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

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Published in 2006

RuHCl(CO)(PPh3)3-Catalyzed Reductive Dimerization of α,β-Unsaturated Aldehydes Leading to α-Hydroxymethyl Ketones
Takashi Doi, Takahide Fukuyama, Satoshi Minamino, Ilhyong Ryu
Synlett, 2006, 18, pp. 3013 - 3016
DOI: 10.1055/s-2006-951518
The reductive dimerization α,β-unsaturated aldehydes to give saturated ketones was achieved using RuHCl(CO)(PPh3)3 as a catalyst in the presence of secondary alcohols as hydrogen source. The reaction is likely to proceed via the hydroruthenation of α,β-unsaturated aldehydes followed by aldol reaction of the resultant ruthenium enolates with α,β-unsaturated aldehydes to give unsaturated α-hydroxymethyl ketones, which undergo transfer hydrogenation to give α-hydroxymethyl ketones.

Trifluoromethyl-Radical-Mediated Carbonylation of Alkanes Leading to Ethynyl Ketones
Uenoyama, Y., Fukuyama, T., Morimoto, K., Nobuta, O., Nagai, H., Ryu, I.
Helvetica. Chem., 2006, 89, pp. 2483 - 2494
DOI: 10.1002/hlca.200690228

The carbonylation of alkanes 1 under radical-reaction conditions was examined by using ethynyl triflone A as the unimolecular chain-transfer (UMCT) reagent. Good to moderate yields of ethynyl ketones 2 were prepared by means of this three-component coupling reaction. Higher CO pressures as well as lower concentrations of triflone A improved the efficiency of the reaction over the direct addition, the latter leading to alkylated ethynes 3. In contrast to the reaction with A, the reaction of cyclohexane (1a) with allyl triflone B (= ethyl 2-methylene-3-[(trifluoromethyl)sulfonyl]propanoate) in the presence of CO gave a mixture of carbonylation products, including 8a formed from two molecules each of cyclohexane, CO, and allyl triflone B.

Low Pressure Pd-Catalyzed Carbonylation in an Ionic Liquid Using a Multiphase Microflow System
Rahman, M. T., Fukuyama, T., Kamata, N., Ryu, I.
Chem. Commun., 2006, 21, pp. 2236 - 2238
DOI: 10.1039/b600970k

A low pressure microflow system was developed for palladium-catalyzed multiphase carbonylation reactions in an ionic liquid. The microflow system resulted in superior selectivity and higher yields in carbonylative Sonogashira coupling and amidation reactions of aryl iodides compared to the conventional batch system.

Radicals Masquerading as Electrophiles: a Computational Study of the Intramolecular Addition Reactions of Acyl Radicals to Imines
Matsubara, H., Falzon, C. T., Ryu, I., Schiesser, C. H.
Org. Biomol. Chem., 2006, 10, pp. 1920 - 1926
DOI: 10.1039/b603024f

Ab initio calculations using 6-311G**, cc-pVDZ, and aug-cc-pVDZ, with (MP2, QCISD, CCSD(T)) and without (UHF) electron correlation, and density functional methods (BHandHLYP and B3LYP) predict that cyclization of the 5-aza-5-hexenoyl and (E)-6-aza-5-hexenoyl radicals proceed to afford the 5-exo products. At the CCSD(T)/cc-pVDZ//BHandHLYP/cc-pVDZ level of theory, energy barriers (ΔE) of 36.1 and 47.0 kJ mol–1 were calculated for the 5-exo and 6-endo pathways for the cyclization of the 5-aza-5-hexenoyl radical. On the other hand, at the same level of theory, E of 38.9 and 45.4 kJ mol–1 were obtained for the 5-exo and 6-endo cyclization modes of (ΔE)-6-aza-5-hexenoyl radical, with exothermicities of about 27 and 110 kJ mol–1 calculated for the exo and endo modes, respectively. Under suitable experimental conditions, the 6-endo cyclization product is likely to dominate. Analysis of the molecular orbitals involved in these ring-closure reactions indicate that both reactions at nitrogen are assisted by dual orbital interactions involving simultaneous SOMO–π* and LP–π* overlap in the transitions states. Interestingly, the (Z)-6-aza-5-hexenoyl radical, that cannot benefit from these dual orbital effects is predicted to ring-close exclusively in the 5-exo fashion.

Cascade Radical Carbonylations Leading to 3-Substituted Cyclohexanones
Uenoyama, Y., Fukuyama, T., Ryu, I.
Synlett., 2006, 14, pp. 2342 - 2344
DOI: 10.1055/s-2006-949643

Tin radical mediated [5+1]-annulation methods leading to 3-substituted cyclohexanones were investigated. Cyclohexanones having a quaternary center at the 3-position were synthesized in good yields by allyltin-mediated three- and four-component cascade reactions that involve (i) radical carbonylation, (ii) 6-endo cyclization, and (iii) alkene addition.

Reaction of Ketone Dilithio α,β-Dianions with Imines and Hydrozones: an Anionic Acess to γ-Amino Ketones
Ryu, I., Yamamura, G., Omura, S., Minakata, S., Komatsu, M.
Tetrahedron Lett., 2006, 47, pp. 2283 - 2286
DOI: 10.1016/j.tetlet.2006.02.026

The reactions of ketone dilithio α,β-dianions with imines and hydrazones were investigated. The nucleophilic addition reaction to C–N double bonds took place selectively at the β-position of dianions to form lithium Z-enolates containing a lithium amide portion, which is then transformed into γ-amino ketones and related compounds by the subsequent reaction with electrophiles.

