Sonogashira-type cross-coupling reactions catalyzed by copper complexes of pincer N-heterocyclic carbenes

Article abstract of DOI:10.1016/j.jorganchem.2018.02.028

Copper complexes of N-heterocyclic carbenes (NHC) have recently received great attention in catalysis, however, the application scope has been limited to neutral complexes bearing monodentate ligands. Herein, we report the synthesis and full characterization of a cationic Cu-pincer bis(NHC) complex with bulky tert-butyl wingtips that serves as catalyst for the coupling of aryl iodides and phenylacetylene, alongside its analogs with small alkyl substituents. Unlike other copper catalysts that require an inert atmosphere to prevent alkyne homocoupling, a competing side reaction to Sonogashira reaction, the Cu-pincer bis(NHC) complexes provide good to excellent cross-coupling yields in air. Interestingly, the reaction under argon affords substantially reduced cross-coupling, indicative of the oxygen involvement and its facilitating effect in the mechanism. In our controlled studies, the air-assisted cross-coupling reaction came to a complete stop when using a radical trap, suggesting the presence of a radical in the mechanism. Examining the reaction of Cu-pincer bis(NHC) complexes with oxygen via UV–vis spectroscopy reveals a dark green chromophore formation at ?40 °C with strong absorbance (ε > 400 M^?1cm^?1) at 460 nm and 500 nm, likely due to a high-valent copper-oxygen adduct.

Full text of DOI:10.1016/j.jorganchem.2018.02.028

Accepted Manuscript
Sonogashira-type cross-coupling reactions catalyzed by copper complexes of pincer
n-heterocyclic carbenes
Doaa Domyati, Reza Latifi, Laleh Tahsini
PII:
S0022-328X(18)30127-X
10.1016/j.jorganchem.2018.02.028
JOM 20327
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 29 December 2017
Revised Date: 18 February 2018
Accepted Date: 19 February 2018
Please cite this article as: D. Domyati, R. Latifi, L. Tahsini, Sonogashira-type cross-coupling reactions
catalyzed by copper complexes of pincer n-heterocyclic carbenes, Journal of Organometallic Chemistry
(2018), doi: 10.1016/j.jorganchem.2018.02.028.
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ACCEPTED MANUSCRIPT
Sonogashira-Type Cross-Coupling Reactions Catalyzed by Copper
Complexes of Pincer N-Heterocyclic Carbenes
Doaa Domyati, Reza Latifi, and Laleh Tahsini*
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078, United States
Supporting Information Placeholder
ABSTRACT: Copper complexes of N-heterocyclic carbenes (NHC) have recently received great attention in catalysis, however,
the application scope has been limited to neutral complexes bearing monodentate ligands. Herein, we report the synthesis and full
characterization of a cationic Cu-pincer bis(NHC) complex with bulky tert-butyl wingtips that serves as catalyst for the coupling of
aryl iodides and phenylacetylene, alongside its analogs with small alkyl substituents. Unlike other copper catalysts that require an
inert atmosphere to prevent alkyne homocoupling, a competing side reaction to Sonogashira reaction, the Cu-pincer bis(NHC)
complexes provide good to excellent cross-coupling yields in air. Interestingly, the reaction under argon affords substantially re-
duced cross-coupling, indicative of the oxygen involvement and its facilitating effect in the mechanism. In our controlled studies,
the air-assisted cross-coupling reaction came to a complete stop when using a radical trap, suggesting the presence of a radical in
the mechanism. Examining the reaction of Cu-pincer bis(NHC) complexes with oxygen via UV-vis spectroscopy reveals a dark
green chromophore formation at -40 °C with strong absorbance (ε > 400 M-1cm-1) at 460 nm and 500 nm, likely due to a high-
valent copper-oxygen adduct.
Keywords: Copper-pincer NHC complexes, Sonogashira-type cross-coupling reactions, copper-oxygen adducts, radical trap
and polymer chemistry [22-24], material science [25], and
organic synthesis [26-28]. In Sonogashira procedure, the
INTRODUCTION
Since the first application of copper-NHC complexes in catal-
ysis reported by Woodward [1], they have become increasing-
ly popular over the last decade. Although the first studies of
Cu-NHC complexes were focused on mimicking the reactivity
of their phosphine counterparts [1-3], the breadth of recent
advancements encompasses hydrosilylation, click chemistry,
cross-coupling, C–H activation, and some others [4-6]. De-
spite the diversity of copper complexes bearing mono-, bis-
and poly-NHC ligands [7-11], only neutral Cu(NHC)X com-
plexes with mono-NHC ligands (X = halide, hydroxide, etc.)
