The Diels–Alder reaction, a concerted [4+2] cycloaddition of a conjugated diene and a dienophile, is a powerful tool for the regio- and stereoselective construction of six-membered rings [1,2,3,4,5,6]. In its original version, two new C–C bonds are created in the Diels–Alder reaction and six-membered carbocyclic systems are obtained. Beyond this classical Diels–Alder reaction, other well-known types include the hetero-Diels–Alder reaction (at least one heteroatom is present on the diene or dienophile) leading to six-membered heterocycles and the intramolecular Diels–Alder reaction in which fused cyclic systems are obtained. Additionally, the Lewis acid catalyzed and organocatalytic Diels–Alder reactions have been developed, widening the scope of these reactions, namely the synthesis of optically active compounds via catalyzed asymmetric Diels–Alder reactions. Notably, a century after its discovery, the Diels–Alder reaction remains one of the most important green synthetic methodologies due to its theoretical 100% atom economy [7].

Driven by the green chemistry principles [8], the demand for sustainable and safe chemical processes over the last two decades has promoted the replacement of volatile organic compounds (VOCs) traditionally used as solvent media in synthetic chemistry with alternative green solvents [9,10,11,12,13,14] or even solvent-free conditions [15]. This endeavor gave rise to the introduction of new solvent media for chemical transformations featuring reduced environmental risk, reduced toxicity, reduced flammability, cost-effectiveness and reusability properties as the major advantages. Leading VOC alternatives for organic transformations are bio-based derived solvents (e.g., glycerol, lactic acid, gluconic acid) [16,17,18,19], liquid polymers (e.g., PEG) [20], ionic liquids [21,22], deep eutectic solvents [23,24,25,26], supercritical fluids [27,28,29,30,31], water and water-based aqueous systems [32,33,34,35,36,37]. 

Glycerol, the main by-product in the biodiesel industry, is a nontoxic, biodegradable, recyclable and inexpensive viscous liquid. These properties, allied with the high stability, biocompatibility and ability to dissolve organic compounds poorly miscible in water as well as inorganic compounds, make glycerol a valuable green solvent in synthetic organic chemistry [38,39,40].

The three-component aza-Diels–Alder reaction of substituted anilines, aldehydes and electron-rich alkenes, also known as three-component imino-Diels–Alder reaction, or multicomponent Povarov reaction, is one of the most straightforward, efficient and atom-economical strategies towards complex cores starting from simple, inexpensive and available materials. Perin and coworkers explored the intramolecular version of this reaction for the catalyst-free synthesis of octahydroacridines starting from (R)-citronellal (1) and substituted arylamines 2 using glycerol as a recyclable and eco-friendly solvent (Scheme 1) [41]. Cycloadducts 3 and 4 were obtained as diastereoisomeric mixtures in good to high yields (75–98%) and moderate cis-selectivity when the reaction was carried out at 90 °C. Cycloadducts 3/4 (R = H) were obtained in lower yield (62%) using water as solvent, whereas the reaction carried out in organic solvents afforded the corresponding adducts in only trace amounts. Due to the insolubility of 3 and 4 in glycerol, products could be removed from the reaction medium by decantation, and the solvent could be reused for further aza-Diels–Alder reactions without loss of activity.

Scheme 1. Catalyst-free intramolecular aza-Diels–Alder reaction of (R)-citronellal and substituted arylamines in glycerol.

Gluconic acid (GA) can be obtained from biomass and possesses the ideal properties for being classified as a green and sustainable solvent (e.g., nontoxicity, biodegradability, recyclability, high boiling point, low vapor pressure) [42]. Due to the high solubility of gluconic acid in water, gluconic acid aqueous solutions (GAASs) have found wide application as solvent media for organic reactions, namely for the Knoevenagel condensation reaction. The Gu group reported the synthesis of 2H-pyrans by a one-pot multicomponent reaction between β-ketosulfones, formaldehyde and styrenes in a bio-based binary mixture solvent system composed of GAAS and a sugar-based organic base, meglumine [43]. The disclosed protocol involves the in situ generation of α-methylene-β-ketosulfones 21 through a Knoevenagel reaction of β-ketosulfones 19 and formaldehyde. Next, nucleophilic trap of 21 with styrenes 22 via oxa-Diels–Alder reaction afforded 2,6-diaryl-5-(phenylsulfonyl)-3,4-dihydro-2H-pyrans 23 in moderate to good yields (50–82%) (Scheme 2). The binary solvent system GAAS/meglumine proved to play a pivotal role in controlling the selectivity of the hydroxymethylation step. Moreover, the hydrophilic properties of bio-based solvent meglumine allowed it to be easily recycled and reused in the GAAS/meglumine system without significant loss of activity.

