Investigation of the mechanism of C(sp3)-H bond cleavage in Pd(0)-catalyzed intramolecular alkane arylation adjacent to amides and sulfonamides

Article abstract of DOI:10.1021/ja103081n

The reactivity of C(sp³)-H bonds adjacent to a nitrogen atom can be tuned to allow intramolecular alkane arylation under Pd(0) catalysis. Diminishing the Lewis basicity of the nitrogen lone pair is crucial for this catalytic activity. A range of N-methylamides and sulfonamides react exclusively at primary C(sp³)-H bonds to afford the products of alkane arylation in good yields. The isolation of a Pd(II) reaction intermediate has enabled an evaluation of the reaction mechanism with a focus on the role of the bases in the C(sp³)-H bond cleaving step. The results of these stoichiometric studies, together with kinetic isotope effect experiments, provide rare experimental support for a concerted metalation-deprotonation (CMD) transition state, which has previously been proposed in alkane C(sp³)-H arylation. Moreover, DFT calculations have uncovered the additional role of the pivalate additive as a promoter of phosphine dissociation from the Pd(II) intermediate, enabling the CMD transition state. Finally, kinetic studies were performed, revealing the reaction rate expression and its relationship with the concentration of pivalate.

Full text of DOI:10.1021/ja103081n

Published on Web 07/21/2010
Investigation of the Mechanism of C(sp3)-H Bond Cleavage in
Pd(0)-Catalyzed Intramolecular Alkane Arylation Adjacent to
Amides and Sulfonamides
Sophie Rousseaux,* Serge I. Gorelsky, Benjamin K. W. Chung, and Keith Fagnou
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of Ottawa,
10 Marie Curie, Ottawa, Ontario, K1N 6N5, Canada
Received April 12, 2010; E-mail: srous100@uottawa.ca
Abstract: The reactivity of C(sp3)-H bonds adjacent to a nitrogen atom can be tuned to allow intramolecular
alkane arylation under Pd(0) catalysis. Diminishing the Lewis basicity of the nitrogen lone pair is crucial for
this catalytic activity. A range of N-methylamides and sulfonamides react exclusively at primary C(sp3)-H
bonds to afford the products of alkane arylation in good yields. The isolation of a Pd(II) reaction intermediate
has enabled an evaluation of the reaction mechanism with a focus on the role of the bases in the C(sp3)-H
bond cleaving step. The results of these stoichiometric studies, together with kinetic isotope effect
experiments, provide rare experimental support for a concerted metalation-deprotonation (CMD) transition
state, which has previously been proposed in alkane C(sp3)-H arylation. Moreover, DFT calculations have
uncovered the additional role of the pivalate additive as a promoter of phosphine dissociation from the
Pd(II) intermediate, enabling the CMD transition state. Finally, kinetic studies were performed, revealing
the reaction rate expression and its relationship with the concentration of pivalate.
1. Introduction
since these systems do not benefit from catalyst-reactant
interactions through the π-system of the substrate, as opposed
to their sp2 hybridized counterparts.19
In recent years, significant progress has been made in the
establishment of transition-metal catalyzed transformations at
sp3carbon-hydrogenbondsfortheformationofcarbon-carbon,1-4
carbon-halide,5 carbon-boron,6 carbon-silicon,7 carbon-
oxygen,8 carbon-nitrogen,9 and carbon-sulfur10 bonds.11,12
Within the domain of carbon-carbon bond formation, mecha-
nistic investigations related to catalytic transformations at arene,
heteroarene, and alkene C(sp2)-H bonds have enabled chemists
to extend the boundaries of substrates that may be functionalized
to include a wide scope of synthetically useful motifs.13-16
However, the development of catalytic C-C bond formations
at nonacidic C(sp3)-H bonds has been less forthcoming,11,12,17,18
In the context of transition-metal catalyzed arylations at
C(sp2)-H bonds, the mechanism of C-H bond cleavage is
currently the subject of much discussion. Several groups have
(3) For examples of Pd(0)/Pd(II)-catalyzed transformations at C(sp3)-H
bonds for C-C bond formation: (a) Dyker, G. Angew. Chem., Int.
Ed. Engl. 1992, 31, 1023. (b) Dyker, G. J. Org. Chem. 1993, 58, 6426.
(c) Dyker, G. Angew. Chem., Int. Ed. Engl. 1994, 33, 103. (d) Baudoin,
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44, 1873. (f) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 4685. (g) Ren, H.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 3462. (h) Dong, C.-G.; Hu, Q.-S.
Angew. Chem., Int. Ed. 2006, 45, 2289. (i) Dong, C.-G.; Hu, Q.-S.
Org. Lett. 2006, 8, 5057. (j) Lafrance, M.; Gorelsky, S. I.; Fagnou,
K. J. Am. Chem. Soc. 2007, 129, 14570. (k) Niwa, T.; Yorimitsu, H.;
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Q.-S. Org. Lett. 2007, 9, 363. (o) Liron, F.; Knochel, P. Tetrahedron
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bonds for C-C bond formation: (a) Periana, R. A.; Mironov, O.;
Taube, D.; Bhalla, G.; Jones, C. J. Science 2003, 301, 814. (b) Zerella,
M.; Mukhopadhyay, S.; Bell, A. T. Chem. Commun. 2004, 1948. (c)
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H bonds for C-C bond formation: (a) Catellani, M.; Motti, E.; Ghelli,
S. Chem. Commun. 2000, 2003. (b) Zaitsev, V. D.; Shabashov, D.;
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3965. See also ref 1d.
9
10692 J. AM. CHEM. SOC. 2010, 132, 10692–10705
10.1021/ja103081n  2010 American Chemical Society

C(sp3)-H Bond Cleavage in Alkane Arylation
A R T I C L E S
validated a concerted metalation-deprotonation (CMD) pathway
for C-C bond formation at C(sp2)-H bonds with computational
and experimental studies.20,21 This mechanism features
C(sp2)-H deprotonation with concomitant (hetero)arene meta-
lation. Importantly, the concerted nature of this process opens
the door for similar reactivity at nonacidic C(sp3)-H bonds
which cannot react in a stepwise fashion.
a CMD mechanism, similar to arylations at C(sp2)-H bonds.
These findings highlight the possibility of a common mechanism
for C-C bond formations at C-H bonds. Computational results
point to the involvement of a three-center two-electron agostic
interaction22 between the Pd(II) center and the C(sp3)-H bond
being cleaved at the transition state (Figure 1).3j,v These
calculations also highlight the critical role of the basic additives
in the CMD transition state of the reaction, typically in the form
of carbonate or carboxylate derivatives. While computational
Due to the tolerance of a wide range of functional groups in
Pd(0) catalysis, our group3j,p,x and others have investigated its
use in C-C bond formation at C(sp3)-H bonds.3 The preference
for Pd(0) catalysis lies in the ability to use inexpensive,
commercially available (or easily accessible) aryl bromides and
chlorides as coupling partners. While the aryl halide remains
an element of preactivation in the coupling process, it also
enables the necessary change in metal oxidation state for C-H
bond cleavage to occur. Despite recent advances in Pd(0)-
catalyzed arylation at C(sp3)-H bonds,3 the scope of this
reactivity remains limited and is mirrored by our incomplete
mechanistic understanding of the C-H bond-cleaving event.
