No.166 No.166

ResearchResearch ArticleArticle

Invention of Synthetic Reactions Based on σ−Bond Activation

Tamejiro Hiyama

RDI Professor Research and Development Initiative, Chuo University

1. Introduction 2. Organosilicon Reagent/Fluoride Ion

During my studies with Professor Hitosi Nozaki, we It would be fascinating if both the cationic and anionic had weekly discussions about the present and future of our species were generated by the cleavage of element–element chemistry. It may have been in the summer of 1980 that bonds. I pictured a reaction scheme in which disilane and a Professor Nozaki said one day “When I gave a lecture in fluoride ion produce a silyl anion and fluorosilane, with the Europe, I asked the audience ‘Do you know a reaction system fluorosilane behaving similar to an electrophilic silyl cation. I that involves both carbanionic and carbocationic species?’ No found that when hexamethyldisilane and tetrabutylammonium one gave me the correct answer.” He then suggested the reaction fluoride (TBAF) are mixed in hexamethylphosophric triamide of allylic acetate with trialkylaluminum, R3Al, whereby an (HMPA) in the presence of an aldehyde, carbonyl attack of the allylic cation and alanate are produced and the alanate delivers trimethylsilyl anion occurs, followed by O-trimethylsilylation. an alkyl anion to the allylic cationic center. The audience then After aqueous workup, we obtained an α-silyl alcohol, understood his meaning. The reaction of organoaluminums is demonstrating that the designed reaction2 works well. well-documented, but Professor Nozaki’s view is quite unique Heterolysis of an element–element bond is conceptually and straightforward. I am convinced this new point of view, rewarding and is closely related to the recently established or philosophy, is essential for devising and developing novel activation of molecular hydrogen by a frustrated base pair synthetic reactions. We have observed that the reaction of (Scheme 2). trimethylaluminum with diastereometric cyclopropylmethyl- type acetates provides the same product, endo-methylated norcarane, and have shown that the reaction1 proceeds via a common cyclopropylmethyl-type carbocationic intermediate (Scheme 1).

OCOCH3 CH3 OCOCH3 Al(CH3)3 Me Al Me Al O CH3 3 3 H Al H H3C O CH3 + CH3

Scheme 1.

TBAF H H (5 mol%) H3O Si Si + n-C10H21CHO n-C10H21 C O n-C10H21 C OH HMPA Me3Si SiMe3 Me3Si 67%

Scheme 2.

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During this research, Dr. Kiyosi Kondo, who later became and trifluorovinyllithium are both unstable organometallic the president of the Sagami Chemical Research Center (SCRC), species and were thought only to be generated at extremely often visited Kyoto. Dr. Kondo repeatedly and earnestly invited low temperatures. Thus, the idea that removal of a metal me to move to Kyoto. I finally agreed, and in 1981 started counter-ion from carbenoids (i.e., organometals with a leaving my own research group at SCRC at the age of 34. Dr. Michio group on the α-carbon) to generate naked carbanionic species Obayashi, one of my first PhD coworkers, soon discovered that with a leaving group on the α-carbon led to the discovery of hexamethyldisilane/TBAF reductively disilylates butadienes. useful synthetic reactions that can be conducted at ambient For example, 2,3-dimethyl-1,3-butadiene is converted to temperature. We further extended the concept of organosilicon (E)-1,4-bis(trimethylsilyl)-2,3-dimethyl-2-butene.2 Product reagents/fluoride ion-based reaction to hydrosilane/fluoride ion formation is believed to involve a trimethylsilyl anion which in the hope of generating a naked hydride. Dr. Makoto Fujita, undergoes single electron transfer (SET) to butadiene to give a currently a professor at the University of Tokyo, carried out trimethylsilyl radical and a butadiene radical anion. Coupling of reactions of α-chiral ketones with dimethylphenylsilane/fluoride 3 these at the terminal carbon should give a TMSCH2-substituted ion and observed threo-selective reduction. We expected that allylic anion, which attacks hexamethyldisilane to give the a pentacoordinate hydrosilicate should be sufficiently bulky product and a silyl anion. In HMPA, SET should readily occur to stereoselectively reduce ketone carbonyls according to the from a naked (i.e., in the absence of a metal counter-ion) hard Felkin-Ahn model transition state. silyl anion. Regardless, you may consider the net transformation as an insertion of butadiene between the Si-Si σ-bond of It is reasonable to assume that hydrido and electronegative hexamethyldisilanes (Scheme 3). fluoro groups in trigonal bipyramidal pentacoordinate silicate should be both apical, and organic substituents locating at We set about generalizing the basic concept of equatorial positions. Since the bond angles of H–Si–organic organosilicon compound/fluoride ion-based reaction to groups in the trigonal bipyramide are 90°, the pentacoordiante generate metal-free (naked) anionic species, and found that hydride is likely bulkier than tetrahedral (109.5°) borohydrides. halomethyl(trimethyl)silanes and trifluorovinyl(trimethyl) Consequently, carbonyl groups are reduced with a high level silane undergo an addition reaction3 with aldehydes, even at of stereoselectivity. In any event, we failed to produce a naked room temperature, upon treatment with tris(dimethylamino) hydride (Scheme 4, 5).4 sulfur difluoro(trimethyl)silicate (TASF) in HMPA or THF. This finding is remarkable given that halomethyllithiums

