Organic Synthesis II: Selectivity & Control
8 lectures, TT 2011
MeO
O
H
HN
Handout 1
Handouts will be available at:
http://msmith.chem.ox.ac.uk/teaching.html
Dr Martin Smith
Office: CRL 1st floor 30.087
Telephone: (2) 85103
Email: martin.smith@chem.ox.ac.uk
! Organic Synthesis II: Selectivity & Control. Handout 1
! Selectivity and Control
! Definitions: Chemo- and Regio-selectivity
! Recap of selective reactions: reductive amination
1,4 vs 1,2 addition
Electrophilic aromatic substitution
Nucleophilic aromatic substitution
! Stereoselectivity: definitions and recap
! Selectivity and disconnection
! The finished product: total synthesis of (+-) methyl homosecodaphniphyllate
! Chemo- and Regio-selectivity in oxidation of alcohols
! Oxidation as a common functional group interconversion
! Oxidation of alcohols: Cr(VI) oxidants
! Activated DMSO oxidants: Swern, Moffatt and Parikh-Doering procedures
! Application to the generation of bis-aldehydes : (+-) methyl homosecodaphniphyllate
! Hypervalent iodine: Dess-Martin periodinane
! MnO2 and Oppenauer Oxidations
! Catalytic Oxidants: TPAP and TEMPO
! Chemo- and Regio-selectivity in reduction of carbonyl derivatives
! Selectivity in DIBALH reductions: stopping reactions half-way
! Selectivity in (general) hydride reductions
! Using amides as electrophiles: Weinreb amides and examples; the problem of C-acylation
! An aside: acylation at carbon - kinetic and thermodynamic control
! Kinetic control: use of methylcyanoformate
! Selectivity in hydride reducing agents:
Lithium Aluminium Hydride
Lithium Borohydride
Borane (and related complexes)
NaBH4; modified borohydrides & the Luche reduction
! Organic Synthesis II: Selectivity & Control. Handout 1
!Stereoselectivity in hydride reductions:
1,2 stereoinduction (Felkin models and variants)
1,3 stereoinduction (1,3-syn and 1,3-anti diols
Additions to cyclohexanones (torsional control)
Enantioselectivity in hydride reduction
A catalytic asymmetric hydride reduction
! Recap: reduction of alkynes
! Dissolving metal reductions: the Birch reduction
! Dissolving metal reductions of !,"-unsaturated ketones (and esters)
! Hydrogenation
! Oxidation reactions involving alkenes
! Recap: dihydroxylation and allylic alcohol reactions
! Osmium-mediated hydroxylation
! Allylic alcohol mediated alkene functionalization
! Titanium mediated epoxidation: the Sharpless Epoxidation
! The Wacker oxidation
! Epoxidation vs Baeyer-Villiger
! Nucleophilic epoxidation of electron deficient alkenes
! Books & other resources:
1. Oxidation & Reduction in Organic Synthesis (T. J. Donohoe, OUP)
2. Organic Chemistry (Clayden, Greene, Wothers & Warren, OUP)
3. Professor Andrew Myers website (Harvard).
http://www.chem.harvard.edu/groups/myers/page8/page8.html
4. Molecular Orbitals and Organic Chemical Reactions
(I. Fleming, Wiley, 2nd Edn.)
Mechanisms for many oxidation reactions (even well-known ones) are significantly more complex
than drawn throughout this course (and in many cases are not known or understood). Some are
based on factual mechanistic data; some should be treated more as a mnemonic than explanation.
! What is ‘Selectivity & Control’? (and why do we need it?)
! Chemo-selectivity
Selectivity between two functional groups
with nucleophiles
or reducing agents
O
Which
group
reacts?
O
O
OMe
reaction with
peroxy-acids
! Regio-selectivity
Selectivity between different aspects of the same functional group
direct or conjugate
addition with nucleophiles
or reducing agents
Where
does it
react?
X
ortho-, para- or metawith electrophiles
and selectivity
between o- and p-
O
! Chemoselectivity: reactions you have already seen…
! Functional groups have different kinds of reactivity
NaBH4
OH
H2
O
O
C=C weaker #bond than C=O
Pd/C
use nucleophilic
reagent
ketoneelectrophilic
alkene- not
electrophilic
use catalytic
hydrogenation
! Functional groups have similar reactivity
OH
O
NaBH4
O
OMe
use selective
reagent
O
O
OMe
ketone- more
electrophilic
ester- less
electrophilic
OH
protect more
reactive group
! Chemoselectivity: reactions you have already seen…
! Functional group may react twice (is the product more reactive than the SM?)
control?
R1
R2
Br
NH2
R1
R2
N
H
Br
R2
R1
R2
N
R2
Chemoselectivity needed between Starting Material and Product
! Solution: use reductive amination (more on reduction later)
H
R1
O
NH2
H
R2
R1
R2
N
NaB(CN)H3
R1
R2
N
H
or H2, Pd/C
Chemoselectivity: NaBH3CN only reduces imine, not aldehyde starting material
[NaBH3CN is a less nucleophilic source of hydride than NaBH4 due to the
electron-withdrawing nature of the cyanide ligand. As a consequence it will
generally not reduce aldehydes and ketones at neutral pH]
! Regioselectivity: reactions you have already seen…
! Conjugate and Direct Addition to Enones
kinetic product
OH
O
Direct
Nu
Nu
thermodynamic product
Conjugate
[Michael]
O
Nu
Nu
hard nucleophiles
the enone is electrophilic
at two different sites
soft nucleophiles
! Electrophilic Aromatic substitution
X
X
X
E
E
X
E
and/or
E
E
choose 'ortho, para-'directing
group X: Alk, OH, F etc
choose 'meta'directing group X
COR, NO2 etc
! What is ‘Selectivity & Control’ ? (and why do we need it?)
! Stereo-selectivity
Selectivity between two (or more!) possible stereochemical outcomes
Examples you’ve already seen: (I) reduction of cyclohexanones
(see course from Dr E. Anderson, HT 2011)
"H- "
O
Which face
is attacked?
