- Coupling of Reformatsky Reagents with Aryl Chlorides Enabled by Ylide-Functionalized Phosphine Ligands
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The coupling of aryl chlorides with Reformatsky reagents is a desirable strategy for the construction of α-aryl esters but has so far been substantially limited in the substrate scope due to many challenges posed by various possible side reactions. This limitation has now been overcome by the tailoring of ylide-functionalized phosphines to fit the requirements of Negishi couplings. Record-setting activities were achieved in palladium-catalyzed arylations of organozinc reagents with aryl electrophiles using a cyclohexyl-YPhos ligand bearing an ortho-tolyl-substituent in the backbone. This highly electron-rich, bulky ligand enables the use of aryl chlorides in room temperature couplings of Reformatsky reagents. The reaction scope covers diversely functionalized arylacetic and arylpropionic acid derivatives. Aryl bromides and chlorides can be converted selectively over triflate electrophiles, which permits consecutive coupling strategies.
- Hu, Zhiyong,Wei, Xiao-Jing,Handelmann, Jens,Seitz, Ann-Katrin,Rodstein, Ilja,Gessner, Viktoria H.,Goo?en, Lukas J.
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supporting information
p. 6778 - 6783
(2021/02/01)
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- Tetrazolylhydrazides as selective fragment-like inhibitors of the JumonjiC-domain-containing histone demethylase KDM4A
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The JumonjiC-domain-containing histone demethylase 2A (JMJD2A, KDM4A) is a key player in the epigenetic regulation of gene expression. Previous publications have shown that both elevated and lowered enzyme levels are associated with certain types of cancer, and therefore the definite role of KDM4A in oncogenesis remains elusive. To identify a novel molecular starting point with favorable physicochemical properties for the investigation of the physiological role of KDM4A, we screened a number of molecules bearing an iron-chelating moiety by using two independent assays. In this way, we were able to identify 2-(1H-tetrazol-5-yl)acetohydrazide as a novel fragment-like lead structure with low relative molecular mass (Mr=142 Da), low complexity, and an IC50 value of 46.6 μm in a formaldehyde dehydrogenase (FDH)-coupled assay and 2.4 μm in an antibody-based assay. Despite its small size, relative selectivity against two other demethylases could be demonstrated for this compound. This is the first example of a tetrazole group as a warhead in JMJD demethylases. Anchor fragment: To develop non-promiscuous metalloenzyme inhibitors, a metal-complexing acetohydrazide group was integrated in a tetrazolyl fragment, which can be matured into a scaffold to promote further selectivity at the ligand backbone binding site of these emerging drug targets.
- Rüger, Nicole,Roatsch, Martin,Emmrich, Thomas,Franz, Henriette,Schüle, Roland,Jung, Manfred,Link, Andreas
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p. 1875 - 1883
(2015/11/10)
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- Alcohol assisted C-C bond breaking: Copper-catalyzed deacetylative α-arylation of β-keto esters and amides
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A method of alcohol-assisted copper-catalyzed highly selective deacetylative α-arylation of β-keto esters and amides has been demonstrated, which illustrated an efficient example of achieving α-aryl esters and amides. From the synthetic point of view, this arylation protocol is general and practical, representing a simple way to produce α-arylated carbonyl compounds from basic starting materials at low cost.
- Ke, Jie,He, Chuan,Liu, Huiying,Xu, Huan,Lei, Aiwen
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supporting information
p. 6767 - 6769
(2013/07/26)
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- Synthesis of arylacetates from benzylic alcohols and oxalate esters through decarboxylative coupling
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Follow that dream: By combining a reversible transesterification between benzylic alcohols and dialkyl oxalates with catalytic decarboxylation of the resulting esters, a regiospecific C-C-bond-forming reaction to give α-arylacetates was achieved. In the overall process, CO2 and a volatile alcohol are the only byproducts. Various α-arylacetates were thus synthesized in high yields from easily accessible starting materials in the presence of catalytic amounts of Pd(OAc)2, dppp, and DABCO (see scheme). Copyright
- Gruenberg, Matthias F.,Goossen, Lukas J.
