- Discovery, characterisation, and utilisation of selenoxide-sulfonic acid salts: A new class of selenoxide-based oxidant and stable selenoxide equivalent
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The preparation and characterisation of a novel class of salts of selenoxides with sulfonic acids are described. They are readily prepared by simple addition of the sulfonic acid to a solution of selenoxide, and removal of solvent. In most cases they are colourless crystalline solids and are considerably more stable than the parent selenoxides, allowing full characterisation and X-ray crystallographic analysis. They also efficiently oxidise sulfides to sulfoxides, with no overoxidation, and clean regeneration of selenide. Their structure has been confirmed by 1H NMR spectroscopy and X-ray crystallography.
- Procter, D. John,Thornton-Pett, Mark,Rayner, Christopher M.
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Read Online
- Recyclable Lucas reagent in converting aliphatic alcohols to chlorides
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An industrially viable and environmentally friendly process is developed for the synthesis of menthyl chloride from the corresponding alcohol. Menthyl chloride was made in high yield by the reaction of menthol with the Lucas reagent. This chlorinating reagent was then recycled in the subsequent runs by simply replenishing the HCI, making the process simple and commercially viable. This improved procedure minimized the costly disposal of used Zn salts.
- Senaratne, Pushpananda A.,Orihuela, Felix M.,Malcolm, Arcelio J.,Anderson, Keith G.
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Read Online
- Matteson Reaction under Flow Conditions: Iterative Homologations of Terpenes
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The Matteson reaction is ideally suited for flow chemistry since it allows iterative homologation of boronate esters. The present study provides accurate data on reaction times of the individual steps of the Matteson reaction, which occurs in less than 10 s in total. The protocol allows terpenes to be (per-)homologated in a controlled manner to yield homo-, bishomo-, and trishomo-terpenols after oxidative workup. The new terpene alcohols are validated with respect to their olfactoric properties.
- Kuhwald, Conrad,Kirschning, Andreas
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supporting information
p. 4300 - 4304
(2021/05/26)
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- Synthesis, characterization and hplc analysis of the (1S,2S,5R)-diastereomer and the enantiomer of the clinical candidate ar-15512
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AR-15512 (formerly known as AVX-012 and WS-12) is a TRPM8 receptor agonist currently in phase 2b clinical trials for the treatment of dry eye. This bioactive compound with menthol-like cooling activity has three stereogenic centers, and its final structure and absolute configuration, (1R,2S,5R), have been previously solved by cryo-electron microscopy. The route of synthesis of AR-15512 has also been reported, revealing that epimerization processes at the C-1 can occur at specific stages of the synthesis. In order to confirm that the desired configuration of AR-15512 does not change throughout the process and to discard the presence of the enantiomer in the final product due to possible contamination of the initial starting material, both the enantiomer of AR-15512 and the diastereomer at the C-1 were synthesized and fully characterized. In addition, the absolute configuration of the (1S,2S,5R)-diastereomer was determined by X-ray crystallographic analysis, and new HPLC methods were designed and developed for the identification of the two stereoisomers and their comparison with the clinical candidate AR-15512.
- Abás, Sònia,Escolano, Carmen,Galdeano, Carles,Pujol, Eugènia,Rodríguez-Arévalo, Sergio,Vázquez, Santiago
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- Method for preparing menthane carboxamide by taking L-menthol as raw material
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The invention relates to a method for preparing menthane carboxamide by taking L-menthol as a raw material. The menthane carboxamide is prepared through the processes of chlorination, a Grignard reaction, acidification, acylating chlorination, amidation, distillation, recrystallization and the like in sequence. The process route is mature, has the advantages of operation management simplicity andsecurity risk reduction, during a chlorination process, lower-layer waste acid water is collected and reduced pressure distillation is carried out; H2O and HCl in the acid water are removed; recoveryof ZnCl2 is realized, reduced pressure distillation completion is realized, and a reagent, namely concentrated HCl, is added into the recovered ZnCl2; a ZnCl2/HCl saturated solution is prepared again,the L-menthol is added for chlorination reaction again, the steps are repeated, the waste acid water in the chlorination reaction can be repeatedly used, the production cost is saved, the wastewatertreatment cost is reduced, and the economic benefit is improved.
