Asymmetric catalytic decarboxylative alkyl alkylation using low catalyst concentrations and a robust precatalyst

A method for the preparation of a compound of formula (I):

• the preparing comprising treating, with a Pd(II) catalyst in an organic solvent,
• (i) a compound of formula (II) or (III) or a salt thereof:
• or
• (ii) a compound of formula (IV) or (V) or a salt thereof:
• and a compound of formula (X):
• wherein the Pd(II) catalyst is used in an amount from about 0.01 mol % to about 3 mol % relative to the compound of formula (II), (III), (IV), or (V),
• wherein, as valence and stability permit,
• R1 represents hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, amino, or halo;
• R2, R3, R4, R5, R12, R13, R14, and R15 are independently selected for each occurrence from hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group, thioether group, ester group, amide, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, acylamino, aryl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 3- to 10-membered heterocyclyl, aralkyl, arylalkoxy, (5- to 10-membered heteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to 10-membered heterocyclyl)alkyl;
• W represents, as valence permits, —O—, —S—, —NR6—, —CR7R8—, —C(O)—, —CR7═, or —N═;
• R6 represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O) (5- to 10-membered heteroaryl), —C(O)-(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(5- to 10-membered heteroaryl), —C(O)O-(5- to 10-membered heteroaryl)alkyl, —S(O)2(aryl), —S(O)2(alkyl), —S(O)2(haloalkyl), —OR10, —SR10, or —NR10R11;
• R7 and R8 each independently represent hydrogen, hydroxyl, halo, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, haloalkyl, ether group, thioether group, ester group, amido, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, or acylamino;
• or R6, R7, and R8 taken together with a substituent on ring A and the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl;
• R10 and R11 are independently selected for each occurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, and alkynyl;
• and
• ring A represents an optionally substituted cycloalkyl, 5- to 10-membered heterocyclyl, cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl,
• wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N, O, and S;
• and
• wherein substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkoxy, or amino are selected from halo, hydroxyl, carboxyl, alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group, thioformate group, alkoxy, phosphate group, phosphonate group, phosphinate, amino, amido, amidine group, imine group, cyano, nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group.

A method of preparing a pharmaceutical agent, comprising preparing a compound of formula (I):

• the preparing comprising treating, with a Pd(II) catalyst in an organic solvent,
• (i) a compound of formula (II) or (III) or a salt thereof:
• or
• (ii) a compound of formula (IV) or (V) or a salt thereof:
• and a compound of formula (X):
• wherein the Pd(II) catalyst is used in an amount from about 0.01 mol % to about 3 mol % relative to the compound of formula (II), (III), (IV), or (V),
• wherein, as valence and stability permit,
• R1 represents hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, amino, or halo;
• R2, R3, R4, R5, R12, R13, R14, and R15 are independently selected for each occurrence from hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group, thioether group, ester group, amide, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, acylamino, aryl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 3- to 10-membered heterocyclyl, aralkyl, arylalkoxy, (5- to 10-membered heteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to 10-membered heterocyclyl)alkyl;
• W represents, as valence permits, —O—, —S—, —NR6—, —CR7R8—, —C(O)—, —CR7═, or —N═;
• R6 represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O) (5- to 10-membered heteroaryl), —C(O)-(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(5- to 10-membered heteroaryl), —C(O)O-(5- to 10-membered heteroaryl)alkyl, —S(O)2(aryl), —S(O)2(alkyl), —S(O)2(haloalkyl), —OR10, —SR10, or —NR10R11;
• R7 and R8 each independently represent hydrogen, hydroxyl, halo, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, haloalkyl, ether group, thioether group, ester group, amido, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, or acylamino;
• or R6, R7, and R8 taken together with a substituent on ring A and the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl;
• R10 and R11 are independently selected for each occurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, and alkynyl;
• and
• ring A represents an optionally substituted cycloalkyl, 5- to 10-membered heterocyclyl, cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl,
• wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N, O, and S;
• and
• wherein substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkoxy, or amino are selected from halo, hydroxyl, carboxyl, alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group, thioformate group, alkoxy, phosphate group, phosphonate group, phosphinate, amino, amido, amidine group, imine group, cyano, nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group.

A method comprising

• (a) preparing a compound of formula (I):
• the preparing comprising treating with a Pd(II) catalyst in an organic solvent,
• (i) a compound of formula (II) or (III) or a salt thereof:
• or
• (ii) a compound of formula (IV) or (V) or a salt thereof:
• and a compound of formula (X):
• wherein the Pd(II) catalyst is used in an amount from about 0.01 mol % to about 3 mol % relative to the compound of formula (II), (III), (IV), or (V);
• and
• (b) synthesizing a pharmaceutical agent from the compound of formula (I),
• wherein, as valence and stability permit,
• R1 represents hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, amino, or halo;
• R2, R3, R4, R5, R12, R13, R14, and R15 are independently selected for each occurrence from hydrogen, hydroxyl, halo, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group, thioether group, ester group, amide, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, acylamino, aryl, (5- to 10-membered heteroaryl)alkyl, cycloalkyl, 3- to 10-membered heterocyclyl, aralkyl, arylalkoxy, (5- to 10-membered heteroaryl)alkyl, (cycloalkyl)alkyl, and (3- to 10-membered heterocyclyl)alkyl;
• W represents, as valence permits, —O—, —S—, —NR6—, —CR7R8—, —C(O)—, —CR7═, or —N═;
• R6 represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O) (5- to 10-membered heteroaryl), —C(O)-(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(5- to 10-membered heteroaryl), —C(O)O-(5- to 10-membered heteroaryl)alkyl, —S(O)2(aryl), —S(O)2(alkyl), —S(O)2(haloalkyl), —OR10, —SR10, or —NR10R11;
• R7 and R8 each independently represent hydrogen, hydroxyl, halo, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, haloalkyl, ether group, thioether group, ester group, amido, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, or acylamino;
• or R6, R7, and R8 taken together with a substituent on ring A and the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 5- to 10-membered heterocyclyl, or (5- to 10-membered heterocyclyl)alkenyl;
• R10 and R11 are independently selected for each occurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkenyl, and alkynyl;
• and
• ring A represents an optionally substituted cycloalkyl, 5- to 10-membered heterocyclyl, cycloalkenyl, or (5- to 10-membered heterocyclyl)alkenyl,
• wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N, O, and S;
• and
• wherein substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (5- to 10-membered heterocyclyl)alkyl, 5- to 10-membered heterocyclyl, alkoxy, or amino are selected from halo, hydroxyl, carboxyl, alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group, thioformate group, alkoxy, phosphate group, phosphonate group, phosphinate, amino, amido, amidine group, imine group, cyano, nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group.