A convenient microwave-assisted desulfitative dimethylamination of the 2(1H)-pyrazinone scaffold using N,N-dimethylformamide

Article abstract of DOI:10.1016/j.tet.2008.01.030

A convenient microwave-assisted methodology is developed for the generation of 5-chloro-3-(dimethylamino)pyrazin-2(1H)-ones. The method entails a chemoselective desulfitative removal of a phenylthioether bond upon DMF/H₂O treatment in the prese

Full text of DOI:10.1016/j.tet.2008.01.030

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2605e2610
www.elsevier.com/locate/tet
A convenient microwave-assisted desulfitative dimethylamination of the
2(1H)-pyrazinone scaffold using N,N-dimethylformamide
*
Anuj Sharma, Vaibhav Pravinchandra Mehta, Erik Van der Eycken
Laboratory for Organic and Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven,
Celestijnenlaan 200F, B-3001 Leuven, Belgium
Received 5 December 2007; received in revised form 28 December 2007; accepted 7 January 2008
Available online 11 January 2008
Abstract
A convenient microwave-assisted methodology is developed for the generation of 5-chloro-3-(dimethylamino)pyrazin-2(1H)-ones. The
method entails a chemoselective desulfitative removal of a phenylthioether bond upon DMF/H2O treatment in the presence of sodium carbonate,
yielding the desired compounds in 73e96%.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Microwave-assisted organic synthesis (MAOS); 2(1H)-Pyrazinone; Dimethylamination; Desulfitative; DMF
1. Introduction
the reaction proceeds slowly although resulting in rather good
yields. It is also reported that thioethers could be used in ami-
nation reactions applying a two-step protocol involving previ-
ous oxidation to the sulfoxide followed by substitution with
a suitable amine.8 However, direct amination without prior ox-
idation of the thioether, has rarely been described9 and, to the
best of our knowledge, dimethylamination using DMF as the
amine source applying thioether compounds, has only been
mentioned once as a side reaction upon treatment of a 2-meth-
ylthiotetrahydroquinazolinone with morpholine in DMF at
180 ꢀC, without further exploring the scope and limitations
of this coversion.10 Here we will comment on an unprece-
dented and convenient microwave-assisted dimethylamination
of 5-chloro-3-(phenylsulfanyl)pyrazin-2(1H)-ones applying
a mixture of DMF/H2O (1:1) in the presence of sodium
carbonate.
We have previously explored a number of transition metal
catalyzed cross-coupling reactions, at the reactive imidoyl
chloride moiety in C3-position as well as at the unreactive
C5-position of the 3,5-dichloro-2(1H)-pyrazinone scaffold ap-
plying microwave-assisted protocols.11 During our endeavors
to perform microwave-assisted Suzuki-arylation at the unreac-
tive C5-position11a of 5-chloro-1-(4-methoxybenzyl)-3-(phe-
nylsulfanyl)pyrazin-2(1H)-one (1a) with phenylboronic acid
There is no dearth of compounds containing a dimethyl-
amino functionality in nature as well as in the organic chemist’s
arsenal.1 For example, taxoids, a series of anti-cancer drugs,
which inhibit cell growth by interacting with microtubules,
often contain a dimethylamino moiety as part of the pharma-
cophore.2 The dimethylamino moiety is also found in a number
of active tetracyclines.3 Similarly, a compound like austro-
spicatine, bearing a dimethylamino function, has shown
promising insecticidal activity.4 Moreover, many of the di-
methylamino substituted heterocyclic compounds represent
important drugs like, e.g., ampyzine, triampyzine, and metha-
done.5 6-Dimethylamino-purine is useful as inhibitor of cyclin
dependent kinase and in cloning of animals via nuclear trans-
fer from adult somatic cells.6 A convenient method for the
introduction of a dimethylamino group in (hetero-)aromatic
compounds is the reaction of halogenated substrates with
DMF at elevated temperature in the presence of a base,7 as
this avoids the handling of low boiling dimethylamine. Mostly
* Corresponding author. Tel.: þ32 16 327406; fax: þ32 16 327990.
E-mail address: erik.vandereycken@chem.kuleuven.be (E. Van der
Eycken).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.030

2606
A. Sharma et al. / Tetrahedron 64 (2008) 2605e2610
OMe
OMe
OMe
PhB(OH)2
Pd(PPh3)4 / Na2CO3
DMF-H2O (1:1)
+
N
O
N
N
N
O
S
N
N
O
S
Me
Cl
N
Ph
Cl
MW, 140 °C, 100W, 30 min.
