康 · 学术 | Pharmaron Launches the 47th Pharmaron Virtual Lecture_新浪财经

康龙化成举办第四十七期“合成与药物化学前沿”名师线上讲座

2024年7月4日，北京—美国科罗拉多州立大学的安迪-麦克纳利教授做客康龙化成第四十七期“合成与药物化学前沿”名师线上讲座，报告主题为“通过非常规中间体对吡啶、二氮杂苯和药物分子的选择性官能团化”。麦克纳利教授的报告详细介绍了其团队使用杂环季磷盐、Zincke 亚胺、嘧啶盐等非常规中间体，通过条件控制及开环-闭环等方法实现了吡啶、二氮杂苯和药物分子的选择性官能化。

吡啶和二氮杂苯是药物化学的重要结构单元，现有的吡啶功能化方法主要生成2 -位和3 -位取代产物。麦克纳利教授团队设想通过磷盐实现吡啶4位的选择性官能化。麦克纳利教授首先介绍了文献中杂环磷鎓盐的合成方法，底物范围及磷鎓盐主要发生在吡啶4位的原因（计算化学发现PPh3对吡啶4位进攻具有最低的吉布斯自由能）。接下来麦克纳利教授团队以该磷鎓盐为底物通过配体-偶联途径实现了吡啶4位的亲核取代（醇、硫醇、酚、硫酚、苯胺、吡咯、吡唑、咪唑）、三氟甲基化、二氟甲基化等。该磷𬭩盐还能够通过水合物中间体实现从吡啶到吡啶酮的后期转化。吡啶和改性的磷试剂通过类似的方法先生成磷鎓盐，然后在醋酸铵的存在下加热可直接在吡啶的2位和4位引入氨基。

随后麦克纳利教授介绍了该磷鎓盐通过环-开环-环化的策略实现3位和5位的选择性卤代。吡啶及含吡啶的药物分子在低温下逐步加入Tf2O，二苄胺，三甲基吡啶形成Zincke亚胺，Zincke亚胺在酸性条件下可以再关环生成吡啶环。基于这样的策略，Zincke亚胺通过条件控制可以实现其3位及5位的选择性Br/I代（Cl代收率较低，选择性也较差），然后关环即可得到3位和5位卤代的吡啶。Zincke亚胺也可以和F试剂及其他一系列的碳亲电试剂经这一策略生成3位的F代及其他加成产物。此外，Zincke亚胺的形成是一个碱控制的过程，当使用三乙胺等强碱时，N-Tf -吡啶盐只能生成4位胺加成的吡啶。除二苄胺外，别的脂肪二级胺，苯胺，杂环芳胺也可以实现吡啶4位的选择性胺化反应。在Zincke亚胺环化生成吡啶环时使用N15标记的氯化铵可以直接得到N15标记的产物，这一策略也可以实现其他复杂吡啶分子的后期同位素标记。N-Tf Zincke亚胺也可以和(杂芳基)苯胺生成N-(杂)芳基吡啶盐中间体，再氢化还原得到N-取代哌啶类化合物。

最后，麦克纳利教授展示了一种嘧啶多样化的解构-重建策略。4-苯基嘧啶和苯胺进行取代反应得到N-苯基嘧啶鎓盐，随后可切除C2碳原子得到亚氨基烯胺。亚氨基烯胺可作为前体，形成各种2-取代嘧啶和1,2-唑类化合物。含嘧啶结构的复杂药物分子也可使用该策略实现嘧啶到吡啶的后期转化。

会后，麦克纳利教授在问答环节中与听众进行了热烈的讨论。

Frontiers in Synthetic and Medicinal Chemistry

--The 47th Pharmaron Virtual Lecture

Beijing,China, July 4th, 2024 -Pharmaron held its 47thvirtual lecture in the Frontiers ofSynthetic and Medicinal Chemistry series, which was delivered by Prof. Andy McNally from Colorado State University. The presentation was titled "Selective Functionalization of Pyridines, Diazines and Pharmaceuticalsvia Unconventional Intermediates." In this lecture, Prof. McNallydetailed the use of heterocyclic phosphonium salts, Zincke imines, pyrimidiniumsalts and other unconventional intermediates to achieve selectivefunctionalization of pyridines, diazines and drug molecules through controlledconditions and ring-opening and ring-closing strategies.

Pyridines and diazines are key buildingblocks of pharmaceuticals. The existing methods for pyridine functionalizationmainly produce 2- and 3-substituted products. Prof. McNally's team envisionedselective functionalization at the 4-position of pyridine through phosphoniumsalts. Prof. McNally first introduced the synthetic methods of heterocyclicphosphonium salts that had been reported in the literature, the substratescope, and the main reason for the occurrence of phosphonium salts at the4-position of pyridine (computational studies indicated that the addition of PPh3at the 4-position has the lowest ΔG).Next, Prof. McNally's team used this phosphonium salt as a starting material toachieve a number of selective functionalization at 4-position of pyridines,e.g. with nucleophiles, including alcohols, thiols, phenols, thiophenols,anilines, pyrroles, pyrazoles and imidazoles, trifluoromethylation,difluoromethylation, etc. through a ligand-coupling pathway. This phosphoniumsalt could also lead to late-stage transformation from pyridine to pyridonethrough a hydrate intermediate. Pyridine could also react with modifiedphosphorus reagents to form phosphonium salts first followed by amino groupintroduction at the 2- and 4-positions of pyridine under the presence ofammonium acetate by heating.

Subsequently, Prof. McNally introducedselective halogenation at the 3- and 5-positions through a ring-opening andring-closing strategy using the phosphonium salt. To pyridine andpyridine-containing drug molecules were gradually added Tf2O at low temperatures, dibenzylamine, andtrimethylpyridine, the Zincke imines were formed. Zincke imines could be closedto form a pyridine ring under acidic conditions. Based on this strategy, Zinckeimines could lead to selective Br/I substitution at the 3- and 5-positions ofpyridine through condition control (the yield of Cl substitution was lower andthe selectivity was also poor). Zincke imines could also afford 3-fluorinatedand other additional products with F reagents and a series of carbon electrophiles,respectively. In addition, the formation of Zincke imines was a base-controlledprocess. When triethylamine was used, N-Tf-pyridinium salt could only produce4-position aminated pyridine. Besides dibenzylamine, other alkyl secondaryamines, anilines, and heterocyclic aromatic amines could also afford selectiveamination at the 4-position of pyridine. When Zincke imine cyclized to form apyridine ring, N15-labeled ammonium chloride could be used to directly formN15-labeled product. This strategy could also be used for the late-stageisotope labeling of other complex pyridine molecules. N-Tf Zincke imines couldalso form N-(hetero)arylpyridinium salt intermediates with(heteroaromatic)anilines and then were hydrogenated to produce N-substitutedpiperidine compounds.

Finally, Prof. McNally discussedpyrimidine diversification via a deconstruction-reconstruction strategy.4-Phenylpyrimidine undergoes a substitution reaction with aniline to generateN-phenylpyrimidinium salts, which could then lead to the elimination of the C2carbon atom to form iminoenamines. Iminoenamines could serve as precursors toform various 2-substituted pyrimidines and 1,2-azole compounds. Complex drugmolecules containing pyrimidine structure could lead to the late-stageconversion of pyrimidine to pyridine with this strategy as well.

Following the presentation, Prof. McNallyengaged in a Q&A session with the audience.