Myers The Heck Reaction Chem 115

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

Belestskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009–3066. phosphine ligand.

• Intramolecular:
Link, J. T.; Overman, L. E. In Metal-catalyzed Cross-coupling Reactions, Diederich, F., and Pd(OAc)2 + H2O + nPR3 + 2R'3N Pd(PR3)n-1 + O=PR3 + 2R'3N•HOAc
Eds.; Wiley-VCH: New York, 1998, pp. 231–269.
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
• Solid phase: addition. Reductive elimination from the cationic complex is probably irreversible.

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 catalyst

Ph–Br Ph
CH3O2C CH3O2C
Pd(II) or Pd(0) catalyst Ag+
R–X + R' + HX
R' R
base

R = alkenyl, aryl, allyl, alkynyl, benzyl X = halide, triflate R' = alkyl, alkenyl, aryl, CO2R, OR, SiR3
Pd(II)
AgHCO3 2 L; 2 e –
• Proposed mechanism involving neutral Pd:
reductive elimination AgCO3– Ph–Br oxidative addition
Pd(0)L2
Mechanism:
Pd catalyst H–Pd(II)L2+ Ph–Pd(II)L2–Br
Ph–Br Ph
CH3O2C CH3O2C
Ph Ag +
CH3O2C
Pd(II)
KHCO3 + KBr 2 L; 2 e – syn elimination AgBr halide abstraction
Pd(II)L2+
reductive elimination oxidative addition H +
K2CO3 Ph–Br H Ph–Pd(II)L2
Pd(0)L2 CH3O2C Ph
H
H–Pd(II)L2–Br Pd(II)L2+
Ph–Pd(II)L2–Br H
Ph CH3O2C
syn elimination CH3O2C H
CH3O2C internal rotation syn addition
H
Ph
CH3O2C
Pd(II)L2Br Pd(II)L2Br syn addition
H H
H Ph
CH3O2C Ph CH3O2C H
H H Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4133–4135.
internal rotation Andrew Haidle, James Mousseau
 Myers The Heck Reaction Chem 115
• Reactions with vinyl or aryl triflates often parallel those of the corresponding halides in the
Ag2CO3, eq Time, h Yield, %
presence of silver salts in yields. I Pd(OAc)2 (3 mol %)
PPh3 (6 mol %) 1 24 50
TMS TMS N 1 48 35
DMF, 23 °C N
I I SO2Ph SO2Ph 2
Pd(OAc)2 (3 mol %) 5 80

Et3N
DMSO, 100 °C, 15 h CH3
12% 57% 30%
Sakamoto, T.; Kondo, Y.; Uchiyama, M.; Yamanaka, H. By-product:
GC yields
J. Chem. Soc. Perkin Trans. 1 1993, 1941–1942. N
SO2Ph
TMS
TMS TMS
I Pd(OAc)2 (3 mol %) Pd(OAc)2 (3 mol%) OTf
• With some ligands, experimental evidence points to a Pd(II)/Pd(IV) catalytic cycle.
AgNO3, Et3N Et3N
DMSO, 50 °C, 3 h DMSO, 50 °C, 3 h Ohff, M.; Ohff, A.; van der Boom, M. E.; Milstein, D. J. Am. Chem. Soc. 1997, 119, 11687–11688.

64% Shaw, B. L.; Perera, S. D.; Staley, E. A. J. Chem. Soc., Chem. Commun. 1998, 1361–1362.
61%
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.

Conditions:
H–Pd Pd Pd H
* * * Pd(OAc)2 Pd2(dba)3
• Catalysts:

• Use of silver salts can minimize alkene isomerization.

stable Pd(0) source; useful if substrate
most common is sensitive to oxidation
CH3 CH3
O O O
N N
O
N
CH3 I dba =

Conditions

Pd(OAc)2 (1 mol %) • Ligands: Phosphines (PR3), used to prevent deposition of Pd(0) mirror.
PPh3 (3 mol %) 1 : 1
Et3N (2 equiv)
• Solvents: Typically aprotic; a range of polarities.
acetonitrile, 3h, reflux

as above, plus 1,1-dichloroethane

Solvent toluene THF DMF
AgNO3 (1 equiv) and 23 °C 26 : 1
Dielectric constant 2.4 7.6 10.5 38.3

Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4133–4135. Andrew Haidle, Fan Liu
 Myers The Heck Reaction Chem 115
• Bases: both soluble and insoluble bases are used. Regiochemistry of addition:

Soluble examples Insoluble examples • Neutral Pd complexes: regiochemistry is governed by sterics; position of Ar attachment:

Et3N K2CO3 Ag2CO3 10

CH3 CH3
N
CH3 CH3
CH3 CH3 OH
Ph
1,2,2,6,6-pentamethylpiperidine (PMP) OH
100 90 100

40 20
• Jeffery conditions: The combination of tetraalkylammonium salts (phase-transfer catalysts) and O
insoluble bases accelerates the rate to the extent that lower reaction temperatures are possible.
Y N OH OAc

mixture
I CO2CH3 CO2CH3 100 60 80
Pd(OAc)2 (5 mol %)
NaHCO3, 3Å-MS Y = CO2R
DMF, 50 °C, 2 h CN
CONH2
Equiv. of n-Bu4NCl GC Yield(%)
0 2
• Cationic Pd complexes: regiochemistry is affected by electronics. The cationic Pd complex
1 99
increases the polarization of the alkene favoring transfer of the vinyl or aryl group to the site of
Jeffery, T. Tetrahedron 1996, 52, 10113–10130. least electron density.

40 95 100
• One proposed explanation for this rate enhancement is based on the fact that palladium
complexes can be stabilized by the coordination of halide ions; thus, the catalyst is less CH3 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 OAc
OH

100 10 5
Pd2(dba)3 (1.5 mol %)
P(t-Bu)3 (6 mol %) Y = CO2R
Cl CO2CH3 CO2CH3
CN
Cs2CO3 (1.1 equiv) CONH2
CH3O dioxane, 120 °C, 24 h CH3O

82% 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 The Heck Reaction Chem 115
• 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 LnPd
LnPd
endo smaller rings. The eclipsed orientation is preferred for R R
the reaction, even if this means the rest of the molecule
H eclipsed twisted
PdLn must adopt a less than ideal conformation.
exo endo
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
enforce endo selectivity. O

• The Heck reaction is useful for macrocylization. O

Pd(OAc)2 (10 mol %)
O O PPh3 (40 mol %)
Ag2CO3, THF, 66 °C
PdCl2(CH3CN)2 (100 mol %)
I 73%
Et3N

O CH3CN, 25 °C O O PdLn PdLn

55% O NHCO2CH3 CH3O2CN
CH3 O H
CH3 H O H O O
H
O O
Ziegler, F. E.; Chakraborty, U. R.; Weisenfeld, R. B. Tetrahedron 1981, 37, 4035–4040.
O eclipsed (boat) O
twisted (chair)

• Five-, six-, and seven-membered ring closures (the most efficient Heck ring closures) give
O O
predominantly exo products.
O NHCO2CH3 H O
O O

DBSN Pd(OCOCF3)2(PPh3)2 OCH3 CH3O2CN

H
H (10 mol %)
O O
OBn O O
PMP, toluene, 120 °C
CH3O I DBSN > 20 : 1
OBn 60% H
O OH

O O
OH

(–)-Morphine OH
O CH3O N
H CH
H 3
CH3N
DBS = dibenzosuberyl H (±)-6a-epipretazettine
Overman, L. E. Pure & Appl. Chem. 1994, 66, 1423–1430.
Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 11028–11029. Andrew Haidle
 Myers The Heck Reaction Chem 115
• Variation of reaction conditions can greatly influence exo versus endo selectivity in small rings. Dehydrogenative Process
• It is possible to generate an aryl palladium(II) intermediate for Heck coupling from an arene by C–H
insertion.
OTBS TBSO
TBSO • An oxidant is required.
Pd(OAc)2 (6 mol %) TBSO
n–Bu4NCl NHR General transformation:
CH3O I CH3O
KOAc, DMF N Pd(II) catalyst, oxdidant
N NHR O R
CH3O 80 °C, 22h CH3O Ar–H + R Ar + HX
base
O 58%