Me
1a
2'a
2a
12% (expected product) 71% (unexpected product)
Scheme 1. Attempted arylation of 5-chloro substituted pyrazin-2(1H)-one (1a).
in the presence of tetrakis(triphenylphosphine)palladium
(Pd(PPh3)4) and sodium carbonate as the base, we evaluated
a solvent mixture of DMF/H2O (1:1) (Scheme 1). To our sur-
prise, only 12% of the desired C5-arylated compound 20a was
obtained. Instead, the reaction proceeded chemoselectively to
produce 71% of the C3-aminated 5-chloro-3-(dimethylamino)-
1-(4-methoxybenzyl)pyrazin-2(1H)-one (2a).
was subjected to amination reaction (Table 2). The respective
dimethylamino products 2beh were obtained in good to
excellent yields.
Next, we were interested to see if an alkylthio substituent in
C3-position, instead of a phenylthio substituent, would allow
the same transformation. Therefore the ethylthio-substituted
pyrazinone 1i was subjected to the optimized protocol. Grati-
fyingly the reaction proceeded smoothly upon irradiation for
These results prompted us to explore further this desulfita-
tive dimethylamination reaction using DMF as amine source,
and an optimization study was undertaken. All inorganic bases
explored, resulted in the formation of 2a in good to excellent
yields (Table 1, entries 1e3 and 6e8). On the contrary, when
no base was added, the reaction did not proceed (Table 1, entry
4). Also the presence of water seemed to be crucial for the
amination (Table 1, entry 5). This might be attributed to a bet-
ter solvation of the inorganic base. Best conditions were found
to be focused microwave irradiation for 30 min at 150 W max-
imum power and a ceiling temperature of 140 ꢀC of a mixture
of compound 1a together with 2 equiv of Na2CO3 in DMF/
water (1:1) yielding compound 2a in 96% (Table 1, entry 2).
After having an efficient protocol for dimethylamination
at hand, we next investigated the scope and limitations of
the optimized protocol. A series of differently substituted
Table 2
Evaluation of the scope of dimethylamination for different pyrazinones
(1aeh)a
R1
N
R1
N
R6
Cl
O
N
R6
Cl
O
S
DMF-H2O (1:1)
Me
Na2CO3
MW 140 °C
N
N
Me
2a-h
1a-h
Entry
1
R1
R6
H
Compd. Time (min) Yieldb (%)
OMe
2a
30
96
*
5-chloro-3-(phenylsulfanyl)pyrazin-2(1H)-ones11f
(1beh)
2
3
Me
Me
2b
2c
30
91
*
Me
60c
73d
Table 1
Optimization of the desulfitative dimethylamination of 1aa
PMB
N
PMB
N
4
H
H
2d
30
81
(H2C)3
*
O
S
O
N
Solvent
Base (2 equiv)
MW
Me
Cl
N
N
Cl
5
6
2e
2f
60c
30
85
92
Me
2a
1a
*
PMB = p-methoxy benzyl
OMe
OMe
OMe
OMe
Entry
Base
Solvent (1:1)
Time (min)
Yieldb (%)
*
*
1
2
3
4
5
6
7
8
a
Na2CO3
Na2CO3
Na2CO3
d
DMF/H2O
DMF/H2O
DMF/H2O
DMF/H2O
DMF
20
30
45
60
60
30
30
30
71
96
94
7
2g
2h
30
30
94
83
0c
*
*
*
Na2CO3
NaOH
K2CO3
KOH
63 (30)d
85
91
DMF/H2O
DMF/H2O
DMF/H2O
8
H
87
a
Reactions were run on a 0.3 mmol scale of 1aeh in DMF/H2O (1:1)
(3 mL) with 2 equiv of base (0.6 mmol). The mixture was irradiated in a sealed
tube at a ceiling temperature of 140 ꢀC and 150 W maximum power for the
stipulated time.
Reactions were run on a 0.3 mmol scale of 1a in DMF/H2O (1:1) (3 mL)
with 2 equiv of base (0.6 mmol). The mixture was irradiated in a sealed tube at
a ceiling temperature of 140 ꢀC and 150 W maximum power for the stipulated
time.
b
Isolated yield.
As some unreacted starting material was observed by GCeMS, the reac-
b
c
Isolated yield.
All starting materials recovered.
Value in parenthesis indicate yield of unreacted starting material.
c
tion mixture was subsequently run for another 30 min.
d
Around 15e20% starting material still remained based on GC analysis.
d

A. Sharma et al. / Tetrahedron 64 (2008) 2605e2610
2607
Table 3
Extension of the procedure to alkylthio-substituted and solid phase linked
pyrazinonesa
bond at its C3-position, was subjected to the same procedure.
To our delight we notified that, applying the standard condi-
tions, the aminated pyrazinone 2a was isolated in 71% yield,
after an irradiation time of only 30 min (Table 3, entry 2).
To the best of our knowledge, there are no precedents de-
scribed in literature, where a desulfitative amination protocol
is used as traceless linking concept for solid phase organic
synthesis.11e This interesting extension of our methodology
opens the way for the fast generation of small combinatorial
libraries of valuable C3-dimethylaminated pyrazinones, which
will be investigated in due course.
