Key Synthon Research Articles

New 1,3-diaryl-5-thioxo-imidazolidin-2,4-dione derivatives: synthesis, reactions and evaluation of antibacterial and antifungal activities

Abstract New cyanothioformamide derivative 1 was prepared by treatment of 3,5-dichlorophenyl isothiocyanate with potassium cyanide at room temperature. Cycloaddition of cyanothioformamide 1 with phenyl isocyanate as electrophile furnished the corresponding imidazolidine 2. Imine hydrolysis of 2 with ethanolic HCl produced the corresponding 4-thioxo-2,5-imidazolidinedione 3. This compound was used as key synthon for the preparation of a wide variety of new substituted imidazole compounds. Condensation of 3 with different types of hydrazine derivatives furnished new series of hydrazone 4a, b, thiosemicarbazone 5a, b and cyanoacetohydrazide 6 derivatives incorporating imidazolidine moiety. Finally, cyanoacetohydrazide 6 was used as intermediate for synthesizing new compounds. Evaluation of the antibacterial and antifungal activities for the synthesized compounds was carried out to probe their activities. Most of the tested compounds showed significant activities. The dione derivative 3 and the imidazolidine derivative 9a, which incorporates a chromene moiety, exhibited high activity near the reference drug against all tested organisms.

Chemoenzymatic Synthesis of Chiral 1‐Benzyl‐5‐(hydroxymethyl)‐2‐piperidone Enabled by Lipase AK‐Mediated Desymmetrization of Prochiral 1,3‐Diol and Its Diacetate

The synthesis of (R)‐1‐benzyl‐5‐(hydroxymethyl)‐2‐piperidone (1) from key synthon monoacetate (R)‐3 has been accomplished conveniently in 6 steps with 93 % ee and in 44 % overall yield. The key step involved lipase AK‐mediated desymmetrization of diol 4 to produce monoacetate (R)‐3 in 93 % ee and 93 % yield. Additionally, lipase AK‐mediated desymmetrization of diacetate 5 readily provided access to monoacetate (S)‐3 in 93 % ee and 54 % yield.

Pyrene-fused Acenes and Azaacenes: Synthesis and Applications.

In this account, the synthesis and applications of pyrene-fused acenes, as well as pyrene-fused azaacenes, have been carefully reviewed. Moreover, the synthetic methods involving two key synthons (different lengths of dienes and ynes) have been included. Furthermore, the "clean reaction" strategy has been introduced for the preparation of pyrene-fused acenes with a single terminal-pyrene unit from tetracene to octacene, as well as for the synthesis of pyrene-fused octatwistacenes and nonatwistacenes with double terminal-pyrene units. Similarly, the synthons and the synthetic methods for pyrene-fused azaacenes have also been summarized. The applications of pyrene-fused acenes and pyrene-fused azaacenes have been included.

Efficient Syntheses of Some New Thiophene‐Based Heterocycles

In this effort, 2‐aminothiophene‐3‐carboxylate (1) was prepared using Gewald's methodology. This 2‐aminothiophene derivative was diazotized and coupled with malononitrile to obtain the nitrile derivative (2), which was utilized as key synthon for the synthesis of polyfunctionally substituted heterocycles via its reactions with some nitrogen and carbon nucleophiles. On the other hand, a facile and convenient syntheses of thiazolidinone, pyrrolidinone, and chromene derivatives incorporating thiophene moiety via the versatile, readily accessible 2‐aminothiophene‐3‐carboxylate (1) were also described.

New Imidazolidineiminothione, Imidazolidin-2-one and Imidazoquinoxaline Derivatives: Synthesis and Evaluation of Antibacterial and Antifungal Activities.

A series of new 5-imino-4-thioxo-2-imidazolidinone derivatives 3 with various halogenated and alkylated aromatic substituents at N1 and N3 was synthesized. Imidazolidineiminothione derivatives 3 were prepared from the reaction of N-arylcyanothioformamide derivatives with aryl isocyanates. These compounds were used as key synthons for the preparation of wide variety of new substituted imidazole compounds. Imine hydrolysis of 3 with ethanolic HCl produced the corresponding 4-thioxo-2,5-imidazolidindiones 4. Condensation of 3 with benzophenonhydrazone furnished the corresponding 4-azine derivatives 5. Monohydrazono and dihydrazono derivatives 6 and 8 were obtained upon treatment of imidazolidinone derivatives 3 with hydrazine hydrate. Finally, imidazolidinones 3 were reacted with o-phenylenediamines or pyrazol-5(4H)-ones and afforded the corresponding imidazoquinoxaline and imidazolidin-4-ylidenepyrazolone-5(4H)-one derivatives 11 and 12, respectively. Evaluation of the antibacterial and antifungal activities for the synthesized compounds was carried out to probe their activities. Most of the tested compounds showed significant activities. The best antimicrobial activity was observed for 1-(3-ethoxyphenyl)-6-methyl-1-phenyl-1H-imidazo[4,5-b]quinoxalin-2(3H)-ones (11c) followed by 5-imino-3-(3-methoxy- phenyl)-1-phenyl-4-thioxoimidazolidin-2-one (3f).

