Retrosynthetic analysis and Synthesis

The synthesis of a desired organic molecule (Target Molecule) from commercially available simple starting materials is
fundamental to nearly all aspect of synthetic organic chemistry. The planning of multi-step synthesis is a challenging
task that requires not only a thorough knowledge of synthetic reaction, but also a logical approach for disconnecting a
complex target molecule (TM). The following points must be taken into consideration for designing a possible route to
the synthesis of a target molecule.

1. The synthetic design must lead to the construction of the required carbon skeleton with all the substituents and
functional groups in correct position (region chemistry) and with the requisite orientations (stereochemistry) which is
essential for forward synthesis.

2. Ideally the shortest route with high yield to the product is required. A ten step synthesis with 80% yield at each step
would give only a 10.7% overall yield of the final product.

3. Each stage of the synthesis should provide only the desired product or desired product with very minimum amount of
side product.

Chemist have developed a logical approach for the designing of routes for the synthesis of compounds which involves
working the synthesis backwards by making strategic carbon-carbon bond cleavages at points where, in the forward
direction, bond forming reactions may be achieved by reliable chemical reactions. This is known as retrosynthetic
analysis or antithetic analysis, which is the key to design of efficient synthesis.

There are some terminologies which are used in retrosynthetic analysis of a target molecule. The most common
terminologies used in retrosynthetic analysis, opposed to synthesis are summarized below:

Terms for Synthesis Retrosynthesis

Starting structure Starting material (SM) Target molucule (TM)

Steps Reactions Transform/Disconnection

Steps indicated by

Structure features required Functional groups Retron

Product after each step Intermediate Synthon/precursor

Ending structure desired product probable starting material

Retrosynthetic analysis: Retrosynthetic analysis is the process of “breaking down” a target molecule into readily
available starting materials by means of imaginary breaking of bonds (disconnection) and by the conversion of one
functional group into another by efficient chemical reactions. Retrosynthetic analysis is basically the overall plan to
achieve the ultimate synthetic target. The disconnection is represented by a wavy line through the bond to be broken
and the retrosynthetic arrow represents going from the target molecule “backwards” to the pair of charged
fragments (known as synthons). In general,
 B C E C + E
A B C D E F A
+ D F D F

disconnection
A + B C + D E + F
Transform (Disconnection): It is the exact reverse of a synthetic reaction to the target molecule such that when applied
to the structure of the reaction product, the synthetic precursor is generated. Therefore, this is an analytical operation
which breaks a bond within the desired molecule and converts it into possible starting materials. The retrosynthetic
bond-disconnections are only mental processes, which may, however, coincide with actual processes in the laboratory
provided that the reactions under consideration are reversible.

For example,
O O
O Br
CO2 Et CO2 Et
CO2 Et +
Ph
Ph Ph
(synthons) (synthetic equivalents)

A good disconnection is recognized by:

i) a good mechanism ii) greatest possible simplification iii) give recognizable and inexpensive starting materials.

What is meant by “readily available starting materials”?

Readily available starting materials are very simple molecules which contain five carbon atoms or less (apart from units
such an aromatic rings) and only one or two functional groups. However there are many exceptions to this rule.

Synthon: Idealized fragments, usually cations and anions, which result from a disconnection of a bond in TM during
retrosynthetic analysis, are called synthons.

Synthetic equivalent: Synthetic equivalents are the reagents or small molecules which carry out the function of
synthons.
Synthons Synthetic equivalen ts
It is worth familiarizing
R+ yourself with some of the R-X,
synthetic equivalents
where X = -Br, -Cl, -I,which
-OMs, correspond
-OTs to common synthons. These
are given below. R = Alkyl groups but not aryl groups
OH O

OH O
R
R
O O
O O
Or
Br
O NO2 O
Or X (where X = -Cl, -Br, -I)
R R R

R- RMgBr, RLi, R2 CuLi, R2 Cd

O O O
Or CO2 Et Or N
R R R
R
O
RCOCl, RCOOCOR, RCOOR'
R
NO2
O Or
S S
R
R R H
O O
Or CN
RO HO
Retron: This is the minimum structural subunit on the target molecule that enables a transform to operate. For
example,

Retro-Michael O
O Retro-Aldol O O
+
O

Target molecule O
O
O

,-unsaturated ketone 1,5-dicarbonyl

Retron Retron

Functional group interconversions (FGI):

Sometimes, in the disconnection process, it may be convenient to interconvert functional groups (FGI) with the aim of
modifying either some highly reactive or unstable functional groups or to modify a double bond, or to perform a
"reactivity inversion" (Umpolung). FGI is the process of transformation of one functional group into another to allow
disconnections corresponding to appropriate reactions.

The usefulness of FGI operations is easily understood considering a very simple example. 1,3-Butanediol, being a 1,3-
difunctional system, does not offer a reasonable disconnection mechanism. However, if the primary hydroxyl group is
converted to a carbonyl group, the resulting product can be then disconnected into two stable identical molecules
of acetaldehyde, according to a reasonable retro-aldol mechanism, and the whole process represents a simple
solution in accordance with the criterium of maximum simplicity.
 OH FGI OH Retro-aldol O
+ O
OH O
1,3-Butanediol
Two molecules of acetaldehyde

Functional group addition (FGA): Sometimes, it is necessary to add a functional group (FGA), either to functionalize the
carbon skeleton or to create a new consonant system which can provide valid bond disconnection mechanisms. This is
the operation of adding a new functional group to make the disconnection feasible. For instance, 4-methylbutan-2-one,
being a monofunctional system, does not provide a valid disconnection mechanism for its synthesis. However, if a
hydroxyl group is introduced at C-4 carbon, the resulting product can be then disconnected into two stable identical
molecules of acetone, according to a reasonable retro-aldol mechanism. For example,

FGA OH O Retro-aldol O O
O +
1

4-methylbutan-2-one
Two molecules of acetone

O
FGA Retro-aldol
2
O O

Functional group reconnections:

During retrosynthetic analysis, reconnection of two functional groups to give a ring is important. This new technique
does not represent any simplification, but rather in creating new bonds introduces a greater complexity. However, this
technique is justified since it is very efficient and works perfectly in most of the cases in which it has been applied.
Reconnection of two carbonyl groups to give either a double bond or a 1,2-diol system in "normal-sized" ring, is
especially useful because nowadays different and efficient methods for constructing them exist. In the following
example two carbonyl groups (1,6-dicarbonyl) are reconnected to an unsaturated six-membered ring, which, in the
synthetic direction, may be constructed by a Birch reduction of the corresponding aromatic molecule.

OMe Birch reduction OMe

1 6
2 transform
MeO2 C 4 CHO Reconnection
5
3
Me
Me Me

An unsaturated six-membered ring may also be constructed by a Diels-Alder reaction.

