Zhuo-Zhuo Zhang

Cobalt(III)-Catalyzed C2-Selective C–H Alkynylation of Indoles

A cobalt(III)-catalyzed C-2 selective C-H alkynylation of indoles using hypervalent iodine-alkyne reagents is described. A broad range of synthetically useful functional groups (-F, -Cl, -Br, -CO2Me, -CN) were tolerated, providing an efficient and robust protocol for the synthesis of C-2 alkynylated indoles. The pyrimidyl and silyl protecting groups could be easily removed to give the corresponding 2-ethynyl-1H-indole.

Indole Synthesis via Cobalt(III)-Catalyzed Oxidative Coupling of N-Arylureas and Internal Alkynes

A mild Co(III)-catalyzed oxidative annulation of N-arylureas and internal alkynes has been developed. The use of less electrophilic ureas other than acetamides as directing groups is crucial for the reaction. A broad range of synthetically useful functional groups are compatible with this reaction, thus providing a new opportunity for the synthesis of diverse indoles.

Pd(II)-Catalyzed Direct Sulfonylation of Unactivated C(sp3)–H Bonds with Sodium Sulfinates

A Pd(II)-catalyzed sulfonylation of unactivated C(sp(3))-H bonds with sodium arylsulfinates using an 8-aminoquinoline auxiliary is described. This reaction demonstrates excellent functional group tolerance with respect to both the caboxamide starting material and the sodium arylsulfinate coupling partner, affording a broad range of aryl alkyl sulfones. Moreover, the late-stage modification of complex molecules was achieved via this sulfonylation protocol.

Site-Selective Alkenylation of δ-C(sp3)–H Bonds with Alkynes via a Six-Membered Palladacycle

Most chelation-assisted aliphatic C-H activation proceeds through a kinetically favored five-membered cyclometalated intermediate. Here, we report the first site-selective alkenylation of δ-C(sp(3))-H in the presence of more accessible γ-C(sp(3))-H bonds via a kinetically less favored six-membered palladacycle. A wide range of functional groups are tolerated, and the unique protocol can be applied to the synthesis of chiral piperidines. Moreover, mechanistic insights have been conducted to elucidate the origin of the unusual site-selectivity.

Copper-/Silver-Mediated Arylation of C(sp2)–H Bonds with 2-Thiophenecarboxylic Acids

A copper/silver-mediated arylation of (hetero)aryl C-H bonds with 2-thiophenecarboxylic acids has been achieved. The protocol features a broad substrate scope and high functional group tolerance. Preliminary mechanistic studies indicate that a cascade protodecarboxylation/dehydrogenative coupling process is likely involved.

Divergent and Stereoselective Synthesis of β‐Silyl‐α‐Amino Acids through Palladium‐Catalyzed Intermolecular Silylation of Unactivated Primary and Secondary C−H Bonds

A general and practical PdII -catalyzed intermolecular silylation of primary and secondary C-H bonds of α-amino acids and simple aliphatic acids is reported. This method provides divergent and stereoselective access to a variety of optical pure β-silyl-α-amino acids, which are useful for genetic technologies and proteomics. It can also be readily performed on a gram scale and the auxiliary can be easily removed with retention of configuration. The synthetic importance of this method is further demonstrated by the late-stage functionalization of biological small molecules, such as (-)-santonin and β-cholic acid. Moreover, several key palladacycles were successfully isolated and characterized to elucidate the mechanism of this β-C(sp3 )-H silylation process.

Synthesis of Bicyclo[n.1.0]alkanes by a Cobalt‐Catalyzed Multiple C(sp3)−H Activation Strategy

