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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 L; 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 L; 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 %) 24 50 DMF, 23 °C 48 35 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 1993, 1941–1942 TMS OTf Pd(OAc)2 (3 mol%) AgNO3, Et3N Et3N DMSO, 50 °C, h DMSO, 50 °C, 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 : • Solvents: Typically aprotic; a range of polarities acetonitrile, 3h, reflux as above, plus AgNO3 (1 equiv) and 23 °C 26 : 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, h Equiv of n-Bu4NCl GC Yield(%) 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 40 100 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 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 : 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 (±)-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, 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 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, 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 • 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, 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 %) 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 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 : 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 work-up purify + B work-up purify C D work-up 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 flow reactor flow reactor 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 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 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 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 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 ... 1994, 35 , 34 53? ? ?34 56 • 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... 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... 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,