Aerobic oxidative amination of unactivated alkenes catalyzed by palladium

Article abstract of DOI:10.1021/ja0433020

The first examples of palladium-catalyzed oxidative amination of unactivated alkyl olefins have been identified. To be successful, these reactions must be conducted under cocatalyst-free conditions that involve direct dioxygen-coupled turnover of the palladium catalyst. The oxidative amination products of norbornene and other cyclic alkenes implicate a cis-aminopalladation mechanism. Copyright

Full text of DOI:10.1021/ja0433020

Published on Web 02/11/2005
Aerobic Oxidative Amination of Unactivated Alkenes Catalyzed by Palladium
Jodie L. Brice, Jenna E. Harang, Vitaliy I. Timokhin, Natia R. Anastasi, and Shannon S. Stahl*
Department of Chemistry, UniVersity of WisconsinsMadison, 1101 UniVersity AVenue, Madison, Wisconsin 53706
Received November 6, 2004; E-mail: stahl@chem.wisc.edu
Metal-catalyzed addition of amines and related nucleophiles to
alkenes represents a challenging but attractive strategy for the
preparation of nitrogen-containing molecules.1,2 Despite significant
recent advances in this area, unactivated alkyl olefins, the most
abundant and least expensive class of alkenes, are generally
ineffective substrates.2a,3 Since the discovery of the Wacker process
(eq 1) in 1959,4 significant efforts have focused on development
of related methods for the oxidative amination of alkenes (eq 2).5
Amines, however, often coordinate more strongly to palladium than
alkenes and inhibit catalytic turnover. Recently, we and others
demonstrated that nonbasic nitrogen nucleophiles, such as carbox-
amides, carbamates, and sulfonamides, undergo effective oxidative
coupling with activated alkenes, including acrylic esters and
styrene.6,7 Here, we report the first general method for oxidative
amination of unactivated alkyl olefins made possible by cocatalyst-
free reaction conditions, in which the palladium catalyst undergoes
direct dioxygen-coupled turnover.8
the relative stability of intermediates 2 and 3 toward â-hydride
elimination. The â-hydrogens in both structures either lie on the
opposite face of the ring or occupy a bridgehead position.13
The oxidative amination of linear alkyl olefins exhibits some
success under these reaction conditions. For example, 1-octene
reacts with the secondary nucleophile phthalimide to generate
amination products in ∼60% yield, but a complex mixture of alkene
isomers is formed. A solution to this problem arose from concurrent
studies with styrene that revealed Pd(OAc)2 is an effective oxidative
amination catalyst even in the absence of a copper cocatalyst. For
example, the oxidative amination of styrene with phthalimide
generates the Markovnikov enimide product in good isolated yield
(eq 3). With p-toluenesulfonamide as the nucleophile, the N-tosyl
ketimine product is obtained (eq 4).
The lack of precedent for oxidative amination of alkyl olefins
prompted us to investigate the reactivity of norbornene, a strained
cyclic alkene that undergoes metal-catalyzed hydroamination in
certain cases.9 Under conditions similar to those we employed
previously for the oxidative amination of styrene, norbornene reacts
with TsNH2 to form a racemic mixture of the C2-symmetric
pyrrolidine, 1, in good yield (Scheme 1). The product arises from
On the basis of these results, we screened a series of catalyst
combinations for the reaction between 1-octene and phthalimide
(Table 1). Amination products are formed in several cases with
catalytic PdCl2, Pd(OAc)2, or Pd(O2CCF3)2; however, the desired
terminal enimide, 6, is obtained in good yield only with Pd(OAc)2
as the catalyst in the absence of a copper cocatalyst (entries 8, 10,
and 12). Significant alkene isomerization occurs when CuCl2 is
added as a cocatalyst (entries 5, 13, and 17). Under these reaction
conditions, rapid alkene isomerization occurs even in the absence
of phthalimide.14 Although the mechanism of alkene isomerization
has not been established, acetate might serve as a base to
deprotonate palladium hydrides that could isomerize alkenes. The
ability of triethylamine to attenuate alkene isomerization with PdCl2
as the catalyst is consistent with this hypothesis (entries 1 and 2).
Pyridine and triphenylphosphine have little effect on the reaction
at 5 mol % loading (entries 10 and 12), but larger quantities of
pyridine inhibit the reaction (entry 11). 31P NMR spectroscopy
reveals that PPh3 undergoes complete oxidation to the phosphine
oxide during the reaction. The detrimental effect of cocatalysts and
stoichiometric oxidants other than molecular oxygen (CuCl2, entry
6; benzoquinone, entries 7 and 14) indicates that the use of
molecular oxygen without cocatalysts may be essential to achieve
the desired reactivity in palladium-catalyzed oxidation reactions.
