The reaction of dipyrromethanedicarbinols with pyrrole leading to meso-substituted corroles was investigated to determine whether mild acid catalysts [Dy(OTf)(3), Yb(OTf)(3), Sc(OTf)(3), and InCl(3)] known to provide porphyrins from dipyrromethanecarbinol species while suppressing undesired reversibility (resulting in scrambling) are applicable to reactions affording corrole, and to explore the requirements of the oxidation step. We examined a model reaction leading to meso-triphenylcorrole (TPC) to survey the effect of acid catalyst, acid concentration, ratio of pyrrole to dipyrromethanedicarbinol, oxidant, oxidant quantity, and reaction time on the yield of TPC (by UV-vis) in reactions performed at room temperature in CH(2)Cl(2). Key to this survey was a modification of the well-known spectrophotometric method for monitoring reactions leading to porphyrin. The survey revealed that TPC could be prepared via a subset of the mild acid catalysts [Dy(OTf)(3) and Yb(OTf)(3)], and a preparative-scale reaction afforded an isolated yield of TPC of 49%, devoid of porphyrin. Suppression of reversible processes was further demonstrated by the synthesis of three corroles bearing different meso substituents in defined locations in isolated yields ranging from 50% to 80%. The reaction conditions were applicable to a dipyrromethanedicarbinol bearing electron-withdrawing pentafluorophenyl substituents-provided that the reaction time of the condensation step was increased. We identified circumstances under which DDQ can cause severe interference with the detection and isolation of some corroles, we found that the yield and purity of the corrole depend on judicious selection of oxidation conditions, and we assessed the sensitivity toward light of dilute solutions of the corroles prepared in this study.

The process used to prepare a functionalized dihydrobenzothiadiazole S,S-dioxide on a pilot plant scale is described. Key changes to the original synthesis included: modifying S N Ar reaction conditions between a substituted aniline and 2-fluoronitrobenzene from n-BuLi/-78 °C to KOtAm/0 to 15 °C; replacement of a NaIO 4 -RuCl 3 oxidizing system with bleach under phase transfer conditions; and a late-stage Mitsunobu reaction. The Mitsunobu reaction was used to prepare the penultimate intermediate and the process was telescoped forward through an N-Boc deprotection step that generated the active pharmaceutical ingredient. The product was efficiently extracted into the aqueous phase under acidic conditions so that the Mitsunobu byproducts could be washed away from the product with toluene. Although Mitsunobu reactions appear to be rarely used on scale, our results indicate that extraction of the API into an aqueous layer is an efficient way to separate the API from triphenylphosphineoxide and hydrazinedicarboxylate byproducts.

Synthesis of Meso-Substituted Corroles via Dipyrromethanedicarbinols and Pyrrole. -A model reaction leading to corrole (IVa) is examined to study the effect of acid catalyst, acid concentration, ratio of pyrrole to methanedicarbinol, oxidant, oxidant quantity, and the reaction time on the yield. It is found that mild acid Dy(O-Tf)3 [as well as Yb(O-Tf) 3 and TFA] can be applied to prepare corroles (IV) devoid of porphyrins. A critical role of the choice and quantity of oxidant is identified, including a direct comparison of p-chloranil and DDQ. Dilute corrole solutions are found to be instable toward light and air. -(GEIER*, G. R. I.; CHICK, J. F. B.; CALLINAN, J. B.; REID, C. G.; AUGUSCINSKI, W. P.; J. Org. Chem. 69 (2004) 12, 4159-4169; Dep. Chem., Colgate Univ., Hamilton, NY 13346, USA; Eng.) -Klein 41-121