Scheme 2. Multicomponent reaction of β-ketosulfones, formaldehyde and styrenes in a bio-based binary mixture of GAAS and meglumine.

Polyethylene glycol (PEG), HO–(CH₂CH₂O)_n–H, is a biodegradable, nontoxic, odorless, neutral, nonvolatile and inexpensive water-soluble polymer that has found widespread application as a green reaction medium for several organic transformations [44]. The Kouznetsov group reported the diastereoselective synthesis of heterolignan-like 6,7-methylendioxy-tetrahydroquinolines via a BF₃^.OEt-catalyzed three-component Povarov reaction using clove bud essential oil as a renewable raw material and PEG-400 as green solvent (Scheme 3) [45]. Clove bud essential oil enriched with eugenol 24 (60.5%) was obtained by hydrodistillation of dried flower buds and then subjected to a solid base-catalyzed isomerization to give trans/cis-isoeugenol 25, which could be used as a dienophile in the multicomponent hetero-Diels–Alder reaction without further purification. The reaction of 25 with aldimines generated in situ from substituted benzaldehydes 27 and 3,4-(methylendioxy)aniline (26) afforded trans-2,4-diaryl-1,2,3,4-tetrahydroquinolines 28 as racemic mixtures in moderate yields (35–55%). The reaction with phthalaldehydic acid (29) afforded isoindolo[2,1-a]quinolin-11(5H)-one 30 via an intramolecular condensation of the initially generated NH-tetrahydroquinoline core with the o-carboxylic acid function leading to the formation of the γ-lactam ring. It is noteworthy that these reactions also worked using acetonitrile as solvent media; however, less solvent volume and reduced reaction times were required when using PEG-400.

Scheme 3. BF₃^.OEt-catalyzed one-pot multicomponent aza-Diels–Alder reaction of 3,4-(methylendioxy)aniline, aromatic aldehydes and trans/cis-isoeugenol in PEG-400.

Propylene carbonate (PC) is a polar aprotic solvent that can be obtained from propylene oxide and carbon dioxide, a renewable source of carbon, in a 100% atom economy reaction with relevance regarding the development of CO₂ fixation processes. The noncorrosive, nontoxic, odorless and biodegradable properties of PC, allied with high boiling point, low vapor pressure and low cost, make this solvent a green and sustainable alternative to conventional organic solvents [46]. The Povarov reaction has also been explored using PC as an environmentally friendly solvent [47]. The one-pot iodine-catalyzed reaction of mono- or disubstituted anilines 2, aromatic aldehydes 5 and isoeugenol (45) carried out at room temperature using PC as solvent medium afforded functionalized tetrahydroquinolines 46 in good to high yields (77–95%) and high diastereoselectivity (dr up to >99:1) (Scheme 4). The same cycloadducts were obtained using organic solvents, albeit in low yields and requiring longer reaction times. It is noteworthy that, in general, products precipitated from the reaction medium and were purified by recrystallization.

First introduced by Abbot [48], deep eutectic solvents (DESs) are low melting mixtures obtained by combination of at least two components, a hydrogen bond acceptor (HBA), generally a quaternary ammonium or metal salt, and a hydrogen bond donor (HBD), to form a eutectic phase via hydrogen bond interactions. DESs are characterized by a melting point lower than those of the single components. The properties of DESs are very similar to those of room-temperature ionic liquids; however, the main difference from ionic liquids is that DESs also contain an organic molecular component, the HBD (e.g., urea, amide, polyol), generally as a major component. Due to their low vapor pressure, nonflammability, thermal and chemical stability, nontoxicity, biodegradability, recyclability and low price, DESs have emerged as green and sustainable media in different areas of chemical research [49,50], namely organic synthesis and catalysis [51,52].

