Catalytic direct arylation with aryl chlorides, bromides, and iodides: Intramolecular studies leading to new intermolecular reactions

Article abstract of DOI:10.1021/ja055819x

A catalyst for the intramolecular direct arylation of a broad range of simple and heterocyclic arenes with aryl iodides, bromides, and chlorides has been developed. These reactions occur in excellent yield and are highly selective. Studies with aryl iodides substrates revealed that catalyst poisoning occurs due to the accumulation of iodide in the reaction media. This can be overcome by the addition of silver salts which also permits these reactions to occur at lower temperature. The utility of the methodology is illustrated by a rapid synthesis of a carbazole natural product and by the synthesis of sterically encumbered tetra-ortho-substituted biaryls via ring-opening reactions of the direct arylation products. Mechanistic investigations have provided insight into the catalyst's mode of action and show the presence of a kinetically significant C-H bond cleavage in palladium-catalyzed direct arylation of simple arenes. Knowledge garnered from these studies has led to the development of new intermolecular arylation reactions with previously inaccessible arenes, opening the door for the development of other new direct arylation processes.

Full text of DOI:10.1021/ja055819x

Published on Web 12/16/2005
Catalytic Direct Arylation with Aryl Chlorides, Bromides, and
Iodides: Intramolecular Studies Leading to New
Intermolecular Reactions
Louis-Charles Campeau, Mathieu Parisien, Annie Jean, and Keith Fagnou*
Contribution from the Center for Catalysis Research and InnoVation, Department of Chemistry,
UniVersity of Ottawa, 10 Marie Curie, Ottawa, Canada K1N 6N5
Received August 30, 2005; E-mail: keith.fagnou@science.uottawa.ca
Abstract: A catalyst for the intramolecular direct arylation of a broad range of simple and heterocyclic
arenes with aryl iodides, bromides, and chlorides has been developed. These reactions occur in excellent
yield and are highly selective. Studies with aryl iodides substrates revealed that catalyst poisoning occurs
due to the accumulation of iodide in the reaction media. This can be overcome by the addition of silver
salts which also permits these reactions to occur at lower temperature. The utility of the methodology is
illustrated by a rapid synthesis of a carbazole natural product and by the synthesis of sterically encumbered
tetra-ortho-substituted biaryls via ring-opening reactions of the direct arylation products. Mechanistic
investigations have provided insight into the catalyst’s mode of action and show the presence of a kinetically
significant C-H bond cleavage in palladium-catalyzed direct arylation of simple arenes. Knowledge garnered
from these studies has led to the development of new intermolecular arylation reactions with previously
inaccessible arenes, opening the door for the development of other new direct arylation processes.
Scheme 1. Cross-Coupling Methods for the Preparation of Biaryl
Molecules
Introduction
The utility of the biaryl structural motif has prompted intense
research directed at discovering efficient and high-yielding
methods for its preparation. Transition metal catalysis has
featured prominently in these efforts, leading to the establish-
ment of a range of useful cross-coupling reactions.1 A common
element in all of these processes is the need for two activated
arenes that can react selectively with the metal catalyst. While
high yields can be achieved with preactivated substrates, the
need for dual preactivation is inherently wasteful since these
groups may require multiple steps for their installation and none
of the preactivation groups appear in the final product.
Furthermore, not all regioisomers of the organometallic or aryl
halide are readily available making some biaryl compounds
difficult to access. In some instances the preactivated species
may not be stable thus complicating application of this
methodology.
In recent years, direct arylation reactions have emerged as
attractive alternatives to these more commonly employed cross-
coupling reactions.2 These reactions substitute one of the
preactivated arenes with a simple arene (Scheme 1). Importantly,
it is typically the more expensive and difficult to prepare
organometallic coupling partner that is replaced. Several
electron-rich heteroarenes such as imidazoles, indoles, pyrroles,
thiazole, and imidazo[1,2-a]pyrimidines can now be employed,3
and progress has been made in the use of the more challenging
unactivated simple arenes4,8 and π-electron deficient hetero-
cycles.5 Despite these advances, several important challenges
remain. For example, the predominance of direct arylation
(3) (a) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996.
(b) Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897. (c) Lewis, J. C.;
Wiedemann, S. H.; Bergmann, R. G.; Ellman, J. A. Org. Lett. 2004, 6, 35.
(d) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan,
V. Org. Lett. 2004, 6, 1159. (e) Li, W.; Nelson, D. P.; Jensen, M. S.;
Hoerrner, R. S.; Javadi, G. J.; Cai, D.; Larsen, R. D. Org. Lett. 2003, 5,
4835. (f) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125, 5274. (g)
Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2002,
124, 5286. (h) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S. J. Am.
Chem. Soc. 2003, 125, 1698. (i) McClure, M. S.; Glover, B.; McSorley,
E.; Millar, A.; Osterhout, M. H.; Roschangar, F. Org. Lett. 2001, 3, 1677.
(1) For reviews on this topic, see: (a) Metal-catalyzed Cross-coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998.
(b) Hassan, J.; Se´vignon, M.; Gozzi, C.; Shulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359.
(2) For recent reviews, see: (a) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002,
35, 826. (b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731.
(c) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211. (d) Kakiuchi,
F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077.
9
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J. AM. CHEM. SOC. 2006, 128, 581-590
581

A R T I C L E S
Campeau et al.
reactions employs aryl iodides as coupling partners.3a,4e,4j,22 Even
with electron-rich heterocyclic arenes, use of aryl chlorides is
rare despite the fact that aryl chlorides are more readily available
and less expensive.6 Furthermore, no single catalyst has been
shown to be capable of achieving catalytic arylation with simple
arenes and aryl iodides, bromides, and chlorides.
