Tatsuhiko Yoshino

Pyrroloindolone Synthesis via a Cp*CoIII-Catalyzed Redox-Neutral Directed C–H Alkenylation/Annulation Sequence

A unique synthetic utility of a Cp*Co(III) catalyst in comparison with related Cp*Rh(III) catalysts is described. A C2-selective indole alkenylation/annulation sequence proceeded smoothly with catalytic amount of a [Cp*Co(III)(C6H6)](PF6)2 complex and KOAc. Intramolecular addition of an alkenyl-Cp*Co species to a carbamoyl moiety gave pyrroloindolones in 58-89% yield in one pot. Clear difference was observed between the catalytic activity of the Cp*Co(III) complex and those of Cp*Rh(III) complexes, highlighting the unique nucleophilic activity of the organocobalt species. The Cp*Co(III) catalysis was also suitable for simple alkenylation process of N-carbamoyl indoles, and broad range of alkynes, including terminal alkynes, were applicable to give C2-alkenylated indoles in 50-99% yield. Mechanistic studies on C-H activation step under Cp*Co(III) catalysis with the aid of an acetate unit as well as evaluation of the difference between organo-Co(III) species and organo-Rh(III) species are also described.

Cp*Co-III Catalyzed Site-Selective C-H Activation of Unsymmetrical O-Acyl Oximes: Synthesis of Multisubstituted Isoquinolines from Terminal and Internal Alkynes

The synthesis of isoquinolines by site-selective C-H activation of O-acyl oximes with a Cp*Co(III) catalyst is described. In the presence of this catalyst, the C-H activation of various unsymmetrically substituted O-acyl oximes selectively occurred at the sterically less hindered site, and reactions with terminal as well as internal alkynes afforded the corresponding products in up to 98 % yield. Whereas the reactions catalyzed by the Cp*Co(III) system proceeded with high site selectivity (15:1 to 20:1), use of the corresponding Cp*Rh(III) catalysts led to low selectivities and/or yields when unsymmetrical O-acyl oximes and terminal alkynes were used. Deuterium labeling studies indicate a clear difference in the site selectivity of the C-H activation step under Cp*Co(III) and Cp*Rh(III) catalysis.

Dehydrative Direct CH Allylation with Allylic Alcohols under [Cp*CoIII] Catalysis†

The unique reactivity of [Cp*Co(III)] over [Cp*Rh(III)] was demonstrated. A cationic [Cp*Co(III)] catalyst promoted direct dehydrative C-H allylation with non-activated allyl alcohols, thus giving C2-allylated indoles, pyrrole, and phenyl-pyrazole in good yields, while analogous [Cp*Rh(III)] catalysts were not effective. The high γ-selectivity and C2-selectivity indicated that the reaction proceeded by directing-group-assisted C-H metalation. DFT calculations suggested that the γ-selective substitution reaction proceeded by C-H metalation and insertion of a C-C double bond, with subsequent β-hydroxide elimination. The [Cp*Co(III)] catalyst favored β-hydroxide elimination over β-hydride elimination.

Lewis Acid Catalyzed Benzylic C−H Bond Functionalization of Azaarenes: Addition to Enones

A Lewis acid catalyzed benzylic C-H bond functionalization of alkyl-substituted azaarenes is described. Sc(OTf)(3) and Y(OTf)(3) promoted the direct addition of alkyl-substituted azaarenes and benzoxazole to enones and an α,β-unsaturated N-acylpyrrole. Products were obtained in 60-96% yield.

Stereodivergent Direct Catalytic Asymmetric Mannich‐Type Reactions of α‐Isothiocyanato Ester with Ketimines

