N-heterocyclic carbene catalyzed aroylation of 3,5-dichloro-2(1 H)-pyrazinones

Article abstract of DOI:10.1021/jo200155n

The N-heterocyclic carbene catalyzed chemoselective C3-aroylation of 3,5-dichloro-2(1H)-pyrazinones with various aldehydes is reported. We herein describe results of this remarkable mild and efficient procedure.

Full text of DOI:10.1021/jo200155n

NOTE
pubs.acs.org/joc
N-Heterocyclic Carbene Catalyzed Aroylation of 3,5-Dichloro-2
(1H)-pyrazinones
Vaibhav P. Mehta,† Ajendra kumar Sharma,† Sachin G. Modha,† Sweta Sharma,†,‡ Thirumal Meganathan,‡
Virinder Singh Parmar,‡ and Erik Van der Eycken*,†
†Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke Universiteit Leuven,
Celestijnenlaan 200F, B-3001 Leuven, Belgium
‡Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 100007, India
S Supporting Information
b
ABSTRACT: The N-heterocyclic carbene catalyzed chemose-
lective C3-aroylation of 3,5-dichloro-2(1H)-pyrazinones with
various aldehydes is reported. We herein describe results of this
remarkable mild and efficient procedure.
n the past two decades 2(1H)-pyrazinones emerged as useful
starting materials for the elaboration of different types of skeletons
under mildly basic conditions, resulting in the generation of a
thiazolydinene species. Since then an increasing interest in the
application of nucleophilic carbenes as organocatalysts has emerged.
Metal-free catalyzed processes are interesting alternatives to organo-
metal-catalyzed processes since they are often more economical and
have a benign environmental impact. Initially primarily studied to
promote the benzoin condensation,12 a tremendous increase of the
scope of NHCs was reported through the years, resulting in an ever-
increasing number of reactions that can be promoted, for example,
the Stetter reaction,13,14 hydroacylation reactions,15 homoenolate
generation,16 1,2-additions,17 polymerizations,18 etc.
Of particular interest in the light of solving our problem is the
application of NHCs for performing aroylation reactions. Although
this process has been scarcely described with activated halides such as
benzyl halides,19 p-nitrofluorobenzenes,20 and heteroaryl-chlorides21
as electrophilic substrates, to the best of our knowledge there is no
single report regarding the coupling of a Breslow intermediate with
the imidoylchloride system of a 3-chloro-2(1H)-pyrazinone. We were
therefore keen to know whether the Breslow intermediate, which is
generated in situ from an aromatic aldehyde and a suitable NHC, can
react with the 3-chloro-2(1H)-pyrazinone to afford the desired and
hitherto unknown aroylated system (Figure 2).
I
of biologically interesting compounds.1 The 2(1H)-pyrazinone
scaffold allows the easy introduction of a wide range of pharmaco-
logically active groups with the ability to address a diverse set of
biological targets.2 A versatile synthesis of the 2(1H)-pyrazinone
scaffold was developed,3 and simultaneously we have shown that
microwave-assisted cross-coupling reactions constitute a very mild
method to introduce different alkyl and aryl groups to the most
active C3-position of the pyrazinone ring.4
We became interested in investigating the possible bioactivity of
C3-aroylated 2(1H)-pyrazinones. This was inspired by the fact that
related 3-aroylquinoxalin-2(1H)-ones I have been described as late
sodium channel inhibitors5 and 3-benzoyl-2-piperazinyl-quinoxalines
II have been reported as potential antitumor agents6 (Figure 1).
Although the synthesis of highly functionalized 3-carboxamide
2(1H)-pyrazinone derivatives has been recently reported,7 to the
best of our knowledge the selective aroylation of the C3-position of
the 2(1H)-pyrazinone system has not yet been described. Preliminary
experiments using a Stille protocol, combining the C3-stannylated
pyrazinone with a suitable aroyl chloride, failed to give acceptable
yields in our hands.8 In light of the possible medicinal use of our
aroylated compounds, we decided to avoid the use of transition metal
catalysis and explored a carbene-catalyzed protocol.
