- Copper-Catalyzed Ullmann-Type Coupling and Decarboxylation Cascade of Arylhalides with Malonates to Access α-Aryl Esters
-
We have developed a high-efficiency and practical Cu-catalyzed cross-coupling to directly construct versatile α-aryl-esters by utilizing readily available aryl bromides (or chlorides) and malonates. These gram-scale approaches occur with turnovers of up to 1560 and are smoothly conducted by the usage of a low catalyst loading, a new available ligand, and a green solvent. A variety of functional groups are tolerated, and the application occurs with α-aryl-esters to access nonsteroidal anti-inflammatory drugs (NSAIDs) on the gram scale.
- Cheng, Fei,Chen, Tao,Huang, Yin-Qiu,Li, Jia-Wei,Zhou, Chen,Xiao, Xiao,Chen, Fen-Er
-
supporting information
p. 115 - 120
(2022/01/04)
-
- Iridium-Catalyzed Amidation of in Situ Prepared Silyl Ketene Acetals to Access α-Amino Esters
-
Disclosed herein is a convenient Ir-catalyzed amidation of esters to access α-amido esters. Initially prepared silyl ketene acetals are directly employed, without separate purification, for subsequent amidation with an oxycarbonylnitrenoid precursor using the Cp*(LX)Ir(III) catalyst. The α-amidation was facile for both α-aryl and α-alkyl esters. Density functional theory studies revealed that the generation of a putative Ir-nitrenoid is facilitated by the chelation of the countercation additive during the N-O bond cleavage of the nitrene precursor.
- Chang, Sukbok,Gwon, Yunyeong,Kim, Dongwook,Lee, Minhan
-
supporting information
p. 1088 - 1093
(2022/02/10)
-
- Preparation method of carboxylic ester compound
-
The invention relates to a preparation method of a carboxylic ester compound, which comprises the following steps: reacting carboxylic acid with methanol in air under the catalysis of nitrite to obtain an ester compound, the preparation method disclosed by the invention has the advantages of rich raw material sources, cheap and easily available catalyst, mild reaction conditions, simplicity and convenience in operation and the like, a series of fatty carboxylic acids can be modified with high yield, and particularly, the traditional esterification method is generally not suitable for esterification of drug molecules. By utilizing the method, a series of known drug molecules can be modified, so that a shortcut is provided for discovering new drug molecules.
- -
-
Paragraph 0066-0067
(2021/03/30)
-
- Green Esterification of Carboxylic Acids Promoted by tert-Butyl Nitrite
-
In this work, the green esterification of carboxylic acids promoted by tert-butyl nitrite has been well developed. This transformation is compatible with a broad range of substrates and exhibits excellent functional group tolerance. Various drugs and substituted amino acids are applicable to this reaction under near neutral conditions, with good to excellent yields.
- Cheng, Xionglve,Jiang, Gangzhong,Li, Xingxing,Tao, Suyan,Wan, Xiaobing,Zhao, Yanwei,Zheng, Yonggao
-
supporting information
p. 2713 - 2718
(2021/06/25)
-
- B(C6F5)3-catalyzed O-H insertion reactions of diazoalkanes with phosphinic acids
-
A highly efficient base-, metal-, and oxidant-free catalytic O-H insertion reaction of diazoalkanes and phosphinic acids in the presence of B(C6F5)3has been developed. This powerful methodology provides a green approach towards the synthesis of a broad spectrum of α-phosphoryloxy carbonyl compounds with good to excellent yields (up to 99% yield). The protocol features the advantages of operational simplicity, high atom economy, practicality, easy scalability and environmental friendliness.
- Jiang, Jun,Zhang, Xinzhi,Zhang, Yangyang,Zhao, Jincheng
-
supporting information
p. 5772 - 5776
(2021/07/12)
-
- Insertion of Diazo Esters into C-F Bonds toward Diastereoselective One-Carbon Elongation of Benzylic Fluorides: Unprecedented BF3Catalysis with C-F Bond Cleavage and Re-formation
-
Selective transformation of C-F bonds remains a significant goal in organic chemistry, but C-F insertion of a one-carbon-atom unit has never been established. Herein we report the BF3-catalyzed formal insertion of diazo esters as one-carbon-atom sources into C-F bonds to accomplish one-carbon elongation of benzylic fluorides. A DFT calculation study revealed that the BF3 catalyst could contribute to both C-F bond cleavage and re-formation. This elongation provided α-fluoro-α,β-diaryl esters with a high level of diastereoselectivity. Various benzylic fluorides and diazo esters were applicable. The synthetic utility of this method was demonstrated by the synthesis of a fluoro analogue of a compound that is used as a transient receptor and potential canonical channel inhibitor.
- Wang, Fei,Nishimoto, Yoshihiro,Yasuda, Makoto
-
supporting information
p. 20616 - 20621
(2021/11/23)
-
- Electrochemical oxidative: Z -selective C(sp2)-H chlorination of acrylamides
-
An electrochemical method for the oxidative Z-selective C(sp2)-H chlorination of acrylamides has been developed. This catalyst and organic oxidant free method is applicable across various substituted tertiary acrylamides, and provides access to a broad range of synthetically useful Z-β-chloroacrylamides in good yields (22 examples, 73% average yield). The orthogonal derivatization of the products was demonstrated through chemoselective transformations and the electrochemical process was performed on gram scale in flow.
- Coles, Simon J.,Hareram, Mishra Deepak,Harnedy, James,Morrill, Louis C.,Tizzard, Graham J.