Scheme 1. Aerobic Oxidative Amination of Norbornene
the oxidative coupling of two alkenes and the sulfonamide
nucleophile. Its structure, established by X-ray crystallography,
reveals that both equivalents of norbornene undergo cis-difunc-
tionalization on the exo face of the alkene.10 A mechanism consistent
with these observations involves cis-aminopalladation of nor-
bornene, alkene insertion into the Pd-C bond, and C-N reductive
elimination. Documented examples of cis-aminopalladation are quite
rare,11,12 but two reasonable pathways include alkene insertion into
a Pd-N bond (4)11 or coordination of the sulfonyl oxygen to
palladium followed by C-N bond formation via a six-membered
transition state (5). Studies to probe these possibilities are ongoing.
The multicomponent coupling sequence is probably facilitated by
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C O M M U N I C A T I O N S
Table 1. Catalyst Screening Data for the Aerobic Oxidative
The oxidative amination of cyclic olefins, cyclooctene, and
cyclopentene (entries 4-6) yields allylic amine products rather than
the corresponding enamine or imine derivatives. These observations
are readily explained if amination of the double bond occurs via
cis-aminopalladation, as observed for norbornene (Scheme 1). If
cyclic alkenes react in this manner, only the allylic C-H bond in
the intermediate can achieve the orientation necessary for syn-â-
hydride elimination.13
In conclusion, we have achieved a remarkably general method
for aerobic oxidative amination of unactivated alkyl olefins, and
the results highlight the value of cocatalyst-free oxidation condi-
tions. Ongoing studies are focused on exploring the scope of this
reactivity and probing the catalytic mechanism.
Acknowledgment. We thank Ilia A. Guzei for X-ray crystal-
lographic characterization of 1, and we gratefully acknowledge
financial support from the National Institutes of Health (RO1
GM67173-01), Dreyfus Foundation (Teacher-Scholar Award), and
the Sloan Foundation (Research Fellowship).
Supporting Information Available: Experimental descriptions
(PDF) and X-ray crystallographic data (PDF, CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
Amination of 1-Octene with Phthalimidea
entry
catalyst
additive
yieldb (%)
1
2
3
Pd(CH3CN)2Cl2
PdCl2
<1 (32)
17 (37)
<1 (40)
3 (5)
5% NEt3
5% pyridine
10% pyridine
4
5
6
7
8
5% CuCl2
3 equiv of CuCl2
2 equiv of benzoquinone
<1 (66)
NR
10 (28)
81 (4)
17 (3)
82 (3)
<1 (0)
70 (5)
<1 (79)
10 (<1)
4 (1)
Pd(OAc)2
9
5% NEt3
10
11
12
13
14
15
16
17
5% pyridine
10% pyridine
5% PPh3
5% CuCl2
2 equiv of benzoquinone
Pd(O2CCF3)2
5% pyridine
5% CuCl2
3 (1)
<1 (79)
a Reaction conditions: 3 mmol 1-octene, 0.5 mmol phthalimide, 0.025
mmol [Pd], additive, 0.75 M phthalimide in PhCN, 1 atm O2, 60 °C, 24 h.
b 1H NMR yield of product containing terminal methylene with 1,3,5-
trimethoxybenzene internal standard, based on initial phthalimide. Paren-
theses contain combined yield of all amination products with internal alkenes
detected by gas chromatography.
References
(1) For recent reviews, see: (a) Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998,
98, 675-703. (b) Brunet, J. J.; Neibecker, D. In Catalytic Heterofunc-
tionalization; Togni, A., Gru¨tzmacher, H., Eds.; Wiley-VCH: 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.
(2) For additional leading references, see: (a) Ryu, J.-S.; Li, G. Y.; Marks,
T. J. J. Am. Chem. Soc. 2003, 125, 12584-12605. (b) Kawatsura, M.;
Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546-9547. (c) Utsunomiya,
M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 14286-14287. (d)
Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 2702-
2703.
Table 2. Cocatalyst-Free Aerobic Oxidative Amination of Aliphatic
a
Olefins Catalyzed by Pd(OAc)2
(3) Alkyl olefin reactivity has generally been limited to reactions with ethylene
and propylene under elevated pressure: (a) Coulson, D. R. Tetrahedron
Lett. 1971, 12, 429-430. (b) Brunet, J.-J.; Cadena, M.; Chu, N. C.; Diallo,
O.; Jacob, K.; Mothes, E. Organometallics 2004, 23, 1264-1268. (c)
Wang, X.; Widenhoefer, R. A. Organometallics 2004, 23, 1649-1651.
