Correction: Droplet microfluidics: fundamentals and its advanced applications

Correction for ‘Droplet microfluidics: fundamentals and its advanced applications’ by Somayeh Sohrabi et al., RSC Adv., 2020, 10, 27560–27574, DOI: 10.1039/D0RA04566G.

The authors regret the omission of a funding acknowledgement in the original article. This acknowledgement is given below.The authors would like to acknowledge the financial support of the Iran National Science Foundation (INSF), grant number 98017171.In addition, the authors regret that incorrect reference numbers were given in

Catalyzed ring transformation of cyclic N-aryl-azadiperoxides with participation of α,ω-dithiols

Co(OAc)₂-catalyzed ring transformation reaction of 10-aryl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecanes with α,ω-dithiols (ethane-1,2-, propane-1,3-, butane-1,4-, pentane-1,5-, and hexane-1,6-dithiols, 3,6-dioxaoctane-1,8-dithiol) giving 3-aryl-1,5,3-dithiazacyclanes was studied.

Co(OAc)₂-catalyzed ring transformation reaction of 10-aryl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecanes with α,ω-dithiols giving 3-aryl-1,5,3-dithiazacyclanes was studied.

Cyclic peroxides attract attention for their antimalarial,¹ antibacterial,² and antitumor³ activities. Among numerous cyclic peroxides, heteroatomic cyclic peroxides occupy a special place owing to their high biological activities.⁴ The methods of synthesis of heteroatom-containing cyclic peroxides are limited. Recently,^5–10 nitrogen- and sulfur-containing cyclic di- and triperoxides with antitumor activity have been synthesized.^5–9 The development of efficient methods for the preparation of new cyclic hetero-di(tri)peroxides^5–10 promotes active investigation of their transformations. It was shown that the reduction of silatriperoxycycloalkanes with PPh₃ affords siladiperoxycycloalkanes;¹¹ the reaction of spiro{adamantane-[2,3′]-(pentaoxacane)} with o-phenylenediamine results in the synthesis of benzodioxazocine.⁵ The implemented conversion of pentaoxacane with o-phenylenediamine to benzodioxazocine⁵ suggests that cyclic N-containing peroxides can be involved in reactions with binucleophilic reagents, in particular α,ω-dithiols, to give new heterocycles. In contrast to the previously described methods of synthesis^5–10 and transformation of the peroxide ring,^5,11 this work for the first time discusses the method of catalytic conversion of tetraoxazaspirotridecane to dithiazacycloalkanes.It was shown by preliminary experiments that the reaction of 10-phenyl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecane 1 with ethane-1,2-dithiol 2 does not proceed without a catalyst. The reaction of azadiperoxide 1 with ethane-1,2-dithiol 2 catalyzed by Sm(NO₃)₃·6H₂O, H₂SO₄ or BF₃·Et₂O in THF as a solvent affords 3-phenyl-1,5,3-dithiazepane 8 in 10–15% yield (Scheme 1, 12 is affected by the nature of the catalyst. When the reaction is carried out in a polar solvent (MeOH) in the presence of catalytic amounts of Sm(NO₃)₃·6H₂O, H₂SO₄ or BF₃·Et₂O, the yield of the target product 8 increases to 30%. In the presence of the Co(OAc)₂ catalyst, the yield of heterocycle 8 is 85%. When AlCl₃ or CuCl catalysts are used, the yields of heterocycle 8 are 55% and 75%, respectively (Scheme 1). All reactions were carried out at room temperature for 20 h.Open in a separate windowScheme 1Ring transformation reaction of 10-phenyl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecane with α,ω-dithiols.Effect of the catalyst and solvent nature on the yield of 3-phenyl-1,5,3-dithiazacyclanes (∼20 °C, 20 h)

Facile synthesis of highly porous CuO nanoplates (NPs) for ultrasensitive and highly selective nitrogen dioxide/nitrite sensing

Copper oxide (CuO) nanoplates (NPs of ∼100 nm width) were successfully synthesized via a chemical method (emulsion method). Superior catalytic activities towards both chemical and electrochemical sensing of nitrite were achieved.

Copper oxide (CuO) nanoplates (NPs of ∼100 nm width) have been successfully synthesized by using a chemical method (emulsion method). Superior catalytic activities towards both chemical and electrochemical sensing of nitrite were achieved.

In recent years, the living standards of humans have grown immensely due to the industrial revolution. However, excessive industrialization has also caused a negative impact on human health due to the environmental degradation caused by the release of toxic gases. Air pollution is becoming more and more serious due to the increase in the concentration of toxic gases like sulphur dioxide (SO₂), carbon monoxide (CO), ammonia (NH₃), carbon dioxide (CO₂), nitrogen dioxide (NO₂), and hydrocarbons (CH)_x,^1,2 which directly impact human health. Among these toxic gases, NO₂ is a common air pollutant that causes respiratory diseases such as emphysema and bronchitis and can aggravate existing heart diseases. (NO)_x is a family of poisonous and highly reactive gases emitted by various non-road vehicles, automobiles, trucks (e.g., boats, construction, and other equipments) as well as industrial sources such as power plants, industrial boilers, cement kilns, turbines and fertilizer industries. NO_x is a strong oxidizing agent and plays a major role in the characteristic reactions with volatile organic compounds (VOC). In addition, NO₂ gas is a potential source for nitrous and nitric acid that are responsible for acid rains, which result in the destruction of the ozone layer in the troposphere.³ Consequently, to detect the highly toxic NO₂ gas, there is a need to develop low cost, highly sensitive, reliable and reproducible gas sensor systems.Many transition metal oxides (WO₃, TiO₂, CuO, ZnO, MoO₃ and many more) have been broadly used in the field of environmental monitoring, military technologies, safety engineering, and others.^4–8 Among the various transition metal oxides, CuO has been widely studied because of its size-tunable surface features that can be utilized as gas sensors having long term stability with selectivity at comparatively low temperatures. Moreover, CuO being a wide band gap p-type semiconductor metal oxide exhibits excellent sensitivity towards gas sensing. The typical p-type semiconducting metal oxides, such as nickel oxide (NiO), possess distinct characteristics.⁹ Nitrite ions (NO₂⁻) are hazardous, which widely exist in nature, food, physiological and manufacturing systems.¹⁰ Under the weakly acidic conditions in the stomach, nitrite is simply transformed into carcinogenic N-nitrosamines when it combines with tertiary amines present in food; this becomes the most vital reason for causing gastric cancer.¹¹ It induces disintegration when dissolved in water and can act as an environmentally harmful genus for the degradation of some important fertilizers in soil. Moreover, nitrite is often used as an additive in food products because it can protect against harmful microorganisms that cause food poisoning. Therefore, it is essential to detect and examine the allowed concentration levels of nitrite ions in both physiological and environmental systems.¹² In current years, many precise analytical techniques, such as gas chromatography,¹³ spectrophotometry,¹⁴ chemiluminescence,¹⁵ capillary electrophoresis,¹⁶ high performance liquid chromatography¹⁷ and electrochemical methods,¹⁸ have been developed and utilized to investigate the nitrite ion concentration, which is crucial for environmental and human health.Among the various noble metal and metal oxide NPs, CuO NPs have gained widespread attention for various applications because of their low cost, high catalytic, optical, antimicrobial and electrical conductivity properties.¹⁹ Highly stable CuO NPs were synthesized in a facile manner through self-oxidation of the surface using a chemical emulsion method and subsequent calcination at 400 °C (Scheme 1). The resulting NPs were utilized further for environmental monitoring of NO₂ by chemical and electrochemical approaches. The detailed synthesis procedure and other supporting experimental details are presented in ESI (ESI-I^†) and are shown schematically in Scheme S1.^†Open in a separate windowScheme 1Environmental monitoring of NO₂ using both chemical and electrochemical methods.Accordingly, the surface morphology of the chemically synthesised CuO NPs was examined by FESEM. As can be seen in Fig. 1(a) and (b), a large yield of homogenously dispersed NPs was obtained. These NPs are interconnected with each other and are consistently distributed with clear edges. The obtained dimensions of NPs varied between edge widths of ∼100 nm to ∼500 nm, as confirmed by the TEM analysis shown in the ESI.^† This type of morphology is quite different from the morphology reported for other NPs in the literature,²⁰ which could be due to the role of PVP as a surface directing molecule and the reaction conditions maintained during nucleation followed by growth. The XRD pattern shown in Fig. 1(c) illustrates the characteristic peaks of CuO indicating its crystalline nature. Considerably, the peaks at 2θ values match with the crystal planes of (110), (−111), (111), (−202), (020), (202), (−113), (022), (220), (113) and (203), and are in good agreement with the previous report on a similar system.²¹ Furthermore, the diffraction peaks have also been confirmed with the JCPDS card # 00-045-0937, indicating that the structure of the CuO NPs is hexagonal. No representative characteristic peaks for other impurity phases were detected, suggesting that the high quality single phase of CuO NPs was formed. The average crystallite size (d = ∼100 nm) of CuO NPs was estimated by Scherrer''s formula and is in good agreement with the morphological findings from SEM.Open in a separate windowFig. 1(a) and (b) SEM images of CuO NPs having an edge width of ∼100 nm. (c) X-ray diffraction pattern of (110), (−111), (111), (−202), (020), (202), (−113), (022), (220), (113), (203) corresponding to CuO NPs having a hexagonal crystal structure (d) EDAX of CuO nanoplates.Further, the EDAX analysis (Fig. 1(d)) shows the signals at 1.01 keV and 8.06 keV corresponding to Cu and the signal at 0.29 keV corresponding to O, clearly indicating the 79 : 21 ratio of Cu : O, which is in good agreement with the theoretical ratio for CuO reported in literature.²² These NPs were further characterized by TGA (Fig. S1^†) and BET (Fig. S2^†) surface area measurements. Accordingly, the thermogram depicts the weight loss (w₁) of 0.5 to 1% below 150 °C corresponding to physically absorbed water. The weight drop (w₂) of almost (1%) from 200–500 °C corresponds to the decomposition of Cu(ii) to CuO. Further weight loss (w₃) above 500 °C can be attributed to the thermal degradation of the surfactant, leaving 2.5–10% of CuO in the N₂ atmosphere. Moreover, the BET profile of CuO NPs (Fig. S2^†) displays a type II isotherm with a hysteresis loop in the relative pressure (P/P₀) range from 0.8 to 0.9, indicating its mesoporous nature that could be due to the thermal decomposition of polyvinyl pyrrolidone (PVP) on the CuO surface. The BET (Brunauer–Emmett–Teller) surface area calculated from the adsorption branch of the isotherm is found to be 23.60 m² g⁻¹. The inset in Fig. S2^† illustrates the corresponding pore size distribution plot calculated by BJH (Barrett–Joyner–Halenda) from the adsorption data. The average pore radius and pore volume of the CuO NPS was calculated to be 2.3 nm and 2.599 × 10^−0.1 cm³ g⁻¹, showing that the particles have a high surface area from its nanodimensions and features.The plot of decreasing electrical resistance of the CuO NPs sensor upon the exposure of 100 ppm oxidizing NO₂ gas at 150 °C is shown in Fig. 2(a). The recovery of the sensor was recorded by exposing the sensor to air. From the response curves, the response% (S) was calculated using the following relation:1where, R_g and R_a are the resistances of the film in the presence of NO₂ and absence of NO₂ (in air), respectively. The response and recovery times were defined as the times needed for a 90% total resistance change on exposure to gas and air, respectively.²³ The response time is the time over which the resistance reaches a fixed percentage (usually 90%) of the final value when the sensor is exposed to the full scale gas concentration. The time response is particularly dependent on the sensor properties, such as electrode geometry, crystallite size, additives, diffusion rates, and electrode position. A shorter response time is indicative of a good sensor. The recovery time is the time interval over which the sensor resistance reduces to 10% of the saturation value when the sensor is exposed to the full scale concentration of the gas and then exposed to clean air. A good sensor should have a small recovery time so that the sensor can be used repeatedly.²³ It has been observed that the operating temperature plays an important role in the gas sensing performance, which influences the adsorption/desorption process of oxygen ions on the CuO surface. The metal oxide-based sensors adsorb oxygen from air and form O⁻, O₂⁻ and O²⁻ species. The experimental results from the sensing response with respect to the operating temperature in the range of 150–250 °C is shown in Fig. 2(b). The plot exhibits a maximum response value of 88% at the operating temperature of 150 °C towards 100 ppm NO₂ gas. The response of the CuO NPs sensor is restricted at lower temperatures (below 150 °C), which could be due to the low rate of diffusion of NO₂ gas at the sensor surface; however, at higher temperatures (above 150 °C) the rate of diffusion of NO₂ gas molecules increases. Thus, for the further gas sensing studies, 150 °C is used as the optimized sensing temperature for CuO NPs sensors.Open in a separate windowFig. 2(a) Variation in resistance of CuO NPs-based films with respect to time in contact with NO₂ gas (b) temperature dependent response of CuO for NO₂ gas sensing (c) energetic response of CuO NPs sensor towards 5, 25, 50 and 100 ppm NO₂ gas concentrations at the same time and (d) gas selectivity of the CuO NPs sensor to other gas species.The response curve of the CuO NPs sensor with respect to different concentrations (5–100 ppm) of NO₂ gas at 150 °C is shown in Fig. 2(c) and demonstrates that the response values of the sensor increase with an increase in the concentration of NO₂ gas. For example, at 5 ppm of NO₂, the response of the sensor was observed as ∼14%, whereas a maximum response value of 88% toward 100 ppm NO₂ at 150 °C was recorded. This could be due to decreased contact between the sensor surface of CuO NPs and NO₂ gas at lower concentrations, which subsequently led to a smaller response value. Conversely, at high concentrations of NO₂ gas, the gas molecules cover more of the CuO NPs surface. As a result, a higher response value was achieved due to the greater surface interactions.²⁴ Furthermore, as shown in Fig. 2(d), there were minimal changes in the selectivity of the CuO NPs towards different target gases at a fixed 100 ppm concentration of each of them. Selectivity studies evidently suggest that the CuO NPs are more sensitive towards NO₂ gas compared to other test gases, viz., liquefied CO, SO₂, CH₃OH, and Cl₂. This high selectivity towards NO₂ is probably due to the greater rate of reaction between the CuO NPs surface and NO₂ gas molecules compared to those of the other gases.Furthermore, a comparison of gas-sensing parameters of the present compound with those reported in the literature for NO₂ gas is shown in MaterialsSynthesis methodOperating temperature (°C)Gas response %Ref. no.CuO nanowireThermal oxidation2008.9 for 5 ppm 25 CuO nanoparticleThermal evaporation1505 for 5 ppm 26 CuO nanoparticleChemical bath deposition2003.5 for 5 ppm 27 CuO nanoparticleSolid state reaction method60018 for 25 ppm 28 Ag–CuO NPsSolid state reaction method6505 for 25 ppm 29 CuO nanofiberElectrospinning method4004 for 10 ppm 30 MoO₃–V₂O₅Chemical spray pyrolysis20025 for 20 ppm 31 Aluminium doped ZnO thin filmsSol–gel method2005 for 5 ppm 32 Nb₂O₅-SESol–gel method78017 for 50 ppm 33 ZnO nanorodsHydrothermal2005 for 10 ppm 34 (Ni, Co, Fe)–SnO₂Chemical method6504–14 for 10 ppm 35 CuO nanoplatesChemical method15014 for 5 ppmPresent workOpen in a separate windowIn general, the semiconducting metal oxide-based gas sensing mechanism is predominantly associated with the change in electrical resistance due to contact of the target gases.³⁶ The variation in electrical resistance of the sensor is principally due to the adsorption/desorption processes taking place with target gases on the surface. CuO is a p-type semiconductor that contains holes as the bulk charge carriers. When the CuO NPs sensor is exposed to normal atmospheric air, the oxygen molecules from the air adsorb on the peak of the sensor surface, which leads to an increase in the adsorbed oxygen species (Scheme 1).CuO + O₂ → (CuO)·2O⁻2The reaction between the adsorbed NO₂ gas molecules and CuO NPs is presented schematically in Fig. 3(a). NO₂ is an oxidizing gas (electron tolerant in nature) and its contact with the p-type CuO leads to the rise in conductivity due to the enhancement in hole concentration in the conduction band of p-type CuO by decreasing the rate of resistance. Upon exposure to NO₂ gas, the probable reaction occurring at the CuO NPs surface is given below:(CuO)·2O + NO₂ → (CuO)·O²⁻₂ + NO↑3Open in a separate windowFig. 3(a) Scheme showing the mechanism of the CuO NPs sensor for NO₂ gas sensing, where an electron transfers to the air and a NO₂ gas molecule hole–electron pair transfers from the VB to CB. (b) Superimposed anodic segments for GC modified by CuO in (I) 0.5 M KOH (black), and (II) of the same with 20 μM nitrite in 0.5 M KOH (red).It is known that the NO₂ sensing mechanism on CuO NPs depends on the active surface oxygen centres that exist on the CuO NPs surface. Linear sweep voltammetric (LSV) experiments on the electrochemical oxidation of nitrite were carried out to further determine/support the earlier findings of oxidative sensing on the CuO surface. Accordingly, the limit of detection (LOD) of our systems with results from literature compared in Sensor materialAnalytical techniqueLimit of detection (LOD) μMRef.PPy-NWsCV50 38 f-ZnO@rFGOLSV33 39 ZnTiO₃–TiO₂Amperometry3.98 40 Graphene-nafion/GCECV11.61 41 EPPGE-MWCNT-PBAmperometry6.1 42 rGO-Co₃O₄@Pt/GCECV1.73 43 CuO NPs LSV 1.1 Present work Open in a separate windowThe selectivity study of a CuO NPs-based gas sensor was performed for nitrogen dioxide (NO₂), methanol (CH₃OH), chlorine (Cl₂), carbon monoxide (CO) and sulphur dioxide (SO₂) at 100 ppm concentrations of each gas, as shown in Fig. 2(d). The resistance of the CuO film sensor did not change for Cl₂, CO, SO₂ and CH₃OH gases, hence, the response was considered to be minor, confirming that these gases were not interacting with the CuO sensor. Consequently, the metal oxide-based gas sensor works on the principle of chemiresistance, viz., the change in resistivity or electrical conductivity of thin films upon contact with the target gas. The gas molecules interacting with the metal oxides either act as a donor or an acceptor of charge carriers (receptor function), and alter the resistivity of the metal oxide. The decrease or increase in the resistance of the metal oxide thin film depends upon the type of majority carriers in the oxide film and also the nature of the gas molecules (whether oxidizing or reducing) in an ambient atmosphere.⁹ For n-type materials, oxidizing gases (acceptors) increase the resistance of the thin film, while reducing gases (donors) decrease the resistance and are correspondingly converse for p-type materials. The binding energies also confirm that the physisorption occurs between the molecule and the surface for CH₃OH, CO, SO₂, and Cl₂, with NO₂ being the most strongly bound species. The binding energy for NO₂ is approximately greater than those of the other gas molecules. On exposure to NO₂ oxidizing gas, the CuO film resistance decreases, suggesting a p-type conduction behaviour of CuO. The NO₂ sensing of CuO depends on the surface oxygen adsorbed on the CuO NPs surface. The sensing device involves the adsorption of oxygen species on the surface of CuO NPs, which results in more electron density, and thus, causes a decrease in the potential barrier at the grain boundaries. The gas molecules interact with the oxygen species and produce a notable change in the electronic properties of the material. Thus, the density of oxygen species on the surface defines the rate of reaction and the catalytic properties. NO₂ is an oxidizing gas with an electron affinity much higher than that of oxygen (0.48 eV); NO₂ can interact with CuO by trapping electrons directly through the surface oxygen ions thereby forming new surface electron acceptor levels.⁸Accordingly, Fig. 3(b) shows a comparison of the CuO in 20 μM nitrite in 0.5 M KOH at a scan rate of 50 mV s⁻¹. It is clearly seen that the modified CuO/GC (black line) in 0.5 M KOH displayed no signal corresponding to nitrate. However, in the presence of 20 μM nitrate (red line) in 0.5 M KOH, a fine additional oxidation peak at −0.30 V vs. SCE corresponding to nitrate is observed. This sensitivity can be attributed to the large surface area created by stabilized CuO NPs, which makes it easier for the adsorption of nitrite and provides adequate and successful reaction sites. These results extensively reveal how the electrocatalytic activity of CuO NPs in an aqueous system may afford an indirect link via NO₂⁻ oxidation and confirms the electrochemical sensing capability of CuO NPs towards NO₂⁻ determination as one of the intermediate species of NO₂ in aqueous systems. Furthermore, the influence of the increase in concentration of NO₂⁻ on the electrocatalytic oxidation on CuO NPs in 0.5 M KOH was studied using an LSV segment in Fig. S4(a).^†The oxidation peak current at −0.30 V vs. RCE shows a linear response with the increase in concentration of NO₂⁻ ions in the range of 10–50 μM and this linear range is much broader than those of the reported comparable electrocatalytic systems. Furthermore, the influence of the scan rate on the electrocatalytic oxidation peak potential (Epa) and peak current for a 20 μM concentration of NO₂⁻ at the CuO/GCE electrode in 0.5 M KOH was studied using LSV, as shown in Fig. S4(b).^† The current values were observed to increase with an increase in the scan rate from 10 to 100 mV s⁻¹. The linear association between the anodic peak currents and the square root of the scan rate³⁷ showed that the electro-oxidation of NO₂⁻ is diffusion-controlled.The overall LSV result for the electrochemical mechanism³⁷ of nitrite ions (NO₂⁻) involves a reversible charge transfer reaction (eqn (4)), the obtained NO₂ disproportionation into NO₃⁻ and NO₂⁻ (eqn (5)), and in the end, the NO₂⁻ undergoing a unidirectional reaction for the oxidation of nitrite at the CuO modified GC electrode in an irreversible approach (eqn (6)).^44–48 This is in good agreement with the above presented chemical sensing studies on CuO in the solid state.2NO⁻₂ ⇋ NO₂ + 2e⁻42NO₂ + H₂O → NO⁻₂ + NO⁻₃5NO⁻₂ + H₂O → NO⁻₃ + 2H⁺ + 2e⁻6In conclusion, CuO NPs were synthesized using a chemical method (emulsion) and their gas sensing activity was studied towards a series of gases. The gas sensing studies revealed that the CuO NPs sensor was capable of detecting very low concentrations (5 ppm) of NO₂ gas at a low operating temperature of 150 °C. The CuO NPs sensor exhibited a maximum response value of 88% upon exposure to 100 ppm NO₂ gas. The change in electrical resistance of the CuO NPs sensor following the interaction of NO₂ gas molecules was mainly contributed by the adsorbed oxygen species at the grain boundaries. Moreover the fabricated CuO/GC modified electrode was effectively applied for electrochemical nitrite sensing. It was found that Cu NPs showed improved electrocatalytic behaviour towards nitrite. This proposed sensor exhibited a wide linear range with high sensitivity and low detection limit along with fast response/recovery time, excellent repeatability and stability.     

