A palladium Chugaev carbene complex as a modular, air-stable catalyst for Suzuki-Miyaura cross-coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2005.01.033

A new Chugaev-type palladium carbene complex was prepared via a convenient metal-templated route and fully characterized by X-ray crystallography, NMR, and IR. This complex proved effective as a precatalyst for Suzuki-Miyaura cross-coupling reactions of a range of aryl bromides, even under aerobic conditions, and its modular synthesis should allow for further catalyst fine-tuning.

Full text of DOI:10.1016/j.tetlet.2005.01.033

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1399–1403
A palladium Chugaev carbene complex as a modular,
air-stable catalyst for Suzuki–Miyaura cross-coupling reactions
Adriana I. Moncada,a Masood A. Khanb and LeGrande M. Slaughtera,*
aDepartment of Chemistry, Oklahoma State University, 107 Physical Science I, Stillwater, OK 74078, USA
bDepartment of Chemistry and Biochemistry, University of Oklahoma, 620 Parrington Oval, Norman, OK 73019, USA
Received 6 January 2005; accepted 10 January 2005
Available online 25 January 2005
Abstract—A new Chugaev-type palladium carbene complex was prepared via a convenient metal-templated route and fully
characterized by X-ray crystallography, NMR, and IR. This complex proved effective as a precatalyst for Suzuki–Miyaura cross-
coupling reactions of a range of aryl bromides, even under aerobic conditions, and its modular synthesis should allow for further
catalyst fine-tuning.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Recent advances in ligand design have dramatically
improved the scope and utility of metal-catalyzed
cross-coupling reactions.1 This is exemplified by the
palladium-catalyzed Suzuki–Miyaura coupling of aryl
halides with arylboron reagents,2 a reaction that has
attracted growing interest due to its high functional
group tolerance as well as the prevalence of biaryl
moieties in natural products, organic materials, and
new ligands.3 A guiding theme has been the combination
Figure 1. Chelating NHC (a, Ref. 11) and Chugaev carbene (b)
ligands.
of strong r-donor ligands, which are thought to facili-
tate aryl halide oxidative addition, with steric bulk,
which promotes biaryl reductive elimination.4 Littke
ing Herrmannꢀs initial report of Suzuki coupling with
a palladium–NHC catalyst,11 Nolan and co-workers
developed catalyst systems based on palladium precur-
sors combined with imidazolium salts that allowed prac-
tical Suzuki–Miyaura coupling of deactivated aryl
chlorides.4,12 Palladium complexes of bulky NHCꢀs were
reported by Herrmann and co-workers to catalyze
Suzuki–Miyaura coupling of unhindered aryl chlorides
at room temperature.13 Subsequently, Glorius and
co-workers achieved the formation of di- and tri-
ortho-substituted biaryls at room temperature from aryl
chlorides using an NHC ligand containing ꢁflexible steric
bulkꢀ,14 and systematic variation of ligand sterics by
these authors recently resulted in the unprecedented
Suzuki–Miyaura synthesis of a range of tetra-ortho-
substituted biaryls from aryl chlorides.15
and Fu5 and Buchwald and co-workers6 first demon-
strated that electron-rich, sterically hindered phosphine
ligands facilitate Suzuki–Miyaura couplings of elec-
tron-rich aryl chlorides, a substrate class that had previ-
ously been inaccessible. Rational modification of bulky
phosphines by Buchwald and co-workers has led to a
general catalyst system that shows high coupling activity
for a wide range of aryl bromides and chlorides, in many
cases at room temperature.7
Parallel to the development of phosphines, N-heterocy-
clic carbene (NHC) ligands (e.g., a, Fig. 1)8 have been
pursued in cross-coupling catalysis primarily due to
their potentially stronger r-donating ability9 and en-
hanced stability to air and high temperature.10 Follow-
Given the recent successes in tuning cross-coupling cata-
lyst activity through ligand modification, a ligand
design that combines strong r-donor groups with a
Keywords: Carbene ligands; Palladium; Suzuki; Air-stable.
