Yusuke Makida

Palladium-Catalyzed γ-Selective and Stereospecific Allyl−Aryl Coupling between Acyclic Allylic Esters and Arylboronic Acids

Reactions between acyclic (E)-allylic acetates and arylboronic acids in the presence of a palladium catalyst prepared from Pd(OAc)(2), phenanthroline (or bipyridine), and AgSbF(6) (1:1.2:1) proceeded with excellent gamma-selectivity to afford allyl-aryl coupling products with E-configuration. The reactions of alpha-chiral allylic acetates took place with excellent alpha-to-gamma chirality transfer with syn stereochemistry to give allylated arenes with a stereogenic center at the benzylic position. The reaction tolerated a broad range of functional groups in both the allylic acetates and the arylboronic acids. Furthermore, gamma-arylation of cinnamyl alcohol derivatives afforded gem-diarylalkane derivatives containing an unconjugated alkenic substituent. The synthetic utility of this method was demonstrated by its utilization in an efficient synthesis of (+)-sertraline, an antidepressant agent. The observed gamma-regioselectivity and E-1,3-syn stereochemistry were rationalized based on a Pd(II) mechanism involving transmetalation between a cationic mono(acyloxo)palladium(II) complex and arylboronic acid, and directed carbopalladation followed by syn-beta-acyloxy elimination. The results of stoichiometric reactions of palladium complexes related to possible intermediates were fully consistent with the proposed mechanism.

Regio- and Stereocontrolled Introduction of Secondary Alkyl Groups to Electron-Deficient Arenes through Copper-Catalyzed Allylic Alkylation†

Heteroarenes are important structural motifs found in many pharmaceuticals, agrochemicals and natural products. Accordingly, the development of efficient methods for heteroarene functionalization is important. Although there are various methods for accessing functionalized heteroarenes, the C-alkylation of these species is still severely limited in scope. Indeed, conventional methods involving stoichiometric metalation of electron-deficient heteroarenes followed by trapping with alkyl halides or pseudo halides are generally difficult because heteroarylmetal species are unstable compared with arylmetals. Friedel–Crafts-type reactions also allow for alkylation, but these methods are only applicable to electron-rich heteroarenes. Recently, transition-metal-catalyzed Csp2 H functionalizations of (hetero)arenes, such as alkene hydro(hetero)arylations 5] or couplings with alkyl halides, 7] have been introduced as new approaches for heteroarene C-alkylation. However, even with these methods the introduction of secondary alkyl groups is quite difficult. 8] In particular, the stereocontrolled introduction of a secondary alkyl group remains underdeveloped, although it was achieved in the intramolecular alkene hydroarylations of Ellman, Bergman and co-workers. Earlier, we reported organoboron-based Pdor Cucatalyzed approaches for the allylic alkylation of arenes (Scheme 1a). High g-regioselectivity, 1,3-anti or syn stereoselectivities, and broad functional group compatibilities are all attractive features of these approaches. Therefore, the extension of these organoboron-based approaches to the alkylation of heteroarenes might be expected. We did not take this approach, however, because we knew that aborylheteroarenes are generally unstable and difficult to prepare. Instead, we envisioned that the base-assisted direct cupration of heteroarenes under the conditions of Daugulis might be effective and more straightforward for the catalytic generation of heteroarylcopper(I) species that are reactive in the g-selective allyl–aryl coupling (Scheme 1b). Herein we report a Cu-catalyzed allylic alkylation of electron-deficient heteroarenes with internal secondary allylic phosphates, which proceeded with excellent g-regioselectivity and E-stereoselectivity. This copper catalyst system was similarly applicable to fluoroarenes. Furthermore, the reaction of enantioenriched secondary allylic phosphates proceeded with 1,3-anti stereoselectivity to afford the corresponding alkylated (hetero)arenes with a controlled secondary stereogenic center. Thus, this Cu-catalyzed alkylation is a straightforward method for the stereocontrolled introduction of secondary alkyl groups to electron-deficient (hetero)arenes. Specifically, the g-substitution reaction of 4-phenyloxazole (1a ; 0.6 mmol) with Z allylic phosphate 2a (0.5 mmol) in the presence of CuCl (10 mol%) and LiOtBu (0.5 mmol) in THF (1 mL) at 40 8C for 10 h afforded alkylated arene product 3aa in 78% yield (87 % conversion) with excellent regio(3aa/3aa’ 99:1) and stereoselectivities (E/Z > 99:1) [Eq. (1)]. On the other hand, the reaction of the isomeric

Copper-Catalyzed γ-Selective Allyl−Alkyl Coupling between Allylic Phosphates and Alkylboranes

Copper-catalyzed allyl-alkyl coupling between allylic phosphates and alkylboranes, prepared by hydroboration of alkenes with 9-BBN-H, takes place with complete gamma- and E-selectivities and with preferential 1,3-anti stereochemistry. The reaction tolerates various functional groups in both the allylic phosphate and alkylborane. Catalytic mechanisms involving transmetalation between a trialkyl(alkoxo)borate and a copper(I) complex to form an alkylcopper(I) species are proposed.