PMB
PMB
N
N
O
N
O
S
DMF:H2O (1:1)
Na2CO3
MW 140 °C
Me
R
Cl
N
Cl
N
2a
Me
1i, j
Entry
1
R
Compd.
Time (min)
60
Yieldb (%)
62
Ethyl
2a
2c
2a
30
71
Finally, we decided to investigate the possibility to intro-
duce amines other than dimethylamine using our desulfitative
protocol. Obviously, a possible competition with dimethylami-
nation could be expected. Therefore we decided to perform the
experiments applying three different conditions: (i) standard
conditions using DMF/H2O (1:1) and Na2CO3, (ii) DMF,
and (iii) dioxane/H2O (1:1) and Na2CO3 (Table 4).
a
Reactions were run on a 0.3 mmol scale of 1i, j in DMF/H2O (1:1) (3 mL)
with 2 equiv of base (0.6 mmol). The mixture was irradiated in a sealed tube at
a ceiling temperature of 140 ꢀC and 150 W maximum power for the stipulated
time.
b
Isolated yield.
The calculated loading of the pyrazinone bound to the mercapto phenyl-
propionyl AM resin was found to be 0.84 mmol/g.
c
When DMF/H2O (1:1) with Na2CO3 was used (Table 4,
entries 1, 4, 7, 10, 13, and 16) a strong preference for the for-
mation of the dimethylaminated compound was observed,
which is consistent with the conclusions drawn from Table
1. However, when solely DMF was used, the amines reacted
60 min, yielding the desired compound in 62% (Table 3, entry
1). Moreover, to broaden the scope of our protocol, a pyrazi-
none 1j linked with a commercially available mercapto phe-
nylpropionyl AM resin (loading 0.88 mmol/g) via a thioether
Table 4
Evaluation of other amines for the desulfitative protocola
PMB
PMB
N
PMB
N
O
S
N
O
O
Solvent
OR
NHR1R2 (2.0 equiv)
Me
Cl
N
Cl
NR1R2
N
Cl
N
N
MW, 140 °C
Me
3a-c, 3e
1a
2a
Entry
NHR1R2
Solvent
Time (min)
Product yieldb (%)
1
2
3
DMF/H2O
DMF
Dioxane/H2O
30
30
30
2a (81)
2a (5)
d
3a (12)
3a (91)
3a (96)
N
H
O
4
5
6
DMF/H2O
DMF
Dioxane/H2O
30
30
30
2a (79)
2a (5)
d
3b (14)
3b (91)
3b (95)
N
H
7
8
9
DMF/H2O
DMF
Dioxane/H2O
60
60
60
2a (68)
2a (15)
2a (0)
3c (12)c
3c (72)c
3c (15)c,d
N
H
10
11
12
NH(hex)2
DMF/H2O
DMF
Dioxane/H2O
60
60
60
2a (81)
2a (0)
2a (0)
3d (traces)
3d (0)e
3d (traces)c,d
13
14
15
Isobutyl amine
DMF/H2O
DMF
Dioxane/H2O
30
30
30
2a (75)
2a (38)
2a (0)
3e (5)
3e (55)
3e (26)d
16
17
18
DMF/H2O
DMF
Dioxane/H2O
60
60
60
2a (83)
2a (0)
2a (0)
3f (0)
3f (0)e
3f (0)c,d
NH2
19
NH(CH3)2
Dioxane/H2O
60
2a (25)c
d
a
Reactions were run on a 0.3 mmol scale of 1a in DMF/H2O (1:1) or dioxane/H2O (1:1) (3 mL) with 2 equiv of amine (0.6 mmol) and 2.0 equiv of Na2CO3
(0.6 mmol). Alternatively, reactions were run on a 0.3 mmol scale of 1a in DMF (3 mL) with 2 equiv of amine (0.6 mmol). The mixture was irradiated in a sealed
tube at a ceiling temperature of 140 ꢀC and 150 W maximum power for the stipulated time.
b
Isolated yield.
Some unreacted starting material was recovered despite an extended irradiation time.
c
d
Unidentified side product formed.
Only starting material recovered.
e

2608
A. Sharma et al. / Tetrahedron 64 (2008) 2605e2610
preferentially forming compounds 3a, 3b, 3c, and 3e (Table 4,
entries 2, 5, 8, and 14). In the case of the strongly basic piper-
idine and morpholine, only traces of the dimethylaminated
product were formed while the respective aminated product
was isolated in excellent yield (Table 4, entries 2 and 5). Sim-
ilarly, the respective aminated products 3c and 3e formed in
better yield than the dimethylaminated product 2a in case of
benzylmethylamine and isobutyl amine (Table 4, entries 8
and 14). However, in the case of the weakly basic amines di-
hexylamine and aniline, neither the aminated nor the dimethy-
laminated product formed (Table 4, entries 11 and 17). Finally,
when dioxane/H2O (1:1) was used as alternative solvent mix-
ture, with the exception of piperidine and morpholine (Table 4,
entries 3 and 6), the amines reacted very poorly (Table 4, en-
tries 9, 12, 15, and 18). It is worth mentioning that in the latter
cases, little or no starting material could be recovered as some
unidentified side products were formed. Conclusively, the
DMF method can be successfully applied as an amination
tool for strongly basic amines. Next we were interested in
comparing the potential of DMF as a dimethylamination
source with the direct use of dimethylamine (Table 4, entry
19). When a mixture of 1a and 2.0 equiv of an aqueous solu-
tion of dimethylamine (40%) was irradiated at 140 ꢀC (150 W)
for 30 min in presence of 2.0 equiv of Na2CO3 and 3 mL of
dioxane/H2O (1:1), surprisingly, a poor yield of only 25% of
the dimethylaminated product was obtained. This clearly
underscores the importance of our DMF-protocol as a better
aminating source than dimethylamine itself.
