4.3.

Bicyclic and tricyclic five-membered heterocycles

The benzo [b] fused analogues of pyrrole, furan and thiophene are respectively called indole,
benzofuran and benzothiophene. The [c]fused analogues are called isoindole, isobenzofuran
and isobenzothiophene. The latter class of compounds has much lower stability than the first
since there is no Kekulé-structure. A [a]fused analogue of pyrrole also exists, it is called
indolizine. Dibenzo fused analogues are carbazole, dibenzofuran and dibenzothiophene.

The benzo fused analogues of the azoles are also known, they have the expected names. Some
can tautomerize between a [b] and [c]fused isomer.

4.3.1. Synthesis

One of the most useful and general methods for indole synthesis is the Fischer indole
synthesis of hydrazones in acidic medium (via a 3,3-sigmatropic rearrangement and loss of
ammonia).
A modern, versatile method for indole synthesis is the cyclisation of 2-alkynylanilines. This
cyclisation can be catalysed with base, or with transition metals. The alkynylanilines are
prepared from the 2-iodoanilines or 2-bromoanilines via a Sonogashira reaction (see
organometallic chemistry). This cyclisation reaction can also be applied to the synthesis of
benzofurans. Thus, basic decomposition of 4-(2-hydroxyphenyl)-1,2,3-thiadiazole leads after
cyclisation to the thiolate, which could be S-alkylated.

Benzothiophenes can be prepared via cyclisation of α-(phenylsulfanyl)ketones in acidic

medium. The oxygen analogues can be prepared in the same way.
Benzothiophene and benzofuran analogues are also accessible via [4+1] condensation of 2-
hydroxy or 2-mercaptobenzaldehyde with chloroacetic esters in basic medium. The initial
alkylation products undergo Knoevenagel condensations to the fused heterocyclic esters.

Carbazoles are prepared from ortho-nitro or ortho azidobiphenyls after generation and
insertion of the nitrene.
The most common synthesis of benzo fused 1,3-azoles is the [4+1] condensation of 2-
substituted anilines (bisnucleophiles) with acid derivatives or aldehydes (oxidative
conditions). Nitrosation of 1,2-diaminobenzene gives benzotriazole.

4.3.2. Reactivity

Indole undergoes electrophilic substitution at the 3-position because of the stabilisation of the
intermediate by the nitrogen atom. The related fused heterocycles (benzothiophene,
benzofuran) have a much less pronounced reactivity and selectivity. In the latter case, the 2-
substituted isomer is even the most abundant.
Carbazole has the same reactivity as aniline: the 3,6- (“para”) positions react first, then the 1,8
(“ortho”) positions. The dibenzothiophenes and dibenzofurans are less reactive and less
selective.

Indolizines are reactive towards electrophilic substitution (see resonance forms), they are
substituted at C1 and C3.

The benzo-1,3-azoles are less reactive towards electrophilic substitutions, in fact the
electrophilic substitution takes place on the benzene ring. Indazole reacts, similarly to indole,
at its 3-position.

Nucleophilic substitution on indoles, benzofurans and benzofurans is not straightforward

unless an activating group is present. In the example below, the chlorine can be substituted
because of the activation of the aldehyde group. Subsequent condensationreaction leads to a
thieno[2,3-b]indole.
The benzo analogues of the 1,3-azoles are rather reactive towards nucleophilic aromatic
substitution at their 2-position, whereas the benzo fused 1,2-azoles react at C3. Quaternisation
increases the reactivity.

N-Unsubstituted indole can be deprotonated at the nitrogen. Alkylation again can occur either
on the “hard” nitrogen or on the “soft” carbon-3, depending on the counter ion and the
polarity of the solvent. Polar solvents in combination with larger counterions (potassium)
favor N-alkylation. Apolar solvents in combination with smaller cations favor C-3 alkylation,
even when this position is already substituted. Even the relatively hard benzaldehyde will
react at the 3-position when indolylmagnesium iodide is used.

Lithiation of N-substituted indole and benzothiophene occurs at the 2-position. When the N-
unsubstituted indole is needed, protection with phenylsulfonate, lithiation, reaction with the
electrophile and deprotection gives the desired 2-substituted indole. Metallation at other
position needs to be directed by halogenation and transmetallation.
5. Six-membered rings

Uncharged aromatic six-membered rings mostly have nitrogen atoms in their structure, such
as pyridine, the diazines, triazines and tetrazoles. The aromaticity goes decreases as the
amount of nitrogens increases. Six-membered aromatic rings with oxygen (pyrylium) or
sulfur (thiopyrylium) also exist, but they are charged and therefore quite reactive, especially
towards nucleophiles.

