Amidate Complexes of Tantalum and Niobium for the Hydroaminoalkylation of Unactivated Alkenes

Article abstract of DOI:10.1021/acscatal.7b01293

A series of mono(amidate) Ta and Nb complexes with varying steric and electronic properties were synthesized. These complexes were screened as precatalysts for the hydroaminoalkylation of alkenes with secondary amines. Sterically demanding mono(amidate) T

Full text of DOI:10.1021/acscatal.7b01293

Research Article
pubs.acs.org/acscatalysis
Amidate Complexes of Tantalum and Niobium for the
Hydroaminoalkylation of Unactivated Alkenes
Jean Michel Lauzon, Patrick Eisenberger, Sorin-Claudiu Rosç a, and Laurel L. Schafer*
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, Canada V6T 1Z1
S
* Supporting Information
ABSTRACT: A series of mono(amidate) Ta and Nb
complexes with varying steric and electronic properties were
synthesized. These complexes were screened as precatalysts for
the hydroaminoalkylation of alkenes with secondary amines.
Sterically demanding mono(amidate) Ta complexes were
determined to be the most effective precatalysts. Isotopic
labeling and kinetic studies were undertaken in an effort to
elucidate the mechanism. The reaction was shown to be
dependent upon catalyst and alkene concentration while being
zero order in amine concentration. Mechanistic probes for
radical species support a two-electron mechanism. Bis-
(amidate) species of Ta and Nb were also synthesized, with metallaaziridine formation observed for both metals. Insertion of
acetonitrile into the reactive M−C bond yielded a representative five-membered metallacycle. Off-cycle equilibria and catalyst
dormant states have been identified as areas for future catalyst development efforts.
KEYWORDS: hydroaminoalkylation, tantalum, niobium, metallaaziridine, amidates, amine synthesis, kinetics
hydroaminoalkylation. Specifically, Sc(III) is useful for hydro-
aminoalkylation with 3° amines.4 Ti (IV) and Zr(IV)
complexes have demonstrated potential for intramolecular α-
alkylation of 1° amines5,6 and intra- and intermolecular α-
alkylation of 2° amines with alkenes.5b,c,7−9 Furthermore,
inspired by the pioneering studies of Clerici and Maspero10 and
later Nugent and co-workers,11 Herzon and Hartwig conducted
a detailed study using Ta(V) amido complexes as catalysts to
promote hydroaminoalkylation, resulting in a broadened
substrate scope and a more efficient catalytic system.12,13
Using deuterium labeling experiments,12 a mechanism (Scheme
2) has been proposed for such group 5 catalysts.
INTRODUCTION
■
Selective catalytic processes for the rapid synthesis of N-
containing small molecules are the subject of intense current
academic and industrial research.1 Specifically, the catalytic α-
alkylation of amines, or hydroaminoalkylation, via C(sp3)−H
bond activation α to N and subsequent C−C bond formation
has recently emerged as a promising tool for the synthesis of
selectively substituted amines (Scheme 1).2,3 This process is
Scheme 1. α-Alkylation of Amines: Formal Addition of an
C(sp3)−H Bond α to N across a CC Double Bond
During the course of previous investigations, an extensive
screen of commonly used ancillary ligand motifs combined with
Ta(NMe2)5 did not provide an efficient catalyst formulation.14
Notably, trends in auxiliary ligand design to promote desirable
reactivity have not yet been established and features required to
promote effective catalysis remain ill-understood for this
transformation. To address these limitations, a number of Ta
a m i d a t e c o m p l e x e s w i t h t h e c o m p o s i t i o n
TaV(amidate)n(amido)5−n (n = 1, 2) have been identified as
promising precatalysts, including enantioselective reactions.15,16
Hultzsch reported the use of axially chiral, silylated
binaphtholate group 5 complexes as precatalysts for hydro-
aminoalkylation with ee values as high as 98%.17 Amidates as
ancillary ligands have proved promising in supporting a number
comprised of the formal addition of an C(sp3)−H bond α to an
amine across a CC bond, resulting in the α-alkylation of
amines. This process offers access to N-containing molecules
with 100% atom economy and the use of common olefinic feed
stock chemicals and unprotected amines. Notably this method
avoids the use of stoichiometric coreagents (bases, oxidants) or
additive cocatalysts or photocatalysts. However, this reaction
demands a high degree of chemo-, regio-, and stereocontrol for
it to become a valuable and reliable tool for synthesis. Thus, we
have identified this little explored transformation as a desirable
target for effort in catalyst development.2
Received: April 21, 2017
Revised: June 28, 2017
To this end, several early-transition-metal complexes based
on group 3−5 elements have been identified to catalyze
© XXXX American Chemical Society
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Scheme 2. Proposed Mechanism for Hydroaminoalkylation
Using a Group 5 Metal Catalyst
Scheme 3. Synthesis of Nb- and
Ta(amidate)(tetrakisdimethylamido) Complexes 1−6 via
Protonolysis
hexanes at −30 °C. In the absence of air and moisture these
materials are stable at ambient temperature, and after several
months, no change in appearance and spectroscopic behavior is
observed.
The synthetic accessibility of a large variety of group 5
mono(amidate) complexes allows for the systematic explora-
tion of reactivity. For group 5, the steric congestion about the
metal center with four amido ligands, in addition to the amidate
ligand, rationalizes the ease of formation and isolation of group
5 mono(amidate) systems.
