Controllable mono-/di-alkenylation of aryl alkyl thioethers tuned by oxidants via Pd-catalysis

Abstract

Oxidant-controlled selective mono-/di-alkenylation of aryl C–H bonds via Pd-catalysis is reported. The substrate scopes for both the mono- and di-alkenylation were good. Thioether was used as the directing group and the product can be transformed to a useful sulfoxide-olefin ligand by simple oxidation in quantitative yield.

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Transition-metal-catalyzed oxidative alkenylation (Fujiwara reaction) has attracted much attention in recent years¹ due to its high atom-economy, high efficiency, low waste production and potential applications in complex molecule synthesis.² To approach the high regio- and chemo-selectivity, a directing strategy³ has been well applied in such alkenylations. While two C–H bonds beside the directing group exist in the molecule, it is always difficult to control the selectivity between mono- and di-alkenylation and a mixture of them was usually obtained (Scheme 1, (1)). In the past, some successful strategies have been well established to approach high selectivity between mono- and di-alkenylation, such as by the amount of alkenylating reagents, oxidants, reaction time and temperature,^4,5 by solvent effects^6,7 and by others,^8–11 although in almost all cases multi-factors were changed to tune the selectivity. Herein, we report a controllable selective mono- or di-alkenylation of aryl C–H bonds by changing only one factor for the first time, with thioether as a new directing group. The oxidants with different anions were found to be crucial to approach high selectivity. Although oxidants have been found to tune the regio-selectivities of C–H activation,¹² no report on the oxidant controlled mono-/di-functionalization selectivity exists.

Scheme 1 Selectivities of mono-functionalization and di-functionalization in the transition-metal-catalyzed C–H bond activation.

Although S-contained groups were considered not to be good directing groups in C–H activation due to their easy oxidation and potential ability to poison the late transition-metal catalysts, recent advances unveiled the success to adapt such groups as directing groups in C–H activation.^13,14 We recently reported the alkenylation of benzyl methyl sulfide with thioether as a directing group, in which a five-membered rhodacycle was considered as a key intermediate.^6b The extension of such studies showed that homobenzyl methyl sulfide showed very low reactivity, probably arising from the less rigid 6-membered metallocycle intermediate.^13d We envisioned that biphenyl-2-yl(methyl)sulfane (1a) could be the appropriate substrate by enhancing the rigidity of the key intermediate to promote the efficiency. Structurally, the desired product is indeed important since the sulfide group can be transformed into different functionalities, for example, the sulfoxide-olefin ligands.^15,16

Although initial screenings of rhodium catalysts based on our previous work showed low efficiency (see ESI†), palladium catalysts showed very good activity. With AgOAc as the oxidant, the mono-alkenylated product could be obtained as the major product in 78% NMR yield (Table 1, entry 1). Interestingly and importantly, further screening showed that the selectivity of the mono-alkenylation and di-alkenylation could be controlled by the oxidant. When AgOTFA was used as an oxidant, the mono-alkenylated product was obtained in 92% NMR yield, while only changing the oxidant to AgNO₃ gave the di-alkenylated product in 93% NMR yield (Table 1, entries 6 and 7). Further investigation revealed that the catalyst loading could be reduced to 5 mol% and the yield was not affected when the reaction was conducted on a 0.2 mmol scale (Table 1, entries 12 and 13).

Table 1 Condition screening for the thioether directed selective C–H bond alkenylation

a NMR yield with CH₂Br₂ as an internal standard. b 5 mol% of catalyst. c 2 mL DCE. d Isolated yield.

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We first investigated the substrate scope for the mono-alkenylation (Table 2). For the thioethers, both electron rich (3n, 3o, 3p and 3v) and electron poor (3l, 3m, 3q–3t, 3u) ones are tolerated very well. The group compatibility of this monoalkenylation (3l–3m, 3q–3v) showed its wide substrate scope. Notably, methyl ethenesulfonate is also a suitable alkenylating reagent in this reaction (3w), expanding the application of this method. It should be noted that the di-substituted alkene was also an applicable coupling partner, and the isomerized product was obtained in relative lower efficiency (3x). Apart from a variety of acrylates (3a–3d), styrene derivatives also reacted smoothly in moderate to good yields (3e–3k). Although the efficiency of electron-rich styrene was low, the yield can be improved by blocking the other ortho-position with the methyl group (3j and 3k).

