Synthesis of acyclic and cyclic amines using iron-catalyzed nitrene group transfer

Patent metadata

Field	Value
Publication number	US-9724682-B2
Application number	US-201615345266-A
Country	US
Kind code	B2
Filing date	Nov 7, 2016
Priority date	Feb 26, 2013
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

Abstract

The present invention provides novel synthetic methods for making acyclic secondary amines by reacting an azide with a compound bearing one or more C—H groups, catalyzed by a Fe II -dipyrromethene complex. The acyclic secondary amines are thought to be formed through an intermolecular nitrene transfer. Also provided herein are methods of synthesizing protected (e.g., Boc- or Fmoc-protected) cyclic secondary amines (e.g., 5-, 6-, and 7-membered cyclic secondary amines) by reacting an azide that bears one or more C—H groups, catalyzed by a Fe II -dipyrromethene complex. The protected cyclic secondary amines are thought to be formed through an intramolecular nitrene transfer and may be subsequently deprotected to yield cyclic secondary amines.

First claim

What is claimed is:

1. A method of preparing a compound of Formula (II-1):

or a salt thereof, the method comprising reacting an azide of Formula (F), or a salt thereof, with a ferrous compound of Formula (G), or a salt thereof:

wherein:
W is selected from the group consisting of mesityl and 2,6-dichlorophenyl;
each occurrence of X is independently selected from the group consisting of —O—, —S—, —NR c —, and —C(R d ) 2 —;
R c is selected from the group consisting of hydrogen, a nitrogen protecting group, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
each one of R 7 , R 8 , R 9 , and R 10 , and each occurrence of R d , are independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR e , —N(R e ) 2 , —SR e , —CN, —C(═NR e )R e , —C(═NR e )OR e , —C(═NR e )N(R e ) 2 , —NO 2 , —NR e C(═O)R e , —NR e C(═O)OR e , —NR e C(═O)N(R e ) 2 , —OC(═O)R e , —OC(═O)OR e , —OC(═O)N(R e ) 2 , and —ON(R e ) 2 ;
each occurrence of R e is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R e groups are joined to form an optionally substituted heterocyclic ring;
or two of R 7 , R 8 , R 9 , R 10 , R c , and R d groups are joined to form an optionally substituted carbocyclyl or optionally substituted heterocyclic ring;
Y is selected from the group consisting of N(R f ) 3 , R f —O—R f , R f —S—R f , optionally substituted heterocyclyl, and optionally substituted heteroaryl;
each occurrence of R f is independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and
n is 1, 2, 3, 4, or 5.

2. The method of claim 1 , further comprising reacting the compound of Formula (II-1), or a salt thereof, with di-t-butyl dicarbonate (Boc 2 O) to provide a compound of Formula (II-2-A), or a salt thereof, or with 9-fluorenylmethyl N-succinimidyl carbonate (Fmoc-OSuc) to provide a compound of Formula (II-2-B), or a salt thereof:

3. The method of claim 2 , further comprising deprotecting the compound of Formula (II-2-A) or (II-2-B), or a salt thereof, to provide a cyclic amine of Formula (II-3):

or a salt thereof.

4. The method of claim 3 , wherein the deprotection step comprises reacting an acidic compound, a nucleophilic compound, or a reductive compound with the compound of Formula (II-2-A), or a salt thereof, or reacting a nucleophilic compound, a basic compound, a reductive compound, or an oxidative compound with the compound of Formula (II-2-B), or a salt thereof, to provide the cyclic amine of Formula (II-3), or a salt thereof.

5. The method of claim 1 , wherein R 7 and R 8 are each hydrogen.

6. The method of claim 1 , wherein R 7 is hydrogen; and R 8 is optionally substituted alkyl.

7. The method of claim 1 , wherein R 7 and R 8 are each optionally substituted alkyl.

8. The method of claim 1 , wherein Y is R f —O—R f ; and each occurrence of R f is independently optionally substituted alkyl.

9. The method of claim 1 , wherein Y is optionally substituted heterocyclyl.

10. The method of claim 1 , wherein Y is optionally substituted tetrahydrofuran or optionally substituted tetrahydropyran.

11. The method of claim 1 , wherein Y is optionally substituted heteroaryl.

12. The method of claim 1 , wherein Y is optionally substituted pyridine.

13. The method of claim 1 , wherein n is 2.

14. The method of claim 1 , wherein n is 3.

15. The method of claim 1 , wherein n is 4.

16. The method of claim 1 , wherein W is mesityl.

17. The method of claim 1 , wherein W is 2,6-dichlorophenyl.

18. The method of claim 1 , wherein Y is diethyl ether.

19. The method of claim 1 , wherein the ferrous compound of Formula (G) is of Formula (3A):

20. The method of claim 1 , wherein the ferrous compound of Formula (G) is of Formula (3B):

Assignees

• Harvard College

Inventors

• Betley Theodore Alexander
• Hennessy Elisabeth Therese

Classifications

• C07C209/02 Primary

  by substitution of hydrogen atoms by amino groups · CPC title

• C07D209/54

  Spiro-condensed · CPC title

• C07D263/04

  having no double bonds between ring members or between ring members and non-ring members · CPC title

• C07D207/06

  with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms · CPC title

• C07C211/38

  containing condensed ring systems · CPC title