Br?nsted acid-mediated cyclization-dehydrosulfonylation/reduction sequences: An easy access to pyrazinoisoquinolines and pyridopyrazines

Article abstract of DOI:10.3762/bjoc.13.46

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 Br?nsted 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.

Full text of DOI:10.3762/bjoc.13.46

Brønsted acid-mediated cyclization–dehydrosulfonylation/
reduction sequences: An easy access to
pyrazinoisoquinolines and pyridopyrazines
Ramana Sreenivasa Rao and Chinnasamy Ramaraj Ramanathan*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 428–440.
Department of Chemistry, Pondicherry University, Puducherry – 605
014, India
doi:10.3762/bjoc.13.46
Received: 27 December 2016
Accepted: 16 February 2017
Published: 07 March 2017
Email:
Chinnasamy Ramaraj Ramanathan* - crrnath.che@pondiuni.edu.in
* Corresponding author
Associate Editor: T. P. Yoon
Keywords:
© 2017 Rao and Ramanathan; licensee Beilstein-Institut.
License and terms: see end of document.
Brønsted acid; piperazine-2,6-diones; praziquantel;
pyrazinoisoquinoline; pyridopyrazine
Abstract
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 dehy-
drosulfonylation 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 biolog- none condensed tetrahydroisoquinolines (THIQs) are wide-
ically active natural products [1]. Piperazines are also useful spread in nature with interesting biological activities [15]. They
intermediates in the synthesis of a variety of drug molecules are also found to be building blocks for the synthesis of many
having important biological activities such as anticancer [2,3], alkaloids (Figure 1) [16].
antifungal [4], amoebiasis, trypanosomiasis, bilharziasis [5,6],
and schistosomiasis [7,8]. Some are cell adhesion inhibitors [9] To synthesize pyrazinoisoquinoline and its derivatives, various
brandykinin receptor antagonists [10,11] and chymase inhibi- approaches such as the Ugi multicomponent reaction [17]
tors [12]. Quinoxaline derivatives are known to act as aldose amidoalkylation [18,19], N-acyliminium ion cyclization [20]
reductase (ALR2) inhibitors and are active towards chronic and a radical cyclization [21] have been reported. To this end,
diabetic complications including neuropathy, nephropathy, recently, we have reported the activation of an imide carbonyl
cataracts and retinopathy [13,14]. On the other hand, piperazi- group with TfOH, for the synthesis of tetrahydroisoquinoline
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Beilstein J. Org. Chem. 2017, 13, 428–440.
Figure 1: Selected active pyrazinoisoquinolines, 2-oxopiperazines and aldose reductase inhibitors (ALR2).
(THIQ) and tetrahydro-β-carboline (THBC) skeletons and CDI/THF at reflux leads also to the formation of piperazine-2,6-
related alkaloids [22-26].
diones (Scheme 1). Using CDI/THF under reflux conditions, the
piperazine-2,6-dione 7a from 4-benzenesulfonyliminodiacetic
The present study, describes the synthesis of 4-benzenesul- acid was obtained only in 50% yield along with the formation
fonylpiperazine-2,6-dione derivatives by using the combination of benzenesulfonic acid (Table 1, entry 1). The formation of
of carbonyldiimidazole/4-dimethylaminopyridine (CDI/ benzenesulfonic acid may be due to the labile nature of the
DMAP). Even though there are an adequate number of reports benzenesulfonyl protecting group. Therefore, the reactions were
available in the literature for the synthesis of piperazine-2,6- performed at temperatures below 70 °C and a higher yield of
dione derivatives [27]. To the best of our knowledge, this is the piperazine-2,6-dione 7a was observed at 60 °C (Table 1, entry
first report describing the synthesis of 4-benzenesulfonylpiper- 2). Further lowering of the reaction temperature did not improve
azine-2,6-diones at ambient temperature. The advantage of this the yield of 7a (Table 1, entry 3). Hence, there is a need to
methodology is that the more reactive and acid labile groups develop a method for the preparation of piperazine-2,6-dione
can be installed to the piperazine-2,6-diones at N-4 position, derivatives from N-benzenesulfonyliminodiacetic acid at room
which would then be utilized for synthetically useful transfor- temperature. After careful reviewing of reagents for amide bond
mations to yield the corresponding products.
