Green synthesis of 2-pyrazinones in deep eutectic solvents: From α-chloro oximes to peptidomimetic scaffolds

Article abstract of DOI:10.1016/j.tet.2017.09.013

A novel and green synthesis of 2-pyrazinones in deep eutectic solvents (DESs) is described. Treatment of aromatic α-chloro oximes with aliphatic amines at 110 °C in choline chloride based DESs resulted in a straightforward and efficient assembly of 1,3,5-

Full text of DOI:10.1016/j.tet.2017.09.013

Accepted Manuscript
Green synthesis of 2-pyrazinones in deep eutectic solvents: From α-chloro oximes to
peptidomimetic scaffolds
Serena Perrone, Martina Capua, Francesco Messa, Antonio Salomone, Luigino Troisi
PII:
S0040-4020(17)30935-3
10.1016/j.tet.2017.09.013
TET 28964
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 July 2017
Revised Date: 23 August 2017
Accepted Date: 11 September 2017
Please cite this article as: Perrone S, Capua M, Messa F, Salomone A, Troisi L, Green synthesis of 2-
pyrazinones in deep eutectic solvents: From α-chloro oximes to peptidomimetic scaffolds, Tetrahedron
(2017), doi: 10.1016/j.tet.2017.09.013.
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Green Synthesis of 2-Pyrazinones in Deep
Eutectic Solvents: from α-Chloro Oximes to
Peptidomimetic Scaffolds
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a
a
a,b
a,
a
Serena Perrone , Martina Capua , Francesco Messa , Antonio Salomone * and Luigino Troisi
a
Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Prov.le Lecce-
Monteroni, Lecce I-73100;
Dipartimento di Farmacia–Scienze del farmaco, Università degli Studi di Bari «Aldo Moro», Consorzio
b
C.I.N.M.P.I.S., Via E. Orabona 4, Bari I-70125, Italy;

1
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Tetrahedron
journal homepage: www.elsevier.com
Green Synthesis of 2-Pyrazinones in Deep Eutectic Solvents: from
to Peptidomimetic Scaffolds
α
-Chloro Oximes
a
a
a,b
a,
a
Serena Perrone , Martina Capua Francesco Messa, Antonio Salomone * and Luigino Troisi
,
a
Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Prov.le Lecce-Monteroni, Lecce I-73100;
Dipartimento di Farmacia–Scienze del farmaco, Università degli Studi di Bari « Aldo Moro », Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, Bari I-70125, Italy;
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel and green synthesis of 2-pyrazinones in deep eutectic solvents (DESs) is described.
Treatment of aromatic α-chloro oximes with aliphatic amines at 110 °C in choline chloride
based DESs resulted in a straightforward and efficient assembly of 1,3,5-trisubstituted-2(1H)-
pyrazinones. The protocol, featuring mild reaction conditions and avoiding common volatile
organic solvents, affords a safe and sustainable approach to original peptidomimetic scaffolds.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
α-chloro oxime
2
-Pyrazinone
Deep Eutectic Solvents
Green Chemistry
Peptidomimetics
1
. Introduction
In the last few years, 2(1H)–pyrazinones have aroused
considerable interest since they may represent a significant
scaffold in peptidomimetic chemistry. Recently the use of
pyrazinones as a part of a number of macromolecular
peptidomimetic ligands acting as protease inhibitors has been
reported. In particular, the introduction of a pyrazinone in the
Scheme 1. Synthesis of 3,5-dichloro-2(1H)-pyrazinones from α-amino
nitriles and oxalyl chloride.
1
2a-e
3
caspase-3, thrombin and tryptase peptide-like inhibitors leads
to a reduction of the peptidyl nature of these compounds, while
preserving their binding potency and selectivity to modulate
protease activity. Inhibition of specific proteases may offer
significant opportunity for therapeutic intervention in several
diseases such as neurodegenerative diseases and autoimmune
disorders. A pyrazinone unit also replaced a disulfide portion in a
somatostatin derivative leading to a compound with high anti-
The reactive 3-Cl position of 3,5-dichloro-2(1H)-pyrazinones
can be easily functionalized with (hetero)aryl, alkyl and alkenyl
groups by means of Suzuki cross-coupling reactions using
organoboron reagents. Furthermore, Heck coupling of vinyl
compounds at C-3 of 2(1H)-pyrazinones provides 3-alkenyl-5-
7
cloro-2(1H)-pyrazinones. The 5-Cl position is inert towards
4
proliferative activity. Moreover, investigations of a tunicate-
Suzuki and Heck cross-coupling reactions and its
functionalization is proved to be more difficult. Indeed, before
carrying out cross coupling reactions, a prior trans-halogenation
of the 5-Cl substituent to produce a 5-Br or 5-I-2(1H)-
derived actinomycete Streptomyces sp. afforded new 2(1H)–
pyrazinone-based molecules providing further understanding
about the chemistry and bioactivities of the alkylated 2(1H)–
5
7
pyrazinone derivatives.
pyrazinones is required.