have been intensely examined in catalysis [6, 12, 13]. The
easy synthesis and enhanced solubility of neutral mono-NHC-
copper complexes in organic solvents accounts for such versa-
tile application. With the development of new synthetic strate-
gies, however, the copper complexes of bis-NHC and poly-
NHC ligands have started emerging in catalysis as well [14-
16].
cross-coupling yield of aryl halides and terminal alkynes was
improved by using a copper co-catalyst, likely due to the for-
mation of reactive copper acetylide. The high cost and toxicity
of palladium has been a motivation for many groups to devel-
op efficient catalysts using copper-based systems (So-
nogashira-like) [29] or significantly reducing the amounts of
palladium and copper (sub-mol%) in Sonogashira reaction
[30-33]. Regardless of the type, a typical burden with So-
nogashira cross-coupling reactions is the requirement of oxy-
gen-free conditions to prevent the homocoupling of alkynes
(Glaser-Hay coupling) [34, 35]. Alkynes oxidative homocou-
pling can compete with Sonogashira reaction leading to re-
duced yields of cross-coupled products.
A sensible strategy to restrain Glaser-Hay coupling is to use
air-stable and moisture-resistant coordination environment or
auxiliary ligands with copper/palladium catalysts as shown by
Hierso [32], Navarro [33], and others [36, 37]. The desired
cross-coupled products were prepared selectively with no or
minor homocoupling in these systems. Although the catalytic
reaction mixtures were prepared mostly under inert atmos-
phere, the oxidation-resistance of the catalyst was shown via
efficient Sonogashira coupling achieved in air in one case
[33]. To the best of our knowledge, however, there has been
no report of aryl alkyne and aryl halide reaction where the
cross-coupling was improved in the presence of oxygen. Here-
in, we report the development of Sonogashira-like oxidative
cross-coupling reactions using well-characterized Cu(I)-pincer
bis(NHC) complexes as well as the synthesis of mononuclear
[Cu{I(tBu)C^N^C]PF6 complex where I(tBu)C^N^C = 2,6-bis(3-
Recently, we have developed mononuclear pyridylmethyl-
i
linked copper(I)-bis(NHC) complexes bearing Me, Et and Pr
wingtips that show a reversible Cu(II)/Cu(I) redox couple in
electrochemical studies [17]. To assess their potential reactivi-
ty and application in catalysis, we were inspired by the earlier
reports of pyridyl-linked Pd-bis(NHC) [18] and triscarbene-
ligated trinuclear Cu-NHC complexes [14] in Sonogashira
cross-coupling reactions. This general protocol was developed
by Sonogashira [19] for aryl alkynes synthesis after the first
report of palladium-catalyzed C(sp)–C(sp2) bond formation by
Heck and Cassar groups [20, 21]. Functionalized alkynes are
among the most prominent structural motifs in pharmaceutical
1

ACCEPTED MANUSCRIPT
tert-butylimidazol-2-yldene)methylpyridine for our mechanis-
tic studies.
the presence of a vacant site below the coordination plane in
complexes 1-3, in contrast to sterically congested area around
the coordination plane in 4.
RESULTS AND DISCUSSION
Coupling Reaction Optimization. For the initial screening,
we chose the coupling of phenylacetylene and iodobenzene as
the model reaction (Table 1). All reactions were carried out in
screw-cap 20 mL reaction vial and loaded with reagents in air
using 5mL reagent-grade solvents. The model reaction was
initially performed using [Cu{I(Me)C^N^C}]PF6 (1) in different
solvents at 120 °C and provided the highest yield of the prod-
uct in DMF after 48 hours (Table 1, entry 4). A steady in-
crease in the yield was observed for 4 days at 120 °C indicat-
ing a fairly stable catalyst (Figure S2). Increasing the tempera-
ture to 140 °C afforded diphenylacetylene at a much higher
yield after 24 hours (Table 1, entry 8). To examine the effect
of catalyst, the model reaction was tested with complexes 2-4
providing the highest and lowest isolated yields with 3 and 4,
respectively (Table 1, entry 10 and 12). The amount of unre-
acted iodobenzene after 24 hours was estimated by GC as 14%
for 1, 13% for 2, 22% for 4, and 17% for 3 at 0.05 mmol load-
ing (Table 1, entries 8-12). Controlled reactions using insolu-
ble metallic copper or copper(I)/(II) oxide provided only 10%
Synthesis of Cu−NHC Complexes 1−4. The copper-pincer
bis(NHC) complexes bearing Me, Et, and Pr wingtips (Figure
i
1a) were prepared via the reaction of an in-situ generated car-
bene and [Cu(CH3CN)4]PF6 as described in our earlier work
[17]. To examine the effect of substituents on the catalyst ac-
tivity, we have prepared the imidazolium salt, ItBuC^N^C.2HBr,
and its copper(I) complex, 4, via modifying the previous pro-
cedure and characterized them by H NMR, 13C NMR, and
1
elemental analysis. Single crystal X-ray structure of the com-
plex was also determined (Figure 2). The acidic proton signal
of the imidazolium ring (H2) has completely disappeared in the
1H NMR spectrum of the complex as compared to the imidaz-
olium salt (Figure S1). The 13C NMR spectrum of the complex
displays signal at 179 ppm due to the carbenic carbon center,
consistent with the shifts reported for other Cu–NHC com-
Table 1. Reaction of phenylacetylene with iodobenzene cata-
lyzed by [Cu{I(R)C^N^C}]PF6 complexes a
Entry [Cu]
Solvent
Temp.
