A! Aalto university School of Chemical Technology © Ari Koskinen KE-4.4120 Organic Synthesis 15....

A!Aalto universitySchool of Chemical Technology

© Ari Koskinen

KE-4.4120 Organic Synthesis15. Chemistry of the Double Bond:

Reactions at -Center (Enolate Chemistry)

Prof. Ari KoskinenLaboratory of Organic Chemistry

C318


© Ari Koskinen

Chemistry of the Double Bond1. Reactions of the Carbonyl Group1.1 At Carbonyl1.1.1 Reduction (hydride

addition)1.1.2 Alkylation1.1.3 Allylation/Propargylation1.2 At -Center (Enolate

Chemistry)1.2.1 Alkylation1.2.2 Aldol Reaction1.3 At -Carbon of Enone1.3.1 Michael (1,4-) Addition2. Reactions of Olefins2.1 Oxidation2.1.1 Epoxidation2.1.2 Dihydroxylation2.1.3 Aminohydroxylation2.2 Reduction


© Ari Koskinen

Reactions of the Carbonyl Group

• Protons on the a-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 H

O-Li+Me

MeLi

Enolisation

Addition to carbonyl


© Ari Koskinen

Acidity of carbonyl compounds

O

HH

HH

acetaldehydepKa 13.5

O

H3CH

HH

acetonepKa 20

O

EtOH

HH

ethyl acetatepKa 25

O

HHH

propandialpKa ca. 5

O

H3CHH

ethyl acetoacetatepKa 10.6

O

EtOHH

diethyl malonatepKa 12.9

H

O

OEt

O

OEt

O


© Ari Koskinen

Acidity of keto and enol tautomers

OH

enol

O

keto

pK = 8.22

O

enolateenol

pK = 10.94O

H

(1)

(2)

(1) + (2) = (3)O

keto

pK = 19.16O

enolate

Compare with the pKa of phenol (9.95)


© Ari Koskinen

Simple carbonyls prefer keto form

Bond strengths (kJ/mol)

s bond p bonde Sum

keto form (C-H) 440 (C=O) 720 1160

enol form (O-H) 500 (C=C) 620 1120

The enol form is usually less stable than the keto form. However, even small quantities of the enol form can be important!

O OH

keto form enol f orm

K

keto

enolG°inc r

e as i

n g e

nerg

y


© Ari Koskinen

Carbonyl enolization in water

H3C H

O

H3CH

H

O

H

O

O O

Carbonylcompound

Kenol/keto

10-5

10-7

5x10-6

0.23

O

OEt

O

O O

O

H

O

0.07

20

50

Carbonylcompound

Kenol/keto


© Ari Koskinen

Catalytic enolization in water: base

H

O

H

H

H

OH

O

HH

H

enolateanion

OHHOH

HH

H

enol formof aldehyde

loss ofH f rom carbon

protonationon oxygen

OH+


© Ari Koskinen

Catalytic enolization in water: acid

In both acid- and base-catalyzed enolizations, two things need to happen: 1) loss of proton from carbon and 2) protonation on oxygen.

In the base-catalyzed enolization, these events take place in this order. In the acid-catalyzed enolization, the carbonyl is activated towards enolization by protonation at oxygen. A weak base (e.g. water) is then enough to pull off the proton.

H

O

H

H

H

OH2

O

HH

H

OH

HH

H

enol formof aldehyde

loss ofH f rom carbon

protonationon oxygen

+

H

H

H2O H

H2O H


© Ari Koskinen

The enolate anion

The enolate ion is quite nucleophilic and comparable to the allyl anion in its reactivity. The oxygen has more of the overall negative charge, but the carbonhas more of the HOMO.

O-

O

HOMOO

bonding

nonbonding

antibonding O LUMO

ener

gy

HOMOO

nucleophilic at both ends

O O


© Ari Koskinen

Reactivity of the enolate anion

O

enolate anionreacts through oxygen

SiH3C CH3

H3CCl

O base OSi

CH3

CH3CH3

silyl enol ether(or enol silane)

O

enolate anionreacts through

carbonI

O base

pentan-2-one(alkylated enolate)

O

Silylation

Alkylation


© Ari Koskinen

Reactivity of the enolate ion

In the enolate ion

• the oxygen atom has more of the overall negative charge• the carbon atom has more of the HOMO

• Hard electrophiles (charged, polar electrophiles, RCOCl, R3SiCl, H+) react preferably at the oxygen end

• Soft electrophiles (maximal orbital overlap; R-halides, I2) react preferably at the carbon end


© Ari Koskinen

Enolate Chemistry – The Beginning

O CHO

OO

O

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 O

CO2Et1. 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


© Ari Koskinen

Enolate Chemistry – The 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

benzeneClOEt

OOH

CHO

ONa O O

Ac2O


© Ari Koskinen

Enolates

• 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 Vo 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.

t-BuO

O

t-BuO

O

Me

OH

Ph

Ph

O

76 %

LiNH2, NH3

H C C O H C C O H C C OHB B


© Ari Koskinen

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 aldol condensation’.

