– 1 –

Organometallic Chemistry — for organic synthesis Contents 1. Main group organometallic chemistry

1-1. Preparations 1-2. Reactions

2. Reactions of organic molecules and transition-metal complexes 3. Reactions catalyzed by transition-metal complexes

3-1. Hydrogenation 3-2. Cross-coupling and related reactions 3-3. Olefin metathesis 3-4. Homogeneous metal catalysts in chemical industry

Books 1. Comprehensive Organometallic Chemistry III

eds. by D. M. P. Mingos and R. H. Crabtree, Elsevier, Oxford, 2007. (https://www.sciencedirect.com/science/referenceworks/9780080450476)

2. 第５版 実験化学講座 有機化合物の合成 VI 金属を用いる有機合成 日本化学会 編, 丸善, 2004. (ISBN4-621-07317-6)

3. 有機金属化学 山本明夫, 東京化学同人, 2015. (ISBN978-4-8079-0857-8)

4. Organotransition Metal Chemistry: From Bonding to Catalysis J. F. Hartwig, University Science Books, Sausalito, 2010. (ISBN978-1-8913-8953-5, 日本語訳あり)

5. Organic Syntheses http://www.orgsyn.org/Default.aspx

Abbreviations in Chemical Structures

Me CH3- methyl Bz PhC(O)- benzoyl Et MeCH2- ethyl Boc t-BuOCO tert-butoxycarbonyl Pr EtCH2- n-propyl Ts p-TolSO2- p-toluenesulfonyl Bu PrCH2- n-butyl Ms MeSO2- methanesulfonyl Pent BuCH2- n-pentyl Tf CF3SO2- trifluoromethanesulfonyl Hex PentCH2- n-hexyl TMS Me3Si- trimethylsilyl i-Pr Me2CH- isopropyl TES Et3Si- triethylsilyl i-Bu i-PrCH- isobutyl TBS t-BuMe2Si- tert-butyldimethylsilyl s-Bu EtMeCH- sec-butyl t-Bu Me3C- tert-butyl c-Pent c-C5H9- cyclopentyl t-Am EtMe2C- tert-amyl Cy (c-Hex) c-C6H11- cyclohexyl Ph C6H5- phenyl pin -OCMe2CMe2O- pinacolate Bn PhCH2- benzyl cat 1,2-C6H4O2 catecholate o-Tol 2-MeC6H4- 2-methylphenyl m-Tol 3-MeC6H4- 3-methylphenyl R any C substituents p-Anis 4-MeOC6H4- 4-methoxyphenyl Ar any aromatic substituents PMB p-AnisCH2- 4-methoxybenzyl X any halogen and related leaving group Xyl 5-Me-m-Tol- 3,5-dimethylphenyl M any metal substituents Mes 2,4,6-Me3C6H2- mesityl 1-(a-)Np 1-C10H7- 1-naphtyl TMEDA Me2NCH2CH2NMe2 2-(b-)Np 2-C10H7- 2-naphtyl HMPA (Me2N)3P=O Ac MeC(O)- acetyl

Periodic Table

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 H

He

Li Be B C N O F Ne Na Mg Al Si P S Cl Ar K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn Ga Ge As Se Br Kr

Rb Sr Y Zr Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te I Xe Cs Ba Ln Hf Ta W Re Os Ir Pt Au Hg Tl Pb Bi Po At Rn

Lanthanoids (Ln) La Ce Pr Nd Pm Sm Eu Gd Tb Dy Ho Er Tm Yb Lu

– 2 –

1. Main group organometallic chemistry 1-1. Preparations (0) What is organometallic compounds?

“Organometallic compounds” means the compounds containing one or more carbon–metal (C–M) covalent bonds.

Features and properties • The organometallic compound has one or more C–M bonds • It behaves as a carbanion (carbon nucleophiles) to react with electrophilic compounds • Reactivity of the C–M bond is greatly affected by electronegativity (c) of the metal atom.

Li, Mg etc. (small c) Unstable to water and oxygen Not easy to handle in air Too reactive. B, Si, Sn etc. (large c) Relatively stable to water and oxygen Possible to be purifies with extraction and/or chromatography

(1) Preparation from organic halides and metal (direct method) Some main group organometals are prepared from the corresponding organic halides

through the reaction with metal elemental substance. This method offers the most fundamental preparation of organolithium and magnesium compounds.

Notice • The reactions are greatly affected by shape of the metal (dispersion, granular, or ingot). • Reactivity of lithium metal is affected by sodium impurity (<1%). The impurity facilitates the

reaction. • Lithium or magnesium can be activated with a small piece of iodine or 1,2-dibromoethane. • Some organozincs, e.g. Reformatsky and Simmons–Smith reagents, can be obtained from

the reaction of the halide and zinc metal. Zinc–copper couple (alloy) is frequently employed for the preparation.

• Optimal solvent depends on the halide as well as the metal. Therefore, the solvent must be carefully chosen for each combination. Et2O and THF is favorable for the preparation of Grignard reagent and aryllithium. The preparation of alkyllithium is ordinarily carried out in hydrocarbon solvent.

• The organic halide should be carefully and slowly (0.1–3 h) added to the metal suspension to avoid Wurtz reaction.

Half lives of organolithium compounds in ethereal solvents (min)

–40°C –20°C 0°C 20°C 35°C

in Et2O n-BuLi 9180 1860 s-BuLi 1187 139 t-BuLi 483 61 complex

in THF n-BuLi 1039 107 s-BuLi 78 t-BuLi 338 42

P. Stanetty, J. Org. Chem., 62, 1514 (1997). Mechanism

• The generation of Grignard reagent starts from the electron transfer from metal to organic

halide. • The reaction proceeds through the radical species, which must be kept low concentration to

avoid its homocoupling. • In the case of lithium, LiX is generated in the second step. The radical species, R•, reacted

with Li atom in place of •MgX.

(a) Lithium arenide

• Lithium give an electron to the LUMO of naphthalene, forming a radical anion, lithium

naphthalenide (LN). • The redox potential of naphthalenide is higher than that of the metal, but LN is soluble in

THF (or related solvent). The high solubility of naphthalenide much facilitates the electron transfer to organic halides.

• Use of LN allows preparation of organolithiums at low temperature. The mild condition leads to restriction of the undesired Wurtz reaction.

• A catalytic amount of naphthalene is enough for efficient production of organolithiums. • Arenes below are also usable for the generation of anion radical in place of naphthalene.

Application

L. Duhamel, Tetrahedron Lett., 39, 8975 (1998).

M = Li etc. (alkali metal)

M = Mg etc. (alkaline earth metal)

R X + 2 M R M + MX

R X + M R MX (X = I, Br, Cl)

R XMg0

Mg+ • R X – • R• •MgX R MgX

Li +THF

– •

Li+R X

R Li

lithium naphthalenide (LN)

NMe2t-Bu t-Bu

DMAN DBB

Cl OEt

OEtLi

DBB (10%)

THF, –20°CLi

OEt

OEt PhCMeO

OEt

OEt

Ph

OLiMe

H2O

CO2EtPh

OHMe

– 3 –

(b) Rieke metal

R. D. Rieke, Acc. Chem. Res., 10, 301 (1977); Tetrahedron 53, 1925 (1997).

• Metal halides, MXn, are reduced with sodium arenide to fine metal particles, which are named Rieke metal.

• Rieke metal is more reactive than common metal powder. • Various organometals, e.g. Mg, Zn, In, Ca, Cu etc., can be prepared under mild conditions

through the reaction of organic halide with Rieke metal.

(c) Knochel’s organozinc preparation

P. Knochel, Angew. Chem. Int. Ed., 45, 6040 (2006).

• The addition of LiCl remarkably enhance the reactivity of purchasable zinc powder. • The zinc is activated by catalytic 1,2-dibromoethane and TMSCl in the presence of LiCl.

The resulting Zn•LiCl readily reacts with various iodo-, bromoarenes, and bromoalkanes. • This method is applicable for the generation of various functionalized organometal species,

because organizinc compounds are commonly inert to various functional groups, e.g. ketone, ester, and nitrile.

(2) Metal–halogen (M–X) exchange reaction

• In the mixture of an organohalide (R–X) and organometal (R’–M), the halogen in R–X is

readily replaced by the metal R’–M to give another organometal R–M. • The metal–halogen exchange reaction is more convenient for preparing the aryl and alkenyl-

lithiums in small scale than the direct method. • In this reaction, R’–M and R–M are in equilibrium. The equilibrium is affected by the

thermal stability of each carbanion. The reaction proceeds to the right, when R’–H is larger in pKa than R–H.

• The lithiation of organohalides through M–X exchange reaction proceeds well at much lower temperature (–78°C) than the direct method.

• Butyllithium or tert-butyllithium is frequently employed for the lithiation, because it is reactive and easily available from reagent company. ・ Caution! The organolithium prepared from this method contains stoichiometric haloalkane

R’–X as the by-product. Users must consider the side reactions caused by the haloalkane, e.g. the cross-coupling reaction to form R–R’.

H. Gilman, J. Am. Chem. Soc., 62, 2327 (1940).

N. Furukawa, Tetrahedron Lett., 28, 5845 (1987).

Turbo Grignard Reagent (i-PrMgCl•LiCl)

P. Knochel, Angew. Chem. Int. Ed., 43, 3333 (2004).

• Turbo Grignard reagent, i-PrMgCl•LiCl, is more reactive for the X–Mg exchange reaction than common Grignard reagents. With the reagent, the desired organomagnesiums can be prepared from the corresponding bromoarenes at low temperature (< 0°C).

• Turbo Grignard reagent is generated from the reaction of i-PrCl and magnesium turnings in the presence of anhydrous LiCl.

• This method is applicable for the generation of various Grignard reagents bearing various reactive functional groups, such as carboxylate and nitrile.

(3) Metal–metal (M–M’) exchange reaction (transmetalation) (a) Exchange reaction between organometallic compound and metal halide

• This reaction is the most reliable method for preparing less reactive organometals, Zn, Al,

Sn, Si, B etc. Organolithium or magnesium is mostly employed as the starting material. • This reaction is also in equilibrium. Nevertheless, the desired organometals are obtained

in high yields in most cases, because insoluble or thermally stable metal salt is generated as a by-product.

• The corresponding metal halide, e.g. ZnCl2, Bu3SnCl, Me3SiCl, is used for the synthesis of the target organometal. To prepare alkyl-, alkenyl- or arylboronic acid, the most suitable metal source is trialkyl borates, B(OR)3.

• The resulting organometals are used as the nucleophilic substrates in various reactions, such as the palladium-catalyzed cross-coupling reactions.

MXn + n Na or Kcat. naphthalene

– n NaX or KX"M"

Rieke metal

R XR M

Zn+

LiCl

cat. BrCH2CH2Br (5%) Me3SiCl (1%)

R I

R

ZnI•LiCl

(R = CO2Et)

Br

cat. CuCN•2LiCl

R

R X R' M+ R M R' X+ M = Li, MgX etc.X = I, Br, SeR, TeR etc.

Br Li+ Bu LiEt2O

+ Bu Br

(pKa = 50) (pKa = 43)

1. CO2CO2H

2. H3O+

84%

NI + EtMgBr

THF

rt NMgBr

1. PhCHO

2. H3O+ N

OH

Ph91%

i-Pr Cl + Mg + LiClTHF, rt, 12 h

i-Pr MgCl•LiCl

Br

Br

Br

i-Pr MgCl•LiCl

THF, –50°C, 2 h Br

Br

MgCl•LiCl

t-BuCHOBr

Br

OH

t-Bu89%

R M’ + MXn R MXn–1 + M’X MXn = ZnCl2, R3SnCl, R3SiCl, R2B(OMe), etc.M’ = Li, MgX

– 4 –

E. Negishi, Org. Synth., 66, 67 (1987).

D. Seyferth J. Am. Chem. Soc., 79, 515 (1957).

(b) Exchange reaction between two organometallic compounds

• This method is sometimes useful for generating highly reactive organometallic species,

e.g. allyllithium, but it is not common. • This reaction is also in equilibrium. The equilibrium is affected by the thermal stability of

each carbanion. • The reaction proceeds to the right, when R’–H is larger in pKa than R–H and M is much

smaller in electronegativity than M’.

D. Seyferth J. Org. Chem., 26, 4797 (1961).

(4) Metal–hydrogen (M–H) exchange reaction (deprotonation)

• If a substrate has an acidic C–H bond (less than pKa 40), it will be deprotonated on the

carbon with a strong base (e.g. t-BuLi) to give the corresponding organometal. This reaction can be classified into an acid–base reaction.

• The deprotonation is in equilibrium. The equilibrium is controlled by the thermodynamic stabilities of the corresponding carbanions, R– and R’–. The reaction proceeds to right, when R’–H is larger in pKa than R–H.

pKa in hydrocarbons Me3C–H Me2CH–H MeCH2–H CH2=CH–H Ph–H PhCH2–H HC≡C–H

pKa 53 51 50 44 43 41 25

• Suitable bases for the M–H exchange reaction: (purchasable) BuLi, s-BuLi, t-BuLi, EtMgBr, i-Pr2NLi (pKa 38), NaH (pKa 35) etc. (preparation for use) Schlosser base, i-Pr2NMgBr, Knochel–Hauser base etc.

• This reaction is useful for generating lithium acetylide, heteroaryllithiums, and a-oxa- or aza-alkyllithiums.

M. M. Midland, Org. Synth., 68, 14 (1990).

E. Jones, Org. Synth., 50, 104 (1970).

P. Beak, J. Am. Chem. Soc., 113, 9708 (1991).

• A Lewis basic directing group often facilitates the site-selective M–H exchange on a specific C–H bond (e.g. ortho-metalation).

I. Ugi, J. Am. Chem. Soc., 92, 5389 (1970).

H. W. Gschwend, J. Org. Chem., 40, 2008 (1975).

Schlosser–Lochmann base • Schlosser–Lochmann base is prepared by mixing butyllithium (or tert-butyllithium) and

potassium tert-butoxide in 1:1 ratio. The resulting mixture works as a superbase. L. Lochmann, Tetrahedron Lett., 257 (1966); M. Schlosser, Angew. Chem. Int. Ed. Engl., 12, 508 (1973)

R. W. Hoffmann, J. Org. Chem., 46, 1309 (1981); W. R. Roush, Tetrahedron Lett., 29, 5579 (1988).

Knochel–Hauser base • Knochel–Hauser base (1) is prepared from i-PrMgCl•LiCl and 2,2,6,6-tetramethylpiperidine

(TMPH).

t-BuLiMe

I

Me

LiEt2O THF

ZnCl2Me

ZnCl cat. Pd(PPh3)4THF

NO2

Br

o-Tol NO2

78%

Mg

THF

Bu3SnCl

THF, refluxBr MgBr SnBu3

85%

R M’ + R' M R M + R' M’ M = Na, Li, MgX etc.M’ = SnR3, BR2 etc.

Sn + 4 BuLi 44

Li + Bu4Snpentane

R H + R' M R M + R' H

HC CH + BuLiTHF

HC CLiOH

90%endo:exo = 97:3

O

S+ BuLiH THF S Li

NBoc

H + s-BuLiTHF, –78°C

TMEDANBoc

LiBu3SnCl

–78°C to rtNBoc

SnBu3

66%

Fe

NMe2

HMe + BuLi Fe NMe2Et2O Li

TMSClFe

NMe2

HMe

TMS

MeH

O

N s-BuLi

Et2O, –78 to 0°CO

NLi

t-BuNCO

O

N

t-BuHNO

81%

MeMe BuLi, t-BuOK

Me K Me

B(pin)

E : Z = <5 : >95

1. ClB(NMe2)2

2.HO OH

THF, rt, 24 hNH

Me

MeMe

+ i-PrMgCl•LiCl

Me

NMgCl•LiCl

Me

MeMe

Me 1

– 5 –

• The base 1 deprotonates from various arenes bearing a Lewis basic directing group and heteroarenes to give the corresponding Grignard reagents.

• Meanwhile, the M–X exchange reaction scarcely proceeds when 1 is used as the metalation reagent. The magnesium amide has no C–M bond.

• The lithium salt remarkably enhances the reactivity of the magnesium amide as with turbo Grignard reagent.

P. Knochel, Angew. Chem. Int. Ed., 45, 2958 (2006).

(5) Hydrometalation

• Hydrometalation is the addition of metal hydride (M–H) across unsaturated bond, e.g. alkene

or alkynes. • This reaction is often used for preparing organoboron, organosilane, and organotin

compounds etc. • Regio- and stereoselectivity must be controlled to obtain the desired product in high yield.

However, the hydrometalation proceeds through syn addition with high regioselectivity in many cases. The metal substituent is installed on the less congested site.

(a) Hydroboration • Borane (BH3) or dialkylborane readily reacts with alkene or alkyne in the 1,2-addition

manner without catalyst to produce the corresponding alkyl or alkenylborane. • The installed boryl group can be transformed into various functional groups. Moreover,

the alkenylboranes is usable for Suzuki–Miyaura coupling.

Regioselectivity • The boryl group is installed at the terminus in the terminal alkene or alkyne substrate (anti-

Markovnikov selective). • The hydroboration of terminal alkynes is accompanied by a small amount of undesired

formation of the dihydroboration product.

R BH3 Sia2BH 9-BBN Bu 94: 6 99: 1 >99.9:0.1 Ph 80:20 98: 2 98.5:1.5 MeOCH2 81:19 98: 2 98.4:1.6 AcOCH2 65:35 98: 2 97.6:2.4

H. C. Brown, J. Am. Chem. Soc., 96, 7765 (1974); J. Org. Chem., 46, 3978 (1981).

H. C. Brown, J. Am. Chem. Soc., 101, 96 (1979).

• Dialkoxyboranes, such as catecholborane and pinacolborane, are less reactive than dialkylboranes. The hydroboration with a dialkoxyborane requires higher temperature or transition-metal catalyst to give the hydroboration product in high yield.

• The hydroboration of styrene selectively provides 1-boryl-1-phenylethane, Markovnikov product, when it is carried out in the presence of a cationic rhodium complex.

• Chiral alkylborane can be obtained with high enantioselectivity (up to 96% ee) from the rhodium-catalyzed hydroboration when BINAP is used as the chiral ligand.

T. Hayashi, Y. Ito, J. Am. Chem. Soc., 111, 3426 (1989); Tetrahedron: Asymmetry, 2, 601 (1991).

Stereochemistry • Commonly, the hydroboration proceeds with syn stereospecificity. • The hydroboration of 1-substituted cyclic alkenes gives trans-cycloalkylborane product as

the sole or major product. • Terminal alkynes are selectively converted into trans-alkenyl borane. • The reaction of internal alkynes also proceeds in syn stereochemistry. In this case, it is

difficult to control the regioselectivity.

