80418-13-9Relevant articles and documents
Trifluoromethyl reagent as well as synthesis method and application thereof
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Paragraph 0105-0109, (2022/01/08)
The invention discloses a trifluoromethyl reagent as well as a synthesis method and application thereof, wherein the structural formula of the trifluoromethyl reagent is as shown in formula I in the specification. According to the invention, diphenyl trifluoromethylphosphine and iodomethane are used as raw materials, and are heated in an organic solvent to carry out an addition reaction to prepare the trifluoromethylation reagent. The method is simple and convenient in process, high in yield and capable of realizing 10-gram-level large-scale preparation; more importantly, the trifluoromethylation reagent can be used as a free radical and a nucleophilic reagent to be applied to free radical addition reaction and simple nucleophilic addition reaction to prepare different types of trifluoromethylation products, so that the method has important application value.
Photochemical C-H Activation Enables Nickel-Catalyzed Olefin Dicarbofunctionalization
Campbell, Mark W.,Yuan, Mingbin,Polites, Viktor C.,Gutierrez, Osvaldo,Molander, Gary A.
supporting information, p. 3901 - 3910 (2021/04/06)
Alkenes, ethers, and alcohols account for a significant percentage of bulk reagents available to the chemistry community. The petrochemical, pharmaceutical, and agrochemical industries each consume gigagrams of these materials as fuels and solvents each year. However, the utilization of such materials as building blocks for the construction of complex small molecules is limited by the necessity of prefunctionalization to achieve chemoselective reactivity. Herein, we report the implementation of efficient, sustainable, diaryl ketone hydrogen-atom transfer (HAT) catalysis to activate native C-H bonds for multicomponent dicarbofunctionalization of alkenes. The ability to forge new carbon-carbon bonds between reagents typically viewed as commodity solvents provides a new, more atom-economic outlook for organic synthesis. Through detailed experimental and computational investigation, the critical effect of hydrogen bonding on the reactivity of this transformation was uncovered.
Highly enantioselective construction of CF3-bearing all-carbon quaternary stereocenters: Hiral spiro-fused bisoxazoline ligands with 1,1′-binaphthyl sidearm for asymmetric Michael-type Friedel-Crafts reaction
Bao, Robert Li-Yuan,Fu, Kang,Shi, Lei
supporting information, (2021/11/27)
A novel class of chiral spiro-fused bisoxazoline ligands possessing a deep chiral pocket was prepared. The developed ligands have been employed in the nickel-catalyzed highly enantioselective Michael-type Friedel-Crafts reaction, affording the products bearing a trifluoromethylated all-carbon quaternary stereocenter with moderate to excellent yields (up to 99%) and good to excellent enantioselectivies (up to > 99.9% ee). Moreover, a proposed model of chiral pocket revealed that the attack of indole from the Re-face of β-CF3-β-disubstituted nitroalkene was favorable.
Process Development of Tryptophan Hydroxylase Inhibitor LX1031, a Drug Candidate for the Treatment of Irritable Bowel Syndrome
Bednarz, Mark S.,Iimura, Shinya,Kanamarlapudi, Ramanaiah C.,Lim, Ngiap-Kie,Wu, Wenxue,Yan, Jie,Zhang, Haiming,Zhao, Matthew M.
, p. 261 - 273 (2020/03/10)
Two process routes for LX1031, a tryptophan hydroxylase inhibitor for the treatment of irritable bowel syndrome, were developed. They shared the same left-hand and right-hand starting materials as well as the penultimate intermediate. The chiral center in
C1-Symmetric PNP Ligands for Manganese-Catalyzed Enantioselective Hydrogenation of Ketones: Reaction Scope and Enantioinduction Model
Zeng, Liyao,Yang, Huaxin,Zhao, Menglong,Wen, Jialin,Tucker, James H. R.,Zhang, Xumu
, p. 13794 - 13799 (2020/11/30)
A family of ferrocene-based chiral PNP ligands is reported. These tridentate ligands were successfully applied in Mn-catalyzed asymmetric hydrogenation of ketones, giving high enantioselectivities (92%～99% ee for aryl alkyl ketones) as well as high efficiencies (TON up to 2000). In addition, dialkyl ketones could also be hydrogenated smoothly. Manganese intermediates that might be involved in the catalytic cycle were analyzed. DFT calculation was carried out to help understand the chiral induction model. The Mn/PNP catalyst could discriminate two groups with different steric properties by deformation of the phosphine moiety in the flexible 5-membered ring.
