Palladium-catalyzed ortho-fluorination

A method of making a fluorinated compound comprising:

• (a) reacting a compound having the formula:
• each Y is CR1, CH, N, O, or S, wherein if Y is N, O, or S, at least one ring atom adjacent to Y is CR1;
• each R1 is independently selected from the group of radicals consisting of C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C1-C20 alkoxy, C6-C20 aryl, C7-C20 alkylaryl, C4-C20 heterocycle, C4-C20 heteroaryl, C4-C20 alkylheterocycle, C7-C20 allcylheteroaryl, C6-C20 aryloxy, —OH, —CO, —COOH, —CN, —N3, halo, —CF3, —OCF3, —NH2, —NO2, —NR3R3′, —N(O)R3, —SH, —SR3, —SOR3, —SO2R3, —C(O)R3, —CO2R3, —C(O)NR3R3′, and —OC(O)R3;
• wherein the alkyl, alkenyl, alkynyl, alkoxy, aryl, heterocycle, heteroaryl, or aryloxy may be substituted or unsubstituted and wherein in the alkyl portion one or more:
• —CH2—, CH2CH2—, —(CH2)n- groups are each optionally replaced by —O— or —NH—;
• wherein n is an integer equal to or greater than 1.
• or wherein two R1 are joined together to form a bicyclic or tricyclic alkyl or aryl with the ring to which they are attached, wherein if the bicyclic or tricyclic alkyl or aryl is a heterocycle, at least one ring atom adjacent to the heteroatom is substituted;
• R3 and R3′ are each independently selected from the group of radicals consisting of H, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C6-C20 aryl;
• C7-C20 alkylaryl, C4-C20 heterocycle, C4-C20 heteroaryl, C4-C20 alkylheterocycle, and C7-C20 alkylheteroaryl;
• wherein the alkyl, alkenyl, alkynyl, aryl, heterocycle, or heteroaryl, be substituted or unsubstituted and wherein in the alkyl portion one or more CH2—, CH2CH2—, —(CH2)n- —CH2CH2— groups are each optionally replaced by —O‘— or —NH—;
• wherein n is an integer equal to or greater than 1;
• Pr is a protecting group;
• and
• x is 0, 1, 2, 3, or 4;
• a palladium (II) catalyst;
• a fluorinating reagent;
• and
• a promoter having the formula
• wherein
• R6 and R6′ are each H or a C1-6 alkyl, wherein at least one of R6 and R6′ is not H,
• R7 is H or a C1-6 alkyl,
• or wherein either R6 and R6′ together with the nitrogen to which they are attached or R6 and R7 together with the nitrogen and carbonyl to which they are attached form a 5- or 6-membered ring which may be unsubstituted or substituted with one or more C1-6 alkyl groups;
• to form at least one of the ortho-fluorinated compounds having the formulas:
• wherein R1, x, and Pr are described above;
• and
• (b) reacting the compound of formula (IV) or (V) with a reagent to obtain at least one of the compounds having the formula:
• wherein each R2 is independently selected from the group of radicals consisting of C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C1-C20 alkoxy, C6-C20 aryl, C7-C20 alkylaryl, C4-C20 heterocycle, C4-C20 heteroaryl, C4-C20 alkylheterocycle, C7-C20 alkylheteroaryl, C6-C20 aryloxy, —OH, —CO, —COOH, —CN, —N3, halo, —CF3, —OCF3, —NH2, —NO2, —NR3R3′, —N(O)R3, —SH, —SR3, —SOR3, —SO2R3, —C(O)R3, —CO2R3, —C(O)NR3R3′, and —OC(O)R3;
• wherein the alkyl, alkenyl, alkynyl, alkoxy, aryl, heterocycle, heteroaryl, or aryloxy be substituted or unsubstituted and wherein in the alkyl portion one or more —CH2—, CH2CH2—, —(CH2)n- groups are each optionally replaced by —O— or —NH—;
• wherein n is an integer equal to or greater than 1;
• and
• R3 and R3′ are each independently selected from the group of radicals consisting of H, C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, C6-C20 aryl;
• C7-C20 alkylaryl, C4-C20 heterocycle, C4-C20 heteroaryl, C4-C20 alkylheterocycle, and C7-C20 alkylheteroaryl;
• wherein the alkyl, alkenyl, allcynyl, aryl, heterocycle, or heteroaryl, be substituted or unsubstituted and wherein in the alkyl portion one or more:
• —CH2—, —CH2CH2—, —(CH2)n- groups are each optionally replaced by —O— or —NH—;
• wherein n is an integer equal to or greater than 1;
• and
• each of R1, Y, and x are described above.