Prob & Solu of Retrosynthesis

B.
Sc

SEMESTER-IV

(HONS) ORGANIC CHEMISTRY; PAPER-CC-10
Dr. Shyamal K. Jash

Selective Problem & Solution of
Retrosynthesis
Assistant Professor
Dept. of Chemistry
K. C. College, Hetampur

PROBLEM 1
How would you make these four compounds? Give your disconnections, explain
why you chose them and then give reagents for the synthesis.
H H
N N
O2N NO2
O
S
MeO
Purpose of the problem

Exercises in basic one-‐group C–X disconnections.
Suggested solution
We wish to disconnect one of the C–N bonds and prefer the one not to
the benzene ring as we aim to use reductive amination (p. 234) as the
best way to make amines.
synthesis
H reductive
N FGI N amination H2N
O
+
analysis
H
H 2N Na(CN)BH4 N
O
+
or catalytic
hydrogenation
However the second aromatic amine can be made a different way.

The two nitro groups promote nucleophilic aromatic substitution (p.
514) and the compound can be made by the addition-‐elimination
mechanism from the dinitro chloro compound that can be made by
direct nitration.
2 Solutions Manual to accompany Organic Chemistry 2e
analysis
H
N C–N NH2 Cl
+
nucleophilic aromatic
O2N NO2 substitution O2 N NO2
synthesis
H
Cl Cl N
HNO3 i-PrNH2
H2SO4
O2N NO2 O2N NO2
For the ether we again have a choice from two C–O disconnections.
We prefer not to add the t-‐butyl group by SN2 (though we could by SN1)
and disconnect on the other side. The synthesis is trivial: we just mix
the two reagents with base or make the anion from the alcohol first.
Cl
nucleophilic
substitution + HO
O
MeO MeO
For the sulfide we shall want to use an SN2 reaction and there is a
slight preference for the disconnection we show as the allylic halide is
very reactive. You would not be wrong if you had chosen the alternative
C–S bond. This time only a weak base will be needed as the SH group is
much more acidic than the OH group.
nucleophilic
substitution
+
S Br HS
SN2
PROBLEM 2
How would you make these compounds? Give your disconnections, explain why
you chose them and then give reagents for the synthesis.
Ph
OH

Exercises in basic one-‐group C–C disconnections.
Solutions for Chapter 28 – Retrosynthetic Analysis 3
Suggested solution
There are obviously more choices when you use C–C disconnections,
but choose wisely! We suggest a solution, but you may have thought of
others. The first compound is an alkyne and disconnection next to the
alkyne (but not on the side of the benzene ring) makes a simple
synthesis.
analysis Ph nucleophilic Ph
substitution
SN2 Br
synthesis
Ph Ph
BuLi RBr Ph
H Li
The alcohol has some symmetry: you will want to use Grignard or
organolithium chemistry (chapter 9) and you could disconnect one or
two of the identical groups using a ketone or an ester as the
electrophile. The double disconnection leads to a shorter synthesis.
analysis
C–C
MeCO2Et +2x MgBr
OH
synthesis
1. Mg, Et2O
Br 2. MeCO2Et
OH

PROBLEM 3
Suggest ways to make these two compounds. Show your disconnections and
make sure you number the functional group relationships.
MeO OMe
O O
OH

First steps in using two functional groups to design a synthesis.
Suggested solution
Both compounds have two oxygens singly bonded to the same carbon
atom: they are acetals so they come from a carbonyl compound.
Disconnecting the acetals helps us see what we are really trying to
make.
O O acetal OH OH
+
1,1-diX O
MeO OMe
acetal CHO
+ 2 MeOH
OH 1,1-diX OH

The diol has a 1,3-‐relationship between the two alcohols so we need
aldol or Claisen ester chemistry (chapter 26). One alcohol will have to
be changed into a carbonyl group, perhaps an aldehyde or ester. Since
we shall reduce all carbonyl groups to alcohols, it doesn’t really matter
whether we have aldehydes, ketones, or esters.
OH OH OH OH
FGI
2 1 CHO or CO2Et
3

We prefer to make the disconnection between C2 and C3 to cut the

molecule more or less in half and simplify the problem. There are
various ways to do this—either the lithium or the zinc enolate would
do, and below we show the use of zinc in a Reformatsky reaction.
OH O
2 CO2Et CO2Et use Li enolate
3 1 or Zn enolate
OH
Br CO2Et 1. Zn 1. LiAlH4 O O
CO2Et
2. EtCHO 2. Me2CO
acid

