Enantiopure Ferrocene-Based Planar-Chiral Iridacycles: Stereospecific Control of Iridium-Centred Chirality

Article abstract of DOI:10.1002/chem.201504458

Reaction of [IrCp?Cl₂]₂ with ferrocenylimines (Fc=NAr, Ar=Ph, p-MeOC₆H₄) results in ferrocene C-H activation and the diastereoselective synthesis of half-sandwich iridacycles of relative configuration S_p?,R_Ir?. Extension to (S)-2-ferrocenyl-4-(1-methylethyl)oxazoline gave highly diastereoselective control over the new elements of planar chirality and metal-based pseudo-tetrahedral chirality, to give both neutral and cationic half-sandwich iridacycles of absolute configuration S_c,S_p,R_Ir. Substitution reactions proceed with retention of configuration, with the planar chirality controlling the metal-centred chirality through an iron-iridium interaction in the coordinatively unsaturated cationic intermediate.

Full text of DOI:10.1002/chem.201504458

DOI: 10.1002/chem.201504458
Full Paper
&
Organometallic Stereochemistry
Enantiopure Ferrocene-Based Planar-Chiral Iridacycles:
Stereospecific Control of Iridium-Centred Chirality
Ross A. Arthurs,[a] Muhammad Ismail,[a, b] Christopher C. Prior,[a] Vasily S. Oganesyan,[a]
Peter N. Horton,[c] Simon J. Coles,[c] and Christopher J. Richards*[a]
Abstract: Reaction of [IrCp*Cl2]2 with ferrocenylimines
(Fc=NAr, Ar=Ph, p-MeOC6H4) results in ferrocene CÀH acti-
vation and the diastereoselective synthesis of half-sandwich
iridacycles of relative configuration Sp*,RIr*. Extension to
(S)-2-ferrocenyl-4-(1-methylethyl)oxazoline gave highly dia-
stereoselective control over the new elements of planar
chirality and metal-based pseudo-tetrahedral chirality, to
give both neutral and cationic half-sandwich iridacycles of
absolute configuration Sc,Sp,RIr. Substitution reactions pro-
ceed with retention of configuration, with the planar
chirality controlling the metal-centred chirality through an
iron–iridium interaction in the coordinatively unsaturated
cationic intermediate.
Introduction
Transition-metal-derived cyclometallated complexes have
found many applications in catalysis, energy transfer, and bio-
medical science.[1] Of the many chiral non-racemic versions
known, those displaying planar chirality have two distinctive
features that make them especially attractive for further inves-
tigation. 1) Planar chirality may be obtained efficiently by
a one-step diastereoselective or enantioselective CÀH activa-
Scheme 1. Stereoselective CÀH activation as a route to non-racemic
ferrocene-based planar-chiral metallacycles.
tion reaction of, typically,
a ferrocene-based substrate
(Scheme 1).[2] 2) The metal introduced is then a direct compo-
nent of the new element of chirality, and as such, is in an envi-
ronment of pronounced asymmetry. Stereoselective CÀH acti-
vation/metallation has been utilised principally with palladium,
and the resulting planar-chiral palladacycles are highly enantio-
selective catalysts for a number of asymmetric organic transfor-
mations.[3] Extension of stereoselective CÀH activation to the
synthesis of other non-racemic planar-chiral metallacycles has,
to date, been limited to cyclomanganation,[4] cycloplatination[5]
and cyclomercuration.[6,7]
ligand of general structures 1a/b (Figure 1) have been the sub-
ject of many further investigations.[9] In particular, the recent
literature contains numerous reports on the application of
such iridacycle complexes to catalytic transformations,[10] in-
cluding reactive oxygen species generation for potential
cancer chemotherapy.[11] Non-racemic chiral derivatives are
known,[8,12] as exemplified by oxazoline and imidazoline deriva-
tives 2a/b[12f–h] and amine derivatives 3.[12a–e,h] These are
frequently obtained as mixtures of diastereoisomers, and the
absence of control of the iridium-based stereogenic centre
that this reveals is a key factor that has to date limited the
impact of these complexes as catalysts in asymmetric
synthesis.