(°C)
Time
(h)
Yield
(%)b
Figure 1. Pincer Cu-NHC Complexes used in this study
plexes [12, 15, 17].
1
1
1
1
DMSO
Toluene
n-BuOH
DMF
120
“
48
“
58
10
5
1
X-ray Crystallography of Complex 4. Single crystals of the
complex were obtained by slow diffusion of diethyl ether into
a dichloromethane solution of 4 at room temperature. An
ORTEP diagram of the complex is given in Figure 2 with a
summary of crystallographic data collection parameters in
Table S1. In the crystal structure, each copper is ligated by
two NHC moieties from the same pincer ligand, similar to its
analogs with smaller wingtips (Figure 1a). The average Cu–
CNHC bond distances of two isostructural cations in the unit
cell are 1.931(4) Å and 1.914(3) Å, in the range of other Cu–
NHC complexes [38-40]. However, the Cu–Npy distances of
2.265(3) Å and 2.221(2) Å are substantially shorter than those
determined for the smaller wingtip derivatives [17] indicating
a stronger interaction with ancillary pyridine in 4. The stereo-
chemistry of the Cu–NHC unit in 4 is also distinct from its
analogs as indicated by the dihedral angle (θ) between the
NHC rings (Figure 1). A major influence of this difference is
2
“
“
3
“
“
63
2
4
Cu(0) DMF
“
“
5
Cu2O
DMF
“
“
10
22
84
86
96
83d
80
6
2c
1
2
3
3
4
DMF
“
“
7
DMF
140
“
24
“
8
9
“
“
“
“
“
“
10
11
“
“
“
“
12
a
Reaction conditions were as follows: iodobenzene (0.5
mmol), phenylacetylene (0.75 mmol), K2CO3 (0.75 mmol),
[Cu{I(R)C^N^C}]+ (0.1 mmol), solvent (5 mL) in air. b Isolated
c
yield. Complex 2 was made by mixing Cu2O (0.05 mmol),
IEtC^N^C.2HBr (0.1 mmol), and K2CO3 (1 mmol). d 0.05 mmol
of [Cu{I(R)C^N^C}]+ was used.
2
Figure 2. ORTEP diagram of [Cu(ItBuC^N^C)]+,4. Ellipsoids
are shown at the 50% probability level. Anions and hydrogen
are omitted for clarity.

ACCEPTED MANUSCRIPT
yield or less under the same conditions, supporting a soluble
substituted aryl iodides (Scheme 1, 4, 6‒8, 22, 23) afforded
greater cross-coupling yields than their p-substituted analogs
(Scheme 1, 3, 21, 24). As expected, the steric hindrance of
alkyl groups in 2,6-dimethyl- and 2-ethyl-iodobenzene led to a
lower cross-coupled product (Scheme 1, 6, 7) than what was
obtained with 2-iodotoluene (Scheme 1, 4). The cross-
coupling of iodobenzene with phenylacetylene bearing elec-
tron-donating (Scheme 1, 30, 32) and electron-withdrawing
(Scheme 1, 29, 31) groups provided comparable good yields.
Additionally, the catalytic system presented a high toleration
of chloride and bromide substituents on aryl iodide and termi-
nal alkyne. The cross-coupled products were obtained in great
yields ranging from 68% to 80% with aryl iodide (Scheme 1,
21‒24) and moderate yields of 45‒55% with phenylacetylene
derivatives (Scheme 1, 26‒28). At this point, it is also worth
mentioning that the amount of Glaser homocoupling (HC)
product was equal to or less than 5% in most of the reactions
copper species as the active catalyst (Table 1, entries 5, 6).
