Quaternary heteroatom containing compounds

Abstract

The invention provides heterocyclic compounds with quaternary centers and methods of preparing compounds. Methods include the method for the preparation of a compound of Formula (II): comprising treating a compound of Formula (I): with a transition metal catalyst and under alkylation conditions as valence and stability permit.

What is claimed is: 
     
         1 . A method for the preparation of a compound of Formula (II): 
       
         
           
           
               
               
           
         
         comprising treating a compound of Formula (I): 
       
       
         
           
           
               
               
           
         
         with a transition metal catalyst under alkylation conditions, wherein, as valence and stability permit,
 ring B represents an optionally substituted heterocycle; 
 X is a heteroatom; 
 R 1  is selected from optionally substituted alkyl, alkenyl, alkynyl, carbocyclyl, heterocycle, aryl, heteroaryl, and halogen; 
 R 2 , R 3 , R 4 , R 5 , R 12 , R 13 , R 14 , and R 15  are independently selected at each occurrence from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, and heterocyclylalkyl. 
 
       
     
     
         2 . The method of  claim 1 , for preparation of a compound of Formula (IV): 
       
         
           
           
               
               
           
         
         comprising treating a compound of Formula (III): 
       
       
         
           
           
               
               
           
         
         with a transition metal catalyst under alkylation conditions, wherein, as valence and stability permit,
 X is selected from —NR 6 — and —O—; 
 Z is selected from —C(O)— and —CR 7 R 7 —; 
 A is independently selected at each occurrence from —CR 8 R 8 — and —NR 9 —; 
 W is absent or selected from —O—, —NR 10 —, and —CR 11 R 11 —; 
 R 1  is selected from optionally substituted alkyl, alkenyl, alkynyl, carbocyclyl, heterocycle, aryl, heteroaryl, and halogen; 
 R 2 , R 3 , R 4 , R 5 , R 12 , R 13 , R 14 , and R 15  are independently selected at each occurrence from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, and heterocyclylalkyl; 
 R 7 , R 8 , and R 11  are independently selected at each occurrence from hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, hydroxyl, thiol, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, and heterocyclylalkyl;
 wherein R 7  and R 8  may combine with the carbons to which they are bound to form an optionally substituted 3-8-membered ring, R 8  and R 11  may combine with the carbons to which they are bound to form an optionally substituted 3-8-membered ring, and when n is 2 or 3, R 8  attached to one carbon may combine with R 8  attached to another carbon to combine with the carbons to which they are bound to form a 3-8-membered ring; 
 
 R 6 , R 9  and R 10  are independently selected at each occurrence from hydrogen, hydroxyl and optionally substituted alkyl, alkoxy, alkylthio, aryloxy, carbocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aralkyloxy, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy, sulfone, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and amide; and 
 n is 0-3. 
 
       
     
     
         3 . The method of  claim 2 , wherein:
 R 1  is selected from halogen and an optionally substituted group selected from alkyl, carbocyclyl, carbocyclylalkyl, cyanoalkyl, aralkyl, heteroaralkyl, hydroxyalkyl, haloalkyl, acylalkyl, alkoxycarbonylalkyl, and aryloxycarbonylalkyl;   R 2 , R 12 , R 7 , R 8 , and R 11  are independently selected at each occurrence from hydrogen, halogen, hydroxyl, haloalkyl, cyano, alkyl, alkoxy, alkylthio, amide, amine, and carbocyclyl;   R 3 , R 4 , R 5 , R 13 , R 14 , and R 15  are independently selected at each occurrence from hydrogen, halogen, haloalkyl, cyano, alkyl, alkoxy, alkylthio, amide, amine, aryloxy, and aralkyloxy;   R 6 , R 9 , and R 10  are independently selected at each occurrence from hydrogen, hydroxyl, and optionally substituted alkyl, alkoxy, alkylthio, aryloxy, carbocyclyl, aryl, arylcarbonyl, aralkylcarbonyl, heteroaryl, aralkyl, heteroaralkyl, aralkyloxy, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and amide.   
     