According to Agarwal et al.,7f the reaction should start with a nu-
cleophilic attack of DMF on the C3-position of the pyrazinone
followed by loss of carbon monoxide resulting in the dimethy-
laminated product (Pathway I). However, more likely the reac-
tion starts with a base assisted cleavage of DMF to form the
required dimethylamine,12 which is acting as the nucleophile
for the formation of the required product (Pathway II).
To get some hint for the actual mechanism, we performed
a blank run, irradiating a DMF/H2O (1:1) mixture in the pres-
ence of Na2CO3 applying exactly the same conditions as used
in our experiments but without the addition of the pyrazinone.
GCeMS analysis at low temperature13 as well as FTIR anal-
ysis revealed that this crude reaction mixture contained di-
methylamine, suggesting a reaction Pathway II.14
In conclusion, we have elaborated a convenient and
fast, microwave-assisted chemoselective procedure for the
desulfitative dimethylamination of variously substituted
5-chloro-3-(phenylsulfanyl)pyrazin-2(1H)-ones using a DMF/
water mixture in the presence of sodium carbonate. The ami-
nated compounds are obtained in excellent yields. The merits
of the protocol are (i) DMF as an easy to handle substitute for
dimethylamine, (ii) a one-step desulfitative amination without
the necessity of prior oxidation of the thioether, and (iii) short
reaction times and high yields applying microwave irradiation.
We have demonstrated that the method could be extended to
alkylthio-substituted pyrazinones as well as to solid phase
linked pyrazinones providing a way of traceless linking.
Finally, the usefulness of this methodology was also inves-
tigated on an alternative heterocyclic system different from
pyrazinones. Oxazinone 4a was reacted in a DMF/H2O (1:1)
mixture under the optimized conditions, and to our delight,
the product 5a was formed in 72% yield (Scheme 2).
2. Experimental section
2.1. General experimental methods
1H NMR spectra were recorded on a Bruker Avance
300 MHz instrument using CDCl3 as solvent unless otherwise
stated. The 1H and 13C chemical shifts are reported in parts per
million relative to tetramethylsilane using the residual solvent
signal as an internal reference. Mass spectra were recorded by
using a Kratos MS50TC and a Kratos Mach III system. The
ion source temperature was 150e250 ꢀC, as required. High-
resolution EI-mass spectra were performed with a resolution
of 10,000. The low-resolution spectra were obtained with
a HP5989A MS instrument. For thin layer chromatography,
analytical TLC plates (Alugram SIL G/UV254 and 70e230
mesh silica gel (E. M. Merck)) were used. Melting points of
the compounds were determined using a Reichert-Jung Ther-
movar apparatus and are uncorrected.
Me
Me
O
O
N
O
O
S
DMF: H2O (1:1)
Na2CO3, MW 150 W,
140 °C, 30 min
Me
S
N
5a
S
N
4a
Me
Scheme 2. Dimethylamination of oxazinone 4a.
Regarding the mechanism of the developed amination
protocol, there are two possibilities as shown in Scheme 3.
PMB
O
N
O
S
+
Base
DMF/H2O
Base
N
H
-CO
Pathway I
2.2. Microwave irradiation experiments
Cl
N
1a
HN
All microwave irradiation experiments were carried out in
a dedicated CEM Discover monomode microwave apparatus,
operating at a frequency of 2.45 GHz with continuous irradia-
tion power from 0 to 300 W with utilization of the standard
absorbance level of 300 W maximum power. The reactions
were carried out in 10-mL glass tubes, sealed with Teflon sep-
tum and placed in the microwave cavity. Initially, microwave
irradiation of required watts was used and the temperature is
-PhSH
PMB
N
PMB
N
O
N
Pathway II
H
O
N
-CO
X
Cl
N
O
Cl
N
2a
Scheme 3. Plausible mechanisms for the amination protocol.

A. Sharma et al. / Tetrahedron 64 (2008) 2605e2610
2609
being ramped from room temperature to the desired tempera-
ture. Once this was reached the reaction mixture was held at
this temperature for the required time. The reaction mixture
was continuously stirred during the reaction. The temperature
was measured with an IR sensor on the outer surface of the
process vial. After the irradiation period, gas jet cooling
cooled the reaction vessel rapidly to ambient temperature.
