N-Polyfluoro(trimethylsilyl)ethyl azole derivatives

A facile synthetic route to N-polyfluoro(trimethylsilyl)ethyl azole derivatives was developed starting from N-bromo(chloro)polyfluoroethyl-substituted azoles. The silanes thus obtained were reacted with various electrophiles in the presence of the fluoride ion to yield the corresponding fluorinated carbinols, ketones, carboxylic acids, and methyl dithiocarboxylates as well as N-pentafluoroethylbenzimidazole.     

Preparation of trifluoromethylated ynamines and their reactions with some electrophilic reagents

N,N-Dialkyl(3,3,3-trifluoro-1-propynyl)amines were prepared by a three-step procedure starting from commercially available 2,2,3,3,3-pentafluoropropanol. The reactions of these trifluoromethylated ynamines with some electrophiles, such as aldehydes, halogens or N-halosuccinimides (NXS), were investigated. The fluorinated ynamines reacted with aldehydes in the presence of a catalytic amount of Lewis acid to provide the corresponding α-(trifluoromethyl)-α,β-unsaturated amides in good to excellent yields with high Z-stereoselectivity. These ynamines reacted with molecular bomine to give, after treatment with sodium hydrogen carbonate, N,N-dialkyl-2-bromo-3,3,3-trifluoropropanamides in good yields. The reaction with an equimolecular amount of NXS in aqueous acetonitrile also gave the corresponding 2-halo-3,3,3-trifluoropropanamides in good to excellent yields. On the other hand, the reaction of the ynamine with NXS in anhydrous acetonitrile led to the formation of the addition products in high yields. Upon treating the addition products with an equimolecular amount of NX′S in aqueous acetonitrile, the corresponding 2,2-dihalo(X,X′)-3,3,3-trifluoropropanamides were produced in nearly quantitative yields.     

Nucleophilic difluoromethylation and trifluoromethylation using tetrakis(dimethylamino)ethylene (TDAE) reagent

In an effort to find new methodologies to introduce difluoromethylene and trifluoromethyl moieties into organic molecules of synthetic and biological interest, tetrakis(dimethylamino)ethylene (TDAE) was found to be an effective reductant of a series of good electron-acceptors such as bromodifluoromethyl heterocycles, chlorodifluoromethylated ketones as well as perfluoroalkyl iodides; the corresponding anions thus generated under very mild conditions, were successfully engaged in a number of intra- and intermolecular coupling reactions with a series of electrophiles (aldehydes, ketones, α-keto esters, N-tosyl aldimines, acyl chlorides, diol sulphates, disulfides, and diselenides). The corresponding adducts were usually obtained in moderate to good yields and the present method was found to be as good or even better as other most popular approaches. This paper gives an overview of our research efforts in this area as well as results from other groups.     

Expeditive synthesis of homochiral fused tri- and tetrazoles-piperazines from β-amino alcohols

N-Cyanomethyl and N-propargyl β-amino alcohols are chlorinated with SOCl₂ and treated with NaN₃ in DMSO. A substitution/cycloaddition process affords in good yields, with high diastereoselectivity and a regioselectivity depending on the substitution pattern of the starting amino alcohol, fused tri- and tetrazoles-piperazines. These heterocycles were further lithiated with n-BuLi at the benzylic position and reacted diastereoselectively with a range of electrophiles.     

A new method for generation of non-stabilized α-amino-substituted carbanions by the reaction of magnesium carbenoids with N-lithio arylamines: their reactivity and a new synthesis of α-amino acid derivatives

Magnesium carbenoids were generated from aryl 1-chloroalkyl sulfoxides with i-PrMgCl in THF at low temperature in quantitative yields. The magnesium carbenoids were found to be reactive with N-lithio alkylamines to afford an olefin, which was derived from dimerization of the magnesium carbenoid, in moderate yield. On the other hand, reaction of the magnesium carbenoids with N-substituted N-lithio arylamines gave non-stabilized α-amino-substituted carbanions in good yields. Reactivity of the α-amino-substituted carbanions with some electrophiles was investigated and it was found that ethyl chloroformate reacted to give α-amino acid derivatives in good yields. As a whole, a new method for one-pot, three-component combined synthesis of α-amino acid derivatives from aryl 1-chloroalkyl sulfoxides was realized.     

Thioorthoesters in the activated Pictet-Spengler cyclization. Synthesis of 1-thiosubstituted tetrahydroisoquinolines and carboncarbon bond formation via sulfonyl iminium ions generated from N,S-sulfonyl acetals

The elaboration of 1-alkylthio- and 1-arylthio-tetrahydroisoquinolines by means of the activated Pictet-Spengler reaction of N-sulfonyl-β-phenethylamines with thioorthoesters as electrophiles, and their use as sulfonyl iminium ion precursors for carboncarbon bond formation, leading to 1-substituted tetrahydroisoquinoline derivatives, is reported.     

