Synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2014.06.100

Different approaches for the synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives from simple amino acids have been investigated. A library of 33 precursors for the preparation of N-hydroxy pyrazinones was obtained in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2014.06.100

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives
⇑
Anh Hung Mai, Sonalika Pawar , Wim M. De Borggraeve
Molecular Design and Synthesis, Chemistry Department, University of Leuven, Celestijnenlaan 200F-box 2404, 3001 Heverlee, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Different approaches for the synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives from simple amino
acids have been investigated. A library of 33 precursors for the preparation of N-hydroxy pyrazinones was
obtained in moderate to good yields.
Received 30 May 2014
Revised 23 June 2014
Accepted 25 June 2014
Available online xxxx
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Aspergillic acid
Hydroxamic acid
Pyrazin-2(1H)-one
Amidation
The pyrazinone is a valuable scaffold in medicinal chemistry. It
is present amongst others in the inhibition of HCV NS3 protease,1,2
neutrophil elastase,3 prolyl oligopeptidase,4 TF-FVIIa5 and throm-
bin.6,7 A lot of research in our group was directed towards the
development of synthetic strategies for highly functionalized
pyrazinones.8–15 Since there are bioactive compounds known in
nature containing an N-hydroxypyrazinone core (e.g., aspergillic
acid, Fig. 1),16–18 we focused our attention to the development of
new strategies to synthesize pyrazinones containing 1-benzyloxy
functionality. These compounds can potentially give rise to asperg-
illic acid-like hydroxamic acids upon deprotection. Furthermore, in
extension of our work on 1-alkyl/aryl functionalized pyrazinone-
3-carboxamides,15 we also intended to prepare the corresponding
1-benzyloxy-3-carboxamide pyrazinones.
course of 30–120 min. The regioselectivity of this reaction with an
unsymmetrical glyoxal derivative (methyl/phenyl glyoxal) was
reported before19,20 and was confirmed by us via NMR analysis.
Proton H-6 in compounds 3b,c,e,f,m,n,q,t,w,y,zc,zg (unsubstituted
at position 6, but substituted at position 5) shows a clear NOE
correlation with the methylene protons of the O-benzyl group, as
well as an HMBC correlation with C-2 (Fig. 2).
The synthesis of 1-benzyloxy-3-alkylpyrazin-2(1H)-ones (3a–f,
Scheme 1) was achieved by amidation of N-Boc protected amino
acids
1 using O-benzyl hydroxylamine in combination with
HOBt/EDCI/DIPEA/DMF, followed by Boc-deprotection and conden-
sation. O-Benzyl hydroxamate 2a could also be prepared via direct
Our synthetic scheme for the synthesis of 1-benzyloxypyrazin-
2(1H)-ones improves upon reported procedures19–23 and is similar
to chemistry we already applied in the preparation of 1-alkyl/aryl
pyrazinones.11,12 It relies on the base catalysed condensation of a
glyoxal derivative with an amino acid hydroxamate. The condensa-
tions with phenyl glyoxal and diacetyl need a higher reaction tem-
perature (50–70 °C) compared to those with glyoxal and methyl
glyoxal. In order to avoid excessive side reactions resulting in very
complex mixtures, it was important to use the glyoxal derivative as
a limiting reagent (0.9 equiv, see Supplementary information) and
to add it slowly to the reaction mixture via a syringe pump over the
Figure 1. Aspergillic acid (1).
⇑
Corresponding author. Tel.: +32 16 327693; fax: +32 16 327990.
E-mail address: wim.deborggraeve@chem.kuleuven.be (W.M. De Borggraeve).
Current address: Chemistry Department, Fergusson College, F.C. Road, 411004
Pune, India.
Figure 2. NOE and HMBC correlations of H-6 in compounds 3.
http://dx.doi.org/10.1016/j.tetlet.2014.06.100
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mai, A. H.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.100

