Design of a New Chiral Deep Eutectic Solvent Based on 3-Amino-1,2-propanediol and Its Application in Organolithium Chemistry.

A chiral glycerol derivative, namely 3-amino-1,2-propanediol, was employed for as the hydrogen bond donor (HBD) in the design of a new deep eutectic solvent (DES) with choline chloride acting as the hydrogen bond acceptor (HBA). The novel mixture was characterized and unambiguously classified as a DES. Furthermore, its synthetic usefulness was demonstrated in the room-temperature n-butyllithium-addition under air to carbonyl compounds and benzyl chloride. In some cases, pure products (100% conversion) were obtained by a simple extractive work-up in up to 72% isolated yield, thus suggesting the potential practical usefulness of this procedure as a green alternative to the classical Schenk procedure in volatile organic solvents for the synthesis of tertiary alcohols. The chirality of the HBD, bearing an interesting basic primary amino group, is an intriguing feature currently under investigation for further exploitation.

Ullmann homocoupling of arenediazonium salts in a deep eutectic solvent. Synthetic and mechanistic aspects.

A deep eutectic solvent (DES) based on glycerol and KF is successfully exploited as a solvent medium in Ullmann homocoupling of arenediazonium salts. The reactions were carried out in mild conditions and target products were obtained in fairly good yields. A computational study is presented aiming to understand the reaction mechanism and Raman spectroscopy is employed as an experimental tool to support it.

Chemo- and Regioselective Anionic Fries Rearrangement Promoted by Lithium Amides under Aerobic Conditions in Sustainable Reaction Media.

A straightforward and efficient protocol to promote the metalation/anionic Fries rearrangements of O-aryl carbamates, using for the first time a lithium amide as metalating agent under aerobic/ambient-friendly reaction conditions, is reported. This approach enables the sustainable preparation of salicylamide derivatives with high levels of chemoselectivity within ultrafast reaction times, working at room temperature in the presence of air/moisture, and using environmentally responsible cyclopentyl methyl ether as a solvent. Furthermore, the regioselective manipulation of O-2-tolyl carbamates has been accomplished using interchangeably alkyllithiums or lithium amides, with an unexpected beneficial contribution from the employment of biorenewable protic eutectic mixtures as non-innocent reaction media.

Copper-Free Halodediazoniation of Arenediazonium Tetrafluoroborates in Deep Eutectic Solvents-like Mixtures.

Deep Eutectic Solvent (DES)-like mixtures, based on glycerol and different halide organic and inorganic salts, are successfully exploited as new media in copper-free halodediazoniation of arenediazonium salts. The reactions are carried out in absence of metal-based catalysts, at room temperature and in a short time. Pure target products are obtained without the need for chromatographic separation. The solvents are fully characterized, and a computational study is presented aiming to understand the reaction mechanism.

Critical Assessment of the Sustainability of Deep Eutectic Solvents: A Case Study on Six Choline Chloride-Based Mixtures.

An outline of the advantages, in terms of sustainability, of Deep Eutectic Solvents (DESs) is provided, by analyzing some of the most popular DESs, obtained by the combination of choline chloride, as a hydrogen bond acceptor, and six hydrogen bond donors. The analysis is articulated into four main issues related to sustainability, which are recurrently mentioned in the literature, but are often taken for granted without any further critical elaboration, as the prominent green features of DESs: their low toxicity, good biodegradability, renewable sourcing, and low cost. This contribution is intended to provide a more tangible, evidence-based evaluation of the actual green credentials of the considered DESs, to reinforce or question their supposed sustainability, also in mutual comparison with one another.

Green Chemistry Meets Asymmetric Organocatalysis: A Critical Overview on Catalysts Synthesis.

Can green chemistry be the right reading key to let organocatalyst design take a step forward towards sustainable catalysis? What if the intriguing chemistry promoted by more engineered organocatalysts was carried on by using renewable and naturally occurring molecular scaffolds, or at least synthetic catalysts more respectful towards the principles of green chemistry? Within the frame of these questions, this Review will tackle the most commonly occurring organic chiral catalysts from the perspective of their synthesis rather than their employment in chemical methodologies or processes. A classification of the catalyst scaffolds based on their E factor will be provided, and the global E factor (EG factor) will be proposed as a new green chemistry metric to consider, also, the synthetic route to the catalyst within a given organocatalytic process.