-
supporting information
p. 12643 - 12646
(2021/12/07)
-
- Oxidation of Alkynyl Boronates to Carboxylic Acids, Esters, and Amides
-
A general efficient protocol was developed for the synthesis of carboxylic acids, esters, and amides through oxidation of alkynyl boronates, generated directly from terminal alkynes. This protocol represents the first example of C(sp)?B bond oxidation. This approach displays a broad substrate scope, including aryl and alkyl alkynes, and exhibits excellent functional group tolerance. Water, primary and secondary alcohols, and amines are suitable nucleophiles for this transformation. Notably, amino acids and peptides can be used as nucleophiles, providing an efficient method for the synthesis and modification of peptides. The practicability of this methodology was further highlighted by the preparation of pharmaceutical molecules.
- Li, Chenchen,Li, Ruoling,Zhang, Bing,Zhao, Pei,Zhao, Wanxiang
-
supporting information
p. 10913 - 10917
(2020/05/25)
-
- 3,3′-Disubstituted Oxindoles Formation via Copper-Catalyzed Arylboration and Arylsilylation of Alkenes
-
Arylboration and arylsilylation reactions of N-(2-iodoaryl)acrylamides with bis(pinacolato)-diboron (B2pin2) or PhMe2Si-Bpin are developed by using simple CuOAc as the sole catalyst. A range of boron-or silane-bearing 3,3′-disubstituted oxindoles are obtained in moderate to excellent yields. The reaction is proposed to proceed via a domino sequence involving intermolecular olefin borylcupration or silylcupration followed by intramolecular coupling of an alkyl-Cu intermediate with aryl iodide.
- Liang, Ren-Xiao,Chen, Ru-Yi,Zhong, Chao,Zhu, Jia-Wen,Cao, Zhong-Yan,Jia, Yi-Xia
-
supporting information
p. 3215 - 3218
(2020/04/10)
-
- Pd-Catalyzed Decarboxylative Olefination: Stereoselective Synthesis of Polysubstituted Butadienes and Macrocyclic P-glycoprotein Inhibitors
-
The efficient and stereoselective synthesis of polysubstituted butadienes, especially the multifunctional butadienes, represents a great challenge in organic synthesis. Herein, we wish to report a distinctive Pd(0) carbene-initiated decarboxylative olefination approach that enables the direct coupling of diazo esters with vinylethylene carbonates (VECs), vinyl oxazolidinones, or vinyl benzoxazinones to afford alcohol-, amine-, or aniline-containing 1,3-dienes in moderate to high yields and with excellent stereoselectivity. This protocol features operational simplicity, mild reaction conditions, a broad substrate scope, and gram-scalability. Notably, a structurally unique allylic Pd(II) intermediate was isolated and characterized. DFT calculation and control experiments demonstrated that a rare Pd(0) carbene intermediate could be involved in this reaction. Moreover, the polysubstituted butadienes as novel building blocks were unprecedentedly assembled into macrocycles, which efficiently inhibited the P-glycoprotein and dramatically reversed multidrug resistance in cancer cells by 190-fold.
- Chen, Xiangyang,Hao, Jiping,Houk, K. N.,Li, Yingzi,Lou, Liguang,Quan, Haitian,Song, Bichao,Wang, Lu,Xia, Yuanzhi,Xie, Peipei,Xu, Zhongliang,Yang, Weibo
-
supporting information
p. 9982 - 9992
(2020/06/27)
-
- Palladium-catalyzed intermolecular C-H silylation initiated by aminopalladation
-
A Pd(ii)-catalyzed intermolecular C-H silylation reaction initiated by aminopalladation has been developed. The C-H bonds were activated by an alkyl Pd(ii) species generated through aminopalladation and then disilylated with hexamethyldisilane to form disilylated indolines as the final products. The reaction provides a new method for the introduction of silyl groups into complex organic molecules.
- Ji, Xiaoming,Wei, Feng,Wan, Bin,Cheng, Cang,Zhang, Yanghui
-
supporting information
p. 7801 - 7804
(2020/07/27)
-
- Generation of Carbocations under Photoredox Catalysis: Electrophilic Aromatic Substitution with 1-Fluoroalkylbenzyl Bromides
-
A novel Friedel-Crafts-type alkylation of arenes to access valuable 1-fluoroalkyl-1,1-biaryl compounds is established under mild conditions. The key to success is the efficient generation of a destabilized benzylic carbocation intermediate via two consecutive single-electron transfer processes by virtue of visible-light photoredox catalysis. This unique activation pattern avoids using strong Lewis acids and high temperatures that are required for generation of destabilized carbocations in traditional Friedel-Crafts reactions. This protocol demonstrates the first example of photoredox-catalyzed heterolysis of electronically deactivated benzylic C-Br bonds for the formation of destabilized carbocation intermediates.
