Question

The correct option(s) of reagents and reaction sequences suitable for carrying out the following transformation is/are 

• A. (i) Li-C\( \equiv \)C-H, THF, -70 \(^\circ \)C; (ii) cat. HgSO\( _4 \), H\( _2 \)SO\( _4 \), H\( _2 \)O; (iii) aqueous acid, \( \Delta \)
• B.
• C. (i) LDA, TfNPh\( _2 \); (ii) cat. [(dppe)Pd(0)], (iii) aqueous acid, \( \Delta \) (dppe = diphenylphosphinoethane)
• D. (i) H\( _3 \)C-NO\( _2 \), NaOCH\( _3 \); (ii) sat. NaCl; (iii) TiCl\( _3 \), H\( _2 \)O; (iv) aqueous acid, \( \Delta \)

Hint:

For introducing an acetyl group at the alpha-position and forming an alpha,beta-unsaturated ketone, consider reactions that involve enolate chemistry, alkyne hydration, or palladium-catalyzed coupling reactions of enol derivatives. Pay attention to the regioselectivity of enolate formation and subsequent reactions.

Answer 1

The Correct Option is A, C

The desired transformation involves the conversion of cyclohexanone to 2-acetylcyclohexene. This requires:

• Introduction of an acetyl group at the α-position to the carbonyl
• Formation of a double bond at the α,β-position

 

(A)

• (i) Li–C≡C–H, THF, −70 °C: Lithium acetylide adds to the ketone, forming an alkoxide.
• (ii) cat. HgSO₄, H₂SO₄, H₂O: Hydration of the terminal alkyne via Markovnikov addition gives a methyl ketone at the acetylide terminus.
• (iii) Aqueous acid, Δ: Promotes dehydration, forming a conjugated enone. Final product is 2-acetylcyclohexene.

✅ Suitable route

(B)

• (i) Ethyl vinyl ether with NaH deprotonates cyclohexanone to form an enolate, which reacts in an aldol-like fashion to give a β-alkoxy ketone.
• (ii) Aqueous acid and heat hydrolyze the ether and cause dehydration, but regioselectivity is uncertain.

⚠️ Less reliable due to poor regioselectivity

(C)

• (i) LDA forms the kinetic enolate; TfNPh₂ traps it as an enol triflate.
• (ii) Pd(0)-catalyzed Heck coupling with a vinyl ketone forms the C–C bond. β-Hydride elimination yields the enone.
• (iii) Aqueous acid/heat ensures workup to yield 2-acetylcyclohexene.

✅ Excellent modern synthetic route

(D)

• (i) CH₃NO₂, NaOCH₃: Henry (nitroaldol) reaction introduces a nitro group α to the ketone.
• (ii) sat. NaCl; (iii) TiCl₃, H₂O: Nef reaction converts nitro to a carbonyl, but no controlled α,β-unsaturation.

⚠️ Mechanistically possible, but less direct and lower regioselectivity

Conclusion:
The most suitable reaction sequences for the transformation are:

• Option (A) – via acetylide addition and hydration
• Option (C) – via enol triflate and Heck coupling