O
O O
OH Reconnection
FGI Retro-aldol 6 4 2 1
3 CHO
5

1,6-dicarbonyl

retro-Diels-Alder

A very simple example of "functional group reconnections" is provided by the reconnection of a carboxylic group with a
hydroxy group to give a lactone. This is quite a normal operation since, in the synthetic direction, it represents a
2
Baeyer-Villiger oxidation of a ketone.
 O O
OH Bayer-Villiger
Reconnection transform
O
HO2C

Latent Polarity:

The most important organic reactions leading to the formation of carbon-carbon (or carbon-heteroatom) bonds are
generally of ionic or polar nature. Keeping in mind this generalization, organic molecules may be considered as
aggregates of ions and therefore, they can be represented with formal charges on the atoms. The distribution of formal
charges in the carbon skeleton is determined by the functional groups or hetero atoms attached to it. In this context is
very useful to use the "Lapworth model" of alternating polarities which states that chemical bonds in organic
compounds are partially polar, and can be associated with alternating positive and negative charges. This "alternating
latent polarities" is induced by the presence of polar functional groups or hetero-atoms in a chain of atoms. For
example,

OH

The alternating latent polarities in a chain of atoms can be assigned according to the electronic character of the
functional group or heteroatoms attached to the carbon chain. For example, methyl crotonate shows the following
pattern of alternating polarities:
E
O

OMe

Nu

The electrophilic or nucleophilic character of each one of the carbon atoms being in accordance with that found
experimentally. Thus, a nucleophile, such as a Grignard reagent, reacts with the electrophilic carbonyl carbon atom
(1,2-addition), but the same reagent, in the presence of copper (I) or as an organocuprate, reacts at the β-carbon
atom in a Michael reaction (1,4-addition). On the other hand, whereas an electrophile such as a proton will react with
the nucleophilic α-carbon atom, a positive bromine ion will react with the nucleophilic γ-carbon atom.

Definition of latent polarity: This is the imaginary pattern of alternating positive and negative charges used on organic
molecules to assist in choice of disconnections leading to appropriate synthons. Knowledge about latent polarity usually
gives the best choice of synthons, though this is not always possible.

Consonant and dissonant bifunctional relationships:

1,3-dioxygen functions
From a synthetic point of view it is necessary to analyse the organic molecules in terms of paired functional group
O O
O two
relationships. Since there are Disconnection
O ideal kinds of functional groups, electron releasing and electron attracting groups, it is
+
possible to define two different bifunctional relationships:
(Natural synthon) (Natural synthon)
a) The consonant systems (1,3-dicarbonyl)
(or molecules): The consonant systems are those systems in which the alternating latent
polarities always match whatever the starting functional group O
from which the polarities are assigned. For example,
OH
organic molecules with 1,3-O andOH 1,5-dioxygen functions are consonant +systems because the assigned alternating latent
Disconnection
polarities starting either from the left hand side or from the right hand side of the molecule are same. Therefore,
disconnections on those systems can provide synthons of normal
(Natural polarity (Natural
synthon) (naturalsynthon)
synthons).
(-hydroxy carbonyl)

1,5-dioxygen functions

O O Disconnection O O
+

(1,5-dicarbonyl) (Natural synthon) (Natural synthon)

b) The dissonant systems (or molecules): The dissonant systems are those systems in which the alternating latent
polarities assigned from either side do not match. It is not possible to apply alternating polarities to dissonant
molecules. For example, organic molecules with 1,2- and 1,4-dioxygen functions are dissonant systems because the
assigned alternating latent polarities starting from the left hand side are different from the alternating latent polarities
assigned from the right hand side of the molecule. Therefore, disconnections on those systems can provide synthons of
abnormal polarity (unnatural synthons).
1,2-dioxygen functions
O O O
Disconnection
+

O
(Natural synthon) (Unnatural synthon)
(1,2-dicarbonyl)

O O OH
Disconnection +

OH
(Unnatural synthon) (Natural synthon)
(-hydroxy carbonyl)

OH O
OH
Disconnection +
OH OH

O (Natural synthon) (Unnatural synthon)

(-hydroxy carboxyl)

1,4-dioxygen functions

O Disconnection O O
+

O
(Natural synthon) (Unnatural synthon)
(1,4-dicarbonyl)

O O
Disconnection O
OH +
OH
O
(Natural synthon) (Unnatural synthon)
(1,4-dicarboxyl)

O Disconnection O
+
OH
OH
(Natural synthon) (Unnatural synthon)
(-hydroxy carbonyl)
The rings, even if they have one functionality, can be classified as either consonant or dissonant depending upon
whether they have an even or an odd number of carbon atoms in the ring. When more than one functional group
are present, the classification also depends on the relative position of functional groups.

Consonent Carbocyclic systems

O O

Rings with enen number of atoms

O O

Dissonent Carbocyclic systems

O O O

O Rings with odd number of atoms

SYNTHESIS OF TARGET MOLECULES VIA LOGICAL DISCONNECTIONS:

The generation of the intermediate precursors and the synthetic sequences is carried out by a retrosynthetic process
that involves the disconnection of bonds. By analogy with the organic bond-forming reactions, it is assumed that bond
disconnection takes place heterolytically to lead to an electrophile and a nucleophile. The disconnection can be
classified as "logical disconnections" if the three following criteria are met:

i) that a reasonable disconnection mechanism exists,

ii) that the disconnection leads to stable fragments (ions or molecules), and

iii) that the disconnection represents the greatest possible simplification.

The knowledge of synthetic methods and the reaction mechanisms itself (electronic theory of valence and the
theory of frontier molecular orbitals) must be applied in order to generate the intermediate precursors for the
synthesis of TM. And this will determine the correctness of a synthesis design and, ultimately, the success of synthesis.

Only consonant molecules can offer reasonable bond-disconnection mechanisms, as it is required by "logical bond
disconnections". Therefore, the synthesis of a consonant molecule does not offer too many difficulties. All the classical
synthetic methods of carbon-carbon bond formation lead to target molecule of consonant relationships.
The following four classical condensation reactions (and their variants): Claisen condensation, aldol condensation,
Mannich condensation and Michael addition are most commonly used for the synthesis of 1,3- and 1,5-difunctional
consonant molecules. Consequently, the recognition of consonant bifunctional relationships in the TM allows their
disconnection by a retro-Claisen, a retro-aldol or a retro-Mannich condensation or by retro-Michael addition

O O O O
+ Via Claisen condensation
OR'
(1,3-dicarbonyl)

O OH
O O
+ Via Aldol condensation
(-hydroxy carbonyl) H

O NR2 O O
+ + R2 NH Via Mannich reaction
H H H
(-dialkylamino carbonyl)

O O
O O Via Michael reaction
+

(1,5-dicarbonyl)

Retrosynthesis and forward synthesis of monofunctional molecules (One Group Disconnection):

With monofunctionalised chains and rings it may be advised to disconnect those bonds which are near to functional
groups (ipso disconnection).
ipso
disconnection OH
OH
+

O
BrMg
The addition (FGA) or interconversion (FGI) of the functional groups may also be done prior to a disconnection. In
principle, depending upon the oxidation level of the heteroatom, disconnections at ipso-, α- and β-positions are
possible. The resulting fragments must be then properly functionalised in order to create the charge distribution
generated by the disconnection.

ipso
FGI O FGI NO2 disconnection NO2
OH + R
R R
R

NO2 Br
R

Forward synthesis:

Br 1. NaBH4 /MeOH OH
NO2 pyperidine R NO2 1. TiCl3 O
NO2
R R 2. H2 O R
2. H2 O
Nef reaction

Whenever the anion of acetone is generated, it must be replaced by the more stable acetoacetic ester anion which does
not undergo self-condensation. Similarly, the anion of acetic esters may be replaced by the more stable malonic ester
anion.

