using H/D exchange experiments.⁸ A significant level of deuterium incorporation (after 15 min, 41% D) was observed at the C3 position of sulfocoumarin (1b) when the reaction mixture was treated with AcOD as a deuterium source under the optimized conditions and in the absence of the alkene, as shown in Fig. 1 (see the ESI† for the full spectra).

Fig. 1 Proposed mechanistic pathways of the present reactions.

Based on our observations, a plausible catalytic mechanism for the alkenylation of sulfocoumarin involves the aforementioned electrophilic palladation pathway at the C3 position, followed by H-abstraction by the pivalate ligand to provide the intermediate II. In the presence of an alkene substrate, the C3-palladated species II inserts into the olefin, and the subsequent C–Pd β-hydride elimination of intermediate III provides the desired coupled product 3. Finally, the reoxidation of Pd(0) to Pd(II) by molecular oxygen completes the catalytic cycle.

Both sulfocoumarin and alkene substrates were next investigated to extend the utility and generality of this methodology. In general, the present C3-alkenylation process was amenable to alkene substrates conjugated with a variety of functional groups from electron-donating to electron-withdrawing groups, as described in Table 2. For example, alkene substrates conjugated with ester (3a, 3b, and 3c), sulfonate (3d), amide (3e), or phosphonate (3f) groups smoothly coupled with 7-methoxy sulfocoumarin at the C3 position. When 2-methyl substituted methyl acrylate was employed as a substrate, a mixture of regioisomers 3g (endo : exo, 1 : 3) formed. The addition of the styryl group to the 3-position of the sulfocoumarin core was expected to induce a red-shift in the emission wavelength by extending the π-electron system.⁹ To our delight, various styrene substrates were compatible with the coupling reaction conditions, and modest to good yields of the desired products were obtained (3k–3q, 3w). For broad utility, the scope of the sulfocoumarin substrates was examined, and a broad range of functional groups (e.g., methoxy, benzoxy, chloro, diethylamino, alkyl, and nitro) on the sulfocoumarin core were compatible with the coupling conditions. Substitution with an electron-donating OMe group at the 7-position enhanced the reaction efficiency (3avs. 4a).

Table 2 Direct C3-olefination of sulfocoumarins with various alkenes^a

a Reactions were conducted with coumarin, alkene (2.0 equiv.), Pd(OPiv)2 (0.2 equiv.), and K2CO3 (3 equiv.) in PivOH at 80 °C under an O2 atmosphere for 3–36 h. b A 1 : 3 mixture of isomers was produced.

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The C–H alkenylation of phosphacoumarin is less reactive compared to coumarin and sulfocoumarin counterparts, and the use of AgOAc as an oxidant was required to get comparable reactivity. When a competition experiment between sulfocoumarin and coumarin substrates was carried out under the optimized conditions, the sulfocoumarin substrate reacts preferentially over coumarin in the ratio of 3 : 1 (eqn (2)).

To showcase the applicability of the developed method, the present strategy was employed as a straightforward synthetic route to benzosulfocoumarin (eqn (3)). When 3-alkenylated sulfocoumarin 3a was treated with acetone and pyrrolidine in the presence of MgSO₄, the desired benzosulfocoumarin (3aa) was produced in 82% yield via the inverse electron demand Diels–Alder reaction.¹⁰

We next examined the photophysical and spectroscopic properties of 3-alkenylsulfocoumarins, and some of the new derivatives exhibited promising photonic luminescence (Table 3). The introduction of electron-donating NEt₂ at position 7 on the sulfocoumarin core ring and the p-nitro group on styrene gave rise to notably red-shifted maxima and increased the value of Φ_F. The comparison of the photophysical properties indicated that the coumarin core possesses higher photoluminescence efficiencies than those of sulfocoumarin and phosphacoumarin counterparts.

Table 3 Photophysical properties^a

Compd	λ abs ^a (nm)	λ em ^b (nm)	ϕ F ^c
a Only the longest absorption maxima are shown. b Excited at the maximum excitation wavelength. c Fluorescence quantum yield.
	350	391	0.0007
	376	520	0.1222
	454	661	0.1624
	357	414	0.0005
	360	460	0.8307
	355	435	0.03

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In summary, we developed a new protocol for effecting the direct C–H olefination of sulfocoumarins via a palladium-catalyzed oxidative Heck reaction using O₂ as the sole oxidant. The reaction scope exhibits broad utility and functional group tolerance with complete regioselectivity. This simple and efficient approach offers convenient access to a variety of 3-vinyl and 3-styryl sulfocoumarin scaffolds, which are privileged structures in many biologically active compounds. In addition, our synthetic strategy led to the discovery of new sulfocoumarin-based derivatives that show promising photonic luminescence.

Acknowledgements

This research was supported financially by the Institute for Basic Science (IBS-R010-G1).