H. C. Brown, J. Am. Chem. Soc., 99, 3427 (1977).

EtO2C CO2Et

Br

1

THF–25°C, 0.5 h

EtO2C CO2Et

Br MgCl•LiCl

I2EtO2C CO2Et

Br I88%

S

N 1

THF, 0°C, 0.1 h S

NMgCl•LiCl

PhCHO

S

N OH

Ph94%

R RR

HM

R

HM+ M H

R

MH

R

MH

or

RR

BR'2 R

BR'2R'2B H+ H

H

1 2

(i-PrCH)2BHMe

BH

Sia2BH 9-BBN

Bu + 9-BBN BuBR'2 Bu

BR'2

BR'2BR'2 = B

94% 3%

PhO

BHO

+cat. [Rh]

THF Ph

B(cat)Ph B(cat)

[Rh] = RhCl(PPh3)3[Rh] = [Rh(cod)(dppb)]BF4[Rh] = [Rh(cod)2]BF4—(R)-BINAP

10>99>99(96% ee (R))

111

Me+ 9-BBN

Me

BR'2

MeBR'2

others

>99.9%

PPh2PPh2

(R)-BINAP

PPh2PPh2

DPPB

– 6 –

(b) Hydrostannation • The Sn–H bond in trialkyltins can react with C–C double and triple bonds in the presence

of a catalyst or radical initiator, while the hydroboration proceeds without catalyst. • In particular, the hydrostannation of alkynes is often used for the preparation of alkenyltin,

which is useful as the substrate for Kosugi–Migita–Stille coupling. • In the radical hydrostannation of terminal alkynes, the stannyl group is installed on the

terminus. The stereoselectivity is affected by the thermodynamic stability of the radical intermediate. Commonly, trans-stannylalkenes are preferentially obtained from the radical-mediated hydrometalation.

• 2,2’-Azobis(isobutyronitrile) (AIBN) is widely used as the radical initiator for the hydrostannation.

A. B. Smith, III, J. Am. Chem. Soc., 119, 962 (1997).

• The hydrostannation is facilitated by a catalytic amount of various transition-metal complexes. The regio- and stereoselectivity is affected by the substrate as well as the catalyst.

K. C. Nicolaou, J. Am. Chem. Soc., 122, 3830 (2000).

(c) Hydroalumination • Dialkylaluminum hydride, e.g. i-Bu2AlH (DIBAH), also can be added to C–C double or triple

bond with syn stereochemistry to give alkyl- or (E)-alkenylaluminum. • The hydroalumination is often applied to the selective reduction of alkyne to cis-alkene in

combination with the following hydrolysis (protonation) of the alkenylaluminium product. • The trans-cis isomerization of the alkenylaluminum is often induced by the solvent and/or

the functional group around the C–C double bond. In this case, stereochemistry of the product would be controlled by the thermodymanic stability of each isomer.

E.-I. Negishi, Org. Synth., 66, 60 (1988).

J. J. Eisch, J. Org. Chem., 36, 3520 (1971).

W. T. Borden, J. Am. Chem. Soc., 92, 4898 (1970).

(d) Hydrozirconation • Cp2ZrHCl (Schwaltz’s reagent), which can be prepared from Cp2ZrCl2 and LiAlH4, also

works as the metal hydride reagent for the hydrometalations of alkenes and alkynes. • The hydrozirconation is superior to the other hydrometalation in the regio- and

stereoselectivity. • In the hydrozirconation of internal alkenes, the installed zirconium atom moves to the

terminus of the carbon chain.

S. L. Buchwald, Org. Synth., 71, 77 (1993).

J. Schwartz, Org. Synth., 71, 83 (1993).

J. Schwartz, J. Am. Chem. Soc., 96, 8115 (1974).

OOO

OMeBu3SnH, AIBN

toluene, reflux

49%

OOO

OMe

SnBu3

AIBN

NC N N CN

OH

OOcat. PdCl2(PhCN)2 – P(o-Tol)3

i-Pr2NEt, CH2Cl2–20°C, 1 h

+ Bu3SnH

OH

OO

Bu3Sn

80%

C8H17hexane50°C

i-Bu2AlH C8H17 Al(i-Bu)2 ZnCl2cat. Pd(PPh3)4THF, rt

(Z)-ICH=CHBuC8H17

Bu

65%

t-Bu Phheptane, 50°C

i-Bu2AlHt-Bu

Al(i-Bu)2

Ph

H H2O t-BuPh

84%

t-BuPh

OH

THF, reflux

LiAlH4t-Bu

OH

HPh

Al H2Ot-Bu

OH

Ph98%

Zr ClCl + LiAlH4

THF

CH2Cl2

Cp2ZrCl2 75%

Cp2ZrHCl Cp2ZrH2

HexTHF

ZrClCp2HexCp2ZrHCl O

cat. Ni(acac)2O

Hex

61%

benzene

Cp2ZrHClZrClCp2

I2n-C8H17 I

– 7 –

1-2. Reactions (1) Nucleophilic addition

(a) Ketones and aldehydes

(i) Common organomatals

M = Li, MgX, etc. • The nucleophilic addition proceeds well without any catalyst. • Some organometallic compounds may work as reducing agents or strong bases rather

than nucleophilic carbanions.

F. C. Whitmore, J. Am. Chem. Soc., 64, 1239 (1942).

• Mechanism of the reduction with i-BuMgBr is as follows:

M = CeX2 (?) • The organocerium can be prepared by mixing anhydrous CeCl3 and organolithium or

Grignard reagents in THF. The anhydrous CeCl3 is prepared from CeCl3•7H2O by heating at 100–140°C in vacuo.

• The use of cerium allows the highly enolizable ketones to undergo the nucleophilic addition of organometal reagents in high yields.

T. Imamoto, J. Am. Chem. Soc., 111, 4392 (1989); Org. Synth., 76, 228 (1999).

M = LaCl2•2LiCl (?) • The side reactions in Grignard reaction are suppressed by conducting it in the presence

of LaCl3•2LiCl, which is soluble in THF. • The THF solution of lanthanide–lithium salt is prepared by mixing LaCl3•6H2O and LiCl

in water, drying the mixture in vacuo, and then dissolved the residue in THF.

• The combination of Grignard reagent and LaCl3•2LiCl is effective for improving the

nucleophilic addition of the organometal to imines. In this case, high yield was achieved with a catalytic amount of the lanthanide salt.

P. Knochel, Angew. Chem. Int. Ed., 45, 497 (2006).

M = Zn (enantioselective) • Dialkylzinc also undergoes the nucleophilic addition to aldehydes, but the reaction

requires a Lewis acid catalyst for efficient production of the desired secondary alcohol. • Addition of a catalytic amount of a b-aminoalcohol (DAIB) facilitates the nucleophilic

addition of dialkylzinc. The aminoalcohol reacts with dialkylzinc to form the chelate zinc alkoxide 1. Alkoxide 1 can work as the Lewis acid catalyst for the nucleophilic addition.

R. Noyori, J. Am. Chem. Soc., 111, 4028 (1989); ibid., 117, 4832 (1995).

(ii) Allylmetals Feature of allylmetals

• Most of main group metals form a s-bond with the allylic carbon to form s-allylmetal.

However, the p-structure (ion pair?) is preferable to the s-structure in allylithium or allylpotassium.

R’R

O H3O+

ROH

R”R’R" M+

O+ BrMg

Et2O

BrMgO

i-Pri-Pr

BrMgO HOMgBr

8% 11% 78%

O

R R

i-BuMgBr O

H

Mg

RR

Br

MeMe

‡

BrMgO

R R

H+

MeMe

PhPhO

PhPhHO Bu

18-36% 98%

1. BuMgBr, additive, THF

2. H3O+

without additivewith CeCl3 (1:1)

(Ln = La, Ce, Nd)(0.3-0.5 M solution)

O + MgCl•LiCl

N.D.93%

77%N.D.

LnCl3•6H2O + 2 LiCl1. mixed in water2. dried in vacuo3. dissolved in THF

LnCl3•2LiCl

c-PentOH

1. additive, THF

2. H3O+OH

without additivewith LaCl3•2LiCl (1 eq)

NMgCl+

THF, rt, 1 h

LaCl3•2LiCl (10%) H3O+ HN

87%

H

O

Et

OH

+ Et2Zncat. (–)-DAIB

toluene, 0°C, 6 h

Me Me

OHNMe2

Me(–)-DAIB

(–)-DAIB

0 mol%2 mol%

100 mol%

yield (%) ee (%)

097

0

–98

–

OZn

N

ZnO

N

Et

Et

1

Mα

β

γ

RR

M

R

Mσ-allylmetal (α-) π-allylmetal σ-allylmetal (γ-)

R–

M+or

?(ion pair?)

– 8 –

• The metal substituent on the allylic position is possible to shift to the g-position when the M–C bond exhibits some degree of ionic character. In this case, the structure is ambiguous and unstable.

• The rearrangement is scarcely observed when the allylic C–M bond has strong covalent character.

• Transition metals can bond to the allyl group through the p-coordination. The d-orbitals on the metal can interact with the p-orbitals of the allyl ligand.

Regioselectivity

• As with other organomatals, the C–M bond in allylmatal can add to the carbonyl C–O

double bond. In this case, the a-carbon of allylmetal forms a C–C bond with the carbonyl carbon.

• The g-carbon of allylmetal is also possible to attack on the carbonyl carbon. The g-attack ordinarily proceeds through the 6-membered ring transition state.

• The regioselectivity (a vs g) is affected by metal substituent as well as reaction conditions.

H. Yamamoto, J. Am. Chem. Soc., 113, 5893 (1991); ibid., 116, 6130 (1994).

Stereoselectivity • The nucleophilic addition of g-substituted allylmetal through the a-attack yields the

homoallyl alcohol bearing an internal alkene. In this case, the geometric isomerism must be considered for obtaining the desired product in high yield.

• The homoallyl alcohol having vicinal stereogenic centers is obtained from the nucleophilic addition, when the reaction proceeds through the g-attack. In this case, the diastereoselectivity must be controlled for obtaining the target product in high yield.

Reaction of allylborane (through cyclic TS) • In the nucleophilic addition of allylborane, its g-carbon attacks on the carbonyl carbon. • The reaction proceeds through the 6-membered ring transition state, in which the

carbonyl oxygen is bound to the boron atom and the substituent of aldehyde locates in the equatorial position.

• Therefore, stereochemistry of the product reflects the geometry of the C–C double bond in the g-substituted allylborane, e.g. crotylborane.

• The product is obtained with anti-selectivity in the reaction of (E)-crotylborane. • The reaction of (Z)-crotylborane selectively provides syn-homoallyl alcohol.

R. W. Hoffmann, J. Org. Chem., 46, 1309 (1981).

Reaction of allylsilane (through acyclic TS, Hosomi–Sakurai reaction) • Commonly, the g-carbon of allylsilane attacks on the carbonyl carbon. • In this reaction, a Lewis acid interacts with the carbonyl oxygen to enhance the

electrophilicity of the aldehyde. The oxygen atom cannot be bound to the silicon atom. Therefore, the nucleophilic addition proceeds through the acyclic transition state.

• In the transition state, its stereochemistry is mainly controlled by the steric repulsion between the g-substituent of allylsilane and the substituent on the carbonyl carbon.

• The nucleophilic addition of g-substituted allylsilane preferentially yields syn-product regardless of the stereochemistry of its C–C double bond.

γ-attackR’ H

O

R M+

αγ R R’

OHα-attack

or

RR’

OH

OH

R’R

OH

R’R

E Z

syn anti

O

MH

R’R

‡

M

R

PhCHO

‒78℃R Ph

OH

PhR

OH

γ-adductα-adduct

LiMgClCaClBaClCeCl2

α/γ E/Z (α)

47/53<1/9912/8892/ 872/28

>99/1

98/298/2

>99/1

M

=

Me 1. Mg Me B(NMe2)2

E : Z = 93 : 7

PhCHO

anti : syn = 94 : 6

O

B(pin)Me

H

H

Ph

2. (Me2N)2BCl‡

OH

PhMe

pinacolMe B(pin)

MeMe

E : Z = 5 : >95

anti : syn = 4 : 96

1. BuLi, t-BuOK

2. (Me2N)2BCl Me

B(NMe2)2 pinacol

Me

B(pin)

PhCHOO

B(pin)H

Me

H

Ph

‡OH

PhMe

Cl

– 9 –

T. Hayashi, M. Kumada, Tetrahedron Lett., 24, 2865 (1983).

(b) a,b-Unsaturated carbonyl compounds General

• Two possible reaction pathways, 1,2- and 1,4-additions, must be considered for the

reaction of organometals with a,b-unsaturated carbonyl compounds. • In the 1,2-addition, the nucleophilic organometal attacks the carbonyl carbon to give the

corresponding allyl alcohol. • In the 1,4-addtion (conjugate addition), the nucleophile attacks the b-carbon atom to give

the enolate, which leads to the corresponding ketone or aldehyde. • The chemoselectivity is affected by electron density on each atom, orbital coefficient of

LUMO, and steric demand in the a,b-unsaturated carbonyl. Moreover, the polarizability (hard or soft) of the nucleophile also affects the reaction. Commonly, the 1,4-addtion is preferable to the 1,2-addition when the nucleophile has large polarizability.

Electron density and LUMO coefficient of acrolein

(i) a,b-Unsaturated aldehydes • Organometals mostly reacts with a,b-unsaturated aldehydes through 1,2-addtion. The

nucleophile easily accesses to the carbonyl carbon because of little steric hindrance around the reaction site.

• In some exceptional cases, organometals can react with the b-carbon to lead to selective formation of the 1,4-addition product.

(1,4-addition) J. F. Normant, Tetrahedron, 36, 2305 (1980).

E. J. Sorensen, Angew. Chem. Int. Ed., 38, 971 (1999).

(ii) a,b-Unsaturated ketones • In the case of organolithium, the 1,2-addition is commonly preferable to the 1,4-addition.

Size of the substituent on carbonyl carbon affects the chemoselectivity. • In the case of Grignard reagent, the chemoselectivity depends on the substrate

combination of organometals and enones. In general, the 1,2-addition is preferable to the 1,4-addtion, when the organometal can interact to the enone with small or no steric repulsion.

T. Imamoto, J. Am. Chem. Soc., 111, 4392 (1989).

SiMe3PhTiCl4

t-Bu

OH

Phsyn : anti = >99 : 1

Ph

SiMe3

+ t-BuCHO t-Bu

OH

PhCH2Cl2, 0°CE : Z = >99 : 1

+ t-BuCHOTiCl4CH2Cl2, 0°C t-Bu

OH

Pht-Bu

OH

PhE : Z = 6 : 94 syn : anti = 75 : 25

Ph

HO t-Bu

HSiMe3 Ph

HO H

t-BuSiMe3syn anti

H

PhO H

t-BuSiMe3 H

PhO t-Bu

HSiMe3syn anti

Ti

Ti Ti

Ti

R R’

O

R R R’

OR”

1,2-addition (path a)

OH

R’R”R” M+ or

1,4-addition (path b)

αβ

–0.327–0.427

–0.489+0.598

+0.365–0.533

–0.366+0.616

O blue: electron densityred: orbital coefficient of LUMO

Me H

O+

Me R

OH

Me H

OR

1,2-addition 1,4-addition

1,2- : 1,4-

BuLiMeMgBrBu2CuLi + TMSCl

>99 : 1>99 : 1 1 : >99

R M

R M

CHO

OO Cu(CN)Li

S+

CHO

OO

BF3•OEt2

Et2O

46%

Ph Ph

O

Ph

OH

Ph Ph

OPh

1,2-addition 1,4-additionPh

M

LiLi + CeCl3MgBrMgBr + CeCl3

85 : 1598 : 2<1 : 9991 : 9

Ph+ Ph M

1,2- : 1,4-

– 10 –

H. Yamamoto, J. Am. Chem. Soc., 116, 6130 (1994).

• Use of organocerium reagents, which are generated by mixing Grignard reagent (or R–Li) and CeCl3, facilitate the selective 1,2-addition.

• Organocuprates is suitable as the organometallic reagent for the conjugate addition to enones. Grignard reagent selectively attacks on the b-carbon of enone in the presence of catalytic amount of a copper(I) salt, CuBr•SMe2 and CuI etc.

B. H. Lipshutz, Tetrahedron Lett., 23, 3755 (1982).

P. Helquist, J. Org. Chem., 47, 5045 (1982).

(iii) Three-component coupling

• The conjugate addition of organometal to enone directly affords the enolate. The

resulting enolate can react with electrophiles, e.g. haloalkanes and aldehydes. • This type of reactions is called ‘three-component coupling’, because the target product

is obtained from three compounds, organometal, enone, and electrophile.

Y. Ito, M. Nakatsuka, T. Saegusa, J. Am. Chem. Soc., 104, 7609 (1982).

M. Shibasaki, Angew. Chem. Int. Ed., 35, 104 (1996).

(c) Carboxylic acid and its derivatives General

• Organometal attacks on the carbonyl carbon to give ketal analogue 2. The intermediate

2 usually decomposes into ketone 3 even under the anhydrous reaction condition. The ketone 3 easily undergoes the nucleophilic attack of the organometal, because ketone is more reactive than the carboxylic acid or its ester. The nucleophilic attack leads to the formation of the tert-alkoxide 4.

• Acyl halides and acid anhydrides are preferable for the selective formation of ketones 3, because they are more reactive to the organometallic reagent than ketone. To obtain 3 in high yield, the reaction condition should be carefully set to avoid the overreaction.

• Alternatively, the intermediate 2 should be designed to remain intact under the reaction condition until the following hydrolysis process.

+ MO

>99 : 1 38 : 62 95 : 5 72 : 28< 1 : 99

OH O

1,4-addition1,2-addition

M 1,2- : 1,4-

LiKMgClCaClBaCl

O

+ Cu(CN)Li22 2. NH4Cl aq.

1. Et2O, –50°CO

88%

O+ MgClO

O

CuBr•SMe2 (25%)

THF, Et2O, –78°C

O

O

O

75%

R R’

OR” M+

R R’

O–R” E (electrophile)R R’

OR”

E

O CH2=CHMgBrCuI (3.2%)

THF, Me2S–50°C

O–

Br CO2(t-Bu)

THF, HMPA–78°C to rt

OCO2(t-Bu)

O+ Me

CO2Me

CO2Me+ Ph CHO

OALB (10%)

CO2Me

CO2Me

Ph

64%, 91% ee

O

O OAl

O

OH

ALB

Me

Li

THF, rt

R X

O

R R’

O

2 3

H3O+

R R’R’

O–

4

R’ M O–

R R’X

R’ MR R’

R’

OH

X = OR” (ester), Cl (acyl halide), OH (carboxylic acid)

1

R X

O

X M product

OR

OH (OLi)Cl

LiMgXLiLiMgXCu (cuprate)

+ R’ MR

OH

R’R’ R R’

OH3O+or

◎◎×○○×

××○○○◎

– 11 –

(i) Carboxylates • Commonly, carboxylates react with two molar equivalents of organometal (R’–Li or R’–

MgX) to give the corresponding tert-alcohol. • In specific cases, the reaction can selectively provide the ketone product in high yield.

W. E. Bachmann, Org. Synth., 23, 98 (1943).

X. Creary, J. Org. Chem., 52, 5026 (1987).

(ii) Carboxylic acids • Carboxylic acid is immediately neutralized with organometal to form the metal

carboxylate salt, which is ordinarily too inactive to undergo the nucleophilic addition. • Organolithium can react with the metal carboxylate salt to give bisalkoxide 1. The

intermediate 1 remains intact in the absence of acidic proton because OLi cannot function as the leaving group well.