5.1 Monocyclic systems: synthesis

5.1.1. From an acyclic precursor

This is not a very common synthetic pathway to six-membered (di- and tri-)azines.
Piperidines, tetrahydropyrans and tetrahydrothiapyrans can be prepared from an open chain
precursor by cyclisation. The latter may be available from 1,5-dihalogenopentane and its
analogues by reaction with amines, hydroxide and sulfide (making it a [5+1]-approach). An
industry synthesis of pyrazine starts from (2-N-(hydroxyethyl)amino)ethylamine which is
pyrolysed over an alumina-nickel catalyst.
5.1.2. [3+3] approaches

The bisnucleophilic 1,3-dicarbonyl compounds may be condensed with bisnucleophiles such

as urea or amidines to give pyrimidine derivatives. Barbituric acid may be prepared from
malonic acid and urea. Similarly, the bisnucleophilic 2-cyanoacetamide gives pyridone
derivatives in a base-catalyzed condensation reaction with 1,3-dicarbonyl compounds.

In general, enamines may be condensed with biselectrophiles such as 1,3-dicarbonyl

compounds or α,β-unsaturated carbonyl species to form pyridines. The conjugated carbonyl
derivatives may be formed in situ before reaction with the enamine. Michael addition of the
enamine β-carbon to the β-carbon of the electron poor alkene, followed by cyclisation of the
open chain precursor, gives good yields of the pyridine derivatives. The mechanism is
analogous to the Hantsch pyridine synthesis (see 5.1.6), but this [3+3] variant allows to obtain
unsymmetrical pyridines.
Pyrazines can be prepared by cyclisation of complementary three-atomic fragments that have
both a nucleophilic and electrophilic end. Thus, α-aminoketones rapidly dimerize to form
dihydropyrazines, that spontaneously aromatize to 2,5-disubstituted pyrazines.
α-Amino acids dimerize at higher temperatures into stable 2,5-diketopiperazines.

5.1.3. [4+2]-approaches

Diels-Alder cycloadditions, starting from oxazoles and dienophiles such as acrylic acid, at
first give an unstable bridged intermediate, which is aromatized to a pyridine-4-carboxylic
acid derivative.
The biselectrophilic 1,4-dicarbonyl compounds can be condensed with hydrazine to afford
pyridazine derivatives after oxidation/aromatization of the intermediate dihydropyridazines.
maleic anhydride reacts with hydrazone to give the 3,6-dioxygenated derivative. Chlorination
and subsequent reduction leads to the parent pyridazine.

1,2-Diketones react with four-atomic bisnucleophiles such as 1,2-diaminobenzene to

dihydropyrazines, that oxidize to pyrazines. Thus, condensation of glyoxal with α-
aminoamides gives pyrazinones. Thiosemicarbazides analogously afford 1,2,4-triazine-3-
thione derivatives.

A general synthesis of 3,5-dichloro-1,4-oxazin-2-ones and -pyrazin-2-ones starts from four-

atom reagents cyanohydrins and α-aminonitriles, respectively, and oxalyl chloride as the two-
atom reagent. Hydrochloric acid present in the oxalyl chloride adds to the nitrile function,
generating an imine chloride that reacts with the oxalyl chloride to form the six-membered
ring. The excess oxalyl chloride chlorinates the oxazinone/pyrazinone ring to afford the 3,5-
dichloro substituted derivatives.

5.1.4. [5+1]-approaches

Starting from 1,5-dicarbonyl compounds and ammonia, 1,4-dihydropyridines are generated

that spontaneously (in the presence of air oxygen) aromatize to pyridines. With
hydroxylamine, the reaction leads directly to pyridines. Dehydration of the same diketones in
the presence of a mild oxidation agent gives the pyrylium salts via the 4-pyrans.

5.1.5. Ring transformations from other heterocycles

Pyrylium salts may be useful intermediates in pyridine synthesis. The 2,4,6-triphenyl

pyrylium salt is relatively stable and may be formed from condensation of acetophenone and
the adduct between acetophenone and benzaldehyde in strongly acidic medium in the
presence of an oxidant. As before, the mechanism involves a 1,5-diketone and pyran
intermediate (not shown). Treatment with ammonia gives the pyridine, whilst primary amines
afford pyridinium salts. The reaction occurs via addition, ring opening, ring closure and
dehydratation. Thiapyrylium salts are prepared analogously from pyrylium salts with
hydrosulfide anion.
In the Zincke reaction, one N-aryl group of a pyridinium group is exchanged for another one
by adding an aniline. The mechanism is completely analogous to the one described above for
pyrylium salts. The reaction goes to the right because the 2,4-dinitroaniline is hardly
nucleophilic, whereas the pyridinium salt thus obtained is less electron poor and therefore less
reactive than the Zincke salt. The latter are easily formed from pyridine and the reactive 2,4-
dinitro-1-chlorobenzene. Arylation of pyridine normally is a difficult reaction, therefore the
Zincke reaction offers an alternative.

5.1.6. More than two components/miscellaneous

The Hantsch pyridine synthesis is a four component one-pot [2+1+2+1]-approach. It uses β-

ketoesters (2 equivalents), ammonia and an aldehyde. In a first step, an enamine is formed
between a ketoester and ammonia. Under the influence of the ammonia (base), a Knoevenagel
reaction occurs between the aldehyde and the second equivalent of the active methylene,
generating an electron poor α,β-unsaturated ketone. Then, [3+3] cyclocondensation gives the
dihydropyridine, which can either be isolated or oxidized in mild conditions to the
symmetrical, highly substituted pyridine.
The Hansch synthesis might also be applied to the synthesis of triarylpyrylium salts (see
above) by a three component reaction of one equivalent of benzaldehyde and two equivalents
of acetophenone.

