Intramolecular palladium-catalyzed alkane C-H arylation from aryl chlorides

Article abstract of DOI:10.1021/ja1048847

The first examples of efficient and general palladium-catalyzed intramolecular C(sp³)-H arylation of (hetero)aryl chlorides, giving rise to a variety of valuable cyclobutarenes, indanes, indolines, dihydrobenzofurans, and indanones, are described. The use of aryl and heteroaryl chlorides significantly improves the scope of C(sp³)-H arylation by facilitating the preparation of reaction substrates. Careful optimization studies have shown that the palladium ligand and the base/solvent combination are crucial to obtaining the desired class of product in high yields. Overall, three sets of reaction conditions employing P^tBu₃, PCyp₃, or PCy₃ as the palladium ligand and K ₂CO₃/DMF or Cs₂CO₃/pivalic acid/mesitylene as the base/solvent combination allowed five different classes of products to be accessed using this methodology. In total, more than 40 examples of C-H arylation have been performed successfully. When several types of C(sp³)-H bond were present in the substrate, the arylation was found to occur regioselectively at primary C-H bonds vs secondary or tertiary positions. In addition, in the presence of several primary C-H bonds, selectivity trends correlate with the size of the palladacyclic intermediate, with five-membered rings being favored over six- and seven-membered rings. Regio- and diastereoselectivity issues were studied computationally in the prototypal case of indane formation. DFT(B3PW91) calculations demonstrated that C-H activation is the rate-determining step and that the creation of a C-H agostic interaction, increasing the acidity of a geminal C-H bond, is a critical factor for the regiochemistry control.

Full text of DOI:10.1021/ja1048847

Published on Web 07/21/2010
Intramolecular Palladium-Catalyzed Alkane C-H Arylation
from Aryl Chlorides
Sophie Rousseaux,*,† Michae¨l Davi,‡ Julien Sofack-Kreutzer,‡ Cathleen Pierre,‡
Christos E. Kefalidis,§ Eric Clot,*,§ Keith Fagnou,†,# and Olivier Baudoin*,‡
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of Ottawa,
10 Marie Curie, Ottawa, Ontario K1N 6N5, Canada, CNRS UMR5246sInstitut de Chimie et
Biochimie Mole´culaires et Supramole´culaires, UniVersite´ Claude Bernard Lyon 1, CPE Lyon, 43
BouleVard du 11 NoVembre 1918, 69622 Villeurbanne, France, and Institut Charles Gerhardt,
UniVersite´ Montpellier 2, CNRS UMR5253, case courrier 1501, Place Euge`ne Bataillon,
34095 Montpellier, France
Received June 15, 2010; E-mail: srous100@uottawa.ca; clot@univ-montp2.fr;
olivier.baudoin@univ-lyon1.fr
Abstract: The first examples of efficient and general palladium-catalyzed intramolecular C(sp3)-H arylation
of (hetero)aryl chlorides, giving rise to a variety of valuable cyclobutarenes, indanes, indolines, dihydroben-
zofurans, and indanones, are described. The use of aryl and heteroaryl chlorides significantly improves
the scope of C(sp3)-H arylation by facilitating the preparation of reaction substrates. Careful optimization
studies have shown that the palladium ligand and the base/solvent combination are crucial to obtaining
the desired class of product in high yields. Overall, three sets of reaction conditions employing PtBu3, PCyp3,
or PCy3 as the palladium ligand and K2CO3/DMF or Cs2CO3/pivalic acid/mesitylene as the base/solvent
combination allowed five different classes of products to be accessed using this methodology. In total,
more than 40 examples of C-H arylation have been performed successfully. When several types of
C(sp3)-H bond were present in the substrate, the arylation was found to occur regioselectively at primary
C-H bonds vs secondary or tertiary positions. In addition, in the presence of several primary C-H bonds,
selectivity trends correlate with the size of the palladacyclic intermediate, with five-membered rings being
favored over six- and seven-membered rings. Regio- and diastereoselectivity issues were studied
computationally in the prototypal case of indane formation. DFT(B3PW91) calculations demonstrated that
C-H activation is the rate-determining step and that the creation of a C-H agostic interaction, increasing
the acidity of a geminal C-H bond, is a critical factor for the regiochemistry control.
the arylation of unreactive C(sp3)-H bonds of alkyl groups.4
Introduction
Efforts by our groups5,6 and others7 in the context of alkane
In recent years, transition-metal-catalyzed C-H functional-
ization has emerged as a powerful tool to transform otherwise
unreactive C-H bonds into carbon-carbon or carbon-heteroatom
bonds.1,2 In particular, C-H arylation has become an attractive
alternative to traditional C-C cross-coupling reactions due to
the minimization of stoichiometric metallic waste and the costs
associated with the preparation of starting materials.3 In regard
to the wealth of methods recently developed for the arylation
of arene and heteroarene C(sp2)-H bonds by aryl halides or
other aryl electrophiles, relatively little work has focused on
arylation under palladium(0) catalysis have led to greater scope
for intramolecular reactions, generating various motifs of
synthetically useful fused carbocycles and heterocycles.8 Despite
these significant advances in C(sp3)-H arylation, the aryl halide
(3) Selected recent reviews: (a) Hassan, J.; Se´vignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359. (b) Goj, L. A.;
Gunnoe, T. B. Curr. Org. Chem. 2005, 9, 671. (c) Campeau, L.-C.;
Fagnou, K. Chem. Commun. 2006, 1253. (d) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. ReV. 2007, 107, 174. (e) Seregin, I. V.; Gevorgyan,
V. Chem. Soc. ReV. 2007, 36, 1173. (f) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (g)
McGlacken, G. P.; Bateman, L. M. Chem. Soc. ReV. 2009, 38, 2447.
(h) Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269. (i) Ackermann,
L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792.
(4) Review on catalytic C(sp3)-H activation: Jazzar, R.; Hitce, J.;
Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem.sEur. J. 2010,
16, 2654.
† University of Ottawa.
‡ Universite´ Claude Bernard Lyon 1.
§ Universite´ Montpellier 2.
# Deceased November 11, 2009.
(1) Handbook of C-H Transformations; Dyker, G., Ed.; Wiley-VCH:
Weinheim, 2005.
(5) (a) Baudoin, O.; Herrbach, A.; Gue´ritte, F. Angew. Chem., Int. Ed.
2003, 42, 5736. (b) Hitce, J.; Retailleau, P.; Baudoin, O. Chem.sEur.
J. 2007, 13, 792. (c) Hitce, J.; Baudoin, O. AdV. Synth. Catal. 2007,
349, 2054. (d) Chaumontet, M.; Piccardi, R.; Audic, N.; Hitce, J.;
Peglion, J.-L.; Clot, E.; Baudoin, O. J. Am. Chem. Soc. 2008, 130,
15157. (e) Chaumontet, M.; Piccardi, R.; Baudoin, O. Angew. Chem.,
Int. Ed. 2009, 48, 179.
