Advanced Organic Synthesis
Chem 640
Dr. Nabila Al-Jaber
njaber@ksu.edu.sa
1431-1432
9. Latent Polarity
Think about some of the reactions we've looked at for carbonyl compounds:
2
Let, 2/11-10-2010
3
Let, 2/11-10-2010
10. Latent polarity in bifunctional compounds
Consider a 1,3-disubstituted molecule, e.g.
Latent Polarities:
O
starting from C=O
OH

O
OH
  

Ph
O
starting from C

4
Ph
Let, 2/11-10-2010
OH


Ph


O
OH


O
OH


Ph
O
+
Ph
PhCHO
Thus
O
O
base
O
O
PhCHO
Cross Aldol
Ph
Acidic protne
H 3O+
O
OH
O
Na2SO 4
Ph
TM
TM2
5
Ph
- H2O
Let, 2/11-10-2010

R


O
O




O
O


R
R
R
O
e.g.
+
R
O
O
NaOH

O
R
R
R
6
O
Let, 2/11-10-2010
R
But what about 1,4-disubstitution?

O
O








O 
O
O
O
synthons
O
O
O
?
+ base
7
Let, 2/11-10-2010
equivalents
O
O


 Br
O
O
O
Br
O
base
O
8
Let, 2/11-10-2010
The German word UMPOLUNG, meaning polarity reversal is used to describe
the situation where the polarity in a compound is deliberately changed to facilitate a
particular reaction.
reacts with
nucleophiles

example:
O
+
H
HS
SH
cat. BF3·OEt 2
u
mp
olu
ng
OH
SH
S
H
- H2O
S
S
acidic proton
(pKa ~ 32)
H
n-Butyllithium
Let, 2/11-10-2010
S
reacts with
electrophiles
S

Li
+
11. Strategy in retrosynthesis
1) Consider
different possibilities.
2) Try a number of disconnections and FGI's.
3) Try to keep the number of steps down, and stick to
known & reliable reactions.
4) In real life, a synthesis has to be economically viable.
5) Whenever possible, go for a convergent route rather
than a linear one, as this will lead to a higher overall
yield
10
Let, 2/11-10-2010
ABCDEF
ABCD
+
ABCDE + F
ABCD + E
EF
linear
convergent
eg.
AB + CD , E + F
ABC + D
AB + C
A+B ,C+D
A+B
Linear vs. convergent synthesis assume 80% yields (optimistic!)
11
Let, 2/11-10-2010
Linear:
step 1
2
A
AB
approx
overall yield: 80%
5
4
3
...10
...15
ABC
ABCD
ABCDE
ABCDEF
A...K
A......P
64%
51%
40%
32%
...10%
...3.5%
Convergent:
A
AB
ABCD
C
E
CD
ABCDEF
A...K
EF
G...K
A......P
L...P
80%
12
64%
51%
Let, 2/11-10-2010
40%
32%
12. Aim for the greatest simplification
1. make disconnections towards the middle of the molecule
(this is more convergent anyway)
2. disconnect at branch points
3. use symmetry where possible
eg. (towards the middle)
O
O
O
Ph
O
Ph
O

O
O
O
base
Ph
13
MVK
Ph
methyl vinyl ketone
MVK
Let, 2/11-10-2010
eg. (at branches)
O
O
CO 2Et
CO 2Et
Ph
Ph
O
O

?
CO 2Et
Ph
CO 2Et
Ph
NaOEt
Br
O
CO 2Et
Ph
14
Let, 2/11-10-2010
eg. (look for symmetry)
O
O
O
HO
HO
self -condensation
O
O
O
O
NaOEt
HO
 H2O
O
Let, 2/11-10-2010
Alternatively, potentially reactive groups can be protected or masked so
they don't react, eg. reduction of an ester in the presence of a ketone
OH
O
HO
O
O
CO2Me
Ph
CO2Me
cat. TsOH
Ph
Ketal
(stable to
bases and
nucleophiles)
O
Ph
H3O+
LiAlH4
Et2O
O
O
OH
Ph
OH
Note that protection strategy requires two extra steps (must be efficient);
better syntheses minimise the use of protecting groups.
16
Let, 2/11-10-2010
Sometimes it helps the retrosynthesis
if you add a functional group to facilitate bond formation
(Functional Group Addition, FGA).
An example of this is acetoacetic ester synthesis:
O
O
O