The reaction of N-(2,6-diisopropylphenyl)pivalamide with
Ta- or Nb(NMe2)5 results in the clean formation of
isostructural mono(amidate) complexes 115 and 2 (Figure 1).
of mono- and dinuclear complexes of catalytically competent
high-oxidation-state early-transition-metal centers.18 Specifi-
cally, bis(amidate) complexes of Ti(IV) and Zr(IV) have
been shown to efficiently catalyze the intermolecular hydro-
amination19,20 of alkynes and allenes and more recently the
corresponding intramolecular hydroaminoalkylation reaction.5
In the coordination sphere of such transition metals, amidate
ligands can adopt a number of bonding motifs ranging from
chelating to bidentate (κ2-N,O), monodentate (κ1-O or -N),
and bridging (μ-amidate).17,21,22 More recently, related Ta
complexes have been prepared that exhibit increased
enantioselectivity for select substrates.15,16,23 Notably, piper-
idine and protected alcohols have only been reported as
substrates for our Ta amidate catalytic systems,14 demonstrat-
ing the ability of group 5 mono(amidate) precatalysts to
perform challenging transformations.
Here we report mechanistic insights to guide efforts in
catalyst development. A series of group 5 amidate amido
complexes have been prepared and characterized, and their
activity as catalysts for hydroaminoalkylation and their behavior
in stoichiometric reactions has been explored. Favorable ligand
steric properties that exhibit enhanced reactivity have been
identified. The solution-phase behavior of select complexes
offers the opportunity to probe the hemilability of amidate
ligands. Preliminary reaction kinetics, including labeling studies,
are presented.
Figure 1. ORTEP representation of 2 drawn with 50% probability
thermal ellipsoids. Hydrogen atoms are omitted for clarity. Metrical
data for 1 and 2 are presented for comparison.15 Select bond lengths
(Å) and angles (deg): 1, Ta−O1 2.099(3), Ta−N1 2.447(3), O1−
Ta−N1 56.90(10), ∑∠(N3) 360; 2, Nb−O1 2.1133(8), Nb−N1
2.4651(9), O1−Nb−N1 56.59(3), N3−Nb−N5 101.06(4), ∑∠(N5)
360.
RESULTS AND DISCUSSION
■
Synthesis and Characterization of Group 5 Mono-
amidate Complexes. Early-transition-metal amidate com-
plexes are synthesized efficiently using a protonolysis approach,
in which a metal amido moiety is converted to a metal amidate
species with concomitant neutral amine elimination.17 The
reaction of equimolar amounts of M(NMe2)5 (M = Nb,24 Ta)
and a corresponding organic amide at ambient temperature
under an inert atmosphere in hexanes results in the high-
yielding synthesis of mono(amidate) tetrakis(dimethylamido)
complexes 1−6 (Scheme 3) These materials are highly
crystalline and are easily purified by recrystallization from
The metrical parallels between 1 and 2 can be explained by the
ionic radii of the Nb and Ta centers (Nb(V), 0.78 Å; Ta(V),
0.78 Å).25 Bond distances and angles for the amidate ligand
motif are found to lie in the range typical for early-transition-
metal amidates.26,27 Both complexes exhibit short M−Oamidate
and long M−Namidate bonds. The amido ligands exhibit planar
nitrogen, with sums of bond angles close to 360°. The axial M−
N
amido bonds are longer (2.047(4) Å average) than those in the
equatorial plane of the chelating atoms, with the amido pseudo-
trans to Oamidate (1.974(3) Å average) having a shorter M−N
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distance than that pseudo-trans to Namidate (1.995(4) Å
average).
little effect on the Ta−Namido contacts in the plane of the
amidate chelate but does cause a change of the axial amido
bonds. The complexes also show a propensity to adopt an
idealized trigonal geometry, on the basis of the increasing Neq−
Ta−Neq bond angle, as the steric demand of the amidate ligand
decreases (Table 1).
In the extreme case of the N-supermesityl benzamidate 5, a
κ1-O coordination mode with a very short Ta−Oamidate bond
distance of 2.0586(15) Å is observed. This is accompanied by a
decreased Camidate−Namidate distance and an obtuse O−C−N
bond angle (127.34(18)°) in comparison to the chelating
amidates (113.5(2)° average). The large C−O−Ta bond angle
of 152.33(12)° and the data presented above suggest that the
amidate in 5 is best described as an κ1-O-coordinated
iminoalkoxide ligand occupying an axial position. Furthermore,
the 13C{1H} NMR data for the amidate carbonyl carbon in 5
(δC 160.3) support κ1-O coordination in solution (δC 167.3−
180.4 for κ2-N,O species).
In solution, complexes 1 and 2 show characteristic signals for
κ2-N,O amidate binding with carbonyl group signals at δC 177.7
and 177.3 ppm, respectively.28 These mono(amidate) com-
plexes adopt a pseudo-trigonal-bipyramidal geometry where the
amidate ligand is considered to be occupying one coordination
site and the Ta−Camidate vector is used for determining bond
angles. On average, the bond angles in the plane of the amidate
are closer to 120° than to 90°, with a small O−Ta−N bite
angle. The binding mode of the amidate chelate to the metal
center depends upon the steric bulk of the N substituent
(Figure 2 and Table 1). In contrast, the ligand steric bulk has
In contrast to altering the Namidate substituent, varying the
moiety bound to the Camidate has little effect on the metrical
parameters of these mono(amidate) complexes. Of particular
note is the Camidate−Namidate−Cipso bond angle, which is within
experimental error for complexes 1 and 6 (125.1(3) and
124.7(2)°, respectively).
