Synthesis of symmetrical acetylenic hydrocarbons and their α,ω-di-derivatives from α,α,α-trichloro- and α,α,α,ω-tetrachloro-alkanes

Summary By the action of sodium in xylene on polychloro hydrocarbons containing -CCl₂-CCl₂- or- CC1=CC1-, groupings the corresponding symmetrical acetylenic hydrocarbons containing 10,14, and 18 carbon atoms in the molecule were obtained. From ,-disubstituted tetrachloroalkanes by the same method 1,10-diethoxy-5-decyne, 1,14-diethoxy-7-tetradecyne, and 1,14-bisdiethylamino-7-tetradecyne were obtained.The spectra were determined in the Optical Laboratory of the Institute of Heteroorganic Compounds of the USSR by N. A. Chumaevskii, who we thank.     

Conformation of α,α,α′-Trisubstituted Cyclododecanone

Ten α,α,α′-trisubstituted cyclododecanones were synthesized and characterized by elemental analyses, infrared, 1^H NMR and 13^C NMR spectra, and X-ray diffraction. NMR data could not give conformational information clearly, but some of their ring skeleton conformations of cyclododecanone moiety were showed to remain the unchanged [3333]-2-one conformation with little distortion, while the others were changed to the [3324]-2-one conformation in their crystal structures. These are consistent with the results of molecular mechanics calculation with Sybyl 6.9 software and Tripos force field, and semi-empirical quantum calculation with AM 1 method in Gaussian 98 software. Two geminal substituting groups are located at α-corner carbon atom, and the third group is at α-side-exo carbon atom in both conformations. Both [3333]-2-one and [3324]-2-one conformations are present in a dynamic equilibrium in the solution, but only one preferred conformation exists in the crystal solid.     

New general synthesis of α-alkoxyketones via α'-alkylation, α-alkylation and α,α'-dialkylation of α-alkoxyketimines

α-Methoxy- and α-ethoxyketones, as important intermediates in organic synthesis and flavor compounds in food chemistry, were synthesized by deprotonation of N-(1-alkoxy-2-propylidene)isopropylamine, prepared by condensation of the corresponding α-alkoxyacetone with isopropylamine, and subsequent reaction of the corresponding 1-azaallylic anions with alkyl halides to afford α'-alkylated, α-alkylated and α,α'-dialkylated ketimines. Hydrolysis of the imino function led to the desired substituted α-alkoxyketones. The ratio of α-, α'-, and α,α'-(di)alkylated compounds depended on the amount of base used and on the nature of the alkylating reagent.     

A Convenient Synthesis of α-Phenylsclcno-α, β-unsaturated Nitriles via Arsonium Salt

a-Phenylseleno-a,0-unsaturatednitrilesareusefulintermediatesinorganicsynthesisinconsequenceoftheconsiderableversatilityofthetransformationofseleno"andcyano.gooddienophilesandradicophiles'.However,onlyonemethodfortheirpreparationhavebeenreported,'butitsyieldisverylow.Recently,ourinterestinsynthesisandapplicationofa-selenoarsoniumylidesledustoexploita-selenenylationofarsoniumsalt1andconsequentcondensationwitharomaticaldehydesunderweaklybasiccondition.Hereinwewishtoreportanefficientonepotsynthesi…     

Preparation of α,α-difluoroalkanesulfonic acids

Chlorodifluoromethanesulfonic acid (1) was prepared using a new procedure starting from perchloromercaptan, which is readily obtained from chlorination of CS₂. Modified Swarts reaction transformed N,N-diethyl trichloromethanesulfenamide into N,N-diethyl chlorodifluoromethanesulfenamide, and the latter species was further oxidized and hydrolyzed into chlorodifluoromethanesulfonic acid. The preparations of other two new α,α-difluoroalkanesulfonic acids, phenyl difluoromethanesulfonic acid (2) and 2-phenyl-1,1,2,2,-tetrafluoroethanesulfonic acid (3), are also disclosed. The acids 2 and 3 are stable in the forms of sodium (lithium) salts or in aqueous solutions; however, the pure forms of 2 and 3 can readily undergo defluorinations. 1-3 and their salts have potential applications as superacid catalysts and lithium battery electrolytes.     

Photochemical Chlorination of α,α-Difluoroanisole

Chlorination of ,-difluoroanisole was performed. The yield of chlorodifluoromethoxybenzene was studied in relation to the mode of reaction initiation.     

Conformational studies on peptides containing α,α-disubstituted α-amino acids: chiral cyclic α,α-disubstituted α-amino acid as an α-helical inducer

Four types of α,α-disubstituted amino acids {i.e., α-aminoisobutyric acid (Aib), 1-aminocyclopentanecarboxylic acid (Ac(5)c), (3S,4S)-1-amino-(3,4-dimethoxy)cyclopentanecarboxylic acid [(S,S)-Ac(5)c(dOM)] and its enantiomer (R,R)-Ac(5)c(dOM)} were introduced into l-leucine-based hexapeptides and nonapeptides. The dominant conformations of eight peptides: Cbz-(L-Leu-L-Leu-dAA)(2)-OMe [dAA = 1: Aib; 2: Ac(5)c; 3: (S,S)-Ac(5)c(dOM); 4: (R,R)-Ac(5)c(dOM)] and Boc-(L-Leu-L-Leu-dAA)(3)-OMe [dAA = 5: Aib; 6: Ac(5)c; 7: (S,S)-Ac(5)c(dOM); 8: (R,R)-Ac(5)c(dOM)], were investigated by IR, CD spectra and X-ray crystallographic analysis. The CD spectra revealed that Aib hexapeptide 1 and Ac(5)c hexapeptide 2 formed right-handed (P) 3(10)-helices, while Ac(5)c(dOM) hexapeptides 3 and 4 formed a mixture of (P) 3(10)- and α-helices. The Aib nonapeptide 5 formed a (P) 3(10)-helix, the Ac(5)c nonapeptide 6 formed a mixture of (P) 3(10)- and α-helices, and the Ac(5)c(dOM) nonapeptides 7 and 8 formed (P) α-helices. X-Ray crystallographic analysis revealed that the Aib hexapeptide 1 formed a (P) 3(10)-helix, while (S,S)-Ac(5)c(dOM) hexapeptide 3 formed a (P) α-helix. In addition, the Ac(5)c nonapeptide 6 and (R,R)-Ac(5)c(dOM) nonapeptide 8 formed (P) α-helices. The Aib and achiral Ac(5)c residues have the propensity to form 3(10)-helices in short peptides, whereas the chiral Ac(5)c(dOM) residues have a penchant for forming α-helices.     

