Easily assembled, modular N,O-chelating ligands for Ta(V) complexation: A comparative study of ligand effects in hydroaminoalkylation with N-methylaniline and 4-methoxy-N-methylaniline

Article abstract of DOI:10.1016/j.tet.2013.04.070

The influence of structurally related N,O-chelating ligands with additional heteroatoms (N, O, P, S) on the reactivity of in situ generated tantalum complexes for the hydroaminoalkylation of amines has been explored. Reactivity was probed by evaluating the catalytic ability of these N,O-chelating systems with N-methylaniline and 4-methoxy-N-methylaniline substrates. Enhanced reactivity is observed with amide proligands bearing an ortho-methoxyphenyl group on the nitrogen. 4-Methoxy-N-methylaniline is found to be more prone to undergo C-H functionalization via hydroaminoalkylation than N-methylaniline. The use of the related substrate 2-methoxy-N-methylaniline is not tolerated, and instead C(sp³)-O bond cleavage was observed.

Full text of DOI:10.1016/j.tet.2013.04.070

Tetrahedron 69 (2013) 5737e5743
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Easily assembled, modular N,O-chelating ligands for Ta(V)
complexation: a comparative study of ligand effects in
hydroaminoalkylation with N-methylaniline and
4-methoxy-N-methylaniline
Pierre Garcia a, Philippa R. Payne a, Eugene Chong a, Ruth L. Webster a,
,
Benedict J. Barron a, Andrew C. Behrle b, Joseph A.R. Schmidt b, Laurel L. Schafer a
*
a Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, Canada V6T 1Z1
b Department of Chemistry, School of Green Chemistry and Engineering, College of Natural Sciences and Mathematics, The University of Toledo, 2801 W.
Bancroft Street, MS 602, Toledo, OH 43606-3390, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The influence of structurally related N,O-chelating ligands with additional heteroatoms (N, O, P, S) on the
reactivity of in situ generated tantalum complexes for the hydroaminoalkylation of amines has been
explored. Reactivity was probed by evaluating the catalytic ability of these N,O-chelating systems with N-
methylaniline and 4-methoxy-N-methylaniline substrates. Enhanced reactivity is observed with amide
proligands bearing an ortho-methoxyphenyl group on the nitrogen. 4-Methoxy-N-methylaniline is found
to be more prone to undergo CeH functionalization via hydroaminoalkylation than N-methylaniline. The
use of the related substrate 2-methoxy-N-methylaniline is not tolerated, and instead C(sp3)eO bond
cleavage was observed.
Received 23 March 2013
Received in revised form 13 April 2013
Accepted 15 April 2013
Available online 18 April 2013
Keywords:
Hydroaminoalkylation
Tantalum
Ó 2013 Elsevier Ltd. All rights reserved.
Amidate-like ligands
Heteroatom
C(sp3)eO bond cleavage
1. Introduction
While initial investigations into this transformation were
reported in the early 1980s,5 further developments have only
Amine moieties are prevalent in biologically active compounds,1
and the development of efficient and selective methods to syn-
thesize substituted amines is an important area of research. Cata-
lytic preparative routes toward amine building blocks are
attractive, as byproducts are reduced by means of step and atom
economies.2,3 Methodologies that do not require the use of pro-
tecting groups are also desirable for the synthesis of reactive amine
intermediates that can be readily substituted. To this end, an at-
tractive approach is early transition metal catalyzed hydro-
aminoalkylation, a 100% atom economic CeH alkylation reaction
been reported recently.6,7 A series of Ta(V) systems have been
reported for intermolecular hydroaminoalkylation and collec-
tively this work has shown that slight modifications of the an-
cillary ligands dramatically impacts the reactivity of these
catalytic systems.7 These advances in ligand design have
resulted in improved reaction conditions, enhanced substrate
scope, and enantioselective variants of this transformation.6,7
However, detailed investigations into ligand features that pro-
mote enhanced catalyst activity have not been extensively
explored.
Previously, our group showed that N,O-chelating amidate li-
gands for tantalum hydroaminoalkylation catalysis results in the
preparation of complexes that show good reactivity with a broad
range of substrates.7c By using the electron-withdrawing properties
of these ligands to advantage, the electrophilicity of the metal
center can be enhanced to access improved reactivity profiles.8
Another advantage that may be critical to the improved reactivity
of these N,O-chelates with tight bite-angles is the availability of
different potential coordination modes (Scheme 2). Access to k1
binding modes could allow for release of steric crowding about the
occurring at the
a
-position of an unprotected amine (Scheme 1).4
H
H
N
[M]Ln
N
H
+
R''
R
R
R'
R''
R'
R'
R'
[M] = Ti, Zr, Nb, Ta
Scheme 1. Hydroaminoalkylation of alkenes with unprotected secondary amines.
* Corresponding author. Tel.: þ1 604 822 9264; fax: þ1 604 822 8296; e-mail
address: schafer@chem.ubc.ca (L.L. Schafer).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.070

5738
P. Garcia et al. / Tetrahedron 69 (2013) 5737e5743
metal center, while creating an open-coordination site for reagent
binding.
Scheme 3. Synthesis of HL-1.
Scheme 2. Different binding modes of N,O-chelating ligands.
In order to examine type B ligands we targeted phosphine-
carboxamide HL-2, which can be easily obtained in a one-step
procedure (Scheme 4).10 To isolate and compare the effect of this
heteroatom addition to the backbone to L-0 for hydro-
aminoalkylation, the aryl group on the nitrogen has been
maintained.
To further explore the ability of related N,O-chelating ligands to
support highly reactive hydroaminoalkylation catalyst systems we
decided to investigate the impact of modifications to the successful
ligand framework of previously reported L-0 (Fig. 1).7c These in-
vestigations included altering the ligand backbone with the in-
corporation of additional heteroatoms (N, O, P, S) as well as altering
the ligand substituent pattern (Fig. 1). The design, synthesis, and
influence of these proligands on Ta(V) catalyzed hydro-
aminoalkylation are reported through a comparative study of the
reaction of 1-octene with N-methylaniline and 4-methoxy-N-
methylaniline.
