The Ryu Research Group, Department of Chemistry, Graduate School of Science, Osaka Prefecture University

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Published in 2012

100 Gram Scale Synthesis of a Key Intermediate of Matrix Metalloproteinase Inhibitor in a Continuous-Flow System Based on a Copper-Free Sonogashira Reaction Using an Ionic Liquid as a Catalyst Support
Fukuyama, T., Taifur R. M., Sumino, Y., Ryu, I.
Synlett, 2012, 23, 15 pp. 2279 - 2283
DOI: 10.1055/s-0031-1290456

The key intermediate of matrix metalloproteinase (MMP) inhibitor was synthesized using a flow microreactor for a copper-free Sonogashira coupling reaction in an ionic liquid. The ionic liquid [emim]NTf2 was used as a solvent and a catalyst support. A 100 g scale synthesis was achieved in combination with a flow-extraction/catalyst-recycling system, in which the ionic liquid containing the palladium catalyst was continuously recycled.

Synthesis of Carbamoylacetates from α-Iodoacetate, CO, and Amines under Pd/Light Combined Conditions
Sumino, S., Fusano, A., Fukuyama, T., Ryu, I.
Synlett, 2012, 23, 9 pp. 1331 - 1334
DOI: 10.1055/s-0031-1290690

We developed a novel synthetic method of carbamoylacetates from α-iodoacetate, carbon monoxide, and amines under photoirradiation conditions in the presence of a Pd catalyst. This reaction likely proceeds via interplay of radical and organopalladium species.

RuHCl(CO)(PPh3)3-Catalyzed α-Alkylation of Ketones with Primary Alcohols
Kuwahara, T., Fukuyama, T., Ryu, I.
Org. Lett., 2012, 14, 18 pp. 4703 - 4705
DOI: 10.1021/ol302145a

The α-alkylation reaction of ketones with primary alcohols to give α-alkylated ketones was achieved using RuHCl(CO)(PPh3)3 as a catalyst in the presence of Cs2CO3 as a base. This reaction proceeds via an aldol condensation of ketones with aldehydes, formed via transfer dehydrogenation of alcohols, to give α,β-unsaturated ketones, which then undergo transfer hydrogenation with primary alcohols to give α-alkylated ketones and aldehydes, the latter of which participate in the next catalytic cycle. While the reaction of aliphatic primary alcohols was sluggish compared with that of benzylic alcohols, a catalytic amount of 1,10-phenanthroline was found to promote the alkylation dramatically.

Nitroxide-Mediated Polymerization of Styrene, Butyl Acrylate, or Methyl Methacrylate by Microflow Reactor Technology
Fukuyama, T., Kajihara, Y., Ryu, I., Studer, A.
Synthesis, 2012, 44, 16 pp. 2555 - 2559
DOI: 10.1055/s-0031-1290780

The nitroxide-mediated radical polymerization (NMP) of styrene and butyl acrylate in microflow tubular reactors was examined. In comparison with polymerizations conducted in a batch reactor under otherwise identical conditions, the microflow setup gave higher conversions and produced polymers with lower polydispersity indices. Block copolymers of the two monomers could be synthesized by connecting two microflow tubular reactors through a T-junction. The NMP of methyl methacrylate in a microflow tubular reactor was also investigated.

Pd/Light-Accelerated Atom-Transfer Carbonylation of Alkyl Iodides: Applications in Multicomponent Coupling Processes Leading to Functionalized Carboxylic Acid Derivatives
Fusano, A., Sumino, S., Nishitani, S., Inoue, T., Morimoto, K., Fukuyama, T., Ryu, I.
Chem. Eur. J., 2012, 18, 30 pp. 9415 - 9422
DOI: 10.1002/chem.201200752

The atom-transfer carbonylation reaction of various alkyl iodides thereby leading to carboxylic acid esters was effectively accelerated by the addition of transition-metal catalysts under photoirradiation conditions. By using a combined Pd/ reaction system, vicinal C-functionalization of alkenes was attained in which α-substituted iodoalkanes, alkenes, carbon monoxide, and alcohols were coupled to give functionalized esters. When alkenyl alcohols were used as acceptor alkenes, three-component coupling reactions, which were accompanied by intramolecular esterification, proceeded to give lactones. Pd-dimer complex [Pd2(CNMe)6][PF6]2, which is known to undergo homolysis under photoirradiation conditions, worked quite well as a catalyst in these three- or four-component coupling reactions. In this metal/radical hybrid system, both Pd radicals and acyl radicals are key players and a stereochemical study confirmed the carbonylation step proceeded through a radical carbonylation mechanism.

