The first palladium-catalyzed desulfitative sonogashira-type cross-coupling of (hetero)aryl thioethers with terminal alkynes

Article abstract of DOI:10.1021/ol800054b

An unprecedented desulfitative Sonogashira-type cross-coupling protocol is exemplified by the synthesis of substituted 5-chloro-3-alkynylpyrazinones from the corresponding 5-chloro-3-(phenylsulfanyl) pyrazin-2(1 H)-ones. The applicability of the method is

Full text of DOI:10.1021/ol800054b

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1147-1150
The First Palladium-Catalyzed
Desulfitative Sonogashira-Type
Cross-Coupling of (Hetero)aryl
Thioethers with Terminal Alkynes
Vaibhav Pravinchandra Mehta, Anuj Sharma, and Erik Van der Eycken*
Laboratory for Organic & MicrowaVe-Assisted Chemistry (LOMAC), Department of
Chemistry, UniVersity of LeuVen (K. U. LeuVen), Celestijnenlaan 200F, B-3001,
LeuVen, Belgium
erik.Vandereycken@chem.kuleuVen.be
Received January 9, 2008
ABSTRACT
An unprecedented desulfitative Sonogashira-type cross-coupling protocol is exemplified by the synthesis of substituted 5-chloro-3-
alkynylpyrazinones from the corresponding 5-chloro-3-(phenylsulfanyl) pyrazin-2(1H)-ones. The applicability of the method is extended to
solid-phase linked pyrazin-2(1H)-ones as well as to some oxazinones, pyrazines, and phenyl thioesters.
Palladium-catalyzed C-C and C-heteroatom bond forming
reactions are among the most powerful methods in organic
synthesis.1 The Sonogashira cross-coupling reaction is an
illustrative example representing an important tool for the
coupling of a terminal alkyne with an aromatic halide in the
presence of a copper cocatalyst and a base.2 The past few
years have witnessed a fierce search for convenient condi-
tions, better yields, and shorter reaction times for this
protocol.3 Notwithstanding the continued interest in the
transition-metal-catalyzed cross-coupling reactions during the
past years, organometallic cross-coupling reactions involving
the desulfitative removal of the C-S bond of aryl and alkyl
thioethers, sulfones, and sulfonyls as electrophilic partners
have gained attention rather recently.4 Seminal work by
Liebeskind and co-workers described the application of
(3) See, for example: (a) Kabalka, G. W.; Wang, L.; Namboodiri, V,
Pagni, R. M. Tetrahedron Lett. 2000, 41, 5151. (b) Erdelyi, M; Adolf, G.
J. Org. Chem. 2001, 66, 4165. (c) Appukkuttan, P.; Dehaen W.; Van der
Eycken, E. Eur. J. Org. Chem. 2003, 24, 4713. (d) Park S. B.; Alper H.
Chem. Commun. 2004, 10, 1306. (e) Consorti, C. S.; Flores, F. R.; Rominger,
F.; Dupont, J. AdV. Synth. Catal. 2006, 348, 133. (f) Dhudshia, B.; Thadani,
A. N. Chem. Commun. 2006, 6, 668. (g) Kawanami, H.; Matsushima, K.;
Sato, M.; Ikushima, Y. Angew. Chem., Int. Ed. 2007, 46, 5129.
(4) See, for example: (a) Erdelmeier I.; Gais, H. J. J. Am. Chem. Soc.
1989, 111, 1125. (b) Srogl, J.; Liu, W.; Marshall, D.; Liebeskind, L. S. J.
Am. Chem. Soc. 1997, 119, 12376. (c) Itami, K.; Yamazaki D.; Yoshida, J.
I. J. Am. Chem. Soc. 2004, 126, 15396. (d) Liu, J.; Robins, M. J. Org. Lett.
2005, 7, 1149.
(1) (a) Beller, M.; Bolm, C. Transition metals for Organic Synthesis;
Wiley-VCH: Weinheim, 1998. (b) Meijere, de A.; Diederich, F. Metal-
catalyzed Cross-coupling Reactions, 2nd ed.; Wiley-VCH: New York, 2004.
(c) Kentchev, E. A. V.; Obrien, C. J.; Organ, M. G. Angew. Chem., Int.
Ed. 2007, 46, 2768.
(2) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467. (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.
10.1021/ol800054b CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/20/2008

