Pd(II)-catalyzed enantioselective β-methylene C(sp3)—H bond activation

Patent metadata

Field	Value
Publication number	US-11186563-B2
Application number	US-201716086535-A
Country	US
Kind code	B2
Filing date	Mar 20, 2017
Priority date	Mar 21, 2016
Publication date	Nov 30, 2021
Grant date	Nov 30, 2021

Abstract

Chiral acetyl-protected aminoethyl quinoline (APAQ), pyridine and imazoline ligands are disclosed that enable Pd (II)-catalyzed enantioselective arylation or heteroarylation of ubiquitous prochiral β-methylene C—H bonds of aliphatic amides offers an alternative disconnection for constructing β-chiral centers. Systematic tuning of the ligand structure reveals that a six-membered instead of a five-membered chelation of these types of ligands with the Pd(II) is important for accelerating the C(sp3)-H activation thereby achieving enantioselectivity for quinoline and pyridine ligands.

First claim

The invention claimed is:

1. A method for carrying out a Pd(II)-catalyzed chiral insertion of an aryl or heteroaryl substituent at the β-carbon of a protected prochiral carboxylic acid substrate to provide an insertion product whose enantiomeric ratio is greater for one enantiomer than the other that comprises the steps of
a) heating a reaction mixture containing a solvent having dispersed or dissolved therein (i) a protected carboxylic acid substrate molecule of Formula I, (ii) an excess of an aromatic or

heteroaromatic iodide reactant relative to said substrate, (iii) a catalytic amount of a Pd(II) catalyst, (iv) a chiral acyl-protected ligand (L) of Formula A present in an amount of about 5 to about 20 mole percent based on the amount of protected carboxylic acid substrate molecule of Formula I, and (v) an excess of silver compound oxidant relative to said protected carboxylic acid substrate at a temperature of about 70° to about 120° C. in a sealed pressure vessel; and
b) maintaining said reaction mixture for a time and at a temperature sufficient to carry out said insertion and form an insertion product;
wherein in a compound of Formula I, i) R a is hydrido, a protected amino group (NPG), or a C 1 -C 6 hydrocarbyl straight or branched chain substituent, and one or two of R b and R c is hydrido, and when other than hydrido, a R b and R c group is a C 1 -C 13 hydrocarbyl straight or branched chain or cyclic aliphatic group; or a (methyl)C 6 -C 10 aromatic or heteroaromatic group containing up to three heteroatoms that can each be nitrogen, or can be two nitrogens and an oxygen, and wherein the ring of a (methyl)C 6 -C 10 aromatic or heteroaromatic group is unsubstituted or substituted with up to three substituents that are independently selected from one or more of the group consisting of halogen other than iodo, C 1 -C 6 hydrocarbyl, C 1 -C 6 hydrocarbyloxy, carboxy C 1 -C 6 hydrocarbyl, trifluoromethyl, C 1 -C 6 hydrocarboyl, C 1 -C 6 hydrocarbyl carboxylate, nitro, C 1 -C 6 hydrocarbylthiooxy, cyano and protected amino; and
(ii) X of a molecule of Formula I is a NHR 2 group, in which R 2 is a perfluorinated p-tolyl group [4-(CF 3 )C 6 F 4 ], OH, or —O—C 1 -C 12 hydrocarbyl group so that X is NH[4-(CF 3 )C 6 F 4 ], NOH or NH—O—C 1 -C 12 hydrocarbyl group;
said aromatic or heteroaromatic iodide reactant is unsubstituted, or contains up to three substituents in addition to the iodo group, wherein the additional substituents are independently selected from one or more of the group consisting of halogen other than iodo, C 1 -C 6 hydrocarbyl, C 1 -C 6 hydrocarbyloxy, trifluoromethyl, trifluoromethoxy, C 1 -C 6 hydrocarboyl, C 1 -C 6 hydrocarbyl carboxylate, hydrocarbylthiooxy, nitro, cyano, methylene dioxy, C 1 -C 6 vicinyl dioxy alkyl group, and C 1 -C 6 hydrocarbyl di-C 1 -C 6 alkyl phosphonate; and
said protected ligand, L, is a compound of Formula A

