13 heck 3 20 17

Myers

Chem 115

The Heck Reaction

Reviews:
Felpin, F.-X.; Nassar-Hardy, L.; Le Callonnec, F.; Fouquet, E.Tetrahedron 2011, 67, 2815–2831.

• Pd(II) is reduced to the catalytically active Pd(0) in situ, typically through the oxidation of a
phosphine ligand.

Belestskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009–3066.
• Intramolecular:
Link, J. T.; Overman, L. E. In Metal-catalyzed Cross-coupling Reactions, Diederich, F., and

Pd(OAc)2 + H2O + nPR3 + 2R'3N

Eds.; Wiley-VCH: New York, 1998, pp. 231–269.

Pd(PR3)n-1 + O=PR3 + 2R'3N•HOAc

Gibson, S. E.; Middleton, R. J. Contemp. Org. Synth. 1996, 3, 447–471.
Ozawa, F.; Kubo, A.; Hayashi, T. Chemistry Lett. 1992, 2177–2180.
• Asymmetric:
McCartney, D.; Guiry, P. J. Chem. Soc. Rev. 2011, 40, 5122–5150.

• Ag+ / Tl+ salts irreversibly abstract a halide ion from the Pd complex formed by oxidative
addition. Reductive elimination from the cationic complex is probably irreversible.

• Solid phase:

Franzén, R. Can. J. Chem. 2000, 78, 957–962.
• Dehydrogenative:

• An example of a proposed mechanism involving cationic Pd:

Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170–1214.
General transformation:
Pd(II) or Pd(0) catalyst

R–X

+

Pd catalyst

Ph–Br
R'

R = alkenyl, aryl, allyl, alkynyl, benzyl

R'

R

base
X = halide, triflate

CH3O2C

R' = alkyl, alkenyl, aryl, CO2R, OR, SiR3

Pd(II)
AgCO3–

reductive elimination
Mechanism:
Pd catalyst

CH3O2C
2 L; 2 e –

KHCO3 + KBr
K2CO3
H–Pd(II)L2–Br

Ph–Pd(II)L2–Br

syn elimination
CH3O2C

oxidative addition

internal rotation

CH3O2C

Ph
H
CH3O2C

H
CH3O2C

Pd(II)L2Br
H
Ph
H

H
CH3O2C

internal rotation

Pd(II)L2Br
Ph
H
H

Ph–Br

oxidative addition

Ph–Pd(II)L2–Br

Ph

syn elimination
Ph–Br

Pd(0)L2

Pd(0)L2

H–Pd(II)L2+

Ph

CH3O2C
Pd(II)

reductive elimination

2 L; 2 e –

AgHCO3

CH3O2C

Ph

HX

+

• Proposed mechanism involving neutral Pd:

Ph–Br

CH3O2C

Ag+

Ag +
AgBr

Pd(II)L2+
H
Ph
H

Ph–Pd(II)L2

H
CH3O2C

Pd(II)L2+
Ph
H
H

halide abstraction

+

CH3O2C

syn addition

syn addition
Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4133–4135.

Andrew Haidle, James Mousseau


Myers

Chem 115

The Heck Reaction

• Reactions with vinyl or aryl triflates often parallel those of the corresponding halides in the
presence of silver salts in yields.
TMS

TMS
I

I

Time, h

Yield, %

PPh3 (6 mol %)

1

24

50

DMF, 23 °C

1

48

35

2

5

80

N
SO2Ph

I

Pd(OAc)2 (3 mol %)

Ag2CO3, eq

Pd(OAc)2 (3 mol %)
N
SO2Ph

Et3N
DMSO, 100 °C, 15 h

57%

12%

CH3

30%
Sakamoto, T.; Kondo, Y.; Uchiyama, M.; Yamanaka, H.

