- Discovery of 4-chloro-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl)benzamides as novel RET kinase inhibitors
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A series of novel 4-chloro-benzamides derivatives containing substituted five-membered heteroaryl ring were designed, synthesized and evaluated as RET kinase inhibitors for cancer therapy. Most of compounds exhibited moderate to high potency in ELISA-based kinase assay. In particular, compound I-8 containing 1,2,4-oxadiazole strongly inhibited RET kinase activity both in molecular and cellular level. In turn, I-8 inhibited cell proliferation driven by RET wildtype and gatekeeper mutation. The results implied that 4-chloro-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl)benzamides are promising lead compounds as novel RET kinase inhibitor for further investigation.
- Han, Mei,Li, Shan,Ai, Jing,Sheng, Rong,Hu, Yongzhou,Hu, Youhong,Geng, Meiyu
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Read Online
- Mild Copper-Catalyzed Addition of Arylboronic Esters to Di- tert -butyl Dicarbonate: An Easy Access to Methyl Arylcarboxylates
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An efficient copper-catalyzed addition of arylboronic esters to (Boc) 2O was developed. The reaction can be conducted under exceedingly mild conditions and is compatible with a variety of synthetically relevant functional groups. It therefore represents a useful alternative route for the synthesis of methyl arylcarboxylates. A preliminary mechanistic study indicated the involvement of an addition-elimination mechanism.
- Xu, Jin-Di,Su, Xiao-Bo,Wang, Cai,Yao, Li-Wei,Liu, Jing-Hui,Hu, Guo-Qin
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supporting information
p. 833 - 837
(2021/02/26)
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- Pyrazol-1, 2, 4-oxadiazole substituted benzamide compound as well as preparation method and application of pyrazol-1, 2, 4-oxadiazole substituted benzamide compound
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The invention belongs to the technical field of chemical synthesis and medicine application, and particularly relates to a pyrazol-1, 2, 4-oxadiazole substituted benzamide compound as well as a preparation method and application of the pyrazol-1, 2, 4-oxadiazole substituted benzamide compound. The preparation method comprises the following steps: reacting methyl 3-cyanobenzoate with hydroxylamine hydrochloride to obtain an intermediate 3, then carrying out ring synthesis on the intermediate 3 and pyrazole acid to obtain pyrazol-1, 2, 4-oxadiazole substituted methyl benzoate, and finally carrying out hydrolysis and condensation to obtain the pyrazol-1, 2, 4-oxadiazole substituted benzamide compound. According to the present invention, the structure of the obtained product is confirmed through the nuclear magnetic hydrogen spectrum, the bactericidal activity test is performed on the obtained 18 target products, and the results show that the target product obtained through the preparation method has good antibacterial activity at the concentration of 50 ppm, and the inhibition rate on the rhizoctonia solani within 7 h can achieve 100%.
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Paragraph 0023-0024
(2021/06/22)
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- Synthesis, characterization, and biological evaluation of new derivatives targeting MbtI as antitubercular agents
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Tuberculosis (TB) causes millions of deaths every year, ranking as one of the most dangerous infectious diseases worldwide. Because several pathogenic strains of Mycobacterium tuberculosis (Mtb) have developed resistance against most of the established anti-TB drugs, new therapeutic options are urgently needed. An attractive target for the development of new antitubercular agents is the salicylate synthase MbtI, an essential enzyme for the mycobacterial siderophore biochemical machinery, absent in human cells. A set of analogues of I and II, two of the most potent MbtI inhibitors identified to date, was synthesized, characterized, and tested to elucidate the structural requirements for achieving an efficient MbtI inhibition and a potent antitubercular activity with this class of compounds. The structure-activity relationships (SAR) here discussed evidenced the importance of the furan as part of the pharmacophore and led to the preparation of six new compounds (IV-IX), which gave us the opportunity to examine a hitherto unexplored position of the phenyl ring. Among them emerged 5-(3-cyano-5-(trifluoromethyl)phenyl)furan-2-carboxylic acid (IV), endowed with comparable inhibitory properties to the previous leads, but a better antitubercular activity, which is a key issue in MbtI inhibitor research. Therefore, compound IV offers promising prospects for future studies on the development of novel agents against mycobacterial infections.
- Mori, Matteo,Stelitano, Giovanni,Chiarelli, Laurent R.,Cazzaniga, Giulia,Gelain, Arianna,Barlocco, Daniela,Pini, Elena,Meneghetti, Fiorella,Villa, Stefania
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- Visible-Light-Promoted Metal-Free Synthesis of (Hetero)Aromatic Nitriles from C(sp3)?H Bonds**
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The metal-free activation of C(sp3)?H bonds to value-added products is of paramount importance in organic synthesis. We report the use of the commercially available organic dye 2,4,6-triphenylpyrylium tetrafluoroborate (TPP) for the conversion of methylarenes to the corresponding aryl nitriles via a photocatalytic process. Applying this methodology, a variety of cyanobenzenes have been synthesized in good to excellent yield under metal- and cyanide-free conditions. We demonstrate the scope of the method with over 50 examples including late-stage functionalization of drug molecules (celecoxib) and complex structures such as l-menthol, amino acids, and cholesterol derivatives. Furthermore, the presented synthetic protocol is applicable for gram-scale reactions. In addition to methylarenes, selected examples for the cyanation of aldehydes, alcohols and oximes are demonstrated as well. Detailed mechanistic investigations have been carried out using time-resolved luminescence quenching studies, control experiments, and NMR spectroscopy as well as kinetic studies, all supporting the proposed catalytic cycle.
