Methyl Ketones as Alkyl Halide Surrogates: A Deacylative Halogenation Approach for Strategic Functional Group Conversions.

Alkyl halides are versatile precursors to access diverse functional groups (FGs). Due to their lability, the development of surrogates for alkyl halides is strategically important for complex molecule synthesis. Given the stability and ease of derivatization inherent in common alkyl ketones, here we report a deacylative halogenation approach to convert various methyl ketones to the corresponding alkyl chlorides, bromides, and iodides. The reaction is driven by forming an aromatic byproduct, i.e., 1,2,4-triazole, in which N'-methylpicolinohydrazonamide (MPHA) is employed to form a prearomatic intermediate and halogen atom-transfer (XAT) reagents are used to quench the alkyl radical intermediate. The reaction is efficient in yielding primary and secondary alkyl halides from a wide range of methyl ketones with broad FG tolerance. It also works for complex natural-product-derived and fluoro-containing substrates. In addition, one-pot conversions of methyl ketones to various other FGs and annulations with alkenes and alkynes through deacylative halogenation are realized. Moreover, an unusual iterative homologation of alkyl iodides is also demonstrated. Finally, mechanistic studies reveal an intriguing double XAT process for the deacylative iodination reaction, which could have implications beyond this work.

Deacylative Thiolation by Redox-Neutral Aromatization-Driven C-C Fragmentation of Ketones.

Herein we report the development of deacylative thiolation of diverse methyl ketones. The reaction is redox-neutral, and heavy-metal-free, which provides a new way to introduce thioether groups site-specifically to unactivated aliphatic positions. It also features excellent functional group tolerance and broad substrate scope, thus allowing late-stage derivatization. The process benefits from efficient condensation between the activation reagent and ketone substrates, which triggers aromatization-driven C-C fragmentation and rapid radical coupling with thiosulfonates. Experimental and computational mechanistic studies suggest the involvement of a radical chain pathway.

Site-Specific and Degree-Controlled Alkyl Deuteration via Cu-Catalyzed Redox-Neutral Deacylation.

Deuterated organic compounds have become increasingly important in many areas; however, it remains challenging to install deuterium site-selectively to unactivated aliphatic positions with control of the degree of deuteration. Here, we report a Cu-catalyzed degree-controlled deacylative deuteration of diverse alkyl groups with the methylketone (acetyl) moiety as a traceless activating group. The use of N-methylpicolino-hydrazonamide (MPHA) promotes efficient aromatization-driven C-C cleavage. Mono-, di-, and trideuteration at specific sites can be selectively achieved. The reaction is redox-neutral with broad functional group tolerance. The utility of this method has been demonstrated in forming a complete set of deuterated ethyl groups, merging with the Diels-Alder reaction, a net devinylative deuteration, and the synthesis of the d2-analogue of Austedo.

Rhodium-Catalyzed Atroposelective Access to Axially Chiral Olefins via C-H Bond Activation and Directing Group Migration.

Axially chiral open-chain olefins represent an underexplored class of chiral platform. In this report, two classes of tetrasubstituted axially chiral acyclic olefins have been accessed in excellent enantioselectivity and regioselectivity via C-H activation of (hetero)arenes assisted by a migratable directing group en route to coupling with sterically hindered alkynes. The coupling of indoles bearing an N-aminocarbonyl directing group afforded C-N axially chiral acrylamides with the assistance of a racemic zinc carboxylate additive. DFT studies suggest a ß-nitrogen elimination-reinsertion pathway for the directing group migration. Meanwhile, the employment of N-phenoxycarboxamide delivered C-C axially chiral enamides via migration of the oxidizing directing group. Experiments suggest that in both cases the (hetero)arene substrate adopts a well-defined orientation during the C-H activation, which in turn determines the disposition of the alkyne in migratory insertion. Synthetic applications of representative chiral olefins are demonstrated.

Olefination via Cu-Mediated Dehydroacylation of Unstrained Ketones.

The dehydroacylation of ketones to olefins is realized under mild conditions, which exhibits a unique reaction pathway involving aromatization-driven C-C cleavage to remove the acyl moiety, followed by Cu-mediated oxidative elimination to form an alkene between the α and ß carbons. The newly adopted N'-methylpicolinohydrazonamide (MPHA) reagent is key to enable efficient cleavage of ketone C-C bonds at room temperature. Diverse alkyl- and aryl-substituted olefins, dienes, and special alkenes are generated with broad functional group tolerance. Strategic applications of this method are also demonstrated.