Chiral a,b-diamino acids are key structural motifs in many biologically active compounds. Catalytic asymmetric direct Mannich-type reactions of aldimines and nucleophiles, which contain an a-amino equivalent unit, provide straightforward access to chiral a,b-diamino acids. Unnatural amino acids that contain tetrasubstituted carbon centers are useful chiral building blocks for the synthesis of pharmaceuticals, and artificial peptides with distinctive chemical and biological properties. Several research groups including ours, have reported Mannich-type reactions of aldimines with a-substituted donors, such as an alanine methyl ester Schiff base, asubstituted nitroacetates, and a-substituted oxazolones, for the synthesis of a,b-diamino acid surrogates bearing an a-tetrasubstituted carbon center. In contrast, there are no reports of the catalytic asymmetric synthesis of b-tetrasubstituted chiral a,b-diamino acids, which require the reaction of much less reactive ketimines. Thus, there is a high demand for the development of a new method for the synthesis of a,btetrasubstituted a,b-diamino acid surrogates. To address this issue, we herein report the utility of group 2 metal/Schiff base 1 complexes (Figure 1). The Sr/1 and Mg/1 catalysts promoted a direct Mannich-type reaction of a-methyl-a-isothiocyanato ester 2 with ketimines 3 (see Table 1), thus providing stereodivergent access to a,b-diamino esters with vicinal tetrasubstituted carbon stereocenters. We have previously reported the direct asymmetric aldol reaction of a-methyl-a-isothiocyanato ester 2 with ketones, catalyzed by Bu2Mg/Schiff base 1a. [8] Therefore, we initially utilized Bu2Mg/1a for the reaction of 2 with ketimines. [9] Among the ketimines screened, diphenylphosphinoyl (Dpp) imine 3a gave promising results in terms of reactivity and selectivity. Optimization studies using 3 a are summarized in Table 1. A 1:1 ratio of Bu2Mg/1a (10 mol%) promoted the

Construction of Contiguous Tetrasubstituted Chiral Carbon Stereocenters via Direct Catalytic Asymmetric Aldol Reaction of α-Isothiocyanato Esters with Ketones

Construction of contiguous tetrasubstituted chiral carbon stereocenters via direct catalytic asymmetric aldol reaction of alpha-substituted alpha-isothiocyanato esters with unactivated simple ketones is described. A Bu(2)Mg/Schiff base catalyst promoted the aldol addition/cyclization sequence at room temperature, giving protected alpha-amino-beta-hydroxy esters with contiguous tetrasubstituted chiral carbon stereocenters in 99 to 68% yield, 98:2 to 74:26 dr, and 98 to 82% ee.

Sultam Synthesis via Cu-Catalyzed Intermolecular Carboamination of Alkenes with N-Fluorobenzenesulfonimide

Cu-catalyzed intermolecular carboamination of alkenes is described. The reaction of terminal alkenes and an internal alkene with N-fluorobenzenesulfonimide was promoted by 2.5 mol % of a Cu(I)-salt at 60 °C, and six-membered ring sultams were obtained in 91-44% yields.

Cp*CoIII-Catalyzed Dehydrative C–H Allylation of 6-Arylpurines and Aromatic Amides Using Allyl Alcohols in Fluorinated Alcohols

Cp*Co(III)-catalyzed C-H allylation of various aromatic C-H bonds using allyl alcohols as allylating reagents is described. Improved reaction conditions using fluorinated alcohol solvents afforded efficient directed C-H allylation of 6-arylpurines, benzamides, and a synthetically useful Weinreb amide with good functional group compatibility.

Stereoselective Synthesis of Tetrasubstituted Alkenes via a Cp*CoIII-Catalyzed C-H Alkenylation/Directing Group Migration Sequence

A highly atom economical and stereoselective synthesis of tetrasubstituted α,β-unsaturated amides was achieved by a Cp*CoIII -catalyzed C-H alkenylation/directing group migration sequence. A carbamoyl directing group, which is typically removed after C-H functionalization, worked as an internal acylating agent and migrated onto the alkene moiety of the product. The directing group migration was realized with the Cp*CoIII catalyst, while a related Cp*RhIII catalyst did not promote the migration process. The product was further converted into two types of tricyclic compounds, one of which had fluorescent properties.

Construction of contiguous tetrasubstituted chiral carbon stereocenters via direct catalytic asymmetric aldol and mannich‐type reactions

Catalytic asymmetric synthesis of unnatural amino acids with vicinal tetrasubstituted chiral carbon stereocenters is described. In the first part, direct catalytic asymmetric aldol reaction of simple non-activated ketone electrophiles with α-substituted α-isothiocyanato ester donors was realized. A Mg/Schiff base catalyst promoted the aldol reaction, and α-amino-β-hydroxy esters were obtained in up to 98% ee and 98:2 d.r. In the second part, the Mg/Schiff base catalyst and a Sr/Schiff base catalyst were utilized for stereodivergent direct asymmetric Mannich-type reaction of ketimines. The Mg/Schiff base catalyst gave syn-α,β-diamino esters, while the Sr/Schiff base catalyst produced anti-α,β-diamino esters in good to high enantioselectivity, up to 97% ee.