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１．　有機金属化学の基礎

２．　パラジウムの化学

_{Allyl Palladium の反応}

　　　　Mizoroki-Heck反応

　　　　Migita-Kosugi-Stille カップリング反応

　　　　Miyaura-Suzuki カップリング反応

(Tamao-Kumada-Corriu カップリング反応)

-３．　カルベンの化学

４．　不斉合成

Schrock carbene

Fischer carbene

Grubbs catalyst RCM （閉環メタセシス）

光学活性化合物の入手方法

不斉還元

不斉酸化

不斉アルキル化

不斉1,4付加

酸化と還元、元素の酸化数および原子価

白金の酸化数は＋２

元素の酸化数：ある元素が関与する結合中の電子対を電気陰性度の大きい元素に

割り当てたとき、その元素の原子上に残る電荷の数

中性分子

アニオン

実際の酸化数と違うので、形式酸化数と呼ぶ

formal oxidation number _

酸化的付加と還元的脱離

酸化的付加

還元的脱離

酸化的付加

還元的脱離

配位子のハプト数

形式酸化数、ｄ電子数、総電子数

白金の形式酸化数：

金属のｄ電子数：

総電子数：

中性分子

アニオン

配位子のハプト数、形式電荷、供与電子数

配位子のハプト数、形式電荷、供与電子数

配位子のハプト数、形式電荷、供与電子数

配位子のハプト数、形式電荷、供与電子数

ハプト数 形式電荷 供与電子数 M -halide 1 -1 2 X M M X M X M M X M halide 1 -1 4 -hydride 1 -1 2 M H M H M hydride 1 -1 2

金属の形式酸化数、ｄ電子、錯体の電子数

１８電子則、有効原子番号則

18-electron rule, effective atomic number rule

[Co(H

O)

]

V(CO)

RuCl

(PPh

)

RuH

(PPh

)

Ir Ph₃P CO

Quiz 1.

Hydroformylation

酸化的付加

L Pt L + H H L Pt L _H H _L Pt L _H H キ Pt(0), d10, 14e Pt(II), d 8_{, 16e} L Pt L H H _L Pt L H H L Pt L _H H _L Pt L _H H

水素の酸化的付加

+ R X キ

ハロゲン化アルキルの酸化的付加

Pd(0), d10, 14e _{Pd(II), d}8_{, 14e} Pd(II), d8, 16e 

-+

X

-10 8

+ R X キ

ハロゲン化アルキルの酸化的付加

Ph₃P Pd Ph₃P + H₃C CH₃ Pd PhEt₂P PhEt₂P + _ キ Pd CH₃ PhEt₂P PhEt₂P Pd(II), d8, 16e Pd(0), d10, 14e

還元的脱離

ＣＯ挿入

ＣＯ挿入

CO insertion

25%

75%

cis

-

CO

- CO

ＣＯ挿入

Rh

Cl

PPh

Ph

P

_R

CO

Cl

Rh

Cl

PPh

Ph

P

_Cl

ROC

K

R

K

C

H

, C

H

CH

> 50

C

H

CH

CH

17

CH

3.4+0.2

-p-ClC

H

CH

C

H

ClCH

, H

0.07

< 0.05

<0.02

アルケン、アルキン挿入反応、

脱離反応



-トランス影響、トランス効果

trans influence, trans effect

T M X L L T M Y L L T Y X M L L Y d8平面正方形16電子錯体

配位子置換反応

HCo(CO)₄ HCo(CO)₃ HCo(CH2=CH2)(CO)3

- CO + CO

H₂C CH₂

Co(I), d8, 18e Co(I), d8, 16e Co(I), d8, 18e

会合機構（配位不飽和16電子錯体）

- X

トランス効果の序列

- - - - - -

トランス効果の序列 トランス影響の序列 CO, CN-, CH₂=CH₂ > PR₃, H- > CH₃- > C₆H₅-, I- > Br-, Cl- > NH₃, H₂O H-, CH₃-, C₆H₅- > PR₃, CN- > CO, CH₂=CH₂ > I-, Br- > Cl- > NH₃, H₂O 置換反応に及ぼす配位子Ｔの動的効果 配位子ＴによってＭ－Ｘ結合がどの程度弱められているかを示す静的効果 Ｍ－Ｘ結合距離のＸ線構造解析 Ｍ－Ｘ結合のＩＲ伸縮振動 Ｍ－Ｘ結合のＮＭＲ結合定数

 供与と 逆供与

M



_{ 供与}

M

 逆供与

IR 伸縮振動波数



50-60 cm

低波数シフト

C

C

(d

)

C

C

 (d

)