First reported in 1998,[8] iridium(III) half-sandwich complexes
containing an h5-pentamethylcyclopentadienyl group (Cp*),
a CÀN bidentate ligand, and one further neutral or anionic
[a] R. A. Arthurs, Dr. M. Ismail, C. C. Prior, Dr. V. S. Oganesyan, Dr. C. J. Richards
School of Chemistry, University of East Anglia
Norwich Research Park, Norwich, NR4 7TJ (UK)
E-mail: Chris.Richards@uea.ac.uk
[b] Dr. M. Ismail
Current address: Department of Chemistry
Karakoram International University, University Road
Gilgit-15100 (Pakistan)
[c] Dr. P. N. Horton, Dr. S. J. Coles
EPSRC National Crystallography Service, School of Chemistry
University of Southampton, Highfield, Southampton, SO17 1BJ (UK)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504458.
Figure 1. Representative chiral iridacycle half-sandwich complexes.
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In this paper we report the synthesis of planar-chiral irida-
cycles by highly diastereoselective CÀH activation, with control
of the absolute configuration of planar chirality and iridium-
centred chirality.
Results and Discussion
Two methods are generally employed for the synthesis of half-
sandwich iridacycles from [IrCp*Cl2]2 by CÀH activation. Neutral
chloride-coordinated complexes 1a are obtained with NaOAc,
with ligand exchange generating an iridium-coordinated ace-
tate which participates in a concerted metallation-deprotona-
tion (CMD) pathway (method 1).[12f] Alternatively, addition of
NaOH and KPF6 in MeCN results in the formation of cationic
complexes 1b, with evidence from related reactions pointing
again to a CMD pathway via an iridium-coordinated hydroxide
intermediate (method 2).[13]
Scheme 3. Cycloiridation of ferrocenylimines 7a and 7b.
Starting with a prochiral ferrocene-based substrate 4a, appli-
cation of method 1 resulted predominantly in a-substitution to
give ester 5 (Scheme 2). In contrast, method 2 gave ferrocene-
1
carboxaldehyde 6 as the major product observed by H NMR
of the crude product mixture after workup.[14] Use of primary
amine 4b as the substrate with method 1 resulted in both a-
substitution and oxidation to give 5 and 6 in a 0.7:1 ratio. The
product obtained after workup by method 2 also contained 6,
1
with the H NMR spectrum also having several signals between
Figure 2. Representation of the X-ray structure of (Rp*,SIr*)-8a (hydrogen
atoms omitted for clarity). Principal bond lengths [Š] include: Ir(1)À
C(1)=2.045(10), Ir(1)ÀN(1)=2.107(9), Ir(1)ÀCl(1)=2.410(2), Ir(1)ÀCp* (centre
of mass)=1.824(5). Principal bond angles [8] include: N(1)-Ir(1)-C(1)=77.5(4),
Cl(1)-Ir(1)-C(1)=86.8(3), Cl(1)-Ir(1)-N(1)=82.5(2), N(1)-Ir(1)-Cp*=135.9(3),
C(1)-Ir(1)-Cp*=133.8(3).
7.48 and 8.65 ppm, consistent with
a primary aldimine
functionality (potentially metal-coordinated), although the
exact nature of these compounds could not be determined.
Imine 7b was also successfully cycloiridated to give 8b,
however changing from a para-methoxy to a para-nitro sub-
stituent with imine 7c resulted in no corresponding iridacycle,
but instead in the recovery of 7c and ferrocenecarboxaldehyde
(ratio 3:1). Thus, too great a reduction in the basicity of the
imine nitrogen likely correlates with reduced iridium coordina-
tion and no cycloiridation. The reaction of imine 7a using
method 2 resulted only in imine hydrolysis and recovery of
ferrocenecarboxaldehyde.
Scheme 2. Attempted cycloiridation of ferrocenylmethylamines.
