Functional group interconversion 777
This guideline helps us in the next retrosynthetic step for the ICI-D7114 intermediate.
Disconnection (c) gave us a compound with two ethers that might be disconnected further by dis-
connection (e) or (f).
e ICI-D7114 intermediate: retrosynthetic analysis
Br O Ph
e
Br O Ph
f e Ph
f OH
HO C–O Br C–O
C–O ether e ether O ether
Br
OH target molecule O
Ph
HO
Disconnection (e) requires alkylation of a compound that is itself an alkylating agent.
Disconnection (f) is much more satisfactory, and leads to a compound that is easily disconnected to
4-hydroxyphenol (para-cresol) and 1,2-dibromethane. Using Guideline 3, we can say that it’s best to
disconnect the bromoethyl group (f) before the benzyl group because the bromoethyl group is more
reactive and more likely to cause problems of chemoselectivity.
ICI-D7114 intermediate: synthesis
OH O Ph O Ph
BnCl base BnNH2
Br TM
HO Br O
HO Br
Functional group interconversion
The antihypertensive drug ofornine contains an amide and an amine functional group, and we need
to decide which to disconnect first. If we disconnect the secondary amine first (b), we will have
chemoselectivity problems constructing the amide in the presence of the resulting NH2 group.
ofornine: retrosynthetic analysis
O O O
a
b a
N N Cl HN
NH2 NH NH
b
N N N
L
Yet disconnection (a), on the face of it, seems to pose an even greater problem because we now We discussed nucleophilic
have to construct an amine in the presence of an acyl chloride! However, we shall want to make the substitutions on electron-poor aromatic
rings like this in Chapter 23 and there
acyl chloride from the carboxylic acid, which can then easily be disconnected to 2-aminobenzoic is more detail on chloropyridines in
acid (anthranilic acid) and 4-chloropyridine. Chapter 43.
ofornine: O O O
retrosynthetic analysis
Cl FGI OH C–N amine OH
NH NH NH2
b
N N N
778 30 . Retrosynthetic analysis
The retrosynthetic transformation of an acyl chloride to a carboxylic acid is not really a discon-
nection because nothing is being disconnected. We call it instead a functional group interconver-
sion, or FGI, as written above the retrosynthetic arrow. Functional group interconversions often aid
disconnections because the sort of reactive functional groups (acyl chlorides, alkyl halides) we want
in starting materials are not desirable in compounds to be disconnected because they pose chemose-
lectivity problems. They are also useful if the target molecule contains functional groups that are not
easily disconnected.
ofornine: synthesis O O
O
OH Cl HN
OH
Cl NH SOCl2 NH
NH2 + TM
N N N
By using an appropriate reagent or series of reagents, almost any functional group can be convert-
ed into any other. You should already have a fair grasp of reasonable functional group interconver-
sions. They mostly fall into the categories of oxidations, reductions, and substitutions (Chapters 12,
14, 17, and 24).
Amine synthesis using functional group interconversions
The synthesis of amines poses a special problem because only in certain cases is the obvious discon-
nection successful.
H C–N amine
R1 N R2 R1 NH2 X R2
L
We discussed this in Chapters 14 and The problem is that the product is usually more reactive than the starting material and there is a
24. danger that multiple alkylation will take place.
R2 R2
2
X R H X R2 X R2
R1 NH2 R1 N R2 R1 N R2 R1 N R2
secondary amine is more
reactive than primary amine R2 X
The few successful examples you have seen so far in this chapter have been exceptions, either
for steric or electronic reasons, and from now on we advise you to avoid disconnecting an
amine in this way. Sometimes further alkylation is made unfavourable by the increased steric
hindrance that would result: this is probably the case for the cetaben ethyl ester we made by this
reaction.
O O O
steric hindrance
R Br
×
OEt OEt prevents further reaction OEt
NaOH
H2N R N R N
H
R
If the alkylating agent contains an inductive electron-withdrawing group, the product may be
less reactive than the starting material—benzylamine was only alkylated once by the alkyl bromide in
the synthesis of ICI-D7114 on p. 000 because of the electron-withdrawing effect of the aryloxy
group.
