Expanding the substitution pattern of 2(1H)-pyrazinones via Suzuki and Heck reactions

Article abstract of DOI:10.1016/j.tet.2005.02.056

Various 3,5-dichloropyrazinones were substituted at the C-3 position with (hetero)aryl, alkyl and alkenyl groups by means of Suzuki and Heck reactions. The methodology could be extended to reactions on the far less reactive C-5 position by transhalogenati

Full text of DOI:10.1016/j.tet.2005.02.056

Tetrahedron 61 (2005) 3953–3962
Expanding the substitution pattern of 2(1H)-pyrazinones
via Suzuki and Heck reactions
†
Rasha Azzam, Wim M. De Borggraeve, Frans Compernolle and Georges J. Hoornaert
*
Laboratorium voor Organische Synthese, K.U.Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Received 17 December 2004; accepted 21 February 2005
Abstract—Various 3,5-dichloropyrazinones were substituted at the C-3 position with (hetero)aryl, alkyl and alkenyl groups by means of
Suzuki and Heck reactions. The methodology could be extended to reactions on the far less reactive C-5 position by transhalogenation of the
5-Cl substituent to a 5-Br or a 5-I group prior to performing the cross-coupling.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
possibilities of functionalising this scaffold. Indeed, being
able to modify the substitution pattern on the pyrazinone
core can be advantageous if fine-tuning of pharmaceutically
relevant compound properties like, e.g. lipophilicity and
hydrogen bonding capacity is required.
In the past few years, 2(1H)-pyrazinones started to emerge
as valuable platforms in peptidomimetic chemistry. It has
been shown that the diazine core is able to reduce the
peptidyl features of peptide-like compounds, rendering
them more interesting for pharmaceutical applications:
a number of protease inhibitors have been designed around
this template (Fig. 1). A pyrazinone was introduced at the
P2–P3 (modified amino acid) positions of tryptase inhibitors
(e.g., 1),1 thrombin inhibitors (e.g., 2)2–6 and caspase-3
inhibitors (e.g., 3).7 In all these cases, variation of the
pyrazinone substituents representing the P1 and P4 residues
led to potent compounds.
Another example is the application of a pyrazinone unit in
somatostatin analogue 4 (Fig. 1) where it replaced a
disulfide moiety, resulting in a compound with a high
degree of antiproliferative activity.8 The pyrazinone core
also appears in an opioid-mimetic compound 5 (Fig. 1)
which was shown to be able to cross epithelial tissue in the
gastrointestinal tract and the blood–brain barrier, paving the
way for new orally bioavailable synthetic opioid-mimetic
substances.9–11
Considering the above mentioned applications of pyrazi-
none systems it is of interest to further explore the
Keywords: 3- and 5-Substituted 2(1H)-pyrazinones; Heterocyclic com-
pounds; Suzuki reaction; Heck reaction.
*
Corresponding author. Tel.: C32 16 32 74 07; fax: C32 16 32 79 90;
e-mail: frans.compernolle@chem.kuleuven.ac.be
† Present address: Department of Chemistry, Helwan University, Ain-
Helwan, Cairo, 11795, Egypt
Figure 1. Pyrazinone containing compounds.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.056

3954
R. Azzam et al. / Tetrahedron 61 (2005) 3953–3962
In this paper, in which we elaborate the results of a previous
short communication,12 we focus on the introduction of
substituents like, e.g. alkenyl and (hetero)aryl groups at
the reactive C-3 and the more challenging C-5 position of
3,5-dihalo-2(1H)-pyrazinones. In this respect, Suzuki and
Heck cross coupling reactions using organoboron reagents
or vinyl compounds appeared to be an attractive way of
introducing the abovementioned functionalities. As far as
the C-3 position is concerned, these methodologies are
complementary to the methods described earlier.13,14
As a second class of boron containing reagents, alkyl-9-
BBN derivatives were submitted to the coupling reaction
with pyrazinones (Scheme 2).19–21 The latter boron
derivatives were prepared in situ by adding 9-BBN (solution
in THF) to a THF solution of alkenes under argon
atmosphere. The mixture was stirred for 6 h at room
temperature before the 2(1H)-pyrazinone, Pd(dppf)Cl2 and
aqueous NaOH were added. The reaction was allowed to
proceed at room temperature for 16 h after which complete
conversion into 3-substituted products 8a–d was observed.
From the results displayed, it is apparent that primary alkyl-
9-BBN reagents having either a single (phenyl, alkyl, tri-
methylsilyl) or double (cyclohexyl branching) substitution
in b-position of the alkyl group attached to boron, all react
well with 3,5-dichloro-2(1H)-pyrazinone 6b to give the
corresponding products 8a–d in moderate to good yield.
However, no coupling was observed in the reaction of 6b
with the secondary cyclopentyl-9-BBN reagent prepared
from cyclopentene.
2. Results and discussion
2.1. Functionalisation of the C-3 position
2.1.1. Coupling with boron reagents. We first tried
introducing (hetero)aryl- and alkenylboronic acids on
3,5-dichloro-2(1H)-pyrazinones. In agreement with earlier
observations made in the Stille reaction, the initial
oxidative addition occurs exclusively at the C-3 position
of the pyrazinone. We used coupling conditions that were
optimised previously for the Suzuki coupling of p-deficient
heteroaryl chlorides.15,16 The best results were obtained
using tetrakis(triphenyl-phosphine)palladium(0) as a cata-
lyst, aqueous Na2CO3 as the base and toluene as solvent.
Thus reaction of pyrazinones 6a17 and 6b18 with 1.2 equiv
of arylboronic acid and 3 mol % of tetrakis in toluene under
reflux conditions produced 3-aryl-2(1H)-pyrazinones 7a
and 7b,c in good yields (Scheme 1). After completion of the
reaction and extractive workup, the mixture was subjected
to column chromatography. A similar cross-coupling
reaction of pyrazinones 6a and 6b with (E)-2-phenylethe-
nylboronic acid produced the corresponding 3-(2-phenyl-
ethenyl)pyrazinones 7d and 7e in 87 and 98% yield,
respectively. In the latter two reactions, the coupling
succeeded in dimethoxyethane (DME) but not in toluene.
Scheme 2. Pd-catalysed cross-coupling of alkyl-9-BBN derivatives at the
C-3 position of 2(1H)-pyrazinone 6b to form 3-alkyl-5-chloro-2(1H)-
pyrazinones 8a–d.
2.1.2. Heck reactions. Applying the Heck reaction to
3,5-dichloro-2(1H)-pyrazinones provides a direct method
for preparing 3-alkenyl-5-chloro-2(1H)-pyrazinones. Thus
reaction of pyrazinone 6b with various alkenes afforded the
corresponding 3-alkenyl substituted products 7e and 9a–e in
good yield. The best conditions consisted of using 3 mol %
of Pd(OAc)2, 7 mol % of tri-o-tolylphosphine and 2 equiv of
triethylamine in DMF at 100 8C. Less satisfactory results or
no conversion at all were observed when replacing DMF
with acetonitrile (Scheme 3). To avoid evaporation and/or
oxidation of volatile vinylic starting materials, the reaction
was carried out under argon in a capped heavy-walled
glass tube heated in an oil bath. Styrene, methyl acrylate,
and acrylonitrile reacted in the expected way to produce
7e, 9a, and 9b in 80, 75, and 70% yield, respectively.
A lower yield was observed in the reaction of 6b with
1-hexene and cyclohexene. The reaction of 6b with ethyl
vinyl ether afforded the enol ether product 9c that was
isolated in 87% yield by flash chromatography. The
(E)-configuration of the double bond was established by
the magnitude of the coupling constant between the two
vinylic protons in 7e, and 9a,b,d (16 Hz) and in the enol
ether product 9c (12 Hz).
Scheme 1. Suzuki-coupling of (hetero)aryl- and 1-alkenylboronic acid at
C-3 of 2(1H)-pyrazinones 6a,b to form 3-(hetero)aryl- and (E)-3-(2-
phenylethenyl)-5-chloro-2(1H)-pyrazinones 7a–e.

R. Azzam et al. / Tetrahedron 61 (2005) 3953–3962
3955
i.e. the conditions used for the synthesis of biaryl
compounds starting from an aryl chloride,24 were also
unsuccessful.
A single-case solution to this reactivity issue has been
reported by Kaval et al. who achieved a microwave
enhanced Suzuki coupling reaction of phenylboronic acid
with 1-benzyl-3,5-dichloro-2(1H)-pyrazinone to form the
corresponding 3,5-diphenyl pyrazinone.14 We followed a
more general approach towards solving the problem by
increasing the reactivity of the substrate: indeed, 5-bromo or
5-iodo-2(1H)-pyrazinones had to be better candidates as
precursors for 5-aryl/alkenyl substituted compounds in this
type of coupling reactions.
Scheme 3. Heck reaction at C-3 position of 2(1H)-pyrazinone 6b to form
3-vinyl-5-chloro-2(1H)-pyrazinones 7e and 9a–e.
