Intramolecular hydroamination of unactivated alkenes with secondary alkyl-And arylamines employing [Ir(COD)Cl]2 as a catalyst precursor

Article abstract of DOI:10.1021/ol900174f

Commercially available [lr(COD)CI]₂ is an effective precatalyst for the intramolecular hydroamination of a range of unactivated alkenes with pendant secondary alkyl-or arylamines, at relatively low loadings (typically 0.25-5.0 mol % Ir) and without the need for added ligands or other cocatalysts.

Full text of DOI:10.1021/ol900174f

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1449-1452
Intramolecular Hydroamination of
Unactivated Alkenes with Secondary
Alkyl- and Arylamines Employing
[Ir(COD)Cl]2 as a Catalyst Precursor
Kevin D. Hesp and Mark Stradiotto*
Department of Chemistry, Dalhousie UniVersity, Halifax, NoVa Scotia, Canada B3H 4J3
mark.stradiotto@dal.ca
Received January 27, 2009
ABSTRACT
Commercially available [Ir(COD)Cl]2 is an effective precatalyst for the intramolecular hydroamination of a range of unactivated alkenes with
pendant secondary alkyl- or arylamines, at relatively low loadings (typically 0.25-5.0 mol % Ir) and without the need for added ligands or
other cocatalysts.
Current interest in the identification of catalysts for the
intramolecular hydroamination of unactivated alkenes arises
from the utility of this C-N bond-forming reaction as an
atom economical route to synthetically useful nitrogen
heterocycles.1 Notwithstanding the progress that has been
made by use of lanthanide and early metal catalysts,1,2 their
air-sensitivity and lack of functional group tolerance has
prompted the development of late metal catalysts for such
challenging transformations. While significant advances have
been made in the use of late metal catalysts for the
intramolecular addition of amides and carbamates to unac-
tivated alkenes,3 related transformations involving simple
alkyl- or arylamines are extremely rare.4-6 The first catalyst
of this type was disclosed by Widenhoefer and co-workers,4
who employed [PtCl2(H2CdCH2)]2/PPh3 and later PtCl2/
biarylphosphine (5-10 mol % Pt) for the cyclization of
secondary alkylamines. More recently, Hollis and co-
workers5 reported the use of Rh and Ir complexes supported
by pincer-type N-heterocyclic carbene ligands (5 mol % M)
for the hydroamination of terminal alkenes by tethered
secondary alkyl- and phenylamines, while Liu and Hartwig6
disclosed the use of [Rh(COD)2]BF4/Cy-DavePhos (COD )
η4-cyclooctadiene; Cy-DavePhos ) 2-dicyclohexylphos-
phino-2′-N,N-dimethylamino-biphenyl; 2.5-7.5 mol % Rh)
for the cyclization of aminoalkenes that contain primary or
secondary alkylamines and terminal or internal alkenes. In
the quest to expand the synthetic repertoire of late metal-
mediated hydroamination, and encouraged by breakthroughs
in Ir-mediated intermolecular hydroamination of activated
olefins,7,8 we sought to identify commercially available
single-component Ir precatalysts that complement established
late metal catalysts and which exhibit broad substrate scope
in the intramolecular hydroamination of unactivated alkenes.9
(1) For a comprehensive review, see: Mu¨ller, T. E.; Hultzsch, K. C.;
Yus, M.; Foubelo, F.; Tada, M. Chem. ReV. 2008, 108, 3795.
(2) Selected recent examples: (a) Stubbert, B. C.; Marks, T. J. J. Am.
Chem. Soc. 2007, 129, 6149. (b) Wood, M. C.; Leitch, D. C.; Yeung, C. S.;
Kozak, J. A.; Schafer, L. L. Angew. Chem., Int. Ed. 2007, 46, 354
.
(3) Representative examples: (a) Michael, F. E.; Cochran, B. M. J. Am.
Chem. Soc. 2008, 130, 2786. (b) Hamilton, G. L.; Kang, E. J.; Mba, M.;
Toste, F. D. Science 2007, 317, 496. (c) Komeyama, K.; Morimoto, T.;
Takaki, K. Angew. Chem., Int. Ed. 2006, 45, 2938. (d) Han, X.; Widen-
hoefer, R. A. Angew. Chem., Int. Ed. 2006, 45, 1747.
(5) Bauer, E. B.; Andavan, G. T. S.; Hollis, T. K.; Rubio, R. J.; Cho, J.;
Kuchenbeiser, G. R.; Helgert, T. R.; Letko, C. S.; Tham, F. S. Org. Lett.
2008, 10, 1175.
(6) Liu, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 1570.
(7) (a) Casalnuovo, A. L.; Calabrese, J. C.; Milstein, D. J. Am. Chem.
Soc. 1988, 110, 6738. (b) Dorta, R.; Egli, P.; Zu¨rcher, F.; Togni, A. J. Am.
(4) (a) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127,
1070. (b) Bender, C. F.; Hudson, W. B.; Widenhoefer, R. A. Organome-
Chem. Soc. 1997, 119, 10857
.
tallics 2008, 27, 2356
.
(8) Zhou, J.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 12220.
10.1021/ol900174f CCC: $40.75
Published on Web 02/20/2009
2009 American Chemical Society

