January 2008 Heterocyclic Chemistry: Exam Questions and Model Answers

4. Answer ALL of the following parts.

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

O
N CO2Me
C

MeO2C CO2Me MeO2C

benzonitrile oxide dimethyl maleate dimethyl fumarate

(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:

MeO MeO
MeO step 1 H+
N NH
NH2 step 2
A Ph B Ph

(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 N H2
O C Pd-C D
85 C o C14H19NO2 C14H21NO2
OMe max 3400 cm-1
(broad)

(4, 3 marks)

1
January 2008 Heterocyclic Chemistry: Exam Questions and Model Answers
Q4 Model answer

(a) (i)
HO e.g. HO e.g.
O NH2OH N NCS N Et3N
H H Cl O N C Ph
Ph Ph Ph
NCS = N-chlorosuccinimide
(ii)
MeO2C O CO2Me MeO2C O
N N
MeO2C CO2Me
MeO2C Ph MeO2C MeO2C Ph
cis alkene () syn isomer trans alkene () anti isomer

(b)
MeO MeO
MeO step 1 H+
N NH
NH2 step 2
A Ph B Ph

(i) PhCHO / catal. H+.

(ii) Mechanism for step 2.

MeO MeO MeO
H+ MeO
N NH NH
NH
Ph Ph H Ph
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.
H
Ph N

MeO

(c)
exo attack
H H
Me N Me H2 Me N
N H
O O Pd-C
OH
85 oC H H
OMe OMe OMe -1
max 3400 cm
C D

2
January 2009 Heterocyclic Chemistry: Exam Questions and Model Answers
4. Answer all of the following parts.

(a) In the Fischer indole synthesis acetone and phenylhydrazine (PhNHNH 2) react
to give 2-methylindole (A). Using this fact and the data for C provided, work out
the structures of B, C and D.

O
NHNH2 + A
H3C CH3
N CH3
H

Br
O B
+ C12H12BrN
NHNH2

O2N NHNH2 D
+ C C11H10N2O4

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

(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.

Ph CO2Et

NH Et3N
N CO2Et F
E
C21H22N2O4
Ph Cl

Me Me
1. NaNO2 / HCl
G H
Ph NH2 C10H13N3
2. NaN3
(sodium azide)
(5 marks)

3
January 2009 Heterocyclic Chemistry: Exam Questions and Model Answers
Q4 Model answer
(a)
Br
O
+ N
NHNH2 H
Br
B
1731 and 1751 cm-1
O O2N
O2N NHNH2 + O

1.3 (3H, t)
O
N

4.2 (2H, q)
2.2 (3H, s)
O H
Br O
D

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.

more substituted enamine

NHNH2 N N N
H H H
+
N N
H

O N
N N
H H H
less substituted enamine

(c) E.g.
HO e.g. HO e.g.
O NH2OH N NCS N Et3N
H H Cl O N C Ph
Ph Ph Ph
NCS = N-chlorosuccinimide
(d)
Ph Ph CO2Et Ph
N CO2Et
N
NH Et3N N syn
N CO2Et
N
CO2Et
cis Ph
Ph Cl
Ph ()-F
E
Me

N Me
N
1. NaNO2 / HCl N Me anti
N
Ph NH2 N trans N Me
2. NaN3
(sodium azide) Ph Ph
G ()-H

4
January 2010 Heterocyclic Chemistry: Exam Questions and Model Answers
4. Answer part (a) and three from parts (b)-(e).
(a) Consider the sequence below and identify compounds B, D, E and F.

NH2OH Cl
NaOAc B NCS
O C6H13NO NOH
A C
Et3N
O
Raney-Ni, H2
F MeOH-H2O E D
C10H18O3 C10H17NO2 C6H11NO

NCS = N-chlorosuccinimide

(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.

*
NMe
H2C=O
NMe
*
+ NMe
N NHMe NMe NMe
N N
H G H * H 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
O
H+
NHNH2 +
N
O H
I

(5 marks)

(Question 4 continued overleaf)

5
January 2010 Heterocyclic Chemistry: Exam Questions and Model Answers
(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.

