ラジカル機構による炭素置換フロキサンの合成と含窒素化合物への変換反応

概要

Introduction:
Heterocyclic system is an important component of novel functional molecules in pharmaceuticals and agrichemicals. Furoxan (1,2,5-oxadiazole-2-oxide) is one such this heterocyclic system. It was originally synthesized by Kekule in the late of 19th century, 1 but the structure was not immediately identified due to the undeveloped technology at that time. Based on many arguments, furoxan was identified as a five-membered structure with three heteroatoms in which 2-position nitrogen atoms is attached with an exo-ring oxygen atom. The oxan different functional groups are substituted at 3-and 4-positions, which build the library of furoxan derivatives and exhibit different biological activities.

Furoxan has weak aromaticity and is prone to ring-opening under some strong reaction reagents. It is also the reason for the slow development of direct construction of C-C bonds on the furoxan ring. However, furoxans which reported with biological activity mostly are those substituted by one or two carbon functional groups.

Based on previous research,2 radical reaction is a newly developed method with good regioselectivity, which insteads of nucleophilic substitution to form C-C bond on furoxan ring and avoids harsh conditions leading to the ring-opening. It is a more convenient strategy that is dedicated to build a library of furoxan derivatives and provides a broader scope for the screening of biologically active structures.

Result and discussion:
I. C H furoxanization
The C-H bonds are considered as inactive functional groups, but the advantages of high atom utilization and easy availability make them a reliable source for providing complex molecules. The hydrogen atom transfer (HAT) process, in which carbon radicals are generated from C-H bonds by reactive radical species, such as oxygen-or nitrogen-centered radicals, is a useful method, and subsequent reactions with radical acceptors result in C-C bond formation.

We envisioned that a method for the direct introduction of a furoxan ring into C-H bonds, or C-H bond "furoxanization", would not only serve as a unique C-C bond forming reaction for accessing a variety of alkylated furoxan derivatives but also provide a facile route for C-H bond insertion of nitrogen-containing functional groups that are otherwise difficult to prepare in a few steps (Figure 1).

Firstly, our investigation into C-H furoxanization commenced using toluene as the substrate. The reaction of toluene (5 equiv) and 3-sulfonylfuroxan (l equiv) in the presence of potassium persulfate, kふ Os(1.5 equiv) at 70 °C gave desired furoxan in 70% yield. With the optimized conditions in hand, we examined the substrate scope and good to high yields were obtained when the radical precursors were used in excess (mainly 3-5 equiv). With the successful incorporation of a furoxanyl group into various types ofC-H bonds, we turned our attention to transfonning the furoxan ring into nitrogen-containing functional groups, including diamine, dioxime, amine, nitro, oxime, and isoxazole. Therefore, nitrogen-containing functionalぎoupswere readily inserted into C-H bonds. It should be noted that some of the functional groups obtained herein cannot be accessed in such few steps using existing C-H activation techniques.

Next, the proposed mechanism of C-H bond furoxanization is described (Figure 2). The reaction is initiated by the heat-induced splitting of a persulfate anion into sulfate radical anions. The sulfate radical anion abstracts a hydrogen atom from the substrate to fo1m a carbon-centered radical, which adds to the 3-position of 3-sulfonylfuroxan affording adduct A. Radical adduct A is the resonance f01m of nitroxyl radical A', a well-known stable radical, as exemplified by TEMPO. Hence, the stability of the formed radical species is the driving force for this radical addition reaction. A stoichiometric amount of persulfate was required in the present system, implying that the arylsulfonyl radical cannot abstract the hydrogen atom from the C-H function of the substrates.

In conclusion, we have developed a radical-mediated C-C bond forming method entailing the introduction of a furoxan ring into C-H bonds. This study achieved two notable synthetic advancements. First, an unusual C-C bond forming method was developed for functionalizing the furoxan ring. Second, further manipulation of the resultant釦roxanenables the incorporation of various nitJ・ogen-containing functional臣oupsinto the C-H bond of the original substrate in 2 to 3steps. Thus, such a structural diversification protocol, wherein abundant C-H bonds are utilized as a synthetic handle, is anticipated to find wide applicability in pharmaceutical and agrochemical research as it would facilitate target synthesis.

2. Directarylation of furoxan
As far as we know, they are two strategies for obtaining aryl-substituted furoxan. The most conventional method is to install the aryl group before the furoxan ring fom1ation. However, this method requires tedious synthesis of precursors with various aryl substituents, and for some unstable aryl derivatives, the preparation is difficult. Another strategy is to introduce the aryl group after the furoxan ring formation, which was first achieved by Gasco in 2005. Herein, we have focused on the direct introduction of aryl substituents on the furoxan ring (Figure 3).

We observed that sulfonyl furoxan (1 equiv) reacted with potassium phenyltrifluoroborate (3 equiv) in the presence of Kふ Os(3 equiv) at 80 °C to afford aryl furoxan product in a 46% yield. During the screening process, we found that: I) most of the phenyltrifluoroborate was consumed rather than reacted with furoxan; 2) potassium organotrifluoroborate (RB民K)hydrolyzed to boronic acid in the presence of H20; 3) The reaction became heterogeneous and basically stopped after 4 h. Based on these discoveries, several strategies were set out to achieve further optimization. They are briefly described below: (a) other aryl radical precursors were performed to improve the utilization of aryl radical; (b) Phase transfer catalyst (PTC) was added to improve the heterogeneous reaction; (c) other oxidants that are soluble in organic solvents were investigated, avoiding the use ofH20. Unfortunately, despite our best efforts, the yield of aryl furoxan product could not be further improved.

What is the main reason for the moderate yield? We next computed the reaction process (Figure 4). Comparing the energy barriers for radical addition and elimination process between methyl radical and phenyl radical, there is not much difference in energy. This result may suggest that the different reactivity of these two radicals with furoxan is due to their stability.3 The decomposition rate of phenyl radical is faster than reacting with furoxan, resulting in moderate yield of the radical reaction.

As a part of the research, we next examined the substrate scope under the optimized conditions and this method can tolerate many substituted aryl groups. The reaction mechanism is the same as C-H furoxanization (Figure 2).

Figure 4: OFT calculations of addition and elimination process of furoxan RT with methyl radical and phenyl radical.

In conclusion, we developed a novel method for the introduction of an aryl group on the furoxan ring. This method is expected to be applicable in the synthesis of biologically active furoxans.

Conclusion:
Furoxans are considered as potential biologically active compounds due to their special cyclic structure. However, the special structure also leads to its electron-deficient character, making it unstable under some strong reagents. Our study mainly focuses on the establish.rnent of C-C bonds on furoxan via a radical pathway that avoids the utilization of strong agents. This protocol is expected to facilitate the synthesis of furoxan derivatives and promote the research of these compounds.