Myers
Chem 215
The Heck Reaction
Reviews:
• Pd(II) is reduced to the catalytically active Pd(0) in situ, typically through the oxidation of a
Belestskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009–3066.
Brase, S.; de Meijere, A. In Metal-catalyzed Cross-coupling Reactions, Diederich, F., and Stang, P. J.,
Eds.; Wiley-VCH: New York, 1998, pp. 99–166.
phosphine ligand.
Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7.
Pd(OAc)2 + H2O + nPR3 + 2R'3N
de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379–2411.
Pd(PR3)n-1 + O=PR3 + 2R'3N•HOAc
• Intramolecular:
Ozawa, F.; Kubo, A.; Hayashi, T. Chemistry Lett. 1992, 2177–2180.
Link, J. T.; Overman, L. E. In Metal-catalyzed Cross-coupling Reactions, Diederich, F., and
Eds.; Wiley-VCH: New York, 1998, pp. 231–269.
Gibson, S. E.; Middleton, R. J. Contemp. Org. Synth. 1996, 3, 447–471.
• 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.
• Asymmetric:
Shibasaki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371–7393.
• An example of a proposed mechanism involving cationic Pd:
• Solid phase:
Franzén, R. Can. J. Chem. 2000, 78, 957–962.
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
Mechanism:
Pd(II)
reductive elimination
AgCO3–
• Proposed mechanism involving neutral Pd:
Pd catalyst
CH3O2C
2 L; 2 e –
Pd(0)L2
H–Pd(II)L2+
Ph
CH3O2C
CH3O2C
reductive elimination
K2CO3
oxidative addition
Ph–Br
Pd(0)L2
H–Pd(II)L2–Br
syn elimination
internal rotation
CH3O2C
CH3O2C
AgBr
Pd(II)L2+
H
H
CH3O2C
Ph
H
Ph–Pd(II)L2–Br
oxidative addition
Ag +
syn elimination
2 L; 2 e –
Ph–Br
Ph–Pd(II)L2–Br
Ph
Pd(II)
KHCO3 + KBr
Ph
HX
AgHCO3
Ph–Br
CH3O2C
Ag+
Ph–Pd(II)L2
H
CH3O2C
Pd(II)L2+
Ph
H
H
halide abstraction
+
CH3O2C
syn addition
Ph
H
CH3O2C
Pd(II)L2Br
H
Ph
H
H
CH3O2C
internal rotation
Pd(II)L2Br
Ph
H
H
syn addition
Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4133–4135.
Andrew Haidle
• Reactions with vinyl or aryl triflates often parallel those of the corresponding halides in the
I
presence of silver salts.
PPh3 (6 mol %)
N
SO2Ph
TMS
TMS
I
Pd(OAc)2 (3 mol %)
N
SO2Ph
DMF, 23 °C
Ag2CO3, eq
Time, h
Yield, %
1
24
50
1
48
35
2
5
80
I
Pd(OAc)2 (3 mol %)
Et3N
CH3
DMSO, 100 °C, 15 h
57%
12%
30%
TMS
I
N
SO2Ph
J. Chem. Soc. Perkin Trans. 1 1993, 1941–1942.
GC yields
TMS
By-product:
Sakamoto, T.; Kondo, Y.; Uchiyama, M.; Yamanaka, H.
TMS
Pd(OAc)2 (3 mol %)
Pd(OAc)2 (3 mol%)
AgNO3, Et3N
Et3N
DMSO, 50 °C, 3 h
DMSO, 50 °C, 3 h
64%
61%
OTf
• With some ligands, experimental evidence points to a Pd(II)/Pd(IV) catalytic cycle, although the
debate is ongoing.
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.
Karabelas, K.; Hallberg, A. J. Org. Chem. 1988, 53, 4909–4914.
• Reversible β-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
Solvent
toluene
THF
1,1-dichloroethane
DMF
2.4
7.6
10.5
38.3
26 : 1
Dielectric constant
Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4133–4135.
