Heterogeneous Organocatalyst Research Articles

A convenient one-pot –three component syntheses of a new diaminophosphonate via heterogeneous organo-catalyst, and its application for titanium recovery: design, optimization and kinetic aspects

A convenient one-pot –three component syntheses of a new diaminophosphonate via heterogeneous organo-catalyst, and its application for titanium recovery: design, optimization and kinetic aspects

Synthesis and Characterization of New Chiral Polyurea‐Polyurethane Nanocomposites Incorporating Cinchona‐Derived Urea Organocatalysts

AbstractThe field of asymmetric organocatalysis has witnessed significant advancements in recent years, with chiral urea and thioureas emerging as powerful catalysts. In this study, we aimed to design novel polyurea‐polyurethane nanocomposites functionalized with cinchona urea groups, incorporating organoclay and graphene oxide, to serve as heterogeneous organocatalysts in asymmetric synthesis. The synthesis of these polyurea‐polyurethane nanocomposites was achieved through a two‐component polycondensation reaction. The resulting chiral polyurea‐polyurethanes (PU‐PURs) exhibited favorable yields and demonstrated precise control over stereochemistry, resulting in high enantioselectivity. The incorporation of nanocomposites, such as CU‐MMT and graphene oxide (GO), significantly enhanced the catalytic performance of the PU‐PURs. The CU‐MMT nanocomposites exhibited higher catalytic activity, while the PU‐PURs/GO still exhibited enantioselectivity greater than 99 %. Overall, this study highlights the potential of these novel polyurea‐polyurethane nanocomposites as efficient and versatile heterogeneous organocatalysts in asymmetric synthesis.

MPC@But-SO3H a mesoporous heterogeneous organocatalyst in one-pot tandem synthesis of dihydroindeno[1,2-b]pyrrole derivatives

A sustainable, metal-free, and highly efficient protocol for the synthesis of dihydroindeno[1,2-b]pyrrole derivatives via a tandem one-pot three-component reaction in aqueous medium at room temperature using an effective and reusable mesoporous heterogeneous organocatalyst, MPC@But-SO3H has been developed. MPC@But-SO3H was easily synthesized using a melamine-based covalent organic polymer and 1,4-butane sultone. The organocatalyst was well characterized by numerous spectroscopic techniques such as Fourier Transform Infrared (FTIR), Brunauer-Emmett-Teller (BET), X-ray photoelectron spectroscopy (XPS), Powder X-ray diffraction (PXRD), Scanning Electron Microscope (SEM), Energy Dispersive X-ray (EDX), elemental mapping, and Thermal Gravimetric (TG) analyses. The catalyst displayed excellent catalytic potential, high thermochemical stability, and reusability for up to eight catalytic cycles. It offered the title compounds in excellent yields (˃90%) in a short reaction time (9-14 min). The synthesized compounds were characterized through FTIR, 1H, and 13C Nuclear Magnetic Resonance (NMR), and the molecular structure of 2-(benzylamino)-3a,8b-dihydroxy-1-methyl-3-nitro-3a,8b-dihydroindeno[1,2-b]pyrrol-4(1H)-one (4a) was confirmed by the Single Crystal XRD (SC-XRD) analysis. The key features of the present protocol include the use of water as a green solvent, zero involvement of any metal, sustainable reaction conditions, easy catalyst recovery, and a simple work-up procedure. The calculations for green metrics parameters further supported the greenness and sustainability of the protocol.

MTP−IL] as Mesoporous Heterogeneous Organocatalyst for the One‐Pot Synthesis of Indeno [1,2‐b] Quinoxalin‐11‐Ylidenamine Derivatives: A Green, Sustainable, and Metal‐Free Protocol

AbstractHerein, we report a green, sustainable, and metal‐free, one‐pot three‐component protocol for the synthesis of indeno [1, 2‐b] quinoxalin‐11‐ylidenamine derivatives using a novel, effective, and recyclable mesoporous heterogeneous organocatalyst [MTP−IL]. [MTP−IL] was constructed by immobilizing an imidazolium‐cation‐based ionic liquid on a melamine−terephthalaldehyde covalent organic polymer and was thoroughly characterized using several analytical techniques. It displayed high thermochemical stability and catalytic efficacy, offering title compounds with 90–94 % yields in a short reaction time, and was recyclable for up to six cycles. The synthesized compounds were characterized through FTIR, 1H, and 13C Nuclear Magnetic Resonance (NMR), and the molecular structure of N′‐(11H‐indeno[1,2‐b]quinoxalin‐11‐ylidene)benzohydrazide (7) was confirmed by the Single Crystal XRD (SCXRD) analysis. The key features of the present protocol are the use of ethanol as a green solvent, easy catalyst recovery, a simple work‐up procedure, and zero involvement of any metal.

