Q8(a). Starting compounds for five heterocycles
Suggest suitable starting compounds and structures for the synthesis of the following heterocyclic compounds.
(i) [structure] (ii) [structure] (iii) [structure]
(iv) [structure] (v) [structure]
Answer in brief
(i) p-Anisidine + crotonaldehyde (Doebner–Miller); (ii) N-acetyl-2-phenylethylamine, POCl₃, then dehydrogenation (Bischler–Napieralski); (iii) phenylhydrazine + hexan-2-one (Fischer); (iv) salicylaldehyde + ethyl acetoacetate (Knoevenagel); (v) tetrahydropyran-4-one + triethyl phosphonoacetate (HWE).
Key points
- Introduction. Each ring is built by a named ring-forming reaction: Skraup/Doebner–Miller (quinoline), Bischler–Napieralski (isoquinoline), Fischer (indole), Knoevenagel–lactonisation (coumarin); (v) is an olefination of a…
- Conclusion. (i) p-Anisidine + crotonaldehyde (Doebner–Miller); (ii) N-acetyl-2-phenylethylamine, POCl₃, then dehydrogenation (Bischler–Napieralski); (iii) phenylhydrazine + hexan-2-one (Fischer); (iv) salicylaldehyde + ethyl…
The full model answer
Written out in full, as it should go in the answer booklet. The solution page with its diagrams follows it.
Introduction. Each ring is built by a named ring-forming reaction: Skraup/Doebner–Miller (quinoline), Bischler–Napieralski (isoquinoline), Fischer (indole), Knoevenagel–lactonisation (coumarin); (v) is an olefination of a heterocyclic ketone.
| Target | Starting compounds | Reaction and key step |
| (i) 6-methoxy-2-methylquinoline | p-anisidine + crotonaldehyde (or 2 CH₃CHO) | Doebner–Miller: conjugate addition of ArNH₂, acid cyclisation onto the ring ortho to N, dehydration, oxidation (nitrobenzene or air) |
| (ii) 1-methylisoquinoline | N-acetyl-2-phenyl-ethylamine (2-phenylethylamine + Ac₂O) | Bischler–Napieralski: POCl₃ (or P₂O₅), nitrilium ion attacks the ring → 1-methyl-3,4-dihydroisoquinoline; Pd/C, heat dehydrogenates |
| (iii) 2-methyl-3-propylindole | phenylhydrazine + hexan-2-one | Fischer indole: phenylhydrazone → ene-hydrazine on the CH₂ side → [3,3]-shift, cyclisation, loss of NH₃ (ZnCl₂ or PPA) |
| (iv) 3-acetylcoumarin | salicylaldehyde + ethyl acetoacetate | Knoevenagel (piperidine): C=C forms at the active CH₂, phenolic OH closes the lactone with loss of EtOH |
| (v) ethyl (oxan-4-ylidene)acetate | tetrahydropyran-4-one + triethyl phosphonoacetate (EtO)₂P(O)CH₂CO₂Et | Horner–Wadsworth–Emmons (NaH, THF); or Wittig with Ph₃P=CHCO₂Et |
Scheme:
Conclusion. (i) p-Anisidine + crotonaldehyde (Doebner–Miller); (ii) N-acetyl-2-phenylethylamine, POCl₃, then dehydrogenation (Bischler–Napieralski); (iii) phenylhydrazine + hexan-2-one (Fischer); (iv) salicylaldehyde + ethyl acetoacetate (Knoevenagel); (v) tetrahydropyran-4-one + triethyl phosphonoacetate (HWE).
Application. The Fischer synthesis is used industrially for the triptan antimigraine drugs and indomethacin; the Bischler–Napieralski reaction is the route to papaverine and other isoquinoline alkaloids.
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All parts of Question 8
- 8(a) Starting compounds for five heterocycles10 marks
- 8(b) Mass spectra of 4-phenylbutan-2-one and 4-ethylanisole10 marks
- 8(c) Birch-type reduction of α-cyperone: trans ring fusion10 marks
- 8(d) Structure of C₉H₁₀O₂ from UV, IR and NMR10 marks
- 8(e) Preparation of five compounds (pericyclic routes)10 marks