Considering the importance of the above-mentioned
applications and activities, methods for the synthesis of the
Alternatively, 5-alkyl and 5-aryl-2(1H)-pyrazinones can be
prepared, using H O/MeOH as solvent, via a direct condensation
2
2
(1H)–pyrazinone core are of great interest. As previously
of carboxamide derivatives with dicarbonyl compounds
6
3
4
reported by Hoornaert and coworkers, the treatment of
hydrohalides of 2-sec-aminoalkanenitriles (I) with an excess of
oxalyl chloride, using o-dichlorobenzene (ODCB) as reaction
solvent, afforded intermediate (II) and then 3,5-dihalo-2(1H)-
pyrazinones, of which the 3-halo substituent is easily replaced by
producing a pyrazinone product when R and R are the same, or
3 4
a mixture of regioisomers when R and R are different from each
8
other (Scheme 2).
7
nucleophiles (Scheme 1).

2
Tetrahedron
ACCEPTED MA
Mor
NU
eov
S
e
C
r,
R
α-
I
chloro oximes have been involved in umpolung
P
T
carbon sulfur bond-forming reactions by nucleophilic addition of
16
thiolate and sulfinate ions. However, no application of α-chloro
oximes in the synthesis of the 2(1H)-pyrazinone core has been
reported.
Scheme 2. Synthesis of 5-substituted 2(1H)-pyrazinones from
amides.
α-amino
Here we describe a novel, safe and convenient coupling
reaction of α-chloro oximes with primary amines to furnish
2(1H)-pyrazinone derivatives. The α-chlorinated oximes used
were easily prepared according to a known protocol based on
direct condensation of the α-chloroketones with hydroxylamine
In terms of the reactivity of 2(1H)-pyrazinones, several
heterocycles containing a 2-azadiene moiety are subject to
cycloaddition reactions. The 2-azadiene system of 2(1H)–
pyrazinones has been shown to be involved in [4+2]
cycloaddition reactions with a variety of dienophiles such as
singlet oxygen, 1,2,4-triazoline-3,5-diones, olefins and acetylenic
compounds. Furthermore, 2(1H)–pyrazinones with either a 3-
or 4- alkynyloxy side chain in the 3-position underwent
intramolecular Diels-Alder reactions providing furo/pyrano-
17
hydrochloride.
At first, the reaction of 2-chloro-1-
phenylethanone oxime 1a with butan-1-amine 2a, under Pd–
catalyzed carbonylation conditions previously reported,
carried out. (Table 1, entry 1).
9a-b
12-13
was
1
10
After a reaction time of 10 h, GC-MS and H NMR
spectroscopic analysis of the crude reaction mixture showed the
formation of a new coupling molecule as main reaction product.
pyridines and/or –pyridinones.
Therefore, development of new approaches for the synthesis
of 2(1H)–pyrazinones could be relevant from both chemical and
biological viewpoints. In addition, it should also be noted how
the methods previously reported are performed in toxic,
hazardous volatile organic solvents (VOCs, e.g. ODCB, DMF,
toluene, etc.).
1
13
H, C NMR spectroscopic analysis and NOESY experiments
performed on the product, after its isolation by column
chromatography on silica gel, proved that coupling between
oxime 1a and amine 2a occurred to provide the 1-butyl-3,5-
diphenylpyrazin-2(1H)-one 3a in 32% yield.
In this paper, we describe a novel synthetic method for the
assembly of the 2(1H)–pyrazinone core by means of a coupling
reaction between aromatic α-chloro oximes and aliphatic amines.
Table 1. Optimization of the experimental conditions for the
coupling between 2-chloro-1-phenylethanone oxime and
a
butan-1-amine
Moreover, this process, representative of
a direct and
straightforward methodology to obtain 1-alkyl-3,5-aryl
trisubstituted 2(1H)-pyrazinones, was successfully accomplished
in “green” reaction media such as DESs (deep eutectic
11a-c
solvents).
DESs represent an emerging class of
unconventional and bio-renewable solvents that could
satisfactorily replace any common VOC solvents in organic
reactions. They are generally composed of two or three safe and
inexpensive components, which are involved in hydrogen bond
interactions with each other to obtain a eutectic mixture with a
melting point much lower than that of each component species.
Since their typical components [e.g., choline chloride (ChCl),
urea, glycerol (Gly), natural carboxylic acids, amino acids and
carbohydrates, polyalcohols, etc.] come from natural sources,
DESs display low toxicity, high thermal stability, high
biodegradability, high recyclability, low inflammability and
volatility, avoiding many disadvantages of common hazardous
organic solvents (VOCs).
Oxime
1a (equiv.)
1.0
Amine
2a (equiv.)