TBAF + Si Si Si HMPA Si 81%, 99 : 1

Scheme 3.

OH O OH HSiMe Ph HSiMe Ph Z 2 Z 2 Z R F– R H+ R Me >95 : 5 Me >93 : 7 Me Z = OR', NR'2, CONR'2

Scheme 4.

H Me PhSiMe2-H + F Ph Si H + PhSiMe F Me 2 F bulky reductant naked hydride? counter ion: Bu4N or (Et2N)3S

Scheme 5.

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3. Cross-Coupling Reaction with Organosilicon accessible compared to Suzuki-Miyaura coupling. Accordingly, Compounds while Professor Kyoko Nozaki was working with me in Kyoto, she showed that one organic group on tetraorganosilanes can We next envisaged what would happen if a transition be in situ converted to a halo- or alkoxy group by the action metal catalyst was present in the organosilicon/fluoride ion of a fluoride ion. We recently found that C–N coupling7 is system. Is the organic group on silicon successfully transferred conveniently achieved with trimethylsilylamines and allows to the transition metal, or does the fluoride ion simply attack easy synthesis of triarylamines which display a characteristic the transition metal center to give metal fluoride and lose reactivity profile different from that obtained using Hartwig– catalytic activity? To find out, Dr. Yasuo Hatanaka, who is Buchwald coupling (Scheme 7). currently a professor at Osaka City University, mixed Pd(II) complex, TASF as a fluoride source, trimethylvinylsilane and In 2004, Dr. Yoshiaki Nakao, who is currently a professor 1-iodonaphthalene in HMPA, and isolated 1-vinylnaphthalene at Kyoto University, suggested using HOMSi (dimethyl(o- in a nearly quantitative yield.5 His findings demonstrate that hydroxymethylphenyl)silane) tetraorgansilane reagents8, our working hypothesis was correct; this new silicon-based predicting that they would be converted to a pentacoordinate cross-coupling reaction was later named Hiyama Coupling. structure by intramolecular nucleophilic attack of the hydroxyl The TASF fluoride source may be replaced with TBAF or group. Protection of the hydroxyl group with a common KF. To our surprise, KOH could also activate the C–Si bond. protecting group significantly stabilizes the silicon reagents However, attempts to extend this approach to substituted under chromatographic separation and common reaction vinylsilanes were unsuccessful. This limitation was overcome conditions; upon deprotection, the reagents become coupling- by introducing a fluorine or alkoxy group on silicon: this active. After the reaction, the silicon residue is recovered as effectively extended the scope of the cross-coupling reaction a cyclic silyl ether, which is reconverted back to the HOMSi and demonstrated that a heteroatom on silicon assists formation reagent by reaction with organolithium or –magnesium of pentacoordiate silicates, an essential species for successful reagents. Recently, direct C–H silylation of (hetero)aromatics reaction. A theoretical study6 and our intuition both suggested and terminal alkenes has been demonstrated starting with a a four-membered cyclic transition state for the transmetalation THP-protected HOMSi hydride reagent and an iridium catalyst from Si to Pd. Fluoride is believed to play a key role in the (Scheme 8). transmetalation. The following scheme summarizes the silicon- based cross-coupling reaction (Scheme 6). Cross-coupling reaction with HOMSi reagents has recently been applied to polymer synthesis under mild conditions. The Halosilanes and alkoxysilanes are sensitive to moisture resulting π-conjugated polymers find important applications as and are thus incompatible with chromatographic purification, light-emitting and solar-cell materials (Scheme 9).9 so cross-coupling with these organosilicon reagents is less

