Heck反应

Chem 115The Heck ReactionMyers R' R R' Reviews: Brase, S.; de Meijere, A. In Metal-catalyzed Cross-coupling Reactions, Diederich, F., and Stang, P. J., Link, J. T.; Overman, L. E. In Metal-catalyzed Cross-coupling Reactions, Diederich, F., and • General: • Intramolecular: Gibson, S. E.; Middleton, R. J. Contemp. Org. Synth. 1996, 3, 447–471. Eds.; Wiley-VCH: New York, 1998, pp. 99–166. Eds.; Wiley-VCH: New York, 1998, pp. 231–269. Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7. • Asymmetric: Shibasaki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53, 7371–7393. General transformation: R–X Pd(II) or Pd(0) catalyst base R = alkenyl, aryl, allyl, alkynyl, benzyl R' = alkyl, alkenyl, aryl, CO2R, OR, SiR3 de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379–2411. X = halide, triflate Pd(II) CH3O2C CH3O2C Pd(II)L2Br PhCH3O2C Pd(II)L2Br H Ph CH3O2C Ph H HH Ph–BrK2CO3 Mechanism: 2 L; 2 e – Pd(0)L2 Ph–Pd(II)L2–Br oxidative addition syn addition H–Pd(II)L2–Br syn elimination internal rotation KHCO3 + KBr reductive elimination • Proposed mechanism involving neutral Pd: • 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. Pd(II) CH3O2C Pd(II)L2+ Ph CH3O2C Pd(II)L2+ H Ph CH3O2C Ph H H H AgBr Ph–BrAgCO3– AgHCO3 Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4133–4135. 2 L; 2 e – Pd(0)L2 Ph–Pd(II)L2–Br oxidative addition syn addition H–Pd(II)L2+ syn elimination internal rotation reductive elimination Ph–Pd(II)L2 + Ag + halide abstraction • An example of a proposed mechanism involving cationic Pd: HH CH3O2C H H Ph–Br PhCH3O2CCH3O2C Pd catalyst Ph–Br PhCH3O2CCH3O2C Ag+ Pd catalyst • Pd(II) is reduced to the catalytically active Pd(0) in situ, typically through the oxidation of a phosphine ligand. Pd(OAc)2 + H2O + nPR3 + 2R'3N Pd(PR3)n-1 + O=PR3 + 2R'3N•HOAc Ozawa, F.; Kubo, A.; Hayashi, T. Chemistry Lett. 1992, 2177–2180. Andrew Haidle HX N SO2Ph I N SO2Ph PPh3 (6 mol %) Pd(OAc)2 (3 mol %) DMF, 23 °C Ag2CO3, eq Time, h Yield, % 1 1 24 2 48 5 80 35 50 N SO2Ph CH3 By-product:Sakamoto, T.; Kondo, Y.; Uchiyama, M.; Yamanaka, H. J. Chem. Soc. Perkin Trans. 1 1993, 1941–1942. • Use of silver salts can minimize alkene isomerization. Conditions: • Catalysts: Pd(OAc)2 most common Pd2(dba)3 stable Pd(0) source; useful if substrate • Ligands: Phosphines (PR3), used to prevent deposition of Pd(0) mirror. • Solvents: Typically aprotic; a range of polarities. toluene THF 1,1-dichloroethane DMF 2.4 7.6 10.5 Solvent Dielectric constant 38.3 • Reactions with vinyl or aryl triflates often parallel those of the corresponding halides in the presence of silver salts. I TMS OTf AgNO3, Et3N Et3N TMS TMS Pd(OAc)2 (3 mol %) DMSO, 50 °C, 3 h Pd(OAc)2 (3 mol%) DMSO, 50 °C, 3 h 64% 61% Karabelas, K.; Hallberg, A. J. Org. Chem. 1988, 53, 4909–4914. I TMS TMS I Et3N GC yields 12% 57% 30% Pd(OAc)2 (3 mol %) DMSO, 100 °C, 15 h Pd Pd HH–Pd * * • Reversible β-hydride elimination can lead to alkene isomerization. N O CH3 I N O CH3 N O CH3 Pd(OAc)2 (1 mol %) PPh3 (3 mol %) acetonitrile, 3h, reflux Et3N (2 equiv) Conditions as above, plus AgNO3 (1 equiv) and 23 °C 1 : 1 26 : 1 Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4133–4135. is sensitive to oxidation O dba = • With some ligands, experimental evidence points to a Pd(II)/Pd(IV) catalytic cycle, although the debate is ongoing. 