A Direct, Regioselective and Atom-Economical Synthesis of 3-Aroyl-N-hydroxy-5-nitroindoles by Cycloaddition of 4-Nitronitrosobenzene with Alkynones

Aromatic C-nitroso compounds¹ and alkynones² are versatile reactants that are continuously and deeply used and studied as starting materials for the preparation of high valuable compounds. Nitrosoarenes play an ever-growing role in the organic synthesis. They are used for many different purposes (e.g., hetero Diels-Alder reaction^3,4, Nitroso-Aldol reaction^5,6, Nitroso-Ene reaction⁷, synthesis of azocompounds^8,9,10). Very recently they were even used as starting materials to afford different heterocyclic compounds^11,12,13. In the last decades, conjugated ynones were investigated for their role as very interesting and useful scaffolds in the achievement of many high valuable derivatives and heterocyclic products^{14,15,16,17,18}. C-Nitrosoaromatics can be afforded by oxidation reactions of the corresponding and commercially available anilines using different oxidizing agents as potassium peroxymonosulfate (KHSO₅·0.5KHSO₄·0.5K₂SO₄)¹⁹, Na₂WO₄/H₂O₂²⁰, Mo(VI)-complexes/H₂O₂^21,22,23, selenium derivatives²⁴. Alkynones are easily prepared by the oxidation of the corresponding alkynols using various oxidants (CrO₃²⁵ even known as Jones' reagent or mild reactants as MnO₂²⁶ and Dess-Martin periodinane²⁷). The alkynols can be achieved by direct reaction of ethynylmagnesium bromide with commercially available arylaldehydes or heteroarylaldehydes²⁸.

Indole is probably the most studied heterocyclic compound and indole derivatives have wide and various applications in many different research fields. Both medicinal chemists and material scientists produced many indole-based products that cover different functions and potential activities. Indole compounds have been investigated by many research groups and both naturally occurring products and synthetic derivatives containing the indole framework show relevant and peculiar properties^29,30,31,32. Among the plethora of indole compounds, the 3-aroylindoles have a relevant role among molecules that show biological activities (Figure 1). Different indole products belong to diverse classes of pharmaceutical candidates to become potential novel drugs³³. Synthetic and naturally occurring 3-aroylindoles are known to play a role as antibacterial, antimitotic, analgesic, antiviral, anti-inflammatory, antinociceptic, antidiabetic and anticancer^34,35. The '1-hydroxyindole hypothesis' was provocatively introduced by Somei and coworkers as an interesting and stimulating supposition to support the biological role of N-hydroxyindoles in the biosynthesis and functionalization of indole alkaloids^36,37,38,39. This assumption was recently reinforced by the observation of many endogen N-hydroxy heterocyclic compounds that show relevant biological activities and an interesting role for many purposes as pro-drugs⁴⁰. In the recent years, the search for novel active pharmaceutical ingredients revealed that different N-hydroxyindole fragments were detected and discovered in natural products and bioactive compounds (Figure 2): Stephacidin B⁴¹ and Coproverdine⁴² are known as antitumor alkaloids, Thiazomycins⁴³ (A and D), Notoamide G⁴⁴ and Nocathacins^45,46,47 (I, III, and IV) are deeply studied antibiotics, Opacaline B⁴⁸ is a natural alkaloid from ascidian Pseudodistoma opacum and Birnbaumin A and B are two pigments from Leucocoprinus birnbaumii⁴⁹. New and efficient N-hydroxyindole-based inhibitors of LDH-A (Lactate DeHydrogenase-A) and their ability to reduce the glucose to lactate conversion inside the cell were developed^{50,51,52,53,54,55,56}. Other researchers repeated that indole compounds, that did not show biological activities, became useful pro-drugs after the insertion of a N-hydroxy group⁵⁷.

A motif of debate was the stability of N-hydroxyindoles and some of these compounds gave easily a dehydrodimerization reaction that leads to the formation of a class of novel compounds, subsequently renamed as kabutanes^58,59,60,61, by the formation of a new C-C bond and two new C-O bonds. Due to the importance of stable N-hydroxyindoles the study of different synthetic approaches for the easy preparation of such compounds becomes a fundamental topic. In a previous research by some of us, an intramolecular cyclization by a Cadogan-Sundberg-type reaction was reported using nitrostyrenes and nitrostilbene as starting materials⁶². In the last decades we developed a novel cycloaddition between nitro- and nitrosoarenes with different alkynes in an intermolecular fashion affording indoles, N-hydroxy- and N-alkoxyindoles as major products (Figure 3).

At the beginning, using aromatic and aliphatic alkynes^{63,64,65,66,67} the reactions were carried out in large excess of alkyne (10 or 12-fold) and sometimes under alkylative conditions to avoid the formation of kabutanes. 3-Substituted indole products were achieved regioselectively in moderate to good yields. Using electron poor alkynes, like 4-ethynylpyrimidine derivatives as privileged substrates we could carry out the reactions for this one-pot synthetic protocol using a 1/1 nitrosoarene/alkyne molar ratio⁶⁸. With this protocol, an interesting class of kinase inhibitors as meridianins, marine alkaloids isolated from Aplidium meridianum⁶⁹, was prepared showing a different approach to meridianins through an indolization procedure (Figure 4)⁶⁸. Meridianins were generally produced so far with synthetic tools starting from preformed indole reactants. To the best of our knowledge, only a couple of methodologies reported the total synthesis of meridianins or meridianin derivatives through an indolization procedure^68,70.

In a more recent development on the use of electron poor alkynes it was worthwhile to test the employ of terminal alkynones as substrates for the indolization procedure and this led us to disclose an intermolecular synthetic technique to afford 3-aroyl-N-hydroxyindole products^71,72. Analogously to the process studied for the preparation of meridianins, using terminal arylalkynone compounds the 1/1 Ar-N=O/Ar-(C=O)-C≡CH molar ratio was used (Figure 5). Working with alkynones as privileged starting materials, the general indole synthesis was performed with different reactants exploring a wide substrate survey and changing the nature of the substituents both on nitrosoarenes and on the aromatic ynones. Electron-withdrawing groups on the C-nitrosaromatic compound led us to observe an improvement both in reaction times and in products yields. An interesting synthetic approach that makes easily available a stable library of these compounds could be very useful and, after a preliminary study, we optimized our synthetic protocol using this stoichiometric reaction between alkynones and 4-nitronitrosobenzene to afford stable 3-aroyl-N-hydroxy-5-nitroindoles. Basically, this easy access to N-hydroxyindoles led us to evidence as the cycloaddition reaction between nitrosoarene and alkynone is a very atom-economical process.