2.2.2. Synthesis of 5-Br and 5-I pyrazinones. To the best
of our knowledge, the synthesis of 3-substituted 5-iodo-
2(1H)-pyrazinones bearing various substituents at the N-1
position has not yet been described. However, 3,6-
disubstituted 5-halo-2-pyrazinols have been prepared by
halogenation at C-5 of the corresponding 2-pyrazinols.25
Accordingly, we studied the analogous halogenation of
3-methoxy, 3-phenyl and 3-methyl-2(1H)-pyrazinones
11a–g with N-bromo and N-iodosuccinimide (NBS, NIS)
in DMF. The required 5-unsubstituted starting compounds
11a–g were generated by hydrogenolysis of pyrazinones
10a–f and 7a using 10% Pd/C in methanol (Scheme 5).26–28
2.2. Functionalisation of the C-5 position
2.2.1. Attempts to functionalise the 5-chloro compounds.
From previous research in our group, it is known that in
contrast to the easy reaction of the 3-imidoyl chloride
function, analogous substitution at the vinylic C-5-chloro
position of 3,5-dichloro-2(1H)-pyrazinones via, e.g. Stille
reaction is much more difficult. In fact, this has only been
achieved by us in an indirect way via isomerisation of
6-alkyl- or 6-benzyl-5-chloro-3-methoxy-2(1H)-pyrazi-
nones to form the tautomeric 6-alkylidene/benzylidene-5-
chloro-3,6-dihydropyrazin-2(1H)-ones having a reactive
5-imidoyl chloride group: subsequent reaction with orga-
notin reagents or amines then produced the corresponding
5-alkyl/aryl or 5-amino-alkylidene/benzylidene-3,6-di-
hydropyrazin-2(1H)-ones, respectively.22 Alternatively,
2(1H)-pyrazinones bearing a 5-alkyl substituent (and their
5-H analogues) can be obtained directly by base-catalyzed
condensation of 1,2-dicarbonyl compounds with various
a-amino N-substituted carboxamide derivatives (Scheme
4).23 However, this reaction is only interesting in the case
that R5 and R6 are the same, since otherwise a mixture of
regiomeric pyrazinones is formed.
Scheme 5. 5-Bromination and 5-iodination of 2(1H)-pyrazinones.
Scheme 4. Synthesis of 5-alkyl and 5-aryl-2(1H)-pyrazinones.
In each of the reactions studied, bromine and iodine were
introduced selectively at the C-5 position, even when R6Z
H. Halogenation of compounds 11a–d (3-methoxy), 11e
(3-methyl), and 11f and 11g (3-phenyl) provided the
corresponding products 12a–d, 12e and 12f,g, respectively.
Presumably electrophilic attack at C-5 is facilitated by
delocalisation of the lone pair on N-1. Thus bromination of
the 2(1H)-pyrazinones by NBS in DMF already proceeded
at room temperature in the dark and was completed within
1 h. In contrast, iodination of 11b, 11d, 11f and 11g by NIS
in DMF occurred only at higher temperature to produce the
5-iodo compounds in yields ranging from 66 to 78%.
Consistent with a better electron donation of 3-OMe to the
pyrazinone ring system, iodination of the 3-OMe com-
pounds already was completed after 8 h at 50 8C whereas
Thus exploring the possibilities for substitution at C-5 of the
pyrazinone system via the methods described above for the
C-3 position would be of great interest.
Similarly however as with our failure in effecting Stille
couplings at the C-5 position, we were not successful in
substituting the otherwise easily accessible 3-substituted
5-chloropyrazinones by means of a Suzuki-coupling
methodology using Pd(PPh3)4 catalyst and aqueous
Na2CO3 in either toluene or DME at reflux temperature.
Not even a trace of the 5-aryl substituted compounds was
formed. Other conditions involving the use of Pd2(dba)3,
combined with P(t-Bu)3 and CsF or KF in THF or dioxane,

3956
R. Azzam et al. / Tetrahedron 61 (2005) 3953–3962
conversion of the less reactive 3-Ph-substituted pyrazinones
required heating at 100 8C.
2.2.3. Functionalisation of the 5-Br and 5-I compounds.
Cross-coupling of both 5-bromo- and 5-iodopyrazinones
with aryl-, heteroaryl- and 1-alkenylboronic acids in all
cases proceeded well to produce the corresponding 5-aryl-
and 5-alkenyl-2(1H)-pyrazinones. The reactions involving
arylboronic acids were carried out using aqueous Na2CO3
and Pd(PPh3)4 and went to completion after heating in
toluene or DME at reflux temperature for 18 h. The resulting
5-arylpyrazinones were isolated in excellent yields. Similar
cross-coupling of 12a and 12d with (E)-2-phenylethenyl-
boronic acid in DME afforded compounds 13d and 13h in
80 and 95% yield (Scheme 6).
1
The position of the 5-halo substituent was verified by H
coupled 13C NMR analysis of 12b0, 12d, 12d0 and 12f, and
confirmed by heteronuclear multiple bond correlation
3
(HMBC) spectroscopy (2J and J) of 12d0. In the 1H
13
coupled C NMR spectrum of 6-H compound 12b0, the
methylene C-atom of the N-benzyl group appears as a triplet
1
3
of quartets (tq) with JZ284.8 Hz and JZ3.2 Hz: these J
values are due to coupling with the two attached protons (1J)
and to coupling with the two ortho-protons of the phenyl
ring plus the 6-H atom on the 2(1H)-pyrazinone ring (3J).
For the carbonyl carbon atom C-2 a doublet of triplets (dt)
coupling pattern was observed with 3JZ5 and 3 Hz, which
can be related to coupling of C-2 with H-6 and the
methylene protons of the N-benzyl group. The carbon atom
The Heck reaction of 5-bromo-2(1H)-pyrazinones 12c,e
with alkenes was carried out in a similar way as described
above for 3-chloro-2(1H)-pyrazinones. Thus treatment of
12c,e with 3 mol % of Pd(OAc)2, 7 mol % of tri-o-
tolylphosphine and 2 equiv of triethylamine in DMF at
100 8C was found to be most effective for conversion into
the 5-substituted alkenyl-2(1H)-pyrazinones 14a–e
(Scheme 7).
2
C-5 attached to the I-atom appears as a doublet (d, JZ
2.5 Hz) at d 78.7 ppm, due to coupling with H-6. The C-6
atom in turn is detected as a doublet of triplets (dt) with 1JZ
3
189 Hz and JZ4.6 Hz, due to coupling with H-6 and the
methylene protons of the N-benzyl group.
1
In the H coupled 13C NMR spectrum of the N-Ph-6-Me
compound 12d0, C-2 is observed as a singlet at d 151.4 ppm
as expected. Owing to coupling with the OMe protons, C-3
3
appears as a multiplet. The quartet pattern with JZ7 Hz
observed for C-5 reveals coupling with the 6-Me group.
Finally, C-6 appears as a quartet with 2JZ6 Hz due to
coupling with the protons of the methyl group. In the
HMBC spectrum of 12d0, protons of the 6-methyl group are
correlated with C-5 and C-6 whereas those of the methoxy
group are correlated with C-3.
Scheme 7. Heck-coupling of 5-bromopyrazinones with alkenes.
3. Conclusion
The reactive 3-Cl position of 3,5-dichloropyrazinones is
easily substituted by means of palladium-catalysed Suzuki
and Heck reactions providing easy access to 3-(hetero)aryl,
3-alkenyl and 3-alkyl derived pyrazinone compounds. The
5-Cl atom in these systems is inert towards these cross-
coupling conditions and substitution at this position there-
fore requires prior transhalogenation proceeding via a
reduction/bromination (or iodination) sequence. The result-
ing 5-Br and 5-I compounds smoothly undergo the expected
cross-coupling reactions.
4. Experimental
Melting points were taken using an Electrothermal IA 9000
digital melting point apparatus and were uncorrected.
Infrared spectra were recorded on a Perkin–Elmer 1600
Fouriertransform IR spectrometer. Mass spectra were run
using a Hewlett Packard MS-Engine 5989A apparatus for
EI and CI spectra, and a Kratos MS50TC instrument for
exact mass measurements performed in the EI mode at a
resolution of 10000. NMR spectra were recorded on a
Bruker AMX 300 and 400. They were taken using CDCl3 as
Scheme 6. Suzuki-coupling reaction of aryl- and 1-alkenylboronic acid and
5-bromo and 5-iodo-2(1H)-pyrazinones.

R. Azzam et al. / Tetrahedron 61 (2005) 3953–3962
3957
a solvent and the 1H and 13C chemical shifts are reported in
ppm relative to TMS.
133.7 (ArC-ipso), 130.6, 130.0, 129.5, 129.2, 128.1, 127.5
(ArCH), 126.9 (C5), 122.9 (HC]), 18.7 (CH3); EIMS m/z
(%): 322 (MC, 100), 293 (–CO, 81); HRMS: C19H15ClN2O,
calculated: 322.0873, found: 322.0866.
