Ruchun Yangab,
Si Dengb,
Xiang-you Dongb,
Xianrong Songb,
Hu Cai
*a,
Jiang Baib and
Qiang Xiao
*b
aInstitute of Chemistry, Nanchang University, Nanchang 330031, Jiangxi Province, China. E-mail: caihu@ncu.edu.cn
bInstitute of Organic Chemistry, Jiangxi Science & Technology Normal University, Key Laboratory of Organic Chemistry, Nanchang 330013, Jiangxi Province, China. E-mail: xiaoqiang@tsinghua.org.cn
First published on 26th November 2019
In the present paper, an efficient approach for the construction of 1,N6-ethenoadenines from conveniently prepared N6-propargyl-adenines is developed. This reaction merges N-iodosuccinimide radical initiation and aerobic aminooxygenation in dioxane. This mild, 5-exo-dig, and metal-free cascade reaction could be applied to a wide substrate scope to provide 1,N6-ethenoadenines in moderate to good yields. The reaction mechanism was proposed and tested using radical inhibitor (butylated hydroxytoluene) and isotopic labelling (18O2) experiments.
In our continuous effort to develop fluorogenic nucleosides for nucleic acid analysis,4 1,N6-ethenoadenosines have attracted our attention because of their unique biological activities and conjugated structural skeleton (Fig. 1).5 Specifically, 1,N6-ethenoadenine 1 showed strongly fluorescent emission depending on the surrounding environment, which has been extensively used in analyzing the structure and functions of nucleic acids.6 Furthermore, it has been also recognized as a biomarker for the study of oxidative stress-related diseases and genetic damages associated with cancer.7 In addition, 9-hydroxy-1,N6-benzetheno-2′-deoxyadenosine 2 was firstly identified as DNA adduct with p-benzoquinone formed by peroxidase activation of benzene metabolites, which is well-known to cause acute leukemia in humans and bone marrow toxicity.8 Ethenoadenine 3 is another adducts of adenosine with 4-oxo-2-nonenal, which is a novel product of lipid peroxidation and may play an important role in lipid hydroperoxide-mediated carcinogenesis.9
Despite of the significance of 1,N6-ethenoadenosines mentioned above, literatures survey revealed that the availability of their synthetic approaches was very rare. The typical synthetic route is the reaction of α-halocarbonyl compounds with purine.10 Therefore, the development of novel methodology with high efficiency and structural diversity is in high demand.
In recent years, propargylamine derivatives, bearing electrophilic triple bonds, have emerged as promising cascade synthons for heterocycle synthesis.11 For example, imidazo[1,2-a]pyridines were readily prepared from 3-phenylpropiolaldehyde and 2-aminopyridine by using either copper(I) or gold(I) catalyst along with air as the oxidant (Scheme 1a, (1) and (2)).12 Later on, Das et al. further developed an improved and general metal-free aminooxygenation of alkynes for the rapid construction of 3-aroylimidazo[1,2-a]pyridines (Scheme 1a, (3)).13 According to the proposed mechanism, NIS works as an iodine cation donor, which may coordinate with the alkyne to form iodonium intermediate. Then nucleophilic addition of water followed by elimination of hydrogen iodide afforded the target product. Very recently, Huang et al. reported a metal free synthesis of aroylimidazo[1,2-a]pyridine via intramolecular dehydrogenative aminooxygenation of alkynes, which use I2 as catalyst and TBHP as an oxidant (Scheme 1b).14 But this approach has never been applied to purine substrates. In 2014, Guo et al. developed a novel approach to construct purine-fused 1,N6-ethenoadenine via copper-catalysed intramolecular cyclization of N6-propargyl-adenine at high temperature. However, this approach always affords two regioisomers (Scheme 1c).15
Based on examples mentioned previously in the literature, we envisioned that N6-propargyl-adenine could be activated by NIS to form iodonium intermediate. The subsequent N-1 mediated nucleophilic attacking to the resulting iodonium intermediate would generate 1,N6-ethenoadenines products directly. If it works, this new metal free synthetic route could provide direct access to 1,N6-ethenoadenines in one step cascade reaction from readily available starting material.