FGI O disconnection O
OH
+ R
R
R

O
CO 2Et Br R

Acetoacetic ester

Forward synthesis

NaOEt/EtOH O Br R O 1. [Link] O
O
CO 2Et CO 2Et
R R
2. H3 O+ /heat
CO2 Et
1. NaBH4 /MeOH

2. H2 O
(work up) OH

R
In the case of monofunctionalized rings, the direct disconnection of carbon-carbon (or carbon-heteroatom) bonds of the
cyclic network at the ipso-, α- or β-positions leads to a single fragment in which some functional group incompatibilities
may be present. In such a case, the disconnections are better performed if a functional group is first introduced (FGA)
in such a manner that a new consonant relationship is created. The disconnection of the resulting bifunctional
consonant relationship leads then to an intermediate precursor which is usually easily available. For example, the direct
disconnection of cyclopentanone at the o-position would lead to the "unusual" synthetic equivalent, but the
introduction of a carboxylic ester group at the α-position affords 1,3-dicarbonyl molecule which can then be
disconnected by a retro-Dieckmann condensation leading to a diester.

O
n
t io
ec
onn (Difficult to synthesize)
isc
-d Br
OH O
FGI
Retro-Dieckmann
O
condensation CO2Et
EtO2C
CO2Et
FGA

Forward synthesis:

O O
O 1. [Link]
NaOEt/EtOH 2. H2 O
EtO2 C CO2 Et CO2 Et
CO2 Et
(work up) 2. H3 O+ /heat
Dieckmann
condensation
1. NaBH4 /MeOH
2. H2 O
(work up) OH

Retrosynthesis and synthesis of consonant bifunctional molecules:

In the case of bifunctional molecules only two alternatives are possible: the bifunctional relationships are either
"consonant" or "dissonant". In the case of consonant relationships, the synthetic problem will be solved by
disconnecting the molecule according to a retro-Claisen, a retro-aldol or a retro-Mannich condensation, or a retro-
Michael addition, if necessary, by a prior adjustment of the heteroatom oxidation level (FGI). These are illustrated in the
different chapter.

SYNTHESIS OF DISSONANT MOLECULES VIA “ILLOGICAL DISCONNECTIONS”:

 α-Disconnections may be performed directly in alcohols by reconnecting the oxygen atom to the α-carbon atom. In this
case an epoxide is formed as the synthetic equivalent. Although this kind of disconnection leads to the illogical synthon,
it may be valid because the resulting epoxide can easily be prepared by epoxidation of an alkene and it is
unsymmetrically substituted so that satisfactory regioselective control can be exerted.

disconnection OH
OH
+
R
R
illogical synthon illogical synthon

O
BrMg R
Forward synthesis:

m-CPBA O
[Link]
CH2 Cl2 (SN 2) OH

2.H2O (work-up) R
Mg
R Br R MgBr
THF

The same molecule can also be disconnected at ipso- or β-position by the following strategies.

disconnection O
FGI O + R
OH
R Path a illogical synthon
R logical synthon

ipso
Path b disconnection
O
R2CuLi
O
+ R

illogical synthon logical synthon

Br
S S R
Li

Forward synthesis:

Path a
1. H+ O R2 CuLi 1. NaBH4 /MeOH OH
O O
+ HCHO + R2NH R
2. H2 O
2. Me-I THF R
(work up)
3. NaOH/heat

Path b
n-BuLi Br Hg2 +,MeOH 1. NaBH4 /MeOH OH
R O
S S S S 2. H2 O R
S S THF H2 O R
Li R (work up)
H
If a "dissonant" bifunctional relationship is present in the molecule under consideration, then the synthetic problem
may be much more complex. Because it is not possible to apply alternating polarities to dissonant molecules, the
easiest method of dealing with them is to proceed as in the case of monofunctional molecules; i.e., the
dissonant molecule is disconnected at the ipso-, α- or β-position with respect to one of the two functional groups
and then alternating polarities are assigned to the resulting fragments. This will indeed lead the illogical nature of the
disconnection and the polarity of either one of the two fragments or both are then inverted.

Disconnection of 1,2-dioxygenated dissonant systems:

illogical polarity E E
E disconnection E E inversion
Or
E E
E E E

Disconnection of 1,4-dioxygenated dissonant systems:

ipso polarity
E E E E
disconnection inversion

E illogical E
E E
disconnection
Or
E

polarity
E E E E
-disconnection inversion

E illogical E E
E
disconnection
Or
E

Definition of illogical disconnections: We have seen that the disconnections of consonant target molecules containing
two functional groups are logical ones leading to recognizable nucleophiles and electrophiles. However, when two
functional groups in a TM are in dissonant relationship as in 1,2, 1,4 and 1,6-dioxygen functionality, the resulting
disconnection does not result in a logical electrophile and nucleophile, rather leads to a illogical electrophile and
nucleophile. Such kinds of disconnections are called “ILLOGICAL DISCONNECTIONS”. Reactivity inversions of some of the
starting reagents or synthons and reconnection to rings are the most important strategies used for the synthesis of
dissonant molecules.

An example of an “illogical” synthon is a negatively charged carbonyl nucleophile. Since carbonyls are normally
electrophilic, a reversal of polarity (called “umpolung”) must occur in order to accomplish the synthesis. In this section,
we will explore appropriate synthetic strategies by using “illogical” synthons to achieve the synthesis of these 1,n-
dioxygenated target molecules, where n = 0, 2 and 4.

Definition of illogical nucleophile and illogical electrophile:

Disconnection of a target molecule sometimes leads to a synthon which has the polarity that is reversed to its normal
latent polarity. Such synthons are called illogical synthons. If the illogical synthon is a nucleophile, it is called illogical
nucleophile, and if the illogical synthon is an electrophile, it is called illogical electrophile.

1. Synthesis of α-Hydroxy Carboxylic Acid TMs:

Disconnection of an α-hydroxy carboxylic acid results in an illogical synthon: a carboxylic acid moiety that is nucleophilic
at the carboxyl carbon. The carboxyl carbon is incompatible with a negative charge and this unnatural nucleophilic
carboxylic acid synthon does not exist. Therefore, a reactivity inversion must be done to get the stable nucleophilic
synthetic equivalent of this illogical synthon. The required reactivity inversion can be achieved by using cyanide as
a synthetic equivalent of the carboxyl anion, since the cyano group can be converted to a carboxylic acid by hydrolysis.

OH
OH OH need to make carbonyl
OH + carbn nucleophilic
O
O
logical synthon illogical synthon
-hydroxy acid

O C N

Therefore, the synthesis of an α-hydroxycarboxylic acid can be achieved by the addition of cyanide to a ketone or an
aldehyde, followed by hydrolysis of the resulting cyanohydrin.
OH H3O+ OH
O 1. KCN
OH
H CN heat
2. H2 O O

2. Synthesis of α-Hydroxy Ketone TMs: Umpolung (polarity reversal)

Disconnection of the TM at the newly formed C–C bond results in an illogical synthon (an acyl anion) that requires a
nucleophilic carbonyl carbon. One method that achieves the required umpolung is using a 1,3-dithiane anion as a
synthetic equivalent of the acyl anion. While the acyl anion is unstable and cannot be prepared, the 1,3-dithiane anion is
stable due to the inductive withdrawal of electron density by the two sulfur atoms. The 1,3-dithiane anion can be used
as a nucleophile and then converted to a carbonyl group by hydrolysis.

O OH
Ph OH O
+
Ph
illogical synthon logical synthon

S S
Ph Li
To make a 1,3-dithiane anion, an aldehyde is first converted to a thioacetal by reaction with 1,3-propanedithiol and a
Lewis acid, such as BF3. The resulting thioacetal is then deprotonated with a strong base, such as n-butyllithium.