- Gu, Yucheng,Hu, Jinbo,Kuang, Cuiwen,Ni, Chuanfa,Xie, Qiqiang,Zhou, Xin
-
supporting information
(2020/11/13)
-
- A process for preparing halogenated biphenyl (by machine translation)
-
A process for preparing halogenated biphenyl compound of the method, it is in order to aryl borate and aryl silane reagent as a raw material, 1, 1, 2 - trichloroethane as solvent, oxygenated esters of acetic acid as the oxidizing agent, paratoluene sulfonic acid silver as silver salts. In 110 °C lower, N - (diphenyl phosphate alkyl) - N - isopropyl - 1, 1 - diphenyl phosphine amine [...] 1 a catalytic cross-coupling, and efficient synthesis of aryl compounds of the halogenating is joint method. (by machine translation)
- -
-
Paragraph 0078-0080
(2019/05/08)
-
- METHOD FOR THE METAL-FREE PREPARATION OF A BIARYL BY A PHOTOSPLICING REACTION AND THEIR USES
-
The present invention relates to a method for the metal-free preparation of a biaryl compound by a photosplicing reaction and its use in the preparation of chemical compounds, preferably of active ingredients e.g. in the fields of pharmaceuticals and agrochemicals. In particular, it refers to a method for the regiocontrolled preparation of a biaryl compound of formula (I): Ar-Ar' by photochemically reacting a precursor compound of formula (II): Ar-L-Ar' to form a biaryl compound of general formula: Ar-L-Ar' (II) → Ar-Ar' (I) wherein Ar and Ar', independently of each other, represent an unsubstituted or substituted C6-C20 aryl group or a heteroaryl group with 5–20 ring atoms selected from carbon, nitrogen, oxygen and sulfur, and L represents a group –X–Y–Z– as defined herein. The biaryl compounds are generally suitable as intermediates or key building blocks in a very broad spectrum of organic chemical syntheses and their respective utilities. Their use within the field of synthesis of active ingredients is an aspect of the invention, and their use in the preparation of pharmaceutically active ingredients is particularly preferred.
- -
-
Page/Page column 39; 51; 52; 53
(2019/06/11)
-
- Copper-Catalyzed and Indium-Mediated Methoxycarbonylation of Unactivated Alkyl Iodides with Balloon CO
-
This work emphasizes the synthesis of alkyl esters via Cu-catalyzed and In-mediated alkoxycarbonylation of unactivated alkyl iodides in the presence of In or InI. The reactions were suitable for the preparation of primary, secondary, and even tertiary alkyl esters, representing an exceptionally rare example for the creation of quaternary carbon centers upon formation of esters. The preliminary mechanistic studies indicated that alkyl radicals were involved, and Cu/In/CO played a cooperative role in the carbonylation event.
- Chen, Yanchi,Su, Lei,Gong, Hegui
-
supporting information
p. 4689 - 4693
(2019/06/27)
-
- Hydroximoyl fluorides as the precursors of nitrile oxides: Synthesis, stability and [3 + 2]-cycloaddition with alkynes
-
The transformation of hydroximoyl fluorides to nitrile oxides for [3 + 2]-cycloaddition with alkynes has been achieved for the first time. The hydroximoyl fluorides used in this work appeared to be not stable, which was proved by a series of experiments. A DFT calculation was performed to better understand the properties of hydroximoyl fluorides. Although not stable, the hydroximoyl fluorides could be successfully converted to the corresponding nitrile oxides for in situ [3 + 2]-cycloaddition with alkynes to yield the isoxazoles. Furthermore, it was feasible to conduct [3 + 2]-cycloaddition reaction without purification after the synthesis of hydroximoyl fluorides from gem-difluoroalkenes. By investigating a class of interesting yet previously rarely explored fluorinated compounds, this work sheds new light on the stability and reactivity of a C-F bond on a CN double bond.
- Gao, Feng-Teng,Fang, Zheng,Su, Rui-Rui,Rui, Pei-Xin,Hu, Xiang-Guo
-
p. 9211 - 9217
(2019/01/03)
-
- Metal-Free Synthesis of Pharmaceutically Important Biaryls by Photosplicing
-
Many pharmaceuticals feature biaryl motifs that are crucial for their binding to the target. Yet, benchmark methods for selective cross-couplings rely on highly toxic heavy metal catalysts, which are unfavorable in the synthesis of pharmaceuticals. Metal-free coupling reactions, on the other hand, may require harsh conditions and lack selectivity. We report a novel, metal-free cross-coupling reaction that involves the tethering of two phenyl groups by a temporary, traceless sulfonamide linker that directs a photochemical aryl fusion into a single coupling product. The perfect regio- and chemoselectivity of the reaction could be rationalized by a cyclic intermediate, which fragments into the biaryl and volatile side products. Using a flow reactor, we synthesized numerous substituted biaryl building blocks for important therapeutics in high yields, such as antibiotics, antitumor, neuroprotective and cholesterol-lowering agents as well as antiarthritic non-steroidal antiinflammatory drugs (NSAIDs). The new method was successfully employed in a total synthesis of cannabinol, an important analgesic and antiemetic therapeutic. We also report a metal-free synthesis of key building blocks used for the preparation of sartans, antihypertensive agents that rank among the top blockbuster drugs worldwide. This safe and convenient protocol is a valuable alternative for the widely used metal-dependent aryl cross-coupling methods.
- Kloss, Florian,Neuwirth, Toni,Haensch, Veit G.,Hertweck, Christian
-
supporting information
p. 14476 - 14481
(2018/09/06)
-
- Palladium-Catalyzed Carbonylative Direct Transformation of Benzyl Amines under Additive-Free Conditions
-
In this communication, we developed a new procedure for the direct carbonylative transformation of benzyl amines. Using dimethyl carbonate as the solvent, methyl 2-arylacetates can be produced in good to excellent yields from the corresponding primary, secondary, and tertiary benzyl amines with palladium as the catalyst. Notably, no base or any other additive is required here. In addition, our procedure can also be applied in the preparation of methylphenidate, which is a marketing drug and used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.
