One‐Pot Synthesis of 1,3‐Cyclohexadienes by Birch Reduction in the Presence of Carbonyl Compounds

• Published in: Angewandte Chemie International Edition 2024-09, Vol.63 (39), p.e202407568-n/a
• Main Authors: Krüger‐Braunert, Tobias, Linker, Torsten
• Format: Article
• Language: English
• Subjects: Aldehydes; Alkylation; Aromatic compounds; Benzoic acid; Birch Reduction; Carbonyl compounds; Carbonyls; Chemical synthesis; Cycloaddition; Cyclohexadienes; Dienes; Isomers; Ketones; Regioselectivity; Selectivity; Singlet oxygen; Steric hindrance; Synthetic methods; Toluic acid
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202407568

Birch reductions are well‐known transformations of arenes, applied for large scale synthesis of 1,4‐cyclohexadienes. Herein, we describe first reactions of benzoic acids in the presence of carbonyl compounds, affording aldol products in moderate to high yields. Alkyl aldehydes give the expected nonconjugated dienes by reaction at the α‐position. Interestingly, the intermediately formed enolate attacks aryl aldehydes and ketones from its γ‐position, which can be explained by steric hindrance. This opens the door for the one‐pot synthesis of 1,3‐cyclohexadienes, which are not accessible by classical Birch reductions. Our method is applicable to benzoic, m‐ and p‐toluic acid and various carbonyl compounds, and more than 25 new products were isolated in up to 93 % yield. Prochiral aryl aldehydes afford diastereomeric mixtures in ratios of about 4 : 1, but in the cyclohexadiene ring only trans isomers are formed with high selectivity. Finally, the 1,3‐cyclohexadienes are suitable precursors for further transformations, which we have demonstrated in first examples. Thus, aromatization affords products of a formal meta selective Friedel–Crafts alkylation, and four new stereocenters were generated by cycloaddition of singlet oxygen with excellent selectivity. A complete change in regioselectivity has been observed during the Birch reduction of benzoic acids in the presence of carbonyl compounds. Alkyl aldehydes afford exclusively 1,4‐isomers, whereas with ketones and aryl aldehydes, 1,3‐cyclohexadienes are isolated in good yields on a large scale. Such compounds are suitable precursors for further transformations.