CHAPTER 1
HETEROCYCLIC COMPOUNDS
1.1 Motivation and background
Heterocyclic compounds form the core structural moiety of most
marketed drugs. Among the top five US small molecule drug sales in 2014,
four drug molecules are with heterocyclic fragments in their overall structure
(Fig 1.1).1
O
Cl
NH
Cl
O N O N
O
Ph P O
O
NH N
H3C HO F
O H O
N
O
O
CH3
H3C
(a) Sovaldi (sofosbuvir) (b) Abilify (Aripiprazole)
Antiviral Antipsychotic
Fig 1.1a US drug molecules with heterocyclic ring structure
1
O
F
O CH3 S O
N
S OCH3 N N
H3CO N
H N N
CH3
HO
O OH OH
(c) Nexium (Esomeprazole) (d) Crestor (Rosuvostatin)
Antiulcerant Cholesterol regulator
Fig 1.1b US drug molecules with heterocyclic ring structure
Several natural drugs2-5 such as papaverine, quinine, emetine,
theobromine, codeine, theophylline, reserpine, morphine, atropine and
procaine are heterocycles. Some dyes (e.g. Mauvine), pesticides (e.g.
Diazinon), luminophores (e.g. Acridine orange), herbicides (e.g. Paraquat) are
heterocyclic in nature. All these synthetic and natural heterocyclic structures
can and do participate in biological processes6 in the human body. Such
fundamental phenomenon of life as the provision of energy, transmission of
nerve impulses, sight, metabolism and transfer of hereditary information are
all based on chemical reactions involving the participation of many
heterocyclic compounds such as vitamins, enzymes, ATP, nucleic acids, and
serotonin.7 Heterocyclic compounds play significant role in supramolecular8a-d
and polymer chemistry.8e Heterocycles are also of considerable interest
because of their synthetic utility as protecting groups,9 synthetic
intermediates,10 chiral auxiliaries,11 and organic catalysts.12
Alkaloids,13 a class of naturally occurring heterocycles with
nitrogen being the heteroatom in most of them, expressing varied bioactive
properties. An indole-based alkaloid, ergotamine exhibits antimigraine
2
activity. Cinchonine, a quinoline-based alkaloid displays antimalarial activity.
HO N O
O N
H3C
O NH O
N
HO
N H
CH3
H
HN N
Ergotamine Cinchonine
Fig 1.2 Indoline and quinoline based alkaloids
Posaconazole, a triazole antifungal drug14 is active against Candida,
Aspergillus, and Zygomycetes species.
N
N
O O
OH
F N
O N N N
F N
Posaconazole
Fig 1.3 Triazole antifungal drug
Aromatase inhibiting drug, Anastrozole has been approved for the
best cancer treatment after surgery, as well as for the metastasis treatment in
both pre and post-menopausal women. The sex hormone, oestrogen increases
3
the severity of breast cancer, resulting in hyperplasia and differentiation at
oestrogen receptor sites.15,16 Anastrozole functions by inhibiting oestrogen
synthesis.
N N
N
N
Anastrozole
Fig 1.4 Aromatase inhibiting drug
Many essential vitamins and three out of twenty natural amino
acids are heterocyclic in nature. They are extremely important due to their
association with a wide range of physiological activities.
1.2 Heterocyclic compounds
Heterocyclic compounds17 form by far the largest class of organic
chemistry and of immense importance industrially and biologically.18 IUPAC
defines heterocyclic compounds as “Cyclic compounds having as ring
members of atoms of at least two different elements”.19 Heterocyclic ring
structures are essentially composed of elements other than carbon, most
frequently the substituents are nitrogen, oxygen, and sulfur.20,21 Based on the
heteroatom (s) present in the ring structure, heterocycles can be classified as
oxygen, nitrogen or sulphur based and, within each class, heterocycles are
organised depending on the size of the ring determined by the total number of
4
atoms.23 The type and size of ring structure, along with the substituent groups
of the core scaffold, impact strongly on the physicochemical properties.21,23
Heterocyclic compounds may be classified into aliphatic and
aromatic. The aliphatic heterocycles are the cyclic analogues of amines,
amides, ethers, thioethers etc. Their properties are particularly influenced by
the presence of strain in the ring. These compounds generally consist of small
(3 – and 4 – membered) and common (5 – 7 membered) ring systems (Fig
1.5). Whereas, the aromatic heterocyclic compounds are those which have a
heteroatom in the ring and behave in a manner similar to benzene in some of
their properties. Further, these compounds satisfy the general rule proposed by
Huckel.
