- Nickel-Catalyzed Reductive Carboxylation of Cyclopropyl Motifs with Carbon Dioxide
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A nickel-catalyzed reductive carboxylation technique for the synthesis of cyclopropanecarboxylic acids has been developed. This user-friendly and mild transformation operates at atmospheric pressure of carbon dioxide and utilizes either organic halides or alkene precursors, thus representing the first example of catalytic reductive carboxylation of secondary counterparts lacking adjacent π-components.
- Moragas, Toni,Martin, Ruben
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p. 2816 - 2822
(2016/08/26)
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- 1-[(E)-2-arylethenyl]-2,2-diphenylcyclopropanes: Kinetics and mechanism of rearrangement to cyclopentenes
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Kinetic measurements for the thermal rearrangement of 2,2-diphenyl-1-[(E)- styryl]cyclopropane (22a) to 3,4,4-triphenylcyclopent-1-ene (23a) in decalin furnished ΔHρm{{-{isom}^{ne }}}$=31.0±1.2kcal mol-1 and ΔSρm{{-{isom}^{ne }}}$=-6. 0±2.6e.u. The lowering of ΔHa‰ by 20kcal mol-1, compared with the rearrangement of the vinylcyclopropane parent, is ascribed to the stabilization of a transition structure (TS) with allylic diradical character. The racemization of (+)-(S)-22a proceeds with ΔHρm{{-{rac}^{ne }}}$=28.2±0.8kcal mol -1 and ΔSρm{{-{rac}^{ne }}}$=-5±2e.u., and is at 150° 106 times faster than the rearrangement. Seven further 1-(2-arylethenyl)-2,2-diphenylcyclopropanes 22, (E)- and (Z)-isomers, were synthesized and characterized. The (E)-compounds showed only modest substituent influence in their krac (at 119.4°) and kisom (at 159.3°) values. The lack of solvent dependence of rate opposes charge separation in the TS, but a linear relation of log krac with log p.r.f., i.e., partial rate factors of radical phenylations of ArH, agrees with a diradical TS. The ring-opening of the preponderant s-trans-conformation of 22 gives rise to the 1-exo-phenylallyl radical 26 that bears the diphenylethyl radical in 3-exo-position, and is responsible for racemization. The 1-exo-3-endo-substituted allylic diradical 27 arises from the minor s-gauche-conformation of 22 and is capable of closing the three- or the five-membered ring, 22 or 23, respectively. The discussion centers on the question whether the allylic diradical is an intermediate or merely a TS. Quantum-chemical calculations by Houk etal. (1997) for the parent vinylcyclopropane reveal the lack of an intermediate. Can the conjugation of the allylic diradical with three Ph groups carve the well of an intermediate? Copyright
- Mulzer, Johann,Huisgen, Rolf,Arion, Vladimir,Sustmann, Reiner
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experimental part
p. 1359 - 1388
(2011/10/09)
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- Diazodiphenylmethane and monosubstituted butadienes: Kinetics and a new chapter of vinylcyclopropane chemistry
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Diazodiphenylmethane (DDM) undergoes cycloadditions to 1-substituted buta-1,3-dienes exclusively at the C(3)=C(4) bond. At room temperature, the N2 loss from the initially formed 4,5-dihydro-3H-pyrazoles 2 is faster than the cycloaddition and furnishes the vinylcyclopropane derivatives 7 and 9 with structural retention at the C(1)=C(2) bond. 2-Substituted butadienes react with DDM at the C(3)=C(4) bond to give 12; isoprene, however, affords 3,4/1,2 products in the ratio of 86:14. DDM is a nucleophilic 1,3-dipole: 1-Cyanobutadiene reacts 400 times faster than 1-methoxybuta-1,3-diene (DMF, 40°). The log k2 for the additions to six 1-substituted butadienes show a linear correlation with σp (Hammett) and ρ = +2.9; the log k2 of five 2-substituted butadienes are linearly related to Taft's σI (ρ = +1.7). The structures of the vinylcyclopropanes 7, 9, and 12 are established by NMR spectra and oxidation. A cyclopropyl carbinyl cation is made responsible for the isomerization of 12, R = Ph, Me, by acetic acid to 4-substituted 1,1-diphenylpenta-1,3-dienes 25 and 29; TsOH at 200° converts 25 further to 9,10-dihydro-9-methyl-10-phenyl-9,10-ethanoanthracene (27). Thermal rearrangement of 7, 9, and 12 at 200-300° produces the 3- or 1-substituted 4,4-diphenylcyclopentenes 30 and 31. These give the same mass spectra as the vinylcyclopropanes, and an open-chain distonic radical cation is suggested as common intermediate. Besides spectroscopic evidence for the cyclopentene structures, hydrogenation and epoxidation are described; NMR data support the trans-attack by perbenzoic acid.
