Mild room-temperature palladium-catalyzed C3-arylation of 2(1H)-pyrazinones via a desulfitative kumada-type cross-coupling reaction

Article abstract of DOI:10.1021/jo901327y

(Chemical Equation Presented) An efficient desulfitative Kumada-type cross-coupling protocol is reported for the C3-arylation of 5-chloro-3- (phenylsulfanyl)pyrazin-2(1H)-ones. The method has also been successfully extended to the arylation of some (heter

Full text of DOI:10.1021/jo901327y

pubs.acs.org/joc
activated or unactivated electrophilic partner4 with a nucleo-
Mild Room-Temperature Palladium-Catalyzed
C3-Arylation of 2(1H)-Pyrazinones via a Desulfitative
Kumada-Type Cross-Coupling Reaction†
philic organometallic donor. The use of organo-sulfur
compounds as the electrophilic reaction partner has also
been described.5 Inspired by recent developments in the field
of desulfitative6a-c C-C cross-coupling methodologies
using organometallic donors like organoborons,6d organos-
tannanes,6e and organozinc6f and as a result of our recent
investigations on the desulfitative Hiyama-type cross-cou-
pling,6g we were keen to explore the use of Grignard reagents
(GR) as organometallic partners7 for the desulfitative C-C
bond formation. GR are economical and easy to synthe-
size,7d and many of them are commercially available. The
coupling of an aryl GR with an aryl halide is one of the most
powerful and versatile approaches for the construction of a
variety of biaryls, terphenyls, and oligoaryls, which are
important building blocks for the synthesis of natural pro-
ducts and bioactive compounds.8 A number of nickel and
palladium complexes have been reported to catalyze the
coupling of GR with aryl bromides and iodides.9 In a recent
report by Vogel and co-worker10 the use of iron catalysts
for the desulfitative C-C cross-coupling reaction applying
sulfonyl chlorides and GR was described. Other substrates,
including vinyl sulfides, have also been reported to under-
go cross-coupling. Early reports by Wenkert11 and Takei12
independently revealed that alkenyl and allyl sulfides
could undergo Ni-catalyzed Kumada type cross-coupling.13
Vaibhav P. Mehta, Sachin G. Modha, and
Erik 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 June 22, 2009
An efficient desulfitative Kumada-type cross-coupling
protocol is reported for the C3-arylation of 5-chloro-
3-(phenylsulfanyl)pyrazin-2(1H)-ones. The method has
also been successfully extended to the arylation of some
(hetero)aryl thioethers and thioesters.
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short review on non-activated alkyl halides, see: Frisch, A. C.; Beller, M. Angew.
Chem. Int. Ed. 2005, 44, 674.
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Chem., Int. Ed. 2005, 44, 7674.
The use of a transition-metal catalyst for C-C1 and C-
heteroatom2 cross-coupling reactions has revolutionized
the art and practice of organic synthesis in the last couple
of decades.1 The generally mild reaction conditions, high
functional group tolerance, and broad availability of the
reagents have contributed to the success of these bond-
forming reactions. Although in most of these protocols a
Pd(0) catalyst3a,b is used, other transition metals such as
Cu(I),3c Ni(0),3d Co(II),3e and Fe(II or III)3f-i have also been
investigated. These procedures involve the coupling of an
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Huang, Y.-L; Liao, J.-H. Organometallics 2006, 25, 1399–1411. (e) Horibe,
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† Dedicated to Academician Prof. Dr. Oleg. N. Chupakin on the occasion of his
75th birthday.
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C., Eds.; Wiley-VCH: Weinheim, 2004. (b) Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004; Vols. 1 and 2. (c) Beller, M.; Zapf, A. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-I., de Meijere, A., Eds.; Wiley:
New York, 2002; Vol. 1.
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Published on Web 08/03/2009
DOI: 10.1021/jo901327y
r
2009 American Chemical Society

Mehta et al.