In contrast to benzylamines, ferrocenylmethylamines are
clearly unsuitable as substrates for cycloiridation due to en-
hancement by the metallocene of a-substitution[15] or a-hydro-
gen abstraction. Thus increasing the oxidation level with the
use of imine substrates 7a–c was attempted next (Scheme 3).
Application of the NaOAc conditions (method 1) with 7a re-
sulted in the generation of a single new species identified as
Asymmetric synthesis of planar-chiral iridacycles
One method that may be used to control the absolute config-
uration of planar chirality generation is auxiliary-controlled dia-
stereoselective CÀH activation.[2,16] Ferrocenyl oxazoline 9,
readily derived from (S)-valine, has been demonstrated to un-
dergo highly diastereoselective a-lithiation[17] and a-pallada-
tion.[18] Following the reaction of 9 with [IrCp*Cl2]2, KPF6 and
an excess (four equivalents with respect to 9) of NaOH for
18 h, a new complex was isolated by column chromatography
(Scheme 4, Table 1, entry 1).
1
an iridacycle by there being three signals in the H NMR spec-
trum for the substituted cyclopentadienyl ring (at 4.61, 4.65,
and 4.76 ppm), the change from 8.34 to 8.15 ppm of the imine
proton signal, and the correspondence by integration of these
signals to the Cp (4.12 ppm) and Cp* (1.59 ppm) singlets.
Recrystallisation led to an X-ray structure analysis which con-
firmed the iridacycle structure of 8a, and revealed the relative
configuration as Rp*,SIr* (Figure 2).
In addition to the characteristic signals of a half-sandwich iri-
1
dacycle, its H NMR spectrum contained two doublets (1H, J=
15.0 Hz) at 1.27 and À0.06 ppm. Following recrystallisation, X-
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Scheme 4. Cycloiridation of ferrocenyl oxazoline 9 (method 2).
Table 1. Cycloiridation of ferrocenyl oxazoline 9.
Figure 3. Representation of the X-ray structure of (S,Sp,RIr)-10 (hydrogen
atoms omitted for clarity). Principal bond lengths [Š] include: Ir(1)À
C(1)=2.056(6), Ir(1)ÀN(1)=2.093(5), Ir(1)ÀC(31)=2.127(7), Ir(1)ÀCp* (centre
of mass)=1.844(3). Principal bond angles [8] include: N(1)-Ir(1)-C(1)=77.8(2),
C(1)-Ir(1)-C(31)=81.5(2), N(1)-Ir(1)-C(31)=83.5(2), N(1)-Ir(1)-Cp*=137.05(17),
C(1)-Ir(1)-Cp*=132.93(18).
Entry
Base
Equiv
Product
Yield [%]
1
2
3
4
5
NaOH
NaOH
NaOH
KOtBu
KOtBu
4
2
1
1
2
10[a]
10/11[c]
11
11
11[g]
45[b]
n.d.
51[d,e]
63[d,f]
19[d,h]
sulted in the isolation of a small quantity of this second irida-
cycle in addition to 9 and 10 (Table 1, entry 2). With one equiv-
alent of NaOH, this new iridacycle was formed as the major
product, allowing isolation by chromatography on alumina
with acetonitrile as the eluent. It was identified as the expect-
ed acetonitrile ligated complex 11, and further analysis re-
vealed that this was isolated with a second cationic iridacycle
in a ratio of 7:1 (entry 3). Replacing very hygroscopic NaOH
with KOtBu improved the practicality of the procedure, and
with one equivalent of this base, the cationic iridacycle 11 was
formed in good yield in a 20:1 ratio with the same second
complex (entry 4). This ratio increased to 100:1 with two equiv-
alents of KOtBu, albeit with a reduction in overall yield
(entry 5). The conversion of 11 into 10 was also demonstrated
by the reaction of the former with one equivalent of NaOH in
acetonitrile (Scheme 4).
[a] Ratio of 9/10 in mixture prior to purification=1:1.7. [b] Isolated by
column chromatography (SiO2). [c] Ratio 9/10/11=1:1:0.1. [d] Isolated by
column chromatography (Al2O3). [e] Isolated as a 7:1 mixture of isomers.
