- Programmed Sequential Additions to Halogenated Mucononitriles
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Dihalomucononitriles were synthesized and their reactivity evaluated to assess their ability to function as linchpin reagents. Bis(2-chloroacrylonitrile) and bis(2-bromoacrylonitrile) were synthesized from 2,1,3-benzothiadiazole and undergo conjugate addition/elimination reactions with both nitrogen (40-95% yield) and carbon nucleophiles (72-93% yield). Secondary amines undergo monosubstitutions, while carbon nucleophiles are added twice. The sequence of addition of the nucleophiles could be controlled to give mixed addition products. The multicomponent coupling products could then be converted to natural product like motifs using intramolecular cyclization reactions.
- Zahara, Adam J.,Hinds, Elsa M.,Nguyen, Andrew L.,Wilkerson-Hill, Sidney M.
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p. 8065 - 8069
(2020/11/02)
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- Validating the 1,2-Difluoro Motif As a Hybrid Bioisostere of CF3and et Using Matrix Metalloproteinases As Structural Probes
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Matrix metalloproteinases (MMPs) are involved in a spectrum of physiological processes, rendering them attractive targets for small-molecule drug discovery. Strategies to achieve selective inhibition continue to be intensively pursued, facilitated by advances in structural biology. Herein, we harness MMPs 2, 8, 9, and 13 to validate the vicinal difluoro motif as a hybrid bioisostere of CF3 and Et (BITE) in a series of modified barbiturate inhibitors. Crystallographic analyses of representative structures reveal conformations of the vicinal difluoro motif that manifest stabilizing hyperconjugative interactions consistent with the stereoelectronic gauche effect. Detailed docking studies of a potent difluorinated probe with MMP-9 are also disclosed and indicate that the structural basis of inhibition is a consequence of the anisotropic nature of the motif. Significant selectivity of MMP 13 versus MMP-2 can be achieved by subtle chain contraction in a BITE-modified inhibitor.
- Erdeljac, Nathalie,Thiehoff, Christian,Jumde, Ravindra P.,Daniliuc, Constantin G.,H?ppner, Sandra,Faust, Andreas,Hirsch, Anna K. H.,Gilmour, Ryan
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p. 6225 - 6237
(2020/07/14)
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- Environmentally benign nucleophilic substitution reaction of arylalkyl halides in water using CTAB as the inverse phase transfer catalyst
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An environmentally benign, practically scalable and highly selective C-arylalkylation of active methylene compounds is developed using CTAB as the inverse phase transfer catalyst in water. The methodology developed is elaborated into the one-pot synthesis of quinoline derivatives and also applicable to the regioselective N-aralkyl of 2-pyridones.
- Godha, Atul K.,Thiruvengadam, Jayaraman,Abhilash, Viswanadhan,Balgi, Prajwal,Narayanareddy,Vignesh, Kumaresan,Gadakh, Amol V.,Sathiyanarayanan,Ganesh, Sambasivam
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supporting information
p. 16041 - 16045
(2019/10/28)
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- Biocatalytic Desymmetrization of Prochiral 3-Aryl and 3-Arylmethyl Glutaramides: Different Remote Substituent Effect on Catalytic Efficiency and Enantioselectivity
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Catalyzed by an amidase-containing Rhodococcus erythropolis AJ270 microbial whole cell catalyst in neutral phosphate buffer at 30 °C, desymmetric hydrolysis of a series of prochiral 3-aryl and 3-arylmethylglutaramides efficiently afforded 3-substituted glutaric acid monoamides in up to 95% yield and >99.5% ee. Even far away from the reaction site, the substituents on the aryl still have a significant effect on the catalytic activity and enantioselectivity and different remote substituent effect was observed for the two types of substrates. The synthetic application of biocatalytic desymmetrization was demonstrated by the facile transformation of the obtained enantiopure (R)-3-substituted 4-carbamoylbutanoic acid products to chiral dihydroquinolinone and δ-lactone compounds. (Figure presented.).
- Ao, Yu-Fei,Zhang, Li-Bin,Wang, Qi-Qiang,Wang, De-Xian,Wang, Mei-Xiang
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supporting information
p. 4594 - 4603
(2018/10/31)
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- Synthesis and insecticidal activity of mesoionic pyrido[1,2-α]pyrimidinone derivatives containing a neonicotinoid moiety
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Mesoionic pyrido[1,2-α]pyrimidinone derivatives containing a neonicotinoid moiety were designed, synthesized, and evaluated for their insecticidal activity. Some of the title compounds showed remarkable insecticidal properties against Aphis craccivora. Compound I13 exhibited satisfactory insecticidal activity against A. craccivora. Meanwhile, label-free proteomics analysis of compound I13 treatment identified a total of 821 proteins. Of these, 35 proteins were up-regulated, whereas 108 proteins were down-regulated. Differential expressions of these proteins reflected a change in cellular structure and metabolism.
