Method for producing an arene with an aromatic C—N bond ortho to an aromatic C—O bond

Patent metadata

Field	Value
Publication number	US-9856208-B2
Application number	US-201615255957-A
Country	US
Kind code	B2
Filing date	Sep 2, 2016
Priority date	Sep 3, 2015
Publication date	Jan 2, 2018
Grant date	Jan 2, 2018

Abstract

A method for producing an arene with an aromatic C—N bond ortho to an aromatic C—O bond from a hydroxy arene comprising said aromatic C—O bond is provided. This method comprising the steps a) ortho-oxygenating the hydroxy arene to produce an ortho-quinone, b) condensating the ortho-quinone with a nitrogen nucleophile to generate a compound of Formula (IVa) or (IVb), and c) allowing 1,5-hydrogen atom shift of the compound of Formula (IVa) or (IVb), thereby producing arenes with a C—N bond ortho to a C—O bond of Formula (Va) and (Vb), respectively:

First claim

The invention claimed is:

1. A method for producing an arene with an aromatic C—N bond ortho to an aromatic C—O bond from a hydroxy arene comprising said aromatic C—O bond, the method comprising the following steps:
a. ortho-oxygenating a hydroxy arene of Formula (I) to produce an ortho-quinone of Formula (II):

b. condensating the ortho-quinone of Formula (II) with a nitrogen nucleophile of Formula (IIIa):

 or (IIIb):

 to generate a compound of Formula (IVa) or (IVb), respectively:

 and
c. allowing 1,5-hydrogen atom shift of the compound of Formula (IVa) or (IVb), thereby producing arenes with a C—N bond ortho to a C—O bond of Formula (Va) and (Vb), respectively:

wherein R 1 , R 2 , and R 3 each independently represent:
a hydrogen atom,
alkyl unsubstituted or substituted with one or more one or more substituents selected from the group consisting of:
aryl unsubstituted or substituted with one or more hydroxy,
hydroxy,
alkoxy unsubstituted or substituted with one or more aryl,
aminoalkyl or aminodialkyl,
alkoxy carbonyl,
alkylthio,
heterocycloalkyl, and
halogen atom,

cycloalkyl,
alkenyl,
hydroxyl,
—C(═O)—O—R 20 , wherein R 20 is an aliphatic or aromatic group, unsubstituted or substituted, or
aryl or heteroaryl unsubstituted or substituted with one or more one or more substituents selected from the group consisting of:
alkyl unsubstituted or substituted with one or more halogen atoms,
alkoxy,
aryl unsubstituted or substituted with one or more alkyl, the alkyl being unsubstituted or substituted with one or more halogen atoms,
nitro,
sulfonamine, and
halogen atom; or

R 1 and R 3 together with the carbon atom to which they are attached form a ring; or
R 1 and R 2 together with the carbon and nitrogen atoms to which they are attached form a ring, that:
is saturated or unsaturated;
is unsubstituted or substituted with one or more hydroxy;
optionally comprises, in addition to the nitrogen atom to which R 2 is attached, one or more additional heteroatom; and

is optionally fused with an aromatic ring that is unsubstituted or substituted with one or more alkyloxy,
wherein R 10 represents:
aryl substituted with one or more substituents selected from the group consisting of:
—NO 2 ,
—SO 2 ,
halogen atom, and
perfluorinated alkyl,

heteroaryl unsubstituted or substituted with one or more:
—NO 2 ,
—SO 2 ,
halogen atom, and
perfluorinated alkyl, or

—C(═O)—R 11 , wherein R 11 represents:
aryl or heteroaryl unsubstituted or substituted with one or more aryl, or
alkyloxy

with the proviso that nitrogen nucleophile is Formula (IIIb) is not

 and
wherein

 denotes an unsubstituted or substituted arene, an arene being an aromatic hydrocarbon with its carbon atoms arranged into one or more rings, the ring(s) presenting alternating double and single bonds between the ring atoms, and wherein one or more of the carbon ring atoms may be replaced by a heteroatom, the arene being optionally fused with an optionally substituted cycloalkyl.

2. The method of claim 1 , wherein the nitrogen nucleophile is of Formula (IIIa).

3. The method of claim 2 , wherein R 2 represents a hydrogen atom.

4. The method of claim 3 , wherein R 3 represents a hydrogen atom and wherein the compound of Formula (Va) spontaneously forms an oxazole arene of Formula (VI):

5. The method of claim 3 , wherein R 3 does not represent a hydrogen atom.

6. The method of claim 5 , further comprising hydrolysis to produce an ortho-amino-hydroxy arene of Formula (X):

7. The method of claim 5 , further comprising reaction with an organometallic reagent of formula R 4 -M, wherein M is a metal and R 4 is alkyl, alkenyl, aryl, O—R 30 , or N(R 30 ) 2 , wherein is R 30 is H, or an aliphatic or aromatic group, to yield an α,α,α-trisubstituted compound of Formula (XI):

8. The method of claim 5 , wherein R 3 represents —C(═O)—O—R 20 , wherein R 20 is an aliphatic or aromatic group, unsubstituted or substituted, and the method further comprises lactonization to produce an oxazinone arene of Formula (IX):

9. The method of claim 8 , wherein R 1 in the oxazinone arene of Formula (IX) comprises a hydroxy arene and steps a) to c) followed by lactonization are repeated multiple times to produce a heterocyclic polymer.

10. The method of claim 2 , wherein R 3 represents a hydrogen atom and R 1 and R 2 together with the carbon and nitrogen atoms to which they are attached form said ring that:
is saturated or unsaturated;
is unsubstituted or substituted with one or more hydroxy;
optionally comprises, in addition to the nitrogen atom to which R 2 is attached, one or more additional heteroatom; and
is optionally fused with an aromatic ring that is unsubstituted or substituted with one or more alkyloxy.

11. The method of claim 10 , wherein said ring is pyrrolidine, piperazine, morpholine, indoline, iso-indoline, tetrahydroisoquinoline, piperidine, 2,5-dihydropyrrole, dihydropyrrolidine, dihydroindoline, or dihydroisoindoline or one of their substituted derivatives.

12. The method of claim 10 , further comprising quenching the reaction mixture to produce a dihydrooxazole arene of Formula (XII):

13. The method of claim 12 , further comprising reducing the dihydrooxazole arene of Formula (XII) to yield to yield an ortho-amino-hydroxy arene of Formula (XIII):

14. The method of claim 13 , further comprising reacting with an aryl boronic acid to yield a compound of Formula (XV):

15. The method of claim 2 , wherein arene A is benzene unsubstituted or substituted by one or more substituents selected from the group consisting of:
alkyl unsubstituted or substituted with one or more:
aryl,
sulfoamidoaryl unsubstituted or substituted with one or more alkyl,
hydroxy, and/or
aryl carbamoyl,

cycloalkyl,
alkenyl, and
aryl unsubstituted or substituted with one or more:
alkyl,
alkyloxy,
halogen atom,
trialkylsilyl, and/or
halogen atoms.

16. The method of claim 1 , wherein the nitrogen nucleophile is of Formula (IIIb).

Assignees

• The Royal Institution For The Advancement Of Learning/Mcgill Univ

Inventors

• Lumb Jean-Philip
• Esguerra Kenneth V N

Classifications

• C07C2601/14

  The ring being saturated · CPC title

• C07C2601/16

  the ring being unsaturated · CPC title

• C07C46/08

  with molecular oxygen · CPC title

• C07F7/00

  Compounds containing elements of Groups 4 or 14 of the Periodic Table · CPC title

• C07D265/36 Primary

  condensed with one six-membered ring · CPC title