Pyridine ligands as promoters in PdII/0-catalyzed C-H olefination reactions

Article abstract of DOI:10.1021/ol300281p

Commercially available pyridine ligands can significantly enhance the rate, yield, substrate scope, and site selectivity of arene C-H olefination (Fujiwara-Moritani) reactions. The use of a 1:1 ratio of Pd/pyridine proved critical to maximize reaction rates and yields.

Full text of DOI:10.1021/ol300281p

ORGANIC
LETTERS
Pyridine Ligands as Promoters in PdII/0-
2012
Vol. 14, No. 7
1760–1763
Catalyzed CÀH Olefination Reactions
Asako Kubota, Marion H. Emmert, and Melanie S. Sanford*
University of Michigan, Department of Chemistry, 930 North University Avenue, Ann
Arbor, Michigan 48109-1055, United States
mssanfor@umich.edu
Received February 14, 2012
ABSTRACT
Commercially available pyridine ligands can significantly enhance the rate, yield, substrate scope, and site selectivity of arene CÀH olefination
(FujiwaraÀMoritani) reactions. The use of a 1:1 ratio of Pd/pyridine proved critical to maximize reaction rates and yields.
The Pd-mediated CÀH olefination of benzene was first
reported in 1967 by Fujiwara and Moritani.1 Since this
initial publication, numerous catalytic versions of this
transformation have been developed. The vast majority of
these catalytic protocols proceed under “ligandless” condi-
tions (with PdII salts such as Pd(OAc)2 as catalysts) and use
oxidants such as peroxides, peroxyesters, dioxygen, poly-
oxometalates, CuII, or AgI to achieve catalytic turnover.2
A variety of aromatic compounds can be employed as arene
substrates,2 and high levels of site selectivity are possible
using substrates that contain directing groups.2À5
Despite the above illustrated advances, several signifi-
cant problems remain unsolved.6,7 First, the substrate
scope for simple aromatics that do not contain directing
groups remains primarily limited to electron-rich and
-neutral derivatives; in general, electron-deficient arenes
exhibit sluggish reactivity.7e,h Second, most substituted
aromatic substrates react to afford mixtures of isomeric
products.6,7e While there has been some success in the use
of solvent and/or oxidant to control site selectivity in the
CÀH olefination of heterocycles (e.g., indole, pyrrole),8
catalyst controlled selectivity remains challenging for most
other classes of arene substrates. Third, the vast majority
of catalytic FujiwaraÀMoritani (FÀM) reactions require
(1) Moritani, I.; Fujiwara, Y. Tetrahedron Lett. 1967, 1119.
(2) (a) Moritani, I.; Fujiwara, Y. Synthesis 1973, 524. (b) Karimi, B.;
Behzadnia, H.; Elhamifar, D.; Akhavan, P. F.; Esfahani, F. K.; Zamani,
A. Synthesis 2010, 1399. (c) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111,
1170.
(3) For recent examples of substrate-directed CÀH olefination, see: (a)
Wang, D. H.; Engle, K. M.; Shi, B. F.; Yu, J.-Q. Science 2010, 327, 315.
(b) Lu, Y.; Wang, D. H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010,
132, 5916. (c) Garcia-Rubia, A.; Urones, B.; Arrayas, R. G.; Carretero,
J. C. Angew. Chem., Int. Ed. 2011, 50, 10927. (d) Garcia-Rubia, A.;
Fernandez-Ibanez, M. A.; Arrayas, R. G.; Carretero, J. C. Chem.;Eur.
J. 2011, 17, 3567. (e) Dai, H. X.; Stepan, A. F.; Plummer, M. S.; Zhang,
Y. H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7222. (f) Zhu, C.; Falck,
J. R. Org. Lett. 2011, 13, 1214. (g) Wang, L.; Liu, S.; Li, Z.; Yu, Y. Org.
Lett. 2011, 13, 6137.
