Mechanism of catalytic cyclohydroamination by zirconium salicyloxazoline complexes

Article abstract of DOI:10.1021/ja106588m

The mechanism of hydroamination/cyclization of primary aminoalkenes by catalysts based on Cp*LZr(NMe₂)₂ (L = κ²-salicyloxazoline) is investigated in a range of kinetic, stoichiometric, and structural studies. The rate law

Full text of DOI:10.1021/ja106588m

Published on Web 10/12/2010
Mechanism of Catalytic Cyclohydroamination by Zirconium
Salicyloxazoline Complexes
Laura E. N. Allan, Guy J. Clarkson, David J. Fox,* Andrew L. Gott, and Peter Scott*
Department of Chemistry, UniVersity of Warwick, Gibbet Hill Road, CoVentry CV7 4AL, U.K.
Received July 25, 2010; E-mail: peter.scott@warwick.ac.uk
Abstract: The mechanism of hydroamination/cyclization of primary aminoalkenes by catalysts based on
2
Cp*LZr(NMe
2
)
2
(L ) κ -salicyloxazoline) is investigated in a range of kinetic, stoichiometric, and structural
1
0
studies. The rate law is found to be d[substrate]/dt ) k[catalyst] [substrate] for all catalysts and aminoalkenes
studied. The overall rate is similar for formation of five- and six-membered rings, and a substantial KIE
(k /k ) is observed, indicating the involvement of N-H bond-breaking in a rate-determining step (RDS)
H D
which is not ring-closure. Remarkably, the reaction proceeds at the same rate in THF as it does in toluene,
but added non-cyclizable amine slows the reaction, indicating that while the metal is not acting as a Lewis
acid in the RDS, the activated substrate is involved. Also in contrast to other catalysts, increasing steric
bulk improves the rate, and the origins of this are investigated by X-ray crystallography. Thermodynamic
q
parameters extracted from eight independent kinetic studies indicate moderate ordering (∆S ) -13 to
q
-
23 cal/K·mol) and substantial overall bond disruption (∆H ) 17 to 21 kcal/mol) in the rate-determining
transition state. Secondary amines are unreactive, as is a catalyst with a single aminolyzable site, thus
excluding an amido mechanism. A catalytic cycle involving rate-determining formation of a reactive imido
species is proposed. Stoichiometric steps in the process are shown to be feasible and have appropriate
rates by synthetic and in situ NMR spectroscopic studies. The fate of the catalyst in the absence of excess
amine (at the end of the catalytic reaction) is conversion to a metallacyclic species arising from CH activation
of a peripheral substituent.
2
0-25
Introduction
complexes,
which were followed some years later by non-
2
6-35
cyclopentadienyl lanthanide catalysts.
Recent interest has
Hydroamination, the addition of an N-H bond across an
unsaturated C-C bond, is an atom-economical method for the
efficient formation of N-C bonds and thus a topic of consider-
1
-14
(17) Kumar, K.; Michalik, D.; Castro, I. G.; Tillack, A.; Zapf, A.; Arlt,
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M.; Heinrich, T.; B o¨ ttcher, H.; Beller, M. Chem.sEur. J. 2004, 10,
lecular cyclohydroamination of aminoalkenes has attracted much
recent attention since chiral N-heterocycles have applications
in the pharmaceutical and fine chemical industries.
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7
46.
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10.1021/ja106588m  2010 American Chemical Society

Mechanism of Cyclohydroamination by Zirconium
A R T I C L E S
focused on group 4 complexes, with cationic zirconium
Scheme 1. The σ-Bond Insertative Mechanism (Amido) for
Cyclohydroamination
36,37
38-53
43,48,49,54-59
catalysts
systems.
and neutral zirconium
and titanium
The established mechanism for lanthanide systems involves
turnover-limiting CdC insertion into the Ln-N amido
2
0,23,25
1
0
σ-bond.
The observed rate law, ∼[Ln] [aminoalkene] ,
thermodynamic parameters, and other observations are consistent
6
0
with this mechanism (Scheme 1). The precatalyst I reacts
quickly with the aminoalkene substrate to give the activated
amido catalyst II, which is in equilibrium with the amino-amido
complex III. The coordination isomer of II, i.e., II′, undergoes
rate-limiting insertion of the coordinated alkene into the Ln-N
bond via transition state IV to form the heterocyclic product
V, which is protolyzed via VI and VII and releases product to
regenerate II.
While a similar amido mechanism may be operative for the
3
6,37
cationic zirconium species,
recent cyclohydroamination
studies using neutral group 4 complexes allow the possibility
of an imido mechanism (Scheme 2) analogous to Bergman’s
6
1
hydroamination of alkynes/allenes. Nevertheless, while the
[
2+2] cycloadditions of group 4 imides with alkynes and allenes
61-64
have been investigated using both experimental
computational
and
6
5-67
methods, such a reaction of unstrained
(
(
(
35) Rast a¨ tter, M.; Zulys, A.; Roesky, Peter, W. Chem.sEur. J. 2007, 13,
Scheme 2. Imido Mechanism for Cyclohydroamination
3
606.
36) Knight, P. D.; Munslow, I.; O’Shaughnessy, P. N.; Scott, P. Chem.
Commun. 2004, 894.
37) Gribkov, D. V.; Hultzsch, K. C. Angew. Chem., Int. Ed. 2004, 43,
5
542.
(
(
38) Kim, H.; Lee, P. H.; Livinghouse, T. Chem. Commun. 2005, 5205.
39) Kim, H.; Kim, Y. K.; Shim, J. H.; Kim, M.; Han, M.; Livinghouse,
T.; Lee, P. H. AdV. Synth. Catal. 2006, 348, 2609.
(
(
(
(
(
(
(
40) Thomson, R. K.; Bexrud, J. A.; Schafer, L. L. Organometallics 2006,
2
5, 4069.
41) Watson, D. A.; Chiu, M.; Bergman, R. G. Organometallics 2006, 25,
731.
42) Gott, A. L.; Clarke, A. J.; Clarkson, G. J.; Scott, P. Organometallics
007, 26, 1729.
43) Marcsekov a´ , C.; Loos, C.; Rominger, F.; Doye, S. Synlett 2007, 16,
4
2
2
564.
44) Wood, M. C.; Leitch, D. C.; Yeung, C. S.; Kozak, J. A.; Schafer,
L. L. Angew. Chem., Int. Ed. 2007, 46, 354.
45) Gott, A. L.; Clarke, A. J.; Clarkson, G. J.; Scott, P. Chem. Commun.
2
008, 1422.
46) Gott, A. L.; Clarkson, G. J.; Deeth, R. J.; Hammond, M. L.; Morton,
C.; Scott, P. Dalton Trans. 2008, 2983.
alkenes (e.g., at VIII, Scheme 2) is otherwise essentially
6
8,69
(
(
(
(
(
47) Li, X.; Haibin, S.; Zi, G. Eur. J. Inorg. Chem. 2008, 2008, 1135.
48) Majumder, S.; Odom, A. L. Organometallics 2008, 27, 1174.
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51) Leitch, D. C.; Payne, P. R.; Dunbar, C. R.; Schafer, L. L. J. Am. Chem.
Soc. 2009, 131, 18246.
unprecedented.
Schafer showed that bis(amido) complex X (Chart 1) and
imido species XI had similar activity for aminoalkene cyclo-
hydroamination, with turnover numbers of up to 12 h at 110
-
1
40
°C, and thus a common catalytic intermediate was proposed.
(
(
(
52) Zi, G.; Liu, X.; Xiang, L.; Song, H. Organometallics 2009, 28, 1127.
53) Reznichenko, A. L.; Hultzsch, K. C. Organometallics 2010, 29, 24.
54) Bexrud, J. A.; Beard, J. D.; Leitch, D. C.; Schafer, L. L. Org. Lett.
The inactivity for secondary amines was attributed to their
inability to form imido species. It was noted, however, that a
lanthanide-like amido mechanism was not excluded.
2
005, 7, 1959.
(
(
55) Lee, A. V.; Schafer, L. L. Organometallics 2006, 25, 5249.
In a thorough investigation into the mechanism of actinide
and Zr constrained geometry catalysts (CGCs), it was shown
that, e.g., XII (Chart 1) was moderately active in the cyclohy-
56) M u¨ ller, C.; Loos, C.; Schulenberg, N.; Doye, S. Eur. J. Org. Chem.
2
006, 2006, 2499.
(
(
(
57) Bexrud, J. A.; Li, C.; Schafer, L. L. Organometallics 2007, 26, 6366.
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J. Eur. J. Inorg. Chem. 2009, 2009, 429.
60
droamination of a range of substrates. Rates were much lower
2
4
70
than those of the analogous Ln and An systems, and the
mixed chloro-amido complex XIII was a significantly more
active catalyst for the cyclohydroamination of both primary and
(
(
60) Stubbert, B. D.; Marks, T. J. J. Am. Chem. Soc. 2007, 129, 6149.
61) Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc.
1
992, 114, 1708.
(
62) Baranger, A. M.; Walsh, P. J.; Bergman, R. G. J. Am. Chem. Soc.
1
993, 115, 2753.
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(
(
(
(
(
63) Sun Yeoul, L.; Bergman, R. G. Tetrahedron 1995, 51, 4255.
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120, 13405.
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67) Tobisch, S. Chem.sEur. J. 2007, 13, 4884.
4836.
J. AM. CHEM. SOC. 9 VOL. 132, NO. 43, 2010 15309