Recent efforts by our group3j as well as the groups of Clot and
Baudoin3v have led to a better understanding of this reactivity
which has been proposed, based on density functional theory
(DFT) calculations and KIE measurements, to proceed through
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for the formation of C-C and C-X bonds: (a) Kakiuchi, F.; Chatani,
N. AdV. Synth. Catal. 2003, 345, 1077. (b) Handbook of C-H
Transformations; Dyker, G., Ed.; Wiley-VCH: Weinheim, 2005. (c)
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A R T I C L E S
Rousseaux et al.
a Pd(0) catalyst as a tool to functionalize C(sp3)-H bonds
adjacent to oxygen by effectively bringing the catalyst in close
proximity to the aliphatic positions.3a To our knowledge, little
progress has since been reported for Pd(0)-catalyzed arylation
at aliphatic positions adjacent to heteroatoms,23 with no
examples of reactivity at C(sp3)-H bonds adjacent to nitrogen
being reported to date.12b,24 The apparent modest developments
in this area of C(sp3)-H bond functionalization can be attributed
to the R-heteroatom effect25 and the intrinsic hurdle it poses to
the desired reactivity. Indeed, heteroatom binding to Pd(II)
through its lone pair and subsequent ꢀ-hydride elimination can
lead to the overall unproductive dehalogenation of the starting
material, a well documented process in Pd(0)/Pd(II) catalysis
(Scheme 1).26
Herein, we describe (1) the establishment of a Pd(0)-catalyzed
intramolecular arylation reaction at aliphatic positions adjacent
to a nitrogen atom in amides and sulfonamides, (2) the rare
example of an isolated, catalytically active Pd(II) intermediate
in Pd(0)-catalyzed C-C bond formation at nonacidic C(sp3)-H
bonds, (3) mechanistic studies to evaluate the purpose of both
Figure 1. Transition states for concerted metalation-deprotonation (CMD)
in Pd(0)/Pd(II)-catalyzed C(sp3)-H bond functionalization
results accurately predict the reaction outcomes from the
proposed CMD transition state, few experimental studies have
been carried out to directly probe the mechanism of these
transformations. Furthermore, theoretical calculations related to
the mechanism of carbon-carbon bond formation at C-H bonds
under Pd(0) catalysis heavily rely on the assumption of a Pd(0)/
Pd(II) catalytic cycle being operative with C-H bond cleavage
occurring at a Pd(II) species. However, the isolation of a Pd(II)
catalytic intermediate and the direct observation of C-C bond
formation Via C-H bond cleavage from this intermediate have
not been previously reported.
Examples of arylation at aliphatic positions adjacent to a
heteroatom under Pd(0)/Pd(II) catalysis remain limited despite
the general perception of these C-H bonds as “activated”
toward transition-metal catalysis. Pioneering work by Dyker
demonstrated the use of oxidative addition of an aryl-halide to
(20) For selected reviews: (a) Biswas, B.; Sugimoto, M.; Sakaki, S.
Organometallics 2000, 19, 3895. (b) Pascual, S.; de Mendoza, P.;
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Dalton Trans. 2009, 5820. (d) Balcells, D.; Clot, E.; Eisenstein, O.
Chem. ReV. 2010, 110, 749.
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pathway in transition-metal-catalyzed transformations at C(sp2)-H
bonds: (a) Mota, A. J.; Dedieu, A.; Bour, C.; Suffert, J. J. Am. Chem.
Soc. 2005, 127, 7171. (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) Davies, D. L.; Donald, S. M. A.; Al-Duaij, O.;
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129, 6880. (h) Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett.
2008, 10, 2299. (i) Caron, L.; Campeau, L.-C.; Fagnou, K. Org. Lett.
2008, 10, 4533. (j) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am.
Chem. Soc. 2008, 130, 10848. (k) Lafrance, M.; Lapointe, D.; Fagnou,
K. Tetrahedron 2008, 64, 6015. (l) Pascual, S.; de Mendoza, P.; Braga,
A. A. C.; Maseras, F.; Echavarren, A. M. Tetrahedron 2008, 64, 6021.
(14) For selected reviews on catalytic transformations at C-H bonds for
the formation of C-C bonds: (a) Dyker, G. Angew. Chem., Int. Ed.
1999, 38, 1698. (b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV.
2002, 102, 1731. (c) Goj, L. A.; Gunnoe, T. B. Curr. Org. Chem.
2005, 9, 671. (d) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham,
Q. N.; Lazareva, A. Synlett 2006, 3382. (e) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. ReV. 2007, 107, 174. (f) Seregin, I. V.; Gevorgyan,
V. Chem. Soc. ReV. 2007, 36, 1173. (g) Satoh, T.; Miura, M. Chem.
Lett. 2007, 36, 200. (h) Campeau, L.-C.; Stuart, D. R.; Fagnou, K.
Aldrich. Chim. Acta 2007, 40, 35. (i) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (j) Daugulis,
O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (k)
McGlacken, G. P.; Bateman, L. M. Chem. Soc. ReV. 2009, 38, 2447.
(15) For selected reviews on palladium-catalyzed C-C bond formation at
C(sp2)-H bonds: (a) Campeau, L.-C.; Fagnou, K. Chem. Commun.
2006, 1253. (b) Li, B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949.
(16) For selected reviews on ruthenium- or rhodium-catalyzed C-C bond
formation at C(sp2)-H bonds: (a) Kakiuchi, F.; Murai, S. Acc. Chem.
Res. 2002, 35, 826. (b) Lewis, J. C.; Bergman, R. G.; Ellman, J. A.
Acc. Chem. Res. 2008, 41, 1013. (c) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. ReV. 2010, 110, 624.
¨
(m) Ozdemir, I.; Demir, S.; C¸ etinkaya, B.; Gourlaouen, C.; Maseras,
F.; Bruneau, C.; Dixneuf, P. H. J. Am. Chem. Soc. 2008, 130, 1156.
(n) Lie´gault, B.; Lapointe, D.; Caron, L.; Vlassova, A.; Fagnou, K. J.
Org. Chem. 2009, 74, 1826. (o) Lie´gault, B.; Petrov, I.; Gorelsky,
S. I.; Fagnou, K. J. Org. Chem. 2010, 75, 1047.
(22) For a review on agostic interactions in transition metal compounds:
Brookhart, M.; Green, M. L. H.; Parkin, G. Proc. Natl. Acad. Sci.
U.S.A. 2007, 104, 6908.
(23) For examples utilizing Dyker’s methodology: (a) Kim, H. S.; Gow-
risankar, S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2008, 49, 3858.
(b) Suau, R.; Lo´pez-Romero, J. M.; Rico, R. Tetrahedron Lett. 1996,
37, 9357.
(17) For selected reviews on transformations at C(sp3)-H bonds involving
an outer-sphere mechanism: (a) Davies, H. M. L.; Beckwith, R. E. J.
Chem. ReV. 2003, 103, 2861. (b) Davies, H. M. L.; Loe, Ø. Synthesis
2004, 2595. (c) Davies, H. M. L.; Manning, J. R. Nature 2008, 451,
417. (d) D´ıaz-Requejo, M. M.; Pe´rez, P. J. Chem. ReV. 2008, 108,
3379. (e) Zalatan, D. N.; Du Bois, J. Top. Curr. Chem. 2009, 1436.
(f) Collet, F.; Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 5061.
(g) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. ReV. 2010,
110, 704. See also ref 13d.
(18) For selected examples of stoichiometric inner-sphere reactions at
C(sp3)-H bonds: (a) Shilov, A. E.; Shteinman, A. A. Coord. Chem.
ReV. 1977, 24, 97, and references therein. (b) Labinger, J. A. J. Mol.
Catal. A: Chem. 2004, 220, 27, and references therein.
