Metal-free direct arylation of dialkyl phosphonates for the synthesis of mixed alkyl aryl phosphonates

A method of making a compound having a structure represented by a formula:

• wherein n is 0 or 1;
• wherein A is selected from O, S, NR20, and CHR21;
• wherein R20, when present, is selected from hydrogen and methyl;
• wherein R21, when present, is selected from hydrogen and methyl;
• wherein Z is selected from O, S, and NR23;
• wherein R23, when present, is selected from hydrogen and methyl;
• wherein R1 is selected from C1-C8 alkyl, C2-C10 alkenyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, —(C1-C4 alkyl)Ar1, —(C2-C4 alkenyl)Ar1, —(C2-C4 alkynyl)Ar1, Ar1, and a structure represented by a formula selected from:
• and wherein the C3-C6 cycloalkyl, when present, is substituted with 0 or 1 C1-C4 alkyl group;
• wherein Ar1, when present, is selected from aryl and heteroaryl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NO2, —CN, —OH, —SH, —NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO2R30, —CO2R30, —(C1-C4 alkyl)CO2R30, —(C2-C4 alkenyl)CO2R33, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO2(C1-C4 alkyl), —(C═O)NR31aR31b, —SO2NR31aR31b, —O(C═O)NR31aR31b, —NHSO2NR3laR3lb, —NH(C═O)NR3laR3lb, and —N═NR32;
• wherein R30, when present, is selected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by a formula:
• wherein each of R3la and R31b, when present, is independently selected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;
• wherein R32, when present, is selected from hydrogen, C1-C4 alkyl, and phenyl;
• or wherein each of R1 and R20, when present, are optionally covalently bonded together and, together with the intermediate carbon atoms, comprise a 3- to 6-membered heterocycloalkyl;
• wherein Ar2 is selected from aryl and heteroaryl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NO2, —CN, —OH, —SH, —NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO2R33, —CO2R33, —(C1-C4 alkyl)CO2R33, —(C2-C4 alkenyl)CO2R33, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO2(C1-C4 alkyl), —(C═O)NR34aR34b, —SO2NR34aR34b, —O(C═O)NR34aR34b, —NHSO2NR34aR34b, —NH(C═O)NR34aR34b, and —N═NR35;
• wherein R33, when present, is selected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by a formula:
• wherein each of R34a and R34b, when present, is independently selected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;
• wherein R35, when present, is selected from hydrogen, C1-C4 alkyl, and phenyl;
• wherein Ar3 is selected from aryl and heteroaryl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —NO2, —CN, —OH, —SH, —NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkyl(C1-C4 alkoxy), C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C3-C7 cycloalkyl, C6-C10 aryl, —O(C2-C4 alkenyl), —OCO2R36, —CO2R36, —(C1-C4 alkyl)CO2R36, —(C2-C4 alkenyl)CO2R36, —(C═O)(C1-C4 alkyl), —(S═O)(C1-C4 alkyl), —SO2(C1-C4 alkyl), —(C═O)NR37aR37b, —SO2NR37aR37b, —O(C═O)NR37aR37b, —NHSO2NR37aR37b, —NH(C═O)NR37aR37b, and —N═NR38;
• wherein R36, when present, is selected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, phenyl, and a structure represented by a formula:
• wherein each of R37a and R37b, when present, is independently selected from hydrogen, C1-C8 alkyl, —(C1-C4 alkyl)phenyl, and phenyl;
• wherein R38, when present, is selected from hydrogen, C1-C4 alkyl, and phenyl,
• or a salt thereof, the method comprising the step of reacting a phosphinate derivative having a structure represented by a formula:
• wherein R3 is C1-C4 alkyl,
• or a salt thereof, with a nucleophile having a structure represented by a formula:
• in the presence of an activating agent, wherein the activating agent is selected from triflic anhydride, mesyl chloride, tosyl chloride, oxalyl chloride, thionyl chloride, acetic anhydride, benzoic anhydride, and trifluoroacetic anhydride, and a base.