A R T I C L E S
Allan et al.
Chart 1. Selection of Recent Zr Catalysts for Cyclohydroamination
Scheme 3. Synthesis of Precatalysts 1
here, we chose to study in the main two readily available
1
C 2 2
precatalysts: (i) S ,SZr-[Cp*L Zr(NMe ) ] (1a) contains an
optically pure phenylglycinol-derived ligand and is present as
a single diastereomer with respect to the stereogenic center at
4
5
2
2 2
Zr; (ii) [Cp*L Zr(NMe ) ] (1b) contains a more sterically
demanding but achiral ligand and is formed as a racemic
mixture. We have shown that chloride and alkyl complexes
related to 1b undergo slow racemization on the NMR chemical
q
-1
shift time scale (∆G 298 ≈ 75 kJ mol ) and also are modestly
active though stable and well-defined single-site precatalysts
for olefin polymerization.
7
3
Aminopentenes 2a,b and aminohexenes 3a,b were chosen
as test substrates in order to probe the effect of substituent bulk
and ring size on the rate of cyclization (Table 1).
Kinetic Studies toward the Rate Equation. Quantitative
kinetic studies of the cyclohydroamination of aminoalkene
secondary aminoalkenes than the bis(amido) complex XII. This
is particularly interesting as XIII cannot form an imido species,
ruling out that pathway. Thermodynamic and rate law data were
also consistent with an amido mechanism analogous to that
1
substrates were carried out using in situ H NMR monitoring.
1
Ferrocene was employed as an internal H NMR integration
standard, as it can be readily differentiated from the substrate,
product, and catalyst resonances. The disappearance of the
substrate olefinic CH signal was monitored as a function of time
and normalized versus the internal standard. Cyclizations were
performed with 10 mol % catalyst so that reactions could be
run to completion or at least span sufficient half-lives within a
reasonable time period.
Linear plots of substrate concentration versus time were
obtained for runs in the range 60-90 °C, indicating that the
reactions are zero-order in substrate. Figure 1 shows a typical
series of runs for the cyclization of 4-pentenylamine 2a catalyzed
by 1a.
The linear response of the observed rate of reaction versus
precatalyst concentration is shown in Figure 1b. The initial
substrate concentration was kept constant. In addition, the van’t
Hoff plot of Figure 1c has a slope of ca. 1.1, indicating that the
reaction is first-order in catalyst.
6
0
followed by the Ln and An CGCs, and it was argued that it
was unnecessary to invoke the imido mechanism for group 4
complexes elsewhere.
5
3
71
More recently, the very active Zr systems XIV and XV
have been reported for the cyclohydroamination of a range of
aminoalkene substrates, although not secondary aminoalkenes,
even at elevated temperatures. Preliminary kinetic studies
indicated in both cases that the catalysis was first-order in both
substrate and catalyst and that substantial kinetic isotope effects
were observed.
Hence, it would seem that our observation in 2008 of an
unexpectedly fast and efficient enantioselective cyclohydroami-
nation of aminoalkenes using chiral-at-metal half-sandwich
4
5
diamide catalysts has been followed by still faster systems.
This rise of the importance of zirconium in cyclohydroamination
catalysis is accompanied by a number of recent preliminary
mechanistic studies which propose productive imido intermedi-
ates akin to those present in Bergman’s alkyne/allene hydroami-
The rate equation thus determined for this catalytic process
is given in eq 1.
61,62
nation system.
Here we report kinetic and other mechanistic
1
0
investigations into our half-sandwich system which exclude the
amido insertative mechanism and are consistent with an imido/
alkene cycloaddition mechanism in which, like the Bergman
alkyne catalysts, the imido formation is rate-limiting.
-
d[substrate]/dt ) k[catalyst] [substrate]
(1)
Given that the precatalysts used here are strictly mononuclear,
with sterically bulky ligands and high coordination number, the
observation of first-order kinetics in catalyst is as expected. We
note that preliminary evidence for a first-order dependence of
rate on [aminoalkene] has been presented for other zirconium
Results and Discussion
The Zr precatalysts were obtained through the reaction of
4
0,49,53,71
7
2
catalysts.
These systems are, however, strikingly dif-
Cp*Zr(NMe
2
)
3
with the appropriate salicyloxazoline proligand
4
5,73-75
ferent from the present system in that they have lower
coordination number and/or are sterically unencumbered. The
(
Scheme 3).
For the detailed kinetic studies described
(
(
71) Manna, K.; Ellern, A.; Sadow, A. D. Chem. Commun. 2010, 46, 339.
72) Irigoyen, A. M.; Martin, A.; Mena, M.; Palacios, F.; Y e´ lamos, C. J.
Organomet. Chem. 1995, 494, 255.
(74) Westmoreland, I.; Munslow, I. J.; Clarke, A. J.; Clarkson, G.; Deeth,
R. J.; Scott, P. J. Organomet. Chem. 2006, 691, 2228.
(73) Coles, S. R.; Clarkson, G. J.; Gott, A. L.; Munslow, I. J.; Spitzmesser,
(75) Gott, A. L.; Clarke, A. J.; Clarkson, G. J.; Munslow, I. J.; Wade, A. R.;
Scott, P. Organometallics 2008, 27, 2706.
S. K.; Scott, P. Organometallics 2006, 25, 6019.
1
5310 J. AM. CHEM. SOC. 9 VOL. 132, NO. 43, 2010

Mechanism of Cyclohydroamination by Zirconium
A R T I C L E S
1
Table 1. Effect of Varying Substrate on Kinetic and Thermodynamic Parameters for Cyclohydroamination Mediated by [Cp*L Zr(NMe
2 2
) ], 1a,
2
a
and [Cp*L Zr (NMe
2
)
2
], 1b
a
b
1
0 mol % of catalyst used, 90 °C, toluene-d
8
.
t
N calculated from least-squares fit to data, over at least three half-lives. Parameters in parentheses
represent 3σ values derived from the least-squares fit.
most fruitful comparison is with Marks’s lanthanide systems,
for which a wealth of mechanistic information is available, and
for which an imido mechanism is excluded; a comparison of
these f-element data with those obtained for the current
zirconium system is given in Table 2.
consistent with the olefin insertion process of Scheme 1. In the
-
1
current zirconium system, the values of -13 to -23 cal K
-
1
mol indicate significantly less ordering in the transition state,
and our proposed mechanism needs to take this into account.
Catalyst Steric Effects. In preliminary work, we noted that
the more sterically encumbered salicyloxazoline zirconium
systems appeared to be faster catalysts for cyclohydroamina-
Thermodynamic Parameters. The kinetic data obtained at a
range of temperatures (e.g., Figure 1a) were used in standard
Eyring (Figure 2a) and Arrhenius (Figure 2b) analyses to obtain
thermodynamic parameters for the reactions. The results are
detailed in Table 1 and summarized alongside other mechanistic
observations in Table 2.
4
5
tion. The kinetic results summarized in Table 1 also demon-
strate this trend, with bulkier complex 1b giving consistently
higher turnover frequency than 1a. Examination of the ac-
companying thermodynamic factors would indicate, for example,
that the increase in observed rate from entry 1 to 2 is
q
The ∆H values for all zirconium catalyst/substrate combina-
q
tions in Table 1 fall within a narrow range: ca. 17-21 kcal
accompanied by lower entropy penalty ∆S . The rate difference
-
1
q
mol (eight examples). The ∆S value range of ca. -13 to -23
between entries 3 and 4, however, while less substantial, arises
cal K- mol is also remarkably uniform, given the many
potential influences on this parameter. This is all consistent with
a common transition-state mechanism in the catalysis.
1
-1
q
from the lower ∆H more than compensating for a more negative
q
q
∆S . For entries 5 and 6, the difference in ∆H clearly
dominates. Whatever the detail of the origins of this phenom-
enon, the higher activity of the bulkier catalysts in this series is
in contravention with the otherwise universal trend of faster
cyclohydroamination catalysis by systems with greater metal
accessibility. For example, the lanthanide cyclopentadienyl
catalysts with more open coordination spheres have the higher
While to our knowledge no thermodynamic parameters are
available for other zirconium catalysts for this type of reaction,
q
-1
23
2 2
the ∆H value of 12.7(1.4) kcal mol for Cp* LaCH(TMS)
is substantially lower than those observed here. This implies
that the bond-making/breaking events in the region of transition
state are less well balanced in the case of the current system
than for the lanthanides, and it is this matter that appears to be
at the heart of the relative activities of the two classes of catalyst
2
5
turnover frequencies.
We have previously reported the molecular structure of 1c,
45
and this is shown with the molecular structure of 1b in Figure
3. The two structures were compared using the align algorithm
(
i.e., why Zr, even in this relatively fast system, is slower than
7
6
lanthanide). Even though direct comparison between the catalyst
systems is not a simple matter, Hammond’s postulate suggests
that a more endothermic rate-determining step implies a less
stable reactive intermediate for the current system than for the
lanthanide catalysts.
in PyMol. Corresponding atom pairs from each molecule are
overlaid and optimized to minimize the root-mean-square
deviation (rmsd) between the structures. A good fit was obtained
from aligning (from the structure of 1b) the Zr atom, the
The ∆S value of -27.0(4.6) cal K mol-1 for the lantha-
q
-1
(
76) DeLano, W. L. The PyMOL Molecular Graphics System; DeLano
2
3
nocene indicates a highly ordered transition state; this is
Scientific: San Carlos, CA, 2002; http://www.pymol.org.
J. AM. CHEM. SOC. 9 VOL. 132, NO. 43, 2010 15311

