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C-C BOND FORMATION 72 Carbon- Carbon Bond Formation 1 C-C BOND FORMATION 72 Carbon- Carbon Bond Formation 1. Alkylation of enolates, enamines and hydrazones C&S: Chapt. 1, 2.1, 2.2 problems Ch 1: 1; 2; 3, 7; 8a-d; 9; 14 Ch. 2: 1; 2; 4) Smith: Chapt. 9 2. Alkylation of heteroatom stabilized anions C&S :Chapt. 2.4 - 2.6) 3. Umpolung Smith: Chapt. 8.6 4. Organometallic Reagents C&S: Chapt. 7, 8, 9 problems ch 7: 1; 2; 3, 6; 13 Ch. 8: 1; 2 Smith: Chapt. 8 5. Sigmatropic Rearrangements . C&S Chapt. 6.5, 6.6, 6.7 # 1e,f,h,op Smith Chapt. 11.12, 11.13 Enolates Comprehensive Organic Synthesis 1991, vol. 2, 99. - a -deprotonation of a ketone, aldehyde or ester by treatment with a strong non- nucleophillic base. - carbonyl group stabilizes the resulting negative charge. O O O - B: H H - H R R R H H H H - Base is chosen so as to favor enolate formation. Acidity of C-H bond must be greater (lower pKa value) than that of the conjugate acid of the base (C&S table 1.1, pg 3) O MeO- pK = 15 unfavorable enolate pK = 20 a H C CH a - concentration 3 3 tBuO pKa = 19 O O more favorable pKa = 10 enolate concentration H3C CH2 OEt - Common bases: NaH, EtONa, tBuOK, NaNH2, LiNiPr2, M N(SiMe3)2, Na CH2S(O)CH3 Enolate Formation: - H+ Catalyzed (thermodynamic) O OH H+ - Base induced (thermodynamic or kinetic) O O - :B +B:H H Regioselective Enolate Formation Tetrahedron 1976, 32, 2979. - Kinetic enolate- deprotonation of the most accessable proton (relative rates of deprotonation). Reaction done under essentially irreversible conditions. O O - Li+ LDA, THF, -78°C C-C BOND FORMATION 73 typical conditions: strong hindered (non-nucleophilic) base such as LDA R2NH pKa= ~30 Li N Ester Enolates- Esters are susceptible to substitution by the base, even LDA can be problematic. Use very hindered non-nucleophillic base (Li isopropylcyclohexyl amide) O O OR' LDA, THF, -78°C N E+ R R O O- Li+ N Li R OR' OR' R THF, -78°C - Thermodynamic Enolate- Reversible deprotonation to give the most stable enolate: more highly substituted C=C of the enol form - + O K O O - K+ - + tBuO K , tBuOH kinetic thermodynamic typical conditions: RO- M+ in ROH , protic solvent allows reversible enolate formation. Enolate in small concentration (pKa of ROH= 15-18 range) - note: the kinetic and thermodynamic enolate in some cases may be the same - for a,b -unsaturated ketones O thermodynamic kinetic site site Trapping of Kinetic Enolates - enol acetates 1) NaH, DME 2) Ac O Ph Ph 2 Ph + O O kinetic O O O isolatable separate & purify CH3Li, THF CH3Li, THF Regiochemically pure enolates Ph Ph O- Li+ O- Li+ C-C BOND FORMATION 74 - silyl enolethers Synthesis 1977, 91. Acc. Chem. Res. 1985, 18, 181. 1) LDA 2) Me SiCl Ph Ph 3 Ph + OTMS O kinetic OTMS isolatable separate & purify CH3Li, THF CH Li, THF -or- 3 Bu4NF -or- TiCl4 Geometrically Ph Ph pure enolates O- M+ O- M+ - tetraalkylammonium enolates- "naked" enolates - TMS silyl enol ethers are labile: can also use Et3Si-, iPr3Si- etc. - Silyl enol ether formation with R3SiCl+ Et3N gives thermodyanamic silyl enol ether - From Enones 1) MeLi 1) Li, NH3 + 2) TMS-Cl 2) E O TMSO O H H E O OSiMe OSiMe3 3 TMS-Cl, Et3N TMS-OTf Et3N O OSiMe3 Li, NH3, tBuOH TMS-Cl - From conjugate (1,4-) additions O O- Li+ O + (CH3)2CuLi E E Trap or use directly - From reduction of a -halo carbonyls O O- M+ Br Zn or Mg Alkylation of Enolates (condensation of enolates with alkyl halides and epoxides) Comprehensive Organic Synthesis 1991, vol. 3, 1. 