Brønsted acid-mediated cyclization–dehydrosulfonylation/reduction sequences: An easy access to pyrazinoisoquinolines and pyridopyrazines

An efficient and alternative synthetic approach has been developed to prepare various N-(arylethyl)piperazine-2,6-diones from 4-benzenesulfonyliminodiacetic acid and primary amines using carbonyldiimidazole in the presence of a catalytic amount of DMAP at ambient temperature. Piperazine-2,6-diones are successfully transformed to pharmaceutically useful pyridopyrazines or pyrazinoisoquinolines and ene-diamides via an imide carbonyl group activation strategy using a Brønsted acid. Subsequent dehydrosulfonylation reactions of the ene-diamides, in a one pot manner, smoothly transformed them to substituted pyrazinones. A concise synthesis of praziquantel (1) has also been achieved through this method.


Introduction
Piperazine is an important structural core found in many biologically active natural products [1]. Piperazines are also useful intermediates in the synthesis of a variety of drug molecules having important biological activities such as anticancer [2,3], antifungal [4], amoebiasis, trypanosomiasis, bilharziasis [5,6], and schistosomiasis [7,8]. Some are cell adhesion inhibitors [9] brandykinin receptor antagonists [10,11] and chymase inhibitors [12]. Quinoxaline derivatives are known to act as aldose reductase (ALR 2 ) inhibitors and are active towards chronic diabetic complications including neuropathy, nephropathy, cataracts and retinopathy [13,14]. On the other hand, piperazi-none condensed tetrahydroisoquinolines (THIQs) are widespread in nature with interesting biological activities [15]. They are also found to be building blocks for the synthesis of many alkaloids ( Figure 1) [16].
The present study, describes the synthesis of 4-benzenesulfonylpiperazine-2,6-dione derivatives by using the combination of carbonyldiimidazole/4-dimethylaminopyridine (CDI/ DMAP). Even though there are an adequate number of reports available in the literature for the synthesis of piperazine-2,6dione derivatives [27]. To the best of our knowledge, this is the first report describing the synthesis of 4-benzenesulfonylpiperazine-2,6-diones at ambient temperature. The advantage of this methodology is that the more reactive and acid labile groups can be installed to the piperazine-2,6-diones at N-4 position, which would then be utilized for synthetically useful transformations to yield the corresponding products.