(6) (a) Jia, C.; Lu, W.; Kitamura, T.; Fujiwara, Y. Org. Lett. 1999, 1,
2097. (b) Dams, M.; De Vos, D. E.; Celen, S.; Jacobs, P. A. Angew.
Chem., Int. Ed. 2003, 42, 3512. (c) Obora, Y.; Okabe, Y.; Ishii, Y. Org.
Biomol. Chem. 2010, 8, 4071.
(7) (a) Fujiwara, Y.; Moritani, I.; Matsuda, M.; Teranishi, S.
Tetrahedron Lett. 1968, 3863. (b) Fujiwara, Y.; Moritani, I.; Danno,
S.; Asano, R.; Teranishi, S. J. Am. Chem. Soc. 1969, 91, 7166. (c) Shue,
R. S. J. Chem. Soc. D 1971, 1510. (d) Shue, R. S. J. Catal. 1972, 26, 112.
(e) Fujiwara, Y.; Asano, R.; Moritani, I.; Teranishi, S. J. Org. Chem.
1976, 41, 1681. (f) Zhang, X.; Fan, S.; He, C. Y.; Wan, X.; Min, Q. Q.;
Yang, J.; Jiang, Z. X. J. Am. Chem. Soc. 2010, 132, 4506. (g) Li, Z.;
Zhang, Y.; Liu, Z. Q. Org. Lett. 2012, 14, 74. (h) Zhang, Y.; Li, Z.; Liu,
Z. Q. Org. Lett. 2012, 14, 226.
(8) (a) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J.
Angew. Chem., Int. Ed. 2005, 44, 3125. (b) Beck, E. M.; Grimster, N. P.;
Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528. (c) Beck,
E. M.; Hatley, R.; Gaunt, M. J. Angew. Chem., Int. Ed. 2008, 47, 3004.
(d) Potavathri, S.; Dumas, A. S.; Dwight, T. A.; Naumiec, G. R.;
Hammann, J. M.; DeBoef, B. Tetrahedron Lett. 2008, 49, 4050.
(4) For sp3-CÀH olefination, see: (a) Zhang, Y. H.; Shi, B. F.; Yu,
J.-Q. J. Am. Chem. Soc. 2009, 131, 5072. (b) Stowers, K. J.; Fortner,
K. C.; Sanford, M. S. J. Am. Chem. Soc. 2011, 133, 6541. (c) Wang, C.;
Ge, H. Synthesis 2011, 2590.
(5) (a) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M.
J. Org. Chem. 1998, 63, 5211. (b) 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, 7904. (c) Zaitsev, V. G.; Daugulis, O.
J. Am. Chem. Soc. 2005, 127, 4156. (d) Cai, G.; Fu, Y.; Li, Y.; Wan, X.;
Shi, Z. J. Am. Chem. Soc. 2007, 129, 7666. (e) Wang, J. R.; Yang, C. T.;
Liu, L.; Guo, Q. X. Tetrahedron Lett. 2007, 48, 5449. (f) Li, J. J.; Mei, T. S.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 6452.
r
10.1021/ol300281p
Published on Web 03/12/2012
2012 American Chemical Society

R,β-unsaturated olefins as the alkene substrate. While some
examples with styrene and ethylene have been reported,7 the
use of R-olefins remains problematic in most cases.7fÀh
An attractive strategy to address all three of these chal-
lenges would be to develop supporting ligands that enhance
the reactivity and selectivity of the PdII catalyst,9 as has been
demonstrated in related biaryl coupling reactions.10 Recently
Yu et al. demonstrated promising preliminary success toward
this goal. As shown in Scheme 1, the use of 2,6-dialkylpyr-
idine ligand L1 enabled the coupling of several electron-
deficient aromatic substrates with R,β-unsaturated olefins
using O2 as the terminal oxidant.11 Notably, the monoligand
complex (L1)Pd(OAc)2 was proposed as the catalytically
active species in this system on the basis of NMR analysis.
