Tandem Protocol Research Articles

Synthesis of new bis(pyrazolo[1,5-a]pyrimidines) linked to different spacers with potential MurB inhibitory activity utilizing 1H-pyrazole-3,5-diamines

Recently, there has been an increased interest in developing new antibacterial agents that target the MurB inhibition, which is necessary for bacterial survival. We developed a two-step tandem protocol to synthesize 15 new bis(pyrazolo[1,5-a]pyrimidines), which are attached to alkane cores by amide linkages. The protocol involved reacting the appropriate bis(2-cyanoacetamides) with dimethylformamide-dimethylacetal in toluene at 80 °C for 3-4 h. The crude bis(2-cyano-3-(dimethylamino)acrylamides) was collected, then reacted with 3,5-diamino-1H-pyrazoles. The reaction gave the desired products in 82-92% yields after 5-6 h of heating at reflux in pyridine. Bis(2,7-diamino-3-(4-methoxybenzyl)pyrazolo[1,5-a]pyrimidine-6-carboxamides) demonstrated comparable efficacy to ciprofloxacin. Their MIC and MBC ranged from 2.8-3.0 and 5.7-6.0 µM, respectively, against S. aureus and E. coli. Moreover, these products displayed promising MurB inhibitory activity with IC50 ranging from 7.8 to 8.0 µM.

New Arene and/or Heteroarene‐Linked 1,3,4‐Oxadiazoles: Synthesis of Potential Methicillin‐Resistant Staphylococcus aureus and Vancomycin‐Resistant Enterococcus Inhibitors

AbstractBacterial infections, particularly those associated with methicillin‐resistant Staphylococcus aureus (MRSA) and vancomycin‐resistant Enterococcus (VRE), threaten public health and economies, with rising antibiotic resistance resulting in more deaths yearly. In this study, we investigated the bacterial inhibitory activity of some new 1,3,4‐oxadiazoles prepared, in good yields, using a two‐step tandem protocol. Therefore, the appropriate N‐benzoylhydrazones were prepared first, then, without isolation, underwent oxidative‐cyclization in the presence of chloramine trihydrate. More 4‐acyloxyphenyl‐linked 1,3,4‐oxadiazoles were prepared by the pyridine‐mediated acylation of 2‐(4‐hydroxyphenyl)‐1,3,4‐oxadiazoles with the appropriate acyl chlorides. Some new products demonstrated good activity, particularly against S. aureus and Enterococcus faecalis strains. The 4‐(5‐(furan‐2‐yl)‐1,3,4‐oxadiazol‐2‐yl)phenyl acetate showed comparable antibacterial activity to ciprofloxacin, with MIC/MBC values up to 3.6/7.2 µM against the previous strains. Moreover, it demonstrated good inhibitory activity against different MRSA and VRE strains when compared to linezolid. It had MIC/MBC values of 7.2/14.4 and 14.4/57.8 µM against MRSA and VRE strains, respectively.

Synthesis of Highly π-Extended Dihydrobenzo[a]indenocarbazole Scaffolds via Tandem Benzannulation and Friedel-Crafts Reaction of 2-Alkynylanilines and 2-Alkynylbenzaldehydes Promoted by Lewis Acid.

A novel and efficient tandem protocol for the swift synthesis of dihydrobenzo[a]indenocarbazole frameworks from 2-alkynylanilines and 2-alkynylbenzaldehydes via BF3·OEt2-facilitated benzannulation and Friedel-Crafts reaction has been described. This innovative approach accommodates a wide array of functional groups, offering a myriad of diversified carbazole products. Later, postsynthetic modification leads to its C(sp3)-H hydroxylation. Furthermore, the photophysical properties of some selected synthesized moieties have been meticulously investigated, promising exciting avenues for further exploration.

Tandem Protocol for Diversified Deuteration of Secondary Aliphatic Amines under Mild Conditions.

Deuteration of amine compounds has been widely of concern because of its practical role in organic reaction mechanisms and drug research; however, only limited deuteration label methods are accessible with D2O as a deuterium source. Herein, we propose a convenient deuteration protocol, including preparing D2 by the AlGa activation method, using PtRu nanowires as catalysts, and utilizing the elementary step in the couple reaction involving an imine unit, to realize the rapid preparation of a secondary amine with a diversified deuteration label. The self-coupling between nitriles not only provides a symmetric secondary amine with four α-D atoms but also produces high-valued ND3 in an atomic-economic way.

Photocatalytic Tandem Protocol for the Synthesis of Bis(indolyl)methanes using Cu-g-C3N4-Imine Decorated on TiO2 Nanoparticles under Visible Light Irradiation.

