q4 06710-12-14 qs and as

January 2008 Heterocyclic Chemistry: Exam Questions and Model Answers

1

4. Answer ALL of the following parts.

(a) The structure of benzonitrile oxide is given below.

CN

O

MeO2C

CO2Me

dimethyl maleate dimethyl fumaratebenzonitrile oxide

CO2MeMeO2C

(i) Give the reagents that are needed to make benzonitrile oxide from benzaldehyde.

(ii) Work out the cycloaddition product of benzonitrile oxide with dimethyl maleate and dimethyl fumarate showing clearly the stereochemistry in

each case. (2, 6 marks)

(b) Consider the scheme below:

NH2

MeO

N

MeO

NH

MeO

PhPh

step 1 H+

A

step 2

B

(i) Give the reactant and reagent needed in step 1. (ii) Show the mechanism for step 2. (iii) What would happen to the rate of reaction of step 2 if the methoxy group

in A was replaced by a nitro group? Explain your answer. (iv) In step 2 an alternative product to B may be formed in theory. Draw this

product and explain why it is not formed in practice.

(1, 3, 2, 4 marks)

(c) Consider the following scheme and work out the structures of C and D.

Me

OMe

CC14H19NO285 oC

H2Pd-C D

C14H21NO2

max 3400 cm-1

(broad)

N

O

(4, 3 marks)


2

Q4 Model answer

(a) (i)

O

Ph

NHO

Ph

NHO

Ph

CNO PhH H Cl

NH2OHe.g.NCS

e.g.Et3N

NCS = N-chlorosuccinimide (ii)

MeO2C

CO2Me

CO2MeMeO2C

NOMeO2C

PhMeO2C

NOMeO2C

PhMeO2C

() syn isomer () anti isomercis alkene trans alkene

(b)

NH2

MeO

N

MeO

NH

MeO

PhPh

step 1 H+

A

step 2

B

(i) PhCHO / catal. H+.

(ii) Mechanism for step 2.

N

MeO

NH

MeO

PhPh

H+

NH

MeO

Ph H

NH

MeO

Ph

(iii) Switching from +M OMe to M NO2 makes the ring less nucleophilic and so the

rate of cyclisation would decrease. (iv) Cyclisation ortho to the OMe is disfavoured due to steric factors.

MeO

HNPh

(c)

Me

OMe85 oC

H2Pd-C

D

N

O

Me

OMe

ON

H

H

C

exo attack

Me

OMe

OH

NH

H

H

max 3400 cm-1


3

4. Answer all of the following parts.

(a) In the Fischer indole synthesis acetone and phenylhydrazine (PhNHNH2) react

to give 2-methylindole (A). Using this fact and the data for C provided, work out the structures of B, C and D.

CH3

O

H3C+NHNH2

NH

CH3

NHNH2 +

NHNH2+

DC11H10N2O4

BC12H12BrN

Br

O2N

O

C

data for C: C5H8O3, max(CHCl3) 1731 and 1751 cm-1, H 4.2 (2H, q), 2.2 (3H, s), 1.3 (3H, t)

A

(10 marks)

(b) Explain why the reaction of phenylhydrazine with butan-2-one may lead to two isomeric indoles. A full mechanism of the Fischer indole synthesis is not required, though you should give the key intermediates to explain your answer.

(5 marks)

(c) Using an appropriate example and reaction mechanism, describe one method

that can be used for the generation of nitrile oxides. (5 marks)

(d) For the following cycloaddition reactions involving 1,3-dipoles, identify EITHER

the structures of intermediate E and product F, OR the structures of intermediate G and product H. Indicate clearly the relative stereochemistry of

the product.

NNH

Ph Cl

NH2Ph

CO2Et

Me Me1. NaNO2 / HCl

2. NaN3 (sodium azide)

Et3NE

G

FC21H22N2O4

HC10H13N3

CO2Et

Ph

(5 marks)


4

Q4 Model answer (a)

NHNH2 +

NHNH2+

D

B

Br

O2N

O

1.3

(3H

, t)

NH

Br

NH

Br

O

O2N

O

O

O

O

1731 and 1751 cm-1

4.2

(2H

, q)

2.2

(3H

, s)

C = C5H8O3

(b) Tautomerisation of the hydrazone can lead to two different enamines, and thus two different indoles. Depending on the acid catalyst the ratio may be altered, though typically the more substiututed enamine is favoured.

NHNH2

+

O

NH

N

NH

NH

NH

NH

NH

NH

more substituted enamine

less substituted enamine

(c) E.g.

