Suzuki-Miyaura, α-ketone arylation and dehalogenation reactions catalyzed by a versatile N-heterocyclic carbene-palladacycle complex

Article abstract of DOI:10.1021/jo0521201

The activity of the complex (IPr)PdCl(η²-N,C-C ₁₂H₇NMe₂), 1 [IPr = (N,N′-bis(2,6- diisopropylphenyl)-imidazol)-2-ylidene], in the Suzuki-Miyaura cross-coupling reaction involving unactivated aryl chlorides and triflates with arylboronic acids at room temperature in technical grade 2-propanol is described. These conditions allow for the synthesis of di- and tri-ortho-substituted biaryls in very short reaction times. This complex also displays very high activity for α-ketone arylation and dehalogenation reactions of activated and unactivated aryl chlorides.

Full text of DOI:10.1021/jo0521201

Suzuki-Miyaura, r-Ketone Arylation and Dehalogenation Reactions
Catalyzed by a Versatile N-Heterocyclic Carbene-Palladacycle
Complex
Oscar Navarro, Nicolas Marion, Yoshihiro Oonishi,† Roy A. Kelly III, and
Steven P. Nolan*
Department of Chemistry, UniVersity of New Orleans, New Orleans, Louisiana 70148
snolan@uno.edu
ReceiVed October 10, 2005
The activity of the complex (IPr)PdCl(η2-N,C-C12H7NMe2), 1 [IPr ) (N,N′-bis(2,6-diisopropylphenyl)-
imidazol)-2-ylidene], in the Suzuki-Miyaura cross-coupling reaction involving unactivated aryl chlorides
and triflates with arylboronic acids at room temperature in technical grade 2-propanol is described. These
conditions allow for the synthesis of di- and tri-ortho-substituted biaryls in very short reaction times.
This complex also displays very high activity for R-ketone arylation and dehalogenation reactions of
activated and unactivated aryl chlorides.
Introduction
activations. One particular interest has been the development
of catalysts that can operate at very low metal loadings. To
achieve this, catalytic species must be highly reactive while
decomposition should be minimal. Palladacyclic complexes have
Cross-coupling reactions have become a powerful tool in the
arsenal of methods available to chemists for the formation of
new Csp2-Csp2 or Csp2-Csp3 bonds.1 While from the late 1970s
to the early 1990s research focused mainly on finding new
coupling partners, especially organometallic partners, attention
during the past 10 years has turned toward the development of
more powerful catalysts that allow reactions to be conducted
using milder reaction conditions and unprecedented substrate
(1) General reviews on cross-coupling reactions: (a) ComprehensiVe
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G.,
Eds.; Pergamon Press: New York, 1995. (b) Tsuji, J. Transition Metal
Reagents and Catalysts; Wiley: Bath, England, 2000; pp 56-76. (c) de
Meijere, A., Diederich, F., Eds. Metal-Catalyzed Cross-Coupling Reactions,
2nd ed; Wiley-VCH: Weinheim, Germany, 2004. (d) Beller, M.; Bolm, C.
Transition Metals for Organic Chemistry, Vol. 1; Wiley-VCH: Weinheim,
Germany, 1998; pp 158-193.
† Visiting student from Hokkaido University.
10.1021/jo0521201 CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/16/2005
J. Org. Chem. 2006, 71, 685-692
685

Navarro et al.
played a significant role in this regard. Although the vast
majority of palladacycles reported to date contain phosphines,
especially bulky tertiary and secondary phosphines, as ancillary
ligands to stabilize the palladium center,2 the costly price usually
associated with this phosphine type, along with phosphine ligand
and ligand decomposition byproduct removal difficulties, have
led to the use of N-heterocyclic carbenes (NHCs)3 as a very
attractive ligand alternative.4 We have reported preliminary
results on the very efficient performance of such palladacyclic
complexes as precatalysts in aryl amination reactions and
R-ketone arylation reactions of aryl chlorides and triflates.5
Later, we reported on the use of 1 in room temperature Suzuki-
Miyaura reactions.6 Herein, we expand the substrate scope of 1
for the R-ketone arylation and the Suzuki-Miyaura reaction
and also report on the use of this complex as an active
precatalyst for the dehalogenation of aryl chlorides at room
temperature.
