Microwave-Assisted Kabachnik–Fields Reaction for the Synthesis ofα-Aminophosphonate Derivatives: A Fast and Effective Approach

Microwave-assisted organic synthesis is an area of increasing interest for promoting clean, reproducible, high-yielding reactions under mild conditions.1,2 This is evident from the large number of papers and reviews that have appeared on this topic in the recent literature.3–8 In the current work, microwave irradiation was employed to facilitate the intermolecular formation of C–C bonds using a palladium-catalyzed Heck coupling reaction. Microwave conditions have previously been used to accelerate this type of reaction9,10 as well as other metal-catalyzed processes such as the Suzuki, Sonogashira and Negishi couplings.11,12 However, the use of microwave irradiation to induce reactions of highly functionalized molecules has not been studied in detail. We, therefore, wish to report our work on a microwave-assisted Heck reaction to prepare a series of antibacterials bearing a variety of functional groups. The goal of the current project is the synthesis 2,4-diaminopyrimidine antibiotics 3a–h, which have potential for the treatment of inhalation anthrax, a bioterror threat. The most important aspect of these drugs is that they selectively inhibit the activity of Bacillus anthracis dihydrofolate reductase (DHFR) but not human DHFR.13,14 DHFR plays a critical role in folate metabolism and is a good target for antibiotic drug candidates. Furthermore, since our compounds incorporate several structural units common to drugs that inhibit DHFR, it is less likely that bacteria exposed to these agents will readily develop a resistance to them. The synthesis involves a Heck reaction of 2,4-diamino-5-(5-iodo-3,4-dimethoxy-benzyl)pyrimidine (1) with a series of (±)-1-(1-substituted-1H-phthalazin-2-yl)prop-2-en-1-ones 2, both of which are available by known methods.13,15 Earlier syntheses of certain examples of 3 by conventional Heck procedures13,15 gave yields of 10%–37%. The products obtained by this method, however, were difficult to purify from the reaction mixture due to extensive side-product formation. We have successfully improved the synthesis by employing microwave irradiation to assist the Heck coupling process. The conventional reactions were carried out using 2.07 mmol each of 1 and 2, 2.27 mmol of N-ethylpiperidine and 0.026 mmol (1.24 mol % relative to substrates 1 and 2) of bis(triphenylphosphine)palladium(II) dichloride catalyst in 8 mL of DMF under argon at 140°C–150°C for 18 h.13,15 This procedure generally afforded the coupled product in low yield (10%–37%) with substantial side-product formation. In an effort to improve this outcome, substrate concentrations and temperatures were varied, but neither of these changes resulted in significant improvement. Attempts to adjust the catalyst loading for this transformation were also examined. An increase in catalyst loading to 2.00 mol % decreased the yield of the product and added to the impurity profile, making isolation of the product more difficult. A decrease in catalyst loading to 0.96 mol % led to incomplete reaction and recovery of starting material along with the desired product. Thus, a catalyst loading of 1.24 mol % proved optimum for the complete conversion to the product with a minimum of side reactions. Finally, the use of other catalysts (e.g. Pd(OAc)2, PdCl2, (Ph3P)4Pd, Pd/C and CuI)13 and bases (e.g. Et3N, DBU, K2CO3 and Cs2CO3)13 failed to improve the conversion to product. Reactions were also carried out on the same molar scale in sealed tubes. This resulted in slightly improved yields (42%–65%), but side-reactions were still problematic. It is conceivable that prolonged heating under conventional and sealed tube conditions caused degradation of the substrates and the catalyst, leading to a more complex product mixture. Thus, a method was sought to decrease the reaction time, which led us to the use of microwave irradiation. Microwave-assisted reactions were run on the same scale as above at 400 W and 150°C under argon for 60–80 min and gave superior conversions to products with far fewer impurities. A comparison of yields obtained using conventional, sealed tube and microwave conditions is shown in Table 1. Microwave irradiation as an alternative source of heating expedited the reaction, decreased the required catalyst loading by 20% (to 0.96 mol %) and reduced the amount of solvent needed by 25%. A series of reactions was carried out with R = propyl, isobutyl, isobutenyl, phenyl, 4-fluorophenyl, benzyl, 4-methylbenzyl and 4-trifluoromethoxybenzyl to establish the generality of the method. Products prepared in this manner were conveniently purified by placing the crude reaction mixture directly onto a silica gel column and eluting with increasing concentrations of methanol in dichloromethane. The target molecules were isolated as hydrates or solvates16 and were characterized by elemental and spectral analysis. Table 1 Yields of 3 Using Conventional, Sealed Tube and Microwave Conditions 1+2a-h→N-ethylpiperidineDMF,Δ(Ph3P)2PdCl23a-h We have successfully developed a synthesis of 2,4-diaminopyrimidine-based antibiotics that utilizes a microwave-assisted Heck reaction on highly functionalized substrates in the final step. The reaction is superior to reactions performed under conventional or sealed tube conditions, requiring less solvent and catalyst. More importantly, the use of microwave conditions reduced reaction times and provided higher coupling yields with fewer side products.

