Sonogashira cross-coupling in a designer ionic liquid (IL) without copper, external base, or additive, and with recycling and reuse of the IL

Article abstract of DOI:10.1016/j.tetlet.2015.06.067

Application of a piperidine-appended dimethyl-imidazolium-NTf₂ ionic liquid as dual solvent and base in the Sonogashira cross-coupling reaction of aryl-iodides with terminal acetylenes under mild conditions has been demonstrated. The method employs PdCl₂(PPh₃)₂ without copper and external base. It is applicable to the synthesis of SF₅-substituted diaryl- and aryl-alkyl-acetylenes, and can also be utilized for efficient homo-coupling of terminal acetylenes under aerobic conditions. The potential for recycling and reuse of this designer-IL offers an added advantage.

Full text of DOI:10.1016/j.tetlet.2015.06.067

Tetrahedron Letters 56 (2015) 4807–4810
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sonogashira cross-coupling in a designer ionic liquid (IL) without
copper, external base, or additive, and with recycling and reuse of the
IL
⇑
A. Srinivas Reddy, Kenneth K. Laali
Department of Chemistry, University of North Florida, 1 UNF Drive, Jacksonville, FL 32224, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Application of a piperidine-appended dimethyl-imidazolium-NTf2 ionic liquid as dual solvent and base in
the Sonogashira cross-coupling reaction of aryl-iodides with terminal acetylenes under mild conditions
has been demonstrated. The method employs PdCl2(PPh3)2 without copper and external base. It is
applicable to the synthesis of SF5-substituted diaryl- and aryl-alkyl-acetylenes, and can also be utilized
for efficient homo-coupling of terminal acetylenes under aerobic conditions. The potential for recycling
and reuse of this designer-IL offers an added advantage.
Received 6 May 2015
Revised 11 June 2015
Accepted 22 June 2015
Available online 26 June 2015
Keywords:
Ó 2015 Elsevier Ltd. All rights reserved.
Sonogashira cross coupling
Piperidine-tethered imidazolium-NTf2
Designer-IL
Synthesis of SF5-substituted diarylethynes
Homo-coupling of alkynes
Recycling and reuse of IL
The Sonogashira cross-coupling reaction is a powerful method
for the synthesis of internal alkynes and enynes. This highly
versatile Csp2–Csp bond forming protocol is widely exploited in
the synthesis of natural products, pharmaceuticals, agrochemicals,
and materials. The reactions are typically carried out by using
catalytic amounts of palladium (most commonly Pd(Ph3P)2Cl2)
along with a copper halide (typically CuI) in the presence of an
amine, used either as solvent or as cosolvent along with solvents
such as DMF, THF, or toluene. Both homogeneous and heteroge-
neous Sonogashira coupling have been extensively studied, and
progress in this ever expanding research area has been summa-
rized in timely reviews.1–5
Research aimed at: (a) replacing Pd for the more readily avail-
able, cheaper metals, (b) copper-free conditions, (c) avoiding the
use of large quantities of base, (d) replacing solvents such as
DMF and DMSO with environmentally more acceptable alterna-
tives, and (e) minimizing competing formation of homocoupling
products, constitute active areas that are under continuous devel-
opment. Along these lines, ligand-free Fe/Cu co-catalyzed
Sonogashira coupling reactions have been reported by using
Fe(acac)3/CuI and Fe2O3/Cu(acac)2.6,7 These methods still require
base and are typically performed at high temperatures in DMF or
DMSO. By using PdCl2 along with a water soluble phosphine
ligand,8 or by employing Pd-nanoparticles9, the coupling reaction
could be carried out in water/amine mixtures. Competing homo-
coupling was greatly lowered by performing the reaction in
Pd(Ph3P)2Cl2/CuI/TEA/MeCN under reflux and by working under
H2 + N2 atmosphere.10 Efficient homocoupling of terminal alkynes
was reported with Pd(OAc)2/DABCO/CuI/air/MeCN,11 or via
a
Cu(I)-catalyzed method employing CuCl/O2 together with an
amine ligand (TMEDA, DBEDA, DABCO) in MeCN as solvent.12
Ionic liquids (ILs) have shown promise as versatile media for
various Pd-catalyzed reactions including Sonogashira.13 Apart from
[BMIM][PF6],14–16 phosphonium type amino acid-ILs,17 and
biodegradable ILs18 have been employed along with the Pd
catalyst [Pd(OAc)2, PdCl2, or Pd(Ph3P)2Cl2, or a phosphine-ligated
Pd-complex] together with a base (TEA, iPr2NH, or piperidine).
The copper-free Sonogashira reaction employed ultrasound,15 or
a phosphine-ligated Pd-complex.18
A basic-IL with appended iPr2N-groups was previously used
in representative C–C bond forming reactions including
Sonogashira.19 The method utilized Pd(Ph3P)2Cl2 along with
piperidine or methanol and was accompanied by noticeable
homocoupling (10–40%).
In continuation of our previous studies on metal-mediated
transformations in ILs,20 and in connection to our continuing inter-
est in the synthesis of SF5-aromatics,21 we report here on the appli-
cation of a piperidine-appended dimethyl-imidazolium-NTf2 IL-1
acting as dual solvent and base in the Sonogashira cross-coupling
⇑
Corresponding author. Tel.: +1 904 620 1503; fax: +1 904 620 3535.
E-mail address: kenneth.laali@UNF.edu (K.K. Laali).
http://dx.doi.org/10.1016/j.tetlet.2015.06.067
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