The 2(1H)-pyrazinones 6a and 6b were prepared as
described previously.17,18
4.1.5. 1-Benzyl-5-chloro-6-phenyl-3-[(E)-2-phenyl-
ethenyl]-2(1H)-pyrazinone 7e. Yield: 98%; solid, mp:
182.2 8C; H NMR (CDCl3, 300 MHz): 8.12 (d, JZ16 Hz,
4.1. Synthesis of 3-(hetero)aryl, 3-alkenyl-2(1H)-
pyrazinones 7a–e via Suzuki-coupling reaction
1
1H, HC]), 7.66–6.84 (m, 16H, ArH), 5.10 (s, 2H, CH2Ph);
13C NMR (CDCl3, 75 MHz): 155.7 (C2), 151.0 (C3), 137.8
(C6), 138.8 (HC]), 136.6, 135.8, 130.4 (ArC-ipso), 131.5,
129.9, 129.7, 129.23, 129.2, 128.9, 128.3, 128.1, 127.6
(ArCH), 127.5 (C5), 122.2 (HC]), 50.4 (CH2Ph); EIMS
m/z (%): 398 (MC, 100), 307 (–C7H7, 79), 91 (C7HC7 , 90);
HRMS: C25H19ClN2O, calculated: 398.1186, found:
398.1179.
General procedure. A mixture of pyrazinone 6a and 6b
(1 mmol) and 28 mg of tetrakis Pd(PPh3)4 (2.5 mol %) in
dry toluene or DME (for the synthesis of 3-alkenyl-2(1H)-
pyrazinones) was stirred under nitrogen for 10 min.
Following addition of (hetero)aryl boronic acid
(1.5 mmol), the mixture was stirred further for 10 min
whereupon 2 M aqueous sodium carbonate (3 mL) was
added. The reaction mixture was then heated at reflux for
18 h (1.5 h for the synthesis of 3-alkenyl-2(1H)-pyrazi-
nones) and cooled to RT. The mixture was distributed
between 50 mL of water and CH2Cl2 (50 mL) and the
aqueous phase further extracted with CH2Cl2 two times
(50 mL). The combined organic layers were dried over
MgSO4 and the solvent was evaporated under reduced
pressure to afford a pale residue, which was subjected to
column chromatography (silica gel, 100% CH2Cl2).
4.2. Synthesis of 3-alkyl-2(1H)-pyrazinones 8a–d using
alkyl-9-BBN reagents
General procedure. A dry flask equipped with magnetic
stirring bar, septum inlet, and condenser was flushed with
nitrogen. To the flask was added an alkene (1.1 mmol) and
1 mL of dry THF and then 2.2 mL of a solution of 9-BBN
(0.5 M solution in THF, 1.1 mmol) at 0 8C. The mixture was
warmed up slowly to RT and then stirred for 4–6 h to give a
solution of alkyl-9-BBN. To this solution were added 24 mg
of Pd(dppf)Cl2 (0.03 mmol, 3 mol %), 330 mg of pyrazi-
none 6b (1 mmol), additional 5 mL of THF, 1 mL of
aqueous NaOH (3 M solution) at RT. The mixture was
stirred at RT for 14–16 h. After the reaction was completed,
the reaction mixture was diluted with 50 mL of toluene and
water. The mixture was extracted with toluene, washed with
brine and dried over MgSO4, followed by purification using
column chromatography (silica gel, 50% heptane/
CH2Cl2/20% heptane/CH2Cl2).
4.1.1. 5-Chloro-6-methyl-1,3-diphenyl-2(1H)-pyrazinone
7a. Yield: 87%; solid, mp: 165 8C; IR (KBr) cmK1: 1665
(s, CO), 1600 (s, C]N); 1H NMR (CDCl3, 300 MHz):
8.50–7.25 (m, 10H, ArH), 2.20 (s, 3H, CH3); EIMS m/z (%):
296 (MC, 95), 77 (C6H5C, 100); HRMS: C17H13ClN2O,
calculated: 296.0716, found: 296.0722.
4.1.2. 5-(4-Benzyl-6-chloro-3-oxo-5-phenyl-3,4-dihydro-
2-pyrazinyl)-2-methoxy-benzaldehyde 7b. Yield: 65%;
1
solid, mp: 170 8C; H NMR (CDCl3, 300 MHz): 10.48 (s,
1H, CHO), 8.99 (d, JZ2.2 Hz, 1H, H60), 8.79 (dd, JZ2.6,
9.1 Hz, 1H, H40), 7.49–6.85 (m, 11H, ArH), 5.14 (s, 2H,
CH2Ph), 4.00 (s, 3H, OCH3); 13C NMR (CDCl3, 75 MHz):
189.8 (CHO), 163.4 (C-OCH3), 155.3 (C3), 149.5 (C2),
137.7 (C5), 135.8, 131.3, 127.1 (ArC-ipso), 137.2, 131.2,
130.5, 129.8, 129.2, 128.9, 128.1, 127.6, 111.7 (ArCH),
128.3 (C6), 124.9 (C-CHO), 56.3 (OCH3), 50.6 (CH2Ph);
EIMS m/z (%): 430 (MC, 77), 91 (C7HC7 , 100); HRMS:
C25H19ClN2O3, calculated: 430.1084, found: 430.1063.
4.2.1. 1-Benzyl-5-chloro-3-phenethyl-6-phenyl-2(1H)-
pyrazinone 8a. Yield: 60%; oil; IR (KBr) cmK1: 1651 (s,
CO), 1560 (C]N); 1H NMR (CDCl3, 300 MHz): 7.49–6.77
(m, 15H, ArH), 5.03 (s, 2H, CH2Ph), 3.28–3.09 (m, 4H,
2CH2); 13C NMR (CDCl3, 75 MHz): 159.1 (C2), 155.9
(C3), 141.7 (C6), 136.7, 135.8, 130.4 (ArC-ipso), 131.3,
129.8, 129.2, 129.0, 128.9, 128.8, 128.1, 127.6, 126.4
(ArCH), 126.5 (C5), 50.2 (CH2Ph), 35.7, 32.8 (CH2); EIMS
m/z (%): 400 (MC, 33), 309 (–C7H7, 100), 91 (C7HC7 , 100);
HRMS: C25H21ClN2O, calculated: 400.1342, found:
400.1339.
4.1.3. 1-Benzyl-5-chloro-6-phenyl-3-(3-thienyl)-2(1H)-
1
pyrazinone 7c. Yield: 70%; solid, mp: 164.2 8C; H NMR
(CDCl3, 300 MHz): 8.94 (dd, JZ1.1, 2.9 Hz, 1H, H20), 8.00
(dd, JZ1.1, 5.1 Hz, 1H, H40), 7.50–6.83 (m, 11H, ArH),
5.14 (s, 2H, CH2Ph); 13C NMR (CDCl3, 75 MHz):
154.9 (C2), 147.3 (C3), 137.4 (C6), 136.6, 135.9, 131.5
(ArC-ipso), 131.4, 130.4, 129.8, 129.2, 128.9, 128.3, 128.1,
127.4, 125.3 (ArCH), 126.9 (C6), 50.5 (CH2Ph);
EIMS m/z (%): 378 (MC, 91), 91 (C7HC7 , 100); HRMS:
C21H15ClN2OS, calculated: 378.0593, found: 378.0589.
4.2.2. 1-Benzyl-5-chloro-3-hexyl-6-phenyl-2(1H)-pyrazi-
none 8b. Yield: 30%; oil; H NMR (CDCl3, 300 MHz):
1
7.45–6.83 (m, 10H, ArH), 5.10 (s, 2H, CH2Ph), 2.90 (d, JZ
7.3 Hz, 2H, CH2), 1.62–0.85 (m, 11H, 4CH2CCH3); 13C
NMR (CDCl3, 75 MHz): 159.9 (C2), 156.9 (C3), 136.3
(C6), 136.2, 130.5 (ArC-ipso), 130.4, 130.0, 129.5, 129.3,
128.7, 128.1 (ArCH), 126.9 (C5), 50.4 (CH2Ph), 33.1, 29.5,
29.2, 28.5, 22.7 (CH2), 14.0 (CH3); EIMS m/z (%): 380
(MC, 6), 287 (–C7H7, 15), 91 (C7HC7 , 100).
4.1.4. 5-Chloro-6-methyl-1-phenyl-3-[(E)-2-phenyl-
ethenyl]-2(1H)-pyrazinone 7d. Yield: 87%; solid, mp:
1
178.5 8C; H NMR (CDCl3, 300 MHz): 8.15 (d, JZ16 Hz,
4.2.3. 1-Benzyl-5-chloro-3-cyclohexylmethyl-6-phenyl-
2(1H)-pyrazinone 8c. Yield: 80%; oil; H NMR (CDCl3,
1
1H, HC]), 7.45 (d, JZ16 Hz, 1H, HC]), 7.63–7.21 (m,
10H, ArH), 2.14 (s, 3H, CH3); 13C NMR (CDCl3, 75 MHz):
156.0 (C2), 149.6 (C3), 137.9 (C6), 138.5 (HC]), 136.9,
300 MHz): 7.48–6.78 (m, 10H, ArH), 5.03 (s, 2H, CH2Ph),
2.80 (d, JZ7.3 Hz, 2H, CH2), 2.05–1.05 (m, 11H, CHC

3958
R. Azzam et al. / Tetrahedron 61 (2005) 3953–3962
5CH2); 13C NMR (CDCl3, 75 MHz): 159.7 (C2), 156.1
(C3), 136.3 (C6), 136.0, 131.4 (ArC-ipso), 130.3, 129.8,
129.2, 128.8, 128.0, 127.6 (ArCH), 126.2 (C5), 50.1
(CH2Ph), 41.5 (CH2), 36.7 (CH), 33.7, 26.8, 26.6 (CH2);
EIMS m/z (%): 392 (MC, 8), 310 (–C6H10, 37), 301 (–C7H7,
100), 91 (C7H7C, 65); HRMS: C24H25ClN2O, calculated:
392.1655, found: 392.1653.