The use of microwave (MW) irradiation for the condensation reaction between acetophenone and alpha-phenylethylamine to prepare (R,R)-bis[alpha-phenylethyl]amine results in significantly reduced reaction times relative to the use of conventional heating. In this protocol, a secondary amine, (R,R)-bis(alpha-phenylethyl)amine is treated with acryloyl chloride to afford conjugated amide N,N-bis[(R)-alpha-phenylethyl]prop-2-enamide, (R,R)-3. 1,4-Addition of alpha-phenylethylamine to unsaturated (R,R)-3 affords propanamide N,N-Bis[(R)-alpha-phenylethyl]-3-N-[(S)-alpha-phenylethyl]amino-propanamide, (R,R,S)-4, which can be alkylated with high diastereoselectivity to give derivative N,N-Bis[(R)-alpha-phenylethyl]-3-N'-[(S)-alpha-phenylethyl]amino-propanamide, (R,R,S,S)-5. Hydrogenolysis of (R,R,S,S)-5 catalyzed by palladium hydroxide and final hydrolysis (4 N HCl) resulting in the formation of (S)-alpha-benzyl-beta-alanine, (S)-7, is facilitated by MW irradiation. The use of MW irradiation in this step prevents racemization of the desired amino acid. The present protocol constitutes one of the simplest strategies for the asymmetric synthesis of biologically relevant alpha-substituted-beta-amino acids since it takes advantage of inexpensive, commercially available beta-Ala and either (R)- or (S)-alpha-phenylethylamine as chiral auxiliary. The required time for this protocol is approximately 90 h, which can be carried out in 5 d.

Efficient removal of dye from an aqueous phase using activated carbon supported ferrihydrite as heterogeneous Fenton-like catalyst under assistance of microwave irradiation

Combination use of microwave irradiation and ionic liquid in enzymatic isomerization of xylose to xylulose

Amide linkages are present in key natural products and in many biologically active molecules. Therefore, the formation of amide bonds is important to both synthetic chemists and biologists. Approximately 66% of all preliminary screening reactions in industrial medicinal chemistry laboratories involve amide formation. Although many methods have been developed for amide synthesis, a procedure for the direct coupling of amines with an acid in the presence of coupling agents without prior activation would be useful for building small-molecule libraries and for key steps in total syntheses. Condensing agents such as carbodiimides or other activating agents are generally employed under dry conditions. However, the condensing agent 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4methylmorpholium chloride (DMT-MM) can be used to prepare carboxamides in alcohol or water. This reaction is technically simple and relatively easy to implement, requiring only a mixing of acids, amines, and DMTMM in MeOH or H2O. The synthesis of DMT-MM is also relatively simple, and it can be prepared from CDMT (2chloro-4,6 dimethoxy-1,3,5-triazine) and N-metheylmorphorine (NMM) in THF. The current report describes the application of microwave-induced acceleration to further improve the reaction conditions for amide synthesis using DMT-MM. Highspeed synthesis using microwave technology has attracted considerable attention in organic chemistry. Microwave irradiation provides advantages over conventional heating for chemical transformations, including accelerated reaction rates (and consequently reduced reaction times), higher yields, and cleaner reactions. These advantages led us to evaluate the use of microwave irradiation for amidation reactions involving less reactive secondary and primary amines with acid in the presence of DMT-MM. We also compared the effectiveness of dicyclohexylcarbodiimide (DCC), a well-known condensing reagent, when coupled with microwave irradiation versus classical thermal methods. The reactions were performed by dissolving amines, carboxylic acids, and the condensing agent in solvent, followed by irradiation in a temperature-controlled microwave oven. For comparison, the same reactions were carried out under conventional heating conditions. The amidation of 2-phenylethylamine (a primary amine) with substituted benzoic acid in the presence of DMT-MM in MeOH gave a yield of over 90% products within 25 min at 110 C with microwave irradiation. The reaction time with conventional heating was seven times that with microwave irradiation, and the yield was less than 10-20% of the yield with the microwave-assisted method. The reaction of piperidine (a secondary amine) with benzoic acid afforded a 91% yield within 30 min at 150 C with microwave irradiation; note the higher reaction temperature and longer reaction time compared with those of the primary amine reaction. Amidation of piperidine with substituted benzoic acid in the presence of DCC with pyridine in THF yielded more than 60% products within 25 min at 120 C with microwave irradiation. Thus, DMT-MM was a much more effective coupling agent than DCC. Further increases in reaction temperature were limited by the potential of solvents for producing an explosive atmosphere within the micro-