By far the most studied members of nucleophilic carbenes are the
N-heterocyclic carbenes (NHCs).9,10 The term NHC came into use
only recently, but the existence of such species was clearly established
half a century ago when Breslow11 postulated in 1958 that the
thiazolium moiety in thiamine, a coenzyme that catalyzes decarbox-
ylation of pyruvic acid, is acidic enough to be deprotonated
To our satisfaction, when model substrate 3,5-dichloro-1-(4-meth-
oxybenzyl)-6-methylpyrazin-2(1H)-one (1a) was subjected to aroy-
lation with 4-methoxybenzaldehyde (2a) using NHC catalyst A and
NaH as base in DMF as described in the literature,20 the desired
aroylated product 5-chloro-3-(4-methoxybenzoyl)-1-(4-methoxybe-
Received: January 26, 2011
Published: March 15, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Figure 1. Bioactive 3-aroylquinoxalin-2(1H)-ones I and 3-benzoyl-2-piperazinylquinoxalines II.
nzyl)-6-methylpyrazin-2(1H)-one (3a) was obtained in 62% isolated
yield (Table 1, entry 1). Screening further different organic and
inorganic bases either gave no reaction with decomposition of starting
materials or traces of the corresponding product as was determined
via GC/MS or TLC analysis (Table 1, entries 2ꢀ5). However,
changing the solvent from DMF to DMSO resulted in a major
improvement of the reaction outcome yielding product 3a in 83%
(Table 1, entry 7). No improvement was seen when switching to less
polar solvents or different NHCs (B, C, and D) (Table 1, entries
8ꢀ13). Lowering the catalyst loading to 5 mol % did not affect the
reaction outcome and the product was isolated in 84% yield. The best
condition was obtained using catalyst A (5 mol %), NaH (2.0 equiv)
as base and DMSO (4 mL) as solvent and stirring the reaction
mixture at rt for 0.5 h (Table 1, entry 14).
With this optimized condition in hand, the scope of the NHC-
catalyzed aroylation of 3,5-dichloro-2-(1H)-pyrazinones 1bꢀk
was investigated (Table 2). It was found that most of the
reactions proceeded well with good to excellent yield. The nature
of the C6-substituent of the pyrazinone does not seem to play a
significant role for the outcome of the reaction (Table 2, entries
1ꢀ9). Only when a benzyl group was present at the C6-position,
the yield dropped to 52% (Table 2, entry 10).
Figure 2. Proposed approach to 3-aroyl-2(1H)-pyrazinones applying a
Breslow intermediate.
’ EXPERIMENTAL SECTION
General Procedure for N-Heterocyclic Carbene Catalyzed
Aroylation of 3,5-Dichloro-2(1H)-pyrazinone 1aꢀl (Tables 1
and 2, and Scheme 1). To a oven-dried two-necked flask
equipped with rubber septum and stir bar were added 3,5-dichloro-
2(1H)-pyrazinone 1aꢀl (0.33 mmol, 1 equiv), NHC catalyst A (5 mol
%), corresponding aldehyde 2aꢀo (0.4 mmol, 1.2 equiv), and DMSO
(4 mL) as solvent. The resulting solution was flushed with argon (3 times),
stirred for 10 min, and then cooled to 0 °C. Then NaH (2.0 equiv, 60%
in mineral oil) was added in one shot, and the reaction mixture was
allowed to warm to room temperature and was further stirred for 0.5ꢀ3 h.
The reaction was monitored via TLC analysis, and conversion was
determined via GC/MS and TLC analysis. After the reaction was
complete, H2O (20 mL) was added, and the mixture was extracted by
CH2Cl2 (3 ꢁ 50 mL). The combined organic layers were extracted with
brine (25 mL) and H2O (20 mL), dried over Na2SO4, filtered, and
concentrated by rotary evaporation. The resulting crude product was
purified by silica gel column chromatography using (hexane/EtOAc 9:1
to 7:3) to afford corresponding C3-aroylated products 3aꢀy in the below
mentioned yields.
Next the optimized protocol was explored for variously substi-
tuted (hetero)aromatic aldehydes as well as some aliphatic alde-
hydes. The desired aroylated products 3lꢀy were obtained in good
yields (Scheme 1).