In this account we report (1) the development of an
operationally simple catalyst system for direct intramolecular
arylation processes exhibiting broad scope for aryl chlorides,
bromides, and iodides including previously incompatible steri-
cally encumbered aryl chlorides and bromides; (2) evidence that,
despite their widespread use, aryl iodides exhibit inferior
reactivity compared to that of aryl bromides and chlorides in
the direct arylation reactions studied; (3) insight into catalyst
poisoning with aryl iodides leading to new reaction conditions
showing increased reactivity; (4) application of these processes
to the synthesis of a carbazole natural product, Mukonine, in
three steps from simple starting materials; (5) conditions for
the efficient formation of tetra-ortho-substituted biaryls and their
conversion to acyclic tetra-ortho-substituted biaryls; (6) mecha-
nistic studies pointing to a kinetically significant C-H bond
cleavage step in the direct arylation of simple arenes; (7) the
development of the first intermolecular direct arylation reactions
of a simple arene with aryl chlorides and bromides thus setting
the stage for further expansion in these previously inaccessible
processes.
(4) (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 7330. (b) Ackermann, L. Org. Lett. 2005, 7, 3123 and
references therein. (c) Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N. J.
Am. Chem. Soc. 2005, 127, 5936 and references therein. (d) Wakui, H.;
Kawasaki, S.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2004,
126, 8658 and references therein. (e) Campo, M. A.; Huang, Q.; Yao, T.;
Tian, Q.; Larock, R. C. J. Am. Chem. Soc. 2003, 125, 11506. (f) Huang,
Q.; Fazio, A.; Dai, G.; Campo, M. A.; Larock, R. C. J. Am. Chem. Soc.
2004, 126, 7460. (g) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 3739. (h)
Bedford, R. B.; Coles, S. J.; Hursthouse, M. B.; Limmert, M. E. Angew.
Chem., Int. Ed. 2003, 42, 112. (i) Oi, S.; Ogino, Y.; Fukita, S.; Inoue, Y.
Org. Lett. 2002, 4, 1783. (j) Hennings, D. D.; Iwasa, S.; Rawal, V. H. J.
Org. Chem. 1997, 62, 2.
(5) (a) Godula, K.; Sezen, B.; Sames, D. J. Am. Chem. Soc. 2005, 127, 3648.
(b) Mukhopadhyay, S.; Rothenberg, G.; Gitis, D.; Baidossi, M.; Ponde, D.
E.; Sasson, Y. J. Chem. Soc., Perkin Trans. 2 2000, 1809.
(6) (a) For example, see: ref 4b. Successful reaction with simple aryl chlorides
has also been achieved in intermolecular reactions with electron-rich zinc
pyrrole anions (b) and in the formation of five-membered rings in moderate
yield (c). (b) Rieth, R. D.; Mankad, N. P.; Calimano, E.; Sadighi, J. P.
Org. Lett. 2004, 6, 3981. (c) Bedford, R. B.; Cazin, C. S. J. Chem. Commun.
2002, 2310.
Results and Discussion
As part of a research program targeted at the development
of new direct arylation reactions we sought to develop catalyst
systems that enable efficient reaction with unactivated arenes.
As a first step into the development of these processes we
explored an intramolecular variant. Although intramolecular
direct arylations with unactivated arenes were known prior to
our work, they typically suffered from low selectivity and very
low catalyst turnover numbers; indeed very high catalyst
loadings of greater than 20 mol % were frequently employed.7
Initial investigations revealed a catalyst system that enabled
selective functionalization of unactivated arenes with aryl
bromides exhibiting high catalyst activity and selectivity (eq
1).8 Encouraged by this initial discovery, the scope of this
(7) With 30 mol % catalyst: (a) Kitamura, M.; Ohmori, K.; Kawase, T.; Suzuki,
K. Angew. Chem., Int. Ed. 1999, 38, 1229. (b) Rice, J. E.; Cai, Z.-W.; He,
Z.-M.; LaVaoie, E. J. J. Org. Chem. 1995, 60, 8101. With 26 mol %
catalyst: (c) Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am.
Chem. Soc. 1994, 116, 1004. With 25 mol % catalyst: (d) Matsumoto, T.;
Hosoya, T.; Suzuki, K. J. Am. Chem. Soc. 1992, 114, 3568. With 20-25
mol % catalyst: (e) Cuny, G. D. Tetrahedron Lett. 2003, 44, 8149. (f)
Qabaja, G.; Jones, G. B. J. Org. Chem. 2000, 65, 7187. With as low as 10
mol % catalyst: (g) Bringmann, G.; Heubes, M.; Breuning, M.; Gobel, L.;
Ochse, M.; Schoner, B.; Schupp, O. J. Org. Chem. 2000, 65, 722. (h)
Bringmann, G.; Ochse, M.; Gotz, R. J. Org. Chem. 2000, 65, 2069. (i)
Harayama, T.; Yasuda, H. Heterocycles 1997, 46, 61. Larock has reported
a catalyst system that has been used with 5 mol % loading in analogous
processes, see ref 4e.
catalyst system with other aryl halides was investigated. While
good outcomes were obtained in the direct arylation of bromo-
arenes, inferior results were obtained with aryl chlorides.
Intriguingly, poor outcomes were also obtained with aryl iodide
substrates, despite the fact that aryl iodides are typically regarded
as providing greater reactivity in cross-coupling reactions.
Aryl Chlorides as Substrates. Significant progress has been
made in the use of aryl chlorides as substrates in palladium-
mediated cross-coupling reactions, and many reactions with aryl
chlorides can now be performed under very mild conditions.9
In contrast, direct arylation reactions rarely employ aryl chloride
substrates.6 In an initial report we described the use of
N-heterocyclic carbene (NHC) ligands for the direct arylation
of aryl chlorides.10 In subsequent studies, we discovered that
these catalysts failed to induce complete reaction when more
sterically encumbered substrates were employed.11 This limita-
tion prompted a reinvestigation of the potential catalysts capable
of performing direct arylation with aryl chlorides. Catalyst
screens were performed with aryl chloride 1 in the presence of
1 mol % Pd(OAc)2, 2 mol % ligand, and 2 equiv of K2CO3 in
dimethylacetamide (DMA) at 130 °C. Results are outlined in
Scheme 2. Triarylphosphines (3-6) as well as ortho-biaryl
phosphines (7-11) gave inferior reactivity in the direct arylation
of aryl chlorides. Better results were obtained with some
trialkylphosphines (13-15) as well as N-heterocyclic carbenes
(12). Tricyclohexylphosphine and di-tert-butylmethylphosphine
(8) Campeau, L.-C.; Parisien, M.; Leblanc, M.; Fagnou, K. J. Am. Chem. Soc.
