Umpolung direct arylation reactions: Facile process requiring only catalytic palladium and substoichiometric amount of silver salts

Article abstract of DOI:10.1021/ja107541w

An umpolung direct arylation process is described. The reaction requires only a catalytic amount of Pd(OAc)₂ and a substoichiometric amount of silver salts, without any external base or ligand to proceed. The directed oxidative insertion of the transition metal followed by the coupling into the C-H bond of an unactivated arene has surprisingly not yet been reported, despite the clear advantages in the ease of starting material synthesis. The reaction is regioselective with regards to the arene partner, and the role of the acetate and carbonate groups has been elucidated. This methodology adds to the very few examples of benzene coupling without the inclusion of electron-withdrawing groups to increase acidity.

Full text of DOI:10.1021/ja107541w

Published on Web 09/27/2010
Umpolung Direct Arylation Reactions: Facile Process Requiring Only
Catalytic Palladium and Substoichiometric Amount of Silver Salts
James J. Mousseau, Fre´de´ric Valle´e, Melanie M. Lorion, and Andre´ B. Charette*
Department of Chemistry, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Quebec, Canada, H3C 3J7
Received August 20, 2010; E-mail: andre.charette@umontreal.ca
Given these realities, more focus has been dedicated over the
Abstract: An umpolung direct arylation process is described. The
reaction requires only a catalytic amount of Pd(OAc)2 and a
substoichiometric amount of silver salts, without any external base
or ligand to proceed. The directed oxidative insertion of the
transition metal followed by the coupling into the C-H bond of
an unactivated arene has surprisingly not yet been reported,
despite the clear advantages in the ease of starting material
synthesis. The reaction is regioselective with regards to the arene
partner, and the role of the acetate and carbonate groups has
been elucidated. This methodology adds to the very few examples
of benzene coupling without the inclusion of electron-withdrawing
groups to increase acidity.
past half decade to the development of direct arylation reactions.3
Through the use of such methodology, the elimination of one, if
not both, of the required preactivations on the starting materials is
achieved. As such, these transformations are greener, while
improving the overall economy of the reaction.4 Of the direct
arylation reactions reported, the most dominant class involves the
use of a directing group to direct a transition metal into a C-H
bond.5 The resulting metallocycle then reacts with an aryl halide
via oxidative addition, affording the desired biaryl product following
reductive elimination. However, the reverse, or umpolung, version
of this reaction involving the application of a directing group to
facilitate transition metal oxidative addition and the reaction of such
a metallocycle with an unactivated arene has received little or no
attention. In addition, although there have been few reports on the
arylation of benzene6 and other electron-poor arenes,7 they often
require several reagents, increasing the cost of the reaction and
decreasing their atom economy. The advantage of using such an
umpolung technique includes that the aryl halide can be readily
prepared using efficient directed orthometalation reactions from
inexpensive starting materials,8 and the arene can be not only used
as a reaction feedstock, but also separated and reused for further
reaction. Herein we report a facile, high-yielding, Pd-catalyzed
direct arylation reaction involving aryl halides containing an
R-directing group with an unactivated arene. The protocol is
conducted under phosphine-free conditions, requiring only 0.51
equiv of silver carbonate.
The biaryl motif is a privileged structure, omnipresent in many
facets of chemistry and biology. These important compounds are
key components of many pharmaceutically active reagents, natural
products, agrochemicals, dyes, and are of much interest in material
and supramolecular sciences.1 Cross-coupling reactions developed
since the 1970s provide powerful tools for the preparation of these
scaffolds, and as such, these methods have dominated the way these
compounds are synthesized.2 Despite their remarkable effectiveness,
they suffer from several key drawbacks. Most notably, they rely
on the synthesis of pseudo nucleophile and electrophile starting
materials and generate stoichiometric amounts of sometimes toxic
metal salts as reaction byproducts. Consequently, these reactions
are neither atom- nor time-economical and may negatively con-
tribute to the environment (Figure 1).
Scheme 1. Scope of the Directing Group with Isolated Yields
The optimized conditions require only 5 mol % of Pd(OAc)2
and 0.51 equiv of Ag2CO3 to execute the desired arylation of
2-bromoethylbenzoate by benzene (Scheme 1).9 With these condi-
tions in hand, we proceeded to explore the scope of the directing
group for the reaction. Indeed, the presence of a directing group
ortho to the halide was needed. While aryl bromides and iodides
were tolerated, aryl chlorides did not react. A range of directing
Figure 1. Importance of biaryl compounds and direct methods for their
synthesis.