Pd(II)-Catalyzed Aminofluorination of Alkenes in Total Synthesis 6-(R)-Fluoroswainsonine and 5-(R)-Fluorofebrifugine.

The total syntheses of two fluorinated alkaloids, 6-(R)-fluoroswainsonine and 5-(R)-fluorofebrifugine, are described. Both encompass (4aS,7R,8aR)-7-fluoro-5-tosylhexahydro-4H-[1,3]dioxino[5,4-b]pyridine as a key synthon which is obtained through a further optimized palladium-catalyzed aminofluorination of alkenes with high diastereoselectivity. 6-(R)-Fluoroswainsonine is synthesized from the key synthon in 14 steps, and 5-(R)-fluorofebrifugine requires a sequential 15-step transformation.

Meso-Pyrrole-Substituted 22-Oxacorroles: Building Blocks for the Synthesis of BODIPY-Bridged 22-Oxacorrole Dyads.

Novel boron-dipyrromethene (BODIPY)-bridged 22-oxacorrole dyads, using meso-pyrrolyl 22-oxacorrole as a key synthon, have been synthesized. The reactivity of the meso-pyrrolyl group of 22-oxacorrole was exploited to synthesize the first examples of BODIPY-bridged 22-oxacorrole dyads in ≈40 % yield. The dyads are stable and exhibited interesting spectral and electrochemical properties.

2-Formyl boron-dipyrromethene as a key synthon to prepare functionalized meso-boron dipyrromethenyl porphyrin building blocks

A series of functionalized meso-boron dipyrromethenyl porphyrin building blocks were synthesized by condensing one equivalent of readily available 2-formyl boron dipyrromethene (2-formyl BODIPY) with two equivalents of meso-anisyl dipyrromethane and one equivalent of functionalized aldehyde under mild acid catalyzed conditions followed by column chromatographic purification and afforded in 5–7% yields. The meso-BODIPYnyl porphyrins are freely soluble in common organic solvents and characterized by mass, spectral and electrochemical techniques. The presence of a BODIPY unit directly at the meso-position alters the π-delocalization of the porphyrin macrocycle. The compounds are weakly fluorescent because of effective charge transfer between the porphyrin and BODIPY units leading to the formation of a low lying charge transfer state. The meso-BODIPYnyl porphyrin–BF2–smaragdyrin conjugate was synthesized by coupling a meso-BODIPYnyl porphyrin building block containing a meso-iodophenyl group with ethynyl BF2–smaragdyrin under Pd(0) coupling conditions. The spectral and electrochemical studies indicated that the photo-induced electron transfer is the predominant process in the meso-BODIPYnyl porphyrin–BF2–smaragdyrin conjugate.

Modular assembly of purine-like bisphosphonates as inhibitors of HIV-1 reverse transcriptase.

Bisphosphonates can mimic the pyrophosphate leaving group of the nucleotidyl transfer reaction and effectively inhibit RNA/DNA polymerases. In a search of HIV-1 reverse transcriptase (RT) inhibitors, a new chemotype of nonhydrolyzable purine diphosphate mimic was synthesized. A modular synthetic protocol was developed, utilizing 2-amino-6-(methylthio)-4-(trimethylsilyl)nicotinonitrile as the key synthon in the preparation of highly substituted 2-aminonicotinonitriles. These building blocks were subsequently elaborated to the pyrido[2,3-d]pyrimidine bisphosphonates (PYPY-BPs). Biochemical screening identified analogs of PYPY-BPs that inhibit HIV-1 RT-catalyzed DNA synthesis.

From 2-aminomethyl-1,4-benzodioxane enantiomers to unichiral 2-cyano- and 2-carbonyl-substituted benzodioxanes via dichloroamine.

2-Substituted 1,4-benzodioxanes, such as 2-cyano-, 2-methoxycarbonyl-, 2-aminocarbonyl-, and 2-formyl-1,4-benzodioxane, are key synthons that for the most part are never described as enantiomers or are inadequately characterized for enantiomeric purity. They were prepared by quantitative N,N-dichlorination of (R)- and (S)-2-aminomethyl-1,4-benzodioxane and successive functional group conversions in high yields without any racemization of the stereogenic benzodioxane C(2).