Solvent
3a Yield
(%)
32
Entry
b
c
1.3
THF
1
2
3
4
5
6
7
8
9
d
1
.0
1.3
1.3
1.3
1.3
1.3
1.0
1.0
1.3
1.3
THF
39
1.0
Toluene
DMF
traces
58
1
1
1
1
2
1
1
.0
.0
.0
.0
.0
.0
.0
e
Gly/ChCl
70
e
urea/ChCl
68
Gly/ChCl
43
Gly/ChCl
55
2
. Results and discussion
f
THF/H
2
O
22
In the recent past, our research group has been interested in
f
DMF/H
2
O
35
1
0
the study of the reactivity of halides characterized by a π
C−C,C−O or C−N bond such as allyl, benzyl halides, α-chloro-
a
Reagents and conditions on 1 mmol scale: 2-chloro-1-phenylethanone oxime
(1.5 to 3.0 mmol), 1-butanamine (1.5 to 2.0 mmol), Et N (3.0 mmol),
common volatile organic solvents (THF, toluene, DMF, 10 mL) or DES (3
mL), 110 °C, 10 h. All reactions were run in duplicate.
12,13
ketones and -imines.
These unsaturated halides, via a Pd-
3
catalyzed carbonylation process, were efficiently coupled with a
variety of nucleophiles to afford a wide range of carbonyl-
containing organic molecules such as functionalized β-
b
Isolated yield.
1
2a-c
12d
12e
12f
12g-i
lactams,
imides, esters, acetylenic ketones, amides,
c
Reaction carried out in autoclave at a temperature of 110 °C under CO
pressure (27.0 atm) with 5 mol% of Pd(PPh ) .
3 4
13a
13b
13c
pyranones,1 uracil, pyrazolone derivatives, and isocytosine
analogues.
3d
d
Reaction carried out in autoclave at a temperature of 110 °C.
In line with our research work, we then started an
investigation of the reactivity α-chloro oximes towards primary
amines as nucleophiles. α-Chloro oximes are highly reactive and
unstable molecules, the utility of which in organic synthesis has
remained little explored. In particular, α-chloro oximes are
known to undergo a base-induced condensation to provide both
e
f
-1
-1
DES mixture: Gly−ChCl, 2:1 mol mol or urea−ChCl, 2:1 mol mol .
:
Solvents were mixed in a 1:1 ratio.
The analysis of the atomic connectivity in 3a prompted us to
perform the same reaction without carbon monoxide and Pd-
source; the pyrazinone nucleus was again obtained in a similar
yield, highlighting how the Pd-catalysis is not necessary in such a
reaction (Table 1, entry 2).
14
alkynyl oxime ethers with lithium diisopropylamide and 2,4,6-
15
trisubstituted pyrimidines in the presence of Grignard reagents.

3
Indeed, to improve the coupling process yiel
A
d,
C
an
C
op
E
ti
P
m
T
iza
E
ti
D
on MAN
T
U
ab
S
le
C
2
R
. Synthesis of 2(1H)–pyrazinone derivatives 3b-j
I
P
T
of reaction conditions was carried out by changing some
parameters such as the reaction solvent as well as the amounts of
oxime and amine used. As shown in Table 1, the nature of the
solvent was proven to be crucial for the final product yield, and
good results were achieved using polar common organic solvents
with an increase in the yield as the solvent polarity increases
from toluene to DMF (Table 1, entries 2-4).
in Deep Eutectic Solvents
OH
N
Ar
N
Ar
O
NEt3
Cl
+
H N R
2
Ar
N
R
Gly/ChCl
10 °C , 10 h
1
1
a-c
2a-e
3b-j
a
However, to our delight the best product yields were obtained
when the experiments were run, under air, in environmentally
friendly solvents (DESs). In particular, Gly/ChCl and urea/ChCl
were tested (Table 1, entries 5-8) as eutectic solvents. The
reaction proved to be very clean, in both cases, without the
detection of other byproducts. The pyrazinone 3a was easily
isolated in 70% and 68% yield, respectively (Table 1, entries 5
and 6), after a simple reaction workup involving dilution of the
crude reaction with an equal volume of water and AcOEt,
separation of the organic layer followed by chromatography on
silica gel (see Experimental Section). In addition, it was possible
to recover and recycle Gly/ChCl and urea/ChCl DES mixtures.
Indeed, a further addition of water (2 mL) to the aqueous layer
containing the DES leads to the precipitation of the unreacted
reagents and small amounts of other organic byproducts that
were removed by filtration. Subsequent evaporation of water
under reduced pressure, afforded a DES mixture that was
successfully reused for the synthesis of 3a without a significant
drop in the chemical yield (67%) after three experiments. As far
as we are aware, this represents the first example of the
preparation of 2(1H)-pyrazinones performed in low melting
green mixtures.
Reagents and conditions: oxime (1.5 mmol), primary amine (2.0 mmol),
Oxime
1
Amine
2
2-Pyrazinone
3 (Yield %)
Entry
R
Ar
Ph
1
2
3
2b
2c
2d
Bn
1a
1a
3
b (78)
Ph
Ph
i-Pr
3
c (89)
1a
1a
t-Bu
3
d (91)
4
5
Ph
2e
2a
3e (93)
Moreover, a brief screening about the relative amounts of
reagents revealed that formation of the 2(1H)-pyrazinone 3a was
higher when an excess of the primary amine was employed
1b
1b
4-ClC
6
H
4
n-Bu
(
Table 1, entry 5); if an equimolar amount of 1a and 2a, or an
excess of oxime were used, the pyrazinone yield dropped
considerably (Table 1, entries 7-8). In addition, we experimented
with two mixed solvents containing an equal volume of a polar
aprotic solvent (THF, DMF) and water. This was done in order to
check if the addition of water, as a proton source, to a VOC
solvent could be equivalent to using DES. Although the product
3f (88)
Cl
Cl
N
N
6
7
4-ClC
4-ClC
6
H
4
2c
i-Pr
O
3
a could be isolated in both cases (22 and 35% yield, Table 1,
entries 9-10), the use of DESs resulted far more efficient.
