A Stepwise Annulation for the Transformation of Cyclic Ketones to Fused 6 and 7‐Membered Cyclic Enimines and Enones

The efficient construction of functionalized polycyclic structures is an important objective in organic synthesis. Herein, we disclose a three‐step “[2 + n]” annulation method for the transformation of cyclic ketones to fused enimines and enones. The method relies on the Suzuki coupling reaction and the amide reductive alkenylation reaction. A series of fused bicyclic (6/6, 6/7, 8/7) and tricyclic (6/6/6; 6/6/7, 6/5/7) ring systems bearing an α,β‐enimine or an α,β‐enone functionality have been synthetized in good overall yields.     

A facile method for the synthesis of 1,3-oxathiolan-2-ones by reaction of oxiranes, sulfur, and carbon monoxide

A new method for the synthesis of 1,3-oxathiolan-2-ones has been developed. When oxiranes were allowed to react with sulfur in the presence of a catalytic amount of sodium hydride under pressurized carbon monoxide, the three-component coupling of oxiranes, sulfur, and carbon monoxide smoothly proceeded to give the 1,3-oxathiolan-2-ones in moderate to good yields. The reaction proceeded with a high regioselectivity and stereospecificity. For the reaction of oxiranes possessing an aromatic ring, the yields of the 1,3-oxathiolan-2-ones were lower than that of the oxiranes possessing no aromatic ring due to the formation of alkenes and thiiranes as byproducts. However, the product yields were improved by the addition of a catalytic amount of selenium.     

Palladium-catalyzed cyclization reactions of 2-vinylthiiranes with heterocumulenes. Regioselective and enantioselective formation of thiazolidine, oxathiolane, and dithiolane derivatives

The first palladium-catalyzed ring-expansion reaction of 2-vinylthiiranes with heterocumulenes to form sulfur-containing five-membered-ring heterocycles is described. This regioselective reaction requires 5 mol % of Pd(2)(dba)(3).CHCl(3) and 10 mol % of bidendate phosphine ligand (dppp, BINAP), at 50-80 degrees C, in THF. The reaction of 2-vinylthiiranes with carbodiimides, isocyanates, and ketenimines affords 1,3-thiazolidine derivatives, whereas the reaction with diphenylketene or isothiocyanates results in the formation of 1,3-oxathiolane or 1,3-dithiolane compounds in good to excellent isolated yields and in up to 78% ee.     

Fluoro-Julia olefination as a mild, high-yielding route to alpha-fluoro acrylonitriles

Synthesis of a novel, stable reagent (1,3-benzothiazol-2-ylsulfonyl)fluoroacetonitrile from readily synthesized ethyl alpha-(1,3-benzothiazol-2-ylsulfanyl)-alpha-fluoroacetate is reported. Aldehydes undergo condensations with (1,3-benzothiazol-2-ylsulfonyl)fluoroacetonitrile in the presence of DBU leading to alpha-fluoro acrylonitriles in high yields and with good Z-stereoselectivity. Lowering of reaction temperature increases the Z selectivity.     

Highly efficient synthesis of stereodefined multisubstituted 1,4-dicyano- and 1-cyano-1,3-butadienes and their reactions with organolithium reagents

Stereodefined multisubstituted 1-cyano- and 1,4-dicyano-1,3-butadiene derivatives were obtained in excellent yields of the isolated product from their corresponding monohalo- and dihalobutadienes and CuCN. This reaction proceeded with high stereoselectivity and retention of the stereochemistry of the starting halobutadienes. A study of the utility of the thus-obtained 1-cyano- and 1,4-dicyano-1,3-butadiene derivatives was demonstrated by their reactions with organolithium reagents. 2H-Pyrrole or iminocyclopentadiene derivatives were formed in high yields from 1-cyano-4-halo-1,3-butadienes and organolithium reagents. When 1,4-dicyano-1,3-butadienes were treated with organolithium reagents followed by trapping with electrophiles, a tandem process took place to afford 2H-pyrrolyl nitriles in excellent yields. Reduction of 1,4-dicyano-1,3-butadiene derivatives with LiAlH4 showed novel reaction patterns relative to normal nitriles.     

