catalytic cross-coupling reactions with unactivated alkyl electrophiles and alkyl nucleophiles heng...

Catalytic Cross-coupling Reactions with Unactivated Alkyl Electrophiles

and Alkyl Nucleophiles

Heng Su

04/11/2008

Department of Chemistry

Brandeis University

Outline

• Introduction General reaction pattern and mechanism

Difficulties for unactivated alkyl substrates

• Several Reaction Types Kumada type (RMgX by Mn/Cu/Ni/Pd)

Suzuki type (RBR’2 by Pd/Ni )

Negishi type (RZnX / R2Zn by Ni/Pd)

• Conclusion

• Outlook

General Reaction Pattern and Mechanism

Activated alkyl electrophiles:

RMX +

R'X'

M'Ln R-R'

M'Ln

LnM'R'

X'LnM'

R'

R

R'X'

RMXMXX'

R-R'Oxidative Addition

Transmetalation

Reductive Elimination

OH

O

R

Difficulties of Unactivated Alkyl Substrates

RMX +M'Ln R-R'

M'Ln

LnM'X'

LnM'R

R'

RMXMXX'

R-R'

X'

H

R'X'

H

H

R'R'

H

-hydride elimination

LnM'H

R+ R'

RH

-hydride elimination

LnM'H

X'+ R'

SlowSlow

Slow

M’ = Pd

accelerate accelerate

Kumada-type: Dramatic Enhancement by Additive

Cahiez, G. et al. Tetrahedron. 2000, 56, 2733

Kochi, J. et al. Synthesis 1971, 303

RMgBr + R'Br Li2CuCl4 (0.3%)

THF, 0°C, 3h0.9~0.94eqR R'

78~45% yieldR = 1° R' = 1°

N

ONMP:RMgCl + R'XLi2CuCl4 (3%)

THF, NMP (4eq)R R'

BrMgCl

BrMgCl

85% 8%

76% 5%

R' = 1°X = I Br OTs

R = 1° 2° 3°

with NMP without NMP

Alkyl Chlorides as Electrophiles: First Example

RMgX + R'X' NiCl2 (cat.)1,3-butadiene (10~100mol%)

THF, 0 °CR R'R = 1°

i-PrX = Cl, Br, OTs

R' = 1°

NiCl2 Pd(acac)2

Cl OTs

Br OTs

Br Ph

Ph Ph

Cl Et

Et EtEtMgBr

PhMgBr

cat.

cat.

87%

13%

86%

0%

27%

20%

69%

8%

Kambe, N. et al. Chem. Lett. 2003, 32, 890

Kambe, N. et al. J. Am. Chem. Soc. 2002, 124, 4222

MgCl n-Oct Br >99%

R'MgX' + RX Pd(acac)2 (1~3 mol%)1,3-butadiene (30~100 mol%)

THFR R'R = 1°

2°R = 1°X = Br OTs

MgCl n-Hep OTs

n-Oct ClMgCl N.R.

71%

NiCl2 Pd(acac)2

96%

45%

86%

Reaction Mechanism and EvidencesNi NiNiNi(0)

R'MgX'

R' MgX+ R'R

R' R

RX

NiNi(0)

Z

Z

Kambe, N. et al. Angew. Chem. Int. Ed. 2004, 43, 6180


NiR' MgX+

R3SiCl

NiR'

SiR3 SiR3

R'


Alkyl Fluorides as Electrophiles

RMgX + R'X'

CuCl2 (3 mol%)1,3-butadiene (10 mol%)

THF, r.t.R-R'

R = 1° 2° 3°

R' = 1°X' = Br F

1.3 eq

RMgX + R'X'

CuCl2 (2 mol%)

THF, refluxR-R'

R = 1° 2° 3°

R' = 1°X' = Br OTs OMs F Cl

1.5 eq

Ph CH3 (10 mol%)

R = n-Pent, Br>FR = Ph, F>Br



Br>OTs>OMs>F>Cl

Difference in Chemoselectivity

CuCl2 (3 mol%)1,3-butadiene (10 mol%)

n-Pent-MgBrn-NonFn-OctCln-DecBr

16%0%

40%

CuCl2 (2 mol%)

Ph CH3 (10 mol%)

n-OctFn-NonCln-DecBr

2%0%

98%

95%5%

didn't addn-BuMgCl


BrCl

+

CuCl2 (2 mol%)

Ph CH3 (10 mol%)

n-BuMgCl (1.1 eq)THF, 0 °C, 15min

t-BuMgCl (1.3 eq)THF, reflux, 3h

n-But-Bu

>98%

Cl

Cl

CuCl2 (2 mol%)

