Introduction to Organic Synthesis

CM3001 Dr. Alan Ford (Lab 415)

text: Willis & Wills Organic Synthesis (OUP)

To state the obvious:

Synthesis is the process of making a desired compound using chemical reactions. More often than not,
more than one step is involved.

The importance of synthesis

1. Total synthesis of interesting and/or useful natural products

2. Industrially important compounds
3. compounds of theoretical interest
4. structure proof
5. development of new synthetic methodology
6. importance to other areas of science and technology

Examples

• Natural products eg. steroids, prostaglandins, alkaloids

Cl
HO

CO2Me N
H
N

HO
OH
15-Methyl PGF2α (prostaglandin) Epibatidine (South American frog alkaloid)
< 15 mg isolated from 750 frogs

• Industrially important compounds such as pharmaceuticals, agrochemicals, flavours, dyes,

cosmetics, monomers and polymers
O

O NHMe
O
CO2H O
P

Me F
MeO

Naproxen (painkiller) Carbaryl (insecticide) Sarin (nerve gas)

 CHO
O
O

O NHMe
O
OMe
Isobutavan Methylenedioxymethamphetamine, MDMA
(smells of mint chocolate) (Ecstasy)

H
N
CN
O

N
H

n
O
"5 CB" (liquid crystal) Kevlar (fancy polymer)

• Theoretically interesting molecules

Cubane meta para Cyclophane

• Structure proof While spectroscopy and crystallography are used to determine molecular
structures, unambiguous total synthesis is still important
OH

H
N

NH

MeO

Br

S-(+)-Chelonin B (marine sponge alkaloid)

• New methodology New ways to make molecules, improvement of existing ways, ways of doing
what was previously impossible

• Science and Technology Materials with special applications; molecular switches, non-linear
optics, nanotechnology

2
Basic Steps of Solving Synthetic Problems

1) Choice of TARGET MOLECULE (TM)

2) Consideration of applicable synthetic methodology

3) Design of synthetic pathway

4) Execution of the synthesis

—these steps are highly interactive

Approaching the design of a synthesis (Part One)

For simple molecules it can be obvious just by looking at the target structure, for example:
Br

Cyclohexyl bromide

Bromoalkanes are available from alkenes or from alcohols

Br
HBr

OH Br
PBr3

CO2Me

Methyl benzoate

Esters are available from carboxylic acids by reaction with alcohols; benzoic acid is available from
toluene

CO2H CO2Me
KMnO4 MeOH

H2SO4

3
 cis-3-octene

cis-Alkenes can be selectively prepared by partial reduction of alkynes; alkynes are accessible via
acetylide chemistry.

NaNH2
H NaNH2

H Br
EtBr
H2
Lindlar's
catalyst

Approaching the design of a synthesis (Part Two)

For more complex molecules, it helps to have a formalised, logic-centred approach;

RETROSYNTHETIC ANALYSIS

Retrosynthetic analysis is the process of working backwards from the target molecule to progressively
simpler molecules by means of DISCONNECTIONS and/or FUNCTIONAL GROUP
INTERCONVERSIONS that correspond to known reactions. When you've got to a simple enough
starting material (like something you can buy [and usually is cheap]) then the synthetic plan is simply
the reverse of the analysis. The design of a synthesis needs to take into account some important factors.
1) it has to actually work
2) in general, it should be as short as possible
3) each step should be efficient
4) side products (if formed) and impurities (there always are) should be easily separable from the
desired product
5) environmental issues may be relevant
6) there's more than one way to skin a cat

4
Example retrosynthetic analysis

Target molecule:
OH

DISCONNECT

A B

OH OH

SYNTHONS
SYNTHONS

REAGENTS
REAGENTS ? ? PhMgBr
H

therefore the target molecule could be synthesised as follows:

OH
Br
i) Mg/Et2O

ii) CHO

What is a synthon?

When we disconnect a bond in the target molecule, we are imagining a pair of charged fragments that
we could stick together, like Lego® bricks, to make the molecule we want. These imaginary charged
species are called SYNTHONS. When you can think of a chemical with polarity that matches the
synthon, you can consider that a SYNTHETIC EQUIVALENT of the synthon. Thus,
OH Oδ

δ
R H
≡R H

an aldehyde is a synthetic equivalent for the above synthon.

There can be more than one synthetic equivalent for a given synthon, but if you can't think of one...try a
different disconnection.