When aliphatic aldehydes were used, the reaction did not
proceed at all, and the corresponding starting materials were
decomposed.22 Interestingly, ortho-substituted benzaldehydes
also give good yields. When furfural was employed as heteroaro-
matic aldehyde, the corresponding aroylated product was formed
in mere 36% isolated yield (Scheme 1).
In summary, we have successfully elaborated an organo-catalyzed
chemoselective procedure for the C3-aroylation of 3,5-dichloro-
2-(1H)-pyrazinones using NHCs. This method is mild and efficient,
and different substituents on the pyrazinone scaffold are tolerated, as
well as variously substituted benzaldehydes. To the best of our
knowledge this is the first report regarding the coupling of a Breslow
intermediate with the imidoylchloride system of a 3,5-dichloro-
2(1H)-pyrazinone.
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The Journal of Organic Chemistry
NOTE
Table 1. Preliminary Study for NHC-Catalyzed Aroylation of
Table 2. Investigation of the Substrate Scopea
3,5-Dichloro-2(1H)-pyrazinone 1aa
entry
R1
PMB
R2
product
yieldb (%)
entry catalyst (mol %) base (equiv) time (h) solvent yieldb (%)
1
2
isobutyl 1b
H 1c
3b
3c
3d
3e
3f
78
70
67
81
66
84
79
75
82
52
PMB
PMB
PMB
Ph
1
A (30)
A (30)
A (30)
A (30)
A (30)
A (30)
A (30)
A (30)
A (30)
A (30)
B (30)
C (30)
D (30)
A (5)
NaH (2.0)
DIEA (1.2)
Cs2CO3 (1.2)
Et3N (1.2)
DBU (1.2)
LiHMDS (1.2)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
NaH (2.0)
0.5
1
DMF
62
3
Bn 1d
2
DMF
NRc
NRc
tracesd
NRc
36
4
4-MeO-Ph 1e
4-MeO-Ph 1f
Ph 1g
3
24
DMF
5
4
1
DMF
6
Me
3g
3h
3i
5
1
DMF
7
Ph
Me 1h
6
0.5
0.5
4
DMF
8
Me
Me 1i
7
DMSO
THF
83
9
Ph
2-MeO-Ph 1j
Bn 1k
3j
8
tracesd
tracesd
tracesd
NRc
tracesd
NRc
84
10
2-MeO-Bn
3k
9
4
dioxane
CH3CN
DMSO
DMSO
DMSO
DMSO
DMA
a See Experimental Section b Isolated yields.
10
11
12
13
14
15
16
17
18
4
1
3H), 7.17ꢀ7.12 (m, 4H), 6.97 (d, J = 8.80 Hz, 2H), 6.88 (d, J = 8.56 Hz,
2H), 5.13 (s, 2H), 4.23 (s, 2H), 3.88 (s, 3H), 3.80 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 188.7, 164.4, 159.5, 154.4, 150.2, 140.1, 133.8, 132.6,
129.5, 128.0, 127.8, 127.5, 127.1, 126.5, 114.6, 114.0, 55.5, 55.3, 48.0, 35.6.
HRMS (EI): calcd for C27H23ClN2O4 474.1346, found 474.1360.
5-Chloro-3-(4-methoxybenzoyl)-1-(4-methoxybenzyl)-6-(4-
methoxyphenyl)pyrazin-2(1H)-one (3e). Yellow solid, mp 147ꢀ
148 °C, yield 87%. 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 9.04 Hz,
2H), 7.09 (d, J = 8.80 Hz, 2H), 7.01ꢀ6.96 (m, 4H) 6.83 (d, J = 8.56 Hz,
2H), 6.72 (d, J = 8.80 Hz, 2H), 5.07 (s, 2H), 3.89 (s, 6H), 3.76 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 188.9, 164.4, 161.0, 159.3, 154.1,
151.0, 141.0, 132.6, 130.7, 129.5, 128.0, 127.2, 126.6, 122.6, 114.4, 113.9,
113.8, 55.5, 55.4, 55.2, 49.5. HRMS (EI): calcd for C27H23ClN2O5
490.1295, found 490.1318.
5-chloro-3-(4-methoxybenzoyl)-6-(4-methoxyphenyl)-1-phe-
nylpyrazin-2(1H)-one (3f). Yellow solid, mp 101ꢀ102 °C, yield 66%.
