Aqueous Synthesis of Monosquaramides

Monosquaramides are an increasingly important organic building block utilized in drug design, metal chelation, and organocatalysis. Typical syntheses require the use of organic solvents such as diethyl ether, acetonitrile, dimethyl sulfoxide. Additionally, long reaction times, high temperatures, and organobase additives are commonly used. Herein, we discuss the successful synthesis of short chain monosquaramides and asymmetrical disquaramides using aqueous solvent conditions in moderate to high isolated yield (35.2-99.7%). Additionally, both mono- and disquaramides were successfully synthesized in pure aqueous conditions.