L-Ascorbic acid as an efficient organocatalyst for the synthesis of dispiro[tetrahydroquinoline-bis(1,3-dioxane-4,6-dione)] derivatives

An efficient four-component reaction between aromatic aldehydes, 1,3-dioxane-4,6-dione, arylamines and acetone for the synthesis of dispiro[tetrahydroquinoline-bis(1,3-dioxane-4,6-dione)] derivatives in the presence of L-ascorbic acid as an efficient organocatalyst, is described. The remarkable advantages offered by this protocol are an inexpensive catalyst, good yields, a broad substrate scope, mild conditions and, a simple and easy work-up procedure. This method affords the end products through a combination of the Knoevenagel, Michael, Diels-Alder and an intramolecular reaction.


Introduction
][3] Some hydroquinoline structures are potent tetrahydroquinoline-derived antibiotics extracted from Janibecter limosus. 4Particularly, tetrahydroquinoline derivatives have exhibited a wide range of interesting biological activitives, for example, antiproliferation, 5 antifungal, 6 antihyperalgesia, 7 anticancer, 8,9 antituberculosis, 10 neuronal nitric oxide synthase (nNOS) inhibition, 11 5-HT2C receptor agonism, 12 anti-Inflammatory, 13 and anti-HIV activity. 14Tetrahydroquinolines including Meldrum's acid structure can provide attractive building blocks for the synthesis of natural products.They are also the starting materials for the synthesis of exotic amino acids that are used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins. 15,16Therefore, the development of new methods for the synthesis of hydroquinoline ring compounds is of continuous interest to synthetic as well as medicinal chemists.
Multicomponent reactions with features such as easy operation, high efficiency, high selectivity and atomic economy are considered to be the closest to the ideal synthesis process and have been widely used in the fields of the total synthesis of natural products, heterocyclic compounds and combinatorial chemistry. 17,18iastereoselective synthesis of dispiro[tetrahydroquinoline-bis(2,2-dimethyl [1,3]dioxan-4,6-dione)] derivatives through a three-component reaction of amines, aromatic aldehydes, and Meldrum's acid has been reported in the presence of various Brønsted acids such as acetic acid, 19 benzoic acid, 20 trichloroacetic acid, 21 citric acid, 22 salicylic acid, 23 phthalic acid. 244-(sulfobutyl)tris(4-sulfophenyl)phosphonium hydrogen sulfate can also achieve good catalytic effect in this reaction 25 (Scheme 1).However, many of these methodologies are associated with limitations such as low yields, long reaction times, high catalyst loading, and environmentally unfavorable solvents.Therefore, an efficient, and enviromentally friendly method for the synthesis of hydroquinoline compounds is certainly desirable.
Ascorbic acid, also known as vitamin C, is a polyhydroxy compound with acidic and reducing properties.In recent years, it has received considerable attention as a green, mild and inexpensive catalyst for various organic transformations, such as multicomponent reactions, 18,26,27 the degradation of cyanidin-3-O-βglucoside, 28 benzaldehyde formation, 29 and ipso-hydroxylation of arylboronic acid. 30Due to its wide applicability as an efficient organocatalyst, L-ascorbic acid is herein reported as an effective catalyst for the synthesis of dispiro[tetrahydroquinoline-bis(1,3-dioxane-4,6-dione)] derivatives via a four-component reaction involving an initial Knoevenagel reaction, followed by a Diels-Alder, Michael addition and finally an intramolecular reaction (Scheme 2).

Conclusions
In conclusion, an efficient four-component reaction between aromatic aldehydes, 1,3-dioxane-4,6-dione, arylamines and acetone for the synthesis of dispiro[tetrahydroquinoline-bis(1,3-dioxane-4,6-dione)] derivatives in good yields was reported catalyzed by L-ascorbic acid.The operation and work-up procedures are straightforward and no column chrommatography purification is needed as well.These advantages will make this method a valid contribution to existing methodologies for hydroquinoline containing ring compounds.

Experimental Section
General.1,3-dioxane-4,6-dione was prepared according to literature. 32,33The other chemicals were purchased from Aladdin, Aldrich and Fluka Chemical Companies and without further purification.Melting points were measured on XT-4 digital micro melting point apparatus and are uncorrected. 1H NMR spectra were recorded on a BRUKER AVANCE 400 MHz spectrometer using CDCl3 as the solvent and TMS as the internal standard. 13C NMR data were collected on a BRUKER AVANCE 100 MHz instrument with CDCl3 as the solvent and TMS as the internal standard.The analytical MS of the compounds was performed on Agilent LC-MSD Trap VL Apparatus.The crystal structure was determined by Siemens P4 four circle diffractometer.

Table 1 .
Optimization of reaction conditions for the synthesis of 5a a