Reactions of the

O-Li+ MeLi Enolisation

CH3CHO Me O-Li+ Addition to carbonyl Me H

! on the α-carbon are, in principle, acidic, and a non-nucleophilic base can deprotonate the carbon. ! A prerequisite for deprotonation is a correct conformation!

Enolate Chemistry – The Beginning

CLAISEN-SCHMIDT CONDENSATION

O NaOH, EtOH O O CHO O

Schmidt, J.G. Ber. Dtsch. Chem. Ges. 1880, 13, 2341; 1881, 14, 1459. Claisen, L.; Claparède, A. Ber. Dtsch. Chem. Ges.1881, 14, 349. Claisen, L. Ber. Dtsch. Chem. Ges. 1887, 20, 655. Claisen, L. Justus Liebigs Ann. Chem. 1899, 306, 322.

ACETOACETIC CONDENSATION

O O 1. NaH, Et2O CO2Et + OEt 2. H3O

Geuther, A. Arch. Pharm. (Weinheim) 1863, 106, 97. Claisen, L.; Claparède, A. Ber. Dtsch. Chem. Ges. 1881, 14, 2460. Claisen, L.; Lowman, O. Ber. Dtsch. Chem. Ges. 1887, 20, 651. Enolate Chemistry – The Beginning

REFORMATSKY REACTION

OZn, Me2CO OH O Cl OEt benzene OEt

Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210. J. Russ. Phys. Chem. Soc. 1890, 22, 44.

PERKIN REACTION

CHO Ac2O

ONa O O

Perkin, W.H. J. Chem. Soc. 1868, 21, 53, 181; 1877, 31, 388.

Enolates

! The term enolate first appeared in 1907, when Hans Stobbe discussed the FeCl3 color test for in terms of ‘das violette Eisenenolat’. The term was first applied to describe C=C-O- species in 1920, when Scheibler and Voβ described the preparation of several ester enolates. The first explicit formulation of a delocalized enolate was by Ingold, Shoppee and Thorpe in 1926, who represented base-catalyzed tautomerisms as shown below. The authors did not, however, use the term ‘enolate’, not even thirty years later!

B HCCO CCO CCOH

! The ambident nucleophilic nature of enolates was established by 1937, when Hauser accurately described the base-promoted enolisation in the mechanism of acetoacetic ester condensation. ! In the early days, the enolates were generated in the presence of the . It was only in the ‘50’s that Hauser first reported the use of a preformed enolate to obtain cross-coupling products of and . O

OH O LiNH2, NH3 Ph O Me t-BuO t-BuO Ph

76 % Enolates

! The first important base of reduced nucleophilicity was BMDA (bromomagnesium di- isopropylamide), which was first used by Hauser in 1949 as a catalyst for acetoacetic ester condensation. The first useful, nowadays perhaps the most popular base, was LDA (lithium di- isopropylamide), used originally by Levine for the same purpose in 1950 [Hamell, M.; Levine, R. J. Org. Chem. 1950, 15, 162; Levine, R. Chem. Rev. 1954, 54, 467.] However, it took another decade until Wittig employed LDA for the deprotonation of aldimines in the ‘Wittig directed ’.

LDA, ether O 25 ºC, 15 min

EtO CO2Et O

Hauser, 1950 47 %

LDA, THF Ph2C=O H H3O+ Ph NLi ON N Ph CHO Ph Ph Wittig, 1963

Enolates

! Hydrophobic strong bases (triphenylmethylsodium, -potassium, and -lithium) were developed in the ‘50’s and ‘60’s as reagents soluble in most common organic solvents and basic enough to deprotonate and esters. Furthermore, they are highly colored, and can thus serve as indicators - this is their principal use nowadays. Early examples of stoichiometric enolisation from normal ketones originated from the laboratories of Herbert O. House. OOLiOLi LDA, DME -78 ºC +

99 % 1 %

O OLi OLi H H LDA, DME -78 ºC +

H H H

98 % 2 % Kinetic and thermodynamic control

Kinetic vs. thermodynamic control

R R R

-O O -O

Thermodynamically favored Kinetically favored More stable Forms faster

Kinetic and thermodynamic control

-O Me O Me -O Me CH

Me Me H3CMe Me AB

3 H 1H ! A tetrasubstituted A is more stable ! If A and B can equilibrate, and [A] > [B] – A is the thermodynamic enolate ! If equilibration is not possible (e.g. large, strong base, which only ‘sees’ the methyl group), a kinetically controlled product mixture is formed; – B is the kinetic enolate Kinetic and thermodynamic control

t-BuOK O t-BuOH, ∆

O 86-94 %

Br

O OLi 65 ºC

LDA, THF, Br hexane, -72 ºC 77-84 %

House, H.O.; Sayer, T.S.B.; Yau, C.-C. J. Org. Chem. 1978, 43, 2153.