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Paragraph 0055-0063
(2020/08/18)
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- Enantiospecific Synthesis of ortho-Substituted 1,1-Diarylalkanes by a 1,2-Metalate Rearrangement/anti-SN2′ Elimination/Rearomatizing Allylic Suzuki–Miyaura Reaction Sequence
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The one-pot sequential coupling of benzylamines, boronic esters, and aryl iodides has been investigated. In the presence of an N-activator, the boronate complex formed from an ortho-lithiated benzylamine and a boronic ester undergoes stereospecific 1,2-metalate rearrangement/anti-SN2′ elimination to form a dearomatized tertiary boronic ester. Treatment with an aryl iodide under palladium catalysis leads to rearomatizing γ-selective allylic Suzuki–Miyaura cross-coupling to generate 1,1-diarylalkanes. When enantioenriched α-substituted benzylamines are employed, the corresponding 1,1-diarylalkanes are formed with high stereospecificity.
- Rubial, Belén,Collins, Beatrice S. L.,Bigler, Raphael,Aichhorn, Stefan,Noble, Adam,Aggarwal, Varinder K.
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supporting information
p. 1366 - 1370
(2019/01/04)
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- Ti-Catalyzed Radical Alkylation of Secondary and Tertiary Alkyl Chlorides Using Michael Acceptors
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Alkyl chlorides are common functional groups in synthetic organic chemistry. However, the engagement of unactivated alkyl chlorides, especially tertiary alkyl chlorides, in transition-metal-catalyzed C-C bond formation remains challenging. Herein, we describe the development of a TiIII-catalyzed radical addition of 2° and 3° alkyl chlorides to electron-deficient alkenes. Mechanistic data are consistent with inner-sphere activation of the C-Cl bond featuring TiIII-mediated Cl atom abstraction. Evidence suggests that the active TiIII catalyst is generated from the TiIV precursor in a Lewis-acid-assisted electron transfer process.
- Wu, Xiangyu,Hao, Wei,Ye, Ke-Yin,Jiang, Binyang,Pombar, Gisselle,Song, Zhidong,Lin, Song
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supporting information
p. 14836 - 14843
(2018/11/10)
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- Chiral menthyl phenyl phosphonamide compound and preparation method thereof
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The invention belongs to the field of organic synthesis, and particularly relates to a chiral menthyl phenylphosphonamide compound and a preparation method thereof. The chiral menthyl phenylphosphonamide compound has the following general formula (referring to the specification), wherein R1 is hydroxyl; R2 is hydroxyl, propyl, butyl, isopropyl, cyclopentyl, 2-chlorobenzyl, 2-methylidenefuran, 1-phenethyl or phenyl. The phosphonamide compound uses a phosphorus atom as a chiral source, has a more obvious chiral induction effect, and is more suitable for use in a chiral catalytic reaction; the phosphonamide compound has potentials of both drug activity and catalytic activity, and has development and application prospects; the phosphonamide compound is simple in synthesis method, easy to obtain and relatively good in application prospect.
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Paragraph 0062; 0067
(2018/07/07)
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- Radical Deoxychlorination of Cesium Oxalates for the Synthesis of Alkyl Chlorides
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A radical deoxychlorination of cesium oxalates has been developed for the preparation of hindered secondary and tertiary alkyl chlorides. The reaction tolerates a number of functional groups, including ketones, alcohols, and amides, and provides complementary reactivity to standard deoxychlorination reactions proceeding by heterolytic mechanisms. Preliminary studies demonstrate that the developed conditions can also be applied to deoxybromination and deoxyfluorination reactions.
- Su, Justin Y.,Grünenfelder, Denise C.,Takeuchi, Kohei,Reisman, Sarah E.
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p. 4912 - 4916
(2018/08/24)
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- Rearrangement in Stereoretentive Syntheses of Menthyl Chloride from Menthol: Insight into Competing Reaction Pathways through Component Quantification Analysis
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The enantiopure reagent menthyl chloride (2) is generally prepared from (–)-(1R)-menthol (1) with Lucas' reagent (ZnCl2 in conc. aqueous HCl) in a stereoretentive reaction that appeared to be free from accompanying rearrangements. The same was assumed for a recent synthesis of 2 through TiCl4-catalyzed extrusion of SO2 from menthyl chlorosulfite (3). The products of both syntheses have now been analyzed by quantitative 1H and 13C NMR methods, and all reaction components have been identified down to the ≤ 0.5 mol-% level. Either reaction is accompanied by cationic rearrangement to the considerable extent of 18–25 mol-%. Besides the expected 2, neomenthylchloride (4) and five rearrangement products have been identified, among them three regioisomeric tertiary chloromenthanes (9, 10, 11), and both a secondary (12) and tertiary chloride (16) derived from ψ-menthane (1-isobutyl-3-methylcyclopentane). A scheme of rearrangement pathways starting from a common menthyl carbenium ion pair is derived. The effect of purification protocols on crude 2 has been studied quantitatively. Either selective solvolysis of tertiary sideproducts (98 mol-% purity) or low-temperature crystallization (≥ 97 mol-% purity) was successful. An improved, scalable synthesis of 2 through the catalytic rearrangement of chlorosulfite 3 is reported.
