Proton abstraction mechanism for the palladium-catalyzed intramolecular arylation

Article abstract of DOI:10.1021/ja056165v

Under the usual conditions, the Pd-catalyzed arylation does not involve an electrophilic aromatic substitution reaction. On the basis of DFT calculations, we propose a mechanism for the Pd-catalyzed arylation that involves a proton abstraction by a carbon

Full text of DOI:10.1021/ja056165v

Published on Web 01/06/2006
Proton Abstraction Mechanism for the Palladium-Catalyzed Intramolecular
Arylation
Domingo Garc´ıa-Cuadrado, Ataualpa A. C. Braga, Feliu Maseras,*,† and Antonio M. Echavarren*,‡
Institute of Chemical Research of Catalonia (ICIQ), AV. Pa¨ısos Catalans 16, 43007 Tarragona, Spain
Received September 15, 2005; E-mail: fmaseras@iciq.es; aechavarren@iciq.es
Scheme 1
The arylation of arenes catalyzed by palladium is a more direct
alternative for the construction of biaryls1 than methods based on
cross-coupling reactions.2 Particularly useful is the intramolecular
version that allows one to cyclize substrates 1 to form carbo- and
heterocycles 2 (Scheme 1).1,3,4 Intramolecular arylations are also
involved in reactions mediated by palladacycles.5,6
In contrast to cross-coupling reactions,2 little is known about
the mechanism of the Pd-catalyzed arylation. The initially formed
oxidative addition complex 3 could evolve by different mechanisms
via intermediates 4-6. An insertion into the arene (Heck-like)
would give 4,7 which should undergo a trans â-hydrogen elimination
to give 2. An electrophilic aromatic substitution (SEAr) via
intermediates 5 has been usually favored.8,9 However, in one case,
an intramolecular isotope effect of kH/kD ) 3.5 has been
Table 1. Pd-Catalyzed Arylation of Substrates 7a-ga
determined.4a,10 In addition, we have found that the arylation on
nitrofluorene11a or nitrocarbazole11b gives substantial amounts of
products by reaction at the positions ortho or para to a strong
electron-withdrawing NO2 group. An interesting alternative is a
σ-bond metathesis via intermediates 6,10a which seems more likely
than processes involving C-H oxidative addition.12
To determine the mechanism of the Pd-catalyzed arylation, we
decided to study more precisely the effect of substituents on
substrates 7a-g13a with an alkyl tether CH(R) between the two
aryls, which should present minimum steric and/or electronic bias
in this reaction. As standard conditions, we adopted those developed
by Fagnou et al.,4a using bulky phosphine 10a as the ligand for Pd.
Under these conditions, the corresponding 9,10-dihydrophenan-
threnes were obtained along with small amounts of phenanthrenes.
To facilitate determining the ratio of regioisomers, the crude
mixtures were treated with DDQ to give phenanthrenes 8a-g/9a-g
(Table 1).13b Satisfactory results were obtained with K2CO3, whereas
Et3N or DBU led to unchanged starting material. Reduction was
observed with KO-t-Bu as the base.
Similar regioisomeric ratios (1.1-2.4:1), favoring reaction at the
substituted aryl ring, were obtained from substrates 7a-e bearing
groups that are electron-releasing (OMe) or electron-withdrawing
(CF3, Cl) in SEAr processes (Table 1, entries 1-10). In the case of
7a, a similar result was obtained with ligand 10b14 (Table 1, entries
1 and 2). However, 10b led to a better selectivity with substrate
7d (Table 1, entries 6 and 7). Cyclizations could be also carried
out in DMA or DMF at 100 °C (Table 1, entries 3, 8, 9, and 13).
Remarkably, reaction of 7f occurred almost exclusively at the
trifluorophenyl ring to give 8f (Table 1, entry 11). This result is
clearly incompatible with the SEAr mechanism. Reaction of 7g gave
0.2:1 (135 °C) and 0.15:1 (100 °C) ratios of 8g and 9g (Table 1,
entries 12 and 13), which correspond to intramolecular isotope
effects kH/kD ) 5.0 (135 °C) and 6.7 (100 °C).
entry
substrate
Lb
solvent
T (
°
C)
yield (%)
8/9 ratio
1
2
3
4
5
6
7
8
7a
7a
7a
7b
7c
7d
7d
7d
7d
7e
7f
10a
10b
10a
10a
10a
10a
10b
10a
10a
10a
10a
10a
10a
DMA
DMA
DMF
DMA
DMA
DMA
DMA
DMA
DMF
DMA
DMA
DMA
DMF
135
135
100
135
135
135
135
100
100
135
135
135
100
90
93
91
75
71
66
66
98d
84
54
82
82
92
1.1:1
1.1:1
1.1:1
1.4c:1
1.3:1
1.5:1
2.4:1
2:1
9
2:1
10
11
12
13
1.9e:1
25:1
7g
7g
0.2:1
0.15:1
a 5% mol Pd(OAc)2, 10 mol % L, and 3 equiv of K2CO3 for 16 h (DMA)
or 24 h (DMF). b 10a: 2-(Diphenylphosphino)-2′-(N,N-dimethylamino)bi-
phenyl, 10b: 2-(dicyclohexylphosphino)-2′,4′,6′-(triisopropyl)biphenyl.c 3.7:
1 ratio of 2-methoxy- (8b) and 4-methoxy-10-phenylphenanthrene (8′b).
