- Synthesis of fused tricyclic amines unsubstituted at the ring-junction positions by a cascade condensation, cyclization, cycloaddition then decarbonylation strategy
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Heating aldehydes that contain a protected hydroxymethyl group, a tethered alkyl chloride and a tethered alkenyl group at the α-position of the aldehyde with an amine sets up a cascade (tandem) reaction sequence involving condensation to an intermediate imine, then cyclization and formation of an intermediate azomethine ylide and then intramolecular dipolar cycloaddition. The fused tricyclic products are formed with complete or very high stereochemical control. The hydroxymethyl group was converted into an aldehyde - which could be removed to give the tricyclic amine products that are unsubstituted at the ring junction positions - or was converted into an alkene, which allowed the formation of the core ring system of the alkaloids scandine and meloscine.
- Coldham, Iain,Burrell, Adam J.M.,Guerrand, Helene D.S.,Watson, Luke,Martin, Nathaniel G.,Oram, Niall
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Read Online
- Preparation method of 1, 1-cycloalkane dicarboxylic acid and derivatives thereof
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The invention discloses a preparation method of 1, 1-cycloalkane dicarboxylic acid and derivatives thereof, which at least comprises the following steps of: forming a mixed system from malonic acid or derivatives thereof, dihalogenated hydrocarbon, tert-butyl alcohol salt and a solvent in a reactor; AND according to the method, the raw material conversion rate and the product selectivity are improved, and side reactions are hardly generated.
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Paragraph 0057-0060
(2021/05/05)
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- Method for mildly preparing 2-azaspiro [3.3] heptane hydrochloride
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The invention relates to a method for mildly preparing 2-azaspiro [3.3] heptane hydrochloride, and solves the technical problem that in historical literatures, harsh conditions of strong base sodium are needed. The synthesis method comprises the following steps: (1) reducing cyclobutane-1,1-dicarboxylic acid into dimethyl alcohol; (2) reacting the 1, 1-cyclobutane dimethyl carbinol with methanesulfonyl chloride to generate 1,1-cyclobutane dimethyl carbinol dimethyl sulfonate; (3) carrying out ring closing on the 1,1-cyclobutane dimethyl carbinol dimethyl sulfonate and the 2-nitrobenzene sulfonamide to generate 2-(2-nitrobenzenesulfonyl)-2-azaspiro [3.3] heptane; (4) enabling the 2-(2-nitrobenzenesulfonyl)-2-azaspiro [3.3] heptane to react with dodecanethiol under the action of DBU to remove the 2-nitrobenzenesulfonyl so as to generate 2-azaspiro [3.3] heptane; and (5) reacting the 2-azaspiro [3.3] heptane with BOC anhydride to generate Boc-2-azaspiro [3.3] heptane, and then performing treatment with hydrochloric acid to obtain the 2-azaspiro [3.3] heptane hydrochloride. The method is mild and easy to operate, and avoids violent conditions of removing amino protecting groups by strong base at high temperature.
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Paragraph 0006-0007
(2021/06/09)
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- Discovery of potent c-MET inhibitors with new scaffold having different quinazoline, pyridine and tetrahydro-pyridothienopyrimidine headgroups
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Cellular mesenchymal-epithelial transition factor (c-MET) is closely linked to human malignancies, which makes it an important target for treatment of cancer. In this study, a series of 3-methoxy-N-phenylbenzamide derivatives, N-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl) benzamide derivatives and N1-(3-fluoro-4-methoxyphenyl)-N3-(4-fluorophenyl) malonamide derivatives were designed and synthesized, some of them were identified as c-MET inhibitors. Among these compounds with new scaffolds having different quinazoline, pyridine and tetrahydro-pyridothienopyrimidine head groups, compound 11c, 11i, 13b, 13h exhibited both potent inhibitory activities against c-MET and high anticancer activity against tested cancer cell lines in vitro. In addition, kinase selectivity assay further demonstrated that both 13b and 13h are potent and selective c-MET inhibitors. Molecular docking supported that they bound well to c-MET and VEGFR2, which demonstrates that they are potential c-MET RTK inhibitors for cancer therapy.
