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1 Common rganometallic eagents Li Et 2 Li Mg Et 2 Li alkyllithium rignard Mg Mg Li Zn TF ZnCl 2 TF dialkylzinc Zn 2 2 Zn Li CuI TF ganocuprate CuI 2 2 CuI common electrophile pairings ' Cl ' '' ' ' ' ' ' ' Ts ' 2 CuLi Li Mg 2 Zn Li Mg 2 Zn Li Mg Li (2 equiv) Li Mg 2 CuLi typical products ' ' ' ' '' ' ' ' Ether TF typically used as solvents since these solvents can dissolve the polar ganometallic reagents Dry solvents and avoidance of water is a MUST since these reagents are also strong bases and will react immediately with water to fm eactions often carried out at -78 C to control the reactivity and prevent further undesired reactions eaction products shown typicall require neutralization of the rxn mixture at the end of the reaction ( 3 + ) The related nucleophile generated from terminal alkynes reacts with aldehydes, ketones, epoxides and - to affd similar products Some vinyl/aryl Li can be generated from commercially available alkyl Li by taking advantage of the different stabilities of - at SP 2 hybridized carbons over SP 3 hybridized carbons LDA Na deprotonated terminal alkyne nbuli tbuli TF Li Li

2 1. Aldehydes (aldol reaction) keto K, 2 tautomerization Simple Condensation eactions enol 2 aldol product *enerally limited to "self"-condensation since if there are two different aldehydes present several different products could result. owever, a "crossed"-aldol reaction is possible if one of the aldehydes does not have any α-protons available. 2. Ketones (aldol reaction) ' keto K, 2 ' enol ' possible crossed-aldol participant 2 ' ' aldol product *enerally most useful f symmetrical ketones unsymmetrical ketones that have only one set of α- proton available. As f the aldehyde reactions, "crossed"-aldols are possible if one of the ketones does not have any α-protons available. *Aldehyde and Ketone aldol reactions are both equilibrium processes that typically fav the aldo product when starting with an aldehyde, but the starting material when starting with a ketone. *Upon heating, however all aldol products are subject to loss of a molecule of water (dehydration) to fm the cresponding conjugated α,β-unsaturated product. This process is non-reversible and drives the reaction to completion ()' ()' heat '() '() 3. Esters (Claisen condensation) ' Na, *few percent conversion ' ' ' ' ' ' ' *enerally limited to "self"-condensation since if there are two different esters are present several different products could result. owever, a "crossed"-claisen reaction is possible if one of the esters does not have any α-protons available. Unlike the aldo reaction, this process is non-reversible. '

3 1. Aldehydes, Symmetrical Ketones, and Esters =, ', ' LDA, TF 78 C *K, tbuli, KMDS are also good bases " Cl " β-diketone Enolates *100% conversion " ( ketone f ester enolates) " " Ts " " α-alkylation β-hydroxyketone 2. Dealing with unsymmetrical ketones A. Kinetic vs. thermodynamic enolates E "thermodynamic" "kinetic" 1. Na, TF, rt 2. Et *me substituted C=C bond; fmed under conditions that allow f equilibration e.g., Na, 25 C, slight excess of ketone *substituted C=C bond (and slightly me acidic protons); fmed under conditions that do NT allow f equilibration e.g., addition of ketone to LDA, 78 C 1. LDA, -78 C, TF 2. Et B. Silyl enol ethers TMS TMS TMS Et 3 N, ClSiMe TMS 1. C 3 Li, TF 2. Et separate

4 Cyclopropanation 1. eneral comments *difficult to do via simple cyclization reactions *generate a carbene in the presence of a C=C bond C ' 1. Simmons-Smith ' "carbene" C 2 I 2 Zn-Cu C 2 "carbenoid" ' ' stereospecific C 2 I 2 Zn-Cu 2. Base-promoted elimination C tbuk C C nbu 3 Sn AIBN Δ = Cl, 3. α-diazoalkanes Cu(I) C 2 Et N N h(iv) 58% "carbenoid" intermediate

5 C=C Bond Fmation 1. Wittig reaction () + PPh 3 ()' () ()' phosphonium salt Wittig precurs acidic proton LDA Na BuLi () ()' () ()' Wittig reagent "ylide" () ()' () '() " '''() " '''() ' ' (Ph) 3 P ' ' ' = ', ' * stabilized ylides automatically lead to E stereochemistry * keep solution cold ( 78 C) * add strong base (e.g., PhLi) tbu (Ph) 3 P (Ph) 3 P ' Li ' "Schlosser modification" 2. elated reactions A. Wittig-ner reaction C 2 ' P(C 3 ) 3 3 C P Na " '''() 3 C P ' ' ' 3 C 3 C " '''() me stable alkene product usually fmed B. Peterson olefination LDA (Me) 3 Si ' (Me) 3 Si ' " '''() C 2 ' " '''() me stable alkene product usually fmed

6 Palladium-Catalyzed C-C Bond Fmation Pd (PPh 3 ) 4 Pd (PPh 3 ) 2 *active Pd species codinatively unsaturated - "insertion" = vinyl aryl 1. eck eaction: Addition to C=C bonds followed by elimination ' ' Pd (PPh 3 ) 2 *reactive intermediate ' Pd (PPh 3 ) 2 *addition Pd(PPh 3 ) 2 *elimination eneral: = Cl,, I, Tf Pd, base ' ' * base = Et 3 N, K 2 C 3, KAc + others Pd(Ac) 2, Ph 3 P, Et 3 N N N(C)C 3 2. Suzuki Coupling: transmetallation of bonated compounds followed by reductive elimination Pd (PPh 3 ) 2 ' B(" 2 ) Pd Pd ' ' *B(") 2 often = B() 2 [bonic acid] B(") 2 [bonic esters] eneral: = Cl,, I, Tf Pd, base (') 2 B * base = K 2 C 3, K NaEt + others (') 2 B C 3 + F 3 C B Pd(Ac)2 K 2 C 3

7 3. Stille Coupling: transmetallation of ganotin compounds followed by reductive elimination Pd (PPh 3 ) 2 ' Sn(" 3 ) Pd Pd ' ' *B(")2 often = B()2 [bonic acid] B(")2 [bonic esters] eneral: = Cl,, I, Tf Pd, base () 3 Sn * base = K 2 C 3, K NaEt + others () 3 Sn Tf + (nbu)3 Sn Pd(PPh 3 ) 4 rubbs ing-pening Metathesis Cl 2 (PCy 3 ) 2 u Ph + 2 C=C 2 *Cy = cyclohexyl (Cl 2 )u Ph intermediates 5 mol-% rubbs catalyst 0.1 equiv benzoquinone C 2 Cl 2, 40 C, 24 h