(2) Selected general reviews: (a) Arndtsen, B. A.; Bergman, R. G.; Mobley,
T. A.; Peterson, T. H. Acc. Chem. Res. 1995, 28, 154. (b) Shilov,
A. E.; Shul’pin, G. B. Chem. ReV. 1997, 97, 2879. (c) Dyker, G.
Angew. Chem., Int. Ed. 1999, 38, 1698. (d) Labinger, J. A.; Bercaw,
J. E. Nature 2002, 417, 507. (e) Kakiuchi, F.; Chatani, N. AdV. Synth.
Catal. 2003, 345, 1077. (f) Dick, A. R.; Sanford, M. S. Tetrahedron
2006, 62, 2439. (g) Godula, K.; Sames, D. Science 2006, 312, 67. (h)
Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.
(6) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007,
129, 14570.
9
10706 J. AM. CHEM. SOC. 2010, 132, 10706–10716
10.1021/ja1048847  2010 American Chemical Society

Intramolecular C(sp3)-H Arylation from Aryl Chlorides
A R T I C L E S
Table 1. Synthesis of Cyclobutarenes: Study of C(sp3)-H Arylation Parameters
a
entry
halide
Pd source
ligand
solvent
T (°C)
time (h)
conversion (%)a
ratio 2:2′
GC yield in 2 (%)a,b
c
1
2
3
4
5
6
7
8
1b
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PtBu3
DMF
100
100
140
140
140
140
140
140
140
140
140
140
140
140
1
16
3
16
16
16
3
3
16
3
>98
35
>98
60
32
95
29
60
<2
94
9
>40:1
>40:1
>40:1
4.3:1
3.1:1
13.1:1
9.4:1
25:1
>98
29
89 (83)
49
16
52
7
33
-
41
c
c
PtBu3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
NMP
mesitylenef
PtBu3
c
PCy3
c
MePtBu2
d
nBuPAd2
JohnPhos
Q-Phos
9
P(o-tol)3
-
c
10
11
12
13
14
PtBu3
2.7:1
1:1.3
41:1
e
c
Pd2dba3
PtBu3
3
3
4
5
4
c
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PtBu3
>98
94
92
92 (77)
82
45
c
PtBu3
43:1
7.3:1
c
PtBu3
a Calculated using tetradecane as internal standard. b Yield of the isolated product in parentheses. c Introduced as HBF4 salt. d Introduced as HI salt.
e 5 mol % Pd2dba3/10 mol % PtBu3. f With 30 mol % pivalic acid as an additive. JohnPhos ) 2-(di-tert-butylphosphino)biphenyl; Q-Phos )
1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene.
coupling partners remain almost exclusively aryl iodides or
bromides. The limited use of (hetero)aryl chlorides in these
reactions is surprising, considering the advances that have been
made in C(sp2)-H arylations as well as in other cross-
couplings.9 This may be attributed in part to the greater strength
of the C-Cl bond rendering oxidative addition less facile,10 in
addition to the well-established lack of reactivity of nonacidic
C(sp3)-H bonds.4 However, using aryl and heteroaryl chlorides
as substrates for intramolecular C(sp3)-H arylations would have
two important advantages over the use of bromides and iodides:
(1) lower cost and greater number of commercially available
starting materials and (2) improved synthesis of the C-H
arylation substrates due to reduced steric hindrance.11 Herein,
we describe our joint efforts to expand the scope of intramo-
lecular C(sp3)-H arylations to include aryl and heteroaryl
chlorides for the synthesis of a wide range of polycyclic
molecules, including cyclobutarenes, indanes, indolines, dihy-
drobenzofurans, and indanones, some of which have not been
described previously and are hard to access from other aryl
halides (eq 1). We also disclose new theoretical studies which
greatly improve our understanding of C(sp3)-H activation with
regard to regio- and stereoselectivity issues through the use of
DFT calculations.
Results and Discussion
1. Synthesis of Cyclobutarenes. Cyclobutarenes are both
important structural elements in active pharmaceutical ingre-
dients and valuable reactive intermediates for organic synthe-
sis.12 Despite their high synthetic value, very few general and
chemoselective methods exist for the preparation of function-
alized cyclobutarenes, limiting their availability and their use
as synthetic intermediates. On the basis of previous results from
one of our groups on the synthesis of benzocyclobutenes (BCBs)
from aryl bromides by intramolecular C(sp3)-H arylation,5d we
examined the use of aryl chlorides as substrates for this reaction
which, if successful, would significantly improve synthetic
access to this important class of molecules. The conditions
previously described for the reaction of aryl bromide 1b giving
BCB 2 (Table 1) employed Pd(OAc)2/PtBu3 as the catalytic
system and K2CO3 as the base in N,N-dimethylformamide
(DMF) at 140 °C. More recently, we found that the reaction
could be run at 100 °C without affecting the reaction efficiency
(entry 1). Under the same conditions, only low conversion of
aryl chloride 1a was observed, even after prolonged heating
(entry 2). Gratifyingly, by increasing the temperature to 140
(7) (a) Dong, C.-G.; Hu, Q.-S. Angew. Chem., Int. Ed. 2006, 45, 2289.
(b) Ren, H.; Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 3462. (c)
Ren, H.; Zi, L.; Knochel, P. Chem. Asian J. 2007, 2, 416. (d) Liron,
F.; Knochel, P. Tetrahedron Lett. 2007, 48, 4943. (e) Dong, C.-G.;
Hu, Q.-S. Tetrahedron 2008, 64, 2537. (f) Watanabe, T.; Oishi, S.;
Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 1759. (g) Salcedo, A.; Neuville,
L.; Zhu, J. J. Org. Chem. 2008, 73, 3600. (h) Kim, H. S.; Gowrisankar,
S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2008, 49, 3858. (i) Huang,
Q.; Larock, R. C. Tetrahedron Lett. 2009, 50, 7235. (j) Kim, K. H.;
Lee, H. S.; Kim, S. H.; Kim, S. H.; Kim, J. N. Chem.sEur. J. 2010,
16, 2375.
(8) Intermolecular C(sp3)-H arylation under Pd0/phosphine catalysis: (a)
Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685. (b) Niwa, T.; Yorimitsu, H.; Oshima,
K. Org. Lett. 2007, 9, 2373. (c) Campeau, L.-C.; Schipper, D. J.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 3266. (d) Mousseau, J. J.;
Larive´e, A.; Charette, A. B. Org. Lett. 2008, 10, 1641. (e) Niwa, T.;
Yorimitsu, H.; Oshima, K. Org. Lett. 2008, 10, 4689. (f) Schipper,
D. J.; Campeau, L.-C.; Fagnou, K. Tetrahedron 2009, 65, 3155. (g)
Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 9886.
(9) Review on the use of aryl chlorides in palladium-catalyzed coupling
reactions: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4176.
(10) Bond dissociation energies for Ph-X: Cl, 95.5 kcal mol-1; Br, 80.4
kcal mol-1; I, 65.0 kcal mol-1. Luo, Y. R. Handbook of Bond
Dissociation Energies in Organic Compounds; CRC Press: Boca
Raton, FL, 2003; Chapter 5.
(11) Van der Waals radii: Cl, 1.75 Å; Br, 1.85 Å; I, 1.98 Å. Handbook of
Chemistry and Physics; CRC Press: Boca Raton, FL, 2008.