High throughput Evaluation of the Production of Substituted Acetylenes by the Sonogashira Reaction followed by the Mizoroki-Heck Reaction in Ionic Liquids, in situ, using a Novel Array Reactor
Rahman, Md. T., Fukuyama, T., Ryu, I., Suzuki, K., Yonemura, K., Hughes, P. F., Nokihara, K.
Tetrahedron Lett., 2006, 47, pp. 2703 - 2706
DOI: 10.1016/j.tetlet.2006.02.084

The parallel Sonogashira coupling reaction was carried out under copper-free condition by integrating the advantages of ionic liquids as the reaction media followed by the simultaneous-multiple Mizoroki–Heck reaction in situ by the use of a novel array reactor (SynArray-24). The device provides rapid evaluation of reactions in a short period.

Selective 6-Endo Cyclization of the Acyl Radicals onto Nitrogen of Imine and Oxazoline C-N Bonds
Tojino, M., Otsuka, N., Fukuyama, T., Matsubara, H., Ryu, I.
J. Am. Chem. Soc., 2006, 128, 24 pp. 7712 - 7713
DOI: 10.1021/ja0623865

Acyl radicals generated by the addition of alkyl or vinyl radicals to carbon monoxide cyclized onto the C−N bonds of imines and oxazoline with perfect 6-endo selectivity, driven by a preference for attack at nitrogen.

Carbonylative Approaches to α,β-Unsaturated Acyl Radical and α-Ketenyl Radicals
Ryu, I., Uenoyama, Y., Matsubara, H.
Bull. Chem. Soc. Jpn., 2006, 79, 10 pp. 1476 - 1488
DOI: 10.1246/bcsj.79.1476

The carbonylation of vinyl radicals gives α,β-unsaturated acyl radicals. This transformation was successfully applied to tandem radical reactions, resulting in assembling three and four components. In these reactions, both halogen abstraction from vinyl halides and hetero atom radical additions to alkynes are used to generate the parent vinyl radicals. Ab initio calculations and density functional methods predict that α,β-unsaturated acyl radicals and the isomeric α-ketenyl radicals are not canonical forms, but are isomeric species that undergo interconversion. Calculations also indicate that α,β-unsaturated acyl radicals are more stable than α-ketenyl radicals, whereas α-ketenyl radicals containing a heteroatom, such as Si, Ge, and Sn, at α-position are more stable than the corresponding α,β-unsaturated acyl radicals. This represents a promising resource for developing new synthetic applications that involve the use of the α-ketenyl radicals. Indeed, following the prediction by calculation, we succeeded in trapping of a tin-attached α-ketenyl radical by imines and amines in an intramolecular fashion. We were also able to achieve the intermolecular trapping of α-ketenyl radicals, providing a new method for alkyne carbonylation by hybrid radical/ionic reactions.

An Unusual Ruthenium Hybride-Catalyzed Dimerrization of Primary Unsaturated Alcohols
Doi, T., Fukuyama, T., Minamino, S., Husson, G., Ryu, I.
Chem. Commun., 2006, 17, pp. 1875 - 1877
DOI: 10.1039/b602103d

When primary unsaturated alcohols were treated with a catalytic amount of RuHCl(CO)(PPh3)3 in benzene under reflux, dimerization reactions took place to give α-hydroxymethyl ketones as major product.

Effective Acceleration of Atom Transfer Carbonylation of Alkyl Iodides by Metal Complexes. Application to the Synthesis of Hinokinin Precursor and Dihydrocapsaicin
Fukuyama, T., Nishitani, S., Inouye, T., Morimoto, K., Ryu, I.
Org. Lett., 2006, 8, pp. 1383 - 1386
DOI: 10.1021/ol060123+

Atom transfer carbonylation (ATC) of alkyl iodides leading to carboxylic acid esters is effectively accelerated by Pd(PPh3)4 and Mn2(CO)10 under photoirradiation conditions. In the presence of amines, Pd(0) complexes affected double carbonylations leading to α-keto amides, whereas Mn2(CO)10 accelerated only a single carbonylation reaction leading to the corresponding amides. The Pd(0)-accelerated ATC system was successfully applied to the synthesis of hinokinin and dihydrocapsaicin.

RuHCl(CO)(PPh3)3-Catalyzed Chemoselective Transfer Hydrogenation of Enones Leading to Saturated Ketones
Doi, T., Fukuyama, T., Horiguchi, J., Okamura, T., Ryu, I.
Synlett., 2006, 5, pp. 721 - 724
DOI: 10.1055/s-2006-933133

The highly chemoselective transfer-hydrogenation of α,β-unsaturated ketones to give saturated ketones was achieved using RuHCl(CO)(PPh3)3 as a catalyst. In addition to α,β-unsaturated ketones, other enones, containing a remote C=C bond, were also reduced to give saturated ketones in good to excellent yields with high selectivity.

The Barton Reaction Using a Microreactor and Black Light. Continuous-Flow Synthesis of a Key Steroid Intermediate for an Endothelin Receptor Antagonist
Sugimoto, A., Sumino, Y., Takagi, M., Fukuyama, T., Ryu, I.
Tetrahedron Lett., 2006, 47, pp. 6197 - 6200
DOI: 10.1016/j.tetlet.2006.06.153

The Barton reaction (nitrite photolysis) of a steroidal substrate 1, to give 2, a key intermediate for the synthesis of an endothelin receptor antagonist, was successfully carried out in a continuous microflow system using a pyrex glass-covered stainless-steel microreactor having a microchannel (Type A: 1000 μm width, 107 μm depth, 2.2 m length). We found that a 15 W black light (peak wavelength: 352 nm) as the light source, suffices for the Barton reaction, creating a compact photo-micro reaction system. Multi-gram scale production was attained using two serially connected, multi-lane microreactors (Type B).



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