Mesoporous MPC@TMG, a basic heterogeneous organocatalyst in C–C/C–N bond forming reactions: Tandem multicomponent synthesis of 5-amino-pyrazole-4-carbonitriles and 1H-pyrazolo [1,2-b] phthalazine-5, 10-dione derivatives under sustainable reaction conditions

A metal-free, effective, and sustainable protocol has been developed to carry out C–N and C–C bond-forming reactions leading to the formation of 5-amino-pyrazole-4-carbonitriles and 1H-pyrazolo [1,2-b] phthalazine-5, 10-dione derivatives via a tandem multicomponent reaction using mesoporous MPC@TMG as a basic heterogeneous organocatalyst. The reactions were performed in aqueous medium at room temperature. The synthesized organocatalyst MPC@TMG was characterized by numerous spectroscopic techniques such as Fourier Transform Infrared (FTIR), Powder X-ray diffraction (PXRD), Brunauer-Emmett-Teller (BET), Scanning Electron Microscope (SEM), Energy Dispersive X-ray (EDX), elemental mapping, and Thermal Gravimetric (TG) analyses. MPC@TMG displayed excellent catalytic potential, high thermochemical stability, and reusability for up to eight catalytic runs and offered the title compounds in excellent yields (>90 %) in a short reaction time (6–15 min). The synthesized compounds were characterized through FTIR, 1H, and 13C Nuclear Magnetic Resonance (NMR) spectroscopy. The use of water as a green solvent, the generality of the method, easy catalyst recovery, a simple work-up procedure, and zero involvement of any metal are the key features of the present protocol making it green and sustainable for the synthesis of the desired heterocycles and is supported by the calculations for green metrics parameters.

Easy functionalization of carbon nano-onions with disulfides and their use as recyclable heterogeneous organocatalysts

A facile functionalization of carbon nano-onions (CNO), through an atom economical one-step process, with a series of different generation (2.0, 2.5, and 3.0G) poly(amidoamine) (PAMAM) dendrimers with a cystamine core and endowed with either methyl ester or amino groups in the periphery has been reported. The radical addition reaction onto CNO surface, after the homolytic rupture of the S–S bond of cystamine, afforded CNO-PAMAM hybrids, which were extensively characterized using various analytical and spectroscopic techniques such as thermogravimetric analysis (TGA), attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, solid state 13C NMR, Raman, X-ray photoelectron spectroscopy (XPS), dynamic light scattering (DLS) and zeta potential (ZP). Morphological and textural properties were also investigated by high-resolution transmission electron microscopy (HRTEM) analysis and N2 adsorption/desorption isotherms. Furthermore, the presence and availability of –NH2 groups has been demonstrated by applying the functionalized CNO with PAMAM 2.0G and 3.0G as heterogeneous and recyclable organocatalysts in the one-pot three-component synthesis of 2-amino-4H-chromene derivatives.

Heterogeneous Organocatalysts for Light-Driven Reactions in Continuous Flow.

Within the realm of organic synthesis, photocatalysis has blossomed since the beginning of the last decade. A plethora of classical reactivities, such as selective oxidation of alcohol and amines, redox radical formation of reactive species in situ, and indirect activation of an organic substrate for cycloaddition by EnT, have been revised in a milder and more sustainable fashion via photocatalysis. However, even though the spark of creativity leads scientists to explore new reactions and reactivities, the urgency of replacing the toxic and critical metals that are involved as catalysts has encouraged chemists to find alternatives in the branch of science called organocatalysis. Unfortunately, replacing metal catalysts with organic analogues can be too expensive sometimes; however, this drawback can be solved by the reutilization of the catalyst if it is heterogeneous. The aim of this review is to present the recent works in the field of heterogeneous photocatalysis, applied to organic synthesis, enabled by continuous flow. In detail, among the heterogeneous catalysts, g-CN, polymeric photoactive materials, and supported molecular catalysts have been discussed within their specific sections, rather than focusing on the types of reactions.

