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Published in Reviews

Continuous Flow Synthesis Using Recyclable Reaction Media
Takahide Fukuyama, Akihiro Furuta, Ilhyong Ryu
Sustainable Flow Chemistry, 2017, , pp. -
DOI: 10.1002/9783527689118.ch2

カルボニル化の新手法/ Innovative Carbonylation Methods
Kawamoto, T., Fukuyama, T., Ryu, I.
有機合成化学協会誌/ J. Synth. Org. Chem. Jpn., 2014, 72, 5 pp. 493 - 505
DOI: 10.5059/yukigoseikyokaishi.72.493


Having a variety of species including radicals, cations, anions, and transition metal species as part of the repertoire, carbonylation chemistry is becoming more and more rich in synthetic methodology. Recent innovations with regard to the reaction devices available for carbonylation have been significant, including autoclaves that have the ability to permit light irradiation under CO pressure, compact CO boosters to create very high CO pressure conditions, flow reactor systems equipped with a mass flow controllers to ensure excellent gas-liquid mixing, and twin-tube reactors available for carbonylation with ex-situ generated CO. In this account, we survey the recent evolution of modern carbonylation techniques beginning with novel carbonylation reactions developed in our laboratory, like borohydride-mediated carbonylation, light induced carbonylation, and carbonylation based on radical/ion hybrid reactions. We believe that with innovations in synthetic methods and equipment, each carbonylation reaction will be easily run in a device specifically suitable for optimal performance in that reaction.


Carbonylation Reactions of Alkyl Iodides through the Interplay of Carbon Radicals and Pd Catalysts
Sumino, S., Fusano, A., Fukuyama, T., Ryu, I.
Acc. Chem. Res., 2014, 47, 5 pp. 1563 - 1574
DOI: 10.1021/ar500035q
Numerous methods for transition metal catalyzed carbonylation reactions have been established. Examples that start from aryl, vinyl, allyl, and benzyl halides to give the corresponding carboxylic acid derivatives have all been well documented. In contrast, the corresponding alkyl halides often encounter difficulty. This is inherent to the relatively slow oxidative addition step onto the metal center and subsequent β-hydride elimination which causes isomerization of the alkyl metal species. Radical carbonylation reactions can override such problems of reactivity; however, carbonylation coupled to iodine atom transfer (atom transfer carbonylation), though useful, often suffers from a slow iodine atom transfer step that affects the outcome of the reaction. We found that atom transfer carbonylation of primary, secondary, and tertiary alkyl iodides was efficiently accelerated by the addition of a palladium catalyst under light irradiation. Stereochemical studies support a mechanistic pathway based on the synergic interplay of radical and Pd-catalyzed reaction steps which ultimately lead to an acylpalladium species. The radical/Pd-combined reaction system has a wide range of applications, including the synthesis of carboxylic acid esters, lactones, amides, lactams, and unsymmetrical ketones such as alkyl alkynyl and alkyl aryl ketones. The design of unique multicomponent carbonylation reactions involving vicinal C-functionalization of alkenes, double and triple carbonylation reactions, in tandem with radical cyclization reactions, has also been achieved. Thus, the radical/Pd-combined strategy provides a solution to a longstanding problem of reactivity involving the carbonylation of alkyl halides. This novel methodology expands the breadth and utility of carbonylation chemistry over either the original radical carbonylation reactions or metal-catalyzed carbonylation reactions.

Green Chem
Carbonylation in microflow: close encounters of CO and reactive species
Fukuyama, T., Totoki, T., Ryu, I.
Green Chem., 2014, 16, 4 pp. 2042 -
DOI: 10.1039/C3GC41789A
Microreactors have brought significant improvements to chemical synthesis and production because of their advantageous characteristics over batch reactors, which include highly efficient mixing, efficient heat and mass transfer ability, precise control of the residence time, large surface area-to-volume ratio and high operational safety. Microreactor technology has been found to be beneficial for gas–liquid biphasic reactions, for which the large interfacial area between the two phases is ensured. Carbonylation reactions with carbon monoxide, by which a wide range of carbonyl compounds can be prepared, deal with a variety of reactive species, such as organo transition metals, radicals, cations and anions. These reactions have long been carried out using a glass batch flask or a stainless-steel made autoclave, however, carbonylation reactions using a flow microreactor are now rapidly increasing in popularity. This review focuses on a new greener wave of carbonylation reactions using a flow microreactor.

