New routes for the synthesis of 3- and 5-substituted 2(1H)-pyrazinones

Article abstract of DOI:10.1016/j.tetlet.2004.01.017

Various 3-(hetero)aryl, 3-alkyl and 3-alkenyl-2(1H)-pyrazinones were prepared by applying the Suzuki and Heck reaction methodology to 3,5-dichloro-2(1H)-pyrazinones. Furthermore, following hydrogenolysis of the 5-chloro substituent and regioselective 5-br

Full text of DOI:10.1016/j.tetlet.2004.01.017

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1885–1888
New routes for the synthesis of 3- and 5-substituted
2(1H)-pyrazinones
Rasha Azzam, Wim De Borggraeve, Frans Compernolle* and Georges J. Hoornaert
Laboratorium voor Organische Synthese, K.U. Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Received 28 November 2003; revised 23 December 2003; accepted 5 January 2004
Abstract—Various 3-(hetero)aryl, 3-alkyl and 3-alkenyl-2(1H)-pyrazinones were prepared by applying the Suzuki and Heck reaction
methodology to 3,5-dichloro-2(1H)-pyrazinones. Furthermore, following hydrogenolysis of the 5-chloro substituent and regio-
selective 5-bromination, this palladium-catalysed cross-coupling approach could be extended to the synthesis of the analogous
5-substituted 2(1H)-pyrazinones.
Ó 2004 Elsevier Ltd. All rights reserved.
R1
The 2(1H)-pyrazinone ring system can be utilised as a
scaffold to introduce an assembly of pharmacophoric
groups designed to fit the active site of a receptor or
enzyme. Specifically, this scaffolding strategy has been
applied for the construction of inhibitors of HIV reverse
transcriptase.1 Pyrazinones 1a and 1b are well-recogni-
sed ligands that bind to a new site on the GABAA/
chloride ionophore complex.2 Pyrazinones 2 bearing
various ortho-substituted phenylsulfonylurea groups at
the C-3 position display selective herbicidal and growth-
regulating properties.3 On the other hand, 2(1H)-pyr-
azinones such as 3 that are substituted with alkyl amino
groups at the C-3 position are useful inhibitors of
thrombin and associated thrombotic occlusions.4;5
Other 2(1H)-pyrazinones bearing substituted alkyl
groups at N-1 and alkyl and phenyl groups at C-3 show
an inhibitory action on platelet aggregation, vasodilat-
ing activity and/or inhibitory action on lipoperoxide
generation.6 Finally, polysubstituted pyrazinone deriv-
atives such as 4 and 5 have been found useful in the
treatment of various CRF (corticotrophin releasing
factor)-related disorders,7 and a variety of neurodegen-
erative and stress-related disorders.8
CH3
N
R6
Cl
N
O
O
O
O
S
N
Cl
Cl
N
N
H
N
O
R
H
1a: R1=Bn, R6=2-chlorophenyl
1b: R1=2-furylmethyl, R6=Ph
2: R=COOCH3, OC2H5, SO2N(CH3)2
O
CH3
N
O
N
N
O
N
H3C
N
N
R
N
NH2
Cl
N
H
OCH3
4: R=Cl, Br, H, alkyl
3
R1
5: R1=Et2CH, CH(CH3OCH2)2,
R5= Cl, CN, Br, alkyl,
Y=NH, NEt, O, S,
N
O
.
Ar
R5
N
Y
Ar=phenyl, pyridyl, pyrimidinyl
Therefore, major interest centres around developing new
routes for the introduction of more challenging sub-
stituents, for example, alkenyl and heteroaryl groups, at
the reactive C-3 position and especially at the less
accessible C-5 position of 2(1H)-pyrazinones. In this
respect, Suzuki and Heck cross-coupling using organo-
boron reagents or vinyl compounds could offer an
interesting route for introduction of a variety of (het-
ero)aryl and vinyl groups.
Keywords: 3- and 5-Substituted 2(1H)-pyrazinones; Heterocyclic com-
pounds; Suzuki reaction; Heck reaction.
