No.171 No.171

ResearchResearch ArticleArticle

Development of Novel Methodologies in Organic Synthesis Based on Ate Complex Formation

Keiichi Hirano1* and Masanobu Uchiyama1,2*

1 Graduate School of Pharmaceutical Sciences, The University of Tokyo,7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan 2 Elements Laboratory, RIKEN,2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan E-mail: [email protected]; [email protected]

Abstract: We have been focusing on development of novel synthetic methodologies based on ate complex formation. By fine-tuning of coordination environments of various main-group metals (Zn, Al, and B) as well as transition metal (Cu), a wide range of carbon-carbon bond and carbon-heteroatom bond (C–I, C–O, C–N, C–H, C–Si, and C–B) formation reactions have been realized in highly regio- and chemoselective manner taking advantage of characteristics of the elements.

Keywords: Ate complex, Halogen-metal exchange, Deprotonative metalation, Chemoselectivity, Regioselectivity

1. Introduction 2. Ate Complexes

Ate complexes are known to be anionic organometallic Discovery of the first mono-anion type zincate, Na[ZnEt3], complexes, whose central metals have increased valence by by James A. Wanklyn dates back to 1859,1) and even di-anion accepting Lewis basic ligands to their vacant orbitals. They type zincate, Li2[ZnMe4], was already reported by Dallas T. are attractive chemical species offering tunable reactivity due Hurd in 1948.2) Zincates experienced a long blank after these to their flexible choices of central metals, counter cations, important findings before they started to attract attentions and coordination environments. We have been working on in terms of their unique reactivity and selectivity and enjoy development of novel methodologies in organic synthesis extensive uses in chemical synthesis. Generally, diorganozinc by designing of various ate complexes including zincates, reagents (RZnR) and organozinc halides (RZnX) exhibit low aluminates, cuprates, and borates. This review article gives ligand transfer ability, in other words, low reactivity. Reactivity an overview of the ate complex chemistry developed in our of these species is significantly boosted by adding external laboratory. ligands, so called ate complex formation.

Zn Zn Zn

Di-coordinated Tri-coordinated Tetra-coordinated Neutral Organozinc Mono-anionic Organozinate Di-anionic Organozinate

3d10 4s2 4p2 3d10 4s2 4p4 3d10 4s2 4p6 14 electrons 16 electrons 18 electrons

poor selectivity

Li Li synergy Zn

Zn low reactivity high selectivity & reactivity

Figure 1. Ate Complexes

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The difference in reactivity between a neutral organozinc 3. Di-anion Type Zincate compound and an ate complex can be understood by their electronic structures in the outer shell of zinc (Figure 1). 3-1. Mono-anion Type Zincates and Di-anion Type In neutral organozinc compounds, the outer shell of zinc is Zincates 14-electron form. Such an electron-deficient nature makes RZnX or R2Zn able to act more as a Lewis acid to accept electrons In 1994, Kondo et al. reported that Li[ZnMe3] undergoes instead of donating the R anion as a nucleophile. Coordination the halogen-metal exchange reaction of various aryl iodides at of an additional anionic ligand to the vacant orbital of zinc –78 °C and the generating aryl zincates react with electrophiles 3) forms a 16-electron state, which makes the zincate species more (Scheme 1). On the other hand, Li[ZnMe3] is unreactive to stable (enhancing thermodynamic stability and reducing the metalate synthetically more desirable aryl bromides. Lewis acidity). On the other hand, with more anionic ligands, the whole molecule becomes more electronegative, facilitating In 1996, we discovered that di-anion type zincates, anion-transfer (promoting kinetic activity). Li2[Zn(X)Me3] (X = Me, CN, or SCN), smoothly react with aryl bromides at ambient temperature and the resultant aryl zincate intermediates are trapped with aldehydes in high yields (Table 1, entries 1-6).4) Base-susceptible functionality such as methyl ester is not tolerated due to high reactivity of the zincate to give complex mixture (entries 7-9).

Di-anion type aryl zincates, Li2[ArZnMe3], exhibit higher reactivity than Li[ArZnMe2] (Scheme 2). In contrast with the reaction between Li[ZnMe3] and aryl iodide 1, ends up only with iodine-zinc exchange, treatment of 1 with Li2[ZnMe4] provides the indoline product 2 via iodine-zinc exchange followed by intramolecular conjugate addition. Metallation of 2-allyloxyiodobenzene (3) with Li2[ZnMe4] affords the dihydrobenzofuran 5 via carbozincation reaction of the unactivated double bond.5)

I MeO

54%

Li[ZnMe3] PhCHO OH R I R ZnMe2Li R THF, –78 °C, 1 h –78 °C to rt Ph 60–74% (R = H, Me, OMe, CO2Me, NO2) Ph–I, Pd(PPh3)4 MeO Ph THF, –78 °C to rt 26%

Scheme 1. Halogen-zinc Exchange Reaction with Li[ZnMe3] by Kondo et al.

Table 1. Reactivity of Di-anion Type Zincate: Li2[Zn(X)Me3]

Li2[Zn(X)Me3] PhCHO OH R I R Zn(X)Me2Li R THF rt, 3 h Ph Temp., 2 h

Temp. Yield Temp. Entry RX Entry RX Yield [°C] [%] [°C] [%]

1 H Me 090 6 MeO SCN rt 92

2 HCN rt 90 7 CO2Me Me 0 trace

3 H SCN rt 89 8 CO2Me CN 0 trace

4MeO Me 084 9 CO2Me SCN 0 trace 5MeO CN rt 90

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t 3-2. Highly Bulky Di-anion Type Zincate: Li2[Zn Bu4] O–H group and N–H group of carboxyamides, and selectively metalates aromatic rings. 3-2-1. Halogen–zinc Exchange in the Presence of Proton Sources Additionally, tBu ligands played an important role in In 2006, we developed a highly chemoselective zincation controlling the regioselectivity in the substitution reactions of methodology of aryl bromides and aryl iodides using the newly propargyl bromide. In sharp contrast to the t designed extremely sterically encumbered di-anion type zincate, and the cuprate, the Li2[ArZn Bu3] was found to deliver t 6) Li2[Zn Bu4] (Scheme 3). This zincate is characterized by the aryl ligand in a highly selective SN2′ fashion to give the unprecedented compatibility with protic functionalities such corresponding allene product (Table 2).7) as alcoholic O–H group as well as even more acidic phenolic

CO2Me CO Me I Lin[ZnMe2+n] 2

N THF, –40 °C, 4 h; N then rt, overnight SO Ph SO2Ph 2 1 2: 0% (n = 1) 66% (n = 2)

Li[ZnMe3] H THF, 0 °C, 2 h; O then rt, 48 h I 4 :quant.