1 2 Pd cat 1 2 R –SiYmRn + R –X R —R + SiXYmRn F

1 2 Pd(0) 1 R R X R2 SiYmRn: R : 2 1 R F R Si F SiMe3 vinyl, alkynyl, silyl, NR2 reductive X F oxidative Pd Y SiMe2F, SiMe2OR alkenyl, aryl elimination Si 1 Y addition 1 SiF2R aryl (R = Et, n-Pr, Cy) R Si Y R 1 2 Y Y allyl (R = Ph) R Pd R Y X Pd R2 F Y X = F etc SiF3 alkyl, allyl X Si Y transmetalation Y Scheme 6.

Ar–Br Ar + Pd(dba)2 (1 mol%) XPhos (2 mol%) N SiMe3 CsF (1.1 eq) P N DMI, 100 °C Ar = Ph 90% p-Tolyl 97% p-Ph2N-C6H4 95% Xphos 2-Naph 99%

Scheme 7.

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O R MgX/H2O R R' Si or Me 2 LiAlH4, alkyne, Pt cat. PdCl cat. 2 K CO (CuI cat.) 2 3 DMSO ligand O HO Me I R' Si K R Si Me R, R' = alkenyl, aryl Me2 R

Orthogonally THPO CH3COO t-BuPh2SiO protected HOMSi reagents R Si R Si R Si Me2 Me2 Me2

Deprotection PPTS/MeOH OH, HAI(i-Bu)2 F

Scheme 8.

Pd[P(o-tolyl)3]2 (5.0 mol %) S S Oct Oct ® Oct Oct N N DPPF (5.3 mol %) N N CuBr·SMe2 (7.5 mol %) + Si Si X Y + O Br Br Si Cs2CO3 (4.0 mmol) Me2 MS 3A X = Br, H; Y = Si, H quant toluene/DME Mw = 2.3 x 103; PDI = 2.97 50 °C, 24 h

Scheme 9.

4. Conjugate addition of HOMSi Reagents 5. Carbostannylation Reaction of Alkynes and Dienes Once we discovered that transmetalation from Si to Pd is possible, we assumed that the same transformation from Si to In 1997, I was invited back to Kyoto University to head the Rh could be achieved. Indeed, Rh-catalyzed conjugate addition research group of the late Professor Hidemasa Takaya, and to of organosilicon reagents had some precedents. We collaborated begin research with Dr. Eiji Shirakawa, currently a professor at with Professor Tamio Hayashi, then at Kyoto University and Kwansei Gakuin University. Dr. Shirakawa had been examining currently a professor at Singapore National University, and the Migita-Kosugi-Stille coupling reaction mechanism and had with Dr. Ryo Shintani, currently a professor at the University evidence for a novel catalytic cycle involving oxidative addition of Tokyo. Together, we showed that HOMSi reagents undergo of Pd(0) to the C–Sn bond, followed by transmetalation with conjugate addition to enones, α,β-unsaturated esters, and amides organic halides. I was surprised at his proposed mechanism, and with high enantioselection using a chiral diene ligand.10 Here suggested that involvement of the oxidative adduct C–Pd(II)–Sn again, the cogenerated cyclic silyl ether is readily recovered may lead to the insertion of an unsaturated C–C bond between and converted back to the corresponding HOMSi reagent the C–Pd or Pd–Sn bond; if this was indeed the case, then a new (Scheme 10). synthetic reaction might be realized, leading to insertion of an

[RhCl(C2H4)2]2 O (1.5 mol%) O HO (R,R)-Ph-bod (3.3 mol%) + Ph Si 1.0 M KOH aq. Me Me2 (15 mol%) Ph 1.5 : 1 THF, Me (R,R )-Ph-bod 50 °C, 5–10 h 85%, 96% ee

Scheme 10.

