Synthesis I

Lecture 2
Synthesis I Dr. Ahmed Zaed Lecture 2

Wadsworth-Emmons Reaction

Very similar to Wittig reaction except that a phosphonate ester is used instead
of a phosphorous ylide:

Wittig Reaction: Wadsworth-Emmons Reaction:

OEt
R PPh3 R P OEt
O

In general:
Phosphonate
Br- Ester

+ OEt
EtO2C Br + P(OEt)3 EtO2C P OEt
EtO2C P O
Triethyl OEt O
OEt
phosphite
NaH
O
Ph CO2Et Ph CO2Et -
Ph H OEt
- O P OEt EtO2C P OEt
O P OEt OEt
- O OEt O O

Ph OEt
P OEt
CO2Et O-
+

OEt- +
EtO O Na
P
O

Reaction has several advantages over the Wittig:

1) Phosphorus by-product is soluble in water, thus can be washed out in work-
up (Ph3P=O in Wittig requires chromatography to remove from product).

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Synthesis I Dr. Ahmed Zaed Lecture 2

2) Phosphonate ester is a more powerful nucleophile than the Wittig ylide.

Thus can also react with unreactive / hindered ketones.

- + - OEt
EtO2C PPh3 vs EtO2C P OEt
O

Thus tend to use Wadsworth-Emmons reaction for stabilised species:

EtO R
EtO P CO2Et CN
O O
NO2
Ph

3) Phosphonate ester can also be further functionalised to give more

substituted alkenes:

CH3 1) NaH
EtO 1) NaOEt EtO Et CH3
EtO P CO2Et
2) CH3Br EtO P CO2Et 2) EtCHO H CO2Et
O O

Stereoselectivity of W/E:
1) Normal W/E reaction gives almost only the E-alkene. Due to reversibility
of steps after reaction with aldehyde.

2) Can make W/E selective for Z-alkene by carrying out reaction under kinetic
conditions:
Use trifluoroethyl phosphonate, non-complexing base and crown ether to
remove metal.

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Synthesis I Dr. Ahmed Zaed Lecture 2

- SiMe3
F3CH2CO - K+ N
F3CH2CO P CO2Et SiMe3
O KHMDS
potassium hexamethyldisilazide

This makes all steps irreversible leading to Z-alkene:

F3CH2CO KHMDS F3CH2CO K+

-
F3CH2CO P CO2Et F3CH2CO P CO2Et
O O

18-Crown-6

O
O
H3C H F3CH2CO - O O
H3 C CO2Et
F3CH2CO P CO2Et K+
O O O
Z-alkene
O

For example:
Z E
EtO 1) NaH H3C CO2Et H CO2Et
EtO P CO2Et
2) MeCHO H H H3C H
O
1 : 12

F3CH2CO 1) KHMDS / 18-crown-6

F3CH2CO P CO2Et 11 : 1
O 2) MeCHO

Retrosynthetic analysis on double bond:

Bu CO2Et Bu EtO CO2Et EtO CO2Et

O + EtO P EtO P + Pr I
Me Pr Me Pr
O O

P(OEt)3 + Br CO2Et

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Synthesis I Dr. Ahmed Zaed Lecture 2

The Horner Reaction

Very similar to the W/E reaction except that a phosphine oxide is used instead
of a phosphonate ester:
Ph EtO
Ph P R EtO P R
O O

Handout 4

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Synthesis I Dr. Ahmed Zaed Lecture 2

Handout 4 The Horner Reaction

1) Na or K base
Ph O
(e.g. NaOEt) H3C Et H3C H
Ph P CH3 + + Ph P O-Na+
O 2) EtCHO H H H Et Ph

Use of Na or K base leads directly to the alkenes (intermediates cannot be isolated).

Thus get mixture of E- and Z-alkenes.

However, use of a Li base allows isolation of the -hydroxyphosphine oxides.

These can be isolated by column chromatography and then treated separately with NaH to
give either the E- or Z-alkene.

O O
Ph 1) LiHMDS Ph P Ph P OH
OH
Ph P CH3 Ph + Ph
O 2) EtCHO Me Et Me H
H H H Et

NaH NaH

H3 C Et H3C H

H H H Et

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Synthesis I Dr. Ahmed Zaed Lecture 2

Reduction of Alkynes

E- and Z-alkenes can also be prepared by selective reduction of alkynes

Three good methods:

Synthesis of Z-Alkenes using Lindlar’s Catalyst:

Hydrogenation of alkynes using Lindlar’s catalyst (Pd, CaCO3, Pb(OAc)2)
gives only Z-alkenes.
This is due to both hydrogens being delivered from the same face.

