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. 2024 Feb 22;26(9):1868–1873. doi: 10.1021/acs.orglett.4c00097

Visible Light-Mediated Heterodifunctionalization of Alkynylazobenzenes for 2H-Indazole Synthesis

Clara Mañas †,‡, Estíbaliz Merino †,‡,*
PMCID: PMC10928707  PMID: 38386928

Abstract

graphic file with name ol4c00097_0006.jpg

We disclose the heterodifunctionalization of alkynylazobenzenes promoted exclusively by visible light in the absence of any transition metal and/or photocatalyst. This reaction features excellent regioselectivity on a broad variety of substrates with perfect atom economy. Alcohols, carboxylic acids, thiols, amides, heterocycles, and even water are suitable substrates for the promotion of the oxyamination, sulfenoamination, and diamination reactions. In this manner, biologically active indazole scaffolds can be rapidly assembled from alkyne feedstocks.

Alkynes are some of the most common fundamental and sustainable chemical raw materials for the pharmaceutical, agrochemical, and materials industries, and their use in chemical reactions forms the basis of modern catalysis and synthesis.1,2 The most prevalent mode of reaction of alkynes is the formation of alkenes via a metal-mediated π-insertion process of the triple bond.3,4 Difunctionalization of alkynes is an efficient and straightforward strategy for the synthesis of sophisticated scaffolds. This methodology represents one of the most efficient methods for the formation of C–C and C–heteroatom bonds, as there is a simultaneous installation of two functional groups at vicinal positions in a single synthetic step leading to the straightforward construction of complex molecules from simple alkyne feedstocks. Many methods have been developed for C–C and C–X bond formation with photoredox catalysis5−7 or metal-mediated cross couplings.8−10 The regioselective construction of the C–N bond under mild conditions exemplifies a class of reactions with significant synthetic potential due to the ubiquitous presence of amines in both naturally occurring and synthetic compounds, which manifest high levels of biological activity.11,12 The direct amination reaction of simple alkynes, which results in the formation of a C–N bond along with a C–O, C–S, or C–N bond, has scarcely been explored. Some examples such as oxynitration,13 thiocyanation–amination,14 or sulfonylamination15 have been reported to occur via radical mechanisms. The reported examples from Yamame and Lin using alkynylazobenzenes as substrates showed the viability for enabling the formation of C–N and C–C16 and C–P17 bonds using a Pd/Cu system (Figure 1a). However, the difunctionalization of alkynylazobenzenes by the formation of C–N and C–N, C–O, and C–S bonds is still an uncharted transformation. Despite progress in addressing this issue, regioselective heterodifunctionalization of alkynes under mild conditions in the absence of a transition metal or organophotocatalyst via a polar mechanism remains an exciting synthetic challenge.

Figure 1.

Figure 1

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Strategies for the heterodifunctionalization of alkynylazobenzenes.

2H-Indazoles constitute prevalent structural motifs in bioactive natural products,18,19 and drugs such as niraparib20 and pazopanib21 (Figure 1b) and 2-aryl indazoles exhibit interesting spectrophotometric properties.22 Their preparation from alkynylazobenzenes has been reported using transition metals such as Pd/Cu16,17 and Rh23 or sensitive reagents such as TBAF.24,25 No examples reporting the synthesis of 2H-indazoles in the absence of a catalyst or excess of additives have been published to date. Considering their applications, it is of paramount importance to have new and general environmentally sustainable procedures in organic synthesis that reduce the cost of energy. These methods aim to reduce energy costs, minimize the generation of waste, and either reduce or eliminate the use of transition metals.

We decided to investigate the reactivity of alkynylazobenzenes under visible light irradiation, given that these compounds present an alkynyl moiety, which adds an additional point of reactivity to their azobenzene backbone that can be activated by visible light.26−28

Herein, we describe the regioselective heterodifunctionalization of terminal and internal alkynylazobenzenes exclusively promoted by irradiation with blue light in the absence of a catalyst or an additive (Figure 1c). In a single reaction step and in the presence of a variety of nucleophiles, two new C–heteroatom bonds are formed with perfect atom economy. The excellent regioselectivity, combined with broad functional group tolerance and mild reaction conditions, showcases the synthetic utility and generality of this transformation. This makes it a valuable tool for assembling relevant blueprints such as 2H-indazoles used in the production of pharmaceuticals, bioactive natural products, and ligands for transition metal catalysis.

We started our investigation with 1a, which was dissolved in methanol (0.1 M) and upon irradiation with blue light (40 W) furnished 2H-indazol 2a in 95% yield (Scheme 1). When the scale was increased 10 times (1 mmol), product 2a was isolated in 90% yield after filtration over silica gel. X-ray crystallographic analysis of compound 2a confirmed the structure of the product (details in the Supporting Information).

Scheme 1. Azobenzene and Alkyne Scope of the Oxyamination Reaction.