GC yields
TMS

TMS
I Pd(OAc)2 (3 mol %)

By-product:
N
SO2Ph

J. Chem. Soc. Perkin Trans. 1 1993, 1941–1942.

TMS
OTf

Pd(OAc)2 (3 mol%)

AgNO3, Et3N

Et3N

DMSO, 50 °C, 3 h

DMSO, 50 °C, 3 h

64%

61%

• With some ligands, experimental evidence points to a Pd(II)/Pd(IV) catalytic cycle.
Ohff, M.; Ohff, A.; van der Boom, M. E.; Milstein, D. J. Am. Chem. Soc. 1997, 119, 11687–11688.
Shaw, B. L.; Perera, S. D.; Staley, E. A. J. Chem. Soc., Chem. Commun. 1998, 1361–1362.
Sehnal, P.; Taylor, R. J. K.; Fairlamb, I. J. S.; Chem. Rev. 2010, 110, 824–889.

Karabelas, K.; Hallberg, A. J. Org. Chem. 1988, 53, 4909–4914.
• Reversible !-hydride elimination can lead to alkene isomerization.
H–Pd

*

*

*

Conditions:

Pd H

Pd

Pd(OAc)2

• Catalysts:

Pd2(dba)3

• Use of silver salts can minimize alkene isomerization.

stable Pd(0) source; useful if substrate
O

O

CH3
N

O

most common

CH3
N

is sensitive to oxidation
O

N
CH3 I

dba

=

Conditions
Pd(OAc)2 (1 mol %)
PPh3 (3 mol %)
Et3N (2 equiv)

• Ligands: Phosphines (PR3), used to prevent deposition of Pd(0) mirror.
1 : 1
• Solvents: Typically aprotic; a range of polarities.

acetonitrile, 3h, reflux
as above, plus
AgNO3 (1 equiv) and 23 °C

26 : 1

Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4133–4135.

Solvent
Dielectric constant

toluene

THF

1,1-dichloroethane

DMF

2.4

7.6

10.5

38.3
Andrew Haidle, Fan Liu


Myers

Chem 115

The Heck Reaction
Regiochemistry of addition:

• Bases: both soluble and insoluble bases are used.
Soluble examples

Insoluble examples

Et3N

CH3
CH3
N
CH3
CH3
CH3

K2CO3

• Neutral Pd complexes: regiochemistry is governed by sterics; position of Ar attachment:
10

Ag2CO3

CH3

Ph

OH

1,2,2,6,6-pentamethylpiperidine (PMP)
40

• Jeffery conditions: The combination of tetraalkylammonium salts (phase-transfer catalysts) and

CO2CH3

Pd(OAc)2 (5 mol %)
NaHCO3, 3Å-MS
DMF, 50 °C, 2 h
Equiv. of n-Bu4NCl

GC Yield(%)

0

2

1

99

Jeffery, T. Tetrahedron 1996, 52, 10113–10130.

20
O

insoluble bases accelerates the rate to the extent that lower reaction temperatures are possible.

CO2CH3

100

90

100

I

Y

N

100

• Cationic Pd complexes: regiochemistry is affected by electronics. The cationic Pd complex

increases the polarization of the alkene favoring transfer of the vinyl or aryl group to the site of
least electron density.

95

40

5
100

Y

N

100
Pd2(dba)3 (1.5 mol %)
P(t-Bu)3 (6 mol %)

CO2CH3

Cs2CO3 (1.1 equiv)
dioxane, 120 °C, 24 h
82%

CH3O

95

90

O
• Conditions for the Heck coupling of aryl chlorides have been developed.

OH

OH

60

Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991, 113, 8375–8384.

100
CH3

Ph

likely to decompose under the Heck reaction conditions.

CH3O

mixture

80

Y = CO2R
CN
CONH2

complexes can be stabilized by the coordination of halide ions; thus, the catalyst is less

CO2CH3

OAc

OH

60

• One proposed explanation for this rate enhancement is based on the fact that palladium

Cl

OH

OAc

OH
10

5

Y = CO2R
CN
CONH2
Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7.
Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J. Org. Chem. 1992, 57, 1481–1486.

Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10–11.

Andrew Haidle

Myers

Chem 115

The Heck Reaction

• A major issue in intramolecular Heck reactions is the mode of ring closure, i.e., exo versus endo.

• Conformational effects are more important when forming

endo

the reaction, even if this means the rest of the molecule
H

PdLn

exo

endo

LnPd

LnPd
R

smaller rings. The eclipsed orientation is preferred for

R

eclipsed

must adopt a less than ideal conformation.

twisted

O
O
exo

I

stereochemistry defines the
incipient quaternary center

O
• For large rings, conformational effects can be minimal. If a neutral Pd complex is used, sterics

NHCO2CH3
O

enforce endo selectivity.

O

• The Heck reaction is useful for macrocylization.

Pd(OAc)2 (10 mol %)

O
I
O

PPh3 (40 mol %)

O

Ag2CO3, THF, 66 °C

PdCl2(CH3CN)2 (100 mol %)

73%

Et3N
CH3CN, 25 °C
55%

CH3 H O

O

O
CH3

H

PdLn

O

CH3O2CN
H

NHCO2CH3
O

O

PdLn
O

H
O

• Five-, six-, and seven-membered ring closures (the most efficient Heck ring closures) give
predominantly exo products.

H
I
OBn

O

O

H
O
CH3O2CN
H

O

OBn

O

O

DBSN

O

> 20 : 1
H
O
O

OH
(–)-Morphine

O

OH
H

CH3N
DBS = dibenzosuberyl

O

NHCO2CH3

OCH3

60%

O

twisted (chair)

O

(10 mol %)
PMP, toluene, 120 °C

CH3O

eclipsed (boat)

O
Pd(OCOCF3)2(PPh3)2

DBSN

O

O

Ziegler, F. E.; Chakraborty, U. R.; Weisenfeld, R. B. Tetrahedron 1981, 37, 4035–4040.

H

Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 11028–11029.

CH3O

OH
O

N
H CH
3

(±)-6a-epipretazettine

Overman, L. E. Pure & Appl. Chem. 1994, 66, 1423–1430.
Andrew Haidle


Myers

• Variation of reaction conditions can greatly influence exo versus endo selectivity in small rings.

Pd(OAc)2 (6 mol %)

NHR

N

CH3O

O

N

O

CH3O

NHR

NHR
N

CH3

CH3O

O

O

H

OBn

O

4Å MS, 90 °C

O

49%

O

O
N
H

syn addition

Ar

H–Pd–X

R

!-H elimination
Ar

R

Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170–1214.
• Early examples of dehydrogenative processes did not employ oxidants and were stoichiometric in
palladium.

O
O

Ar–Pd–X

PdX
O2, HPMo11V, PhI(OAc)2,
benzoquinone, t-BuOOH,
KMnO4, Na2S2O8, Cu(OAc)2

O

H3C

• Steric and electronic effects begin to
compete with conformational effects
when forming medium–sized rings.

H–X

H–X

O

H OBn

Ar–H

Pd0

CH3
CH3

K2CO3, CH3CN
O

Some oxidants:

oxidative addition
PdX2

oxidant

CH3 OTBS

HX

R' = alkyl, alkenyl, aryl, CO2R, OR, SiR3

reduced oxidant

Catalyst
Regeneration

Pd(PPh3)4 (100 mol %) CH3

+

Mechanism:

32%

CH3

X = halide, triflate

O

Rigby, J. H.; Hughes, R. C.; Heeg, M. J. J. Am. Chem. Soc. 1995, 117, 7834–7835.

R

Ar

base

• Proposed mechanism:

CH3O

Et3N, CH3CN
80 °C, 2 h

• The authors' rationale for these results is that under the Jeffery conditions, the coordination sphere
of palladium is smaller, and thus the metal can be accommodated at the more substituted alkene
site during migratory insertion.