A R T I C L E S
Allan et al.
with the Cp* ligand. This is discussed further in the context of
the shape of the proposed transition state for the catalytic
reaction.
A number of further observations substantiate the idea that
catalysts 1 are fast as a result of, rather than despite, their high
coordination number and their steric bulk. For example, unlike
5
4
72
1
Zr(NMe
2
)
4
,
six-coordinate Cp*Zr(NMe
2
)
3
2
and L Zr-
7
4
(
2 2
NMe )
show respectively little and no conversion of these
4
2,44
substrates. Chiral amidate
and phosphinic/thiophosphinic
catalysts are sterically unsaturated but are neverthe-
3
8,41
amidate
less substantially slower than 1a-c. The turnover frequencies
observed for seven-coordinate 1b are at least 2 orders of
magnitude higher than those of the less congested, six-coordinate
t
-1
60
(
2 2 2 t
Cp′SiMe NBu )Zr(NMe ) (N ) 0.07 h at 100 °C). We
note, however, that a very recent preliminary study of a
zwitterionic zirconium diamido catalyst, employing a mixed
cyclopentadienyl-bisoxazolinyl borato ligand, indicates sub-
7
1
stantial activity at room temperature.
Ring Size. To our knowledge, all previously reported cyclo-
20,23,77-79
hydroamination catalysts based on lanthanides
cyclize
five-membered (pyrrolidine) rings at significantly higher rates
than six-membered (piperidine) rings. This is unsurprising for
processes in which the cyclization is the rate-determining step.
For systems based on group 4 metals, the general trend is the
3
8,40,53,54,56,80
same.
In Table 1, comparison of the turnover frequencies for entries
1
2
and 3 shows that, in the case of the gem-dimethyl substrates
-
1
t
a and 3a, the six-membered ring (N ) 8.7 h ) is cyclized
1
-
noticeably faster than the five-membered ring (2.4 h ) using
catalyst 1a. For the faster, bulkier catalyst 1b, the trend is still
evident although less pronounced (entries 2 and 4). Hence,
cyclization cannot be rate-determining for these catalytic
systems. Catalyst 1a is capable of cyclizing 2,2-dimethyl-6-
-
1
heptenylamine, albeit very slowly (N
no reactivity toward this substrate was observed with catalyst
b. This implies that ring-closure may be rate-determining for
t
) 0.05 h ); however,
1
larger rings and that the increased steric bulk of 1b disfavors
this cyclization.
Interestingly also, comparison of entries 1 and 5 shows that
there is little effect on the performance of catalyst 1a upon
increasing the size of the gem-dialkyl group from methyl to
phenyl. At the same time, the bulkier catalyst 1b (entries 2 and
Figure 1. Kinetic plots of hydroamination/cyclization of 2a using pre-
catalyst 1a in toluene-d : (a) zero-order plots of [substrate] versus time,
8
6
0-90 °C; (b) determination of order with respect to catalyst at 90 °C; (c)
-
1
Van’t Hoff plot for 90 °C data using the precatalyst. The lines are least-
squares fits to the data points.
6
t
) shows a dramatic increase in N , from 7.9 to 48.3 h , on
moving to the bulkier substrate.
Effect of Added Bases. Lewis acidic catalysts for cyclohy-
heteroatoms of the ligands [O(1), N(1), N(2), N(3)], the
interconnecting carbon atoms of the salicyloxazoline ligand
23
droamination, such as lanthanide and rare-earth metal
32,81
systems,
are strongly affected by the presence of non-protic
[
C(1), C(6), C(7)], the geminally substituted carbon atom of
bases such as THF. For the lanthanocenes, using THF as the
reaction solvent decreases the rate and causes a departure from
the standard rate law; THF competes very effectively for
coordination sites at the metal. The yttrium systems are sensitive
to even a few equivalents of THF, with turnover numbers
the oxazoline C(9), the methyl group C(10), and the ring carbons
of the Cp*, all with the corresponding atoms on 1c. The
optimized overlay of the two structures is shown in Figure 4.
Qualitatively, it can be seen that, despite the dimethyl substitu-
tion at the oxazoline C(9), the inner coordination spheres of
the two complexes have very similar arrangements of these
moieties, and the rmsd fit was found to be 0.114 Å. Correspond-
ingly, most of the relevant bond lengths and angles are very
similar between structures. The steric demand of the additional
substituent at C(9) in 1b compared with 1a and 1c is, however,
manifest in the orientation of the dimethylamido substituents.
In 1c, this unit is free to rotate to attain a sterically undemanding
orientation [torsion angle Cpcentroid-Zr(1)-N(2)-C(23) ca.
8
1
decreasing by almost 50% after addition of 5 equiv.
Remarkably, the cyclohydroamination reactions of substrates
2a and 3a using catalysts 1a and 1b conducted in neat THF
(77) Giardello, M. A.; Conticello, V. P.; Brard, L.; Gagne, M. R.; Marks,
T. J. J. Am. Chem. Soc. 1994, 116, 10241.
(
78) Hong, S.; Tian, S.; Metz, M. V.; Marks, T. J. J. Am. Chem. Soc. 2003,
1
25, 14768.
(79) Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006,
1
28, 3748.
(
(
80) Bexrud, J. A.; Schafer, L. L. Dalton Trans. 2010, 39, 361.
81) Hultzsch, K. C.; Hampel, F.; Wagner, T. Organometallics 2004, 23,
2601.
5
0.3°], while for 1b it is required to orient “vertically” [torsion
angle Cpcentroid-Zr(1)-N(2)-C(21) ca. 12.5°], thus interacting
1
5312 J. AM. CHEM. SOC. 9 VOL. 132, NO. 43, 2010

