Download - CH4103 Tutorial 3 (Ans)
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CH4103: Tutorial 3
1. -aminocarbonyl compounds [e.g. (A) - (C )] are important intermediates for thesynthesis of heterocyclic compounds. Suggest a suitable synthesis of compound (A)from ethyl acetoacetate (i.e. ethyl 3-oxobutanoate) and ethyl nitrite (EtO-N=O).
Accordingly, outline a strategy for the synthesis of compounds (B)& (C ).
CO 2Et
O
H2N
(A)
Et
O
H2N
(B )
EtO
H2N
(C)
2. How would you synthesize (i) 1-phenylbutan-1,3-dione (ii) 1-phenylpentan-1,4-dione and (iii) 1-phenylhexan-1,5-dione
3. Provide mechanisms, chemical structures of intermediates and of the finalheterocycles in the following:
(a) 1-phenylpentan-1,4-dione reaction with (i) H2S/HClor (ii) n-hexylamine(b) 1-phenylhexan-1,5-dione reaction with H3PO4
(c)
CO2Et
O
H2NO
EtO 2C
+(d) C5H11O
H2NEtO 2C O
EtO 2C
+
(e)O
Ph
+
O
NH2OH
(f)
NH 2
O
Ph
Me
+
Et (with p-toluenesulfonic acid as catalyst)
4. Provide a retrosynthetic analysis of thefollowing target molecules(TM ) andthereafter propose a reasonable synthesis route to each TM
(a)
O
(b)
N
Ph
O O
Ph
CO 2Et
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(c)HN NH
O O
Me Et
O
(d)
N
Me
PhCO 2Et
(e)
N MeMe
CO 2EtEtO 2C
(f)
NPh
CO 2H
Me Me
5. Celebrex is a non-steroidal anti-inflammatory agent used for example in the
treatment of arthritis. Provide a retrosynthetic analysis of an analogous compound(D) and thereafter propose a reasonable synthesis route to (D)
N N
CF 3
SH2N
O
O
Celebrex
N N
(D)
6. Pyrrole esters such as (E ) are needed for the synthesis of porphyrins (as inhaemoglobin), chlorins (as in chlorophyll) and corrins (vitamin B12). Ester (E ) has aside chain and can be converted by hydrolysis and decarboxylation into a pyrrole (F )with a reactive free -H. Provide a retrosynthetic analysis of ester (E ) and thereafter propose a reasonable synthesis route to (E )
NH
EtO 2C
CO 2tBu
H+
(-CO 2) NH
EtO 2C
H
(E) (F)
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Q1
O
CO 2Et AcOH
O
CO 2Et
H
NOC 5H11O
- C5H11OHO
CO 2Et
NH OH+
O
CO 2Et
NOH
O
CO 2Et
NH 2
Zn/ AcOH
reducing agent
another selectivereductant for oxime to amino:Na 2S 2O 4 oxime
( A )
ethyl acetoacetate
Compound (B) can be built upfrom ethyl acetoacetate, byrecognizing that there is anadditional Et group & the CO2Etgroup can be decarboxylated (-CO2) by hydrolysis 1st to a -ketoacid which is unstable to heat.
O
CO 2Et
NH2( B )
Et
decarboxylatedvia hydrolysis &
O
CO 2Et
O
CO 2Et
1. C 5H11 ON=O/ H +
O
CO 2Et
O
CO 2Et
O
Et
NH 2
H3O+
( B )
EtO -/ EtOH
Et
2. Zn/ AcOH
NH 2Et
O
NH 2Et
OH
O
-keto acid
- CO 2
Et I
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Compound (C ) can be built upfrom ethyl acetoacetate, byrecognizing that there areadditional Me groups (as indicated
in red) followed bydecarboxylation of -CO2Et group.
O
CO 2Et
NH2( C )decarboxylate
O
CO 2Et
O
CO 2Et
1. C 5H11 ON=O/ H +
O
CO 2Et
O
CO 2Et
O
NH2
H3O+
( C )
2 x LDA 2 x Me-I
v. strong basegenerates dianion
2. Zn/ AcOH
NH2
O
NH2
OH
O
-keto acid
- CO 2
Q2
(i)
Ph
O O
(a) (b)Ph
O O(a)
(b)
synthons
Ph
O O
OEt
synthetic equiv.