OTBS

Pd(II) catalyst, oxdidant
R

R = alkenyl, aryl, allyl, alkynyl, benzyl

TBSO

PPh3 (6 mol %)

O

CH3 CH3

+

Ar–H

TBSO
Pd(OAc)2 (2 mol %)

N

CH3O

KOAc, DMF
80 °C, 22h

General transformation:

58%

I

CH3O

NHR

CH3O

OTBS

TBSO

• An oxidant is required.

TBSO

n–Bu4NCl

I

CH3O

Dehydrogenative Process
• It is possible to generate an aryl palladium(II) intermediate for Heck coupling from an arene by C–H
insertion.

TBSO

OTBS

TBSO

TfO

Chem 115

The Heck Reaction

CH3
O

OH

• Mechanistic studies suggest a concerted metallation-deprotonation sequence for C–H insertion,
facilitated by acetate.

O
O
OH
CH3
CH3
CH3

OH O
O

H

Pd(OAc)2 (1 equiv)
O
CH3

O

MeO

AcOH
63%

MeO

O

Taxol
Masters, J. J.; Link, J. T.; Snyder, L. B.; Young, W. B.; Danishefsky, S. J. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1723–1726.

Fujiwara, Y.; Moritani, I.; Asano, R.; Tanaka, H.; Teranishi, S. Tetrahedron 1969, 25, 4815–4818.
Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848–10849.
Andrew Haidle, James Mousseau


Tandem Reaction:

• Control of regioselectivity may be problematic with substituted arenes.

• Additional reaction pathways become available when the initial Pd–C species does not (or can not)
decompose via !-hydride elimination.

• In the case below, benzoquinone (BQ) was the oxidant and silver carbonate was essential.
Pd(OAc)2 (5 mol %)
BQ (2 equiv)
Ag2CO3 (0.6 equiv)

OAc
Cl
100 equiv

n-BuCO2H (16 equiv)
100 °C, 48 h

1 equiv

Cl
34 : 36 : 30 o : m :p

Me

CO2n-Bu

O

MeO

Cl

H
N
O

!-hydride
elimination

CH3OH

R3
R1

Oxidation, Nu

R2

–

Alkylation
Nu

R1
R1

82%

Heck sp cascade

R3–X

R2

Carbonylation

R2

R2

CO
CO2CH3

CO2n-Bu

R1

R2

R1

R3

PdX

R3M

Me

R1

R1PdX

R3

Transmetalation

MeO

AcOH, PhMe
22 °C, 16 h

R2

M
R1

• Directing groups may be applied to control the site of reaction.

H
N

R2

Heck sp2 cascade

Pan, D.; Yu, M.; Chen, W.; Jiao, N. Chem. Asian J. 2010, 5, 1090–1093.

Pd(OAc)2 (5 mol %)
BQ (1 equiv)
TsOH•H2O (1 equiv)

PdX

PdX
R1

52%

Cl

R3

R3
OAc

R2

R2
Nucleophilic attack

Heck reaction

Lee, G. T.; Jian, X.; Prasad, K.; Repic, O.; Blacklock, T. J. Adv. Synth. Catal. 2005, 347, 1921–1924.
• Various heterocycles are effective substrates, including indoles, thiazoles, oxazoles, pyrroles,
furans and activated pyridines.

• Tandem Heck reactions:
R

I

• Site selectivity with pyrrole substrates can be achieved by the use of directing (carbamate) or
blocking (triisopropylsilyl) groups on the nitrogen atom.