Deacylation-Aided C─H Alkylative Annulation through C─C Cleavage of Unstrained Ketones.

Arene- and heteroarene-fused rings are pervasive in biologically active molecules. Direct annulation between a C─H bond on the aromatic core and a tethered alkyl moiety provides a straightforward approach to access these scaffolds; however, such a strategy is often hampered by the need of special reactive groups and/or less compatible cyclization conditions. It would be synthetically appealing if a common native functional group can be used as a handle to enable a general C─H annulation with diverse aromatic rings. Here, we show a deacylative annulation strategy for preparing a large variety of aromatic-fused rings from linear simple ketone precursors. The reaction starts with homolytic cleavage of the ketone α C─C bond via a pre-aromatic intermediate, followed by a radical-mediated dehydrogenative cyclization. Using widely available ketones as the robust radical precursors, this deconstructive approach allows streamlined assembly of complex polycyclic structures with broad functional group tolerance.

Divergent Coupling of Anilines and Enones by Integration of C-H Activation and Transfer Hydrogenation.

Cp*RhIII /IrIII complexes are known to play important roles in both C-H activation and transfer hydrogenation (TH). However, these two areas evolved separately. They have been integrated in redox- and chemodivergent coupling reactions of N-pyridylanilines with enones. The iridium-catalyzed coupling with enones leads to the efficient synthesis of tetrahydroquinolines through TH from i PrOH. Counterintuitively, i PrOH does not serve as the sole hydride source, and the major reaction pathway involves disproportionation of a dihydroquinoline intermediate, followed by the convergent and iterative reduction of quinolinium species.

Rh(III)-Catalyzed Acceptorless Dehydrogenative Coupling of (Hetero)arenes with 2-Carboxyl Allylic Alcohols.

Rhodium(III)-catalyzed C-H activation of (hetero)arenes and redox-neutral coupling with 2-carboxyl allylic alcohols has been realized for the construction of ß-aryl ketones. This reaction occurred efficiently at a relatively low catalyst loading via initial dehydrogenative alkylation to give a ß-keto carboxylic acid, followed by decarboxylation.

Access to Substituted Propenoic Acids via Rh(III)-Catalyzed C-H Allylation of (Hetero)Arenes with Methyleneoxetanones.

An efficient synthesis of disubstituted acrylic acids has been realized via Rh(III)-catalyzed C-H activation of (hetero)arenes and coupling with four-membered methyleneoxetanones under redox-neutral conditions. In most cases, the reactions are silver-free, and the products are exclusively E-selective with a broad substrate scope. The transformation proceeds via ortho C-H activation followed by selective olefin insertion and ß-oxygen elimination.

Rhodium(iii)-catalyzed regio- and stereoselective benzylic α-fluoroalkenylation with gem-difluorostyrenes.

Rhodium(iii)-catalyzed mild benzylic α-fluoroalkenylation of 8-methylquinolines with gem-difluorostyrenes has been developed. This reaction occurred via C-H activation and C-F cleavage and is applicable to a wide range of substrates, leading to the synthesis of Z-alkenyl fluorides under mild and redox-neutral conditions with high regio- and stereoselectivity.

Sulfoxonium Ylides as a Carbene Precursor in Rh(III)-Catalyzed C-H Acylmethylation of Arenes.

Sulfoxonium ylides act as an efficient carbene precursor in rhodium(III)-catalyzed C-H acylmethlyation of a variety of arenes assisted by different chelating groups, and both aryl- and alkyl-substituted ß-carbonyl sulfoxonium ylides are applicable. The system proceeded under redox-neutral conditions with a broad scope, high efficiency, and functional group tolerance.

Rhodium(III)-Catalyzed Synthesis of Naphthols via C-H Activation of Sulfoxonium Ylides.

Direct and efficient synthesis of 1-naphthols has been realized via Rh(III)-catalyzed C-H activation of sulfoxonium ylides and subsequent annulation with alkynes, where the sulfoxonium ylide functioned as a new traceless bifunctional directing group. This reaction occurred under redox-neutral conditions with a broad substrate scope.

Rhodium(III)-Catalyzed Acylation of C(sp3)-H Bonds with Cyclopropenones.