- Pan, Jianke,Yu, Lu,Liu, Dengyue,Hu, Deyu
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- Palladium-Catalyzed, Ring-Forming Aromatic C-H Alkylations with Unactivated Alkyl Halides
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A catalytic C-H alkylation using unactivated alkyl halides and a variety of arenes and heteroarenes is described. This ring-forming process is successful with a variety of unactivated primary and secondary alkyl halides, including those with β-hydrogens. In contrast to standard polar or radical cyclizations of aromatic systems, electronic activation of the substrate is not required. The mild, catalytic reaction conditions are highly functional group tolerant and facilitate access to a diverse range of synthetically and medicinally important carbocyclic and heterocyclic systems.
- Venning, Alexander R. O.,Bohan, Patrick T.,Alexanian, Erik J.
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supporting information
p. 3731 - 3734
(2015/04/14)
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- Tuning the lewis acidity of boranes in frustrated lewis pair chemistry: Implications for the hydrogenation of electron-poor alkenes
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An analysis of the metal-free reduction of electron deficient olefins by frustrated Lewis pairs indicates that the rate-determining step might be either the heterolytic cleavage of H2 to form an -onium borohydride salt, or the subsequent transfer of the hydride moiety to the substrate following a Michael-type addition reaction. While the use of strong Lewis acids such as B(C6F5)3 facilitates the first of these processes, hydride transfer to the olefin should be contrarily favoured by the use of weak Lewis acids which, for this very same reason, might be unable to promote the prior H2 split. After systematic testing of several boranes of different Lewis acidity (assessed by using the Childs' method) and steric demand, an optimal situation that employs tris(2,4,6-trifluorophenyl) borane was reached. Mixtures of this borane with 1,4-diazabicyclo[2.2.2]octane (DABCO) exhibited excellent catalytic activity for the hydrogenation of alkylidene malonates. In fact, this transformation could be achieved under milder conditions than those we reported previously. Moreover, the reaction scope could be expanded to other electron deficient olefins containing esters, sulfones or nitro functionalities as electron-withdrawing substituents.
- Nicasio, Juan A.,Steinberg, Sebastian,Ines, Blanca,Alcarazo, Manuel
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p. 11016 - 11020
(2013/09/02)
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- Metal-free hydrogenation of electron-poor allenes and alkenes
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The poorer, the better: A metal-free catalytic procedure for the reduction of electron-poor allenes and alkenes has been developed. The method employs a frustrated Lewis pair based catalyst. 1,4-Diazabicyclo[2.2.2]octane (DABCO)/B(C6F5)3 was shown to be the best combination in optimization studies. Copyright
- Ines, Blanca,Palomas, David,Holle, Sigrid,Steinberg, Sebastian,Nicasio, Juan A.,Alcarazo, Manuel
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supporting information
p. 12367 - 12369
(2013/02/22)
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- Pd(II)-catalyzed intramolecular amidoarylation of alkenes with molecular oxygen as sole oxidant
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Stereoselective palladium-catalyzed synthesis of structurally versatile indoline derivatives, using molecular oxygen as the sole oxidant, is described. New C-N and C-C bonds form across an alkene in an intramolecular manner. The C-N bond-forming step proceeds via a syn-amidopalladation pathway. The moderate kinetic isotope effects (intramolecular KIE = 3.56) suggest that electrophilic aromatic substitution occurs in the arylation step.
- Yip, Kai-Tai,Yang, Dan
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supporting information; experimental part
p. 2134 - 2137
(2011/06/19)
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- NOVEL MALONIC ACID SULFONAMIDE DERIVATIVE AND PHARMACEUTICAL USE THEREOF
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The present invention provides a novel compound having an agonist action at AT2 receptor and expected as a pharmaceutical product, and also provides a method of treating or preventing various diseases. The novel sulfonyl malonamide derivative,
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Page/Page column 50
(2010/04/25)
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- Highly efficient synthesis of functionalized dihydronaphthalenes, tetrahydronaphthalenes, and tetrahydroisoquinolines by iron-catalyzed intramolecular Friedel-Crafts reaction of aryl-containing propargylic alcohols
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An efficient, convenient, and one-pot procedure for the synthesis of a series of new dihydro- and tetrahydronaphthalenes as well as tetrahydroisoquinolines has been established through Lewis acid-catalyzed intramolecular Friedel-Crafts reaction of aryl-substituted propargylic alcohols.