- Hintermann, Lukas,Wong, Kit Ming
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supporting information
p. 5527 - 5536
(2017/10/06)
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- Sulfonyl halide synthesis by thiol oxyhalogenation using NBS/NCS – iPrOH
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A rapid and facile method provides a general route to sulfonyl bromides/chlorides by the oxidation of thiols using NXS – ROH (X?=?Br,Cl, R?=?iPr) as an oxyhalogenation reagent. Control experiments suggest that the alcohol component is the source of oxygen. The proposed method enable the access to structurally diverse sulfonyl bromides and chlorides including challenging examples, inaccessible by other synthetic methods.
- Silva-Cuevas, Carolina,Perez-Arrieta, Carlos,Polindara-García, Luis A.,Lujan-Montelongo, J. Armando
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p. 2244 - 2247
(2017/05/16)
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- Stereoretentive chlorination of cyclic alcohols catalyzed by titanium(IV) tetrachloride: Evidence for a front side attack mechanism
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A mild chlorination reaction of alcohols was developed using the classical thionyl chloride reagent but with added catalytic titanium(IV) chloride. These reactions proceeded rapidly to afford chlorination products in excellent yields and with preference for retention of configuration. Stereoselectivities were high for a variety of chiral cyclic secondary substrates including sterically hindered systems. Chlorosulfites were first generated in situ and converted to alkyl chlorides by the action of titanium tetrachloride which is thought to chelate the chlorosulfite leaving group and deliver the halogen nucleophile from the front face. To better understand this novel reaction pathway, an ab initio study was undertaken at the DFT level of theory using two different computational approaches. This computational evidence suggests that while the reaction proceeds through a carbocation intermediate, this charged species likely retains pyramidal geometry existing as a conformational isomer stabilized through hyperconjugation (hyperconjomers). These carbocations are then essentially "frozen" in their original configurations at the time of nucleophilic capture.
- Mondal, Deboprosad,Li, Song Ye,Bellucci, Luca,Laino, Teodoro,Tafi, Andrea,Guccione, Salvatore,Lepore, Salvatore D.
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p. 2118 - 2127
(2013/04/10)
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- A convenient and mild chromatography-free method for the purification of the products of Wittig and Appel reactions
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A mild method for the facile removal of phosphine oxide from the crude products of Wittig and Appel reactions is described. Work-up with oxalyl chloride to generate insoluble chlorophosphonium salt (CPS) yields phosphorus-free products for a wide variety of these reactions. The CPS product can be further converted into phosphine.
- Byrne, Peter A.,Rajendran, Kamalraj V.,Muldoon, Jimmy,Gilheany, Declan G.
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supporting information; experimental part
p. 3531 - 3537
(2012/05/20)
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- Iron(III)-catalyzed halogenations by substitution of sulfonate esters
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A novel halogenation reaction from sulfonates catalyzed by iron(III) is described. The reaction can be performed as a stoichiometric or a catalytic version. This reaction provides a convenient strategy for the efficient access to structurally diverse secondary chlorides, bromides and iodides. The stereochemical course of the reaction is governed by the substrate and the experimental conditions. Secondary alcohols modified as quisylates or pysylates are substantially more reactive. Aliphatic quisylates proceed with overall inversion of configuration under catalytic conditions. Chemoselectivity in bismesylates was observed in favour of the secondary mesylate. Additionally, based on the experimental results, a possible catalytic cycle for the halogenation has been proposed.
- Ortega, Nuria,Feher-Voelger, Andres,Brovetto, Margarita,Padron, Juan I.,Martin, Victor S.,Martin, Tomas
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p. 963 - 972
(2011/06/20)
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- A direct and stereoretentive synthesis of amides from cyclic alcohols
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Chlorosulfites prepared in situ using thionyl chloride react with nitrile complexes of titanium(IV) fluoride to give a one-pot conversion of alcohols into amides. For the first time, amides are obtained from cyclic alcohols with stereoretention. Critical to the design of these new TiIV reactions has been the use of little-explored TiIV nitrile complexes that are thought to chelate chlorosulfites in the transition state tocreate a carbocation that is rapidly captured by the nitrile nucleophile through a front-side attack mechanism.