formation, the reagent CDI proved to be a very successful
reagent for the preparation of imides, amides, esters and
Further, these 4-benzenesulfonylpiperazine-2,6-diones were thioesters. Therefore, the reaction was carried out with
subjected to an imide carbonyl group activation strategy, to N-benzenesulfonyliminodiacetic acid, a primary amine and CDI
develop a practical approach to synthesize pyrazinoisoquino- (2 equiv) in THF, the corresponding piperazine-2,6-dione 7a
line and pyridopyrazines via Brønsted acid assisted 6-exo-trig was obtained in 21% yield at room temperature (Table 1, entry
cyclization of arylethylpiperazine-2,6-diones.
4).
Results and Discussion
To facilitate the peptide bond formation DMAP has been used
Piperazine-2,6-diones are usually synthesized through an Ugi in conjuncture with coupling reagents such as DCC. We
[30] multicomponent approach. The condensation of primary presumed that the use of DMAP along with CDI may facilitate
amines with benzyliminodiacetic acid at high temperatures or the imide bond formation at room temperature. Hence, the reac-
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Scheme 1: Comparison of previous reports with present work for piperazine-2,6-dione synthesis.
Table 1: Standardization for the preparation of piperazine-2,6-dione.a
Entry
Reagents
Equivalent
Temp (°C )
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
CDI
CDI
2
2
70
60
40
rt
24
24
24
48
24
24
24
24
50
61
42
21
35
50
57
72
CDI
2
CDI
2
CDI/DMAP
CDI/DMAP
CDI/DMAP
CDI/DMAP
2/1
2/0.5
2/0.25
2/0.1
rt
rt
rt
rt
aReaction conditions: amine 5a (1 mmol), benzenesulfonyl substituted iminodiacetic acid (1 mmol), THF (15 mL), rt. bYields of isolated products.
tion of 5a with N-benzenesulfonyliminodiacetic acid was The successful development of this methodology for the synthe-
carried out using CDI in the presence of DMAP (Table 1, sis of 1-arylethylpiperazine-2,6-diones intrigued us to examine
entries 5–8). Piperazine-2,6-dione 7a was obtained in 72% yield them in 6-exo-trig cyclization using TfOH followed by reduc-
at room temperature in the presence of 10 mol % of DMAP. tion with NaBH4/MeOH to accomplish the synthesis of tetrahy-
Similarly, this strategy has been extended to couple various dropyrazinoisoquinoline. Surprisingly, the reaction of 7a
arylethylamines with N-benzenesulfonyliminodiacetic acid at furnished a mixture of ene-diamide 9a and substituted pyrazi-
room temperature to furnish expected imides 7a–h in good none 10a in 90:10 ratio. Generally, the syntheses of these types
yields (Scheme 2).
of units are very limited in the literature [31]. Under controlled
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Scheme 2: Coupling of N-benzenesulfonyliminodiacetic acid with primary amines using CDI/DMAP.
experimental conditions, in the absence of NaBH4/MeOH, the been paid to find suitable conditions for the formation of pyrazi-
ene-diamide 9a was successfully generated in 90% yield using nones directly from piperazine-2,6-diones via cyclization fol-
4 equivalents of TfOH in 30 minutes from 7a.
lowed by dehydrosulfonylation (Scheme 3).
