Regioselectivity in palladium-catalyzed C-H activation/oxygenation reactions

Article abstract of DOI:10.1021/ol051486x

(Chemical Equation Presented) Palladium-catalyzed directed C-H activation/oxygenation reactions have been explored in a series of meta-substituted aryl pyridine and aryl amide derivatives. These transformations tolerate a diverse array of electron-donatin

Full text of DOI:10.1021/ol051486x

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4149-4152
Regioselectivity in Palladium-Catalyzed
H Activation/Oxygenation Reactions
C−
Dipannita Kalyani and Melanie S. Sanford*
Department of Chemistry, UniVersity of Michigan, 930 N. UniVersity AVenue,
Ann Arbor, Michigan 48109-1055
mssanfor@umich.edu
Received June 24, 2005
ABSTRACT
Palladium-catalyzed directed C
amide derivatives. These transformations tolerate a diverse array of electron-donating and electron-withdrawing meta-substituents and generally
proceed with high levels of regioselectivity for functionalization of the less sterically hindered ortho-C H bond.
−H activation/oxygenation reactions have been explored in a series of meta-substituted aryl pyridine and aryl
−
The development of mild methods for the selective func-
tionalization of carbon-hydrogen bonds in complex mol-
ecules remains a significant challenge in organic synthesis.1-5
Such reactions can facilitate the construction of diverse
compounds, including organic materials, natural products,
and pharmacophores. Recently, we2 and others3 have reported
PdII-catalyzed methods for the heteroatom-directed function-
alization of arene and alkane C-H bonds. These transforma-
tions offer the advantages that (i) they generally do not
require the use of strong acids/bases or expensive ancillary
ligands, (ii) they are tolerant of ambient air and moisture,
(iii) they can be used to install carbon-oxygen,2b,c carbon-
halogen,2c,3b and carbon-carbon bonds,2a,3a,c-f and (iv) they
proceed with very high levels of ortho-regioselectivity.
Despite significant recent advances in this area,2-4 fun-
damental questions concerning the selectivity of these PdII-
catalyzed transformations remain. In particular, the func-
tionalization of meta-substituted arenes (which contain two
different ortho-C-H bonds) has not been systematically
explored (Scheme 1).2-4,6 The ability to achieve high and
predictable levels of regioselectivity in the ortho-function-
(1) For a recent review, see: Kakiuchi, F.; Chatani, N. AdV. Synth. Catal.
2003, 345, 1077.
(2) (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am.
Chem. Soc. 2005, 127, 7330. (b) Desai, L. V.; Hull, K. L.; Sanford, M. S.
J. Am. Chem. Soc. 2004, 126, 9542. (c) Dick, A. R.; Hull, K. L.; Sanford,
M. S. J. Am. Chem. Soc. 2004, 126, 2300.
(5) For other recent examples of the metal-catalyzed oxidative function-
alization of C-H bonds, see: (a) Chen, M. S.; Prabagaran, N.; Labenz, N.
A.; White, M. C. J. Am. Chem. Soc. 2005, 127, 6970. (b) Li, Z.; Li, C.-J.
J. Am. Chem. Soc. 2005, 127, 6968. (c) Espino, C. G.; Fiori, K. M.; Kim,
M.; Du Bois, J. J. Am. Chem. Soc. 2004, 126, 15378. (d) Lawrence, J. D.;
Takahashi, M.; Bae, C.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 15334.
(e) Hamilton, C. W.; Laitar, D. S.; Sadighi, J. P. Chem. Commun. 2004,
1628. (f) Diaz-Requejo, M. M.; Belderrain, T. R.; Nicasio, M. C.;
Trofimenko, S.; Perez, P. J. J. Am. Chem. Soc. 2003, 125, 12078. (g)
Maleczka, R. E.; Shi, F.; Holmes, D.; Smith, M. R., III. J. Am. Chem. Soc.
2003, 125, 7792. (h) Dangel, B. D.; Johnson, J. A.; Sames, D. J. Am. Chem.