The Biginelli synthesis is a multicomponent reaction that leads to pyrimidine derivatives

starting from an active methylene such as ethyl acetoacetate, an aryl aldehyde and a urea. The
reaction is acid-catalysed and has been extensively used in combinatorial chemistry due to the
large availability of the three classes of starting materials. Different mechanisms may be
proposed, one involving a Knoevenagel/Michael addition sequence, the other involving an
aldimine derived from the urea.

Other syntheses of pyridine compounds, that may be of importance commercially, are

difficult to explain mechanistically. For instance, the Chichibabin synthesis of 2-methyl-5-
ethylpyridine starts from acetaldehyde and ammonium acetate and involves several aldol
condensations.

5.2 Monocyclic systems: reactivity

5.2.1. Reaction with electrophiles

The pyridine nitrogen is basic and nucleophilic, therefore electrophiles such as protons and
alkylating agents form pyridinium salts. Acylating agents lead to reactive intermediate salts
that are of importance as acyl transfer reagents for acid-labile compounds. Many other
electrophiles react with the pyridine nitrogen, such as SO3 (this complex is a mild sulfonating
agent), and bromine. Lewis acids such as AlCl3 also form a strong complex with the pyridine
nitrogen.

Electrophilic substitution at carbon is not very easy on pyridine unless electron releasing
substituents are present. The circumstances of electrophilic substitution often involve acidic
conditions, and after protonation (or complexation with Lewis acid) the pyridine is further
deactivated. If the ring is substituted at all, this occurs at the 3-position. Thus the reactivity of
pyridine is similar (or even lower) to that of nitrobenzene.
Chlorination and bromination is possible under drastic conditions, giving 3-halogenated
pyridines in low yield. The azines are even less electron rich, but may react when strongly
activating substituents are present.

The N-oxide of pyridine can be prepared by reaction with hydrogen peroxide or peroxyacid.
The oxide substituent is one of the strongest electron releasing substituents, therefore the
para-position now can be substituted with electrophiles under relatively mild conditions.
Strong acid is to be avoided since the oxygen could then be protonated, giving a N-
hydroxypyridinium salt (pKa = 0.79) that is much less reactive, and reacts at the 3-position.
Thus nitration of pyridine-N-oxide gives the 4-nitro substituted compound that may be
reduced with trivalent phosphorous compounds (PCl3, PPh3) to afford the free pyridines.
Alternatively, the N-oxide compound may be hydrogenated, leading immediately to 4-
aminopyridine.
5.2.2. Nucleophilic substitution

Pyridines are activated towards nucleophilic substitution provided the leaving group is placed
at the 2, 4, and 6-position. In this case, the nitrogen can take up the charge of the nucleophile
before releasing the chloride (addition/elimination mechanism). Again, there is analogy with
nitrosubstituted benzenes. With 4,6-dichloropyrimidines and substituted resorcinol,
oxacalixarene macrorings may be formed.

The reactivity is even higher for azines or on quaternization. Some azines undergo ring
transformation via a ring opening/ring closure mechanism, instead of straightforward
substitution, as can be shown by 15N labeling.
An alternative for the addition/elimination mechanism is the elimination/addition (pyridyne-
mechanism) that will take place in strongly basic medium. 3-Bromopyridine when treated
with sodium amide in ammonia gives a mixture of isomeric 3- and 4-aminopyridines. This
shows that a 3,4-pyridyne is the intermediate. The alternative 2,3-pyridyne is not formed
because the intermediate where the anion would be present at the 2-position, is highly
destabilized because of repulsion with the free electron pair of the pyridine.
The isomeric 4-bromopyridine also gives a 3,4-pyridyne intermediate (only possibility) and
thus leads to the same mixture of aminopyridines.

2-Bromopyridine gives the 2,3-pyridyne, and after addition of ammonia the 2-aminopyridine
is formed exclusively. Again, addition to the 3-position would lead to an intermediate with
repulsion between two free electron pairs. Thus, the result is the same as for the “normal”
nucleophilic substitution.
The Chichibabin reaction of unsubstituted pyridine with amide anion to prepare 2-
aminopyridine formally is the substitution of a hydride. Since hydride is a very poor leaving
group, a mechanism is formulated in which a second equivalent of amide catalyses the
transfer of a hydride, immediately forming the more stable molecular hydrogen. The reaction
of sodium amide is selective at the 2-position because of preliminary coordination of the
sodium cation to the pyridine nitrogen.

The pyrylium salts are very sensitive towards the attack of nucleophiles as we have seen
before in their reaction with nucleophiles such as amines, where ring transformations to
pyridinium salts occur. Addition of water gives an acyclic diketone that in some cases (R =
Me) may be condensed to phenol derivatives. Addition of nitromethane to pyrylium salts
gives nitroarenes via a mechanism analogous to the synthesis of pyridinium salts. Secondary
amines and methylated pyrylium salts also afford benzene derivatives after ring closure of the
enamine formed.
5.2.3. Rearrangements

2-Aminopyrimidine can exchange the three nitrogens under the influence of base. The
mechanism again involves ring opening after addition of the base to the 4- or 6-position,
followed by alternative ring closure (Dimroth rearrangement). Again 15N labeling may be
used, since the rearrangement is degenerate, to indicate the extent of the rearrangement.

