We report herein a clean multistep flow process that starting from α,β-unsaturated ketones 1 allows the preparation of N-Boc-γ-amino alcohols 3 in high yields. The final products have been isolated in pure form without any additional purification step. The cleanness and environmental efficiency achieved using our protocol are proven by the calculation of green metrics such as E-factors.

PS-BEMP was used as a heterogeneous catalyst for the phospha-Michael addition to electron-poor alkenes giving generally good yields, up to 90%.

An efficient protocol for the synthesis of beta-amino acids starting from easily accessible alpha,beta-unsaturated carboxylic acids based on the combination of two heterogeneous catalytic systems is reported. This multistep approach is based on the direct beta-azidation of alpha,beta-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.

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

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.

γ-Valerolactone (GVL) can be used as an efficient and practical alternative to the banned and commonly used dipolar aprotic solvents.

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 (<5 ppm) without any purification step.

Stable L -proline-functionalized zirconium methyl- and/or phenylphosphonates have been prepared as amorphous solids by the precipitation of (4 R )-4-[(4′-phosphonobenzyl)oxy]- L -proline and methyl- and/or phenylphosphonic acid with ZrOCl 2 . 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.

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.

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

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.

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.

Under solvent-free conditions the reaction of epoxides 1a-i with trimethylsilylazide (2) catalyzed by polystiryl-supported fluoride (PS-DABCOF(2)) 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.

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 beta-azidation of a,beta-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 5.910.5 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 1.71.9, 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-beta-amino ketones starting from the corresponding enones with E-factors of 3.2 and 2.7, respectively.