HETEROCYCLES: "molecular rings studded with jewels"

CH3
N
NEt2
HO HN
H
MeO

Cl N
N

QUININE CHLOROQUINE
natural product - antimalarial synthetic antimalarial

MeO H3C
N
N
MeO

N
H CH3

OMe
PAPAVERINE ELLIPTICINE
smooth muscle relaxant OMe
anti-tumour agent
and vasodilator

O
Me
H H
N N

NH
N O
MeO H
N O
H N

LYSERGIC ACID
DIETHYLAMIDE
FUMITREMORGIN C semi-synthetic compound with
reverses multidrug resistance psychadelic properties
in cells transfected with BCRP

1
 SOME HETEROCYCLES IN THIS COURSE

N
N H
PYRIDINE PYRROLE

N N O
H N
H
QUINOLINE 2-QUINOLONE 4-QUINOLONE

N
N
N N
H H

ISOQUINOLINE INDOLE β-CARBOLINE

O H O
N
N N NH

ISOXAZOLE PYRAZOLE ISOXAZOLIDINE

Fusion of simpler aromatics can form new poly(hetero)cycles in which the

reactivity of each ring , in general, is very similar to the individual ring systems.
However some changes in regioselectivity of reactions are observed.

2
 DEMYSTIFYING HETEROCYCLE NOMENCLATURE

Cl
CH3

(4aS, 8aR)-4-chloro-4a-methyl-8a-phenyl-
4a,7, 8, 8a-tetrahydroisoquinoline
N

Ph

5 4
6 4a 3

7 8a N 2
N N
8 H H
1
QUINOLINE 1,2-DIHYDROQUINOLINE 1,2,3,4-TETRAHYDRO
QUINOLINE
5 4
6 4a 3

7 N2 N
8a
8 1
ISOQUINOLINE 3,4-DIHYDROISOQUINOLINE

* Numbering starts adjacent to the bridgehead closest to the atom of highest priority.
* Prefix "hydro" indicates a (partially) reduced ring system with numbers say where the
reduced bonds(s) is (are).
* Quaternary bridgehead atoms in parent heterocycles given an "a" suffix e.g. 4a, 8a etc.

1 1 1
O O 5 O
5 5 2
N2 N2 NH
4 4 4
3 3 3
ISOXAZOLE ISOXAZOLINE ISOXAZOLIDINE
(4,5-dihydroisoxazole) (tetrahydroisoxazole)

H H 1H
N N1 5 N 2
5
N N2 NH
4 4
3 3
PYRAZOLE PYRAZOLINE PYRAZOLIDINE
(4,5-dihydropyrazole) (tetrahydropyrazole)

3
DEMYSTIFYING HETEROCYCLE NOMENCLATURE
POLYHETEROCYCLES - SOME BRIEF RULES

4 3 4
3 4 3a 5 3
5 4a 3a
2 2
2 6
5 6
N 7a N N N
H 1 7 H 7H 7a 8a H
1 8 1
PYRROLE INDOLE PYRROLOINDOLE

Naming is based upon individual ring systems within the polyheterocycle.

minor ring[number, number-letter]major ring

pyrrolo[number, number-letter]indole

* The letter defines the position of attachment of the minor ring to the major ring
* The numbers indicate which atoms in the minor ring are common to the major ring.
* The order of the numbers indicates which atom of the minor ring is encountered
closest to atom 1 in the major ring numbering system.
* The numbering system for the final polycycle is not the same as the numbers in the
square brackets.

( )n

( )n
N N
N

.....-a]quinolinium .....-b]quinoline .....-d]4a,8a-dihydroisoquinoline

NH
H 1
N 4 2
b 3 1 3
2 1 b 2 c
3
N N
H N
N

pyrrolo[2,3-b]pyridine pyrrolo[3,2-b]pyridine pyrrolo[3,4-c]pyridine

4
CLASSIFICATION OF RING FORMING REACTIONS
Classification is based upon the number of bonds formed (usually I or II) and letter(s) -
the same as those which are used to define the position of attachment of a minor ring to
a major ring in polyheteocycle nomenclature.

