Platinum-catalyzed alkene cyclohydroamination: Evaluating the utility of bidentate P,N/P,P ligation and phosphine-free catalyst systems

Article abstract of DOI:10.1021/om1006984

The efficacy of phosphine-free Pt precatalysts including PtCl₂ and (COD)PtCl₂ in promoting the cyclohydroamination of primary as well as secondary alkyl/arylamines tethered to α-olefins is demonstrated for the first time. Further cat

Full text of DOI:10.1021/om1006984

Organometallics 2010, 29, 6125–6128 6125
DOI: 10.1021/om1006984
Platinum-Catalyzed Alkene Cyclohydroamination: Evaluating the Utility
of Bidentate P,N/P,P Ligation and Phosphine-Free Catalyst Systems
Christopher B. Lavery,† Michael J. Ferguson,‡ and Mark Stradiotto*,†
†Department of Chemistry, Dalhousie University, Halifax, NS Canada B3H 4J3, and
‡X-ray Crystallography Laboratory, Department of Chemistry, University of Alberta, Edmonton,
AB Canada T6G 2G2
Received July 15, 2010
Summary: The efficacy of phosphine-free Pt precatalysts
including PtCl2 and (COD)PtCl2 in promoting the cyclohy-
droamination of primary as well as secondary alkyl/aryl-
amines tethered to R-olefins is demonstrated for the first time.
Further catalytic studies examining the use of phenylene-P,N
co-ligands, as well as neutral, cationic, and formally zwitter-
ionic complexes derived from the new ligand precursor 1-PPh2-
2-P(tBu)2-indene, revealed comparable reactivity in Pt-catalyzed
cyclohydroamination catalysis relative to these phosphine-free
catalysts.
and co-workers4 surveyed a more broad collection of sterically
demanding monodentate phosphines and N-heterocyclic car-
benes in this chemistry, in anticipation that such bulky co-ligands
might promote the key C-H reductive elimination step. In the
course of this investigation, it was discovered that mixtures
of PtCl2 and biarylphosphines including tBu-DavePhos (2-di-
tert-butylphosphino-20-N,N-dimethylaminobiphenyl) offer im-
proved substrate scope under less harsh conditions (60-80 °C)
for the cyclohydroamination of alkylaminoalkenes relative to
the Pt(II)/PPh3 catalyst system.4 While further advances in the
late metal-mediated cyclohydroamination of primary and/or
secondary alkyl/arylamines and terminal or internal alkenes
have been achieved by use of rhodium,5 iridium,5b,6 and copper7
catalysts, the identification of increasingly effective late metal
catalysts for use in promoting the cyclohydroamination of
simple aminoalkene substrates under mild conditions and with
broad substrate scope remains an important and significant
challenge.
Intrigued by the apparent reactivity benefits derived from
the use of bulky monodentate phosphines in Pt-mediated
cyclohydroamination,4 we became interested in examining
the influence of sterically demanding bidentate ancillary
ligands on such catalytic chemistry, including P,N ligands
recently developed in our group that feature a phenylene
backbone,8 as well as a new P,P-indene ligand that enables
the construction of neutral, cationic, and formally zwitter-
ionic complexes.9 Herein we report on the results of our
synthetic and catalytic studies in this area, including the
observation that PtCl2 and (COD)PtCl2 alone are capable of
promoting the cyclohydroamination of primary as well as
secondary alkyl/arylamines tethered to R-olefins.10
Introduction
Notwithstanding the significant advances that have been
achieved in Buchwald-Hartwig amination in recent years,1
the inherent lack of atom economy associated with such proce-
dures has prompted the continued development of hydroamina-
tion techniques, including cyclohydroamination protocols that
enable concomitant ring closure and C-N bond formation via
the direct addition of N-H bonds to unsaturated substrates.2
In this context, the pursuit of general methods for promoting
the cyclization of rather simple aminoalkene substrates featuring
primary (-NH2) or secondary (-NHR; R=alkyl or aryl)
amino substituents tethered to R-olefins represents an active area
of inquiry in the field of organometallic catalysis. While a diver-
sity of catalysts for cyclohydroamination have been reported,2
those based on the late transition metals have proven to be partic-
ularly effective for the cyclization of the aforementioned amino-
alkene substrate classes. The first late metal catalyst system of
this type was described in 2005 by Bender and Widenhoefer,3
who reported the use of a catalyst mixture comprised of [PtCl2-
(H2CdCH2)]2 (2.5 mol %) and PPh3 (5 mol %) (or alternatively
2.5 mol % [PtCl2(PPh3)]2) for the cyclization of secondary
alkylaminoalkenes at 120 °C. Spectroscopic data obtained in
the course of this investigation support a reaction pathway
involving nucleophilic attack by a pendant amine fragment on
a Pt-coordinated alkene, followed by rapid and reversible
protonation at Pt and rate-limiting C-H reductive elimination.3
Encouraged by these mechanistic observations, Widenhoefer
(4) Bender, C. F.; Hudson, W. B.; Widenhoefer, R. A. Organometallics
2008, 27, 2356.
