Direct C3 Carbamoylation of 2H‐Indazoles

Abstract

We developed a novel method for direct C3 carbamoylation of 2H-indazoles using oxamic acids as carbamoyl radical sources. In the presence of ammonium persulfate, carbamoyl radicals were generated from oxamic acids, then used for further reactions with 2H-indazoles to afford the desired products. The reaction proceeds under metal-and catalyst-free conditions. This simple process allows for the efficient synthesis of C3 carbamoylated 2H-indazoles, which are important scaffolds in organic synthesis.Indazoles, nitrogen-containing heterocycles, are important scaffolds in organic synthesis and have been found in many biologically active compounds. [1] 2H-Indazoles are of particular interest, as they have recently been confirmed to exhibit many significant biological activities, including antitumor and antiinflammatory properties (Figure 1). [2] While there have been no shortage of attempts to synthesize indazole scaffolds, many studies on the synthesis of 2H-indazoles have some limitations due to their thermodynamically less favored properties. [3] Direct functionalization of 2H-indazoles at the C3 position has been particularly challenging because of low reactivity at that site. [4] Nevertheless, direct C3 functionalization of 2H-indazoles remains a target worth pursuing, as it would provide an efficient route for the synthesis of various 2H-indazole derivatives. Very recently, some remarkable breakthroughs concerning C3 functionalization of 2H-indazoles through acylation, [4c,5] arylation, [4d,6] alkylation, [5b] alkenylation, [7] trifluoromethylation, [8] selenylation, [9] and phosphorylation, [10] have been achieved using pioneering approaches, including visible-light-mediated reactions (Scheme 1, I). [11,12] While a number of different approaches to the synthesis of C3 functionalization of 2Hindazoles have been developed, successful direct C3 carbamoylation of 2H-indazoles is comparatively rarely reported (Scheme 1, II). Carbamoylation is one of the most efficient methods to introduce an amide motif into a molecule. [13] Carbamoylation reactions provide rapid CÀ H carbamoylated heterocycles that would typically otherwise be synthesized from conventional amide-coupling reactions, which require the use of prefunctionalized starting compounds and wasteful coupling reagents. [14] Amide motifs have been found in many natural products, pharmaceuticals, and specialized materials, and amide-functionalized N-heterocycles are important scaffolds in medicinal chemistry. 2H-indazoles containing amide motifs also demonstrate biological properties (Figure 1).With this in mind, the development of a direct and efficient method for the carbamoylation of 2H-indazoles that relies on simple processes would be significant. We envisioned that direct C3 carbamoylation of 2H-indazoles might be possible [a] V.

Oxamic acids: useful precursors of carbamoyl radicals

“…It is worth noticing that the use of silver salts to decompose persulfate is now unnecessary and has been superseded by the simple heating of the persulfate with DMSO. 24–26 The radicals thus produced add efficiently to a broad range of unsaturated systems, including alkenes, both electron-rich and electron-poor and aromatic heterocycles (Minisci reaction) giving access to diversely functionalized amides. Finally, oxidation of oxamic acids in the presence of alcohols, amines, or thiols gives access to the corresponding urethanes, ureas and thioureas.…”

“…A silver-free version of the above Minisci reaction was recently reported by different laboratories and demonstrated to be efficient for carbamoylation of a variety of heteroarenes, including quinoxalin-2(1 H )-ones, 24 phenanthrolines 25 and 2 H -indazoles (Scheme 3). 26 This procedure relies on the use of (NH 4 ) 2 S 2 O 8 as an oxidant, DMSO/H 2 O as solvents, and a temperature between 40–60 °C to furnish the corresponding amides 3 in moderate to high yield, without the need for a silver salt catalyst or acidification. The choice of solvent proved to be crucial, the reaction being greatly accelerated in a DMSO : H 2 O (600 : 1) mixture.…”

“…The procedure led to high yield of amidation of quinolines (Scheme 3, (a)) 25 a quinoxalin-2(1 H )-ones, (b) 24 and 2 H -indazoles, (c). 26 A direct C–H functionalization of phenanthrolines, useful ligands in Cu- or Fe-catalyzed processes, has also been carried out using this strategy, (d). 25 b Polyamides were thus at hand through a simple treatment of phenanthroline precursors with excess oxamic acid.…”

Photoinduced carbamoylation reactions: unlocking new reactivities towards amide synthesis

“…These acids can be easily prepared by combining amines with oxalic acid derivatives. 84 Although reliable, the need for high amounts of strong oxidants, elevated temperatures, and poor functional group tolerance has prompted the synthetic community to develop more efficient methods.…”

The development of an unexpected Cu(I)‐pyrazolo pyrimidine‐based complex: Synthesis, spectroscopic characterizations, and biological activity

“…Their fascinating characteristics captivated researchers in basic and applied investigations as well as biological applications. [ 8 ]…”