1H NMR (300 MHz, CDCl3): δ 8.03 (d, J = 8.85 Hz, 2H), 7.30ꢀ7.23
(m, 3H), 7.09ꢀ7.03 (m, 4H) 6.98 (d, J = 8.85 Hz, 2H), 6.77 (d, J = 8.85
Hz, 2H), 3.89 (s, 3H), 3.75 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 188.7, 164.4, 160.2, 153.6, 151.7, 140.6, 136.6, 132.6, 131.2, 129.1,
128.9, 128.0, 125.9, 122.8, 113.9, 113.8, 55.5, 55.2. HRMS (EI): calcd for
C25H19ClN2O4 446.1033, found 446.1048.
1
1
0.5
0.5
0.5
0.5
A (5)
75
A (5)
NMP
71
A (1)
NMP
tracesd
tracesd
A (1)
0.5
c
DMSO
a See Experimental Section. b Isolated yields. NR = no reaction with
decomposition of starting materials was observed. d Detected via GC/
MS and/or TLC analysis.
5-Chloro-3-(4-methoxybenzoyl)-1-(4-methoxybenzyl)-6-
methyl-pyrazin-2(1H)-one (3a). Yellow solid, mp 172ꢀ174 °C,
yield 83%. 1H NMR (300 MHz, CDCl3): δ 7.94 (d, J = 8.85 Hz, 2H), 7.21
(d, J = 8.46 Hz, 2H), 6.94 (d, J = 8.85 Hz, 2H), 6.87 (d, J = 8.67 Hz, 2H),
5.30 (s, 2H), 3.87 (s, 3H), 3.79 (s, 3H), 2.52 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 188.8, 164.3, 159.5, 154.3, 148.6, 139.2, 132.5, 128.1, 126.1,
125.8, 114.50 113.9, 55.5, 55.3, 48.5, 17.3. HRMS (EI): calcd for
C21H19ClN2O4 398.1033, found 398.1044.
5-Chloro-6-isobutyl-3-(4-methoxybenzoyl)-1-(4-ethoxybenzyl)-
pyrazin-2(1H)-one (3b). Brown viscous oil, yield 78%. 1H NMR (300
MHz, CDCl3): δ 7.92 (d, J = 8.85 Hz, 2H), 7.15 (d, J = 8.46 Hz, 2H),
6.94 (d, J = 8.85 Hz, 2H), 6.87 (d, J = 8.67 Hz, 2H), 5.32 (s, 2H), 3.86
(s, 3H), 3.78 (s, 3H), 2.79 (d, J = 7.32 Hz, 2H), 2.20ꢀ2.11(m, 1H), 1.08
(d, J = 6.57 Hz, 6H). 13C NMR (75 MHz, CDCl3): δ 188.8, 164.3, 159.4,
154.3, 148.9, 142.0, 132.5, 128.5, 128.0, 126.6 (x 2), 114.4, 113.9, 55.5,
55.3, 48.1, 38.3, 28.9, 22.5. HRMS (EI): calcd for C24H25ClN2O4
440.1503, found 440.1497.
5-Chloro-3-(4-methoxybenzoyl)-1-(4-methoxybenzyl)pyrazin
-2(1H)-one (3c). Yellow solid, mp 124ꢀ125 °C, yield 70%. 1H NMR
(300 MHz, CDCl3): δ 7.91 (d, J = 8.67 Hz, 2H), 7.33ꢀ7.29 (m, 3H),
6.96ꢀ6.91 (m, 4H), 5.04 (s, 2H), 3.87 (s, 3H), 3.82 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 188.6, 164.5, 160.2, 153.1, 152.5, 132.6, 132.3,
130.8, 128.1, 127.7, 125.8, 125.3, 114.8, 114.0, 113.7, 55.5, 55.3, 52.3.
HRMS (EI): calcd for C20H17ClN2O4 384.0877, found 384.0884.
6-Benzyl-5-chloro-3-(4-methoxybenzoyl)-1-(4-methoxyben-
zyl)-pyrazin-2(1H)-one (3d). Yellow solid, mp 107ꢀ108 °C, yield 67%.