An analogous process may lead to ring transformation of a pyrimidine into a 1,3,5-triazine

ring. After ring opening/elimination an intermediate acetylene is formed, that is attacked by
the amidine function.

5.2.4. Cycloaddition reactions

Pyridine itself is too aromatic to undergo Diels-Alder cycloaddition reactions. Diazines, 1,2,4-
triazines and 1,2,4,5-tetrazines are much less aromatic, and therefore have the possibility to be
reacted with (electron rich) alkenes or alkynes (inverse electron demand or hetero-Diels Alder
cycloaddition). The reactivity is increased when acids are added, or when some of the
nitrogens are quaternized.

Pyrones undergo Diels-Alder cycloadditions since they are only partly aromatic (weak
resonance). They react at high temperature with dimethyl acetylenedicarboxylate or maleic
anhydride. The even less aromatic oxazinones and pyrazinones are reactive partners in hetero-
Diels Alder cycloadditions. Pyrazinones may give two different products after extrusion of
either a nitrile or an isocyanate.
5.2.5. Reduction of pyridine derivatives

Pyridine can be completely reduced to piperidine in very high yield at atmospheric pressure
and room temperature. The reaction is catalysed by platinum and protonation of the pyridine
nitrogen lowers the aromaticity and may be the reason of this smooth reduction.

Pyridinium salts can react with mild reduction agents such as sodium borohydride, whereas
pyridine itself does not react. In the former case, a mixture of 1,4- and 1,2-dihydropyridines is
formed. These compounds are electron rich and readily reoxidized, e.g. in air, to the starting
pyridinium salts.
When an electron withdrawing group is present in the 3-position, as in nicotinamides, the
main product after mild reduction is the 1,4-dihydropyridine, which is stabilized (a
vinylogous urea). The biochemical NAD+/NADH redox couple is based on this stability.

5.2.6. Reactivity of the side chain

As for the azoles, methyls placed in direct conjugation with the azine nitrogen(s) are acidic
and can be alkylated or condensed with electrophiles after proton abstraction. Quaternisation
increases the acidity.
Diazonium salts derived of 2-amino- and 4-aminopyridine are unstable. Thus the main
product from diazotiation of 2-aminopyridine is 2-pyridone, after hydrolysis. The amines of
the pyridine-N-oxides lead to diazonium salts that are better stabilized, and the normal
diazotation products are obtained.

5.3. Fused six-membered rings

Three ring systems result from the subsitutution of a CH (or C) of naphthalene with a
nitrogen: quinoline, isoquinoline and the quinolizinium salts.
More than one C(H) can be replaced, either on the same or on different benzene rings.
The oxygen analogues also exist, but the aromatic derivatives are positively charged. Several
of these occur in Nature as glycosides with polyphenolic derivatives. The neutal carbonyl
derivatives likewise are abundant in Nature.

5.3.1. Synthesis

The synthesis of isoquinolines from a single acyclic fragment can be done starting from 2-
phenylethylamine or its derivatives. First, an amide or imine derivative is prepared. These are
converted to electrophiles, respectively with PCl5 or by protonation. Intramolecular
electrophilic substitution affords dihydro- and tetrahydroisoquinolines, respectively, which
can be converted to isoquinolines by oxidation. These two approaches to isoquinoline
derivatives are called respectively the Bischler-Napieralski and the Pictet-Spengler synthesis.
Often in the latter case the imine is formed in situ rather than isolated, and then it becomes a
[5+1] strategy rather than one starting from an acyclic fragment.

A similar strategy is the Pomeranz-Fritsch synthesis. A benzaldehyde is condensed with an

aminoacetal, affording an imine that is cyclized in acidic medium, directly forming an
iqoquinoline. In all these electrophilic cyclisations, the best yields are obtained when electron
rich aromatic rings are used.

Acyclic fragments may also be used for the synthesis of tricyclic pyridines in acidic medium,
such as the phenanthridines or acridines that are obtained by intramolecular electrophilic
substitutions.
Quinolines may be prepared with a [3+3]-approach staring from aniline derivatives
(bisnucleophilic) together with 1,3-dicarbonyl compounds (biselectrophilic). This reaction is
called the Combes synthesis. Unsymmetrical diketones give mixtures of compounds.
In the closely related Skraup synthesis that uses an aniline together with acrolein (may be
generated from glycerol at high temperature) or any α,β-unsaturated carbonyl compound,
quinolines are formed after reaction with a mild oxidation agent such as nitrobenzene. The
first step of this reaction is the Michael addition of the aniline to the alkene carbon. Thus
control over the regiochemistry is exerted.

