Axially Chiral 2-Hydroxybiaryls by Palladium-Catalyzed Enantioselective C-H Activation.

This article describes the discovery and development of a palladium-catalyzed asymmetric C-H olefination of 2-hydroxybiaryls. The strategy allows a direct assembly of optically active, axially chiral 2-substituted-2'-hydroxybiaryls from readily available precursors and demonstrates that the native hydroxy unit of the substrates can work as an efficient directing group for the C-H activation. This represents a substantial advantage over other approaches that require the preinstallation of metal coordinating units. The simplicity of the approach and versatility of the products allow a practical and efficient synthesis of a broad variety of optically active binaphthyl derivatives.

Chiral Ligands Based on Binaphthyl Scaffolds for Pd-Catalyzed Enantioselective C-H Activation/Cycloaddition Reactions.

We report the first examples of the use of a new class of ligands (NOBINAc) for performing asymmetric C-H activations using palladium catalysts. These ligands combine the axial chirality of binaphthyl scaffolds with the bifunctional and bidentate coordination properties of mono-N-protected amino acids (MPAAs), which are well-known to favor Pd-promoted C-H activations via concerted metalation-deprotonation mechanisms. We demonstrate that our new ligands enable substantially higher enantioselectivities than MPAAs in the assembly of 2-benzazepines through formal (5 + 2) cycloadditions between homobenzyltriflamides or o-methylbenzyltriflamides and allenes.

Transition-Metal-Catalyzed Annulations Involving the Activation of C(sp3 )-H Bonds.

The selective functionalization of C(sp3 )-H bonds using transition-metal catalysis is among the more attractive transformations of modern synthetic chemistry. In addition to its inherent atom economy, such reactions open unconventional retrosynthetic pathways that can streamline synthetic processes. However, the activation of intrinsically inert C(sp3 )-H bonds, and the selection among very similar C-H bonds, represent highly challenging goals. In recent years there has been notable progress tackling these issues, especially with regard to the development of intermolecular reactions entailing the formation of C-C and C-heteroatom bonds. Conversely, the assembly of cyclic products from simple acyclic precursors using metal-catalyzed C(sp3 )-H bond activations has been less explored. Only recently has the number of reports on such annulations started to grow. Herein we give an overview of some of the more relevant advances in this exciting topic.

Assembly of Tetrahydroquinolines and 2-Benzazepines by Pd-Catalyzed Cycloadditions Involving the Activation of C(sp3)-H Bonds.

Cycloaddition reactions are among the most practical strategies to assemble cyclic products; however, they usually require the presence of reactive functional groups in the reactants. Here, we report a palladium-catalyzed formal (4 + 2) cycloaddition that involves the activation of C(sp3)-H bonds and provides a direct, unconventional entry to tetrahydroquinoline skeletons. The reaction utilizes amidotolyl precursors and allenes as annulation partners, and is catalyzed by Pd(II) precursors in combination with specific N-acetylated amino acid ligands. The reactivity can be extended to ortho-methyl benzylamides, which provide for the assembly of appealing tetrahydro-2-benzazepines in a formal (5 + 2) annulation process.

Kinetic Resolution of Allyltriflamides through a Pd-Catalyzed C-H Functionalization with Allenes: Asymmetric Assembly of Tetrahydropyridines.

Enantioenriched, six-membered azacycles are essential structural motifs in many products of pharmaceutical or agrochemical interest. Here we report a simple and practical method for enantioselective assembly of tetrahydropyridines, which is paired to a kinetic resolution of α-branched allyltriflamides. The reaction consists of a formal (4+2) cycloaddition between the allylamine derivatives and allenes and is initiated by a palladium(II)-catalyzed C-H activation process. Both the chiral allylamide precursors and the tetrahydropyridine adducts were successfully obtained in high yields, with excellent enantioselectivity (up to 99% ee) and selectivity values of up to 127.

Photocatalytic trifluoromethoxylation of arenes and heteroarenes in continuous-flow.

The first example of photocatalytic trifluoromethoxylation of arenes and heteroarenes under continuous-flow conditions is described. Application of continuous-flow microreactor technology allowed to reduce the residence time up to 16 times in comparison to the batch procedure, while achieving similar or higher yields. In addition, the use of inorganic bases was demonstrated to increase the reaction yield under batch conditions.

Rhodium(III)-Catalyzed Intramolecular Annulations of Acrylic and Benzoic Acids to Alkynes.

Rh(III) catalysts can promote a formal (4 + 2) intramolecular oxidative annulation between acrylic or benzoic acid derivatives and alkynes. The reaction, which involves a C-H activation process, allows for a rapid assembly of appealing bicyclic pyran-2-ones and tricyclic isocoumarin derivatives in moderate to good yields. The α-pyrone moiety of the products provides for further manipulations to obtain relatively complex cyclic skeletons in a very simple manner.

