- Formamide-Catalyzed Nucleophilic Substitutions: Mechanistic Insight and Rationalization of Catalytic Activity
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Herein, detailed mechanistic investigations into formamide-catalyzed nucleophilic substitution (SN) of alcohols are reported. Alkoxyiminium chlorides and hexafluorophosphates were synthesized and characterized as a key intermediate of the catalytic cycle. The determination of reaction orders and control experiments indicated that the nucleophilic attack of the formamide catalyst onto the reagent BzCl is the rate-determining step. Linear free energy relationship revealed a correlation between the quantified Lewis basicity strength of formamides by means of 11B NMR spectroscopy and their catalytic activity in SN-transformations. The observed difference in catalytic ability was attributed to the natural bond order charge, dipole moment, and Sterimol parameter B5. Importantly, this rationalization enables the prediction of the capacity of formamides to promote SN-type transformations in general.
- Hilt, Gerhard,Huy, Peter H.,Kohlmeyer, Corinna,Sch?fer, André
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p. 11567 - 11577
(2020/11/17)
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- Optically Active 1-Deuterio-1-phenylethane – Preparation and Proof of Enantiopurity
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Enantiopure (S)-(1-2H)ethylbenzene was prepared in two steps from optically active (S)-1-phenylethanol via (R)-(1-chloroethyl)benzene (two inversions of configuration). Since the value for the specific rotation [α] is very low for the enantiomers of (1-2H)ethylbenzene, the enantiopurity of the synthetic product could not be determined with certainty by polarimetry. Therefore, bis-sulfonamides were prepared by twofold chlorosulfonation (para and ortho) of (S)-(1-2H)ethylbenzene and subsequent amidation with (R)- and (S)-α-phenethylamine. For both diastereoisomers, the (R,R,S)- and the (S,S,S)-sulfonamides, 92 % de was determined by 1H NMR spectroscopy. Therefore, it could be concluded, that (S)-(1-2H)ethylbenzene had been obtained with 92 % ee.
- Küppers, Julian,Rabus, Ralf,Wilkes, Heinz,Christoffers, Jens
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p. 2629 - 2634
(2019/03/28)
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- Systematic Evaluation of Sulfoxides as Catalysts in Nucleophilic Substitutions of Alcohols
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Herein, a method for the nucleophilic substitution (SN) of benzyl alcohols yielding chloro alkanes is introduced that relies on aromatic sulfoxides as Lewis base catalysts (down to 1.5 mol-%) and benzoyl chloride (BzCl) as reagent. A systematic screening of various sulfoxides and other sulfinyl containing Lewis bases afforded (2-methoxyphenyl)methyl sulfoxide as optimal catalyst. In contrast to reported formamide catalysts, sulfoxides also enable the application of plain acetyl chloride (AcCl) as reagent. In addition, it was demonstrated that weakly electrophilic carboxylic acid chlorides like BzCl promote Pummerer rearrangement of sulfoxides already at room temperature. This side-reaction also provided the explanation, why sulfoxide catalyzed SN-reactions of alcohols do not allow the effective production of aliphatic and electron deficient chloro alkanes. Comparison experiments provided further insight into the reaction mechanism.
- Motsch, Sebastian,Schütz, Christian,Huy, Peter H.
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supporting information
p. 4541 - 4547
(2018/09/13)
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- A General Catalytic Method for Highly Cost- and Atom-Efficient Nucleophilic Substitutions
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A general formamide-catalyzed protocol for the efficient transformation of alcohols into alkyl chlorides, which is promoted by substoichiometric amounts (down to 34 mol %) of inexpensive trichlorotriazine (TCT), is introduced. This is the first example of a TCT-mediated dihydroxychlorination of an OH-containing substrate (e.g., alcohols and carboxylic acids) in which all three chlorine atoms of TCT are transferred to the starting material. The consequently enhanced atom economy facilitates a significantly improved waste balance (E-factors down to 4), cost efficiency, and scalability (>50 g). Furthermore, the current procedure is distinguished by high levels of functional-group compatibility and stereoselectivity, as only weakly acidic cyanuric acid is released as exclusive byproduct. Finally, a one-pot protocol for the preparation of amines, azides, ethers, and sulfides enabled the synthesis of the drug rivastigmine with twofold SN2 inversion, which demonstrates the high practical value of the presented method.