A mild one-pot synthesis of 2-iminothiazolines from thioureas and 1-bromo-1-nitroalkenes

A mild method to access functionalized 2-iminothiazolines in a facile and efficient manner has been developed. The reaction started from 1,3-disubstituted thioureas and 1-bromo-1-nitroalkenes in the presence of triethylamine in THF and proceeded smoothly in air to afford 2-iminothiazoline derivatives in moderate to good yields.

A mild method to access functionalized 2-iminothiazolines in a facile and efficient manner has been developed.

Functionalized 2-iminothiazoline has been an important building block in organic chemistry.¹ Its derivatives show significant pharmacological activities such as bactericidal and fungicidal activity.² In addition, they are found in drug applications for treatment of allergies, hypertension, inflammations, bacterial and HIV infections.³ Pifithrin (Pft-α) (Fig. 1), isolated by screening of chemical libraries using 2-iminothiazoline skeleton, is a lead compound for p53 inactivation and has received increasing attention due to its possible applications in therapy of Alzheimer''s disease, Parkinson''s disease, stroke and other pathologies related to various signalling pathways.⁴ Hence, its utility and applicability are widely recognized in organic and biological areas.Open in a separate windowFig. 1Pharmacologically important molecules consisting of 2-iminothiazoline core structure. (a) p53 inactivator; (b) skin whitening agent; (c) anti-inflammatory agent.The classical synthesis of 2-aminothiazole moiety involves the Hantzsch condensation reaction of thioureas and α-haloketones.⁵ Birkinshaw et al. reported the synthesis of N-alkylated imino-thiazolines by replacing thioureas with mono-N-substituted thioureas.⁶ Also, several alternative strategies have been devised, which include synthesis of highly functionalized thiazoles and 2-iminothiazolines by replacing α-haloketone with 2,2-dicyano-3,3-bis(trifluoromethyl)oxirane⁷ and 2-chlorooxirane,⁸ treatment of α-bromoketimines with potassium thiocyanate,⁹ reaction of N-monoalkylated thioureas with 3-bromomethyl-2-cyanocinnamonitrile,¹⁰ cycloadditions followed by elimination of 5-imino-1,2,4-thiazolidin-3-ones with enamines and ester enolate,¹¹ ring transformation of 1-arylmethyl-2-(thiocyanomethyl)aziridines in the presence of TiCl₄ and acyl chloride,¹² reaction of N-propargylaniline with acyl isothiocyanates.¹³ Less general approaches towards the synthesis of these compounds involve the reaction of ketone either with N-alkyl rhodanamine or bisbenzyl formamidine disulfide¹⁴ or the reaction of α-chloroketones with thiosemicarbazide in an acidic medium,¹⁵ condensation of α-haloketones with N-benzoyl-N′-arylthioureas or N,N′-disubstituted thioureas.¹⁶Although some of the methods used for preparing 2-iminothiazolines are convenient and effective, most procedures reported in literatures require arduous preparation of precursor substrates or harsh reaction conditions. Till now, only a few procedures on the one-pot synthesis of 2-iminothiazoline from N,N′-dialkylthiourea and in situ generated α-bromoketones have been reported.¹⁷ Herein, we reported a novel and efficient methodology for the synthesis of 2-imino-5-nitrothiazolines using 1,3-diarylthioureas and 1-bromo-1-nitroalkenes as starting materials.The β-bromo-β-nitrostyrenes, with β-disubstituted styrene structure, showed versatile reactivity as a trifunctional synthon. Previous literatures showed their activity as Michael acceptors and [3 + 2] and [4 + 2] cycloaddition partners.¹⁸ In our preliminary experiments, the reaction of 1,3-diphenylthiourea and β-bromo-β-nitrostyrene 1a was studied, while the latter one could easily be prepared according to the reported procedure.^18e We found that when these two reactants were treated with base such as K₂CO₃ in THF at room temperature under atmospheric air, a red crystalline product was obtained ( Entry^aBaseSolventTemperature (°C)Time (h)Yield (%)1K₂CO₃THFrt24622^bK₂CO₃THF7010603Et₃NTHFrt24724^bEt₃NTHF7010655DBUTHFrt24636^bDBUTHF7010587KHCO₃THFrt24558^bKHCO₃THF7010609DIPEATHFrt246810NoneTHFrt242911^cEt₃NTHFrt246412^dEt₃NTHFrt245813^eEt₃NTHFrt241714Et₃NCH₂Cl₂rt244515Et₃NToluenert244216^bEt₃NToluene110540Open in a separate window^aReactions were performed with β-bromo-β-nitrostyrene 1a (0.10 mmol) and 1,3-diphenylthiourea 2a (0.11 mmol) with base (0.02 mmol) in the indicated solvent (2.0 mL) under atmospheric air.^bβ-Bromo-β-nitrostyrene was completely consumed.^cReaction was carried out with 0.04 mmol of base.^dReaction was carried out with 0.01 mmol of base.^eReaction was carried out with 0.1 mmol of base.This structure was later confirmed by single crystal X-ray analysis as shown in Fig. 2. When the reaction temperature was increased to 70 °C, the reaction was completed in shorter time. However, the yield was lower due to an increase of side products (Open in a separate windowFig. 2X-ray crystallography of compound 3a.Several other bases were tested such as K₂CO₃, Et₃N, DBU, KHCO₃, DIPEA, and Et₃N was found to give the best results ( Open in a separate window^aReactions were performed with 1-bromo-1-nitroalkenes 1a–1n (0.10 mmol) and 1,3-diarylthioureas 2 (0.11 mmol) with Et₃N (0.02 mmol) in THF (2.0 mL) at room temperature in the air for 24 hours.A plausible mechanism for this reaction has been proposed as shown in Scheme 1. Initially, a typical Michael addition happens with the β-bromo-β-nitrostyrene 1a,¹⁹ which is initiated by the attack of lone pair of nitrogen atom in 1,3-diphenylthiourea 2a, affording intermediate II. The successive tautomerism of thiourea structure and nucleophilic substitution in intermediate II generates five-membered ring intermediate III. Deprotonation of intermediate III by preceding bromide ion affords intermediate IV which subsequently undergoes aromatization with aid of atmospheric oxygen,²⁰ yielding final product 3a.Open in a separate windowScheme 1Plausible reaction pathway.     

Pd-catalyzed [3 + 2] cycloaddition of vinylcyclopropanes with 1-azadienes: synthesis of 4-cyclopentylbenzo[e][1,2,3]oxathiazine 2,2-dioxides

The palladium-catalyzed [3 + 2] cycloaddition of vinylcyclopropanes and 1-azadienes has been developed under mild reaction conditions, giving the multisubstituted cyclopentane derivatives in good to excellent yields with moderate to good diastereoselectivities. The relative configuration of both diastereomers of the products have been determined through X-ray crystallographic diffraction.