Dewar-Chatt-Duncanson モデル

C

C

M

M

C

C

 供与の寄与大

 供与の寄与大



150-160 cm

低波数シフト

 供与と 逆供与

M

C

O

d



 供与

M

_C

_O

d

  逆供与

M C

O

M C

O

M C

O

_

+

_ +

IR 伸縮振動波数

CO 2143 cm

末端カルボニル　2125-1850 cm

ホスフィン配位子

M

d



 相互作用

P

X

X

X

酸性度定数 (pK

)

11.40

9.65

8.69

8.65

2.73

 受容性

NO > CO > RNC > PF

> PCl

> P(OR)

> PR

> RCN > RNH

> NH

4.59

PMePh

P(t-Bu)

P(c-C

H

)

PEt

PMe

PPh

ホスフィン配位子

立体因子

P

M

194

182

179

145

132

136

PBu

P(o-MeC

H

)

P(t-Bu)

P(c-C

H

)

PPh

PEt

118

107

円錐角



(cone angle)

P

M





1

/2



₂

/2



₃

/2



= (1/3)





PMe

P(OEt)

ホスフィン配位子

立体因子

配位挟角



(bite angle)

P

P

M



P

Ph

Rh(cod)

ClO

-Ph

P

83.8

O

O

_PPh

Rh(nbd)

ClO

-PPh

98

PPh

PPh

Rh(ndb)

ClO

91.8

X Nu

O

EtOOC COOEt _O O

-Allyl Palladium Chemistry

+ Pd(0)L_n

PdL₂+

Nu _ _

X = OAc (most common), OCO₂R, OP(O)(OR)₂, OPh, OH, halide, SO₂Ph, NO₂, NR₂, NR₃X, PPh₃X,

Nu_ = malonate, O,N,S nucleophiles, R-M (M = Mg, Zn, B, Al, Sn, Si) catalyst= Pd(0)

+ Pd(0)L_n + X _ X

X

PdL

Nu

Nu

PdL

X

Catalytic Cycle

PdL

_

PdL

- 2L

PdL

Nu

_

X

R PdL₂+ X R Nu L_nPd Nu R PdL2 Nu R Nu L_nPd R Nu _ Nu Nu _ _

ligand attack

metal attack

ligand attack; soft carbanions suh as malonate, enolates, amines metal attack: RSnBu₃, RZnX, Cp₂Zr(R)Cl, RAlMe₂, RMgX, RLi, NaBH₄

CO₂Me OAc CO₂Me CO₂Me CO₂Me CO₂Me PdL₂+ OAc CO₂Me OAc CO₂Me CO₂Me CO₂Me CO₂Me PdL₂+ OAc Pd(PPh₃)₄ + CH(CO₂Me)₂ _ THF _ Pd(PPh₃)₄ + CH(CO2Me)2 _ THF _

Stereochemistry

retention

retention

CO

Me

Cl

CO

Me

PdCl

+

Stereochemistry

Pd

(dba)

CO

Me

PdCl

benzene

THF

acetone

DMF

DMSO

100 : 0

95 : 5

75 : 25

29 : 71

3 : 97

retention

inversion

CO

Me

Cl

CO

Me

PdCl

inversion

Pd(PPh

)

benzene

R X R X R Pd X R Nu R R' R Ar R R CO2R R' R M'R' R R R' M'

Pd-Catalyzed Reactions Involving -Allyl Palladium

Pd (0) NuH C, O, N nucleophiles M'R' transmetallation M'Ar transmetallation transmetallation CO, ROH carbonylation R'M'M'R' metallation H_ hydrogenolysis -elimination

NaCH CO₂CH₃ SO₂Ph PPh₂ PPh₂ O O CO₂Me PhO₂S CO₂CH₃ CO₂Me Pd *L L* H H CO₂Me OAc +

B. M. Trost, J. Am. Chem. Soc., 99, 1649 (1977) Pd(PPh₃)₄ / L* L* = (+) DIOP refluxing DME optical yield 46% + Nu _

Asymmetric Alkylation

Review: B. M. Trost, Chem. Rev., 96, 395 (1996)

Ph Ph Ph OAc Ph Ph Ph (CH₃O₂C)₂HC PPh₂ Ph₂P Ph Ph OAc Ph Ph (CH₃O₂C)₂HC NaCH(CO₂CH₃)₂ + [-C₃H₅PdCl]₂ / L* THF, 25 °C optical yield 84% L* = S,S-Chiraphos NaCH(CO₂CH₃)₂ + [-C₃H₅PdCl]₂ / L* THF, 25 °C optical yield 22%