4808
A. Srinivas Reddy, K. K. Laali / Tetrahedron Letters 56 (2015) 4807–4810
reaction of aryl-iodides with terminal acetylenes under mild condi-
tions with minimal competing homocoupling.22 The method
employs PdCl2(PPh3)2 and is copper and external-base free. The
efficacy of the method was tested in the synthesis of SF5-substi-
tuted diaryl- and aryl-alkyl-acetylenes. The IL-1 was also utilized
for efficient homo-coupling of terminal acetylenes under aerobic
conditions.23 The potential for recycling and reuse of this
designer-IL was also studied.24
Figure 2 gives a summary of the alkynes and the iodides used in
this study and Table 1 gives a summary of the experimental
results.
The efficacy of the IL-1 catalyzed Sonogashira reaction was sub-
sequently tested in the synthesis of SF5-substituted analogs (Fig. 3)
and results are summarized in Table 2.
The iodo-pentafluorosulfanylbenzene was prepared via the dia-
zonium salt21 by reaction with KI (see Supplementary file).
The method was also applied to the synthesis of diynes via
homocoupling under aerobic condition and the results are summa-
rized in Table 3.
The IL-1 (Fig. 1) is a dark-brown oily liquid at room temperature
and is conveniently prepared from the chloride salt by standard
metathesis with LiNTf2 (see Supplementary file).
The potential for recycling and reuse of IL-1 was tested in the
Sonogashira reaction of 4-iodoacetophenone and phenylacetylene
(entry 4 in Table 1) by repeating the reaction four additional times
using the same IL. The results (Chart 1) show a gradual decrease in
the isolated yields from 85% to 68% after a total of 5 runs.
In summary we have discovered a facile one-pot approach for
the preparation of a library of diaryl- and aryl-alkyl-acetylenes
including the SF5-substituted derivatives by using a designer IL
functioning as dual solvent/base in the Sonogashira reaction with-
out the need for any other additive. The method is also suitable for
N
N
N
Me
Me
NTf2
IL-1
Figure 1. Task-specific IL as dual solvent/base for the Sonogashira reaction.
R
OH
(R = H; tBu; F)
IL-1
Sonogashire Cross Coupling
TMS
PdCl2(PPh3)2
5 mol% (65o C; 8-15 h)
IL-1
R
+
Ar
F5S
I
F5S
Ar
I
PdCl2(PPh3)2
5 mol%
I
S
(Ar: H; p-F; p-tBu; cyclopentyl)
(74-81%)
(R = H; m-OMe; p-Me; p-CF3; p-COMe; p-NO2)
(65o C; 10-12 h)
Figure 2. Scope of the Sonogashira cross-coupling reaction using IL-1.
Figure 3. Synthesis of SF5-substituted analogs.
Table 1
Scope of the Sonogashira coupling reaction in IL-1
Entry
ArX
Alkyne
Product
Time (h)
10
Temp (°C)
Yielda,b (%)
84
Homocoupling (%)
8
I
MeO
1
65
MeO
I
2
3
12
10
65
65
76
83
11
12
I
F3C
O
F3C
O
I
4
5
12
12
65
65
85
79
9
I
O
F
13
O
F
I
O2N
6
7
8
10
8
65
65
65
78
79
81
15
No
No
O2N
I
MeO
O2N
Si
Si
Si
MeO
I
Si
8
O2N
S
I
S
9
12
15
65
65
78
72
6
MeO
I
OH
MeO
HO
10
19
a
Product characterized by NMR, IR, and MS.
Yields refer to isolated products after purification; no = not observed.
b

