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Palladium nanoparticles on layered potassium α-zirconium phosphate (PdNP/α-ZrPK) with high palladium loading (10.6 wt%) have been prepared and used as catalyst in low amount (0.1 mol% of Pd) in the Heck reaction of methyl acrylate and styrene with a series of aryl iodides in CH3CN/H2O azeotrope as a green medium. The procedure has been optimized under flow conditions obtaining an extremely low waste production (E-factor) and allowing to isolate the final product with very low residual palladium content without any purification step.

A highly sustainable and waste-minimized protocol for Heck coupling has been defined. Optimal conditions have been defined by exploiting a heterogeneous catalyst based on supported ionic liquid-like phases featuring high Pd loading (10 wt %) and by optimizing its efficiency in a recoverable green reaction medium (acetonitrile/water azeotrope). Pure products 4a–l and 6a–h have been isolated chromatography-free in high yields (74–99%) and with extremely low environmental factor (E-factor) values (2.3–5.0). With the application of flow technology, the selected heterogeneous base and Pd catalyst have been fully recovered and reused, and minimum palladium leaching allowed for isolation of the final products with low residual palladium content (

Stable L-proline-functionalized zirconium methyl- and/or phenylphosphonates have been prepared as amorphous solids by the precipitation of (4R)-4-[(4′-phosphonobenzyl)oxy]-L-proline and methyl- and/or phenylphosphonic acid with ZrOCl2. The supported L-proline catalysts were tested in the direct asymmetric aldol addition between several ketones and p-substituted benzaldehydes. High yields, diastereoselectivities (anti/syn up to 92:8) and enantiomeric excesses (up to 99 % ee) have been achieved. Moreover, an easy protocol for the efficient recovery of the catalytic system by simple centrifugation has been defined, and the effective reuse of the catalyst has been reported in the representative aldol addition of cyclohexanone with p-nitrobenzaldehyde. This study has shown that these L-proline immobilized catalytic systems can be used at least six times without loss of activity and with reproducible anti/syn and ee values.

PS-BEMP was used as a heterogeneous catalyst for the phospha-Michael addition of phosphorus nucleophiles to a variety of electron-poor alkenes. The addition reactions were generally performed with equimolar amounts of reagents under solvent free conditions. The protocol proved to be very efficient for the addition to aromatic, non-aromatic and cyclic ketones, giving good yields (78-85%) in all cases. The protocol was also extended with good results to α,β-unsaturated esters and nitriles. This demonstrates that PS-BEMP is a good catalyst for the phospha-Michael addition to electron-poor alkenes.

The reactions between N -benzylideneanilines and ­Danishefsky’s diene proceed smoothly in acidic aqueous medium in the presence of a catalytic amount of copper(II) triflate–sodium dodecyl sulfate [Cu(OTf) 2 –SDS] to afford the corresponding 1,2-diphenyl-2,3-dihydro-4-pyridones in excellent yields of 84–95%. The aqueous solution containing the catalyst is recovered and reused without any loss in efficiency.

Novel solid fluorides were prepared to optimize the β-azidation of α,β-unsaturated ketones. The higher loading of these catalysts compared to that of commercially available fluorides has allowed the use of a smaller mass of catalyst helping the mixing of the reaction mixture. Porous polymeric supports have proved to be more efficient in the presence of water as reaction medium. Water has played a crucial role showing a beneficial effect on the reactivity by improving dispersion of the reaction mixture and also by avoiding organic fouling caused by the retention of the reaction mixture within the polymeric matrix. This has facilitated the recovery of the products from the catalyst. The protocol reported has allowed a significant reduction in the organic solvent required for the complete recovery of the pure product whilst leaving the catalyst clean and reusable. E-factors are in the range of 5.9–10.5 and therefore ca. 3 times smaller than previous procedures operating under solvent-free conditions. To further improve the efficiency of our approach we have developed a protocol operating in a continuous-flow manner that has allowed us to achieve an E-factor of 1.7–1.9, with a reduction of ca. 80% of the corresponding batch conditions. The continuous-flow protocol has allowed us to minimize the use of trimethylsilyl azide making the recovery and reuse of water and catalyst 5f very efficient and simple. Finally, a novel reduction system using palladium on alumina (5 mol%) and equimolar amount of formic acid has been used in the presence of 1 equivalent of di-tert-butyl pyrocarbonate to set a multistep protocol operating in continuous-flow conditions for the preparation of two representative N-Boc-β-amino ketones starting from the corresponding enones with E-factors of 3.2 and 2.7, respectively.