O 3 Me3 Li2 Li2[ZnMe4] Zn + H THF, 0 °C, 2 h; then rt, 48 h O O 5: 42%

Scheme 2. High Reactivity of Di-anion Type Zincate

t Br FG Li2[Zn Bu4] FG FG t I Zn Bu3Li2 THF rt, 12 h Temp., 2 h

O HO HO iPr NH 100% (rt) 79% (40 °C) 62% (0 °C)

t Scheme 3. Chemoselective Zincation of Aryl Halides with Li2[Zn Bu4]

t Table 2. Reaction of Li2[Zn Bu4] with Propargyl Bromide: SN2 vs. SN2′

O

EtO •

SN2' product O Metalation O Br I M vs. EtO EtO Temp., 16h O

EtO

SN2 product

Temp. Yield Ratio Entry Metalation Reagent and Conditions [°C] [%] [SN2'/SN2]

t 1Li2[Zn Bu4] (1.1 eq.), THF, 0 °C, 2 h 25 100 98 : 2 iPrMgBr (1.1 eq.), THF, –40 °C, 1 h, 2 –4076 79 : 21 then CuCN (10 mol%)

3Li2[Cu(CN)Me2] (1.1 eq.), THF, 0 °C, 2 h 25 54 63 : 37

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3-2-2. Anionic Polymerization in Water 3-3. Cross-coupling Reaction via C–O Bond Cleavage t The di-anion type zincate Li2[Zn Bu4] can be utilized as an initiator of anionic polymerization.8) With this organometallic In 2012, we reported the Negishi coupling reaction using initiator, polymerization of N-isopropylacrylamide (NIPAm) aryl ethers as electrophiles (Scheme 4).9) With the aid of the proceeds especially rapidly in protic solvents such as MeOH and nickel catalyst, the cross-coupling reactions between the di- H2O to give poly(NIPAm) in high yields (Table 3). It should anion type zincates Li2[ArZnMe3] and aryl ethers uniquely be emphasized that the reaction completes within 15 minutes in proceed to give biaryl products in good yields at ambient H2O. This polymerization method is applicable to other acrylic temperature. On the other hand, neutral organozinc reagents acid-based monomers including N,N-dimethylacrylamide, (ArZnX or Ar2Zn) and mono-anion type zincates Li[ArZnMe2] acrylamide, and 2-hydroxyethyl methacrylate. did not lead to biaryl formation. The high chemoselectivity of the zincate as well as the mild reaction conditions of this coupling reaction allow the substitution of methoxy group of (+)-naproxene 6 with phenyl group without loss of optical purity to give 7. Since aryl ethers are ubiquitously found in natural products and biologically active substances, this cross- coupling reaction is a powerful tool to rapidly fine-tune activity of those compounds by modification of the parent molecular architectures.

t Table 3. Polymerization of N-Isopropylacrylamide using Li2[Zn Bu4] as an Initiator

t n Li2[Zn Bu4] (2.0 mol%) O NH Solvent O NH i Pr rt, Time iPr

Time Yield Time Yield Entry Solvent M PDI Entry Solvent M PDI [h] [%] n [h] [%] n

1 THF 24 8 7000 1.50 3 MeOH 376 18000 1.65

2 THF 16833 7000 2.71 4H2O< 192 27000 2.72

[NiCl2(PCy3)2] (4 mol%) or [Ni(cod)2]/PCy3 (8 mol%) 1 2 Ar OMe + Li2Me3Zn Ar Ar1 Ar2 toluene, rt 6-12 h

OMe NMe2

OTBS

82% 85% 72% 62% NMe2 Me

N O O

i i Pr2N Pr2N 63% 71% 45% 40%

i OMe Li2[PhZnMe3] (3.0 eq.) i Ph Pr2N Pr2N Ni(cod)2 (4.0 mol%)/PCy3 (8.0 mol%) O toluene, rt O Me Me 6 (98% ee) 7: 65% (96% ee)

Scheme 4. Negishi Cross-coupling via C–O Bond Cleavage

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4. Heteroleptic Ate Complexes 4-1-1. Amidozincate Base: Li[(TMP)ZnR2] In 1999, we reported the deprotonative zincation 4-1. Deprotonative Metalation of Aromatic C–H reaction by a newly designed amidozincate base, Li[(TMP) t t Bonds Zn Bu2], prepared from Bu2Zn and LiTMP (lithium 2,2,6,6-tetramethylpiperidide) (Scheme 5).12) This ate base Deprotonative metalation utilizing ate bases10) is a highly enabled directed ortho metalation of aromatic rings substituted regio- and chemoselective process to functionalize aromatic with ester, amide, and cyano groups without damaging these rings directly, and thus very efficient synthetic process. functionalities. Moreover, π-electron-rich heteroaromatics such Reactivity and selectivity of ate complexes depend on the as thiophenes and furans as well as electoron-deficient ones characteristics of the elements and can be tuned flexibly by such as pyridines, quinolines, and isoquinolines are smoothly changing the central metal. “Heteroleptic” ate complexes are metalated in good yields. especially fine-tunable by endowing different functions to each ligand (Figure 2).11) Generally, ortho metalation of bromobenzenes smoothly generates corresponding benzynes via facile elimination of

Non-transferable Ligand

R + R' Zn M RZn R R' M R

Reactive Ligand

Figure 2. Heteroleptic Zincates

CN OH PhCHO (excess) Ph rt, 12 h 96% DMG = CO Me : 73% DMG DMG 2 DMG t I2 (excess) CO2Et : 94% Li[(TMP)Zn Bu2] (2 eq.) I i Zn CO2 Pr : 98% 0 °C to rt, >1 h t THF, rt, 3 h CO2 Bu : 99% i CO2N Pr2 : 95% Ar–I (2.0 eq.) O OEt DMG = Directed Metalation Group: CN, Ester, Amide, etc. Pd(PPh3)4 (cat.) Ar = rt, 24 h Ar Ph : 58% 3-Py : 43%

Zincation–iodination of Heteroaromatic Compounds:

CO2Et I I N I CO2Et 2 S O N I 8 N I 89% 71% 76% 61% (C8) 26% (C2) 93%

Scheme 5. Highly Regio- and Chemoselective Zincation of Aromatics

DMG DMG DMG t I (excess) Li[(TMP)Zn Bu2] (2 eq.) Zn 2 I THF, conditions 0 °C to rt, >1 h Br Br Br

O OEt O OtBu O NiPr OMe F Cl 2 CN I I I I I I I Br Br Br Br Br Br Br 95% 93% 77% 92% 98% 84% 96% (–30 °C, 12 h) (–30 °C, 2 h) (–20 °C, 2 h) (rt, 3 h) (rt, 3 h) (0 °C, 3 h) (0 °C, 3 h)

Scheme 6. ortho Iodination of Bromobenzenes

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t i metal bromide salts. Li[(TMP)Zn Bu2] deprotonates their ortho 4-1-2. Amidoaluminate Base: Li[(TMP)Al Bu3] C–H bond without releasing bromide anion and the resultant Organoaluminum reagents have long been utilized in aryl zincate can be trapped with various electrophiles in high organic synthesis, but their usage has been limited to mainly yields (Scheme 6).13) aliphatic chemistry. In general, arylaluminum compounds are prepared via transmetalation from aryl lithiums and –Grignard On the contrary, ortho metalation with Li[(TMP)ZnMe2], reagents to aluminum halides, and this protocol has been which has smaller alkyl ligands smoothly generates benzynes. confining functional groups on aromatic rings only to robust This method enables efficient generation of substituted benzynes ones due to too high reactivity of those reagents. We developed taking advantage of highly chemoselective nature of the a preparative method for functionalized arylaluminums amidozincate base, and Diels-Alder reactions of benzynes with via deprotonative metalation with our newly developed i 1,3-diphenylisobenzofuran (8) proceed in high yields (Table 4). amidoaluminate base, Li[(TMP)Al Bu3]. A number of functional groups including heteroaromatic rings (14 and 15) are tolerated in this metalation reaction (Scheme 7).14) One of notable features of this aluminate base is its low halogen-metal exchange ability. Taking advantage of this unique reactivity, deprotonative ortho metalations of 4-iodoanisole (10) and 4-iodobenzonitrile (11) proceed chemo- and regioselectively in high yields, while C–I bond at the 4-position remains intact.

