‘Solvent-free’ and ‘on-solvent’ multicomponent reaction of isatins, malononitrile, and bicyclic CH-acids: a fast and efficient way to a medicinally-privileged spiro-oxindole scaffold

The fast (15 min) PASE-' solvent-free ' and ' on-solvent ' multicomponent reactions of isatins, malononitrile and bicyclic CH-acids catalyzed by sodium acetate result in efficient formation of substituted spiro-oxindoles in 90– 98% yields. These methods are fast multicomponent approaches to the spiro-oxindoles, substances with promising anticancer activities. These new ' solvent-free ' and ' on-solvent ' techniques reduce solvent use, thereby leading to reduced waste, in connection with a new concept of solvent-assisted domino-reaction strategy


Introduction
Domino reactions are an up-to-date method to obtain ideal synthesis 1 in one-pot reactions.Domino reaction strategy has substantial advantages over conventional linear-type synthesis due to its flexible, convergent and atom efficient nature. 2 In this way, domino processes overlap with PASE (Pot, Atom, Step Economic)strategy, 3s which claims pot and step economy, and introduces atom economy, meaning that ideally the number of atoms of all reagents should be present in the final compound.
With the advent of domino processes, solvent-free chemistry has emerged as a powerful tool for creating molecular complexity by much greener ways.The use of costly, explosive, toxic and carcinogenic chemicals (catalyst, reagents or solvents) do not qualify them under sustainability metrics as they augment the ecosystem toxicity resulting in socioeconomic burden.Solvent-free methods, in comparison with classic synthesis, produce many advantages such as high efficiency and selectivity and operational simplicity. 4owever, the solvent assisted ('on-water' and 'on-solvent') methods in comparison with solventless mechanochemical processes have many more application areas due to greater flexibility, selectivity, and reduced reaction time. 5he design of functional organic and hybrid molecular systems has shown outstanding recent growth, and of high priority is the development of new technologies and novel functional materials.In this connection, the concept of 'privileged medicinal structures or scaffolds' has emerged as one of the guiding principles of drug discovery design. 6Such privileged scaffolds commonly consist of a rigid heterocyclic ring system that assigns well-defined orientation of appended functionalities for target recognition.
The privileged heterocyclic spiro-oxindole scaffold is a widely distributed structural framework in a number of pharmaceuticals and natural products, 7 including such cytostatic alkaloids as spirotryprostatins A, B, and strychnophylline. 8The unique structural array and the pronounced pharmacological activity displayed by the class of spiro-oxindole compounds have made them attractive synthetic targets. 9,10mong nitrogen-containing heterocyclic systems, functionalized pyranoquinolines have received considerable attention owing to their wide range of diverse pharmacological activity, such as psychotropic, antiallergenic, and estrogenic activity. 11,12Functionalized pyranochromenes are also relevant from the medicinal viewpoint because of revealed activity against human breast and human alveolar adenocarcinoma cells. 13Fused coumarin derivatives exhibit anti-inflammatory and antiviral activities. 14For pyranocoumarins anti-cancer activity is known. 15hus, a spiro-oxindole fragment connected with a nitrogen-containing heterocyclic system is pharmacologically promising in respect to various biological responses.
In recent years, multicomponent reactions have been suggested for the synthesis of spiro-oxindole scaffolds assembled from isatin, CH-acids and malononitrile in solution under different conditions.As for spiroindoline-3,4'-pyrano[3,2-c]quinolones, one of these methods utilizes extremely complex catalysts FeNi 3 -SiO 2 -nanoparticles in PEG as a solvent, which are prepared in multi-step syntheses with non-eco-friendly N 2 H 4 •H 2 O solution. 16Another method utilized ionic liquid as solvents: 1-butyl-3-methylimidazoliumtetrafluoroborate or DBU acetate, very expensive and hazardous agents. 17,18Other known methodologies utilize techniques such as microwave irradiation and sonication with heating, which generally result in insufficient yields of spiroindoline-3,4'-pyrano[3,2-c]quinolones. 19,20In regard to spiroindoline-3,4'-pyrano[3,2c]chromenes, most methods are concerned either with only one or two examples of the synthesis of spiroindoline-3,4'-pyrano[3,2-c]chromenes, 16,[21][22][23][24] or suffer from high temperatures, extremely expensive catalysts [25][26][27] and also long reaction times (of the order of two days). 28hus, each of the known procedures for the synthesis of the spiro-oxindole fragments connected with a nitrogen-containing heterocyclic system has its merits; however, a fast and efficient PASE 'solvent-free' and 'on-solvent' method for this process has yet to be developed.
Considering our results on the 'solvent-free' and 'on-solvent' multicomponent transformations of carbonyl compounds and CH-acids, [29][30][31][32][33] and also the wide biomedical applications of spiro-oxindoles mentioned above, we were prompted to design a convenient fast and facile PASE solvent-assisted methodology for the efficient and clean multicomponent assembling of isatins, malononitrile and bicyclic CH-acids.