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supporting information
p. 7334 - 7337
(2013/06/27)
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- Practical and scalable synthesis of ethyl (R)-piperidine-3-acetate
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A practical and scalable synthesis of ethyl (R)-piperidine-3-acetate was achieved from commercially available 3-pyridylacetic acid in 76% overall yield. The practical synthesis was demonstrated on 100-g scale. One-pot reductive N-ethylation of the pyridinium salt with acetonitrile gave an N-ethyl piperidine derivative. Copyright Taylor & Francis Group, LLC.
- Zhu, Ying-Guang,Kan, Hong-Zhu,Jiang, Li-Qin,Hu, Wen-Hao
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experimental part
p. 1137 - 1145
(2012/05/05)
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- Synthesis, anticonvulsant activity, and neuropathic pain-attenuating activity of N-benzyl 2-amino-2-(hetero)aromatic acetamides
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N-Benzyl 2-acetamido-2-substituted acetamides, where the 2-substituent is a (hetero)aromatic moiety, are potent anticonvulsants. We report the synthesis and whole animal pharmacological evaluation of 16 analogues where the terminal 2-acetyl group was removed to give the corresponding primary amino acid derivatives (PAADs). Conversion to the PAAD structure led to a substantial drop in seizure protection in animal tests, demonstrating the importance of the N-acetyl moiety for anticonvulsant activity. However, several of the PAADs displayed notable pain-attenuating activities in a mouse model.
- Baruah, Pranjal K.,Dinsmore, Jason,King, Amber M.,Salomé, Christophe,De Ryck, Marc,Kaminski, Rafal,Provins, Laurent,Kohn, Harold
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supporting information; experimental part
p. 3551 - 3564
(2012/07/28)
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- COMPOUNDS
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Disclosed are compounds that inhibit Lp-PLA2 activity, processes for their preparation, compositions containing them and their use in the treatment of diseases associated with the activity of Lp-PLA2, for example atherosclerosis, Alzheimer's disease, and/or diabetic macular edema.
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Page/Page column 36
(2012/06/30)
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- Pd-catalyzed decarboxylative cross-couplings of potassium malonate monoesters with aryl halides
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An efficient catalytic protocol for Pd-catalyzed decarboxylative cross-coupling of potassium malonate monoesters and derivatives with aryl bromides and chlorides are described. Because of its broad applicability, this new catalytic system provides an alternative method for the preparation of diverse aryl acetic acids and derivatives.
- Feng, Yi-Si,Wu, Wei,Xu, Zhong-Qiu,Li, Yan,Li, Ming,Xu, Hua-Jian
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experimental part
p. 2113 - 2120
(2012/03/26)
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- Synthesis of α-Aryl nitriles through palladium-catalyzed decarboxylative coupling of cyanoacetate salts with aryl halides and triflates
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Worth its salt: The palladium-catalyzed decarboxylative coupling of the cyanoacetate salt as well as its mono- and disubstituted derivatives with aryl chlorides, bromides, and triflates is described (see scheme). This reaction is potentially useful for the preparation of a diverse array of α-aryl nitriles and has good functional group tolerance. S-Phos=2-(2,6- dimethoxybiphenyl)dicyclohexylphosphine), Xant-Phos=4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene. Copyright
- Shang, Rui,Ji, Dong-Sheng,Chu, Ling,Fu, Yao,Liu, Lei
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supporting information; experimental part
p. 4470 - 4474
(2011/06/24)
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- Cu(I)Br-mediated preparation of 14C-labeled 3-pyridine-acetate derivatives and synthesis of a novel 14C-labeled PDE-IV inhibitor
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An efficient protocol for the synthesis of 14C-labeled 3-pyridineacetate (1) and its N-oxide ([14C]2) is described. Oxidation of this pyridine ([14C]1) to its N-oxide ([ 14C]2) proceeded in high yield using H2O2 with MeReO3 as a catalyst. The reaction employs readily available diethyl [2-14C]malonate. This method has proven to be general in preparation of other pyridineacetate derivatives and their N-oxides which have been typically difficult to prepare by other means. Our development of the Cu(I)Br-coupling methodology as well as application to the synthesis of a 14C-labeled phosphodiesterase-IV (PDE-IV) inhibitor, [ 14C]3, are also reported. Copyright
- Ho, Jonathan Z.,Braun, Matthew P.
