Microwave-assisted palladium-catalyzed phosphonium coupling of 2(1H)-pyrazinones

Article abstract of DOI:10.1021/jo9024754

(Chemical Equation Presented) An expedient route for the synthesis of differently substituted 2(1H)-pyrazinones applying a microwave-assisted palladium-catalyzed phosphonium coupling procedure is reported.The method has also beensuccessfullyextended to some other tautomerizable heterocycles for efficient C-C cross-coupling.

Full text of DOI:10.1021/jo9024754

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other with the aid of a suitable catalyst. Recently Kang et al.
Microwave-Assisted Palladium-Catalyzed
Phosphonium Coupling of 2(1H)-Pyrazinones
disclosed the palladium-catalyzed cross-coupling reaction
of boronic acids with tautomerizable heterocycles via C-OH
bond activation using phosphonium salts as activating
agents.6 Pursuant to our long-standing interest in the synth-
esis and decoration of the 2(1H)-pyrazinone scaffold7
and to our recently described novel and versatile protocol
for the generation of asymmetrically tetrasubstituted pyra-
zines8 starting from 2(1H)-pyrazinones, we envisaged that
successive C-OH bond activation6c,d of this tautomerizable
heterocycle, followed by palladium-catalyzed cross-coupling,
would allow the generation of variously substituted pyrazines.
To evaluate this hypothesis, test reactions were carried out
using 5-chloro-3-methoxy-6-methylpyrazin-2(1H)-one (1a) as
model substrate with p-tolylboronic acid (2a) (Table 1). Using
the conditions previously described by Kang et al.,6a the
reaction was performed with (benzotriazol-1-yloxy)tripyrro-
lidinophosphonium hexafluorophosphate (PyBOP) as phos-
phonium coupling reagent under conventional heating condi-
tions. A mixture of pyrazinone 1a (0.25 mmol), PyBOP
(1.1 equiv), and Et3N (2 equiv) in 1,4-dioxane (2 mL) was
stirred at room temp for 2 h. Then, Pd(PPh3)2Cl2 (5 mol %),
p-tolylboronic acid (2 equiv), Na2CO3 (2 equiv), and water
(1 mL) were added, and the mixture was stirred in a sealed tube
at 100 °C for 2 h (Table 1, entry 1). However, only the undesired
C2,C5-disubstituted compound 5a together with the C5-mono-
substituted pyrazine 4a were detected in the reaction mixture
(GC-MS analysis). Although our first attempt met with failure,
this result clearly indicates that the cross-coupling seems to be
feasible with the 2(1H)-pyrazinone system. The C5-chlorine
is far less reactive compared to the C3-chlorine of the 3,5-
dichloro-2(1H)-pyrazinone system,7a but it becomes suscepti-
ble to palladium-catalyzed Suzuki cross-coupling reaction once
the pyrazine system of 3a is formed, as we have previously
demonstrated.8 This explains the easy formation of the disub-
stituted 5a as soon as 3a is formed. To circumvent this problem
the number of equivalents of the p-tolylboronic acid (2a) was
decreased from 2.0 to 1.05 equiv (Table 1, entry 3). Gratifyingly
this resulted in the formation of the desired C2-monosubsti-
tuted pyrazine 3a in a moderate yield of 65%, together with
traces of the disubstituted compound 5a. When switching from
PyBOP to bromotripyrrolidinophosphonium hexafluorophos-
phate (PyBroP), 3a could be obtained with an excellent yield of
84%, although we were not able to fully suppress the formation
Vaibhav P. Mehta, Sachin G. Modha, and
Erik V. Van der Eycken*
Laboratory for Organic & Microwave-Assisted Chemistry
(LOMAC), Department of Chemistry, University of Leuven,
Celestijnenlaan 200F, B-3001 Leuven, Belgium
erik.vandereycken@chem.kuleuven.be
Received November 19, 2009
An expedient route for the synthesis of differently sub-
stituted 2(1H)-pyrazinones applying a microwave-assisted
palladium-catalyzed phosphonium coupling procedure is
reported. The method has also been successfully extended to
some other tautomerizable heterocycles for efficient C-C
cross-coupling.