- Jiang, Yingnan,Zhang, Ke,Gao, Suyu,Wang, Guihua,Huang, Jian,Wang, Jinhui,Chen, Lixia
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- Ruthenium-catalyzed asymmetric hydrogenation of 3-oxoglutaric acid derivatives: A study of unconventional solvent and substituent effects
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A series of 3-oxoglutaric acid derivatives have been hydrogenated in different solvents in the presence of [RuCl(benzene)(S)-SunPhos]Cl (SunPhos=(2,2,2′,2′-tetramethyl-[4,4′-bibenzo[d][1,3]dioxole] -5,5′-diyl)bis(diphenylphosphine)). Unlike simple β-keto acid derivatives, these advanced analogues can be readily hydrogenated in uncommon solvents such as THF, CH2Cl2, acetone, and dioxane with high enantioselectivities. Two possible catalytic cycles have been proposed to explain the different reactivities of these 1,3,5-tricarbonyl substrates in the tested solvents. The C-2 and C-4 substituents had notable but irregular influence on the reactivity and enantioselectivity of the reactions. More pronounced solvent effects were observed: the ee values increased from around 20 % in EtOH or THF to 90 % in acetone. Inversion of the product configuration was observed when the solvent was changed from EtOH to THF or acetone, and a mixed solvent system can lead to better enantioselectivity than a single solvent. Pronounced solvent effects: 3-Oxoglutaric acid derivatives have been hydrogenated in various solvents with high enantioselectivities (see scheme). Inversions of the product configuration were observed when the solvent was changed. Mixed solvent systems can give better enantioselectivities than a single solvent.
- Li, Wanfang,Tao, Xiaoming,Ma, Xin,Fan, Weizheng,Li, Xiaoming,Zhao, Mengmeng,Xie, Xiaomin,Zhang, Zhaoguo
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supporting information
p. 16531 - 16539
(2013/02/22)
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- Selective reactions of 1,1-cycloalkanedicarboxylic acids with SF4. a route to 1,1-bis(trifluoromethyl)cycloalkanes, 1-fluoroformyl-1-(trifluoromethyl)cycloalkanes and 1-(trifluoromethyl)-1-cycloalkanecarboxylic acids
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Six-, five-, four- and three-membered 1,1-cycloalkanedicarboxylic acid (2a-d) were synthesized by alkaline hydrolysis of the corresponding diesters (1a-d) and the reactions of the formers with SF4 were investigated. 1,1-Bis(trifluoromethyl)cycloalkanes (3a-d) were the products of the reactions conducted at 120-150°C while at 30°C 1-fluoroformyl-1-(trifluoromethyl)cycloalkanes (4a-d) were exclusively formed. The latter were isolated as pure compounds or converted in situ into 1-(trifluoromethyl)-1-cycloalkanecarboxylic acids (5a-d).
