- Decarboxylative Alkylation of Heteroarenes Using N-Hydroxybenzimidoyl Chloride Esters
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Functionalized N-heteroarenes are highly desired motifs in medicinal chemistry and pharmaceutical industry. Minisci-type reactions usually require a protonated N-heteroarene for the alkyl radical to attack. This work describes a leaving-group-assisted redox-active ester to enable direct coupling of an amino acid with N-heteroarenes. The efficient and sustainable photoredox strategy provides rapid access to an alkylated heterocyclic manifold.
- Li, Xiaojuan,Zhang, Qiang,Zhang, Weigang,Wang, Yi,Pan, Yi
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Read Online
- Leaving Group Assisted Strategy for Photoinduced Fluoroalkylations Using N-Hydroxybenzimidoyl Chloride Esters
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Redox-active esters (RAEs) as alkyl radical precursors have been extensively developed for C?C bond formations. However, the analogous transformations of fluoroalkyl radicals from the corresponding acid or ester precursors remain challenging because of the high oxidation potential of the fluoroalkyl carboxylate anions. The newly developed N-hydroxybenzimidoylchloride (NHBC) ester provides a general leaving group assisted strategy to generate a portfolio of fluoroalkyl radicals, and can be successfully applied in photoinduced decarboxylative hydrofluoroalkylation and heteroarylation of unactivated olefins. In addition, DFT calculations revealed that the NHBC ester proceeds by the fluorocarbon radical pathway, whereas other well-known RAEs proceed by the nitrogen radical pathway.
- Zhang, Weigang,Zou, Zhenlei,Wang, Yuanheng,Wang, Yi,Liang, Yong,Wu, Zhengguang,Zheng, Youxuan,Pan, Yi
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supporting information
p. 624 - 627
(2018/12/13)
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- Terminal Alkyne-Assisted One-Pot Synthesis of Arylamidines: Carbon Source of the Amidine Group from Oxime Chlorides
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A terminal alkyne-assisted protocol for the one-pot formation of a diverse range of arylamidines from a novel cascade reaction of in situ generated nitrile oxides, sulfonyl azides, terminal alkynes, and water by [3 + 2] cycloaddition and ring opening sequ
- Yi, Fengping,Sun, Qihui,Sun, Jing,Fu, Chao,Yi, Weiyin
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supporting information
p. 6780 - 6787
(2019/06/14)
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- Valdecoxib: Vs. borazavaldecoxib: Isoxazole BN/CC isosterism as a case study in designing and stabilizing boron heterocycles
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A comprehensive study on the preparation, hydrolytic stability, and the structural and spectrophotometric properties of 1,2,4,5-oxadiazaboroles is presented by way of a comparison between the NSAID drug valdecoxib (1) and its unprecedented B-N isostere, borazavaldecoxib (2). Knowledge gained from this study was employed in the design of oxadiazaborate salts, a novel class of tetrahedral boron heterocycles displaying good stability in aqueous conditions with promising antifungal and antibacterial properties.
- Boghi, Michele,Hall, Dennis G.
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supporting information
p. 4849 - 4856
(2018/07/13)
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- Reaction between (Z)-Arylchlorooximes and α-Isocyanoacetamides: A procedure for the synthesis of Aryl-α-ketoamide amides
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(Z)-Arylchlorooximes and α-isocyanoacetamides undergo a smooth reaction to produce 1,3-oxazol-2-oxime derivatives in good yields. Opening of the oxazole ring and deoximation reaction give a facile access to aryl-α-ketoamide amides, a class of privileged s
- Giustiniano, Mariateresa,Mercalli, Valentina,Cassese, Hilde,Di Maro, Salvatore,Galli, Ubaldina,Novellino, Ettore,Tron, Gian Cesare
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p. 6006 - 6014
(2014/07/21)
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- Isocyanide-mediated multicomponent synthesis of C-oximinoamidines
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By capitalizing on the different reactivity of nitrile N-oxides with isocyanides and amine, α-oximinoamidines, a so far elusive class of compounds, have been synthesized in a straightforward way by reacting isocyanides, syn-chlorooximes, and amines in a multicomponent fashion.
- Mercalli, Valentina,Meneghetti, Fiorella,Tron, Gian Cesare
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supporting information
p. 5902 - 5905
(2013/12/04)
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- HETEROCYCLIC COMPOUNDS AS S1P1 AGONISTS FOR THE TREATMENT OF AUTOIMMUNE AND VASCULAR DISEASES
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Disclosed are compounds of Formula (I) or stereoisomers, salts, or prodrugs thereof, wherein: W is CH2 or O; Q is Formula (II), Formula (III) or Formula (IV); and R1, R2, R3, R4, n, and G are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.