If the keto-‐ester is used as a starting material it can be made by the
same strategy (disconnection A) or alternatively (disconnection B) by
first removing just one methyl group to reveal a symmetrical keto-‐ester
made by a Claisen ester condensation.
Disconnection A
O O
CO2Et CO2Et
OEt
Disconnection B
O O O
CO2Et CO2Et CO2Et
OEt

The advantage of disconnection B is that the synthesis involves a

simple self-‐condensation of ethyl propionate. Methylation of the
resulting keto-‐ester followed by reduction to the diol and acetal
formation gives the target molecule.
O O 1. EtO O 1. LiAlH4 O O
EtO
CO2Et CO2Et
OEt 2. MeI 2. Me2CO, target molecule
H+

The other compound has a 1,5-‐relationship between the two

functional groups and will need some sort of conjugate addition of an
enolate (chapter 25). This time we want to reduce only one of the two
carbonyl groups so we must make sure they are different. We already
have an aldehyde so we choose an ester for the other one.
5 CHO 5 CHO CHO

FGI 1,5-diO
3 1 OH 3 1
4 2 4 2 CO Me
2
+ CO2Me

We must use a specific enol equivalent for the aldehyde enolate to

avoid self-‐condensation: an enamine or a silyl enol ether would be fine.
Since we must reduce the ester in the presence of the aldehyde, it
makes sense to put the acetal in before we do this.
NR2
CHO CHO 1. MeOH
R2NH acid
target
molecule
CO2Me 2. LiAlH4
CO2Me

PROBLEM 4
Propose syntheses of these two compounds, explaining your choice of
reagents and how any selectivity is achieved.
O
O


First steps in designing syntheses in which selectivity is required.
Suggested solution
The first compound is an α,β-‐unsaturated carbonyl compound and this
is one of the most important functional group combinations for you to
recognise in planning syntheses. It is the product of an aldol reaction so
simply disconnect the alkene and write a new carbonyl group at the far
end of the old one. Don’t lose any carbon atoms!
aldol O
+
O O specific enol(ate)
equivalent needed
We need a crossed aldol reaction between two ketones so we also

need chemoselectivity. We have to make one enol(ate) from an
unsymmetrical ketone so we need regioselectivity as well. The obvious
solution is to use a lithium enolate, a silyl enol ether, or a β-‐ketoester.
Here is one solution.
O
OH
O LDA OLi TsOH target
molecule
O

The second compound contains another common functional group: a

lactone or cyclic ester. We should first disconnect the structural C–O
bond to see the carbon skeleton.
O CO2H
C–O redraw OH
OH
O 5
ester HO2C
3 1
4 2

We discover that we have a 1,5-‐relationship between the functional

groups and so we shall need conjugate addition. We must change the
alcohol into a ketone, and the acid group to an ester. Notice that there
are two reasonable disconnections and that we have added an ester
group to each potential enolate as the way of making a specific enolate.
O OH O
EtO2C 1,5-diCO 5 a b 1,5-diCO
HO2C EtO2oCf using
3 1 ■ The strategy
a 4 2 b
CO2Et decarboxylation of a β-‐dicarbonyl
compound is described on p. 597 oCO
f 2Et
the textbook.
One possibility is to add malonate to the unsaturated ketone, which is
an aldol dimer of acetone and readily available. We can reduce the
ketone, expecting cyclisation to be spontaneous, and decarboxylate to
give our target molecule.
EtO2C CO2Et O
O O
EtO NaBH4 EtO C
2
EtO2C O
CO2Et

PROBLEM 5
The reactions to be discussed in this problem were planned to give syntheses of
these three molecules.
O O
Ph CO2Me
O
1 2 3
In the event each reaction gave a different product from what was expected, as
shown below. What went wrong? Suggest syntheses that would give the target
molecules above.
O O
PhCHO
H
Ph
O Cl CO2Me O
CO2Me
MeO
MeOH
O
HO
+
O O