Multi-Task Catalyst: Ruthenium Hydride Catalyzed Atom-Economical Bond Forming Reactions
Fukuyama, T., Omura, S., Ryu, I

Phase-Vanishing Methods Based on Fluorous Phase Screen: A Simple Way for Efficient Execution of Organic Synthesis
Ryu, I., Matsubara, H., Nakamura, H., Curran, D. P.
Chemical Record 2008, 2008, 8, 6 pp. 351 - 363
DOI: 10.1002/tcr.20161

The phase-vanishing (PV) method is based on spontaneous reaction controlled by diffusion of reagents into fluorous media, such as perfluorohexanes (FC-72) and polyperfluoroethers. Thus, the original PV reaction utilizes a triphasic test tube method composed of a bottom reagent phase, a middle fluorous phase, and a top substrate phase. In such a triphasic system, the fluorous phase acts as a liquid membrane to transport the bottom reagents to the top organic phase containing substrates. In the end, the bottom layer disappears and two phases remain. Since the first demonstration of the PV method by bromination of alkenes with molecular bromine, a number of applications have been developed thus far. These include halogenation of alcohols with SOBr2 and PBr3, demethylation of methoxyarenes with BBr3, cyclopropanation of alkenes by CH2I2-AlEt3, and Friedel–Crafts acylation of aromatic compounds with SnCl4. A fluorous triphasic U-tube method is effective for chlorination of alcohols based on lighter (less dense) reagents such as SOCl2 and PCl3. A system using a solution containing reagents as a bottom phase is useful for oxidation with m-CPBA, which may be defined as a new category for the “extractive PV” method. Recent advances include a “quadraphasic” PV method, in which an aqueous “scavenger” phase is added to the original triphasic PV method to remove acidic by-products. © 2008 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 8: 351–363; 2008: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.20161

Adventures in Inner Space: Microflow Systems for Practical Organic Synthesis
Fukuyama, T., Rahman, M. T., Sato, M., Ryu, I.
Synlett, 2008, , pp. 151 - 163
DOI: 10.1055/s-2007-1000884

This account presents an overview of our recent endeavors to achieve practical organic syntheses using a variety of microreaction devices. Herein are our achievements in ionic liquid-based catalytic reactions, photochemical transformation, and heterogenous hydrogenation reactions, where flow regime precisely controls residence time and product selectivity.

Radicals Masquerading as Electrophiles: Dual Orbital Effects in Nitrogen-Philic Acyl Radical Cyclization and Related Addition Reactions
Schiesser, C. H., Wille, U., Matsubara, H., Ryu, I.
Acc. Chem. Res., 2007, 40, 5 pp. 303 - 313
DOI: 10.1021/ar600015v

Free-radical chemistry has come a long way in a relatively short period of time. The synthetic practitioner takes for granted the wealth of mechanistic and rate constant data now available and can apply free-radical techniques to the synthesis of many different classes of target molecule with confidence. Despite this, there are still mechanistic anomalies that need to be addressed. This Account highlights recent work involving nucleophilic radicals with low-lying unoccupied orbitals, such as acyl, oxyacyl, silyl, stannyl, and germyl radicals. Through interesting singly occupied molecular orbital (SOMO)–π* and highest occupied molecular orbital (HOMO)–lowest unoccupied molecular orbital (LUMO) interactions during these reactions, the radicals involved are able to mask as electrophiles, providing high levels of regiocontrol and efficient methods for the synthesis of important heterocycles.

Carbonylative approaches to alpha,beta-unsaturated acyl radicals and alpha-ketenyl radicals. Their structure and applications in synthesis
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.

