Efficient preparation of secondary aminoalcohols through a Ti(IV) reductive amination procedure. Application to the synthesis and antibacterial evaluation of new 3β-N-[hydroxyalkyl]aminosteroid derivatives

An efficient method for the synthesis of various secondary aminoalcohols through a titanium(IV) isopropoxide-mediated reductive amination reaction of ketones is reported. Thus, different ketones gave the expected products in moderate to excellent yields up to 89% in numerous cases. A series of 3β-N-[hydroxyalkyl]aminosteroid derivatives were prepared according to this methodology and evaluated for their in vitro antimicrobial properties against human pathogens. All the compounds showed moderate to excellent activities against Gram-positive bacteria exhibiting similar results against Staphylococcus aureus and Streptococcus faecalis with Minimum Inhibitory Concentrations (MICs) varying from 3.12 to 25 μg/mL. No significant antibacterial activities are encountered against Gram-negative bacteria.     

Synthesis of pyrrole N-derivatives from oxazolidines

Transformations of oxazolidine derivatives synthesized from industrially produced amino alcohols, aldehydes, and ketones under basic or acidic catalysis lead to the formation of N-alkyl- and N-(hydroxyalkyl)-substituted pyrroles in 19-81% yields.     

二氧化硅负载的胂钯(0)配合物作为丙烯酸丁酯和丙烯酰胺芳基化反应高活性和高立体选择性的催化剂

A silica-supported arsine palladium(O) complex has been prepared from y-chloropropyltriethoxysilane via immobilization on fumed silica, followed by reaction with potassium diphenylarsenide and palladium chloride, and then reduction with hydrazine hydrate. The complex has been characterized by X-ray photoelectron spectroscopy (XPS) and it is a highly active and stereoselective catalyst for arylation of butyl acrylate and acrylamide with aryl halides, affording a variety of tram-butyl cinnamates and trans-cinnamamides in high yields.     

One-Pot Synthesis of 3-(Trimethylsilyl)propynamides

A highly efficient one-pot procedure was developed for the synthesis of 3-trimethylsilylpropynamides by acylation of amines with trimethylsilylpropynoyl chloride generated in situ. Selective N-acylation and N,O-bis-acylation of ß-amino alcohols with formation of, respectively, N-(hydroxyalkyl)propynamides and 2-methyl-2-[3-(trimethylsilyl)propynoylamino]propyl 3-(trimethylsilyl)propynoate were accomplished with high yields.     

Synthesis,In Silico and In Vivo Toxicity Assessment of Functionalized Pyridophenanthridinones via Sequential MW-Assisted Intramolecular Friedel-Crafts Alkylation and Direct C–H Arylation

A rapid, efficient, and original synthesis of novel pyrido[3,2,1-de]phenanthridin-6-ones is reported. First, the key cinnamamide intermediates 8a–f were easily prepared from commercial substituted anilines, cinnamic acid, and 2-bromobenzylbromide in a tandem amidation and N-alkylation protocol. Then, these N-aryl-N-(2-bromobenzyl) cinnamamides 8a–f were subjected to a TFA-mediated intramolecular Friedel-Crafts alkylation followed by a Pd-catalyzed direct C–H arylation to obtain a series of potentially bioactive 4-phenyl-4,5-dihydro-6H,8H-pyrido[3,2,1-de]phenanthridin-6-one derivatives 4a–f in good yields. Finally, the toxicological profile of the prepared final compounds, including their corresponding intermediates, was explored through in silico computational methods, while the acute toxicity toward zebrafish embryos (96 hpf-LC₅₀, 50% lethal concentration) was also determined in the present study.     

Synthesis of sulfur-containing vicinal aminoalcohols on the basis of N-(oxiran-2-ylmethyl)amines

The reaction of (methanediyldibenzene-4,1-diyl)dimethanethiol, (oxydibenzene-4,1-diyl)dimethanethiol, biphenyl-4,4′-diyldimethanethiol with 1-(oxiran-2-ylmethyl)piperidine and N-(oxiran-2-ylmethyl)-N-ethylaniline afforded the corresponding sulfur-containing vicinal aminoalcohols resulting from the opening of the oxirane ring in keeping with Krasusky rule.     

The acid-mediated ring opening/cyclisation reaction of N-benzyl-α-aryl-azetidinones

N-Benzyl-4-aryl-azetidinones undergo ring opening with triflic acid to form N-benzyl-cinnamamides, which either undergo cyclisation to give 5-aryl-benzazepin-3-ones or N-debenzylation to give cinnamamides.     

Synthesis and structure of 3-(3-acetoxyalkylcarbamoyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-1-yl)propanoic acids

Treatment of 1-(2-cyanoethyl)-4-hydroxy-N-(hydroxyalkyl)-2-oxo-1,2-dihydroquinoline-3-carboxamides with a solution of hydrogen chloride in aqueous acetic acid ensures selective transformation of the cyano group into amide or carboxy with simultaneous acetylation of the hydroxyalkyl fragments.     