1° alkyl halides, allylic and benzylic halides work well 2° alkyl halides can be troublesome 3° alkyl halides don't work C-C BOND FORMATION 75 O O a) LDA, THF, -78°C Me b) MeI - Rate of alkylation is increased in more polar solvents (or addition of additive) O O O O NMe2 (Me2N)3P O S CH3N CH3N NCH3 R NMe2 H3C CH3 HMPA Me2N R= H DMF DMSO R-CH3 DMA TMEDA Mechanism of Enolate Alkylation: SN2 reaction, inversion of electrophile stereochemistry X C 180 ° M+ -O Alkylation of 4-t-butylcyclohexanone: O O E R R equitorial anchor E H A E H tBu A favored Chair tBu R O R B O- M+ H E O Twist Boat B tBu R E on cyclohexanone enolates, the electrophile approaches from an "axial" trajectory. This approach leads directly into a chair-like product. "Equitorial apprach leads to a higher energy twist-boat conformation. Alkylation of a,b -unsaturated carbonyls - + O M O R R E 1 2 R1 R2 O Kinetic H E H R1 R2 H H O- M+ O E R1 R2 R1 R2 H H E Thermodynamic C-C BOND FORMATION 76 Stork-Danheiser Enone Transposition: - overall g-alkylation of an a,b -unsaturated ketone O O LDA HO CH3 CH3 PhCH OCH Cl CH Li H O+ 2 2 PhO 3 3 PhO PhO OMe OMe OMe O J. Org. Chem. 1995, 60, 7837. Chiral enolates- Chiral auxilaries. D.A. Evans JACS 1982, 104 , 1737; Aldrichimica Acta 1982,15 , 23. Asymmetric Synthesis 1984, 3, 1. - N-Acyl oxazolidinones O O H N OH R 2 N O Me Ph Me Ph norephedrine O O R H2N OH N O valinol O O O O O R LDA, THF R O O LiOH, H2O, THF R N N OH Et-I Me Ph Me Ph Complimentary Methods major product for enantiospecific alkylations (96:4) O O O O O Diastereoselectivity: 92 - 98 % R LDA, THF N O R LiOH, H2O, THF R for most alkyl halides N O OH Et-I major product (96:4) Enolate Oxidation Chem. Rev. 1992, 92, 919. O O O O NaN(SiMe ) , R 3 2 R N O THF, -78°C N O O OH N (88 - 98 % de) Ph SO2Ph 1) HO- O O 2) CH N LDA, THF 2 2 O R 3) TFA N O R O Boc N 4) Raney Ni OMe N OtBu NH2 tBuO N HN (94 - 98 % de) O Boc C-C BOND FORMATION 77 Bu Bu O O B O O O O NBS - R Bu2BOTf, Et3N N3 N O R R N O N O Br Ph Ph Ph O O 1) LiOH O R 2) H2, Pd/C N O R OH N3 NH2 Ph D- amino acids O O O O R KN(SiMe3)2, THF R N O N O N3 SO2N3 Ph Ph Oppolzer Camphor based auxillaries Tetrahedron, 1987, 43, 1969. diastereoselectivities on the order of 50 : 1 SO2Ph R N Ar Ar N O R O SO2Ph R O O O N O S O SO2N(C6H11)2 O R 2 H H Et Cu•BF LDA, NBS H O 2 3 O O Br HO O O NH O 2 SO2N(C6H11)2 SO2N(C6H11)2 O SO2N(C6H11)2 Asymmetric Acetate Aldol O S O TIPSO O 1) Br H N O J. Am. Chem. Soc. 1998, 120, 591 Br NH2 J. Org. Chem. 1986, 51, 2391 Sn(OTf)2, CH2Cl2, R3N, -40°C 2) TIPS-OTf, pyridine 85 %, 19:1 de 3) NH3 Chiral lithium amide basess CH3 CH Ph N OMe 3 MeO Li MeO O CO2Et THF, -78°C (CH3)2C=O OMe OMe O (72% ee) C-C BOND FORMATION 78 H N Ph OTMS O But H N Ph N N O Li Li N THF, HMPA (97 % ee) TMSCl N tBu tBu Me Lewis Acid Mediated Alkylation of Silyl Enolethers- SN1 like alkylations OTMS O tBu-Cl, TiCl4, CH3 CH2Cl2, -40°C note: alkylation with a 3° alkyl halide (79%) C(CH3)3 ACIEE1978, 17, 48 SPh TL 1979, 1427 OTMS O SPh O Raney Ni R Cl R R (95 %) TiCl4, CH2Cl2, -40°C (78%) Enamines Gilbert Stork Tetrahedron 1982, 38, 1975, 3363. - Advantages: mono-alkylation, usually gives product from kinetic enolization O O N N can not become coplanar "Kinetic" "Thermodynamic" O O O O •• + N N N O H R-I H2O R E + H , (-H2O) enamine -Chiral enamines O N E Imines Isoelectronic with ketones Me Ph O Li OMe Ph O E = -CH , -Et, Pr, N N 1) E 3 + PhCH2-, allyl- LDA, THF, -20°C 2) H3O E ee 87 - 99 % C-C BOND FORMATION 79 Hydrazones isoelectronic with ketones Comprehensive Organic Synthesis 1991, 2, 503 N N O N N N - N Me2N-NH2 LDA, THF - + H , (-H2O) N + N O E hydrolysis E E - Hydrazone anions are more reactive than the corresponding ketone or aldehyde enolate. - Drawback: can be difficult to hydrolyze. - Chiral hydrazones for asymmetric alkylations (RAMP/SAMP hydrazones- D. Enders "Asymmetric Synthesis" vol 3, chapt 4, Academic Press; 1983) OMe MeO N N NH2 H2N SAMP RAMP N N LDA O N OMe N OMe O3 H I OTBS (95 % de) TBSO TBSO 1) LDA N 2) Ts-CH3, THF N -95 - -20 °C O OMe 3) MeI, 2N HCl CH3 (100 % ee) Me O Li •• MeO R1 N N R1 N N E (C,C) R R2 H 2 H Z (C,N) E E Aldol Condensation Comprehensive Organic Synthesis 1991, 2, 133, 181. O a) LDA, THF, -78°C O OH b-hydroxyl aldehyde b R'CHO (aldol) R H H R' R - The effects of the counterion on the reactivity of the enolates can be important Reactivity Li+ < Na+ < K+ < R4N+ addition of crown ethers C-C BOND FORMATION 80 - The aldol reaction is an equilibrium which can be "driven" to completion.
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