Andrew Haidle
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
OH
1,2,2,6,6-pentamethylpiperidine (PMP)
90
100
CO2CH3
Pd(OAc)2 (5 mol %)
NaHCO3, 3 A ms
DMF, 50 °C, 2 h
Equiv. of n–Bu4NCl
GC Yield(%)
0
2
1
99
20
O
insoluble bases accelerates the rate to the extent that lower reaction temperatures are possible.
CO2CH3
100
40
• Jeffery conditions: The combination of tetraalkylammonium salts (phase-transfer catalysts) and
I
OH
Ph
Y
N
100
OAc
OH
mixture
60
80
Y = CO2R
CN
CONH2
• Cationic Pd complexes: regiochemistry is affected by electronics. The cationic Pd complex
Jeffery, T. Tetrahedron 1996, 52, 10113–10130.
increases the polarization of the alkene favoring transfer of the vinyl or aryl group to the site of
least electron density.
95
40
• One proposed explanation for this rate enhancement is based on the fact that palladium
100
CH3
complexes can be stabilized by the coordination of halide ions; thus, the catalyst is less
OH
Ph
likely to decompose under the Heck reaction conditions.
OH
60
5
Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991, 113, 8375–8384.
100
95
90
O
• Conditions for the Heck coupling of aryl chlorides have been developed.
Y
N
100
OAc
OH
10
5
Pd2(dba)3 (1.5 mol %)
Cl
CO2CH3
P(t-Bu)3 (6 mol %)
CO2CH3
Cs2CO3 (1.1 equiv)
CH3O
dioxane, 120 °C, 24 h
82%
CH3O
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
• A major issue in intramolecular Heck reactions is the mode of ring closure, i.e., exo versus endo.
LnPd
• Conformational effects are more important when forming
LnPd
R
smaller rings. The eclipsed orientation is preferred for
endo
the reaction, even if this means the rest of the molecule
H
PdLn
exo
endo
R
eclipsed
must adopt a less than ideal conformation.
twisted
O
O
stereochemistry defines the
incipient quaternary center
I
exo
O
• For large rings, conformational effects can be minimal. If a neutral Pd complex is used, sterics
NHCO2CH3
enforce endo selectivity.
O
O
• The Heck reaction is useful for macrocylization.
Pd(OAc)2 (10 mol %)
I
O
PPh3 (40 mol %)
O
O
Ag2CO3, THF, 66 °C
73%
PdCl2(CH3CN)2 (100 mol %)
Et3N
O
CH3CN, 25 °C
O
55%
CH3 H O
CH3
H
PdLn
PdLn
CH3O2CN
H
NHCO2CH3
O
O
O
O
H
O
O
O
Ziegler, F. E.; Chakraborty, U. R.; Weisenfeld, R. B. Tetrahedron 1981, 37, 4035–4040.
Pd(OCOCF3)2 (PPh3)2
H
OBn
CH3O2CN
H
O
(10 mol %)
I
O
O
O
OBn
> 20 : 1
DBSN
60%
H
O
O
OH
(–)-Morphine
O
OH
O
OH
H
CH3N
DBS = dibenzosuberyl
O
H
O
OCH3
PMP, toluene, 120 °C
CH3O
O
NHCO2CH3
O
O
predominantly exo products.
O
twisted (chair)
O
• Five-, six-, and seven-membered ring closures (the most efficient Heck ring closures) give
DBSN
eclipsed (boat)
H
Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 11028–11029.
CH3O
N
H CH
3
(±)-6a-epipretazettine
Overman, L. E. Pure & Appl. Chem. 1994, 66, 1423–1430.
Andrew Haidle
• Variation of reaction conditions can greatly influence exo versus endo selectivity in small rings.
