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CH4301: Tutorial 3 P a g e | 1

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

ch4103 tutorial 3 (ans)

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