In this article, the visible-light-assisted photocatalytic activity of TiO2 nanoparticles functionalized with Cu(II) g-C3N4-imine was exploited for aerobic oxidation of alcohols to aldehydes followed by condensation with indoles in the presence of 2,2,6,6-tetramethylpiperidinyloxy to present a one-pot tandem strategy for the synthesis of bis(indolyl)methanes (BIMs) under solvent-free conditions. The synergistic effect between the components to improve the photocatalytic activity of the as-prepared Cu-g-C3N4-imine/TiO2 nanoparticles resulting from electron-hole separation was approved by PL spectroscopy. Moreover, action spectra showed a light-dependent photocatalysis with effective visible-light responsivity of the photocatalyst. The present method includes different aspects of green chemistry: one-pot tandem synthesis of a variety of BIMs using alcohols that are less toxic, more available, more economical, and more stable than aldehydes; removing the byproducts resulting from overoxidation of alcohols and polymerization of aldehydes and indoles; the use of air as a safe oxidant; visible light as a safe energy source; and solvent-free conditions. A reusability test demonstrated that the catalyst retained its efficiency even after five runs.

Synergistic One‐pot Tandem Combination of Cu and Proline Catalysis: Stereodivergent Synthesis of Chiral Aldols from Primary Alcohols

AbstractA new stereodivergent one‐pot tandem protocol, which granted diastereo‐ and enantioselective access to chiral aldols by starting from simple primary alcohols, is presented as a proof‐of‐concept. The synergistic combination of a chemoselective Cu(II)‐catalyzed oxidation of primary alcohols into the corresponding aldehydes (without the expected overoxidation into the corresponding carboxylic acids and using simple aerial O2 as co‐oxidant), followed by a concomitant organocatalyzed enantioselective aldol coupling promoted by the system (S)‐proline/HTBD‐BF4 [TBD=1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene], was achieved after fine‐tuning and compatibilizing the conditions required for the successful performance of both catalytic systems. Here, we demonstrated that selection and pairing of both catalysts needs to be extremely judicious to avoid orthogonality, kinetic, concentration or reciprocal poisoning issues. Refinement of the overall tandem protocol allowed us to design a synergistic and stereodivergent protocol which affords comparable or even better diastereoselective results than the organocatalytic system by itself. Finally, the following key factors (from a sustainable point of view) should be highlighted: i) no external VOC solvents are needed during our one‐pot tandem synthetic protocol (by working under neat conditions); and ii) isolation/purification of any intermediate is not required, thus reducing the chemical waste and energy/time costs, simplifying the practical aspects of our synthetic methodology.

Harnessing Visible Light for the Synthesis of N‐Aryl Oxazolidines: Organocatalyzed Tandem Decarboxylation‐Cyclization

AbstractHerein, we have developed an organophotocatalyzed, visible‐light mediated tandem decarboxylation‐cyclization method. The Eosin‐Y as organophotocatalyst drives photoredox tandem protocol to construct C−N, C−O, and C−C bonds in a single operation. The reaction mechanism proceeds through decarboxylation followed by amino alcohol intermediate formation from N‐arylglycine and formaldehyde followed by cyclization with another formaldehyde delivers N‐arylloxazolidine derivatives.

Orange Peel Waste as Feedstock for the Production of Glycerol-Free Biodiesel by the Microalgae Nannochloropsis oculata.

The bioconversion of agri-food waste into high-value products is gaining growing interest worldwide. Orange peel waste (OPW) is the main by-product of orange juice production and contains high levels of moisture and carbohydrates. In this study, the orange waste extract (OWE) obtained through acid hydrolysis of OPW was used as a substrate in the cultivation of the marine microalgae Nannochloropsis oculata. Photoheterotrophic (PH) and Photoautotrophic (PA) cultivations were performed in OWE medium and f/2 medium (obtained by supplementing OWE with macro- and micronutrients of f/2 medium), respectively, for 14 days. The biomass yields in PA and PH cultures were 390 mg L-1 and 450 mg L-1, while oil yields were 15% and 28%, respectively. The fatty acid (FA) profiles of PA cultures were mostly represented by saturated (43%) and monounsaturated (46%) FAs, whereas polyunsaturated FAs accounted for about 10% of the FAs. In PH cultures, FA profiles changed remarkably, with a strong increase in monounsaturated FAs (77.49%) and reduced levels of saturated (19.79%) and polyunsaturated (2.72%) FAs. Lipids obtained from PH cultures were simultaneously extracted and converted into glycerol-free biodiesel using an innovative microwave-assisted one-pot tandem protocol. FA methyl esters were then analyzed, and the absence of glycerol was confirmed. The FA profile was highly suitable for biodiesel production and the microwave-assisted one-pot tandem protocol was more effective than traditional extraction techniques. In conclusion, N. oculata used OWE photoheterotrophically, resulting in increased biomass and oil yield. Additionally, a more efficient procedure for simultaneous oil extraction and conversion into glycerol-free biodiesel is proposed.

