Synthesis of 5-(phenylsulfanyl)-1,4-dihydropyrazine-2,3-diones via an unexpected microwave-assisted cascade reaction

Article abstract of DOI:10.1016/j.tetlet.2008.06.063

An unprecedented route for the synthesis of N-1 substituted 5-(phenylsulfanyl)-1,4-dihydropyrazine-2,3-diones is disclosed starting from 5-chloro-3-(phenylsulfanyl)pyrazin-2(1H)-ones. The method comprises treatment of various 5-chloro-3-(phenylsulfanyl)py

Full text of DOI:10.1016/j.tetlet.2008.06.063

Tetrahedron Letters 49 (2008) 4993–4996
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Tetrahedron Letters
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Synthesis of 5-(phenylsulfanyl)-1,4-dihydropyrazine-2,3-diones
via an unexpected microwave-assisted cascade reaction
Anuj Sharma a, Vaibhav Pravinchandra Mehta a, Kristof Van Hecke b, Luc Van Meervelt b,
Erik Van der Eycken a,
*
a Laboratory for Organic and Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001, Leuven, Belgium
b Biomolecular Architecture, Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001, Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
An unprecedented route for the synthesis of N-1 substituted 5-(phenylsulfanyl)-1,4-dihydropyrazine-
2,3-diones is disclosed starting from 5-chloro-3-(phenylsulfanyl)pyrazin-2(1H)-ones. The method com-
prises treatment of various 5-chloro-3-(phenylsulfanyl)pyrazin-2(1H)-ones with Na2CO3 in water under
microwave irradiation providing the respective 5-(phenylsulfanyl)-1,4-dihydropyrazine-2,3-diones in
good yields, via hydrolysis of the thioether bond and subsequent nucleophilic displacement of the
chlorine by the in situ generated thiophenol. The obtained compounds are excellent precursors for the
Received 12 May 2008
Revised 11 June 2008
Accepted 13 June 2008
Available online 18 June 2008
Dedicated to Prof. Dr. Georges Hoornaert on
the occasion of his 70th birthday
diversity oriented synthesis of pharmacologically active
a
,b-dicarbonyl compounds.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazine-2,3-diones
3-(Phenylsulfanyl)pyrazin-2(1H)-one
Aqueous media
Microwave-assisted organic synthesis
(MAOS)
The
a
,b-dicarbonyl group is a unique functionality in organic
diketopiperazines have been shown to exhibit l-opioid receptor
chemistry. There are a number of natural as well as synthetic
heterocyclic molecules as, for example, substituted quinoxalinedi-
antagonists activity.4a Structurally related quinoxalinediones have
been shown to act as an inhibitor for dipeptidyl peptidase-IV.4b
Apart from the pharmacological activities, quinoxalinediones have
been reported to exhibit excellent metal binding properties to gen-
erate 3D coordination polymeric material.5 Herein we disclose an
unexpected formation of 5-(phenylsulfanyl)-1,4-dihydropyrazine-
2,3-diones, a member of a hitherto unexplored class of pyrazine-
2,3-diones, through an unusual cascade sequence.
ones,1 containing such an
a
,b-dicarbonyl unit. A substantial num-
ber of compounds with structural similarities to ,b-dicarbonyl
a
compounds are pharmacologically active as glycogen phosphory-
lase inhibitor for diabetes prevention,2 as antagonists for AMPA
and kainic acid for the prevention of neurodegenerative dis-
eases3a–d or as NMDA-glycine polyamine receptor antagonists.3h
A benzothieno fused and substituted thieno fused pyrazine(2,3)-
diones have been reported to be useful in the treatment of neuro-
logical and psychiatric diseases.3i–k Recently some substituted
We were recently investigating the dimethyl amination of the
C3-position of 5-chloro-1-(4-methoxybenzyl)-3-(phenylsulfanyl)-
pyrazin-2(1H)-one (1a) (Scheme 1) without prior oxidation of
PMB
PMB
PMB
N
O
NH(CH3)2 (2 equiv)
N
O
S
O
O
+
N
Na2CO3 (2 equiv)
Dioxane:H2O (1:1)
Me
Cl
N
2a
N
N
H
S
Cl
N
1a
3a
MW 150 W, 140 ˚C, 30 min
Me
71%
8%
PMB = p-methoxybenzyl
Scheme 1. Attempted dimethylamination on the thioether linkage of pyrazinone 1a.
* Corresponding author. Tel.: +32 16 32 4706; fax: +32 16 32 7990.
E-mail address: erik.vandereycken@chem.kuleuven.be (E. Van der Eycken).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.063

