Myers

Reviews: Belestskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 30093066.

The Heck Reaction

Chem 215

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

Brase, S.; de Meijere, A. In Metal-catalyzed Cross-coupling Reactions, Diederich, F., and Stang, P. J., Eds.; Wiley-VCH: New York, 1998, pp. 99166. Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 27. de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 23792411. Intramolecular: Link, J. T.; Overman, L. E. In Metal-catalyzed Cross-coupling Reactions, Diederich, F., and Eds.; Wiley-VCH: New York, 1998, pp. 231269. Gibson, S. E.; Middleton, R. J. Contemp. Org. Synth. 1996, 3, 447471. Asymmetric: Shibasaki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53, 73717393. Solid phase: Franzn, R. Can. J. Chem. 2000, 78, 957962. General transformation: Pd(II) or Pd(0) catalyst RX R' base X = halide, triflate R R' HX

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

Pd(PR3)n-1 + O=PR3 + 2R'3NHOAc

Ozawa, F.; Kubo, A.; Hayashi, T. Chemistry Lett. 1992, 21772180.

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.

An example of a proposed mechanism involving cationic Pd:

PhBr

Pd catalyst CH3O2C Ag+ CH3O2C

Ph

R = alkenyl, aryl, allyl, alkynyl, benzyl Mechanism:

R' = alkyl, alkenyl, aryl, CO2R, OR, SiR3 AgHCO3 reductive elimination AgCO3 HPd(II)L2+ CH3O2C Ph

Pd(II) 2 L; 2 e Pd(0)L2 PhBr oxidative addition

Proposed mechanism involving neutral Pd: PhBr Pd catalyst CH3O2C Pd(II) KHCO3 + KBr reductive elimination K2CO3 HPd(II)L2Br Pd(0)L2 2 L; 2 e PhBr oxidative addition CH3O2C Ph

PhPd(II)L2Br Ag + AgBr PhPd(II)L2 Pd(II)L2+ Ph H H

+

syn elimination

Pd(II)L2+ H H CH3O2C Ph H H CH3O2C

halide abstraction

PhPd(II)L2Br CH3O2C internal rotation

syn elimination
CH3O2C Ph H CH3O2C Pd(II)L2Br H Ph H H CH3O2C Pd(II)L2Br Ph H H

CH3O2C

syn addition

syn addition
Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 41334135. Andrew Haidle

internal rotation

 Reactions with vinyl or aryl triflates often parallel those of the corresponding halides in the presence of silver salts. TMS I I N SO2Ph

Pd(OAc)2 (3 mol %) PPh3 (6 mol %) DMF, 23 C N SO2Ph

Ag2CO3, eq 1 1 2

Time, h 24 48 5

Yield, % 50 35 80

TMS I Pd(OAc)2 (3 mol %) Et3N DMSO, 100 C, 15 h 12%

CH3 57% GC yields TMS 30% Sakamoto, T.; Kondo, Y.; Uchiyama, M.; Yamanaka, H. J. Chem. Soc. Perkin Trans. 1 1993, 19411942. By-product: N SO2Ph

TMS I Pd(OAc)2 (3 mol %) AgNO3, Et3N DMSO, 50 C, 3 h 64%

TMS Pd(OAc)2 (3 mol%) Et3N DMSO, 50 C, 3 h Ohff, M.; Ohff, A.; van der Boom, M. E.; Milstein, D. J. Am. Chem. Soc. 1997, 119, 1168711688. 61% Shaw, B. L.; Perera, S. D.; Staley, E. A. J. Chem. Soc., Chem. Commun. 1998, 13611362. OTf With some ligands, experimental evidence points to a Pd(II)/Pd(IV) catalytic cycle, although the debate is ongoing.

