cross coupling reactions -...

Cross Coupling Reactions

Stille Coupling ! ! !

• general principles

- Pd catalyzed reaction of aryl or vinyl halide with an aryl or vinyl stannane

R’ = aryl, vinyl X = I > OTf > Br >> Cl Pd cat: Pd(PPh3)4, Pd(OAc)2, Pd2(dba)3

solvent: DMF, dioxane, DMSO, THF, NMP

Pd(0) cat+R X R' SnR3 R' R'




- Pd catalyzed reaction of aryl or vinyl halide with a vinyl or aryl stannane

Cl

MeO Bu3Sn

OEtPd2(dba)3, P(tBu)3

CsF, dioxane, 100°C+

MeO

OEt

ISnBu3

HO+

Pd(PPh3)4DMF

OH



• mechanism

Ln PdII

X

Ln Pd0Pd0 or PdII

complexes

oxidativeaddition

transmetallation

reductiveelimination

R'X

R'R

Bu3Sn

Bu3Sn X

Ln

PdII

R'

R

R'R

rate of group transfer: alkynyl > vinyl > aryl > allyl = benzyl >>>> alkyl



• problems & solutions

- electron-rich and sterically hindered aryl halides undergo slower oxidative addition - electron-poor stannanes undergo slower transmetallation

- 1-substituted vinylstannanes can be poor substrates for the Stille reaction (steric)

Br

MeO

Pd2Cl2, P(tBu)3CuI, CsF, DMF, 45°C

+

MeOOMe

NO2

Bu3SnOMe

NO2

89%electron

richelectron

poor

ONfBu3Sn Me

OMOM

MeOH

Pd(PPh3)4, LiClCuCl, DMSO, 60°C Me

OMOM

MeOH92%

+

Nf = C4H9SO2



• applications

OHO2C IH H

Bu3SnH

H

OHN

+ Pd(PPh3)4DMF

61%

H

H

OHN

OHO2CH H

indanomycin

O O

NH

HO OMe

O

HOMeO O

NH

IITIPSO OMe

MeO

TBSO

SnBu3Bu3Sn1. Pd(MeCN)cl2, iPr2NEt2. CAN, THF/H2O3. HF (aq), MeCN

(+)-mycotrienol



• applications

Lett Tetrahedron Lett. 1992, 33, 777.

O

Cl

OTBSO

TBSO

HO

Bu3Sn OMOM

O+ Pd(MeCN)2Cl2

PPh3, DMF, Δ

HO

OMOM

OO

TBSO

TBSO

O

75%

HO

OH

O

OO O

H

monocillin I



• sp2-sp3 coupling

O

O

Br

MeBu3Sn

OTHP

[(allyl)PdCl2]2, [HP(tBu)2Me]+BF4-

Me4NF, 3Å MS, THF, rt

O

O

Me

OTHP53%

+

EtO BrO

EtO

O OMe

Bu3Sn

OMe[(allyl)PdCl2]2, [PCy(pyrrolidinyl)2

Me4NF, 3Å MS, MTBE, rt

71%



• sp2-sp3 coupling (2° alkyl halides)

tin free!

Br

Cl3SnNiCl2, 2,2'-bipyridine

KOtBu, tBuOH, iBuOH, 60°C

72%

+



• related processes

- Stille reaction with acid chlorides

- Carbonylative cross coupling

R X R' SnBu3 R C R'

OPd0 catCO, ligand

Cl

O

H2N

Bu3Sn O

O

BnPdCl(PPh3)2CuI, THF, 50°C

93%H2N

O

O

O



• applications – carbonylative coupling

N N

NI OMe

Me

OtBu

TIPSO

Bu3Sn+

OtBu

TIPSO

CO

N

N

N

OMe

Me

Pd2(dba)3, AsPh3CO, LiCl, NMP, Δ

80%

N

C

N

O

H

O Hstrychnime

O

O

OTfSnBu3

Pd(MeCN)2Cl2DMF, CO, LiCl; 13h

53%

O

O

CO

jatrophone



• stannane prep

aryl stannanes

trans vinyl stannanes



• stannane prep

1-substituted vinyl stannanes

cis vinyl stannanes


Suzuki Coupling ! ! !

