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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
A!Aalto universitySchool of Chemical Technology
© 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
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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
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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
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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)
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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
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© 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
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© 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+
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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
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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
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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
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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
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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
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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
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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
A!Aalto universitySchool of Chemical Technology
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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
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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
A!Aalto universitySchool of Chemical Technology
© 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
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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.
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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
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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
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Kinetic and thermodynamic control
Kinetic vs. thermodynamic control
R
-O
R
O
R
-O
Thermodynamically favoredMore stable
Kinetically favoredForms faster
A!Aalto universitySchool of Chemical Technology
© 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.
A!Aalto universitySchool of Chemical Technology
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Kinetic and thermodynamic control
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
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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
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Kinetic and thermodynamic control
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%
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Kinetic and thermodynamic control
House, H. J. Org. Chem. 1979, 44, 2400.
O-
H
O
H
MeMeI
MeI MeO
H
Ainoa tuote!
Aksiaalinen
Me
O
H
O-
O-
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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
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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
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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
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Regioselective Enolate Formation
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
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Regioselective Enolate Formation
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
>
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Regioselective Enolate Formation
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
A!Aalto universitySchool of Chemical Technology
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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
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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%)
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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
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Regioselective Enolate Formation
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
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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
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Regioselective Enolate Formation
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
A!Aalto universitySchool of Chemical Technology
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Regioselective Enolate Formation
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
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Regioselective Enolate Formation
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.
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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.
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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
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Regioselective Enolization
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
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Regioselective Enolization
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.
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Regioselective Enolization
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%
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Regioselective Enolization
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
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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
A!Aalto universitySchool of Chemical Technology
© 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
A!Aalto universitySchool of Chemical Technology
© 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.
A!Aalto universitySchool of Chemical Technology
© 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.
A!Aalto universitySchool of Chemical Technology
© 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 universitySchool of Chemical Technology
© Ari Koskinen
Explanation
Mo, F.; Dong, G. Science 2014, 345, 68–72.