Catalyst-free photooxidation reaction from 1,4-dihydropyridazine to pyridazine under air
Introduction
Click reactions are a class of reactions that conjugate two components with high selectivity, high yield, and few byproducts. Due to their easy-to-perform protocols, they are used in a broad range of research areas including medicinal chemistry, chemical biology, and material science [1,2]. Of them, the most famous and widely used transformation is copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC), which is a reaction between an azide and a terminal alkyne under the catalysis of copper(I). Despite its many advantages, CuAAC seems to be less biocompatible due to the cytotoxicity of the copper catalysts [3]. To overcome this issue, many metal catalyst-free click reactions have been established so far. The cycloaddition reaction between an azide and a cyclooctyne (strain-promoted azide alkyne cycloaddition, SPAAC) is a representative example [4].
The inverse electron-demand Diels–Alder reaction (iEDDA) between 1,2,4,5-tetrazines and strained alkynes or alkenes is another class of metal-free click reactions (Scheme 1) [5]. In these reactions, an electron-deficient diene tetrazine reacts with a strained alkyne or alkene to form a highly strained bicyclic intermediate 1 or 1'. In the reactions of strained alkynes, such as cyclooctyne and bicyclononyne, a molecular nitrogen is expelled from the intermediate 1 by a retro-Diels–Alder reaction, to directly afford a pyridazine product 2. On the other hand, in the reactions of strained alkenes as trans-cyclooctene and norbornene, which is orthogonal to CuAAC and SPAAC as the alkenes do not react with azides [6,7], 4,5-dihydropyridazine 3 is formed by the retro-Diels–Alder reaction. Then the 4,5-dihydropyridazine 3 is isomerized to a more stable isomer 1,4-dihydropyridazine 4, and this intermediate is known to be automatically oxidized to pyridazine 2. However, the oxidation rate is quite low in some substrates [5,8,9], and in these cases, oxidizing agents as DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) are required to obtain pyridazine 2 as the sole product [10,11]. This may add a burden with the purification process and undermine the benefits of click reactions.
To address this issue, we set out to develop a catalyst-free photooxidation reaction of dihydropyridazines which use molecular oxygen, as both light and oxygen are regarded as clean reagents which do not require a purification process. Singlet oxygen is one of the reactive oxygen species, which is generated when the ground state oxygen receives the excitation energy from a photosensitizer in the triplet excited state. It has been shown that pyridazines are excited to the triplet state by photoirradiation [12,13]. After the completion of the iEDDA reaction, a few pyridazine molecules would be present in the reaction mixture even in the case of the substrates which are resistant to autooxidation. From this we speculated that by photoexciting these pyridazine molecules to the triplet states, we could generate singlet oxygen via the energy transfer process and oxidize the remaining dihydropyridazine molecules—i.e., we could use one pyridazine molecule as the photosensitizer to generate singlet oxygen, to generate another pyridazine molecule.
Section snippets
Optimization of the reaction conditions
Using commercially available 3,6-di(2-pyridyl)-1,2,4,5-tetrazine (5a) and norbornene, we sought for and optimized the conditions of the photooxidation reaction (Table 1). As the unsubstituted pyridazine molecule has been reported to absorb light at wavelengths shorter than 440 nm [12], we tested the light sources in this wavelength region. In the absence of light, the yield of pyridazine 2a was only 2% at 14 h after the completion of the iEDDA reaction (entry 1). In this case, unoxidized
Conclusion
In this study, we developed an oxidation reaction that converts dihydropyridazines to pyridazines with ultraviolet light irradiation under an air atmosphere. Our experiments suggested that singlet oxygen was generated in the reactions and functioned as the oxidant, and that hydrogen peroxide was also formed in the reactions. From these observations and the results of our calculations, we proposed a plausible reaction mechanism. The scope of this reaction is currently difficult to explain. This
General
3,6-Di(2-pyridyl)-1,2,4,5-tetrazine (5a), 3,6-di(4-pyridyl)-1,2,4,5-tetrazine (5b), 3,6-diphenyl-1,2,4,5-tetrazine (5g) and 2-norbornene were purchased from Tokyo Chemical Industry Co., Ltd. and used for the reactions without purification (cat. D3640, D3211, D3175 and N0166). The trans-cyclooctene derivatives (TCOs) were prepared according to the literature procedures [20,21], and only the equatorial isomer was used for the photooxidation reactions. Tris [(1-benzyl-1H
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We are grateful to Dr. Kenichiro Nagai (Analytical Unit for Organic Chemistry, School of Pharmacy, Kitasato University) for help with the structure determination of the newly synthesized compounds. This work was supported by a JSPS KAKENHI, Japan (Grand-in-Aid for Young Scientists (B), grand number: 16K18912) and a Kitasato University, Japan (Research Grant for Young Researchers).
References (24)
- et al.
J. Med. Chem.
(2019) Trends Chem
(2019)- et al.
Bioconjugate Chem.
(2010) - et al.
J. Am. Chem. Soc.
(2004) - et al.
Chem. Soc. Rev.
(2013) - et al.
Org. Biomol. Chem.
(2016) - et al.
Sci. Rep.
(2016) - et al.
Nat. Chem.
(2012) - et al.
Angew. Chem. Int. Ed.
(2017) - et al.
Tetrahedron Lett.
(2014)