Catalytic Reactivity and Selectivity of Group 5
Amidate Amido Complexes in Hydroaminoalkylation.
The homoleptic group 5 amido complexes used for early α-
alkylation studies were found to catalyze the reaction between
terminal olefins and short-chain dialkyl amines, in modest
yields (<40%) and at elevated temperatures (≥160 °C).10,11
The first report of high-yielding hydroaminoalkylation using
Ta(NMe2)5 as the precatalyst was restricted to reactions
between arylamines and terminal olefins at temperatures of 160
°C.12 These temperatures were reduced to 90 °C when the
more electrophilic dimer [TaCl3(NEt2)2]2 was employed as the
catalyst.13 However, elevated temperatures (150 °C) were
required to expand the substrate scope to dialkylamines. Group
4 systems are also known to be competent catalysts for
hydroaminoalkylation with regioselectivity complementary to
that of Ta systems.5b,8a
In order to probe the ligand substituent effects in group 5
mono(amidate) catalyzed hydroaminoalkylation, complexes 1−
6 have been screened in the reaction of N-methylaniline and 1-
octene to afford product 7 (Table 2). This model reaction has
been chosen due to the diagnostic spectroscopic signal for the
ortho protons of N-methylaniline (δH 6.40) and product 7 (δH
6.48) in the 1H NMR spectrum. Only the branched
hydroaminoalkylation product is observed for all of the
precatalysts screened, consistent with the proposed mechanism
Figure 2. ORTEP representation of the solid-state molecular
structures 5 and 6 drawn with 50% probability thermal ellipsoids.
Hydrogen atoms are omitted for clarity.
Table 1. Bond Lengths (Å) and Angles (deg) for 3−6
a
b
c
d
e
Trans to Namidate. Trans to Oamidate. Ta−N2. Ta−N5. Ta−N3.
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Having identified complex 1 as the most promising catalyst
for hydroaminoalkylation, we undertook a substrate scope
investigation (Table 3).15,30,31 In all cases the branched isomer
Table 2. Screening of Nb and Ta Mono(amidates) 1−6 as
Precatalysts for the Hydroaminoalkylation of N-
Methylaniline with 1-Octene
Table 3. Selected Hydroaminoalkylation Substrate Scope of
1
c
a
entry
catalyst
TOF (h−1
)
conversn (%)
1
2
3
4
5
6
7
1
2
3
4
5
6
0.30
0.25
0.28
0.28
0.05
0.22
0
96
83
89
93
16
85
0
[Ta(NMe)2)5]12
b
13
8
[TaCl3(NMePh)2]2
0.75
72
a
1
Conversion to product determined by H NMR spectroscopy using
b
internal standard (1,3,5-trimethoxybenzene). Conditions: 1.25 equiv
of 1-octene, 4 mol % of catalyst, 90 °C in toluene. Averaged TOF for
c
the maximum consumption of aniline substrate, average of a minimum
of three runs.
(Scheme 2) and previously reported examples for group 5
complexes.10−13,15,16,23,29,30
At 110 °C in [D6]benzene, 1 was found to be the most
reactive precatalyst, with 96% conversion to form 7 in 63 h
(Table 2, entry 1). As previously reported, the homoleptic
complex Ta(NMe2)5 catalyzes hydroaminoalkylation at temper-
atures above 130 °C12 but cannot perform the transformation
at 110 °C (Table 2, entry 7). To investigate the thermal
stability of 1 at these increased temperatures, a sample was
heated to 130 °C and monitored using 1H NMR spectroscopy.
Over a 36 h period, only signals assignable to 1 (∼80%),
liberated dimethylamine (HN(CH3)2, δH 2.21), and the
corresponding tantalaaziridine (Scheme 2A; Ta−CH2, δH 2.27
and 2.32) are present.
a
b
[N-methylaniline] = 1 M. N-methylaniline/alkene 1/3, 10 mol % of
c
1. A greater than 20:1 dr as estimated by NMR spectroscopy.
d
Isolated after derivatization as the N-tosylamide.
Though it has been reported that Nb amidate complexes are
not able to catalyze intermolecular hydroaminoalkylation,16,29
the Nb congener 2 proved to be a competent, yet less reactive,
precatalyst for the transformation (Table 2, entry 2). This result
compares with a recent report from the Hultzsch group that
shows that enantiopure 3,3′-silylated binaphtholate complexes
of Ta and Nb are both competent precatalysts for
intermolecular hydroaminoalkylation.23 Interestingly, in con-
trast to our results, in the binaphtholate chemistry the Nb
species are found to be more reactive, completing the reaction
in half the time of the Ta congeners.
The catalysis comparisons show that the relative reactivity of
the amidate precatalysts is related to the steric bulk at the 2,6-
positions of the aryl-Namidate moiety. However, when the bulk is
increased to tBu (5; Table 2, entry 5), a stark decrease in
reactivity is observed (16% conversion), accompanied by metal
complex decomposition. This observation suggests that the κ2-
N,O bonding of mono(amidates) results in more robust
complexes in comparison to the related κ1-O systems.
