Multigram synthesis of N-alkyl bis-ureas for asymmetric hydrogen bonding phase-transfer catalysis.
Multigram synthesis of N-alkyl bis-ureas for asymmetric hydrogen bonding phase-transfer catalysis.
复制标题
用于不对称氢键相转移催化的 N-烷基双脲的多克合成。
DOI：
10.1038/s41596-021-00625-y
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发表时间：
2021
期刊：
影响因子：
14.8
通讯作者：
Vicini AC
中科院分区：
文献类型：
--
作者：
Vicini AC
氟是一种关键元素，存在于约35%的农用化学品和25%的市售药物中。因此，可靠的合成方案的可用性，以制备催化剂，使氟在有机分子中的有效结合是至关重要的广泛的适用性。本文报道了一种由（S）-（-）-1，1 ′-联萘-2，2 ′-二胺（（S）-BINAM）合成两种具有代表性的对映体脲-N-烷基双脲有机催化剂的方法。这些三齿氢键供体是高效的相转移催化剂，用于在有机溶剂中增溶安全且廉价的金属碱氟化物（KF和CsF），用于对映选择性亲核氟化。第一种催化剂，其特征在于N-异丙基取代，通过使用由还原胺化和尿素偶联组成的两步序列从市售的起始原料获得（14 g，48%收率和5-d总合成时间）。第二种催化剂，具有N-乙基烷基化和间三联苯取代基，通过一种新的，可扩展的，收敛的路线获得，该路线以N-乙基化的（S）-BINAM和预先形成的异氰酸酯之间的偶联（52 g和52%总产率）结束。在这种规模下，合成需要~10 d。这可以通过并行执行一些步骤来减少到5 d。与以前的合成路线相比，该方案避免了最终的色谱纯化，并以非常高的纯度和提高的产率生产所需的催化剂。
Fluorine is a key element present in ~35% of agrochemicals and 25% of marketed pharmaceutical drugs. The availability of reliable synthetic protocols to prepare catalysts that allow the efficient incorporation of fluorine in organic molecules is therefore essential for broad applicability. Herein, we report a protocol for the multigram synthesis of two representative enantiopureN-alkylbis-urea organocatalysts derived from (S)-(–)-1,1′-binaphthyl-2,2′-diamine ((S)-BINAM). These tridentate hydrogen bond donors are highly effective phase-transfer catalysts for solubilizing safe and inexpensive metal alkali fluorides (KF and CsF) in organic solvents for enantioselective nucleophilic fluorinations. The first catalyst, characterized byN-isopropyl substitution, was obtained by using a two-step sequence consisting of reductive amination followed by urea coupling from commercially available starting materials (14 g, 48% yield and 5-d total synthesis time). The second catalyst, featuringN-ethyl alkylation andmeta-terphenyl substituents, was accessed via a novel, scalable, convergent route that concluded with the coupling betweenN-ethylated (S)-BINAM and a preformed isocyanate (52 g and 52% overall yield). On this scale, the synthesis requires ~10 d. This can be reduced to 5 d by performing some steps in parallel. Compared to the previous synthetic route, this protocol avoids the final chromatographic purification and produces the desired catalysts in very high purity and improved yield.