In this vein, we report herein that [Ir(COD)Cl]2 is an effective
precatalyst for the hydroamination of unactivated alkenes
with pendant secondary alkyl- or arylamines, at relatively
low loadings (typically 0.25-5 mol % Ir) and without the
need for added ligands or cocatalysts.
Table 1. Intramolecular Hydroamination of Unactivated Alkenes
by Secondary Alkylamines Employing [Ir(COD)Cl]2 as a
Pre-Catalysta
The cyclization of 1a (R ) Bn, R′ ) Ph) to 2a in 1,4-
dioxane (eq 1) was selected as a test reaction for canvassing
the catalytic abilities of group 9 complexes for the intramo-
lecular hydroamination of unactivated alkenes at relatively
low catalyst loadings (1.0 mol % Rh or Ir). Gratifyingly,
[Ir(COD)Cl]2 proved to be a highly effective precatalyst
1
under these conditions, affording 2a cleanly (>95%, H
NMR) after only 1 h at 110 °C.10a Other commercially
available group 9 precatalysts including [Ir(η2-cyclooctene)2-
Cl]2, [Ir(COD)OMe]2, [(η5-C5Me5)IrCl2]2, [(COD)Ir(PCy3)-
-
(pyridine)]+PF6 (Crabtree’s catalyst), and [Rh(COD)Cl]2
were significantly less effective under these conditions, as
was [Ir(MeCN)2(COD)]BF4 (Table S1, Supporting
Information10b). However, the observation that the perfor-
mance of [Ir(COD)Cl]2/2 AgBF4 mirrors that of [Ir(COD)Cl]2
suggests that the formation of [Ir(1,4-dioxane)2(COD)]Cl
may figure importantly in hydroamination reactions employ-
ing [Ir(COD)Cl]2 in 1,4-dioxane.
Catalyst optimization studies revealed that the clean
conversion of 1a into 2a in 1,4-dioxane can also be achieved
by use of only 0.125 mol % [Ir(COD)Cl]2 (3 h, 110 °C; Table
1, entry 1-1), or by employing higher Ir loadings at lower
temperatures (2.5 mol % Ir; 7 h, 80 °C11).
a Conditions: 0.25 mmol aminoalkene in 0.5 mL 1,4-dioxane at 110
°C; conversion to product >95% (1H NMR) unless stated. b Isolated yield
c
unless stated (average of two runs). 1H NMR yield, with the balance
corresponding to an alkene isomerization product (ca. 10%) and unreacted
aminoalkene (ca. 5%). d Diastereomeric ratio (dr, 1H NMR). e Reaction run
at 80 °C; conversion to the piperidine was 75% (1H NMR) with the balance
f
corresponding to an alkene isomerization product. 1H NMR yield, with
the balance corresponding to unreacted aminoalkene.
Despite the utility of late metal complexes in promoting
the intramolecular hydroamination of carbamates,3 the N-Boc
aminoalkene 1b proved unreactive (1H NMR) in the presence
of [Ir(COD)Cl]2 (1.0 mol % Ir; 3 h, 110 °C, 1,4-dioxane).
However, the observation that the cyclization of 1a (entry
1-1) proceeds unhampered (1H NMR) when using a 1:1
mixture of 1a,b (eq 2) suggests that 1b does not poison the
active catalyst derived from [Ir(COD)Cl]2; rather, [Ir-
(COD)Cl]2 may offer chemoselectivity in the hydroamination
of more complex olefinic substrates that contain both
carbamate- and benzyl-protected amines.
substitution on the benzyl fragment in derivatives of 1a, the
presence of halide (entry 1-2), ester (entry 1-3), or alkoxy
(entry 1-4) substituents did not significantly influence the
reaction; also tolerated was the bulky N-methylcyclohexyl
derivative (entry 1-5). Notably, the catalytic performance
of [Ir(COD)Cl]2 in the aforementioned hydroamination
reactions is on par with, and in some cases is superior to (in
terms of catalyst loading), that of all reported4-6 late metal
catalysts with comparable substrates.
Alternative gem-disubstituted relatives of 1 also proved
to be suitable hydroamination substrates (entries 1-6 and
(9) For some recent reports of Ir-mediated intramolecular hydroamination
of alkynes, see: (a) Ebrahimi, D.; Kennedy, D. F.; Messerle, B. A.; Hibbert,
D. B. Analyst 2008, 817. (b) Burling, S.; Field, L. D.; Messerle, B. A.;
Rumble, S. L. Organometallics 2007, 26, 4335. (c) Lai, R.-Y.; Surekha,
K.; Hayashi, A.; Ozawa, F.; Liu, Y.-H.; Peng, S.-M.; Liu, S.-T. Organo-
metallics 2007, 26, 1062. (d) Li, X.; Chianese, A. R.; Vogel, T.; Crabtree,
R. H. Org. Lett. 2005, 7, 5437.
(10) (a) The intramolecular hydroamination of 2-(phenylethynyl)-
aniline proceeded cleanly in the presence of [Ir(COD)Cl]2 (2.5 mol %
Ir; 3 h, 110 °C, 1,4-dioxane; 96% isolated yield), in keeping with a
recent combinatorial survey.9a(b) Tables S1 and S2 are provided in the
Supporting Information.
(11) 1,2-Dichloroethane, 1,2-dimethoxyethane, and toluene each proved
to be less a effective solvent under these conditions (45-76%; see Table
S2 in the Supporting Information).
The use of [Ir(COD)Cl]2 as a precatalyst proved effective
for the hydroamination of a range of unactivated alkenes
tethered to secondary alkylamines, including those featuring
polar groups (Table 1). In exploring the influence of para-
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Org. Lett., Vol. 11, No. 6, 2009