- Mondal, Deboprosad,Bellucci, Luca,Lepore, Salvatore D.
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p. 7057 - 7061
(2012/01/03)
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- Clarification of the stereochemical course of nucleophilic substitution of arylsulfonate-based nucleophile assisting leaving groups
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(Chemical Equation Presented) Secondary alcohols modified as tosylates, PEG-sulfonates, or quisylates undergo inversion of configuration at the reacting center when treated with lithium halide in acetone at reflux, where the PEG-sulfonates and quisylates are substantially more reactive. In sterically hindered cases, elimination is a competing process. In contrast, when treated with TiCl4, simple secondary sulfonates give chloride products with partial inversion of configuration. Any observed retention of configuration in a given alkyl sulfonate substrate under these conditions is likely due to neighboring group participation or diastereoselective attack on a carbocation (or ion pair) rather than an SNi mechanism.
- Braddock, D. Christopher,Pouwer, Rebecca H.,Burton, Jonathan W.,Broadwith, Phillip
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experimental part
p. 6042 - 6049
(2009/12/24)
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- Synthesis of the new chiral tridentate ligand bis(pyrid-2-ylethyl) menthylphosphine and its use in the palladium-catalyzed allylic alkylations
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We describe the synthesis of a new asymmetric P,N,N′-tridentate ligand (bis(pyrid-2-ylethyl) menthylphosphine, BPEMP), containing two pyridyl rings and (1S,2R,5S)-menthylphosphino group. The ligand is obtained in five steps from natural abundant l-menthol. The coordination behavior of the ligand toward cationic (allylic)Pd(II) moiety and its first application in palladium-catalyzed asymmetric allylic alkylation are presented. Crystallographic and spectroscopic analyses reveal that [(η3-allylic)Pd(BPEMP)]+ complex forms only one isomer in the solid state as well as in solution.
- Minato, Makoto,Kaneko, Takefumi,Masauji, Shogo,Ito, Takashi
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p. 2483 - 2488
(2007/10/03)
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- Synthesis and characterisation of a suite of four chiral pyridyl alcohols derived from (-)-menthol
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Reaction of menthylmagnesium chloride with pyridine-2-carbaldehyde gives a mixture of four isomeric chiral menthyl- and neomenthyl-substituted pyridylcarbinols which were fully characterised by a combination of spectroscopic and X-ray crystallographic methods. All of these alcohols catalyse the addition of diethylzinc to benzaldehyde, but with disappointing enantioselectivities.
- Cunningham, Desmond,Gallagher, Eva T.,Grayson, David H.,McArdle, Patrick J.,Storey, Christina B.,Wilcock, Deborah J.
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p. 2692 - 2698
(2007/10/03)
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- Crystallization-Induced Asymmetric Transformation of a Tertiary Phosphine
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An equilibrating diastereomer mixture of the tertiary phosphines 5 and 6 (2.5:1 equilibrium ratio) undergoes crystallization-induced asymmetric transformation upon slow evaporation of solvent from refluxing heptane to give a 20:1 ratio in favor of the more stable crystalline isomer 5. The process can also be carried out at room temperature by using iodine to catalyze the interconversion of 5 and 6 via a pentavalent intermediate 8. However, this variation is more sensitive to the purity of the starting phosphine. Crystalline 5 can be converted to the stable borane complex 3, and reductive cleavage of the fluorenyl group using lithium naphthalenide affords the corresponding lithio derivative 10. Alkylation with iodomethane or benzyl bromide affords 13 or 17, respectively, with retention of phosphorus configuration.
- Vedejs, Edwin,Donde, Yariv
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p. 2337 - 2343
(2007/10/03)
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- BiX3 as an efficient and selective reagent for the halogen exchange reaction
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Bismuth halides are efficient and selective reagents in the halogen exchange reactions carried out under mild conditions. This rapid, high yield reaction proceeds mainly with retention of configuration.
- Boyer, Bernard,Keramane, El Mehdi,Arpin, Severine,Montero, Jean-Louis,Roque, Jean-Pierre
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p. 1971 - 1976
(2007/10/03)
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- One-step conversion of protected alcohols into alkyl halides using dimethylphosgeniminium salt
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Efficient conversion of tetrahydro-2-pyranyl (THP)protected alcohols into the corresponding halides using dichlorophosgeniminium chloride in the presence of tetraalkylammonium halide.