2004, 126, 9186.
(9) For a review of palladium-catalyzed cross-coupling reactions of aryl
chlorides, see: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4176.
(10) Campeau, L.-C.; Thansandote, P.; Fagnou, K. Org. Lett. 2005, 7, 1857.
(11) Leblanc, M.; Fagnou, K. Org. Lett. 2005, 7, 2849.
(12) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(13) (a) Martin, S. In The Alkaloids; Brossi, A., Ed.; Academic Press: New
York, 1987; Vol. 30, Chapter 3, pp 252-369. (b) Cook, J. W.; Loudon, J.
D. In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1952;
Vol. 2, Chapter 11, p 331. (c) Lewis, J. R. Nat. Prod. Rep. 1995, 12, 339.
(14) For examples using heterocyclic arenes, see: (a) Kozikowski, A. P.; Ma,
D. Tetrahedron Lett. 1991, 32, 3317. (b) Hughes, C. C.; Trauner, D. Angew.
Chem., Int. Ed. 2002, 41, 1569. For examples using nonheteroaromatic
arenes, see: (c) Ref 11. (d) Ref 8.
(15) For a review on biologically active carbazole alkaloids, see: Kno¨lker, H.-
J.; Reddy, K. R. Chem. ReV. 2002, 102, 4303.
(16) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org.
Chem. 2000, 65, 1158.
(17) For recent advances, see: (a) Milne, J. E.; Buchwald, S. L. J. Am. Chem.
Soc. 2005, 126, 13028. (b) Walker, S. D.; Barder, T. E.; Martinelli, J. R.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871.
(18) Punna, S.; Meunier, S.; Finn, M. G. Org. Lett. 2004, 6, 2777.
(19) Catalytic direct arylation of aryl iodides can be achieved using heteroge-
neous catalysts, see: Parisien, M.; Valette, D.; Fagnou, K. J. Org. Chem.
2005, 70, 7578.
(20) For a discussion, see: (a) Grushin, V. V.; Alper, H. In ActiVation of
UnreactiVe Bonds and Organic Synthesis; Murai, S., Ed.; Springer: Berlin,
1999; pp 193-226. (b) Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94,
1047.
(21) Similarly this diminished reactivity was observed with benzothiophene:
Chabert, J. F. D.; Joucla, L.; David, E.; Lemaire, M. Tetrahedron 2004,
60, 3221.
(22) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem.
Soc. Jpn. 1998, 71, 467.
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Catalytic Direct Arylation with Aryl Halides
A R T I C L E S
Scheme 2. Screen of Various Ligands for Direct Arylation of 1a
a Conditions: substrate 1, Pd(OAc)2 (1 mol %), ligand (2 mol %), and K2CO3 (2 equiv) are dissolved in DMA (0.2 M) and heated to 130 °C until catalyst
deactivation has occurred.
Table 1. Base Effects in Direct Arylation of Aryl Chloridesa
gives optimal results (entry 2), both Na2CO3 and Cs2CO3 are
ineffective, giving low conversion and leading to inferior ratios
of coupling versus hydrodechlorination (entries 1 and 3).
Alkoxide bases such as KOtBu also lead to increased amount
of dehalogenation (entry 4). KOAc gives good selectivity but
lower conversion (entry 6). The same base counterion effect is
b
entry
base
conversion (%)
ratio 2:2′
also observed with acetate bases since NaOAc gives lower
conversion and selectivity than KOAc (entries 6 and 7). Organic
bases such as Et3N, Cy2MeN, and diisopropylethylamine
(DIPEA) lead to hydrodechlorination as the major product and
very low conversion (entries 8-10).
1
2
3
4
5
6
7
8
9
Na2CO3
K2CO3
Cs2CO3
KOtBu
K3PO4
KOAc
NaOAc
Et3N
DIPEA
Cy2MeN
11
100
25
84
13
81
41
3
20:1
>99:1
15:1
2.3:1
5:1
>99:1
28:1
2:1
To probe the origin of the base counterion effect, we
compared the relative solubility of sodium, potassium, and
cesium carbonate. Mimicking the reaction conditions, we heated
the base in DMA at 100 °C for 30 min, then filtered the hot
solution. Distillation of the DMA from the filtrate revealed that
in all three cases, only trace amounts (1-2%) of the carbonate
base is dissolved. In light of the dramatic halide effect observed
with the use of aryl iodide substrates (vide infra), we also
evaluated the relative solubility of sodium, potassium, and
cesium chloride, which would be generated as a byproduct of
the reaction as it progressed. Again all of the salts were
effectively insoluble under the reaction conditions indicating
that this cannot account for the observed base counterion effect.
2
4
1.8:1
3:1
10
a Conditions: substrate, Pd(PCy3)2, and base (2 equiv) are dissolved in
DMA (0.2 M) and heated to 130 °C until catalyst deactivation has occurred.
b Determined by GC-MS.
(added as the air-stable HBF4 salts12) showed increased reactivity
and robustness compared to those of the NHC system, affording
complete conversion with only 1 mol % Pd(OAc)2.
The influence of base was also examined (Table 1). The
nature of the base and its counterion have a significant impact
on catalyst reactivity and selectivity. For example, while K2CO3
9
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A R T I C L E S
Campeau et al.
Table 2. Scope of Intramolecular Direct Arylation of Aryl Chloridesa
a Conditions: substrate, Pd(OAc)2, ligand (2 equiv per Pd), and K2CO3 (2 equiv) are dissolved in DMA (0.2 M) and heated to 130 °C for 8-16 h.
b Isolated yields. Ms ) CH3SO2-, Bz ) PhC(O)-.
While the reason for the base effect remains elusive when aryl
chlorides are employed, the observation that potassium bases
provide superior reaction outcomes should be of use in the
development of other arylation processes.
