Regioselective synthesis of β-fluoro-α,β-unsaturated ketones by the reaction of β-diketones with DFMBA

The deoxyfluorination reaction of β-diketones with N,N-diethyl-α,α-difluoro-m-methylbenzylamine (DFMBA) gave β-fluoro-α,β-unsaturated ketones in good yields. The reaction proceeded regioselectively, and only one regioisomer was obtained from the unsymmetrical 1-aryl-1,3-diketones. The reaction is applicable to diketones with a trifluoromethyl group, obtaining good yields of 3,4,4,4-tetrafluorobutenones. We used the resulting β-fluoro-α,β-unsaturated ketones for the reaction with lithium dialkyl cuprates.     

Synthesis of photolabile o-nitroveratryloxycarbonyl (NVOC) protected peptide nucleic acid monomers

The chemical synthesis of peptide nucleic acid (PNA) monomers was accomplished using various combinations of the o-nitroveratryloxycarbonyl (NVOC) group (N-aminoethylglycine backbone) and base labile acyl-type nucleobase protecting groups (anisoyl for adenine and cytosine; isobutyryl for guanine), thus offering a photolithographic solid-phase PNA synthetic strategy compatible with photolithographic oligonucleotide synthesis conditions and allowing the in situ synthesis of PNA microarrays in an essentially neutral medium, by avoiding the use of the commonly used deprotection reagents such as trifluoroacetic acid or piperidine. Convenient methods were also explored to prepare 1-(carboxymethyl)-4-N-(4-methoxybenzoyl)cytosine and 9-(carboxymethyl)-2-N-(isobutyryl)guanine with good yields.     

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.     

Synthesis and kinetic investigation of the selective acidolysis of para-substituted N-benzyl- or N-phenyl-N-phenylacetyl-α,α-dialkylglycine cyclohexylamides

Several derivatives of N-phenylacetyl-N-benzyl-α,α-dimethylglycine cyclohexylamide and their α,α-dibenzylglycine analogues were synthesised by a Ugi-Passerini reaction. In addition, a few analogues of the former but having an N-phenyl instead of a benzyl group at the nitrogen atom were synthesised. The compounds in each of these three sets differed from each other at position 4 of the N-benzyl (and N-phenyl) group. These adducts were submitted to acidolysis with TFA to obtain the corresponding free acids, the reactions being monitored by HPLC and data collected for kinetic purposes. The kinetic data were submitted to Hammett uni- and biparametric relationships and the results were analysed in terms of structure-reactivity in connection with the sensitivity of the reaction rates to the electronic contributions of the various substituents at position 4 of the aromatic rings. The results allowed comparison with information obtained in previous investigations and rationalise the contribution of the substituent at the nitrogen atom to the lability of the C-terminal amide bond.     

Facile construction of 1,2-cis glucosidic linkage using sequential oxidation-reduction route for synthesis of an ER processing α-glucosidase I substrate

The fluorescence-labeled hexasaccharide (Glcα1-2Glcα1-3Glcα1-3Manα1-2Manα1-2Manα) was synthesized as a substrate for the processing enzyme α-glucosidase I. To construct the 1,2-cis glucosidic linkages, we employed an α stereoselective coupling using the mannosyl donor by assisted neighboring-group participation, followed by conversion of the stereochemistry of the C-2 hydroxyl group in the mannose residue using sequential oxidation of C-2 hydroxyl group to a 2-keto group and stereoselective reduction of the hydroxyl group to the gluco-configuration to provide the corresponding α-glucoside derivative. Using this strategy, the three consecutive α-glucosidic linkages were easily obtained in a stereoselective manner. Finally, the Dansyl labeled hexasaccharide derivative was used to measure the activity of processing α-glucosidase I.     

Quinoxaline synthesis in novel tandem one-pot protocol

A variety of quinoxalines were synthesized via tandem one-pot procedure for the first time in water medium. The key strategy was the in situ preparation of α-halo-β-keto esters by the reaction of N-bromo succinimide with β-keto esters and further condensation with phenylene diamines. This novel eco-friendly approach offers an easy, efficient, and mild synthesis of highly substituted quinoxalines in good yields.     

A facile synthesis of 2-(N-alkylamino)-pyrimidin-4-one derivatives

Substituted 2-(N-alkylamino)-pyrimidin-4-ones were synthesized from N-alkyl β-amino acid esters starting with guanidinylation using Pbf-activated thiourea. The six-membered pyrimidinones were obtained in good yields via intramolecular cyclization during TFA cleavage of the Pbf protecting group.     

