Rhodium(III)-Catalyzed Atroposelective Synthesis of Biaryls by C-H Activation and Intermolecular Coupling with Sterically Hindered Alkynes.

Reported herein is the atroposelective synthesis of biaryl NH isoquinolones by RhIII -catalyzed C-H activation of benzamides and intermolecular [4+2] annulation for a broad scope of 2-substituted 1-alkynylnaphthalenes, as well as sterically hindered, symmetric diarylacetylenes. The axial chirality is constructed based on dynamic kinetic transformation of the alkyne in redox-neutral annulation with benzamides, with alkyne insertion being stereodetermining. The reaction accommodates both benzamides and heteroaryl carboxamides and proceeds in excellent regioselectivity (if applicable) and enantioselectivities (average 91.8 % ee). An enantiomerically and diastereomerically pure rhodacyclic complex was prepared and offers insight into enantiomeric control of the coupling system, wherein the steric interactions between the amide directing group and the alkyne substrate dictate both the regio- and enantioselectivity.

Rhodium-Catalyzed Enantioselective Oxidative [3+2] Annulation of Arenes and Azabicyclic Olefins through Twofold C-H Activation.

C-H bond activation is mostly limited to ortho selectivity. Activation of both ortho and meta C-H bonds constitutes a particularly important strategy for annulation, but has rarely been studied in enantioselective systems. Reported herein is rhodium(III)-catalyzed asymmetric [3+2] transannulation of arenes with 7-azabenzonorbornadienes. Two distinct classes of arenes have been identified as substrates, and the coupling proceeded with high enantioselectivity and excellent diastereoselectivity through sequential activation of ortho and meta C-H bonds.

Experimental and Theoretical Studies on Rhodium-Catalyzed Coupling of Benzamides with 2,2-Difluorovinyl Tosylate: Diverse Synthesis of Fluorinated Heterocycles.

Fluorinated heterocycles play an important role in pharmaceutical and agrochemical industries. Herein, we report on the synthesis of four types of fluorinated heterocycles via rhodium(III)-catalyzed C-H activation of arenes/alkenes and versatile coupling with 2,2-difluorovinyl tosylate. With N-OMe benzamide being a directing group (DG), the reaction delivered a monofluorinated alkene with the retention of the tosylate functionality. Subsequent one-pot acid treatment allowed the efficient synthesis of 4-fluoroisoquinolin-1(2H)-ones and 5-fluoropyridin-2(1H)-ones. When N-OPiv benzamides were used, however, [4 + 2] cyclization occurred to provide gem-difluorinated dihydroisoquinolin-1(2H)-ones. Synthetic applications have been demonstrated and the ready availability of both the arene and the coupling partner highlighted the synthetic potentials of these protocols. Mechanistically, these two processes share a common process involving N-H deprotonation, C-H activation, and olefin insertion to form a 7-membered rhodacycle. Thereafter, different reaction pathways featuring ß-F elimination and C-N bond formation are followed on the basis of density functional theory (DFT) studies. These two pathways are DG-dependent and led to the open chain and cyclization products, respectively. The mechanistic rationale was supported by detailed DFT studies. In particular, the origins of the intriguing selectivity in the competing ß-F elimination versus C-N bond formation were elucidated. It was found that ß-F elimination is a facile event and proceeds via a syn-coplanar transition state with a low energy barrier. The C-N bond formation proceeds via a facile migratory insertion of the Rh-C(alkyl) into the Rh(V) amido species. In both reactions, the migratory insertion of the alkene is turnover-limiting, which stays in good agreement with the experimental studies.

Rhodium-Catalyzed C-S and C-N Functionalization of Arenes: Combination of C-H Activation and Hypervalent Iodine Chemistry.

Rhodium-catalyzed sulfonylation, thioetherification, thiocyanation, and other heterofunctionalizations of arenes bearing a heterocyclic directing group have been realized. The reaction proceeds by initial Rh(III) -catalyzed C-H hyperiodination of arene at room temperature followed by uncatalyzed nucleophilic functionalization. A diaryliodonium salt is isolated as an intermediate, which represents umpolung of the arene substrate, in contrast to previous studies that suggested umpolung of the coupling partner.

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.

Nitrone Directing Groups in Rhodium(III)-Catalyzed C-H Activation of Arenes: 1,3-Dipoles versus Traceless Directing Groups.

Functionalizable directing groups (DGs) are highly desirable in C-H activation chemistry. The nitrone DGs are explored in rhodium(III)-catalyzed C-H activation of arenes and couplings with cyclopropenones. N-tert-butyl nitrones bearing a small ortho substituent coupled to afford 1-naphthols, where the nitrone acts as a traceless DG. In contrast, coupling of N-tert-butyl nitrones bearing a bulky ortho group follows a C-H acylation/[3+2] dipolar addition pathway to give bicyclics. The coupling of N-arylnitrones follows the same acylation/[3+2] addition process but delivers different bicyclics.

