Arene amination is achieved by site-selective C–H zincation followed by copper-catalyzed coupling with O-benzoylhydroxylamines under mild conditions. Key to this success is ortho-zincation mediated by lithium amido diethylzincate base that is effective for a wide range of arenes, including non-activated arenes bearing simple functionalities such as fluoride, chloride, ester, amide, ether, nitrile, and trifluoromethyl groups as well as heteroarenes including indole, thiophene, pyridine and isoquinoline. An analogous C–H azidation is also accomplished using azidoiodinane for direct introduction of a useful azide group onto a broad scope of arenes and heteroarenes. These new transformations offer rapid access to valuable, diverse chemical space of aminoarenes. Their broad applications in organic synthesis and drug discovery are demonstrated in the synthesis of novel analogs of natural product (–)-nicotine and antidepressant sertraline by late-stage amination and azidation reactions.

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This article discusses about the copper‐catalyzed electrophilic amination of heteroaromatic and aromatic C–H Bonds via TMPZnCl•LiCl mediated metalation.The importance of nitrogen‐containing compounds continues to drive the development of new C–N bond‐forming transformations. C–H amination offers a direct method to introduce amino groups into molecules without stepwise functional group manipulations. Organozinc reagents can be generated in situ using the strong and non‐nucleophilic base TMPZnCl•LiCl. Additionally, readily available O ‐benzoylhydroxylamines is demonstrated as an effective electrophilic nitrogen source in this C–H amination reaction.

IntroductionAnaphylaxis represents the most extreme and life-threatening form of allergic disease and is considered a medical emergency requiring immediate intervention. Additionally, some people with mastocytosis experience recurrent episodes of anaphylaxis during normal daily activities without exposure to known triggers. While acute therapy consists primarily of epinephrine and supportive care, chronic therapy relies mostly on desensitization and immunotherapy against the offending allergen, which is a time-consuming and sometimes unsuccessful process. These treatments also necessitate identification of the triggering allergen which is not always possible, and thus highlighting a need for alternative treatments for mast cell-mediated diseases.MethodsThe exon-skipping oligonucleotide KitStop was administered to mice intradermally, intraperitoneally, or systemically at a dose of 12.5 mg/kg. Local mast cell numbers were enumerated via peritoneal lavage or skin histology, and passive systemic anaphylaxis was induced to evaluate KitStop’s global systemic effect. A complete blood count and biochemistry panel were performed to assess the risk of acute toxicity following KitStop administration.ResultsHere, we report the use of an exon-skipping oligonucleotide, which we have previously termed KitStop, to safely reduce the severity and duration of the anaphylactic response via mast cell depopulation in tissues. KitStop administration results in the integration of a premature stop codon within the mRNA transcript of the KIT receptor—a receptor tyrosine kinase found primarily on mast cells and whose gain-of-function mutation can lead to systemic mastocytosis. Following either local or systemic KitStop treatment, mice had significantly reduced mast cell numbers in the skin and peritoneum. In addition, KitStop-treated mice experienced a significantly diminished anaphylactic response using a model of passive systemic anaphylaxis when compared with control mice.DiscussionKitStop treatment results in a significant reduction in systemic mast cell responses, thus offering the potential to serve as a powerful additional treatment modality for patients that suffer from anaphylaxis.