The Friedlaender condensation (a [4+2] approach) of 2-acylanilines and enolizable carbonyl

compounds, both of amphiphilic nature, may take different regiochemistry dependent on the
conditions. Acid catalysys via the thermodynamically more stable enamine (the more highly
substituted one) gives the 2,3dimethylquinoline, whereas base catalysis with the intermediacy
of the kinetic enolate and derived aldol, affords the 2-ethylquinoline.
The Pfitzinger synthesis is based on the same principle, but here isatin, a 2,3-dioxoindole, is
the starting material that is transformed in situ in the presence of the carbonyl compound. The
result is a quinoline-4-carboxylic acid.

The cinnolines are prepared by a [5+1] approach starting from 2-alkenylanilines that are
converted to the diazonium salt.

The oxygen containing fused heterocycles (chromylium) can be prepared using similar
strategies as for the nitrogen-containing rings. Here the starting materials may be (electron
rich) phenols, or 2-acylphenols and the corresponding (di)carbonyl compounds.
Coumarin and its analogues can be prepared from the same phenols and esters or other
carboxylic acid derivatives. Malonic esters or other active methylenes condense under very
mild conditions.

The chromones and flavones are prepared in a [5+1] approach from 2-acylphenols by Claisen
or Knoevenagel condensation reactions with an acid or aldehyde derivative, followed by
cyclisation of the acyclic precursor. In the latter case, an oxidation is needed.

Quinoxalines and pteridines can be prepared from ortho-diamino compounds and 1,2-
diketones. This is a [4+2] approach with a bisnucleophile and a biselectrophile. Purine is
formed in the same way from 4,5-diaminopyrimidine and formic acid.
The synthesis of the phthalazines from aromatic 1,2-dicarbonyl compounds and hydrazine
follows a similar logic. The quinazolines may be prepared from 2-acylanilines and nitriles.

Several of the different naphthyridine isomers may be prepared from aminopyridines using
the Skraup synthesis. Also phenanthroline is obtained from a Skraup synthesis of 8-
aminoquinoline.

The quinolizinium salts may be prepared ina [3+3] approach starting from pyridine
derivatives such as 2-methylpyridine (picoline) or 2-acetylpyridine. In the first case,
picolinyllithium is generated and reacted with an unsaturated carbonyl compound, followed
by acidic cyclisation. The second method is similar but now the organometallic (Grignard)
reagent is on the other part.
5.3.2. Reactivity

The electrophilic substitution on quinoline takes place on the carbocyclic ring. Similar to
naphthalene, the attack happens with preference at the α-position (5- and 8- substitution
almost equally in this case). Likewise, isoquinoline reacts, in this case with a preference for
the 5-isomer.

The naphthyrines and pteridines do not have a ring that is electron rich enough to react with
electrophiles, while the benzodiazines may react similarly to the (iso)quinolines with
electrophiles. Phenanthroline is nitrated at the 5-position.

Oxidation of benzo fused azines and diazines with powerful reagents attacks the benzene ring
rather than the heterocyclic, electron poor part of the molecule. Thus, dicarboxylic acids are
obtained. N-Oxides are readily formed and direct the electrophilic substitution to the 4-
position (in quinolines).
Nucleophilic substitution again works very well if the charge developed in the ring can be
delocalized to the nitrogen(s) of the ring. The 2- and 4-haloquinolines may be substituted by
nucleophiles. However, 1,3-dichloroisoquinoline is substituted much more readily at C-1 than
at C-3. Acridine is readily substituted at C-9, phenanthridine at C-6.

The Chichibabin reaction occurs for quinolines at the 2-position and for isoquinolines at the
1-position. Organolithium reagents also add to the C-2 of quinolines and the C-1 of
isoquinolines, forming the substituted derivatives after air oxidation.
The quaternary salts readily undergo additions, forming rather stable adducts. The Reissert
reaction is the acylation of quinoline in the presence of (cyanide) nucleophile, giving the
Reissert compounds that may be cleaved with acid in an aldehyde and quinoline-2-carboxylic
acid (quinaldic acid).

Pteridines that are not very aromatic and very electron poor, even add water in their neutral
form, forming a “pseudobase”. This compound with its amidine structure is much more basic
than pteridine itself. Flavine-Adenine-Dinucleotide contains a benzo fused pteridine
derivative that is a coenzyme in dehydrogenations of alkanes and alcohols. This may be
compared to the quinone-hydroquinone redox system.

Nucleophilic addition at C-2 is the principal reaction of chromylium- (flavylium) salts.

Addition of ammonia does not lead, in contrast to the corresponding pyrylium salts, to
quinoline derivates and in some cases the addition products (e.g. with secondary amines) can
be isolated. Softer and milder nucleophiles may react at C-4.
The 2-benzopyrylium salts afford isoquinolines after addition of ammonia at C-2.

The tricyclic xanthylium salts are known as (fluorescing) dyes. The most famous are
fluoresceine, eosine and mercurochrome. These products may be in a closed form (lactone) or
in several open forms, of which the charge is dependant on the pH. These dyes are prepared
by condensation of phthalic anhydride with electron rich phenols.
6. Seven-membered heterocycles and macrorings

These rings are less common than the five-and six-membered heterocycles. Nevertheless,
many natural products and synthetic drugs contain seven-membered (or higher) rings, mostly
in a (partially) reduced form and fused to other rings.

