Alkylation
Reactions ! ! !
- primary, allylic, and benzylic halides work well - secondary halides can be problematic competing elimination - tertiary, aryl, and vinyl, halides don’t react
• Limitations of R’X
R
O
R
OR'
R
O
R
O
R'X
OMe
MeI
R
OMe
OH
R'
O
R'X
R
O R'
O
R'
Br OMe
O
Br
R
O
Alkylation
Potential Problems ! ! !
• Enolate Basicity
O Br O
+
R HO
RO HO
H HO
RO OR
O O
HR OR
O O
HR R
O O
Hbasic non-basic
- more basic enolate, more E2 elimination
X RX
RR R
X
Alkylation
Potential Problems ! ! !
• Polyalkylation
O
KOtButBuOH
O O
+MeI
(1 equiv)
O O O OMe MeMe MeMe
MeMe
+ + +
40% 21% 6% 9%
Alkylation
Potential Problems ! ! !
- cyclopentanones are especially problematic
• Polyalkylation
OLDA;MeI
O
+ polyalkylation
THFTHF / HMPA
79 : 1594 : 3
- ratio of alkylation:proton transfer much higher with Li+ vs. K+ or Na+
O
LDA
OMe
O
MeI(1 equiv)
Alkylation
Enamines ! ! !
- give monoalkylation products - kinetic enolization - will react with highly reactive R-X, aldehydes, and acid chlorides
• Polyalkylation Solution (And More!)
- other enamine derivatives:
O NNH
H+ or Δ
RXN
RO
RH2O
N
O
N N
Alkylation
Enamines ! ! !
- sometimes useful for aldehyde alkylation - but less reactive alkylating agents give N alkylation!
- also good for conjugate addition reactions
O
H
HN O
pTsOH (cat)
N
H
O
BrO
H
N
O
CN
OCN
Alkylation
Metalloenamines ! ! !
- react with less reactive electrophiles – 1° and 2° alkyl halides - can use for aldehyde alkylations where simple enamines fail - substitution at less substituted carbon of imine
Stork J. Am. Chem. Soc. 1963, 85, 2178.
O NNH2
Cy N Cy
N Cy OH2O
IEtMgBror LDA
M
M = BrMg, Li
Alkylation
C versus O Alkylation ! ! !
- stabilized enolates
• Substrate Effects
O OO
baseRX
baseRX
R
R
O-alkylationC-alkylation
O
OH
O
OMe
MeI, K2CO3acetone
OEt
O O
OEt
MeO ODMF-Me2SO4Et3N, CH2Cl2
Alkylation
C versus O Alkylation ! ! !
- reactivity of the alkylating agent
• Substrate Effects
O O
+
O
baseRX
Et-BrEt-OTs
major : trace 1 : 1
R-I > R-Br > R-OTs > R-OTf > RO-S(O2)-OR
R X R X
O
R3Si X> >
C-alkylation O-alkylation (soft Nu) (hard Nu)
Alkylation
C versus O Alkylation ! ! !
• Solvent Effects
C-alkylation THF, Et2O, tBuOH vs. DMF, DMSO O-alkylation
apolar protic
polar aprotic
solvent C-alkylation O-alkylation
HMPA 15% 83%
t-BuOH 94% 0%
THF 94% 0%
OEt
O OEtO S OEt
O
OOEt
O O
OEt
EtO O
EtC-alkylation O-alkylation
+
K
Alkylation
C versus O Alkylation ! ! !
X solvent C : O ratio
OS(O)2OEt THF 100 : 0
tBuOH 100 : 0
DMSO 30 : 70
DMF 21 : 79
HMPA 17 : 83
OTs HMPA 12 : 88
Cl HMPA 40 : 60
Br HMPA 61 : 39
I HMPA 87 : 13
OEt
O O
OEt
EtO O
Et
Et-XsolventOEt
O OK
C-alkylation O-alkylation
Alkylation
C versus O Alkylation ! ! !
- polar additives
• Counterion Effects
C-alkylation Li > Na > K > Cs > NR4 O-alkylation
aggregated charge dissociation
N N
O
N,N'-dimethylpropyleneurea(DMPU)
hexamethylphosphoramide(HMPA)
Me2NP NMe2
O
NMe2
N N
O
N,N'-dimethylethyleneurea(DMEU)
N
O
N-methyl-2-pyrrolidone(NMP)
C-alkylation: ethereal solvent; Li+ / Na+ counterion; soft Nu (RI, RBr) O-alkylation: polar solvent, K+ / Me4N+ counterion; hard Nu (RCl, ROTs)
• Summary
Alkylation
β-Dicarbonyl Compounds ! ! !
decarboxylation
• Malonic Ester Synthesis
• Acetoacetic Ester Synthesis
OEtEtO
O O NaOEt / EtOHRX OEtEtO
O O H3O+
Δ
ROH
OR
EtO
O O NaOEt / EtOHRX EtO
O O H3O+
Δ
R
OR
O
O O
R
H O
R
H OR
-CO2
EtO
O O
R
hydrolysis
Alkylation
β-Dicarbonyl Compounds ! ! !
