Aerobic Pd-catalyzed sp3 C-H olefination: A route to both N-heterocyclic scaffolds and alkenes

Article abstract of DOI:10.1021/ja2015586

This communication describes a new method for the Pd/polyoxometalate- catalyzed aerobic olefination of unactivated sp³ C-H bonds. Nitrogen heterocycles serve as directing groups, and air is used as the terminal oxidant. The products undergo reversible intramolecular Michael addition, which protects the monoalkenylated product from overfunctionalization. Hydrogenation of the Michael adducts provides access to bicyclic nitrogen-containing scaffolds that are prevalent in alkaloid natural products. Additionally, the cationic Michael adducts undergo facile elimination to release α,β-unsaturated olefins, which can be further elaborated via C-C and C-heteroatom bond-forming reactions.

Full text of DOI:10.1021/ja2015586

COMMUNICATION
pubs.acs.org/JACS
Aerobic Pd-Catalyzed sp3 CÀH Olefination: A Route to Both
N-Heterocyclic Scaffolds and Alkenes
Kara J. Stowers, Kevin C. Fortner, and Melanie S. Sanford*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
S Supporting Information
b
benzyl acrylate (eq 1).5 Although this was a landmark report, the
ABSTRACT: This communication describes a new method
for the Pd/polyoxometalate-catalyzed aerobic olefination of
unactivated sp3 CÀH bonds. Nitrogen heterocycles serve as
directing groups, and air is used as the terminal oxidant. The
products undergo reversible intramolecular Michael addi-
tion, which protects the monoalkenylated product from
overfunctionalization. Hydrogenation of the Michael ad-
ducts provides access to bicyclic nitrogen-containing scaf-
folds that are prevalent in alkaloid natural products.
Additionally, the cationic Michael adducts undergo facile
elimination to release R,β-unsaturated olefins, which can be
further elaborated via CÀC and CÀheteroatom bond-
forming reactions.
transformation has a limited substrate scope, requires stoichiometric
CuII and AgI salts as oxidants, and yields cyclic products derived
from irreversible Michael addition of the amide to the alkene.
As part of a program aimed at developing Pd-catalyzed
methods for the functionalization of unactivated CÀH bonds,10
we report herein a new nitrogen heterocycle-directed sp3 CÀH
olefination reaction. This transformation utilizes air as the
terminal oxidant and proceeds efficiently with a series of different
2-alkylpyridines and R,β-unsaturated alkenes. The olefin-con-
taining products can be elaborated using a variety of synthetic
methods. In addition, this reaction provides a conceptually novel
entry to 6,5-nitrogen heterocycles, which constitute the cores of
numerous alkaloid natural products.
ransition-metal-catalyzed CÀH olefination reactions have
T
been the subject of tremendous research activity over the
past 20 years.1 These transformations provide atom economical
methods for replacing simple carbonÀhydrogen bonds with
readily derivatizable alkene functional groups. A variety of
different metals (for example, Pd, Cu, Ni, Co, Rh, and Ru)
catalyze the olefination of arenes,2 and these transformations
have been applied to the synthesis and functionalization of
biologically active target molecules.3 Pd-based catalysts have
been particularly well studied and effectively promote the reac-
tion of alkenes with diverse arene and heteroarene substrates.4
While the olefination of sp2 CÀH bonds is a reliable and
widely used synthetic method, analogous transformations at
unactivated sp3 CÀH sites remain extremely rare.5,6 Expanding
this chemistry to unactivated alkyl groups is challenging for
several reasons. First, metal-mediated cleavage of sp3 CÀH
bonds is typically slow7 and is expected to be even slower in
the presence of an alkene, which can compete for coordination
sites at the metal center. Second, the key CÀC bond-forming
event requires carbometalation of a Pd-alkyl intermediate. Such
reactions (particularly intermolecular variants) are difficult,
because they are frequently plagued by competing β-hydride
elimination.8,9 Finally, the nucleophilic directing groups required
to promote sp3 CÀH activation can undergo intramolecular
Michael addition to the olefinated products, thereby removing
the versatile olefin functional group that was installed in the first
step. Due to these challenges, there is currently only one report of
the CÀH olefination of unactivated sp3 CÀH bonds.5 As shown
in eq 1, this study by Yu and co-workers described the Pd-
catalyzed reaction of pentafluorophenyl-substituted amides with
Our first efforts toward sp3 CÀH olefination focused on the
reaction of 2-tert-butylpyridine (2-tbp) with electron-deficient
alkenes (eq 2). Extensive previous work from our group10a,b and
others11 has shown that pyridine and quinoline derivatives are
effective directing groups for the Pd-mediated cleavage of sp3
CÀH bonds. The resulting palladacyclic intermediates are gen-
erally slow to undergo β-hydride elimination (presumably due to
the strong coordinating ability of pyridine), making them amen-
able to subsequent functionalization. In addition, we reasoned
that a pyridine directing group could undergo reversible intramo-
lecular Michael addition to the olefin product, thereby providing
access to either olefin (A) or a cyclic pyridinium salt (B),
depending on the reaction conditions (eq 2).
Dioxygen is the most cost-effective and environmentally
benign terminal oxidant for this transformation. As such, we first
examined the reaction of 2-tbp with ethyl acrylate under conditions
reported by Ishii for the Pd/polyoxometalate cocatalyzed aerobic
Received: February 18, 2011
Published: April 08, 2011
r
2011 American Chemical Society
6541
dx.doi.org/10.1021/ja2015586 J. Am. Chem. Soc. 2011, 133, 6541–6544
|