     
         4 . The method of  claim 3 , wherein:
 R 1  is selected from halogen, alkyl, optionally substituted aralkyl, optionally substituted alkoxycarbonylalkyl, optionally substituted cyanoalkyl, and optionally substituted hydroxyalkyl; and   R 6 , R 9 , and R 10  are independently selected at each occurrence from optionally substituted aralkyloxy, aralkoxycarbonyl, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, arylsulfonyl, alkoxycarbonyl, and aryloxycarbonyl.   
     
     
         5 . The method of  claim 4 , wherein:
 X is —NR 6 —;   Z is selected from —C(O)— and —CR 7 R 7 —;   A at each occurrence is —CR 8 R 8 —;   W is selected from —NR 10 — and —CR 11 R 11 —; and   n is 0-2.   
     
     
         6 . The method of  claim 5 , wherein Z is —CR 7 R 7 —. 
     
     
         7 . The method of  claim 5 , wherein W is —NR 10 —. 
     
     
         8 . The method of  claim 2 , wherein n is 1. 
     
     
         9 . The method of  claim 4 , wherein:
 X is —O—;   Z is selected from —C(O)— and —CR 7 R 7 —;   A at each occurrence is —CR 8 R 8 —;   W is selected from —NR 10 —, and —CR 11 R 11 —; and   n is 0-2.   
     
     
         10 . The method of  claim 9 , wherein Z is —CR 7 R 7 —. 
     
     
         11 . The method of  claim 9 , wherein W is —NR 10 —. 
     
     
         12 . The method of  claim 1  or  2 , wherein the transition metal catalyst is a palladium catalyst. 
     
     
         13 . The method of  claim 12 , wherein the transition metal catalyst is selected from Pd 2 (dba) 3  and Pd 2 (pmdba) 3 . 
     
     
         14 . The method of  claim 12 , wherein the palladium catalyst is used in an amount selected from 1 mol % to 20 mol % relative to the substrate. 
     
     
         15 . The method of  claim 14 , wherein the palladium catalyst is used in an amount selected from 2 mol % to 8 mol % relative to the substrate. 
     
     
         16 . The method of  claim 1  or  2 , wherein the method further comprises a chiral ligand. 
     
     
         17 . The method of  claim 16 , wherein the chiral ligand is a phosphine ligand. 
     
     
         18 . The method of  claim 17 , wherein the chiral ligand is selected from (S)—(CF 3 ) 3 -tBuPHOX and (S)-tBuPHOX. 
     
     
         19 . The method of  claim 16 , wherein the chiral ligand is used in an amount selected from 2.5 mol % to 13 mol % relative to the subtrate. 
     
     
         20 . A compound represented by Formula (V): 
       
         
           
           
               
               
           
         
         or a tautomer and/or salt thereof, wherein: 
         X is selected from —NR 6 — and —O—;
 Z is selected from —C(O)— and —CR 7 R 7 —; 
 A is independently selected at each occurrence from —CR 8 R 8 — and —NR 9 —; 
 W is absent or selected from —O—, —NR 10 —, and —CR 11 R 11 —; 
 R 1  is selected from optionally substituted alkyl, alkenyl, alkynyl, carbocyclyl, heterocycle, aryl, heteroaryl, and halogen; 
 R 12 , R 13 , R 14  and R 15  are independently selected at each occurrence from hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, and heterocyclylalkyl; 
 R 7 , R 8 , and R 11  are independently selected at each occurrence from hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, hydroxyl, thiol, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, and heterocyclylalkyl;
 wherein R 7  and R 8  may combine with the carbons to which they are bound to form an optionally substituted 3-8-membered ring, R 8  and R 11  may combine with the carbons to which they are bound to form an optionally substituted 3-8-membered ring, and when n is 2 or 3, R 8  attached to one carbon may combine with R 8  attached to another carbon to combine with the carbons to which they are bound to form a 3-8-membered ring; 
 
 R 6 , R 9  and R 19  are independently selected at each occurrence from hydrogen, hydroxyl and optionally substituted alkyl, alkoxy, alkylthio, aryloxy, carbocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aralkyloxy, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy, sulfone, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and amide; and 
 n is 0-3. 
 
