Highly convenient amine-free sonogashira coupling in air in a polar mixed aqueous medium by trans- and cis-[(NHC)2PdX2] (X = Cl, Br) complexes of N/O-functionalized N-heterocyclic carbenes

Article abstract of DOI:10.1002/chem.200800301

Two new trans- and cis[(NHC)₂PdX₂] (X = Cl, Br) complexes of MO-functionalized N-heterocyclic carbenes employed in a highly convenient amine-free Sonogashira cross-coupling reaction in air in a polar mixed aqueous medium are reported. Specifically, the trans-[{1-benzyl-3-(3,3- dimethyl-2-oxobutyl)imidazol-2-ylidene}₂PdBr₂] (3) and cw-[{l-benzyl-3-(N-ferf-butylacetamido)imidazol-2-ylid-ene}₂PdCl ₂] (4) complexes effectively catalyzed the Sonogashira cross-coupling reaction of aryl iodides with substituted acetylenes in air in a mixed solvent (DMF/H₂O, 3:1 v/v) under amine-free conditions. Interestingly, these trans- and c/s-[(NHC)₂PdX₂] (X = Cl, Br) complexes, with two N-heterocyclic carbene ligands, exhibited superior activity compared with the now popular PEPPSI (pyridine enhanced precatalyst preparation, stabilization and initiation)-themed analogues, trans-[(NHC)Pd(pyridine)X₂] (X = Cl, Br), 3a and 4a, with one N-heterocyclic carbene ligand and a "throw away" pyridine ligand in a trans disposition to each other. The higher activities of 3 and 4 compared with PEPPSI analogues 3a and 4a are attributed to more-electron-rich metal centers, as revealed by DFT studies, in the former complexes and is in concurrence with a more electron-rich metal center being effective in facilitating the oxidative addition of aryl halide, often a rate-determining step in palladium-mediated cross-coupling reactions. Complexes 3 and 4 were prepared from the corresponding silver analogues by transmetalation with [(COd)PdCl₂], whereas the corresponding PEPPSI analogues 3a and 4a were obtained directly from the imidazolium halide salts by reaction with PdCl₂ in pyridine in the presence of K₂CO₃ as base.

Full text of DOI:10.1002/chem.200800301

DOI: 10.1002/chem.200800301
Highly Convenient Amine-Free Sonogashira Coupling in Air in a Polar
Mixed AqueousMedium by trans- and cis-[(NHC)2PdX2] (X=Cl, Br)
Complexesof N/O-Functionalized N-Heterocyclic Carbenes
G
Lipika Ray,[a] Samir Barman,[a] Mobin M. Shaikh,[b] and Prasenjit Ghosh*[a]
Abstract: Two new trans- and cis-
[(NHC)2PdX2] (X=Cl, Br) complexes
of N/O-functionalized N-heterocyclic
carbenes employed in a highly conven-
ient amine-free Sonogashira cross-cou-
pling reaction in air in a polar mixed
aqueous medium are reported. Specifi-
cally, the trans-[{1-benzyl-3-(3,3-di-
methyl-2-oxobutyl)imidazol-2-ylid-
(X=Cl, Br) complexes, with two N-
heterocyclic carbene ligands, exhibited
superior activity compared with the
now popular PEPPSI (pyridine en-
hanced precatalyst preparation, stabili-
zation and initiation)-themed ana-
tributed to more-electron-rich metal
centers, as revealed by DFT studies, in
the former complexes and is in concur-
rence with a more electron-rich metal
center being effective in facilitating the
oxidative addition of aryl halide, often
a rate-determining step in palladium-
mediated cross-coupling reactions.
Complexes 3 and 4 were prepared
from the corresponding silver ana-
logues,
(X=Cl, Br), 3a and 4a, with one N-
heterocyclic carbene ligand and
trans-[(NHC)Pd(pyridine)X2]
T
a
A
N
“throw away” pyridine ligand in a trans
disposition to each other. The higher
activities of 3 and 4 compared with
PEPPSI analogues 3a and 4a are at-
logues
by
transmetalation
with
A
N
[(cod)PdCl2], whereas the correspond-
ing PEPPSI analogues 3a and 4a were
obtained directly from the imidazolium
halide salts by reaction with PdCl2 in
pyridine in the presence of K2CO3 as
base.