Pd-catalyzed [3 + 2] cycloaddition of vinylcyclopropanes with 1-azadienes gave highly functionalized cyclopentane derivatives in high yields.

The cyclopentane framework is ubiquitous in nature and it is also an important structural moiety in many pharmaceuticals, agrochemicals, and materials.¹ The development of simple, fast and efficient synthetic methods for highly substituted cyclopentanes has attracted much attention. Among various methods for synthesis of cyclopentane structure, the cycloaddition reaction is a very attractive one.²Under palladium catalysis conditions, vinylcyclopropane derivatives underwent a ring-opening reaction to generate the zwitterionic allylpalladium intermediate, which reacted with carbon–carbon, carbon–oxygen, carbon–nitrogen double bonds and diazo compounds to provide a variety of five-membered cyclic compounds.³ In the past decades, this type of annulation reactions has emerged as a powerful tool for the synthesis of carbocyclic and heterocyclic compounds.² Diverse substrates including isocyanates,⁴ aldehydes,⁵ isatins,⁶ 3-diazooxindoles,⁷ electron-deficient alkenes such as para-quinone methides,⁸ α,β-unsaturated aldehydes,⁹ β,γ-unsaturated α-keto esters,¹⁰ nitroolefins,¹¹ azlactone- and Meldrum''s acid alkylidenes,¹² and α-nucleobase substituted acrylates,¹³ have been exploited in palladium-catalyzed [3 + 2] cycloadditions of vinyl cyclopropane, delivering biologically interesting functionalized heterocyclic compounds and cyclopentane derivatives. In 2015, Liu and He reported a palladium-catalyzed [3 + 2] cycloaddition of vinyl cyclopropane and α,β-unsaturated imines generated in situ from aryl sulfonyl indoles, providing the optically enriched spirocyclopentane-1,3′-indolenines with high diastereoselectivity.¹⁴ This is the only example where α,β-unsaturated imines were employed in Pd-catalyzed [3 + 2] cycloaddition reaction of vinyl cyclopropane.As a type of α,β-unsaturated imines, cyclic 1-azadienes such as (E)-4-styrylbenzo[e][1,2,3]oxathiazine 2,2-dioxides 2 are easily accessible and stable (Scheme 1). In particular, they contain the sulfonate-moiety, which is an interesting biologically important motif, and has a great potential in the synthesis of bioactive molecules.¹⁵ The cyclic 1-azadienes have been used in a series of annulation reactions such as [2 + n],^16–18 [3 + n],¹⁹ and [4 + n]²⁰ annulation reactions. Based on the electron-deficient nature of the carbon–carbon double bond in these cyclic 1-azadienes, in 2016, Chen and Ouyang developed cinchona-derived tertiary amine-catalyzed asymmetric [3 + 2] annulation of isatin-derived Morita–Baylis–Hillman (MBH) carbonates with cyclic 1-azadienes to form spirooxindole.¹⁷ In the same year, our group demonstrated a phosphine-catalyzed [3 + 2] annulation of MBH carbonates with cyclic 1-azadienes.¹⁸ Considering that the 1-azadiene 2 is an electron-deficient alkene with good reactivity, its reaction with a zwitterionic π-allyl Pd complex formed via ring-opening of vinylcyclopropane may be feasible. However, this type of cyclic 1-azadienes have never been used in Pd-catalyzed annulation reactions involving vinylcyclopropanes. As our continuing interest on cycloaddition reactions,²¹ herein we disclose a [3 + 2] cycloaddition of palladium-catalyzed vinyl cyclopropane with cyclic 1-azadienes to afford the multisubstituted cyclopentane derivatives (Scheme 1).Open in a separate windowScheme 1[3 + 2] Cycloaddition of 1,3-zwitterions with cyclic 1-azadienes.We carried out an initial screening with 2-vinylcyclopropane-1,1-dicarbonitrile 1a and (E)-4-styrylbenzo[e][1,2,3]oxathiazine 2,2-dioxide 2a in CH₂Cl₂ (DCM) at room temperature in the presence of Pd₂(dba)₃·CHCl₃ (2.5 mol%) (22 Under the optimized reaction conditions, we attempted to develop asymmetric variant of this reaction. Unfortunately, the two enantiomers of the product could not be resolved at present stage.²³Optimization of the reaction conditions^a

Aqueous Suzuki couplings mediated by a hydrophobic catalyst

The catalytic activity of [(Ph₂P-o-C₆H₄)₂N]PdCl in aerobic aqueous Suzuki couplings is described. Though hydrophobic, this molecular catalyst is competent in cross-coupling reactions of arylboronic acids with a variety of electronically activated, unactivated, and deactivated aryl iodides, bromides, and chlorides upon heating in aqueous solutions under aerobic conditions to give biphenyl derivatives without the necessity of amphiphiles even in the presence of an excess amount of mercury.

Though hydrophobic, the amido PNP complex [(Ph₂P-o-C₆H₄)₂N]PdCl is a competent catalyst in aqueous Suzuki couplings under aerobic conditions without the necessity of amphiphiles even in the presence of an excess amount of mercury.

Transition metal-mediated cross-coupling catalysis has evolved over the last decades into one of the most powerful methodologies in organic synthesis, pharmaceutics, and materials chemistry.^1–12 The advance of this catalysis in aqueous media is attractive given the non-toxic, non-flammable, and abundant nature of water.^13–15 Successful examples of aqueous cross-coupling catalysis by well-defined molecular catalysts, however, are rather limited due to the low stability or solubility of catalytically active species in aqueous solutions.¹⁶ To improve aqueous solubility, catalysts are typically designed to contain hydrophilic ligands¹⁷ such as those bearing carboxylate,^18,19 ammonium,²⁰ sulfonate,^20–22 or polyol²³ functional groups, etc. Utilization of amphiphilic additives^24–26 is almost inevitable for hydrophobic catalysts in aqueous cross-coupling reactions. Microwave irradiation^27–29 and heterogeneous catalysis by means of immobilized catalysts^30–33 or metal nanoparticles produced upon decomposition of molecular precatalysts^34–37 represent alternative prevalent approaches.Metal nanoparticles³⁸ differ inherently in size and shape, typically rendering rather undesirable multiple active sites comprising different compositions for catalysis. The constitutions and thus activities of these active sites could be very sensitive to their formation procedures and the presence of traces of usually unnoticed components, particularly those prepared in situ when molecular precatalysts decompose under catalytic conditions. Reproducibility of catalysis of this type could be troublesome. In this regard, there have been several reports addressing this challenge,^39,40 including concerns of commercially available molecular precatalysts.^41,42 The development of well-defined molecular catalysts where leaching of the metal does not occur during catalysis is therefore of interest and benefit.Palladium-catalyzed Suzuki couplings are versatile in the development of biaryl derivatives.⁶ We have previously reported the catalytic competence of amido phosphine complexes of palladium, e.g., 1 and 2 in Fig. 1, for Suzuki couplings in organic solvents.^43,44 Of note are reactions conducted under aerobic conditions in the presence of exogenous water, an unusual result considering the inherently high basicity of a Pd–amide bond.⁴⁵ Note that water in these attempts is not a major solvent. We were therefore interested in aerobic aqueous Suzuki couplings with these promising catalysts. We report herein the catalytic activity of 2a in this regard without the requirement of any amphiphilic additives despite the hydrophobic nature of this catalyst. Of interest is also its unchanged activity in the presence of mercury,^39,40,46,47 consistent with homogeneous catalysis by a well-defined molecular catalyst that contrasts with the heterogeneous feature of palladium nanoparticles derived in situ from the decomposition of other molecular precatalysts such as commercially available Pd(PPh₃)₄ and Pd(OAc)₂ (vide infra).Open in a separate windowFig. 1Representative examples of amido phosphine complexes of palladium.Complex 2a is thermally stable at temperatures as high as 200 °C.⁴⁸ To survey reaction parameters, we chose to examine the reaction of 4-tolyl bromide with phenylboronic acid catalyzed by 0.1 mol% 2a in water at 100 °C. Among eight inorganic bases examined (17–21,23 or an amphiphile^24–26 to assist a hydrophobic catalyst in aqueous catalysis.^13–15 The methodology developed herein thus represents to date a rare example in this regard.Optimization of reaction parameters^a

Mesoporous PbO nanoparticle-catalyzed synthesis of arylbenzodioxy xanthenedione scaffolds under solvent-free conditions in a ball mill

A protocol for the efficient synthesis of arylbenzodioxy xanthenedione scaffolds was developed via a one-pot multi-component reaction of aromatic aldehydes, 2-hydroxy-1,4-naphthoquinone, and 3,4-methylenedioxy phenol using mesoporous PbO nanoparticles (NPs) as a catalyst under ball milling conditions. The synthesis protocol offers outstanding advantages, including short reaction time (60 min), excellent yields of the products (92–97%), solvent-free conditions, use of mild and reusable PbO NPs as a catalyst, simple purification of the products by recrystallization, and finally, the use of a green process of dry ball milling.

An efficient one-pot multicomponent protocol was developed for the synthesis of arylbenzodioxy xanthenedione scaffolds using mesoporous PbO nanoparticles as reusable catalyst under solvent-free ball milling conditions.

Recently, the ball milling technique has received great attention as an environmentally benign strategy in the context of green organic synthesis.^1a The process of “ball milling” has been developed by adding mechanical grinding to the mixer or shaker mills. The ball milling generates a mechanochemical energy, which promotes the rupture and formation of the chemical bonds in organic transformations.^1b Subsequently, detailed literature^1c and books on this novel matter have been published.^2a,b Several typical examples include carbon–carbon and carbon–heteroatom bond formation,^2c organocatalytic reactions,^2d oxidation by using solid oxidants,^2e dehydrogenative coupling, asymmetric, and peptide or polymeric material synthesis, which have been reported under ball milling conditions.^2e Hence, the organic reactions using ball milling activation carried out under neat reaction environments, exhibit major advantages,^2f including short reaction time, lower energy consumption, quantitatively high yields and superior safety with the prospective for more improvement than the additional solvent-free conditions and clear-cut work-up.^3–5On the other hand, the organic transformations using metal and metal oxide nanoparticles⁶ are attracting enormous interest due to the unique and interesting properties of the NPs.^7,8,9a Particularly, PbO NPs^9b provide higher selectivity in some organic reactions^9c and find applications in various organic reactions, like Paal–Knorr reaction,¹⁰ synthesis of diethyl carbonate,¹¹ phthalazinediones,¹² disproportionation of methyl phenyl carbonate to synthesize diphenyl carbonate,¹³ the capping agent in organic synthesis, and selective conversion of methanol to propylene.¹⁴ In addition, the PbO NPs are also used in many industrial materials.^15,16However, till date, PbO NPs have not been explored in MCRs leading to biologically important scaffolds. Among others, the xanthene scaffolds¹⁷ are one of the important heterocyclic compounds¹⁸ and are extensively used as dyes, fluorescent ingredients for visual imaging of the bio-molecules, and in optical device technology because of their valuable chemical properties.¹⁹ The xanthene molecules have conjointly been expressed for their antibacterial activity,²⁰ photodynamic medical care, anti-inflammatory drug impact, and antiviral activity. Because of their various applications, the synthesis of these compounds has received a great deal of attention.²¹ Similarly, vitamin K nucleus^22,23 shows a broad spectrum of biological properties, like anti-inflammatory, antiviral, antiproliferative, antifungal, antibiotic, and antipyretic.^24a As a consequence, a variety of strategies^24b have been demonstrated in the literature for the synthesis of xanthenes and their keto derivatives, like rhodomyrtosone-B,^25a rhodomyrtosone-I,^25b and BF-6 ^25c as well as their connected bioactive moieties. Few biologically active xanthene scaffolds are shown in (Fig. 1).Open in a separate windowFig. 1Some biologically important xanthenes and their keto derivatives.Due to the significance of these compounds, the synthesis of xanthenes and their keto derivatives using green protocols is highly desirable. Reported studies reveal that these scaffolds are synthesized by three-component condensations using p-TSA²⁶ and scolecite²⁷ as catalysts. However, these methods suffer from the use of toxic acidic catalysts like p-TSA, long reaction times (3 h), harsh refluxing²⁶ or microwave reaction conditions,²⁷ and tedious work-up procedures. The previously reported methods for the synthesis of xanthenediones are shown in Scheme 1.Open in a separate windowScheme 1Previous protocol for the synthesis of xanthenedione derivatives.Herein, we report an economical and facile multicomponent protocol, using ball milling, for the synthesis of 7-aryl-6H-benzo[H][1,3]dioxolo[4,5-b]xanthene-5,6(7H)-dione using PbO NPs as a heterogeneous catalyst (Scheme 2). The PbO NPs are non-corrosive, inexpensive, and easily accessible.Open in a separate windowScheme 2General reaction scheme of PbO NP-catalyzed synthesis of the xanthenedione scaffolds under ball milling conditions.In our protocol,²⁸ the PbO NPs were initially prepared by mixing sodium dodecyl sulphate (2.5 mmol) and sodium hydroxide (10 mL, 0.1 N) with an aqueous methanolic solution of lead nitrate (2 mmol) under magnetic stirring at 30 °C by continuing the reaction for 2 h. Then, the obtained white polycrystalline product was filtered, washed with H₂O, and dried at 120 °C, followed by calcination at 650 °C for 2 h. During this step, the white PbO NPs turned pale yellow in colour. Eventually, the synthesized PbO was then characterized by spectroscopic and analytical techniques.The powder X-ray diffraction (XRD) pattern revealed the crystalline nature of the PbO NPs as the diffraction peaks corresponding to (131), (311), (222), (022), (210), (200), (002), and (111) crystal planes were identified (Fig. 2). The XRD outline of the synthesized PbO NPs was further established for the formation of space group Pca2₁ ²⁹ with a single orthorhombic structure (JCPDS card number 76-1796). The sharp diffraction peaks indicated good crystallinity, and the average particle size of the PbO NPs was estimated to be 69 nm, as calculated using the Debye–Scherer equation.Open in a separate windowFig. 2The powder XRD pattern of PbO NPs.The surface morphology of the PbO NPs was analyzed by scanning electron microscopy (SEM), and the SEM image revealed the discrete and spongy appearance of the PbO NPs (Fig. 3).Open in a separate windowFig. 3The SEM image of PbO NPs.Moreover, the elemental composition obtained from energy dispersive X-ray (EDX) analysis confirmed that the material contains Pb and O elements, and no other impurity was present (Fig. 4).Open in a separate windowFig. 4The EDAX spectrum of crystalline PbO NPs.The transmission electron microscopy (TEM) image shown in Fig. 5 indicated the formation of orthorhombic crystallites of PbO with several hexagon-shaped particles. The dark spot in the TEM micrograph further confirmed the synthesis of PbO NPs, as the selected area diffraction pattern associated with such spots reveals the occurrence of the PbO NPs in total agreement with the X-ray diffraction data (Fig. 6). The average size of the PbO nanocrystals by TEM was approximated to be around 20 nm.Open in a separate windowFig. 5The TEM image of nanocrystalline PbO NPs.Open in a separate windowFig. 6The SAED image of nanocrystalline PbO NPs.The Fourier transform infrared (FT-IR) spectrum (ESI, S6^†) of the PbO NPs displayed peaks at 575, 641, and 848 cm⁻¹, which corresponds to the Pb–O vibrations. Furthermore, the absorption band at ∼3315 cm⁻¹ was due to the presence of the hydroxyl group (–OH) in the NPs.The N₂ adsorption–desorption isotherms of the PbO nanoparticles shown in Fig. 7 was consistent with type IV adsorption–desorption isotherms with H1 hysteresis corresponding to the cylindrical mesoporous structure. Moreover, the surface area, pore-volume, and BJH pore diameter were found to be 32.0 m² g⁻¹, 0.023 cm³ g⁻¹, and 30.9 Å, respectively.Open in a separate windowFig. 7BET surface area and pore size of nanocrystalline PbO catalyst.The catalytic activity of the synthesized PbO NPs was tested in a one-pot multicomponent synthesis of arylbenzodioxoloyl xanthenedione derivative under ball milling condition according to the reaction scheme 2a, with 3,4-dimethoxybenzaldehyde (166.2 mg, 1.0 mmol), 3,4-methylenedioxyphenol (138.0 mg, 1.0 mmol), and 2-hydroxy-1,4-naphthoquinone (174.0 mg, 1.0 mmol) as reactants. The reaction conditions, the ball milling parameters (speed, time, and ball to solids ratio), and the PbO nanocatalyst amount were first optimized to produce the highest yield using experimental design as shown in EntryConditionsRotation (rpm)Catalyst (mol%)Time (min)Yield (%)^a1Ball milling4000050212Ball milling4001050483Ball milling4001560544Ball milling4002070595Ball milling5001050626Ball milling5001550657Ball milling5002060678Ball milling6001070719Ball milling60015507710Ball milling60020608211Ball milling60005709012Ball milling600105091 13 Ball milling ^b 600 15 60 97 14Ball milling60020709715No ball milling^c—1560—Open in a separate window^aIsolated yield; model reaction: 3,4-dimethoxybenzaldehyde (166.2 mg, 1.0 mmol), 3,4-methylenedioxyphenol (138.1 mg, 1.0 mmol), 2-hydroxy-1,4-naphthoquinone (174.1 mg, 1.0 mmol) under ball milling.^bOptimized reaction conditions.^cThe reaction was performed under stirring condition in a RB flask.Next, by utilizing the general experimental procedure (ESI^† for detail experimental procedure; S2) and the aforementioned optimized conditions (29 we also investigated the possible scopes of the reactants as revealed in 26 These data are available in S4 (see ESI^† for the spectroscopic data). The aromatic aldehydes comprising both electron-withdrawing (e.g., nitro group) and electron-donating (e.g., –OMe, –OH, –Cl, –Me, and –Br) groups participated proficiently in the reaction without including any electronic effects. The aromatic aldehyde with electron-donating groups (e.g., –OMe, –OH, –Cl, –Me, and –Br) increased the product yield, while in the case of aryl aldehyde having an electron-withdrawing group (e.g., –NO₂), both the product yield as well as the reaction rate decreased. These findings are depicted in †Scope of the PbO NP-catalyzed synthesis of arylbenzodioxoloyl xanthenedione derivatives

