Nitrogen-containing heterocyclic compounds and methods of making the same

Abstract

The present invention relates to 7-membered nitrogen-containing heterocyclic compounds and methods of making the same. Using a novel aza-[4+3] cycloaddition reaction, the 7-membered heterocyclic compounds are synthesized by reacting a first reactant and a second reactant. Exemplary first reactants and second reactants include α-halohydroxamates and dienes, respectively.

1 . A 7-membered nitrogen-containing heterocyclic compound represented by structural Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  are the same or different and are independently selected from hydrogen, halide, a substituted or un-substituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino, amido, alkoxy, acyloxy, thio, or silyl, or R 1  and R 2  in combination form a cycloalkyl or a heterocycle; 
 R 3  is a substituted or unsubstituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, sulfinyl, sulfonyl, or silyl; 
 R 4 , R 5 , R 6 , and R 7  are the same or different and are independently selected from hydrogen, halide, a substituted or un-substituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino, amido, alkoxy, acyloxy, thio, or silyl, wherein optionally R 4  and R 6 , or R 5  and R 7  combine to form a bridging moiety in a cyclic substructure, the bridging moiety including at least one of carbon, oxygen, nitrogen, or sulfur, wherein optionally R 4  or R 5  are covalently bonded to R 1  or R 2 , or wherein optionally R 6  or R 7  are covalently bonded to R 3 ; and 
 R 8  and R 9  are the same or different and are independently selected from hydrogen, halide, a substituted or un-substituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino, amido, alkoxy, acyloxy, thio, or silyl, or R 8  and R 9  combine to form a carbon-containing cyclic substructure; and 
 Y is O, S, SO, or NR 10 , wherein R 10  is a hydrogen, acyl, a substituted or unsubstituted alkyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, sulfinyl, sulfonyl, or silyl; wherein optionally R 10  is covalently bonded to R 6  or R 7 . 
 
     
     
         2 . A [4+3] cycloaddition reaction product of
 a first reactant represented by general formula R 1 R 2 XC—CO—NHYR 3 , wherein R 1  and R 2  are the same or different and independently selected from hydrogen, halide, a substituted or un-substituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino, amido, alkoxy, acyloxy, thio, or silyl, or R 1  and R 2  in combination form a cycloalkyl or a heterocycle; R 3  is a substituted or unsubstituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, sulfinyl, sulfonyl, or silyl; X is a leaving group; and Y is O, S, SO, or NR 10 , wherein R 10  is a hydrogen, a substituted or unsubstituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, sulfinyl, sulfonyl, or silyl; and   a second reactant having a diene moiety.   
     
     
         3 . A method of making a 7-membered nitrogen-containing heterocyclic compound via a [4+3] cycloaddition reaction, the method comprising:
 combining a first reactant, a second reactant, and an activator to form a reaction mixture, the first reactant represented by general formula R 1 R 2 XC—CO—NHYR 3 , wherein R 1  and R 2  are the same or different and are independently selected from hydrogen, halide, a substituted or un-substituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, amino, amido, alkoxy, acyloxy, thio, or silyl, or R 1  and R 2  in combination form a cycloalkyl or a heterocycle; R 3  is a substituted or unsubstituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, sulfinyl, sulfonyl, or silyl; X is a leaving group; and Y is O, S, SO, or NR 10 , wherein R 10  is a hydrogen, a substituted or unsubstituted alkyl, acyl, aryl, alkaryl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocycle, sulfinyl, sulfonyl, or silyl; the second reactant having a diene moiety; and   reacting the first reactant and the second reactant in the presence of the activator to form the nitrogen-containing heterocyclic compound.