Takashi Ikawa

Synthesis of biaryl compounds through three-component assembly: ambidentate effect of the tert-butyldimethylsilyl group for regioselective Diels-Alder and Hiyama coupling reactions.

The biaryl moiety is ubiquitous in natural products, pharmaceuticals, polymers, sensors, and in ligands for transition-metal catalysts. A number of useful methods for the preparation of these compounds have been developed based on the transition-metal-catalyzed cross-coupling of aryl halides with aryl metal species through Stille, Suzuki, Negishi, and Hiyama reactions. Multicomponent assembly protocols have been recognized as a powerful means for the preparation of molecular complexity and diversity, and are thus particularly suited for combinatorial chemistry and diversity-oriented synthesis. As an approach towards this goal, we now report the novel preparation of multisubstituted unsymmetrical biaryl compounds through the assembly of the following three components: a silylated benzyne, a furan derivative, and an aryl iodide [Eq. (1)]. Thus, this methodology involves the construction of silylnaphthalene derivatives by a regioselective Diels–Alder reaction of 3-tert-butyldimethylsilylbenzynes (3-TBDMS-benzynes) with furan derivatives followed by a Hiyama cross-coupling reaction of the generated TBDMSsubstituted cycloadducts with aryl iodides. We initially examined the Diels–Alder reaction of 3-phenylbenzyne (3a, R=Ph, R=H), generated in situ by treatment of 2-bromo-6-phenylphenyl triflate (1a) with nBuLi at 78 8C, and 2-tert-butylfuran (2a) to synthesize a multisubstituted biaryl compound. However, the regioselectivity of the reaction was quite low and afforded a 1:1.3 mixture of the head-to-tail (anti) and the head-to-head (syn) cycloaddition products 4a (Table 1, entry 1). We devised

Preparation of silk fibroin-supported Pd(0) catalyst for chemoselective hydrogenation: reduction of palladium(II) acetate by methanol on the protein

The Pd/fibroin (Fib) was easily prepared by the auto-reduction of the silk-fibroin conjugated Pd(OAc)2 using MeOH as a solvent and a reductant and exhibited good chemoselectivity in the hydrogenation of olefins and azides in the presence of aromatic carbonyls and/or halogens or an O-benzyl protective group.

Regiocomplementary cycloaddition reactions of boryl- and silylbenzynes with 1,3-dipoles: selective synthesis of benzo-fused azole derivatives.

Benzo-fused nitrogen-containing heterocycles are abundant in biologically active compounds. One of the most important methods for preparing such heterocycles is the (3 + 2) cycloaddition reaction of benzynes with 1,3-dipolar compounds. However, the reactions of unsymmetrically substituted benzynes generally show low selectivity and hence yield mixtures of two regioisomers. In this paper, we describe the synthesis of both regioisomers of multisubstituted benzo-fused azole derivatives such as benzotriazoles, 1H-indazoles, and benzo[d]isoxazoles through the regiocomplementary (3 + 2) cycloaddition reactions of 3-boryl- and 3-silylbenzynes with 1,3-dipoles. The improved generation of 3-borylbenzynes from new precursors was one of the most important results of this work, which produced the successful (3 + 2) cycloaddition reactions with exclusive and proximal selectivities. On the other hand, similar reactions of 3-silylbenzynes selectively afforded distal cycloadducts. Analysis of the reaction pathways of these amazing regioselectivities by density functional theory calculations revealed that the (3 + 2) cycloadditions of borylbenzynes are controlled by the electrostatic effect of the boryl group, while those of silylbenzynes are controlled mainly by the steric effect of the bulky silyl groups that produced electrostatically unfavorable adducts via anomalous transition states.

A remarkable solvent effect toward the Pd/C-catalyzed cleavage of silyl ethersElectronic supplementary information (ESI) available: characterization data and references and supplementary Tables 4 and 5. See http://www.rsc.org/suppdata/cc/b2/b211313a/

Selective hydrogenation conditions of olefin, benzyl ether and acetylene functionalities in the presence of TBDMS or TES ether have been developed.

A Domino Process for Benzyne Preparation: Dual Activation of o-(Trimethylsilyl)phenols by Nonafluorobutanesulfonyl Fluoride

Benzynes were generated from o-(trimethylsilyl)phenols using nonafluorobutanesulfonyl fluoride (NfF) by a domino process, i.e., the nonaflation of the phenolic hydroxyl group of o-(trimethylsilyl)phenols by NfF followed by the attack of the produced fluoride ion on the trimethylsilyl group. The generated benzyne immediately underwent various reactions to give polysubstituted benzenes.

