Continuous-Flow Suzuki-Miyaura and Mizoroki-Heck Reactions under Microwave Heating Conditions.

Microwave-assisted continuous-flow reactions have attracted significant interest from synthetic organic chemists, especially process chemists from practical points of view, due to a less complicated shift to large-scale synthesis based on simple and continuous access to products with low energy requirements. In this personal account, we focused on the Suzuki-Miyaura and Mizoroki-Heck reactions, both of which are significantly important cross-coupling reactions for the synthesis of various functional materials. Microwave power is effective for heating. Typical homogeneous palladium catalysts, such as PdCl2 (PPh3 )2 , Pd(PPh3 )4 , and Pd(OAc)2 , as well as heterogeneous palladium catalysts, such as Pd-film, Pd/Al2 O3 , Pd/SiO2 , and Pd supported on polymers, can be used for these reactions.

Heterogeneous One-Pot Carbonylation and Mizoroki-Heck Reaction in a Parallel Manner Following the Cleavage of Cinnamaldehyde Derivatives.

Carbon monoxide (CO) and styrene derivatives that can be both generated by a palladium on carbon (Pd/C)-catalyzed carbon-carbon (C-C) bond cleavage reaction of cinnamaldehyde derivatives were effectively utilized in further palladium-catalyzed C-C bond forming reactions in a direct and practical way. CO derived from simple and affordable CO carriers such as cinnamaldehyde or terephthalaldehyde was efficiently employed in the in situ CO fixation with various aromatic iodides through a palladium-catalyzed carbonylation followed by an inter- or intramolecular coupling reaction with alcohols to afford the corresponding esters or lactones, respectively. Styrene derivatives were also efficient substrates in an in situ Mizoroki-Heck-type cross-coupling reaction with aryl iodides, leading to the effective formation of asymmetric stilbenes. The decarbonylation of cinnamaldehyde derivatives and the subsequent independent syntheses of both esters/lactones and 1,2-diarylethenes could be achieved in a virtual one-pot and in situ reaction using a H-shaped pressure-tight glass-sealed tube consisting of two independent but laterally connected reaction tubes in the gas space.

Palladium on Carbon-Catalyzed Benzylic Methoxylation for Synthesis of Mixed Acetals and Orthoesters.

The palladium on carbon (Pd/C)-catalyzed direct methoxylation of the benzylic positions of linear benzyl and cyclic ether substrates proceeded in the presence of i-Pr2 NEt under an oxygen atmosphere to give the corresponding mixed acetals. Cyclic acetal derivatives could also be converted into orthoesters. The present direct methoxylation via a carbon-hydrogen (C-H) functionalization can be accomplished using the easily-removed Pd/C and molecular oxygen as a green oxidant. The obtained mixed acetals were transformed into the corresponding ether products by chemoselective substitution of the methoxy group using a silyltriflate, 2,4,6-collidine, and a nucleophile. The orthoester derivative could also be transformed into the cyclic ketal under similar reaction conditions.

Catalyst-Dependent Selective Hydrogenation of Nitriles: Selective Synthesis of Tertiary and Secondary Amines.

In the presence of palladium on carbon (Pd/C) as a catalyst, hydrogenation of aliphatic nitriles in cyclohexane efficiently proceeded at 25-60 °C under ordinary hydrogen gas pressure to afford the corresponding tertiary amines. However, the use of rhodium on carbon (Rh/C) led to the highly selective generation of secondary amines. Hydrogenation of aromatic nitriles and cyclohexanecarbonitrile selectively produced secondary amines in the presence of either Pd/C or Rh/C.

Recent Development of Palladium-Supported Catalysts for Chemoselective Hydrogenation.

This paper describes practical and selective hydrogenation methodologies using heterogeneous palladium catalysts. Chemoselectivity develops dependent on the catalyst activity based on the characteristic of the supports, derived from structural components, functional groups, and/or morphologies. We especially focus on our recent development of heterogeneous palladium catalysts supported on chelate resin, ceramic, and spherically shaped activated carbon. In addition, the application of flow technology for chemoselective hydrogenation using the palladium catalysts immobilized on molecular sieves 3A and boron nitride is outlined.

Versatile Oxidation Methods for Organic and Inorganic Substrates Catalyzed by Platinum-Group Metals on Carbons.