柳 日馨
「最新有機合成化学 ヘテロ原子・遷移金属化合物を用いる合成」 東京化学同人、奈良坂紘一・岩澤伸治 編 , , , pp. -


化学同人、井上将彦・柳 日馨 編著 , , , pp. -

Carbon Monoxide
Fukuyama, T., Ryu, I.
Electronic Encyclopedia of Reagents for Organic Synthesis, 2006, , pp. -

Chemistry of Ketone Dilithio Dianiones
Ryu, I., Nakahira, H.
The Chemistry of Organolithium Compounds, 2006, 2, 9 pp. 647 - 674

Ionic liquids and catalyst immobilization. Reacent advances
Fukuyama, T., Ryu, I.
J. Synth. Org. Chem. Jpn., 2005, 63, pp. 503 -

柳 日馨
「フルオラスケミストリー」大寺純蔵監修、シーエムシー出版, 2005, , pp. -

Fluorinated solvents
Matsubara, H., Ryu, I.
Green Separation Processes: Fundamentals and Applications, 2005, , pp. 219 -

Fluorous Solvent
Matsubara, H., Ryu, I.
Green Reaction Media in Organic Synthesis, 2005, , pp. -

柳 日馨, 松原 浩
ファルマシア, 2005, 41, 2 pp. 111 - 116

"1H, 1H, 2H, 2H-Perfluorooctyl 1,3-dimethylbutyl ether"
Matsubara, H., Ryu, I.
e-EROS Encyclopedia of Reagents for Organic Synthesis, 2004, , pp. -

1-Hydroxymethylation with a Fluorous Tin Hydride
Ryu, I., Matsubara, H., Curran, D. P.
Handbook of Fluorous Chemistry, 2004, , pp. 470 -

New approaches in radical carbonylation chemistry: Fluorous applications and designed tandem processes by species-hybridization with anions and transition metal species
Ryu, I.
Chem. Rec., 2002, 2, 4 pp. 249 - 258
DOI: 10.1002/tcr.10026

New approaches in radical carbonylation chemistry are described. We have successfully integrated tin mediated radical carbonylation chemistry into modern fluorous applications and separation techniques. We revealed that radical carbonylation reactions can be performed using fluorous tin mediators, such as fluorous tin hydride and fluorous allyltin reagents. Fine tuning of the reaction conditions resulted in a good efficiency equivalent to conventional tin mediators. The tedious procedure of removing organotin byproducts can be circumvented through the use of fluorous/organic liquid-liquid extraction or fluorous liquid-solid phase extraction with fluorous reverse phase silica (FRPS). Also described are newly developed tandem carbonylation reactions that are based on species hybridization approaches. Using a radical/anionic hybrid system based on zinc-induced one-electron reduction, we achieved a three-component coupling reaction consisting of 4-alkenyl iodides, carbon monoxide, and electron-deficient alkenes. We observed two types of annulations processes, namely [4 + 1](radical)/[3 + 2](anionic) and [5 + 1](radical)/[3 + 2](anionic), which lead to the production of bicyclo[3.3.0]octanols and bicyclo[3.2.1]octanols, respectively. We found a radical/palladium hybrid system to be useful in the construction of new cyclic systems that incorporate two or three molecules of carbon monoxide. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 2: 249–258, 2002: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.10026

Radical carboxylations of idoalkanes and saturated alcohols using carbon monoxide
Ryu, I.
Chem. Soc. Rev., 2001, 30, pp. 16 - 25
DOI: 10.1039/A904591K