Scheme 4. Synthesis of HL-2.
Another related type B proligand that has been explored con-
tains a heteroaromatic structure (Scheme 5). The proligand HL-3
with a 4-hydroxy-1,3-thiazole backbone and a phenyl group adja-
cent to the carbonyl and the nitrogen has been synthesized in 52%
yield in
a
single step from commercially available starting
materials.11
Fig. 1. New N,O-heteroatom containing-chelating Ta(V) complexes.
2. Results and discussion
2.1. Ligand design and synthesis
Four classes of N,O-chelating proligands have been designed for
investigation (Fig. 2). We first envisioned modification of the
electronic properties of the reactive complex by incorporating an
electron-withdrawing group at the nitrogen (A) of the ligand
framework while keeping the tert-butyl moiety consistent to HL-0t-
Bu. Introduction of heteroatoms directly linked to the carbonyl
moiety (B) have also been examined to vary the electronic prop-
erties of the ligand. Finally, the addition of a pendent neutral donor
heteroatom has been incorporated into the ligand framework in an
effort to modify steric and electronic properties through the access
of alternative coordination geometries. For this purpose, two sys-
tems have been explored; one with an extra donor on the nitrogen
substituent (C) and another with the donor atom incorporated into
the carbonyl backbone (D).
Scheme 5. Synthesis of HL-3.
For proligands of type C, an ortho-methoxy group has been
chosen as a potential additional donor. The amide proligand HL-4
has been prepared in 52% recrystallized yield from a straightfor-
ward amidation reaction with 2-methoxyaniline and 2,4,6-
trimethylbenzoylchloride (Scheme 6).
Scheme 6. Synthesis of HL-4.
The synthesis of ligand D, with a donor on the carbonyl moiety
has been realized through a one-pot, two-step sequence: amidation
reaction of aniline with 3-chloropropanoyl chloride, followed by
nucleophilic displacement of Cl with a secondary amine (Scheme
7). Two ligands of varying steric bulk on the aryl ring have been
prepared by this method (HL-5 and HL-6). These ligands also have
varied steric bulk on the pendant amine moiety. Here, the two
carbon tether length provides flexibility to allow for coordination to
the metal center.
Fig. 2. Proligand motifs reported herein.
Our investigations began with the synthesis of a chiral linear
proligand of type A, by taking advantage of naturally occurring
amino acids. Proligand HL-1 is prepared from L-valine (Scheme 3)
via the known pivaloyl protected amino acid.9 The treatment of N-t-
Bu-Val-COOH with ethyl chloroformate and piperidine furnishes
HL-1 in 22% recrystallized yield.
In light of the recent work from both Doye6g and ourselves12
regarding the advantageous use of the
k
2-N,N-chelating amino-

P. Garcia et al. / Tetrahedron 69 (2013) 5737e5743
5739
Scheme 9. Synthesis of L-4-Ta(NMe2)4 and ORTEP representation of the molecular
structure (ellipsoids drawn at 50% probability, hydrogen atoms are omitted). Selected
ꢁ
ꢀ
bond lengths (A) and angles ( ):TaeO1 2.148(2), TaeN1 2.351(2), TaeN2 2.040(3),
TaeN3 1.981(3), TaeN4 2.037(3), TaeN5 1.998(3), N1-TaeO1 57.70(8).
Scheme 7. Synthesis of type D proligands: HL-5 and HL-6.
pyridinate ligands in group 4 metal catalyzed hydroaminoalky-
lation and hydroamination reactions, we present our evaluation of
a bulky aminopyridinate ligand. The proligand HL-7, is anticipated
to maintain a similar asymmetric coordination mode to HL-0 t-Bu,7c
although significantly enhanced steric bulk has been incorporated
into this proligand than is accessible with N,O-chelating ligands
(Fig. 3).13
Scheme 10. Synthesis of L-7-Ta(NMe2)4 and ORTEP representation of the molecular
structure (ellipsoids drawn at 50% probability, hydrogen atoms are omitted). Selected
ꢀ
bond lengths (A) : TaeN1 2.300(3), TaeN2 2.320(4), TaeN3 2.039(4), TaeN4 2.003(4),
TaeN5 1.975(4), TaeN6 2.082(4).
analysis by X-ray diffraction in 72% yield (Scheme 9).15 The solid-
state molecular structure of the complex is consistent with the
solution phase NMR data, indicating formation of a monomeric
Fig. 3. Design of HL-7.
species with the amidate ligand bound in a k
2 fashion to the metal
center. The ortho-methoxy group of the ligand is situated away
from the metal center and is not acting as a neutral donor in the
solid state.
2.2. Catalyst preparation and performance
The synthesis of the Ta(V) complexes has been achieved by the
protonolysis reaction of Ta(NMe2)5 with the proligand in a 1:1 ratio
at room temperature (Schemes 8e10). Using this route, crystalline
samples of complexes L-1-Ta(NMe2)4, L-4-Ta(NMe2)4, and L-7-
Ta(NMe2)4 have been isolated and fully characterized. Un-
fortunately, the combination of proligands HL-2, HL-3, HL-5 or HL-
6 did not afford comparable crystalline complexes and thus these
systems were not isolated before use in catalytic investigations
(vide infra). The complex L-1-Ta(NMe2)4 was obtained as yellow
crystals by recrystallization from hexanes in 56% yield, and its solid-
state molecular structure was obtained by X-ray diffraction
(Scheme 8).14 This complex exhibits a pseudo-octahedral geometry
with L-1 bound to the metal center through the two oxygen atoms
of the ligand, highlighting the oxophilicity of this early-transition
metal. The secondary amide component of the ligand shows an
imide alkoxide binding mode to the metal center [C5eO1
The analogous protonolysis route has been used to prepare the
aminopyridinate complex L-7-Ta(NMe2)4 (Scheme 10).16 After re-
crystallization from a toluene/hexanes solution at ꢀ35 ꢁC, the
complex is obtained as golden-brown crystals in 69% yield. In
contrast to other aminopyridinate supported tantalum com-
plexes,17 the solid-state molecular structure of the complex shows
a symmetric N,N-binding mode, evident by the near equidistant
ꢀ
ꢀ
TaeN bond lengths [TaeN1 2.300(3) A, TaeN2 2.320(4) A].