Microwave-assisted conversion of biomass and waste materials to biofuels

A simple, efficient and general method has been developed for the high diastereoselective synthesis of α-aminophosphonates through “one-pot” three-component reaction of alkyl and aryl aldehydes with (S)-α-methylbenzylamine or (S)-3,3-dimethyl-2-butylamine and dimethyl phosphite (Kabachnik-Fields reaction), which proceeds in short time using microwave irradiation under solvent and catalyst free-conditions. This method could be useful in the large-scale synthesis of α-aminophosphonates in short reaction time

The Kabachnik–Fields (phospha-Mannich) reaction involving the condensation of primary or secondary amines, oxo compounds (aldehydes and ketones) and >P(O)H species, especially dialkyl phosphites, represents a good choice for the synthesis of α-aminophosphonates that are of significant importance due to their biological activity. In general, these three-component reactions may take place via an imine or an α-hydroxy-phosphonate intermediate. The monitoring of a few Kabachnik–Fields reactions by in situ Fourier transform IR spectroscopy has indicated the involvement of the imine intermediate that was also justified by theoretical calculations. The Kabachnik–Fields reaction was extended to >P(O)H species, comprising cyclic phosphites, acyclic and cyclic H-phosphinates, as well as secondary phosphine oxides. On the other hand, heterocyclic amines were also used to prepare new α-amino phosphonic, phosphinic and phosphine oxide derivatives. In most cases, the synthesis under solvent-free microwave (MW) conditions is the method of choice. It was proved that, in the cases studied by us, there was no need for the use of any catalyst. Moreover, it can be said that sophisticated and environmentally unfriendly catalysts suggested are completely unnecessary under MW conditions. Finally, the double Kabachnik–Fields reaction has made available bis(phosphonomethyl)amines, bis(phosphinoxidomethyl)amines and related species. The bis(phosphinoxidomethyl)amines serve as precursors for bisphosphines that furnish ring platinum complexes on reaction with dichlorodibenzonitriloplatinum.

Chapter 9 - Current status of rapid enzyme inactivation through the use of microwave irradiation

In industry, synthetic zeolites are commonly used as ion-exchange materials, catalyst supports, and adsorbents. As a result, a more energy-efficient alternative for its synthesis from low-cost and accessible raw materials is needed. This study, presents the possibility of using class F South African coal fly ash (SACFA) from Lethaba thermal-power station as a precursor to produce zeolites via a microwave (MW) assisted synthesis route. The mineral content of synthetic materials was determined using X-ray florescence (XRF). Morphology was determined using a Scanning electron microscopy (SEM), elemental composition by energy dispersive spectrometer (EDS). X-ray diffractometry (XRD) was used to get structural characterization. Microwave (MW) irradiation time and intensity enhance the crystallization of the zeolite phase as a result of sufficient energy required to enable the solubility of alumina and silica from coal fly ash. The use of MW irradiation provides a green alternative to zeolite synthesis from fly ash (FA) than traditional thermal and fusion techniques, which uses a great deal of energy consumption and a longer reaction time.

Promoting effect of microwave irradiation on CeO2-TiO2 catalyst for selective catalytic reduction of NO by NH3

A series of novel α-aminophosphonates of diethyl (2,4-difluorobenzylamino)methylphosphonate derivatives (4a–4g) have been synthesized by applying three-component Kabachnik–Fields reaction, using fluoro derivatives of aldehydes and substituted amines, diethyl phosphonate in the presence of a catalytic amount of methanesulfonic acid (MSA) in good yields with high enantioselectivities (up to 98% ee). The enantioselectivitiy of compounds (4a–4g) was confirmed by chiral HPLC. The direct Kabachnik–Fields reaction with high reactivity under mild reaction conditions and significantly used for synthesis of the α-aminophosphonate. The novel products were characterized by spectral and analytical data.

