Chiral tridentate bis(oxazol-2-ylimino) isoindoline-based pincer ligands: isolation and characterizationviadeligation fromin situprepared Cd-ligand complexes

Article abstract of DOI:10.1039/d0dt02531c

The first isolation and structural characterization of a series of chiral trinitrogen 1,3-bis(4,5-dihydrooxazol-2-ylimino)isoindoline-based pincer ligands are reported. Cadmium complexes, isolated as Cd(L₂X)₂where L₂X is t

Full text of DOI:10.1039/d0dt02531c

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Volume 50
Number 29
Chiral tridentate bis(oxazol-2-ylimino) isoindoline-based
pincer ligands: isolation and characterization via deligation
from in situ prepared Cd-ligand complexes
7
August 2021
Pages 9971-10312
Dalton
Transactions
An international journal of inorganic chemistry
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Chiral tridentate bis(oxazol-2-ylimino) isoindoline-
based pincer ligands (L2XH) are prepared in situ, in their
deprotonated form, as Cd(L2X)2 complexes. Addition of
excess thiol to the individual Cd complexes allows for the
isolation of each ligand in their free, enantiopure, protio form
(L2XH). The potential for these chiral ligands to be used in
enantioselective catalysis is indicated by the preparation of a
1 : 1 ligand : Pd model catalyst complex.
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Chiral tridentate bis(oxazol-2-ylimino)
isoindoline-based pincer ligands: isolation and
characterization via deligation from in situ
prepared Cd-ligand complexes†
Cite this: Dalton Trans., 2021, 50,
10041
Kristina Zivkovic, a Lilia M. Baldauf,a Jessica L. Cryder,a Alexa Villaseñor,a
Valeria Reyes,a Lauren E. Bernier,a Theresa J. Thomas,a Maxwell O’Toole,a
Kayleen Fulton,a Curtis E. Moore,b Arnold L. Rheingoldb and
a
Christopher J. A. Daley
*
The first isolation and structural characterization of a series of chiral trinitrogen 1,3-bis(4,5-dihydrooxazol-
2-ylimino)isoindoline-based pincer ligands are reported. Cadmium complexes, isolated as Cd(L2X)2 where
L2X is the deprotonated form of L2XH = 1,3-bis(4,5-dihydro-4-(R)-phenyloxazol-2-ylimino)-isoindoline
((R,R)-5H) or 1,3-bis(4,5-dihydro-4-(S)-iso-propyloxazol-2-ylimino)isoindoline ((S,S)-6H) were prepared
in situ via traditional or microwave-based techniques with the latter being more efficient but less able to be
scaled up at this time. Ligands (R,R)-5H and (S,S)-6H were isolated via deligation from their respective
cadmium complexes using a thiol-based ligand exchange protocol. The characterization of ligands and
their respective cadmium complexes, in both the solid (X-ray crystallography) and solution (NMR spec-
troscopy) states are reported. Pd((S,S)-6)(OAc) is reported as a proof-of-concept of the ability to prepare
1 : 1 ligand to metal ratio complexes that are believed to be necessary as potential enantioselective catalysts.
Received 17th July 2020,
Accepted 11th June 2021
DOI: 10.1039/d0dt02531c
rsc.li/dalton
increasingly impactful in recent years.2 Some of the earliest
systems, like the 1,3-bis(2-arylimino)isoindoline pincer
Introduction
Control of the steric and electronic environments about a ligands3 (e.g. aryl = pyridine), have been studied for over 60
metal centre are keys to develop efficient and selective catalyst years. Studies on these systems has found a resurgence due in
systems for use in enantioselective homogeneous catalysis. part to their rich palladium chemistry4 and their success in
Since the first boom of reports in the late 1960s, the design of homogeneous catalysis including oxidations,5 hydrogen-
new ligand architectures has been highly successful in modu- ations,6 and radical polymerizations.7 Architectural derviatiza-
lating the reactivity and selectivity of transition metal catalysts tion on these systems by Bröring’s8 and Gade’s9 groups have
in homogeneous catalysis as most notably recognized by the generated chiral bis(pyridylimino)isoindoline ligands for use
pioneering 2001 Nobel Prize award work of Knowles,1a in enantioselective homogeneous catalysis. Other mer-triden-
Noyori,1b and Sharpless.1c To this day, new ligand architectures tate pincer ligands used in enantioselective catalysis include
are necessary to increase the overall efficiency and selectivity Gade’s bis(oxazolinylmethyl)pyrrole- and bis(oxazolinylmethyl-
of developed catalysis reactions as well as for the development idene)-isoindole-based ligands,10 Nakada’s bis(oxazolinyl)car-
of new catalytic reactions. Of the ligand systems developed, the bazole ligands,11 the independently developed bis(oxazolinyl)
mer-coordinating pincer-type ligand systems have become phenyl (‘phebox’) ligands,12 and Nishiyama’s highly successful
chiral C2 symmetric 2,6-bis(2-oxazolinyl)-pyridine (‘pybox’)
ligand;13 a standard in the chiral “tool kit” of stereodirecting
ligands.