While increasing the reaction time from 30 minutes to 2 h, the Following extensive optimization, it was realized that after
formation of biologically active pyrazinone 10a has been real- cyclization, addition of MeOH followed by reflux proved to be
ized as a major product along with ene-diamide 9a. A literature suitable conditions to generate the substituted pyrazinones. The
survey revealed that sulfonamides are known to undergo hydro- formation of substituted pyrazinones through dehydrosulfonyla-
lysis in the presence of a Brønsted acid [32]. Sulfonamides also tion (1,2-elimination) may be facilitated by 3-factors, such as,
participate in amide hydrolysis with external nucleophiles such (i) extended conjugation in pyrazinones, (ii) good leaving
as phosphide anions [33] or phenyldimethylsilyllithium [34]. capacity of the benzenesulfonyl group and (iii) the presence of
The combinations of thiophenol/K2CO3 [35] or NaOH/MeOH an acidic proton which is α to the amide carbonyl group. Hence,
[36] are also known to hydrolyse sulfonamides. These methods we believe that the selective elimination of the sulfonyl group in
lead to the formation of the corresponding free amines. Such refluxing methanol would serve as a simple and novel alternate
desulfonylation of sulfonamides has been less utilized to make methodology to the reported oxidative strategy [37] for the syn-
an unsaturated bond, for example, imine. Hence, attention has theses of substituted pyrazinones. To demonstrate the gener-
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Scheme 3: Formation of ene-diamides 9a–g and pyrazinones 10a–f.
ality of this procedure various methoxy/methyl substituted nones, the aliquot obtained from the reaction of 7c with TfOH
phenethyl and heterocyclic ethylpiperazine-2,6-diones 7a–g followed by reflux in MeOH, was analyzed through
have been successfully converted to the substituted pyrazinones ESI–HRMS technique. The appearance of peaks at m/z =
10a–f in excellent yields as shown in Scheme 3. To elucidate 143.0030 and m/z = 159.0773 indicates the formation of
the mechanism involved in the formation of substituted pyrazi- benzenesulfinic acid and benzenesulfonic acid, respectively.
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Scheme 4: Mechanism for the formation of substituted pyrazinones.
Figure 2: HRMS spectra of aliquot generated from cyclization reaction of 7c.
The formation of benzenesulfinic acid could be explained rivative 10a. To begin with, the phenyl group was proposed to
through a desulfonylization reaction via a 1,2-elimination introduce at the 3-position in substituted pyrazinone via regiose-
process (Scheme 4 and Figure 2).
lective bromination followed by Suzuki coupling with phenyl-
boronic acid. Accordingly, the bromination of 10a was success-
The structural evidence for cyclized compounds 9b and 10a fully carried out to furnish regioisomers 12a and 12b in 82%
was supported by single-crystal X-ray diffraction analysis yield upon treatment with bromodimethylsulfonium bromide
(Figure 3) in addition to IR, NMR and HRMS data.
(BDMS) [38] in dichloromethane at 0 °C to room temperature.
The conventional Suzuki coupling of the regioisomers 12a and
To show the synthetic utility of substituted pyrazinones, we 12b with phenylboronic acid furnished the corresponding
introduce a phenyl group at the C-3 position in pyrazinone de- arylated products 13a and 13b in excellent yield (Scheme 5).
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Beilstein J. Org. Chem. 2017, 13, 428–440.
Figure 3: ORTEP diagrams of compound 9b and 10a.
Scheme 5: Synthesis of 3-phenylpyrazinone.
To our dismay, the imide 7h did not participate in the cycliza- N-benzyliminodiacetic acid in THF at reflux to furnish the ex-
tion reaction in the presence of TfOH at room temperature to pected imides 8a–c, 8h, and 8i in good yields (Scheme 6).
generate a potential precursor for the synthesis of praziquantel.
To realize the cyclization, the imide 7h was treated with TfOH The imide 8h was subjected to the cyclization reaction condi-
under neat conditions at 70 °C, quite unfortunately to witness tions using 6 equivalents of TfOH under neat conditions at
the decomposition of imide 7h. This may be due to the labile 70 °C followed by reduction using NaBH4/MeOH at room tem-
nature of the benzenesulfonyl group in 7h. To avoid this de- perature, which successfully furnished N-benzylpraziquantel
composition problem, the amino group in iminodiacetic acid 11h in 75% yield. The electron rich phenethyl group containing
was protected as a N-benzyl group instead of a N-benzenesul- imides 8a–c, electron rich heteroaryl ethyl imide 8i, smoothly
fonyl group. Accordingly, the potassium salt of N-benzylimino- delivered the cyclized products 11a–c and 11i in excellent
diacetic acid was synthesized following the reported procedure yields through the cyclization followed by the reduction se-
[39]. The N-protected N-phenethylpiperazine-2,6-dione 8h was quence at room temperature (Scheme 7).
formed, while treating the potassium salt of N-benzyliminodi-
acetic acid with phenethylamine in presence of CDI in THF The synthesis of praziquantel from intermediate 11h was
under reflux conditions. Similarly, this strategy has been ex- accomplished through N-debenzylation at 80 °C under 1 atmo-
tended to couple arylethylamines with the potassium salt of sphere of H2 in the presence of Pd/C [40]. The present synthe-
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Scheme 6: Synthesis of 4-N-benzyl-1-N-(aryl/heteroarylethyl)piperazine-2,6-dione.