Soc. 2001, 123, 8149.
(6) For representative studies of regioselectivity in stoichiometric cy-
clopalladation, see: (a) Teijido, B.; Fernandez, A.; Lopez-Torres, M.; Castro-
Juiz, S.; Suarez, A.; Ortigueira, J. M.; Vila, J. M.; Fernandez, J. J. J.
Organomet. Chem. 2000, 598, 71. (b) Gutierrez, M. A.; Newkome, G. R.;
Selbin, J. J. Organomet. Chem. 1980, 202, 341. (c) Holton, R. A.; Davis,
R. G. J. Am. Chem. Soc. 1977, 99, 4175.
(3) For additional recent examples of PdII-catalyzed ligand-directed C-H
activation/functionalization reactions, see: (a) Daugulis, O.; Zaitsev, V. G.
Angew. Chem., Int. Ed. 2005, 44, 4046. (b) Giri, R.; Chen, X.; Yu, J. Q.
Angew. Chem., Int. Ed. 2005, 44, 2112. (c) Daugulis, O.; Zaitsev, V. G. J.
Am. Chem. Soc. 2005, 127, 4156. (d) Orito, K.; Horibata, A.; Nakamura,
T.; Ushito, H.; Nagasaki, H.; Yuguchi, M.; Yamashita, S.; Tokuda, M. J.
Am. Chem. Soc. 2004, 126, 14342. (e) Sezen, B.; Franz, R.; Sames, D. J.
Am. Chem. Soc. 2002, 124, 13372. (f) Boele, M. D. K.; van Strijdonck, G.
P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen,
P. W. N. M. J. Am. Chem. Soc. 2002, 124, 1586.
(4) For other examples of regioselectivity in PdII-catalyzed C-H
activation/C-C bond-forming reactions of meta-substituted arenes, see: (a)
Campeau, L.-C.; Parisien, M.; Leblanc, M.; Fagnou, K. J. Am. Chem. Soc.
2004, 126, 9186. (b) Zhang, H.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem.,
Int. Ed. 2004, 43, 6144. (c) Huang, Q.; Campo, M. A.; Yao, T.; Tian, Q.;
Larock, R. C. J. Org. Chem. 2004, 69, 8251. (d) Buchwald, S. L.; Hennessy,
E. J. J. Am. Chem. Soc. 2003, 125, 12084.
10.1021/ol051486x CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/20/2005

cleanly with 5 mol % Pd(OAc)2 and 1-3 equiv of PhI(OAc)2
to produce mono-oxygenated products in good to excellent
yields (Table 1). Notably, these reactions proceeded to
Scheme 1. Possible Products from C-H Activation/
Functionalization of meta-Substituted Arenes
Table 1. Palladium-Catalyzed Acetoxylation of
2-Arylpyridinesa
alization of 1 (a commonly encountered structural motif)
would significantly expand the synthetic utility of these
methods. Sporadic reports have suggested that isomer A is
often favored in PdII-catalyzed reactions; however, the data
are difficult to generalize because of the very limited set of
meta-substituents that have been examined.2-4,6 We report
herein the first detailed, systematic study of regioselectivity
in the PdII-catalyzed C-H activation/functionalization of
meta-substituted arenes. We demonstrate that these trans-
formations typically proceed with high (>20:1) selectivity
and serve as a potentially valuable complement to widely
practiced directed ortho-lithiation.7
The effect of meta-substitution on the regioselectivity of
ortho-lithiation reactions of 1 has been well documented in
the literature.7 In general, substituents that can act as
secondary chelating groups to a Li cation (e.g., OMe,
OMOM, F, Cl) lead to highly selective formation of
regioisomer B, whereas noncoordinating substituents (e.g.,
CH3) afford the less sterically hindered product A.7 The
regioselectivity of Ru0-catalyzed C-H activation/olefin ad-
dition reactions of meta-substituted aryl ketones has also been
systematically explored and shown to proceed with selectivity
similar to that of ortho-lithiation.8 For example, when X is
a potential ligand for Ru (e.g., X ) OMe, F, OCH2O), isomer
B is obtained with modest to good regioselectivity, whereas
when X is a noncoordinating substituent, A is the major
product.8-11 In contrast, as detailed above, analogous sys-
tematic studies of regioselectivity in the PdII-catalyzed C-H
activation/functionalization of 1 have not been reported.2-4,6
Our initial studies in this area focused on the Pd(OAc)2-
catalyzed acetoxylation of a series of meta-substituted
2-phenylpyridine derivatives 2-8. These substrates reacted
a Conditions: 5 mol % Pd(OAc)2, 1.1-3.0 equiv of PhI(OAc)2, AcOH,
C6H6, or C6H6/Ac2O, 100 °C, 0.5-4 h. b A single regioisomer was observed
by GC and 1H NMR spectroscopy. c Ratio of A:B determined by 1H NMR.