JOCNote
TABLE 1. Preliminary Screening of the Conditions for the Desulfitative Cross-Coupling Reactiona
conditions
catalyst (mol %), ligand (mol %), solvent (in case 3:1), T, time, GR
ratiob
entry
3a/1a/c
1
2
3
Fe(acac)3 (5), THF, 65 °C, 8 h, 2.0 equiv
0/99/c
0/99/c
0/99/c
15/80/c
96e/1/c
75/20/c
0/99/c
Fe(acac)3 (5), THF/NMP, 80 °C, 6 h, 2.0 equiv
Ni(OAc)2 (5), PPh3 (10), THF, 65 °C, 6 h, 2.0 equiv
Pd(dba)2 (5), TFP (10), THF, 65 °C, 3 h, 2.0 equiv
Pd(dba)2 (5), TFP (10), THF/NMP, rt, 3 h, 1.2 equiv
Pd(PPh3)4 (5), THF/NMP, rt, 5 h, 1.2 equiv
THF/NMP, rt, 16 h, 1.2 equiv
4
5d
6
7
8
9
Pd(PPh3)2Cl2 (5), THF/NMP, rt, 6 h, 1.2 equiv
Herrmann’s palladacycle (5), THF/NMP, rt, 4 h, 1.2 equiv
Pd(dba)2 (5), THF/NMP, rt, 6 h, 1.2 equiv
50/39/c
72/24/c
60/40/c
20/75/c
2/95/c
92/5/c
5/94/c
50/45/c
0/100/c
10/90/c
0/96/c
10
11
12
13
14
15
16f
17g
18h
Pd(dba)2 (5), SPhos (10), THF/NMP, rt, 5 h, 1.2 equiv
Pd(dba)2 (5), BINAP (10), THF/NMP, rt, 8 h, 1.2 equiv
Pd(dba)2 (5), TBP HBF4 (10), THF/NMP, rt, 4 h, 1.2 equiv
3
Pd(dba)2 (5), TMEDA (10), THF/NMP, rt, 8 h, 1.2 equiv
Pd(dba)2 (2), TFP (10), THF/NMP, rt, 6 h, 1.2 equiv
Pd(dba)2 (5), TFP (10), THF/NMP, rt, 3 h, 1.2 equiv
Pd(dba)2 (5), TFP (10), THF/NMP, rt, 3 h, 2.0 equiv
Pd(dba)2 (5), TFP (10), THF/NMP, rt, 3 h, 2.0 equiv
aCompound 1a (0.3 mmol) was mixed with catalyst (mol %) and ligand (mol %). The flask was flushed three times with argon,
and the mixture was dissolved in the indicated solvent. The flask was flushed three more times with argon, and then
phenylmagnesium bromide 2a (1.0 M in THF, 1.2-2.0 equiv) was added via syringe and the reaction was allowed to stir for
b
c
d
the stipulated time. Ratio based on GC-MS analysis. Homocoupled GR was detected. Dropwise addition of GR using
syringe drive at a flow rate of 2 mL/h. e92% isolated yield (single run). fReaction mixture was cooled to -78 °C, and then GR was
added dropwise. gReaction mixture was dissolved at rt and then cooled to 0 °C; GR was added dropwise, and the mixture was
h
allowed to stir at rt. PhMgCl (2 equiv, 2.0 M in THF) was used. TFP = tri-2-furylphosphine, SPhos=2-dicyclohexylpho-
sphino-20,60-dimethoxybiphenyl, (()BINAP = (()-2,20-bis(diphenylphosphino)-1,10-binaphthalene, TBP HBF4 = tri-tert-
butylphosphonium tetrafluoroborate, TMEDA = tetramethylethylenediamine, NMP = N-methyl-2-pyrrolidinone, acac =
acetylacetonate.