Results and Discussion
In the present study, we report our results on multicomponent 'solvent-free' and 'on-solvent' reactions of isatins 1a-d, malononitrile and bicyclic CH-acids 2a-c leading to spiro-oxindoles 3a-k (Scheme 1, Table 1).
Recently we have found that small additives of water or alcohols have improved thermal multicomponent processes or assembling initiated by grinding. 34,35Thus, the next stage was to carry out experiments with a small addition of water ('on-water' conditions).
Nowadays, solvent assisted ('on-solvent') methods in comparison with solventless mechano-chemical processes have much more application areas due to their greater flexibility, high rates and selectivity, as well as reduced reaction times. 36These 'on-solvent' methodologies 37,38 have been suggested for cascade and multicomponent reactions in a minimum quantity of solvent -in reagent mixtures or emulsions without the complete solution of components to increase the efficiency of the desired complex synthetic organic chemistry processes.

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With the above results and the data on mechanisms of the multicomponent transformation of isatins and CH-acids [39][40][41] the following process for the multicomponent assemblage of isatins 1a-d malononitrile and bicyclic CH-acids 2a-c into substituted spiro-oxindoles 3a-k is proposed (Scheme 2).
The initiation step of the catalytic cycle begins with the sodium acetate-induced deprotonation of a molecule of malononitrile, which leads to malononitrile anion (A) formation.Then Knoevenagel condensation of the anion A with isatin 1 takes place with the elimination of a hydroxide anion and formation of Knoevenagel adduct 4. 42 The subsequent hydroxide-promoted Michael addition of bicyclic CH-acid 2 to electron-deficient Knoevenagel adduct 4 results in formation of the anions B and C. Further cyclization of anion C and protonation with the participation of the next molecule of malononitrile leads to the corresponding spiro-oxindole 3 with the regeneration of malononitrile anion at the last step of the catalytic cycle (Scheme 2).

Conclusions
Under simple and efficient 'solvent-free' and 'on-solvent' conditions sodium acetate as a catalyst can produce, without any heating, a very fast (15 min) and selective multicomponent transformation of isatins, malononitrile and bicyclic CH-acids into substituted spiro-oxindoles in 90-98% yields.This developed multicomponent method is a significant approach to these substituted spiro-oxindoles, pharmacologically important substances with pronounced anticancer activities.The 'solvent-free' and 'on-solvent' green variants of this multicomponent process reduce the quantity of waste, being appealing to chemical industry, and present a new concept of 'on-solvent' domino strategy.It utilizes simple procedures and equipment; it is easy to carry out in the laboratory and to adapt to large-scale processes.

Experimental Section
General.All melting points were measured with a Gallenkamp melting point apparatus. 1H-and 13 C-NMR spectra were recorded in DMSO-d 6 with a Bruker Avance II 300 spectrometer at ambient temperature.Chemical shifts values are relative to Me 4 Si.IR spectra were recorded with a Bruker ALPHA-T FT-IR spectrometer in KBr pellets.Mass-spectra (EI = 70 eV) were obtained directly with a Finningan MAT INCOS 50 spectrometer.HRMS (ESI) was measured on a Bruker microTOF II instrument; external or internal calibration was effected with Electrospray Calibrant Solution (Fluka).All chemicals used in this study are commercially available.