Silica gel-immobilised chiral 1,2-benzenedisulfonimide: a Brønsted acid heterogeneous catalyst for enantioselective multicomponent Passerini reaction.

A chiral heterogeneous catalyst derivative of (-)-4,5-dimethyl-3,6-bis(1-naphthyl)-1,2-benzenedisulfonimide is proven here to be efficient in a three-component asymmetric Passerini protocol, carried out in a deep eutectic solvent. Reaction conditions are mild and green, while enantioselectivity is excellent. The catalyst was easily recovered and reused with no decrease in its catalytic activity.

Organocatalytic Synthesis of Benzazetidines by Trapping Hemiaminals with Protecting Groups.

Benzazetidines are highly strained and inherently unstable heterocycles. There are only few methodologies for assembling these compounds. Here, a protocol is presented to trap an elusive cyclic, four-membered hemiaminal structure. This method affords several benzazetidines in moderate to good yields (up to 81%), and it uses inexpensive materials and does not require catalysts based on transition metals. The high ring strain energy of these benzazetidine systems was estimated by density functional theory calculations to be about 32 kcal mol-1. This synthesis can be applied also on gram scale with reaction yield essentially unchanged.

Organocatalysis and catalyst aggregation: a study using the asymmetric synthesis of benzofuranones as a test reaction.

A common problem encountered in enantioselective organocatalysis is the aggregation of the catalyst, which can result in a relevant decrease of the efficiency and selectivity of the process. In the asymmetric synthesis of chiral benzofuranones, recently reported by us, we noted a remarkable increase of the reaction yield upon the addition of one of the reagents in a portionwise manner rather than in a single addition. We investigated this phenomenon by several experimental techniques such as 1D and 2D NMR experiments, UV-Vis spectroscopy, circular dichroism and dynamic light scattering. In addition, we studied the kinetic profile of this reaction using a simple numerical model and carried out in silico investigations. All these different approaches point to the conclusion that in the reaction medium a supramolecular polymerization/aggregation phenomenon, based on weak interactions, occurs and such a process is promoted by a quinone, which is one of the reagents of the benzofuranone synthesis. The portionwise mode of addition is a known strategy which can improve the performance of many synthetic procedures and this strategy is commonly adopted on account of empirical experience. However, our results provide an explanation, based on a chemical kinetic model, of the reason why the portionwise addition affects in such a dramatic way the yield of the benzofuranone synthesis catalyzed by Cinchona alkaloids.

Synthesis of Benzofuranones via Malonates Desymmetrization: Yield Increase by the Portion-wise Addition of Quinones.

The organocatalyzed addition of several malonates to 1,4-benzoquinones affords benzofuranones bearing a quaternary stereocenter with good enantioselectivity. This reaction is an intramolecular desymmetrization since it proceeds through the formation of an arylated achiral malonate that cyclizes to give the reaction product. The addition rate of the quinone dramatically affects the reaction yield which was originally low. The yield was considerably increased, in some cases, from less than 20 % to over 95 %, by adding the quinone in portions rather than at once, keeping similar enantioselectivity. A possible rationalization for the preferential formation of the indicated enantiomer has been investigated by DFT calculations.

Quinine-Catalyzed Asymmetric Synthesis of 2,2'-Binaphthol-Type Biaryls under Mild Reaction Conditions.

Simple quinine as an organocatalyst mediates the addition of various naphthols to halogenated quinones to afford non-C2 -symmetrical, axially chiral biaryl products, which are promising compounds as chiral ligands and organocatalysts. The rotational barrier required to have two distinct atropisomers has been evaluated in the products generated from the addition of naphthols to various quinones by means of DFT calculations and HPLC. The use of halogenated quinones as reagents was necessary to have configurationally stable enantiomeric products which can be obtained in good yield and stereoselectivity. These compounds have also been prepared in gram quantities and recrystallized to near enantiopurity.