O

EtOO

CO2Et

Hauser, 1950 47 %

LDA, ether25 ºC, 15 min

N N O NH

PhPh Ph

PhCHO

Wittig, 1963

LDA, THFH3O+

Ph2C=O

Li


© Ari Koskinen

Methods for Enolate Generation

R2

O

R1

R2

OMLn

R1

O

R1

R2

O

R1

R2

Metallo-Enolates and

Enol Derivatives

Acid/BaseChemistry

Reduction of-Halocarbonyls

1,4-Reduction1,4-Addition

A Vast Number ofTransformations

OMLn

R1

R2

Isomerization ofAllylic Alkoxides

XR1

R2

Isomerizationof Epoxides

O

Addition toKetenes

O

C

R2

R1 Li


© Ari Koskinen

Catalytic Cycloreductions, Cycloadditions and Cycloisomerizations: Enones as Latent Enolates in Catalysis

Michael J. Krische, Univeristy of Texas at Austin

Deprotonation-Derivatization of Unmodified Carbonyl Compounds

Hauser (1951): First Use of Preformed Enolates (LiNH2/NH3).

Wittig (1963): First Use of LDA for Preformation of Aldimine Anion.

Rathke (1970): First Use of LHMDS for Ester Enolate Preformation.

Posner (1972): First Use of LDA for Ester Enolate Preformation.

Metallo-Enolates and Related Enol Derivatives

Stoichiometric Enolate Preformation

Enolates from Carbonyls

R

H

O Lewis Acid(MLn)

R

H

OMLn

:Base

R

OMLn

Base

E


© Ari Koskinen

Regioselective enolisation of ketones

•Thermodynamic enolates:

• more substituted• more stable• favored by excess ketone, high temperature, long reaction time•less than stoichiometric amount of base•weak, sterically non-hindered base•protic solvents

•Kinetic enolates:

• less substituted• less stable• favored by strong, hindered bases, low temperature, short reaction time•at least stoichiometric amount of base•strong, bulky base•polar aprotic solvents

O

R

H H

base baseO

R

H

thermodynamicenolate

kineticenolate

O

R

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


© Ari Koskinen

Regioselective enolizationO LDA

O

Ph

LDA

O LDA

O

Me

LDA

OLi

OLi

OLi

Ph

OLi

Me

OLi

OLi

OLi

Ph

OLi

Me

(Z) + (E)THF, -78 °C

+

71 : 29

(Z) + (E)THF, -78 °C

+

14 : 86

THF, -78 °C+

99 : 1

THF, -78 °C+

90 : 10


© Ari Koskinen

Kinetic and thermodynamic control

• 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


© Ari Koskinen


Kinetic vs. thermodynamic control

R

-O

R

O

R

-O

Thermodynamically favoredMore stable

Kinetically favoredForms faster


© Ari Koskinen

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.


© Ari Koskinen


O

O

OH

H

O-

O-

O-

H

O-

O-

O-

H

H

Ph3CLiequil.

2894

72

6

LDA

equil.

1

789922

Ph3CLiequil.

1353

87

47

Ketone

Enolate

Thermodynamic Kinetic


© Ari Koskinen

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 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


© Ari Koskinen


House, H.O.; Sayer, T.S.B.; Yau, C.-C. J. Org. Chem. 1978, 3, 2153.

Br

O

Br

OLi

O

OH

tBuOKtBuOH,

86-94%

LDA, THF,

hexane, -72oC 65oC

77-84%


© Ari Koskinen


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

O-

H

O

H

MeMeI

MeI MeO

H

Ainoa tuote!

Aksiaalinen

Me

O

H

O-

O-


© Ari Koskinen

Enolates, enol equivalents and metalloenamines

OR3Si

NR1 R2

OM

NR1M

metal enolatesilyl enol ether(enol equivalent)

enamine(enol equivalent)

metalloenamine(enol equivalent)

reactivity increases predicted by electronegativity:

- enamines more reactive than enols (O vs. N)

- metal enolates more reactive than enols (M vs. C; more e-density to oxygen)

- the same applies to metalloenamines vs. enamines

Reviews: Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66 (reactivity) Arya, P.; Qin.; H. Tetrahedron 2000, 56, 917 (asymmetric synthesis via enolates) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1-200 (boron enolate aldols)

increasing reactivity


© Ari Koskinen

Reactivity scale for neutral enol equivalents

OMe3Si

N

Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66

increasing reactivity

3.94N

OMe3Si

4.83

OMe3Si

5.21

OMe3Si

5.41

OMe3Si

6.22

Ph

OMe3Si

6.57

OMe3Si

8.23

PhO

OMe3Si

9.00

MeO

OMe3Si

10.61

O

OMe3Si

12.56

O

5.02

N

9.96

O

Ph

N

11.40

O

N

13.36

log k = s(N + E) s = nucleophile-specif ic parameter (typically between 0.7 and 1)N = nucleophilicity parameterE = electrophilicity parameter


© Ari Koskinen

Regioselective Enolate Formation1. Use of Activating Groups

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

Coates, Tetrahedron Lett. 1974, 1955.