Synthesis of 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands for use in Suzuki–Miyaura cross-coupling reactions

3-Aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were synthesized from 2-aminomethylpyridine as the initial substrate via two complementary routes. The first synthetic pathway underwent the coupling of 2-aminomethylpyridine with substituted benzoyl chlorides, followed by cyclization, iodination and palladium-catalyzed cross-coupling phosphination reactions sequence to give our phosphorus ligands. In the second route, 2-aminomethylpyridine was cyclized with aryl aldehydes, followed by the iodination and palladium-catalyzed cross-coupling phosphination reactions to yield our phosphorus ligands. The 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were evaluated in palladium-catalyzed sterically-hindered biaryl and heterobiaryl Suzuki–Miyaura cross-coupling reactions.

3-Aryl-1-phosphinoimidazo[1,5-a]pyridine ligands were synthesized from 2-aminomethylpyridine as the initial substrate via two complementary routes and were evaluated in the Suzuki–Miyaura cross-coupling reactions.

Palladium-catalyzed cross-coupling methodologies have become common themes in modern organic synthesis.^1–5 A decade before his death, Snieckus presented in his 2010 Nobel Prize review that privileged ligands represented the “third wave” in the cross-coupling reactions where the “first wave” was the investigation of the metal catalyst – the rise of palladium and the “second wave” was the exploration of the organometallic coupling partner.⁶ In the last two decades, it was recognized that the choice of ligand facilitated the oxidative addition and reductive-elimination steps of the catalytic cycle of transition metal-catalyzed cross-coupling reactions. The overall rate of the reaction was increased with bulky trialkylphosphine or N-heterocyclic carbene ligands, which facilitated the oxidative addition processes of electron-rich, unactivated substrates like aryl chlorides.^7,8 Monophosphine ligands have found wide-spread use in metal-catalyzed cross-coupling reactions.^9–13 Privileged ligands such as Buchwald''s biarylphosphines,^14–17 Stradiotto''s biaryl P–N phosphines,^18–21 Fu/Koie/Shaughnessy''s trialkylphosphines,^7,8,22 Hartwig''s ferrocenes,^23,24 Ackermann''s diaminochlorophosphines,^25,26 Beller''s bis(adamantyl)phosphines²⁷ and N-aryl(benz)imidazolyl- or N-pyrrolyl-monophosphines,^28–30 Kwong''s indolyl-based monophosphines,^31–35 Zhang''s ClickPhos ligands,^36,37 Singer''s bippyPhos ligands,^38,39 Rodriguez/Tang''s oxaphospholes,^40,41 and Verkade''s proazaphosphatranes^42,43 have found wide-spread use in Suzuki–Miyaura, Corriu–Kumada, Heck, Negishi, Sonagashira, carbon–heteroatom cross-coupling and Buchwald–Hartwig amination reactions (Fig. 1). Preformed catalysts with these ligands attached to the palladium metal center are also recognized in cross-coupling methodologies.^44,45Open in a separate windowFig. 1Representative monophosphine ligands for palladium-catalyzed cross-coupling reactions.Our group is interested in a long-standing research program directed at the use of unexplored heterocyclic potential phosphorus ligands for cross-coupling reactions. Our first entry into the use of new heterocyclic phosphorus ligands was our previously developed complementary synthetic routes for the preparation of 3-aryl-2-phosphino[1,2-a]pyridine ligands 2 from 2-aminopyridine (1) (Fig. 2).⁴⁶ In this current work, we have developed synthetic protocols to access 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands 4 from 2-aminomethylpyridine (3) as our starting material.Open in a separate windowFig. 2Our previous and current syntheses of imidazopyridine phosphorus ligands.The parent 1-phosphinoimidazo[1,5-a]pyridine ligands 7a–c were synthesized from imidazo[1,5-a]pyridine (5). Imidazo[1,5-a]pyridine (5), which is commercially available, was conveniently prepared in a two-step sequence via formylation and cyclization with phosphorus oxychloride from 2-aminomethylpyridine (3, Scheme 1).⁴⁷ Reaction of imidazo[1,5-a]pyridine (5) with N-iodosuccinimide (NIS) afforded 1-iodoimidazo[1,5-a]pyridine (6),⁴⁸ which underwent palladium-catalyzed reactions with different phosphines in the presence of 1,1′-bis(diisopropylphosphino)ferrocene (DIPPF) to deliver our 1-phosphino imidazo[1,5-a]pyridine 7a–c ligands.⁴⁹Open in a separate windowScheme 1Preparation of 1-phosphinoimidazo[1,5-a]pyridine ligands 7a–c from 2-aminomethylpyridine (3).We were then interested in the preparation of various methoxy-substituted aryl imidazo[1,5-a]pyridine phosphorus ligands. 2-Aminomethylpyridine (3) reacted in with various mono-, di, and trimethoxy-substituted benzoyl chlorides, prepared from the corresponding benzoic acids with oxalyl chloride, to afford N-[(pyridin-2-yl)methyl]arylamides 8c–i in excellent yields (Scheme 2, Route A).⁵⁰ The arylamides 8c–i were then cyclized to generate 3-arylimidazo[1,5-a]pyridines 9c–i in the presence of phosphorus oxychloride under reflux in good yields, which were very pure and carried onto the next step without further purification.⁵¹ Route B showed that 2-methoxy-, 3-methoxy- and 3,4,5-trimethoxybenzaldehydes were reacted with 2-aminomethylpyridine (3) in the presence of TBHP and I₂ in DMF at 70 °C to afford 3-arylimidazo[1,5-a]pyridines 9a–b/j in moderate yields.⁵² We found that Route A was more convenient compared to Route B in terms of yields, time, and purification.Open in a separate windowScheme 2Preparation of 3-aryl-1-phosphinoimidazo[1,5-a]pyridine ligands 4a–s from 2-aminomethylpyridine (3) via Routes A and B.With intermediates 9a–j obtained from Routes A and B in hand, two different conditions to iodinate at the C-1 position were explored. Substrates 9a–j were successfully iodinated at the C-1 position using either NIS in acetonitrile⁴⁸ at room temperature or I₂ in THF under reflux to give 1-iodo-3-arylimidazo[1,5-a]pyridines 10a–j in low to excellent yields.⁵³ It was noted that mono- and dimethoxy substrates must be iodinated with NIS in acetonitrile within 3 h. Otherwise, the compounds would be over-iodinated on multiple carbons. However, the trimethoxy substrates were unsuccessful with NIS in acetonitrile within 3 h, but successful with I₂ in THF under reflux to give moderate yields. The trimethoxy substrates could be iodinated with NIS in acetonitrile but the time of the reaction needed to be 24 h at room temperature as shown for compound 9h (46 Iodo substrates 10a–j were successfully phosphinated at the C-1 position via the palladium-catalyzed reaction with diphenylphosphine and dicyclohexylphosphine to give new ligands 4a–s in low to moderate yields.⁴⁹ Many attempts to attach a di-tert-butylphosphine group to the iodo intermediates met with complete failure. Our early attempts to perform the metal–halogen exchange of the iodo intermediates followed by trapping with disubstituted chlorophosphines failed to yield any trace of phosphinated products.Iodination and palladium-catalyzed phosphination sequence reactions of 2-iodoimidazo[1,5-a]pyridines 9 and 10

An expeditious and efficient bromomethylation of thiols: enabling bromomethyl sulfides as useful building blocks

A facile and highly efficient method for the bromomethylation of thiols, using paraformaldehyde and HBr/AcOH, has been developed, which advantageously minimizes the generation of highly toxic byproducts. The preparation of 22 structurally diverse α-bromomethyl sulfides illustrates the chemo-tolerant applicability while bromo-lithium exchange and functionalization sequences, free radical reductions, and additions of the title compounds demonstrate their synthetic utility.

A new method for the bromomethylation of thiols using paraformaldehyde and HBr/AcOH, minimizes the generation of toxic byproducts. Synthetic utility of α-bromomethyl sulfides was demonstrated through umpolung and free radical chemistry.

Heteroatom halomethylations¹ have proven to be extremely useful for the generation of valuable synthetic intermediates.² Halomethylation of thiols provides synthetically valuable chloromethylated intermediates (chloromethyl sulfides), which are typically prepared by condensation with bromochloromethane in basic media,³ or with HCl and a formaldehyde source (paraformaldehyde, polyoxymethylene, etc.).⁴ While chloromethyl sulfides have been traditionally used as alkylating reagents, the analogous bromomethyl counterparts offer superior electrophilicity, recognized since the earliest report describing their syntheses using hydrogen bromide and paraformaldehyde,⁵ yet they are often overlooked in this role. Moreover, the reactivity scope of bromomethyl thiol derivatives remains largely unexplored, despite a potentially broader synthetic range (e.g. for the generation of organometallics by metal–halogen exchange).⁶Other methods for the generation of bromomethylated thiol derivatives consist of replacing hydrogen bromide gas with concentrated aqueous hydrobromic acid, along with a formaldehyde source (usually paraformaldehyde),⁷ or by using dibromomethane⁸ in basic media.⁹ Two or three-step procedures consisting of hydroxymethylation followed by substitution have also been developed.¹⁰ A desilylative rearrangement of α-TMS sulfides has also been used for the generation of bromomethylsulfides.¹¹As part of our interest in the preparation and application of structurally diverse sulfur-based building blocks,¹² we investigated the preparation of benzyl(bromomethyl)sulfane (2a), previously used as an olefination reagent.¹³ However, several attempts to prepare 2a through exposure of benzylmercaptan (1a) to paraformaldehyde and hydrobromic acid,^7b led to a ca. 1.5 : 1 mixture of 2a (32%) and bis(benzylthio)methane 3a (21%, Scheme 1a). Iterations of the experiment always delivered important and variable amounts of the dithioacetal by-product 3a. On the other hand, an alternate approach to the bromomethylation of a cyclohexanethiol bromomethyl derivative 2b, using dibromomethane and K₂CO₃, resulted in trace amounts of the dithioacetal derivative 3b only (Scheme 1b).¹⁴Open in a separate windowScheme 1Attempts for the bromomethylation of 1a or 1b under (a) acidic or (b) basic media. (c) and (d) A highly efficient and direct approach for thiol bromomethylation (this work).HBr/AcOH is a convenient hydrogen bromide source that minimizes exposure to risky set-ups and has been employed as a surrogate to highly corrosive and toxic hydrogen bromide gas in numerous applications.¹⁵ Although this reagent has been used previously in the generation of bromomethyl sulfides, installation of the methylene bridge required first a S-pivaloxymethylation of a mercaptan, followed by cleavage by HBr/AcOH.¹⁶Surprisingly, sequential exposure of thiols 1a or 1b to paraformaldehyde and HBr/AcOH,¹⁷ rapidly delivered bromomethylated derivatives 2a and 2b with outstanding yields (Scheme 1). The simple experimental setup and straightforward purification procedure offer methodological utility; in most cases extraction with a low-boiling point hydrocarbon such as pentane or hexanes is sufficient to recover the material in high purity (>95%).¹⁸ Traces of impurities can be easily discarded through bulb-to-bulb vacuum distillation.The reaction scope was explored with a series of structurally diverse thiols (19 was prepared satisfactorily in 76% yield. Fluorinated bromomethyl 2e has been used for the preparation of fluorinated surfactants,^10a,20 which some exhibit antimicrobial activity. As a previous method involves a 2-step sequence involving thiol hydroxymethylation and substitution by PBr₃, our method directly delivered 2e in 88% yield.Thiol bromomethylation with HBr/paraformaldehyde^a

ortho-Naphthoquinone-catalyzed aerobic oxidation of amines to fused pyrimidin-4(3H)-ones: a convergent synthetic route to bouchardatine and sildenafil

A facile access to fused pyrimidin-4(3H)-one derivatives has been established by using the metal-free ortho-naphthoquinone-catalyzed aerobic cross-coupling reactions of amines. The utilization of two readily available amines allowed a direct coupling strategy to quinazolinone natural product, bouchardatine, as well as sildenafil (Viagra™) in a highly convergent manner.

