- Pharmacological characterization of a new series of carbamoylguanidines reveals potent agonism at the H2R and D3R
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Even today, the role of the histamine H2 receptor (H2R) in the central nervous system (CNS) is widely unknown. In previous research, many dimeric, high-affinity and subtype-selective carbamoylguanidine-type ligands such as UR-NK22 (5, pKi = 8.07) were reported as H2R agonists. However, their applicability to the study of the H2R in the CNS is compromised by their molecular and pharmacokinetic properties, such as high molecular weight and, consequently, a limited bioavailability. To address the need for more drug-like H2R agonists with high affinity, we synthesized a series of monomeric (thio)carbamoylguanidine-type ligands containing various spacers and side-chain moieties. This structural simplification resulted in potent (partial) agonists (guinea pig right atrium, [35S]GTPγS and β-arrestin2 recruitment assays) with human (h) H2R affinities in the one-digit nanomolar range (pKi (139, UR-KAT523): 8.35; pKi (157, UR-MB-69): 8.69). Most of the compounds presented here exhibited an excellent selectivity profile towards the hH2R, e.g. 157 being at least 3800-fold selective within the histamine receptor family. The structural similarities of our monomeric ligands to pramipexole (6), a dopamine receptor agonist, suggested an investigation of the binding behavior at those receptors. The target compounds were (partial) agonists with moderate affinity at the hD2longR and agonists with high affinity at the hD3R (e.g. pKi (139, UR-KAT523): 7.80; pKi (157, UR-MB-69): 8.06). In summary, we developed a series of novel, more drug-like H2R and D3R agonists for the application in recombinant systems in which either the H2R or the D3R is solely expressed. Furthermore, our ligands are promising lead compounds in the development of selective H2R agonists for future in vivo studies or experiments utilizing primary tissue to unravel the role and function of the H2R in the CNS.
- Biselli, Sabrina,Bresinsky, Merlin,Buschauer, Armin,Forster, Lisa,Honisch, Claudia,Pockes, Steffen,Tropmann, Katharina,Bernhardt, Günther
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supporting information
(2021/02/12)
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- Photocatalyzed Triplet Sensitization of Oximes Using Visible Light Provides a Route to Nonclassical Beckmann Rearrangement Products
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Oximes are valuable synthetic intermediates for the preparation of a variety of functional groups. To date, the stereoselective synthesis of oximes remains a major challenge, as most current synthetic methods either provide mixtures of E and Z isomers or furnish the thermodynamically preferred E isomer. Herein we report a mild and general method to achieve Z isomers of aryl oximes by photoisomerization of oximes via visible-light-mediated energy transfer (EnT) catalysis. Facile access to (Z)-oximes provides opportunities to achieve regio- and chemoselectivity complementary to those of widely used transformations employing oxime starting materials. We show an enhanced one-pot protocol for photocatalyzed oxime isomerization and subsequent Beckmann rearrangement that enables novel reactivity with alkyl groups migrating preferentially over aryl groups, reversing the regioselectivity of the traditional Beckmann reaction. Chemodivergent N- or O- cyclizations of alkenyl oximes are also demonstrated, leading to nitrones or cyclic oxime ethers, respectively.
- Zhang, Xiao,Rovis, Tomislav
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supporting information
p. 21211 - 21217
(2021/12/27)
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- Copper-catalyzed synthesis of oxime ethers from iminoxy radical (C[dbnd]N–O[rad]) and maleimides via radical addition
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An efficient Cu(II)-catalyzed radical addition of maleimides has been achieved. The identified copper catalyst enables the formation of oxime radicals (N–O[rad]) by cleaving the O–H bond in ketoximes, followed by the radical addition to N-substituted male
- Han, Ziwei,Shen, Subo,Zheng, Feng,Hu, Han,Zhang, Jianmin,Zhu, Shizheng
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supporting information
(2019/09/30)
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- Copper-Catalyzed Unstrained C-C Single Bond Cleavage of Acyclic Oxime Acetates Using Air: An Internal Oxidant-Triggered Strategy toward Nitriles and Ketones
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A copper-catalyzed aerobic oxidative C-C single bond cleavage of acyclic unstrained oxime acetates is reported, providing various aryl nitriles and ketones in good yields. Mechanistic studies indicate a radical procedure is involved in this transformation, and the oxygen atom in the ketone products is originated from O2 in the air. Oxime acetates as an internal oxidant have been proved to be an initiator, which may promote the discovery of novel protocol for C-C bond cleavage and dioxygen activation.
