Synthesis, characterization, and catalytic activity of N-heterocyclic carbene (NHC) palladacycle complexes

Article abstract of DOI:10.1021/ol034264c

(Matrix presented) Palladacycle dimers possessing bridging halides can be easily cleaved by using N-heterocyclic carbenes (NHCs) to generate novel monomeric complexes. The structure of one of these was determined by single-crystal diffraction study and consists of a square-planar coordination around the palladium center where the NHC ligand is trans to the amine of the palladacycle. The complex was found to be equally active in aryl amination and α-arylation of ketones even at very low catalyst loading (0.02 mol %). Primary and secondary alkyl/arylamines are equally active partners in coupling reactions.

Full text of DOI:10.1021/ol034264c

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1479-1482
Synthesis, Characterization, and
Catalytic Activity of N-Heterocyclic
Carbene (NHC) Palladacycle Complexes
Mihai S. Viciu,† Roy A. Kelly III,† Edwin D. Stevens,† Fre´de´ric Naud,‡
,†
Martin Studer,‡ and Steven P. Nolan*
Department of Chemistry, UniVersity of New Orleans, New Orleans, Louisiana 70148,
and SolVias AG, WRO-1055.6.16, Klybeckstrasse 191, Basel, Switzerland CH-4002
snolan@uno.edu
Received February 14, 2003
ABSTRACT
Palladacycle dimers possessing bridging halides can be easily cleaved by using N-heterocyclic carbenes (NHCs) to generate novel monomeric
complexes. The structure of one of these was determined by single-crystal diffraction study and consists of a square-planar coordination
around the palladium center where the NHC ligand is trans to the amine of the palladacycle. The complex was found to be equally active in
aryl amination and r-arylation of ketones even at very low catalyst loading (0.02 mol %). Primary and secondary alkyl/arylamines are equally
active partners in coupling reactions.
Rapid developments in the area of metal-mediated cross-
coupling reactions involving unactivated substrates, espe-
cially aryl chlorides, have highlighted both the positive and
negative properties of phosphines as supporting ligands.1 The
high price associated with bulky tertiary phosphines and/or
difficulties associated with removal of the ligands and their
degradation byproducts, phosphine oxides, have encouraged
researchers to explore alternative catalytic systems. To this
end N-heterocyclic carbenes2 (NHCs) and metallacycle3
scaffolds have been used as ancillary ligands.
addition of the aryl halide to palladium facile. In addition,
the significant steric demand brought about by the presence
of bulky substituents on the NHC facilitates elimination of
the product. The strong interaction between metal and
carbenic carbon of the imidazole moiety inhibits the dis-
sociation, thereby minimizing the need for excess ligand.4
The second class of alternative catalysts focuses on palla-
(2) For reviews see: (a) Jafarpour, L.; Grasa, G. A.; Viciu, M. S.; Hillier,
A. C.; Nolan, S. P. Chim. Oggi 2001, 7/8, 10-16. (b) Jafarpour, L.; Nolan
S. P. AdV. Organomet. Chem. 2000, 46, 181-222. (c) Weskamp, T.; Bohm,
V. P. W.; Herrmann, W. A. J. Organomet. Chem., 2000, 1-2, 12-22. (d)
Rigby, J. H.; Cavezza, A.; Ahmed, G. J. Am. Chem. Soc. 1996, 118, 12848-
12849. (e) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 8, 1290-1309.
(3) (a) Herrmann, W. A.; Bohm, V. P. W.; Reisenger, C. P. J. Organomet.
Chem. 1999, 576, 23-41. (b) Miyazaki, F.; Yamaguchi, K.; Shibasaki, M.
Tetrahedron Lett. 1999, 40, 7379-7383. (c) Shaw, B. L.; Perera, S. D.;
Staley, E. A. Chem. Commun. 1998, 1361-1362. (d) Ohff, M.; Ohff, A.;
Milstein, D. Chem. Commun. 1999, 357-338. (e) Gruber, A. S.; Zim, D.;
Ebeling, G.; Monteiro, A. L.; Dupont, J. Org. Lett. 2000, 2, 1287-1290.
(f) Alonso, D. A.; Najera, C.; Pacheco, M. C. Org. Lett. 2000, 2, 1823-
1826. (g) Bedford, R. B.; Hazelwood, S. L.; Limmert, M. E.; Brown, J.
M.; Ramdeehul, S.; Cowley, A. R.; Coles, S. J.; Hursthouse, M. B.
Organometallics, 2003, 22, 1364-1371. (h) Bedford, R. B.; Cazin, C. S.
T.; Coles, S. J.; Gelbrich, T.; Horton, P. N.; Hursthouse, M. B.; Light, M.
E. Organometallics, 2003, 22, 987-999.
The NHCs have the general advantage of being better
σ-donors than tertiary phosphines rendering the oxidative
† University of New Orleans.
‡ Solvias AG.
(1) (a) Littke, A. F.; Fu, C. J. Org. Chem. 1999, 64, 10-11. (b) Reetz,
M. T.; Lohmer, G.; Schwickardi, R. Angew. Chem., Int. Ed. 1998, 37, 481-
485. (c) Portnoy, M.; Ben-David, Y.; Milstein, D. Organometallics 1993,
12, 4734-4735. (d) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000,
100, 3009-3066. (e) Littke, A. F.; Fu, C. Angew. Chem., Int. Ed. 2002,
41, 4176-4211. (f) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaugh-
nessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575-5580.
(g) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 9473-9474.
10.1021/ol034264c CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/10/2003