HS SH
O n-BuLi
S S S S
THF
Ph H BF3 -ether Ph H Ph Li

Oxidation of cyclohexanol starting material (via PCC or Swern conditions) produces the needed carbonyl. Reaction of a
1,3-dithiane anion nucleophile with the resulting cyclohexanone electrophile, followed by a mercury-assisted
hydrolysis, affords the desired TM.
O O
OH
PCC/CH2 Cl2 1. S S S S OH Ph OH
Ph Li Hg2 +, H2 O
Ph
2. H2 O (Work up)

Q. Provide the reagents necessary to transform the given starting material into the desired product. More than one step
may be required.
O
OH
? OH

3. Synthesis of γ-Hydroxy Ketone TMs:

The disconnection of a γ-hydroxy carbonyl can be done at the alpha carbon as shown below. This disconnection is
illogical because the carbonyl alpha carbon is the nucleophile as expected, but the electrophilic synthon has a positive
charge on the adjacent carbon which is nucleophilic according to latent polarity. However, this disconnection may be
valid as this reactivity can be achieved by using an epoxide ring, because when a nucleophile attacks an epoxide, the
hydroxyl group of the product is on the carbon next to the carbon that was attacked.

O -disconnection
O Ph
Ph +
Ph
Ph OH
OH
logical nucleophile illogical electrophile

Ph
O

Ph O
Forward synthesis:

Ph
1. O
O LDA/THF O O Ph
Ph
Ph o
- 78 C Ph 2. Aq. NH4Cl OH
(work up)

The same synthesis may also be carried out through enamine synthesis or acetoacetic ester synthesis.
Q. Provide the reagents necessary to transform the given starting material into the desired product. Show possible
retrosyntheses.

O O
Ph

OH

4. Synthesis of 1,4-dicarbonyl TMs:

The 1,4-dicarbonyl pattern is illogical because such a target molecule has two alpha carbons connected to one another.
Disconnection between the two alpha carbons leads to one alpha carbon as the nucleophile (logical), and the other
alpha carbon as an electrophile (illogical). This reversal of reactivity is achieved by placing a halogen leaving group on
the alpha carbon.
-
O disconnection O Ph
Ph +
O O
logical nucleophile illogical electrophile

O Ph
Br
O

α-Brominated ketones can be prepared by the reaction of the ketone with bromine in acidic reactions conditions (Br 2
in HBr or HOAc). When a nucleophile attacks α-halogenated ketones, an S N2 substitution mechanism is preferred over
addition to the carbonyl. However, since the bromine increases the acidity of the alpha proton, an ordinary enolate
would more likely act as a base rather than a nucleophile and will pick-up a proton from the α-halogenated ketones. So
the synthesis would not work.

H
O LDA/THF O O Ph
Ph +
+ Br Br
- 78 oC O O
enolate

O
Ph

Instead, a stabilized enolate (or an enamine equivalent) must be used or the S N2 displacement.
 Via acetoacetic ester:

NaOEt O O
O Ph
CO 2Et + Br Ph
CO 2Et
O EtO 2C O
stabilized enolate
1. [Link]
2. H3 O+ /heat
O
Ph

Via enamine:

H3 O+ /heat O
O N N
H N Ph Ph
+ Br Ph
p-TsOH/C6 H6 O O
O
reflux enaime

Q. Provide the reagents necessary to transform the given starting materials into the desired products. Show possible
retrosyntheses.

O O O O

CO2 Et ii) CHO

i)

Moreover, we can also disconnect the 1,4-dicarbonyl TM at ipso-position. Disconnections at ipso-position lead to:

a) carbonyl carbon of one carbonyl fragment as the nucleophile (illogical), and the β-carbon of the other carbonyl
fragment as an electrophile (logical) or

b) carbonyl carbon of one carbonyl fragment as the electrophile (logical), and the β-carbon of the other carbonyl
fragment as the nucleophile (illogical).

In the first case, the reversal of reactivity can be achieved either by the use of nitroalkane or by the use of 1,3-dithiane
derivative as an equivalent of an "acetyl anion".

ipso ipso
O O disconnection O
Ph disconnection Ph
+ Ph +
O b a O
O illogical
logical illogical logical
electrophile nucleophile nucleophile electrophile

BrMg Ph NO2 Ph
O
or S S
O O
X H
In the forward synthesis by path a, anion of nitroethane reacts with an α,β-unsaturated ketone to give the
corresponding 1,4- bifunctional system which can then be transformed by a Nef-type reaction into the desired 1,4-
dicarbonyl compound.

H2 O
NO 2 1. TiCl3 O
O O Ph work up
NO 2 NaOEt N Ph Ph
O 2. H2 O
O O
Nef reaction

Alternatively, the acetaldehyde is transformed ("masked") into a corresponding thioacetal which is treated with a strong
base to generate the stable anion. The resulting anion is then coupled with the α,β-unsaturated ketone to form a new
carbon-carbon bond and finally the thioacetal group is hydrolyzed (or "unmasked") to give the same 1,4-dicarbonyl
compound.

H2 O
HS SH n-BuLi work up
O Ph S S
S S S S Ph
THF O
Ph H BF3 -ether Ph H Ph Li O
Hg2+,MeOH
H2 O

O
Ph

O
In the forward synthesis by path b, the Grignard reagent may reacts with an carboxylic acid halide to give the desired
1,4-dicarbonyl compound. However, the presence of reactive keto group in the Grignard reagent itself makes the
synthesis of the target molecule unsuccessful. This is because the keto group reacts preferentially with the Grignard
reagent intramolecularly or intermolecularly to give abnormal product. Therefore, to direct the Grignard reagent to add
to the carboxylic acid halide, it is necessary to protect the reactive keto group before attempting to prepare Grignard
reagents. This is done by ketal formation.

HO OH Br Ph Mg BrMg Ph
HBr Br Ph
Ph O O
O O
peroxide O DRY H+ ether
O
O
1.
X
2. H3 O+

O
Ph
Q. Provide the reagents necessary to transform the given starting material into the desired product. Show possible
retrosyntheses. O

O
O O
O ii)
i)
CO2 H

SYNTHESIS OF TARGET MOLECULES BY TWO FUNCTIONAL GROUPS DISCONNECTIONS:

When a target molecule (TM) contains two functional groups, the best disconnection is one that incorporates both
groups and provides two synthons. Such disconnections are called two group disconnections.
Definition of two groups disconnection: When we use one functional to help disconnect another group in a bifunctional
target molecule, then the disconnections are known as two group disconnections. In bifunctional target molecules two
group disconnections are more efficient than one group disconnections. For instance, we can consider the following
target molecule. For target molecules consisting of two fragments joined by a heteroatom, we should disconnect the
bond next to the heteroatom. Therefore, in the following TM, we can disconnect on either side of the ether oxygen
atom to get synthons. However, the disconnection b is the best choice.
Br OH

Disconnection a OH Disconnection b O
a b
O
+ Ph
+
TM
OH OH
O
Ph Ph

OH O
HO Ph
Ph

Cause: Disconnection a does not correspond to a reliable reaction because it might be very difficult to control chemo-
selective alkylation of a primary hydroxyl group in the presence of the secondary one.