*
Corresponding author. Tel.: +1 405 744 5941; fax: +1 405 744
6007; e-mail: lms@chem.okstate.edu
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.033

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A. I. Moncada et al. / Tetrahedron Letters 46 (2005) 1399–1403
readily altered structural framework would clearly be
advantageous. While investigating synthetically flexible
routes to chelating carbenes that possess these attri-
butes, we became intrigued by ꢁChugaev-typeꢀ carbenes
(b, Fig. 1),16 a relatively unexplored class of chelate li-
gands that are formed via the metal-templated addition
of hydrazines or other bifunctional nucleophiles to
cis-coordinated isocyanides. Platinum complexes of
these ligands were prepared as early as 1915,16 but their
structures were unknown until spectroscopic studies by
Rouschias and Shaw17 and crystallographic studies by
Balch and co-workers18 in 1970revealed their chelating
nature. These ligands contain nitrogen-stabilized carb-
ene donors analogous to NHCꢀs, but they have never
been investigated in catalysis. Additionally, reports of
similar chelate ligands synthesized from diamines such
as 2,6-diaminopyridine19 and 1,2-ethylenediamine20 sug-
gest that the metal-templated synthetic strategy could be
extended to a wide range of structures, potentially
including sterically hindered or chiral examples.
troscopic changes accompanied the conversion of 1 into
2, including replacement of three NH peaks in the H
NMR (DMSO-d6) of 1 (d 4.49, 6.79, 10.09) with two
NH peaks for 2 (d 7.71, 11.15), as well as disappearance
of the isocyanide stretches of 1 (m(C„N) 2220,
2210cm ꢀ1) in the IR spectrum.
1
X-ray crystallographic analysis of 225 revealed the
expected chelating carbene ligand with
a planar
NCNNCN backbone (Fig. 2). The coordination about
palladium is almost perfectly planar (sum of angles
359.96(9)ꢁ), but the five-membered chelate ring of the
dicarbene constrains the C–Pd–C angle to a small value
of 79.91(6)ꢁ. The N–Ccarbene distances of the ligand
˚
(average 1.326 A) are slightly smaller than the normal
˚
range of 1.34–1.37 A for imidazolium-based NHC
ligands, indicating substantial p-interaction within the
dicarbene unit. In addition, the Pd–Ccarbene distances
˚
(1.9583(15), 1.9638(15) A) are slightly shorter than those
in comparable Pd–NHC complexes (typically 1.99–
8,11
suggesting possibly stronger binding to the
˚
2.00 A),
As a starting point to explore the scope of Chugaev carb-
ene synthesis, we targeted palladium dicarbene com-
plexes derived from hydrazine and bulky isocyanides.
Palladium complexes of methylisocyanide-derived Chu-
gaev carbenes are known,18 but the only reported exam-
ple synthesized from a sterically encumbered isocyanide
is a platinum dicarbene complex prepared from tert-
butylisocyanide.21 Herein we report a new Chugaev carb-
ene complex of palladium and its use as an air-stable
catalyst for Suzuki–Miyaura cross-coupling reactions.
The convenient synthesis of this complex opens new
opportunities for the modular design of novel chelating
carbene ligands.
metal. The steric bulk of the cyclohexyl groups is direc-
ted away from the palladium coordination sphere and
does not substantially perturb the ligand backbone.
Thus, the use of even larger isocyanides appears feasible.
An intriguing feature is hydrogen bonding of the back-
bone NH units with DMSO solvent molecules. Interest-
ingly, X-ray quality crystals could only be grown from
DMSO.
In view of the similarity of Chugaev carbene ligands to
NHCꢀs, we have tested the catalytic activity of 2 in Su-
zuki–Miyaura cross-coupling reactions. Complex 2 is
stable to air and moisture, and therefore we regarded
it as potentially useful under aerobic conditions. The
ability to operate under air would greatly increase the
practicality of the reaction. However, only a few palla-
dium Suzuki catalysts have been reported to function
under air,26 primarily involving nitrogen ligands,27 with
only one example of an aerobic Suzuki reaction reported
using a Pd–NHC catalyst.28
Addition of excess hydrazine hydrate to a stirred solu-
tion of [Pd(CNCy)4]Cl2,22 generated in situ from PdCl2
and cyclohexylisocyanide, provided a yellow precipitate,
which was washed with aqueous LiClO4 and water
and then dried in vacuo.23 Consistent with the ori-
ginal reports of methylisocyanide-derived Chugaev
carbene complexes,17,18 this product is assigned as
[Pd(C14H25N4)(CNCy)2][ClO4] (1, Scheme 1), contain-
ing a deprotonated form of the chelating dicarbene
ligand. Treatment of an acetonitrile solution of 1 with
3 M HCl followed by addition of Et2O afforded neutral
Pd(C14H26N4)Cl2 2 in 65% yield.24 Characteristic spec-
Figure 2. ORTEP diagram of 2 (50% probability ellipsoids). Selected
˚
distances (A) and angles (ꢁ): Pd(1)–C(7) = 1.9583(15), Pd(1)–C(8) =
1.9638(15), C(7)–N(1) = 1.3205(19), C(7)–N(2) = 1.332(2), C(8)–
N(3) = 1.3311(19), C(8)–N(4) = 1.3191(19), C(7)–Pd(1)–C(8) = 79.91(6),
C(7)–Pd(1)–Cl(1) = 93.26(5), C(8)–Pd(1)–Cl(2) = 92.97(4), Cl(1)–
Pd(1)–Cl(2) = 93.818(14).