- Murugesan, Kathiravan,Donabauer, Karsten,K?nig, Burkhard
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supporting information
p. 2439 - 2445
(2020/12/07)
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- Pd/C-Catalyzed methoxycarbonylation of aryl chlorides
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A new protocol for the methoxycarbonylation of aryl chlorides has been developed. Various methyl benzoates were produced in good to excellent yields. Several parameters are crucial for the success of this procedure: 1) the usage of LiOMe as the base or co-nucleophile which facilitate the carbonylative transformation; 2) employing Pd/C as the catalyst to prevent the palladium reduced by MeOH and subsequent agglomerate; 3) CO concentration, excessive CO concentration will directly lead to the termination of the reaction.
- Ai, Han-Jun,Franke, Robert,Wu, Xiao-Feng
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- Photocatalytic Conversion of Benzyl Alcohols/Methyl Arenes to Aryl Nitriles via H-Abstraction by Azide Radical
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This report presents the visible-light-assisted synthesis of aryl nitriles from easily accessible alcohols or methyl arenes in the presence of O2. Organic photoredox catalyst, 4CzIPN (1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene), induces single electron transfer (SET) from azide N3? and generates azide radical N3?.The photogenerated N3? abstracts H atom from α-C?H bond of benzylic system, which provides aldehyde and hydrazoic acid (HN3) in situ. This reaction subsequently forms azido alcohol intermediate that transforms into nitrile with the assistance of triflic acid (Br?nsted acid). A range of alcohols and methyl arenes successfully underwent cyanation at room temperature with good to excellent yields and showed good functional group tolerance.
- Shee, Maniklal,Shah, Sk. Sheriff,Singh, N. D. Pradeep
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supporting information
p. 14070 - 14074
(2020/10/12)
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- Organophotoredox assisted cyanation of bromoarenes: via silyl-radical-mediated bromine abstraction
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The insertion of a nitrile (-CN) group into arenes through the direct functionalization of the C(sp2)-Br bond is a challenging reaction. Herein, we report an organophotoredox method for the cyanation of aryl bromides using the organic photoredox catalyst 4CzIPN and tosyl cyanide (TsCN) as the nitrile source. A photogenerated silyl radical, via a single electron transfer (SET) mechanism, was employed to abstract bromine from aryl bromide to provide an aryl radical, which was concomitantly intercepted by TsCN to afford the aromatic nitrile. A range of substrates containing electron-donating and -withdrawing groups was demonstrated to undergo cyanation at room temperature in good yields.
- Shah, Sk. Sheriff,Shee, Maniklal,Singh, N. D. Pradeep
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supporting information
p. 4240 - 4243
(2020/04/22)
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- Palladium-Catalyzed, Copper(I)-Promoted Methoxycarbonylation of Arylboronic Acids with O-Methyl S-Aryl Thiocarbonates
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Here, we report O-methyl S-aryl thiocarbonates as a versatile esterification reagent for palladium-catalyzed methoxycarbonylation of arylboronic acid in the presence of copper(I) thiophene-2-carboxylate (CuTC). The reaction condition is mild, and a variety of substituents including sensitive-Cl,-Br, and free-NH2 could be tolerated. Further applications in the late-stage esterification of some pharmaceutical drugs demonstrate the broad utility of this method.
- Cao, Ya-Fang,Li, Ling-Jun,Liu, Min,Xu, Hui,Dai, Hui-Xiong
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p. 4475 - 4481
(2020/04/10)
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- Application of Continuous Flow-Flash Chemistry to Scale-up Synthesis of 5-Cyano-2-formylbenzoic Acid
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Efficient scale-up synthesis of 5-cyano-2-formylbenzoic acid or its cyclic isomer 6-cyano-3-hydroxy-2-benzofuran-1(3H)-one (1) as a key intermediate for various biologically important compounds has been achieved from isopropyl 2-bromo-5-cyanobenzoate (8c) by means of continuous flow-flash chemistry using flow microreactors. It was found that Br/Li exchange reaction of 8c, bearing both a carboisopropoxy group and a cyano group, with BuLi took place within 0.1 s at -50 °C, and the resulting highly reactive aryllithium intermediate underwent formylation with DMF to afford 1, which is extremely difficult to achieve by a conventional batch process. Optimization of the continuous flow-flash reaction conditions and modification of the reaction system brought about the production of 237 g of 1 from 897 g of 8c in 270 min, without purification by column chromatography. The results suggest that phthalaldehydic acid derivatives bearing electrophilic group(s) can be synthesized conveniently from the corresponding 2-bromobenzoic acid esters by means of flow-flash chemistry using flow microreactors.
- Seto, Masaki,Masada, Shinichi,Usutani, Hirotsugu,Cork, David G.,Fukuda, Koichiro,Kawamoto, Tetsuji
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p. 1420 - 1428
(2019/07/03)
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- Palladium-Catalyzed Late-Stage Direct Arene Cyanation
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Methods for direct benzonitrile synthesis are sparse, despite the versatility of cyano groups in organic synthesis and the importance of benzonitriles for the dye, agrochemical, and pharmaceutical industries. We report the first general late-stage aryl C–H cyanation with broad substrate scope and functional-group tolerance. The reaction is enabled by a dual-ligand combination of quinoxaline and an amino acid-derived ligand. The method is applicable to direct cyanation of several marketed small-molecule drugs, common pharmacophores, and organic dyes. Benzonitriles are some of the most versatile building blocks for organic synthesis, in particular in the pharmaceutical industry, but general methods to make them by direct C–H functionalization are unknown. In this issue of Chem, Ritter and coworkers describe a late-stage aryl C–H cyanation with broad substrate scope and functional-group tolerance, enabled by a palladium-dual-ligand catalyst system. The reaction may serve for the late-stage modification of drug candidates. Aryl nitriles constitute an important class of organic compounds that are widely found in natural products, pharmaceuticals, agricultural chemicals, dyes, and materials. Moreover, nitriles are versatile building blocks to access numerous other important molecular structure groups. However, no general method for direct aromatic C–H cyanation is known. All approaches to date require either an appropriate directing group or reactive electron-rich substrates, such as indoles, which limit their synthetic applications. Here we describe an undirected, palladium-catalyzed late-stage aryl C–H cyanation reaction for the synthesis of complex aryl nitriles that would otherwise be more challenging to produce. The wide substrate scope and good functional-group tolerance of this reaction provide direct and quick access to structural diversity for pharmaceutical and agrochemical development.