Fused pyrimidin-4(3H)-one derivatives have been accessed by using the ortho-naphthoquinone-catalyzed aerobic cross-coupling reactions of amines.

N-Heterocyclic compounds with a pyrimidin-4(3H)-one core constitute a large number of natural products and biologically active molecules. For example, quinazolinone alkaloids possess a phenyl-fused pyrimidin-4(3H)-one structure and display a wide spectrum of pharmacological activities (Scheme 1a).¹ Sildenafil (Viagra™), a potent and selective inhibitor of type 5 phosphodiesterases on smooth muscle cell, is based on the pyrazole-fused pyrimidin-4(3H)-one structure and marketed for erectile dysfunction.² The synthetic approaches to the phenyl-fused pyrimidin-4(3H)-ones, quinazolinones, typically involve the condensation between anthranilamides and aldehydes to give aminal intermediates that in turn oxidized to quinazolinones under oxidation conditions (Scheme 1b). The oxidation catalysts include Cu,³ Fe,⁴ Ga,⁵ Ir,⁶ Mn,⁷ iodine,⁸ peroxide,⁹ however the aerobic oxidation of aminal intermediates is also known at 150 °C.¹⁰ The utilization of alcohols also effects the one-pot synthesis of quinazolinones through in situ oxidation to aldehydes in the presence of Fe,¹¹ Ir,¹² Mn,¹³ Ni,¹⁴ Pd,¹⁵ Ru,¹⁶ V,¹⁷ Zn,¹⁸ and iodine catalysts.¹⁹ Other precursors to aldehydes have been also identified using alkynes,²⁰ benzoic acids,²¹ indoles,²² α-keto acid salts,²³ β-keto esters,²⁴ styrenes,²⁵ sulfoxides,²⁶ and toluenes.²⁷ Non-aldehyde approaches to quinazolinones have been also demonstrated in the cross coupling of amidines,²⁸ amines,²⁹ benzamides,³⁰ isocyanides,³¹ and nitriles.³² In 2013, the Nguyen group disclosed the synthesis of four quinazolinones, utilizing the autooxidation of benzylamines to imines that subsequently condensed with anthranilamides.³³ While a closed system at 150 °C was necessary, the use of 40 mol% AcOH without solvent provided the quinazolinones in 46–75% yields. The Nguyen group also developed the FeCl₃·6H₂O-catalyzed condensation of 2-nitroanilines and benzylamines in the presence of 20 mol% of S₈, where six quinazolinones were obtained in 68–75% yields.³⁴ While the cross condensation of anthranilamides and benzylamines was accomplished, there exists a significant knowledge gap due to the limited substrate scope combined with less optimal reaction conditions (i.e. high reaction temperature, closed system in neat conditions and excess use of amines). In addition, it is not entirely clear if the cross condensation of amide-containing amines and benzylamines would work for other fused pyrimidin-4(3H)-one derivatives.³⁵ To address such shortcomings in the cross condensation of amines, the ortho-naphthoquinone (o-NQ)-catalyzed aerobic cross amination strategy was investigated (Scheme 1c).³⁶ Herein, we report a highly general approach to fused pyrimidin-4(3H)-one derivatives in the presence of o-NQ catalyst, culminating to the direct aerobic coupling of two amines to bouchardatine and sildenafil.Open in a separate windowScheme 1Biologically active fused pyrimidin-4(3H)-one derivatives and their synthetic methods.Given that the o-NQ-catalyzed aerobic cross coupling of benzylamines and aniline derivatives such as o-phenylenediamines provided a facile approach to heterocyclic compounds including benzoimidazoles,³⁷ the use of anthranilamide 1a and benzylamine 2a was examined as a model study (38 The reaction in DMSO lowered down the ratio of 1a and 2a from 1.0 : 1.5 to 1.0 : 1.2 (entry 12) and the catalyst loading to 5 mol% without affecting the overall reaction efficiency (entry 13). The control experiments confirmed the critical roles of both o-NQ1 and TFA (entries 15–18), and the reaction utilized molecular oxygen as a terminal oxidant (entries 19 and 20). Piecing together the experimental data, the employment of 5 mol% o-NQ1 and 20 mol% TFA in DMSO at 100 °C was selected for further studies.Optimization of o-NQ-catalyzed aerobic cross-coupling of amines to quinazolinone^a

Diastereoselective synthesis of chroman bearing spirobenzofuranone scaffolds via oxa-Michael/1,6-conjugated addition of para-quinone methides with benzofuranone-type olefins

A simple and convenient cyclization of ortho-hydroxyphenyl-substituted para-quinone methides with benzofuran-2-one type active olefins via oxa-Michael/1,6-conjugated addition has been developed, which afforded an easy access to enriched functionalized chroman-spirobenzofuran-2-one scaffolds with good to excellent yields (up to 90%) and diastereoselectivities (up to >19 : 1 dr). This reaction provided an efficient method for constructing desired spirocyclic compounds combining both well-known heterocyclic pharmacophores chroman and benzofuran-2-one.

Highly diastereoselective synthesis of spirocyclic compounds combining both well-known heterocyclic pharmacophores chroman and benzofuran-2-one.

The chroman framework represents a privileged heterocyclic core commonly found within a wide variety of biologically active natural products¹ and synthetic compounds of medicinal interest (Fig. 1).² Owing to the wide application of these heterocyclic molecules, over the past few decades, numerous efforts have been devoted to the efficient synthesis of chroman nucleus motifs.^3,4 In particular, incorporating chroman into spiro-bridged and spiro-fused heterocyclic systems is appealing due to its fascinating molecular architecture and proven biological activity.⁵ Among the existing methods, the [4 + m] cycloaddition of para-quinone methides (p-QMs) is found to be an efficient pathway to access these valuable spirocyclic skeletons.⁶ For instance, the Enders group synthesized functionalized chromans with an oxindole motif by the asymmetric organocatalytic domino oxa-Michael/1,6-addition reaction.⁷ After that, the Hao,^8a Peng,^8b Shi,^8c,d Zhou,^8e Liang^8f and Wang^8g groups developed convenient methods to construct chromans bearing spirocyclic skeletons from p-QMs, respectively. Despite all these shining achievements, however, it is still very challenging to simply and conveniently construct chromans bearing quaternary carbon spirals for organic chemical or drug discovery among these [4 + m] cycloaddition reactions.Open in a separate windowFig. 1Representative chroman compounds.Benzofuran-2-(3H)-ones as one of the important oxygen-containing heterocycles that exist in a broad array of natural products⁹ and potential medicines.¹⁰ The streamlined synthesis of benzofuran-2-ones pose considerable challenge due to their quaternary carbon centers at the C-3 position,¹¹ especially those featuring relatively congested spirocyclic motifs represent challenging synthetic targets.^12,13 In our continuous interests in developing efficient method for the synthesis of spirocyclic compounds based on cyclization reaction,¹⁴ we wish to report a cycloaddition of para-quinone methides with benzofuranone derived olefins, affording the spiro-cycloadducts in good to excellent yields and diastereoselectivities. This cyclization features the simultaneous formation of chroman and spirobenzofuran-2-one skeletons in a single step (Scheme 1), which may be potentially applied as pharmaceutical agents.Open in a separate windowScheme 1Strategy for the synthesis of chroman-spirobenzofuran-2-one.We initiated our investigations with the readily available ortho-hydroxyphenyl-substituted para-quinone methides 1a and 3-benzylidenebenzofuran-2-one 2a in toluene at room temperature in the presence of base. Unfortunately, no desired chroman derivatives bearing spirobenzofuranone scaffolds 3a was isolated in the presence of 2 eq. Na₂CO₃ after stirring at room temperature for 48 h (entry 1, EntryBaseSolventYield^b (%)Dr^c1Na₂CO₃Toluene——2DMAPToluene——3K₂CO₃Toluene253 : 14CsFToluene525 : 15Cs₂CO₃Toluene706 : 16Cs₂CO₃THF68>19 : 17Cs₂CO₃Et₂O608 : 18Cs₂CO₃Dioxane537 : 19Cs₂CO₃CH₃CN50>19 : 110Cs₂CO₃DMF3115 : 111^dCs₂CO₃THF65>19 : 112^eCs₂CO₃THF75>19 : 113^fCs₂CO₃THF64>19 : 1Open in a separate window^aReaction conditions: p-QMs 1a (0.1 mmol), benzofuranones 2a (0.12 mmol) and base (0.2 mmol) in 2 mL of solvent for 6–48 h.^bIsolated yields.^cDetermined by crude ¹H NMR analysis.^dPerformed at 30 °C.^ePerformed at 10 °C.^fPerformed at 0 °C.With the optimized reaction conditions in hand, we explored the substrate scope of this cyclization reaction with a selection of benzofuranones. The results are shown in EntryR3Yield^b (%)Dr^c1C₆H₅3a75>19 : 122-ClC₆H₄3b69>19 : 132-BrC₆H₄3c6715 : 142-CH₃C₆H₄3d64>19 : 153-CH₃C₆H₄3e75>19 : 163-MeOC₆H₄3f72>19 : 173-NO₂C₆H₄3g71>19 : 183-BrC₆H₄3h75>19 : 194-CH₃C₆H₄3i7310 : 1104-MeOC₆H₄3j86>19 : 1114-CF₃C₆H₄3k8212 : 1124-NO₂C₆H₄3l8512 : 1134-ClC₆H₄3m83>19 : 1144-BrC₆H₄3n8112 : 1152-Naphthyl3o74>19 : 1163,4,5-(OMe)₃C₆H₂3p8812 : 1173-Pyridinyl3q79>19 : 1183-Thiophenyl3r80>19 : 1Open in a separate window^aReaction conditions: p-QMs 1a (0.1 mmol), benzofuranones 2 (0.12 mmol) and Cs₂CO₃ (0.2 mmol) in 2 mL of THF.^bIsolated yields for 4–48 h.^cDetermined by crude ¹H NMR analysis.Subsequently, the generality of this cyclization reaction was further evaluated through varying p-QMs 1. As shown in EntryR4Yield^b (%)Dr^c15-Cl4a73>19 : 125-Br4b65>19 : 135-CH₃4c90>19 : 145-OCH₃4d8010 : 154-CH₃4e72>19 : 164-OCH₃4f6610 : 1Open in a separate window^aReaction conditions: p-QMs 1 (0.1 mmol), benzofuranones 2a (0.12 mmol) and Cs₂CO₃ (0.2 mmol) in 2 mL of THF for 6–48 h.^bIsolated yields.^cDetermined by crude ¹H NMR analysis.The structure and relative configuration of 3a were determined by HRMS, NMR spectroscopy and single-crystal X-ray analysis.¹⁵ The relative configuration of other cycloadducts were tentatively assigned by analogy (Fig. 2 and see ESI^†).Open in a separate windowFig. 2X-ray crystal structure of 3a.     

DIAGNOSING SARCOPENIA: FUNCTIONAL PERSPECTIVES AND A NEW ALGORITHM FROM ISarcoPRM

Sarcopenia is an important public health problem, characterized by age-related loss of muscle mass and muscle function. It is a precursor of physical frailty, mobility limitation, and premature death. Muscle loss is mainly due to the loss of type II muscle fibres, and progressive loss of motor neurones is thought to be the primary underlying factor. Anterior thigh muscles undergo atrophy earlier, and the loss of anterior thigh muscle function may therefore be an antecedent finding. The aim of this review is to provide an in-depth (and holistic) neuromusculoskeletal approach to sarcopenia. In addition, under the umbrella of the International Society of Physical and Rehabilitation Medicine (ISPRM), a novel diagnostic algorithm is proposed, developed with the consensus of experts in the special interest group on sarcopenia (ISarcoPRM). The advantages of this algorithm over the others are: special caution concerning disorders related to the renin-angiotensin system at the case finding stage; emphasis on anterior thigh muscle mass and function loss; incorporation of ultrasound for the first time to measure the anterior thigh muscle; and addition of a chair stand test as a power/performance test to assess anterior thigh muscle function. Refining and testing the algorithm remains a priority for future research. LAY ABSTRACTSarcopenia is an important public health problem, characterized by age-related loss of muscle mass and muscle function. The diagnostic recommendations published to date have addressed total or appendicular muscle mass. However, under the umbrella of the International Society of Physical and Rehabilitation Medicine (ISPRM), experts in the special interest group on sarcopenia (ISarcoPRM) developed a new algorithm, based on regional measurements and functional evaluations of the anterior thigh muscle, which is the most commonly and initially affected condition in sarcopenia. Unlike other suggestions, diseases associated with the renin-angiotensin system are emphasized in this algorithm, and ultrasound has been used for measurement of anterior thigh muscle mass. Key words: ultrasound, quadriceps, muscle, Sonographic Thigh Adjustment Ratio, function, frailty, International Society of Physical and Rehabilitation Medicine

In 1989, Rosenberg first suggested the term “sarcopenia”’ (from the Greek sarx for flesh and penia for loss) to define the age-related loss of muscle mass (1). However, with increasing interest in sarcopenia in the last 2 decades (2), its definition has evolved to “age-related loss of muscle mass and muscle function”. Although sarcopenia was accepted as a disease in the International Classification of Disease – 10^th Revision – Clinical Modification in 2016 (3), it still has no universally agreed clinical definition or diagnostic criteria (4–13). Of note, the lack of consensus for identifying sarcopenia prevents estimation of the accurate prevalence, prognosis, and effectiveness of interventions. According to various working groups, the prevalence of sarcopenia ranges from approximately 10% to 40% due to different methodology, diagnostic criteria, ethnicity, and selected populations (14).Table IFormer and ISarcoPRM diagnostic criteria for sarcopenia by different working groups (in chronological order)

Synthesis of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands for use in palladium-catalyzed cross-coupling reactions

3-Aryl-2-phosphinoimidazo[1,2-a]pyridine ligands were synthesized from 2-aminopyridine via two complementary routes. The first synthetic route involves the copper-catalyzed iodine-mediated cyclizations of 2-aminopyridine with arylacetylenes followed by palladium-catalyzed cross-coupling reactions with phosphines. The second synthetic route requires the preparation of 2,3-diiodoimidazo[1,2-a]pyridine or 2-iodo-3-bromoimidazo[1,2-a]pyridine from 2-aminopyridine followed by palladium-catalyzed Suzuki/phosphination or a phosphination/Suzuki cross-coupling reactions sequence, respectively. Preliminary model studies on the Suzuki synthesis of sterically-hindered biaryl and Buchwald–Hartwig amination compounds are presented with these ligands.