Palladium-Catalyzed, Enantioselective Formal Cycloaddition between Benzyltriflamides and Allenes: Straightforward Access to Enantioenriched Isoquinolines.

Benzyl and allyltriflamides can engage in Pd-catalyzed oxidative (4+2) annulations with allenes, to produce highly valuable tetrahydroisoquinoline or dihydropyridine skeletons. The reaction is especially efficient when carried out in the presence of designed N-protected amino acids as metal ligands. More importantly, using this type of chiral ligands, it is possible to perform desymmetrizing, annulative C-H activations of prochiral diarylmethylphenyl amides, and thus obtain the corresponding isoquinolines with high enantiomeric ratios.

Rhodium-Catalyzed Annulation of ortho-Alkenyl Anilides with Alkynes: Formation of Unexpected Naphthalene Adducts.

o-Alkenyl N-triflylanilides underwent rhodium(III)-catalyzed oxidative annulations with alkynes to produce different types of naphthylamides in a process which involves the cleavage of two C-H bonds. Remarkably, besides formal dehydrogenative (4C+2C) cycloadducts, the reaction also produces variable amounts of isomeric naphthylamides, whose formation requires a formal migration of the alkenyl moiety from the ortho to the meta position of the anilide. The annulation reaction can be efficiently carried out in the absence of external oxidants, such as Cu(OAc)2 .

Rhodium(III)-Catalyzed Annulation of 2-Alkenyl Anilides with Alkynes through C-H Activation: Direct Access to 2-Substituted Indolines.

A RhIII complex featuring an electron-deficient η5 -cyclopentadienyl ligand catalyzed an unusual annulation between alkynes and 2-alkenyl anilides to form synthetically appealing 2-substituted indolines. Formally, the process can be viewed as an allylic amination with concomitant hydrocarbonation of the alkyne. Mechanistic experiments indicate that this transformation involves an unusual rhodium migration with a concomitant 1,5-H shift.

Iridium(I)-Catalyzed Intramolecular Hydrocarbonation of Alkenes: Efficient Access to Cyclic Systems Bearing Quaternary Stereocenters.

A catalytic, versatile and atom-economical C-H functionalization process that provides a wide variety of cyclic systems featuring methyl-substituted quaternary stereocenters is described. The method relies on the use of a cationic IrI -bisphosphine catalyst, which promotes a carboxamide-assisted activation of an olefinic C(sp2 )-H bond followed by exo-cyclization to a tethered 1,1-disubstituted alkene. The extension of the method to aromatic and heteroaromatic C-H bonds, as well as developments on an enantioselective variant, are also described.

Palladium-Catalyzed Formal (5 + 2) Annulation between ortho-Alkenylanilides and Allenes.

2-Alkenyltriflylanilides react with allenes upon treatment with catalytic amounts of Pd(OAc)2 and Cu(II) to give highly valuable 2,3-dihydro-1H-benzo[b]azepines, in good yields, and with very high regio- and diastereoselectivities. Density functional theory (DFT) calculations suggest that the C-H activation of the alkenylanilide involves a classical concerted metalation-deprotonation (CMD) mechanism.

Palladium(II)-Catalyzed Annulation between ortho-Alkenylphenols and Allenes. Key Role of the Metal Geometry in Determining the Reaction Outcome.

2-Alkenylphenols react with allenes, upon treatment with catalytic amounts of Pd(II) and Cu(II), to give benzoxepine products in high yields and with very good regio- and diastereoselectivities. This contrasts with the results obtained with Rh catalysts, which provided chromene-like products through a pathway involving a ß-hydrogen elimination step. Computational studies suggest that the square planar geometry of the palladium is critical to favor the reductive elimination process required for the formation of the oxepine products.

Concise, Enantioselective, and Versatile Synthesis of (-)-Englerin†A Based on a Platinum-Catalyzed [4C+3C] Cycloaddition of Allenedienes.

A practical synthesis of (-)-englerin A was accomplished in 17 steps and 11 % global yield from commercially available achiral precursors. The key step consists of a platinum-catalyzed [4C+3C] allenediene cycloaddition that directly delivers the trans-fused guaiane skeleton with complete diastereoselectivity. The high enantioselectivity (99 % ee) stems from an asymmetric ruthenium-catalyzed transfer hydrogenation of a readily assembled diene-ynone. The synthesis also features a highly stereoselective oxygenation, and a late-stage cuprate alkylation that enables the preparation of previously inaccessible structural analogues.

Metal-Catalyzed Annulations through Activation and Cleavage of C-H Bonds.