3
g (89)
Once the optimal experimental conditions were identified
(
Table 1, entry 5), the coupling reaction of various aromatic α-
chloro oximes with aliphatic primary amines, under the same
conditions, was examined (Table 2). In particular, we synthesized
in high yields (78-93%) 1-alkyl-3,5-phenyl trisubstituted 2(1H)-
pyrazinones 3b-e starting from 2-chloro-1-phenylethanone oxime
1b
6
H
4
2d
t-Bu
3
h (95)
1
a and the aliphatic amines 2b-e as nucleophiles. Notably, the
methodology works efficiently also with sterically demanding
amines, as proved with the synthesis of 1-tert-butyl and 1-
phenylethyl substituted derivatives 3d and 3e obtained in
excellent yields (Table 2, entries 3-4).
8
9
1c
1c
4-FC
4-FC
6
H
4
2c
i-Pr
3
i (93)
The same experimental procedure was also efficiently applied
to the p-Cl- and p-F- substituted oximes 1b and 1c; in fact, they
proved to be good partners with aliphatic amines affording the
corresponding 1-alkyl-3,5-aryl trisubstituted 2(1H)-pyrazinones
6
H
4
2d
t-Bu
3
f-3j in high yield (88-95%, Table 2, entries 5-9).
However, any attempts to perform coupling between aliphatic
3
j (92)
α-chlorinated oximes (e.g. 2-chlorocyclohexanone oxime or 1-
chloropropan-2-one oxime) and aromatic (such as aniline) or
aliphatic amines resulted in a complex mixture of unidentified
products.
3
Et N (3.0 mmol), DES (Gly/ChCl, 3 mL), 110 °C, 10 h. All reactions were
run in duplicate.
b
After isolation by column chromatography on silica gel.

4
Tetrahedron
ticEDα- MAN
Furthermore, in the reactions betwe
A
enCCaro
E
m
P
a
T
R
U
ea
S
ge
C
nt
R
s
I
a
P
nd solvents, unless otherwise specified, were
T
chlorinated oximes and aniline no coupling product was
obtained, pointing out how this synthetic procedure works well
with the use of aromatic oximes and aliphatic amines.
purchased from Sigma-Aldrich (Sigma-Aldrich, St. Louis, MO,
USA) and used without any further purification. THF was
purified by distillation from sodium/benzophenone before use.
1
Petroleum ether refers to the 40−60 °C boiling fraction. The H
and the C NMR spectra were recorded with a Bruker Avance
Although the chemical impact of our method relies basically
on its synthetic utility as a fast, green and simple way to 2-
pyrazinones, some considerations about the reaction mechanism
are needed. On the basis of a recent investigation on the
reactivity of α-chloro oximes in DESs, we hypothesize that the
first step of our domino process should be the nucleophilic attack
of the amine 2 to the oxime 1 affording the α-amino oxime
intermediate A (Scheme 3).
13
1
13
4
00 apparatus (400.13 and 100.62 MHz, for H and C,
respectively) with CDCl as the solvent and TMS as an internal
standard (δ = 7.26 ppm for H spectra; δ = 77.0 ppm for
3
1
13
16
C
spectra). The IR spectra were recorded with an FT-IR
spectrophotometer Digilab Scimitar Series FTS 2000. Gas
chromatography (GC) was conducted on an Rtx-5 30-m fused
silica capillary column (split ratio 100:1). The following program
was used: method A = initial temperature of 100 °C for 0.0 min,
ramp 10 °C/min to 280 °C, and hold for 15 min; the standard
operating conditions were 300 °C injector temperature and 290
°
C detector temperature. GC-MS analyses, conducted using
method A temperature programme, were performed with an
Agilent Technologies 6850 series II gas chromatograph (5%
phenylpolymethylsiloxane capillary column, 30 m, 0.25 mmi.d.),
equipped with a 5973 Network mass-selective detector operating
at 70 eV. The electrospray ionization [HRMS (ESI)] experiments
were carried out in a hybrid QqTOF mass spectrometer (PE
SCIEX-QSTAR) equipped with an ion-spray ionization source.
-
1
MS (+) spectra were acquired by direct infusion (5 mL min ) of
-
1
a solution containing the appropriate sample (10 pmol mL )
dissolved in a solution 0.1% acetic acid, methanol/water (50:50)
at the optimum ion voltage of 4800 V. The nitrogen gas flow was
set at 30 psi (pounds per square inch) and the potentials of the
orifice, the focusing ring and the skimmer were kept at 30, 50
and 25 V relative to ground, respectively. Melting points were
determined with an Electrothermal melting point apparatus and
are uncorrected. TLC was performed on Merck silica gel plates
with F-254 indicator; viewing was by UV light (254 nm) or p-
anisaldehyde and phosphomolybdic acid staining solution.
