Conventional retrosynthetic analysis in electrophilic aromatic substitution (EAS) reactions has a different “flavor” than in alkyne reactions. There are a variety of functional groups, with corresponding directing effects, leading to many more interesting possibilities. Even when the number of functional groups on the aromatic ring is limited, the syntheses can still present challenge. Take, for example, the synthesis of tetrahydro-indacene-dione (dubbed by a friend as “mad beetle dione”) 2 starting with bromohexynyl-arene 1 (Scheme 1).
Long ago I learned a simple rule in Organic Chemistry. Practically every synthetic organic transformation and corresponding reaction mechanism can be described in entirety as a series of attacks of nucleophiles (Nu) on electrophiles (E). This simple rule was so etched into my psyche that it became unconscious. This article is dedicated to my current students who are voluntarily, and quite eagerly, undergoing my facilitated “reorganization” of their thought patterns in their endeavor to learn the logic of Organic Chemistry.
One of the exercises practiced by distinguished professors of Organic Chemistry at leading universities is having their graduate students propose a multi-step total synthesis for an interesting natural product surfacing in the literature. To date, I’ve never seen a professor do this for an undergraduate class, however I believe it would be a positive exercise in a group environment to facilitate mastery of the principles. Easily assigned as a graded homework assignment, it could be used in place of a midterm to permit students the opportunity of performing without the pressure of a timed exam.