- Ohta, Akihiro,Dahl, Klaus,Raab, Rainer,Geittner, Jochen,Huisgen, Rolf
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experimental part
p. 783 - 804
(2009/03/11)
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- The cyclopropyl group as a hypersensitive probe in the singlet oxygen ene reaction mechanism
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(Chemical Equation Presented) Cyclopropyl-substituted olefins are employed as mechanistic probes in the singlet oxygen-alkene ene reaction. In MeOH and aprotic solvents [CHCl3, (CH3)2CO, CH 3CN], only the allylic hydroperoxides bearing an intact cyclopropyl group are detected. The reaction mechanism is independent of solvent polarity. Our findings, to a certain experimental limit, exclude a biradical or dipolar intermediate.
- Alberti, Mariza N.,Orfanopoulos, Michael
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supporting information; experimental part
p. 2465 - 2468
(2009/05/27)
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- Facile synthesis of substituted trans-2-arylcyclopropylamine inhibitors of the human histone demethylase LSD1 and monoamine oxidases A and B
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A facile synthetic route to substituted trans-2-arylcyclopropylamines was developed to provide access to mechanism-based inhibitors of the human flavoenzyme oxidase lysine-specific histone demethylase LSD1 and related enzyme family members such as monoamine oxidases A and B.
- Gooden, David M.,Schmidt, Dawn M.Z.,Pollock, Julie A.,Kabadi, Ami M.,McCafferty, Dewey G.
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p. 3047 - 3051
(2008/12/23)
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- Thermal C2-C6 cyclization of enyne-allenes. Experimental evidence for a stepwise mechanism and for an unusual thermal silyl shift
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Enyne-allenes 4a-c bearing various cyclopropyl systems as radical clock reporter groups at the allene terminus have been synthesized and subjected to thermal C2-C6 cyclization. The ratio of ene versus formal Diels-Alder products could be rationalized on the basis of steric effects. Only the thermolysis of 4c, equipped with the fast diphenylcyclopropylcarbinyl radical clock, afforded a 1,3-butadienyl benzofulvene clearly formed via cyclopropyl ring opening. This finding provides unambiguous evidence for a stepwise mechanism of the C2-C6 cyclization making it possible to suggest a lifetime for the intermediate diradical of > 1 × 10-10 s (at 170 °C). An interesting corollary was the isolation of an unexpected silyl shift product in the thermolysis of all three enyne-allenes that allows explanation of the loss of the TIPS group in some of the Diels-Alder products. For a full understanding of the mechanism, silyl and hydrogen shift processes were interrogated using DFT.
- Schmittel, Michael,Mahajan, Atul A.,Bucher, Goetz,Bats, Jan W.
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p. 2166 - 2173
(2007/10/03)
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- Dipolar cycloaddition of carbonyl ylides generated from methyl cis-2-diazoacetyl-1-cyclopropanecarboxylates
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Carbonyl ylide generated from methyl cis-3-diazoacetyl-2,2-diphenyl-1- cyclopropanecarboxylate in the presence of Rh2(OAc)4 when brought into reaction of 1,3-dipolar cycloadditionCyrillic small letter YA sign with N-arylmaleimides afforded substituted 4-aryl-7-methoxy-9,9-diphenyl-12-oxa- 4-azatetracyclo-[5.4.1.02,6.08,10]dodecene-3,5,11-triones. Concurrent processes resulted in formation of cycloheptatrienes, hydroxyacetylcyclopropanecarboxylates, and benzophenone. Carbonyl ylide generated from methyl cis-2-diazoacetyl-1-cyclopropanecarboxylate in the same reaction gave rise to exo- and endo-4-aryl-7-methoxy-12-oxa-4-azatetracyclo[5.4. 1.02,6 .08,10] dodecene-3,5,11-triones. 2005 Pleiades Publishing, Inc.
