IG. The Synthetic & Mechanistic Chemistry of CupratesI. Basic PrinciplesDr. P. WipfPage 1 of 402/4/2008History & Structure ofCuprates• In 1952, Gilman reported the in situ preparation of Me2CuLi (J. Org.Chem. 1952, 17, 1630).• House and others subsequently demonstrated that the chemistry of CuI-derived organometallics was distinctively different from their lithium- ormagnesium-based precursors (House, H. O.; Respess, W. L.; Whitesides, G.M. J. Org. Chem. 1966, 31, 3138).• Structural information on organocopper derivatives is scarce. Mixing MeLi-MeCu in different stoichiometric ratios provides an equilibrium mixture ofMe2CuLi, Me3Cu2Li, and Me3CuLi2. The latter reagent is supposed to bemore stereoselective and more reactive than Me2CuLi (Ashby, E. C. et al. J.Am. Chem. Soc. 1977, 99, 5312; J. Org. Chem. 1977, 42, 2805).Dr. P. WipfPage 2 of 402/4/2008Structure of Cuprates - TheControversy Begins….• In 1981, Lipshutz proposed the formation of “higher-order mixedcyanocuprates” (H.O. cuprates) by the addition of 2 equiv of anorganolithium reagent to 1 equiv of copper cyanide.• These Me2Cu(CN)Li2 reagents were assumed to be dianionic saltswith the cyano group bound to copper (Lipshutz et al. J. Am. Chem.Soc. 1981, 103, 7672).• Furthermore, it was reported that H.O. cuprates are more reactivethan lower order Gilman cuprates and be more stable due tobackbonding from the filled d-orbital on copper to the empty p*-orbital on the nitrile (Lipshutz et al. Synthesis 1987, 325; J. Org.Chem. 1983, 48, 546).Dr. P. WipfPage 3 of 402/4/2008Structure of HO (?) Cuprates• Whether or not the cyanide ligand is bound to copper has been acontroversial topic (Bertz, S. H. J. Am. Chem. Soc. 1991, 113, 5470).• The Bertz proposal has the cyano group coordinated as lithium cyanide toa Gilman-like species. In the presence of HMPA, some free LiCN is indeeddetected (Cabezas, J. A.; Oehlschlager, A. C. J. Am. Chem. Soc. 1997,119, 3878; no trace of LiCN is found if the cuprate is prepared in THFonly).• Also, EXAFS and XANES studies have shown that the addition of cyanideto dimethylcuprate does not cause a significant change at the copper center(Barnhart, T. M.; Huang, H.; Penner-Hahn, J. E. J. Org. Chem. 1995, 60,4310).• However, addition of methyl E-cinnamate led to changes attributed to acuprate-enoate π-complex.Dr. P. WipfPage 4 of 402/4/2008Structure of Cyano CupratesLiLiHHHHHHS SC NCuProposed solution structure for Me2CuLi-LiCNArArLiLiSSC NCuX-ray structure for Ar2CuLi-LiCNSSDr. P. WipfPage 5 of 402/4/2008Conjugate AdditionsOL Cu RLiLiR Cu LLL The formation of a π−complex appears to be followed by σ-complex formation andreductive elimination. The reductive elimination is rate-determining (Frantz, D. E.;Singleton, D. A.; Snyder, J. P., "13C Kinetic isotope effects for the addition of lithiumdibutylcuprate to cyclohexenone. Reductive elimination is rate-determining." J. Am.Chem. Soc. 1997, 119, 3383).Dr. P. WipfPage 6 of 402/4/2008Conjugate Additions - To Beor Not To Be A RadicalO-R2CuLi•++OCuR2LiOLiCuIIIR2-CuROLiRDr. P. WipfPage 7 of 402/4/2008Evidence for ionicmechanismEvidence for radical anionmechanismOCutBuOCutBuO==retention of configurationOWhitesides J. Org. Chem. 1972, 37, 3718.Whitesides J. Am. Chem. Soc. 1969, 91, 6542.OMe2CuLiOMe55%Marshall Tetrahedron Lett. 1971, 2875.O39%may be formed via intermediateradical anionO49%O43%Me2CuLiODr. P. WipfPage 8 of 402/4/2008- butCO2tBuMe2CuLiOLiOtBuk = 10-2s-1OtBuOLiCO2tBuMe2CuLitBuOtBuOLiLiOtBu- Half-life of intermediate radical anion is very short.