B. Bosnich, J. Am. Chem. Soc., 107, 2033 (1985) B. Bosnich, J. Am. Chem. Soc., 107, 2046 (1985)

Pd P _P Pd P _P Nu Nu Pd P _P Pd P _P * major * minor

 interconversion

Ph Ph OAc Ph Ph CH(CO₂CH₃)₂ PPh₂ PPh₂ H Me X Fe MeN OH N OH OH NaCH(CO₂CH₃)₂ + [-C3H5PdCl]2 / L* THF, 40 °C 90% ee

T. Hayashi, Tetrahedron Lett., 27, 191 (1986) L* = (R)-(S)-BPPF-X 1a: X = 1b: X = 1c: X = OH OH NMe Fe P Ph _Ph Pd P Ph Ph CH Me N H C C H₂ R H R O Nu

-OAc Ph Ph CH(CO₂CH₃)₂ N O PPh₂ Pri CH₂(CO₂CH₃)₂ + [-C₃H₅PdCl]₂ / L* CH₂Cl₂, rt 98% ee KOAc / BSA

G. Helmchen, Tetrahedron Lett., 34, 1769 (1993) A. Pfaltz, Angew. Chem., 32, 566 (1993) L* =

J. M. J. Williams, Tetrahedron Lett., 34, 3149 (1993)

N O H Me Me PdP Ph Ph Nu -N O H Me Me PdP Ph Ph Nu -or

R

R

OAc

R

R

CH(CO

CH

)

HN

NH

O

O

PPh

Ph

P

Chiral Pocket

When R = Ph, 9% yield along with 79% recovery of the starting material When R = Me, 98% with 92% ee

Review: B. M. Trost, J. Org. Chem. 69, 5813 (2004)

CH₂(CO₂CH₃)₂

CH₂Cl₂ Cs₂CO₃

O O O NHTs O TsHN N O Ts O O O NHTs O TsHN Pd L* _L* Pd₂(dba)₃ CHCl₃ / L* THF, 0 °C 88% ee L* =

B. M. Trost, Angew. Chem., Int. Ed. Engl., 31, 228 (1992) H N H N O PPh₂ Ph2P O

N O O Ts O O O NHTs O TsHN Pd L* _L* O O NHTs Pd L* L* + Pd L* L* N O O Ts 脱離 攻撃 O O O NHTs O TsHN Pd L* _L* 脱離 O O TsHN Pd L* L* 攻撃 O N O Ts Pd L* L* O N O

HN NH O O PPh₂Ph₂P CO₂CH₂Ph O OAc CO₂CH₂Ph O OCO₂CH₃ CO₂CH₂Ph O CO₂CH₂Ph H L* = + [-C₃H₅PdCl]₂ / L* toluene, 0 °C teramethylguanidine 86% ee + [-C₃H₅PdCl]₂ / L* toluene, 0 °C teramethylguanidine 88% dr 97% ee

HN NH O O PPh₂ Ph₂P OAc O O L* = + [-C₃H₅PdCl]₂ / L* 99% (88% ee)

B. M. Trost, J. Am. Chem. Soc., 121, 6759 (1999) LDA/Me₃SnCl

DME. rt

nitoroalkane

O O

78% (78% ee)

B. M. Trost, J. Am. Chem. Soc., 127, 2846 (2005) B. M. Trost, J. Am. Chem. Soc., 131, 18343 (2009) O O Pd₂(dba)₃CHCl₃/L* toluene, 23 °C, 20 h L* = H N H N O PPh₂ Ph2P O O O 85% (87% ee) O Pd₂(dba)₃CHCl₃/L* THF, 25 °C, 2 h N O PPh2 But L* =

O O 88% (94% ee) Pd(OAc)₂/L*/HCOOH dioxane, 40 °C, 10 h N O PPh₂ But L* =

B. M. Stoltz, J. Am. Chem. Soc., 128, 11348 (2006) O O O O O _ Pd+ O _ Pd+ -CO₂

HN NH O O PPh₂Ph2P L* = + [-C₃H₅PdCl]₂ / L* LiHMDS, BF3.OEt2 dioxane, 25 °C 86% (95%ee)