R

O

R

O

CHO

R

-O

CHO

R

O

R

O

CHO

O

overall

HCO2EtNaOEt

Acid or base

base

R

O

SPh

R

-O

SPh

base


© Ari Koskinen


2. Use of Blocking Groups

Woodward J. Chem. Soc. 1957, 1131.

R

O

R

O

CHO

HCO2EtNaOEt

R

O

CHOH

TsS STs

R

OS S

KOAc

Removal: Ra-Ni


© Ari Koskinen


3. Use of Enamines

Augustine Org. Synth Coll Vol V 1973, 869.

Erel = 1.6 kcal/molErel = 0

R

O

R

R'2N

R

R'2N

+ R'2NHH+ cat.

- H2O

>


© Ari Koskinen


4. Use of Enamines - Robinson type

Augustine Org. Synth Coll Vol V 1973, 869.

R

R'2N

R

R'2N

-O

O

R

R'2N

-O

R

O

R'2N

R

O

- R'2NH


© Ari Koskinen

Use of enol equivalents: enamines

The overall process achieves an alkylation of a ketone but strong basesare avoided altogether so there is no danger of uncontrolled addition reactions.

O NH

cat. H+

N 1. R—X

2. H2O, H+

enamine

O

R

NR X

N

H R

N

R

enamineiminiumion

hydrolysis


© Ari Koskinen

Alkylation of enamines

Enamines can be used only with the most reactive alkylating agents:• allylic and benzylic halides• a-halo carbonyl compounds• methyl iodide

N 1.

2. H2O, 82 °C

Br O

O R2NH

cat. H+

NR2 BrPh

O

1.

2. H2O

O

Ph

O

(59%)


© Ari Koskinen

Alkylation of aldehydes via enamines

OHC

HN

cat. H+i-Bu2N

BrOEt

O

1.

2. H2O

OHC

EtO2C

CHO

cat. H+

1.

2. H2O

NH N

BrCHO


© Ari Koskinen


5. Enones as Enolate Precursors

O

Li, NH3

t-BuOH LiO

O

Et3Si

O

Boeckman JACS 1974, 96, 6179Stork JACS 1974, 96, 6181

O CuO

O

Et3Si

O

Boeckman JACS 1973, 95, 6867

Me2CuLi


© Ari Koskinen

Enones as Latent Enolates in Catalysis

O

CH3

99 01 LiN(i-Pr)2, THF, -78oC1

22 78 Me3SiCl, TEA, DMF, 80oC1

03 97 BrMgN(i-Pr)2, HMPA, 25oC, then Me3SiCl, TEA2

OM

CH3

OM

CH3 H3C

OH

Favored

Disfavored

H

H

CH3

H

CH3

CH3H3C

3-Enolate

2-Enolate

7,8-UnsaturationInverts Regiochemical

Preference!(Toromanof f !)

H3C

O

Na/NH3

H3C

OH

Then R-X

R

R1

Rh(I)Ln

Silane

O

H

O

R2 R1

O

CH3

OH

R2

Rovis Tetrahedron Lett. 1987, 28, 4809.Morken J. Am. Chem. Soc. 2000, 122, 4528.

Corey J. Am. Chem. Soc. 1955, 77, 2505.Djerassi J. Chem. Soc. 1962, 1323.

Sondheimer J. Am. Chem. Soc. 1958, 80, 6296.

1House J. Org. Chem. 1969, 34, 2324.2Holton Tetrahedron Lett. 1983, 24, 1345.

Stork J. Am. Chem. Soc. 1961, 83, 2965.

Problem: Regioselectivity in Enolisation

Catalytic: Reductive Generation of Enolates


© Ari Koskinen


6. Enol Derivativesa) Enol acetates

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

Erel = 2.3 kcal/mol

Erel = 0

R

O

R

HO

R

AcO

R

AcO

R

-O

R

O

Me

-O

Me- Me2CO

Favored

MeLi


© Ari Koskinen


6. Enol Derivativesb) Silyl enolates

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.