In the forward synthesis by path b, nucleophilic attack on the less hindered terminal carbon atom of the epoxide, the
reagent of disconnection b, can give the desired molecule selectively.
O O OH
H2O
Ph O O
NaH O Ph Ph
OH
workup

SYNTHESIS OF β-HYDROXY CARBONYLS AND α,β-UNSATURATED CARBONYLS:

BY ALDOL REACTION:

The aldol reaction of aldehydes and ketones is one of the most important methods for the synthesis of β-hydroxy
carbonyls and α,β-unsaturated carbonyls. For example,

With Acetaldehyde :

O OH O H3 O+ O
aq. NaOH
2
H3C H H3C H H3C H
(Aldol) (Crotonaldehyde)

With Acetone :

O OH O H3 O+ CH3 O
aq. NaOH H3C
2
H3C CH3 H3C CH3 H3C CH3

(Diacetone alcohol) (4-Methyl-pent-3-en-2-one)

Mechanism:
Base catalyzed aldol reaction:
O
O O O R CH3
aq. NaOH O O H2 O O OH
R CH2 R CH2 R CH2 R CH3 R CH3
H R R
OH- (enolate anion)
(X)

Acid catalyzed aldol reaction:

OH
O OH
H+ OH R CH3 OH OH - H+ O OH
R CH3 R CH2 R CH2 R CH3 R CH3
H R R
(enol)

Mechanism of the dehydration of β-hydroxy carbonyl product:

Acid catalyzed dehydration:

OH O H3 O+ OH2 O (-H2O) O H2 O O

E1
H
OH2

Base catalyzed dehydration:

OH O OH OH O OH O - OH O
E 1cb
H OH

Mixed aldol reactions:

CHO CHO CHO CHO
OH
R + R' CHO R R + R' R' + R' R + R R'
CHO
OH OH OH OH

(Self-condensation products) (Crossed condensation products)

On the other hand, if only one of the two aldehydes has an α-hydrogen, then two aldol products are formed.
OH Ph H 3C
CH3CHO + PhCHO CHO + CHO
OH OH
When one of the reactant involved in mixed aldol reaction is aromatic aldehyde such as benzaldehyde, furfural etc, the
-hydrogen no -hydrogen
reaction is known as Claisen-Schmidt condensation. In this case aromatic aldehyde cannot act as a nucleophilic
component due to the absence of α-protons for enolization.
O O OH Ph Ph
+ Ph Ph
i)
Ph CH3 Ph H EtOH, heat OH O O
Ph Ph
Ph O Ph
OH
ii) + O O
Ph O EtOH, heat
Ph
Ph Ph

O O OH
iii) + Ph
CH3 Ph H EtOH, heat
O
Intramolecular aldol reactions:

H 3C CH3
O NaOEt/ EtOH O OH H+

(-H2 O)
O O
Nucleophile O O
Electrophilic

OH O O H3 C
NaOEt/ EtOH NaOEt/ EtOH O OH

O O O O
1,4-dicarbonyl compound O
Strained and
not formed (Formed)

O O O
H KOH/MeOH H not
O heat
O CHO
more reactive
aldehyde group

Synthesis of O2 N CHO

Retrosynthesis:
OH
OH Retro-Aldol O 2N CHO
O 2N CHO FGI O 2N CHO +

O 2N CHO
CH3 CHO

Synthesis:
O2N CHO
OH
1. KHSO4 O 2N CHO
O2N CHO
O LDA/THF O
dehydration
H - 78 o C H 2. Aq. NH4 Cl
(work up)

Work backward and identify the starting materials of the following products by aldol condensation and also point out
which syntheses are particularly feasible.
Me CO2Et O O OH
i) ii) iii)
Ph Ph
Me

Answer: Retrosynthesis:

Me CO2Et Me
i) O + CH3CO2 Et
Me Me
Synthesis of the given molecule with these substrates will not be successful. Because when the carbanion derived from
ethyl acetate mixed with acetone, proton transfer occurs more rapidly than the condensation occurs and forms the
carbanion of acetone. The carbanion of acetone reacts with ethyl acetate to give Claisen condensation product after
final work up with dilute acid.
 O
NaOEt O
CH3CO2 Et CH2CO2 Et + CH3CO2 Et

O O H3 O+ O O NaOEt O O
CH3 CH3 CH3

So the given molecule can be synthesized by aldol reaction. But other methods such as Reformasky reaction,Wittig
reaction or Knoevenagal reaction may be used for this purpose.
Retrosynthesis:
ii)
O O
+ 2 PhCHO
Ph Ph

Synthesis of the given molecule by mixed aldol condensation using one molecule of acetone and two molecules of
benzaldehyde is feasible. This is because only acetone has α-protons and benzaldehyde does not have any α-protons
and therefore, the carbanion of acetone reacts with highly reactive benzaldehyde to give the desired product. The self-
condensation of acetone is not feasible because of its unfavourable equilibrium constant.

O NaOEt O O
NaOEt
PhCHO Ph Ph Ph
PhCHO

iii)
Retrosynthesis:

O OH O O
+
H

Synthesis:
O
1. H O OH
O LDA/THF O

- 78 oC 2. Aq. NH4Cl
(work up)

Synthesis of O

Ph CO2 H

Retrosynthesis:
OH O Retro-Aldol OH O
O FGI
+
Ph CO2 H Ph CO2 H
Ph CO2 H

O O

CO2 Et
Synthesis: Ph H
O
1. 1. Dil. KOH O
EtO O Ph H OH O
O
Ph CO2 H
CO2 Et Ph CO2 Et 2. H3 O+ /heat
CO2 Et 2. Aq. NH4 Cl
(work up)
Synthesis of
CHO

from
 Retrosynthesis:

CHO CHO
Reconnection

CHO

Synthesis: CHO CHO

OsO4 OH NaIO4 Aq. NaOH
CHO CH O
NMO OH

CHO
CHO
CHO CHO OH H2 O
- OH E1cb O
OH
OH

How will you bring about the following transformation?

O

Answer:
O O
O
1. O 3 NaOEt/EtOH H+

2. Me 2S; CH2Cl2 Aldol deaction Dehydration

O OH

Synthesis of O
O

Ph
Ph OH

Retrosynthesis:

O O
O Path b O O
Ph Path a O
Ph b +
+ Ph Ph
OH a Ph
Ph OH OH

O O O
NO2
Ph
Ph Ph
Ph
O
O

Path a is the best choice, because:

The starting materials of path a are cyclohexanone and benzyl, which are simple starting materials and readily available.
But 2-benzoylcyclohexanone, one of the starting materials of path b, is complicated and it has to be synthesized from
cyclohexanone and ethyl benzoate by Claisen condensation. Again, since 2-benzoylcyclohexanone is an unsymmetrical
1,3-diketone, nucleophilic addition of enolate of nitroalkane may occur at both carbonyl to provide mixture of products.
 Synthesis: O
Ph
O O Ph O
1.
O O
LDA/THF
Ph
-78 oC 2. H2 O
Ph OH
workup

BY REFORMATSKY REACTION:

The reaction of α-halo ester with an aldehyde or ketone having α-hydrogen or without having α-hydrogen to form β-
hydroxy ester in the presence of zinc metal is referred to as the Reformatsky reaction.
Zn
Ether-Benzene OZnBr Dil. H+ OH
O
+ Br CO2 Et CO2 Et CO2 Et
Reflux
-Hydroxy ester
Mechanism:

EtO O

O Zn O ZnBr O O Zn
Br
Br Zn Br
EtO EtO EtO Zn O
THF Br
O OEt

Dimer of zinc enolate

O

O O
Br Br
Zn O
O OH OEt Zn
Dil. H+ O O O O
Zn
EtO O
EtO Br EtO
-Hydroxy ester O

When a nitrile is allowed to react with the zinc enolatederived from ethyl bromoacetate the corresponding β-keto ester
is obtained. This is known as Blaise reaction.
O
CN 1. Zn(0), THF, reflux CO2 Et
+ Br CO2 Et
2. Aq. HCl,

Suggest suitable method for the synthesis of the following compounds using the given reaction.
CO2 Et
Using Reformatsky reaction

Answer:

O Zn OH
OZnBr dil H+
Ether-Benzene
CO2 Et CO2 Et
+ Br CO2 Et
Reflux

Ac2 O, heat

Transformation of CO2 Et
O CH2 CO 2Et
Answer:
CO 2Et CO2Et
O CO2Et
HO
BrCH2 CO2Et KHSO4 Pd/ heat

Heat
Zn, THF-Benzene
heat
Then dil HCl

How would synthesize the following molecule using Reformatsky reaction?

