Microwave-assisted Sonogashira-type cross couplings of various heterocyclic methylthioethers

Article abstract of DOI:10.1016/j.tetlet.2008.12.055

A novel, microwave-assisted, palladium-catalyzed Sonogashira-type coupling of terminal alkynes with a variety of heteroaryl thiomethylethers is reported. The developed protocol allows for further utility and diversification of a number of chemically and b

Full text of DOI:10.1016/j.tetlet.2008.12.055

Tetrahedron Letters 50 (2009) 1013–1015
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted Sonogashira-type cross couplings of various heterocyclic
methylthioethers
*
Brian C. Shook , Devraj Chakravarty, Paul F. Jackson
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh and McKean Roads, PO Box 776, Spring House, PA 19477, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel, microwave-assisted, palladium-catalyzed Sonogashira-type coupling of terminal alkynes with a
variety of heteroaryl thiomethylethers is reported. The developed protocol allows for further utility and
diversification of a number of chemically and biologically interesting scaffolds.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 7 November 2008
Revised 9 December 2008
Accepted 11 December 2008
Available online 16 December 2008
Palladium-catalyzed cross-coupling reactions are one of the
most versatile procedures used in organic synthesis.1 Typical reac-
tions of this sort generally involve the coupling of organometallic
reagents or boronic acids with vinyl or aryl halides and triflates.
There are numerous reports describing the Stille,2 Suzuki–Miya-
ura,3 Negishi,4 and Sonogashira5 reactions with vinyl or aryl halides
and triflates. Unfortunately, the availability of many heteroaryl
halides and triflates is limited and requires alternative coupling
partners to access a wider variety of molecules. Recently, a new
class of coupling partners was developed to extend the scope of
these versatile reactions.
biological activity.10 The propensity of drugs to have substituted aryl
and heteroaryl moieties is unrivaled and the development of new
methods to diversify structural scaffolds is particularly appealing.
Recently, it was reported that boronic acids could be successfully
coupled to cyclic thioamides using the Liebeskind protocol under
microwave irradiation.11 Microwaves provide a powerful way to
do synthetic chemistry, and the ability of microwaves to shorten
reaction times, increase reaction yields, and to facilitate reactions
that are otherwise unsuccessful under conventional hood condi-
tions is the property that medicinal chemists are looking for to
optimize their everyday procedures.12
Liebeskind reported palladium-catalyzed, Cu(I)-mediated cou-
plings of boronic acids with a variety of thioorganics, including
heteroaryl methylthioethers, under neutral conditions to form car-
bon–carbon bonds.6 The methodology was also extended to couple
organotin reagents with heteroaryl thioethers under similar condi-
tions.7 There are a few examples of carbon–carbon cross couplings
involving Ni-catalyzed Kumada-type couplings of heteroaromatic
thioethers with Grignard reagents, but reaction conditions are
harsh and not compatible with most functionalities.8 The copper-
mediated couplings, however, are quite facile and allow most
functionalities to be present. Heteroaryl thioethers have also been
successfully coupled with organozinc reagents in the absence of
the Cu(I) additive.9 Surprisingly, there are limited reports using
thioethers as coupling partners despite their inherent reactivity
and compatibility with numerous transformations. It is our intent
to expand the scope of Sonogashira reactions using methylthioe-
thers as coupling partners. The methodology reported herein will
investigate the reactivity of heterocyclic methylthioethers with
alkynes using both conventional Sonogashira reaction protocols
as well as the effect of microwaves on the reaction.
The afore-mentioned palladium-catalyzed reactions using vari-
ous thiol derivatives compelled us to explore the scope and reactiv-
ity of a variety of heteroaryl methylthioethers using microwaves.