H. O. House, Org. Synth., 49, 81 (1969).

(iii) Acyl halides and acid anhydrides • Acyl halide also reacts with two molar equivalents of organometal (R’–Li or R’–MgX) to

give the corresponding tert-alcohol. • Ketones are obtained in high yields from the nucleophilic addition by carefully controlling

temperature and/or stoichiometry of organometallic reagent.

J. Barluenga, Synthesis, 819 (1987).

J. Ciabattoni, Org. Synth., 54, 97 (1974).

• Organocuprate also reacts with acyl halide to give the ketone product in high yield.

G. H. Posner, Org. Synth., 55, 122 (1976).

• Alkyl chloroformate is often used as the electrophilic substrate for the direct synthesis of carboxylates.

H. Fisher, Org. Synth., 17, 48 (1937).

(iv) Carboxamides • Organolithium or Grignard reagent can react with carboxamides to give the

corresponding ketones. However, carboxamide functionality is often insufficient in electrophilicity for the nucleophilic addition.

• The reaction of N,N-dimethylformamide or N-formylpiperidine with organometals is useful for preparing aldehydes.

G. A. Olah, Angew. Chem., Int. Ed. Engl., 20, 878 (1981); Org. Synth. 64, 114 (1986).

• To avoid the overreaction, N-methoxy-N-methylamide (Weinreb amide) is frequently used as the electrophilic substrate for the ketone synthesis.

• The methoxy oxygen interacts with the lithium or magnesium atom to form a chelate structure in the aminal-like intermediate. The chelation restricts the decomposition of the intermediate to the ketone in the reaction mixture.

• Weinreb amide is readily prepared by treating the corresponding carboxylate with aluminium amide, which was generated in situ from N-methoxy-N-methylammonium chloride and trimethylaluminum.

S. M. Weinreb, Tetrahedron Lett., 22, 3815 (1981).

(d) Nitriles

• Nitriles undergo the nucleophilic attack of Grignard reagent to give intermediate 1, which

is readily hydrolyzed with aqueous acid to give ketones. • The intermediate 1 is stable to the organometal at ambient temperature.

R. B. Moffett, Org. Synth., 21, 79 (1941).

Ph CO2Et + 2 Ph MgBr1. Et2O2. H3O+ Ph OH

PhPh

93%

F3C CO2Et + Ph MgBr1. Et2O2. H3O+ F3C Ph

O

86%

OH

OLiH

DMEreflux

OLi

OMe Li

OLi

Me OLiH3O+

O

Me

1 91%

Cl(CH2)4

O

ClEt MgBr+

THF–Et2O

–10 to 20°C Cl(CH2)4

OMgBr

EtEt

1. Li

2. D2O D(CH2)4

OH

EtEt

81%

t-BuO

Clt-Bu MgCl+ t-Bu

Ot-Bu

1. Et2O, 0°C

2. H3O+ 90%

t-BuLi + PhSCu PhS(t-Bu)CuLiPhCOCl

t-Bu Ph

O

87%–60°C

NH

EtMgBr

Et2O NMgBr

NH

MgBrClCO2Et

NH

CO2Et

58%

ClPhMg

THFMgClPh

N CHO

THF, 23°C Ph CHO

R N OMe

Me

O

M = MgX, Li

H3O+

R R’

O

R OR”

O

OMeHNMe • HCl

AlMe3 +toluene

OMeNMe

Me2Al

Me2Al N OMe

Me R’ M O

N OMeM+

RMe

R’

R R’

N

R R’

O+R C N R’ MgX

MgX

1

H3O+

MeO CN + PhMgBr1. Et2O, r.t.

2. H3O+ MeOO

Ph

– 12 –

(2) Nucleophilic substitution of haloalkanes (a) Wurtz reaction

• Alkyl and aryl halides is dimerized in the presence of sodium metal. • Sodium reduces the halide to give the carboradical. The radical randomly couples with

the halide or another radical species. • This reaction is not suitable for the cross-coupling reaction between two organohalides. • However, this method is applicable to the cross-coupling reaction between aryl and alkyl

halides (Wurtz–Fittig reaction).

R. R. Read, Org. Synth., 25, 11 (1945).

(b) Organocuprate (i) Lithium diorganocuprate (Gilman reagent)

H. Gilman, J. Org. Chem., 17, 1630 (1952); E. J. Corey, J. Am. Chem. Soc., 89, 3911 (1967).

(review) G. H. Posner, Org. React., 22, 253 (1975). • Diorganocuprate (Gilman reagent) is generated by mixing copper(I) iodide and 2 molar

equivalents of organolithium, magnesium, or zinc. The cuprate is soluble in ethereal solvent.

• Gilman reagent reacts with primary or secondary alkyl halides to form the new C–C bond. The C–C bond formation proceeds through the SN2-pathway or the oxidative addition followed by reductive elimination.

• The organocuprates are unstable for heat. Therefore, the nucleophilic substitution is usually carried out at low temperature (< 0°C).

• Gilman reagent has two same alkyl substituents on its copper, but only one of them can participate in the target reaction.

Reactivity (for substitution) • R on copper: alkyl (primary > secondary > tertiary) > alkenyl, aryl > alkynyl • R’ on electrophile: allyl, benzyl > alkyl (primary > secondary >> tertiary) > alkenyl, aryl • X on electrophile: tosylate, epoxide > iodide > bromide >> chloride > acetate • Functional group compatibility: ketones, carboxylates, nitriles

G. H. Posner, Org. React., 22, 253 (1975).

(ii) Higher order cyanocuprate (Lipshutz cuprate)

B. H. Lipshutz, J. Am. Chem. Soc., 103, 7672 (1981).

• Copper(I) cyanide is believed to react with the two molar equivalents of organolithium without elimination of cyanide from copper. The resulting diorganocyanocuprate is called ‘higher order cyano cuprate.’

• The higher order cyanocuprate is more reactive than Gilman reagent. • Lipshutz cuprate also has two same alkyl substituents, but only one of them participate

in the nucleophilic substitution.

H. O. Hause, J. Am. Chem. Soc., 91, 4871 (1969); B. H. Lipshutz, J. Org. Chem., 48, 3334 (1983).

(iii) Mixed ligand cyanocuprate

B. H. Lipshutz, J. Organomet. Chem., 285, 437 (1985); B. H. Lipshutz, Tetrahedron Lett., 28, 945 (1987).

• Lithium 2-thienyl(cyano)cuprate(I) (1), which is prepared from 2-thienyllithium and copper(I) cyanide, is storable over 2 months and commercially available.

• The cuprate 1 reacts with equimolar organolithium or magnesium to give the higher order mixed ligand cyanocuprate.

• Commonly, the 2-thienyl substituent is inert as compared to the latter-installed substituent R. Therefore, R selectively reacts with various electrophile. The thienyl group functions as the dummy ligand.

• Alkynyl and other 5-membered heteroaryl groups similarly work as the dummy ligands. • The cuprate 1 is very useful for organic synthesis, when the organolithium is prepared

through multistep synthesis.

B. H. Lipshutz, J. Organomet. Chem., 285, 437 (1985).

(vi) Substitution of allylic electrophiles with organocuprate • In the reaction of organocuprates with allylic electrophiles, the nucleophilic species

commonly attacks on the g-carbon. The reaction proceeds in the SN2’ manner. • Acetoxy, hydroxyl, and other groups is usable for the leaving group of the allylic substrate.

R–Br R–RNa

2

BrNa

Et2OBu 70%Br Bu+

R2CuLiR’ X

R Li2 + CuI R R’

I (CH2)10CO

NPh

MeMe Li2 + CuI Me2CuLi

Et2O

–20°CMe (CH2)10C

ON

Ph

Me–20°C65%

R2Cu(CN)Li2R Li2 + CuCN

BrBu2Cu(CN)Li2

Bu2CuLiTHF, 0°C to r.t.

THF, –50°C, 3 h

Bu

70%

95%

BuLi

S THF–20°C

S LiCuCN

THF–78 to –40°C

S Cu(CN)LiR Li R

Cu(CN)Li2

S12

S

Cu(CN)Li2

MeMe

BrCN Me

CN

Me+ THF

–78 to 0°C1 h 82%

– 13 –

Y. Yamamoto, J. Am. Chem. Soc., 108, 7420 (1986).

• Propargyl electrophiles also react with organocuprates in the SN2’ manner to give the allene products.

K. M. Brummnond, J. Org. Chem., 67, 5156 (2002).

(c) Grignard reagent and related organometals (i) Without catalyst

• Commonly, no SN2 substitution is observed in the mixture of Grignard reagents and haloalkanes without any transition-metal compound. However, alkynyl metals can work as the nucleophiles in the SN2 reaction of haloalkanes.

K. N. Cambell, Org. Synth., 30, 15 (1950).

• Some reactive haloalkanes (e.g. allyl halides) or alkyl sulfonates undergo the nucleophilic attack of the organomagnesium.

R. Lespieau, Org. Synth., 6, 20 (1926).

(ii) With copper catalyst • As with the 1,4-addition, the substitution of haloalkanes with Grignard reagents is

catalyzed by some copper salts, CuI, Li2CuCl4, and CuBr•SMe2 etc. In the copper catalysis, organocuprate species would be generated from the organomagnesium and copper(I).

B. Breit, Angew. Chem. Int. Ed., 44, 5267 (2005).

(3) Nucleophilic ring-opening reaction of epoxides

(a) Grignard reagent and organolithium

• Epoxides are sufficiently electrophilic to be attacked by the organolithiums and magnesiums, although these organometals cannot work as the nucleophiles to ordinary haloalkanes in general.

• This reaction with ethylene oxide is useful for the two-carbon homologation of primary alcohols.

E. E. Dreger, Org. Synth., 6, 54 (1926).

• However, the ring-opening reaction of substituted epoxides is often accompanied by the undesired side reactions, e.g. M–H exchange reaction, formation of halohydrins. The side reaction is often supressed by addition of Lewis acid, such as BF3•Et2O.

B. Ganem, J. Am. Chem. Soc., 106, 3693 (1984).

• Use of copper catalyst leads to the remarkable improvement of the ring-opening reaction of epoxides with Grignard reagents.

T. Oh, Org. Synth., 76, 101 (1999).

(b) Higher order cyanocuprate • Higher order cyanocuprates are preferred for the ring-opening reaction of substituted

epoxides to avoid the above side reactions. • For the reaction of epoxide, higher order cyanocuprate is preferable to lower one. • The organometallic species preferentially attacks on the less hindered carbon atom to give

the more congested alcohol as the major product.

B. Lipshutz, J. Am. Chem. Soc., 104, 2305 (1982).

J. R. Panek, J. Am. Chem. Soc., 122, 11090 (2000).

CO2MeOTBS

OTs

Me2Cu(CN)Li2•BF3

THF–Et2O, –78°CCO2Me

OTBS

Me 96%

n-C8H17

H OMs TMSMgCl

95% eeCuBr, LiBr, THF, –60°C

•

Hn-C8H17

H

TMS 90%, 95% ee

HC CHNa, NH3

HC CNaBu Br

77%

BrMg

BrBr +

1. Et2O, reflux

2. H3O+

Br

64%

OTf

MgBr

+Et2O

Li2CuCl4 (4%)

92%

O + HO RR MH3O+

M = Li, Na, Mg, Cu etc.

Bu BrMg

Et2OBu MgBr

O1.

2. H3O+OHBuBu OH

O Bu Li+

1. BF3•Et2O THF, –78 °C2. H3O+

OH

Bu

97%

O O 1. cat. CuI, THF; –30 to 0°C+ Ph MgBr

2. H3O+ Ph Ph

HO OH

88%

+Pr

OPr

OHPr

Pr Cu0°C, 6 h PrCu = Pr2Cu(CN)Li2

PrCu = PrCu(CN)Li86%15–30%

t-BuO2CO

Bu3Sn Cu(CN)Li2

S+

THF

–78°C t-BuO2C

OHSnBu3

76%

– 14 –

(4) Halogenations (a) Grignard reagent and organolithium

• The metal substituent in reactive organometallic species is replaced by halogen atom with

halogen cation or its equivalent. • Some excellent halogen sources are known for the iodination or bromination. • From the viewpoint of organic synthesis, this reaction is useful for the synthesis of organic

halides by a combination of M–H exchange reaction.

For iodination: I2, ICH2CH2I For bromination: Br2, BrCH2CH2Br, BrCCl2CCl2Br, BrCN For chlorination: NCS (N-chlorosuccinimide)

R. C. Ronald, J. Org. Chem., 47, 2541 (1982).

(b) Organoborane, organostannne etc. • These oraganometallic compounds can be transformed into the corresponding organic

bromides or iodides by treatment with Br2 or I2. • Stereochemistry of the transformation depends on the reaction conditions. • This transformation is useful for the stereoselective synthesis of haloalkenes in

combination with the hydrometalation of terminal alkynes. (i) Organoboranes

• Both geometric isomers of haloalkenes can be obtained from (E)-alkenylborons, which are obtained from the hydroboration of terminal alkynes, by choosing reaction conditions.

• Selective formation of (Z)-Iodoalkenes is accomplished by treating the alkenyl borane with iodine in the absence of the base. This transformation starts from the anti-addition of iodine across the C–C double bond. The iodo and boron substituents are eliminated from the intermediate to give the iodoalkene with Z configuration.

• (E)-Alkenylboronic acids are selectively transformed into (E)-iodoalkenes, when the organoboranes are reacted with iodine after treatment with a base (e.g. OH–). The base may activate the boron substituent through the formation of borate.

H. C. Brown, J. Org. Chem., 54, 6068 (1989); ibid., 54, 6075 (1989).

• This methodology, treatment with a base and then I2, is applicable to the conversion of alkylboranes to iodoalkane. The stereochemistry of this transformation is inversion.

H. C. Brown, J. Am. Chem. Soc., 98, 1290 (1976).

(ii) Organostannanes • The combination of hydrostannation and treatment with I2 is frequently used for the

transformation of terminal alkynes into trans-iodoalkenes.

M. E. Jung, Tetrahedron Lett., 23, 3851 (1982).

(iii) Miscellaneous • The silyl group in organosilicate (RSiF4–) can be replaced by halogen atom. This

transformation is effective for the preparation of optically active haloalkanes by combination with enantioselective hydrosilylation of alkenes.

K. Tamao, M. Kumada, J. Am. Chem. Soc., 102, 3267 (1980); T. Hayashi, Tetrahedron Lett., 33, 7185 (1992).

• Hydrozirconation and hydroalumination are often used for the transformation of alkynes to iodoalkenes.

K. C. Nicolaou, Angew. Chem. Int. Ed., 40, 3854 (2001).

R M + [X+] R X M = Li, MgX, ZnX etc.

OMe

OMe

O BuLipentane0°C

OMe

OMe

O

Li Et2O, 0°C

I ClOMe

OMe

O

I51%

Hex +1. 70°C

2. H2O, 25°C B(OH)2Hex

Et2O–THF, 0°CI2

HexI

73% (from 1)

1. NaOH aq., Et2O

2. I2, 0°C IHex

80%(from 2)

(cat)BH1 2

BH3•THF

THF, 25°CB

H3

I2, NaOMe

THF, 0°C I 78% (endo:exo = 80:20)

Pent

OH Bu3SnH, cat. AIBN

80°C Pent

OH

SnBu3

I2, CH2Cl2

25°C Pent

OH

I84%75%

+ HSiCl3

[PdCl(π-C3H5)]2 (0.005%)(R)-MOP (0.02%)

–20°C, 3 daysSiCl3 1. KF

2. NBS Br99%, 96% ee 81%

PPh2

OMe

(R)-MOP

O OMe

OTBS

MeO

ODMB

OPMB

OTBS

OO H

MeO

= R

1. Cp2ZrClH

2. I2

R

I90%

– 15 –

(5) Olefinations (a) Tebbe and Petasis reagents

• Tebbe reagent 1 reacts with various carbonyl functionalities, including carboxylates and carboxamides, to give the exo-methylene products in high yields. This reagent is very useful for the synthesis of enol ethers and enamines.

• The titanium reagent 1 is generated by mixing titanocene dichloride and 2 equivalents of trimethylaluminum.

• Titanium carbene species 2 is generated by treating 1 with pyridines. The intermediate 2 acts like a phosphorus ylide to react with a C–O double bond.

F. N. Tebbe, G. W. Parshall, J. Am. Chem. Soc., 100, 3611 (1978).

L. A. Paquette, J. Am. Chem. Soc., 119, 8438 (1997).

• Dimethyl titanocene, Petasis reagent, is also useful for the methylenylation of various carbonyl functionalities.

N. A. Petasis, J. Am. Chem. Soc., 112, 6392 (1990).

(b) Takai reaction

K. Takai, J. Am. Chem. Soc., 108, 7408 (1986); ibid., 109, 951 (1987).

• Aldehydes react with gem-dihaloalkanes and anhydrous chromium(II) chloride to form new C–C double bonds. The reaction selectively yields the alkenes with trans geometry.

• The gem-dihaloalkane was reduced with two CrCl2 to give gem-metal species 1. The nucleophilic addition of 1 to aldehyde gives b-oxychromium intermediate 2. The desired (E)-alkenes forms through the b-elimination of CrCl2 and OCrCl2 from 2.

• Formation of 2 proceeds with high stereoselectivity to avoid the steric repulsion between R and R’. The following b-elimination from 2 is anti-specific.

F. R. Kinder, S. Wattanasin, R. W. Versace, J. Org. Chem., 66, 2118 (2001).

• This method is very useful for the preparation of trans-haloalkenes. Iodoform or bromoform is frequently used as the substrate for Takai reaction.

S. V. Ley, Angew. Chem. Int. Ed., 41, 2786 (2002).

(c) Peterson olefination

D. J. Peterson, J. Org. Chem., 33, 780 (1968).

• a-Silyl organolithium or magnesium 1 is usable as an alternative of the corresponding Wittig ylide. Carbonyl compounds bearing an acidic a-proton can be transformed to the alkenes through Peterson reaction, which is the olefination of carbonyl with a-silyl organometallic compound.

• The nucleophilic addition of 1 to aldehyde affords the b-hydroxysilane 2. The following b-elimination of Si–OH from 2 leads to the formation of a C–C double bond.

• The b-elimination from 2 proceeds with syn-stereochemistry, when 2 is treated with a strong base. The resulting alkoxide attacks on the silicon atom to facilitate the elimination.

• Under acidic conditions, the b-elimination proceeds through E2-mechanism.