Although its intriguing features, such as uniform functionalization through the entire beads and a very high-loading capacity are suitable candidates for solid-phase synthesis and reagent-scavenging, the use of Rasta resin as support for organocatalysis has been little explored. In this contribution, Rasta polymer has been used to preparation of high-loading Rasta-TBD. This catalyst has been able to efficiently promote several organic transformations with constantly good and promising results.

Zirconium phosphates methyl and/or phenyl phosphonates-supported l-proline have been prepared as amorphous solids by precipitation of (4R)-4-(phosphonooxy)-l-proline, methyl and/or phenyl phosphonic acid with ZrOCl2. The supported l-proline catalysts were tested on the direct asymmetric aldol addition of cyclohexanone to p-nitrobenzaldehyde in DMF/H2O (9:1) and in sole water. The hydrophobic groups on solid surface favor reagents’ diffusion toward proline chiral moiety increasing the catalytic activity of supported l-proline. High diastereoselectivity (anti/syn up to 94:6) and high enantiomeric excess up to 97% have been obtained.

The first catalytic approach to the nucleophilic addition of silyl ketene acetals 2 to epoxides 1 is reported. The defined protocol is metal-free using tetrabutylammonioum fluoride as the catalyst. It works in a very efficient manner under solvent-free conditions (SolFC) allowing γ-lactones 3 to be directly obtained with high regioselectivities and yields.

The aza-Diels–Alder reaction between benzaldimines 1 and Danishefsky's diene in solvent-free conditions is reported for the first time. The reaction occurs rapidly at 30 °C and is catalyzed by porous α-zirconium hydrogen phosphate (p-αZrP) in the presence of sodium dodecyl sulfate (SDS). The yields were excellent. The recycling of the catalyst has also been investigated.

The direct aza-Diels–Alder reaction between 2-cyclohexen-1-one (1) and benzaldimines 2 in water is reported for the first time. The reaction occurs at 30 °C, is catalyzed by layered α-zirconium hydrogen phosphate (α-ZrP) and requires the presence of sodium dodecyl sulfate (SDS). The reaction yield is excellent, the reaction is faster and the exo diastereoselectivity is higher than when organic solvent is used. The one-pot, three-component version of the reaction and the recycling of both the catalyst and the aqueous mother liquor in toto (water, α-ZrP and SDS) have also been investigated. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

2-tert-Butylimino -2-diethylamino-1,3 -dimethylperhydro-1,3,2 -diazaphosphorine supported on polystyrene (PS-BEMP) is an efficient catalyst for the addition of nitroalkanes (1-1.5 equiv.) to α,β-unsaturated carbonyl compounds (1.0 equiv.) in the absence of a reaction medium (solvent-free conditions). The corresponding γ-nitro carbonyl compounds have been isolated in excellent yields but the catalyst can be satisfactorily recovered and used for only 3 times due to the magnetic stirring which caused crunching of the catalyst beads thus hampering its complete recovery. To optimize the catalyst's reuse and improve the environmental efficacy of solvent-free conditions, the first solvent-free cyclic continuous-flow reactor has been set up. This reactor has allowed the product to be isolated in an almost quantitative yield by using a very small amount of organic solvent, making the recovery and reuse of the catalyst efficient and reproducible.

The simple protocol provides γ-lactones with high regioselectivities [except for styrene epoxide (II)].

An efficient protocol for the synthesis of β-amino acids starting from easily accessible α,β-unsaturated carboxylic acids based on the combination of two heterogeneous catalytic systems is reported. This multistep approach is based on the direct β-azidation of α,β-unsaturated carboxylic acids and subsequent azido group reduction performed in flow conditions. It has been demonstrated that the catalysts can be easily recovered and reused conserving its complete efficiency. The green metrics calculations proved the high environmental efficiency of the protocol characterized by very low waste production.

γ-Valerolactone (GVL) can be used as an efficient and practical alternative to the banned and commonly used dipolar aprotic solvents. In this contribution GVL has been used as a non-toxic, biodegradable, biomass-derived medium, for the definition of a simple and general protocol for the Sonogashira cross-coupling reaction. The chemical efficiency of GVL as a medium is excellent and the best results have been obtained using DABCO as the base allowing the isolation of products 3a–q in 60–96% yields. These results represent an example which proves that biomass-derived safer solvents can be used efficiently in common transformations reaching higher greenness/sustainability as well as high chemical efficiency.