Solid-phase synthesis of 2-imidazolidinethiones via Mitsunobu reaction of N-(2-hydroxyethyl)thioureas

This letter reports the solid-phase synthesis of 2-imidazolidinethiones via the N-cyclization of N-(2-hydroxyethyl)thioureas using the Mitsunobu reaction in good yield and purity. This process employed the reductive amination of an ArgoGel-MB-CHO resin to anchor the aminoalcohols, followed by a reaction with isothiocyanates to give the resin-attached N-(2-hydroxyethyl)thioureas. Cleavage of the 2-imidazolidinethiones was performed with trifluoroacetic acid.     

Facile generation of vicinal bromoazides from olefins using TMSN3 and TsNBr2 without any catalyst

A very rapid and efficient method has been developed for the synthesis of vicinal bromoazides directly from olefin using N,N-dibromo-p-toluenesulfonamide (TsNBr₂) without any catalyst. The reaction is extremely fast which goes into completion instantaneously to produce bromoazides. This procedure is applicable to various olefins such as cinnamates, chalcone, styrenes, and acrylate to give the corresponding 1,2-bromoazide in an excellent yield.     

Synthesis of chiral ferrocenyl aminoalcohols involving a diastereospecific oxidation: use in asymmetric catalysis

The synthesis of six new chiral ferrocenic aminoalcohols has been performed. One step of this synthesis was a diastereospecific oxidation of diastereomeric mixtures of 1-[2-(N,N-dimethylaminomethyl)ferrocenyl]alcohols by manganese dioxide: one diastereomer was oxidized, while the other stayed inert. The six new chiral compounds in association with ZnEt₂ proved to be good catalysts in the asymmetric ethylation of benzaldehyde (77 to 88% ee).     

Facile stereoselective synthesis of (E)- and (Z)-α-substituted cinnamates: stereospecific dehydration reaction with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and copper(II) chloride

A highly stereoselective method for the synthesis of (E)- and (Z)-α-substituted cinnamates in good yield has been achieved by dehydration reaction of anti- and syn-α-substituted-β-hydroxyphenylpropiolate using EDC. This facile method has been used to synthesize various (E)- and (Z)-α-substituted cinnamates and (E)- and (Z)-α-alkylidene-γ-butyrolactones. The reaction mechanism of this highly stereospecific dehydration using EDC can be elucidated by the ω-dimethylamino group of EDC, which is believed to facilitate the deprotonation step.     

Stereocontrolled synthesis of 3-amino-2-hydroxyalkyl diphenylphosphine oxides mediated by chiral azetidinium salts and epoxyamines

The stereocontrolled synthesis of amino hydroxyalkyl diphenylphosphine oxides has been achieved starting from (2S,3S)-N,N-dibenzyl-3-hydroxy-2-methylazetidinium bromide or (1R),[1′(S)-(dibenzylamino)ethyl]oxirane. The regioselective ring opening of both heterocyclic systems at the less substituted carbon atom with phosphorus nucleophiles proceeded with full stereochemical integrity.     

α-Thioureidoalkylation of functionally substituted ureas: II. Synthesis of thio analogs of N-hydroxyalkyl-1,5-diphenylglycolurils

Reactions of N-(hydroxyalkyl)ureas with 4,5-dihydroxy-4,5-diphenylimidazolidine-2-thiones gave previously unknown 4,6-dialkyl-1-hydroxyalkyl-3a,6a-diphenyl-5-thioxooctahydroimidazo[4,5-d]imidazol-2-ones which may be regarded as thio analogs of N-(hydroxyalkyl)glycolurils.     

Conformational studies of copoly (N 5-ω-hydroxyalkyl-L-glutamine-L-glutamic acid)s

Copoly (α-amino acid)s consisting ofL-glutamic acid residue andN ⁵-ω hydroxyalkyl-L-glutamine residue, i.e., 2-hydroxyethyl, 3-hydroxypropyl, and di-2-hydroxyethyl derivatives were prepared by the reactions of copoly (L-glutamic acid) containing succinimide ester with corresponding amino alcohols. The conformation of these copolymers was examined by the CD and infrared measurements. These three copolymers containing about 20–30% hydroxyalkyl groups undergo a methanol-induced and a pH-induced conformational transitions. The copolymer containing about 50% 3-hydroxypropyl group assumes the α-helical conformation in the pH region from 2.5 to 11.6, and in a methanol-water mixture (9∶1). On the other hand, the copolymer containing about 60% di-2-hydroxyethyl groups does not allow any helical conformation even at lower pH and also even in a trifluoroethanol-water mixture (9∶1), suggesting that the branched hydroxyalkyl group is unfavorable for the formation of α-helix. Furthermore, the poly(N ⁵-di-2-hydroxyethyl-L-glutamine) is shown to have a rather disordered structure in the solid state.     

