Enantioselective Hetero-Diels-Alder Reaction of Aromatic Aldehydes Catalyzed by ((R)-1,1´-Bi-2-naphthoxy)titanium Dichloride: Experimental and Theoretical Results

Background: The hetero-Diels-Alder (HDA) reaction of the carbonyl compounds with conjugated dienes, sometimes referred to as oxa-DA reaction, is an important method for the preparation of dihydropyrans, which are useful starting materials for the synthesis of several natural products including carbohydrates. However, carbonyl group as such is a less reactive dienophile and usually requires the use of a catalyst to enhance its reactivity. Methods: The catalyst, namely ((R)-1,1´-bi-2-naphthoxy)titanium dichloride (15% mol) was generated in situ. On adding aldehyde, red brown colour developed and the solution was cooled to -15ºC followed by addition of dimethylbutadiene. The reaction mixture was stirred at the same temperature for 4-5 h under nitrogen atmosphere. Results: The hetero-Diels-Alder reaction of X-C6H4CHO (X=m-NO2, o-OMe, p-CF3, m-CF3) with DMB in the presence of ((R)-1,1´-bi-2-naphthoxy)titanium dichloride (15% mol) at ~ -10 - -15°C (ice-sodium chloride bath)) gave 3,6-dihydro-2H-pyrans in 37- 74% yields with 68- 95% ee. Diels-Alder reaction of the 1:1 complex of benzaldehyde with the catalyst, ((R)-1,1´-bi-2-naphthoxy)titanium dichloride with 2,3-dimethyl-1,3- butadiene was investigated at the DFT (B3LYP) level using minimal basis set, (STO-3G). The values of the activation enthalpies (ΔH≠) for the attack of DMB on the Re and Si faces differ by 1.37 kcal mol-1 indicating ee >90% for the Si face. Conclusion: Aromatic aldehydes undergo HDA reaction with DMB in the presence of ((R)-1,1´-bi-2- naphthoxy)titanium dichloride as catalyst to give the cycloadducts in 37-74% yields with the ee ranging from 68 to 95%.