Ruthenium(II)-Catalyzed C-H Activation of Imidamides and Divergent Couplings with Diazo Compounds: Substrate-Controlled Synthesis of Indoles and 3H-Indoles.

Indoles are an important structural motif that is commonly found in biologically active molecules. In this work, conditions for divergent couplings between imidamides and acceptor-acceptor diazo compounds were developed that afforded NH indoles and 3H-indoles under ruthenium catalysis. The coupling of α-diazoketoesters afforded NH indoles by cleavage of the C(N2 )-C(acyl) bond whereas α-diazomalonates gave 3H-indoles by C-N bond cleavage. This reaction constitutes the first intermolecular coupling of diazo substrates with arenes by ruthenium-catalyzed C-H activation.

The Mechanism of N-O Bond Cleavage in Rhodium-Catalyzed C-H Bond Functionalization of Quinoline N-oxides with Alkynes: A Computational Study.

Metal-catalyzed C-H activation not only offers important strategies to construct new bonds, it also allows the merge of important research areas. When quinoline N-oxide is used as an arene source in C-H activation studies, the N-O bond can act as a directing group as well as an O-atom donor. The newly reported density functional theory method, M11L, has been used to elucidate the mechanistic details of the coupling between quinoline N-O bond and alkynes, which results in C-H activation and O-atom transfer. The computational results indicated that the most favorable pathway involves an electrophilic deprotonation, an insertion of an acetylene group into a Rh-C bond, a reductive elimination to form an oxazinoquinolinium-coordinated Rh(I) intermediate, an oxidative addition to break the N-O bond, and a protonation reaction to regenerate the active catalyst. The regioselectivity of the reaction has also been studied by using prop-1-yn-1-ylbenzene as a model unsymmetrical substrate. Theoretical calculations suggested that 1-phenyl-2-quinolinylpropanone would be the major product because of better conjugation between the phenyl group and enolate moiety in the corresponding transition state of the regioselectivity-determining step. These calculated data are consistent with the experimental observations.

Rh(III)-catalyzed oxidative annulation of 2-phenylimidazo[1,2-a]pyridines with alkynes: mono versus double C-H activation.

Rh(III)-catalyzed C-H activation of 2-phenylimidazo[1,2-a]pyridines in divergent oxidative coupling with alkynes has been achieved. Selective mono versus 2-fold C-H activation has been attained under condition control. When AgOAc was used as an oxidant, the coupling afforded 5,6-disubstituted naphtho[1',2':4,5]imidazo[1,2-a]pyridines as a result of initial nitrogen chelation-assisted C-H activation at the benzene ring followed by rollover C-H activation. In contrast, the reaction afforded a fused isoquinolinium salt as a result of C-C and C-N coupling when AgBF4 was employed as a co-oxidant. A rhodacyclic intermediate has been isolated.

Rhodium(iii)-catalyzed annulation of arenes with alkynes assisted by an internal oxidizing N-O bond.

Rh(iii)-catalyzed C-H activation of 3-aryl-dihydroisoxazoles in the coupling with diarylacetylenes has been developed under redox-neutral conditions. This reaction occurred under mild conditions with no by-product, and the N-O bond functions as an oxidizing directing group, leading to efficient synthesis of isoquinolines functionalized with a proximal secondary alcohol.

Rh(III)- and Ir(III)-catalyzed C-H alkynylation of arenes under chelation assistance.

An efficient Rh(III)- and Ir(III)-catalyzed, chelation-assisted C-H alkynylation of a broad scope of (hetero)arenes has been developed using hypervalent iodine-alkyne reagents. Heterocycles, N-methoxy imines, azomethine imines, secondary carboxamides, azo compounds, N-nitrosoamines, and nitrones are viable directing groups to entail ortho C-H alkynylation. The reaction proceeded under mild conditions and with controllable mono- and dialkynylation selectivity when both mono- and dialkynylation was observed. Rh(III) and Ir(III) catalysts exhibited complementary substrate scope in this reaction. The synthetic applications of the coupled products have been demonstrated in subsequent derivatization reactions. Some mechanistic studies have been conducted, and two Rh(III) complexes have been established as key reaction intermediates. The current C-H alkynylation system complements those previously reported under gold or palladium catalysis using hypervalent iodine reagents.

Rh(III) -catalyzed hydroacylation reactions between N-sulfonyl 2-aminobenzaldehydes and olefins.

Metal-catalyzed hydroacylation of olefins represents an important atom-economic synthetic process in CH activation. For the first time highly efficient Rh(III) Cp*-catalyzed hydroacylation was realized in the coupling of N-sulfonyl 2-aminobenzaldehydes with both conjugated and aliphatic olefins, leading to the synthesis of various aryl ketones. Occasionally, oxidative coupling occurred when a silver(I) oxidant was used.