(5) (a) Shen, X.; Buchwald, S. L. Angew. Chem., Int. Ed. 2010, 49, 564.
(b) 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. (c) Liu, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 1570.
(6) (a) Hesp, K. D.; Tobisch, S.; Stradiotto, M. J. Am. Chem. Soc.
2010, 132, 413. (b) Kashiwame, Y.; Kuwata, S.; Ikariya, T. Chem.—Eur. J.
2010, 16, 766. (c) Hesp, K. D.; Stradiotto, M. Org. Lett. 2009, 11, 1449.
(7) Ohmiya, H.; Moriya, T.; Sawamura, M. Org. Lett. 2009, 11, 2145.
(8) (a) Lundgren, R. J.; Peters, B. D.; Alsabeh, P. G.; Stradiotto, M.
Angew. Chem., Int. Ed. 2010, 49, 4071. (b) Lundgren, R. J.; Sappong-
Kumankumah, A.; Stradiotto, M. Chem.—Eur. J. 2010, 16, 1983. (c) Lundgren,
R. J.; Stradiotto, M. Chem.—Eur. J. 2008, 14, 10388.
(9) For a review featuring our work in the area of zwitterionic catalyst
design, see: Stradiotto, M.; Hesp, K. D.; Lundgren, R. J. Angew. Chem.,
Int. Ed. 2010, 49, 494.
(10) For related studies examining phosphine-free Pt catalysts for the
hydroamination of ethylene with aniline, see: Dub, P. A.; Rodriguez-
Zubiri, M.; Daran, J.-C.; Brunet, J.-J.; Poli, R. Organometallics 2009, 28,
4764.
*To whom correspondence should be addressed. Fax: 1-902-494-
1310. Tel: 1-902-494-7190. E-mail: mark.stradiotto@dal.ca.
(1) For selected reviews, see: (a) Metal-Catalyzed Cross-Coupling Reac-
tions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2.
(b) Hartwig, J. F. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH:
Weinheim, 2002; p 107. (c) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002,
219, 131. (d) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534.
€
(2) For a comprehensive recent review, see: Muller, T. E.; Hultzsch,
K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795.
(3) Bender, C. F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127, 1070.
r
2010 American Chemical Society
Published on Web 10/07/2010
pubs.acs.org/Organometallics

6126 Organometallics, Vol. 29, No. 22, 2010
Lavery et al.