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Page/Page column 44; 45
(2012/05/20)
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- AMINOPYRAZINE COMPOUNDS USEFUL AS INHIBITORS OF TRA KINASE
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The present invention relates to compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. The compounds of this invention have formula (I): wherein the variables are as defined herein.
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Page/Page column 97
(2012/10/18)
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- Stereospecific synthesis of syn -α-oximinoamides by a three-component reaction of isocyanides, syn -chlorooximes, and carboxylic acids
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A stereospecific multicomponent reaction among isocyanides, syn-chlorooximes, and carboxylic acids provides an efficient synthesis of biologically relevant syn-α-oximinoamides.
- Pirali, Tracey,Mossetti, Riccardo,Galli, Simona,Tron, Gian Cesare
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supporting information; experimental part
p. 3734 - 3737
(2011/09/15)
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- SPHINGOSINE-1-PHOSPHATE RECEPTOR AGONISTS
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Disclosed are compounds of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: A is formula (II) Q is a substituted 5-membered monocyclic heteroaryl group; W is CH2, O, or NH; and R1, R2, R3, R4, R5, R6, m, n, t, and x are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.
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Page/Page column 67-68
(2011/02/24)
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- TRICYCLIC HETEROCYCLIC COMPOUNDS
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Disclosed are compounds of Formula (I) or stereoisomers or salts thereof, wherein: X1, X2, X3, W, Q1, Q2, and G2 are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.
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Page/Page column 80
(2011/06/16)
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- 4 - (5 - ISOXAZOLYL OR 5 - PYRRAZOLYL -1,2,4- OXADIAZOL - 3 - YL) -MANDELIC ACID AMIDES AS SPHINGOSIN- 1 - PHOSPHATE 1 RRECEPTOR AGONISTS
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Disclosed are compounds of Formula (I) or stereoisomers, salts, or prodrugs thereof, wherein: Q is, or R1 is phenyl substituted with zero to 3 substituents; and R1, R2, R3, R4, R5, and G are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.
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Page/Page column 56-57
(2011/11/06)
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- Studies of nitrile oxide cycloadditions, and the phenolic oxidative coupling of vanillin aldoxime by Geobacillus sp. DDS012 from Italian rye grass silage
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During studies directed towards the discovery of nitrile hydrolysing enzymes from thermophiles, vanillin aldoxime was incubated with the thermophilic organism, Geobacillus sp. DDS012 isolated from Italian rye grass (Lolium multiflorum) silage. The predominant product was a dihydro-dimer, which could only be characterised by LC-MS. This was initially imagined to be the product of cycloaddition of vanillin aldoxime with the corresponding nitrile oxide, but preparation of the supposed adduct and model studies excluded this possibility. The rate constant for the second order dimerisation of 4-O-acetyl vanillin nitrile oxide was measured (1.21 × 10-4 M-1 s -1, 0.413 M, 25 °C) and the 13C-NMR signal for the nitrile oxide carbon was observed (δC 34.4, br. t 1J13C,14N circa 50 Hz). Treatment of vanillin aldoxime with potassium persulfate and iron sulfate gave material with the same LC-MS properties as the natural product, which is therefore identified as 5,5′-dehydro-di-(vanillin aldoxime) 1d formed by phenolic oxidative coupling. This journal is The Royal Society of Chemistry.
- Kelly, David R.,Baker, Simon C.,King, David S.,De Silva, Deepa S.,Lord, Gwyn,Taylor, Jason P.
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p. XX787-796
(2008/09/17)
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- Diastereoselective cycloadditions of a soluble polymer-supported substituted allyl alcohol derived from Baylis-Hillman reaction with nitrile oxides
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A diastereoselective cycloaddition of a soluble polymer-supported Baylis-Hillman adduct with nitrile oxides is described. The reaction has shown to proceed with moderate diastereoselectivity, favoring the syn isomer of the resulting 3,5-substituted isoxazolines. The stereochemistry of the products has been assigned using 1H NMR studies. The structure of one of the diastereomers has been determined by single-crystal X-ray crystallographic analysis.
- Shang, Yongjia,Feng, Zhijun,Yuan, Lili,Wang, Shaowu
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p. 5779 - 5783
(2008/09/21)
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- Substituted Spiro Compounds and Their Use for Producing Pain-Relief Medicaments
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The present invention relates to substituted spiro compounds, to processes for preparing them, to medicaments comprising these compounds and to the use of these compounds for producing medicaments.