(%): 347 (MC, 44), 91 (C7H7C, 100); HRMS: C20H14ClN3O,
calculated: 347.0825, found: 347.0822.
4.3.3. 1-Benzyl-5-chloro-3-[(E)-2-ethoxyethenyl]-6-phe-
nyl-2(1H)-pyrazinone 9c. Yield: 87%; solvent system B;
1
oil. H NMR (CDCl3, 300 MHz): 8.24 (d, JZ12 Hz, 1H,
HC]), 7.46–6.80 (m, 10H, ArH), 6.27 (d, JZ12 Hz, 1H,
HC]), 5.04 (s, 2H, CH2Ph), 4.03 (q, JZ6.9 Hz, 2H, CH2),
1.36 (t, JZ6.9 Hz, 3H, CH3); 13C NMR (CDCl3, 75 MHz):
159.2 (HC]), 155.0 (C2), 152.2 (C3), 136.0 (C6), 133.4,
131.7 (ArC-ipso), 130.2, 130.1, 129.1, 128.8, 127.9, 127.4
(ArCH), 127.2 (C5), 102.9 (HC]), 67.1 (CH2CH3), 50.2
(CH2Ph), 15.1 (CH2CH3); EIMS m/z (%): 366 (MC, 40),
338 (–C2H2, 50), 91 (C7HC7 , 100).
4.2.4. 1-Benzyl-5-chloro-6-phenyl-3-[3-(trimethylsilyl)-
propyl]-2(1H)-pyrazinone 8d. Yield: 40%; oil; H NMR
1
(CDCl3, 300 MHz): 7.45–6.77 (m, 10H, ArH), 5.02 (s, 2H,
CH2Ph), 2.91 (d, JZ7.6 Hz, 2H, CH2), 1.83–1.72 (m, 2H,
CH2), 0.66–0.60 (m, 2H, CH2), 0.01 (s, 9H, Si(CH3)3); 13
C
NMR (CDCl3, 75 MHz): 161.5 (C2), 157.2 (C3), 137.6
(C6), 137.2, 132.6 (ArC-ipso), 131.6, 131.1, 130.4, 130.1,
129.3, 128.9 (ArCH), 127.6 (C5), 51.3 (CH2Ph), 39.2, 23.2,
18.5 (CH2), 0.01 (Si(CH3)3); EIMS m/z (%): 410 (MC, 8),
319 (–C7H7, 100), 91 (C7HC7 , 88); HRMS: C23H27ClN2OSi,
calculated: 410.1581, found: 410.1568.
4.3.4. 1-Benzyl-5-chloro-3-(1-hexenyl)-6-phenyl-2(1H)-
pyrazinone 9d. Yield: 53%; solvent system A; oil; 1H
NMR (CDCl3, 300 MHz): 7.47–6.81 (m, 12H, ArH), 5.05
(s, 2H, CH2Ph), 1.56–0.90 (m, 9H, 3CH2CCH3); 13C NMR
(CDCl3, 75 MHz): 155.4 (C2), 151.2 (C3), 144.1 (HC]),
136.1 (C6), 135.9, 130.3 (ArC-ipso), 131.5, 129.9, 129.1,
128.8, 128.0, 127.6 (ArCH), 127.3 (C5), 124.5 (HC]), 50.3
(CH2Ph), 33.6, 31.2, 22.7 (CH2), 14.3 (CH3); EIMS m/z
(%): 378 (MC, 3), 287 (–C7H7, 10), 91 (C7HC7 , 100);
HRMS: C23H23ClN2O, calculated: 378.1499, found:
378.1486.
4.3. Synthesis of 3-alkenyl-2(1H)-pyrazinones via Heck-
coupling reaction
General procedure. A mixture of 330 mg of pyrazinone
6b (1 mmol), 7 mg of Pd(OAc)2 (3 mol %) and 26 mg of
P(o-tolyl)3 (7 mol %) was stirred at room temperature under
argon for 10 min. Add 1.5 mmol of alkene, 300 mg of dry
Et3N (3 mmol) and 1 mL DMF. The reaction mixture was
heated at 100 8C in a capped heavy-walled glass tube in an
oil bath for 18 h. After the completion of the reaction, the
mixture was poured in water and extracted with 50 mL of
CH2Cl2 three times. The organic layer was collected and
dried over MgSO4. After filtration and evaporation of
CH2Cl2, the mixture was subjected to column chromato-
graphy (silica gel, A: 30% heptane/CH2Cl2 or B: 100%
CH2Cl2/5% EtOAc/CH2Cl2).
4.3.5. 1-Benzyl-5-chloro-3-(1-cyclohexenyl)-6-phenyl-
2(1H)-pyrazinone 9e. Yield: 50%; solvent system B; oil;
1H NMR (CDCl3, 400 MHz): 7.86 (t, JZ3.1 Hz, 1H,
HC]), 7.44–6.81 (m, 10H, ArH), 5.06 (s, 2H, CH2Ph),
2.57–2.54 (m, 2H, CH2), 2.37–2.34 (m, 2H, CH2), 1.78–1.75
(m, 2H, CH2), 1.70–1.65 (m, 2H, CH2); 13C NMR (CDCl3,
100 MHz): 154.8 (C2), 151.6 (C3), 138.3 (HC]), 135.2
(C6), 135.8, 131.3 (ArC-ipso), 134.6 (CaCH), 129.8, 129.4,
128.7, 128.4, 127.5, 127.0 (ArCH), 126.1 (C5), 49.9
(CH2Ph), 26.6, 25.8, 22.6, 21.7 (CH2); EIMS m/z (%): 376
(MC, 5), 91 (C7HC7 , 100); HRMS: C23H21ClN2O, calcu-
lated: 376.1342, found: 376.1338.
Compound 7e was isolated in 80% yield (solvent system A)
using the present method.
4.3.1. Methyl (2E)-3-(4-benzyl-6-chloro-3-oxo-5-phenyl-
3,4-dihydro-2-pyrazinyl)-2-propenoate 9a. Yield: 75%;
solvent system B; solid, mp: 93.5 8C; H NMR (CDCl3,
4.4. Synthesis of 2(1H)-pyrazinones 10a–f
1
The 3-methoxy-2(1H)-pyrazinones 10a–d were prepared as
described previously22,26 The 3-methyl- and 3-phenyl-
2(1H)-pyrazinones 10e–f were prepared via Pd-catalysed
reaction according to procedures described previously.17,27
400 MHz): 7.93 (d, JZ16 Hz, 1H, HC]), 7.34 (d, JZ
16 Hz, 1H, HC]), 7.50–6.81 (m, 10H, ArH), 5.10 (s, 2H,
CH2Ph), 3.81 (s, 3H, OCH3); 13C NMR (CDCl3, 100 MHz):
166.7 (COO), 155.0 (C3), 147.8 (C2), 139.7 (C5), 137.4
(HC]), 135.0, 130.6 (ArC-ipso), 130.3, 129.0, 128.9,
128.5, 127.9, 127.2 (ArCH), 127.3 (C6), 126.6 (HC]), 51.9
(OCH3), 50.2 (CH2Ph); EIMS m/z (%): 380 (MC, 25), 321
(–COOCH3, 13), 91 (C7HC7 , 100); HRMS: C21H17ClN2O3,
calculated: 380.0928, found: 380.0927.
4.5. Dechlorination of C-5 position of 2(1H)-pyrazinones
10a–f and 7a
General procedure. A mixture of 2(1H)-pyrazinone 10a–f
or 7a (2 mmol) in 10 mL of MeOH and 280 mg (2 mmol) of
K2CO3 was hydrogenated for 0.5–8 h in the presence of
catalyst (10% Pd/C; 50 mg) under H2 at atmospheric
pressure. After removal of the catalyst by filtration, the
filtrate was evaporated and the residue was dissolved in
dichloromethane. The solution was washed twice with
20 mL of water, dried over MgSO4, filtered and evaporated.