Interestingly, when the electronic nature of the substituent on
the Camidate is altered (6; Table 2, entry 6), a drop in relative
reactivity is observed. Even with extended reaction times,
comparable conversions could not be obtained for complexes 1
and 6. In contrast to the aforementioned thermal stability
studies of 1, significant decomposition of 6 is observed to occur
at 90 °C.
is the only regioisomer observed regardless of the nature of the
alkene or amine. This contrasts with group 4 metal catalyzed
hydroaminoalkylation, where a mixture of both regioisomers is
frequently observed.5c,8a Interestingly, when N-methylbenzyl-
amine is used as a substrate for hydroaminoalkylation catalyzed
by 1, C−C bond formation occurs exclusively at the benzylic
position rather than the N-methyl position, consistent with
comparative C−H bond dissociation energies.14 This is in
contrast to [TaCl3(NEt2)2]2 and group 5 binaphtholate
precatalysts, where the kinetically favored N-methyl position
is preferred.13,23 In addition to exclusive regioselectivity,
diastereomeric ratios of >20:1 are observed by 1H NMR
spectroscopy. For example, the hydroaminoalkylation product
of N-methylbenzylamine and allylbenzene is observed as a
single diastereomer in the solution phase (δH 4.88, doublet)
and can be isolated after N-tosylation (product 8, Scheme 4).32
The exclusive diastereoselectivity arises from the insertion of
allylbenzene into the tantalaaziridine Ta−C bond (Scheme 4, I)
with the phenyl group on the opposite face of the intermediate
metallacyclic product (Scheme 4, II), thereby minimizing steric
interactions. Once the five-membered metallacycle intermediate
is formed, the relative stereochemistry of the product is defined.
By varying reaction conditions (including catalyst loading,
temperature, and reaction time), some known challenging
substrates, such as unactivated 1,2-disubstituted alkenes (Table
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Scheme 4. Synthesis of syn-N,4-Dimethyl-N-(2-methyl-1,3-diphenylpropyl)benzenesulfonamide (8) and Catalytic Intermediate
II That Gives Rise to the Observed Diastereoselectivity
3, entries 1 and 2) and heterocycles (entries 3 and 4), can
undergo this reaction.33 To date, no other catalyst system has
been reported that uses fully saturated heterocycles, such as
piperidine, as substrates for hydroaminoalkylation (product
12). Importantly, amines bearing an N-(p-methoxyphenyl)
moiety can be used as substrates (entries 5 and 6), giving access
to 1° amines after oxidative deprotection. Similarly, alkenes that
bear a terminal protected alcohol are also efficient substrates
(product 14).
Scheme 6. Proposed Mechanism for Tantalum Catalyzed
Hydroaminoalkylation Including Reactions off the Catalytic
Pathway
Probing Mechanism in Ta Amidate Catalyzed Hydro-
aminoalkylation. In order to further expand the substrate
scope and improve catalyst TOF and TONs, a deeper
understanding of the reaction mechanism is required. To this
end, both stoichiometric and kinetic investigations, including
deuterium labeling studies, using precatalyst 1 have been
carried out.
During the course of these investigations, byproducts 15 and
16 were identified (Scheme 5). These byproducts arise from
Scheme 5. Byproducts 15 and 16 Formed from the
Hydroaminoalkylation of 1-Octene and Dimethylamine
Liberated from the Precatalyst
substantial H incorporation into the methyl group of the
labeled amine, indicating reversible tantalaaziridine formation at
subcatalytic temperatures. In addition to the scrambling of
isotopes at the methyl position, the integration of the signal
corresponding to the ortho protons of the phenyl ring of aniline
decreases slightly, showing that ortho metalation is a competing
side reaction that also occurs at mild temperatures. These
results are consistent with intermediate D undergoing
reversible ortho metalation. To date, 1 has not demonstrated
any catalytic reactivity at these lower temperatures. Despite the
observed deuterium-scrambling consistent with ortho metal-
ation, under the reaction conditions no productive hydro-
arylation of olefins has been observed.
To this end, [D3]-N-methylaniline can be reacted with 1-
octene in the presence of group 5 precatalysts to yield the
deuterated product 7-d (Scheme 7). When Ta(NMe2)5 is used
as the precatalyst, only 45% of the deuterium label is retained α
to N with 46% deuterium incorporation into the ortho
positions.11 In contrast, when [Cl3Ta(NMePh)2]2 or silylated
binaphtholate niobium complexes are employed, >90% of the
methylene group remains labeled.13,17 These contrasting results
suggest that reversible tantalaaziridine formation and ortho
metalation are more facile in the homoleptic system, whereas
[Cl3Ta(NMePh)2]2 has a strong preference for alkene insertion
(pathway B) over reversible tantalaaziridine formation (path-
way D).
the hydroaminoalkylation of 1-octene with the dimethylamine
liberated from the precatalyst upon transamination with the N-
methylaniline substrate. However, diagnostic signals cannot be
distinguished by 1H NMR spectroscopy, due to overlap with 1-
octene and product 7. Over the course of catalytic hydro-
aminoalkylation with 1, byproduct 16 is produced in quantities
large enough to be tosylated and isolated by chromatography.34
This byproduct formation impedes quantitative monitoring
of alkene consumption as the reaction progresses, thereby
limiting the possibility of a complete kinetic analysis. However,
early research into transition-metal-catalyzed hydroaminoalky-
lation has used deuterium-labeled substrates to provide insight
into reaction kinetics via isotope effects and labeling studies.