N-[1-(Benzotriazol-1-yl)alkyl]amides from N-acyl-α-amino acids or N-alkylamides

A variety of N-(1-methoxyalkyl)amides react with benzotriazole in the presence of PPh₃·HBF₄ and organic bases (Hünig's base, DBU or DABCO) or solid-state-supported bases (SiO₂-Pip or IRA-67) in CHCl₃ to give N-[1-(benzotriazol-1-yl)alkyl]amides in good yields. The most convenient and efficient procedure for obtaining N-[1-(benzotriazol-1-yl)alkyl]amides consists, however, of the addition of benzotriazole sodium salt to a solution of crude 1-(N-acylamino)alkyltriphenylphosphonium salt, obtained in situ from N-(1-methoxyalkyl)amides and PPh₃·HBF₄. A combination of these reactions with the recently described electrochemical decarboxylative α-methoxylation of N-acyl-α-amino acids in the presence of SiO₂-Pip enables an effective two-pot transformation of N-acyl-α-amino acids to N-[1-(benzotriazol-1-yl)alkyl]amides.     

Elimination of benzotriazolyl group in N-(α-benzotriazol-1-ylalkyl)amides and N-(α-benzotriazol-1-ylalkyl)sulfonamides: their self-coupling and cross-coupling reactions with carbonyl compounds

The elimination of benzotriazolyl group from N-(α-benzotriazol-1-ylalkyl)amides and N-(α-benzotriazol-1-ylalkyl)sulfonamides are readily realized with samarium diiodide as a reducing agent. The resulting intermediates undergo a dimerization or cross-coupling reaction with carbonyl compounds, thus affording the corresponding dimers or α-hydroxyalkylated sulfonamides in moderate yields.     

A new convenient synthesis of N-acyl-2-(dimethoxyphosphoryl)glycinates

Easily accessible N-acyl-2-triphenylphosphonioglycinate tetrafluoroborates react smoothly with trimethylphosphite in the presence of methyltriphenylphosphonium iodide to give N-acyl-2-(dimethoxyphosphoryl)glycinates in good or very good yields. The dimethoxyphosphorylglycinates may be isolated by column chromatography, or used directly for the Wadsworth-Emmons synthesis of α,β-dehydro-α-amino acids in a one-pot procedure without purification.     

Simple and efficient cleavage of the N-(1-phenylethyl) unit of carboxamides with methanesulfonic acid

Cleavage of the N-(1-phenylethyl) unit of carboxamides using less than 1 equiv of MsOH in refluxing toluene was found to be simple and very efficient leading to the desired amides in good to excellent yields, and also proved to be more effective compared with reductive methods using hydrogen sources, or acid hydrolysis reagents such as TFA and TsOH. The method selectively cleaved only the N-(1-phenylethyl) group of N-benzyl-N-(1-phenylethyl)amides.     

A fast and highly efficient protocol for Michael addition of N-heterocycles to α,β-unsaturated compound using basic ionic liquid [bmIm]OH as catalyst and green solvent

A fast and green protocol for the Michael addition of N-heterocycles to α,β-unsaturated compounds at room temperature was developed using a basic ionic liquid, 1-methyl-3-butylimidazolium hydroxide, [bmIm]OH, as a catalyst and a reaction medium. The reactions were performed at room temperature with good yields in short reaction times (0.5-3 h). This strategy is quite general and it works with a broad range of N-heterocycles, including five-membered N-heterocycles, pyrimidines and purines. The recovered ionic liquid could be reused for several cycles with consistent activity.     

Selective mono-acylation of 1,2- and 1,3-diols using (α,α-difluoroalkyl)amines

In the reaction of N,N-diethyl-α,α-difluorobenzylamine (DFBA) with 1,2- or 1,3-diols, selective mono-benzoylation occurs to afford mono-esters of the diols in good yield. The reaction is completed under mild conditions in a short reaction time. Further, prim-, sec-, and tert-diols and catechol can be converted to the corresponding mono-benzoates. DFBA is used for the protection of the hydroxy group in sugars. The selective mono-nicotinylation, formylation and pivaloylation of diols are also performed by using the corresponding difluoroalkylamines.     

Chiral N-phosphonyl imine chemistry: asymmetric 1,2-additions of allylmagnesium bromides

Chiral N-phosphonyl homoallylic amines were synthesized by the reaction of allylmagnesium bromide with chiral N-phosphonyl imines. The C₂-symmetric chiral N-phosphonyl group was optimized for this reaction. Excellent yields and good diastereoselectivities were obtained for eight examples.     