- Zhao, Da,Xu, Peng,Ritter, Tobias
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supporting information
p. 97 - 107
(2019/01/21)
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- Pd-Colloids-Catalyzed/Ag2O-Oxidized General and Selective Esterification of Benzylic Alcohols
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Palladium colloids obtained from the degradation of Hermann–Beller palladacycle proved to be an efficient catalytic system in combination with silver oxide as a selective oxidant for the oxidative esterification of differently substituted benzyl alcohols in MeOH as solvent. Excellent reactivity exhibited by the catalytic system also allowed the alcoholic coupling partner to be changed from MeOH to a wide range of alcohols having diverse functionalities. The mildness of the developed protocol also made it possible to employ propargyl alcohol as the coupling partner without any observation of any interference of the terminal alkyne. Selective oxidative coupling of a primary alcoholic functional group over secondary in the case of glycols and glycerols was also made possible using the developed catalyst system. To test the relevancy of Pd/Ag combined catalysis mixed Pd/Ag colloids were synthesized, characterized by TEM, XRD and XPS and applied to oxidative-esterification successfully.
- Sable, Vaibhav,Shah, Jagrut,Sharma, Anuja,Kapdi, Anant R.
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supporting information
p. 2639 - 2647
(2019/07/08)
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- Pd(II)-Catalyzed Direct Sulfonylation of Benzylamines Using Sodium Sulfinates
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A Pd(II)-catalyzed direct sulfonylation of benzylamines with sodium sulfinates using a removable bidentate directing group is illustrated. The transformation is highly regioselective and tolerates wide functional groups. The mechanistic study reveals that radical species are involved in this reaction. This method delivers a direct synthetic strategy to obtain highly functionalized sulfonylated benzylamines.
- Karmakar, Ujjwal,Samanta, Rajarshi
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p. 2850 - 2861
(2019/03/29)
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- Ligand-Promoted Non-Directed C?H Cyanation of Arenes
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This article reports the first example of a 2-pyridone accelerated non-directed C?H cyanation with an arene as the limiting reagent. This protocol is compatible with a broad scope of arenes, including advanced intermediates, drug molecules, and natural products. A kinetic isotope experiment (kH/kD=4.40) indicates that the C?H bond cleavage is the rate-limiting step. Also, the reaction is readily scalable, further showcasing the synthetic utility of this method.
- Liu, Luo-Yan,Yeung, Kap-Sun,Yu, Jin-Quan
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supporting information
p. 2199 - 2202
(2019/01/24)
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- A biocatalytic method for the chemoselective aerobic oxidation of aldehydes to carboxylic acids
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Herein, we present a study on the oxidation of aldehydes to carboxylic acids using three recombinant aldehyde dehydrogenases (ALDHs). The ALDHs were used in purified form with a nicotinamide oxidase (NOx), which recycles the catalytic NAD+ at the expense of dioxygen (air at atmospheric pressure). The reaction was studied also with lyophilised whole cell as well as resting cell biocatalysts for more convenient practical application. The optimised biocatalytic oxidation runs in phosphate buffer at pH 8.5 and at 40 °C. From a set of sixty-one aliphatic, aryl-Aliphatic, benzylic, hetero-Aromatic and bicyclic aldehydes, fifty were converted with elevated yield (up to >99%). The exceptions were a few ortho-substituted benzaldehydes, bicyclic heteroaromatic aldehydes and 2-phenylpropanal. In all cases, the expected carboxylic acid was shown to be the only product (>99% chemoselectivity). Other oxidisable functionalities within the same molecule (e.g. hydroxyl, alkene, and heteroaromatic nitrogen or sulphur atoms) remained untouched. The reaction was scaled for the oxidation of 5-(hydroxymethyl)furfural (2 g), a bio-based starting material, to afford 5-(hydroxymethyl)furoic acid in 61% isolated yield. The new biocatalytic method avoids the use of toxic or unsafe oxidants, strong acids or bases, or undesired solvents. It shows applicability across a wide range of substrates, and retains perfect chemoselectivity. Alternative oxidisable groups were not converted, and other classical side-reactions (e.g. halogenation of unsaturated functionalities, Dakin-Type oxidation) did not occur. In comparison to other established enzymatic methods such as the use of oxidases (where the concomitant oxidation of alcohols and aldehydes is common), ALDHs offer greatly improved selectivity.
- Knaus, Tanja,Tseliou, Vasilis,Humphreys, Luke D.,Scrutton, Nigel S.,Mutti, Francesco G.
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p. 3931 - 3943
(2018/09/11)
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- Improved Substrate Scope in the Potassium Hexacyanoferrate(II)-Based Cyanation for the Synthesis of Benzonitriles and Their Heterocyclic Analogues
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The use of Pd(DPEPhos)Cl2 (P26) as a catalyst for the formation of benzonitriles and their heterocyclic analogues provides excellent complementarity to existing catalysts, allowing highly electron-deficient heterocyclic aryl halides to be effic
- Richardson, Jeffery,Mutton, Simon P.