The residue was purified by column chromatography (silica
gel, 10% EtOAc/CH2Cl2—100%CH2Cl2) to give the
corresponding dechlorinated compounds 11a–g. Com-
pounds 11a,d,e,g have been described previously.26–28
4.3.2. (2E)-3-(4-benzyl-6-chloro-3-oxo-5-phenyl-3,4-
dihydro-2-pyrazinyl)-2-propenenitrile 9b. Yield: 70%;
solvent system B; solid, mp: 117.5 8C; H NMR (CDCl3,
1
300 MHz): 7.63 (d, JZ16 Hz, 1H, HC]), 7.02 (d, JZ
16 Hz, 1H, HC]), 7.55–6.80 (m, 10H, ArH), 5.11 (s, 2H,
CH2Ph); 13C NMR (CDCl3, 75 MHz): 155.1 (C3), 146.1
(C2), 141.4 (C5), 143.9 (HC]), 135.0, 131.0 (ArC-ipso),
130.6, 129.4, 129.3, 129.0, 128.5, 127.6 (ArCH), 127.9
(C6), 118.1 (CN), 105.8 (HC]), 50.8 (CH2Ph); EIMS m/z

R. Azzam et al. / Tetrahedron 61 (2005) 3953–3962
3959
4.5.1. 1-Benzyl-3-methoxy-2(1H)-pyrazinone 11b. Yield:
92%; solid, mp: 78.5–79.0 8C; 1H NMR (CDCl3, 300 MHz):
7.34–7.28 (m, 5H, ArH), 6.78 (d, JZ4.6 Hz, 1H, H5/H6),
6.73 (d, JZ4.6 Hz, 1H, H6/H5), 5.1 (s, 2H, CH2Ph), 3.96 (s,
3H, OCH3); 13C NMR (CDCl3, 75 MHz): 157.2 (C3), 151.9
(C2), 135.6 (ArC-ipso), 129.3, 128.8, 128.7 (ArCH), 122.0
(C6), 119.7 (C5), 54.9 (OCH3), 51.8 (CH2Ph); EIMS m/z
(%): 216 (MC, 70), 91 (C7H7C, 100); HRMS: C12H12N2O2,
calculated: 216.0899, found: 216.0896.
4.6.3. 1-Benzyl-5-iodo-3-methoxy-2(1H)-pyrazinone
1
12b0. Yield: 75%; oil; H NMR (CDCl3, 400 MHz): 7.36–
7.29 (m, 5H, ArH), 7.01 (s, 1H, H6), 5.02 (s, 2H, CH2Ph),
3.95 (s, 3H, OCH3); 13C NMR (CDCl3, 100 MHz): 155.5
(C3), 151.4 (C2), 134.7 (ArC-ipso), 129.0, 128.6, 128.4
(ArCH), 127.2 (C6), 78.6 (C5), 55.2 (OCH3), 51.5 (CH2Ph);
EIMS m/z (%): 341 (MC, 40), 215 (–I, 8), 91 (C7HC7 , 100);
HRMS: C12H11IN2O2, calculated: 341.9865, found:
341.9860.
4.6.4. 1-Benzyl-5-bromo-3-methoxy-6-phenyl-2(1H)-
pyrazinone 12c. Yield: 82%; solid, mp: 138.4–139.4 8C;
1H NMR (CDCl3, 300 MHz): 7.45–6.77 (m, 10H, ArH),
5.04 (s, 2H, CH2Ph), 4.06 (s, 3H, OCH3); 13C NMR (CDCl3,
75 MHz): 154.8 (C3), 151.6 (C2), 133.0 (C6), 135.9, 132.9
(ArC-ipso), 130.5, 130.1, 129.0, 128.7, 128.0, 127.8
(ArCH), 112.7 (C5), 55.6 (OCH3), 50.3 (CH2Ph); EIMS
m/z (%): 370 (MC, 40), 91 (C7HC7 , 100); HRMS:
C18H15BrN2O2, calculated: 370.0317, found: 370.0300.
4.5.2. 1-Benzyl-3-methoxy-6-phenyl-2(1H)-pyrazinone
11c. Yield: 30%; solid, mp: 116.5 8C; H NMR (CDCl3,
1
300 MHz): 7.42–6.85 (m, 10H, ArH), 6.73 (s, 1H, H5), 5.14
(s, 2H, CH2Ph), 4.02 (s, 3H, OCH3); 13C NMR (CDCl3,
75 MHz): 156.2 (C3), 152.3 (C2), 136.4 (C6), 135.2, 132.3
(ArC-ipso), 130.2, 129.7, 128.8, 128.7, 127.86, 127.82
(ArCH), 119.9 (C5), 54.8 (OCH3), 48.8 (CH2Ph); EIMS m/z
(%): 292 (MC, 90), 91 (C7H7C, 100); HRMS: C18H16N2O2,
calculated: 292.1212, found: 292.1203.
4.6.5. 5-Bromo-3-methoxy-6-methyl-1-phenyl-2(1H)-
pyrazinone 12d. Yield: 73%; solid, mp: 141.1–141.8 8C;
1H NMR (CDCl3, 400 MHz): 7.57–7.15 (m, 5H, ArH), 4.00
(s, 3H, OCH3), 2.00 (s, 3H, CH3); 13C NMR (CDCl3,
100 MHz): 154.2 (C3), 151.3 (C2), 135.9 (ArC-ipso), 129.8
(C6), 130.5, 129.8, 127.8 (ArCH), 115.6 (C5), 55.6 (OCH3),
22.8 (CH3); EIMS m/z (%): 294 (MC, 100), 264 (–CO, 31),
77 (C6HC5 , 79); HRMS: C12H11BrN2O2, calculated:
294.0003, found: 293.9982.
4.5.3. 1-Benzyl-3-phenyl-2(1H)-pyrazinone 11f. Yield:
84%; oil; H NMR (CDCl3, 300 MHz): 8.32–8.28 (m, 2H,
1
ArH), 7.44–7.37 (m, 9H, ArH), 7.08 (d, JZ4.3 Hz, 1H, H5/
H6), 5.17 (s, 2H, CH2Ph); 13C NMR (CDCl3, 75 MHz):
155.9 (C2), 154.2 (C3), 136.3, 135.3 (ArC-ipso), 130.4,
129.5, 129.4, 128.97, 128.95, 128.4 (ArCH), 127.8 (C6),
123.8 (C5), 52.8 (CH2Ph); EIMS m/z (%): 262 (MC, 80), 91
(C7HC7 , 100); HRMS: C17H14N2O, calculated: 262.1106,
found: 262.1103.
4.6.6. 5-Iodo-3-methoxy-6-methyl-1-phenyl-2(1H)-pyra-
zinone 12d0. Yield: 78%; solid, mp: 128 8C; 1H NMR
(CDCl3, 400 MHz): 7.53–7.13 (m, 5H, ArH), 3.97 (s, 3H,
OCH3), 2.07 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz):
153.3 (C3), 151.4 (C2), 138.0 (ArC-ipso),131.9 (C6), 130.0,
129.5, 127.3 (ArCH), 83.3 (C5), 54.9 (OCH3), 23.2 (CH3);
EIMS m/z (%): 341 (MC, 100), 312 (–CO, 12); HRMS:
C12H11IN2O2, calculated: 341.9865, found: 341.9861.
4.6. Synthesis of 5-bromo and 5-iodo-2(1H)-pyrazinones
12a–g
General procedure. To a solution of pyrazinone 11a–g
(2 mmol) in DMF (2 mL) was added NBS or NIS
(2.2 mmol). The reaction mixture was stirred in the dark
under nitrogen atmosphere at RT for 1–2 h (NBS) or at 50–
100 8C for 8–12 h (NIS). The mixture was poured into
50 mL of ice-water and extracted three times with CH2Cl2.
After the usual work up, the residue was purified by column
chromatography (silica gel, 100% CH2Cl2/5%EtOAc/
CH2Cl2).
4.6.7. 1-Benzyl-5-bromo-3-methyl-6-phenyl-2(1H)-pyra-
zinone 12e. Yield: 75%; solid, mp: 136.2–136.6 8C; 1H
NMR (CDCl3, 300 MHz): 7.49–6.79 (m, 10H, ArH), 5.03
(s, 2H, CH2Ph), 2.57 (s, 3H, CH3); 13C NMR (CDCl3,
75 MHz): 157.6 (C2), 156.3 (C3), 138.6 (C6), 135.8, 132.7
(ArC-ipso), 130.4, 129.8, 129.2, 128.8, 128.1, 127.7
(ArCH), 115.9 (C5), 50.5 (CH2Ph), 21.4 (CH3); EIMS m/z
(%): 354 (MC, 60), 275 (–Br, 6), 91 (C7HC7 , 100); HRMS:
C18H15BrN2O, calculated: 354.0368, found: 354.0362.
4.6.1. 1-Benzyl-5-bromo-3-methoxy-6-methyl-2(1H)-
pyrazinone 12a. Yield: 90%; solid, mp: 85.5 8C; 1H
NMR (CDCl3, 300 MHz): 7.35–7.15 (m, 5H, ArH), 5.34
(s, 2H, CH2Ph), 4.01 (s, 3H, OCH3), 2.34 (s, 3H, CH3); 13
C
NMR (CDCl3, 75 MHz): 153.5 (C3), 152.0 (C2), 135.3
(ArC-ipso), 129.2 (C6), 129.3, 128.3, 127.1 (ArCH), 112.1
(C5), 55.4 (OCH3), 49.2 (CH2Ph), 18.6 (CH3); EIMS m/z
(%): 308 (MC, 100), 229 (–Br, 57); HRMS: C13H13BrN2O2,
calculated: 308.0160, found: 308.0149.