catalyzed the Sonogashira cross-cou-
pling reaction of aryl iodides with sub-
stituted acetylenes in air in a mixed
solvent (DMF/H2O, 3:1 v/v) under
amine-free conditions. Interestingly,
these trans- and cis-[(NHC)2PdX2]
Keywords: carbenes
·
cross-cou-
pling · heterocycles · palladium ·
Sonogashira reaction
Introduction
ceuticals,[4] biologically active molecules,[5] and molecular
electronics.[6] The very popular Sonogashira cross-coupling
reaction is catalyzed by palladium in a basic medium in the
presence of copper as a co-catalyst. A copper–acetylide spe-
cies is generated in situ, which transfers the acetylide moiety
on to the palladium center for the desired sp2–sp coupling
by a reductive elimination pathway.[7] Note, despite its criti-
cal role in catalysis, upon exposure to air or any oxidizing
agents the copper–acetylide species also yields an unwanted
homocoupled side-product by the so-called Glaser coupling
reaction,[8] thereby seriously undermining the cross-coupling
reaction. The extremely high reactivity and the explosive
nature of the copper–acetylide species makes the Sonoga-
shira reaction sensitive to air and moisture.[7,8] Consequently,
a formidable challenge in this area lies in broadening the
scope of the reaction by designing suitable catalysts that
enable the reaction to be carried out under mild conditions
without the need for any additional stringent measures, such
as the exclusion of air and moisture. In this regard it is
worth mentioning that a report of the Sonogashira cross-
The Sonogashira cross-coupling reaction provides an all im-
portant answer to the direct alkynation of aryl and alkenyl
halides[1] and, not surprisingly, it has been effectively utilized
over the years to construct conjugated enyne and arylalkyne
frameworks in, for example, natural products,[2,3] pharma-
[a] L. Ray, S. Barman, Prof. Dr. P. Ghosh
Department of Chemistry, Indian Institute of Technology Bombay
Powai, Mumbai 400 076 (India)
Fax: ( +91)22-2572-3480
E-mail: pghosh@chem.iitb.ac.in
[b] M. M. Shaikh
National Single-Crystal X-ray Diffraction Facility
Indian Institute of Technology Bombay
Powai, Mumbai 400 076 (India)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org or from the author. It contains the
CIF file with crystallographic data for 3 and 4 and the B3LYP coordi-
nates of the optimized geometries of 3, 3a, 4, and 4a.
6646
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FULL PAPER
coupling reaction in air and in water has appeared only re-
cently.[9] The other approach towards circumventing the dif-
ficulties associated with this reaction had been to develop a
copper-free Sonogashira[10] cross-coupling reaction that fo-
cuses on enhancing the reactivity of the catalytic system so
as to make the presence of copper unnecessary. However,
this strategy was of limited success because these copper-
free methods often involve the use of excess amines (even
as solvents), which is not deemed to be environmentally
friendly, and so the ultimate goal lies in developing a
copper- and amine-free Sonogashira coupling reaction.[11]
Our objective was to advance the chemistry of nonfunc-
tionalized and N/O-functionalized N-heterocyclic car-
benes[12,13] for their use in biomedical applications[14] and in
chemical catalysis.[15,16] Of special interest to us are palladi-
um-mediated cross-coupling reactions, and in this regard we
recently reported a highly efficient palladium precatalyst[17]
that exhibits ultrahigh turnover numbers and also a series of
convenient-to-handle air-stable PEPPSI (pyridine-enhanced
precatalyst preparation, stabilization and initiation)-themed
precatalysts[18] for the Suzuki–Miyaura cross-coupling reac-
tion. During the design of these catalysts for cross-coupling
reactions, we became particularly interested in knowing
which of the two types of complexes, that is, the
[(NHC)2PdX2] (X=Cl, Br) complexes with two NHC li-
gands or the newly popular PEPPSI-themed trans-
aim being to explore the utility of N-heterocyclic carbenes
in palladium-mediated cross-coupling reactions, we became
interested in designing N-heterocyclic carbene based preca-
talysts for Sonogashira coupling reactions. In particular, we
were looking to develop highly efficient and robust catalysts
that were tolerant to air, moisture, and various functional
groups so as to allow Sonogashira cross-coupling reactions
in mild aerobic conditions. With regards to the design of
NHC-based catalysts for the cross-coupling reaction, we also
wanted to know whether the more electron-rich
[(NHC)2PdX2] (X=Cl, Br)-type complexes with two NHC
ligands would make better catalysts than the newly popular
PEPPSI-themed trans-[(NHC)Pd(pyridine)X2] (X=Cl, Br)-
A
type complexes containing one NHC ligand, and hence, to
address this issue we set out to synthesize both these types
of complexes to perform a comparative study.
The two new trans- and cis-[(NHC)2PdX2] (X=Cl, Br)
complexes 3 (Scheme 1) and 4 (Scheme 2) were synthesized
from the corresponding silver complexes by a transmetala-
tion reaction with [(cod)PdCl2] in yields of 80–87%, where-
as the corresponding PEPPSI analogues 3a and 4a[18] were
synthesized directly from the corresponding imidazolium
[(NHC)Pd
(pyridine)X2] (X=Cl, Br) complexes[19] with one
N
NHC ligand, would make a better catalyst? We rationalized
that the NHCs, which are extremely good s-donating li-
gands,[12,13,16b,18,20] would make the metal center in
[(NHC)2PdX2] more electron-rich, thereby assisting the aryl
halide oxidative addition step compared with the corre-
sponding PEPPSI analogues. Our other objective was to
design highly efficient and robust catalysts that would be
air-, moisture-, and functional-group-tolerant, which would
facilitate cross-coupling reactions under ambient aerobic
conditions.
Herein we report two new trans- and cis-[(NHC)2PdX2]
(X=Cl, Br) complexes of N/O-functionalized N-heterocyclic
carbenes, namely, trans-[{1-benzyl-3-(3,3-dimethyl-2-oxobu-
tyl)imidazol-2-ylidene}2PdBr2] (3) and cis-[{1-benzyl-3-(N-
tert-butylacetamido)imidazol-2-ylidene}2PdCl2]
(4),
for
highly convenient Sonogashira coupling of aryl iodides with
substituted acetylenes in air in a mixed solvent (DMF/H2O,
3:1 v/v) under amine-free conditions. More interestingly,
complexes 3 and 4 were found to exhibit superior activity
compared with the corresponding PEPPSI counterparts 3a
and 4a, which implies that a more electron-rich metal center
yields a better catalyst.
