Transition Metal-Catalyzed Direct Alkenylation of Arenes with Removable Directing

In recent years, directing group-assisted transition metal-catalyzed oxidative alkenylations have been achieved with great progress, and a large variety of decorated styrenes were prepared from this protocol. However, the directing groups are always difficult to be removed or transformed to other functional groups under mild conditions. This restriction has greatly limited the structural diversity of the products and subsequent application in the synthesis of complex molecules.

Therefore, the necessity of novel, readily accessible substrates containing easily attachable and removable directing groups is obvious (Scheme 24).^54aa

Introduction

Scheme 24 Comparison of two strategies for C–H bond alkenylations.

In 2008, Miura⁶³ succeeded in preparing a series of meta-substituted stilbenes and 2- or 3-vinylindole derivatives 71 from readily available carboxylic acids and alkenes through precisely ordered ortho-olefination/decarboxylation under palladium and rhodium catalysis (Scheme 25).

For the unsubstituted benzoic acid 25, double olefination took place at the 2- and 6-positions to form selective 1,3-dialkenylbenzenes 72 which are important organic intermediates in material science (Scheme 25b).

Scheme 25 Palladium- and rhodium-catalyzed oxidative alkenylations of carboxylic acids.

In 2011, Zhang’s group⁶⁴ disclosed an efficient method for the palladium(II)-catalyzed alkenylation and arylation of arenes 73 by using 2-pyridyl sulfoxide as the directing group (Scheme 26). The directing group can easily be removed or converted to another synthetically useful moiety.

63 (a) A. Maehara, H. Tsurugi, T. Satoh, M. Miura, Org. Lett. 2008, 10, 1159–1162; (b) S. Mochida, K. Hirano, T.

Satoh, M. Miura, Org. Lett. 2010, 12, 5776–5779.

64 M. Yu, Z. Liang, Y. Wang, Y. Zhang, J. Org. Chem. 2011, 76, 4987–4994.

Scheme 26 Palladium-catalyzed alkenylations of substituted 2-pyridyl sulfoxides 73.

Subsequently, Huang and coworkers⁶⁵ developed the triazene-directed aromatic C–H bond activation followed by oxidative coupling to synthesize olefinated arenes 71 (Scheme 27). This versatile directing group can participate in various transformations such as facile removal, halogen exchange, and direct C–H cross-coupling.

Scheme 27 Rhodium-catalyzed oxidative alkenylations of triazene 75.

Ackermann’s⁶⁶ and subsequently Wang’s⁶⁷ group reported ruthenium(II)-catalyzed oxidative C–

H alkenylations using carbamates as the directing groups. Substrates 77 decorated with different functional groups, such as halides, were tolerated very well and afforded the corresponding products 78 in good yields with high regio- and stereo-selectivities. Importantly, the carbamate directing group was easily removed under basic reaction conditions to deliver the desired phenol derivatives 71 (Scheme 28).

Scheme28 Ruthenium-catalyzed C–H alkenylations of aryl carbamates 77.

Besides this, You’s group⁶⁸ found that (2-pyridyl)methylether can serve as an efficient directing group for amino acid ligand-accelerated ortho-C–H olefination of aryl (2-pyridyl)methyl ethers 79.

Introduction

A variety of differently substituted substrates 79 could be employed in this transformation, giving the ortho-alkenylated products 80 in good to excellent yields with high regioselectivity. Especially, non-activated alkenes can also serve as coupling partners. Additionally, the scope of this methodology can be expanded to the diolefination of substrate 79. At last, the 2-pyridylmethyl group can easily be removed through several different methods giving the ortho-alkenyl phenols 71 or ortho-alkylphenols (Scheme 29).

Scheme 29 Palladium-catalyzed C–H alkenylations of aryl (2-pyridyl)methyl ethers 79.

The 2-pyridylsulfonyl directing group was found to be efficient for the palladium-catalyzed alkenylation of pyrroles and indoles 81, as was reported by Carretero and coworkers (Scheme 30a).^69a Both electron-withdrawing and electron-donating substituents on the aryl ring of the indole 81 did not significantly affect the transformation. It is noteworthy that substituted alkenes 82, such as methylmethacrylate, α-ethylacrolein, and methyl styrene also reacted smoothly under this reaction condition. Subsequently, it was found that this directing group was also suitable for carbazole substrates 85 when changing the oxidant to N-fluoro-2,4,6-trimethylpyridinium triflate ([F⁺] in Scheme 30b).^70b Importantly, the 2-pyridylsulfonyl group can easily be removed under reductive conditions to generate the potential bioactive NH-free pyrrole, indole and carbazole derivatives 84 and 87 (Scheme 30).

a)

69 (a) A. Garca-Rubia, R. G. Arras, J. C. Carretero, Angew. Chem. Int. Ed. 2009, 48, 6511–6515; (b) B. Urones, R.