4.6.8. 1-Benzyl-5-iodo-3-phenyl-2(1H)-pyrazinone 12f.
Yield: 72%; solid, mp: 140.3–141 8C; H NMR (CDCl3,
1
400 MHz): 8.34–8.31 (m, 2H, ArH), 7.42–7.33 (m, 8H,
ArH), 5.09 (s, 2H, CH2Ph); 13C NMR (CDCl3, 100 MHz):
154.4 (C2), 154.1 (C3), 134.9, 134.5 (ArC-ipso), 133.2
(C6), 130.5, 129.2, 129.1, 128.7, 128.6, 128.0 (ArCH), 83.2
(C5), 52.4 (CH2Ph); EIMS m/z (%): 388 (MC, 30), 91
(C7HC7 , 100); HRMS: C17H13IN2O, calculated: 388.0073,
found: 388.0069.
4.6.2. 1-Benzyl-5-bromo-3-methoxy-2(1H)-pyrazinone
12b. Yield: 75%; solid, mp: 75 8C; 1H NMR (CDCl3,
300 MHz): 7.37–7.23 (m, 5H, ArH), 7.04 (s, 1H, H6), 5.04
(s, 2H, CH2Ph), 3.92 (s, 3H, OCH3); 13C NMR (CDCl3,
75 MHz): 156.2 (C3), 151.0 (C2), 135.0 (ArC-ipso), 129.2,
128.4, 128.1 (ArCH), 125.3 (C6), 115.2 (C5), 55.3 (OCH3),
51.5 (CH2Ph); EIMS m/z (%): 294 (MC, 60), 215 (–Br, 20),
91 (C7HC7 , 100); HRMS: C12H11BrN2O2, calculated:
294.0004, found: 294.0001.
4.6.9. 5-Iodo-1,3-diphenyl-6-methyl-2(1H)-pyrazinone
12g. Yield: 66%; solid, mp: 184.8 8C; H NMR (CDCl3,
1
300 MHz): 8.38–8.34 (m, 2H, ArH), 7.60–7.18 (m, 8H,
ArH), 2.22 (s, 3H, CH3); 13C NMR (CDCl3, 75 MHz): 155.8

3960
R. Azzam et al. / Tetrahedron 61 (2005) 3953–3962
(C2), 150.9 (C3), 139.5 (C6), 138.7, 135.3 (ArC-ipso),
130.6, 130.5, 129.9, 129.3, 128.4, 127.4 (ArCH), 89.7 (C5),
24.6 (CH3); EIMS m/z (%): 388 (MC, 100), 360 (–CO, 36),
77 (C6HC5 , 50); HRMS: C17H13IN2O, calculated: 388.0073,
found: 388.0051.
221 (–C7H7, 60), 91 (C7HC7 , 95); HRMS: C17H16N2O2S,
calculated: 312.0933, found: 312.0930.
4.7.4. 1-Benzyl-3-methoxy-6-methyl-5-[(E)-2-phenyl-
ethenyl]-2(1H)-pyrazinone 13d. Yield: 80%; solid, mp:
194.4–195 8C; 1H NMR (CDCl3, 400 MHz): 7.48–7.14 (m,
11H, ArH), 7.01 (d, JZ15 Hz, 1H, HC]), 5.34 (s, 2H,
CH2Ph), 4.09 (s, 3H, OCH3), 2.30 (s, 3H, CH3); 13C NMR
(CDCl3, 100 MHz): 153.0 (C3), 151.8 (C2), 137.4, 135.4
(ArC-ipso), 129.8 (HC]), 128.8, 128.5, 127.6, 127.4,
126.5, 126.4 (ArCH), 127.2 (C5/C6), 125.4 (C6/C5), 122.2
(HC]), 54.8 (OCH3), 50.4 (CH2Ph), 14.2 (CH3); EIMS m/z
(%): 332 (MC, 28), 241 (–C7H7, 16), 91 (C7HC7 , 100);
HRMS: C21H20N2O2, calculated: 332.1525, found:
332.1522.
4.7. Synthesis of 5-(hetero)aryl and 5-alkenyl-2(1H)-
pyrazinones 13a–j by Suzuki coupling of 5-bromo or
5-iodo-2(1H)-pyrazinones
General procedure. A mixture of pyrazinone 12a,b0,d, d0, e
and f (1 mmol) and 28 mg of tetrakis Pd(PPh3)4 (2.5 mol %)
in dry toluene or DME (for the synthesis of 3-alkenyl-
2(1H)-pyrazinones) was stirred under nitrogen for 10 min.
Following addition of (hetero)aryl boronic acid (1.5 mmol),
the mixture was stirred further for 10 min whereupon 2 M
aqueous sodium carbonate (3 mL) was added. The reaction
mixture was then heated at reflux for 18 h (1.5 h for the
synthesis of 3-alkenyl-2(1H)-pyrazinones) and cooled to
RT. The mixture was distributed between 50 mL of water
and CH2Cl2 (50 mL) and the aqueous phase further
extracted with CH2Cl2 two times (50 mL). The combined
organic layers were dried over MgSO4 and the solvent was
evaporated under reduced pressure to afford a pale residue,
which was subjected to column chromatography (silica gel,
100% CH2Cl2).
4.7.5. 1-Benzyl-3-methoxy-5-phenyl-2(1H)-pyrazinone
13e. Yield: 78%, oil; H NMR (CDCl3, 300 MHz): 8.05–
1
7.32 (m, 11H, ArH), 5.05 (s, 2H, CH2Ph); EIMS m/z (%):
292 (MC, 100), 91 (C7HC7 , 60).
4.7.6. 3-Methoxy-6-methyl-1,5-diphenyl-2(1H)-pyrazi-
none 13f. Yield: 94%; solid, mp: 160 8C; 1H NMR
(CDCl3, 300 MHz): 7.58–7.24 (m, 10H, ArH), 4.02 (s,
2H, CH2Ph), 1.93 (s, 3H, CH3); 13C NMR (CDCl3,
75 MHz): 154.3 (C3), 151.9 (C2), 138.7, 138.1 (ArC-
ipso), 128.8 (C6/C5), 127.9 (C5/C6), 130.3, 129.8, 129.6,
128.5, 128.1, 127.6 (ArCH), 54.7 (OCH3), 18.5 (CH3);
EIMS m/z (%): 306 (MC, 100), 215 (–C7H7, 65), 91 (C7HC7 ,
90); HRMS: C19H18N2O, calculated: 306.1368, found:
306.1366.
4.7.1. 1-Benzyl-3-methoxy-6-methyl-5-phenyl-2(1H)-
pyrazinone 13a. Yield: 92%; solid, mp: 115 8C; H NMR
1
(CDCl3, 300 MHz): 7.44–7.20 (m, 10H, ArH), 5.39 (s, 2H,
CH2Ph), 4.00 (s, 3H, OCH3), 2.25 (s, 3H, CH3); 13C NMR
(CDCl3, 75 MHz): 153.8 (C3), 152.2 (C2), 138.8, 136.0
(ArC-ipso), 129.4 (C6/C5), 127.8 (C5/C6), 129.9, 129.2,
128.5, 128.0, 127.9, 127.1 (ArCH), 54.7 (OCH3), 48.3
(CH2Ph), 16.9 (CH3); EIMS m/z (%): 306 (MC, 100), 215
(–C7H7, 65), 91 (C7HC7 , 90); HRMS: C19H18N2O, calcu-
lated: 306.1368, found: 306.1366.
The same compound 13f was isolated in 85% yield when
applying Suzuki coupling of 5-iodo compound 12d0 with
phenylboronic acid.
4.7.7.
3-Methoxy-6-methyl-1-phenyl-5-(3-thienyl)-
2(1H)-pyrazinone 13g. Yield: 55%; solid, mp: 165.5 8C;
1H NMR (CDCl3, 300 MHz): 7.57–7.21 (m, 8H, ArH), 4.02
(s, 3H, OCH3), 2.00 (s, 3H, CH3); 13C NMR (CDCl3,
75 MHz): 154.1 (C3), 151.8 (C2), 139.7, 138.0 (ArC-ipso),
127.5 (C5/C6), 124.6 (C6/C5), 130.3, 129.6, 129.0, 128.0,
125.5, 124.0 (ArCH), 54.6 (OCH3), 18.4 (CH3); EIMS m/z
(%): 298 (MC, 100); HRMS: C16H14N2O2S, calculated:
298.0776, found: 298.0770.
4.7.2. 5-(4-Benzyl-6-methoxy-3-methyl-5-oxo-4,5-di-
hydro-2-pyrazinyl)-2-methoxy-benzaldehyde
13b.