1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.80 Hz, 2H), 7.40ꢀ7.34 (m,
5-Chloro-3-(4-methoxybenzoyl)-1-methyl-6-phenylpyrazin-
2(1H)-one (3g). Yellow viscous oil, yield 84%. H NMR (300 MHz,
1
CDCl3): δ 8.01 (d, J = 8.85 Hz, 2H), 7.60ꢀ7.58 (m, 3H), 7.38ꢀ7.35
(m, 2H), 6.98 (d, J = 8.85 Hz, 2H), 3.89 (s, 3H), 3.34 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 188.8, 164.5, 153.9, 150.1, 141.2, 132.7, 130.8,
130.6, 129.5, 128.5, 127.9, 125.5, 113.9, 55.6, 35.1. HRMS (EI): calcd for
C19H15ClN2O3 354.0771, found 354.0768.
5-Chloro-3-(4-methoxybenzoyl)-6-methyl-1-phenylpyrazin-
2(1H)-one (3h). Brown solid, mp 105ꢀ106 °C, yield 79%. 1H NMR
(300 MHz, CDCl3): δ 7.97 (d, J = 8.85 Hz, 2H), 7.59ꢀ7.47 (m, 3H),
7.23ꢀ7.21 (m, 2H), 6.95 (d, J = 8.85 Hz, 2H), 3.87 (s, 3H), 2.19 (s, 3H).
13C NMR (75 MHz, CDCl3): δ 188.5, 164.3, 153.9, 149.6, 139.0, 136.6,
132.6, 130.2, 129.9, 128.0, 127.0, 125.2, 113.9, 55.5, 18.7. HRMS (EI):
calcd for C19H15ClN2O3 354.0771, found 354.0774.
5-Chloro-3-(4-methoxybenzoyl)-1,6-dimethylpyrazin-2(1H)-
one (3i). Yellow solid, mp 151ꢀ152 °C, yield 75%. H NMR (400
1
MHz, CDCl3): δ 7.92 (d, J = 8.56 Hz, 2H), 6.94 (d, J = 8.80 Hz, 2H),
3.87 (s, 3H), 3.63 (s, 3H), 2.57 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
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NOTE
Scheme 1. Evaluation of the Scope with Variously Substituted Aldehydesa
a See Experimental Section. All yields are isolated after column chromatography. b NR = no reaction and only decomposition of starting materials was
observed. c Determined via GC/MS and TLC analysis.
188.8, 164.3, 154.0, 147.8, 139.2, 132.5, 128.1, 125.3, 113.8, 55.5, 32.7,
17.5. HRMS (EI): calcd for C14H13ClN2O3 292.0615, found 292.0597.
5-Chloro-3-(4-methoxybenzoyl)-1,6-dimethylpyrazin-2(1H)-
4H), 7.13 (d, J = 7.28 Hz, 2H), 6.97- 6.87 (m, 5H), 5.25 (s, 2H), 4.19 (s,
2H), 3.88 (s, 3H), 3.85 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 188.8,
164.4, 156.4, 154.5, 150.0, 140.6, 134.1, 132.5, 129.3, 129.1, 128.1, 127.7,
127.6, 127.4, 122.4, 121.1, 113.9, 110.6, 55.5, 55.3, 48.8, 35.7. HRMS
(EI): calcd for C27H23ClN2O4 474.1346, found 474.1360.
1
one (3j). Yellow solid, mp 177ꢀ178 °C, yield 82%. H NMR (400
MHz, CDCl3): δ 8.05 (d, J = 8.80 Hz, 2H), 7.28ꢀ7.23 (m, 2H),
7.20ꢀ7.18 (m, 3H), 7.11 (dd, J = 1.24, 7.56 Hz, 1H), 6.99ꢀ6.97 (m,
3H) 6.88 (t, J = 7.52 Hz, 1H), 6.72 (d, J = 8.28 Hz, 1H), 3.88 (s, 3H),
3.74 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 188.9, 164.4, 156.0,
153.7, 151.8, 138.7, 136.5, 132.7, 131.8, 130.7, 129.0, 128.5 (x 2), 128.0,
127.7, 127.2, 126.2, 120.4, 120.0, 113.9, 110.9, 55.5, 55.3. HRMS (EI):
calcd for C25H19ClN2O4 446.1033, found 446.1033.