- Li, Yahui,Wang, Zechao,Wu, Xiao-Feng
-
p. 738 - 741
(2018/01/17)
-
- Palladium-Catalyzed C?H Silylation through Palladacycles Generated from Aryl Halides
-
A highly efficient palladium-catalyzed disilylation reaction of aryl halides through C?H activation has been developed for the first time. The reaction has broad substrate scope. A variety of aryl halides can be disilylated by three types of C?H activation, including C(sp2)?H, C(sp3)?H, and remote C?H activation. In particular, the reactions are also unusually efficient. The yields are essentially quantitative in many cases, even in the presence of less than 1 mol % catalyst and 1 equivalent of the silylating reagent under relatively mild conditions. The disilylated biphenyls can be converted into disiloxane-bridged biphenyls.
- Lu, Ailan,Ji, Xiaoming,Zhou, Bo,Wu, Zhuo,Zhang, Yanghui
-
supporting information
p. 3233 - 3237
(2018/02/23)
-
- Macrolide Synthesis through Intramolecular Oxidative Cross-Coupling of Alkenes
-
A RhIII-catalyzed intramolecular oxidative cross-coupling between double bonds for the synthesis of macrolides is described. Under the optimized reaction conditions, macrocycles containing a diene moiety can be formed in reasonable yields and with excellent chemo- and stereoselectivity. This method provides an efficient approach to synthesize macrocyclic compounds containing a 1,3-conjugated diene structure.
- Jiang, Bing,Zhao, Meng,Li, Shu-Sen,Xu, Yun-He,Loh, Teck-Peng
-
supporting information
p. 555 - 559
(2018/02/21)
-
- Synergistic Catalysis for the Umpolung Trifluoromethylthiolation of Tertiary Ethers
-
The first transition-metal-free, site-specific umpolung trifluoromethylthiolation of tertiary alkyl ethers has been developed, achieving the challenging tertiary C(sp3)–SCF3 coupling under redox-neutral conditions. The synergism of organophotocatalyst 4CzIPN and BINOL-based phosphorothiols can site-selectively cleave tertiary sp3 C(sp3)–O ether bonds in complex molecules initiated by a polarity-matching hydrogen-atom-transfer (HAT) event. The incorporation of several competing benzylic and methine C(sp3)?H bonds in alkyl ethers has little influence on the regioselectivity. Selective difluoromethylthiolation of C?O bonds has also been achieved. This represents not only an important step forward in trifluoromethylthiolation but also a promising means for site-selective C?O bond functionalization of unsymmetrical tertiary alkyl ethers.
- Xu, Wentao,Ma, Junyang,Yuan, Xiang-Ai,Dai, Jie,Xie, Jin,Zhu, Chengjian
-
supporting information
p. 10357 - 10361
(2018/08/06)
-
- Preparation and purification methods of 4-biphenylacetic acid
-
The invention relates to the field of production preparation of compounds, in particular to preparation and purification methods of 4-biphenylacetic acid. The preparation and purification methods comprise steps as follows: 1) biphenyl is subjected to a chloromethylation reaction to produce 4-phenyl benzyl chloride; 2) 4-phenyl benzyl chloride reacts with sodium cyanide to produce 4-biphenyl acetonitrile; 3) 4-biphenyl acetonitrile is hydrolyzed and a crude 4-bphenylacetic acid product is obtained; 4) the crude 4-bphenylacetic acid product and methanol are subjected to an esterification reaction to produce 4-biphenyl methyl acetate, 4-biphenyl methyl acetate is purified and hydrolyzed into 4-biohenylacetic acid, 4-bihenylacetic acid is refined, and a finished product is prepared.
- -
-
Paragraph 0063; 0068; 0075; 0082
(2017/04/03)
-
- Water as a Hydride Source in Palladium-Catalyzed Enantioselective Reductive Heck Reactions
-
Pd-catalyzed intramolecular asymmetric carbopalladation of N-aryl acrylamides followed by reduction of C(sp3)-Pd intermediate using diboron–water as a hydride source afforded enantioenriched 3,3-disubstituted oxindoles in high yields and enantioselectivities. When heavy water was used as a deuterium donor in combination with bis(catecholato)diboron (Cat2B2), deuterium was incorporated into the products with high synthetic efficiency. The ligand determined both the enantioselectivity of the reaction and the reaction pathways, thereby affording either hydroarylation (reductive Heck) or carboborylation products.
- Kong, Wangqing,Wang, Qian,Zhu, Jieping
-
supporting information
p. 3987 - 3991
(2017/03/27)
-
- An approach to spirooxindoles: Via palladium-catalyzed remote C-H activation and dual alkylation with CH2Br2
-
A facile and efficient approach for the synthesis of spirooxindoles has been developed via the coupling of spirocyclic C,C-palladacycles with CH2Br2. The key spirocyclic palladacycles are generated catalytically via remote C-H activation. A range of spirooxindoles can be synthesized in good to excellent yields from readily available starting material.
- Shao, Changdong,Wu, Zhuo,Ji, Xiaoming,Zhou, Bo,Zhang, Yanghui
-
supporting information
p. 10429 - 10432
(2017/09/25)
-
- Therapeutic methods and compounds
-
The invention provides diketopiperazines of formula I. The invention also provides pharmaceutical compositions comprising the diketopiperazines, or pharmaceutically-acceptable salts or prodrugs thereof, as the active ingredient. The invention further prov
- -
-
Page/Page column 21
(2017/01/05)
-
- USE OF TETRAHYDROPYRIDINES IN THE TREATMENT OF SODIUM CHANNEL RELATED DISEASE AND DISORDERS
-
The present invention provides a method of treating one or more sodium channel related diseases or disorders in an individual, including related symptoms. The method comprises administering to the individual a tetrahydropyridine derivative in an amount effective to treat sodium channel related diseases or disorders in individuals. These compounds are generally categorised as Ritalin related compounds. The present invention also provides compounds for use in the treatment of and also for use in the manufacture of a medicament for the treatment of sodium channel related diseases or disorders in an individual. A method is further provided for the preparation and isolation of the derivatives of the compound of the present invention.