Table 1. Cyclohydroamination of Aminoalkenes Employing
Platinum Pre-catalystsa
Chart 1
entry
precatalyst
(COD)PtCl2
PtCl2
R, (R0)2
temp (°C) conv (%)b
1
Bn, (CH2)5
Bn, (CH2)5
Bn, (CH2)5
Bn, (CH2)5
Bn, (CH2)5
Bn, (CH2)5
p-tolyl, (Ph)2
110
110
110
65
82
79
PtCl2/PPh3 (80 °C, 13%, entry 6) was found to be inferior to
that of (COD)PtCl2.11a The ability of Pt complexes lacking
phosphine or carbene ligation to mediate such alkylamine
cyclohydroamination reactions had not previously been demon-
strated in the literature, and collectively the observations re-
ported herein bring into question the direct involvement of PPh3
in supporting a catalytically active Pt(II) species in this partic-
ular reaction system. Nonetheless, the outstanding catalytic
behavior exhibited by the PtCl2/tBu-DavePhos catalyst system4
with this test substrate (e.g., 80 °C, diglyme, 6 h, >99%) as well
as with alternative alkylamines featuring a range of substitution
patterns demonstrates that appropriately designed (dialkyl)-
phosphine co-ligands can indeed offer reactivity advantages in
Pt-catalyzed cyclohydroamination.
2
3
PtCl2 þ PPh3
(COD)PtCl2
(COD)PtCl2
PtCl2 þ PPh3
(COD)PtCl2
82
28
4
5
80
80
42
13
6
7
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
92
8
PtCl2 þ tBu-DavePhosc p-tolyl, (Ph)2
>95
61
9
(COD)PtCl2
H, (Ph)2
10
11
12
13
14
15
16
17
18
19
20
21
PtCl2 þ tBu-DavePhosc H, (Ph)2
90
59
PtCl2 þ L1
PtCl2 þ L2
PtCl2 þ L3
PtCl2 þ L4
PtCl2 þ L5
PtCl2 þ L6
PtCl2 þ L7
(L1)PtCl2
2
Bn, (CH2)5
Bn, (CH2)5
Bn, (CH2)5
Bn, (CH2)5
Bn, (CH2)5
Bn, (CH2)5
Bn, (CH2)5
Bn, (CH2)5
Bn, (CH2)5
Bn, (CH2)5
Bn, (CH2)5
8
<5
<5
38
11
8
83
Despite recent progress in late-metal hydroamination
catalyst design, the identification of catalysts that can pro-
mote the intramolecular addition of primary amines as well
as secondary alkyl- and arylamines to unactivated olefins has
proven difficult; to the best of our knowledge, such scope
has only been demonstrated by the [Ir(COD)Cl]2/HNEt3Cl
system.6a In this context, and given that previous examina-
tions of cyclohydroamination employing the PtCl2/tBu-Da-
vePhos catalyst system are limited almost exclusively to
secondary alkylamines,4,11b we sought to conduct proof-of-
principle experiments using (COD)PtCl2 (entries 7 and 9)
and PtCl2/tBu-DavePhos (entries 8 and 10) as precatalysts
for the cyclization of secondary arylamine and primary
amine test substrates under similar experimental conditions
(Table 1). Gratifyingly, each catalyst proved capable of
promoting the cyclohydroamination of these test substrates
to a significant extent, with the PtCl2/tBu-DavePhos system
offering substantially improved catalytic performance in the
case of the primary amine substrate (61% versus 90%).
