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Derivatives

In 2015, the group of Li achieved the first meta‐C–H olefination of N‐methyl‐phenylethylamine derivatives using the 2‐cyanobenzoyl group as the CF (Scheme 2.26) [34], followed by the isolated examples of meta‐C–H olefination of tertiary phenylethylamine derivatives mentioned in Section 2.2.3.2 [33]. In presence of Pd(OAc)₂ and Ac‐Gly‐OH under nitrogen atmosphere, the reaction proceeded smoothly with a broad scope of substrate, and the directing template is structurally very simple and commercially available. Moreover, to increase the potential of application of direct C–H transformations in organic synthesis, using 2‐cyanobenzoyl group as the common original directing functionality to access regiodivergent C–H activation was also demonstrated in a sequential remote‐selective C–H olefination of 2‐fluorophenylethylamine (Scheme 2.27). Notably, the first remote‐selective C–H olefination occurs with the secondary amide 67 leaving the proximal aromatic ortho‐C

H bond intact in an ortho‐selective manner and proceeds with an imidamide directing group that was formed through cyclization of the 2‐cyanobenzoyl motif. The desired meta‐directing template was reconstructed with methylation by using LiHMDS as the base to afford substrate 69 after hydrogenation. Finally, the second C–H olefination of 69 led to the production of tetra‐substituted phenylethylamide 70 in a meta‐selective manner under standard reaction conditions, enabling the building of molecular complexity in a concise manner.

Chemical reaction depicts the meta-C–H olefination of phenylethylamine derivatives.

Scheme 2.26 meta‐C–H olefination of phenylethylamine derivatives.

Source: Modified from Li et al. [34].

Chemical reaction depicts the sequential remote-selective regiodivergent C–H olefination of 2-fluorophenylethylamine.

Scheme 2.27 Sequential remote‐selective regiodivergent C–H olefination of 2‐fluorophenylethylamine.

2.2.3.4 N‐Heterocyclic Arene Derivatives

Due to the prevalence of N‐heterocycles in biologically important molecules, selective activation of a C

H bond of N‐heterocyclic arenes is a conceptually intriguing and synthetically important challenge. For example, to selective activation of C

H bonds at C7 of bicyclic tetrahydroquinolines, a novel template will be required since a highly strained intermediate with a tricyclic cyclophane structure will be encountered. In 2014, Yu and coworkers found the template conformation was a critical factor in controlling remote meta‐ or ortho‐selectivity, and when a fluorine substituent was introduced into the auxiliary, the conformation that favored the meta‐selectivity would be dominant in the presence of the MPAA ligand Ac‐Gly‐OH (Scheme 2.28a) [31]. Intriguingly, when the substituents in the auxiliary scaffold were switched to methyl groups, high ortho‐C–H activation at C7 of bicyclic tetrahydroquinolines was observed. With this new directing template by taking advantage of conformation control, remote meta‐C–H olefination of tetrahydroquinolines was achieved in good yield and with high levels of site selectivity (Scheme 2.28b).

Chemical reaction depicts the (a) Conformation promoted meta-selective activation. (b) meta-C–H olefination of tetrahydroquinoline derivatives. .

Scheme 2.28 (a) Conformation promoted meta‐selective activation. (b) meta‐C–H olefination of tetrahydroquinoline derivatives.

Source: (a) Modified from Tang et al. [31].

Subsequently, Movassaghi, Yu, and coworkers developed a novel nitrile‐based sulfonamide directing template for indolines, since previous directing template for tetrahydroquinolines was not viable presumably due to that the aryl group of indolines is more electron rich and the new skeleton requires a different template to accommodate (Scheme 2.29a) [35]. The new electronically withdrawing sulfonamide linkage is crucial for the meta‐selective C–H functionalization of electron‐rich indolines that are otherwise highly reactive toward electrophilic palladation at the electron‐rich C5‐positions. With this new template and the established reaction conditions, a range of synthetically useful and advanced indoline analogues were efficiently olefinated at the C6 position, meta to the nitrogen atom. Moreover, the sulfonamide template could be removed at room temperature with magnesium turnings in methanol to afford meta‐alkylated indoline derivatives through simultaneous reduction of the newly installed olefins (Scheme 2.29b).

Chemical reaction depicts the (a) meta-C–H olefination of indoline derivatives. (b) Removal of directing template.

Scheme 2.29 (a) meta‐C–H olefination of indoline derivatives. (b) Removal of directing template.

Source: (a) Modified from Yang et al. [35].

Based on the success of meta‐C–H olefination of electron‐rich indolines, the meta‐C–H arylation of indolines under previously reported meta‐C–H cross‐coupling reaction conditions for hydrocinnamic acid derivatives was also achieved, demonstrating the versatility of this new template for diverse meta‐C–H functionalizations of indolines (Scheme 2.30) [35]. Several indoline substrates reacted with arylboronic acid pinacol esters to afford meta‐arylated indoline derivatives in synthetically useful yields.

Chemical reaction depicts the meta-C–H arylation of indoline derivatives.

Scheme 2.30 meta‐C–H arylation of indoline derivatives.

Source: Modified from Yang et al. [35].

Since the meta‐hydroxylated indolines are biologically important, meta‐C–H acetoxylation of indolines using the well‐established oxidation conditions was also investigated (Scheme 2.31) [35]. It was found that although the meta‐acetoxylated indolines were obtained as the major products, the meta‐selectivity was much lower than olefination and para‐acetoxylated indolines (∼10%) were also formed probably due to the electrophilic palladation at the electron‐rich C5 position under the reaction conditions. It should be mentioned that the nonsubstituted indoline substrate was not compatible with these oxidation conditions, since the indoline was readily oxidized to give a mixture of unidentified compounds instead. Further investigation of this

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