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p. 4922 - 4931
(2018/05/22)
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- Improving Robustness: In Situ Generation of a Pd(0) Catalyst for the Cyanation of Aryl Bromides
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Conditions have been developed for the palladium-catalyzed cyanation of aryl bromides utilizing the air-stable XantPhos-PdCl2 precatalyst. By employing a trialkylamine as a reducing agent, the active Pd(0) species is generated in situ, alleviating the need to employ the air-sensitive Pd2(dba)3. Twenty-two substituted benzonitriles have been synthesized using this method.
- Coombs, John R.,Fraunhoffer, Kenneth J.,Simmons, Eric M.,Stevens, Jason M.,Wisniewski, Steven R.,Yu, Miao
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p. 7040 - 7044
(2017/07/17)
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- Cyanation of Phenol Derivatives with Aminoacetonitriles by Nickel Catalysis
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Generation of useful arylnitrile structures from simple aromatic feedstock chemicals represents a fundamentally important reaction in chemical synthesis. The first nickel-catalyzed cyanation of phenol derivatives with metal-free cyanating agents, aminoacetonitriles, is described. A nickel-based catalytic system consisting of a unique diphosphine ligand such as dcype or dcypt enables the cyanation of versatile phenol derivatives such as aryl carbamates and aryl pivalates. The use of aminoacetonitriles as a cyanating agent leads to an environmentally and easy-to-use method for arylnitrile synthesis.
- Takise, Ryosuke,Itami, Kenichiro,Yamaguchi, Junichiro
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supporting information
p. 4428 - 4431
(2016/10/12)
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- A Homogeneous Method for the Conveniently Scalable Palladium- and Nickel-Catalyzed Cyanation of Aryl Halides
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Homogeneous conditions for the palladium-catalyzed cyanation of aryl halides were developed. This new system features a broad scope of aryl chlorides and bromides, uses 2-propanol or 1-butanol as solvent, and is readily scalable. The same conditions can also provide simple benzonitriles using the recently developed (TMEDA)NiCl(o-tolyl) precatalyst in conjunction with 1,1′-bis(diphenylphosphino)ferrocene (dppf) as a ligand.
- Burg, Finn,Egger, Julian,Deutsch, Johannes,Guimond, Nicolas
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p. 1540 - 1545
(2016/08/30)
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- Oxidative Esterification of Aromatic Aldehydes Using Polymer-Supported Green Bromine
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A facile one-pot green chemical conversion of aromatic aldehydes to alkyl esters is described using polymer-supported bromine chloride resin in the presence of potassium carbonate at room temperature. This eco-friendly methodology with simple workup procedure and recovery and recyclability of the resin makes the transformation simple and efficient.
- Sridhar,Swarnalakshmi,Selvaraj
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p. 1344 - 1348
(2016/06/01)
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- Rhodium-Catalyzed Transnitrilation of Aryl Boronic Acids with Dimethylmalononitrile
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An efficient transnitrilation of aryl boronic acids with dimethylmalononitrile (DMMN) is described. This rhodium-catalyzed electrophilic cyanation presents a novel approach to prepare aryl nitriles by using a carbon-bound cyanating reagent which undergoes cross-coupling with the aryl boronic acid. The reaction expands the degree of functional-group compatibility exhibited by the transnitrilation of aryl Grignard and aryllithium reagents. A variety of aryl boronic acid derivatives and dialkylmalononitriles were amenable to the transnitrilation.
- Malapit, Christian A.,Reeves, Jonathan T.,Busacca, Carl A.,Howell, Amy R.,Senanayake, Chris H.
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supporting information
p. 326 - 330
(2016/01/25)
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- Oxdiazole compound solvate and preparation method thereof
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The present invention relates to the dimethyl sulfoxide solvate of 3-[5-(2-fluorophenyl)-[1,2,4]oxdiazole-3-yl]benzoic acid, wherein the dimethyl sulfoxide solvate has characteristics of good stability, high purity, excellent particle and excellent shape, and is suitable for pharmaceutical preparation applications. The present invention further relates to a preparation method of the dimethyl sulfoxide solvate, a pharmaceutical composition of the dimethyl sulfoxide solvate, and uses of the dimethyl sulfoxide solvate in preparation of drugs for treatment of genetic diseases.
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Paragraph 0075; 0078
(2017/03/08)
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- BENZENE SULFONAMIDES AS CCR9 INHIBITORS
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The present invention relates to compounds useful as CCR9 modulators, to compositions containing them, to methods of making them, and to methods of using them. In particular, the present invention relates to compounds capable of modulating the function of the CCR9 receptor by acting as partial agonists, antagonists or inverse agonists. Such compounds may be useful to treat, prevent or ameliorate a disease or condition associated with CCR9 activation, including inflammatory and immune disorder diseases or conditions such as inflammatory bowel diseases (IBD).