- Huy, Peter H.,Filbrich, Isabel
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supporting information
p. 7410 - 7416
(2018/04/30)
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- METHOD OF CONVERTING ALCOHOL TO HALIDE
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The present invention relates to a method of converting an alcohol into a corresponding halide. This method comprises reacting the alcohol with an optionally substituted aromatic carboxylic acid halide in presence of an N-substituted formamide to replace a hydroxyl group of the alcohol by a halogen atom. The present invention also relates to a method of converting an alcohol into a corresponding substitution product. The second method comprises: (a) performing the method of the invention of converting an alcohol into the corresponding halide; and (b) reacting the corresponding halide with a nucleophile to convert the halide into the nucleophilic substitution product.
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Page/Page column 56; 154
(2017/01/02)
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- Nucleophilic substitution catalyzed by a supramolecular cavity proceeds with retention of absolute stereochemistry
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While the reactive pocket of many enzymes has been shown to modify reactions of substrates by changing their chemical properties, examples of reactions whose stereochemical course is completely reversed are exceedingly rare. We report herein a class of wa
- Zhao, Chen,Toste, F. Dean,Raymond, Kenneth N.,Bergman, Robert G.
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supporting information
p. 14409 - 14412
(2015/02/02)
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- IMIDAZOTRIAZINONE COMPOUNDS
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The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9 and pharmaceutically acceptable salt thereof. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including humans.
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Paragraph 0533; 0534
(2013/10/08)
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- Supercritical carbon dioxide: A promoter of carbon-halogen bond heterolysis
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Amazing reaction medium: Supercritical carbon dioxide, with zero dipole moment, lower dielectric constant than pentane, and non-hydrogen-bonding behavior, ionizes carbon-halogen bonds, dissociates the resulting ion pairs, and escapes from capture by the carbocation intermediates at temperatures above 40 °C. These properties allow the observation of carbocation chemistry in the absence of acids.
- Delgado-Abad, Thais,Martinez-Ferrer, Jaime,Caballero, Ana,Olmos, Andrea,Mello, Rossella,Gonzalez-Nunez, Maria Elena,Perez, Pedro J.,Asensio, Gregorio
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p. 13298 - 13301
(2014/01/06)
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- DMSO-catalyzed chlorination of alcohols using N-phenylbenzimidoyl chloride
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N-phenylbenzimidoyl chloride has been demonstrated as an efficient chlorination reagent catalyzed by dimethyl sulfoxide (DMSO) in conversion of alcohols to corresponding chlorides. The reaction conditions were mild, and most of the substrates gave satisfactory yields. The configuration inversion of the chlorination was proved using optically active phenyl alcohols. The amount of DMSO can be as low as 0.001 eq without reducing the efficiency of the chlorination. A plausible mechanism for the reaction was proposed and proved by experiments. The reaction is stereoselective and potentially chemoselective among primary benzyl alcohols, secondary benzyl alcohols, and unactivated aliphatic alcohols.
- Wang, Qiang,Xu, Jian,Xu, Zhou-Qing,Yan, Ji-Dan
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p. 2071 - 2076
(2013/06/05)
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- IMIDAZOTRIAZINONE COMPOUNDS
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The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including CNS or neurodegeneration disorder.
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Page/Page column 88-89
(2012/04/10)
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- Development of a catalytic platform for nucleophilic substitution: Cyclopropenone-catalyzed chlorodehydration of alcohols
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Cyclopropenone makes the switch: 2,3-Bis-(p-methoxyphenyl)cyclopropenone is a highly efficient catalyst for the chlorodehydration of 20 diverse alcohol substrates (see scheme; X=Cl). With oxalyl chloride as catalytic activator, this nucleophilic substitution proceeded through cyclopropenium-activated intermediates and resulted in complete stereochemical inversion in substrates with chiral centers.
- Vanos, Christine M.,Lambert, Tristan H.