9
14412 J. AM. CHEM. SOC. 2010, 132, 14412–14414
10.1021/ja107541w  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Pd-Catalyzed Direct Arylation of Benzene with Aryl
groups could be employed. A trend of note includes improved yields
as the Lewis basicity of the group is increased. As a result, phenyl
ketones (1e) are more efficient that esters (1a, 1c) and amides are
also quite effective (1d). 2′-Bromoacetophenone (1f) is viable in
moderate yield despite the presence of an enolizable center. Full
conversion is observed with 2-bromobenzoic acid, though the
desired biphenyl product 2g was only isolated in 42% yield. This
is thought to be due to the decarboxylation of the product with the
resulting biphenyl being removed upon purification.10 The poten-
tially sensitive 2-bromobenzaldehyde 1h gives the product in good
yields. Compounds 1i and 1j were less efficient, giving the products
in 25% and 33% yields respectively. This is believed to be the
result of the formation of a six-membered palladacycle intermediate
rather than the five-membered cycle, as the Lewis basicity of the
O- and N-Piv carbonyl groups are comparable to those of the ester
and aldehyde respectively.11
Bromidesa
We next considered the functional group tolerance of the halide
coupling component. Although 2-bromobenzophenone was deter-
mined to be the optimal directing group, we elected to pursue the
reaction scope with the methyl and ethyl esters, due to the plethora
of chemistry that can be performed on these functional groups. A
methyl group meta to the bromide is well tolerated (Table 1, entry
1), although, when the methyl is ortho to the halide, the arylation
only proceeds with 25% conversion, indicating some sensitivity to
steric hindrance. Electron-poor substrates bearing even a potentially
problematic nitro group perform very well,2a presumably due to
their increased reactivity toward oxidative addition (entries 2, 3).
Coincidentally, electron-rich substrates provide the biaryl products
in moderate, though synthetically useful, yields (entries 4, 5).12
Cognizant of the interest in arenes other than benzene, we
considered the scope of the C-H coupling partner. Whereas the
reaction had been performed with 100 equiv of the benzene for a
cleaner process, it was found that 50 equiv of arene for high-boiling
reagents were sufficient to provide the desired product in acceptable
yields. Generally speaking, the reaction products are obtained in
moderate to very good yields. There was a noticeable difference
between 1,3,5-trifluorobenzene and 1,3-bis(trifluoromethyl)benzene
(entries 7, 8). The former provided the arylated product in good
yield while the latter in low yield.12 The phenomenon of Pd
inserting ortho to fluorine has been well documented, owing to a
combination of the increased Brønsted acidity of the C-H bond
and interactions between the transition metal and the halogen lone
pairs directing metalation.7,13 In the case of 1,3-bis(trifluorometh-
yl)benzene, the low yield may be the result of poor π-complexation
with the metal catalyst. A striking feature of the reaction is the
high regioselectivity of the process, as, in many examples, only
one regioisomer was observed (entries 6, 8, 9).
Given the lack of need for a phosphine ligand, and the
requirement of only a substoichiometric amount of Ag2CO3, we
explored the possible mechanistic pathway of the reaction. A PdII
source seems to be vital for the reaction to proceed, as Pd2dba3
was ineffective both with and without the presence of a phosphine
ligand (Table 2, entries 2, 3). Curiously, Pd2dba3 is operative when
a catalytic amount of KOAc is present (2:1 with respect to Pd),
with most of the activity being restored, clearly demonstrating the
importance of acetate in the reaction (entry 4). It has been
demonstrated by Fagnou and Echavarren that acetate and carbonate
motifs are vital proton shuttles in metalation/deprotonation se-
quences.11 As a result, we attempted the reaction in the presence
of Pd(TFA)2, as the TFA moiety should be a less effective shuttle
due to its increased acidity. Indeed a 51% yield was obtained,
demonstrating a decrease in activity (entry 5). Furthermore,
reactivity could be restored with the addition of KOAc (entry 6).
a Reaction conditions: 1 (1 equiv), arene (100 equiv), Pd(OAc)2 (5
mol %), Ag2CO3 (0.51 equiv), 125 °C, 16-20 h. b Same conditions as
those for (a) except that 50 equiv of the arene were applied. c Same
conditions as those for (b) except that 1 equiv of Ag2CO3 was applied.
d Yield of isolated product. e Combined yield of products.
