Synthesis Of Chromone-containing Polycyclic Compounds By Palladium-catalyzed[2+2+1] Domino Annulation

Objective:Based on palladium catalyzed reaction conditions,a novel three-component[2+2+1]domino annulation was established.It provides an efficient method for the construction of chromone-containing polycyclic compounds bearing norbornane fragment.This reaction provided a series of compounds for bioactivity screening,and it would be potential application value in drug screening and pharmaceutical industry.Methods:Using 3-iodochromone,benzyl bromide and norbornene as model substrates,the optimal reaction conditions were constructed by screening palladium catalysts,ligands,bases and solvents,and the scope of the substrates was investigated;Under the optimal reaction conditions,gram-scale experiment and derivative experiments were performed;the possible mechanism was proposed through the control experiments.Results:(1)The optimal reaction condition for the synthesis of endo isomer was obtained as follows:Pd(OAc)₂(10 mol%),P(o-tol)₃(20 mol%),K₃PO₄(2.0 equiv.),mesitylene(1.2m L)/CH₃CN(0.8 m L),100°C,24 h;(2)The optimal reaction condition for the synthesis of exo isomer was obtained as follows:Pd(OAc)₂(10 mol%),P(o-tol)₃(20 mol%),K₃PO₄(2.0equiv.),mesitylene(2 m L),100°C,24 h;(3)Under the optimum reaction conditions,46chromone-containing polycyclic compounds were synthesized in up to 94%yield and 99:1 dr.Gram-scale was also conducted,giving 6a in 1.07 g with 65%yield.Moreover,the derivative experiments of 6s were realized in good result.Lastly,the possible mechanism was proposed through the control experiments and related literatures.Conclusion:A new method for the synthesis of chromone-containing polycyclic compounds was developed.Based on a novel palladium-catalyzed[2+2+1]domino annulation starting from 3-iodochrones,benzyl bromides and norbornene to synthesized of chromone-containing polycyclic compounds with five contiguous tertiary carbon centers in up to 94%yield and 99:1 dr(46 examples).Additionally,the stereoselectivity of the product was controlled by changing the reaction solvents.Endo isomers were obtained by using mesitylene/CH₃CN as solvents.Exo isomers were obtained by using mesitylene as solvent.The mechanism shows that the activation of C(sp³)-H bond is realized via a concerted metalation-deprotonation(CMD)pathway.Finally,the practicability of this reaction was further proved by gram-scale experiment and derivative experiments.