6.1. Synthesis

There are a variety of synthetic methods, including synthesis from acyclic fragments, [6+1],
[5+2], [4+3] or multicomponent approaches, we describe only a few that give access to some
of the more interesting ring systems.
Caprolactam (2-azepinone) may be one of the most important seven-membered rings as it is
the precursor for Nylon-6. It is prepared from cyclohexanone oxime using the Beckmann
rearrangement. Caprolacton is also prepared by ring expansion via Baeyer-Villiger oxidation
of cyclohexanone.
Benzodiazepines are prepared from 2-aminobenzophenones by a [4+3] or [5+2] strategy,
condensing with amino acid derivatives or chloroacetyl chloride, respectively, or with a
related [6+1] approach. A different polyphosphoric acid (PPA)- catalysed approach starts
from acyclic fragments and is similar to the Bischler-Napieralski isoquinoline synthesis.
Diltiazem is synthesized starting from an epoxide and 2-nitrothiophenol. This adduct is then
resolved and reduced to the amine and cyclodehydrated to the lactam. N-Functionalisation and
acylation of the secondary alcohol completes the synthesis.

Nevirapine is prepared by combination of two monocyclic pyridine building blocks, followed

by substitution with cyclopropylamine and cyclisation (intramolecular nucleophilic
substitution) of an acyclic precursor
7. Selected heterocyclic natural products

7.1. Purines

Purine, is formed in a [4+2] approach from 4,5-diaminopyrimidine and formic acid. There
are also approaches that start from imidazole building blocks, e.g. in the synthesis of
hypoxanthine.

Adenine, one of the molecules of life, can be prepared from simple molecules such as NH3
and HCN. Aminomalononitrile is a trimer of hydrocyanic acid that can be converted to a
bisamidine with two molecules of ammonia. Double ring closure with HCN then generates
adenine.

Purine is relatively acidic (pKa = 8.9) because the negative charge can be delocalized over
four nitrogen atoms. Alkylation of this anion may take place on different nitrogens (mainly 7-
and 9), depending on the circumstances. Note: the numbering of purine is strange : it is based
on the pyrimidine system.
Trichloropurine may be prepared from uric acid by chlorination and this compound undergoes
selective nucleophilic substitition reactions. The order of reactivity of the different positions is
6 > 2 > 8. Thus, guanine may be prepared.

7.2. Alkaloids

Many alkaloids of complex structure have been synthesized in the laboratory. In the context
of this part on heterocyclic chemistry we will treat some of these total syntheses in detail.

7.2.1. Quinine

Quinine occurs in the bark of Cinchona trees and is an antimalarial agent. The Woodward
synthesis (JACS 1945, 67, 860) starts from 3-hydroxybenzaldehydethat is converted to 7-
hydroxyisoquinoline in a Pomeranz-Fritsch reaction. Mannich reaction goes regioselectively
to the 8-position. Methoxide anion at high temperature acts as a hydride transfer reagent,
affording the methyl derivative. This compound is reduced, acetylated, and reduced again.
The last reduction gives an equimolar mixture of the cis-and trans-decahydroisoquinoline.
Oxidation with chromic acid then affords a ketone and at this stage the two isomers are
separated.

The cyclohexanone ring is cleaved by (1) nitrosation of the enolate (2) “retro-Claisen”
reaction of the ethoxide adduct. Reduction of the oxime affords an amine, that is
permethylated and Hofmann elimination, accompanied by saponification and amide cleavage
then yields a 3-vinylpiperidine derivative.

This piperidine is re-esterified and benzoylated and after that a crossed Claisen condensation
is carried out together with a quinoline ester derivative that is prepared in a few steps from 4-
methoxyaniline (Conrad-Limpach procedure, [3+3] approach). The 2-quinolone is converted
to the 2-chloro derivative with POCl3 and reduced with aluminium.
The ketoester is then saponified and decarboxylated, while the benzoyl group is removed.
This compound is known as DL-quinotoxine. At this point, a resolution is done of the two
enantiomers. Treatment with sodium hypobromite gives an α-bromoketone, that is cyclized
with the amine function. The reaction is completed with aluminium/ethoxide reduction of the
ketone, leading to quinine.

7.2.2. (+)Camptothecin

Camptothecin is a pentacyclic alkaloid with antitumour activity present in the bark and stem
of Camptotheca acuminata, a Chinese plant.
Retrosynthetic analysis shows that two parts can be developed separately, namely a
pyrrolo[3,4-b]quinoline and a dihydropyranone derivative.

In the Corey synthesis (E. J. Corey et al., J. Org. Chem. 1975 pp 2140,) indeed these two parts
are synthesized and then combined. Firstly, the furan 3,4-dicarboxylate ester is
monosaponified and transformed in a few steps to the protected alcohol ester. With a similar
sequence, followed by oxidation the aldehyde is obtained. Then the ketone is prepared by
Grignard reaction and oxidation, and this ketone is hydrocyanated with a silyl reagent.
Hydrolysis and deprotection gives the hydroxyester. A resolution step is made at this point
with quinine. Afterwards lactonisation gives bicyclic furan that is photooxygenated. Two
regioisomers are formed (only one shown), and chlorination transforms this building block in
a reactive chloride.
The other (“left”) part of the molecule is simply prepared staring from acridine that is
ozonized, reduced, mesylated and converted with aq. ammonia to the desired compound. Both
molecules then are combined, giving the acetate precursor that is deprotected to give
camptothecin.