- Zhu, Chuanle,Chen, Fulin,Liu, Chi,Zeng, Hao,Yang, Zhiyi,Wu, Wanqing,Jiang, Huanfeng
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p. 14713 - 14722
(2018/12/14)
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- Scope and mechanism of a true organocatalytic beckmann rearrangement with a boronic acid/perfluoropinacol system under ambient conditions
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Catalytic activation of hydroxyl functionalities is of great interest for the production of pharmaceuticals and commodity chemicals. Here, 2-alkoxycarbonyl- and 2-phenoxycarbonyl-phenylboronic acid were identified as efficient catalysts for the direct and chemoselective activation of oxime N-OH bonds in the Beckmann rearrangement. This classical organic reaction provides a unique approach to prepare functionalized amide products that may be difficult to access using traditional amide coupling between carboxylic acids and amines. Using only 5 mol % of boronic acid catalyst and perfluoropinacol as an additive in a polar solvent mixture, the operationally simple protocol features mild conditions, a broad substrate scope, and a high functional group tolerance. A wide variety of diaryl, aryl-alkyl, heteroaryl-alkyl, and dialkyl oximes react under ambient conditions to afford high yields of amide products. Free alcohols, amides, carboxyesters, and many other functionalities are compatible with the reaction conditions. Investigations of the catalytic cycle revealed a novel boron-induced oxime transesterification providing an acyl oxime intermediate involved in a fully catalytic nonself-propagating Beckmann rearrangement mechanism. The acyl oxime intermediate was prepared independently and was subjected to the reaction conditions. It was found to be self-sufficient; it reacts rapidly, unimolecularly without the need for free oxime. A series of control experiments and 18O labeling studies support a true catalytic pathway involving an ionic transition structure with an active and essential role for the boronyl moiety in both steps of transesterification and rearrangement. According to 11B NMR spectroscopic studies, the additive perfluoropinacol provides a transient, electrophilic boronic ester that is thought to serve as an internal Lewis acid to activate the ortho-carboxyester and accelerate the initial, rate-limiting step of transesterification between the precatalyst and the oxime substrate.
- Mo, Xiaobin,Morgan, Timothy D. R.,Ang, Hwee Ting,Hall, Dennis G.
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supporting information
p. 5264 - 5271
(2018/04/24)
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- Axial stereocontrol in: Tropos dibenz [c, e] azepines: The individual and cooperative effects of alkyl substituents
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6,7-Dihydro-5H-dibenz[c,e]azepines, a class of secondary amine incorporating a centre-axis chirality relay, can be prepared from N-(2-bromobenzyl)-N-(1-arylalkyl)methanesulfonamides via Pd-catalysed intramolecular direct arylation, and methylated at C(7)
- Balgobin, Sinead M. C.,Brookes, Dominic J.,Jiang, Junxiang,Pritchard, Robin G.,Wallace, Timothy W.
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supporting information
p. 10184 - 10199
(2017/12/26)
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- The fullerene dieno 3, 4 - dihydro pyrrole derivative and its preparation method
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The invention relates to a fullereno-3,4-dihydropyrrole derivative and a preparation method thereof. The compound has the structure as shown in the specification, wherein R1 is -Ar or -CH3; R2 is -H or -CH3; and R3 is -H, -CH3 or -Ph. The novel [60] fullereno-3,4-dihydropyrrole compound indicates that [60]fullerene exhibits uniqueness in structure and has specialty in reactivity which is deficient in general substances. As an important intermediate of fine chemical products, the product dihydropyrrole has wide application in the fields such as medicines, pesticides, coatings, daily chemicals and polymer materials.