The [Cu{I(Et)C^N^C}]+ complex, generated in-situ by mixing 10
mol% Cu2O and 20 mol% IEtC^N^C.2HBr, afforded only 22%
diphenylacetylene, revealing the importance of using a pre-
made catalyst (Table 1, entry 7).
Reaction Scope. To examine the application scope of the
cross-coupling catalysts, we applied the optimized conditions
to a range of electronically and sterically diverse substrates.
The coupling of aryl-substituted terminal alkynes with aryl
iodides bearing electron-donating and electron-withdrawing
groups provided the cross-coupled products in moderate
(45%) to excellent (99%) yields (Scheme 1). In general, the
reactions involving electron-withdrawing substituents on aryl
iodide provided greater yields, however, two substrates fell
outside of this trend. Methyl 4-iodobenzoate (Scheme 1, 2)
was less active than 4-iodotoluene (Scheme 1, 3), and 1-iodo-
4-nitrobenzene (Scheme 1, 14) was the least reactive substrate
among the p-substituted iodobenzene derivatives. Phenyla-
cetylene was also coupled with a series of heterocyclic aryl
iodides, in yields ranging from 54 to 66% (Scheme 1, 17‒20).
The presence of heterocycle on terminal alkyne proved detri-
mental with only 35% cross-coupled product obtained for 2-
ethynylpyridine (Scheme 1, 25). Furthermore, the o-
1
as determined by H NMR spectroscopy, except for amino,
nitro-, and 2-bromoiodobenzene derivatives (Scheme 1, 13‒
15, 23), 2-iodothiophene (Scheme 1, 17), and 2-iodonaphthyl
(Scheme 1, 16). This finding is significant since the oxidative
coupling of alkynes is typically promoted by copper(I) salts in
the presence of oxygen [34]. Our controlled reactions under
anaerobic conditions, however, have shown the essential role
Scheme 1. The coupling of aryl iodides and phenylacetylene derivatives catalyzed by Cu-pincer NHC complex 3a
3

ACCEPTED MANUSCRIPT
of air in the Cu-pincer NHC-catalyzed cross-coupling reac-
spectra. The absorption bands at 460 and 600 nm disappear
upon warming the solution to room temperature and are re-
placed by a broad band at 640 nm (ε = 21 M-1 cm-1) pertinent
to the ligand-field transitions of Cu(II) complexes (Figure S5).
tions (vide infra). We also carried out the coupling between 4-
bromobenzotrifluoride and phenylacetylene, but only 8% of
the cross-coupled product was isolated. Furthermore, our at-
tempts to conduct the reaction of iodobenzene and cyclohex-
ylacetylene under optimized conditions did not provide isola-
ble cross-coupled product.
To further examine the role of oxygen and potential copper-
oxygen adduct(s), we carried out the coupling of 4-
iodotoluene and phenylacetylene in the presence of Galvinox-
yl as a radical trap. Interestingly, a significant drop in the
cross-coupling yield to 20% and increase in the homocoupling
to 33% was found, suggesting a radical-based mechanism for
the reaction. The radical mechanism is suppressed in the pres-
ence of inhibitor, precluding the copper-oxygen-derived cross-
coupling and re-directing the reaction to the path in the ab-
sence of oxygen (Classical Sonogashira) [44]. A plausible
mechanism for the catalytic reaction in the absence of oxygen
is depicted in Scheme 2. The feasible reaction of Cu(I)-NHC
complexes with oxygen, shown by the UV-vis studies, renders
the temperature-sensitive Cu–O2 adducts as reactive species in
the current system. High-valent Cu–O2 intermediates capable
of activating weak (ca. 88 kcal mol-1) and strong (> 93 kcal
mol-1) C–H bonds are found in Cu-containing enzymes such as
mononuclear Cu monooxygenases [45-47] and multinuclear
particulate methane monooxygenase (pMMO) [48-50], as well
as in synthetic copper complexes [51-56]. The highly reactive
Cu-O2 adducts supported by pincer bis-NHC ligands can acti-
vate the susceptible bonds in the reaction media leading to a
more active catalyst than initial Cu-I(R)C^N^C precatalyst. The
mechanism of the coupling reaction in the presence of oxygen
is currently under investigation in our group to clarify the in-
termediates involved following the Cu-O2 species formation.
Mechanistic Study. To clarify the role of oxygen in the pre-
sent system, we performed the coupling reaction under argon.