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R Sn R Sn R Sn + Pd or Ni cat or Sn Sn = SnBu3 R = acyl, alkynyl • R Sn R SnMe3 allyl, vinyl Scheme 11.

[PdCl(π-C3H5)]2, L Ph (5 mol %) Ph SnBu + H H 3 SnBu 1 atm THF, 50 °C 3 Ph N L = 81%

PPh2

Scheme 12. alkyne between the C–Sn bond. This reaction proceeded well addition of Ni(0) to C–CN bonds. I immediately suggested and was named ‘transition metal-catalyzed carbostannylation’.11 examining the reaction in the presence of unsaturated substrates, Various organostannane reagents, and alkynes or dienes are as we did for the carbostannylation reaction. To our delight, a applicable to the transformation. A typical example, shown couple of weeks later Dr. Nakao twittered that this approach below, is the addition of alkynylstannane to ethyne to give would be feasible. However, the initial protocol needed 10 (Z)-but-3-yn-1-enyl(tributyl)stannane. This carbostannylation mol% of Ni(0) catalyst and required a 1 or 2 days to achieve reaction has made various π-conjugated organostannanes synthetically meaningful yields. Although the catalyst was lazy accessible (Scheme 11, 12). (the turn over number was roughly 6~7), we called the new reaction carbocyanation (Scheme 13).11

6. Carbocyanation Reaction of Alkynes and After we published the first paper on the new reaction, we Alkenes improved the catalytic efficiency by adding a mild Lewis acid such as organoaluminum, -borane, or -zinc to make the reaction In 2002, Professor Kyoto Nozaki moved to the University truly catalytic.12 Under these new conditions, not only aryl of Tokyo as a full professor and Dr. Yoshiaki Nakao, currently cyanides, but allyl and alkenyl cyanides were also applicable, a professor at Kyoto University, joined my research group. One as were acetonitriles: CH3–CN was cleaved into CH3 and day he visited me to discuss the work of Professor W. D. Jones CN fragments and added to internal alkynes in a syn manner at Rochester University on the synthetic potential of oxidative (Scheme 14).

Ni(cod)2 (10 mol %) (pin)B (pin)B CN PMe3 (20 mol %) + Pr Pr Pr CN toluene, 100 °C, 30 h 1 : 1 61% Pr

Scheme 13.

Ni(cod)2 (1 mol %) PMe2Ph (2 mol %) R R CN AlMe2Cl (4 mol %) Pr Pr toluene Pr CN Pr (1.0 mmol) (1.0 mmol) Ni/PMe3 (10 mol %) at 100 °C R = MeO: 96% (50 °C, 16 h) 54% (111 h) Me2N:87% (80 °C, 21 h) no reaction

Ni(cod)2 (5 mol%) CH3 CN PCy2Ph (10 mol%) CH CN + AlMe2Cl (20 mol%) 3 Hex SiMe3 toluene, 80 °C, 12~21 h Hex SiMe3 1 : 1 74%, E/Z = 91 : 9

Scheme 14.

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7. Hydro(hetero)arylation of Alkynes and to C(4)–H, (5) hydronickelation of the terminal olefins occurs, Alkenes and (6) quick reductive elimination is caused by the two bulky ligands. Accordingly, the bulkiness of the Ni ligands and the While studying the carbocyanation of N-protected aluminum metal are key to selective alkylation (Scheme 16). 3-cyanoindoles under the original conditions, we observed the formation of a small amount of byproduct and attributed it to The concept of Ni(0)/Lewis acid is applicable to N,N- C(2)–H activation followed by alkyne insertion. Tuning the dimethylformamide (DMF), whose formyl C–H bond protecting group and ligand resulted in C–H activation occurring oxidatively adds to Ni(0). The resulting Ni–H bond undergoes uniformly with heteroaromatics and polyfluoroaromatic regioselective addition to terminal olefins, then subsequent compounds.13 The most synthetically significant discovery was reductive elimination to produce alkanamide under one-carbon C(4)-selective normal alkylation14 of pyridines with terminal homologation of olefin (Scheme 17).15 olefins using Ni(cod)2/iPr ligand and an aluminum Lewis acid MAD. Given that pyridine and its homologs are inert towards Polyfluorobenzenes undergo C–H activation by Ni(0) Friedel-Crafts reaction, site-selective heteroarylation with in the absence of a Lewis acid; it is possible that the most terminal olefins provides a new route to the n-alkylation of electrophilic position is activated to effect hydroarylation.16 pyridines (Scheme 15). Accordingly, polyfluorobenzonitriles first undergo carbocyanation and then hydroarylation of the internal alkynes The observed regioselectivity is understood insofar as (1) to give extensively π-conjugated polyfluorobenzenes.17 The the bulky MAD is coordinated by the pyridine nitrogen, (2) structure of the oxidative adduct of the C–CN bond to Ni(0) Ni-Ipr interacts with the pyridine ring π-electrons, (3) steric can be unambiguously determined by X-ray crystallography repulsion between the metal centers causes Ni to locate far from (Scheme 18). the nitrogen and interact at C(4), (4) Ni(0) is oxidatively added

