Solid phase synthesis of functionalized indazoles using triazenes – scope and limitations

Abstract

Indazoles are important heterocycles as they are a substantial part in many drugs. In this study we present a modular synthesis of highly substituted indazoles via a strategy on solid supports. The heterocyclic nitrogen atoms are originated from diazonium salts being cleaved from triazene containing resins. The scope and limitations of this process are explored considering especially the competitive occurrence of triazines and the cleavage of hydrolyzed and traceless side products

Monitoring Reactions on Solid Phases with Raman Spectroscopy

“…The intensity of the normalised alkyne band (2112 cm −1 ) was shown to reach its maximum value after a reaction time of 5 h. A similar procedure was used to determine the reaction time for the attachment of diazonium salts to immobilised amines to give triazene linkers . This reaction is well known as a prominent procedure for the synthesis of diverse heterocycles or the introduction of valuable functionalities into an aromatic building block . We adapted the above‐described method using alkynes to a very similar approach using nitriles, which are more suitable building blocks for the reactions, as they are cheap, commercially available reagents.…”

“…Since the differentiation of internal and terminal alkynes on solid supports was successful, we installed a linker unit to prove that detection of an alkyne in the presence of a nitrile group is possible (Scheme ). Such an analytical tool is suitable for monitoring the progress of nitrile‐to‐amine transformations or vice versa for the investigation of, for example, alkyne‐to‐nitrile conversion on solid phases . To prove the benefit of real‐time Raman measurements for monitoring of the latter reaction, resin 8 was treated with TMS‐azide ( 9 ) in the presence of N ‐iodosuccinimide (NIS).…”

“…Diazonium alts are prominent functional groups that offer unique transformations in organic chemistry, such as the Balz–Schiemann reaction, Sandmeyer reaction and the formation of triazenes. The latter have been used extensively for the introduction of functional groups and heterocycle synthesis on solid supports . To the best of our knowledge, in situ monitoring of the nascent diazonium species by Raman or IR spectroscopy has not been reported before, although it is expected to be a suitable model system for real‐time measurements by vibrational spectroscopy due to its Raman‐active N≡N bond.…”

“…Such an analytical tool is suitable for monitoring the progress of nitrile-to-amine transformations or vice versa for the investigationo f, for example, alkyne-to-nitrile conversion on solidp hases. [56,63] To prove the benefito f real-time Ramanm easurements for monitoring of the latter reaction, resin 8 was treated with TMS-azide (9)i nt he presence of N-iodosuccinimide (NIS). To the best of our knowledge,t his reaction is herein shown for the first time on solids upports.…”

“…[71] Scheme1.Alkyne-and nitrile-bearingr esins for monitoring of buildingblocka ttachment on solid phases. well knowna saprominent procedure for the synthesis of diverse heterocycles [54][55][56] or the introduction of valuablef unctionalitiesi nto an aromatic building block. [57][58][59][60] We adapted the above-described methodu sing alkynes to av ery similar approachu sing nitriles, which are more suitable building blocks for the reactions, as they are cheap,c ommerciallya vailable reagents.…”