Scheme 7: Cyclization of pyrazinoisoquinolines.
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Beilstein J. Org. Chem. 2017, 13, 428–440.
tic protocol involves the debenzylation reaction under milder reduced pressure. The crude reaction product was purified by
conditions using Pd(OH)2 on charcoal/H2 at room temperature chromatography on a short silica gel column using ethyl
followed by coupling the secondary amine with cyclohexane- acetate/hexane, (30:70) as eluent to afford 7a–h in pure form.
carboxylic acid using CDI. Praziquantel (1) was obtained in
80% overall yield from 11h (Scheme 8).
1-(3,4-Dimethoxyphenethyl)-4-(phenylsulfonyl)piper-
azine-2,6-dione (7a)
Conclusion
300 mg, (72% yield) colorless solid; mp 138–139 °C; IR (KBr,
In conclusion, an efficient and alternative synthetic approach cm−1): 3002, 2937, 2835, 1686, 1515, 1447, 1391, 1270, 1237,
has been developed to prepare various N-(arylethyl)piperazine- 1171, 1114, 1026, 960, 852, 811, 811, 690, 668, 572, 525; 1H
2,6-diones. Brønsted acid assisted 6-exo-trig cyclization of NMR (400 MHz, CDCl3) δ 7.79–7.78 (m, 2H), 7.66–7.62 (m,
piperazine-2,6-dione derivatives of aryl/heteroarylethylamines 1H), 7.59–7.55 (m, 2H), 7.67 (d, J = 7.3 Hz, 1H), 6.69–6.66 (m,
through carbonyl group activation to assemble the pyridoiso- 2H), 4.11 (s, 4H), 3.86 (s, 3H), 3.84 (s, 3H), 3.6–3.65 (m, 2H),
quinoline and pyrazinoisoquinoline derivatives have been 2.43–2.47 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 166.4,
demonstrated. The ene-diamides furnished the substituted 149.0, 147.9, 135.6, 134.2, 130.0, 127.7, 120.9, 112.1, 111.4,
pyrazinones through an acid–mediated dehydrosulfonylation in 56.0, 48.9, 40.1, 33.4; HRMS–ESI (m/z): [M + H] calcd for
methanol. This strategy can be adopted to develop value added C20H22N2O6S, 419.1277; found, 419.1268.
pyrazinone-based potential precursors useful to synthesize
General procedure for synthesis of
various drug targets. Further, the synthetic utility of pyrazi-
noisoquinoline was exemplified by the successful synthesis of 4-benzylpiperazinone-2,6-diones 8a–c, 8h, 8i
fused tetrahydroisoquinoline drug molecule, praziquantel. An oven-dried two-neck round-bottom flask that had a septum
Extending this strategy towards the stereoselective reduction of in the side arm was cooled to room temperature under a steady
pyrazinones/ene-diamides is under investigation in our laborato- stream of nitrogen. The flask was charged with a stir bar, the
ry.