An alternative synthesis with a slightly different disconnection starts for the first part from a
deracemised malonic monoester that is amidated by treatment with the Mukiyama reagent and
amine. Reduction with DIBAH gives the aldehyde.

The second part starts with a quinoline synthesis, using the Vilsmeier reaction of N-
propanoylanilide. Pd-catalysed carbonylation in MeOH leads to the methyl ester, which is
subsequently brominated, methanolized and subjected to a Claisen condensation with the
anion of methyl phosphonate.
These two building blocks were then combined by a Wittig-Horner reaction, leading to a
trans-alkene. The latter is converted into a piperidone by a [3+3] approach. The latter is
oxidized to a pseudoaromatic pyridone. Acidic cleavage affords the lactone which then is
reduced to a diol. This diol can under the influence of strong acid undergo a double
cyclisation with formation of camptothecin.
7.2.3. Strychnine

Strychnine is an alkaloid that is present in Strychnos species. It may be used as pesticide or rat
poison and 50 mg may be sufficient to kill an adult human. Sir Robert Robinson remarked
after the structure elucidation in 1946 that “For its molecular size it may be the most complex
substance known”. Indeed strychnine has 6 stereocenters and seven rings, of which most are
heterocyclic.

The Woodward synthesis starts with a Fischer indole synthesis (ring 1 and 2), followed by
introduction of a ethyleneamine group by classical synthesis (Mannich reaction, methylation
of the gramine analog, treatment of the ammonium salt with cyanide and reduction of the
nitrile). This amine is then condensed with ethyl glyoxalate. The resulting imine is
transformed into a spiro compound (one diastereomer, ring 3). Reduction of this indolenine
creates another stereocenter selectively, but the latter is not retained in the final structure.
The synthesis is continued with an ozonolysis of the more electron rich aryl ring. This gives a
diester in rather poor yield. After acid-catalysed amide cleavage and isomerization, a fused
pyridone is obtained (ring 4). The latter is hydrolysed, acylated and reesterified after which
the product is epimerized. After this epimerization, a Dieckmann ester condensation affords
the fifth ring.

The enol is O-tosylated and substituted with benzylthiol. Raney Nickel then removes the
sulfur function. Further catalytic reduction reduces the cyclohexene, but not the
pseudoaromatic pyridone. Saponification is accompanied with epimerisation, and this less
sterically hindered acid is treated with acetic anhydride in pyridine, to yield the acyl
compound. The latter is oxidized with selenium dioxide to a glyoxal, that undergoes in situ
cyclization (ring 6), and further oxidation affords a dione (dehydrostrychninone)
Starting from dehydrostrychninone, acetylide can be added to the more reactive carbonyl and
the resulting product reduced to an allyl alcohol. Reduction of the latter gave selectively a
dihydropyrimidinone, which could be isomerized to isostrychnine. Basic treatment of
isostrychine completes the synthesis (ring 7).
In the Overman synthesis of strychnine, a different and more sophisticated strategy is
followed. We give only the highlights. Via a multistep procedure, a protected ortho-
acylaniline is prepared. Diastereoselective epoxidation followed by Wittig reaction and
selective deprotection with fluoride anion gives an alcohol, which is mesylated, transformed
in the chloride and substituted with trifluoroacetamide. Base-catalysed attack on the oxirane
affords a bridged piperidine, which is N-deprotected in basic medium.

The next synthetic step is a crucial cascade reaction and involves first the formation of a
Mannich reagent, followed by an aza-Cope rearrangement and then an intramolecular
Mannich reaction, all happening in situ. The resulting ketone is converted with LDA to an
enolate which is combined with methyl cyanoformate, affording a β-ketoester after loss of
cyanide. Now the aniline function is released in acidic medium, after which the indole ring is
created by acid-catalyzed condensation of the ketone and amine and tautomerization of the
intermediate imine to the conjugated enamine, while at the same time the tert-butylgroup is
cleaved.
Reduction of the conjugated enamine with zinc in acidic methanol leads to an epimer mixture
that can be transformed to the thermodynamically most stable (and desired) isomer by
treatment with base. Subsequently, the lactone is formed by attack of the alcoholate on the
ester function. This lactone is then reduced to the so-called Wieland-Gumlich aldehyde,
which can be converted to strychnine by treatment with malonic acid and acetic anhydride.
The reaction with malonate in basic medium (piperidine) gives the unsaturated acid (Doebner
modification of Knoevenagel reaction) that undergoes intramolecular reaction to isostrychnic
acid. The latter has a configuration that does not allow cyclization, epimerisation to strychnic
acid is accompanied by formation of the mixed anhydride and lactamization to strychnine.
7.2.4. Reserpine

Reserpine is a CNS-active alkaloid that is found in the roots of the Indian plant Rauwolfia
serpentina. It is an effective medicine for the treatment of hypertensive, neural and mental
diseases. Below we treat the Woodward synthesis (R. Woodward et. al, JACS 1956, 23,
2023).

