- Synthesis of spiro[cycloalkane-pyridazinones] with high Fsp3 character
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Background: Nowadays, in course of the drug design and discovery much attention is paid to the physicochemical parameters of a drug candidate, in addition to their biological activity. Disadvantageous physicochemical parameters can hinder the success of a drug candidate. Objective: Lovering et al. introduced the Fsp3 character as a measure of carbon bond saturation, which is related to the physicochemical paramethers of the drug. The pharmaceutical research focuses on the synthesis of compounds with high Fsp3 character. Method: To improve the physicochemical properties (clogP, solubility, more advantageous ADME profile, etc.) of drug-candidate molecules one possibility is the replacement of all-carbon aromatic systems with bioisoster heteroaromatic moieties, e.g. with one or two nitrogen atom containing systems, such as pyridines and pyridazines, etc. The other option is to increase the Fsp3 character of the drug candidates. Both of these aspects were considered in the design the new spiro[cycloalkanepyridazinones], the synthesis of which is described in the present study. Results: Starting from 2-oxaspiro[4.5]decane-1,3-dione or 2-oxaspiro[4.4]nonane-1,3-dione, the corresponding ketocarboxylic acids were obtained by Friedel-Crafts reaction with anisole or veratrole. The ketocarboxylic acids were treated by hydrazine, methylhydrazine or phenylhydrazine to form the pyridazinone ring. N-Alkylation reaction of the pyridazinones resulted in the formation of further derivatives with high Fsp3 character. Conclusion: A small compound library was obtained incorporating compounds with high Fsp3 characters, which predicts advantageous physico-chemical parameters (LogP, ClogP and TPSA) for potential applications in medicinal chemistry.
- Für, Csilla Sepsey,Riszter, Gergo,Gerencsér, János,Szigetvári, áron,Dékány, Miklós,Hazai, László,Keglevich, Gy?rgy,B?lcskei, Hedvig
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p. 731 - 744
(2020/06/22)
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- Johnson-Corey-Chaykovsky fluorocyclopropanation of double activated alkenes: Scope and limitations
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Johnson-Corey-Chaykovsky fluorocyclopropanation of double activated alkenes utilizing S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium tetrafluoroborate is an efficient approach to obtain a range of monofluorocyclopropane derivatives. So far, fluoromethylsulfonium salts have displayed the broadest scope for direct fluoromethylene transfer. In contrast to more commonly used fluorohalomethanes or freon derivatives, diarylfluoromethylsulfonium salts are bench stable, easy-to use reagents useful for the direct transfer of a fluoromethylene group to alkenes giving access to the challenging products-fluorocyclopropane derivatives. Interplay between the reactivity of the starting materials and stability of the fluorocyclopropanes formed determines the outcome of the process.
- Kazia, Armands,Melngaile, Renate,Mishnev, Anatoly,Veliks, Janis
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supporting information
p. 1384 - 1388
(2020/03/03)
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- Amino Acid Amide based Ionic Liquid as an Efficient Organo-Catalyst for Solvent-free Knoevenagel Condensation at Room Temperature
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Abstract: Ionic liquids of amino acid amide were synthesized and used as an efficient catalyst for solvent-free Knoevenagel condensation. Synthesized ionic liquids are an environmentally benign, inexpensive, metal free and plays the dual role of solvent as well as an efficient catalyst for Knoevenagel condensation. A wide range of aliphatic, aromatic and heteroaromatic aldehydes easily undergo condensation with malononitrile and ethyl cyanoacetate. The reaction proceeds at room temperature without using any organic solvent and is very fast with good to excellent yield. Additionally, the catalyst is easily separable and recyclable without loss of activity. Graphic Abstract: [Figure not available: see fulltext.].
- Burate, Pralhad A.,Javle, Balasaheb R.,Desale, Pranjal H.,Kinage, Anil K.
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p. 2368 - 2375
(2019/06/17)
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- Vanadium-Catalyzed Condensation of Ethyl Cyanoacetate with Ketones
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Vanadium compounds and complexes activated by pyridine or morpholine catalyze condensation of ethyl cyanoacetate with ketones and aldehydes leading to alkylidenecyanoacetates in 75–100% yield.