reaction conditions, and organoboron reagents have been
developed by a number of research groups. Nowadays, the
method is routinely employed in retrosynthetic schemes, and a
large number of drugs,10 polymers,11 and natural products12
make use of a Suzuki-Miyaura cross-coupling step in their
assembly. Pioneering work in the use of palladacycles for the
Suzuki-Miyaura reaction was performed by Herrmann and co-
workers using a phosphine-bearing palladacycle in the coupling
of activated chlorides with precatalyst loadings of 0.1 mol %.13
Good activity is not limited to phosphorus donor systems14,15
because N-donor,16,17 oxime-containing,18 and S-donor19 pal-
ladacycles have also been described with good results. Tertiary
phosphine adducts of phosphorus-, imine-, and amine-based
palladacycles20,21 show excellent activity at very low catalyst
loadings when aryl chlorides, both activated and unactivated,
are used as substrates. Our group reported on the activity of
the NHC-bearing palladacycle 1 for the Suzuki-Miyaura cross-
coupling of sterically hindered unactivated aryl chlorides with
sterically hindered boronic acids, allowing for the synthesis in
high yields of di- and tri-ortho-substituted biaryls at room
(10) (a) References 8b-d. (b) Chemler, S. R.; Trauner, D.; Danishefsky,
S. J. Angew. Chem., Int. Ed. 2001, 40, 4544-4568. (c) Konno, T.; Daitoh,
T.; Noiri, A.; Chae, J.; Ishihara, T.; Yamanaka, H. Org. Lett. 2004, 6, 933-
936.
(11) (a) Yamamoto, T.; Kobayashi, K.; Yasuda, T.; Zhou, Z.-H.;
Yamaguchi, I.; Ishikawa, T.; Koshihara, S. Polym. Bull. 2004, 52, 315-
319. (b) Bo, Z.; Qiu, J.; Li, J.; Schlueter, A. D. Org. Lett. 2004, 6, 667-
669. (c) Beinhoff, M.; Karakaya, B.; Schluter, A. D. Synthesis 2003, 79-
90. (d) Yamaguchi, S.; Goto, T.; Tamao, K. Angew. Chem., Int. Ed. 2000,
39, 1695-1697.
(12) (a) Lin, S.; Yang, Z.-Q.; Kwok, B. H. B.; Koldobskiy, M.; Crews,
C. M.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 6347-6355. (b)
Yuan, Y.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 14720-14721.
(c) Suzuki, T.; Usui, K.; Miyake, Y.; Namikoshi, M.; Nakada, M. Org.
Lett. 2004, 6, 553-556. (d) Tsukano, C.; Sasaki, M. J. Am. Chem. Soc.
2003, 125, 14294-14295. (e) Miyashita, K.; Sakai, T.; Imanishi, T. Org.
Lett. 2003, 5, 2683-2686. (f) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki,
M. J. Am. Chem. Soc. 2002, 124, 14983-14992. (g) Mandal, A. K. Org.
Lett. 2002, 4, 2043-2045. (h) Sasaki, M.; Fuwa, H. Synlett 2004, 1851-
1874.
FIGURE 1. NHC-bearing palladacycles.
Results and Discussion
Suzuki-Miyaura Cross-Coupling Reactions. Since its
discovery in 1979,7 the Suzuki-Miyaura reaction8 involving
the coupling of organoboron reagents with organic halides has
widened its scope, becoming arguably one of the most important
transformations leading to the formation of a C-C bond. One
major reason is that organoboron reagents show many advan-
tages,9 for example, (1) ready availability of reagents by
hydroboration and transmetalation, (2) inert to water and related
solvents, as well as oxygen, (3) generally thermally stable, (4)
tolerant toward various functional groups, and (5) low toxicity
of starting materials and byproducts. A plethora of new catalysts,
(13) Beller, M.; Fischer, H.; Herrmann, W. A.; O¨ fele, K.; Brossmer, C.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1848-1849.