Scheme 1

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Next, we turned our focus to explore the generality of this oxyamination reaction through the simple procedure of dissolving a variety of alkynylazobenzenes 1 in methanol and irradiating them with a blue light-emitting diode (40 W) (Scheme 1). Alkynylazobenzenes that bear a halogen atom in the ortho, meta, or para position on Ar1 furnished the corresponding products (2b–2e) in excellent yields. Electron-withdrawing groups [CN, NO2, C(O)Me, and CO2Me] were evaluated, and the corresponding 2H-indazoles 2 were also obtained in excellent yields. Rings with two substituents successfully gave the oxyamination reaction (2j and 2k). The fluorinated compounds are of great interest in medicinal chemistry because they have a beneficial effect in modulating the physicochemical properties of active pharmaceutical ingredients.29 Under the standard conditions, 1l and 1s afforded 2H-indazoles 2l and 2s, respectively, in excellent yields. Methyl (2m), dimethylamine (2n), and methoxy (2p) derivatives confirmed the compatibility of electron-donating substituents under the reaction conditions.

Amides and esters were also revealed as suitable substituents for obtaining 2o and 2q by simple irradiation of a solution of the corresponding alkynylazobenzene 1 in methanol. Modification of Ar2 of the substrates with electron-withdrawing and electron-donating groups in different positions of the aromatic rings afforded in excellent yields products 2r–2v. Attempts to synthesize azo compounds with an alkyl moiety instead of Ar1 were unsuccessful (details in the Supporting Information).30,31 Modifications of the alkynyl moiety offered an additional reason for structural diversification. The substrate with a terminal alkyne provided product 2w in 62% yield probably due to its low stability. Branched chains and cycloalkyls such as cyclohexyl and cyclopropyl provided the products (2x–2z) in excellent yields. Halogen chains are also compatible with this transformation (2aa). Remarkably, 2ab with a primary free alcohol was synthesized in moderate yield. An aromatic ring on the alkyne also led to the corresponding product (2ac) in almost quantitative yield. Substrates with a phenyl ring directly attached to the alkyne group were also revealed as compatible substrates under the reaction conditions, furnishing 2ad in 99% yield.

Encouraged by the general application of a wide variety of alkynylazobenzenes with methanol under irradiation with blue light in the oxyamination reaction, we then systematically evaluated the transformation with respect to the scope of different alcohols (Scheme 2). In this case, a solution of 1a in acetonitrile (0.1 M) was prepared and 1.5 equiv of the alcohol were used. Ethanol was successfully incorporated into 2ae in 75% yield. Bulkier alcohols such as tert-butanol (2af) or iso-propanol (2ag) confirmed that the oxyamination reaction under standard conditions is not sensitive to the steric constraints. X-ray crystallographic analysis of the latter compound confirmed the structure (details in the Supporting Information). Terminal alkenyl and alkynyl alcohols are also compatible with the reaction conditions (2ah and 2ai, respectively). Alcohols with terminal halogens such as fluorine (2aj) or iodine (2ak) were successfully incorporated into the corresponding alkynylazobenzene 1a. Less nucleophilic alcohols such as phenol furnished the product (2al) in high yield. Interestingly, norbornanyl and adamantyl alcohols were also incorporated under the standard conditions (2am and 2an, respectively). We next sought to explore the possibility of applying this transformation in the context of a structural diversification natural product synthesis setting.32,33 To this end, we were pleased to observe the successful conversion of the tocopherol-derived alcohol into product 2ao in 40% yield. Product 2ap was produced when the oxyamination protocol was applied with an estrone-derived alcohol in a similar yield. Hydroxyamination was suitable when water was used, allowing the isolation of free alcohol 2aq in very good yield. These transformations highlight the potential of this methodology to broaden the structural diversity of complex biologically active molecules and influence structure–activity relationship (SAR) optimization in medicinal chemistry studies. Next, we focused our attention on exploring other types of nucleophiles as carboxylic acids. As shown in Scheme 2, with aliphatic and aromatic carboxylic acids, oxyamination took place with moderate to good yields (2ar and 2as, respectively). Cyclic tertiary carboxylic acids could be utilized as counterparts, giving the transformation in an efficient manner (2at and 2au). Similarly, this practical protocol was applied in the sulfenoamination reaction, exhibiting excellent functional compatibility and efficiency with aliphatic and aromatic thiols (2av and 2aw, respectively). Interestingly, when the reaction was performed with 2-mercaptoethanol, a mixture of compounds was obtained (2ax and 2ax′). The major product, isolated in 65% yield, is the outcome of the attack by the most nucleophilic sulfur atom, and the product resulting from the attack of the alcohol was isolated in 23% yield. Attempts to react with primary and secondary amines, such as isopropylamine and diethylamine, as well as with aromatic amines, like aniline, proved to be unsuccessful (Figure S9). Amides have been shown to be powerful nucleophiles in the presence of strong bases.34 We were able to achieve the incorporation of acetamide into the 2H-indazole scaffold through the nitrogen atom with a moderate yield, even in the absence of a base (2ay). This result highlights the reactivity of the excited species generated by the irradiation of alkynylazobenzene 1. Finally, indole was tested to extend the synthetic potential of this transformation to heterocycles, leading to 2az in 62% yield.