1
Given the similar H NMR spectra of diphenylacetylene and
diphenylbutadiyne (Figure S3), we used 4-iodotoluene instead
of iodobenzene to quantify the amount of homo- and cross-
coupled products. Interestingly, the reaction of phenylacety-
lene and 4-iodotoluene under argon provided three times less
of the cross-coupled product compared to that obtained under
air (Figure 3). The homocoupling yield was also reduced by
Figure 3. Reaction of phenylacetylene with 4-iodotoluene under
air and argon.
half.
The assistant role of oxygen in the present cross-coupling sys-
tem is presumably related to the oxidation of copper(I) com-
plexes. To elaborate this reactivity, we carried out the oxygen-
ation of [Cu(IiPrC^N^C]PF6 at low temperatures and monitored
the spectral changes via UV-vis spectroscopy. When pure
oxygen gas was bubbled through a light yellow solution of 3
in CH3CN at -40 °C, a dark green color developed over the
course of an hour (Figure 4). The chromophore shows strong
charge transfer bands at around 275 and 305 nm, a strong
shoulder at 370 nm (ε ~ 1166 M-1 cm-1), and two medium in-
tensity bands at 460 nm (ε ~ 500 M-1 cm-1) and 600 nm (ε ~
400 M-1 cm-1). The UV-vis features resemble those reported
previously for copper-oxygen adducts such as peroxo-bridged
dicopper [41, 42] or copper-superoxo species [43]. Our pre-
liminary O2-uptake studies via spectrophotometric titration
reveals a 2:1 Cu/O2 stoichiometry at copper(I) concentrations
between 5 and 10 mM (Figure S4). Interestingly, no spectral
change was observed upon oxygenation of solutions of 3 at
[CuI] < 5mM. The generated Cu-oxygen chromophore is high-
ly reactive as shown by their temperature-dependent UV-vis
To examine the reactivity of Cu(I)-pincer bis(NHC) complex-
es towards aryl iodides (Scheme 2), we performed a stoichio-
metric reaction between 4-iodotoluene and complex 3 under
1
argon. The H NMR spectrum of the reaction mixture shows
no change to the Cu(I) complex after 24 hours of stirring at
room temperature (Figure S6). However, raising the tempera-
ture to 140 °C reveals a complex spectrum consisting of two
septet signals due to the CH proton on NHC rings, two singlets
due to the CH3 group of 4-iodotoluene, and a relatively acidic
proton due to an imidazolium moiety (Figure S7). Our at-
Scheme 2. Plausible mechanism for Sonogashira-type coupling
catalyzed by complexes 1-4 under argon.
tempts to obtain crystals of copper-containing species has
failed, likely due to the complex mixture of solution. The
presence of unreacted 4-iodotoluene in the mixture after 24
4
Figure 4. UV-vis spectral changes upon introduction of O2
into a 9.8 mM solution of 3 in CH3CN at ˗40 °C. The inset
shows the time profile of absorbance at 600 nm due to the
Cu–O2 adduct.

ACCEPTED MANUSCRIPT
hours indicates a much slower reaction rate between aryl io-
suppressed to a great extent (<5%). Further mechanistic stud-
ies to elucidate the structure and reactivity of Cu-oxygen ad-
ducts and the details of homo-coupling suppression are cur-
rently ongoing in our group.
dides and copper complexes in the absence of oxygen than its
presence. The reactivity difference is also revealed by three
times greater yield of the cross-coupled product obtained in air
than under argon.
EXPERIMENTAL SECTION
Given the mixed composition of air due to the presence of
oxygen, nitrogen, and other components, we performed the
coupling reaction using pure O2 gas to verify its participation
in catalysis. A concentration of 5.03 mM was calculated for
the oxygen-saturated DMF using solubility values found in
O2-uptake measurements by static method [57]. To achieve the
same concentration of oxygen in air, a dilution factor of one-
fifth was used to dilute an O2-saturated DMF solution. As ex-
pected, the phenylacetylene reaction with 4-iodotoluene in the
presence of 1.01 mM pure oxygen provided 70% cross-
coupled product, resembling that obtained in air.