Mechanism of Cyclohydroamination by Zirconium
A R T I C L E S
Table 2. Comparison of Mechanistic Data for Lanthanocene Catalysts and the Current Zr System
observation
2
Cp′ LnX
Cp*LZr(NMe
)
2 2
conclusion
1
0
1
0
-
d[substrate]/dt ∝
[Ln] [substrate]
inhibits
[Zr] [substrate]
no effect
substrate not lost or gained before rate-determining TS of either catalyst
Zr not acting as Lewis acid in RDS
added THF
added non-cyclizable amine
rate dependence on ring size
inhibits
5 . 6
2.7-5.2
-27(2)
13(5)
inhibits
substrate activated as amido unit is involved in both RDSs
Cyclization is RDS for Ln but not for Zr
both have N-H bond breaking in RDS
highly ordered TS for Ln, less ordered for Zr
bond-breaking/making less in balance for Zr
progression to TS involves increased crowding for Ln but reduced
crowding for Zr
5 ∼ 6
KIE (k
H
/k
D
)
2.5-3.0
q
∆
S (cal/K·mol)
-13 to -23
17-21
q
∆
H (kcal/mol)
ligand steric bulk
reduces rate
increases rate
secondary aminoalkenes?
valencies required at M
yes (slower)
1
no
2
implies imido for Zr
excludes amido for Zr
proceeded at rates which were indistinguishable from those of
the same reactions conducted in the more conventional toluene
solvent. A comparison of two such reactions is shown in Figure
appears to move from zero- toward first-order in substrate with
increasing concentration of hexylamine.
5
. Unlike previous systems, the rate-limiting step for these
catalyses does not involve the metal acting as a Lewis acid in
the rate-determining step. There are no free coordination sites
in the four-legged piano stool structure at which THF might be
expected to bind strongly. Also, we know that the six-coordinate
+
F
-
cationic center in [Cp*LZrMe] [BAr
coordinate ethylene (vide infra).
4
]
does not readily
7
3
Marks has shown that the addition of a non-cyclizable amine
such as n-propylamine to cyclohydroamination reactions cata-
lyzed by lanthanocenes significantly decreases the rate of the
2
3
reaction and has interpreted this behavior on the basis of
competition between the cyclizable and non-cyclizable amines
for binding to the metal as amido units. In the present zirconium
system, the behavior was qualitatively similar. Figure 6a shows
how the rate of substrate consumption is affected by increasing
concentration of n-hexylamine. As can be seen in the plots of
ln[substrate] versus time in Figure 6b, the order of reaction
Figure 3. Molecular structures of (a) 1c and (b) 1b. Hydrogen atoms have
been removed for clarity. Thermal parameters are drawn at 50% probability.
For both structures, only one of the very similar crystallographically
independent molecules is shown. For 1b, the two independent molecules
are diastereomeric.
Figure 2. Cyclohydroamination of 2a using precatalyst 1a in toluene-d
a) Eyring plot and (b) Arrhenius plot. The lines are least-squares fits to
the data points.
8
:
(
J. AM. CHEM. SOC. 9 VOL. 132, NO. 43, 2010 15313

A R T I C L E S
Allan et al.
Figure 4. Overlay plot of the molecular structure of 1c (gray) with the
appropriate diastereomer of 1b (black).
Figure 6. (a) Kinetic plots of [substrate] versus time for cyclohydroami-
nation of 3a using precatalyst 1a in toluene-d at 90 °C as a function of
8
concentration of added n-hexylamine (A). (b) First-order plots of the same
data. [cat.] ) 0.025 M in all cases. The lines are least-squares fits to the
data points.
t
showed that (Cp′SiMe
2
NBu )Zr(NMe
2
)Cl, with its single readily
aminolyzable amido site (single available valency), was a
-
1
competent cyclohydroamination catalyst (N
was in fact significantly faster than (Cp′SiMe
t
) 0.14 h ) and
t
2
2 2
NBu )Zr(NMe )
-
1
Figure 5. Kinetic plots of [substrate] versus time for cyclohydroamination
t
(N ) 0.07 h ) for steric reasons. This excludes the imido
of 3a at 60 °C, using precatalyst 1a in toluene-d
8 8
(blue) and THF-d (red).
cat.] ) 0.025 M. The lines are least-squares fits to the data points.
mechanism in that system, and it is concluded that a conven-
[
0
tional (lanthanide-like) amido process is in play.
1
By reaction of Cp*L ZrCl
2
with LiNMe
)Cl] as a 2.3:1 diastereomeric mixture,
the isomers differing only in the site substituted by NMe . This
2
, we synthesized the
Kinetic Isotope Effect. Measurement of the rate of cyclization
1
) 0.78 h- and thus a KIE
1
system [Cp*L Zr(NMe
2
of N-deuterated 2a with 1a led to N
/k ) 3.0 at 90 °C. For 1b, the turnover number was decreased
to 3.2 h , giving k
t
2
k
H
D
-1
isomeric mixture was completely inactive as a catalyst for
cyclohydroamination of 2a. In a control experiment, a standard
catalytic run using 1a doped with 1 molar equiv of
H
D
/k ) 2.5 at 90 °C. This result suggests
that the rate-determining step in this catalytic process involves
N-H bond-breaking.
1
-1
[
Cp*L Zr(NMe
2 t
)Cl] cyclized 2a with N ) 2.20 h , slightly
Valencies Required at Nitrogen and Metal. We have previ-
ously noted that all catalysts 1 are inactive for the cyclohy-
droamination of secondary amine substrates. This contrasts with
the behavior of the related constrained geometry catalysts
lower than that recorded in Table 1 (entry 1). Hence, assuming
that [Cp*L Zr(NMe )Cl] does not decompose to some unknown
2
1
catalytically active species, it appears that two readily amino-
lyzable sites are required at the metal center in the current
system. This is not consistent with the operation of an amido
process.
t
60
2 2
(CGCs) (Cp′SiMe NBu )ZrX , which have lower coordination
numbers and are rather less sterically encumbered than 1.
Secondary amine substrates cannot be cyclohydroaminated via
an imido mechanism, since only one N atom valency is
available. It does not follow, however, that the absence of
catalytic activity for secondary amines excludes the possibility
of an amido mechanism or indeed proves an imido mechanism.
Secondary amine substrates are commonly cyclized at substan-
tially lower rates than the corresponding primary amines, and
given the general sluggish nature of almost all preceding
zirconium-based systems, any lack of activity for secondary
amines might simply arise from a negligible rate of decomposi-
tion of the catalyst under the forcing conditions required.
The mechanism of operation of the aforementioned CGC
Probing Catalyst Activation and Deactivation. The triamido
t
82
compound Cp*Zr(NHBu )
3
does not react with salicyloxazo-
n
lines HL (n ) 1, 3) at ambient temperature, but over 3 d at 60
C the metalated species 4 (Scheme 4) were produced cleanly
°
and could be isolated by sublimation. The presumed intermediate
diamides 1d and 1e were not observed by NMR spectroscopy
at this temperature. Since species like 4 are implicated in the
catalysis under study here, we investigated their formation under
catalytically relevant conditions.
(
82) Bai, Y.; Roesky, H. W.; Noltemeyer, M.; Witt, M. Chem. Ber. 1992,
125, 825.
6
0
compounds is investigated in some detail by Marks, who
1
5314 J. AM. CHEM. SOC. 9 VOL. 132, NO. 43, 2010

Mechanism of Cyclohydroamination by Zirconium
A R T I C L E S
Scheme 4. Synthesis of Metalated 4d,e and Amido Cations 5a,b
Figure 7. Kinetic plot of [substrate] versus time for cyclohydroamination
of 3a using precatalyst 1a in toluene-d
fit to the data points (up to t ) 75 min).
8
at 90 °C. The line is a least-squares
1
This complex, like 4d,e, has characteristic H NMR resonances
in the aromatic region (δ 6.52, 7.01, 7.11, and 7.32 ppm), quite
separate from other peaks, thus allowing us to detect readily
the presence of this and similar metalated species. In another
NMR tube reaction, precatalyst 1a was treated with excess (10
equivalents) n-BuNH
a species for which NMR spectra are consistent with the
bis(butylamido) structure 1f. Two equivalents of Me NH was
2
at ambient temperature, rapidly producing
2
released, and the new zirconium amide NH protons were
observed at δ 3.47 and 4.71 ppm. Heating this sample to 90 °C
for 6 h led to some broadening, but crucially no characteristic
resonances for a metalated species like 4a were observed. Hence,
while the diamido precatalyst undergoes transamination rapidly,
it does not convert to a metalated species in the presence of
excess amine.
Scheme 5. Stoichiometric Reactions To Probe Activation and
Deactivation Pathways
Precatalyst 1a was treated with 1 equiv of aminoalkene 2a
at room temperature to give the transamination product 1g (two
diastereomers in ca. 9:1 ratio, see Supporting Information) and
dimethylamine (Scheme 5). Heating the sample to 90 °C resulted
in the rapid formation of cyclized product 2,4,4-trimethylpyr-
rolidine and metalated 4a.
We attempted to detect the presence of orthometalated species
during a cyclohydroamination run using catalyst 1a and ami-
noalkene 3a in toluene-d
As before, the observed strictly linear plot of [substrate] vs time
Figure 7) for the first four half-lives of the reaction indicates
8
using a 600 MHz NMR spectrometer.
(
the presence of a single kinetically important catalytic species
whose concentration is not varying significantly with time. No
metalated species were detected until t ) 75 min (90%
conversion), when characteristic resonances were detected at δ
6
.52 ppm (Figure 8). The appearance of metalated species is
accompanied by a reduction in the observed rate (Figure 7).
Overall, this behavior during a catalytic run corresponds with
that observed in the stoichiometric and model reactions de-
scribed above in that the metalated species is not formed to a
significant degree until the concentration of primary amine is
low. Rate reductions at low substrate concentrations are observed
with Ln and An complexes, but this has been attributed to
6
0,83
product inhibition.
A catalytic reaction was conducted using 10 equiv of
NCH CMe CH CHdCH (d -2a) and 1a. Analysis of the
D
2
2
2
2
2
2
NMR spectrum of the final metalated product showed that partial
Heating pure 1a in toluene-d
conversion to a metalated species 4a (similar to 4d,e) with loss
of HNMe (Scheme 5). This reaction could also be performed
on a preparative scale, with essentially quantitative conversion.
8
at 90 °C for 24 h gave clean
deuteration of the phenyl ring had occurred (Scheme 6).
Resonances at δ 7.15 ppm in the H NMR spectrum and δ 138.4
2
2
(83) Stubbert, B. D.; Marks, T. J. J. Am. Chem. Soc. 2007, 129, 4253.
J. AM. CHEM. SOC. 9 VOL. 132, NO. 43, 2010 15315