3
However, (hetero)aryl thioethers have scarcely been re-
ported in the literature.12b,14 Due to our long withstanding
interest in the chemistry of 2(1H)-pyrazinones,15 we have
been exploring several methods for the efficient transition-
metal-catalyzed C3-decoration of the scaffold.16a In view of
generating small libraries of C3-arylated compounds,16b-e
we previously developed a solid-phase organic synthesis
(SPOS) approach applying a thiophenyl linker which could
simultaneously be cleaved and substituted (traceless linking)
resulting in C3-arylation of the pyrazinones scaffold by
applying a Liebeskind-Srogl cross-coupling protocol.16f
We were now eager to know whether a desulfitative Kuma-
da-type coupling could equally do this job, as this should
broaden the scope of potential substituents at the C3-posi-
tion of the pyrazinone scaffold (Scheme 1). As a proof of
SCHEME 1. Traceless Linking Concept using a Desulfitative
Kumada-Type Cross-Coupling
concept we examined this reaction in the solution phase,
mimicking the sulfur linker with a thiophenol substituent.
10
First we evaluated the application of Fe(acac)3 or Ni-
17
(OAc)2/PPh3 as catalyst for the desulfitative cross-cou-
pling (Table 1, entries 1-3). Unfortunately, after several
hours of heating, the corresponding cross-coupled product
could not be observed, and only an extensive amount of
aryl-aryl homocoupling product along with starting ma-
terial was formed. Therefore, we switched to the use of Pd18
as catalyst. We first studied the application of Pd(dba)2 with
TFP (tri-2-furylphosphine) as ligand and THF as solvent at a
temperature of 65 °C for 3 h (Table 1, entry 4). A mixture of
the desired cross-coupled product along with starting ma-
terial (15:80) was obtained as was determined by GC-MS
(14) Itami, K.; Mineno, M.; Muraoka, N.; Yoshida, J.-i. J. Am. Chem.
Soc. 2004, 126, 11778.
(15) (a) Appukkuttan, P.; Van der Eycken, E. Eur. J. Org. Chem. 2008,
1133. (b) Topics in Heterocyclic Chemistry; Van der Eycken, E., Kappe, C. O.,
Eds.; Springer Verlag: Berlin, 2006; Vol. 1, p 267.
(16) (a) Kaval, N.; Bisztray, K.; Dehaen, W.; Kappe, C. O.; Van der
Eycken, E. Molecular Diversity 2003, 7, 125. (b) Singh, B. K.; Parmar, V. S.;
Van der Eycken, E. Synlett 2008, 3021. (c) Mehta, V. P.; Sharma, A.; Van der
Eycken, E. Org. Lett. 2008, 10, 1147. (d) Sharma, A.; Mehta, V. P.; Van der
Eycken, E. Tetrahedron 2008, 64, 2605. (e) Singh, B. K.; Mehta, V. P.;
Parmar, V. S.; Van der Eycken, E. Org. Biomol. Chem. 2007, 5, 2962.
(f) 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.
(17) Venkatesh, C.; Singh, B.; Mahata, P. K.; Ila, H.; Junjappa, H. Org.
Lett. 2005, 7, 2169.
(18) (a) Martin, R.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3844.
(b) Ackermann, L.; Althammer, A. Org. Lett. 2006, 8, 3457.
J. Org. Chem. Vol. 74, No. 17, 2009 6871

Mehta et al.