Karabelas, K.; Hallberg, A. J. Org. Chem. 1988, 53, 49094914. Reversible -hydride elimination can lead to alkene isomerization. HPd * Pd * Pd H * Conditions: Catalysts: Pd(OAc)2 Pd2(dba)3 stable Pd(0) source; useful if substrate O N CH3 I Conditions Pd(OAc)2 (1 mol %) PPh3 (3 mol %) Et3N (2 equiv) acetonitrile, 3h, reflux as above, plus AgNO3 (1 equiv) and 23 C 26 : 1 Dielectric constant 2.4 7.6 10.5 38.3 Solvent toluene THF 1,1-dichloroethane DMF 1 : 1 Solvents: Typically aprotic; a range of polarities. CH3 N O CH3 N most common is sensitive to oxidation O dba =

Use of silver salts can minimize alkene isomerization.

Ligands: Phosphines (PR3), used to prevent deposition of Pd(0) mirror.

Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 41334135. Andrew Haidle

 Bases: Both soluble and insoluble bases are used. Soluble examples Insoluble examples

Regiochemistry of addition: Neutral Pd complexes: regiochemistry is governed by sterics; position of Ar attachment: 10 CH3 Ph OH 100 90 40 O Y 100 Y = CO2R CN CONH2 60 N 80 OH OAc mixture 20 100 OH

CH3 CH3 N CH3 CH3 CH3

Et3N

K2CO3

Ag2CO3

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

Jeffery conditions: The combination of tetraalkylammonium salts (phase-transfer catalysts) and insoluble bases accelerates the rate to the extent that lower reaction temperatures are possible.

CO2CH3

Pd(OAc)2 (5 mol %) NaHCO3, 3 A ms DMF, 50 C, 2 h Equiv. of nBu4NCl 0 1

CO2CH3

GC Yield(%) 2

Cationic Pd complexes: regiochemistry is affected by electronics. The cationic Pd complex 99 increases the polarization of the alkene favoring transfer of the vinyl or aryl group to the site of least electron density. Jeffery, T. Tetrahedron 1996, 52, 1011310130.

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 likely to decompose under the Heck reaction conditions. 60 Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991 , 113, 83758384.

40 Ph

95 CH3 OH 5 100 O 90 OH 10

100 OH

95 OAc 5

Conditions for the Heck coupling of aryl chlorides have been developed. 100 Pd2(dba)3 (1.5 mol %) Cl CH3O CO2CH3 P(t-Bu)3 (6 mol %) Cs2CO3 (1.1 equiv) dioxane, 120 C, 24 h 82% CH3O CO2CH3

Y = CO2R CN CONH2

Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 27. Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J. Org. Chem. 1992, 57, 14811486.

Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 1011. Andrew Haidle

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

Conformational effects are more important when forming smaller rings. The eclipsed orientation is preferred for the reaction, even if this means the rest of the molecule must adopt a less than ideal conformation. O O

LnPd LnPd R eclipsed R twisted

exo

exo O For large rings, conformational effects can be minimal. If a neutral Pd complex is used, sterics enforce endo selectivity. The Heck reaction is useful for macrocylization. O PdCl2(CH3CN)2 (100 mol %) Et3N CH3CN, 25 C 55% CH3 H O H O Ziegler, F. E.; Chakraborty, U. R.; Weisenfeld, R. B. Tetrahedron 1981, 37, 40354040. O eclipsed (boat) O O O PdLn NHCO2CH3 O O O O

stereochemistry defines the incipient quaternary center NHCO2CH3

Pd(OAc)2 (10 mol %) PPh3 (40 mol %) Ag2CO3, THF, 66 C 73% PdLn CH3O2CN H O O twisted (chair) O

I O CH3 H O

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

O NHCO2CH3 O H O CH3O2CN H O O > 20 : 1 O

O O

DBSN H

Pd(OCOCF3)2 (PPh3)2 (10 mol %) PMP, toluene, 120 C

OCH3 OBn DBSN

CH3O OBn

I 60%

H O OH ()-Morphine O CH3N OH H H CH3O

O OH O N H CH 3

DBS = dibenzosuberyl

()-6a-epipretazettine Overman, L. E. Pure & Appl. Chem. 1994, 66, 14231430. Andrew Haidle

Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 1102811029.