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Page/Page column 88
(2015/07/15)
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- NOVEL TRIAZINE COMPOUND, ULTRAVIOLET ABSORBER AND RESIN COMPOSITION USING THE SAME
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PROBLEM TO BE SOLVED: To provide a triazine compound useful as an ultraviolet absorber in fields of a polymeric material, a coating, a fiber, a surface coating material, a cosmetic raw material and a photography material or the like. SOLUTION: There is provided the compound represented by the general formula (I). (I), where R represents an alkyl group, an aryl group, a hydroxyl group, an alkoxy group, an aryloxy group, a heterocyclic oxy group, an alkylcarbonyloxy group, an arylcarbonyloxy group, a carbamoyloxy group, a formyl group, a carboxyl group, an alkylcarbonyl group, an arylcarbonyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a cyano group, a nitro group, an amino group, an ureido group, a carbamoyl group, a sulfamoyl group, a sulfonic group, an alkylthio group, an arylthio group, a heterocyclic thio group, an alkylsulfonyl group, arylsulfonyl group, a heterocyclic residue or a halogen atom. These substituents may further be substituted. COPYRIGHT: (C)2016,JPO&INPIT
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Paragraph 0062
(2018/10/24)
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- Synthesis and evaluation of novel azoles as potent antifungal agents
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Using a rational approach to the design of antifungal agents, a series of azole agents with 1,3,4-oxadiazole side chains were designed and synthesized. The results of preliminary in vitro antifungal tests with eight human pathogenic compounds showed that all of the title compounds exhibited excellent activities against all of the tested fungi except Aspergillus fumigatus. Compounds 11e and 11f were found to be the most effective, with a minimum inhibitory concentration of 0.0039 μg/mL, followed by voriconazole, which has a MIC of 0.0625 μg/mL. The 1,3,4-oxadiazole side chain is not the major contributor but plays a role in eliciting the observed antifungal activity.
- Li, Liangjing,Ding, Hao,Wang, Baogang,Yu, Shichong,Zou, Yan,Chai, Xiaoyun,Wu, Qiuye
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supporting information
p. 192 - 194
(2014/01/17)
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- Copper-catalyzed decarboxylative methylation of aromatic carboxylic acids with PhI(OAc)2
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The copper-catalyzed decarboxylative methylation of aromatic carboxylic acids was developed by using PhI(OAc)2 to provide a new strategy for the methylation of aryl acids through the decarboxylation of alkyl acids. The mechanism and the roles of each reactant in the reaction were investigated extensively. Copyright
- Jiang, Yuyu,Pan, Shulei,Zhang, Yanghui,Yu, Jingxun,Liu, Hongqiang
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supporting information
p. 2027 - 2031
(2014/04/17)
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- A general continuous flow method for palladium catalysed carbonylation reactions using single and multiple tube-in-tube gas-liquid microreactors
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A series of continuous flow chemistry processes that facilitate the palladium-catalysed carbonylation of aryl and vinyl iodides and aryl bromides with a range of alkoxy, hydroxy and amino nucleophiles is reported. Harnessing a semipermeable Teflon AF-2400 Tube-in-Tube assembly, these reactors permit the controlled transport of carbon monoxide into solution at elevated pressure to generate homogeneous flow streams, avoiding some potential issues associated with segmented flow gas-liquid reactors. As the volume of pressurised gas contained within the device is low, the hazards associated with this are potentially mitigated relative to comparable batch processes. We also show how the incorporation of a second in-line gas-flow reactor allows for the sequential introduction of two gases (carbon monoxide and a gaseous nucleophile) into the reaction stream. A Teflon AF-2400 Tube-in-Tube reactor facilitates the use of carbon monoxide in continuous-flow C-C bond forming reactions providing esters, amides, carboxylic acids, lactones and lactams. Two reactors can be used in series to permit the sequential addition of two reactive gases (CO and Me2NH) into the flow stream.
- Gross, Ulrike,Koos, Peter,O'brien, Matthew,Polyzos, Anastasios,Ley, Steven V.
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supporting information
p. 6418 - 6430
(2016/02/18)
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- Aromatics from pyrones: Esters of terephthalic acid and isophthalic acid from methyl coumalate
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The Diels-Alder reaction of methyl coumalate with alkenes bearing electron-withdrawing groups provides terephthalates or isophthalates in good yields, with the regioselectivity depending on the electron-withdrawing group. The reaction of methyl coumalate with the salt of acrylic acid gave only the monoester of isophthalic acid. Density functional theory (B3LYP/6-31 + G(d,p)) computations of the energies of the competing transition states of the para-selective Diels-Alder reactions are in good agreement with experiment. The surprising regioselectivity of methyl coumalate with activated alkenes is attributed to a secondary orbital interaction between the pyrone oxygen and the dienophile LUMO, which switches the regiochemistry expected from simple frontier molecular orbital theory arguments. The Royal Society of Chemistry 2013.
- Kraus, George A.,Pollock III, Gerald R.,Beck, Christie L.,Palmer, Kyle,Winter, Arthur H.
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p. 12721 - 12725
(2013/08/23)
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- Conversion of aldoximes into nitriles and amides under mild conditions
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A series of Pd(en)X2 salts were used as catalysts for the conversion of aldoximes into nitriles and amides. Highlights of this protocol include the use of inexpensive polar solvents, including water, and moderate reaction temperatures. A high degree of selectivity in the reaction outcome was observed when using aliphatic vs. aromatic/conjugated aldoximes. The Royal Society of Chemistry 2013.
- Tambara, Koujiro,Pantos, G. Dan
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p. 2466 - 2472
(2013/06/05)
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- The first example for cyanation of arylboronic acids with nontoxic and inexpensive K4[Fe(CN)6]
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Nontoxic and inexpensive K4[Fe(CN)6] is first introduced as a cyanating agent to cyanation of arylboronic acids. The present method is simple, practical, and allowed a wide range of substrates including functionalized phenylboronic acids, 1-naphthylboronic acid as well as heterocyclic boronic acids to be smoothly converted into the corresponding products in moderate to high yields.
- Tian, Xinzhe,Sun, Yanpei,Dong, Chuanhua,Zhang, Kaixuan,Liang, Tengfei,Zhang, Yu,Hou, Chaodong
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supporting information; experimental part
p. 719 - 721
(2012/09/22)
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- A general and efficient zinc-catalyzed oxidation of benzyl alcohols to aldehydes and esters
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Go green: A general and efficient zinc-catalyzed oxidation of benzyl alcohols has been developed. In the presence of a zinc catalyst, various aldehydes and esters have been prepared in good to excellent yields under mild conditions (see scheme).
