Room temperature palladium-catalyzed intramolecular hydroamination of unactivated alkenes

Article abstract of DOI:10.1021/ja060126h

A mild and facile Pd-catalyzed intramolecular hydroamination of unactivated alkenes is described. This reaction takes place at room temperature and is tolerant of synthetically useful acid-sensitive functional groups. The formation of hydroamination products rather than oxidative amination products is due to the use of a tridentate ligand on Pd which effectively inhibits β-hydride elimination. Copyright

Full text of DOI:10.1021/ja060126h

Published on Web 03/14/2006
Room Temperature Palladium-Catalyzed Intramolecular Hydroamination of
Unactivated Alkenes
Forrest E. Michael* and Brian M. Cochran
UniVersity of Washington, Box 351700, Seattle, Washington 98195-1700
Received January 6, 2006; E-mail: fmichael@chem.washington.edu
Scheme 1. Tridentate Ligands Inhibit â-Hydride Elimination
The direct addition of N-H bonds across alkenes and alkynes
(hydroamination) is an efficient method for the formation of
carbon-nitrogen bonds.1 Although numerous catalysts for this
transformation have been developed recently, the hydroamination
of unactivated alkenes remains a significant challenge. Lanthanide
and group 4 complexes are effective for hydroaminations of
unactivated alkenes, but the low functional group tolerance and
extreme air and water sensitivity of these catalysts severely limit
their synthetic utility.2 Recently, both platinum catalysts3 and strong
Brønsted acids4 have been reported to catalyze inter- and intramo-
lecular hydroaminations of alkenes. Unfortunately, elevated tem-
peratures (85-150 °C) are required for reasonable reaction rates.
Herein we report a room temperature, functional group tolerant
Pd-catalyzed method for the intramolecular hydroamination of
unactivated alkenes.
Table 1. Hydroamination of Protected Aminoalkene 2a
One of the complications of Pd-catalyzed additions to alkenes
is the strong tendency for the alkylpalladium intermediates to
undergo â-hydride elimination (Scheme 1).5 We hypothesized that
the use of a tridentate ligand would block the open coordination
sites required for â-hydride elimination, and thereby prevent this
process and promote alternate reactions of the alkylpalladium
species. Stoichiometric studies of palladium complexes of bis-
(diphenylphosphinomethyl)pyridine have shown that â-hydride
elimination is effectively inhibited by this ligand.6 We therefore
chose to investigate the catalytic activity of palladium complex 1
in the cyclization of amidoalkenes.
Reaction of protected aminoalkene 2a using 20 mol % of Pd
complex 1, 40 mol % of AgBF4, and 2 equiv of Cu(OTf)2 at room
temperature gave hydroamination product 3a in 98% yield (Table
1). In contrast, reaction of 2a in the absence of ligand (20 mol %
of PdCl2(CH3CN)2 and 2 equiv of Cu(OTf)2) yielded Wacker
oxidation product 5, presumably via the intermediacy of enamide
4 (eq 1). This difference in reactivity strongly suggests that the
tridentate ligand was effectively inhibiting â-hydride elimination.
entry
[Pd] (
×
mol %)
Cu(OTf)2(mol %)
% yield (GC)
1
2
3
4
5
20
5
200
10
5
10
10
98
97
93
91
84
2.5
1
0.5
A variety of other ligands for palladium were assayed in the hy-
droamination of substrate 2a (Chart 1). Interestingly, the original
catalyst 1 was the only complex to catalyze the hydroamination
reaction. Complexes of mono-, bi-, and even other tridentate ligands
did not afford detectable amounts of product. It was especially sur-
prising that the corresponding Pt complex 7 was also unreactive
given the established reports of Pt-catalyzed hydroamination of
unactivated alkenes.
Substrates bearing a variety of substituents on nitrogen were
tolerated by catalyst 1 (Table 2). Amides and carbamates 2a-d
cyclize most readily. Despite the greater synthetic utility of the Cbz
and Boc protecting groups, hydroaminations of carbamates are
extremely rare.7 It is particularly interesting that the acid-labile Boc
protecting group survives these reaction conditions. Substrates
bearing a tosyl substituent on nitrogen failed to cyclize. This
selectivity is in contrast to that observed in the acid-catalyzed