Platinum-group metals on activated carbon catalysts, represented by Pd/C, Ru/C, Rh/C, etc., are widely utilized to accomplish green and sustainable organic reactions due to their favorable features, such as easy handling, recoverability, and reusability. The efficient oxidation methods of various organic compounds using heterogeneous platinum-group metals on carbons with or without added oxidants are summarized in this Personal Account. The oxidation of internal alkynes into diketones was effectively catalyzed by Pd/C in the presence of dimethyl sulfoxide and molecular oxygen or pyridine N-oxide. The Pd/C-catalyzed mild combustion of gaseous hydrogen with molecular oxygen provided hydrogen peroxide, which could be directly utilized for the oxidation of sulfide derivatives into sulfoxides. Furthermore, the Ru/C-catalyzed aerobic oxidation of primary and secondary alcohols gave the corresponding aldehydes and ketones, respectively. On the other hand, the dehydrogenative oxidation of secondary alcohols into ketones was achieved using Rh/C in water, and primary alcohols were effectively dehydrogenated by Pd/C in water under mildly reduced pressure to produce carboxylic acids.

Switching the Cleavage Sites in Palladium on Carbon-Catalyzed Carbon-Carbon Bond Disconnection.

We have demonstrated a palladium on carbon-catalyzed approach to regioselectively alter the cleavage sites of the C-C bonds of cinnamaldehyde derivatives by a slight change in the reaction conditions in isopropanol under an O2 atmosphere. Styrene derivatives could be selectively formed by the addition of Na2CO3 in association with the dissociation of carbon monoxide, while benzaldehyde derivatives were generated by the addition of CuCl and morpholine instead of Na2CO3.

Disiloxane Synthesis Based on Silicon-Hydrogen Bond Activation using Gold and Platinum on Carbon in Water or Heavy Water.

Disiloxanes possessing a silicon-oxygen linkage are important as frameworks for functional materials and coupling partners for Hiyama-type cross coupling. We found that disiloxanes were effectively constructed of hydrosilanes catalyzed by gold on carbon in water as the solvent and oxidant in association with the emission of hydrogen gas at room temperature. The present oxidation could proceed via various reaction pathways, such as the hydration of hydrosilane into silanol, dehydrogenative coupling of hydrosilane into disilane, and the subsequent corresponding reactions to disiloxane. Additionally, the platinum on carbon catalyzed hydrogen-deuterium exchange reaction of arylhydrosilanes as substrates in heavy water proceeded on the aromatic nuclei at 80 °C with high deuterium efficiency and high regioselectivity at the only meta and para positions of the aromatic-silicon bond to give the deuterium-labeled disiloxanes.

Additional Nucleophile-Free FeCl3-Catalyzed Green Deprotection of 2,4-Dimethoxyphenylmethyl-Protected Alcohols and Carboxylic Acids.

The deprotection of the methoxyphenylmethyl (MPM) ether and ester derivatives can be generally achieved by the combinatorial use of a catalytic Lewis acid and stoichiometric nucleophile. The deprotections of 2,4-dimethoxyphenylmethyl (DMPM)-protected alcohols and carboxylic acids were found to be effectively catalyzed by iron(III) chloride without any additional nucleophile to form the deprotected mother alcohols and carboxylic acids in excellent yields. Since the present deprotection proceeds via the self-assembling mechanism of the 2,4-DMPM protective group itself to give the hardly-soluble resorcinarene derivative as a precipitate, the rigorous purification process by silica-gel column chromatography was unnecessary and the sufficiently-pure alcohols and carboxylic acids were easily obtained in satisfactory yields after simple filtration.

Biaryl synthesis by ring-opening Friedel-Crafts arylation of 1,4-epoxy-1,4-dihydronaphthalenes catalyzed by iron trichloride.

Biaryl and heterobiaryl compounds are important frameworks across a range of fields including pharmaceutical and functional material chemistries. We have accomplished the efficient synthesis of various naphthalene-linked arenes and heteroarenes as biaryls and heterobiaryls by the FeCl3 -catalyzed Friedel-Crafts reactions accompanied by the ring-opening of the 1,4-epoxy moiety of 1,4-epoxy-1,4-dihydronaphthalenes. Especially, it is noteworthy that 1-silylated substrates were regioselectively transformed to the 3-aryl-1-silylnaphthalenes and the double Friedel-Crafts reactions using thiophene derivatives could directly produce the corresponding bis-naphthlated thiophene derivatives.