These reports disclosed side reactions such as reversible
tantalaaziridine formation (Scheme 6, D) and ortho metalation
of an aryl substrate (E).11,12
To investigate amido ligand exchange in Ta amidate species
(Scheme 6), 1 was exposed to excess [D3]-N-methylaniline in a
Teflon-sealed NMR tube. Complex 1 eliminates dimethyl-
amine, detectable by 1H NMR (δH 2.21), at room temperature
over a 24 h period, suggesting that ligand exchange and/or
tantalaaziridine formation is facile for these systems, even at
room temperature. Gentle heating to 65 °C results in
When the Ta amidate 1 is subjected to these catalytic
reaction conditions, the deuterated product 7-d is isolated in
excellent yield (93%) with 60% of the deuterium label
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Scheme 7. Comparison of Deuterium Incorporation or
Retention in 7-d for Ta Catalysts
remaining in the methylene group α to N and 23% D
incorporation observed in the ortho positions. These results
confirm that tantalaaziridine formation is rapid and reversible
for precatalyst 1. Comparison of the relative initial rates (up to
20% consumption of amine) of the reaction of 1-octene with
[D3]- and [D4]-N-methylaniline and its unlabeled congener
using 10 mol % of 1 revealed a small kinetic isotope effect (kH/
kD = 1.4(1) and 1.5(1), respectively). These small effects may
arise from the extensive equilibria that we have shown to be
prevalent in this system and further corroborate a mechanism
where the tantalaaziridine formation is not involved in the
turnover-limiting step.17
Figure 3. Consumption of amine as a function of time for the
hydroaminoalkylation of N-methylaniline with 1-octene catalyzed by
varying concentrations of 1.
with the relative molar ratios of N-methylaniline, 1-octene, and
1 (1:1.5:0.05) held constant while the absolute concentration
of the reaction mixtures in 0.5 mL of [D8]-toluene was varied.
Interestingly, the initial rates (up to 30% amine consumption)
were found to be indistinguishable for all concentrations
measured (2, 1, 0.5, 0.25, and 0.125 M in amine) within 2
standard deviations. This suggests that increases in catalyst
concentration relative to the substrates, rather than the absolute
concentration of the catalytic species present in the reaction
mixture, are the determining factors for the formation of off-
cycle catalytic species.
Regrettably, pseudo-first-order conditions could not be
employed for elucidation of the alkene reaction order. The
large excess of N-methylaniline causes an overlap in substrate
and product signals (δH 6.40 and 6.48, respectively), making
quantitative analysis impossible. Alternatively, in attempts to
employ initial rate methods, monitoring of alkene consumption
is complicated by the formation of byproducts 15 and 16 and is
thus unreliable. Therefore, in order to probe reaction order in
alkene, a series of experiments was conducted in which the
initial concentration of alkene was varied while catalyst loading,
amine concentration, and reaction volume were held constant.
Under these conditions, a positive, linear relationship between
both the initial rate of consumption of N-methylaniline and the
initial rate of formation of 7 was observed. Though byproduct
formation continues to plague the quantitative analysis of this
data, as noted by the different rates of substrate consumption
and product formation (Table 4), it can be stated that the rate
of hydroaminoalkylation catalyzed by mono(amidate) 1 is
dependent on the initial concentration of alkene.
In addition to labeling experiments, a preliminary kinetic
study using precatalyst 1, N-methylaniline, and 1-octene in
[D8]toluene at 130 °C was performed in Teflon-cap-sealed
1
NMR tubes with monitoring by H NMR spectroscopy using
1,3,5-trimethoxybenzene as an internal standard. First, under
pseudo-first-order conditions (10-fold excess of 1-octene and
10 mol % of catalyst), a linear plot was observed for over 2 half-
lives (75% consumption) of N-methylaniline before a sharp
decrease in rate (Figure S5 in the Supporting Information).
This observation suggests a zero-order dependence on amine
concentration and contrasts with other catalysts that display a
first-order dependence in amine.17
Next, the reaction was carried out with various catalyst
loadings (1, 1.5, 2, 2.5, 3, 4, 5, and 7.5 mol %, 4.3−32.2 mM),
using a 1:1.5 ratio of N-methylaniline to 1-octene in a constant
volume of [D8]-toluene, while the consumption of N-
methylaniline was monitored. Figure 3 shows a linear behavior
vs reaction time, consistent with the reaction being zero order
in amine. However, when the observed initial rates derived
from the linear models are plotted as a function of catalyst
concentration, two different regimes are observed over the
concentration range (Figure S6b in the Supporting Informa-
tion).
Analysis of the data obtained with up to 5 mol % catalyst
loading revealed a linear correlation, suggesting first-order
behavior.17 However, increasing the loading above this
threshold, up to 20 mol % (85.9 mM), does not increase the
rate of reaction, indicative of the formation of dormant states
and/or unfavorable equilibria off the catalytic cycle. These
species are proposed to be inactive multimetallic species, as
recently proposed for the homoleptic titanium catalyst
Ti(NMe2)4.5d
These combined preliminary kinetic data suggest an
empirical rate law at low catalyst loadings that is zero order
in amine, is first order in catalyst, and has a nonzero
dependence on alkene concentration. Labeling experiments
have demonstrated that the turnover-limiting step does not
involve tantalaaziridine formation and that ortho metalation is a
competing nonproductive side reaction.