- Khusnutdinov,Shchadneva,Mayakova, Yu. Yu.
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p. 403 - 409
(2018/04/24)
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- Polyoxoniobates as a superior Lewis base efficiently catalyzed Knoevenagel condensation
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The outstanding basicity of negative charged Lindqvist type Polyoxoniobate K7HNb6O19·13H2O (Nb6) have been proved experimentally as well as by theoretical NBO calculations, the results insights high electron density on terminal and bridging oxygen atoms of niobate anion. The most negative Natural Bond Orbital charge (NBO) of oxygen in Nb6 is ?1.001, which is a much more negative value than those reported in other polyoxometalates, that corroborates its high basicity thus likely to be employed as a strong base catalyst. Experimental study suggests that Nb6 can efficiently catalyze Knoevenagel condensation of various carbonyl compounds with active methylene compounds neglecting the steric and electronic effect of aromatic aldehydes under mild conditions. Kinetic test shows that Knoevenagel condensation of benzaldehyde with ethyl cyanoacetate exhibits second-order kinetics in the presence of Nb6 and the calculated activation energy is 43.3 kJ mol?1. Meanwhile, a proper mechanism according to the NBO study speculates that the most negative charged terminal oxygens in Nb6 would be pivotal in this transformation.
- Xu, Qiaofei,Niu, Yanjun,Wang, Guan,Li, Yingguang,Zhao, Yuan,Singh, Vikram,Niu, Jingyang,Wang, Jingping
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- IMINE DERIVATIVES AS HERBICIDAL COMPOUNDS
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The invention relates to haloalkysulphonamide derivatives of formula (I) wherein A, W, m, n, p, R, R1, R2, R5, R6, R7, R8 and R9 are as defined in the specification. Furthermore, the present invention relates to processes for making compounds of formula (I), to herbicidal compositions comprising these compounds and to methods of using these compounds to control or inhibit plant growth.
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Page/Page column 80
(2017/01/09)
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- HERBICIDAL COMPOUNDS
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The invention relates to haloalkylsulphonamide derivatives of the formula (I) wherein A, W, X, m, n, p, R, R1, R2, R5, R6, R7 and R8 are as defined in the specification. Furthermore, the present invention relates to processes for making compounds of formula (I), to herbicidal compositions comprising these compounds and to methods of using these compounds to control or inhibit plant growth.
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Page/Page column 84
(2017/01/31)
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- HERBICIDAL HALOALKYLSULPHONAMIDE COMPOUNDS
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The invention relates to haloalkylsulphonamide derivatives of the formula (I) wherein A, W, X, m, n, p, R, R1, R2, R5, R6, R7and R8 are as defined in the specification. Furthermore, the present invention relates to processes for making compounds of formula (I), to herbicidal compositions comprising these compounds and to methods of using these compounds to control or inhibit plant growth.
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Page/Page column 75
(2017/04/19)
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- Base-free Knoevenagel condensation catalyzed by copper metal surfaces
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For the first time Knoevenagel condensation has been catalyzed by elemental copper with unexpected activity and excellent isolated yields. Inexpensive, widely available copper powder was used to catalyze the condensation of cyanoacetate and benzaldehyde under mild conditions. To ensure general applicability, a wide variety of different substrates was successfully reacted.
- Schneider,Zeltner,Kr?nzlin,Grass,Stark
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supporting information
p. 10695 - 10698
(2015/06/30)
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- Aqueous DABCO, an efficient medium for rapid organocatalyzed Knoevenagel condensation and the Gewald reaction
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In the presence of water and 1,4-diazabicyclo[2.2.2]octane, several aldehydes and cyclic ketones underwent efficient Knoevenagel condensation with malononitrile and ethyl cyanoacetate to produce the respective α.β-unsaturated systems within fairly short time periods. As a result, high yields of conjugated products were easily obtained. Products could be engaged in a Gewald reaction, either stepwise or in situ, to produce efficiently their respective 2-aminothiophenes within 4-7 h. TUeBITAK.