A R T I C L E S
Allan et al.
1
Figure 8. (A) Initial H NMR spectrum (δ 6.5-8.5 ppm) of 1a and substrate 3a in toluene-d
activated catalyst, where one or both NMe
C) t ) 75 min, showing activated catalyst and a small amount of CH-activated species at a low [substrate]. (D) t ) 185 min, showing several CH-activated
species but no coordinated or free substrate.
8
at ambient temperature. Minor resonances correspond to the
groups have been replaced by substrate. (B) t ) 25 min, showing activated catalyst but no CH-activated species.
2
(
Scheme 6. Partial Deuteration of Catalyst during Reaction with
N-Deuterated Substrate
Scheme 7. Formation of “Tuck-In” Complex 4b
catalysts for homogeneous Ziegler-Natta polymerization of
8
4
olefins by a migratory insertion mechanism. These catalysts
are nevertheless unusual in that they are active only for
36
secondary amines, and thus an imido mechanism is excluded.
(
t, 1JCD ) 21 Hz) ppm in the 13C NMR correspond to the
We were thus interested to look at the behavior of cationic
deuterated ligand, while the non-deuterated species was also
evident in the 13C NMR spectrum. This indicates that amido
species 1 are in equilibrium with the metalated compounds at
derivatives of precatalysts 1.
+
We have previously reported complexes [Cp*ZrLMe] -
BArF
-
[
4
] to be stable single-site catalysts for ethene polymer-
9
0 °C.
ization. Calculations indicate that the modest catalytic activity
results from the reluctance of this six-coordinate species to bind
Precatalyst 1b reacts with primary amines in a similar manner
73
to 1a (Scheme 5), forming the transaminated products with
the olefin to form a four-legged piano stool. Correspondingly,
we have found that treatment of this cationic compound with
aminoalkene 2a leads to no detectable turnover of cyclohy-
droamination at 90 °C.
n
BuNH
through CH-activation of the salicyloxazoline ligand. Prolonged
heating (48 h at 90 °C) of 1b in benzene-d resulted in the slow
and incomplete formation of a “tuck-in” complex, 4b (Scheme
), as evidenced by the loss of the Cp* protons at δ 1.81 ppm
and the formation of four new methyl groups (δ 1.83, 1.90,
.04, and 2.09 ppm). HNMe was produced, and the metalated
CH group was observed as two doublets at δ 3.22 and 3.55
2
and 2a. However, 1b does not undergo metalation
6
Treatment of metalated species 4d and 4e with [PhNMe
B(C ] yielded the complexes 5a and 5b, respectively, via
protonolysis of the metallacyclic alkyl (Scheme 4). No evidence
was found for the binding of the co-product PhNMe or added
2
H]-
7
[
6 5 4
F )
2
2
2
85
2
THF to the metal center. These rare examples of cationic
2
ppm ( JHH ) 13 Hz). There is no spectroscopic evidence for
the formation of 4b during catalysis.
82
amides are quite thermally stable (toluene, 90 °C). Despite
Cationic Systems. The first enantioselective catalysts for
(
(
84) Chen, E. Y.-X.; Marks, T. J. Chem. ReV. 2000, 100, 1391.
85) Kissounko, D. A.; Epshteyn, A.; Fettinger, J. C.; Sita, L. R.
Organometallics 2006, 25, 1076.
cyclohydroamination based on group 4 metals were alkyl cations
36
with a weakly coordinating anion, i.e., analogous to the many
1
5316 J. AM. CHEM. SOC. 9 VOL. 132, NO. 43, 2010

Mechanism of Cyclohydroamination by Zirconium
A R T I C L E S
Scheme 8. Catalytic Cycle for Cyclohydroamination by Catalysts 1
their coordination number being lower than those of the neutral
starting materials, 5a and 5b are not catalysts for cyclohy-
droamination of primary aminoalkene 2a or secondary ami-
noalkenes. For secondary amines, the lack of σ-insertion
catalysis (amido mechanism) could be ascribed to the absence
of an accessible coordination site. For primary amine substrates,
which may react via an imido mechanism, the reasons are less
obvious; retardation of catalysis by adduct formation is highly
unlikely (vide supra). We have observed, however, that cation
any equilibrium is not significantly disturbed by the removal
(by reaction or heating) of amido ligand as amine from the
system. Indeed, it is clear that bis(amides) 1 are converted to
metalated species 4 on heating in the absence of excess amine
(steps 4, 4′). The NMR experiments above also show that
bis(dimethylamido) complex 1a reacts with pentenylamine 2a
to exchange amido ligands (step 5) rapidly at ambient temper-
ature and at a rate that is substantially faster than the cyclization
reaction (steps 1-3). Overall, these observations suggest that
the resting state of the catalytic cycle at the start of the reaction,
when there is excess 2a, is the pentenylamido complex 1g
(which we have detected above) or 1h.
Rate-determining step: The kinetic experiments indicate that
initially the reaction is first-order in catalyst and zero-order in
pentenylamine starting material. Given our proposal that the
mechanism of the reaction occurs via reactive imido intermediate
6b, the rate-determining step could be the loss of an amine from
the resting state to generate the imido complex (step 1). If step
1 is reversible and the reaction of this imido complex to give
the metallacycle 7 by a [2+2] addition (step 2) is rate-
determining, then the reaction would be inverse-order in starting
material. If the reaction of this latter complex 7 with penteny-
lamine 2a to regenerate the resting state (step 3) is rate-
determining and the previous two steps are reversible, then,
again, the reaction would be zero-order in starting material.
Therefore, step 1 or 3 is rate-determining. The presence of a
significant, probably primary, kinetic isotope effect on replace-
5a is stable with respect to reaction with excess amine 2a under
catalytic conditions; i.e., it is not deprotonated by amine base
at the secondary amide to give [Cp*LZrdNR] or indeed to give
metalated 4a. This accords with our expectations in that the
a
pK of the NH proton in cationic zirconium primary amido
species 5a is expected to be high. The lack of catalysis is thus
most probably due to the inaccessibility of the imido species
from 5 under these conditions.
Catalytic Cycle. A mechanism for cyclohydroamination by
precatalysts 1a and 1b consistent with all the observations
detailed above is given in Scheme 8. In addition to the main
productive cycle 1-6-7-1, we have depicted the amide
metathesis process for catalyst activation, e.g., 1a-1g, and the
catalyst deactivation processes to give (principally) 4f.
On the basis of the kinetics and NMR experiments discussed
above, we will identify the catalyst resting state and the rate-
determining step, and the changes to the nature of these two
elements of the mechanism, as the reaction proceeds.
Resting state: The stability of the bis-dimethylamido complex
2 2
ment of NH with ND in 2a indicates that proton transfer to
1
a suggests that other similar bis-amido complexes may also
and from the nitrogen atoms is rate-determining. Again, this
eliminates step 2 as rate-determining, as it does not involve
proton transfer. If step 3 is rate-determining, with bis-amido
be relatively stable compared to, say, the imido complex 6b,
the metalated species 4, and the metallacycle 7, providing that
J. AM. CHEM. SOC. 9 VOL. 132, NO. 43, 2010 15317