(14) (a) Bedford, R. B.; Draper, S. M.; Scully, P. N.; Weilch, S. L. New
J. Chem. 2000, 24, 745-747. (b) Albisson, D. A.; Bedford, R. B.; Lawrence,
S. E.; Scully, P. N. Chem. Commun. 1998, 2095-2096. (c) Bedford, R. B.;
Welch, S. L. Chem. Commun. 2001, 129-130. (d) Bedford, R. B.;
Hazelwood, S. L.; Limmert, M. E.; Albisson, D. A.; Draper, S. M.; Scully,
P. N.; Coles, S. J.; Hursthouse, M. B. Chem.sEur. J. 2003, 9, 3216-3227.
(e) Bedford, R. B.; Hazelwood, S. L.; Horton, P. N.; Hursthouse, M. B.
Dalton Trans. 2003, 4164-4174.
(15) Gibson, S.; Foster, D. F.; Eastman, G. R.; Tooze, R. P.; Cole-
Hamilton, D. J. Chem. Commun. 2001, 779-780.
(2) (a) Bedford, R.; Cazin, C. S. J.; Hursthose, M. B.; Light, M. E.;
Scordia, V. J. M. Dalton Trans. 2004, 3864-3868. (b) Bedford, R.; Cazin,
C. S. J.; Holder, D. Coord. Chem. ReV. 2004, 248, 2283-2321. (c) Bedford,
R. B. Chem. Commun. 2003, 1787-1796. (d) Nettekoven, U.; Naud, F.;
Schnyder, A.; Blaser, H.-U. Synlett 2004, 2549-2552.
(3) (a) Arduengo, A. J., III; Rasika Dias, H. V.; Harlow, R. L.; Kine, M.
J. Am. Chem. Soc. 1992, 114, 5530-5534. (b) Regitz, M. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 725-728. (c) Arduengo, A. J., III; Krafczyc, R.
Chem. -Ztg. 1998, 32, 6-14.
(4) (a) Scott, N. M.; Nolan, S. P. Eur. J. Inorg. Chem. 2005, 1815-
1828. (b) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290-1309.
(5) Viciu, M. S.; Kelly, R. A., III; Stevens, E. D.; Naud, F.; Studer, M.;
Nolan, S. P. Org. Lett. 2003, 5, 1479-1482.
(16) (a) Albisson, D. A.; Bedford, R. B.; Scully, P. N. Tetrahedron Lett.
1998, 39, 9793-9796. (b) Iyer, S.; Ramesh, C. Tetrahedron Lett. 2000,
41, 8981-8984. (c) Beletskaya, I. P.; Kashin, A. N.; Karslted, N. B.; Mitin,
A. V.; Cheprakov, A. V.; Kazankov, G. M. J. Organomet. Chem. 2001,
622, 89-96. (d) Yang, F.; Zhang, Y.; Zheng, R.; Tie, J.; He, M. J.
Organomet. Chem. 2002, 651, 146-148.
(17) Weissman, H.; Milstein, D. Chem. Commun. 1999, 1901-1902.
(18) (a) Alonso, D. A.; Na´jera, C.; Pacheco, M. C. J. Org. Chem. 2002,
67, 5588-5594. (b) Botella, L.; Na´jera, C. Angew. Chem., Int. Ed. 2002,
41, 179-181. (c) Botella, L.; Na´jera, C. J. Organomet. Chem. 2002, 663,
46-57. (d) Alonso, D. A.; Botella, L.; Na´jera, C.; Pacheco, M. C. Synthesis
2004, 1713-1718.