       
     
     
         21 . The compound of  claim 20 , wherein:
 R 1  is selected from halogen and an optionally substituted group selected from alkyl, carbocyclyl, carbocyclylalkyl, cyanoalkyl, aralkyl, heteroaralkyl, hydroxyalkyl, haloalkyl, acylalkyl, alkoxycarbonylalkyl, and aryloxycarbonylalkyl;   R 12 , R 7 , R 8  and R 11  are independently selected at each occurrence from hydrogen, halogen, hydroxyl, haloalkyl, cyano, alkyl, alkoxy, alkylthio, amide, amine, and carbocyclyl;   R 13 , R 14  and R 15  are independently selected at each occurrence from hydrogen, halogen, haloalkyl, cyano, alkyl, alkoxy, alkylthio, amide, amine, aryloxy, and aralkyloxy;   R 6 , R 9 , and R 19  are independently selected at each occurrence from hydrogen, hydroxyl, alkyl, alkoxy, alkylthio, aryloxy, carbocyclyl, aryl, arylcarbonyl, aralkylcarbonyl, heteroaryl, aralkyl, heteroaralkyl, aralkyloxy, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and amide.   
     
     
         22 . The compound of  claim 21 , wherein:
 R 1  is selected from halogen, alkyl, optionally substituted aralkyl, optionally substituted alkoxycarbonylalkyl, optionally substituted cyanoalkyl, and optionally substituted hydroxyalkyl; and   R 6 , R 9 , and R 19  are independently selected at each occurrence from aralkyloxy, aralkoxycarbonyl, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, arylsulfonyl, alkoxycarbonyl, and aryloxycarbonyl.   
     
     
         23 . The compound of  claim 22 , wherein:
 X is —NR 6 —;   Z is selected from —C(O)— and —CR 7 R 7 —;   A at each occurrence is —CR 8 R 8 —;   W is selected from —NR 10 — and —CR 11 R 11 —; and   n is 0-2.   
     
     
         24 . The compound of  claim 23 , wherein Z is —CR 7 R 7 —. 
     
     
         25 . The compound of  claim 23 , wherein W is —NR 10 —. 
     
     
         26 . The compound of  claim 23 , wherein n is 1. 
     
     
         27 . The compound of  claim 22 , wherein:
 X is —O—;   Z is selected from —C(O)— and —CR 7 R 7 —;   A at each occurrence is —CR 8 R 8 —;   W is selected from —NR 10 —, and —Cr 11 R 11 —; and   n is 0-2.   
     
     
         28 . The compound of  claim 27 , wherein Z is —CR 7 R 7 —. 
     
     
         29 . The compound of  claim 27 , wherein W is —NR 10 —. 
     
     
         30 . A compound represented by Formula (VI): 
       
         
           
           
               
               
           
         
         or a tautomer and/or salt thereof, wherein:
 X is selected from —NR 6 — and —O—; 
 Z is selected from —C(O)— and —CR 7 R 7 —; 
 A is independently selected at each occurrence from —CR 8 R 8 — and —NR 9 —; 
 W is absent or selected from —O—, —NR 10 —, and —CR 11 R 11 —; 
 R 1  is selected from optionally substituted alkyl, alkenyl, alkynyl, carbocyclyl, heterocycle, aryl, heteroaryl, and halogen; 
 R 2 , R 3 , R 4  and R 5  are independently selected at each occurrence from hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, and heterocyclylalkyl; 
 R 7 , R 8 , and R 11  are independently selected at each occurrence from hydrogen, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, hydroxyl, thiol, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, carbocyclyl, heterocyclyl, aralkyl, aralkyloxy, hetaralkyl, carbocyclylalkyl, and heterocyclylalkyl;
 wherein R 7  and R 8  may combine with the carbons to which they are bound to form an optionally substituted 3-8-membered ring, R 8  and R 11  may combine with the carbons to which they are bound to form an optionally substituted 3-8-membered ring, and when n is 2 or 3, R 8  attached to one carbon may combine with R 8  attached to another carbon to combine with the carbons to which they are bound to form a 3-8-membered ring; 
 
 R 6 , R 9  and R 19  are independently selected at each occurrence from hydrogen, hydroxyl and optionally substituted alkyl, alkoxy, alkylthio, aryloxy, carbocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aralkyloxy, heteroaryloxy, acyl, arylcarbonyl, aralkylcarbonyl, acyloxy, sulfone, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, and amide; and 
 n is 0-3.