Results and Discussion
Despite being phenomenally successful in the catalysis of
many important transformations,[21–23] the application of N-
heterocyclic carbenes in Sonogashira cross-coupling reac-
tions has remained surprisingly unexplored.[24,25] With our
Scheme 1.
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6647

P. Ghosh et al.
Scheme 2.
Figure 1. ORTEP drawing of 3 with thermal ellipsoids drawn at the 50%
ꢀ
probability level. Selected bond lengths [Š] and angles [8]: N1 C1
ꢀ
ꢀ
ꢀ
1.365(12), N2 C1 1.359(12), Pd1 C1 2.018(9), Pd1 Br1 2.3750(13); C1-
Pd1-Br1 90.8(2), C1-Pd1-C1 180.0(7).
Scheme 3.
halide salts (Scheme 3) by reaction with PdCl2 in pyridine in
the presence of K2CO3 as base.
Remarkably, two different molecular geometries were ob-
tained for 3 and 4 even though they were synthesized under
very similar conditions. Specifically, the molecular structures
of these complexes revealed that, whereas 3 (Figure 1) ex-
hibited the expected trans geometry around the metal
center, a unique hydrogen-bonded cis arrangement was ob-
served in the case of 4 (Figure 2). In particular, a hydrogen-
ꢀ
bonding interaction was seen between the amido N H
proton of the functionalized side-arm of one NHC ligand
and the amido oxygen atom of the functionalized side-arm
ꢀ
of the other displaying a close N H···O contact of 3.061 Š,
which is shorter than the sum of the van der Waals radii of
nitrogen and oxygen (3.27 Š).[26] Such a cis arrangement is a
rare consequence of a hydrogen-bonding interaction be-
tween the amido-functionalized side-arms of the NHC li-
gands in 4, in the absence of which the trans geometry
would be sterically preferred. The hydrogen-bonding inter-
action in cis complex 4 seriously highlights the rare and in-
teresting structural possibility that emerges as a result of N/
O-functionalization of the N-substituted side-arms of the N-
heterocyclic carbene ligand. To the best of our knowledge,
complex 4 represents the only structurally characterized ex-
ample of a cis-[(NHC)2PdX2] (X=halide)-type complexin
which the two NHC ligands are not conjoined by any cova-
lent linker.
Figure 2. ORTEP drawing of 4 with thermal ellipsoids drawn at the 50%
ꢀ
probability level. Selected bond lengths [Š] and angles [8]: N1 C1
ꢀ
ꢀ
ꢀ
ꢀ
1.355(2), N2 C1 1.357(2), N5 C17 1.349(2), N4 C17 1.346(2), Pd1 C17
ꢀ
ꢀ
ꢀ
1.975(2), Pd1 C1 1.998(2), Pd1 Cl1 2.3615(5), Pd1 Cl2 2.3541(5); C17-
Pd1-C1 92.50(8), C1-Pd1-Cl1 90.00(6). The phenyl group is disordered
and for clarity one set of disordered atoms is not shown.
Barring the hydrogen-bonding interaction, the other struc-
tural aspects of complexes 3 and 4 are similar, including the
(2.055 Š)[27] and also falls well within the range (2.10–
1.93 Š) observed in other structurally characterized exam-
ples.[28] The two imidazolyl rings in 3 are coplanar, similar to
that observed in another related trans-(NHC) complex, [{1-
(o-methoxybenzyl)-3-tert-butylimidazol-2-ylidene}2PdCl2].[17]
Significantly, complex 3 also represents the only example of
ꢀ
square-planar metal centers. The metal–carbene (Pd Ccarb
)
distance in 3 (2.018(9) Š) is slightly longer than in 4
(1.975(2) and 1.998(2) Š), but compares well with the sum
of the individual covalent radii of palladium and carbon
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Sonogashira Coupling of Heterocyclic Carbenes
FULL PAPER
a structurally characterized palladium bromide derivative of
the type [(NHC)2PdX2] (X=halide).
To obtain a better understanding of the nature of the
Figure S1 of the Supporting Information). The correspond-
ꢀ
ing NHC Pd s interactions in cis complex 4 consist of two
adjacent interactions, HOMO-35 (47% NHC, 38% PdCl2)
and HOMO-36 (37% NHC, 38% PdCl2). In HOMO-35, the
carbene lone-pairs (HOMO (11%) and HOMO-1 (31%))
of the two free NHC fragments were seen to interact with
another metal-based vacant LUMO+1 orbital (92% palla-
dium with 69% s and 18% p character) of the PdCl2 frag-
ment (Figures 4 and 5 and Figure S2 of the Supporting In-
ꢀ
NHC Pd interaction in the trans and cis complexes 3 and 4,
detailed density functional theory (DFT) studies were car-
ried out by computing the geometry-optimized structures of
3 and 4 at the B3LYP/SDD level of theory with the 6-
31G(d) basis set using the atomic coordinates determined
by X-ray analysis. Subsequently a single-point calculation
was performed at the same level of theory for a detailed
prediction of the electronic properties of these complexes.
ꢀ
formation). Likewise, the other NHC Pd s-bonding orbital,
HOMO-36 (37% NHC, 38% PdCl2), showed an interaction
of the carbene lone-pairs (HOMO (11%) and HOMO-1
(31%)) of the two free NHC fragments with the vacant
LUMO (51% Pd, 49% Cl with 39% d character) of the
PdCl2 fragment.