R1 R2
R1 R2
H H
H H

Surface of
Catalyst

As hydrogenation is a mild procedure, this is a good way of preparing Z-

alkenes in the presence of other functional groups:

Lindlar's
Catalyst Et
O O O
O
Et
85% (only Z-isomer)

Synthesis of E-Alkenes using Sodium in Liquid Ammonia:

This is a reductive method where sodium delivers 2 electrons sequentially

followed by protonation by the solvent:

Handout 5

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Synthesis I Dr. Ahmed Zaed Lecture 2

Handout 5 Reduction of Alkynes to Give E-Alkenes

Sodium / Liquid Ammonia: E-alkenes

Na + NH3 Na + NH3

H H
Na. + e- R2 tBuOH Na. + e-
R1 R2 R1 R2 R2
R1 R1

tBuOH
Note: Final anion adopts the more stable trans geometry which gives
the E-alkene. H
R2
R1
H

e.g. H
Na, NH3

tBuOH
H

85% (only E-alkene)

Lithium Aluminium Hydride Reduction: E-alkenes

Widely used procedure for making E-alkenes from alkynes. However, only works if alkynes contains
a hydroxy or ether group close to triple bond. This coordinates to aluminium and deliver hydride
to triple bond.

e.g. H3Al
OH OH
H
OH LiAlH4
OH

H+

OH
H OH

H
80% (only E-alkene)

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Synthesis I Dr. Ahmed Zaed Lecture 2

Reactivity of Alkenes

There are many routes to prepare alkenes mainly because they can be further
transformed to give a wide range of different functional groups.

Look at the following: Hydrogenation, Addition, Hydroboration, Epoxidation,

Dihydroxylation, Ozonolysis and the Diels-Alder reaction.

Catalytic Hydrogenation
This allows reduction of alkenes to alkanes under mild conditions:

R1 R3
R2 R4
H2 H H
R1 R3
Pd on a R2 R4
Carbon surface H H

Both hydrogens come from the same face, thus hydrogenation is

stereospecific.
e.g.
CH3 H3C H
Pd / C
H2

Combination of Wittig and hydrogenation is a good way of preparing C-C

single bonds:

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Synthesis I Dr. Ahmed Zaed Lecture 2

CO2Me FGI CO2Me

MeO2C MeO2C
NHBoc NHBoc

-aminopimelic Acid

Boc= tert-butoxycarbonyl + O CO2Me

MeO2C PPh3 +
H NHBoc

Addition Reactions

Alkenes are electron rich and can therefore act like nucleophiles with
electrophilic reagents:
Cl-
H3C CH3 H Cl H3C H CH H3C H CH
3 3

H3CH2C H H3CH2C H H3CH2C Cl H

Most stable carbocation

(tertiary vs secondary)

Thus addition reactions are regiospecific.

Can also easily add water and halogens across C=C bonds:

H+ H3 C HH H2O H3 C HH
H3C H

H3C H H2O H3 C H H3C O+ H

H
H
most stable carbocation
(tertiary vs primary)
-H+

Note: Hydroxy group becomes attached to the more

H3C HH
substituted carbon (Markovnikov addition)
H3C OH H

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Synthesis I Dr. Ahmed Zaed Lecture 2

Addition of halogens across C=C bonds is anti:

Br
Br Br +
Br
Br
Br-

H2O

Br

OH

Note: Can trap bromonium intermediate with a large excess of other

nucleophiles.

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Synthesis I Dr. Ahmed Zaed Lecture 2

Handout 6 Hydroboration-Oxidation (Anti-Markovnikov Addition)

Reaction of alkenes with borane lead to a trialkylborane. Addition takes place regioselectively
via a four centre transition state.

H BH2 H BH2
H3C BH3 H3C Boron adds to least
H3C substituted carbon
H3C H3C H3C

H3 C
2 x
H3 C H
CH3
CH3
H B Trialkylborane
H3C
H3C CH3
H
CH3

Trialkylborane can then be oxidised using hydrogen peroxide / sodium hydroxide. A concerted
rearrangement then takes place (retention of configuration) with insertion of oxygen into the
carbon-boron bond.

R HO R
-OOH R
H B O B
H B H O R
H3C R R
H3C H3C
H3 C H3C H3C

2 x -OOH

H
CH3
ONa CH3
H OH 3 x NaOH
3x + B O
H3C NaO ONa
H3C H B
O O
anti-Markovnikov H3C CH3
Addition H3C
H CH3

Overall:

H3C 1. BH3, THF H OH

H3C H3C
2. H2O2, NaOH H3C 84%

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Synthesis I Dr. Ahmed Zaed Lecture 2

Epoxidation

Reaction of alkenes with peroxycarboxylic acids leads to the formation of

epoxides.
O

 OH
R O O
O
+
R OH

The nucleophilic alkene reacts with the electrophilic oxygen via a concerted
mechanism. As mechanism is concerted, we get retention of configuration:

O R

H O O
O O
H +
H R OH
H
H

Also the more substituted an alkene, the more nucleophilic it is, therefore the
faster the reaction (due to inductive effect):

O
OH
O
O 86%

Due to ring strain epoxides are very reactive to nucleophilic attack.

CH3MgBr OH
O H
H
CH3

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Synthesis I Dr. Ahmed Zaed Lecture 2

How could we make the above tertiary alcohol from cyclohexanone:

OH OH O
H H H
CH3- +
CH3

O H
H
O + EtO P
EtO

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