3-Aryl-2-phosphoimidazo[1,2-a]pyridine ligands were prepared via two complimentary synthetic routes and were evaluated in the Suzuki–Miyaura and Buchwald–Hartwig amination cross-coupling reactions.

Palladium-catalyzed cross-coupling reactions have revolutionized the formation of C–C and C–X bond formation in the academic and industrial synthetic organic chemistry sectors.^1,2 Applications such as synthesis of natural products,³ active pharmaceutical ingredients (API),⁴ agrochemicals,⁵ and materials for electronic applications⁶ are showcased. Snieckus described in his 2010 Nobel Prize review that privileged ligand scaffolds represented the “third wave” in the cross-coupling reactions where the “first wave” was the investigation of the metal catalyst-the rise of palladium and the “second wave” was the exploration of the organometallic coupling partner.¹ In the last twenty years, it was recognized that the choice of ligand facilitated the oxidative addition and reductive-elimination steps of the catalytic cycle of transition metal-catalyzed cross-coupling reactions, increasing the overall rate of the reaction. For example, bulky trialkylphosphines facilitated the oxidative addition processes of electron-rich, unactivated substrates such as aryl chlorides.^7,8 Sterically demanding ligands also provided enhanced rates of reductive elimination from [(L)_nPd(aryl)(R), R = aryl, amido, phenoxo, etc.] species by alleviation of steric congestion.⁹ Privileged ligands such as Buchwald''s biarylphosphines,^10,11 Fu''s trialkylphosphines,^7,8,12 Nolan–Hermann''s N-heterocyclic carbenes (NHC),^13–15 Hartwig''s ferrocenes,^16,17 Beller''s bis(adamantyl)phosphines^18,19 and N-aryl(benz)imidazolyl or N-pyrrolylphosphines,^20,21 Zhang''s ClickPhos ligands,^22,23 and Stradiotto''s biaryl P–N phosphines,^24,25 to mention a few, have found wide-spread use in Suzuki–Miyaura, Corriu–Kumada, Heck, Negishi, Sonogashira, C–X (X = S, O, P) cross-coupling and Buchwald–Hartwig amination reactions (Fig. 1). Preformed catalysts with these ligands attached to the palladium metal center are also recognized as well-defined entities in cross-coupling reactions.²⁶Open in a separate windowFig. 1Privileged ligands for palladium-catalyzed cross-coupling reactions.The term privileged structure was first coined by Evans et al. in 1988 and was defined as “a single molecular framework able to provide ligands for diverse receptors”.²⁷ In the last three decades, it is clear that privileged structures are exploited as opportunities in drug discovery programs.^28–31 For example, imidazo[1,2-a]pyridines are privileged structures in medicinal chemistry programs (Fig. 2).³² Imidazo[1,2-a]pyridines are a represented motif in several drugs on the market such as zolpidem, marketed as Ambien™ for the treatment of insomnia,³³ minodronic acid, marketed as Bonoteo™ for oral treatment of osteoporosis,³⁴ and olprinone, sold as Coretec™ as a cardiotonic agent.³⁵Open in a separate windowFig. 2Imidazo[1,2-a]pyridines as privileged structures in medicinal chemistry and in our cross-coupling reactions approach.Our group is interested in a long-term research program directed at the use of key privileged structures that are employed in drug discovery programs as potential phosphorus ligands for cross-coupling reactions. In our entry into the use of privileged structures from the medicinal chemistry literature for our investigation into new phosphorus ligands, we have developed two complementary synthetic routes for the preparation of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands from 2-aminopyridine as our initial substrate.Our first synthetic route for the preparation of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands 3a–3l required the copper(ii) acetate iodine-mediated double oxidative C–H amination of 2-aminopyridine (1) with arylacetylenes under an oxygen atmosphere to give 3-aryl-2-iodoimidazo[1,2-a]pyridines 2a–2d (Scheme 1).^36,37Open in a separate windowScheme 1Preparation of 3-aryl-2-phosphinoimidazo[1,2-a]pyridine ligands 3a–3l from 2-aminopyridine via copper-catalyzed arylacetylene cyclizations/palladium-catalyzed phosphination reactions sequences.Phenylacetylene and 2-/3-/4-methoxyphenylacetylenes were commercially available reagents. With intermediates 2a–d in hand, we explored several cross-coupling phosphination reactions and we found that palladium-catalyzed phosphination with DIPPF ligand in the presence of cesium carbonate as the base in 1,4-dioxane under reflux provided twelve new ligands 3a–3l as shown in 38 Moderate to good yields were obtained under these cross-coupling conditions. There are few commercially available dimethoxyphenylacetylenes, and most are prohibitively expensive, and so an alternative synthetic strategy was explored.Palladium-catalyzed phosphination of 3-aryl-2-iodoimidazo[1,2-a]pyridines 2a–2d^a

Silica based inorganic–organic hybrid materials for the adsorptive removal of chromium

We employed polymer functionalized silica gel as an adsorbent for the removal of Cr(vi) from water. The chains of 2-aminoethyl methacrylate hydrochloride (AEMA·HCl) polymer were grown from the surface of silica gel via surface-initiated conventional radical polymerization and the resulting hybrid material exhibited high affinity for chromium(vi). To investigate the adsorption behavior of Cr(vi) on diverse polymer based hybrid materials, the removal capacity of (SG-AEMH) was compared with our previously reported branched polyamine functionalized mesoporous silica (MS-PEI). The adsorption capacities of polymer based materials were also compared with their respective monolayer based platforms comprising a 3-aminopropyltriethoxysilane (APTES) functionalized silica gel (SG-APTES) and mesoporous silica (MS-APTES). The polymer based systems showed excellent Cr(vi) adsorption efficiencies compared to monolayer counterparts. The structural characteristics and surface modification of these adsorbents were examined by Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and thermogravimetric analysis (TGA). The experimental data were analyzed using the Langmuir and Freundlich models. Correlation coefficients were determined by analyzing each isotherm. The kinetic data of adsorption reactions were described by pseudo-first-order and pseudo-second-order equations. Thermodynamic parameters, i.e., change in the free energy (ΔG°), the enthalpy (ΔH°), and the entropy (ΔS°), were also evaluated. The synthesized hybrid materials exhibited a high adsorption capacity for chromium ions. Furthermore, they could be regenerated and recycled effectively.

We employed and compared polymer functionalized silica gel and mesoporous silica as adsorbents for the removal of Cr(vi) from water.

Environmental pollution has become one of the most severe problems, which is harmful to human health and ecological systems. According to recent reports, heavy metals have been considered as the most chronic and acute contaminants globally.^1,2 Various industries such as printed board manufacturing, semiconductor manufacturing, electroplating, leather tanning, mining, steel making, textile dyes and pigments are the major sources of aquatic pollution. Industrial effluent contains different harmful heavy metals such as chromium, copper, lead, mercury.³ Chromium is considered highly alarming for human, animals and plants life. In wastewater, chromium exists in two stable states i.e., Cr(vi) and Cr(iii). Cr(vi) is more lethal due to its solubility within almost the whole pH range and greater mobility in the waterbed.⁴ Various methods such as chemical precipitation, membrane filtration, ion exchange, electrochemical processes, chemical coagulation and adsorption have been utilized to remove heavy metals from wastewater.⁵ Among these methods, adsorption is known to be the most efficient method. A large number of natural and synthetic materials have been used for the adsorption-based removal of heavy metals from wastewater.^6–9 These materials include zeolites, clays, biosorbents, resins, activated carbon magnetic particles and silica. Simple and low cost adsorbents have been synthesized by several researchers for an effective removal of heavy metals including Cr(vi) even at low concentration.^10–17 Li et al., demonstrated the preparation of chitosan nanofibers with an average diameter of 75 nm and cross linked with glutaraldehyde for the removal of Cr(vi).¹⁸ Aboutorabi et al., employed TMU-30 based metal–organic framework (MOF) containing isonicotinate N-oxide as adsorptive sites for the adsorption of Cr(vi) from aqueous solution.¹⁹ Recently, Dong et al., prepared the ionic liquid functionalized cellulose (ILFC) through the grafting of glycidyl methacrylate onto cellulose microsphere followed by reaction with ionic liquid 1-aminopropyl-3-methyl imidazolium nitrate for the adsorptive removal of Cr(vi).²⁰vi).Comparison of adsorption capacities of different adsorbents for Cr(vi) removal

Sr. no	Adsorbents	Adsorption capacity qmax (mg g−1)	Time (min)	pH	References
1	Carbon/boehmite (AlOOH) composite	25.6	360	2.0	51
2	Titanium oxide-Ag composite	25.7	720	2.0	52
3	Polydopamine coated maghemite NPS (MNP@PDA)	38.6	240	3.0	53
4	Fe3O4@NiO nanocomposite	6.9	40	5–10	54
5	MnFe2O4@SiO2-CTAB	25.0	30	3.0	55
6	ZnO/biochar	43.5	120	Natural pH	56
7	γ-AlOOH/PVA granules	35.9	200	5.5	57
8	Yarrowia lipolytica	5.2	120	1.0	58
9	β-Cyclodextrin ionic liquid polyurethane modified magnetic NPs (Fe3O4-CDI-IL MNPs)	2.6	180	3.0	59
10	Blends of henna with chitosan microparticles	17.4	66.21	3.8	60
11	Silver-triazolate MOF	37.0	240	6	61
12	p-Toluidine formaldehyde resin (PTFR) on silica	43.5	300	1.0	62
13	SG-AEMH	63.3	30	4.0	Current study
14	MS-PEI	50.26	30	4.0	Current study

Open in a separate windowSilica based porous materials are considered as promising adsorbents for water remediation due to their high surface area, well defined tunable pore size and high adsorption capacity.^21,22 Owing to their economic feasibility, high thermal and mechanical stabilities, they can be utilized as inorganic solid matrixes in the inorganic–organic hybrid materials.^23,24 Several researchers have contributed in the development of functionalized silica based adsorbents for the removal of heavy metals.^25–31 Fan et al., prepared the Schiff base functionalized Pb(ii) imprinted silica-supported organic–inorganic hybrid adsorbent for the selective removal of Pb(ii) from aqueous solution.³² Radi et al., reported the synthesis of chelate β-ketoenol furan functionalized silica particles (SiNFn) for the selective adsorption of Cd(ii).³³ More Recently, Qihui et al., demonstrated the fabrication of thiol functionalized silica microspheres doped with CdTe quantum dots (CQDSMs) for the efficient adsorption of Ag⁺.³⁴ The surface of silica can be tailored with different functional groups to enhance their selectivity towards specific pollutants.^35,36 Modification can be achieved via post-synthesis grafting and co-condensation.³⁷ Post-synthesis grafting offers a facile avenue to controlling surface properties of materials and facilitates the functionalization of the internal pores of porous materials, ultimately helping in developing material with optimized bulk and interfacial properties.³⁸ Numerous organic functional groups such as amine, thiol, carboxylate, alkyl chloride, and aromatic functional groups have been incorporated through post-synthesis grafting strategy.^39–44 In case of silica based materials, the silanol groups present on the surface assist the covalent introduction of a wide range of functional groups, which act as stable and efficient chelating moieties towards a variety of metal ions. The excellent metal adsorption property of these functionalized silica materials are attributed to the presence of electron donor heteroatoms such as O, S and N in the incorporated functional groups.^45,46 The surface functionalization can be either monolayer or polymer based. The polymer based surface functionalization results in a higher surface functional group density that ultimately improves the absorption capacity of the functionalized material. Despite obvious advantages of the polymer based surface functionalization, majority of the efforts in the field of developing materials for water remediation have been focused on monolayer based surface functionalizations.Herein, we demonstrated the potential of polymer functionalized silica based inorganic–organic hybrid materials for Cr(vi) adsorption (Scheme 1). The chains of 2-aminoethyl methacrylate hydrochloride were grafted on the surface of silica gel via surface-initiated conventional radical polymerization (SI-cRP) approach. We have also compared the adsorption capacity of SG-AEMH with polyamine functionalized MCM-41 mesoporous silica (MS-PEI).⁴⁷ The APTES derived monolayer based amine functionalized silica gel (SG-APTES) and mesoporous silica (MS-APTES) were also examined and compared with polymer grafted silica materials. Our results show that SG-AEMH and MS-PEI were more effective for chromium adsorption. Furthermore, the experimental data were fitted to different adsorption models, and the corresponding parameters were determined. In addition, kinetic and thermodynamic analyses were performed to understand the mechanism of the adsorption processes.Open in a separate windowScheme 1Schematic illustration of (a) synthesis of APTES based monolayer (SG-APTES) and AEMH based polymer functionalized silica gel (SG-AEMH), (b) polyamine functionalized mesoporous silica (MS-PEI).     

One-pot reductive amination of carbonyl compounds with nitro compounds over a Ni/NiO composite

Easily prepared Ni/NiO acts as a heterogeneous catalyst for the one-pot reductive amination of carbonyl compounds with nitroarenes to afford secondary amines with H₂ as a hydride source. This catalytic system does not require a special technique to avoid air-exposure, in contrast to the common heterogeneous Ni catalysts.

Easy-to-prepare Ni/NiO acts as an efficient heterogeneous catalyst for one-pot reductive amination of carbonyl compounds with nitroarenes.