1-7), as did the monosubstituted isopropyl variant featured
in entry 1-8 (cf. 62% yield and 1.2:1 dr obtained using
[PtCl2(H2C)CH2)]2/PPh3, 5 mol % Pt4a). The gem-disubsti-
tuted N-benzylhex-5-en-1-amine featured in entry 1-9 was
also cyclized in the presence of [Ir(COD)Cl]2. However, in
contrast to the established ability of PtCl2/biarylphosphine4b
and [Rh(COD)2]BF4/biarylphosphine6 to mediate the hy-
droamination of unactivated 4-pentenyl4b and 5-hexenyl4b,6
alkylamines that lack substituents on the linker chain which
bias the substrate toward cyclization, [Ir(COD)Cl]2 proved
incapable of inducing the hydroamination of these substrates,
as well as primary amine substrates, under our typical
reaction conditions (Table 1).
Given the particular challenge presented by the intramo-
lecular hydroamination of unactivated disubstituted alkenes,
we turned our attention to such transformations; notably,
[Ir(COD)Cl]2 proved capable of mediating the cyclization
of a gem-disubstituted olefin (entry 1-10), as well as an
unstrained internal alkene (entry 1-1112).
known for the intramolecular hydroamination of unactivated
alkenes revealed that the cyclization of such arylamines can
be problematic. Whereas the catalytic performance of PtCl2/
tBu-DavePhos4b in the hydroamination of 1c proved to be
competitive with [Ir(COD)Cl]2 (entry 2-5), both [Rh(COD)2]-
BF4/Cy-DavePhos6 (entry 2-6) and Au(o-tBu2P-biphenyl)Cl/
AgOTf3d (entry 2-7) proved to be ineffective in mediating
this transformation under similar conditions.
Our observation that the intramolecular hydroamination
of arylamines (Table 2) is enhanced by para-methyl or
-methoxy substitution on the N-aryl fragment is divergent
from trends documented by Zhou and Hartwig.8 These
workers reported that both electron-rich and -poor anilines
were less reactive than electron-neutral anilines in the
(bisphosphine)Ir-mediated intermolecular hydroamination of
activated bicyclic alkenes, which was shown to proceed by
way of N-H oxidative addition/alkene insertion reaction
cycle.8
While a comprehensive mechanistic evaluation of hy-
droamination catalysis mediated by [Ir(COD)Cl]2 is ongoing
in our laboratory, preliminary observations documented
herein may point to a reaction pathway in 1,4-dioxane
involving attack by a tethered nitrogen nucleophile on an
olefin that is coordinated to a cationic IrLn fragment (in
keeping with well-documented Pd,3a Pt,4 and Au3d hy-
droamination catalyst systems), rather than N-H oxidative
addition/alkene insertion reaction sequences that have been
documented for (bisphosphine)Ir systems.7a,8 This mecha-
nistic proposal is consistent with our observations that the
performance of [Ir(COD)Cl]2/2 AgBF4 mirrors that of
[Ir(COD)Cl]2 (Vide supra), and that hydroamination is
promoted by increasing the nucleophilicity of the arylamine
nitrogen (Table 2). Furthermore, the conversion of 1a to 2a
was completely inhibited when employing 0.5 mol %
[Ir(COD)Cl]2 at 110 °C in 1,4-dioxane in the presence of an
equivalent of K2CO3 (relative to 1a) or 1.0 mol % DBU,
possibly underscoring the involvement of a key Ir-C
protonolysis step en route to 2a. While definitive NMR
spectroscopic characterization data that would enable the
identification of intermediates in hydroamination catalysis