5-Chloro-6-isobutyl-1-(4-methoxybenzyl)-3-(4-
methylbenzoyl)-pyrazin-2(1H)-one (3m). Yellow oil, yield 72%.
1H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 8.04 Hz, 2H), 7.27ꢀ7.25 (m,
2H), 7.15 (d, J = 8.56 Hz, 2H), 6.87 (d, J = 8.56 Hz, 2H), 5.29 (s, 2H), 3.79
(s, 3H), 2.79 (d, J = 7.28 Hz, 2H), 2.41 (s, 3H), 2.20ꢀ2.13 (m, 1H), 1.09
(d, J = 6.80 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ 189.9, 159.5, 154.3,
148.6, 145.0, 142.3, 132.6, 130.2, 129.2, 128.5, 126.7, 126.6 114.5, 55.3, 48.1,
38.3, 28.9, 22.5, 21.8. HRMS (EI): calcd for C24H25ClN2O3 424.1554,
found 424.1538.
5-Benzyl-5-chloro-3-(4-methoxybenzoyl)-1-(2-methoxy-benzyl)
pyrazin-2(1H)-one (3k). Yellow solid, mp 90ꢀ91 °C, yield 52%. H
1
NMR (400 MHz, CDCl3): δ 7.96 (d, J = 8.56 Hz, 2H), 7.37ꢀ7.27 (m,
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NOTE
3-(4-(Benzyloxy)benzoyl)-5-chloro-6-isobutyl-1-(4-methoxy-
benzyl)pyrazin-2(1H)-one (3n). Yellow solid, mp 158ꢀ159 °C, yield
5-Chloro-3-(2-chloro-6-fluorobenzoyl)-1-(4-methoxybenzyl)
pyrazine-2(1H)-one (3v). Yellow solid, mp 111ꢀ112 °C, yield 81%.
1H NMR (300 MHz, CDCl3): δ 7.41 (s, 1H), 7.37 (dd, J = 2.25, 8.10 Hz,
1H), 7.31 (d, J = 8.67 Hz, 2H), 7.22 (d, J = 8.10 Hz, 1H), 7.05 (t, J = 8.67
Hz, 1H), 6.94 (d, J = 8.46 Hz, 2H), 5.09 (s, 2H), 3.83 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 186.3, 161.7, 160.3, 158.3, 152.5, 145.3, 132.6,
132.3, 132.2, 131.8, 131.7, 130.8, 127.2, 126.9, 125.6, 125.5 (x 2), 125.1,
114.8, 114.5, 114.2, 55.3, 52.5. HRMS (EI): calcd for C19H13Cl2FN2O3
406.0287, found 406.0305.
5-Chloro-1-(4-methoxybenzyl)-3-(2,4,6-trimethylbenzoyl)-
pyrazin-2(1H)-one (3w). Yellow viscous oil, yield 82%. 1H NMR (300
MHz, CDCl3): δ 7.32ꢀ7.28 (m, 3H), 6.93 (d, J = 8.46 Hz, 2H), 6.84
(s, 2H), 5.06 (s, 2H), 3.82 (s, 3H), 2.29 (s, 3H), 2.19 (s, 6H). 13C NMR
(75MHz, CDCl3): δ 196.2, 160.3, 149.0, 139.5, 136.2, 135.1, 130.7, 130.5,
128.6, 125.5, 125.3, 114.8, 55.3, 52.3, 21.2, 19.9. HRMS (EI): calcd for
C22H21ClN2O3 396.1241, found 396.1289.