Asymmetric aldol reactions using (S,S)-(+)-pseudoephedrine-based amides: stereoselective synthesis of alpha-methyl-beta-hydroxy acids, esters, ketones, and 1,3-Syn and 1,3-anti diols

A very efficient method for performing stereoselective aldol reactions is reported. The reaction of (S, S)-(+)-pseudoephedrine-derived propionamide enolates with several aldehydes yielded exclusively one of the four possible diastereomers in good yields, although transmetalation of the firstly generated lithium enolate with a zirconium(II) salt, prior to the addition of the aldehyde, is necessary in order to achieve high syn selectivity. The so-formed syn-alpha-methyl-beta-hydroxy amides were transformed into other valuable chiral nonracemic synthons such as alpha-methyl-beta-hydroxyacids, esters, and ketones. Finally, a stereocontrolled reduction procedure starting from the so-obtained alpha-methyl-beta-hydroxy ketones has been developed allowing the synthesis of either 1,3-syn- or 1,3-anti-alpha-methyl-1,3-diols in almost enantiopure form by choosing the appropriate reaction conditions.     

Diverse reactions of 1,4-dilithio-1,3-dienes with nitriles: facile access to tricyclic Delta1-bipyrrolines, multiply substituted pyridines, siloles, and (Z,Z)-dienylsilanes by tuning of substituents on the butadienyl skeleton

Addition cyclization of 1,2,3,4-tetrasubstituted 1,4-dilithio-1,3-dienes (Type I) with four equivalents of various aromatic nitriles in the presence of hexamethylphosphoramide (HMPA) gives exclusively fully substituted pyridines in moderate to good yields. Similarly, trisubstituted pyridines can be prepared by the reaction of 2,3-dialkyl- or diaryl-substituted 1,4-dilithio-1,3-dienes (Type II) with nitriles. However, five- or six-membered-ring fused 2,3-disubstituted 1,4-dilithio-1,3-dienes (Type III) reacted with various aromatic and aliphatic nitriles without alpha-hydrogen atoms to afford tricyclic Delta1-bipyrrolines in high yields. The reaction of six-membered-ring fused 2,3-disubstituted 1,4-dilithio-1,3-diene (Type III) with 2-cyanopyridine afforded the corresponding pyridine, and no tricyclic Delta1-bipyrroline was observed. Seven-membered-ring fused dilithiodienes reacted with PhCN or trimethylacetonitrile to afford the corresponding pyridines in good yield. When 1,2,3,4-tetrasubstituted dilithio reagents (Type I) were treated with Me3SiCN, a tandem silylation/intramolecular substitution process readily occurred to yield siloles, whereas the reaction of 2,3-disubstituted dilithio reagents (Types II and III) with Me3SiCN gave rise to (Z,Z)-dienylsilanes with high stereoselectivity. These results revealed that the formation of tricyclic Delta1-bipyrrolines, pyridines, siloles, and (Z,Z)-dienylsilanes are strongly dependent on the substitution patterns of the dilithio butadienes and the nature of the nitriles employed.     

LDA-mediated selective addition reaction of vinylidenecyclopropanes with aldehydes, ketones, and enones: facile synthesis of vinylcyclopropenes, allenols, and 1,3-enynes

Highly selective addition reaction of vinylidenecyclopropanes 1 was realized by treatment with LDA in THF and quenching with aldehydes, ketones, and enones. A number of vinylcyclopropenes, allenols, and 1,3-enynes were obtained selectively in moderate to good yields depending on the nature of different electrophiles.     