B. M. Trost, J. Am. Chem. Soc., 130, 14092 (2008) N

OBoc

N

Asymmetric Inducion with Mono-substituted Allyl Systems

Dynamic Kinetic Asymmetric Transformation

enantiodiscrimination step +

N O O HN NH O O PPh₂Ph₂P [-C₃H₅PdCl]₂ / L* CH₂Cl₂, rt 99% (75:1) 98%ee L* =

B. M. Trost, J. Am. Chem. Soc., 122, 5968 (2000) + O HN O O O Pd+ _ H Nu

Ph Ph OAc [(C₃H₅)PdCl]₂ / L* + CH₂(COOMe)₂ CH₂Cl₂, 0 oC Ph Ph CH(COOMe)₂ S O Me Pri Ph₂P R R L* = S O Me Pri Ph₂P R L* = Ph 4-MeOC₆H₄ 2,3,5,6-F₄C₆H 4-tBuC₆H₄ 3,5-Me₂C₆H₃ 3,5-tBu₂C₆H₃ 1-Nap 2-Nap Bn Cy 42 44 18 70 63 33 60 56 89 91 70 58 22 77 85 51 74 76 75 81 BSA, KOAc

Ph Ph OAc 3 5 2 + CH₂(COOMe)₂ CH₂Cl₂, -20 oC Ph Ph CH(COOMe)₂ S O R' Pri Ph₂P But R' L* = S O R' Pri Ph₂P But L* = Me i Pr 91 75 75 98 91 69 Ph S O R1 Pri Ph₂P But L* = R2 R1 H Me H Me R2 H H Me Me 67%ee 91%ee 98%ee 85%ee BSA, KOAc

O P Pd S But Me Ph Ph Me Me Ph Ph H H + SbF₆ -O P Pd S But Me Ph Ph Me Me Ph Ph H H + SbF₆ -2.3 : 1 Nu- Nu -fast _slow O P Pd S But Me Ph Ph Me Me H Nu Ph H O P Pd S But Me Ph Ph Me Me Ph H H Ph

CH(COOEt)₂ N N O PPh₂ M H (CH₂)₃ C O HN O O PS OCOOMe OCOOMe + CH₂(COOEt)₂ [-C₃H₅PdCl]₂ / L* Li₂CO₃ H₂O, 40 oC, 12 h 94% yield 98%ee M = PdCl(3-C₃H₅) n

Y. Uozumi, J. Am. Chem.Soc., 123, 2919 (2001) recyclable amphiphilic resin-supported catalyst

recyclable by filtration 1st run 2nd run 3rd run 60% 91%ee 70% 90%ee 65% 90%ee at 25 o C

CO₂Me OC(O)OMe

+

_

CpRu(cod)Cl

_NH

PF

decane, 60

C

+

99% (trans/cis = 97/3)

立体反転

立体反転

Ruthenium-Catalyzed Reaction

Ph Ph OAc Ph Ph CH(CO₂CH₃)₂ + THF, 20 °C 98% (97%ee) NaCH(CO₂CH₃)₂ t Bu Me O Ru O AN AN _ArP ₂

Ruthenium-Catalyzed Reaction

Me OCO₂Me Me CH(CO₂Me)₂ S S

Rhodium-Catalyzed Reaction

Ph OCO₂Me + PhOLi [IrCl(cod)]₂ Ph OPh 86% (96%ee) O OP N Ph Ph THF, 50 oC, 20 h 96 : 4 Ph OPh + minor

Iridium-Catalyzed Reaction

Ph +

Allylic C-H Alkylation

M. C. White, J. Am. Chem. Soc., 130, 14090 (2008) NO₂ COOMe S S O O Ph Ph dioxane/DMSO DMBQ/AcOH 45 °C, 24 h Ph NO₂ COOMe 83% H Ph PdX/₂ Pd(OAc)₂ Pd(II)X₂ NO₂ COOMe _ Pd(0) oxidant

R1 X _R2 R1 R2 Cl O

Mizoroki-Heck Reaction

-Reviews: de Meijere, Angew. Chem., Int. Ed. Engl., 33, 2379 (1994)

catalyst = Pd(0)

Ar Br Ar Pd L L Br Ar Pd L Br Ar Pd(L)Br H Pd L Br Ar Ar

Mechanism

Br (I) R1 R2 R2 R1 CO₂Me CN Me CO₂Me Me OMe MeO Me Me OMe Me Bu

Regioselectivity

The First Report

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

"Mizoroki and coworkers have recently reported a palladium-catalyzed arylation reaction of olefinic compounds with aryl iodides and potassium acetate in methanol at 120 oC. We have independently discovered this reaction and find that it can be carried out under much more convenient laboratory conditions than were used by Mizoroki and that the reaction provides an extremely convenient method for preparing a variety of olefinic compounds."