ꢀ
Further insights into the carbene metal bond came from a
post-wavefunction analysis using the natural bond orbital
(NBO) method,[29] which was performed on these complexes
as well as on the corresponding ligands and metal-ion frag-
ments. Specifically, both natural and Mulliken charge analy-
ses revealed that upon binding of the two NHC ligands to
the PdX2 (X=Cl, Br) fragment, the metal center in 3 and 4
becomes more electron-rich compared with the free ion and
the PdX2 (X=Cl, Br) fragment (see Tables S4–S7, S12, and
S13 of the Supporting Information). Consequently, the elec-
tron density at the carbene carbon atom in 3 and 4 is lower
relative to that of the free NHC ligand upon coordination to
the PdX2 (X=Cl, Br) fragment. Comparison of the electron-
ic configurations of the metal centers in 3 and 4 with that of
the PdX2 (X=Cl, Br) fragment reveals that electron dona-
tion from the free NHC ligand
A charge decomposition analysis (CDA) of 3 and 4 high-
lighted the relative extent of the [NHC s PdX ] forward
!
2
donation (X=Br, Cl), designated d, and the [NHC p PdX ]
2
backward donation (X=Br, Cl), designated b, that occurs in
these complexes. The d/b ratio, a measure of the forward s
donation relative to the backward p donation, for 3 (2.90)
and 4 (2.98) suggests the predominance of the s-bonding in-
teraction in concurrence with the greater s-donating abilities
of the NHC ligands, and the values compare well with those
ꢀ
reported for other Pd NHC complexes, namely, trans-[{1-
benzyl-3-(N-tert-butylacetamido)imidazol-2-ylidene}Pd(pyr
A
to the unfilled 5s orbital of pal-
ladium occurs in these com-
plexes (see Tables S14 and S15
of the Supporting Information).
Further insights into the
ꢀ
nature of the NHC metal inter-
action were obtained from cor-
relation diagrams depicting the
fragment molecular orbital con-
tribution of the free NHC
ligand and the PdX2 (X=Cl,
Br) fragments to the frontier
molecular orbitals (MOs) of
complexes 3 and 4. Of particu-
lar interest are the molecular
orbitals that represent the
ꢀ
NHC Pd s interactions, which
were found to be low-lying in 3
(HOMO-37) and 4 (HOMO-35
and HOMO-36). Specifically,
ꢀ
the NHC Pd s-bonding orbital,
HOMO-37 (53% NHC, 29%
PdBr2), in trans complex
3
showed an interaction of the
carbene lone-pair (HOMO-1 of
the free-NHC fragments) with
a metal-based vacant LUMO
(75% palladium with 33% s
and 40% d character) of the
ꢀ
Figure 3. Simplified orbital interaction diagram showing the major contributions of the NHC palladium bond
PdBr2 fragment (Figure 3 and in 3.
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6649

P. Ghosh et al.
version to products within two
hours was observed for most of
the substrates, which reflects
the high performances of 3 and
4.
Also remarkable is the robust
nature of precatalysts 3 and 4
because the coupling reactions
were successfully carried out in
air in a polar DMF/H2O (3:1
v/v) mixed medium. Thus, the
present catalysis by 3 and 4
under aerobic mixed aqueous
conditions marks a significant
improvement against the back-
drop of the fact that Sonoga-
shira reactions are traditionally
air-
and
moisture-sensitive
owing to the formation of a
highly reactive copper–acety-
lide intermediate in the catalyt-
ic cycle.[7,8] Another very impor-
tant feature of 3 and 4 is their
high selectivity with regards to
the formation of the desired
cross-coupled product along
with the negligible formation of
the homocoupled product (up
ꢀ
Figure 4. Simplified orbital interaction diagram showing the major contributions of the NHC Pd s-bonding or- to 15% for 3 and 21% for 4).
bital HOMO-35 in 4.
ACHTREUNG
AHCTREUNG
A
ACHTREUNG
Scheme 4.
ACHTREUNG
ꢀ
Lastly, the strength of the NHC Pd interactions in 3 and
4 were computed at the B3LYP/SDD level of theory with
Note that the homocoupled products arise from an unwant-
ed side-reaction of the reactive copper–acetylide intermedi-
ate by the so-called Glaser coupling reaction upon exposure
to trace amounts of air or any oxidizing agent (Tables 1 and
2).[8] Lastly, these coupling reactions were carried out in
amine-free conditions with Cs2CO3 as the base instead of
the more frequently used amines, which is of considerable
importance given the fact that amines are not considered
environmentally benign and substantial efforts, at present,
are being directed towards the development of amine-free
Sonogashira cross-coupling reactions.
Note that the Sonogashira cross-coupling reaction can be
extended to heterocyclic terminal alkynes, which has much
potential, particularly from a synthetic perspective, because
many heterocyclic compounds are known to exhibit impor-
tant biological properties.[30] Another notable aspect of the
two precatalysts 3 and 4 is their selectivity towards the iodo
derivative. This is evident from the reactions of the p-bro-
moiodobenzene substrate; Sonogashira coupling was seen to
occur at the iodo end and not at the bromo end, which re-
mained intact.