Table 4. Regioselective Generation of Substituted Benzynes with Li[(TMP)ZnMe2]

DMG Ph DMG Li[(TMP)ZnMe2] (2.2 eq.) DMG O Ph 8 (2.2 eq) O THF, conditions Br Ph Ph 8 9

Yield Yield Entry Substrate Conditions Benzyne Entry Substrate Conditions Benzyne [%] [%] O OEt OMe OMe O OEt 1 rt, 12 h 100 5 reflux, 3 h 55

Br Br

t t F F O O Bu O O Bu 2 60 °C, 15 h 71 6 reflux, 6 h 88

Br Br O NiPr i Cl Cl 2 O N Pr2 3 rt, 48 h 72 7 reflux, 12 h 100

Br Br

CF3 CF3 CN CN 4 rt, 12 h 100 8 reflux, 12 h 90

Br Br

DMG DMG DMG i I (excess) Li[(TMP)Al Bu3] (2.2 eq.) i 2 I Al Bu3Li FG THF, conditions FG 0 °C to rt, >1 h FG

OMe CN OMe Cl OMe I I I I I I N N OMe Cl Boc I I 10: 100% 11: 90% 12: 92% 13: 74% 14: 82% 15: 64% (–78 °C, 2 h) (–78 °C, 2 h) (0 °C, 4 h) (–78 °C, 12 h) (–78 °C, 5 h) (–78 °C, 1 h)

i Scheme 7. Chemoselective Deprotonative ortho Metalation with Li[(TMP)Al Bu3]

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t 4-1-3. Amidocuprate Base: Li2[(TMP)Cu(CN)R] hydroperoxide (ROOH) including BuOOH (TBHP) and cumene Organocuprates are frequently used for various types hydroperoxide (CHP) affords the corresponding phenol product of C–C bond forming reactions utilizing the redox activity in high yield (Scheme 10).16) This approach delivers diverse of copper. Envisioning to establish a new method to prepare phenols based on high compatibility of the functionalized arylcopper species via deprotonative cupration cuprate base. reactions, we designed a novel Lipshutz-type amidocuprate 15) base, Li2[(TMP)Cu(CN)R]. A series of aromatics with polar DFT calculation suggests that this oxygenation reaction functional groups such as methoxy, cyano, and amide groups occurs via the redox reactions of copper more likely rather than and heteroaromatics are regioselectively deprotonated with direct nucleophilic attack of arylanion to peroxide (Scheme 11). Li2[(TMP)Cu(CN)Me] (Scheme 8). Based on the mechanism by DFT calculations, we also The intermediary arylcuprate reacts with various achieved the direct amination reaction using BnONH2 instead electrophiles in excellent yields thanks to its high nucleophilicity of ROOH (Scheme 12). This amination is supposed to proceed (Scheme 9). in the same way as the hydroxylation, and to the best of our knowledge, this is the first truly efficient and straightforward We have recently reported that the combination of method to prepare N-unsubstituted anilines from their C–H the arylcuprate intermediate generated by the reaction counterparts. of Li2[(TMP)2Cu(CN)] with an aromatic compound and

DMG DMG DMG Li [(TMP)Cu(CN)Me] (2.0 eq.) I2 (excess) 2 Cu I FG THF, conditions FG 0 °C to rt, >1 h FG

i CN O N Pr2 OMe I I I N I I I N S O OMe Boc I I 95% 96% 100% 90% 70% 88% (0 °C, 3 h) (–78 °C, 3 h) (–78 °C, 3 h) (0 °C, 3 h) (0 °C, 3 h) (–40 °C, 3 h)

Scheme 8. Chemoselective ortho Metalation with Li2[(TMP)Cu(CN)R]

i O N Pr2

i i O N Pr2 O N Pr2

TMS D

Li2[(TMP)Cu(CN)Me] THF, 0 °C, 3 h 99% (2.0 eq.) 100% (50 °C, 16 h) (0 °C, 30 min) TMSCl D2O i O N Pr2

Cu(CN)(Me)Li2

BzCl MeI i Br i O N Pr2 O N Pr2 i Bz O N Pr2 Me

84% 99% (80 °C, 16 h) 99% (rt, 16 h) (rt, 16 h)

Scheme 9. Variety of Applications of Arylcuprate

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H 1) Li2[(TMP)2Cu(CN)] (X eq.) OH DMG THF, Temp., 2 h DMG FG 2) TBHP (Y eq.) FG –78 °C, 30 min

OH O OH O OH O OH O OH O i N Pr2 i i NiPr i N Pr2 N Pr2 2 N Pr2

I CF3

94% 92% 92% 71% 89% (X = 1.3, Y = 2.0, 0 °C) (X = 1.3, Y = 2.0, –78 °C) (X = 1.3, Y = 2.0, 0 °C) (X = 1.3, Y = 1.5, 0 °C) (X = 1.3, Y = 2.0, 0 °C)

OH O OH OH OH OH O

CN OMOM OMe PPh2 NEt2 tBu Ph Ph 90% 87% 82% 83% 86% (X = 1.5, Y = 2.0, 0 °C) (X = 1.5, Y = 1.4, 0 °C) (X = 1.5, Y = 1.4, 0 °C) (X = 2.2, Y = 2.0, 0 °C) (X = 1.5, Y = 2.0, 0 °C)

O OH O OH O O OH

t HN S O O Bu OH NH Cl S i N Pr2 83% 67% 86% 64% 86% (X = 2.2, Y = 2.0 (CHP), 0 °C) (X = 2.2, Y = 2.0, 0 °C) (X = 1.5, Y = 1.4, 0 °C) (X = 1.3, Y = 2.0, 0 °C)(X = 1.3, Y = 2.0, –78 °C) Scheme 10. Direct Hydroxylation of Aromatics

N Li C H O R N Li Li2[(R2N)2Cu(CN)] 2 MeOOH O NMe2 Cu – R2N-H – R2N-H NMe2 RT Directed ortho Cupration IM1 Ligand Exchange

N N N Li Li C Li C C MeO MeO Li Li O E = 12.9 I Li ∆E = 25.4 MeO O ∆ Cu CuI O III O O ∆E = 6.8 Cu ∆E = –92.7 O

NMe2 NMe2 NMe2

IM2 Oxidative Addition IM3 Reductive Elimination IM4

Scheme 11. Model DFT Calculations of the Reaction Mechanism @M06/SVP (Cu) and 6-31+G* (others); ΔE (kcal/mol)

1) Li [(TMP) Cu(CN)] (X eq.) H 2 2 NH2 DMG THF, Temp., 2 h DMG

FG 2) BnONH2 (Y eq.) FG rt, 30 min

NH2 O NH O NH2 O NH2 O 2 NH2 O i N Pr2 i i NiPr N Pr2 N Pr2 2 NEt2

I CF3 93% 84% 92% 76% 92% (X = 1.3, Y = 2.0, 0 °C) (X = 1.3, Y = 2.0, –78 °C) (X = 1.3, Y = 2.0, 0 °C) (X = 1.3, Y = 2.0, 0 °C) (X = 1.3, Y = 2.0, 0 °C)

NH2 NH2 NH2 O NH2 O NH2 CN OMe PPh 2 OtBu N tBu Ph 84% 86% 94% 79% 87% (X = 1.3, Y = 2.0, 0 °C) (X = 1.3, Y = 2.0, 0 °C) (X = 1.5, Y = 2.0, 0 °C) (X = 2.2, Y = 2.0, 0 °C) (X = 1.3, Y = 2.0, 0 °C)

