Modular ligand variation in calcium bisimidazoline complexes: Effects on ligand redistribution and hydroamination catalysis

Article abstract of DOI:10.1039/c1dt10732a

A series of calcium complexes supported by chiral bisimidazoline ligands have been studied in the catalytic intramolecular hydroamination/cyclisation of amino-olefins. The complexes [Ca(R-BIM){N(SiMe₃)₂}(THF)] (R = 4-C₆H

Full text of DOI:10.1039/c1dt10732a

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COMMUNICATION
Modular ligand variation in calcium bisimidazoline complexes: effects on
ligand redistribution and hydroamination catalysis†
James S. Wixey and Benjamin D. Ward*
Received 21st April 2011, Accepted 16th May 2011
DOI: 10.1039/c1dt10732a
A series of calcium complexes supported by chiral bisimida-
zoline ligands have been studied in the catalytic intramolec-
ular hydroamination/cyclisation of amino-olefins. The com-
plexes [Ca(R-BIM){N(SiMe3)2}(THF)] (R = 4-C6H4Me, 5a, 4-
C6H4F, 5b and tBu, 5c) have given competitive enantioselectiv-
ities (up to 12%) when compared to current literature studies
involving calcium. Bisimidazolines offer a significant advance
over similar bisoxazoline ligands, by allowing a greater
structural variance through a modular synthetic pathway.
The implementation of alkaline earth (AE) metals in asymmetric
hydroamination catalysis has received increasing interest over
the past few years, particularly with calcium.1,2 Whilst most
studies have involved the b-diketiminato complex (I, Fig. 1),3
the development of chiral derivatives is very much in its infancy.
Few examples of chiral calcium complexes have emerged (II–
IV),4–6 and with enantioselectivities below 30%, this is indicative
of the challenging nature of calcium in asymmetric catalysis.
Whilst significant developments have been made within the area,
developments are often hindered by the lability of AE complexes,
exemplified by the eponymous Grignard reagents.2a,2c,7,8 Their
susceptibility to undergo rapid Schlenk-type ligand redistribu-
tion understandably renders complexes catalytically inactive or
greatly inhibits regio- or stereoselectivity, ultimately leading to
poor enantioselectivities. A detailed understanding of how to
suppress/control such redistribution processes is crucial in order
to facilitate the further development of asymmetric catalysis
with the AE metals; we herein report further insight into the
redistribution processes with calcium bisimidazoline complexes,
and the corresponding impact on catalytic performance.
Fig. 1 Calcium complexes employed in hydroamination catalysis.
using III improved the selectivity to 18% ee; we recently reported
selectivities of up to 26% ee using IV.6 It is apparent from
this trend, that progress towards greater enanatioselectivities is
highly dependent on a judicious choice of supporting ligand, but
may not necessarily depend on completely suppressing the ligand
redistribution processes, since IV was highly labile in solution.
Chiral bisimidazolines (Scheme 1) offer an advantage over the
aforementioned bisoxazolines as a ligand platform for the AE
metals. The incorporation of an additional N–R moiety allows
for alteration of electronic, in addition to the steric, properties
of the ligand;9–11 we have therefore systematically varied the N–R
The first example of calcium employed in asymmetric hy-
droamination catalysis was contributed by Buch and Harder
employing the bisoxazoline containing complex II,4 giving 4–
6% ee. The low enantioselectivities were attributed to the rapid
redistribution of the ligand in solution giving the unreactive
homoleptic complex [Ca(BOX)2] and the non-selective calcium
amide complex, Ca{N(SiMe3)2}2(THF)2. Work by Sadow et al.5
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff,
UK, CF10 3AT. E-mail: WardBD@Cardiff.ac.uk; Fax: +44 (0)29 208
74030; Tel: +44 (0)29 208 70302
† Electronic supplementary information (ESI) available: Experimental
procedures, characterising data, conversion curves, and kinetics method-
ology. See DOI: 10.1039/c1dt10732a
Scheme 1 Preparation of bisimidazoline ligands (R = 4-C6H4Me 2a,
4-C6H4F 2b, tBu 2c).
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Table 1 Redistribution of [Ca(R-BIM){N(SiMe3)2}(py)]
[Ca(BIMR)2] 4 and Ca{N(SiMe3)2}2(py)2 at 293 K
3
to
substituent in order to determine the effect on the coordination
chemistry and catalytic ability of the complexes.
A series of chiral bisimidazoline derivatives (R-BIM, R =
4-C6H4Me, 2a, 4-C6H4F, 2b and Bu, 2c) have been prepared
Entry
Complex
3:4a
Kb
DG293 (kJ mol-1)
t
from the condensation of the corresponding diamine (1a–c)6
and Pinner salt12 in refluxing CH2Cl2 for 48 h, as reported
by Pflatz et al.13 We have found this method convenient for
preparing the corresponding bisimidazoline in up to 40% yield,
based on starting diamine. Though typically moderate yields were
obtained, higher yields were not realised by extending reaction