[f] Isolated as
a 20:1 mixture of isomers. [g] Ratio 9/10=1:0.26.
[h] Isolated as a 100:1 mixture of isomers. n.d.=not determined.
1
ray crystal structure analysis revealed that these H NMR sig-
nals arise from the diastereotopic geminal hydrogen atoms of
the metal-ligated cyanomethyl component of neutral iridacycle
10 (Figure 3). This is one of the four possible diastereoisomers
that may be formed on cycloiridation, for which the two new
elements of chirality are Sp,RIr. No other iridacycle species were
1
observed by H NMR spectroscopic examination of the crude
reaction product prior to chromatography.
The use of NaOAc as the base in CH2Cl2 (i.e., method 1) re-
sulted in partial formation of the chloride-ligated iridacycle 12,
and even the use of excess [IrCp*Cl2]2 and NaOAc led to the
isolation of 12 containing a small quantity of starting material
(Scheme 5). In contrast to neutral cyanomethyl congener 10,
chloride-ligated 12 could not be purified by chromatography
on either SiO2 or Al2O3 due to the formation of an intense blue
colour and decomposition (vide infra).
The Sp planar-chiral configuration of 10, in which the isopro-
pyl group of the oxazoline is orientated towards ferrocene, is
the same sense of diastereoselectivity observed previously on
metallation.[17,18] For lithiation, kinetic control is rationalised by
the approach of the nitrogen-coordinated alkyl lithium reagent
opposite both the FeCp component of the metallocene and
the isopropyl group of the rotatable oxazoline.[17b,19] By exten-
sion, the Sp configuration of 10 is also the result of kinetic
control, cycloiridation proceeding through the exo approach of
a nitrogen-coordinated iridium species.
Complexes with
a diastereomeric relationship to 10,
containing the opposite configuration of planar chirality, were
synthesised following prior introduction of a methyl or trime-
thylsilyl blocking group. Ferrocenyl oxazolines 13a/b were syn-
thesised from 9 by highly diastereoselective lithiation followed
by addition of MeI or TMSCl (TMS=trimethylsilyl).[17b,d] Subse-
quent cycloiridation with excess NaOH gave neutral complexes
14a/b (Scheme 6), and the structure and stereochemistry of
the latter product were confirmed by X-ray crystallography
(Figure 4). That this was formed by selective CÀH over CÀSi ac-
tivation is consistent with cycloiridation proceeding via a CMD
The cyanomethyl ligand points to the intermediacy in the
reaction of a precursor cationic acetonitrile-ligated iridacycle,
as other examples of cyanomethyl-ligated transition metal
complexes have been obtained by acetonitrile deprotonation
and ligand flip.[20,21] Repeating the reaction that gave 10, and
1
following by H NMR spectroscopy, revealed a second iridacy-
cle species that disappeared after 18 h. Reducing the NaOH
quantity in the cycloiridation reaction to two equivalents re-
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the proximity of the ferrocene Cp and iridium Cp* groups (see
the Supporting Information). This proximity is also the case in
the minor isomer formed with 11 on cycloiridation (Table 1, en-
tries 3–5), revealing that this contains a different element of
planar chirality [major (11)=S,Sp,RIr, minor=S,Rp,SIr]. These
data, obtained from all the NOESY experiments, are consistent
with the absence of chiral-at-iridium epimers, and no signifi-
cant differences were observed in a series of variable-tempera-
1
Scheme 5. Cycloiridation of ferrocenyl oxazoline 9 (method 1).
ture H NMR experiments with 11 in CD3CN between À408C
and +408C. These observations are also consistent with the
absence of chiral-at-iridium epimers, assuming that these
would give rise to different signals and that the percentage of
a minor isomer is not too small.