Finding out what might go wrong is an important part of planning a
synthesis.
Suggested solution
The aldol reaction planned for target molecule 1 looks all right but enol
formation has occurred on the wrong side. This is not surprising in acid
solution, so use base instead.
O OH O
PhCHO H PhCHO
1
NaOH
Ph
In the second case, alkylation of the enolate of the ketone was

planned but evidently it is easier to form the enolate of the chloro-‐ester.
■ TheDarzens condensation is on
p. 639 of the textbook.
The reaction that occurred is the Darzens condensation. To avoid this

problem use a specific enolate of the ketone such as an enamine or a β-‐
ketoester.
O O
MeO CO2Me
OMe O
Cl CO2Me Cl CO2Me
MeOH
Cl
O
O R 2N Cl CO2Me O
R2NH
target 2
CO2Me
aqueous acid
work-up
■ The Robinson annelation: p.
638 of the textbook.
In the third case, the cyclopentanone has self-‐condensed and ignored
the enone. The answer again is to use a specific enolate, such as the
easily made β-‐keto-‐ester below. The six-‐membered ring is then easily
formed by intramolecular aldol reaction. These two reactions together
make a Robinson annelation. Finally the CO2Me group must be removed
by hydrolysis and decarboxylation.
CO2Me CO2Me O
MeO CO2Me
+
O O O
O
CO2Me
MeO H
target molecule 3
H2O
O
O
PROBLEM 6
The natural product nuciferal was synthesised by the route summarised here.
OH
BrMg
? ?
O
O
O
O
CHO CHO
(a) Suggest a synthesis of the starting material.

(b) Suggest reagents for each step.
(c) Draw the retrosynthetic analysis giving the disconnections that you consider
the planners may have used and label them suitably.
(d) Which synthon does the starting material represent?

Practice at an important skill—learning from published syntheses—as
well as a popular style of exam question.
Suggested solution
(a) Grignard reagents are made from the corresponding halide and the
rest of the analysis used simple C–X disconnections.
BrMg Br Br
FGI 1,1-diX 1,3-diX HBr +
O O acetal HO CHO
CHO
O O HO

It turns out that the addition of HBr to the unsaturated aldehyde

(trivially known as acrolein) and the protection as an acetal can be
carried out in a single step as both are acid-‐catalysed.
Br BrMg
HO OH Mg
CHO O O
HBr Et2O
acrolein O O

(b) The Grignard has obviously been added to a ketone to give the
tertiary alcohol, but how do we replace OH by H? One way is direct
catalytic hydrogenation but an easier way is to eliminate the tertiary
(and benzylic) alcohol and hydrogenate the alkene. The acid used for
dehydration will also remove the acetal.
O OH
RMgBr H H2
H2O Pd/C
O
CHO CHO
O
The last step is an aldol reaction between two aldehydes. The easiest
way to do this is by a Wittig reaction but a specific enol of propanal
would also be fine.
Ph3P CHO
+
CHO CHO
(c) and (d) The retrosynthetic analysis is straightforward except for the
last step. It is not obvious what reagent to use for the synthon in
brackets. But you already know what was used: a Grignard reagent with
a protected aldehyde, i.e. a d3 reagent. This is needed because the 1,4
relationship between OH and CHO requires umpolung (p. 720).
OH
aldol FGI
+
CHO CHO CHO
CHO
d3 synthon

PROBLEM 7
Show how the relationship between the alkene and the carboxylic acid
influences your suggestions for a synthesis of these three compounds.
CO2H CO2H CO2H

An exploration of the importance of functional group relationships.
Suggested solution
The first is an α,β-‐unsaturated carbonyl compound and can best be
made by an aldol reaction using some sort of specific enol equivalent
for the acid part. A Wittig reagent, a malonate, or a silyl enol ether look
the best.
analysis
FGI aldol
CO2H CO2Et + CO2Et
CHO
synthesis
1. EtO HO
Ph3P CO2Et 2. EtCHO CO2Et CO2H
H2O
The second synthesis is difficult because the alkene can easily slip
into conjugation with the carbonyl group. Perhaps the easiest strategy
is to use cyanide ion as synthetic equivalent of —CO2H since then the
electrophile is an allylic halide. Other alternative routes could include
alkyne reduction.
analysis
FGI C–C
CO2H CN Br + CN
synthesis
NaCN HO
Br CN CO2H
H 2O
The third is best approached by alkylation of a malonate with allyl

bromide itself followed by hydrolysis and decarboxylation.
analysis
CO2Et
FGI C–C
CO2H CO2Et CO2Et
Br
synthesis
CO2Et 1. EtO CO2Et 1. NaOH, H2O
CO2H
CO2Et 2. Br CO2Et 2. H , heat

PROBLEM 8
How would you make these compounds?
OH CO2H NH2
H
N

A reminder of reductive amination and that simple syntheses of
apparently related compounds may require very different chemistry.
Suggested solution
The secondary amine is best made by reductive amination via the imine
(not usually isolated).
analysis
H
N N H2N
FGI C=N
+
imine O
synthesis
H
O H2N NaB(CN)H3 N
+
or Li(AcO)3BH

