Heterocycle ring synthesis

What is the heterocycle ring synthesis?

Heterocycle ring synthesis addresses general methods for the construction of heterocyclic compounds from open-chain precursors. The chemical reactions of ring formation are not limited to a particular heteroatom, but apply to a wider range of structures. The nature of the ring closure depends more on size and unsaturation than on the heteroatom and substituents.

The types of ring formation reactions can be divided into two major groups:

  • Cyclization reactions: in these reactions, a single ring bond is formed.
  • Cycloaddition reactions: two ring bonds are formed and no small molecules are removed during the process.

When designing the synthesis of a particular heterocycle the following considerations must be taken into account:

  • What is the most suitable bond to form at the ring construction stage.
  • What degree of unsaturation is required in the heterocycle.
  • What functional groups are needed, and whether these are best introduced in a step before, during or after ring formation.
  • What stereochemistry, if any, is present in the heterocycle.

The synthesis of any molecule can be approached by the so-called retrosynthetic analysis, in which bond building processes are designed, in reverse order, starting from the target.

Example of retrosynthetic analysis for the synthesis of the thiazole ring.



The result of this retrosynthetic analysis indicates the starting substances needed to form the ring. It may happen that no intermediates are isolated from these reactions, and even the sequences of the reactions may vary.

Cyclization reactions (ring formation)

Displacement at saturated carbon

SN2 intramolecular reactions are widely used for the construction of saturated heterocyclic compounds.

The 5-membered rings are, in general, the easiest to form. This is because this ring size represents the best balance between the entropy ΔS and enthalpy ΔH terms. Thus the rings are stress-free and the transition states are accessible.

In Table 1, the influence of chain length on nucleophilic substitution cyclization rates for the cyclization of bromo alkyl amines are shown.

Table 1: Values of rate constants of the Br—(CH2)n-1 —NH2 cyclization reaction in water at 25 ºC.


As can be seen in Table 1, the formation of 5- and 6-membered cycles is particularly favored. When n=3 the process is relatively favorable, despite the aziridine strain. This is due to the low degree of ordering required by the transition state.

In cases where the ring closure rates are low, it may happen that they do not compete effectively with the intermolecular reactions and therefore the yields of the products are low.

For example, in the cyclization reaction of 3-chloropropanol (ClCH2CH2CH2OH) with sodium hydroxide (HO⊖) in aqueous methanol (MeOH/H2O). A 78 % yield of the open-chain product of the solvolysis is obtained, and in 14 % yield oxetane.


Cyclization reactions extend their scope with in situ formation methods of appropriate precursors.

For example, in the Darzens reaction for the synthesis of oxiranes from carbonyl compounds with anions of α-haloesters.


This reaction leads to the formation of intermediates that cycle by internal nucleophilic displacement.

On the other hand, exo-tet cyclization can be affected by various types of internal nucleophiles other than amino and hydroxyl groups.

Some examples of cyclization reactions are carried out with enolizable ketones and amide functions as nucleophiles in the presence of bases.


In the cyclization intermediate, a nucleophilic shift occurs on a saturated carbon atom.

Intramolecular nucleophilic addition to carbonyl groups

This is the most common cyclization process in the synthesis of heterocycles. The internal nucleophilic attack on the carbonyl group of esters, acyl chloride, etc., is followed by the displacement of a leaving group while retaining the carbonyl function in the cyclic product.

After the attack of a nucleophile on the carbonyl group of an aldehyde or ketone, dehydration of the intermediate usually occurs, especially when this leads to the formation of a heteroaromatic system.

Such cyclizations can be acid catalyzed, when the nucleophile is weak, and in this case the attack probably occurs on the protonated carbonyl function.

Examples of aldol type cyclization (attack by a nucleophilic carbon)

  • Hinsberg Synthesis of thiophenes (from 3,4-disubstituted compounds)


  • Paal-Korr synthesis of pyrrole


  • Madelung indole synthesis


  • Aldol cyclization


Examples of cyclizations by nucleophilic heteroatoms



Examples of cyclizations on ortho positions

  • Bischer synthesis of indoles


  • Skraup quinoline synthesis (Doebner-von Miller)


  • Bischler-napieralski isoquinoline synthesis


Intramolecular addition of nucleophiles to other double bonds

Activated carbon-sulfur (C=S) and carbon-nitrogen (C=N) double bonds can act as electrophiles. Thus, like the activated carbon-carbon (C=C) double bond on which an internal conjugate addition can take place.