Tandem synthesis and antibacterial screening of new thieno[2,3-b]pyridine-fused pyrimidin-4(3H)-ones linked to thiazole or oxazole units

New two series of thieno[2,3-b]pyridine-fused pyrimidinones 1 and 2 linked to thiazole or oxazole units were prepared utilizing a three-component tandem protocol. Therefore, a mixture of 1 equiv. of 3-aminothieno[2,3-b]pyridine-2-carboxylate was first microwave irradiated with 1.5 equiv. of dimethylformamide-dimethylacetal in toluene was at 110 °C for 15 min. Next, the crude enamine was dissolved in dioxane and 1 equiv. of the respective 4-arylazole-based amines was added. The mixture was microwaved at 100 °C for 20–30 min, resulting in a 74–89% yield of the target pyrimidinones. The new products showed a wide spectrum of antibacterial activity. In general, oxazole-linked pyrimidinones 2 exceeded their analogs 1 attached to thiazole units in antibacterial activity. Hybrids 2d, and 2e, with 4-(p-tolyl)oxazole and 4-(4-methoxyphenyl)oxazole units, demonstrated the best antibacterial potency among the new products with MIC/MBC values of 4.4/8.8 and 4.2/8.5 µM, respectively. According to SwissADME, all new pyrimidinones could be classified as drug-like.

New thieno[2,3-b]pyridine-fused pyrimidin-4(3H)-ones as potential thymidylate synthase inhibitors: Synthesis, SAR, in vitro and in silico study

Cancer is the second leading cause of death, following cardiovascular disease. Thymidylate synthase (TS) has long been identified as a significant target for chemotherapy due to its critical role in DNA biosynthesis. New thieno[2,3-b]pyridine-fused pyrimidinones were prepared utilizing a three-component tandem protocol. One equivalent of 3-aminothieno[2,3-b]pyridine-2-carboxylate and 1.5 equivalents of dimethylformamide-dimethylacetal in toluene was microwave irradiated at 110 °C for 15 min. Next, the crude enamine was dissolved in dioxane and one equivalent of the respective aromatic amines or 3-aryl-1H-pyrazol-5-amines was added. The mixture was irradiated by microwaves at 100 °C for 20–45 min to produce the desired pyrimidinones in 72–89% yields. Examination of the in vitro cytotoxicity of the new products revealed a wide range of activity. Pyrazole-linked pyrimidinones 2b and 2c, attached to p-Cl and p-NO2, demonstrated the best cytotoxicity with IC50 values up to 6.59 and 3.65 µM, respectively, against MCF-7, HEPG2, and Caco2. The in vitro TS inhibitory activity of 2b and 2c was also assessed. 2b demonstrated comparable activity to the standard pemetrexed with inhibition percentages up to 86.3, whereas 2c inhibited TS the best with inhibition percentages up to 91.5. The Ames test revealed that 2b and 2c had no or weakly mutagenic potential to the Salmonella TA 98 or TA 100 strain in the presence or absence of metabolic activation. Docking study predicted the promising TS inhibitory activity of pyrimidinones 2b and 2c. According to SwissADME and Lipinski's rule of five, all new pyrimidinones could be classified as drug-like.

Tandem Protocol of Hexahydroquinoline Synthesis Using [H2-DABCO][HSO4]2 Ionic Liquid as a Green Catalyst at Room Temperature.

Green, eco-benign, and sustainable synthesis is paramount in present chemistry. Here, a facile, efficient, and [H2-DABCO][HSO4]2 ionic-liquid-catalyzed one-pot multicomponent synthesis of hexahydroquinolines was reported under ambient reaction conditions. The reaction of 1,3-dicarbonyls, malononitrile, and ammonium acetate with various aldehydes in the presence of an ionic liquid catalyst and EtOH solvent at room temperature afforded excellent yields (76-100%) of hexahydroquinolines under a short reaction time (5-15 min). Mild reaction conditions, broad substrate scope (28 derivatives), and column-chromatography-free synthesis with excellent catalytic efficiency and good recyclability rendered this protocol superior and practical. The greenness of the present method was assessed through eco-score and E-factor. The significant results in gram-scale synthetic conditions validate its applicability in industries as well as academia in the near future.

