Access to chiral bisphenol (BPOL) ligands through desymmetrizing asymmetric ortho-selective mono-halogenation

Patent metadata

Field	Value
Publication number	US-11905237-B2
Application number	US-202117212605-A
Country	US
Kind code	B2
Filing date	Mar 25, 2021
Priority date	Mar 30, 2020
Publication date	Feb 20, 2024
Grant date	Feb 20, 2024

Abstract

The subject invention pertains to a method of halogenating phenols, yielding a range of halogenated phenols with enantiomeric ratio of up to 99.5:0.5. In certain embodiments, the subject invention pertains to a method of asymmetric halogenation of bisphenol, yielding a range of chiral bisphenol ligands. The novel chiral bisphenols are potent privileged catalyst cores that can be applied to the preparation of ligands for various catalytic asymmetric reactions. The catalyst library can easily be accessed because late-stage modification of the scaffold can readily be executed through cross-coupling of the halogen handles on the bisphenols.

First claim

We claim:

1. A method of halogenation, the method comprising contacting a reactant bisphenol with a source of a halogen in the presence of a catalyst under process conditions sufficient to prepare a halogenated bisphenol, wherein
the halogen source is bromine, N-bromosuccinimide (NBS), N-bromophthalimide (NBP), N-bromoacetamide (NBA), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), 1,3-di bromo-5,5-diphenylhydantoin (DBDMH), 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TBCO), chlorine, N-chlorosuccinimide (NCS), N-chlorophthalimide (NCP), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), 1,3-di chloro-5,5-diphenylhydantoin (DCDPH), 1-(4-methylbenzoyl)-3-chloro-5,5-diphenylhydantoin, iodine, or N-iodosuccinimide; and
the catalyst is N-[3,5-bis(trifluoromethyl)phenyl]-N′-[(1S,2S)-2-(dimethylamino)cyclohexyl]urea; N-[3,5-bis(trifluoromethyl)phenyl]-N′-[(1S,2S)-2-(di-n-pentylamino)cyclohexyl]urea; 3-[[3,5-bis(trifluoromethyl)phenyl]amino]-4-[[(1S,2S)-2-(dimethylamino)cyclohexyl]amino]-3-cyclobutene-1,2-dione; N-[3,5-bis(trifluoromethyl)phenyl]-N′-[(1S,2S)-2-[(11bS)-3,5-dihydro-4H-dinaphth[2,1-c:1′,2′-e]azepin-4-yl]cyclohexyl]urea; or N-[3,5-bis(trifluoromethyl)phenyl]-N′-[(1S,2S)-2-[(11bR)-3,5-dihydro-4H-dinaphth[2,1-c:1′,2′-e] azepin-4-yl]cyclohexyl]urea.

2. The method of claim 1 , wherein the bisphenol is a mono-halogenated bisphenol and has alkyl, aryl, and/or electron-withdrawing substituents.

3. The method of claim 1 , wherein the halogen source is a source of chlorine or a source of bromine.

4. The method of claim 3 , wherein the chlorine source is DCDPH and the bromine source is NBS.

5. The method of claim 1 , wherein the process conditions comprise the presence of a solvent; and, the process occurs at a temperature of about −80° C. to about 80° C., about −78° C. to about 0° C., or about −78° C. to about −40° C. for about 2 hours to about 7 days, about 1 day to about 5 days, or about 4 days to about 5 days.

6. The method of claim 5 , wherein the solvent is an aromatic hydrocarbon, a carbon tetrachloride, or a combination thereof; and the ratio of aromatic hydrocarbon to carbon tetrachloride in the solvent is 2:1, 3:1, 4:1, or 5:1.

7. The method of claim 6 , wherein the aromatic hydrocarbon is toluene.

8. The method of claim 5 , wherein the process conditions further comprise the addition of a molecular sieve with a pore size of about 0.1 Å to about 100 Å, about 1 Å to about 10 Å, or about 4 Å.

9. The method of claim 1 , further comprising cross-coupling the halogenated bisphenol to prepare a substituted bisphenol, wherein the halogen of the halogenated bisphenol is substituted with an acid.

10. The method of claim 9 , wherein the acid is 1-naphthyl boronic acid and/or 2-naphthyl boronic acid.

11. The method of claim 9 , further comprising preparing a dihydroxyl catalyst from the acid-substituted bisphenol.

12. The method of claim 11 , wherein the dihydroxyl catalyst is a chiral phosphoric acid catalyst.

13. The method of claim 11 , further comprising using the dihydroxyl catalyst to catalyze an asymmetric catalytic reaction.

14. The method claim 13 , wherein the asymmetric catalytic reaction is an addition of an indole to an imine to prepare an adduct corresponding to the indole and the imine addition or a preparation of 3,4-dihydropyrimin-2(1H)-one using aldehyde, urea, and ethyl acetoacetate.

15. The method of claim 1 , further comprising preparing a chiral phosphoramidite ligand from the halogenated bisphenol.

Assignees

• Univ Hong Kong Chinese

Inventors

• Yeung Ying-Yeung
• Xiong Xiaodong
• Zheng Tianyu
• Wang Xinyan
• Tse Ying-Lung Steve

Classifications

• C07C37/62 Primary

  by introduction of halogen; by substitution of halogen atoms by other halogen atoms · CPC title

• B01J31/2404

  Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring · CPC title

• C07C37/18

  by condensation involving halogen atoms of halogenated compounds · CPC title

• C07C39/367

  polycyclic non-condensed, containing only six-membered aromatic rings as cyclic parts, e.g. halogenated poly-hydroxyphenylalkanes · CPC title

• C07F9/2404

  the ester moiety containing a substituent or a structure which is considered as characteristic · CPC title