- Schlama,Gouverneur,Mioskowski
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p. 3517 - 3520
(2007/10/03)
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- Determination of the absolute configurations of the epimers of the P-chiral phosphine Ph2PCH2CH2P*Ph(L-(-)-menthyl) by use of two-dimensional NMR spectroscopy in combination with a palladium(II) "reporter complex"
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The two epimers of the new P-chiral phosphine Ph2PCH2CH2P*Ph(L-(-)-menthyl) (1-Rp and 1-Sp) were synthesized by treating Ph2PH with the diastereometrically pure forms of Ph(L-(-)-menthyl)CH=CH2)P.The palladium(II) complexes , 2-Rp, and , 2-Sp, were obtained by treating the corresponding bisphosphines with .Each of these complexes exists in the form of two regioisomers differing in the orientation of the chiral phosphine relative to the C-donor.Constraints from close interligand, intramolecular hydrogen-hydrogen contacts within three of these palladium complexes were detected by two-dimensional NOE spectroscopy, and were used to determine the absolute configurations at the chiral phosphorus centers in the Ph2PCH2CH2PPh(L-(-)-menthyl)isomers.The conformations of the two chelate rings in the more abundant of these isomers were also determined. Keywords: Chiral phosphine; Absolute configuration; Two-dimensional NMR; Palladium; Solution structure
- Jiang, Qiongzhong,Rueegger, Heinz,Venanzi, Luigi M.
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p. 233 - 240
(2007/10/03)
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- Reactions of Cyclohexane Derivatives in Superacids
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The reactions of menthol with FSO3H-SO2 and neomenthyl chloride with SbF5-SO2ClF follow different routes.The first yields a substituted cyclopentyl cation and the second a substituted cyclohexyl cation.Experiments on substituted cyclohexyl chlorides show that replacement of all the hydrogen atoms on the next but one carbon atom to the reaction centre blocks formation of a carbocation.It is suggested that ionisation of an equatorial chlorine atom takes place with assistance from an intramolecular electronic interaction, forming the methyl cyclopentyl carbocation in a synchronous process, rather than stepwise via the cyclohexyl carbocation.Reasons for contrasting behaviour in solvolytic reactions are discussed.
- Dean, Christopher,Whittaker, David
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p. 1541 - 1543
(2007/10/02)
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- Chiral Picket Fence Porphyrins
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The preparation of (+)-and (-)-meso-α,α,α,α-tetrakisphenyl>porphyrin as chiral picket fence porphyrins is described.The orientation of the p-menth-3-yl-carbonyl groups can be derived from proton NMR chemical shift data.Preparation procedures for the starting materials are described.
- Pfeiffer, Heinz-Peter,Sander, Hiltrud,Breitmaier, Eberhard
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p. 725 - 726
(2007/10/02)
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- Models for the Ion-Pair Cluster Mechanism in Nucleophilic Substitution Reactions
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Several bis(alkoxytriphenylphosphonium) salts have been prepared.When sterically constrained, as close neighbors, the leaving groups of these cations react rapidly at room temperature with negative nucleophiles to produce the expected substitution product.When sterically unconstrained, these types of functional groups behave as if they were mono(alkoxytriphenylphosphonium) salts, substituting very slowly or not at all at room temperature.The ion-pair cluster mechanism is discussed in light of these results.
- Ramos, Socorro,Rosen, William
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p. 3530 - 3533
(2007/10/02)
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- Nucleophilic Substitution and Competing Elimination in Cyclohexane and Steroid Reactions. A Comparison of Experiments and Force Field Calculations including the Regioselectivity of Steroid Eliminations
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A number of nucleophilic replacements including hydroxyl group substitutions are reported which show clean inversion with 3β-substituted cholestanes, whereas comparable cyclohexanes yield largely olefinic byproducts.Model calculations with the MM1 molecular mechanics force field demonstrate that twist boot intermediates as proposed in the literature for cyclohexane eliminations will require significantly higher strain energy in the steroid only if the interaction of both leaving group and attacking agent at Cβ-H is included.The predominance of Δ2 over Δ3 products in the steroid eliminations is based less on steric energy differences of these olefins, than on those of the preceding transition states.For the steroid all-chair ground state MM1, MM2 and crystal structure results are found to be in agreement.The calculations show the absence of conformational transmission of the A-ring twist-boat distortions in the C and D rings.
- Gschwendtner, W.,Hoppen, V.,Schneider, H.-J.
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p. 1201 - 1226
(2007/10/02)
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