A comparison of the axial Taedimethylamido bond lengths in
these three solid-state molecular structures shows negligible dif-
ferences in TaeN bond lengths, indicating limited steric differences
between the N,O- or N,N-chelating ligands. However, for both N,O
L-1-Ta(NMe2)4 and L-4-Ta(NMe2)4 the equatorial dimethylamido
ꢀ
ligands show similar bond lengths (approximately 1.98e1.99 A),
while L-7-Ta(NMe2)4 shows two distinct equatorial dimethylamido
ꢀ
ꢀ
ꢀ
ꢀ
ligand bond lengths to tantalum [TaeN4 2.003(4) A, TaeN5
1.326(2) A, C5eN1 1.282(2) A, TaeO1 2.043(1) A], while the other
ꢀ
1.975(4) A].
oxygen atom of the tertiary amide component binds as a neutral
ꢀ
ꢀ
ꢀ
Most importantly, the influence of ligands L-1eL-7 has been
evaluated for Ta(V) catalyzed hydroaminoalkylation through
a comparative study of the reactivity of 1-octene with N-methyl-
aniline and 4-methoxy-N-methylaniline as amine substrates (Table
1). This study provides key information on the ligand parameters
that influence catalytic activity.18 As a point of reference, the
homoleptic Ta(NMe2)5 has been evaluated for both substrates and
poor reactivity is observed in 20 h at 130 ꢁC (entry 1). This is in
agreement with Hartwig’s earlier work, which required higher re-
action temperatures to achieve full conversion.7a For the homo-
leptic complex a slight increase in reactivity is observed when 4-
methoxy-N-methylaniline is used as the amine substrate. The in-
donor [C10eO2 1.262(2) A, C10eN2 1.335(2) A, TaeO2 2.283(1) A].
The synthesis of L-4-Ta(NMe2)4 proceeds to generate a yellow-
orange solid after removal of volatiles under reduced pressure.
Recrystallization from hexanes afforded yellow crystals suitable for
7c
troduction of parent amide proligand HL-0t-Bu resulted in a dra-
Scheme 8. Synthesis of L-1-Ta(NMe2)4 and ORTEP representation of the molecular
matic increase in the hydroaminoalkylation reactivity (entry 2),
structure (ellipsoids drawn at 50% probability, hydrogen atoms are omitted). Selected
with
a marked improvement on conversion again when 4-
ꢀ
bond lengths (A) : TaeO1 2.043(1), TaeO2 2.283(1), TaeN3 2.051(2), TaeN4 1.996(2),
methoxy-N-methylaniline is used (87%). The reaction has been
repeated at a lower temperature to see whether the reactivity could
TaeN5 1.996(2), TaeN6 2.047(2), C5eO1 1.326(2), C5eN1 1.282(2), C10eO2 1.262(2),
C10eN2 1.335(2).

5740
P. Garcia et al. / Tetrahedron 69 (2013) 5737e5743
Table 1
a system with negligible reactivity even with 10 mol % catalyst
loading (entry 5).
Screening of proligands and comparison of N-methylaniline versus 4-methoxy-N-
methylanilinea
The complex L-4-Ta(NMe2)4 with the type
C ligand in-
corporating a pendant donor on the N-substituent is shown to be
particularly promising as it results in full conversions in situ with
both of the substrates within 20 h (entry 7). Although the solid state
structure shows no interaction with the extra ortho-methoxy sub-
stituent in solid state (Scheme 9) it is possible that under the re-
action conditions (solution phase, high temperature) more
flexibility in coordination modes are realized, thereby enhancing
reactivity. Good reactivity can even be achieved at lower reaction
temperatures (110 ꢁC) and once more 4-methoxy-N-methylaniline
is the more reactive substrate with a conversion of 60% at this lower
temperature. The comparison of reactivity of the isolated complex
L-4-Ta(NMe2)4 and in situ reaction at 110 ꢁC shows, indeed, the
same reactivity and confirms that the presence of dimethylamine
generated upon ligand substitution does not significantly affect the
reaction (entry 7).
Type D proligands with an extra donor on the side arm of the
carbonyl moiety show similar reactivity that is not dramatically
impacted by the different steric bulk of the N-substituents (entries
8 and 9). However, unlike most other types of proligands in this
study, attempts to prepare discrete complexes utilizing these pro-
ligands have been unsuccessful, and the role of the extra donor in
terms of metal coordination remains unclear.
Entry
1b
Ligand
NMe2
R¼H
R¼OMe
7%
13%
2b
33%
87%
(19%)d
3b
4c
2%
5%
de
40%
(43%)f
5c
6c
4%f
5%f
29%
61%
Lastly, the use of L-7-Ta(NMe2)4 was completely unsuccessful,
with no reactivity observed for either of the amine substrates
(entry 10). This is in sharp contrast to the recently disclosed Ti(IV)
aminopyridinate-catalyzed hydroaminoalkylation report from
Doye.6g In Doye’s example, a less sterically demanding amino-
pyridinate was used at a higher catalyst loading, a higher reaction
temperature, and for longer reaction times to give a mixture of
linear and branched hydroaminoalkylation products.
7b
>98%c
>98%c
(51%)c,d
(50%)b,d
(60%)c,d
(55%)b,d
8c
42%
53%
40%
50%
In summary, the results in Table
1 show that hydro-
aminoalkylation with N,O-chelated Ta complexes is an efficient way
to construct branched secondary amines via hydroaminoalkylation.
Importantly, products bearing a 4-methoxyphenyl (PMP) protect-
ing group on nitrogen, can be deprotected to realize the preparation
of selectively substituted primary amines. However, due to the
quite harsh conditions required for the oxidative cleavage of the 4-
methoxyphenyl group,19 we wanted to consider 2-methoxy-N-
methylaniline as an alternative hydroaminoalkylation substrate.