• Dianion Alkylation
EtO
O O base(2 equiv) EtO
O O
EtO
O ORXR
- base: NaH (1 equiv) then LDA (1 equiv) or LDA (2 equiv)
H
H
O
KOtButBuOH,MeI
H
H
OMe
kinetic & thermodynamicproduct
H
H
OCO2Et
H
O O
OEtR
H
O1. RX2. H3O+, Δ
1. NaH2. tBuLi
LDA;O
EtO OEt
Alkylation
Stork-Danheiser Alkylation ! ! !
O
O
OR
O
O
O
O
R
R
R
• Synthesis of Substituted Cyclohexenones
Alkylation
Stork-Danheiser Alkylation ! ! !
• 4-substituted cyclohexenones
O
O
OEt
O
EtOHpTsOH (cat)
LDA;RX
OEt
OR
LiAlH4
OEt
OHR
H3O+
O
R
• 3-substituted cyclohexenones
OEt
O
RMgXor RLi
OEtH3O+
O
OHR
R
Alkylation
Stork-Danheiser Alkylation ! ! !
• 2-substituted cyclohexenones
• systems
O
O
O
O
EtOHpTsOH (cat)
NaOEtRX
OEt
O
LiAlH4
OEt
OH
H3O+
O
RR
R R
O
R
O
R
OR* * *
ORR
RR
Alkylation
Stork-Danheiser Alkylation ! ! !
• β-vetivone
≡O
R4R1
R2 R3
Oprotect as enol ether
alkyl Li additionto ketone
alkylation ofenolate
present in SM
O
OEt
O
OEt
O
O
Alkylation
Stork-Danheiser Alkylation ! ! !
• β-vetivone
O
O
OEt
O
EtOHpTsOH (cat)
LDA;OEt
OCl
ClCl
LDAO
OEt O
1. MeLi2. H3O+
MeH
EtO
O
Cl
Alkylation
Stereochemistry of Alkylation ! ! !
• simple enolates
- in absence of features that differentiate faces, expect equal mix of diastereomers
OR R2
R1
E+
E+
a
b
O
RR2
R1
E
O
R R1R2
E
a
b
OEt
OH O LDA;MeI OEt
OH O
OEt
OH O+
95 : 5Me Me
• Fráter-Seebach alkylation
Alkylation
Stereochemistry of Alkylation: Cyclic Ketones ! ! !
• stereoelectronic effects
OR R2
R1
E+105°
E+O O
LDAO
O
tBu
tBu
E
E
trans
cis
Alkylation
Stereochemistry of Alkylation: Cyclic Ketones ! ! !
• stereoelectronic effects
OR R2
R1
E+105°
E+O O
LDAO
O
tBu
tBu
E
E
trans
cis
Alkylation
Stereochemistry of Alkylation: Cyclic Ketones ! ! !
• stereoelectronic effects
H O
E
tBu
O
tBuE
tBu
E
O
O
tBuE
E
twist boat
energy
rxn coordinate
trans
cis
- consider transition states
Alkylation
Stereochemistry of Alkylation: Cyclic Ketones ! ! !
• steric effects
endocyclic enolates:
O O
R
EE
R
exocyclic enolates:
OLiRH
H
axial
equatorial
Alkylation
Stereochemistry of Alkylation: Cyclic Ketones ! ! !
• exocyclic enolates
1,2-stereocontrol:
Me
CO2Me
H
LDA;MeI
CO2Me
MeMe ≡H Me
CO2Me
H
MeMe
Me
H
CO2Me+
80 : 20
CO2Me
OMe
OMeBr
LDA;CO2Me
OMe
OMe
MeO2C
OMe
OMe
+
95 : 5
- also seen in other ring sizes
Alkylation
Stereochemistry of Alkylation: Cyclic Ketones ! ! !
• exocyclic enolates
1,3-stereocontrol:
1,4-stereocontrol:
CO2MeLDA;MeI
CO2Me
Me ≡CO2Me
MeMe
CO2Me+
90 : 10Me Me Me
H
Me
CO2Me CO2Me
Me ≡CO2Me
MeMe
CO2Me+
89 : 11
tBu tButBu tBu
LDA;MeI
Alkylation
Stereochemistry of Alkylation: Cyclic Ketones ! ! !
• endocyclic enolates
1,2-stereocontrol:
1,3-stereocontrol:
O
Me
O
MeBr
LDA;O
Me
OLi
RH
H+
89 : 11
O OO
Me
Me+
73 : 27tBu tBu tBu
NaOtAmMeI
Alkylation
Stereochemistry of Alkylation: Cyclic Ketones ! ! !
• endocyclic enolates
1,4-stereocontrol:
other systems:
O O
LDA;CD3I
O OLi
+
83 : 17
tBu tBu tBu tBu
CD3
MeMe
CD3Me Me
MeO
R
H
LDA;CD3I
MeO
R
HCD3
O
R
HMeCD3
+
83 : 175 : 95
R = HR = Me
Alkylation
Stereochemistry of Alkylation ! ! !