Garcia-Álvarez’s group reported a one-pot tandem cycloisomerization/Diels–Alder reaction using a ChCl (choline chloride)-based eutectic mixture as solvent [53]. The protocol involves the in situ generation of furans 59 by cycloisomerization of (Z)-enynols 57 using a ChCl/Gly (1:2) eutectic mixture as solvent and bis(iminophosphorane)-Au(i) complex 58 as catalyst (Scheme 5). The Diels–Alder reaction of furans 59 with activated alkynes 60 afforded 7-oxanorbornadienes 61, whereas the reaction with activated alkenes, 55b or 62, afforded selectively exo-7-oxanorbornenes 63. The authors have demonstrated that complex 58 is crucial for the cycloisomerization step; however, it does not participate in the cycloaddition step.

Scheme 5. One-pot tandem cycloisomerization/Diels–Alder reaction of (Z)-enynols in a ChCl/Gly deep eutectic solvent.

6. Supercritical Carbon Dioxide

Supercritical carbon dioxide (scCO₂) is an abundant, low-cost, nontoxic and nonflammable fluid. The physical properties of scCO₂ are intermediate between the gas and the liquid phases. These properties can be tuned by changing pressure and temperature; in particular, changes close to the critical point enable drastic changes in density, viscosity and diffusion. Among supercritical fluids, scCO₂ has received special attention since it is readily accessible at a low critical temperature (T_c = 31 °C) and moderate critical pressure (P_c = 75.8 bar) [54]. In addition, scCO₂ has the ability to dissolve organic compounds and can be easily removed from the reaction mixture, making it a sustainable alternative to conventional organic solvents in synthetic transformations [55,56,57,58]. Keshtov et al. disclosed a green approach for the synthesis of photoluminescent polymers based on phenyl-substituted polyfluorenes using scCO₂ as the solvent medium [59]. Phenylated polyfluorenes 88 were synthesized through a catalyst-free Diels–Alder reaction of fluorene-containing bis(tetraarylcyclopentadienone) monomer 86, acting as diene, with bis(acetylenes) 87 acting as 2π-component (Scheme 6). Phenyl-substituted polyfluorenes synthesized using scCO₂ as solvent showed similar properties to those synthesized using chloronaphthalene as solvent, demonstrating that scCO₂ is a suitable alternative to organic solvents for the synthesis of phenylated polyfluorenes via the Diels–Alder reaction.

Scheme 6. Diels–Alder reaction of fluorene-containing bis(tetraarylcyclopentadienone) and bis(acetylenes) in scCO₂.

The use of water as an alternative benign and sustainable solvent in promoting Diels–Alder cycloaddition reactions has been widely explored since the seminal work of Breslow’s and Grieco’s groups [60,61,62,63]. The remarkable rate enhancements and selectivities achieved on moving from conventional organic solvents to aqueous conditions are the major driving force behind the growing interest in the study of the Diels–Alder reaction in this medium [64,65].

7.1. The Water Effect: Experimental and Theoretical Studies

Hydrophobic interactions, along with hydrogen bonding, polarity and cohesive energy density, are the major factors responsible for the rate enhancement in “on-water” Diels–Alder cycloadditions. Several systematic experimental and theoretical studies analyzing the pivotal role of water in the rate enhancement and selectivity of the Diels–Alder cycloaddition reactions have been disclosed. Shrinidhi reported a comparative study of the rates and efficiency of the Diels–Alder cycloaddition reaction between cyclopentadiene (39) and electron-poor alkenes 95 in solvent media featuring different polarities (organic solvents and water) (Scheme 7) [66]. For each dienophile, it was observed that cycloadducts 96 yield increases with the increase in solvent polarity (hexane < dichloromethane < THF–water < water) and concomitantly with the solvophilicity of the dienophile. The effect of adding a catalytic amount of water along with organic solvents (dichloromethane and THF) was also explored, demonstrating that the reaction is more efficient in the presence of catalytic amounts of water than in pure organic solvents. Based on these results, combined hydrophobic and hydrogen bonding effects were attributed to the rate enhancement of the Diels–Alder reaction when carried out in water as compared to conventional organic solvents. The hydrogen bonding effect was previously reported by Domingo’s group supported by a density functional theory (DFT) study on the catalytic effect of water in the intramolecular Diels–Alder reaction of a quinone system [67]. Theoretical calculations demonstrated the pivotal role of water in stabilizing the polarized transition state through hydrogen bond formation with the internal electron-deficient dienophile.