H
TBSO

Pd(OAc)2 (10 mol %)

PhCO3t-Bu (1 equiv)
N
R

CO2Bn

AcOH, dioxane, DMSO
t-BuO
35 °C, 24–48 h

R = CO2t-Bu
or
Si(i-Pr)3

TBAF, THF, 23°C

75%

N
O

CO2t-Bu

dioxane, 100 °C, 12 h
91%

CH3

N
O

CO2t-Bu

CH3

O
CH3

81%

Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528–2529.
Pd(OAc)2 (10 mol %)
Ag2CO3 (1.5 equiv)
pyridine (1 equiv)

82%

N
Si(i-Pr)3

O

H
OTBS

CO2Bn

N

R

H

CH3

CH3

CO2Bn

OTBS

R

Ag2CO3, THF, 65 °C

CH3

PdLn

LnPd

Pd(OAc)2 (10 mol %)
PPh3 (20 mol %)

R =

H

O
O

HO2C
HO

H

R
H

O

OH
O

Scopadulcic acid A
Kucera, D. J.; O'Connor, S. J.; Overman, L. E. J. Org. Chem. 1993, 58, 5304–5306.
Fox, M. E.; Li, C; Marino, J. P.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 5467–5480.

Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254–9256.

Andrew Haidle, James Mousseau


• Tandem Heck/!–allylpalladium reactions

• Tandem Heck reaction, intermolecular
H3C
H3C
TDSO

OTBS

CH3
H

CH3

Pd2(dba)3 (5 mol %)
PPh3 (48 mol %)
Et3N, toluene
120 °C, 1.5 h

H
Br

CH3O2C

OCH3

N
H

H3C
H3C

CH3O

PdLn

N

56%

OH

CH3
H

PMP, toluene, 120 °C

I

CH3O

OH

O

Pd(TFA)2(PPh3)2 (20 mol %)

76% overall

CH3
OH

OCH3

H
O
PdLn

OH

O

H

CH3N

CH3O

H

TDSO

O
N

(–)-Morphine

TBSO

Hong, C. Y.; Overman, L. E. Tetrahedron Lett. 1994, 35, 3453–3456.

• Tandem Suzuki/Heck reactions
H3C
H3C
H3C
H3C
TBSO

CH3

CH3
CH3

CH3
H

[1,7]-H-shift

H

1:9

TDSO

H

H3C
O
I

9-BBN
TfO

TfO

H
CO2CH3

H
CO2CH3

OTDS

PdCl2(dppf) (10 mol %)
AsPh3 (10 mol %)
CsHCO3, DMSO, 85 °C

OTBS

H3C O

TBAF
THF
79%

OH

H3C O

O

CH3
CH3

HO

H3C O

B
TDSO

H3C
H3C

CH3

Alphacalcidiol

TDSO

H3C O

O

O

H3C
H
CO2CH3

65%

TfO
CH3

H
CO2CH3

OTDS
Kojima, A.; Honzawa, S.; Boden, C. D. J.; Shibasaki, M. Tetrahedron Lett. 1997, 38, 3455–3458.

Trost, B. M.; Dumas, J.; Villa, M. J. Am. Chem. Soc. 1992, 114, 9836–9845.

Andrew Haidle


• The ease of reaction (Heck versus Suzuki) is highly dependent upon the reaction conditions:

Enantioselective Heck Reactions:

Pd(OAc)2 (1 mol %)

• Typical yields = 50–80%

PPh3 (5 mol %)
B
O

O

CH3
CH3

:

87

• Formation of tertiary stereocenters:

H3CO

CH3 CH3
I

13

Bu3N, CH3CN, 120 °C

O

O
OCH3

B
O

OCH3

Pd(OAc)2 (5 mol %)

O

Phenanthroline (5 mol %)

O

Pd2(dba)3•CHCl3 (2.5 mol %)

CH3O

CH3
+
CH3

I

CH3

Si(CH3)3

Ag3PO4 (1.1 equiv)
DMF, 48 h, 80 °C

Pd[(R)–BINAP]2 (3 mol %)
(CH3)2N

CO2Et

• Tandem Heck/6!-electrocyclization reactions:

BrPdLn
EtO2C

N
H3CO2C
benzene, 60 °C, 20 h

H

Ag2CO3 (2 eq)
CH3CN, 80 °C, 3 h

H CO2Et

N(CH3)2

N
CO2CH3

OTf

Pd(OAc)2 (3 mol %)
PPh3 (6 mol %)
OH

7-Desmethyl-2-methoxycalamenene

Tietze, L. F.; Raschke, T. Synlett 1995, 597–598.