R R
IIeg
N
H
R R
N Ia N IIac

R R R
Ib e d c
b
R f R R
a
N g h i N
H N IIab
INDOLE

R
Ic
R
Id
R N
H
Ih
N
R
N
H

Some cyclization reaction types which have been used to make indoles

5
 CYCLIZATION REACTIONS
Cyclizations are stepwise reaction going through one or more intermediates, involving the
expulsion of a small molecule such as an alcohol or water.

Reagents encountered have either one or more electrophilic centers.......

O O O
δ+ δ+ δ+
R H R R OEt

R
or nucleophilic centers......
δ-
XH
δ-
δ-
δ- R NH2
XH XH
δ- δ-

O
or both X = O, S, NR
δ+ O
R H2N δ+
δ- δ- OEt
XH R

Matching the polarity of electrophilic and nucleophilic centres often gives a good clue as to
the way in which molecules can be 'knitted together'. Analogies can then be made between
say nitrogen and oxygen heterocycles.

O δ+
C
δ- C
δ+ C δ-
δ- C δ+
δ- C δ+ NH2
NH2

C
C
C
N
H

6
 SOME KEY REACTIONS: a refresher
Reations already encountered in Year 1 and 2 are fundamental to classical heterocyclic
chemistry, where precursors and final products are built up in a stepwise fashion via
identifiable (and often isolable) intermediates. Other examples will include Claisen and aldol
reactions etc. Detailed mechanisms for these can be found in earlier notes or standard texts.

AMIDE formation

O O O
-R2OH
+ H2N R3 R3 + H2N R3
R1 Cl R1 N R1 OR2
H

IMINE / ENAMINE formation

O -H2O H H
tautomerization
+ H2N R3 R3
R3 R1CH N
R1CH2 H R1CH2 N H

FRIEDEL CRAFTS-LIKE ALKYLATIONS

O OH
cat.
H+ -H2O

N N N
H H H

FRIEDEL CRAFTS-LIKE AROMATIC ACYLATIONS

O
RO2C
heat
N -EtOH
H N
H

CONJUGATE ADDITION REACTIONS

H
OH O
HO
H H

NH2 N N
H2 H

7
 WHAT WILL I NEED TO KNOW?
KEY LEARNING OUTCOMES

1. Distinguish between cyclization and cycloaddition reactions

2. Be able to identify, draw and be familiar with the names of the classes of bicyclic and
polyheterocyclic molecules covered in the course (not detailed nomenclature)

3. Formulate products arising from cyclization reactions

i.e. Work out what heterocycle is produced from a given set of reagents

4. Draw the mechanism of cyclization reactions

i.e. Give a detailed sequence of selected mechanisms from the course

5. Describe some reactions of bicyclic and polyheterocyclic systems

6. Describe the influence of reaction conditions on product distribution

7. Thermodynamic and kinetic effects in cyclization reactions

8. Effect of substitutents: rates of reaction and isomer distribution

MAIN HETEROCYCLES COVERED

QUINOLINES
QUINOLONES
ISOQUINOLINES
INDOLES
ISOXAZOLES AND ISOXAZOLINES
PYRAZOLES AND TRIAZOLES
ISOXAZOLIDINES

An overall hope is that you will take away some concepts regarding heterocycle formation
and be able to recognize and apply these in the syntheses and reactions of other heterocycles
not specifically covered in this course.

8
CLASSICAL METHODS OF SYNTHESIZING QUINOLINES
The most obvious starting material for making a quinoline is aniline (aminobenzene) as this
and substituted variants can be readily obtained (e.g. via the sequence of nitration and NO2
reduction).

Skraup Synthesis of Quinolines (1880)

C OH
HO C
C
NH2 HO N

Doebner-von Miller Variation of the Skraup Synthesis (1887)

R3 R3
C R2 R2
O C
NH2 C N R1
R1

Friedlaender Synthesis of Quinolines (1882)

O H R R3
2
C H C R2
R3
C
O R1
NH2 N R1

Conrad-Limpach Synthesis of Quinolones (1887)

O R
O O
C C and/or
NH2 R C OR1
N R N O
H H

Combes Synthesis of Quinolines (1888)

O R1
C R1
C
NH2 C R1
O N R1

This reaction will not specifically covered. The mechanism is basically like the first
half of the Friedlaender method (imine formation) and second half of the Skraup
(acid-catalyzed condensation of the second ketone with the aromatic ring).