A novel approach to l-tryptophan grafting on mesoporous MCM-41: A recoverable heterogeneous material for organocatalyzed benzo[N,N]-heterocyclic condensation

An unprecedented strategy has been developed to introduce l-tryptophan into MCM-41 by binding the indolic NH group of l-tryptophan to modified MCM-41, resulting in the creation of l-Tryp-N-pMCM-41. Initially, 3-Cl-pMCM-41 was prepared by modifying activated MCM-41 with 3-chloropropyltrimethoxysilane. Subsequently, the covalent attachment between the indolic NH group of l-tryptophan and 3-Cl-pMCM-41 was achieved using n‑butyl lithium in THF at -78 °C under an argon atmosphere. l-Tryp-N-pMCM-41 has been characterized by FT-IR, XRD, TGA, EDS, BET and nitrogen physisorption measurements. The organocatalytic performance of this chemically stable material was assessed in the synthesis of both symmetrical and unsymmetrical quinoxalines. The reaction involved the condensation of a series of aromatic 1,2-diamines with 1,2-diketones in methanol at room temperature. Overall, the organocatalytic reaction proceeded smoothly to afford the corresponding quinoxalines in moderate to excellent yields. Furthermore, the crystal structure of an unsymmetrical quinoxaline has been determined by single crystal X-ray diffraction. This metal-free procedure offers several noteworthy advantages, including the simplicity of the reaction, minimal catalyst usage, recyclability of the catalyst and environmentally friendly characteristics. Moreover, this green heterogeneous organocatalyst is a suitable candidate for preparing various valuable pharmaceutical compounds under ambient conditions avoiding the use of strong acids and without any possibility of metal contamination.

Dicationic ionic liquid immobilized on polystyrene as an acidic, reusable, and efficient heterogeneous organocatalyst in organic transformations

Supported ionic liquids onto solid catalysts are among the most popular catalysts in chemical reactions with several unique advantages. However, the harsh reaction conditions, long reaction times, low product yields, and tedious work-up, are still the challenges for its application. A novel polystyrene-modified dicationic ion liquid [PS-(Im)2-SO3H] was synthesized through the reaction of chloromethyl polystyrene with imidazole, 1,4-dichlorobutane and 1,3-propanesultone. Its structure was characterized and confirmed using Fourier Transform Infrared spectroscopy (FT-IR), Thermogravimetric analysis (TGA), X-ray diffraction (XRD), Dynamic Light Scattering (DLS), Scanning Electron Micrograph (SEM), Energy Dispersive Spectroscopy (EDS), and Elemental analyses. This polymer-supported dicationic ion liquid was used as an acidic heterogeneous catalyst for the synthesis of xanthene derivatives through condensation of aldehydes, dimedone, and β-naphthol. The products were obtained in high yields (88–97 %) at room temperature and short reaction time in ethanol as a green solvent. The reaction mixture was easily filtered to isolate the heterogeneous catalyst, which could be reused for at least eight cycles without any significant activity loss.

Ionic hyper-cross-linked porous polymer networks with achiral and chiral pyridinium-type segments

A new type of ionic porous polymer networks (PPNs) is reported containing (i) N-alkyl pyridinium bromide ionic groups and (ii) a hyper-cross-linked scaffold based on polyacetylene (polyene) chains the rigidity of which contributes to the permanent porosity the PPNs. The ionic PPNs were prepared by a combination of chain-growth polymerization of acetylenic monomers and quaternization reactions of pyridine and alkyl bromide moieties. The wide variability of this synthetic concept enabled the preparation of covalently diverse PPNs with ionic groups located either in the pendant groups or in the knots of the networks, as well as the preparation of PPNs with chiral ionic groups. The content of ionic groups in PPNs ranged from 1.5 to 4.2 mmol/g, and the BET area was from 67 to 744 m2/g. The mode of quaternization used (prepolymerization or postpolymerization) controlled the contribution of micropores and mesopores to the porosity of the ionic PPNs. The polyacetylene ionic PPNs were active as heterogeneous organocatalysts (applied without a cocatalyst) for the cycloaddition of CO2 to styrene oxide yielding styrene carbonate as the only product (up to 96 %). PPNs with chiral ionic groups showed potential for enantioselective catalysis of this reaction. The catalytic activity was controlled by the accessibility of pyridinium active centres for the substrate molecules. Ionic PPNs prepared were also efficient in reversible water vapour capturing and releasing (capacity up to 361 mg/g at 298 K and RH = 90 %). Both surface adsorption and capillary condensation of H2O contributed to the water vapour capture on reported PPNs.

