Synthesis of (±)-brazilin using IBX - ResearchGate
Some time ago, we revealed the first convenient method for regioselective formation of an o-quinone such as 7 from a phenol such as 8 and established the first step of this mechanism to be an intramolecular electrophilic aromatic substitution. Unlike the Fremy’s salt procedure, our IBX procedure proves successful in oxidizing phenols to o-quinones even in the absence of a para substituent. Our disclosure of this transformation was followed by several publications from others. These included the development of a benzoic acid stabilized and supposedly nonexplosive IBX reagent, as well as the use of Dess-Martin periodane. In addition, our method found application in several syntheses. We expect that it should enable improved synthetic access to a variety of biologically active catechols, such as those that inhibit protein tyrosine phosphatase 1B, decrease anxiety, and serve as a 5-HT2C receptor agonists. Given our considerable experience using this reagent for o-quinone formation, we were surprised by a recent article reporting low yields and poor selectivity when IBX was applied to the 2,3-dimethylphenol 12 and a tetralin system similar to 14 shown in . Because of our intended strategy for the synthesis of 1, we paused to consider the cause of these potentially problematic findings. We began by evaluating literature examples of other electrophillic aromatic substitution reactions. As expected, trends in regioselective substitution have been known for some time. Among the most comprehensive and enlightening investigations are studies examining the regiochemistry for bromination and amino-methylation. An abbreviated excerpt from these studies is shown in for 2,3-dimethyl phenol 12, 2,3-dihydro-1H-inden-5-ol 13, and 5,6,7,8-tetrahydro-naphthalen-2-ol 14.
Synthesis of (±)-brazilin using IBX (RSC Publishing)
Our retrosynthetic plan for brazilin (1) is depicted in . The brazilin skeleton 6 would emerge from the symmetric o-quinone 7 by a tautomerization to the corresponding p-quinone methide and an intramolecular aryl cyclization. The o-quinone 7 would form upon the oxidation of the phenol 8 using a method developed by our group. The phenol 8 should appear upon addition of the metal species 10 to the indanone 9, a ring system that seemed accessible from 3-hydroxy phenyl acetic acid 11 by homologation and aryl C-H insertion.
A short synthesis of (±)-brazilin is reported. This synthesis uses several interesting and underutilized transformations including a regioselective dirhodium-catalyzed aryl C–H insertion, a regioselective IBX phenol → o-quinone oxidation, a tautomerization of an o-quinone to a p-quinone methide, and an intramolecular aryl cyclization with a p-quinone methide.
EFFICIENT SYNTHESIS OF THE 5-HT2C RECEPTOR …
A short synthesis of (±)-brazilin is reported. This synthesis uses several interesting and underutilized transformations including a regioselective dirhodium-catalyzed aryl C−H insertion, a regioselective IBX phenol → -quinone oxidation, a tautomerization of an -quinone to a -quinone methide, and an intramolecular aryl cyclization with a -quinone methide.