Previous research in the Stradiotto group has established the
utility of appropriately designed κ2-P,N ligands featuring bulky
(dialkyl)phosphino substituents in the Ir-mediated transfer
hydrogenation of ketones (L2), as well as in the Pd-catalyzed
amination of aryl and heteroaryl halides and pseudohalides (L1,
Me-DalPhos; L5, Mor-DalPhos; Chart 1).8 In an effort to
evaluate if bulky co-ligands of this type might provide improved
catalytic performance in Pt-catalyzed cyclohydroamination
relative to phosphine-free catalysts, the cyclization of a repre-
sentative secondary benzylamine substrate was examined under
the conditions employed for PtCl2 (entry 2), but with the
inclusion of 6 mol % of L1-L7 (entries 11-17). In all cases,
the in situ-prepared PtCl2/L catalyst mixture proved signifi-
cantly inferior to PtCl2 alone, with L1 affording the most active
catalyst among the P,N ligands surveyed (59%). While im-
provements in conversion relative to those obtained when using
the PtCl2/L1 mixture were achieved by using the preformed
coordination complex (L1)PtCl2 (83%, entry 18), these catalytic
results are still only on par with those obtained when using PtCl2
in the absence of a co-ligand (79%, entry 2). Further efforts to
improve the catalytic activity of (L1)PtCl2 through the addition
of halide-abstracting agents (5 mol % AgOTf or AgB(C6F5)4) or
76
81
86d
2 þ AgOTf
3a
a Reaction conditions: 0.25 mmol of aminoalkene in 0.50 mL of 1,4-
dioxane, 5 h. See the Supporting Information for complete experimental
details. b Except where noted, clean conversion to the pyrrolidine was
monitored by use of GC techniques with less than 3% byproduct
observed in each case; product identity was confirmed by comparison
with authentic samples. c tBu-DavePhos = 2-di-tert-butylphosphino-20-
N,N-dimethylaminobiphenyl. d Complete consumption of the starting
aminoalkene observed, along with ca. 14% conversion to an alkene
isomerization byproduct.
Results and Discussion
Given our previous observation that [Ir(COD)Cl]2 is an
active precatalyst for the intramolecular addition of primary
(using HNEt3Cl as a cocatalyst) as well as secondary alkyl/
arylamines to unactivated olefins,6a we sought to establish the
catalytic abilities of the phosphine-free species (COD)PtCl2 and
PtCl2 prior to exploring the influence of P,N and P,P ligands on
Pt-mediated cyclohydroamination. Preliminary experiments of
this type were conducted using a representative secondary
benzylamine substrate under conditions similar to those that
proved effective for the Pt(II)/PPh3 catalyst system3 (5 mol %
Pt, 110 °C, 1,4-dioxane, 5 h; Table 1). Notably, under these
reaction conditions each of (COD)PtCl2 (entry 1) and PtCl2
(entry 2) was found to be a competent precatalyst for the
cyclohydroamination of this alkylamine substrate, affording
conversions to the corresponding pyrrolidine (ca. 80%) that
were comparable to those reported previously3 and to those
obtained in our laboratory (entry 3), when using a Pt(II)/PPh3
catalyst system. Furthermore, while diminished conversions
were achieved when using (COD)PtCl2 at lower temperatures
(65 °C, 28%, entry 4; 80 °C, 42%, entry 5), the performance of
(11) (a) In keeping with our observations, Widenhoefer and co-
workers have reported that a mixture of [PtCl2(H2CdCH2)]2 (2.5 mol %)
and PPh3 (5 mol %) under similar conditions using diglyme as the
solvent exhibits negligible catalytic activity for this cyclohydroamina-
tion reaction.4 (b) The use of PtCl2/tBu-DavePhos as a catalyst for the
cyclohydroamination of one secondary arylamine substrate has been
reported.6c

Note
Organometallics, Vol. 29, No. 22, 2010 6127
Scheme 1. Synthesis of 1 and the Derived Coordination
Complexes 2 and 3a,ba
Figure 1. ORTEP diagram for 2 depicting the atomic numbering
scheme and shown with 50% displacement ellipsoids. Selected hy-
drogen atoms have been removed for clarity. Selected interatomic
a DMAP = 4-dimethylaminopyridine.
˚
distances (A): Pt-Cl1, 2.3574(8); Pt-Cl2, 2.3618(9); Pt-P1,
2.2534(8); Pt-P2, 2.2155(8); P1-C2, 1.823(3); P2-C3, 1.808(3);
C1-C2, 1.524(5); C2-C3, 1.348(5).
Brønsted acids (5 mol % HOTf or HNEt3Cl) were unsuccessful,
affording inferior results. Moreover, attempts to employ
(L1)PtCl2 (as well as 2, 2/AgOTf, or 3a, vide infra) for the
cyclization of secondary arylamine and primary amine test
substrates under conditions similar to those featured in
entries 7-10 in each case resulted in <15% consumption
of the aminoalkene substrate.