dacycles. Pioneering work by the Herrmann group and
others3 has shown these catalysts to be very robust and
capable of high turnover numbers, especially in Heck
coupling reactions. Conceptually, some of these catalysts can
be viewed as oxidative addition products of an aryl halide
to palladium. The use of these catalysts on unactivated
substrates usually requires long reaction times.
CH2Cl2 solutions. The X-ray data confirmed the complex to
have a distorted square-planar geometry with the NHC ligand
trans to the amino group. The biphenyl geometry is twisted
probably to accommodate the steric bulk of the IPr ligand.
(Figure 1).
Recently, a combination of a palladacycle framework with
highly donating, sterically demanding secondary phosphines
has been reported.5 These catalysts combine the stability
induced by the presence of a palladacycle framework with
the high activity commonly associated with palladium/
phosphine complexes. The mechanism of activation and the
exact nature of the active catalytic species are still in question
in this system. We were interested in an approach that would
combine the important donating properties of NHC with the
stability imparted by the palladacycle framework.
Recently, we reported the synthesis of monomeric NHC-
Pd(allyl)Cl species6 by the reaction of NHC and [(η3-allyl)-
PdCl]2. We speculated that a similar reactivity pattern
between palladacycle dimers and NHC could be applied to
generate monomeric palladium complexes.
Herein, we describe the synthesis, characterization, and
catalytic activity of a novel class of palladacycle/NHC
complexes (NHC is IPr [N,N′-bis((2,6-diisopropylphenyl)-
imidazol)-2-ylidene], IMes [N,N′-bis((2,4,6-trimethylphenyl)-
imidazol)-2-ylidene]). Scheme 1 depicts the reaction between
Figure 1. ORTEP drawing of 1. Hydrogens are omitted for clarity.
Selected bond distances (Å) and angles (deg): Pd-Cl, 2.403; Pd-
C(1), 1.992; Pd-C(2), 1.981; Pd-N(3), 2.195; C(2)-Pd-Cl, 176.8;
C(1)-Pd-N(3), 172.62.
We investigated the catalytic activity of NHC modified
palladacycles (1 and 2) in the aryl amination7 using 4-chlo-
rotoluene and morpholine as standard substrates. When 2
was used as the catalyst the reaction reached completion in
1.5 h at 70 °C. On the other hand, aniline is completely inert
under these conditions. However, the use of 1 in this reaction
involving aniline leads to quantitative product formation. It
should be noted here that the secondary phosphine congeners
to 1 and 2 perform arylation of amines but require much
harsher conditions.5 Considering the existence of similar
electronic effects in both catalysts (1 and 2), we suspect the
difference in reactivity must be associated with a different
rate of reductive elimination. Faster rates were observed for
the more bulky ligand, IPr. Among bases, NaOtBu was found
to be the most effective in terms of conversion and price.
Cs2CO3 and K3PO4 were completely ineffective, supporting
the hypothesis of Hartwig that two different mechanisms can
operate in arylation of amines.8
Scheme 1. Synthetic Protocol Leading to NHC Modified
Palladacycles
IPr and a palladacycle dimer. The reaction was performed
in THF at room temperature for 2 h and afforded 1 in 67%
yield after recrystallization. The product is a 16-electron
species that is air and moisture stable. Crystals suitable for
single-crystal X-ray diffraction were obtained from hexanes/
A survey of catalytic cross-coupling of aryl halides with
a wide range of amines performed at 70 °C is provided in
Table 1.
Aryl chlorides were used as coupling partners in most
reactions. Despite the unreactive nature of the C-Cl bond
these reactions required low catalyst loading and reaction
times ranging from 20 min to a maximum of 4 h. It was
(4) (a) Voges, M. H.; Romming, C.; Tilset, M. Organometallics 1999,
18, 529-533. (b) Herrmann, W. A.; Kocher, C. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2163-2187.
(5) Schnyder, A.; Indolese, A. F.; Studer, M.; Blaser, H.-U. Angew.
Chem., Int. Ed. 2002, 41, 3668-3671.
(6) (a) Viciu, M. S.; Germaneau, R. F.; Navarro-Fernandez, O.; Stevens,
E. D.; Nolan, S. P. Organometallics 2002, 21, 5470-5472. (b) Viciu, M.
S.; Germaneau, R. F.; Nolan, S. P. Org. Lett. 2002, 23, 4053-4056. (c)
The related NHC bearing palladium complex described in a and b, (IPr)-
Pd(allyl)Cl, is now commercially available from Strem.
(7) For reviews on aryl amination see: (a) Hartwig, J. F. Angew. Chem.,
Int. Ed. 1998, 37, 2046-2067. (b) Muci, A. R.; Buchwald, S. L. Top. Curr.
Chem. 2002, 219, 131-209.
(8) Alcazar-Roman, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123,
12905-12906.
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Org. Lett., Vol. 5, No. 9, 2003

