Highly efficient synthesis of 7 - aryl-pyrano[3,4-c ]pyrazolo [4,3-f ]quinoline derivatives catalyzed by iodine

A mild and efficient method for the synthesis of 7-arylpyrano[3,4-c ]pyrazolo[3,4-f ]quinoline derivatives via a three-component reaction of aromatic aldehyde, 1 H -Indazol-5-amine and tetrahydropyran-4-one catalyzed by iodine is described. This new procedure has the advantages of mild reaction condition, high yields, one-pot and metal-free catalyst.


Introduction
Pyranoquinoline derivatives are found to possess a wide spectrum of biological activities, such as psychotropic, anti-allergenic, anti-inflammatory and estrogenic activities. 1 Pyrazoloquinoline derivatives are also an important class of heterocylcles due to their promising materials for optoelectronic applications. 2In addition, they are reported to possess anti-leishmanial and antimicrobial activities. 3Some of them are used as modulators of cytokine biosynthesis for treatment of viral and neoplastic diseases, 4 and immuno modulators for inducing cytokine biosynthesis in animals. 5lthough a number of useful synthetic procedures to prepare pyranoquinoline 6 and pyrazoloquinoline 7 derivatives have been developed, to the best of our acknowledge, there is no literature about the synthesis of fused heterocycle containing both pyran, pyrazole and quinoline rings, this novel skeleton may posses potential bioactive for screening.Thus, simple and efficient method to synthesize pyranopyrazoloquinolines would be attractive, Over the past few years, molecular iodine (I2) has emerged as a powerful catalyst for various organic transformations due to several advantages such as its inexpensive, nontoxic, and ecofriendly nature. 8As a continuation of our research devoted to the development of new methods for the preparation of heterocycles via multi-component reactions catalyzed by iodine, 9 herein, we would like to report the synthesis of 7-aryl-pyrano[3,4-c]pyrazolo[3,4-f]quinoline derivatives by a reaction of aromatic aldehyde, 1H-indazol-5-amine and tetrahydropyran-4-one in THF catalyzed by iodine.

Results and Discussion
Treatment of aromatic aldehyde 1a-l, 1H-indazol-5-amine 2 and tetrahydropyran-4-one 3 in THF in the presence of 5 mol% iodine at reflux condition afforded the corresponding 7-arylpyrano[3,4-c]pyrazolo[3,4-f]quinoline derivatives 4a-l in high yields (Scheme 1).Scheme 1.The reaction of 1a-l, 2 and cyclopentanone 3. Using the conversion of 2-chlorobenzaldehyde 1a, 2 and 3 as a model, several parameters were explored as shown in Table 1.The 4a was not detected by TLC at room temperature and reflux in the absence of iodine (Table 1, Entries 1 and 2), and much greater in the presence of various quantities of the catalyst (I2), reaching a maximum of 93 % yield with 5 mol% iodine (Table 1, entries 5-7).The yield of 4a was also dependent on temperature (entries 3~5), proceeding smoothly at reflux in high yield.Different solvents were also tested, and THF appeared to be the best medium for this transformation (entry 5 vs. 8-11).In addition, other Lewis acids, such as TsOH, ZnCl2, Yb(OTf)3 and Sc(OTf)3, were selected as catalysts to this reaction in 5 mol%, they all gave slightly lower yields.
These optimized conditions were applied to the conversion of various kinds of aromatic aldehydes 1a-l into the corresponding 7-aryl-pyrano[3,4-c]pyrazolo[3,4-f]quinoline analogues 4a-l.Reactions using aldehydes containing electron-withdrawing groups (such as halide) or electron-donating groups (such as alkyl and alkoxy group) all proceeded smoothly within a few hours, giving 4a-l in high yields.It should be noted that only 7-aryl-pyrano[3,4-c]pyrazolo[3,4f]quinolines were obtained in high region-chemistry.The best reason is that the 4-position is not only the ortho-position to amino group, but also the -position of the benzene ring in 1Hindazol-5-amine, which is more active than 6-position.According to the literatures, 10 we think that iodine catalyzes the reaction as a mild Lewis acid.The mechanism was tentatively proposed as shown in Scheme 2. In the presence of iodine, tetrahydropyran-4-one is in equilibrium with its enol form.10b The Schiff base I may be formed by the reaction of aromatic aldehyde and 1H-indazol-5-amine firstly.And then imino-Diels-Alder reaction between the iodine-activated Schiff base II and enol takes place selectively to form the intermediate III for its stability.The dehydration of III results in dihydro pyrano[3,4c]pyrazolo[3,4-f]quinoline IV, which is further oxidized by air to afford aromatized final products 4. Scheme 2. The possible mechanism for the formation of products 4.

Conclusions
In conclusion, we found a mild and efficient method for the synthesis of 7-aryl-pyrano[3,4c]pyrazolo[3,4-f]quinoline derivatives via three-component reactions of aromatic aldehyde, 1Hindazol-5-amine and tetrahydropyran-4-one catalyzed by iodine.The features of this procedure are mild reaction conditions, high yields, operational simplicity, one-pot and metal-free catalyst.

Experimental Section
General.Melting points were determined in open capillaries and are uncorrected.IR spectra were recorded on a Tensor 27 spectrometer in KBr pellet. 1 H NMR spectra and 13 C NMR was obtained from a solution in CDCl3 or DMSO-d6 with Me4Si as internal standard using a Bruker-400 spectrometer.HRMS analyses were carried out using a Bruker-micro-TOF-Q-MS analyzer.

Table 2 .
Synthetic results of 4a-l catalyzed by iodine a b Isolated yields.