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supporting information; experimental part
p. 12222 - 12226
(2012/02/02)
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- Ate complexes of secondary boronic esters as chiral organometallic-type nucleophiles for asymmetric synthesis
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The addition of an aryllithium reagent to a secondary boronic ester leads to an intermediate boron-ate complex that behaves as a chiral nucleophile, reacting with a broad range of electrophiles with inversion of stereochemistry. Depending on the electrophile, the C-B bond can be converted into C-I, C-Br, C-Cl, C-N, C-O, and C-C, all with very high levels of stereocontrol. This discovery now adds a new, readily available, configurationally stable, chiral organometallic-type reagent to the arsenal of methods for use in asymmetric organic synthesis.
- Larouche-Gauthier, Robin,Elford, Tim G.,Aggarwal, Varinder K.
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supporting information; experimental part
p. 16794 - 16797
(2011/12/04)
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- A highly chemoselective and rapid chlorination of benzyl alcohols under neutral conditions
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A rapid and highly selective chlorination method has been developed using 2,4,6-trichloro-1,3,5-triazine (TCT) catalyzed by dimethyl sulfoxide. The reactions take 10 to 40 minutes, and the yields are almost quantitative. The neutral reaction conditions are compatible with substrates bearing acid-labile functional groups. Both competitive intramolecular and intermolecular reactions for benzyl alcohols in the presence of aliphatic alcohols indicate high selectivity. The procedure has been successfully used in the selective chlorination of gastrodin, a clinically used neuromedicine. This procedure represents a useful new tool in organic and medicinal chemistry. Georg Thieme Verlag Stuttgart.
- Sun, Lili,Peng, Guisheng,Niu, Hongmei,Wang, Qiang,Li, Chunbao
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experimental part
p. 3919 - 3924
(2009/05/26)
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- The mechanism of 1,4 alkyl group migration in hypervalent halonium ylides: The stereochemical course
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Rhodium(II)-acetate-catalyzed decomposition of either 1,3-cyclohexanedione phenyliodonium ylide or 5,5-dimethyl-1,3-cyclohexanedione phenyliodonium ylide in the presence of alkyl halides yields the corresponding 3-alkoxy-2-halocyclohex-2-enones via a 1,4 alkyl group migration shown to be concerted and intramolecular. In the case of (S)-α-phenethyl chloride, the rearrangement proceeds with essentially 88.6% retention of configuration. Theoretical calculations at the B3LYP/6-31G level reveal an activation energy of 5.4 kcal/mol for the process. A Claisen-like rearrangement occurs in the case where allylic halides, such as dimethylallyl or methallyl chorides, are used. The mechanistic pathway proposed for these processes involves addition of the halogen atom of the alkyl or allyl halide to the rhodium carbenoid from the iodonium ylide to yield a halonium intermediate that undergoes halogen to oxygen group migration. Aryl halides, such as chloro-, bromo-, iodo-, and fluorobenzene, behave differently under the same reaction conditions, yielding the product of electrophilic aromatic substitution, namely, the 2-(4-halophenyl) 1,3-cyclohexanedione. Copyright
- Moriarty, Robert M.,Tyagi, Sachin,Ivanov, Daniela,Constantinescu, Mircea
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p. 7564 - 7565
(2008/12/22)
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- Rhodium-catalyzed reaction of thiols with polychloroalkanes in the presence of triethylamine
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(Chemical Equation Presented) RhCl(PPh3)3 catalyzes a reaction of thiols with polychloroalkanes in the presence of triethylamine. This reaction serves as a convenient new method to produce formaldehyde dithioacetals, ethylenedithioethers, thioformates, and dithiocarbonic esters under mild conditions.
- Tanaka, Ken,Ajiki, Kaori
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p. 1537 - 1539
(2007/10/03)
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- Reactivity of bismuth(III) halides towards alcohols. A tentative to mechanistic investigation
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The reactivity of bismuth(III) halides (BiX3; X=Cl, Br and I) towards a series of alcohols has been investigated. Three different reactions have been studied, namely: halogenation, dehydration and etherification. The behaviour of these bismuth derivatives was found to depend on the nature of the halide bonded to the bismuth atom. Their reactivities can be interpreted on the basis of the Hard and Soft Acids and Bases (HSAB) principle. A mechanism is proposed which involves the formation of a complex of the alcohol with Bi(III).