Retrosynthetically, the indole of reserpine is disconnected from a highly functionalized all-

carbon ring in a few simple steps. The carbocyclic ring can be brought back to a Diels-Alder
reaction of a diene and a dienophile (quinone).

Thus, Diels-Alder reaction of quinone and methyl pentadienoate gives the endo-adduct that
can be reduced and epoxidized (on the most electron rich side). This already affords three of
the five stereocenters of reserpine. Meerwein-Pondorff-Verley reduction of this bicyclic
adduct gives first a diol (stereoselective reduction on convex side) and then a lactone, which
is further cyclized with bromine. Dehydrobromination via a E1cb-mechanism and Michael
addition of methoxide gives a methyl ether (retention of configuration again because of steric
reasons). In this tetracyclic product, five of the six stereocenters of reserpine are already
present.

Starting from this tetracyclic product, a bromohydrin is obtained (regio- and stereoselectively)
that is subsequently oxidized. The resulting α-bromoketone is treated with zinc in acetic acid
to give (1) reductive cleavage of the lactone and (2) a zinc enolate (cf Reformatski reaction)
that ring opens (E1cb). Thus, the tetracyclic compound is converted back into a bicyclic one.
Mild esterification of the latter compound with diazomethane is followed by acetylation of the
alcohol function with acetic anhydride. The alkene function is then selectively dihydroxylated
with the very expensive and toxic osmium tetroxide, potassium chlorate acting as the
stoichiometric oxidant. Finally, the bicyclic building block is converted to a monocyclic
compound by cleavage of the diol with periodate and mild esterification. One carbon atom is
removed as CO2, as this reagent also cleaves dicarbonyls. The result of this lengthy synthesis
is a highly functionalize cyclohexane, and epimerisation of the carbon next to the formyl
function is blocked because of the chair conformation with four of the five substituents in
equatorial position.
This cyclohexane building block is now combined with 6-methoxytryptamine, yielding the
imine intermediate that is reduced with sodium borohydride to afford a lactam after
cyclisation. The next step is a Bischler-Napieralski cyclisation, affording an iminium salt that
is reduced with sodium borohydride by attack on the less sterically hindered side.
The newly created stereocenter is not correct in comparison with reserpine, it needs to be
inverted. This epimerisation can be carried out with acid and works via protonation of the
indole ring at the (indole) C-3. A shift of the double bond to the third ring occurs, and
reprotonation gives the correct stereoisomer after regeneration of the indole ring.
Unfortunately, the equilibrium is to the left. An elegant way to shift this equilibrium is by
making a lactone bridge between the carboxylate and protected alcohol functions on the fifth
ring. The lactonisation is carried out with dicyclohexylcarbodiimide, a known coupling
reagent for esters and amides. The final steps of the reserpine total synthesis are lactone
cleavage (transesterification) and attachment of the 3,4,5-trimethoxybenzoyl group.

7.2.5. Thienamycine

Thienamycin is a carbapenem antibiotic of which the structure was determined, and the total
synthesis reported, by Merck scientists (1980). The carbapenem structure is rather unstable
and quite reactive, and therefore it is best to generate it later in the synthesis.
Retrosynthetically, thienamycin can be derived from its β-ketoester analog that can be formed
from a diazoester by carbene insertion. The azetidinone can be prepared in a few steps starting
from L-aspartic acid.
Thus, the dibenzylated aspartic acid was N-silylated and combined with a sterically hindered
Grignard reagent and worked up with acid. The resulting azetidinone ester was reduced with
sodium borohydride to the alcohol and transformed to the iodide by mesylation and
Finkelstein reaction. Furthermore, this building block is N-protected with a tert-
butyldimethylsilyl group.

A lithiated 1,3-dithiane is used to introduce an extra carbon atom. This compound can be
lithiated next to the carbonyl function. Combination with acetaldehyde gives two isomers of
the aldol (1:1 mixture), therefore the alcohol is oxidized to a ketone, and again reduced with
L-Selectride to give a 9:1 mixture in favor of the desired epimer (the one shown). The ketone
can also be prepared directly from the lithiated intermediate by treatment with acetylated
imidazole (azolide).
Hydrolysis of the purified alcohol occurs with a mercuric salt, and the resulting acylsilane is
then oxidized to a carboxylic acid, converted to an azolide and condensed with a magnesium
salt of monoprotected malonic acid. This affords the β-ketoester needed for the diazo transfer
with 4-carboxyphenylsulfonyl azide (after acid-catalyzed removal of the TBDMS group).

The diazo group may be decomposed in the presence of a rhodium salt, and the carbene
generated will then insert in the N-H function. The cyclic β-ketoester is then converted in an
enol phosphonate, and substituted with a protected cysteamine. Finally, hydrogenolytic
deprotection affords the desired (+)-thienamycin.