pathway. The alternative CÀSi over CÀH activation, as observed
for the palladation of trimethylsilyl arenes, is attributed to an
electrophilic cyclometallation pathway.[22]
Conversion of 11 into 10 proceeds with the retention of
configuration. Further investigation of the stereochemistry of
ligand substitution (Scheme 7) started with the observation
that dissolution of brown/orange 11 (d.r.=20:1) in dichlorome-
thane resulted in an intense blue solution (lmax ꢀ640 nm). Ad-
dition to this of triphenylphosphine resulted in immediate
quenching of the intense colour and the formation of orange
adduct 16 (d.r.=20:1; a video of this sequence is available in
the Supporting Information). Following isolation, the iridium-
based stereochemistry was again established by a NOESY ex-
periment, and following recrystallisation, confirmed by X-ray
crystallography (Figure 5). Thus, dissolution of 11 in dichloro-
methane, a weakly coordinating solvent, results in what is es-
sentially a coordinatively unsaturated cationic complex 15,
with phosphine addition occurring with overall retention of
configuration (Scheme 7).[23,24] Two structures of 16 are present
in the unit cell that differ in the configuration of the coordinat-
ed phosphine. The M isomer is represented in Figure 5.[25] Inter-
conversion of the M/P isomers appears to be rapid at room
Scheme 6. Cycloiridation of presubstituted ferrocenyl oxazolines 13a/b.
1
temperature, as the H and 31P NMR spectra of 16 obtained by
recrystallisation each contain only a single set of signals.[26]
Following dissolution of a further batch of 11 (d.r.=20:1) in
dichloromethane, addition of tetrabutylammonium chloride
(TBAC) again resulted in an immediate change in colour to
orange (see Supporting Information), followed by isolation of
the crude chloride adduct 12. Due to broad signals in the
1H NMR spectrum of this compound, the diastereomeric purity
was not clear. Addition to 12 of KPF6 in acetonitrile reformed
11 with a d.r. of 20:1, revealing no overall stereochemical leak-
age. Addition of KPF6 in acetonitrile to 12 derived from cyclo-
iridation with NaOAc as base (Scheme 5) gave 11 with a d.r. of
Figure 4. Representation of one of the two different conformations of the
X-ray structure of (S,Rp,SIr)-14b (hydrogen atoms and hexane solvent of
crystallisation omitted for clarity). Corresponding values for the second
conformation are given in parentheses. Principal bond lengths [Š] include:
Ir(1)ÀC(1)=2.053(10) [2.043(9)], Ir(1)ÀN(1)=2.095(8) [2.122(8)], Ir(1)À
C(41)=2.135(11) [2.141(9)], Ir(1)ÀCp* (centre of mass)=1.849(4) [1.847(7)].
Principal bond angles [8] include: N(1)-Ir(1)-C(1)=76.3(4) [77.3(4)], C(1)-Ir(1)-
C(41)=83.1(4) [81.9(4)], N(1)-Ir(1)-C(41)=84.5(4) [83.9(4)], N(1)-Ir(1)-
Cp*=133.5(3) [134.9(3)], C(1)-Ir(1)-Cp*=134.7(3) [133.7(3)].
The X-ray structures of 8a, 10 and 14b reveal, respectively,
Rp*,SIr*, Sp,RIr and Rp,SIr relationships between the planar and iri-
dium-centred elements of chirality, such that the Cp* group is,
in all cases, oriented towards the h5-cyclopentadienyl group of
the metallocene. That this iridium-based configuration is main-
tained in solution, and is also present in iridacycles 8b, 11 and
14a, was established by NOESY experiments which revealed
Scheme 7. Stereospecific substitution at iridium via intermediate 15.
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Figure 6. Representations of the minimised structures of 8a, 17 and 18
(from left to right, hydrogen atoms omitted for clarity).
Table 2. Selected bond lengths and bond angles of computed iridacycles
8a, 17 and 18.