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Paragraph 0052
(2017/10/31)
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- C-H Activation Induced by Oxidative Addition of N-O Bonds in Oxime Esters: Formation of Rhodacycles and Cycloaddition with Alkynes
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The reaction of oxime esters with a rhodium(I) precursor to form five-membered rhodacycles via N-O bond cleavage followed by C-H bond activation has been investigated by isolating these complexes. Kinetic studies on the formation of rhodacycles show that the reversible oxidative addition of the N-O bond in the oxime ester to RhCl(PPh3)3 occurs at room temperature. The E-isomer of the oxime ester was found to undergo rhodacycle formation faster than the Z-isomer, which suggests that the geometry of the oxime esters reflects the geometry of intermediates during C-H activation. The rhodacycle reacted with an alkyne to construct an isoquinoline ring in both stoichiometric and catalytic conditions, despite its basic stability in air, in moisture, and even during heating, which demonstrates the potential of the rhodacycle as an intermediate for further catalytic transformation of oxime esters.
- Shimbayashi, Takuya,Okamoto, Kazuhiro,Ohe, Kouichi
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supporting information
p. 2026 - 2031
(2016/07/06)
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- Rh(III)- and Zn(II)-Catalyzed Synthesis of Quinazoline N-Oxides via C-H Amidation-Cyclization of Oximes
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Quinazoline N-oxides have been prepared from simple ketoximes and 1,4,2-dioxazol-5-ones via Rh(III)-catalyzed C-H activation-amidation of the ketoximes and subsequent Zn(II)-catalyzed cyclization. The substrate scope and functional group compatibility were examined. The reaction features relay catalysis by Rh(III) and Zn(II).
- Wang, Qiang,Wang, Fen,Yang, Xifa,Zhou, Xukai,Li, Xingwei
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supporting information
p. 6144 - 6147
(2016/12/09)
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- Palladium-Catalyzed C-H Functionalization of Aromatic Oximes: A Strategy for the Synthesis of Isoquinolines
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An efficient strategy for synthesis of isoquinolines via Pd(II)-catalyzed cyclization reaction of oximes with vinyl azides or homocoupling of oximes is reported. Oximes could serve as a directing group and an internal oxidant in the transformation. This reaction features good functional group tolerance and provides a useful protocol for the synthesis of different kinds of isoquinolines under mild conditions. Some control experiments and 15N isotope labeling experiments were conducted for the mechanistic research. (Chemical Equation Presented).
- Zhu, Zhongzhi,Tang, Xiaodong,Li, Xianwei,Wu, Wanqing,Deng, Guohua,Jiang, Huanfeng
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p. 1401 - 1409
(2016/03/01)
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- Easy Access to 1-Amino and 1-Carbon Substituted Isoquinolines via Cobalt-Catalyzed C - H/N - O Bond Activation
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A green atom-economical method for the synthesis of highly functionalized 1-amino and 1-carbon substituted isoquinolines from the reaction of N′-hydroxybenzimidamides and aryl ketoximes, respectively, with alkynes via pentamethylcyclopentadienylcobalt(III)-catalyzed C - H/N - O bond activation is described. The external oxidant-free annulation reaction uses the =NOH moiety in N′-hydroxybenzimidamides or N-aromatic ketone oximes as the directing group and internal oxidant. This first row transition metal-catalyzed annulation serves as an efficient alternative for the synthesis of isoquinolines, as water is the only by-product and expensive noble metals such as rhodium(III), iridium(III), palladium(II), and ruthenium(II) are not required. The reaction proceeds via C - H activation, alkyne insertion, reductive elimination, and N - O activation.
- Muralirajan, Krishnamoorthy,Kuppusamy, Ramajayam,Prakash, Sekar,Cheng, Chien-Hong
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supporting information
p. 774 - 783
(2016/03/09)
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- Synthesis of Air- and Moisture-Stable, Storable Chiral Oxorhenium Complexes and Their Application as Catalysts for the Enantioselective Imine Reduction
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Air-/moisture-stable, crystalline, and storable chiral salicyloxazoline based oxorhenium(V) complexes have been synthesized and their catalytic application for the asymmetric reduction of ketimines using hydrosilane as hydride source is disclosed. A broad substrate scope, high yields, and excellent enantioselectivities (up to 99 %) are attained. Furthermore, the syntheses of enantiopure α-amino esters, γ- and δ-lactams, and isoindolinones have also been carried out using this methodology. Finally, the method has been applied to synthetic targets of pharmaceutical relevance, such as R-(+)-salsolidine and R-(+)-crispine A.