Transition-metal-catalyzed cross-coupling reactions are
nowadays indispensable tools for C-C1 and C-hetero-
atom2 bond formation, being particularly useful for the
synthesis of diversely functionalized heterocycles. Organic
(pseudo)halides3 and organometallic reagents4,5 as electro-
philes and nucleophiles, respectively, are reacted with each
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Palladium Reagents and Catalysts: Innovations in Organic Synthesis; Wiley:
Chichester, 1995. (d) F€urstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41,
609 and references therein. (e) Duplais, C.; Bures, F.; Sapountzis, I.; Korn, T. J.;
Cahiez, G.; Knochel, P. Angew. Chem. 2004, 116, 3028. Angew. Chem., Int. Ed.
2004, 43, 2968. (f) Bolm, C.; Legros, J.; Paih, J, Le.; Zani, L. Chem. Rev. 2004,
104, 6217. (g) Tsuji, J. In Palladium in Organic Synthesis: Topics in Organo-
metallic Chemistry; Springler: New York, 2005. (h) Taillefer, M.; Xia, N.; Ouali,
A. Angew. Chem., Int. Ed., 2007, 47, 934 and references therein. (i) Sherry,
B. D.; Furstner, A. Acc. Chem. Res. 2008, 41, 1500.
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(c) Ackermann, L.; Mulzer, M. Org. Lett. 2008, 10, 5043. (d) Luo, Y.; Wu, J.
Tetrahedron 2009, 65, 6810.
(7) (a) Kaval, N.; Bisztray, K.; Dehaen, W.; Kappe, C. O.; Van der
Eycken, E. Mol. Diversity 2003, 7, 125. (b) Topics in Heterocyclic Chemistry;
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p 267. (c) Kaval, N.; Singh, B. K.; Ermolat'ev, D. S.; Claerhout, S.; Van der
Eycken, J.; Van der Eycken, E. J. Comb. Chem. 2007, 9, 446. (d) Singh, B. K.;
Mehta, V. P.; Parmar, V. S.; Van der Eycken, E. Org. Biomol. Chem. 2007, 5,
2962. (e) Sharma, A.; Mehta, V. P.; Van der Eycken, E. Tetrahedron 2008, 64,
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Published on Web 12/29/2009
DOI: 10.1021/jo9024754
r
2009 American Chemical Society

Mehta et al.
JOCNote
TABLE 1. Optimization of the Tautomerization-Activation-Coupling of 5-Chloro-3-methoxy-6-methylpyrazin-2(1H)-one (1a) with p-Tolylboronic Acid (2a)a
entry
reaction conditions (equiv of reagents)a
method
yield (%) 3a
ratio (4a/5a)b
1
2
3
4
5
6
7
8
9
PyBOP (1.1), Et3N (2.0), 2a (2.0), Pd(PPh3)2Cl2 (0.05), Na2CO3 (2.0)
PyBOP (1.1), Et3N (2.0), 2a (1.2), Pd(PPh3)2Cl2 (0.05), Na2CO3 (2.0)
PyBOP (1.1), Et3N (2.0), 2a (1.05), Pd(PPh3)2Cl2 (0.05), Na2CO3 (2.0)
PyBroP (1.1), Et3N (2.0), 2a (1.05), Pd(PPh3)2Cl2 (0.05), Na2CO3 (2.0)
PyBroP (1.1), Et3N (2.0), 2a (1.05), Pd(PPh3)4 (0.05), Na2CO3 (2.0)
PyBrOP (1.1), Et3N (2.0), 2a (1.05), Pd(PPh3)2Cl2 (0.05), Na2CO3 (2.0)
PyBroP (1.1), Et3N (2.0), 2a (1.05), Pd(PPh3)2Cl2 (0.05), Na2CO3 (2.0)
PyBroP (1.1), Et3N (2.0), 2a (1.05), Pd(PPh3)2Cl2 (0.05), Na2CO3 (2.0)
PyBroP (1.1), Et3N (2.0), 2a (1.05), Pd(PPh3)2Cl2 (0.05), K2CO3 (2.0)
A
A
A
A
A
Bc
Bd
B
trace
54
65
84
79
43
59
82
81
10/60
-/30
-/14
2/10
-/15
10/30