(12) (a) Mehta, G.; Kotha, S. Tetrahedron 2001, 57, 625. (b) Sadana, A. K.;
Saini, R. K.; Billups, W. E. Chem. ReV. 2003, 103, 1539.
9
J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010 10707

A R T I C L E S
Rousseaux et al.
°C (entry 3), complete conversion of 1a was reached, and BCB
2 was obtained in 89% GC yield (83% isolated yield). No trace
of the protodehalogenated product 2′, the usual side product in
these reactions, was observed. Other catalysts and solvents
provided different outcomes for the reactions of 1a and 1b. In
particular, tri-tert-butylphosphine was by far the most efficient
ligand with 1a among a panel of monophosphine ligands (entries
3-9), whereas bulkier monophosphine ligands such as JohnPhos,
Q-Phos, and P(o-tol)3 gave good results with 1b.5d Thus, PtBu3
appears to have the optimal electronic and steric properties
(Tolman cone angle ) 182°) for the intramolecular C-H
arylation of chloride 1a.13,14 Palladium acetate (entry 3) was
also the most active palladium precatalyst (see entries 10 and
11 for examples of other Pd sources). Finally, solvents other
than DMF could be employed for the arylation of 1a, including
N,N-dimethylacetamide (DMA) and N-methylpyrrolidone (NMP)
(entries 12 and 13), but DMF gave the highest yield of isolated
BCB. Interestingly, using mesitylene as the solvent with 30 mol
% of pivalic acid as an additive, a combination that gave good
results in other intramolecular C(sp3)-H arylations (Vide infra),6
led to irreproducible yields of 2 (entry 14).
The optimal set of conditions was applied to the C(sp3)-H
arylation of a wide range of aryl and heteroaryl chlorides (Table
2). As anticipated, the presence of the chlorine atom greatly
facilitated the synthesis of most arylation substrates due to the
better availability of starting materials and to the reduced
influence of steric hindrance.15 For instance, dichloride 15 was
prepared in one step from a commercially available material
using a stoichiometric amount of reagents, whereas four steps
and an excess in reagents were required for the corresponding
bromide.5d Moreover, in some cases, for example chlorides 13,
27, and 29, the corresponding aryl bromide would be almost
inaccessible by typical synthetic routes.
The standard arylation conditions were found to be compatible
with a wide range of substituents on the benzylic carbon (entries
1-6) and the aromatic ring (entries 7-12), giving rise to the
corresponding BCBs in 65-87% yield. In the case of substrates
with mutiple arylation sites (entries 4 and 5), the reaction showed
complete regioselectivity for arylation at the methyl group. In
the case of dichloride 15 (entry 8), careful monitoring of the
reaction conversion allowed BCB 16 to be obtained in good
yield after 30 min, whereas with prolonged heating a mixture
of 16 and the corresponding dechlorinated product was obtained.
Arylation of chloride 19 gave rise to a 3.6:1 mixture of BCB
isomers 20a,b (entry 10). The formation of isomer 20b, which
was also observed from the corresponding aryl bromide,5d
presumably arises from a palladium migration within the
catalytic cycle.16 Indeed, DFT calculations have demonstrated
that reductive elimination to form the strained BCB four-
membered ring is highly energetic and thus is in competition
with palladium migration.5d The reaction conditions were also
effective for heteroaryl chlorides. Indeed, chloropyridine 25
(entry 13), chloroquinoline 27 (entry 14), and chloroindole 29
(entry 15) yielded valuable heterocycles that are typically
unaccessible through more traditional synthetic methods. For
quinoline 27 (entry 14), the reaction was conducted at a lower
temperature (110 °C) to avoid the formation of a side product
arising from cyclobutene ring-opening.17 From indole 29 (entry
15), a 2:5 separable mixture of isomers 30a and 30b, arising
from cyclization at the C-5 and C-3 position of the indole
nucleus, respectively, was obtained. To the best of our knowl-
edge, compound 30b is surprisingly the first isolated molecule
with the 3,4-dihydro-1H-cyclopenta[c,d]indole scaffold, which
is structurally related to the orchid alkaloid dendrobine.18 This
isomer most likely arises from palladium migration, similar to
that observed with aryl chloride 19 (entry 10). Research is
ongoing to further study this rearrangement in detail.
2. Synthesis of Indanes. In a previous report, some of us
described the synthesis of indanes from aryl bromides by
intramolecular C(sp3)-H arylation at the terminal carbon of an
isopropyl group.5b For instance, the reaction of bromide 31b
using 5 mol % Pd(OAc)2 and 20 mol % F-TOTP as catalyst in
DMF at 100 °C furnished a 4:1 mixture of indane 32a (as a
single diastereoisomer) and the dehydrogenation product 33
(Table 3, entry 1). This catalyst was found to be ineffective in
the reaction of the corresponding aryl chloride 31a, even at 140
°C (entry 2). A rapid ligand screen (entries 3-9) revealed that
trialkylphosphines with cone angles between 160 and 170° have
optimal steric properties for this reaction,14 with PCy3, PCyp3,
and PiPr3 giving rise to an inseparable diastereoisomeric mixture
of 32a:32b (dr ) 4:1 in favor of the cis diastereoisomer 32a)19
in high yield and with no trace of olefin 33 (entries 5-7).
Interestingly, lower selectivity of indane vs olefin product with
concomitant higher diastereoselectivity was obtained with PtBu3,
compared to less bulky trialkylphosphines (entry 3). Tricyclo-
pentylphosphine, which gave the highest isolated yield of
diastereoisomers 32a,b (92%, entry 6), was retained for further
scope studies (Vide infra). Decreasing the temperature to 120
°C led to incomplete conversion (entry 9). Finally, replacing
DMF by other solvents such as DMA or mesitylene (with 30
mol % of pivalic acid as an additive)6 gave lower yields of
indane products.
The optimal conditions were applied to a range of other aryl
and heteroaryl chlorides (Table 4). Again, the ease of synthesis
of most arylation substrates was significantly improved com-
pared to that of the corresponding aryl bromides. The presence
of electron-withdrawing (entries 2 and 3) or -donating (entry
4) substituents on the aromatic ring did not affect the efficiency
of the reaction, and the corresponding indanes were obtained
in very good yields as 3.3:1 to 4:1 diastereoisomeric mixtures,
always in favor of the cis diastereoisomer.19 Interestingly, no
isomerized product arising from palladium migration was
observed in the reaction of aryl chloride 34 (entry 2), in contrast
to BCB formation from the analogous substrate 19 (Table 2,
entry 10). This observation indicates that reductive elimination
to form the indane five-membered ring is faster than palladium
migration. Remarkably, the intramolecular arylation of homo-
chiral trans-dimethylcyclopentane compounds 40 and 42 fur-
nished tricyclic products 41 and 43, respectively, in very good
yield and as a single stereoisomer (entries 5 and 6). The reaction
(13) (a) Tolman, C. A. Chem. ReV. 1977, 77, 313. (b) Brown, T. L.; Lee,
K. J. Coord. Chem. ReV. 1993, 128, 89. (c) Clavier, H.; Nolan, S. P.
Chem. Commun. 2010, 46, 841.