(t, J¼8.3 Hz, 2H), 3.30 (s, 6H, Ne(CH3)2), 2.68 (t,
J¼8.3 Hz, 2H, eCeCH2), 2.10e2.00 (m, 2H, eCeCH2eC).
13C NMR (75 MHz, CDCl3): d 151.5, 151.4, 140.6, 128.6,
128.4, 126.3, 125.9, 114.0, 49.3, 40.4, 32.9, 29.9. HRMS
(EI): C15H18ClN3O calcd 291.1138, found 291.1140.
2.3.5. 5-Chloro-1-(cyclohexylmethyl)-3-(dimethyl-
amino)pyrazin-2(1H)-one (2e)
Yield 85%, light yellow oil. H NMR (300 MHz, CDCl3):
2.3. General procedure for preparation of compounds 2aeh,
3aec, 3e, 5a
1
d 6.49 (s, 1H), 3.58 (d, J¼7.96 Hz, 2H), 3.30 (s, 6H, Ne
(CH3)2), 1.79e1.66 (m, 6H), 1.24e1.17 (m, 3H), 1.02e0.09
(m, 2H). 13C NMR (75 MHz, CDCl3): d 151.6, 151.5, 140.6,
125.5, 114.9, 55.8, 40.4, 36.9, 30.7, 26.3, 25.7. HRMS (EI):
C13H20ClN3O calcd 269.1295, found 269.1290.
In a 10 mL reaction glass vial containing a stirring bar were
added successively sulfanyl pyrazinone (0.3 mmol), Na2CO3
(0.60 mmol, 2 equiv), amine (0.6 mmol, 2.0 equiv), and/or
DMF/H2O (1:1) (3 mL). Alternatively, in case of 3c, sulfanyl
pyrazinone (0.3 mmol), amine (0.6 mmol, 2.0 equiv) in 3 mL
of DMF is taken. The vial was sealed tightly with a Teflon
septum and irradiated for the stipulated time using 150 W
maximum power at a ceiling temperature of 140 ꢀC (CEM
DiscoverÒ monomode instrument, 2.45 GHz with a power limit
of 300 W). The temperaturewas ramped from room temperature
to 140 ꢀC in 2 min. After completion of the reaction, thevial was
cooled with gas jet cooling to ambient temperature. The mixture
was extracted with ethyl acetate (3ꢁ15 mL) and the organic
layer was dried over MgSO4. The solvent was evaporated under
reduced pressure and the crude product was chromatographed
over silica gel (40% EtOAc/heptane) to yield the products.
2.3.6. 1-(4-Methoxybenzyl)-5-chloro-3-(dimethylamino)-6-
(4-methoxyphenyl)pyrazin-2(1H)-one (2f)
1
Yield 92%, dark brown oil. H NMR (300 MHz, CDCl3):
d 7.01 (d, J¼9.3 Hz, 2H), 6.87 (d, J¼9.3 Hz, 2H), 6.80 (d,
J¼9.6 Hz, 2H), 6.72 (d, J¼9.4 Hz, 2H), 4.90 (s, 2H), 3.84
(s, 3H, eOMe), 3.76 (s, 3H, eOMe), 3.34 (s, 6H, Ne
(CH3)2). 13C NMR (75 MHz, CDCl3): d 160.6, 159.3, 158.0,
153.7, 135.3, 133.0, 131.4, 129.5, 129.4, 129.3, 128.0,
127.6, 127.5, 123.1, 113.9, 113.8, 55.4, 55.3, 49.0, 40.4.
HRMS (EI): C21H22ClN3O3 calcd 399.1350, found 399.1347.
2.3.7. 1-(4-Methoxybenzyl)-6-benzyl-5-chloro-3-
(dimethylamino)pyrazin-2(1H)-one (2g)
2.3.1. 1-(4-Methoxybenzyl)-5-chloro-3-(dimethylamino)-
pyrazin-2(1H)-one (2a)
Yield 94%, yellow oil. 1H NMR (300 MHz, CDCl3):
d 7.35e7.26 (m, 3H), 7.13 (d, J¼8.1 Hz, 2H), 7.02 (d,
J¼9.3 Hz, 2H), 6.85 (d, J¼9.3 Hz, 2H), 4.96 (s, 2H), 3.98
(s, 2H, ePheCH2), 3.79 (s, 3H, eOMe), 3.33 (s, 6H, Ne
(CH3)2). 13C NMR (75 MHz, CDCl3): d 159.1, 152.8, 150.4,
136.9, 129.2, 128.1, 127.6, 127.5, 127.1, 126.9, 122.9,
114.5, 55.4, 47.5, 40.3, 34.9. HRMS (EI): C21H22ClN3O2
calcd 383.1401, found 383.1406.