10/20
3/7
B
-/9
aReaction conditions. Method A: 1a (0.25 mmol, 1.0 equiv), phosphonium salt (0.275 mmol, 1.1 equiv), Et3N (0.50 mmol, 2.0 equiv), 1,4-dioxane
(2 mL), rt, 2 h; then 2a (0.262-0.50 mmol, 1.05-2.0 equiv), Pd catalyst (5 mol %), base (0.50 mmol, 2.0 equiv), H2O (1 mL), 100 °C, 2 h. Method B: 1a (0.25
mmol, 1.0 equiv), phosphonium salt (0.275 mmol, 1.1 equiv), Et3N (0.50 mmol, 2.0 equiv), 1,4-dioxane (2 mL), MW, 65 °C, 10 W, 25 min; then 2a (0.262-0.50
mmol, 1.05-2.0 equiv), Pd catalyst (5 mol %), base (0.50 mmol, 2.0 equiv), H2O (1 mL), MW, 85 °C, 15 W, 30 min.; bThe ratio 4a/5a was determined by
d
GC-MS analysis. cMW, 65 °C, 10 W, 10 min; then MW, 80 °C, 20 W, 10 min. MW, 65 °C, 10 W, 20 min; then MW, 80 °C, 25 W, 10 min. [PyBOP =
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; PyBroP = bromotripyrrolidinophosphonium hexafluorophosphate]
of the disubstituted compound 5a as was indicated by GC-MS
analysis (Table 1, entry 4). Replacing the Pd(PPh3)2Cl2 catalyst
by Pd(PPh3)4, no significant changes in product distribu-
tion were noticed (Table 1, entry 5). Next we investigated the
application of microwave irradiation. A mixture of pyrazinone
1a (0.25 mmol), PyBroP (1.1 equiv), and Et3N (2 equiv) in
1,4-dioxane (2 mL) was irradiated at a ceiling temperature of
65 °C and a maximum power of 10 W for 10 min. Then, Pd-
(PPh3)2Cl2 (5 mol %), p-tolylboronic acid (1.05 equiv),
Na2CO3 (2 equiv), and water (1 mL) were added, and the
mixture was irradiated at a ceiling temperature of 80 °C and a
maximum power of 20 W for 10 min (Table 1, entry 6). The
mono cross-coupled compound 3a was obtained in 43% yield
along with a mixture of 4a/5a in a ratio of 10/30 according to
GC-MS analysis. The optimal conditions were obtained by
increasing the irradiation time of the first step to 25 min and
that of the second step to 30 min at a slightly higher temperature
of 85 °C (Table 1, entry 8). The desired product 3a was obtained
in 82% yield along with a mixture of 4a/5a in a ratio of 3/7 as
indicated by GC-MS analysis.
We next explored the scope of this protocol. An array of
substituted 2(1H)-pyrazinones 1a-h (Table 2) were reacted
with various aryl or (hetero)aryl boronic acids 2a-q using
our optimized conditions. In all cases the mono- and/or the
C2,C5-disubstituted cross-coupled product was formed. For
the substrates bearing a methoxy or amino butyl group at the
C3-position, the corresponding C2-monosubstituted pro-
duct was predominantly formed (Table 2, entries 1-7 and
16-19, with the exception of 7 and 17). The 2(1H)-pyrazi-
nones bearing a 4-tolyl- or styryl substituent in the C3-
position tend to give the disubstituted product (Table 2,
entries 8-15, with the exception of 10 and 11). Substrates
bearing an -SPh or -NH2 at the C3-position were less
successful by applying these conditions (Table 2, entries 21
and 22).