(4) Jira, R. In Applied Homogeneous Catalysis with Organometallic Com-
pounds; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH: New York,
2002; Vol. 1, pp 386-405.
(5) Hegedus, L. S. Tetrahedron 1984, 40, 2415-2434.
(6) (a) Hosokawa, T.; Takano, M.; Kuroki, Y.; Murahashi, S.-I. Tetrahedron
Lett. 1992, 33, 6643-6646. (b) Ragaini, F.; Longo, T.; Cenini, S. J. Mol.
Catal. A: Chem. 1996, 110, L171-L175.
(7) Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2003,
125, 12996-12997.
(8) A complementary catalytic strategy for the oxidative amination of alkenes
features catalytic transfer of an electrophilic nitrene (or nitrenoid) to the
alkene and commonly employs a hypervalent iodine-based oxidant. For
leading references, see: (a) Mu¨ller, P. In AdVances in Catalytic Processes;
Doyle, M. P., Ed.; JAI Press Inc.: Greenwich, CT, 1997; Vol. 2, pp 113-
151. (b) Jacobsen, E. N. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamomoto, H., Eds.; Springer-Verlag: Berlin,
1999; Vol. 2, pp 607-618. (c) Guthikonda, K.; Du Bois, J. J. Am. Chem.
Soc. 2002, 124, 13672-13673.
(9) (a) Casalnuovo, A. L.; Calabrese, J. C.; Milstein, D. J. Am. Chem. Soc.
1988, 110, 6738-6744. (b) Dorta, R.; Egli, P.; Zu¨rcher, F.; Togni, A. J.
Am. Chem. Soc. 1997, 119, 10857-10858. (c) Brunet, J.-J.; Chu, N. C.;
Diallo, O.; Mothes, E. J. Mol. Catal. A: Chem. 2003, 198, 107-110. (d)
Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Org. Lett. 2004, 6, 2515-
2518. (e) Anderson, L. L.; Arnold, J.; Bergman, R. G. Org. Lett. 2004, 6,
2519-2522.
a Reaction conditions: 12 mmol alkene, 2 mmol nucleophile, 0.1 mmol
Pd(OAc)2, 0.75 M HNRR′ in PhCN, 1 atm O2, 60 °C, 24 h. b Isolated yield
based on nitrogen nucleophile after purification by flash column chroma-
tography. Ratio in parentheses is (isomer shown:all other observed isomers).
c With 24 mmol alkene, all other conditions the same. d Reaction performed
under 3.5 atm O2 in a sealed vessel. e After 48 h.
(10) This stereochemistry differs from that of a stoichiometric Ni-promoted
oxidative coupling reaction between norbornene and N2O that produces
a tetrahydrofuran structure: Koo, K.; Hillhouse, G. L. Organometallics
1998, 17, 2924-2925.
Cocatalyst-free conditions enable the aerobic oxidative amination
of various other alkyl olefins, including both acyclic and cyclic
substrates (Table 2). Good yields are obtained in the reaction
between phthalimide and 1-hexene, 1-octene, and vinylcyclohexane
(entries 1, 2, and 9), and an ester functionality is compatible with
the reaction (entry 3). The reaction with vinylcyclohexene (entry
10) reveals that the terminal alkene can react selectively in the
presence of an internal double bond. Sulfonamides also serve as
effective nucleophiles (entries 7 and 8).
(11) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605-3608
and references therein.
(12) Examples of trans-aminopalladation are well documented. For leading
references, see: (a) Ba¨ckvall, J.-E. Acc. Chem. Res. 1983, 16, 335-342.
(b) Åkermark, B.; Zetterberg, K. J. Am. Chem. Soc. 1984, 106, 5560-
5561. (c) Hegedus, L. S.; Åkermark, B.; Zetterberg, K.; Olsson, L. F. J.
Am. Chem. Soc. 1984, 106, 7122-7126.
(13) For examples of anti-â-hydride elimination, see: Ikeda, M.; El Bialy, S.
A. A.; Yakura, T. Heterocycles 1999, 51, 1957-1970.
(14) (a) Sparke, M. B.; Turner, L.; Wenham, A. J. M. J. Catal. 1965, 4, 332-
340. (b) Sen, A.; Lai, T. W. Inorg. Chem. 1984, 23, 3257-3258.
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