Birch+reduction

e.g. LiEt3BD
Br
H
H D
(D = deuterium = 2H)
Epoxides are a special class of C-X species: there are two possible sites of attack and we can tailor our reaction conditions to gain access to either. Thus, nucleophilic conditions give rise to attack at the less hindered carbon, while the use of a Lewis acid promotes attack at the best cation-stabilising centre (usually more substituted) on account of the polarised transition state. (Again, inversion of stereochemistry is seen at the centre being attacked by “H-“).
Functional Group Reactivity with Various Reducing Agents
Reagent NaBH4/EtOH LiAlH4 LiAlH(OtBu)3 BH3-THF (i-Bu)2AlH (DIBALH) Catalytic hydrogenation
Reaction
CO2Et
1. e-
2. H-OtBu 3. e-
CO2Et
add E+
EtO2C E
(e.g. haloalkane)
1
e.g.
OMe
CO2H Na, liq. NH3
2.O1 Organic Synthesis – A. Armstrong
OMe CO2-
C3H7Br
OMe CO2-
H3O+
O
R1
R2
OH
R1
R2
H Al O HH
H3O+ (work up)
2
2.O1 Organic Synthesis – A. Armstrong
Outcome B – reduction of the alkene – can often be done by using H2 and a catalyst (e.g. Pd/C). Alternatively, we can use Na in liquid NH3, which allows the useful possibility of trapping the intermediate enolate with electrophiles. This process allows regiospecific enolate formation from the enone.
Section 4: Reductive cleavage of C-X bonds
4.1 Hydride displacements LiAlH4, NaCNBH3 and LiEt3BH (sold as “Super hydride”!) can all displace halides, tosylates and mesylates from primary and secondary alkyl positions. Since the reactions are SN2 in nature, this is a useful way of making stereospecifically deuterated compounds through the corresponding deutero reducing agents. This is of much use in biosynthetic studies.
RCHO RCOR'
RCH2OH RCH(OH)R'
+ + ++++ + + ++++
RCOCl RCOCl
RCHO RCH2OH
n/a n/a n/a - +* n/a n/a + + - + +
Lactone Epoxide RCOOR' RCOOH RCONR'R" RCONR'R" RCN
RNO2 RCH=CHR
Birch reduction
· Partial reduction of an aromatic ring
R
to a non-conjugated, 1,4-diene
Li or Na
liquid NH3
R

ROH (often tBuOH)
H-OR
HH
H-OR
EWG = CO2R, CN, etc.
+ = gives reaction shown
- = does not give reaction shown
n/+a-
= gives other = borderline
reaction case
* = if one equivalent used
5
2.O1 Organic Synthesis – A. Armstrong
HO R
LiAlH4
NaBH3CN BF3·OEt2 (Lewis acid)
4.2 Radical reactions Don't need to worry about these at the moment (await 3rd year!) but they are very useful, and not just for C-X reductions. Much of the work was pioneered by the Nobel Laureate Sir Derek Barton, who spent most of his career at Imperial College.
undergo hydrogen bonding to the carbonyl group in the enone).
O
NaBH4
MeOH
OH
OH
+
with no CeCl3: 59:41 with CeCl3: 99:1
3
2.O1 Organic Synthesis – A. Armstrong
via enol ether hydrolysis; decarboxylation of β-ketoacid; migration of alkene into conjugation with carbonyl
3.5 Reduction of α,β-unsaturated carbonyl compounds There are three possible outcomes to this: total reduction to the saturated alcohol; partial reduction to the unsaturated ketone; and partial reduction to the allylic alcohol:
O
Na liq. NH3
ONa
H3O+
E+
For outcome C – reduction of the carbonyl group only - one of the most reliable methods involves the use of NaBH4 along with CeCl3 in MeOH (known as the Luche reduction). (Mechanistically, the CeCl3 is believed to accelerate the reaction between NaBH4 and MeOH to give alkoxyborohydrides (see Lecture 1), as well as increasing the ability of the MeOH to
R OBn = R O Ph or
R
NHBn = R
N H
Ph
H2, Pd/C
Next time: Oxidation of C-H bonds, alcohols 4
AA 10.11.05
2.O1 Organic Synthesis – A. Armstrong
REFERENCE SECTION!
Diol Alcohol RCH2OH + R'OH RCH2OH
- + +- + + +
- + +- + + +
-
+ +-
+- + +
- + - ++-
RCH2NR'R" RCHO
- + - +++ - + - n/a + +
RCH2NH2 RNH2 RCH2CH2R
- + - +++ - +- - ++ - - - +- +
(relatively fast reaction)
EWG
EWG
EWG
EDG =
EDG
EDG
EDG
alkyl, OMe, NR2, etc.