(19) Zim, D.; Gruber, A. S.; Ebeling, G.; Dupont, J.; Monteiro, A. L.
Org. Lett. 2000, 2, 2881-2884.
(20) (a) Bedford, R. B.; Cazin, C. S. J. Chem. Commun. 2001, 1540-
1541. (b) Bedford, R. B.; Cazin, C. S. J.; Coles, S. J.; Gelbrich, T.; Horton,
P. N.; Hurtshouse, M. B.; Light, M. E. Organometallics 2003, 22, 987-
999.
(6) Navarro, O.; Kelly, R. A., III; Nolan, S. P. J. Am. Chem. Soc. 2003,
125, 16194-16195.
(7) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36,
3437-3439.
(8) For reviews, see: (a) Suzuki, A. J. Organomet. Chem. 1999, 576,
147-168. (b) Miyaura, N. Top. Curr. Chem. 2002, 219, 11-59. (c) Kotha,
S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633-9695. (d) For a
recent review covering up to March 2004: Bellina, F.; Carpita, A.; Rossi,
R. Synthesis 2004, 15, 2419-2440.
(21) (a) Bedford, R. B.; Cazin, C. S. J.; Hazelwood, S. L. Angew. Chem.,
Int. Ed. 2002, 41, 4120-4122. (b) Bedford, R. B.; Cazin, C. S. J.;
Hazelwood, S. L. Chem. Commun. 2002, 2608-2609. (c) Bedford, R. B.;
Hazelwood, S. L.; Limmert, M. E. Chem. Commun. 2002, 2610-2611.
(9) Suzuki, A. J. Organomet. Chem. 2002, 653, 83-90.
686 J. Org. Chem., Vol. 71, No. 2, 2006

Catalyzed Arylation and Dehalogenation Reactions
SCHEME 1. Proposed Mechanism for the Activation of 1
SCHEME 2. Proposed Catalytic Cycle
temperature and in very short reaction times. We proposed that
the activity of the complex at room temperature was directly
related to its particular activation mode, shown in Scheme 1,
generating a catalytically very efficient Pd(0) species at room
temperature.
In our initial experiments, we observed the formation to a
large extent, 10-50% depending on the substrates, of the
corresponding dehalogenated species as a side product. The
coupling of either sterically demanding chlorides or boronic
acids (or both) produced a larger amount of dehalogenated
byproduct. Because we22 and others23 have reported on the use
of 2-propanol as a hydrogen source for palladium-catalyzed
dehalogenation of aryl halides, we propose that in the present
system both processes, the Suzuki-Miyaura reaction and the
catalytic dehalogenation, are intertwined, sharing the oxidative
addition step (Scheme 2, intermediate a) and leading in both
instances to the (IPr)-Pd(0) species after one turnover.24
Sterically demanding substrates should lead to a decrease in
the rate of transmetalation, favoring then the dehalogenation
(22) (a) Viciu, M. S.; Grasa, G. A.; Nolan, S. P. Organometallics 2001,
20, 3607-3612. (b) Navarro, O.; Kaur, H.; Mahjoor, P.; Nolan, S. P. J.
Org. Chem. 2004, 69, 3173-3180.
(23) Desmarets, C.; Kuhl, S.; Schneider, R.; Fort, Y. Organometallics
2002, 21, 1554-1559.
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Navarro et al.
TABLE 1. Suzuki-Miyaura Cross-Coupling Reactions with Aryl
Chlorides
pathway. A proposal in line with our experimental observations
is depicted in Scheme 2.
