Dipolar aprotic solvents (DMSO, DMF, DMAc, NMP, etc.) have been widely used in organic synthesis and pharmaceutical research because of their remarkable polarities and solubilities, while most of them are not green because of their detrimental effects on human health and hazards to the natural environment caused by their inescapable toxicity as well as large wastewater streams and high-energy-input requirements. This dangerous situation is further complicated by the surging demand of dipolar aprotic solvents in the research and development in the pharmaceutical industry and other chemical processes. Therefore, minimizing and avoiding the use of such solvents has become one of the most important facets of green chemistry. So far, substantial efforts have been devoted in response to this problem that has entailed the development of green and novel reaction systems that fulfill numerous requirements, which are also met by traditional dipolar aprotic solvents. In this context, this review summarizes the methods and strategies for replacing non-green polar aprotic solvents, which mainly include direct replacement with new green alternatives and utilization of polarized catalysts in common green solvents for avoiding the use of conventional polar aprotic solvents. Besides, the strengths and weaknesses of these two strategies are analyzed. Compared with the direct replacement strategy, the rational design of polarized catalysts not only expands the choice of green solvents, but also provides new possibilities for the design and preparation of multifunctional catalysts, suggesting a promising prospect in substitution strategies for non-green polar aprotic solvents. Certainly, other methods are being explored to realize the green and sustainable replacement of conventional dipolar aprotic solvents in an economical and handy tactic.

Three-component reactions of salicylaldehydes, 1,3-cyclohexanediones and a sulfur, carbon, or nitrogen-based nucleophile were developed, for the first time, by using L-proline as a catalyst, which generated various substituted 4H-chromene derivatives in good to excellent yields. The reactions were performed in ethanol under mild and metal-free conditions. In these reactions, the use of L-proline as a catalyst was proven to be key for rendering the reactions possible because replacing L-proline with other acids or bases resulted in the generation of many side products. Many nucleophiles, such as thiophenols, mercaptans, indoles, sulfinic acid, benzotriazole, 2-naphthol, 5-methyl-2-phenyl-1,2-dihydropyrazol-3-one, 6-aminouracil, 6-amino-1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione and some commonly used C–H acids including 4-hydroxycoumarin, 2-hydroxy-1,4-naphthoquinone and barbituric acid could be successively used to assemble with dimedone and salicylaldehyde. Particularly, the product generated from the reaction of benzotriazole, 3-methoxysalicylaldehyde and dimedone can also be used as a starting material, in which the fragment of benzotriazole acts as a leaving group, for the synthesis of some important compounds by reacting with many carbon-based nucleophiles, such as dibenzoylmethane, ethyl benzoylacetate, 1,3-cyclohexanedione, N,N-dimethylaniline, 2-methylfuran and sesamol in acidic conditions. This offers a complementary route to access some 4H-chromenes that cannot be attained with the above-mentioned three-component reactions.

Many multicomponent reactions (MCRs) of 1,3-disubstituted 5-pyrazolones and formaldehyde were developed in environmentally benign solvent systems. Styrenes, vinylferrocene and 2-phenylindoles could easily react, under solvent-free conditions or in glycerol solvent, with 1,3-disubstituted 5-pyrazolones and paraformaldehyde in the absence of any catalyst to afford a variety of complex skeletons in moderate to excellent yields. Particularly, these MCRs are proved to be combinable with the synthesis of 1,3-disubstituted 5-pyrazolones from phenylhydrazines and β-ketone esters in glycerol or a carboxylic acid-functionalized ionic liquid, [MIm-CO₂H]BF₄. Therefore, some two-step sequential reactions of phenylhydrazines, β-ketone esters, formaldehyde and styrenes or indoles were developed for the first time. All these MCRs were conducted in environmentally benign solvent systems that not only minimize generation of wastes but also simplify the work-up procedure.

For the first time, gluconic acid aqueous solution (GAAS), a biobased weakly acidic liquid, was used as an effective promoting medium for organic reactions, such as the Michael addition of indoles to α,β-unsaturated ketones, the electrophilic ring-opening reaction of 3,4-dihydropyran with indoles and Friedel–Crafts alkylation of electron-rich aromatics with benzyl alcohols. The concept of using GAAS as a solvent for organic reactions not only offers a sustainable candidate for progress in solvent innovation, but also opens up a new avenue for the utilization of this biobased polyhydroxylated acid. Among the features that render GAAS as a solvent so interesting is the ability to act as both the reaction medium and catalyst. Moreover, this methodology offers significant improvements with regard to the yield of products, simplicity in operation, cost efficiency and green aspects, in terms of avoiding toxic catalysts and minimizing the generation of waste.