(24) For selected examples of transition-metal catalyzed transformations
at C(sp3)-H bonds adjacent to nitrogen for the formation of C-C
bonds, see ref 4a,d,f. For metal-catalyzed transformations proceeding
Via a radical mechanism: (a) Basle´, O.; Li, C.-J. Org. Lett. 2008, 10,
3661. (b) Yoshikai, N.; Mieczkowski, A.; Matsumoto, A.; Ilies, L.;
Nakamura, E. J. Am. Chem. Soc. 2010, 132, 5568.
(25) For a review: Murahashi, S.-I.; Takaya, H. Acc. Chem. Res. 2000, 33,
225.
(26) This pathway is indeed a well-known mechanism for the generation
of Pd(0) from the reaction of Pd(II) precatalysts with triethylamine in
other traditional cross-coupling reactions. As well, the undesired
dehalogenation of aryl halides Via this mechanism has been previously
documented in the development of palladium-catalyzed aryl amination
reactions as well as other palladium-catalyzed cross-coupling processes.
See: (a) Brenda, M.; Knebelkamp, A.; Greiner, A.; Heitz, W. Synlett
1991, 809. (b) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1348. (c) Hartwig, J. F.; Richards, S.;
Baran˜ano, D.; Paul, F. J. Am. Chem. Soc. 1996, 118, 3626.
(19) For selected reviews related to the mechanism of transformations at
C(sp3)-H bonds: (a) Ryabov, A. D. Chem. ReV. 1990, 90, 403. (b)
Shilov, A. E.; Shul’pin, G. B. Chem. ReV. 1997, 97, 2879. (c) Stahl,
S. S.; Labinger, J. A.; Bercaw, J. E. Angew. Chem., Int. Ed. 1998, 37,
2180. (d) Crabtree, R. H. J. Chem. Soc., Dalton Trans. 2001, 2437.
(e) Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507. (f) Crabtree,
R. H. J. Organomet. Chem. 2004, 689, 4083. (g) Lersch, M.; Tilset,
M. Chem. ReV. 2005, 105, 2471.
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C(sp3)-H Bond Cleavage in Alkane Arylation
A R T I C L E S
Scheme 1. Alkane C(sp3)-H Arylation Adjacent to a Heteroatom
arise from the formation of a problematic unreactive intermedi-
ate 2 (Scheme 3). Indeed, a 31P NMR spectrum of the crude
reaction mixture reveals a signal at 47 ppm, correlating with
previous literature reports for similar complexes.27
To further probe the lack of reactivity with amine 1, one-pot
reactions were performed with either amine 1 or 4 in the
presence of ether 3 in a 1:1 ratio. Ether 3 was chosen as a probe
for catalyst availability as it is a highly reactive substrate toward
alkane arylation (Scheme 4).28 While reaction of 3 in the
presence of 1 led to starting material recovery (eq 2), reactivity
was completely restored in the presence of amine 4 (eq 3). This
supports the hypothesis of catalyst sequestration in the former
reaction through the formation of intermediate 2 where the
nitrogen lone pair of the substrate coordinates the Pd(II) center,
inhibiting further reactivity. Similar experiments performed with
amine 1 (or 4) in the presence of ether 6 (eqs 4 and 5),
containing an electron-withdrawing group on the arene ring,
led to the same conclusion as to the problematic formation of
palladacycle 2. Nonetheless, in this situation some product of
alkane arylation 7 is observed in the presence of amine 1 (eq
4), highlighting the greater ease of oxidative insertion of
electron-deficient aryl bromides to Pd(0).
Scheme 2. Pd(0)-Catalyzed Arylation at C(sp3)-H Bonds Adjacent
to Amides and Sulfonamides
Hypothesizing that a less Lewis basic nitrogen was required
to avoid the undesired formation of palladacycle 2, we chose
amide 8 as a substrate for alkane arylation adjacent to a
heteroatom. A screening of reaction conditions (Vide infra)
uncovered that amide 8 reacts smoothly to afford the product
of alkane arylation 9 (Scheme 5).
Scheme 3. Initial Investigation of Alkane Arylation Adjacent to a
Heteroatom
Over the course of these studies, the base demonstrated an
important influence on the outcome of the reaction. Similar to
previous reports,3j,ab,21h,i,k,o both the carbonate and the pivalate
additives appear to play an important role (Table 1). When the
reaction was carried out in the presence of a stoichiometric
amount of Cs2CO3, an insoluble base under the reaction
conditions, 15% conversion to product was observed (Table 1,
entry 1). Changing the base to the more soluble CsOPiv led to
6% conversion (entry 2). However, when a stoichiometric
quantity of a carbonate base in combination with a catalytic or
stoichiometric amount of pivalate was used, complete conversion
of starting material was obtained with the desired product
isolated in yields greater than 83% (entries 4-5). In comparison,
the use of cesium carbonate as the stoichiometric base in
conjunction with a catalytic amount of acetic acid leads to a
significantly decreased product yield (entry 3).29
A further screen of alkali carbonates showed a surprising
counterion effect for the alkane arylation of N-methylamides
(Table 2). While the reaction with Na2CO3 provides no product
(Table 2, entry 1), the reaction with K2CO3 gives incomplete
conversions and significant amounts of dehalogenated starting
material as a reaction byproduct (entry 2). Rb2CO3 was found
to be the optimal base for the cyclization of 2-bromoaryl amides.
The use of this base was particularly successful in cases where
the pivalate and carbonate bases in the CMD mechanism, (4)
computational results to further elucidate the roles of both bases
in C(sp3)-H bond cleavage, and (5) kinetic studies to gain
insight into the factors that govern catalysis (Scheme 2).
2. Results and Discussion
(27) A signal (s) at 45 ppm was observed for the corresponding N-(2-
bromobenzyl)-N-dimethylamine derived complex, see: Bedford, R. B.;
Cazin, C. S. J. Organometallics 2003, 22, 987.
2.1. Reaction Development and Scope. Inspired by our report
of an intramolecular Pd(0)-catalyzed alkane arylation to generate
2,2-dialkyldihydrobenzofurans (Scheme 3, eq 1),3j a preliminary
screening of reaction conditions for the cyclization of amine 1
led to the recovery of starting material. Increasing the catalyst
loading to 20 mol % Pd(OAc)2 also did not afford the desired
product, and starting material 1 was recovered in 83% yield.
The latter result suggests that the proportional decrease in
starting material recovery with a higher catalyst loading might
(28) Under reaction conditions previously reported by our group for alkane
arylation of these types of ethers, substrate 3 is converted to
2,2-dialkyldihydrobenzofuran 5 in 97% yield and 6 is converted to 7
in 91% yield (see ref 3j).
(29) The nature of the intrinsic difference in reactivity of pivalate vs acetate
additives remains ellusive at this time. The significant decrease in yield
when acetic acid is used instead of pivalic acid as an additive in Pd(0)-
catalyzed transformations at C-H bonds has been previously observed
(see refs 3j and 21f,k). Efforts are underway to further understand
these observations.
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Scheme 4. Catalyst Sequestration Investigationsa
a
1
Reaction outcomes were determined by GC/MS using 1,3,5-trimethoxybenzene as an internal standard. Formation of 5 and 7 were confirmed by H
NMR.
Scheme 5. Arylation at a C(sp3)-H Bond Adjacent to a Nitrogen
Atom by Tuning the Lewis Basicity of the Heteroatom
Table 1. Effect of the Base and the Additive on the Alkane
Arylation of N-Methylamides
Entry
Base
Additive
Yield (%)a
1
2
3
4
5
Cs2CO3
CsOPiv
Cs2CO3
Cs2CO3
Cs2CO3
none
none
14b
5b
AcOH (30 mol %)
PivOH (30 mol %)
CsOPiv (110 mol %)
27b
83
88
a Isolated yields. b Determined by GC-MS using 1,3,5-trimethoxy-
benzene as an internal standard.
less sterically demanding substituents were present on the amide
nitrogen to minimize the undesired formation of dehalogenated
starting material. Indeed, lactam 11 was isolated in 56% yield
when Rb2CO3 was chosen as the source of base compared to
48% for Cs2CO3 (entries 3 and 4).
triarylphosphines demonstrates the importance of employing
electron-rich ligands to promote product formation (entries 5-6).