9
 Skraup Synthesis of Quinolines

Overall transformation
PhNO2 5 4
OH 6 4a
HO c. H2SO4 3
R R
7
NH2 HO 130 oC 8a N 2
8
1

H
H
OH H H
HO O tautomerize
glycerol acrolein
O
HO -H2O HO -H2O
H
Glycerol is dehydrated in situ to give acrolein.

Mechanism H
O
H
OH O
H -H
H H
NH2 tautomerize
N N
H2 H

OH OH OH
H
re-aromatize
H
N -H N
H H N
H

+H -H2O

oxidation*

N N
H

*oxidation can be acheived in situ by using nitrobenzene as co-solvent or by

using an oxdxant such as iodine or an iron(III) salt.

10
 Doebner-von Miller Variation of the Skraup Reaction

Overall transformation R3
R3
R2 R2
O
NH2 N R1
R1

* Uses pre-formed α,β-unsaturated carbonyl compounds instead of acrolein

* Used to provide alkyl and aryl substituents in the "pyridine half" of the quinoline
* The intermediate β-aminocarbonyl compound can be isolated.
* Shows the mechanism starts with a conjugate addition.

R3
R2 O
O
1,4-addition R2
R3
R1
NH2
N R1
H
R1
R2 1,2-addition R1
R2
NH2
O R3 X
N R3

H
crotonaldehyde
O O

CH3 H
NH2 N CH3
N CH3
H 2-methylquinoline
(quinaldine)
CH3 methyl vinyl ketone
O CH3
O
CH3
NH2 N
H N
4-methylquinoline
(lepidine)

11
 Skraup / Doebner-von Miller Syntheses:
using substituted anilines

para-substituted aniline
O
O
R R R

NH2 N N
H
6-substituted isomer
both positions ortho to the R R
amine are equivalent R
NH N
N
O

ortho-substituted aniline
O 8-substituted isomer
O

H
NH2 N
N
R H R
R

can only cyclize to the unsubstituted ortho position

meta-substituted aniline - electronic and steric factors influence cyclization orientation

O
7-substituted isomer
O
favoured

R NH2 if R is +M R N
R N
H +
can cyclize to either ortho
positions but this gives rise 5-substituted isomer
to two possible isomers R
favoured
R NH R N
if R is -M
O N

Rate of Reaction: as the ring acts as a nuclophile to attack the protonated aldehyde (see
previous slide), an electron withdrawing group R group slows the rate of cyclization whereas
an electron donating group increases the rate of cyclization.

12
 Conrad-Limpach Synthesis of Quinolones

Overall transformation
O CH3
O O

H3C OEt and/or

NH2 N CH3 N O
β-ketoester H H

water must be removed using

Mechanism a Dean-Stark trap or MgSO4 O O

H3C OEt
between RT and 110oC
NH2
CH3 O cat. H -H2O
N OEt imine formation is still
150oC
faster, but reversible
imine-enamine -EtOH
if water is not removed
tautomerization

O thermodynamic OH

EtO kinetic product H3C

product
N CH3 N O
H H

Ph2O, heat +H c.H2SO4

~250 oC

EtO O HO CH3
H H

N CH3 N O
H H

-H -EtOH -H -H2O

O CH3

N CH3 N O
H H
4-quinolone 2-quinolone

13
 Friedlaender Synthesis of Quinolines
Overall transformation
O H R3
R2
H R2
R3
O R1
NH2 N R1

Mechanism - using an unsymmterical dialkyketone as an example

CH3
CH3 -H+ / -H2O
H CH3 base conditions and
imine formation O
O H lower T leads to
O CH3 N kinetic product
NH2 CH3
H3C

c. H2SO4, AcOH, ∆ aq. KOH,EtOH, 0 oC

different reaction
acid conditions and conditions will
higher T leads to OH
alter ratio of
O
themodynamic product enamines formed
CH3 CH3