H
OH
'Hydride'
tBu
H
tBu
H
H
"H- "
OH
tBu
H
equatorial
attack
axial
attack
Examples you’ve already seen: (II) Additions to chiral aldehydes & ketones (Felkin-Anh model)
O
Ph
Me
Me
OH
LiBH(s-Bu)3
Ph
[bulky hydride]
Me
Me
1. Reactive conformation
2. Bürgi-Dunitz trajectory
3. Attack away from RL
and over RS
4. TS is SM-like
RM O
RL
Nu
RS H
! Selectivity defines strategy in disconnection
! Reminder of basic principles: where and when to disconnect?
(i) branch points (ii) heteroatoms (iii) functional groups
(iv) simplifying transformations (v) the order of events
(see 1st year course from Prof Gouverneur)
! Disconnections that require selectivity: simple aromatic derivatives
O
O2 N
O
NO2
Esterification
Dinocap - fungicide
directs orthoand para- for
nitration
OH
C-O
OH
O2 N
Friedel
Crafts
(issues?)
C-N
Nitration
O2 N
NO2
C-C
OH
directs orthofor C-C bond
formation
NO2
para- position
blocked
Order is important (the alternative C-N disconnection prior to the C-C disconnection
would not lead to appropriate selectivity)
! Selectivity defines strategy in disconnection
! The 1,2 difunctional disconnection
OH
R2N
OH
RS
OH
HO
! Two group disconnections: Fluconazole
2
N N
OH
N
1
F
N
C-N
N
1,2 di-X
2
NH
N
N N
sulfur
ylid
F
N
O
1
F
N
N
F
F
Deactivating: only
monoacylation
F is o-, pdirecting
F
O
Cl
X-
least hindered
end attacked
N N
F
+
1,2 di-X
O
OH 2
N
OH
X
Cl
F
C-C
Friedel
Crafts
C-N
1,2 di-X
O
Cl
NH
N
F
N
F
! Complex molecule synthesis
! We need to exert control to be able to construct complex molecules efficiently
! Selectivity - as defined by disconnection - offers an opportunity to do this
CO2Me
H
HN
Methyl homosecodaphniphyllate
! Isolated from the bark of Daphiphyllum macropodum
! Structure confirmed by X-ray crystallography
! Complex architecture contains five fused rings
! Selectivity defines strategy in disconnection
! Starting at the end: the same disconnections work regardless of complexity
BnO
BnO
MeO2C
OBn
H
1
H
FGI (ox)
1,1 C-X
(Prins)
HN
H
redrawn
Diels
Alder
N
H
H
2 x C-C
H
N
N
H
R
Methyl
homosecodaphniphyllate
imine
formation
2 x C-N
OBn
OBn
C-C
(1,4 addition)
N
O
N
I
OBn
H
O
FGI (ox)
O
O
MeO2C
C-C
(enolate
alkyation)
MeO2C
H
R
R
R
R=
! Synthesis of (+/-) methyl homosecodaphniphyllate (I)
! An elegant, selective and controlled approach:
MeO
OBn
H
N
1. LDA
O
H
N
N
Generate lithium
enolate
O
OBn
OBn
Regioselective
1,4 addition
OLi
O
LiO
OMe
Amide gives
predominantly Z enolate
SN2 alkylation
[on carbon, not
oxygen]
I
H
O
O
OBn 1. KOH, 95˚C
2. H+
OBn
N
Amide hydrolysis
and lactonization
O
HO
H
OBn
DIBALH
N
Chemoselective
reduction (ester vs
amide)
H
O
MeO2C
Heathcock et al., J. Am. Chem. Soc., 1988, 10, 8734
! Synthesis of (+/-) methyl homosecodaphniphyllate (II)
! An elegant, selective and controlled approach:
OBn
1.LiAlH4
H
O
HO
Chemoselective
reduction of
lactone to diol
O
OBn
(COCl)2, DMSO
Et3N, CH2Cl2
H
OBn
O
Swern Oxidation
Chemoselective
oxidation to
bis-aldehyde
HO
H
O
NH3
OBn
OBn
H
H
N
N
N-protonation
OBn
NH3
AcOH
H
Imine formation
H
O
Enamine
formation
HN
! Synthesis of (+/-) methyl homosecodaphniphyllate (III)
! An elegant, selective and controlled approach:
BnO
OBn
!2s
H
AcOH, 25˚C
redrawn as:
H
H
N
H
N
Regioselective and
Chemoselective
intramolecular Diels
Alder reaction
H
N
!4s
!4s + !2s
BnO
BnO
BnO
AcOH, 75˚C
-H+
H
H
HN
HN
Prins reaction
Electron rich alkene
traps electron poor iminium
cation (to give a tertiary
carbocation)
H
H
N
! Synthesis of (+/-) methyl homosecodaphniphyllate (IV)
! Final steps:
BnO
HO
H2, Pd-C
H
H
Removes benzyl
protecting group
and reduces alkene
HN
CO2Me
1. CrO3, H2SO4,
H2O, Acetone
2. MeOH, H+
H
Chemoselective
oxidation to acid;
Esterification
HN
HN
! A series of simple but selective steps
! Chemo-selectivity, regio-selectivity (and stereoselectivity) are
exploited throughout the synthesis to great effect.
! Overall: nine steps - a spectacularly elegant and efficient approach
We will cover the details of many of these steps throughout the course
! Oxidation is a very common synthetic transformation
! Many functional group transformations are redox reactions
bromonium
cation
electrophilic attack
elimination
Br
SN2
Br
Br
Br
inversion
Br
Br
Enters as Br+
Base
-2HBr
dibromide product
Leaves as Br-
2 electron oxidation
Oxidation = Electrophilic attack = Removal of electrons
So functional groups that react readily with electrophiles are easily oxidized
This includes: alcohols, alkenes, amines and phenols
! Common 2-electron transformations:
-2e
R
OH
alcohol
-2e
R
O
aldehyde
-2e
O
R
R
OH
acid
NH2
amine
-2e
R
imine
NH
NH
R
nitrile
! Selectivity in oxidation of alcohols
! Selective oxidation is a challenging transformation
+H2O
[ox]
R
R
OH
primary alcohol
O
[ox]
OH
-H2O
R
aldehyde
OH
O
R
hydrate
OH
acid
Generally use Cr(VI), Mn(VII), high oxidation state Sulfur or Iodine
Problems: aldehydes are reactive so over-oxidation can be a problem - avoid water!
