Palladium-catalyzed oxidative amination of alkenes: Improved catalyst reoxidation enables the use of alkene as the limiting reagent

Article abstract of DOI:10.1021/ol701903r

Palladium-catalyzed methods for intermolecular aerobic oxidative amination of alkenes have been identified that are compatible with the use of alkene as the limiting reagent. These procedures, which enhance the utility of this reaction with alkenes that a

Full text of DOI:10.1021/ol701903r

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4331-4334
Palladium-Catalyzed Oxidative Amination
of Alkenes: Improved Catalyst
Reoxidation Enables the Use of Alkene
as the Limiting Reagent
Michelle M. Rogers, Vasily Kotov, Jaruwan Chatwichien, and Shannon S. Stahl*
Department of Chemistry, UniVersity of WisconsinsMadison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706
stahl@chem.wisc.edu
Received August 5, 2007
ABSTRACT
Palladium-catalyzed methods for intermolecular aerobic oxidative amination of alkenes have been identified that are compatible with the use
of alkene as the limiting reagent. These procedures, which enhance the utility of this reaction with alkenes that are not commercially available,
are demonstrated with substrates bearing dialkyl ether, carboxyester, epoxide, and silyl ether groups.
Metal-catalyzed addition of nitrogen nucleophiles (e.g.,
amines, amides, carbamates) to alkenes represents a long-
standing challenge in organic chemistry and an attractive
target for the preparation of nitrogen-containing organic
molecules.1 Despite recent progress in this area, fundamental
limitations remain. For example, innovative methods for the
amination of vinyl arenes and dienes have been developed,2
but in most cases, they are ineffective with alkyl olefins.3
Moreover, most of the amination reactions of this type
reported to date require the use of excess alkene (2-6 equiv
relative to the nitrogen nucleophile).2-5 This feature limits
the utility of these methods to commercially available or
readily (and inexpensively) prepared alkenes. Recent efforts
in our laboratory have been focused on Pd-catalyzed methods
for intermolecular oxidative amination of alkenes, particularly
(4) (a) Qian, H.; Widenhoefer, R. A. Org. Lett. 2005, 7, 2635-2638.
(b) Johns, A. M.; Utsunomiya, M.; Incarvito, C. D.; Hartwig, J. F. J. Am.
Chem. Soc. 2006, 128, 1828-1839. (c) Li, Z.; Zhang, J.; Brouwer, C.; Yang,
C.-G.; Reich, N. W.; He, C. Org. Lett. 2006, 8, 4175-4178. (d) Li, Z.;
Ding, X.; He, C. J. Org. Chem. 2006, 71, 5876-5880. (e) Lee, J. M.; Ahn,
D.-S.; Jung, D. Y.; Lee, J.; Do, Y.; Kim, S. K.; Chang, S. J. Am. Chem.
Soc. 2006, 128, 12954-12962.
(5) For examples of metal-catalyzed alkene-amination methods that
employ alkene as the limiting reagent, see: (a) So¨dergren, M. J.; Alonso,
D. A.; Bedekar, A. V.; Andersson, P. G. Tetrahedron Lett. 1997, 38, 6897-
6900. (b) Guthikonda, K.; Du Bois, J. J. Am. Chem. Soc. 2002, 124, 13672-
13673. (c) Siu, T.; Yudin, A. K. J. Am. Chem. Soc. 2002, 124, 530-531.
(d) Di Chenna, P. H.; Robert-Peillard, F.; Dauban, P.; Dodd, R. H. Org.
Lett. 2004, 6, 4503-4505. (e) Fruit, C.; Robert-Peillard, F.; Bernardinelli,
G.; Mu¨ller, P.; Dodd, R. H.; Dauban, P. Tetrahedron: Asymmetry 2005,
16, 3484-3487. (f) Zhang, J.-L.; Che, C.-M. Org. Lett. 2002, 4, 1911-
1914. (g) Li, J.; Chan, P. W. H.; Che, C.-M. Org. Lett. 2005, 7, 5801-
5804. (h) Waser, J.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 4099-
4102. (i) Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am. Chem.
Soc. 2006, 128, 11693-11712. (j) Taylor, J. G.; Whittall, H. N.; Hii, K. K.
Org. Lett. 2006, 8, 3561-3564.
(1) For reviews, see: (a) Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98,
675-703. (b) Brunet, J. J.; Neibecker, D. Catalytic Heterofunctionalization;
Togni, A., Gru¨tzmacher, H., Eds.; Wiley-VHC: New York, New York,
2001; pp 91-141. (c) Beller, M.; Breindl, C.; Eichberger, M.; Hartung, C.
G.; Seayad, J.; Thiel, O. R.; Tillack, A.; Trauthwein, H. Synlett 2002, 1579-
1594. (d) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673-686. (e)
Hartwig, J. F. Pure Appl. Chem. 2004, 76, 507-516. (f) Kotov, V.;
Scarborough, C. C.; Stahl, S. S. Inorg. Chem. 2007, 46, 1910-1923.
(2) (a) Beller, M.; Eichberger, M.; Trauthwein, H. Angew. Chem., Int.
Ed. 1997, 36, 2225-2227. (b) Kawatsura, M.; Hartwig, J. F. J. Am. Chem.
Soc. 2000, 122, 9546-9547. (c) Utsunomiya, M.; Kuwano, R.; Kawatsura,
M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 5608-5609. (d)
Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 2702-2703.
(3) For recent methods compatible with the use of unactivated alkyl
olefins as substrates, see: (a) Ryu, J.-S.; Li, G. Y.; Marks, T. J. J. Am.
Chem. Soc. 2003, 125, 12584-12605. (b) Zhang, J.; Yang, C.-G.; He, C.
J. Am. Chem. Soc. 2006, 128, 1798-1799.
10.1021/ol701903r CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/21/2007

