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' R–X + R' + HX base R

R = alkenyl, aryl, allyl, alkynyl, benzyl X = halide, triflate R' = alkyl, alkenyl, aryl, CO R, OR, SiR 2 3 Pd(II) AgHCO 2 L; 2 e – • Proposed mechanism involving neutral Pd: 3 – reductive elimination AgCO3 Ph–Br oxidative addition Pd(0)L2 Mechanism: Pd catalyst + Ph–Br Ph H–Pd(II)L2 Ph–Pd(II)L2–Br CH3O2C CH3O2C Ph Ag + CH3O2C Pd(II) KHCO + KBr 2 L; 2 e – AgBr 3 syn elimination + halide abstraction Pd(II)L2 reductive elimination oxidative addition H + K2CO3 Ph–Br H Ph–Pd(II)L2 Pd(0)L2 CH3O2C Ph H + Pd(II)L2 H–Pd(II)L2–Br Ph–Pd(II)L2–Br H Ph CH3O2C syn elimination CH3O2C H internal rotation syn addition CH3O2C H Ph CH3O2C Pd(II)L2Br syn addition H Pd(II)L2Br H H CH O C Ph 3 2 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 DMF, 23 °C N 1 48 35

I I SO2Ph SO2Ph Pd(OAc)2 (3 mol %) 2 5 80

Et3N DMSO, 100 °C, 15 h CH 12% 57% 30% 3 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.

Shaw, B. L.; Perera, S. D.; Staley, E. A. J. Chem. Soc., Chem. Commun. 1998, 1361–1362. 64% 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 * * * • Catalysts: Pd(OAc)2 Pd2(dba)3

• Use of silver salts can minimize alkene isomerization. stable Pd(0) source; useful if substrate most common is sensitive to oxidation CH CH O 3 O 3 O N N O N dba = CH3 I Conditions

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

as above, plus Solvent toluene THF 1,1-dichloroethane 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:

Et N K CO Ag CO 10 CH CH 3 2 3 2 3 3 N 3 CH CH3 3 CH CH3 OH 3 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 100 60 I CO2CH3 CO2CH3 80 Pd(OAc)2 (5 mol %) NaHCO , 3Å-MS 3 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.

95 100 • One proposed explanation for this rate enhancement is based on the fact that palladium 40

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. 95 100 90 O • Conditions for the Heck coupling of aryl chlorides have been developed. Y N OH OAc

100 10 5

Pd2(dba)3 (1.5 mol %) P(t-Bu) (6 mol %) Y = CO2R Cl CO2CH3 3 CO CH 2 3 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 smaller rings. The eclipsed orientation is preferred for endo R R the reaction, even if this means the rest of the molecule eclipsed twisted H must adopt a less than ideal conformation. exo PdLn 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

CH3CN, 25 °C O PdLn O O PdLn 55% O NHCO2CH3 CH3O2CN O CH3 O H CH3 H H O O H O Ziegler, F. E.; Chakraborty, U. R.; Weisenfeld, R. B. Tetrahedron 1981, 37, 4035–4040. O O O eclipsed (boat) 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 OH O

(–)-Morphine OH O CH O N 3 H H CH3 CH3N H (±)-6a-epipretazettine DBS = dibenzosuberyl 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: I CH3O CH3O KOAc, DMF N Pd(II) catalyst, oxdidant N NHR O R CH O 80 °C, 22h CH O Ar–H + R + HX 3 3 base Ar O 58%