NH N
CH3 CH3
H3C H2C

more substituted enamine less substituted azaenolate

(thermodynamic product) (enamine anion) (kinetic product)

acid catalyzed base catalyzed

aldol-like reaction aldol-like reaction

HO CH3 H3C O
CH3
H
N CH3 N CH2CH3
H

-H -H2O -H2O

CH3 CH3
CH3

N CH3 N CH2CH3

Product distribution is dependent on both reaction conditions and the ketone used (see
Fischer indole synthesis for a related discussion). Even different acids (i.e acid strength)
can produce different product ratios.

14
CLASSICAL METHODS OF SYNTHESIZING ISOQUINOLINES
Arylethylamines
The most common starting material for making isoquinolines are arylethylamines.
These can be readily obtained via chemistry already encountered (see Year 2
bifunctional chemistry notes).

O NO2 NH2
Nitro aldol LiAlH4
CH3NO2
the 'Henry
reaction'

O NaNO2 O O OH
O
HCl N NOH LiAlH4 NH2

via enol

Pictet Spengler Synthesis of (tetrahydro)Isoquinolines

Overall transformation
O
NH
NH2 R
R

Mechanism of the Pictet Spengler reaction

MeO MeO MeO

-H2O H
NH2 N NH
O R R
IMINE
R

MeO [O] MeO MeO

-H
N NH NH
H
R R R
1,2,3,4-tetrahydro- rate of cyclization accelerated
isoquinoline by a +M group ortho or para to
the position of ring closure.
isomer arising from attack
para to the +M group

15
 Bischler Napieralski Synthesis of Isoquinolines

Overall transformation
O
N
NH2 R Cl
R

Mechanism * alternatives are P4O10 or PCl5

R1 O R1 *POCl R1
base 3
NH2 R Cl HN R N R

O Cl
AMIDE

Pd-C
R1 R1 R1
190 oC -HCl
N N N
H
R R R Cl
isoquinoline 3,4-dihydroisoquinoline

separate oxidation to the fully isomer arising from attack

aromatic heteocycle can be para to the R1 group is formed
achieved with a variety of reagents exclusively due to steric factors

Reaction Cyclization precursor Oxidation state of product

Pictet Spengler imine tetrahydroisoquinoline
Bischler Napieralski and amide dihydroisoquinoline
Pictet-Gams modification amide + hydroxyl isoquinoline
OH
latent double bond
e.g. (elimination of H2O)
HN R

Reaction with substituted arylethylamines can produce isomeric isoquinolines (c.f.

Skraup reaction). Also rate of cyclization is increased with electron donating
groups in the aromatic ring.

16
 Pomerantz Fritsch Synthesis of Isoquinolines

Overall transformation
EtO OEt
R
R or R
H2N NH N
O

Mechanism:
(c) OEt (d)
EtO OEt c. H2SO4
R -H2O OEt
R R
N N
(a) H2N
O
isoquinoline
(b) IMINE
H2 / Pd-C
H
OEt OEt OEt
H2O
-EtOH H
OEt HCl O
R R R
NH H2O NH NH H
H

-H+
- EtOH
OH OH
H+ H
+
-H2O -H OH
R R R R
NH NH NH NH

1,2-dihydroisoquinoline 1,2,3,4-tetrahydroisoquinoline

(a) Electron releasing groups, R, preferred - c.f. previous reactions

(b) Not useful for aromatic ketones as imine formation is difficult.
(c) Diethyl acetal is a "protected" form of an aldehyde.
(d) Yields variable as the imine is prone to hydrolysis back to the amine and aldehyde.

17
 Reactions of (iso)Quinolines
benzenoid ring: pyrido ring:
More susceptible to electrophilic substitution Lone pair is readily protonated/coordinates to
but resistant to nucleophilic substitution Lewis acids so deactivating the pyrido ring.
N More resistant to electrophilic substitution but
susceptible to nucleophilic substitution.

