Diversity-oriented synthesis of N,N,O-trisubstituted hydroxylamines from alcohols and amines by N—O bond formation

Patent metadata

Field	Value
Publication number	US-11912647-B2
Application number	US-202117325291-A
Country	US
Kind code	B2
Filing date	May 20, 2021
Priority date	May 22, 2020
Publication date	Feb 27, 2024
Grant date	Feb 27, 2024

Abstract

In one aspect, the disclosure relates to a method for the direct synthesis of complex N,N,O-trisubstituted hydroxylamines by N—O bond formation. In another aspect, the method can successfully be employed using a wide variety of commercially available alcohols and secondary amines and enables the construction of large fragment-based libraries of trisubstituted hydroxylamines for drug discovery purposes. Also disclosed are N,N,O-trisubstituted hydroxylamines having low basicity, high stability at ambient temperatures, and an inherent lack of reactivity towards acetylating and sulfonylating enzymes that confer mutagenicity on less-substituted hydroxylamines.

First claim

What is claimed is:

1. A method for producing a trisubstituted hydroxylamine, the method comprising reacting a monoperoxyacetal compound with a secondary amide, wherein the monoperoxyacetal compound has the structure I or II

wherein
R 1 is a substituted or unsubstituted linear or branched alkyl group, a substituted or unsubstituted cycloalkyl group or heterocycloalkyl group, a polyether group, an alkylpolyether group, or a protected or unprotected monosaccharide, disaccharide, or polysaccharide, and
R 2 is hydrogen, an aryl group, a heteroaryl group, or a substituted or unsubstituted alkyl group; and
the secondary amide has the structure IV

wherein
R 5 and R 6 are, independently, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group or heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group, or wherein R 5 and R 6 together form a substituted or unsubstituted cycloalkyl group or heterocycloalkyl group, and
M + is Li, MgBr, MgCI, or Mgl, wherein the secondary amide is produced by reacting a secondary amine with a Grignard reagent or an alkyl lithium, and
wherein the trisubstituted hydroxylamine has the structure V

wherein a molar ratio of monoperoxyacetal compound to the secondary amide is from 1:1 to 1:5.

2. The method of claim 1 , wherein R 1 is a substituted or unsubstituted linear or branched alkyl group.

3. The method of claim 1 , wherein the substituted alkyl group comprises:

and wherein n is from 1 to 5.

4. The method of claim 1 , wherein R 1 is 1-piperidinylethyl, 1-morpholinoethyl

5. The method of claim 1 , wherein R 2 is methyl or phenyl.

6. The method of claim 1 , wherein R 5 and R 6 are both benzyl, phenyl, or ethyl, or wherein R 5 is phenyl and R 6 is 4-chlorophenyl, or wherein R 5 methyl and R 6 is phenyl, or wherein R 5 and R 6 together form a substituted or unsubstituted piperidine, piperazine, pyrrolidine, morpholine, indoline, or 1,2,3,4-tetrahydroquinoline ring system.

7. The method of claim 1 , wherein the Grignard agent is an alkyl Grignard agent.

8. The method of claim 1 , wherein the secondary amine is an alkaloid or is derived from an alkaloid.

9. The method of claim 1 , wherein the monoperoxyacetal compound and secondary amide are reacted in an organic solvent selected from the group consisting of tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methyl THF), diethyl ether, methyl tent-butyl ether (MTBE), 1,4-dioxane, 1,2-dimethoxyethane, pentane, hexanes, heptanes, cyclohexanes, N,N′-dimethylpropyleneurea (DMPU), and a combination thereof.

10. The method of claim 1 , wherein the monoperoxyacetal compound and secondary amide are reacted in an organic solvent, wherein the solvent is tetrahydrofuran (THF).

11. The method of claim 1 , wherein the monoperoxyacetal compound and the secondary amide are reacted at a temperature of from about −10° C. to about 25° C.

12. The method of claim 1 , wherein the alkyl lithium is n-butyl lithium.

Assignees

• Univ Georgia

Inventors

• Crich David
• Hettikankanamalage Asiri
• Hill Jarvis

Classifications

• C07C239/20 Primary

  having oxygen atoms of hydroxylamino groups etherified · CPC title

• C07B43/00

  Formation or introduction of functional groups containing nitrogen · CPC title

• C07D207/46

  with hetero atoms directly attached to the ring nitrogen atom · CPC title

• C07D209/08 Primary

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring · CPC title

• C07D265/30

  not condensed with other rings · CPC title