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- Synthesis of [2,3,4,5,6-2H5]phenyl glucosinolate
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Starting from commercially available [2,3,4,5,6-2H 5]benzoic acid, [2,3,4,5,6-2H5]phenyl glucosinolate was synthesized. Under negative-ion electrospray-ionization mass spectrometric conditions, this compound affords a peak at m/z 399. Since this m/z value is not known from the ions derived from natural glucosinolates, the [2,3,4,5,6-2H5]phenyl glucosinolate reported here is useful as an internal standard for the quantification of glucosinolates by negative-ion mass spectrometry (MS) and liquid chromatography (LC)/MS techniques. Copyright
- Bialecki, Jason B.,Ruzicka, Josef,Attygalle, Athula B.
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p. 711 - 715
(2008/02/11)
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- N,N′-dihydroxyamidines: A new prodrug principle to improve the oral bioavailability of amidines
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N,N′-Dihydroxybenzamdine represents a model compound for a new prodrug principle to improve the oral bioavailability of drugs containing amidine functions. The activation of the prodrug could be demonstrated in vitro by porcine and human subcellular enzyme fractions, the mitochondrial benzamidoxime reducing system, and porcine hepatocytes. In vivo, the bioavailability of benzamidine after oral application of N,N′- dihydroxybenzamidine was about 91% and exceeded that of benzamidine after oral application of benzamidoxime, being about 74% (Liu, L.; Ling, Y.; Havel, C.; Bashnick, L.; Young, W.; Rai, R.; Vijaykumar, D.; Riggs, J. R.; Ton, T.; Shaghafi, M.; Graupe, D.; Mordenti, J.; Sukbuntherng, J. Species comparison of in vitro and in vivo conversion of five N-hydroxyamidine prodrugs of fVIIA inhibitors to their corresponding active amidines. Presented at the 13th North America ISSX Meeting, Maui, HI, 2005).
- Reeh, Christiane,Wundt, Judith,Clement, Bernd
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p. 6730 - 6734
(2008/09/17)
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- Potent inhibitors of lipoprotein-associated phospholipase A2: Benzaldehyde O-heterocycle-4-carbonyloxime
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A series of multi-substituted oximes were prepared and their potencies for inhibiting lipoprotein-associated phospholipase A2 (Lp-PLA2) activity were evaluated in vitro. Among them, compounds 3a, 3b, and 3m were identified to display a micromolar potency for inhibiting Lp-PLA2 in whole human plasma and isolated human LDL. Based on these results, structure-activity relationship was studied on modification of three parts of R1, R2, and R3 to identify a potent pharmacophore for Lp-PLA2. In an attempt to introduce various functional groups at R2 and R3, we discovered that replacement of less lipophilic groups led to an increase of inhibitory activity. Among the tested oxime derivatives, cyano- and morpholino-substituted analogue 4f at R2 and R3 had the highest potency with an IC50 value of 0.05 μM in whole human plasma.
- Jeong, Hyung Jae,Park, Yong-Dae,Park, Ho-Yong,Jeong, Il Yun,Jeong, Tae-Sook,Lee, Woo Song
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p. 5576 - 5579
(2007/10/03)
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- SUBSTITUTED SPIRO COMPOUNDS AND THEIR USE FOR PRODUCING PAIN-RELIEF MEDICAMENTS
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The present invention relates to substituted spiro compounds, processes for preparing them, medicaments comprising these compounds, and the use of these compounds for producing medicaments.
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Page/Page column 73
(2010/11/24)
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- SUBSTITUTED SPIRO-COMPOUNDS AND THE USE THEREOF FOR PRODUCING MEDICAMENTS
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The invention relates to substituted spiro-compounds, to methods for producing the same, to medicaments comprising said compounds and to the use of said compounds for producing medicaments.
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Page/Page column 90-91
(2008/06/13)
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- A modular approach to polyketide building blocks: Cycloadditions of nitrile oxides and homoallylic alcohols
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(Chemical Equation Presented) A general approach to the diastereoselective synthesis of Δ2-isoxazolines via magnesium-mediated, hydroxyl-directed diastereoselective nitrile oxide cycloadditions of homoallylic alcohols and monoprotected homoallylic diols is disclosed. A broad spectrum of aliphatic and aromatic nitrile oxides and a variety of homoallylic alcohols participate in the cycloaddition, thus expanding the scope of polyketide building blocks that can be accessed using this strategy.
- Lohse-Fraefel, Nina,Carreira, Erick M.
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p. 2011 - 2014
(2007/10/03)
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- COMPOUNDS AND COMPOSITIONS AS PPAR MODULATORS
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The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of the Peroxisome Proliferator-Activated Receptor (PPAR) families, particularly the activity of PPAR .