Electrophilic aromatic substitution NO2

H2SO4, HNO3
1:1
N 0 oC N N
NO2 NO2
H2SO4, HNO3
N 9:1 N
N 0 oC
Br Br
NO2
Br2, AlCl3

N 80 oC N N N
44% 25% 8%
Br Br Br
Br2, AlCl3
N 75 oC, 78% N

Substitution next to a bridgehead position is favoured. This maximises the resonance delocalization
in the intermediate without disrupting aromaticity of the second ring. This is a common idea used to
explain regioselectivity of such reactions in polycyclic aromatic systems.

Nucleophilic aromatic substitution X = O or NH

Displacement of halogens ortho or para to the nitrogen. RONa or
Also works with stablized enolates as nucleophile (e.g.
malonates and related 1,3-dicarbonyl enolates). N Cl RNH2 N XR

Cl OR
RONa RONa or
N N N N
RNH2
-Cl Cl XR

Cl XR
Cl Cl
OR RONa or
OR
N N RNH2
N N

delocalization of the charge to N

disrupts the aromaticity of the Cl Cl OR
second ring. More forcing
RNH2 RONa
conditions are therefore needed
N N N
for the displacement of a 3-
chloro group in an isoquinoline
Cl NHR NHR
1-chloro displaced first

18
 Further Reactions of (Iso)quinolines
Synthesis of chloro(iso)quinolines
(iso)Quinolones (from Conrad-Limpach) can be chlorinated with POCl3 or PCl5
Cl
P
Cl Cl Cl Cl O O
Cl Cl P P
O Cl P Cl O O Cl O O Cl
O POCl3

heat N
N N N
H
H H

POCl3 POCl3
also and N N
N O heat N Cl H heat
H O Cl

Acidity of 2-alkylquinoline - analogous reactions for 4-alkyl isomer

NaOEt PhCO2Et O
EtOH
N N N Claisen N Ph
H
OEt

KNH2
Et-Br

N N N N
H
NH2

DMFDMA/heat NMe2
NMe2
OMe
N N N OMe
NMe2
H
OMe +
OMe

heat
-H NMe2
NMe2
N NMe2 N
MeO OMe H

DMFDMA, dimethylformamide dimethyl acetal, decomposes

on heating to give methoxide and a Mannich-type electrophile.
(see also the Reissert indole synthesis later on)

19
 Fischer Indole Cyclisation

Overall transformation
4
H R1
5
3a
R1
R 3
R H 6 2
NH-NH2 2 7 7a N1 R2
O R
H

Mechanism H R1
H

O R H R1 H+ (cat) R1
H
-H2O
NH-NH2 N N R can also be N N R
H calalyzed using H H
aryl hydrazone formation Lewis acids
cf imine formation
R1 R1
R1 H
R H+ transfer R
R NH2 NH
N NH2 NH2 NH
H2
H+
re-aromatization
H+ transfer

R1 -NH3 H R1 R1
-H+

R R
N N N R
H NH3 H H

Japp-Klingemann route to aryl hydrazones

O O A procedure using aryldiazonium salts and β-keto esters or carboxylates.
Method also works with a variety of similar 1,3-dicarbonyl and related species.
R OR2
CH2R1 HO O
O R1
KOH CO2Et R1CH2
EtOH OEt R
R OEt
reaction via R2 = Et R1CH2 N N
NH N
the enolate O O N H O
Ar Ar

R OR2 O O O
CH2R1 R1
R2 = Na R1CH2 R
R O R
Ar N N N R
R1CH2 N
NH N
(diazonium salt N H
formed separately) Ar Ar O

20
 Fischer Indole Cyclisation - examples

MeO
MeO MeO Ph Ph
Ph
O
NH-NH2 H N N N
H H H
aldehyde only one tautomer can form

( )n ( )n
O
( )n N N N
NH-NH2
H H Me H
Me Me
symmetrical cyclic ketone only one tautomer can form

Ph Ph
Ph
O Et Et
NH-NH2 Et N N N
H H H
unsymmetrical cyclic ketone one tautomer favoured due to conjugation

