Process for the synthesis of biaryl oxazolidinones

A process for preparing a compound having the formula:

• the process comprising the steps of:
• combining a compound of formula (I):
• with a compound of formula (II):
• in a solvent in the presence of a base and a palladium catalyst, wherein
• A is selected from the group consisting of:
• phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;
• B is selected from the group consisting of:
• phenyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl;
• Het-CH2—R3 is selected from the group consisting of:
• M-L is selected from the group consisting of:
• a) M-X, b) M-L1, c) M-L1-X, d) M-X-L2, e) M-L1-X-L2, f) M-X-L1-X-L2, g) M-L1-X-L2-X, h) M-X—X—, i) M-L1-X—X—, j) M-X—X-L2, and k) M-L1-X—X-L2, wherein
• X, at each occurrence, independently is selected from the group consisting of:
• a) —O—, b) —NR4—, c) —N(O)13 , d) —N(OR4)—, e) —S(O)p—, f) —SO2NR4—, g) —NR4SO2—, h) —NR4—N═, i) ═N—NR4—, j) —O—N═, k) ═N—O—, l) —N═, m) ═N—, n) —NR4—NR4—, o) —NR4C(O)O—, p) —OC(O)NR4—, q) —NR4C(O)NR4— r) —NR4C(NR4)NR4—, and
• L1 is selected from the group consisting of:
• a) C1-6 alkyl, b) C2-6 alkenyl, and c) C2-6 alkynyl,
• wherein any of a)-c) optionally is substituted with one or more R5 groups;
• and
• L2 is selected from the group consisting of:
• a) C1-6 alkyl, b) C2-6 alkenyl, and c) C2-6 alkynyl,
• wherein any of a)-c) optionally is substituted with one or more R5 groups;
• alternatively, L in M-L is a bond;
• M is selected from the group consisting of:
• a) C3-14 saturated, unsaturated, or aromatic carbocycle, b) 3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, c) C1-6 alkyl, d) C2-6 alkenyl, e) C2-6 alkynyl, and f) —CN,
• wherein any of a)-e) optionally is substituted with one or more R5 groups;
• Q is a borane having the formula —BY2, wherein
• Y, at each occurrence, independently is selected from the group consisting of:
• a) —OH, b) —OC1-6 alkyl, c) —OC2-6 alkenyl, d) —OC2-6 alkynyl, e) —OC1-14 saturated, unsaturated, or aromatic carbocycle, f) C1-6 alkyl, g) C2-6 alkenyl, h) C2-6 alkynyl, and i) C1-14 saturated, unsaturated, or aromatic carbocycle,
• wherein any of b)-i) optionally is substituted with one or more halogens;
• alternatively, two Y groups taken together comprise a chemical moiety selected from the group consisting of:
• a) —OC(R4)(R4)C(R4)(R4)O—, and b) —OC(R4)(R4)CH2C(R4)(R4)O—;
• alternatively, Q is a BF3 alkali metal salt or 9-borabicyclo[3.3.1]nonane;
• Z is selected from the group consisting of:
• a) I, b) Br, c) Cl, and d) R9SO3—;
• R1, at each occurrence, independently is selected from the group consisting of:
• a) F, b) Cl, c) Br, d) I, e) —CF3, f) —OR4, g) —CN, h) —NO2, i) —NR4R4, j) —C(O)R4, k) —C(O)OR4, l) —OC(O)R4, m) —C(O)NR4R4, n) —NR4C(O)R4, o) —OC(O)NR4R4, p) —NR4C(O)OR4, q) —NR4C(O)NR4R4, r) —C(S)R4, s) —C(S)OR4, t) —OC(S)R4, u) —C(S)NR4R4, v) —NR4C(S)R4, w) —OC(S)NR4R4, x) —NR4C(S)OR4, y) —NR4C(S)NR4R4, z) —C(NR4)R4, aa) —C(NR4)OR4, bb) —OC(NR4)R4, cc) —C(NR4)NR4R4, dd) —NR4C(NR4)R4, ee) —OC(NR4)NR4R4, ff) —NR4C(NR4)OR4, gg) —NR4C(NR4)NR4R4, hh) —S(O)pR4, ii) —SO2NR4R4, and jj) R4;
