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The Heck Reaction Chem 115 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.
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