- Molchanov,Diev,Kopf,Kostikov
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p. 194 - 203
(2007/10/03)
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- Exploring distal regions of the A3 adenosine receptor binding site: Sterically constrained N6-(2-phenylethyl)adenosine derivatives as potent ligands
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We synthesized phenyl ring-substituted analogues of N6-(1S,2R)- (2-phenyl-1-cyclopropyl)adenosine, which is highly potent in binding to the human A3AR with a Ki value of 0.63nM. The effects of these structural changes on affinity at human and rat adenosine receptors and on intrinsic efficacy at the hA3AR were measured. A 3-nitrophenyl analogue was resolved chromatographically into pure diastereomers, which displayed 10-fold stereoselectivity in A3AR binding in favor of the 1S,2R isomer. A molecular model defined a hydrophobic region (Phe168) in the putative A3AR binding site around the phenyl moiety. A heteroaromatic group (3-thienyl) could substitute for the phenyl moiety with retention of high affinity of A3AR binding. Other related N6-substituted adenosine derivatives were included for comparison. Although the N 6-(2-phenyl-1-cyclopropyl) derivatives were full A3AR agonists, several other derivatives had greatly reduced efficacy. N 6-Cyclopropyladenosine was an A3AR antagonist, and adding either one or two phenyl rings at the 2-position of the cyclopropyl moiety restored efficacy. N6-(2,2-Diphenylethyl)adenosine was an A 3AR antagonist, and either adding a bond between the two phenyl rings (N6-9-fluorenylmethyl) or shortening the ethyl moiety (N 6-diphenylmethyl) restored efficacy. A QSAR study of the N 6 region provided a model that was complementary to the putative A3AR binding site in a rhodopsin-based homology model. Thus, a new series of high-affinity A3AR agonists and related nucleoside antagonists was explored through both empirical and theoretical approaches.
- Tchilibon, Susanna,Kim, Soo-Kyung,Gao, Zhan-Guo,Harris, Brian A.,Blaustein, Joshua B.,Gross, Ariel S.,Duong, Heng T.,Melman, Neli,Jacobson, Kenneth A.
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p. 2021 - 2034
(2007/10/03)
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- The tandem intermolecular Paterno-Buechi reaction: Formation of tetrahydrooxepins
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The Paterno-Buechi reaction is the [2 + 2] photocycloaddition between carbonyl compounds and electron rich alkenes to generate oxetane products. By the introduction of substituted cyclopropyl rings to the alkene components, the utility of this reaction has been extended to facilitate the synthesis of substituted tetrahydrooxepins. It is proposed that initial addition of oxygen radicals to cyclopropyl enol ethers generates cyclopropylmethyl radicals which, when the cyclopropane ring bears appropriate radical-stabilising groups (e.g. phenyl, CO2Et), undergo rapid fragmentation to form homoallylic 1,7-biradicals which then recombine to deliver the observed tetrahydrooxepin products. The importance of various radical-stabilising substituents on the efficiency of tetrahydrooxepin formation is examined.
- Gan, Chee Yong,Lambert, John N.
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p. 2363 - 2372
(2007/10/03)
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- Trans N-Methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] cycloprop-2-ene-1-carboxamides: Novel lipophilic kappa opioid agonists
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The synthesis and kappa opioid agonist activities of some lipophilic analogues of the kappa opioid agonist U-50488 incorporating motifs bearing two aromatic rings in place of the 3,4-dichlorophenyl group are described. Trans 2,3-diphenyl-N-methyl-N[2-(1-pyrrolidinyl)cyclohexyl]-2-cyclopropene-1 -carboxamide, 7, is a potent kappa opioid agonist. A diphenylcyclopropene analogue of CI-977, trans 2,3-diphenyl-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-2 -cyclopropene-1-carboxamide, 13, is a highly lipophilic chemically novel potent selective kappa opioid agonist.
- Sabin,Horwell,McKnight,Broqua
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p. 291 - 296
(2007/10/03)
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- Metal catalyzed carbonylation of gem-dibromocyclopropanes
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The first examples of the catalytic carbonylation of gem-dibromocyclopropanes is described, using cobalt and nickel salts as catalysts under phase transfer conditions.