d Ratio of A:B determined by GC.
completion in similar times (0.5-4 h) with electron-donating
and electron-withdrawing meta-substituents; furthermore,
comparable yields were obtained regardless of the electronic
nature of X. In addition, a variety of functional groups,
including aryl halides, ethers, benzylic hydrogens, nitro
groups, and enolizable ketones, oximes, and amides (vide
infra) were well-tolerated in these transformations.
The regioselectivity of acetoxylation was assessed using
1H NMR spectroscopy and gas chromatography.12 As sum-
marized in Table 1, regioisomer A was obtained as the major
product in synthetically useful ratios ranging from 6:1 (entry
3) to >20:1 (entries 1, 2, and 4-7). The electronic nature
of the substituent did not have an appreciable effect on
regioselectivity, and both electron-donating and electron-
withdrawing groups afforded comparable preference for A.
Furthermore, in contrast to directed ortho-lithiation7 and to
Ru-catalyzed C-H activation/olefin addition reactions,8
(7) Snieckus, V. Chem. ReV. 1990, 90, 879.
(8) Sonoda, M.; Kakiuchi, F.; Chatani, N.; Murai, S. Bull. Chem. Soc.
Jpn. 1997, 70, 3117.
(9) Ru0-catalyzed C-H activation/carbonylation generally shows higher
selectivity for A [A:B > 20:1 except when X ) F (2.5:1) and OCH2O
(1:5.5)]. This preference for A (in comparison to the analogous C-H
activation/olefin additions) may be due to the high CO pressures (5-20
atm) used in these experiments, which are expected to limit the open sites
at Ru for weak secondary coordination interactions. (a) Asaumi, T.; Matsuo,
T.; Fukuyama, T.; Ie, Y.; Kakiuchi, F.; Chatani, N. J. Org. Chem. 2004,
69, 4433. (b) Ie, Y.; Chatani, N.; Ogo, T.; Marshall, D. R.; Fukuyama, T.;
Kakiuchi, F.; Murai, S. J. Org. Chem. 2000, 65, 1475. (c) Fukuyama, T.;
Chatani, N.; Kakiuchi, F.; Murai, S. J. Org. Chem. 1997, 62, 5647. (d)
Chatani, N.; Ie, Y.; Kakiuchi, F.; Murai, S. J. Org. Chem. 1997, 62, 2604.
(10) Rh-catalyzed C-H activation/alkylation of aldimines proceeds to
afford A as the major regioisomer with good selectivity except when X )
F (A:B ) 1:3). Lim, Y.-G.; Han, J.-S.; Koo, B. T.; Kang, J.-B. J. Mol.
Catal. A 2004, 209, 41.
(12) Authentic samples of a number of the products were prepared
(particularly for 4a and 18a/b, where the regioselectivity was difficult to
assess by 1H NMR spectroscopy). See Supporting Information for full
details.
(11) For Ru-catalyzed pyridine-directed C-H activation/arylation, see:
Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y. Org.
Lett. 2001, 3, 2579.