Development of a Practical and Scalable Preparation using Sonication of Pd/Fibroin Catalyst for Chemoselective Hydrogenation

Abstract A practical and efficient preparation method of palladium‐fibroin (Pd/Fib), silk‐fibroin‐supported Pd(0) by means of sonication, has been developed. The Pd/Fib catalyst could be prepared within 12 h at room temperature starting from commercial silk‐fibroin and Pd(OAc)2 in MeOH, whereas our previous preparation method required at least 4 days. The present improved process is applicable to a large‐scale preparation of Pd/Fib. The Pd/Fib prepared by the present method also catalyzed chemoselective hydrogenation of acetylenes, olefins, and azides in the presence of aromatic ketones, aldehydes, and halides; N‐Cbz protective groups; and benzyl esters, which are readily hydrogenated under the Pd/C‐ or Pd/C(en)‐catalyzed hydrogenation conditions.

Synthesis of Fluorinated Aromatic Compounds by One-Pot Benzyne Generation and Nucleophilic Fluorination

The fluorination of substituted benzenes using fluoride ions under mild reaction conditions has been one of the most important challenges for the synthesis of biologically active fluorinated aromatic compounds; however, only a few synthetically useful methods are known. In this paper, it is reported that the nucleophilic fluorination of benzynes, generated from either 2-(trialkylsilyl)phenyl nonafluorobutanesulfonates or 2-(trialkylsilyl)phenols, meets this challenge. In particular, the fluorination starting from 2-(trialkylsilyl)phenols for fabricating aryl fluorides involves three sequential reactions in one-pot: the nonaflylation of phenols, benzyne generation, and nucleophilic fluorination of the benzynes. The regioselectivities of these reactions are controlled by the substituents at the C3-position of the benzynes.

Development of a highly efficient single-mode microwave applicator with a resonant cavity and its application to continuous flow syntheses

Microwave-assisted organic synthesis has many advantages and is widely applied to a variety of reactions. We have developed a new single-mode microwave applicator, specific to continuous flow synthesis, whose main feature is that it generates a uniform electromagnetic field inside its resonant cavity. Two well-known reactions, the Fischer indole synthesis and the Diels–Alder reaction, proceeded very quickly when a solution of substrates was pumped through a helical glass tube reactor inside the resonant cavity, under a pressure of 2.5 MPa. The desired products were obtained in high yields. This compact apparatus constitutes a new method for switching organic synthesis from batch to continuous flow, and enables continuous synthesis of products at a scale of 100 g h−1 or more.

Spatial effects of oxovanadium-immobilized mesoporous silica on racemization of alcohols and application in lipase-catalyzed dynamic kinetic resolution

We recently reported a new dynamic kinetic resolution (DKR) method based on the combination of lipase-catalyzed kinetic resolution of racemic alcohols and the V-MPS3-catalyzed in situ racemization of less reactive alcohol enantiomers. In V-MPS3, oxovanadium moieties were covalently bound to the inner surface of mesoporous silica (MPS) with a pore size of about 3 nm. The catalytic activity of V-MPS3 was much higher than that of related vanadium compounds; however, we could neither explain its unusually high activity nor confirm that the racemization predominantly occurred inside the V-MPS pores. Therefore, in this study, we prepared V-MPS2 and V-MPS4 from the corresponding MPS with pore diameters of approximately 2 nm and 4 nm, respectively and compared their racemization activities with that of V-MPS3 using some optically active alcohols with different molecular sizes and polarities. We discovered a positive correlation between the pore size of V-MPS and substrate racemization rate as well as the high polarity of the MPS pores. The results suggested that the racemization predominantly occurs in the pores of V-MPS and that a small pore size (2–4 nm) is essential to generate the polar environment of V-MPS, which probably accelerates the racemization by facilitating the C–O bond cleavage of the vanadate intermediates. Using V-MPS with a pore size suitable for each substrate, lipase/oxovanadium combo-catalyzed DKR could be applied to a wider range of alcohols including allyl alcohols, benzylic alcohols, and propargyl alcohols to give the corresponding esters in excellent isolated yields and enantioselectivities.

Concise Synthesis of Multisubstituted Isoquinolines from Pyridines by Regioselective Diels–Alder Reactions of 2‐Silyl‐3,4‐pyridynes

A four-step regioselective synthesis of multisubstituted isoquinoline derivatives from 3-bromopyridines was developed by the Diels-Alder (DA) reactions of 2-silyl-3,4-pyridynes with furans, followed by functional-group transformations. In particular, the silyl group at the C2-position of the 3,4-pyridynes played two important roles: firstly, it functioned as the directing group for the DA reaction, and secondly, it served to introduce diverse substituents at the C1-position of the isoquinolines by electrophilic ipso-substitution.