- Grushin,Alper
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p. 3349 - 3352
(2007/10/02)
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- New Host Family Based on Small-Ring Compounds
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Three- and four-membered ring compounds with functional groups and bulky substituents have proved to be a rewarding new source of inclusion hosts.These hosts form clathrates with a variety of uncharged organic molecules ranging from protic dipolar to apolar compounds (168 different inclusion species).Formation and selectivity depend in a systematic manner on structural parameters of the host, such as the nature, number, and position of functional groups, the substituents, and ring size.X-ray structure analyses of two inclusion compounds 12121; = 9.782 (1), b = 11.376 (1), c = 17.603 (1) Angstroem; Z = 4. 17*MeCN (1:1): Pbcn; a = 12.314 (1), b = 16.074 (1), c = 12.938 (1) Angstroem; Z = 4> and of a free host molecule 1; a = 7.339 (2), b = 11.657 (4), c = 9.149 (3) Angstroem; β = 110.070; Z = 2> are reported, revealing the building principles of the new clathrate family.The structures exhibit linear chains of inter-/intramolecular H bridges between carboxylic groups in the free host 1 and H-bridge aggregation of host and guest molecules in infinite helical chains for the 1*t-BuOH (1:1) inclusion.In 17*MeCN (1:1), the guest molecules are tightly enclosed by the host framework without further specific interactions.
- Weber, Edwin,Hecker, Manfred,Csoeregh, Ingeborg,Czugler, Matyas
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p. 7866 - 7872
(2007/10/02)
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- STEREOCHEMISTRY OF ELECTROREDUCTIONS OF BROMOCYCLOPROPANES 1-ASYMMETRIC ELECTROCHEMICAL SYNTHESIS BY REDUCTION AT A MERCURY CATHODE IN THE PRESENCE OF ADSORBED ALKALOIDS
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The electrochemical behaviours of 1-bromo-2,2-diphenylcyclopropane carboxylic acid, its methyl ester and 1,1-dibromo-2,2-diphenylcyclopropane are investigated in the presence of strongly adsorbed alkaloids: yohimbine, emetine, brucine, strychnine and methylstrichninium cations.The polarographic study evidences the existence of interactions between the alkyl bromides and nitrogen cations; these interactions make easier the 2e cleavage of the carbon-halogen bond.Whatever the alkaloid used, rather poor optical yields are obtained after electroreduction of monobromo compounds.On the contrary, notably optically active products are obtained from the dibromide derivative, but only when the inductor can act as a protonating species; 45percent optical yield can be achieved in the presence of emetine.The mechanism of asymmetric electrochemical synthesis is interpreted in terms of (i) preferential presentation of one of the two stereotopic faces of the substrate the mercury cathode, made chiral by the adsorption of the alkaloid and (ii) protonation by the acidic form of the inductor of the carbanion resulting from a 2e reduction.
- Hazard, R.,Jaouannet, S.,Tallec, A.
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- Steric Course of the Substitution at the Cyclopropane Skeleton by Cobal(I)oxime. Synthesis and Characterisation of Cyclopropylcobaloximes
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7,7-Dibromodibenzonorcaradiene (1) as well as exo- and endo-7-bromodibenzonorcaradiene (2a and b) were synthesized and reacted with cobal(I)oxime. (7-Bromodibenzonorcaradien-7-yl)(pyridine)cobaloxime (5) was formed from 1 beside some (dibenzonorcaradien-7-yl)(pyridine)cobaloxime (6) and (dibenzocycloheptatrien-6-yl)(pyridine)cobaloxime (4), whereas the reaction of 2a yielded 6 as the sole alkylcobaloxime.Under the same conditions 2b was inert. 4 - 6 were characterized by X-ray crystallography and spectroscopic methods.The substitution in 2a took place with retention, whereas the analogous substitution in the two enantiomeric 1-bromo-1-methyl-2,2-diphenylcyclopropanes (8a and b) occurred with racemisation.This shows that the observed retention was caused merely by steric effects and that cyclopropyl radical intermediates occurred in both cases.
- Schaeffler, Juergen,Deppisch, Bertold,Retey, Janos
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p. 2229 - 2241
(2007/10/02)
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