TABLE 2. Evaluation of the Scope of the Optimized Tautomerization-
Activation-Couplinga
entry
R3
OMe
OMe
OMe
OMe
OMe
OMe
OMe
4-tolyl
4-tolyl
4-tolyl
4-tolyl
styryl
R6
R2
yield (3:4:5) (%)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
H
5-Me-thiophene-2-
4-MeO-C6H4
2,4-diCl-C6H3
4-COCH3-C6H4
2-F-C6H4
4-COOEt-C6H4
3-MeO-C6H4
4-MeO-C6H4
4-COCH3-C6H4
3-CF3-C6H4
85/0/5
84/0/10
94/0/0
82/0/10
74/0/12
54/0/29
12/0/69
0/0/64
9
0/0/59
72/0/9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
b
4-N(CH3)2-C6H4
4-CN-C6H4
0/0/48
0/0/54
0/0/45
0/0/64
styryl
styryl
styryl
4-COOEt-C6H4
2-BnO-C6H4
4-tBu-C6H4
NH-nBu
NH-nBu
NH-nBu
NH-nBu
4-MeO-Ph
S-Ph
3,5-diMe-C6H3
3-CHO-thiophene-2-
4-CONH2-C6H4
4-tBu-C6H4
2-F-C6H4
4-EtO-C6H4
85/0/10
c
62/0/15
92/0/0
trace/60/20
c
H
c
NH2
Ph
4-MeO-Ph 4-MeO-C6H4
4-MeO-Ph 4-EtO-C6H4
d
aReaction conditions. 1a-h (0.25 mmol, 1.0 equiv), PyBroP (0.275
mmol, 1.1 equiv), Et3N (0.50 mmol, 2.0 equiv), 1,4-dioxane (2 mL), MW,
65 °C, 10 W, 25 min; then 2a-q (0.262 mmol, 1.05 equiv), Pd(PPh3)2Cl2
(5 mol %), Na2CO3 (0.50 mmol, 2.0 equiv), H2O (1 mL), MW, 85 °C,
15 W, 30 min. bSluggish reaction due to instability of the boronic acid.
cNo starting material or product were detected according to GC-MS
analysis due to sluggish reaction mixture. dOnly starting material 1h was
recovered after completion of the reaction.
We also evaluated the phosphonium-mediated Sonoga-
shira-Hagihara-type9 cross-coupling of 5-chloro-3-meth-
oxy-6-methylpyrazin-2(1H)-one 1a (Scheme 1). A mixture
of pyrazinone 1a (0.25 mmol), PyBroP (1.1 equiv), and Et3N
J. Org. Chem. Vol. 75, No. 3, 2010 977

Mehta et al.
JOCNote
SCHEME 1. Phosphonium-Mediated Sonogashira-Hagihara-
Type Cross-Coupling Reaction
TABLE 3. Application of the Optimized Phophonium Coupling for
Some Other Heterocyclesa
(2 equiv) in 1,4-dioxane (2 mL) was irradiated at a ceiling
temperature of 65 °C and a maximum power of 20 W for 25
min. Then, Pd(PPh3)2Cl2 (5 mol %), CuI (10 mol %), and p-
tolyl acetylene (20a) (1.1 equiv) in DMF (1 mL) were added, and
the mixture was irradiated at a ceiling temperature of 85 °C and a
maximum power of 15 W for 25 min. The corresponding mono-
alkynylated product 3t was obtained in 69% yield next to 5%
disubstituted alkynylated product 5t as determined by GC-MS
analysis (Scheme 1).
Having successfully established the optimized condition for
the pyrazinone scaffold, we next explored the scope of the
protocol for some other tautomerizable heterocycles.6b,10 We
selected the pyridazinone scaffold 6a as this is present in a wide
range of commercially important drugs and agrochemicals
such as the antiplatelet clotting agent Zardaverine, the anti-
inflammatory Emorfazone,11a and the COX-2 inhibitor ABT-
963,11b as well as the herbicide Norflurazon. Gratifyingly,
applying our optimized protocol, the corresponding arylated
products 6b-d were obtained in excellent yields starting
from 6a upon reaction with various boronic acids (Table 3,
entries 1-3). However, the arylation did not proceed when
2-bromo-phenylboronic acid was applied probably because of
steric hindrance (Table 3, entry 4). When 2-methylpyrimidine-
4,6-diol 7a was reacted with 2a, the corresponding disubsti-
tuted product 7b was obtained in 72% yield (Table 3, entry 5).
However, when the thymine derivative 8a or 6-amino-2-
methylpyrimidin-4(3H)-one 9a was used, the corresponding
cross-coupled product was not formed, and all starting material
was recovered (Table 3, entries 6 and 7). Similarly no reaction
occurred when 3-methyl-1H-pyrazol-5(4H)-one was used
(Table 3, entry 8).
aReaction conditions: 6a-10a (0.25 mmol, 1.0 equiv), PyBroP (0.275
mmol, 1.1 equiv), Et3N (0.50 mmol, 2.0 equiv), 1,4-dioxane (2 mL), MW,
65 °C, 10 W, 25 min; then 2 (0.275 mmol, 1.1 equiv), Pd(PPh3)2Cl2
(5 mol %), Na2CO3 (0.50 mmol, 2.0 equiv), H2O (1 mL), MW, 85 °C,
15 W, 30 min. bNo cross-coupled product was observed, and the
starting material was fully recovered. According to GC-MS analysis
no homocoupled boronic acid was formed during the reaction. cPyBroP
(0.55 mmol, 2.2 equiv), Et3N (0.50 mmol, 2.0 equiv), and 2a (0.55 mmol,
2.2 equiv) were used.