• Akira Suzuki: Nobel Prize 2010

For palladium-catalyzed cross couplings in organic synthesis. Shared Prize with Heck and Negishi

RBY2

BY2R

+

+

XR'

R'X

R

R

R'

R'Pd

Pd




- Pd catalyzed reaction of aryl or vinyl halide with an organoborane

X = I > OTf > Br >> Cl R’ = H, aryl, alkenyl, alkynyl, allyl, alkyl

Pd cat: Pd(PPh3)4, PdCl2(dppf)2, Pd2(dba)3, Pd(OAc)2, etc. base: Na2CO3, Ba(OH)2, K3PO4, Cs2CO3, KF, RONa, TlOEt, etc. solvent: MeCN, THF, EtOAc, benzene, DMF

Pd(0) cat+ R' BR2

X R'

base, ligand

R B R B

R BF3K

OH

OH

OiPr

OiPr

OBO

RO

BO

R

BR




- Pd catalyzed reaction of aryl or vinyl halide with an organoborane

Pd(PPh3)4NaOEt, EtOH, Δ

Ph Br Ph B(OR)2+ Ph Ph

B(OH)2 CHOBr+Pd(OAc)2, PPh3

Na2CO3, iPrOH/H2O, Δ CHO

Ph Br 69-BBN 6Ph+

PdCl2(dppf)NaOH, THF, Δ

85%



• mechanism

Ln Pd0 Ln PdII

X

Ln PdII

OEtLn PdII

R

R

X

oxidativeaddition

transmetallation


R BR'2 R BR'2EtONa

EtONa

NaX

metathesis

L

OEtEtO BR'2

OEtL +



• mechanism

- during oxidative addition

- during reductive elimination

isomerization

!

!



• modifications

base temp time yield rel rate

KOH 50°C 30 min 87% 1

TlOH rt <30 sec 92% >60

Kishi J. Am. Chem. Soc. 1987, 109, 4756.

OTBSO

TBSOTBSO

OMe

OH

IH

OTBSO

TBSO

OHTBSO

OMe

H

OTBS

TBSO OTBSOTBS

Pd(PPh3)4base+ OTBS

TBSO OTBSOTBS

(HO)2B



• modifications

Roush Org. Lett. 2000, 2, 2691.

TlX source reagent age yield TlOH (10% stock soln) 1 month 71%

TlOH (10% stock soln)* 5 months 50%

TlOH (fresh, from solid)* 12 months 52%

TlOEt --- 83%

* precipitate formed over time; removed by filtration

OTBS

I

TBSO

OOO

(HO)2B OH

OTBS

OTBS

TBSO

OOO

OH

OTBS

Pd(PPh3)4, TlX, THF, H2O



• examples

BNH

OHI O

O

O+

Pd(OAc)2, TPPTSiPrNEt2, MeCN/H2O

OOH

myxalamide A

44% (2 steps)

Heathcock J. Org. Chem. 1999, 64, 23.



• examples

OH O

OBn

OMOM

Br

OH

O

O

OBn

OMOM

BrBF3K

O

OOH OH

O

OOH OMOM

BnOHN

O NOMe

, BH3•DMS

Pd(PPh3)4, Cs2CO3THF/H2O, Δ, 20h

then H2Oi.

ii. KHF2

oximidine II

99%

42%

Molander J. Am. Chem. Soc. 2004, 126, 10313.


B-Alkyl Suzuki Coupling ! ! !

• sp2-sp3 coupling

O

IO OO

9-BBN; TlOEtPdCl2(dppf), AsPh3

THF, H2O

48%

O

O OO

CN9-BBN

CNR2B

O

Br

O

PdCl2(dppf), K2CO3DMF, THF, 50°C CN

81%


B-Alkyl Suzuki Coupling ! ! !

