Methods for 1,4-diazo N-heterocycle synthesis

Patent metadata

Field	Value
Publication number	US-11739062-B2
Application number	US-202016989960-A
Country	US
Kind code	B2
Filing date	Aug 11, 2020
Priority date	Aug 18, 2017
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

The present disclosure relates to novel synthetic method of making 1, 4-diazo N-heterocycles via intermolecular amphoteric diamination of allenes, and to the compounds made by the novel synthetic method.

First claim

We claim:

1. A method of preparing a compound of formula II, wherein the method comprises a first step of reacting a compound of R 1 NHXNYR 2 with a compound of CH 2 ═C═CR 3 R 4 to provide a compound of formula I:

and
a second step of a reduction reaction by converting the compound of formula I to the compound of formula II,

wherein:
R 1 is R 5 —S(═O) 2 — or a nitrogen: protecting group selected from the group consisting of acetyl (Ac), trifluoroacetyl (TFA), trichloroacetyl (TCA), tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), vinyloxycarbonyl (Voc), allyloxycarbonyl (Alloc), and 9-fluorenylmethyloxycarbonyl (Fmoc);
R 2 is optionally substituted C 1 -C 12 straight or branched alkyl, C 1 -C 12 alkenyl, C 1 -C 12 alkynyl, C 3 -C 10 cycloalkyl, or C 3 -C 10 hetero cycloalkyl, wherein one or more hydrogen is optionally substituted by an optionally substituted aryl, heteroaryl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetero cycloalkyl, F, Cl, Br, I, hydroxyl, C 1 -C 8 alkoxyl, amino group, or NHBoc, or R 2 may form a fused ring with one adjacent carbon atom next to the nitrogen to which R 2 is attached;
R 3 and R 4 are each independently H, optionally substituted C 1 -C 12 straight or branched alkyl, C 1 -C 12 alkenyl, C 1 -C 12 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetero cycloalkyl, or an electron-withdrawing group (EWG), wherein at least one of R 3 and R 4 is an EWG selected from the grout consisting of methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, phenoxycarbonyl, (3-methoxyphenoxy)carbonyl, ((3-methoxybenzyl)oxy)carbonyl, furan-2-carbonyl, benzoyl, fluorobenzoyl, chlorobenzoylmethoxybenzoyl, trifluoromethylbenzoyl, diethoxyphosphoryl, diphenylphosphoryl, phenylsulfonyl, cyano, and 2-oxy-4-phenylbutyl;
R 5 is optionally substituted C 1 -C 12 straight or branched alkyl, C 1 -C 12 alkenyl, C 1 -C 12 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetero cycloalkyl, aryl, or heteroaryl;
R 6 is H, nitro, F, Cl, Br, I, amino, cyano, C 1 -C 4 straight, branched, or cycloalkyl, C 1 -C 4 trifluoroalkyl, hydroxyl, C 1 -C 4 alkoxyl, or —SH;
R 7 is H or C 1 -C 4 straight, branched, or cycloalkyl;
X is a C 2 -C 4 saturated carbon linker, wherein C 2 -C 4 saturated carbon linker is optionally substituted with 4-8 hydrogen, 4-8 optionally substituted C 1 -C 12 straight or branched alkyl, wherein one of the 4-8 optionally substituted C 1 -C 12 straight or branched alkyl may form a fused ring with the C 2 -C 4 saturated carbon linker or with R 1 , or form a spiro ring with the carbon atom on the C 2 -C 4 saturated carbon linker to which the straight or branched alkyl is attached; and
Y is H, Cl, Br, or I.

2. The method of claim 1 , wherein R 1 is R 5 —S(═O) 2 —, and R 5 is selected from the group consisting of:

3. The method of claim 1 , wherein R 2 is optionally substituted C 1 -C 12 straight or branched alkyl, C 1 -C 12 alkenyl, C 3 -C 10 cycloalkyl, wherein one or more hydrogen of the C 1 -C 12 straight or branched alkyl, C 1 -C 12 alkenyl, or C 3 -C 10 cycloalkyl is optionally substituted with a benzene ring, quinolin ring, pyrrol ring, furan ring, or indole ring, wherein the benzene ring, quinolin ring, pyrrol ring, furan ring, or indole ring is further optionally substituted with 1-3 C 1 -C 6 alkyl, halide, C 1 -C 4 alkoxyl, trihalide methyl, or nitro group.

