Idea Transcript
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 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 Al H
4. Diisobutylaluminum Hydride (DIBAL, DIBAL-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
Aluminum Hydrides Epoxide Opening: Red-Al vs. DIBAL
O BnO
OH OH
OH
BnO
+
OH Red-Al DIBAL
Red-Al
DIBAL
150 : 1 1 : 13
BnO
OH
Boron Hydrides 1. Sodium Borohydride (NaBH4) • general
Na
H H B H H
k1
OR H B H H
k2
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
k4
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, nitiriles 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 5. Sodium Cyanoborohydride (NaCNBH3) • hydrazone mechanisms
!
!
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(OAc)3 ) • 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