TiCH2

Cl AlMe

MeCp2TiCl2 + Me3Al

baseTi CH2

O

R R’ CH2

R R’Cp2Ti O–

1 2

OO

MeH H

Me

i-PrCp2Ti AlMe2

Cl+

pyridine

THF–toluene–55°C O

CH2

MeH H

Me

i-Pr98%

OO Ti

CH3

CH3+toluene65°C

OCH2

70%(3 equiv)

R

H

XX

2 CrCl2 R

H

CrCl2CrCl2

R’ H

OO

R’ HR

CrCl2

HCrCl2

Cl2Cr

OCrCl2HR

R’H

R R’

1 2

OO

CHO

OO

MeOO

O

OO

MeO+ I

I+ CrCl2 rt, 1.5 h

THF

29%

CHO

CHO

I

I+ CHI3 + CrCl2

THF

0°C to rt, 2 h 40%

R

HOCH2

RTMSCH2 MgClTMSCH2 ClMg R H

OTMS NaH

1 2

TMS

R’H

OH

RH

H3O+

KH

TMS

R’R

H

O+H2H

TMS

R’H

HR

O–

anti-elimination

syn-elimination

R’

H H

R

R’

H R

H

Me3Si O

R’H

HR

– 16 –

(6) Miscellaneous (a) Insertion of carbon monoxide

(i) Organolithium

D. Seyferth, J. Org. Chem., 48, 1144 (1983); Tetrahedron Lett., 24, 4907 (1983).

• Organolithium reacts with carbon monoxide to give the acyllithium species 1, which behaves as an acyl anion, which is potentially useful for organic synthesis.

• The nucleophilic addition of 1 to various carbonyl groups leads to the formation of a-hydroxyketones or 1,2-diketones.

• Cabanion 1 should be very unstable because of its self-condensation. Carbonyl group of one acyllithium 1 undergoes the nucleophilic attack of another 1. Therefore, the solution of 1 must be kept at very low temperature.

(ii) Organoboron

H. C. Brown, Acc. Chem. Res., 2, 65 (1969).

• Carbon monoxide, which is Lewis basic, is bound to Lewis acidic boron atom in R3B to form boron–carbon monoxide complex A. The alkyl groups R in A migrate to the carbon atom in CO stepwise.

• Only one R moves from boron to carbon when the trialkylborane reacts with CO in the presence of an appropriate hydride reducing agent, e.g. LiAlH(OMe)3. The reaction selectively provides a-hydroxyalkylborane E because the C–O double bond in B is rapidly reduced with the reducing agent. The intermediate E is converted to the primary alcohol through alkaline protonation. Meanwhile, the aldehyde is obtained from the treatment of E with H2O2 under an alkaline condition.

• Two R substituents migrate to the carbon atom in the presence of water to form boraepoxide C. The water molecule attacks on the boron in C, leading to the selective formation of intermediate F or its cyclic dimer. Aqueous alkaline solution transforms F

into the secondary alcohol, while the oxidative treatment gave the ketone. • At high temperature (e.g. 150°C) in ethylene glycol, all Rs migrate on the CO moiety to

give the tert-alkylborane D. The oxidation of D with H2O2 gave the tertiary alcohol product.

(b) Installing functional groups (i) Organolithium and magnesium

(ii) Organoboron

Bu Li + CO– 110°C Bu Li

O

R R’

O

R OR’

O

Bu

O

OH

RR’

Bu

O

O

R1

R BR

R

COR B

R

RC O+–

BR

RC RO

B C RR

O

R O B CR

RR

B C

B R

OHR

R

D

[H–]

OH–

[O]

OH–

[O]R CHO

R OH R R

OH

R R

O

CR

RR

[O]HO

E

H2O

Δ

B ROH

HO

R FR

A

SO

R R

PR3

SOCl2

HP(OR’)2

PCl3

CO2

O2

S

SO2Cl2

R MM = Li, MgX

R CO2H

R OH

R SH

R SO2Cl

OHP RR

O

R B

R OH

R D

R Br

R COHR

R

R NR1

R2

R NH2

H2O2, OH-

CH3CO2D

Br2

R’NH

R

Cl2CHOMe

Et3COLi

R1R2NCl

H2NOSO3H

R’ N3

– 17 –

2. Reactions of organic molecule with transition-metal complex (1) Oxidative addition

General J. A. Labinger, Organometallics, 34, 4784 (2015).

• Oxidative addition is the addition of a covalent bond A–B to a low-valent metal atom. • In the oxidative addition, two electrons are apparently transferred from the metal to the

covalent bond. As a result of the electron transfer, the cleavage of A–B gives two anionic ligands, A– and B–, which bond to the metal atom.

• The oxidation number of the metal increases by two through the oxidative addition. • In general, higher electron density on the metal atom accelerates the oxidative addition.

Electron-donating spectator ligands facilitates the oxidative addition. • Less steric hindrance and vacant coordination site around the metal is favorable for the

oxidative addition. • Three types of mechanism are conceivable for the oxidative addition.

(a) Three-centered mechanism

• Oxidative addition of non- or less-polar covalent bond, e.g. H–H, C–H, C–C, Si–H,

commonly proceeds through a concerted three-centered transition state. • LUMO on the metal atom interacts with the s-orbital of A–B. The interaction leads to the

bond cleavage between A and B. • HOMO on the metal atom interacts with the s*-orbital of A–B. The interaction results in

the formation of metal–ligand bonds, M–A and M–B. • The stereochemistry on A or B is retained during this process. • Ligands A and B on the metal locate in cis-position each other.

C. A. Tolman, J. Am. Chem. Soc., 96, 2762 (1974).

Oxidative addition of haloarenes

• C–X bonds in aryl and vinyl halides are polar. However, their oxidative additions proceed

through the three-centered pathway, because nucleophilic low-valent transition metal is hard to access behind the C–X bond.

• The oxidative addition of C–X bond may proceed through a pathway similar to aromatic nucleophilic substitution.

• Reactivity of the leaving groups: I > Br, OTf > Cl >> F • Vacant coordination site on the metal is required for the efficient oxidative addition.

J.-F. Fauvarque, J. Organomet. Chem., 208, 419 (1981); C. Amatore, Organometallics, 9, 2276 (1990).

(b) SN2-type mechanism

• Oxidative addition of polar covalent bond, e.g. C–X, C–O, H–X, commonly proceeds

through the backside attack of nucleophile. • As with SN2 reaction, the HOMO on the metal atom provides its electrons to the vacant s*-

orbital of C–X bond. • The stereogenic center of the chiral alkyl halide is inverted through this type of oxidative

addition.

J. K. Stille, J. Am. Chem. Soc., 98, 5832 (1976); ibid, 100, 838 (1978).

(c) SN2’-like mechanism for allylic substrate

• Allylic electrophiles, e.g. allyl chloride and acetate, also undergo the nucleophilic attack of

low-valent transition metal. • The oxidative addition of allylic electrophiles starts from the coordination of the C–C double

bond to the low-valent metal atom. The coordination induces the elimination of leaving group X to form allylmetal complex, in which the allyl ligand coordinates on the metal through its p-orbital.

• The stereochemistry of the oxidative addition is also inversion.

T. Hayashi, J. Am. Chem. Soc., 105, 7767 (1983); J. Org. Chem, 61, 5391 (1986).

Mn + AB

A, B = C, H, Cl, Br, I etc. (any elements)M = transition metal

AM(n+2)

B

M + AB

MB

AM A

B

‡ AM

BAB

MAB

Mdz2

dyz σ*σ

orbital interactions in TS

RhCl(PPh3)3 =L

RhL

L

ClL

RhL

L

H

H

ClL = PPh3

H2L2RhCl

[L2RhCl]2

L2RhClH2

X

X =I, Br, Cl, OTf

M +XM+

–XM+

–‡ X

M

Pd(PPh3)4 Pd(PPh3)3 Pd(PPh3)2Ph I Ph

(Ph3P)2PdI

Xa

bcM + M C X

a

c b

δ+ δ–‡

M+a

bc X– M

a

bc

X

ClPh

HDPd(PEt3)3 + Pd

Ph

HD

Et3PCl

Et3P

PdEt3P

ClEt3P

O

D PhH

CO 1. Cl2, –78°C

2. MeOH MeOPh

D H

O

63% ee88% ee

X

b aM +

b aX

M M+

π-allyl metal complexb

aX–

Me Ph

OAc

1. PdCl2(dppe), PPh3, i-Bu2AlH

2. NaBF4

PhMe

Pd

Ph2P

PPh258% ee

DPPE =PPh2

PPh2

47% ee

– 18 –

(d) One-electron transfer mechanism

• Some oxidative additions involve radical species, which is generated from one-electron

transfer from metal to organic halide. • This radical pathway is the most plausible for the oxidative addition of alkyl halides. • With the coordinatively unsaturated metal complex, the reaction commonly proceeds

through inner-sphere mechanism, which starts from coordination of the substrate to the metal. The electron transfer directly induces the homolytic C–X bond cleavage to yield carboradical species.

• The oxidative addition proceeds through the outer-sphere mechanism, when the metal species is an 18-electon complex.

• The radical pathway mostly accompanies with racemization, when the leaving group bonds to stereogenic center in the substrate.

• The pathway is most common with transition metal complex of the first row.

J. K. Kochi, J. Am. Chem. Soc., 101, 6319 (1979).

• Mechanism of oxidative addition is affected by the substrate, spectator ligand on metal, and other reaction parameters. For example, Ni(PPh3)4 would react with iodoarenes through the three-centered mechanism, although radical species is involved with the oxidative addition of Ar–I to Ni(PEt3)4.

(2) Reductive elimination General

• Reductive elimination is the reverse of oxidative addition through the three-centered

mechanism. • The anionic ligands A and B are eliminated from the metal to form the covalent bond

between A and B. • In this process, two electrons are apparently transferred from the ligands to the metal atom.

As a result of the electron transfer, the cleavage of A–B gives two radical species, A• and B•, which coupled with each other.

• The oxidation number of the metal decreases by two through the reductive elimination. • The reductive elimination requires cis-geometry of the eliminating ligands, A and B, on the

metal atom. • In general, lower electron density and larger steric hindrance of the spectator ligand

accelerates the reductive elimination. Electron-withdrawing ligands are preferable for the reductive elimination to electron-donating ones.

• Reactivity of the eliminating ligand: alkyl [C(sp3)] < aryl, alkenyl [C(sp2)] < H

• The reductive elimination is often promoted in the presence of additional neutral donor ligand,

such as PR3, alkene. The donor ligand stabilizes the coordinatively unsaturated metal product and makes the reaction thermodynamically favorable. Alternatively, the coordination of the additional ligands may accelerate the reductive elimination.

A. Yamamoto, Bull. Chem. Soc. Jpn., 54, 1868 (1981).

• For the reductive elimination from symmetrical di(p-substituted aryl)platinum complex, the electron-donating substituents are preferable to the electron-withdrawing one. However, unsymmetrical complex bearing electron-rich and deficient aryl groups is more reactive than the symmetrical ones.

J. F. Hartwig, J. Am. Chem. Soc., 126, 13016 (2004).

(3) Migratory insertion General

R X MXRMn+ +R• X M•(n+1)R

M(n+2)X

Mn

R M•(n+1)

Inner-sphere mechanism

Outer-sphere mechanism

R X M+ R X–• R•X–

M+

R M+R

MX

(Et3P)4Ni = L4Ni0– L

L3Ni0Ar X

L3NiI Ar X–•– L Ar

NiIIL2X(L = PEt3)

M(n–2) + AB

A, B = C, H, O, N etc. (any elements)M = transition metal

AMn

B

CM

CH

σ*M

HσH

MH

π

π*

MePh2PPd

MePh2P

Me

Me+

CO2Me

CO2Me toluene, 60°CMe Me

MePh2PPd

MePh2P

CO2Me

CO2Me+

(dppf)Pt

X

Y

10 PPh3

toluene-d8, 95°CX Y

kobs

kobs: X = NMe2, Y = CF3 > X = Y = NMe2 > X = Y = CF3

DPPF = FePPh2

PPh2

X CR’2

C Y

Mn R MnX

R = alkyl, aryl, acyl, H etc.X = CR”2 (alkene), NR” (imine), O (ketone), & alkyneY = O (carbon monoxide), NR” (isocyanide)

Mn RX CR’2

Mn RCY

C RR’2

Mn

C RY

– 19 –

• Various unsaturated compounds apparently insert into the transition-metal–carbon bond. • R group on the metal migrates to the unsaturated substrates to form a new organometallic

species, in which the original position of R is a vacant coordination site. • The oxidation number of the metal remains unchanged during the process. • Multiple unsaturated substrates can be successively inserted into the M–R bond. This

multiple insertion leads to polymerization. • The insertion process is commonly reversible (see, (4) b-Elimination).

(a) 1,2-Insertions of alkene, alkyne, and others • The migratory insertions of alkene, ketone, imine, alkyne, and other multiple bonds are

equivalent to the 1,2-addition of M–R to the X–C multiple bond. • Commonly, the 1,2-insertion proceeds with syn-stereochemistry. • The regioselectivity of the 1,2-insertion is controlled by reaction conditions as well as the

structure of ligand. • It is not easy to study the 1,2-insertion of alkenes, because the resulting alkyl–metal

species rapidly decomposes into the corresponding alkene and hydridometal through b-hydride elimination.

M. Brookhart, Organometallics, 17, 1530 (1998).

(b) 1,1-Insertions of carbon monoxide and isocyanides • The M–R bond is added to the carbon atom in carbon monoxide (or isocyanide) to give

acylmetal species. The terminal carbon of CO (or CNR) behaves as a carbene in the 1,1-insertion.

• Commonly, the stereochemistry of R is retained during the 1,1-insertion. • Isocyanides successively inserts into the M–R bond to form poly(imine). Meanwhile, the

double insertion of carbon monoxide is not easy.

(4) Elimination (a) b-Elimination

• When an organometal has a good leaving group Y on its b-carbon, the metal substituent

M and Y are readily eliminated to form M–Y bond and alkenes. The b-elimination is observed in metal alkoxides and amides as well as organometals.

• This b-elimination is the reverse of migratory insertion of alkenes, ketones, and imines. • The hydrogen atom also works as the good leaving group in the b-elimination. The b-

elimination of M–H from organometal is ‘b-hydride elimination.’ • The oxidation number of the metal remains unchanged during the process. • The stereochemistry of the b-elimination is commonly syn.

R. Heck, J. Am. Chem. Soc., 91, 6707 (1969).

(b) Decarbonylation

• Carbon monoxide is also eliminated from acylmetal complex. The decarbonylation is the

reverse of migratory insertion of carbon monoxide.

(5) Transmetalation General

• Transition metal complex bearing X ligand (halogen, alkoxide etc.) reacts with various

reactive organometals, M’–R. Through the reaction, the X ligand is replaced by R. • The substituent R on the metal having lower electronegativity transfers to the metal with

higher electronegativity as with the main group organometallic chemistry. • The oxidation number of the metal remains unchanged during the process.

(6) Nucleophilic attack on the p-ligand on metal General • Various nucleophiles can attack on the unsaturated bond interacting with a transition-metal

through p-coordination. • The Lewis acidic metal atom withdraws the p-electron to enhance the electrophilicity of the p-ligand.

• The nucleophile commonly accesses the p-face that is opposite from the metal. As the result of the reaction pathway, the metal and nucleophile adds across the p-bond with anti-stereochemistry.

N

NAr

Me

MeAr

PdNCMe

Me+

+

Bu= Pd–MeBu

Pd Me Pd Me

Bu

A B

Ar = p-TolAr = 2,6-Me2C6H3Ar = 2,6-(i-Pr)2C6H3

A : B = 71 : 29A : B = 51 : 49A : B = 30 : 70

X CYMn

RR

X CR

R+ X = CR’2, NR’, O, etc.

Y = H, halogen, OR”, (CR”3), etc.Mn Y

PhHgOAc+

Pd(OAc)2Ph Pd(OAc)

Ph PhPh Pd(OAc)

HMe

PhH

Me Ph

H Pd(OAc)

MePh

PhHMe Ph Me

99.5%

Me PhPh Pd(OAc)

MeH

PhH

H Pd(OAc)

PhMe

PhH

Ph

90%

Mn R

OMn R C O+

Mn X M’ R+ Mn R M’ X+M = transition metalM’ = Li, B, Al, Si, Mg, Zn, Sn, etc.X = Cl, Br, I, OR etc.

– 20 –

(a) Nucleophilic attack on neutral p-ligand

• Many transition metal atoms strongly interacts with alkene or alkyne through the donation

and back donation of electrons.

• The electron donation from the ligand to metal occurs through the interaction between the

ligand p-orbital and the metal LUMO (d-p interaction). The interaction enhances the electrophilicity of the ligand.

• Meanwhile, the metal provides its electrons to the ligand through the interaction between the metal HOMO and the ligand p*-orbital (back donation).

• Cationic metal giving weak back donation is preferable for the activation of alkenes and alkynes.

• The oxidation number of the metal remains unchanged during the process. • In this pathway, the nucleophiles attack the p-bond from the opposite side from the metal

to give the anti-addition product.

J. Tsuji, J. Am. Chem. Soc., 90, 2387 (1968); G. K. Anderson, Organometallics, 17, 1155 (1998).

• Sometimes, selective formation of the syn-adduct may be observed in the reaction of alkene–metal complex with nucleophile. The syn-product will be generated through the nucleophilic attack on the metal followed by the migrate insertion of the alkene into the C–Nu bond.

(b) Nucleophilic attack on anionic p-ligand (p-allyl, cyclopentadienyl)

• In transition-metal–allyl species, its C–C double bond interacts to the metal atom as well

as its allylic sp3 carbon. As a result of the unique interaction, two allylic termini are equivalent to each other. The metal atom bonds to the delocalized allyl anion through its p-orbital to form h3-allylmetal (p-allylmetal) complex.

• The p-allyl ligand is usually electrophilic rather than nucleophilic although it is anionic. The p-allylmetal species readily reacts with various soft nucleophlies, such as stabilized carbanions, amines, and phenoxides, to give the corresponding products.

• The oxidation number of the metal decreases by two through the process. • In most cases, the nucleophilic attack is accompanied with the inversion of the stereogenic

center on the allylic ligands.

T. Hayashi, J. Am. Chem. Soc., 105, 7767 (1983); Chem. Commun., 107 (1984).

(7) Oxidative cyclization General

• A low-valent transition-metal complex provides two electrons to multiple bond(s) to form 3-,

5-, or 7-membered ring containing the metal atom (metallacycle). This cyclization is called ‘oxidative cyclization’.

• The electron transfer leads to the formation of two M–C bonds with each terminus of the unsaturated bond(s).

• The oxidation number of the metal increases by two through the oxidative cyclization. • Two or more multiple bonds can participate in the oxidative cyclization. In this case, the

remaining termini forms a new C–C bond to form a 5-membered or larger metallacycle. • Various unsaturated bonds, such as alkene, alkyne, diene, ketone, and nitriles, undergo the

oxidative cyclization.

(8) Concerted metalation–deprotonation mechanism General D. Lapointe, Chem. Lett., 39, 4784 (2010).

• The C–H bond in organic molecules is often cleaved with an electron-deficient transition-

metal through a simultaneous metalation and deprotonation. The mechanism of C–H bond cleavage is named ‘CMD (concerted metalation–deprotonation) mechanism.’

• In this process, a base removes the H atom as proton from the substrate and the remaining carbon atom bearing lone pair concurrently reacts with the electron-deficient metal atom to form the M–C bond.