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. * Andrew Haidle I NaHCO3, 3 A ms CO2CH3 insoluble bases accelerates the rate to the extent that lower reaction temperatures are possible. Pd(OAc)2 (5 mol %) DMF, 50 °C, 2 h 0 1 2 99 Equiv. of n–Bu4NCl GC Yield(%) Jeffery, T. Tetrahedron 1996, 52, 10113–10130. • Jeffery conditions: The combination of tetraalkylammonium salts (phase-transfer catalysts) and • 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 Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc. 1991, 113, 8375–8384. likely to decompose under the Heck reaction conditions. • Bases: Both soluble and insoluble bases are used. N CH3 CH3CH3 CH3 CH3 Et3N K2CO3 Ag2CO3 Soluble examples Insoluble examples 1,2,2,6,6-pentamethylpiperidine (PMP) • Conditions for the Heck coupling of aryl chlorides have been developed. Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10–11. Cl CH3O CO2CH3 CH3O CO2CH3 Pd2(dba)3 (1.5 mol %) P(t-Bu)3 (6 mol %) Cs2CO3 (1.1 equiv) dioxane, 120 °C, 24 h 82% CO2CH3 Regiochemistry of addition: • Neutral Pd complexes: regiochemistry is governed by sterics; position of Ar attachment: Y = CO2R • Cationic Pd complexes: regiochemistry is affected by electronics. The cationic Pd complex Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7. increases the polarization of the alkene favoring transfer of the vinyl or aryl group to the site of Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J. Org. Chem. 1992, 57, 1481–1486. OHY Ph N O CH3 OH OH OAc 100 100 100 60 90 20 80 mixture 40 10 CN CONH2 Y = CO2R OHY Ph N O CH3 OH OH OAc 100 60 5 90 10 100 95 CN CONH2 least electron density. 40 100 5 95 Andrew Haidle • A major issue in intramolecular Heck reactions is the mode of ring closure, i.e., exo versus endo. O O O CH3 I O O O CH3 PdCl2(CH3CN)2 (100 mol %) Et3N Ziegler, F. E.; Chakraborty, U. R.; Weisenfeld, R. B. Tetrahedron 1981, 37, 4035–4040. CH3CN, 25 °C 55% • For large rings, conformational effects can be minimal. If a neutral Pd complex is used, sterics enforce endo selectivity. PdLn endo exo endoexo • The Heck reaction is useful for macrocylization. HH CH3N OH OHO (–)-Morphine DBSN I OBn CH3O H DBSN OBn OCH3Pd(OCOCF3)2(PPh3)2 • Five-, six-, and seven-membered ring closures (the most efficient Heck ring closures) give predominantly exo products. Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 11028–11029. PMP, toluene, 120 °C 60% (10 mol %) H H DBS = dibenzosuberyl O O NHCO2CH3 O I O O O O O O O PdLn CH3O2CN PdLnO O O NHCO2CH3 H Pd R LnPd R Ag2CO3, THF, 66 °C eclipsed twisted eclipsed (boat) twisted (chair) Pd(OAc)2 (10 mol %) PPh3 (40 mol %) 73% > 20 : 1 Overman, L. E. Pure & Appl. Chem. 1994, 66, 1423–1430. • 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. NCH3O O OH H O O CH3 (±)-6a-epipretazettine Ln stereochemistry defines the incipient quaternary center H O OO O O H O NHCO2CH3 O O O O Andrew Haidle H CH3O2CN H H CH3O CH3O I N O OTBSTBSO NHR CH3O CH3O N O TBSO