Ni(cod)2 (5 mol %) IPr (5 mol %) N H N H MAD (20 mol %) 1 1 N N N 1 R R R + R2 2 + toluene, 130 °C R 1 : 1.5 major minor R2 IPr N H N H N H O t-Bu C11H23 3 MeAl O Me O 87% 91% 61% 2 (5 h, 95 : 5) (10 h, >95 : 5) (23 h, 90 : 10) MAD

Scheme 15.

N H Al N Al N R H H Ni0 Ni0 L L N N 0 H L = IPr; Al = MAD Al Ni L Al N Al R N NiII H II L H Ni L

Al H N R Al NiII N L H NiII L R

Scheme 16.

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Ni(cod)2 (5 mol %) O IAd (5 mol %) O H Me R AlEt (20 mol %) Me R N H + 3 N Me toluene, 100 °C Me 1 : 1.5 O H R = n-C10H21: 84% Me N NN R = n-C5H11: 51% 2 .. R = CH2CH2OTBS: 77% 90% IAd R = CH2CH2OPiv: 59%

Scheme 17.

F Ni(cod)2 (3 mol %) F DPEPhos (3 mol %) H F H F BPh (12 mol %) CN + Pr Pr 3 F CN CPME, 100 °C, 8 h F Pr F F Pr

SiMe3

Me3Si Me3Si F Ni(cod)2 (7 mol %) F PCyp3 (10 mol %) Me3Si CN toluene, 80 °C, 15 h F Pr 72% overall yield F Pr

Scheme 18.

8. ortho-C–H Activation of Phenyl Silylethynyl ethereal C–O bonds. However, to our surprise, the ortho- Ethers and Cromane Ring Formation with C–H bond was found to be selectively activated by Pd(0), Alkynes allowing incorporation of 4-octyne to give 2-(TIPS-methylene) benzochromene. This reaction is attributed to nucleophilic I retired from Kyoto University in 2010 and immediately attack of Pd(0) on the α-carbon of the ethynyloxy group to give moved to my present position at the Research and Development a Pd(II) intermediate, which then oxidatively adds to the ortho- Initiative (RDI), Chuo University. Dr. Yasunori Minami joined C–H bond to mediate chromene annulation.18 Worthy of note me soon after receiving his PhD from Osaka University. We is the silylethynoxy group behaved as an acceptor of Pd(0) to started studying the interaction of transition metal complexes produce Pd(II) temporalily before oxidative addition to an ortho- with p-methoxyphenyl TIPS-ethynyl ether in the presence C–H bond. This is a new type of directing group of ortho-C–H of 4-octyne, with the intention of cleaving either of the activation (Scheme 19).

Pd(OAc)2 (5 mol %) TIPS O PCy3 (10 mol %) O Zn (5 mol %) + Pr Pr H TIPS toluene, 90 °C MeO H (1.1 equiv.) MeO Pr Pr 84%

Scheme 19.