ꢀ
the 6-31G(d) basis set and NHC Pd bond energies (De) of
74.8 kcalmolꢀ1 in 3 and 75.1 kcalmolꢀ1 in 4 are suggestive of
a strong interaction comparable to those reported for trans-
[{1-benzyl-3-(N-tert-butylacetamido)imidazol-2-ylidene}Pd-
(pyridine)Cl2] (81.9 kcalmolꢀ1),[18] trans-[{1-(2-hydroxycyclo-
hexyl)-3-benzylimidazol-2-ylidene}Pd
A
(82.4
kcalmolꢀ1),[18] and trans-[{1-(o-methoxybenzyl)-3-tert-butyl-
imidazol-2-ylidene}Pd
(pyridine)Br2] (77.6 kcalmolꢀ1).[18] The
C
ꢀ
stronger NHC Pd interactions in 3 and 4 imply tighter bind-
ing of the ancillary NHC ligand to the metal center, which
imparts greater stability to these complexes.
Significantly, both complexes 3 and 4 enabled highly con-
venient amine-free Sonogashira coupling reactions to take
place in ambient aerobic conditions in a polar mixed aque-
ous medium (Scheme 4 and Tables 1 and 2). Specifically,
when substituted terminal acetylenes were treated with aryl
iodides in the presence of precatalysts 3 or 4 along with the
co-catalyst CuBr, and Cs2CO3 as the base in a mixed DMF/
H2O (3:1 v/v) medium in air, Sonogashira cross-coupled
products were obtained in high yields. A rapid rate of con-
6650
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Sonogashira Coupling of Heterocyclic Carbenes
FULL PAPER
examples of well-defined N-het-
erocyclic carbene-based palladi-
um precatalysts known for ho-
mogeneous Sonogashira cross-
coupling reactions.
With regards to our initial
objective of finding out whether
mono- or di-NHC-substituted
palladium complexes would ex-
hibit greater activity, a detailed
comparative study of the trans-
and cis-[(NHC)2PdX2] (X=Cl,
Br)-type complexes
3 and 4
were performed with the corre-
sponding PEPPSI analogues 3a
and 4a. Interestingly, complexes
3 and 4, which have two NHC
ligands, were found to exhibit
superior activity compared with
3a and 4a (Tables 1–4). The
better performances of 3 and 4
can be correlated to more-elec-
tron-rich metal centers in these
complexes. For example, a com-
parison of both the natural and
Mulliken charges reveal that
the palladium centers in 3 and
4, which contain two strongly s-
donating NHC ligands, are
more electron-rich than those
ꢀ
Figure 5. Simplified orbital interaction diagram showing the major contributions of the NHC Pd s-bonding or-
bital HOMO-36 in 4.
Despite the existence of numerous phosphine-based cata-
lysts for the Sonogashira reaction,[10] few N-heterocyclic car-
bene-based catalysts are known.[24,25] Also, in the light of the
extraordinary successes enjoyed by NHCs in various catalyt-
ic reactions in general, and in palladium-mediated cross-cou-
pling reactions in particular, the dearth of NHC-based cata-
lysts for Sonogashira reactions prompted us to undertake
the current study. Against this backdrop, complexes 3 and 4
assume importance because they represent the handful of
of the PEPPSI analogues 3a and 4a stabilized by a single
NHC ligand (see Tables S4–S13 of the Supporting Informa-
tion). In this regard, the more electron-rich metal centers
would greatly promote the oxidative addition of the aryl
halide, which represents a key step in the palladium-mediat-
ed cross-coupling reaction.
A comparison of the N-heterocyclic carbene-based palla-
dium precatalysts 3 and 4 with the related phosphine-based
precatalysts is important.[10] The NHC precatalysts 3 and 4
Table 1. Selected results of the Sonogashira cross-coupling reaction of aryl halides (ArX, X=I) catalyzed by 3.[a]
Catalyst
Reagent
Reagent
Desired cross-coupled
product
Yield[b] [%]
Time [h]
Unwanted homocoupled
product
Yield[b] [%]
98
80
75
97
85
68
2
2
2
2
2
2
2
3
4
0
15
0
[a] Reaction conditions: aryl halide (ArX, X=I; 0.49 mmol), phenylacetylene (0.98 mmol), Cs2CO3 (2 mmol), catalyst (3 mol%), CuBr (10 mol%),
DMF/H2O (3:1; 10 mL), at 1008C. [b] The yields were determined by GC using diethyleneglycol-di-n-butyl ether as the internal standard.
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P. Ghosh et al.
Table 2. Selected results of the Sonogashira cross-coupling reaction of aryl halides (ArX, X=I) catalyzed by 4.[a]
Catalyst
Reagent
Reagent
Desired cross-coupled
product
Yield[b] [%] Time [h] Unwanted homocoupled Yield[b] [%]
product
84
88
94
81
90
12
2
0
9
2
6
2
0
2
21
[a] Reaction conditions: aryl halide (0.49 mmol) (ArX, X=I), phenylacetylene (0.98 mmol), Cs2CO3 (2 mmol), catalyst (3 mol%), CuBr (10 mol%),
DMF/H2O (3:1; 10 mL), at 1008C. [b] The yields were determined by GC using diethyleneglycol-di-n-butyl ether as the internal standard.
Table 3. Selected results of the Sonogashira cross-coupling reaction of aryl halides (ArI) catalyzed by 3a.[a]
Catalyst
Reagent
Reagent
Desired cross-coupled
product
Yield[b] [%]
Time [h]
Unwanted homocoupled
product
Yield[b] [%]
4
2
2
2
2
2
2
5
76
5
42
0
no reaction
28
0
14
0
no reaction
[a] Reaction conditions: aryl halide (0.49 mmol) (ArX, X=I), phenylacetylene (0.98 mmol), Cs2CO3 (2 mmol), CuBr (10 mol%), catalyst (3 mol%),
DMF/H2O (3:1; 10 mL) at 1008C. [b] The yields were determined by GC using diethyleneglycol-di-n-butyl ether as the internal standard.