Chromatographic separations were performed on silica gel
Scheme 3. Mechanistic hypothesis for the formation of 1-alkyl-3,5-
trisubstituted 2(1H)-pyrazinones from α-chloro oximes and amines.
The absence of a N-O bond in the final product prompted us
to consider that an elimination of the OH group from the nitrogen
atom must occur. This process may consist of two steps: firstly, a
base-catalyzed tautomerism could promote the formation of B,
the enaminic form of A, favored by the extensive electronic
conjugation. A subsequent base-catalyzed elimination and NO
bond breaking, should afford the intermediate C.
(63−200 mesh) using petroleum ether/ethyl acetate (AcOEt)
mixture as the eluent. All reactions involving air-sensitive
reagents were performed under an atmosphere of nitrogen in
oven-dried glassware by using syringe/septum cap techniques.
The deep eutectic solvents ChCl–Gly (1:2 mol.mol-1) and ChCl–
urea (1:2 mol.mol-1) were prepared by gently heating under
stirring at 70 °C for 5 min the corresponding individual
components until a clear solution was obtained.
Once formed, the 1,4-diaza-1,3-diene C could undergo a [4+2]
cycloaddition with 1', the enolic form of 1, to assemble the six-
18
membered ring D.
The subsequent elimination of the
4
.2. General procedure for the synthesis of α-chlorinated oximes
hydroxylamine and the chloride ion should afford the aromatic
1
a-c
pyrazinium E that, after the nucleophilic attack of a molecule of
19
water and air-promoted dehydrogenation/aromatization, should
To a stirred mixture of α-chlorinated aromatic ketone (38
give the 1-alkyl-3,5-diaryl trisubstituted 2-pyrazinone product 3.
Mmol) and hydroxylamine hydrochloride (115 mmol) in water (8
mL), methanol was added (60 mL) to yield a clear solution that
was stirred overnight at room temperature. Subsequently, water
(80 mL) was added and the oxime product precipitated out as a
solid. The solid was filtered out, washed several times with water
3
. Conclusions
A direct and easy method for the synthesis of 1-alkyl-3,5-aryl
trisubstituted 2(1H)-pyrazinones, biologically valuable products
like peptidomimetics, is described. In particular, we have found
that aromatic α-chloro oximes can be safely and conveniently
coupled with aliphatic primary amines using DESs as privileged
and green solvents for the reactions. This methodology, by which
and dried over CaCl
for 2-chloro-1-phenylethanone oxime 1a, obtained in 91% yield,
in a vacuum desiccator. Spectroscopic data
2
1
7
were in agreement with those reported in the literature.
Spectroscopic data for oximes 1b and 1c are reported below.
2
(1H)-pyrazinones are obtained with high yields, has the
2
-Chloro-1-(4-chlorophenyl)ethanone oxime (1b): white solid
1
advantage of working in biodegradable and cost-effective
reaction solvents so avoiding the use of toxic and hazardous
volatile organic solvents.
(
7.1 g, 92%), m.p. 100-102 °C. H NMR (400.13 MHz, CDCl ):
δ = 4.59 (s, 2 H), 7.40 (d, J = 8.6 Hz, 2 H), 7.62 (d, J = 8.6 Hz, 2
H), 9.36 (broad s, 1 H) ppm. C NMR (100.62 MHz, CDCl ): δ
3
13
3
=
=
32.0, 127.5, 129.0, 131.6, 136.0, 153.4 ppm. FT-IR (CHCl ): ν
4
. Experimental section
3
3574, 3289 (broad), 1604, 1512, 1496, 1442, 1291, 1263, 1096
-
1
4
.1. General Information
cm .GC-MS (70 eV): m/z (%) = 207 (7) [M+4], 205 (47) [M+2],
+
2
03 (70) [M] , 154 (65), 137 (100), 111 (68), 75 (60), 51 (30).

5
+
A
HRMS (ESI): calcd. for C H Cl NO [M+H]
2
C
03
C
.99
E
8
P
4;
T
fo
E
u
D
nd MA22
N
0
U CR
(1
S
0
0),
1
I
1
P
6 +(26), 89 (29). HRMS (ESI): calcd. for
T
8
8
2
2
03.9987.
C H N O [M+H] 305,1655; found 305,1653.