This review covers two radical carboxylation methods using carbon monoxide, both of which were developed by our group. The first method, atom transfer carbonylation, converts alkyl iodides into carboxylic acid esters or amides and the second method, remote carboxylation, converts saturated alcohols into δ-lactones. Both methods rely upon radical carbonylation chemistry to introduce carbon monoxide, but the key steps are conceptually different. The first method utilizes an atom transfer reaction from an alkyl iodide to an acyl radical leading to an acyl iodide and the latter employs a one-electron oxidation reaction to convert an acyl radical into an acyl cation. The iodine atom transfer carbonylation process is reversible and therefore highly inefficient unless it is performed in concert with an ionic system to shift the equilibrium in the direction of an acyl iodide. In the latter process, a 1,5-translocation scheme to shift the radical from oxygen to the δ-carbon is successfully coupled with the carbonylation–oxidation sequence. Carboxylations of alkyl halides by transition metal catalyzed methods are often problematic because of the inherent weakness of alkyl–metal bonds. Existing methods for carbonylative δ-lactone synthesis using transition metal catalysts are limited to unsaturated alcohols. Thus, these two radical carboxylation methods nicely complement existing transition metal catalyzed carboxylations.

Radical carbonylations mediated by tin, germanium, and silicon
Ryu, I.
Radicals in Organic Synthesis; P. Renaud and M. P. Sibi, 2001, 2, pp. 22 -

Modern free radical methods for the synthesis of carbonyl compounds
Ryu, I., Komatsu, M.
Modern Carbonyl Chemistry; J. Otera, 2000, , pp. 93 -

Isomerization of oxygen-substituted cyclopropanes by metal ctalysis
Sugimura, T., Ryu, I.
J. Synth. Org. Chem., Japan, 2000, 58, pp. 1100 -

Chemistry of acyl radicals
Chatgilialoglu, C., Crich, D., Komatsu, M., Ryu, I.
Chem. Rev., 1999, 99, 8 pp. 1991 - 2070
DOI: 10.1021/cr9601425

Donor-substtuted cyclopropanes
Ryu, I., Murai, S.
Methoden der Organisches Chemie(houben-Weyl), 1997, E17, pp. 1985 -

応用化学講座4「有機合成化学」朝倉書店、[第2章 有機工業基礎]
柳 日馨, 園田 昇, 他6名
, 1997, , pp. 58 - 95

Tandem radical reactions of carbon monoxide, isonitriles, and other reagent equivalents of geminal radical acceptor/radical precursor synthon
Ryu, I., Sonoda, N., Curran, D. P.
Chem. Rev., 1996, 96, 1 pp. 177 - 194
DOI: 10.1021/cr9400626

Free-radical carbonylations: Then and now
Ryu, I., Sonoda, N.
Angew. Chem. Int. Ed., 1996, 35, 10 pp. 1050 - 1066
DOI: 10.1002/anie.199610501

Although known since the 1950s, free-radical carbonylation has not received much attention until only recently. In the last few years the application of modern free-radical techniques has revealed the high synthetic potential of this reaction as a tool for introducing CO into organic molecules. Clearly now is the time for a renaissance of this chemistry. Under standard conditions (tributyltin hydride/CO) primary, secondary, as well as tertiary alkyl bromides and iodides can be efficiently converted into the corresponding aldehydes. Aromatic and α,β-unsaturated aldehydes can also be prepared from the parent aromatic and vinylic iodides. If the reaction is carried out in the presence of alkenes containing an electron-withdrawing substituent, the initially formed acyl radical subsequently adds to the alkene, leading to a general method for the synthesis of unsymmetrical ketones. This three-component coupling reaction can be extended successfully to allyltin-mediated reactions. Thus, β,γ-enones can be prepared from organic halides, CO, and allyltributylstannanes. In a remarkable one-pot procedure alkyl halides can be treated with a mixture of alkene, allyltributylstannane, and carbon monoxide in a four-component coupling reaction that provides β-functionalized δ,ϵ-unsaturated ketones by the formation of three new C―C bonds. The reaction of 4-pentenyl radicals with CO leads to acyl radical cyclization, which provides a useful method for the synthesis of cyclopentanones. Certain useful one-electron oxidations can be combined efficiently with free-radical carbonylations. These findings and others discussed in this article clearly demonstrate that free-radical carbonylation can now be considered a practical alternative to transition metal mediated carbonylation.





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