O O NH2 NH2 NH2 NiPr 2 NiPr O 2 O O NH Cl Ph 2 S O i NH2 Fe i i N N Pr2 N Pr2 N Pr2 N

68% 46% 69% 69% 63% (X = 1.3, Y = 2.0, –78 °C) (X = 1.3, Y = 2.0, –78 °C) (X = 1.3, Y = 2.0, 0 °C) (X = 1.3, Y = 2.0, 0 °C) (X = 1.3, Y = 2.0, –78 °C) Scheme 12. Direct Amination of Aromatics

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4-2. Hydridozincate: M[HZnMe2] Additionally, Li[HZnMe2] uniquely semi-reduces carboxylic acids to aldehydes, and no over-reduced alcohol Although trihydrido-type zincates have been known in products are obtained (Scheme 14). This is explained by the the fields of and coordination chemistry, formation of the zincioacetal intermediate after hydride transfer reactivities of heteroleptic hydridozincates remained unrevealed. to the carbonyl group, and this tetrahedral structure is stable We discovered that the hydrodozincates M[HZnMe2] (M = in the reaction mixture. Aldehyde is released eventually upon Li or Na) deliver the hydrido ligand preferentially to a variety quenching. of carbonyl compounds to give the corresponding alcohols (Scheme 13).17) A noteworthy fact is that no methylation product This phenomenon can be applied to the direct was obtained in all cases. Therefore, this reduction possibly transformation of carboxylic acids to ketones. Both of the proceeds catalytically. Indeed, the reduction of carbonyl reaction between di-anion type zincate and a carboxylic acid and compounds with NaH/LiH in the presence of catalytic amounts the reaction between a mono-anion type zincate and a lithium of Me2Zn proceeded smoothly to give the corresponding form the similar stable zincioketal intermediate to alcohols in high yields. avoid the formation of an undesired tertiary alcohol by-product (Scheme 15).18)

Reduction of Carbonyl Compounds with M[HZnMe2] O

Ph Ph MH (1.0 eq.) OH + M[HZnMe2] H THF Ph (1.1 eq.) Ph Me2Zn rt, 12 h M =Li: 96% Ate Complex Formation Na: 99%

Reduction of Carbonyl Compounds Catalyzed by Me2Zn

OM MH 2 R H Me2Zn R1

‡ Me M M Me O Zn Me HZn H Me R2 R1 O

R1 R2

Scheme 13. Reduction of Carbonyl Compounds to Alcohols by M[HZnMe2]

Me 2Li O LiH O Li[HZnMe2] O H O 2 H O O 2 Zn 3 Zn Me Me R OH R OLi R O H O R H Me 2Li R Zincioacetal

Scheme 14. Semi-reduction of Carboxylic Acids to Aldehydes by Li[HZnMe2]

2 Li2[R ZnMe3] Me 2 O O Zn H3O O Me 2 R1 OH R O R1 R2 R1 2Li 1) MeLi 2) Li[R2ZnMe ] 2 Zincioketal

Scheme 15. Direct Conversion of Carboxylic Acids to Ketones

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4-3. Silylzincates 4-3-2. Silylzincation of Alkenes (1): Synthesis of Allylsilanes C–C multiple bond is a versatile platform for myriad Silylzincates by themselves are not reactive towards chemical transformations and addition of organometallic alkenes. We found that our SiSiNOL-Zn-ate undergoes the reagents across it is a fundamental and important reaction silylzincation reaction across terminal alkenes in the presence of 20) to increase molecular complexity. We designed various a catalytic amount of Cp2TiCl2 (Scheme 17). Regioselective silylzincates and realized regioselective silylzincation reactions addition of the SiSiNOL-Zn-ate to alkenes and following of alkynes and alkenes as follows. β-hydride elimination afford Z-configurated allylic silanes in preference to E-isomers. No trace of alkylsilanes nor migration 4-3-1. Silylzincation of Alkynes of double bonds is observed. Our di-anion type silyl zincate, SiBNOL-Zn-ate, adds chemoselectively across various terminal alkynes without the aid of transition metal catalysts (Scheme 16).19) Functionalized branched vinylsilane products are obtained in high yields with high to excellent regioselectivities.

SiBNOL-Zn-ate tBu R H R H O (1.1 eq.) Zn 2 R H + O SiMe Ph THF PhMe2Si H H SiMe2Ph 2 rt, 12 h Li MgCl Branched Linear SiBNOL-Zn-ate

Cl iBu H Cy H H EtO H Et2N H O O PhMe2Si H PhMe2Si H PhMe2Si H PhMe2Si H PhMe2Si H 88% 94% 89% 100% 92% (B : L = 95 : 5) (B : L = 92 : 8) (B : L = 94 : 6) (B : L = 86 : 14) (B : L = 74 : 26)

Scheme 16. Silylzincation of Alkynes

SiSiNOL-Zn-ate (1.1 eq.) SiMe2Ph O Cp2TiCl2 (5 mol%) Zn 2 R R SiMe2Ph O SiMe2Ph THF 2MgCl rt, 18 h SiSiNOL-Zn-ate

t SiMe Ph t BuPh2SiO SiMe2Ph BnO 2 BuS SiMe2Ph

95% 92% 88% (E : Z = 24 : 76) (E : Z = 28 : 72) (E : Z = 26 : 74)

EtO O SiMe2Ph O Bn N SiMe Ph 2 2 SiMe Ph O MeO 2 75% 79% 80% (E : Z = 21 : 79) (E : Z = 27 : 73) (E : Z = 23 : 77)

Scheme 17. Silylzincation of Alkenes Catalyzed by Cp2TiCl2

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4-3-3. Silylzincation of Alkenes (1): Synthesis of and the generating RF–zinc was trapped at ambient temperature Alkylsilanes (Scheme 19). Ate complexes Li[ZnMe3] and Li2[ZnMe4] did By using CuCN as a catalyst, silylzincation reaction of alkenes not give the desired adduct 16 under these reaction conditions, by our SiBNOL-Zn-ate proceeds in high yields (Scheme 18).21) whereas 16 was obtained in moderate yields at –78 °C. Contrary In this catalyst system, linear alkylsilanes are obtained as major to unproductive results using MeZnCl and Me2Zn, Me2Zn products without β-hydride elimination. On the other hand, prepared from ZnCl2 and 2 equivalents of MeLi succesessfully alkenes bearing a highly coordinating unit such as cyano group gave 16 in 62% yield. Moreover, 16 was obtained by addition and phosphine oxide gives the branched isomer with perfect of 2 equivalents of LiCl to Me2Zn and there results imply regioselectivities. the perfluoroalkylzincate Li[RFZn(Me)Cl] is generated from Li[Me2ZnCl], and this ate complex is “thermally stable” and “highly reactive” at the same time. 4-4. Perfluoroalkylzincate: Li[RFZnMe2] & RFZnR RF-zincates add to various carbonyl compounds with good 3 Perfluoroalkyl (RF) organometallics are known to be functional group tolerance, and offer a facile access to Csp –RF 3 23) thermally unstable and easily decompose via α- or β- and Csp –ArF bond formation (Scheme 20). elimination. Therefore, generation and use of those species require cryogenic reaction conditions and strict temperature Development of efficient methods for introduction of control (Figure 3).22) fluorine-containing functional groups to aromatic rings attracts more and more attention. As an initial attempt, we performed We launched the projects on development of novel a reaction between Li[RFZn(Me)Cl] and aryl halide 17 in the perfluoroalkylation reactions using zinc as a key element based presence of CuCl and obtained the desired coupling product 18 on relatively stable nature of C–Zn bond. First of all, metalation in 17% yield (Scheme 21). of C4F9–I with various zinc reagents was investigated at 0 °C