General Procedure. Imidazolium salts and Cu(I) complex-
es (1-3) were synthesized according to published procedure
using standard Schlenk techniques or in an MBraun glovebox
under Ar atmosphere. The solvents used for the syntheses and
UV-vis studies were purified and distilled under N2 atmos-
phere before being stored over activated molecular sieves (4
Å) in the glovebox. Tetrahydrofuran and diethyl ether were
purified by refluxing over Na/benzophenone under a N2 at-
mosphere and distilled. Acetonitrile and hexane were distilled
from CaH2 under N2. Anhydrous 1,4-dioxane was obtained
from Sigma-Aldrich and used as received. Potassium tert-
butoxide (97%) was obtained from Sigma-Aldrich and tritu-
rated with THF in the glovebox. NMR samples of 4 and its
reaction with 4-iodotoluene were prepared under Ar in deuter-
ated solvents, CD3CN or DMSO-d6 containing 0.05% TMS as
internal standard. The imidazolium salt, I(tBu)C^N^C.2HBr and
complex 4 were synthesized by some modification of the pub-
lished procedure. Flash chromatography was performed on
Merck silica gel 60 (230-400 mesh). Gas chromatography
(GC) data were recorded on an Agilent Technologies 6850 N
instrument with a HP1-MS 30.0 m × 0.32 mm × 0.25 µm ca-
pillary apolar column. The conversion of iodobenzene as limit-
ing reagent in Table 1 was calculated in the presence of dodec-
ane as an internal standard using relative peak areas before and
after the catalytic reaction. NMR spectra were measured using
a 400 MHz Bruker Avance III spectrometer. Chemical shifts
Finally, we have examined the effect of wingtip substituents of
complexes 1-4 on the distribution of cross-coupled and homo-
coupled products. Under optimized conditions, the reaction of
phenylacetylene and 4-iodotoluene provided the highest and
lowest cross-coupling yields with 1 and 4, respectively (Figure
5). Despite the comparable homocoupling (3-5%) obtained
with complexes 1-3, 4 gave 18% diphenyldiacetylene. The
significant increase of the homo-coupled product with 4 can
be rationalized by structural considerations. In complexes 1-3,
the potential formation of a Cu-oxygen intermediate is facili-
tated by the presence of a vacant site, below the coordination
plane and away from the wingtips and methylene linkers (Fig-
ure 1). The formation of such species in 4 is sterically hin-
dered, and/or the species is likely prone to intramolecular de-
activation processes. The enhanced homocoupling with com-
plex 4 can be attributed to such processes generating free cop-
1
(δ) for H and 13C NMR spectra were referenced to the reso-
nance of TMS as an internal reference or the residual protio
solvent. Elemental analyses were performed by Atlantic Mi-
crolabs, Inc. (Norcross, Georgia).
Ligand Synthesis. ItBuC^N^C.2HBr. Under an Ar atmos-
phere, a portion of 2,6-dibromomethylpyridine (0.725 g, 2.74
mmol) was dissolved in 25 mL distilled tetrahydrofuran (THF)
and added to a portion of 1-tert-butylimidazole (0.750 g, 6.03
mmol) at room temperature. The reaction mixture was then
allowed to heat and stir at 70-75 °C for four days after which
point, it was filtered through a fritted funnel. The solid was
triturated with distilled THF (30 mL) and diethyl ether (60
mL) and dried under vacuum. It was then transferred into a
glovebox and triturated with acetonitrile and ether affording a
Figure 5. Reaction of phenylacetylene with 4-iodotoluene
under air using complexes 1-4.
1
white solid in 67% yield (1.013 g). H NMR (MeOD with
3
0.05% v/v TMS, 400 MHz): δ = 9.33 (t, 2H; HCNIm, JHH
=
3
1.8 Hz), 7.99 (t, 1H; p-C5H3N, JHH = 7.8 Hz), 7.91 (d, 2H;
HCCHIm, JHH = 1.8 Hz), 7.68 (t, 2H; HCCHIm, JHH = 1.9 Hz),
7.51 (d, 2H; m-C5H3N, 3JHH = 7.8 Hz), 5.55 (s, 4H; CH2), 1.70
ppm (s, 18H; C(CH3)3). 13C{1H} NMR (MeOD with 0.05%
v/v TMS, 101 MHz): δ 155.10, 140.47, 136.37, 124.73,
123.91, 121.59, 61.61, 54.71, 29.90 ppm. Elemental analysis
(%) calcd. for C23H36Br2N5O1.5: C, 48.77; H, 6.41; N, 12.37,
found: C, 48.59; H, 6.47; N, 12.54. The calculated data in-
cludes 0.5 equiv. water and 0.5 equiv. THF which could not be
removed by long vacuum exposure.
per(I) ions in solution performing Glazer reaction.