SB‐2 cationic resin: an efficient and reusable organocatalyst for the synthesis of α‐aminophosphonates, DFT calculations and, computer aided design in antifungal activity

AbstractSB‐2 cationic resin has been employed as an unexpected and reusable heterogeneous organocatalyst in multicomponents reaction for the synthesis of the α‐aminophosphonates derivatives that act as antifungal agents, this reaction proceeds under eco‐friendly and simple procedure by condensation in one pot of substituted aromatic aldehydes, anilines and diethylphosphite. Excellent isolated product yields are obtained (up to 70 %) for (4 a–o) within shorter reaction times in solvent‐free condition. The synthesized compounds were determined by spectroscopic analyses such as: NMR (1H, 13C and 31P), IR and HRMS.Molecular geometries, electronic properties, stability and reactivity such as: HOMO/LUMO, , dipole moment (6.1308<D<10.5829), electronegativity (2.3490<X<3.5892), electrophilicity (1.1046<ω<3.2185) and the calculated thermodynamic descriptors (Zero‐point Energies, Enthalpy and Gibbs Free Energy) of four trimethoxy α‐aminophosphonates derivatives (4 j, 4 k, 4 l and 4 m) were carried by DFT at B3LYP 6‐31G (d, p) basis set. Computer aided design by molecular docking of studied compounds revealed a good binding energy against 5HS1 receptor to be considered as antifungal candidates and compared with Voriconazole. In additionally, druglikeness parameters of selected compounds were found through in silico pharmacological ADME/T properties estimation.

Novel porous organic polymer supported chloramphenicol base derivatives: A highly enantioselective, recyclable heterogeneous organocatalyst for asymmetric desymmetrization reaction

A series of porous organic polymer (POP) supported chloramphenicol base (ANP) derived catalysts are designed and prepared. A deep study of the polymerization condition, including reaction temperature, the ratio of monomers and the option of polymetric position on ANP scaffold was conducted. The best catalyst, poly-Ia, performs high stereoselectivity and catalytic activity (up to 98% yield and 99% ee) in asymmetric alcoholysis of meso-cyclic anhydride with the possibility of high recyclability (at least 10 times). More importantly, poly-Ia even obtains higher enantioselectivity compared to its homogeneous monomer, which overcomes the common drawback of heterogeneous organocatalysts, for instance, lower selectivity and diminished reactivity.

Magnetic decorated 5-sulfosalicylic acid grafted to chitosan: A solid acid organocatalyst for green synthesis of quinazoline derivatives

In this research, a new magnetically decorated multifunctional solid acid was designed and prepared conveniently by grafting of 5-sulfosalicylic acid (SSA) onto the chitosan (CS) backbone using toluene-2,4-diisocyanate (TDI) linker for the first time. The obtained magnetic biopolymeric nanomaterial, CS-TDI-SSA-Fe3O4, was properly characterized by using spectroscopic, microscopic, or analytical methods including FT-IR, EDX, XRD, BET, FESEM, TGA, and VSM. The supramolecular CS-TDI-SSA-Fe3O4 nanocomposite was investigated, as a heterogeneous organocatalyst, to promote the three-component synthesis of 2,3-dihydroquinazoline-4(1H)-one derivatives under green conditions. The solid acidic CS-TDI-SSA-Fe3O4 nanocatalyst demonstrates highly efficient activity for the synthesis of a wide range of quinazoline derivatives, as an important pharmaceutical scaffold, through the multicomponent strategy. The reaction proceeds very well in the presence of CS-TDI-SSA-Fe3O4 solid acid in EtOH to afford corresponding 2,3-dihydroquinazoline-4(1H)-one (DHQ) derivatives in high to excellent yields. The key advantages of the present protocol are the use of a novel, renewable, biopolymeric, and biodegradable solid acid as well as a simple procedure for the preparation of the hybrid material. Furthermore, the CS-TDI-SSA-Fe3O4 catalyst can be used at least five times for the synthesis of DHQ derivatives with a slight decrease in its catalytic activity.

Preparations of spherical nanoparticles of chiral Cinchona alkaloid-based bridged silsesquioxanes and their use in heterogeneous catalysis of enantioselective reactions.