A R T I C L E S
Allan et al.
complex 1 of some kind as the resting state, then steps 1 and 2
must be reversible. Bergman et al. have shown that primary
amines react with imido complexes quickly to give bis-amido
complexes, and that related [2+2] addition reactions can be
Chart 2. Transition States for Cyclization of Amidoalkenyl Units: (a)
Amine-Assisted Insertative Transition State Suggested by Marks,
IV′, and a Similar Non-insertative Process, IV′′, and (b) Similar
Six-Membered Cyclic Transition State Applied to the Current Zr
System
61
reversible. In our case, however, the reaction of pentenylamine
starting material with metallacycle 7 may occur via a fast
σ-metathesis/proton-transfer mechanism similar to that suggested
in the fast exchange of amido ligands discussed above. Such a
reaction of metallacycle 7 with the primary amine would involve
the formation of a relatively unstrained bis-amido complex 1
from a strained amido-alkyl complex 7 and is therefore expected
to be, if anything, faster than step 5. A high rate of forward
reaction of metallacycle 7 with amine would render the [2+2]
reaction irreversible under normal reaction conditions, and as
step 2 cannot be rate-determining, step 1 must be the rate-
8
6
determining step for the majority of the reaction.
At the end of the reaction, when the concentration of primary
amine starting material is low, the rate of step 3 may, however,
fall until it becomes rate-determining. In this case the reaction
would continue to be zero-order in starting material as long as
both steps 1 and 2 are reversible. The fall in rate in step 3 would,
however, be met by a possible fall in the reverse rate of step 1.
Therefore, the rate of back-reaction of imido complex 6b and
the rate of forward reaction of metallacycle 7 would fall, and a
buildup in concentration of these two reactive intermediates
would occur if no other reaction path was available. The NMR
spectra indicate, however, that at the end of the reaction the
metalated species 4 are formed. This may occur from a bis-
amido complex 1 (step 4/4′), imido complex 6 (step 7), or
metallacycle 7 (step 6). Metalated compounds such as 4a are,
however, poor catalysts for the cyclohydroamination reaction.
The observed lowering of the reaction rate at the end the reaction
is therefore caused by a reduction in the concentration of bis-
amido complexes 1.
via transition state IV (Scheme 1)sand thus inconsistent with
our values of ∆S ; (ii) the increased crowding in the active site
would lead to lower activity for more crowded systems, contrary
to our observations; and (iii) it involves rate-limiting ring closure
and would thus be expected to lead to a significant difference
between five- and six-membered cyclizations.
q
Nature of the Rate-Determining Transition State. In Scheme
8
we depict a rate-limiting transition state 8 (step 1) in which
one amido unit deprotonates the NH group of a pentenylamido
unit to give the imido species 6b. The approach to this
R-elimination transition state requires some ordering of the two
amido ligands. Our comparisons of the molecular structures of
Conclusion
1
b and 1c above indicate that steric compression in the former
Given the sluggish nature of all but the most recent Zr-based
catalysts for aminoalkene cyclohydroamination, the rate of
catalysis by complexes 1 is exceptionally high. This circum-
stance has allowed us to perform a large number of kinetic
experiments, leading to the establishment of a rate law (eq 1)
which is the same as that for the original lanthanocene system,
for which we find a direct comparison very helpful (Table 2).
While the lanthanocenes are slowed by the presence of exog-
enous THF, which coordinated competitively with tethered olefin
would tend to reduce the amido N-Zr-N angle and facilitate
bridging of an H (or D) atom between the two N atoms. We
consider this to be consistent with (Table 2) the energy of this
transition state not being significantly affected by the presence
of THF, the observed k
∆
of the reaction rate by steric crowding in the catalyst. We note,
however, that the presence of a similar KIE in lanthanide-based
cyclohydroamination led Marks some time ago to suggest an
amine-assisted σ-insertative mechanism via a transition state
H
/k
D
KIE, the magnitude of the negative
q
q
S values, the relatively high ∆H values, and the promotion
(Scheme 1), catalysts 1 are completely unaffected. This observa-
tion accords with the lack of free coordination sites at the metal
in precatalysts 1. Nevertheless, the presence of diluting non-
cyclizable primary amine slows both catalysts in a qualitatively
similar manner by reducing the concentration of active species
containing at least one amidoalkene ligand. Another striking
difference between the lanthanocenes and 1 is the independence
of catalytic rate on the ring size being formed and thus the
positioning of the ring-closure after the RDS. Nevertheless, both
2
3
IV′ (Chart 2a, cf. IV, Scheme 1) that involves a Ln-C bond.
An isomeric (non-insertative) transition state IV′′ leading to
concerted cyclization and protonolysis is also shown. In the
present system, a similar transition state 9 is appealing since it
leads to formation of cyclized product directly. Nevertheless,
we can exclude the productive operation of this transition state
here on the basis that (i) the bicyclic structure is highly
orderedsmore so than that in Marks’ σ-insertative mechanism
classes of catalyst display a significant KIE (k
H D
/k ) in the
presence of -ND
2
aminoalkenes, thus indicating the importance
of this bond in the RDS.
(
86) Two alternative modifications of this mechanism may be in force: (i)
steps 1 and 2 are concerted and rate-determining, with step 3 fast, or
Eight sets of thermodynamic parameters were determined for
combinations of catalysts 1 and substrates 2 and 3. These paint
(
ii) step 1 is rate-determining and steps 2 and 3 are concerted. We
will consider this in future computational work.
1
5318 J. AM. CHEM. SOC. 9 VOL. 132, NO. 43, 2010