TBSO NHR CH3O CH3O N O TBSO TBSO NHR Pd(OAc)2 (2 mol %) Et3N, CH3CN KOAc, DMF • Variation of reaction conditions can greatly influence exo versus endo selectivity in small rings. Rigby, J. H.; Hughes, R. C.; Heeg, M. J. J. Am. Chem. Soc. 1995, 117, 7834–7835. PPh3 (6 mol %) 80 °C, 2 h 32% Pd(OAc)2 (6 mol %) n–Bu4NCl 80 °C, 22h 58% CH3O CH3O I N O OTBSTBSO NHR CH3OH O H O CH3 CH3 OOH CH3 ON H O OH O O O CH3 OO O CH3 Taxol CH3 CH3 CH3 OTBS O O O O CH3 H OBn TfO Pd(PPh3)4 (100 mol %) CH3 OTBS O H OBn CH3 CH3 OO CH3 O K2CO3, CH3CN 4 A ms, 90 °C 49% Angew. Chem., Int. Ed. Engl. 1995, 34, 1723–1726. Masters, J. J.; Link, J. T.; Snyder, L. B.; Young, W. B.; Danishefsky, S. J. • Steric and electronic effects begin to compete with conformational effects when forming medium–sized rings. • The authors' rationale for these results is that under the Jeffery conditions, the coordination sphere of palladium is relatively smaller, and thus the metal can be accommodated at the more substituted alkene site during migratory insertion. R1 PdX R2 R2 R1 R2 R1 R3 R2 R1 Nu R2 R1 R2 R1 CO2CH3 R2 R1 M R2 R1 R2 R3 PdX R3 PdX R3 CO CH3OH R3R1PdX β-hydride elimination Heck reaction Nucleophilic attack Alkylation Heck sp cascadeHeck sp2 cascade Transmetalation Carbonylation R3M R3–X Oxidation, Nu – Tandem Reaction: • Additional reaction pathways become available when the initial Pd–C species does not (or can not) decompose via β-hydride elimination. Kucera, D. J.; O'Connor, S. J.; Overman, L. E. J. Org. Chem. 1993, 58, 5304–5306. O CH3 H HO2C HO O H CH3 R OH CH3 H LnPd R OTBS H CH3 I CH3 H TBSO R Ag2CO3, THF, 65 °C Scopadulcic acid A Pd(OAc)2 (10 mol %) PPh3 (20 mol %) TBAF, THF, 23°C 82% • Tandem Heck reactions: Fox, M. E.; Li, C; Marino, J. P.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 5467–5480. R CH3 H OTBS O O R = Andrew Haidle LnPd O CH3 CH3 CH3 CH3 H Br OTBSTDSO CH3 CH3 CH3 CH3 H PdLn TBSO TDSO CH3 CH3 CH3 CH3 H TDSO OTBS CH3 CH3 CH3 CH3 H CH3 TDSO TBSO Pd2(dba)3 (5 mol %) PPh3 (48 mol %) Et3N, toluene 120 °C, 1.5 h 76% overall Trost, B. M.; Dumas, J.; Villa, M. J. Am. Chem. Soc. 1992, 114, 9836–9845. CH3 CH3 CH3 CH3 H HO OH Alphacalcidiol TBAF THF 79% N I OH CH3O H CH3O2C N OH OCH3 O CH3O Pd(TFA)2(PPh3)2 (20 mol %) PMP, toluene, 120 °C 56% N O OCH3 O CH3O (–)-Morphine • Tandem Heck/π–allylpalladium reactions Hong, C. Y.; Overman, L. E. Tetrahedron Lett. 1994, 35, 3453–3456. 1 : 9 [1,7]-H-shift H H PdLn CH3N OH OHO H H Andrew Haidle OOCH3 CO2CH3 TfO H CH3 I OTDS CH3 CH3TDSO OTDS • Tandem Suzuki/Heck reactions 9-BBN PdCl2(dppf) (10 mol %) AsPh3 (10 mol %) CsHCO3, DMSO, 85 °C 65% Kojima, A.; Honzawa, S.; Boden, C. D. J.; Shibasaki, M. Tetrahedron Lett. 1997, 38, 3455–3458. B OOCH3 CO2CH3 TfO H OOCH3 CO2CH3 TfO H OOCH3 CO2CH3 H • Tandem Heck reaction, intermolecular Br OH EtO2C EtO2C EtO2C EtO2C BrPdLn HO H EtO2C EtO2C HO H PdLnBr EtO2C EtO2C HO H HO H EtO2C CO2Et Pd(OAc)2 (3 mol %) PPh3 (6 mol %) Ag2CO3 (2 eq) CH3CN, 80 °C, 3 h 85% Henniges, H.; Meyer, F. E.; Schick, U.; Funke, F.; Parsons, P. J.; de Meijere, A. Tetrahedron 1996, • Tandem Heck/6π-electrocyclization reactions: 52, 11545–11578. • The ease of