Two spherical nanoparticulate materials were prepared by base-catalyzed sol-gel hydrolysis/self-condensation of the bis-Cinchona alkaloid-phthalazine-based bridged bis(triethoxysilanes). For the purpose of comparing the catalytic properties, two compact materials were also prepared from the same precursors using a fluoride-catalyzed sol-gel process. All materials were characterized by SEM, TEM, solid-state 29Si NMR and 13C NMR, TGA, and FTIR. The prepared silsesquioxane-based materials were studied as potential heterogeneous catalysts for selected enantioselective reactions. The spherical material with regularly incorporated bis-quinine-phthalazine chiral units exhibited good to excellent enantioselectivities in osmium-catalyzed dihydroxylations of alkenes. Enantioselectivities observed in dihydroxylations of aromatic trans-alkenes were as excellent as those observed with the homogeneous catalyst (DHQ)2-PHAL. One compact and one nanoparticulate material was successfully recycled and reused five times without loss of enantioselectivity. Furthermore, both quinine-based and cinchonine-based materials were tested as heterogeneous organocatalysts for chlorolactonization of 4-arylpent-4-enoic acids. The materials showed only moderate enantioselectivities; however, these are the first heterogeneous catalysts for enantioselective chlorolactonization published so far.

Heterogeneous solvent-metal-free aerobic oxidation of alcohol under ambient conditions catalyzed by TEMPO-functionalized porous poly(ionic liquid)s.

Heterogeneous solvent-metal-free aerobic oxidation of alcohols under ambient conditions is interesting but remains a significant challenge. Herein, a series of porous TEMPO-functionalized poly(ionic liquid)s (TEMPO-PILs) featuring a pure polycationic framework were successfully developed through the free radical polymerization of the ionic liquid 3-(2-chloroacetic acid-2,2,6,6-tetramethyl-1-oxo-4-piperidyl)-1-vinylimidazolium chloride and bis-vinylimidazolium bromide salt. Characterizations revealed that the obtained TEMPO-PILs possessed a high TEMPO density, abundant bromide ions, and a tunable porous structure, which enabled them to serve as solvent-free heterogeneous organocatalysts for the metal-free aerobic oxidation of benzyl alcohol under ambient conditions, exhibiting high catalytic activity and stable recyclability. A high yield of 99% coupled with a turnover frequency (TOF) of 13.3 h-1 was obtainable, which is higher than most of the reported TEMPO-based heterogeneous catalysts, even superior to homogeneous TEMPO-functionalized ionic liquids. Furthermore, a broad range of alcohols were effectively converted into their corresponding ketones and aldehydes. A possible reaction mechanism is proposed for understanding the catalytic oxidation behavior, indicative of the synergistic effect of TEMPO moieties and bromide ions.

Enantioselective Amination of 4-Substituted Pyrazolones Catalyzed by Oxindole-Containing Thioureas and by a Recyclable Linear-Polymer-Supported Analogue in a Continuous Flow Process.

A highly efficient organocatalytic amination of 4-substituted pyrazolones with azodicarboxylates mediated by a novel quinine-derived thiourea with a 3,3-diaryl-oxindole scaffold is reported. This synthetic method furnished 4-amino-5-pyrazolones in high yields and with excellent enantioselectivities (up to 97:3 er) at room temperature in short reaction times. Moreover, a linear-polymer-supported bifunctional thiourea, synthesized by reacting a bifunctional aromatic monomer (biphenyl) with isatin in superacidic media and further derivatization, was proven to be also an efficient heterogeneous organocatalyst for this α-amination reaction. The practical value of this process was demonstrated by the use of the immobilized catalyst in recycling experiments, maintaining the activity without additional reactivation, and in flow processes, allowing the synthesis of 4-amino-pyrazolone derivatives in a gram scale with high yield and enantioselectivity.

Concerted Hydrosilylation Catalysis by Silica-Immobilized Cyclic Carbonates and Surface Silanols.