4150
Org. Lett., Vol. 7, No. 19, 2005

substituents such as OMe, OMOM, and F did not exhibit
secondary directing effects, and all resulted in clean and
selective formation of A. Comparable levels of selectivity
were also observed when the directing group was changed
from a pyridine to a pyrrolidinone (Table 2); furthermore,
Table 3. Palladium-Catalyzed Acetoxylation of Substrates with
Potential Dual Chelating Groupsa
Table 2. Palladium-Catalyzed Acetoxylation of Aryl
Pyrrolidinonesa
a Conditions: 5 mol % Pd(OAc)2, 1.1-2.2 equiv of PhI(OAc)2 in AcOH
or AcOH/Ac2O, 100 °C, 3-12 h. b Oxidant ) PhI(TFA)2 in AcOH/Ac2O.
c Ratio of A:B determined by GCMS. d A single regioisomer was observed
1
by H NMR and GC.
similar results have been reported for the C-H activation/
oxidative arylation of related substrates.2a This preliminary
data suggests that selectivity for A may be general over many
classes of directing groups and types of PdII-catalyzed C-H
activation/oxidative functionalization reactions.
a Conditions: 5 mol % Pd(OAc)2, 1.5-1.8 equiv of PhI(OAc)2, C6H6/
Ac2O, or C6H6, 100 °C. b A single regioisomer was observed by 1H NMR
d
and GC. c Ratio of A:B determined by GC. Reaction carried out at 60
°C.
We were intrigued by the lack of secondary directing
effects with OMe, MOM, and halide substituents and felt
that this could be due to (i) the poor ligand abilities of these
groups for PdII and/or (ii) the unfavorable ring sizes (fused
4,5 ring systems) required for secondary coordination in these
systems. As such, we next examined phenylpyridine deriva-
tives 13-16 (Table 3), which (i) contain meta-ketone and
oxime ether substituents (significantly better ligands for
PdII)2b,13 and (ii) can form more favorable 5,5 or 5,6 ring
systems upon coodination of the two directing groups.
However, treatment of 13-16 with 5 mol % Pd(OAc)2 and
1.5-1.8 equiv PhI(OAc)2 afforded regioisomer A in >20:1
selectivity, indicating no coopertivity between the two
potential ligands. Interestingly, a single regioisomeric product
was detected even in substrates containing a pyridine and
an oxime ether, which are each independently competent as
directing groups (Table 3, entries 2 and 4). In both cases,
the acetoxy group was installed adjacent to the pyridine
moiety, suggesting that this ligand out-competes the oxime
for binding the PdII catalyst. This result provides promising
precedent that highly selective C-H bond oxygenation can
be achieved in complex molecules containing multiple basic
sites.
In a further attempt to obtain selectivity for isomer B, we
explored substrate 17 (Table 3, entry 5), which contains two
symmetrically disposed, strongly coordinating pyridine ligands.
As shown in Scheme 2, 17 is known to undergo clean
Scheme 2. Synthesis and Stoichiometric Reaction of 19 with
PhI(OAc)2
(13) For representative examples of ketones acting as L-type ligands for
PdII, see: (a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2000, 122, 1360. (b) Nozaki, K.; Sato, N.; Takaya, H. J. Am.
Chem. Soc. 1995, 117, 9911.
stoichiometric C-H activation at Pd(OAc)2 to afford regio-
isomer B in high yield.14 However, treatment of 17 with
catalytic Pd(OAc)2 and 1.5 equiv of PhI(OAc)2 returned
Org. Lett., Vol. 7, No. 19, 2005
4151

unreacted starting material as the sole organic product. In
addition, no acetoxylated product was obtained when pal-
ladacycle 19 was subjected to stoichiometric oxidation with
PhI(OAc)2 (Scheme 2). These results suggest that dual
chelation of the pyridine ligands (which is necessary for the
selective formation of isomer B) effectively prevents the
functionalization step required for catalyst turnover.
substrates 4 and 9, which show g6:1 preference for reaction
adjacent to H versus F, are particularly remarkable, as these
two atoms are sterically quite similar.18 It appears that PdII
is very sensitive to even minor steric perturbations in these
systems. This steric preference can be overcome by the use
of substrate 17, which contains two strongly donating
pyridine ligands; however, the tight chelation required to
achieve selectivity prevents catalyst turnover.