Various palladium sources such as PdBr2, PdCl2, Pd(acac)2,
Pd(TFA)2, and Pd2(dba)3 were also examined. These studies
reconfirmed that Pd(OAc)2 is the optimal palladium catalyst
source. The optimal reaction concentration remained 0.2 M and
heating to temperatures lower than 130 °C necessitated an
increase in catalyst loading with certain substrates. These
conditions, Pd(OAc)2, PCy3‚HBF4 (2 equiv per Pd), and 2 equiv
of K2CO3 in DMA (0.2 M) at 130 °C were therefore selected
for further study.
The scope of the reaction with aryl chlorides is outlined in
Table 2. Typically reactions were left to react overnight but in
some cases were done within 8 h. Various tethers including
carbon (entries 6, 11, 12, and 14), oxygen (entries 1, 2, and 7),
and nitrogen (entries 3-5, 8-10, and 13) can be effectively
employed in these transformations. In the formation of six-
membered rings with a nitrogen atom in the tether, an amide
or a sulfonamide protecting group can be employed (entries
3-5). Five-membered ring carbazole products can be obtained
without the installation of a nitrogen protecting group (entries
8-10). The synthesis of hindered biaryls is also facilitated by
this catalyst as demonstrated by entries 3 and 10 which is an
improvement over our previously reported conditions which fail
to induce complete reactions.10,11 Z-Alkenes undergo intra-
molecular direct arylation with complete selectivity over a
possible competitive intermolecular Heck pathway (entry 6).
Substitution is also tolerated on the aryl halide moiety with
fluoro (entries 2 and 8) and trifluoromethyl (entry 9) aryl
chlorides reacting readily. Additional catalyst is needed in the
case of deactivated aryl chlorides as illustrated with methoxy-
substituted substrate (entry 7). This catalyst system also allows
the use of heterocycles in these processes (entries 11-14).
N-alkyl indole reacts at the 2-position to afford the biaryl product
in high yield (entry 11). When the 2-position is blocked with a
methyl group arylation occurs on the adjacent phenyl ring of
indole to afford the pyrrolophenanthridine-like class of natural
products13 (entry 12). Furans can also be arylated as illustrated
by the synthesis of a furoquinolinone product (entry 13).
Unprotected indoles also react (entry 14), in this case to form
9
584 J. AM. CHEM. SOC. VOL. 128, NO. 2, 2006

Catalytic Direct Arylation with Aryl Halides
A R T I C L E S
Scheme 3. Synthesis of Mukoninea
a Conditions: (a) Tf2O (1.1 equiv), DIPEA (2 equiv), THF -78 °C to 0 °C; (b) Pd2(dba)3 (2.5 mol %), 2-(di-tert-butylphosphino)-2′-methylbiphenyl (10
mol %), K3PO4 (1.4 equiv), 2-chloroaniline (1.2 equiv), DME 80 °C; (c) Pd(OAc)2 (3 mol %), PCy3-HBF4 (6 mol %), K2CO3 (2 equiv), DMA 130 °C.
Table 3. Scope of Intramolecular Direct Arylation of Aryl Bromidesa
a Conditions: substrate, Pd(OAc)2, ligand (2 equiv per Pd), and K2CO3 (2 equiv) are dissolved in DMA (0.2 M) and heated to 130 °C for 8-16 h.
b Isolated yields. c Heated to 145 °C. Ts ) 4-MePhSO2-, Ms ) CH3SO2-, Bz ) PhC(O)-.
a seven-membered ring which has been scarcely explored in
direct arylation reactions.14
Aryl Bromides as Substrates. Direct arylation of aryl
bromides can be achieved without modification to the protocol
developed for aryl chlorides. The scope of reactions employing
aryl bromides is outlined in Table 3. Selective arylation in the
presence of a chloride functionality is possible, providing a
useful handle for further cross-coupling reactions (entry 1).
Electron-rich as well as electron-poor arenes are compatible
(entries 2 and 3). Deactivated aryl bromides can be used
although increased catalyst loading is required for the reaction
to complete (entry 4). Tosyl protecting groups are compatible
when a nitrogen atom is in the tether (entry 5). Activated aryl
Carbazole alkaloids have attracted significant interest due to
their structural features and biological activity.15 Scheme 3
shows a short and high-yielding route to Mukonine. Triflation
of methyl vanillate proceeds smoothly to afford aryl triflate in
92% yield, and Buchwald-Hartwig amination with 2-chloro-
aniline affords diarylamine in 85% yield.16 Direct arylation
without protection of the nitrogen moiety proceeds smoothly
using 3 mol % palladium to afford Mukonine in three steps
with a 75% overall yield.
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A R T I C L E S
Campeau et al.
Table 4. Scope of Ring-Opening Reactionsa
Table 5. Halide Effect in Direct Arylation Reactionsa
entry
halide
base
additive
yieldb
1
2
3
4
5
6
Br
I
Br
I
I
I
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
none
99
none
64c
<5
89e
99
KId
none
AgOTfd
Ag2CO3
f
99
a Conditions: substrate, Pd(OAc)2 (1 mol %), ligand (2 equiv per Pd),
and K2CO3 (2 equiv) are dissolved in DMA (0.2 M) and heated to 130 °C
for 12 h. b GC-Ms yields. c 2:2′ ) 8:1. d 1 equiv. e 2:2′)8.5:1. f 0.5 equiv.
reactions, we were surprised to find that aryl iodides reacted
very poorly under our optimized conditions. For example,
reaction of aryl iodide 16 under the conditions optimized for
aryl chlorides and bromides gave only 64% conversion, even
after prolonged reaction times.21 We have established that this
poor reactivity is due to the accumulation of iodide anions in
the reaction mixture and that this catalyst poisoning may be
overcome. Although bromide 17 and iodide 16 react at similar
rates at early conversions, the conversion of iodide 16 reaches
a plateau at 64% conversion (Table 5, entries 1 and 2).