While the results in Scheme 1 are exciting, much room for
improvement remains. For example, high catalyst loadings
of Pd(OAc)2/L1 (10 mol %/20 mol %) were required, site
selectivity was modest for most substrates, and L1 is not
commercially available. Notably, Yu reported that the use
of commercial ligands such as pyridine and lutidine under
his optimized aerobic conditions (1:2 ratio of Pd/mono-
dentate ligand) completely inhibited catalytic turnover.
Figure 1. Formation of 1 over 24 h as a function of catalyst [1:1
Pd(OAc)2/py ([),1:2 Pd(OAc)2/py(9), Pd(OAc)2 (2)].
Scheme 1. Pd(OAc)2/L1-Catalyzed CÀH Olefination Reactions
with O2 as the Terminal Oxidant11a
Figure 2. Yield of 1 after 3 h as a function of mol % pyridine.
of Pd(OAc)2 to pyridine would have an analogous accel-
erating effect on this transformation.
Our initial studies to test this hypothesis focused on the
Pd(OAc)2/pyridine-catalyzed CÀH olefination of benzene
with ethyl cinnamate to afford ethyl 3,3-diphenylacrylate (1).
The reaction was first examined using 1 atm of O2 as
the oxidant (in analogy to Scheme 1). However, in our hands,
these conditions provided irreproducible rates and reaction
yields. This might be due to challenges associated with con-
trolling the concentration of O2 (g) and due to slow oxida-
tion of Pd(0) (which could lead to catalyst decomposition).
We were pleased to find that substitution of O2 with tert-
butylperoxybenzoate as the terminal oxidant resulted in
reproducible rates and yields and enabled us to assess the
influence of pyridine on this transformation.8a,b,9b,9c,13
The time study shown in Figure 1 revealed that Pd(OAc)2
with no added ligand was a moderately effective catalyst.
For example, 5 mol % of Pd(OAc)2 provided complete
conversion (and ∼70% yield of 1) after 18 h at 100 °C. The
addition of 2 equiv of pyridine per Pd (10 mol % pyridine)
slowed the rate, affording an ∼55% yield of 1 after 18 h.
However, the use of a 1:1 ratio of Pd(OAc)2 to pyridine
resulted in a 76% yield of 1 after just 6 h at 100 °C.14
A recent report from our group suggested that it might
bepossibletoutilizemuchsimplerpyridine ligands than L1
to enhance reactivity and modulate site selectivity in Pd-
catalyzed FÀM reactions.12 Our studies showed that the use
of a 1:1 ratio of Pd(OAc)2/pyridine (pyr) leads to a dramatic
acceleration of the PdII/IV-catalyzed CÀH acetoxylation of
benzene derivatives. The observed effect was proposed to
result from an increased rate of CÀH activation at the
coordinatively unsaturated catalyst (pyr)Pd(OAc)2.12 Since
a similar arene CÀHactivationstepisproposedintheFÀM
reaction, we hypothesized that the use of an equimolar ratio
(9) For intermolecular reactions, see: (a) Mikami, K.; Hatano, M.;
Terada, M. Chem. Lett. 1999, 55. For intramolecular reaction, see:
(b) Schiffner, J. A.; Machotta, A. B.; Oestreich, M. Synlett 2008, 2271.
(c) Schiffner, J. A.; Woste, T. H.; Oestreich, M. Eur. J. Org. Chem.
2010, 174.
(10) For recent examples, see: (a) Stuart, D. R.; Fagnou, K. Science
2007, 316, 1172. (b) Izawa, Y.; Stahl, S. S. Adv. Synth. Catal. 2010, 352,
3223. (c) Campbell, A. N.; Meyer, E. B.; Stahl, S. S. Chem. Commun.
2011, 47, 10257.
(11) (a) Zhang, Y. H.; Shi, B. F.; Yu, J.-Q. J. Am. Chem. Soc. 2009,
131, 5072. (b) Zhang, S.; Shi, L.; Ding, Y. J. Am. Chem. Soc. 2011, 133,
20218.