One-Pot Successive Turbo Grignard Reactions for the Facile Synthesis of α-Aryl-α-Trifluoromethyl Alcohols
Kani, Ryunosuke,Inuzuka, Toshiyasu,Kubota, Yasuhiro,Funabiki, Kazumasa
supporting information, p. 4487 - 4493 (2020/06/01)
A novel straightforward one-pot methodology for two successive turbo Grignard reagent (iPrMgCl·LiCl) reactions, was developed for a facile synthesis of α-aryl-α-trifluoromethyl alcohols, motifs of value in pharmaceutical chemistry. The method displayed broad functional group tolerance, including reducible groups. Dual roles of iPrMgCl·LiCl were exploited in the tandem reaction with commercially available iodoarenes or iodoheteroarenes and 2,2,2-trifluoroethyl trifluoroacetate. The process encompasses three successive reactions in a one-pot process: the iPrMgCl·LiCl-mediated iodine/magnesium-exchange reaction of iodoarenes or iodoheteroarenes; nucleophilic addition of various generated aryl or heteroarylmagnesium reagents to 2,2,2-trifluoroethyl trifluoroacetate; and the reduction of in-situ generated aryl trifluoromethyl ketones with iPrMgCl·LiCl, to produce the corresponding α-aryl or α-heteroaryl-α-trifluoromethyl alcohols bearing various substituents, including reducible functional groups in good to excellent yields.
A Hammett Study of Clostridium acetobutylicum Alcohol Dehydrogenase (CaADH): An Enzyme with Remarkable Substrate Promiscuity and Utility for Organic Synthesis
Berkowitz, David B.,Kudalkar, Gaurav P.,Lee, Joshua D.,Tiwari, Virendra K.
supporting information, p. 237 - 247 (2020/02/18)
Described is a physical organic study of the reduction of three sets of carbonyl compounds by the NADPH-dependent enzyme Clostridium acetobutylicum alcohol dehydrogenase (CaADH). Previous studies in our group have shown this enzyme to display broad substrate promiscuity, yet remarkable stereochemical fidelity, in the reduction of carbonyl compounds, including α-, β- and γ-keto esters (d -stereochemistry), as well as α,α-difluorinated-β-keto phosphonate esters (l -stereochemistry). To better mechanistically characterize this promising dehydrogenase enzyme, we report here the results of a Hammett linear free-energy relationship (LFER) study across three distinct classes of carbonyl substrates; namely aryl aldehydes, aryl β-keto esters and aryl trifluoromethyl ketones. Rates are measured by monitoring the decrease in NADPH fluorescence at 460 nm with time across a range of substrate concentrations for each member of each carbonyl compound class. The resulting v 0 versus [S] data are subjected to least-squares hyperbolic fitting to the Michaelis-Menton equation. Hammett plots of log(V max) versus σ X yield the following Hammett parameters: (i) for p -substituted aldehydes, ρ = 0.99 ± 0.10, ρ = 0.40 ± 0.09; two domains observed, (ii) for p -substituted β-keto esters ρ = 1.02 ± 0.31, and (iii) for p -substituted aryl trifluoromethyl ketones ρ = -0.97 ± 0.12. The positive sign of ρ indicated for the first two compound classes suggests that the hydride transfer from the nicotinamide cofactor is at least partially rate-limiting, whereas the negative sign of ρ for the aryl trifluoromethyl ketone class suggests that dehydration of the ketone hydrate may be rate-limiting for this compound class. Consistent with this notion, examination of the 13 C NMR spectra for the set of p -substituted aryl trifluo romethyl ketones in 2percent aqueous DMSO reveals significant formation of the hydrate (gem -diol) for this compound family, with compounds bearing the more electron-withdrawing groups showing greater degrees of hydration. This work also presents the first examples of the CaADH-mediated reduction of aryl trifluoromethyl ketones, and chiral HPLC analysis indicates that the parent compound α,α,α-trifluoroacetophenone is enzymatically reduced in 99percent ee and 95percent yield, providing the (S)-stereoisomer, suggesting yet another compound class for which this enzyme displays high enantioselectivity.
