Abstract: Simple and green synthetic procedures constitute an important goal in organic synthesis. The combination of multicomponent reactions (MCRs) and unconventional solvents has become a new research direction, which enables simultaneous growth of both MCRs and green solvents toward ideal organic synthesis. This review summarizes recent results of MCRs obtained in unconventional media including water, ionic liquids, polyethylene glycol and bio-based solvents.

Conclusions and perspectives

MCRs were considered as an important instrument to perform an “ideal synthesis” that was defined by Wender et al., where the target molecules were synthesized in one step, in quantitative yield from easily available and inexpensive starting materials in resource effective and environmentally acceptable process. On the other hand, to combat the harmful effect of organic solvents frequently used in large quantities for organic transformations, many liquid substances (or fluids) have been recently proposed as alternative green reaction media. Combination of MCRs and unconventional green solvents has originated a new research direction that has emerged as an important facet of green chemistry, from which both MCRs and green solvents can simultaneously benefit. These researches not only offered facile preparation of various highly functionalized organic molecules by environmentally benign routes, but also opened an avenue to further strengthen the current innovation of green solvents.

Many new MCRs have been developed by using water, ionic liquids, polyethylene glycol and some bio-based chemicals as alternative media to conventional organic solvents. Indeed, these solvents have an indispensable role in the development of many new MCRs. Modification of known MCRs with green characteristics remains a challenge, but the utilization of unconventional media offers researchers an important vehicle to realize this idea. Although some of them can be performed in conventional solvents or under solvent-free conditions, the use of unconventional solvents often endowed the system some concomitant advantages that cannot be attained by other ways. For example, by means of controlling the solubility of the starting materials in water, the performance of some MCRs could be changed, to some extent, because the reactions were carried out either “in water” or “on water”. In order to fit the requirements of some MCRs, the reaction media, such as ionic liquids, can also be derivatized to be task-specific by means of post modifications. Using water and ionic liquids in metal-catalyzed MCRs also facilitates the recovery of metal catalysts. Some unique properties of unconventional solvents also allow the use of assisting techniques such as microwave irradiation. The low toxicity of some unconventional solvents, such as PEG and glycerol, also allows their use as a solvent in the multicomponent synthesis of pharmaceutically active ingredients, in which the toxicity and residue of solvents have to be carefully controlled. During the investigation of some MCRs, the necessity of using a new candidate as green solvent has also been well documented.

Looking back over the past decades, endeavors of performing MCRs in unconventional solvents are mostly driven by the concept of using an unusual solvent as reaction medium. However, the catalogues of MCRs that can be performed in these solvents are rather limited. This can be partially ascribed to the deficiency in the diversity of unconventional green solvents. Therefore, development of new green solvents will be beneficial for the chemistry of MCRs. When MCRs are used in the preparation of pharmaceutical chemicals, careful attention is needed in selecting reaction solvents. The green image of ionic liquids is currently under scrutiny on the grounds of combustibility, toxicity, and biodegradability. Fortunately, knowledge of the toxicity profiles of ionic liquids will help us find ionic liquids that are less toxic. For example, the toxicity of [BMIm]-based ionic liquids is dependent on the counteranion, and halide, tetrafluoroborate, and hexafluorophosphate ionic liquids are more toxic than alkyl sulfate-containing ionic liquids. Although MCRs in bio-based solvents have been rarely investigated so far, in view of the low toxicity and good bio-compatibility of these solvents, it is not unreasonable to expect that MCRs in bio-based solvents will be a noticeable topic in the future.

Published in Green Chem., 2012, 14, 2091–2128