5
Always consider alternative strategies.
OH

DISCONNECT

A B

OH OH

SYNTHONS
SYNTHONS

Br Synthetic
Synthetic PhCHO
BrMg
? equivalents
equivalents

∴ a second possible synthesis:

OH

Br i) Mg/Et2O
Ph
ii) PhCHO

Similarly

OH OH

Ph Ph

BrMg
Ph

thus a third possible synthesis is

OH
O
BrMg

Ph Ph

6
Besides disconnections, we can also consider functional group interconversion. Our target molecule is
a secondary alcohol, which could be prepared by reduction of a ketone. This is represented as follows:
O
OH
FGI
Ph
Ph

DISCONNECT

O
O

Ph Br

Ph
(as enolate)

∴ synthesis number four

O
O
i) base LiAlH4
T.M.
Ph
Ph
ii) Br

Analysis number five:

O O

Ph Ph

LiCu( )2
Ph

Synthesis number five:

O O

t-Bu2CuLi NaBH4
T.M.
Ph Ph

Disconnecting heteroatoms can also be a good idea:

7
 OH OH "H2O"

Ph
Ph Ph

6th approach:
OH
i) Hg(OAc)2
Ph
ii) NaBH4 Ph

There are other possibilities, but let's not bother with any more.

How do you choose which method?

Personal choice. If you have a favourite reagent, or if you are familiar with a particular reaction (or if
you have a strong aversion to a reaction/reagent) then this will affect your choice. Also you need to
bear in mind the efficiency of the reactions involved, and any potential side reactions (for example,
self-condensation of PhCOMe in method 4).

DEFINITIONS

TARGET MOLECULE (TM) what you need to make

RETROSYNTHETIC ANALYSIS the process of deconstructing the TM by

breaking it into simpler molecules until you get
to a recognisable SM

STARTING MATERIAL (SM) an available chemical that you can arrive at by

retrosynthetic analysis and thus probably
convert into the target molecule

DISCONNECTION taking apart a bond in the TM to see if it gives

a pair of reagents

FUNCTIONAL GROUP changing a group in the TM into a different one

INTERCONVERSION (FGI) to see if it gives an accessible intermediate

SYNTHON conceptual fragments that arise from

disconnection

SYNTHETIC EQUIVALENT chemical that reacts as if it was a synthon

8
Some synthons and synthetic equivalents

synthon equivalent(s)

R RCl, RBr, RI, ROMs, ROTs

only when R = ALKYL
OH O

R R R R

OH O OH

Br
R R , R

O O

R R

O O O O O

R R OEt , R Cl , R O R

R RMgBr, RLi, R2CuLi, other organometallic

(alkyl; NOT "RH + base") reagents

O O O

CO2Et
R R , R

nb// make sure you don't lose CH2 groups if you represent eg. RCH2 ⊕ as R— ⊕ (viz. make sure the
product has the right number of carbon atoms!)

9
Latent Polarity

Think about some of the reactions we've looked at for carbonyl compounds:

O OH δ−
O
Nu
A
Nu δ+

O O

: base
B H

δ−
O
E

δ+ δ−
O

O O

Nu
C Nu δ−
O

E
δ+ δ− δ+
O

Nu

E
i.e.
δ−
O

δ+ δ− δ− δ+ δ− δ+ etc.
δ+

these polarities apply quite generally:

δ− δ−
OH Br

δ− δ− δ− δ− δ− δ− δ− δ−
δ+ δ+ δ+ δ+ δ+ δ+

δ−
δ−
NR NHR

δ− δ− δ− δ− δ− δ− δ− δ−
δ+ δ+ δ+ δ+ δ+ δ+

10
The partial positive and negative charges indicate the latent polarity of the bonds in a molecule. They
help us choose the synthons for key disconnections in a retrosynthetic analysis. viz.

δ−
OH
OH

δ−
δ+

one of the disconnections we saw earlier.

Latent polarity in bifunctional compounds

Consider a 1,3-disubstituted molecule, e.g.

δ−
Latent Polarities: O OH

O OH starting from C=O δ−

δ+ δ+ Ph

Ph δ−
O OH

starting from CΟΗ

δ−
δ+ δ+ Ph

When the latent polarities in a bifunctional molecule overlap they reinforce each other, this is termed
CONSONANT POLARITY. In these circumstances the analysis is straightforward.
thus,

δ− δ−
O OH O OH
O

δ+ δ− δ+
≡ + PhCHO
Ph Ph

O O OH
i) base
∴
ii) PhCHO
Ph

Similar principles apply for other 1,3-systems:

δ− δ− δ− δ− δ− δ−
O O OH OH O NR2

δ− δ− δ− δ− δ− δ− δ− δ− δ−
etc.