Kinetic and thermodynamic control

Enolaatti

Ketoni Termodynaaminen Kineettinen

- O O O-

Ph3CLi 28 72 tasapain. 94 6

- O O O-

LDA 1 99 tasapain. 78 22

- O O O- H H

H H H

Ph3CLi 13 87 tasapain. 53 47 Kinetic and thermodynamic control

O- O Me MeI Ainoa tuote!

H H

Aksiaalinen

H Me MeI O Me H O- O

O-

House, H. J. Org. Chem. 1979, 44, 2400.

Regioselective Enolate Formation

1. Use of Activating Groups R R Overall

O O

HCO2Et Acid or base NaOEt ∆

R R R O - O O CHO CHO CHO O Baisted, J. Chem. Soc. 1965, 2340. Johnson, J. Am. Chem. Soc. 1960, 82, 614. R R base

O -O SPh SPh Coates, Tetrahedron Lett. 1974, 1955. Regioselective Enolate Formation

2. Use of Blocking Groups

R R R HCO2Et

O O O CHO CHOH

TsS STs KOAc

R

O SS Removal: RaNi

Woodward J. Chem. Soc. 1957, 1131.

Regioselective Enolate Formation

3. Use of

R R R H+ cat. + R'2NH > - H2O O R'2N R'2N

E = 0 rel Erel = 1.6 kcal/mol

Augustine Org. Synth Coll Vol V 1973, 869. Regioselective Enolate Formation

3. Use of Enamines - Robinson type

R R R

R'2N R'2N R'2N - O -O

O

R R '- R'2NH' R'2N

O O

Augustine Org. Synth Coll Vol V 1973, 869.

Regioselective Enolate Formation

4. Thermodynamic vs. Kinetic Control

R R R

-O O -O

Thermodynamically preferred Kinetically preferred More stable More rapidly formed Regioselective Enolate Formation

THERMODYNAMIC ENOLATE FORMATION: ! less than stoichiometric amount of base ! weak, sterically non-hindered base ! protic solvents

KINETIC ENOLATE FORMATION: ! at least stoichiometric amount of base ! strong, bulky base ! polar aprotic solvents

House J. Org. Chem. 1971, 36, 2361. Stork J. Org. Chem. 1974, 39, 3459.

Regioselective Enolate Formation

5. Enones as Enolate Precursors

Et3Si

Li, NH3 O t O BuOH -OO

Boeckman J. Am. Chem. Soc. 1974, 96, 6179. Stork, J. Am. Chem. Soc. 1974, 96, 6181.

Et Si Me3 Me

Me2CuLi O

O -OO

Boeckman J. Am. Chem. Soc. 1973, 95, 6867. Regioselective Enolate Formation

6. Derivatives a) Enol acetates

RR R R

OHO AcO AcO

Favored

Erel = 0

R R Me Me -O -O O

Me2CO

Erel = 2.3 kcal/mol

House J. Org. Chem. 1965, 30, 1341, 2502.

Regioselective Enolate Formation

6. Enol Derivatives b) Silyl enolates

TMSCl, Et3N + DMF TMSO TMSO

991: (80 %) O 1) LDA 99: 1 (74 %) 2) TMSCl Stork, G. J. Am. Chem. Soc. 1968, 90, 4462. House, H.O. J. Org. Chem. 1969, 34, 2324.

1) Li/NH3 2) TMSCl O TMSO

Stork, G. J. Am. Chem. Soc. 1974, 96, 7114. Regioselective Enolate Formation

1) Me2CuLi > 90 % O 2) TMSCl TMSO

Boeckman J. Am. Chem. Soc. 1974, 96, 6179.

SiEt3

MeLi O etc.

TMSO -O O > 80 % Stork, G. J. Am. Chem. Soc. 1973, 95, 6152.