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
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 under reduced pressure. The crude product was purified on a
in the side arm was cooled to room temperature under a steady short silica gel column chromatography using ethyl acetate/
stream of nitrogen. The flask was charged with a stir bar, hexane (2:3) as eluent to afford 8a–c, 8h, and 8i in pure form.
benzenesulfonyliminodiacetic acid (1 mmol), carbonyldiimida-
zole (2 mmol) and 10 mol % DMAP and dry THF (25 mL). 4-Benzyl-1-(3,4-dimethoxyphenethyl)piperazine-2,6-
Stirring was continued at room temperature to provide a clear dione (8a)
solution. To this mixture was added aryl and heteroarylethyl- 250 mg, (68% yield) yellow liquid; IR (KBr, cm−1): 2950,
amine (5a–h) (1 mmol) and the resulting solution was stirred at 2853, 1734, 1683, 1594, 1514, 1453, 1348, 1268, 1156, 1028,
room temperature for 24 h (monitored by TLC). The solution 806, 755, 704, 631; 1H NMR (400 MHz, CDCl3) δ 7.29–7.26
was concentrated to dryness using a rotary evaporator under (m, 1H), 7.24–7.21 (m, 2H), 7.19–7.16 (m, 2H), 6.70 (s, 2H),
Scheme 8: Synthesis of the drug praziquantel 1.
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Beilstein J. Org. Chem. 2017, 13, 428–440.
6.68 (s, 1H), 3.94–3.86 (m, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.49 to the crude reaction mixture, the contents were refluxed for 1 h
(s, 2H), 3.29 (s, 4H), 2.72-2.68 (m, 2H); 13C NMR (100 MHz, and then the solvent was evaporated to dryness under reduced
CDCl3) δ 169.8, 148.9, 147.7, 135.4, 130.8, 129.1, 128.7, pressure. The solid residue was dissolved in water and the
129.0, 121.0, 112.2, 111.3, 60.7, 56.3, 55.9, 40.4, 33.5; aqueous layer was extracted with dichloromethane (2 × 15 mL).
HRMS–ESI (m/z): [M + H] calcd for C21H24N2O4, 369.1814; The combined organic extracts were washed with brine solu-
found, 369.1808.
tion, dried over anhydrous Na2SO4 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-benzenesulfonylpiperazinone-2,6-diones
7a–g
Analogous as described in [26] 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, 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 mix-
ture was quenched with aqueous NaHCO3. 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 Na2SO4
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.
9,10-Dimethoxy-6,7-dihydro-4H-pyrazino[2,1-a]iso-
quinolin-4-one (10a)
240 mg, (93% yield) yellow solid; mp 132–133 °C; IR (KBr,
cm−1): 2926, 2850, 1680, 1514, 1354, 1162, 1030, 993, 732; 1H
NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.74 (s, 1H), 7.17 (s,
1H), 6.74 (s, 1H), 4.23–4.17 (m, 2H), 3.94 (s, 3H), 3.93 (s, 3H),
3.04–2.85 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 155.8,
151.7, 148.9, 145.3, 135.5, 129.0, 119.8, 118.7, 110.8, 107.7,
56.3, 56.2, 38.7, 27.0; HRMS–ESI (m/z): [M + H] calcd for
C14H14N2O3, 259.1083; found, 259.1073.
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 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, 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 NaBH4 (2 mmol). The solution was stirred until the
color disappeared (Additional NaBH4 and MeOH were used if
the color persisted for a long time). The solution was evaporat-
ed to dryness under reduced pressure. The residue was dis-
solved in water and extracted with dichloromethane
(2 × 20 mL). The organic layer was dried over anhydrous
Na2SO4 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.
9,10-Dimethoxy-2-(phenylsulfonyl)-2,3,6,7-
tetrahydro-4H-pyrazino[2,1-a]isoquinolin-4-
one (9a)
360 mg, (90% yield) colorless liquid; IR (KBr, cm−1): 2927,
2854, 1679, 1513, 1406, 1389, 1355, 1272, 1209, 1163, 1030,
992, 726, 576; 1H NMR (400 MHz, CDCl3) δ 7.82–7.79 (m,
2H), 7.59–7.55 (m, 1H), 7.51–7.47 (m, 2H), 6.92 (s, 1H), 6.58
(d, J = 7.6 Hz, 2H), 4.18 (s, 2H), 3.91 (s, 3H), 3.86 (s, 3H),
3.48–3.45 (m, 2H), 2.58–2.55 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 162.0, 149.9, 148.6, 137.0, 133.6, 129.3, 127.3,
127.0, 119.9, 110.9, 106.4, 104.0, 56.4, 56.0, 48.3, 38.1, 28.0;
HRMS–ESI (m/z): [M + H] calcd for C20H20N2O5S, 401.1171;
found, 401.1156.