NH O S
N O S
H
Aziridine Oxirane Thiirane Azetidine Oxetane Thietane
N O S
H N
H
Pyrrolidine Tetrahydro Tetrahydro
furan thiophene Piperidine
Fig 1.5 Aliphatic heterocycles
In Fig 1.6, five-membered heterocycles are shown in the first row,
starting with the aromatic derivative, furan, while tetrahydrofuran,
dihydrofuran – 2(3H) – one, and dihydrofuran – 2,5 – dione are not aromatic
and their reactivity would be comparable to that of an ether, an ester, and a
5
carboxylic anhydride, respectively. The second row displays other five-
membered aromatic heterocycles having one or more than one heteroatom in
their ring structure.
O O O O O O
O
Furan Tetrahydro Dihydrofuran dihydrofuran
furan -2(3H)-one -2,5-dione
N N
N N
N N N S S O
H H H
1H-pyrrole 1H-pyrazole 1H-imidazole thiophene thiazole isoxazole
N N N O N
H H H
pyridine piperidine piperidin-2-one 1,2,3,4-tetrahydro
pyridine
Fig 1.6 Heterocycles with one or more than one heteroatom
The third row displays six-membered rings, starting with the
aromatic form pyridine and the non-aromatic forms piperidine, piperidine – 2
– one and 1,2,3,4 – tetrahydropyridine. Their reactivity would be similar to
that of an amine, amide or enamine, respectively. By and large, the reactivity
of aromatic heterocycles, which is a combination of that expected from an
aromatic system along with the effect of the heteroatom, is usually more
complex whereas, the reactivity of non – aromatic systems is not so different
from their non – cyclic counterparts. Thus, much of the available literature on
heterocyclic systems is devoted to the reactivity of aromatic heterocyclic
compounds.
6
As reported in most of the textbooks of heterocyclic chemistry,24, 25
a pictorial illustration of valence bond resonance is used as a simple way to
describe the reactivity of aromatic heterocycles. Among the aromatic
heterocyclic rings considered, two representative examples are described in
detail.
The aromatic N – heterocycles, pyrrole is isoelectronic with
cyclopentadienyl anion but is electrically neutral with a pair of electrons on
nitrogen, which is a part of the aromatic sextet. Its resonance hybrid can be
represented as an amalgamation of main forms I – V (Fig 1.7). As anticipated,
not all forms contribute equally to the structure of pyrrole, with the order of
importance, I > III, IV > II, V i.e. the major contribution is by the
non – charged form and the charged ones in which nitrogen is using its lone
pair of electrons. Combining all the resonance forms, structure VII shows how
the heteroatom bears a partial positive charge, while the carbon positions
indicate an increase in electron density, in comparison with the typical
aromatic systems like benzene.
N N N N N
H H H H H
I II III IV V
N
H
VI
Fig 1.7 Resonance forms of pyrrole
7
The attack of the electrophile generally proceeds as indicated in Fig
1.8. The major isomer X is generated through intermediates VII – VIII – IX,
among which the isomer VIII contributes its major share to stabilize the
intermediate. On the contrary, a minor isomer XIII is generated through the
less stable intermediates, XI and XII.
E E E -H
N N N N E
H H H H H H H
VII VIII IX X
N E E E
H
VI H H
-H
N N N
Minor isomer
H H H
XI XII XIII
Fig 1.8 Electrophilic attack on pyrrole
Fig 1.9 indicates the nucleophilic attack on pyrrole. Intermediate
XIV is not stabilized, and a lone pair of electrons on the nitrogen atom do not
involve in the reaction progress. The only observed reaction is the
deprotonation of the N – H bond to generate pyrrolate XV, which can be used
to produce N – substituted pyrroles with suitable electrophiles (i.e. Alkyl
halides).