d Yield determined by 1H NMR. e 1:1.5 ratio of 2-chloro- (8e) and 4-chloro-
10-phenylphenanthrene (8′e).
We also submitted 5H-indeno[1,2-b]pyridine derivative 1113a to
the Pd-catalyzed arylation (Scheme 2). As anticipated from the
results in Table 1, the reaction provided 12 as the major regioisomer
(12/13 ) 2.1:1), as a result of the arylation para to the pyridine
ring.
These results would fit better in a mechanism where the hydrogen
from the phenyl is transferred as a proton in the step deciding the
selectivity. To our knowledge, these type of processes have been
† Additional affiliation: Unitat de Qu´ımica F´ısica, Universitat Auto`noma de
Barcelona, 08193 Bellaterra, Catalonia, Spain.
‡ Additional affiliation: Departamento de Qu´ımica Orga´nica, Universidad
Auto´noma de Madrid, Cantoblanco, 28049 Madrid, Spain.
9
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J. AM. CHEM. SOC. 2006, 128, 1066-1067
10.1021/ja056165v CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
In summary, our experimental and theoretical results demonstrate
that, for these systems, the Pd-catalyzed arylation does not involve
an electrophilic aromatic substitution reaction. A mechanism for
the Pd-catalyzed arylation involving a proton abstraction by a
carbonate, or related ligand, provides a satisfactory explanation for
the experimental data.
Acknowledgment. This work was supported by the MEC
(CTQ2004-02869 to A.M.E. and BQU2002-04110-C02-02 to F.M.)
and the ICIQ Foundation. We thank Prof. Timothy Gallagher for
helpful comments and exchange of information, E. Gonza´lez-
Cantalapiedra for the synthesis of 5H-indeno[1,2-b]pyridine, and
Johnson Matthey PLC for palladium salts.
seldom considered in arylation processes, with the notable exception
of a recent computational work by Dedieu and co-workers, where
a proton transfer assisted by a palladium center was shown to be
the key step for a vinyl to aryl shift.12
Supporting Information Available: Experimental details, char-
acterization data, computational details, Cartesian coordinates, Mulliken
charges, and absolute energies. This material is available free of charge
via the Internet at http://pubs.acs.org.
We carried out a computational DFT study with the B3LYP
method on the mechanism of the reaction.13a Such studies have
been shown recently to provide useful insights into the mechanistic
features of cross-coupling reactions.2c,12,15 Our first set of calcula-
tions was carried out on a [Pd(PH3)Br(o-(CH2-Ph)Ph)] system, a
model of the experimental system where hydrogen atoms replace
the phosphine substituents and the spectator phenyl group. A single
phosphine ligand was considered because of the bulky ligands used
in the experiments and because in fact such mechanisms are
operative for cross-coupling processes.15c A reactant R1 and a
transition state TS1 could indeed be located, but the computed
barrier of 43.3 kcal/mol was too high. The problem seems to be
that bromide is not basic enough to abstract a proton from the
phenyl, even with the assistance of the palladium center.
This particular reaction takes place in the presence of an excess
of carbonate, and basic anions have been shown to replace bromine
along the reaction mechanism in related processes.2c Therefore, we
considered an alternative process where the starting species R2
contains HCO3- instead of Br-. Similar processes with formate or
acetate have been reported in related palladations.16 The computed
structures for reactant R2, transition state TS2, and palladacycle
P2 are shown in Figure 1. Geometrical changes with respect to R1
and TS1 are minor, but the energetics are completely different.
The energy barrier is as low as 23.5 kcal/mol, an acceptable value
for a reaction at 100-135 °C. An additional set of calculations
with three fluorine substituents in the phenyl ring produced species
R3 and TS3, with a lower barrier of 13.2 kcal/mol, thus confirming
the experimental observation that electron-withdrawing substituents
accelerate the reaction. A final set of calculations evaluated the
effect of deuterium substitution for transition state TS2. The
computed values for kH/kD were 4.3 at 100 °C and 3.7 at 135 °C,
again in good agreement with experiment. Similar results have been
obtained from a related intermolecular mechanism, with no previous
coordination of hydrogencarbonate to palladium.13a,17
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Figure 1. B3LYP optimized structures of species R2, TS2, and P2.
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