The secondary alcohol can be made by some sort of Grignard

chemistry. Cyclohexyl Grignard could be added twice to ethyl formate
or once to the cyclohexane aldehyde.
analysis OH
C–C CHO BrMg FGI Br

+
synthesis
Br 1. Mg, Et2O Br 1. Mg, Et2O R=

TM or TM cyclohexyl
2. HCO2Et 2. RCHO

The carboxylic acid could be made by double alkylation of malonate
or some other specific enol equivalent.
analysis
CO2H
Br Br
C–C EtO2C CO2Et
+ +
alkylation
synthesis CO2H
1. EtO EtO2C CO2Et 1. NaOH

EtO2C CO2Et
2. RBr R R 2. H , heat
(excess) R=
cyclohexyl
Finally the primary amine could be made by reductive amination of a

ketone that could in turn be made by oxidation of the secondary alcohol
we have already made. Among many alternatives is the displacement of
the tosylate of the same alcohol with azide ion and reduction of the
azide.
NH2 1. TsCl
pyridine
O 2. NaN3 OH
NaB(CN)H3
R R NH4OAc 3. H2, Pd/C R R
R=
cyclohexyl

PROBLEM 9
Show how the relationship between the two carbonyl groups influences
your choice of disconnection when you design a synthesis for each of
these ketones.
O O O O O
R
R R
O

An exercise in counting to reinforce the way that odd and even
relationships affect the choice of a synthetic route.
Suggested solution
The three diketones have 1,3-‐, 1,4-‐, and 1,5-‐dicarbonyl relationships. In
each case the obvious disconnection is of the bond joining the ring to
the chain. But the chemistry is very different in each case. The 1,3-‐
diketone can be made by acylation of a specific enolate. An enamine or a
silyl enol ether is a good choice.
analysis
O O O
O
1,3-diCO specific enol(ate)
R X R equivalent needed
synthesis
O OSiMe3 O O
Me3SiCl RCOCl
Et3N R
TiCl4

The same disconnection on the 1,4-‐diketone leads to different

chemistry (alkylation of an enolate) and requires an enamine as the
specific enol.
analysis
O
O non-basic
R 1,4-diCO R specific
Br enol(ate)
equivalent
O O needed
synthesis
O NR2 O
R2NH R R
+ Br
Et3N
O O
The 1,5-‐diketone requires conjugate addition of the same enolate and
we suggest a different specific enolate equivalent though other would
be just as good. This time the specific enol equivalent is needed to stop
self-‐condensation of the cyclopentanone.
analysis
O O O O specific
1,5-diCO enol(ate)
R R equivalent
needed
synthesis
O O 1. NaOH
1. EtO O
CO2Et target molecule
CO2Et 2. H , heat
2. O
R
R

Prob & Solu of Retrosynthesis

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B.

Dr. Shyamal K. Jash

Purpose of the problem

However the second aromatic amine can be made a different way.

Purpose of the problem

Purpose of the problem

We prefer to make the disconnection between C2 and C3 to cut the

The advantage of disconnection B is that the synthesis involves a

The other compound has a 1,5-­‐relationship between the two

5 CHO 5 CHO CHO

We must use a specific enol equivalent for the aldehyde enolate to

Purpose of the problem

We need a crossed aldol reaction between two ketones so we also

The second compound contains another common functional group: a

We discover that we have a 1,5-­‐relationship between the functional

Purpose of the problem

In the second case, alkylation of the enolate of the ketone was

Solutions for Chapter 28 – Retrosynthetic Analysis 9

The reaction that occurred is the Darzens condensation. To avoid this

(a) Suggest a synthesis of the starting material.

Purpose of the problem

It turns out that the addition of HBr to the unsaturated aldehyde

CHO CHO CHO

CO2H CO2H CO2H

Purpose of the problem

The third is best approached by alkylation of a malonate with allyl

Purpose of the problem

The secondary alcohol can be made by some sort of Grignard

C–C CHO BrMg FGI Br

Br 1. Mg, Et2O Br 1. Mg, Et2O R=

1. EtO EtO2C CO2Et 1. NaOH

Finally the primary amine could be made by reductive amination of a

Purpose of the problem

The same disconnection on the 1,4-­‐diketone leads to different

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The other compound has a 1,5-‐relationship between the two

We discover that we have a 1,5-‐relationship between the functional

The same disconnection on the 1,4-‐diketone leads to different