ILLOGICAL TWO-GROUP DISCONNECTIONS

(a) -HYDROXY-CARBONYL COMPOUNDS

1. THE 1,2-DIOXYGENATION PATTERN (b) 1,2 DIOLS
(c) ILLOGICAL ELECTROPHILES

(a) 1,4-DICARBONYL COMPOUNDS

2. THE 1,4-DIOXYGENATION PATTERN (b) -HYDROXY CARBONYL COMPOUNDS
(c) OTHER ILLOGICAL SYNTHONS

3. 1,6-DICARBONYL COMPOUNDS

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1. THE 1,2-DIOXYGENATION PATTERN
(a) -HYDROXY-CARBONYL COMPOUNDS
So far all our two group disconnections have sensible synthons with anions or cations all
stabilised by functional groups in the right positions. This won't always be the case.
Supposing we wanted to make the hydroxy-acid TM 131; we could treat it as an alcohol:
H
O
O
Ph
+ -
CO2H Absurd synthon
Ph CH3
H3C CO2H
In fact there is a common reagent for this synthon - a simple one-carbon
TM 131
anion which adds to ketones and could easily be converted into TM 131.

O - OH
CN NaOH
Ph
TM 131
Ph CH3 H+ H3C CN H2O

2
A more elaborate variation gives a general amino acid synthesis. If the
reaction between an aldehyde and cyanide is done in the presence of
ammonia, the product is an -amino-nitrile:
NH2
NH3, -CN
RCHO
R CN

NH NH2 NH2
NH3
RCHO
R R CN R CO2H
-
CN
H 3C CH3

How could you make the amino acid Valine (TM 138)?
HO2C NH2

3
Analysis:
H3C CH3 H3C CH3 H3C CH3

- + + NH3
CN

HO2C NH2 NH O

Synthesis:

H 3C CH3 H 3C CH3
NH3
This is the Strecker amino acid synthesis
-
CN
O HO2C NH2
TM 138

4
Strecker amino acid synthesis

5
 :B
Ph OH
H
Ph OH Strangely enough, cyanide ion is also involved in one
C special reaction giving an -hydroxy-ketone.

N-
N
This anion now reacts with another molecule of benzaldehyde to give
eventually the -hydroxy-ketone
Ph OH
Ph Ph The product is called
benzoin and the reaction is
+ PhCHO known therefore as the
C
O
benzoin condensation. No
OH
-
N base is needed other than
Draw mechanisms for these steps cyanide ion.

6
How could benzoin be elaborated into the more complex molecule TM
143?
Ph Ph Ph
Ph Ph
O FGI
O + O OH HCO2Et + PhCH2MgBr
Ph O
Ph
Ph Ph Synthesis
Ph
TM 143
H
O

The same problem of +

illogicality arises with other O
O
-hydroxyketones: TM 145
O
We need a reagent for an acyl anion synthon
7
We find this in the acetylide ion since substituted acetylenes can be
hydrated to ketones:

8
How then could one make TM 145?
H
OH O
2+ +
1. Na, lig NH3 1. Hg , H
H H
2. Acetone 2. H2O

O O
The reaction can be used for disubstituted acetylenes, but it
is unambiguous only when they are symmetrical. Suggest a
synthesis for TM 146.
O CH3
CH3
TM 146 O TM 148
OH
-Hydroxy ketones take part in condensation
reactions too. How would you make TM 148? O

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1. THE 1,2-DIOXYGENATION PATTERN
(b) 1,2 DIOLS
An osmate (1R,2S)-1-methylcyclohexane-1,2-diol
CH3 CH3
OsO4 O O OH
NaHSO3
Os
Pyridine H2O
CH3 O O OH
H H

CH3 OH
1-methylcyclohex-1-ene CH3
RCO3H H3O+
O
CH2Cl2 OH
H H
(1R,6S)-1-methyl-7-oxa-bicyclo[4.1.0]heptane
(1S,2S)-1-methylcyclohexane-1,2-diol