Ph
O O O
OEtPh
O
1,3-di C=O
Disconnection (a) would be a better choice since only acetone possesses acidic hydrogens. Thus, upon deprotonation to acarbanion, it can react with ethyl benzoate to afford TM with minimal
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side products.
Ph
O O
OEt
EtO -/ EtOH
Ph
O O
(ii)synthons
Ph
O O
synthetic equiv.
O
Ph
O
1,4-di C=O
PhO O
PhO O
Br
Ph O O
Br CO 2Et
(a)
(b)
ethylacetoacetate
Either disconnection (a) or (b) is fine using either Stork-enamine oractivated C- reaction with -bromoketone. If the latter is used than (b)is better since one of the starting material ethyl acetoacetate is readilyavailable.
With the Stork-enamine approach, then (a) may be better since bromoacetone can readily be generated.
O
CO 2Et
O
CO 2Et
PhBr
O
Ph
O
Br 2
H+
O
CO 2Et
Ph
O
EtO -
EtOH
TM
-keto acid
H3O+
(-CO 2)
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Stork-enamine synthesis:
O
Ph Ph
Br
OO
Br 2
H+
Ph
O
TMH3O
+H+
NH
(or any 2 o amines)
N Br - N+
(iii)synthons synth etic equiv.1,5-di C=O
ethylacetoacetate
Ph O O Ph O O Ph O O
CO 2Et
1
23 4
5
Although there are various disconnections possible along the C 2-C3 andC3-C4, we choose the disconnection leading to the starting material ethylacetoacetate.
O
CO2Et
O
CO 2EtO
CO 2Et
EtO -
EtOH
TM
-keto ester
H3O+
(-CO 2)Ph
OPh
O
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(f)
H+
- H+
NH2
O
Ph
Et
- H+ NH
Et
OH
Ph
N
Et
OPh
Et
N
H
Ph OHH
H+
H+Et
NH
Ph OH
- H2O
Et
NH
Ph
enol keto
Michael rxn
Q4
(a)
Analysis :
O O O12
34
1,4-diC=O O
+
Br
O
O
CO 2Et
NR 2
ORUse Stockenaminesynthesis
Synthesis :
O H+
NH
N
Br
OTM
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(b) Analysis:
N
Ph
CO 2Et
OO
Ph
Ph
CO 2Et
CO 2Et
NH2
Ph
EtO 2C CO 2Et
CO 2Et
Ph
CO 2Et1,5-diC=Odiethymalonate
-unsat.C=O
Ph
OCH 2
CO 2Et
Synthesis :
H+
keto acid
PhCH=OEtO -/EtOH
Ph
CO 2Et
Ph
CO 2Et
CO 2Et
CO 2Et
PhNH 2
CO 2Et
CO 2Et
CO 2Et
CO 2Et
Ph H3O
+
C
CPh O
OH
OH
O
- CO 2
CPh O
OHEtOH/ H +CO 2Et
CO 2Et
EtO -/EtOH
TM
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(c) Analysis:
HN NH
O O
Me Et
O
H2N NH2
O
O O
Me Et
OEt OEt
EtO 2C CO 2Et
Et-I
Me-I
urea
Synthesis :
1.EtO - Na +
TM
2. Me-IEtO 2C CO 2Et EtO 2C CO 2Et
Me
1.EtO - Na +
2. Et-IEtO
2C CO
2Et
Me Et
urea
(d) Analysis:
N
Me
PhCO 2Et
PhCO 2Et
NH2Me
OO1,5-di C=O
CO 2Et
OCHO
Ph
Synthesis :
CO 2Et
O
MeNH 2
CO 2Et
MeNH
CHO
Ph
TM
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Q6
NH
CO 2Bu- t
MeO 2C
H2N
CO 2Bu- t
MeO 2C
O
OR
H2NCO 2Bu- t
MeO 2C
O
H2NCO 2Bu- t
MeO 2C
O
unsat.C=O
MeO 2C
O
1,5-diC=O
MeO 2C
+
Oactivate
+
CO 2Bu- t
H2N
O
CO 2Bu- t
HON
O
Synthesis :
O
CO 2Me
1. MeO -
2. CO 2Me
MeO 2C
CO 2Me
O
O
CO 2tBu HONO O
HON
CO 2tBu
Zn
HOAcNH
CO 2tBu
MeO 2C
or
EtO-NO/H+
as i n Q1