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Page/Page column 63-64
(2010/02/14)
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- Inhibitors of c-Jun N terminal kinases (JNK) and other protein kinases
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The present invention provides compounds of formula I: 1where R1 is H, CONH2, T(n)—R, or T(n)—Ar2, n may be zero or one, and G, XYZ, and Q are as described below. These compounds are inhibitors of protein kinase, particularly inhibitors of JNK, a mammalian protein kinase involved cell proliferation, cell death and response to extracellular stimuli. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.
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- Substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones as hypoglycemic agents
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A series of substituted tetrahydropyrrolo[2,1-b]oxazol-5(6H)-ones and tetrahydropyrrolo[2,1-b]thiazol-5(6H)-ones was synthesized from amino alcohols or amino thiols and keto acids. A pharmacological model based on the results obtained with these compounds led to the synthesis and evaluation of a series of isoxazoles and other monocyclic compounds. These were evaluated for their ability to enhance glucose utilization in cultured L6 myocytes. The in vivo hypoglycemic efficacy and potency of these compounds were evaluated in a model of type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus), the ob/ob mouse. 25a(2S) (SDZ PGU 693) was selected for further pharmacological studies.
- Aicher, Thomas D.,Balkan, Bork,Bell, Philip A.,Brand, Leonard J.,Cheon,Deems, Rhonda O.,Fell, Jay B.,Fillers, William S.,Fraser, James D.,Gao, Jiaping,Knorr, Douglas C.,Kahle, Gerald G.,Leone, Christina L.,Nadelson, Jeffrey,Simpson, Ronald,Smith, Howard C.
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p. 4556 - 4566
(2007/10/03)
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- Unusual Regioselectivity of the Dipolar Cycloaddition Reactions of Nitrile Oxides and Tertiary Cinnamides and Crotonamides
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Benzonitrile oxides undergo 1,3-dipolar cycloaddition reactions with methyl cinnamate to produce the 5-phenyl and 4-phenyl regioisomers in approximately an 80:20 ratio. However, use of N,N-diethylcinnamide as the dipolarophile unexpectedly resulted in the formation of the 5-phenyl and 4-phenyl regioisomers in a 23:77 ratio. Studies have shown that this phenomena occurs only for tertiary cinnamides. In addition, it has been demonstrated that the phenyl group of tertiary cinnamides is not essential for the reversal of regioselectivity since crotonamides produce the same results and trends as the cinnamides. However, since acrylates and acrylamides both produce the 5-carbonyl regioisomers, it can be concluded that the β-substituent is playing a key role for the unexpected results by possibly increasing steric interactions between the dipole and dipolarophile in the transition state. Transition state energies were calculated for the regioisomeric cycloadduct pairs derived from several crotonamides as well as methyl crotonate. These calculations indicate that steric factors are indeed responsible for the reversal of regioselectivity.
- Weidner-Wells, Michele A.,Fraga-Spano, Stephanie A.,Turchi, Ignatius J.
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p. 6319 - 6328
(2007/10/03)
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- Rearrangement Reactions of Aziridinylbenzaldoximes
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Reactions of 2,2-dimethylaziridine with benzohydroximoyl chlorides [ArC(Cl)=NOH] give aziridinyl-benzaldoximes 1. It has been found that the aziridine ring in these compounds undergoes ring opening in hydrogen chloride-dioxane solution to give (Z)-N-hydro
- Johnson, James E.,Nwoko, Delphine,Hotema, Martha,Sanchez, Natalia,Alderman, Reidun,Lynch, Vincent
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p. 1583 - 1592
(2007/10/03)
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- Fungicides
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This invention relates to derivatives of propanoic acid of the formula STR1 Useful as fungicides, insecticides and miticides, to processes for preparing them, to compositions containing them, and to methods of using them to combat fungi, especially fungal infections of plants, and to kill or control insects and mites.
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- A Clear Demonstration of the Stereoelectronic Effect of Nitrogen in Chloride Ion loss by (E)- and (Z)-Hydroximoyl Chlorides
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(E)-Benzohydroximoyl chlorides have been examined for the first time and are shown to react (as the conjugate ion) > 10E7-fold more slowly than the corresponding (Z)-benzohydroximoyl chloride anions.This large rate difference is attributed to the favourab
- Hegarty, Anthony F.,Mullane, Maria
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p. 995 - 1002
(2007/10/02)
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- Large Stereoelectronic Effect in 1,3-Dehydrohalogenation to form a 1,3-Dipole
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The E-hydroximidoyl chloride (5), prepared on photoisomerisation of (1) to (2) and by subsequent hydrolysis, is shown to lose HCl to give benzonitrile oxide 6*107 fold slower than the Z-isomer (3).
- Hegarty, Anthony F.,Mullane, Maria
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p. 229 - 230
(2007/10/02)
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