Crosslinked enzyme aggregates of hydroxynitrile lyase partially purified from Prunus dulcis seeds and its application for the synthesis of enantiopure cyanohydrins

Hydroxynitrile lyases are powerful catalysts in the synthesis of enantiopure cyanohydrins which are key synthons in the preparations of a variety of important chemicals. The response surface methodology including three-factor and three-level Box-Behnken design was applied to optimize immobilization of hydroxynitrile lyase purified partially from Prunus dulcis seeds as crosslinked enzyme aggregates (PdHNL-CLEAs). The quadratic model was developed for predicting the response and its adequacy was validated with the analysis of variance test. The optimized immobilization parameters were initial glutaraldehyde concentration, ammonium sulfate saturation concentration, and crosslinking time, and the response was relative activity of PdHNL-CLEA. The optimal conditions were determined as initial glutaraldehyde concentration of 25% w/v, ammonium sulfate saturation concentration of 43% w/v, and crosslinking time of 18 h. The preparations of PdHNL-CLEA were examined for the synthesis of (R)-mandelonitrile, (R)-2-chloromandelonitrile, (R)-3,4-dihydroxymandelonitrile, (R)-2-hydroxy-4-phenyl butyronitrile, (R)-4-bromomandelonitrile, (R)-4-fluoromandelonitrile, and (R)-4-nitromandelonitrile from their corresponding aldehydes and hydrocyanic acid. After 96-h reaction time, the yield-enantiomeric excess values (%) were 100-99, 100-21, 100-99, 83-91, 100-99, 100-72, and 100-14%, respectively, for (R)-mandelonitrile, (R)-2-chloromandelonitrile, (R)-3,4-dihydroxymandelonitrile, (R)-2-hydroxy-4-phenyl butyronitrile, (R)-4-bromomandelonitrile, (R)-4-fluoromandelonitrile, and (R)-4-nitromandelonitrile. The results show that PdHNL-CLEA offers a promising potential for the preparation of enantiopure (R)-mandelonitrile, (R)-3,4-dihydroxymandelonitrile, (R)-2-hydroxy-4-phenyl butyronitrile, and (R)-4-bromomandelonitrile with a high yield and enantiopurity.

Synthetic strategies to 2′-hydroxy-4′-methylsulfonylacetophenone, a key compound for the preparation of flavonoid derivatives

Abstract Different strategies for the synthesis of 2′-hydroxy-4′-methylsulfonylacetophenone are reported in the present paper. This compound is considered as a key synthon for the synthesis of new flavonoid derivatives designed as potential cyclooxygenase-2 inhibitors. The retrosynthetic approach via 3′-methylsulfonylacetophenone, which included three synthetic pathways, did not allow us to obtain the expected compound. However, a synthesis from 3-mercaptophenol led to the desired acetophenone in three steps: thiophenol methylation, Friedel–Crafts acetylation and oxidation of the sulphide to the corresponding sulfone. The desired compound, 2′-hydroxy-4′-methylsulfonylacetophenone, will be used as a synthon for the preparation of novel flavonoid derivatives, such as 2′-hydroxychalcones, flavanones, flavones, and flavonols.

A concise synthetic approach toward tamiflu (oseltamivir phosphate): cis-aziridine as the key synthon and RCM

The key synthon cis-aziridine has been efficiently utilised for the synthesis of tamiflu (oseltamivir phosphate), using Wittig olefination, Barbier addition, Mitsunobu reaction and ring closing metathesis (RCM) as key essentials.

CO2fixation employing an iridium(i)-hydroxide complex

The reactivity of a number of Ir(I) complexes towards CO2 is explored using [Ir(NHC)(OH)] as a key synthon. CO2 insertion into Ir-O and Ir-N bonds proved facile, yielding a number of Ir(I)-carbonates and -carbamates. Most importantly, reaction between CO2 and Ir(I)-OH led to isolation of the novel [{Ir(I)}2-(μ-κ(1):κ(2)-CO3)] complex.

Direct observation of a lithiated oxirane: a synergistic study using spectroscopic, crystallographic, and theoretical methods on the structure and stereodynamics of lithiated ortho-trifluoromethyl styrene oxide

α-Lithiated epoxides, long considered “fleeting” intermediates in the reactions of epoxides with strong bases, have nowadays proven to be key synthons for asymmetric synthesis. In this study, the solution and the solid state structure of an α-lithiated aryloxirane, namely α-lithiated ortho-trifluoromethyl styrene oxide (1-Li), were determined. Single crystal X-ray diffraction analysis of 1-Li performed at 100 K applying the X-TEMP-2 device revealed a self-assembled heterochiral dimeric structure with a rare central six-membered (O–Li–C)2 planar core, which is unprecedented in Li/oxygen carbenoids. Multinuclear magnetic resonance (1H, 13C, 19F, 7Li) studies suggested that 1-Li exists in THF solution as a mixture of two interconverting diastereomeric dimeric aggregates, each one featuring a single σ-contact between lithium and a carbon atom. Line shape analysis provided activation parameters for both the dynamic interconversion of the two dimers and the enantiomerisation of 1-Li, which proved to be mostly entropy controlled. The structural assignment in solution was supported by density functional theory computations through the investigation of conformers of monomeric and dimeric complexes of 1-Li featuring different degrees of specific solvation. A mechanism based on the equilibration of six-membered homo- and heterochiral dimers was proposed to explain the configurational instability exhibited by 1-Li in THF.