Table 1. Optimization Study for the Desulfitative Alkynylation of 1aa
entry
substrate
Pd catalyst (mol %)
Cu source
base
solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
MeCN
1,4-Dioxane
time (min)
yield of 2ab (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
Pd(OAc)2 (5)
PdCl2(5)/PPh3(10)
Pd(PPh3)4 (5)
CuI
CuI
CuI
CuI
CuI
CuI
Et3Nc
40
40
40
60
60
40
60
60
60
60
60
45
60
60
60
60
54
45
65
0d
Et3Nc
Et3Nc
Pd2(dba)3 (5)
Et3Nc
Pd(dppf)Cl2 (5)
Pd(PPh3)Cl2 (5)
Pd(PPh3)2Cl2 (5)
Et3Nc
0d
Et3Nc
74
28
0d
57
0d
58
79
75
62
49
55
Et3Nc
Et3Nc
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
CuBr
CuTC
CuI
CuI
CuI
CuI
CuI
CuI
Et3Nc
Et3Nc
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
a Reactions were run on a 0.1mmol scale of 1a, applying phenylacetylene (1.2 equiv), Pd catalyst (5 mol %), Cu source (10 mol %), base (2.0 equiv), and
solvent (3.0 mL). The reaction was irradiated (monomode microwave instrument) for the stipulated time at 95 °C ceiling temperature using a
maximum power of 75 W. b Isolated yields of the products (single runs). c Et3N was used as a mixture with DMF (1:1). d Only unreacted starting material
was recovered.
CuTC as an effective cocatalyst for the coupling of aryl
heteroaryl thioethers with organoboron, organotin, or orga-
noindium compounds.5 The same authors also reported the
coupling of electrophilic thioalkynes with arylboronic acids.6
Desulfitative Stille-, Suzuki-Miyaura-, and Sonogashira-
Hagihara cross-couplings as well as Mizoroki-Heck cou-
plings of sulfonyl chlorides have been described by Vogel
and co-workers.7 However, to the best of our knowledge, to
date, no report has appeared regarding the coupling of an
electrophilic aryl or heteroaryl thioether with a terminal
alkyne applying a transition-metal-catalyzed cross-coupling
protocol. We here disclose the unprecedented desulfitative
Sonogashira-type cross-coupling reaction of an aromatic
thioether applying 5-chloro-3-(phenylsulfanyl)pyrazin-2(1H)-
ones and variously substituted terminal alkynes. The ap-
plicability of the method was extended to solid-phase linked
pyrazin-2(1H)-ones as well as to some oxazinones, pyrazines,
and phenyl thioester.
Pursuant to our longstanding interest in the synthesis and
microwave-assisted decoration of the pyrazin-2(1H)-one
scaffold8 and to our recently described protocol for the
transition-metal-catalyzed orthogonal solid-phase decoration
of the 2(1H)-pyrazinone scaffold using a sulfur linker,9 we
were keen to investigate whether a desulfitative Sonogashira-
type reaction at the C3-position of 5-chloro-3-(phenylsulfa-
nyl) pyrazin-2(1H)-ones should be possible. The test reac-
tions were performed with 5-chloro-1-(4-methoxybenzyl)-
3-(phenylsulfanyl)pyrazin-2(1H)-one (1a) and phenylacetylene
as a model system. Different palladium catalysts, cocatalysts,
bases, and solvents were screened to derive an optimized
protocol (Table 1).
Six different palladium catalysts were investigated (Table
1, entries 1-6). All of these reactions were performed, as
per the standard Sonogashira protocol,2 by applying 10 mol
% of CuI as the cocatalyst and Et3N as the base in dry DMF
under microwave irradiation at 95 °C ceiling temperature
for the stipulated time. Among these different palladium
catalysts, Pd(PPh3)2Cl2 provided the best yield of 74% (Table
1, entry 6). Reaction with Pd(PPh3)4 resulted in a moderate
yield of 65% (Table 1, entry 3), while the reaction did not
proceed at all when Pd2(dba)3 or Pd(dppf)Cl2 were used even
(5) (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260.
(b) Yu, Y.; Liebeskind, L. S. J. Org. Chem. 2004, 69, 3554. (c) Yu, Y.;
Srogl, J.; Liebeskind, L. S. Org. Lett. 2004, 6, 2631. (d) Lengar, A.; Kappe,
C. O. Org. Lett. 2004, 6, 771. (e) Fausett, B. W.; Liebeskind, L. S. J. Org.
Chem. 2005, 70, 4851. (f) Zhnag, Z.; Liebeskind, L. S. Org. Lett. 2006, 8,
4331. (g) Aquilar-auilar, A.; Liebeskind, L. S.; Pena-Cabrera, E. J. Org.
Chem. 2007, 72, 8539. (h) Aquilar-auilar, A.; Pena-Cabrera, E. Org. Lett.
2007, 9, 4163. (i) Yang, H.; Li, Y.; Wittenberg, R.; Egi, M.; Huang, W.;
Liebeskind, L. S. J. Am. Chem. Soc. 2007, 129, 1132. (j) Villalobos, J. M.;
Srogl, J.; Liebeskind, L. S. J. Am. Chem. Soc. 2007, 129, 15734.
(6) Savarin, C.; Srogl J.; Liebeskind, L. S. Org. Lett. 2001, 3, 91.
(7) (a) Dubbaka, S. R.; Vogel, P. J. Am. Chem. Soc. 2003, 125, 15292.
(b) Dubbaka, S. R.; Vogel, P. AdV. Syn. Catal. 2004, 346, 1793. (c) Dubbaka
S. R.; Vogel, P. Org. Lett. 2004, 6, 95. (d) Dubbaka, S. R.; Vogel, P. Angew.
Chem., Int. Ed. 2005, 44, 7674 and references cited therein. (e) Vogel P.
Pierre; Turks M. S.; Bouchez L. Laure; Markovic´ D. Dean; Varela-AÄ lvarez
A. Adria´n; Sordo J. A. Acc. Chem. Res. 2007, 40, 931.
(8) Van der Eycken, E.; Kappe, C. O. Topics in Heterocyclic Chemistry;
Springer: Berlin, 2006; Vol. 1, p 267.
(9) 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.
1148
Org. Lett., Vol. 10, No. 6, 2008