THF, 25 °C, 15 min

Ph CH3 (10 mol%)+ n-BrMgCl

n-Bu

Cl

89%

Kinetic Study and Proposed Mechanism


R' Cu

Ph Me

R' Cu

Ph MePh Me

Ph Me

Ph Me

RMgCl

R' Cu

Ph Me

R

(MgCl)+

R' Cu

Ph Me

R' Cu

Ph Me

(MgCl)+R

Ph Me

Active species

Decomposition

Resting state

Resting state

Fe Catalyst: Sec-alkyl Electrophiles

64%

43%

8%

n-NonMgBr n-BuBr

MgBr

n-HexMgBr Br

Br

Chai, C. L. L. et al. Adv. Synth. Catal. 2007, 349, 1015

RMgX + R'Br

Fe(OAc)2 (3 mol%)

Et2O, 25 °C, 15 min

Xantphos (6 mol%)R-R'

R = 1° R' = 1° 2°

64~43% yield O

PPh2 PPh2Xantphos

OMgBr

OMgBr

Br

Br

OPh

PhO

95% in isolated product

>96% in isolated product

Radical mechanism:

Brief Summary of Kumada-type Cross-coupling

3.

Fe(OAc)2 (3 mol%) +O

PPh2 PPh2Xantphos

2°alkyl electrophiles, radical

1. NiCl2 + 1,3-butadiene vs Pd(acac)2 + 1,3-butadiene

1°RCl

2°Chemoselectivity

-Ni complex

2. CuCl2 + 1,3-butadiene vs CuCl2 + 1-phenylpropyne

F

Chemoselectivity

Suzuki-type: Phosphine did Make Differences

R-9-BBN + R'IPd(PPh3)4

K3PO4, 1,4-dioxaneR-R'

R = 1° R' = 1° 71~45% yield

Fu, G.C. et al. J. Am. Chem. Soc. 2001, 123, 10099

Water is necessary:1. Non-hydrate salt gave no reaction.2. Non-hydrate salt + water gave

comparable yields

Suzuki, A. etc. Chem. Lett. 1992, 691

R-9-BBN + R'BrK3PO4H2O

THF, r.t.

R-R'

R = 1° R' = 1°93~58% yield

Pd(PPh3)4 (4 mol%)PCy3 (8 mol%)

1.2 eq

n-DecBr

n-Hex9-BBN

PCy3 (170°) 85%P(i-Pr)3 (160°) 68%P(t-Bu)3 (182°) <2%P(n-Bu)3 (132°) 9%

Alkyl Chlorides and Sulfonates as Electrophiles

Fu, G.C. et al. Angew. Chem. Int. Ed. 2002, 41, 1945


R-9-BBN + R'ClCsOHH2O (1.1 eq)

dioxane, 90 °C

R-R'

R = 1° R' = 1°83~65% yield

Pd2(dba)3 (5 mol%)PCy3 (20 mol%)

1.2 eq

n-DodecCl

n-Oct9-BBN

PCy3 85%PCyp3 57%P(i-Pr)3 53%

R-9-BBN + R'OTsNaOH (1.2 eq)dioxane, 50 °C

R-R'

R = 1° R' = 1°80~55% yield

Pd(OAc)2 (4 mol%)P(t-Bu)2Me (16 mol%)

1.2 eq

n-DodecOTs

n-Oct9-BBN

PCy2RP(t-Bu)2R

R =

i-Pr

44%<2%

Et

70%<2%

Me

48%78%

for PCy3: 46% yield

P(t-Bu)2Me [HP(t-Bu)2Me]BF4

Boronic Acids as Coupling Partners

RB(OH)2 + R'Clt-BuOK (3 eq)

t-amyl alcohol, r.t.

R-R'

R = 1° R' = 1°

Pd(OAc)2 (5 mol%)P(t-Bu)2Me (10 mol%)

1.5 eq

n-DodecBr

n-HexB(OH)2

P(t-Bu)2Me [HP(t-Bu)2Me]BF4

66% 62%

Br Ph

+

PdL L

L = P(t-Bu)2Me

Et2O

0 °C94%

Pd

Ph

L

Br

L

o-tol-B(OH)2 (1.1 eq)t-BuOK

t-amyl alcoholr.t.

94%

lot-o Ph


How do Phosphine Ligands Effect?