• examples

I

PMBO OTES

tBuLi (2 equiv), then

B OMeB

MeO

PMBO OTES

O O

PMP

ORI

OMOM

OR'

R = TBS; R' = MOM

K3PO4; A, DMF;PdCl2(dppf) O O

PMP

OR

OMOM

OR'

R = TBS; R' = MOM; R" = PMB

OR" OTES

A

O

OH

OH OH O

HO

O NH2

O

discodermolide

40%

Marshall J. Org. Chem. 1998, 63, 7885.



• boronic ester prep

aryl boronic esters

trans vinyl organoborane derivatives



• boronic ester prep

substituted vinyl boronic esters

cis vinyl boronic esters


Nozaki-Hiyama-Kishi (NHK) Reaction ! ! !

• general properties

R X2 CrCl2 R CrClX R' R"

R' R"

O

R OH

(CrII) (CrIII)

X = Cl, Br, I, OTf R = vinyl, aryl, alkynyl, allyl, propargyl R’, R” = H, aryl, alkenyl, alkyl solvent: DMF, DMSO, THF

O

CrCl3: LiAlH4 (2:1)Br

HO

78%

CHO

CrCl2, DMF

I

100%

OH



• reaction features

- both inter- and intramolecular processes known - aldehydes react faster than ketones (selectivity if both FG present) - organochromium reagents show low basicity

CHO

OBr

CrCl2/NiCl2, THF

O

OH66%

OI

OMeMOMOH

O

CHOPMBOCrCl2/NiCl2DMSO

92%

PMBO

PMBO

OO

OMOM

OMe

H




- allylic halides react to give SN2’ type products

- addition of crotyl chromium gives anti product, regardles of stereochem of starting crotyl halide

OBr

CrCl2/NiCl2

HO

BrPhCHO

CrCl2/NiCl2 BrPhCHO

CrCl2/NiCl2Ph

OH




- favors Felkin product even with adjacent heteroatom

- variations catalytic in chromium are known

I

O

OO

O

OBnBnO OBn

OMeOHC

BnO O

OO

BnO

OHO

OBnBnO OBn

OMeCrCl2/NiCl2

82%

*

* dr = 5:1

OTf

O

OO

HCrCl2 (15mol%), NiCl2 (cat)

Mn (1.7 equiv), TMSCl (2.4 equiv)O

OOH

+

80%



• mechanism

oxidativeaddition

transmetallation


CrIIINiII

NiIIX

X

CrIII 2 CrIII

2 CrII

Ni0

R R'OH R R'

O



• examples

I

O

TBSOTBSO

O CHO

CrCl2/NiCl2

O

OH

O

TBSOTBSO

49%

O

O

OCHO

BrOTIPSO

Me

H

HMe

Me

CrCl3, LiAlH4

81%

O

O

O

OTIPSO

Me

H

HMe

Me

HO Me

O

OH

OO

CHO

MeO2CH

H

O

OH

OO

MeO2CH

HTMS

OH

Br TMS

CrCl2, NiCl2

81%

dr = 10:1

*

*


Negishi Coupling ! ! !

• Ei-ichi Negishi: Nobel Prize 2010

For palladium-catalyzed cross couplings in organic synthesis. Shared Prize with Heck and Suzuki

R ZnCl + XR' R

R'Pd




- Pd (or Ni) catalyzed reaction of aryl or vinyl halide with an organozinc reagent

X = Cl, Br, I, OTf, OAc R = aryl, vinyl, allyl, benzyl, 1° alkyl Pd cat: Pd(PPh3)4, Pd2(dba)3, Cl2Pd(PPh3)2, etc.

Pd(0) cat+ R ZnXX R



• mechanism

oxidativeaddition

transmetallation


LnPd0X

PdL

LX

II

R ZnXZnX2

PdL

LR

II

R



• examples

O Me

O

TfO

Me

Me2ZnPd(PPh3)4

84%

O Me

O

Me

Me

OTHP

I tBuLi (2 equiv);then ZnCl2

OTHP

ClZn I

OSEM

OTBDPS

Pd(PPh3)4OTHP

SEMO OTBDPS

84%



• examples

IO

O

OTBS

ZnBr

O

O

OTBSPd(dba)2, TFP

80%

cross coupling reactions -...

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