Snapper and Hoveyda have shown that milder deprotection con-
ditions are effective for the generation of primary amines with this
protecting group.20
To further explore alkene substrate scope, an alkene bearing
a tert-butyldimethylsilyl protected alcohol has also been tested
(Scheme 11). In the presence of 5 mol % of HL-0t-Bu and 5 mol %
Ta(NMe2)5, 4-methoxy-N-methylaniline is well tolerated to give the
predicted product in high conversion (90%).7c However, 2-
methoxy-N-methylaniline is incompatible with this catalyst sys-
tem, and instead a color change of the reaction mixture from yellow
to deep red is noted along with the observation of N-(2,6-
diisopropylphenyl)pivalamide as the free proligand, as evidenced
by the diagnostic chemical shift for the doublet corresponding to
the i-Pr groups of the free ligand (1.2 ppm).
9c
10b
0%
0%
a
Reaction conversion determined by 1H NMR spectroscopy.
Isolated complex.
In situ prepared complexes.
110 ꢁC.
Reaction not performed.
10 mol %.
b
c
d
e
f
be sustained. At 110 ꢁC, the reaction is feasible, but the conversion
within 20 h is significantly lowered. The complex L-1-Ta(NMe2)4
with the type A ligand is not a good catalyst system for hydro-
aminoalkylation, and negligible conversion is observed in 20 h
(entry 3). Here the six-membered O,O-chelating motif dramatically
impacts reactivity at the metal center.
Evaluation of the type B proligands indicates that use of the
aromatic HL-3 proligand incorporating the thiazole backbone re-
sults in much more favorable hydroaminoalkylation reactivity than
the phosphinecarboxamide ligands HL-2 (entries 4e6). The use of
HL-2-OMe did not afford improved reactivity and increasing the
catalyst loading to 10 mol % did not help to reach a better conver-
sion (entry 4). Once more however, 4-methoxy-N-methylaniline
was shown to be a better substrate. It is noteworthy that the use of
the more electron-withdrawing proligand HL-2-CF3 results in
Scheme 11. Evaluation of 2- and 4-methoxy-N-methylaniline.
In order to determine the impact of this substrate, the stoi-
chiometric protonolysis reaction of Ta(NMe2)5 with 2-methoxy-N-

P. Garcia et al. / Tetrahedron 69 (2013) 5737e5743
5741
methylaniline was performed (Scheme 12). When the two com-
pounds are heated to 70 ꢁC for 18 h, a complex mixture of products
are observed by 1H NMR spectroscopy, from which complex 1 could
be isolated as a crystalline solid in modest yield.21 Notably, this
dianionic ligand is formed upon cleavage of the OeMe bond to
generate a new N,O-chelated Ta complex with a five-membered
metallacycle, which contrasts with our most successful catalyst
systems disclosed thus far with four-membered metallacycles. This
selective C(sp3)eO bond cleavage reactivity is, to the best of our
knowledge, unknown for Ta amido complexes, however related
examples have been realized using niobium and tantalum penta-
halides.22,23 Disappointingly, a crystalline sample of 1 shows no
catalytic activity when evaluated using the same reaction condi-
tions as described in Table 1.
techniques or a glove box under an atmosphere of dry nitrogen.
Experiments on the NMR tube scale were carried out in Teflon cap
sealed NMR tubes (5 mm). Toluene, benzene, hexanes, and pentane
were purified by passage over an activated aluminum oxide column
and degassed prior to use. Benzene-d6 and toluene-d8 were dried
over 4 A molecular sieves and degassed by 3 freeze-pump-thaw
cycles. Solvents for chromatography were used as received from
commercial sources. Silica gel F60: 40e63 mm (230e400 mesh) was
ꢀ
purchased from Silicycle. TLC were run on silica gel coated alumi-
num plates Merck 60 F254 and revealed with UV at 254 nm and by
dipping in aqueous potassium permanganate solution.
4.2. Reagents and materials
Commercial amines and olefins were distilled under reduced
pressure from CaH2 and degassed by 3 freeze-pump-thaw cycles or
sublimed in the case of solids. Ta(NMe2)5 was purchased from
Strem and used as received. Commercially available reagents were
used as received unless indicated otherwise.
NH
+ Ta(NMe2)5
O
N
O
Ta(NMe2)3
benzene
70 °C
1
4.3. Characterization
NMR spectrawere recordedon Bruker Avance 300, Bruker Avance
400 MHz, and Bruker Avance 600 MHz instruments. The samples
were measured as solutions in the indicated solvent at ambient
temperature in non-spinning mode unless mentioned otherwise. To
specify the signal multiplicity, the following abbreviations are used:
s¼singlet, d¼doublet, t¼triplet, q¼quartet, and m¼multiplet; br
indicates a broad resonance and app indicates apparent multiplicity.
Scheme 12. Reaction between 2-methoxy-N-methylaniline and Ta(NMe2)5 and ORTEP
representation of the molecular structure (ellipsoids drawn at 50% probability, hy-
ꢀ
drogen atoms are omitted). Selected bond lengths (A): TaeO1 2.032(2), TaeN1
2.063(2), TaeN2 1.961(2), TaeN3 1.975(3), TaeN4 2.014(2), O1eC1 1.348(3), N1eC2
1.404(4).
3. Summary and conclusion
Chemical shifts
d are reported in parts per million (ppm) and cali-
The influence of eight related N,O-chelating ligands, one of
which was found to bind as O,O-ligand, and one N,N-chelating li-
gand on Ta(V) catalyzed hydroaminoalkylation has been studied
through the assessment of the reactivity of N-methylaniline and 4-
methoxy N-methylaniline with 1-octene. The use of proligand HL-
4, an aromatic amide bearing an ortho-methoxyphenyl group on
nitrogen, enables a notable improvement of the reaction conditions
over the previously reported HL-0t-Bu. The 4-methoxy-N-methyl-
aniline substrate has been shown to promote enhanced hydro-
aminoalkylation over N-methylaniline with this class of catalysts,
presumably due to the enhanced nucleophilicity of this amine to
promote protonolysis. Protonolysis has been proposed to be the
turnover limiting step in BINOLate chelated Ta(V) catalyzed
hydroaminoalkylation.7g Generally, the incorporation of hetero-
atoms into the ligand set did not promote improved reactivity and
ligands that can adopt chelating modes that are less strained than
the four-membered N,O-metallacycles, such as five- and seven-
membered metallacycles do not yield favorable catalytic results.