- -
-
Page/Page column 12
(2016/06/28)
-
- Tandem Chemoselective Suzuki-Miyaura Cross-Coupling Enabled by Nucleophile Speciation Control
-
Control of boronic acid speciation is presented as a strategy to achieve nucleophile chemoselectivity in the Suzuki-Miyaura reaction. Combined with simultaneous control of oxidative addition and transmetalation, this enables chemoselective formation of two C-C bonds in a single operation, providing a method for the rapid preparation of highly functionalized carbogenic frameworks.
- Seath, Ciaran P.,Fyfe, James W. B.,Molloy, John J.,Watson, Allan J. B.
-
p. 9976 - 9979
(2015/08/19)
-
- Visible-Light-Induced Meerwein Cascade Reactions for the Preparation of α-Aryl Esters
-
A practical strategy has been developed for preparation of α-aryl ester derivatives by using a visible-light-induced Meerwein cascade reaction. This method uses molecular oxygen as an oxidant at room temperature without the need of hazardous reagents or harsh reaction conditions and provides a straightforward approach to pharmaceutically and synthetically useful α-aryl esters in moderate to good yields from simple and readily available starting materials. Oxindoles were also prepared by this protocol. A new strategy for the synthesis of α-aryl esters has been reported. This protocol utilizes acrylonitrile as a "bridge molecule" to combine a visible-light-induced Meerwein reaction and a hydrolysis reaction to generate α-aryl esters. This method was also employed for the preparation of oxindoles.
- Niu, Teng-Fei,Li, Liang,Ni, Bang-Qing,Bu, Mei-Jie,Cai, Chun,Jiang, Hui-Liang
-
p. 5775 - 5780
(2015/09/15)
-
- Safe palladium-catalyzed cross-couplings with microwave heating using continuous-flow silicon carbide reactors
-
Herein we present a 200 mm × 3 mm i silicon carbide (SiC) tube reactor for use in a commercially available microwave heated continuous-flow system. The SiC flow reactor enables palladium(0)-catalyzed reactions that, due to precipitation and subsequent hot spot formation, often followed by reactor failure, are unsuitable to conduct in standard microwave-transparent borosilicate glass reactors. We report continuous-flow protocols for the Mizoroki-Heck reaction (10 examples, 81-86% yield) as well as the Suzuki-Miyaura cross-coupling (14 examples, 70-87% yield), showing the utility of the SiC reactor. Furthermore, we performed a scale-out of the NSAID biphenylacetic acid, achieving outputs of 14 mmol/h of the Suzuki-Miyaura reaction, and a 72% overall yield over three steps. The SiC reactor enabled fast and efficient temperature control, high robustness, and easy maintenance.
- Konda, Vivek,Rydfjord, Jonas,S?vmarker, Jonas,Larhed, Mats
-
p. 1413 - 1418
(2015/02/19)
-
- The ketene-surrogate coupling: Catalytic conversion of aryl iodides into aryl ketenes through ynol ethers
-
tert-Butoxyacetylene is shown to undergo Sonogashira coupling with aryl iodides to yield aryl-substituted tert-butyl ynol ethers. These intermediates participate in a [1,5]-hydride shift, which results in the extrusion of isobutylene and the generation of aryl ketenes. The ketenes are trapped in situ with multiple nucleophiles or undergo electrocyclic ring closure to yield hydroxynaphthalenes and quinolines.
- Zhang, Wenhan,Ready, Joseph M.
-
supporting information
p. 8980 - 8984
(2014/11/07)
-
- Discovery of biphenylacetamide-derived inhibitors of BACE1 using de novo structure-based molecular design
-
β-Secretase (BACE1), the enzyme responsible for the first and rate-limiting step in the production of amyloid-β peptides, is an attractive target for the treatment of Alzheimer's disease. In this study, we report the application of the de novo fragment-based molecular design program SPROUT to the discovery of a series of nonpeptide BACE1 inhibitors based upon a biphenylacetamide scaffold. The binding affinity of molecules based upon this designed molecular scaffold was increased from an initial BACE1 IC50 of 323 μM to 27 μM following the synthesis of a library of optimized ligands whose structures were refined using the recently developed SPROUT-HitOpt software. Although a number of inhibitors were found to exhibit cellular toxicity, one compound in the series was found to have useful BACE1 inhibitory activity in a cellular assay with minimal cellular toxicity. This work demonstrates the power of an in silico fragment-based molecular design approach in the discovery of novel BACE1 inhibitors.
- Mok, N. Yi,Chadwick, James,Kellett, Katherine A. B.,Casas-Arce, Eva,Hooper, Nigel M.,Johnson, A. Peter,Fishwick, Colin W. G.
-
supporting information
p. 1843 - 1852
(2013/05/08)
-
- A fluorous Mukaiyama coupling reagent for a concise condensation reaction: Utility of medium-fluorous strategy
-
The entire study of condensation reactions using various fluorous Mukaiyama reagents, including a novel medium-fluorous strategy, is described. A Mukaiyama reagent bearing a medium-fluorous content tag, between 40 and 60% fluorine by weight, was prepared and examined in ester and amide-forming condensation reactions. At the end of the reactions, the fluorous pyridone by-product was effectively separated from non-fluorous components by increasing the water content of the crude reaction mixture and subsequent filtration of the precipitate. It is also shown that Mukaiyama reagents bearing a fluorous tag increase the reaction rate considerably when compared to their non-fluorous tagged counterpart. Interestingly, it was observed that the longer the fluorous chain, the higher the activity of the Mukaiyama reagent.