2 OSiR₃ R₃SiO Br Pd(OAc)2, PPh3 K₂CO₃, MeCN R₃SiO OSiR₃ 2 PdX R₃SiO OSiR₃ H CO2Et H H R₃SiO OSiR₃ EtO₂C PdX H - HPdX syn elimination syn addition

N OBn I MeO DBS H Pd(OCOCF3)2/PPh3 toluene, 120 oC N Me Me Me Me Me N DBS OBn OMe N DBS PdX H N Me O OMe OH

L. E. Overman, J. Am. Chem. Soc., 115, 11028 (1993) (-)-morphine syn addition

N O H N OH H Pd+ H N O H N I OTBS N O H N OH H N O H N H O H Bu₄NCl, DMF, K₂CO₃ 70 °C 2N HCl isostrychine

V. H. Rawal, J. Org. Chem., 59, 2685 (1994) strychine

71% Pd(OAc)₂

COOMe I NMe O COOMe H

Asymmetric Mizoroki-Heck Reaction: Intramolecular

Pd(OAc)₂ / (R)-BINAP Ag₂CO₃

46% ee 60 °C

Ref: M. Shibasaki, J. Am. Chem. Soc., 118, 7108 (1996) and references cited therein.

pioneer works

O _O O Pd+ O Pd(OAc)₂ / DIOP 45% ee benzene, rt

L. E. Overman, J. Org. Chem., 54, 5846 (1989) cf. L. E. Overman, J. Am. Chem. Soc., 125, 6261 (2003)

OTf X O O X O X

Asymmetric Mizoroki-Heck Reaction: Intermolecular

+ Pd(OAc)₂ 3 mol% (R)-BINAP 6 mol% ₊ / i Pr₂NEt (3 equiv) 30-40 °C 1 equiv 5 equiv 71-89% >90%ee 29-11% 50-60%ee

TfO is necessary, racemic products observed for idodide Reaction are very slow, 22-72 h

73 Pd P P O Ar Pd P P Ar O Ar Pd P P O Ar O O O Ar Pd P P H * + OTf_ * * + + + _{1. Insert} 2. -H 3. dissociate thermodynamic product * O Pd P P Ar O Ar Pd P P O Ar Pd P P H O Ar * + _* + *

OTf O O PPh₂ N O But

Asymmetric Mizoroki-Heck Reaction: Intermolecular

+ Pd(dba)₂ (3 mol%) i Pr₂NEt (2 equiv) C₆H₆, 30 °C, 3 days 1 equiv 3.9 equiv 92% yield >99%ee No 2,3-isomer detected

Slow reactions (3-7 days)

Ph

Cl

Ph

Ph

Ph

OMe

MeO

MeO

P

+

cat. Pd

(dba)

/ PBu

Cs

CO

dioxane, 120 °C, 120 h

80%

_{TON = 400}

G. C. Fu, J. Org. Chem., 64, 10 (1999)

3

not effective (<2%)

O O X MeO O O O O O O O O O O O PBut₂ PBu t 2 Pd(dba)₂ / L NaOAc DMF, 100 °C 1. TFA 2. TMSCHN₂, MeOH

A Fluorescence-based Assay

O₂S NMe₂ N Me strong fluorescence N N N Br Boc + O₂S NMe₂ N Me weak fluorescence Boc N N N

Screening of Homogeneous Catalysts

by Fluorescence Resonance Energy Transfer

Pd(dba)₂/ 70 different ligand

Me O O n OMs n = 110 N O K DMF reflux, 5 h N O O O O Me n 87% H₂NNH₂, EtOH reflux, 20 h Me O O n NH2 Me O O H N n H N O O Pd SPh SPh Cl

D. E. Bergbreiter, J. Am. Chem. Soc., 121, 9531 (1999)

HO HN O O Pd SPh SPh Cl DMF, rt, 14 h 98%

Recovery of Catalyst

PhI + _Ph Ph Ph cat. 1 mol% DME, Et₃N 115 o_{C, 6.5 h} 1st cycle 91% 2nd cycle 95% 3rd cycle 92% PhI + _COOMe Ph COOMe cat. 1 mol% DME, Et₃N 115 o_{C, 2.5 h} 1st cycle 85% 2nd cycle 87% 3rd cycle 95% 触媒はジエチルエーテルを加えて沈殿させ、回収

R X R' SnR"_{3 R R' X SnR"}

3

Migita-Kosugi-Stille Coupling

+ cat. Pd (0)

R' = H, aryl, Alkenyl, allyl, benzyl, alkynyl, alkyl

Reviews: J. K. Stille, Angew. Chem., Int. Ed. Engl., 25, 508 (1986)

catalyst = Pd(0)

+ R = aryl, RC(O), allyl, benzyl, vinyl, Ar, RCXH(COOR') X = halogen, OTf

V. Farina, V. Krishnamurthy, W. J. Scott, Org. React., 50, 1 (1998) P. Espinet, A. M. Echavarren, Angew. Chem. Int. Ed., 43, 4704 (2004)