(12) Emmert, M. H.; Cook, A. K.; Xie, Y. J.; Sanford, M. S. Angew.
Chem., Int. Ed. 2011, 50, 9409.
(13) Tsuji, J.; Nagashima, H. Tetrahedron 1984, 40, 2699.
(14) Notably, under these conditions, ligand L1 performed much
more poorly than simple pyridine; furthermore, the ratio of L1:Pd (1:1
versus 2:1) had minimal influence on the rate or final yield of the reaction
(Figures S1 and S3).
Org. Lett., Vol. 14, No. 7, 2012
1761

Table 1. Optimization of CÀH Olefination Reaction
Table 3. CÀH Olefination of Benzene with Different Alkenes
entry
Pd/pyr (mol %)
oxidant
% yielda
t
1
2
3
4
5
6
7
Pd (5)/pyr (5)
Pd (2.5)/pyr (2.5)
Pd(1)/pyr(1)
PhCO3 Bu
78
73
58
8
t
PhCO3 Bu
t
PhCO3 Bu
Pd (5)/pyr (5)
Pd (5)/pyr (5)
Pd (5)/pyr (5)
Pd (5)/pyr (5)
Benzoquinone
tBuOOH
AgOAc
41
49
57
K2S2O8
a NMR average yields based on 1,3-dinitrobenzene standard. Re-
ported yields represent averages of at least two reactions.
Table 2. Ligand Effects on CÀH Olefination
entry
ligand
% yielda
1
2
3
4
5
6
7
pyridine
76
69
69
78
80
81
61
2-picoline
4-methoxypyridine
3-nitropyridine
acridine
a Isolated yield. b Yield determined by 1H NMR analysis of crude
reaction mixture. c Isolated as a mixture with the byproduct phenylated
at the R-methyl. d Isolated as a mixture with the corresponding dipheny-
lated product. e Oxidant used as the limiting reagent with an excess of
ethylene.
3,5-dichloropyridine (L2)
L1
a NMR average yields based on 1,3-dinitrobenzene standard. Re-
ported yields represent averages of at least two reactions.
We next conducted a more detailed assessment of the
influence of the Pd to pyridine ratio on this reaction by
determining reaction yields for various Pd/pyr ratios after
3 h. As shown in Figure 2, significantly higher yields were
observed with 2.5À6.2 mol % of pyridine (corresponding
to Pd/pyr between 1:0.5 and ∼1:1).
using 3-nitropyridine, acridine, and 3,5-dichloropyridine
(Table 2, entries 4À6). Of all the investigated ligands, 3,5-
dichloropyridine (L2) afforded the highest yield (81%);
therefore, L2 was used in further studies to assess the
substrate scope of this transformation. Interestingly, L1
(entry 7) gave slower rates and lower yields of the product
than pyridine (Table 2, entry 1; Figure S3) under our
conditions. This is particularly remarkable because L1
was reported to be uniquely effective for the aerobic reaction
in Scheme 1.11 These results suggest that ligand effects on
the reactivity of Pd catalysts in FÀM reactions can be highly
oxidant-dependent.16
A variety of alkenes participate in the Pd(OAc)2/L2-
catalyzed CÀH olefination, with R,β-unsaturated olefins
serving as particularly effective substrates. For example,
the reactions of benzene (40 equiv) with acrylate deriva-
tives proceeded in 34À95% yield (Table 3, entries 1À7).
Additional optimization of this transformation is sum-
marized in Table 1. As shown in entries 1À3, the Pd(OAc)2
/pyr loading could be lowered to 2.5 mol % without a
major drop in reaction yield. Even just 1 mol % of
Pd(OAc)2/pyr provided synthetically useful yields of 1.