1
85%. H NMR (400 MHz, CDCl3): δ 7.92 (d, J = 8.84 Hz, 2H),
7.42ꢀ7.33 (m, 5H), 7.15 (d, J = 8.56 Hz, 2H), 7.01 (d, J = 9.08 Hz, 2H),
6.86 (d, J = 8.80 Hz, 2H), 5.32 (s, 2H), 5.14 (s, 2H), 3.79 (s, 3H), 2.78
(d, J = 7.28 Hz, 2H), 2.21ꢀ2.11 (m, 1H), 1.09 (d, J = 6.80 Hz, 2H). 13C
NMR (100 MHz, CDCl3): δ 188.8, 163.5, 159.5, 154.3, 148.9, 142.1,
136.0, 132.5, 128.7, 128.5, 128.3, 128.2, 127.4, 126.6, 126.1, 114.7, 114.5,
70.2, 55.3, 48.1, 38.3, 28.9, 22.5. HRMS (EI): calcd for C30H29ClN2O4
516.1816, found 516.1829.
3-(2-naphthoyl)-5-chloro-6-isobutyl-1-(4-methoxyben-
zyl)pyrazin-2(1H)-one (3p). Yellow viscous oil, yield 82%. 1H NMR
(300 MHz, CDCl3): δ 8.85 (d, J = 8.49 Hz, 1H), 8.05 (d, J = 8.28 Hz,
1H), 7.90 (d, J = 7.92 Hz, 1H), 7.77 (d, J = 6.60 Hz, 1H), 7.62 (t, J = 6.94
Hz, 1H), 7.55 (t, J = 6.96 Hz, 1H), 7.48 (t, J = 7.71 Hz, 1H), 7.13
(d, J = 8.64 Hz, 2H),6.87 (d, J = 8.46 Hz, 2H), 5.33 (s, 2H), 3.79 (s, 3H),
2.80 (d, J = 7.35 Hz, 2H), 2.22ꢀ2.13 (m, 1H), 1.09 (d, J = 6.60 Hz, 6H).
13C NMR (75 MHz, CDCl3): δ 192.6, 159.5, 154.3, 149.2, 148.6, 142.8,
134.1, 133.9, 132.5, 131.7, 131.0, 128.5, 128.4, 126.8, 126.6, 126.5,
125.9, 124.2, 114.5, 55.3, 48.1, 38.4, 28.9, 22.6. HRMS (EI): calcd for
C27H25ClN2O3 460.1554, found 460.1552.
5-Chloro-3-(4-fluorobenzoyl)-6-isobutyl-1-(4-methoxybenzyl)-
pyrazin-2(1H)-one (3q). Yellow semisolid, yield 83%. 1H NMR (400
MHz, CDCl3): δ 7.99ꢀ7.96 (m, 2H), 7.16ꢀ7.12 (m, 4H), 6.87 (d, J =
8.56 Hz, 2H), 5.33 (s, 2H), 3.79 (s, 3H), 2.81 (d, J = 7.32 Hz, 2H),
2.21ꢀ2.14 (m, 1H), 1.09 (d, J = 6.52 Hz, 6H). 13C NMR (100 MHz,
CDCl3): δ 188.5, 167.5, 164.9, 159.5, 154.2, 147.5, 143.1, 132.9,
132.8, 128.5, 126.6, 126.4, 115.8, 115.6, 114.5, 55.3, 48.3, 38.4, 29.0,
22.5. HRMS (EI): calcd for C23H22ClFN2O3 428.1303, found 428.
1303.
5-Chloro-3-(2,3-dihydrobenzo[b][1,4]dioxine-6-carbonyl)-
1-(4-methoxy-benzyl)pyrazin-2(1H)-one (3x). Yellow solid, mp
1
151ꢀ152 °C, yield 78%. H NMR (400 MHz, CDCl3): δ 7.46ꢀ7.44
(m, 2H), 7.31 (d, J = 8.56 Hz, 2H), 7.25 (bs, 1H(merged with chloroform
peak)), 6.94ꢀ6.90 (m, 3H), 5.03 (s, 2H), 4.33ꢀ4.31 (m, 2H), 4.28ꢀ4.26
(m, 2H), 3.82 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 188.6, 160.2,
153.1, 152.4, 149.2, 143.4, 130.7, 128.4, 128.2, 125.7, 125.4, 124.5, 119.5,
117.5, 114.7, 64.7, 64.0, 55.3, 52.2. HRMS (EI): calcd for C21H17ClN2O5
412.0826, found 412.0812.
5-Chloro-3-(furan-2-carbonyl)-1-benzylpyrazin-2(1H)-one (3y).