With 1, it is proposed that these catalytically inactive species
are formed at catalyst loadings above 5 mol %. To confirm this
hypothesis, a series of five catalytic reactions was performed
To date, the possibility of a mechanism for the hydro-
aminoalkylation with early transition metals involving one-
electron radical processes has not been explored in the
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(amidate) complexes were synthesized. Indeed, these com-
plexes were found to be catalytically competent (vide infra) but
significantly less reactive than their mono(amidate) counter-
parts. This decrease in catalytic efficiency suggests that
bis(amidate) complexes could be used as model systems to
characterize products relevant to catalytic intermediates.
To this end, the reaction of 2 equiv of N-phenylpivalamide
and Ta(NMe2)5 formed tantalum(V) bis(amidate)tris-
(dimethylamido) complex 18 (Scheme 9). This complex
Table 4. Initial Rate of Consumption of N-Methylaniline and
Initial Rate of Formation of 7 as a Function of Initial Alkene
Concentration
rate of N-methylaniline
rate of formation of 7
(M h−1
c(t0)alkene (M)
consumption (M h−1
)
)
0.25
0.50
0.75
1.00
0.045(5)
0.070(5)
0.090(3)
0.127(2)
0.043(2)
0.067(3)
0.090(6)
0.106(9)
Scheme 9. Synthesis of 18 and ORTEP Representation of
the Solid-State Molecular Structure Drawn with 50%
Probability Thermal Ellipsoids
literature. However, the redox couple is accessible between d0
Ta(V) and d1 Ta(IV) and has been reported to occur between
0.31 and 0.74 V in traditional organic solvents.35 Synthetically,
Ta(V) centers can be efficiently reduced to d1 species with
nucleophilic reagents such as n-butyllithium.36 On the basis of
this ease of reduction, the possibility of radical participation
from a Ta(IV) center during catalysis is plausible and should be
considered.
a
In our work, the absence of ambient light, which can initiate
radical processes, does not affect the rate of hydroaminoalky-
lation catalyzed by mono(amidate) tantalum complexes.
Furthermore, a cyclopropyl moiety was built into an alkene
substrate (17) in order to probe the possibility of one-electron
processes in hydroaminoalkylation. The radically induced ring
opening of cyclopropyl rings has been used extensively to study
radical mechanisms in a variety of systems.37 Assuming a radical
process for the insertion of the alkene into the Ta−C bond of
the tantalaaziridine, instead of the expected hydroaminoalkyla-
tion product, a ring-opened alkene containing linear α-
alkylation product could be formed.
When the hydroaminoalkylation of N-methylaniline with
substrate 17 was performed under catalytic conditions (Scheme
8), complete consumption of the cyclopropyl-containing alkene
Scheme 8. Hydroaminoalkylation of N-Methylaniline with
Substrate 17
a
Hydrogen atoms are omitted for clarity. Select bond lengths (Å) and
angles (deg): Ta1−N1 2.2746(15), Ta1−O1 2.1510(12), Ta1−O2
2.0035(12), Ta1−N3 1.9602(16), Ta1−N4 1.9698(17), Ta1−N5
1.9872(16), N1−C1 1.300(2), C1−O1 1.289(2), O2−C12 1.317(2),
C12−N2 1.273(2); N1−Ta1−O1 58.27(5), N1−C1−O1 112.89(15),
O2−C12−N2 125.81(15).
was observed after 24 h. On the basis of the 1H NMR spectrum
the cyclopropyl ring remained intact even after the alkene
substrate was consumed. The four distinct signals were shifted
slightly upfield to δH 0.62, 0.72, 1.37, and 1.53, respectively, and
retained the diagnostic coupling patterns associated with
cyclopropyl moieties. Additionally, whereas 17 has three
distinct multiplets (δH 4.88, 5.02, 5.35) assignable to alkene
protons, there were no signals in the region between 3.5 and
6.0 ppm, suggesting no alkene functionality in the product.
This result suggests that hydroaminoalkylation catalyzed by
tantalum amidate complexes proceeds via a two-electron
mechanism as previously postulated (Scheme 2).
Synthesis and Characterization of Model Systems for
Catalysis. In an effort to investigate the mechanistic proposal
in Scheme 2, attempts to isolate catalytic intermediates were
carried out using mono(amidate) complex 1. Unfortunately,
none of the target compounds (Scheme 2A−C) could be
identified while the catalytic reaction was monitored by NMR
spectroscopy. In an effort to isolate intermediates by using less
reactive complexes,15 more sterically bulky group 5 bis-
exhibits a pseudo-trigonal-bipyramidal coordination geometry
about Ta, with one amidate ligand coordinated in a κ1-O
fashion and the other κ2-N,O. Notably, the monodentate κ1-O-
bound amidate fragment shows considerable CN double-
bond character (C12−N2 1.273(2) Å) and an obtuse bond
angle (O2−C12−N2 125.81(15)°) in comparison to the
chelating amidate ligand (N1−C1 1.300(2) Å, N1−C1−O1
112.89(15)°).