Furthermore, if 1 equiv of KI is added to a reaction of bromide
17, the arylation reaction is completely inhibited (Table 5, entry
3).
a Conditions: (1) biaryl, BBr3 1.0 M solution in heptane (1 equiv), DCM,
room temperature; (2) crude benzyl bromide from step 1, Ac2O (excess),
2,6-lutidine (2 equiv), PhH, 0 °C to room temperature. b Isolated yields.
bromides react to yield the corresponding phenanthredinone
product in good yield (entry 6).
Recent advances in catalyst development for biaryl synthesis
have been directed at the formation of sterically hindered
biaryls.17 In the context of these challenging cross-coupling
reactions, we were interested in determining whether this catalyst
system could achieve direct arylation reactions of more sterically
demanding substrates such as tetra-ortho-substituted substrates.
We were pleased to find that under our optimized conditions,
the synthesis of tri- (entries 9 and 10) and tetra-ortho-substituted
(entries 11-13) biaryls was feasible. A mesylate protecting
group can be used when a nitrogen atom is in the tether (entries
9 and 11). Ester groups also remain intact under reaction
conditions (entry 13).
To grant access to acyclic biaryl molecules, we also explored
ring-opening reactions in the context of hindered biaryl syn-
thesis. Treatment of the direct arylation products with 1.1 equiv
of BBr3 in CH2Cl2 at room temperature followed by trapping
with acetic anhydride yields the acyclic biaryl products in good
yield (Table 4).18 This sequence of direct arylation/ring cleavage
is a complimentary entry point to these challenging biaryl
substrates and may offer an attractive alternative to cross-
coupling protocols in some cases.
Aryl Iodides as Substrates. The use of aryl iodides in direct
arylation is well precedented.3a,4e,4j,19,22 The disproportionate
attention focused on the use of aryl iodides compared to aryl
bromides and especially aryl chlorides may be rationalized, at
least in part, by the desire to reduce catalytic demand. It is well
precedented that oxidative insertion into a C-X bond is most
facile for aryl iodides,20 so use of aryl iodides can permit the
chemist to focus their reaction/catalyst development efforts on
the challenging arylation step of the catalytic cycle. Given the
strong precedent for the use of aryl iodides in direct arylation
To sequester iodide, we explored the use of different bases
and silver additives. In some cases, superior results can be
achieved by using Cs2CO3 instead of K2CO3.22 With the reaction
of 16, the use of Cs2CO3 was ineffective, resulting in an erosion
of selectivity for cyclization to hydrodehalogenation from greater
than 99:1 with K2CO3 to 8.5:1 with Cs2CO3. (Table 5, entry
4). Of the silver sources tested, AgOTf and Ag2CO3 gave the
best results (Table 5, entries 5 and 6). We opted to use silver
carbonate because of its increased ease of handling and lower
cost.23 We also found that addition of silver additives accelerated
reaction times and that reactions could be carried out at
temperatures as low as 80 °C with 5 mol % catalyst. These
observations warn against the presumption of the increased
reactivity of aryl iodides in catalyst/reaction development efforts
in direct arylation processes and indicate that catalyst and
substrate screens in the search for new reactions may best be
performed with aryl bromides and/or chlorides, and not with
aryl iodides as is commonly the case.
With these new reaction conditions, other reaction parameters
were reinvestigated including solvent and temperature. Use of
Ag2CO3 provides complete conversion of aryl iodide 16 with 5
mol % catalyst in refluxing dioxane. In contrast no reaction is
observed in dioxane in the absence of Ag2CO3. It is also possible
to achieve good conversion in refluxing THF if 2 equiv of
HMPA are used as an additive. The scope of direct arylation
with aryl iodides is outlined in Table 6. Pivaloyl (entries 4 and
5) and MOM ethers (entry 3) can be used as protecting groups
for amine and alcohol functional groups. Thiophenes are suitable
(23) Ag2CO3 (272CAD$/100 g, Aldrich 2005) 377CAD$/mol Ag; AgOTf
(196CAD$/25 g, Aldrich 2005) 2008CAD$/mol Ag.
9
586 J. AM. CHEM. SOC. VOL. 128, NO. 2, 2006

Catalytic Direct Arylation with Aryl Halides
A R T I C L E S
Table 6. Scope of Intramolecular Direct Arylation of Aryl Iodidesa
a Conditions: substrate, Pd(OAc)2, ligand (2 equiv per Pd), Ag2CO3 (0.5 equiv), and K2CO3 (2 equiv) are dissolved in solvent (0.2 M) and heated (DMA,
t
130 °C; dioxane, 100 °C; THF, 70 °C) for 8-16 h. b Isolated yields. c 2 equiv HMPA added. MOM ) MeOCH2-, Piv ) BuC(O)-.
Table 7. Catalyst Selectivity in Direct Arylationa
reaction partners for the transformation (entry 7). Five-
membered ring biaryls can also be formed to afford the carbazole
(entry 8), benzopyrane (entry 9), and fluorene (entry 10)
products.
Regioselectivity and Selectivity in Direct Arylation Reac-
tions. While regioselectivity is an important factor when con-
entry
substituent
halide
ligand
ratio A:Bb
sidering the application of a methodology in synthesis, regio-
selectivity issues in direct arylation have been scarcely stud-
ied.24,25 Consequently, various ether substrates were synthesized
to study the influence of sterics and electronics on arylation
regioselectivity of nonsymmetrical arenes (Table 7). In general,
we have determined that arylation occurs at the most sterically
accessible site to give regioisomer A preferentially. In the case
of large alkyl substituents (entries 3 and 4) only one product is
detected by NMR. Diminished but still synthetically useful
selectivity is obtained when using a smaller alkyl substituent
such as a methyl group (entry 2) or a methoxy group26 (entry
1). In the case of electron-withdrawing groups (entries 5-7),
arylation is very selective, giving only one product by NMR.
Halide substituents give poorer regioselectivities. For example,
a chlorine substituent gives a 3.2:1 ratio in favor of isomer A.
Interestingly, when the arene is substituted with a fluorine atom,
isomer B is produced as the major product in a 1:4.3 ratio.27
The reason for this reversal in selectivity is under investigation.