! Reagents you’ve seen: Cr(VI) oxidation to generate ketones (idealized mech.)
Cr(VI)
O
Cr
Cr(IV)
O
H
O
OH
OH
O
RDS
Cr O
O
O
Chromate Ester
! Selectivity: variants of chromium oxidants
! Common Cr reagents:
H2Cr2O7
Jones reagent
Chromic acid in H2SO4
Usually acetone
co-solvent
OTBS
BnO
O
Oxidizes 1˚ alcohols to
carboxylic acids; 2˚ alcohols
to ketones. Not suitable for
acid sensitive substrates
Jones
reagent
BnO
CO2H
O
N
H
Cr2O722
Pyridinium dichromate
(PDC)
PDC in dry DCM works
well for 1˚ alcohol to
aldehyde oxidation. In
DMF oxidation to acids
occurs
CO2Me
N
H
Acid-mediated
desilylation and
subsequent oxidation
TBS =tbutyldimethylsilyl
Bn = benzyl
CO2Me
ClCrO3-
Pyridinium
chlorochromate (PCC)
PCC will oxidize 2˚
alcohols to ketones
and 1˚ alcohols to
aldehydes (if kept dry!)
Selective oxidation can be problematic with these reagents & stoichiometric chromium
can create waste disposal problems - so many alternatives.
! Selectivity in oxidation of alcohols
! The Swern oxidation: (i) activation of DMSO
Chlorosulfonium
salt
O
O
Cl
Cl
S
-78˚C
O
ClS
DCM
S
Cl
O
O
O
+
C
+ CO
O
Cl
O
Oxalyl chloride
DMSO
Chlorosulfonium salt is effectively the oxidant - unstable above approx -60˚C
! The Swern oxidation: (ii) activation of the alcohol
S
R1
OH
Cl
R1
primary alcohol
H
NEt3
H
-HCl
O
S
H
R1
alkoxysulfonium
salt
H
O
+
S
R1
Me2S
O
aldehyde
alkoxysulfonium
ylide
1.
Effective for primary and secondary alcohols
2. Amine base is necessary to facilitate breakdown of alkoxysulfonium salt
This is an excellent method for the selective oxidation of primary alcohols to aldehydes
! Selectivity in oxidation of alcohols
! The Swern oxidation: (i) activation of DMSO
Chlorosulfonium
salt
O
O
Cl
Cl
S
-78˚C
O
ClS
DCM
O
O
S
Cl
O
+
C
+ CO
O
Cl
O
Oxalyl chloride
DMSO
Chlorosulfonium salt is effectively the oxidant - unstable above approx -60˚C
! The Swern oxidation: (ii) activation of the alcohol
S
R1
OH
primary alcohol
Cl
R1
H
NEt3
H
-HCl
O
S
H
alkoxysulfonium
salt
R1
H
O
+
S
alkoxysulfonium
ylide
R1
O
aldehyde
1.
Effective for primary and secondary alcohols
2. Amine base is necessary to facilitate breakdown of alkoxysulfonium salt
This is an excellent method for the selective oxidation of primary alcohols to aldehydes
Me2S
! Swern oxidation: methyl homosecodaphniphyllate
! Revisit complex example: the order of addition is important
Key: never unmask aldehyde in the presence of reactive functional groups
OBn
HO
HO
then add
Et3N
H
O
-78˚C
OBn
OBn
S
(COCl)2, DMSO,
CH2Cl2
H
O
O
O
S
H
bis-alkoxysulfonium salt
mono-oxidation
[generates mono-aldehyde]
in situ
OBn
H
O
OBn
hemiacetal
formation
H
HO
HO
OBn
further
oxidation
H
O
O
O
There is no control over which alcohol is oxidised first in the ‘lower’ route.
! Alcohol oxidation: other DMSO-based reagents
! Parikh-Doering oxidation (SO3.pyridine is the DMSO activator)
OTBS
OTBS
SO3.py, Et3N
S
H
S HO
S
CH2Cl2/DMSO, rt
SO3.pyr is a crystalline solid
Mild and scaleable oxidation
Selective for 1˚ alcohol ^ aldehyde
H
S HO
O
HO
No diol cleavage
! Pfitzer-Moffat oxidation (DCC is the DMSO activator)
N
OtBu
Cl
OH
DMSO, DCC
Cl
H+, pyridine
Possible side reactions: Pummerer
rearrangement, and acid-induced
problems for sensitive substrates
C
N
OtBu
O
DCC = Dicylclohexylcarbodiimide
[the dicylohexylurea biproduct of this
reaction can be difficult to remove
from the reaction mixture]
Mechanisms are essentially the same as the Swern,
but with the electrophilic DMSO activator being SO3 or DCC
! Dess-Martin Periodinane (‘DMP’)
! Hypervalent iodine oxidant: mild, reliable and works at RT (stylized mech.)
