Rapid, Two-Step Microwave-Assisted Synthesis of Acetaminophen

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Nearly any synthetic transformation can experience the benefits of microwave heating, which include shortened reaction times, decreased waste generation, and higher product purity. Small molecule synthesis, in particular, has seen great success with microwave irradiation; from rearrangements to transition-metal catalysis, microwaves have proved an effective and efficient synthesis tool. Hydrogenation, carbonylations, and other transformations requiring gaseous synthons can be performed readily but rely on reagents (often in excess) that generate gas in situ, which minimizes atom economy, complicates product purification, and leads to rapid increase of vessel pressure. The Gas Addition Kit for the Discover SP™ microwave, however, enables the safe, simple, and direct use of gaseous reagents with microwave irradiation.


To demonstrate the ease of microwave-assisted synthesis with gaseous reagent addition, a two-step synthesis of acetaminophen, a common pain medication, from 4-nitrophenol was developed. Using the Gas Addition Kit, hydrogenation of 4-nitrophenol was performed, and upon subsequent acetylation of the resulting 4-aminophenol, acetaminophen was afforded.