O O
O O
O
O
O
O NH-NH2 O N N N
O H H H
symmetrical cyclic diketone one tautomer favoured due to conjugation cyclization to para
to O preferred

Br
Br CH3 CH3
A
N N CH3 CH3
N
Br CH3 H H H
which tautomer is formed
O
depends on conditions
NH-NH2 CH3 Br
Br B
CH2
unsymmetrical ketone CH3 CH3
N N N
H H H
A:B
100 : 0 AcOH
50 : 50 polyphosphoric acid
22 : 78 P4O10 - MeSO3H

21
 Leimgruber-Batcho and Reissert Indole Syntheses
Overall transformations
CH3 i, heat R
R + (MeO)2CHNMe2 Leimgruber-
NO2 ii, H2 / Pd-C Batcho
N
H

CH3 i, EtOK/EtOH R Reissert

R + (CO2Et)2
ii, H2 / Pd-C N CO2Et
NO2
H

These methods both rely on the acidity of the methyl protons ortho to the electron
withdrawing nitro group. The resulting conjugate base can be stabilized by resonance.

CH2 CH2 CH2

Electron withdrawing
R R R groups R increase the
O O O
N N N acidity of the CH3.
O O O

Reaction outline <

NMe2
Me EtOK/EtOH O
CH3
N MeO OMe (CO2Et)2
Me OEt
heat NO2 Claisen-like O
NO2 reaction NO2

H2, Pd/C H2, Pd/C

Me Me O
N N
Me Me OEt
O
NH2 NH2 NH2

imine -H2O
formation

These latter stages are in many ways

NMe2 similar to the last stages of the CO2Et
N Fischer Indole Synthesis N
H

-HNMe2 tautomerization

CO2Et
N N
H H

< see Aromatic Heterocyclic Chemistry, D.T. Davies, Oxford Primer No. 2, p 56
see also handout 'further reactions of (iso)quinolines' for a related reaction

22
 Reactivity of indole
facile electrophilic substitution Lithiation of N-
at C3; reaction at C2 if C3 substituted
E blocked derivatives N Li
occurs at C2 R
E -H
N
H -H R1
R

H H N N N
H
H R
indoles are very indolyl anion indolyl anion N R1
N weakly basic and generated by reacts to provide
protonate at C3 deprotonation N-substituted R
H
derivatives

Electrophilic reactions of indole

comparison with pyrrole
Pyrrole reacts preferentially with electrophiles at C2 and then C5. This maximises the
resonance forms in the intermediate (greater charge delocalization making it more stable).
Indole however reacts preferentially with electrophiles at C3. Reaction at C2 would mean
disruption of the aromaticity in the benzene ring during charge delocalization.

H H -H+
H
N E N E N E N E
H H H H
E
N
H H H E
E E -H+

N N N
H H preferred H

O O
NO2 Br
N Br2 / pyridine
Ph O O

N Me N Me N
generates +NO2 under H N
H H H
neutral conditions 35% 64%

The Vilsmeier formylation

Cl Me H Cl Cl
HCONMe2 N H aq
POCl3 CHO
H Me NMe2 NMe2 NaOH

N N N N
H generates H H H
97%

23
 Electrophilic Reactions of indole
Initial protonation at C3 with strong acid can lead to some more unusual reaction.
semi stable adduct
H+ c. H2SO4 H O2N
H
c. HNO3 H H nitrates
Me Me Me like an
N N N Me
H N
H H OSO3H aniline
84% H

Me c. HCl H H
H+ DMSO Me Me -Me2S H Me
H
N N N O -H+ O
H H N
O H S H
c.f Swern oxidation
S probably via ylid

