Synthesis of Tricyclic Condensed Rings Incorporating the Pyrazole or Isoxazole Moieties Bonded to a 4-Piperidinyl Substituent

In this paper we report the synthesis of new compounds based on the pyrazole and isoxazole framework fused to a cycloalkene unit, and bearing as a substituent the 1-piperidinyl group as new examples of potential antipsychotic molecules. The general synthesis involves the acylation of a chloro-substituted cyclic ketone with a 1-substituted piperidine-4-carboxylate derivative, followed by heterocyclization of the formed 1,3-dioxo compound with a hydrazine or hydroxylamine.


Introduction
Among the compounds with antipsychotic properties [1] there are the heteropentalenes A-C [2], characterized by a pyrazole and isoxazole framework bonded to p-chlorophenyl and 4-piperidinyl substituents ( Figure 1). In continuation of our interest in the field of the synthesis of biologically active OPEN ACCESS compounds [3], we have now devoted our attention to obtain tricyclic compounds E related to the heteropentalenes A-C as new potential antipsychotic compounds.
A well known strategy to affect the biological activity of organic compounds is to decrease their conformational flexibility. In fact, it has been proposed that appropriate structural constraints could restrict a pharmacophoric structural element to a sufficiently small region of conformational space thereby permitting the ligand to bind to its designated receptor with high affinity and selectivity [4,5]. A way to achieve this goal with heteropentalenes A-C could be to connect the unsubstituted central carbon of the heteropentalene and the α-carbon of the phenyl group with an alkylidene bridge (formula D, Figure 1).
In this line, we have developed a practical and extensible method to build compounds with a tricyclic framework incorporating the pyrazole and isoxazole framework and with the central ring that can be modulated in size, namely compounds with the general formula E shown in Figure 1  The planned retrosynthesis of the derivatives E is shown in Scheme 1. In this approach, the final heterocyclization of the 1,3-dioxo compounds F with hydrazine or hydroxylamine is preceded by acylation of the chloro-substituted cyclic ketones G with the 1-substituted piperidine-4-carboxylate derivatives H. Scheme 1. Retrosynthesis approach.

Results and Discussion
To begin the synthesis of the target derivatives E (Scheme 1), the known cyclic ketones 1a-c [6,7] were acylated by reaction of the corresponding sodium enolate, obtained by reaction with sodium hydride, with the reagent formed by reaction of the N-Boc protected isonipecotic acid 9 with 1,1′-carbonyldiimidazole [8] (Scheme 2). In this way, 1,3-dicarbonyl derivatives 2a-c were obtained in 62-63% yields. Next, these compounds were submitted to N-deprotection by treatment with trifluoroacetic acid in CH 2 Cl 2 . However, while 2b and 2c were easily deprotected giving compounds 3b and 3c in high yields (92-95%), the removal of the N-Boc group from 2a failed. Further attempts to deprotect 2a with HCOOH, 3N HCl in AcOEt, CF 3 COOH and Et 3 SiH, and SnCl 4 in AcOEt all failed unexpectedly, therefore, alternative approaches to the target compounds 6a, 7a and 8a were investigated next (see below).
Compounds 3b,c were converted in 59-72% yields into the related N-benzyl and N-phenylethyl derivatives 4b,c and 5b,c by reaction with benzyl chloride and 2-phenyl-1-iodoethane, respectively. With the key 1,3-dicarbonyl derivatives 4b,c and 5b,c in hand, their conversion into the desired derivatives E was pursued according to the planned retrosynthetic scheme. Compounds 4b,c and hydrazine in methanol were stirred at room temperature to afford the pyrazole derivatives 6b and 6c in good yields (78% and 50%, respectively). Treatment of 5b,c with hydroxylamine hydrochloride in EtOH/AcOH at 80 °C gave isoxazoles 7b,c and 8b,c as mixtures of regioisomers in moderate to good yields. With 5b isoxazoles 7b and 8b were obtained in a 4/1 ratio, while 5c gave isoxazoles 7c and 8c in a 3.2/1 ratio [9]. Scheme 2. Synthesis of compounds 6b, 6c, 7b, 7c, 8b and 8c. HN  To obtain compound 6a the synthetic routes outlined in Scheme 3 were followed. Firstly, the sodium enolate of the ketone 1a was reacted with phenyl 1-benzylpiperidine-4-carboxylate 12, but the 1,3-dicarbonyl intermediate 4a failed to give the expected pyrazole 6a by treatment with hydrazine in AcOH/MeOH at 80 °C. However, when the same enolate was treated with phenyl 1-(phenylcarbonyl)piperidine-4-carboxylate 13 [10], obtained by esterification with phenol of the parent acid (Scheme 5), the formed 1,3-dicarbonyl 10b afforded by treatment with hydrazine in AcOH/MeOH at 80 °C the substituted pyrazole 11 in 82% yield. Finally, LiAlH 4 reduction of the carbonyl group to the methylene unit afforded the target pyrazole 6a in 80% yield (66% overall yield from 1a).
This satisfactory result appeared to open a way to isoxazoles 7a and 8a by simple replacing of the piperidine derivative 13 with the analogue 16 (Scheme 4). However, the treatment of the 1,3-dicarbonyl intermediate 14, obtained in turn by reaction of 1a with 16, with hydroxylamine hydrochloride in EtOH/AcOH at 80 °C failed to afford the expected isoxazoles 15. This unexpected result prompted us to verify another route based on the on the use of the N-benzylpyperidine 17 that was obtained by esterification with phenol of the parent acid (Scheme 5). We were pleased to find that the1,3-dicarbonyl intermediate 5a, formed by reaction of the enolate of the ketone 1a with 17, could be directly converted in the usual way into a mixture of isoxazoles 7a and 8a in 41% and 12% yield, respectively (Scheme 4).

