Formation of chiral 4-chromanones using chiral pyrrolidines in the presence of phenols or thiophenols

Patent metadata

Field	Value
Publication number	US-2016168111-A1
Application number	US-201414902662-A
Country	US
Kind code	A1
Filing date	Jul 3, 2014
Priority date	Jul 5, 2013
Publication date	Jun 16, 2016
Grant date	—

Abstract

The present invention relates to a synthesis of chromanones or chromanes in a stereospecific matter in view of the 2-position in the chromanone or chromane ring. It has been found that this synthesis is particularly possible in the presence of a chiral compound of formula of a specific type and of at least one phenol or thiophenol.

First claim

1 . Process for the manufacturing of compound of formula (I)

comprising the step of reacting compound of formula (II-A) and compound of formula (II-B) in the presence of
at least one chiral compound of formula (II-C) and
of at least one organic catalyst having at least one phenolic group or thiophenolic group

wherein R 1 , R 3 and R 4 are independently from each other hydrogen or methyl groups;
R 2 and R 2′ represents hydrogen or a phenol protection group;
R 5 represents either a linear or branched completely saturated C 6-25 -alkyl group or a linear or branched C 6-25 -alkyl group comprising at least one carbon-carbon double bond;
Y 1 represents either CH 2 Y 2 or

wherein R 6 represents a linear or branched C 1-12 -alkyl group which optionally further comprises at least one aromatic group and/or C═O and/or NH and/or NH 2 group;
Y 2 represents either OH or OR 7 or NHR 7 or NHCOOR 7 or

wherein R 7 represents either
a linear or branched C 1-12 -alkyl group which optionally further comprises
at least one aromatic group and/or C═O and/or NH and/or NH 2 group or
an aryl group or a substituted aryl group or a heteroaryl group or a substituted heteroaryl group

and the dotted line(s) represents the bond(s) by which the corresponding substituent is bound to the rest of formula (II-C);
and wherein * represents the chiral centre of the chiral isomer of formula (I).

2 . Process according to claim 1 wherein R 5 is of formula (III)

wherein m and p stand independently from each other for a value of 0 to 5 provided that the sum of m and p is 1 to 5,
and where the substructures in formula (III) represented by s1 and s2 can be in any sequence;
and the dotted line represents the bond by which the substituent of formula (III) is bound to the rest of formula (II-B) or formula (I);
and wherein # represents a chiral centre, obviously except in case where said centre is linked to two methyl groups.

3 . Process according to claim 1 wherein
R 1 ′R 3 ═R 4 ═CH 3

or
R 1 ═R 4 ═CH 3 , R 3 ═H

or
R 1 ═H, R 3 ═R 4 ═CH 3 .

or
R 1 ═R 3 ═H, R 4 ═CH 3 .

4 . Process according to claim 1 wherein formula (II-C) is selected from the group consisting of

5 . Process according to claim 1 wherein the organic catalyst having at least one phenolic group or thiophenolic group is a selected from the group consisting of phenol, 4-nitrophenol, 2,4-dinitrophenol, 1-naphthol, 2-naphthol and 8-hydroxyquinoline.

6 . Process according to claim 1 wherein the organic catalyst having at least one phenolic group or thiophenolic group is a selected from the group consisting of thiophenol, p-nitrothiophenol, 2,4-dinitrothiophenol, 1-naphthalenethiol, 2-naphthalenethiol and 4-trifluormethyl-tetrafluorthiophenol.

7 . Process of manufacturing compound of formula (V) comprising the step of
i) process of manufacturing of formula (I) according to claim 1 ; ii) reducing of compound of formula (I)

8 . Process according to claim 1 , wherein the isomer having the R-configuration at the chiral centre marked by * in formula (I) or (V) is preferentially formed in respect to the corresponding isomer having the S-configuration at said chiral centre.

9 . Composition comprising
a) at least one compound of formula (II-A) and b) at least one ketone of formula (II-B) and c) at least one chiral compound of formula (II-C) and d) at least one organic catalyst having at least one phenolic group or thiophenolic group

wherein R 1 , R 3 and R 4 are independently from each other hydrogen or methyl groups;
R 2′ represents hydrogen or a phenol protection group;
R 5 represents either a linear or branched completely saturated C 6-25 -alkyl group or a linear or branched C 6-25 -alkyl group comprising at least one carbon-carbon double bond;
Y 1 represents either CH 2 Y 2 or

wherein R 6 represents a linear or branched C 1-12 -alkyl group which optionally further comprises at least one aromatic group and/or C═O and/or NH and/or NH 2 group;
Y 2 represents either OH or OR' or NHR 7 or NHCOOR 7 or

wherein R 7 represents either
a linear or branched C 1-12 -alkyl group which optionally further comprises
at least one aromatic group and/or C═O and/or NH and/or NH 2 group or
an aryl group or a substituted aryl group or a heteroaryl group or a substituted heteroaryl group

and the dotted line(s) represents the bond(s) by which the corresponding substituent is bound to the rest of formula (II-C).

10 . Composition according to claim 9 , wherein R 5 is of formula (III)

wherein m and p stand independently from each other for a value of 0 to 5 provided that the sum of m and p is 1 to 5,
and where the substructures in formula (III) represented by s1 and s2 can be in any sequence;
and the dotted line represents the bond by which the substituent of formula (III) is bound to the rest of formula (II-B);
and wherein # represents a chiral centre, obviously except in case where said centre is linked to two methyl groups.

11 . Composition according to claim 9 wherein
R 1 ═R 3 ═R 4 ═CH 3

or
R 1 ═R 4 ═CH 3 , R 3 ═H

or
R 1 ═H, R 3 ═R 4 ═CH 3

or
R 1 ═R 3 ═H, R 4 ═CH 3 .

12 . Composition according to claim 9 wherein formula (II-C) is selected from the group consisting of

13 . Composition according to claim 9 wherein the organic catalyst having at least one phenolic group or thiophenolic group is a selected from the group consisting of 4-nitrophenol, phenol, 1-naphthol, 2-naphthol and 8-hydroxyquinoline.

14 . Composition according to claim 9 wherein the organic catalyst having at least one phenolic group or thiophenolic group is a selected from the group consisting of thiophenol, p-nitrothiophenol, 1-naphthalenethiol, 2-naphthalenethiol and 4-trifluormethyl-tetrafluorthiophenol.

Assignees

• Dsm Ip Assets Bv

Inventors

• Letinois Ulla
• Netscher Thomas

Classifications

• C07D311/22 Primary

  with oxygen or sulfur atoms directly attached in position 4 · CPC title

• C07B2200/09

  Geometrical isomers · CPC title