Hafnium chloride tetrahydrofuran complex (HfCl 4 ·2 THF) is an efficient catalyst for the Diels-Alder cycloadditions of 3-ethoxycarbonylcoumarins la-c and 1,3-butadienes 2x-z under solvent-free conditions furnishing the corresponding cycloadducts in excellent yields. This salt is an air stable Lewis acid and therefore the reactions can be performed in air atmosphere making the procedure simple to be carried out.

The efficiency of In(III)-catalyzed thiolysis of safrole oxide (1) by phenylthiol (2a) under SFC or in an organic medium, strongly depends on its associated counterion. In(OTf)3 has proven to be a very efficient catalyst and the use of solvent-free condition (SFC) results in the highest catalytic efficiency. In the presence of 2 mol% of this salt the reactions of 1,2-epoxides 1, 5, and 8 by thiols 2a–f, have allowed the corresponding β-hydroxy sulfides to be obtained at 30 °C in generally short times, high yields and with C-β-regioselectivity. In addition two representatives of a new class of [1,3]thiazolo[3,2-a]pyridin-4-ium-based ionic liquids, 11 and 12, have been prepared by a simple one-pot procedure by using as a key step the thiolysis of 1,2-epoxyhexane (5) by 2-mercaptopyridine 2f.

The catalyst is easily recoverable and can be used at least 6 times without any significant loss in activity.

[reaction: see text] The thiolysis of alpha,beta-epoxycarboxylic acids 1a-e by thiols 2a,b is more efficient in water than in dichloromethane or SFC. At pH 9.0 phenylthiolate generally attacks the C-alpha carbon while at pH 4.0, and in the presence of InCl3 (10 mol %), the thiolysis is exclusively C-beta regioselective. In all cases, the processes are completely anti-diasteroselective, and the corresponding products 3, 4, and 5 have been isolated in good yields. Both water and catalysts have been recovered and reused.

NaOH (0.02-0.3 molar equiv) is an efficient catalyst for the thiolysis reactions of alpha,beta-epoxy ketones with alkyl and aryl thiols in water. Thiolysis of 3,4-epoxyheptan-2-one (1) with thiols 2a-d has been accomplished in mild conditions (30 degrees C and pH 6 or 9) with complete C-alpha-regioselectivity and anti-stereoselectivity, and the corresponding anti-beta-carbonyl-beta-hydroxysulfides 3a-d have been prepared in excellent yields (95-98%). Compounds 3a-d, depending on their nature and pH conditions, have undergone dehydration, C-3 epimerization reaction, and retroaldol condensation. Dehydration of anti-3a-d has been chemoselectively carried out by in situ acidic treatment at 70 degrees C, giving stereoselectively the related (Z)-vinyl sulfides 4 in 89-94% overall yields. Under NaOH-catalyzed thiolysis conditions, cyclic alpha,beta-epoxyketones 6-9 have shown C-alpha attack only and spontaneously dehydrated to furnish the corresponding vinyl sulfides in high yields (90-96%). The reactions of calchone oxide (10) with thiols 2b-d have exclusively resulted in the formation of beta-carbonylsulfides 10b-d (82-93% yield), coming from the nucleophilic attack at the alpha-position and retroaldol condensation. To highlight the synthetic utility of this procedure, one-pot multisteps preparation of vinyl sulfides 7b and 7c, vinyl sulfoxides 12 and 13, and 1,5,6,7-tetrahydro-4H-1,2,3-benzotriazol-4-one (14) starting from 2-cyclohexen-1-one (11) have also been reported.

ZnCl 2 (5 mol%) is an efficient catalyst for the thiolysis of 1,2-epoxides by thiophenol in water at pH 4.0. A variety of β-hydroxy phenylsulfides were obtained in short reaction times and excellent yields. Starting from cyclohexene oxide (1), two one-pot multi-step procedures in sole water (thiolysis/oxidation with H 2 O 2 ) have been realized, for the chemoselective synthesis of the corresponding β-hydroxysulfoxides 19 or for the related β-hydroxysulfone 20.

The pH dependence of thiolysis of 1,2-epoxides with thiophenol in water and the influence of a Lewis acid catalyst is investigated. InCl3 showed a very high efficiency in catalyzing this process at pH 4.0. The regioselectivity of the nucleophilic attack is markedly influenced going from pH 9.0 to pH 4.0. A one-pot procedure running solely in water to prepare trans-2-(phenylsulphinyl)cyclohexan-1-ol is reported starting from epoxycyclohexane, via thiolysis reaction and oxidation with t-butyl hydroperoxide.