4994
A. Sharma et al. / Tetrahedron Letters 49 (2008) 4993–4996
the thioether bond.6 This should allow traceless linking of the pyr-
azinone scaffold with a thiophenyl resin for the generation of a
small library of C3-aminated compounds in accordance with our
previously reported protocol for the orthogonal functionalization
of the pyrazin-2(1H)-one scaffold.7 In one such amination experi-
ment compound 1a was reacted with dimethyl amine (40% solu-
tion in water, 2 equiv) using Na2CO3 (2 equiv) as the base in
dioxane/H2O (1:1) under focused microwave irradiation for
30 min at a ceiling temperature of 140 °C and 150 W maximum
power (Scheme 1).6 However, to our disappointment, this resulted
in a meagre yield of only 8% of the desired 5-chloro-3-(dimethyl-
amino)-1-(4-methoxybenzyl)pyrazin-2(1H)-one (2a), next to the
formation of an unidentified side compound as the major product.
A revisit of the above conditions with different amines such as iso-
butyl amine, allylamine or dihexylamine revealed the formation of
the same side product in each case, albeit in varying yields. Careful
spectroscopic analysis8 allowed to determine the structure as
being the 2,3-diketo pyrazine 3a. This substantial low value of
109.7 ppm points to a thioether bond at C5, suggesting that a
migration of the thiophenyl group from the C3- to the C5-position
occurred. This is also in accordance with the NMR and mass spectra
indicating that a thiophenol group is still present and that the
chloro substituent is absent. Conclusively this pointed towards
the unexpected formation of 1-(4-methoxybenzyl)-5-(phenylsulf-
anyl)-1,4-dihydropyrazine-2,3-dione (3a) (Scheme 1). The struc-
ture of compound 3a was finally unambiguously confirmed by
X-ray crystallographic analysis (Fig. 1).9
The proposed mechanism was supported by the isolation of
intermediate I, albeit the yield was not higher than 6%. Further-
more, some Ph2S2 was isolated from the reaction mixture support-
ing the postulated mechanism. The C5-position of the pyrazinone
is preferentially attacked by the nucleophilic thiophenol.
Table 1
Optimization of the desulfitative amidation of 1aa
PMB
PMB
N
N
O
S
Solvent
O
O
N
Base (2 equiv)
MW
N
H
Cl
S
1a
3a
PMB = p-methoxybenzyl
Entry
Base (equiv)
Solvent (1:1)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Na2CO3(2)
Na2CO3(1)
Na2CO3(1)
Na2CO3(2)
—
Na2CO3(2)
Na2CO3(2)
NaOH (2)
K2CO3(2)
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane
H2O
H2O
H2O
30
30
45
15
30
30
30
30
30
87
73
72
52
0c
12d
84
79
83
a
Reactions were run on a 0.3 mmol scale of 1a in the solvent (3 mL) with indi-
cated amount of base. The mixture was irradiated in a sealed vial at a ceiling
temperature of 140 °C and 150 W maximum power for the stipulated time. All
microwave irradiation experiments were carried out in a dedicated CEM-Discover
monomode microwave apparatus.
Hence it was clear that compound 3a was formed from 1a via
hydrolysis of the thioether moiety at C3-position, with consecutive
substitution of the C5-chloro substituent by the in situ generated
thiophenol (Scheme 2). This is interesting as the C5-chloro substi-
tuent of the starting 2(1H)-pyrazinone 1a, is known to be rather
reluctant towards substitution.10
b
Isolated yield.
All starting material was recovered.
c
d
The major compound was the unreacted starting material.
Figure 1. X-ray crystal structure of 3a with atom labelling scheme and thermal ellipsoids at the 50% probability level.9
PMB
N
PMB
N
PMB
N
O
S
O
O
O
OH
Cl
N
H
Cl
N
I
OH
Cl
N
1a
II
Preferential
attack of PhSH
PMB = p-methoxybenzyl
PMB
N
O
S
N
H
O
3a
Scheme 2. Plausible mechanism for the generation of the pyrazine 2,3-dione.