- Wu, Xiao-Feng
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experimental part
p. 8912 - 8915
(2012/09/22)
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- Cyanation of aryl bromides with K4[Fe(CN)6] catalyzed by dichloro[bis{1-(dicyclohexylphosphanyl)piperidine}]palladium, a molecular source of nanoparticles, and the reactions involved in the catalyst-deactivation processes
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Dichloro[bis{1-(dicyclohexylphosphanyl)piperidine}]palladium [(P{(NC 5H10)(C6H11)2}) 2PdCl2] (1) is a highly active and generally applicable C-C cross-coupling catalyst. Apart from its high catalytic activity in Suzuki, Heck, and Negishi reactions, compound 1 also efficiently converted various electronically activated, nonactivated, and deactivated aryl bromides, which may contain fluoride atoms, trifluoromethane groups, nitriles, acetals, ketones, aldehydes, ethers, esters, amides, as well as heterocyclic aryl bromides, such as pyridines and their derivatives, or thiophenes into their respective aromatic nitriles with K4[Fe(CN)6] as a cyanating agent within 24 h in NMP at 140 °C in the presence of only 0.05 mol % catalyst. Catalyst-deactivation processes showed that excess cyanide efficiently affected the molecular mechanisms as well as inhibited the catalysis when nanoparticles were involved, owing to the formation of inactive cyanide complexes, such as [Pd(CN)4]2-, [(CN)3Pd(H)]2-, and [(CN)3Pd(Ar)]2-. Thus, the choice of cyanating agent is crucial for the success of the reaction because there is a sharp balance between the rate of cyanide production, efficient product formation, and catalyst poisoning. For example, whereas no product formation was obtained when cyanation reactions were examined with Zn(CN)2 as the cyanating agent, aromatic nitriles were smoothly formed when hexacyanoferrate(II) was used instead. The reason for this striking difference in reactivity was due to the higher stability of hexacyanoferrate(II), which led to a lower rate of cyanide production, and hence, prevented catalyst-deactivation processes. This pathway was confirmed by the colorimetric detection of cyanides: whereas the conversion of β-solvato-α-cyanocobyrinic acid heptamethyl ester into dicyanocobyrinic acid heptamethyl ester indicated that the cyanide production of Zn(CN)2 proceeded at 25 °C in NMP, reaction temperatures of >100 °C were required for cyanide production with K4[Fe(CN) 6]. Mechanistic investigations demonstrate that palladium nanoparticles were the catalytically active form of compound 1. A balancing act: Compound 1 (see scheme) is a highly active cyanation catalyst. Furthermore, a sharp balance between the rates of cyanide generation, efficient product formation, and catalyst deactivation owing to excess cyanide was observed in deactivation processes. Copyright
- Gerber, Roman,Oberholzer, Miriam,Frech, Christian M.
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supporting information; experimental part
p. 2978 - 2986
(2012/04/04)
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- Rhodium-catalyzed asymmetric hydrogenation of olefins with PhthalaPhos, a new class of chiral supramolecular ligands
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A library of 19 binol-derived chiral monophosphites that contain a phthalic acid diamide group (Phthala- Phos) has been designed and synthesized in four steps. These new ligands were screened in the rhodium-catalyzed enantioselective hydrogenation of prochiral dehydroamino esters and enamides. Several members of the library showed excellent enantioselectivity with methyl 2-acetamido acrylate (6 ligands gave >97% ee), methyl (Z)-2- acetamido cinnamate (6 ligands gave >94% ee), and N-(1-phenylvinyl)acetamide (9 ligands gave >95% ee), whilst only a few representatives afforded high enantioselectivities for challenging and industrially relevant substrates N-(3,4-dihydronaphthalen-1- yl)-acetamide (96% ee in one case) and methyl (E)-2-(acetamidomethyl)-3- phenylacrylate (99% ee in one case). In most cases, the new ligands were more active and more stereoselective than their structurally related monodentate phosphites (which are devoid of functional groups that are capable of hydrogen-bonding interactions). Control experiments and kinetic studies were carried out that allowed us to demonstrate that hydrogen-bonding interactions involving the diamide group of the PhthalaPhos ligands strongly contribute to their outstanding catalytic properties. Computational studies carried out on a rhodium precatalyst and on a conceivable intermediate in the hydrogenation catalytic cycle shed some light on the role played by hydrogen bonding, which is likely to act in a substrate-orientation effect.
- Pignataro, Luca,Boghi, Michele,Civera, Monica,Carboni, Stefano,Piarulli, Umberto,Gennari, Cesare
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supporting information; experimental part
p. 1383 - 1400
(2012/03/27)
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- A mild and efficient palladium-catalyzed cyanation of aryl chlorides with K4[Fe(CN)6]
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An efficient palladium-catalyzed cyanation of aryl chlorides is established. In the presence of a highly effective Pd/CM-phos catalyst, cyanation of aryl chlorides proceeds at 70 °C in general, which is the mildest reaction temperature achieved so far for this process. Common functional groups such as keto, aldehyde, ester, nitrile and-NH2, and heterocyclic coupling partners including N-H indoles are well tolerated. Moreover, a sterically hindered nonactivated ortho,ortho-disubstituted electrophile is shown to be a feasible coupling partner in cyanation.