Scheme 1. Synthesis of palladium Chugaev carbene complexes.

A. I. Moncada et al. / Tetrahedron Letters 46 (2005) 1399–1403
1401
Table 1. Suzuki–Miyaura cross-coupling reactions catalyzed by Chugaev carbene complex 2a
Entry
ArX
R0
H
Conditions
Yield (%)b
Homocoupling product (TON)c
Br
1a
1b
N2
Air
99 (99)
98
0.025
0.25
O2N
NC
Br
2a
2b
H
N2
Air
99 (95)
99
ndd
0.21
Br
3a
3b
H
N2
Air
97
93
0.004
0.25
Ac
Br
4a
4b
H
N2
Air
99
93
—
—
Br
5a
5b
H
N2
Air
93
67
ndd
0.72
Me
Br
6a
6b
H
N2
Air
87
59
0.010
0.70
MeO
Br
7a
7b
Me
N2
Air
89
79
ndd
ndd
Cl
8
H
H
H
N2
N2
N2
79
25
3
ndd
O2N
NC
Cl
Cl
9
ndd
10
0.071
Me
a Reactions conditions: 1 mol % 2, 1.7 mmol ArX, 2.6 mmol Ar0B(OH)2, 2.6 mmol K3PO4, DMA, 120 ꢁC, 24 h; reaction times not optimized.
b Yields determined by 1H NMR; isolated yields in parentheses.
c TON = moles biphenyl/moles catalyst; determined by GC.
d None detected.
The results of Suzuki–Miyaura cross-coupling reactions
using 1 mol % of 2 as a precatalyst are presented in
Table 1.29 With DMA as solvent and K3PO4 as a mild
base additive, this system catalyzes couplings of phenyl-
boronic acid with a range of aryl bromides having both
electron-donating and electron-withdrawing substitu-
ents (entries 1–6) in high yield, though a temperature
of 120 ꢁC is necessary to obtain >90% yields. In addi-
tion, ortho-methyl substituents on the arylboron reagent
are well tolerated (entry 7). Suzuki–Miyaura reactions of
electron-poor and electron-neutral aryl bromides were
performed open to air in wet DMA solvent with only
minimal loss of yield (entries 1–4). Electron-rich aryl
bromides (entries 5 and 6) gave poorer yields under
aerobic conditions, possibly due to oxidation of the
substrate or product methyl groups at the high
temperatures used. Reasonable yields were obtained
for 4-chloronitrobenzene (entry 8), but this catalyst
system did not prove effective for less ꢁactivatedꢀ aryl
chlorides (entries 9 and 10).
To assess whether aerobic reaction conditions affect the
product distribution, we measured the amount of biphen-
yl homocoupling product produced in each reaction.
Homocoupling can result from ꢁdouble transmetalationꢀ
by the arylboron reagent followed by biaryl reductive
elimination,30 and this side pathway could become more
important if the key Pd(0) intermediate of the Suzuki
catalytic cycle2 is depleted by aerobic oxidation to
Pd(II). While larger amounts of homocoupling products
were observed under air compared with reactions under
nitrogen, the largest quantities produced still amounted
to less than one catalytic turnover and ꢁ1% of the total
product (entries 5 and 6). Thus, precatalyst 2 is capable
of sustaining the catalytic Suzuki–Miyaura reaction
under air without substantial byproduct formation.
In summary, we have developed a convenient synthetic
route to a novel palladium Chugaev carbene complex
and found it to be a promising precatalyst for aerobic
Suzuki–Miyaura cross-coupling reactions. While this

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A. I. Moncada et al. / Tetrahedron Letters 46 (2005) 1399–1403
22. Miller, J. S.; Balch, A. L. Inorg. Chem. 1972, 11, 2069–
2074.
system lacks the low-temperature activity and ability to
couple aryl chlorides displayed by the best catalysts,7 the
potentially modular synthetic procedure should allow
substantial tuning of catalyst activity through systematic
modification of ligand electronic and steric properties.
Further efforts to design highly active cross-coupling
catalysts by modular variation of the Chugaev carbene
structure, as well as to develop chiral variants of these
ligands from optically active diamines, will be reported
in due course.