Illustrative examples of the scope of the reaction with respect
to substitution on both the aliphatic and aromatic portions of
the amide are shown in Table 4. 2-Bromo-N,N-dimethylben-
zamide 12 reacts smoothly to give product 13 in 76% isolated
yield (Table 4, entry 1). The alkane arylation of more sterically
encumbered cyclohexyl and iso-butyl substitued N-methyla-
mides proceeds in good yields, affording products 9 and 15 in
83% and 68% yield respectively (entries 2 and 3). Exclusive
selectivity is observed for arylation at methyl over methylene
or methyne C(sp3)-H bonds, which correlates with previous
experimental and computational results.3j,v The reaction of 16,
possessing a remote phenyl functionality, gives rise to isoin-
The formation of product 13 from amide 12 was studied with
a variety of ligands possessing different steric and electronic
properties (Table 3). While PCy3 ·HBF4 was found to be the
optimal ligand for good product yields (entry 1), interesting
steric and electronic trends were uncovered. The reaction appears
to be very sensitive to the steric bulk of the ligand. Indeed,
minimal product formation is observed in the presence of
PtBu3 ·HBF4 compared to the 76% yield of 13 when PCy3 ·HBF4
is used (entries 1-2). In addition, the significant difference in
yield for reactions employing electron-poor and electron-rich
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C(sp3)-H Bond Cleavage in Alkane Arylation
A R T I C L E S
Table 2. Optimization of the Source of Alkali Carbonates in Alkane
Arylation of N-Methylamides
Table 4. Scope of the Intramolecular Alkane Arylation of
N-Methylamidesa
Entry
Base
Yield (%)a
1
2
3
4
Na2CO3
K2CO3
Rb2CO3
Cs2CO3
0b
31
56
48
a Isolated yields. b Determined by GC-MS using 1,3,5-trimethoxy-
benzene as an internal standard.
Table 3. Effect of the Ligand on the Alkane Arylation of
N-Methylamides
Entry
Ligand
Yield (%)a
1
2
3
4
5
6
PCy3 ·HBF4
76b
5
13
17
9
PtBu3 ·HBF4
PtBu2Me·HBF4
CyJohnPhosc
P(p-F-C6H4)3
P(p-OMe-C6H4)3
24
a Determined by GC-MS using 1,3,5-trimethoxy-benzene as an
internal standard. b Isolated yield. c CyJohnPhos ) 2-(Dicyclohexyl-
phosphino)biphenyl.
doline 17 albeit in lower yield (entry 4). On the aromatic portion
of the amide, the presence of an electron-donating group leads
to slightly attenuated reactivity. For example, methoxy-
substituted 2-bromoaryl amides 10 and 18 generate products
11 and 19 in 56% and 44% yield respectively (entries 5 and 6).
Fluorinated arene 20 also reacts well, yielding product 21 in
70% (entry 7).
a Isolated yields.
The functionalization of C-H bonds adjacent to other
electron-poor nitrogen-containing functional groups was also
investigated. Sulfonamides were found to be compatible sub-
strates for this transformation when Cs2CO3 was used as a base
(Table 5). Indeed, aryl bromide 22 provides product 23 in 62%
yield (entry 1). Other simple alkane substituents on the
sulfonamide are tolerated under the reaction conditions as
exemplified by n-butyl-substituted sulfonamide 24 and dimeth-
ylsulfonamide 26 (entries 2 and 3). The presence of functional
groups such as an ether (entry 4) and a TIPS-protected alcohol
(entry 5) does not hinder product formation as 29 and 31 are
obtained in moderate yields (59% and 47% respectively).
Finally, Lewis basic functional groups such as amines are well
tolerated as exemplified by the formation of product 33 in 71%
yield (entry 6).
An intramolecular competition reaction was designed to probe
the preference of the catalyst system for reactivity at sp2 vs sp3
C-H bonds. When 2-bromo-N-methyl-N-phenylbenzamide 34
was exposed to the standard reaction conditions for arylation
at aliphatic positions, exclusive selectivity for reaction at the
arene C-H bond was observed, with product 35 being obtained
in 88% yield (Scheme 6). A similar result was obtained for the
corresponding sulfonamide 36, which exclusively gave the
product of direct arylation 37 in 83% yield. The complete
selectivity for C(sp2)-H arylation, despite the formation of a
seven-membered palladacycle in this reaction pathway, com-
pared to alkane arylation Via a six-membered palladacycle, is
dictated by more facile catalyst-substrate interactions through
the π-system of the arene.
2.2. Mechanistic Studies. Initial computational evaluations of
intramolecular Pd(0)-catalyzed alkane arylation reactions have
begun to shed light on the mechanism of this reaction.3j,v
Although computational results correlate with experimental
observations, little direct experimental evidence pertaining to
the mechanism of C-H bond cleavage exists. Such mechanistic
knowledge is required to facilitate further reaction development
and catalyst design in this expanding area of research. To this
effect, both mechanistic and kinetic experiments were devised
to further our awareness of the parameters that guide reactivity
in arylation reactions at aliphatic positions adjacent to heteroatoms.
2.2.1. Kinetic Isotope Effect. An intramolecular kinetic
isotope effect (KIE) study was conducted with substrate 38,
designed to observe the preference of the catalyst for C-H(D)
bond cleavage without the bias of potential amide rotamers
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A R T I C L E S
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Scheme 7. Intra- and Intermolecular Kinetic Isotope Effects
Table 5. Scope of the Intramolecular Alkane Arylation of
N-Methylsulfonamides
Scheme 8. General Catalytic Cycle for the Alkane Arylation of
N-Methylamides
that the C-H(D) bond is cleaved during the rate-determining
step of the reaction.31,32
a Isolated yields.
2.2.2. Isolation and Characterization of a Catalytically
Competent Pd(II) Intermediate. The catalytic cycle for alkane
arylation can be simplified to three steps: (1) oxidative addition
of the aryl bromide to the Pd(0) catalyst, (2) C-H bond
cleavage, and (3) reductive elimination of the desired product
from the Pd(II) intermediate to regenerate the Pd(0) species
(Scheme 8). Oxidative addition of aryl halides to Pd(0)-
phosphine complexes and reductive elimination from Pd(II)
complexes to form carbon-carbon bonds are well documented
reactions whose mechanisms have been extensively studied.33,34
However, little experimental work has been done concerning
Scheme 6. Intramolecular Competition for Preferential Arylation at
sp2 vs sp3 Positions
(31) The larger KIE value for intermolecular Vs intramolecular competitions
is atypical and is not fully understood at this time although errors on
side-by-side intermolecular competitions are intrinsically larger due
to the nature of the experiment. In any case, the conclusion of a rate-
limiting C-H bond cleaving event remains.
(32) See Supporting Information for further details on kinetic experiments.
(33) For selected mechanistic studies on oxidative addition of Pd(0) to aryl
halides: (a) Amatore, C.; Pflu¨ger, F. Organometallics 1990, 9, 2276.
(b) Hartwig, J. F.; Fre´de´ric, P. J. Am. Chem. Soc. 1995, 117, 5373.