These results suggest that systems that have ligand hemi-lability
are favorable for accessing improved reactivity profiles. Notably,
the use of the related 2-methoxy-N-methylaniline cannot be tol-
erated as a hydroaminoalkylation substrate and an unexpected
C(sp3)eO bond cleavage has been observed to yield a new Ta(V)
complex. In conclusion, hemi-labile N,O-chelated Ta metallacyclic
complexes show promise as easily modified ligand backbones to
support catalytically active complexes. The incorporation of a po-
tentially labile donor atom on the N-substituent shows improved
reactivity and provides a basis for ongoing ligand development
efforts.
brated against the residual solvent signal. Coupling constants J are
given in Hertz (Hz). Low resolution mass spectra (EI-MS and ESI-MS),
high resolution mass-spectra (HRMS), and elemental analyses (EA)
were measured by the mass spectrometry and microanalysis service
at University of British Columbia. Mass spectra were measured on
a Kratos MS-50. Fragment signals are given in mass per charge
number (m/z). Elemental analyses were performed on a Carlo Erba
Elemental Analyzer EA 1108. The content of the specified element is
expressed in percent (%).
4.4. Proligands
Proligands HL-0t-Bu
were synthesized following reported procedures.
,
7c HL-2-OMe,10 HL-2-CF3,10 HL-3,11 and HL-723
4.4.1. HL-1:
N-(3-methyl-1-oxo-1-(piperidin-1-yl)butan-2-yl)piv-
alamide. To a solution of Piv-Val-COOH9 (2.0 g, 10 mmol) and
triethylamine (1.53 mL,11 mmol) in dry THF (35 mL) at ꢀ15 ꢁC were
successively added dropwise ethyl chloroformate (0.96 mL,
10 mmol) and piperidine (1.09 mL, 11 mmol). After one night at
room temperature, the volatiles were removed under reduced
pressure and the residual yellow oil diluted in EtOAc (20 mL),
washed with 0.5 M aqueous NaHCO3, 1 M aqueous HCl, brine, and
dried over MgSO4. Removal of the volatiles under reduced pressure
yielded a white powder recrystallized from hexanes/EtOAc (9:1) at
ꢀ10 ꢁC to give HL-1 as a white crystalline solid in 22% yield (0.59 g).
Mp: 114 ꢁC. 1H NMR (600 MHz, CDCl3)
d
0.84 (d, J¼6.9 Hz, 3H), 0.94
(d, J¼6.8 Hz, 3H), 1.21 (s, 9H), 1.48e1.68 (m, 6H), 1.91e2.03 (m, 1H),
3.43e3.50 (m, 2H), 3.50e3.63 (m, 2H), 4.85 (dd, J¼8.58, 5.12 Hz,
1H), 6.54 (d, J¼8.06 Hz, 1H). 13C NMR (150 MHz, CDCl3)
d 17.0, 19.9,
4. Experimental section
24.4, 25.6, 26.4, 27.5, 31.7, 38.8, 43.1, 46.7, 52.7, 170.0, 178.2. MS (CI):
m/z¼269 (MþH)þ. EA calcd for C15H28N2O2: C, 67.13; N, 10.44; H,
10.52; found: C, 67.01; N, 10.20; H, 10.52.
4.1. Synthesis and techniques
All preparative scale reactions were conducted using oven dried
(160 ꢁC) glassware with magnetic stirring using Schlenk-line
4.4.2. HL-3: 2,5-diphenylthiazol-4-ol (Adapted from literature).24
mixture of thiobenzamide (1.37 g, 10.0 mmol), ethyl -bromop-
A
a

5742
P. Garcia et al. / Tetrahedron 69 (2013) 5737e5743
henylacetate (1.93 mL, 11.0 mmol), and pyridine (0.243 mL,
3.00 mmol) was stirred under nitrogen at 110 ꢁC for 3 h. The
resulting solidified yellow mixture was diluted with EtOH (15 mL)
and stirred at room temperature for 30 min. The crude product was
filtered, and recrystallized from EtOHeDMF to give yellow needles
toluene (80 mL) and Na2CO3 (4.14 g, 39.1 mmol) was added fol-
lowed by 2,6-diisopropylaniline (3.69 mL, 19.55 mmol) added
dropwise over 30 min. After addition the reaction mixture was left
to stir for 1 h at room temperature and then diluted with water
(50 mL). After addition of Na2CO3 (8.29 g, 78.20 mmol) and
Me2NH2Cl (6.38 g, 78.20 mmol) the reaction mixture was heated to
reflux overnight. After cooling to room temperature the organic
layer was collected and washed with water (3ꢂ50 mL). The organic
layer was then dried over MgSO4, filtered, and the solvent removed
under reduced pressure. The resulting solid was rinsed repeatedly
with hexanes until a white powder was obtained. Recrystallization
from hot hexanes afforded HL-6 in 48% yield. 1H NMR (400 MHz,
in 52% (1.32 g). Mp 199.9 ꢁC. 1H NMR (400 MHz, DMSO-d6):
d 7.21 (t,
J¼7.4 Hz, 1H), 7.39 (t, J¼7.8 Hz, 2H), 7.54e7.36 (m, 3H), 7.72 (d,
J¼7.4 Hz, 2H), 7.89 (dd, J¼8.0, 1.7 Hz, 2H), 11.6 (br s, 1H). 13C NMR
(100 MHz, DMSO-d6):
d 107.5, 125.2, 125.9, 126.1, 128.8, 129.3,
130.2, 131.8, 132.9, 158.4, 159.6. HRMS (EI) calcd for C15H11NOS: m/z
253.05614 (Mþ); found: m/z 253.05631 (Mþ). EA calcd for
C15H11NOS: C, 71.12; H, 4.38; N, 5.53; found: C, 71.05; H, 4.34;
N, 5.34.
