Carbon-Carbon Bond Forming Reactions

I. Substitution Reaction II. Addition Reaction

Carbon-Carbon Bond Forming Reactions I. Substitution Reaction a.More Acidic Carbon Centers : cyanide, acetylide, hetero-atom substituted centers b. Less Acidic Carbon Centers : alkyl anions Acidity of compounds --

Chapter 1 : Alkylation of enolates, enamines, imine anions Mostly S N 2 type RXN. Depends on the solvent counter ion temperature structure additives

1. Generation of carbanion by Deprotonation Stabilization by resonance induction Activating Power : NO 2 > RCO > RSO 2 > COOH, COOR, CN, CONH 2 ** extra-alkyl group increases pKa Base : NaNH 2, n-BuLi, NaOR, NaH, LiNR 2 ** Stronger base is required for complete conversion **

1. Generation of carbanion by Deprotonation ** Comparison of pKa values is important ** Some bases are nuclephiles as well !!!

2-1. Regioselectivity in enolate formation Under kinetic control : strong base, aprotic solvent, complete consumption of the ketone kaka kbkb If k a > k b Major product is Under thermodynamic control : at Equilibrium – excess ketone, protic solvent or slow deprotonation An enolate through Kinetic Control is easier to obtain exclusively than the other enolate through Thermodynamic Control.

2-2. Stereoselectivity in enolate formation Major thermodynamic control kinetic control Major T.S. for kinetic product Not Real

2-3. Enantioselectivity in enolate formation Chiral bases enable to distinguish enantiotopic protons. 95%, 84% e.e.

3. Other means to generate enolate (exclusive generation of single isomeric enolate) a. From TMS ethers

3. Other means to generate enolate (exclusive generation of single isomeric enolate) b. From enones

4. Alkylation of enolates a. Generation of enolates Amide base : LDA (since 1968) : for less acidic proton Stable under 0 o C Non-nucleophilic Stable at r.t. No reducing ability NaOEt/EtOH, or NaH/solvent : for more acidic proton DBU, DBN Et 3 N NaOH

strong non-ionic base : Phosphazene base Synlett 752(2000) and ref. BEMP P 2 EtP 4 t-Bu pKa=27.6 pKa=32.7 pKa=42.1

strong non-ionic base : Phosphazene base Synlett 752(2000) and ref. BuLi 67 : 33 P 4 tBu 98 : 2 JOC 5343(1994)

4. Alkylation of enolates b. Factors affecting alkylation process : ** S N 2 reaction** i)Electrophile : mostly primary alkyls. Secondary reacts very slow Tertiary does not substitue. Methyl, allylic, benzylics are most reactive ii) Solvent : the more polar, the faster the reaction it’s more related to the aggregation state of enolates iii) Counter ion : “ more naked anion is more reactive ” M : Li, Mg, Na, K, NR 4 More reactive iv) Additives : TMEDA, HMPA, Crown ether ( 18-C-6 : Na +, K + 12-C-4 : Li + )

4. Alkylation of enolates b. Malonate ester,  ketoester synthesis i)Monoalkylation v.s. Dialkyation Formation of cyclic compounds ; rates (3>5>6>4) ii)Decarboxylation ; Krapcho (TL, 215(1967)) nucleophilic, nonhydrolytic c. Alkylation of dianions

4. Alkylation of enolates d. O-alkylation v.s. C-alkylation i)More naked anion gives more O-alkylation : K + with HMPA ii)Hard electrophile prefers O-alkylation : X= OTs, OTf conformational effect

Alkylation of conjugated enolate

4. Alkylation of enolates e. Alkylation of aldehyde : self-condensation is fast. Used base : KH, KNH 2 TL 3791 (1977)

f. Acid derivatives : acid, ester, amide, nitrile, lactone, lactam – more reactive Nitrile anion reacts well with epoxides

Acid derivatives offer chiral auxiliaries for asymmetric alkylation Evans’ chiral oxazolidinone E : alkyl, halogen nitrogen, sulfur

4. Alkylation of enamines, imine anions a. enamines Neutral, isolable enolate equivalent – more nucleophilic than enolate Robinson Annulation

4. Alkylation of enamines, imine anions b. Imine anion : metalloenamine reactive enolate equivalent Chiral induction possible

c. Hydrazone anion

4. Conjugate addition of enolates : Michael addition Lewis acid with silyl enolether Can be carried out with catalytic amount of base : depends on enolate. Successive reaction is possible. Diethylaluminum Cyanide : CN - Enamine for Robinson Annulation

Homewrok Problems : 2, 4, 7, 9, 11, 13, 15, 19, 20 Due date :