(17) Jefford, C. W.; Bernardinelli, G.; Wang, Y.; Spellmeyer, D. C.; Buda,
A.; Houk, K. N. J. Am. Chem. Soc. 1992, 114, 1157.
(14) Tolman cone angles θ:13 JohnPhos, 246°; CyJohnPhos, 226°; P(o-
tol)3, 194°; PtBu3, 182°; PCy3, 170°; MePtBu2, 161°; PiPr3, 160°; PnBu3,
132°.
(18) (a) Yamamura, S.; Hirata, Y. Tetrahedron Lett. 1964, 5, 79. (b)
Inubushi, Y.; Sasaki, Y.; Tsuda, Y.; Yasui, B.; Konita, T.; Matsumoto,
J.; Katarao, E.; Nakano, J. Tetrahedron 1964, 20, 2007. (c) Onaka,
R.; Kamata, S.; Maeda, T.; Kawazoe, Y.; Natsume, M.; Okamoto, T.;
Uchimaru, F.; Shimizu, M. Chem. Pharm. Bull. 1964, 12, 506.
(19) Relative configurations were ascribed by NOESY experiments.
(15) See the Supporting Information for detailed experimental procedures.
(16) Reviews on palladium migrations: (a) Ma, S.; Gu, Z. Angew. Chem.,
Int. Ed. 2005, 44, 7512. (b) Shi, F.; Larock, R. C. Top. Curr. Chem.
2010, 292, 123.
9
10708 J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010

Intramolecular C(sp3)-H Arylation from Aryl Chlorides
A R T I C L E S
Table 2. Scope of Cyclobutarenes Synthesized by Intramolecular C(sp3)-H Arylationa
a Reaction conditions: Pd(OAc)2, 10 mol %; (tBu3PH)BF4, 20 mol %; K2CO3, 1.3 equiv; DMF; 140 °C. b The ratio of isomers (when applicable) was measured by
1H NMR of the crude mixture. c Yields of isolated products. d DMA was used instead of DMF. e Reaction performed at 110 °C. TIPS ) triisopropylsilyl.
9
J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010 10709

A R T I C L E S
Rousseaux et al.
Table 3. Synthesis of Indanes: Study of C(sp3)-H Arylation Parameters
selectivity
(32a + 32b):33b
GC yield 32a +
conversion (%)a
32b (%)a c
dr 32a:32bb
,
entry
halide
ligand
T (°C)
1
2
3
4
5
6
7
8
9
31b
31a
31a
31a
31a
31a
31a
31a
31a
F-TOTP
F-TOTP
100
140
140
140
140
140
140
140
120
>98
20
>98
54
>98
>98
>98
29
4:1
-
66 (50)
0
53
>40:1
-
d
PtBu3
1:1
20:1
4:1
4:1
4:1
4:1
-
CyJohnPhos
>40:1
>40:1
>40:1
>40:1
>40:1
>40:1
18
d
PCy3
88 (83)
94 (92)
93 (87)
27
d
PCyp3
d
PiPr3
d
PnBu3
d
PCy3
52
49
4:1
a Calculated using tetradecane as internal standard. b Determined by 1H NMR of the crude mixture. c Yield of the isolated product in parentheses.
d Introduced as HBF4 salt. F-TOTP
tricyclopentylphosphine.
) tris(5-fluoro-2-methylphenyl)phosphine; CyJohnPhos ) 2-(dicyclohexylphosphino)biphenyl; PCyp3 )
was also effective from heteroaryl chlorides 44 and 46 (entries
7 and 8), giving rise to original fused thiophenes 45a,b and
indole 47, respectively, in good yield. Interestingly, higher
diastereoselectivity was attained in the latter case, with only
one diastereoisomer being observed due to additional substitu-
tion on the aromatic ring at the positon ortho to the activated
alkyl group. In this study, it is interesting to note that C-H
arylation occurs exclusively on the terminal methyl group of
aryl chloride substrates, giving rise to five-membered rings
(entries 1-8). No trace of arylation at the methyne C-H bond
yielding a cyclobutarene was detected.
The mechanism of formation of 32a and 32b from 31a has
been studied computationally at the B3PW91 level (see Com-
putational Details). Only the C-H activation and C-C coupling
steps have been considered. We have already shown that, for
the formation of BCBs from aryl bromides, C-H activation is
the rate-determining step through a concerted metalation-
deprotonation (CMD) mechanism6,20,21 with the base coordi-
nated cis to the aryl group.5d Kinetic studies by Hartwig22 and
Baird23 of C-X oxidative addition have shown that, for C-Br,
reaction at both the bisphosphine and monophosphine Pd0
complexes is possible, whereas for C-Cl, formation of the
monophosphine Pd0 complex is mandatory to achieve any
oxidative addition. The C-X oxidative addition of 31a (X )
Cl) and 31b (X ) Br) to Pd(PCyp3) has been computed; as
expected, the activation barrier for X ) Cl is higher than for X
) Br (12.3 vs 4.7 kcal mol-1), but the values are very low
compared to the activation barriers for C-H activation (Vide
infra). Therefore, we can assume that the C-Cl oxidative
addition occurs on a monophosphine Pd0 complex and is not
rate-limiting. Substitution of the halide by the base affords an
ML3 complex that is the reactant for further functionalization.
The transformation studied in the present work is shown in
Scheme 1. The calculations make explicit use of the experi-
mental phosphine PCyp3 and bicarbonate (HCO3-) as the base.
Formation of the experimentally nonobserved BCB 32c was also
characterized computationally to better highlight the factors at
the origin of the regioselectivity in the C-H activation.
The starting reactant features a vacant site prone to the
establishment of an agostic interaction with a C-H bond of
one of the isopropyl groups. Three different agostic complexes
(Agos-a, Agos-b, and Agos-c) have been located on the potential
energy surface (PES), and they constitute the starting point for
the formation of 32a, 32b, and 32c, respectively (Figure 1).
Agos-a is the most stable structure, with Agos-b and Agos-c
lying ∆G ) 4.1 and 6.8 kcal mol-1 higher in energy,
respectively. In the three complexes, the agostic C-H bond is
elongated and has a similar length (1.146 Å, Agos-a; 1.144 Å,
Agos-b; 1.144 Å, Agos-c). The H · · · Pd distance does not
mirror the relative stability of the agostic complexes, with
the shortest value (1.802 Å) obtained with Agos-b and the
longest (1.858 Å) with Agos-c (H · · · Pd ) 1.814 Å in Agos-
a). The critical geometrical parameter that explains the
relative stability of the agostic complexes is the value of the
incipient Pd · · · C bond distance, with a smaller value for
Agos-a (2.408 Å) than for the two less stable complexes
(2.430 Å, Agos-b; 2.819 Å, Agos-c).
(20) Computational studies on the CMD pathway in C(sp2)-H activation: (a)
Biswas, B.; Sugimoto, M.; Sakaki, S. Organometallics 2000, 19, 3895.
(b) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem.