Ar Br Ar Pd L L Br Ar Pd L L R' _{Ar Pd} L R' L R' SnR"₃ R R' X SnR"₃

Mechanism

Reactivity

SnBu₃ Br O Ph Cl O Ph Me O Ph Cl O Ph Me

The first paper

+ cat. Pd(PPh₃)₄ benzene 100 °C, 20 h 96% + Bu₃SnBr

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

M. Kosugi, T. Migita, Chem. Lett., 1423 (1977) + Me₄Sn cat. Pd(PPh₃)₄ benzene 140 °C, 5 h 54% + Me₃SnCl

J. K. Stille, J. Am. Chem. Soc., 100, 3636 (1978) + Me₄Sn

cat. PhCH₂Pd(PPh₃)₂Cl HMPA, 65 °C, 10 min

89%

CO₂Me Cl CO₂CH₂Ph Bu₃Sn + Pd(dba)2 / 2PPh3 THF 50 °C CO₂Me CO₂CH₂Ph 87%

J. K. Stille, J. Am. Chem. Soc., 106, 4833 (1984) CO₂Me PdClL₂ S N ButHNOC Br + N S Me₃Sn TMS benzene S N ButHNOC _N S TMS micrococcinic acid inversion Pd(PPh₃)₂Cl₂

I OH OH SnBu₃ + 2 2 DMF 25 °C 73%

J. K. Stille, J. Am. Chem. Soc., 109, 813 (1987)

N N N N OMe O OTBDMS TBDMSO TBDMSO I SnBu₃ + PdCl2(MeCN)2 toluene N N N N OMe O OTBDMS TBDMSO TBDMSO >90% V. Nair, J. Am. Chem. Soc., 109, 7223 (1987)

MeO TIPSO O O TBSO OMe O Bu₃Sn O N O O O TESO I OMe MeO TIPSO O O TBSO OMe O O N O O O TESO MeO

HO O O HO (-)-Macrolactine A Bu₃Sn OTBS TBSO OH O TBSO I OH

A. B. Smith, III, J. Am. Chem. Soc., 120, 3935 (1998)

OTBS TBSO OH O TBSO OH OPiv SnBu₃ I I Bu₃Sn

OMe OMe NH O I OMe Me I TBSO Me TIPSO Bu₃Sn SnBu₃ Pd(MeCN)₂Cl₂ OMe OMe NH O OMe Me TBSO Me TIPSO DMF/THF 2) CAN THF/H₂O 3) aq. HF/CH₃CN 1) O O NH O OMe Me HO Me TIPSO

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

O NH OH O O O N NH OH O H N NH O O O OH Sanglifehrin A (SFA) O NH HO OH O O O N NH O O H N NH O O O OH SnBu₃ I +

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

O O N NH O O H N NH O O O OH I O O N NH O O NH₂ NH O O O OH I I Bu₃Sn HO +

R'

B

R

X

R

R'

B X

Pd

R Pd

X

R Pd

R'

oxidative

addition

transmetallation

reductive

elimination

- Pd

R'

B OR

_

R'

B

OR

_

R Pd

X

OR

_

role of base

_{R Pd}

_OR

R Pd

OR

R' B

R'

B

ate complex

Et

P

Rh

O

Et

P

PEt

B

Ph

OH

PEt

(4 equiv)

C

D

, 70 °C

Et

P

Rh

Ph

Et

P

PEt

cf. B. P. Carrow, J. F. Hartwig, J. Am. Chem. Soc., 133, 2116 (2011). C. Amatore, Chem. Eur. J., 18, 6616 (2012).

Br O B O I O B Pd(PPh₃)₄ + cat. Pd(PPh₃)₄ benzene NaOEt / EtOH reflux, 2 h

N. Miyaura, A. Suzuki, Tetradedron Lett., 3437 (1979) 81% + CO + K₃PO₄ dioxane rt, 5 h Carbonylative coupling 90%

B NC I ₊ Pd(PPh₃)₄ K₃PO₄ dioxane 60 °C 61%

N. Miyaura, A. Suzuki, Chem. Lett., 691 (1992)

Alkyl-Alkyl coupling

Scope of Palladium-Catalyzed Miyaura-Suzuki Cross-Coupling Reaction

Alkyl B CH₂=CHCH₂ B RCH=CH B B RC C B

N O CO₂PNB OTf TESO H H + _(HO) 2B CN Pd₂(dba)₃ aq. KOH, THF _O N CO₂PNB TESO H H CN 95% -78 °C → rt

Yasuda, N.; Xavier, L.; Rieger, D. L.; Li, Y.; DeDamp, A. E.; Dolling, U. H.

