A Highly Selective Catalytic Method for the Oxidative Functionalization of C-H Bonds

Article abstract of DOI:10.1021/ja031543m

This communication describes a new and highly practical Pd(II)-catalyzed method for the regio- and chemoselective oxidative functionalization of arenes and alkanes. Carbon?hydrogen bonds of substrates that contain a variety of directing groups (e.g., pyridine, azobenzene, pyrazole, and imine derivatives) are selectively transformed into esters, ethers, and aryl-halides under mild conditions. The scope of this reaction in terms of substrate, directing group, and oxidant is described, and a preliminary catalytic cycle is proposed. Copyright

Full text of DOI:10.1021/ja031543m

Published on Web 02/03/2004
A Highly Selective Catalytic Method for the Oxidative Functionalization of
C-H Bonds
Allison R. Dick, Kami L. Hull, and Melanie S. Sanford*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue, Ann Arbor, Michigan 48109-1055
Received December 5, 2003; E-mail: mssanfor@umich.edu
Table 1. Regioselective Oxidation of Benzo[h]quinolinea
The development of metal-catalyzed methods for the regio- and
chemoselective oxidative functionalization of arene and alkane
carbon-hydrogen bonds remains a tremendous challenge in organic
and organometallic chemistry.1,2 Rare examples of such transforma-
tions have been described; however, their application to the
elaboration of complex organic structures is generally limited by
the harsh reaction conditions, low TON, low functional group
tolerance, significant formation of byproducts, and large excesses
of substrate relative to oxidant typically required in such reactions.1,2
Additionally, most oxidation catalysts have been developed for
substrates containing a single type of C-H bond (e.g., C6H6 or
CH4), and low levels of regioselectivity are typically observed in
the presence of multiple C-H bonds.1,2 Recent elegant work3-5
has begun to successfully address some of these challenges, but a
general solution, particularly for arene/alkane oxygenation, has thus
far remained elusive.
Our approach to regioselective C-H bond oxidation involves
the use of substrates containing coordinating functional groups that
can bind to a metal catalyst and direct oxidation to a specific C-H
bond within the molecule. We felt that recent progress in related
C-H activation/C-C bond-forming reactions provided good
precedent that such transformations could proceed with high levels
of efficiency and selectivity.6,7 We report herein a new and
operationally simple Pd-catalyzed reaction for the chelate-directed
oxidative functionalization of sp2 and sp3 C-H bonds.
entry
oxidant
solvent
X (product)
yieldb (%)
1c
2c
3c
4c
5c
6e
7e
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
NCS
CH3CN
MeOH
EtOH
i-PrOH/HOAc
CF3CH2OH
CH2CN
OAc (3a): OH (3b)
OMe (3c)
OEt (3d)
OiPr (3d)
OCH2CF3 (3f)
Cl (3g)
86d
95
80
72
71
95
93
NBS
CH3CN
Br (3h)
a 1 equiv of 1 (0.12 M), 1-2 equiv of oxidant, 1-5 mol % Pd(OAc)2 or
2, 75-100 °C. b Isolated yields. c 12 h. d 11:1 mixture of 3a:3b. e 1-3 days.
sterically and electronically diverse alkyl-aryl ethers [e.g., X )
OMe (3c), OEt (3d), Oi-Pr (3e), and OCH2CF3 (3f)] in good yields.
Alternatively, when oxidation is carried out in the presence of excess
LiX (X ) Cl, Br) in CH3CN, traces of mono-halogenated 3g and
3h are formed. The yields of these products can be optimized by
the use of N-chloro- or N-bromosuccinimide (NCS or NBS) in place
of PhI(OAc)2 as the stoichiometric oxidant. Importantly, the rigorous
exclusion of air/moisture is not required in any of these transforma-
tions, and comparable results are obtained in the presence and
absence of air, as well as in freshly distilled versus commercial
solvents. As such, this represents an exceedingly practical method
for functional group-directed oxidation of arene C-H bonds and
offers an attractive alternative to more traditional ortho-lithiation/
electrophilic addition procedures.10
As summarized in Table 2, chelate-directed oxidation can be
extended to a wide variety of substrates. For example, the sp3 C-H
bond of 8-methylquinoline reacts readily with 1.1 equiv of PhI-
(OAc)2/1-2 mol % Pd(OAc)2 in AcOH or MeOH to afford benzyl
ester 4a or benzyl ether 4b in good yield (entries 1 and 2). Although
these products contain additional benzylic hydrogens, essentially
no over-oxidation is observed under our reaction conditions. Further
C-H activation/oxidation of the product is likely inhibited due to
steric hindrance at the more substituted benzylic position. Impor-
tantly, an appropriate directing group is absolutely required to
achieve high yields and selectivities for benzylic oxidation. For
instance, under our reaction conditions, 5,8-dimethylquinoline is
oxidized exclusively at the 8-position to afford 5 (entry 3),11 while
1-methylnaphthalene affords low yields of a complex mixture of
benzylic and ring oxidation products.
