- Low-Temperature Nickel-Catalyzed C?N Cross-Coupling via Kinetic Resolution Enabled by a Bulky and Flexible Chiral N-Heterocyclic Carbene Ligand
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The transition-metal-catalyzed C?N cross-coupling has revolutionized the construction of amines. Despite the innovations of multiple generations of ligands to modulate the reactivity of the metal center, ligands for the low-temperature enantioselective amination of aryl halides remain a coveted target of catalyst engineering. Designs that promote one elementary reaction often create bottlenecks at other steps. We here report an unprecedented low-temperature (as low as ?50 °C), enantioselective Ni-catalyzed C?N cross-coupling of aryl chlorides with sterically hindered secondary amines via a kinetic resolution process (s factor up to >300). A bulky yet flexible chiral N-heterocyclic carbene (NHC) ligand is leveraged to drive both oxidative addition and reductive elimination with low barriers and control the enantioselectivity. Computational studies indicate that the rotations of multiple σ-bonds on the C2-symmetric chiral ligand adapt to the changing needs of catalytic processes. We expect this design would be widely applicable to diverse transition states to achieve other challenging metal-catalyzed asymmetric cross-coupling reactions.
- Hong, Xin,Shi, Shi-Liang,Wang, Zi-Chao,Xie, Pei-Pei,Xu, Youjun
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supporting information
p. 16077 - 16084
(2021/06/17)
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- Biocatalytic Access to Piperazines from Diamines and Dicarbonyls
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Given the widespread importance of piperazines as building blocks for the production of pharmaceuticals, an efficient and selective synthesis is highly desirable. Here we show the direct synthesis of piperazines from 1,2-dicarbonyl and 1,2-diamine substrates using the R-selective imine reductase from Myxococcus stipitatus as biocatalyst. Various N- and C-substituted piperazines with high activity and excellent enantioselectivity were obtained under mild reaction conditions reaching up to 8.1 g per liter.
- Borlinghaus, Niels,Gergel, Sebastian,Nestl, Bettina M.
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p. 3727 - 3732
(2018/04/14)
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- Efficient one-pot synthesis of enantiomerically pure: N -protected-α-substituted piperazines from readily available α-amino acids
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A new pathway towards enantiomerically pure 3-substituted piperazines, bearing a benzyl protecting group, has been developed in good overall yields (83-92%), starting from commercially available N-protected amino acids. The methodology represents an efficient and simple one-pot procedure, employing a synthetic sequence consisting of an Ugi-4 component reaction, a Boc-deprotection, an intramolecular cyclisation reaction and a final reduction (UDCR). From the benzyl protected precursors, the 2-substituted piperazines bearing a Boc-protecting group could consequently also be obtained via a simple protection and deprotection step of the corresponding piperazines. The practical utility of this methodology was demonstrated for chiral drug synthesis.
- Jida, Mouhamad,Ballet, Steven
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p. 1595 - 1599
(2018/02/09)
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- Iridium-Catalyzed Asymmetric Hydrogenation of Unsaturated Piperazin-2-ones
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Two different iridium catalyst systems, generated from the ruthenocene-based phosphine-oxazoline ligand tBu-mono-RuPHOX or the diphosphine ligand BINAP, were developed for the asymmetric hydrogenation of 5,6-dihydropyrazin-2(1H)-ones, affording chiral piperazin-2-ones in good yields and with moderate to good ees. Different catalytic behaviors for the hydrogenation of these types of substrate were observed with these two catalyst systems. Our tBu-mono-RuPHOX ligand, which bears a ruthenocene scaffold with planar chirality, was found to be the best ligand for the [Ir(L)(COD)]BArF catalyst system, affording the desired products with up to 94% ee. (Figure presented.).
- Wang, Yanzhao,Liu, Yuanyuan,Li, Kun,Yang, Guoqiang,Zhang, Wanbin
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p. 1933 - 1941
(2017/06/09)
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- Synthesis of Chiral Piperazines via Hydrogenation of Pyrazines Activated by Alkyl Halides
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A facile method has been developed for the synthesis of chiral piperazines through Ir-catalyzed hydrogenation of pyrazines activated by alkyl halides, giving a wide range of chiral piperazines including 3-substituted as well as 2,3- and 3,5-disubstituted
- Huang, Wen-Xue,Liu, Lian-Jin,Wu, Bo,Feng, Guang-Shou,Wang, Baomin,Zhou, Yong-Gui
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supporting information
p. 3082 - 3085
(2016/07/13)
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- Catalytic kinetic resolution of cyclic secondary amines
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The catalytic resolution of racemic cyclic amines has been achieved by an enantioselective amidation reaction featuring an achiral N-heterocyclic carbene catalyst and a new chiral hydroxamic acid cocatalyst working in concert. The reactions proceed at room temperature, do not generate nonvolatile byproducts, and provide enantioenriched amines by aqueous extraction.
