Palladium-catalyzed methylation of aryl C-H bond by using peroxides

Article abstract of DOI:10.1021/ja0775063

A novel Pd(OAc)₂-catalyzed methylation reaction by dicumyl peroxide via aryl C-H bond activation was discovered. Various 2-phenylpyridine and acetanilides can be used as reactants in these reactions. Peroxide was used as both the methylating reagent and the hydrogen acceptor. Copyright

Full text of DOI:10.1021/ja0775063

Published on Web 02/13/2008
Palladium-Catalyzed Methylation of Aryl C-H Bond by Using Peroxides
Yuhua Zhang,† Jianqing Feng,‡ and Chao-Jun Li*,†,‡
Department of Chemistry, Tulane UniVersity, New Orleans, Louisiana 70118, and Department of Chemistry,
McGill UniVersity, 801 Sherbrooke Street West, Montreal, Quebec H3A 2K6, Canada
Received October 4, 2007; E-mail: cj.li@McGill.ca
Scheme 1. Pd-Catalyzed Functionalization of Aryl C-H Bond
Transition-metal-catalyzed activation of aryl C-H bonds fol-
lowed by C-C bond formation provides a promising alternative
to the standard coupling reactions using preformed organometallic
reagents. In this area of research, various functional groups contain-
ing heteroatoms such as acetyl, acetoamino, oxazolyl, pyridyl, and
imino groups can provide an anchor for either stoichiometric or
catalytic ortho-metalation of aromatic rings, which leads to subse-
quent regioselective formation of C-C bonds for synthetic pur-
poses.1 Ru and Rh complexes are the hors d’oeuvres of effective
catalysts which have succeeded in performing carbo-functional-
ization of aryl C-H bonds by reacting with olefins or aryl
organometallic reagents.1a,2
Table 1. Optimization of Reaction Conditionsa
Recently, Pd-catalyzed direct functionalizations of aryl C-H to
form C-C bonds have been investigated intensively (Scheme 1).
Among them, alkenylation of aryl C-H bonds via Pd(II)/Pd(0)
catalysis generated Heck-type reaction3 products (route a).4 For
alkylation of aryl C-H bonds, recently Yu and co-workers reported
the aryl methylation with methylboronic acids (analogous to the
Suzuki-type reaction5) and organotin reagents catalyzed by Pd
together with an oxidizing reagent (route b).6 Alternatively, a Pd-
catalyzed aryl-aryl coupling via aryl C-H bond by using arylsi-
lanes has been achieved,7 analogous to the Corriu-Kumada-
Hiyama coupling.8 Herein, we wish to report an unprecedented
palladium-catalyzed methylation of arenes by using peroxides,
serving as both a novel methylating reagent and the hydrogen
acceptor (route c).
To begin our study, we discovered that the reaction of 2-phe-
nylpyridine (1a) with tert-butyl peroxide (2a) catalyzed by Pd-
(OAc)2 at 140 °C under an atmosphere of nitrogen generated 20%
of 2-o-tolylpyridine (3a) (Table 1, entry 1) (Caution: heating large
amounts of peroxide at high temperature is potentially dangerous).
Further optimization showed that 40% of 3a and 5% of 2-(2,6-
dimethylphenyl)pyridine 4a (a bismethylation product) could be
obtained when tert-butylbenzene was used as solvent (Table 1, entry
2). Interestingly, no reaction was observed when tert-butyl hydro-
peroxide instead of tert-butyl peroxide was used. On the other hand,
tert-butyl peroxybenzoate, tert-butyl cumyl peroxide, and di(tert-
butyl peroxyisopropyl)benzene were also found to be effective in
generating the desired product without any solvent (Table 1, entries
4-6), with dicumyl peroxide providing the best results under the
neat conditions (Table 1, entry 7). It should be mentioned that the
remaining unreacted phenylpyridine can be recovered nearly
quantitatively and no other significant product could be detected
in the reaction. Subsequently, various palladium catalysts were
examined under these conditions (Table 1, entries 8-13). PdCl2
and (CH3CN)2PdCl2 also gave good yields of the methylation
product (Table 1, entries 8 and 9), whereas Pd(CF3CO2)2, Pd(PPh3)4,
Pd(C5H7O2)2, and (PPh3)2PdCl2 were less effective (Table 1, entries
10-13) as catalysts for this transformation. When 1 equiv of the
peroxide 2f was used, only a small amount of the double methyla-
tion product was observed (Table 1, entry 14). With 4 equiv of the
a Conditions: all reactions were carried out with 1a (0.2 mmol), 12 h
under N2 in a closed reaction vessel, unless otherwise noted. b 1H NMR
yields determined by using 1,4-dioxane as an internal standard. c Reaction
1
time: 5 h. d tert-Butylbenzene (0.1 mL) as solvent. e Not detected by H
1
NMR; 90% of 1a remained. f Not detected by H NMR.
peroxide 2f, the double methylation product 4a was the only pro-
duct, obtained in 70% yield (Table 1, entry 15). Raising the reaction
temperature slightly increases the product yield (Table 1, entry 16).
Lowering the reaction temperature or reducing the amount of cata-
lyst markedly decreases the product yield (Table 1, entries 17 and
18). No product was detected in the absence of Pd(OAc)2 (Table
1, entry 19).
Under the optimized reaction conditions, various 2-phenylpyri-
dine derivatives were examined (Table 2, entries 4-10). With
benzo[h]quinoline (1d), only one reactive site being available for
the reaction, as the substrate, 76% of the monomethylation product
3d was obtained (Table 2, entry 7). The electronic effect does not
affect the reaction significantly (compare entries 5, 8, and 9). The
† Tulane University.
‡ McGill University.
9
