Tin (IV) Chloride-Promoted One-Pot Synthesis of Novel Tacrine Analogues

A facile synthesis of potential acetylcholinesterase (AChE) inhibitors, the tacrine analogues 3a-p, has been accomplished by direct cyclocondensation of 1-aryl-4-cyano-5-aminopyrazole with β-ketoesters using tin(IV) chloride as catalyst. The structures of all the compounds have been confirmed by IR, 1H- and 13C-NMR.


Introduction
Alzheimer's disease (AD), the most common form of dementia among the elderly, is a progressive, degenerative disorder of the brain with a loss of memory and cognition [1]. Tacrine is a reversible inhibitor of acetylcholinesterase (AChE) that was launched in 1993 as the first drug for the treatment of AD [2]. The evaluation of the clinical effects of tacrine has shown efficacy in delaying the deterioration of the symptoms of AD, but the poor selectivity of this drug for AChE has resulted in a number of side effects, specially hepatotoxicity [3], and current research is focused on developing new AChE inhibitors with improved activity and reduced adverse side effects, therefore novel tacrine analogues have been reported [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18].
Friedlander annulation is one of the simplest and most straightforward protocols for the preparation of quinoline derivatives [19,20]. Although it has been known for more than a century, it is still a hotspot of research. Herein, we report that the Friedlander annulation of 1-aryl-4-cyano-5-

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aminopyrazole with β-ketoesters using SnCl 4 as catalyst afforded the novel tacrine analogues 3a-p in good yields.
For the investigation of reaction conditions for cyclocondensation of 1-aryl-4-cyano-5-aminopyrazole with β-ketoesters, we chose the reaction of 1-phenyl-4-cyano-5-aminopyrazole (1a) with methyl acetoacetate as a model reaction. Because the choice of the catalyst played a crucial role, we initially studied the effect of several catalysts on the yields and found the use of anhydrous AlCl 3 , ZnCl 2 and TiCl 4 to be much less effective and tacrine analogue 3a was obtained in less than 43% yield. Moreover, none of the product desired 3a was obtained when we used CuCl and CuCl 2 as catalysts. However, when a mixture of 1-phenyl-4-cyano-5-aminopyrazole (1a) and methyl acetoacetate in toluene was stirred under reflux in the presence of SnCl 4 , the reaction was complete within 3 h and after work up, the product 3a was obtained in 78% yield (Table 1) A profound solvent effect on the reaction was observed. We initially studied the effect on the reaction of non-polar solvents, such as DCM, DCE, THF and toluene, in which SnCl 4 is easily dissolved. Then we went on to study the polar solvent DMF. The results are summarized in Table 2. These results suggest that the solvent had a dramatic effect on the yields. Toluene was found to be the best solvent.  Under the optimized reaction conditions (SnCl 4 as catalyst and anhydrous toluene as solvent, reflux for 3 h), a series of reactions between 1-aryl-4-cyano-5-aminopyrazoles and β-ketoesters were tested and a series of tacrine analogues 3 was thus prepared in good yields, regardless of the position of the group R 1 on the aromatic ring. The results were summarized in Table 3.  3a  3b  3c  3d  3e  3f  3g  3h  3i  3j  3k  3l  3m  3n  3o  3p   78  75  70  74  72  65  62  58  76  74  71  75  73  64 60 57 a All reactions were carried out using 1a (10 mmol), β-ketoesters (10 mmol), SnCl 4 (20 mmol) and toluene (20 mL), reflux for 3 h; b Isolated yields.
The mechanism of formation of tacrine analogue 3 can be explained by Scheme 2. The attack of the amino group of 1 onto the carbonyl carbon atom of 2 gave intermediate I, from which product 3 was obtained through the Friedlander reaction.

General
All melting points were determined on an XT-4A apparatus. TLC was performed using precoated silica gel GF 254 (0.25 mm), column chromatography was performed using silica gel (200-300 mesh). The 1 H-and 13 C-NMR spectra were measured at 300 and 75 MHz, respectively, on a Bruker Advance 300 spectrometer at 25 °C, using TMS as internal standard. J-values are given in Hz. The IR spectra were taken on a Bruker Vector 55 spectrometer. 1-Aryl-4-cyano-5-aminopyrazoles 1 were prepared according to a reported procedure [22].

Typical procedure
1-Aryl-4-cyano-5-aminopyrazole 1 (10 mmol) and SnCl 4 (2.3 mL, 20 mmol) were added to a stirred solution of β-ketoester (10 mmol) in dry toluene (20 mL). The reaction mixture was stirred under nitrogen at room temperature for 30 min and then heated under reflux for 3 h. The reaction mixture was cooled and dispersed into water and titrated to pH 12-13 with a saturated aqueous solution of Na 2 CO 3 . After filtration, the filtrate was extracted three times with ethyl acetate, the organic layers were dried and evaporated at reduced pressure to give the solid product. The product was purified by silica gel column chromatography to give 3a-p.

Conclusions
We have developed an efficient catalyst system using SnCl 4 in anhydrous toluene for the reaction between o-aminonitriles containing pyrazole moieties with β-ketoesters. A series of novel tacrine analogues 3a-p has been thus synthesized and their spectroscopic characterization and structural features have been presented.