- Subsequent coupling with cuprate reagent (after e-transfer) is faster than other radical reactions in some cases.- However, competitive single electron reductions with cuprates have been observed and they may be used to effect reductive elimination reactions analogous to dissolving metal or Zn reductions.Dr. P. WipfPage 9 of 402/4/2008LiOOTsOTsOOeLiOAc2OAcO- Key piece of evidence for electron transfer mechanismTrap of intermediate radical anion (Hannah; Tetrahedron Lett. 1975, 187)OOTsMe2CuLiDr. P. WipfPage 10 of 402/4/2008PhOCO2EtCO2EtMeO2CCOMetBuOOOCH3Ered-1.63 v-2.13 v-2.14 v-2.12 v-2.20 vCO2MenPrtBuOOCH3OOAll can accept an e-(undergo reduction)by Me2CuLiEo = -2.35 vEred-2.26 v-2.25 v-2.33 v-2.35 vDr. P. WipfPage 11 of 402/4/2008these substrates do not react with Me2CuLi:OBuO-2.43 v-2.54 vtBuCO2CH3tBuCO2CH3-2.50 vtBuCN-2.55 v -House estimation ofR4R3R2R1Obase value = -1.9 vR2R1Obase value = -1.8 v substituent R1 R2 R3/R4 substituent R1 R2 alkyl -0.1 -0.1 -0.1 alkyl -0.1 -0.1 alkoxy -0.3 0 -0.3 alkoxy -0.3 --- phenyl +0.4 +0.1 +0.4 RR CNRbase value = -2.3 v Dr. P. WipfPage 12 of 402/4/2008Conjugate Additions• Caveat: The mechanism of cuprate additionsdepends on cuprate structure, substrate,solvent, additives (e.g. TMS-Cl), and thespecific reaction conditions.• Review: Woodward, S., "Decoding the"black box" reactivity that is organocuprateconjugate addition chemistry." Chem. Soc.Rev. 2000, 29, 393-401.Dr. P. WipfPage 13 of 402/4/2008-Effect of substrates:O>OROCN>>O-OORORO- Unsaturated esters are less reactive than enones.- !,!"Disubstitution slows reaction.-unreactive substrates willreact if Lewis acids areadded to activatesubstrate towardnucleophilic addition -also note the alternativeuse of higher ordercuprates [R2CuCN]Li2-Maruyama J. Am. Chem.Soc. 1977, 99, 5652.-Yamamoto J. Am. Chem.Soc. 1978, 100, 3240.Dr. P. WipfPage 14 of 402/4/2008Other Cuprates• In addition to Gilman and Cyanocuprate reagents, Yamamoto-typecuprates (Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1986, 25, 947)and cuprate/TMS-Cl mixtures have interesting reactivity. Organocoppercompounds can also be obtained via transmetalation (Kharasch-Grignard; Wipf, P., "Transmetalation reactions in organocopperchemistry." Synthesis 1993, 537-557):Me2CuLi TMSCICorey Tetrahedron Lett, 1985, 26, 6015.OOOOMe2CuLiOOMe2CuLiTMSCIDr. P. WipfPage 15 of 402/4/2008Mechanism of TMSCl-accelerated additions ofcuprates to enones• Several conflicting theories have been proposed to explain this effect. Corey andBoaz suggested that TMS-Cl accelerates the conjugate addition by the silylationof a d,π*-complex to produce the silyl enol ether of a Cu(III)-adduct and thusmake the process irreversible (e.g., 2→7).OR2CuLiOCuR2LiOLiCuR2XOLiROTMSOTMSCuR2LiOTMSCuR2XOTMSRTMS-Cl TMS-ClTMS-ClTMS-Cl1 2 3 45 6 7 8ClDr. P. WipfPage
View Full Document
Unlocking...