G. Arrayás, J. C. Carretero, Org. Lett. 2013, 15, 1120–1123.

b)

Scheme 30 Palladium-catalyzed C–H alkenylations of substituted indoles, pyrroles and carbazoles.

Furthermore, Ge⁷⁰ and Gevorgyan⁷¹ introduced silanol as an effective directing group for the direct olefination of arenes through palladium-catalyzed C–H activation. Substrates 88 decorated with both electron-donating and electron-withdrawing groups were successfully transformed under this reaction conditions to afford the desired products 89 in high yields. Some important functional groups, such as chloride and ester, were well tolerated in this catalytic system. In addition, the silanol group can be removed in the presence of TBAF at ambient temperature.

Importantly, the C–H activation/desilylation transformation of benzyldiisopropylsilanol and phenol-derived silanols 88 can be achieved in an one-pot or a semi-one-pot fashion which provided a novel and attractive approach for the synthesis of ortho-alkenyl-substituted styrene derivatives 71 (Scheme 31).

Scheme 31 Palladium-catalyzed direct alkenylations of arenes 88 with silanol as a removable directing group.

Additionally, Song⁷² and Wang⁷³ reported highly efficient and selective ruthenium-catalyzed C2-olefination of indoles 90 by using the N,N-dimethylcarbamoyl as a removable directing group.

In this olefination reaction, the non-activated styrene derivatives 82 successfully participated as well. Other related N-heteroarenes such as pyrroles and carbazoles could also be used and yielded the corresponding products in good yields with high site-selectivity. The employment of O2 as the terminal oxidant allows performing this reaction in an economical fashion (Scheme 32).

Introduction

Scheme 32 Ruthenium-catalyzed C–H alkenylations of indoles 90.

Afterwards, rhodium-catalyzed C(sp²)–H bond alkenylation by using the thioether directing group has been achieved by Shi’s group.⁷⁴ Interestingly, monoalkenylated products 93 could be obtained selectively by using MeOH as the solvent, whereas only dialkenylation can be achieved in tBuOH. The directing group can easily be removed at ambient temperature in the presence of Raney nickel (Scheme 33). Notably, the double C–H bond functionalization of alkenes could not be preserved under these conditions, thus providing o-tolylpropanoates 94, which are also important substrates in organic synthesis.

Scheme 33 Controllable (di)alkenylations of benzyl thioether 92 through rhodium-catalyzed C–H activation.

So far, great progress has been achieved in transition metal-catalyzed oxidative alkenylations with different removable directing groups. These protocols usually use the σ-chelating directing groups, which lead to ortho-selectivity through the formation of conformationally rigid five- to seven-membered cyclic intermediates. Despite the broad utility of this approach, proximity-driven reactivity prevents the activation of remote C–H bonds. Subsequently, Yu^75a–d developed a template approach to activate remote meta C–H bonds of several different classes of substrates (Scheme 34). The detailed strategy was the installation of a linear “end-on” coordinative nitrile group which can be accommodated in a macrocyclic cyclophane-like pre-transitionstate, thus overcoming the inherent limitations of traditional directed ortho C–H activation. After the removal of the directing group, a series of 7-vinylquinoline derivates 100 and diacids 97, which

74 X. Zhang, Q. Zhu,Y. Zhang, Y. Li, Z.-J. Shi, Chem. Eur. J. 2013, 19, 11898–11903.

75 (a) D. Leow, G. Li, T.-S. Mei, J.-Q. Yu, Nature 2012,486, 518–522; (b) Y.-F. Yang, G.-J. Cheng, P. Liu, D. Leow, T.-Y. Sun, P. Chen, X. Zhang, J.-Q. Yu, Y.-D. Wu, K. N. Houk, J. Am. Chem. Soc. 2014, 136, 344–355;(c) R. Tang, G. Li, J.-Q. Yu, Nature 2014, 215–220; (d) Y. Deng, J.-Q. Yu, Angew. Chem. Int. Ed. 2015, 54, 888–891; (e) For the review on this topic, see: (f) J. Yang, Org. Biomol. Chem.2015, 13, 1930–1941.

are commonly used as building blocks in drug discovery, were obtained.

a)