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. Diazo compounds are invaluable intermediates in organic synthesis, however, traditional C–H diazotization methods often face environmental and safety challenges due to the use of azide compounds and excessive acid/base. Here, the authors introduce a protocol using 2-methoxyethyl nitrite, achieving efficient diazotization of 2-substituted indoles with high reactivity and selectivity.