Further Developments on the Regioselective Synthesis of 3-Aroylindole Derivatives from C -Nitrosoaromatics and Alkynones: A Novel Synthetic Approach to Pravadoline, JWH-073, Indothiazinone Analogues and Related Compounds

An uncatalyzed and easily accessible synthetic approach for the preparation of 3-aroylindoles was investigated using nitrosoarenes and aromatic terminal ethynyl ketones. Indole derivatives were produced in good yields and excel-lent regioselectivity. Functionalizations of the indole products were carried out affording highly valuable and versatile compounds. The indolization protocol was studied as a fundamental step for the preparation of pravadoline and 1-butyl-3-(1-naphthoyl)indole (JWH-073), bioactive molecules showing an-tinociceptic properties. times were registered; c product precipitated; d reaction carried out in dioxane; e product recrystallised; f product isolated by chromatography.


Introduction
Conjugated alkynones are generally known as an extremely useful and flexible class of organic compounds [1] [2] [3] [4] that can be used in a multiplicity of as kinase inhibitors [58], an equimolar ratio between the nitrosoarene and the alkyne could be used.  In our more recent work describing the synthesis of 3-aroylindoles with conjugated alkynones and nitrosoarenes, the optimal 1:1 stoichiometric ratio between the two coupling partners was also achieved [59] [60] [61]. Thus, the use of conjugated alkynones instead of simple aromatic alkynes has dramatically improved our indolization strategy. Alkynones can be easily prepared by oxidation of the corresponding alkynols, which, in turn, are obtained from aromatic aldehydes and ethynylmagnesium bromide. C-Nitrosoaromatics are instead easily accessible via oxidation of the corresponding anilines with different oxidizing agents (Oxone ® [62], Na 2 WO 4 -H 2 O 2 [63], Mo(O) 2 (acac)-H 2 O 2 [64], Selenium derivatives [65]).
Herein, we report a more comprehensive investigation of the substrate scope with respect to both nitrosoarenes and (hetero)arylalkynones coupling partners for our recently disclosed strategy for accessing (N-hydroxy)-3-aroylindole derivatives. Moreover, the synthethic versatility of some targeted compounds deriving from our indolization method was also demonstrated by their consequent functionalisation, achieving valuable molecular diversity.
In Table 1, novel combinations of nitrosoarenes and conjugated arylalkynones were investigated, affording N-hydroxy-3-aroylindole compounds and, in some cases, simple 3-aroylindoles. Although the reason behind N-OH/N-H selectivity is still under investigation in our laboratories, while nitrosoarenes that bear highly electron-withdrawing (EWG) groups preferentially yield N-OH-3-aroylindoles (entries 1-6, 13), nitrosoarenes with moderately EW substituents or EDGs afford either mixtures of N-OH and N-H compounds (entries 8, 10, 12) or selectively 3-aroylindoles (entries 7,9,11). To the best of our knowledge, this single-step procedure represents a synthetic shortcut to generate 3-aroylindoles via the simultaneous formation of new C-N and C-C bonds.
Exploring different alkynone substrates 19a -k to broaden the scope of the reaction, we then used heteroarenes and other arenes with terminal alkynyl ketone motifs and fragments. Indole derivatives were produced regioselectively and in moderate to good yields ( Table 2). The structure of the indole products was determined by spectroscopic data. Recently, a X-ray characterization led us to determine the regioselectivity of the reaction and results were detected here by analogy [60]. The indole compounds were collected as the major products, together with the azoxyarene by-products that originate from the reductive dimerization of nitrosoarenes [66]. Most of the products of this substrate scope survey show promise to be further functionalized. Our future and next study will be to employ the annulation of nitrosoarenes with alkynones for the total synthesis of high valuable compounds, natural products, and interesting frameworks with potential bioactivity. Compounds that are formed by the reactions of alkynones with 4-nitronitrosobenzene and other electron-poor C-nitrosoaromatics generally precipitated from the reaction mixture affording N-hydroxyindoles as major products [61]. Pictures and photos of used reactants and afforded products are reported in Supplementary Materials. International Journal of Organic Chemistry and ArC(=O)C≡CH (1 mmol) in 10 -15 ml of toluene; b this reaction was carried out even using a large excess of alkyne but no better yields were collected and only faster reaction times were registered; c product precipitated; d reaction carried out in dioxane; e product recrystallised; f product isolated by chromatography.