CDCl3)
d 1.12e1.42 (m, 12H), 2.44 (s, 6H), 2.64e2.71 (m, 2H),
2.77e2.83 (m, 2H), 3.16 (dt, J¼13.8, 6.8 Hz, 2H), 7.25 (s, 2H),
4.4.3. HL-4:
Methoxyaniline (0.34 mL,
N-(2-methoxyphenyl)-2,4,6-trimethylbenzamide. 2-
mmol) was added to dichloro-
7.32e7.38 (m, 1H), 10.30 (br s, 1H). 13C NMR (100 MHz, CDCl3)
3
d 23.6, 28.8, 32.7, 44.5, 55.3, 123.3, 127.7, 132.0, 145.6, 171.7. HRMS
methane (100 mL) in a round bottom flask equipped with a stir bar.
After addition of triethylamine (2.1 mL, 15 mmol), the mixture was
cooled to ꢀ78 ꢁC and 2,4,6-trimethylbenzylchloride (0.5 mL,
3 mmol) added dropwise. The reaction was left to warm to room
temperature, stirred overnight and then quenched with saturated
aqueous NaHCO3, extracted with dichloromethane (3ꢂ20 mL), and
dried over MgSO4. After filtration, and removal of volatiles under
reduced pressure, a pinkish solid was obtained, which upon re-
crystallization from dichloromethane/hexane, afforded HL-4 as
(EI) calcd for C17H28N2O: m/z 276.22016 (Mþ); found: m/z
276.22009 (Mþ).
4.5. Complexes
4.5.1. L-1-Ta(NMe2)4: (Z)-(2,2-dimethyl-1-((3-methyl-1-oxo-1-(pi-
peridin-1-yl)butan-2-yl)imino)propoxy)tetrakis(dimethylamido)tan-
talum. HL-1 (36.1 g, 0.135 mmol) and Ta(NMe2)5 (54.0 mg,
0.135 mmol) in hexanes (3 mL) were stirred overnight at room
temperature. Removal of volatiles under reduced pressure and
crystallization at ꢀ30 ꢁC from hexanes afforded L-1-Ta(NMe2)4 in
a white solid in 52% yield (0.42 g). 1H NMR (400 MHz, CDCl3)
d 2.35
(s, 3H), 2.40 (s, 6H), 3.86 (s, 3H), 6.87e6.96 (m, 3H), 6.99e7.18 (m,
2H), 7.95 (br s, 1H), 8.62 (dd, J¼7.9, 1.4 Hz, 1H); 13C NMR (100 MHz,
56% yield (47.3 mg). 1H NMR (600 MHz, C6D6):
d
0.96 (d, J¼6.8 Hz,
CDCl3)
d
19.2, 21.0, 55.5, 109.9, 119.9, 121.0, 123.9, 127.5, 128.3, 134.4,
3H), 0.99e1.05 (m, 1H), 1.05e1.15 (m, 3H), 1.15e1.22 (m, 1H),
1.22e1.29 (m, 1H), 1.25 (d, J¼6.4 Hz, 3H), 1.49 (s, 9H), 1.97e2.15 (m,
1H), 2.84 (br s, 2H), 3.53 (br s, 24H), 3.77 (d, J¼11.5 Hz, 1H), 3.89 (br
135.3, 138.7, 148.0, 168.4. HRMS (EI) calcd for C17H19NO2: m/z
269.14158 (Mþ); found: m/z 269.14142 (Mþ).
s, 2H). 13C NMR (150 MHz, C6D6)
d 20.1, 21.8, 24.6, 25.8, 25.8, 25.9,
4.4.4. HL-5: N-(2,6-dimethylphenyl)-3-(piperidin-1-yl)propanamide
(Adapted from literature).25,26 3-Chloropropanoic acid (2.35 g,
21.7 mmol) was dissolved in toluene in a round bottom Schlenk
flask equipped with a condenser and a stir bar. Thionyl chloride
(15.7 mL, 216.6 mmol) was added through the top of the condenser
and the solution heated to reflux for 1.5 h. The reaction mixture was
cooled to room temperature and the excess thionyl chloride and
toluene were removed under reduced pressure. Dry toluene
(100 mL) and Na2CO3 (4.59 g, 43.3 mmol) was then added to the
crude product followed by 2,6-dimethylaniline (2.23 mL,
18.1 mmol) added dropwise over 15 min resulting in a bright yellow
solution. After addition the reaction mixture was left to stir for 1 h
at room temperature. The mixture was then diluted with water
(50 mL), piperidine (8.6 mL, 86.7 mmol) added and the reaction
mixture was refluxed for 8 h. After cooling to room temperature the
organic layer was collected and washed with water (3ꢂ50 mL). The
organic layer was then dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification by column chromatography
(MeOH/DCM 1:99 to 5:95) and recrystallization from hot hexanes
afforded HL-5 in 20% yield (0.95 g). 1H NMR (400 MHz, CDCl3)
30.1, 31.6, 39.2, 45.2, 47.5, 47.6, 69.5, 175.1, 178.5. MS (EI): m/z¼580
(MþꢀNMe2). EA calcd for C23H51N6O2Ta: C, 44.22; N, 13.45; H, 8.23;
found: C, 44.00; N, 13.31; H, 8.22. Characterized by X-ray
crystallography.
4.5.2. L-4-Ta(NMe2)4: mono(N-(2-methoxyphenyl)-2,4,6-
trimethylbenzamidate)
tetrakis(dimethylamido)tantalum. HL-4
(0.135 g, 0.5 mmol) and Ta(NMe2)5 (0.200 g, 0.5 mmol) in hexanes
were stirred overnight at room temperature. Removal of volatiles
under reduced pressure afforded a yellow powder, which after
recrystallization from hexanes yielded L-4-Ta(NMe2)4 in 72% yield
(225 mg) as yellow crystals. 1H NMR (400 MHz, C6D6)
d 1.98 (s,
3H), 2.43 (s, 6H), 3.10 (s, 3H), 3.56 (s, 24H), 6.34e6.41 (m, 1H), 6.57
(s, 2H), 6.72e6.82 (m, 2H), 7.06e7.22 (m, 2H). 13C NMR (100 MHz,
C6D6)
d 21.3 (CH3), 21.4 (CH3), 47.4 (CH3), 54.6 (CH3), 111.9 (CH),
120.8 (CH), 125.3 (CH), 126.5 (CH), 129.0 (CH), 134.8 (C), 135.4 (C),
135.7 (C), 138.2 (C), 153.0 (C), 177.3 (C). MS (EI): m/z¼581 (Mþ-
NMe2). EA calcd for C25H5N2O2Ta: C, 48.00; N, 11.19; H, 6.77;
found: C, 48.02; N, 10.93; H, 7.01. Characterized by X-ray
crystallography.