M'Ln

LnM'X'

LnM'R

RMXMXX'

R-R'R'

X'

H

H

R'R'

H

LnM'H

X'+ R'

LnM'H

R+ R'

RH

Increase electron density

Raising empty obital energyIncrease steric hindrance


PdP Pt-Bu

t-Bu

t-Bu

t-Bu PdP Pt-Bu

t-Bu

t-Bu

t-Buvs

RX

Sec-Alkyl Electrophiles


R-9-BBN + R'X

NiCl2•glyme (6 mol%)L (8 mol%)

L =t-BuOK (1.2 eq)i-BuOH (2.0 eq)

dioxane, r.t.

R-R'

R' = 1° 2°X = Br I

R = 1°1.8 eq 94~64%

MeHN

MeHN

Ph 9-BBN

Br

Br

PhMe

Br

TBSO 9-BBNMe I

Me

75%

75%

82%

94%

Brief Summary of Suzuki-type Cross-coupling

3. Ni + diamine: 2°electrophiles

1. RI, RBr, RCl, ROTs: phosphine ligand, base

2. Electronic effect and steric effect of PR3

Negishi-type: Styrene Additive

Br

Bu

BrMe

Bu

Ni(acac)2 (7.5 mol%)LiI (20 mol%)

Et2Zn

-35 °C, THF18h

Et

Bu

XZnMe

Bu

82%

>85%

Ni

R

X Ni

R

R'R'2Zn

Knochel, P. et al. Angew. Chem. Int. Ed. 1995, 34, 2723


PhI

O

nNi(acac)2 (10 mol%)

Pent2Zn

THF/NMP-35 °C, 4h

PhPent

O

n

65% (n = 2)71% (n = 3)

BuI

O

3 BuPent

O

3

20%71%

PhCOMe (0 eq)PhCOMe (1 eq)

BuZnI

O

+

57%<5%

O2N NO23

CF3

suitable

Replace Diorganozinc by Organozinc Halide

RZnI / R2Zn + R'X

Ni(acac)2 (10 mol%)THF/NMP

R R'

F(20 mol%)

THF/NMP 2:1-5°C, 16h

73~55%3eqR' = 1°X = I Br

R = 1° 2°

TBAI (3eq) for RZnI

Zn

I

R I

R2Zn + R'I

[Ni(acac)2] (10 mol%)THF/NMP

CF3

O

or

R R'

78~66%R = 1° R' = 1°2 eq


Knochel, P. et al. J. Org. Chem. 2002, 67, 79

n-Pent2Zn

PhS(CH2)3I

N I

O

71%

70%

i-Pr2Zn PhCO(CH2)3I

c-HexZnI

N Br

O

63%

63%

n-Pent2Zn 55%

Pd-Catalyzed Coupling

RZnX + R'X'

Pd2(dba)3 (2 mol%)PCyp3 (8 mol%)

R R'NMI (1.2 eq)THF/NMP 2:1

80 °C, 14h

97~48%R' = 1°X' = I Br Cl OTs

R = 1°X = Br

1.3 eq

RZnX (1.6 eq)[HPCyp3]BF4

RZnX (1.3 eq)PCyp3

EtOZnBr

O

NCBr

65%

N I

O

O

n-BuZnBr

n-BuZnBrBr

Cl

48%

70%

BnO Brn-BuZnBr 70%

Fu, G. C. et al. J. Am. Chem. Soc. 2003, 125, 12527

PCy3P(i-Pr)3P(t-Bu)2Me

65%59%55%

Pd-NHC Catalyst

RZnBr + R'BrPd2(dba)3 (2 mol%)

NHC (8 mol%) R R'THF/NMP 2:1

r.t., 24h 92~61%R' = 1°R = 1°

1.3 eq NHC =

n-BuZnBr: When R is large

Organ, M. G. etc. Org. Lett. 2005, 7, 3805

Organ, M. G. et al. Chem. Eur. J. 2006, 12, 4749

RZnX + R'X' Pd-NHC (1 mol%) R R'THF/NMP or THF/DMI

LiBr/Cl (3.2 eq)r.t., 24h

87~70%R' = 1°X' = I Br Cl OTf OTs OMs

R = 1°X = Br Cl

1.6 eq

Pd-NHC =

LiBr/Cl: form zincate

Sec-Alkyl Halides as Electrophiles

NO

N N

O

s-Bu s-Bu

RZnX + R'X'Ni(cod)2 (10 mol%)

s-Bu-Pybox (8 mol%) R R'DMA, r.t.