AcO
I
OAc
OAc
O
R2
HO
2
R1 R
H
O
AcO
I O
O
1.5 eq DMP
DCM, RT
R1
O
OAc
O
I
O
O
O
R1
R2
O
AcOH biproduct can be buffered for
very sensitve substrates
! Examples (often used for complex, highly functionalized materials)
Me
Me
Me
Me H
Me
H
TBSO
1.5 eq DMP
Me H
Me
DCM, RT TBSO
O
H
RT
MeO
I
O
DMP
O
O
I
O
O
Me
MeO
O
OH
O
HO
Selective for oxidation of 1˚ alcohols to aldehydes with no overoxidation
! Dess-Martin Periodinane (‘DMP’)
! Mechanistically, the first step is ligand exchange so we would expect to be
able to kinetically discriminate between primary and secondary alcohols:
HO
HO
O
HO
OTBS
O
TBSO
DMP
O
O
O
DCM, RT
OTBS OMe
OTBS
TBSO
OTBS
OTBS OMe
OTBS
1˚ alcohol oxidized preferentially;
2˚ alcohol left untouched
! Allylic and benzylic alcohols oxidized faster (but can & will oxidize 2˚ alcohols)
O
O
O
O
DMP
DCM, RT
H
HO
2˚ allylic alcohol
oxidized faster than
‘normal’ 2˚ alcohol
H
HO
OH
O
Limitations: can cleave diols (like periodate, another hypervalent iodine oxidant)
! MnO2: a selective oxidant for allylic and benzylic alcohols
! Selective for allylic and benzylic alcohols (will not usually oxidize 2˚ alcohols)
OH
OH
MnO2
OH
O
DCM
Allylic alcohol oxidized selectively
! Selectivity is probably a consequence of a radical mechanism
Mn(IV)
O
OH Mn(IV)
Mn
HO
O
O
R1
Mn
R1
allylic/benzylic
alcohol
OH Mn(III)
O
O
Mn
Mn(II)
OH
O
R1
H
OH
Mn
R1
OH
Manganate ester
aldehyde/ketone
Hydrogen abstraction is faster for allylic/benzylic alcohols
(the radical that is produced is delocalized and hence more stable)
! MnO2: a selective oxidant for allylic and benzylic alcohols
! Selective for allylic and benzylic alcohols (will not usually oxidize 2˚ alcohols)
MnO2
Bu3Sn
OH
CH2Cl2
O
Bu3Sn
Mild conditions; can retain vinyl stannane group
! The aldehyde products can be used in-situ with other reagents (MnO2 is v. mild)
Oxidant (MnO2) compatible with reductant (NaBH4) in same vessel
OH
MnO2, CH2Cl2
NaBH4, 4Å sieves
amine
N
[red]
N
then methanol
aldehyde formed in-situ, condenses with amine
to form intermediate imine
NaBH4 reduction of imine faster in polar
protic solvent (MeOH)
MnO2 is a heterogeneous oxidant: workup is generally just filtration
! A Catalytic Oxidant: Tetra-N-Propyl Ammonium Perruthenate ‘TPAP’
! Ru(VII) with organic-soluble counterion is a selective oxidant and can be
used catalytically with a co-oxidant (mechanistically complex!)
O
Pr
O
O
Pr
O
O
Pr
N
Ru
Pr
R2
HO
Ru(VII)
N
R1
O
O
+2e
Ru O
1˚/2˚ alcohol
Ru
O
Ru(VI): active
O
Ru(IV): inactive
O
R2
O
N O
disproportionation
Co-oxidant
‘NMO’
R1
O
Aldehyde/ketone
Ru
O
O
Ru(V)
Selective for oxidation of 1˚ alcohols to aldehydes with no overoxidation
! A Catalytic Oxidant: Tetra-N-Propyl Ammonium Perruthenate ‘TPAP’
! Mechanism: consistent with ruthenate ester (though complex & unproven!)
Ru(VII)
O
O
Ru
O O
R2
R1
Ru(VII)
H
R2
R1
OH
O
O
Ru
O
Ru(V)
R1
OH
Ruthenate ester
1˚/2˚ alcohol
OH
R2
O
Ru
O
O
O
aldehyde/ketone
! Examples (4A sieves remove water to prevent hydration and overoxidation)
H MeO
MeO
MeO
H
O
O
TPAP (10 mol%)
H
O
HO
TBSO
O
H MeO
MeO
OTBS
NMO, DCM
4Å sieves
MeO
H
O
O
OTBS
H
O
O
TBSO
O
Limitations: Can cleave diols (like high valent Manganese and periodate)
! A Catalytic Oxidant: Tetra-N-Propyl Ammonium Perruthenate ‘TPAP’
! Can use in conjunction with the Wittig reaction for reactive aldehydes
O
O
O
TPAP (10%), NMO
DCM, 4Å sieves
OH
CO2Et
O
CO2Et
Ph3P
Stabilized ylide; E/Z >20:1
! Steric selectivity can be exploited: generation of lactones (compare Swern)
OH
O
TPAP (10%)
NMO
OH
O
O
OH
O
O
[ox]
OH
DCM
4Å sieves
O
O
1˚ alcohol
O
Lactol
readily oxidized
Lactone
TPAP will also oxidize sulfur but not other heteroatoms
! Thermodynamics in Oxidation: the Oppenauer reaction
! The reverse of the Meerwin-Pondorrf-Verley reduction (see Dr E. Anderson course, HT 2011)
O
R1
OH
R2
R3
H
Metal
Alkoxide
R4
Oxidant
R1
L
R3
2
M
R
O
L
H
O
R4
OH
R1
H
O
R2
Reduced
R3
R4
Oxidized
M = Al, Zr, B, Ru,
! Very mild, uses non-toxic reagents and can be employed on a large scale
MeO
MeO
O
O
O
NMe
HO
Cl3C
O
Al(OiPr)
3
NMe
OH
H
Zr(OtBu)4
O
Generally superceded by other oxidants, but inexpensive and non-toxic.
O
! Oxoammonium-mediated oxidations
! Most common reagent is TEMPO: 2,2,6,6-tetramethyl-1-piperidinyloxy
N
Oxoammonium
Actual oxidizing agent
O
TEMPO
N
I
Cl2
R2
HO
O
or
R1
1˚/2˚ alcohol
disproportionation
N
AcO
NaOCl
I
O
OAc
TEMPO
R2
O
or
R1
Aldehyde/ketone
'BAIB'
N
OH
Co-oxidant
TEMPO is used catalytically with a co-oxidant
! Oxoammonium-mediated oxidations
! Mechanism:
reoxidation
R2
O
Actual oxidant
‘oxoammonium’
N
N
O
O
R2
HO
1˚/2˚ alcohol
H
R2
R1
N
R1
O
OH
aldehyde
or ketone
R1
! Examples:
PMBO
N
HO
OH
TEMPO
NaOCl
TBSO
PMBO
O
OMe
O
TEMPO
BAIB
KHCO3
PMB =
O
N
MeO
TBSO
Generally: mild, functional group tolerant reagent
O
OMe
! Selectivity in reduction: hydride reducing agents
! Functional groups have different kinds of reactivity
NaBH4
OH
H2
O
O
Pd/C
use nucleophilic
reagent
ketoneelectrophilic
use catalytic
hydrogenation
alkene- not
electrophilic
! For chemoselective and regioselective hydride reduction - which reagent?