Critical assessment of two classical synthetic methods for preparation of thiophene-substituted isoxazoles

Formation of thiophene-substituted isoxazoles by reaction of chalcone dibromides and 1,3-diketones with hydroxylamine hydrochloride has been examined under different conditions. Use of KOH as base in the reaction of dibromide chalcone analogs with hydroxylamine hydrochloride yields mixtures of isomeric isoxazoles in modest yields. Replacement of KOH with pyridine affords negligible amounts of isoxazoles only, the intermediate 2-bromoprop-2-en-1-one being isolated from the reaction as the major product. Substitution of the β-bromine atom from a chalcone dibromides with a methoxy group by solvolysis occurred when no base was used. Mixtures of isomeric isoxazoles in which the isoxazole that had a 2-thienyl group at position 5 were always major components, were obtained in good yields from reaction of thiophene-containing 1,3-diketones with hydroxylamine hydrochloride, irrespective of reaction pH. At low pH, regioselectivity was poorer than that observed for reaction of chalcone dibromides with hydroxylamine hydrochloride, but yields were substantially better. At high pH, yields were comparable with those at low pH and regioselectivity for 3-aryl-5-(2-thiophenyl)isoxazole was slightly enhanced, but the dioxime corresponding to the initial 1,3-diketone was also produced in low yields as a mixture of stereoisomers.     

The first nonthiolic, odorless 1,3-propanedithiol equivalent and its application in thioacetalization

2-[2-Chloro-1-(1-chlorovinyl)allylidene]-1,3-dithiane 1 was synthesized by the chlorination of 3-(1,3)-dithianylidenepentane-2,4-dione 2 using the Vilsmeier-Haack reagent in 99% yield. As a novel nonthiolic, odorless 1,3-propanedithiol equivalent, 1 was investigated in the thioacetalization reaction. Various types of aldehydes and ketones 3 were converted to the corresponding dithianes 4 in the presence of 1 in high yields (79-97%). Moreover, 1 exhibited obvious chemoselectivity between aldehyde and ketone in this thioacetalization reaction. A mechanism for this thioacetalization reaction is proposed.     

Cycloaddition reactions of 1-lithio-1,3-dienes with aromatic nitriles affording multiply substituted pyridines, pyrroles, and linear butadienylimines

Fully or partially substituted 1-iodo- or 1-bromo-1,3-dienes could be readily lithiated using t-BuLi or n-BuLi to afford their corresponding 1-lithio-1,3-diene derivatives in quantitative yields. When these in situ generated lithium reagents were treated with organonitriles, depending on the substitution patterns of the butadienyl skeletons, substituted pyridines, pyrroles, and/or linear butadienyl imines were formed in good to excellent yields via N-lithioketimine intermediates. In the cases of 1,2,3,4-tetrasubstituted and 2,3-disubstituted 1-lithio-1,3-dienes, pyridine derivatives or linear butadienyl imines were generally formed depending on the reaction temperatures. When 1,2,3,4-tetrasubstituted 4-halo-1-lithio-1,3-dienes and 1,2-disubstituted 1-lithio-1,3-dienes were treated with organonitriles, pyrrole derivatives or linear butadienyl imines were obtained. Competition between 5-exo and 6-endo cyclization was found to be responsible for the formation of either pyrroles or pyridines. Selective elimination of RLi from the lithiated cyclic N-containing intermediates was observed. The order of elimination was found to be LiCl > Me3SiLi > LiH.     

Synthesis of zwitterionic salts via three component reactions of nitrogen-containing heterocycles, acetylenedicarboxylate and cyclic 1,3-dicarbonyl compounds

A practical synthetic procedure for the preparation of the charge-separated pyridinium-Meldrum acid zwitterionic salts was developed through a unique one-pot three component reaction of pyridine, acetylenedicarboxylate and Meldrum acid. Other nitrogen-containing heterocycles such as N-methylimidazole, 2-picoline, quinoline, isoquinoline and other cyclic 1,3-dicarbonyl compounds such as 1,3-cyclopentanedione, 1,3-cyclohexanedione, barbituric acid also took part in the reaction to give corresponding zwitterionic salts in moderate yields, respectively. In one case an unusual isoquinolinium 1,3-cyclopentanedionate was obtained. A feasible explanation is given for this novel one-pot tandem reaction and the formation of different kinds of products.     

Cobalt-catalyzed three-component coupling reaction of alkyl halides, 1,3-dienes, and trimethylsilylmethylmagnesium chloride

[reaction: see text] A combination of CoCl(2) and 1,6-bis(diphenylphosphino)hexane catalyzes a novel three-component coupling reaction of alkyl bromides, 1,3-dienes, and silylmethylmagnesium chloride, yielding homoallylsilanes in good to excellent yields. The reaction involves a radical species from alkyl halides.     