- Keramane, El Mehdi,Boyer, Bernard,Roque, Jean-Pierre
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p. 1909 - 1916
(2007/10/03)
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- EFFECT OF THE NATURE OF THE ACYLATING AGENT ON THE ASYMMETRIC ACYLATION OF ALCOHOLS
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During the acylation of racemic 1-phenylethanol by the action of carboxylic acid anhydrides in the presence of S-(-)-N,N-dimethyl-α-phenylethylamine the unreacted alcohol is enriched in the S isomer.Its optical purity increases with increase in the steric demands of the anhydride from 2percent for acetic anhydride to 9percent for benzoic anhydride.When carboxylic acid chlorides are used, optically active 1-phenyl-1-chloroethane and bis-1-phenylethyl ether are isolated in addition to S-(-)-1-phenylethanol.
- Potapov, V. M.,Dem'yanovich, V. M.,Klebnikov, V. A.,Korovina, T. G.
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p. 1095 - 1097
(2007/10/02)
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- Occurrence of Electron Transfer in the Reduction of Organic Halides by LiAlH4 and AlH3
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A variety of methods have been utilized to detect the occurrence of a single electron transfer pathway in the reduction of alkyl halides by LiAlH4 and AlH3, i.e., (1) product studies of reduction of cyclizable alkyl halides containing the 5-hexenyl group, (2) trapping of intermediate radicals by dicyclohexylphosphine and other trapping agents, (3) direct EPR observation of the trityl radical in the reduction of trityl bromide, and (4) stereochemical studies of the reduction of secondary halides by lithium aluminum deuteride.The extent of electron transfer was found to be a function of the solvent, the substrate, the leaving group, and the hydride reagent.For alkyl iodides, and to a lesser extent bromides, electron transfer was found to be the major reaction pathway; however, no evidence for electron transfer was found for the corresponding chlorides or tosylates.Reduction of (+)-2-octyl iodide by LiAlD4 was found to be much less stereospecific than the corresponding reduction of bromide, chloride, or tosylate, indicating intermediate radical formation in the reduction of the secondary iodide.
- Ashby, E. C.,DePriest, R. N.,Goel, A. B.,Wenderoth, Bernd,Pham, Tung N.
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p. 3545 - 3556
(2007/10/02)
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- Stereochemical Aspects of Conjugation Reactions Catalyzed by Rat Liver Glutathione S-Transferase Isozymes
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Substrate enantioselectivity in the conjugation of phenethyl halides catalyzed by the glutathione S-transferases was studied with partially purified isozymes from rat liver.All of the isozymes tested possessed measurable activity with phenethyl chloride.Transferase A was the most active isozyme tested.Each of the isozymes demonstrated a high degree of substrate enantioselectivity, with transferase A being the most enantioselective isozyme.The enantioselectivity was determined by high-pressure liquid chromatographic analysis of the enzymatically formed diastereomeric products.The effect of limiting glutathione concentrations on the stereochemical outcome of the transferase A catalyzed conjugation of the chiral substrate, (S)-phenethyl chloride (4mM), was investigated.The stereochemical course of the enzymatic reaction was not significantly altered at glutathione concentrations as low as 25 μM.The major product of conjugation had the opposite stereochemistry at the benzylic carbon, indicating that the reaction proceeded primarily with inversion of configuration.The glutathione conjugates, S-glutathione, S-glutathione, S-benzylglutathione, and S-methylglutathione were studied as inhibitors of the transferase A catalysed conjugation of 1-chloro-2,4-dinitrobenzene.The order of the inhibitory potency was S-glutathione = S-benzylglutathione > S-glutathione > S-methylglutathione.This represented the first demonstration of the stereoselective product inhibition of the glutathione S-transferases.
- Mangold, James B.,Abdel-Monem, Mahmoud M.
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