Classical Lewis acids such as AlCl(3), TiCl(4), and SnCl(4), believed to be unusable as catalysts in aqueous medium, efficiently catalyzed regio- and stereoselective azidolysis and iodolysis of alpha,beta-epoxycarboxylic acids in water at pH 4.0 and 1.5, respectively. The concept of water-tolerant metal-salt is reexamined in direct relationship to the aqua ion hydrolysis constant.

Recently the aqueous medium has attracted the interest of organic chemists, and many, sometimes surprising, discoveries have been made. Among the organic reactions investigated in aqueous medium, the Diels−Alder cycloaddition has been the most widely studied because of its great importance in the synthetic and theoretical fields. The Diels−Alder reaction is greatly enhanced by Lewis acid catalysis, and this review illustrates recent significant results in this field when the reaction is performed in aqueous medium.

via azidolysis of epoxides under solvent-free conditions in the presence of a polystyrene-supported bisfluoride DABCO catalyst

PS-BEMP is found to promote the title reaction (Pudovik reaction) between alkyl or aryl aldehydes (I) and diethyl phosphite (II) giving the corresponding α-hydroxyphosphonates (III) in high yields and low E-Factor values.

Azidolysis of 2,3-epoxycarboxylic acids occurs quantita- tively and with complete regio- and stereoselectivity at C-3 in water as reaction medium in the presence of a catalytic amount of Cu(NO3)2.

An efficient protocol for the hydrophosphonylation of aromatic and aliphatic aldehydes catalyzed by PS-BEMP under solvent-free conditions (SolFC) has been reported. Addition reactions were performed by using equimolar amounts of reagents and the resulting α-hydroxyphosphonates were isolated with simple workup procedures. A large scale protocol for the preparation of a representative α-hydroxyphosphonate 3a has been also set up using a flow reactor.

The cyanosilylation of carbonyl compounds (I) and (IV) using TmsCN (II) and triphenylphosphine supported on polystyrene as catalyst under solvent-free conditions is described.

Under solvent-free conditions the reaction of epoxides 1a–i with trimethylsilylazide (2) catalyzed by polystiryl-supported fluoride (PS-DABCOF2) has led to the efficient preparation of the corresponding O-TMS protected 1,2-azido alcohols 3a–i that, by treatment with Dowex-H, gave the related 1,2-azido alcohols 4a–i in excellent yields (83–99% and 82–96%, respectively). The use of a flow procedure has allowed us to significantly minimize waste in the preparation of representative 1,2-azido alcohols 4a, 4c and 4i that have been obtained with E-factors of 1.6, 2.1, and 1.9, respectively. The 1,2-amino alcohols 5a, 5c and 5f have been also prepared, in quantitative yields, by reduction of the corresponding O-TMS protected 1,2-azido alcohols 3a, 3c, and 3f by Pd on the Al2O3/HCOOH system.

Here we report a sustainable protocol for the cyanosilylation of carbonyl compounds 1a–g and 3a–m using trimethylsilyl cyanide and triphenylphosphine supported on polystyrene as a catalyst under solvent-free conditions. It has been shown that a small amount of the catalyst allows the chemoselective 1,2-addition of trimethylsilyl cyanide to α,β-unsaturated carbonyls 1a–g (5 mol%) and to saturated carbonyls 3a–m (2 mol%). The preparation of cyanohydrin trimethylsilyl ethers 2a–g and 4a–m has been accomplished in good yields (72–99%) and very low E-factor values (5–10). Finally, efficiency has been further improved by setting two different flow procedures that have allowed us to perform the representative preparation of cyanohydrin trimethylsilyl ether 4a on a large scale and with the E-factor of 0.16 or 0.47 consisting in a reduction of 90 or 72% of waste compared to our batch conditions.

Tetrabutylammonium fluoride (TBAF) is an efficient catalyst in the [3 + 2] cycloaddition reaction of organic nitriles 1 with trimethylsilyl azide (TMSN(3)) in solventless conditions. The corresponding 5-substituted 1H-tetrazoles 2 were obtained under mild conditions and in 80-97% yields.

Thiolysis of alkyl- and aryl-1,2-epoxides was investigated under solvent-free conditions in the presence of Lewis and Bronsted acid and base catalysts (InCl3, p-TsOH, n-Bu3P, K2CO3). Five mol% of catalyst was sufficient and the best results were obtained by using InCl3 and K2CO3. β-Hydroxy sulfide was isolated in excellent yields.

Optimized conditions allow the direct synthesis of title compounds from Danishefsky′s diene and N-benzylideneanilines.