Hunt, A. R.; Stewart, S. K.; Whiting, A. Tetrahedron Lett., 1993, 34, 3599–3602.

EtO2C
EtO2C

H

100

t-BuOK, CH3CN, 45 °C

Br

CH3

91%, 92% ee
:

CH3O

(R)–BINAP (7.0 mol %)

H3C CH3
0

• Typical ee's = 80–95%

95%, > 99% ee

HO
CO2Et

• Note that the alkene within the intially formed pyrrolidine has migrated under the reaction conditions.
Ozawa, F.; Kobatake, Y.; Hayashi, T. Tetrahedron Lett. 1993, 34, 2505–2508.
PdLnBr

CO2CH3

H

EtO2C

85%

CO2Et

EtO2C

CO2Et

CO2CH3

H

HO

K2CO3 (2 equiv)

TfO

HO
EtO2C
CO2Et

O

H

(+)-Vernolepin

Ohari, K.; Kondo, K.; Sodeoka, M.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 11737–11748.

TfO
Me
Me
OH

H3CO
CO2Et

Li2CO3, C6F6
80 ºC, 71%
L = (+)-Menthyl(O2C)-Leu-OH

H3CO

Me
Me
O

O
O

ClCH2CH2Cl, 60 °C, 41 h

• Tandem dehydrogenative Heck/oxidative cyclization

Pd(OAc)2 (10 mol %)

L (40 mol %)
AgOAc (4 equiv)

H

KOAc (1 equiv)
70%, 86% ee

Henniges, H.; Meyer, F. E.; Schick, U.; Funke, F.; Parsons, P. J.; de Meijere, A. Tetrahedron 1996, 52,
11545–11578.

OH

O

(R)–BINAP (10 mol %)

H
HO

Pd(OAc)2 (5 mol %)

O

Pd2(dba)3 (3 mol %)
L (6 mol %)
(i-Pr)2NEt
benzene, 30 °C, 72 h

H

O

O
L=

Ph2P

N
t-Bu

92%, > 99% ee

CO2Et

Lu, Y.; Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc, 2010, 132, 5916–5921.

Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis 1997, 1338–1345.
Andrew Haidle, James Mousseau


• Formation of quaternary stereocenters:
CH3
CH3O

• Kinetic Resolution:
Pd(OAc)2 (7 mol %)

(R)–BINAP (17 mol %)

OTf

CH3O

K2CO3 (3 equiv)
THF, 60 °C, 72 h

OTDS

MOMO
H3C

TfO
H3C

OTDS

90%, 90% ee
CH3
N

H3C O

O

Pd(OAc)2 (20 mol %)

TDSO

(R)–Tol–BINAP (40 mol %)

H

1.7%

OTDS

OH
AcO

CH3
CH3O

(–)-Eptazocine

J. Am. Chem. Soc. 1993, 115, 8477–8488.

N

O

CH3
I

O

18.3%, 96% ee

O
O

Pd2(dba)3 (5 mol %)
(R)–BINAP (11 mol %)
PMP (5 equiv)
DMA, 110 °C, 8 h

O

H

H
O

O

influence the stereochemical outcome.

TDSO

H3C O

H3C O

MOMO
H3C

H3C
O

• The choice of base influences whether the Pd complex is neutral or cationic; this in turn can

O

O

H

K2CO3 (2.5 equiv)
toluene, 100 °C

racemic

Takemoto, T.; Sodeoka, M.; Sasai, H.; Shibasaki, M.

H3C O

MOMO
H3C

CH3
N

(+)-Wortmannin
neutral

O

• The enantiomer of the major product not observed. Instead, a complex mixture of products was
O

formed.