Soc. 2005, 127, 13754. (c) Garc´ıa-Cuadrado, D.; Braga, A. A. C.;
Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2006, 128, 1066.
(d) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 8754. (e) Alonso, I.; Alcam´ı, M.; Mauleo´n, P.;
Carretero, J. C. Chem.sEur. J. 2006, 12, 4576. (f) Garc´ıa-Cuadrado,
D.; de Mendoza, P.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M.
¨
J. Am. Chem. Soc. 2007, 129, 6880. (g) Ozdemir, I.; Demir, S.;
C¸ etinkaya, B.; Gourlaouen, C.; Maseras, F.; Bruneau, C.; Dixneuf,
P. H. J. Am. Chem. Soc. 2008, 130, 1156. (h) Gorelsky, S. I.; Lapointe,
D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848. (i) Pascual, S.;
de Mendoza, P.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M.
Tetrahedron 2008, 64, 6021.
(21) Reviews: (a) Boutadla, Y.; Davies, D. L.; Macgregor, S. A.; Poblador-
Bahamonde, A. I. Dalton Trans. 2009, 5820. (b) Balcells, D.; Clot,
E.; Eisenstein, O. Chem. ReV. 2010, 110, 749.
(22) Barrios-Landeros, F.; Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc.
2009, 131, 8141.
(23) Mitchell, E. A.; Jessop, P. G.; Baird, M. C. Organometallics 2009,
28, 6732.
9
10710 J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010

Intramolecular C(sp3)-H Arylation from Aryl Chlorides
A R T I C L E S
Table 4. Scope of Indanes Synthesized by Intramolecular C(sp3)-H Arylationa
a Reaction conditions: Pd(OAc)2, 5 mol %; (Cyp3PH)BF4, 20 mol %; K2CO3, 2 equiv; DMF; 140 °C. b All products are racemic mixtures except for
entries 5 and 6. The ratio of diastereoisomers was measured by H NMR of the crude mixture. c Yields of isolated products.
1
Scheme 1. Transformation of ML3 Intermediate to Potential Alkane C-H Arylation Products Evaluated in the Computational Study
It is interesting to note that, in Agos-a and Agos-b, the agostic
C-H bond is trans to the coordinated base. In the classical
picture where creation of an agostic interaction weakens the
C-H bond to be cleaved, this trans geometry constitutes a
hurdle to overcome. However, Macgregor has recently dem-
onstrated that an agostic interaction can promote the deproto-
nation of a geminal C-H bond.24 The geometry in Agos-a and
Agos-b is particularly adapted to deprotonation of a geminal
Figure 1. Optimized geometries for agostic complexes Agos-a, Agos-b, and Agos-c. Most H atoms have been omitted for clarity.
9
J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010 10711

A R T I C L E S
Rousseaux et al.
Figure 2. Optimized geometries for the CMD transition states for C-H bond cleavage, TSCH-a, TSCH-b, and TSCH-c. Most H atoms have been omitted
for clarity.
Figure 3. Optimized geometries for palladacycles Cyc-a, Cyc-b, and Cyc-c produced by C-H activation. All H atoms have been omitted for clarity.
C-H bond by the coordinated base, as illustrated by the
optimized structure of the transition states TSCH-a and
TSCH-b (Figure 2). In the case of Agos-c, the agostic
interaction must be cleaved prior to actual C-H bond cleavage,
as illustrated by the geometry of TSCH-c in Figure 2. The
geometries of the transition states for C-H bond cleavage are
typical of CMD processes with concerted cleavage of the C-H
bond (1.404 Å, TSCH-a; 1.407 Å, TSCH-b; 1.539 Å, TSCH-
c) and formation of O-H (1.495 Å, TSCH-a; 1.486 Å, TSCH-
Figure 4. Optimized geometries for the transition states for C-C coupling,
TSCC-a, TSCC-b, and TSCC-c. All H atoms have been omitted for clarity.
b; 1.421 Å, TSCH-c) and Pd-C bonds (2.232 Å, TSCH-a;
2.221 Å, TSCH-b; 2.344 Å, TSCH-c). The activation barrier,
∆G1,x#, estimated as the Gibbs free energy difference between
TSCH-x and the agostic complex Agos-x (x ) a, b, or c) from
which it originates, varies as follows: ∆G1,a# ) 26.2 kcal mol-1,
∆G1,b# ) 27.5 kcal mol-1, and ∆G1,c# ) 33.8 kcal mol-1. There
is thus a clear energetic preference to activate the primary C-H
isopropyl bond with respect to the tertiary one. For activation
at the primary carbon, the pathway leading to 32a is preferred
over that leading to 32b by 1.3 kcal mol-1. It is interesting to
note that the experimental ratio of 4:1 between 32a and 32b at
140 °C corresponds to a difference in activation energy between
the two pathways of ca. 1.1 kcal mol-1. The more facile
activation in TSCH-a can be traced back to the stronger Pd · · ·C
interaction in Agos-a leading to more acidic character on the
geminal hydrogen atom to be transferred. This is illustrated by
the shorter C· · ·H and longer O· · ·H bonds in TSCH-a. The
Pd· · ·C bond is ca. 0.1 Å longer in TSCH-c than in TSCH-b,
as a result of the intrinsic weaker bond energy for a Pd-C bond
at a tertiary carbon with respect to a Pd-C bond at a primary
carbon.
∆Gc ) -18.3 kcal mol-1) due to the dissociation of the
protonated base.
As expected, C-C reductive elimination through TSCC-x
(x ) a, b, or c, Figure 4) is easier from six-membered
#
palladacycles Cyc-a and Cyc-b, with activation barriers ∆G2,a
) 10.4 kcal mol-1 and ∆G2,b ) 12.6 kcal mol-1. In contrast,
#
the formation of BCB 32c through TSCC-c is more difficult,
with ∆G2,c ) 24.7 kcal mol-1. This result clearly shows that
#
reductive elimination to form strained BCBs is much less
favored than that giving rise to indanes, explaining why
palladium migration is operative in the former reaction (Table
2, entries 10 and 15), whereas it is not observed in the latter
(Table 4, entry 2). The activation barrier for C-C coupling
results essentially from the necessary loss of Pd-C bonding in
order to reach a geometry adapted to C-C bond formation
2
(Figure 4). In the case of TSCC-a, the Pd-Csp bond length
increases from 1.994 Å in Cyc-a to 2.010 Å in TSCC-a, while
3
the Pd-Csp bond increases from 2.030 to 2.143 Å. As a
2
3
Following proton transfer to the base, the latter dissociates,
and six- or five-membered palladacycles Cyc-a, Cyc-b, and
Cyc-c are formed (Figure 3). Cyc-a is the most stable palla-
dacycle, with Cyc-b and Cyc-c lying 1.3 and 5.3 kcal mol-1
higher, respectively. With respect to the agostic complex Agos-
x, the C-H activation is exoergic on the Gibbs free energy
consequence, the forming Csp · · ·Csp bond is 2.069 Å in TSCC-
a. For TSCC-b, the variations are similar, with an increase of
2
Pd-Csp from 1.996 Å in Cyc-b to 2.005 Å in the transition
3
state, while Pd-Csp increases from 2.025 to 2.146 Å. This
2
3
results in a Csp · · ·Csp bond of 2.111 Å at the transition state.