To minimize this undesirable side reaction, the aryl chlorides
were initially required to be slowly added to the catalytic
reaction mixture at an injection rate of 20 µL/30 s.25 This
procedure permitted the couplings to occur with less than 5%
of the dehalogenation byproducts regardless of the substrates
coupled. Although it might not seem to be a big difference in
the process to account for the suppression of the dehalogenated
byproduct, it is needed to explain that, for these reactions, more
than 75% of the desired product is produced in half of the
reaction time, as monitored by gas chromatography. Also, the
dehalogenation byproduct is formed in the first minutes of the
reaction and its amount does not increase with time. We will
show later how the dehalogenation reactions we carried out at
room temperature require shorter reaction times and, even more
important, only half of the catalyst loading (1 mol %), which
again suggests an extremely rapid oxidative addition process
even for deactivated aryl chlorides (vide infra). In the initial
stages of the reaction, once intermediate a has been formed,
the possible lack of the in situ formed tetracoordinate boronate,
together with the “large” concentration of aryl chloride and
isopropoxide, might shift the equilibrium toward the dehalo-
genation process.
As we previously reported, activated and unactivated aryl
chlorides couple smoothly with phenylboronic acid at room
temperature in short reaction times (Table 1). Di- and tri-
ortho-substituted biaryls can also be synthesized using the
same conditions in high yields (Table 2). These results are ob-
tained at room temperature in remarkably short reaction
times! From a practical point of view, these conditions are very
appealing, especially considering the use of an inexpensive
and environmentally friendly solvent without predrying or
purification. An experiment on the scale of 2.5 mmol of aryl
chloride was carried out for the reaction depicted in entry 4
(Table 2) and afforded 428 mg (87%) of the desired product in
75 min.
Heterocyclic moieties are of great importance because they
are ubiquitous in pharmaceutically active compounds.26 Despite
their importance, the cross-coupling reaction of heterohalides
remains a challenge, especially at low temperatures. The use
of 1 allows for the coupling of 2-chlorothiophene, 2-benzimi-
dazole, and 2-chloropyridine with phenylboronic acid at room
temperature within 1 h. The more deactivated substrates,
3-chlorothiophene and 3-chloropyridine, require a slightly higher
temperature and longer reaction times (Table 3). To the best of
our knowledge, the Suzuki-Miyaura cross-coupling reaction
of chlorothiophenes at such low temperatures and in such yields
has not been reported to date.
a Isolated yields are the average of two runs. b Reaction at 45 °C.
r-Ketone Arylation Reactions. The coupling of enolizable
ketones and aryl halides, despite its great synthetic importance,
has been less explored.28 Because this reaction requires the
formation of an enolate that further binds to the palladium center,
a possible side reaction is the condensation of two ketone
molecules to form an R-hydroxyketone.29 After optimization,
we were able to successfully carry out the R-arylation of a series
of aryl and alkyl ketones at 70 °C in dry THF in the presence
of sodium tert-butoxide using a variety of aryl halides. It is
noteworthy that we were able to perform every reaction with
as low as 0.25 mol % of palladium precatalyst. Results with
aryl chlorides are presented in Table 5. These substrates are of
significant interest because they have in general lower costs
and wide availability. Propiophenone can be efficiently coupled
with neutral (entry 1), activated (entry 2), unactivated (entry
3), and sterically hindered (entry 4) aryl chlorides. We observed
the same trend for acetophenone with slightly longer reaction
times (entries 6-8). Satisfyingly, our catalytic system allows
for the R-arylation of tetralone, even with an ortho-substituted
substrate (entries 9 and 10). Dialkyl ketones are also suitable
partners, as highlighted by the reaction of cyclohexanone and
3-pentanone with chlorobenzene (entries 11 and 12). In the latter
case, the use of our standard reaction conditions always resulted
in mixtures of mono- and diarylated products, even with a large
excess of ketone. Then we decided to take advantage of this
feature by synthesizing the diarylated ketone as the only product.
This can be easily achieved in only 30 min when 2 equiv of
The present catalytic system also allows for the coupling of
activated and unactivated aryl triflates under the same conditions
in high yields (Table 4). From a synthetic point of view, aryl
triflates are a very interesting type of substrate for the Suzuki-
Miyaura reaction because they can be readily synthesized from
the corresponding phenols in high yields.27
(24) Another possibility would be that both catalytic cycles are connected
at intermediate c, what has been described as a suitable intermediate for
the Suzuki-Miyaura reaction, which can undergo direct transmetalation
with the boronic acid (ref 7b). Studies aimed at elucidating the mechanism
at play in this system are currently ongoing.