JOCNote
TABLE 2. Evaluation and Scope of the Optimized Cross-Coupling
Protocola
TABLE 3. Application of the Optimized Cross-Coupling Protocol for
Some Thioethers and Thioesters
time
product (h)
yieldb
(%)
entry
R1
PMB
PMB
PMB
PMB
PMB
PMB
PMB
R6
R3
1
2
3
4
5
6
7
H
H
H
H
H
H
H
Ph
3a
3b
3c
3d
3e
3f
3
3
92
82
4-Me-Ph
4-MeO-Ph
2-thienyl
1-naphthyl
2-MeO-Ph
Ph-
2.5 94
3
4
6
92
84
64
3g
4.5 89
acetylene
Ethyl
Vinyl
8
PMB
PMB
H
H
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3a
3s
3t
1.5 63
9c
2
3
3
82
74
79
10 PMB
11 PMB
12 PMB
13 PMB
14 PMB
15 PMB
16 PMB
17 PMB
18 PMB
19 f PMB
20 Ph
21 Ph
22 Bn
23 CH2-Cy
24 (CH2)3-
Ph
Me
Me
Me
Me
Me
Me
Ph
4-Me-Ph
4-MeO-Ph
2-thienyl
1-naphthyl
2-MeO-Ph
2.5 68
5
6
8
4
5
<5d,e
tracesd,e
tracesd,e
82
4-MeO-Ph Ph
Bn
H
H
Me
Me
Me
H
Ph
59d
aCompounds 4a-8a (0.5 mmol) were mixed with Pd(dba)2
(5 mol %) and TFP (10 mol %). The flask was then flushed
three times with argon; the mixture was dissolved in THF/
NMP (3:1) (4 mL) and again flushed three times with argon.
Then GR (1.2 equiv) was added dropwise using a syringe
drive at a flow rate of 2 mL/h, and the reaction was allowed
to stir for the stipulated time at rt. bIsolated yields are
octyl
Ph
Ph
4-Me-Ph
Ph
Ph
2.5 68
4.5 72
12 35e
12 tracesd,e
3u
3v
3w
6
8
6
71
70
69
H
Ph
aCompounds 1a-h (0.3 mmol) were mixed with Pd(dba)2
(5 mol %) and TFP (10 mol %). The flask was then
flushed three times with argon, and the mixture was dis-
solved in THF/NMP (3:1) (4 mL) and again flushed three
times with argon. Then GR (1.2 equiv) was added drop-
wise using a syringe drive at a flow rate of 2 mL/h, and
the reaction was allowed to stir for the stipulated time at rt.
bIsolated yields are reported (average of two runs). c1.5 equiv
of GR was used. dNo C-C cross-coupling product was
observed; only starting material was recovered. eHomo-
c
reported (single runs). No cross-coupled product was ob-
served, and the starting material was fully decomposed after
6 h. dAll starting material was consumed after 4 h.
analysis confirm the presence of starting material in the
reaction mixture (Table 1, entry 18).
Encouraged by these findings, we explored the scope of
this protocol. An array of phenylsulfinylated pyrazinones
1a-h (Table 2) were reacted with various alkyl- or
(hetero)arylmagnesium bromides using our optimized con-
ditions.19 In most cases, the reactions proceeded well afford-
ing the cross-coupled product in good to excellent yields
(Table 2, entries 1-12). When pyrazinones bearing a methyl
substitution at the 6-position were reacted with heteroaryl or
sterically hindered GR, the reaction did not proceed, even
after an extended reaction time (Table 2, entries 13-15).
Also with a phenyl substitution in 1-position, the reaction
either proceeded partially or not at all (Table 2, entry 20, 21).
Having successfully established the methodology for the
pyrazinone scaffold, we next explored the scope of the
protocol for some thioethers and thioesters. Gratifyingly,
the diaryl ketones 4b,c were obtained in high yields starting
from the thioester 4a (Table 3, entries 1 and 2). The reaction
also proceeded well with heteroaryl thioethers 5a and 6a
(Table 3, entries 3 and 4). However, when 1-methylimidazole
was used, exclusive decomposition of the starting material
was observed (Table 3, entry 5). Interestingly, when ethyl
f
coupling of GR was observed. S-ethyl was used instead of
S-phenyl.