Yield: 90%; solid, mp: 68 8C; 1H NMR (CDCl3,
300 MHz): 10.48 (s, 1H, CHO), 7.85 (d, JZ2.5 Hz, 1H,
H60), 7.67 (dd, JZ2.6,8.8 Hz, 1H, 0H40), 7.33–7.19 (m, 5H,
ArH), 7.05 (d, JZ8.8 Hz, 1H, H3 ), 5.39 (s, 2H, CH2Ph),
3.99 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 2.25 (s, 3H, CH3);
13C NMR (CDCl3, 75 MHz): 189.9 (CHO), 161.6
(C–OCH3), 153.9 (C6), 152.1 (C5), 135.8, 131.4 (ArC-
ipso), 137.4, 129.5, 129.3, 128.1, 127.1, 112.1 (ArCH),
128.1 (C2/C3), 127.8 (C3/C2), 124.9 (C–CHO), 56.2
(ArOCH3), 54.7 (OCH3), 48.3 (CH2Ph), 16.9 (CH3);
EIMS m/z (%): 364 (MC, 100), 273 (–C7H7, 37), 41
(–C7H7C(–CO), 37), 91 (C7HC7 , 79); HRMS: C21H20N2O4,
calculated: 364.1423, found: 364.1420.
4.7.8. 3-Methoxy-6-methyl-1-phenyl-5-[(E)-2-phenyl-
ethenyl]-2(1H)-pyrazinone 13h. Yield: 95%; solid, mp:
186 8C; H NMR (CDCl3, 300 MHz): 7.58–7.17 (m, 11H,
1
ArH), 7.05 (d, JZ15 Hz, 1H, HC]), 4.11 (s, 3H, OCH3),
2.01 (s, 3H, CH3); 13C NMR (CDCl3, 75 MHz): 153.9 (C3),
152.0 (C2), 137.9 2x(ArC-ipso), 129.7 (HC]), 130.4,
130.1, 129.1, 128.0, 127.9, 127.9 (ArCH), 127.6 (C5/C6),
125.4 (C5/C6), 122.7 (HC]), 54.6 (OCH3), 16.1 (CH3);
EIMS m/z (%): 318 (MC, 100); HRMS: C20H18N2O2,
calculated: 318.1368, found: 318.1368.
4.7.3. 1-Benzyl-3-methoxy-6-methyl-5-(3-thienyl)-2(1H)-
pyrazinone 13c. Yield: 95%; solid, mp: 112–112.5 8C; H
1
NMR (CDCl3, 300 MHz): 7.34–7.18 (m, 8H, ArH), 5.38 (s,
2H, CH2Ph), 4.00 (s, 3H, OCH3), 2.32 (s, 3H, CH3); 13C
NMR (CDCl3, 75 MHz): 153.6 (C3), 152.1 (C2), 139.7,
135.9 (ArC-ipso), 127.7 (C5/C6), 125.1 (C6/C5), 129.3,
129.1, 128.0, 127.1, 125.5, 124.2 (ArCH), 54.6 (OCH3),
48.3 (CH2Ph), 16.8 (CH3); EIMS m/z (%): 312 (MC, 100),
4.7.9. 1-Benzyl-3-methyl-5,6-diphenyl-2(1H)-pyrazinone
13i. Yield: 87%; solid, mp: 123.7 8C; H NMR (CDCl3,
300 MHz): 7.34–6.87 (m, 15H, ArH), 5.13 (s, 2H, CH2Ph),
2.64 (s, 3H, CH3); 13C NMR (CDCl3, 75 MHz): 156.6 (C2),
156.2 (C3), 138.2 (C6), 136.8, 136.6, 132.4 (ArC-ipso),
133.1 (C5), 131.1, 129.7, 129.6, 128.8, 128.8, 128.1, 127.8,
1

R. Azzam et al. / Tetrahedron 61 (2005) 3953–3962
3961
127.6, 127.3 (ArCH), 49.3 (CH2Ph), 21.7 (CH3); EIMS m/z
(%): 352 (MC, 100), 91 (C7HC7 , 64); HRMS: C24H20N2O,
calculated: 352.1576, found: 352.1573.
127.8, 127.7, 127.6, 126.9 (ArCH), 127.0 (C5), 123.7
(HC]), 54.8 (OCH3), 49.3 (CH2Ph); EIMS m/z (%): 394
(MC, 100), 303 (–C7H7, 36), 91 (C7H7C, 80); HRMS:
C26H22N2O2, calculated: 394.1681, found: 394.1674.
4.7.10. 1-Benzyl-3,5-diphenyl-2(1H)-pyrazinone 13j.
Yield: 70%, oil; H NMR (CDCl3, 300 MHz): 8.49–8.46
1
4.8.4. Methyl (2E)-3-(4-benzyl-6-methoxy-5-oxo-3-phe-
nyl-4,5-dihydro-2-pyrazinyl)-2-propenoate 14d. Yield:
66%; solid, mp: 173.7 8C; H NMR (CDCl3, 300 MHz):
(m, 2H, ArH), 7.79–7.29 (m, 14H, ArH), 5.17 (s, 2H,
CH2Ph); 13C NMR (CDCl3, 75 MHz): 155.1 (C2), 152.3
(C3), 136.6, 136.3, 135.6 (ArC-ipso), 133.2 (C5), 130.4
(C6), 129.7, 129.5, 129.2, 128.9, 128.8, 128.4, 128.3, 125.4,
124.0 (ArCH), 53.3 (CH2Ph); EIMS m/z (%): 338 (MC,
100), 91 (C7HC7 , 40).
1
6.94 (d, JZ15 Hz, 1H, HC]), 7.50–7.02 (m, 8H, ArH),
6.80–6.77 (m, 2H, ArH), 6.66 (d, JZ15 Hz, 1H, HC]),
5.03 (s, 2H, CH2Ph), 4.09 (s, 3H, OCH3), 3.67 (s, 3H,
COOCH3); 13C NMR (CDCl3, 75 MHz): 167.9 (COO),
154.8 (C6), 152.1 (C5), 136.6 (C3), 139.8, 135.9 (ArC-
ipso), 130.4 (HC]), 130.8, 130.5, 129.1, 128.7, 128.0,
127.7 (ArCH), 124.9 (C2), 118.5 (HC]), 55.0 (OCH3),
51.8 (COOCH3), 49.4 (CH2Ph); EIMS m/z (%): 376 (MC,
61), 317 (–COOCH3, 11), 91 (C7HC7 , 100); HRMS:
C22H20N2O4, calculated: 376.1423, found: 376.1422.
4.8. Synthesis of 5-alkenyl-2(1H)-pyrazinones 14a–e via
Heck-coupling reaction of 5-bromo-2(1H)-pyrazinones
General procedure. A mixture of pyrazinone 12c or 12e
(1 mmol), 7 mg of Pd(OAc)2 (3 mol %) and 26 mg of
P(o-tolyl)3 (7 mol %) was stirred at room temperature under
argon for 10 min. Add 1.5 mmol of alkene, 300 mg of dry
Et3N (3 mmol) and 1 mL DMF. The reaction mixture was
heated at 100 8C in a capped heavy-walled glass tube in an
oil bath for 18 h. After the completion of the reaction, the
mixture was poured in water and extracted with 50 mL of
CH2Cl2 three times. The organic layer was collected and
dried over MgSO4. After filtration and evaporation of
CH2Cl2, the mixture was subjected to column chroma-
tography (silica gel, A: 30% heptane/CH2Cl2 or B: 100%
CH2Cl2/5% EtOAc/CH2Cl2).
4.8.5. 1-Benzyl-5-cyclohexylidenemethyl-3-methoxy-6-
phenyl-2(1H)-pyrazinone 14e. Yield: 60%; oil; H NMR
1
(CDCl3, 400 MHz): 7.38–6.79 (m, 10H, ArH), 5.33 (s, 1H,
HC]), 5.03 (s, 2H, CH2Ph), 2.74 (t, JZ6.1 Hz, 2H, CH2),
1.94 (t, JZ6.1 Hz, 2H, CH2), 1.58–1.47 (m, 6H, 3CH2); 13
C
NMR (CDCl3, 100 MHz): 153.8 (C2), 150.8 (C3), 145.5
(C]CH), 136.1, 131.2 (ArC-ipso), 131.5 (C6), 130.6,
129.0, 128.4, 128.1, 127.3, 127.2 (ArCH), 127.6 (C5), 1160.4
(CH]), 54.3 (OCH3), 48.7 (CH2Ph), 38.4 (C20), 29.9 (C6 ),
28.8, 27.7, 26.5 (CH2); EIMS m/z (%): 386 (MC, 55), 295
(–C7H7, 50), 91 (C7HC7 , 100); HRMS: C25H26N2O2,
calculated: 386.1994, found: 386.1993.
4.8.1. 1-Benzyl-3-methyl-6-phenyl-5-[(E)-2-phenylethe-
nyl]-2(1H)-pyrazinone 14a. Yield: 71%; oil; 1H NMR
(CDCl3, 300 MHz): 7.50–6.81 (m, 16H, ArH), 6.35 (d, JZ
16 Hz, 1H, HC]), 5.03 (s, 2H, CH2Ph), 2.65 (s, 3H, CH3);
13C NMR (CDCl3, 75 MHz): 157.0 (C2), 156.3 (C3), 137.7,
136.4, 131.4 (ArC-ipso), 130.1 (C6), 129.6 (HC]), 130.6,
129.6, 129.1, 128.9, 128.8, 127.9, 12.8, 127.5, 126.9
(ArCH), 127.8 (C5), 123.6 (HC]), 49.3(CH2Ph), 21.9
(CH3); EIMS m/z (%): 378 (MC, 100), 287 (–C7H7, 38), 91
(C7HC7 , 50); HRMS: C26H22N2O, calculated: 378.1732,
found: 378.1729.