Tetrahedron Lett. 1993, 34, 3211. N O CO₂PNB OTf TESO H H + (HO)2B Pd(dba)₂ N O CO PNB TESO H H Me Me OSiMe₃ O THF, H₂O, Et₃N 30 °C, 2-3 h OSiMe₃ O 996 g

Industrial Application

O OY X O O O O OY YO OY OY YO OY OY OY OY Me Me OMe OAc O O YO P OY OY OY OY YO OY OY OY

Y. Kishi, J. Am. Chem. Soc., 111, 7525 (1989) Palytoxin caboxylic acid

MeO MeO

Recent Advances in Cross-Coupling Reactions

Use of

Cl

Design of Ligand

OTs

For a review on monoligated Pd species:

bulky and electron-rich phosphine

N-heterocyclic carbene

For a review on Pd-catalyzed coupling reactions of aryl chlorides:

G. C. Fu, Angew. Chem. Int. Ed., 41, 4176 (2002).

Cl

Me + _B(OH)2 cat. Pd(OAc)2 / L

CsF dioxane, rt, Me 94% S. L. Buchwald, JACS, 120, 9722 (1998) Cl

Me + _B(OH)2 cat. Pd2(dba)3 / PBu

t 3 Cs₂CO₃ dioxane, 80 °C, 5 h Me 86%

G. C. Fu, Angew. Chem., Int. Ed., 37, 3387 (1998) L =

PCy₂

Me₂N

Room-temperature Miyaura-Suzuki Coupling of Unactivated Aryl Chlorides

active Pd species bears a single PBut₃ steric bulk and electron-richness

JACS, 121, 9550 (1999)

JACS, 122, 4020 (2000)

cf. A review of Pd-catalyzed coupling reactions of aryl chlorides G. C. Fu, Angew. Chem. Int. Ed., 41, 4176 (2002)

(HO)₂B Me Cl Me Me Pd(OAc)₂ K₃PO₄ toluene 90 °C, 12 min Me Me Me + 98% PCy₂ OMe MeO

S. L. Buchwald, Angew. Chem. Int. Ed., 43, 1871 (2004). oxygen lone pair may

stabilize Pd complex

increases electron density in biaryl backbone

increases steric bulk

prevents cyclometalation (HO)₂B Me Br Me Me Pd(OAc)₂ K₃PO₄ toluene 110 °, 18 h Me Me Me + 82% Me Me Me Me 0.2 mol%

OMs + (HO)₂B NiCl₂(dppe)/PPh₃ MeO toluene, K₃PO₄ 80 °C, 14 h MeO 80% OMs + (HO)₂B t_Bu THF, K₃PO₄ 80 °C, 3 h t_Bu 91%

H. N. Nguyen, X. Huang, S. L. Buchwald, J. Am. Chem. Soc., 125, 11818 (2003).

MeO MeO Pd(OAc)₂ Pri i_Pr Pri XPhos OTs _{+ (HO)2B} Ni(cod)₂/PCy₃ MeO THF, K₃PO₄ rt, 8 h MeO 86%

Z.-Y. Tang, Q.-S. Hu, J. Am. Chem. Soc., 126, 3058 (2004). Z.-Y. Tang, Q.-S. Hu, J. Org. Chem., 71, 2167 (2006).

Cl + _{HN NH} cat. Pd2(dba)3 / PBu t 3 o-xylene, 120 °C Me N NH 88% Me

Y. Koie (Tosoh Co.), Tetrahedron Lett., 39, 617 (1998)

imidazol-2-ylidene ligand

N N _{S. P. Nolan, J. Org. Chem., 64, 3804 (1999)} For a review on N-Heterocyclic Carbenes, see:

W. A. Herrmann, Angew. Chem. Int. Ed. 41, 1290 (2002) M. G. Organ, Angew. Chem. Int. Ed. 46, 2768 (2007) cf.

(HO)₂B Me Cl Me Pd(OAc)₂ K₃PO₄ THF/toluene 110 °C, 16 h Me Me + 96% N N O O Me Me

Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. N

N

Pd

N N

Gstottmayr, C. W. K.; Bohm, V. P. W.; Herdtweck, E.; Grosche, M.; Herrmann, W. A. Angew. Chem. Int. Ed. 2002, 41, 1363.

B(OH)₂ + Me Me CsF dioxane rt, 2 h 80% Me Me 12 12 Me Me

(HO)₂B Me Cl Me NaOBut i_PrOH rt, 75 min Me Me + 88% Me Me NMe₂ Pd _Cl NAr ArN Ar = 2,6-(iPr)₂C₆H₃

Navarro, O.; Kelly, R. A.; Nolan, S. P. J. Am. Chem. Soc. 2003, 125, 16194.