Because palladium insertion into the carbon-sulfur bond is quite
facile,6 it should be possible to access other types of reactions in
addition to the Suzuki- and Stille-type of protocols mentioned
above. There has been only one report, which has recently pub-
lished, of Sonogashira-type couplings using terminal alkynes and
thiophenyl-substituted pyrazinones.13 We wish to report herein
Sonogashira-type couplings of terminal alkynes to a variety of het-
eroaromatic methylthioethers using microwave irradiation.
Commercially available 2-(methylthio)pyridine was chosen to
investigate the coupling of alkynes and heteroaromatic thioethers.
Phenylacetylene was used initially as the coupling partner as a
number of reaction conditions were tried. Various Cu(I) salts such
as CuI, CuOTf, and CuTC (copper(I) 2-thiophene carboxylate) were
used in combination with a palladium(II) catalyst to carry out the
reaction. CuI proved to be the copper salt of choice, which is also
true for typical Sonogashira reactions. Initially, reactions were
run in refluxing THF using conventional heating conditions in the
hood. Unfortunately, only starting materials were recovered from
the reactions as no desired coupling products were formed after
16 h (Table 1, entries 1 and 2), suggesting that more vigorous
conditions were required to facilitate the reaction. We then tried
running the reactions in the microwave at 100 °C for 0.5 h (Table
1, entry 3) and the coupling product was formed in 24% yield.
Medicinal chemistry is a practice that is challenging and
requires the ability to diversify particular structural scaffolds to
develop structure–activity relationships (SARs) and to optimize for
* Corresponding author. Tel.: +1 215 628 7047; fax: +1 215 628 5047.
E-mail addresses: author@institute.edu, bshook@its.jnj.com (B.C. Shook).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.055

1014
B. C. Shook et al. / Tetrahedron Letters 50 (2009) 1013–1015
Table 1
Table 216
Optimization of coupling protocola
Scope of Sonogashira couplingsa
(2.4 eq.)
H
(2.4 eq.),
Ph
H
R
N
N
CuI (0.2 eq.),
CuI (0.2 eq.),
MeS
Pd(dppf)Cl2 (0.1 eq)
Et3N, THF, ∝W 100 o
Cat. (0.1 eq),
Et3N, THF
HetAr SMe
HetAr
Yield (%)
71
R
C
Entry
HetAr
Product
# of 1 h Runs
2
Entry
Catalyst
Heat source
Temperature (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
Pd(dppf)Cl2
Pd(PPh3)2Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(PPh3)2Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Hood
Hood
66
66
100
100
66
100
100
100
100
16
16
0.5
1
1
1
1
0
0
24
35
6
20
40
53
65
1b
SMe
OMe
N
N
lw
lw
lw
lw
lw
lw
lw
N
N
N
N
N
N
N
N
2
74
70
48
24
68
60
31
72
35
68
17
1
1
1
1
1
1
1
2
1
2
2
SMe
SMe
SMe
SMe
SMe
SMe
SMe
SMe
SMe
N
N
N
N
N
N
b
c
2 Â 0.5 h
N
N
d
2 Â 1 h
3
OMe
F
a
Typical reaction uses CuI (0.2 equiv), Pd (0.1 equiv), and Et3N (2 equiv).
Used CuI (0.4 equiv), Pd (0.2 equiv), and Et3N (4 equiv).
Typical reaction for 0.5 h then add additional CuI (0.2 equiv), Pd (0.1 equiv), and
b
c
N
N
4c
5c
6
Et3N (2 equiv).
d
Typical reaction for 1 h then add additional CuI (0.2 equiv), Pd (0.1 equiv), and
Et3N (2 equiv).
N
N
CN
Increasing reaction time to 1 h resulted in only a slight increase in
yield (Table 1, entry 4). It was unclear at this point if the micro-
waves were facilitating the reaction or if product was being formed
simply from increased reaction temperature. Running the reaction
in the microwave at 66 °C, the boiling point of THF (Table 1, entry
5), gave only traces of product, suggesting that increased temper-
ature is essential for the reaction to take place, but does not explain
what effect the microwaves have on the reaction. One major
advantage of using the microwave to run reactions is the ability
to superheat solvent without using pressure tubes. Using a more
common palladium catalyst, Pd(PPh3)Cl2, for Sonogashira reactions
gave lower yield of the desired product (Table 1, entry 6).