(S), 71%, 66% ee
O
N

O

CH3
I

O

O

Pd2(dba)3 (5 mol %)
(R)–BINAP (11 mol %)
Ag3PO4 (2 equiv)

Honzawa, S.; Mizutani, T.; Shibasaki, M. Tetrahedron Lett. 1999, 40, 311–314.

CH3
N
cationic

O

OTf
O

NMP, 80 °C, 26 h

Pd(OAc)2 (3 mol %)
(R)–Tol–BINAP (6 mol %)

O

(R), 86%, 70% ee

(i–Pr)2NEt (3 equiv)
benzene, 30 °C

O
(R), 71%, 93% ee

O
(S), 7%, 67% ee

Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6477–6487.

CH3O

I

O

N
CH3 CH3

OTIPS Pd2(dba)3•CHCl3 (10 mol %)

CH3O

(S)–BINAP (23 mol %)

3 M HCl

PMP, DMA, 100 °C

23 °C

H3C
CHO
O

• Initial products are 2,5 dihydrofurans:

O

O

N
CH3
(S), 84%, 95% ee
• Only the (R) isomer can isomerize due
to the asymmetric environment of the ligand.

CH3

H
N

O

Matsuura, T.; Overman, L. E.; Poon, D. J.
J. Am. Chem. Soc. 1998, 120, 6500–6503.

O

(–)-Physostigmine

O

H3C
N
N H
CH3

CH3

Ozawa, F.; Kubo, F.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.; Yanagi, K.; Moriguchi, K.
Organometallics 1993, 12, 4188–4196.

Andrew Haidle


• An Enantioselective redox-relay Heck process was achieved by a regioselective Heck coupling
followed by isomerization of the transient allylic double bond to generate the aldehyde shown:
Pd(CH3CN)2(OTs)2 (6 mol %)
Cu(OTf)2, (6 mol %)
OH
ligand (13 mol %), O2

B(OH)2
Me
via
Pd

H

OH

Pd

Me

I

CH3

Me
Ar

[bmim]NTf2 = 1-butyl-3-methylimidazolium
bis(tri-fluoromethylsulfonyl)imide

Pd

Me

t-Bu

OH
Ar

Mei, T.-S.; Werner, E. W.; Burckly, A. J.; Sigman, M. S. J. Am. Chem. Soc. 2013, 135, 6830–6833.

product
base•HX
Pd-cat
[bmim]NTf2

O
O

CH3

130 °C, 50 min
99%

OH

work-up procedure

N

N

Pd cat. (recycled)
N(i-Pr)3 (1.2 equiv)
[bmim]NTf2

O

O
Ligand = F3C

O

Cl

Ar

Ar

• By immobilizing the catalyst in an ionic liquid, [bmim]NTf2, the catalyst and product can be easily
separated from the reaction media.

H

OH

Me

Me

• Using flow microsystems, shorter reaction times are possible due to improved mixing.

O

DMF, 23 ºC, 24 h
65%, 99 : 1 er

Cl

• Continuous flow techniques have been applied in the Heck reaction.

H3C N

hexane

N n-Bu

Tf

N

Tf

Pd cat.
H3C

CH3

N

Ph3P Pd Cl
Cl

product
hexane
base•HX

Pd-cat
[bmim]NTf2

Heck Reactions in Continuous Flow:
• Continuous flow techniques have become an increasingly popular approach to streamlining multistep syntheses. A comparison between traditional and continuous flow multi-step synthesis is
shown below (Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675–680.):

H2O

H2O
base•HX
Pd-cat
[bmim]NTf2

reuse

Traditional Multi-Step Synthesis:
Liu, S.; Fukuyama, T.; Sato, M.; Ryu, I. Org. Proc. Res. Dev. 2004, 8, 477–481.
A
1. work-up
2. purify

+
B

1. work-up
2. purify

C

D

1. work-up
2. purify

E

• Supported Pd0 nanoparticles have also been employed as catalysts in flow Heck reactions and can
be reused.
• Reactions are performed ligand-free under "Jeffery-like" conditions.
• No additional purification is required as 100% conversion is achieved.