This study evaluated the incorporation of linoleic acid (LA) into canola oil (CO) through enzymatic interesterification reactions aided by microwave irradiation and catalyzed by TL IM lipase enzyme (sn-1,3). To optimize the process and identify the best reaction conditions, an experimental design utilizing a central composite experiment was implemented to analyze the effects of time (1.5-3.5 h), the reactant ratio LA:CO (0.3:1) and temperature (50-75°C). The linoleic acid (LA) extract was obtained from grapeseeds through extraction and purification techniques. Under optimal conditions (73°C, 48 min and an LA:CO ratio of 1.2), a 69.80% incorporation of linoleic acid was achieved. Moreover, the reactant ratio emerged as the most crucial factor shaping the outcome of the reaction, underscoring its vital role in achieving optimal results. The quality analysis of the crude oil, obtained as a reaction product, revealed a variation in the saponification index (177.5 ± 0.7 mg KOH/g), with respect to the starting substrates, indicating modifications in its composition. This value is higher than the saponification index reported for canola oil (172.82 ± 1.92 mg KOH/g) but lower than that of grapeseed oil (184.56 ± 0.45 mg KOH/g). This variation may be attributed to differences in fatty acid composition; specifically, the crude oil contains a lower proportion of long-chain fatty acids compared to canola oil. This study emphasizes the potential of grapeseeds as a sustainable source of polyunsaturated fatty acids (PUFA). Additionally, the use of microwave irradiation has proven to be a viable alternative to traditional methods by reducing reaction times, minimizing energy consumption and increasing yield percentages. These advancements support green chemistry, the circular economy and the creation of value-added products that can benefit various industries.

Microwave irradiation has been applied with success to cycloaddition reactions. The special characteristics of such irradiation entails the use of new methodologies, including equipment, glassware, solvents, and solid supports. All of these aspects are described in this review. Under classical heating conditions, these reactions usually require long reaction times, high temperatures, and/or Lewis acid catalysts, resulting in partial or total decomposition of sensitive compounds. This is a particularly significant problem in the synthesis of natural products. These problems have been conveniently overcome by the use of microwave irradiation. The short reaction time associated with microwave activation avoids decomposition of reagents and products, and prevents polymerization of the diene or dienophile. Heterocyclic compounds have been synthesized by cycloaddition reactions, or have been observed to react as dienes and dipoles under microwave irradiation conditions. Even those heterocyclic systems that are very reluctant to participate in cycloaddition reactions, such as pyrazoles, can be induced to react under microwave irradiation conditions. The application of this method to the chemistry of [60]fullerene has permitted derivatization of this system while avoiding the problems of polycycloaddition and cycloreversion. In most cases, spectacular accelerations and great improvements in yields and reaction conditions are observed. Finally, in some cases, changes in the chemo-, regio-, or stereoselectivity have been observed. These changes have been connected with the absolute hardness of the transition state, with the harder state being favored under microwave irradiation conditions. Microwave chemistry thus opens new possibilities for modifying the result of competitive reactions by considering the relative hardness of the transition states.

The development of effective strategies for fabrication of fluorescent organic nanoparticles (FONs) with an aggregation-induced emission (AIE) feature has an important impact on the biomedical applications of these AIE-active FONs. In the current work, an ultrafast strategy for fabricating AIE-active FONs is developed through a "one-pot" microwave-assisted, catalysts-free, and solvent-free Kabachnik-Fields (KF) reaction for the first time. It is demonstrated that such organophosphorous-containing AIE-active block polymers can be synthesized within 2 min under air atmosphere through the microwave-assisted KF reaction. These polymers show amphiphilic properties and can self-assemble into mPEG-CHO-Phe-NH2 -DEP FONs, which display high water dispersibility and desirable optical properties. Biological evaluation results suggest that the mPEG-CHO-Phe-NH2 -DEP FONs exhibit low toxicity and are potential for biological imaging applications. More importantly, many other multifunctional AIE-active FONs can also be fabricated through the strategy described in this work owing to the universality of KF reaction. Besides, combined with the excellent properties of mPEG-CHO-Phe-NH2 -DEP FONs, it is believed that such microwave-assisted KF reaction shall be an effective route for designing various AIE-active nanomaterials for different biomedical applications.