Yield 96%, yellow oil. 1H NMR (300 MHz, CDCl3): d 7.24
(d, J¼9.4 Hz, 2H), 6.87 (d, J¼9.3 Hz, 2H), 6.53 (s, 1H), 4.88
(s, 2H), 3.79 (s, 3H, eOMe), 3.31 (s, 6H, Ne(CH3)2). 13C
NMR (75 MHz, CDCl3): d 159.7, 151.5, 129.9, 127.5 (ꢁ2),
126.0, 114.4 (ꢁ2), 113.5, 55.4, 51.6, 40.4. HRMS (EI):
C14H16ClN3O2 calcd 293.0931, found 293.0933.
2.3.2. 1-Benzyl-5-chloro-3-(dimethylamino)-6-
methylpyrazin-2(1H)-one (2b)
2.3.8. 5-Chloro-3-(dimethylamino)-1-(4-methoxy-
phenyl)pyrazin-2(1H)-one (2h)
Yield 73%, yellow oil. 1H NMR (300 MHz, CDCl3):
d 7.34e7.30 (m, 2H), 7.24e7.21(m, 3H), 4.89 (s, 2H), 3.30
(s, 6H, Ne(CH3)2), 2.34 (s, 3H, eCH3). 13C NMR (75 MHz,
CDCl3): d 159.8, 151.5, 139.9, 130.1, 128.6, 128.4, 127.5,
126.4, 125.9, 114.1, 51.5, 40.1, 16.4. HRMS (EI):
C14H16ClN3O calcd 277.0982, found 277.0989.
Yield 83%, brown solid, mp 70e72 ꢀC. 1H NMR
(300 MHz, CDCl3): d 7.25 (d, J¼9.8 Hz, 2H), 6.97 (d,
J¼9.8 Hz, 2H), 6.63 (s, 1H), 3.83 (s, 3H, eOMe), 3.33 (s,
6H, Ne(CH3)2). 13C NMR (75 MHz, CDCl3): d 159.6,
151.5, 132.6, 127.3, 125.9, 114.9, 114.7, 55.7, 40.6. HRMS
(EI): C13H12ClN3O2 calcd 279.0775, found 279.0778.
2.3.3. 5-Chloro-3-(dimethylamino)-1,6-dimethylpyrazin-
2(1H)-one (2c)
Yield 73%, yellow oil. 1H NMR (300 MHz, CDCl3): d 3.47 (s,
3H), 3.24 (s, 6H, Ne(CH3)2), 2.33 (s, 3H, eCH3). 13C NMR
(75 MHz, CDCl3): d 152.7, 149.6, 124.7, 121.5, 40.1, 32.4,
16.3. HRMS(EI):C8H12ClN3Ocalcd201.0669, found201.0674.
2.3.9. 3-(Dimethylamino)-5-(phenylthio)-6-o-tolyl-2H-1,4-
oxazin-2-one (5a)
Yield 72%, yellow crystalline, mp 87e89 ꢀC. 1H NMR
(300 MHz, CDCl3): d 7.86 (d, J¼8.3 Hz, 1H), 7.38 (t,
J¼7.4 Hz, 1H), 7.29 (m, 4H), 7.16 (t, J¼5.6 Hz, 3H), 3.30
(s, 6H), 2.50 (s, 3H). 13C NMR (75 MHz, CDCl3): d 180.1,
160.3, 148.9, 138.9, 136.5, 135.9, 131.4, 130.9, 129.2,
126.5, 126.1, 125.8, 125.4, 125.1, 102.7, 39.4, 20.6. HRMS
(EI): C19H18N2O2S calcd 338.1089, found 338.1093.
2.3.4. 5-Chloro-3-(dimethylamino)-1-(3-phenylpropyl)-
pyrazin-2(1H)-one (2d)
Yield 81%, yellowish oil. 1H NMR (300 MHz, CDCl3):
d 7.31e7.26 (m, 2H), 7.22e7.17(m, 3H), 6.48 (s, 1H), 3.77

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A. Sharma et al. / Tetrahedron 64 (2008) 2605e2610
2.3.10. 1-(4-Methoxybenzyl)-5-chloro-3-(piperidin-1-
References and notes
yl)pyrazin-2(1H)-one (3a)
1
Yield 98%, orange crystalline, mp 125e126 ꢀC. H NMR
(300 MHz, CDCl3): d 7.24 (d, J¼9.1 Hz, 2H), 6.86 (d,
J¼10.1 Hz, 2H), 6.60 (s, 1H), 4.89 (s, 2H), 3.83 (s, 4H,
eNe(CH2)2), 3.77 (s, 3H, eOMe), 1.64 (s, 6H, eCe(CH2)3).
13C NMR (75 MHz, CDCl3): d 159.6, 151.3, 151.2, 129.8,
127.3, 125.6, 114.3, 114.2, 55.3, 51.6, 47.9, 26.1, 24.7.
HRMS (EI): C17H20ClN3O2 calcd 333.1244, found 333.1241.
