Reduction of Carbonyl

Hydride Reducing Agents
General Mechanism: !
!
!
• reduction of aldehydes & ketones
O
R
O
MHn
R'
R
MHn-1
H
OH
H3O+
R'
R
H
R'
H
• reduction of carboxylic acids & derivatives
O
R
O
MHn
X
R
H
MHn-1
O
R
X
H
H
H
O
R
H
ML3
OH
H3O+
H
R
H
H
Aluminum Hydrides
1. Lithium Aluminum Hydride (LiAlH4)
!
!
• general
H
Li
H
H Al H
H
O
H
O
O
H Al H
H
k1
O
H Al O
H
k2
H
(fast)
H
H
O
k3
O
H Al O
O
O
H
H
k4
(slow)
O
O Al O
O
H
H
k1 > k2 > k3 > k4
LiAlH4 > LiAl(OR)H3 > LiAl(OR)2H2 > LiAl(OR)H
3 ROH
H
Aluminum Hydrides
1. Lithium Aluminum Hydride (LiAlH4)
!
!
!
• reactivity
- highly reactive, non-selective reducing agent
- use with caution! Highly flammable solid!
- one equivalent of LiAlH4 delivers 4 equivalents of hydride; still typically used in excess
- reduces carboxylic acids, esters, lactones, acid chlorides, anhydrides, aldehydes,
ketones, epoxides to give alcohols
- reduces amides, lactams, nitriles, azides, aryl nitro groups to give amines
- other reactive FG include: epoxides, alkyl halides, propargyl alcohols, etc.
• examples
O
N Me
H
MeO
N Me
LiAlH4
THF
O
H
70%
O
H
MeO
O
H
OH
Aluminum Hydrides
1. Lithium Aluminum Hydride (LiAlH4)
!
!
!
• examples
MeO2C
MeO2C
OH
O
HO
O
OH
LiAlH4
THF, reflux
H
72%
H
CO2H
OH
O CO Me
2
HO
OH
LiAlH4
THF, 65°C
O
98%
H
O
OH
H
O
OTIPS
O
O
O
1. LiAlH4, THF, rt
2. PhCOCl, Et3N, DMAP
90%
O
O
OTIPS
OBz
Aluminum Hydrides
2. Trialkoxyaluminum hydrides: LiAl(OtBu)3H , LiAl(OMe)3H
!
• reactivity
- much less reactive than LiAlH4
- hindered, will reduce only most reactive FG (aldehydes, ketones, acid chlorides)
• examples
O
O
O
Li(OtBu)3AlH
Et2O, 0°C
O
O
O
O
O
O
Li(OtBu)3AlH
O
EtO2C
O
Amberlite IR-20
benzene, 80°C
HO
THF, -10°C
EtO2C
O
O
O
OHC
OH
O
O
O
- LiAl(OtBu)3H can also be used to reduce acid chlorides to aldehydes
O
Aluminum Hydrides
3. Sodium Bis(2-Methoxyethoxy)aluminum Hydride (Red-Al, Vitride, SMEAH)
• reactivity
H
- similar reactivity to LiAlH4
H
• examples
TBSO
O
S
S
RedAl
toluene, -78°C
TBSO
OH
S
S
80%
O
BnO
OH
OH
OH
BnO
+
OH
Red-Al
DIBAL
LiAlH4
150 : 1
1 : 13
1:1
BnO
OMe
O
OMe
Al
Na
- moisture sensitive, but not pyrophoric; thermally stable to 200°C
O
OH
Aluminum Hydrides
4. Diisobutylaluminum Hydride (DIBAL, DIBAL-H)
Al
H
• reactivity
- strong reducing agent, but bulky  sometimes see selectivity
- reduces aldehydes, ketones, esters, epoxides to alcohol; lactones to lactols
- pyrophoric liquid, typically purchased in solution
• examples
OTBS
TBSO
OTBS
DIBAL
CO2Me
CH2Cl2, -78°C
TBSO
OH
93%
O
TBSO
DIBAL
OEt
hexanes, -78°C
O
TBSO
H
91%
TBSO
PMBO
O
TBSO
Me
N
OMe
O
DIBAL
THF
89%
PMBO
H
Boron Hydrides
1. Sodium Borohydride (NaBH4)
• general
Na
H
H B H
H
k3
OR
H B H
H
k3
k3
OR
H B OR
H
OR
H B OR
OR
k1 = k2 = k3 = k4
- requires activation:
H
R'
δ+
O
O
H
H B H
H
half life of NaBH4 at 25°C
MeOH
EtOH
iPrOH
tBuOH
30 min
slow
stable
k3
OR
RO B OR
OR
Boron Hydrides
1. Sodium Borohydride (NaBH4)
• reactivity
- selective reducing agent
- reduces aldehydes and ketones to alcohols; imines to amines
- carboxylic acids, esters, lactones, epoxides, nitirles and nitro groups do not react
• examples
O
I
HO
I
NaBH4
MeOH
O
OPiv
O
OPiv
99%
O
O
O
HO
NaBH4
S
S
EtOH-CH2Cl2
S
S
Boron Hydrides
2. Lithium Borohydride (LiBH4)
• reactivity
- reduces aldehydes, ketones, esters, lactones, epoxides
- does not react with carboxylic acids, amides, nitriles, etc.