R = alkenyl, aryl, allyl, alkynyl, benzyl X = halide, triflate R' = alkyl, alkenyl, aryl, CO2R, OR, SiR3
OTBS TBSO
TBSO Pd(OAc)2 (2 mol %)
NHR Mechanism:
PPh3 (6 mol %) TBSO
I • Proposed mechanism: oxidative addition
CH3O CH3O reduced oxidant
Et3N, CH3CN N O Ar–H
N NHR PdX2
CH3O 80 °C, 2 h CH3O H–X
oxidant
O 32%
Catalyst Pd0 Ar–Pd–X
Regeneration
• The authors' rationale for these results is that under the Jeffery conditions, the coordination sphere syn addition
of palladium is smaller, and thus the metal can be accommodated at the more substituted alkene H–X
Some oxidants:
site during migratory insertion.
PdX
O2, HPMo11V, PhI(OAc)2, Ar
Rigby, J. H.; Hughes, R. C.; Heeg, M. J. J. Am. Chem. Soc. 1995, 117, 7834–7835. H–Pd–X R
benzoquinone, t-BuOOH,
KMnO4, Na2S2O8, Cu(OAc)2
TfO OTBS CH3 OTBS
CH3 CH3 Pd(PPh3)4 (100 mol %) CH3 !-H elimination
CH3 CH3
CH3 K2CO3, CH3CN CH3 Ar
O R
O H OBn
H 4Å MS, 90 °C Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170–1214.
O O OBn O O
49%
O O
• Early examples of dehydrogenative processes did not employ oxidants and were stoichiometric in
palladium.

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

H3C facilitated by acetate.
O
O O OH
CH3
CH3
O O CH3 Pd(OAc)2 (1 equiv)
• Steric and electronic effects begin to CH3
compete with conformational effects N O O
H MeO AcOH
when forming medium–sized rings. OH H MeO
OH O O CH3 63%
O
O

Taxol
Fujiwara, Y.; Moritani, I.; Asano, R.; Tanaka, H.; Teranishi, S. Tetrahedron 1969, 25, 4815–4818.
Masters, J. J.; Link, J. T.; Snyder, L. B.; Young, W. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848–10849.
Engl. 1995, 34, 1723–1726. Andrew Haidle, James Mousseau
• Control of regioselectivity may be problematic with substituted arenes. Tandem Reaction:

• In the case below, benzoquinone (BQ) was the oxidant and silver carbonate was essential. • Additional reaction pathways become available when the initial Pd–C species does not (or can not)
decompose via !-hydride elimination.

Pd(OAc)2 (5 mol %)
R3 R3
BQ (2 equiv)
OAc
OAc Ag2CO3 (0.6 equiv) PdX PdX
Cl R1 R2 R1
n-BuCO2H (16 equiv) Cl R2 R2
100 equiv 1 equiv 100 °C, 48 h 34 : 36 : 30 o : m :p R3
Heck sp2 cascade R3 R1PdX Heck sp cascade
52%
M PdX R3
Pan, D.; Yu, M.; Chen, W.; Jiao, N. Chem. Asian J. 2010, 5, 1090–1093. R3M R3–X
R1 R1 R1
R2 R2 R2
• Directing groups may be applied to control the site of reaction. –
CO Oxidation, Nu
Transmetalation !-hydride Alkylation
Pd(OAc)2 (5 mol %) H CH3OH elimination
H BQ (1 equiv) Cl N Me CO2CH3 Nu
Cl N Me TsOH•H2O (1 equiv) R1 R1
CO2n-Bu O R2 R2
O MeO
MeO AcOH, PhMe R1
22 °C, 16 h CO2n-Bu Carbonylation R2 Nucleophilic attack
82%
Heck reaction

Lee, G. T.; Jian, X.; Prasad, K.; Repic, O.; Blacklock, T. J. Adv. Synth. Catal. 2005, 347, 1921–1924.
• Tandem Heck reactions:
• Various heterocycles are effective substrates, including indoles, thiazoles, oxazoles, pyrroles,
furans and activated pyridines. CH3
R I Pd(OAc)2 (10 mol %) LnPd PdLn
• Site selectivity with pyrrole substrates can be achieved by the use of directing (carbamate) or H PPh3 (20 mol %)
blocking (triisopropylsilyl) groups on the nitrogen atom. OTBS R
R
Ag2CO3, THF, 65 °C H
TBSO H
CH3
CO2Bn CH3 OTBS
Pd(OAc)2 (10 mol %)
PhCO3t-Bu (1 equiv)
N CO2Bn N CO2Bn TBAF, THF, 23°C
AcOH, dioxane, DMSO 82%
R t-BuO O N
35 °C, 24–48 h CH3
Si(i-Pr)3
R = CO2t-Bu O CH3
or 75% 81% CH3
Si(i-Pr)3
H R
Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528–2529. O H
R = H
O HO2C O
Pd(OAc)2 (10 mol %) HO OH
Ag2CO3 (1.5 equiv) O
pyridine (1 equiv)
CO2t-Bu Scopadulcic acid A
N N CO2t-Bu
dioxane, 100 °C, 12 h
O O Kucera, D. J.; O'Connor, S. J.; Overman, L. E. J. Org. Chem. 1993, 58, 5304–5306.
91%
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 reaction, intermolecular • Tandem Heck/!–allylpalladium reactions

