Copper(I) Oxide‐Mediated Cyclization of o‐Haloaryl N‐Tosylhydrazones: Efficient Synthesis of Indazoles

Abstract

An efficient synthesis of indazoles from readily accessible E/Z mixtures of o‐haloaryl N‐tosylhydrazones has been developed. The thermo‐induced isomerization of N‐tosylhydrazones is discussed. A series of valuable indazole derivatives are prepared in good yields, and the method has been successfully applied to the synthesis of the bioactive compounds, lonidamine, AF‐2785, axitinib, YC‐1 and YD‐3.magnified image

Copper‐Catalyzed Isomerization and Cyclization of E/Z‐o‐Haloaryl N‐Sulfonylhydrazones: Convenient Access to 1H‐Indazoles

“…In a previous study, the N ‐sulfonyl moiety in the substrates affected the reactivity . Thus the N‐sulfonyl moiety was then examined.…”

“…More recently, Tang et al. reported an elegant thermoinduced isomerization of o ‐haloaryl N ‐tosylhydrazones and Cu 2 O‐mediated cyclization to synthesize 1 H ‐indazoles . Despite the fact that this approach was a great breakthrough to the previous methods, it suffered from the following challenges: 1) high temperature (140 °C) for the isomerization of C=N double bond in hydrazone; 2) stoichiometric amounts of copper loading (Cu 2 O, 0.5 equiv.)…”

Synthesis of 1H‐Indazoles and Quinazolines Using Additive Intermediates of Grignard Reagents to 2‐Amino Benzonitriles

“…Undoubtly, the synthesis of these heterocycles was aroused lasting concern for synthetic chemists. The well known approaches to gain 1 H ‐indazoles were using hydrazone deriviatives, including but not limited 1) a transition‐metal‐free oxidative C–N coupling of easily accessible hydrazones was developed by Rao and co‐wokers; 2) C–H amination of N ‐acetyl‐hydrazones in the presence of manganese dioxide under microwave was reported by Duan and co‐workers; 3) by employing molecular iodine as the sole oxidant, Chang and co‐wokers developed a divergent intramolecular C−H amination of hydrazones; 4) a cleavable directing group assisted intramolecular C–H amination of hydrazones was developed by Ding and co‐workers; 5) The nickel‐catalyzed cyclization of in situ generated ortho‐chlorobenzophenone hydrazone derivatives, to afford 3‐(hetero)aryl‐1 H ‐indazoles was documented by Stradiotto in 2017 . Limited number of examples showed that 1 H ‐indazoles could also be delivered via a N−N bond formation pathway.…”

Copper‐catalyzed C‐N coupling reaction of tosylhydrazones

“…Sulfonamides and indazoles are important building blocks for pharmaceuticals and bioactive compounds. For example, ionidamine is an anticancer drug; YC‐1 is reported to exhibit anticancer activity; YD‐3 is an angiogenic drug; and WXL‐1 is a potent antimicrobial agent, newbouldine and neuro‐transmitter inhibitors (Figure ) …”

“…For example, ionidamine is an anticancer drug; YC-1 is reported to exhibit anticancer activity; YD-3 is an angiogenic drug; and WXL-1 is a potent antimicrobial agent, newbouldine and neuro-transmitter inhibitors ( Figure 2). [49][50][51] 2 | EXPERIMENTAL…”