OMe
O
CO2 Et 4. O
3. HO CO2Et
2. CO 2Et
1.
HO
MeO OMe
Ph CO2 Et

BY KNOVENAGEL REACTION

Condensation of aldehydes or ketones with a compound having active methylene group in the presence of a weak base
to form an α,β-unsaturated compound is known as Knoevenagel condensation. Weak bases like amines or buffer
systems containing an amine and a weak acid catalyze these reactions.
O
CN cat. pyrrolidine CO2 Et
+
CO2 Et CN

Mechanism:
CN CN
+ +
CO2 Et N CO2 Et N
H H H

O H O N O N HO N N
N H - H+ + H+
+
+ H+ - H+
(Iminium ion)

N CN CN
EtO2 C
CN EtO 2C N + + N
N N H
+ H
H H
CO2 Et H

EtO2 C CN CN
+ EtO 2C N +
N N
H
H H
H
Regenerated
catalyst

Describe the synthesis of the following compound with proper retrosynthetic analysis.

CO2H
Answer:
Retrosynthesis:

CO 2H EtO2 C CO 2Et
O
CO2 Et
+
CO2 Et

Forward synthesis: EtO2 C CO2Et CO2H

O H3 O+
Py, Piperidine
CO2 Et
+ heat
heat
CO2 Et

Synthesis of α,β-Unsaturated Ketones via Mannich Bases:

The Mannich reaction is the condensation of an enolizable carbonyl compound with an iminium ion derived from the
reaction between an aldehyde (usually formaldehyde) and a secondary amine in presence of an acid to give, after
basification, an amino methyl derivative.
1. H+ O
O
+ HCHO + R2 NH R1 NR2
R2 R1 2. OH-
R2
Mechanism:

O HO
OH
+ R2 NH2 +Cl- + R2 NH NHR2
H H H
H H H

- H2O H2 O
H2C NR2 H2C NR2
H NR2
(iminium ion) H

O + H+ OH OH H2C NR 2 OH - H+ O
- H+
Ph - H+ Ph + H+ Ph Ph NR2 + H
+
Ph NR2

(+ HCl) (- HCl)

O O
OH-
Ph NR2 Ph NHR2
Cl

Convert acetophenone to PhCOCH=CH2 via a Mannich base.

Answer:
i) HCHO, Et2NH/H+ O
O O Ag2 O
O heat Me-I
Ph N(Me)Et2 Ph
Ph Ph NEt2 heat
ii) OH- I

Synthesis of α,β-Unsaturated Ketones via Wittig reaction:

The Wittig reaction, which combines a ketone or an aldehyde with a Wittig reagent, is used to create alkenes. If the
Wittig reagent itself contains an ester group, then the resulting product will be an α,β-unsaturated ester. Such Wittig
reagents are known as “stabilized ylides” since the ester electron-withdrawing group offers resonance stabilization to
the negative charge.
Stabilized Wittig reagent
O O
O
Ph3P Ph3P Ph3P
OEt OEt
OEt
While the Wittig reaction typically gives the (Z)-alkene as the major product, stabilized ylides usually give the (E)
stereoisomer. For example,
O
O O
+ Ph 3P R OEt
R H OEt
(E)-Alkene

The related Horner–Wadsworth–Emmons (HWE) reagent, a phosphonate-stabilized ylide that is prepared from P(OEt) 3
rather than PPh3, may be used for this purpose. This reagent has the advantage of being more reactive (reacts with both
aldehydes and ketones) and offering better stereoselectivity.
O CO 2Et
O O
+ (EtO) 2P
OEt

Two possible routes can be proposed for the synthesis of the (E)-isomer of ethyl cinnamate using Wittig reaction.

Route I Ph Route II
O
+ Ph3 P CHPh Ph3 P CHCO2Et + PhCHO
EtO CHO H CO2 Et

Route II is more efficient because

i) The Wittig reagent of the route II is a stabilized yilde, and therefore, its reaction with benzaldehyde is stereoselective
and gives the desired (E)-alkene as the major product.

ii) The alternate route “I” would result in a more complicated starting material and would give the (Z)-alkene as the
major product.
Synthesis:
O O Ph
O PPh3 n-BuLi PhCHO
Ph 3P Ph 3P
Br OEt THF OEt
OEt H CO2 Et
Br
Other examples:

CHO
CO2 H

PPh3 , THF 1. PhLi CO2 Et hydrolysis

CO2 H
iii) EtO2C EtO2C PPh3
Br CHO
Br 2.
(Only trans product is formed)

Ph Ph CHO
O
Ph Ph

1. Ph3 P/ Ph
O Ph
Cl2 , MeOH, H + OEt ether Ph3 P Ph
i) CH3CH2 OH OEt OEt
heat OEt Ph
Cl 2. n-BuLi EtO EtO
THF -10o C

H+ , H2O

Ph CHO

Ph
SYNTHESIS OF 1,3-DICARBONYLS:

Two alternative two groups disconnections can be possible for 1,3-dicarbonyls (Consonant systems): one lead to two
synthons of natural polarity and the other lead to two synthons of unnatural polarity. The disconnection leading to
natural synthons is the best choice because of the simplicity in synthesis and the synthetic equivalents of natural
synthons are readily accessible.
O O O O O
O
+ +

unnatural unnatural Natural Natural

synthon synthon synthon synthon

NO2 O NO2 O O
Or O
Or Or
S S X EtO 2C
X
Li

Claisen condensation is most commonly used for the synthesis of 1,3-dicarbonyl compounds.

CLAISEN CONDENSATION:

The ester having α-hydrogen atoms undergo base catalyzed self condensation reaction to form a 1,3-dicarbonyl
compound alternatively known as β-ketoester. This self condensation of ester is known as claisen condensation.