O
O
1. NaOH
2. BH3
HO
O
O
NaBH4
CeCl3
EtO
OH
EtO
LiAlH4
OH
HO
Important to use the correct hydride for the correct transformation!
! Selectivity: hydride reducing agents (not ALWAYS reliable..)
Reduced
"
Not usually reduced
!
Slow
NHR
R'
H
O
O
!
R
imine
R
H
aldehyde
!
R
R'
R
ketone
R
OR'
ester
!
!
NaBH4
!
LiBH4
H
via Acid
Chloride
O
O
O
H
LiAlH4
(low temp)
DIBALH
(low temp)
O
R
H
O
R
O
NR'2
R
OH
amide
acid
"
"
"
!
!
"
"
!
!
!
"
"
LiAlH4
!
!
!
!
!
BH3
!
!
!
!
!
NaBH3CN
OH
R'
NHR
amine
R
OH
1˚ alcohol
R
R'
2˚ alcohol
R
OH
1˚ alcohol
R
NR'2
amine
R
OH
1˚ alcohol
! Selectivity in reduction: hydride reducing agents
! DIBALH (Di-Iso-Butyl Aluminium Hydride)
Exists as H-bridged
dimer but reacts as
monomer.
H
Al H
Al
Al
Al has empty p-orbital
in monomer so is
electrophilic.
H
! DIBALH becomes a good reducing agent after reacting with a nucleophile
R2Al
H
O
R
R
OR
destroys any excess DIBALH
tetrahedral
intermediate
R R
Al
H
O
R2AlO H
R
OR
DIBALH reduces most
nucleophilic C=O group
H , H2O
H , H2O
HO H
R
OR
OR
R
unstable
hemiacetal
stable at low
temperatures
O
H
ester reduced to
aldehyde with DIBALH
at low temperature
! Selectivity in reduction: hydride reducing agents
! DIBALH is a powerful and less selective reagent at higher temperatures
R2Al
H
O
R
tetrahedral
intermediate
R R
Al
H
O
R
OR
R2AlO
R
OR
aldehyde - much more
reactive than ester SM
O
H
OR
R
OH
H
R
H
rapid reduction
to alcohol
at RT this intermediate
is NOT stable
! Often used at RT for reduction of esters to alcohols
O
tBuO
OTBS
Ph
MeO
N
H
Complete reduction of
ester to 1˚ alcohol
with excess DIBALH
at RT
CH2Cl2, RT
O
tBuO
DIBALH
CH2Cl2, RT
OTBS
MeO
Ph
N
H
O
O
O
DIBALH
BF3.OEt2
Selective 1,2reduction
OMe
OEt
OH
O
OH
! Stopping reactions half way: reduction
! Application: the reduction of lactones
O
O
DIBALH
O
O
H , H2O
OAlR2
H
Ph3P
R
HO
OH
H
2 equivalents
R
stable cyclic
hemiacetal
The reactive aldehyde is never unmasked in the presence of reactive functionality
the tetrahedral intermediate is stable under the reaction conditions
! Is this approach a solution to a common problem?
O
R1
O
R2MgBr
or R2Li
OR
ester
less electrophilic
O
OH
R2MgBr
R1
R1
or R2Li
R2
ketone
more electrophilic
O
BuLi
R2
R2
product formed
OH
BuLi
OMe
note regioselectivity too: direct rather than conjugate addition
! Stopping reactions half way: Weinreb amides
! Solution: use amides as electrophiles
Li
O
R OLi
R
H
NMe2
H
DMF
NMe2
H2O
O
R O H
H
H
NMe2
H
As seen in
ortho-lithiation
R
H
stable under
reaction conditions
! A Weinreb amide is a better solution to this problem
Li
O
R1
R2
O
Cl
HN
OMe
R1
Me
R2
R1
O Li
OMe
N
Me
N
OMe
Me
a Weinreb amide
H
H2O
R2 O Li
OMe
R1
N
Me
N
R-Li
R-MgX
tetrahedral intermediate
stabilised by coordination
Li
OLi
R2 OH
R1
Acceptable
nucleophiles:
LiN
O
OMe
R1
RO
R
DIBALH
LiAlH4
R2
Me
decomposes during
acidic work-up
! Examples of the use of Weinreb amides
! Grignard addition
OTBS
O
Me
OTBS
N
Ar
O
Me
TBSO
N
O
OMe OMe
N
OMe Me
Me
O
O2 N
Me
O
Ar
tetrahedral intermediate
stabilized by coordination
! DIBALH reduction
OMe OMe
OTBS
N
O
O Mg
N
Ar
Me
THF, 0˚C
99% yield
N
O
Me
MeMgBr
OMe
Me
Me
OMe
DIBALH
Me
Me
TBSO
OMe Me
Me
O
O2 N
H
Me
THF, -78˚C
95% yield
OMe
Me
OMe
! Enolate additions
Li O
OLi
O
N
Me
O
O
tBu
NMe
CO2tBu
O
O
83 % yield
OtBu
THF, -78˚C
OMe
"-keto ester:
C-acylation requires control
tetrahedral intermediate
stabilized by coordination
! Stopping reactions half way: Acylation at Carbon
! The problem: acylation of ketones can be difficult to control
O
O
R1
O
R2
OR
ester
O
O
R1
R2
R2
further
reaction?