- Sugiyama, Yuya,Kurata, Yuki,Kunda, Yoko,Miyazaki, Atsushi,Matsui, Junko,Nakamura, Shuichi,Hamamoto, Hiromi,Shioiri, Takayuki,Matsugi, Masato
-
scheme or table
p. 3885 - 3892
(2012/07/02)
-
- Structure-activity relationship of a new series of reversible dual monoacylglycerol lipase/fatty acid amide hydrolase inhibitors
-
The two endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), play independent and nonredundant roles in the body. This makes the development of both selective and dual inhibitors of their inactivation an important priority. In this work we report a new series of inhibitors of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Among them, (±)-oxiran-2-ylmethyl 6-(1,1′-biphenyl-4-yl)hexanoate (8) and (2R)-(-)-oxiran-2-ylmethyl(4-benzylphenyl)acetate (30) stand out as potent inhibitors of human recombinant MAGL (IC50 (8) = 4.1 μM; IC 50 (30) = 2.4 μM), rat brain monoacylglycerol hydrolysis (IC 50 (8) = 1.8 μM; IC50 (30) = 0.68 μM), and rat brain FAAH (IC50 (8) = 5.1 μM; IC50 (30) = 0.29 μM). Importantly, and in contrast to the other previously described MAGL inhibitors, these compounds behave as reversible inhibitors either of competitive (8) or noncompetitive nature (30). Hence, they could be useful to explore the therapeutic potential of reversible MAGL inhibitors.
- Cisneros, José A.,Bj?rklund, Emmelie,González-Gil, Inés,Hu, Yanling,Canales, ángeles,Medrano, Francisco J.,Romero, Antonio,Ortega-Gutiérrez, Silvia,Fowler, Christopher J.,López-Rodríguez, María L.
-
supporting information; experimental part
p. 824 - 836
(2012/04/10)
-
- Palladium-catalyzed asymmetric synthesis of 2-pyrrolidinones with a quaternary carbon stereocenter
-
A palladium-catalyzed asymmetric synthesis of 2-pyrrolidinones with a quaternary stereocenter at the 3-position has been achieved by the reaction of γ-methylidene-δ-valerolactones with alkyl isocyanates. High enantioselectivity has been realized by employing a newly synthesized chiral phosphoramidite ligand. The Royal Society of Chemistry 2012.
- Shintani, Ryo,Ito, Tomoaki,Nagamoto, Midori,Otomo, Haruka,Hayashi, Tamio
-
supporting information
p. 9936 - 9938
(2012/10/29)
-
- CYCLOPROPYL DERIVATIVES AND METHODS OF USE
-
The disclosure relates to cyclopropyl derivatives and methods of use. In some embodiments, the disclosure relates to methods of managing medical disorders with pharmaceutical compositions disclosed herein administered to subject in need thereof. In certain embodiments, the disclosure relates to methods of managing mental disorders, mood disorders, pain, and fibromyalgia and related conditions with pharmaceutical compositions disclosed herein.
- -
-
Page/Page column 29
(2012/11/07)
-
- A Simple, efficient, green, cost effective and chemoselective process for the esterification of carboxylic acids
-
Carboxylic acids have been esterified under mild and solvent-free conditions in high yield and purity using the green reagents, dimethyl carbonate and diethyl carbonate, under acid catalysis. The present methodology is free of the disadvantages of base catalysis described earlier, such as high temperatures, use of autoclaves, use of the expensive DBU as base in stoichiometric amounts and the carbonate as solvent. High chemoselectivity is observed in the case of hydroxybenzoic acids.
- Rekha,Ramani, Modukuri V.,Ratnamala,Rupakalpana, Vempati,Subbaraju, Gottumukkala V.,Satyanarayana, Chava,Rao, C. Someswara
-
experimental part
p. 769 - 773
(2010/04/22)
-
- Very fast Suzuki-Miyaura reaction catalyzed by Pd(OAc)2 under aerobic conditions at room temperature in EGME/H2O
-
The results of a ligand-free Pd(OAc)2-catalyzed Suzuki-Miyaura C-C coupling performed at room temperature under aerobic conditions are presented. It was found that the use of an ethylene glycol monomethyl ether/H2O mixture as the solvent resulted in very rapid reactions of aryl bromides with arylboronic acids. As a matter of fact, under optimized conditions, some substrates were converted quantitatively in less than 1 min with exceptionally high TOF values. For example, the reaction between 4-methoxyphenylboronic acid and bromobenzene afforded 4-methoxybiphenyl in 30 s with TOF = 180000 h-1. Furthermore, the reaction tolerates a wide range of functional groups and can be successfully applied to heteroaryl bromides such as 2-bromopyridine and 5-bromopyrimidine. Interestingly, also an activated aryl chloride such as 1-chloro-4-nitrobenzene reacted quantitatively with phenylboronic acid at 373 K. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.
- Del Zotto, Alessandro,Amoroso, Francesco,Baratta, Walter,Rigo, Pierluigi
-
experimental part
p. 110 - 116
(2009/06/28)
-
- Synthesis, biological evaluation, and molecular docking of Ugi products containing a zinc-chelating moiety as novel inhibitors of histone deacetylases
-
HDAC inhibitors show great promise for the treatment of cancer. As part of a broader effort to explore the SAR of HDAC inhibitors, synthesis, biological evaluation, and molecular docking of novel Ugi products containing a zinc-chelating moiety are presented. One compound shows improved inhibitory potencies compared to SAHA, demonstrating that hindered lipophilic residues grafted on the peptide scaffold of the α-aminoacylamides can be favorable in the interaction with the enzyme.