Synthesis of α-alkyl- and α,α-dialkyl-β-phenyltryptamines

A new method was developed for the synthesis of -alkyl- and ,-dialkyl--phenyltryptamines based on alkylation of nitroalkanes with -phenyl-nor-gramine.     

Asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives

Herein we report the asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives 22, 25 and 26, key intermediates of a novel immunomodulator, using Seebach’s method. This synthetic method can be applied to the large scale synthesis of chiral sphingosine 1-phosphate-1 (S1P₁) receptor agonists, with significant improvements to the previously reported method with regard to the reaction temperature.     

Synthesis of new racemic α-heterocyclic α,α-diaminoesters and α-aminoester carboxylic

New racemic α-aminoester and α,α-diaminoesters derivatives were synthesized by nucleophilic substitution of methyl α-azido glycinate N-benzoylated with 3-amino-1,2,4-triazole, 2-tetrahydrofuran-2-ylmethan-amine and 2-methyl quinolin-4-amine.     

Synthesis of new α,α,β,β-tetrafluoroesters

Substituted phenyl iodides or diiodides reacted with ethyl iodotetrafluoroproponylate ICF₂CF₂CO₂Et, 1 in the presence of copper powder to give the coupled products 2 or 3 in good yields. Addition of 1 to ethylene and allyl acetate proceeded smoothly under thermal and radical conditions to give the corresponding adducts, which underwent elimination reaction to give β-vinyl and β-allyl α,α,β,β-tetrafluoroesters, CH₂CHCF₂CF₂CO₂Et, 4 and CH₂CHCH₂CF₂CF₂CO₂Et, 5, respectively. 1 also readily reacted with 1,5-hexadiene and 1-hexene with copper or palladium complex, followed by reduction to remove iodine to produce ω-alkenyl-α,α,β,β-tetrafluoroester CH₂CH(CH₂)₄CF₂CF₂CO₂Et 6 and α,α,β,β-tetrafluoroester C₄H₉CH₂CHICF₂CF₂CO₂Et.     

Conversion of methyl ketones and methyl sulfones into α-deutero-α,α-difluoromethyl ketones and α-deutero-α,α-difluoromethyl sulfones in three synthetic steps

Deuterodifluoromethyl ketones and sulfones were assembled in three synthetic steps from methyl ketones and sulfones, respectively. The key synthetic transformation is the deuteration of the difluorocarbanion generated by the release of trifluoroacetate from highly α-fluorinated gem-diols. High levels of deuterium on the “CF₂D” group were routinely observed. This strategy is mild and versatile and it can be applied to both ketones and sulfones without additional concerns of over- or under-fluorination. Additional examples address issues of over-deuteration when compounds with other acidic protons are subjected to the reaction conditions. This process not only demonstrates a new method to install a “CF₂D” group but also extends the scope of trifluoroacetate release to sulfones.     

Conformation and chiral effects in α,β,α-tripeptides

Short α,β,α-tripeptides comprising a central chiral trisubstituted β(2,2,3)*-amino acid residue form unusual γ-turns and δ-turns in CDCl(3) and DMSO-d(6) solutions but do not form β-turns. Thermal coefficients of backbone amide protons, 2D-NMR spectra, and molecular modeling revealed that these motifs were strongly dependent on the configuration (chiral effect) of the central β-amino acid residue within the triad. Accordingly, SSS tripeptides adopted an intraresidual γ-turn like (C6) arrangement in the central β-amino acid, whereas SRS diastereomers preferred an extended δ-turn (C9) conformation. A different SRS-stabilizing bias was observed in the crystal structures of the same compounds, which shared the extended δ-turn (C9) found in solution, but incorporated an additional extended β-turn (C11) to form an overlapped double turn motif.     

Tricomponent catalytic α,α-difluorination of acid chlorides

The selective α,α-difluorination of carbonyl compounds remains a challenge in modern organic synthesis; current methods often incorporate stepwise processes and/or harsh conditions, providing unsatisfactory mixtures of mono- and difluorinated products. In this communication, a practical, mild, and one-pot method for the selective α,α-difluorination of readily available acid chlorides is reported in which three separate catalysts act synergistically to form products in outstanding selectivity and fair to excellent yields.     

Catalytic, asymmetric synthesis of α,α-disubstituted amino acids

Copper(salen) complex 1 has been found to catalyse the asymmetric alkylation of enolates derived from a variety of amino acids. There is a clear relationship between the size of the side chain in the substrate and the enantioselectivity of the process, so that the enantioselectivity decreases in the order alanine>aminobutyric acid>allylglycine>leucine>phenylalanine>valine. A transition state model which accounts for the influence of the size of the side chain on the enantioselectivity of the reactions is presented.