Regio-controllable [2+2] benzannulation with two adjacent c(sp3)-h bonds
AssigneeThe Scripps Research Institute
InventorsJin-Quan YU, Ji-Min YANG, Yu-Kun LIN
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Abstract
This application discloses methods of twofold β,γ-methylene C(sp3)-H activation/C—C bond formation using a Pd(II) catalyst bound to amide-pyridone ligands, resulting in regio-controllable [2+2] annulation between aliphatic acids and dihaloarenes.
Claims119
A method of twofold β,γ-methylene C(sp3)-H activation/C—C bond formation, comprising regio-controllable [2+2] annulation between an aliphatic acid and a dihaloarene in the presence of a Pd(II) catalyst bound to an amide-pyridone ligand.
The method of any one of claims 34-45, wherein r is 0.
The method of any one of claims 2-99, wherein the solvent is HFIP.
The method of any one of claims 2-107, wherein the reaction temperature is between approximately 70-110° C.
The method of any one of claims 2-107, wherein the reaction temperature is between approximately 100-110° C.
A compound having the structure selected from the group consisting of:
- including enantiomers, scalemic or racemic mixtures, and pharmaceutically acceptable salts thereof.
A compound having the structure selected from the group consisting of:
- including enantiomers, scalemic or racemic mixtures, and pharmaceutically acceptable salts thereof.
A compound having the structure selected from the group consisting of:
- including enantiomers, scalemic or racemic mixtures, and pharmaceutically acceptable salts thereof.
A compound having the structure selected from the group consisting of:
- including enantiomers, scalemic or racemic mixtures, and pharmaceutically acceptable salts thereof.
A compound having the structure selected from the group consisting of:
A method of preparing the Compound 6, comprising the following steps:
A method of preparing the Compound 7, comprising the following steps:
A method of preparing the Compound 10, comprising the following steps:
A method of preparing the Compound 11, comprising the following steps:
A compound having the Formula I
- wherein:
- Q is Ar or Het;
- Ar is (C6-C10)aryl, optionally substituted with one or more Ra;
- Het is (C5-C8)heteroaryl, optionally substituted with one or more Ra;
- R1 and R2 are independently H or (C1-C6)alkyl, wherein both R1 and R2 are not H;
- R3 is (C1-C6)alkyl, (C1-C6)heteroalkyl, halo (C1-C6)alkyl, (C1-C6)alkyl-OTBS, —C(═O)OH, —C(═O)O(C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, (C6-C10)aryl, (C5-C6)heteroaryl, (C1-C6)alkyl (C3-C7)cycloalkyl, (C1-C6)alkyl (C3-C7)heterocycloalkyl, (C1-C6)alkyl (C6-C10)aryl, —O(C6-C10)aryl, and (C1-C6)alkyl (C5-C6)heteroaryl, wherein each is optionally and independently substituted with one or more Ra;
- each Ra is independently selected from halo, —OH, —C(═O)O(C1-C6)alkyl, CN, NO2, —P(═O)(O(C1-C6)alkyl)2-C(═O)H, NH2, (C1-C6)alkyl, halo (C1-C6)alkyl, (C1-C6)heteroalkyl, —C(═O)(C1-C6)alkyl, oxo, Ts, —S(═O)2F, —OS(═O)2F, or —S(═O)2(C1-C6)alkyl, and —C(═O)NH(C1-C6)alkyl;
- each R5 is independently halo, OH, CN, NO2,-OTf, (C1-C6)alkyl, —C(═O)OH, —C(═O)O(C1-C6)alkyl, —C(═O)H, —C(═O)(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)heteroalkyl, halo (C1-C6)alkyl, —C(═O)(C1-C6)alkyl, —C(═O)(C3-C7)heterocycloalkyl, (C5-C6)heteroaryl, or —C(═O)NH(C1-C6)alkyl(C5-C6)heteroaryl;
- or two R5 may together form (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, (C6-C10)aryl, or (C5-C6)heteroaryl, wherein each is optionally and independently substituted with one or more Ra;
- and
- m is 0, 1, or 2;
- including enantiomers, scalemic or racemic mixtures, and pharmaceutically acceptable salts thereof.
A compound having the Formula II
- wherein:
- Q is Ar or Het;
- Ar is (C6-C10)aryl, optionally substituted with one or more Ra;
- Het is (C5-C8)heteroaryl, optionally substituted with one or more Ra;
- R1 is (C1-C6)alkyl, (C1-C6)heteroalkyl, halo (C1-C6)alkyl, (C1-C6)alkyl-OTBS, (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, (C6-C10)aryl, (C5-C6)heteroaryl, (C1-C6)alkyl (C3-C7)cycloalkyl, (C1-C6)alkyl (C3-C7)heterocycloalkyl, (C1-C6)alkyl (C6-C10)aryl, and (C1-C6)alkyl (C5-C6)heteroaryl, wherein each is optionally and independently substituted with one or more Ra;
- each Ra is independently selected from halo, —OH, (C1-C6)alkyl, —C(═O)O(C1-C6)alkyl, CN, NO2, —P(═O)(O(C1-C6)alkyl)2-C(═O)H, —C(═O)(C1-C6)alkyl, —C(═O)OH, —C(═O)O(C1-C6)alkyl, NH2, halo (C1-C6)alkyl, (C1-C6)heteroalkyl, —C(═O)(C1-C6)alkyl, oxo, Ts, —S(═O)2F, —OS(═O)2F, or —S(═O)2(C1-C6)alkyl, and —C(═O)NH(C1-C6)alkyl;
- each R5 is independently halo, OH, CN, NO2,-OTf, (C1-C6)alkyl, —C(═O)OH, —C(═O)O(C1-C6)alkyl, —C(═O)H, —C(═O)(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)heteroalkyl, halo (C1-C6)alkyl, —C(═O)(C1-C6)alkyl, —C(═O)(C3-C7)heterocycloalkyl, (C5-C6)heteroaryl, —C(═O)NH(C1-C6)alkyl(C5-C6)heteroaryl;
- or two R5 may together form (C3-C7)cycloalkyl, (C3-C7)heterocycloalkyl, (C6-C10)aryl, or (C5-C6)heteroaryl, wherein each is optionally and independently substituted with one or more Ra;
- and
- each R6 is independently halo, OH, CN, (C1-C6)alkyl, (C1-C6)heteroalkyl, or halo (C1-C6)alkyl;
- n is 1, 2, 3, 4, 7, 8, or 11;
- and
- r is 0, 1, or 2;
- including enantiomers, scalemic or racemic mixtures, and pharmaceutically acceptable salts thereof.
Any method of twofold β,γ-methylene C(sp3)-H activation/C—C bond formation, comprising regio-controllable [2+2] annulation between an aliphatic acid and a dihaloarene in the presence of a Pd(II) catalyst bound to an amide-pyridone ligand, the product thereof, any amide-pyridone ligand, or preparation thereof, as described herein.
Dependencies are inferred from the claim text.