(25) See Supporting Information.
(26) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127-2198.
(27) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478-
5486.
(28) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234-245.
(29) March, J.; Smith, M. B. AdVanced Organic Chemistry, 5th ed.; John
Wiley & Sons: New York, 2001; pp 1218-1223.
688 J. Org. Chem., Vol. 71, No. 2, 2006

Catalyzed Arylation and Dehalogenation Reactions
TABLE 2. Synthesis of Di- and Tri-Ortho-Substituted Biaryls
a Isolated yields are the average of two runs.
TABLE 3. Suzuki-Miyaura Cross-Coupling Reactions with
Heteroaryl Chlorides
TABLE 4. Suzuki-Miyaura Cross-Coupling Reactions with Aryl
Triflates
a Isolated yields are the average of two runs.
(entry 13); this can be explained by the greater stability of the
internal enolate compared to that of the terminal one. Finally,
regarding the significant role of the heterocyclic moiety in
biologically active compounds, we attempted the coupling of
3-chloropyridine and propiophenone. Pleasantly, the correspond-
ing heterocyclic ketone was obtained in good yield (entry 15).
In addition, large-scale reactions (10 mmol of aryl chloride)
a Isolated yields are the average of two runs. b 45 °C.
aryl chloride are used (entry 12). When a nonsymmetrical dialkyl
ketone was used, a mixture of monoarylated products was
observed. Butanone reacted preferentially at the internal position
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Navarro et al.
TABLE 5. r-Ketone Arylation Using Aryl Chlorides
a Isolated yields are the average of two runs. b Aryl chloride, 10 mmol; ketone, 10 mmol; NaOt-Bu, 11 mmol; THF, 30 mL. c A total of 1 mmol of ketone,
2.1 mmol of aryl chloride, and 2.2 mmol of NaOt-Bu were used.
were carried out for entries 1 and 6 with similar yields in slightly
longer reaction times.
transformation.32 In light of our findings in the Suzuki-Miyaura
cross-coupling reaction, we carried out dehalogenation reactions
using the same system but without the presence of a boronic
acid. The ability of the (IPr)-Pd(0) species to activate the C-Cl
bond at ambient temperatures translates into a very active system
for the dehalogenation of aryl chlorides at rt. We observed that
the use of the stronger base KOt-Bu permitted a catalyst loading
reduction to 1 mol % using the same conditions (room tem-
perature and technical grade 2-propanol). A variety of aryl
chlorides (unactivated, activated, and heterocyclic) yielded the
corresponding dehalogenated products in excellent yields and
in short reaction times (Table 8). The catalytic performance is
excellent considering these reactions are carried out at room
temperature and require such short reaction times. Unfortunately,
attempts to effectively dehalogenate polychlorinated substrates
in these conditions led to incomplete reactions. Interestingly,
electron-rich chlorides (entries 4-6) require shorter reaction
times than electron-poor chlorides (entries 8-10). Because
This coupling reaction was also tested using microwave
heating with excellent results (Table 6). When the temperature
is raised to 130 °C with this rapid heating mode, reactions could
reach completion within 2 min with no decrease in the yields.
Interestingly, we observed a higher selectivity in the arylation
of butanone under microwave heating mode, presumably
because of conditions favoring the more stable enolate. Decreas-
ing the temperature might shift the regioselectivity toward the
terminal arylated ketone, but all attempts to perform R-ketone
arylation at room temperature were unsuccessful.
As expected, aryl bromides were suitable substrates for
reactions under these conditions, and a variety of aryl and alkyl
ketones could be easily arylated using unactivated and sterically
demanding aryl bromides in very good yields and, in general,
shorter reaction times than for the analogous chlorides (Table
7). Gratifyingly, the use of sterically hindered aryl bromides
did not appear to be a limiting factor with our catalytic system.
