IP Library › Granted Patent US 11,918,984

Granted Patent B2

US 11,918,984 · App. 17/276,855 · Granted Mar 5, 2024

Annulation catalysts via direct C—H bond amination

Inventors: Theodore Alexander Betley (Cambridge, MA); Alexandre Mikhailine (Cambridge, MA); Claudia Kleinlein (Cambridge, MA); Yuyang Dong (Cambridge, MA); Yunjung Baek (Cambridge, MA)

Assignee: President and Fellows of Harvard College

B01J31/1815 B01J31/2243 C07D207/06 C07D209/04 C07D209/44 C07D209/54 C07D211/70 C07D263/04 C07D401/04 C07D403/04 C07D471/04 C07D471/08 C07D487/08 B01J2231/4283 B01J2531/0216 B01J2531/842 B01J2531/845 B01J2531/847 B01J2540/66

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Quick Facts

Patent No.: US 11,918,984
App. No.: 17/276,855
Granted: Mar 5, 2024
Kind: B2

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Abstract

Disclosed are compounds, methods, reagents, systems, and kits for the preparation and utilization of monomeric or polymeric metal-based compounds. These metal-based compounds are organometallic catalysts composed of substituted dipyrrin ligands bound to transition metals. C—H bond functionalization catalysis can be performed with the disclosed organometallic catalysts to yield C—N bonds to generate substituted bicyclic, spiro, and fused nitrogen-containing heterocycles, all common motifs in various pharmaceutical and bioactive molecules.

Claims (112)

1. A compound of Formula (I):

or a salt thereof,

wherein:

each R 1 independently is branched or unbranched, substituted or unsubstituted, cyclic or acyclic aliphatic; branched or unbranched, substituted or unsubstituted, cyclic or acyclic heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl;

A is substituted or unsubstituted arylene; or substituted or unsubstituted heteroarylene;

L is branched or unbranched, substituted or unsubstituted, cyclic or acyclic aliphatic; or

branched or unbranched, substituted or unsubstituted, cyclic or acyclic heteroaliphatic;

X is S, O, or NR X , wherein R X is hydrogen; nitrogen protecting group; branched or unbranched, substituted or unsubstituted, cyclic or acyclic aliphatic; branched or unbranched, substituted or unsubstituted, cyclic or acyclic heteroaliphatic; substituted or unsubstituted arylene; or substituted or unsubstituted heteroarylene;

M is a transition metal; and

n is an integer between 2 and 10, inclusive;

wherein the atom X labeled “*” of one monomer is bonded to the transition metal M labeled “**” of another monomer.

2. The compound of claim 1 , or a salt thereof, wherein the compound is of formula:

and

each R 2 is of the formula

3. The compound of claim 1 , or a salt thereof, wherein the compound is of formula:

and

each R 2 is of the formula

4. The compound of claim 1 , or a salt thereof, wherein the compound is of formula:

and

each R 2 is of the formula

5. A method of preparing a compound of Formula (IV):

or a salt thereof, comprising:

reacting an azide of Formula (IV-a) with a compound of claim 1 , or a salt thereof, to produce a cyclic amine of Formula (IV);

wherein:

an azide of Formula (IV-a) is of formula

each R 4 independently is hydrogen; branched or unbranched, substituted or unsubstituted, cyclic or acyclic aliphatic; branched or unbranched, substituted or unsubstituted, cyclic or acyclic heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; two R 4 bonded to the same atom are taken together to form an oxo group or a cyclic aliphatic or cyclic heteroaliphatic moiety; two R 4 bonded to different atoms are taken together to form a cyclic aliphatic, cyclic heteroaliphatic, arylene, or heteroarylene moiety; two R 4 bonded to two adjacent atoms are replaced with a π bond between the two adjacent atoms; or absent;

m is an integer between 2 and 8, inclusive;

each A independently is C, S, O, or N.

6. The method of claim 5 , wherein the azide of Formula (IV-a) is selected from the group consisting of:

7. A method of preparing a compound of claim 1 , or a salt thereof, comprising:

reacting a compound of Formula (I-a):

or a salt thereof, with an organometallic iron compound to produce a compound of claim 1 , or a salt thereof, wherein:

A is substituted or unsubstituted arylene; or substituted or unsubstituted heteroarylene;

L is branched or unbranched, substituted or unsubstituted, cyclic or acyclic aliphatic; or branched or unbranched, substituted or unsubstituted, cyclic or acyclic heteroaliphatic; and

8. A kit comprising:

a) a compound of claim 1 , or a salt thereof, in a first container;

b) an azide of Formula (IV-a) in a second container,

wherein:

m is an integer between 2 and 8, inclusive;

each A independently is C, S, O, or N;

c) optionally, one or more solvents; and

d) optionally, instructions for use.