Table 4. Selected results of the Sonogashira cross-coupling reaction of aryl halides (ArX, X=I) catalyzed by 4a.[a]
Catalyst
Reagent
Reagent
Desired cross-coupled
product
Yield[b] [%]
Time [h]
Unwanted homocoupled
product
Yield[b] [%]
27
2
2
2
2
2
2
13
6
66
11
12
0
no reaction
24
0
no reaction
0
[a] Reaction conditions: aryl halide (ArX, X=I; 0.49 mmol), phenylacetylene (0.98 mmol), Cs2CO3 (2 mmol), CuBr (10 mol%), catalyst (3 mol%),
DMF/H2O (3:1; 10 mL) at 1008C. [b] The yields were determined by GC using diethyleneglycol-di-n-butyl ether as the internal standard.
were found to be comparable to many of the phosphine-
based precatalysts. Note that the latter are usually air- and
moisture-sensitive and hence require anaerobic conditions,
higher catalyst loading,[11] and also a longer reaction time
(up to 48 h)[10] at higher temperatures (up to 1408C).[9]
A tentative mechanism for the Sonogashira cross-coupling
reaction is proposed in Scheme 5. Note that the mechanism
excludes the formation of a copper–acetylide intermediate
in view of the fact that very little or almost negligible
amounts of Glaser-type homocoupled products were ob-
served despite the coupling reactions being performed in air
6652
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6646 – 6655

Sonogashira Coupling of Heterocyclic Carbenes
FULL PAPER
[{1-benzyl-3-(N-tert-butylacetamido)imidazol-2-ylidene}Pd(pyridine)Cl2]
A
(4a)[18] were prepared according to reported literature procedures. 1H
and 13C{1H} NMR spectra were recorded in CDCl3 on a Varian 400 MHz
NMR spectrometer. 1H NMR signals are labeled as singlet (s), doublet
(d), and multiplet (m). Infrared spectra were recorded on a Perkin–
Elmer Spectrum One FTIR spectrometer with samples as KBr pellets.
Mass spectrometry measurements were performed on a Micromass Q-
Tof spectrometer. GC was carried out on a Shimadzu GC-15A gas chro-
matograph equipped with a FID detector. X-ray diffraction data for 3
and 4 were collected on an Oxford Diffraction Excaliber-S diffractome-
ter. The crystal data collection and refinement parameters are summar-
ized in Table 5. The structures were solved by using direct methods and
standard difference map techniques and were refined by full-matrixleast-
squares procedures on F2 with SHELXTL (Version 6.10).[33]
Table 5. X-ray crystallographic data for 3 and 4.
Compound
3
4
Scheme 5.
lattice
monoclinic
C16H20BrN2O·0.5Pd
389.45
monoclinic
C32H42Cl2N6O2Pd
720.02
formula
formula weight
space group
a [Š]
b [Š]
c [Š]
in a mixed aqueous solvent. The copper–acetylide species is
extremely sensitive to air and moisture, and its formation
under these reaction conditions seems highly unlikely. Thus,
the role of the CuBr co-catalyst is restricted to the reduction
of the PdII center in 3 and 4 to the corresponding catalytical-
ly active Pd0 species, which undergoes oxidative addition of
the aryl iodide followed by the coordination and deprotona-
tion of the terminal acetylene in the presence of a base,
which leads to the desired cross-coupled product by a final
reductive elimination step. In this regard, note that our at-
tempt to independently synthesize and isolate the
[(NHC)2Pd0] species for a direct entry to the catalytic cycle
was not successful.
P21/a
C2/c
7.4702(2)
27.2734(7)
7.9624(2)
90.00
94.639(3)
90.00
1616.93(7)
4
120(2)
0.71073
1.600
3.079
2.97–25.00
2848
190
24.2317(5)
15.2987(4)
17.7705(4)
90.00
91.655(2)
90.00
6585.0(3)
8
120(2)
0.71073
1.453
0.765
3.05–25.00
5775
421
a [8]
b [8]
g [8]
V [Š3]
Z
temperature [K]
radiation (l [Š])
1calcd [gcmꢀ3
]
m
A
]
q [8]
no. of data
no. of parameters
R1
0.0830
0.0226
wR2
GOF
0.2354
1.060
0.0559
0.922
Conclusions
In summary, two new precatalysts, namely, trans-[{1-benzyl-
CCDC-643953 (3) and 637065 (4) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
3-(3,3-dimethyl-2-oxobutyl)imidazol-2-ylidene}2PdBr2]
and cis-[{1-benzyl-3-(N-tert-butylacetamido)imidazol-2-ylid-
ene}2PdCl2} (4), have been designed and used in a highly
(3)
ACHTREUNG
convenient Sonogashira cross-coupling reaction of aryl io-
dides with substituted acetylenes in air in a mixed solvent
(DMF/H2O, 3:1 v/v) under amine-free conditions. More im-
portantly, these complexes, which have two strong s-donat-
ing NHC ligands, were found to exhibit superior activity
compared with their corresponding PEPPSI counterparts,
3a and 4a, which support a single NHC ligand. Thus, a
more electron-rich metal center acts as a better catalyst for
the cross-coupling reaction.