O 1. EtO- , EtOH O O
2 
R R
OEt 2. H3 O+  OEt
R
-ketoester
Mechanism:

O O O
+ EtO EtOH + O OEt
OEt OEt OEt
pKa = 25 pKa = 15.5 O OEt O

more acidic proton OEt

less acidic protons - EtO-

O O O O O O Na+ O O
+ EtOH EtO +
OEt OEt OEt OEt
pKa = 10.7
H+
highly acidic proton
O O

OEt
Describe the synthesis of the following compound with proper retrosynthetic analysis.
O O

Ph Ph

Synthesis:
Retrosynthesis: 1. NaOEt (1 eq.),
O O O O xylene, heat O O
O O
+ +
Ph Ph Ph Me EtO Ph Ph Me EtO Ph 2. H3O+ Ph Ph
Show two retrosynthetic pathways differing in the position of disconnection for the following compound. Which
pathway will lead to efficient synthesis and why?
CO2 Et

Ph Ph
O

Retrosynthesis:
Path b b CO2Et Path a
O OEt CO 2Et
+ Ph Ph Ph +
EtO OEt Ph Ph Ph
O a O
O
Via Grignard
synthesis
O
2 Ph Br +
H OEt

The path a would lead to the efficient synthesis because: i) path a involves only a single substrate, ethyl
phenylacetate, which is inexpensive and readily available; ii) path a leads to a single step synthesis; iii) dibenzyl
ketone, one of the starting materials of path b would probably have to be synthesized in a multistep synthesis.
Synthesis:
1. NaOEt (1 eq.),
xylene, heat CO2 Et
OEt CO2 Et
Ph +
Ph Ph
O Ph 2. H3O +
O

O O
from pinacol

Retrosynthesis:
O O O O O HO OH
+
EtO

Synthesis:

HO OH conc. H2 SO4 i) I2/Aq. NaOH

OEt
+
Pinacol- ii) H3O
O O
pinacolone iii) EtOH/H+
Pinacol rearrangement

O O 1. NaOEt (1 eq.), O O
xylene, heat
+
EtO
2. H3O +

Synthesize the following compound form the indicated starting material.

O

Ph

O
ONa
Dil HNO 3 i) NaOEt/EtOH EtO2 C
CO2 H EtOH CO2 Et CO2 Et Ph
CO2 H + CO2 Et
heat H ii) PhCH2 Br
i) dil NaOH
ii) H3O+
iii) Heat

Ph
Q. Synthesize the following target molecule using readily available starting materials and reagents. Show all possible
retrosynthetic routes. O O

OEt

SYNTHESIS OF 1,4-DICARBONYLS:

The 1,4-dicarbonyl pattern is illogical because such a target molecule has two alpha carbons connected to one another.
Disconnection between the two alpha carbons leads to one alpha carbon as the nucleophile (logical), and the other
alpha carbon as an electrophile (illogical). This reversal of reactivity is achieved by placing a halogen leaving group on
the alpha carbon.
-
O disconnection O Ph
Ph +
O O
logical nucleophile illogical electrophile

O Ph
Br
O

α-Brominated ketones can be prepared by the reaction of the ketone with bromine in acidic reactions conditions (Br 2
in HBr or HOAc). When a nucleophile attacks α-halogenated ketones, an S N2 substitution mechanism is preferred over
addition to the carbonyl. However, since the bromine increases the acidity of the alpha proton, an ordinary enolate
would more likely act as a base rather than a nucleophile and will pick-up a proton from the α-halogenated ketones. So
the synthesis would not work.

H
O LDA/THF O O Ph
Ph +
+ Br Br
- 78 oC O O
enolate

O
Ph

Instead, a stabilized enolate (or an enamine equivalent) must be used or the S N2 displacement.

Via acetoacetic ester:

NaOEt O O
O Ph
CO 2Et + Br Ph
CO 2Et
O EtO 2C O
stabilized enolate
1. [Link]
2. H3 O+ /heat
O
Ph

Via enamine:

H3 O+ /heat O
O N N
H N Ph Ph
+ Br Ph
p-TsOH/C6 H6 O O
O
reflux enaime
Q. Provide the reagents necessary to transform the given starting materials into the desired products. Show possible
retrosyntheses.
O O O O

CO2 Et ii) CHO

i)

Moreover, we can also disconnect the 1,4-dicarbonyl TM at ipso-position. Disconnections at ipso-position lead to:

a) carbonyl carbon of one carbonyl fragment as the nucleophile (illogical), and the β-carbon of the other carbonyl
fragment as an electrophile (logical) or

b) carbonyl carbon of one carbonyl fragment as the electrophile (logical), and the β-carbon of the other carbonyl
fragment as the nucleophile (illogical).

In the first case, the reversal of reactivity can be achieved either by the use of nitroalkane or by the use of 1,3-dithiane
derivative as an equivalent of an "acetyl anion".

ipso ipso
O O disconnection O
Ph disconnection Ph
+ Ph +
O b a O
O illogical
logical illogical logical
electrophile nucleophile nucleophile electrophile

BrMg Ph NO2 Ph
O
or S S
O O
X H

In the forward synthesis by path a, anion of nitroethane reacts with an α,β-unsaturated ketone to give the
corresponding 1,4- bifunctional system which can then be transformed by a Nef-type reaction into the desired 1,4-
dicarbonyl compound.
H2 O
NO 2 1. TiCl3 O
O O Ph work up
NO 2 NaOEt N Ph Ph
O 2. H2 O
O O
Nef reaction
Alternatively, the acetaldehyde is transformed ("masked") into a corresponding thioacetal which is treated with a strong
base to generate the stable anion. The resulting anion is then coupled with the α,β-unsaturated ketone to form a new
carbon-carbon bond and finally the thioacetal group is hydrolyzed (or "unmasked") to give the same 1,4-dicarbonyl
compound.
H2 O
HS SH n-BuLi work up
O Ph S S
S S S S Ph
THF O
Ph H BF3 -ether Ph H Ph Li O
Hg2+,MeOH
H2 O

O
Ph

O
In the forward synthesis by path b, the Grignard reagent may reacts with an carboxylic acid halide to give the desired
1,4-dicarbonyl compound. However, the presence of reactive keto group in the Grignard reagent itself makes the
synthesis of the target molecule unsuccessful. This is because the keto group reacts preferentially with the Grignard
reagent intramolecularly or intermolecularly to give abnormal product. Therefore, to direct the Grignard reagent to add
to the carboxylic acid halide, it is necessary to protect the reactive keto group before attempting to prepare Grignard
reagents. This is done by ketal formation.
HO OH Br Ph Mg BrMg Ph
HBr Br Ph
Ph O O
O O
peroxide O DRY H+ ether
O
O
1.
X
2. H3 O+

O
Ph

O
Q. Provide the reagents necessary to transform the given starting material into the desired product. Show possible
retrosyntheses.
O
O O
O ii)
i)
CO2 H

SYNTHESIS OF 1,5-DICARBONYLS:

1,5-Dicarbonyls (Consonant systems) can be disconnected at ipso- or α-position with respect to one of the two carbonyl
groups. Of the four possible routes, the route that uses ethyl acetoacetate as the nucleophilic component and αβ-
unsaturated carbonyl compound as the electrophilic component is the best one.

O
S S O O O O
Br X
Li BrMg

O O
O
O +
+ ipso-
-disconnection
disconnection O O
OR
OR
O O
O
O +
+

O O
O CO2Et
O O
BrMg
X

Easily accessible

1,5-Dicarbonyl compounds can be synthesized by direct attack of the enolate anion derived from ethyl acetoacetate to
the α,β-unsaturated carbonyl compounds which function as the electrophile.