Enantioselective Copper‐Catalyzed Conjugate Addition of Trimethylaluminum to β,γ‐Unsaturated α‐Ketoamides: Efficient Access to γ‐Methyl‐Substituted Carbonyl Compounds

Picture perfect: By using the reagent trimethylaluminium and β,γ-unsaturated α-ketoamides, 1,4-adducts were obtained with perfect 1,4-regioselectivity and good to excellent yields and ee values. The potential synthetic utility of the methodology was highlighted by preparation of γ-methyl-substituted carbonyls, key synthons to many natural products. binap=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, TC=thiophene carboxylate.

Eleuthesides and their analogs: IV. Synthesis of (1R,5R,6S)-6-(1,3-dithian-2-yl)-1-(2-hydroxyethyl)-5-methylcyclohex-3-ene and its O-tert-butyldimethylsilyl derivative

Two schemes for the preparation of chiral alcohols as key synthons for the synthesis of eleutheside analog at the A ring have been developed on the basis of the Diels-Alder adduct of levoglucosenone with piperylene.

1′-Trimethylsilylethynyl-, 1′-ethenyl- and 1′-formyl-1-ethynylferrocenes: syntheses and electrochemical properties

Efficient syntheses of 1′-trimethylsilylethynyl-, 1′-ethenyl-, and 1′-formyl-1-ethynylferrocenes are reported. The majority of these compounds exhibit chemically reversible ferrocene-based oxidation processes from cyclic voltammetry and thereby constitute key synthons for the development of redox-switchable molecular systems.

Synthesis of novel 2,4-bis(substituted phenoxy)-6-(phenylthio) pyrimidine analogs and their antimicrobial activities

Background/aimsPyrimidines have a long and distinguished history extending from the days of their discovery as important constituents of nucleic acids to their current use in medicinal chemistry. As a part of project devoted to the development of pyrimidine analogs as antimicrobial agents we have focused our attention on synthesis of C5/C6 substituted pyrimidine derivatives, specifically C6 substituted pyrimidine analogs which have emerged as potent molecule in recent years. Methods2,4-Bis(substituted phenoxy)-6-(phenylthio)pyrimidines were prepared in five steps starting from barbituric acid. Initial reaction of barbituric acid (1) with POCl3 in presence of N,N-dimethylaniline under reflux furnished 2,4,6-trichloropyrimidine (2), which on hydrolysis with aq. NaOH under reflux yielded 6-chlorouracil (3). 6-Chlorourail on treatment with thiophenol in dry pyridine generated 6-phenylthiouracil (4), chlorination of 4 using excess POCl3 under reflux afforded the key synthon 2,4-dichloro-6-(phenylthio)pyrimidine (5). Aromatic nucleophillic substitution reaction of 5 with oxygen nucleophiles like sodium phenoxides provided the desired targeted compounds 6a–g in 62–86% yield. Structural assignments of the synthesized compounds were based on their IR, 1H NMR, mass and analytical data. The antimicrobial evaluation of newly synthesized compounds was carried out by cup–plate method. ResultsThe investigation of antimicrobial screening reveals that the compounds 5, 6b, 6c and 6f showed good activity against fungal strains comparable to the standard drug Flucanazole. Remaining compounds exhibited moderate activity against bacterial and fungal strains compared to standard drug. ConclusionWe have developed a facile methodology which avoids the use of moisture sensitive reagents like organolithiums, diphenyl disulphide, etc. The C6 substituted pyrimidine analogs can be considered for further studies as potent antifungal agents.

Solid-Phase Synthesis of 4,7,8-Trisubstituted 1,2,3,4-Tetrahydro-benzo[e][1,4]diazepin-5-ones

Solid-phase synthesis of 1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-ones with use of polystyrene resin is described. The starting material was polymer supported 1,2-diaminoethane and as a key synthon, 4-chloro-2-fluoro-5-nitrobenzoic acid was used. The synthetic approach allows the preparation of derivatives with variable substitution at positions 4 and 8. Additionally, a skeletal diversity was increased when the nitro group was reduced and some benzene fused heterocycles were prepared. An expansion of a diazepinone to a benzodiazocinone scaffold was also successful although some limitations in a diversity of target derivatives were observed.