Reactions of indole with aldehydes and iminium salts

H+
indolium cation
O R R R
H
OH H+
H R OH

N N N N X
H H H H
not isolable isolable

R R excess
-H+ H indole :
bis indole reacts at
C3 too!
HN NH HN NH

H+ / HNMe2 H gramine
NMe2
CH2O H NMe2
H
NMe2 MeI NMe3
X
N generates N N isolable N
H H H H
"Mannich reaction"
R2 70-115 oC
R2
R1
R1 = H, R2 =NO2 R1
R1 = CO2Et, R2 =CO2Et N N The NMe3 group
R1 = CO2Et, R2 =NO2 H H can be displaced
with a wide variety
of nucleophiles via
CN CN the indolium cation
N
H

24
 The Indole Pictet Spengler Reaction

Synthesis of tetrahydro-β-carbolines

overall transformation
i) RCHO, weak H+ cat.
NH2 ii) CF3CO2H NH
N N
H H R

imine formation
Dean-Stark trap
NH2 N
N - H2O N
H H R

CF3CO2H (strong H+ cat.)

NH+
N R
H
2
attack at C attack at C3

NH
NH spiro intermediate
N
H H R formed rapidly and
-H+ R reversibly
N
H

NH
N
H R
13
C label

* *
BF3OEt *
+

N N N *
H OH N H H
H
symmetrical (ignoring migration of either CH2 leads to equal distribution
isotope) spiro intermediate of the labelled carbon atom between C1 and C4

25
 Other Heterocycles
S
NH2 O N
+ H S
O2N N QUINOXALINE
O2N NH2
O

Me Me
O H2N NH2 N
PHTHALAZINE
O N

Ph
i)
Me Me
O Cl
O N QUINAZOLINE
ii) NH3
NH2 N Ph
OMe OMe

Cl
Me i) Me

O O Cl N
1,3-DIHYDRO-1,4-BENZODIAZEPIN-2-ONE
NH2 ii) NH3 N
H O

O O CO2H
Br KOH Br
O QUINOLINE
+
N H2O-EtOH
H N Ph

H piperdine
CO2Et piperdine acetate CO2Et
O + COUMARIN
CO2Et O O
OH
CH3 O
i) KOH
O
CHROMONE
ii) c. H2SO4
O O Ph
AcOH
O Ph
O
c HCl / AcOH
H Me 1-BENZOPYRILIUM ION
+
O Ph
OH O Ph

26
 Other Heterocycles

NH2 S
NH2 N
O2N NH2 -H2O -H2O
O O2N N S O2N N
imine imine
H S formation O formation
QUINOXALINE
O

The amine para to the -M NO2 is less nucleophilic and so reacts less readily than the meta
amine. The aldehyde is more electrophilic than the ketone and so only one product is
formed.

Me Me Me
-H2O NH2 -H2O
O N N
H2N NH2
O O N
hydrazone hydrazone
formation formation
Ph Ph Ph
PHTHALAZINE

Me Me Me Me
Ph NH
O NH3
O O O -H2O N
O Cl
NH2 N imine N heat N Ph
Ph formation Ph
amide H H
OMe OMe OMe OMe
formation
QUINAZOLINE

Me Cl Me Me Me
O NH3 NH -Cl N
O O Cl O Cl
Cl
NH2 N imine N SN2 N
amide H O H O
formation formation H
1,3-DIHYDRO-
1,4-BENZODIAZEPIN-2-ONE

27
 Other Heterocycles
CO2K CO2K
O CO2K
KOH Br Br
Br Br -H2O O O
O O
amide imine N
N N
hydrolysis NH2 formation
H
+ O Ph Ph
'aza-aldol'
reaction
CO2H
HO CO2K
Br -H2O Br
QUINOLINE
N Ph N Ph

H
CO2Et piperdine CO2Et CO2Et
O acetate
+ CO2Et
CO2Et -H2O OH O
OH O
OEt
Knoevenagel condensation
"trans-
esterification" -EtOH

CO2Et
COUMARIN
O O

O O O O O O
CH3 Ph Cl CH3 KOH CH2 Ph
OH ester
formation O O OH
O Ph O Ph cH2SO4
AcOH
O O
-H2O

CHROMONE OH
O Ph O Ph

O c HCl O
Me AcOH H+ -H2O
H + Ph OH
O Ph aldol O Ph O Ph
OH reaction OH

1-BENZOPYRILIUM ION

28