Other functional groups, including azobenzene (entry 4), pyrazole
(entry 5), imine (entry 6), and pyridine (entries 7-11) derivatives
can also be utilized to direct arene C-H bond oxidation. In
substrates that present two o-C-H bonds, modest to good yields
of the mono-oxidized products 6-10 are obtained upon addition
of 1.1-1.6 equiv of PhI(OAc)2 relative to substrate (entries 4-8).
Furthermore, the use of 2.3-2.5 equiv of PhI(OAc)2 results in clean
formation of the dioxidized adducts 11-13 (entries 9-11). This
reaction is tolerant of a variety of readily oxidizable functional
groups including benzylic hydrogens and aromatic aldehydes
(entries 10, 11). Notably, the oxidation of 4-(2-pyridyl)benzaldehyde
Our first studies in this area focused on the Pd(II)-catalyzed
oxidation of benzo[h]quinoline (1). This substrate was selected for
initial investigation because it presents a single bond [C-H(10)]
for directed C-H activation and is well-known to undergo
cyclopalladation under mild conditions (eq 1).8 Iodobenzene
diacetate was chosen as the oxidant on the basis of its commercial
availability, ease of handling, and utility in a related Pd-catalyzed
arene oxidation reaction.2c The combination of 1 equiv of benzo-
[h]quinoline with PhI(OAc)2 (2 equiv) and 2 mol % Pd(OAc)2 in
CH3CN at 75 °C for 12 h produces an 11:1 ratio of the mono-
acetoxylated product 3a and the analogous phenol 3b in 86%
isolated yield.9 Oxidation also proceeds in comparable yield and
efficiency when cyclopalladated complex 2 is used as the catalyst.
This reaction exhibits extraordinarily high selectivity for oxidation
at C10, and regioisomeric oxidized products are not observed by
1
GC or H NMR spectroscopy.
We have found that simple modification of the reaction condi-
tions allows the selective installation of a variety of different
functional groups at C10 (Table 1). For example, reaction of 1 with
PhI(OAc)2/catalytic Pd(II) in alcohol solvents produces a range of
9
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10.1021/ja031543m CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Chelate-Directed Oxidation of sp2 and sp3 C-H Bondsa,b
more, no product is formed in the presence of benzoquinone or
Cu(OAc)2 (oxidants that typically mediate Pd(0)/Pd(II) catalysis)13
or when the putative intermediate 2 is subjected to the reaction
conditions in the absence of oxidant. The final step (iii) involves
carbon-heteroatom bond-forming reductive elimination to afford
the product. Such reactions have significant precedent1,2,12 and
typically proceed either by intramolecular C-X bond elimination
from the metal center12b,c or by attack of an external nucleophile
(X) in an SN2-like reaction.12a,d
In conclusion, this report describes a new, highly regio- and
chemoselective Pd-catalyzed procedure for the conversion of sp2
and sp3 C-H bonds to esters, ethers, and aryl-halides. A wide
variety of substrates are readily oxidized under mild and operation-
ally simple reaction conditions. Current studies are focused on
further exploration of the substrate scope and synthetic utility of
this methodology as well as on probing the mechanism of this
transformation.
Acknowledgment. We thank the University of Michigan for
generous support of this research. We also thank Professors J. P.
Wolfe and E. Vedejs for helpful discussions.