8
Nu
N No stabilization
H H
XIV
N
H E+
N Nu- H+ N
E
XV XVI
Fig 1.9 Nucleophilic attack on pyrrole
The other π – excessive heterocycles also exhibit similar behaviour,
with the limit due to the presence or absence of N – H bond at position 1.
Aromatic heterocycles like isoxazole and thiazole fail to execute the process
VI – XV – XVI due to lack of acidic bond. Further, the attack of radicals or
complex organo-metallic reagents is more complicated.
1.3 Fused heterocycles
1.3.1 Heterocycles with fused five-membered ring
In addition to the monocyclic heterocycles, there are fused or
annulated heterocyclic compounds exhibiting interesting chemical properties.
Fig 1.10 display a range of five-membered aromatic heterocycles
fused with the benzene ring to give various possible structures.
9
NH
N N
H N
indolizine H
1H-indole 2H-isoindole
9H-carbazole
O
O O
benzofuran isobenzofuran dibenzofuran
S
S S
benzo[b]thiophene isobenzothiophene dibenzothiophene
Fig 1.10 Fused aromatic heterocycles
Indole, benzofuran, and benzothiophene are planar heterocycles
with π – electrons along with the non – bonding pair of electrons as seen in
monocyclic heterocycles. All these 10 π – electrons are delocalized over the
ring. Due to the involvement of non – bonding lone pair of electrons on
heteroatom in aromatization, it makes the 5 – membered rings more
susceptible to the electrophilic attack.
[Link] Indole
Benzo pyrrole is also referred as Indole, a pleasant smelling solid,
mostly used as a perfume base. Indole is a planar aromatic molecule with
conjugated π – electrons furnished by eight carbon atoms and a lone pair
contributed by nitrogen. As the lone pair of nitrogen is involved, charge
separated resonance hybrids can be written for indole as shown in Fig 1.11.
The calculated resonance energy is around 47 – 49 Kcal/mol.
10
4 3
5 9
2
6 8 N1 N N N
7 H H H H
Fig 1.11 Canonical forms of Indole
1.3.2 Fused six – membered heterocycles
[Link] Quinoline and Isoquinoline
Two faced heterocycles quinoline and Isoquinoline are formed by
the unification of pyridine whereas isoquinoline is a low melting solid (M.P
265 oC, B.P 243 oC). All the atoms in quinoline and isoquinoline are sp2
hybridized with 10 π – electrons and furnish one electron each in orthogonal
p – orbitals for delocalization over the rings.
5 4 5 4
6 10 10 3
3 6
2 7 N2
7 9 N 9
8 1 8 1
quinoline isoquinoline
Fig 1.12 Quinoline and isoquinoline
For both quinoline and isoquinoline, charge separated canonical
forms can be written depicting the resonance energies of 198 and 143 KJ/mol.,
respectively (Fig 1.13 & 1.14). The first three resonance hybrids (i - iii) of
both quinoline and isoquinoline are of low energy and contribute appreciably
to aromatic character compared to the other charge separated structures (iv -
v). Even though, quinoline and isoquinoline are slightly more basic in nature
11
than pyridine but less basic than amines. This can be attributed to the sp2
hybridization of nitrogen in quinoline and isoquinoline compared to sp3
hybridized nitrogen of anilines, resulting in high electro negativity of the
former. The dipole moment of isoquinoline (2.6 D) is greater than quinoline
(2.1 D)
N N N N N
(i) (ii) (iii) (iv) (v)
Fig 1.13 Canonical forms of quinoline
N N N N N
(i) (ii) (iii) (iv) (v)
Fig 1.14 Canonical forms of isoquinoline
1.4 Preparation of Aromatic heterocycles
1.4.1 Synthesis of Furan
(a) A dehydration followed by cyclization of pentoses will result in a furfural.
This further undergoes decarboxylation to give furan.
CHO
HCl CaCO3
(CHOH)3
O CHO 625 K
CH2OH O
Scheme 1.1 Furan synthesis via furfural intermediate
12
(b) Furans are synthesized through widely adopted Paal – Knorr method,
which involves the cyclization of 1,4 – diketones in the presence of acid
catalysts such as sulfuric acid, phosphorus (V) oxide, zinc chloride, acidic
ion – exchange resin etc. Using this method, pyrroles and thiophenes can be
obtained by heating 1,4 – diketones with ammonia (or primary amines) and
phosphorus pentasulfide, respectively.