- Dmowski, Wojciech,Wolniewicz, Adam
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p. 141 - 146
(2007/10/03)
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- Spiro-Tenside und -Phospholipide: Synthese und Eigenschaften
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Keywords: Micellen; Spiroverbindungen; Tenside
- Menger, Fredric M.,Ding, Julia
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p. 2266 - 2268
(2007/10/03)
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- Octacidomycins, III: Synthetic Structural Analogues from C5-Units
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The total synthesis of an isoprenoid-like analogue (2) of octacidomycin (1), a novel oligocarboxylic acid antibiotic, is described.Starting from 3 (Scheme 1) and the tetraethylester of 1,11-dibromoundecane-4,4,8,8-tetracarboxylic acid (6) as a key compound systematical fragment condensations lead to the pepntadecacarboxylic acid 12 and hence to the 1,3,7,11,15,19,23,27-heptacosane-octacarboxylic acid 2.This contains regularly connected C5- instead of C7-units and shows contracted distances between the acid groups.The newly developed synthesis yields a hitherto unknown type of oligocarboxylic acids and some useful intermediates with one or two terminal vinylic functions (13-15). - Keywords: Antibiotics, Octacidomycins, Oligocarboxylic Acids, Synthesis
- Krause, Andreas,Lackner, Helmut
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p. 1550 - 1556
(2007/10/03)
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- Laser-Powered Decomposition of Spiroalkanes (n = 2-5)
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The laser heating of spiroalkanes (n=2-5) and of their 1,1,2,2-tetradeuterated isotopomers reveals dissimilar modes of their thermal decomposition.Spiropentane decomposes into ethene and propadiene via two competing routes: the direct cleavage and the more important cleavage via intermediary methylenecyclobutane.Spirohexane decomposes through two important concurrent pathways which are the expulsions of ethene from the three-membered ring and a more feasible expulsion of ethene from the four-membered ring.Spiroheptane and spirooctane decompose by a radical-chain mechanism and afford complex mixtures of products; upon addition of propene both compounds rearrange into two cycloalkanes wherein the larger ring of the spiroalkane is preserved and substituted with ethylidene and a vinyl group.
- Fajgar, Radek,Pola, Josef
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p. 7709 - 7717
(2007/10/02)
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- General Synthesis of Methyl- and Dimethyl-cyclobutanes from Simple 1,3-Diols by Phase Transfer Catalysis
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A general method is described for the preparation of methyl- and dimethyl-cyclobutanes from simple 1,3-diols.The key steps of the procedure are a phase transfer catalysed ring closure and the transformation of a carboxyl group to a methyl group.Phase transfer catalysis provides good yields in the synthesis of the cyclobutane skeleton.
- Toeroek, Bela,Molnar, Arpad
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p. 801 - 804
(2007/10/02)
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- CATHODIC SYNTHESIS OF CYCLOBUTANES
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Cathodic electrolysis of compounds with an activated methylene group in the presence of 1,3-dibromopropane affords 1,1-disubstituted cyclobutanes.
- Vasil'ev, A. A.,Tatarinova, V. I.,Petrosyan, V. A.
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p. 1221 - 1224
(2007/10/02)
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- Synthesis and Liquid Crystal Properties of Dimethylene Linked Compounds Incorporating the Cyclobutane or Spiroheptane Rings
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The preparation of sixteen dimethylene linked compounds is described heptane ring>, and a comparison is made between the transition temperatures of these compounds and those of the corresponding esters.This comparison once again highlights the fact that the cyclobutane ring should be regarded, in terms of its ability to promote nematic thermal stability, as a "chain stiffener rather than as a ring system.A comparison is also made of the nematic thermal stabilities of the trans-cyclobutane and the spiroheptane systems and of the trans-cyclohexane and the spiroundecane systems.
- Chan, L. K. M.,Gemmell, P. A.,Gray, G. W.,Lacey, D.,Toyne, K. J.
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p. 229 - 246
(2007/10/02)
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- ANALYSE STRUCTURALE EN SERIE CYCLOBUTANIQUE. Partie 1. Derives monosubstitues et gem disubstitues du cyclobutane
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Methylene bending mode analysis of some cyclobutane-d2 molecules reveals that in the dissolved state (solvent CCl4), bromocyclobutane occurs exclusively in a pseudo-equatorial form, whereas, under the same conditions, cyclobutanol and 1-bromocyclobutane carbonitrile exist both in pseudo-axial and pseudo-equatorial conformations.NMR spectroscopy confirms the results obtained for bromocyclobutane and leads to the conclusion that the pseudo-equatorial conformer is predominant in the case of cyclobutanol as well as in that of cyclobutane carbonitrile.A theoretical study of cyclobutanol in the gaseous state by the P.C.I.L.O. method gives results which are consistent with a pseudo-equatorial conformer.