Parameter[a]
(Rp*,SIr*)-8a
(Rp*,RIr*)-17
Cation 18
Figure 5. Representation of the X-ray structure of (S,Sp,RIr,M)-16 (hydrogen
atoms, hexafluorophosphate anion and CDCl3 solvent of crystallisation
omitted for clarity). Corresponding values for (S,Sp,RIr,P)-16 are given in par-
entheses. Principal bond lengths [Š] include: Ir(1)ÀC(1)=2.082(7) [2.077(7)],
Ir(1)ÀN(1)=2.127(5) [2.138(6)], Ir(1)ÀP(1)=2.3173(18) [2.3144(18)], Ir(1)ÀCp*
(centre of mass)=1.885(3) [1.879(3)]. Principal bond angles [8] include:
N(1)-Ir(1)-C(1)=77.2(2) [77.0(3)], C(1)-Ir(1)-P(1)=84.7(2) [86.4(2)], N(1)-Ir(1)-
P(1)=89.39(18) [88.45(18)], N(1)-Ir(1)-Cp*=129.03(18) [131.4(2)], C(1)-Ir(1)-
Cp*=131.0(2) [129.7(2)].
IrÀFe
3.882
2.124
2.034
1.861
136.0
135.6
3.874
2.140
2.036
1.856
2.1
3.269
2.117
1.986
1.854
137.5
139.2
IrÀN
IrÀC (CpFe)
IrÀCp*[b]
NÀIrÀCp*[b]
CÀIrÀCp*[b]
130.2
[a] Distances [Š]; angles [o]. [b] To the centre of mass of the h5-ligand.
substituted cyclopentadienyl ring, and a shorter IrÀC(Cp) bond
length. The iridium–iron bonding parameter of 1.25 in the
cationic complex 18 is significantly greater than the value
determined for the two chloride diastereoisomers (Table 3).
Furthermore, the calculated Mulliken charges reveal a partial
delocalisation onto iron for the cation 18 (Table 4). The iron–
iridium interaction is illustrated in Figure 7, highlighting the
significance of the unsaturated cyclopentadienyl carbon to
which both iron and iridium are attached.
approximately 3:1. Thus, this cycloiridation method is sig-
nificantly less selective than those employing NaOH or KOtBu.
Computational studies
A computational investigation was undertaken to determine
the relative energies of diastereoisomers containing planar and
chiral-at-metal elements of chirality, and to further investigate
the nature of a coordinatively unsaturated iridium complex.
For the former, (Rp*,SIr*)-8a was compared to its corresponding
Rp*,RIr* diastereoisomer 17, and for the latter, chloride-abstract-
ed complex 18 was studied. All calculations were performed
by using the Gaussian 09 set of programs[27] and employing
the Tao–Perdew–Staroverov–Scuseria (TPSS)[28] functional. Iridi-
um, iron and chlorine atoms were described using the
LAN2LDZ basis set and effective core potential,[29,30] with all
other atoms being described with the all electron 6-31+G**
basis set.[31] All structures were optimised in the gas phase and
confirmed as minima by frequency analysis with thermody-
namic properties extracted for the gas phase at 298.15 K and
1 atm. Bonding parameters between different pairs of atoms
were calculated as the absolute values of the associated non-
diagonal elements of the condensed to atoms electron density
matrix. (Figure 6, Tables 2–4).
As a consequence, the vacant iridium-based orbital into
which a nucleophile adds is oriented away from the iron atom
of the ferrocene moiety, resulting in stereospecific addition
(Figure 8, Scheme 8). The microreversibility principle requires
that loss of a nucleofuge occurs along the same trajectory,
such that substitution occurs with overall retention of configu-
ration (this may also be described as a double inversion
The minimum energy structure obtained for 8a is very simi-
lar to that determined by X-ray crystallography. This study re-
vealed that the Rp*,RIr* diastereoisomer 17 is lower in energy
by approximately 2 kcalmolÀ1 than the Rp*,SIr* diastereoisomer.
Thus, the generation of this latter observed complex is clearly
not under thermodynamic control. Compared to these two
chloride adducts, the cationic complex 18 has a notably short-
er FeÀIr distance of 3.269 Š (Table 2), which arises from a tilt of
iridium towards iron of 20.88 with respect to the plane of the
Figure 7. Representation of the iron–iridium interaction in 18.