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Conducting the reaction using an allene in lieu of an Acknowledgments internal alkyne produced 2,3-bismethylenechromane.19a This readily underwent Diels–Alder reaction to stereoselectively The author is deeply indebted to Kyoto University, Sagami provide the tetracyclic ring structure. Isocyanates also react with Chemical Research Center, Tokyo Institute of Technology, the same alkynyl ether to give solid benzoxazine19b which emits and Chuo University: all kindly provided research laboratories light upon UV irradiation, even in the solid state (Scheme 20). and financial support. In addition, the Ministry of Education, Culture, Science, Sports, and Technology, the Japan Society for The Pd(II)/Zn catalyst promotes cyclization of the Promotion of Science, the Japan Science and Technology 2,6-dimethylphenyl TIPS-ethynyl ether to give 2-(TIPS- Agency, and Sumitomo Chemicals Ltd. are gratefully methylene)dihydrobenzofuran. Thus, γ-C–H bond activation is acknowledged for financial support. I sincerely thank all my made feasible (Scheme 21).20 collaborators, whose names are listed in the literature cited below, for their dedication to helping me discover and confirm Under similar conditions, 2-(TIPS-ethynyloxy)-2-biphenyl the chemistry I described above. underwent δ-C–H activation to form an oxatricyclic product 21 which was readily converted to the 10,10-disubstituted 9-oxaphenanthrene framework, often used as potent electron carrier materials (Scheme 22).

In summary, this is the story to date of how I have invented synthetic reactions for C-C formation. I, of course, encountered problems during my research; now readers know how I analyzed the problems, how I constructed working hypotheses, and how I solved the problems. Invention of reactions described herein would suggest how it is essential to understand reaction mechanism and pay attention to relating science and technology.

Pd(OAc)2 (5 mol %) TIPS O PCy3 (5 mol %) Zn (5 mol %) O + • H TIPS MeO H Hex toluene MeO (3.0 eq) 100 °C, 2 h Hex TIPS one-pot synthesis H O N-Ph-MI O (3.0 eq) N Ph DCE MeO H 100 °C Hex O 12 h 74% overall yield

Scheme 20.

Pd(OAc)2 (5 mol %) CH3 PCy3 (10 mol %) O Zn (5 mol %) O TIPS AcOH O TIPS toluene H TIPS H H H 90 °C, 18 h H >99% (NMR) 98%

Scheme 21.

Pd(OAc)2 (5 mol %) iPr Si O SiiPr PCy (10 mol %) 3 α 3 3 H Zn (5 mol %) O toluene (0.1 M) δ H 90 °C, 6 h 88%

Scheme 22.

