Chapter 4

N

OS Ring Synthesis of

Aromatic Heterocycles

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6.1 Reaction Types Most Frequently Used in Heterocyclic Ring Synthesis By far the most frequently used process is the addition of a nucleophile to a carbonyl carbon (or the more reactive carbon of an O - protonated carbonyl). When the reaction leads to C–C bond formation, then the nucleophile is the β - carbon of an enol or an enolate anion, or of an enamine.

4.1 Typical Reactant Combinations

I. Carbonyl condensation type reactions II. Cycloadditions a) with 1,3-dipoles b) with ortho-quinodimethanes (DA type react.) III. Nitrene insertion

Carbonyl condensations

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By far the most frequently used process is the addition of a nucleophile to a carbonyl carbon (or the more reactive carbon of an O-protonated carbonyl)

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4.1 Typical Reactant Combinations

Strategy a: Involving Only C-Heteroatom Bond Formation. 5-membered rings

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Strategy a: Involving Only C-Heteroatom Bond Formation 6-membered rings

For six-membered rings, the 1,5-dicarbonyl precursor has to contain a C-C double bond in order to lead directly to the aromatic system.

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The use of an otherwise saturated 1,5 - dicarbonyl compound does not lead directly to an aromatic pyridine, though it is easy to dehydrogenate the dihydro - heterocycle.

Strategy b: 5-membered rings one component must contain an enol/enolate/enamine, or the equivalent thereof

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the second obviously must have electrophilic centres to match.

+ -H+

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6-membered rings

Where a carbonyl component at the oxidation level of an acid is used then the resultant product carries an oxygen substituent at that carbon.

Similarly, if a nitrile group is used instead of a carbonyl group, as an electrophilic centre, then the resulting heterocycle carries an amino group at that carbon

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Amongst often used 1,3-difunctionalised compounds are the doubly electrophilic 1,3-dicarbonyl compounds and α,β-unsaturated carbonyl compounds (C=C-C=O), doubly nucleophilic HX-C-YH (amidines and ureas are examples), and α-amino- or α-hydroxycarbonyl compounds (HX-C-C=O), which have an electrophilic and a nucleophilic centre.

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amidines pyrimidines pyrazoles

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In syntheses of benzanellated systems, phenols can take the part of enols, and anilines react in the same way as enamines

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The ring synthesis of 2,4,6-triphenylpyrylium cation

Write a plausible mechanism!

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Possible Mechanism:

An equally plausible sequence, shown below, starts with the nucleophilic addition of the enolic hydroxyl of the diketone to protonated acetophenone.

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4.2 Electrocyclic Processes in Heterocyclic Ring Synthesis

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1,3-Dipolar Cycloaddition

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Example:

Alkene dipolarophiles, with a group that can be eliminated following cycloaddition, for example enamines as the dipolarophile.

Many mesoionic substances can act as 1,3 - dipoles, and, after elimination of a small molecule (carbon dioxide in the example shown ) produce aromatic heterocycles.

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4.3 Nitrenes in Heterocyclic Ring Synthesis

Nitrene insertion

A nitrene is a monovalent, six - electron, neutral nitrogen, most often generated by thermolysis or photolysis of an azide or by deoxygenation of a nitro group.

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The preparation of an indole and of carbazole

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nitrene generated from an azide

nitrene generated by deoxygenation of a nitro group

Hemetsberger – Knittel synthesis

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4.4 ortho-Quinodimethanes in heterocyclic compound synthesis

a) Apart from studies of spectroscopic and other physical properties, the unstable and reactive ortho-quinodimethanes are not isolated but are generated in the presence of the trapping reactant. b) Their adducts with sulfur dioxide can be a convenient way in which to store ortho-quinodimethanes generated by other means.

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4.4 ortho-Quinodimethanes in heterocyclic compound synthesis

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The extrusion of sulfur dioxide from heterocyclic sulfones is probably the most generally used method for the generation of ortho-quinodimethanes. Such sulfones are generally stable and easy to synthesise, by various routes. In addition, the acidity of the protons adjacent to the sulfone unit allows for base-promoted introduction of substituents, before thermolytic extrusion and the Diels-Alder step.

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The generation then trapping of ortho-quinodimethanes, in both intermolecular and intramolecular reactions, has become an important route for the construction of polycyclic heterocyclic compounds. From the point of view of ring construction, the most important trapping reactions are those in which the ortho-quinodimethane acts as a diene in Diels-Alder cycloadditions, thereby regaining a fully aromatic ring, as illustrated below.

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1,4-Eliminations have involved l,2-bis(bromomethyl)-heterocycles with hot sodium iodide:

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1,4-Eliminations have involved ortho-(trimethylsilylmethyl) heterene-methylammonium salts, ortho-(trimethylsilylmethyl) heterenecarbinol mesylates, each with a source of fluoride.

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4.4 ortho-Quinodimethanes in heterocyclic compound synthesis

1,4-Eliminations have involved o-(tri-n-butylstannyl-methyl)heterene-carbinol acetates with a Lewis acid.

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4.4 ortho-Quinodimethanes in heterocyclic compound synthesis

1,4-Eliminations: An extensively developed route involves loss of a proton from indol-3-ylcarboxaldehyde imines (or their pyrrolic counterparts), following reaction with an acylating agent,

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The use of cyclobuteno-heterocycles is of course dependent on a convenient synthesis (for an example, see section 11.14.2.3), but when available, they are excellent precursors, only rather moderate heating being required for ring opening, as shown by the example below, in which the initial Diels-Alder adduct is aromatised by reaction with excess quinone.

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