Carboxylate-assisted ruthenium(II)-catalyzed C–H activations of monodentate amides with conjugated alkenes

Abstract

Carboxylate assistance enabled efficient and chemoselective ruthenium(II)-catalyzed hydroarylations of α,β-unsaturated ketones via C–H activation on monodentate benzamides. Furthermore, the versatile ruthenium(II) catalyst set the stage for oxidative C–H functionalization on acetanilides, furnishing diversely decorated quinolines in a step-economical fashion.

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Transition metal-catalyzed C–H functionalizations have been recognized as increasingly viable tools for the step-economical formation of C–C bonds.¹ Particularly, metal-catalyzed hydroarylation reactions²via C–H activation are attractive because of their excellent atom-economy.³ Early findings by Lewis and Smith⁴ as well as Murai and co-workers^5,6 indicated the considerable power of ruthenium(0) complexes as effective catalysts for hydroarylations through chelation-assisted C–H activation, which were proposed to proceed by oxidative addition of the C–H bond. Practical advances were achieved by Darses and Genet and co-workers through the in situ formation of [RuH₂(PPh₃)₄] from [RuCl₂(p-cymene)]₂, NaO₂CH and PPh₃,⁷ thus avoiding sensitive and expensive ruthenium(0) complexes, such as [Ru₃(CO)₁₂], [RuH₂(PPh₃)₄], [Ru(CO)₂(PPh₃)₃], or [RuH₂(CO)(PPh₃)₃]. As a part of our ongoing program on transition-metal-catalyzed C–H functionalizations,⁸ we recently developed ruthenium(II)-catalyzed hydroarylations via carboxylate-assisted C–H cleavages.⁹ Despite of these remarkable advances, the synthetically useful family of electron-deficient olefins,¹⁰ such as α,β-unsaturated ketones were thus far not viable substrates. While such transformations were accomplished with among others relatively expensive rhodium¹¹ or rhenium¹² catalysts, notable progress with ruthenium(II) complexes was very recently made by Chatani and co-workers highlighting that hydroarylations of α,β-unsaturated ketones could be realized, given that substrates displaying bidentate directing groups were employed.^13,14 Herein, we report on an expedient access to β-aryl ketones and quinolines through ruthenium(II)-catalyzed hydroarylations and oxidative cascade annulations with α,β-unsaturated ketones, respectively. It is noteworthy that the ruthenium(II)-catalyzed C–H activation strategy was realized with synthetically useful amides as atom-economical mono-dentate directing groups.

We initiated our studies by testing the feasibility of the envisioned ruthenium(II)-catalyzed C–H alkylation of benzamide 1a with methyl vinyl ketone (2a) (Table 1). Interestingly, RuCl₂(PPh₃)₃, which was previously used for hydroarylations with bidentate directing groups,¹³ unfortunately, failed to deliver the desired product 3aa with the assistance of the simple amide 1a (entries 1 and 2). Similar trends were observed when employing [RuCl₂(p-cymene)]₂ in combination with various additives (entries 3–5).

Table 1 Optimization of ruthenium(II)-catalyzed C–H alkylation with benzamide 1a^a

Entry	Additive A [mol%]	Additive B [equiv.]	Solvent	Yield^b [%]
a General reaction conditions: 1a (0.50 mmol), 2a (1.00 mmol), [RuCl2(p-cymene)]2 (5.0 mol%), KO2CMes (30 mol%), MesCO2H (1.00 equiv.), solvent (2.0 mL), under N2, 120 °C, 20 h. b Isolated yield. c RuCl2(PPh3)3 (10 mol%). d Without [Ru].
1	NaOAc (30)	—	PhMe	—^c
2	NaOAc (30)	—	H2O	—^c
3	KPF6 (20)	—	H2O	—
4	KPF6 (20)	NaOAc (2.00)	H2O	—
5	PPh3 (15)	NaO2CH (0.30)	PhMe	—
6	KOAc (30)	HOAc (1.00)	H2O	64
7	KO2CMes (30)	MesCO2H (0.30)	H2O	69
8	KO 2 CMes (30)	MesCO 2 H (1.00)	H 2 O	80
9	KO2CMes (30)	—	H2O	51
10	KO2CMes (30)	MesCO2H (1.00)	H2O	—^d
11	—	MesCO2H (1.00)	H2O	29

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A significant improvement was realized using cocatalytic amounts of KOAc and stoichiometric amounts of HOAc as the additives with H₂O as inexpensive and nontoxic reaction medium^15,16 (entry 6). Improved yields of the target compound 3aa were obtained when employing the bulky MesCO₂K and MesCO₂H as the cocatalysts (entry 7). Here, the use of stoichiometric MesCO₂H provided the optimal results (entry 8). Furthermore, it is worth noting that the omission of either of the two additives resulted in significantly reduced yields of the alkylated benzamide 3aa (entries 9–11).