• R2, at each occurrence, independently is selected from the group consisting of:
• a) F, b) Cl, c) Br, d) I, e) —CF3, f) —OR4, g) —CN, h) —NO2, i) —NR4R4, j) —C(O)R4, k) —C(O)O R4, l) —OC(O)R4, m) —C(O)NR4R4, n) —NR4C(O)R4, o) —OC(O)NR4R4, p) —NR4C(O)OR4, q) —NR4C(O)NR4R4, r) —C(S)R4, s) —C(S)OR4, t) —OC(S)R4, u) —C(S)NR4R4, v) —NR4C(S)R4, w) —OC(S)NR4R4, x) —NR4C(S)OR4, y) —NR4C(S)NR4R4, z) —C(NR4)R4, aa) —C(NR4)OR4, bb) —OC(NR4)R4, cc) —C(NR4)NR4R4, dd) —NR4C(NR4)R4, ee) —OC(NR4)NR4R4, ff) —NR4C(NR4)OR4, gg) —NR4C(NR4)NR4R4, hh) —S(O)pR4, ii) —SO2NR4R4, and jj) R4;
• R3 is selected from the group consisting of:
• a) —OR4, b) —NR4R4, c) —C(O)R4, d) —C(O)OR4, e) —OC(O)R4, f) —C(O)NR4R4, g) —NR4C(O)R4, h) —OC(O)NR4R4, i) —NR4C(O)OR4, j) —NR4C(O)NR4R4, k) —C(S)R4, l) —C(S)OR4, m) —OC(S)R4, n) —C(S)NR4R4, o) —NR4C(S)R4, p) —OC(S)NR4R4, q) —NR4C(S)OR4, r) —NR4C(S)NR4R4, s) —C(NR4)R4, t) —C(NR4)OR4, u) —OC(NR4)R4, v) —C(NR4)NR4R4, w) —NR4C(NR4)R4, x) —OC(NR4)NR4R4, y) —NR4C(NR4)OR4, z) —NR4C(NR4)NR4R4, aa) —S(O)pR4, bb) —SO2NR4R4, and cc) R4;
• R4, at each occurrence, independently is selected from the group consisting of:
• a) H, b) —OR6, c) an amine protecting group, d) C1-6 alkyl, e) C2-6 alkenyl, f) C2-6 alkynyl, g) C3-14 saturated, unsaturated, or aromatic carbocycle, h) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, i) —C(O)—C1-6 alkyl, j) —C(O)—C2-6 alkenyl, k) —C(O)—C2-6 alkynyl, l) —C(O)—C3-14 saturated, unsaturated, or aromatic carbocycle, m) —C(O)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, n) —C(O)O—C1-6 alkyl, o) —C(O)O—C2-6 alkenyl, p) —C(O)O—C2-6 alkynyl, q) —C(O)O—C3-14 saturated, unsaturated, or aromatic carbocycle, and r) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
• wherein any of d)-r) optionally is substituted with one or more R5 groups;
• R5, at each occurrence, is independently selected from the group consisting of:
• a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR6, h) ═NOR6, i) ═N—NR6R6, j) —CF3, k) —OR6, l) —CN, m) —NO2, n) —NR6R6, o) —C(O)R6, p) —C(O)OR6, q) —OC(O)R6, r) —C(O)NR6R6, s) —NR6C(O)R6, t) —OC(O)NR6R6, u) —NR6C(O)OR6, v) —NR6C(O)NR6R6, w) —C(S)R6, x) —C(S)OR6, y) —OC(S)R6, z) —C(S)NR6R6, aa) —NR6C(S)R6, bb) —OC(S)NR6R6, cc) —NR6C(S)OR6, dd) —NR6C(S)NR6R6, ee) —C(NR6)R6, ff) —C(NR6)OR6, gg) —OC(NR6)R6, hh) —C(NR6)NR6R6, ii) —NR6C(NR6)R6, jj) —OC(NR6)NR6R6, kk) —NR6C(NR6)OR6, ll) —NR6 C(NR6)NR6R6, mm) —S(O)pR6, nn) —SO2NR6R6, and oo) R6;
• R6, at each occurrence, independently is selected from the group consisting of:
• a) H, b) —OR8, c) an amine protecting group, d) C1-6 alkyl, e) C2-6 alkenyl, f) C2-6 alkynyl, g) C3-14 saturated, unsaturated, or aromatic carbocycle, h) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, i) —C(O)—C1-6 alkyl, j) —C(O)—C2-6 alkenyl, k) —C(O)—C2-6 alkynyl, l) —C(O)—C3-14 saturated, unsaturated, or aromatic carbocycle, m) —C(O)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, n) —C(O)O—C1-6 alkyl, o) —C(O)O—C2-6 alkenyl, p) —C(O)O—C2-6 alkynyl, q) —C(O)O—C3-14 saturated, unsaturated, or aromatic carbocycle, and r) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