Based on Bröring’s and Gade’s success in enantioselective
aDepartment of Chemistry and Biochemistry, University of San Diego, 5998 Alcalá
Park, San Diego, USA. E-mail: cjdaley@sandiego.edu; Tel: +1 619 260-4033
bDepartment of Chemistry and Biochemistry, University of California, San Diego,
9500 Gilman Drive, MC 0332, La Jolla, CA, USA
catalysis with chiral bis(pyridylimino)isoindoline ligands and
the structural similarity of 1,3-bis(2-pyridylimino)isoindoline
to the pybox ligand we pursued the synthesis of a new class of
chiral mer-coordinating ligands, 1,3-bis(4,5-dihydrooxazol-2-
ylimino)isoindolines for potential use in enantioselective cata-
lysis. Replacement of the 2-aminopyridine units of 1,3-bis(2-
†Electronic supplementary information (ESI) available: X-ray diffraction analysis
files for compounds Cd((R,R)-5)2, Cd((S,S)-6)2, (R,R)-5H, (S,S)-6H, and Pd((S,S)-6)
(OAc). CCDC 1952889, 1952586, 1953332, 2016087 and 2016649. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
d0dt02531c
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pyridylimino)isoindoline for enantiopure 2-amino-4-substi- (R,R)-5H and (S,S)-6H from reaction of phthalonitrile and 2 equiv.
tuted-oxazoline was chosen as the oxazolines (i) are readily of (R)-3 or (S)-4, respectively was not successful using reported
commercially available, or are easily prepared, in enantiopure methods that afford the similar achiral bis(2-pyridylimino)iso-
form and (ii) are successful in enantioselective homogeneous indoline systems.18 However, using ZnCl2 as catalyst, we suc-
catalysis as demonstrated by examples that include the bis(ox- cessfully made the complexes Zn(L2X)2, where L2X = (R,R)-5−
azoline),14
bis(oxazolinylmethyl)pyrrole,15
bis(oxazolinyl- and (S,S)-6−, which contain the desired ligand, formed in situ,
methylidene)isoindole,16 and pybox13 ligand systems. Our bound in their deprotonated form.17 Attempts to prepare the
earlier investigations showed that reaction of 2 equivalents of ligands directly, in their free, unbound, neutral form, using
enantiopure 4-substituted-2-aminooxazoline with 1 equivalent several other metal salts as potential catalysts, under similar
of phthalonitrile, through the use of conventional heating reaction conditions were unsuccessful. Several reactions
methods, with ZnCl2 as catalyst produces the desired 1,3-bis afforded low yields of complexes analogous to the Zn(L2X)2
(4,5-dihydrooxazol-2-ylimino)isoindoline (L2XH) ligand archi- compounds however when Cd(OAc)2 was used as catalyst it
tecture in situ as neutral Zn(L2X)2 complexes, having 2 equiva- fared the best of all investigated including the reported zinc
lents of the ligand coordinated in mer-fashion in their depro- systems. Using a similar protocol as for the Zn(L2X)2 com-
tonated anionic form in low-to-modest yields.17 Herein we plexes (Scheme 1: reaction (2); four equivalents of (R)-3 or (S)-4
report our continued studies on the development of this new reacted with two equivalents of phthalonitrile with one equi-
class of chiral ligand through (i) the improved synthesis of Cd valent of Cd(OAc)2 in dry toluene at 80 °C) resulted in the iso-
(L2X)2 complexes, structurally analogous to the Zn(L2X)2 lation, after chromatographic workup and recrystallization, of
systems reported earlier, and (ii) the deligation, isolation, and Cd((R,R)-5)2 (35%) and Cd((S,S)-6)2 (34%), respectively in
characterization of the ligands in their free neutral protio modest yields.
forms. Finally, a proof-of-concept 1 : 1 ligand to metal ratio
complex is reported as a model of a potential enantioselective trying to boost the yields of Cd((R,R)-5)2 and Cd((S,S)-6)2 by
As was observed with the analogous zinc complexes,17
catalyst precursor.
increasing the temperature of reaction using traditional
heating was ineffective; resulting in lower yields and an
increase in byproduct formation. The methodology of conven-
tional heating at 80 °C was used to prepare and characterize
the cadmium complexes however exploration of alternative
methods to increase the efficiency of the reactions continued.
