Methods for preparing butenolides

Patent metadata

Field	Value
Publication number	US-2024400530-A1
Application number	US-202418635130-A
Country	US
Kind code	A1
Filing date	Apr 15, 2024
Priority date	May 30, 2023
Publication date	Dec 5, 2024
Grant date	—

Abstract

A method useful for preparing butenolides in high yield, the method comprising: contacting an aldehyde, malonic acid, and an organic base thereby forming a Knoevenagel condensation product; and contacting the Knoevenagel condensation product, an oxidant, a metal halide, and optionally an inorganic base thereby forming the butenolide.

First claim

What is claimed is:

1 . A method of preparing a butenolide, the method comprising: contacting an aldehyde, malonic acid, and an organic base thereby forming a Knoevenagel condensation product; and contacting the Knoevenagel condensation product, an oxidant, a metal halide, and optionally an inorganic base thereby forming the butenolide.

2 . The method of claim 1 , wherein the organic base is an organic amine, an organic amidine, or an organic guanidine.

3 . The method of claim 1 , wherein the oxidant is a peroxide or oxone.

4 . The method of claim 1 , wherein the metal halide is a Group I or Group II metal salt of chloride, bromide, or iodide.

5 . The method of claim 1 , wherein the butenolide has Formula 1:

wherein R 1 is alkyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl, heteroaryl, or —(CR 2 ) m Y, wherein m is a whole number selected from 1-10; R for each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and Y is selected from the group consisting of —CN, —(C═O)OR, —OR, —O(C═O)R, —OSiR 3 , —O(C═O)OR, —(C═O)NR 2 , —(NR)(C═O)R, —(NR)(C═O)OR, —O(C═O)NR 2 , —O(C═NR)NR 2 , —(NR)(C═O)NR 2 , —(S═O)R, —S(O) 2 R, —S(O) 2 OR, —S(O) 2 NR 2 , —OS(O) 2 R, —(NR)S(O) 2 R, and —(NR)S(O) 2 NR 2 , wherein R for each instance is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl, or heteroaryl.

6 . The method of claim 5 , wherein the organic base is an organic amine.

7 . The method of claim 6 , wherein the organic base is selected from the group consisting of diethyl amine, diisopropyl amine, pyrrolidine, piperidine, hexamethyleneimine, proline, morpholine, piperazine, imidazole, pyridine, triethylamine, N,N-diisopropylethylamine, N-ethyl pyrrolidine, N-nethyl morpholine, quinuclidine, and 1,4-diazabicyclo[2.2.2]octane.

8 . The method of claim 6 , wherein the organic base comprises piperidine.

9 . The method of claim 8 , wherein the step of contacting the aldehyde, malonic acid, and piperidine is conducted in a solvent comprising dimethyl sulfoxide, dimethyl formamide, or a mixture thereof; and piperidine is present at 0.5-3 mol % relative to the aldehyde.

10 . The method of claim 8 , wherein the step of contacting the aldehyde, malonic acid, and piperidine is conducted in a solvent comprising dimethyl sulfoxide at 50-100° C.

11 . The method of claim 8 , wherein the step of contacting the aldehyde, malonic acid, and piperidine is conducted in a flow chemistry reactor in a solvent comprising dimethyl sulfoxide, dimethyl formamide, or a mixture thereof at 100-140° C.

12 . The method of claim 11 , wherein the flow chemistry reactor is operated at a flow rate of 0.4 mL/min to 6.0 mL/min.

13 . The method of claim 5 , wherein the oxidant comprises oxone; the metal halide comprises a Group I metal salt of iodide; and the inorganic base comprises a Group I or Group II metal carbonate or bicarbonate.

14 . The method of claim 13 , wherein the inorganic base comprises sodium carbonate, the metal halide comprises potassium iodide, and the step of contacting the Knoevenagel condensation product, oxone, the potassium iodide, and sodium carbonate is conducted in a solvent comprising acetonitrile and water in a volume ratio of 2:1 to 1:2, respectively.

15 . The method of claim 14 , wherein the step of contacting the Knoevenagel condensation product, oxone, potassium iodide, and sodium carbonate is conducted at −10 to 23° C.

16 . The method of claim 5 , wherein the oxidant comprises hydrogen peroxide; and the metal halide comprises a Group I or Group II metal bromide or iodide.

17 . The method of claim 16 , wherein the metal halide comprises sodium iodide and the step of contacting the Knoevenagel condensation product, hydrogen peroxide, and sodium iodide is conducted in a solvent comprising acetonitrile and water in a volume ratio of 2:1 to 1:2, respectively.

18 . The method of claim 17 , wherein the step of contacting the Knoevenagel condensation product, hydrogen peroxide, and sodium iodide is conducted at −10 to 23° C.

19 . The method of claim 1 , wherein the method comprises:
contacting an aldehyde having the formula R 1 CH 2 CHO, malonic acid and piperdine in a solvent comprising dimethyl sulfoxide at 50-100° C., wherein piperidine is present at 0.5-3 mol % relative to the aldehyde; or contacting an aldehyde having the formula R 1 CH 2 CHO, malonic acid, and piperdine in a solvent comprising dimethyl formamide in a flow chemistry reactor at a temperature of 100-140° C. and a flow rate of 0.4 mL/min to 6.0 mL/min; thereby forming the Knoevenagel condensation product; and contacting the Knoevenagel condensation product, oxone, potassium iodide, and sodium carbonate in a solvent comprising acetonitrile and water in a volume ratio of 2:1 to 1:2, respectively at −10 to 23° C.; or contacting the Knoevenagel condensation product, hydrogen peroxide, and sodium iodide in a solvent comprising acetonitrile and water in a volume ratio of 2:1 to 1:2, respectively at −10 to 23° C.; thereby forming the butenolide, wherein R 1 is is alkyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl, heteroaryl, or —(CR 2 ) m Y, wherein m is a whole number selected from 1-10; R for each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and Y is selected from the group consisting of —CN, —(C═O)OR, —O(C═O)R, —O(C═O)OR, —(C═O)NR 2 , —(NR)(C═O)R, —(NR)(C═O)OR, —O(C═O)NR 2 , —O(C═NR)NR 2 , —(NR)(C═O)NR 2 , —(S═O)R, —S(O) 2 R, —S(O) 2 OR, —S(O) 2 NR 2 , —OS(O) 2 R, —(NR)S(O) 2 R, and —(NR)S(O) 2 NR 2 , wherein R for each instance is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, aryl, or heteroaryl.

20 . The method of claim 19 , wherein the method comprises: contacting the aldehyde having the formula R 1 CH 2 CHO, malonic acid, and piperdine in a solvent comprising dimethyl formamide in a flow chemistry reactor at a temperature of 100-140° C. and a flow rate of 0.4 mL/min to 6.0 mL/min thereby forming the Knoevenagel condensation product; and
contacting the Knoevenagel condensation product, oxone, potassium iodide, and sodium carbonate in a solvent comprising acetonitrile and water in a volume ratio of 2:1 to 1:2, respectively at −10 to 23° C.; or
contacting the Knoevenagel condensation product, hydrogen peroxide, and sodium iodide in a solvent comprising acetonitrile and water in a volume ratio of 2:1 to 1:2, respectively at −10 to 23° C. thereby forming the butenolide.

Assignees

• Univ Hong Kong Science & Tech

Inventors

• Tong Rongbiao
• Cheung Yuen Tsz

Classifications

• C07D307/58 Primary

  One oxygen atom, e.g. butenolide · CPC title

• C07D307/33 Primary

  in position 2, the oxygen atom being in its keto or unsubstituted enol form · CPC title