1
2
3
4
5
6
7
8
9
OMe
Me
i-Pr
t-Bu
CF3
NO2
CO2Me
Cl
F
F
F
F
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Br
Br
PCy3-HBF4
PCy3-HBF4
PCy3-HBF4
PCy3-HBF4
PCy3-HBF4
PCy3-HBF4
PCy3-HBF4
PCy3-HBF4
PCy3-HBF4
PCy3-HBF4
PtBu3-HBF4
PtBu2Me-HBF4
10:1
15:1
>30:1
>30:1
>30:1
>30:1
>30:1
3.2:1
1:4:3
1:8.3
1:1.3
10
11
12
1:6.9
a Conditions: aryl halide, Pd(OAc)2 (3 mol %), ligand (6 mol %), and
K2CO3 (2 equiv) are dissolved in DMA (0.2 M) and heated to 130 °C for
8-16 h. b Ratio determined by 1H NMR. All reactions reached 100%
1
conversion as determined by crude H NMR analysis.
It is worth noting that this reversal contrasts recent reports in
palladium-catalyzed C-H activation/oxygenation reactions.24
The regioselectivity is also affected by the halide functionality
on the substrate. For example, a ratio of A:B of 1:8.3 is obtained
from the reaction of fluoro-substitued aryl chloride (entry 10)
compared to a ratio of 1:4.3 when the corresponding aryl
bromide is used (entry 9). This indicates that the halide may
(24) For examples of such studies in other types of arene functionalization
reactions, see: Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149 and
references therein.
(25) For stoichiometric studies dealing with palladacycle formation, see: (a)
Teijido, B.; Fernandez, A.; Lopez-Torres, M.; Castro-Juiz, S.; Suarez, A.;
Ortigueira, J. M.; Vila, J. M.; Fernandez, J. J. J. Organomet. Chem. 2000,
598, 71. (b) Gutierrez, M. A.; Newkome, G. R.; Selbin, J. J. Organomet.
Chem. 1980, 202, 341. (c) Holton, R. A.; Davis, R. G. J. Am. Chem. Soc.
1977, 99, 4175.
(27) This type of effect with fluorine has also been observed in direct borylation
of aromatic C-H bonds (a) and ruthenium-catalyzed C-H/olefin coupling
(b): (a) Chotana, G. A.; Rak, M. A.; Smith, M. R., III. J. Am. Chem. Soc.
2005, 127, 10539. (b) Sonoda, M.; Kakiuchi, F.; Chatani, N.; Murai, S.
Bull. Chem. Soc. Jpn. 1997, 70, 3117.
(26) We had previously reported a ratio of 20:1 for this substrate which might
be an indication of the increased reactivity of this system; see ref 8.
9
J. AM. CHEM. SOC. VOL. 128, NO. 2, 2006 587

A R T I C L E S
Campeau et al.
Scheme 4. Electronic Preference in Direct Arylation
interact with the metal during the arylation step of the catalytic
cycle. We also observe an effect of the phosphine ligand on
product ratio as illustrated by entries 9, 11, and 12 where the
ratio changes from 1:4.3 with PCy3‚HBF4, to 1:6.9 with
PtBu2Me‚HBF4, to 1:1.3 when PtBu3‚HBF4 is used.
primary intramolecular kinetic isotope effect (KIE) of 3.5.8 With
the new conditions described in this account, a larger primary
kinetic isotope effect of 4.25 is observed (eq 3). This value does
not change in the presence of a silver additive.
Mechanistic Investigations. To probe for the presence of
an electronic bias in the direct arylation reaction, competition
experiments were devised to ascertain if the catalyst would
selectively react with an electron-rich or electron-poor aromatic
ring. Two amide substrates were synthesized. With amide 18,
reaction could occur with an “activated” ring bearing a methoxy
substituent or at an unactivated ring. With amide 19, the catalyst
could select for reaction at an unactivated ring or a “deactivated”
ring that is substituted with a nitro functionality. With both
substrates, small selectivity is obtained for reaction at the more
electron-rich ring (Scheme 4).
Reaction of naphthyl substrate 20 is also informative. In this
case, two regioisomeric products are possible. It is well
documented that electrophilic additions to naphthalenes occurs
preferentially at the 1-position.28 When 20 is reacted under the
standard arylation conditions, a 1.3:1 ratio of 21:22 is obtained.
While it is important not to over interpret the reaction preference
when such low selectivities are obtained, the fact that such low
selectivities are observed is informative since this is not a
characteristic outcome of electrophilic aromatic substitutions on
this substrate class (eq 2).
Several mechanistic scenarios have been proposed for direct
arylation reactions. The pathway with the strongest experi-
mental support is electrophilic palladation.29,30 Oxidative C-H
insertion to palladium (IV) has also been proposed4e as has a
carbopalladation (Heck-type) pathway requiring a formal anti
â-hydride elimination.31 Carbene intermediates have been
demonstrated with other metals such as rhodium,32 but analogous
reactivity in palladium arylations has not appeared.
While it cannot be definitively ruled out, the carbopalladation
or Heck-type route is unlikely. It is reasonable to assume that
the mechanism of these processes should parallel that involved
in the preparation of palladacycles.33 In these cases, there exists
ample evidence pointing to an electrophilic metalation or C-H
oxidative insertion. The oxidative C-H insertion pathway fits
with our experimental observations, but recently reported
(29) With simple arenes: (a) Martin-Matute, B.; Matea, C.; Cardenas, D. J.;
Echavarren, A. M. Chem. Eur. J. 2001, 7, 234. (b) Echavarren, A. M.;
Go`mez-Lor, B.; Gonza`lez, J. J.; de Fruto, O.; Synlett 2003, 5, 585. (c)
Gonzalez, J. J.; Garcia, N.; Gomez-Lor, B.; Echavarren, A. M. J. Org.
Chem. 1997, 62, 1286. (d) Hennessy, E. J.; Buchwald, S. L. J. Am. Chem.
Soc. 2003 125, 12084. (e) Boele, M. D. K.; van Strijdonck, G. P. F.; de
Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N.
M. J. Am. Chem. Soc. 2002, 124, 1586. (f) Shue, R. S. J. Am. Chem. Soc.
1971, 93, 7116. (g) Parshall, G. W. Acc. Chem. Res. 1970, 3, 139.