upon an extended reaction time (Table 1, entries 4 and 5).
Having established Pd(PPh3)2Cl2 as the optimal catalyst, we
investigated the influence of the cocatalyst. However,
replacement of CuI for CuBr or CuTC resulted in a low yield
or no conversion at all (Table 1, entries 9 and 10). Moreover,
it was observed that both the catalyst and the cocatalyst were
mandatory for successfully performing the reaction, as very
little or even no product was formed in the absence of one
or both of them (Table 1, entries 7 and 8). Having found the
optimum catalyst/cocatalyst combination, further investiga-
tions were made for the choice of the base (Table 1, entries
11 and 12), the solvent (Table 1, entries 14-16), and reaction
time (Table 1, entries 12 and 13). Interestingly, we found
that when Et3N was replaced by Cs2CO3 an increased yield
of 79% was obtained (Table 1, entry 12). Finally, optimum
reaction conditions were achieved when a mixture of 1.2
equiv of phenyl acetylene, 5 mol % of Pd(PPh3)2Cl2, 10 mol
% of CuI, and 2.0 equiv of Cs2CO3 in 3.0 mL of DMF was
irradiated for 45 min at a ceiling temperature of 95 °C
applying a maximum power of 75 W, affording the desired
compound 2a in 79% yield (Table 1, entry 12). The protocol
was checked with conventional heating conditions providing
lower yield of 35% of 2a after 6 h.
Next, we were interested to see if an alkylthio substituent
in C3-position, instead of a phenylthio substituent, would
also allow the same Sonogashira-type transformation. There-
fore the ethylthio-substituted pyrazinone 1l was subjected
to the newly developed protocol. Gratifyingly the reaction
proceeded smoothly upon irradiation for 60 min, yielding
the desired compound 2a in 65% (Table 3, entry 1).
Table 3. Extension of the Procedure to Alkylthio-Substituted
and Resin-Linked Pyrazinonesa
a Reactions were run on a 0.3 mmol scale of 1l,m using the optimized
protocol. The mixture was irradiated for 60 min in a sealed tube (monomode
microwave instrument) at a ceiling temperature of 95 °C and 75 W
maximum power. b Isolated yields of the products (single runs). c A
commercially available mercapto phenylpropionyl AM resin (loading 0.88
mmol/g) was used; 3.0 equiv of acetylene was applied.
Having found the optimal conditions for the desulfitative
alkynylation reaction, we next investigated the scope and
limitations of the protocol. A series of differently substituted
5-chloro-3-(phenylsulfanyl)pyrazin-2(1H)-ones (1b-k) was
subjected to the optimized conditions (Table 2). The reaction
Moreover, to broaden the scope of our protocol, a resin-
linked pyrazinone 1m, was subjected to the same procedure.
This resulted in the formation of the desired alkynylated
pyrazinone 2a in 54% yield, after an irradiation time of 90
min (Table 3, entry 2). The resin used was a commercially
available mercaptophenylpropionyl AM resin (loading 0.88
mmol/g) while the pyrazinone was linked via a thioether
bond at its C3-position. This interesting extension of our
methodology opens the way for the fast generation of a small
combinatorial library of valuable C3-alkynylated pyrazino-
nes, using our previously described transition-metal-atalyzed
orthogonal solid-phase protocol using a sulfur linker.9
Table 2. Investigation of the Scope and Limitations of the
Optimized Desulfitative Alkynylation Protocola
yieldb
product (%)
entry
R1
R6
R
1
2
3
4
5
6
7
8
9
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
H
H
H
4-tBu-Ph
hexyl
2-Me-Ph
2b
2c
2d
2e
2f
2g
2h
2i
85
78
79
88
84
72
80
81
82
69
Table 4. Desulfitative Alkynylation of Compounds 3a-ea
entry
substrate
acetylene
product
yieldb (%)
4-OMe-Ph 4-F-Ph
4-OMe-Ph 4-Et-Ph
Bn
Bn
Me
H
1
2
3
4
5c
6
7d
3a
3b
3c
3d
3d
3e
3e
phenylacetylene
p-tolylacetylene
phenylacetylene
phenylacetylene
p-tolylacetylene
phenylacetylene
1-hexyne
4a
4b
4c
4d
4e
4f
79
65
45
72
52
58
42
Ph
4-CH3-Ph
cyclohexyl
4-OMe-Ph
3-thiophenyl
CH2-cyclohexyl
2j
2k
10 (CH2)3-Ph
H
4g
a Reactions were run on a 0.3 mmol scale of 1b-k using the optimized
protocol. The mixture was irradiated for 45 min in a sealed tube (monomode
microwave instrument) at a ceiling temperature of 95 °C and 75 W
maximum power. b Isolated yields of the products (single runs).
a Reactions were run on a 0.3 mmol scale of 3a-e using the optimized
protocol. The mixture was irradiated for 45 min in a sealed tube (monomode
microwave instrument) at a ceiling temperature of 95 °C and 75W maximum
power. b Isolated yields of the products (single runs). c Reaction was run
for 60 min. d Reaction was run for 60 min with 3.0 equiv of acetylene.
progressed excellently in case of either alkyl or aryl
acetylenes and irrespective the substitution pattern of the
pyrazinone. Also the 3-thiophenyl acetylene worked well
yielding compound 2k in 69% yield (Table 2, entry 10).
The scope of the protocol was also investigated for systems
other than pyrazinones (Table 4).10 A mixture of oxazinone
3a, phenyl acetylene (1.2 equiv), Pd(PPh3)2Cl2 (5 mol %),
Org. Lett., Vol. 10, No. 6, 2008
1149