ketone
less electrophilic
more electrophilic
! Solution: Employ kinetic or thermodynamic control in Claisen condensation
O
R1
OR2
R1
O
O
O
R2O
OR2
R1
OR2
R1
acylation
at carbon
H
O
R2O
OR2
R1
electrophilic ketone
O
O
R1
OR2
R1
stable, non-electrophilic
enolate - the product under
the reaction conditions
Note: The final enolization is reversible, but the equilibrium lies over to the RHS
! Thermodynamic control
! Intramolecular (Dieckmann) condensation can offer a solution to C-acylation
O
O
EtO
OEt
H
O
CO2Et
O
EtO
CO2Et
MeI
CO2Et
Me
CO2Et
Irreversible
alkylation
! Regioselectivity through thermodynamic control
O
O
O
O
EtO
EtO2C
OEt
O
EtO
EtO
OEt
H
CO2Et
EtO
Cannot form a
stable enolate
Can form a
stable enolate
Note: The final enolization is reversible, but the equilibrium lies over to the RHS
! Acylation at Carbon - Kinetic vs thermodynamic
! Enolate stability can control regiochemistry of C-acylation
O
CO2Me
O
NC
O
O
OMe
MeO
LDA, -78˚C
O
OMe
NaH, 0˚C
Kinetic product
CO2Me
Thermodynamic product
! With reversible enolization conditions we get equilibration between all species
CO2Me
H
CO2Me
O
O
O
O
O
O
CO2Me
CO2Me
This enolate destabilized by
interaction with aromatic
C-H bond - precludes
planarity
No such destabilizing
interaction - more stable
enolate
Note: The final enolization is reversible, but the equilibrium lies over to the RHS
! Acylation at Carbon - Kinetic vs thermodynamic
! Enolate stability can control regiochemistry of C-acylation
O
CO2Me
O
NC
O
O
OMe
MeO
LDA, -78˚C
O
OMe
NaH, 0˚C
Kinetic product
CO2Me
Thermodynamic product
! Stabilizing the intermediate precludes proton transfer under reaction conditions
O
O
O
R1
LDA
OLi
R1
R2
NC
Li
O
O
slow
R2
-78˚C
fast
R2
O
OMe
R1
R2
OMe
CN
OMe
R1
! Example:
O
O
Me
NC
Me
O
OMe
O
Me
LDA, -78˚C
OMe
Notes: pKa MeOH = 16, pKa HCN = 9.5
! Specific reducing agents: Lithium Aluminium Hydride LiAlH4
! Powerful and (somewhat) non-selective reducing agent: will reduce
aldehydes, ketones, esters and amides (anomalous: see mechanism below)
[AlH4]- or [AlH(4-n)ORn] -
Li counterion important
(reaction ineffective without it)
H
O
R1
O
N
R2
R1
H
3
H R
H
Al
H
Li
N
O
R2
R1
H
R3
All 4 hydrides
active in principle
H
H
Al
N
H
R2
H
H
Al
H
Retain C-N bond (compare
with ester reduction)
H
H
R1
R3
N
H
R2
R1
R3
Al is Lewis
acidic
H
N
R2
R3
Iminium much
more reactive
! Examples:
O
H H
N Me
N Me
MeO
H
O
H
O
THF
O
O
LiAlH4
O
MeO
H
O
H
Reduces amide and leads to 1,2-reduction of
!,"-unsaturated ketone (hard nucleophile)
OH
Me
LiAlH4
THF
HO
HO
Me
Me
Me
Lactone (ester) reduction leads to diol
production (note cleavage of C-O bond)
O
! Specific reducing agents: Lithium Borohydride LiBH4
! Typically used for the selective reduction of esters in the presence of
amides, nitriles and carboxylic acids (will also reduce aldehydes and ketones)
F
F
O2N
O
H
N
CO2Me
OTBS
N
H
O
O2 N
LiBH4
H
N
OH
O
OTBS
N
H
THF
O
Ester is reduced (with cleavage of the C-O
alkyl bond) but amide is left untouched
! Examples:
HO CH3
MeO2C
LiBH4
CO2H
O
HO CH3
O
N
THF
HOH2C
CO2H
CO2Me
LiBH4
N
OH
THF
CN
Ester is reduced (with cleavage of the C-O
alkyl bond) but acid is left untouched
CN
Selective ester reduction; nitrile and
amide are left untouched
Can be made in situ: LiI or LiBr + NaBH4
! Specific reducing agents: Sodium Borohydride NaBH4
! Less reactive (than LiAlH4 & LiBH4), more selective. Generally used in MeOH
or EtOH & will not usually reduce esters, epoxides, lactones, nitriles. Mech:
Na+ counterion less
important than solvent
H
OMe
O
R1
H
O
R2
R1
H
H
B
H
H
H
H
R2
OR
B
H
H
NaBH4 slowly reacts with protic
solvents (or alcohol products) to
generate alkoxy borohydrides
All 4 hydrides
active in principle
! Examples:
O
I
OH
O
O
O
I
OMe O
NaBH4
MeOH
O
NEt2
O
O
O
1. NaBH4,
MeOH
OMe
2. 6M HCl
H
ketone is reduced but ester and vinyl iodide
are left untouched
aldehyde is reduced but amide left
untouched (by reduction, anyway…)
O
O
! The Luche reduction: NaBH4 + CeCl3.7H2O
! NaBH4 is not selective for 1,2 vs 1,4 reduction: CeCl3 increases selectivity
O
OH
1,2-reduction favored by addition of Ce salt
OH
CeCl3 accelerates rate of reaction of protic solvent
with NaBH4 to generate alkoxyborohydrides
Reductant
MeOH
NaBH4
51%
49%
NaBH4, CeCl3
99%
trace
NaBH[4-n]OMen
These are harder reducing agents and favour attack
at the hard rather than the soft center
! Examples:
O
N3
CO2Me
OH
O
H
NaBH4
CeCl3.7H2O
H
MeOH
O
O
NaBH4
CeCl3.7H2O
MeOH
OH
O
O
OBn
OBn
N3
CO2Me
Exclusive 1,2-reduction
No ester reduction
Exclusive 1,2-reduction
! Other modified Borohydrides
! NaBH3CN and NaBH(OAc)3: reagents of choice for reductive amination
OTBS
Ph
O
N
H
Me
H
Ph
NaBH3CN
CH2O
O
pH 5
N
Me
AcO
OTBS
Me
O
R
H
NaBH(OAc)3
SnCl2
N
O
H H
Reduces intermediate imine/iminium NOT
aldehyde: selective reductive amination
Me
N
AcO
H
O
R
Me
Reduces intermediate imine/iminium NOT aldehyde. SnCl2
Lewis acid accelerates iminium formation
! Super-HydrideTM: alkyl groups make it the most nucleophilic hydride source
challenging SN2 (neopentyl)
Ph
Ph
MsCl, Et3N
HO
MsO
Ph
LiEt3BH
THF
H
The most nucleophilic hydride: especially effective for
SN2 type reactions on activated leaving groups
Electron donating groups
increase hydride donor
ability of B-H bond
! Specific reducing agents: Borane BH3
! Reagent for rapid reduction of acids (compare LiAlH4); idealized mechanism:
H
O
R1
B
H
O H
THF
H
OH
R1
O
H+ workup
R1
H
H
O
R1
B
O
O
R1
H
H OR2
B
H
O
‘OR2’ group could be
THF or substrate
HO
OH
R1
H
H
B is Lewis
acidic
Only 1 eq. BH3 per
acid required
B
OR2
H
O
-H2
H
B
OR2
B is Lewis
acidic
OR
HO B
H
H
O
R1
H
O
R1
H
H OR2
B
H
O
! Examples
O
O
O
H
O
BH3.THF
Me
Br
H
Me
CO2Et
OH
Br
CO2H
BH3.THF
HO2C
Selective acid reduction - no
reduction of lactone
HO
CO2Et
Selective acid reduction
No 1,4-reduction; no ester reduction
! Chemoselectivity with hydrides: recap
NHR
R'
O
H
imine
R
H
aldehyde
!