11
The same applies to 1,5-disubstitution

δ− δ−
O O O O

δ− δ− δ− δ−
R δ+ δ+ δ+ R R R

O
e.g.
+
R

O
NaOH O O

∴ O
R
R R

But what about 1,4-disubstitution?

δ− O
O

δ+ δ− δ+
δ− δ− δ−
δ+ δ+
O δ−
O

The polarities don't overlap and are termed DISSONANT. Any disconnection we try will result in a
synthon that has the "wrong" polarity.
O
O

synthons

O
O

? equivalents

+ base

One way to get around this is by judicious placement of heteroatoms:

12
 O O
δ−
≡ δ+
Br

O O
base
∴ O

Br
O

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.

example:

δ− reacts with
nucleophiles
O

δ+ H

HS SH
cat. BF3·OEt2

l u ng S S

m po H
acidic proton
(pKa ~ 32)
u
n-Butyllithium

reacts with
S S electrophiles

δ− δ+
Li

13
Equivalents for synthons with reversed polarity

synthon equivalent(s)
OH O OH

Br
R R R , or R

O O O
R Br
Br
R
R , or

O OEt

+ sec-BuLi
Me

O
S "Corey-
+ n-BuLi Seebach
R
reaction"
R S

S S
O
+ n-BuLi

H
S ,
or MeNO2 + base ("Nef reaction")
O
NaCN

HO

footnote to table
OEt OEt
OEt
s-BuLi E

(VERY strong base) E

Li

ethoxyvinyllithium
EVL H3O+

similarly from acetylene:

O
i) base + OH
E H3O
tautom.
ii) E E
HgO
E

14
Latent polarity and FGI (a quick consideration)
O

Ph Ph

FGI
δ−
O δ− δ− Leads to
O OH obvious
disconnection O O
δ−
Ph δ+ Ph
δ− δ+
Ph δ+ δ+ Ph
δ+ δ− δ+ Ph Ph
OH
δ−
δ− {PhCOMe & PhCHO}
Mismatched Matched
(dissonant) (consonant)

SURVEY OF FUNCTIONAL GROUP INTERCONVERSIONS

note: This is not supposed to be an exhaustive list of organic chemistry, nor is it supposed to tell you
anything you don't already know [for more information see relevant lecture notes or consult a
textbook]. The idea is to demonstrate how functional groups are related.

--note 2: the schemes are not repeated here; consult the paper copy that was given out during the
lecture. You were there, right?

15
Strategy in retrosynthesis

1) Consider different possibilities. Try a number of disconnections and FGI's. Try to keep the
number of steps down, and stick to known & reliable reactions. In real life, a synthesis has to be
economically viable.
2) Whenever possible, go for a convergent route rather than a linear one, as this will lead to a
higher overall yield

eg.
ABCDEF ABCDE + F

ABCD + EF ABCD + E
convergent

linear
ABC + D
AB + CD , E + F

AB + C
A+B ,C+D
A+B

Linear vs. convergent synthesis:

assume 80% yields (optimistic!)

Linear:

step 1 2 3 4 5 ...10 ...15

A AB ABC ABCD ABCDE ABCDEF A...K A......P
approx
overall yield: 80% 64% 51% 40% 32% ...10% ...3.5%

Convergent:

A AB
ABCD
C CD
ABCDEF
A...K
E EF G...K A......P
L...P
80% 64% 51% 40% 32%

The purely convergent synthesis is an ideal; virtually all real synthesis are linear to some degree

16
3) Aim for the greatest simplification

• make disconnections towards the middle of the molecule (this is more convergent
anyway)
• disconnect at branch points
• use symmetry where possible

eg. (towards the middle)

O O O O

Ph Ph

O O O

∴ base O

Ph MVK Ph
methyl vinyl ketone
MVK

eg. (at branches)

O O

CO2Et CO2Et
Ph Ph

O NaOEt CO2Et
∴ CO2Et
Ph

Ph Br

eg. (look for symmetry)

O O
O

HO
HO

O O
O

NaOEt HO
∴ − H2O
self-condensation

17
4) Add reactive functional groups at a late stage in the synthesis so they aren't carried through
steps where they could react to give side products.
NMe NMe
NMe

DiBAlH O
m-CPBA

O
OH OH

OH
O
DiBAlH
R' R'
R R

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

O OH
HO O O
CO2Me
CO2Me
Ph
cat. TsOH Ph
Ketal
(stable to LiAlH4
bases and
nucleophiles) Et2O

O
H3O+
O O

Ph OH
Ph OH

Note that protection strategy requires two extra steps (must be efficient); better syntheses
minimise the use of protecting groups.