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References 10) (a) E. Shirakawa, K. Yamasaki, H. Yoshida, T. Hiyama, J. Am. Chem. Soc. 1999, 121, 10221. (b) E. Shirakawa, 1) A. Itoh, S. Ozawa, K. Oshima, S. Sasaki, H. Yamamoto, T. T. Hiyama, Bull. Chem. Soc. Jpn. 2002, 75, 1435. (c) E. Hiyama, H. Nozaki, Bull. Chem. Soc. Jpn. 1980, 53, 2357. Shirakawa, T. Hiyama, J. Organomet. Chem. 2002, 653, 2) T. Hiyama, M. Obayashi, I. Mori, H. Nozaki, J. Org. Chem. 114. 1983, 48, 912. 11) Y. Nakao, S. Oda, T. Hiyama, J. Am. Chem. Soc. 2004, 3) (a) M. Fujita, T. Hiyama, J. Am. Chem. Soc. 1984, 106, 126, 13904. 4629. (b) M. Fujita, T. Hiyama, J. Am. Chem. Soc. 1985, 12) (a) Y. Nakao, A. Yada, S. Ebata, T. Hiyama, J. Am. Chem. 107, 8294. (c) M. Fujita, T. Hiyama, Tetrahedron Lett. Soc. 2007, 129, 2428. (b) Y. Nakao. Bull. Chem. Soc. Jpn. 1987, 28, 2263. (d) M. Fujita, T. Hiyama, J. Org. Chem. 2012, 85, 731. 1988, 53, 5405. (e) M. Fujita, T. Hiyama, J. Org. Chem. 13) Y. Nakao. Chem. Rec. 2011, 11, 242. 1988, 53, 5415. (f) M. Fujita, H. Oishi, T. Hiyama, Chem. 14) Y. Nakao, Y. Yamada, N. Kashihara, T. Hiyama, J. Am. Lett. 1986, 15, 837. Chem. Soc. 2010, 132, 13666. 4) Y. Hatanaka, T. Hiyama, J. Org. Chem. 1988, 53, 918. 15) Y. Miyazaki, Y. Yamada, Y. Nakao, T. Hiyama, Chem. 5) A. Sugiyama, Y.-y. Ohnishi, M. Nakaoka, Y. Nakao, H. Lett. 2012, 41, 298. Sato, S. Sakaki, Y. Nakao, T. Hiyama, J. Am. Chem. Soc. 16) (a) K. S. Kanyiva, Y. Nakao, T. Hiyama, Angew. Chem. 2008, 130, 12975. Int. Ed. 2007, 46, 8872. (b) Y. Nakao, K. S. Kanyiva, 6) K. Shimizu, Y. Minami, O. Goto, H. Ikehira, T. Hiyama, T. Hiyama, J. Am. Chem. Soc. 2008, 130, 2448. (c) Y. Chem. Lett. 2014, 43, 438. Nakao, N. Kashihara, K. S. Kanyiva, T. Hiyama, J. Am. 7) (a) Y. Nakao, H. Imanaka, A. K. Sahoo, A. Yada, T. Chem. Soc. 2008, 130, 16170. (d) Y. Nakao, H. Idei, K. S. Hiyama, J. Am. Chem. Soc. 2005, 127, 6952. (b) Y. Nakao, Kanyiva, T. Hiyama, J. Am. Chem. Soc. 2009, 131, 5070. A. K. Sahoo, H. Imanaka, A. Yada, T. Hiyama, Pure (e) K. S. Kanyiva, F, Löbermann, Y. Nakao, T. Hiyama, Appl. Chem. 2006, 78, 435. (c) J. Chen, M. Tanaka, A. K. T. Tetrahedron Lett. 2009, 50, 3463. (f) Y. Nakao, H. Idei, Sahoo, M. Takeda, A. Yada, Y. Nakao, T. Hiyama, Bull. K. S. Kanyiva, T. Hiyama, J. Am. Chem. Soc. 2009, 131, Chem. Soc. Jpn. 2010, 83, 554. (d) Y. Nakao, M. Takeda, 15996. T. Matsumoto, T. Hiyama, Angew. Chem. Int. Ed. 2010, 17) Y. Minami, H. Yoshiyasu, Y. Nakao, T. Hiyama, Angew. 49, 4447. (e) S. Tang, M. Takeda, Y. Nakao, T. Hiyama, Chem. Int. Ed. 2013, 52, 883. Chem. Commun. 2011, 47, 307. (f) T. Hiyama, J. Synth. 18) Y. Minami, Y. Shiraishi, K. Yamada, T. Hiyama, J. Am. Org. Chem. Jpn. 2010, 68, 729. (g) Y. Nakao, T. Hiyama, Chem. Soc. 2012, 134, 6124. J. Synth. Org. Chem. Jpn. 2011, 69, 1221. (h) Y. Nakao, T. 19) (a) Y. Minami, M. Kanda, T. Hiyama, Chem. Lett. 2014, Hiyama, Chem. Soc. Rev. 2011, 40, 4893. 43, 1791. (b) Y. Minami, M. Kanda, T. Hiyama, Chem. 8) K. Shimizu, Y. Minami, Y. Nakao, K. Ohya, H. Ikehira, T. Lett. 2014, 43, 1408. Hiyama, Chem. Lett. 2013, 42, 45. 20) Y. Minami, K. Yamada, T. Hiyama, Angew. Chem. Int. Ed. 9) (a) Y. Nakao, J. Chen, H. Imanaka, T. Hiyama, Y. 2013, 52, 10611. Ichikawa, W.-L. Duan, R. Shintani, T. Hayashi, J. Am. 21) Y. Minami, T. Anami, T. Hiyama, Chem. Lett. 2013, 43, Chem. Soc. 2007, 129, 9137. (b) R. Shintani, Y. Ichikawa, T. 1791. Hayashi, J. Chen, Y. Nakao, T. Hiyama, Org. Lett. 2007, 9, 4643.