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

Tandem Reaction: Additional reaction pathways become available when the initial PdC species does not (or can not)

TBSO CH3O CH3O I N

OTBS Pd(OAc)2 (6 mol %) nBu4NCl NHR O OTBS Pd(OAc)2 (2 mol %) PPh3 (6 mol %) N O NHR Et3N, CH3CN 80 C, 2 h 32% TBSO CH3O CH3O KOAc, DMF 80 C, 22h 58% CH3O CH3O

TBSO TBSO NHR N O

decompose via -hydride elimination. R3 PdX R1 Heck sp cascade

2

R3 PdX R2 R3 R1PdX PdX R1 R2 -hydride elimination Oxidation, Nu

R2

R1 R3

R2 Heck sp cascade R3 R1 R2 Alkylation Nu

TBSO CH3O CH3O I

TBSO NHR N O R1

M R2

R3M CO CH3OH CO 2CH3

R3X

Transmetalation

R1 The authors' rationale for these results is that under the Jeffery conditions, the coordination Carbonylation sphere of palladium is relatively smaller, and thus the metal can be accommodated at the more substituted alkene site during migratory insertion.

R2 R1 R2

R1

R2 Nucleophilic attack

Heck reaction Tandem Heck reactions:

Rigby, J. H.; Hughes, R. C.; Heeg, M. J. J. Am. Chem. Soc. 1995, 117, 78347835. R CH3 OTBS Pd(PPh3)4 (100 mol %) CH3 K2CO3, CH3CN O OBn 4 A ms, 90 C 49% O O CH3 Steric and electronic effects begin to compete with conformational effects when forming mediumsized rings. O N H Masters, J. J.; Link, J. T.; Snyder, L. B.; Young, W. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 17231726. Taxol O CH3 O OH CH3 O O OCH OH 3 CH3 CH3 OH O O H O O O CH3 R = O O HO2C HO H O O Scopadulcic acid A Kucera, D. J.; O'Connor, S. J.; Overman, L. E. J. Org. Chem. 1993, 58, 53045306. Fox, M. E.; Li, C; Marino, J. P.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 54675480. OH H R CH3 CH3 H O OBn I H TfO CH3 CH3 CH3 CH3 O O O H OTBS TBSO CH3 O Pd(OAc)2 (10 mol %) PPh3 (20 mol %) Ag2CO3, THF, 65 C LnPd R CH3 H OTBS LnPd R

CH3

H OTBS TBAF, THF, 23C 82%

CH3 O

CH3

Andrew Haidle

 Tandem Heck reaction, intermolecular CH3 CH3 TDSO OTBS Br

Tandem Heck/allylpalladium reactions

CH3 H CH3

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

OCH3 OH PdLn

OCH3 O N O

TDSO TBSO

Hong, C. Y.; Overman, L. E. Tetrahedron Lett. 1994, 35, 34533456.

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

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

CH3 O

H CO2CH3

HO

OH

Alphacalcidiol

OTDS Kojima, A.; Honzawa, S.; Boden, C. D. J.; Shibasaki, M. Tetrahedron Lett. 1997, 38, 34553458.

Trost, B. M.; Dumas, J.; Villa, M. J. Am. Chem. Soc. 1992, 114, 98369845.

Andrew Haidle

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

Enantioselective Heck Reactions: Typical yields = 5080% Typical ee's = 8095%

Pd(OAc)2 (1 mol %) PPh3 (5 mol %) B O O 87 CH3 CH3 Bu3N, CH3CN, 120 C H3CO B O O CH3 CH3 O : 13

Formation of tertiary stereocenters: Pd2(dba)3CHCl3 (2.5 mol %) CH3O CH3 I Si(CH3)3 (R)BINAP (7.0 mol %) Ag3PO4 (1.1 equiv) DMF, 48 h, 80 C 91%, 92% ee Tietze, L. F.; Raschke, T. Synlett 1995, 597598. Pd[(R)BINAP]2 (3 mol %) CO2Et (CH3)2N N CO2CH3 benzene, 60 C, 20 h 95%, > 99% ee N(CH3)2 N H3CO2C H CO2Et

CH3O CH3

CH3 CH3 I O OCH3 Pd(OAc)2 (5 mol %) Phenanthroline (5 mol %) t-BuOK, CH3CN, 45 C

OCH3

H3C CH3 0 : 100

7-Desmethyl-2-methoxycalamenene

Hunt, A. R.; Stewart, S. K.; Whiting, A. Tetrahedron Lett., 1993, 34, 35993602.