Entry | Halo source | Solvent | Time | Yieldb |
---|---|---|---|---|
a Reaction conditions: 0.1 mmol 1a, 1.0 eq. NIS, in 2.0 mL dioxane under air, room temperature.b Isolated yields.c Reaction performed at 50 °C.d Reaction performed at 80 °C.e Dark, 1 atm O2.f Sunlight, argon atmosphere. | ||||
1 | NIS | DCM | 12 h | 46 |
2 | NIS | CH3OH | 12 h | 34 |
3 | NIS | DMSO | 12 h | 36 |
4 | NIS | Dioxane | 12 h | 74 |
5 | NIS | DMF | 12 h | 23 |
6 | NIS | CH3CN | 12 h | 52 |
7 | NIS | THF | 12 h | 48 |
8 | — | Dioxane | 12 h | None |
9 | NIS (0.5 eq.) | Dioxane | 12 h | 33 |
10 | NIS (1.2 eq.) | Dioxane | 12 h | 75 |
11 | NIS (1.5 eq.) | Dioxane | 12 h | 73 |
12c | NIS (1.2 eq.) | Dioxane | 12 h | 65 |
13d | NIS (1.2 eq.) | Dioxane | 12 h | 63 |
14 | NBS | Dioxane | 12 h | Trace |
15 | NCS | Dioxane | 12 h | None |
16 | I2 | Dioxane | 12 h | 13 |
17e | NIS (1.2 eq.) | Dioxane | 12 h | 46 |
18f | NIS (1.2 eq.) | Dioxane | 12 h | Trace |
In order to improve the efficiency, a series of solvents with different polarity, such as DMF, dioxane, CH3CN, CH3OH, and DMSO, were screened (entries 1–7). Dioxane proved to be optimal and gave the best yield of 74% (entry 4). Moreover, 1.2 eq. NIS is sufficient to complete this transformation (entry 10). Increasing the reaction temperature led to slightly lower yields (entries 12–13). Furthermore, the effect of different halo sources (NCS, NBS and iodine) were examined (entries 14–16). Neither NBS nor NCS could promote the cascade reaction and only trace amount of desired product could be detected. Using iodine only provided 13% yield. In addition, the reaction performed under argon gave only trace amount of product, revealing the essential role of oxygen. Furthermore, the reaction became sluggish in absence of light. Thus, we chose dioxane as solvent, 1.2 eq. NIS, room temperature, and opening to air as the reaction conditions for further investigation (Table 2).
a Reaction conditions: 0.1 mmol 1a–1s, 1.2 eq. NIS, in 2.0 mL dioxane under air; isolated yields. |
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To demonstrate the generality of this transformation, various substituted N6-propargyl-adenines were subjected to the optimized conditions. Firstly, the effect of aromatic ring bearing different R substituents attached to alkyne was evaluated. A series of halogens including F, Cl and Br were compatible with this cascade reaction and the desired products were generated in good yields (2b–2d). It was found that substrates bearing electron-withdrawing substituents (CN, NO2, CF3 etc.) afforded product in higher yield than the substrate bearing electron-donating substitutes (Me, OMe, phenyl etc.). However, the strong electron-donating group substituted at the para position of the alkyne remarkably retarded the reaction (2m, trace). The electron-donating group at the meta position also significantly reduced the reaction yield (2n, 56%). Steric hindered substrates proved to be not suitable for the reaction and only low yields were obtained (2k, 2o and 2q). Furthermore, the effect of the substituent attached on purine, including N7-benzyl and N9-Ts substituted substrates also gave the corresponding 1,N6-ethenoadenines in good yields (2r, 65%; 2s, 83%). Fortunately, a single crystal suitable for X-ray crystallography of 2n was obtained and its structure was unambiguously confirmed in Fig. 2, which further verified the proposed structure.
Next, substrate scope was extended to ribose nucleoside substrates 1t–1w under the optimized reaction condition (Table 3). The corresponding 1,N6-ethenoadenosines were also obtained in good yields (2t–2w). Their UV and fluorescent spectroscopies were recorded. From UV spectrum, they showed a unique adsorption at 340 nm (see ESI†). Furthermore, fluorescence spectrum of 2w showed emission wave at 437 nm and excitation at 270 nm, which is very useful for nucleic acid research when incorporated into oligonucleotides. The related work is on-going and will be reported in due course.
a Reaction conditions: 0.1 mmol 1t–1w, 1.2 eq. NIS, in 2.0 mL dioxane under air; isolated yields. |
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To gain insights into the reaction mechanism, we revisited the optimization process. We observed three clear facts: (1) the oxygen is essential for this transformation. (2) Other NXS except for NIS cannot afford the desired products in good yield. (3) Retarded reaction was observed under dark environment. Considering NIS could generate iodine radical, we assumed that the reaction might be a radical mechanism, which is contrary to our initially proposed mechanism through iodonium intermediate.
In order to test our hypothesis, control experiments were performed as shown in Scheme 2. When the radical inhibitor butylated hydroxytoluene (BHT) was added to the reaction, we observed that the reaction was almost inhibited, which indicated that a radical intermediate maybe involved in this cascade reaction (Scheme 2a). In order to further verify the resource of oxygen atom in oxidation products, isotopic labelling experiment using 18O2 were conducted. The labeled product 2f-O18 can be confirmed by HRMS analysis (Scheme 2b). The result demonstrated that the oxygen atom of oxidation product 2a was utmost originated from O2. To the best of our knowledge, bifunctionalization of alkyne by radical reaction and aerobic aminooxygenation is rarely reported.16 In addition, the cyclization reaction cannot happen if the NH-6 was blocked by methyl group.
Based on these preliminary mechanistic studies and previous reports, a plausible mechanism for this cascade reaction is proposed as shown in Scheme 3. Initially, the reaction of the N6–H of starting material 1 with NIS gave intermediate A, which is easily hemolytic to form radical intermediate B. The tautomerism of radical intermediate B could deliver N-1 radical intermediate C. Then, the N-1 radical attack the triple bond through 5-exo-dig configuration to afford cyclized radical intermediate D in higher yields. After oxidation of D using molecular O2, the resulted intermediate E rearranged to give ethenoadenine 2 after elimination of HOI.
Footnote |
† Electronic supplementary information (ESI) available. CCDC 1955922. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c9ra09198j |
This journal is © The Royal Society of Chemistry 2019 |