Processes for the preparation of
The present application describes process for preparing an ortho-allylated hydroxy aryl compounds such as compounds of Formula (I) by reacting an allylic alcohol with a hydroxy aryl compound in the presence of aluminum compound selected from alumina and aluminum alkoxides and in a non-protic solvent wherein at least one carbon atom ortho to the hydroxy group in the hydroxy aryl compound is unsubstituted. The present application also includes compounds of Formula (I).
1. A process for preparing a compound of Formula (I-A)
comprising:
reacting a compound of Formula (II)
with a compound of Formula (III)
in the presence of acidic alumina and in a non-protic solvent to form the compound of Formula (I-A),
wherein
R 1 is C 1-12 alkyl;
R 2 is H;
R 3 is selected from H and CH 3 ;
R 4 is selected from H and CH 3 ; and
R 5 is selected from
wherein
represents a point of covalent attachment.
2. The process of claim 1 , wherein the a non-protic solvent is selected from hexane, hexanes, heptane, heptanes, cyclohexane, petroleum ether, octane, diglyme, toluene, xylenes, benzene, chloroform, fluorinated alkanes, dichloromethane (DCM), 1,2-dichloroethane (DCE), ethyl acetate, carbon tetrachloride, tetrahydrofuran (THF), diethyl ether, diisopropyl ether, isooctane, methyl ethyl ketone, acetone, dimethyl sulfoxide, dimethylformamide, methyl tert-butyl ether, trichloroethane, n-butyl acetate, chlorobenzene acetonitrile, and trifluorotoluene, and mixtures thereof.
3. The process of claim 1 , wherein the process further comprises a dehydrating agent and/or an acid.
4. The process of claim 1 , wherein the process provides the compound of Formula (I-A) as the as the major product of the process and in a yield of greater than about 50%.
5. The process of claim 1 , wherein the forming of the compound of Formula (I-A) further comprises mixing the compound of Formula (II), the compound of Formula (III) and the acidic alumina in the non-protic solvent with the addition of the acidic alumina in the amount of about 1 g to about 3 g per 1 mmol of the compound of Formula II).
6. The process of claim 1 , wherein R 1 is C 1-6 alkyl.
7. The process of claim 1 , wherein R 1 is C 1-4 alkyl.
8. The process of claim 1 , wherein R 1 is C 1 alkyl.
9. The process of claim 1 , wherein R 1 is C 2 alkyl.
10. The process of claim 1 , wherein R 1 is C 3 alkyl.
11. The process of claim 1 , wherein R 1 is C 4 alkyl.
12. The process of claim 1 , wherein R 1 is C5alkyl.
13. The process of claim 1 , wherein R 3 is H.
14. The process of claim 1 , wherein R 4 is CH 3 .
15. The process of claim 1 , wherein the compound of Formula (I-A) is a compound selected from:
16. The process of claim 1 , wherein the forming of the compound of Formula I-A comprises reacting about 1.1 to about 5 molar equivalents of the compound of Formula II relative to the compound of Formula III.
17. The process of claim 1 , wherein the forming of the compound of Formula (I-A) comprises reacting the compound of Formula (II) with the compound of Formula (III) and under heating in the presence of the acid alumina and the non-protic solvent.
18. The process of claim 17 , wherein the compound of Formula (II) and the compound of Formula (III) are present in a (II):(III) ratio of about 5:1.1 to about 1:5.
19. The process of claim 1 , wherein the reacting of the compound of Formula (II) with the compound of Formula (III) in the presence of acidic alumina and in a non-protic solvent provides a reaction mixture and the process further comprises separating the compound of Formula (I-A) from by one or more of a chromatography step, a distillation step or a crystallization step.
20. The process of claim 1 , wherein non-protic solvent selected from hexane, heptane, cyclohexane, toluene, chloroform, dichloromethane (DCM), 1,2-dichloroethane (DCE), diethyl ether, methyl tert-butyl ether, and trifluorotoluene, and mixtures thereof.
21. the process of claim 1 , wherein the acid alumina is in an amount of about 2.16 to about 147 molar equivalents with respect to the compound (II).