Catalyst R2
R1 O
RNH2 R2
R1 R2
O O N
R1 R
P2S5 R2
S
R1
Scheme 1.2 Paal – Knorr synthesis of furan, pyrrole, and thiophene
(c) Cyclization of (z) butane – 1,2 – diols with pyridinium chlorochromate
(PCC) will result in 3 – substituted furans.
R R
PCC
OH HO O
Scheme 1.3 Substituted furan synthesis
1.4.2 Synthesis of pyrrole
(a) A mixture of furan, ammonia, and steam on Al2O3 at 675 K results in
13
pyrrole.
NH3, Steam
O Al2O3, N
H
Scheme 1.4 Pyrrole synthesis from furan
(b) Knorr synthesis is the widely employed method for the synthesis of
pyrrole using two equivalents of ethyl acetoacetate.
(1) NaNO2, AcOH
2 MeCOCH2CO2Et
(2) Zn-AcOH N
H
Scheme 1.5 Knorr pyrrole synthesis
(c) Pyrrole can be produced by passing a mixture of acetylene and ammonia
through a red-hot tube.
NH3
2 CH CH
N
H
Scheme 1.6 Ethyne mediated pyrrole synthesis
1.4.3 Synthesis of thiophene
(a) Thiophene can be generated by passing a mixture of ethyne and H2S on
Al2O3 at 675 K.
14
H2S, Al2O3
2 CH CH
675 K S
Scheme 1.7 Alumina assisted thiophene synthesis
(b) Substituted thiophenes can be obtained from 1,3 – diynes and H2S.
H2 S, Ba (OH)2
RC C C CR
R S R
Scheme 1.8 2,5-Substituted thiophene synthesis
(c) 1,2 – diketones and diylide undergo cyclization to produce a variety of
thiophenes.
R1 R2
R1 R2
Ph3P S PPh3
O O S
Scheme 1.9 3,4-Substituted thiophene synthesis
1.4.4 Synthesis of pyridine
(a) Hantzch synthesis: Hantzch method is one of the most convenient
procedures for the synthesis of pyridine derivatives. The method involves the
reaction of two equivalents of β – keto ester or other activated methylene
derivatives with an aldehyde in the presence of ammonia to give
dihydropyridine, which upon oxidation results in pyridine derivative.
15
EtO2C CO2Et EtO2C CO
Oxidation
2 CH3COCH2CO2Et HCHO NH3
H3 C N CH3 H3 C N CH
H
Scheme 1.10 Hantzch synthesis of pyridine
(b) Pyrrole on reacting with dichlorocarbene undergoes ring expansion
resulting in 3 – chloropyridine.
Cl
Cl
CHCl3, NaOH Cl
N N
H N
H
Scheme 1.11 Functionalized pyridine synthesis
1.4.5 Synthesis of pyridones
Pyrones react with ammonia or amine to produce pyridones.
Aromatic amines fail to give good yields.
RNH2
O O N O
R
Scheme 1.12 Pyridone synthesis from pyrones
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1.4.6 Synthesis of Indoles
(a) Fischer – indole synthesis: This is the most important and widely used
method for the preparation of indoles. Thermal elimination of ammonia from
phenylhydrazine or substituted hydrazine of an aldehyde or ketone. The
reaction is catalyzed by phosphoric acid, sulphuric acid, ZnCl2 or BF3.
Me Me
ZnCl2
N Me
N N
H H
Ph Ph
H3PO4 Ph
N N
N
H H
Scheme 1.13 Indole synthesis via Fischer – indole method
(b) Madelung synthesis: O – toluidine on reaction with acyl chloride results
in o – acylamino toluene which undergoes cyclization in the presence of
strong base followed by dehydration to give indole or 2 – substituted indole
derivatives.
Me Me
RCOCl (1) KOtBu
R
NH2 (2) H3O+ N
NHCOR
H
Scheme 1.14 Madelung synthesis of substituted indoles
(c) Bischler synthesis: The method involves the reaction of aniline or
17
substituted anilines with α – halo ketone or aldehyde to give α – arylamino
ketone or aldehyde, which undergoes cyclization on heating with an acid or
ZnCl2 to produce substituted indoles.