Keeping Pd(dppf)Cl2 as the palladium source, we tried increas-
ing the reaction time to 2 h, but it did not increase the conversion.
We then decided to change the amounts of reagents, while keeping
the same reaction time. Doubling the reagents, CuI (0.4 equiv),
Pd(dppf)Cl2 (0.2 equiv), and Et3N (4 equiv), at the beginning of
the reaction followed by irradiation for 1 h gave a slightly higher
yield (40%, Table 1, entry 7). Interestingly, when additional fresh
CuI (0.2 equiv), Pd(dppf)Cl2 (0.1 equiv), and Et3N (2 equiv) were
added to the original reaction mixture after 0.5 h followed by irra-
diation for an additional 0.5 h the product was formed in 53%
(Table 1, entry 8). This represents a significant increase in yield
when comparing entries 7 and 8 which have the same reaction
time and reagents equivalents, but the addition of reagents at the
beginning and halfway through the reaction resulted in higher
yield of product (entry 8) than that obtained from adding all the re-
agents at the beginning of the reaction (entry 7). This suggests that
the catalyst decomposes under the reaction conditions, and that it
is somewhat overcome when the reagents are added portionwise.
Increasing the reaction time from 0.5 h to 1 h for the portionwise
protocol gave a reasonable 65% yield (Table 1, entry 9), and it
was this procedure that was used to determine generality and
scope of the reaction.14
N
N
N
N
7
N
S
N
8
S
N
S
N
S
9b
10
11b
12b
N
S
N
S
OMe
OMe
N
S
N
S
SMe
SMe
O
O
a
Typical reaction uses CuI (0.2 equiv), Pd (0.1 equiv), and Et3N (2 equiv).
Typical reaction for 1 h then add additional CuI (0.2 equiv), Pd (0.1 equiv), and
b
Et3N (2 equiv).
c
An additional run yielded 65% and 31% of the F and CN analogs, respectively.
their reactivity with respect to 2-(methylthio)pyridine. 2-(Methyl-
thio)pyrazine proved to be more reactive than the 2-(methyl-
thio)pyridine as just one 1 h run using phenylacetylene gave 74%
(Table 2, entry 2) of the coupled product and only 35% for the pyr-
idine analog (Table 1, entry 4). The 4-methoxyphenyl acetylene
works well with 2-(methylthio)pyrazine and again showed no dif-
ference when compared to phenylacetylene (Table 2, entry 3).
Interestingly, when entry 3 (Table 2) was run in the hood, not
shown, in refluxing THF for 16 h, only 32% of the desired product
was formed. This result suggests that higher temperature and
microwaves, or both are required to form product in appreciable
yields. Using phenylacetylenes that contain electron-withdrawing
groups, like the 4-fluoro and 4-cyano analogs, gave lower yields,
48% and 24%, respectively (Table 2, entries 4 and 5). An additional
run with the fluoro analog gave a good 65% yield of product, but
the yield of cyano derivative only increased slightly to 31%. The
With a better understanding of the reaction conditions and
which protocol that should be followed, we explored the scope of
the reaction using various heteroaromatic thiomethylethers and
substituted alkynes. 4-Methoxyphenyl acetylene reacted with
2-(methylthio)pyridine to give yield (71%) comparable to that ob-
tained with phenylacetylene (compare Table 1, entry 9, with Table
2, entry 1) indicating that the electron-donating group did not
increase reactivity for this particular example. Attention then
turned to different heterocyclic thiomethyl ethers to determine

B. C. Shook et al. / Tetrahedron Letters 50 (2009) 1013–1015
1015
Kusturin, C. L.; Liebeskind, L. S.; Neumann, W. L. Org. Lett. 2002, 4, 983; (e)
Liebeskind, J. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260.