Scheme 1. Palladium-Catalyzed Intermolecular Aerobic
Table 1. Evaluation of Catalytic Conditions for Intermolecular
Oxidative Amination of Alkenesa
Oxidative Amination of Alkenes
yieldb (%)
2/3 (1/4)
entry
Pd (mol %)
Cu (mol %)
additive
1
2
3
4
5
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
-
-
-
-
-
-
22/4 (44/13)c
42/8 (18/17)c
36/8 (18/13)c
51/11 (6/13)c
0/0 (0/95)c
Cu (OAc)2 (5)
-
Cu(OAc)2 (10)
those that employ O2 as the stoichiometric oxidant (Scheme
1).1f,6 Initial results with vinyl arenes6a were later extended
to applications with unactivated alkyl olefins.6b These results
demonstrate a new class of oxidative C-N bond-forming
reactions and represent a very efficient route to terminal
enimides.7 Nevertheless, the utility of these reactions is
diminished by the requirement for excess alkene. Here, we
describe the development and application of aerobic oxidative
amination methods compatible with the use of alkene as the
limiting reagent. The results enhance the utility of these
catalytic methods and provide a basis for the rational
development of improved Pd catalysts.
Two observations from our prior studies illuminate the
origin of the challenge in using alkenes as the limiting
reagent: (1) the rate of Pd-catalyzed oxidative amination of
alkenes depends upon the alkene concentration (ranging from
first-order to saturation dependence)6c and (2) a significant
amount of catalyst decomposition occurs during the reactions
in the form of Pd black. These observations indicate that
lower alkene concentrations will reduce the catalytic turnover
rate and increase complications associated with competing
catalyst decomposition. The development of improved
methods for catalyst oxidation should enhance catalyst
stability and, potentially, lead to enhanced product yields at
lower alkene concentrations.
(CH3CN)2PdCl2 CuCl2 (5)
(5)
6
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Cu(OAc)2
(2 equiv)
-
-
36/6d
7
benzoquinone 5/1d
(1 equiv)
8
Cu(OAc)2 (5) 3 Å MS
13/3
(10 mg)
9
Cu(OAc)2 (5) NaOAc
(1 equiv)
Cu(OAc)2 (5) KH2PO4
0/0 (96/0)
52/11 (12/11)
49/10
10
11
12
13
(1 equiv)
Cu(OAc)2 (5) PhCO2H
(20 mol %)
Cu(OAc)2 (5) cyclooctadiene 49/10
(5 mol %)
Cu(OAc)2 (5) methyl
acrylate
58/13 (6/13)c
(1 equiv)
14e Pd(OAc)2 (5)
Cu(OAc)2 (5) methyl
45/9 (19/14)c
acrylate
(1 equiv)
15e Pd(OAc)2 (10)
16e Pd(OAc)2 (10)
Cu(OAc)2 (10) 4 atm O2
Cu(OAc)2 (10) methyl
acrylate
50/12 (0/11)c
57/12 (0/11)c
(1 equiv),
4 atm O2
17e Pd(OAc)2 (10)
-
4 atm O2
68/12 (5/11)c
a
Reaction conditions: tetradecene (375 µmol), phthalimide (450 µmol),
b
c
1 atm of O2, 400 µL of PhCN. GC; int. std. ) octadecane. Yields
1
d
determined by H NMR; int. std. ) 1,3,5-trimethoxybenzene. Reactions
e
performed with 1 atm of ambient air. Reaction conditions: tetradecene
(1.0 mmol), phthalimide (1.2 mmol), 1.3 mL of benzonitrile.
Catalytic conditions were evaluated for the oxidative
amination of tetradecene (1), a representative unactivated
alkyl olefin, with phthalimide as the nitrogen nucleophile
(Table 1). When the previously identified Pd(OAc)2/ben-
zonitrile catalyst system was used with 1 as the limiting
reagent and 1.2 equiv of phthalimide, the yield of the desired
enimide product 2 was only 22% (entry 1). Substantial
unreacted alkene was recovered (44%), together with alkene
isomers of the product (3) and starting material (4). The
internal alkenes 4 are unreactive toward oxidative amination
under the reaction conditions.
increased catalyst loading (entries 2-4). Pd and Cu chloride
complexes promoted nearly complete isomerization of the
starting alkene, without forming 2 (entry 5). Cu(OAc)2 was
less effective when used as a stoichiometric oxidant rather
than as a cocatalyst (entries 2 vs 6), and very little product
was obtained with benzoquinone as a stoichiometric oxidant
(entry 7).
Previous studies in our laboratory and others have
demonstrated the ability of various additives to improve
catalyst stability, including molecular sieves,8 anionic Brøn-
sted bases,9 Brønsted acids,10 cyclooctadiene (COD), and
methyl acrylate.6d,11 The beneficial effects of these additives
have different origins. Molecular sieves provide a hetero-
The yield of the desired product 2 increased when the
reaction was performed in the presence of Cu(OAc)2 and
(6) (a) Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc.
2003, 125, 12996-12997. (b) Brice, J. L.; Harang, J. E.; Timokhin, V. I.;
Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 2868-2869. (c)
Timokhin, V. I.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 17888-17893.
(d) Scarborough, C. C.; Stahl, S. S. Org. Lett. 2006, 8, 3251-3254. (e)
Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179-7181.
(7) Enamides are common susbstrates for asymmetric hydrogenation.
Zhang and co-workers recently demonstrated that N-phthaloyl enimides
undergo enantioselective hydrogenation with enantioselectivities comparable
to those of traditional N-acetyl enamides: Yang, Q.; Gao, W.; Deng, J.;
Zhang, X. Tetrahedron Lett. 2006, 47, 821-823.
(8) Steinhoff, B. A.; King, A. E.; Stahl, S. S. J. Org. Chem. 2006, 71,
1861-1868.
(9) (a) ten Brink, G.-J.; Arends, I. W. C. E.; Sheldon, R. A. AdV. Synth.
Catal. 2002, 344, 355-369. (b) Steinhoff, B. A.; Guzei, I. A.; Stahl, S. S.
J. Am. Chem. Soc. 2004, 126, 11268-11278.
(10) (a) Ba¨ckvall, J.-E.; Hopkins, R. B.; Grennberg, H.; Mader, M. M.;
Awasthi, A. K. J. Am. Chem. Soc. 1990, 112, 5160-5166. (b) Mueller, J.
A.; Goller, C. P.; Sigman, M. S. J. Am. Chem. Soc. 2004, 126, 9724-
9734. (c) Rogers, M. M.; Wendlandt, J. E.; Guzei, I. A.; Stahl, S. S. Org.
Lett. 2006, 8, 2257-2260.
4332
Org. Lett., Vol. 9, No. 21, 2007