88~62%R' = 1° 2°X' = I Br

R = 1°X = I Br

MeI

Me MeBrZn Ph 73%

TsN BrIZn Me

Me66%

BrMe

Men-NonZnBr 91%

Fu, G. C. et al. J. Am. Chem. Soc. 2003, 125, 14726

t-Bu-Pyboxi-Pr-PyboxPh-PyboxIndanyl-Pybox

<5%71%80%42%

NO

N N

OH

H H

H

Enantioselective Negishi Cross-coupling

Bn R'

Ph Br

O

X

R'

RZnX (1.6 eq)NiCl2·glyme (10 mol%)

(R)-(i-Pr)-Pybox (13 mol%)solvent, 0 °C

racemic

racemic

X = Br Cl

or

Bn R'

Ph R

O

R

R'

or

90~51% yield96~77% ee

89~39% yield99~75% ee


RZnBr (1.2 eq)NiCl2·glyme (5 mol%)

(S)-(BnCH2)-Pybox (5.5 mol%)NaCl (4.0 eq)

DMA/DMF (1:1), -10 °Cracemic 97~57% yield

96~81% ee

R1 Me

Cl

R1 Me

R

R2 R2

R1 = n-Bu, regioselectivity = 1.9:1 = others, >20:1

Fu, G.C. et al. J. Am. Chem. Soc. 2005, 127, 4594Fu, G.C. et al. J. Am. Chem. Soc. 2005, 127, 10482

Radical or Nonradical Pathway?

N

N N

RZnBr + R'Iterpyridine-Ni-Me (5 mol%)

R R'THF, r.t.

65~60%R' = 1°R = 1°

Ni

Me

NNi

N Me

Meterpyridine N

N NNi

Me

N

N NNiMe Me

+ CH3

ethane

NNi

N Me

Me

terpyridine (2eq) N

N NNi

Me

+ 1eq ethane2eq- 1eq ethane

terpyridine-Ni(II)Me2+ terpyridine-Ni(0)

Vicic, D. A. et al. J. Am. Chem. Soc. 2006, 128, 13175

Only C2H6 and C2D6 was observedNNi

N CD3

CD3

Formal Synthesis of Fluvircinine A1


NH

OMe

OH

Me

Et

NHCbz

O

Me

Et

EtO2C

Me

Cl

BrZn

O

OCl

CO2Et

Et

Fluvirucinine A1 1

Formal Synthesis of Fluvircinine A1: Retrosynthesis


CO2Et

Me

Et

EtO2C

Me

Cl

BrZn

O

O

Cl

CO2Et

Et

racemic

Ni* (5 mol%)

93% EtO2C

Me

O

O

>20:1 regioselectivity96% ee

Me

O

O

Br

racemic

Zn, I2;Ni* (5 mol%)

82%

1. H2, Pd/C; LiAlH42.

O

O

SCbzN NEt3

O O

then HCl

58%1

Brief Summary of Negishi-type Cross-coupling


3. Pd-NHC: broad scope of electrophiles

1. Ni(acac)2 +

2. Pd2(dba)3 + PCyp3: alkyl chloride

O

F

CF3

: R2Zn / RZnI, radical

4. Ni + Pybox: 2° electrophiles and enantioselective cross-coupling

5. Terpyridine-Ni-Me: nonradical

Conclusion

RMX

R'X'

Catalysts

Compatible with

I, Br, Cl, F,OTf, OMs1°,2°

I, Br, Cl, OTf, OMs, OTf1°,2°

I, Br, Cl, OTf1°,2°

Ni, Pd, Cu, Fe Pd, NiNi, Pd

Additives/Ligands1,3-butadiene,1-Phenylpropyne,tetraene, xantphos

PCy3, P(t-Bu)2Mediamine

styrene, phenyl methyl ketone,PCyp3, NHC, Pybox, terpyridine

RMgX1°,2°,3°

R2Zn, RZnX1°,2°

RBR'21°

ether,acetal

ether, acetal,ketone, ester,tertiary amide,nitrile, thioether,thioacetal, carbamate

alkyne, ether, acetal,silyl, tertiary amine,ketone, ester, amide,nitrile, thioether, thioacetal,sulfone, carboxylic acid,tertiary alcohols,aqueous solvents

Outlook

• Unactivated tertiary alkyl chlorides as electrophiles

• Tertiary alkyl boron compounds as nucleophiles

• Enantioselective cross-coupling of unactivated electrophiles

Acknowledgement

AdvisorProfessor Dr. Li Deng

Group members

Dr. Yanbiao KangDr. Ravi P. Singh

Keith BartelsonJung Hwa LeeTeresa Marshall

Dr. Yan LiuDr. Bingfeng Sun

Jihan KhanXiaojie LuBrian Provencher

catalytic cross-coupling reactions with unactivated alkyl electrophiles and alkyl nucleophiles heng...

Documents