R = alkenyl, aryl, allyl, alkynyl, benzyl X = halide, triflate R' = alkyl, alkenyl, aryl, CO R, OR, SiR OTBS TBSO 2 3 TBSO Pd(OAc)2 (2 mol %) Mechanism: TBSO NHR PPh3 (6 mol %) I • Proposed mechanism: oxidative addition CH3O CH3O reduced oxidant Et N, CH CN N O Ar–H N NHR 3 3 80 °C, 2 h PdX2 CH3O CH3O oxidant H–X 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 benzoquinone, t-BuOOH, R OTBS KMnO4, Na2S2O8, Cu(OAc)2 TfO OTBS CH3 CH CH3 3 Pd(PPh ) (100 mol %) CH3 !-H elimination CH3 3 4 CH3 CH 3 K2CO3, CH3CN CH3 Ar O R O H H 4Å MS, 90 °C OBn 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 CH 3 CH O O 3 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 OH O O CH3 63% MeO 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) (5 mol %) 2 R R BQ (2 equiv) 3 3 OAc OAc Ag2CO3 (0.6 equiv) PdX PdX Cl R1 R2 R1 n-BuCO2H (16 equiv) Cl R2 R2 100 equiv 1 equiv 34 : 36 : 30 o : m :p R3 100 °C, 48 h 2 R PdX Heck sp cascade R3 1 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 Nu H BQ (1 equiv) Cl N Me CO2CH3 Cl N Me TsOH•H2O (1 equiv) R1 R1 CO n-Bu O R R2 2 MeO 2 O AcOH, PhMe MeO R1 R2 22 °C, 16 h CO2n-Bu Carbonylation 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 L Pd PdL Pd(OAc)2 (10 mol %) n n • Site selectivity with pyrrole substrates can be achieved by the use of directing (carbamate) or H PPh (20 mol %) 3 OTBS R blocking (triisopropylsilyl) groups on the nitrogen atom. R Ag2CO3, THF, 65 °C H TBSO H CH3 CH CO2Bn 3 OTBS Pd(OAc)2 (10 mol %) PhCO3t-Bu (1 equiv) N CO Bn TBAF, THF, 23°C N CO2Bn 2 AcOH, dioxane, DMSO R N 82% 35 °C, 24–48 h t-BuO O Si(i-Pr) CH3 3 CH R = CO2t-Bu O 3 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 OH Pd(OAc)2 (10 mol %) HO O Ag2CO3 (1.5 equiv) pyridine (1 equiv) Scopadulcic acid A N CO2t-Bu 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 CH 3 Pd (dba) (5 mol %) H3C 2 3 H PPh (48 mol %) CH3 3 OCH3 Et3N, toluene N TDSO OTBS CH3O2C H 120 °C, 1.5 h H OH Pd(TFA) (PPh ) (20 mol %) O Br 2 3 2 76% overall PdLn PMP, toluene, 120 °C CH3O N CH3O I H C 56% 3 CH3 OH H3C H CH3 OH OCH3 H OH O O O H PdLn CH N 3 CH3O N TDSO H (–)-Morphine TBSO

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

• Tandem Suzuki/Heck reactions H C 3 CH3 H3C H3C CH3 H3C O H3C O H C O O 3 CH3 I OTDS H3C 9-BBN CH H TBSO 3 [1,7]-H-shift TfO TfO PdCl2(dppf) (10 mol %) CH3 H H AsPh (10 mol %) CO CH 3 CO2CH3 2 3 CsHCO , DMSO, 85 °C H 1 : 9 3 B TDSO TDSO OTBS

H C 3 CH3 H C 3 H3C O O CH 3 H3C O O TBAF H C 3 TfO H THF TDSO H CH H 65% 3 CO2CH3 79% CO2CH3

OTDS HO OH Alphacalcidiol

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 CH B 3 Bu3N, CH3CN, 120 °C CH O 3 H3CO O Pd2(dba)3•CHCl3 (2.5 mol %) CH3 CH O CH3O CH3 3 (R)–BINAP (7.0 mol %) O CH3 B + CH3 CH I Ag3PO4 (1.1 equiv) CH3 I O O 3 H O OCH3 DMF, 48 h, 80 °C CH Si(CH3)3 H3C 3 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] (3 mol %) Hunt, A. R.; Stewart, S. K.; Whiting, A. Tetrahedron Lett., 1993, 34, 3599–3602. 2 CO Et CO Et (CH ) N N(CH ) H 2 • Tandem Heck/6!-electrocyclization reactions: 2 3 2 3 2 N N