Rhodium(III)-catalyzed C-H alkynylation of azomethine ylides under mild conditions.

Rh(III)-catalyzed efficient C-H alkynylation of azomethine imines with alkynylated hypervalent iodine is developed under mild conditions. A broad scope of azomethine imines and alkyne substrates is established. The azomethine acts as a masked aldehyde and circumvents its poor directing effect.

Rhodium(III)-catalyzed C-C and C-O coupling of quinoline N-oxides with alkynes: combination of C-H activation with O-atom transfer.

[Cp*Rh(III)]-catalyzed C-H activation of arenes assisted by an oxidizing N-O or N-N directing group has allowed the construction of a number of hetercycles. In contrast, a polar N-O bond is well-known to undergo O-atom transfer (OAT) to alkynes. Despite the liability of N-O bonds in both C-H activation and OAT, these two important areas evolved separately. In this report, [Cp*Rh(III)] catalysts integrate both areas in an efficient redox-neutral coupling of quinoline N-oxides with alkynes to afford α-(8-quinolyl)acetophenones. In this process the N-O bond acts as both a directing group for C-H activation and as an O-atom donor.

Palladium-Catalyzed Regio- and Enantioselective Hydrophosphination of gem-Difluoroallenes.

Chiral allylic phosphines and gem-difluoroalkenes are both important structural motifs in various bioactive molecules, chiral ligands, and natural products. These two motifs are now integrated, and we herein report a straightforward and atom-economical enantioselective hydrophosphination of gem-difluoroallenes using disubstituted phosphines. A wide array of enantioenriched fluorinated allylic phosphines has been accessed with excellent regio- and enantioselectivity and high efficiency. Synthetic and catalytic applications of phosphine products have been demonstrated.

Rhodium-Catalyzed Enantioselective Addition of Heteroarenium Salts Enabled by Nucleophilic Cyclization of 2-Alkynylanilines.

Transition-metal-catalyzed cyclative coupling of 2-alkynylanilines provides a feasible routine for accessing functionalized indoles. Herein, a rhodium-catalyzed highly enantioselective addition of heteroarenium salts is presented, which is enabled by the nucleophilic cyclization of 2-alkynylanilines. It offers feasible protocols to access enantioenriched functionalized indoles tethered to 1,2-dihydropyridine and 1,2-dihydroquinoline motifs with excellent enantioselectivities.

Cobalt/Rhodium-Catalyzed Diversified Amidation of Benzocyclobutenols via C-C Cleavage under Catalyst and Condition Control.

Cobalt(III) and rhodium(III)-catalyzed regio- and chemoselective amidation of benzocyclobutenols has been realized using dioxazolone as the amidating reagent to afford three classes of C-N-coupled products via ß-carbon elimination of the benzocyclobutenol. The Co(III)-catalyzed coupling initially afforded an isolable o-(N-acylamino)arylmethyl ketone, which could further cyclize to the corresponding indole derivatives under condition control. In contrast, efficient stepwise diamidation has been achieved under Rh(III) catalyst control. The chemoselectivities are jointly controlled by the catalyst and reactions conditions.

Palladium-catalyzed oxidative Heck coupling reaction for direct synthesis of 4-arylcoumarins using coumarins and arylboronic acids.

An efficient protocol for the direct synthesis of 4-arylcoumarins via palladium-catalyzed oxidative Heck coupling reaction of coumarins and arylboronic acids was developed. 4-Arylcoumarins were obtained in moderate to excellent yields, and the reaction also showed tolerance toward functional groups such as hydro, methoxy, diethylamino, nitro, and chloro groups.

Palladium-Catalyzed Synthesis of Functionalized Indoles by Acylation/Allylation of 2-Alkynylanilines with Three-Membered Rings.

Palladium-catalyzed synthesis of 3-acyl and -allyl indoles has been realized by merging nucleophilic cyclization of ortho-alkynylanilines with ring opening of three-membered rings such as cyclopropenones and gem-difluorinated cyclopropanes. These functionalized indoles were obtained in moderate to high yields with high stereoselectivity in both cases. This protocol provides an alternative method toward functionalized indoles under mild and redox-neutral conditions.

Palladium-Catalyzed [3 + 2] Annulation of Aryl Halides with 7-Oxa- and 7-Azabenzonorbornadienes via C(sp2 or sp3)-H Activation.

A series of epoxybenzo[k]fluoranthenes, epoxy-5H-benzo[b]fluorenes, and their aza analogues have been accessed via palladium-catalyzed exo-selective [3 + 2] annulation between aryl halides and 7-oxa- and 7-azabenzonorbornadienes. The reaction is initiated by the oxidative addition of a carbon-halogen bond, with intramolecular C(sp2 or sp3)-H activation being a key step. The enantioselective version of the reaction was also briefly explored.