Acknowledgements
The authors wish to thank the Johnson and Johnson
Pharmaceutical Research Foundation for financial support.
They are indebted to R. De Boer and Prof. S. Toppet for
mass and NMR measurements. WMDB (Postdoctoral
fellow of the FWO—Vlaanderen) thanks the FWO for the
fellowship received.
4.8.2. Methyl (2E)-3-(4-benzyl-6-methyl-5-oxo-3-phenyl-
4,5-dihydro-2-pyrazinyl)-2-propenoate 14b. Yield: 84%;
solid, mp: 141.5–142.2 8C; H NMR (CDCl3, 300 MHz):
1
References and notes
6.96 (d, JZ15 Hz, 1H, HC]), 7.51–7.02 (m, 8H, ArH),
6.81–6.78 (m, 2H, ArH), 6.76 (d, JZ15 Hz, 1H, HC]),
5.00 (s, 2H, CH2Ph), 3.66 (s, 3H, OCH3), 2.59 (CH3); 13C
NMR (CDCl3, 75 MHz): 168.0 (COO), 157.3 (C5), 156.4
(C6), 140.7 (C3), 139.7, 136.0 (ArC-ipso), 130.5 (HC]),
130.3, 130.2, 129.3, 128.8, 128.0, 127.5 (ArCH), 127.6
(C2), 118.6 (HC]), 51.8 (COOCH3), 49.4 (CH2Ph), 21.7
(CH3); EIMS m/z (%): 360 (MC, 65), 301 (–COOCH3, 16),
91 (C7HC7 , 100); HRMS: C22H20N2O3, calculated:
360.1474, found: 360.1464.
1. Hopkins, C. R.; Neuenschwander, K.; Scotese, A.; Jackson, S.;
Nieduzak, T.; Pauls, H.; Liang, G. Y.; Sides, K.; Cramer, D.;
Cairns, J.; Maignan, S.; Mathieu, M. Bioorg. Med. Chem. Lett.
2004, 14, 4819–4823.
2. Nantermet, P. G.; Barrow, J. C.; Newton, C. L.; Pellicore,
J. M.; Young, M. B.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.;
McMasters, D. R.; Yan, Y. W.; Kuo, L. C.; Vacca, J. P.;
Selnick, H. G. Bioorg. Med. Chem. Lett. 2003, 13, 2781–2784.
3. Chung, J. Y. L.; Cvetovich, R. J.; Tsay, F. R.; Dormer, P. G.;
DiMichele, L.; Mathre, D. J.; Chilenski, J. R.; Mao, B.;
Wenslow, R. J. Org. Chem. 2003, 68, 8838–8846.
4.8.3. 1-Benzyl-3-methoxy-6-phenyl-5-[(E)-2-phenyl-
ethenyl]-2(1H)-pyrazinone 14c. Yield: 71%; solid, mp:
148 8C; H NMR (CDCl3, 300 MHz): 7.46–6.80 (m, 16H,
1
4. Parlow, J. J.; Case, B. L.; Dice, T. A.; Fenton, R. L.; Hayes,
M. J.; Jones, D. E.; Neumann, W. L.; Wood, R. S.; Lachance,
R. M.; Girard, T. J.; Nicholson, N. S.; Clare, M.; Stegeman,
R. A.; Stevens, A. M.; Stallings, W. C.; Kurumbail, R. G.;
South, M. S. J. Med. Chem. 2003, 46, 4050–4062.
ArH), 6.34 (d, JZ15 Hz, 1H, HC]), 5.05 (s, 2H, CH2Ph),
4.16 (s, 3H, OCH3); 13C NMR (CDCl3, 75 MHz): 154.9
(C3), 151.9 (C2), 137.6, 136.3, 131.6 (ArC-ipso), 132.0
(C6), 129.6 (HC]), 131.2, 129.9, 129.0, 128.9, 128.7,

3962
R. Azzam et al. / Tetrahedron 61 (2005) 3953–3962
5. Young, M. B.; Barrow, J. C.; Glass, K. L.; Lundell, G. F.;
Compernolle, F.; Hoornaert, G. J. Tetrahedron 2003, 59,
5047–5054.
Newton, C. L.; Pellicore, J. M.; Rittle, K. E.; Selnick, H. G.;
Stauffer, K. J.; Vacca, J. P.; Williams, P. D.; Bohn, D.;
Clayton, F. C.; Cook, J. J.; Krueger, J. A.; Kuo, L. C.; Lewis,
S. D.; Lucas, B. J.; McMasters, D. R.; Miller-Stein, C.; Pietrak,
B. L.; Wallace, A. A.; White, R. B.; Wong, B.; Yan, Y. W.;
Nantermet, P. G. J. Med. Chem. 2004, 47, 2995–3008.
6. South, M. S.; Case, B. L.; Wood, R. S.; Jones, D. E.; Hayes,
M. J.; Girard, T. J.; Lachance, R. M.; Nicholson, N. S.; Clare,
M.; Stevens, A. M.; Stegeman, R. A.; Stallings, W. C.;
Kurumbail, R. G.; Parlow J. Bioorg. Med. Chem. Lett. 2003,
13, 2319–2325.
14. Kaval, N.; Bisztray, K.; Dehaen, W.; Kappe, C. O.; Van der
Eycken, E. Mol. Divers. 2003, 7, 125–134.
15. Achab, S.; Guyot, M.; Potier, P. Tetrahedron Lett. 1993, 34,
2127–2130.
16. Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979,
866–867.
17. Vandenberghe, S. M.; Buysens, K. J.; Meerpoel, L.; Loosen,
P. K.; Toppet, S. M.; Hoornaert, G. J. J. Org. Chem. 1996, 61,
304–308.
18. Loosen, P. K.; Tutonda, M. G.; Khorasani, M. F.;
Compernolle, F.; Hoornaert, G. J. Tetrahedron 1991, 47,
9259–9268.
7. Becker, J. W.; Rotonda, J.; Soisson, S. M.; Aspiotis, R.; Bayly,
C.; Francoeur, S.; Gallant, M.; Garcia-Calvo, M.; Giroux, A.;
Grimm, E.; Han, Y. X.; McKay, D.; Nicholson, D. W.;
Peterson, E.; Renaud, J.; Roy, S.; Thornberry, N.; Zamboni, R.
J. Med. Chem. 2004, 47, 2466–2474.
19. Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh,
M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314–321.
20. Ishiyama, T.; Miyaura, N.; Suzuki, A. Synlett 1991, 687–688.
21. Nomoto, Y.; Miyaura, N.; Suzuki, A. Synlett 1992, 727–729.
22. Buysens, K. J.; Vandenberghe, D. M.; Toppet, S. M.;
Hoornaert, G. J. J. Chem. Soc., Perkin Trans. 1 1996, 231–237.
23. Vanchuyen, N.; Kurata, T.; Fujimaki, M. Agr. Biol. Chem.
1973, 37, 327–334.
8. Miyazaki, A.; Tsuda, Y.; Tachibana, Y.; Yokoi, T.; Bryant,
S. D.; Lazarus, L. H.; Keri, G.; Okada, Y. Biopolymers 2003,
71, 367.
9. Jinsmaa, Y.; Miyazaki, A.; Fujita, Y.; Li, T. Y.; Fujisawa, Y.;
Shiotani, K.; Tsuda, Y.; Yokoi, T.; Ambo, A.; Sasaki, Y.;
Bryant, S. D.; Lazarus, L. H.; Okada, Y. J. Med. Chem. 2004,
47, 2599–2610.
24. Littke, A. F.; Dai, C. Y.; Fu, G. C. J. Am. Chem. Soc. 2000,
122, 4020–4028.
10. Jinsmaa, Y.; Okada, Y.; Tsuda, Y.; Sasaki, T. Y.; Ambo, A.;
Bryant, S. D.; Lazarus, L. H. Biopolymers 2003, 71, 371.
11. Jinsmaa, Y.; Okada, Y.; Tsuda, Y.; Shiotani, K.; Sasaki, Y.;
Ambo, A.; Bryant, S. D.; Lazarus, L. H. J. Pharmacol. Exp.
Ther. 2004, 309, 432–438.
25. Aoyagi, Y.; Fujiwara, T.; Ohta, A. Heterocycles 1991, 32,
2407–2415.
26. Buysens, K. PhD Thesis, K. U. Leuven 1996.
27. Tutonda, M.; Vanderzande, D.; Hendrickx, M.; Hoornaert, G.
Tetrahedron 1990, 46, 5715–5732.
12. Azzam, R.; De Borggraeve, W.; Compernolle, F.; Hoornaert,
G. J. Tetrahedron Lett. 2004, 45, 1885–1888.
13. Rogiers, J.; De Borggraeve, W. M.; Toppet, S. M.;
28. Buysens, K. J.; Vandenberghe, D. M.; Hoornaert, G. J.
Tetrahedron 1996, 52, 9161–9178.