7. (a) Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 801; (b) Alphonse, F.-A.; Suzenet,
F.; Keromnes, A.; Lebret, B.; Guillaumet, G. Org. Lett. 2003, 5, 803.
8. (a) Takei, H.; Miura, M.; Sugimura, H.; Okamura, H. Chem. Lett. 1979, 1447; (b)
Wenkert, E.; Ferreira, T. W.; Michelotti, E. L. J. Chem. Soc., Chem. Commun. 1979,
637.
2-(methylthio)pyrazine was generally more reactive as it also re-
acts with non-aromatic and acyclic alkynes (Table 2, entries 6
and 7) to give good yields of the coupled products after a single
1 h run.
There are a large number of drugs that contain five-membered
heterocycles, so application of this methodology to those systems
would be essential.15 2-Methylthio-1,3-thiazole reacts with phen-
ylacetylene giving a surprisingly low (31%) yield of the coupled
product as we expected more robust reactivity of this methylthioe-
ther (Table 2, entry 8). A second run, however, afforded a good 72%
yield of the desired product (Table 2, entry 9). 4-Methoxyphenyl
acetylene gives yields comparable to those given by phenylacety-
lene after both one and two runs (Table 2, entries 10 and 11). To
our delight, the very unreactive 2-methylthiofuran gave desired
product albeit in low yield even after two runs (Table 2, entry 12).
In conclusion, we report novel Sonogashira-type couplings
using microwave irradiation with a variety of heterocyclic meth-
ylthioethers as coupling partners. The standard protocol is general
across a number of heterocyclic methylthioethers and terminal
alkynes. The generality of these reactions will continue to be
explored as they can offer unique utility and diversification to a
variety of biological systems.
9. Angiolelli, M. E.; Casalnuovo, A. L.; Selby, T. P. Synlett 2000, 905.
10. The
Practice of Medicinal Chemistry; Wermuth, C. G., Ed.; Academic Press: San
Diego, 1996.
11. Prokopcova, H.; Kappe, C. O. J. Org. Chem. 2007, 72, 4440.
12. (a) Kappe, C. O.; Dallinger, D. Nat. Rev. Drug Disc. 2006, 5, 51; (b) Kappe, C. O.
Angew. Chem., Int. Ed. 2004, 43, 6250.
13. Mehta, V. P.; Sharma, A.; Van der Eycken, E. Org. Lett. 2008, 10, 1147.
14. Representative procedure for coupling heteroaromatic thiomethylethers: Solid CuI
(30 mg, 0.16 mmol) and Pd(dppf)Cl2 (65 mg, 0.08 mmol) were added to a THF
solution (3 mL) of 2-(methylthio)pyridine (89 lL, 0.80 mmol), phenylacetylene
(0.17 mL, 1.60 mmol), and Et3N (0.22 mL, 1.60 mmol) and the mixture was
heated in the microwave at 100 °C for 1 h. Additional solid CuI (30 mg,
0.16 mmol), Pd(dppf)Cl2 (65 mg, 0.08 mmol), and Et3N (0.22 mL, 1.60 mmol)
were added and the mixture was heated in the microwave at 100 °C for 1 h .
The mixture was diluted with EtOAc and the organic layer was washed with
10% aq NH4OH, water, and then with brine; dried (Na2SO4); concentrated; and
purified via column chromatography (20–80% EtOAc/heptane) to give 93 mg
(65%) of 2-phenylethynyl-pyridine.