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 A good approach to 1,2-diols is hydroxylation of an olefin with reagents
such as OsO4 or KMnO4. The olefin can be made by the Wittig reaction so
the disconnections are: HO OH
FGI
Wittig

Analysis: Back to the olefin - either Wittig is possible but one pair of starting materials is
more readily available:
OH OH
FGI Wittig
+ Ph3P
O
Ph Ph
Ph

Synthesis:
Br
BuLi OH OH
Ph3P Ph3P OsO4 or KMnO4
Ph
Ph
Ph Ph
O

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1. THE 1,2-DIOXYGENATION PATTERN
(c) ILLOGICAL ELECTROPHILES
So far we have used illogical nucleophiles and special methods to got round the difficulty
of making 1,2-dioxygenated compounds. Another approach is obviously to use an
illogicial electrophile and among the most important of these are -halo-carbonyl
compounds. We can make these easily from carbonyl compounds by halogenation of the
enol.
O OH O
Br2 The enol is nucleophilic at the
Br carbon atom but the -bromoketone
R R R is electrophilie at the a carbon atom:
by halogenation we have inverted the
natural polarity of the molecule.

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How could you make TM 158? O

O CH3
Ph
Analysis: As usual remove the ester first: TM 158
O
O
HO CH3 O O
FGI FGI
O CH3
+
Ph OH Br
O Ph Ph
O

Synthesis: Since -halo-carbonyl compounds are very reactive electrophiles, we can use a
short cut:
O
O Br2 O NaOAc
O CH3
Br Ph
Ph CH3 AcOH Ph
O
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 O CO2H
The hormone weed-killer MGPA (TM 160) is H3C
needed in large quantities. Suggest an
economical synthesis for it.
TM 160
Cl

The other main illogical electrophiles are

epoxides, easily made from an olefin and a O
per-acid, the usual one being m- m-CPBA
chloroperbenzoic acid (MCPBA) a R R
commercial product.

14
What product would you get from this and sodium methoxide in
methanol?
O OH
O MeOH

R
-
OMe
OMe OMe

In acid solution, the other regioisomer would be formed because the transition state has a
partial positive change on carbon stabilised by R:

H
OH O R OH

R R
-
OMe MeOH MeO

15
How would you make TM 163 from simple starting materials?

Analysis: This is the substitution pattern for a base-catalysed epoxide opening:

PhH2CO OH O
FGI
PhCH2O- + Wittig
TM 163

Synthesis:
O O PhH2CO OH
Ph3P=CH2 m-CPBA PhCH2OH

Na

16
Amines also react with epoxides at the less substituted carbon atom. As
a slightly more testing problem, suggest a synthesis of the alcohol (TM
165) whose derivatives are used in disinfectants ("phemeride" etc.).

Analysis: There is a series of 1,2 relationships here: it's easiest to start with the free
hydroxyl group:

Cl-
O O HO O
HO N + N + N Ph
Ph Ph
TM 165
Synthesis: It might be better to add the benzyl group at the end so that we can use
dimethylamine.
O O
OH O PhCH2Cl
Me2NH
Me2N Me2N OH TM 165
Neutral Base

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2. THE 1,4-DIOXYGENATION PATTERN
(a) 1,4-DICARBONYL COMPOUNDS
The obvious disconnection on a 1,4-dicarbonyl compound gives us a logical nucleophilic
synthon (an enolate anion) A but an illogical electrophilic synthon B:
O
O We need for B a derivative of a
+ ketone in which the normal polarity
O is inverted, and the -halo carbonyl
O
A B compound is ideal.

Analysis: Either way round will do, so let's arbitrarily chose ketone and -halo ester:
O O

CO2Et + Br CO2Et

TM 171
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 Synthesis: Our problems are not yet over because if we combine
ketone and -halo ester in base, quite a different reaction occurs.
OEt
O CO2Et
Br
O
O
This, the Darzens reaction, is useful in other
circumstances but a nuisance here. EtO-

Br OEt
Br Br
O
-
OEt -
O OEt
H O
+
EtO - O O

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 O NR2 We must use some means to make the
R2NH ketone act as the nucleophile in the initial
H+ condensation. One effective way is to
convert it into an enamine.