9
J. AM. CHEM. SOC. VOL. 132, NO. 41, 2010 14413

C O M M U N I C A T I O N S
Silver acetate was applied as a base, with the product being observed
in 50% yield (entry 7). This yield could be increased to 65% through
the inclusion of K2CO3 (entry 8), suggesting that the carbonate may
play a role in regulating the pH of the reaction mixture and ensuring
the presence of -OAc and not necessarily be involved in the
deprotonation. Lastly, a KIE of 5.4 was observed, indicating that
the C-H breaking event is rate-limiting.
further insights into the reaction’s mechanism, and results will be
disclosed in due course.
Acknowledgment. This work was supported by the Natural
Science and Engineering Research Council of Canada (NSERC),
the Canada Research Chairs Program, the Canada Foundation for
Innovation, and the Universite´ de Montre´al. Vincent N. G. Lindsay
is also thanked for comments on the manuscript.
Table 2. Determination of the Role of the Reagentsa
Note Added after ASAP Publication. Structure 4e was corrected
in Table 1 on September 29, 2010.
entry
Pd source
Ag
additive
yieldb
c
e
e
e
e
e
e
1
2
3
4
5
6
7
8
Pd(OAc)2
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
none
none
PCy3 (7.5 mol %)
KOAc (10 mol %)
none
KOAc (10 mol %)
none
K2CO3 (0.51 equiv)
90
<5
<5
76
51
73
50
65
d
Supporting Information Available: Experimental procedures,
sample spectra, and compound characterization data for each reaction.
This material is available free of charge via the Internet at http://
pubs.acs.org.
Pd2dba3
Pd2dba3
d
d
Pd2dba3
c
c
c
c
Pd(TFA)2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
AgOAcf
AgOAcf
References
(1) (a) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359. (b) Laird, T. Org. Process Res. DeV. 2006, 10, 851.
(c) Evans, D. A.; Dinsmore, C. J.; Watson, P. S.; Wood, M. R.; Richardson,
T. I.; Trotter, B. W.; Katz, J. L. Angew. Chem., Int. Ed. 1998, 37, 2704.
(d) Lehn, J.-M. Science 2002, 295, 2400.
(2) (a) Tsuji, J. Palladium Reagents and Catalysts: New PerspectiVes for the
21st Century; Wiley: London, 2004. (b) Miyaura, N.; Suzuki, A. Chem.
ReV. 1995, 95, 2457.
a Reaction conditions: 1a (1 equiv), benzene (100 equiv), 125 °C,
20 h. b Yield (%) determined by 1H NMR analysis using an internal
standard. c 5 mol % of catalyst. d 2.5 mol % of catalyst. e 0.51 equiv. f 1
equiv.
(3) For selected reviews, see: (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
ReV. 2007, 107, 174. (b) Miura, M.; Satoh, T. Top. Organomet. Chem.
2005, 14, 55. (c) Campeau, L. C.; Fagnou, K. Chem. Commun. 2006, 1253.
(d) Seregin, I. Y.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (e)
Lyons, T. W.; Sanford, M. S. Chem. ReV. 2010, 110, 1147. (f) Chen, X.;
Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48,
5094. (g) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009,
42, 1074.
(4) Recent examples from our group: (a) Valle´e, F.; Mousseau, J. J.; Charette,
A. B. J. Am. Chem. Soc. 2010, 132, 1514. (b) Mousseau, J. J.; Bull, J. A.;
Charette, A. B. Angew. Chem., Int. Ed. 2010, 49, 1115. (c) Larive´e, A.;
Mousseau, J. J.; Charette, A. B. J. Am. Chem. Soc. 2008, 130, 52.
(5) For selected recent examples, see: (a) Ackermann, L.; Born, R.; Alvarez-
Bercedo, P. Angew. Chem., Int. Ed. 2007, 46, 6364. (b) Kim, M.; Kwak,
J.; Chang, S. Angew. Chem., Int. Ed. 2009, 48, 8935. (c) Yang, S.; Li, B.;
Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 6066. (d) Zhao, X.; Yeung,
C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 5837. (e) Hull, K. L.;
Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 9651. (f) Deprez, N. R.;
Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234. (g) Xiao, B.; Fu, Y.;
Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc. 2010, 132,
468. (h) Nishikata, T.; Abela, A. R.; Huang, S.; Lipshutz, B. H. J. Am.