1. Dictionary of Natural products; Buckingham, J., Ed.; Chapman and Hall:
London, 1993; (b) Dictionary of Organic Compounds; Buckingham, J.,
MacDonald, F., Eds.; Chapman and Hall: London, 1996.
2. (a) For detailed description, see review: Baloglu, E.; Kingston, D. G. I.
J. Nat. Prod. 1999, 62, 1448e1472 and references cited therein; (b) Ste-
fanowicz, P.; Prasain, J. K.; Yeboah, K. F.; Konishi, Y. Anal. Chem. 2001,
73, 3583e3589.
3. (a) Charest, M. G.; Lerner, C. D.; Brubakar, J. D.; Siegel, D. R.; Myers,
A. G. Science 2005, 308, 395e398; (b) Charest, M. G.; Siegel, D. R.;
Myers, A. G. J. Am. Chem. Soc. 2005, 127, 8292e8293.
2.3.11. 1-(4-Methoxybenzyl)-5-chloro-3-morpholino-
pyrazin-2(1H)-one (3b)
4. Doss, R. P.; Carney, J. R.; Shanks, C. H., Jr.; Williamson, R. T.; Chamber-
lain, J. D. J. Nat. Prod. 1997, 60, 1130e1133.
1
Yield 91%, brown crystalline, mp 168e170 ꢀC. H NMR
5. (a) Schultz, E. M.; Robb, C. M.; Sprague, J. M. J. Am. Chem. Soc. 1947,
69, 2454e2459; (b) Takahashi, T.; Kenematsu, K. Chem. Pharm. Bull.
1958, 6, 98; (c) Elias, R. S.; Shephard, M. C.; Snell, B. K.; Stubbs, J.
Nature 1968, 219, 1160; (d) Hutzenlaub, W.; Tolman, R. L.; Robins,
R. K. J. Med. Chem. 1972, 15, 879e883.
(300 MHz, CDCl3): d 7.25 (d, J¼9.4 Hz, 2H), 6.88 (d,
J¼9.4 Hz, 2H), 6.67 (s, 1H), 4.89 (s, 2H), 3.93e3.90 (m,
4H, eNe(CH2)2), 3.79 (s, 3H, eOMe), 3.70 (d, 4H, eOe
(CH2)2). 13C NMR (75 MHz, CDCl3): d 159.8, 151.2, 150.8,
130.0, 127.1, 125.5, 115.4, 114.4, 66.8, 55.4, 51.7, 47.2.
HRMS (EI): C17H20ClN3O2 calcd 335.1037, found 335.1046.
´
6. (a) Neant, I.; Guerrier, P. Exp. Cell Res. 1988, 176, 68e79; (b) Rime, H.;
Neant, I.; Guerrier, P.; Ozon, R. Dev. Biol. 1989, 133, 169e179; (c) Beux,
G. L.; Richard, F. J.; Sirard, M.-A. Theriogenology 2003, 60, 1049e1058.
7. (a) Lurthy, N. G.; Bergstrom, F. W.; Mosher, H. S. J. Am. Chem. Soc.
1949, 71, 1109e1110; (b) Coppinger, G. M. J. Am. Chem. Soc. 1954,
76, 1372e1373; (c) Heindel, N.; Kennewell, P. J. Chem. Soc., Chem.
Commun. 1969, 38; (d) Watanabe, T.; Tanaka, Y.; Sekiya, K.; Akita, Y.;
Ohta, A. Synthesis 1980, 39; (e) Cho, Y. H.; Park, J. C. Tetrahedron
Lett. 1997, 38, 8331e8334; (f) Agarwal, A.; Chauhan, P. M. S. Synth.
Commun. 2004, 34, 2925e2930.
2.3.12. 1-(4-Methoxybenzyl)-3-(N-benzyl-N-methylamino)-
5-chloropyrazin-2(1H)-one (3c)
Yield 72%, yellow oil. 1H NMR (300 MHz, CDCl3):
d 7.29e7.23 (m, 7H), 6.87 (d, J¼9.1 Hz, 2H), 6.59 (s, 1H),
5.12 (s, 2H), 4.91 (s, 2H), 3.79 (s, 3H), 3.14 (s, 3H). 13C
NMR (75 MHz, CDCl3): d 159.7, 151.3, 151.1, 142.7, 138.2,
129.8, 128.0, 127.7, 127.4, 126.8, 125.9, 114.1, 54.9, 51.6,
51.2, 38.3. HRMS (EI): C20H20ClN3O2 calcd 369.1244, found
369.1248.
8. (a) Radi, M.; Petricci, E.; Maga, G.; Corelli, F.; Botta, M. J. Comb. Chem.
2005, 7, 117e122; (b) Rombouts, F. J. R.; Fridkin, G.; Lubell, W. D.
