Versatile ligand for palladium-catalyzed meta-C—H functionalizations of aromatic substrates

Patent metadata

Field	Value
Publication number	US-10696635-B2
Application number	US-201716094707-A
Country	US
Kind code	B2
Filing date	Apr 18, 2017
Priority date	Apr 18, 2016
Publication date	Jun 30, 2020
Grant date	Jun 30, 2020

Abstract

A class of mono-protected 3-amino-2-hydroxypyridine (MPAHP) ligands that enable the meta-C—H arylation of anilines, phenols, phenylacetic acids, and biologically relevant heterocyclic compounds using norbornene as a transient mediator is disclosed, such as in the formation of a reaction product of Formula IA:

The applicability of this meta-arylation methodology in the pharmaceutical industry is illustrated for heteroaryl substrates and heteroaryl iodide coupling partners, a feat made possible by using the MPAHP ligand. The enabling nature of MPAHP ligands to achieve other meta-C—H functionalization processes is also illustrated by the development of a meta-C—H amination reaction and a meta-C—H alkynylation reaction.

First claim

The invention claimed is:

1. A method for preparing a compound of Formula IA:

wherein:
Ar is aryl or heteroaryl;
Ring A is a carbocyclic ring selected from the group consisting of:

or
Ring A is a heterocyclic ring selected from the group consisting of:

wherein:
PG is selected from the group consisting of acetyl, pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 9-fluorenylmethoxycarbonyl, methanesulfonyl, trifluoromethanesulfonyl, and nitrobenzenesulfonyl;
* is the point of attachment to Ar; and
is the point of attachment to X;

Ring B is a heteroaromatic ring selected from the group consisting of:

wherein:
is the point of attachment to Y;
X is —CH 2 —, —O—, or —N-PG-;
Y is —CH 2 —;
PG is benzyl or tert-butoxycarbonyl; and
n is 0 or 1;
wherein aryl is optionally substituted at the meta and para positions with one or two substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, nitro, cyano, C 1 -C 7 -hydrocarbyl, C 1 -C 7 -hydrocarbyl substituted by protected hydroxy, perfluoro-C 1 -C 3 -hydrocarbyl, C(O)—C 1 -C 7 -hydrocarbyl, C(O)O—C 1 -C 7 -hydrocarbyl, protected amino, di-(C 1 -C 7 -hydrocarbyl) C 1 -C 7 -hydrocarbylphosphonate, protected hydroxy, —O—C 1 -C 7 -hydrocarbyl, —S—C 1 -C 7 -hydrocarbyl, C 3 -C 7 cyclic hydrocarbyl, C 3 -C 7 cyclic hydrocarbyl substituted by protected hydroxy, and a fused ring having 3 or 4 added ring atoms; or
wherein aryl is optionally substituted at the ortho position with a substituent selected from the group consisting of C(O)O—C 1 -C 7 -hydrocarbyl and NHC(O)—C 1 -C 7 -hydrocarbyl;
wherein heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, C 1 -C 7 -hydrocarbyl, perfluoro-C 1 -C 3 -hydrocarbyl, C(O)—C 1 -C 7 -hydrocarbyl, C(O)O—C 1 -C 7 -hydrocarbyl, —O—C 1 -C 7 -hydrocarbyl, —S—C 1 -C 7 -hydrocarbyl, C 3 -C 7 cyclic hydrocarbyl, and a fused ring having 3 or 4 added ring atoms in which any nitrogen atom is free of reactive hydrogens;
wherein Ring A is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, C 1 -C 7 -hydrocarbyl, perfluoro-C 1 -C 3 -hydrocarbyl, C 1 -C 7 -hydrocarbyl-4- to 6-membered ring, C(O)—C 1 -C 7 -hydrocarbyl, C(O)O—C 1 -C 7 -hydrocarbyl, protected amino, —O—C 1 -C 7 -hydrocarbyl, —S—C 1 -C 7 -hydrocarbyl, and C 3 -C 7 cyclic hydrocarbyl;
wherein Ring B is optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 7 -hydrocarbyl, C 1 -C 3 -hydrocarbyl-CF 3 , C 1 -C 7 -hydrocarbyl-4- to 6-membered ring, —O—C 1 -C 7 -hydrocarbyl, and —O—C 1 -C 7 -hydrocarbyl-CF 3 ; and
wherein the hydroxy and amino protecting groups are independently selected from the group consisting of acetyl, pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 9-fluorenylmethoxycarbonyl, methanesulfonyl, trifluoromethanesulfonyl, and nitrobenzenesulfonyl;

provided that:
(a) when n is 0, X is —CH 2 — or —N-PG-; and
(b) when n is 1, X is —O— or —N-PG-;

wherein the method comprises the following steps:
(A) reacting a compound of Formula I:

wherein:
Ring A is a carbocyclic ring selected from the group consisting of:

 or
Ring A is a heterocyclic ring selected from the group consisting of:

wherein:
PG is selected from the group consisting of acetyl, pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 9-fluorenylmethoxycarbonyl, methanesulfonyl, trifluoromethanesulfonyl, and nitrobenzenesulfonyl;
* is the point of attachment to Ar; and
is the point of attachment to X;