• When the anionic ligand on metal has a Lewis basic site such as acetate, the ligand works as the base for the intramolecular deprotonation.

• Commonly, the oxidation number of the metal remains unchanged during the process. • The CMD process may be a variant of transmetalation if the H atom (H+?) is regarded as an

equivalent of metal cation.

Mn Nu+ Mn Nu Nu = nucleophile

CCM

(LUMO)x2–y2d π

(HOMO)

CCM

(HOMO)xyd π*

(LUMO)

donation back-donation

PdCl

Cl+

CO2Et

CO2Et EtOH–DMSO–

Pd Cl

EtO2C CO2Et

+ Nu Nu + Mn–2Mn Nu = nucleophile

MePh

Pd Cl

82% ee2

+ NaCH(CO2Me)22 PPh3

benzene, r.t.

Me Ph

CO2MeMeO2C

Me Ph

CO2MeMeO2C79% ee

Mn+2Mn Mn+2 Mn

MnB

H+ Mn

BHB = anionic ligand bearing Lewis basic site

– 21 –

(9) Metathesis General

• Metathesis means the redistribution of fragments resulting from bond cleavage. • In the case of olefin metathesis, the metal–carbon double bond in metal–carbene complex

undergoes the concerted [2+2] cycloaddition with an olefinic substrate to form the metallacyclobutane. The 4-membered ring decomposes into other alkene and metal–carbene complex through the retro [2+2] cycloaddition.

• The metathesis is commonly reversible. • Alkynes and carbonyl groups also undergo metathesis with metal–carbene complex.

• Metathesis is often observed in the reaction between M–E s-bond and the E–E s-bond, in

which E represents main group element. The reaction is called ‘s-bond metathesis’.

CM

CC

C CCM C C M C+ +

C M + M C M + O C C M O+

EM

E’E”

+EM E”

E’ ‡M E” + E E’ E = H, B, Si etc.

– 22 –

3. Reactions catalyzed by transition-metal complexes 3-1. Hydrogenation (1) Hydrogenation of alkenes

G. Wilkinson, Chem. Commun., 131 (1965); Nature, 208, 1203 (1965).

• As with metal-particle catalysts such as palladium on charcoal, Wilkinson complex, RhCl(PPh3)3, catalyzes the hydrogenation of alkenes.

• Some other metal complexes also work as catalysts for the hydrogenation. • The homogeneous metal-complex catalysts are as useful for organic synthesis as the

heterogeneous metal-particle catalysts, because the former exhibits setreo- and/or site-selectivity different from the latter.

(a) Reactivity of C–C double bond • Reaction rate of the rhodium-catalyzed hydrogenation is sensitive to the steric effect of the

substituents on the C–C double bond. • The reactivity depends on the binding constant of olefin to the metal atom.

• An electron-withdrawing group enhances the reactivity. • Lewis basic functional group neighboring on the alkene often works as the directing group

to facilitate the hydrogenation.

D. A. Evans, J. Am. Chem. Soc., 106, 3866 (1984).

A. G. Schultz, J. Org. Chem., 50, 5905 (1985).

W. R. Roush, Org. Lett., 7, 1411 (2005).

(b) Mechanism of the hydrogenation with Wilkinson catalyst

• A typical catalytic cycle of the hydrogenation of alkenes with Wilkinson complex is as

follows: i) Dissociation of L: One of phosphine ligands on Rh is replaced by a solvent molecule. ii) Oxidative addition of H2: The rhodium(I) species is inserted into the H–H bond. iii) Coordination of alkene: The solvent on rhodium is replaced by the alkene substrate. iv) Migratory insertion of alkene: One of the Rh–H bond adds to the C–C double bond. v) Reductive elimination: The resulting alkyl group and hydride are eliminated from the

Rh to form the C–H bond. • The mechanism is affected by the substrate, catalyst, and reaction conditions. For

example, the C–C double bond will interact with the rhodium(I) prior to the oxidative addition of H2 when the substrate has an appropriate directing group. In some cases, monohydridometal species participates in the catalytic cycle.

BuBu

HH

H2cat. RhCl(PPh3)3+

R >R

R> R

R> R

R RR

R> R

R

R

R>

for RhCl(PPh3)3

cat. [Rh(nbd)(dppb)]BF4

70 : 1

Me

i-PrOH

Me

i-PrOHH

+ H2

Me

i-PrOHH

THF95%

Me

N

Ocat.

H2 MeN

O

HMe

N

O

H IrN

PCy3cat. = [Ir(cod)(py)(PCy3)]PF6cat. = 5% Pd/C

130 : 11.6 : 1 [Ir(cod)(py)(PCy3)]+

TBSOTBSO TBSO TBSO

OH cat. Ru(OAc)2(binap)

H2

88%

Me

OTBS

OO

BnO

O

TBSOTBSO TBSO TBSO

OH

Me

OTBS

OO

BnO

O

amphidinol 3 ?

LRh

ClLL

LRh

ClSL

LRh

ClHL

H

S

LRh

ClHL

H

R

LRh

Cl L

H

S

R

H

S L

LS

H2 RS

SH R

H

i)ii) iii)

iv)v)

L = PPh3S = solvent (e.g. MeOH, THF)

RhCl(PPh3)3 =

– 23 –

(c) Enantioselective hydrogenation of alkenes with asymmetric catalysis

• The hydrogenation of prochiral alkenes must yield the racemic products when an achiral

or racemic metal complex is employed as the catalyst, because the frontside attack of H2 equally takes place to the backside attack.

• The frontside (or backside) attack may be restricted when the metal complex has a well-designed phosphine ligand in place of PPh3.

(i) Initial attempts

W. S. Knowles, Chem. Commun., 1445 (1968); L. Horner, Angew. Chem. Int. Ed., 7, 942 (1968).

• To achieve the asymmetric catalysis, the PPh3 ligands in Wilkinson complex were replaced by the optically active phosphine bearing three different substituents.

• The chiral ligand possesses its stereogenic center on its phosphorus atom. • These reports proved the chiral spectator ligand possible to control the stereochemistry

in catalytic reactions. However, the enantioselectivities are very low and insufficient for organic synthesis.

(ii) Progress of asymmetric hydrogenation of 2-(N-acylamino)cinnamates

• The asymmetric hydrogenation transforms the substrate, 2-(N-acylamono)cinnamate or

related compound, into the optically active protected phenylalanine. • The C–C double bond and amide carbonyl oxygen in the substrate chelate the rhodium

atom. The chelation restricts the conformation of the substrate–catalyst complex. i) Optimization of P-chiral monophosphine (–1972)

W. S. Knowles, J. Chem. Soc., Chem. Commun., 10 (1972).

ii) Application and improvement of bidentate bisphosphine (1971–1980)

Review: W. S. Knowles, Acc. Chem. Res., 16, 106 (1983). 1) H. Kagan, J. Chem. Soc., Chem. Commun., 481 (1971); J. Am. Chem. Soc., 94, 6429 (1972). 2) W. S. Knowles, J. Am. Chem. Soc., 97, 2567 (1975); J. Am. Chem. Soc., 99, 5946 (1977). 3) B. Bosnich, J. Am. Chem. Soc., 99, 6262 (1977). 4) R. Noyori, J. Am. Chem. Soc., 102, 2567 (1980).

• The bidentate ligands form the chelate complex with various metal atom. The chelation restricts the position and arrangement of the P-substituents, which create rigid steric hindrance (chiral reaction field) around the rhodium atom.

D. Heller, Tetrahedron: Asymmetry, 15, 2139 (2004); R. Noyori, J. Am. Chem. Soc., 102, 2567 (1980).

iii) Further improvement of chiral bisphosphine ligand

1) U. Nagel, Chem. Ber., 119, 3326 (1986). 2) M. J. Burk, J. Am. Chem. Soc., 113, 8518 (1991); 115, 10125 (1993). 3) T. Imamoto, J. Am. Chem. Soc., 120, 1635 (1998).

• Commonly, 5-membered chelation is favorable to the asymmetric hydrogenation of a-(N-acylamino)acrylates.

• Alkyl substituent, which is electron-donating, is preferable for enhancing the catalytic activity to aryl one, because the rate-determining oxidative addition is accelerated by the resulting electron-rich phosphorus. However, the alkyl group is disadvantageous to create the rigid chiral reaction field, because it is flexible.

• Nowadays, a broad range of chiral ligand, including monophosphine, amino-phosphine, phosphoramidite ones.

R1 R2

cat. RhCl(PPh3)3

H2R1 R2 R1 R2

HH

HH

50%

cat. [Rh] – L*

H2 R1 R2 R1 R2

HH

HH

50% 100%? 0%?L* = optically active phosphine

CO2HPh Ph CO2H

MeHP

PhMe

i-PrH2+

15 ± 4% ee

cat. RhCl(L1)3L1 =

EtPh Ph Et

MeHP

Ph

Pr7–8% ee MeH2+cat. [RhCl(cod)]2 – L2

L2 =

NHAc

CO2R cat. [Rh] & L* CO2R

H NHAc+ H2 L*: chiral phosphine ligand

PPh

PrMe

(90% ee)

28% ee

PPr

Me

(95% ee)55% ee

OMe PPh

Me

(95% ee)58% ee

OMe PCy

Me

(95% ee)90% ee

OMe

Me PPh2

PPh2Me

O

O

MeMe

PPh2PPh2

P

P

o-AnisPh

o-Anis Ph

PPh2

PPh2

DIOP71% ee1)

DIPAMP95% ee2)

Chiraphos99% ee3)

BINAP>99% ee4)

(a) (b)

Crystal structure of {Rh(cod)[(R,R)-dipamp]}BF4 (All H atoms, COD, and BF4 are omitted for simplification). (a) Front view. (b) Side view.

Crystal structure of {Rh(nbd)[(R)-binap]}ClO4 (All H atoms, NBD, and ClO4 are omitted for simplification). (a) Front view. (b) Side view.

(a) (b)

NPPh2

PPh2O

Ph

Deguphos99% ee1)

P P

R

RR

R

Duphos99% ee2)

P

P

Met-Bu

Me t-BuBisP*

99% ee3)

– 24 –

(iii) Reaction mechanism of the asymmetric hydrogenation with Rh–DIPAMP catalyst

J. Halpern, J. Am, Chem. Soc., 109, 1746 (1987).

• The hydrogenation of 1 with (R,R)-DIPAMP–rhodium catalyst yields (S)-2 as the major enantiomeric product.

• The hydrogenation starts from the coordination of substrate 1 on the solvated rhodium(I) cation A. Then, the 1–rhodium(I) B undergoes the oxidative addition of H2 to give dihydridorhodium(III) C. The C–C double bond on rhodium inserts into one of the Rh–H bonds. The remaining hydride and alkyl ligand are eliminated from intermediate D to form another C–H bond.

• The diastereoisomeric intermediates BR and BS are in equilibrium. The alkene–rhodium(I) BS is less thermodynamically stable than BR, which leads to the formation of the minor enantiomer (R)-2.

J. Halpern, C. R. Landis, Organometallics., 9, 1392 (1990).

• However, BR is too inert to undergo the oxidative addition of H2. Therefore, molecular hydrogen preferentially reacts with BS, leading to the selective formation of (S)-2.

• When BS is consumed, the remaining BR isomerizes to the more reactive BS to keep the equilibrium between BR and BS.

• Caution! Don’t generalize the above mechanism for asymmetric hydrogenation. Profile of the asymmetric hydrogenation strongly depends on chiral ligand and reaction conditions.

T. Imamoto, J. Am. Chem. Soc., 122, 7183 (2000); 130, 2560 (2008); ACS Catal., 5 2911 (2015).

(iv) Asymmetric hydrogenation of other alkenes • Nowadays, a broad range of prochiral alkenes can be hydrogenated with high

enantioselectivities through asymmetric catalysis. The highly enantioselective catalysts have been applied to the synthesis of various useful compounds.

R. Imwinkelried, Chimia, 51, 300 (1997); EP 602653 (1994).

R. Noyori, H. Takaya, J. Am. Chem. Soc., 108, 7117 (1986); J. Org. Chem., 59, 297 (1994).

A. Pfaltz, Science, 311, 642 (2006).

Ph

MeO2C NH

P Rh OP

Me Ph

CO2MeHN

PRhOP

Me

Ph

MeO2C NH

H Rh OP

MeP

H

Ph

CO2MeHN

HRhOP

Me P

H

P Rh OP

MeO2C HNH

SMe

PhPRhO

P

CO2MeHN H

SMe

Ph

PRh

P

S

S

H2 H2

Ph

AcHN CO2Me

CR CS

DS

BR

MeO2C NHAc

H Ph

CO2MeAcHN

HPh

1

(R)-2 (S)-2

k–1R

k1R

k2R

k3R k4

R

k–1S

k1S

k2S

k3Sk4

S

P

P= (R,R)-DIPAMP

oxidativeaddition

migratoryinsertionreductive

elimination

A

DR

BS

cycle A cycle B

resting state

Crystal structure of {Rh(substrate)[(R,R)-dipamp]}BF4 BR (All H atoms and BF4 are omitted for simplification). (a) View adjusted to BR in the above scheme. (b) Front view.

(a) (b)

CR

BR BS

CS

E

Energy diagram for the oxidative addtions of diastereoisomeric intermmediates BR and BS.

N NH

O O

O

Ph

MeN NH

O O

O

Ph

Me

H H+ H2cat. [Rh] – L*

99% de

FeL* =

Josiphos

PPh2

P(t-Bu)2

Me

CHON

MeO

MeOOMe

OMe

N

MeO

MeOOMe

OMe

cat. Ru(OAc)2[(R)-binap]

100%, >99.5% ee

CHOH2MeOH–CH2Cl2

various isoquinoline alkaloids (morphine etc.)

O

AcO

O

AcO

cat. [Ir(cod)L*]BArF

RRR : RRS : RSR : RSS = >98 : < 0.5 : < 0.5 : < 0.5

L* =

CH2Cl2+ 3 H2

NOP(o-Tol)2

Ph

(R)

(R)

– 25 –

(2) Catalytic asymmetric hydrogenation of ketones • Ketone carbonyl groups can be reduced with molecular hydrogen by transition-metal

complex catalysts, such as RhCl(PPh3)3 and RuCl2(PPh3)3. • The reaction pathway depends on the catalyst or conditions. In most cases, the

monohydridometal species seems to participate in the catalytic cycle.

(a) Asymmetric hydrogenation of functionalized ketones (i) General

R. Noyori, H. Takaya, S. Akutagawa, J. Am, Chem. Soc., 109, 5856 (1987); 110, 629 (1988).

• Various ketones bearing a Lewis basic functional group at a-, b-, or g-position are converted the corresponding chiral secondary alcohols with high enantiomeric excesses through the chiral BINAP–ruthenium catalysis.

(ii) Mechanism • The following catalytic cycle was proposed for the ruthenium-catalyzed asymmetric

hydrogenation of functionalized ketones.

R. Noyori, Angew. Chem. Int. Ed., 40, 40 (2001); Proc. Nat. Acad. Sci., 101, 5356 (2004).

i) Generation of monohydridoruthenium(II) species A from the catalyst precursor ii) Coordination of the substrate: The ketone carbonyl coordinates to the ruthenium

through its p-bond in h2 manner because of the following migratory insertion.

iii) Migratory insertion of ketone: The stereoselectivity is determined in this process. iv) Methanolysis of the ruthenium alkoxide C: The product is eliminated from Ru. v) Regeneration of A: The ruthenium methoxide D induces the heterolysis of

molecular hydrogen. • In the intermediate B, the ester carbonyl oxygen, which is Lewis basic, coordinates to the

ruthenium and works as the directing group. The coordination results in restricting the conformation of the substrate in the TS of the following migratory insertion.

• In the model (b) leading to the minor enantiomer, the methyl group on the carbonyl carbon

undergoes the steric repulsion from one of P-phenyl groups of BINAP. Therefore, the model (a) is preferable to the model (b).

(iii) Dynamic kinetic resolution in asymmetric hydrogenation

R. Noyori, S. Akutagawa, J. Am. Chem. Soc., 111, 9134 (1989); 115, 144 (1993).

• Racemic a-substituted b-keto esters are converted to a-substituted b-hydroxy ester in high diastereoselectivities as well as high enantioselectivities.

• Commonly, the b-keto ester is possible to racemize through their enol during the hydrogenation.

• The hydrogenation of 1 proceeds in similar manner to that of b-keto esters to give the

product bearing S configuration at its a-carbon (kS >> kR). • The major stereoisomer (2S,3R)-2 will be selectively obtained from the asymmetric

hydrogenation of racemic 1, when its racemization is much faster than the hydrogenation of (R)-1 with the chiral catalyst (k >> kR).

R

O cat. RuX2[(R)-BINAP]+ H2 MeOH

LB

R

HO LBHLB = Lewis basic functional groupX = Cl, Br, or OAc

high ee

Me

OHCO2Me

>99% ee (R)

CO2EtOH

85% ee (S)

Me NMe2

OH

96% ee (R)Me OH

OH

92% ee (R)PPh2

PPh2

(R)-BINAP

Me

OH

98% ee (R)OH

OH

Me

Br

85% ee (R)

OH

Me100% ee (R,R)dl:meso = 99:1

Me

OHOH

CO2MeBnO99% ee (R)

(binap)RuCl2S2

(binap)RuCl

H

O

H2

– HCl

O

Me

OMe

(binap)RuClS2

H(binap)Ru

Cl OO

OMe

MeHMeO H

(binap)RuS2

Cl

MeO

Me CO2MeO

2 MeOH

S = MeOH (solvent)

MeOH

Me CO2MeOH

2 MeOH

H2

MeOH

H

i) ii) iii)

vi)v)

A

B

C

D

Ru LB

(b)(a)

O

MeRu LB

O

Me

3D models of the interaction between (S)-BINAP–Ru and the substrate. (a) The model leading to (S)-alcohol (major product). (b) The model leading to (R)-alcohol (minor product).

R

OH LB

S

R

OH LB

R

Me CO2MeO

CH2Cl2

cat. RuBr2[(R)-binap]Me CO2Me

OH

NHAc NHAcsyn/anti = 99/198% ee (2S,3R)

+ H2

Me CO2MeO

NHAc

Me CO2MeOH

NHAc

Me CO2MeOH

NHAc

Me CO2MeO

NHAc (S)-1

(R)-1

cat. RuBr2[(R)-binap]

H2

cat. RuBr2[(R)-binap]

H2Me CO2Me

OH

NHAc

Me CO2MeOH

NHAc

kkS

kR

(2S,3R)-2 (2S,3S)-2

(2R,3R)-2 (2R,3S)-2

– 26 –

(iv) Applications • The highly enantioselective hydrogenation of functionalized ketones has been applied to

the synthesis of various useful biologically active compounds, including medicines.

X. Zhang, Angew. Chem. Int. Ed., 44, 1687 (2005).

T. Saito, Adv. Synth. Catal., 343, 264 (2001).

T. Saito, Adv. Synth. Catal., 343, 264 (2001).

(b) Asymmetric hydrogenation of simple ketones (i) General

R. Noyori, J. Am. Chem. Soc., 117, 2675 (1995); 120, 13529 (1998);.124, 6508 (2002).

• Simple ketones, which has no directing group, had been formidable substrates for the catalytic asymmetric hydrogenation as compared to the functionalized ketones.