Biarylmethane and Fused Heterocyclic Arene Synthesis via in Situ Generated o- and/or p-Naphthoquinone Methides.

o- and/or p-naphthoquinone methides (NQMs) can be selectively prepared by the ring opening of 1-(siloxymethyl)-1,4-epoxy-1,4-dihydronaphthalene derivatives based on a substituent effect at the 4 position of the substrates. The 4-alkyl- or silyl-substituted 1-(siloxymethyl)-1,4-epoxy-1,4-dihydronaphthalene was transformed to o-NQM (1-naphthoquinone-2-methide), which underwent Friedel-Crafts 1,4-addition of the α,ß-unsaturated carbonyl moiety to provide the 2-benzyl-1-naphthol as the biarylmethane and [4 + 2]-cycloaddition with a dienophile to give the fused heterocyclic arene. Meanwhile, the 4-unsubstituted 1-(siloxymethyl)-1,4-epoxy-1,4-dihydronaphthalene could be converted to the corresponding 4-benzyl-1-naphthol by the Friedel-Crafts 1,6-addition of p-NQM (1-naphthoquinone-4-methide) generated by the site-selective ring opening of the 1,4-epoxy moiety. Furthermore, the 4-(siloxymethyl)-(1,4-bis(siloxymethyl))-1,4-epoxy-1,4-dihydronaphthalene was transformed into a 2,4-bisbenzyl-1-naphthol or pentacyclic derivative via both the o- and p-NQM intermediates.

Gold-Catalyzed Benzylic Azidation of Phthalans and Isochromans and Subsequent FeCl3-Catalyzed Nucleophilic Substitutions.

The benzylic positions of the phthalan and isochroman derivatives (1) as benzene-fused cyclic ethers effectively underwent gold-catalyzed direct azidation using trimethylsilylazide (TMSN3) to give the corresponding 1-azidated products (2) possessing the N,O-acetal partial structure. The azido group of the N,O-acetal behaved as a leaving group in the presence of catalytic iron(III) chloride, and 1-aryl or allyl phthalan and isochroman derivatives were obtained by nucleophilic arylation or allylation, respectively. Meanwhile, a double nucleophilic substitution toward the 1-azidated products (2) occurred at the 1-position using indole derivatives as a nucleophile accompanied by elimination of the azido group and subsequent ring opening of the cyclic ether nucleus produced the bisindolylarylmethane derivatives.

Chemoselective and direct functionalization of methyl benzyl ethers and unsymmetrical dibenzyl ethers by using iron trichloride.

Methyl and benzyl ethers are widely utilized as protected alcohols due to their chemical stability, such as the low reactivity of the methoxy and benzyloxy groups as leaving groups under nucleophilic conditions. We have established the direct azidation of chemically stable methyl and benzyl ethers derived from secondary and tertiary benzyl alcohols. The present azidation chemoselectively proceeds at the secondary or tertiary benzylic positions of methyl benzyl ethers or unsymmetrical dibenzyl ethers and is also applicable to direct allylation, alkynylation, and cyanation reactions, as well as the azidation. The present methodologies provide not only a novel chemoselectivity but also the advantage of shortened synthetic steps, due to the direct process without the deprotection of the methyl and benzyl ethers.

Iron-catalyzed Friedel-Crafts benzylation with benzyl TMS ethers at room temperature.

Friedel-Crafts benzylations between unactivated arenes and benzyl alcohol derivatives are clean and straightforward processes to construct biologically useful di- and tri-arylmethanes. We have established an efficient iron-catalyzed Friedel-Crafts benzylation method at room temperature that uses benzyl TMS ethers as substrates, which are poorly reactive under common nucleophilic substitution conditions. The reaction seems to progress through iron-catalyzed self-condensation of the benzyl TMS ether to the corresponding dibenzylic ether. The use of excess arene relative to benzyl TMS ether produced mono-benzylated arene (di- and tri-arylmethane products), whereas the use of excess benzyl TMS ether versus arene provided bis-benzylated arene (polyarylated products) in high yields and regioselectivities. In previous methods, the latter double Friedel-Crafts benzylations hardly proceed.

Mechanism study of copper-mediated one-pot reductive amination of aryl halides using trimethylsilyl azide.