For the five-membered ring in Cyc-c, the situation is drastically
surface (∆Ga ) -16.9 kcal mol-1, ∆Gb ) -19.7 kcal mol-1
,
2
different. While the Pd-Csp bond is again only slightly
elongated in the TS (1.994 Å, Cyc-c; 2.030 Å, TSCC-c), a
3
significant elongation of the Pd-Csp bond from 2.076 to 2.397
(24) Ha¨ller, L. J. L.; Page, M. J.; Macgregor, S. A.; Mahon, M. F.;
Whittlesey, M. K. J. Am. Chem. Soc. 2009, 131, 4604.
Å is observed. This decrease in Pd-C bonding explains the
9
10712 J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010

Intramolecular C(sp3)-H Arylation from Aryl Chlorides
A R T I C L E S
possible to 31a. Reaction with Pd(PCyp3) and bicarbonate has
been considered. In addition to pathways a, b, and c, there is
now a new pathway (d) corresponding to C-H activation at
the methyl group and formation of a BCB similar to 10. The
geometries of the agostic complexes, the transition states for
C-H activation, the palladacycles, and the transition states for
C-C coupling are shown in Figure S1 of the Supporting
Information, and a comparison of the Gibbs free energy profiles
at 298 K is given in Figure S2. The most stable agostic complex
is Agos-d′, with Agos-a′ lying only 0.5 kcal mol-1 above. There
is thus no particular difference in stability between the agostic
complexes leading to five- and six-membered palladacycles,
provided two hydrogen atoms are present on the agostic carbon
(Agos-c′ is 4.4 kcal mol-1 above Agos-d′). The lowest transition
state is TSCH-d′, corresponding to C-H activation at the
methyl group, and the activation barrier from Agos-d′ is 25.6
kcal mol-1. The transition state for C-H activation at the
terminal position of the isopropyl group, TSCH-a′, leading to
an indane diastereoisomer similar to 32a, lies 2.0 kcal mol-1
above TSCH-d′, while that corresponding to the other terminal
C-H activation, TSCH-b′, is 2.6 kcal mol-1 above TSCH-d′.
As expected, the transition state for C-H activation at the
tertiary position of the isopropyl group, TSCH-c′, lies at
significantly higher energy than TSCH-d′ (13.4 kcal mol-1).
Here again, the C-H activation is the rate-determining step,
even though the C-C coupling process is more difficult for
formation of the four-membered ring with respect to the five-
membered ring (Figure S2). Qualitatively, there is thus a
significant preference for C-H activation at the methyl group
in 9′, leading to formation of the BCB product. The ∆∆G# value
of 2.0 kcal mol-1 between TSCH-d′ and TSCH-a′ is in
agreement with the exclusive formation of the BCB observed
experimentally in the case of 9. However, experimentally 9 is
converted to 10 with PtBu3 as the phosphine ligand, and the
present calculations were carried out with PCyp3. The actual
nature of the phosphine ligand could have an important role in
the quantitative description of the regiochemistry of the C-H
functionalization. More calculations are needed to test the
influence of the nature of the phosphine ligand and of the base
to orient the regiochemistry toward a desired target; computa-
tions are presently being carried out to study this aspect.
3. Synthesis of Dihydrobenzofurans and Indolines. Some of
us recently developed conditions for the formation of 2,2-
dialkyldihydrobenzofurans from aryl bromides by intramolecular
C(sp3)-H arylation.6 Given the relevance of this motif in
biological25 and medicinal compounds,26 the use of aryl
chlorides for their formation was investigated. When aryl
chloride 48, possessing an ortho tert-butoxy substituent, was
subjected to Pd(OAc)2 (5 mol %), (Cy3PH)BF4 (10 mol %),
Cs2CO3 (1.1 equiv), and PivOH (30 mol %) in mesitylene at
140 °C for 16 h, the desired product 49 was generated in 77%
Figure 5. Gibbs free energy (kcal mol-1) profiles for the formation of
32a, 32b, and 32c from the corresponding agostic complexes.
higher value of the activation energy for TSCC-c. To compen-
sate for this loss and to accommodate the strain in the forming
2
3
four-membered ring, the Csp · · ·Csp bond is shorter in TSCC-c
(1.933 Å) than in the other transition states.
A comparison of the Gibbs free energy profiles at 298 K for
the formation of the three different isomers 32a, 32b, and 32c
from the respective agostic complexes Agos-a, Agos-b, and
Agos-c is given in Figure 5. In the three cases, C-H activation
is the rate-determining step, and activation at the primary
position of the isopropyl group is clearly preferred over
activation at the tertiary position. If activation barriers are
estimated from the most stable agostic complex, Agos-a, then
the difference between pathways a and b (∆∆G# ) 5.4 kcal
mol-1) would preclude any observation of 32b. However, the
Gibbs free energy in the present work is estimated as a
combination of solvent-corrected energy (PCM model) and gas-
phase Gibbs free energy corrections (see Computational Details).
The latter is obtained within the harmonic approximation for
the vibrational component, and this may introduce errors. As a
matter of fact, whereas the relative energy of Agos-a and Agos-b
is the same when PCM energies or Gibbs free energies are
considered (4.2 vs 4.1 kcal mol-1), the situation is different for
the relative energy of the two transition states (3.2 kcal mol-1
,
PCM; 5.4 kcal mol-1 PCM + gas-phase correction). In the
transition state for C-H bond cleavage, the incipient six-
membered palladacycle presents 1,2-diaxial alkyl groups in
TSCH-a, while these groups are axial-equatorial in TSCH-b.
This introduces extra stabilization in the latter and may
contribute to reducing the energy difference between the two
activation barriers, leading finally to the observation of two
diastereoisomers. Nevertheless, according to the calculations,
32a is the major product of the reaction, and no BCB is likely
to be formed.
This result is to be compared to the outcome of the reaction
of aryl chloride 9 (Table 2, entry 5), where BCB formation is
preferred over indane formation. In the case of 9, the methyl
group can create a stabilizing agostic interaction with a C-H
bond, while preserving an acidic geminal C-H bond to be
deprotonated by the coordinated base. The situation is different
in aryl chloride 31a, where this dual behavior is possible only
at the terminal position of the isopropyl group, leading to indane
formation. To test the validity of our model for the regiochem-
istry of C-H activation, calculations were carried out on a
model system (9′) related to 9, where the ester group has been
substituted with CN in order to keep a system as close as
(25) (a) Gerwick, W. H.; Fenical, W. J. Org. Chem. 1981, 46, 22. (b) Torres,
R.; Villarroel, L.; Urzua, A.; Delle Monache, F.; Delle Monache, G.;
Gacs-Baitz, E. Phytochemistry 1994, 36, 249.
(26) (a) Cohen, M. L.; Bloomquist, W.; Gidda, J. S.; Lacefield, W.