* Corresponding author. Tel.: +32-16-32-74-07; fax: +32-16-32-79-90;
e-mail: frans.compernolle@chem.kuleuven.ac.be
Present address: Department of Chemistry, Helwan University, Ain-
Helwan, Cairo, Egypt, 11795.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.017

1886
R. Azzam et al. / Tetrahedron Letters 45 (2004) 1885–1888
Table 1. Suzuki-coupling of (hetero)arylboronic acid at C-3 of 2(1H)-
pyrazinones 6a,b to form 3-(hetero)aryl-5-chloro-2(1H)-pyrazinones
7a–c
situ by adding 9-BBN in THF to a THF solution of
some representative alkenes under an argon atmosphere.
The mixture was stirred for 6 h at room temperature,
and 2(1H)-pyrazinone, Pd(dppf)Cl2 and aq NaOH were
added. After reaction at room temperature overnight,
complete conversion into 3-substituted products 8a,b
was observed.
R1
N
R1
N
R3-B(OH)2
R6
Cl
O
R6
Cl
O
Pd(PPh3)4, aq. Na2CO3
toluene or DME, reflux
R3
N
Cl
N
6a,b
7a-c
From the results displayed, it appears that primary
alkyl-9-BBN reagents having either a single (phenyl) or
double (cyclohexyl branching) substitution at the b-po-
sition of the alkyl group attached to boron, all react well
with 3,5-dichloro-2(1H)-pyrazinone 6b to give the cor-
responding products 8a,b in good yields. However, no
coupling was observed for the reaction of 6b with the
secondary cyclopentyl-9-BBN reagent prepared from
cyclopentene.
R1
R3
R6
Solvent
Toluene
Yield (%)
92
7a
7b
Ph
Ph
CH3
Bn
Ph
Toluene
Toluene
65
70
OCH3
CHO
7c
Bn
Ph
S
Applying the Heck reaction to 3,5-dichloro-2(1H)-pyr-
azinones provides a direct method for preparing the
corresponding 3-alkenyl derivatives. Thus reaction of 6b
with various alkenes afforded 3-alkenyl products 9a–d in
good yield (Table 3). The best conditions consisted of
using 3 mol % of Pd(OAc)2, 7 mol % of tri-o-tolylphos-
phine and 2 equiv of triethylamine in DMF at 100 °C.
Less satisfactory results or no conversion at all were
observed when replacing DMF with acetonitrile.
We studied the cross-coupling reaction of (hetero)aryl-
boronic acids with 3,5-dichloro-2(1H)-pyrazinones with
the intention of introducing groups different from those
obtained previously by using organotin reagents.9 As
seen before for the Stille reaction, the initial oxidative
addition occurs preferentially at the more reactive C-3
position (Table 1). We chose coupling conditions that
were optimised previously for the Suzuki coupling of p-
deficient heteroaryl chlorides.10;11 The best results were
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. Both styrene and methyl acrylate reacted
in the expected way to produce 9a and 9b in 80% and
75% yields, respectively. A lower yield was observed for
the reaction of 6b with cyclohexene. The reaction of 6b
with ethyl vinyl ether afforded an unstable enol ether
product 9c, which was isolated in 87% yield by flash
column chromatography. The (E)-configuration of the
double bond was established by the magnitude of the
coupling constant between the two vinylic protons in
9a,b (16 Hz) and in the enol ether product 9c (12 Hz).
obtained
using
tetrakis(triphenylphosphine)palla-
dium(0) as a catalyst, aqueous Na2CO3 as base and
toluene as solvent. Thus reaction of pyrazinones 6a12
and 6b13 with 1.2 equiv of (hetero)arylboronic acids and
3 mol % of Pd(PPh3)4 in toluene under reflux overnight
produced 3-aryl-2(1H)-pyrazinones 7a,b and the corre-
sponding 3-thienyl product 7c in good yields. After
completion of the reaction and usual workup, the
mixture was subjected to column chromatography to
remove Ph3PO.