From oximes to tertiary alcohols in water, at room temperature and under air: a hybrid one-pot tandem assembly of enzymatic deoximation and RLi/RMgX reagents.

The highly efficient biodeoximation of aromatic ketoximes, promoted by the enzymatic oxidative system laccase/TEMPO/O2, has been successfully assembled with the fast and chemoselective addition of highly-polar s-block organometallic reagents (RLi/RMgX) en route to highly-substituted tertiary alcohols. By using this hybrid one-pot tandem protocol, tertiary alcohols have been selectively synthesized in good yields and under mild and bench-type reaction conditions (room temperature, the absence of a protecting atmosphere and aqueous media, which are non-typical conditions for polar organometallic reagents). The overall hybrid one-pot tandem transformation amalgamates two distant organic synthetic tools (RLi/RMgX reagents and enzymes) without the need for any tedious and energy/time-consuming intermediate isolation/purification steps.

Pummerer-like Rearrangement Induced Cascade Reactions: Synthesis of Highly Functionalized Imidazoles.

Imidazoles are among the most important pharmacophores in medicinal chemistry. Herein we report a tandem protocol for the synthesis of highly substituted imidazoles through Pummerer-like rearrangement induced cascade reactions including two carbon-nitrogen bond formations, and concomitant aromatization under mild reaction conditions. This procedure gives imidazole derivatives bearing numerous functional groups and could be used for modifying natural products as well as pharmaceuticals.

A One‐Pot Tandem Synthesis of Sulfoximine‐Based Urea From Organic Acid via Curtius Rearrangement

Herein, we report one-pot synthetic route to prepare unsymmetrical sulfonimine-based urea from aromatic/aliphatic carboxylic acids and sulfoximine using DPPA via Curtius rearrangement and demonstrate their synthetic utility by preparing various sulfoximine analogue of key biologically active compounds, such as tolbutamide, chlorpropamide, and oncolytic sulfonyl urea.

New thiazole-based bis(Schiff bases) linked to arene units as potential MRSA inhibitors

A new series of thiazole-based bis(Schiff bases) attached to different arene units were efficiently prepared using a three-component tandem protocol. The proposed protocol involved the reaction of aromatic aldehydes, thiosemicarbazide, and bis(α-haloketone) to produce the desired products. The target hybrids were formed by an initial thiosemicarbazone formation in ethanol at 80 °C for 120–150 min, followed by triethylamine-mediated Hantzsch thiazole synthesis in dioxane at 100 °C for 150–180 min. The new hybrids were screened against diverse bacterial strains. The hybrids attached to p-Cl, p-Br, and p-Me had more effective efficacy than ciprofloxacin against S. aureus, and E. coli strains, while they had comparable efficacy to ciprofloxacin against S. mutans, and K. pneumonia strains. Their MIC/MBC values ranged between 1.3–3.2 and 2.6–6.5 µM, respectively, against the previous strains. Additionally, they displayed more effective MRSA inhibitory activity than linezolid with MIC/MBC values in the range of 3.0–21.3 µM.

Tandem Protocol for the Synthesis of Pyrano[3,2-c]quinolone Derivatives Using Taurine as a Green Bio-Organic Catalyst in Aqueous Medium.

A series of pyrano[3,2-c]quinolone derivatives has been synthesized in the presence of taurine (2-aminoethanesulfonic acid) as a green bio-organic catalyst and water as the solvent. The target compounds were synthesized through the three-component reaction between aldehydes, malononitrile/ethylcyanoacetate, and 4-hydroxy-1-methyl-2(1H)-quinolone. The advantages of this protocol are excellent yields of products, short reaction times, cost efficiency, atom economy, and a simple work-up procedure with no need for extra purification techniques. Moreover, the catalyst can be easily recovered and reused for up to three cycles without losing any significant activity.

Tandem synthesis, antibacterial evaluation and SwissADME prediction study of new bis(1,3,4-oxadiazoles) linked to arene units

A three-component tandem protocol involving the reactions of bis(benzohydrazides), aromatic aldehydes and chloramine trihydrate yielded a new series of bis(1,3,4-oxadiazoles). The target hybrids were formed by an initial bis(N-benzoyl-hydrazones) formation, followed by chloramine trihydrate- mediated oxidative cyclization. The 4-methoxyphenyl-containing compounds demonstrated promising antibacterial activity against the Staphylococcus aureus and Pseudomonas aeruginosa strains with MIC value of 1.6 µm.