Table 1. Cross-Coupling of Aryl Halides and Amines
Mediated by 1a
Table 2. R-Arylation of Ketonesa
a Conditions: 1.1 mmol of NaOtBu, 1 mol % of 1, 1 mmol of ArX. (a)
3 mL of dioxane. (b) 3 mL of toluene. GC yields. Isolated yields are braketed
and are an average of two runs.
observed with this system. The reactivity of the present
system compares favorably to that displayed by systems
reported by Buchwald.9
We were interested in the activity of the catalyst at lower
catalyst loadings. For this facet of the study, the reaction
between p-chloroanisole and aniline was chosen as it involves
a coupling of an electron-rich aryl with a poorly activated
amine. The experiments showed that the TON can be nearly
doubled by increasing the temperature of the reaction from
70 (TON ) 160) to 110 °C (TON ) 305). Under the more
forcing conditions no formation of palladium black was
observed. Harsher conditions were tested with use of 0.05
mol % of catalyst 1 and TON of up to 460 were obtained.
Further studies in this direction are presently ongoing and
are aimed at understanding the fate of the catalytic species.
While reaction conditions are still being optimized, initial
results show that reactions involving 4-methoxychloroben-
zene or 4-chlorotoluene and morpholine can be carried out
at room temperature. These reactions reach completion within
2 h.
An attractive alternative to the use of aryl chlorides as a
substrate in cross-coupling chemistry is the use of aryl
triflates which are easily synthesized from phenols.10 We
found that an important factor enabling the use of triflates
is solvent selection. Standard reaction conditions involving
dioxane as solvent led to no significant amount of products.
The use of toluene led to conversions similar to those
involving aryl chlorides.
a Conditions: 1.1 mmol of NaOtBu, 1 mol % of 1, 1 mmol of ArX.; (a)
Unless otherwise stated reactions were carried out with 3 mL of dioxane.
(b) Reaction carried out with 3 mL of toluene. Yields were determined by
GC. Isolated yields are braketed and are an average of two runs.
We investigated the use of palladacycle-NHC complexes
as catalysts in the arylation of simple ketones with aryl
halides and pseudohalides at 70 °C. The NaOtBu base plays
a dual role, it generates the active catalytic species (as
described above) and it deprotonates the ketone. In our initial
studies multiple arylations are not observed probably due to
steric constraints.
interesting to observe that varying the nature of aryl group
substituents had minimal influence on reaction rates. Steri-
cally hindered aryl chlorides such as 2-methoxychloroben-
zene or 2-methylchlorobenzene have rates slightly lower than
nonhindered relatives. We were pleased to find that a large
variety of substratessheterocyclic alkylamines, dialkyl-
amines, aryl-alkylamines and primary aminessare all effi-
cient coupling partners. Furthermore, it should be pointed
out that substrates such as aniline, hexylamine, and other
primary amines have oftentimes been found to undergo a
second arylation under catalytic conditions. This is not
(9) Harris, M. C.; Huang, X.; Buchwald, S. L. Org. Lett. 2002, 4, 2885-
2888 and references cited therein.
(10) (a) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109,
5478-5486. (b) Louie, J.; Driver, M. S.; Hamann, B. C.; Hartwig, J. F. J.
Org. Chem. 1997, 62, 1268-1273. (c) Wolfe, J. P.; Tomori, H.; Sadighi,
J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158-1174.
Org. Lett., Vol. 5, No. 9, 2003
1481

