- General and selective synthesis of primary amines using Ni-based homogeneous catalysts
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The development of base metal catalysts for industrially relevant amination and hydrogenation reactions by applying abundant and atom economical reagents continues to be important for the cost-effective and sustainable synthesis of amines which represent highly essential chemicals. In particular, the synthesis of primary amines is of central importance because these compounds serve as key precursors and central intermediates to produce value-added fine and bulk chemicals as well as pharmaceuticals, agrochemicals and materials. Here we report a Ni-triphos complex as the first Ni-based homogeneous catalyst for both reductive amination of carbonyl compounds with ammonia and hydrogenation of nitroarenes to prepare all kinds of primary amines. Remarkably, this Ni-complex enabled the synthesis of functionalized and structurally diverse benzylic, heterocyclic and aliphatic linear and branched primary amines as well as aromatic primary amines starting from inexpensive and easily accessible carbonyl compounds (aldehydes and ketones) and nitroarenes using ammonia and molecular hydrogen. This Ni-catalyzed reductive amination methodology has been applied for the amination of more complex pharmaceuticals and steroid derivatives. Detailed DFT computations have been performed for the Ni-triphos based reductive amination reaction, and they revealed that the overall reaction has an inner-sphere mechanism with H2metathesis as the rate-determining step.
- Beller, Matthias,Chandrashekhar, Vishwas G.,Jagadeesh, Rajenahally V.,Jiao, Haijun,Murugesan, Kathiravan,Wei, Zhihong
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p. 4332 - 4339
(2020/05/18)
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- Systematic structure-activity relationship (SAR) exploration of diarylmethane backbone and discovery of a highly potent novel uric acid transporter 1 (URAT1) inhibitor
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In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (1a-1x and 1ha-1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200-and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0.035 μM against human URAT1 for 1h vs. 7.18 μM and 0.28 μM for lesinurad and benzbromarone, respectively). Compound 1h is the most potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the most potent ones currently under development in clinical trials. The present study demonstrates that the diarylmethane backbone represents a very promising molecular scaffold for the design of potent URAT1 inhibitors.
- Cai, Wenqing,Wu, Jingwei,Liu, Wei,Xie, Yafei,Liu, Yuqiang,Zhang, Shuo,Xu, Weiren,Tang, Lida,Wang, Jianwu,Zhao, Guilong
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