R
O
O
O
ketone
R'
R
OR'
ester
!
!
NaBH4
!
LiBH4
R
O
NR'2
R
OH
amide
acid
"
"
"
!
!
"
"
!
!
!
"
"
LiAlH4
!
!
!
!
!
BH3
!
!
!
!
!
NaBH3CN
OH
R'
NHR
amine
R
OH
1˚ alcohol
R
R'
2˚ alcohol
R
OH
1˚ alcohol
R
NR'2
amine
What about stereoselectivity in reduction?
R
OH
1˚ alcohol
! Diastereoselectivity with hydrides: 1,2-stereoinduction
! Felkin-Anh model (see Dr E. Anderson course HT 2011)
O
OH
LiBH(s-Bu)3
Ph
Me
Ph
Me
THF
Me
Me
O
Me
1. Reactive conformation
2. Bürgi-Dunitz trajectory
3. Attack away from RL
4. TS is SM-like
R
R
Ph
B
R
H Me
H
‘Felkin’ product
! Felkin Polar model
O
LiBH(s-Bu)3
Ph
1. Electronegative group is
treated as large
2. #* C=O overlap with $*
C-S (lower LUMO)
3. Forming C-Nu bond
stabilized by C-X $*
OH
Ph
Me
THF
Me
SMe
O
iPr
MeS
R
R
B
Me H
H
R
‘anti-Felkin’ product
! Felkin Chelation model
Me
Zn(BH4)2
Ph
Me
THF
OMe
Zn2+
1. Lewis acid metal
2. electronegative group
coordinates to metal
3. Controls reactive
conformation
OH
O
Ph
OMe
MeO O
R
Me
R
B
R
‘Felkin’ product
H Ph
H
! Diastereoselectivity with hydrides: 1,3-stereoinduction
! 1,3 polyols are components of many natural products
(+)-Roxaticin
OH
OH
OH
OH
OH
Me
OH
O
OH
OH
OH
HO
O
1,3-syn
OH
1,3-anti
Me
! A disconnection approach indicates how to assemble the 1,3-arrangement
OH
OH
R1
R2
OH
FGI
[red]
R1
O
OH
FGI
R2
[red]
1,3-syn
OH
R2
R2
1,3-anti
Can we use the stereochemistry of
this product to direct hydride
reduction to afford either the syn- or
anti- product?
! Diastereoselectivity with hydrides: 1,3-stereoinduction
! 1,3-syn diols may be generated by using a Lewis acid to favor intermolecular
hydride delivery from the least hindered face:
HOH
R3B, MeOH
O
R1
R
R1
NaBH4
R2
R2
Boron is
Lewis acidic
B
O
O
OH
OH
R1
R
Chair-like TS
axial attack of hydride
R2
1,3-syn
! 1,3-anti diols may be generated by using intramolecular delivery of the
hydride nucleophile
OH
R1
H
Me4NBH(OAc)3
O
R2
H
Boron is
Lewis acidic
H
R1
H
OAc
O
B
O
R2
H
OH
OAc
OH
R1
R2
1,3-anti
Chair-like TS
put substituents pseudo-equatorial
Intramolecular delivery
! Diastereoselectivity with hydrides
! Size matters: addition to cyclohexanones (see Dr E. Anderson course HT 2011)
HH
H
H
OH
H
Small
Hydride
O
H
'Axial
attack'
Large
Hydride
H
OH
H
H
'Equatorial
attack'
LiAlH4
Small H9:1, axial/equat. attack
H-
Na(s-Bu)3BH
Big H96:4, equat./axial attack
So equatorial attack appears to be favoured, as it does not require the hydride to approach
across the ring (where 1,3-diaxial interactions hinder trajectory)
! Why is axial attack then favoured for small hydrides (nucleophiles)?
axial
H
O
H
equatorial
Equatorial: O moves towards
C-H, leading to higher
torsional strain in the TS
Axial: O moves away from
C-H, leading to lower
torsional strain in the TS
! Enantioselectivity with hydrides I
! How does Nature perform reductions?
O
S-(+)-lactate
CO2
NH2
N
Histidine
H
O
O H
O
Enzyme holds groups in H
appropriate position for
reactivity (to stabilize TS)
and provide selectivity
NH2
N
NAD
R*
N
NH
O
lactate
dehydrogenase
NADH
Asparagine
N H
CO2
H O
H
HN
H OH
R*
H N
H O H
NH2
N
NADH
R*
! We can mimic this in the lab by using Mg2+ to control conformation
Me
lactatelike
H
O
N
O
O
Ph
N
O
Ph
Ph
Me
H
Mg2+
O
MeO-
Ph
O
Mg2+
N
Ph
NADH-like
O
Me
O
O
H
OH
OH
(S)-(+)-enantiomer
Ph
Mg activates and
controls conformation
Ph
MeO
Aromatic biproduct
(a pyridinium salt)
Single enantiomer
produced
! Enantioselectivity with hydrides II
! We can put the chiral group on the reagent too (‘chiral NaBH4’)
H
N
Ph
H
Ph
Made from Proline
!