Synthesis of 1-benzyl-3-(3,3-dimethyl-2-oxobutyl)imidazolium bromide
(1): A mixture of benzylimidazole (0.889 g, 5.50 mmol) and a-bromopina-
colone (1.00 g, 5.50 mmol) was dissolved in toluene (ca. 50 mL) and the
reaction mixture was heated at reflux at 1108C for 12 h until a white
solid separated out. The solid was isolated by decanting off the solvent
and washed with hot hexane (3”ca. 10 mL) to give 1 as a white solid
1
(1.12 g, 61%). H NMR (CDCl3, 400 MHz, 258C, TMS): d=10.07 (s, 1H;
NCHN), 7.56 (brs 1H; NCHCHN), 7.42–7.38 (m, 5H; C6H5), 7.24 (brs
1H; NCHCHN), 5.93 (s, 2H; CH2), 5.47 (s, 2H; CH2), 1.28 ppm (s, 9H;
C
(CH3)3); 13C{1H} NMR (CDCl3, 100 MHz, 258C): d=206.2 (CO), 136.9
A
(NCN), 132.5 (ipso-C6H5), 128.9 (m-C6H5), 128.2 (p-C6H5), 124.1 (o-
C6H5), 120.6 (NCHCHN), 54.2 (CH2), 52.7 (CH2), 42.9 (C(CH3)3),
25.8 ppm (C
(CH3)3); IR (KBr): n˜ =1717 cmꢀ1 (nCO); HRMS (ES): m/z
calcd: 257.1654 [NHC-ligand]+; found: 257.1643.
Synthesis of [{1-benzyl-3-(3,3-dimethyl-2-oxobutyl)imidazol-2-ylid
g]Br (2): A mixture of 1-benzyl-3-(3,3-dimethyl-2-oxobutyl)imidazoli-
ACHTREUNG
AHCTREUNG
Experimental Section
A
AHCTREUNG
General procedures: All manipulations were carried out by using stan-
dard Schlenk techniques. Solvents were purified and degassed by stan-
dard procedures. Ag2O was purchased from SD-Fine Chemicals (India)
and used without any further purification. [(cod)PdCl2],[31] benzylimida-
zole,[32] 1-benzyl-3-(N-tert-butylacetamido)imidazolium chloride,[18] [{1-
benzyl-3-(N-tert-butylacetamido)imidazol-2-ylidene}AgCl],[13] and trans-
um bromide (1) (0.500 g, 1.49 mmol) and Ag2O (0.171 g, 0.740 mmol) in
dichloromethane (ca. 60 mL) was stirred at room temperature for 6 h.
The reaction mixture was filtered and the solvent was removed under
vacuum to give 2 as a brown solid (0.412 g, 80%). 1H NMR (CDCl3,
400 MHz, 258C, TMS): d=7.34–7.31 (m, 5H; C6H5), 6.92 (brs, 1H;
Chem. Eur. J. 2008, 14, 6646 – 6655
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6653

P. Ghosh et al.
NCHCHN), 6.89 (brs, 1H; NCHCHN), 5.39 (s, 2H; CH2), 5.29 (s, 2H;
CH2), 1.30 ppm (s, 9H; C
(CH3)3); 13C {1H} NMR (CDCl3, 100 MHz,
258C): d=208.6 (CO), 183.9 (NCN-Ag), 135.7 (ipso-C6H5), 128.6 (m-
C6H5), 127.9 (p-C6H5), 127.5 (o-C6H5), 122.8 (NCHCHN), 120.4
along with valence basis sets (SDD) were used for palladium.[37, 38] All
other atoms were treated with the 6-31G(d) basis set.[39] The metal–
ligand donor–acceptor interactions were inspected by using charge de-
composition analysis (CDA).[40] CDA is a valuable tool for analyzing the
interactions between molecular fragments on a quantitative basis, with an
emphasis on electron donation.[41] The orbital contributions in the
[(NHC)2PdX2] (X=Br, Cl)-type complexes 3 and 4 can be divided into
AHCTREUNG
(NCHCHN), 55.1 (CH2), 50.5 (CH2), 43.1 (C(CH3)3), 26.0 ppm (C-
A
A
[(NHC)2Ag]+; found: 619.2212; elemental analysis calcd (%) for
C32H40N4O2AgBr: C 54.87, H 5.76, N 8.00; found: C 55.23, H 6.53, N
8.16.
three parts: 1) s donation from the [NHC s PdX ] fragment, 2) p back
!
2
donation from the [NHC p PdX ] fragment, and 3) a repulsive interaction
2
between the occupied MOs of these two fragments.
Synthesis of [{1-benzyl-3-(3,3-dimethyl-2-oxobutyl)imidazol-2-ylid
A
[42]
The CDA calculations were performed by using the AOMixprogram
ACHTREUNG
with the B3LYP/SDD, 6-31G(d) wavefunction. Molecular orbital (MO)
2-ylidene}2Ag}Br (2) (0.151 g, 0.236 mmol) and [(cod)PdCl2] (0.030 g,
0.107 mmol) was heated at refluxin acetonitrile (ca. 30 mL) at 85 8C for
6 h until the formation of an off-white AgBr precipitate was observed.
The reaction mixture was filtered and the solvent was removed under
vacuum to give 3 as a yellow solid (0.067 g, 81%). 1H NMR (CDCl3,
400 MHz, 258C, TMS): d=7.37–7.31 (m, 5H; C6H5), 6.92 (brs, 1H;
NCHCHN), 6.86 (brs, 1H; NCHCHN), 5.38 (s, 2H; CH2), 5.21 (s, 2H;
compositions and the overlap populations were calculated by using the
[43]
AOMixprogram.