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blue or purple cationic complexes reveal tilting towards the
iron of the a-carbon, with FeÀC(a) distances varying between
2.957 and 2.567 Š.[32] The double-bond character of C(1)ÀC(a)
slows its rotation, which would otherwise result in
racemisation. Stereospecific addition of a nucleophile results in
the formation of 22, typically with overall retention of
configuration.[15]
Table 3. Selected iridium bonding parameters of iridacycles 8a, 17 and
18.
Bonding parameter for Ir
(Rp*,SIr*)-8a
(Rp*,RIr*)-17
Cation 18
IrÀFe
IrÀCl
0.4
0.9
0.62
0.72
1.25
n/a
n/a=not applicable.
Table 4. Selected Mulliken partial charges of iridacycles 8a, 17 and 18.
Mulliken partial charge
(Rp*,SIr*)-8a
(Rp*,RIr*)-17
Cation 18
Ir
Fe
À0.3450
À1.7807
À0.4512
À1.7037
0.6573
À1.5852
Scheme 9. Stereospecific a-substitution via a configurationally stable
a-ferrocenyl carbenium ion.
pathway). The cationic complex 18 is much more similar in
structure to (Rp*,SIr*)-8a than diastereomeric (Rp*,RIr*)-17, as re-
vealed by comparison of the NÀIrÀCp* and CÀIrÀCp* bond
angles (Table 2). This similarity is also apparent by comparison
of the representations of the iridium-based LUMO of 18 with
the IrÀCl bonding orbital in 8a (Figure 8).
The formation solely of (Rp*,SIr*)-8a and (Sp,RIr)-10 (and by
extension (Rp,SIr)-14a/b) on cycloiridation may also be ex-
plained, in part, by the intermediacy of a cationic coordinative-
ly unsaturated complex of general structure 19. The proposal
that acetate-promoted cycloiridation (method 1) proceeds
through the initial formation of an iridium-coordinated acetic
acid complex, followed by ligand exchange,[12f,33] requires the
intermediacy of cation 19 for the complexes synthesised in
this work (Scheme 10). A similar water or tBuOH-coordinated
intermediate likely results from the use as base of hydroxide or
tert-butoxide, respectively. The alternative relative stereochem-
istry (Rp*,RIr*) could also be set during CÀH activation, and
from such an initial structure the formation of 19 would likely
be slower,[34] but that chloride or acetonitrile complexes are
isolated does require ligand substitution to have occurred.
Thus, the configuration at iridium is set by the kinetic
preference for exo ligation due to the IrÀFe interaction in the
coordinatively unsaturated precursor.
Iridium-centred substitution reactions, via a generalised in-
termediate of structure 19 (Scheme 8), are related to the sub-
stitution reactions of compounds containing a carbon-based
stereogenic centre where one of the substituents is a ferrocenyl
group (e.g., 20; Scheme 9). Here, stereospecific loss of the nu-
cleofuge generates an intermediate a-ferrocenyl carbenium
ion 21. X-ray structure determinations of a number of these
Scheme 8. Stereospecific substitution in planar-chiral iridacycles.
Scheme 10. Components of the cycloiridation pathway to give 19.
It is of note that the relative stereochemistry of all known
(racemic) chromium tricarbonyl h6-arene-based metallacycles
containing IrCp* (e.g., 23) or RhCp* (e.g., 24) are also exclu-
sively Rp*,SIr* (Figure 9),[35,36] and that, in the iridium series,
stereospecific substitution has been established through the
dissociative formation of a chromium-stabilised cationic inter-
mediate.[35b] Complexes 23 and 24 were synthesised from
[Cp*MCl2]2 by CÀH activation with sodium acetate. The stereo-
chemistry is accounted for by the thermodynamic preference
for the observed diastereoisomer by the avoidance of an un-
Figure 8. Representations of the iridium-based LUMO of 18 (left) and the
IrÀCl bonding orbital in 8a (right).