Amines are among the most important organic compounds for the chemical, materials, pharmaceutical and agrochemical industries.¹ In particular, aromatic and heteroaromatic amines occupy a privileged position in medicinal chemistry,^1c,2 as exemplified in top-selling drugs such as atorvastatin, hydrochlorothiazide, furosemide and acetaminophen.³ The general methods to prepare aryl and heteroaryl amines are the reductive amination of carbonyl compounds,⁴ direct alkylation of amines with alkyl halides,⁵ Buchwald–Hartwig amination⁶ and Ullman-type C–N bond formation.⁷ These amination systems utilize aniline derivatives which are usually prepared in advance by hydrogenation of nitroarenes.⁸ Direct amine synthesis using nitroarenes is attractive because it eliminates the hydrogenation step, which saves time, energy and cost. Among the amination reactions, reductive amination has been actively investigated due to its high atom economy and ease of industrial application (Scheme 1);⁹ however, reductive amination has frequently been accompanied by unwanted side products due to the reduction of carbonyl compounds to alcohols and/or over-alkylation of product amines. One-pot reductive amination with nitro compounds has been achieved by precious metal catalysis.¹⁰ Recently, precious metal alloy nanoparticles were demonstrated to exhibit high catalytic performance for one-pot reductive amination with nitro compounds, even under mild reaction conditions.¹¹ In the context of economic efficiency and a ubiquitous element strategy, the replacement of precious metals with earth-abundant metals has gained much attention. Although some catalytic systems based on Fe,¹² Cu,¹³ Co ¹⁴ and Mo ¹⁵ have been reported using H₂ as a reductant, severe reaction conditions are typically required (Table S1, ESI^†). It is noteworthy that the nitrogen-doped carbon supported cobalt catalysts were reported to be active for one-pot reductive amination using nitroarenes using formic acid or CO/H₂O as a reductant though high temperature was required (Table S2, ESI^†).¹⁶Open in a separate windowScheme 1One-pot reductive amination using nitroarenes.To develop active catalysts for one-pot reductive amination using nitro compounds, we have focused on nickel catalysts, which are known as active catalysts for many transformation reactions.^17,18 The active species is typically metallic nickel, which is easily oxidized in air and becomes covered with NiO.¹⁹ Therefore, special techniques to avoid air-exposure (i.e., pre-reduction in the reaction vessel, glovebox) are required to achieve high catalytic performance for liquid phase reactions. Herein we report an easily prepared Ni/NiO composite as a heterogeneous catalyst for one-pot reductive amination using nitro compounds. This Ni catalyst can be handled under an air atmosphere, even though the supposedly active species, metallic nickel, is oxidized by air-exposure.Ni/NiO was prepared by the partial reduction of NiO with H₂ in the temperature range from 200 to 500 °C (Ni/NiO-X: X = reduction temperature). X-ray diffraction (XRD) patterns of the prepared Ni catalysts after exposure to air are summarized in Fig. 1(A). When NiO is treated in H₂ at 200 °C, the dominant phase produced is still nickel oxide. Metallic nickel was formed by reduction at ≥250 °C, which is consistent with the H₂-temperature programmed reduction (H₂-TPR) profile of NiO in which the H₂ consumption peak begins to increase at around 250 °C.²⁰ The ratio of Ni to NiO, determined by Rietveld analysis, increased with increasing reduction temperature and no peaks attributed to metallic nickel were evident for Ni/NiO-500 (†) and crystallite diameter estimated from (111) diffraction lines using Scherrer''s equation (Table S3, ESI^†). Fig. 1(C) shows an SEM image of Ni/NiO-300, where the particle size was estimated to be 0.5–3 μm, and the layered structure of NiO was maintained after the reduction treatment (see also Fig. S4, ESI^†).Open in a separate windowFig. 1(A) XRD patterns for Ni/NiO-X; (a) Ni/NiO-500, (b) Ni/NiO-400, (c) Ni/NiO-350, (d) Ni/NiO-300, (e) Ni/NiO-250, and (f) Ni/NiO-200 (♦: Ni, ○: NiO), and (B) SEM images of Ni/NiO-300.Specific surface areas and weight ratios of Ni to NiO

Advanced palladium free approach to the synthesis of substituted alkene oxindoles via aluminum-promoted Knoevenagel reaction

A synthetic route for the synthesis of C24, as well as for the design of focused libraries of direct AMPK activators was developed based on a convergent strategy. The proposed scheme corresponds to the current trends in C–H bond functionalization. The use of aluminum isopropoxide for the Knoevenagel condensation of oxindole with benzophenones is a noticeable point of this work.

A synthetic route for the synthesis of C24, as well as for the design of focused libraries of direct AMPK activators was developed based on a convergent strategy.

AMP-activated protein kinase (AMPK) has been extensively studied over the last decades. A key role of AMPK in the regulation of energy balance suggests it to be a promising target for energy metabolism-related diseases.¹ To date, AMPK is considered as a therapeutic target in type 2 diabetes, obesity, cardiovascular diseases, atherosclerosis, and cancer.² A number of indirect AMPK activators are already used in clinical practice for their beneficial metabolic effects.³ However, there are no drugs that directly activate AMPK on the pharmaceutical market yet.The demand for direct AMPK activators inspired pharmaceutical companies to start a campaign to design such molecules.⁴ To date, several classes of compounds that potently activate AMPK have been identified: AICAR and other AMP mimetics,⁵ thienopyridones,⁶ benzimidazoles,⁷ and alkene oxindole derivatives.⁸ The latter activate AMPK by the most interesting and least studied mechanism.⁹ These compounds show good target activity, and C24 (YLF-466D; (E)-3-((3-((4-chlorophenyl)(phenyl)methylene)-2-oxoindolin-1-yl)methyl) benzoic acid) is the most potent 2-oxindole derivative.⁸ The structure of these compounds provides ample opportunities for both the development of soluble forms and wide structural variations. Small molecules based on 2-oxindole scaffold have a broad spectrum of biological activity.¹⁰ The high druglikeness of these compounds is determined by the fact that 2-oxindole is a tryptophan metabolite and can mimic its affinity to various protein substrates. Antitumor activity, identified for 3-(benzylidene)indolin-2-ones,¹¹ allows to design multitarget compounds that affect both the metabolic signaling cascades of a cancer cell through AMPK and the proliferative signaling pathway by reactivating p53,¹² since high lipophilicity of the considered structures provides potent binding to the active cavity of the MDM2 protein.¹³Despite all the advantages of 2-oxindole derivatives in studying the AMPK activation and the small molecule development, the synthetic routes for obtaining this series remain rather laborious. Here, we present a simple and effective route of C24 synthesis. This route takes into account both the possibility of synthesis of small molecule libraries as well as current trends in organic synthesis.Linear synthesis and convergent synthesis are the main strategies in organic chemistry. The convergent strategy is much more suitable for providing the diversity of a library of complex biologically active compounds. The diversity is realized through divergent stages of the synthetic scheme. However, the divergence of the synthetic scheme at earlier stages leads to the individualization of the synthesis of each compound and, consequently, an increase in the efforts to synthesize a compound library.¹⁴Following the linear scheme, we synthesized C24 from 3-phenylpropiolic acid by amidation with aniline, alkylation with 3-(bromomethyl)benzoic acid methyl ester, ring formation of the resulting intermediate, followed by removal of the ester group (Scheme 1).¹⁵ It is interesting that at the ring formation step we observed the formation of dehalogenated compound along with the target product. The resulting mixture of the products cannot be separated by crystallization. Single crystals of mixed composition are formed when crystallizing (Fig. 1). They can be separated only using reversed-phase silica gel, but extremely low solubility of the esters makes the purification process difficult. In addition to the above difficulties, the first stages of the synthesis are divergent, so to introduce a substituent into ring A it is necessary to obtain substituted phenylpropiolic acid, for example, by the Sonogashira coupling. It appears that the diversity is provided before the most difficult stage of building the carbon skeleton.Open in a separate windowScheme 1Linear scheme of C24 synthesis.Open in a separate windowFig. 1ORTEP representation of the crystal structure corresponding to C₃₀H_22.25Cl_0.75NO₃ crystals.Current synthetic schemes based on propiolic acid have various modifications, including one pot and domino multicomponent ones.¹⁶ However, the modern names do not relieve them of the shortcomings inherent to the linear scheme; moreover, the use of active catalysts can lead to undesirable rearrangements of the carbon skeleton of the target substrate.¹⁷The convergent synthesis (Scheme 2) can be implemented based on the route obtained using obvious disconnections. The simplest way to build the carbon skeleton of substituted alkene oxindoles is to perform the Knoevenagel condensation of oxindole with benzophenones. The condensation of oxindole with aldehydes and alkylphenones proceeds practically with quantitative yields under common conditions: toluene, pyrrolidine, azeotropic distillation of water. Reduction of yields is observed only in the case of ketones and aldehydes substituted in position 2 of the aromatic ring. However, there is the difficulty to realize the condensation of oxindole with benzophenones,¹⁸ and under the same conditions the reaction product is formed only in trace amounts when benzophenone is taken as a carbonyl compound (Open in a separate windowScheme 2Convergent scheme of C24 synthesis.Knoevenagel condensation of carbonyl compounds with unsubstituted oxindole

Rapid and halide compatible synthesis of 2-N-substituted indazolone derivatives via photochemical cyclization in aqueous media

Indazolone derivatives exhibit a wide range of biological and pharmaceutical properties. We report a rapid and efficient approach to provide structurally diverse 2-N-substituted indazolones via photochemical cyclization in aqueous media at room temperature. This straightforward protocol is halide compatible for the synthesis of halogenated indazolones bearing a broad scope of substrates, which suggests a new avenue of great importance to medicinal chemistry.

A straightforward protocol for the rapid construction of privileged indazolone architectures suggests a new avenue of great importance to medicinal chemistry.

The indazolone ring system constitutes the core structural element found in a large family of nitrogen heterocycles as exemplified by those shown in Scheme 1.¹ Indazolone derivatives have been receiving much attention due to their promising pharmacological activities. Given the unique bioactive core skeleton, indazolone derivatives exhibit a wide range of biological and pharmaceutical properties such as antiviral and antibacterial activities (1–4),² new prototypes for antichagasic drugs (5),³ antihyperglycemic properties (6),⁴ TRPV1 receptor antagonists for analgesics (7),⁵ anti-flammatory agents (8),⁶ angiotensin II receptor antagonists (9),⁷ highly potent CDKs inhibitors for anticancer (10)⁸ and so on.⁹ The privileged indazolone structures have high potential as core components for the development of related compounds leading to medicinal agents.Open in a separate windowScheme 1Biologically active molecules containing indazolone skeletons.Due to their versatility in pharmaceutical applications, many synthetic approaches have been developed for the construction of indazolone skeletons (Scheme 2), including CuO-mediated coupling of 2-haloarylcarboxylic acids with methylhydrazine,¹⁰ cyclization of N-aryl-o-nitrobenzamides through Ti(vi) reagent or Zn(ii) reagent,¹¹ Cu(i)-mediated intramolecular C–N bond formation or a base-mediated intramolecular SNAr reaction of 2-halobenzohydrazides,¹² Cu(i)-catalyzed oxidative C–N cross-coupling and dehydrogenative N–N formation sequence,¹³ Rh-catalyzed C–H activation/C–N bond formation and Cu-catalyzed N–N bond formation between azides and arylimidates,¹⁴ Friedel–Crafts cyclization of N-isocyanates using Masked N-isocyanate precursors,¹⁵ PIFA-mediated intramolecular oxidative N–N bond formation by trapping of N-acylnitrenium intermediates,¹⁶ and recently reported reaction of o-nitrobenzyl alcohol with primary amines in basic conditions.¹⁷ These approaches are complementary providing avenue to access various substitution patterns,¹⁸ however most methods rely on the requirements for transition-metal catalysts. In fact, the procedures for synthesis indazolone skeletons from Friedel–Crafts cyclization of N-isocyanates and Davis–Beirut derived reaction still suffer from harsh reaction conditions such as high reaction temperature (i.e. more than 150 °C or 20 equiv. of KOH at 100 °C for 24 h).^15,17b Very recently, one photochemical route was reported for preparation of indazolone skeletons from o-nitrobenzyl alcohols and primary amines,¹⁹ however, this approach still need long reaction time (24 hours) and halogen substituted substrate could not be compatible in the reaction conditions.^19b Thus, the efficient and general methods tolerating a wide scope of readily available starting materials for synthesis of indazolones without a transition-metal catalyst involved are still in great demand.Open in a separate windowScheme 2Representative approaches for the preparation of indazolone skeletons. o-Nitrobenzyl alcohol derivatives have shown many applications in material science and chemical biology area as a photolabile protecting group (Scheme 3a).²⁰ Upon UV light-activation, o-nitrobenzyl alcohol derivatives generate corresponding aryl-nitroso compounds via photoisomerization.²¹ Based on the distinguishing feature of highly reactive of these photogenerated intermediates, we assumed that the reaction conditions would be crucial for the photoisomerization,^20,22 thus the reactive intermediates should spontaneously and rapidly form indazolone structures via cyclization in the presence of primary amines in suitable reaction conditions (Scheme 3b). Herein, we report a rapid and efficient approach to provide structural diversity 2-N-substituted indazolones via photochemical cyclization in aqueous media at room temperature. This photochemical cyclization reaction is halide compatible for synthesis of halogen substituted indazolones, bearing a broad scope of substrates. This straightforward protocol for rapid construction of halogenated indazolone architectures suggests a new avenue of great importance to medicinal chemistry.Open in a separate windowScheme 3Synthesis of indazolone derivatives via photochemical cyclization.The initial investigation to develop a method for synthesis of indazolone derivatives via photochemical cyclization started with 4-(hydroxymethyl)-3-nitro-N-propylbenzamide 11 and heptan-1-amine 12 upon UV light-activation in methanol, smoothly leading to the formation of indazolone 13 in 52% yield ( EntrySolvent11 : 12Time (h)Yield^f (%)1MeOH2.5 : 13522THF2.5 : 13583 n-BuOH2.5 : 13574CH₃CN2.5 : 13615CH₃CN : H₂O = 3 : 12.5 : 13676CH₃CN : PBS = 3 : 12.5 : 1361 7 n-BuOH : H ₂ O = 3:1 2.5 : 1 3 82 8 n-BuOH : PBS = 3 : 12.5 : 13569MeOH : H₂O = 3 : 12.5 : 133810i-PrOH : H₂O = 3 : 12.5 : 136311 tBuOH : H₂O = 3 : 12.5 : 135512THF : H₂O = 3 : 12.5 : 134913DMF : H₂O = 3 : 12.5 : 134514Dioxane : H₂O = 3 : 12.5 : 136715^b n-BuOH : H₂O = 3 : 12.5 : 13<1016^c n-BuOH : H₂O = 3 : 12.5 : 132217^d n-BuOH : H₂O = 3 : 11.5 : 134518^e n-BuOH : H₂O = 3 : 12.5 : 132819 n-BuOH : H₂O = 3 : 12.5 : 168520PBS2.5 : 131921 n-BuOH : H₂O = 3 : 11 : 2.5346Open in a separate window^aReaction conditions: heptan-1-amine (12, 0.3 mmol), 4-(hydroxymethyl)-3-nitro-N-propylbenzamide (11, 0.75 mmol), solvent 6 mL, exposed to UV lamp with 365 nm, at R.T.^bUV lamp with 254 nm.^cUsing blue light.^dThe ratio of 11/12 = 1.5/1.^eReaction carried out at 50 °C.^fIsolated yield.With the optimal conditions in hand, we investigated the generality for the scope of o-nitrobenzyl alcohols and primary amines ( Open in a separate window^aReaction conditions: primary amines (15, 0.3 mmol), o-nitrobenzyl alcohols derivatives (14, 0.75 mmol), solvent 6 mL, isolated yield.Many drug candidates and drugs are halogenated structures. In drug discovery, insertion of halogen atoms on hit or lead compounds was predominantly performed, with the aim to exploit their steric effects and structure–activity relationship, to form halogen bonds in ligand–target complexes, to optimize the ADME/T property.²³ Given the versatility of halogen atom on bioactive molecules, we next investigated the halogen substituted o-nitrobenzyl alcohols as starting materials for construction of indazolone skeletons (17b as well as aniline failed to give product in the recently reported photochemical approach (see ESI, Fig. S1^†).^19b Of note, in the recently reported photochemical approach, the reaction of chloride substituted o-nitrobenzyl alcohol with alkylamine gave indazolone with low yield, possibly because photocleavage of aryl halide bond is involved in that reaction conditions.^19b These outcomes are significant in view of the challenges in construction of indazolone skeletons, in which additional halogen substitution on substrates is incompatible for indazolones synthesis.^10,19b Importantly, our reaction condition is compatible with halide substrates, suggests a new protocol of importance to photochemical reactions, in which dehalogenation of aryl halide is known to be radical-mediated and exist in some reaction conditions.²⁴Scope of halogen substituted o-nitrobenzyl alcohols for indazolone formation^a

Synthesis of tetrahydrochromenes and dihydronaphthofurans via a cascade process of [3 + 3] and [3 + 2] annulation reactions: mechanistic insight for 6-endo-trig and 5-exo-trig cyclisation

Substituted tetrahydrochromenes and dihydronaphthofurans are easily accessible by the treatment of β-tetralone with trans-β-nitro styrene derived Morita–Baylis–Hillman (MBH) acetates through a formal [3 + 3]/[3 + 2] annulation. The reaction proceeds through a cascade Michael/oxa-Michael pathway with moderate to good yields. A DFT study was carried out to account for the formation of the corresponding six and five-membered heterocycles via 6-endo-trig and 5-exo-trig cyclization.