SiBNOL-Zn-ate (1.1 eq.) tBu CuCN (10 mol%) SiMe2Ph O 2 SiMe2Ph + Zn R R O THF R Me SiMe2Ph rt, 15 h Linear Branched Li MgCl SiBNOL-Zn-ate

SiMe2Ph SiMe2Ph SiMe Ph SiMe Ph Cl 2 BnO 2 OMe MeO 81% 97% 73% 66% (L : B = 90 : 10) (L : B = 86 : 14) (L : B = 84 : 16) (L : B = 86 : 14)

O SiMe2Ph SiMe2Ph tBuS SiMe Ph P 2 Ph Me NC Me Ph 76% 85% 79% (L : B = 79 : 21) (L : B = 1 : 99) (L : B = 1 : 99) Scheme 18. Silylzincation of Alkenes Catalyzed by CuCN

F α-elimination F RF RM – MF + F F F RF F F M R – R–I FF F I – MF F FF RF M = Li, MgX β-elimination F F

Figure 3. Common Decomposition Pathways of RF-organometallics

Zinc reagent (1.0 eq.) PhCHO OH C4F9 I C4F9–"Zn" Et O Ph C F (1.5 eq.) 2 rt, 16 h 4 9 R -zinc reagent 0 °C, 1 h F 16

Me Me 2 Me Zn Li Me Zn Me 2Li Me Zn Cl Me Me 0% (73% at –78 °C) 0% (62% at –78 °C) 0%

Me Zn Me Me Zn Me • LiCl 0% (LiCl-free) 43% (Me2Zn + 2LiCl) 62% (ZnCl2 + 2MeLi)

Scheme 19. Zincation of RF–I

12 No.171

O Me2Zn (1.0 eq.) OH LiCl (2.2 eq.) Ar R RF–I RF–"Zn" Ar RF (1.2 eq.) THF rt, 16 h R 0 °C, 1 h

OH RF = C4F9 : 89% OH OH NC MeO C OH C6F13 : 90% 2 RF RF RF C8F17 : 91% I RF RF = C4F9 : 94% 92% 80% C6F5 : 92% C6F5 : 97% 95% 90%

HO HO HO C F C6F5 C4F9 OH S OH 6 5 OEt O O N RF RF O N Me O RF = C4F9 : 40% 86% 64% 57% 80% C6F5 : 44% 97%

Scheme 20. Perfluoroalkylation and Perfluoroarylation of Carbonyl Compounds

OC12H25

Me2Zn O (1.0 eq.) I + 17 (1.0 eq.) OC12H25 Me O LiCl phen (20 mol%), CuCl (10 mol%) (2.2 eq.) C4F9 Zn Li THF 70 °C, 16 h C4F9 + 0 °C, 1 h Cl C4F9 I 18: 17% (1.2 eq.) Scheme 21. Initial Attempt on Perfluoroalkylation of Aryl Halide

Et2Zn (1.5 eq.) FG CuI (10 mol%) FG RF–I + I RF DMPU 90 °C, >16 h

OC H OC12H25 RF = C3F7 19: 91% 12 25 OC H F O 12 25 C5F11 20: 91% F O CO2C12H25 O C6F13 21: 91% C4F9 C4F9 C8F17 22: 86% F a RF 23: 94% 18: 89% C10F21 24: 72% F F i meta : 27: 87% 93%, 1.18 g C3F7 25: 0% 26: 88%b para : 28: 72% R R O O O O O B C4F9 OR C4F9 CN C4F9 C4F9 C4F9 R = Ph: 29: 95%b R = H: 33: 68%b R = Bn: 35: 89%b,c,d i b b b b,c,d N Pr2: 30: 61% 31: 60% 32: 65% CN: 34: 54% Ts: 36: 81% O-p-Tol OTBS O R N S NTs C4F9 Cl C4F9 C4F9 C4F9 C4F9 R R = H: 37: 80%b R = H: 40: 90%b 39: 47%b 42: 50%b 43: 55% (82%)b OMe: 38: 82%b Cl: 41: 83%e Me O Me N Me N N N N C4F9 C4F9 C4F9 C4F9 O C4F9 N N S N N O N Me O Me 44: 47% (89%)b 45: 35% (41%)b 46: 56% (66%)b,e 47: 60%b 48: 57%c

C4F9 C4F9 C4F9 C4F9 C4F9 C4F9

b,c,f b,c,f 49: 38% (50%) 50: 78% OMe F F F F OMe

F F C4F9

C4F9 C4F9 F F F F 51: 90%b,c,f 52: 51%b,c,f 53: 70% (95%)b,c,g Scheme 22. Substrate Scope of Aromatic Perfluoroalkylation a b c Isolated yields. NMR yields are given in parentheses. C8F17–Br was used. 1,10-Phenanthroline (20 mol%) was added. 120 °C. d e f g CuI (20 mol%) was added. Me2Zn was used instead of Et2Zn. Amounts of the reagents were doubled. Amounts of the reagents were tripled.

13 No.171 No.171

This low yield was attributed to instability of 4-5. Design of Borylanion Equivalents and Li[C4F9Zn(Me)Cl] under heating conditions generally required Applications in Synthetic Chemistry for cross-coupling reaction by catalytic copper . Thus, we systematically screened neutral Lewis basic solvents in order Borylanion is a highly reactive species and an attractive to activate zinc species in an ad-hoc manner, and found N,N'- tool to synthesize -containing compounds. However, dimethylpropyleneurea (DMPU) to be the best solvent giving borylanions have been regarded as difficult to generate with 18 in 89% yield. None-coordinating solvents such as toluene a few sophisticated exception such as a finely stabilized and dichloromethane hardly promote the desired reaction. These borylanion reported by Yamashita and Nozaki26) and the results indicate that DMPU coordinates the vacant orbitals of borylcopper complex reported by Sadighi.27) We have been zinc24) and this coordination plays important roles to stabilize interested in stabilization and control of reactivity of borylanion and activate the RF-zinc complex. Difference in catalytic activity by ate complex formation and developing novel nucleophilic among cuprous halides was not observed and thus air-stable CuI borylation methodologies. was chosen as the optimal catalyst. 4-5-1. Borylzincate: M[(pinB)ZnEt2] This perfluoroalkylation reaction displays a wide substrate In the course of our research programs on heteroleptic generality and various RF groups can be introduced onto ate complexes, we got interested in formation and reactivity aromatic rings (Scheme 22).25) Scaling-up of this reaction is of borylzincates bearing borylanion as a ligand to zinc. facile and the coupling product 18 is obtained in 93% yield on We hypothesized that borylzincate can be generated via a gram-scale. Perfluoroaryl group can also be installed with transmetalation of boryl group from alkoxide-activated diboron 1,10-phananthroline as a ligand to copper (26). This method to dialkylzinc and performed model DFT calculations (Figure is applicable to multiple perfluoroalkylations of substrates 4). The results implied that the formation of borylzincate is possessing more than one reactive site (49-53), and is expected kinetically well feasible process with an activation barrier to contribute in chemical elaboration of functional materials by of 15.8 kcal/mol, and the small stabilization energy for the RF-groups. formation of borylzincate appears to be a hurdle for utilization of this species for chemical synthesis. If this thermodynamically unfavorable energy loss could be compensated by following reactions, borylzincate can be used in borylation reactions as a transient reactive intermediate.