(c) Amatore, C.; Bucaille, A.; Fuxa, A.; Jutand, A.; Meyer, G.; Ntepe,
A. N. Chem.sEur. J. 2001, 7, 2134. (d) Amatore, C.; Jutand, A.;
Thuilliez, A. J. Organomet. Chem. 2002, 643-644, 416. (e) Barrios-
Landeros, F.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 6944. (f)
Barrios-Landeros, F.; Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc.
2008, 130, 5842. (g) Barrios-Landeros, F.; Carrow, B. P.; Hartwig,
J. F. J. Am. Chem. Soc. 2009, 131, 8141, and references therein.
(34) For selected mechanistic studies on reductive elimination for C-C
bond formation:(a) Culkin, D. A.; Hartwig, J. F. Organometallics 2004,
23, 3398. (b) Racowski, J. M.; Dick, A. R.; Sanford, M. S. J. Am.
Chem. Soc. 2009, 131, 10974.
(Scheme 7A).30 The kH/kD value of 3.4 is indicative of a
kinetically significant C-H bond-cleaving reaction step. To
determine the importance of C-H bond cleavage in the overall
reaction rate, an intermolecular KIE experiment was also carried
out (Scheme 7B). A side-by-side comparison of reaction rates
for 2-bromo-N,N-dimethylbenzamide 12 and d6-2-bromo-N,N-
dimethylbenzamide d6-12 led to a kH/kD value of 6.5 indicating
(30) Signals for both amide conformations do not coalesce even at 120 °C
1
on the H NMR time scale.
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C(sp3)-H Bond Cleavage in Alkane Arylation
A R T I C L E S
Figure 2. ORTEP plot of [(PCy3)2Pd(C6H4CONMe2)(Br)] 40. All H atoms
have been omitted for clarity. Anisotropic displacement ellipsoids are shown
at the 50% probability level. Selected bond lengths (Å) are indicated on
the diagram.
the mechanism of C-H bond cleavage at aliphatic positions as
well as the role of the bases involved in this elementary reaction
step.
Figure 3. Initial formation of product 13 over time under different catalytic
conditions: Pd(OAc)2 (5 mol %) + PCy3 ·HBF4 (10 mol %) (Conditions
A, red [), [(PCy3)2Pd(C6H4CONMe2)(Br)] 40 (5 mol %) (Conditions B,
green 9), Pd(PCy3)2 (5 mol %) (Conditions C, blue 2) and Pd(PCy3)2 (5
mol %) without pivalic acid (Conditions D, black b). The data points for
product concentrations are the average of two runs and were determined
by GC/MS using 1,3,5-trimethoxybenzene as an internal standard.
To examine this catalytic step, Pd(II) intermediate 40 resulting
from oxidative insertion of 2-bromo-N,N-dimethylbenzamide 12
to LnPd(0) was prepared. Reaction of 1.5 equiv of 12 with
Pd(PCy3)2 in benzene at room temperature for 24 h led to the
isolation of air-stable Pd(II) complex 40 in 70% yield (eq 6).35
Similarly, the Pd(II) intermediate 41, resulting from oxidative
insertion of Pd(PCy3)2 to 2-bromo-N,N-dimethylbenzenesulfona-
mide 26, was also prepared in 76% yield (eq 7). The structure
of 40 was confirmed by X-ray crystallography and revealed a
four-coordinate square planar complex containing two trans
PCy3 ligands (Figure 2). No significant interactions between the
amide moiety and the Pd(II) center are present in the structure
as the distances between Pd(1) and O(1) or N(1) are 3.09 and
4.50 Å respectively.
the standard reaction conditions, indicating that 40 is a catalyst
precursor for the reaction (eq 8).
2.2.3. Comparative Reaction Kinetics for Different
Catalyst Systems. The kinetic competence of [(PCy3)2Pd(C6H4-
CONMe2)(Br)] 40, as well as other Pd catalyst systems, for
product formation was evaluated by following the reaction
kinetics. The appearance of product over time was monitored
by GC/MS using 1,3,5-trimethoxybenzene as an internal stan-
dard.32 Comparable rates of product formation were observed
using three catalyst systems (Figure 3): the standard catalyst
combination of Pd(OAc)2 (5 mol %) and PCy3 ·HBF4 (10 mol
%) (Conditions A), [(PCy3)2Pd(C6H4CONMe2)(Br)] 40 (5 mol
%) (Conditions B), and the commercially available Pd(0) catalyst
Pd(PCy3)2 (5 mol %) (Conditions C). These comparable rates
indicate the absence of a catalyst initiation period to generate
Pd(0) from Pd(OAc)2 under the standard reaction conditions
(Conditions A) since rates of catalysis are comparable to those
when Pd(0) systems are used (Conditions C). Moreover, these
results demonstrate the ability of [(PCy3)2Pd(C6H4CONMe2)-
(Br)] 40 to rapidly generate the active catalytic species for the
CMD reaction step. A control reaction using Pd(PCy3)2 in the
absence of a pivalate source (Conditions D) emphasizes once
again the crucial role of this base for catalysis to occur.
Prior to probing the mechanism of C-H bond cleavage with
[(PCy3)2Pd(C6H4CONMe2)(Br)] 40, its nature as a catalytically
relevant intermediate was first established to shed any potential
doubt that it may represent an off-cycle unreactive catalytic
species. To this effect, 2-bromo-N,N-dimethylbenzamide 12 was
subjected to the standard reaction conditions, replacing Pd(OAc)2
(5 mol %) and PCy3 · HBF4 (10 mol %) with [(PCy3)2Pd-
(C6H4CONMe2)(Br)] 40 (5 mol %). The product of alkane
arylation 13 was obtained in 67% yield, compared to 76% under
(35) Stambuli, J. P.; Incarvito, C. D.; Bu¨hl, M.; Hartwig, J. F. J. Am. Chem.
Soc. 2004, 126, 1184.
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A R T I C L E S
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Table 6. Stoichiometric Studies with [(PCy3)2Pd(Ar)(Br)] 40 and 41
To Probe the Role of Pivalate and Carbonate Bases in the CMD
Pathway
and characterization of a Pd(II) intermediate of general structure
[(PCy3)nPd(Ar)(OPiv)] and its evaluation as a catalytically and
kinetically competent species should be investigated. Unfortu-
nately all attempts at synthesizing this potential catalytic
intermediate were unsuccessful, leading us to examine its role
through the use of computational studies.
2.3.1. Methods. DFT calculations were performed using the
Gaussian 03 program.37 Stationary points on the potential energy
surface were obtained using the B3LYP exchange-correlation
functional38,39 with the TZVP basis set40 for all atoms except
Pd. For Pd, the DZVP basis set41 was used. Tight SCF
convergence criteria (10-8 a.u.) were used for all calculations.
The converged wave functions were tested to confirm that they
correspond to the ground-state surface. Harmonic frequency
calculations were used to determine the nature of the stationary
points. The analysis of two- and three-center bond orders were
carried out using the AOMix program.42 Solvation energies of
species in toluene were calculated using the gas-phase geom-
etries and the PCM implicit solvent solvation model43 with the
UFF atomic radii. Gibbs free energies of different species in
toluene were estimated by addition of the solvation energy
∆Gsolv to gas-phase Gibbs free energies.
a Determined by 1H NMR using 1,3,5-trimethoxybenzene as an
internal standard.