- Das, Braja Gopal,Nallagonda, Rajender,Dey, Dhananjay,Ghorai, Prasanta
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supporting information
p. 12601 - 12605
(2015/09/01)
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- APPLICATIONS OF N6-SUBSTITUTED ADENOSINE DERIVATIVE AND N6-SUBSTITUTED ADENINE DERIVATIVE TO CALMING, HYPNOSES, CONVULSION RESISTANCE, EPILEPTIC RESISTANCE, PARKINSON DISEASE RESISTANCE, AND DEMENTIA PREVENTION AND TREATMENT
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PROBLEM TO BE SOLVED: To prepare analgesics, hypnotic agents, anticonvulsant agents, antiepileptics, antiparkinson drugs, dementia prophylactics, and health care food. SOLUTION: The present invention relates to an N6-substituted adenosine derivative and an N6-substituted adenine derivative selected from the group consisting of specific compounds. The present invention also relates to a pharmaceutical composition at least comprising a therapeutically effective amount of the compounds and a pharmaceutically acceptable carrier. The invention further relates to the compounds used in preparation of analgesics, hypnotic agents, anticonvulsant agents, antiepileptics, antiparkinson drugs, dementia prophylactics, and health care food. COPYRIGHT: (C)2016,JPO&INPIT
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Paragraph 0184
(2018/10/27)
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- N6-SUBSTITUTED ADENOSINE DERIVATIVES AND N6-SUBSTITUTED ADENINE DERIVATIVES AND USES THEREOF
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The present invention provides N6-substituted adenosine derivatives and N6-substituted adenine derivatives, manufacturing methods thereof, a pharmaceutical composition comprising the said compounds above, and uses of these compounds in manufacturing medicaments and health-care products for treating insomnia, convulsion, epilepsy, and Parkinson's diseases, and preventing and treating dementia.
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Paragraph 0366
(2013/03/26)
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- N6-SUBSTITUTED ADENOSINE DERIVATIVES, N6-SUBSTITUTED ADENINE DERIVATIVES AND USES THEREOF
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The present invention provides N6-substituted adenosine derivatives and N6-substituted adenine derivatives, manufacturing methods thereof, a pharmaceutical composition comprising the said compounds above, and uses of of these compounds in manufacturing medicaments and health-care products for treating insomnia, convulsion, epilepsy, and Parkinson's diseases, and preventing and treating dementia.
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Page/Page column 89
(2012/11/06)
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- Synthesis of azaheterocycles from aryl ketone O-acetyl oximes and internal alkynes by Cu-Rh bimetallic relay catalysts
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A synthetic method for azaheterocycles from aryl ketone O-acetyl oximes and internal alkynes has been developed by using the Cu(OAc)2- [Cp*RhCl2]2 bimetallic catalytic system. The reactions proceeded with both of anti- and syn-isomers of oximes with a wide scope of substituents. The Cu-Rh bimetallic system could be applied for the synthesis of isoquinolines as well as β-carboline, furo[2.3-c]pyridine, pyrrolo[2,3-c]pyridine, and thieno[2,3-c]pyridine derivatives.
- Too, Pei Chui,Chua, Sze Hui,Wong, Siong Heng,Chiba, Shunsuke
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scheme or table
p. 6159 - 6168
(2011/10/04)
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- Regioselective synthesis of heterocycles containing nitrogen neighboring an aromatic ring by reductive ring expansion using diisobutylaluminum hydride and studies on the reaction mechanism
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(Chemical Equation Presented) A systematic investigation of the reductive ring-expansion reaction of cyclic ketoximes fused to aromatic ringswith diisobutylaluminum hydride (DIBALH) is described. This reaction regioselectively afforded a variety of five- to eight-membered bicyclic heterocycles or tricyclic heterocycles containing nitrogen neighboring an aromatic ring, including indoline, 1,2,3,4,5,6-hexahydrobenz[b]azocine, 3,4-dihydro-2H-benzo[b] [1,4]oxazine, 2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine, 1,2,3,4,5,6- hexahydroazepino[3,2-b]-indole, 2,3,4,5-tetrahydro-1H-benzothieno[2,3-b]azepine, 2,3,4,5-tetrahydro-1H-benzothieno[3,2-b]-azepine, 5,6-dihydrophenanthridine, and 5,6,11,12-tetrahydrodibenz[b, f]azocine. The reaction mechanism leading to the rearrangement was investigated on the basis of the restricted Becke three-parameter plus Lee-Yang-Parr (B3LYP) density functional theory (DFT) with the 6-31G (d) basis set. It was found that the reaction proceeds through a three-centered transition state via a stepwise mechanism because the potential energy curve along the intrinsic reaction coordinate (IRC) had twomaxima (saddle points; TS1 and TS2) and the partial phenonium cation intermediate C. In addition to cyclic ketoximes fused to aromatic rings, the reactions of various cyclic and acyclic ketoximeswere examined to investigate preference of migrating group. It was found that themore electron-rich group migrated preferentially to give the corresponding secondary amines.