hydroamination reported by Hartwig, where only sulfonamides
could be cyclized.4a
Other successful hydroamination reactions are depicted in
Scheme 2. Formation of both five- and six-membered rings is facile,
and the presence of gem-dimethyl substituents on the alkyl chain
to promote ring closure is not required, as indicated by the
cyclization of unsubstituted alkenes (eqs 4 and 5). Protected aniline
13b was also a substrate for the hydroamination reaction, albeit in
lower yield. The unprotected alcohol in 17a,b did not effect the
cyclization efficiency. Notably, all substrates in Scheme 2 contain
functional groups that are unlikely to be compatible with lanthanide
and group 4 hydroamination catalysts.
Further optimization of reaction conditions revealed that the
amount of Cu(OTf)2 could be reduced with no effect on the yield
of hydroamination product (Table 1). As little as 1 mol % of the
palladium catalyst could be employed with minimal loss in yield.
Toluene and CH2Cl2 were identified as equally suitable solvents
for this transformation, but the use of coordinating solvents, such
as CH3CN, THF, or Et2O, completely inhibited the reaction.
During early investigations, the reaction was found to be sensitive
to the presence of water, resulting in inconsistent yields. Addition
of a drying agent (K2CO3, MgSO4, or powdered 3 Å sieves) to the
reaction mixture easily and effectively solved this problem. This
protocol allowed for complete conversion even using unpurified
(“wet”) commercial reagents and solvents.
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10.1021/ja060126h CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Proposed Mechanistic Cycle
Chart 1. Palladium Complexes that Do Not Catalyze Equation 2
Table 2. Effect of Nitrogen Protecting Group on Hydroamination
PG
alkene
product
% yield (isolated)
carbamate to form alkylpalladium intermediate 22. In the absence
of the tridentate ligand, â-hydride elimination is facile, and the
enamide product 4 is formed. With the tridentate ligand, â-hydride
elimination is suppressed, and protonolysis of the Pd-C bond is
favored. Consistent with this mechanism, the product of cyclization
of deuterium-labeled substrate 2a-d is deuterated exclusively at the
terminal methyl group. Further investigations of the mechanism of
this reaction are underway.
Cbz
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
82
75
92
68
0
Boc
p-toluoyl
Ac
Ts
Scheme 2. Hydroaminations of Other Aminoalkenesa
In conclusion, a mild and facile Pd-catalyzed intramolecular
hydroamination of unactivated alkenes has been described. This
reaction takes place at room temperature and is tolerant of
synthetically useful acid-sensitive functional groups. The formation
of hydroamination products rather than oxidative amination products
is due to the use of a tridentate ligand on Pd which effectively
inhibits â-hydride elimination.
Acknowledgment. The University of Washington is acknowl-
edged for financial support.
Supporting Information Available: Reaction conditions and
experimental data for synthesis of all starting materials, catalysts, and
cyclization products. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
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a Conditions: 5 mol % of 1, 10 mol % of AgBF4, 10 mol % of Cu(OTf)2,
MgSO4.
Substrates bearing a stereogenic center in the tether gave mod-
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of diastereomers, favoring the cis isomer.8 Substrates 17a,b were
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catalyzed by trace acids.4,9 Several factors argue against such a
pathway in this system. First, neither HOTf nor HBF4‚OEt2
catalyzes any appreciable reaction of substrate 2b at room tem-
perature. Second, 1,1-disubstituted alkene 19a, which should be
more active under acid-catalyzed conditions, does not cyclize at
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(8) This compares favorably to the ratio observed in ref 2b (58:42).
The proposed reaction mechanism is illustrated in Scheme 3.
Coordination of the alkene to the dicationic palladium complex
activates the alkene toward nucleophilic attack by the amide or
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