Synthesis of dihalohydrins and tri- and tetra-substituted olefins
View Patent ↗A novel synthesis reaction for highly stereospecific tri- and tetra-substituted olefins is described. A single stereoisomer of stable α-halo-α,β-ester is produced in high yield by the reaction of aldehyde or ketone with a trihalogenated compound such as trichloroacetate in the presence of CrCl 2 in a solvent. By varying the amount of CrCl 2 used, the stable dihalohydrin intermediate may be obtained as well.
1. A method for the synthesis of a stereospecific tri-substituted olefin, comprising: reacting an aldehyde substrate with a halogenated compound and 4 equivalents of CrCl 2 in a solvent under an inert atmosphere for a sufficient amount of time, wherein the aldehyde substrate is selected from the group consisting of hydrocinnamaldehyde, cinnamaldehyde, chiral glyceraldehyde, 3-bromo-benzaldehyde, p-trifluoromethylbenzaldehyde, p-methoxybenzaldehyde, 4-benzyloxy-3-methoxy-benzaldehyde, 4-dimethylaminobenzaldehyde, and indole aldehyde.
2. The method of claim 1 , wherein the halogenated compound is a dihalogenated propionate.
3. The method of claim 2 , wherein the dihalogenated propionate is α,α-dichloropropiophenone or methyl 2,2-dichloropropionate.
4. The method of claim 1 , wherein the halogenated compound is a trihalogenated compound.
5. The method of claim 4 , wherein the trihalogenated compound is selected from the group consisting of methyl trichloroacetate, methyl tribromoacetate, 2,2,2-trichloroacetamide, 1,1,1-trichlorotoluene, 1,1,1-trichloroacetone, and ethyl dibromofluoroacetate.
6. A method for the synthesis of stereospecific tri-substituted olefins, comprising: reacting an aldehyde substrate with a halogenated compound, catalytic chromium, Mn, and TMSCl in a solvent under an inert atmosphere for a sufficient amount of time.
7. The method of claim 6 , wherein the aldehyde substrate is selected from the group consisting of aliphatic aldehyde, aryl aldehyde, cycloaliphatic aldehyde, and heteroaromatic aldehyde.
8. The method of claim 6 , wherein the aldehyde substrate is selected from the group consisting of hydrocinnamaldehyde, cinnamaldehyde, chiral glyceraldehyde, 3-bromo-benzaldehyde, p-trifluoromethylbenzaldehyde, p-methoxybenzaldehyde, 4-benzyloxy-3-methoxy-benzaldehyde, 4-dimethylaminobenzaldehyde, and indole aldehyde.
9. The method of claim 6 , wherein the halogenated compound is a dihalogenated propionate.
10. The method of claim 9 , wherein the dihalogenated propionate is α,α-dichloropropiophenone or methyl 2,2-dichloropropionate.
11. The method of claim 6 , wherein the halogenated compound is a trihalogenated compound.
12. The method of claim 11 , wherein the trihalogenated compound is selected from the group consisting of methyl trichloroacetate, methyl tribromoacetate, 2,2,2-trichloroacetamide, 1,1,1-trichlorotoluene, 1,1,1-trichloroacetone, and ethyl difluorobromoacetate.
13. The method of claim 6 , wherein the catalytic chromium is anhydrous CrCl 2 at 50 mol % concentration.
14. The method of claim 6 , wherein the solvent is THF, DME, or a mixture thereof.
15. The method of claim 6 , wherein the synthesis takes place at room temperature.
16. The method of claim 6 , wherein the inert atmosphere is an argon atmosphere or a nitrogen atmosphere.
17. The method of claim 6 , wherein the amount of time is about 12 hours.
18. A method for the synthesis of a stereospecific tri-substituted olefin, comprising: reacting an aldehyde substrate with a dihalogenated compound, wherein the dihalogenated compound is dihalogenated propionate or a homolog of dihalogenated propionate with a longer carbon chain, and 4 equivalents of CrCl 2 in a solvent under an argon atmosphere for about 0.5 hours.
19. A method for the synthesis of stereospecific tetra-substituted olefins, comprising: reacting a ketone substrate with a trihalogenated compound and 4 equivalents of CrCl 2 in a solvent under an inert atmosphere for a sufficient amount of time.
20. The method of claim 19 , wherein the ketone substrate is selected from the group consisting of aliphatic ketone, aromatic ketone, conjugated ketone, and hindered ketone.
21. The method of claim 19 , wherein the ketone substrate is acetophenone or α-ionone.
22. The method of claim 19 , wherein the trihalogenated compound is methyl trichloroacetate or methyl tribromoacetate.
23. The method of claim 19 , wherein the solvent is selected from the group consisting of THF, DMF, DME, and a mixture thereof.
24. The method of claim 19 , wherein the synthesis takes place at room temperature.
25. The method of claim 19 , wherein the inert atmosphere is an argon atmosphere or a nitrogen atmosphere.
26. The method of claim 19 , wherein the amount of time is about 2 hours.
27. A method for the synthesis of dihalohydrins, comprising: reacting a substrate, wherein the substrate is an aldehyde or a ketone, and a trihalogenated compound with 2 equivalents of CrCl 2 in a solvent under an inert atmosphere for a sufficient amount of time.
28. The method of claim 27 , wherein the substrate is selected from the group consisting of aliphatic aldehyde, aryl aldehyde, cycloaliphatic aldehyde, and heteroaromatic aldehyde.
29. The method of claim 27 , wherein the trihalogenated compound is methyl trichloroacetate, methyl tribromoacetate, or ethyl difluorobromoacetate.
30. The method of claim 27 , wherein the solvent is THF, DME, or a mixture thereof.
31. The method of claim 27 , wherein the synthesis takes place at about 0° C.
32. The method of claim 27 , wherein the inert atmosphere is an argon atmosphere or a nitrogen atmosphere.
33. The method of claim 27 , wherein the amount of time is about 6 hours.