H3C CH3
H3C Pd2(dba)3 (5 mol %)
H PPh3 (48 mol %)
CH3
OCH3
Et3N, toluene N
TDSO OTBS CH3O2C
H 120 °C, 1.5 h H OH
Pd(TFA)2(PPh3)2 (20 mol %) O
Br PdLn
76% overall
PMP, toluene, 120 °C CH3O N
CH3O I
H3C 56%
CH3 OH
H3C
H CH3
OH
OCH3
H
OH
O O O
PdLn H
CH3N CH3O N
TDSO H
(–)-Morphine
TBSO

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

• Tandem Suzuki/Heck reactions

H3C CH3
H3C H3C
CH3 H3C O H3C O
H3C O O
CH3 I OTDS
H3C 9-BBN
TBSO CH3 [1,7]-H-shift H PdCl2(dppf) (10 mol %)
TfO TfO
CH3 H H AsPh3 (10 mol %)
CO2CH3 CO2CH3
CsHCO3, DMSO, 85 °C
H 1:9
B
TDSO
TDSO OTBS

H3C CH3
H3C H3C O O
CH3 H3C O O
TBAF
H3C
H TDSO TfO
THF H
65% CH3 CO2CH3
H
79% CO2CH3

Alphacalcidiol OTDS
HO OH

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% • Typical ee's = 80–95%

PPh3 (5 mol %)
87 : 13 • Formation of tertiary stereocenters:
O CH3 Bu3N, CH3CN, 120 °C
B
CH3
O H3CO O Pd2(dba)3•CHCl3 (2.5 mol %)
CH3 CH3 CH3O CH3O
(R)–BINAP (7.0 mol %)
O CH3
B +
CH3 CH3 I Ag3PO4 (1.1 equiv) CH3
I O O H
O OCH3 Si(CH3)3 DMF, 48 h, 80 °C
H3C CH3
OCH3 91%, 92% ee
Pd(OAc)2 (5 mol %) 7-Desmethyl-2-methoxycalamenene
0 : 100
Phenanthroline (5 mol %)
Tietze, L. F.; Raschke, T. Synlett 1995, 597–598.
t-BuOK, CH3CN, 45 °C
Pd[(R)–BINAP]2 (3 mol %)
Hunt, A. R.; Stewart, S. K.; Whiting, A. Tetrahedron Lett., 1993, 34, 3599–3602.
CO2Et (CH3)2N N(CH3)2 H CO2Et
• Tandem Heck/6!-electrocyclization reactions:
N N
OTf CO2CH3 H3CO2C
Pd(OAc)2 (3 mol %)
PPh3 (6 mol %) BrPdLn benzene, 60 °C, 20 h
H
Br Ag2CO3 (2 eq) 95%, > 99% ee
EtO2C OH EtO2C HO
CH3CN, 80 °C, 3 h
EtO2C 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
CO2CH3 Pd(OAc)2 (5 mol %) OH
H O
(R)–BINAP (10 mol %)
H H O
K2CO3 (2 equiv) H H
HO TfO O
85% EtO2C HO EtO2C HO KOAc (1 equiv)
EtO2C CO2Et CO2Et O
CO2Et ClCH2CH2Cl, 60 °C, 41 h
(+)-Vernolepin
70%, 86% ee

Henniges, H.; Meyer, F. E.; Schick, U.; Funke, F.; Parsons, P. J.; de Meijere, A. Tetrahedron 1996, 52,
Ohari, K.; Kondo, K.; Sodeoka, M.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 11737–11748.
11545–11578.