We also investigated the cross-coupling reaction of 3,5-
dichloro-2(1H)-pyrazinone 6b and some alkyl-9-BBN
derivatives (Table 2).14–16 The latter were prepared in
In contrast to the easy addition–elimination reaction of
the 3-imidoyl chloride function, analogous substitution
at the C-5-chloro position of 3,5-dichloro-2(1H)-pyrazi-
nones appears difficult. Substitution of this group has
Table 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,b
Table 3. Heck reaction at the C-3 position of 2(1H)-pyrazinone 6b to
form 3-vinyl-5-chloro-2(1H)-pyrazinones 9a–d
R'
THF, RT
BH
B
+
Bn
N
R"
Bn
N
R
R1
"R
R'
Ph
Cl
O
R
Ph
Cl
O
N
R1
Bn
N
Bn
N
N
Cl
Pd(OAc)2, P(o-tolyl)3,
Ph
Cl
O
Ph
Cl
O
Pd(dppf)Cl2,
Et3N, DMF, 100 °C
B
9a-d
+
6b
aq. NaOH,
THF, RT
N
Cl
N
"R
R'
R
R1
AcCN
yield (%)
DMF
yield (%)
"R
8a,b
R'
6b
9a
9b
9c
9d
H
H
H
Ph
CO2CH3
OC2H5
60
50
––
––
80
75
87
50
R0
H
R00
Ph
Yield (%)
8a
8b
60
80
–CH2(CH2)3CH2–
–CH2(CH2)2CH2–

R. Azzam et al. / Tetrahedron Letters 45 (2004) 1885–1888
1887
R1
Table 4. 5-Bromination of 2(1H)-pyrazinones
R1
N
R5
R6
O
O
HN
O
R6
R5
O
R1
N
R1
N
Base
R1
N
R6
H
O
R6
Br
O
+
R6
Cl
O
NBS
DMF
H2,Pd/C
MeOH
H2N
R3
N
R3
N
OMe
N
OMe
N
OMe
Scheme 1. Synthesis of 5-alkyl and 5-aryl-2(1H)-pyrazinones.
11a-c
12a-c
10a-c
Starting
compound
Product 12
R1
R6
H
Yield (%)
been achieved only in an indirect way via isomerisation
of 6-alkyl- or 6-benzyl-5-chloro-3-methoxy-2(1H)-pyr-
azinones to form the tautomeric 6-alkylidene/benzylid-
ene-5-chloro-3,6-dihydropyrazin-2(1H)-ones having a
reactive 5-imidoyl chloride group: subsequent reaction
with organotin reagents or amines then produced the
corresponding 5-alkyl/aryl or 5-amino-6-alkylidene/benz-
ylidene-3,6-dihydropyrazin-2(1H)-ones, respectively.17
11a
11b
11c
12a
12b
12c
Bn
Ph
Bn
75
73
82
CH3
Ph
attached protons (1J) and to coupling with 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 3J ¼ 5 and 3 Hz, which can be related
to the coupling of C-2 with H-6 and the methylene
protons of the N-benzyl group. The carbon atom C-5
attached to the Br-atom appears as a doublet (d,
2J ¼ 2:5 Hz) at d 78.7 ppm, due to coupling with H-6.
Carbon C-6 in turn is detected as a doublet of triplets
2(1H)-Pyrazinones bearing a 5-alkyl substituent (and
their 5-H analogues) can also be obtained directly by
base-catalysed condensation of 1,2-dicarbonyl com-
pounds with various a-amino N-substituted carbox-
amide derivatives (Scheme 1).18 However, this reaction
is useful only for equal substituents R5 and R6, since a
mixture of regioisomeric pyrazinones is produced when
R5 and R6 are different.
1
3
(dt) with J ¼ 189 Hz and J ¼ 4:6 Hz, due to coupling
with H-6 and the methylene protons of the N-benzyl
group.
The easy access to 3-substituted 5-chloropyrazinones
prompted us to apply the Suzuki-coupling methodology
firstly to these compounds. However, using Pd(PPh3)4
catalyst and aq Na2CO3 in either toluene or DME at
reflux failed to produce the corresponding 5-aryl-2(1H)-
pyrazinones. Other conditions involving the use of
Pd2(dba)3, combined with P(t-Bu)3 and CsF or KF in
THF or dioxane, that is, the conditions used for the
synthesis of biaryl compounds starting from an aryl
chloride,19 were also unsuccessful. Therefore we turned
our attention to the corresponding 5-bromo-2(1H)-
pyrazinones to introduce the desired 5-aryl/alkyl sub-
stituents.