Table 2 Substrate scope for mono-alkenylation

Conditions: 1 (0.1 mmol or 0.2 mmol), 2 (2.0 eq.), Pd(OAc)₂ (5 mol%) and AgOTFA (2.0 eq.) were mixed in DCE (0.1 M) at 120 °C under air for 6 h.a 10 mol% of Pd(OAc)₂ was used.b After the reaction, another 2 (2.0 eq.), Pd(OAc)₂ (5 mol%) and AgOTFA (1.0 eq.) were added to react for further 10 h for full conversion.

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Under di-alkenylation conditions, with only the change of the oxidant to AgNO₃, a variety of alkenes and bi-phenyl arenes were tolerated very well, providing good to excellent yields (Table 3). A variety of acrylates, both alkyl (4a–4d) and aryl acrylates (4e), reacted smoothly to give the desired products in high yields. For the thioethers, both electron-rich and electron-deficient substituents can be tolerated very well (4f, 4g). Functional groups like acyl were untouched (4h).

Table 3 Substrate scope for di-alkenylation

Conditions: 1 (0.1 mmol or 0.2 mmol), 2 (2.0 eq.), Pd(OAc)₂ (5 mol%) and AgNO₃ (2.0 eq.) were mixed in DCE (0.1 M) at 120 °C under air for 6 h.a 10 mol% of Pd(OAc)₂ was used.

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To explore the potential applications, both reactions (mono-alkenylation and di-alkenylation) were scaled up to the 1 mmol scale and the yields were not affected intensively, although for the di-alkenylation a longer reaction time was needed (Scheme 2, eqn (1) and (2)). In addition, the mono-alkenylated product can be transformed to the sulfoxide-olefin ligand in quantitative yield by simple oxidation (dr = 60 : 40) (Scheme 2, eqn (3)).

Scheme 2 Large scale reaction and transformation of the product to synthesize the ligand.

In order to gain some insights into the mechanism, we conducted several control experiments. When the S-atom was changed to the O-atom, the ether directed alkenylation also occurred, albeit in a lower yield and low selectivity, showing the importance of the S-atom (Scheme 3, eqn (4)).^13a,17 The competing experiments showed that the electron rich arenes reacted much faster (Scheme 4, eqn (5) and eqn (6)). The deuterium labeling experiment showed that the C–H bond activation was not reversible and gave a KIE value of 5.6, indicating that the C–H activation was possibly involved in the turnover limiting step (Scheme 4, eqn (7) and eqn (8)). As a result, the C–H bond activation was proposed to undergo an electrophilic metalation pathway.

Scheme 3 Ether as the directing group.

Scheme 4 Mechanistic studies.

On the other hand, the oxidant controlled selective C–H bond mono- and di-functionalization is interesting and the reason is not clear at this stage. To clarify the reason for the oxidant controlled selectivity, we investigated the additive effect (Scheme 5) by adding some inorganic salts. We found that when NaNO₃ was added to the mono-alkenylation system, the ratio of mono-alkenylated product reduced. And when NaOAc was added to the di-alkenylation system, the ratio of the di-alkenylated product reduced. However, when NaOTFA was added to the di-alkenylation system, no obvious change in mono-/di-selectivity was observed. Based on these results, we conclude that it is possibly the coordinating ability of the counter anion of the oxidant that affected the selectivity.

Scheme 5 The effect of additives on the selectivity.

Based on the above mentioned experiments and mechanism studies, the detailed mechanism is depicted in Scheme 6. Pd-catalyzed first C–H bond activation formed intermediate I, alkene insertion and β-H elimination produced Pd(0) complex III with the mono-alkenylated product coordinating as a ligand, which was oxidized to Pd(II) complex IV. Weak coordinating NO₃⁻ can be exchanged by another molecule of alkene (2) and further promote the second C–H bond activation (Path a). However, the relatively strong coordinating ⁻OAc could not be exchanged by another molecule of alkene, so the coordination of another molecule of thioether (1) released the mono-alkenylated product (3) (Path b).