reaction (Heck versus Suzuki) is highly dependent upon the reaction conditions: Hunt, A. R.; Stewart, S. K.; Whiting, A. Tetrahedron Lett., 1993, 34, 3599–3602. O OCH3 I B O O CH3 CH3 CH3 CH3 B O O CH3 H3C CH3 CH3 O OCH3 H3CO O Pd(OAc)2 (1 mol %) Bu3N, CH3CN, 120 °C PPh3 (5 mol %) 87 13 0 100 Pd(OAc)2 (5 mol %) Phenanthroline (5 mol %) t-BuOK, CH3CN, 45 °C : : Enantioselective Heck Reactions: • Typical yields = 50–80% • Typical ee's = 80–95% • Formation of tertiary stereocenters: CH3O CH3 I Si(CH3)3 CH3O CH3 H Pd2(dba)3•CHCl3 (2.5 mol %) (R)–BINAP (7.0 mol %) Ag3PO4 (1.1 equiv) DMF, 48 h, 80 °C 91%, 92% ee Tietze, L. F.; Raschke, T. Synlett 1995, 597–598. 7-Desmethyl-2-methoxycalamenene OTf CO2Et N CO2CH3 N(CH3)2(CH3)2N N H3CO2C CO2Et benzene, 60 °C, 20 h 95%, > 99% ee Pd[(R)–BINAP]2 (3 mol %) Ozawa, F.; Kobatake, Y.; Hayashi, T. Tetrahedron Lett. 1993, 34, 2505–2508. CO2CH3 TfO CO2CH3 H Pd(OAc)2 (5 mol %) (R)–BINAP (10 mol %) K2CO3 (2 equiv) ClCH2CH2Cl, 60 °C, 41 h 70%, 86% ee Ohari, K.; Kondo, K.; Sodeoka, M.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 11737–11748. O H O O O OH (+)-Vernolepin O TfO O N O Ph2P Pd2(dba)3 (3 mol %) L (6 mol %) L = benzene, 30 °C, 72 h 92%, > 99% ee Loiseleur, O.; Hayashi, M.; Schmees, N.; Pfaltz, A. Synthesis 1997, 1338–1345. H • Note that the alkene within the intially formed pyrrolidine has migrated under the reaction conditions. H KOAc (1 equiv) Andrew Haidle (i-Pr)2NEt • 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 I CH3 O O N CH3O O O N CH3OPd2(dba)3 (5 mol %) (R)–BINAP (11 mol %) Ag3PO4 (2 equiv) PMP (5 equiv) NMP, 80 °C, 26 h (R), 86%, 70% ee Pd2(dba)3 (5 mol %) (R)–BINAP (11 mol %) DMA, 110 °C, 8 h (S), 71%, 66% ee Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6477–6487. O O O N I CH3 neutral cationic • Formation of quaternary stereocenters: HO CH3 N CH3 (–)-Eptazocine OTfCH3O CH3 OTDS CH3O CH3 OTDS Pd(OAc)2 (7 mol %) (R)–BINAP (17 mol %) K2CO3 (3 equiv) THF, 60 °C, 72 h 90%, 90% ee Takemoto, T.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1993, 115, 8477–8488. CH3O I N O CH3 OTIPS CH3 CH3O N CH3 O CH3 CHO PMP, DMA, 100 °C Pd2(dba)3•CHCl3 (10 mol %) (S)–BINAP (23 mol %) 3 M HCl 23 °C (S), 84%, 95% ee Matsuura, T.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6500–6503. N N CH3 CH3 H CH3 O O H NCH3 (–)-Physostigmine O OCH3 H MOMO CH3TDSO O OCH3 H MOMO TDSO CH3 18.3%, 96% ee 1.7% O OCH3 TfO H MOMO CH3 OTDS Pd(OAc)2 (20 mol %) (R)–Tol–BINAP (40 mol %) K2CO3 (2.5 equiv) toluene, 100 °C racemic • Kinetic Resolution: O O O CH3 OAcO CH3 CH3O O H (+)-Wortmannin Honzawa, S.; Mizutani, T.; Shibasaki, M. Tetrahedron Lett. 1999, 40, 311–314. O O O OTf (R), 71%, 93% ee Pd(OAc)2 (3 mol %) (R)–Tol–BINAP (6 mol %) (i–Pr)2NEt (3 equiv) benzene, 30 °C (S), 7%, 67% ee • Initial products are 2,3 dihydrofurans: O O O • Only the (R) isomer can isomerize due to the asymmetric environment of the ligand. Organometallics 1993, 12, 4188–4196. Ozawa, F.; Kubo, F.; Matsumoto, Y.; Hayashi, T.; Nishioka, E.; Yanagi, K.; Moriguchi, K. • The enantiomer of the major product not observed. Instead, a complex mixture of products was Andrew Haidle formed.