- Abaee, Mohammad Saeed,Cheraghi, Somayeh
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p. 650 - 660
(2014/07/07)
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- A highly negatively charged γ-Keggin germanodecatungstate efficient for Knoevenagel condensation
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A tetra-n-butylammonium (TBA) salt of a γ-Keggin -6-charged germanodecatungstate, [γ-H2GeW10O36] 6- (I), could act as an efficient homogeneous catalyst for Knoevenagel condensation of active methylene compounds with carbonyl compounds.
- Sugahara, Kosei,Kimura, Toshihiro,Kamata, Keigo,Yamaguchi, Kazuya,Mizuno, Noritaka
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supporting information
p. 8422 - 8424
(2012/10/29)
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- Schiff base structured acid-base cooperative dual sites in an ionic solid catalyst lead to efficient heterogeneous knoevenagel condensations
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An acid-base bifunctional ionic solid catalyst [PySaIm]3PW was synthesized by the anion exchange of the ionic-liquid (IL) precursor 1-(2-salicylaldimine)pyridinium bromide ([PySaIm]Br) with the Keggin-structured sodium phosphotungstate (Na
- Zhang, Mingjue,Zhao, Pingping,Leng, Yan,Chen, Guojian,Wang, Jun,Huang, Jun
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p. 12773 - 12782
(2012/11/07)
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- Improved synthesis of γ-lactones from cyclopropyl cyanoesters
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Cyclopropyl cyanoesters 2 were reliably converted to c-lactones 4 on treatment with aqueous sulfuric acid. The cyanoesters could be easily prepared from ketones or aldehydes in two steps, making this process particularly attractive from an efficiency standpoint. Copyright
- Patel, Nandini C.,Schwarz, Jacob B.,Islam, Khondaker,Miller, Whitney,Tran, Tuan P.,Wei, Yunjing
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experimental part
p. 2209 - 2215
(2011/07/07)
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- The Knoevenagel reaction in water catalyzed by zwitterionic liquids
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Three hydroxyl functionalized zwitterionic liquids (ZILs) were found to be novel recyclable catalysts for the Knoevenagel condensation between aldehydes or ketones and active methylene compounds in aqueous medium. Both aldehydes and ketones gave satisfactory results. The products could simply be separated from the catalysts/water, and the catalysts could be recycled six times without noticeably decreasing the catalytic activity.
- Fang, Dong,Fei, Zheng-Hao,Liu, Zu-Liang
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experimental part
p. 799 - 803
(2009/09/28)
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- INHIBITORS OF DIACYLGLYCEROL O-ACYLTRANSFERASE TYPE 1 ENZYME
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The present invention relates to compounds of formula (I): wherein Q, G1, G2, and G3, are defined herein. Pharmaceutical compositions and methods for treating DGAT-1 related diseases or conditions are also disclosed.
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Page/Page column 87
(2008/12/08)
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- Nitrilase-catalyzed selective hydrolysis of dinitriles and green access to the cyanocarboxylic acids of pharmaceutical importance
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To further explore its synthetic applications, the nitrilase bll6402 from Bradyrhizobium japonicum strain USDA110 has been examined toward the hydrolysis of various dinitriles. It has been found that nitrilase bll6402 effectively hydrolyzed α,ω-dinitriles to ω-cyanocarboxylic acids, and the selectivity was independent of the substrate chain length. This feature is distinct from all the known nitrilases of various sources. Nitrilase bll6402 was thus applied to the synthesis of 1-cyanocycloalkaneacetic acids, the useful precursors for the synthesis of gabapentin and its analogues.
- Zhu, Dunming,Mukherjee, Chandrani,Biehl, Edward R.,Hua, Ling
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p. 1667 - 1670
(2008/02/11)
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- Efficient synthesis of substituted 2-amino-3-carbethoxythiophenes
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A microwave-assisted method for the synthesis of a variety of thiophene o-aminoesters (2a-l) has been developed, starting from an appropriate aldehyde, methyl ketone or acetoacetate ester with ethyl cyanoacetate in the presence of elemental sulfur. Copyright Taylor & Francis Group, LLC.