Journal of the American Chemical Society
COMMUNICATION
olefination of benzene derivatives.12 Gratifyingly, the use of 10 mol %
of Pd(OAc)2 and 10 mol % of acetylacetone (acac) along with
3 mol % of H4[PMo11VO40] in AcOH at 90 °C under 1 atm of
O2 provided a 49% yield of product 1 (Table 1, entry 1). Increas-
ing the temperature to 110 °C under 1 atm of O2 significantly
improved the yield to 81% (entry 2).
We were pleased to find that ambient air could be used in place
of 1 atm of O2 without any detrimental effect on the overall yield
(Table 1, entry 3). Finally, removing the acac ligand (entry 4) and
replacing Pd(OAc)2 with the cationic catalyst Pd(MeCN)4(BF4)2
13
(entry 5) both accelerated olefination and limited the formation of
olefin-derived byproducts.14 Interestingly, despite the presence of an
excess (5 equiv) of alkene, this reaction exclusively afforded the
monofunctionalized product 1. This is in marked contrast to the
CÀH acetoxylation of 2-tbp with PhI(OAc)2, which forms mixtures
of mono-, di-, and triacetoxylated products.10b In the current system,
the intramolecular Michael addition appears to play a key role in
protecting the product from overfunctionalization.
As shown in Table 2, a variety of other 2-alkylpyridine
derivatives participate in this sp3 CÀH olefination/cyclization
reaction. We found that replacing NaOAc with 1.1 equiv of NaOTf
allowed for the olefination of substrates lacking geminal dimethyl
groups; for example, both 2-ethyl- and 2-iso-propylpyridine afforded
high yields of the desired products (entries 1 and 2).
Table 1. Optimization of Pd-Catalyzed Reaction between
2-tert-Butylpyridine and Ethyl Acrylate
CÀH activation/CÀC coupling proceeded with >20:1 selec-
tivity for 1° over 2° sp3 CÀH bonds (for example, see entry 3).
However, a 2° CÀH bond on the cyclopropane ring of 2-cyclo-
propyl-3-methylpyridine could be functionalized to form tricyclic
product 5 in modest yield (entry 4). Both electron-withdrawing
and electron-donating substituents were tolerated on the pyridine
ring (entries 5À7), and a tethered ester functional group was also
compatible with the reaction conditions (entry 9). Remarkably,
even 2-methyl-6-tert-butylpyridine provided a moderate (36%)
yield, despite the sterically crowded environment around the
pyridine moiety (entry 8). Finally, quinoline was a useful directing
group for sp3 CÀH olefination under these conditions (entry 10).
Entry
[Pd]
Pd(OAc)2
Conditions
Yield 1 (%)a
1
2
3
4
5
90 °C, O2, acac
110 °C, O2, acac
110 °C, air, acac
110 °C, air
49
81
83
89
92
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(MeCN)4(BF4)2
110 °C, air
a Yield determined by 1H NMR spectroscopic analysis.
Table 2. Pd-Catalyzed Olefination and Cyclization between Various Pyridines and Ethyl Acrylate
a Conditions: 1.1 equiv of NaOTf, 10 mol % of Pd(MeCN)4(BF4)2, 3 mol % of H4[PMo11VO40], 5 equiv of ethyl acrylate, AcOH, air, 110 °C, 18 h.
b Conditions: (i) 10 mol % of NaOAc, 10 mol % of Pd(MeCN)4(BF4)2, 3 mol % of H4[PMo11VO40], 5 equiv of ethyl acrylate, AcOH, air, 110 °C, 18 h;
(ii) saturated aq. NaBF4.
6542
dx.doi.org/10.1021/ja2015586 |J. Am. Chem. Soc. 2011, 133, 6541–6544