- Cho, Hidetsura,Iwama, Yusuke,Sugimoto, Kenji,Mori, Seiji,Tokuyama, Hidetoshi
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scheme or table
p. 627 - 636
(2010/04/29)
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- A facile and practical synthesis of N-acetyl enamides
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(Chemical Equation Presented) A facile and practical method for the synthesis of N-acetyl α-arylenamides has been developed from corresponding ketoximes as the starting materials with ferrous acetate as the reducing reagent. This methodology offers mild reaction conditions, simple purification procedures, and high yields for a variety of N-acetyl enamides.
- Tang, Wenjun,Capacci, Andrew,Sarvestani, Max,Wei, Xudong,Yee, Nathan K.,Senanayake, Chris H.
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supporting information; body text
p. 9528 - 9530
(2010/03/24)
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- Palladium-catalyzed annulation of acyloximes with arynes (or alkynes): Synthesis of phenanthridines and isoquinolines
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(Chemical Equation Presented) Intermolecular insertion: A palladium-catalyzed domino aminopalladation/C-H functionalization sequence has been developed, and provides access to functionalized phenanthridines and isoquinolines (see scheme; Tf = triflate, TM
- Gerfaud, Thibaud,Neuville, Luc,Zhu, Jieping
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supporting information; experimental part
p. 572 - 577
(2009/04/14)
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- PREPARATION OF CHIRAL AMIDES AND AMINES
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This invention provides a convenient method for converting oximes into enamides. The process does not require the use of metallic reagents. Accordingly, it produces the desired compounds without the concomitant production of a large volume of metallic waste. The enamides are useful precursors to amides and amines. The invention provides a process to convert a prochiral enamide into the corresponding chiral amide. In an exemplary process, a chiral amino center is introduced during hydrogenation through the use of a chiral hydrogenation catalyst. In selected embodiments, the invention provides methods of preparing amides and amines that include the 1,2,3,4-tetrahydro-N-alkyl-1-naphthalenamine or 1,2,3,4-tetrahydro-1-naphthalenamine substructure.
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Page/Page column 23
(2009/06/27)
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- Enantioselective Strecker-type reaction of phosphinoyl ketimines catalyzed by a chiral Zr-bipyridyldiol catalyst
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An enantioselective Strecker reaction of N-diphenylphosphinoyl ketimines with TMSCN employing a chiral zirconium complex formed from chiral bipyridyl diol 1 as catalyst is described. The catalytic efficiency of chiral ligand 1 with other Lewis acids was also explored. Higher yields (50-85%) with moderate to good enantioselectivities (30-80%) were achieved for a variety of N-diphenylphosphinoyl ketimines.
- Chen, Yi-Jing,Chen, Chinpiao
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experimental part
p. 2201 - 2209
(2009/04/05)
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- Cyanuric chloride as a mild and active Beckmann rearrangement catalyst
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The first general organocatalytic Beckmann rearrangement of ketoximes into amides has been realized by the catalytic use of cyanuric chloride. Furthermore, acids such as HCl and ZnCl2 are effective as cocatalysts with cyanuric chloride. For example, azacyclotridecan-2-one, which is synthetically useful as a starting material for nylon-12, was prepared in quantitative yield by the Beckmann rearrangement of cyclododecanone oxime (100 mmol scale) catalyzed by cyanuric chloride (0.5 mol %) and ZnCl2 (1 mol %). Copyright
- Furuya, Yoshiro,Ishihara, Kazuaki,Yamamoto, Hisashi
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p. 11240 - 11241
(2007/10/03)
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