General procedure for the synthesis of
pyrazinones 10a–f
Similar as described in [26] an oven-dried two-neck round-
2-Benzyl-1,2,3,6,7,11b-hexahydro-4H-
bottomed flask that had septum in the side arm was cooled to pyrazino[2,1-a]isoquinolin-4-one (11h)
room temperature under a steady stream of nitrogen. The flask 219 mg, (75% yield) yellow liquid; IR (KBr, cm−1): 2926,
was charged with a stir bar, imide 7a–f (0.5 mmol), and dry 2824, 1646, 1517, 1457, 1258, 1147, 1033, 744; 1H NMR (400
dichloromethane (15 mL), and the resulting solution was cooled MHz, CDCl3) δ 7.28–7.23 (m, 4H), 7.24–7.16 (m, 1H),
to 0 °C. To this solution was added TfOH (0.2 mL, 2 mmol) 7.11–7.08 (m, 2H), 7.07–7.04 (m, 1H), 6.94–6.92 (m, 1H), 4.78
with stirring. After the stipulated time, the contents were (dd, J = 12.0, 8.0 Hz, 1H), 4.70–4.65 (m, 1H), 3.55–3.51 (m,
warmed to room temperature and methanol (25 mL) was added 2H), 3.50–3.41 (m, 2H), 2.91–2.87 (m, 2H), 2.85–2.77 (m, 2H),
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Beilstein J. Org. Chem. 2017, 13, 428–440.
2.67–2.62 (m, 1H), 2.30–1.96 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 8.35–8.30 (m, 2H), 7.89 (s, 1H), 7.46–7.39 (m, 3H),
CDCl3) δ 166.7, 136.5, 134.9, 132.2, 129.3, 129.2,128.6, 127.7, 7.22 (s, 1H), 6.76 (s, 1H), 4.30 (t, J = 6.4 Hz, 2H), 3.95 (s, 3H),
127.1, 126.6, 124.7, 61.6, 57.0, 55.7, 55.5, 39.0, 28.7, 20.9; 3.94 (s, 3H), 2.98 (t, J = 6.4 Hz 2H); 13C NMR (100 MHz,
HRMS–ESI (m/z): [M + H] calcd for C19H20N2O, 293.1654; CDCl3) δ 154.9, 151.5, 149.1, 148.9, 136.6, 134.6, 129.5,
found, 293.1730.
128.8, 128.1, 119.5, 119.3, 110.8, 107.5, 56.4, 56.2, 39.2, 27.3;
HRMS–ESI (m/z): [M + H] calcd for C20H18N2O3, 335.1396;
found, 335.1383.
Procedure for the synthesis 9,10-dimethoxy-
3-phenyl-6,7-dihydro-4H-pyrazino[2,1-a]iso-
quinolin-4-one (13)
Procedure for the synthesis of praziquantel
[2-(cyclohexanecarbonyl)-1,2,3,6,7,11b-
hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-
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, 3,4-
dimethoxypyrazinone 10a (1.0 mmol) and CH2Cl2 (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 CH2Cl2 (2 × 10 mL). The organic layers were
combined and dried over anhydrous Na2SO4. Solvents were re-
moved by evaporation in a rotary evaporator. The crude reac-
tion mixture was purified through silica gel column chromatog-
raphy using ethyl acetate/hexane, 30:70 as eluent to afford 12a
and 12b in the ratio 79:21.
one]
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]iso-
quinolin-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 at-
mosphere. After 24 h, the reaction mixture was filtered through
a small bed of celite and washed with ethyl acetate (2 × 10 mL).