Supporting Information Available: Experimental details and
spectroscopic/analytical data for all new compounds (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
a For mono-oxidation: 1 equiv of substrate [0.12 M in AcOH (entries
1, 3, 5), MeOH (entry 2), or CH3CN (entries 4-8)], 1.1-1.6 equiv of
PhI(OAc)2, 1-6 mol % Pd(OAc)2, 100 °C, 12-20 h. b For dioxidation: 1
equiv substrate (0.12 M in CH3CN), 2.3-2.5 equiv of PhI(OAc)2, 6-8
mol % Pd(OAc)2, 100 °C, 12 h. c Isolated yields. d Yield determined by
GC.
(1) (a) Fekl, U.; Goldberg, K. I. AdV. Inorg. Chem. 2003, 54, 259. (b) Groves,
J. T. J. Porphyrins Phthalocyanines 2000, 4, 350. (c) Stahl, S. S.; Labinger,
J. A.; Bercaw, J. E. Angew. Chem., Int. Ed. 1998, 37, 2181. (d) Sen, A.
Acc. Chem. Res. 1998, 31, 550. (e) Shilov, A. E.; Shul’pin, G. B. Chem.
ReV. 1997, 97, 2879. (f) Henry, P. M. Catalysis by Metal Complexes;
Palladium Catalyzed Oxidation of Hydrocarbons, Vol. 2; Reidel: Dor-
drecht, 1980.
(2) Selected recent examples: (a) Mukhopadhyay, S.; Bell, A. T. Angew.
Chem., Int. Ed. 2003, 42, 2990. (b) Periana, R. A.; Taube, D. J.; Gamble,
S.; Taube, H.; Satoh, T.; Fujii, H. Science 1998, 280, 560. (c) Yoneyama,
T.; Crabtree R. H. J. Mol. Catal. A 1996, 108, 35.
Scheme 1. Proposed Catalytic Cycle
(3) (a) Maleczka, R. E.; Shi, F.; Holmes, D.; Smith, M. R. J. Am. Chem. Soc.
2003, 125, 7792. (b) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.;
Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390.
(4) (a) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510. (b)
Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc.
2001, 123, 6935.
(5) Dangel, B. D.; Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2001, 123,
8149.
(6) (a) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077. (b)
Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (c)
Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826.
(7) Related stoichiometric cyclopalladation/oxidation reactions have also been
reported. For example, see: (a) Valk, J.-M.; Boersma, J.; van Koten, G.
Organometallics 1996, 15, 4366. (b) Carr, K.; Saxton, H. M.; Sutherland,
J. K. J. Chem. Soc., Perkin Trans 1 1988, 1599.
(entry 11) is directed by the pyridine rather than the aldehyde
moiety,11 presumably because the former is a better ligand for
Pd(II).
(8) Hartwell, G. E.; Lawrence, R. V.; Smas, M. J. J. Chem. Soc., Chem.
A possible mechanism for this new transformation is outlined
in Scheme 1. Step (i) involves chelate-directed C-H activation of
the substrate to afford a cyclopalladated intermediate. The extra-
ordinarily high regioselectivity of these reactions (particularly in
substrates such as 5,8-dimethylquinoline that present two otherwise
identical functional groups) as well as the high catalytic activity of
the isolated cyclopalladated complex 2 provides strong evidence
in support of this step. Step (ii) of the proposed catalytic cycle
involves oxidation of Pd(II) to Pd(IV). While the Pd(0)/Pd(II) couple
is more common in catalysis,12b,13 Pd(II)/Pd(IV) cycles have been
implicated in related benzene acetoxylation reactions.1f,2c Further-
Commun. 1970, 912.
(9) Traces of 3b are observed in crude GC traces of the reaction, but this
product forms predominantly via ester hydrolysis during purification on
1
silica gel. The ratio of 3a:3b was determined by H NMR spectroscopy.
(10) Snieckus, V. Chem. ReV. 1990, 90, 879.
(11) The regioselectivity of oxidation was confirmed by nOe experiments (see
Supporting Information for details).
(12) (a) Williams, B. S.; Goldberg, K. I. J. Am. Chem. Soc. 2001, 123, 2576.
(b) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (c) Han, R. Y.; Hillhouse,
G. L. J. Am. Chem. Soc. 1997, 119, 8135. (d) Backvall, J. E. Acc. Chem.
Res. 1983, 16, 335.
(13) For example, see: Jonasson, C.; Horvath, A.; Backvall, J. E. J. Am. Chem.
Soc. 2000, 122, 9600.
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