Direct organocatalytic asymmetric α-oxidation of ketones with iodosobenzene and N-sulfonyloxaziridines

The novel, direct amino acid-catalyzed α-oxidation of ketones with iodosobenzene and N-sulfonyloxaziridines is presented. A screen of several synthetically common oxidants revealed that iodosobenzene and N-sulfonyloxaziridines act as electrophiles in the direct organocatalytic asymmetric α-hydroxylation of ketones. The direct proline-catalyzed asymmetric α-oxidation of ketones with iodosobenzene yielded the corresponding α-hydroxylated ketones with up to 77% ee. Furthermore, several amino acid derivatives catalyze the stereoselective α-oxidation of ketones with N-sulfonyloxaziridines. For example, the direct diamine-catalyzed enantioselective α-hydroxylation of ketones with N-sulfonyloxaziridines furnished the corresponding α-hydroxylated products in moderate yield with up to 63% ee.     

Asymmetric synthesis of α-amino acids using polymer-supported Cinchona alkaloid-derived ammonium salts as chiral phase-transfer catalysts

Cinchonidine and cinchonine have been N-alkylated with Merrifield resin and employed as chiral phase-transfer catalysts for the enantioselective alkylation of enolates from N-(diphenylmethylene)glycine esters with activated electrophiles (up to 90% ee). The use of the polymer-supported cinchonidine ammonium salt afforded the corresponding (S)-isomers, whereas the (R)-isomers were obtained using related cinchonine-supported polymers.     

Regioselectivity of the reaction of 4H-1,2,4-triazole-3-thiol derivatives with chloroethynylphosphonates and structure of the products

Chloroethynylphosphonates reacted with 4H-1,2,4-triazole-3-thiols in anhydrous acetonitrile to afford fused heterocyclic compounds, 6-(dialkoxyphosphoryl)-3H-thiazolo[3,2-b][1,2,4]triazol-7-ium chlorides, with high regioselectivity. The products were converted into inner salts (zwitterions) of the corresponding phosphonic acids or their monoesters with the positive charge localized on N⁷. A probable reaction mechanism implies initial formation of sulfonium ion via attack by the thionic sulfur atom on the acetylenic carbon atom linked to chlorine, followed by intramolecular cyclization involving attack on the other acetylenic carbon atom by N² of the triazole ring.     

Asymmetric Synthesis of α‐Substituted N‐Methylsulfonamides

A novel amine auxiliary for the asymmetric synthesis of α‐substituted N‐methylsulfonamides is described. The reaction of 4‐([1,1′‐biphenyl]‐4‐yl)‐2,2‐dimethyl‐1,3‐dioxan‐5‐amine ( 16 ) with various aliphatic sulfonyl chlorides afforded the corresponding sulfonamides, which were lithiated and subsequently reacted with electrophiles to give the corresponding products in high yields and good‐to‐excellent asymmetric inductions (de 83–95%). Racemization‐free cleavage of the auxiliary led to the α‐alkylated N‐methylsulfonamides in acceptable yields and high enantiomer purities (ee 91 to ≥98).     

Optically active imidazole N-oxides derived from l-prolinamine1

Starting with (S)-1-benzylprolinamine and α-hydroxyimino ketones, enantiomerically pure bisheterocyclic imidazole N-oxides bearing the (S)-configured N-benzyl(pyrrolidin-2-yl)methyl residue were prepared. These N-oxides reacted with 2,2,4,4-tetramethylcyclobutane-1,3-dithione to give the corresponding optically active imidazole-2-thione derivatives via a sulfur transfer reaction. Reduction of the N-oxides with Raney-nickel led to deoxygenation, whereas catalytic hydrogenation (Pd/C) in ethanol occurred with simultaneous deoxygenation and debenzylation, leading to optically active 1-(pyrrolidin-2-yl)methyl-1H-imidazoles. Alkylation of the prepared imidazole N-oxides and their respective imidazoles with butyl and hexyl bromide and subsequent anion exchange gave optically active N-alkoxy- and N-alkylimidazolium tetrafluoroborates, respectively, with the properties of ‘room temperature ionic liquids’.     

Stereoselective synthesis of heterosubstituted aziridines and their functionalization

Lithiated (α-chloroalkyl)heterocycles, generated by deprotonation with LDA at −78 °C in THF, add to various enantiopure imines affording ‘one pot’ chiral heterosubstituted aziridines in a diastereoselective manner. Lithiated heterosubstituted aziridines, obtained by deprotonation of the corresponding aziridines with n-BuLi at −78 °C in THF, were trapped by electrophiles (D₂O or CH₃I) with high stereoselectivity.     

A rapid and convergent synthesis of α,α-difluoro-β-hydroxyketones through regiospecific defluorinative alkylation reaction

Both the defluorinative alkylation reaction of trifluoroacetaldehyde N,O-acetals using alkyllithiums and the following C-C bond formation with carbonyls as electrophiles were accelerated by a suitable diamine additive such as (−)-sparteine to give α,α-difluoro-β-hydroxyketone N,O-acetal products in an excellent yield. We also found that N-benzyl-N,O-acetal group of the resultant products can be removed under palladium-catalyzed hydrogenolysis conditions giving rise to the corresponding α,α-difluoro-β-hydroxyketones. The present two-step procedure is a useful and novel synthetic approach for functionalized α,α-difluoroketones.     