mediated by [Ir(COD)Cl]2 have thus far remained elusive,
no Ir-H resonances were observed (1H NMR) when
examining the reaction of 1a with [Ir(COD)Cl]2 in dioxane-
d8 over a range of temperatures. Encouraged by the pos-
sibility that such catalysis may involve reactive [LnIr(COD)]+
species, we are currently targeting enantioselective variants
of these transformations by using Ir precatalysts supported
by chiral diene ligands.
The metal-mediated intramolecular hydroamination of
unactivated alkenes by secondary arylamines remains es-
sentially unexplored, and is limited to a single report by
Hollis and co-workers featuring two simple N-Ph substrates.5
In a preliminary study, [Ir(COD)Cl]2 proved capable of
promoting the cyclization of secondary arylamines (Table
2), including the parent substrate 1c (R, R′ ) Ph; eq 1), as
Table 2. Late Metal-Mediated Intramolecular Hydroamination
of Unactivated Alkenes by Secondary Arylaminesa
a Conditions: 0.25 mmol aminoalkene in 0.5 mL 1,4-dioxane at 110 °C
for 7 h, using 0.25-1.25 mol % [Ir(COD)Cl]2, unless stated. b Isolated yields
c
d
(average of two runs), unless stated. 1H NMR yield. Using PtCl2/tBu-
DavePhos (2.5 mol % Pt and 2.5 mol % ligand) in place of [Ir(COD)Cl]2.
e Using [Rh(COD)2]BF4/Cy-DavePhos (2.5 mol % Rh and 3 mol % ligand
at 70 or 110 °C) in place of [Ir(COD)Cl]2. f Using Au(o-tBu2P-biphenyl)Cl/
AgOTf (5 mol % Au and 5 mol % Ag) in place of [Ir(COD)Cl]2.
well as for the first time arylamine substrates featuring
electron-withdrawing (entry 2-2) and electron-donating
(entries 2-3 and 2-4) substituents. At first glance, the lower
basicity of the nitrogen center in arylamines such as 1c,
relative to related alkylamines (e.g., 1a), could be envisioned
to render arylamine substrates more susceptible to metal-
mediated hydroamination; however, a comparative survey
involving some of the most effective late metal catalysts
In summary, we have identified [Ir(COD)Cl]2 as an
effective precatalyst for the intramolecular hydroamination
of a range of unactivated alkenes with pendant secondary
alkyl- or arylamines. This represents the first commercially
available late metal catalyst system to function at relatively
low catalyst loading without the need for added ligands or
cocatalysts, and serves to complement the few other late
metal catalysts4-6 that mediate such challenging transforma-
tions. The quest to develop mechanistic insights into hy-
droamination catalysis employing [Ir(COD)Cl]2, as well as
(12) The performance of [Ir(COD)Cl]2/2 AgBF4 mirrored that of
[Ir(COD)Cl]2 in entry 1-11.
Org. Lett., Vol. 11, No. 6, 2009
1451

to establish chemoselective and asymmetric variants of these
Ir-mediated intramolecular hydroaminations, is ongoing.
Lumsden (Atlantic Region Magnetic Resonance Center,
Dalhousie) for assistance in the acquisition of NMR data.
Supporting Information Available: Full experimental
details, characterization data, and tabulated catalysis results.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada (including a
Discovery Grant for M. S. and a Canada Graduate Scholar-
ship for K. D. H.) and Dalhousie University for their
generous support of this work. We also thank Dr. Michael
OL900174F
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