In solution at ambient temperature, a species consistent with
the solid-state coordination mode is observed by NMR
spectroscopy. Two different amidate environments, mono-
dentate (κ1-O) and chelating, bidentate (κ2-N,O), are observed
with carbonyl resonances at δC 168.1 and 184.5, respectively.
Two broad, overlapping methyl amido resonances are observed
1
in both H and 13C{1H} NMR spectra (δH 3.42 and 2.84, δC
45.2 and 48.7), consistent with two equatorial and one axial
amido ligand slowly exchanging on the NMR time scale. At low
temperature (T = −81 °C) these broad resonances start to
sharpen and eventually six distinct (although broad) signals for
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each of the amido CH3 groups are observed. Figure 4 shows the
aliphatic region (0.0−4.0 ppm) of the temperature-dependent
with simultaneous release of dimethylamine. New signals at δH
1.03 and 1.11 accompany the dimethylamine signal, suggestive
of two additional tBu environments other than the broad signal
attributed to 18 (δH 1.27, T = 101 °C).
Additional signals at δH 2.16 an 2.26 and at δH 3.22, 3.35, and
3.38 can be assigned as the diastereotopic Ta−CH2 protons and
amido-N−CH3 environments generated during tantalaaziridine
formation, respectively.14 When a constant temperature of 101
°C is maintained, numerous amido and tBu CH3 signals emerge
that cannot be assigned to 18 or the corresponding
tantalaaziridine. These signals persist even after the sample
has been cooled to room temperature, suggesting that new
species are being formed that are not in equilibrium with
complex 18. Such undefined species may be dormant
multimetallic Ta complexes. In an effort to hinder these
dynamic processes, steric bulk could be added to the ortho
positions of the amidate N substituent. To this end, the
reaction of Ta(NMe2)5 and 2 equiv of N-(2,6-dimethylphenyl)-
pivalamide gave a product with magnetically inequivalent
amidate ligand resonances (Scheme 11). In this case, in
Scheme 11. Synthesis of Stable, Crystalline Nb and Ta
Aziridines Supported by Two Amidate Ligands
1
Figure 4. Variable temperature (−80.9 to +101.3 °C) 400 MHz H
NMR study of 18.
1H NMR spectra of 18 from −81 to 101 °C, which reveals
several dynamic processes occurring in the Ta coordination
sphere. The dynamic processes observed in the cold regime,
from −81 to −6 °C, are completely reversible and are
unaffected by repeated cooling and warming of the sample
within this range. At temperatures above 41 °C, the amido
methyl signals coalesce, suggesting fast exchange on the NMR
time scale. Further upfield, two distinct amidate ligand tBu
signals also coalesce at elevated temperatures (73.3 °C),
indicative of a dynamic exchange between the κ1-O and the κ2-
N,O binding modes (Scheme 10).
addition to the 2 equiv of HNMe2 stemming from the
protonolysis by the amide proligands, an extra 1 equiv of
HNMe2 was spontaneously eliminated, resulting in the
formation of the isolable tantalaaziridine 19. Presumably, the
increase in steric bulk at the ligand induces the spontaneous
room-temperature elimination of neutral amine from the metal
center. The spontaneous C−H bond activation α to N with
concomitant amine elimination to yield tantalaaziridine
complexes has rarely been documented for d0 systems.6,8f,38
More commonly, mixed alkyl amido systems form metal-
laaziridines by alkane elimination.39 The resulting complex 19
can be isolated in excellent yield (84%) with analytically pure
samples, suitable for single-crystal X-ray analysis.15 The solid-
state molecular structure of 19 has been previously reported. In
the solution phase the signals corresponding to the
diastereotopic protons of the metallaaziridine moieties resonate
at δH 2.34 and 2.49 (2JH,H = 3.5 Hz) and δC 59.1 for 19.
Interestingly, the amidate bite angles in the mono(amidate)
complexes (56.9−57.7°) tend to be slightly more acute in
comparison to the bis(amidate) 19 (59.3°). By replacement of
Ta(NMe2)5 with the lighter, homologous, homoleptic Nb-
(NMe2)524 complex the corresponding niobaaziridine 20 could
be prepared in quantitative yield.
At temperatures above 25 °C, a doublet corresponding to the
methyl substituents of neutral dimethylamine appears at δH
2.21, presumably originating from tantalaaziridine formation
Scheme 10. Proposed Equilibrium between Coordination
Modes of 18 Illustrating the Dynamic Exchange of Amidate
a
Binding Modes Observed on the NMR Time Scale
Complex 20 crystallizes in the P21/n space group and
exhibits a coordination geometry similar to that of its tantalum
analogue 19, as depicted in Figure 5. The two amidate ligands
are bound to the metal in a κ2-N,O fashion displaying identical
tight bite angles (59°), as found for 19.
a
Amidate N and O atoms are labeled for illustrative purposes.
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products. However, when complex 19 was reacted with
acetonitrile in benzene at room temperature, the CN bond
inserted into the Ta−C bond of the metallaaziridine creating a
five-membered metallacycle that was ultimately observed as the
isomerized product 21 (Scheme 12). Such isomerizations have
been previously observed for nitrile insertions into early-
transition-metal−carbon bonds.42 Complex 21 can be isolated
as a blood red powder that can be recrystallized from refluxing
hexanes to give single crystals suitable for X-ray diffraction. The
molecular structure of 21 is shown in Figure 6. The solitary
olefinic proton of the metallacycle 21 (δH 5.86 ppm) serves as
an informative, diagnostic spectroscopic handle.