Michael Addition:
Conjugate addition (1,4 addition) of a stabilized carbanion nucleophile derived from active methylene compound with
activated carbon-carbon multiple bonds (Michael acceptor) is known as Michael addition reaction.
2 1 Me
i) NaOEt, EtOH
O CO2 Et 3
+ 5 4 O
+
CO 2Et ii) H3O EtO2 C CO2 Et
(1,5-dicarbonyl compound)

Mechanism Me
Me H OEt Me
CO2Et + EtO (cat.) CO 2Et O
H2 C HC O OH + EtO
CO2Et - EtOH CO2Et
EtO 2C CO2Et EtO2C CO2 Et

Regenerated
catalyst
Me
Suggest two alternative possible pairs of starting materials for the synthesis of compound A by Michael reaction. Which
O
pair will you prefer for actual synthesis and why?
EtO2 C CO2 Et
O Ph
COOEt
Ph
COOEt
A

In the given 1,5-dicarbonyl, a disconnection can be made at either alpha carbon between the two carbonyls to get
two pair of Michael acceptors and Michael donors. Retrosynthetic analyses for the synthesis of the following molecules
are shown below

O O Ph b
COOEt Path b Path a O COOEt
+ H2C COOEt +
Ph Ph Ph
COOEt a Ph Ph COOEt
COOEt

The question is which of the two pairs would be best choice in practice?

The choice of pair depends on the following factors:

a) The softer nucleophile tends to give conjugate addition and the harder nucleophile tends to give carbonyl addition.
-
CH(CO2Et)2 is a softer nucleophile than -CH2COCH3 and hence -CH(CO2Et)2 has a tendency to give conjugate addition
product while -CH2COCH3 gives carbonyl addition products.

b) CH2(CO2Et)2 gives corresponding enolate anion in the presence of weaker base but formation of enolate anion from
CH3COCH3 requires a strong base and drastic reaction conditions.

Consequently, starting materials of path b will be the best choice for the synthesis.
Synthesis:
COOEt
HC
O O i) Aq. NaOH O COOEt O Ph
+ COOEt
Ph Ph H ii) H3O+ Ph Ph Michael Ph
reaction COOEt
Aldol reaction
Aq. NH4Cl

O Ph
COOEt
Ph
COOEt
Q. Analyze the following molecules and determine what starting materials would be required for their synthesis.

O O O
CO2H CO2Et
3. Ph
2.
1. Ph
CO2 H

OMe
CN

5 EtO2 C
4. O O Ph O

ROBINSON ANNULATION:

Robinson annulation reaction is the process of formation of a new six membered ring involving intramolecular aldol
condensation of the initial Michael addition product and subsequent dehydration. For example,

O O O O
Me
Me KOH, MeOH Me

reflux Michael
O O reaction O
O
H3 O+
aldol
O O
dehydration

O O
OH

If the four-carbon methyl vinyl ketone unit within the cyclohexenone ring is present in a target molecule, it is an
indication that the TM could be prepared by Robinson annulation reactions. For example;
Retrosynthesis:

Cyclohexenone
moiety
O O
O O
O CO2 Et +

CO2 Et CO2 Et

Synthesis:
O O
O O
EtONa/EtOH O (-H2 O)
CO2 Et +
Heat CO2 Et Aldol reaction CO2 Et
Michael reaction

Problems :-

1. Synthesize the following molecules from the indicated starting materials

O
CO2Et CO2Et
a. O
b.
O
O
2. Synthesize the following molecules using Robinson annulation.
CO2Et
Me
N

Complete the following reactions scheme.

CHO
O dil KOH KOH/MeOH H+
+ (A) ( B) (C)
O -H2O

Answer:
O H
CHO O
O O
dil KOH O CH2
O OH
H
Michael CHO O
addition O O
(A)
Aldol
reaction

HO
H+
O O
-H2O
O O
(C) (B)

Outline steps for the synthesis of following compound from the indicated starting materials. Also show the
retrosynthetic analysis.
O O
CO2 Et
Me CO 2Et
ii) from acyclic molecules
i) from
O
O

Synthesize the following molecule using Robinson annulation. Show retrosynthetic analysis also.

O
Me Me
Answer:
Retrosynthesis:
CO 2Et
FGA
FGA CO2 Et
O O O O O
Me Me Me MeOH O O
Me Me Me Me
+
O

Forward synthesis:

CO 2Et CO2H
CO2 Et 1. NaOEt, EtOH H+/H2O (-CO2)
2. Heat -H2O
O O O
O O HO Me Me
Me Me
O
Michael reaction
SYNTHESIS OF 1,6-DICARBONYLS (Reconnections):

We have learnt before that during retrosynthetic analysis of1,6-dicarbonyls, reconnection of two functional groups to
give a six-membered ring is important because these six-membered ring, which, in the synthetic direction, may be
constructed by a Birch reduction of the corresponding aromatic molecule or by cycloaddition reaction between a
suitable diene and a dienophile.

Synthesis of
OH
EtO2 C

Me

Retrosynthesis:

OH OMe Birch reduction OMe

1 6
FGI 2
Reconnection transform
EtO2 C MeO2 C 4 CHO
5
3
Me Me
Me Me

More electron rich

Forward synthesis: C=C bond
OMe OMe OMe
1. Li/liq. NH3 O 1. H3 O+
EtOH m-CPBA (1 eq.)
MeO2 C CHO

2. Aq. NH4Cl 2. NaIO4 Me

Me Me Me or
Pb(OAC)4 1. NaBH4 /MeOH
2. H2 O (workup)

O OH
Synthesis of
EtO2 C

Me

Retrosynthesis:

O
O O
OH Reconnection
FGI Retro-aldol 6 4 2 1
3 CHO
5

1,6-dicarbonyl

retro-Diels-Alder

2
 More electron rich
C=C bond
Forward synthesis: O
OH
OH NaIO4
Heat 1. m-CPBA CHO
+
[4 + 2]- 2. H3O+
cycloaddition

1. [Link]
2. H3O+ /heat

Synthesis of

O
MeO
1
Retrosynthesis CO2Me CO2Et
FGA 2

O O 3 6CO2 Et
MeO MeO MeO 4 MeO
5

Br
+
MeO MeO
Forward synthesis:
NaNH2 / CO2H
Br Liq.NH3 1.O3
CO2 H
MeO MeO D.A. Reaction MeO 2. Zn/H2O2 MeO

EtOH/H+
heat
1. [Link]
2. H3 O+ /heat CO2Me CO2Et
-CO2 1. NaOMe
O O CO2 Et
MeO MeO 2. H3 O+ MeO
Retrosynthesis workup
Synthesis of O
O OH
O
O FGI

CHO
1,6-dicarbonyl

OMe
 Forward synthesis
OMe OMe O O O
1. Na/ liq. NH3
+
H3O /heat isomerization Na/Lig. NH3
EtOH

1. Me-Li/ether
2. H3 O+
OH
O NaOMe/heat O 1. O3 Ac2O, heat

Aldol CHO 2. Me2 S

Synthesis of
OH Me
OH

Retrosynthesis O
Reconnec. O O
OH Me FGI OH Me
OH
CO2Et

Me Me

OMe O

Me Me
Forward synthesis:
O O O
OMe 1. Li/liq. NH3 OMe Li/ liq. NH3
Dil HCl 1 eq. EtOH m-CPBA O
EtOH

heat then
2. Aq. NH4 Cl
Me-I Me
Me Me
Me Me
LiAlH4/THF
then
workup

HO
Me OH

Synthesis of
O
Retrosynthesis
HO OH O
O O Reconnection FGI
2 4 6
HO 1 3 5

+ Me-I
 Synthesis

O N O
N N
H Me-I H3O+

TsOH/C6 H6
reflux
1.NaBH4/MeOH
2. workup

O OH
1. O3 Ac2O/heat
HO
O
2. Zn/H2O 2

Q. Propose a possible disconnection/retrosynthesis for each of the following target molecules. Consider the pattern of
functional groups when determining the best site for a disconnection.
O
O
OH
2. 3.
1.
HO 2C
O CO2 H