• wherein any of d)-r) optionally is substituted with one or more R7 groups;
• R7, at each occurrence, independently is selected from the group consisting of:
• a) F, b) Cl, c) Br, d) I, e) ═O, f) ═S, g) ═NR8, h) ═NOR8, i) ═N—NR8R8, j) —CF3, k) —OR8, l) —CN, m) —NO2, n) —NR8R8, o) —C(O)R8, p) —C(O)OR8, q) —OC(O)R8, r) —C(O)NR8R8, s) —NR8C(O)R8, t) —OC(O)NR8R8, u) —NR8C(O)OR8, v) —NR8C(O)NR8R8, w) —C(S)R8, x) —C(S)OR8, y) —OC(S)R8, z) —C(S)NR8R8, aa) —NR8C(S)R8, bb) —OC(S)NR8R8, cc) —NR8C(S)OR8, dd) —NR8C(S)NR8R8, ee) —C(NR8)R8, ff) —C(NR8)OR8, gg) —OC(NR8)R8, hh) —C(NR8)NR8R8, ii) —NR8C(NR8)R8, jj) —OC(NR8)NR8R8, kk) —NR8C(NR8)OR8, ll) —NR8C(NR8)NR8R8, mm) —S(O)pR8, nn) —SO2NR8R8, oo) C1-6 alkyl, pp) C2-6 alkenyl, qq) C2-6 alkynyl, rr) C3-14 saturated, unsaturated, or aromatic carbocycle, and ss) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
• wherein any of oo)-ss) optionally is substituted with one or more moieties selected from the group consisting of R8, F, Cl, Br, I, —CF3, —OR8, —SR8, —CN, —NO2, —NR8R8, —C(O)R8, —C(O)OR8, —OC(O)R8, —C(O)NR8R8, —NR8C(O)R8, —OC(O)NR8R8, —NR8C(O)OR8, —NR8C(O)NR8R8, —C(S)R8, —C(S)OR8, —OC(S)R8, —C(S)NR8R8, —NR8C(S)R8, —OC(S)NR8R8, —NR8C(S)OR8, —NR8C(S)NR8R8, —C(NR8)R8, —C(NR8)OR8, —OC(NR8)R8, —C(NR8)NR8R8, —NR8C(NR8)R8, —OC(NR8)NR8R8, —NR8C(NR8)OR8, —NR8C(NR8)NR8R8, —SO2NR8R8, and —S(O)pR8;
• R8, at each occurrence, independently is selected from the group consisting of:
• a) H, b) an amine protecting group, c) C1-6 alkyl, d) C2-6 alkenyl, e) C2-6 alkynyl, f) C3-14 saturated, unsaturated, or aromatic carbocycle, g) 3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, h) —C(O)—C1-6 alkyl, i) —C(O)—C2-6 alkenyl, j) —C(O)—C2-6 alkynyl, k) —C(O)—C3-14 saturated, unsaturated, or aromatic carbocycle, l) —C(O)-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, m) —C(O)O—C1-6 alkyl, n) —C(O)O—C2-6 alkenyl, o) —C(O)O—C2-6 alkynyl, p) —C(O)O—C3-14 saturated, unsaturated, or aromatic carbocycle, and q) —C(O)O-3-14 membered saturated, unsaturated, or aromatic heterocycle comprising one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
• wherein any of c)-q) optionally is substituted with one or more moieties selected from the group consisting of F, Cl, Br, I, —CF3, —OH, —OC1-6 alkyl, —SH, —SC1-6 alkyl, —CN, —NO2, —NH2, —NHC1-6 alkyl, —N(C1-6 alkyl)2, —C(O)C1-6 alkyl, —C(O)OC1-6 alkyl, —C(O)NH2, —C(O)NHC1-6 alkyl, —C(O)N(C1-6 alkyl)2, —NHC(O)C1-6 alkyl, —SO2NH2—, —SO2NHC1-6 alkyl, —SO2N(C1-6 alkyl)2, and —S(O)pC1-6 alkyl;
• R9 is selected from the group consisting of:
• a) C1-6 alkyl, b) phenyl, and c) toluoyl;
• wherein any of a)-c) optionally is substituted with one or more moieties selected from the group consisting of F, Cl, Br, and I;
• m is 0, 1, 2, 3, or 4;
• n is 0, 1, 2, 3, or 4;
• and
• p, at each occurrence, independently is 0, 1, or 2.