Other terminal oxidants were effective; most notably,
K2S2O8 afforded a 57% yield of the CÀH olefination pro-
t
duct (entry 7). Overall, PhCO3 Bu provided the best results
of the oxidants examined.15
Other pyridine ligands were also evaluated for this trans-
formation. Many commercially available mono- and disub-
stituted pyridines afforded comparable results to pyridine
(Tables 2 and S8). Furthermore, yields could be improved
(16) Ligand L1 may be susceptible to benzylic oxidation in the
presence of oxidants like PhCO3 Bu, which could account for the
t
t
differences in reactivity with O2 vs PhCO3 Bu as the terminal oxidant.
(15) For a complete list of oxidants examined, see Table S7.
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Org. Lett., Vol. 14, No. 7, 2012

Table 4. CÀH Olefination of Different Arenes with Ethyl
Table 5. Ligand Effects on Site Selectivity
Acrylate
entry
ligand (mol %)
% yielda
β/R
1
2
3
4
5
none
61
61
81
62
63
2.8 ( 0.1
2.6 ( 0.1
2.9 ( 0.1
4.2 ( 0.5
4.7 ( 0.3
L1 (5)
L2 (5)
acridine (5)
acridine (15)
a Yield and isomer ratio determined by 1H NMR spectroscopic
analysis of crude reaction mixture based on 1,3-dinitrobenzene stan-
dard. Reported yields represent averages of three reactions.
site selectivity of CÀH olefination. For example, as shown
in Table 5, with o-xylene as the substrate the ratio of β/R
isomeric products changed from 2.8:1 to 4.2:1 upon mov-
ing from Pd(OAc)2 to Pd(OAc)2/acridine (1:1) as the
catalyst. Furthermore, increasing the Pd/acridine ratio to
1:3 further enhanced the selectivity to 4.7:1. While this
selectivity remains modest, the results provide promising
support for the viability of catalyst control over site selec-
tivity in these and related CÀH functionalization reactions.
In conclusion, this report demonstrates that simple
a [arene] = 1 M. b Product ratios determined from isolated mixtures.
Ratio reported as o/m/p or R/β. c [arene] = 0.28 M.
pyridine ligands serve as efficient promoters for the PdII/0
-
Moderate yields (62À76%) were obtained even upon low-
ering the equivalents of benzene from 40 to 11 equiv for
many of these substrates. Styrene, allyl acetate, and ethy-
lene (entries 8À10) also afforded olefinated products in
moderate yields under these conditions.
catalyzed FujiwaraÀMoritani reaction. Ongoing efforts
are focused on identifying ligands to further improve both
the reactivity and selectivity in these systems.
Acknowledgment. We thank the NSF for support of
this work through the Center for Enabling New Technolo-
gies through Catalysis (CENTC) and Professors Karen
Goldberg (University of Washington), Bill Jones
(University of Rochester), Mike Heinekey (University of
Washington), and Elon Ison (NC State) for valuable
discussions. M.H.E. thanks the DFG (German Research
Council) for a postdoctoral fellowship (EM 219/1-1). We
thank Amanda K. Cook (University of Michigan) for
preliminary studies of aerobic CÀH olefination reactions.
As shown in Table 4, many different arene substrates
participate in Pd(OAc)2/L2-catalyzed CÀH olefination
with ethyl acrylate. Electron-rich arenes such as toluene,
anisole, and o-xylenes afforded good yields (69À75%) of
mono-olefinated products (entries 1À4). Naphthalene also
provided good results, affording a 1:1 ratio of the R and β
isomeric products in 79% yield (entry 5). Finally, electron-
deficient aromatics (which have traditionally proven to be
challenging substrates for CÀH olefination)7e,h reacted in
moderate to good yields (32À93%, entries 6À10). Nota-
bly, ethyl benzoate and trifluorotoluene preferentially
afforded the meta-olefinated product, with selectivities
very similar to those reported by Yu for related aerobic
reactions using ligand L1 (entries 9À10).11
Supporting Information Available. Complete experimen-
tal details, characterization data for all new compounds, and
additional optimization tables. This material is available free
of charge via the Internet at http://pubs.acs.org.
Preliminary results show that the pyridine ligand can
influence not only the reaction rate and yield but also the
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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