Examples of these types of exo cyclization on trigonal centers (exo-trig) are listed below.

  • Activated C=S and C=N bonds that can act as electrophiles.


  • Activated C=C bonds that can act as electrophiles.


The vast majority of cyclizations are carried out by reaction on an electrophilic carbon. However, there are some heterocycle syntheses that involve cyclization on an electrophilic nitrogen. In the following reaction, the electrophile is the nitro group.


Cyclations on triple bonds

Nucleophilic addition to cyano (-C≡N) groups is an important method for the synthesis of substituted C-amino heterocycles. For example:


In these reactions the initial cyclization product is an imine. A proton shift then takes place to convert the initial product into a more stable aromatic C-amino compound.


Exo addition to triple bonds (-C≡C-) is less common, but has been used to synthesize some 5- and 6-membered heterocycles.


In addition, examples of heterocyclic syntheses involving endo cyclizations over a triple bond have been described.


Radical cyclizations

The intramolecular addition of a radical to a π-bond leads to the formation of a ring. Most of the systems produced by radical cyclizations are 5- and 6-membered, both partially and fully saturated.

The process, generally, consists of a radical carbon being attached to the carbon atom of a π bond which may be C=C or C≡C, or form part of an aromatic ring.

A heterocycle would be formed if heteroatoms are present in the bond chain (exo preference). The final products that are isolated depend on the method used to form radicals.

An example of these reactions is the reductive cyclization caused by tributyltin hydride. As a radical initiator, 2,2′-azobis(isobutyronitrile) is used which decomposes to produce radicals.


In another example the nitrogen-sulfur bond is broken with tertiary butyl tin hydride (Bu3SnH) to form the cycling nitrogen radical.



Other such cyclizations have been described using aromatic diazonium salts, which are converted to aryl radicals by one-electron reduction followed by loss of nitrogen gas N2.


Cyclations of carbenes and nitrenes

Both nitrenes (monovalent nitrogen) and carbenes (divalent carbons) are highly reactive species that can undergo addition reactions of ultralinkages and insert into unactivated C-H bonds.

For example, the following cyclization reaction starts with the thermal (or photochemical) decomposition of an azide (N3), to give the corresponding nitrene (singlet) which cyclizes. Finally, a migration of hydrogen to nitrogen occurs to give the carbazole.


Another example is the synthesis of a β-lactam from a diazocompound (N2) which photochemically generates the corresponding carbene. This carbene has an inactivated C—H bond of the sp3 carbon. This carbene cycles to the β-lactam, which is indicated in the scheme.


Electrocyclic reactions

Electrocyclic reactions are different from the cyclization reactions we have seen so far. Which are intramolecular variants of known processes of σ-bond formation.

However, electrocyclic reactions do not have an analogous intermolecular reaction. The open-chain reagent used in an electrocyclic closure has to be a fully conjugated π-electron system.

El cierre electrocíclico es la reacción en la que se forma un enlace σ en los extremos del sistema π , cerrándose el anillo.

These reactions generally take place with the input of energy in the form of heat (Δ) or light () and without additional reagents. An equilibrium is established between acyclic and cyclic isomers with predominance, in many cases, of the acyclic isomer. Thus, the electrocyclic reaction may be a ring opening rather than a ring formation.


Four types of electrocyclic reactions occur in heterocyclic chemistry:

  • Reagents with 4 π-electrons in 1,3-dipolar species


  • Reagents with 4 π electrons in a heterodiene.


  • Reagents with 6 π electrons in 1,5-dipolar species.


  • Reagents with 6 π electrons in a heterotriene.


Higher order electrocyclic reactions of systems with more than 6 π electrons are also feasible, but these are not commonly encountered.

In principle, any type of electrocyclic reaction can be carried out both thermally and photochemically.