∆G O O B B Li ‡ O Me O Me MeO Zn OMe Me2Zn Li O O O B B MeO B Reactants O O O O Me Zn B –36.2 TS O Me Li Me OMe +15.8 –5.8 O Zn O Borylzincate B B O Me O Intermediate Li

Figure 4. Model DFT Calculation on Borylzincate Formation @M06/SVP (Zn) and 6-31+G* (others); ΔG (kcal/mol)

R'2Zn (cat.) FG OR FG X + B (OR) 2 4 B(OR)2

Ar B(OR)2 R'2Zn (RO)2BB(OR)2 RO + X

RO B(OR)2

3. Formation of 1. Formation of C–B Bond Borylzincate

Ar ZnR'2 + X B(OR)2 R'2Zn B(OR)2

Thermodynamically unfavorable Ar X 2. Halogen-Metal Exchange

Figure 5. Design of Catalytic Borylation of Aryl Halides

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Based on the computation, we envisioned the catalytic to be optimal to borylate various aryl iodides (Scheme 23).28) borylation of aryl halides via a halogen-zinc exchange It is worth mentioning that sterically hindered mesityl substrate reaction with borylzincate (Figure 5). In this reaction design, (58), aryl iodides containing the transition metal-susceptible energetically disfavored borylzincate formation is expected to allyloxy group (59), base-susceptible ester group (65, 66) and be compensated by stepwise formation of the stable C–Zn and cyano group (67), and various heteroaromatic substrates (70-74) C–B bonds. can be employed. Moreover, aryl bromides are also borylated by elevating reaction temperature to 120 °C (54, 56, 60). Diborons After extensive optimization, a set of conditions of Et2Zn other than bis(pinacolato)diboron can also be applied to this (10 mol%), NaOtBu (1.1 eq.), and at 75 °C in THF was found methodology (74, 75).

Et2Zn (10 mol%) FG NaOtBu (1.1 eq.) FG X + B2(OR)4 B(OR)2 THF 75 °C, 24 h

Me Me O O MeO O O B O B Me B O B O O para : 54: 82% (83%) Me O meta : 55: 91% 57: 86% 58: 80%a 59: 71% ortho : 56: 86% (83%) F iPr O O O iPr N B X B O CF3 B O O B O O O 60: 92% (95%) 61: quant. 62: X = Cl: 92% 64: 83% 63: X = Br: 75%

MeO2C O O O S O B NC B B B O O O O para : 65: 63% 1-naphthyl: 68: 93% 2-thienyl: 70: 80% 67: 60% meta : 66: 65% 2-naphthyl: 69: 72% 3-thienyl: 71: 95%

O O O O N B N B MeO B Cl B Ts O O O O 72: 76% 73: 74% 74: 72%a 75: 64%

Scheme 23. Substrate Scope of Aromatic Borylation Reactions Isolated yields. Yields in parentheses are of the reaction with aryl bromides at 120 °C. a Reaction at 120 °C.

FG FG Et2Zn (3 eq.) E O O t I Mg(O Bu)2 (2 eq.) + BB O O O dioxane, 120 °C, 24 h B X then Electrophile (3 eq.) O

+ (pin)B ZnEt2 – IB(pin) + E

FG FG FG + (pin)B ZnEt2 ZnEt2 ZnEt2 – XZnEt2 X B(pin) Allyl Bromide OMe Cl F

B(pin) B(pin) B(pin) B(pin) 84% (X =Br) 81% (X = I) 77%a (X =Br) 72%a,b (X =Br) 51%b (X =Br) 63% (X = OTf)

Iodine H2O OMe OMe CN I I H H

B(pin) B(pin) B(pin) B(pin) 78% (X =Br) 71%b (X =Br) 84% (X =Br) 76%b (X =Br)

Scheme 24. Borylzincation Reactions of Benzynes The reactions with electrophiles were carried at room temperature with H2O for 5 min or with I2 for 3 h, a b or at 75 °C with allyl bromide for 12 h. Isolated yields. NMR yields. 2 eq. of B2(pin)2 were used.

15 No.171 No.171

Next, we designed another strategy to gain a large Initially, exhaustive efforts were devoted to the reactions stabilization energy of the system by the reaction of borylzincate between internal alkynes and diborons activated by Lewis bases with benzyne. Benzynes are highly unstable intermediate and (intermolecular approach),29) but no desired diborylated product form stable benzene rings after the reaction with nucleophiles. was obtained (Scheme 25). Model DFT calculation computed Highly nucleophilic borylzincate undergoes an iodine-zinc the activation barrier for the initial C–B bond formation to be exchange reaction followed by concomitant elimination of an more than 50 kcal/mol and entirely insurmountable, which is ortho leaving group to give a benzyne (Scheme 24). Addition of well consistent with the experimental results. another borylzincate across the benzyne generates functionalized arylzincate, which is trapped by various electrophiles to give Thus, we designed “pseudo-intramolecular reaction” 30) by multiply substituted benzenes with high regioselectivities.28) using alkynes possessing a Lewis basic site within the molecule in order to facilitate a C–B bond forming event in terms of 4-5-2. trans-Diborylation of Alkynes via pseudo- enthalpy and entropy (Figure 7). Intramolecular Reaction Vinylboronates are important and useful synthetic The reaction of bis(pinacolato)diboron with the propargylic precursors in organic synthesis of pharmaceuticals and alkoxide afforded the desired diborylated product 76 in 77% functional molecules. In general, those compounds are prepared yields (Scheme 26).31) This diborylation reaction can be easily through hydroboration, haloboration, and diborylation of operated on a gram­scale and has a broad substrate scope. alkynes. These types of reactions normally utilize the interaction Triple bonds proximal to the alkoxide group react preferentially between triple bond and the vacant p-orbital of boron or over the distal multiple bonds in the cases of enyne and diyne transition metal-boron bond for the C–B bond formation so substrates (91 and 92). Applicable substrate is not limited to that cis-configurated alkene products are generally obtained tertiary alcohols and a range of secondary alcohols is converted (Figure 6). We expected that addition of borylanion (equivalent) to the oxaborole products in high yields (92-98). On the other to a triple bond would lead to unprecedented trans-selective hand, primary alcohols and homopropargylic alcohols do not diborylation reaction. participate in this type of diborylation reaction.

Conventional Borylation Our Approach X X B R1 BX XB X BX2 X 2 X 1 2 2 R1 R2 R R X R 1 2 R R X

Figure 6. Concepts of Borylation of Triple Bonds

O 1 O O Various Conditions R B O R1 R2 + BB O O O B R2 O

No Product Formation

DFT Calculation@B3LYP/6-31+G*(kcal/mol)

Me O ‡ O O O Me B B Li O B O O Me O ∆G = +51.9! O O Me O B B Me O Li O Me Li ∆G = –63.0 O B Me O Me Me Pre-reaction IMinter TSinter CPinter Scheme 25. Attempts on Intermolecular Diborylation of Alkynes

O O BB O O O O B B O + O LB LB FG FG Figure 7. pseudo-Intramolecular Activation of Diborons

16 No.171

The diborylation reaction can be performed in one-pot Furthermore, the fully substituted olefin 102 is synthesized starting with terminal alkynes (Scheme 27). Lithium alkoxides through a sequential diborylation/Suzuki-Miyaura cross- generated in situ by the reaction of a corresponding lithium coupling reaction in one-pot without isolating the borate acetylide with acetone react with diboron smoothly to give intermediate 101 (Scheme 28). This tandem process offers trans-diborylated products 77, 85 and 86 with high efficacy. a rapid and versatile access to fully substituted olefins in a regioselective manner and should surely contribute to exploration of novel biologically active compounds.