• Tandem dehydrogenative Heck/oxidative cyclization

Pd2(dba)3 (3 mol %)
TfO L (6 mol %) H
O
Pd(OAc)2 (10 mol %) O
Me Me O (i-Pr)2NEt
L (40 mol %) L= Ph2P N
Me Me benzene, 30 °C, 72 h
AgOAc (4 equiv) t-Bu
OH O
H3CO Li2CO3, C6F6 H3CO 92%, > 99% ee
80 ºC, 71%
CO2Et
CO2Et L = (+)-Menthyl(O2C)-Leu-OH
Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis 1997, 1338–1345.
Lu, Y.; Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc, 2010, 132, 5916–5921. Andrew Haidle, James Mousseau
 • Formation of quaternary stereocenters:
• Kinetic Resolution:
CH3 Pd(OAc)2 (7 mol %)
(R)–BINAP (17 mol %) H3C O H3C O
MOMO O MOMO O
CH3O OTf CH3O
K2CO3 (3 equiv) Pd(OAc)2 (20 mol %) H3C
OTDS H3C TDSO
THF, 60 °C, 72 h OTDS TfO (R)–Tol–BINAP (40 mol %)
H3C H H
90%, 90% ee K2CO3 (2.5 equiv)
toluene, 100 °C 1.7%
CH3
OTDS
N
racemic H3C O
MOMO O
H3C
OH TDSO
AcO H3C O H
Takemoto, T.; Sodeoka, M.; Sasai, H.; Shibasaki, M. CH3
CH3O H3C
J. Am. Chem. Soc. 1993, 115, 8477–8488. (–)-Eptazocine
O 18.3%, 96% ee
H
• The choice of base influences whether the Pd complex is neutral or cationic; this in turn can O O
influence the stereochemical outcome. O
CH3
O Pd2(dba)3 (5 mol %) O (+)-Wortmannin
N
CH3 (R)–BINAP (11 mol %)
N neutral
O PMP (5 equiv) O
I • The enantiomer of the major product not observed. Instead, a complex mixture of products was
O DMA, 110 °C, 8 h O formed.
(S), 71%, 66% ee

CH3 Honzawa, S.; Mizutani, T.; Shibasaki, M. Tetrahedron Lett. 1999, 40, 311–314.
O O
Pd2(dba)3 (5 mol %) N
CH3 (R)–BINAP (11 mol %)
N cationic
O O Pd(OAc)2 (3 mol %)
I Ag3PO4 (2 equiv) OTf
O NMP, 80 °C, 26 h O (R)–Tol–BINAP (6 mol %) O O
O
(R), 86%, 70% ee (i–Pr)2NEt (3 equiv)
benzene, 30 °C (R), 71%, 93% ee (S), 7%, 67% ee
Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6477–6487.

H3C
CH3O I OTIPS Pd2(dba)3•CHCl3 (10 mol %) CH3O CHO • Initial products are 2,5 dihydrofurans:
O O O
(S)–BINAP (23 mol %) 3 M HCl O
N N
CH3 CH3 PMP, DMA, 100 °C 23 °C CH3
(S), 84%, 95% ee
• Only the (R) isomer can isomerize due
to the asymmetric environment of the ligand. O

H H3C
N O
CH3 N
O CH3 Ozawa, F.; Kubo, F.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.; Yanagi, K.; Moriguchi, K.
Matsuura, T.; Overman, L. E.; Poon, D. J. N H
CH3 Organometallics 1993, 12, 4188–4196.
J. Am. Chem. Soc. 1998, 120, 6500–6503. (–)-Physostigmine Andrew Haidle
• An Enantioselective redox-relay Heck process was achieved by a regioselective Heck coupling • Continuous flow techniques have been applied in the Heck reaction.
followed by isomerization of the transient allylic double bond to generate the aldehyde shown:
• Using flow microsystems, shorter reaction times are possible due to improved mixing.

