A Chitosan‐CatalyzedDomino Aldol‐Hetero‐Diels‐Alder Synthesis of Cyclic Heptanoid‐Annulated Pyran Scaffolds

• Published in: ChemistrySelect (Weinheim) 2021-11, Vol.6 (44), p.12416-12423
• Main Authors: Atara, Hiralben D., Brahmbhatt, Gaurangkumar C., Parmar, Vishalkumar M., Parmar, Narsidas J., Gupta, Vivek K.
• Format: Article
• Language: English
• Subjects: Aldol-hetero-Diels-Alder; Chitosan; Cyclic heptanoid; Green chemistry; Sulfur heterocycles
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202103333

A chitosan‐catalyzed, domino aldol‐hetero‐Diels‐Alder (DAHDA) reaction has been developed in glycerol after combining 2‐alkenyloxynaphthaldehydes 1 a–b/O‐alkenylsalicylaldehydes 2 a–b/5‐alkenyl‐sulfanyl‐pyrazole‐4‐carbaldehydes 3 a–b with the poorly enolizable CH activated but‐3‐en‐2‐ones; monobenzalacetone 4 a/4‐methoxy‐3‐but‐2‐ene 4b/mesityl oxide 4c to achieve pyrano [3,4‐c]chromenes 5 aa–5 bc, 6 aa–6 bc/ thiopyrano[2,3‐c]pyrazoles 7 aa–7 bc all are containing cyclic heptanoid core. The method is highly efficient yielding 91% of the model compound 5 aa in 8 h at 90 oC. The structural investigation of the aldol intermediate which is isolable gave the important insight into the stereochemical output of the second step hetero‐Diels‐Alder(HDA) reaction. 2D NMR NOESY (nuclear overhauser effect spectroscopy) andsingle‐crystal X‐raydiffraction dataof the representative 5 aa confirmed that the E‐aldol intermediate formed initially undergoes HDAreaction via endo‐E‐syn transition state to form cis‐fused product exclusively. Both chitosan and glycerol can be recycled at least five times without the loss of their efficiencies as catalyst and reaction medium respectively. E‐factor (0.15) and EcoScale (77.5 %) valuesof thismethod to afford model DAHDA product 5 aa reveal key green aspects of the present protocol. The biopolymer chitosan has been demonstrated as a highly efficient heterogeneous catalyst to promote the DAHDA reaction.Where poorly enolizable CH activated methyl ketone unitswere reacted with olefin‐tethered aldehydes in glycerol medium to achieve new cyclic heptanoid‐incorporated poly heterocycles. The reaction is diastereoselective in that the E‐aldol intermediate leads the formation of cis‐fused products via endo‐E‐syn transition state. E‐factor (0.15) and EcoScale (77.5 %) values of the method to afford product 5 aa are key green aspects of the protocol.