The Heck Reaction

The Heck reaction is a palladium-catalyzed C-C coupling between aryl halides or vinyl halides (or triflates) and
Activated alkenes in the presence of base.

Example:
Pd(OAc)2 OCH3

+ PPh3
Br OCH3
O
Et3N
O

Mechanism:

migratory
 The Cationic Heck Reaction: Use of Silver Salts

Pd(II)

2 PPh3; 2e
AgHCO3
PhBr
Pd(0) L2

AgCO3- H–Pd(II)L2+
Ph––Pd(II)––Br

Ag+
R Ph
AgBr
!-Hydride elim Ph––Pd(II)+

H L2+(II)Pd Ph
L2+(II)Pd
Ph H R
R R H
H
cis-complex

cationic palladium complex is more reactive toward pi-complexation of alkenes!

 Examples
SiMe3

SiMe3
I
+ desilylation at elevated
Pd(OAc)2, Et3N temperatures!
DMSO, 100°C
12% 57%

SiMe3

SiMe3 SiMe3 OTf

I

Pd(OAc)2, Et3N JOC 1988, 4909

Pd(OAc)2, Et3N
AgNO3 DMSO, DMSO, 50°C
50°C
64%

Reversible !-hydride elimination leads to alkene isomerization:

Pd Pd
H
H H

R R
R

The use of silver slats minimizes alkene isomerization:

I Pd(OAc)2 Ag2CO3 eq. Yield A

PPh3 1 35
+
DMF 2 80
N N N
SO2Ph SO2Ph SO2Ph

A: desired B: by-product Lifetime of HPd(II)L2+ is short in presence

JOC 1987, 4133 of base
 Details of Heck Reaction

Catalysts: Pd2(dba)3, Pd(OAc)a

Solvents: toluene, THF, DMF

Soluble bases: Et3N, H3C CH3 Insoluble bases: K2CO3, Ag2CO3

H3C N CH3

CH3

PMP

Phase Transfer Catalysis: stabilization of Pd complexes by halide ions; allows lower reaction temperatures

O
Pd(OAc)2
O NaHCO3
I
OCH3 99% with nBu4NCl
+ OMe 2% without nBu4NCl
DMF, 50°C
nBu4NCl
Tet. 1996, 10113

Heck Coupling of Aryl Chlorides

O
Pd2dba3
O P(tBu)3
Cl
OCH3
+ OMe JOC, 1999, 10
CsCO3 H3CO
H3CO
dioxane, 82%
120°C
 Regiochemistry of Heck Reactions

Neutral Pd complexes: regiochemistry governed by sterics

40
20
10
O
Ph
N CH3
100 OH

90 OH 80
60
Y

100
Y=CO2R
CN
CONH2
Cationic Pd complexes: regiochemistry governed by electronics; addition to the site of least electron density
40
100

95 90
O
Ph
N CH3
60 OH

5 OH 10
Y

100 Y=CO2R
CN
CONH2 Acc. Chem. Res. 1995, 2.
JOC, 1992, 1482.
 Ring Closure Using the Heck : Endo vs. Exo

X
H
Exo Pd(II)Ln Endo

Useful for macrocyclizations:

O
O

PdCl2(CH3CN)2 Tet, 1981. 4035.

Et3N
H I CH3CN

O
O

O
O

Five, Six, and Seven-membered ring closure gives predominantly exo products:

OCH3

DBSN
OBn
Pd(OCOCF3)2
PMP, toluene
120°C JACS, 1993, 11028.
I
BnO DBSN
OMe
 Tandem Reactions
When β-hydride elimination is not possible, additional reaction pathways may ensue:

R2
Heck-sp2
R1–Pd–X R3
carbonylation
CO2CH3 PdX PdX
CO, CH3OH R3
R1 R1 R1
R2 R2 R2

R3–X
R3
R3

R3
PdX
R1 Heck-sp3
R2 R1
R2
alkylation

Tandem Heck Reactions:

R I LnPd CH3
PdLn
Pd(OAc)2
PPh3 OR

OR Ag2CO3
THF, 65°C
RO OR
JOC, 1993, 5304
JACS, 1999, 5467.
Tandem Heck Reactions, continued:
PdLnBr
Pd(OAc)2, H
BrLnPd
PPh3
Ag2CO3
Br
HO HO
CH3CN, 80°C
OH

Tet, 1996, 11545

6!-electrocyclization

HO HO

Tandem Suzuki-Heck:
85%
H3C

9-BBN I OR
TfO
TfO TfO
CO2Me PdCl2(dppf)
CO2Me CO2Me
AsPh3
B
CsHCO3, DMSO
85°C
OR

TL, 1997, 3455

Me
RO

CO2Me
 Asymmetric Heck Reactions
Pd2(dba)3, provides a chiral
TfO L (6 mol%) H
L= environmanet for Pd
+ O
O iPr2NEt O
PPh2 N

99%ee

Chiral BINAP ligands for Pd:

PPh2 PPh2

PPh2 PPh2

S-BINAP R-BINAP

Pd2dba3
R-BINAP
Ag3PO4 92%ee
Synlett, 1995, 597
DMF
SiMe3 H

Pd(OAc)2 CO2CH3
CO2CH3
R-BINAP
JACS, 1994, 11737
K2CO3
TfO KOAc H

86%ee
 Asymmetric Heck Reactions, Continued

Pd(OAc)2
R-BINAP
JACS, 1993, 8477
H3CO OTf K2CO3, THF H3CO
OR 60°C H3C OR

90%ee

H3CO I OR H3C
Pd2dba3 3M HCl CHO
O
S-BINAP O
N N
CH3 PMP, DMA CH3

95% ee

JACS, 1998, 6500