d
1.45e1.57 (m, 2H), 1.59e1.64 (m, 4H), 2.25 (s, 6H), 2.42e2.64 (m,
6H), 2.70e2.74 (m, 2H), 7.09 (s, 3H), 10.30 (br s, 1H); 13C NMR
(100 MHz, CDCl3) 18.6, 24.2, 25.9, 32.0, 53.8, 54.9, 126.6, 128.0,
134.7, 134.8, 170.9. HRMS (EI) calcd for C16H24N2O: m/z 260.18886
(Mþ); found: m/z 260.18904 (Mþ).
4.5.3. L-7-Ta(NMe2)4: mono(N,6-Dimesityl-2-aminopyridinatetetrakis-
(dimethylamido)tantalum. HL-7 (0.33 g, 1.00 mmol) and Ta(NMe2)5
(0.40 g, 1.00 mmol) in benzene (3 mL) were stirred at room
temperature for 24 h. The volatiles were removed under vacuum,
and the resulting solid was recrystallized from toluene/hexanes
(3:1) at ꢀ35 ꢁC to give the complex as golden-brown crystals
d
4.4.5. HL-6:
N-(2,6-diisopropylphenyl)-3-(dimethylamino)prop-
anamide (Adapted from literature).25,26 3-Chloropropanoic acid
(2.546 g, 23.46 mmol) was dissolved in toluene in a round bottom
Schlenk flask equipped with a condenser and a stir bar. Thionyl
chloride (5.1 mL, 70.38 mmol) was added through the top of the
condenser and the solution heated to reflux for 2 h. The reaction
mixture was cooled to room temperature and the excess thionyl
chloride and toluene were removed under reduced pressure. Dry
(0.477 g, 69%). 1H NMR (400 MHz, C6D6):
d 2.18 (s, 3H), 2.27 (s,
6H), 2.28 (s, 3H), 2.41 (s, 6H), 3.32 (s, 24H), 5.68 (dd, J¼8.7,
0.8 Hz, 1H), 5.85 (dd, J¼6.9, 0.7 Hz, 1H), 6.82 (s, 2H), 6.87 (dd,
J¼8.6, 6.9 Hz, 1H), 6.98 (s, 2H). 13C NMR (100 MHz, C6D6):
d 19.8,
21.3, 21.4, 21.8, 48.0, 107.9, 110.0, 128.7, 130.2, 133.2, 134.8, 137.0,
137.4, 138.3, 138.6, 143.7, 156.8, 167.0. MS (EI): m/z¼642 (Mþ-
NMe2). EA calcd for C31H49N6Ta: C, 54.22; H, 7.19; N, 12.24;

P. Garcia et al. / Tetrahedron 69 (2013) 5737e5743
5743
found: C, 54.53; H, 7.09; N, 11.84. Characterized by X-ray
References and notes
crystallography.
1. McGrath, N. A.; Brichacek, M.; Njardarson, J. T. J. Chem. Educ. 2010, 87, 1348.
2. Step economy: (a) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197; (b) Wender,
P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41, 40.
3. Atom economy: (a) Trost, B. M. Science 1991, 254, 1471; (b) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259.
4. Roesky, P. W. Angew. Chem., Int. Ed. 2009, 48, 4892.
5. (a) Clerici, M. G.; Maspero, F. Synthesis 1980, 305; (b) Nugent, W. A.; Ovenall, D.
W.; Holmes, S. J. Organometallics 1983, 2, 161.
4.6. General procedure for catalysis experiments
4.6.1. Starting from isolated complexes. In a J. Young NMR tube was
added a solution of the corresponding N-methylaniline (0.5 mmol)
and 1-octene (112 mL, 0.75 mmol) in 0.30 g of toluene-d8. A solution
of the complex (5 mol %, 0.025 mmol) in 0.30 g of toluene-d8 was
then added and the mixture warmed to 130 ꢁC. In all cases, con-
version was determined by 1H NMR spectroscopy after 20 h.
6. Group 4 metals: (a) Bexrud, J. A.; Eisenberger, P.; Leitch, D. C.; Payne, P. R.;
Schafer, L. L. J. Am. Chem. Soc. 2009, 131, 2116; (b) Kubiak, R.; Prochnow, I.; Doye,
S. Angew. Chem., Int. Ed. 2009, 48, 1153; (c) Prochnow, I.; Kubiak, R.; Frey, O. N.;
Beckhaus, R.; Doye, S. ChemCatChem 2009, 1, 162; (d) Kubiak, R.; Prochnow, I.;
€
Doye, S. Angew. Chem., Int. Ed. 2010, 49, 2626; (e) Prochnow, I.; Zark, P.; Muller,
T.; Doye, S. Angew. Chem., Int. Ed. 2011, 50, 6401; (f) Jaspers, D.; Saak, W.; Doye,
S. Synlett 2012, 2098; (g) Dorfler, J.; Doye, S. Angew. Chem., Int. Ed. 2013, 52,
4.6.2. Starting from in situ generated complexes. To a solution of the
Ta(NMe2)5 (0.025 mmol) in toluene-d8 (0.30 g) was added the
corresponding proligand (0.025 mmol) at room temperature. After
15 min, the mixture was transferred to a solution of the corre-
€
1806; (h) Preuß, T.; Saak, W.; Doye, S. Chem.dEur. J. 2013, 19, 3833.
7. Groups 5 metals: (a) Herzon, S. B.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129,
6690; (b) Herzon, S. B.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 14940; (c)
Eisenberger, P.; Ayinla, R. O.; Lauzon, J. M.; Schafer, L. L. Angew. Chem., Int. Ed.