OEt
O
Thus:
O
FGA
O
O
CO2Et
discon.
Bu
discon.
CO2Et
CO2Et
SM, Ethylaceto acetate
17
Let, 2/11-10-2010
The synthesis therefore is
O
O
O
NaOEt
MeI
CO2Et
CO2Et
CO 2Et
Acidic proton
NaOEt
BuBr
O
O
Bu
CO2
O
CO2H
Bu
TM
18
Let, 2/11-10-2010
H3O

+
CO 2Et
Bu
13. Ring Closing Reactions
Synthesis of carbocyclic molecules
Same approach as to acyclic systems. The probability
of reaction between two functional groups is higher if:
a) reaction is intramolecular (faster reaction)
b) the distance between the two groups is shorter
e.g. Intramolecular alkylation:
19
Let, 2/11-10-2010
e.g. Intramolecular alkylation:
EtO2 C
CO 2Et
EtO 2C
EtO2C
CO2 Et
CO2 Et
X

EtO2 C
EtO2C
CO 2Et
NaOEt
NaOEt
EtO2C
CO 2Et
BrCH2CH2CH2CH2Br
Br
H 3O +
COOH
Cyclopentanoic acid
20
Let, 2/11-10-2010
heat
CO2 E
t
Intramolecular acylation eg. the Dieckmann cyclisation;
especially good for 5-membered rings:
O
O
CO2Et
CO2Et
O

NaO
CO2Et
OEt
NaOEt
CO 2Et
EtO2C
21
- NaOEt
Let, 2/11-10-2010
CO2Et
Condensation:
O
O
O
OH
OH
1-(2-methylcyclohex-1-enyl)ethanone

O
O
O
O
t-BuOK
- H 2O
nonane-2,8-dione
acidic proton
22
Let, 2/11-10-2010
OH
14. Medium and Large Rings (8-11 membered and 12+)
Intramolecular reaction is less favoured with bigger rings.
Often, high-dilution conditions and slow addition can be
used to suppress intermolecular reaction and hence
promote ring closure.
O
eg.
NaH
(CH2)6
MeO2C(CH2)7CO2Me
ester added over
nine days
CO2Me
similarly
O
EtO2C(CH2)14CO2Et
"
(CH2)13
CO2Et
23
Let, 2/11-10-2010
15. Cycloaddition reaction (Diels-Alder)
Generic reaction (in retrosyntheic terms):
X
X
electron rich
eg
CO2Me
electron poor
CO2Me
concerted reaction
24
X = EWG
(CHO, CO2R, CN)
Let, 2/11-10-2010
Unsymmetrical Diels-Alder reactions:
R
R
R
R'
R'
+
R'
Minor product
Major product
R'
R
R
R
R'
+
R'
Major product
25
Let, 2/11-10-2010
Minor product
note that the 1,3-disubstituted product is the minor
product in both cases
CH3
CH3
CH3
CO2Me
CO2Me
+
CO2Me
61%
26
Let, 2/11-10-2010
only 3%
16. Disconnections & Functional Group Interconversion in Aromatic Systems
Some reactions used in aliphatic systems don't apply for aromatic systems
(SN1 and SN2 reactions, for example, are extremely unfavourable for ArX.
eg.
O
O
R
R