0
2
21
2
2
-Chloro-1-(4-fluorophenyl)ethanone oxime (1c): pale yellow
(±)-3,5-Diphenyl-1-(1-phenylethyl)pyrazin-2(1H)-one
yellow oil (491 mg, 93%). H NMR (400.13 MHz, CDCl ):
(3e):
1
1
solid (6.4 g, 90%), m.p. 64-66 °C. H NMR (400.13 MHz,
3
CDCl ): δ =4.59 (s, 2 H), 7.09-7.13 (m, 2 H), 7.66-7.69 (m, 2 H),
δ=8.50−8.52 (m, 2 H), 7.72−7.76 (m, 2 H), 7.29 – 7.51 (m, 12
H), 6.52 (q, J = 7.1 Hz, 1 H), 1.84 (d, J = 7.1 Hz, 3 H) ppm. C-
3
13
13
9
3
1
1
1
.39 (broad s, 1 H) ppm. C NMR (100.62 MHz, CDCl ): δ =
2.2, 115.8 (d, J = 22 Hz), 128.2 (d, J = 8 Hz), 129.1, 153.4,
3
NMR (100 MHz, CDCl ): δ = 154.5, 151.5, 139.0, 136.3, 133.1,
3
63.7 (d, J = 251 Hz) ppm. FT-IR (CHCl ): 3575, 3300 (broad),
130.0, 129.4, 129.1, 128.8, 128.0, 127.9, 127.6, 126.0, 125.0,
3
-
1
602, 1513, 1442, 1281, 1159 cm . GC-MS (70 eV): m/z (%) =
120.5, 53.9, 18.9 ppm. FT-IR (CHCl ): ν = 3033, 3011, 2960,
3
+
-1
89 (18) [M+2], 187 (53) [M] , 138 (34), 121 (100), 95 (51), 75
2929, 2855, 1729, 1644, 1593, 1454 cm .GC-MS (70 eV): m/z
+
+
(
27). HRMS (ESI): calcd. for C H FClNO [M+H] 188.0279;
(%) = 353(44) [M] , 248 (100), 220 (83), 116 (35), 105 (88), 89
8
8
found 188.0281.
(49), 77 (33). HRMS (ESI): calcd. for C H N O
2
4
21
2
+
[
M+H] 353.1655; found 353.1659.
4
.3. General procedure for the preparation of pyrazin-2(1H)-one
derivatives 3a-j
1-Butyl-3,5-bis(4-chlorophenyl)pyrazin-2(1H)-one
yellow oil (491 mg, 88%). H NMR (400.13 MHz, CDCl ): δ =
.46−8.48 (m, 2 H), 7.77−7.79 (m, 2 H), 7.55 (s, 1 H), 7.41 –
.44 (m, 4 H), 4.00 – 4.09 (m, 2 H), 1.84 (dt, J = 15.2, 7.6 Hz, 2
(3f):
1
3
In a round bottomed flask, aromatic α-chlorinated oxime 1
8
7
(1.5 mmol), aliphatic primary amine 2 (2.0 mmol) and Et N (3.0
3
mmol) were mixed in 3 mL of DES (Gly/ ChCl 2:1 mol/mol or
urea/ ChCl 2:1 mol/mol) for 10 hour at 110 °C. After dilution of
the crude reaction with an equal volume of water, the reaction
mixture was extracted with AcOEt (3 x 5 mL). The combined
organic phases were dried over dry Na SO and the solvent
H), 1.45 (td, J = 14.8, 7.6 Hz, 2 H), 1.00 (t, J = 7.6 Hz, 3 H) ppm.
13
3
C-NMR (100 MHz, CDCl ): δ = 154.5, 150.4, 136.2, 134.4,
1
2
2
3
(
(
34.3, 133.9, 131.6, 130.6, 129.0, 128.2, 126.2, 124.3, 50.7, 30.9,
9.7, 13.6 ppm. FT-IR (CHCl ): ν = 3026, 3011, 2960, 2931,
3
-1
2
4
874, 1727, 1645, 1594, 1451 cm .GC-MS (70 eV): m/z (%) =
removed under reduced pressure. The crude mixture was purified
by column chromatography over silica gel using a mixture of
+
76 (11) [M+4], 374 (66) [M+2], 372 (100) [M] ,355 (45), 316
50), 301 (53), 288 (47), 150 (43), 137 (48), 123 (45). HRMS
9
0:10 to 70:30 petroleum ether/AcOEt as the eluent, to give the
+
ESI): calcd. forC H Cl N O[M+H]
373.0875; found
20
19
2
2
corresponding pyrazin-2(1H)-one derivative 3.
3
73.0876.
Spectroscopic data for 1-Benzyl-3,5-diphenylpyrazin-2(1H)-
one (3b), obtained in 78% yield (395 mg), were in agreement
with those reported in the literature.
3
,5-Bis(4-chlorophenyl)-1-isopropylpyrazin-2(1H)-one (3g):
1
pale yellow oil (478 mg, 89%). H NMR (400.13 MHz, CDCl ):
δ = 8.46 (d, J = 8.6 Hz, 2 H), 7.80 (d, J = 8.6 Hz, 2 H), 7.60 (s, 1
H), 7.42 – 7.44 (m, 4 H), 5.33 (hept, J = 6.8 Hz, 1 H), 1.49 (d, J
6.8 Hz, 6 H) ppm. C-NMR (100 MHz, CDCl ): δ = 154.1,
50.2, 136.1, 134.7, 134.6, 133.9, 132.1, 130.6, 129.0, 128.2,
126.2, 119.6, 47.9, 21.6 ppm. FT-IR (CHCl ): ν = 3028, 3011,
961, 2930, 2876, 1727, 1645, 1592, 1450 cm .GC-MS (70 eV):
m/z (%) = 362 (8) [M+4], 360 (51) [M+2], 358 (77) [M] , 315
60), 288 (100), 150 (39), 123 (43), 89 (23). HRMS (ESI): calcd.
for C H Cl N O [M+H] 359.0719; found 359.0721.