OTf

Tandem Heck/6-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, 25052508.

Pd(OAc)2 (3 mol %) PPh3 (6 mol %) Br EtO2C EtO2C OH Ag2CO3 (2 eq) CH3CN, 80 C, 3 h EtO2C EtO2C

BrPdLn H HO

CO2CH3

Pd(OAc)2 (5 mol %) (R)BINAP (10 mol %) K2CO3 (2 equiv) KOAc (1 equiv) ClCH2CH2Cl, 60 C, 41 h 70%, 86% ee

CO2CH3 O H O H

OH

TfO

O O

(+)-Vernolepin

PdLnBr H H HO EtO2C CO2Et 85% EtO2C EtO2C HO EtO2C EtO2C HO H

Ohari, K.; Kondo, K.; Sodeoka, M.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 1173711748.

TfO O

Pd2(dba)3 (3 mol %) L (6 mol %) (i-Pr)2NEt benzene, 30 C, 72 h 92%, > 99% ee O

H O L= Ph2P N

Henniges, H.; Meyer, F. E.; Schick, U.; Funke, F.; Parsons, P. J.; de Meijere, A. Tetrahedron 1996, 52, 1154511578. Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis 1997, 13381345. Andrew Haidle

 Formation of quaternary stereocenters: CH3 CH3O OTf OTDS Pd(OAc)2 (7 mol %) (R)BINAP (17 mol %) K2CO3 (3 equiv) THF, 60 C, 72 h 90%, 90% ee CH3 N CH3O CH3 OTDS

Kinetic Resolution: CH3 O O H Pd(OAc)2 (20 mol %) (R)TolBINAP (40 mol %) K2CO3 (2.5 equiv) toluene, 100 C TDSO CH3 O O H 1.7% CH3 O O H 18.3%, 96% ee

MOMO TfO CH3

MOMO CH3

OTDS racemic MOMO CH3

HO Takemoto, T.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1993, 115, 84778488. CH3 ()-Eptazocine O O O O O (S), 71%, 66% ee CH3 N neutral CH3O O AcO CH3

CH3 O

TDSO

The choice of base influences whether the Pd complex is neutral or cationic; this in turn can influence the stereochemical outcome. O O O N CH3 I Pd2(dba)3 (5 mol %) (R)BINAP (11 mol %) PMP (5 equiv) DMA, 110 C, 8 h

H O

(+)-Wortmannin The enantiomer of the major product not observed. Instead, a complex mixture of products was formed.

Honzawa, S.; Mizutani, T.; Shibasaki, M. Tetrahedron Lett. 1999, 40, 311314. O O O N CH3 I Pd2(dba)3 (5 mol %) (R)BINAP (11 mol %) Ag3PO4 (2 equiv) NMP, 80 C, 26 h O O (R), 86%, 70% ee Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 64776487. CH3 CH3O I O OTIPS Pd2(dba)3CHCl3 (10 mol %) (S)BINAP (23 mol %) N CH3 CH3 PMP, DMA, 100 C 3 M HCl 23 C CH3O CHO O N CH3 (S), 84%, 95% ee Initial products are 2,3 dihydrofurans: O CH3 N cationic O OTf Pd(OAc)2 (3 mol %) (R)TolBINAP (6 mol %) (iPr)2NEt (3 equiv) benzene, 30 C O (R), 71%, 93% ee O (S), 7%, 67% ee

Only the (R) isomer can isomerize due to the asymmetric environment of the ligand. O

CH3 Matsuura, T.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 65006503.

H N O

CH3 N N H CH3 CH3

Ozawa, F.; Kubo, F.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.; Yanagi, K.; Moriguchi, K. Organometallics 1993, 12, 41884196. Andrew Haidle

()-Physostigmine