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p. 277 - 280
(2008/02/08)
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- 1,2-disubstituted-6-oxo-3-phenyl-piperidine-3-carboxamides and combinatorial libraries thereof
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The invention relates to combinatorial libraries containing two or more novel piperidine-3-carboxamide derivative compounds, methods of preparing the piperidine-3-carboxamide derivative compounds and piperidine-3-carboxamide derivative compounds bound to a resin
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- Syntheses and UV/Vis-spectroscopic properties of hydrophilic 2-, 3-, and 4-pyridyl-substituted solvatochromic and halochromic pyridinium N-phenolate betaine dyes as new empirical solvent polarity indicators
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Syntheses and negative solvatochromism of nine new hydrophilic 2-, 3-, and 4-pyridyl-substituted pyridinium N-phenolate betaine dyes 3-11 are described. These were produced in order to obtain zwitterionic dyes better soluble in water and other aqueous media (such as binary water/solvent mixtures, aqueous ionophore solutions) than the rather hydrophobic standard betaine dyes 1 and 2, which have been used to establish an empirical scale of solvent polarity, called the ET(30) scale. Betaine dye 8, in which three of the peripheral phenyl groups of 1 are replaced by two 3-pyridyl rings and one 4-pyridyl ring, proved to be particularly suitable for the determination of ET(30) values in aqueous media. Wiley-VCH Verlag GmbH, 2001.
- Reichardt, Christian,Che, Daqing,Heckenkemper, Guido,Schaefer, Gerhard
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p. 2343 - 2361
(2007/10/03)
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- Palladium catalyzed arylation of malonate accompanying in situ dealkoxycarbonylation
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One-pot conversion of aryl halides into aryl acetates was achieved by the palladium catalyzed arylation of malonate accompanying in situ dealkoxycarbonylation of aryl malonates using Cs2CO3 as a base and as a catalyst.
- Kondo,Inamoto,Uchiyama,Sakamoto
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p. 2704 - 2705
(2007/10/03)
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- Synthesis of ethoxyethynylarenes by the palladium-catalyzed reaction of aryl iodides with ethoxy(trialkylstannyl)acetylenes
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Palladium-catalyzed reaction of aryl and heteroaryl iodides with ethoxy(trialkylstannyl)acetylenes gave the ethoxyethynylarenes and -heteroarenes, which were easily transformed by hydration reaction into ethyl areneacetates and heteroareneacetates.
- Sakamoto,Yasuhara,Kondo,Yamanaka
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p. 2032 - 2035
(2007/10/02)
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- Studies on Pyrimidine Derivatives. XXXVIII. Cross-Coupling Reaction of N-Heteroaryl Iodides with Ethoxycarbonylmethylzinc Bromide in the Presence of Palladium Catalyst
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In the presence of tetrakis(triphenylphosphine)palladium, 2-iodo-4,6-dimethylpyrimidine and 4-iodo-2,6-dimethylpyrimidine reacted with ethoxycarbonylmethylzinc bromide (Reformatsky reagent) to give ethyl 4,6-dimethyl-2-pyrimidineacetate and ethyl 2,6-dimethyl-4-pyrimidineacetate, respectively.In contrast, the reaction of 5-iodo-2,4-dimethylpyrimidine with the same reagent resulted in recovery of the starting iodide.Similar results were observed in the reactions of various N-heteroaryl iodides.Keywords - Reformatsky reagent; cross-coupling reaction; N-heteroaryl halide; N-heteroarylacetic acid; palladium catalyst; ethyl bromoacetate
- Yamanaka, Hiroshi,An-naka, Masayuki,Kondo, Yoshinori,Sakamoto, Takao
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p. 4309 - 4313
(2007/10/02)
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- THE PREPARATION OF 2-(3-PYRIDYL)MALEIMIDE
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The novel compound, 2-(3-pyridyl)maleimide, 7 was prepared by an efficient sequence involving the synthesis of ethyl 2-(3-pyridyl)acrylate, 3, from ethyl 2-(3-pyridyl)acetate, 1, followed by Michael-addition of HCN (via acetone cyanohydrin-MeOH) to give cyanoester 4.Alteranatively, 4 was prepared from the methyl ester 8 by alkylation with iodoacetonitrile.Acid hydrolysis gave amide-ester 5 which was then cyclized with NaOEt to 2-(3-pyridyl)succimide, 6.Oxidation of 6 to maleimide 7 was achieved with N-chlorosuccinimide in pyridine, to give an overall yield of 58percent.
- Narula, Anubhav P. S.,Epstein, Joseph W.
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p. 3055 - 3058
(2007/10/02)
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