Journal of the American Chemical Society
COMMUNICATION
Table 3. Alkene Scope for CÀH Bond Alkenylation
Scheme 2. Functionalization of CÀH Olefinated Product
15a
Entry
R
Yield (%)
1
2
3
4
5
6
7
8
CO2Et
CO2Bu
CO2Bn
CO2H
CONMe2
COEt
Ph
90a
80a
75a
69b
55b
40a
<5b
nrc
a Conditions: (a) AD-mix β, MeSO2NH2, t-BuOH, H2O, 0 °C, 92%,
97% ee. (b) H2, Pd/C, EtOH, rt, 90%. (c) CuBr, LiCl, EtMgBr, TMSCl,
THF, 0 °C, 94%.
Butyl
a Isolated yield. b Yield determined by 1H NMR spectroscopic analysis.
c nr = no reaction detected.
Scheme 1. Reduction Reactions of 2
pyridine moiety was compatible with various transition-metal-
mediated olefin functionalization reactions. As shown in
Scheme 2, 15 underwent smooth and high yielding asymmetric
dihydroxylation17 (to form 16 in 97% ee), Pd/C-catalyzed
hydrogenation18 (to form 17), and Cu-catalyzed conjugate
addition of EtMgBr19 (to form 18).
In conclusion, this communication describes a new Pd-cata-
lyzed reaction for the pyridine-directed aerobic olefination of
unactivated sp3 CÀH sites. This transformation provides a
convenient route to 6,5-N-fused bicyclic cores as well as readily
functionalizable alkene products. Ongoing work is focused on
expanding the scope of this transformation with respect to both
the directing group and alkene substrate, and these results will be
reported in due course.
The reaction of 2-tbp was also examined with a series of other
olefinic substrates. As shown in Table 3, R,β-unsaturated esters,
amides, and ketones were effective alkene coupling partners.
Remarkably, the free carboxylic acid moiety of acrylic acid was
also well tolerated (entry 4). In contrast, more electron-rich
olefins like styrene and 1-hexene exhibited low reactivity under
the current conditions (entries 7 and 8). This is also a common
limitation of Pd-catalyzed arene CÀH alkenylation reactions.4
The cationic bicyclic products in Tables 1À3 are useful
synthetic intermediates. For example, the PtO2-catalyzed reduc-
tion of 2 with H2 formed piperidine 12 in 75% yield as a 28:1
mixture of cis and trans isomers (Scheme 1).15 In addition, partial
reduction of 2 with NaBH4 in EtOH afforded 1,2,3,6-tetrahy-
dropyridine 13 in 81% yield as a 2.3:1 mixture of readily separable
cis and trans isomers (Scheme 1).16 This chemistry provides an
expedient route to 6,5-nitrogen heterocycles, which are a com-
mon structural motif in naturally occurring alkaloids.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental and isolation
b
procedures, and characterization data for all new compounds.
This material is free of charge via the Internet at http://pubs.acs.
org.
’ AUTHOR INFORMATION
Corresponding Author
mssanfor@umich.edu
The pyridinium products of sp3 CÀH olefination/cyclization
can also be converted to the corresponding alkenes by treatment
with base. For example, the reaction of 2 with 2 equiv of DBU in
CH2Cl2 for 1 h afforded olefin 15 in 95% yield (eq 3).
’ ACKNOWLEDGMENT
We thank the NIH (GM073836 and GM073836-05S1) for
support of this research. K.J.S. thanks the ACS Division of
Organic Chemistry/Eli Lilly for a graduate fellowship. In addi-
tion, we thank Asako Kubota for the preparation of substrate S5.
’ REFERENCES
(1) Oestreich, M., Ed. The MizorokiÀHeck Reaction; John Wiley and
Sons: Chicester, U.K., 2009.
(2) (a) Satoh, T.; Miura, M. Chem.—Eur. J. 2010, 16, 11212.
(b) Reference 1d, pp 383À400.
The ability to readily generate the olefin-containing products
allowed us to explore the further functionalization of these
molecules. In particular, we sought to demonstrate that the
(3) (a) Trost, B. M.; Godleski, S. A.; Genet, J. P. J. Am. Chem. Soc.
1978, 100, 3930. (b) Baran, P. S.; Corey, E. J. J. Am. Chem. Soc. 2002,
124, 7904. (c) Garg, N. K.; Caspi, D. D.; Stoltz, B. M. J. Am. Chem. Soc.
6543
dx.doi.org/10.1021/ja2015586 |J. Am. Chem. Soc. 2011, 133, 6541–6544