Ph
N
H3B B O
R
‘CBS’ reagent
Chiral reducing agent
Ph
H3B B O
R
O
Ph
Ph
O
10 mol% cat.
Me
Trivalent boron is lewis acidic
Hydride delivered from 'top' face
Overall: boat-like arrangement
BH3 used to regenerate active material
BH3
Ph N
H B
H
Me
O
H
Ph
OH
Ph
Me
(R)-alcohol,
97% ee
A highly effective reagent for enantioselective reduction of ketones
H
H
Ph
O
Cl
Ph
B O
R (1 mol%)
BH3, THF
Ph
N
N
Ph
R
B
OH
Ph
Cl
98:2 ratio of
enantiomers
Ph
B O
Bu (1 mol%)
O
TBSO
Me
Me
BH3, THF
OH
TBSO
Me
Me
97:3 ratio of
diastereoisomers
! Reduction of alkynes (recap of 1st year material)
! Overall cis- addition of hydrogen across the alkyne: ‘hydrogenation’
H2 (g)
R1
R2
Lindlar
catalyst
H
H
R2
R1
H H
hydrogen on
catalyst surface
cis alkene
! Overall trans- addition of hydrogen across the alkyne: ‘dissolving metal’
LUMO
!* C C
R2
H
R1
Na
N
H
NH3 (l)
H
R2
R1
NH3 (l)
Anion adopts transconfiguration
H
R2
Na
R1
NH3 (l)
H
R2
NH3 (l)
R1
H
R2
R1
H
Isolated alkenes are not usually
reduced under these conditions
! Dissolving metal reductions: The Birch reduction
! The Birch reduction can be used to partially reduce aromatic rings
H H
A range of metals can be
used: Li, Na, K (sometimes
even Ca and Mg)
Na, NH3 (l), EtOH
Kinetic product is nonconjugated diene
H H
! The regiochemistry of the reduction depends on substitution
OMe
CO2H
OMe
H
H
Na, NH3 (l), EtOH
H CO2H
Na, NH3 (l), EtOH
H
H
Electron-donating groups (OR,
NR2, alkyl) give rise to this
orientation of reduction
H H
Electron-withdrawing groups (CO2H,
CO2 R, COR, CONR2, CN, Ar) give rise
to this orientation of reduction
! Dissolving metal reductions: The Birch reduction
! Mechanism: reduction of arenes bearing EDG (OR, NR2, alkyl)
NH3(l)
Li (or Na)
Li+
A dark blue solution of solvated electrons. This is
the actual reducing agent in the Birch reduction
e [NH3]n
Addition of electron into
benzene LUMO
OMe
Undergoes orthoprotonation (probably)
OMe
OMe
H
Na, NH3(l)
EtOH
"e "
H
H OEt
RDS
H
OMe
OMe
H
H
Na, NH3(l)
EtOH
"e "
H
Delocalized radical anion
H
H
H OEt
OMe
H
1. Reduction of alkyl benzenes and aryl ethers requires a proton
source stronger than ammonia (usually an alcohol).
2. First protonation occurs ortho- as this is the site of highest
charge (and gives the most stable intermediate)
3. Second protonation occurs para- to give the non conjugated
product: kinetic control and a consequence of the pentadienyl
anion HOMO having the largest coefficient in this position
H
Undergoes paraprotonation
H
H
Isolated C=C are not
usually reduced
! Dissolving metal reductions: The Birch reduction
! Mechanism: reduction of arenes bearing EWG (aryl, carbonyl, acid, nitrile)
CO2H
CO2
CO2
Na, NH3(l)
CO2
Na, NH3(l)
H OEt
EtOH
"e "
H H
H
Addition of electron into
benzene LUMO
CO2
EtOH
"e "
H H
Undergoes paraprotonation
1. Carboxylate will be deprotonated under reaction conditions
2. First protonation in para- position: site of highest charge (and
most stable intermediate)
3. Kinetic and irreversible protonation to give non-conjugated
product.
H OEt
H CO2H
Undergoes ipsoprotonation
H H
Isolated C=C are not
usually reduced
! Examples:
Me
OMe Na, NH (l) Me
3
OMe
Me
CO2H Na, NH (l) Me
3
EtOH
EtOH
Both EDG: direct
reduction to same
orientation
One EWG and one
EDG: both direct to
same orientation
CO2H
! Dissolving metal reductions: The Birch reduction
! The proton source is important
OMe
OMe
OMe
H
Na, NH3(l)
Na, NH3(l)
H
H
EtOH
H
‘more’ reduction
without EtOH
non-conjugated
diene (with EtOH)
! NH3 functions as a proton source (to make NH2-) if there is nothing better
‘normal’ nonconjugated product
OMe
OMe
OMe
OMe
H
Na, NH3(l)
thermodynamic
conjugated product
H NH2
H
H
OMe
NH2-
H
H
H
H
NH2- strong base
can isomerize
NH3 functions as
proton donor
conjugated product:
further reduction
Some reductions do not proceed without the proton source.
Applications of the Birch reduction
Reductions of conjugated alkenes
O O
H3C
O O
H3C
H
K, NH3
THF, -70˚C
H
H
H
Conjugated alkene is
reduced more rapidly than
electron-rich arene
MeO
MeO
Reductive alkylation: alkylation of the pentadienyl anion intermediate
OMe
CO2tBu
1. K, NH3
1eq. tBuOH
OMe
CO2tBu
iPr
2. iPrI
CN
OMe
CN
1. Li, NH3
1eq. tBuOH
One equivalent of BuOH to permit
first para- protonation, then kinetic
alkylation of pentadienyl anion
OMe
2.
Br
t
Cl
Cl
Regiochemistry of reduction a consequence
of substitution; note alkylation via
displacement of best leaving group