Representative procedure for coupling to 2-(methylthio)pyrazine: Solid CuI
(30 mg, 0.16 mmol) and Pd(dppf)Cl2 (65 mg, 0.08 mmol) were added to a
THF solution (3 mL) of 2-(methylthio)pyrazine (100 mg, 0.79 mmol),
phenylacetylene (0.17 mL, 1.58 mmol), and Et3N (0.22 mL, 1.58 mmol), and
the mixture was heated in the microwave at 100 °C for 1 h. The mixture was
diluted with EtOAc and the organic layer was washed with 10% aq NH4OH,
water, and then with brine; dried (Na2SO4); concentrated; and purified via
column chromatography (0–50% EtOAc/heptane) to give 105 mg (74%) of 2-
phenylethynyl-pyrazine.All experiments were carried out on a CEM Explorer
microwave system using a 10 mL vial that contained a stir bar and snap-on cap.
The reaction settings were as follows: temperature = 100 °C; power = 300 W;
ramp = 3 min; hold time = 60 min; pressure = 250 psi; stirring on.
References and notes
1. (a) de Meijere, A., Diederich, F., Eds.Metal-Catalyzed Cross-Coupling Reactions;
Wiley-VCH: Weinheim, Germany, 2004; Vols. 1 and 2,. 2nd ed. (b)Transition
Metals for Organic Synthesis; Beller, M., Bolm, C., Eds., 2nd ed.; Wiley-VCH:
Weinheim, Germany, 2004; (c) Stanforth, S. P. Tetrahedron 1998, 54, 263.
2. Farina, V.; Krishnamurthy, V.; Scott, W. J.. In Organic Reaction; Paquette, L., Ed.;
John Wiley and Sons: New York, 1997; Vol. 50,.
3. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (b) Suzuki, A. Pure Appl.
Chem. 1994, 66, 213.
4. (a) Walla, P.; Kappe, C. O. Chem. Commun. 2004, 564; (b) Zhao, J.; Fu, G. J. Am.
Chem. Soc. 2003, 125, 12527.
5. Sonogashira, K.. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: New York, 1991; Vol. 3, p 521; Sonogashira, K.; Tohda,
Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467.
6. (a) Yu, Y.; Liebeskind, L. S. J. Org. Chem. 2004, 69, 3554; (b) Kusturin, C.;
Liebeskind, L. S.; Rahman, H.; Sample, K.; Schweitzer, B.; Srogl, J.; Neumann, W.
L. Org. Lett. 2003, 5, 4349; (c) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979; (d)
15. (a) Polshettiwar, V.; Varma, R. S. Curr. Opin. Drug Disc. Develop. 2007, 10, 723;
(b) Sperry, J. B.; Wright, D. L. Curr. Opin. Drug Disc. Develop. 2005, 8, 723.
16. Spectroscopic data for new compounds in Table 2: Entry 3: 1H NMR (chloroform-
d, 300 MHz): d 8.74 (s, 1H), 8.56 (s, 1H), 8.46 (d, J = 2.6 Hz, 1H), 7.52–7.61 (m,
J = 8.7 Hz, 2H), 6.86–6.96 (m, J = 8.7 Hz, 2H), 3.85 ppm (s, 3H); MS m/z 211
(M+H); Entry 4: 1H NMR (chloroform-d, 300 MHz): d 8.76 (d, J = 1.5 Hz, 1H),
8.59 (s, 1H), 8.50 (d, J = 2.6 Hz, 1H), 7.55–7.69 (m, 2H), 7.05–7.15 ppm (m, 2H),
MS m/z 199 (M+H); Entry 5: 1H NMR (chloroform-d, 300 MHz): d 8.80 (s, 1H),
8.63 (s, 1H), 8.56 (d, J = 2.3 Hz, 1H), 7.70 ppm (s, 4H), MS m/z 206 (M+H); Entry
6: 1H NMR (chloroform-d, 300 MHz): d 8.61 (d, J = 1.5 Hz, 1H), 8.48–8.53 (m,
1H), 8.42 (d, J = 2.3 Hz, 1H), 2.58–2.75 (m, 1H), 1.86–1.99 (m, 2H), 1.70–1.84
(m, 2H), 1.49–1.66 (m, 3H), 1.29–1.45 ppm (m, 3H), MS m/z 187 (M+H).