Initial attempts to use microwave methodologies, at the time
the zinc complexes were reported, were hampered by a micro-
wave reactor system that could not reach sufficiently elevated
temperature to form the metal complexes. However, since that
time, by using a new, more powerful microwave reactor, it was
found that heating the reaction at 200–205 °C for a short
period of time (10 min) successfully prepared the desired
complexes in good yield (81% and 85% for Cd((R,R)-5)2 and
Cd((S,S)-6)2, respectively). Furthermore, less decomposition
and byproduct formation was observed resulting in a signifi-
cantly improved efficiency for the isolation and purification of
the complexes. Only recrystallization of the product mixture
was necessary to obtain the desired complexes as opposed to
the need for column chromatography followed by recrystalliza-
tion using the traditional heating method. Unlike the tra-
ditional heating method, the microwave method does not
allow for single, large scale product preparation but, with the
use of an auto-sampler, gram quantities of the complexes can
be prepared in a day. The characterization of Cd((R,R)-5)2 and
Cd((S,S)-6)2 are detailed in the subsequent sections.
Results and discussion
In situ synthesis of cadmium metal complexes: Cd((R,R)-5)2
and Cd((S,S)-6)2
The precursor chiral oxazoline ligand stereodirecting units
(R)-3 and (S)-4 are prepared in high yields on reacting 1 equiv.
of amino alcohol, (R)-1 and (S)-2, respectively, with 1.2 equiv.
of cyanogen bromide in refluxing ethanol (Scheme 1: reaction
(1)).17 The direct preparation of the desired chiral ligands
Characterization of cadmium metal complexes: Cd((R,R)-5)2
and Cd((S,S)-6)2
Each complex was structurally characterized both in the solu-
tion (NMR) and solid (X-ray) states. In CDCl3 solution (Fig. 1)
each complex was determined to have C2 symmetry based on
the number of signals observed in the H NMR. Analogous to
Zn((R,R)-5)2, the aromatic signals of Cd((R,R)-5)2 are shifted
Scheme 1 Synthesis of the Cd((R,R)-5)2 and Cd((S,S)-6)2 by conven-
tional and microwave heating methods, with the latter being most
successful.
1
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Fig. 1 1H NMR spectra of cadmium complexes Cd((R,R)-5)2 (a) and
Cd((S,S)-6)2 (b) in CDCl3 with assignments made based on their
analogous zinc complexes.17
upfield relative to free (R)-3, a further indication of bound
ligand. Similarly, analogous to Zn((S,S)-6)2, the isopropyl
signals of Cd((S,S)-6)2 are shifted upfield relative to free (S)-4.
Signal assignments for each Cd(II) complex are analogous to
those of the zinc series: Zn((R,R)-5)2 and Zn((S,S)-6)2 previously
reported.17
Crystals suitable for X-ray diffraction were obtained via slow
evaporation of concentrated CH2Cl2 : acetone solutions of the
cadmium complexes in an analogous fashion as to those
reported for Zn((R,R)-5)2 and Zn((S,S)-6)2.17 The structures of
each were determined and are depicted in Fig. 2 and selected
structural data are contained in Table 1. The enantiopurity of
each complex was confirmed via anomalous dispersion ana-
lysis. As was the case for the zinc complexes, the use of the
SQUEEZE19 program was required to account for the void
volumes associated with each structure. They were modelled as
containing 3 molecules of CH2Cl2 in both the Cd((R,R)-5)2 and
Cd((S,S)-6)2 crystals along with an addition 6 acetone mole-
cules in the latter. Complexes Cd((R,R)-5)2 and Cd((S,S)-6)2
were determined to be isomorphous with their reported Zn
analogues. One phenyl group substituent of each ligand in the
structure of Cd((R,R)-5)2 is disordered and is modelled as
being in two positions in 54.7% and 45.3% occupancy (Fig. 2).
The geometry of each complex is slightly disordered octahedral
about the Cd metal centres; with the sum of the angles around
each set of 4-planar bound N-atoms of one ligand and the
central N-bound atom of the second ligand being ∼360°
(plane in Cd((R,R)-5)2 = 360.1°, Cd((S,S)-6)2 = 360.0°. The bite-
angle of each ligand accounts for the largest deviation from
ideal (180°) octahedral, being 159.0° and 158.9°, respectively
for each complex with the bond angle between each bound iso-
indoline-N atom and the Cd centre being closer to ideal at
175.4° and 173.9°, respectively. Of note is the slight distortion
of the ideal 90° angle between each bound ligand, as defined
Fig. 2 Ortep diagrams of Cd((R,R)-5)2 (a) and Cd((S,S)-6)2 (b) deter-
mined by single crystal X-ray diffraction at 150 K and 120 K, respectively.
All atoms are shown at 30% probability with the exception of H-atoms
which are removed for clarity. Details of each analysis are found in
Table 1 and in the ESI.†
by a calculated plane containing each N-atom bound and the
Cd centre, being 82.0° and 82.2° for the smallest angle,
respectively for Cd((R,R)-5)2 and Cd((S,S)-6)2.
Ligand isolation
A major goal of the work was to prepare the chiral substituted
1,3-bis(4,5-dihydrooxazoline)isoindoline-based ligands in their
free, neutral form. As direct synthesis was not achieved in our
hands, attempts were directed to unbind the ligand from the
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