Rapid and halide compatible synthesis of 2-N-substituted indazolone derivatives via photochemical cyclization in aqueous media

Indazolone derivatives exhibit a wide range of biological and pharmaceutical properties. We report a rapid and efficient approach to provide structurally diverse 2-N-substituted indazolones via photochemical cyclization in aqueous media at room temperature. This straightforward protocol is halide compatible for the synthesis of halogenated indazolones bearing a broad scope of substrates, which suggests a new avenue of great importance to medicinal chemistry.

A straightforward protocol for the rapid construction of privileged indazolone architectures suggests a new avenue of great importance to medicinal chemistry.

The indazolone ring system constitutes the core structural element found in a large family of nitrogen heterocycles as exemplified by those shown in Scheme 1.¹ Indazolone derivatives have been receiving much attention due to their promising pharmacological activities. Given the unique bioactive core skeleton, indazolone derivatives exhibit a wide range of biological and pharmaceutical properties such as antiviral and antibacterial activities (1–4),² new prototypes for antichagasic drugs (5),³ antihyperglycemic properties (6),⁴ TRPV1 receptor antagonists for analgesics (7),⁵ anti-flammatory agents (8),⁶ angiotensin II receptor antagonists (9),⁷ highly potent CDKs inhibitors for anticancer (10)⁸ and so on.⁹ The privileged indazolone structures have high potential as core components for the development of related compounds leading to medicinal agents.Open in a separate windowScheme 1Biologically active molecules containing indazolone skeletons.Due to their versatility in pharmaceutical applications, many synthetic approaches have been developed for the construction of indazolone skeletons (Scheme 2), including CuO-mediated coupling of 2-haloarylcarboxylic acids with methylhydrazine,¹⁰ cyclization of N-aryl-o-nitrobenzamides through Ti(vi) reagent or Zn(ii) reagent,¹¹ Cu(i)-mediated intramolecular C–N bond formation or a base-mediated intramolecular SNAr reaction of 2-halobenzohydrazides,¹² Cu(i)-catalyzed oxidative C–N cross-coupling and dehydrogenative N–N formation sequence,¹³ Rh-catalyzed C–H activation/C–N bond formation and Cu-catalyzed N–N bond formation between azides and arylimidates,¹⁴ Friedel–Crafts cyclization of N-isocyanates using Masked N-isocyanate precursors,¹⁵ PIFA-mediated intramolecular oxidative N–N bond formation by trapping of N-acylnitrenium intermediates,¹⁶ and recently reported reaction of o-nitrobenzyl alcohol with primary amines in basic conditions.¹⁷ These approaches are complementary providing avenue to access various substitution patterns,¹⁸ however most methods rely on the requirements for transition-metal catalysts. In fact, the procedures for synthesis indazolone skeletons from Friedel–Crafts cyclization of N-isocyanates and Davis–Beirut derived reaction still suffer from harsh reaction conditions such as high reaction temperature (i.e. more than 150 °C or 20 equiv. of KOH at 100 °C for 24 h).^15,17b Very recently, one photochemical route was reported for preparation of indazolone skeletons from o-nitrobenzyl alcohols and primary amines,¹⁹ however, this approach still need long reaction time (24 hours) and halogen substituted substrate could not be compatible in the reaction conditions.^19b Thus, the efficient and general methods tolerating a wide scope of readily available starting materials for synthesis of indazolones without a transition-metal catalyst involved are still in great demand.Open in a separate windowScheme 2Representative approaches for the preparation of indazolone skeletons. o-Nitrobenzyl alcohol derivatives have shown many applications in material science and chemical biology area as a photolabile protecting group (Scheme 3a).²⁰ Upon UV light-activation, o-nitrobenzyl alcohol derivatives generate corresponding aryl-nitroso compounds via photoisomerization.²¹ Based on the distinguishing feature of highly reactive of these photogenerated intermediates, we assumed that the reaction conditions would be crucial for the photoisomerization,^20,22 thus the reactive intermediates should spontaneously and rapidly form indazolone structures via cyclization in the presence of primary amines in suitable reaction conditions (Scheme 3b). Herein, we report a rapid and efficient approach to provide structural diversity 2-N-substituted indazolones via photochemical cyclization in aqueous media at room temperature. This photochemical cyclization reaction is halide compatible for synthesis of halogen substituted indazolones, bearing a broad scope of substrates. This straightforward protocol for rapid construction of halogenated indazolone architectures suggests a new avenue of great importance to medicinal chemistry.Open in a separate windowScheme 3Synthesis of indazolone derivatives via photochemical cyclization.The initial investigation to develop a method for synthesis of indazolone derivatives via photochemical cyclization started with 4-(hydroxymethyl)-3-nitro-N-propylbenzamide 11 and heptan-1-amine 12 upon UV light-activation in methanol, smoothly leading to the formation of indazolone 13 in 52% yield (