Synthesis,Molecular Modeling,and Antiviral Activity of Novel Triazole Nucleosides and Their Analogs

Russian Journal of General Chemistry - Two new pharmacophoric models incorporating 1,2,3-triazole glycosides have been synthesized in good yields via 1,3-dipolar cycloaddition reaction based on the...     

Iridium-catalyzed reaction of enones with alcohols affording 1,3-diketones

An iridium-catalyzed coupling reaction of alcohols with enones has been successfully developed providing access to 1,3-diketones with high selectivity in good yields. This reaction provides an atom-economical route to 1,3-diketones from readily available alcohols.     

Cycloaddition of Zirconacyclopentadiene with 2-Bromoacrylate, 2-Bromoacrylaldehyde,and 3-Bromofuran-2,5-dione in the Presence of CuCl: A New Pathway for the Formation of Benzene Derivatives and Isobenzofuran-1,3-dione

Reaction of zirconacyclopentadienes with 2-bromoalkenes in the presence of CuCl afforded multisubstituted benzene derivatives. The reactions of 2-bromoacrylate and 2-bromo-3-phenylacrylaldehyde afforded penta- and hexasubstituted benzenes in good yields. The reaction of 3-bromofuran-2,5-dione with zirconacyclopentadienes gave isobenzofuran-1,3-diones in good yields.     

Preparation of 1-silyl- and 1,3-disilyl-adamantanes

1-Dimethylsilyl- and 1,3-bis(dimethylsilyl)adamantane have been prepared in low yield by Wurtz reaction of dimethylchlorosilane with 1-chloroadamantane or 1,3-dichloroadamantane, respectively. On the other hand, reaction of phenyldimethylsilyllithium with 1-bromoadamantane or 1,3-dibromoadamantane gives essentially quantitative yields of 1-phenyldimethylsilyladamantane or 1,3-bis(phenyldimethylsilyl)adamantane, respectively.     

Nickel-catalyzed multicomponent connection of dimethylzinc, alkynes, 1,3-butadiene, aldehydes, and amines

A nickel(0) species catalyzes the five-component connection reaction of dimethylzinc, alkynes, 1,3-butadiene, aldehydes, and amines, furnishing either 1 or 2 selectively in good yields depending on the kinds of amines, aromatic or aliphatic amines, respectively.     

Lewis acid mediated reactions of aldehydes with styrene derivatives: synthesis of 1,3-dihalo-1,3-diarylpropanes and 3-chloro-1,3-diarylpropanols

[reaction: see text] The reactions of aryl aldehydes with styrene derivatives, mediated by various boron Lewis acids, were investigated. 1,3-Dihalo-1,3-diarylpropanes were obtained in high yields with boron trihalides, while 3-chloro-1,3-diarylpropanols were obtained in good to excellent yields with phenylboron dichloride. Reactions involving nonenolizable aliphatic aldehydes, trans-cinnamaldehyde, and beta-substituted styrenes were also investigated for the first time.     

Nickel-catalyzed addition of C-H bonds of terminal alkynes to 1,3-dienes and styrenes

The C-H bond of a terminal alkyne adds to a carbon-carbon double bond of 1,3-dienes, styrenes, and norbornene at room temperature in the presence of a nickel catalyst in regio- and stereoselective manners. Reaction of triisopropylsilylacetylene with 1-substituted 1,3-butadiene derivatives afforded hydroalkynylation products via introduction of a hydrogen atom and a triisopropylsilylethynyl group to 4- and 3-positions of the dienes, respectively. Likewise, 1-triisopropylsiloxy-1,3-butadiene, 1,3-pentadiene, 1-cyclohexen-1-yl-1,3-butadiene, and 1,3-cyclohexadiene underwent the hydroalkynylation reaction, giving the corresponding 1,4-enyne derivatives in good yields at room temperature. Reaction of p-substituted styrene with triisopropylsilylacetylene also proceeded in the presence of the nickel catalyst, giving the branched hydroalkynylation products in good yields. Norbornene gave a exo-addition product in good yield under the same reaction conditions.