(30) With heteroaromatics: (a) Lane, B. S.; Brown, M. A.; Sames, D. J. Am.
Chem. Soc. 2005, 127, 8050. (b) Ref 3d. (c) Trauner, D.; Hughes, C. C.;
Angew. Chem., Int. Ed. 2002, 41, 1569. (d) Glover, B.; Harvey, K. A.;
Liu, B.; Sharp, M. J.; Tymoschenko, M. F. Org. Lett. 2003, 5, 301.
(31) This pathway has been proposed as a possibility before: (a) Toyata, M.;
Ilangovan, A.; Okamoto, R.; Masaki, T.; Arakawa, M.; Ihara, M. Org. Lett.
2002, 4, 4293. (b) Ref 30. (c) Proposed but dismissed: ref 29d.
(32) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2002, 124,
3203.
The presence of kinetic isotope effects can provide valuable
information about the rate-determining steps in complex chemi-
cal processes. In our initial communication we reported a
(28) For a discussion on the preferred site of attack of many ring systems, see:
de la Mare, P. B. D.; Ridd, J. H. Aromatic Substitution Nitration and
Halogenation; Academic Press: New York, 1959; p 169.
(33) For a review, see: Ryabox, A. D. Chem. ReV. 1990, 90, 403.
9
588 J. AM. CHEM. SOC. VOL. 128, NO. 2, 2006

Catalytic Direct Arylation with Aryl Halides
A R T I C L E S
Scheme 5. Plausible Pathways for Direct Arylation
computational studies indicate that C-H insertion is higher in
energy and less favorable than an alternative σ-bond methathesis
pathway that does not require the intermediacy of a palla-
dium(IV) species.34 Furthermore, there is growing evidence for
the implication of an electrophilic-type pathway in the direct
arylation of heterocyclic arenes.30 Thus, while a C-H insertion
pathway cannot be definitively ruled out, evidence points away
from its involvement.
Echavarren and co-workers who found no strong electronic bias
in direct arylation.29a The small electronic bias may point to a
lack of cationic areneium character at the rate-determining step
which may be anticipated in a concerted palladium-carbon/
carbon-hydrogen bond formation/cleavage process.
New Intermolecular Direct Arylation Processes. In addition
to advancing the use of intramolecular direct arylation reactions
with aryl chlorides, bromides, and iodides, these studies were
also conducted with the desire to learn more about the necessary
catalyst, substrate, and reaction parameters necessary to achieve
high levels of reactivity. Our hope was that knowledge garnered
from these efforts would ultimately lead to the establishment
of new intermolecular reactions with previously unknown
substrate classes and open new doors in the direct arylation
methodology. These goals are beginning to be achieved as
illustrated by the first examples of intermolecular direct arylation
of benzodioxole with aryl bromides and chlorides (vide infra).
To achieve the substrate-catalyst interactions necessary to
induce intermolecular direct arylation, researchers have previ-
ously employed very basic directing groups such as phenols,41
amides,42 and pyridyl43 groups (in the absence of which no
reaction occurs). The examples reported below constitute the
first time that such reactivity has been achieved with an ether
directing group on a simple arene. From a synthetic perspective,
these reactions generate products that are regio-complementary
to those readily accessible from commercially available aryl-
halides and organometallics with traditional cross-coupling
techniques.44 Importantly, these results lay the foundation for
the establishment of direct arylation reactions with significantly
improved scope, which is a focus of continued study in our
group.
On the other hand, an electrophilic aromatic substitution
pathway can rationalize the current experimental observations
and has significant mechanistic support in the direct arylation
of other classes of arene. Many electrophilic-aromatic substitu-
tion reactions do not exhibit KIEs because deprotonation is fast
relative to the formation of the arenium σ-complex.35 In some
cases, however, electrophilic aromatic substitution reactions do
exhibit significant KIEs, as exemplified by electrophilic mer-
curations for which KIEs of up to 6 have been documented.36
The presence of a primary kinetic isotope effect in palladium-
catalyzed direct arylation37 can be rationalized by considering
the relative rates for the formation of π,η2-25 and/or π,η1-2538
from the palladium(II) arene intermediate 24 (k1 and k-1) and
deprotonation (k2) (Scheme 5). The presence of a KIE implies
that k1 and k-1 are fast and reversible compared to k2. As a
consequence, [π-25]k2 becomes kinetically significant and would
result in the observed KIE. Either an SE3 process, where an
external base deprotonates the arene as the palladium-carbon
bond is being formed,35 or a σ-bond metathesis mechanism,39
where it is a ligand on the palladium metal that serves as the
base for the deprotonation, could be occurring.29d,40
In this mechanism, it is reasonable to anticipate that the
electronic properties of the arene ring will influence k1, k-1
,
and k2. Our competition experiments (Scheme 4) as well as
reactions with 2-naphthol derived substrates (eq 2) reveal a small
but reproducible bias for the more electron-rich arene (or site),
which is in accord with the qualitative kinetics reported by
To validate the intermolecular reactivity of benzodioxole,
reactions were performed with 10 mol % Pd(OAc)2, 10-30 mol
(41) For examples, see: (a) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.;
Angew. Chem., Int. Ed. Engl. 1997, 36, 1740. (b) Satoh, T.; Inoh, J.-I.;
Kawamura, Y.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc.
Jpn. 1998, 71, 2239. (c) Kawamura, Y.; Satoh, T.; Miura, M.; Nomura,
M. Chem. Lett. 1999, 961. (d) Kawamura, Y.; Satoh, T.; Miura, M.;
Nomura, M. Chem. Lett. 1998, 931.
(34) Mota, A. J.; Dedieu, A.; Bour, C.; Suffert, J. J. Am. Chem. Soc. 2005, 127,
7171.
(35) Zollinger, H. AdV. Phys. Org. Chem. 1964, 2, 162.
(36) Kresge, A. J.; Brennan, J. F. J. Org. Chem. 1967, 32, 752.
