Reactions of the Carbonyl Group - UEF of the Carbonyl Group! ... β-vetivone. Regioselective ......

Reactions of the Carbonyl GroupReactions of the Carbonyl Group

! Protons on the αααα-carbon are, in principle, acidic, and a non-nucleophilic base can deprotonate the carbon.

! A prerequisite for deprotonation is a correct conformation!

CH3CHO

O-Li+

Me HO-Li+Me

MeLi Enolisation

Addition to carbonyl

Enolate Chemistry Enolate Chemistry –– The BeginningThe Beginning

O CHOO

OO

NaOH, EtOH

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.

OEt

O OCO2Et

1. NaH, Et2O

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.

CLAISEN-SCHMIDT CONDENSATION

ACETOACETIC ESTER CONDENSATION

Enolate Chemistry Enolate Chemistry –– The BeginningThe Beginning

OEt

O Zn, Me2CO

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

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

REFORMATSKY REACTION

PERKIN REACTION

benzeneCl OEt

OOH

CHO

ONa O O

Ac2O

EnolatesEnolates! The term enolate first appeared in 1907, when Hans Stobbe discussed the FeCl3 color test for enols

in terms of ‘das violette Eisenenolat’. The term was first applied to describe C=C-O- species in 1920, when Scheibler and Voββββ 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!

! 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 electrophile. It was only in the ‘50’s that Hauser first reported the use of a preformed enolate to obtain cross-coupling products of esters and aldehydes.

H C C OB C C O C C O H

t-BuO

O

t-BuO

O

Me

OH

Ph

Ph

O

76 %

LiNH2, NH3

EnolatesEnolates! 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 ‘Wittigdirected aldol condensation’.

O

EtOO

CO2Et

Hauser, 1950 47 %

LDA, ether25 ºC, 15 min

N NLi O NHPhPh Ph

PhCHO

Wittig, 1963

H3O+Ph2C=OLDA, THF

EnolatesEnolates! 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 ketones 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.

O OLi OLi

H

HO

H

HOLi

H

OLi

2 %

+LDA, DME-78 ºC

98 %

1 %99 %

+

LDA, DME-78 ºC

Kinetic and thermodynamic controlKinetic and thermodynamic control

Kinetic vs. thermodynamic controlKinetic vs. thermodynamic control

R

-O

R

O

R

-O

Thermodynamically favoredMore stable

Kinetically favoredForms faster


! A tetrasubstituted alkene 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

CHH3C Me

MeO

Me Me

Me-O

Me

Me-O

3 H 1 H

A B


Br

O

O

Br

OLi

Ot-BuOK

t-BuOH, ∆

LDA, THF,hexane, -72 ºC

65 ºC

86-94 %

77-84 %

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


O

O

OH

H

O-

O-

O-

H

O-

O-

O-H

H

Ph3CLitasapain.

2894

726

LDAtasapain.

178

9922

Ph3CLitasapain.

1353

8747

Ketoni

Enolaatti

Termodynaaminen Kineettinen


O-

H

O

H

MeMeI

MeI MeO

H

Ainoa tuote!

Aksiaalinen

Me

O

H

O-

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

O-

Regioselective Enolate FormationRegioselective Enolate Formation

R

O

R

O

R

-O

R

O

R

O

CHO CHO

O

CHO

Overall

HCO2EtNaOEt

Acid or base∆

1. Use of Activating Groups1. Use of Activating Groups

R

OSPh

R

-OSPh

base

Baisted, J. Chem. Soc. 1965, 2340.Johnson, J. Am. Chem. Soc. 1960, 82, 614.

Coates, Tetrahedron Lett. 1974, 1955.


2. Use of Blocking Groups2. Use of Blocking Groups

Woodward J. Chem. Soc. 1957, 1131.

R

O

R

OCHO

R

OCHOH

R

OS S

HCO2Et

KOAc

TsS STs

Removal: RaNi


3. Use of Enamines3. Use of Enamines

Augustine Org. Synth Coll Vol V 1973, 869.

R

O+ R'2NH

R

R'2N

R

R'2N>H+ cat.

- H2O

Erel = 1.6 kcal/molErel = 0


3. Use of Enamines 3. Use of Enamines -- Robinson typeRobinson type

Augustine Org. Synth Coll Vol V 1973, 869.

R

R'2N

R

R'2N

-O

R

R'2N

-O

RR'2N

O

R

O

'- R'2NH'

O


4. Thermodynamic vs. Kinetic Control4. Thermodynamic vs. Kinetic Control

R

-O

R

O

R

-O

Thermodynamically preferredMore stable

Kinetically preferredMore rapidly formed


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

KINETIC ENOLATE FORMATIONKINETIC 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.