4. A method of preparing a compound of formula II, wherein the method comprises a first step of reacting a compound of R′NHXNYR 2 with a compound of CH 2 ═C═CR 3 R 4 to provide a compound of formula I:

and
a second step of a reduction reaction by converting the compound of formula I to the compound of formula II,

wherein:
R 1 is R 5 —S(═O) 2 — or a nitrogen-protecting group selected from the group consisting of acetyl (Ac), trifluoroacetyl (TFA), trichloroacetyl (TCA), tert-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), vinyloxycarbonyl (Voc), allyloxycarbonyl (Alloc), and 9-fluorenylmethyloxycarbonyl (Fmoc);
R 2 is optionally substituted C 1 -C 12 straight or branched alkyl, C 1 -C 12 alkenyl, C 1 -C 12 alkynyl, C 3 -C 10 cycloalkyl, or C 3 -C 10 hetero cycloalkyl, wherein one or more hydrogen is optionally substituted by an optionally substituted aryl, heteroaryl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetero cycloalkyl, F, Cl, Br, I, hydroxyl, C 1 -C 8 alkoxyl, amino group, or NHBoc, or R 2 may form a fused ring with one adjacent carbon atom next to the nitrogen that R 2 is attached;
R 3 and R 4 are each independently H, optionally substituted C 1 -C 12 straight or branched alkyl, C 1 -C 12 alkenyl, C 1 -C 12 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetero cycloalkyl, or an electron-withdrawing group (EWG), wherein at least one of R 3 and R 4 is an EWG selected from the group consisting of an aldehyde group, a ketone group, a carboxylic acid group, an acyl group, an ester group, an amide group, a trihalide group, a sulfonyl group, a phosphono group, F, and Cl;
R 5 is optionally substituted C 1 -C 12 straight or branched alkyl, C 1 -C 12 alkenyl, C 1 -C 12 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetero cycloalkyl, aryl, or heteroaryl;
R 6 is H, nitro, F, Cl, Br, I, amino, cyano, C 1 -C 4 straight, branched, or cycloalkyl, C 1 -C 4 trifluoroalkyl, hydroxyl, C 1 -C 4 alkoxyl, or —SH;
R 7 is H or C 1 -C 4 straight, branched, or cycloalkyl;
X is a C 2 -C 4 saturated carbon linker, wherein C 2 -C 4 saturated carbon linker is optionally substituted with 4-8 hydrogen, 4-8 optionally substituted C 1 -C 12 straight or branched alkyl, wherein one of the 4-8 optionally substituted C 1 -C 12 straight or branched alkyl may form a fused ring with the C 2 -C 4 saturated carbon linker or with R 1 , or form a spiro ring with the carbon atom on the C 2 -C 4 saturated carbon linker to which the straight or branched alkyl is attached; and
Y is H, Cl, Br, or I.

5. The method of claim 4 , wherein the EWG is selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, phenoxycarbonyl, (3-methoxyphenoxy)carbonyl, ((3-methoxybenzyl)oxy)carbonyl, furan-2-carbonyl, benzoyl, fluorobenzoyl, chlorobenzoylmethoxybenzoyl, trifluoromethylbenzoyl, diethoxyphosphoryl, diphenylphosphoryl, phenylsulfonyl, cyano, and 2-oxy-4-phenylbutyl.

Assignees

• Purdue Research Foundation

Inventors

• Dai Mingji
• Ye Zhishi

Classifications

• C07D241/50 Primary

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

• C07D241/04

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

• C07D243/08

  not condensed with other rings · CPC title

• C07D243/10

  condensed with carbocyclic rings or ring systems · CPC title

• C07D245/02

  not condensed with other rings · CPC title