O • By immobilizing the catalyst in an ionic liquid, [bmim]NTf2, the catalyst and product can be easily
B(OH)2 Pd(CH3CN)2(OTs)2 (6 mol %) separated from the reaction media.
Cu(OTf)2, (6 mol %) Me H
OH ligand (13 mol %), O2 Pd cat. (recycled)
Me N(i-Pr)3 (1.2 equiv) O
DMF, 23 ºC, 24 h I O CH3 [bmim]NTf2
Cl O CH3
65%, 99 : 1 er
via Cl O 130 °C, 50 min
Pd OH H OH OH 99%
Pd
Me Me Me [bmim]NTf2 = 1-butyl-3-methylimidazolium
Pd cat.
Ar Ar Ar Pd bis(tri-fluoromethylsulfonyl)imide
CH3
N H3C N
work-up procedure H3C N N n-Bu
Tf Tf
Ph3P Pd Cl
O
Ligand = F3C Cl
Me product
N N OH
t-Bu base•HX hexane product
Ar
Pd-cat hexane
Mei, T.-S.; Werner, E. W.; Burckly, A. J.; Sigman, M. S. J. Am. Chem. Soc. 2013, 135, 6830–6833. [bmim]NTf2 H2O H2O
base•HX base•HX
Heck Reactions in Continuous Flow: Pd-cat
• Continuous flow techniques have become an increasingly popular approach to streamlining multi- [bmim]NTf2 Pd-cat reuse
step syntheses. A comparison between traditional and continuous flow multi-step synthesis is [bmim]NTf2
shown below (Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675–680.):
Traditional Multi-Step Synthesis:
Liu, S.; Fukuyama, T.; Sato, M.; Ryu, I. Org. Proc. Res. Dev. 2004, 8, 477–481.

A
+ 1. work-up 1. work-up 1. work-up
2. purify 2. purify 2. purify • Supported Pd0 nanoparticles have also been employed as catalysts in flow Heck reactions and can
B C D E
be reused.
• Reactions are performed ligand-free under "Jeffery-like" conditions.
Continuous Flow Multi-Step Synthesis: • No additional purification is required as 100% conversion is achieved.

A
+ flow reactor 1 flow reactor 2 flow reactor 3 E
I
B
C and D not isolated ArNEt3+Cl– Pd0 N
N CH3
DMF, 130 °C, Et3N CH3
• Advantages of continuous flow:
O
87%, >99% purity O
• 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.
Nikbin, N.; Ladlow, M.; Ley, S.V. Org. Proc. Res. Dev. 2007, 11, 458–462.
Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675–680.
Webb D.; Jamison, T. F. Org. Lett. 2012 14, 568–571. James Mousseau, Fan Liu
 Myers The Heck Reaction Chem 115
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:
CH3
1. Pd(OAc)2 (0.2 mol %) F O
F Br P(o-Tol)3 (0.6 mol %) Pd(OAc)2 (5 mol %) F3C
Et3N, CH3CN, 75 ºC F3C N P(o-tol)3 (10 mol %) O
N
H Et3N, DMF N
N 2. Pd(OAc)2 (1 mol %)
H
Br P(o-Tol)3 (3 mol %) 80 °C, 87%
CO2H Br
(5.0 kg) Et3N, CH3CN, 75 ºC (2.17 kg)

67% CH3
CO2H F
Coe, J. W.; Brooks, P. R.; Vetelino, M. G.; Bashore, C. G.; Bianco, K.; Flick, A. C. Tetrahedron
N Lett. 2011, 52, 953–954.

Cl

HN O Cl • Application in the manufacturing route of 1-hydroxy-4-(3-pyridyl)butan-2-one:

S O • Reaction was optimized to limit the formation of the by-products depicted below.
Cl O
S DG-041

Cl
Pd(OAc)2 (10 mol %)
Zegar, S.; Tokar, C.; Enache, L. A.; Rajagopol, V.; Zeller, W.; O'Connell, M.; Singh, J.; Muellner, F. P(o-tol)3 (40 mol %) O
Br
W.; Zembower, D. E. Org. Proc. Res. Dev. 2007, 11, 747–753. OH Bu3N, toluene OH
OH
• Near the final step of an oncology candidate: N 110 °C, 64%
CH3 N
(200 g)
CH3 NH2 N

N CH3

CH3 1. Pd2(dba)3 (1 mol%) N • 2HCl

Et3N, i-PrOH, 78 ºC O
I N (91.6 kg)
N O
Boc 2. HCl, i-PrOH, 40 ºC O
N N
97% (two steps)
Boc O
(101 kg) NaOH N
H3CO 80%
Cl
Possible by-products (not observed):

O CH3 N
OCH3
HN N OH
OH
CH3 Me OH
N N O

N CP–724,714

Ripin, D.H. B.; Bourassa, D. E.; Brandt, T.; Castaldi, M. J.; Frost, H. N.; Hawkins, J.; Johnson, P. J.;
Ainge, D.; Vaz, L-M. Org. Proc. Res. Dev. 2002, 6, 811.
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. James Mousseau