In a final effort to bias C-H activation/acetoxylation to
the formation of isomer B, we examined meta-methylene-
dioxy substrate 18 (Table 3, entry 6). This cyclic acetal
substituent has been shown to afford isomer B preferentially
in some3d (but not all)4b related PdII-catalyzed C-H activa-
tion/C-C bond-forming reactions.6a,15 When 18 was sub-
jected to 5 mol % Pd(OAc)2 and 1.2 equiv of PhI(OAc)2,
the acetoxylated product was obtained as a 2:1 mixture of
regioisomers in favor of isomer B. The yield of 18a/b was
low (29%), but attempts at further optimization afforded
significant amounts of the corresponding diacetoxylated
product.16 Nonetheless, to date substrate 18 remains a unique
example of the selective formation of isomer B in Pd(OAc)2-
catalyzed C-H activation/acetoxylation.
Arylpyridine 18 is the only catalytically viable substrate
that affords selectivity (albeit modest) for isomer B. Similar
regioselectivity has been reported in the literature for the
C-H activation of other meta-methylene dioxy-substituted
arenes and has been rationalized on the basis of a secondary
coordination interaction between the ether oxygen and the
metal center.3d,6a,15 The accessibility of this oxygen is
proposed to be enhanced by the cyclic nature of the ether
moiety, which decreases the effective size of the meta-
substituent and may also render the oxygen lone pair more
available.3d Current efforts are aimed at obtaining direct
evidence for this secondary interaction to gain further insights
into this unusual regioselectivity.
In conclusion, this paper describes Pd-catalyzed chelate-
directed acetoxylation of meta-substituted arene substrates.
These reactions show remarkably broad scope and functional
group tolerance with respect to the meta-substituent on the
arene. Additionally, they generally exhibit high levels of
regioselectivity for functionalization at the less sterically
hindered ortho-position. Ongoing studies in our laboratories
aim to expand the scope and elucidate the mechanism of
these reactions, and will be reported in due course.
The data presented above are generally consistent with a
strong preference for PdII-mediated C-H activation to
proceed at the less sterically congested site of meta-
substituted substrates.17 This steric effect appears to dominate
in the presence of diverse substituents (including those that
exert both resonance and inductive electron withdrawing and
electron donating effects) and also typically overrides in-
tramolecular secondary coordination by most ether, halide,
ketone, and even oxime groups. The results obtained with
Acknowledgment. We are grateful to the University of
Michigan, the Arnold and Mabel Beckman Foundation, and
the Camille and Henry Dreyfus Foundation for financial
support of this research.
(14) Canty, A. J.; Minchin, N. J.; Skelton, B. W.; White, A. H. J. Chem.
Soc., Dalton Trans. 1987, 1477.
(15) This substituent also gives selectivity for B in Ru0-catalyzed
reactions and similar arguments have been invoked in these systems (see
refs 8 and 9).
Supporting Information Available: Experimental details
and spectroscopic and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) The two regioisomers of 18a react with 5 mol % Pd(OAc)2 and
PhI(OAc)2 to form the diacetoxylated product at similar rates. Therefore,
the observed selectivity appears to be inherent to the C-H activation reaction
of 18 (rather than resulting from selective consumption of one of the
regioisomers after it is formed).
(17) The regioselectivity of transition metal-mediated C-H activation
reactions is frequently dominated by steric effects. For example, see ref
5d,g and refs 8-10.
OL051486X
(18) Chemistry of Organofluorine Compounds 2; Hudlicky, M., Pavlath,
A. E., Eds.; American Chemical Society: Washington, DC, 1995.
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