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this point the liquid was decanted off and the solids washed with
hexane. The decantation and washings were combined and the
solvent removed in vacuo. The resulting solid was rinsed with ice-
cold hexane and dried on a high vacuum line to give a maroon
solid (0.111 g, 71%). The sample for X-ray analysis was obtained by
crystallisation from CDCl3/hexane:[40] M.p. 68.0–72.28C; 1H NMR
(500 MHz, CDCl3): d=8.15 (s, 1H, HC=N), 7.38 (t, J=7.8 Hz, 2H, m-
PhH), 7.32–7.28 (m, 2H, o-PhH), 7.25–7.23 (m, 1H, p-PhH), 4.76 (bs,
1H, CpH), 4.65 (bs, 1H, CpH), 4.61 (bs, 1H, CpH), 4.12 (s, 5H, C5H5),
1.59 ppm (s, 15H, 5”CH3); 13C NMR (125 MHz, CDCl3) d=175.9 (C=
N), 152.9 (ipso-PhC), 128.9 (m-PhC), 126.8 (p-PhC), 122.3 (o-PhC),
98.7 (CpC-Ir), 91.6 (CpC-C=N), 89.0 (C5Me5), 73.5 (CpC), 73.1 (CpC),
68.8 (C5H5), 66.9 (CpC), 9.4 ppm (CH3); IR (film): v˜ =3071, 2983,
2911, 1556, 1454; HRMS (AS) m/z calcd for C27H30ClFeIrN: 652.1033
[M+H]+; found: 652.1036; elemental analysis calcd (%) for
C27H29ClFeIrN: C 49.81, H 4.49, N 2.15; found: C 50.01, H 4.59, N
2.25.
favourable dipolar interaction between the chloride ligand and
the Cr(CO)3 group that would be present in the Rp*,RM* epi-
mers. Given that no such thermodynamic preference exists in
the ferrocene examples of this work, an alternative explanation
is that the metal-based configuration is, in all these cases,
a consequence of stereoelectronic kinetic control of ligand
coordination.
Figure 9. Known h6-arene/Cr(CO)3-based Cp*-containing metallacycles.
Acknowledgements
Conclusions
The AI-Chem Channel (R.A.A.) and the Higher Education Com-
mission Pakistan (M.I.) are thanked for financial support. We
also thank the EPSRC National Mass Spectrometry Centre (Uni-
versity of Wales, Swansea). V.S.O. and C.C.P. wish to thank the
Research Computing Service at the University of East Anglia
for access to the High Performance Computing Cluster.
Cycloiridation with [Cp*IrCl2]2 of ferrocenylimines successfully
results in CÀH activation and formation of an iridacycle, avoid-
ing the oxidation or substitution reactions observed with ferro-
cenylmethylamines as substrates. Only a single diastereoisomer
of the product iridacycle is observed with respect to the new
planar-chiral and chiral-at-metal stereochemical elements. Ex-
tension to cycloiridation of an enantiopure (S)-valine-derived
ferrocenyl oxazoline results in highly selective formation of
one of the four possible diastereoisomers of absolute configu-
ration S,Sp,RIr. Related S,Rp,SIr configured complexes were syn-
thesised by use of a methyl or TMS blocking group. This first
report on the synthesis of enantiopure planar-chiral iridacycles
reveals also that the configuration of iridium-centred chirality
is controlled by a stereoelectronic effect, a consequence of
iron–iridium interaction in the coordinatively unsaturated cat-
ionic complex formed on ligand dissociation. Catalysts based
on chiral-at-metal complexes are attractive, as the metal, which
is usually intimately involved in the catalytic pathway, is central
to the chirality.[37] However, control of the absolute configura-
tion in pseudo-tetrahedral complexes has proven to be a signif-
icant challenge.[38,39] This work provides a solution through
iron–iridium-mediated stereospecific ligand substitution, and
highly stereoselective control of planar chirality.
Keywords: chirality · enantioselectivity · ferrocene · iridacycle ·
stereoselectivity
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À
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For (P)-16 the corresponding values are À6.5, À82.3 and 59.48.
Received: November 5, 2015
Published online on January 25, 2016
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim