Ready; Catalysis Conjugate Addition
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1 eady; Catalysis Conjugate Addition Topics covered 1. 1,4 addition involving copper a. stoichiometric reactions b. catalytic reactions c. allylic substitution. Conjugate addition without copper a. Ni-based systems b. h-based systems 3. Catalytic addition of heteroatoms Topics not covered: enolate conjugate additions, Friedel-Crafts-type conjugate additions
2 eady; Catalysis Conjugate Addition: origin 1,4 addition reactions involving copper eview: rg. xns, 199, 41, st report: Kharasch, JACS, 1941, 308 "Factors Determining the Course and Mechanisms of Grignard eactions" C C 3 3 C 3 MgBr additive 3 C 3 C C C 3 C 3 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 C 3 additive none CuCl (1 mol%) an unusual example of the catalytic reaction predating the stoichiometric one classes of copper reagents: nm + CuX n = 1, X = halide, CN Cu CuM (CN)CuM (CN)CuM M = MgX, Li M = MgX, Li M = MgX, Li organocopper organocuprate (Gilman reagent) lower order cuprate higher order cuprate
3 eady; Catalysis Conjugate Addition: general CuM (M = MgX, Li) Most common for simple conjugate additions Soluble in Et, TF Thermally unstable (usually keep temp < o 0 for = aryl, vinyl; -78 o C for = alkyl) Cu I Cu(0) General reactivity trends X + CuLi Et or TF X = 1 o ~ o >3 o >>>alkynyl α or β sub. K α,β sub usually K β,β ususally difficult, but possible ketones>esters>amides Me CuLi 98% C 3 3 CN aldehydes: 1, addition competes CuLi 75% 3 CN C 3 C 3 C 3 Ac Me CuLi 55% C 3 C 3 Ac LiCu 66%
4 eady; Catalysis Conjugate Addition: mechanism mechanism ecall: εc - εcu = 0.6 (polarization: C-Sn > C-Si ~ C-Cu > C-B) Li CuX Li CuLi LiX Li a Cu-enone intermediate has been observed spectoscopically and implicated kinetically. For lead references, see Krause, ACIEE, 1999, 1644 set Li Li Li Cu II Cu Cu III Li predictions: some - formation (observed, usually use >1 equiv cuprate) Lewis Acids may help Can use enolate for further reaction
5 eady; Catalysis Conjugate Addition: TMSCl Added TMSCl+MPA very common method MgBr + 5 mol% CuBr-Me S additive Nakamura, Tet, 1989, 349 additive none TMSCl (.4 equiv) TMSCl + MPA (.4 equiv) <1 enals usually very difficult b/c 1, addition competes using MgBr + 5 mol% CuBr-Me S with added TMSCl/MPA: TMS TMS TMS 3 C %Y E/Z hex 83 94: :9 %Y E/Z hex 89 96: :4 C 3 %Y E/Z Bu 89 87: :8
6 eady; Catalysis Conjugate Addition-10 Problem with CuLi: Waste 1 equiv Solution: nontransferable ligand t-bu 1. MeLi. CuI 3. MeLi t-bu Cu C 3 Li 76% Whitesides, JACS, 1973, 3893 n-c 3 7 Cu Li + Corey, JACS, 197, 710 =, tbu, vinyl Y > 90% eagents of the form 'Cu have reactivity intermediate between Cu and ' Cu n-bu Cu P Li more reactive than Bu CuLi Stable at 0-5 o C Especially good for alkylations with alkyl halides similar: tbucu(s)li Posner, JACS, 1973, n-bu 88% Bertz, JACS, 198, 585 rigin of selectivity with mixed cuprates: Nakamra, JACS, 005, 4697
7 eady; Catalysis Conjugate Addition-11 alkyl-cyano-cuprates review: Tet, 1984, 5005 Cu(CN)Li - lower order cuprates Cu(CN)Li - igher order cuprates Lower order cuprates have reactivity intermediate between Cu and CuLi i.e. CN similar to alkyne (non-transferable ligand) usually moderate reactivity for 1,4 addns, but K for SN' + Li(NC)Cu C 'single product' 95% yield Trost, JC, 1980, 456
8 eady; Catalysis Conjugate Addition-1 alkyl-cyano-cuprates review: Tet, 1984, 5005 Cu(CN)Li - lower order cuprates Cu(CN)Li - igher order cuprates experimental observation that higher order cuprates display improved reactivity relative to Gilman reagents. I 'Cu' Bu 'Cu' Bu CuLi LiI only none Bu Cu(CN)Li 90% C Et 'Cu' C Et 'Cu' yield CuLi 38 Cu(CN)Li 75 Et n-c % 85% 88%
9 eady; Catalysis Conjugate Addition-13 The structure of higher-order cuprates has been debated: From Chem Comm. 1996
10 eady; Catalysis Conjugate Addition-14 Brief review: Krause, ACIEE, 1999, 79 So why are higher order cuprates more effective?? Not clear
11 eady; Catalysis Conjugate Addition-15 Copper-mediated addition of alkylzinc reagents ften characterized by complicated reaction mixtures: Ms C 3 NBoc 'MeCu' C Me 'MeCu' NBoc C Me NBoc C Me MeCu(CN)MgBr Me Cu(CN)(ZnCl) Mg(Br)Cl 3LiCl MeMgBr + ZnCl --> white suspension MeMgBr + ZnCl + LiCl --> solution TL 199, 3783 for conjugate addtions: review: Chem ev. 1993, 117 NC 65% Piv ZnX + CuCN LiCl soluble in TF TMS 59% Cu(CN)ZnX LiX good thermal stability (reflux TF) Less reactive than MgBr or Li-derived no rxn with epoxides only 1 o iodides Allows functional groups not compatible with MgBr or Li C Me 95% i-pr C 93% P P' n-c %
12 eady; Catalysis Conjugate Addition-16
13 eady; Catalysis Conjugate Addition-17 Problem: often hard to alkylate intermediate Li enolate Solution: transmetalate to Sn 1 (Bu 3 P)Cu C 5 11 TBS (C ) 3 C Me TBS 3 I 3 SnCl (C ) 3 C Me TBS TBS C %, d.r. Noyori, JACS, 1988, 4718 w/o Sn, get complex mixture resulting from enolate equilibration. Li Li Li Li TBS TBS TBS TBS Propose Sn(Cl) 3 Li less basic
14 eady; Catalysis Conjugate Addition-19 1,4 additions to alkynones CuLi Cu Li Cu Cu Cu ' ' ' ' ' ' cis-addn ' trans-addn Note: -Cu can add to unactivated alkynes: Br EtCu(Me S) MgBr + C6 13 C 5 Cu C 5 C 6 13 'carbocupration' get less-hindered organocopper C % rg. Syn. 1985, 64, 1 so 1,4 addn mechanistically between 1,4 addn and carbocupration
15 eady; Catalysis Conjugate Addition-0 alkynones and alkynoates are more reactive than enones, so Cu is enough C Me MgBr/CuBr Me C C Me Et TP somtimes isomerization is good: C Me + C Me Et CuLi Me C = alkyl, vinyl, phenyl, TMS Chem Lett, 1981, 905 and 1363 Cu TP Et Et 81%:1 E:Z TL 1976, 345 C Me Crimmins, JC, 1984, %
16 eady; Catalysis Conjugate Addition- more examples of enoate addn C Et 1. Me CuLi. allyl-br 3. + syn comm. 1980, 751 C Et (TMS) Cu(CN)Li Me 3 Si C Et Marshall, Syn. Comm. 1983, 531 Mg(0) 65 o C MgCl C Me C Me Cl CuI, TMEDA ppolzer, TL, 1986, 5471
17 eady; Catalysis Conjugate Addition-1 Asymmetric 1,4 addn Breakthrough came with observation that Zn are effective alkyl sources -functionalized Nu's -can do catalytically without competing rxns of nucleophile Zn Cu(II) L*, Zn details of mechanism not known stereoselectivity not understood Zn L* Cu(I) Proposals Concerted transfer (ie no Cu(III) intermediate: Noyori, Bull. Chem. Soc. 000, 999; Kitamura, Chem Lett. 003, 4. M = Cu, Zn M Zn CuL* ate limiting A: Gennari, JMC, 005, 689, 169 ate limiting E: Schrader, Chem-E.J. 004, a poorly-defiined complex