(37) (a) Ref 29e. (b) Shue, R. S. J. Am. Chem. Soc. 1971, 93, 7116. (c) Ref
27d.
(42) For examples, see: (a) Kametani, Y.; Satoh, T.; Miura, M.; Nomura, M.
Tetrahedron Lett. 2000, 41, 2655. (b) Ref 4a.
(38) (a) Ca`mpora, J.; Gutie´rrez-Puebla, E.; Lo`pez, J. A.; Monge, A.; Palma, P.;
del Ry´o´, D.; Carmona, E. Angew. Chem., Int. Ed. 2001, 40, 3641. (b)
Ca`mpora, J.; Lo`pez, J. A.; Palma, P.; Valerga, P.; Spillner, E.; Carmona,
E. Angew. Chem., Int. Ed. 1999, 38, 147.
(39) During the submission of this manuscript a paper appeared suggesting this
type of process for cyclometalation with palladium acetate: Davies, D. L.;
Donald, S. M. A.; Macgregor, S. A. J. Am. Chem. Soc. 2005, 127, 13754.
(40) This type of mechanistic dichotomy has been proposed before with Hg
(ref 36) and Rh (ref 3a).
(43) For examples, see: (a) Ref 4a. (b) Oi, S.; Fukita, S.; Hirata, N.; Watanuki,
N.; Miyano, S.; Inoue, Y. Org. Lett. 2001, 3, 2579. (c) Ref 4b.
(44) For recent the use of 1,3-benzodioxl-5-yl boronic acid in Suzuki coupling,
see: (a) Gurjar, M. K.; Cherian, J.; Ramana, C. V. Org. Lett. 2004, 6, 317.
(b) Savarin, C.; Liebeskind, L. S. Org. Lett. 2004, 3, 2149. Cross-coupling
reactions with 4-bromo-1,3-benzodioxle (c) or 4-(1,3-benzodioxolyl)-
boronic acid (d) are exceedingly rare. See: (c) Thibonnet, J.; Abarbri, M.;
Parrain, J.-L.; Ducheˆne, A. Tetrahedron 2003, 59, 4433. (d) Wu, T. Y. H.;
Schultz, P. G. Org. Lett. 2002, 4, 4033.
9
J. AM. CHEM. SOC. VOL. 128, NO. 2, 2006 589

A R T I C L E S
Campeau et al.
Table 8. Direct Arylation of 1,3-Benzodioxlea
% of either PtBu2Me‚HBF4 or PCy3‚HBF4, 1 equiv of AgOTf,
and 2 equiv of K2CO3 in DMA at 145 °C. While Ag2CO3
performed well in intramolecular reactions, its use led to more
homocoupling of aryl bromide in these intermolecular processes
compared to that with AgOTf. A total of 10 equiv of benzo-
dioxole were employed, and initial screens were executed with
4-bromotoluene. Reaction concentration was also evaluated
ranging from 0.1 to 0.8 M. From these initial screens, a 3:1
ligand to palladium ratio was deemed optimal with the
PtBu2Me‚HBF4 preligand performing slightly better than the
tricyclohexylphosphine salt. Optimal results are also achieved
under very concentrated conditions. Reactions are typically
performed at 0.7 M. Under these conditions, we were gratified
to find that an 80% isolated yield of 28 can be obtained as
exclusively one regioisomer (eq 4).
These reaction conditions were used to investigate the
intermolecular direct arylation of benzodioxle (Table 8) with a
range of aryl chlorides and bromides. Both activated and
nonactivated aryl chlorides can be employed (entries 1 and 2).
More sterically encumbered aryl bromides can also be employed
with good yield as illustrated by reaction with bromoanthracene
(entry 6). Interestingly, no cross-coupled direct arylation product
is obtained when these reactions are run with iodobenzene. In
this case, the major product as determined by GC-MS analysis
of the crude reaction mixture is biphenyl arising from homo-
coupling of the iodobenzene. This result underlines our findings
that aryliodides can frequently exhibit inferior reactivity in direct
arylation reaction with simple arenes and that they should not
be used exclusively as model substrates in the development of
new direct arylation processes.
a Conditions: dioxane (10 equiv), aryl halide, Pd(OAc)2 (10 mol %),
ligand (30 mol %), AgOTf (1 equiv), and K2CO3 (2 equiv) are dissolved in
DMA (0.7 M) and heated to 145 °C for 8-16 h. b Isolated yield.
of silver additives. Mechanistic studies revealed a kinetically
significant C-H bond cleavage step during arylation that may
be rationalized by a mechanism proceeding via electrophilic
metalation involving either a σ-bond metathesis or an SE3 C-H
functionalization step. Finally, these studies enabled the devel-
opment of a new intermolecular direct arylation reaction of
benzodioxole with aryl chlorides and bromides, which is the
first time such reactions are possible with these substrates.
Conclusion
Acknowledgment. We thank NSERC, the Research Corpora-
tion (Cottrell Scholar Award; K.F.), the Ontario government
(Premier’s Research Excellence Award, K.F.), and the Univer-
sity of Ottawa for support of this work. L.-C.C. and M.P. thank
the Ontario government for Ontario Graduate Scholarships.
L.-C.C. thanks the Canadian government for an NSERC-PGS
D Scholarship. Glenn Facey is thanked for helpful discussions
on NMR spectroscopy.
In conclusion, we have established a broadly applicable
catalyst for direct intramolecular arylation reactions with aryl
chlorides, bromides, and iodides including sterically encumbered
aryl chlorides and bromides. We have also found that, despite
their widespread use, aryl iodides exhibit inferior reactivity
compared to that of aryl bromides and chlorides in the direct
arylation reactions studied. The inferior reactivity of aryl iodides
was noted in both intramolecular and intermolecular reactions
and warns against the exclusive use of aryl iodides in the
development of other new direct arylation reactions. We have
determined that catalyst poisoning associated with aryl iodides
in intermolecular reactions is due to an accumulation of KI in
the reaction media which can be overcome through the addition
Supporting Information Available: Detailed experimental
procedures and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA055819X
9
590 J. AM. CHEM. SOC. VOL. 128, NO. 2, 2006