Tandem Reaction:
• Additional reaction pathways become available when the initial Pd–C species does not (or can not)
Pd(OAc)2 (6 mol %)
O
TBSO
O
R2
CH3O
N
O
R1
R1
R2
Heck sp cascade
R3
R3–X
R1
R2
CO
β-hydride
elimination
CH3OH
Oxidation, Nu
R1
Nu
R1
R2
• The authors' rationale for these results is that under the Jeffery conditions, the coordination
R1
Carbonylation
R2
–
Alkylation
CO 2CH3
32%
R2
R3
PdX
R3M
Transmetalation
CH3O
R1
R1PdX
R3
M
NHR
TBSO
Et3N, CH3CN
80 °C, 2 h
NHR
R2
Heck sp cascade
PPh3 (6 mol %)
N
CH3O
R1
2
Pd(OAc)2 (2 mol %)
I
PdX
PdX
O
58%
OTBS
TBSO
N
CH3O
R3
R3
NHR
CH3O
KOAc, DMF
80 °C, 22h
NHR
N
CH3O
CH3O
TBSO
n–Bu4NCl
I
CH3O
decompose via β-hydride elimination.
TBSO
OTBS
TBSO
R2
R2
Nucleophilic attack
sphere of palladium is relatively smaller, and thus the metal can be accommodated at the more
Heck reaction
substituted alkene site during migratory insertion.
• Tandem Heck reactions:
Rigby, J. H.; Hughes, R. C.; Heeg, M. J. J. Am. Chem. Soc. 1995, 117, 7834–7835.
R
I
H
TfO
CH3
CH3 CH3
CH3
O
O
H
OTBS
CH3 OTBS
Pd(PPh3)4 (100 mol %) CH3
CH3
CH3
K2CO3, CH3CN
O
OBn
O
4 A ms, 90 °C
49%
H
H
CH3
CH3
R
OTBS
O
H
O
TBSO
OTBS
R
Ag2CO3, THF, 65 °C
OBn
O
CH3
LnPd
LnPd
Pd(OAc)2 (10 mol %)
PPh3 (20 mol %)
TBAF, THF, 23°C
82%
O
CH3
CH3
O
CH3
CH3
• Steric and electronic effects begin to
O
compete with conformational effects
when forming medium–sized rings.
O
O
N
H
CH3
O
OH
Young, W. B.; Danishefsky, S. J.
R =
HO2C
HO
R
H
H
O
OH
O
CH3
H
H
O
O
CH3
OH O
O
Masters, J. J.; Link, J. T.; Snyder, L. B.;
Angew. Chem., Int. Ed. Engl. 1995, 34, 1723–1726.
O
OCH OH
3
O
CH3
O
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.
Taxol
Andrew Haidle
• Tandem Heck/π–allylpalladium reactions
• Tandem Heck reaction, intermolecular
CH3
CH3
TDSO
OTBS
CH3
H
CH3
Pd2(dba)3 (5 mol %)
PPh3 (48 mol %)
OCH3
Et3N, toluene
120 °C, 1.5 h
H
Br
CH3O2C
N
H
76% overall
H
I
CH3O
N
56%
OH
CH3
CH3
PdLn
PMP, toluene, 120 °C
CH3O
CH3
OH
O
Pd(TFA)2(PPh3)2 (20 mol %)
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
CH3
CH3
CH3 O
CH3
CH3
CH3
CH3
TBSO
CH3
CH3
[1,7]-H-shift
H
CH3
H
CH3 O
O
TfO
TfO
H
CO2CH3
1:9
PdCl2(dppf) (10 mol %)
AsPh3 (10 mol %)
CsHCO3, DMSO, 85 °C
CH3
CH3 O
CH3 O
TBAF
H
THF
79%
OH
H
CO2CH3
OTBS
CH3
HO
OTDS
B
TDSO
CH3
I
9-BBN
TDSO
CH3
CH3
O
Alphacalcidiol
TDSO
O
O
CH3
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:
• Typical yields = 50–80%
Pd(OAc)2 (1 mol %)
• Formation of tertiary stereocenters:
PPh3 (5 mol %)
B
O
:
87
O
CH3
CH3
13
Pd2(dba)3•CHCl3 (2.5 mol %)
Bu3N, CH3CN, 120 °C
CH3O
H3CO
CH3 CH3
I
O
O
OCH3
• Typical ee's = 80–95%
Pd(OAc)2 (5 mol %)
B
O
OCH3
O
CH3
CH3
CH3
I
Si(CH3)3
Ag3PO4 (1.1 equiv)
DMF, 48 h, 80 °C
CH3
91%, 92% ee
H3C CH3
:
0
CH3O
(R)–BINAP (7.0 mol %)
O
H
7-Desmethyl-2-methoxycalamenene
Tietze, L. F.; Raschke, T. Synlett 1995, 597–598.
