Hirohisa Ohmiya

Directed Ortho Borylation of Functionalized Arenes Catalyzed by a Silica-Supported Compact Phosphine−Iridium System

An immobilized monophosphine-Ir system, which was prepared in situ from [Ir(OMe)(cod)](2) and a silica-supported, compact phosphine, showed high activities and selectivities for the borylation of aromatic C-H bonds with bis(pinacolato)diboron. This system was effective not only for the borylation of benzene but also for the ortho borylation of arenes with directing groups, such as ester, amide, sulfonate, acetal, alkoxymethyl, and chloro groups, under mild reaction conditions.

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.

Rh-Catalyzed Ortho-Selective C–H Borylation of N-Functionalized Arenes with Silica-Supported Bridgehead Monophosphine Ligands

Supported phosphine-Rh systems, prepared in situ from silica-supported bridgehead monophosphines and [Rh(OH)(cod)](2), have enabled ortho-selective C-H borylation for a range of arenes containing nitrogen-based directing groups. The regioselectivity was excellent with various N-directing groups, including saturated and unsaturated N-heterocycles, tert-aminoalkyl groups, and imine-type C-N double bonds. The reaction showed significant tolerance toward steric repulsion around the reacting C-H bond. This Rh catalysis complements the Ir-catalyzed ortho-borylation, which is effective for arenes with oxygen-based directing groups.

Cu(I)-Catalyzed Intramolecular Hydroamination of Unactivated Alkenes Bearing a Primary or Secondary Amino Group in Alcoholic Solvents

The Cu-Xantphos system [Cu(O-t-Bu)-Xantphos, 10-15 mol %] catalyzes the intramolecular hydroamination of unactivated terminal alkenes bearing an unprotected aminoalkyl substituent in alcoholic solvents, giving pyrrolidine and piperidine derivatives in excellent yields. This system is applicable to both primary and secondary amines and tolerates a variety of functional groups.

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

Directed Ortho Borylation of Phenol Derivatives Catalyzed by a Silica-Supported Iridium Complex

The directed ortho borylation of phenol derivatives protected with an N,N-diethylcarbamoyl group was efficiently catalyzed by an immobilized monophosphine-Ir system, which was prepared in situ from [Ir(OMe)(cod)](2) and a silica-supported, compact phosphine. The utility of the carbamoyloxy group as a leaving group for metal-catalyzed cross-coupling reactions was demonstrated by its utilization in the synthesis of a terphenyl derivative.

Copper-Catalyzed Carboxylation of Alkylboranes with Carbon Dioxide: Formal Reductive Carboxylation of Terminal Alkenes

Carboxylation of alkylboron compounds (alkyl-9-BBN) with CO(2) proceeded in the presence of catalytic amounts of CuOAc/1,10-phenanthroline and a stoichiometric amount of KO(t)Bu. The alkylboranes are easily and widely available through the alkene hydroboration, and thus the overall process represents a reductive carboxylation of alkenes with CO(2). The broad functional group compatibility and the inexpensiveness of the Cu/1,10-phenathoroline catalyst system are attractive features of this protocol.

Rh-Catalyzed Borylation of N-Adjacent C(sp3)–H Bonds with a Silica-Supported Triarylphosphine Ligand

Direct C(sp(3))-H borylation of amides, ureas, and 2-aminopyridine derivatives at the position α to the N atom, which gives the corresponding α-aminoalkylboronates, has been achieved with a heterogeneous catalyst system consisting of [Rh(OMe)(cod)]2 and a silica-supported triarylphosphine ligand (Silica-TRIP) that features an immobilized triptycene-type cage structure with a bridgehead P atom. The reaction occurs not only at terminal C-H bonds but also at internal secondary C-H bonds under mild reaction conditions (25-100 °C, 0.1-0.5 mol % Rh).

Palladium-Catalyzed Borylation of Sterically Demanding Aryl Halides with a Silica-Supported Compact Phosphane Ligand†

Arylboronic acid derivatives are versatile intermediates in organic synthesis because of their broad availability, air stability, and ease of handling. Among the routes to arylboronic acid derivatives, the conventional methods that use aryllithium or Grignard reagents have a problem with functional-group compatibility. More recently, functionalgroup-tolerating approaches such as the transition-metalcatalyzed borylation of aryl halides 3] and the direct C H borylation of arenes have been introduced, and both are complementarily applicable to the preparation of a wide range of arylboronates. Specifically for the borylation of aryl halides, aryl chlorides are the most desirable substrates because of their low cost and broad availability; however, they are less reactive than the corresponding bromides, iodides, and triflates. Accordingly, only a few catalyst systems are effective for reactions of unactivated aryl chlorides. A common feature of effective systems is the use of electronrich and sterically demanding phosphane ligands in combination with a palladium source. The most efficient catalyst systems reported to date are those based on (dicyclohexylphosphino)biphenyl-type ligands such as SPhos and XPhos, which were originally described by Buchwald and co-workers. The use of these catalysts allowed for the borylation of sterically or electronically challenging aryl chlorides such as 1-chloro-2,6-dimethylbenzene (2 mol% Pd/SPhos, RT, 86%) and 4-chloroanisole (0.1 mol% Pd/XPhos, 110 8C, 94 %). Buchwald and co-workers described that the efficacy of biphenyl-type ligands for the borylation is attributed at least in part to their sterically demanding nature, which promotes the formation of a highly reactive 1:1 Pd/P complex over less reactive 1:2 Pd/P species. 5] On the other hand, we have developed Silica-SMAP, which is a silica-supported “compact” phosphane ligand. 7] Because of its immobilized nature, this ligand forms 1:1 metal/P complexes exclusively with a range of transition-metal species, despite its extreme compactness. We demonstrated that the surface-bound 1:1 metal/P complexes afford highly active catalysts for the hydrosilylation and the hydrogenation of ketones (with Rh), and the directed ortho borylation of functionalized arenes (with Ir). In particular, these reactions showed remarkable tolerance toward the reactions of sterically demanding substrates. Accordingly, we envisioned that, despite its compactness, the supported phosphane would be useful in creating a highly active catalytic environment for the palladium-catalyzed borylation of sterically or electronically challenging aryl halides. 8, 9] Furthermore, this utility means that the steric demand of a ligand would not be essential for the high catalytic activity in the palladium-catalyzed borylation of aryl chlorides, as has been proved by the experiments described below. The reaction of 4-chlorotoluene (1 a, 0.5 mmol) with bis(pinacolato)diboron (2, 0.5 mmol) in the presence of Pd(OAc)2 (0.5 mol %), Silica-SMAP (0.5 mol %), and KOAc (3 equiv) in benzene at 60 8C for 10 h gave the desired arylboronate 3a in 84% yield, but the reaction also formed a significant amount of biaryl compound 3a’ (8% yield), which likely resulted from a Suzuki–Miyaura coupling between the arylboronate product 3a and aryl chloride 1a (Scheme 1, catalyst precursor A). The undesired biaryl formation was almost completely inhibited by using the Silica-SMAP/Pd system that was prepared in advance (from Silica-SMAP and [PdCl2(cod)], P/Pd = 1:1, catalyst precursor B), instead of the in situ generated complex (catalyst precursor A); 3a was thus produced in an excellent yield (Scheme 1). Furthermore, another preformed complex Silica-SMAP/[PdCl2(pyridine)2] afforded exclusively the borylation product 3a, albeit in a lower conversion (Scheme 1, catalyst precursor C). It should

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.