3,4-Dimethoxy-3-cyclobutene-1,2-dione, also known as 3,4-二甲氧基-3-环丁烯-1,2-二酮, is a solid compound that appears gray-white to light brown at room temperature and pressure. It has high ring strain in its molecular structure, making it sparingly soluble in water but soluble in strong polar organic solvents such as dimethyl sulfoxide, chloroform, and alcohol. This compound is classified as a cyclobutene ketone and is commonly used as an intermediate in organic synthesis and as a basic reagent in medicinal chemistry for the synthesis of formamide functional organic molecules.

Physical and Chemical Properties

The chemical reactivity of 3,4-Dimethoxy-3-cyclobutene-1,2-dione mainly focuses on the methoxy units in the cyclobutene structure. It can undergo de-methoxylation amidation reactions in the presence of organic amine substances, which can be used for the preparation of cyclobutene amine derivatives. Additionally, the ketone carbonyl units in its structure exhibit strong electrophilicity and can undergo nucleophilic addition reactions with organic lithium reagents to yield corresponding cyclobutene alcohol derivatives.

Amidation Reaction

Figure 1: Amidation reaction of 3,4-Dimethoxy-3-cyclobutene-1,2-dione

In a dry reaction flask, 4-methoxyaniline (33 mmol, 4.1 g) is added to a methanol solution (60 mL) of 3,4-Dimethoxy-3-cyclobutene-1,2-dione (4.3 g, 30 mmol). The reaction mixture is vigorously stirred at room temperature for approximately 24 hours. The progress of the reaction is monitored by TLC, and after completion, the solvent is removed under vacuum. The resulting residue is purified by silica gel column chromatography using a eluent of hexane/ethyl acetate (v/v = 3:1, 200 mL) to obtain the target product of de-methoxy amidation.

Chemical Applications

3,4-Dimethoxy-3-cyclobutene-1,2-dione is primarily used as an organic synthesis intermediate. Its most common chemical transformation is deoxy amidation reaction, which can be used to synthesize compounds with specific biological activities, such as drug candidates and biomarkers, by adjusting reaction conditions and substrate structures. This type of reaction is widely applied in the structural modification and synthesis of formamide organic ligands and bioactive molecules, showing great potential in fundamental chemical research.

References

[1] Murata, Ryuichi; et al, Tetrahedron, 2021, 97, 132381.