In the meantime, searching the literature for novel bioactive compounds containing the 3-aroylindole or the 3-heteroaroylindole fragment, indothiazinone  ml of toluene; b this reaction was carried out even using a large excess of alkyne but no better yields were collected and only faster reaction times were registered; c product precipitated; d reaction carried out in dioxane; e product recrystallised; f product isolated by chromatography.
Some of the indole compounds prepared through this procedure can be fur- can be extraordinarily versatile tools for many organic transformations and we tested some functional group interconversion reactions only in a preliminary and explorative study. Functionalization procedures were subsequently carried out using N-hydroxy-3-aroyl-5-nitroindoles 3 -5 as starting materials as shown in Scheme 1. The methylation was carried out using potassium carbonate as base and dimethyl sulphate as alkylating agent. The products 39 -41 were afforded quantitatively, 96% and 89% yields respectively (Scheme 1, (path (a)).
As a model reaction to obtain an aromatic C-H functionalization, substrate 39 was treated with Mn(OAc) 3 and dimethyl malonate in acetic acid resulting in a 6-membered ring formation [74], to give the benzo [b]-carbazole 42 in 67% yield (Scheme 1, path (b)). This last procedure is an oxidative free radical reaction.  [79] show that N-hydroxyindoles can be selectively and very efficiently reduced using phenacyl bromide and triethylamine at room temperature. Substrate 3 was thus converted to 3-benzoyl-5-nitroindole 44 in 75% yield (Scheme 1, path (d)). N-hydroxy-3-benzoyl-5-nitroindole 3 did react as a Scheme 1. Functionalization reactions of Compounds 3 -5. Moreover, other compounds from Table 2  We were interested in testing our synthetic protocol using an internal alky-   Figure 1 and Scheme 4) with a naphthalene moiety increased the potency by nearly 10-fold in the antinociception activity [86]. Among these compounds, 3-naphthoyl indole derivatives were introduced by the Huffman research group, who found a role for this class of molecules as cannabinoid mimetics with interesting selectivity in the interaction with CB1 and CB2 receptors [87]. JWH-018 and JWH-073 are two studied and developed compounds, investigated as synthetic cannabinoids that show a stronger affinity than that of THC for CB1 receptors [88]. With our procedure both JWH-018 [60] and JWH-073 were easily prepared. JWH-073 57 was synthesized by reaction of nitrosobenzene and 1-naphthoylprop-2-yn-1-one 19g followed by an alkylative step with n-butyl bromide in 25% yield (Scheme 5).

Conclusion
A substrate survey using different conjugated alkynones and various nitrosoarenes led us to expand the synthetic scope of the indolization procedure obtaining different 3-aroylindole products. The procedure shows a general efficiency and versatility with high functional group tolerance. N-hydroxy indoles were afforded as the major products using electron-poor C-nitrosoaromatics. Using other nitrosoarenes, N-H indoles were isolated as the major products. The formation of N-dehydroxylated products is evidence of a plausible redox step in the reaction mechanism. This step will be further and deeply studied by a mechanistic investigation even using electrochemical methods and voltammetry techniques. So far some initial experiments to determine the presence of oxidized compounds via transfer from N-hydroxylated products were unfruitful. The annulation occurs through the formation of new N 1 -C 2 and new C 3 -C 3a bonds. A wide library of functionalizable compounds, that could be easily investigated as privileged substrates for the preparation of highly valuable products, was produced. The indole products can be involved in post-cycloaddition procedures affording scaffolds, building blocks, useful reactants, intermediates for ulterior transformations, and fine chemicals that could find application both in materials science and even for medicinal chemistry studies. Due to the biological activity of different 3-acyl-and 3-aroylindoles a direct synthetic route to this class of compounds is a powerful tool for synthetic organic chemistry.