Intramolecular nucleophilic attack at silicon in o-silylbenzyl alcohols. Generation of allyl and benzyl anion equivalents

Substituted silyl ethers of o-bromobenzyl alcohols and the derived o-silylbenzyl alcohols were used to transfer allyl and benzyl groups from silicon to the electrophiles benzaldehyde and benzophenone in excellent yields. γ-Oxidosilane intermediates (and possibly hypercoordinated silicon intermediates) are postulated.     

Direct N- and C-alkenylation of nitrogen-containing heterocycles with magnesium alkylidene carbenoids

Treatment of magnesium alkylidene carbenoids, which were generated from 1-chlorovinyl p-tolyl sulfoxides with isopropylmagnesium chloride at −78 °C in toluene, with N-lithio nitrogen-containing heterocycles gave N-alkenylated products in moderate to good yields. Also, the reaction of C-lithio indoles, which were generated from N-protected indoles, with magnesium alkylidene carbenoids gave C-2 or C-3 alkenylated products, corresponding to the protective group. The intermediate of these reactions were found to be the alkenyl anion, which could be trapped with electrophiles to give the heterocycles having fully substituted alkenes.     

1,3-phosphorus zwitterions with cyano-group at anion center

This review focuses on synthesis and properties of 1,3-phosphorus-containing zwitterions that have at the anionic center cyano-group and either ester (type one) or carbamate (type two) moieties. Zwitterions belonging to type one possess dual nucleophile reactivity, i.e., depending on the properties of the electrophiles they may form either C- or N-derivatives. Zwitterions belonging to type two possess triple nucleophile reactivity. In their reactions with electrophiles, they may form even three types of derivatives, i.e., at the C-, O- or N-atoms. This nucleophile multiplicity is not just interesting from the theoretical standpoint but may also open the ways to the synthesis of new compounds that can be important from the practical standpoint, such as physiologically active compounds, catalysts, analytical reagents, etc.     

Synthesis of substituted salicylamines and dihydro-2H-1,3-benzoxazines

Phenols were converted to their magnesium salts with the MgCl₂-Et₃N base system and subsequently reacted with Eschenmoser's salt, affording N,N-dimethyl substituted benzylamines in high to excellent yields. A series of mono N-substituted benzylamines were prepared in one-pot syntheses by ortho-formylation of phenols to corresponding salicylaldehydes, which in turn reacted with amines to imines. The imines were subsequently reduced to mono N-substituted benzylamines. Some of these benzylamines were further converted, without work-up, to mono N-substituted dihydro-2H-1,3-benzoxazines.     

Electrochemical reductions of substituted pyridinium 2-pyridylcarbonylmethylides,their Pt(II) complexes,and substituted n-(2-pyridylcarbonyl)methylpyridinium perchlorates

The title pyridinium salts and pyridinium ylide-platinum(II) complexes have been reduced through a one-electron process at more positive potentials by 0.3 $\text{\$}\text{?}$0.6 V than the corresponding ylides. Both the reduced pyridinium salts and Pt(II)-ylide complexes reacted with dioxygen, followed by elimination of the N-methylene and ylide protons to form pyridinium ylides and Pt(II)-pyridinium ylide complexes containing the three-coordinate ylide carbon atom, respectively.     

Highly regio- and stereoselective hydrometallation reactions of fluorine-containing internal alkynes: Novel approaches to fluoroalkylated alkenes

Hydroalumination, hydrocupration, and hydroboration reactions of various fluorine-containing alkynes were investigated. The alkyne reacted smoothly with 2.0 equiv. of Red-Al at −78 °C to give the hydroaluminated adduct in a highly regio- and stereoselective manner, which was treated with iodine, the corresponding vinyliodide being produced in moderate yield. Hydrocupration of the alkynes also took place, but the resulting vinylmetal reacted with various electrophiles sluggishly. In sharp contrast, the reaction with dicyclohexylborane proceeded smoothly to afford the cis-addition products preferentially, which were subjected to Suzuki-Miyaura cross-coupling reaction, leading to trisubstituted alkenes in high yields.     

Synthesis of 3,4,5-trisubstituted indoles via iterative directed lithiation of 1-(triisopropylsilyl)gramines

Directed lithiation of 1-(triisopropylsilyl)gramines 1 with tert-butyllithium followed by reaction with trimethylsilylmethyl azide produced 4-amino-1-(triisopropylsilyl)gramines 7. The N-tert-butoxycarbonyl derivatives 8 were lithiated selectively at C-5 with tert-butyllithium and the lithiated species were reacted with a variety of electrophiles to give 5-functionalized compounds, 9 and 10. A facile method to produce 3,4,5-trisubstituted indoles from readily available gramine derivatives is thereby established.