O

Ph

NHO

Ph

NHO

Ph

CNO PhH H Cl

NH2OHe.g.NCS

e.g.Et3N

NCS = N-chlorosuccinimide (d)

NNH

Ph Cl

NH2Ph

CO2Et

Me

Me1. NaNO2 / HCl

2. NaN3 (sodium azide)

Et3N

E

G

()-F

()-H

CO2Et

PhCO2Et

CO2Et

Me

Me

N

NN

N

N

Ph

Ph

Ph

N

N

Ph

Ph

N

N

N

Ph

cis

syn

anti

trans


5

4. Answer part (a) and three from parts (b)-(e).

(a) Consider the sequence below and identify compounds B, D, E and F.

BC6H13NO

AC

Et3N

DC6H11NO

EC10H17NO2

NCS = N-chlorosuccinimide

O

NH2OHNaOAc

NOH

ClNCS

ORaney-Ni, H2MeOH-H2OF

C10H18O3

(10 marks)

(b) Nitration of quinoline using a mixture of nitric and sulfuric acids gives a mixture of mainly 5-nitro and 8-nitroquinoline. Give an explanation as to why these isomers are formed preferentially.

(5 marks)

(c) When treated with 13C-labelled formaldehyde (methanal, *CH2=O) the indole derivative G undergoes a Pictet-Spengler reaction to give products H and H in which the labelled carbon (*) is found distributed equally between C1 and C4. Account for this observation.

NH

NMe

NMe

NH

NHMe

NMe

NH

NMe

NMe+

*

*

*

G

H2C=O

H H' (5 marks)

(d) Explain why the reaction of phenylhydrazine with cyclohexa-1,3-dione leads to

only one indole product I, as shown below. A full mechanism of the Fischer indole synthesis is not required, though you should give the key intermediates to explain your answer.

O

+NHNH2NH

O

O

H+

I

(5 marks)

(Question 4 continued overleaf)


6

(Question 4 continued)

(e) Work out the cycloaddition product of benzonitrile oxide (J) with (i) dimethyl maleate, K; (ii) dimethyl fumarate, L. Show clearly the stereochemistry in each

case.

CN

O

MeO2C

CO2Me

LJ

CO2MeMeO2C

K (5 marks)

Q4 Model answer

(a)

BC6H13NO

DC6H11NO

EC10H17NO2

FC10H18O3

NOH

H

NO N

OO

C5H11C5H11

O OH

O

(b)

N NH

H+

pyrido ring resistant to electrophilic attack

N

E

N

E

N N

E E

5

8

delocalisation of charge in intermediate arising from C5 or C8 attack provides stability without disrupting aromaticity of the pyrido ring (unlike with C6 or C7 attack)

E+

N N

E

E


7

(c)

NH

NMe

NMe

NH

NHMe

NMe

NH

NMe

NMe+

*

*

*

G

H2C=O

H H'

NH

NMe

NMe

H2C *

iminium ion

NH

NMe

MeN

*

electrophilic attack at C3 preferred!symmetrical intemediate formed

NH

NMe

NMe

H2C

*

position of isotopic label

scrambled

attack at C2 attack at C2

(d)

O

+NHNH2NH

O

O

H+

O

N

HN

symmetry in diketone means only one hydrazone possible

O

NH

HN

O

NH

HN>>

conjugated ene-hydrazine more stable than other possible isomer, hence only one indole formed

NH

O

X

(e)

MeO2C

CO2Me

CO2MeMeO2C

NOMeO2C

PhMeO2C

NOMeO2C

PhMeO2C

() syn isomer () anti isomercis alkene trans alkene


8

4. Answer part (a) and any THREE from parts (b) (e).

(a) Consider the reaction below and answer the following questions.

A

N

O

H

H

NHH2N

+

CH3CO2H

B

O

Cl C (23%)C16H17ClN2O

D (20%)C16H17ClN2O

+

(i) Work out structures for isomers C and D arising from the Fischer indole reaction between phenyl hydrazine A and ketoamide B.

(ii) Given that the major product is a pyrrolo[3,2-c]carbazole and the minor product is a pyrrolo[2,3-b]carbazole identify which of the structures you have drawn is C and which is D.

(iii) Using a brief mechanistic argument explain why two isomers arise from this reaction.

(4, 2, 4 marks)

(b) Given that in the Doebner-von Miller quinoline synthesis trans-but-2-enal and aniline react to give 2-methylquinoline (E), formulate the products F and G.

NH2

O

H3C+

O

H+

NH2

O

H

CH3

+NH2 N CH3

E

F

G

Cl

EtO2C

(5 marks)



9


(c) Using the example below, describe the advantages and disadvantages of the isoxazoline route to forming the -hydroxy ketone (aldol product) H.