Results and Discussion
Piperazine-2,6-diones are usually synthesized through an Ugi [30] multicomponent approach. The condensation of primary amines with benzyliminodiacetic acid at high temperatures or CDI/THF at reflux leads also to the formation of piperazine-2,6diones (Scheme 1). Using CDI/THF under reflux conditions, the piperazine-2,6-dione 7a from 4-benzenesulfonyliminodiacetic acid was obtained only in 50% yield along with the formation of benzenesulfonic acid (Table 1, entry 1). The formation of benzenesulfonic acid may be due to the labile nature of the benzenesulfonyl protecting group. Therefore, the reactions were performed at temperatures below 70 °C and a higher yield of piperazine-2,6-dione 7a was observed at 60 °C (Table 1, entry 2). Further lowering of the reaction temperature did not improve the yield of 7a (Table 1, entry 3). Hence, there is a need to develop a method for the preparation of piperazine-2,6-dione derivatives from N-benzenesulfonyliminodiacetic acid at room temperature. After careful reviewing of reagents for amide bond formation, the reagent CDI proved to be a very successful reagent for the preparation of imides, amides, esters and thioesters. Therefore, the reaction was carried out with N-benzenesulfonyliminodiacetic acid, a primary amine and CDI (2 equiv) in THF, the corresponding piperazine-2,6-dione 7a was obtained in 21% yield at room temperature (Table 1, entry  4).
To facilitate the peptide bond formation DMAP has been used in conjuncture with coupling reagents such as DCC. We presumed that the use of DMAP along with CDI may facilitate the imide bond formation at room temperature. Hence, the reac-Scheme 1: Comparison of previous reports with present work for piperazine-2,6-dione synthesis. The successful development of this methodology for the synthesis of 1-arylethylpiperazine-2,6-diones intrigued us to examine them in 6-exo-trig cyclization using TfOH followed by reduction with NaBH 4 /MeOH to accomplish the synthesis of tetrahydropyrazinoisoquinoline. Surprisingly, the reaction of 7a furnished a mixture of ene-diamide 9a and substituted pyrazinone 10a in 90:10 ratio. Generally, the syntheses of these types of units are very limited in the literature [31]. Under controlled Scheme 2: Coupling of N-benzenesulfonyliminodiacetic acid with primary amines using CDI/DMAP. experimental conditions, in the absence of NaBH 4 /MeOH, the ene-diamide 9a was successfully generated in 90% yield using 4 equivalents of TfOH in 30 minutes from 7a.
While increasing the reaction time from 30 minutes to 2 h, the formation of biologically active pyrazinone 10a has been realized as a major product along with ene-diamide 9a. A literature survey revealed that sulfonamides are known to undergo hydrolysis in the presence of a Brønsted acid [32]. Sulfonamides also participate in amide hydrolysis with external nucleophiles such as phosphide anions [33] or phenyldimethylsilyllithium [34]. The combinations of thiophenol/K 2 CO 3 [35] or NaOH/MeOH [36] are also known to hydrolyse sulfonamides. These methods lead to the formation of the corresponding free amines. Such desulfonylation of sulfonamides has been less utilized to make an unsaturated bond, for example, imine. Hence, attention has been paid to find suitable conditions for the formation of pyrazinones directly from piperazine-2,6-diones via cyclization followed by dehydrosulfonylation (Scheme 3).
Following extensive optimization, it was realized that after cyclization, addition of MeOH followed by reflux proved to be suitable conditions to generate the substituted pyrazinones. The formation of substituted pyrazinones through dehydrosulfonylation (1,2-elimination) may be facilitated by 3-factors, such as, (i) extended conjugation in pyrazinones, (ii) good leaving capacity of the benzenesulfonyl group and (iii) the presence of an acidic proton which is α to the amide carbonyl group. Hence, we believe that the selective elimination of the sulfonyl group in refluxing methanol would serve as a simple and novel alternate methodology to the reported oxidative strategy [37] for the syntheses of substituted pyrazinones. To demonstrate the gener-  The formation of benzenesulfinic acid could be explained through a desulfonylization reaction via a 1,2-elimination process (Scheme 4 and Figure 2).
The structural evidence for cyclized compounds 9b and 10a was supported by single-crystal X-ray diffraction analysis ( Figure 3) in addition to IR, NMR and HRMS data.
To show the synthetic utility of substituted pyrazinones, we introduce a phenyl group at the C-3 position in pyrazinone de-rivative 10a. To begin with, the phenyl group was proposed to introduce at the 3-position in substituted pyrazinone via regioselective bromination followed by Suzuki coupling with phenylboronic acid. Accordingly, the bromination of 10a was successfully carried out to furnish regioisomers 12a and 12b in 82% yield upon treatment with bromodimethylsulfonium bromide (BDMS) [38] in dichloromethane at 0 °C to room temperature. The conventional Suzuki coupling of the regioisomers 12a and 12b with phenylboronic acid furnished the corresponding arylated products 13a and 13b in excellent yield (Scheme 5). To our dismay, the imide 7h did not participate in the cyclization reaction in the presence of TfOH at room temperature to generate a potential precursor for the synthesis of praziquantel.
To realize the cyclization, the imide 7h was treated with TfOH under neat conditions at 70 °C, quite unfortunately to witness the decomposition of imide 7h. This may be due to the labile nature of the benzenesulfonyl group in 7h. To avoid this decomposition problem, the amino group in iminodiacetic acid was protected as a N-benzyl group instead of a N-benzenesulfonyl group. Accordingly, the potassium salt of N-benzyliminodiacetic acid was synthesized following the reported procedure [39]. The N-protected N-phenethylpiperazine-2,6-dione 8h was formed, while treating the potassium salt of N-benzyliminodiacetic acid with phenethylamine in presence of CDI in THF under reflux conditions. Similarly, this strategy has been extended to couple arylethylamines with the potassium salt of N-benzyliminodiacetic acid in THF at reflux to furnish the expected imides 8a-c, 8h, and 8i in good yields (Scheme 6).
The imide 8h was subjected to the cyclization reaction conditions using 6 equivalents of TfOH under neat conditions at 70 °C followed by reduction using NaBH 4 /MeOH at room temperature, which successfully furnished N-benzylpraziquantel 11h in 75% yield. The electron rich phenethyl group containing imides 8a-c, electron rich heteroaryl ethyl imide 8i, smoothly delivered the cyclized products 11a-c and 11i in excellent yields through the cyclization followed by the reduction sequence at room temperature (Scheme 7).
The synthesis of praziquantel from intermediate 11h was accomplished through N-debenzylation at 80 °C under 1 atmosphere of H 2 in the presence of Pd/C [40]. The present synthe- tic protocol involves the debenzylation reaction under milder conditions using Pd(OH) 2 on charcoal/H 2 at room temperature followed by coupling the secondary amine with cyclohexanecarboxylic acid using CDI. Praziquantel (1) was obtained in 80% overall yield from 11h (Scheme 8).