Rh(III)-catalyzed activation and acylation of sp3 C-H bonds has been realized with diarylcyclopropenone as an acylating reagent. Both benzylic C-H in 8-methylquinolines and unactivated C-H in 2-alkylpyridines are applicable in this C-H acylation reaction, providing enones in good yields under redox-neutral conditions.

Catalyst-Controlled Regiodivergent Alkyne Insertion in the Context of C-H Activation and Diels-Alder Reactions: Synthesis of Fused and Bridged Cycles.

Rhodium(III)- and cobalt(III)-catalyzed C-H activation of indoles and coupling with 1,6-enynes is discussed. Under rhodium(III) catalysis, the alkyne insertion follows 2,1-regioselectivity with a subsequent type-I intramolecular Diels-Alder reaction (IMDA) to afford [6,5]-fused cycles. When catalyzed by the cobalt(III) congener, 1,2-insertion of the alkyne is preferred, and followed by a rare type-II IMDA, thus leading to bridged [3,3,1]-cycles. This selectivity of the alkyne insertion was mainly tuned by the steric sensitivity of the catalyst.

Cp*Rh(III)-Catalyzed Mild Addition of C(sp3)-H Bonds to α,ß-Unsaturated Aldehydes and Ketones.

A Rh(III)-catalyzed addition of benzylic C(sp3)-H bond to α,ß-unsaturated ketones/aldehydes has been realized, leading to efficient synthesis of γ-aryl ketones/aldehydes. This atom-economic reaction proceeded under mild and redox-neutral conditions with a broad substrate scope. Besides benzylic C-H, allylic C-H bonds are also applicable when assisted by O-methyl ketoxime directing groups.

Cobalt(III)-Catalyzed Regio- and Stereoselective α-Fluoroalkenylation of Arenes with gem-Difluorostyrenes.

A cobalt(III)-catalyzed α-fluoroalkenylation of different arenes with readily available gem-difluorostyrenes has been realized under mild and redox-neutral conditions. This reaction occurs via a C-H activation pathway and offers a step-economical access to various 1,2-diaryl-substituted monofluoroalkenes in excellent Z selectivity in moderate to excellent yields.

Rh(III)- and Zn(II)-Catalyzed Synthesis of Quinazoline N-Oxides via C-H Amidation-Cyclization of Oximes.

Quinazoline N-oxides have been prepared from simple ketoximes and 1,4,2-dioxazol-5-ones via Rh(III)-catalyzed C-H activation-amidation of the ketoximes and subsequent Zn(II)-catalyzed cyclization. The substrate scope and functional group compatibility were examined. The reaction features relay catalysis by Rh(III) and Zn(II).

Cobalt(III)-Catalyzed C-C Coupling of Arenes with 7-Oxabenzonorbornadiene and 2-Vinyloxirane via C-H Activation.

Co(III)-catalyzed mild C-C couplings of arenes with strained rings such as 7-oxabenzonorbornadienes and 2-vinyloxirane have been realized. The transformation is proposed to undergo ortho C-H activation, olefin insertion, and subsequent ß-oxygen elimination. A broad range of synthetically useful functional groups are compatible, thus providing a new entry to access diversely 2-functionalized indoles.

Access to Structurally Diverse Quinoline-Fused Heterocycles via Rhodium(III)-Catalyzed C-C/C-N Coupling of Bifunctional Substrates.

Rhodium(III)-catalyzed C-H activation of heteroarenes and functionalization with bifunctional substrates such as anthranils allows facile construction of quinoline-fused heterocycles under redox-neutral conditions. The couplings feature broad substrate scope and provide step-economical access to two classes of quinoline-fused condensed heterocycles.

Rhodium(III)-Catalyzed Mild Alkylation of (Hetero)Arenes with Cyclopropanols via C-H Activation and Ring Opening.

The rhodium(III)-catalyzed regioselective alkylation of (hetero)arenes using cyclopropanols as a reactive and efficient coupling partner under oxidative conditions has been developed. This coupling occurred at room temperature via C-H activation of arenes and C-C cleavage of cyclopropanols. Various types of (hetero)arenes (indolines, carbazole, tetrahydrocarbazole, pyrrole, thiophene, etc.) were all successfully reacted under the present conditions. This protocol provides the facile and efficient construction of C7-alkylated indoline scaffolds.