O TMSO TMSO+

TMS-Cl, Et3N, DMF 9 : 91 (88%)

LDA, then TMS-Cl 99 : 1 (74%)

O TMSO

1) Li/NH3

2) TMS-Cl


© Ari Koskinen


OTMSO

TMSO -O O

SiEt3

O

1) Me2CuLi

2) TMS-Cl> 90%

MeLi etc.

>80%

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

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


© Ari Koskinen

LOBA: Bulky base

NH

N

Li

n-BuLi[conditionsunknown]

LOBA

MeBu

O

MeBu

OTMS

MeBu

OTMS

97% 3%

C4H9

OTMS

C4H9

OTMS

C4H9

O

97.5% 2.5%

THF, TMS-Cl

-78 oC

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


© Ari Koskinen

Regioselective Enolization

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.

MeO

TMSO

O

MeO

HO

O

1. LDA, DME, -78oC (92:8 selectiviy in enolisation*)

2. hexanal

3. H2O, HCl

OH

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

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


© Ari Koskinen


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

O

H

LiO

H

KO

H

O

H

O

HMeI

HOAc

kinetic enolate

thermodynamic enolate

LICA, THF

-78oC

t-BuOK,t-BuOH,

N

Li

LICA =Lithium i-propylcyclohexylamide


© Ari Koskinen


O

O

O

Br

1. LDA, THF

2.

1. LiAlH42. H2O

80%

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

O

OEt

O

OEt O

LDATHF, HMPA

1. MeLi2. H3O+Cl

Cl

-vetivone

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

Vetiver oil (originally cous-cous, from Indian perennial grass of Poaceae family) contains vetivones and khusimone, used in nearly 90% of western fragrances. Annual production of Lavania ca 250 tonnes.


© Ari Koskinen


Stork, G.; d’Angelo, J. J. Am. Chem. Soc. 1974, 06, 7114.

O

OH

OH

HO

HO

OH

HO

1. Li, NH3, t-BuOH

2. CH2O, Et2O, -78oC

1. Li, NH3, PhNH2

2. CH2O, Et2O, -78oC

64%

60%


© Ari Koskinen


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

R2 OEt

OO

R3

R1

R4

R2 OEt

OOH

R3

R1

R4

X COOHX C

H2C COOEt

OX C

HC (COOEt)2

O

H2C CH

HC CH

C CH

Me

Me

Me

H2C C

Me

Neat

HC C

Neat

Me Me

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

CCl4CCl4

X


© Ari Koskinen

Synthesis of PGE2 Intermediate

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

I

OTBSOTBS

Ph3SnO

TBSO

I CO2Me

1. CuI, Ph3P, THF2. compound 13. HMPA, Ph3SnCl

TBSO

O

1

OTBS

O

TBSO

CO2Me

PGE2 f amily


© Ari Koskinen

Enolates: Regioselectivity

Krafft, M.E.; Holton, R.A. J. Org. Chem. 1984, 49, 3669.Kharasch reagent: Krafft, M.E.; Holton, R.A. J. Am. Chem. Soc. 1984, 106, 7619.

O

OTMS

OTMS

OTMS

LDA, TMSCl

Fe(0)/TMSCl/TEA

Fe(0)/MeMgBr/TMSCl/TEA


© Ari Koskinen

The ene reaction

O

O

O

O

O

O

H

H H

O

O

O

O

O

O

H

HH

the Diels-Alder reaction the Alder ene reaction

Frontier orbital explanation:

H

H

H

HOMO of ene

H

OO

O

LUMO of anhydride

bonding

bonding

Normally we simply treat the p orbital of an alkene as an independent unit, without considering

combinations with other orbitals. Here we need to do this to form the molecular HOMO.

Review: Conia J.M. Synthesis 1975, 1–19.


© Ari Koskinen

Pd catalyzed alkylation

R

PdCl2(MeCN)2

2 Et3NCO2MeR'

O CO2MeR'

O

R

then add H2

THF, -60 oC to rt

pKa ~10-17

Hegedus, L. J. Am. Chem. Soc. 1977, 99, 7093–7094.J. Am. Chem. Soc. 1980, 102, 4973–4979.


© Ari Koskinen

Greener alkylation?

O

H RO

H

R[Rh(coe)2Cl]2 (2.5 mol%)

IMes (5 mol%), TsOH.H2O (10 mol%)

N NH

(25 mol%)

PhMe (0.2 M), 130 oC, 48 h

+

O O

O

O

PhBu

SiMe3

N N

Me

MeMe Me

Me

Me

IMes

Mo, F.; Dong, G. Science 2014, 345, 68–72.

A! Aalto university School of Chemical Technology © Ari Koskinen KE-4.4120 Organic Synthesis 15....

Documents

Transcript of A! Aalto university School of Chemical Technology © Ari Koskinen KE-4.4120 Organic Synthesis 15....