- Huang, Wen,Hong, Longcheng,Zheng, Pengzhi,Liu, Ruiting,Zhou, Xigeng
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body text
p. 3603 - 3610
(2009/09/06)
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- Controllable one-step synthesis of spirocycles, polycycles, and di- and tetrahydronaphthalenes from aryl-substituted propargylic alcohols
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(Chemical Equation Presented) A novel, convenient, and efficient method has been developed for selective synthesis of spirocycle, polycycle, and di-and tetrahydronaphthalene systems from aryl-substituted propargylic alcohols by FeCl3- or TsOH-catalyzed multiple activations of unsaturated C-C bonds and C-H bonds.
- Huang, Wen,Zheng, Pengzhi,Zhang, Zhengxing,Liu, Rutting,Chen, Zhenxia,Zhou, Xigeng
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p. 6845 - 6848
(2008/12/22)
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- Unprecedented reaction between ethyl α-cyanocinnamate and o-phenylenediamine: Development of an efficient method for the transfer hydrogenation of electronically depleted olefins
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A reaction between ethyl α-cyanocinnamate and o-phenylenediamine under thermal conditions yielded 2-cyano-3-phenyl-propionic acid ethyl ester, 2-phenyl benzimidazole, and ethyl cyanoacetate. The mechanistic revelations led to the development of a simple and efficient transfer-hydrogenation process from the in situ generated benzimidazolines to activated olefins under solventless and catalyst-free conditions. Georg Thieme Verlag Stuttgart.
- Kumar, Satish,Kapoor, Kamal K.
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p. 2809 - 2814
(2008/02/13)
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- Modified pyrimidine glucocorticoid receptor modulators
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The present invention provides a novel class of modified pyrimidine compounds and compositions and methods of using the compounds as glucocorticoid receptor modulators.
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Page/Page column 16
(2008/06/13)
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- A facile experimental method to determine the hydride affinity of polarized olefins in acetonitrile
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(Chemical Equation Presented) Choosing a suitable hydride reducing agent and thermodynamic analysis of reduction mechanisms is facilitated by experimental hydride affinities ΔHH-A, which are reported herein for 28 polarized olefins 1 in acetonitrile (see scheme). The method should also be applicable to ketones, aldehydes, and imines.
- Zhu, Xiao-Qing,Zhang, Min,Liu, Qiao-Yun,Wang, Xiao-Xiao,Zhang, Jian-Yu,Cheng, Jin-Pei
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p. 3954 - 3957
(2007/10/03)
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- Tandem catalytic condensation and hydrogenation processes in ionic liquids
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A domino reaction composed of a Knoevenagel condensation combined with a simultaneous catalytic hydrogenation is reported in an ionic liquid solvent under mild conditions (298-363 K and 300 kPa). No interference between the catalysts (Pd/C and amine acetate salt) of the two diverse steps was monitored. The product could be neatly extracted by diethyl ether and the solvent containing the catalysts could be recycled and reused five times without any loss in activity or selectivity. The same methodology in a common organic solvent such as DMA resulted in significant competing parallel hydrogenation of the aldehyde to alcohol.
- Baidossi, Mubeen,Joshi, Asutosh V.,Mukhopadhyay, Sudip,Sasson, Yoel
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p. 1885 - 1887
(2007/10/03)
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- Structure-activity relationships of dimethindene derivatives as new M2-selective muscarinic receptor antagonists
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A series of 2,3-disubstituted indenes, which are analogues of the widely used histamine H1 receptor antagonist dimethindene, have been synthesized and studied as muscarinic and histamine receptor antagonists. The affinities of these compounds for the five human muscarinic receptor subtypes (M1-M5) and for human histamine H1 receptors were determined in radioligand binding studies using membranes from transfected Chinese hamster ovary (CHO) cells and [3H]N-methylscopolamine ([3H]NMS). The results demonstrate that the diisopropyl analogue 19 has a similar high affinity as (S)-dimethindene at M2 receptors ((S)-dimethindene: pKi = 7.52; (-)-19: pKi = 7.37) with an improved selectivity pattern ((S)-dimethindene: M2/M1 = 6-fold, M2/M3 = 5-fold, M2/M4 = 10-fold, M2/M5 = 25-fold; (-)-19: M2/M1 = 36-fold, M2/M3 = 96-fold, M2/M4 = 42-fold, M2/M5 = 275-fold). In addition, compound (-)-19 showed 35-fold lower affinity at histamine H1 receptors (pKi = 5.61) than (S)-dimethindene (pKi = 7.16). Another interesting compound is the fluoroethyl derivative 20 (pKi/M2 = 7.49), which also exhibits a higher M2 selectivity (M2/M1 = 19-fold; M2/M3 = 22-fold; M2/M4 13-fold; M2/M5 = 62-fold) than (S)-dimethindene. Unfortunately, compound 20 also shows a high affinity for histamine H1 receptors (pKi = 8.14). The compound with the highest affinity for M2 receptors (pKi = 7.91), the dimethylaminomethylene analogue 31, displayed only a small preference for M2 receptors. In conclusion, compound (-)-19 might be useful to test the hypothesis that blockade of muscarinic M2 receptors in the brain is a viable mechanism by which to produce improved cognition. This second-generation dimethindene analogue might also be the starting point for the development of M2-selective muscarinic antagonists useful for quantifying M2 receptors in the central nervous system with positron emission tomography imaging.