geneous surface that inhibits bulk aggregation of Pd metal;
anionic bases promote aerobic oxidation of the reduced
catalyst; Brønsted acids are thought to stabilize Pd0 by
reversible formation of more stable PdII-hydride species;
and COD and methyl acrylate are good ligands for Pd0 that
hinder catalyst aggregation. Representative results with these
additives are shown in Table 1 (entries 8-13). Methyl
acrylate proved to be the most effective additive. A 71%
combined yield of oxidative amination products was ob-
tained, primarily as the terminal enimide 2, when 1 equiv of
methyl acrylate was included in the reaction mixture (entry
13). Products arising from the oxidative amination of methyl
acrylate were not detected. Other solvents were tested
(dimethoxyethane, dimethylformamide, dichloroethane, ac-
etonitrile, and toluene; data not shown), but none of these
resulted in improved yields relative to benzonitrile.
Table 2. Pd-Catalyzed Aerobic Oxidative Amination of
Alkenesa
Increasing the scale of the reaction to 1 mmol of alkene
resulted in a lower product yield (entry 14 vs 13). Therefore,
we reoptimized the reaction at this scale (entries 14-17).
The results revealed that improved yields could be obtained
at elevated O2 pressure (4 atm), and the best outcome was
observed when no cocatalyst or additive was included in the
reaction mixture (entry 17).12 Elevated O2 pressure should
improve catalyst stability by minimizing the steady-state
concentration of Pd0 and thereby reduce its tendency to
decompose via bimolecular aggregation.
The optimized, high-pressure oxidative amination condi-
tions were evaluated with a number of terminal and cyclic
alkenes (Table 2). The results provide some insight into the
scope and limitations of the methods. The oxidative amina-
tion of simple linear alkenes produces enimides in good
isolated yield (entries 1 and 2). Cyclic alkenes react to form
allylic phthalimides. As we have discussed elsewhere,6b
allylic amination of cyclic alkenes probably arises from cis-
aminopalladation to form an alkyl-PdII intermediate A that
cannot undergo â-hydride elimination to form an enimide
because the requisite hydrogen atom, H1, is on the opposite
face of the ring. Instead, â-hydride elimination proceeds away
a
Reaction conditions: Pd(OAc)2 (0.01 mmol), alkene (1.0 mmol),
b
nucleophile (1.2 mmol), benzonitrile (1.33 mL), 60 °C, 24 h. Isolated
yield. Isomer ratio determined by 1H NMR spectroscopy. Yield was
c
from the C-N bond (H2) to produce the allylic product
(entries 3-8). The homoallylic and other isomeric products
arise from Pd-hydride-mediated migration of the double
bond.6b,e,13 The oxidative amination of cyclopentene and
cyclooctene was also achieved with the 2,2,2-trichloroeth-
ylsulfamate nucleophile (entries 4 and 7). For reasons that
are not yet clear, cyclohexene is completely unreactive
1
determined by H NMR relative to 1,3,5-trimethoxybenzene.
toward oxidative amination (entry 5). Styrene undergoes
competitive formation of acetophenone, resulting in a low
yield of the enamide product (entry 8).
The use of alkenes as a limiting reagent in these reactions
is particularly important for more expensive or noncommer-
(11) Intramolecular Pd-catalyzed oxidative amination reactions often
benefit from the use of ligands for the Pd catalyst (e.g., pyridine and
N-heterocyclic carbenes). Our previous studies, however, have shown that
such ligands inhibit intermolecular oxidative amination reactions.6b
(12) Caution should be taken when working with high pressures of O2
in organic solvents, particularly on a large scale. We have demonstrated
that identical results are obtained when the reactions are performed with a
4% O2/N2 mixture if the partial pressure of oxygen remains constant.
(13) (a) Isomura, K.; Okada, N.; Saruwatari, M.; Yamasaki, H.; Tan-
iguchi, H. Chem. Lett. 1985, 385-388. (b) Ney, J. E.; Wolfe, J. P. Angew.
Chem., Int. Ed. 2004, 43, 3605-3608. (c) Ney, J. E.; Wolfe, J. P. J. Am.
Chem. Soc. 2005, 127, 8644-8651. (d) Nakhla, J. S.; Kampf, J. W.; Wolfe,
J. P. J. Am. Chem. Soc. 2006, 128, 2893-2901. (e) Liu, G.; Stahl, S. S. J.
Am. Chem. Soc. 2007, 129, 6328-6335.
Org. Lett., Vol. 9, No. 21, 2007
4333