wherein:
R 3 is a C1-C4 alkyl group or a fluoro-substituted benzoyl group;
the depicted cyclic moiety (Ring) on which R 5 and R 6 can be substituents is a cyclic ring structure containing one ring or two fused rings that each contains 5 or 6 atoms in the ring;
Z is oxygen (O) or CH when part of a double bond;
R 5 and R 6 are the same or different and are independently selected from the group consisting of a hydrido, halogen other than iodo, straight chain, branched chain and cyclic C 1 -C 7 hydrocarbyl, C 1 -C 7 hydrocarbyloxy, carboxy C 1 -C 6 hydrocarbyl, trifluoromethyl, C 1 -C 6 hydrocarboyl, nitro, C 1 -C 6 hydrocarbylthiooxy, and a cyano group, or a benzyl group whose ring is substituted by 1 through five fluoro groups;
R 7 is a straight chain, branched chain or cyclic C 1 -C 6 hydrocarbyl group, or a C 1 -C 6 hydrocarbyloxy group;
“n” is zero or one, such that when n is zero, the carbon atom bearing R 7 and R 7 itself are absent, and the depicted Ring is bonded directly to the carbon atom bearing the R 3 C(O)HN group;
R 10 is a straight chain, branched chain or cyclic C 1 -C 7 hydrocarbyl group, or a C 1 -C 7 hydrocarbyloxy group that is unsubstituted, or R 10 is an optionally substituted cyclic C 5 -C 7 hydrocarbyl group, or an optionally substituted C 5 -C 7 hydrocarbyloxy group whose optional substituent is one or two groups, R 8 and R 9 , that are the same or different and are independently selected from the group consisting of straight chain, branched chain and cyclic C 1 -C 7 hydrocarbyl group, and a C 1 -C 7 hydrocarbyloxy group; and
an atom with an adjacent asterisk is chiral.

2. The method according to claim 1 , wherein Z is CH that is part of a double bond.

3. The method according to claim 2 , wherein n is one.

4. The method according to claim 3 , wherein said Ring contains two fused rings that each contains 6 atoms.

5. The method according to claim 1 , wherein Z is oxygen.

6. The method according to claim 5 , wherein n is zero.

7. The method according to claim 6 , wherein said Ring contains one ring that contains five ring atoms.

8. The method according to claim 1 , R 7 is a straight chain C 1 -C 3 hydrocarbyl group, or a C 1 -C 3 hydrocarbyloxy group.

9. The method according to claim 1 , wherein R 10 is phenyl, R 8 and R 9 are the same substituent, and are bonded a) in the 3- and 5-positions or b) in the 2- and 6-positions.

10. The method according to claim 9 , wherein R7 and the phenyl ring containing R 8 and R 9 substituents are in a syn or anti relationship.

11. The method according to claim 1 , including the further step of recovering said reaction product.

12. The method according to claim 1 , wherein Z is CH that is part of a double bond.

13. The method according to claim 12 , wherein n is one.

14. The method according to claim 12 , wherein said Ring contains two fused rings that each contains 6 atoms.

15. The method according to claim 1 , wherein Z is oxygen.

16. The method according to claim 15 , wherein n is zero.

17. The method according to claim 16 , wherein said Ring contains one ring that contains five ring atoms.

18. The method according to claim 1 , R 7 is a straight chain C 1 -C 3 hydrocarbyl group, or a C 1 -C 3 hydrocarbyloxy group.

19. The method according to claim 1 , wherein R 10 is phenyl, R 8 and R 9 are the same substituent, and are bonded a) in the 3- and 5-positions or b) in the 2- and 6-positions.

20. The method according to claim 1 , wherein R 7 and the phenyl ring containing R 8 and R 9 substituents are in a syn or anti relationship.

21. The method according to claim 1 , wherein n is one, Z is CH and said compound corresponds in structure to Formula A1 or A2

wherein *, R 3 , R 5 , R 6 , R 7 and R 10 are as previously defined.

22. The method according to claim 21 , wherein R 10 is phenyl, R 8 and R 9 are the same substituent, and are bonded a) in the 3- and 5-positions or b) in the 2- and 6-positions.

23. The method according to claim 22 , wherein R 7 and the phenyl ring containing R 8 and R 9 substituents are in a syn or anti relationship.

24. The method according to claim 23 , wherein R 8 and R 9 are t-butyl.

Assignees

• Scripps Research Inst

Inventors

• Yu Jin-Quan

Classifications

• C07D209/48

  with oxygen atoms in positions 1 and 3, e.g. phthalimide · CPC title

• C07D401/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D263/10

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D215/12

  with substituted hydrocarbon radicals attached to ring carbon atoms · CPC title

• B01J31/181

  Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine · CPC title