In conclusion, we have demonstrated that 2(1H)-pyrazi-
nones are good tautomerizable substrates for performing a
cross-coupling protocol through PyBroP-mediated, palladium-
catalyzed arylation. This efficient one-pot, two-step protocol
gives access to asymmetrically substituted pyrazines, although
symmetrical 2,5-disubstitution is difficult to control. We have
also demonstrated the applicability of the optimized protocol
for some other tautomerizable heterocycles.
0.25 mmol), PyBroP (128 mg, 0.275 mmol), Et3N (67 μL,
0.5 mmol), and 1,4-dioxane (2 mL). The reaction tube was
sealed and irradiated at a ceiling temperature of 65 °C using
10 W maximum power for 25 min. The reaction mixture was
cooled with an air flow for 3 min, and Pd(PPh3)2Cl2 (8.8 mg,
5 mol %), boronic acid 2a (36 mg, 0.262 mmol), Na2CO3 (53 mg,
0.5 mmol), and H2O (1 mL) were successively added. The
reaction tube was sealed again and irradiated at a ceiling
temperature of 85 °C using 15 W maximum power for 30 min.
The reaction mixture as cooled with an air flow. The mixture was
washed with brine (50 mL) and extracted with dichloromethane
(2ꢀ50 mL). The organic layer was dried over MgSO4, and
the solvent was removed under reduced pressure. The residue
was subjected to column chromatography over silica gel using
EtOAC/heptane (5:95) to afford the corresponding monosubsti-
tuted product 3a (51 mg) in 82% yield as a light yellow solid: mp
58-60 °C. Rf = 0.47. 1H NMR (300 MHz, CDCl3): δ 7.93-7.91
(d, J = 6.0 Hz, 2H), 7.26-7.24 (d, J = 6.0 Hz, 7H), 4.01 (s, 3H),
2.60 (s, 3H), 2.39 (s, 3H). 13C NMR (75 MHz, CDCl3): 155.3,
Experimental Section
Typical Procedure for the Microwave-Assisted Palladium-
Catalyzed Phosphonium Coupling. Synthesis of 2-Chloro-6-meth-
oxy-3-methyl-5-p-tolylpyrazine, 3a (Method B). To a 10 mL
oven-dried microwave vial were added pyrazinone 1a (44 mg,
(9) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron lett. 1975,
16, 4467. For a recent review see: (b) Agrofoligo, L. A.; Gillaizeau, I.; Saito,
Y. Chem. Rev. 2003, 103, 1875. (c) Negishi, E. I.; Anastasia, L. Chem. Rev.
2003, 103, 1979. (d) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
(e) Douchet, H; Hierso, J, C. Angew. Chem., Int. Ed. 2007, 46, 834.
(10) We selected some tautomerizable heterocycles other than those
described in ref 6b toevaluatethe possibilityofthisnewly developed condition.
(11) (a) DalPiaz, V.; Giovannoni, M. P.; Ciciani, G.; Barlocco, D.;
Giardina, G.; Petrone, G.; Clarke, G. D. Eur. J. Med. Chem. 1996, 31, 65.
(b) Kerdesky, F. A. J.; Leanna, M. R.; Zhang, J.; Li, W. K.; Lallamann, E.; Ji,
J. G.; Morton, H. E. Org. Proc. Res. Dev. 2006, 10, 512.
978 J. Org. Chem. Vol. 75, No. 3, 2010

Mehta et al.
JOCNote
142.4, 141.6, 140.2, 139.4, 132.3, 129.1, 129.0, 54.5, 21.5,
20.8. HRMS (EI): calcd for C13H13ON2Cl 248.0716, found
248.0711.
to the IRO (Interfacultaire Raad voor Ontwikkelingssa-
menwerking) for obtaining a doctoral scholarship. The
authors thank Ir. B. Demarsin for valuable help in HR-MS
spectra.
Acknowledgment. The authors wish to thank the FWO
(Fund for Scientific Research-Flanders (Belgium)) and the
Research Fund of the Katholieke Universiteit Leuven
for financial support to the laboratory. V.P.M. is grateful
Supporting Information Available: Experimental procedure
and spectral data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 3, 2010 979