CuI (10 mol %), and Cs2CO3 (2 equiv) in DMF (3.0 mL)
was irradiated for 45 min at 95 °C and 75 W maximum
power (Table 4, entry 1). Much to our delight, the reaction
proceeded regioselectively at the C3-position of the oxazi-
none affording the desired compound 2a in 79% yield
without any trace of the dialkynylated product.
Finally, the newly developed protocol was applied for
trisubstituted pyrazines bearing a thio methyl functionality.
The reaction proceeded smoothly yielding the desired
compounds in moderate to good yields (Table 4, entries 2
and 3). The application of the methodology was also
extended to the heteroaromatics and thiol esters yielding the
desired compound in good yields (Table 4, entires 4-7).
nylpyrazinones from the corresponding 5-chloro-3-(phenyl-
sulfanyl)pyrazin-2(1H)-ones. Excellent yields and tolerance
of various functional groups toward the reaction conditions
are the merits of this protocol. The possible extension of
the protocol toward solid-phase linked pyrazinones as well
as to other systems as oxazinones, pyrazines, and phenyl
thioester was demonstrated.
Acknowledgment. Support was provided by the research
fund of the University of Leuven and the FWO (Fund for
Scientific Research - Flanders (Belgium)). A.S. is thankful
to the University of Leuven (K. U. Leuven) for a postdoctoral
fellowship.
In conclusion, we have developed a hitherto unknown
desulfitative Sonogashira-type cross-coupling reaction ex-
emplified by the synthesis of substituted 5-chloro-3-alky-
Supporting Information Available: Spectroscopic data
for all new compounds prepared, as well as detailed
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
(10) See the Supporting Information for the structures of starting
substrates and products.
OL800054B
1150
Org. Lett., Vol. 10, No. 6, 2008