NO

EtO2C

OH

Et

OEtO2C

EtPh

Ph

Ti3+ (aq)

N OPh

EtCH=CHCO2Et

H (5 marks)

(

(d) Using benzonitrile oxide (PhCNO), or an example of you own choice, describe one method that can be used to generate a nitrile oxide from a stable precursor.

Give a mechanism for the step in which the 1,3-dipole is generated. (5 marks)

(e) For the following cycloaddition reactions involving 1,3-dipoles, identify EITHER

the structures of intermediate I and product J, OR the structures of intermediate K and product L. Indicate clearly the relative stereochemistry of the product.

NNH

Ph Cl

NH2Ph

1. NaNO2 / HCl

2. NaN3

Et3NI

K

J(C17H12N2O3)

L(C14H17N3O4)

PhOO O

CO2EtEtO2C

(5 marks)


10

4. Answer part (a) and any THREE from parts (b) (e).

(a) Consider the reaction below and answer the following questions.

AB

O

O

O

H

HO

O

HON

H

H

O

O

H

H

O

HHO

reagents NaOCl

reagents

CC10H15NO3

DC10H15NO3

E

(i) Suggest reagents for the transformation A B.

(ii) Identify dipole C and cycloadduct D showing clearly any relevant

stereochemistry.

(iii) Suggest suitable reagents for the transformation D E, and give the product that would arise if D was reacted with H2 / Pd-C.

(1, 5, 4 marks)

(b) When treated with 13C-labelled formaldehyde (methanal, *CH2=O) the indole derivative F undergoes a Pictet-Spengler reaction to give products G and G in which the labelled carbon (*) is found distributed equally between C1 and C4. Account for this observation.

NH

NMe

NMe

NH

NHMe

NMe

NH

NMe

NMe+

*

*

*

F

H2C=O

G G'

(5 marks)

(c) Identify product J, which is obtained when phenylhydrazine (H) is reacted with ketone I in a Fischer indole reaction, and explain why only one structural isomer is formed. A mechanism of the reaction is not required, but you should show

relevant intermediate(s) to help justify your answer.

O+NHNH2

JC15H13N

H+

Ph

H I

(Question 4 continued overleaf) (5 marks)


11


(d) Given that in the Dbner-von Miller quinoline synthesis crotonaldehyde (trans-but-2-enal) and aniline react to give 2-methylquinoline (K), work out the structures of products L and M.

MeO

NH2 O+

BrO

H3C

+NH2

O

CH3

+

NH2 N CH3

K

LC11H11NO

MC12H12BrN

CH3

Et (5 marks)

(e) Indole N was heated with potassium carbonate in acetonitrile to give a low

melting point, crystalline solid, O. Derive the structure of O and explain its formation.

NH

K2CO3, MeCN

N

OC10H9N

Br

(5 marks)


12

Q1c (compulsory)

Consider the sequence below and answer all of the following questions:

J

NH2

CH3

NH

CH3

O

CH3NH

CH3

CH3

O

OEt

N

CH3

Cl

CH3

H+

40 oC 150 oC

POCl3

LK

NC12H13ClN2

MC11H9Cl2N

Cl2CH3NH2

heat

I +

(i) Identify a suitable reactant I that may be used to convert J into K.

(ii) Work out the structure of L, an isomer of L, which is formed when application of the reaction conditions in the first two steps is reversed.

(iii) Work out the structures of products M and N.

(2, 4, 4 marks)

Q4 (optional) 4. Answer THREE of the following parts (a) to (d).

(a) Draw the cycloaddition product of benzonitrile oxide (A) with (i) dimethyl maleate (B); (ii) dimethyl fumarate (C). Show clearly the relative

stereochemistry in each case.

CN

O

MeO2C

CO2Me

CO2MeMeO2C

BA C (5 marks)



13


(b) Consider the scheme below and work out the structure of Pictet-Spengler product E. Explain briefly why the particular isomer identified is formed preferentially.

N

NC

Ph

H+

D

E

OMe

C23H20N2O

(5 marks)

(c) Explain why the reaction of the phenylhydrazine F with cyclohexa-1,3-dione (G)

leads to only one indole product, H. A mechanism of the Fischer indole synthesis is not required, but key intermediates should be drawn.

O

+NHNH2NH

O

O

H+

HGF

MeO

MeO

(5 marks)

(d) Consider the following scheme and work out the structure of I (including stereochemistry). Suggest reagents needed to convert I into J.

IC13H17NO285 oC

reagents

J

N O

MeO

OH

MeO

NH

(5 marks)

q4 06710-12-14 qs and as

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