Aerobic/Room-Temperature-Compatible s-Block Organometallic Chemistry in Neat Conditions: A Missing Synthetic Tool for the Selective Conversion of Nitriles into Asymmetric Alcohols.

Highly-efficient and selective one-pot/two-step modular double addition of different highly polar organometallic reagents (RLi/RMgX) to nitriles en route to asymmetric tertiary alcohols (without the need for isolation/purification of any halfway reaction intermediate) has been studied, for the first time, in the absence of external/additional organic solvents (neat conditions), at room temperature and under air/moisture (no protecting atmosphere is required), which are generally forbidden reaction conditions in the field of highly-reactive organolithium/organomagnesium reagents. The one-pot modular tandem protocol demonstrated high chemoselectivity with a broad range of nitriles, as no side reactions (Li/halogen exchange, ortho-lithiations or benzylic metalations) were detected. Finally, this protocol could be scaled up, thus proving that this environmentally friendly methodology is amenable for a possible applied synthesis of asymmetric tertiary alcohols under bench type reaction conditions and in the absence of external organic solvents.

Chloramine Trihydrate-Mediated Tandem Synthesis of New Pyrrole and/or Arene-Linked Mono- and Bis(1,3,4-Oxadiazole) Hybrids as Potential Bacterial Biofilm and MRSA Inhibitors.

A two-step tandem protocol was used to prepare new pyrrole and/or arene-linked bis(1,3,4-oxadiazoles) as well as their mono-analogs. The appropriate aldehydes and benzohydrazides were first condensed in ethanol at 80 °C to yield the corresponding N-benzoylhydrazones. Without isolation, the previous intermediates were subjected to a chloramine trihydrate-mediated oxidative cyclization in DMSO at 180 °C to yield the target molecules. The antibacterial potency of the (pyrrole-arene)-linked hybrids exceeded the arene-linked hybrids, and the bis(1,3,4-oxadiazoles) exceeded their mono-analogs against six different ATCC strains. Furthermore, the antibacterial efficacy of bis(1,3,4-oxadiazoles) 11c, and 11f, which are linked to pyrrole, and (p-tolylthio)methyl units, was highest against S. aureus, E. coli, and P. aeruginosa strains. Their MIC ranged between 3.8 and 3.9 μM, while their MBC values ranged between 7.7 and 15.8 μM. Additionally, they showed promising bacterial biofilm inhibitory activity against the same strains tested, with IC50 values ranging from 4.7 to 5.3 μM. They were also effective against MRSA ATCC : 33591, and ATCC : 43300 strains, with MIC, and MBC values ranging from 3.8-7.9 and 7.7-15.8 μM, respectively. When tested against the MCF-10A cell lines, hybrids 11c, and 11f are cytotoxic at concEntrations that are more than 6 and 13-fold higher than their MIC values against the S. aureus, E. coli, and P. aeruginosa strains, respectively. This lends support to both hybrids' potential as safe antibacterial agents.

Tandem synthesis, cytotoxicity, and in silico study of new 1,3,4-oxadiazoles as potential thymidylate synthase inhibitors.

A new series of pyrrole-linked mono- and bis(1,3,4-oxadiazole) hybrids, attached to various arene units, was prepared using a two-step tandem protocol. Therefore, a benzohydrazide derivative was condensed with the appropriate aldehydes in ethanol at 80°C for 60-150 min to give the corresponding N-(benzoylhydrazones). Without isolation, the previous intermediates underwent intramolecular oxidative cyclization in dimethyl sulfoxide at 180°C for 90-200 min in the presence of chloramine trihydrate to afford the target hybrids. The cytotoxicity of all hybrids was examined in vitro against the MCF-7, HEPG2, and Caco2 cell lines. Arene-linked hybrids 4i and 4j, attached to p-nitro and p-acetoxy units, were the most potent ones, with IC50 values ranging from 5.47 to 8.80 and 12.75 to 21.22 μM, respectively, when tested on the above cell lines. At the tested concentrations of 5 and 7.5 μM, hybrid 4i inhibited thymidylate synthase (TS) with the best inhibition percentages of 72.3 and 91.3, whereas hybrid 4j displayed comparable inhibitory activity to the reference pemetrexed. Hybrid 4j had inhibition percentages of 62.7 and 82.6, whereas pemetrexed had inhibition percentages of 59.2 and 80.2, respectively. The capability of hybrids 4i and 4j as potential TS inhibitors is supported by molecular docking studies, while SwissADME predicts their efficacy as drug-like scaffolds.