23. Preparation and characterization of 1: cyclohexylisocy-
anide (0.40 g, 3.7 mmol) was added at 25 ꢁC to a stirred
aqueous solution of K2PdCl4, prepared in situ from PdCl2
(163 mg, 0.92 mmol) and KCl (274 mg, 3.68 mmol) in
30mL of H 2O. Excess hydrazine hydrate (1.5 mL,
26 equiv) was added to the resulting colorless solution to
give a yellow precipitate of 1, which was collected by
filtration, washed with aqueous LiClO4 and water, and
dried in vacuo over P2O5 (455 mg, 73%). CAUTION:
perchlorates are potentially explosive and should be
handled carefully and in small amounts. 1H NMR
(300 MHz, DMSO-d6): d 10.09 (s, 1H, NH), 6.79 (s, 1H,
NH), 4.49 (s, 1H, NH), 4.04 (s, 2H, CyNH ipso CH), 3.32
(s, 2H, CyNC ipso CH), 1.0–2.2 (unresolved m, 40H, Cy).
13C NMR (101 MHz, CD3CN): d 188.2 (Pd–C), 53.0(Cy
ipso), 51.2 (Cy ipso), 31.9 (Cy), 31.1 (Cy), 25.1 (Cy), 24.3
(Cy, 2 unresolved), 22.0(Cy). IR (Nujol, cm ꢀ1): m 3381,
3157 (br, NH), 2220, 2210 (m, C„N), 1572, 1539 (m,
C@N). Anal. Calcd for C28H47N6ClO4Pd: C, 49.96; H,
7.03; N, 12.48. Found: C, 50.32; H, 6.65; N, 12.48.
24. Preparation and characterization of 2: aqueous 3 M HCl
was added dropwise to an acetonitrile solution (15 mL) of
1 (201 mg, 0.298 mmol) until a pale yellow solution was
formed. The solution volume was reduced and Et2O was
added dropwise to give a white precipitate of 2, which was
filtered, washed with Et2O, and dried in vacuo (83 mg,
65%). 1H NMR (300 MHz, DMSO-d6): d 11.15 (s, 2H,
Acknowledgements
Acknowledgment is made to the Donors of the Ameri-
can Chemical Society Petroleum Research Fund
(#40196-G1) for support of this research.
References and notes
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NH), 7.71 (d, 2H, JHH = 8 Hz, CyNH), 3.53 (s, 2H, Cy
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25. Crystal
data
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2:
C14H26N4Cl2PdÆ2C2H6SO,
space group P21/c,
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Mr = 583.94,
a = 11.9954(6) A, b = 11.1195(6) A, c = 19.6281(11) A,
˚
˚
˚
3
˚
b = 99.3080(10)ꢁ, U = 2583.6(2) A , T = 103(2) K, Z = 4,
Dc = 1.501 g cmꢀ3, l (MoKa) = 1.108 mmꢀ1, 30772 total
reflections, 6230independent
(
Rint = 0.019). Final
R1(2r) = 0.0208, wR2 (all data) = 0.0544. CCDC 258981
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(1.7 mmol), arylboronic acid (2.55 mmol, 1.5 equiv), and
K3PO4 (anhydrous, 2.55 mmol, 1.5 equiv) were placed in a
flask, and a solution of 2 (7.3 mg, 17 lmol) in DMA
(5 mL) was added. For reactions under N2, all manipu-
lations were done in a dry box, anhydrous DMA (Acros)
was used, and the flask was sealed with a Teflon stopcock.
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and the flask was attached to a reflux condenser open to
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A. I. Moncada et al. / Tetrahedron Letters 46 (2005) 1399–1403
1403
air. The flask was placed in a preheated oil bath at 120 ꢁC
and stirred for 24 h. After cooling, 100 lL of diethylene
glycol dibutyl ether (NMR/GC standard) was added to the
flask. A 200 lL aliquot of the reaction mixture was added
to 10mL of CH 2Cl2, and the resulting mixture was
extracted with 4 · 10mL H 2O and then dried over
MgSO4. The solvent was removed in vacuo, and the
ments were based on authentic samples or published data
(Ref. 6b). In some reactions, the product was isolated by
extraction of the entire reaction mixture with CH2Cl2
followed by silica flash chromatography (4:1 hexanes/
EtOAc).
30. Lei, A.; Zhang, X. Tetrahedron Lett. 2002, 43, 2525–
2528.
1
residue was analyzed by H NMR. Product peak assign-