Journal of the American Chemical Society
COMMUNICATION
2004, 126, 9552. (d) Beck, E. M.; Hatley, R.; Gaunt, M. J. Angew. Chem.,
Int. Ed. 2008, 47, 3004. (e) Wang, D. H.; Engle, K. M.; Shi, B. F.; Yu, J.-Q.
Science 2010, 327, 315.
(4) Reference 1, pp 345À378.
(5) Wasa, M.; Engle, K. M.; Yu, J. Q. J. Am. Chem. Soc. 2010,
132, 3680.
(6) For examples of olefination and alkylation at sp3 CÀH sites
activated by R-heteroatoms or aromatic rings, see: (a) Chatani, N.;
Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai, S. J. Am. Chem.
Soc. 2001, 123, 10935 and references therein. (b) DeBoef, B.; Pastine,
S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126, 6556. (c) Song, C.-X.; Cai,
G.-X.; Farrell, T. R.; Jiang, Z.-P.; Li, H.; Gan, L.-B.; Shi, Z.-J. Chem.
Commun. 2009, 6002.
(7) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin,
O. Chem.—Eur. J. 2010, 16, 2654.
(8) Shultz, L. H.; Tempel, D. J.; Brookhart, M. J. Am. Chem. Soc.
2001, 123, 11539.
(9) (a) Firmansjah, L.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 11340.
(b) Bloome, K. S.; Alexanian, E. J. J. Am. Chem. Soc. 2010, 132, 12823.
(10) (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2004, 126, 2300. (b) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem.
Soc. 2004, 126, 9542. (c) Dick, A. R.; Sanford, M. S. Tetrahedron 2006,
62, 2439. (d) Neufeldt, S. R.; Sanford, M. S. Org. Lett. 2010, 12, 532.
(e) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(11) For examples, see: (a) Zaitsev, V. G.; Shabashov, D.; Daugulis,
O. J. Am. Chem. Soc. 2005, 127, 13154. (b) Shabashov, D.; Daugulis, O.
Org. Lett. 2005, 7, 3657. (c) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J.
Org. Lett. 2006, 8, 3391. (d) Shabashov, D.; Daugulis, O. J. Am. Chem.
Soc. 2010, 132, 3965. (e) Zhang, S.; Luo, F.; Wang, W.; Jia, X.; Hu, M.;
Cheng, J. Tetrahedron Lett. 2010, 51, 3317.
(12) Obora, Y.; Ishii, Y. Molecules 2010, 15, 1487.
(13) Nishikata, T.; Lipshutz, B. H. Org. Lett. 2010, 12, 1972.
(14) Product 1 was also formed when H4[PMo11VO40]/air was
replaced with other oxidants (e.g., Cu(OAc)2 or benzoquinone); how-
ever, significantly lower yields were obtained with these oxidants. See
Table S3 for details.
(15) Azzouz, R.; Fruit, C.; Bischoff, L.; Marsais, F. J. Org. Chem.
2008, 73, 1154.
(16) Sinigaglia, I.; Nguyen, T. M.; Wypych, J. C.; Delpech, B.;
Marazano, C. Chem.—Eur. J. 2010, 16, 3594.
(17) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
(18) Dias, L. C.; de Oliveira, L. G.; Vilcachagua, J. D.; Nigsch, F.
J. Org. Chem. 2005, 70, 2225.
(19) Reetz, M. T.; Kindler, A. J. Organomet. Chem. 1995, 502, C5.
6544
dx.doi.org/10.1021/ja2015586 |J. Am. Chem. Soc. 2011, 133, 6541–6544