CONCLUSION
In summary, we have developed a new protocol for the So-
nogashira-type coupling of aryl iodide and phenylacetylene
derivatives using Cu-pincer bis(NHC) complexes bearing al-
kyl wingtips. The mechanistic studies reveal greater coupling
yields in air than under argon, indicating a possibly different
mechanism than the classical Sonogashira reaction. Oxygen-
reactivity as well as radical trap experiments are supportive of
a high-valent Cu-oxygen adduct being involved. To the best of
our knowledge, this is the first report of Sonogashira-type
cross-coupling reactions under oxidative conditions catalyzed
by well-defined copper catalysts. It presents a unique approach
to the cross-coupled products in air while the homocoupling is
Complex Synthesis. [Cu(ItBuC^N^C)2](PF6), 4. A portion of
ItBuC^N^C.2HBr (0.200 g, 0.390 mmol) was combined with 2
equiv. of KOtBu (0.087 g, 0.780 mmol) in 2 mL THF forming
a pale yellow suspension and was left to stir for a few minutes.
A portion of [Cu(CH3CN)4](PF6) (0.145 g, 0.390 mmol) in
3mL CH3CN/THF (2:1) was added and the reaction mixture
5

ACCEPTED MANUSCRIPT
was left to stir for 21 h. The shiny reaction mixture was then
residue was purified by column chromatography to obtain
analytically pure product.
filtered through a glass frit to separate an off-white solid (KBr)
from a yellow filtrate. The solvent was removed from the fil-
trate under vacuum and the resultant yellow oil was recrystal-
lized from CH3CN/Et2O followed by CH2Cl2/Et2O affording
yellow/orange crystalline solid in 83% yield (0.181 g). Yellow
crystals suitable for X-ray crystallography were grown by
Cu-Catalyzed Coupling of 4-Iodotoluene and Phenyla-
cetylene in the Presence of 1mM O2 in DMF. In an argon-
filled glovebox, a 20 mL scintillation vial was charged with a
Teflon stir bar, copper complex (0.1 mmol), potassium car-
bonate (0.75 mmol), 4-Iodotoluene (0.5 mmol), and phenyla-
cetylene (0.75 mmol) in 0.3 mL anhydrous DMF. The vial was
sealed with a teflon cap bearing a silicone septum and trans-
ferred out of the glovebox where it was charged with 1 mL O2-
saturated DMF and 4 mL argon-saturated DMF, and was then
placed in an oil bath at 135-140 °C. The reaction mixture was
cooled down after 24h, diluted with 25-30 mL ethyl acetate,
and filtered through a pad of silica. The solvent was then re-
moved under vacuum and the residue was purified by column
chromatography.
1
vapor diffusion of Et2O into CH2Cl2. H NMR (CD3CN with
3
0.05% v/v TMS, 400 MHz): δ = 7.89 (t, 1H; p-C5H3N, JHH
=
3
7.7 Hz), 7.50 (d, 2H; m-C5H3N, JHH = 7.8 Hz), 7.29 (d, 2H;
HCCHNHC, JHH = 1.9 Hz), 7.22 (d, 2H; HCCHNHC, JHH = 2.0
Hz), 5.27 (s, 4H; CH2), 1.77 ppm (s, 18H; C(CH3)3). 13C{1H}
NMR (CD3CN with 0.05% v/v TMS, 101 MHz): δ 179.72,
154.07, 140.55, 123.80, 122.38, 58.76, 54.94, 31.94 ppm. El-
emental analysis (%) calcd. for C21H29CuF6N5P: C, 45.04; H,
5.22; N, 12.51, found: C, 44.74; H, 5.28; N, 12.16.
3
3
Cu-Catalyzed Coupling of Aryl iodide and Phenylacety-
lene Derivatives. A 20 mL scintillation vial was charged with
a Teflon stir bar, copper complex (0.1 mmol), potassium car-
bonate (0.75 mmol), aryl iodide (0.5 mmol), phenylacetylene
(0.75 mmol) in 5 mL non-anhydrous DMF in air. The vial was
sealed and placed in an oil bath with pre-adjusted temperature
at 135-140 °C. After the allowed time, the reaction mixture
was cooled down, diluted with 25-30 mL ethyl acetate, and
filtered through a pad of silica gel. The solvent was then re-
moved under vacuum and the residue was purified by column
chromatography using mixtures of hexane and ethyl acetate to
obtain analytically pure product.
Cu-Catalyzed Coupling of 4-Iodotoluene and Phenyla-
cetylene in the Presence of galvinoxyl radical in DMF. A 20
mL scintillation vial was charged with a Teflon stir bar, copper
complex (0.1 mmol), potassium carbonate (0.75 mmol), aryl
iodide (0.5 mmol), phenylacetylene (0.75 mmol), and Gal-
vinoxyl (0.5 mM) in 5 mL non-anhydrous DMF in air. The
vial was caped and placed in an oil bath with pre-adjusted
temperature at 135-140 °C. After the allowed time, the reac-
tion mixture was cooled down, diluted with 25-30 mL ethyl
acetate, and filtered through a pad of silica. The solvent was
then removed under vacuum and the residue was purified by
column chromatography to obtain analytically pure product.