The exponential increase in the number of catalytic transformations that involve a metal-promoted activation of hitherto considered inert C-H bonds is promoting a fundamental change in the field of synthetic chemistry. Although most reactions involving C-H activations consist of simple functionalizations or additions, recent years have witnessed an upsurge in related transformations that can be formally considered as cycloaddition processes. These transformations are particularly appealing from a synthetic perspective because they allow the conversion of readily available substrates into highly valuable cyclic products in a rapid and sustainable manner. In many cases, these annulations involve the formation of metallacyclic intermediates that resemble those proposed for standard metal-catalyzed cycloadditions of unsaturated precursors.

Amide-Directed Formation of Five-Coordinate Osmium Alkylidenes from Alkynes.

The amide-directed synthesis of five-coordinate osmium alkylidene derivatives from alkynes is reported. These types of complexes, which have been elusive until now because of the tendency of osmium to give hydride alkylidyne species, are prepared by reaction of the dihydride OsH2Cl2(PiPr3)2 (1) with terminal alkynes containing a distal amide group. Complex 1 reacts with N-phenylhex-5-ynamide and N-phenylhepta-6-ynamide to give OsCl2{=C(CH3)(CH2) n NH(CO)Ph}(PiPr3)2 (n = 3 (2), 4 (3)). The relative position of carbonyl and NH groups in the organic substrates has no influence on the reaction. Thus, treatment of 1 with N-(pent-4-yn-1-yl)benzamide leads to OsCl2{=C(CH3)(CH2)3NHC(O)Ph}(PiPr3)2 (4). The new compounds are intermediate species in the cleavage of the C-C triple bond of the alkynes. Under mild conditions, they undergo the rupture of the Cα-CH3 bond of the alkylidene, which comes from the alkyne triple bond, to afford six-coordinate hydride-alkylidyne derivatives. In dichloromethane, complex 2 gives a 10:7 mixture of OsHCl2{≡C(CH2)3C(O)NHPh}(PiPr3)2 (5) and OsHCl2{≡CCH(CH3)(CH2)2C(O)NHPh}(PiPr3)2 (6). The first complex contains a linear separation between the alkylidyne Cα atom and the amide group, whereas the spacer is branched in the second complex. In contrast to the case for 2, complex 4 selectively affords OsHCl2{≡C(CH2)3NHC(O)Ph}(PiPr3)2 (7). In spite of their instability, these compounds give the alkylidene-allene metathesis, being a useful entry to five-coordinate vinylidene complexes, including the dicarbon-disubstituted OsCl2(=C=CMe2)(PiPr3)2 (8) and the monosubstituted OsCl2(=C=CHCy)(PiPr3)2 (9).

Rhodium-catalyzed (5+1) annulations between 2-alkenylphenols and allenes: a practical entry to 2,2-disubstituted 2H-chromenes.

Readily available alkenylphenols react with allenes under rhodium catalysis to provide valuable 2,2-disubstituted 2H-chromenes. The whole process, which involves the cleavage of one C-H bond of the alkenyl moiety and the participation of the allene as a one-carbon cycloaddition partner, can be considered a simple, versatile, and atom-economical (5+1) heteroannulation. The reaction tolerates a broad range of substituents both in the alkenylphenol and in the allene, and most probably proceeds through a mechanism involving a rhodium-catalyzed C-C coupling followed by two sequential pericyclic processes.

Rhodium-catalyzed intramolecular [3+2+2] cycloadditions between alkylidenecyclopropanes, alkynes, and alkenes.

A Rh-catalyzed intramolecular [3+2+2] cycloaddition is reported. The cycloaddition affords synthetically relevant 5,7,5-fused tricyclic systems of type 2 from readily available dienyne precursors. The transformation takes place with moderate or good yields, high diastereoselectivity, and total chemoselectivity.

Rhodium(III)-catalyzed dearomatizing (3 + 2) annulation of 2-alkenylphenols and alkynes.

Appropriately substituted 2-alkenylphenols undergo a mild formal [3C+2C] cycloaddition with alkynes when treated with a Rh(III) catalyst and an oxidant. The reaction, which involves the cleavage of the terminal C-H bond of the alkenyl moiety and the dearomatization of the phenol ring, provides a versatile and efficient approach to highly appealing spirocyclic skeletons and occurs with high selectivity.

Straightforward assembly of benzoxepines by means of a rhodium(III)-catalyzed C-H functionalization of o-vinylphenols.

Readily available o-vinylphenols undergo a formal (5 + 2) cycloaddition to alkynes when treated with catalytic amounts of [Cp*RhCl2]2 and Cu(OAc)2. The reaction, which involves the cleavage of the terminal C-H bond of the alkenyl moiety, generates highly valuable benzoxepine skeletons in a practical, versatile, and atom-economical manner. Using carbon monoxide instead of an alkyne as reaction partner leads to coumarin products which formally result from a (5 + 1) cycloaddition.