Indolese and co-workers recently reported a similar
catalytic system but the palladacycle was stabilized and
activated by the presence of a secondary phosphine.5 The
reaction of 1 and tricyclohexylphosphine in the presence of
NaOtBu was monitored by 31P NMR spectroscopy. The
appearance of a peak at 52.6 ppm, similar to the reported
values for mixed NHC phosphine palladium(0) complexes
synthesized by Cloke and co-workers,11 was observed.12 On
the basis of this spectroscopic information, we speculate an
activation mechanism that is initiated by an attack of alkoxide
on palladium resulting in the formation of a palladium
alkoxide. Aryl palladium alkoxide complexes have been
shown to be susceptible to thermal reductive elimination.13
Alternatively, under catalytic conditions, a palladacycle-NHC
aryl complex could form and subsequently eliminate the
arylated aminoaryl fragment thereby generating the “Pd-
NHC” fragment. We are now exploring which of these two
activation modes is operating in the present system. In either
case the generated electron-rich palladium(0) species stabi-
lized by the presence of a NHC ligand then enters the
catalytic cycle performing the oxidative addition of aryl
halides (Scheme 2).
In summary, a new class of catalysts with a broad spectrum
of activity in cross-coupling chemistry has been synthesized
and fully characterized. The catalysts consist of a pallada-
cycle scaffold stabilized by the presence of a highly donating,
sterically demanding NHC ligand. The catalysts are well-
defined, air stable, and very active in cross-coupling of aryl
chlorides or triflates with amines and/or ketones. Their
synthesis is simple and is achieved by mixing a NHC with
a palladacycle in THF at room temperature. The large number
of palladacycles and carbenes reported in the literature leaves
open the possibility of discovering even more active catalysts.
The proposed mechanism of activation is based on the
generation of aryl-alkoxy palladium species that are subject
to thermal elimination of ethers. The palladium(0) species
formed upon elimination of the ether is stabilized by
coordination to an electron-rich, sterically demanding NHC.
Currently, we are expanding the scope and use of of NHC-
palladacycle complexes to other cross-coupling and related
reactions.
Acknowledgment. We gratefully acknowledge financial
support from the National Science Foundation, the Petroleum
Research Fund, administered by the ACS, and the Louisiana
Board of Regents.
Supporting Information Available: Experimental details
for the synthesis of NHC/palladacycle complexes, catalysis
protocol, and product isolation, as well as crystallographic
tables. This material is available free of charge via the
Internet at http://pubs.acs.org.
Scheme 2. Proposed Catalyst Activation Pathway
OL034264C
(11) Titcomb, L. R.; Caddick, S.; Cloke, F. G. N.; Wilson, D. J.;
McKerrecher, D. Chem. Commun. 2001, 1388-1389.
(12) The general biaryl product depicted in Scheme 2 is a proposed
product as GCMS (EI) results indicate the presence of a peak at 197 (269
less the alkoxide moiety). This in conjunction with a stable species indicated
by the GC peak lends indirect support to such a species. Further studies
aimed at unequivocally identifying and characterizing this product are
ongoing.
(13) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am.
Chem. Soc. 1999, 121, 3224-3225.
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