- Yeung, Pui Yee,So, Chau Ming,Lau, Chak Po,Kwong, Fuk Yee
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supporting information; experimental part
p. 648 - 651
(2011/04/15)
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- Teflon AF-2400 mediated gas-liquid contact in continuous flow methoxycarbonylations and in-line FTIR measurement of CO concentration
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We report on the development of a continuous flow process for the palladium catalysed methoxycarbonylation of aryl, heteroaromatic and vinyl iodides and an aryl bromide using a Teflon AF-2400 based Tube-in-Tube reactor to mediate the selective permeation of carbon monoxide into solution at elevated pressures. The low volume of pressurised gas within the reactor (5.6 mL) offers the potential for an enhanced safety profile compared to batch processes. We also present preliminary results for the use of in situ FTIR to measure solution concentrations of carbon monoxide and demonstrate the use of a second reactor to effect the removal of carbon monoxide from the flow stream.
- Koos, Peter,Gross, Ulrike,Polyzos, Anastasios,O'Brien, Matthew,Baxendale, Ian,Ley, Steven V.
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supporting information; experimental part
p. 6903 - 6908
(2011/10/31)
-
- A mild and efficient palladium-catalyzed cyanation of aryl mesylates in water or tBuOH/water
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Cool and compatible: Aryl mesylates and tosylates underwent palladium-catalyzed cyanation under mild, aqueous conditions at 65-80°C (see scheme). In many cases, water could be used as the reaction medium without a cosolvent, and a variety of substituents R, such as keto, aldehyde, ester, free amine, and nitrile groups, remained intact during the transformation. Cy=cyclohexyl, Ms=methanesulfonyl, Ts=p-toluenesulfonyl.
- Yeung, Pui Yee,So, Chau Ming,Lau, Chak Po,Kwong, Fuk Yee
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p. 8918 - 8922
(2011/02/24)
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- Cyanation of arenes via iridium-catalyzed borylation
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We report a method to conduct one-pot meta cyanation of arenes by iridium-catalyzed C-H borylation and copper-mediated cyanation of the resulting arylboronate esters. This process relies on a method to conduct the cyanation of arylboronic esters, and conditions for this new transformation are reported. Conditions for the copper-mediated cyanation of arylboronic acids are also reported. By the resulting sequence of borylation and cyanation, 1,3-disubstituted and 1,2,3-trisubstituted arenes and heteroarenes containing halide, ketone, ester, amide, and protected alcohol functionalities are converted to the corresponding meta-substituted aryl nitriles. The utility of this methodology is demonstrated through the conversion of a protected 2,6-disubstituted phenol to 4-cyano-2,6-dimethylphenol, which is an intermediate in the synthesis of the pharmaceutical etravirine. The utility of the method is further demonstrated by the conversion of 3-chloro-5-methylbenzonitrile, produced through the one-pot C-H borylation and cyanation sequence, to the corresponding 3,5-disubstituted aldehydes, ketones, amides, carboxylic acids, tetrazoles, and benzylamines.
- Liskey, Carl W.,Liao, Xuebin,Hartwig, John F.
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supporting information; experimental part
p. 11389 - 11391
(2010/10/01)
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- Trans-chelating ligands in palladium-catalyzed carbonylative coupling and methoxycarbonylation of aryl halides
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The manuscript describes the use of a trans-chelated palladium complex derived from 1,8-bis-(4-(diphenylphosphino)phenyl)anthracene (1) and p-TolPdI(TMEDA) as a precatalyst in carbonylative Suzuki coupling and methoxycarbonylation of aryl iodides and bromides. The catalyst is active in 0.01-1 mol% loading and demonstrates highly selective transformations. The selectivity is attributed to the unique structural features of the trans-chelating ligands.
- Kaganovsky, Luba,Gelman, Dmitri,Rueck-Braun, Karola
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experimental part
p. 260 - 266
(2010/03/26)
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- CYCLICALLY SUBSTITUTED 3,5-DICYANO-2-THIOPYRIDINES AND USE THEREOF
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The present application relates to novel 4-cycloalkyl- and 4-heterocycloalkyl-3,5-dicyano-2-thio-pyridine derivatives, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, preferably for the treatment and/or prevention of hypertension and other cardiovascular disorders.
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Page/Page column 28
(2010/02/17)
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- Phthalaphos: Chiral supramolecular ligands for enantioselective rhodium-catalyzed hydrogenation reactions
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Interligand hydrogen bonding of chiral monodentate phosphite ligands bearing H-bond donor and acceptor groups leads to formation of supramolecular bidentate ligands, rhodium complexes of which (see picture) afford excellent enantiomeric excesses in catalyzed hydrogenation of classical benchmark and industrially relevant substrates. cod=1,5-cyclooctadiene.
- Pignataro, Luca,Carboni, Stefano,Civera, Monica,Colombo, Raffaele,Piarulli, Umberto,Gennari, Cesare
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supporting information; experimental part
p. 6633 - 6637
(2010/10/21)
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- TRIAZOLE OXADIAZOLES DERIVATIVES
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The invention relates to compounds of formula (I), wherein R1, R2, Ra, Rb, X have the meanings given in claim 1. The compounds are useful e.g. in the treatment of autoimmune disorders, such as multiple sclerosis.
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Page/Page column 97
(2009/07/25)
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- Palladium-catalyzed carbonylation reactions of aryl bromides at atmospheric pressure: A general system based on xantphos
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(Chemical Equation Presented) A method for the Pd-catalyzed carbonylation of aryl bromides has been developed using Xantphos as the ligand. This method is effective for the direct synthesis of Weinreb amides, 1° and 2° benzamides, and methyl esters from the corresponding aryl bromides at atmospheric pressure. In addition, a putative catalytic intermediate, (Xanphos)Pd(Br)benzoyl, was prepared and an X-ray crystal structure was obtained revealing an unusual cis-coordination mode of Xantphos in this palladium-acyl complex.