This contribution reports the preparation and use of a new immobilized catalyst, PS-DABCOF (9), which has been specifically designed to access for the first time the efficient β-azidation of α,β-unsaturated carboxylic acids.

JandaJel with its greater spacing between the linear polymeric chains compared to that of polystyrene matrices, is a very efficient support for improving the catalytic activity of TBD.

There is much chemistry between water and epoxide. This contribution deals with the use of water in processes based on the epoxide ring opening. Reported examples highlight the role of water not as a simple substitution of the organic medium or as an exotic option to claim the greenness of a process, but also show the role of this medium for reaching the highest chemical efficiency. The peculiar properties of water have allowed to realize processes that sometimes cannot even be performed in other reaction media.

The condensation reactions of acetophenone, cyclohexanone, isophorone, phenylacetonitrile, p-nitrophenylacetonitrile, (phenylsulfonyl)acetonitrile and indene with benzaldehyde were studied in water in heterogeneous phase in the presence and absence of anionic and cationic surfactants such as SLS, CTACl, (CTA)2SO4 and CTAOH. All the reactions occur with excellent yields. The cationic surfactants favour the reaction and the comparison with the corresponding tetrabutylammonium salts show that the micellar catalysis is effective mainly towards the dehydration reaction following that of condensation. Anionic surfactant SLS is inactive. 2′-hydroxychalcones were prepared in aqueous medium in good-excellent yields and the one-pot synthesis of 7- and 3′,4′-substituted flavonols was achieved.

Cyclocondensation of salicylic aldehydes (I) with acetoacetate proceeds under solvent-free conditions in the presence of a solid-phase catalyst to give 3-acetylcoumarins (III) [3-nitrocoumarins (X) are formed analogously].

This report concerns Lewis acid catalyzed enantioselective sulfa-Michael addition in neutral water by using a very efficient Sc(OTf)3/bipyridine 1 catalytic system. It is noteworthy that the protocol presented employs water as a reaction medium and allows us to obtain very high stereoselectivity and satisfactory yields for β-keto sulphides deriving from aliphatic thiols. The recovery and reuse of both the aqueous medium and the catalytic system is also reported.

This report concerns Lewis acid catalyzed enantioselective sulfa-Michael addition in neutral water by using a very efficient Sc(OTf)(3)/bipyridine 1 catalytic system. It is noteworthy that the protocol presented employs water as a reaction medium and allows us to obtain very high stereoselectivity and satisfactory yields for β-keto sulphides deriving from aliphatic thiols. The recovery and reuse of both the aqueous medium and the catalytic system is also reported.

This work was aimed at preparing o-(6'-nitrocyclohex-3'-en-1'-yl)phenol and tetrahydro-6H-benzo[c]chromen-6-ol derivatives in three steps starting from salicylaldehydes. Initially 3-acetylcoumarins were prepared in the absence of solvent using a solid base catalyst such as PS-TBD. In the second step, the Diels-Alder reactions of 3-nitrocoumarins and 3-acetylcoumarins under thermal conditions or in the presence of hafnium chloride yielded the corresponding tetrahydrobenzo[c]chromenones. The final part of the work was dedicated to the transformation of nitro-tetrahydrobenzo[c]-chromenones into o-(6'-nitrocyclohex-3'-en-1'-yl)phenol derivatives in aqueous medium and to the conversion of acetyl tetrahydrobenzo[c]chromenones into the corresponding tetrahydro-6H-benzo[c]chromen-6-ol derivatives in tetrahydrofuran (THF), in the presence of tetrabutylammonium fluoride (TBAF) on silica. In every case the diastereoselectivity was complete and the reaction yields were high.

This contribution reports the results obtained in the definition of a catalytic method for the nucleophilic ring opening of epoxides by activated methylenes promoted by a polymer-supported base. The attention has been focused on the use of polymer supported bases and the best results have been obtained by using 4-(dimethylamino)pyridine (PS-DMAP) and 2- tert -butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine both on polystyrene (PS-BEMP). Solvent-free conditions has been essential for reaching a sufficient reactivity to realize this process, in fact when a reaction medium is used, the processes are almost unfeasible.

Azidolysis of 2,3-epoxycarboxylic acids occurs quantita- tively and with complete regio- and stereoselectivity at C-3 in water as reaction medium in the presence of a catalytic amount of Cu(NO3)2.

Reduction of azides to amines and amides was carried out with NaBH4/CoCl2 · 6 H2O in sole water at 25 °C under catalytic heterogeneous conditions. A broad spectrum of azides was reduced in a short time, chemoselectively in high yield and purity.