Introduction of the author:

Tamejiro Hiyama RDI Professor Research and Development Initiative, Chuo University

[Education] 1965 - 1969: Bachelor of Engineering at Kyoto University 1969 - 1972: Master (& 1 year for PhD) of Engineering at Kyoto University 1975.9.23 PhD of Engineering at Kyoto University (Prof. Hitosi Nozaki, mentor) 1975 - 1976: Postdoctoral Fellow at Harvard University (Prof. Yoshito Kishi)

[Academic Career] 1972 - 1981: Assistant Professor at Fac. Engineering, Kyoto University 1981 - 1983: Research Fellow & Group Leader at Sagami Chemical Research Center 1983 - 1988: Senior Research Fellow & GL at SCRC 1988 - 1992: Executive Research Fellow & GL at SCRC 1992 - 1997: Professor at Res. Lab. Resources Utilization, Tokyo Institute of Technology 1997 - 2010: Professor at Graduate School of Eng., Kyoto University 2010 - present: RDI Professor at Chuo University

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[Honors] 1980 The Chemical Society of Japan Award for Young Chemists 2004 The Japanese Liquid Crystal Society (JLCS) Award 2007 The Synthetic Organic Chemistry Award, Japan 2008 The Chemical Society of Japan (CSJ) Award 2012 The Humboldt Research Award

[Research Interests] Novel Organometallic Reagents and Reactions for Selective Organic Synthesis, Organofluorine and Organosilicon Chemistry, Synthesis of Biologically Active Substances, Design and Synthesis of Novel Functionality Molecules and Materials.

[Achievements] Synthetic Reactions with Carbenoid Reagents, Carbon-Carbon Bond Forming Reactions with Cr(II) reagents (Nozaki-Hiyama-Kishi Reaction or NHK Reaction), Condensation of Ester Magnesium Enolates with Nitriles (Hiyama Reaction), Silicon-Based Cross-Coupling Reaction (Hiyama Coupling), Polysilacage Compounds for s-Conjugation Materials, Oxidative-Desulfurization-Fluorination Reactions, Carbostannylation Reaction of Alkynes and Dienes, Carbocyanation Reaction of Alkynes and Alkenes, Hydro(hetero)arylation Reaction of Alkynes and Alkenes, Design and Synthesis of Liquid Crystal and Light-Emitting Materials, Synthesis of Biologically Active Compounds.

[E-mail] [email protected] [Web site] http://www.chem.chuo-u.ac.jp/~omega300/index.html

TCI Related Products Chapter 2 H0638 Hexamethyldisilane 10mL 100mL T1125 TBAF (ca. 1mol/L in Tetrahydrofuran) 25mL 100mL T1037 TBAF Hydrate 25g 100g U0009 Undecanaldehyde 25mL 250mL D1148 2,3-Dimethyl-1,3-butadiene 10mL 25mL D2196 Dimethylphenylsilane 25mL Chapter 3 B1374 Pd(dba)2 1g 5g C2204 Cesium Fluoride 25g 100g D1477 DMI 25mL 100mL 500mL D4243 1,1-Dimethyl-1,3-dihydrobenzo[c][1,2]oxasilole 1g 5g D3842 4,7-Dibromo-2,1,3-benzothiadiazole 1g 5g 25g B2027 1,1'-Bis(diphenylphosphino)ferrocene 1g 5g 25g C2160 Cesium Carbonate 25g 100g Chapter 4 C2461 [RhCl(C2H4)2]2 200mg Chapter 5 A1479 [PdCl(p-C3H5)]2 500mg 1g Chapter 7 M1211 MAD (= Methylaluminum Bis(2,6-di-tert-butyl-4-methylphenoxide) (0.4mol/L in Toluene) 50mL B3465 IPr (= 1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene) 1g 5g T0925 Triethylaluminum (15% in Toluene, ca. 1.1mol/L) 100mL B2867 DPEphos 5g 25g T2248 Tricyclopentylphosphine 1g 5g Chapter 8 A1424 Palladium(II) Acetate 1g 5g P2161 Palladium(II) Acetate (Purified) 1g T1165 Tricyclohexylphosphine (ca. 18% in Toluene, ca. 0.60mol/L) 25mL 11