General
All reagents and solvents were purchased from commercial suppliers and used as received. Low boiling petroleum ether corresponds to the fraction collected between 40 and 60 °C. THF was distilled from sodium-benzophenone ketyl and degassed thoroughly with dry nitrogen directly before use. Melting points were determined on a Büchi 510 capillary apparatus and are uncorrected. IR spectra were recorded on a J ASCO FT/IR-460 plus equipment.The NMR spectra were obtained with a Varian VXR-300 spectrometer at 200 MHz for 1 H and 50 MHz for 13 C. Chemical shifts are reported in ppm downfield from internal Me 4 Si in CDCl 3 . The following abbreviations were used to describe peak patterns where appropriate: singlet (s), doublet (d), triplet (t), multiplet (m) and broad resonances (br). Elemental analyses were performed on a Perkin-Elmer 240 B analyser. TLC was performed on Merck silica gel 60 TLC plates F254 and visualized using UV or phosphomolibdic acid. Flash chromatography was carried out on silica gel (40-60 mesh). The chloroketone 1a was a commercial compound. 6-Chloro-3,4-dihydronaphthalen-1-one (1b) [6], 7-chloro-2,3,4,5-tetrahydrobenzocyclo-heptan-1-one (1c) [7], N-Boc-nipecotic acid [8] and the piperidines 18 [10] and 19 [11] were obtained following the corresponding literature procedures.

General Procedure for the Synthesis of the Compounds 2a-2c
A solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (9, 2.85 g, 12.45 mmol) and 1,1′-carbonyldiimidazole (2.29 g, 14.11 mmol) in DMF (3 mL) was stirred at room temperature for 45 min. This solution was added dropwise to a solution prepared by stirring for 20 min the suitable ketone 1a, 1b or 1c (7.64 mmol) with NaH (60% in oil, 0.93 g, 23.20 mmol) in DMF (20 mL). The resulting mixture was heated for the appropriate time. After cooling, H 2 O was added and the mixture was extracted with Et 2 O (3 × 30 mL). The organic phase was dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography.

General Procedure for the Synthesis of Compounds 3b, 3c
A solution of CF 3 COOH (1.46 g, 12.8 mmol) in CH 2 Cl 2 (4.6 mL) was added dropwise to a solution of the 1,3-dicarbonyl compound 2b or 2c (1.28 mmol) in CH 2 Cl 2 (9.2 mL). After stirring 2 h at room temperature, CH 2 Cl 2 was added. The resulting mixture was washed two times with a 10% solution of K 2 CO 3 and then with H 2 O. The organic phase was dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography.  4b, 4c and 5b, 5c To a solution of the 1,3-dicarbonyl compound 3b or 3c (3.27 mmol) in DMF (18.25 mL) was added i-Pr 2 NEt (0.59 g, 4.58 mmol) and then the appropriate halide (1.1 eq). The mixture was then stirred at room temperature or heated under reflux for the necessary time. Water was added and the mixture was extracted with AcOEt. The organic phase was washed with brine, dried over Na 2 SO 4 , filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography.

General Procedure for the Synthesis of Compounds 6b, 6c
A solution of the 1,3-dicarbonyl compound 4b or 4c (0,68 mmol) and hydrazine hydrate (0.32 g, 6,39 mmol) in MeOH (9 mL) was stirred overnight at room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous Na 2 SO 4 , filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography.

Conclusion
In conclusion, we have reported a practical synthesis of the tricyclic heterocycles E incorporating the pyrazole or isoxazole framework (Figure 1). These new products share with the antipsychotic compounds A-C two substituents, namely the chlorine on the aryl ring and the 4-(1-benzyl)-or 4-(1-phenylethyl)piperidinyl group on the isoxazole and pyrazole moieties. The antipsychotic activity of these new compounds will be determined, thus indicating which further structural modifications should be pursued to advantageously modify their biological activity.