R2 1) nBuLi (1 eq.), rt, 30 min O R1 R3 R1 B O 2) B (pin) (1.1 eq.) OH 2 2 R2 THF, 75 °C, 24 h; B 3 workup HO O R

Acetylenic Terminus 4-OMe : 77: 94% R O O 3-OMe : 78: 88% O O 4-CF : 79: 97% B O B O 3 N B O S B O 4-Cl : 80: 73% Me Me 4-CO Et : 81: 61% Me Me B B 2 B B HO O Me HO O Me 4-CN : 82: 74% HO O Me HO O Me 76: 77% 3-NH2 : 83: 85% 84: 66% (NMR Yield) 85: 96% 87% (1.37 g)

TIPS O O O O C2H4Ph : 87: 56% B O R B O nBu : 88: 89% B O B O Me Me cHex : 89: 84% Me Me B B tBu : 90: 35% B B HO O Me HO O Me HO O Me HO O Me 86: 92% 91: 62% 92: 72% Propargylic Position R O O O O B O HN B O B O B O B NH H H Me HO B B Me O HO B Me HO R HO B Me O O O HO B Me t O H : 94: 93% Bu : 96: 75% 93: 88% (E)-CH=CHMe : 97: 80% 99: 49% 100: 82% OC2H4NMe2 : 95: 75% p-Tol : 98: 27%

Scheme 26. trans-Selective Diborylation of Alkynes

n 1) BuLi (1 eq.) O Me THF, rt, 30 min 3) B2(pin)2 (1.1 eq.) O R H R Me R B 2) acetone (1 eq.) OLi 75 °C, 24 h; workup Me rt, 1 h B HO O Me

MeO

O O O B O S B O B O Me Me Me B B B HO O Me HO O Me HO O Me 77: 83% 85: 81% 86: 85% Scheme 27. One-pot Diborylation Reactions

3) Me Me I 1) nBuLi (1 eq.) O dioxane B O (2.2 eq.) Me rt, 30 min PdCl2(dppf) (5 mol%) H O H B H OH 2) B2(pin)2 (1.1 eq.) O Me dioxane/aq. KOH 75 °C, 24 h O 120 °C, 24 h HO Me Li 101 Me 102: 64% Scheme 28. Sequential Diborylation/Suzuki-Miyaura Cross-coupling Process for Multi-substituted Olefin Synthesis

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5. Conclusion Acknowledgements

This article outlined the design of functional ate complexes Our research works have been done at Graduate School and their applications in synthetic organic chemistry developed of Pharmaceutical Sciences of Tohoku University, Graduate by our research group. By combining “element chemistry” School of Pharmaceutical Sciences of The University of Tokyo, which understands and utilizes characteristics of elements and RIKEN. We are grateful to these institutions and generous with “ate complex formation” which brings out potential of financial supports by the Ministry of Education, Culture, Sports, elements, we realized unprecedented reactivities and chemo-, Science and Technology, Japan Society for the Promotion regio-, and stereoselectivities. In concrete, we have developed of Science, and Japan Science and Technology Agency. “chemoselective metalation of aryl halides”, “development of Magnificent contributions by our co-workers are gratefully novel ate bases and deprotonative metalation of aromatics”, acknowledged. “silylzincation reactions of unsaturated C–C bonds”, “chemo- and regioselective generation of substituted benzynes”, “anionic polymerization reactions in water”, “Ni-catalyzed Negishi cross-coupling reaction using aryl ethers as electrophiles”, “perfluoroalkylation reactions using thermally stable but reactive perfluoroalkylzincs”. Recently, we also focus on utilization of borylanions. By designing novel reaction intermediates and mode of reaction, we achieved “aromatic borylation reaction with borylzincate” and “the first trans-selective diborylation of alkynes via pseudo-intramolecular activation of diborons”.

As reviewed in this article, ate complex formation is a powerful and attractive strategy to create/bring out unprecedented reactivities and functions of organometallic reagents, and believed to continue pioneering the frontiers of synthetic organic chemistry and materials sciences.

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References 26) Y. Segawa, M. Yamashita, K. Nozaki, Science 2006, 314, 113. 1) J. A. Wanklyn, Liebigs Ann. 1858, 108, 67. 27) D. S. Laitar, P. Müller, J. P. Sadighi, J. Am. Chem. Soc. 2) D. T. Hurd, J. Org. Chem. 1948, 13, 711. 2005, 127, 17196. 3) Y. Kondo, N. Takazawa, C. Yamazaki, T. Sakamoto, J. 28) Y. Nagashima, R. Takita, K. Yoshida, K. Hirano, M. Org. Chem. 1994, 59, 4717. Uchiyama, J. Am. Chem. Soc. 2013, 135, 18730. 4) M. Uchiyama, M. Koike, M. Kameda, Y. Kondo, T. 29) For inspiring work on addition of Lewis base activated Sakamoto, J. Am. Chem. Soc. 1996, 118, 8733. diborons to nonactivated olefins, see: A. Bonet, C. Pubill- 5) M. Uchiyama, M. Kameda, O. Mishima, N. Yokoyama, M. Ulldemolins, C. Bo, H. Gulyás, E. Fernández, Angew. Koike, Y. Kondo, T. Sakamoto, J. Am. Chem. Soc. 1998, Chem. Int. Ed. 2011, 50, 7158. 120, 4934. 30) Y. Yamamoto, J.-I. Ishii, H. Nishiyama, K. Itoh, J. Am. 6) M. Uchiyama, T. Furuyama, M. Kobayashi, Y. Matsumoto, Chem. Soc. 2005, 127, 9625. K. Tanaka, J. Am. Chem. Soc. 2006, 128, 8404. 31) Y. Nagashima, K. Hirano, R. Takita, M. Uchiyama, J. Am. 7) T. Furuyama, M. Yonehara, S. Arimoto, M. Kobayashi, Y. Chem. Soc. 2014, 136, 8532. Matsumoto, M. Uchiyama, Chem. Eur. J. 2008, 14, 10348. 8) M. Kobayashi, Y. Matsumoto, M. Uchiyama, T. Ohwada, Macromolecules 2004, 37, 4339. 9) C. Wang, T. Ozaki, R. Takita, M. Uchiyama, Chem. Eur. J. 2012, 18, 3482. 10) R. E. Mulvey, F. Mongin, M. Uchiyama, Y. Kondo, Angew. Chem. Int. Ed. 2007, 46, 3802. 11) W. Tückmantel, K. Oshima, H. Nozaki, Chem. Ber. 1986, 119, 1581. 12) Y. Kondo, M. Shilai, M. Uchiyama, T. Sakamoto, J. Am. Chem. Soc. 1999, 121, 3539. 13) M. Uchiyama, T. Miyoshi, Y. Kajihara, T. Sakamoto, Y. Otani, T. Ohwada, Y. Kondo, J. Am. Chem. Soc. 2002, 124, 8514. See also: M. Uchiyama, Y. Kobayashi, T. Furuyama, S. Nakamura, Y. Kajihara, T. Miyoshi, T. Sakamoto, Y. Kondo, K. Morokuma, J. Am. Chem. Soc. 2008, 130, 472. 14) M. Uchiyama, H. Naka, Y. Matsumoto, T. Ohwada, J. Am. Chem. Soc. 2004, 126, 10526. See also: H. Naka, M. Uchiyama, Y. Matsumoto, A. E. H. Wheatley, M. McPartlin, J. V. Morey, Y. Kondo, J. Am. Chem. Soc. 2007, 129, 1921. 15) S. Usui, Y. Hashimoto, J. V. Morey, A. E. H. Wheatley, M. Uchiyama, J. Am. Chem. Soc. 2007, 129, 15102. See also: S. Komagawa, S. Usui, J. Haywood, P. J. Harford, A. E. H. Wheatley, Y. Matsumoto, K. Hirano, R. Takita, M. Uchiyama, Angew. Chem. Int. Ed. 2012, 51, 12081. 16) N. Tezuka, K. Shimojo, K. Hirano, S. Komagawa, K. Yoshida, C. Wang, K. Miyamoto, T. Saito, R. Takita, M. Uchiyama, J. Am. Chem. Soc. 2016, 138, 9166. 17) M. Uchiyama, S. Furumoto, M. Saito, Y. Kondo, T. Sakamoto, J. Am. Chem. Soc. 1997, 119, 11425. For mechanistic studies by DFT calculations, see: M. Uchiyama, S. Nakamura, T. Ohwada, M. Nakamura, E. Nakamura, J. Am. Chem. Soc. 2004, 126, 10897. 18) R. Murata, K. Hirano, M. Uchiyama, Chem. Asian J. 2015, 10, 1286. 19) S. Nakamura, M. Uchiyama, T. Ohwada, J. Am. Chem. Soc. 2004, 126, 11146. 20) S. Nakamura, M. Uchiyama, T. Ohwada, J. Am. Chem. Soc. 2005, 127, 13116. 21) S. Nakamura, M. Uchiyama, J. Am. Chem. Soc. 2007, 129, 28. 22) For a comprehensive review on RF–organometallics, see: D. J. Burton, Z.-Y. Yang, Tetrahedron 1992, 48, 189. 23) X. Wang, K. Hirano, D. Kurauchi, H. Kato, N. Toriumi, R. Takita, M. Uchiyama, Chem. Eur. J. 2015, 21, 10993. 24) I. Popov, S. Lindeman, O. Daugulis, J. Am. Chem. Soc. 2011, 133, 9286. See also: K. Aikawa, Y. Nakamura, Y. Yokota, W. Toya, K. Mikami, Chem. Eur. J. 2015, 21, 96. 25) H. Kato, K. Hirano, D. Kurauchi, N. Toriumi, M. Uchiyama, Chem. Eur. J. 2015, 21, 3895.