Ring B is a heteroaromatic ring selected from the group consisting of:

wherein:
is the point of attachment to Y;

X is —CH 2 —, —O—, or —N-PG-;
Y is —CH 2 —;
PG is benzyl or tert-butoxycarbonyl; and
n is 0 or 1;
wherein aryl is optionally substituted at the meta and para positions with one or two substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, nitro, cyano, C 1 -C 7 -hydrocarbyl, C 1 -C 7 -hydrocarbyl substituted by protected hydroxy, perfluoro-C 1 -C 3 -hydrocarbyl, C(O)—C 1 -C 7 -hydrocarbyl, C(O)O—C 1 -C 7 -hydrocarbyl, protected amino, di-(C 1 -C 7 -hydrocarbyl) C 1 -C 7 -hydrocarbylphosphonate, protected hydroxy, —O—C 1 -C 7 -hydrocarbyl, —S—C 1 -C 7 -hydrocarbyl, C 3 -C 7 cyclic hydrocarbyl, C 3 -C 7 cyclic hydrocarbyl substituted by protected hydroxy, and a fused ring having 3 or 4 added ring atoms; or
wherein aryl is optionally substituted at the ortho position with a substituent selected from the group consisting of C(O)O—C 1 -C 7 -hydrocarbyl and NHC(O)—C 1 -C 7 -hydrocarbyl;
wherein heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of fluoro, chloro, bromo, iodo, C 1 -C 7 -hydrocarbyl, perfluoro-C 1 -C 3 -hydrocarbyl, C(O)—C 1 -C 7 -hydrocarbyl, C(O)O—C 1 -C 7 -hydrocarbyl, —O—C 1 -C 7 -hydrocarbyl, —S—C 1 -C 7 -hydrocarbyl, C 3 -C 7 cyclic hydrocarbyl, and a fused ring having 3 or 4 added ring atoms in which any nitrogen atom is free of reactive hydrogens;
wherein Ring A is optionally substituted with one, two or three substituents independently selected from the group consisting of fluoro, chloro, bromo, nitro, cyano, C 1 -C 7 -hydrocarbyl, perfluoro-C 1 -C 3 -hydrocarbyl, C 1 -C 7 -hydrocarbyl-4- to 6-membered ring, C(O)—C 1 -C 7 -hydrocarbyl, C(O)O—C 1 -C 7 -hydrocarbyl, protected amino, —O—C 1 -C 7 -hydrocarbyl, —S—C 1 -C 7 -hydrocarbyl, and C 3 -C 7 cyclic hydrocarbyl;
wherein Ring B is optionally substituted with one, two or three substituents independently selected from the group consisting of C 1 -C 7 -hydrocarbyl, C 1 -C 3 -hydrocarbyl-CF 3 , C 1 -C 7 -hydrocarbyl-4- to 6-membered ring, —O—C 1 -C 7 -hydrocarbyl, and —O—C 1 -C 7 -hydrocarbyl-CF 3 ; and
wherein the hydroxy and amino protecting groups are independently selected from the group consisting of acetyl, pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 9-fluorenylmethoxycarbonyl, methanesulfonyl, trifluoromethanesulfonyl, and nitrobenzenesulfonyl;

provided that:
(a) when n is 0, X is —CH 2 — or —N-PG-; and
(b) when n is 1, X is —O— or —N-PG-;

with:
(i) Pd(OAc) 2 ; and
(ii) a ligand of Formula III:

wherein:
 R 15 is —C(O)—C 1 -C 11 hydrocarbyl or perfl

Assignees

• Scripps Research Inst

Inventors

• Yu Jin-Quan

Classifications

• C07D217/12

  with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring · CPC title

• C07D213/36

  Radicals substituted by singly-bound nitrogen atoms (nitro radicals C07D213/26) · CPC title

• C07D241/12

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

• C07D213/26

  Radicals substituted by halogen atoms or nitro radicals · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title