In a preliminary study concerning the application of the
5-bromo-2(1H)-pyrazinones in palladium-catalysed
coupling reactions, we examined the cross-coupling of
12b with some representative boronic acids and alkenes.
Suzuki coupling (Table 5) of 12b with phenylboronic
acid and 3-thienylboronic acid was carried out using aq
Na2CO3 and Pd(PPh3)4 and went to completion after
heating in toluene or DME at reflux for 18 h. The yields
of these coupling procedures were 94% and 55%. Similar
cross-coupling of 12b with (E)-2-phenylethenyl-boronic
acid in DME afforded compound 13c in 95% yield.
To our knowledge, the synthesis of 3-substituted 5-
bromo-2(1H)-pyrazinones possessing various substitu-
ents at the N-1 position has not yet been reported.
However, 3,6-disubstituted 5-halo-2-pyrazinols have
been prepared by halogenation at the C-5 position of the
corresponding 2-pyrazinols.20 Accordingly, we exam-
ined the analogous C-5 bromination of 1-Bn and 1-Ph
substituted pyrazinones 11a–c. Following hydrogenoly-
sis of 10a–c, effected by using a 10% Pd/C catalyst in
methanol,21 the resulting 5-dechlorinated compounds
11a–c were subjected to treatment with N-bromosuc-
cinimide in DMF (Table 4). Bromination with NBS
proceeded at room temperature in the dark and was
complete within 1 h. Bromine was introduced selectively
at the C-5 position, even when R6 ¼ H. Presumably
electrophilic attack at C-5 is facilitated by delocalisation
of the lone pair on N-1.
The Heck reaction of 5-bromo-2(1H)-pyrazinone 12c
with styrene, methyl acrylate and cyclohexene was car-
ried out in a similar manner to that described above for
3-chloro-2(1H)-pyrazinones. Thus treatment of 12c with
Table 5. Suzuki cross-coupling reaction of (hetero)aryl- and
1-alkenylboronic acid with 5-bromo-2(1H)-pyrazinone 12b
Ph
N
Ph
N
R5-B(OH)2
Me
R5
O
Me
Br
O
, Pd(PPh3)4, aq. Na2CO3
toluene or DME, reflux
N
OMe
N
OMe
13a-c
12b
Product
R5
Ph
Yield (%)
94
13a
1
The position of the 5-Br substituent was verified by H-
1
13b
13c
55
95
coupled 13C NMR analysis of 12a. In this H-coupled
spectrum, the methylene C-atom of the N-benzyl group
S
1
appears as a triplet of quartets (tq) with J ¼ 284:8 Hz
Ph
and 3J ¼ 3:2 Hz: these are due to coupling with two

1888
R. Azzam et al. / Tetrahedron Letters 45 (2004) 1885–1888
Table 6. Heck-coupling of 5-bromopyrazinone 12c with alkenes
Johnson Pharmaceutical Research Foundation for
financial support. They are indebted to R. De Boer and
Prof. S. Toppet for mass and NMR measurements.
Bn
N
Bn
N
Ph
Br
O
Ph
O
R
Pd(OAc)2
R
+
P(o-tolyl)3, Et3N
R'
N
OMe
R'
N
OMe
DMF, 100 o
C
12c
14a-c
References and notes
R
R0
Yield (%)
1. Jones, J. UK Patent GB 2266716, 1993; Chem. Abstr.
1993, 120, 217735.
2. Im, K.; Im, B.; Judge, M.; Gammill, B.; Hamilton, J.;
Carter, B. Mol. Pharm. 1993, 44, 468.
14a
14b
14c
H
H
Ph
CO2CH3
71
66
60
–CH2(CH2)3CH2–
3. Boehner, B.; Meyer, W. US 4,940,482, 1990; Chem. Abstr.
1991, 114, 42813.
4. Sanderson, P.; Lyle, T.; Dorsey, B.; Varsolona, R. Patent
Application PCT/US97/06744; WO 97/40024, 1997; Chem.