Scheme 2. Scope of the Oxyamination, Sulfenoamination, and Diamination Reactions.

Scheme 2

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To gain more insight into the mechanism of this heterodifunctionalization of alkynylazobenzenes, several mechanistic experiments were performed. Cis- and trans-1a were separately subjected to the standard reaction conditions, and the isomerization was monitored by 1H nuclear magnetic resonance (NMR). In both cases, 2a was obtained in comparable yields. A plot of the temporal concentration over time revealed that, after only 10 min, both isomers converge to an ∼1:1.9 cis:trans ratio (Figures S3 and S4). Such a photostationary state, reached at a regime much faster than the product reaction itself, suggests that both isomers will be present at the outset of the reaction, regardless of the initial azo group geometry. A deuteration experiment with CD3OD was carried out to observe the formation of deuterated 2a in 92% yield, with >99% deuteration. Analysis of the progress of the reaction by 1H NMR revealed that (Z)-1a is generated during the reaction (Figure S5).

Light proved to be crucial for successfully performing the reaction, pointing to the formation of the S1 excited state of the alkynylazobenzene molecule (Figure S10). Furthermore, when the reaction mixture was heated to 70 °C, 2a was isolated in only 16% yield. This assumption was supported by an additional experiment with (E)-1-(hex-1-yn-1-yl)-2-styrylbenzene, which showed a trans:cis isomerization ratio of 1:2.3 under the given reaction conditions (Figure S8). This experiment seems to indicate that the reaction begins with the absorption of light by alkynylazobenzene 1 and excitation to the S1 state. The reaction of 1a to 2a was performed under standard conditions in the presence of 5 equiv of piperylene, which is an established triplet quencher (Figure S6).35 The fact that there was no reduction in the rate or yield of 2a suggests that the reaction does not involve a triplet intermediate. The yield of the oxyamination reaction was not adversely affected by the presence of radical inhibitors such as TEMPO or 2,2-dimethyl-3,4-dihydro-2H-pyrrole 1-oxide (Figure S7). This result could rule out the formation of radical intermediates, supporting the hypothesis of a polar mechanism. On the basis of the results we achieved, a proposed mechanism is outlined in Figure 2. The first step of the reaction would be the excitation of 1a under visible light irradiation. The nitrogen atom of the azo group of this generated excited species can attack the alkynyl moiety, generating intermediate I by capturing a hydrogen of methanol. The addition of methanol leads to 2a through transition state TSI-2a (ΔG⧧ = 17.7 kcal mol–1).

Figure 2.

Figure 2

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Mechanistic proposal.

To expand the utility of indazoles, we focused our attention on exploring the derivatization of 2H-indazoles 2 (Figure 3). Arylation of 2b by the Suzuki coupling reaction gave access to indazole 2ba with a biphenyl moiety. Amino indazole 2bb could be achieved by reduction of the nitro group of 2g in excellent yield. The hydrolysis of ester groups led to 2bc in almost quantitative yield. Sulfonyl group-containing compounds constitute an important class of therapeutic agents in medicinal chemistry. Oxidation with m-CPBA allowed us to obtain sulfone indazole 2bd in 49% yield.

Figure 3.

Figure 3

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Transformations of 2H-indazoles.

In conclusion, we have overcome a formidable challenge in the heterodifunctionalization of alkynes by carrying out this transformation in the absence of a catalyst and/or additive simply by irradiation of an alkynylazobenzene with visible light. Oxyamination, sulfenoamination, and diamination reactions can be carried out in a single reaction step under mild reaction conditions with a wide range of substrates. The process is regioselective with perfect atom economy and provides access to 2H-indazole skeletons, which are in great demand in medicinal chemistry. We postulate that this method harnesses the great potential of visible light to promote chemical transformations and advances the broader field of alkyne difunctionalization to a new dimension.

Acknowledgments

Financial support was provided by Comunidad de Madrid Research Talent Attraction Program (Grants 2018-T1/IND-10054 and 2022-5A/IND-24227), the Spanish Ministry of Science and Innovation (MICINN) (Grants CNS2022-135304 and TED2021-129634B-I00), and Universidad de Alcalá (Grant IUAH21/CC-003). Computational resources for the density functional theory calculations were provided by the HERMES Cluster at the University of Zaragoza. The authors also gratefully acknowledge the computing time granted by the Spanish Supercomputing Network (Grant QH-2023-2-0005) and provided on CESGA (Galicia Supercomputing Center).

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.4c00097.

  • Experimental procedures, characterization and crystal data, and additional experimental details (PDF)

The authors declare no competing financial interest.

Supplementary Material

ol4c00097_si_001.pdf (23.1MB, pdf)

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Associated Data

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Supplementary Materials

ol4c00097_si_001.pdf (23.1MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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