analysis. It is worth mentioning that 2.0 equiv of GR was
added in one shot after the reaction mixture was flushed with
argon at 65 °C. Therefore, the obtained low conversion could
probably be rationalized by the fast homocoupling of
GR. We then examined the addition of GR in a drop-
wise fashion using a syringe drive at a flow rate of 2 mL/h
at room temperature (Table 1, entry 5). The solvent system
was changed from THF to THF/NMP mixture (3:1) using
5 mol % of Pd(dba)2 and 10 mol % of TFP ligand. To our full
satisfaction, the desired product could be isolated in 92% by
applying different reaction conditions that were examined
after 3 h of stirring at rt. Different Pd catalysts and ligands
applying different reaction conditions were examined; how-
ever, the best results were obtained with the conditions of
entry 5 (Table 1). Finally, we also checked the applicability of
phenylmagnesium chloride for this cross-coupling reaction
that was carried out at 65 °C for 3 h. However, TLC and MS
(19) We preferred to use aryl-, heteroaryl-, and alkylmagnesium bromides
instead of magnesium chlorides as the latter are insufficiently reactive.
6872 J. Org. Chem. Vol. 74, No. 17, 2009

Mehta et al.
JOCNote
2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside was re-
acted with phenylmagnesium bromide, 23% of the desired
arylated product 8b was observed after 4 h along with
decomposition of the starting material (Table 3, entry 6).
In summary, an efficient protocol for the C3-functionaliza-
tion of variously substituted 5-chloro-3-(phenylsulfanyl)-
pyrazin-2(1H)-ones was successfully elaborated by applying
a desulfitative Kumada-type cross-coupling. The method was
also extended to some thioesters and (hetero)aryl thioethers.
The application of this desulfitative cross-coupling for the C3-
decoration of the 2(1H)-pyrazinone scaffold via solid-phase
organic synthesis is under current investigation.
was monitored by GC/MS and/or TLC analysis. After comple-
tion of the reaction, HCl (1 N) was added, and the mixture was
stirred for 15 min and extracted with diethyl ether (2 ꢀ 50 mL).
The combined organic layers were washed with brine and dried
over MgSO4. After filtration, the solvent was removed under
reduced pressure and the residue was subjected to column
chromatography over silica gel applying a mixture of EtOAc/
heptane ranging from 5% to 20% to afford compound 3a in
92% yield.
Compound 3a (5-chloro-3-phenyl-1-(4-methoxybenzyl)-2(1H)-
pyrazinone): yellow oil in 92% yield; 1H NMR (300 MHz,
CDCl3) δ 8.36-8.33 (m, 2H), 7.44-7.42 (m, 3H), 7.31-7.28
(d, 2H, J=8.2 Hz), 7.16 (s, 1H), 6.91-6.88 (d, 2H, J=9.12 Hz),
5.04 (s, 2H), 3.79 (s, 3H); 13C NMR (75 MHz, CDCl3) 160.10,
154.50, 152.24, 134.94, 130.74, 130.46, 129.37, 128.21, 126.56,
126.35, 125.22, 114.68, 55.41, 52.48; HRMS (EI) calcd for
C18H15O2N2Cl 326.0822, found 326.0817.
Experimental Section
Typical Procedure for the Synthesis of Representative Com-
pound 3a. Under air, an oven-dried, two-necked flask equipped
with a stir bar was charged with thioether 1a (0.29 mmol, 100
mg), Pd(dba)2 (5 mol %, 8 mg), and TFP (10 mol %, 7 mg),
sealed with a septum, and purged with argon. Distilled THF/
NMP (3:1) (4 mL) was added by syringe, and the mixture was
stirred for 1-2 min. The reaction mixture initially became dark
red and changed to bright yellow. The flask was again flushed
three times with argon, and the mixture was allowed to stir for 15
min. Then the Grignard reagent 2a (0.36 mmol, 76 mg) (1.0 M
solution in THF) was added under argon over 15 min applying a
syringe drive at a flow rate of 2 mL/min. The reaction mixture
was allowed to stir for approximately 3 h at rt, and the reaction
Acknowledgment. We thank the FWO (Fund for Scienti-
fic Research - Flanders (Belgium)) and the Research Fund
of the Katholieke Universiteit Leuven for financial
support to the laboratory. V.P.M. is grateful to the IRO
(Interfacultaire Raad voor Ontwikkelingssamenwerking)
for a doctoral scholarship.
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. 74, No. 17, 2009 6873