A masked group is a functional group that is introduced and can be converted into a different
one at a later stage ( remember EVL)

OEt OEt OEt O

OEt
sec-BuLi RX steps +
H3O

Li R R' R'

masked acetyl group

18
5) Sometimes it helps the retrosynthesis if you add a functional group to facilitate bond formation
(Functional Group Addition). An example of this is acetoacetic ester synthesis:
O O O

≡
OEt

Thus:
O
O O O
FGA CO2Et discon. discon.
CO2Et CO2Et
Bu

(acetoacetic ester is much more easily deprotonated than acetone)

The synthesis therefore is

O O
O O O
+ CO2H −CO2
NaOEt NaOEt CO2Et H 3O
CO2Et Bu Bu
CO2Et Bu
MeI BuBr ∆

The strategy of FGA applies especially in the case of molecules containing no reactive
functional groups:

FGA discon. OH
OH

∴
OH
Br H2
i) Mg/Et2O H3O+
T.M.
Pd/C
O
ii)

19
alternatively:

FGA discon.
T.M.

O
O

∴ O (p-Tol)2CuLi
Zn-Hg
T.M.
O
HCl

nb// 2 ArLi + CuCl Ar2CuLi + LiCl

20
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:

EtO2C CO2Et EtO2C CO2Et EtO2C CO2Et

∴ EtO2C CO2Et EtO2C CO2Et

NaOEt NaOEt
EtO2C CO2Et Br
BrCH2CH2CH2CH2Br

Intramolecular acylation eg. the Dieckmann cyclisation; especially good for 5-membered rings:

O O

CO2Et CO2Et

O
NaO OEt
∴ CO2Et NaOEt CO2Et
CO2Et
EtO2C

condensation:

O O O

OH OH

∴ O
O

O O
t-BuOK

OH

21
Bicyclic molecules are prepared from cyclic precursors following similar principles.

OTs
diethyl malonate
CO2Et
DEM
DEM
2 NaOEt
CO2Et
CO2Et
OTs EtO2C

O
CO2Et
NaOEt
CO2Et

CO2Et

O KOH
O

A special example of condensation is the Robinson annulation (opinions vary as to the spelling). It has
been widely used in classical steroid synthesis. It involves Michael addition followed by intramolecular
cyclisation:

MVK?
O O see above
O
t-BuOK

MVK

base

OH
O
O
base

"signature" of Robinson annulation

22
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.

eg.

O
NaH
MeO2C(CH2)7CO2Me (CH2)6
ester added over
nine days CO2Me

similarly

"
EtO2C(CH2)14CO2Et (CH2)13

CO2Et

Another reaction which works well for such systems is the acyloin reaction. This is the intramolecular
dimerisation of a diester via a one-electron reduction. The reaction is heterogeneous, taking place at the
surface of molten sodium metal, so high dilution is not required.

eg

O
Na, xylene, ∆
EtO2C(CH2)8CO2Et (CH2)8

OH

and

" (CH2)16
EtO2C(CH2)16CO2Et

OH

Cycloaddition reaction (Diels-Alder)

Generic reaction (in retrosyntheic terms):

X X X = EWG
(CHO, CO2R, CN)

electron rich electron poor

23
eg
CO2Me CO2Me

concerted reaction
&
CO2Et

CO2Et

CO2Et
CO2Et

These reactions are concerted reactions, usually they are highly stereospecific. This is because the
reactions are governed by Frontier Orbital Theory. The actual rules of frontier orbital theory don't
interest us at the moment, all we need is a simple guideline we can remember:

Unsymmetrical Diels-Alder reactions:

R
R R

R' R'

+
R'

Major product Minor product

R R'
R R' R

+
R'

Major product Minor product

note that the 1,3-disubstituted product is the minor product in both cases

specific example:
CH3
CH3 CH3

CO2Me CO2Me

+ FGA now
CO2Me use
D-A
61% only 3%

24
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. There is a whole bunch of other reactions that apply for
aromatic systems.

eg.
O O

R R ≡ PhH + RCOCl + AlCL3

Friedel-Crafts acylation

RCOCl
∴ R

AlCl3

NH2 NO2 NO2

≡ PhH + HNO3 + H2SO4
aromatic nitration

NO2 NH2
fuming HNO3 Sn/HCl
∴ or H2, Pd/C
H2SO4

Br
≡ PhH + Br2 + FeBr3
Br aromatic bromination

Br
≡ PhN2X + CuBr
Sandmeyer reaction

NH2
Br

∴ Br2/FeBr3
i) NaNO2/HCl

ii) CuBr

(can get dibromination) (only monobromination)

25
Some other reactions
CO2H
KMnO4, (OH-)

H2O - t-BuOH

CHO
H2CO/POCl3/DMF Vilsmeier-Haak formylation

H2CO/HCl Cl
chloromethylation
ZnCl2

I R
R2CuLi

The last reaction above is a particularly useful application of organocopper reagents. Although the
mechanism is quite complicated, it's the result we're interested in at the moment. It's a transformation
that is not always easy to achieve by more conventional means.

