Methods and compositions for substituted arylcycloheptane analogs

Patent metadata

Field	Value
Publication number	US-11912704-B2
Application number	US-201917262107-A
Country	US
Kind code	B2
Filing date	Aug 7, 2019
Priority date	Aug 7, 2018
Publication date	Feb 27, 2024
Grant date	Feb 27, 2024

Abstract

In one aspect, the disclosure relates to methods for preparation of intermediates useful for the preparation of aryl-cycloheptene scaffolds. In a further aspect, the disclosed methods pertain to the preparation of compounds comprising an aryl-cycloheptene structure. The disclosed methods utilize abundant starting materials and simple reaction sequences that can be used to modularly and scalably assemble common such cores. In various aspects, the present disclosure pertains to compounds prepared using the disclosed methods. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.

First claim

What is claimed is:

1. A method of synthesizing a bis-allylated compound, the method comprising:
reacting a Knoevenagel adduct and chalcone-derived electrophile in the presence of a palladium catalyst and base at a first reaction temperature for a first reaction time;
wherein the Knoevenagel adduct has a formula represented by a structure:

wherein each of R 1a , R 1b , R 1c , R 1d , R 1e and K 1f is independently selected from hydrogen, halogens, and C1-C8 alkyl; or wherein each of R 1a , R 1b , R 1e and R 1f is independently selected from hydrogen and C1-C8 alkyl, and wherein R 1c and R 1d are optionally combined and form a C 3 to C 8 cycloalkyl, C 3 to C 8 cycloalkenyl, or 5-atom or 6-atom heterocycle containing one or more oxygens;
wherein the chalcone-derived electrophile has a formula represented by a structure:

wherein Ar 1 is a phenyl group optionally substituted with 1, 2, or 3 groups that are electron-withdrawing or electron-donating; and
wherein Ar 2 is a phenyl group optionally substituted with 1, 2, or 3 groups that are electron-withdrawing or electron-donating; and
wherein at least one of Ar 1 and Ar 2 is substituted with 1, 2, or 3 groups that are electron-withdrawing or electron-donating;
after completion of the first reaction time, adding to the reaction an allylic electrophile and continuing the reaction at second reaction temperature for a second reaction time, wherein the allylic electrophile has a formula represented by a structure:

wherein X is a halogen; and wherein R 3 is selected from hydrogen and C1-C8 alkyl;
thereby synthesizing the bis-allylated compound, wherein the bis-allylated compound has a formula represented by a structure:

2. The method of claim 1 , wherein the first reaction temperature is from 0° C. to 50° C.

3. The method of claim 1 , wherein the first reaction temperature is from 20 to 30° C.

4. The method of claim 1 , wherein the second reaction temperature is from 0° C. to 50° C.

5. The method of claim 1 , wherein Ar 1 and Ar 2 are, independently, selected from 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, and 4-chlorophenyl.

6. The method of claim 1 , wherein R 1c and R 1d are fluoro, chloro, bromo, or iodo groups.

7. The method of claim 1 , wherein R 1c and R 1d are combined to form a 5-atom heterocycle with two oxygen atoms.

8. The method of claim 1 , wherein Ar 1 and Ar 2 are phenyl and R 1c and R 1d are combined to form a 5-atom heterocycle with two oxygen atoms.

9. A method of synthesizing an aryl-cycloheptene compound, the method comprising:
reacting a bis-allylated compound in the presence of a Grubbs catalyst, and wherein the bis-allylated compound has a formula represented by a structure:

wherein each of R 1a , R 1b , R 1c , R 1d , R 1e , R 1f and R 3 is independently selected from hydrogen, halogen, and C1-C8 alkyl; or wherein each of R 1a , R 1b , R 1e , R 1f and R 3 is independently selected from hydrogen and C1-C8 alkyl, and wherein R 1c and R 1d are optionally combined to form a C 3 to C 8 cycloalkyl, C 3 to C 8 cycloalkenyl, or 5-atom or 6-atom heterocycle containing one or more oxygens;
wherein Ar 1 is a phenyl group optionally substituted with 1, 2, or 3 groups that are electron-withdrawing or electron-donating; and
wherein Ar 2 is a phenyl group optionally substituted with 1, 2, or 3 groups that are electron-withdrawing or electron-donating; and
wherein at least one of Ar 1 and Ar 2 is substituted with 1, 2, or 3 groups that are electron-withdrawing or electron-donating;

thereby synthesizing an aryl-cycloheptene compound having a formula represented by a structure:

10. The method of claim 9 , wherein Ar 1 and Ar 2 are, independently, selected from 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, and 4-chlorophenyl.

11. The method of claim 9 , wherein R 1c and R 1d are fluoro, chloro, bromo, or iodo groups.

12. The method of claim 9 , wherein R 1c and R 1d are combined to form a C3 cycloalkyl group with two oxygen atoms.

13. The method of claim 9 , wherein Ar 1 and Ar 2 are phenyl and R 1c and R 1d are combined to form a C3 cycloalkyl group with two oxygen atoms.

14. A compound having a formula represented by a structure:

wherein each of R 1a , R 1b , R 1c , R 1d , R 1e , R 1f and R 3 is independently selected from hydrogen and C1-C8 alkyl; or wherein each of R 1a , R 1b , R 1e , R 1f and R 3 is independently selected from hydrogen, halogen, and C1-C8 alkyl, and wherein R 1c and R 1d are optionally combined and form a C 3 to C 8 cycloalkyl, C 3 to C 8 cycloalkenyl, or 5-atom or 6-atom heterocycle containing one or more oxygens; and
wherein Ar 1 is a phenyl group substituted with 1, 2, or 3 groups that are electron-withdrawing or electron-donating.

15. The compound of claim 14 , wherein Ar 1 is selected from 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, and 4-chlorophenyl.

16. The compound of claim 14 , wherein R 1c and R 1d are selected from fluoro, chloro, bromo, and iodo groups.

17. The compound of claim 14 , wherein Ar 1 is phenyl and R 1c and R 1d are combined to form a C3 cycloalkyl group with two oxygen atoms.

18. A pharmaceutical composition comprising the compound of claim 14 and a pharmaceutically acceptable carrier.

Assignees

• Univ Florida
• Univ Florida

Inventors

• Grenning Alexander James
• Fereyduni Ehsan

Classifications

• C07D471/08 Primary

  Bridged systems · CPC title

• C07C255/31 Primary

  having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing rings other than six-membered aromatic rings · CPC title

• C07C255/34

  with cyano groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by unsaturated carbon chains · CPC title

• C07D317/72

  spiro-condensed with carbocyclic rings · CPC title

• C07C255/47

  to carbon atoms of rings being part of condensed ring systems · CPC title