2.3.2. Pivalate As a Promoter of Phosphine Dissociation. KIE
experiments and mechanistic data support a turnover-limiting
C(sp3)-H bond cleavage Via a base-enabled CMD transition
state (Vide supra). DFT calculations were performed to deter-
mine the ground state energies of various potential Pd(II)
intermediates and CMD transition states (Figures 4-5).44
Intermediates III and IV, resulting from PMe3 dissociation from
II and amide coordination through either the oxygen or nitrogen
atom, are respectively 1.7 and 4.8 kcal/mol higher in energy
than structure II. In intermediate IV, the nitrogen lone pair is
no longer in conjugation with the amide carbonyl due to its
coordination to Pd(II). κ2-Acetate complex I is 0.6 kcal/mol
lower in energy than structure II. Therefore, prior to the rate-
limiting CMD process (Figure 6), the thermodynamic equilib-
rium shifts toward intermediate I, a direct precursor to the inner-
sphere pivalate (acetate for computational purposes)-enabled
CMD TS.45 The free energy of the CMD transition state TS-I
is 29.1 kcal/mol and is slightly higher than the free energy of
the corresponding transition state for intramolecular alkane
arylation in the synthesis of dihydrobenzofurans (27.0 kcal/
mol).3j Similar to previous reports,3j,v an agostic three-center
two-electron interaction was found at the transition state between
the Pd(II) center and the C-H σ bond being cleaved (Figure
6).
2.2.4. Stoichiometric Mechanistic Studies with [(PCy3)2Pd-
(Ar)(Br)] 40 and 41. To evaluate the role of both the pivalate
and carbonate bases in the proposed concerted metalation-
deprotonation (CMD) pathway for C(sp3)-H bond cleavage,
stoichiometric studies with [(PCy3)2Pd(Ar)(Br)] 40 and 41 were
carried out. Complexes 40 and 41 were chosen since they allow
for a direct probe of the C-H bond cleaving step. The results
of these stoichiometric studies, performed in mesitylene at 150
°C for 4 h with various bases and additives, are highlighted in
Table 6.
Minimal or no product formation is observed in the absence
of both forms of base (entries 1 and 5) as well as with the use
of a strong carbonate base (entries 2 and 6). The stoichiometric
reaction of complex 40 and 41 with CsOPiv generates products
13 and 27 in low yields (28% and 35% respectively) (entries 3
and 7). These results correlate with those reported in catalytic
studies (Table 1). However, the modest reactivity observed with
CsOPiv in the presence of stoichiometric palladium leads us to
further examine our working hypothesis for the combined use
of catalytic pivalate and stoichiometric carbonate in these
reactions.21f The use of both bases in catalytic transformations
at C-H bonds that proceed Via a CMD transition state has been
rationalized by the requirement for a soluble basic species
responsible for deprotonation (pivalate) and an insoluble proton
sink responsible for sequestration of H+ and pivalate regenera-
tion (carbonate). The latter should therefore not be required for
product formation under stoichiometric conditions. Finally, the
reaction of [(PCy3)2Pd(Ar)(Br)] 40 and 41 with Cs2CO3 (10.0
equiv) and CsOPiv (3.0 equiv) in mesitylene at 150 °C for 4 h
gave 96% and 80% yields of alkane arylation products 13 and
27 respectively (entries 4 and 8).36 These results not only support
the required combination of carbonate and pivalate for produc-
tive reactions (see Table 1) but also underline the complexity
of the role(s) played by these species in the CMD pathway.
2.3. Computational Studies. To gain additional understanding
of the role of pivalate in the CMD mechanism, the isolation
(37) Frisch, M. J. Gaussian 03, revision C.02; Gaussian, Inc.: Wallingford,
CT, 2004.
(38) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(39) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785.
(40) Schafer, A.; Huber, C.; Ahlrichs, R. J. Chem. Phys. 1994, 100, 5829.
(41) Godbout, N.; Salahub, D. R.; Andzelm, J.; Wimmer, E. Can. J. Chem.
1992, 70, 560.
(42) (a) Gorelsky, S. I.; Lever, A. B. P. J. Organomet. Chem. 2001, 635,
187. (b) Gorelsky, S. I. AOMix: software for the MO Analysis, revision
6.35; University of Ottawa: Ottawa, 2007.
(43) Barone, V.; Cossi, M.; Tomasi, J. J. Comput. Chem. 1998, 19, 404.
(44) PCy3 was modeled as PMe3 and pivalate as acetate to minimize
computational costs.
(45) While this discussion does not take into consideration the generation
of II (or III) from I, it is assumed that any transition states (or
other intermediates) along these pathways are not energetically
significant in the global reaction scheme since KIE studies reveal
that C(sp3)-H bond cleavage is involved in the rate-determining
step (Section 2.1).
(36) A 10-fold amount of carbonate and pivalate were used to mimic the
relative base/palladium ratios that are found under the standard catalytic
conditions. See Supporting Information for further experimental details.
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C(sp3)-H Bond Cleavage in Alkane Arylation
A R T I C L E S
Figure 4. Gibbs free energies (at 298 K in toluene) of potential Pd(II) intermediates prior to the CMD transition state. Hydrogen atoms have been omitted
for clarity.
Figure 5. Observation of PCy3 dissociation from Pd(II) intermediate 41 (a) in the absence of CsOPiv and (b) in the presence of 6 equiv of CsOPiv.
Complex 41 and CsOPiv (if added) were stirred in mesitylene at 120 °C for 20 min after which time 31P NMR spectra were collected at 60 °C.
To lend additional support to the hypothesis that pivalate plays
a crucial role in promoting phosphine dissociation from Pd(II)
to increase the concentration of the reactive intermediate,
stoichiometric reactions were performed with Pd(II) intermediate
41. Side-by-side reactions of complex 41 and CsOPiv (if added)
in mesitylene at 120 °C were carried out to observe the effect
of added CsOPiv on the concentration of free PCy3 in solution.
The reaction outcome was monitored by 31P NMR (Figure 5).
In the absence of CsOPiv, starting material 41 remains almost
exclusively the sole product in solution (Figure 5a). Trace
amounts of PCy3 and proposed intermediate 42 could be
detected. When the same experiment is performed in the
presence of CsOPiv (6 equiv), very little starting complex 41
remains after 20 min at 120 °C. Instead, a significant amount
of free PCy3 can be detected with the simultaneous appearance
of a second signal at 43.7 ppm, which is proposed to correspond
to κ2-pivalate complex 43 (Figure 5b). The relative concentra-
tions of Pd(II) intermediates observed under these different
reaction conditions support the results of DFT calculations in
Figure 4 and provide additional evidence for the role of pivalate
as a promoter of phosphine dissociation.
2.3.3. Role of Carbonate in Product Formation. Stoichio-
metric reactions revealed a lack of reactivity in the presence of
only Cs2CO3 or CsOPiv as a source of base compared to a near
quantitative product yield when both were added to the reaction
mixture (Table 6, section 2.2.4). These results appear to indicate
that both carbonate and pivalate play an active role in C-H
bond cleavage. This apparent synergy has been investigated
through the use of DFT calculations which reveal a highly
reactant-biased potential energy surface for the C(sp3)-H bond
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A R T I C L E S
Rousseaux et al.
Figure 6. Gibbs free energies (at 298 K in toluene) of the formation of κ1-acetic acid complex VI from intermediate I Via CMD transition state TS-I
featuring an agostic Pd(II)...C-H interaction. Selected bond distances (Å) are indicated. Hydrogen atoms that do not participate in the CMD process have
been omitted for clarity.