- Karimine, Mohamed,Galsomias, Jacqueline,Lere-Porte, Jean-Pierre,Petrissans, Jean
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p. 321 - 332
(2007/10/02)
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- Perkin-Markovnikov Type Reaction Initiated with Electrogenerated Superoxide Ion
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The cyclic condensation of α,ω-dihaloalkanes with acticvated methylene of malonic acid and acetoacetic acid esters is studied using an electrogenerated superoxide ion.Two possible mechanisms for this reaction are postulated.
- Ojima, Fumihiro,Matsue, Tomokazu,Osa, Tetsuo
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p. 2235 - 2238
(2007/10/02)
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- Ring-Closure Reactions. 22. Kinetics of Cyclization of Diethyl (ο-Bromoalkyl)malonates in the Range of 4- to 21-Membered Rings. Role of Ring Strain
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The kinetics of closure of 1,1-bis(ethoxycarbonyl)cycloalkanes from the anions derived from diethyl (ο-bromoalkyl)malonates have been investigated in Me2SO at 25 degC.Rate constants and effective molarities (EM) have been obtained for the ring sizes 4-13, 17, and 21.This is the first quantitative study on the kinetics of SN2 closure of all-carbon rings, which includes small, common, medium and large rings.The reactivity data span over nine powers of ten, which is the widest reactivity range recorded so far in a cyclization series.Due to the extremely low EM for the 9-, 10-, and 11-membered rings, a special competition technique was developed for these rings.Comparison of the present results with literaturee data on SN2 ring-closure reactions reveals structure-dependent reactivity patterns showing varying features, which are qualitatively accounted for on the basis of structure effects on transition-state strain energies.A dissection of the EM data for the malonate cyclization into strain and probability factors was attempted.Perhaps the most interesting result is a definite tendency for transition-state strain energies to parallel cycloalkane strain energies for the 7-membered and larger rings but not for the smaller rings.In the latter cases the ring product no longer appears to be a proper model for comprehending the transition state.
- Casadei, Maria Antonietta,Galli, Carlo,Mandolini, Luigi
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p. 1051 - 1056
(2007/10/02)
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- CYCLOALKYLATION BY THE α,ω-DIBROMIDES OF COMPOUNDS CONTAINING AN ACTIVATED METHYLENE GROUP AS A METHOD FOR THE SYNTHESIS OF 1,1-DISUBSTITUTED CYCLOALKENES
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A convenient preparative method was developed for the cycloalkylation of active methylene compounds, including β-diketones, by the dibromides BrCH2(CH2)nCH2Br (n = 0,1,2) in the presence of an excess of potassium carbonate in DMSO.The reaction gives high yields for the dibromides with n = 0 and 2, whereas the formation of cyclobutanes (n=1) is complicated by O,C-alkylation.The 1-substituted 1-acylcyclopropanes undergo thermal isomerization to the corresponding dihydrofuranes.
- Zefirov, N. S.,Kuznetsova, T. S.,Kozhushkov, S. I.,Surmina, L. S.,Rashchupkina, Z. A.
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p. 474 - 480
(2007/10/02)
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- Crown ether catalysis of decarboxylation and decarbalkoxylation of β-keto acids and malonates: a synthetic application
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The effect of 18-crown-6 ether on the decarboxylation rates of the sodium and potassium salts of 3-camphor carboxylic acid 1 and of 1-carbomethoxy-1-carboxycyclohexane 2 was studied.For 2 the K-18C6 salt reacted ca. 104 times faster than the parent acid.This remarkable difference in reactivity was used in developing a one-pot, two-step procedure for decarbalkoxylation of malonic esters.This procedure was then applied to a range of malonates, β-keto esters, and an α-cyano ester.The effect of 15C5, other cations, and good nucleophiles was also studied.
- Hunter, Duncan H.,Patel, Vijay,Perry, Richard A.
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p. 2271 - 2277
(2007/10/02)
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