OTf CO2CH3 H3CO2C Pd(OAc)2 (3 mol %) BrPdLn PPh3 (6 mol %) benzene, 60 °C, 20 h H Br Ag2CO3 (2 eq) 95%, > 99% ee EtO C OH HO 2 CH3CN, 80 °C, 3 h EtO2C CO Et EtO2C 2 • 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 CO CH CO2CH3 2 3 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 EtO C HO KOAc (1 equiv) EtO C 2 2 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 H CO 92%, > 99% ee 3 Li2CO3, C6F6 H3CO 80 ºC, 71% CO2Et CO2Et L = (+)-Menthyl(O C)-Leu-OH 2 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 %) O H C O (R)–BINAP (17 mol %) H3C 3 MOMO O MOMO O CH3O OTf CH3O K CO (3 equiv) Pd(OAc)2 (20 mol %) H3C OTDS 2 3 H3C TDSO THF, 60 °C, 72 h OTDS TfO (R)–Tol–BINAP (40 mol %) H H H3C 90%, 90% ee K2CO3 (2.5 equiv) toluene, 100 °C 1.7% CH 3 OTDS N O racemic H3C MOMO O H C OH 3 O TDSO AcO H3C Takemoto, T.; Sodeoka, M.; Sasai, H.; Shibasaki, M. CH3 H 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 CH O 3 (+)-Wortmannin O Pd2(dba)3 (5 mol %) N CH3 (R)–BINAP (11 mol %) N neutral O O I PMP (5 equiv) • The enantiomer of the major product not observed. Instead, a complex mixture of products was DMA, 110 °C, 8 h O O formed. (S), 71%, 66% ee Honzawa, S.; Mizutani, T.; Shibasaki, M. Tetrahedron Lett. 1999, 40, 311–314. CH3 O O Pd2(dba)3 (5 mol %) N CH3 (R)–BINAP (11 mol %) N cationic O O Pd(OAc) (3 mol %) I Ag3PO4 (2 equiv) OTf 2 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 PMP, DMA, 100 °C 23 °C CH CH3 CH3 3 (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 CH3 Matsuura, T.; Overman, L. E.; Poon, D. J. O N H Ozawa, F.; Kubo, F.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.; Yanagi, K.; Moriguchi, K. CH Organometallics 1993, 12, 4188–4196. J. Am. Chem. Soc. 1998, 120, 6500–6503. (–)-Physostigmine 3 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 Pd(CH3CN)2(OTs)2 (6 mol %) B(OH)2 separated from the reaction media. Cu(OTf)2, (6 mol %) Me H OH ligand (13 mol %), O2 Pd cat. (recycled) O Me N(i-Pr)3 (1.2 equiv) DMF, 23 ºC, 24 h I O CH 3 [bmim]NTf2 O CH Cl 65%, 99 : 1 er 3 via Cl O 130 °C, 50 min Pd OH H OH OH 99% Pd Me Me Me [bmim]NTf = 1-butyl-3-methylimidazolium 2 Pd cat. Ar Ar Ar Pd bis(tri-fluoromethylsulfonyl)imide

CH3 N N N H3C N work-up procedure H3C n-Bu Tf Tf Ph P Pd Cl O 3 F C Cl Ligand = 3 product N N Me 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 H O 2 H2O base•HX base•HX Heck Reactions in Continuous Flow: Pd-cat [bmim]NTf • Continuous flow techniques have become an increasingly popular approach to streamlining multi- 2 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 + – 0 C and D not isolated ArNEt3 Cl Pd N N CH3 CH3 • Advantages of continuous flow: DMF, 130 °C, Et3N O 87%, >99% purity • Improved control over mixing and temperature. O • 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 P(o-Tol) (0.6 mol %) Pd(OAc) (5 mol %) F Br 3 2 F3C F3C N Et3N, CH3CN, 75 ºC N P(o-tol)3 (10 mol %) O H Et3N, DMF N N Pd(OAc) (1 mol %) H 2. 2 Br 80 °C, 87% P(o-Tol)3 (3 mol %) Br CO2H (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: O S • Reaction was optimized to limit the formation of the by-products depicted below. Cl O S DG-041 Cl Pd(OAc)2 (10 mol %) O Zegar, S.; Tokar, C.; Enache, L. A.; Rajagopol, V.; Zeller, W.; O'Connell, M.; Singh, J.; Muellner, F. Br P(o-tol)3 (40 mol %) 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) NH N CH3 2

N CH3

1. Pd2(dba)3 (1 mol%) N • 2HCl CH3 Et N, i-PrOH, 78 ºC O I 3 (91.6 kg) N N O Boc 2. HCl, i-PrOH, 40 ºC N O N 97% (two steps) Boc O (101 kg) NaOH H CO N 3 Cl 80% Possible by-products (not observed):

O CH3 N OCH HN 3 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