Direct diazotization of indoles with 2-Methoxyethyl nitrite

In pursuit of the reductive conversion of NO in organic synthesis, this study presents the direct diazotization of indoles using 2-methoxyethyl nitrite (MOE-ONO). Diazo compounds are invaluable intermediates in organic synthesis, serving as carbene precursors for constructing diverse carbon frameworks. However, traditional C-H diazotization methods often require azide compounds or excessive amounts of acid/base, posing significant environmental and safety challenges. Herein, we introduce a sustainable and efficient diazotization protocol that overcomes these problems. The use of 2-methoxyethyl nitrite (MOE-ONO), a stable and highly reactive NO donor developed by our group, in combination with TEMPO and a catalytic amount of Sc(OTf)3, played a significant role in the direct diazotization of 2-substituted indoles. MOE-ONO showed higher reactivity and selectivity than conventional NO donors, even including tert-butyl nitrite or NaNO2/AcOH. Since MOE-ONO is synthesized from NO gas, oxygen, and 2-methoxyethanol, this diazotization serves as an effective utilization of NO. Furthermore, the diazotization proceeds efficiently even in water, which is important for designing clean chemical processes. The synthesized 3-diazoindoles exhibit broad reactivity, such as Grignard reaction at the C2-position and rhodium-catalyzed cyclopropanation at the C3-position. Such reactions can be practical solutions for synthesizing highly functionalized indoles and indolines, which are important for the design and discovery of pharmacologically active compounds.