Brown viscous oil, yield 36%.1H NMR (400 MHz, CDCl3): δ 7.69 (s,
1H), 7.42ꢀ7.35 (m, 7H), 6.59 (q, J = 1.52 Hz, 1H), 5.13 (s, 2H). 13C
NMR (75 MHz, CDCl3): δ 176.6, 152.7, 150.8, 149.3, 148.4, 133.6,
130.1, 129.3, 129.2, 129.1, 125.4, 122.4, 112.7, 52.9. HRMS (EI): calcd
for C16H11ClN2O3 314.0458, found 314.0472.
3-(Benzo[d][1,3]dioxole-5-carbonyl)-5-chloro-6-isobutyl-1-(4-
methoxybenzyl)pyrazin-2(1H)-one (3r). Yellow semisolid, yield
1
83%. H NMR (300 MHz, CDCl3): δ 7.49ꢀ7.46 (m, 2H), 7.15 (d,
’ ASSOCIATED CONTENT
J = 8.67 Hz, 2H), 6.89ꢀ6.83 (m, 3H), 6.06 (s, 2H), 5.32 (s, 2H), 3.79
(s, 3H), 2.79 (d, J = 7.35 Hz, 2H), 2.20ꢀ2.09 (m, 1H), 1.09 (d, J = 6.78
Hz, 6H). 13C NMR (75 MHz, CDCl3): δ 188.4, 159.4, 154.2, 152.7,
148.6, 148.2, 142.2, 129.7, 128.5, 127.5, 126.6, 126.5, 114.5, 109.1, 108.0,
102.0, 55.3, 48.2, 38.3, 29.0, 22.6. HRMS (EI): calcd for C24H23ClN2O5
454.1295, found 454.1301.
1
Supporting Information. Copies of H and 13C NMR
S
b
spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
3-(2-Bromo-5-chlorobenzoyl)-5-chloro-6-isobutyl-1-(4-methoxy-
benzyl)pyrazin-2(1H)-one (3s). Yellow viscous oil, yield 78%. 1H
NMR (300 MHz, CDCl3): δ 7.58 (d, J = 2.46 Hz, 1H), 7.49 (d, J =
8.67 Hz, 1H), 7.31 (dd, J = 2.64, 8.49 Hz, 1H,), 7.11 (d, J = 8.49 Hz, 2H),
6.86 (d, J = 8.64 Hz, 2H), 5.33 (s, 2H), 3.78 (s, 3H), 2.81 (d, J = 7.35 Hz,
2H), 2.22ꢀ2.13 (m, 1H), 1.07 (d, J = 6.57 Hz, 6H). 13C NMR (75 MHz,
CDCl3): δ 189.9, 159.5, 154.0, 145.8, 144.3, 140.9, 134.1, 134.0, 132.3,
130.6, 128.4, 127.3, 126.1, 118.1, 114.5, 55.3, 48.2, 38.7, 28.9, 22.5.
HRMS (EI): calcd for C23H21BrCl2N2O3 522.0113, found 522.0114.
3-(2-Bromo-5-methoxybenzoyl)-5-chloro-1-(4-methoxy-
benzyl)pyrazin-2(1H)-one (3t). Yellow solid, mp 147ꢀ148 °C,
yield 80%. 1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 8.80 Hz, 1H),
7.31ꢀ7.27 (m, 3H), 7.24 (d, J = 2.46 Hz, 1H), 6.95ꢀ6.91 (m, 3H), 5.05
(s, 2H), 3.84 (s, 3H), 3.82 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
190.8, 160.2, 159.0, 153.0, 149.6, 139.1, 134.1, 130.6, 130.3, 126.0, 125.4,
119.9, 115.8, 114.7, 111.3, 55.6, 55.3, 52.1. HRMS (EI): calcd for
C20H16BrClN2O4 461.9982, found 461.9992. LCMS (ESI): 951.1
(2MþþNaþþHþ)
Corresponding Author
*E-mail: erik.vandereycken@chem.kuleuven.be.
’ ACKNOWLEDGMENT
The authors thank the FWO (Fund for Scientific Researchꢀ
Flanders (Belgium)) and the Research Fund of the Katholieke
Universiteit Leuven for financial support to the laboratory.
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