Methods of preparing α,β-unsaturated or α-halo ketones and aldehydes

Patent metadata

Field	Value
Publication number	US-9796653-B2
Application number	US-201615382782-A
Country	US
Kind code	B2
Filing date	Dec 19, 2016
Priority date	Dec 21, 2015
Publication date	Oct 24, 2017
Grant date	Oct 24, 2017

Abstract

Copper(II) bromide mediated oxidation of acylated enol and use of the reaction in the synthesis of α,β-unsaturated or α-bromo ketones or aldehydes are disclosed. The method provides an efficient and practical process for manufacturing dehydrohedione (DHH) and many other versatile α,β-unsaturated or α-bromo ketones or aldehydes in large scales to avoid using precious metal compounds.

First claim

What is claimed is:

1. A method of preparing an α,β-unsaturated or α-bromo ketone or aldehyde, comprising oxidation of a corresponding acylated enol with copper(II) bromide (CuBr 2 ).

2. The method of claim 1 , wherein the oxidation is conducted in a solvent selected from the group consisting of acetonitrile, lower alkyl alcohols, toluene, tetrahydrofuran, dimethyl sulfoxide, water, and combinations thereof.

3. The method of claim 2 , wherein the solvent is acetonitrile, methanol, ethanol, isopropanol, water, or a combination thereof.

4. The method of claim 1 , wherein the reaction is conducted at an elevated temperature.

5. The method of claim 1 , wherein at least 0.1 equivalents of CuBr 2 are used.

6. The method of claim 1 , characterized by equation (A), wherein the α,β-unsaturated ketone or aldehyde has a structure of formula (I), the α-bromo ketone or aldehyde has a structure of formula (II), and the corresponding acylated enol has a structure of formula (III):

wherein:
R 1 and R 2 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, arylalkyl, C 3 -C 8 cycloalkyl, and cycloalkylalkyl, each except hydrogen optionally substituted by one or more R y groups;
or alternatively R 1 and R 2 together form C 2 -C 5 alkylene or 1,2-phenylene, each optionally substituted by one or more R y groups;
R 3 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 6 -C 10 aryl, arylalkyl, and —(CH 2 ) i CO 2 R z , wherein i is 1, 2, or 3, and R z is C 1 -C 4 alkyl;
R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, arylalkyl, and —(CH 2 ) j CO 2 R z , wherein j is 0, 1, 2, or 3, and R z is C 1 -C 4 alkyl;
or alternatively R 3 and R 4 together form a C 3 -C 5 alkylene optionally substituted by one or more R y groups;
R 5 is selected from the group consisting of C 1 -C 6 alkyl, C 6 -C 10 aryl, arylalkyl, C 3 -C 8 cycloalkyl, and cycloalkylalkyl; and
R y at each occurrence is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, halo, and —(CH 2 ) k CO 2 R z , wherein k is 0, 1, 2, or 3, and R z is C 1 -C 4 alkyl.

7. The method of claim 6 , wherein:
R 1 and R 2 together form a C 2 -C 3 alkylene optionally substituted by one or more R y groups;
R y at each occurrence is independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, halo, and —(CH 2 ) k CO 2 R z , wherein k is 0, 1, 2, or 3, and R z is C 1 -C 4 alkyl;
R 3 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, and arylalkyl;
R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 6 -C 10 aryl, arylalkyl, C 3 -C 8 cycloalkyl, cycloalkylalkyl, and —(CH 2 ) j CO 2 R z , wherein j is 1, 2, or 3, and R z is C 1 -C 4 alkyl; and
R 5 is methyl.

8. The method of claim 6 , wherein R 1 and R 2 together form —CH 2 CH 2 — optionally substituted by one or two R y groups, characterized by equation (B):

wherein:
n is 0, 1, or 2;
R 3 is hydrogen, C 1 -C 10 alkyl, or arylalkyl;
R 4 is hydrogen, C 1 -C 6 alkyl, or —(CH 2 ) j CO 2 R z , wherein j is 1, 2, or 3, and R z is C 1 -C 4 alkyl;
R 5 is methyl; and
R y at each occurrence is independent selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, halo, and —(CH 2 ) k CO 2 R z , wherein k is 0, 1, or 2, and R z is C 1 -C 4 alkyl.

9. The method of claim 8 , wherein n is 0; R 3 is hydrogen, C 1 -C 8 alkyl, or benzyl; and R 4 is hydrogen, C 1 -C 4 alkyl, or —CH 2 CO 2 R z , wherein R z is methyl or ethyl.

10. The method of claim 6 , wherein the α,β-unsaturated ketone is selected from the group consisting of:

11. The method of claim 10 , wherein the α,β-unsaturated ketone is dehydrohedione.

12. The method of claim 6 , wherein the ca-bromo ketone or aldehyde is selected from the group consisting of:

13. The method of claim 6 , further comprising preparing the acylated enol intermediate by reacting a corresponding ketone or aldehyde with an acylating agent in the presence of an acid or base, characterized by equation (C):

wherein each of R 1 -R 5 is defined in claim 6 .

14. The method of claim 13 , wherein the acylating agent is acetic anhydride, acetyl chloride, or isopropenyl acetate; wherein the acid is an organic acid or a mineral acid; and wherein the base is an organic or inorganic base.

15. The method of claim 14 , wherein the acylating agent is acetic anhydride or isopropenyl acetate, and the acid is a catalytic amount of p-toluenesulphonic acid.

16. A method of preparing a compound of formula Ib, characterized by equation (D):

the method comprising reacting an enol acetate intermediate of formula IIIb with at least 1.5 equivalents of CuBr 2 in a solvent selected from acetonitrile and lower alkyl alcohols, or a combination thereof, at an elevated temperature until the compound of formula IIIb is substantially consumed; and isolating compound Ib from the reaction mixture, wherein R 3 is C 1 -C 5 alkyl, and R z is C 1 -C 4 alkyl.

17. The method of claim 16 , further comprising preparing the enol acetate intermediate IIIb by reacting a compound of formula IVb with isopropenyl acetate in the presence of p-toluenesulphonic acid (p-TSA), characterized by equation (E):

wherein R 3 is C 1 -C 8 alkyl, and R z is C 1 -C 4 alkyl.

18. The method of claim 17 , wherein the amount of pTSA is about 0.1 to about 0.5 equivalents relative to the compound of IVb.

19. The method of claim 16 , wherein R 3 is C 2 -C 6 alkyl, and R z is methyl or ethyl.

20. The method of claim 16 , wherein R 3 is 1-pentyl, and R z is methyl, the amount of CuBr 2 is about 2 equivalents, the solvent is acetonitrile or methanol, and the elevated temperature is reflux temperature.

Assignees

• Int Flavors & Fragrances Inc

Inventors

• Baxendale Ian R
• Sharley James S
• Miranda Amadeo Fernández
• Pérez Ana Maria Collado

Classifications

• C07C67/00

  Preparation of carboxylic acid esters · CPC title

• C07C2101/10

  Chemistry & Metallurgy · mapped topic

• C07C45/27

  by oxidation (with ozone C07C45/40) · CPC title

• C07C67/317 Primary

  by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups · CPC title

• C07C2101/14

  Chemistry & Metallurgy · mapped topic