Conclusion
In conclusion, an efficient and alternative synthetic approach has been developed to prepare various N-(arylethyl)piperazine-2,6-diones. Brønsted acid assisted 6-exo-trig cyclization of piperazine-2,6-dione derivatives of aryl/heteroarylethylamines through carbonyl group activation to assemble the pyridoisoquinoline and pyrazinoisoquinoline derivatives have been demonstrated. The ene-diamides furnished the substituted pyrazinones through an acid-mediated dehydrosulfonylation in methanol. This strategy can be adopted to develop value added pyrazinone-based potential precursors useful to synthesize various drug targets. Further, the synthetic utility of pyrazinoisoquinoline was exemplified by the successful synthesis of fused tetrahydroisoquinoline drug molecule, praziquantel. Extending this strategy towards the stereoselective reduction of pyrazinones/ene-diamides is under investigation in our laboratory.

Experimental
General procedure for the synthesis of 4-benzenesulfonylpiperazinone-2,6-diones 7a-h An oven-dried two-neck round-bottom flask that had a septum in the side arm was cooled to room temperature under a steady stream of nitrogen. The flask was charged with a stir bar, benzenesulfonyliminodiacetic acid (1 mmol), carbonyldiimidazole (2 mmol) and 10 mol % DMAP and dry THF (25 mL).
Stirring was continued at room temperature to provide a clear solution. To this mixture was added aryl and heteroarylethylamine (5a-h) (1 mmol) and the resulting solution was stirred at room temperature for 24 h (monitored by TLC). The solution was concentrated to dryness using a rotary evaporator under reduced pressure. The crude reaction product was purified by chromatography on a short silica gel column using ethyl acetate/hexane, (30:70) as eluent to afford 7a-h in pure form. General procedure for synthesis of 4-benzylpiperazinone-2,6-diones 8a-c, 8h, 8i An oven-dried two-neck round-bottom flask that had a septum in the side arm was cooled to room temperature under a steady stream of nitrogen. The flask was charged with a stir bar, the potassium salt of benzyliminodiacetic acid (1 mmol) and carbonyldiimidazole (2 mmol) were added to dry THF (25 mL). The mixture was heated at refluxed for 10 min to obtain a clear solution. To this was added the aryl and heteroarylethylamines (5a-c, 5h, 5i) (1 mmol) and the resulting solution was heated at reflux for 24 h, then allowed to cool to room temperature. The solution was concentrated to dryness using a rotary evaporator under reduced pressure. The crude product was purified on a short silica gel column chromatography using ethyl acetate/ hexane (2:3) as eluent to afford 8a-c, 8h, and 8i in pure form. General procedure for the cyclization of 4-benzenesulfonylpiperazinone-2,6-diones 7a-g Analogous as described in [26] an oven-dried two-neck roundbottom flask that had a septum in the side arm was cooled to room temperature under a steady stream of nitrogen. The flask was charged with a stir bar, imide 7a-g (0.5 mmol), and dry dichloromethane (15 mL), and the resulting solution was cooled to 0 °C (by using ice). To this solution was added TfOH (0.2 mL, 2 mmol) with stirring. After 30 min, the reaction mixture was quenched with aqueous NaHCO 3 . The organic layer was separated, and the aqueous layer was extracted with dichloromethane (2 × 15 mL). The combined organic extracts were washed with brine solution, dried over anhydrous Na 2 SO 4 and filtered. The solution was concentrated to dryness by using a rotary evaporator. The dried crude product was purified by chromatography on a short silica gel chromatography column using ethyl acetate/hexane (1:1) as eluent to afford the 9a-g in pure form. General procedure for the synthesis of pyrazinones 10a-f Similar as described in [26] an oven-dried two-neck roundbottomed flask that had septum in the side arm was cooled to room temperature under a steady stream of nitrogen. The flask was charged with a stir bar, imide 7a-f (0.5 mmol), and dry dichloromethane (15 mL), and the resulting solution was cooled to 0 °C. To this solution was added TfOH (0.2 mL, 2 mmol) with stirring. After the stipulated time, the contents were warmed to room temperature and methanol (25 mL) was added to the crude reaction mixture, the contents were refluxed for 1 h and then the solvent was evaporated