Reaction mechanisms of the copper-mediated amination of aryl halides with trimethylsilyl azide (TMSN3) were analyzed on the basis of the time-course study using reaction monitoring FT-IR, trapping an intermediary aryl azide by the Huisgen reaction, and the analysis of the generated N2 gas during the reaction. This amination would proceed through multiple pathways via aryl radicals and copper(I) azide.

Iron-catalyzed chemoselective azidation of benzylic silyl ethers.

Azidation: siloxy groups derived from secondary and tertiary benzyl alcohols can be transformed into azide groups at room temperature using TMSN(3) in the presence of an iron catalyst (TMS=trimethylsilyl). Secondary and tertiary benzylic silyl ethers can be transformed in the presence of primary silyl ethers, and other reactive functional groups, such as alkyl chlorides, α,ß-unsaturated esters, and aldehydes, are stable under the reaction conditions.

Stereo- and regioselective direct multi-deuterium-labeling methods for sugars.

Deuterium-labeled sugars can be utilized as powerful tools for the architectural analyses of high-sugar-containing molecules represented by the nucleic acids and glycoproteins, and chiral building blocks for the syntheses of new drug candidates (heavy drugs) due to their potential characteristics, such as simplifying the (1)H NMR spectra and the stability of C-D bonds compared with C-H bonds. We have established a direct and efficient synthetic method of deuterated sugars from non-labeled sugars by using the heterogeneous Ru/C-catalyzed H-D exchange reaction in D(2)O under a hydrogen atmosphere with perfect chemo- and stereoselectivities. The direct H-D exchange reaction can selectively proceed on carbons adjacent to the free hydroxyl groups, and the deuterium labeling of various pyranosides (such as glucose and disaccharides), as well as furanosides, represented by ribose and deoxyribose was realized. Furthermore, the desired number of deuterium atoms can be freely incorporated into selected positions by the site-selective protection of the hydroxyl groups using acetal-type protective groups because the deuterium exchange reaction never proceeds on positions adjacent to the protected hydroxyl groups.

Selective N-alkylation of amines using nitriles under hydrogenation conditions: facile synthesis of secondary and tertiary amines.

Nitriles were found to be highly effective alkylating reagents for the selective N-alkylation of amines under catalytic hydrogenation conditions. For the aromatic primary amines, the corresponding secondary amines were selectively obtained under Pd/C-catalyzed hydrogenation conditions. Although the use of electron poor aromatic amines or bulky nitriles showed a lower reactivity toward the reductive alkylation, the addition of NH(4)OAc enhanced the reactivity to give secondary aromatic amines in good to excellent yields. Under the same reaction conditions, aromatic nitro compounds instead of the aromatic primary amines could be directly transformed into secondary amines via a domino reaction involving the one-pot hydrogenation of the nitro group and the reductive alkylation of the amines. While aliphatic amines were effectively converted to the corresponding tertiary amines under Pd/C-catalyzed conditions, Rh/C was a highly effective catalyst for the N-monoalkylation of aliphatic primary amines without over-alkylation to the tertiary amines. Furthermore, the combination of the Rh/C-catalyzed N-monoalkylation of the aliphatic primary amines and additional Pd/C-catalyzed alkylation of the resulting secondary aliphatic amines could selectively prepare aliphatic tertiary amines possessing three different alkyl groups. According to the mechanistic studies, it seems reasonable to conclude that nitriles were reduced to aldimines before the nucleophilic attack of the amine during the first step of the reaction.

Development of diversified methods for chemical modification of the 5,6-double bond of uracil derivatives depending on active methylene compounds.

The reaction of 5-halogenouracil and uridine derivatives 1 and 7 with active methylene compounds under basic conditions produced diverse and selective C-C bond formation products by virtue of the nature of the carbanions. Three different types of reactions such as the regioselective C-C bond formation at the 5- and 6-positions of uracil and uridine derivatives (products 2, 5, 8, 17, 20 and 21), and the formation of fused heterocycle derivatives 2,4-diazabicyclo[4.1.0]heptane (15) and 2,4-diazabicyclo-[4.1.0]nonane (16) via dual C-C bond formations at both the 5- and 6-positions were due to the different active methylene compounds used as reagents.

Nitriles for the production of various amines.

Nitriles functionalize amines and ammonia under catalytic hydrogenation conditions.