J. Pharmacol. Exp. Ther. 1990, 254, 350. (b) Ohkawa, S.; Fukatsu,
K.; Miki, S.; Hashimoto, T.; Sakamoto, J.; Doi, T.; Nagai, Y.; Aono,
T. J. Med. Chem. 1997, 40, 559. (c) Tamura, K.; Kato, Y.; Ishikawa,
A.; Kato, Y.; Himori, M.; Yoshida, M.; Takashima, Y.; Suzuki, T.;
Kawabe, Y.; Cynshi, O.; Kodama, T.; Niki, E.; Shimizu, M. J. Med.
Chem. 2003, 46, 3083. (d) Shi, G. Q.; Dropinski, J. F.; Zhang, Y.;
Santini, C.; Sahoo, S. P.; Berger, J. P.; MacNaul, K. L.; Zhou, G.;
Agrawal, A.; Alvaro, R.; Cai, T.-q.; Hernandez, M.; Wright, S. D.;
Moller, D. E.; Heck, J. V.; Meinke, P. T. J. Med. Chem. 2005, 48,
5589.
9
J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010 10713

A R T I C L E S
Rousseaux et al.
yield (eq 2).6 Curiously, application of the conditions optimized
above for the formation of indanes (Table 4) to compound 48
gave an incomplete conversion, even after prolonged heating.
Table 5. Scope of Dihydrobenzofurans and (Aza)Indolines
Synthesized by Intramolecular C(sp3)-H Arylationa
The scope of this intramolecular C(sp3)-H arylation from
aryl chlorides is outlined in Table 5. Electron-donating (entry
1) and -withdrawing (entry 2) groups on the aromatic ring were
well tolerated and generated the corresponding dimethyldihy-
drobenzofurans in high yields. The reactions were highly
regioselective, affording exclusively the products of ring closure
at methyl C-H bonds over analogous methylene or methyne
positions (entries 3-5). Additionally, five-membered ring
closure occurred preferentially over six-membered ring forma-
tion in substrates containing multiple methyl substituents (entries
3 and 5). The compatibility of this method with various
functional groups was also investigated with aryl chlorides 60,
62, and 64. The reaction of protected ketone 60 led to product
61 in excellent yield (entry 6). Silyl-protected alcohols also
reacted nicely, as exemplified by aryl chloride 62 (entry 7).
Finally, a Lewis-basic tertiary amine was tolerated under the
reaction conditions, albeit leading to the dihydrobenzofuran
product in lower yield (entry 8). Of note is the absence of
product resulting from arylation at the more “activated” meth-
ylene C-H bond adjacent to the nitrogen heteroatom.27 Finally,
the intramolecular arylation of 2-chloroaniline-derived sub-
strates, giving rise to indolines and azaindolines, was also
examined (entries 9-13).7f,28 Gratifyingly, chlorobenzenes 66,
68, 70, and 72 and chloropyridine 74 furnished the expected
fused nitrogen heterocycles in high yields under the same
reaction conditions. Again, applying the conditions optimized
above for the synthesis of indanes, requiring a base/solvent
combination of K2CO3/DMF instead of Cs2CO3/PivOH/mesi-
tylene, gave incomplete substrate conversions. These results
indicate that, while the first set of conditions is better adapted
to the construction of carbocycles, the second is better suited
to the construction of heterocycles, reflecting the necessity to
fine-tune the catalytic system depending on the variations of
conformation and coordinating ability of the substrate.
4. Synthesis of Indanones. The C(sp3)-H arylation method-
ology was also extended to new substrate classes containing
other challenging functional groups. Accordingly, (o-chloro)ke-
tophenones were chosen due to the potential problematic
coordination of the carbonyl oxygen to the PdII intermediate
resulting from oxidative addition of the aryl halide. Gratifyingly,
when these substrates were submitted to the conditions previ-
ously developed (eq 2), the desired indanones were obtained in
good to excellent yields (Table 6). These substrates also appear
to be slightly more reactive, since the catalyst loading could be
decreased to 2 mol % without affecting the product yield (Table
6, entry 1). This may be due to the activation of the C-Cl bond
toward oxidative addition by the presence of an ortho electron-
withdrawing group. Aryl bromides may react under these
a Reaction conditions: Pd(OAc)2, 5 mol %; (Cy3PH)BF4, 10 mol %;
Cs2CO3, 1.1 equiv; PivOH, 30 mol %; mesitylene; 140 °C; 16 h.
b Yields of isolated products.
conditions, as demonstrated by the formation of 77 from 76b
in 98% yield (entry 2). The reaction of chloride 78, bearing a
n-propyl substituent, also furnished indanone 79 selectively but
in moderate yield (entry 3). In the presence of an acidic
(27) Campos, K. Chem. Soc. ReV. 2007, 36, 1069.
(28) Alternative synthesis of indolines via C(sp3)-H activation: Neumann,
J. J.; Rakshit, S.; Dro¨ge, T.; Glorius, F. Angew. Chem., Int. Ed. 2009,
48, 6892.
9
10714 J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010

Intramolecular C(sp3)-H Arylation from Aryl Chlorides
A R T I C L E S
Table 6. Scope of Indanones Synthesized by Intramolecular
C(sp3)-H Arylationa
Scheme 2. General Intramolecular C(sp3)-H Arylation Mechanisma
a
t
[Pd] ) Pd-PR3 complex; Y ) Bu or O-; Z ) no atom, CR2, N-R,
O, or CdO.
various aryl and heteroaryl chlorides is proposed (Scheme 2),
based on these and previous computational studies.5d,6 Oxidative
addition of the aryl chloride A to Pd0/PR3 followed by exchange
of the chlorine ligand for carbonate (Y ) O-) or pivalate (Y )
tBu) gives rise to palladium(II) complex C. From complex C,
the base-induced CMD mechanism effects the intramolecular
C-H bond cleavage to furnish five- or six-membered pallada-
cycle D, which, by reductive elimination, gives rise to the C-C
coupling product E. All experimental data in this and previous
studies from our groups concur with the preferential activation
of methyl C-H bonds over methylene and methyne C-H bonds
for the formation of a palladacycle (D) of a given size, even
when an activating group is present on the last two bond types.
In cases where several methyl groups are present on the arylation
substrate, the selectivity trend inversely correlates with the size
of palladacycle D: five-membered > six-membered > seven-
membered. For instance, the exclusive formation of BCB 10
from aryl chloride 9 (Table 2, entry 5) illustrates selectivities
both of methyl vs methyne C-H bond activation and of five-
vs six-membered palladacycle formation. Similarly, the exclu-
sive formation of dihydrobenzofuran 59 from aryl chloride 58
(Table 5, entry 5) illustrates selectivities both of methyl vs
methyne C-H bond activation and of six- vs seven-membered
palladacycle formation.
a Reaction conditions: Pd(OAc)2, 5 mol %; (Cy3PH)BF4, 10 mol %;
Cs2CO3, 1.1 equiv; PivOH, 30 mol %; mesitylene; 140 °C; 16 h.
b Yields of isolated products. c 2 mol
(Cy3PH)BF4.