- B?hme, Thomas M.,Keim, Christine,Kreutzmann, Kai,Linder, Matthias,Dingermann, Theo,Dannhardt, Gerd,Mutschler, Ernst,Lambrecht, Günter
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p. 856 - 867
(2007/10/03)
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- Trichloroacetylhydrazones: New highly reactive alkylating agents
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The behavior of trichloroacylhydrazones as new highly reactive alkylating agents is disclosed; various secondary amines are alkylated within a few minutes at room temperature, and similar alkylating reductions were found with malonates.
- Atlan,Kaim, L. El,Lacroix,Morgentin
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p. 1893 - 1894
(2007/10/03)
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- Asymmetric synthesis of (+)- and (-)-eptazocine via an enzymatic reaction
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Starting from (R)-3-hydroxy-2-(p-methoxybenzyl)propyl acetate (R-(+)-4) prepared by enzymatic monoacetylation of 2-(p-methoxybenzyl)propane-1,3-diol (3) with lipase PS in the presence of vinyl acetate as an acetyl donor, lactones ( (+)- and (-)-6) were ob
- Shiotani, Shunsaku,Okada, Hirohiko,Yaroamoto, Takako,Nakamata, Kumiko,Adachi, Jun,Nakamoto, Hiromasa
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p. 113 - 126
(2007/10/02)
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- A novel class of enkephalinase inhibitors containing a C-terminal sulfo group
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A new series of sulfonic acids were synthesized and tested for their enkephalinase inhibitory activity. Among them, the most potent was N-(2- benzyl-3-mercaptopropionyl)metanilic acid 10i with an IC50 value of 0.27 nM. Several other analogues (10a,b,j,n,o,gg,hh) showed the inhibitory activity comparable to or greater than thiorphan (IC50 = 2.6 nM), a C- terminal carboxyl-containing inhibitor of enkephalinase. Thus compounds containing a C-terminal sulfo group, instead of the C-terminal carboxyl group, were found to show a remarkably high level of inhibition of enkephalinase. The analgesic activity of 10b, (S)-10b, and (R)-10b was also evaluated by the phenylbenzoquinone writhing test.
- Mimura,Nakamura,Nishino,Sawayama,Komiya,Deguchi,Kita,Nakamura,Matsumoto
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p. 602 - 608
(2007/10/02)
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- HYDRIDE TRANSFER IN THE REDUCTION OF SUBSTITUTED BENZYLIDENE MALONIC DIESTERS BY COENZYME NAD(P)H MODEL
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The reduction of substituted benzylidene malonic diesters by 1-benzyl-1,4-dihydronicotinamide (BNAH) is catalyzed by magnesium perchlorate.Kinetic isotope effects studies show that the C(4)-H bond cleavage in BNAH is involved in the rate determining step.Spectroscopic investigations have revealed that the ternary complex is formed in the ground state while complexation of substrate with magnesium ion is rate enhancing.
- Deng, Gang,Yu, Jun,Yang, Xiao-ping,Xu, Hui-jun
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p. 5967 - 5974
(2007/10/02)
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- DOUBLY-DESTABILIZED CARBOCATIONS. DETECTION AND TRAPPING OF ARYL-BISCARBOETHOXYCARBOCATIONS.
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Diethyl bromo(aryl)malonates undergo ionization in superacids at -78 deg C to give the corresponding cations.These doubly destabilized cations can be trapped with benzene or toluene to give the corresponding Friedel-Crafts adducts.
- Fletcher, David,Ablenas, Fred J.,Hopkinson, Alan C.,Lee-Ruff, Edward
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p. 4853 - 4856
(2007/10/02)
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