- Binanzer, Michael,Hsieh, Sheng-Ying,Bode, Jeffrey W.
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supporting information; experimental part
p. 19698 - 19701
(2012/01/13)
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- Asymmetric synthesis of (S)-mirtazapine: Unexpected racemization through an aromatic ipso-attack mechanism
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An asymmetric synthesis of (S)-mirtazapine has been achieved from the synthesis of the racemate by using (S)-1-methyl-3-phenylpiperazine as the starting material. Unfortunately, significant racemization was encountered in the final step, which involved an electrophilic aromatic ring closure of a alcohol by concentrated sulfuric acid. A significantly higher ee was observed when polyphosphoric acid (PPA) was used instead. A remarkable correlation between the amount of PPA used and the ee of the product was revealed, namely, an increase in the ee upon decreasing the amount of PPA. This trend was paralleled by the formation of an increasing amount of a side-product upon lowering the amount of PPA. The racemization and formation of a side-product can be explained by an ipso-attack mechanism during the electrophilic aromatic ring-closure reaction. This mechanism was supported by a mechanistic study using a deuterium-labeled substrate. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Van Der Linden, Marco,Borsboom, Judith,Kaspersen, Frans,Kemperman, Gerjan
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experimental part
p. 2989 - 2997
(2009/04/07)
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- PROCESS FOR PRODUCING OPTICALLY ACTIVE PIPERAZINE COMPOUND
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Provided is a method of producing optically active 1-methyl-3-phenylpiperazine of the formula (11) or salt thereof, comprising the following steps 1 to 4, or steps 5 to 7 and step 4, and a method of producing optically active mirtazapine via this method.
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Page/Page column 22-23
(2008/12/06)
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- METHOD FOR THE PREPARATION OF AN ENANTIOMER OF A TETRACYCLIC BENZAZEPINE
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The present invention relates to a method for the preparation of mirtazapine and tetracyclic analogous compounds having substantial enantiomeric excess of the R or S form. The invention further relates to a novel intermediate and its use for the preparation of mirtazapine having a substantial enantiomeric excess of the R or S form. The method comprising the steps of a: providing a carboxylic acid compound according to Formula I having a substantial enantiomeric excess of the R or S form, b: converting the carboxylic acid group of compound I into a ketone group, producing a ketone compound of Formula II, c: optionally reducing ketone compound II with a mild reduction agent to form the intermediate hydroxy compound of Formula III and d: forming the mirtazapine of Formula IV by reduction of the ketone compound II or of the hydroxy compound III using a strong reduction agent.
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Page/Page column 5
(2008/12/04)
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- A METHOD FOR THE PREPARATION OF AN ENANTIOMER OF A TETRACYCLIC BENZAZEPINE
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The present invention relates to a method for the preparation of mirtazapine and tetracyclic analogous compounds having substantial enantiomeric excess of the R or S form. The invention further relates to a novel intermediate and its use for the preparation of mirtazapine having a substantial enantiomeric excess of the R or S form. The method comprising the steps of a: providing a carboxylic acid compound according to Formula (I) having a substantial enantiomeric excess of the R or S form, b: converting the carboxylic acid group of compound I into a ketone group, producing a ketone compound of Formula (II), c: optionally reducing ketone compound II with a mild reduction agent to form the intermediate hydroxy compound of Formula (III) and d: forming the mirtazapine of Formula (IV) by reduction of the ketone compound II or of the hydroxy compound III using a strong reduction agent.
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Page/Page column 11
(2008/12/08)
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- STEREOSELECTIVE SYNTHESIS OF (S)-1-METHYL-3-PHENYLPIPERAZINE
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This invention provides for a compound according to Formula (1), wherein R1 is methyl, ethyl, n-propyl, isopropyl, benzyl or 2-haloethyl and the use thereof in a method to prepare (S)-1-methyl-3-phenylpiperazine by enzymatic hydrolysis of the c
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