Enolates

n-BuLi [conditions unknown] LOBA N N H Li O

2-hexanone, THF, Me3SiCl, SiCl, THF, Me3 Bu -78 ºC -78 ºC Me

OSiMe3 OSiMe3

OSiMe3 OSiMe3 C H C H 4 9 4 9 Bu Bu Me Me 97.5 % 2.5 % 97 % 3 %

Corey, E.J.; Gross, A.E. Tetrahedron Lett. 1984, 25, 495. Corey, E.J.; Gross, A.G. Org. Synth. 1987, 65, 166. Regioselective Enolization

O 1. LDA, DME, -78ºC (92:8 selectivity in enolisation*) MeO 2. hexanal 3. H2O, HCl

Me3SiO OOH MeO

Me3SiO (rac)-[6]-gingerol (57 %)

*LiHMDS in place of LDA gave only 75:25 selectivity in enolisation

Denniff, P.; Whiting, D.A. J. Chem. Soc., Chem. Commun. 1976, 712. Denniff, P.;Macleod, I.; Whiting, D.A. J. Chem. Soc. Perkin I 1981, 82.

Regioselective Enolization

t-BuOK O t-BuOH, ∆

O 86-94 %

Br

O OLi 65 ºC

LDA, THF, Br hexane, -72 ºC 77-84 %

House, H.O.; Sayer, T.S.B.; Yau, C.-C. J. Org. Chem. 1978, 43, 2153. Regioselective Enolization

LICA, THF -78 ºC MeI

H H LiO O kinetic enolate 85 % H t-BuOK, t-BuOH, ∆ O HOAc

H H KO O

thermodynamic enolate N Li LICA = Lee, R.A.; McAndrews, C.; Patel, K.M.; Reusch, W. Tetrahedron Lett. 1973, 965. Lithium i-propykcyclohexylamide Ringold, J.; Malhotra, S.K. Tetrahedron Lett. 1972, 669.

Regioselective Enolization

O 1. LDA, THF 1. LiAlH4 2. CH2=CHCH2Br 2. H2O

O O 80 %

Stork, G.; Danheiser, R.L. J. Org. Chem. 1973, 38, 1775.

O LDA 1. MeLi Cl O THF-HMPA Cl 2. H3O+

OEt OEt O

β-vetivone

Stork, G.; Danheiser, R.L.; Ganem, B. J. Am. Chem. Soc. 1973, 95, 3414. Regioselective Enolization

Me 1. Li, NH3, t-BuOH Me 2. CH2O, ether, -78 ºC HO

O O 64 % H H Me HO

O 1. Li, NH3, PhNH2 Me 2. CH2O, ether, -78ºC

O 60 % H HO

Stork, G.; d'Angelo, J. J. Am. Chem. Soc. 1974, 96, 7114.

Regioselective Enolization

R1 O O R1 OH O

R2 OEt R2 OEt R3 R4 R3 R4

O O H H X X COOH 2 XC (COOEt) XCC COOEt C 2 5 ka 10 % enol % enol

Neat CCl4 Neat CCl4 H H C 2 C 5,56 68 91

Me H HC C 1,95 40 66 78 89

Me H C C 0,73 17 30 30 44 Me

Me 2,2 26 50 5 5 H2C C

Me Me 1,1 HC C 15 28 5 5

Gelin, S.; Gelin, R. Bull. Chim. Soc. Fr. 1970, 340-341. Regioselective Enolization - Synthesis of PGE2 Intermediate

1. CuI, Ph3P, THF Ph3SnO 2. compound 1 I 3. HMPA, Ph3SnCl OTBS TBSO OTBS

O ICO2Me

TBSO O 1 CO2Me

TBSO OTBS

PGE2 family

Suzuki, M.; Yanagisawa, A.; Noyori, R. J. Am. Chem. Soc. 1985, 107, 3348.

Enolates: Z(O,R)- and E(O,R)-enolates

Regardless of other groups the encircled R' and O- determine whether one is Z(O,R)- or E(O,R)- enolate.

R R O- O- R' H H R'

(E)-enolate (Z)-enolate Enolates: deprotonation

90°

R R H O H O 30° R O R' H H R' H O H Heq π π R' R *C=O R *C=O H H σ O σ O Hax Most stable C-H C-H conformation R' H H R' -12 ° H O

H 104 ° R R - O O- R' H H R'

(E)-enolate (Z)-enolate

Corey, E.J.; Sneen, R.A. J. Am. Chem. Soc. 1956, 78, 6269.

Effect of base on enolisation

! Base must be large and hard. ! Thus functions only as a base and not as a .