Draw a mechanism for this reaction

The complete synthesis of TM 171 now becomes:
+
NR2
O NR2 Br

R 2N H OEt H+
C O 2E t TM 171
H 2O
O

The enamine attacks the reactive -carbonyl

halide rather than the carbonyl group itself. O TM 175
How could you make TM 175?
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Enamines are not always necessary - sometimes the enolate anion is
stable enough by itself. How would you make TM 177?

Analysis: The activating group gives us a guide:

O O

+
B r

C O 2E t O C O 2E t O O

Synthesis: Bromination of butanone in acid gives predominantly the isomer we want, and
again the reactive -carbonyl halide is a good electrophile:
O
O
B r2 C O 2E t

Br
A cO H E tO -
O O C O 2E t O

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2. THE 1,4-DIOXYGENATION PATTERN
(b) -HYDROXY CARBONYL COMPOUNDS
O O
H The -halo carbonyl compounds are
R
'
L
i R R reagents for the synthon +C-C=O. At a lower
R
'
oxidation level, epoxides are reagents for
the synthons +C-C=O as in their reaction
Analysis:
with Grignard or organolithium reagents.
O O

Ph
O
+ Ph
OH Synthesis: Again the enamine can be used
to provide the enolate synthon:
O NR2 O
O
R2NH Ph Ph

H+
H+/H2O OH

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One particular sequence under this general heading is rather important.
How would you make TM 181? O
O
C O 2E t O
Analysis: C O 2E t +

OH

The usual disconnection

Synthesis: In fact this combination of reagents gives a stable anion.
doesn't give TM 181: instead the lactone is formed.
This lactone is useful in all the reactions for which
we might plan to use TM 181. O
O
O O
O
O
OEt O
CO2Et
EtO-
O- Lactone
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How then would you make the -halo ketone TM 183?

O
TM 183
B
r

How would you make this -halo ketone TM 185?

OC
l
P
h
TM 185

We shall need an activating group

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2. THE 1,4-DIOXYGENATION PATTERN
(c) OTHER ILLOGICAL SYNTHONS
Clearly other combinations of logical and illogical synthons could be O

used to make 1,4-dioxygenated compounds. How could you use

cyanide ion (as the CO2H synthon) to make a -keto acid such as: CO2H

All we have to find is the electrophile:

O O
+ -
CN
CO2H

How could you, make the same acid using prepargyl bromide BrCH2CCH as your illogicaI
fragment?

25
Acetylenes can be hydrated to give ketones so propargyl bromide must
provide a MeCOCH2+ synthon:
O O

+ -
CH2CO2H
CO2H
Synthesis: Activation will be needed:
- + 2
+ O
E
t
O C
O
2H H
,Hg
C
H
2(
COE
2t
)2
B
r
HC
2CCH H
O
2 C
OH
O 2

Cyclopentenones (e.g. TM 190) occur in nature and are important in

prostaglandin synthesis. How would you make this one?
TM 190
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 3. 1,6-DICARBONYL COMPOUNDS

Clearly, these too will be illogical 2

R 1
disconnections but we can get round the 3

problem in a different way by using a R econ n ect R

O
disconnection which actually links up the
two carbonyl groups: O
R

6 4
R
5

Try this for TM 194, analysing its synthesis back to simple starting materials.

C O 2H
TM 194
P h

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Analysis:

O
Ph
O H
Ph Ph
R econnect FG I
O + PhM gB r

H O

Synthesis:
OH
O
Ph Ph
Mg,Et2O H3PO4 O3,H2O2
PhBr CO2H
Ph
O

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Since cyclohexenes can also be made by the Diels-Alder reaction we
have access to a wide range of 1,6-dicarbonyl compounds. How about
TM 196?

Analysis: Choosing the 1,6-dicarbonyl relationship first:

H O 2C C O 2H

H O 2C C O 2H

TM 196

Synthesis: Maleic anhydride is the best reagent.

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