7
3
Spectroscopic data for compounds 3a,c-j are reported below.
13
=
1
3
1
-Butyl-3,5-diphenylpyrazin-2(1H)-one (3a): pale yellow oil
1
(
388 mg, 85%). H NMR (400.13 MHz, CDCl ): δ =8.50 – 8.57
3
3
-
1
(m, 2 H), 7.86 – 7.89 (m, 2 H), 7.56 (s, 1 H), 7.44 – 7.47 (m, 5
2
+
H), 7.34 – 7.37 (m, 1 H), 4.03−4.10 (m, 2 H), 1.86 (dt, J = 15.2,
7
3
1
1
3
.4 Hz, 2 H), 1.46 (dq, J = 14.8, 7.4 Hz, 2 H), 1.00 (t, J = 7.4 Hz,
(
13
+
H). ppm. C NMR (100.62 MHz, CDCl ): δ = 154.7, 151.6,
3
19 17 2 2
36.2, 136.0, 132.7, 129.9, 129.3, 128.8, 128.0, 127.9, 125.0,
1
-(tert-butyl)-3,5-Bis(4-chlorophenyl)pyrazin-2(1H)-one (3h):
24.1, 50.6, 30.9, 20.0, 13.7 ppm. FT-IR (CHCl ): ν= 3027,
3
1
-
1
pale yellow oil (530 mg, 95%). H NMR (400.13 MHz, CDCl ):
δ =8.34 (d, J = 8.7 Hz, 2 H), 7.75 – 7.78 (m, 3 H), 7.40 – 7.43
m, 4 H), 1.79 (s, 9 H) ppm. C-NMR (100 MHz, CDCl ): δ =
55.6, 152.1, 135.8, 135.1, 134.8, 133.6, 131.3, 130.8, 129.0,
28.1, 126.2, 120.7, 63.1, 28.0 ppm.FT-IR (CHCl ): ν = 3027,
010, 2962, 2929, 2875, 1724, 1645, 1592, 1450 cm .GC-MS
009, 2961, 2931, 2874, 1728, 1645, 1595, 1455 cm .GC-MS
3
+
(70 eV): m/z (%) = 304 (100) [M] , 287 (35), 262 (21), 248 (53),
13
(
2
33 (70), 220 (50), 116 (30), 103 (45), 89 (40), 77 (15). HRMS
3
+
1
1
3
(ESI): calcd. for C H N O [M+H] 305.1655; found 305.1657.
20 21 2
3
-
1
1
-Isopropyl-3,5-diphenylpyrazin-2(1H)-one (3c): pale yellow
1
oil (387 mg, 89%). H NMR (400.13 MHz, CDCl ): δ
3
(70 eV): m/z (%) = 376 (2) [M+4], 374 (13) [M+2], 372 (20)
+
=
8.45−8.47 (m, 2 H), 7.87−7.89 (m, 2 H), 7.61 (s, 1 H), 7.44 –
[
M] , 316 (100), 288 (75), 207 (23), 150 (30), 123 (35), 89 (23).
+
7
1
1
1
3
.48 (m, 5 H), 7.34−7.38 (m, 1 H), 5.35 (hept, J = 6.8 Hz, 1 H),
.49 (d, J = 6.8 Hz, 6 H) ppm. C-NMR (100 MHz, CDCl3): δ =
54.3, 151.5, 136.4 (2 x C), 133.2, 129.8, 129.3, 128.8, 128.0,
HRMS (ESI): calcd. for C H Cl N O[M+H] 373.0875; found
20
19
2
2
1
3
3
73.0873.
3
,5-Bis(4-fluorophenyl)-1-isopropylpyrazin-2(1H)-one
(3i):
27.9, 125.0, 119.3, 47.7, 29.7, 21.6 ppm. FT-IR (CHCl ): ν =
3
1
-
1
pale yellow oil (455 mg, 93%). H-NMR (400 MHz, CDCl ): δ =
.49 – 8.52 (m, 2 H), 7.80 – 7.83 (m, 2 H), 7.54 (s, 1 H), 7.11 –
.15 (m, 4 H), 5.32 (hept, J = 6.8 Hz, 1 H), 1.47 (d, J = 6.8 Hz, 6
H) ppm. C-NMR (100 MHz, CDCl ): δ = 163.9 (d, J = 250
Hz), 162.7 (d, J = 248 Hz), 154.1, 150.3, 132.4 (2 x C), 132.3,
31.4 (d, J = 8 Hz), 126.8 (d, J = 8 Hz), 118.9, 115.7 (d, J = 21
Hz), 114.9 (d, J = 21 Hz), 47.8, 21.6 ppm. FT-IR (CHCl ): ν =
026, 3012, 2965, 2927, 2870, 1723, 1643, 1591, 1452 cm . GC-
026, 3009, 2963, 2935, 2872, 1726, 1644, 1596, 1455 cm .GC-
3
+
8
7
MS (70 eV): m/z (%) = 290 (93) [M] , 348 (40), 220 (100), 116
(
[
30), 89 (36).HRMS (ESI): calcd. for C H N O
19 19 2
+
13
M+H] 291.1498; found 291.1499.