Chem. Soc. 2010, 132, 4978.
Based on these results, we believe that the reaction proceeds as
follows. First, the palladium inserts into the benzene ring (Scheme
2). This reversible process was first reported in 1965 by Van Helden
and later again by Sasson.14 However, given the importance of
acetate not only in their disclosures but also in our results, in
addition to known work in the area, we propose that this happens
through a concerted metalation deprotonation sequence over the
previously suggested Wheland intermediate.7c,15 The resulting
phenylated Pd then undergoes Ag-assisted oxidative addition to
obtain the corresponding PdIV species that is directed and stabilized
by the presence of a Lewis basic group.16 This intermediate
reductively eliminates to give the observed product. Simultaneously,
the AcOH generated in the carbopalladation step is deprotonated
by the carbonate and ligates to the Pd, regenerating the active
catalyst. This pathway also accounts for the trace amount of
biphenyl observed in the reaction mixture, as a result of homo-
coupling of two benzene molecules.10 Indeed, the phenylated Pd
is known to disproportionate to provide Pd(OAc)2 and PdPh2, the
latter of which reductively eliminates to give biphenyl and Pd0.10
(6) (a) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496. (b)
Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (c) Qin, C.; Lu, W. J.
Org. Chem. 2008, 73, 7424. (d) Kobayashi, O.; Urajuchi, D.; Yamakawa,
T. Org. Lett. 2009, 11, 2679. (e) Liu, W.; Cao, H.; Lei, A. Angew. Chem.,
Int. Ed. 2010, 49, 2004.
(7) (a) Zhang, X.; Fan, S.; He, C.-Y.; Wan, X.; Min, Q.-Q.; Yang, J.; Jiang,
Z.-X. J. Am. Chem. Soc. 2010, 132, 4506. (b) Rene´, O.; Fagnou, K. Org.
Lett. 2010, 12, 2116. (c) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou,
K. J. Am. Chem. Soc. 2006, 128, 8754. (d) Do, H.-Q.; Khan, R. M. K.;
Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185. (e) Do, H. Q.; Daugulis,
O. J. Am. Chem. Soc. 2008, 130, 1128. (f) He, C.-Y.; Fan, S.; Zhang, X.
J. Am. Chem. Soc. 2010, 132, 12850.
Scheme 2. Proposed Catalytic Cycle
(8) Snieckus, V. Chem. ReV. 1990, 90, 879.
(9) Though full conversions were reported with 0.50 equiv of Ag2CO3, more
reproducible results were obtained with slightly more reagent.
(10) Bipenyl is always generated in the reaction in a non-reproducible manner.
In the case where additional biphenyl would be formed due to decarboxyl-
ation, differentiating it from naturally forming byproducts would not be
possible.
(11) In all cases the halide was consummed. The balance of material provided
a complex mixture.
(12) Entries resulting in lower yields are the result of incomplete consumption
of the bromide starting material. Efforts to drive the consumption to
completion were unsuccessful.
(13) Schlosser, M.; Marzi, E. Chem.sEur. J. 2005, 11, 3449.
(14) (a) van Helden, R.; Verberg, G. Recl. TraV. Chim. Pays-Bas 1965, 84,
1263. (b) Mukhopadhyay, S.; Rothenberg, G.; Gitis, D.; Sasson, Y. J. Org.
Chem. 2000, 65, 3107.
(15) (a) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130,
10848. (b) Cardenas, D. J.; Martin-Matute, B.; Echavarren, A. M. J. Am.
Chem. Soc. 2006, 128, 5033. (c) Garcia-Cuadrado, D.; Braga, A. A. C.;
Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066.
(16) For cationic PdIV species, see: (a) Campora, J.; Palma, P.; del Rio, D.;
Carmona, E. Organometallics 2003, 22, 3345. (b) Campora, J.; Palma, P.;
del Rio, D.; Lopez, J. A.; Alvarez, E. Organometallics 2005, 24, 3624.
In conclusion, we have disclosed an efficient Pd-catalyzed direct
arylation process that can be performed in the absence of an external
ligand and that requires only substoichiometric amounts of Ag2CO3.
The reaction displays inverse reactivity to what has been previously
reported, where the reactant is also the solvent that can be recycled
for future transformations. Work is currently underway to gain
JA107541W
9
14414 J. AM. CHEM. SOC. VOL. 132, NO. 41, 2010