A. Sharma et al. / Tetrahedron Letters 49 (2008) 4993–4996
4995
Having identified the side product as being an interesting
a
,b-
mized conditions (Table 2). Apparently the nature of the N1-substi-
tuent has little effect on the outcome and yield of the reaction
(Table 2, entries 1–3). However, bulky substituents at the C6-posi-
tion of the pyrazinone scaffold are hampering the reaction (Table 2,
entries 5–7). The protocol also seemed to work with an aliphatic
thioether at the C3-position as the reaction of 5-chloro-3-(ethyl-
sulfanyl)-1-(4-methoxybenzyl)pyrazin-2(1H)-one (1e) proceeded
well providing the corresponding pyrazinedione 3e in 57% yield
(Table 2, entry 4).
dicarbonyl compound, we envisaged to develop optimized condi-
tions for its formation (Table 1). Initially, the reactions were
performed in a solvent mixture composed of water and an organic
solvent (Table 1, entries 1–5). As we observed that water was
crucial for the completion of the reaction (Table 1, entry 6), trans-
formations were tried out in water as the sole solvent, resulting in
a smooth formation of the desired compound 3a in 84% yield
(Table 1, entry 7). This rendered our procedure a green feature.11
When the base was omitted from the reaction mixture, no reaction
took place (Table 1, entry 5). All inorganic bases tested were almost
equally efficient (Table 1, entry 7–10).
Optimized conditions were achieved by reaction of 1a with
2 equiv of Na2CO3 in H2O under microwave irradiation for 30 min
at a ceiling temperature of 140 °C and a maximum power of
150 W (Table 1, entry 7). We next investigated the scope of the
reaction by reacting various pyrazinones 1b–h, applying the opti-
In conclusion, we have elaborated an unprecedented micro-
wave-assisted cascade sequence for the conversion of
a 3-
(phenylsulfinyl)-5-chloro pyrazinone into a 5-(phenylsulfinyl)-
pyrazine-2,3-dione. The key features of the methodology include
inexpensive reagents, aqueous conditions and a short reaction
time. The generated 2,3-diketones are under current investiga-
tion as interesting precursors for the generation of bioactive
compounds.
Table 2
Evaluation of the scope of the reaction applying different pyrazinones 1b–ha
R1
R1
R6
N
O
S
R6
S
N
O
O
H2O, Na2CO3 (2 equiv)
MW 150 W, 140 oC, 30 min
R
R
Cl
N
1b-h
N
H
3b-h
Entry
1
R1
R6
H
R
Compd
Time (min)
30
Yieldb (%)
74
Ph
3b
*
OMe
2
3
H
H
Ph
Ph
3c
30
30
79
62
*
3d
(H2C)3
*
OMe
4
5
H
Et
3e
3f
60c
60c
57d
39d
*
Me
Ph
*
OMe
OMe
6
4-MeO–Ph
Ph
Ph
3g
3h
60c
60c
0e
*
*
7
Bn
0e
a
Reactions were run on a 0.3 mmol scale of 1b–h in H2O (3 mL) with 2.0 equiv of base (0.6 mmol). The mixture was irradiated in a sealed vial at a ceiling temperature of 140 °C
and 150 W maximum power for the stipulated time. All microwave irradiation experiments were carried out in a dedicated CEM-Discover monomode microwave apparatus.
b
Isolated yield.
c
As some unreacted starting material was observed by GCMS, the reaction mixture was subsequently run for another 30 min.
Around 30% of starting material remained unreacted based on GC analysis.
All starting material was recovered.
d
e

4996
A. Sharma et al. / Tetrahedron Letters 49 (2008) 4993–4996
Ohmori, J.; Shimazu, M. S.; Okada, M.; Sakamoto, S. J. Med. Chem. 1996, 39,
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Support was provided by the research fund of the University of
Leuven and the FWO (Fund for Scientific Research—Flanders (Bel-
gium)). A.S. is thankful to the University of Leuven (KU Leuven)
for obtaining a postdoctoral fellowship. Authors wish to thank S.
Toppet for her valuable help in NMR data analysis. The authors also
wish to thank B. Demarsin and D. Henot for their valuable help in
Mass analysis and HPLC analysis and purification.
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Supplementary data
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signals at 1629 and 1672 cmÀ1
The HMBC experiment revealed clear
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