Me
O Me
HCl Me
NH2 N
Br Me H
Scheme 1.15 Bischler synthesis of substituted indoles
1.4.7 Synthesis of quinoline
(a) Skraup synthesis: Skraup synthesis involves heating of aniline derivative
having free ortho position with glycerol and sulfuric acid and an oxidizing
agent like nitrobenzene. The acid functions as a dehydrating agent and an acid
catalyst.
Glycerol, H2SO4
Nitrogen,
NH2 N
R Glycerol, H SO
2 4
Nitrogen,
NH2 N
R
Scheme 1.16 Skraup synthesis of quinoline
(b) Friedlander synthesis: Friedlander synthesis involves heating a mixture
of o – amino benzaldehyde or o – aminoacetophenone with an aldehyde or
18
ketone having an active methylene group in the presence of a base.
CHO
CH3CHO NaOH
NH2 N
Scheme 1.17 Friedlander synthesis of quinoline
(c) Knorr quinoline synthesis: Heating aniline with β – keto esters in the
presence of acid results in 2 – substituted quinolines.
H2SO4
RCOCH2CO2C2H5
NH2 N
Scheme 1.18 Synthesis of 2 – substituted quinolines
(d) Combes synthesis: Aniline on heating with 1,3 – diketones in the presence
of acid results in 2,4 – disubstituted quinoline.
Conc. H2SO4
RCOCH2COR
NH2 N R
Scheme 1.19 Disubstituted quinoline synthesis
19
1.4.8 Synthesis of isoquinoline
(a) Bischler – Napieralski synthesis: The synthesis involves the reaction of
β – phenylethylamine with acyl chloride to give β – phenylethylamine which
further undergoes cyclodehydration in the presence of POCl3, P2O5, H3PO4, or
ZnCl2 to produce 3,4 – dihydro isoquinoline. 3,4 – dihydro isoquinoline on
dehydration over Pd, S, or Se yields 1 – substituted isoquinoline.
RCOCl - H2 O Pd, S, or Se
NH2 NHCOR N , - H2 N
R R
Scheme 1.20 1 – substituted isoquinoline synthesis
(b) Pictat – Gam synthesis: It is a modified Bischler – Napieralski synthesis
except that a hydroxyl group is introduced in the starting material β –
phenylethylamine.
OH
(1) RCOCl
NH2 (2) POCl3 N
Scheme 1.21 Modified Bischler – Napieralski synthesis of isoquinoline
(c) Pictat – Spengler synthesis: β – phenylethylamine on reaction with an
aldehyde results in an imine, which gets cyclized in the presence of an acid to
yield tetrahydroisoquinoline.
20
H+
RCHO
NH2 NHCOR NH
R
Scheme 1.22 Tetrahydroisoquinoline synthesis
(d) Pomerantz – Fritsch reaction: The method involves the condensation of
an aromatic aldehyde with an amino acetal, which further undergoes
cyclization in the presence of sulfuric acid yielding isoquinoline.
OEt
NH2CH2CH(OEt)2 OEt H2SO4
N N
CHO
Scheme 1.23 Isoquinoline synthesis via Pomerantz – Fritsch reaction
(e) Condensation of benzylamine with acetal followed by cyclization yields
isoquinoline.
OEt
CHOCH(OEt)2 OEt H2SO4
CH2NH2 N N
Scheme 1.24 Isoquinoline synthesis using benzylamine
A platform has been provided by the heterocyclic compounds for
the rapid development of research in the areas of organic, analytical and
medicinal chemistry and continues to motivate researchers around the globe to
develop novel heterocyclic derivatives via existing as well as novel synthesis
methods.
21
Diazo carbonyl compounds are the versatile building units utilized
in the construction of heterocyclic derivatives. In the presence of transition
metal catalysts, diazo group gets dissociated for the in situ generation of metal
carbenoids which undergo 1,3 – dipolar cycloaddition reactions with a variety
of substrates to form heterocyclic compounds. A substantial description was
given in the chapter II on the reason for choosing diazo carbonyl compounds
as the substrates, methods available for the synthesis of diazo compounds and
their ability to undergo a wide range of chemical transformations for the
synthesis of heterocycles.
22