• RuX2(bisphosphine)(1,2-diamine)-type catalyst allows the chemoselective hydrogenation of ketones. This catalyst is compatible with various functional groups, including nitro, olefin, and cyclopropane.

(ii) Mechanism • The hydrogenation through the RuX2(bisphosphine)(1,2-diamine)-type catalyst proceeds

through an outer-sphere mechanism.

R. Noyori, J. Am. Chem. Soc., 125, 13490 (2003); S. H. Bergens, J. Am. Chem. Soc., 130, 11979 (2008).

i) Generation of dihydridoruthenium(II) species A from the catalyst precursor ii) Transfer of hydride (on Ru) and proton (on N) to ketone: The nucleophilic attack of

the hydride to the carbonyl carbon takes place simultaneously with the protonation of carbonyl oxygen through 6-membered transition state TS. The resulting alcoholic product is immediately converted to ruthenium alkoxide B.

iii) Protonation of alkoxide on ruthenium: One of the protons on N reacts with the alkoxo ligand to release the desired product.

iv) Formation of molecular hydrogen complex: The h2-coordination of H2 on Ru leads to the decrease in its pKa.

v) Regeneration of A: The molecular H2 ligand is deprotonated by the amido ligand in D.

(iii) Applications • RuCl2(binap)(diamine)-type catalysts are often used for the preparation of various

biologically active compounds and drug candidates.

C.-y. Chen, Org. Lett., 5, 5039 (2003).

Ph

NHMeO

Ph

NHMeOH

• HCl P Pt-Bu t-Bu

H

H

cat. [Rh(nbd)L*]SbF6

H2, K2CO3MeOH Ph NHMe

O

CF3

(R)-fluoxeline

L* =

Duanphos

OHO

OHOH

cat. [Me2NH2][(RuClL*)2(µ-Cl)3]

H2, MeOH

(S)-ofloxacin

O

O

O

OPPh2PPh2

>99% ee L* =

Segphos

Me CO2MeO cat.

[Ru]–L*Me CO2Me

OH

synlanti = 94/698% ee(2S,3R)

NHBz NMe

HO H MeH

CO2HO

RNHBz

carbapenem antibiotics

H2CH2Cl2

O

O

O

OPAr2PAr2

L* =

DTBM-Segphos(Ar = 4-MeO-3,5-t-Bu2C6H2)

ClRu

P

P

H2N

NH2Cl

R1

R2

R3

Ar2

Ar2

R R’

O+ H2

cat. RuCl2(binap)(diamine)

K2CO3 or t-BuOKi-PrOH

R R’

HO

RuCl2[(S)-binap](diamine)Ar = Ph, p-Tol, XylR1–R3 = H, alkyl, aryl

Me

OH

99% ee

H

Me

OH

97% ee

Me

OHCF3

OH

96% ee 95% ee

PRu

P

H2N

NH2

Y

X

H2

(base)

X, Y = ClX = H, Y = BH4

PRu

P

HN

NH2HP

RuP

HN

NH2H

H H

PRu

P

H2N

NH2

H

H

PRu

P

N

NH2

H

H

H H

OR’R δ+δ–

A

C

D

TSR R’

O

R R’

HO H

H2

i)ii)

iii)

v)

PRu

P

N

NH2

O

H B

R’

H

R

vi)

H H

PP = BINAP

SN

MOMOCF3

CF3

O

OO

F

SN

MOMOCF3

CF3

O

OOH

F

cat. RuCl2[(R)-Xylbinap][(R)-daipen] K2CO3

H2, i-PrOH–THF

>99% eean FDE-IV inhibitor

– 27 –

(3) Catalytic asymmetric hydrogenation of imines • As with ketones, imines are also reduced with molecular hydrogen through transition-metal

catalysis. • Enantioselective hydrogenation of imines is useful for preparing optically active amines,

which are often seen in many useful compounds. • However, the hydrogenation of imines is more formidable than those of alkenes and ketones.

The amine product commonly poisons the metal catalyst, because the lone pair on its N strongly interacts with the metal atom.

• Many excellent chiral catalysts have been developed for the asymmetric hydrogenation of specific imines, which can be converted into useful chiral compounds.

Examples

H.-U. Blaser, Adv. Synth. Catal., 344, 17 (2002).

D. Steinhuebel, K. Matsumura, J. Am. Chem. Soc., 131, 11316 (2009).

(4) Asymmetric reduction other than hydrogenation (a) Transfer hydrogenation of ketones and imines

R. Noyori, J. Am. Chem. Soc., 117, 7562 (1995); 118, 4916 (1996); 119, 8738 (1997).

• The transfer of hydrogen from secondary alcohols to ketones, Meerwein–Ponndolf–Varley-type reduction, is known to proceed in the presence of not only Lewis acid but also transition-metal complex catalyst.

• Optically active Ru(h6-arene)(N-Ts-diamine) complexes work as useful catalysts for the enantioselective transfer hydrogenation of various ketones and imines with 2-propanol.

• The transfer hydrogenation with 2-propanol is an equilibrated reaction. Therefore, the prolonged reaction time and/or high concentration of substrate are disadvantageous for high enantioselectivity.

• A mixture of formic acid and triethylamine is also usable for the asymmetric transfer hydrogenation with Ru(h6-arene)(N-Ts-diamine) catalyst. In this case, the reaction is irreversible.

(b) CBS (Corey–Bakshi–Shibata) reduction

E. J. Corey, J. Am. Chem. Soc., 109, 5551 (1987); 109, 7925 (1987); Angew. Chem. Int. Ed. 37, 1986 (1998).

• Various ketones are reduced to the chiral secondary alcohols with high enantiomeric excesses through CBS reduction.

• In the CBS reduction, oxazaborolidine 1 works as the Lewis acid catalyst for the borane reduction of the carbonyl.

Me

NMeMe

OMe

Me

NHMe

OMe

Me

79% ee

cat. [Ir(cod)Cl]2 – (R)-(S)-Xyliphos Bu4NI

Me

NMe

MeO

Me

OCl

metolachlor

H2, AcOH

Fe

(R)-(S)-Xyliphos

PPh2

P

Me

NN

NN

CF3

F

FF NH2 O

NN

NN

CF3

F

FF NH2 O

cat. Ru(OAc)2L*

SAH, NH4SAMeOH

+ H2

• SAHsitagliptin

>99% eeO

O

O

OPXyl2PXyl2

L* = SA =OH

CO2–

DM-Segphos

NRu

NH2

Cl

TsPh

Ph

R

R R’

Xcat. RuCl(arene)(Tsdpen)

+Me Me

OH

R R’

XH+

Me Me

OH

(solvent)X = O or R”KOH

Me

OH

RuCl(arene)[(S,S)-Tsdpen]97% eeTMS

i-Pr

OH

99% ee

NH

MeMeO

MeO

95% ee (with HCO2H/Et3N)

Me

O

+ BH3cat. 1

THFMe

OH

96.5% ee

N BO

Me

H PhPh

oxazoborolidine 1

– 28 –

3-2. Cross-coupling and related reactions (1) General

See: J. Organomet. Chem., 653, 1–303 (2002) (special issue).

• Nucleophilic substitution of aryl or alkenyl halide, which is believed inert to nucleophilic substitution, took place in the presence of a transition metal complex, such as palladium and nickel.

• The reaction between organohalide and organometal is called ‘cross-coupling reaction’. • The cross-coupling reactions are named according to the organometallic substrate. Typical mechanism

i) Oxidative addition of R–X to palladium(0) A: This step is commonly rate-determining. ii) Transmetalation between Pd–X and R’–M iii) Reductive elimination from C to form the coupling product R–R’ and regenerate A

(2) Kumada–Tamao–Corriu reaction (M = MgX)

K. Tamao, M. Kumada, J. Am. Chem. Soc., 94, 4374 (1972); Bull. Chem. Soc. Jpn., 49, 1958 (1976).

R. J. P. Corriu, Chem. Commun., 144 (1972).

General • When Grignard reagent is used as the organometallic substrate, the cross-coupling reaction

is called Tamao–Kumada–Corriu reaction. • Phosphine–nickel complex is commonly used as the catalyst for the coupling reaction.

Other metal complexes, e.g. palladium, iron, cobalt, also catalyze the reaction. • The catalyst precursor, NiCl2(dppp), is reduced to the nickel(0) species through twice

transmetalations and following reductive elimination.

Considerations for organic synthesis • In the formation of C(sp2)–C(sp3) bond, alkyl magnesium halides should be chosen as the

alkyl substrate to avoid the b-hydride elimination from alkylnickel(II) species. • The reaction of secondary alkyl magnesium is accompanied with the isomerization of the

alkyl group.

T. Hayashi, M. Kumada, J. Am. Chem. Soc., 106, 158 (1984).

Application

E. N. Jacobsen, J. Am. Chem. Soc., 123, 10772 (2001).

(3) Negishi reaction (M = ZnX, Al, Zr etc.)

E.-i. Negishi, J. Org. Chem., 42, 1821 (1977) (Zn, Al); J. Am. Chem. Soc., 99, 3168 (1977) (Zr).

General • Negishi reaction commonly indicates the cross-coupling reaction between organohalides

and organozinc compounds. • The reaction using organoaluminium or zirconium is also called Negishi reaction. • Palladium complex is commonly used as the catalyst for Negishi coupling. • In the original procedure, PdCl2(PPh3)2 was used as the catalyst precursor. The precursor

was reduce to the palladium(0) species through the reduction of the palladium(II) with 2 equiv of (i-Bu)2AlH (DIBAH).

Considerations for organic synthesis • Commonly, the organozinc reagents are generated from the transmetalation between other

reactive organometal (Li or Mg) and zinc chloride, Rieke’s, or Knochel’s direct method. • This reaction is compatible with various reactive functionalities, e.g. carboxylate, ketone,

nitro, cyano groups.

Application

J. S. Panek, J. Org. Chem., 64, 3000 (1999).

R X M R’+catalyst

R R’ X = I, Br, Cl, OTf etc.M = MgX, B(OH)2, ZnCl etc.

LnPd

RLnPd

X

RLnPd

R'

R R’

M R’

R X

MX

i)

ii)

iii) A

BC

Et2O

cat. NiCl2(dppp)+X BrMg R R

R' R' X = Cl. BrR = aryl, alkenyl, 1° alkyl

DPPP = Ph2P PPh2

Ph Br + BrMgMe

Me catalyst

Et2O, rt

catalyst = NiCl2(dppp)catalyst = PdCl2(dppp)catalyst = PdCl2(dppf)

Me

MePh

Me

Ph

29%43%95%

3%19%0%

DPPF = FePPh2

PPh2

IOMe Me

Me

OMe Me

Me

BrMg+cat. Pd(PPh3)4

benzene

88%

(+)-ambruticin

THF

cat. PdCl2(PPh3)2 – 2(i-Bu)2AlH

+X RClZn X = I, BrR = aryl, benzyl

RR' R'

i-PrBocHN

NHOMe

TBDPSO

IPhClZn

MeMe

OMe+

Ph

MeMe

OMeMe

TBDPSO

NHO

i-PrBocHNcat. Pd(PPh3)4

THF

81%(–)-motuporin

– 29 –

(4) Kosugi–Migita–Stille reaction (M = Sn)

M. Kosugi, Chem. Lett., 301 (1977).

J. K. Stille, J. Am. Chem. Soc., 101, 4992 (1979).

General • Organostannnane is used as the organometallic substrate in Kosugi–Migita–Stille reaction. • Palladium complex is the catalyst of choice for the cross-coupling reaction. In particular,

Pd(PPh3)4 or the in-situ-generated palladium(0) from Pd2(dba)3 and a phosphine ligand is commonly employed as the catalyst.

• Additive, e.g. CuI or LiCl, often remarkably facilitates the Kosugi–Migita–Stille reaction.

Considerations for organic synthesis • Organostannane substrates are ordinarily prepared through the transmetalation of reactive

organometals with Bu3SnCl or the hydrostannation of alkynes with Bu3SnH. • Tributylstannyl group is widely used as the tin substituent in the oraganometallic substrate. • Tetraorganostannanes can be purified with extraction and/or silica-gel column

chromatography, because they are commonly stable to oxygen and water in air. • Kosugi–Migita–Stille reaction exhibits larger functional group compatibility than Negishi one. • After the cross-coupling reaction, the reaction mixture is often treated with aqueous KF to

remove the tin by-product. • Organostannanes often have high toxicity for us.

Application

J. S. Panek, J. Am. Chem. Soc., 120, 4123 (1998).

(5) Suzuki–Miyaura reaction (M = B)

Review: N. Miyaura, A. Suzuki, Chem. Rev., 95, 2457 (1995).

N. Miyaura, A. Suzuki, Tetrahedron Lett., 20, 3437 (1979); Synth. Commun., 11, 513 (1981).

General • Organoboron is used as the organometallic substrate in Suzuki–Miyaura reaction. • Phosphine-ligated palladium complex is commonly chosen as the catalyst for the cross-

coupling reaction, while nickel and iron complexes can catalyze the reaction. • Stoichiometric addition of base, such as hydroxide and alkoxide, is required for the Suzuki–

Miyaura reaction to facilitate the transmetalation process. • The base, such as alkoxide, interacts with the boron atom to enhance the reactivity of the

organometallic substrates (path a). Alternatively, the base is replaced by the halide on arylpalladium(II) species (path b). Alkoxopalladium is more reactive to the transmetalation process than halopalladium.

Considerations for organic synthesis • Organoboron substrates are ordinarily prepared through the transmetalation of reactive

organometals with B(OMe)3 or the hydroboration of alkynes with 9-BBN-H. • Most of organoboranes are sufficiently stable to oxygen and water in air. Therefore, the

organometallic substrates can be purified with extraction and/or silica-gel column chromatography.

• Suzuki–Miyaura reaction also exhibits excellent functional group compatibility as with Kosugi–Migita–Stille one.

• Commonly, the boron waste is less toxic than the tin one from Kosugi–Migita–Stille coupling.

R1 X R1 R2cat. [Pd]

+ R2 SnR’3R1 = alkenyl, aryl, benzyl X = Br, I, OTf (Cl)R2 = alkynyl, alkenyl, aryl (methyl) R’ = Bu, Me

BrCl Sn 4+cat. Pd(PPh3)4

benzene, 100°CCl

>99%

Ph4Sncat. (PhCH2)PdCl(PPh3)2

(Me2N)3P=O (HMPA)+Ph Br Ph Ph

91%

Me

ITBSO

Me NH

OMe

MeO O

OMeITIPSO OMe

Me

O

NHO

O

HO

HOMe

1. (E)-Bu3SnCH=CHSnBu3 i-Pr2NEt, cat. PdCl2(MeCN)2 DMF–THF2. (NH4)2Ce(NO3)6 (CAN)3. HF aq., MeCN

54%(–)-mycotrienol

base

cat. [Pd]R1 X + R2 BX2 R1 R2 R1 = alkenyl, aryl X = Br, I, OTf (Cl, OTs)

R2 = alkenyl, aryl (alkyl) BX2 = B(pin), B(cat), 9-BBN

R1Br

R3

R2+ (cat)B

R4cat. Pd(PPh3)4

NaOEt, EtOHR1

R3

R2R4

R B(OR’)2R’O–

ArLPd

X

ArLPd

R

R B(OR’)3–

R’O– ArLPd

OR’

R B(OR’)2 ArLPd

R

path bpath a

– 30 –

Application

J. S. Panek, Org. Lett., 2, 2575 (2000).

(6) Hiyama reaction (M = Si etc.)

Reviews: T. Hiyama, Top. Curr. Chem., 219, 61 (2002); Chem. Soc. Rev., 40, 4893 (2011).

K. Tamao, M. Kumada, Organometallics, 1, 542 (1982).

T. Hiyama, J. Org. Chem., 53, 918 (1988).

General • The cross-coupling reaction using organosilane as the nucleophilic substrate is commonly

called Hiyama coupling reaction. • Stoichiometric fluoride ion, F–, is required for the efficient formation of the cross-coupling

products. • The fluoride ion bonds to the silicon atom to form silicate species. The formation of silicates

facilitates the transmetalation between the organosilyl compound and halopalladium. • Hiyama reaction is possible to proceed in the absence of fluoride ion when the substituents

on silicon are well-designed to activate the C–Si bond.

S. E. Denmark, J. Am. Chem. Soc., 123, 6439 (2001).

Y. Nakao, T. Hiyama, J. Am. Chem. Soc., 127, 6952 (2005).

(7) Palladium-catalyzed coupling reaction with relatively acidic compounds General • Organic compound bearing an acidic proton (pKa < 40), such as malonates, amines, and

alcohols, can couple with haloarene or related compound through palladium catalysis. • The cross-coupling reaction is conducted in the presence of a base, such as alkoxide or

tertiary amines. The base deprotonates the acidic substrate to generate the anionic species, which can work as the nucleophilic substrate in place of the organometallic substrate in the cross-coupling reaction.

(a) Sonogashira reaction

Review: E.-i. Negishi, Chem. Rev., 103, 1979 (2003).

K. Sonogashira, Tetrahedron Lett., 36, 4467 (1975).

General • Sonogashira reaction is the cross-coupling reaction of terminal alkynes with haloarenes or

haloalkenes. • Palladium complex, e.g. PdCl2(PPh3)2, is used as the catalyst. • Commonly, the reaction is carried out in the presence of an amine and copper(I) iodide. • The stoichiometric amount of amine base is required for neutralizing the hydrogen halide

by-product.

Mechanism • The copper(I) salt facilitates the deprotonation from the terminal alkynes with the amine

base. The resulting copper acetylide readily undergoes the transmetalation with halopalladium(II) species.

I

OAc

SN OTBS

OTBS

9-BBN

BnO

OAc

SN

OTBS

BnO OTBS

+cat. PdCl2(dppf)

Cs2CO3, DMF–H2O

60%

epothilone A

cat. [Pd]R1 X + R2 SiR’3 R1 R2 R1 = alkenyl, aryl, allyl X = Br, I, OTf

R2 = alkenyl, aryl, allylF–

IF5Si

Ph2–

2 K++

cat. Pd(OAc)2 – 2 PPh3, Et3N

no solvent Ph Ph

51%

I Me3Si+cat. [Pd(η3-C3H5)Cl]2

[(Et2N)3S](Me3SiF2) (TASF)HMPA

98%

SiMe2

PentI +HO

cat. Pd(dba)2

KOSiMe3DME

Pent

93%

DBA =Ph

O

Ph

OH

Me2Si Hex

I

Me+

Me

Hexcat. PdCl2 – P(2-furyl)3

K2CO3, DMSO

94%

cat. [Pd] & CuIR1 X + R1 = alkenyl, aryl

X = Br, I, OTfbaseR2H R1 R2

I + H

cat. PdCl2(PPh3)2 & CuI

Et2NH90%

LnPd

R1

LnPdX

R1

LnPd

R2

Cu R2

CuX R2H

R3NH+ • X–

R3NR2R1

R1 X

– 31 –

Application

P. A. Wender, Synthesis, 1994, 1278.

G. Hennrich, J. Phys. Chem. B, 114, 4811 (2010).

(b) Buchwald–Hartwig reaction (amination of haloarenes)

Reviews: J. F. Hartwig, Acc. Chem. Res., 31, 851 (1998); Angew. Chem. Int. Ed., 37, 2046 (1998).