5. Enones as Enolate Precursors5. Enones as Enolate Precursors

O -O O

Li, NH3

tBuOH

O

Et3Si

O -O O

Me2CuLi O

Et3SiMe Me

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

Boeckman J. Am. Chem. Soc. 1973, 95, 6867.


6. Enol Derivatives6. Enol Derivativesa) Enol acetatesa) Enol acetates

O HO

R R

AcO

R

AcO

R

O

R

-O

R

-O

MeMe

Favored

Me2CO

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

Erel = 2.3 kcal/mol

Erel = 0


6. Enol Derivatives6. Enol Derivativesb) Silyl enolatesb) Silyl enolates

O

TMSO TMSO

TMSCl, Et3N

DMF

1) LDA

2) TMSCl

+

9 91

99 1

:

:

(80 %)

(74 %)

O TMSO

1) Li/NH3

2) TMSCl

Stork, G. J. Am. Chem. Soc. 1968, 90, 4462.House, H.O. J. Org. Chem. 1969, 34, 2324.

Stork, G. J. Am. Chem. Soc. 1974, 96, 7114.


OTMSO

TMSO -O O

O

SiEt3

1) Me2CuLi

2) TMSCl

MeLi etc.

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

Stork, G. J. Am. Chem. Soc. 1973, 95, 6152.

> 90 %

> 80 %

EnolatesEnolates

NH

NLi

n-BuLi[conditionsunknown]

C4H9

OSiMe3

C4H9

OSiMe3

97.5 % 2.5 %

OSiMe3

MeBu

OSiMe3

MeBu

O

MeBu

97 % 3 %

2-hexanone,THF, Me3SiCl,

-78 ºC

THF, Me3SiCl,-78 ºC

LOBA

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

Regioselective EnolizationRegioselective Enolization

MeO

Me3SiO

O

MeO

Me3SiO

O OH

1. LDA, DME, -78ºC (92:8 selectivity in enolisation*)2. hexanal3. H2O, HCl

(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.


Br

O

O

Br

OLi

Ot-BuOK

t-BuOH, ∆

LDA, THF,hexane, -72 ºC

65 ºC

86-94 %

77-84 %

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


OH

LiOH

KOH

OH

OH

NLi

LICA, THF-78 ºC

t-BuOK,t-BuOH, ∆

MeI

HOAc

kinetic enolate

thermodynamic enolate

85 %

Lee, R.A.; McAndrews, C.; Patel, K.M.; Reusch, W. Tetrahedron Lett. 1973, 965.Ringold, J.; Malhotra, S.K. Tetrahedron Lett. 1972, 669.

LICA =Lithium i-propykcyclohexylamide


O

O

O

1. LDA, THF2. CH2=CHCH2Br

1. LiAlH42. H2O

80 %

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

OEt

O LDATHF-HMPA

1. MeLi2. H3O+

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

OEt

O

O

Cl Cl

β-vetivone


O

Me

O

Me

O

Me

HO

HO

H

H

O

Me

HOH

1. Li, NH3, t-BuOH2. CH2O, ether, -78 ºC

1. Li, NH3, PhNH22. CH2O, ether, -78ºC

64 %

60 %

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


R2 OEt

OO

R3

R1

R4

R2 OEt

OOH

R3

R1

R4

X COOH X CH2C COOEt

OX C

HC (COOEt)2

O

H2CHC

HCHC

CHC

Me

Me

Me

H2C CMe

Neat

HC C

CCl4Neat

Me

CCl4

Me

X

5,56

1,95

0,73

2,2

1,1

68

40

17

26

15

91

66

30

50

28

78

30

5

5

89

44

5

5

% enol % enolka 105

Gelin, S.; Gelin, R. Bull. Chim. Soc. Fr. 1970, 340-341.

Regioselective Enolization Regioselective Enolization --Synthesis of PGESynthesis of PGE22 IntermediateIntermediate

I

OTBS

1. CuI, Ph3P, THF2. compound 1

3. HMPA, Ph3SnCl

O

TBSO

Ph3SnO

TBSO

O

TBSO OTBS

OTBS

I CO2Me

CO2Me1

PGE2 family

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

EnolatesEnolates::ZZ(O,R)(O,R)-- and and EE(O,R)(O,R)--enolatesenolates

R'R

O-

HH

RO-

R'

(E)-enolate (Z)-enolate

Regardless of other groups the encircled R' and O-

determine whether one is Z(O,R)- or E(O,R)- enolate.