2009, 48, 8361; (d) Zi, G.; Zhang, F.; Song, H. Chem. Commun. 2010, 6296; (e)
Zhang, F.; Song, H.; Zi, G. Dalton Trans. 2011, 40, 1547; (f) Reznichenko, A. L.;
sponding N-methylaniline (0.5 mmol) and 1-octene (112
mL,
0.75 mmol) in 0.30 g of toluene-d8 in a J. Young NMR tube. The
mixture warmed to 130 ꢁC. In all cases, conversion was determined
by 1H NMR spectroscopy after 20 h.
€
Emge, T. J.; Audorsch, S.; Klauber, E. G.; Hultzsch, K. C.; Schmidt, B. Organo-
metallics 2011, 30, 921; (g) Reznichenko, A. L.; Hultzsch, K. C. J. Am. Chem. Soc.
2012, 134, 3300.
8. (a) Li, C.; Thomson, R. K.; Gillon, B.; Patrick, B. O.; Schafer, L. L. Chem. Commun.
2003, 2462; (b) Leitch, D. C.; Platel, R.; Schafer, L. L. J. Am. Chem. Soc. 2011, 133,
15453.
4.7. Synthesis of 1
9. Engle, K. M.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 14137.
10. Behrle, A. C.; Schmidt, J. A. R. Organometallics 2013, 32, 1141.
11. Adapted from literature, see: Ref. 24.
12. Chong, E.; Qayyum, S.; Schafer, L. L.; Kempe, R. Organometallics 2013, 32, 1858.
13. (a) Noor, A.; Kretschmer, W. P.; Glatz, G.; Kempe, R. Inorg. Chem. 2011, 50, 4598;
(b) Qayyum, S.; Haberland, K.; Forsyth, C. M.; Junk, P. C.; Deacon, G. B.; Kempe,
R. Eur. J. Inorg. Chem. 2008, 557; (c) Schmalz, T.; Burkhardt, I.; Irrgang, T.;
Kempe, R. Z. Kristallogr.: New Cryst. Struct. 2005, 220, 405.
14. CCDC 926372.
To a solution of the Ta(NMe2)5 (129 mg, 0.32 mmol) in benzene-
d6 (0.60 g) was added 2-methoxy-N-methylaniline (44 mg,
0.32 mmol). After 4 h at room temperature, the mixture was
transferred onto a J. Young NMR tube and warmed to 70 ꢁC for 16 h
and the crude mixture analyzed by 1H NMR. Slow evaporation of the
volatiles enabled the isolation of 1 as red crystals.1H NMR (300 MHz,
C6D6):
d
1.28 (s, 18H), 2.15 (s, 3H), 6.70 (d, J¼7.5 Hz, 1H), 6.96 (dd,
15. CCDC 926371.
16. CCDC 926370.
J¼7.5, 7.4 Hz, 1H), 7.07 (dd, J¼7.6, 7.4 Hz, 1H), 7.20 (d, J¼7.4 Hz, 1H).
17. (a) For a review, see: Kempe, R. Eur. J. Inorg. Chem. 2003, 791 and references
therein (b) Noor, A.; Kretschmer, W.; Kempe, R. Eur. J. Inorg. Chem. 2006, 2683;
MS (EI): m/z¼434 (Mþ). Characterized by X-ray crystallography.
€
(c) Talja, M.; Polamo, M. Polyhedron 2006, 25, 3039; (d) Noor, A.; Doring, C.;
Kempe, R. Z. Kristallogr.: New Cryst. Struct. 2008, 223, 515.
18. When possible, pure crystalline complexes were used. In other cases, the
proligand and Ta(NMe2)5 were premixed and the resulting mixture used. For
reports on the similar catalytic behavior for in situ prepared precatalysts vs in
situ prepared systems see: (a) Payne, P. R.; Bexrud, J. A.; Leitch, D. C.; Schafer, L.
L. Can. J. Chem. 2011, 89, 1222; (b) Ayinla, R. O.; Schafer, L. L. Dalton Trans. 2011,
40, 7769.
19. Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120, 431.
20. (a) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J. Am. Chem. Soc.
2001, 123, 984; (b) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L. J.
Am. Chem. Soc. 2001, 123, 10409; (c) Josephsohn, N. S.; Carswell, E. L.; Snapper,
M. L.; Hoveyda, A. H. Org. Lett. 2005, 7, 2711.
Acknowledgements
The authors thank Mr. Jacky C.-H. Yim for assistance with X-ray
crystallography and NSERC and Boehringer Ingelheim (Canada) Ltd
for financial support of this work. P.R.P. and E.C. thank NSERC for
postgraduate scholarships. R.L.W. thanks the Government of Can-
ada for a Commonwealth Postdoctoral Fellowship. A.C.B. and
J.A.R.S. acknowledge the Donors of the American Chemical Society
Petroleum Research Fund for partial support of this research. This
research was undertaken, in part, thanks to funding from the
Canada Research Chairs program.
21. CCDC 920047.
22. (a) For a review, see: Marchetti, F.; Pampaloni, G. Chem. Commun. 2012, 635; (b)
Marchetti, F.; Pampaloni, G.; Zacchini, S. Eur. J. Inorg. Chem. 2010, 767.
23. Scott, N. M.; Schareina, T.; Tok, O.; Kempe, R. Eur. J. Inorg. Chem. 2004, 3297.
Supplementary data
€
€
24. Tauscher, E.; Weiß, D.; Beckert, R.; Gorls, H. Synthesis 2010, 1603.
25. Costa, J. C. S.; Neves, J. S.; de Souza, M. V. N.; Siqueira, R. A.; Romeiro, N. C.;
Boechat, N.; e Silva, P. M. R.; Martins, M. A. Bioorg. Med. Chem. Lett. 2008, 18,
1162.
These data include NMR spectra and details of X-ray crystallo-
graphic data. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2013.04.070.
26. Sparapani, S.; Haider, S. M.; Doria, F.; Gunaratnam, M.; Neidle, S. J. Am. Chem.
Soc. 2010, 132, 12263.