S. L. Buchwald, Acc. Chem. Res., 31, 805 (1998); Angew. Chem. Int. Ed., 47, 6338 (2008).

J. F. Hartwig, Tetrahedron Lett., 36, 3609 (1995).

S. L. Buchwald, Angew. Chem. Int. Ed. Engl., 34, 1348 (1995).

General • Buchwald–Hartwig reaction is the palladium-catalyzed cross-coupling reaction of amines

with haloarenes. This reaction is applicable to the synthesis of a broad range of substituted anilines.

• Copper complex is known to work as the catalyst for the amination of haloarenes. The copper-catalyzed reaction is called Goldberg amination.

• The amination of haloarenes requires a stoichiometric base, such as NaO(t-Bu) or Cs2CO3 for the efficient formation of C–N bond.

• The palladium catalysis is applicable to the formation of C–O and C–S bonds.

Mechanism • In mechanism (a), the alkoxide base is replaced by the halide on arylpalladium(II) species.

The resulting alkoxy ligand on palladium abstracts a proton from the amine substrate to form amidopalladium species and release the alcohol.

• Alternatively, the coordination of the nitrogen on palladium enhance the acidity of the amine substrate. The proton on the nitrogen is readily abstracted by the base to form amidopalladium species as shown in mechanism (b).

Application

M. P. Wentland, Bioorg. Med. Chem. Lett., 10, 183 (2000).

(c) a-Arylation of carbonyl and related compounds

Reviews: J. F. Hartwig, Acc. Chem. Res., 36, 234 (2003).

M. Miura, Angew. Chem. Int. Ed. Engl., 36, 1740 (1997).

S. L. Buchwald, J. Am. Chem. Soc., 119, 11108 (1997).

J. F. Hartwig, J. Am. Chem. Soc., 119, 12382 (1997).

N

OPhO

H

OH

H

O

Cl

TMS

N

OPhO

H

OH

H

O

TMS

+

cat. Pd(PPh3)4, CuI

BuNH2, benzenedynemicin

analog

BrO

O

O

OTMS

I OC10H21O

OOC10H21

TMS

cat. PdCl2(PPh3)2 CuI

Et3N

K2CO3

MeOH

cat. PdCl2(PPh3)2, CuI

, i-Pr2NH

44%

16% (2 steps) a liquid crystal

XR1

HNR2

+cat. [Pd]

baseN

R1

R2

MeO Br + HNcat. PdCl2[P(o-Tol)3]2

LiNTMS2 (LHMDS)toluene

MeO N

94%

Ph Br + HNMe

Ph cat. Pd(dba)2 – 2 P(o-Tol)3

NaO(t-Bu), toluenePh N

Me

Ph

88%

LnPd

ArLnPd

OR

ArLnPd

X

ArLnPd

NR2NaOR

NaX

Ar X

HNR2

ROH

Ar NR2 LnPd

ArLnPd

X

ArLnPd

X

ArLnPd

NR2

NaOR

Ar X

HNR2

Ar NR2(a) (b)

NR2H

ROHNaX

N

CH3

CH3TfO

N

CH3

CH3PhHN8-aminocyclazocine analog

+ PhNH2cat. Pd2(dba)3–DPPF

NaO(t-Bu), toluene

57%

R2 EWGR1 X +

R3

cat. [Pd]

base

R2 EWG

R3R1

R1 = aryl, alkenyl X = I, Br, OTf (Cl)EWG = ketone, CN, CO2R etc. (electron-withdrawing groups)

Ph PhO

Ph I +cat. PdCl2–4 LiCl

Cs2CO3 (2 eq.)Ph Ph

O

Ph Ph 48%

cat. Pd2(dba)3–BINAP

NaO(t-Bu), THFMeO Br MePh

O+

MePh

O

MeO91%

Me Ph

O

Br

Me+

cat. Pd(dba)2–DTPF

KHMDS, THF Ph

OMe

DTPF = FeP(o-Tol)2

P(o-Tol)294%

– 32 –

General • Palladium catalysis allows the arylations of enolates and related soft carbanions with

haloarenes. • The palladium-catalyzed a-arylation requires a stoichiometric strong base for the efficient

formation of the desired product. The base abstracts a proton from the carbonyl substrate to facilitate the generation of palladium enolate intermediate.

Mechanism • A possible pathway is shown in the following graphic. Relative thermodynamic stabilities

of the palladium C- and O-enolates are affected by the a-substituents of the carbonyl substrate.

(8) Mizoroki–Heck reaction (a) Typical Mizoroki–Heck reaction

Review: I. P. Beletskaya, Chem. Rev., 100, 3009 (2000); S. E. Gibson, Tetrahedron, 57, 7449 (2002).

T. Mizoroki, Bull. Chem. Soc. Jpn., 44, 581 (1971).

R. F. Heck, J. Org. Chem., 37, 2320 (1972).

General • Mizoroki–Heck reaction is the dehydroarylation of alkenes with haloarenes through

palladium catalysis. One of the hydrogen atoms on the C(sp2) is replaced by the aryl group.

• The stoichiometric amount of base is required for neutralizing the hydrogen halide by-product.

• To obtain the Mizoroki–Heck product in high yield, the reaction should be considered from the viewpoint of regio- and stereoselectivities.

Mechanism i) Oxidative addition of R1–X to palladium(0) A ii) Migratory insertion of alkene into Pd–R1

bond iii) b-Hydride elimination from alkylpalladium C iv) Reductive elimination of hydrogen halide

from D

• In the process from B to C, the alkene is inserted into B to form two possible alkylpalladium

species, intermediate C and C’. The formation of C, which is related to the palladium C-enolate, is preferable to that of C’ when R2 is electron-withdrawing.

• The b-H elimination from C leads to the formation of either E- or Z-product through the conformation C(E) or C(Z).

• Commonly, the E-product will be selectively obtained from the reaction, because C(Z) is unfavorable because of the steric repulsion between R1 and R2.

Application

M. P. Wentland, Bioorg. Med. Chem. Lett., 10, 183 (2000).

J. J. Masters, (S. J. Danishefsky,) Angew. Chem. Int. Ed. Engl., 34, 1723 (1995).

LnPd

ArLnPd

X

ArLnPd

R

OAr

LnPdO

RONa

R

O

R

base–

base•HNaX

O

RAr Ar X

R2R1 X +cat. [Pd]

baseR1

R2R1 = aryl (alkenyl) X = I, Br, OTfR2 = EWG (alkyl)

cat. Pd black

KOAc, MeOHI + CO2Me

CO2Me 97%

I + Phcat. Pd(OAc)2

Bu3N PhPh75%

B+

R2

R1LnPd

R2H

HH

HLnPd

R2H

HR1

HLnPd

R2H

R1H

PdLnR1

R2H

HH

R2R1

R2

R1

R1

R2CC’

C(E)

C(Z)

O

O MeOMe

MeO OTf

cat. PdCl2(PPh3)2

+LiCl, Et3NDMF

O

O MeOMe

MeO92%

lasiodiplodin

cat. Pd(PPh3)4

K2CO3, MS 4AMeCN

49%

taxolO

O O

OTBS

HBnO

H

O

OO O

OTBS

HBnO

H

O

TfO

LnPdX

R1

LnPd

LnPdX

R2

R1

LnPdX

H

H

A

B

C

D

R2R2R1

R3NR3N•HX

i)R1 X

iv)

iii) ii)

– 33 –

(b) Mozoroki–Heck reaction of cyclic alkenes

R. F. Heck, J. Org. Chem., 43, 2952 (1978).

• The cyclic alkene is inserted into the Pd–Ph bond to give intermediate A. If the reaction followed the typical pathway, Hb would be dissociated through the b-hydride elimination from A to yield compound 4. However, Hb is impossible to participate the b-elimination because Hb is locates in the anti-position of Pd. Therefore, the Pd eliminates from A with Ha, which is positioned syn, to give 3 and Pd–Ha.

• This type Mizoroki–Heck reaction is often used in total synthesis of natural products.

M. Isobe, Tetrahedron, 50, 11143 (1994).

• The regioselectivity can be controlled by choice of catalyst and/or reaction conditions.

J. H. Rigby, J. Org. Chem., 117, 7834 (1995).

(c) Mozoroki–Heck reaction of allylic alcohols

R. F. Heck, J. Org. Chem., 41, 265 (1976).

• The C–C double bond of 2 is inserted into the Pd–Ph bond to form intermediate A, which might lead to the formation of 4 if the reaction followed the typical pathway. However, the b-elimination from A takes place with Ha rather than Hb to afford the enol and (hydrido)palladium. The enol rapidly tautomerizes into aldehyde 3.

B. M. Trost, Angew. Chem. Int. Ed., 38, 3662 (1999).

I +cat. Pd(OAc)2

Et3N1 2 3 4

Ph Pd

Hb

H HaHHb

H HaH

Ph

PdHb

H H

Ph

– Pd Ha

syn-elimination2 A 3

synanti

72%

HN HN

O

O

O OMe

H

H

O

O OMe

Br

O

HN

O

O

O OMe

H

H

cat. Pd2(dba)3•CHCl3 P(o-Tol)3

i-Pr2NEt, BSADMF

67% 10%

NNHMe

O

TBSOTBSO

MeO

MeO

N

NHMe

O

TBSO

TBSOMeO

MeO

58%

32%

cat. Pd(OAc)2–P(o-Tol)3

Et3NMeCN–H2O (10:1)

N

MeOOMe

I

TBSO OTBS

NHMe

O cat. Pd(OAc)2

KOAc, Bu4NIDMF

a

b

a

b

MeOHI +

cat. Pd(OAc)2

Et3N, MeCN

CHO

Me 91%

PhPd

OH

Hb

Hc

Ha1 2

1 + 2 + Pd(0)

A

PhMe

OH

3

tautomerization3

MeOH0%

4

O

O

OH

H

O

O

CHO

H

Br

cat. Pd2(dba)3•CHCl3 DPPBAg3PO4, CaCO3AcNMe2 (DMA) 79%

saponaceolide B

– 34 –

(d) Cascade Mozoroki–Heck reaction • Multiple alkenes and alkynes are successively inserted into the Pd–C bond in the

intramolecular Mizoroki–Heck reaction. This cascade reaction provides a powerful tool for the construction of complex cyclic structures.

A. de Meijere, J. Org. Chem., 56, 6488 (1991).

(9) Toward the success in the cross-coupling reaction

(a) Combination of substrate

Electrophilic substrate (1) • The relative reactivities of haloarenes follows the trend ArI > ArOTf = ArBr > ArCl, in general. • Electron-deficient haloarenes are commonly preferable for the cross-coupling to electron-

rich ones. • The electrophilic substrates 1 affect the rate of the oxidative addition, which is the rate-

determining step of the cross-coupling reaction in most cases. • Haloalkanes are not suitable for the electrophilic substrates for the cross-coupling,

because the b-hydride elimination from the alkylpalladium intermediate competes with the transmetalation or reductive elimination after the oxidative addition of haloalkane.

Nucleophilic substrate (2) • Electron-rich arylmetals are commonly preferable to electron-deficient ones for the cross-

coupling reaction. • Electron-rich arylmetal and electron-deficient aryl halides is the best substrate combination

for the reductive elimination process. • For the cross-coupling between alkyl and aryl substrates, the alkylmetal rather than than

arylmetal should be chosen as the nucleophilic substrate.

(b) Catalyst Choice of palladium complex • Pd(PPh3)4 is widely used as the palladium catalyst for the various cross-coupling reactions

using aryl or alkenyl iodides or bromides. The palladium complex is one of reliable catalysts, but is sometimes insufficient in catalytic activity.

• When the coupling reaction is carried out with other ligands than PPh3, the palladium(0) catalyst can be generated in situ by mixing Pd2(dba)3 (Pd(dba)2, Pd2(dba)3•C6H6, or Pd2(dba)3•CHCl3) and the ligand.

• In place of Pd2(dba)3, Pd(OAc)2 and PdCl2(MeCN)2 are also usable as the catalyst precursor. However, the palladium(II) complexes require their reduction for working as the catalyst. Grignard reagents, i-Bu2AlH, alkyl amines, and phosphines can be used as the reducing agent for the in-situ conversion of Pd(II) to Pd(0).

Electronic effect of ｌigand • Bulky and electron-donating spectator ligand, such as (t-Bu)3P can remarkably improve

the activity of the palladium catalyst for cross-coupling reaction. • With the (t-Bu)3P ligand, chloroarenes are acceptable as the electrophilic substrate of the

cross-coupling reactions in general use. Furthermore, the ligand enables a remarkable decrease in the catalyst loading.

M. Nishiyama, T. Yamamoto, Y. Koie, Tetrahedron Lett., 39, 617 (1998); 39, 2367 (1998).

• More electron-donation from the ligand to the metal enhances the rate of the oxidative addition process.

• The bulkiness of ligand is favorable for the reductive elimination process. The reductive elimination releases the steric repulsion between the spectator ligand and the organic substituents on palladium.

• Furthermore, use of the larger spectator ligand is advantageous to the oxidative addition, because its bulkiness assists the generation of coordinatively unsaturated species.

O

MeO2C

CO2MeCO2Me

71%

cat. Pd(OAc)2 PPh3

Ag2CO3MeCN

1 2

1 + Pd(0)

O

PdCO2Me

CO2Me

Br

O

MeO2C

CO2MeCO2Me

Pd

MeO2C

O

MeO2C CO2MeMeO2CPd

O

MeO2C

CO2MeMeO2C

Pd

O

MeO2C

CO2MeMeO2C

Pd

O

MeO2C

CO2MeMeO2C

HPd H–

O

MeO2C

CO2MeMeO2C

R X M R’+cat. Pd

R R’1 2

Cl + HN

Me

0.025% cat. Pd(OAc)2 – 4 P(t-Bu)3

NaO(t-Bu)o-xylene, 130℃

N

Me

>99%

– 35 –

• Nowadays, various palladium catalysts and bulky electron-donating ligands for the cross-

coupling reactions are commercially available. see: https://www.strem.com/catalog/ligands.php https://labchem.wako-chem.co.jp/synthesis/organic-synthesis/cross-coupling/ https://www.tcichemicals.com/eshop/ja/jp/category_index/12639/ https://products.kanto.co.jp/web/index.cgi?c=t_product_table&pk=143

PR3

PdR3P

PR3

PR3

PR3

PdR3P PR3

R3P Pd PR3

18e (inert)

+ PR3 + 2 PR3

16e 14e (reactive)

– 36 –

3-3. Olefin metathesis (1) General

Review: A. Fürstner, Angew. Chem. Int. Ed., 39, 3012 (2000).

• In the olefin metathesis, the C–C double bond is cleaved to two carbenes and they reconstruct the new C–C double bond.

• The metathesis is catalyzed by metal–carbene complexes, that have a M–C double bond. • The reaction usually gives an equilibrium mixture of olefins. Some kind of ingenuity is

required for exclusively obtaining the target product in organic synthesis. Mechanism

i) The [2+2] cycloaddition of metal–carbene A and olefin 1 gives the metallacyclobutane B.

Its retro-cycloaddition leads to form the metal–carbene intermediate C. ii) The desired product 3 is formed through D when C reacts with another alkene 2.

• The [2+2] cycloaddition of A and 1 can form the regioisomeric intermediate E. However, the retro-cycloaddition of E gives the starting materials.

• The metal–carbene F would be generated when the reaction of C and 2 proceeds with the reversed regioselectivity. The reaction is accompanied with the formation of 1.

• The dimerization of 1 and/or 2 may accompany the cross-metathesis of 1 and 2. The dimers are formed through the reactions of C and 1 or F and 2.

(2) Ring-closing metathesis (RCM)

• In the alkene metathesis of a,w-diene, one of the terminal alkenes intramolecularly reacts

with another alkene to provide the cyclic alkene and ethylene. • The equilibrium of the intramolecular metathesis shifts toward the products. The cyclic

alkene is less reactive to the metal–carbene species than the terminal alkenes because of

the steric hindrance. Furthermore, the by-product, gaseous ethylene, is evolved from the reaction mixture.

R. H. Grubbs, J. Am. Chem. Soc., 114, 5426 (1992); 114, 7324 (1992).

R. H. Grubbs, J. Am. Chem. Soc., 115, 9856 (1993).

(3) Catalyst for olefin metathesis in organic synthesis (a) Schrock catalysts

R. R. Schrock, Organometallics, 6, 1373 (1987); J. Am. Chem. Soc., 112, 3875 (1990) (for 1); J. Am. Chem. Soc., 120, 4014 (1998) (for 3); V. C. Gibson, J. Chem. Soc., Chem. Commun. 1720 (1991) (for 2). Reviews: R. R. Schrock, Tetrahedron, 55, 8141 (1999); Angew. Chem. Int. Ed., 42, 4592 (2003).

• The molybdenum–carbene catalysts, e.g. 1–3, are highly active for various types of olefin metathesis, polymerization and RCM.

• However, the molybdenum complexes are unstable for O2, H2O, and various protic functional groups. Furthermore, the molybdenum–carbenes readily react with carbonyl groups (see J. Am. Chem. Soc., 115, 3800 (1993)).

• Catalyst 2 is widely used for RCM in organic synthesis.

S. E. Denmark, J. Am. Chem. Soc., 126, 12432 (2004).

A. B. Smith, III, J. Am. Chem. Soc., 122, 4984 (2000).

Cba

Cdc+

Cfe

Chg

cat. M=CR2C

e

fC

a

b+ C

g

hC

c

dC

g

hC

a

bC

e

fC

c

d

...

R + R’ cat.

1 2R’

R

M CH2

M CH2

M

R

R

M

R R’

1

2

3CH2CH2

R’R 3

1

M CH2

R

M

R

R’

2 MR’

RR

R’R’

A C

B

D

FE

M CH2 M CH2M M

H2C CH2 M CH2

O

O Me

MePh O

O

PhC6H6

cat. Mo(CHCMe2Ph)(NAr)[OCMe(CF3)2]

89%

N

O

PhN

O

Ph

cat. RuCl2(CHCHCHCPh2)(PCy3)2

C6H6 81%

t-BuOMo

t-BuO

N

Ph

MeMe

i-Pr

i-Pr OMo

O

N

Ph

MeMe

i-Pr

i-Pr OMo

O

N

Ph

MeMe

i-Pr

i-PrMe

Me

Me

Me t-Bu

t-Bu

1 2 3

MeMe

F3C CF3

CF3F3C

Si OMe

Me

I

EtPMBO

Si OMe

Me

I

EtPMBO

cat. 2

C6H6(+)-brasilenyne

MeO

Bu

OMe

MeTESO

cat. 2

C6H6 MeO

Bu

OMe

TESOMe

Bu

MeO

OTESMe

OMe

77%

(–)-cylindrocyclophane A

– 37 –

• Complex 3 acts as a good chiral catalyst for enantioselective olefin metathesis.