Ortho-substituted (entries 3, 4, and 7) and even di-ortho-sub-
stituted aryl bromides were coupled efficiently and in short
reaction times. Following the same trend, R-tetralone reacted
in high yields with 2-bromotoluene and 2-bromoanisole to afford
the arylated products (entries 9 and 10).
(30) (a) Terstiege, I.; Maleczka, R. E., Jr. J. Org. Chem. 1999, 64, 342-
343. (b) Parry, R. J.; Li, Y.; Gomez, E. E. J. Am. Chem. Soc. 1992, 114,
5946-5959. (c) Dorman, G.; Otszewski, J. D.; Prestwich, G. D. J. Org.
Chem. 1995, 60, 2292-2297.
(31) (a) Hutzinger, O.; Safe, S.; Zitko, V. The Chemistry of PCBs; CRC
Press: Cleveland, OH, 1974. (b) Mincher, B. J.; Randy, D.; Clevenger, T.
E.; Golden, J. U.S. Patent 6 132 561, 2000. (c) McNab, W. W., Jr.; Ruiz,
R.; Pico, T. M. U.S. Patent 6 214 202, 2001. (d) Morra, M. J.; Borek, V.;
Koolpe, J. J. EnViron. Qual. 2000, 29, 706-715.
(32) (a) References 22 and 23. (b) Cellier, P. P.; Spindler, J.-F.; Taillefer,
M.; Cristau, H.-J. Tetrahedron Lett. 2003, 44, 7191-7195. (c) Alonso, F.;
Moglie, Y.; Radivoy, G.; Vitale, C.; Yus, M. Appl. Catal., A 2004, 271,
171-176. (d) For a review, see: Alonso, F.; Beletskaya, I. P.; Yus, M.
Chem. ReV. 2002, 102, 4009-4092.
Catalytic Dehalogenation Reactions. The dehalogenation
of aryl halides, and more specifically aryl chlorides, represents
an important chemical transformation in organic synthesis.30 As
a result of the high toxicity of polychlorinated arenes, it also
has relevance to environmental remediation.31 A plethora of
systems and conditions have been reported to perform this
690 J. Org. Chem., Vol. 71, No. 2, 2006

Catalyzed Arylation and Dehalogenation Reactions
TABLE 6. Microwave-Assisted versus Conventionally Heated r-Ketone Arylation Using Aryl Chlorides
a Average of two runs.
TABLE 7. r-Ketone Arylation Using Aryl Bromides
a Isolated yields are the average of two runs.
electron-poor chlorides are supposed to undergo oxidative
addition easier than electron-rich chlorides, these results suggest
that the rate-determining step in this process is not the oxidative
addition but is either the replacement of the chloride by the
isopropoxide anion or the replacement of the chloride by the
reductive elimination step, if we presume that neither steric nor
electronic effects at the aryl moiety will have a large effect in
the â-hydrogen elimination step (Scheme 2). In the case of entry
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Navarro et al.
TABLE 8. Catalytic Dehalogenation of Aryl Chlorides at Room
Temperature
studies of this and related complexes in various cross-coupling
reactions are ongoing in our laboratories.
Experimental Section
Representative Procedure for the Suzuki-Miyaura Cross-
Coupling Reaction: The Coupling of 2-Chloroanisole and
Phenylboronic Acid. In a glovebox, 1 (2 mol %, 14.6 mg), sodium
tert-butoxide (1.2 mmol, 115 mg), and phenylboronic acid (1.2
mmol, 146 mg) were added in turn to a vial equipped with a
magnetic bar and sealed with a screw cap fitted with a septum. A
parallel reaction was conducted at the same time in another vial.
Outside the glovebox, technical grade 2-propanol (1.5 mL per vial)
was injected into the vials, and the mixtures were stirred on a stirring
plate at room temperature for 15 min. 2-Chloroanisole (1 mmol,
127 µL) was then injected at a rate of 20 µL/30 s into each vial.