Continuous Flow Multi-Step Synthesis:
A
+

flow reactor 1

flow reactor 2

flow reactor 3

E

I

B
C and D not isolated
• Advantages of continuous flow:
• Improved control over mixing and temperature.

• Improved safety: reactions are "scaled out" instead of "scaled up"; if more material is needed, the
process is performed for a longer time. As a result, large amounts of chemicals or reaction
volumes are avoided, which decrease the likelihood of accidents.
• Inline work-up and purification are possible, increasing the overall efficiency of the process.
Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675–680.
Webb D.; Jamison, T. F. Org. Lett. 2012 14, 568–571.

N

CH3
O

ArNEt3+Cl– Pd0

N

DMF, 130 °C, Et3N
87%, >99% purity

CH3
O

Nikbin, N.; Ladlow, M.; Ley, S.V. Org. Proc. Res. Dev. 2007, 11, 458–462.
James Mousseau, Fan Liu


Myers

Chem 115

The Heck Reaction

Selected Applications in Industry:

• Application to the synthesis of the anti-smoking drug, Chantix!:

• Synthesis of an EP3 receptor antagonist via a double Heck cyclization reaction:

F

1. Pd(OAc)2 (0.2 mol %)
P(o-Tol)3 (0.6 mol %)
Et3N, CH3CN, 75 ºC

Br
N
H

Br

O
F3C

N
H

2. Pd(OAc)2 (1 mol %)
P(o-Tol)3 (3 mol %)
Et3N, CH3CN, 75 ºC

(5.0 kg)

CH3

F

Pd(OAc)2 (5 mol %)
P(o-tol)3 (10 mol %)
Et3N, DMF

N

O

N

80 °C, 87%

Br

CO2H

F3C

(2.17 kg)

67%

CH3

F

CO2H

Coe, J. W.; Brooks, P. R.; Vetelino, M. G.; Bashore, C. G.; Bianco, K.; Flick, A. C. Tetrahedron
Lett. 2011, 52, 953–954.

N
Cl

Cl

S

Cl

HN
O
S O
O

• Application in the manufacturing route of 1-hydroxy-4-(3-pyridyl)butan-2-one:
• Reaction was optimized to limit the formation of the by-products depicted below.

DG-041

Cl
Zegar, S.; Tokar, C.; Enache, L. A.; Rajagopol, V.; Zeller, W.; O'Connell, M.; Singh, J.; Muellner, F.
W.; Zembower, D. E. Org. Proc. Res. Dev. 2007, 11, 747–753.
• Near the final step of an oncology candidate:

N

CH3

N
(101 kg)

CH3 1. Pd2(dba)3 (1 mol%)
Et3N, i-PrOH, 78 ºC
Boc

N
Boc

OH

110 °C, 64%

O
OH
N

CH3

N

N

OH

(200 g)

N

NH2

CH3

I

Br

Pd(OAc)2 (10 mol %)
P(o-tol)3 (40 mol %)
Bu3N, toluene

N

• 2HCl
O

(91.6 kg)

N

O

2. HCl, i-PrOH, 40 ºC
97% (two steps)

O
O
H3CO

N
Possible by-products (not observed):

CH3

O
HN

NaOH
80%

Cl

OCH3

N
OH

N

OH

CH3
N

N
N

Me

OH
O

CP–724,714

Ripin, D.H. B.; Bourassa, D. E.; Brandt, T.; Castaldi, M. J.; Frost, H. N.; Hawkins, J.; Johnson, P. J.;
Massett, S. S.; Neumann, K.; Phillips, J.; Raggon, J. W.; Rose, P. R.; Rutherford, J. L.; Sitter, B.;
Stewart, A. M.; Vetelino, M. G.; Wei, L.Org. Proc. Res. Dev. 2005, 9, 440–450.

Ainge, D.; Vaz, L-M. Org. Proc. Res. Dev. 2002, 6, 811.
James Mousseau