- Martinelli, Joseph R.,Watson, Donald A.,Freckmann, Dominique M. M.,Barder, Timothy E.,Buchwald, Stephen L.
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supporting information; experimental part
p. 7102 - 7107
(2009/05/09)
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- METHODS FOR DOSING AN ORALLY ACTIVE 1,2,4-OXADIAZOLE FOR NONSENSE MUTATION SUPPRESSION THERAPY
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The present invention relates to specific doses of and dosing regimens for using a 1,2,4-oxadiazole benzoic acid compound in treating or preventing diseases associated with nonsense mutations. In particular, the invention relates to specific doses and dosing regimens for the use of 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid in mammals having diseases associated with nonsense mutations.
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Page/Page column 24-25
(2008/06/13)
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- New anti-viral drugs for the treatment of the common cold
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Human Rhinovirus (HRV) is the most important aetiologic agent of common cold in adults and children. HRV is a single-stranded, positive sense RNA virus and, despite the high level of conservation among different serotypes, sequence alignment of viral protease 3C with mammalian protease reveals no homology. Thus, protease 3C is an optimal target for the development of anti-HRV agents. In the present work we investigated the design, the synthesis and the development of new potential reversible inhibitors against HRV protease 3C. Docking studies on the crystallized structure of HRV2 protease 3C led us to the design and the synthesis of a series of 3,5 disubstituted benzamides able to act as analogues of the substrate. We also developed 1,3,5 trisubstituted benzamides where aromatic substitutions on the aryl ring led us to investigate the importance of π-π interaction on the stabilization of protease 3C-inhibitor complex. All structures were tested for enzymatic inhibition on HRV14 protease 3C. Results highlighted the inhibitory activity of compounds 13, 14, and 20 (91%, 81%, and 85% at 10 μM, respectively), with the latter exhibiting an ID50 (dose that inhibits 50% of the viral cytopathic effect) on HRV-14 = 25 μg/ml.
- Maugeri, Caterina,Alisi, Maria A.,Apicella, Claudia,Cellai, Luciano,Dragone, Patrizia,Fioravanzo, Elena,Florio, Saverio,Furlotti, Guido,Mangano, Giorgina,Ombrato, Rosella,Luisi, Renzo,Pompei, Raffaello,Rincicotti, Vito,Russo, Vincenzo,Vitiello, Marco,Cazzolla, Nicola
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p. 3091 - 3107
(2008/09/20)
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- METHODS FOR THE PRODUCTION OF FUNCTIONAL PROTEIN FROM DNA HAVING A NONSENSE MUTATION AND THE TREATMENT OF DISORDERS ASSOCIATED THEREWITH
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The present invention relates to functional proteins encoded by nucleic acid sequences comprising a nonsense mutation. The present invention also relates to methods for the production of functional proteins encoded by nucleic acid sequences comprising a nonsense mutation and the use of such proteins for prevention, management and/or treatment of diseases associated with a nonsense mutation(s) in a gene.
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Page/Page column 260
(2008/06/13)
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- COMPOSITIONS OF AN ORALLY ACTIVE 1,2,4-OXADIAZOLE FOR NONSENSE MUTATION SUPPRESSION THERAPY
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The present invention relates to specific doses of and dosing regimens for using a 1,2,4-oxadiazole benzoic acid compound in treating or preventing diseases associated with nonsense mutations. In particular, the invention relates to specific doses and dosing regimens for the use of 3-[5-(2-fluoro-phenyl)-[l,2,4]oxadiazol-3-yl]-benzoic acid in mammals having diseases associated with nonsense mutations.
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Page/Page column 20
(2008/06/13)
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- 11beta-HSD1 Inhibitors
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The invention relates to compounds of formula (I) wherein A, Y, Z1, Z2, R1 to R3 and X1 to X4 have the meaning as cited in the description and the claims. For example A is 4'-fluorobiphen-4-yl; Y is -S(O)2NH-; R1, R2 are H; X1, X2, X4 are CH; X3 is C-F; Z1 is =O; and Z2-R3 is N(CH2CH3)2. Said compounds are useful as 11β-HSD1 inhibitors. The invention also relates to the preparation of such compounds as well as the production and use as medicament.
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Page/Page column 11; 15
(2008/06/13)
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- Cyclic derivatives as modulators of chemokine receptor activity
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The present application describes modulators of MCP-1 of formula (I): or pharmaceutically acceptable salt forms thereof, useful for the treatment of rheumatoid arthritis, multiple sclerosis, atherosclerosis and asthma.
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Page/Page column 46
(2008/06/13)
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- Statistical experimental design-driven discovery of room-temperature conditions for palladium-catalyzed cyanation of aryl bromides
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A combination of Pd2(dba)3·CHCl3 (0.5 mol %) and commercially available, air-stable phosphonium salt [(t-Bu) 3PH]BF4 (1.4 mol %) in a presence of Zn powder and Zn(CN)2 as the cyanide source comprises an extremely efficient catalyst system for the cyanation of a diverse array of aryl bromides, at room temperature. This result emerged from an experimental strategy that combines the advantages of parallel, automated experimentation with the design of experiments (DOE) for the effective definition of an optimal set of reaction conditions.
- Stazi, Federica,Palmisano, Giovanni,Turconi, Marco,Santagostino, Marco
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p. 1815 - 1818
(2007/10/03)
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- Substituted cycloalkylamine derivatives as modulators of chemokine receptor activity
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The present application describes modulators of MCP-1 of formula (I): or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
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Page/Page column 45
(2010/02/11)
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