100
Phenanthroline (5 mol %)
Pd[(R)–BINAP]2 (3 mol %)
t-BuOK, CH3CN, 45 °C
(CH3)2N
CO2Et
N
CO2CH3
OTf
Hunt, A. R.; Stewart, S. K.; Whiting, A. Tetrahedron Lett., 1993, 34, 3599–3602.
H CO2Et
N(CH3)2
N
H3CO2C
benzene, 60 °C, 20 h
95%, > 99% ee
• Tandem Heck/6π-electrocyclization reactions:
• 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.
Pd(OAc)2 (3 mol %)
Br
CH3CN, 80 °C, 3 h
EtO2C
EtO2C
Pd(OAc)2 (5 mol %)
CO2CH3
HO
K2CO3 (2 equiv)
TfO
OH
O
(R)–BINAP (10 mol %)
H
Ag2CO3 (2 eq)
OH
EtO2C
EtO2C
CO2CH3
BrPdLn
PPh3 (6 mol %)
O
H
H
O
KOAc (1 equiv)
O
ClCH2CH2Cl, 60 °C, 41 h
(+)-Vernolepin
70%, 86% ee
Ohari, K.; Kondo, K.; Sodeoka, M.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 11737–11748.
PdLnBr
H
H
HO
EtO2C CO2Et
H
TfO
85%
EtO2C
EtO2C
HO
EtO2C
EtO2C
HO
O
Pd2(dba)3 (3 mol %)
L (6 mol %)
(i-Pr)2NEt
H
O
O
L=
benzene, 30 °C, 72 h
Ph2P
N
92%, > 99% ee
Henniges, H.; Meyer, F. E.; Schick, U.; Funke, F.; Parsons, P. J.; de Meijere, A. Tetrahedron 1996,
52, 11545–11578.
Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis 1997, 1338–1345.
Andrew Haidle
• 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
CH3
OTDS
TfO
CH3
90%, 90% ee
CH3
N
CH3 O
O
Pd(OAc)2 (20 mol %)
TDSO
(R)–Tol–BINAP (40 mol %)
H
1.7%
OTDS
HO
CH3
AcO
CH3O
(–)-Eptazocine
J. Am. Chem. Soc. 1993, 115, 8477–8488.
N
O
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.
CH3
TDSO
CH3 O
CH3 O
MOMO
CH3
CH3
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.
CH3 O
MOMO
CH3
CH3
(+)-Wortmannin
N
• The enantiomer of the major product not observed. Instead, a complex mixture of products was
neutral
O
formed.
O
(S), 71%, 66% ee
Honzawa, S.; Mizutani, T.; Shibasaki, M. Tetrahedron Lett. 1999, 40, 311–314.
O
N
O
CH3
I
O
Pd2(dba)3 (5 mol %)
(R)–BINAP (11 mol %)
Ag3PO4 (2 equiv)
N
cationic
O
OTf
Pd(OAc)2 (3 mol %)
(R)–Tol–BINAP (6 mol %)
O
NMP, 80 °C, 26 h
O
CH3
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.
CH3
CH3O
I
O
N
CH3 CH3
OTIPS Pd2(dba)3•CHCl3 (10 mol %)
• Initial products are 2,3 dihydrofurans:
CH3O
(S)–BINAP (23 mol %)
3 M HCl
PMP, DMA, 100 °C
23 °C
CHO
O
N
CH3
(S), 84%, 95% ee
H
N
(–)-Physostigmine
CH3
O
Ozawa, F.; Kubo, F.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.; Yanagi, K.; Moriguchi, K.
N
O
Matsuura, T.; Overman, L. E.; Poon, D. J.
J. Am. Chem. Soc. 1998, 120, 6500–6503.
O
O
• Only the (R) isomer can isomerize due
to the asymmetric environment of the ligand.
CH3
O
N H
CH3
CH3
Organometallics 1993, 12, 4188–4196.
Andrew Haidle