18 eady; Catalysis Conjugate Addition-3 two best systems: n n + Zn + Zn Cu(Tf) ( mol%) Feringa, Accts, 000, 346 P [Cu(Tf)] (1 mol%) N P i-pr N N 4 mol% NBn Bn.4 mol% overall best ligand, can optimize for individual substrates n n n ee Ac Et Et Et Et ipr n ee Et ipr Et ipr Et ipr oveyda, JACS, 001, 755
19 eady; Catalysis Conjugate Addition Asymmetric addition of Grignards Chemo- and stereoselectivity Feringa: PNAS, 004, 5834 JACS, 004, 1784 ACIEE, 005, 75
20 eady; Catalysis Conjugate Addition-4 SN' additions β LG Nu - β Nu Nu β γ α γ α SN γ SN' α issues: regioselectivity (α vs γ) (usually SN') SN' favored: Cu-BF 3 ; CuLi-ZnCl ; Cu; Cu(Cl or Br)(MgBr), TF SN favored: CuI(MgBr) ; Et stereoselectivity (syn vs anti) (usually anti) substrates X X X = halide, Ac, C, P()(), S()
21 eady; Catalysis Conjugate Addition-5
22 eady; Catalysis Conjugate Addition-6 SN' addns: examples ' ''MgBr/CuBr DMS '' ' C regio 98: 70-90% -'' = alkyl JC, 1986, 161 Me CuLi + Ac cis trans TBS MeCu(CN)Li BF3 LiBr Ms E TBS C Me Ms C Me C Me MgBr minimize A 1,3 JACS, 1986, 740 N 3 Me CuCN N 3 Me Trost, JACS, 1995, 10143
23 eady; Catalysis Conjugate Addition-7 SN' addns involving alkynes Me n-c 8 17 MgBr 10% CuBr n-c 8 17 TMS BuCu Bu S()C 3 sulfinate TMS 91% N EtCu Et N 60%
24 eady; Catalysis Conjugate Addition-8 best systems to date: t-bu C N N NBn note: similar but different than ligand for 1,4 addn P()(Et) + Zn or -AliBu ' or -B(Pin) NC-based ligands Mes N N Me Et = Me, 74% ee 91% ee = Et, 86% ee Cu(Tf) oveyda, JACS, 004, solid state: N N Cu Cu N N oveyda, JACS, 004, JACS, 014, 149 c-c 6 11 c-c 6 1 Me or Et Et 93% ee 94% ee N N S Cu or = Et = e poor, neutral ee's >90 3 C >80%ee >80% ee Me = Me ee's ~ 90 C 3 Boc N >80% ee
25 eady; Catalysis Conjugate Addition-31 h-catalyzed 1,4 addns of boronic acids - a remarkable rxn review: ayashi Chem ev. 003, 89 original report: Miyaura M, 1997, 49 B() + h(acac)(c) dppb /Me moderate yields high temp long times enantioselective version B() + [h()(binap)] /dioxane 35 o C n n 1 3 4Me- 4-F- exenyl ee % ee 9% ee n-c 5 11
26 eady; Catalysis Conjugate Addition-3 Mechanism of h-catalyzed 1,4 addn P = BINAP P h hp No xidation state change on h! P h B() B() 3 hp P h hydrolysis faster than β-hydride elimination P h
27 eady; Catalysis Conjugate Addition-33 h-catalyzed 1,4 addn: other substrates Esters and amides: C Me C Me NBn 89% ee 98% ee 98% ee 98% ee (requires K C 3 ) osphonates P 96% ee Et uses B B B nitro olefins N NaC 3 N 98% ee 9:1 dr initial product 98% ee
28 eady; Catalysis Conjugate Addition-34 ow to do 3 component coupling? + B cat. [h(me)(cod)] BINAP toluene B BuLi, allyl-br n n only for n = 1, n 98% ee D C n D Ti(iPr) 3 TMS n cat. [h()(binap)] 1. LiiPr. TMSCl Ti(i-Pr) 3 n TMS n ee(%) 1 3 4F- 4Me % ee TMS
29 Pd-Catalyzed addition of aryl boronic acids: formation of quaternary stereocenters Stoltz, JACS, 011, 690 Pd(CCF 3 ) ClC C Cl, o C B() PdL B() n + B() N N tbu L n Pd eck-type addition No possibility of!-hydride elimination yields mostly >80%, ee's mostly >90% Me Me Me Me Me (no -substituted) C Me Br Me CF 3 Cl Bn Me Me
30 eady; Catalysis Conjugate Addition-35 1,4-addn of nucleophiles Bergman and Toste, JACS, 003, 8696 EWG PMe 3 (5 mol%) ' EWG ' EWG Y (%) CMe Me 56 CEt Me 77 CMe Me Me 71 CN Me 79 CMe Me 0
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