Asymmetric Hydrogenation of Aryl Perfluoroalkyl Ketones Catalyzed by Rhodium(III) Monohydride Complexes Bearing Josiphos Ligands
Brüning, Fabian,Nagae, Haruki,K?ch, Daniel,Mashima, Kazushi,Togni, Antonio
supporting information, p. 10818 - 10822 (2019/07/31)
The asymmetric hydrogenation of 2,2,2-trifluoroacetophenones and aryl perfluoroalkyl ketones was developed using a unique, well-defined chloride-bridged dinuclear rhodium(III) complex bearing Josiphos-type diphosphine ligands. These complexes were prepared from [RhCl(cod)]2, Josiphos ligands, and hydrochloric acid. As catalyst precursors, they allow for the efficient and enantioselective synthesis (up to 99 % ee) of chiral secondary alcohols with perfluoroalkyl groups. This system does not require an activating base for the hydrogenation of 2,2,2-trifluoroacetophenones. Additionally, the enantioselective C=O hydrogenations of 2-phenyl-3-(haloacetyl)-indoles, a class of privileged structures in medicinal chemistry, is reported for the first time.
Chemoenzymatic Synthesis of an Odanacatib Precursor through a Suzuki-Miyaura Cross-Coupling and Bioreduction Sequence
González-Martínez, Daniel,Gotor, Vicente,Gotor-Fernández, Vicente
, p. 5800 - 5807 (2019/11/05)
A series of 1-aryl-2,2,2-trifluoroethanones has been chemically synthesized to later study their bioreduction using stereocomplementary alcohol dehydrogenases (ADHs). Satisfyingly, (R)-alcohols were obtained in high conversions and selectivities using the ADH from Ralstonia species and the one from Rhodococcus ruber, while the (S)-enantiomers were independently produced using the ADH from Lactobacillus brevis and the commercially available evo-1.1.200. In the search for a stereoselective route towards the Odanacatib, an orally bioavailable and selective inhibitor of Cathepsin K, the development of a sequential methodology combining a palladium-catalyzed cross coupling between 1-(4-bromophenyl)-2,2,2-trifluoroethanone and 4-(methylsulfonyl)phenylboronic acid in aqueous medium with the bioreduction of the resulting 2,2,2-trifluoro-1-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)ethanone has been extensively studied. Finally, the desired (R)-2,2,2-trifluoro-1-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)ethanol was obtained in enantiomerically pure form and 85 % yield with a 128 g L?1 d?1 productivity following a sequential approach.
One-Pot and Reducible-Functional-Group-Tolerant Synthesis of α-Aryl- and α-Heteroaryl-α-Trifluoromethyl Alcohols via Tandem Trifluoroacetylation and MPV Type Reduction
Funabiki, Kazumasa,Hayakawa, Ayaka,Kani, Ryunosuke,Inuzuka, Toshiyasu,Kubota, Yashuhiro
, p. 5978 - 5984 (2019/08/30)
We have developed a new one-pot synthesis of α-aryl- and α-heteroaryl-α-trifluoromethyl alcohols carrying not only arenes with electron-withdrawing groups but also electron-deficient nitrogen-containing heteroarenes, which are of increasing interest becau