Figure 5. ORTEP representation of the solid-state molecular structure
drawn with 50% probability thermal ellipsoids of 20. Hydrogen atoms
are omitted for clarity. Select bond lengths (Å) and angles (deg): Nb−
O1 2.146(4), Nb−N1 1.968(5), Nb−N2 1.926(5), Nb−C1 2.204(6);
O1−Nb−N4 59.05(15), C1−Nb−N2 39.5(2), ∑∠(N1) 360,
∑∠(N2) 360.
In the solution phase the formation of metallaaziridine is
confirmed by NMR spectroscopy with δH 2.42 and 2.50 (2JH,H
= 5.6 Hz) and δC 54.4 for 20 comparing favorably with the data
for 19 listed above. These values are in the typical range of
known pentavalent group 5 metallaaziridine complexes and are
notably different from those observed for the related η2-imine
complexes with typical values for δC being >200 ppm.40
While the less bulky complex 18 displays mono- and
bidentate binding modes at ambient temperature in both
solution and solid phases, at elevated temperatures metal-
laaziridine formation can be induced. We propose that the
hemilabile nature of the amidate ligand allows for coordination-
site variability about the metal center and with suitable steric
bulk, as in 19 and 20, can serve to stabilize the typically reactive
metallaaziridine moiety as an isolable material. Ligand
participation in the H-abstraction mechanism cannot be
excluded, considering that hemilabile ligands, such as
carboxylates, have been shown to actively participate in C−H
activation mechanisms via concerted metalation−deprotona-
tion.41
It has been well documented that tantalaaziridines react with
unsaturated fragments such as alkenes, carbonyls, nitriles, and
isocyanides in a stoichiometric fashion to give the correspond-
ing organic insertion products after workup.40 Surprisingly,
exposing 19 to various alkenes, internal alkynes, and conjugated
ketones results in no reaction, even at temperatures of 90 °C. In
comparison, reactions with terminal alkynes, acetophenone,
benzaldehyde, and phenyl isocyanate yield complex mixtures of
Figure 6. ORTEP representation of the single-crystal X-ray structure
of product 21 drawn with 50% probability thermal ellipsoids. Most
hydrogen atoms are omitted for clarity. Select bond lengths (Å) and
angles (deg): Ta−N1 2.2974(15), Ta−O1 2.1376(13), Ta−N2
2.2223(15), Ta−O2 2.2078(13), Ta−N3 1.9946(16), Ta−N4
2.0623(16), Ta−N5 2.0428(16); N1−Ta−O1 58.56(5), N1−C1−
O1 112.77(16), N2−Ta−O2 58.47(5), N2−C2−O2 112.40(16).
This complex can be viewed as a model of the five-membered
metallacycle proposed in the catalytic cycle. The difficulty
observed in inserting unsaturated molecules into the
tantalaaziridine Ta−C bond corroborates the dependence of
catalytic rate on alkene concentration. To investigate the
effectiveness of bis(amidate) complexes as precatalysts for
hydroaminoalkylation, complex 19 was screened in a manner
similar to that for the aforementioned mono(amidates) (Table
2). Despite the fact that the proposed catalytically relevant
metallaaziridine moiety was preinstalled, 19 displayed sluggish
reactivity in comparison to precatalysts 1−5, achieving just 71%
conversion even with increased temperatures (130 °C) and
Scheme 12. Insertion of Acetonitrile into Tantalaaziridine 19
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Notes
longer reaction times (168 h). Notably, no spectroscopic
signals consistent with loss of proteo ligand were observed.
Thus, if we presume a similar mechanistic profile to the
mono(amidate) precatalyst and consider the mechanistic data
observed to date, the reduced reactivity may be attributed to
sterically hindered alkene insertion.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge Boehringer Ingelheim
(Canada) Ltd and the NSERC (Strategic Grants Program) for
supporting this work. P.E. thanks the Swiss National Science
Foundation for a PDF. J.M.L. thanks the NSERC for a CGS-D
scholarship. This research was undertaken, in part, thanks to
funding from the Canada Research Chairs program. Dr. Neal
Yonson and Mr. Jacky Yim are also acknowledged for their
assistance with X-ray structure determination.
CONCLUSION
■
A series of amides, varying in both steric and electronic
properties, have been reacted with group 5 homoleptic
dimethylamido starting materials to yield mono- and bis-
(amidate) complexes. Steric bulk on the Namidate substituent
plays a determining role in how the amidate binds to the metal
center, while changes in electronic properties evoke minimal
variation. During the screening of mono(amidate) complexes
1−6 as precatalysts for hydroaminoalkylation, a positive
correlation between steric bulk and reactivity was observed.
The tantalum mono(amidate) 1, with isopropyl groups at the
2,6-aryl positions of the amidate, is a promising precatalyst for
this reaction and has a broad substrate scope with excellent
regio- and diastereoselectivity. The ability to use piperidine
(12) and protected alcohols (14) as substrates has yet to be
reported for any other system.
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DOI: 10.1021/acscatal.7b01293
ACS Catal. 2017, 7, 5921−5931