Heterocycles, KIBM

Azoles

1,3-azoles tend to undergo clean electrophilic substitution at C5, but are less reactive than pyrrole
1,2-azoles generally undergo electrophilic substitution at C4

Imidazoles from α-aminoketones and nitriles
Thiazoles from α-haloketones and thioamides
Pyrazoles from 1,3-dicarbonyls and hydrazines
Isoxazoles from 1,3-dicarbonyls and hydroxylamine
1,3-Dipolar cycloadditions: 1,3-dipoles (ozone, azides, nitrile oxides) + alkenes or alkynes
- Azide alkyne Huisgen cycloaddition - click chemistry, forms tetrazoles
- Nitrile oxides from chlorination of oximes, followed by elimination of hydrogen chloride
- Nitrile oxides + alkynes → isoxazoles (as seen in VKA's course)

Lithiation by deprotonation of 1,3-azoles at C2 with butyllithium, followed by an electrophile (e.g. alkyl halide, carbonyl compound)
1,2-azoles are deprotonated at C3, but these can ring-open to give α-cyanoenolates, which react with electrophiles to form α-cyanoketones

Electrophilic substitution at C3 is preferred, but may also get 2,3-disubstitution
- Mannich reaction with formaldehyde and dimethylamine, forming the important building block gramine
- Electrophilic bromination with Br₂
- Friedel-Crafts acylation with Ac₂O and AcOH
- Vilsmeier reaction with DMF and POCl₃

Reissert indole synthesis, starting from ortho-nitrotoluenes
- Leimgruber modification
  - ortho-nitrotoluenes + acetal of an amide → enamine
  - enamine undergoes reductive cyclisation with acid (converts enamine to ketone) and Pd/H₂ (reduces ArNO₂ to ArNH₂)
Bischler-Möhlau indole synthesis
Fischer indole synthesis
- Starts with a phenylhydrazine, which reacts with a ketone to form a hydrazone
- The hydrazone is protonated, tautomerises, then undergoes a [3,3]-sigmatropic rearrangement
- The weak N-N bond is broken, and a stronger C-C bond formed, although the aromaticity of the benzene ring is sacrificed
- Acid-catalysed elimination of ammonia leads to the indole

Fischer synthesis not useful because the requisite ketones exist as their phenol tautomers
Use nitrene pathway or the Graebe-Ullmann reaction

Benzofurans differ from indoles in that they tend to undergo electrophilic substitution in the 2 position, rather than the 3 position
- This is probably because furan is far less aromatic than pyrrole, so the benzene ring of a benzofuran has more influence on the substitution pattern
Vilsmeier reaction, nitration and lithiation at occur at the 2 position
With bromine, benzofurans undergo electrophilic addition across the furan double bond - suggesting less aromaticity than indole

O-Aryl hydroxylamines react with ketones to give O-aryl ketoximes, which cyclize and dehydrate in acid to benzofurans, by a mechanism analogous to that of the Fischer indole synthesis
Sodium phenoxides react with α-bromoketones to give α-phenoxyketones, which cyclize and dehydrate in acid to benzofurans. This is the oxygen equivalent of the Bischler indole synthesis.

Quinoline
Isoquinoline
Both π deficient heterocycles
Their physical properties and chemical reactivity are very similar, but their syntheses are very different

Quinoline undergoes nitration and bromination in the 5 and 8 positions (1:1 mixture of isomers)
Isoquinoline is more selective and only the 5 position is substituted

Both are attacked by nucleophiles at the 2 position, much like imines
A nitrogen-stabilised anion is the intermediate
Acid and oxidation generates the substituted quinoline or isoquinoline
Both undergo the Chichibabin reaction, with potassium amide and high temperatures, forming the 2-amino product
2-chloroquinolines and isoquinolines (much like 2-chloropyridines) are excellent electrophiles and undergo nucleophilic aromatic substitution at much lower temperatures. As chloride is a good leaving group, aromatisation is spontaneous.

2-alkylquinolines have an acidic proton that can be removed by BuLi, forming an aza enolate that reacts with electrophiles

There are a number of important dihydroquinoline and tetrahydroquinoline drugs, so reduction of quinolines is industrially important
Lithium aluminium hydride reduces quinolines to dihydroquinolines, formally adding H₂ across the N=C² double bond
H₂/Pt reduces the pyridine ring, leaving the benzene ring intact, thereby forming the tetrahydroquinoline
H₂/Pd in concentrated hydrochloric acid reduces only the benzene ring, leaving the pyridine ring untouched
- HCl must protonate the nitrogen sp² lone pair, somehow deactivating the pyridine ring to hydrogenation.

Coumarins and chromones
- Bergapten (5-methoxypsoralen) - 1970s sunscreen, now known to be carcinogenic
- Chromone synthesis: Kostanecki-Robinson reaction