EnolatesEnolates:: deprotonationdeprotonation

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

Most stable conformation

ROH

R'H

R

O

R' H

R

O

HR'

ROH

HR'R

HR'

H O

H H

R

HR'

O-R

R'H

O-

σC-H σC-H

π*C=O π*C=O

30°

90°

(E)-enolate (Z)-enolate

O

Heq

Hax

OH

H 104 °

-12 °

Effect of base on Effect of base on enolisationenolisation

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

NLi

NLi

SiN

Si

M

PhSi

NSiPh

MO-K+

LDA LiTMP MHMDS ((Me2Ph)2Si)NLi t-BuOK

pKa 36 37 26 25 18-20M = Li, Na, K

Selective formation of E/ZSelective formation of E/Z--enolatesenolates

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

R

O

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

emäs TMSCl

R

OTMS

R

OTMS

R emäs Z E

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

cC6H11 LDA(Me3Si)2NLi(Et3Si)2NLi(Me2PhSi)2NLi

61 3985 1594 699 1

EnolisationEnolisation::IrelandIreland--mechanismmechanism

! 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 proton abstractor and the role of the metal!

H

NH

O

Li

R'

R

"R

RR

O-

R

O-

R+

NLi

, LiBr

- 78 °C

R = EtR = i-PrR = t-Bu

50211

:::

11>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.

DimericDimeric LiLi--enolate enolate -- LDA complexLDA complex

! First X-ray structure for a dimeric complex.

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

SiOO Li

N LiO

O

LiLiN

O

O SiR3

R3Si200 mol-% LDA

STEREO STRUCTURE:CCSD-code FOGRIC

Application:Application: TaxolTaxol

Stork, G. 1995.

O

OO

O

OO

O

OO

K D

t-BuOK D2O

Ketoni Enolaatti

Approach of the electrophileApproach of the electrophile

R RO RR

E

-O H

E

NB! This angle is similar to the Flippin-Lodge angle!

Houk: 106o (compare:

Burgi-Dunitz angle)

side view end view

O- O

E

E

O

Re

Siaxial

attackequatorial

attack

Agami, C. Tetrahedron Lett. 1977, 2801-2804.Tetrahedron Lett. 1979, 1855-1858.

Tetrahedron 1979, 35, 961-967.Houk, K.N. J. Am. Chem. Soc. 1986,108, 2659-2662.

Asymmetric Induction in Enolate and Asymmetric Induction in Enolate and Azaenolate AlkylationsAzaenolate Alkylations

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

R

OM

R

OM

OM R2

R1

R2

R1

OMO O

MR OO

MR

OM*

OMLn

*

Intraligand asymmetric induction

Interligand asymmetric induction

intraannular extraannular chelate-mediated intraannular

* *

**

*

*

1,3- 1,4- 1,2- 1,2-1,3- 1,3-

Controlling Face SelectivityControlling Face Selectivity

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

NCO2Me

CO2tBu

H

CO2MeO

CO2MeO

1) LDA 2) MeI

N OLi

OMe

OtBuO

L

OLi

NO

L

OtBu

tBuO

MeI L = HMPA

L = THFMeI

hydrolysis

SAMPSAMP--Hydrazones in Ketone AlkylationHydrazones in Ketone Alkylation

NNLi

OMe

NN

OMe

NNLi

Me

OMe

NN

OMe

O

OMe

LDASAMP

Me-XH3O+

NOMe

NH2

or O3

X = IX = OSO2Me

67 %ee99 %ee

SAMPEnders, 1976

Enders, D. Asymmetric Synthesis, vol. 3.

CChiralhiral BBicyclicicyclic LLactamactam EEnolatesnolatesO

OH

N

OH

OH

NH2

OH

N

O

O

R1

H

R1O

OHO

N

O

O

Me

H

p-TsOH, toluene

NH2OH.HCl

acetone

KMnO4

LiAlH4

Oxidation of pinene:Carlson, R.G.; Pierce, J.K. J. Org. Chem. 1971, 36, 2319-2324.

Reduction of oxime:Masui, M.; Shioiri, T. Tetrahedron 1995, 51, 8363-8370.

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

CChiralhiral BBicyclicicyclic LLactamactam EEnolatesnolates

N

O

O

R1

HN

O

OLi

R1

HN

O

O

R1

HR3

R2s-BuLi

exo:endo selectivities typically > 98:2(except: H, Me, H 2:1

R2X

repeat:s-BuLi; R3X

R1 = H, Me, PhR2 = Me, Bn, allylR3 = H, Me, Bn

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

Reactions of the Carbonyl Group - UEF of the Carbonyl Group! ... β-vetivone. Regioselective ......

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