Mechanism of Cyclohydroamination by Zirconium
A R T I C L E S
a consistent picture of a transition state which is less ordered
than that for the lanthanides and in which bond-breaking
outbalances bond-making to the extent that the catalytic rate
for lanthanocenes is substantially higher, even for this relatively
fast Zr system. Also in contrast with the lanthanocenes, rates
are in order of increasing steric bulk of catalyst, e.g., 1a < 1c
ously degassed before use. C
6
D
6
and toluene-d
8
were refluxed in
vacuo for 3 days over potassium metal and vacuum-transferred
before use. CDCl was purchased from Aldrich and stored over 4
3
Å molecular sieves.
7
3,74
72
The salicyloxazoline proligands,
Cp*Zr(NMe )
2
3
and
t
82
45
Cp*Zr(NHBu )
3
,
and complexes 1a,c, 4d,e, and 5a,b were
prepared according to published procedures. LiNMe
was purchased from Chemat Technology and used as received. The
hydroamination substrates 1-amino-2,2-dimethylpent-4-ene (2a),
2
(99.9% grade)
<
1b. This is consistent with a system in which the rate-
determining transition state is approached by compression of
coordinated groups, and this is supported by a comparison of
the molecular structures of 1b and 1c.
While the lanthanocenes have good activity for cyclohy-
droamination with secondary amines, the catalysts 1 are unable
to perform this type of ring-closure. While this observation is
consistent with the need for two available valencies at the N
atom, it is inconclusive because the rates may simply be low
rather than zero. Nevertheless, an amido mechanism is excluded
87
36
1
-amino-2,2-dimethylhex-5-ene (3a), 1-amino-2,2-diphenylpent-
87 88
4-ene (2b), 1-amino-2,2-diphenylhex-5-ene (3b), and 1-amino-
2
3
2,2-dimethylhept-6-ene were prepared according to literature
procedures, dried for 3 days at ambient temperature over CaH
vacuum-transferred, and stored in a glovebox. 1-Amino-2,2-
dimethylpent-4-ene-d was prepared via a variation of the literature
method, using diethyl ether rather than dichloromethane as
solvent. NMR tubes, including those for in situ reactions, were fitted
with a J. Young PTFE concentric stopcock.
2
,
2
6
0
by the requirement for two available valencies at the Zr center;
NMR spectra were recorded on Bruker DPX-400, AV-400, DRX-
00, and AV III 600 spectrometers at 298 K unless otherwise stated.
1
neither diastereomers [Cp*L Zr(NMe
2
)Cl] nor cations 5a and
5
5b are catalysts. In contrast, the slower (CGC)Zr catalysts which
The spectra were internally referenced using the residual protio
solvent resonance relative to tetramethylsilane (δ ) 0 ppm). Routine
NMR assignments were confirmed by H- H (COSY) and C- H
(HMQC) correlation experiments where necessary. Elemental
analyses were obtained by Warwick Analytical Services, Coventry,
UK, and MEDAC Ltd., Surrey, UK.
operate by the Marks amido insertative mechanism require only
6
0
1
1
13
1
one aminolyzable site.
A catalytic cycle is thus proposed which involves rate-
determining formation of an unobserved imido species. A
number of stoichiometric experiments have been conducted
whose rates and products are consistent with the proposed
mechanism. Specifically, metalated species 4 are observed only
at the end of the reaction, when the concentration of primary
amine is low.
A rate-determining transition state, consistent with all the
above observations including kinetic and thermodynamic mea-
surements, is proposed in which one amino group deprotonates
its neighbor, i.e., an R-elimination analogous to that proposed
in Bergman’s study of zirconocene-catalyzed alkyne/allene
hydroamination. A key difference is the ability of catalysts 1
to react with alkenes. The origins of this behavior will be
investigated by computational means and will be reported in
due course.
Crystallography. A suitable crystal of 1b was mounted on a
glass fiber using an inert oil prior to transfer to a cold nitrogen gas
stream and held at 100 K with an Oxford Cryosystems Cobra on
an Oxford Diffraction Gemini four-circle diffractometer system with
a Ruby CCD area detector using Mo KR radiation () 0.71073 Å).
Diffractometer control and data collection were done with a
CrysAlis CCD (Oxford Diffraction, 2008). Data were collected with
1° frame exposures using φ and ω scans. Intensities were corrected
semi-empirically for absorption, based on symmetry-equivalent and
repeated reflections with CrysAlis RED (Oxford Diffraction, 2008).
The structures were solved by direct methods using SHELXS
89,90
(TREF)
with additional light atoms found by Fourier methods.
All non-hydrogen atoms were refined anisotropically. H atoms were
placed at calculated positions and constrained with a riding model
with U(H) set at 1.2 (1.5 for methyl hydrogens) times Ueq for the
Unusually, the RDS (Scheme 8, step 1) and selectivity-
determining step (step 2) in this reaction are different, and this
has implications for future catalyst design. In particular, the
relatively modest enantioselectivities we have observed
parent atom. SHELX97 was used for structure solution, refinement,
91
55 3 2 2
and molecular graphics. Compound 1b: (C33H N O Zr) , M )
6
17.02, colorless block, 0.40 × 0.30 × 0.10 mm, monoclinic, space
group P2 /c, ꢀ )115.4160(10)°, a ) 19.1703(2) Å, b ) 9.71680(10)
1
45
3
(
50-60%) could be improved by the use of very bulky groups
Å, c ) 39.0199(6) Å, V ) 6564.92(14)) Å , Z ) 4, Dcalc ) 1.249
-3
in place of tert-butyl at the salicyl unit since this will regulate
the approach of the olefin to the reactive imido in 6b. This
increased bulk may well also further increase the overall
catalytic rate.
g cm , T ) 100(2) K, with Mo KR (0.71073), 63 819 reflections
measured, 12 294 unique (Rint ) 0.0383), R1 [I > 2σ(I)] ) 0.0444,
wR2 (F, all data) ) 0.904, GoF ) 1.018.
2
Complex Synthesis. [Cp*ZrL (NMe
2
)
2
], 1b. A Schlenk tube
2
2 3
was charged with Cp*Zr(NMe ) (0.50 g, 1.4 mmol) and HL (0.42
Finally, we note that an imido mechanism like that mediated
by half-sandwich catalysts 1 has been excluded for the related
g, 1.4 mmol). Diethyl ether (30 mL) was added, and the reaction
was stirred at ambient temperature for 16 h. The solution was
filtered and concentrated to ca. 10 mL before the resultant precipitate
was collected by filtration and dried in vacuo. Yield: 0.40 g, 47%.
6
0
constrained geometry Zr catalysts XII. A simple explanation
for this difference in behavior would be that in XII the free
coordination site allows migratory insertion and the relatively
low steric profile does not tend to promote R-elimination to an
imido species. A more subtle picture may emerge from
computational studies.
1
H NMR (400 MHz, C D , 283 K): δ 0.85 (s, 3H, CH ), 1.11 (s,
7
8
3
3H, CH
Me ), 3.01 (s, 6H, Zr-NMe
H, OCH
3
), 1.36 (s, 9H, CMe
3
), 1.72 (s, 9H, CMe
3
), 1.81 (s, 15H,
C
5
5
2
), 3.40 (s, 6H, Zr-NMe
2
), 3.44 (d,
2
oxazoline,
2
1
2
oxazoline, JHH ) 8 Hz), 3.53 (d, 1H, OCH
2
4
J
HH ) 8 Hz), 7.68 (d, 1H, Ar C-H, JHH ) 3 Hz), 8.00 (d, 1H, Ar
4 13 1
Experimental Section
C-H, J ) 3 Hz) ppm. C{ H} NMR (100.6 MHz, C D , 283
HH
7
8
General Considerations. All manipulations were conducted
using standard inert-atmosphere techniques using a dual-manifold
argon/vacuum Schlenk line or an MBraun LabStar glovebox. All
glassware and cannulas were stored in an oven at >373 K. Solvents
were (where necessary) pre-dried over sodium wire and then
refluxed under nitrogen and distilled from an appropriate drying
agentstoluene from sodium; pentane and diethyl ether from NaK
(87) Martinez, P. H.; Hultzsch, K. C.; Hampel, F. Chem. Commun. 2006,
2221.
(
88) Kondo, T.; Okada, T.; Mitsudo, T.-A. J. Am. Chem. Soc. 2002, 124,
1
86.
(
(
89) Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467.
90) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008,
6
4, 112.
alloy; acetonitrile from CaH
2
sstored in glass ampules, and rigor-
(91) Sheldrick, G. M. SHELX97; Madison, WI, 1997.
J. AM. CHEM. SOC. 9 VOL. 132, NO. 43, 2010 15319