NMR spectrum. The solid-state structure of 2 was confirmed
on the basis of single-crystal X-ray diffraction data,13 and an
ORTEP diagram14 of 2 is presented in Figure 1. Whereas the
more electron-rich (indene)P(tBu)2 fragment in 2 (versus the
(indene)PPh2 fragment) might be predicted to result in a longer
corresponding trans Pt-Cl linkage, the Pt-Cl distances in 2
With an aim toward evaluating the influence of sterically
demanding and potentially strongly chelating bis(phosphine)
ancillary ligands on Pt-catalyzed cyclohydroamination, we
turned our attention to the study of neutral, cationic, and
formally zwitterionic complexes derived from the new ligand
precursor 1-PPh2-2-P(tBu)2-indene 1 (Scheme 1). Our inspira-
tion for studying Pt precatalysts of this type comes from our
prior observations that formally zwitterionic complexes sup-
ported by donor-substituted indenide ligands in some cases
exhibit stoichiometric and catalytic reactivity patterns that are
divergent from more conventional neutral and cationic com-
plexes of related donor-substituted indenes, owing to the ap-
parent involvement of the indenide framework in substrate
activation.9,12 Furthermore, a recent report by Ikariya and co-
workers6b focusing on (C5Me5)Ir(pyrazolato) precatalysts sup-
ports the viability of metal-ligand bifunctional catalysis in
cyclohydroamination chemistry. Lithiation of 2-P(tBu)2-indene
followed by quenching with ClPPh2 afforded 1 in 85% isolated
yield, which in turn was transformed into the isolable chelate
complex 2 (89%) upon treatment of 1 with (COD)PtCl2. The
connectivity within 2 in solution was confirmed by use of NMR
techniques, including the observation of two doublets (65.9 and
17.6 ppm, with accompanying Pt satellites) in the 31P{1H}
˚
˚
(Pt-Cl1, 2.3574(8) A; Pt-Cl2, 2.3618(9) A) are indistinguish-
˚
able. Furthermore, the Ph2P-Pt distance (2.2155(8) A) is sig-
˚
nificantly shorter than the (tBu)2P-Pt distance (2.2534(8) A)
linkage, which may be attributable to the greater steric demands
of the (dialkyl)phosphino fragment.
In an effort to prepare a formally zwitterionic bis-
(phosphine) Pt complex of the type (κ2-P,P-indenide)Pt-
(THF)Cl 3a, dehydrohalogenation of 2 in THF using
NaN(SiMe3)2 was undertaken. While clean conversion to a
new product that we tentatively assign as 3a was observed
over the course of 20 min when monitoring by use of NMR
techniques in THF-d8 (31P NMR: 55.5 and 7.8 ppm, with
accompanying Pt satellites), we have thus far not been able to
isolate 3a in analytically pure form, due to decomposition
upon removal of solvent or other workup. However, support
for the identity of 3a comes from the isolation of the
corresponding 4-dimethylaminopyridine (DMAP) adduct
3b upon treatment of solutions of putative 3a with DMAP.
Complex 3b was isolated as an analytically pure yellow solid
in 86% yield and was characterized by use of 1H, 13C, and 31
NMR techniques.
P
In surveying the ability of each of 2, 2/AgOTf, and 3a
(cleanly generated in situ) to promote the cyclization of a
representative secondary benzylamine substrate (entries
19-21, Table 1), only minor differences in catalytic perfor-
mance were observed among these complexes, as well as
between these bis(phosphine) species and either (COD)PtCl2
or PtCl2 under similar experimental conditions. One differ-
entiating characteristic associated with the catalytic behavior
of 3a is that among all of the Pt precatalysts investigated
herein, only this putative zwitterion exhibited a propensity
for alkene isomerization within the R-olefinic secondary
benzylamine substrate.