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 Directs Activation

NH2, NR2 (more)
OH, O- activating
NHAc, OR
ortho/para-*
alkyl/aryl/vinyl
CO2-
neutral
X (halogen)
CO2H
CN
COR, CHO
SO3H meta- deactivating
CX3
NO2 (more)
* note that ortho/para- mixtures can be
formed and may have to be separated

26
Examples

CO2Et CO2H CO2H

H2N H2N O2N H2N

benzocaine (painkiller)

from toluene
CO2H CO2H

HNO3 KMNO4 H2 Pd/C EtOH

T.M.
H2SO4 H+

NO2 NH2
NO2

OH Br OH Br Br
Br

HO2C CO2H

I I NH2
I NH2
building block for
homogeneous catalyst
synthesis

Br Br Br

i) Ac2O/AcOH NaOH i) NaNO2/HCl

ii) Br2 57% EtOH ii) KI

NH2 NHAc NH2 I

Br

HO2C CO2H

KMnO4 BH3·SMe2
T.M.
aq. t-BuOH

I
nb// acetanilide prevents polybromination

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 though, and the
Birch reduction is one of them. (also recall the specific reduction of alkynes to trans-alkenes)

27
The typical conditions involve liquid ammonia (bp. −33 °C) and sodium metal, in the presence of a
proton source (usually an alcohol, EtOH).

EWG EWG
Na, NH3 (l), EtOH

eg EWG = CO2H, NO2

EDG EDG
"

eg EDG = Me, OMe

Examples

can be useful because...

O O
OMe
OMe
Na, NH3 (l), EtOH

OMe OMe
OMe
"
nb// not

can you see why?

OMe OMe
OMe
"
and not

OMe OMe
OMe

CO2H CO2H
"

28
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 O

Thus:
O
O O
O

Zn-Hg/HCl

Clemmensen
AlCl3 HO2C
HO2C

i) SOCl2
ii) AlCl3

Pd/C i) RMgx
tetralone
∆ ii) H3O+

R R
O
1-subtitution (aka α-)
via enamine
RBr

Pd/C
i) LiAlH4
∆
R ii) H3O+
R R
2-subtitution (aka β-)
O

other substitution patterns can be similarly obtained.

29
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 dil.

H2SO4 FeBr3 H2SO4

SO3H SO3H

Br Br

NH2 NH2
Br2 i) NaNO2/HCl

ii) H3PO2
Br Br Br Br

Transformations of Aromatic Systems--(Summary Scheme)

Consult the handout.

30
Overall Summary

To devise a synthesis:

1) Examine the TM; recognise functional groups and key structural features. In an exam you may
be given a SM, if this is the case, check how it relates to the TM
2) Use FG's present to help indicate disconnection points. Use latent polarities, umpolung and
FGA to help if neccessary
3) Consider FGI's appropriate to the TM; consider disconnections at branch points and
heteroatoms. Be convergent—disconnect between FG's separated by a couple of carbon atoms
4) Keep the number of steps as low as reasonably possible, but do use protecting groups where
neccessary
5) Disconnect to good SM's:

• straight chain monofunctional compounds

• branched monofunctional compounds containing six carbon atoms or fewer (for these
purposes, including allyl, alkenyl and cycloalkyl compounds)
• simple mono- and disubstituted benzenes
• common bifunctional compounds (acetoacetate esters, malonate derivatives etc.)
• hint: concerning regents & SM's...have you seen them before (like in tutorials?)

Further reading

I take full responsibility for any mistakes and tyops, after all, I'm just a man. I encourage all students
consult with higher authorities, and you could do a lot worse than look at some of these:

o Organic Synthesis: The Disconnection Approach, S. Warren

o Classics in Total Synthesis I & II, K.C. Nicolaou et al.
o Advanced Organic Chemistry, J. March
o Comprehensive Organic Transformations, R.C. Larock
o Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts

Go to the Library, it's free to get in.

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