O
N CO2Me
C

MeO2C CO2Me MeO2C

J K L
(5 marks)

Q4 Model answer

(a)
O O OH
H O
O N O
N
NOH
C5H11 C5H11
B D E F
C6H13NO C6H11NO C10H17NO2 C10H18O3

(b)
5
H+
pyrido ring resistant
to electrophilic attack
N N
8 H
E+
E E

N N N N
E E
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)

N E N

6
January 2010 Heterocyclic Chemistry: Exam Questions and Model Answers
(c)
*
NMe
H2C=O
NMe
*
+ NMe
N NHMe NMe NMe
N N
H G H
H
* H
H'
attack at C2 attack at C2

Me
N
NMe *
NMe NMe
N H C NMe N
* NMe
* N H C
H 2 H H 2

iminium ion electrophilic attack at C3 preferred! position of

symmetrical intemediate formed isotopic label
scrambled

(d)
O
O H+
NHNH2 +
N N O
O H H

X
O O O

H H H
N
N
N
N >> N
N
H H

symmetry in diketone means conjugated ene-hydrazine more stable than other

only one hydrazone possible possible isomer, hence only one indole formed

(e)
MeO2C O CO2Me MeO2C O
N N
MeO2C CO2Me
MeO2C Ph MeO2C MeO2C Ph
cis alkene () syn isomer trans alkene () anti isomer

7
January 2011 Heterocyclic Chemistry: Exam Questions and Model Answers
4. Answer part (a) and any THREE from parts (b) (e).

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

Cl C (23%)
H2N C16H17ClN2O
NH O CH3CO2H
+ N +
H

H D (20%)
C16H17ClN2O
O
A B

(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.

O
+ H E
NH2 N CH3
CH3

EtO2C O
+ F
H3C
NH2

O
Cl
+ H G
NH2 (5 marks)

(Question 4 continued overleaf)

8
January 2011 Heterocyclic Chemistry: Exam Questions and Model Answers
(Question 4 continued)

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

EtO2C O OH O
EtCH=CHCO2Et Ti3+ (aq)
N
Ph N O EtO2C Ph
Et
Ph Et 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.

Ph
O O O
NH Et3N
N I J
(C17H12N2O3)
Ph Cl

EtO2C
1. NaNO2 / HCl CO2Et
K L
Ph NH2 (C14H17N3O4)
2. NaN3

(5 marks)

9
January 2012 Heterocyclic Chemistry: Exam Questions and Model Answers
4. Answer part (a) and any THREE from parts (b) (e).

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

H H
O reagents O NaOCl
C
O O HON O C10H15NO3
H H
B
A

HO
H H
reagents D
O C10H15NO3
O
O
H
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.

*
NMe
H2C=O
NMe
*
+ NMe
N NHMe NMe NMe
N N
H F H * G H 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 H+ J
NHNH2 + Ph C15H13N

H I

(Question 4 continued overleaf) (5 marks)

10
January 2012 Heterocyclic Chemistry: Exam Questions and Model Answers
(Question 4 continued overleaf)

(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.

O
+
NH2 CH3 N CH3

NH2 O CH3 L
+
C11H11NO
MeO

Br
O
NH2 M
+
C12H12BrN
H3C
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.

K2CO3, MeCN
Br
O
N C10H9N
N H
(5 marks)

11
January 2013 Heterocyclic Chemistry: Exam Questions and Model Answers
Q1c (compulsory)

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

O O
H+
40 oC OEt 150 oC
I +
NH2 N CH3 N CH3
H H
CH3 CH3 CH3
J K L
POCl3

Cl
CH3NH2 Cl2
N M
C12H13ClN2 C11H9Cl2N
heat N CH3
CH3

(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.