(12) For representative examples, see: (a) Hesp, K. D.; McDonald,
R.; Ferguson, M. J.; Stradiotto, M. J. Am. Chem. Soc. 2008, 130, 16394.
(b) Lundgren, R. J.; Rankin, M. A.; McDonald, R.; Schatte, G.; Stradiotto, M.
Angew. Chem., Int. Ed. 2007, 46, 4732.
(13) (a) Selected crystallographic data for 2: Empirical formula,
C29H34Cl2P2Pt1; formula weight, 710.49; crystal dimensions, 0.36 ꢀ
0.26 ꢀ 0.04; crystal system, orthorhombic; space group, Pca21 (No. 29);
3
˚
˚
˚
˚
a (A), 19.1456(9); b (A), 8.5058(4); c (A), 16.9601(8); V (A ), 2761.9(2);
Z, 4; Fcalcd (g cm-3), 1.709; μ (mm-1), 5.406; 2θ limit (deg), 55.30 with
-24 e h e 24, -11 e k e 11, -22 e l e 22; total data collected, 23 404;
independent reflections, 6387; Rint = 0.0304; observed reflections, 5934;
absorption correction, Gaussian integration (face-indexed); range of
transmission, 0.8048-0.2436; data/restraints/parameters, 6387/0/307;
Flack absolute structure parameter, 0.001(4); R1 [Fo2 g 2σ(Fo2)], 0.0193;
wR2 [Fo g 3σ(Fo2)], 0.0437; goodness-of-fit, 1.020; largest peak, hole
2
(e A-3), 1.471, -0.321.
(14) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
˚

6128 Organometallics, Vol. 29, No. 22, 2010
Lavery et al.
Summary and Conclusions
Collectively, the observations featured in this report high-
light the complexities associated with design of Pt catalysts
for cyclohydroamination and will contribute to the further
development of increasingly effective catalysts for this
atom-economical transformation.
The proof-of-principle catalytic results featured herein estab-
lish the ability of phosphine-free Pt complexes including PtCl2
and (COD)PtCl2 to function as effective precatalysts for the
cyclohydroamination of primary as well as secondary alkyl/
arylamines tethered to R-olefins. These observations have
important implications with respect to the design of Pt catalysts
for use in such synthetic transformations, most notably asym-
metric variants, in that the contributions from phosphine-free
Pt species may figure significantly in the observed product
distribution. The reactivity benefits associated with the use of
sterically demanding monophosphine co-ligands such as tBu-
DavePhos in the Pt-catalyzed cyclohydroamination of secondary
alkylamine substrates is well established,4 and herein we con-
firm that such precatalysts are also capable of mediating the
cyclization of secondary arylamine and primary amine substrates.
However, improved catalytic activity relative to PtCl2 and
(COD)PtCl2 was not achieved through the use of complexes
supported by the bidentate co-ligands featured in our study,
which included precatalysts featuring phenylene-P,N ligands as
well as neutral, cationic, and formally zwitterionic complexes
derived from the new ligand precursor 1-PPh2-2-P(tBu)2-indene.
Acknowledgment is made to Dalhousie University and
the Natural Sciences and Engineering Research Council
of Canada (including a Discovery Grant for M.S. and a
Canada Graduate Scholarship for C.B.L.). We also thank
Dr. Michael Lumsden (NMR3, Dalhousie) for technical
assistance in the acquisition of NMR data.
Supporting Information Available: Complete experimental
details (PDF) and single-crystal X-ray diffraction data in CIF
format for 2 are available free of charge via the Internet at http://
pubs.acs.org.
Note Added in Proof. Following the acceptance of this
manuscript for publication, a highly effective rhodium catalyst
for the cyclohydroamination of unbiased and functionalized
primary aminoalkenes was reported: Julian, L. D.; Hartwig,
J. F. J. Am. Chem. Soc. 2010, 132, 13813.