A. Srinivas Reddy, K. K. Laali / Tetrahedron Letters 56 (2015) 4807–4810
4809
Table 2
Application of the method in the synthesis of SF5-analogs
Entry
ArX
Alkyne
Product
Time (h)
10
Temp (°C)
Yielda,b (%)
81
Homocoupling (%)
I
I
F5S
11
65
13
14
F5S
F5S
F5S
12
12
65
77
I
I
F
F5S
F5S
13
14
12
10
65
65
76
74
14
17
F5S
F5S
F
a
Products characterized by NMR, IR, and MS.
Yields refer to isolated products after purification.
b
Table 3
Efficacy in the synthesis of diynes by homocoupling
Entry
Alkyne
Product
Time (h)
Temp (°C)
Yielda,b (%)
93
15
10
10
Rt
16
70
92
F
F
17
18
10
10
Rt
89
87
F
70
a
Products characterized by NMR, IR, and MS.
Yields refer to isolated products after purification.
b
this article can be found, in the online version, at http://dx.doi.
org/10.1016/j.tetlet.2015.06.067.
References and notes
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Chart 1. Recycling and reuse of IL-1 in the Sonogashira reaction of 4-iodoace-
tophenone and phenylacetylene.
homocoupling reactions. Simple product isolation and recycling
and reuse of the IL are added advantages of this method.
Acknowledgement
16. Fukuyama, T.; Rahman, M. T.; Maetani, S.; Ryu, I. Chem. Lett. 2011, 40, 1025–
1029.
17. Harjani, J. R.; Abraham, T. J.; Gomez, A. T.; Garcia, M. T.; Singer, R. D.;
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K.L. thanks UNF for the award of Presidential Professorship and
for research support.
Supplementary data
19. Ye, C.; Xiao, J.-C.; Twamley, B.; LaLonde, A. D.; Norton, G. M.; Shreeve, J. M. Eur.
J. Org. Chem. 2007, 5095–5100.
Supplementary data (complete experimental procedures and
characterization data for the reported products) associated with

4810
A. Srinivas Reddy, K. K. Laali / Tetrahedron Letters 56 (2015) 4807–4810
20. (a) Kalkhambkar, R. G.; Laali, K. K. Tetrahedron Lett. 2011, 52, 5525–5529; (b)
Kalkhambkar, R. G.; Laali, K. K. Tetrahedron Lett. 2011, 52, 1733–1737.
21. Okazaki, T.; Laali, K. K.; Bunge, S. D.; Adas, S. K. Eur. J. Org. Chem. 2014, 1630–
1644.
23. General procedure for homocoupling reaction of terminal alkynes: The terminal
alkyne (0.5 mmol) and PdCl2(PPh3)2 (0.025 mmol) were added to the basic IL
(10 equiv) in a reaction tube open to air, and the mixture was stirred at 70 °C
for 8–12 h and in some cases overnight at rt. After completion of the reaction
(TLC monitoring), the reaction mixture was extracted several times with 20%
ethyl acetate in hexane (4 Â 10 mL) and the combined organic extract was
evaporated under vacuum. The crude mixture was purified by silica gel column
chromatography using hexane as eluent.
24. Recycling and re-use of the IL: Following extraction of the product(s) from the
ionic liquid phase (as described above), the reaction tube containing the basic
IL was placed under vacuum at 60 °C for about 8 h. After cooling to rt the
reaction tube was re-charged with the aryl iodide and the alkyne and 1 mol %
of fresh PdCl2(PPh3)2 (refer to Chart 1 for an indication of the efficiency of the
recycling and reuse).
22. General procedure for the coupling of aryl iodides with terminal alkynes: Reactions
were typically carried out on 50–60 mg scale. The basic ionic liquid (15 equiv)
was charged into a 10 mL Schlenk tube and degassed under reduced pressure
at room temperature for 15 min. Following which, PdCl2(PPh3)2 (0.012 mmol),
aryl iodide (0.25 mmol), and the terminal alkyne (0.25 mmol) were introduced
under a blanket of nitrogen, and the resulting mixture was stirred at 65 °C for
8–15 h. After completion of the reaction (TLC monitoring), the reaction mixture
was extracted several times with 40% ethyl acetate in hexane (4 Â 10 mL) and
the combined organic extracts was evaporated under vacuum. The crude
reaction mixture was purified by silica gel column chromatography using
hexane as eluent with up to 5% ethyl acetate (as needed).