9. A compound of Formula (I-a):

or a salt thereof,

wherein:

A is substituted or unsubstituted arylene; or substituted or unsubstituted heteroarylene;

L is branched or unbranched, substituted or unsubstituted, cyclic or acyclic aliphatic; or branched or unbranched, substituted or unsubstituted, cyclic or acyclic heteroaliphatic; and

10. The compound of claim 9 , or a salt thereof, wherein the compound is of the formula:

11. A kit comprising:

a) a compound of claim 9 , or a salt thereof, in a first container;

b) an organometallic compound in a second container;

c) optionally, one or more solvents; and

d) optionally, instructions for use.

12. A compound of Formula (II):

or a salt thereof,

wherein:

each R 3 independently is hydrogen; branched or unbranched, substituted or unsubstituted, cyclic or acyclic aliphatic; branched or unbranched, substituted or unsubstituted, cyclic or acyclic heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —SR X or —OR X , wherein R X is hydrogen; oxygen protecting group; sulfur protecting group; branched or unbranched, substituted or unsubstituted, cyclic or acyclic aliphatic; branched or unbranched, substituted or unsubstituted, cyclic or acyclic heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or —N(R X ) 2 , wherein each R X independently is hydrogen; nitrogen protecting group; branched or unbranched, substituted or unsubstituted, cyclic or acyclic aliphatic; branched or unbranched, substituted or unsubstituted, cyclic or acyclic heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl;

A is substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl;

each B independently is branched or unbranched, substituted or unsubstituted, cyclic or acyclic aliphatic; branched or unbranched, substituted or unsubstituted, cyclic or acyclic heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl;

X 1 is a substituted or unsubstituted, cyclic or acyclic heteroaliphatic; or substituted or unsubstituted heteroarylene; and

M is a transition metal.

13. The compound of claim 12 , or a salt thereof, wherein the compound is selected from the group consisting of:

or a salt thereof.

14. A method of preparing a compound of Formula (IV):

or a salt thereof, comprising:

reacting an azide of Formula (IV-a) with a compound of claim 12 , or a salt thereof, to produce a cyclic amine of Formula (IV);

wherein:

an azide of Formula (IV-a) is of formula

m is an integer between 2 and 8, inclusive;

each A independently is C, S, O, or N.

15. A kit comprising:

a) a compound of claim 12 , or a salt thereof, in a first container;

b) an azide of Formula (IV-a) in a second container,

wherein:

m is an integer between 2 and 8, inclusive;

each A independently is C, S, O, or N;

c) optionally, one or more solvents; and

d) optionally, instructions for use.

16. A compound of Formula (III):

or a salt thereof,

wherein:

A is substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl;

X 2 is branched or unbranched, substituted or unsubstituted, cyclic or acyclic heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl;

. . . is a bond or absent; and

M is a transition metal.

17. The compound of claim 16 , or a salt thereof, wherein the compound is of the formula:

18. The compound of claim 16 , wherein the compound is of the formula:

19. A method of preparing a compound of Formula (IV):

or a salt thereof, comprising:

reacting an azide of Formula (IV-a) with a compound of claim 16 , or a salt thereof, to produce a cyclic amine of Formula (IV);

wherein:

an azide of Formula (IV-a) is of formula

m is an integer between 2 and 8, inclusive;

each A independently is C, S, O, or N.

20. A kit comprising:

a) a compound of claim 16 , or a salt thereof, in a first container;

b) an azide of Formula (IV-a) in a second container,

wherein:

m is an integer between 2 and 8, inclusive;

each A independently is C, S, O, or N;

c) optionally, one or more solvents; and

d) optionally, instructions for use.

Assignments (2)

CONFIRMATORY LICENSE Recorded Nov 22, 2023

From: HARVARD UNIVERSITY

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 065665/0796 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 17, 2022

From: BETLEY, THEODORE ALEXANDER; MIKHAILINE, ALEXANDRE; KLEINLEIN, CLAUDIA; DONG, YUYANG; BAEK, YUNJUNG

To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE

Reel/Frame 060833/0922 →

Continuity (2)

Provisional Application 62733480 · Sep 19, 2018

Related Publication 20220016613A1 · Jan 20, 2022