times or conducting the reaction in higher boiling point solvents,
for example chloroform or chlorobenzene. This simple method
allows a series of bisimidazolines (R-BIM) to be prepared in
which, in principle, the stereodirecting and R substituents can
be independently varied in a modular fashion via the choice of
amino acid and primary amine in the diamine synthesis, without
introducing additional synthetic complexity. In this report we have
concentrated on the isopropyl derivatives starting from L-valine.
Reaction of the protio-ligands 2a–c with Ca{N(SiMe3)2}2-
(THF)2 in C6D6 afforded orange precipitates, which were found
to be soluble only in THF-d8, insoluble in hydrocarbon sol-
vents, and unstable in chlorinated solvents. The low solubility
of calcium-based complexes is well documented and therefore
unsurprising.1b,6,14 No evidence of ether-cleavage was observed in
THF, even though this has been previously reported in calcium
complexes under similar conditions.14
1
2
3
3a
3b
3c
64 : 36
48 : 52
80 : 20
0.31
1.17
0.06
2.8
-0.4
6.8
a Determined by integration of 1H NMR spectra. b Equilibrium coefficient
determined at 293 K.
Scheme 3 Ligand redistribution of [Ca(R-BIM){N(SiMe3)2}(py)] (R¢ =
iPr, R = 4-C6H4Me, 3a 4-C6H4F, 3b and tBu, 3c).
occurred. The values of DG293 were calculated from the equilibrium
coefficients, which were found to be small and almost negligible.
The presence of three bis(trimethylsilyl)amide moieties was
evident from the relative integration of the resonances, at
Although the THF adducts [Ca(R-BIM){N(SiMe3)2}(THF)]
5a–c were employed in hydroamination catalysis (vide infra), for
analysis of the complexes, and in order to determine the extent
of base coordination in THF-d8, the complexes were prepared
using the pyridine analogue Ca{N(SiMe3)2}2(py)2 in the presence
of an excess of pyridine (Scheme 2).15 These complexes are
formulated as [Ca(R-BIM){N(SiMe3)2}(py)] (3a–c). As with the
THF complexes, the pyridine adducts were found to be only
sparingly soluble in benzene and toluene, and decomposed in
chloroform and dichloromethane.
ca. 0 ppm. These can be attributed to the coordinated
bis(trimethylsilyl)amide on the heteroleptic complex 3, the cor-
responding Ca{N(SiMe3)2}2(py)2 redistribution product, and the
liberated amine HN(SiMe3)2.
Although the HN(SiMe3)2, is expected be a highly soluble,
volatile by-product, even after repeated recrystallisation and ex-
tensive drying in vacuo we were unable to fully remove the residue.
This could potentially be attributed to the partial reinsertion of
the HN(SiMe3)2 into the complex when in solution, which has
been previously observed by Ruhlandt-Senge et al.16 In each case,
the complexes were dried in vacuo to 4 ¥ 10-2 mbar, in order to
ensure a consistent level of base coordination, since it is known that
extended exposure to vacuum can remove coordinated pyridine.6
There was consistently only one pyridine ligand bound to the
calcium in the heteroleptic complex 3, which contrasts the BOX
complex II (Fig. 1), in which there were two THF ligands.4
In order to clarify the identity of the homoleptic com-
plexes 4 in the mixture obtained by the redistribution of 3,
Ca{N(SiMe3)2}2(py)2 was reacted with two equivalents of R-
BIM, whereupon two equivalents of HN(SiMe3)2 were eliminated,
forming the homoleptic complex [Ca(R-BIM)2] (R = 4-C6H4Me,
Scheme 2 Preparation of [Ca(R-BIM){N(SiMe3)2}(py)] (R = 4-C6H4Me,
3a, 4-C6H4F, 3b and tBu, 3c).
t
4a, 4-C6H4F, 4b and Bu, 4c). In each case, the complexes were
The NMR spectra of 3a–c in THF-d8 were well-defined at
ambient temperature, but nevertheless showed a mixture of the
heteroleptic species 3 and homoleptic species 4 (Scheme 3). Buch
and Harder report a redistribution ratio of 80 : 20 heteroleptic
to homoleptic respectively in the related bisoxazoline complex
[Ca(BOX){N(SiMe3)}(THF)2];4 however upon varying the N-R
substituent of the bisimidazolines a strong variation in equilibrium
position was observed (Table 1). 1H NMR studies established
that all complexes had reached their irrespective equilibrium
positions within 10 min. Further monitoring over several hours
indicated that no further deviation of the equilibrium position
again dried in vacuo to 4 ¥ 10-2 mbar, which was sufficient to
remove all pyridine traces.
In order to determine the effect of the nitrogen substituent,
and consequently the equilibrium position, on their catalytic
performance, the THF derivatives, 5a–c were employed in the
hydroamination/cyclisation of the amino-olefins A and B (Scheme
4); the conversions, initial rates and enantioselectivities, are listed
in Table 2.‡ Consistent with our previous observations,6 catalytic
hydroamination of the diphenyl substrate B was found to be
much faster than with the dimethyl substrate A, which mirrors
the observations with Ca{N(SiMe3)2}2(THF)2 (23 h for A and
7694 | Dalton Trans., 2011, 40, 7693–7696
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The Royal Society of Chemistry 2011
©