% Pd(OAc)2/4 mol %
C(sp3)-H bond known to readily react under palladium(0)
catalysis to afford the product of R-arylation,29 this catalytic
system favors reactivity at the less activated but more sterically
accessible methyl C-H bond (entry 4). Substrate 82, containing
a trifluoromethyl functional group, reacted smoothly and regi-
oselectively to afford 83 in high yield (entry 5). The arylation
of 84, containing a fluorine atom R to the keto group,
successfully produced fluorinated indanone 85, albeit in moder-
ate yield (entry 6). Aryl chloride 86 demonstrates the preference
for arylation at a methyl C-H bond over arylation at typically
more reactive benzylic C(sp3)-H and aryl C(sp2)-H bonds
(entry 7).3,4 Indeed, indanone 87a was isolated as the major
product in 65% yield, together with the direct arylation product
87b in 32% yield, while no product resulting from arylation at
the benzylic C(sp3)-H bond was detected. These results (Table
6, entries 4, 5, and 7), combined with those for amine 64 (Table
5, entry 8) as well as with previous data,5d appear to indicate
that steric interactions contribute significantly to reaction site
selectivity, overriding electronic influences at the methylene
C(sp3)-H bond known to promote reactivity, such as the R
heteroatom effect30 in 64 and acidity in 80, 82, and 86.
Conclusion
The first efficient and general palladium-catalyzed intramo-
lecular C(sp3)-H arylation of aryl and heteroaryl chlorides has
been performed. This method enables the synthesis of a variety
of valuable cyclobutarenes, indanes, indolines, dihydrobenzo-
furans, and indanones. The use of aryl and heteroaryl chlorides
significantly improves the scope of C-H arylation compared
to the use of the corresponding bromides by facilitating access
to reaction substrates. Careful optimization studies have shown
that the palladium ligand and the base/solvent combination must
be fine-tuned according to the class of product. Overall, three
sets of reaction conditions employing PtBu3, PCyp3, or PCy3 as
the palladium ligand and K2CO3/DMF or Cs2CO3/pivalic acid/
mesitylene as the base/solvent combination gave access to the
five different classes of products described in this work. In total,
5. General Mechanistic Considerations. A simplified general
catalytic cycle for intramolecular C(sp3)-H arylation from
(29) (a) Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed. 2010,
49, 676. (b) Bellina, F.; Rossi, R. Chem. ReV. 2010, 110, 1082.
(30) For selected reviews: (a) Murahashi, S.-I.; Takaya, H. Acc. Chem.
Res. 2000, 33, 225. (b) Murahashi, S.-I. In Handbook of C-H
Transformations; Dyker, G.; Wiley-VCH: Weinheim, 2005; Vol. 2,
pp 319-326.
9
J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010 10715

A R T I C L E S
Rousseaux et al.
(C, H, O, N).37 The geometry optimizations were performed without
any symmetry constraint, followed by analytical frequency calcula-
tions to confirm that a minimum or a transition state had been
reached. The nature of the species connected by a given transition-
state structure was checked by optimization as minima of slightly
altered TS geometries along both directions of the transition-state
vector. Single-point PCM calculations38 in DMF of all the gas-
phase optimized structures yielded the solvent-corrected energy,
Esolv. The united atom topological model with UAKS radii was used,
and for DMF the parameters proposed by Stassen were used.39 For
the PCM calculations, the basis set for Pd was the same as in the
gas-phase calculations, but for all the other atoms a 6-31+G(d,p)
basis set was considered. Gas-phase Gibbs free energy corrections
Gcorr (P ) 1 atm, T ) 298 K) were considered for each species,
and the total Gibbs free energy G of each optimized structure was
taken as G ) Esolv + Gcorr. Throughout the text, only G values as
defined above are given.
more than 40 examples of C-H arylation have been performed
successfully. Selectivity issues in the C-H activation step have
been analyzed. When several C(sp3)-H bond types were present
in the chloro(hetero)arene substrate, the arylation was found to
occur regioselectively on primary C-H bonds vs secondary or
tertiary C-H bonds. In addition, when several primary C-H
bonds were present, selectivity trends correlated with the size
of the palladacyclic intermediate, with five-membered rings
being favored over six- and seven-membered rings. Regio- and
diastereoselectivity issues were studied computationally in the
prototypal case of indane formation. DFT calculations showed
that C-H activation is the rate-determining step and that the
creation of a Pd · · ·C-H agostic interaction, inducing increased
acidity of a geminal C-H bond, is a critical factor for the control
of regiochemistry.
Computational Details
Acknowledgment. This work was financially supported by
NSERC (CGS-D postgraduate fellowship to S.R.), the University
of Ottawa, ANR (programme blanc “AlCaCHA”), Re´gion Rhoˆne-
Alpes (Cluster 5), MESR (grant to C.P.), and CNRS (ATIP grant).
We also thank Johnson Matthey PLC (loan of palladium acetate),
Eli Lilly, Amgen, and Astra Zeneca Montreal for unrestricted
financial support. Christopher Whipp is kindly acknowledged for
the loan of certain (o-chloro)ketophenone starting materials.
The calculations were performed with the Gaussian 03 package31
at the B3PW91 level.32 Palladium was represented by the relativistic
effective core potential (RECP) from the Stuttgart group and the
associated basis set,33 augmented by a f polarization function.34
Phosphorus was represented by the RECP from the Stuttgart group
and the associated basis set,35 augmented by a d polarization
function.36 A 6-31G(d,p) basis set was used for all the other atoms
(31) Frisch, M. J.; et al. Gaussian 03, Revision E.01; Gaussian, Inc.:
Wallingford, CT, 2004.
Supporting Information Available: Full characterization of
all new compounds, detailed experimental procedures, NMR
spectra for target molecules, complete ref 31, Cartesian coor-
dinates, and electronic and Gibbs free energies for the systems
computed. This material is available free of charge via the
Internet at http://pubs.acs.org.
(32) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Perdew, J. P.;
Wang, Y. Phys. ReV. B 1992, 45, 13244.
(33) Andrae, D.; Haussermann, U.; Dolg, M.; Stoll, H.; Preuss, H. Theor.
Chim. Acta 1990, 77, 123.
(34) Ehlers, A. W.; Bohme, M.; Dapprich, S.; Gobbi, A.; Hollwarth, A.;
Jonas, V.; Kohler, K. F.; Stegmann, R.; Veldkamp, A.; Frenking, G.
Chem. Phys. Lett. 1993, 208, 111.
JA1048847
(35) Bergner, A.; Dolg, M.; Kuchle, W.; Stoll, H.; Preuss, H. Mol. Phys.
1993, 80, 1431.
(36) Hollwarth, A.; Bohme, M.; Dapprich, S.; Ehlers, A. W.; Gobbi, A.;
Jonas, V.; Kohler, K. F.; Stegmann, R.; Veldkamp, A.; Frenking, G.
Chem. Phys. Lett. 1993, 208, 237.
(37) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213.
(38) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. ReV. 2005, 105, 2999.
(39) Bo¨es, E. S.; Livotto, P. R.; Stassen, H. Chem. Phys. 2006, 331, 142.
9
10716 J. AM. CHEM. SOC. VOL. 132, NO. 31, 2010