Scheme 9. Proposed Role for the Carbonate Base As the Driving Force of the Reaction by Making C(sp3)-H Bond Cleavage Irreversible
cleaving step (Figure 6). The κ1-pivalic (acetic) acid complex
VI, resulting from pivalate (acetate)-enabled CMD transition
state TS-I, is a highly energetic ground state structure (∆G )
18.2 kcal/mol relative to the reactant complex I). Unless H+ is
quickly removed from the pivalic (acetic) acid ligand, VI can
readily revert to the reactant complex I. Carbonate, or other
bases, may be required as a driving force for the reaction, by
sequestering H+ and pushing intermediate VI toward the desired
product (Scheme 9). These conclusions are consistent with the
experimental observation of low product yields in stoichiometric
studies employing pivalate exclusively as the base (Table 6,
entries 3 and 7).
These results, combined with previous experimental studies
(see section 2.2.4), highlight the importance of both basic species
in Pd(0)-catalyzed arylations at C(sp3)-H bonds. Not only does
the pivalate act as the base which enables C-H bond cleavage,
but it also increases the concentration of Pd(II) reactive
intermediate I prior to the CMD reaction step while also
preventing reaction inhibition by excess free phosphine in
solution. The carbonate base in this system may also have a
more active role in C(sp3)-H bond cleavage than previously
believed by favoring product formation through the irreversible
deprotonation of the post-CMD catalytic intermediate VI.
2.3.4. Effect of Nitrogen Basicity in C(sp3)-H Bond
Cleavage. Catalyst sequestration studies (Scheme 4) and 31P
NMR experiments (Scheme 3) suggest the formation of a
problematic intermediate 2, featuring nitrogen coordination to
the Pd(II) center, as an explanation for the observed lack of
reactivity with more Lewis basic nitrogen-containing substrates.
While the generation of intermediate 2 effectively blocks product
formation, it is interesting to investigate whether the change in
electron density on the heteroatom affects other aspects of C-H
Further computational studies revealed that pivalate (acetate)
also plays a crucial role in blocking potential catalysis inhibition
by excess phosphine in the reaction medium. A computational
minimum for a bisphosphine κ1-acetate complex V was not
found when the CMD transition state (TS-I) was collapsed back
to starting material. Instead, the structure invariably reverts to
κ2-acetate intermediate I (Figure 6). This suggests that V does
not participate in the catalytic cycle.
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C(sp3)-H Bond Cleavage in Alkane Arylation
A R T I C L E S
Figure 7. Gibbs free energies (at 298 K in toluene) of potential Pd(II) intermediates prior to the CMD transition state TS-VIII in the arylation of a
C(sp3)-H bond adjacent to an amine. Selected bond distances (Å) in the CMD transition state are indicated. Hydrogen atoms that do not participate in the
CMD process have been omitted for clarity.
bond cleavage to design future reaction substrates. To this effect,
DFT calculations have been performed to investigate the alkane
arylation of 2′-bromobenzyl-N,N-dimethylamine (Figure 7).
When the potential energy surfaces for C(sp3)-H bond
cleavage in amine and amide substrates are compared, the
explanation for the lack of reactivity with amine derivatives
becomes apparent. In amide derivatives, κ2-acetate complex I
is the direct precursor to CMD transition state TS-I, which is
29.1 kcal/mol uphill from this intermediate (Figure 6). However,
in amine derivatives, κ2-acetate complex VII is not the most
stable ground state structure; κ1-acetate complex VIII is 8.1
kcal/mol lower in energy and is the precursor to CMD transition
state TS-VIII. This increase in the ground state stability of the
intermediate prior to C-H bond cleavage leads to a significantly
higher energy barrier for this transition state (38.4 kcal/mol).
A second CMD transition state TS-VII for C(sp3)-H bond
cleavage from κ2-acetate complex VII can also be found and is
38.8 kcal/mol higher in energy than the most stable ground state
structure VIII. TS-VII and TS-VIII differ in the orientation of
the lone pair and the substituents on the nitrogen atom (Figure
7).
electron interaction between the Pd(II) atom and the C-H σ
bond being cleaved. Similar bond lengths are observed for the
atoms that participate in the concerted metalation-deprotonation
process indicating that the degree of bond formation/bond
cleavage in all three transition states is comparable and that
increased nitrogen atom basicity does not affect the nature of
the transition state for C(sp3)-H bond cleavage.
Combined with experimental observations (see section 2.1,
Schemes 3-4), the results of this DFT study support the
conclusion that the electron density on the nitrogen atom does
not affect C(sp3)-H bond cleavage, or the properties of the C-H
bond, but rather leads to more stable palladium-substrate
interactions, rendering the energy barrier for C-H bond cleavage
too high.
2.4. Kinetic Studies: Reagent Orders. Efforts in future
catalyst and reaction design are best focused on accelerating
the turnover limiting step of a catalytic cycle. To establish the
reaction rate expression, kinetic studies were performed to
determine the order in each component in the reaction of
2-bromo-N,N-dimethylbenzamide 12.32 Initial rates were deter-
mined for reactions where the concentrations in starting material
(Figure 8), palladium (Figure 9), ligand (Figure 10), and pivalate
(Figure 11) were modified independently.
These two possible CMD transition states (TS-VII and TS-
VIII) exhibit features similar to those of TS-I (Figures 6 and
7). TS-VII and TS-VIII feature an agostic three-center two-
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A R T I C L E S
Rousseaux et al.
Figure 8. Dependence of the initial rate on the concentration of 2-bromo-
N,N-dimethylbenzamide 12 (SM) (0.10-0.40 M). Conditions: [Pd(PCy3)2]
) 1.0 × 10-2 M and [PivOH] ) 6.0 × 10-2 M in 2.9 mL of mesitylene
with 0.872 mmol of Cs2CO3 at 150 °C. Yields were determined by GC/MS
using 1,3,5-trimethoxybenzene as an internal standard. Data labels represent
12/palladium ratios.
Figure 10. Dependence of the initial rate on the concentration of
PCy3 ·HBF4 (2.0 × 10-2-1.2 × 10-1 M). Conditions: [2-bromo-N,N-
dimethylbenzamide 12] ) 0.20 M, [Pd(OAc)2] ) 1.0 × 10-2 M, and
[PivOH] ) 6.0 × 10-2 M in 2.9 mL of mesitylene with 0.872-1.16 mmol
of Cs2CO3 at 150 °C. Yields were determined by GC/MS using 1,3,5-
trimethoxybenzene as an internal standard. Data labels represent phosphine/
palladium ratios.
Figure 9. Dependence of the logarithm of the initial rate on the logarithm
of the concentration of Pd(PCy3)2 (5.0 × 10-3-2.0 × 10-2 M). Conditions:
[2-bromo-N,N-dimethylbenzamide 12] ) 0.20 M and [PivOH] ) 6.0 ×
10-2 M in 2.9 mL of mesitylene with 0.872 mmol of Cs2CO3 at 150 °C.
Yields were determined by GC/MS using 1,3,5-trimethoxybenzene as an
internal standard. Data labels represent the catalyst loading.
Figure 11. Dependence of the initial rate on the concentration of CsOPiv
(5.0 × 10-3-2.0 × 10-1 M). Conditions: [2-bromo-N,N-dimethylbenzamide
12] ) 0.20 M and [Pd(PCy3)2] ) 1.0 × 10-2 M in 2.9 mL of mesitylene
with 0.872 mmol of Cs2CO3 at 150 °C. Yields were determined by GC/MS
using 1,3,5-trimethoxybenzene as an internal standard. Data labels represent
pivalate/palladium ratios.