O
N CO2Me
C

MeO2C CO2Me MeO2C

A B C
(5 marks)

(Question 4 continued overleaf)

12
January 2013 Heterocyclic Chemistry: Exam Questions and Model Answers

(Question 4 continued)

(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.
OMe

H+
NC C23H20N2O

N E
D
Ph
(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 O

H+
NHNH2 +
O MeO N
H
MeO F G H
(5 marks)

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

OH
N O
I reagents N
H
o
85 C C13H17NO2
MeO MeO J
(5 marks)

13
January 2014 Heterocyclic Chemistry: Exam Questions and Model Answers
Q1c (compulsory)

Consider the scheme below and identify the structures of H, I, J and K.

NH2OH Cl
NaOAc H NCS
O C3H7NO NOH

Et3N

K Ti3+ (aq) J
Ph H
I
C11H12O2 C11H11NO C3H5NO

NCS = N-chlorosuccinimide
(10 marks)

Q4 (optional)

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

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

MeO MeO

HN O N

A Ph B Ph

(i) Give a suitable reagent to convert A into B.

(ii) What would happen to the rate of reaction if the methoxy group in A was
replaced by a nitro group? Explain your answer.
(iii) An alternative product to B may be formed in theory. Draw this product and
explain why it is not formed in practice.
(5 marks)

(b) In the Fischer indole synthesis acetone and phenylhydrazine (PhNHNH2) react to
give 2-methylindole. Using this information work out the structures of C and D.
O
Br
C
+ C14H10BrN
NHNH2
O

O2N NHNH2 D
+
C14H14N2O3
O

(5 marks)
(Question 4 continued overleaf)

14
January 2014 Heterocyclic Chemistry: Exam Questions and Model Answers

(Question 4 continued)

(c) Describe how the nitrone E may be prepared from simple precursors and show the
cycloadduct formed when it is reacted with cyclopentene.

N
Ph O
E
(5 marks)

(d) Use the following example to discuss the regioselectivity of nucleophilic substitution
in chloroisoquinolines.

Cl Cl Cl Cl Cl NHR2
R1-NH2 R2-NH2
N heat N heat N

Cl NHR1 NHR1

(5 marks)

15
January 2015 Heterocyclic Chemistry: Exam Questions and Model Answers
Q1c (compulsory)

Consider the scheme below and answer the following questions:

(i) Draw cyclic nitrone I.

(ii) Draw cycloadduct J and give a mechanism to show its formation from nitrone I
and phenylacetylene (phenylethyne).

(iii) Identify reduction products K and L, and assign the IR data.

(2, 3, 5 marks)

Q4 (optional)

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

(a) Work out the structures of 1,3-dipoles A and B, and either cycloadduct C or
cycloadduct D. Indicate clearly the stereochemistry of the product chosen.

1. NaOCl Me
OH Me
N 2. Et3N
A C
C11H13NO
Ph
O
1. NaNO2 / HCl
B D
Ph NH2 C11H11N3O
2. NaN3
(sodium azide)
(5 marks)

(Question 4 continued overleaf)

16
January 2015 Heterocyclic Chemistry: Exam Questions and Model Answers

(Question 4 continued)

(b) Identifying G, H and J, explain why the Fischer indole reaction of phenylhydrazine (E)
with ketone F gives G and H, whereas reaction with ketone I only gives one product,
J. Mechanisms are not required.

O CH3CO2H G H
NHNH2 + C16H19N
+
C16H19N
E F

O CH3CO2H J
NHNH2 + C16H13N
E I (5 marks)

(c) When treated with benzaldehyde (PhCHO) in acidic conditions, indole K gives
tricycle L. Giving a mechanism, derive the structure of this product.

MeO

NHMe PhCHO / H+
L
Pictet Spengler C19H20N2O
N
H reaction
K
(5 marks)

(d) When treated with strong acid the isotopically labelled indole derivative M undergoes
a cyclisation reaction to give products N and N in which the labelled carbon (*) is
found distributed equally between C1 and C4. Account for this observation.

* H
*
+
N OH N * N
H M H N H N'

(5 marks)

17