The reactions were monitored by gas chromatography. When the
reactions reached completion, as gauged by GC analysis, both were
combined in one vial, a small amount of silica gel was added, the
solvent was evaporated in vacuo, and the product was isolated by
flash chromatography (hexanes/ethyl acetate, 10:1), yielding 342
mg (93%) of the desired coupling product 2-methoxybiphenyl.
Representative Procedure for the r-Ketone Arylation: The
r-Arylation of Propiophenone with 4-Chlorotoluene. In a
glovebox, 1 (0.25 mol %, 1.8 mg), sodium tert-butoxide (1.1 mmol,
106 mg), and anhydrous THF (3 mL) were added in turn to a vial
equipped with a magnetic bar and sealed with a screw cap fitted
with a septum. A parallel reaction was conducted at the same time
in another vial. Outside the glovebox, propiophenone (1.1 mmol,
134 µL) and 4-chlorotoluene (1 mmol, 118 µL) were injected in
turn through the septum into each vial. The vials were then stirred
on a stirring plate at 70 °C, unless otherwise indicated. The reactions
were monitored by gas chromatography. When no further conver-
sion could be observed, both mixtures were combined, water was
added to the reaction mixture, the organic layer was extracted with
diethyl ether and dried over magnesium sulfate, and the solvent
was evaporated in vacuo. After flash chromatography on silica gel
(hexane/EtOAc, 95:5), 442 mg (99%) of 2-(4-methylphenyl)-1-
phenyl-1-propanone was isolated.
Representative Procedure for the Catalytic Dehalogenation
of Aryl Chlorides: The Catalytic Dehalogenation of 4-Chloro-
toluene. In a glovebox, 1 (1 mol %, 7.3 mg) and potassium tert-
butoxide (1.2 mmol, 134.7 mg) were added in turn to a vial
equipped with a magnetic bar and sealed with a screw cap fitted
with a septum. A parallel reaction was conducted at the same time
in another vial. Outside the glovebox, technical grade 2-propanol
(2 mL per vial) was injected into the vial and the mixtures were
stirred on a stirring plate at room temperature for 15 min.
2-Chloroanisole (1 mmol, 127 µL) was then injected into each vial.
The reactions were monitored by gas chromatography, and the
product identity was compared with authentic samples.
a GC yields. b Reaction at 60 °C.
8, the substituent at the ortho position should enhance the
reductive elimination step, shortening the reaction time when
compared with the para-substituted analogue (entry 9). Studies
in this matter are currently ongoing.
Acknowledgment. The National Science Foundation is
gratefully acknowledged for financial support of this work.
Solvias, Eli Lilly and Co., Umicore AG, and Lonza are
gratefully acknowledged for gifts of materials. Personal Chem-
istry, Inc. (now Biotage), is gratefully acknowledged for the
loan of the Emry optimizer microwave reactor. Y.O. thanks the
JSPS for a visiting fellowship. We are also very grateful to the
University of Ottawa and Boston College (and their Chemistry
Departments) for hosting our group during rebuilding efforts
at the University of New Orleans.
Conclusions
In summary, we have examined the catalytic behavior of the
NHC-palladacycle 1. In particular, a general system involving
the use of 1 and NaOt-Bu has proven suitable for the Suzuki-
Miyaura cross-coupling of activated and unactivated aryl
chlorides or triflates at room temperature, in technical grade
2-propanol, and requiring only short reaction times. In addition,
the catalytic dehalogenation of aryl chlorides and the catalytic
R-arylation of ketones with aryl bromides and chlorides were
carried out using the same complex, highlighting the great
versatility of the precatalyst. Further mechanistic and reactivity
Supporting Information Available: Details for experimental
procedures and product isolation are provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0521201
692 J. Org. Chem., Vol. 71, No. 2, 2006