Free Radical-mediated Hydroxymethylation Using CO and HCHO
Kawamoto, T., Ryu, I.
CHIMIA, 2012, 66, 6 pp. 372 - 376

Tin-free radical hydroxymethylations of haloalkanes using CO and HCHO as a C1 unit proceed efficiently in the presence of borohydrides as radical mediators. In the approach using CO, the formation of aldehydes by radical carbonylation and their subsequent reduction by hydrides lead to alcohols. On the other hand, the use of formaldehyde is more straightforward, in which the key reaction is alkyl radical addition to formaldehyde to give alkoxy radical, which abstracts hydrogen from borohydride reagents. The cascade sequences were observed in the reaction of cholesteryl bromide with HCHO, which displays the diverse applications of HCHO in radical chemistry.

Total Synthesis and Structural Revision of Hericerin
Kobayashi, S., Inoue, T., Ando, A., Tamanoi, H., Ryu, I., Masuyama, A.
J. Org. Chem., 2012, 77, 13 pp. 5819 - 5822
DOI: 10.1021/jo300719m

The total synthesis of hericerin, a pollen growth inhibitor from Hericium erinaceum, was achieved. We found that the reported structure of hericerin should be revised to be the carbonyl regioisomer.

Rh-Catalyzed [5+1] and [4+1] Cycloaddition Reactions of 1,4-Enyne Esters with CO: A Shortcut to Functionalized Resorcinols and Cyclopentenones
Fukuyama, T., Ohta, Y., Brancour, C., Miyagawa, K., Ryu, I., Dhimane, A.-L., Fensterbank, L., Malacria, M.
Chem. Eur. J., 2012, 18, 23 pp. 7243 - 7247
DOI: 10.1002/chem.201200045

We have developed novel Rh-catalyzed [n+1]-type cycloadditions of 1,4-enyne esters, which involve an acyloxy migration as a key step. The efficient preparation of functionalized resorcinols, including biaryl derivatives, from readily available 1,4-enyne esters and CO was achieved by Rh-catalyzed [5+1] cycloaddition accompanied by 1,2-acyloxy migration. When enyne esters had an internal alkyne moiety, the reaction proceeded by a [4+1]-type cycloaddition involving 1,3-acyloxy migration, leading to cyclopentenones.

A Transition-Metal-Free Cross-Coupling Reaction of Allylic Bromides with Aryl- and Vinylboronic Acids
Ueda, M., Nishimura, K., Kashima, R., Ryu, I.
Synlett, 2012, 23, 7 pp. 1085 - 1089
DOI: 10.1055/s-0031-1290656

A cross-coupling reaction between aryl- and vinylboronic acids and various allylic bromides proceeded without the use of a transition-metal catalyst to give the corresponding allylated products in moderate to good yields. The use of an inorganic base (KF or Cs2CO3) and a small amount of water is crucial in obtaining good performance in the present transition-metal-free reaction.

Iron-catalyzed decarbonylation reaction of aliphatic carboxylic acids leading to α-olefins
Maetani, S., Fukuyama, T., Suzuki, N., Ishihara, D., Ryu, I.
Chem. Commun., 2012, 48, 19 pp. 2552 - 2554
DOI: 10.1039/C2CC18093F

Graphical abstract: Iron-catalyzed decarbonylation reaction of aliphatic carboxylic acids leading to α-olefins

The catalytic decarbonylation reaction of aliphatic carboxylic acids can be carried out in the presence of an iron complex, and it proceeds smoothly to give α-olefins with high selectivity.

Radical Addition of Alkyl Halides to Formaldehyde in the Presence of Cyanoborohydride as a Radical Mediator. A New Protocol for Hydroxymethylation Reaction
Kawamoto, T., Fukuyama, T., Ryu, I.
J. Am. Chem. Soc., 2012, 134, 2 pp. 875 - 877
DOI: 10.1021/ja210585n
Abstract Image

Hydroxymethylation of alkyl halides was achieved using paraformaldehyde as a radical C1 synthon in the presence of tetrabutylammonium cyanoborohydride as a hydrogen source. The reaction proceeds via a radical chain mechanism involving an alkyl radical addition to formaldehyde to form an alkoxy radical, which abstracts hydrogen from a hydroborate anion.



Laboratory for Advanced Organic Synthesis
Organization for Research Promotion Osaka Prefecture University
Sakai, Osaka 599-8531, JAPAN
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