to dryness under reduced pressure. The solid residue was dissolved in water and the aqueous layer was extracted with dichloromethane (2 × 15 mL). The combined organic extracts were washed with brine solution, dried over anhydrous Na 2 SO 4 and filtered. The solution was concentrated to dryness by using a rotary evaporator. The dried compound was purified through a short silica gel column chromatography using ethyl acetate/hexane mixture (1:1) as eluent to afford the 10a-f in pure form. General procedure for the cyclization of 4-benzylpiperazine-2,6-diones 8a-c, 8h, 8i Similar as described in [26] an oven-dried two-neck roundbottom flask that had a septum in the side arm was cooled to room temperature under a steady stream of nitrogen. The flask was charged with a stir bar, imide 8a-c, 8h, 8i (0.5 mmol), and dry dichloromethane (10 mL), and the resulting solution was cooled to 0 °C (by using ice). To this solution was added TfOH (0.2 mL, 2 mmol) with stirring. After 6 h the reaction mixture was diluted with methanol (2.5 mL) followed by portion wise addition of NaBH 4 (2 mmol). The solution was stirred until the color disappeared (Additional NaBH 4 and MeOH were used if the color persisted for a long time). The solution was evaporated to dryness under reduced pressure. The residue was dissolved in water and extracted with dichloromethane (2 × 20 mL). The organic layer was dried over anhydrous Na 2 SO 4 and filtered. The solvent was evaporated under vacuum, and the crude product was purified by silica gel column chromatography using ethyl acetate/hexane (1:1) as eluent to afford the 11a-c, 11h, and 11i in pure form. Procedure for the synthesis 9,10-dimethoxy-3-phenyl-6,7-dihydro-4H-pyrazino[2,1-a]isoquinolin-4-one (13) An oven-dried two-neck round-bottom flask that had a septum in the side arm was cooled to room temperature under a steady stream of nitrogen. The flask charged with a stir bar, 3,4dimethoxypyrazinone 10a (1.0 mmol) and CH 2 Cl 2 (5 mL) at 0-5 °C, bromodimethylsulfonium bromide (BDMS) (1.0 mmol, 0.223 g) was added and stirred at room temperature. After 24 h, the reaction mixture was washed with water (2 × 10 mL) and extracted with CH 2 Cl 2 (2 × 10 mL). The organic layers were combined and dried over anhydrous Na 2 SO 4 . Solvents were removed by evaporation in a rotary evaporator. The crude reaction mixture was purified through silica gel column chromatography using ethyl acetate/hexane, 30:70 as eluent to afford 12a and 12b in the ratio 79:21.
The regioisomers of bromopyrazinone (12a and 12b) (1.0 mmol), bis(triphenylphosphine)palladium(II) chloride (10 mol %, 7 mg) in dimethylformamide (2 mL) was added phenylboronic acid (122 mg) and 2 M aqueous sodium carbonate (0.8 mL) under a nitrogen atmosphere. The reaction mixture was heated to 90 °C and stirred for 2 h. The reaction mixture was quenched with water and the mixture was extracted with ethyl acetate. The organic phase was separated, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The crude reaction mixture was purified through a short silica gel column chromatography using ethyl acetate/hexane 10:90 as eluent and afforded 13a and 13b in the ratio of 92:8. An oven-dried two-neck round-bottom flask that had a septum in the side arm was cooled to room temperature under a steady stream of nitrogen. The flask was charged with a stir bar, 2-benzyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one (292 mg, 1 mmol), palladium hydroxide on charcoal (30 mg) and ethyl acetate (15 mL). The reaction flask was degassed and filled with hydrogen gas twice through a rubber bladder and the contents were stirred under hydrogen atmosphere. After 24 h, the reaction mixture was filtered through a small bed of celite and washed with ethyl acetate (2 × 10 mL). The solvents were removed by evaporation using a rotary evaporator. The crude product was used in the next step without further purification

3-Bromo
An oven-dried two-neck round-bottom flask that had a septum in the side arm was cooled to room temperature under a steady stream of nitrogen. The flask was charged with a stir bar, cyclohexanecarboxylic acid (0.14 mL, 1.1 mmol) and carbonyldiimidazole (194 mg, 1.2 mmol) and dry THF (10 mL

Supporting Information
Supporting Information File 1 1 H and 13 C NMR spectra of synthesized compounds.