PhH + RCOCl + AlCL3
Friedel-Crafts acylation
i) RCOCl
AlCl 3
RCO
O
O
H
ii)
27
RCO
R
Let, 2/11-10-2010
R
In planning synthesis of polysubstituted aromatics,
the order of reactions is important to ensure that the reagents are compatible
and to take advantage of the directing effect of existing substituents:
Group
NH2, NR2
OH, ONHAc, OR
alkyl/aryl/vinyl
CO2X (halogen)
CO2H
CN
COR, CHO
SO3H
CX3
NO2
Directs
Activation
(more)
activating
ortho/para-*
neutral
meta-
deactivating
(more)
* note that ortho/para- mixtures can be
formed and may have to be separated
28
Let, 2/11-10-2010
Examples
CO2Et
CO2Et
H2N
CO2H
CO2H
O2N
H 2N
H2N
CO2H
CO2H
H2N
O2N
H 2N
H2N
benzocaine (painkiller)
benzocaine (painkiller)
f rom toluene
CO2H
CO2H
f rom toluene
CO2H
CO2H
HNO3
KMNO4
HNO
H2SO4 3
EtOH
H2 Pd/C
KMNO4
H2 Pd/C
H+
H2SO4
H
NH2
NO2
NO2
NO2
29
T.M.EtOH
NO2
Let, 2/11-10-2010
NH2
+
T.M.
17. Birch Reduction
Partial reduction of aromatic systems by (usually) sodium in liquid
ammonia.
It's an example of dissolving metal reduction.
Such methods used to be quite popular but most applications have
been replace by modern hydride reagents.
Dissolving metal reduction does still have it's uses thoughand the
Birch reduction is one of them, . (also recall the specific reduction of
alkynes totrans-alkenes).
The typical conditions involve liquid ammonia (bp. −33 °C) and
sodium metal,in the presence of a proton source (usually an alcohol,
EtOH).
30
Let, 2/11-10-2010
EWG
EWG
Na, NH3 (l), EtOH
eg EWG = CO2H, NO2
EDG
EDG
"
eg EDG = Me, OMe
31
Let, 2/11-10-2010
18. Fusing Rings onto aromatic systems
The classical Hayworth naphthalene synthesis.
The fused aromatic system is formed by dehydration of a tetralin intermediate,
which is prepared from an existing benzene ring and succinic anhydride.
O
O
discon.
+
O
CO2H
FGI
32
Let, 2/11-10-2010
O
Thus:
O
O
O
O
Zn-Hg/HCl
AlCl 3
Clemmensen
HO 2C
HO2 C
intramolecular
FC
Pd/C
i) RMgx

Dehydrogenation
R
i) SOCl2
ii) AlCl3
ii)
tetralone
H3O+
R
O
1-subtitution ( aka  -)
via enamine
RBr
Pd/C
i) LiAlH4

R
R
ii) H3O+
R
2-subtitution ( aka  -)
O
33
Let, 2/11-10-2010
19. Blocking positions in aromatic rings
Functional groups that are introduced reversibly, or can be easily
cleaved under mild condtions, can be used to access otherwise
hard-to-make compounds
Et
Et
Et
Et
Br
Br
SO3
Br2
H2SO4
dil.
H2SO4
FeBr3
1-bromo-2-ethylbenzene
SO3 H
SO3 H
TM
Br
NH2
NH 2
NaNO2/HCl
Br2
Br
Br
Br
Br
Br
N 2+
H3PO2
Br
Br
Br
1,3,5-tribromobenzene
34
Let, 2/11-10-2010
TM
You have to know the terminology of
stereochemistry
a) Chiral, achiral compounds.
b) Stereogenic, nonstereogenic centers.
c) Enantiomers, diastereomers.
d) Prochiral, prostereogenic.
e) Enantiotopic, diastereotopic atoms and faces.
f) Ways of drawing stereochemistry.
g) For two adjacent stereocenters, we can use
i. (R) and (S)
ii. For cyclic structures, cis and trans
iii. threo and erythro (very old-fashioned)
iv. syn and anti (for a chain drawn in zigzag fashion)
v. like and unlike (only Europeans use this one)
35
Let, 2/11-10-2010