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10.1021/ja0775063 CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Methylation of sp2 C-H Bonds with 2fa
Scheme 2. Tentative Mechanism for the Palladium-Catalyzed
Methylation of Arenes with Peroxides, [Pd] = Pd(0) or Pd(II)
nyl)pyridine as a substrate (Table 2, entry 13), which suggests a
possible alternative (e.g., radical) mechanism.
In summary, we have developed a novel method for the direct
methylation of aryl C-H bonds by using peroxide compounds as
both methylating reagents and hydrogen acceptor. The study
provides a new avenue for the direct alkylation of aryl C-H bonds
by using alkyl radicals rather than organometallic reagents. Further
investigations including the scope, mechanism, and synthetic
application of this reaction are in progress.
Acknowledgment. We are grateful to the Canada Research
Chair (Tier I) Foundation (to C.J.L.), the NSF-EPA Joint Program
for a Sustainable Environment, and NSERC for support.
Supporting Information Available: Representative experimental
procedure and characterization of all new compounds (PDF). This
material is available free of charge via the Internet at http:/pubs.acs.org.
References
(1) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, N. Nature 1993, 366, 529. (b) Lazareva, A.; Daugulis, O.
Org. Lett. 2006, 8, 5211. (c) 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. (d) Tremont, S. J.; ur Rahman,
H. J. Am. Chem. Soc. 1984, 106, 5759. (e) Zaitsev, V. G.; Daugulis, O.
J. Am. Chem. Soc. 2005, 127, 4156. (f) Kalyani, D.; Deprez, N. R.; Desai,
L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330. (g) Dick, A.
R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300. (h)
Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44, 2112. (i)
Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K. J. Am. Chem. Soc. 2006,
128, 11748.
(2) (a) Ackermann, L.; Althammer, A.; Born, R. Angew. Chem., Int. Ed. 2006,
45, 2619. (b) Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 1999, 121,
6616. (c) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S. J. Am.
Chem. Soc. 2003, 125, 1698. (d) Lim, Y.-G.; Ahn, J.-A.; Jun, C.-H. Org.
Lett. 2004, 6, 4687. (e) Thalji, R. K.; Ellman, J. A.; Bergman, R. G. J.
Am. Chem. Soc. 2004, 126, 7192. (f) Oi, S.; Fukita, S.; Inoue, Y. Chem.
Commum. 1998, 2439.
(3) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320.
(4) (a) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633. (b)
Cai, G.; Fu, Y.; Li, Y.; Wan, X.; Shi. Z. J. Am. Chem. Soc. 2007, 129,
7666. (c) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (d) Dwight,
T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007,
9, 3137. (e) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129,
11904. (f) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc.
2007, 129, 12072.
(5) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437.
(6) (a) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 78. (b) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 12634. (c) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D.-H.;
Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007,
129, 3510.
a Conditions: all reactions were carried out with 1 (0.5 mmol), dicumyl
peroxide 2f (1.0 mmol), 12 h under N2, unless otherwise noted. b Isolated
yields. c 1a (0.5 mmol), dicumyl peroxide (0.75 mmol). d 1a (0.5 mmol),
dicumyl peroxide (1.0 mmol). e 1a (0.5 mmol), dicumyl peroxide (2.0
mmol). f 1d (0.5 mmol), dicumyl peroxide (0.75 mmol).
reaction of 2-(3-methylphenyl)pyridine (1g) gave 3g exclusively
(Table 2, entry 10). It is interesting to note that acetanilides are
also effective in this transformation, generating the methylation
product in moderate yields under these conditions (Table 2, entries
11 and 12).
A tentative mechanism to rationalize this novel palladium
catalyzed methylation of aryl C-H bond is illustrated in Scheme
2. Palladium species A, at a lower oxidation state, inserts into the
weak O-O bond of peroxide 2 to generate a higher oxidation state
intermediate B. Heterolytic â-methyl elimination9 of B leads to
ketone C and the methylpalladium intermediate D. Reaction of D
with arenes generates alcohol E and intermediate F, which leads
to methylation product 3 via reductive elimination, and regenerates
the active palladium species A.10 In support of this proposed
mechanism, nearly stoichiometric amounts of both ketone C and
alcohol E were detected in the crude reaction mixture by 1H NMR
and could be isolated nearly quantitatively by column chromatog-
raphy. On the other hand, no significant isotope effect was observed
in an intramolecular competition experiment using 2-(2-deuterophe-
(7) Yang, S.; Li. B.; Wan, X.; Shi. Z. J. Am. Chem. Soc. 2007, 129, 6066.
(8) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918.
(9) For recent reviews and examples on transition-metal-catalyzed transforma-
tions that involve â-hydrocarbyl eliminations, see: (a) Miura, M.; Satoh,
T. Top. Organomet. Chem. 2005, 14, 1. (b) Jun, C.-H.; Moon, C. W.;
Lee, D.-Y. Chem.sEur. J. 2002, 8, 2422. (c) Terao, Y.; Wakui, H.; Satoh,
T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2001, 123, 10407. (d)
Chow, H.-F.; Wan, C.-W.; Low, K.-H.; Yeung, Y.-Y. J. Org. Chem. 2001,
66, 1910. (e) Zhao, P.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 3124.
(10) Tsuji, J. Palladium Reagents and Catalysts, 2nd ed.; John Wiley & Sons:
Chichester, U.K., 2004.
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