Silver-promoted trans-hydrofluorination of ynamides: a regio- and stereoselective approach to (Z)-α-fluoroenamides

A highly regio- and stereoselective trans-hydrofluorination of N-sulfonyl ynamides has been realized with AgF as the fluorination reagent, affording (Z)-α-fluoroenamides in good to excellent yields. The reaction proceeds under mild reaction conditions and shows good functional group compatibility.     

Efficient synthesis of protected sulfonopeptides from N-protected 2-aminoalkyl xanthates and thioacetates

An efficient and convenient method was developed for the synthesis of protected sulfonopeptides via N-chlorosuccimide (NCS)/HCl oxidative chlorination of N-protected 2-aminoalkyl xanthates or thioacetates to the corresponding sulfonyl chlorides followed by aminolysis with amino esters. In the current method, sulfonopeptides containing 1- and 2-substituted taurines were prepared in satisfactory to good yields. It is a useful and efficient strategy for the synthesis of protected sulfonopeptides with functionalized side-chains.     

Stereoselective fluorination of methylenecyclopropanes with N-F reagents: A modular entry to γ-fluorohomoallylic sulfonimides and γ-fluorohomoallylic amides

A convenient and efficient method for fluorination of methylenecyclopropanes is reported. This is exemplified in the stereoselective preparation of N-[(E)-3-fluorobut-3-en-1-yl]-benzenesulfonimides by the reaction of methylenecyclopropanes with N-fluorobenzenesulfonimide in good to excellent yields. Moreover, γ-fluorohomoallylic amides are synthesized using Selectfluor in R₃CN at 60 °C.     

Construction of dihydropyrimidine skeleton using 1,2,4-trisubstituted-1,3-diaza-1,3-butadienes

Construction of a dihydropyrimidine ring was developed that involved the cyclization of 1,3-diaza-1,3-butadienes having an N-protecting group (N-Cbz, N-Boc, N-alkyl, or N-benzyl) with α,β-unsaturated carbonyl compounds such as ethyl acrylate and p-chlorophenyl vinyl ketone. Consequently, 4-dimethylamino-2-phenyl-1,4,5,6-tetrahydropyrimidines were synthesized in good yields. Subsequently, the β-elimination of the dimethylamino group was carried out with MeI or SiO₂ to afford various N-protecting-2,5-disubstituted-1,6-dihydropyrimidines in good yields. Remarkably, the use of 4-chlorophenyl vinyl ketone directly provided the dihydropyrimidine without the tetrahydropyrimidine intermediate in excellent yield.     

Synthesis and optical properties of conjugated N,N-dimethyl and thienyl end-capped 2,5-(arylethynyl)thiophene oligomer structures

End-capped (N,N-dimethylaminophenyl) and 2′-thienylethynyl 2,5-thiophene oligomer structures were synthesized by heterocoupling between the terminal acetylenes such as: p-(N,N-dimethylaminophenyl)ethyne (3) [or 1-(p-(N,N-dimethylaminophenyl)-2-p-(ethynylphenyl)ethyne, 4]; p-(β-ethenyl-2′-thienyl)phenylethyne (E-9) [or p-(β-ethynyl-2′-thienyl)phenylethyne, 11], and 2,5-diiodothiophene, catalyzed by the Cl₂Pd(PPh₃)₂/CuI system, in good to excellent yields. The 2,5-di[(3′,5′-di(trimethylsilylethynyl)phenyl]_x-1-ethynyl]thiophene oligomers were prepared by heterocoupling between 3′,5′-di[(trimethylsilylethynyl)phenyl]_x-1-ethyne (n = 0-2) terminal acetylenes and 2,5-diiodothiophene, in excellent yields. The terminal acetylenes were efficiently prepared by a specific protection-deprotection methodology. All the ethynylphenyl compounds obtained show fluorescence radiation emission, with a bathochromic shift of the wavelength that increases with the chain conjugation.     

Regioselective synthesis of substituted 1-indanols, 2,3-dihydrobenzofurans and 2,3-dihydroindoles by electrochemical radical cyclization using an arene mediator

Electrochemical reduction of haloarenes carrying 2-(1-hydroxybut-3-enyl), 2-allyloxy or N-allyl-N-methylamino group in the presence of phenanthrene as a mediator generated the corresponding aryl radicals and gave the corresponding 5-exo cyclization products in good yields. Higher regio- and stereoselectivities than those of usual radical cyclization using AIBN-Bu₃SnH were achieved.