Analysis of the MO compositions in terms of occu-
pied and unoccupied fragment orbitals (OFOs and UFOs, respectively),
construction of orbital interaction diagrams, and the charge decomposi-
tion analysis (CDA) were performed by using AOMix-CDA.[44] Natural
bond orbital (NBO) analysis was performed by using the NBO 3.1 pro-
gram implemented in the Gaussian 03 package.[34]
CH2), 1.32 ppm (s, 9H;
C
(CH3)3); 13C{1H} NMR (CDCl3, 100 MHz,
A
258C): d=207.1 (CO), 172.2 (NCN-Pd), 134.8 (ipso-C6H5), 129.0 (m-
C6H5), 128.7 (p-C6H5), 127.9 (o-C6H5), 122.8 (NCHCHN), 120.3
General procedure for the Sonogashira coupling reaction: In a typical
run, performed in air, a 25 mL vial was charged with a mixture of aryl
iodide, arylalkyne, Cs2CO3, and diethyleneglycol-di-n-butyl ether (inter-
nal standard) in a molar ratio of 1:2:4:1. Complexes 3, 3a, 4, or 4a
(3 mol%) and CuBr (10 mol%) were added to the mixture (Tables 1–4).
Finally, a mixed solvent (DMF/H2O, 3:1 v/v, 10 mL) was added to the re-
action mixture and heated at 1008C for an appropriate period of time,
after which it was filtered and the product was analyzed by gas chroma-
tography using diethyleneglycol-di-n-butyl ether as the internal standard.
(NCHCHN), 55.0 (CH2), 54.9 (CH2), 43.6 (C
A
ACHTREUNG
C32H40Br2N4O2Pd·2(CH3CN): C 50.22, H 5.38, N 9.76; found: C 49.98, H
H
5.82, N 10.15.
Synthesis
of
trans-[{1-benzyl-3-(3,3-dimethyl-2-oxobutyl)imidazol-2-
ylidene}Pd
ACHTREUNG
oxobutyl)imidazolium bromide (0.306 g, 0.908 mmol), PdCl2 (0.193 g,
1.09 mmol), and K2CO3 (0.627 g, 4.54 mmol) were heated at refluxin pyr-
idine (ca. 5 mL) for 16 h. The reaction mixture was filtered and the sol-
vent was removed under vacuum. Then the residue was washed with
aqueous CuSO4 solution and the aqueous layer was extracted with di-
chloromethane (3”ca. 10 mL). Then the organic layer was collected and
the solvent was removed under vacuum to give 3a as a light-yellow crys-
Acknowledgements
We thank the CSIR, New Delhi, for the financial support of this research.
We are grateful to the National Single-Crystal X-ray Diffraction Facility
and Sophisticated Analytical Instrument Facility at IIT Bombay, India,
for the crystallographic and other characterization data. Use of the com-
putational facilities of the IIT Bombay Computer Center is gratefully ac-
knowledged. L.R. thanks IIT Bombay, India, for a research fellowship.
1
talline solid (0.182 g, 67%). H NMR (CDCl3, 400 MHz, 258C, TMS): d=
8.96 (d, 3JHH =8 Hz, 2H; o-NC5H5), 7.77 (t, 3JHH =8 Hz, 1H; p-NC5H5),
7.50 (t, 3JHH =8 Hz, 2H; m-NC5H5), 7.39–7.35 (m, 5H; C6H5), 6.99 (brs,
1H; NCHCHN), 6.77 (brs, 1H; NCHCHN), 5.84 (s, 2H; CH2), 5.71 (s,
2H; CH2), 1.40 ppm (s, 9H; C
(CH3)3); 13C{1H} NMR (CDCl3, 100 MHz,
E
258C): d=206.8 (CO), 153.3 (NCN-Pd), 151.9 (o-NC5H5), 151.1 (m-
NC5H5), 138.0 (ipso-C6H5), 137.9 (p-NC5H5), 129.0 (o-C6H5), 128.9 (m-
C6H5), 128.4 (p-C6H5), 121.2 (NCHCHN), 121.1 (NCHCHN), 54.7 (CH2),
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C
G
43.35, H 4.28, N 7.43; found: C 43.85, H 4.15, N 8.02.
Synthesis of [{1-benzyl-3-(N-tert-butylacetamido)imidazol-2-ylid
A
ACHTREUNG
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CH2), 4.99 (s, 2H; CH2), 1.35 (s, 9H; C
(CH3)3); 13C{1H} NMR (CDCl3, 100 MHz, 258C): d=164.9 (CO), 160.2
(NCN-Pd), 134.3 (ipso-C6H5), 128.9 (m-C6H5), 128.5 (p-C6H5), 128.4 (o-
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(CH3)3); IR (KBr): n˜1626 cmꢀ1 (nCO); elemental
A
ACHTREUNG
AHCTREUNG
ACHTREUNG
analysis calcd (%) for C32H42N6O2PdCl2: C 53.38, H 5.88, N 11.67; found:
C 53.75, H 5.96, N 11.15.
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6654
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Chem. Eur. J. 2008, 14, 6646 – 6655

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FULL PAPER
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Received: February 18, 2008
Published online: June 18, 2008
Chem. Eur. J. 2008, 14, 6646 – 6655
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6655