Scheme 6 Proposed mechanism.

In summary, with our thioether directing group, we realized the selective mono- and di-alkenylation of aryl C–H bonds in the bi-phenyl framework controlled by the oxidant, mainly by the coordinating ability of the counter anion of the oxidant. The substrate scope for both the mono-alkenylation and the di-alkenylation is very good. A widely used sulfoxide-olefin ligand was also obtained by simple transformation of the product. More detailed mechanism studies and other reactions based on the thioether directing group are underway.

Notes and references

1. (a) V. T. Trepohl and M. Oestreich, Palladium-catalyzed arylation reactions of alkenes (Mizoroki-Heck reaction and related processes), Wiley-VCH Verlag GmbH & Co. KGaA, 2009, p. 221; (b) B. Karimi, H. Behzadnia, D. Elhamifar, P. F. Akhavan, F. K. Esfahani and A. Zamani, Synthesis, 2010, 1399; (c) R. Rossi, F. Bellina and M. Lessi, Synthesis, 2010, 4131; (d) T. Satoh and M. Miura, Synthesis, 2010, 3395; (e) T. Satoh and M. Miura, Chem. – Eur. J., 2010, 16, 11212; (f) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2011, 40, 5068; (g) J. Le Bras and J. Muzart, Chem. Rev., 2011, 111, 1170; (h) C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780; (i) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215; (j) G. Song, F. Wang and X. Li, Chem. Soc. Rev., 2012, 41, 3651; (k) S. I. Kozhushkov and L. Ackermann, Chem. Sci., 2013, 4, 886.
2. (a) P. Thansandote and M. Lautens, Chem. – Eur. J., 2009, 15, 5874; (b) W. R. Gutekunst and P. S. Baran, Chem. Soc. Rev., 2011, 40, 1976; (c) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew. Chem., Int. Ed., 2012, 51, 8960; (d) J. Wencel-Delord and F. Glorius, Nat. Chem., 2013, 5, 369.
3. (a) L. V. Desai, K. J. Stowers and M. S. Sanford, J. Am. Chem. Soc., 2008, 130, 13285; (b) D. A. Colby, R. G. Bergman and J. A. Ellman, Chem. Rev., 2010, 110, 624; (c) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147; (d) K. M. Engle, T.-S. Mei, M. Wasa and J.-Q. Yu, Acc. Chem. Res., 2012, 45, 788; (e) C. Wang and Y. Huang, Synlett, 2013, 145.
4. (a) S. Murai, F. Kakiuchi, S. Sekine, Y. Tanaka, A. Kamatani, M. Sonoda and N. Chatani, Nature, 1993, 366, 529; (b) N. Umeda, K. Hirano, T. Satoh and M. Miura, J. Org. Chem., 2009, 74, 7094; (c) F. W. Patureau and F. Glorius, J. Am. Chem. Soc., 2010, 132, 9982.
5. (a) A. V. Gulevich, F. S. Melkonyan, D. Sarkar and V. Gevorgyan, J. Am. Chem. Soc., 2012, 134, 5528; (b) T. Satoh, Y. Kawamura, M. Miura and M. Nomura, Angew. Chem., Int. Ed. Engl., 1997, 36, 1740; (c) Z. Ni, Q. Zhang, T. Xiong, Y. Zheng, Y. Li, H. Zhang, J. Zhang and Q. Liu, Angew. Chem., Int. Ed., 2012, 51, 1244; (d) Z. Liang, R. Feng, H. Yin and Y. Zhang, Org. Lett., 2013, 15, 4544.