With the optimized reaction conditions in hand, we tested its versatility in the C–H alkylation with weakly coordinating^17,18 amides 1 (Scheme 1). Notably, in these chelation-assisted direct C–H alkylations, both electron-rich as well as electron-poor para-substituted benzamides 1a–1f were identified as viable substrates. Moreover, a variation of the substitution pattern on the amide nitrogen with benzyl (1g–i), cyclohexyl (1j) or methoxyethyl (1k) groups, did not significantly alter the catalytic efficacy, while primary amides proved to be unsuitable substrates. More sterically hindered ortho-substituted benzamide 1l was successfully alkylated as well, albeit the desired product 3la was obtained in a slightly reduced yield. The widely applicable ruthenium(II) catalyst was not limited to aromatic benzamides 1, but the reaction of heteroaromatic indole derivative 1m also led to the site-selective C–H alkylation. In addition, among a representative set of α,β-unsaturated ketones, vinyl alkyl ketones 2b and 2c gave the alkylated products 3db and 3dc, respectively, in high yields. Interestingly, acetanilide 4a was identified as a suitable substrate for hydroarylations likewise.

Scheme 1 Scope of the ruthenium(II)-catalyzed hydroarylation via C–H activation.

Intramolecular competition experiments with meta-methyl- or meta-trifluoromethyl-substituted arenes 1n–1p were largely governed by steric interactions to site-selectively deliver the alkylated products 3na–3pa at the sterically less hindered position (Scheme 2). In contrast, hydroarylations of the meta-substituted benzamides 1q and 1r featured a considerable ortho-orienting effect¹⁹ of the heteroatom substituent, thus leading to the site-selective formation of the sterically more hindered compounds 3qa and 3ra, respectively, as the sole products.

Scheme 2 Site-selective hydroarylations with meta-substituted arenes 1a.

Remarkably, the well-defined, single-component [Ru(MesCO₂)₂(p-cymene)]²⁰ catalyst 7 furnished the desired product, which illustrated the importance of carboxylate assistance (Scheme 3).²¹

Scheme 3 C–H alkylation with single-component ruthenium(II) biscarboxylate catalyst 7.

An intermolecular competition experiment between arenes with different directing groups clearly highlighted that amides 1 are more powerful than ketone 8 in the chelation-assisted C–H alkylation (Scheme 4).

Scheme 4 Competition experiment between amide 1 and ketone 8.

Given the unique reactivity of our carboxylate-assisted ruthenium(II) catalysis, we performed mechanistic studies to unravel its mode of action. To this end, strong evidence for a H/D exchange was gathered from C–H functionalization with starting material 1b in the presence of the deuterated solvent D₂O (Scheme 5).^9c This observation can be rationalized in terms of a reversible C–H metalation step in the ruthenium(II)-catalyzed direct hydroarylation.

Scheme 5 H/D exchange experiment.

Moreover, the ruthenium-catalyzed C–H alkylation with isotopically labeled substrate [D₅]-1a showed a negligible kinetic isotope effect (KIE) of k_H/k_D ≈ 1.3 for the intermolecular KIE experiment (Scheme 6). This data again suggests the C–H bond metalation not to be the rate-determining step.

Scheme 6 Kinetic isotope effect (KIE) studies.

Based on these experimental findings and previous mechanistic insight, we propose a plausible catalytic cycle to involve an initial reversible C–H bond activation by carboxylate assistance, subsequent migratory insertion, and rate-determining reductive elimination (Scheme 7).

Scheme 7 Proposed catalytic cycle for carboxylate-assisted hydroarylation.

Inspired by our previous work on oxidative alkenylations,²² we subsequently probed the oxidative annulation of differently decorated acetanilides 4 with α,β-unsaturated ketone 2a (Scheme 8). Importantly, the catalytic system was not limited to the use of electron-rich N-phenylacetamides 4a–4c, but also allowed for the transformation of electron-poor substrates 4. Valuable electrophilic functional groups, such as fluoro, chloro, bromo and ester substituents, were well tolerated by the versatile ruthenium(II) catalyst. An intramolecular competition experiment with substrate 4h bearing a meta-methyl substituent showed that the cyclization was governed by steric interactions to deliver the product 6ha in high yield.

Scheme 8 Scope of the oxidative alkene annulations with substituted acetanilides 4.

Based on our previous studies,²² we propose an initial C–H ruthenation to yield cycloruthenated complex 9 (Scheme 9). Thereafter, a migratory insertion of alkene 2 occurs to generate the intermediate 10. Then, β-hydride-elimination furnishes the product of oxidative alkenylation 11, while the catalytically active ruthenium(II) complex is regenerated by a sequence of reductive elimination and reoxidation. The desired quinoline 6 is obtained through an intramolecular nucleophilic attack of the anilide in intermediate 11, followed by β-elimination of acetic acid to deliver the desired product 6.

Scheme 9 Plausible catalytic cycle.

Conclusions

In summary, we have developed unprecedented ruthenium(II)-catalyzed hydroarylations and oxidative annulations on benzamides 1 and acetanilides 4 with α,β-unsaturated ketones 2 through C–H activation. The use of benzamides with monodentate directing groups renders our approach highly atom-economical, and the aqueous reaction conditions makes the process environmentally-benign. Detailed experimental mechanistic studies indicated a facile H/D-exchange. In addition, a cascade oxidative annulation of α,β-unsaturated ketones 2a with acetanilides 4 was developed to deliver decorated quinolines 6 in a highly step-economic fashion.

Acknowledgements

Support by the European Research Council under the European Community's Seventh Framework Program (FP7 2007–2013)/ERC Grant agreement no. 307535, and the Chinese Scholarship Council (fellowship to J.L.) is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5qo00167f

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