A cobalt-catalyzed dual C(sp3)@H activation strategy has been developed and it provides a novel strategy for the synthesis of bicyclo[4.1.0]heptanes and bicyclo[3.1.0]hexanes. A key to the success of this reaction is the conformationinduced methylene C(sp3)@H activation of the resulting cobaltabicyclo[4.n.1] intermediate. In addition, the synthesis of bicyclo[3.1.0]hexane from pivalamide, by a triple C(sp3)@H activation, has also been demonstrated. Cyclopropanes and related polycyclic compounds have profound applications in medicinal and synthetic chemistry. In particular, bicyclo[n.1.0] ring systems are prevalent structures in biologically important agents. The bicyclo[3.1.0]hexanes are present in isodebromolaurinterol, Phlain I, and chromolaevane dione, and the bicyclo[4.1.0]heptanecurcumenone is present in sesquicaranoic acids B (Figure 1). Owing to these facts, the synthesis of [n.1.0] bicycles has been the subject of intensive research. Many elegant methods have been developed, including transition metal catalyzed diazo decomposition/alkene insertion, Michael-initiated ring closure, metal-catalyzed cycloisomerization of 1,6-enynes, and intramolecular Simmons– Smith cyclopropanation. An attractive and complementary strategy is reaction sequences which involve C(sp3)@H activation. Recently, transition metal catalyzed direct C(sp3)@H functionalization of cyclopropanes has been well investigated. However, the de novo synthesis of cyclopropanes by C(sp3)@H functionalization remains rare. Sato, Mukai, and Tanaka have reported the rhodium(I)catalyzed oxidative cycloaddition of 1,6-enynes followed by rhodacycle-directed C(sp3)@H bond activation. Another interesting strategy involves oxidative addition of palladium(0) to arylhalides, Heck-type carbopalladation to form a C(sp3)@PdII complex, which enables a subsequent C(sp3)@H bond activation. Herein we report the successful synthesis of [3.1.0] and [4.1.0] bicycloalkanes by a cobalt-catalyzed dual C(sp3)@H bond activation. Recently, cobalt metals have emerged as robust and versatile catalysts for directed C@H activation because of their abundance, cost effectiveness, and unique modes of action. Daugulis and co-workers first realized that the monoanionic, bidentate 8-aminoquinoline (AQ) could enable the use of bench-stable cobalt(II) salts as pre-catalysts by the in situ generation of high-valent cobalt(III) species. This reactivity mode was then used for the functionalization of C(sp3)@H bonds by the groups of Ge, Zhang, Sundararaju, Gaunt, and Lei. Inspired by the unique reactivity of the AQ auxiliary in cobalt-catalyzed C(sp3)@H activation and our continuous interest in C(sp3)@H activation, we speculated that a cobalt-catalyzed methyl C(sp3)@ H activation followed by intramolecular migratory insertion could afford the bridged cobaltacycle intermediate A, which could undergo a methylene C@H activation to form the intermediate B (Figure 2). Subsequent C@C bond reductive elimination would provide the bicyclo[n.1.0] skeletons. Figure 1. Pharmaceutical agents and natural products containing bicyclo[n.1.0] skeletons. Figure 2. Design of a cobalt-catalyzed dual C(sp3)@H activation to access bicyclo[n.1.0] ring systems. [*] Z.-Z. Zhang, Y.-Q. Han, B.-B. Zhan, S. Wang, Prof. Dr. B.-F. Shi Department of Chemistry, Zhejiang University Hangzhou 310027 (China) E-mail: bfshi@zju.edu.cn Homepage: http://mypage.zju.edu.cn/en/bfshi/

Nickel(II)-catalyzed direct arylation of aryl C–H bonds with aryl-boron reagents directed by a removable bidentate auxiliary

Ni(II)-catalyzed C–H arylation using Ar2I+X− or ArX as the arylating reagent via oxidative addition has been well investigated. However, the analogous cross-coupling of C–H bonds with organoboron reagents via transmetallation remains a great challenge. Here we report the first Ni(II)-catalyzed direct C–H arylation with arylboronic acid esters assisted by a removable bidentate auxiliary. This procedure is scalable and compatible with a wide range of functional groups, providing a complementary protocol for the synthesis of biaryl compounds.

Scalable, Stereocontrolled Formal Syntheses of (+)‐Isoschizandrin and (+)‐Steganone: Development and Applications of Palladium(II)‐Catalyzed Atroposelective C−H Alkynylation

Dibenzocyclooctadiene lignans are an interesting class of molecules because of their unique structure based on an axially chiral biaryl moiety as well as their significant biological activity. Herein, we describe the development of a palladium-catalyzed atroposelective C-H alkynylation and its application in gram-scale, stereocontrolled formal syntheses of (+)-isoschizandrin and (+)-steganone. tert-Leucine was identified as an efficient, catalytic transient chiral auxiliary. A wide range of enantiomerically enriched biaryl compounds were prepared by this approach in good yields (up to 99u2009%) with excellent enantioselectivity (up to >99u2009%u2005ee).