Stereoselective syntheses and transformations of chiral 1,3-aminoalcohols and 1,3-diols derived from nopinone

A library of 1,3-difunctionalized pinane derivatives were synthesized and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. 1,3-Aminoalcohol 6a was prepared from (−)-nopinone 2 via stereoselective Mannich condensation and reduction of the resulting β-amino ketone 4. The key aminoalcohol 6a was transformed into primary, secondary and tertiary substituted aminoalcohols in order to study the effect of the substituent on catalytic activity. Starting from (−)-nopinone, cis- and trans-β-hydroxy esters 15 and 16 were prepared in a two-step stereoselective synthesis. Reduction of the hydroxy esters resulted in pinane-based 1,3-diols, while hydrolysis of the esters, followed by DCC-mediated amidation and subsequent reduction, led to cis- and trans-N-benzyl-1,3-aminoalcohols 8 and 23. trans-N-Benzyl-1,3-aminoalcohol 8 was also prepared by selective mono-debenzylation of 6a via a continuous-flow process in an H-Cube® system. The resulting aminoalcohols and diols were applied as chiral catalysts in the reaction of diethylzinc and benzaldehyde.     

Photocatalyzed Intramolecular [2+2] Cycloaddition of N-Alkyl-N-(2-(1-arylvinyl)aryl)cinnamamides

N-Alkyl-N-(2-(1-arylvinyl)aryl)cinnamamides are converted into natural product inspired scaffolds via iridium photocatalyzed intramolecular [2+2] photocycloaddition. The protocol has a broad substrate scope, whilst operating under mild reaction conditions. Tethering four components forming a trisubstituted cyclobutane core builds rapidly high molecular complexity. Our approach allows the design and synthesis of a variety of tetrahydrocyclobuta[c]quinolin-3(1H)-ones, in yields ranging between 20–99 %, and with excellent regio- and diastereoselectivity. Moreover, it was demonstrated that the intramolecular [2+2]-cycloaddition of 1,7-enynes—after fragmentation of the cyclobutane ring—leads to enyne-metathesis-like products.     

Synthesis and PMR spectra of 7-hydroxyalkylguanosinium acetates

Guanosine and 9-methylguanine treated with epoxides in glacial acetic acid are hydroxyalkylated stereoselectively at the N₇ position of the guanine moiety. Previously unreported 7-(hydroxyalkyl)guanosinium acetates from the reactions of six epoxides with guanosine and 7-(hydroxyalkyl)-9-methylguaninium acetates from the reactions of two epoxides with 9-methyl guanine in glacial acetic acid have been prepared and characterized by their pmr spectra. By using an excess of epoxide, quantitative conversion of guanosine or 9-methylguanine to the corresponding 7-hydroxyalkylguanosinium or 7-hydroxyalkyl-9-methylguaninium acetate was achieved. Comparisons of the pmr spectra of the 7-(hydroxyalkyl)guanosinium acetates in DMSO-d₆ to the spectrum of guanosine reveal that the H₈ and amino group proton absorptions common to guanosine are shifted to a lower field, the absorptions of the H₁ proton is absent, and the coupling constant of the H′₁-H′₂ protons of the ribosyl group is decreased from about 5.7 ± 0.1 Hz in guanosine to about 3.5 ± 0.1 Hz in the products. The use of the pmr spectral features of 7-(hydroxyalkyl)-9-methylguaninium compounds in characterizing 7-hydroxyalkylguanosinium compounds is discussed. Evidence is presented which suggests that extensive delocalization of positive charge exists in both the pyrimidine and imidazole rings of N₇-hydroxyalkylated guanosine and N₇-hydroxyalkylated-9-methylguanine. The possible effects of charge delocalization upon the hydrogen bonding potential of 7-hydroxyalkylated guanine moieties in DNA is discussed.     

Room-temperature polycondensation of β-amino acid derivatives,I. Polyamide from amino alcohols and acrylates

Acrylates, such as ethyl acrylate, add with amino alcohol to form N-(hydroxyalkyl) β-alanine ester and room-temperature polycondensation follows, forming polyamide in the presence of a basic catalysts, such as alkali metal alkoxide. The reaction medium has an influence on the course of the polycondensation; that is, N-(hydroxyalkyl) polyamide is formed in methanol solution and polyamide ether in other solvents, such as tetrahydrofuran. These two courses of the room-temperature polycondensation have been studied, and the reaction mechanism is discussed in this paper.     

Asymmetric synthesis of chiral β-iodo Baylis–Hillman esters using MgI2 as promoter via a one-pot three-component reaction

An asymmetric synthesis of β-iodo-α-(hydroxyalkyl)acrylates has been developed involving conjugate addition of I⁻ to menthyl propiolates to give β-iodo allenolate intermediates which undergo 1,2-addition to form β-iodo Baylis–Hillman products. Modest diastereoselectivities (37–58% de) and excellent yields (80–87%) were obtained when (1R,2S,5R)-(−)-menthol was used as a chiral auxiliary. The two diastereoisomers of the product were separated by silica gel chromatography to give diastereomerically pure products.