- Grolla, Ambra A.,Podestà, Valeria,Chini, Maria Giovanna,Di Micco, Simone,Vallario, Antonella,Genazzani, Armando A.,Canonico, Pier Luigi,Bifulco, Giuseppe,Tron, Gian Cesare,Sorba, Giovanni,Pirali, Tracey
-
experimental part
p. 2776 - 2785
(2010/02/28)
-
- Design, synthesis, and structure-affinity relationships of novel series of sialosides as CD22-specific inhibitors
-
Sialosides incorporating substituted amides or amines at 9-position of sialic acid moiety have been synthesized and evaluated as CD22 inhibitors. Several derivatives exhibited inhibitory potency in sub- to low micromolar range (e. g., 80, 9d, 9g, and 9k s
- Abdu-Allah, Hajjaj H. M.,Tamanaka, Taichi,Yu, Jie,Zhuoyuan, Lu,Sadagopan, Magesh,Adachi, Takahiro,Tsubata, Takeshi,Kelm, Soerge,Ishida, Hideharu,Kiso, Makoto
-
body text
p. 6665 - 6681
(2009/11/30)
-
- Ultrafast UV-Vis and IR studies of p-biphenylyl acetyl and carbomethoxy carbenes
-
The photochemistry of a p-biphenylyl diazo ester (BpCN2CO 2CH3) and diazo ketone (BpCN2COCH3) were studied by ultrafast time-resolved UV-vis and IR spectroscopies. The excited states of these diazo compounds were detected and found to decay with lifetimes of less than 300 fs. The diazo ester produces singlet carbene with greater quantum efficiency than the ketone analogue due to competing Wolff rearrangement (WR) in the excited state of the diazo ketone. Carbene BpCCO 2CH3 has a singlet-triplet gap that is close to zero in cyclohexane, but the triplet is the ground state. The two spin states are in rapid equilibrium in this solvent relative to reaction with cyclohexane. There is (for a carbene) a slow rate of singlet to triplet intersystem crossing (isc) in this solvent because the orthogonal singlet must rotate to a higher energy orientation prior to isc. In acetonitrile and in dichloromethane BpCCO 2CH3 has a singlet ground state. Ketocarbene BpCCOCH 3 has a singlet ground state in cyclohexane, in dichloromethane, and in acetonitrile and decays by WR to form a ketene detected by ultrafast IR spectroscopy in these solvents. Ketocarbenes have more stable singlet states, relative to carbene esters, because of the superior conjugation of the filled hybrid orbital of the carbene with the π system of the carbonyl group, the same factor that makes methyl ketones more acidic than the analogous esters. The rate of WR of BpCCOCH3 is faster in cyclohexane than in dichloromethane and acetonitrile because of intimate solute-solvent interactions between the empty p orbital of the carbene and nonbonding electron pairs of heteroatoms of the solvent. These interactions stabilize the carbene and retard the rate of WR.
- Wang, Jin,Burdzinski, Gotard,Kubicki, Jacek,Platz, Matthew S.
-
experimental part
p. 11195 - 11209
(2009/02/05)
-
- Oxidative rearrangements of arylalkanones with 1H-1-hydroxy-5-methyl-1,2,3-benziodoxathiole 3,3-dioxide, a 'green' analog of Koser's reagent
-
Previous methods for the conversion of arylalkanones to alkyl 2-arylesters by oxidative rearrangement utilized reagents which either produced toxic metal salts or halogenated organics as by-products. In this report, 1H-1-hydroxy-5-methyl-1,2,3-benziodoxathiole 3,3-dioxide (HMBI) is used to effect this useful transformation, where the reduced iodine reagent is water-soluble and readily recycled.
- Justik, Michael W.
-
p. 3003 - 3007
(2008/02/06)
-
- An improved chemo-enzymatic synthesis of 1-β-O-acyl glucuronides: Highly chemoselective enzymatic removal of protecting groups from corresponding methyl acetyl derivatives
-
(Chemical Equation Presented) An improved and widely applicable chemo-enzymatic method for the synthesis of a series of 1-β-O-acyl glucuronides 5a-f has been developed from the corresponding methyl acetyl derivatives 3a-f, which were stereospecifically synthesized from cesium salts of carboxylic acids 1a-f and methyl 2,3,4-tri-O-acetyl-1-bromo-1-deoxy-α-D- glucopyranuronate (2). Chemoselectivity of lipase AS Amano (LAS) in the hydrolytic removal of O-acetyl groups of 3a-f to provide methyl esters 4a-f was influenced by the nature of their 1-β-O-acyl groups; high selectivity was evident only for 3b and 3f. Carboxylesterase from Streptomyces rochei (CSR), newly screened as an alternative to LAS, showed much greater chemoselectivity toward the O-acetyl groups than LAS; 3a, 3d, and 3e were chemoselectively hydrolyzed only by CSR. The combination of CSR with LAS yielded better results in the hydrolysis of 3c and 3f than did single usage of CSR. Final deprotection of the methyl ester groups of 4a-f to provide 5a-f was chemoselectively achieved by using lipase from Candida antarctica type B (CAL-B) as well as esterase from porcine liver (PLE), although CAL-B possessed higher chemoselectivity and catalytic efficiency than did PLE. CSR also exhibited high chemoselectivity in the synthesis of (S)-naproxen 1-β-O-acyl glucopyranoside (7) from its 2,3,4,6-tetra-O-acetyl derivative 6.