- Kathiravan,Shishoo,Chitre,Mahadik,Jain
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p. 4273 - 4279
(2008/03/13)
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- Knoevenagel condensation catalyzed by 1,1,3,3-tetramethylguanidium lactate
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Knoevenagel condensation between malononitrile or ethyl cyanoacetate and carbonyl compounds could be effectively promoted by 1,1,3,3-tetramethylguanidium lactate, a basic ionic liquid, under mild conditions. Good to high isolated yields could be obtained.
- Zhang, Jicheng,Jiang, Tao,Han, Buxing,Zhu, Anlian,Ma, Xiumin
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p. 3305 - 3317
(2007/10/03)
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- Organic Reactions in Ionic Liquids: Knoevenagel Condensation Catalyzed by Ethylenediammonium Diacetate
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The moisture and air stable ionic liquids 1-butyl-3-methylimidazonium tetrafluoroborate [bmim]BF4 and 1-butyl-3-methylimidazonium hexafluorophosphate [bmim]PF6 were used as 'green' recycle alternatives to volatile organic solvents (VOCs) for ethylenediammonium diacetate (EDDA) catalyzed Knoevenagel condensation between aldehydes or ketones with active methylene compounds. Both aldehydes and ketones gave satisfactory results. The ionic liquids containing catalyst EDDA were recycled several times with no decrease in yields and reaction rates. In the case of 2-hydroxybenzaldehyde, the reactions led to the formation of 3-substituted coumarins under standard reaction conditions.
- Su, Ce,Chen, Zhen-Chu,Zheng, Qin-Guo
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p. 555 - 559
(2007/10/03)
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- Steric effects in high pressure Knoevenagel reactions
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The pressure effect in Knoevenagel condensations involving ketones and ethyl cyanoacetate is studied. The reactions are diversely affected. For cyclic ketones there is a small effect on the reaction yield. However, in the case of acyclic ketones, the sensitivity of the reaction to pressure increases with increasing steric congestion of the ketone. Such a result highlights the synthetic utility of high pressure for the preparation of hindered functionalized alkenes.
- Jenner, Gérard
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p. 243 - 245
(2007/10/03)
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- Bispidine antiarrhythmic compounds
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There is provided a compound of formula I, wherein R1, R2, R9, R10, R11, R12, X, A and B have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.
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- Transition metal polyhydrides-catalyzed addition of activated nitriles to aldehydes and ketones via Knoevenagel condensation
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Transition metal polyhydrides and dihydrogen complexes catalyze Knoevenagel addition of cyanoacetate to aldehydes and ketones under neutral and mild conditions, the adducts undergo dehydration to give substituted (E)-2-cyano-α,β-unsaturated esters exclusively.
- Lin, Yingrui,Zhu, Xianchao,Xiang, Min
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p. 215 - 218
(2007/10/02)
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- Mechanistic Observations in the Gewald Syntheses of 2-Aminothiophenes
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The Gewald syntheses were employed to prepare a series of 2-amino-3-carboethoxythiophenes, and the syntheses of two of these, namely, the 3,4-trimethylene (1f) and 3,4-tetramethylene (1g) derivatives, were examined in detail.In two preparations of 1f, octahydro-6a-(4-morpholinyl)-2-thioxocyclopentapyrrole-3-carboxylic acid (7) was a co-product.The structure of 7 was ascertained from its 300 MHz 1H nmr and 13C nmr spectra, and by its conversion to 1,4,5,6-tetrahydro-2-mercaptocyclopentapyrrole-3-carboxylic acid ethyl ester (8).Isolation of 7 and other observations led to postulated mechanisms for three of the Gewald thiophene syntheses.
- Peet, Norton P.,Sunder, Shyam,Barbuch, Robert J.,Vinogradoff, Anna P.
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p. 129 - 134
(2007/10/02)
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- SYNTHESIS OF SPIROIMIDES OF PHARMACOLOGIC INTEREST
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Spiroimides of fluorene, indane and cyclopentane have been prepared as potential anticonvulsant agents.Certain azaspirane derivatives of fluorene are also reported.
- Borenstein, Michael R.,Abou-Gharbia, Magid A.,Doukas, Peter H.
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p. 2433 - 2438
(2007/10/02)
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