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Introduction of the authors:

Keiichi Hirano, Dr.rer.nat. Assistant Professor, Graduate School of Pharmaceutical Sciences, The University of Tokyo

Keiichi Hirano received his bachelor and master’s degrees in pharmaceutical sciences from the University of Tokyo. Then, he moved to Marburg to pursue his doctoral studies supported by the DAAD fellowship and obtained his doctoral degree working with Prof. Dr. Frank Glorius at the Westfälishe Wilhelms-Universität Münster in 2009. He then carried out his postdoctoral study with Prof. Barry M. Trost at Stanford University supported by the Uehara Memorial Foundation Postdoctoral Fellowship. After another postdoctoral fellowship with Prof. Masanobu Uchiyama at the University of Tokyo funded by the JSPS postdoctoral fellowship, he was appointed as an assistant professor associated with Prof. Uchiyama in the Graduate School of Pharmaceutical Sciences at the University of Tokyo in 2012. He has received the Wako Pure Chemical Industries Award in Synthetic Organic Chemistry, JAPAN in 2015, the Chemical Society of Japan Presentation Award 2016, and the Pharmaceutical Society of Japan Award for Young Scientists 2016.

Masanobu Uchiyama, Ph.D. Professor, Graduate School of Pharmaceutical Sciences, The University of Tokyo Chief Scientist (Joint Appointment), Elements Chemistry Laboratory, RIKEN

Masanobu Uchiyama received his B.S. degree from Tohoku University in 1993 and M.S. degree from the University of Tokyo in 1995. He was appointed as an assistant professor at Tohoku University in 1995 and then received Ph.D. degree from the University of Tokyo in 1998. He moved to the Graduate School of Pharmaceutical Sciences, the University of Tokyo, as an Assistant Professor in 2001 and was promoted to Lecturer in 2003. He was appointed as an Associate Chief Scientist at RIKEN in 2006. He is now a Professor at the University of Tokyo since 2010. He was promoted to Chief Scientist at RIKEN in 2013 (Joint Appointment). He received Banyu Young Chemist Award (1999), The Pharmaceutical Society of Japan Award for Young Scientists (2001), Inoue Research Award for Young Scientists (2002), Incentive Award in Synthetic Organic Chemistry, Japan (2006), The Young Scientists’ Prize of The Commendation for Science and Technology by the Minister of Education, Culture, Sports, Science and Technology (2009), Nagase Foundation Award 2013 (2013), SSOCJ Nissan Chemical Industries Award for Novel Reaction & Method (2014), and Seiichi Tejima Research Award (2015).

TCI Related Products

B3534 NiCl2(PCy3)2 [= Bis(tricyclohexylphosphine)nickel(II) Dichloride] 1g 5g B3095 Ni(cod)2 [= Bis(1,5-cyclooctadiene)nickel(0)] 5g T1165 PCy3 [= Tricyclohexylphosphine (contains Tricyclohexylphosphine Oxide) (ca. 18% in Toluene, ca. 0.60mol/L)] 25mL B3153 TBHP [= tert-Butyl Hydroperoxide (70% in Water)] 100g C2223 CHP [= Cumene Hydroperoxide (contains ca. 20% Aromatic Hydrocarbon)] 100g T0616 Cp2TiCl2 (= Titanocene Dichloride) 5g 25g C1952 CuCN [= Copper(I) Cyanide] 25g 300g N0499 C4F9–I (= Nonafluorobutyl Iodide) 25g 100g 500g T1098 C6F13–I (= Tridecafluorohexyl Iodide) 5g 25g P1084 C8F17–I (= Heptadecafluoro-n-octyl Iodide) 25g H0844 C10F21–I (= Heneicosafluorodecyl Iodide) 5g 25g P1188 C6F5–I (= Pentafluoroiodobenzene) 5g 25g i H0629 C3F7–I (= Heptafluoroisopropyl Iodide) 25g 100g D2014 DMPU (= N,N'-Dimethylpropyleneurea) 25g 100g 500g D3214 Et2Zn [= Diethylzinc (ca. 17% in Hexane, ca. 1mol/L)] 100mL 500mL D3902 Et2Zn [= Diethylzinc (ca. 15% in Toluene, ca. 1mol/L)] 100mL B1964 B2(pin)2 [= Bis(pinacolato)diboron] 1g 5g 25g 100g B2254 Bis(neopentyl Glycolato)diboron 1g 5g 25g B3757 Bis(catecholato)diboron 1g 5g S0450 NaOtBu (= Sodium tert-Butoxide) 25g 100g 500g B0396 nBuLi [= Butyllithium (ca. 15% in Hexane, ca. 1.6mol/L)] 100mL 500mL B4697 nBuLi [= Butyllithium (ca. 20% in Cyclohexane, ca. 2.3mol/L)] 100mL 500mL 20