• simple enolates
- in absence of features that differentiate faces, expect equal mix of diastereomers
OR R2
R1
E+
E+
a
b
O
RR2
R1
E
O
R R1R2
E
a
b
OEt
OH O LDA;MeI OEt
OH O
OEt
OH O+
95 : 5Me Me
• Fráter-Seebach alkylation
Alkylation
Stereochemistry of Alkylation: Acyclic System ! ! !
• Seebach Alkylation
self regeneration of stereocenters:
RHO
O
OH
RO
O
OtBuCHO
pTsOH (cat)LDA;R'X
RO
O
O
R' H3O+ RHO
O
HO R'
R R'X dr yield Me EtI 97 : 3 82%
Me H2C=CHCH2Br 98 : 2 77%
Ph PrI 95 : 5 84%
OO
OLiR
H
R'X
Alkylation
Asymmetric Alkylation ! ! !
• use of chiral auxiliaries
pseudoephedrine (Meyers):
N H
MeOH
Me R O RO O
NMeOH
Me OR LDA (2 equiv), LiCl;
R'XCl R
Oor, Et3N
NMeOH
Me OR
R'
R R'X dr (crude) yield
Me BnBr 97 : 3 90%
Me iBuI 86 : 1 89%
Bn MeI 97 : 3 99%
Bu MeI 97 : 3 94%
Ph EtI 98 : 2 92%
Cl BnBr 95 : 5 88%
R'X
Alkylation
Asymmetric Alkylation ! ! !
• use of chiral auxiliaries
pseudoephedrine (Meyers):
NMeOH
Me O
Me
H
O
MeHO
Me
HO
O
MeR
O
Me
Ph
Ph Ph
Ph Ph
RLi
LiAlH(OEt)3LiH2NBH3
FeCl3H2O/dioxane
Alkylation
Asymmetric Alkylation ! ! !
• use of chiral auxiliaries
pseudoephedrine (Meyers):
R R' dr (crude) yield
Me Me 96 : 4 88%
Me Ph 95 : 5 90%
Me CH2OTBS 98 : 2 96%
Bn MeI >99 : 1 86%
Bn Ph 98 : 2 86%
Bn CH2OTBS >99 : 1 81%
R'X
OR'
NMeOH
Me OR LDA (2 equiv), LiCl;
, 0°C NMeOH
Me O
RO
R'
R'
OH
Alkylation
Asymmetric Alkylation ! ! !
• use of chiral auxiliaries
1-amino-2-methoxymethylpyrrolidines (Enders):
NOMe
NH2N
OMe
NH2SAMP RAMP
S R
auxilliary cleavage
A: O3, DCM, -78°C B: MeI, 60°C; 5N HCl/pentane C: H2O2, MeOH, pH 7 buffer
recycling the auxilliary
NOMe
NON
OMe
NH2
LiAlH4
R RO
R' HR
R
O
RR
N NOMe
RR
NR'
N
SAMP60°C
LDA;R'X
auxiliarycleavage
OMe
Alkylation
Asymmetric Alkylation ! ! !
• use of chiral auxiliaries
1-amino-2-methoxymethylpyrrolidines (Enders):
selectivity
RR
N NOLi
Me
LL N
H
NRO
Li
MeR
R'X
S
H≡ NH
N RO
MeR
S
H
R'
≡ R RN NXc
R' H
R RO
R' HR
R
O
RR
N NOMe
RR
NR'
N
SAMP60°C
LDA;R'X
auxiliarycleavage
OMe
Alkylation
Asymmetric Alkylation ! ! !
• use of chiral auxiliaries
1-amino-2-methoxymethylpyrrolidines (Enders):
HMe
O
Me
O
Me
O O
MeMe
O
CO2tBu
O
O O
MeMe
HMe
O
Me
71% yielder = >97 : 3
61% yielder = >98 : 2
66% yielder = 93 : 7
70% yielder = >99 : 1
53% yielder = >95 : 5
HMe
O
Me
NH
NRO
Li
MeR
R'X
S
H
RR
O
RR
N NOMe
RR
NR'
N
SAMP60°C
LDA;R'X
auxiliarycleavage
OMe
RR
OR'
Alkylation
Asymmetric Alkylation ! ! !
• use of chiral auxiliaries
oxazolidinones (Evans):
NO
OMe
OLDA orNHMDS
NO
OMe
OM
R'XNO
OMe
O
R'
NO
OMe
O
R'
BnO MeO
R'HO Me
O
R'HO Me
R'
LiOHLiOOH LiAlH4LiOBn
auxiliary cleavage
Alkylation
Asymmetric Alkylation ! ! !
• use of chiral auxiliaries
oxazolidinones (Evans):
NO
O O1. LDA, THF, -78°C2. BnBr
NO
O O
92% yielddr = > 99 : 1
NO
O O
CH3
1. LDA, THF, -78°C2. BnBr
NO
O O
CH3
78% yielddr = > 99 : 1
NO
O O
CH3
1. NaHMDS, THF, -78°C2. EtI
NO
O O
CH3Me
53% yielddr = 94 : 6