A R T I C L E S
Allan et al.
1
K): δ 11.4 (C
5
Me
5
), 24.2, 28.6 (NCMe
), 69.9 (NCMe
), 124.1, 129.5 (Ar C-H), 137.9, 139.7,
oxazoline). Anal. Calcd for C33 Zr:
2
), 30.9, 31.7 (CMe
3
), 34.3,
0.26 g, 87%. H NMR (400 MHz, C
7
D
5
8
): δ 1.13 (s, 9H, CMe
3
),
2
3
1
1
5.8 (CMe
3
), 45.5, 49.0 (Zr-NMe
), 119.7 (C Me
), 169.0 (C
2
2
), 78.1 (OCH
2
),
1.57 (s, 9H, CMe ), 1.85 (s, 15H, C Me ), 2.78 (s, 6H, Zr-NMe ),
3
5
2
3
13.5 (Ar C
65.8 (Ar C
q
5
5
3.89 (dd, 1H, OCH oxazoline, J ) 10 Hz, J ) 8 Hz), 4.40
2
HH
HH
3 3
q
q
55
H N
O
3 2
(dd, 1H, NCH oxazoline, J ) 10 Hz, J ) 8 Hz), 5.50 (t, 1H,
2 3
HH
HH
C, 64.24; H, 8.98; N, 6.81. Found: C, 64.03; H, 8.82; N, 6.32. Single
crystals of 1b suitable for X-ray diffraction analysis were obtained
from a saturated solution from diethyl ether at ambient temperature.
OCH oxazoline, J ) 10 Hz, J ) 10 Hz), 6.57 (d, 1H, Ar
2
HH
HH
3
3
3
C-H, JHH ) 7 Hz), 7.08 (dd, 1H, Ar C-H, JHH ) 7 Hz, JHH ) 7
3
3
Hz), 7.17 (t, 1H, Ar C-H, JHH ) 7 Hz), 7.38 (d, 1H, Ar C-H, JHH
1
n
(S
Zr,S
C
)-[Cp*ZrL (NH Bu)
2
], 1f. An NMR tube was charged
4
)
7 Hz), 7.68 (d, 1H, Ar C-H, JHH ) 3 Hz), 7.91 (d, 1H, Ar C-H,
13 1
n
with 1a (0.02 g, 0.03 mmol), BuNH
benzene-d (0.6 mL). The yellow solution was analyzed by NMR
spectroscopy. H NMR (400 MHz, C
BuNH ), 0.83 (t, 18H, CH
2
(0.02 g, 0.3 mmol), and
4
J
HH ) 3 Hz) ppm. C{ H} NMR (100.6 MHz, C
Me ), 30.9, 32.1 (NCMe ), 31.1, 31.9 (CMe ), 36.2, 39.3 (CMe
2.3 (Zr-NMe ), 74.1 (OCH ), 74.3 (NCH), 111.5 (Ar C ), 119.3
Me ), 121.7 (Ar C-H of metalated Ph), 123.9 (Ar C-H), 126.4,
26.9 (Ar C-H of metalated Ph), 130.5 (Ar C-H), 138.2, 140.7 (Ar
), 138.8 (Ar C-H of metalated Ph), 151.2, 166.1 (Ar C ), 169.2
oxazoline), 189.8 (Zr-CAr) ppm. Anal. Calcd for C35 Zr:
C, 67.80; H, 7.80; N, 4.52. Found: C, 67.41; H, 7.33; N, 3.60.
Cp*′Zr(NMe )(Me PhOx)], 4b. An NMR tube was charged
with 1b (0.02 g, 0.03 mmol) and benzene-d (0.6 mL). The yellow
solution was heated at 90 °C for 48 h and then analyzed by NMR
7
D
8
): δ 11.8
6
(C
5
5
2
3
3
),
1
6
D ): δ 0.47 (br s, 16H,
6
4
2
2
q
3
2
3
of excess amine, JHH ) 7 Hz), 0.86 (t,
(
C
5
5
3
3
3
4
CMe
1
H, CH
H, 2CH
), 1.45 (m, 2H, CH
.95 (s, 15H, C Me ), 2.05 (m, 1H, NHCH
CH of excess amine), 3.21 (m, 1H, NHCH
3
, JHH ) 7 Hz), 0.97 (t, 3H, CH
), 1.21 (m, 32H, 2CH of excess amine), 1.35 (s, 9H,
), 1.55 (m, 2H, CH ), 1.71 (s, 9H, CMe ),
), 2.47 (br m, 16H,
), 3.47 (dd, 1H, NH,
), 3.75 (dd, 1H,
3
, JHH ) 7 Hz), 1.10 (m,
1
2
2
C
q
q
3
2
2
3
(C
q
48 2 2
H N O
5
5
2
2
2
[
2
2
3
3
J
HH ) 9 Hz, JHH ) 9 Hz), 3.59 (m, 2H, NHCH
2
2
3
6
OCH
2
oxazoline, JHH ) 9 Hz, JHH ) 3 Hz), 4.04 (t, 1H, OCH
2
2
3
3
oxazoline, JHH ) 9 Hz, JHH ) 9 Hz), 4.71 (t, 1H, NH, JHH ) 8
1
3
spectroscopy. H NMR (400 MHz, C
.20 (s, 3H, CH ), 1.47 (s, 9H, CMe ), 1.61 (s, 9H, CMe
1.90, 2.04, 2.09 (all s, 3H, 4 × CH of Cp*′), 2.19 (d, 6H, HNMe
2.82 (s, 6H, Zr-NMe ), 3.22 (d, 1H, Zr-CH
d, 1H, OCH oxazoline, JHH ) 7 Hz), 3.55 (d, 1H, Zr-CH
13 Hz), 3.62 (d, 1H, OCH oxazoline, JHH ) 7 Hz), 7.48 (d,
4
6
D
6
): δ 0.99 (s, 3H, CH
), 1.83,
),
, JHH ) 13 Hz), 3.54
3
),
Hz), 4.94 (dd, 1H, NCHPh oxazoline, JHH ) 9 Hz, VHH ) 3 Hz),
1
3
3
3
6
1
.83 (m, 2H, Ar C-H of Ph), 6.91 (m, 3H, Ar C-H of Ph), 7.75 (d,
H, Ar C-H, JHH ) 3 Hz), 8.09 (d, 1H, Ar C-H, JHH ) 3 Hz)
4
4
3
2
2
13
1
2
2
ppm. C{ H} NMR (100.6 MHz, C
and excess amine CH ), 14.2 (CH
CH ), 20.8 (CH ), 30.5, 31.7 (CMe
excess amine CH ), 38.9 (HNMe ), 39.0, 39.2 (CH
amine CH ), 50.3, 50.6 (CH ), 70.4 (NCHPh oxazoline), 74.9
OCH oxazoline), 111.1 (Ar C
6
D
6
): δ 11.4 (C
), 20.3 (CH and excess amine
), 34.4, 35.8 (CMe ), 36.5
), 42.3 (excess
5 5 3
Me ), 14.1 (CH
2
2
(
2
2
, JHH
3
3
2
2
)
1
2
2
2
3
3
4
H, Ar C-H, JHH ) 3 Hz), 8.19 (d, 1H, Ar C-H, JHH ) 3 Hz)
13 1
(
2
2
2
ppm. C{ H} NMR (100.6 MHz, C
(C Me ), 30.3, 31.7 (NCMe ), 30.5, 32.2 (CMe
39.1 (HNMe ), 41.8 (Zr-NMe ), 40.6 (Zr-CH ), 65.8 (NCMe
(OCH ), 104.6 (Ar C ), 115.9, 116.4, 117.3, 119.1, 119.8 (C
6
D
6
): δ 10.1, 10.8, 11.0, 11.4
), 35.7, 35.8 (CMe ),
), 77.8
Me ),
), 169.3 (C
2
2
(
2
q
), 117.9 (C
5
Me
5
), 123.6, 126.0,
),
5
4
2
3
3
1
1
28.3, 129.2, 130.4 (Ar C-H), 137.6, 140.1, 142.8, 166.0 (Ar C
q
2
2
2
2
70.9 (C
q
oxazoline) ppm.
)-[Cp*ZrL (NHCH
2
q
5
4
2
(
S
Zr,S
C
2
CMe
2
CH
2
CHdCH
2
)(NMe
2
)-
121.7, 123.0 (Ar C-H), 124.9, 136.5, 140.6 (Ar C
q
q
(
0
PhPhOx)], 1g. An NMR tube was charged with 1a (0.02 g,
.03 mmol), 2a (0.003 g, 0.03 mmol), and benzene-d (0.6 mL).
The yellow solution was analyzed by NMR spectroscopy. H NMR
400 MHz, C ): δ 0.09 (br s, 1H, HNMe ), 1.01 (s, 3H, CH ),
), 1.38 (s, 9H, CMe ), 1.73 (s, 9H, CMe ), 1.97 (s,
, JHH ) 13 Hz, JHH ) 7 Hz),
oxazoline).
Hydroamination Procedure. The precatalyst (10 mg, 15-16
µmol), substrate (18-38 mg, 150-160 µmol), and internal standard,
ferrocene (4 mg, 22 µmol), were weighed into vials in a glovebox.
6
1
(
6
D
6
2
3
1
1
2
.03 (s, 3H, CH
5H, C Me ), 2.05 (dd, 1H, CH
.20 (s, 6H, HNMe
3
3
2
3
8 8
Toluene-d (600 mg, 0.64 mL) or THF-d (634 mg, 0.64 mL) was
3
5
5
2
used to mix the contents of the vials and transfer the solution to a
J. Young NMR tube, which was sealed and shaken vigorously.
NMR spectra at calibrated temperatures were recorded at appropri-
ate intervals (typically 5-15 min), and the data processing and
calculation of N
and co-workers.
2
3
2
), 2.31 (dd, 1H, CH , JHH ) 13 Hz, JHH ) 7
3
2
Hz), 2.37 (s, 6H, Zr-NMe ), 2.84 (t, 1H, NH, JHH ) 13 Hz), 3.29
2
3
3
(
3
1
d, 1H, CH
2
, JHH ) 12 Hz), 3.36 (d, 1H, CH
2
, JHH ) 12 Hz),
2
3
.72 (dd, 1H, OCH
H, OCH oxazoline, JHH ) 9 Hz, JHH ) 9 Hz), 4.71 (dd, 1H,
2
oxazoline, JHH ) 9 Hz, JHH ) 3 Hz), 4.02 (t,
t
2w3,e7r8e performed according to the method of Marks
2
3
2
3
3
NCHPh oxazoline, JHH ) 9 Hz, JHH ) 3 Hz), 5.10 (m, 2H,
CHdCH ), 6.01 (m, 1H, CHdCH ), 6.75 (m, 2H, Ar C-H of Ph),
.91 (m, 3H, Ar C-H of Ph), 7.76 (d, 1H, Ar C-H, JHH ) 3 Hz),
Acknowledgment. We thank the EPSRC for financial support
including an Advanced Research Fellowship for D.J.F. The Oxford
Diffraction Gemini XRD system was obtained through the Science
City Advanced Materials project: Creating and Characterising Next
Generation Advanced Materials project, with support from Advan-
tage West Midlands (AWM) and part funded by the European
Regional Development Fund (ERDF).
2
2
4
6
8
4
13
1
.16 (d, 1H, Ar C-H, JHH ) 3 Hz) ppm. C{ H} NMR (100.6
MHz, C
6
D
6
): δ 11.4 (C
5.9, 36.1 (CMe ), 38.9 (HNMe
1.0 (CH ), 70.5 (NCHPh oxazoline), 75.2 (OCH
), 116.3 (dCH ), 118.4 (C Me ), 123.7, 126.6, 128.9, 129.3,
30.4 (Ar C-H), 137.0 (dCH), 137.5, 140.1, 142.8, 143.0, 165.7
), 171.0 (C oxazoline) ppm.
)-[Cp*Zr(NMe )(Ph′PhOx)], 4a. A J. Young ampule was
5
Me
5
), 25.0, 26.0 (CH
3
), 30.4, 31.7 (CMe
3
),
3
6
3
2
), 45.3 (CH
2
), 45.4 (Zr-NMe
2
oxazoline), 111.1
2
),
2
(Ar C
q
2
5
5
1
(
Ar C
q
q
Supporting Information Available: Kinetic, Eyring, and
Arrhenius plots for hydroamination reactions; crystallographic
data for 1b in CIF format; NMR spectra of complexes. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(SZr,S
C
2
charged with 1a (0.32 g, 0.5 mmol). Toluene (10 mL) was added,
and the resulting yellow solution was heated at 90 °C for 4 d. The
reaction vessel was allowed to cool to ambient temperature and
the volatiles were removed in vacuo. The yellow oily residue was
dissolved in pentane and dried in vacuo to remove residual toluene,
yielding the title compound as a pale orange microcrystalline solid:
JA106588M
1
5320 J. AM. CHEM. SOC. 9 VOL. 132, NO. 43, 2010