3
1
-(tert-butyl)-3,5-Diphenylpyrazin-2(1H)-one (3d): yellow oil
1
1
(
415 mg, 91%). H NMR (400.13 MHz, CDCl ): δ= 8.33 – 8.36
3
3
-
1
(
m, 2 H), 7.84 - 7.86 (m, 2 H), 7.79 (s, 1 H), 7.43 – 7.47 (m, 5
3
13
+
H), 7.32 – 7.36 (m, 1 H), 1.80 (s, 9 H) ppm. C-NMR (100 MHz,
MS (70 eV): m/z (%) = 326 (85) [M] , 284 (51), 256 (100), 229
(11), 134 (23), 107 (32). HRMS (ESI): calcd. for C H F N O
M+H] 327.1310; found 327.1308.
CDCl ): δ = 155.8, 153.4, 136.8, 136.6, 132.3, 129.6, 129.4,
3
1
9
17
2
2
+
1
28.8, 127.9, 127.6, 125.0, 120.4, 62.7, 28.1 ppm. FT-IR
[
(
1
CHCl ): ν = 3027, 3008, 2962, 2931, 2873, 1728, 1644, 1596,
455 cm .GC-MS (70 eV): m/z (%) = 304 (30) [M] , 248 (99),
3
-
1
+
1
-(tert-butyl)-3,5-Bis(4-fluorophenyl)pyrazin-2(1H)-one (3j):
1
pale yellow oil (469 mg, 92%). H-NMR (400 MHz, CDCl ): δ =
3
8
.38 – 8.41 (m, 2 H), 7.77 – 7.80 (m, 2 H), 7.72 (s, 1 H), 7.10 –

6
Tetrahedron
13
Perrone,S.; Bona, F.; Troisi,L. Tetrahedron 2011, 67, 7386; g)
TED
): MANUSCRIPT
Troisi, L.; Granito, C.; Rosato, F.; Videtta, V. Tetrahedron Lett.
7
.15 (m, 4 H), 1.78 (s, 9 H) ppm. C-NMR (1
A
00
C
M
C
H
E
z,
P
C
DCl
3
δ = 163.7 (d, J = 250 Hz), 162.5 (d, J = 250 Hz), 155.6, 152.2,
2
010, 51, 371; h) Perrone, S.; Salomone, A.; Caroli, A.;
1
1
32.9, 132.5, 131.5 (d, J = 8 Hz), 126.7 (d, J = 8 Hz), 120.1,
15.7 (d, J = 21 Hz), 114.8 (d, J = 21 Hz), 62.9, 28.0 ppm.FT-IR
Falcicchio, A.; Citti, C.; Cannazza, G.; Troisi, L. Eur. J.Org.
Chem. 2014, 5932; i) Perrone, S.; Capua, M.; Cannazza, G.;
Salomone, A.; Troisi, L. Tetrahedron Lett. 2016, 57, 1421.
13. a) Perrone, S.; Caroli, A.;Cannazza, G.; Granito, C.; Salomone,
A.; Troisi, L. Tetrahedron Lett. 2015, 56, 2773; b) Perrone, S.;
Capua, M.; Salomone, A.; Troisi, L. J. Org. Chem. 2015, 80,
(
1
2
CHCl ): ν = 3027, 3015, 2963, 2926, 2871, 1724, 1643, 1591,
3
-1 +
450 cm .GC-MS (70 eV): m/z (%) = 340 (22) [M] , 284 (97),
56 (100), 229 (12), 134 (25), 107 (32), 57 (15). HRMS (ESI):
+
calcd. for C H F N O[M+H] 341.1466; found 341.1464.
20
19
2
2
8
189; c) Capua, M.; Granito, C.; Perrone, S.; Salomone, A.;
Troisi, L. Tetrahedron Lett. 2016, 57, 3363. d) Capua, M.;
Perrone, S.; Bona, F.; Salomone, A.; Troisi, L. Eur. J.Org. Chem.
Acknowledgments
2
017, 1780–1787.
The authors thank the University of Salento and the Consorzio
Interuniversitario Nazionale “Metodologie e Processi Innovativi
di Sintesi” (C.I.N.M.P.I.S.) for financial support.
1
1
4. Tsuritani, T.; Yagi, K.; Shinokubo, H.; Oshima, K. Angew. Chem.
Int. 2003, 42, 5613 –5615.
5. Tsuritani, T.; Shinokubo, H.; Oshima, K.; Chem.Lett. 2004, 33(2),
1
22−123.
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