J. Comb. Chem. 2005, 7, 589e598; (c) Liu, J.; Dang, Q.; Wei, Z.; Zhang,
H.; Bai, X. J. Comb. Chem. 2005, 7, 627e636; (d) Nagashima, S.; Yokota,
M.; Nakai, E.-I.; Kuromitsu, S.; Ohga, K.; Takeuchi, M.; Tsukamoto, S.-I.;
Ohta, M. Biorg. Med. Chem. 2007, 15, 1044e1055; (e) Davey, D. D.;
Adler, M.; Arnaiz, D.; Eagen, K.; Erickson, S.; Guilford, W.; Kenrick,
M.; Morrissey, M. M.; Ohlmeyer, M.; Pan, G.; Paradkar, V. M.; Parkinson,
J.; Polokoff, M.; Saionz, K.; Santos, C.; Subramanyam, B.; Vergona, R.;
Wei, R. G.; Whitlow, M.; Ye, B.; Zhao, Z.; Devlin, J. J.; Phillips, G.
J. Med. Chem. 2007, 50, 1146e1157.
2.3.13. 1-(4-Methoxybenzyl)-5-chloro-3-(isobutyl-
amino)pyrazin-2(1H)-one (3e)
Yield 26%, yellow oil. 1H NMR (300 MHz, CDCl3): d 7.25
(d, J¼9.1 Hz, 2H), 6.86 (d, J¼10.1 Hz, 2H), 6.45 (s, 1H), 6.41
(br s, 1H), 4.93 (s, 2H), 3.80 (s, 3H), 3.24 (t, J¼7.0 Hz, 2H),
1.92 (m, 1H), 0.97 (d, 6H, eCHe(CH3)2). 13C NMR
(75 MHz, CDCl3): d 159.9, 150.6, 130.0, 127.3, 127.0,
114.5, 114.4, 55.4, 51.5, 48.6, 28.1, 20.4. HRMS (EI):
C17H20ClN3O2 calcd 321.1244, found 321.1241.
9. Vu, C. B.; Kiesman, W. F.; Conlon, P. R.; Lin, K.-C.; Tam, M.; Petter,
R. C.; Smits, G.; Lutterodt, F.; Jin, X.; Chen, L.; Zhang, J. J. Med.
Chem. 2006, 49, 7132e7139.
10. Dalai, S.; Below, V. N.; Nizamov, S.; Rauch, K.; Finsinger, D.; de Meijere,
A. Eur. J. Org. Chem. 2006, 12, 2753e2765.
11. (a) Kaval, N.; Bisztray, K.; Dehaen, W.; Kappe, C. O.; Van der Eycken, E.
Mol. Divers. 2003, 7, 125e134; (b) Kaval, N.; Dehaen, W.; Van der
Eycken, E. J. Comb. Chem. 2005, 7, 90e95; (c) Singh, B. K.; Appukkut-
tan, P.; Claerhout, S.; Parmar, V. S.; Van der Eycken, E. Org. Lett. 2006, 8,
1863e1866; (d) Appukkuttan, P.; Husain, M.; Gupta, R. K.; Parmar, V. S.;
Van der Eycken, E. Synlett 2006, 1491; (e) Kaval, N.; Singh, B. K.; Ermo-
Acknowledgements
Support was provided by the research fund of the Uni-
versity of Leuven and the FWO (Fund for Scientific
ResearchdFlanders (Belgium)). A.S. is thankful to the Uni-
versity of Leuven for obtaining a postdoctoral fellowship.
The authors also wish to thank Bart Demarsin for the valuable
help in HRMS data.
´
latev, D. S.; Claerhout, S.; Van der Eycken, J.; Van der Eycken, E.
J. Comb. Chem. 2007, 9, 446e453; (f) Singh, B. K.; Mehta, V. P.; Parmar,
V. S.; Van der Eycken, E. Org. Biomol. Chem. 2007, 5, 2962e2965; (g)
Ermolat’ev, D. S.; Mehta, V. P.; Van der Eycken, E. QSAR Comb. Sci.
2007, 26, 1266e1273.
12. Wan, Y.; Alterman, M.; Larhed, M.; Hallberg, A. J. Org. Chem. 2002, 67,
6232e6235.
13. The GCeLRMS experiment was performed at 160 ꢀC instead of 250 ꢀC
as routinely kept for all GCeLRMS experiments.
Supplementary data
14. Conditions: Na2CO3 (5 mmol) and DMF/H2O (1:1) (3 mL) were irradi-
ated in a sealed vial at a ceiling temperature of 140 ꢀC and a maximum
power of 150 W for 40 min (CEM DiscoverÒ). The crude mixture was
evaluated with GCeLRMS at 180 ꢀC. GCeMS analysis of pure DMF
did not show any traces of dimethylamine clearly indicating in situ gener-
ation of dimethylamine under the conditions used.
Detailed description of the spectral data (NMR, HRMS) is
included in the supplementary data. Supplementary data asso-
ciated with this article can be found in the online version, at
doi:10.1016/j.tet.2008.01.030.