cially available alkenes. We investigated the reactivity of
various alkenes bearing oxygen-containing functional groups,
including benzyl ethers, esters, epoxides, and silyl ethers
(Table 2, entries 9-18). These substrates undergo oxidative
amination with phthalimide to produce amino-oxygenated
products that feature 1,2-1,3- and 1,4-relationships between
the oxygen and nitrogen functional groups. Most of these
reactions proceed in good yield; however, two limitations
that were identified include substrates with a free alcohol or
a trimethylsilyl ether, which react to form a complex product
mixture and low yield of the desired enimide (entries 14 and
15). The latter limitation can be addressed by employing
substrates with more stable silyl ethers (TES, TBS) (entries
16-19).
Wacker reactions, and the ability to employ alkenes as the
limiting reagents should significantly enhance their utility.
Another important conclusion from this study is that even
better aerobic oxidation reactions should be achievable (e.g.,
those compatible with ambient pressures of O2) if more stable
catalyst systems are identified.
Acknowledgment. We thank the NIH (R01 GM67173)
for financial support of this work and Eli Lilly and Johnson-
Matthey for generous donations of Pd salts.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The reactions identified in this study represent the most
effective catalytic methods to date for intermolecular aza-
OL701903R
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Org. Lett., Vol. 9, No. 21, 2007