General Approach to Allenes through Copper-Catalyzed γ-Selective and Stereospecific Coupling between Propargylic Phosphates and Alkylboranes

Copper-catalyzed γ-selective coupling between propargylic phosphates and alkylboron compounds (alkyl-9-BBN, prepared by hydroboration of alkenes with 9-BBN-H) affords multisubstituted allenes with various functional groups. The reaction of enantioenriched propargylic phosphates to give axially chiral allenes proceeds with excellent point-to-axial chirality transfer with 1,3-anti stereochemistry.

Cyclization of Nonterminal Alkynic β-Keto Esters Catalyzed by Gold(I) Complex with a Semihollow, End-Capped Triethynylphosphine Ligand

A cationic gold(I) complex with a semihollow-shaped trialkynylphosphine catalyzed 5-exo-dig and 6-endo-dig cyclizations of various internal alkynic beta-keto esters, showing a marked advantage over a gold(I)-PPh3 complex with respect to the rates of the reactions and the product yields. It is proposed that the gold-bound alkynic substrate in a catalytic pocket must be somewhat folded and that such a steric effect makes the carbon-carbon bond formation entropically more favorable.

Reversible 1,3-anti/syn-stereochemical courses in copper-catalyzed γ-selective allyl-alkyl coupling between chiral allylic phosphates and alkylboranes.

The stereochemical courses of the copper-catalyzed allyl-alkyl coupling between enantioenriched chiral allylic phosphates and alkylboranes were switchable between 1,3-anti and 1,3-syn selectivities by the choice of solvents and achiral alkoxide bases with different steric demands. The reactions with γ-silylated allylic phosphates allow efficient synthesis of enantioenriched chiral allylsilanes with tertiary or quaternary carbon stereogenic centers. Cyclic and acyclic bimodal participation of alkoxyborane species in an organocopper addition-elimination sequence is proposed to account for the phenomenon of the anti/syn-stereochemical reversal.

Copper-catalyzed enantioselective allylic alkylation of terminal alkyne pronucleophiles

The copper-catalyzed enantioselective allylic alkylation of terminal alkynes with primary allylic phosphates was developed by the use of a new chiral N-heterocyclic carbene ligand bearing a phenolic hydroxy group at the ortho position of one of the two N-aryl groups. This reaction occurred with excellent γ-branch regioselectivity and high enantioselectivity, forming a controlled stereogenic center at the allylic/propargylic position. Various terminal alkynes, including silyl, aliphatic, and aromatic alkynes, could be used directly without premetalation of the C(sp)-H bond. On the basis of the results of experiments using an isomeric secondary allylic phosphate, which gave a branched product through an α-selective substitution reaction with retention of configuration, a reaction pathway involving 1,3-allylic migration of Cu in a ([σ + π]-allyl)copper(III) species is proposed.

Au]/[Pd] Multicatalytic processes: direct one-pot access to benzo[c]chromenes and benzo[b]furans

A new synthetic protocol that combines the advantages offered by eco-friendly solvent-free reactions and sequential transformations is reported. This strategy offers straightforward access to benzo[c]chromenes and benzo[b]furans from commercially available starting materials. This two-step, one-pot strategy consists of an Au-catalyzed hydrophenoxylation process followed by Pd-catalyzed C-H activation or Mizoroki-Heck reactions. The selectivity of the process towards C-H activation or Mizoroki-Heck reaction can be easily tuned.

Control of Vicinal Stereocenters through Nickel-Catalyzed Alkyl-Alkyl Cross-Coupling

Vicinal stereocenters are found in many natural and unnatural compounds. Although metal-catalyzed cross-coupling reactions of unactivated alkyl electrophiles are emerging as a powerful tool in organic synthesis, there have been virtually no reports of processes that generate, much less control, vicinal stereocenters. In this investigation, we establish that a chiral nickel catalyst can mediate doubly stereoconvergent alkyl-alkyl cross-coupling, specifically, reactions of a racemic pyrrolidine-derived nucleophile with cyclic alkyl halides (as mixtures of stereoisomers) to produce vicinal stereocenters with very good stereoselectivity.

Asymmetric Hydrogenation of Azaindoles: Chemo- and Enantioselective Reduction of Fused Aromatic Ring Systems Consisting of Two Heteroarenes

High enantioselectivity was achieved for the hydrogenation of azaindoles by using the chiral catalyst, which was prepared from [Ru(η(3) -methallyl)2 (cod)] and a trans-chelating bis(phosphine) ligand (PhTRAP). The dearomative reaction exclusively occurred on the five-membered ring, thus giving the corresponding azaindolines with up to 97:3 enantiomer ratio.