Developing a method for creating a novel catalysis of organic molecules is essential because of the growing interest in organocatalysis. In this study, we found that cyclic carbonates immobilized on a nonporous or mesoporous silica support showed catalytic activity for hydrosilylation, which was not observed for the free cyclic carbonates, silica supports, or their physical mixture. Analysis of the effects of linker lengths and pore sizes on the catalytic activity and carbonate C=O stretching frequency revealed that the proximity of carbonates and surface silanols was crucial for synergistic hydrosilylation catalysis. A carbonate and silanol concertedly activated the silane and aldehyde for efficient hydride transfer. Density functional theory calculations on a model reaction system demonstrated that both the carbonate and silanol contributed to the stabilization of the transition state of hydride transfer, which resulted in a reasonable barrier height of 16.8 kcal mol-1. Furthermore, SiO2/carbonate(C4) enabled the hydrosilylation of an aldehyde with an amino group without catalyst poisoning, owing to the weak acidity of surface silanols, in sharp contrast to previously developed acid catalysts. This study demonstrates that immobilization on a solid support can convert inactive organic molecules into active and heterogeneous organocatalysts.

GO Treated with Aminoethyl‐Piperazine as a Reusable and Eco‐friendly Organocatalyst for Synthesis of Some Xanthen and Pyran Derivatives

AbstractGraphene Oxide (GO) containing 1‐(2‐aminoethyl) piperazine as a reusable, highly efficient and heterogeneous organocatalyst was prepared using a simple and green way. Epoxide groups on the surface of GO layers were replaced with 1‐(2‐aminoethyl) piperazine by an easy and green technique in a mild condition. The prepared catalyst (GO‐A.P.) was characterized using diverse microscopic and spectroscopic techniques. The presence of organic functional groups on the surface of GO‐A.P. was confirmed by Fourier transform infrared and Raman spectroscopy. X‐ray diffraction analysis showed an increase in the catalyst's interlayer spaces which confirm the successful presence of 1‐(2‐aminoethyl) piperazine molecules on the GO surface. Also interaction between the organic molecules and GO was established by thermogravimetric analysis via weight loss steps. Then, the capability of this catalyst was evaluated in a three‐component coupling reaction for one‐pot synthesis of 12‐aryl‐8,9,10,12‐tetrahydrobenzo[a]xanthen‐11‐one (A1–A7) and also 2‐amino‐4H‐pyrans (B1–B8) derivatives. The target products were obtained in high isolated yields. Furthermore, our catalyst was reusable at least for 5 runs with no significant decrease in its activity.

Ionic liquid supported on mesoporous Pd/SBA-15 during the manufacture of 1,3-butadiene using ethanol at lower temperature reaction

Investigating the heterogeneous organo-catalysts such as 1-Ethyl-3-methylimidazolium trifluoromethanesulfonate upon SBA-15, which includes one percent palladium, and their ability to produce 1,3-butadiene from ethanol while supporting them on mesoporous materials. SBA-15 and metal precursors were mixed together and crushed in solid state. By using the TGA, N2 adsorption–desorption, TEM, and XRD procedures, the produced catalysts were studied. Once an organic motif was added to SBA-15, the solid-state grinding procedure produced more accessible acid sites on the catalyst and increased the dispersion of Pd metal. In a fixed-bed reactor, the catalytic performance was assessed, and a selectivity of up to 82% for 1,3-butadiene was achieved. This is brought on by the coupling activity of Pd and ionic liquid species in the porous structure of SBA-15, where the ionic liquid catalyst promotes ethanol dehydrogenation while Pd promotes aldol condensation The solvent-free method also served as the inspiration for a fresh way of synthesizing catalysts for the formation of 1,3-butadiene using ethanol.

POLITAG-M-F as Heterogeneous Organocatalyst for the Waste-Minimized Synthesis of β-Azido Carbonyl Compounds in Batch and under Flow Conditions.

We herein report a waste minimization protocol for the β-azidation of α,β-unsaturated carbonyl compounds using TMSN3. The selection of the appropriate catalyst (POLITAG-M-F), in combination with the reaction medium, resulted in enhanced catalytic efficiency and a low environmental footprint. The thermal and mechanical stability of the polymeric support allowed us to recover the POLITAG-M-F catalyst for up to 10 consecutive runs. The CH3CN:H2O azeotrope has a 2-fold positive effect on the process, increasing the efficiency of the protocol and minimizing waste generation. Indeed, the azeotropic mixture, used as a reaction medium and for the workup procedure, was recovered by distillation, leading to an easy and environmentally friendly procedure for product isolation in high yield and with a low E-factor. A comprehensive evaluation of the environmental profile was performed by the calculation of different green metrics (AE, RME, MRP, 1/SF) and a comparison with other literature available protocols. A flow protocol was defined to scale-up the process, and up to 65 mmol of substrates were efficiently converted with a productivity of 0.3 mmol/min.