6. (a) A. Garcia-Rubia, R. G. Arrayas and J. C. Carretero, Angew. Chem., Int. Ed., 2009, 48, 6511; (b) X.-S. Zhang, Q.-L. Zhu, Y.-F. Zhang, Y.-B. Li and Z.-J. Shi, Chem. – Eur. J., 2013, 19, 11898.
7. (a) D. R. Armstrong, S. C. Ball, D. Barr, W. Clegg, D. J. Linton, L. C. Kerr, D. Moncrieff, P. R. Raithby, R. J. Singer, R. Snaith, D. Stalke, A. E. H. Wheatley and D. S. Wright, J. Chem. Soc., Dalton Trans., 2002, 2505; (b) K. S. L. Chan, M. Wasa, X. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2011, 50, 9081.
8. M. Aoyama, T. Fukuhara and S. Hara, J. Org. Chem., 2008, 73, 4186.
9. T.-S. Mei, R. Giri, N. Maugel and J.-Q. Yu, Angew. Chem., Int. Ed., 2008, 47, 5215.
10. (a) D.-H. Wang, K. M. Engle, B.-F. Shi and J.-Q. Yu, Science, 2010, 327, 315; (b) S. Harada, H. Yano and Y. Obora, ChemCatChem, 2013, 5, 121; (c) J. He, S. Li, Y. Deng, H. Fu, B. N. Laforteza, J. E. Spangler, A. Homs and J.-Q. Yu, Science, 2014, 343, 1216.
11. (a) X. Wang, T.-S. Mei and J.-Q. Yu, J. Am. Chem. Soc., 2009, 131, 7520; (b) S. Rakshit, C. Grohmann, T. Besset and F. Glorius, J. Am. Chem. Soc., 2011, 133, 2350; (c) M. Iwasaki, M. Iyanaga, Y. Tsuchiya, Y. Nishimura, W. Li, Z. Li and Y. Nishihara, Chem. – Eur. J., 2014, 20, 2459.
12. (a) T. A. Dwight, N. R. Rue, D. Charyk, R. Josselyn and B. DeBoef, Org. Lett., 2007, 9, 3137; (b) D. R. Stuart, E. Villemure and K. Fagnou, J. Am. Chem. Soc., 2007, 129, 12072; (c) S. Potavathri, A. S. Dumas, T. A. Dwight, G. R. Naumiec, J. M. Hammann and B. DeBoef, Tetrahedron Lett., 2008, 49, 4050; (d) Z. Liang, J. Zhao and Y. Zhang, J. Org. Chem., 2009, 75, 170; (e) Y. Li, W.-H. Wang, S.-D. Yang, B.-J. Li, C. Feng and Z.-J. Shi, Chem. Commun., 2010, 46, 4553.
13. (a) B. Sezen, R. Franz and D. Sames, J. Am. Chem. Soc., 2002, 124, 13372; (b) D. Shabashov and O. Daugulis, J. Am. Chem. Soc., 2010, 132, 3965; (c) J. Yao, M. Yu and Y. Zhang, Adv. Synth. Catal., 2012, 354, 3205; (d) M. Yu, Y. Xie, C. Xie and Y. Zhang, Org. Lett., 2012, 14, 2164.
14. (a) R. Samanta and A. P. Antonchick, Angew. Chem., Int. Ed., 2011, 50, 5217; (b) T. Wesch, F. R. Leroux and F. Colobert, Adv. Synth. Catal., 2013, 355, 2139; (c) K. Nobushige, K. Hirano, T. Satoh and M. Miura, Org. Lett., 2014, 16, 1188; (d) B. Wang, C. Shen, J. Yao, H. Yin and Y. Zhang, Org. Lett., 2014, 16, 46.
15. Y. Li and M.-H. Xu, Chem. Commun., 2014, 50, 3771.
16. G. Chen, J. Gui, L. Li and J. Liao, Angew. Chem., Int. Ed., 2011, 50, 7681.
17. (a) A. Iglesias, R. Alvarez, A. R. de Lera and K. Muniz, Angew. Chem., Int. Ed., 2012, 51, 2225; (b) J. Oyamada and Z. Hou, Angew. Chem., Int. Ed., 2012, 51, 12828; (c) Z. Ren, F. Mo and G. Dong, J. Am. Chem. Soc., 2012, 134, 16991; (d) G. Li, D. Leow, L. Wan and J.-Q. Yu, Angew. Chem., Int. Ed., 2013, 52, 1245.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4qo00172a

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