The regioisomers of bromopyrazinone (12a and 12b) The solvents were removed by evaporation using a rotary evap-
(1.0 mmol), bis(triphenylphosphine)palladium(II) chloride orator. The crude product was used in the next step without
(10 mol %, 7 mg) in dimethylformamide (2 mL) was added further purification
phenylboronic acid (122 mg) and 2 M aqueous sodium
carbonate (0.8 mL) under a nitrogen atmosphere. The reaction An oven-dried two-neck round-bottom flask that had a septum
mixture was heated to 90 °C and stirred for 2 h. The reaction in the side arm was cooled to room temperature under a steady
mixture was quenched with water and the mixture was extracted stream of nitrogen. The flask was charged with a stir bar, cyclo-
with ethyl acetate. The organic phase was separated, dried over hexanecarboxylic acid (0.14 mL, 1.1 mmol) and carbonyldiimi-
anhydrous Na2SO4, filtered and concentrated. The crude reac- dazole (194 mg, 1.2 mmol) and dry THF (10 mL). The contents
tion mixture was purified through a short silica gel column were stirred to obtain a clear solution. To this solution was
chromatography using ethyl acetate/hexane 10:90 as eluent and added dropwise a solution of 1,2,3,6,7,11b-hexahydro-4H-
afforded 13a and 13b in the ratio of 92:8.
pyrazino[2,1-a]isoquinolin-4-one (200 mg, 2.32 mmol) in dry
THF and the resulting solution was stirred at room temperature
for 24 h. The solution was concentrated to dryness using a
rotary evaporator. The crude reaction mixture was purified by a
3-Bromo-9,10-dimethoxy-6,7-dihydro-4H-
pyrazino[2,1-a]isoquinolin-4-one (12a)
275 mg, (82% yield) orange yellow liquid; IR (KBr, cm−1): short silica gel column chromatography using ethyl acetate/
2924, 2856, 1727, 1511, 1456, 1362, 1272, 845; 1H NMR (400 hexane (10:90) as eluent to furnished praziquantel (1) in
MHz, CDCl3) δ 7.54 (s, 1H), 7.13 (s, 1H), 6.74 (d, J = 9.6 Hz, 249 mg, (80% yield) as a white solid; mp 129–131 °C; IR (KBr,
1H), 4.26 (t, J = 6.4 Hz, 2H), 3.94 (s, 6H), 2.96 (t, J = 6.4 Hz, cm−1): 2928, 2856, 1660, 1452, 1211, 1039, 755, 656;
2H); 13C NMR (100 MHz, CDCl3) δ 152.7, 152.0, 149.0, 137.9, 1H NMR (400 MHz, CDCl3) δ 7.21–7.13 (m, 4H), 5.08 (dd, J =
136.0, 128.8, 118.5, 118.3, 110.9, 107.6, 56.4, 56.3, 40.9, 27.2; 13.2, 2.4 Hz, 1H), 4.79–4.72 (m, 2H), 4.39 (d, J = 17.2 Hz, 1H),
HRMS–ESI (m/z): [M + H] calcd for C14H13BrN2O3, 4.0 (d, J = 13.2 Hz, 1H), 2.91–2.69 (m, 4H), 2.40 (t, J = 11.6
337.0188; found, 337.0171.
Hz, 1H), 1.73–1.65 (m, 5H), 1.53–1.43 (m, 2H), 1.23-1.17 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 174.9, 164.6, 134.6, 132.6,
129.2, 127.4, 126.9, 125.4, 54.9, 48.9, 45.1, 42.8, 40.7, 39.1,
29.1, 28.9, 28.8, 28.6, 25.7, 25.6, 25.3, 20.8; HRMS–ESI
9,10-Dimethoxy-3-phenyl-6,7-dihydro-4H-
pyrazino[2,1-a]isoquinolin-4-one (13a)
290 mg, (87% yield) yellow liquid ; IR (KBr, cm−1): 2924, (m/z): [M + H] calcd for C19H24N2O2, 313.1916; found,
2856, 1728, 1595, 1512, 1458, 1216; 1H NMR (400 MHz, 313.1905.
438

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Supporting Information File 1
1H and 13C NMR spectra of synthesized compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-46-S1.pdf]
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Acknowledgements
We thank DST and CSIR, New Delhi for financial support.
RSR thank UGC, New Delhi for SRF. We gratefully acknowl-
edge the Department of Chemistry, Pondicherry University for
HRMS data (DST-FIST Sponsored) and IR data; CIF,
Pondicherry University for NMR data. We acknowledge IPLS
programme, Pondicherry University.
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