Functional group interconversion 779
What are the alternatives? There are two main ones, and both involve functional group inter-
conversion, with the reactive amine being converted to a less reactive derivative before disconnec-
tion. The first solution is to convert the amine to an amide and then disconnect that. The reduction
of amide to amine is quite reliable, so the FGI is a reasonable one.
amines: retrosynthetic analysis 1
H P
FGI reduction R1 N R2 C–N amide R1 NH2 Cl R2 Notice that we write
H
R1 N R2 + ‘FGI reduction’ above
O the arrow because we
O
are talking about the
amines: synthesis 1 H
Cl R2 forward reaction we are
R1 N R2 LiAlH4 or BH3, THF H going to do at this step.
R1 NH2 + R1 N R2
O O
This approach was used in a synthesis of this amine, though in this case catalytic hydrogenation
was used to reduce the amide.
O
retrosynthetic
FGI reduction O
analysis: N R N R C–N amide NH
R = C5H11
Cl R
O
synthesis:
O H2, catalyst
NH NaOH N R N R
+
Cl R
The second alternative is to convert to an imine, which can be disconnected to amine plus car-
bonyl compound. This approach is known as reductive amination, and we discussed it in detail in
Chapter 14.
amines: retrosynthetic analysis 2
FGI reduction C=N imine H R2
H
R1 N R 2 R1 N R2 R1 NH2 +
O
amines: synthesis 2 (reductive amination)
H R2 H+ cat. NaBH4 or NaCNBH3
H
R1 NH2 + R1 N R2 R1 N R2
or H2, cat.
O
Ocfentanil is an opioid painkiller that lacks the addictive properties of morphine. Disconnection
of the amide gives a secondary amine that we can convert to an imine for disconnection to a ketone
plus 2-fluoro aniline.
ocfentanil: O
retrosynthetic analysis OMe H
C–N amide N O
N OMe
+
N Cl
N Ph F
Ph F
FGI reduction N C–N imine O H2N
+
N N
Ph F Ph F
The synthesis is straightforward: a reductive amination followed by acylation of the only
remaining NH group. The tertiary amine in the left-hand ring interferes with neither of these
reactions.
780 30 . Retrosynthetic analysis
ocfentanil:
synthesis O H2N imine N
formation reduction
+
N N
Ph F Ph F
O
H OMe
N O
+ N
OMe
N Cl
Ph F N
Ph F
There are several conceivable routes to the neuroactive drug fenfluramine—one analysis, which
uses both the amide and the imine FGI methods, is shown below and this was the route used to make
the drug. Notice that the oxime was used instead of the imine. N-unsubstituted imines are very
unstable, and the much more stable, indeed isolable oxime serves the same purpose. Oximes are gen-
erally reduced with LiAlH4.
fenfluramine: retrosynthetic analysis O
FGI C–N reductive
HN reduction HN amide NH2 amination O
F3C F3C F3C F3C
fenfluramine: synthesis
O NH2OH NOH H2, cat. NH2 1. AcCl
TM
F3C F3C reductive F3C 2. LiAlH4
amination
stable oxime
You should now be able to suggest a plausible analysis of the secondary amine terodilin. This is
the structure; write down a retrosynthetic analysis and suggested synthesis before looking at the
Ph HN
actual synthesis below.
You should find yourself quite restricted in choice: the amide route clearly works only if there
Ph
is a CH2 group next to the nitrogen (this comes from the C=O reduction), so we have to use an
terodilin
imine.
terodilin:
retrosynthetic FGI reduction C=N imine Ph O
analysis Ph HN Ph N +
Ph H2N
Ph Ph
terodilin: synthesis
Ph O H+ cat. [H]
+ Ph HN
Ph H2N
Ph
In the synthesis of terodilin, it was not necessary to isolate the imine—reduction of imines is
L
faster than reduction of ketones, so formation of the imine in the presence of a mild reducing agent
See Chapter 24 for more on this.
(usually NaCNBH3 or catalytic hydrogenation) can give the amine directly.
Two-group disconnections are better than one
This compound was needed for some research into the mechanisms of rearrangements. We can dis-
connect on either side of the ether oxygen atom, but (b) is much better because (a) does not corre-
spond to a reliable reaction: it might be hard to control selective alkylation of the primary hydroxyl
group in the presence of the secondary one.