Table 2 Asymmetric hydroamination of amino-olefins using 10 mol%
[Ca(R-BIM){N(SiMe3)2}(THF)]
Entry Complex Substrate Initial Rate/mol dm-3 s-1 Conv.%a ee%b
1
2
3
4
5
6
5a
5a
5b
5b
5c
5c
A
B
A
B
A
B
5.1(5) ¥ 10-7
1.0(1) ¥ 10-4
6.8(3) ¥ 10-8
1.8(1) ¥ 10-5
7.3(4) ¥ 10-7
6.4(3) ¥ 10-5
8
95
3
>99
18
>99
5
0
9
9
12
12
a Determined from 1H NMR spectra. b Determined by 1H NMR spec-
troscopy using (R)-(-)-O-acetylmandelic acid.18
Fig. 2 Conversion for the catalytic hydroamination of substrate B using
[Ca(tBu-BIM){N(SiMe3)2}(THF)] 5c in C6D6 at 293 K.
Scheme 4 Asymmetric hydroamination catalysis (R¢ = Me A, Ph B).
20 min for B at ambient temperature with 10 mol% catalyst),
although all reactions employing complexes 5a–c were signifi-
cantly slower than this, as is expected when using a sterically
demanding spectator ligand. Reactions employing B went to
completion, whereas the analogous reactions with A did not,
reaching only <20% conversion within several days. Despite
this however, the enantioselectivities with a particular catalyst
complex were consistent within error, regardless of the substrate.
This is in stark contrast to the bis-4 and trisoxazoline,5 and
diamine6 complexes which are much more substrate-specific.
The 4-C6H4Me complex 5a gave the fastest conversion but little
the additional nitrogen substituent and their modular synthesis;
variation in the N–R substituent occasions a shift of the equi-
librium position, and has a concomitant impact on the catalytic
performance, although not on the stereocontrol offered by the
ligand. We are undertaking further studies in this regard to
ensure that redistribution processes are more fully understood,
in order that a rational design of calcium complexes for catalytic
applications may be achieved.
We thank the EPSRC (EP/H012109), the Royal Society, and
the Leverhulme Trust (F/00 407/BL) for financial support.
t
stereoselectivity (entries 1 and 2), whereas the 4-C6H4F and Bu
complexes 5b and 5c gave moderate selectivities, comparable to
those obtained with the trisoxazoline complex III, and higher
than with the structurally related bisoxazoline complex II (entries
3–6). Based upon the measurements in Table 1, 5b is expected
to give the highest amount of Ca{N(SiMe3)2}2(THF)2, and yet
the rate of reaction is significantly slower than those of 5a and
5c. This is most likely due to the nature of the equilibrium,
which will be different under catalytic conditions where the
liberated HN(SiMe3)2, catalysis substrate and pyrrolidine product
can take part in the redistribution processes. 5b still invokes a
comparable stereocontrol compared to 5c, suggesting that the
equilibrium position has little effect on the stereoselectivity; this
may suggest that the redistribution process may be more complex
than described by Scheme 3.
The catalytic reactions using 10 and 20 mol% 5a–c were
monitored, and the initial rates are consistent with a first order
reaction with respect to catalyst, in agreement with Marks et al.17
However, with 5 mol% catalyst loading the reactions showed little
to no activity. A representative conversion curve is provided in
Fig. 2.
Notes and references
‡ 42 mmol [Ca(R-BIM){(N(SiMe3)2}(THF)] 5, 0.42 mmol substrate, C6D6,
rt. Reaction progress monitored by 1H NMR spectroscopy. Enantiomeric
excesses determined by 1H NMR spectroscopy after the addition of R-(-)-
O-acetylmandelic acid.18
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Conclusions
7 D. Seyferth, Organometallics, 2009, 28, 1598.
Ligand redistribution is a prominent feature of calcium complexes.
The bisimidazoline complexes described herein are no exception,
but in contrast to the analogous bisoxazoline complexes allow
a greater degree of ligand variation through the presence of
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7696 | Dalton Trans., 2011, 40, 7693–7696
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