Kinetic resolution of substrate

A. H. Hoveyda, R. R. Schrock, J. Am. Chem. Soc., 120, 4041 (1998).

Enantioselective desymmetrization

A. H. Hoveyda, R. R. Schrock, J. Am. Chem. Soc., 120, 9720 (1998).

(b) Grubbs catalysts

R. H. Grubbs, J. Am. Chem. Soc., 114, 3974 (1992) (for 4); Angew. Chem. Int. Ed. Engl., 34, 2039 (1995) (for 5); W. A. Herrmann, Angew. Chem. Int. Ed., 37, 2490, (1998); R. H. Grubbs, Org. Lett., 1, 953 (1999) (for 6); A. H. Hoveyda, J. Am. Chem. Soc., 122, 8168 (2000) (for 7). Reviews: Reviews: R. H. Grubbs, Acc. Chem. Res., 34, 18 (2001); Chem. Rev., 110, 1746 (2010).

• The ruthenium–carbene complexes, in particular 5–7, are frequently used for the olefin metathesis in organic synthesis.

• The ruthenium complexes are stable and work as the metathesis catalyst in the presence of O2 and H2O. The ruthenium-catalyzed metathesis proceeds even in protic solvent including water.

• The ruthenium catalysis is compatible with a broad range of functionalities, including strongly Lewis basic or protic group.

• Complex 5 is more reactive than 4.

A. Nishida, J. Am. Chem. Soc., 125, 7484 (2003).

M. Hirama, Science, 294, 1904 (2001).

C. J. Forsyth, Org. Lett., 8, 5223 (2006); J. Am. Chem. Soc., 133, 1506 (2011).

(4) Selective cross metathesis • Generally, the intermolecular metathesis of equimolar two alkenes provides the mixture of

their cross-coupling product and dimers with statistical ratio, 2:1:1. The product ratio is controlled by the thermodynamic stability of each alkene.

• However, successful cross metatheses have been often seen in total syntheses of natural products.

• To obtain the desired product in high yield, one of the alkene substrates is used in an excess amount to the other.

MeTESO

MeTESO

41%, 97% ee 55%, 65% ee

cat. 3

C6H6

TESOMe

Me MeO O

Me

Me

93%, 86% ee

cat. 3

C6H6

PCy3Ru

ClCl

PCy3

Ph

Ph

4

PCy3Ru

ClCl

PCy3Ph

5

RuClCl

PCy3Ph

NNMes Mes

6

RuClCl

O

NNMes Mes

i-Pr7

N

NO

OHH

O

H

N

NO

OHH

HO

cat. 5

CH2Cl2

26%

(+)-nakadomarin A

O

O

O

O

O

OO

O

OO

O OO

H H H H H H

BnO H H HH Me

H

Me

H H HH H

HH H H

HH

Me

OBn

OBn

Me

cat. 5 CH2Cl2

O

O

O

O

O

OO

O

OO

O OO

H H H H H H

BnO H H HH Me

H

Me

H H HH H

HH H H

HH

Me

OBn

OBn

Me

>60%

O

O

N

O

O

Me

MeO

MeO

NMe Me Boc

OTBDPS

O

O

N

O

Me

Me

MeO

NMe Me Boc

O

O

OTBDPS

cat. 6

hexane

65%

phorboxazole A

– 38 –

T. J. Donohoe, J. Am. Chem. Soc., 128, 13704 (2006).

(5) Ene–yne metathesis

M. Mori, J. Am. Chem. Soc., 119, 12388 (1997).

• Carbon–carbon triple bond can undergo the metathesis in a similar manner to alkenes. The metathesis between alkyne and alkene provides 1,3-diene.

Mechanism

i) The carbene–ruthenium complex reacts with the alkyne substrate to form

metallacyclobutene A (not -butane). ii) As with metallacyclobutane, A undergoes the ring-opening reaction in a similar manner

to the retro [2+2] cycloaddition to form B. In the intermediate B, the C–C double bond in A remains as a C–C single bond.

iii) The M–C double bond in B reacts with the remaining alkene through metallacyclobutane intermediate to give 1,3-diene product.

• The ene-yne metathesis is applicable to a,w-enyne substrate.

J. Xu, J. Am. Chem. Soc., 141, 3435 (2019).

(6) Cascade metathesis • Olefin metathesis is possible to successively take place in a single molecule that has more

than three C–C unsaturated bonds in well-designed positions. • The cascade metathesis often offers a powerful and elegant strategy for constructing

complicated condensed ring systems.

K.-i. Takao, Angew. Chem. Int. Ed., 58, 9851 (2019).

A. J. Phillips, J. Am. Chem. Soc., 128, 1094 (2006).

O

OTBS

OTBS

OC10H21 H H

H HOTBSO

OHMe

O

+cat. 6

CH2Cl2

O

OTBS

OTBS

OC10H21 H H

H HOTBSO

OHMe

O79%

(+)-cis-sylvaticin

(4 equiv.)

R R’ + H2C CH2CH2Cl2

cat. 5

H2C CH2

R R’

M CH2

M CH2

R R’

M CH2

R R’M CH2

R R’

A

B

H2C CH2

R R’R R’

OMe

O

cat. 6

CH2Cl2

OMe

OO

CH2 AlCl3LiAlH4

OMe

OHOH

50%

atropurpuran

O

I

Me Me

O

O

+Me CHO

toluene

cat. 6

OI

Me Me

O

CHOMe

(+)-aquatolide

8

I

Me Me Ru

O

O

8

OI

Me Me

O

Ru

9

Me CHO

9

O

OTIPS

O

O

O

Me Me

+CH2Cl2

cat. 6

OH

H

O

OTIPS

Ru

10 11

10OTIPS

Ru

OHH 11

OTIPS

OO

O

Me Me

1259%

12

(+)-cylindramide A

– 39 –

I. Hanna, Org. Lett., 6, 1817 (2004).

Mei-Pr

Me

MeO2C

Me

Me cat. 6

CH2Cl2

Me

Ru

i-Pr

Me

MeO2C

Me

Me

Mei-Pr

Ru

MeO2C

MeMe

Me

Mei-Pr

MeO2C Ru MeMe

Me

Mei-Pr Me

MeO2C

guanacastepene A

82%13

136

Mei-Pr Me

MeO2C

– 40 –

3-4. Homogeneous metal catalysis in the petrochemical industry (1) Hydroformylation (oxo process)

Review: A. Börner, Chem. Rev., 112, 5675 (2012).

• Syngas, which is a mixture of hydrogen and carbon monoxide, reacts with alkenes in the presence of a transition-metal catalyst to give aldehydes as the major product.

• Through the reaction, a hydrogen atom and formyl (CHO) groups add across the carbon–carbon double bond.

• The hydroformylation used to be carried out with a cobalt catalyst. Nowadays, rhodium is commonly used as the catalyst for the reaction. The use of rhodium leads to improvement of the linear/branch ratio.

• RhH(CO)(PPh3)3 or in-situ-generated complex from Rh(CO)2(acac) and phosphorus ligand (e.g. P(OPh)3 etc.) is commonly used as a catalyst in organic synthesis.

Mechanism

i) The C–C double bond is inserted into the C–Rh bond in A to form alkylrhodium B. ii) A carbon monoxide is inserted into the C–Rh bond in B to form acylrhodium C. iii) The intermediate C reacts with H2 to give the desired aldehyde and regenerate A through

two possible pathways. • Oxidative addition of H2 followed by the reductive elimination of the acyl group and the

hydride from rhodium • s-Bond metathesis between the acyl C–Rh and H–H bond

Applications • Rhodium-catalyzed hydroformylation of terminal alkenes is used for the mass production of

1-butanol and 2-ethylhexanol.

• In total synthesis of natural products

J. L. Leighton, Org. Lett., 7, 3809 (2005).

• Enantioselective hydroformylation

H. Takaya, J. Am. Chem. Soc., 113, 7033 (1993).

R + H2 + COcat. [Rh] (or [Co])

R

H

H

O

R

CHOH

linear product(major)

branched product(minor)

OCRh

Ph3PCO

H

PPh3

Ph3PRh

Ph3P

CO

H

OCRh

Ph3P

H

PPh3

RPh3P

RhPh3P

CO

R

H

OCRh

Ph3P

CO

PPh3

RPh3P

RhPh3P

CO

OR

R

CO

H2R

H

H

O

A

B

C

Me Me CHOMe OH

Me OHEt

cat. Rh

H2, CO

[H–]

1. aldol reaction2. hydrogenation

(+)-SCH 351448

OBnO2COBn O

Me

HSi

Me Me

cat. Rh(acac)(CO)2

CO, benzene

= R

RSiO2

Me

CHO

TBAF

THFR

OR’

Me

OR’

R’ = HR’ = TES

cat. Rh(CO)2(acac) NIXANTPHOS R

OR’

Me

OR’CHO

H2/CO, THF

O

HN

Ph2P PPh2

H2/CO, benzene

(S,R)-BINAPHOS

cat. Rh(acac)(CO)2–(S,R)-BINAPHOS

Me

CHOCHO

O P

PPh2

O

O

88 : 1294% ee

– 41 –

(2) Wacker process

Essay: R. Jira, Angew. Chem. Int. Ed., 48, 9034 (2009). Review: J. Tsuji, Synthesis, 369 (1984).

• Wacker oxidation is the transformation of terminal alkenes into methyl ketones through a palladium catalysis.

• The oxidative reaction is applied to the mass production of acetaldehyde from ethylene (Wacker process).

• In classic Wacker reaction, O2 gas and copper(II) chloride is employed as the oxidant and co-catalyst, respectively.

• Copper(II) salt and benzoquinone are usable as the oxidant in the absence of copper co-catalyst.

Mechanism

Review: J. A. Keith, Angew. Chem. Int. Ed., 48, 9038 (2009).

i) Alkene substrate coordinates to PdCl2 to form intermediate A. The pallaldium(II) withdraws the p-electron to enhance the electrophilicity of the C–C double bond.

ii) Nucleophilic H2O attacks on the alkene ligand on palladium to form B. The regioselectivity follows Markovnikov rule.

iii) The b-hydride elimination from B leads to the formation of the vinyl alcohol, which rapidly tautomerizes to methyl ketone (path a).

J. Smidt, Angew. Chem. Int. Ed. Engl., 1, 80 (1962); P. M. Henry, J. Am. Chem. Soc., 86, 3246 (1964).

iv) The vinyl alcohol intermediate is inserted into the Pd–H bond in C to form D. The resulting alkyl ligand is transformed into the ketone product through the b-hydride elimination from D with the proton of the hydroxy group (path b). J. E. Bäckvall, J. Am. Chem. Soc., 101, 2411 (1979); M. S. Sigman, J. Am. Chem. Soc., 127, 2796 (2005).

W. A. Goddard, III, J. Am. Chem. Soc., 128, 3132 (2006).

v) The reductive elimination of HCl from E gives the palladium(0) species. vi) The palladium(0) is oxidized to PdCl2 with 2 equivalents of CuCl2. vii) The resulting CuCl is oxidized with O2 and HCl to CuCl2.

Applications • Mass production of vinyl acetate

• Application of Wacker oxidation toward total synthesis of natural products

H. Oikawa, A. Ichihara, J. Org. Chem., 60, 5048 (1995).

L. N. Mander, Org. Lett., 6, 703 (2004).

• The palladium-catalyzed oxidation can be expandable to dialkoxylation.

M. S. Sigman, J. Am. Chem. Soc., 128, 1460 (2006); J. Org. Chem. 76, 9210 (2011).

• Enantioselective Wacker-type cyclization

Y. Uozumi, T. Hayashi, J. Am. Chem. Soc., 119, 5063 (1997).

See: T. Hosokawa, S.-i. Murahashi, J. Am. Chem. Soc., 103, 2318 (1981).

R + 1/2 O2cat. PdCl2, CuCl2

R Me

O

PdCl2

Cl2PdR

ClPd

OHR

ClPd H

Pd0

ClPdR

H

OH

ClPdHO

R

H

2 CuCl

2 CuCl2

1/2 O22 HCl

H2OOHR

R Me

OHCl

H2O HCl

R

AB

path a

path b

C

DE

CH2 CH2cat. PdCl2, CuCl2

OAc+ AcOH + 1/2 O2

t-BuO2C O O

OH O OH O OH OH

EtO2C OMeH

PdCl2, CuClO2, DMF–H2O

t-BuO2C O O

OH O OH O OH OH

EtO2C OMeH O

72%

tautomycin

NH

MOMO OMOMPdCl2, CuCl, O2

Bu4NCl, K2CO3CH2CN

N

MOMO OMOM

Me85%

himandrines?

Me cat. PdCl2(MeCN)2, CuCl2

MeOH, MS3A, O2

Me

OMe

OMeOHOH

70% (synlanti = 4.5)

MeMe

Mecat. Pd(OCOCF3)2 (S,S)-ip-boxax

OMeMe

72%97% ee (S)

N

O

N

O

(S,S)-ip-boxax

OHO O , MeOH

i-Pr i-Pr

O

MeMe

PdXMe

– 42 –

(3) Monsant process (Cativa process)

J. F. Roth, Chem. Commun., 1578 (1968); G. J. Sunley, Catalysis Today, 58, 293 (2000).

• Acetic acid used to be produced from methanol and carbon monoxide through a rhodium and hydrogen iodide catalyst. The process is called Monsant process.

• Replacing the rhodium by iridium leads to remarkable improvement of Monsant process. The acetic acid production with iridium catalyst is named Cativa process, which is very similar in mechanism to Monsant process.

Mechanism

i) Hydrogen iodide protonates the oxygen atom of methanol to form its oxonium. The

protonation enhances the reactivity. The protonated methanol reacts with iodide anion to form iodomethane through SN2 pathway.

ii) Oxidative addition of the iodomethane to rhodium(I) A leads to the formation of methylrhodium(III) B.

iii) A carbonyl ligand on the rhodium inserts into the Rh–C bond to form acylrhodium(III) C. The resulting vacant coordination site on rhodium is saturated with carbon monoxide.

iv) The reductive elimination of acyl and iodide ligand from D gives acetyl iodide and A. v) The acyl iodide is rapidly hydrolyzed to acetic acid with the water, which is generated

from the step i).

(4) Coordination polymerization of alkenes

(a) Ziegler–Natta catalyst

K. Ziegler, Angew. Chem., 67, 426 (1955); L. L. Böhm, Angew. Chem. Int. Ed., 42, 5010 (2003).

• A mixture of TiCl4 and AlEt3 allows ethylene to polymerize to high-density polyethylene. • For polymerization of propylene, TiCl3 is preferred to TiCl4. • The polymerization is induced by the alkyltitanium species, which is generated through the

transmetalation between AlEt3 and TiCl4.

Mechanism

i) An ethylene molecule occupies the vacant coordination site on the titanium atom in the

ethyltitanium species. ii) The ethylene ligand inserts into the Ti–C bond to give butyltitanium. iii) The coordination and insertion of ethylene is successively repeated to form the long

alkyl chain on the titanium. iv) The b-hydride elimination of the alkyl chain provides polyethylene and hydridotitanium

species. The polyethylene has a C–C double bond at its terminus. v) Ethylene inserts into the Ti–H bond to regenerate ethyltitanium species.

(b) Kaminsky catalyst (metallocene catalyst)

H. Sinn, Angew. Chem., Int. Ed. Engl., 15, 630 (1976); W. Kaminsky, ibid., 19, 590 (1980).

Review: W. Kaminsky, J. Chem. Soc., Dalton Trans., 1413 (1998).

• Dimethylzirconocene (Cp2ZrMe2) works as the excellent catalyst for the polymerization of ethylene in the presence of methylalumoxane (MAO), which is generated from trimethylaluminum and a small amount of water.

• Zirconocene dichloride (Cp2ZrCl2) is also used as the catalyst precursor. • Reaction of the zirconocene and MAO would generate cationic methylzirconium species

(Cp2ZrMe+), which would be active for the polymerization. • Kaminsky catalyst is useful for the polymerization of 1-alkenes, such as propylene. Its

stereoselectivity (taciticity) is controlled by means of well-designed cyclopentadienyl ligand. • Use of complex 1 leads to the formation of isotactic polypropylene (PP). Meanwhile,

syndiotactic polypropylene is obtained from the polymerization with complex 2. These catalysts were designed for the stereoselective polymerizations according to the steric repulsion between the modified cyclopentadienyl ligands and the methyl group of the monomer. But...

MeOH + COcat. Rh, HI

Me OH

O

Me OH

IRh

I COIMe

OIRh

I

CO

CO

IRh

I

CO

CO

Me

I

IRh

I COIMe

OCO

–

–

–

–

Me OH

O

Me I

H2OHI

Me I

OCO

A

B

C

D

H2C CH2M R

CH2CH2 nM = metal atomR = methyl or alkyl

Cl TiCl

ClEt

Cl

TiCln + AlEt3 Cl TiCl

ClEt

ClCl TiCl

Cl

Cl Eti) ii)

repeats of i) & ii)

Cl TiCl

Cl

Cl (CH2CH2)nHCl TiCl

ClH

Cl

: vacant site

iv)

v)

(CH2CH2)nH

iii)

Zr MeMe + MAO AlMe3 + H2O

(2:1 to 5:1)AlMe

O n MAO

– 43 –

W. Kaminsky, Angew. Chem., Int. Ed. Engl., 24, 507 (1985).

J. Ewen, J. Am. Chem. Soc., 110, 6255 (1988).

(c) Brookhart catalyst

M. Brookhart, J. Am. Chem. Soc., 117, 6414 (1995). Review: C. Chen, Polym. Chem., 10, 2354 (2019).

• Alkenes are inserted into late-transition-metal–carbon, e.g. Pd–C or Ni–C, bond. However, the resulting alkyl ligand on the late transition-metal readily decomposes into the corresponding alkene through its b-hydride elimination. Therefore, the late transition-metal complex had been believed to be wrong for the polymerization catalyst.

• Nevertheless, the palladium and nickel complexes 1–3 are known to function as good or excellent catalysts for the polymerization of terminal alkenes. The nickel complexes 2 and 3 require the activation with MAO for working as the polymerizing the alkenes.

• The o-isopropyl groups in diimine ligand cover the vacant coordination site, which causes the b-agostic interaction of the long alkyl chain. Therefore, the steric hindrance of the isopropyl group restricts the undesirable b-hydride elimination.

ZrClCl

1isotactic PP

M = 24,00098% isotacticity

1MAO

Zr MeMe

ZrMe

Me

MeZr

Me

Me MeMe

Meisotactic PP

MeMe

2

Zr ClCl

syndiotactic PP

M = 133,00086% rrrr

2MAO

Zr MeMe

MeZr

MeMe

MeZr

MeMe Me

Me

syndiotactic PP

NNi

N

i-Pr

i-Pr i-Pr

i-Pr

Br Br

NPd

N

i-Pr

i-Pr i-Pr

i-Pr

Me OEt2

Me Me

BARF–

+

NNi

N

Br Br

i-Pr

i-Pr i-Pr

i-Pr

1 2 3