腺嘌呤苄基化过程中 1H NMR 峰的迁移揭示了 DMSO 中破坏性的 Kornblum 氧化,Journal of Heterocyclic Chemistry

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腺嘌呤苄基化过程中 1H NMR 峰的迁移揭示了 DMSO 中破坏性的 Kornblum 氧化
Journal of Heterocyclic Chemistry ( IF 2.0 ) Pub Date : 2023-07-30 , DOI: 10.1002/jhet.4718
Dominique M. S. Buyens ₁ , Lynne A. Pilcher ₁

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在二甲基亚砜 (DMSO) 中的碱性条件下使用烷基卤化物对腺嘌呤进行烷基化是获得 N9-烷基化腺嘌呤衍生物的常见反应，但由于未反应的腺嘌呤和复杂的反应混合物，收率通常较低。在此，我们报告了在 NaH 存在下使用苄基卤化物通过实时监测 DMSO 中腺嘌呤的烷基化反应¹核磁共振氢谱。NMR 分析表明，在这些常用的反应条件下，当阴离子亲核试剂从通过 Kornblum 氧化反应形成的烷氧基锍离子中间体中夺取不稳定质子时，腺嘌呤酸阴离子起始材料被质子化。为了防止腺嘌呤酸阴离子的质子化，反应在扫尾碱 DBU 存在下进行。以1:1的比例同时增加卤代烷和清理碱的浓度导致反应完全；然而，提高反应温度会促进质子化消耗起始材料，从而降低产物转化率。该结果意味着应避免在 DMSO 中加热此类亲电子试剂。

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Migrating 1H NMR peaks in the benzylation of adenine reveal the disruptive Kornblum oxidation in DMSO

The alkylation of adenine using alkyl halides under basic conditions in dimethyl sulfoxide (DMSO), a common reaction to achieve N9-alkylated adenine derivatives, is often low yielding with unreacted adenine and complicated reaction mixtures. Herein, we report the reaction monitoring of the alkylation of adenine in DMSO in the presence of NaH using benzylic halides via real-time ¹H NMR spectroscopy. NMR analysis revealed that under these generally used reaction conditions, the adeninate anion starting material is protonated as the anionic nucleophile abstracts a labile proton from an alkoxy sulfonium ion intermediate formed via the Kornblum oxidation reaction. To prevent the protonation of the adeninate anion, the reaction was performed in the presence of a mop-up base DBU. Simultaneously increasing the concentration of the alkyl halide and the mop-up base in a 1:1 ratio resulted in a complete reaction; however, increasing the temperature of the reaction promoted depletion of the starting material by protonation and hence reduced conversion to products. This result implies that heating of such electrophiles in DMSO should be avoided. The addition of a mop-up base can help resolve the complication of protonation arising from the Kornblum oxidation reaction in alkylation reactions under similar conditions.

更新日期：2023-07-30

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