- can attenuate reactivity by choice of solvent: in ether > THF > 2-propanol
- reacts violently with water
• examples
HO Me
MeO2C
CO2H
HO Me
LiBH4
81%
HO
F
CO2H
F
O2N
H
N
O
O
N
H
CO2Me
OTBS
O2N
LiBH4
H
N
MeOH-THF-Et2O
83%
O
OH
O
N
H
OTBS
Boron Hydrides
3. Sodium Borhydride / CeCl3: Luche Reduction
• reactivity
- selectively reduces α,β-unsaturated carbonyl compounds to allylic alcohols
- also good for readily enolizable ketones
• examples
N
H
N
NaBH4, CeCl3
H
N
H
MeCN-MeOH
78%
H
MeO2C
N
H
H
MeO2C
O
OH
O
OH
OH
+
NaBH4
NaBH4, CeCl3
51 : 49
>99 : 1
Boron Hydrides
4. Borane (BH3)
• reactivity
- very selective: CO2H ≈ CHO > ketone >> CO2R ≈ CN
- also reacts with alkenes and alkynes
• examples
HO2C
O
O
BH3•SMe2
THF
HO
O
O
Boron Hydrides
5. Sodium Cyanoborohydride (NaCNBH3)
• reactivity
- very mild reducing agent; less reactive than NaBH4
- stable in aqueous solution at pH >3
• examples
O
O
CO2Me
CO2Me
MeCN-H2O
96%
NH2
Me
N
Me
MeO2C
MeO2C
OAc
O
NaCNBH3, H2C=O
O
MeO2C
TsNHNH2
EtOH
OAc
N
TsN
OtBu
OAc
O
O
OtBu
OtBu
O
TsNHNH2
NaCNBH3
79%
NaCNBH3
Boron Hydrides
6. Lithium Triethylborohydride (LiEt3BH): Super Hydride
• reactivity
- very powerful reducing agent  stronger than LiAlH4
- excellent reagent for reduction of sulfonates & epoxides
• examples
OTs
LiEt3BH
BnO
THF
OH
BnO
OH
92%
O
OH
LiEt3BH
THF
HO
HO
H
Br
H
H
LiEt3BD
THF
H
D
Boron Hydrides
7. Lithium or Potassium Tri-s-butylborohydride (Li(sBu)3BH, K(sBu)3BH): L/K-Selectride
• reactivity
M+ HB
- bulky reducing agents
3
- reduce aldehyde & ketones, but not carboxylic acid derivatives
• examples
O
OH
K(sBu)3BH
O
N
O
R
O
THF, -78°C
N
CO2Et
BPSO
CO2Et
BPSO
O
Li(sBu)3BH
O
THF, -78°C
O
O
HO
O
K(sBu)3BH
THF, -78°C
O
O
O
R
Boron Hydrides
8. Zinc Borohydride ( Zn[BH4]2 )
• reactivity
- prep (in ether): NaBH4 + ZnCl2  Zn(BH4)2
- ether solution of Zn(BH4)2 is neutral  good for base sensitive compounds
• examples
O
OBn
Zn(BH4)2
ether
OH
OBn
Boron Hydrides
9. Sodium Triacetoxyborohydride ( NaBH(OAc3 )
• reactivity
- also known with tetraalkylammonium counterions  Me4NBH(OAc)3
- selective reduction of aldehydes in presence of ketones
- hydroxyl directed reduction of ketones
• examples
O
O
CHO
Me4NBH(OAc)3
benzene, reflux
OH
77%
O
HO
OH
Ph
Me4NBH(OAc)3
benzene, reflux
HO
Ph
Silyl Hydrides
1. Triethylsilane / Wilkinson’s Catalyst (Et3SiH / (Ph3P)3RhCl)
• reactivity
- selective 1,4-reduction of enones
• examples
O
Et3SiH
(Ph3P)3RhCl
OSEt3
H3O+
O
Other Reductions of Carbonyls
1. Meerwein-Pondorf-Verely Reduction (MPV)
- reverse of Openauer oxidation
- equilibrium determined by choice of solvent
OH
Al(OiPr)3
O
R
H OH
R'
R
O
Al(OiPr)3
R'
Other Reductions of Carbonyls
2. Clemmensen Reduction
O
Zn(Hg)
HCl
CO2H
MeO
CO2H
MeO
68%
3. Wolff-Kishner Reduction
N
N
N
O
N
Cl
Ph
N
N
CHO
H2NNH, KOtBu
EtOH, reflux
H
N
CH3
O
N
Cl
91%
Ph
H
4. Raney-Nickel
O
Et
HS
N
SH
BF3•OEt2
81%
S
Et
S
Ni(Ra)
N
iPrOH, 70°C
78%
Et
N

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