Abstr. 1997, 127, 248015.
5. 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.
6. Yaso, M.; Suzuki, Y.; Shibata, K.; Hayashi, E. Jpn. Kokai
Tokkyo Koho JP 62,198,671, 1987; Chem. Abstr. 1988,
108, 167500.
7. Arvanitis, A.; Gilligan, P.; Hartz, R. Patent Application
PCT/US02/15493; WO 02/092090, 2002; Chem. Abstr.
2002, 137, 370110.
8. Arvanitis, A.; Olson, R.E.; Arnold, C.; Frietze, W. Patent
Application PCT/US97/16252; WO 98/11075, 1998; Chem.
Abstr. 1998, 128, 2440463.
9. Roegiers, J.; De Borggraeve, W. M.; Toppet, S. M.;
Compernolle, F.; Hoornaert, G. J. Tetrahedron 2003, 59,
5047.
3 mol % of Pd(OAc)2, 7 mol % of tri-o-tolylphosphine
and 2 equiv of triethylamine in DMF at 100 °C was
found to be the most effective for conversion into the
corresponding 5-substituted alkenyl-2(1H)-pyrazinones
14a–c (Table 6).
Obviously, 5-boronic acid or 5-boronate ester deriva-
tives of 3-substituted 2(1H)-pyrazinones would be very
useful as a common intermediate in reverse cross-cou-
pling reactions with various hetero(aryl) and alkenyl
halides. Therefore cross-coupling of 5-bromo-2(1H)-
pyrazinones 12b and tetra(alkoxo)diborons was
attempted using conditions that were previously optimised
for preparing pinacol arylboronates, that is, 1.1 equiv of
bis(pinacolato)diboron, 3 mol % of Pd(dba)2, 3.3 mol % of
P(t-Bu)3 and 3 equiv of KOAc in dioxane at 80 °C.22
However, this procedure failed when applied to 5-bromo-
2(1H)-pyrazinone 12b, and only starting material was
recovered from the reaction mixture.
10. Achab, S.; Guyot, M.; Potier, P. Tetrahedron Lett. 1993,
34, 2127.
Conclusion
11. Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun.
1979, 866.
12. Vandenberghe, D.; Buysens, K.; Meerpoel, L.; Loosen, P.;
Toppet, S.; Hoornaert, G. J. Org. Chem. 1996, 61, 304.
13. Loosen, P.; Tutonda, M.; Khorasani, M.; Compernolle,
F.; Hoornaert, G. Tetrahedron 1991, 47, 9259.
14. Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.;
Satoh, M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314.
15. Ishiyama, T.; Miyaura, N.; Suzuki, A. Synlett 1991, 687.
16. Nomoto, Y.; Miyaura, N.; Suzuki, A. Synlett 1992, 727.
17. Buysens, K.; Vandenberghe, D.; Toppet, S.; Hoornaert,
G. J. Chem. Soc., Perkin Trans. 1 1996, 231.
18. Chuyen, N.; Kurata, T.; Fujimaki, M. Agric. Biol. Chem.
1973, 37, 327.
Palladium-catalysed Suzuki and Heck reactions of 3-
chloro- and 5-bromo-2(1H)-pyrazinones were used suc-
cessfully to introduce (hetero)aryl, alkenyl and alkyl
groups at both C-3 and C-5. The required 5-bromo-
pyrazinone precursors were prepared via dechlorination
followed by electrophilic substitution at C-5. In future
work, this approach will be extended to include palla-
dium-catalysed cross-coupling reactions of other pyr-
azinones, for example, 5-iodo-2(1H)-pyrazinones, and
more extensive boronate or alkene reaction partners.
19. Littke, A.; Dai, C.; Fu, G. J. Am. Chem. Soc. 2000, 122,
4020.
20. Aoyagi, Y.; Fujiwara, T.; Ohta, A. Heterocycles 1991, 32,
2407.
Acknowledgements
21. Buysens, K. Ph.D Thesis, K. U. Leuven, 1996.
22. Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001,
57, 9813.
The authors wish to thank the FWO (Fund for Scientific
Research, Flanders, Belgium) and the Johnson &