Ph Ph

Si Si Si Si - + N N N N O K Li Li M M

LDA LiTMP MHMDS ((Me2Ph)2Si)NLi t-BuOK M = Li, Na, K pKa 36 37 26 25 18-20 Selective formation of E/Z-enolates

O emäs TMSCl OTMS OTMS

R R R

Z(O,R) E(O,R)

RemäsZE Et LDA 30 70 (Me3Si)2NLi 70 30 (Et3Si)2NLi 99 1 (Me2PhSi)2NLi >100 <1

cC6H11 LDA 61 39 (Me3Si)2NLi 85 15 (Et3Si)2NLi 94 6 (Me2PhSi)2NLi 99 1

Masamune, S. Aldrichimica Acta 1982, 15, 47.

Enolisation: Ireland-mechanism

! According to the Ireland-mechanism an (E)-enolate is formed via a chair form transition state (R = large alkyl group) ! If also R’ is large, a (Z)-enolate is formed! ! Note the actual abstractor and the role of the metal!

R , LiBr N Li R N R R + H R - 78 °C - O- O Li H R' 1 O R = Et 50 : R = i-Pr 21 : 1 "R R = t-Bu 1 : >20

Ireland, R.E. J. Am. Chem. Soc. 1976, 98, 2868. Collum, D.B. J. Am. Chem. Soc. 1991, 113, 9571. Collum, D.B. J. Am. Chem. Soc. 1997, 119, 4765. Dimeric Li-enolate - LDA complex

! First X-ray structure for a dimeric complex.

R Si O O 3 200 mol-% LDA Li O Li N O Si Li Li N O O SiR3

STEREO STRUCTURE: CCSD-code FOGRIC

Willard, P.G. J. Am. Chem. Soc. 1987, 109, 5539.

Application: Taxol

D O O K O

t-BuOK D2O

O O O O O O

Ketoni Enolaatti

Stork, G. 1995. Approach of the electrophile

o Houk: 106 (compare: NB! This angle is similar to Burgi-Dunitz angle) the Flippin-Lodge angle!

E E Agami, C. Tetrahedron Lett. 1977, 2801-2804. O R Tetrahedron Lett. 1979, 1855-1858. - RR Tetrahedron 1979, 35, 961-967. R OH Houk, K.N. J. Am. Chem. Soc. 1986,108, 2659-2662.

side view end view

Si O equatorial axial E attack attack

O- O E Re

Asymmetric Induction in Enolate and Azaenolate Alkylations Intraligand asymmetric induction

intraannular extraannular chelate-mediated intraannular OM OM OM O M * R1 R M * R1 OO * O R OM R2 R2 * * * R R 1,3- 1,4- 1,2-1,3- 1,2- 1,3-

Interligand asymmetric induction

M* ML * O O n

Evans, D.A. Asymmetric Synthesis 1984, 3, 1-110. Controlling Face Selectivity

CO2tBu MeI L = HMPA tBuO N H 1) LDA O 2) MeI CO Me L 2 Li NO OtBu N Li O OMe O tBuO L

MeI L = THF

hydrolysis

O O

CO2Me CO2Me

Tomioka, K.; Koga, K. J. Am. Chem. Soc. 1984, 106, 2718. Tomioka, K.; Koga, K. Tetrahedron Lett. 1984, 5677.

SAMP-Hydrazones in Alkylation

O N Li N OMe SAMP N LDA N N

NH2 OMe OMe SAMP Enders, 1976

Me Me O O O + H3O Me-X Me N Li N N N or O 3 Me

X = I 67 %ee 99 %ee X = OSO2Me

Enders, D. Asymmetric Synthesis, vol. 3. Chiral Bicyclic Lactam Enolates

OH O . KMnO4 NH2OH HCl N Oxidation of pinene: OH OH Carlson, R.G.; Pierce, J.K. J. Org. Chem. 1971, 36, 2319-2324. LiAlH4 Reduction of oxime: O Masui, M.; Shioiri, T. Tetrahedron 1995, 51, R1 OH O R1 8363-8370. NH2 O N H O OH p-TsOH, toluene

Me O N H O

Roth, G.P.; Leonard, S.F.; Tong, L. J. Org. Chem. 1996, 61, 5710-5711.

Chiral Bicyclic Lactam Enolates

R1 R1 R1 O O R X O s-BuLi 2 R2 N N repeat: N R3 H O H OLi s-BuLi; R3X H O

R1 = H, Me, Ph exo:endo selectivities typically > 98:2 R2 = Me, Bn, allyl (except: H, Me, H 2:1 R3 = H, Me, Bn

Roth, G.P.; Leonard, S.F.; Tong, L. J. Org. Chem. 1996, 61, 5710-5711.