2
A. H. Mai et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Scheme 1. Synthetic pathway for preparation of 1-benzyloxy-3-alkylpyrazin-2(1H)-ones. Reagents and conditions: (a) BnONH2ÁHCl (1 equiv), HOBt (1.3 equiv), EDCI
(1.3 equiv), DIPEA (2.3 equiv), DMF, À10 °C then rt, 16 h; (b) (i) 4 M HCl (10 equiv) in dioxane, rt, 30 min. (ii) R5R6(CO)2 (0.9 equiv), 2 M NaOH, pH 8–10, MeOH–H2O (2:1),
À35 °C then rt, overnight; (c) BnONH2 (1.1 equiv), LiHMDS (3.1 equiv), THF, À78 °C, 2 h.
amidation of the methyl ester of amino acid 4 using LiHMDS base
in THF.24 A slight reduction in yield and a shorter reaction time are
observed in this instance (Scheme 1, entry 2a). The direct amida-
tion route could also be applied to more complex substrates as
exemplified below in Scheme 3. Using this approach of slow addi-
tion with glyoxal as the limiting reagent, the previously reported
1-benzyloxypyrazin-2(1H)-ones 3a, 3b and 3d were obtained in
better yields as compared to the literature.21–23
The synthesis of the novel and more complex 1-benzyloxypyr-
azin-2(1H)-one 3-carboxamides 3g–zg is described in Schemes 2
and 3. In this pathway, the amino group in diethyl amino malonate
ester hydrochloride (5) is first Boc-protected to form 6. This is fol-
lowed by iterative mono-saponification amidation to generate 10
(Scheme 2). These compounds are then converted to pyrazine-
2(1H)-ones 3g–zg in moderate to good yields after Boc-removal
(Schemes 2 and 3). Compounds 10 can alternatively directly be
obtained via conversion of ethyl ester 11 using LiHMDS and
NH2OBn (Scheme 3). In the case of 3-carboxylated derivatives of
1-benzyloxypyrazin-2(1H)-one, the latter approach is able to
reduce the number of reaction steps leading to the final products;
however, it does limit the late stage diversification at C-3 of the
target compounds, which in terms of library generation is a
drawback.
In a further effort to shorten the synthetic protocol in the syn-
thesis of 1-benzyloxypyrazin-2(1H)-ones 3, we performed the
cyclization of the product of Boc-deprotection of 8 with glyoxals
to generate 1-benzyloxypyrazin-2(1H)-one 3-carboxyl ethyl esters
12, which could be used as precursors in a one-step amidation to
form 3 (Scheme 4) using MgCl2 as Lewis acid catalyst.25 The
desired secondary amide products (3zc, 3zd and 3zg) could be
obtained in high yields by treating ethyl esters 12 with primary
amines. However, no conversion was detected in case of secondary
amines even after prolonged reaction time and heating at a tem-
perature of 50 °C (3zh and 3p however can be synthesized via
methods described in Schemes 2 and 3).
Using these approaches, a 33-component library of 1-benzyl-
oxypyrazin-2(1H)-one derivatives, precursors for the synthesis of
N-hydroxypyrazinones, has been prepared in moderate to good
Scheme 2. Synthetic pathway for preparation of 1-benzyloxypyrazin-2(1H)-one 3-carboxamides 3. Reagents and conditions: (a) Boc2O (1.05 equiv), NaHCO3 (1.05 equiv),
DMAP (0.01 equiv), H2O–dioxane, rt, overnight; (b) KOH (1 equiv), EtOH, rt, overnight; (c) BnONH2ÁHCl (1 equiv), HOBt (1.3 equiv), EDCI (1.3 equiv), DIPEA (2.3 equiv), DMF,
À10 °C then rt, 16 h; (d) R7R8NH (1 equiv), HOBt (1.3 equiv), EDCI (1.3 equiv), DIPEA (1.3 equiv), DMF, À10 °C then rt, 16 h; (e) (i) 4 M HCl (16 equiv) in dioxane, rt, 30 min; (ii)
R5R6(CO)2 (0.9 equiv), 2 M NaOH, pH 8–10, MeOH–H2O (2:1), À35 °C then rt, overnight.
Please cite this article in press as: Mai, A. H.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.100

A. H. Mai et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Acknowledgment
The authors gratefully acknowledge financial support from KU
Leuven via OT/11/047 and the Ministry of Education and Training
(Vietnam International Education Development, VIED).
Supplementary data
Supplementary data (general procedures for synthesis and
characterization of all compounds, copies of 1H and 13C NMR spec-
tra of compounds 3 and 12) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2014.06.100. These data include MOL files and InChiKeys of the
most important compounds described in this article.
References and notes
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Scheme 3. Direct amidation of ethyl ester 11. Reagents and conditions: (a) R7R8NH
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Scheme 4. Synthesis of 3 via amidation of ester 12. Reagents and conditions: (a) (i)
4 M HCl (16 equiv) in dioxane, rt, 30 min. (ii) R5R6(CO)2 (0.9 equiv), 2 M NaOH, pH
7–8, MeOH–H2O (2:1), À35 °C then rt, overnight; (b) (i) MgCl2 (2 equiv), THF, rt,
5 min. (ii) R7R8NH (2.5 equiv), rt, 16 h; (c) No conversion, 12a was recovered (by
LC–MS); (d) 38% yield of 3p (from 8, Scheme 2).
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yields with minimal reaction steps. Pyrazin-2(1H)-ones 3c, 3e, 3f
and 27 other 3-carboxamide substituted analogues 3g–zg are
new compounds. Deprotection of this library will be subject of
another paper.
Please cite this article in press as: Mai, A. H.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.06.100