Low-Temperature Formation of {Cu2–O2}2+ Complexes.
ASSOCIATED CONTENT
Supporting Information
Under an argon atmosphere within
a
glovebox,
[Cu(IiPrC^N^C)]PF6 (5.4, 7.0, 9.8 mM) was dissolved in 3 mL of
O2-free acetonitrile giving a bright yellow solution. The cu-
vette was fully sealed with a septum and quickly removed
from the glovebox and cooled to −40 °C in an Agilent 8454
diode array spectrophotometer equipped with Unisoku ther-
mostatic cell holder. Pure O2 was gently bubbled through the
reaction solution, for 3 min using a stainless steel needle (18
G). The formation of the {Cu2–O2}2+ species was followed by
the change in the absorbance at 460 and 600 nm.
1
Crystallographic data collection table, H and 13C{1H} NMR
spectra for tert-butyl-substituted imidazolium salt, its Cu(I)
complex (4), and cross-coupled products, spectrophotometric
titration graphs, and UV-vis spectra of {Cu2-O2}2+ adduct at
varying temperatures (PDF)
The Supporting Information is available free of charge on the
ACS Publications website.
Spectrophotometric Titration of 3 with O2. Under an ar-
gon atmosphere in a glovebox, [Cu(IiPrC^N^C)]PF6 (5.4 mM)
was dissolved in 3 mL of O2-free acetonitrile giving a bright
yellow solution. The cuvette was fully sealed with a septum
and parafilm, quickly removed from the glovebox, and cooled
to −40 °C in an Agilent 8454 diode array spectrophotometer
equipped with Unisoku thermostatic cell holder. To the cold
solution was added a different aliquot of O2-saturated acetoni-
trile solution (1.16 × 10−2 M)[58] prepared by bubbling O2
through argon-saturated acetonitrile in a Schlenk flask for 30
min at 298 K. The formation of the {Cu2–O2}2+ species was
followed by the change in the absorbance at 460 and 600 nm.
Cu-Catalyzed Coupling of 4-Iodotoluene and Phenyla-
cetylene in O2-Saturated DMF. In an argon-filled glovebox,
a 20 mL scintillation vial was charged with a Teflon stir bar,
copper complex (0.1 mmol), potassium carbonate (0.75
mmol), 4-Iodotoluene (0.5 mmol), and phenylacetylene (0.75
mmol) in 0.3 mL anhydrous DMF. The vial was sealed with a
teflon cap bearing a silicone septum and transferred out of the
glovebox where it was charged with 5 mL O2-saturated DMF
and placed in an oil bath with pre-adjusted temperature at 135-
140 °C. The reaction mixture was cooled down after 24h, di-
luted with 25-30 mL ethyl acetate, and filtered through a pad
of silica. The solvent was then removed under vacuum and the
Crystallographic information file for 4 (CIF)
AUTHOR INFORMATION
Corresponding Author
*Email: tahsini@okstate.edu. Phone: +1 (405) 744 4370. Fax:
(405) 744-6007.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge Oklahoma State University start-
up fund (LT), NSF-BIR 9512269, Oklahoma State Regents for
Higher Education, the W. M. Keck Foundation and Conoco
Inc. (NMR Spectrometers in the research facility center at
Oklahoma State) and OSU fund (Single Crystal X-ray Diffrac-
tion in the OSU core facility center) for financial support.
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Insert Table of Contents artwork here
A new protocol for efficient cross-coupling of aryl- and heterocyclic iodides and aryl alkynes is developed in air using Cu-pincer
bis(NHC) complexes with alkyl wingtips. The reaction involves oxidation of initial Cu(I)-NHC complexes, leading to a more active
catalyst through generation of a high-valent Cu-oxygen intermediate.
9

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Highlights:
1. A mononuclear copper(I)-pincer bis-NHC complex is synthesized and characterized by
X-ray crystallography.
2. Copper(I) complexes with pincer bis(NHC) ligands work as catalysts for Sonogashira-
type coupling of aryl iodides and aryl alkynes.
3. The catalytic cross-coupling reaction proceeds at a much higher rate in air than under
argon.
4. A high-valent copper-oxygen is involved in generating a more active catalyst than Cu(I)-
NHC pre-catalysts in air.
5. The oxidative cross-coupling reaction is halted in the presence of a radical inhibitor
indicative of a radical mechanism.