- Baba, Akiko,Yoshioka, Tadao
-
p. 9541 - 9549
(2008/03/27)
-
- Preparation and condensation reactions of a new light-fluorous Mukaiyama reagent: reliable purification with fluorous solid phase extraction for esters and amides
-
A modified light-fluorous Mukaiyama reagent bearing a C8F17 tag was prepared and examined in ester and amide forming condensation reactions. Following the reactions, the desired product was effectively separated from the fluorous pyridone by-product using a simple fluorous solid phase extraction.
- Matsugi, Masato,Hasegawa, Masakazu,Sadachika, Daisuke,Okamoto, Sachina,Tomioka, Mami,Ikeya, Yoshimi,Masuyama, Araki,Mori, Yuji
-
p. 4147 - 4150
(2008/02/03)
-
- An improved synthesis of the selective matrix metalloproteinase inhibitor, Ro 28-2653
-
An efficient synthesis of Ro 28-2653, a selective matrix metalloproteinase inhibitor, has been developed. The title compound was prepared in four steps and 76% overall yield from 4-biphenylacetic acid. The key, barbituric acid formation step was significantly improved by using 2-propanol and potassium tert-butoxide as the solvent and base, respectively, instead of the typical ethanol and sodium ethoxide combination.
- Daniewski, Andrzej R.,Liu, Wen,Okabe, Masami
-
p. 411 - 414
(2013/09/05)
-
- Polymer-supported mukaiyama reagent: A useful coupling reagent for the synthesis of esters and amides
-
(Chemical equation presented) Polymer-supported N-alkyl-2-chloro pyridinium triflate was synthesized in one step from Wang resin. This reagent proved to be a very effective coupling reagent for the synthesis of esters or amides from carboxylic acids and alcohols or amines (primary and secondary).
- Crosignani, Stefano,Gonzalez, Jerome,Swinnen, Dominique
-
p. 4579 - 4582
(2007/10/03)
-
- Src family SH2 domain inhibitors
-
This invention relates to compounds of formula (1): wherein Ring a, A, B, C, D, E, R and Q are defined herein. These compounds possess the ability to disrupt the interaction between regulatory proteins possessing one or more SH2 domains and their native ligands.
- -
-
-
- beta -thiopropionyl-aminoacid derivatives and their use as beta -lactamase inhibitors
-
PCT No. PCT/EP97/00516 Sec. 371 Date Jan. 13, 1999 Sec. 102(e) Date Jan. 13, 1999 PCT Filed Feb. 3, 1997 PCT Pub. No. WO97/30027 PCT Pub. Date Aug. 21, 1997A method of treatment of bacterial infections in humans or animals which comprises administering, in combination with a beta -lactam antibiotic, a therapeutically effective amount of an amino acid derivative of Formula (I) or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, wherein: R is hydrogen, a salt forming cation or an in vivo hydrolysable ester-forming group; R1 is hydrogen, (C1-6)alkyl optionally substituted by up to three halogen atoms or by a mercapto, (C1-6)alkoxy, hydroxy, amino, nitro, carboxy, (C1-6)alkylcarbonyloxy, (C1-6)alkoxycarbonyl, formyl or (C1-6)alkylcarbonyl group, (C3-7)cycloalkyl, (C3-7)cycloalkyl(C2-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, aryl, aryl(C1-6)alkyl, heterocyclyl or heterocyclyl(C1-6)alkyl; R2 is hydrogen, (C1-6)alkyl or aryl(C1-6)alkyl; R3 is hydrogen, (C1-6)alkyl optionally substituted by up to three halogen atoms, (C3-7)cycloalkyl, fused aryl(C3-7)cycloalkyl, (C3-7)cycloalkyl(C2-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl, aryl, aryl-(CHR10)m-X-(CHR11)n, heterocyclyl or heterocyclyl-(CHR10)m-X-(CHR11)n, where m is 0 to 3, n is 1 to 3, each R10 and R11 is independently hydrogen or (C1-4)alkyl and X is O, S(O)x where x is 0-2, or a bond; R4 is hydrogen, or an in vivo hydrolysable acyl group; and R5 and R6 are independently hydrogen and (C1-6)alkyl or together represent (CH2)p where p is 2 to 5. Some compounds are claimed per se.
- -
-
-
- Esters of α-Arylalkanoic Acids from 'Masked' α-Halogenoalkyl Aryl Ketones and Silver Salts: Synthetic, Kinetic, and Mechanistic Aspects
-
A method for the synthesis of alkyl esters of α-arylalkanoic acids is given based on silver-ion-assisted (AgBF4, AgOSO2CF3, AgSbF6, AgNO3) solvolysis of alkyl acetals of primary and secondary α-halogenoalkyl aryl ketones (Hal = I, Br, Cl) in an alcoholic medium (methanol, ethanol).The reaction is quite selective and alkyl esters are the only reaction products; ethers, which are possible substitution products, are not found.The importance of masking the carbonyl as the acetal is emphasised.The reaction is found to be first-order in AgBF4 and in the primary α-halogeno acetal.A three-point Hammett correlation (ρ = -3.29) between ?+ and the rate constants suggests a large cationic contribution as well as strong aryl participation in the transition state.The role payed by the oxygen of the acetal group in the specificity of the reaction is discussed in comparison with the reactivity of analogous compounds with saturated skeletons and of α-halogenoalkyl aryl ketones.
- Giordano, Claudio,Castaldi, Graziano,Casagrande, Francesco,Belli, Aldo
-
p. 2575 - 2582
(2007/10/02)
-