NMe₂ Pd Cl IPr NMe₂ Pd H IPr NMe₂ Pd O IPr H NMe2 [IPrPd(0)] i_PrOH O

PdL

R

X

H H

R

PdL

H H

X

R

PdL

H H

R'

M X

R' M

R

R'

H H

R

H

PdL

X

+

undesired

-hydride

elimination

Alkyl-Alkyl Coupling

Dec Br + 9-BBN Hex Pd(OAc)₂/PCy₃ K₃PO₄.H₂O THF, rt, 16 h Dec Hex 85%

Netherton, M. R.; Dai, C.; Neuschutz, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099.

Kirchhoff, J. H.; Dai, C.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 1945.

Alkyl-Alkyl Coupling Dec Cl + 9-BBN Hex Pd₂(dba)₃/PCy₃ CsOH.H₂O dioxane, 90 oC 48 h Dec Hex 83% Pd₂(dba)₃/P(cC₅H₉)₃ THF/NMP, NMI 80 °C, 14 h NC Br 5 3 + O OEt BrZn 3 O OEt NC 5 65%

PMetBu₂ PdBr₂

Lee, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 5616. Bu₄NF THF, r.t. + Ph Si(OMe)₃ EtO Br O 4 EtO Ph O 4 79% + _Me 4NF THF, rt

Tang, H.; Menzel, K.; Fu, G. C. Angew. Chem. Int. Ed. 2003, 42, 5079.

EtO Br O 4 Bu₃Sn Ph EtO O 4 Ph [(-ally)PdCl]₂ PCy(pyrrolidinyl)₂ 89% + LiBr THF/NMP 55 °C, 24 h EtO Br O 4 Cp₂ClZr EtO O 4 99% Pd(acac)₂ Ph Ph ligandless

s_Bu-Pybox Ni(cod)₂ DMA, r.t., 20 h N N O N O Bus Bus

Zhou, J.; Fu. G. C. J. Am. Chem. Soc. 2003, 125, 14726.

BrZn OPh

+

Br _OPh

62%

Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340.

+

Cl Et TIPS IZn NiCl₂.glyme / N N N N N THF, rt + Et TIPS 75%

G. C. Fu, Angew. Chem. Int. Ed., 47, 9334 (2008) Cross-Coupling of Secondary Nucluophiles with Secondary Propargylic Electrophiles at RT

+

DMF/Et₂O, 45 °C, 16 h

G. C. Fu, J. Am. Chem. Soc., 125, 13642 (2003)

Sonogashira Coupling

cf. A review: H. Doucet and J.-C. Hierso,

Negishi Coupling

R'

ZnX

R X

+

Pd(0)

R R'

+

ZnX

generaion of Zn reagents

R'MgX + ZnCl

R'Li + ZnCl

R'

Al + ZnCl

+ Zn(Cu)

R'

I

iodine-zinc exchange

inert to ketone, esters, amino and

cyano goups

X = I, Br

R = Ar, vinyl, alkyl

R' = Ar, vinyl, alkyl

A recent review: E. Negishi, Aldrichimica Acta,

38, 71 (2005).

D. Cardenas, Chem. Soc. Rev. 38, 1598 (2009).

Mechanism: J. A. Casares, P. Espinet, J. Am. Chem.

R X + R' SiY₃ R R' ₊ Y₃Si X Y = Cl, F, H, OMe, cyclobutyl, thienyl, OH ...

X = I, Br, OTf

R = Ar, vinyl, alkynyl, allyl R' = Ar, vinyl, allyl, alkynyl

I

+ SiMe₃

[( 3-C₃H₅)PdCl]₂

(Et₂N)₃S+Me₃SiF₂- (TASF) HMPA, 50 °C, 2 h

98%

Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918. review: Hiyama, T. T opp. Curr. Chem. 2002, 219, 61.

Nakano, Y.; Hiyama, T. J. Am. Chem. Soc. 2005, 127, 6952. Review: Denmark, Regens, C. S. Acc. Chem, Res. 2008, 41, 1486.

R R' L₂NiX₂ 2R'MgX 2MgX₂ L₂NiR'₂ R' R' L₂Ni X R L₂Ni R' R R'MgX MgX₂ L₂Ni RX

Tamao-Kumada-Corriu Coupling

R = Ar, vinyl, benzyl R' = Ar, vinyl, ally, alkyl PPh2

PPh₂ dppp = oxidative addition transmetalation reductive elimination