Notes and references

1. (a) A. Maresca, C. Temperini, H. Vu, N. B. Pham, S. A. Poulsen, A. Scozzafava, R. J. Quinn and C. T. Supuran, J. Am. Chem. Soc., 2009, 131, 3057; (b) K. Tars, D. Vullo, A. Kazaks, J. Leitans, A. Lends, A. Grandane, R. Zlubovskis, A. Scozzafava and C. T. Supuran, J. Med. Chem., 2013, 56, 293; (c) A. Grandane, S. Belyakov, P. Trapencieris and R. Zalubovskis, Tetrahedron Lett., 2012, 68, 5541.
2. (a) A. Grandane, M. Tanc, R. Zalubovskis and C. T. Supuran, Bioorg. Med. Chem., 2015, 23, 1430; (b) M. Tanc, F. Carta, M. Bozdaq, A. Scozzafava and C. T. Supuran, Bioorg. Med. Chem., 2013, 21, 4502; (c) A. Grandane, M. Tanc, R. Zalubovskis and C. T. Supuran, Bioorg. Med. Chem., 2014, 22, 1522.
3. (a) I. Moritani and Y. Fujiwara, Tetrahedron Lett., 1968, 35, 3863; (b) Y. Fujiwara, I. Moritani, S. Danno, R. Asano and S. Teranishi, J. Am. Chem. Soc., 1969, 91, 7166.
4. For selected examples, see: (a) N. P. Grimster, C. Gauntlett, C. R. A. Godfrey and M. J. Gaunt, Angew. Chem., Int. Ed., 2005, 44, 3125; (b) Y. Huang, F. Song, Z. Wang, P. Xi, N. Wu, Z. Wang, J. Lan and J. You, Chem. Commun., 2012, 48, 2864; (c) M. Miyasaka, K. Hirano, T. Satoh and M. Miura, J. Org. Chem., 2010, 75, 5421; (d) D. Kim and S. Hong, Org. Lett., 2011, 13, 4466; (e) M. Ye, G. Gao and J. Yu, J. Am. Chem. Soc., 2011, 133, 6964; (f) J. Wu, X. Cui, L. Chen, G. Jiang and Y. Wu, J. Am. Chem. Soc., 2009, 131, 13888; (g) Y. Yu, M. J. Niphakis and G. I. Georg, Org. Lett., 2011, 13, 5932; (h) D. Cheng and T. Gallagher, Org. Lett., 2009, 11, 2639; (i) L. Ming, C. Liu, W. Zhang, C. Zhou and A. Lei, Chem. Commun., 2014, 50, 1110; (j) Y. Moon, D. Kwon and S. Hong, Angew. Chem., Int. Ed., 2012, 51, 11333.
5. (a) M. Min, Y. Kim and S. Hong, Chem. Commun., 2013, 49, 196; (b) C. Kim, J. Son, B. Seo and P. Lee, Org. Lett., 2015, 17, 908; (c) M. Min and S. Hong, Chem. Commun., 2012, 48, 9613.
6. (a) E. M. Beck, N. P. Grimster, R. Hatley and M. J. Gaunt, J. Am. Chem. Soc., 2006, 128, 2528; (b) Y. Xu, Y. Chok and T. P. Loh, Chem. Sci., 2011, 2, 1822; (c) C. Zheng and S. S. Stahl, Chem. Commun., 2015, 51, 12771; (d) J. Lv, Y. Liang, P. He, Z. Cai, J. Liu and F. Huang, RSC Adv., 2015, 5, 36171; (e) W. L. Chen, Y. R. Gao, S. I. Mao, Y. F. Zhang and Y. Q. Wang, Org. Lett., 2012, 14, 5920; (f) Q. Huang, Q. Song, J. Cai, X. Zhang and S. Lin, Adv. Synth. Catal., 2013, 355, 1512.
7. For selected reviews, see: (a) A. N. Campbell and S. S. Stahl, Acc. Chem. Res., 2012, 45, 851; (b) C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780; (c) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215; (d) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094; (e) S. S. Stahl, Angew. Chem., Int. Ed., 2004, 43, 3400; (f) Y. Wu, J. Wnag, F. Mao and F. Y. Kwong, Chem. – Asian J., 2014, 9, 26.
8. (a) C. Hardacre, J. D. Holbrey and S. E. J. McMath, Chem. Commun., 2011, 367; (b) H. Esaki, F. Aoki, M. Umehara, M. Kato, T. Maegawa, Y. Monguchi and H. Sajiki, Chem. – Eur. J., 2007, 13, 4052.
9. (a) G. Kim, K. Lee, H. Kwon and H. Kim, Org. Lett., 2011, 13, 2799; (b) G. Signore, R. Nifosi, L. Albertazzi, B. Storti and R. Bizzarri, J. Am. Chem. Soc., 2010, 132, 1276; (c) M. Min, B. Kim and S. Hong, Org. Biomol. Chem., 2012, 10, 2692.
10. I. R. Pottle, P. R. Nandaluru, W. L. Benoit, D. O. Miller, L. N. Dawe and G. J. Bodwell, J. Org. Chem., 2011, 76, 9015.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5qo00294j

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