The stereochemical distinction between conrotatory and disrotatory processes is lost when one of the terminal atoms of the open π-system is a heteroatom. Therefore, in many reactions leading to the preparation of heterocycles it is not possible to verify the Woodward-Hoffmann rules.

Electrocyclic 4-π-electron reactions occur with substrates containing heteroatoms. That is, with 3-membered heterocycles of the type.


and also of the type shown in the following figure.


Ring opening is the most common process and can be triggered by the action of heat (Δ) or light ().

Ring closure is limited to a few examples and is generally a light-induced process ().


In this other example, the compound 2,5-dihydro-1,3,4-thiadiazole is thermally cleaved to give a thiocarbonyl yllide, which cyclizes and a thiirane is obtained.


Another example, in this case of 3-membered ring opening of 2H-azirines, the opening occurs to generate a 1,3-dipolar compound (nitrile yllide) that can be used as a synthesis intermediate.


On the other hand, 6-electron π-cyclations are much more common and have been generally described as 1,5-dipolar cyclizations.

The 1,5-dipoles are unstable, are prepared in situ and thermally cyclized to give the corresponding 5-membered heterocycles, as indicated in the schemes.


and with respect to 6-membered heterocycles they are formed as follows.



Cycloaddition reactions (ring formation)

A large number of heterocycles can be synthesized by means of cycloaddition reactions, especially those containing 4, 5, or 6 atoms in the ring. The most relevant types of cycloadditions in heterocycle chemistry are the following:

  • 1,3-dipolar reactions

They are carried out with a large number of dipoles, and are indicated to form 5-membered heterocycles.


  • Hetero Diels-Alder reactions

They are used to obtain 6-membered heterocycles.


  • [2+2] Cycloaditions

They are particularly suitable for generating 4-membered heterocycles.


  • Chelotropic reactions

En ellas se dona o acepta un par de electrones para formar dos enlaces σ, se pueden obtener heterociclos de 3 y 5 miembros.


  • Alder-ene reactions

Although strictly speaking, it does not lead to the formation of a cyclic compound, saturated 5- and 6-membered heterocycles can be obtained in a subsequent step.


1,3-dipolar reactions

Hetero Diels-Alder reactions

The cycloaddition of conjugated dienes to activated olefins and acetylenes is known as the Diels-Alder reaction. It has high stereo- and regio-selectivity due to the adducts and the number of substituents. They are used in the synthesis of heterocycles to obtain 6-membered rings.


A summary of the dienes and dienophiles incorporating heteroatoms are grouped in the following figures.




Some examples of these reactions are listed below.



[2+2] Cycloaditions

A variety of 4-membered heterocycles can be prepared by [2+2] cycloaddition reactions.


The most useful reaction components for the formation of heterocycles are ketenes, isocyanates, isothiocyanates, and carbodiimides. Also, azacarbonyl compounds undergo [2+2] additions with various olefins.

Some go well with only a limited number of substituents and the 4-membered transition state when stressed gives predominant side reactions.


The following [2+2] cycloaddition between a ketene and imine is of particular relevance in the synthesis of β-lactams.


These reactions present a transition state with 4 π electrons and are not aromatic (as in the case of the Diels-Alder which presents 6 π electrons).



Chelotropic reactions

Chelotropic reactions occur when two σ-bonds are formed or broken from a single atom in a concerted reaction (without defined reaction intermediates).


Although they present limited utility for the synthesis of heterocycles. However, aziridines can be synthesized by addition of nitrenes to olefins, or carbenes plus C≡N to give aziridines, or also, carbenes and C=S to give thiiranes.


Another example of a chelotrophic reaction would be the addition of sulfur dioxide (SO2) to butadiene to give 2,5-dihydrothiophene-1,1-dioxide (sulfolene). The reaction is reversible and is used to generate butadiene.

Alder-ene reactions

These reactions have a close mechanistic relationship with [4+2] cycloaddition.


Although the intermolecular eno (or Alder-ene) reaction does not lead to a cyclized product, instead, the formation of a σ bond with the allylic carbon atom suffices to produce a new ring system.

The reaction exhibits high stereoselectivity and has been used to synthesize several 5- and 6-membered saturated heterocycles.



An example of this reaction showing stereochemistry are the intramolecular version.