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US 2024/0308931 A1Published application
Ligand-controlled divergent dehydrogenative reactions of aliphatic acids
AssigneeThe Scripps Research Institute
InventorsJin-Quan YU, Zhen WANG, Liang HU
Life of this patent
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Abstract
Disclosed herein are palladium-catalyzed dehydrogenation processes of carboxylic acids to make α, β-unsaturated carboxylic acids or γ-alkylidene butenolides. The processes allow the chemoselective dehydrogenation of carboxylic acids in the presence of other enolizable functionalities such as ketones, providing reactivity that is inaccessible with existing carbonyl desaturation protocols.
Claims36
A process for making a compound of formula (2):
- comprising contacting a compound of formula (1):
- with a source of Pd(II), optionally in the presence of an oxidant, and a ligand of formula (L-1):
- whereby the compound of formula (2) is formed, wherein:
- Y is N or CH;
- R1A and R1B are independently selected from the group consisting of H, C1-C6-alkyl, C3-C20-cycloalkyl, C6-C10-aryl, 3- to 14-membered heterocycloalkyl and —(C1-C6-alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 ring members are independently selected from N, O, and S), 5- to 10-membered heteroaryl and —(C1-C6-alkyl)-(5- to 10-membered heteroaryl) (wherein 1-4 heteroaryl members are independently selected from N, O, and S);
- or R1A and R1B, together with the carbon atoms to which they are bound, form a 5- to 6-membered carbocyclic ring;
- wherein R1A and R1B, or the carbocyclic ring that they form, are independently and optionally substituted with one to five substituents selected from the group consisting of halo, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, —S—(C1-C6-alkyl), C6-C10-aryloxy, —O—(C1-C6-alkyl)(C6-C10-aryl), —S(O)0-2(C6-C10-aryl) (optionally substituted with C1-C6-alkyl), C(O)NRARB, NRAC(O)O(C1-C6-alkyl), —C(O)(C1-C6-alkyl), —C(O)O(C1-C6-alkyl), —C(O)(C6-C10-aryl), and —C(O)O(C6-C10-aryl);
- m1 is selected from 0, 1, 2, 3, and 4;
- n1 is selected from 0, 1, 2, and 3;
- R1-L1 and R2-L1 are independently selected from the group consisting of —CN, halo, NRARB, C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C(O)C1-C6-alkyl, C(O)NRARB, S(O)NRARB, S(O)2NRARB, C3-C14-cycloalkyl, C6-C10-aryl, C6-C10-aryloxy, 3- to 14-membered heterocycloalkyl and —(C1-C6-alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 ring members are independently selected from N, O, and S), and 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), wherein
- each alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl moiety is optionally substituted with one to four substituents selected from the group consisting of halo, oxo, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C(O)NRARB, C1-C6-alkoxy, C6-C10-aryl (optionally substituted by one to three halo and C1-C6-alkyl), and 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S;
- optionally substituted by one to three substituents selected from C1-C6-alkyl and 5- to 10-membered heteroaryl);
- RA and RB are independently selected from the group consisting of H, C1-C6-alkyl, C1-C6-haloalkyl, —C1-C6-alkyl-C6-C10-aryl, C(O)C1-C6-alkyl, C(O)C1-C6-alkyl-C6-C10-aryl, C(O)OC1-C6-alkyl, C6-C10-aryl (optionally fused to C3-C14-cycloalkyl that is optionally substituted by one to four halo and C1-C6-alkyl), wherein
- each aryl is optionally substituted with one to three substituents selected from C1-C6-alkyl, halo, C1-C6-haloalkyl, and 3- to 14-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S);
- each alkyl is optionally substituted with one to three substituents selected from halo, NRR′ (wherein R and R′ are independently selected from H, C1-C6-alkyl, C(O)C1-C6-alkyl, and C(O)C6-C10-aryl);
- or, optionally, when m1 is 2, then two adjacent R1-L1 together with the ring carbon atoms to which they are bound form a fused phenyl ring that is optionally substituted with one to three substituents selected the group consisting of halo, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, and C1-C6-haloalkoxy.
13 more elements
A process for making a compound of formula (5) or (7):
- comprising contacting a compound of formula (3) or (6), respectively:
- with a source of Pd(II), a ligand of formula (L-2), optionally in the presence of an oxidant:
- and a compound of formula (A):
- whereby the compound of formula (5) or (7) is formed, wherein
- the dotted lines represent optional single bonds, and when they are present,
- then p is 1, 2, 3, or 4;
- and
- R4 is —CH2—, wherein the resulting 5- to 8-membered ring is cycloalkyl or heterocycloalkyl (wherein 1-2 ring members are independently selected from N, O, and S),
- wherein the ring is optionally substituted with one to three substituents selected from halo, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, —S(O)0-2(C6-C10-aryl) (optionally substituted with C1-C6-alkyl), and C6-C10-aryl (optionally and independently substituted by one to three halo, C1-C6-alkyl, and C1-C6-haloalkyl);
- when the bonds are not present, then R4 is selected from the group consisting of C1-C20-alkyl, C3-C14-cycloalkyl, —(C1-C6-alkyl)-(C3-C14-cycloalkyl), C6-C10-aryl, —(C1-C6-alkyl)-(C6-C10-aryl), 3- to 14-membered heterocycloalkyl and —(C1-C6-alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 ring members are independently selected from N, O, and S), 5- to 10-membered heteroaryl and —(C1-C6-alkyl)-(5- to 10-membered heteroaryl) (wherein 1-4 heteroaryl members are independently selected from N, O, and S),
- wherein R4 or the ring in which R4 is a member is independently and optionally substituted with one to five substituents selected from the group consisting of halo, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, —S—(C1-C6-alkyl), C6-C10-aryloxy, —O—(C1-C6-alkyl)(C6-C10-aryl), —S(O)0-2(C6-C10-aryl) (optionally substituted with C1-C6-alkyl), C(O)NRARB, NRAC(O)O(C1-C6-alkyl), —C(O)(C1-C6-alkyl), —C(O)O(C1-C6-alkyl), —C(O)(C6-C10-aryl), and —C(O)O(C6-C10-aryl);
- R5 is selected from the group consisting of —SiR3 and —CH(OSiR3)R′, wherein
- each R and R′ is independently selected from the group consisting of C1-C6-alkyl, C1-C6-alkoxy, C1-C6-haloalkyl, and C3-C14-cycloalkyl;
- Ar is
- and is optionally substituted with one to three substituents selected from the group consisting of halo, C1-C6-alkyl, and C1-C6-alkoxy;
- R3-L2 and R4-L2 are independently selected from the group consisting of H, OH, halo, C1-C6-alkyl, C1-C6-haloalkyl, C3-C14-cycloalkyl, —(C1-C6-alkyl)-(C3-C14-cycloalkyl), C6-C10-aryl, and —(C1-C6-alkyl)-(C6-C10-aryl),
- or R3-L2 and R4-L2, together with the carbon atom to which they are bound, form a 5- or 6-membered cycloalkyl,
- or one of R3-L2 and R4-L2, together with the 3-pyridyl carbon when Ar is pyridyl, form a 5- to 6-membered cycloalkyl fused to the pyridyl;
- wherein R3-L2 and R4-L2, or a ring in which either is a member, are independently and optionally substituted by one to three substituents selected from the group consisting of halo, C1-C6-alkyl, C1-C6-haloalkyl, and C1-C6-alkoxy.
16 more elements
Dependencies are inferred from the claim text.