A [3 + 3] and [3 + 2] annulation strategy using nitrostyrene derived MBH primary and secondary nitro allylic acetate for the construction of tetrahydrochromenes and dihydronaphthofurans at room temperature.

The ability to synthesize diverse molecules utilizing nitro allylic MBH acetates in various cascade reactions has received considerable interest.¹ A few molecules synthesized using nitro allylic acetates have shown promising cytotoxic, trypanocidal and AchE inhibition² activity in pharmaceutical and medicinal chemistry. Nitro allylic MBH acetates have been used as main precursors in organocatalysis³ and heterocyclic chemistry,⁴ and as bicyclic skeletons⁵ for the construction of elegant building blocks like tetrahydro-pyranoquinolinones,⁶ sulfonyl furans,⁷ pyranonaphthoquinones,⁸ arenopyrans/arenylsulfanes,⁹ triazoles,^10a tetrasubstituted furans,^10b fused furans,^10c,d tetrasubstituted pyrroles,^11a benzofuranones,^11b and tetrahydropyrano scaffolds/pyranocoumarins.¹² The nitro allylic MBH-acetates can also undergo asymmetric benzylic^13a and allylic alkylation^13b reactions as well as kinetic resolution [KR]^13c,d under normal conditions. These acetates undergo a range of cascade [2 + 3],¹⁴ [3 + 2]¹⁵ and [3 + 3]¹⁶ ring annulation reactions using different substrates. They have been widely utilized in [3 + 2]^17a and [3 + 3]^17b annulation reactions due to their unique nature of 1,2-/1,3-biselectrophilic reactivity to form either five or six membered rings depending on the nature of nucleophiles employed in the reaction^17c,d These adducts are also stable under NHC catalytic conditions to yield cyclopentanes.¹⁸Peng-Fei Xu et al. (Scheme 1, eqn (a)) synthesised tetrahydropyranoindoles through organocatalytic asymmetric C–H functionalization of indoles via [3 + 3] annulation through 6-endo trig cyclization.¹⁹ The Namboothiri group recently developed a metal free regioselective synthesis of α-carbolines via [3 + 3] annulation involving secondary MBH acetate (Scheme 1, eqn (b)).²⁰ Previously, our group carried out a [3 + 3] cyclization reaction of β-naphthol with primary MBH acetate to study the scope of S_N2′ vs. S_N2 reaction.²¹ With our ongoing interest in using nitro styrene derived MBH adducts²² explored the reactivity of primary and secondary MBH acetate with β-tetralone 1 as our model reaction. Initially, the reaction carried out using β-tetralone 1 with primary MBH-acetate 2, predominantly gave a tetrahydrochromene 3via [3 + 3] annulation involving 6-endo trig cyclization through Michael/oxa-Michael cascade process. The possible dihydronaphthofuran product was not observed under the present conditions as primary MBH acetate 2 acts as 1,3-biselectrophile instead of 1,2-biselectrophile (Scheme 1, eqn (c)).Open in a separate windowScheme 1[3 + 3] and [3 + 2] annulation reactions using 1°- and 2°-nitro allylic MBH acetate.On the other hand, the reaction of β-tetralone 1 with secondary MBH acetate 4 gave dihydronaphthofuran instead of the possible tetrahydrochromene product due to the 1,2-biselectrophile nature of secondary MBH acetate (Scheme 1, eqn (d)). The formation of dihydronaphthofuran 5 occurs in an S_N2′ fashion via [3 + 2] annulation involving 5-exo-trig cyclization through Michael followed by intramolecular oxa-Michael reaction with the elimination of HNO₂. Subsequently, we have carried out a DFT calculation to prove the formation of tetrahydrochromene 3 using primary MBH acetate 2 and dihydronaphthofuran 5 in the case of secondary MBH acetate 4.Initially, we carried out the optimization conditions for constructing tetrahydrochromenes 3a using β-tetralone 1 with MBH nitro allylic primary acetate 2a with different bases and solvents. Reaction with organic base, i.e. DABCO using a polar aprotic solvent such as acetonitrile at room temperature gave the desired product in 27% (23 (CCDC-2149875) ( EntryBaseSolventTime (h)Yield (%)dr^b1DABCOCH₃CN52799 : 12DABCOCH₂Cl₂52299 : 13DABCOCHCl₃51999 : 14DMAPTHF54099 : 15TEATHF54599 : 16PPh₃THF54499 : 17K₂CO₃THF46099 : 1 8 Cs ₂ CO ₃ THF 4 77 99 : 19^cCs₂CO₃THF85099 : 110^dCs₂CO₃THF56199 : 111^eCs₂CO₃THF46599 : 112^fCs₂CO₃THF460n.dOpen in a separate window^aUnless otherwise noted, reactions were carried out by and (0.11 mmol) of 1 with (0.11 mmol) of 2a using 0.22 mmol of a base in 1 ml of THF solvent.^bDetermined by ¹H-NMR analysis of crude reaction mixture.^cReaction was carried out using 0.5 equiv. of Cs₂CO₃.^dReaction was carried out using 1.0 equiv. of Cs₂CO₃.^eReaction was carried out using 1.5 equiv. of Cs₂CO₃.^fReaction was carried out using 3.0 equiv. of Cs₂CO₃.Substrate scope for tetrahydrochromenes 3a–f

Palladium catalyst immobilized on functionalized microporous organic polymers for C–C coupling reactions

Two microporous organic polymer immobilized palladium (MOP-Pd) catalysts were prepared from benzene and 1,10-phenanthroline by Scholl coupling reaction and Friedel–Crafts reaction, respectively. The structure and composition of the catalyst were characterized by FT-IR, TGA, N₂ sorption, SEM, TEM, ICP-AES and XPS. MOP-Pd catalysts were found to possess high specific surface areas, large pore volume and low skeletal bone density. Moreover, the immobilized catalyst also had advantages, such as readily available raw materials, chemical and thermal stability, and low synthetic cost. The Pd catalyst is an effective heterogeneous catalyst for carbon–carbon (C–C) coupling reactions, such as the Heck reaction and Suzuki–Miyaura reaction, affording good to high yields. In these reactions, the catalyst was easily recovered and reused five times without significant activity loss.

Two microporous organic polymers were prepared from 1,10-phenanthroline by Scholl coupling reaction and Friedel–Crafts reaction, and applied to Heck reaction and Suzuki–Miyaura reaction as heterogeneous catalysts.

Carbon–carbon (C–C) coupling reactions have become one of the most versatile and utilized reactions for the selective construction of C–C bonds for the formation of functionalised aromatics,¹ natural products,² pharmaceuticals,³ polymers⁴ and advanced materials.⁵ Many transition metals have been used as catalysts in these reactions, aided by a great variety of ligands ranging from simple, commercial phosphines to complex custom-made molecules.⁶ Among these transition metals, palladium plays a significant role in various cross-coupling reactions, such as Suzuki,⁷ Heck,⁸ Sonogashira,⁹ Stille,¹⁰ and Ullmann coupling reactions,¹¹ due to their strong electrical and chemical properties.¹² Over the past decades, various homogeneous catalytic systems have been developed for organic transformations,¹³ which often progress smoothly under the inert atmosphere in organic solvents, for example, toluene or tetrahydrofuran in the presence of soluble palladium complexes as catalysts. However, most homogeneous palladium catalysts suffer from drawbacks such as high-cost of phosphine ligands, use of various additives, difficult separation, metal leaching, recovery, recyclability, and the toxicity of phosphine ligands.Heterogeneous catalysis have attracted increasing attention as they have been proven to be useful for different organic reactions owning to their unique properties, such as high reactivity, stability, easy separation, purification and recyclability.¹⁴ Many active heterogeneous palladium catalysts have been developed and widely applied in the C–C coupling reactions.¹⁵ Palladium has been immobilized on various solid supporting materials, such as zeolite,¹⁶ silica,¹⁷ metal organic frameworks,¹⁸ and functionalized graphene oxide.¹⁹ However, a substantial decrease in activity and selectivity of the heterogeneous palladium catalysts is frequently observed because of their long diffusion pathway to catalytic sites and the difference of electron density on active sites. To address these problems, materials with larger interface and more active site are employed to support palladium as heterogeneous catalysts, such as palladium immobilized on hyper-crosslinked polymers were high activity in Suzuki–Miyaura coupling reaction.²⁰Microporous organic polymers (MOPs) consists of purely organic elements have recently emerged as versatile platforms for heterogeneous catalysts thanks to their unique properties, including superior chemical, thermal and hydrothermal stability, synthetic diversity, low skeletal density and high surface area.^20,21 More importantly, the bottom–up approach of MOPs provides an opportunity for the design of polymer frameworks with a range of functionalities into the porous structure to use as catalysts or ligands.²² Recently, Kaskel reported the incorporation of a thermally fragile imidazolium moiety into MOPs resulted in a heterogeneous organocatalyst active in carbene-catalyzed Umpolung reaction.²³ Wang designed photocatalysts with microporous via the copolymerization from pyrene and dibenzothiophene-S,S-dioxide building blocks and tested the effect of the photocatalytic hydrogen evolution.²⁴ Xu described the synthesis of microporous with N-heterocyclic carbenes by an external cross-linking reaction and applied it in Suzuki reaction.²⁵ Zhou demonstrated for the first time that the microporous structure has a positive effect on controlling selectivities in the hydrosilylation of alkynes.²⁶ Recently, we also reported three pyridine-functionalized N-heterocyclic carbene–palladium complexes and its application in Suzuki–Miyaura coupling reactions.²⁷1,10-phenanthroline is an ideal candidate of ligands due to its structural features such as two N-atom placed in juxta position to provide binding sites for metal cations.²⁸ To utilize the unique structure feature, we employed it in the construction of MOPs via Scholl and Friedel–Crafts reaction, respectively. Therefore, this paper presents our recent studies on the synthesis of two heterogeneous palladium catalysts supported on MOPs through a simple and low-cost procedure. These catalysts displayed remarkable catalytic activity in C–C coupling reactions, including Suzuki–Miyaura reaction and Heck coupling reaction. The properties of simple preparation, wide application of this catalyst and good performance in C–C coupling reactions and adaptability with various substrates make it perfect catalytic option for C–C coupling reactions.The microporous network with 1,10-phenanthroline functional groups and incorporation of Pd metal were confirmed by Fourier transform infrared (FT-IR) spectroscopy. The FT-IR spectra of MOPs and MOPs-Pd (Fig. 1) displayed a series of bands around 2800–3100 cm⁻¹, which were assigned to the C–H stretching band and in-of-plane bending vibrations of the aryl rings. The bands around 1550–1750 cm⁻¹ were attributed to the –C N- stretching band. The bands around 1400–1450 and 850–700 cm⁻¹ were corresponded to the benzene and 1,10-phenanthroline skeletal stretching and the C–H out-of-plane bending vibrations of the aryl rings, respectively. The bond around 1495 cm⁻¹ in MOPs-I and MOPs-Pd-I is assigned to in-of-plane bending vibrations of CH₂, which indicated that 1,10-phenanthroline and benzene were linked by CH₂.Open in a separate windowFig. 1FT-IR spectra of MOPs and MOPs-Pd.The X-ray photoelectron spectroscopy (XPS) analysis of the MOPs-Pd is performed to investigate the coordination states of palladium species (Fig. 2). In Fig. 2, the Pd 3d XPS spectra of the MOPs-Pd-I catalysts reveal that Pd is present in the +2 oxidation state rather than in the metallic state. This is corresponding to the binding energy (B.E.) of 337.4 eV and 342.4 eV, which are assigned to be Pd 3d_5/2 and 3d_3/2 of Pd (+2), respectively. Compared with the PdCl₂ (337.9 eV and 343.1 eV), the Pd²⁺ binding energy in the MOPs-Pd-I catalyst shifts negatively by 0.5 eV and 0.7 eV. This can be attributed to the effect of the coordination with 1,10-phenanthroline in microporous networks. The results show that Pd²⁺ can be immobilized successfully on the MOPs by coordinating to 1,10-phenanthroline rather than by physical adsorption of Pd²⁺ on the surface. XPS graphs of MOPs-Pd-II also reveal that Pd²⁺ is immobilized on MOPs materials.Open in a separate windowFig. 2XPS spectra of the MOPs-Pd.The surface area and pore structure of the MOPs and MOPs-Pd were investigated by nitrogen adsorption analyses at 77.3 K. In Fig. 3, the MOPs-Pd exhibits type I adsorption–desorption isotherms, which is similar to the isotherms exhibited by the parent MOPs polymers. The result implies that these microporous organic polymers and metalized polymers consist of both micropores and mesopores. The apparent Brunauer–Emmett–Teller surface areas (S_BET) of MOPs-Pd are smaller than those of the non-metallized parent networks (Open in a separate windowFig. 3N₂ adsorption–desorption isotherms and corresponding pore size distributions of MOPs and MOPs-Pd.Physical properties of MOPs and MOPs-Pd