Plotting the initial rate against the concentration of 2-bromo-
N,N-dimethylbenzamide 12 reveals that the reaction is zeroth-
order in substrate (Figure 8), indicating that oxidative addition
is not rate-determining. A plot of the logarithm of initial rates
versus the logarithm of the concentration in palladium reveals
a slope of 1.00 for catalyst loadings of 2.5, 5, 7.5, and 10 mol
% (Figure 9). Pd(PCy3)2 was used as the palladium source
instead of Pd(OAc)2 to avoid any potential rate effects due to
the presence of additional acetate ions in solution. The slope of
1.00 is indicative of a first-order rate dependence in catalyst
loading. Next, the effect of excess phosphine on the rate was
examined. The plot of initial rates versus the concentration of
phosphine uncovers that PCy3/Pd ratios in excess of 2:1, i.e.
the standard catalytic conditions, do not inhibit catalysis (Figure
10). This correlates with computational results suggesting that
pivalate coordination to Pd(II) may prevent inhibition of the
CMD step through phosphine coordination to Pd(II) (see section
2.3.3).
The dependence of the initial rate on the concentration of
pivalate changes from first- to zeroth-order, revealing saturation
kinetics when pivalate/palladium ratios exceed 3:1. Figure 11
also reveals an optimal rate acceleration at ∼30 mol % pivalate
additive (6:1 pivalate/palladium), further validating the selection
of this amount of pivalic acid additive during reaction develop-
ment (section 2.1).
From this kinetic data, the rate expression for the formation
of isoindolinones by alkane arylation under standard catalytic
conditions can be expressed as
rate ) k[Pd][PivO-]n
n ) 1 when PivO-/Pd < 3:1
n ) 0 when PivO-/Pd > 3:1
2.5. Proposed Catalytic Cycle. Based on these mechanistic,
kinetic, and computational results, a clearer picture of the
catalytic cycle for arylation at C(sp3)-H bonds emerges
(Scheme 10). Oxidative addition of the desired aryl halide
starting material to Pd(0) occurs rapidly under the reaction
Finally, the effect of pivalate concentrations on initial rates
was also examined. A linear increase in initial rate is observed
for 0.5:1, 1:1, 2:1, and 3:1 pivalate/palladium ratios (Figure 11).
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C(sp3)-H Bond Cleavage in Alkane Arylation
Scheme 10. Proposed Catalytic Cycle
A R T I C L E S
basic additives in catalytic transformations at C-H bonds. The
notion of multiple roles for a single additive at the metal center
should influence future reaction development in this field.
4. Experimental Section
Representative Procedure for the Alkane Arylation of
N-Methylamides. A Radley test tube equipped with a magnetic
stir bar and a rubber septum was flame-dried under vacuum and a
constant flow of argon. Once the test tube was cooled to room
temperature, the vacuum was removed. Subsequent manipulations
were performed under constant argon flow unless noted otherwise
to give reproducible results. The flame-dried test tube was brought
into the glovebox, and dry Rb2CO3 (201 mg, 0.872 mmol, 1.5 equiv)
was added after which it was brought back onto the benchtop.
Pd(OAc)2 (6.5 mg, 0.029 mmol, 5 mol %) and PCy3 ·HBF4 (21.4
mg, 0.0581 mmol, 10 mol %) were quickly added, and the test
tube was put under vacuum for 10 min and refilled with argon (×3).
2-Bromo-N-cyclohexyl-N-methylbenzamide (8) (172.1 mg, 0.5811
mmol, 1.0 equiv) and PivOH (17.8 mg, 0.174 mmol, 30 mol %)
were added as degassed stock solutions in mesitylene (0.32 and
0.16 M respectively) after which the tube was sealed with parafilm
and electrical tape around the rubber septum and placed in a
preheated oil bath at 150 °C for 16 h. Upon cooling to room
temperature, the reaction was quenched with EtOAc (1 mL) and
transferred to a 200 mL round-bottom flask containing 60 mL of
CH2Cl2 and 60 mL of a saturated solution of NH4Cl. After stirring
at room temperature for 15-30 min, the mixture was separated
and the aqueous layer was extracted with 60 mL of CH2Cl2 (×2).
The combined organic phases were washed with brine, dried with
Na2SO4, concentrated under reduced pressure, and purified by silica
gel flash chromatography (30% EtOAc in petroleum ether) to afford
1
9 as a beige solid in 83% yield. H NMR (400 MHz, CDCl3, 293
conditions to afford a Pd(II) intermediate. This species may
undergo a rapid ligand exchange, replacing the halide by a
pivalate ion generated in situ from the reaction of pivalic acid
with carbonate. Kinetic studies reveal the importance of pivalate
concentration on this elementary reaction step as PivO-/Pd ratios
greater than 3:1 lead to palladium saturation in this ligand.
Computational and experimental results further support the
formation of a κ2-pivalate Pd(II) intermediate as the direct
precursor to the CMD reaction step, which is enabled by the
pivalate ligand. The post-CMD intermediate is deprotonated by
the carbonate base which acts as the driving force of the reaction
by making C(sp3)-H bond cleavage irreversible. The cycle is
completed by rapid reductive elimination of the desired product
with regeneration of the Pd(0) catalyst.
K, TMS) δ 7.86-7.84 (m, 1H), 7.54-7.52 (m, 1H), 7.47-7.44
(m, 2H), 4.35 (s, 2H), 4.30-4.22 (m, 1H), 1.89-1.45 (m, 10H).
13C NMR (100 MHz, CDCl3, 293 K, TMS) δ 168.0, 141.4, 133.6,
131.1, 128.0, 123.7, 122.8, 50.6, 46.1, 31.6, 25.8, 25.7. HRMS
Calculated for C14H17NO (M+) 215.1310, Found 215.1288. IR (νmax
/
cm-1) 2931, 2852, 1681, 735 cm-1. Rf 0.27 (30% EtOAc in
petroleum ether). Melting Point 78-82 °C.
Acknowledgment. We thank NSERC and the University of
Ottawa for support of this work. The Research Corporation,
Boehringer Ingelheim (Laval), Merck Frosst Canada, Merck Inc.,
Eli Lilly, Amgen, and Astra Zeneca Montreal are thanked for
additional unrestricted financial support. S.R. thanks NSERC for a
postgraduate scholarship (CGS-D), and B.C. thanks NSERC for
an undergraduate summer research award. Prof. Muralee Murugesu
and Dr. Tara Burchell are gratefully acknowledged for assistance
in obtaining and solving the crystal structure. Prof. Tom K. Woo
is thanked for CFI- and ORF-funded computing facilities. Prof.
Louis Barriault, Prof. Andre´ Beauchemin, and Dr. Louis-Charles
Campeau are thanked for critical reading of this manuscript. Dr.
Benoˆıt Lie´gault is also thanked for assistance in the preparation of
certain figures and critical evaluation of this manuscript. Prof. Keith
Fagnou passed away on November 11, 2009.
3. Conclusion
In conclusion, the Pd(0)-catalyzed intramolecular arylation
at C(sp3)-H bonds adjacent to amides and sulfonamides has
been developed. Tuning the Lewis basicity of the nitrogen atom
is crucial for the transformation. Mechanistic studies confirmed
that C(sp3)-H bond cleavage is the rate-limiting step of the
catalytic cycle. The isolation of a Pd(II) intermediate has
allowed, for the first time, a direct evaluation of the C-H bond
cleaving step in Pd(0)-catalyzed C-C bond formation at
nonacidic C(sp3)-H bonds. This catalytic event appears to occur
through a CMD pathway featuring cooperative assistance by
both pivalate and carbonate bases. Computational studies further
elucidated a second crucial role for the pivalate additive as a
promoter of phosphine dissociation prior to the CMD transition
state. These mechanistic findings highlight the importance of
Supporting Information Available: Detailed experimental
procedures for the synthesis of all compounds. Characterization
1
data and H and 13C NMR spectra for all new compounds.
Kinetic data, computational details and crystallographic infor-
mation files. Complete ref 37. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA103081N
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