Iridium-Catalyzed Acid-Assisted Hydrogenation of Oximes to Hydroxylamines

Article abstract of DOI:10.1002/anie.202103806

We found that cyclometalated cyclopentadienyl iridium(III) complexes are uniquely efficient catalysts in homogeneous hydrogenation of oximes to hydroxylamine products. A stable iridium C,N-chelation is crucial, with alkoxy-substituted aryl ketimine ligand

Full text of DOI:10.1002/anie.202103806

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Iridium-Catalyzed Acid-Assisted Hydrogenation of Oximes to
Hydroxylamines
Authors: Nicolai Cramer, Josep Mas-Roselló, Christopher J. Cope, Eric
Tan, Benjamin Pinson, Alan Robinson, and Tomas Smejkal
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202103806
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10.1002/anie.202103806
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RESEARCH ARTICLE
Iridium-Catalyzed Acid-Assisted Hydrogenation of Oximes to
Hydroxylamines
Josep Mas-Roselló,[a] Christopher J. Cope,[b] Eric Tan,[b] Benjamin Pinson,[b] Alan Robinson,[b] Tomas
Smejkal,*[b] and Nicolai Cramer*[a]
[a]
[b]
Dr. J. Mas-Roselló, Prof. Dr. N. Cramer
Laboratory of Asymmetric Catalysis and Synthesis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL),
Lausanne, Switzerland.
E-mail: nicolai.cramer@epfl.ch
C. J. Cope, Dr. E. Tan, B. Pinson, Dr. A. Robinson, Dr. T. Smejkal
Process Chemistry Research, Syngenta Crop Protection AG, Schaffhauserstrasse 101, 4332 Stein AG, Switzerland.
Supporting information for this article is given via a link at the end of the document.
Abstract: We found that cyclometalated cyclopentadienyl iridium(III)
complexes are uniquely efficient catalysts in homogeneous
hydrogenation of oximes to hydroxylamine products. A stable iridium
C,N-chelation is crucial, with alkoxy-substituted aryl ketimine ligands
providing the best catalytic performance. Several Ir-complexes were
mapped by X-ray crystal analysis in order to collect steric parameters
that might guide a rational design of even more active catalysts. A
broad range of oximes and oxime ethers were activated with
stoichiometric amounts of methanesulfonic acid and reduced at room
temperature, remarkably without cleavage of the fragile N-O bond.
The exquisite functional group compatibility of our hydrogenation
system was further demonstrated by additive tests. Experimental
mechanistic investigations support an ionic hydrogenation platform,
and suggest a role for the Brønsted acid beyond a proton source. Our
studies provide deep understanding of this novel acidic hydrogenation
and may facilitate its improvement and application to other
challenging substrates.
agrochemicals, as well as natural products.[6] Additionally
hydroxylamine
derivatives
are
versatile
synthetic
intermediates,[6c,7a-c] powerful ligands[7d,e] and catalysts.[7f]
Introduction
The catalytic hydrogenation using homogeneous metal catalysts
is among the most important transformations in organic
synthesis.[1] At industrial level, it became the cornerstone of
sustainable manufacturing for both bulk and fine chemical
intermediates.[2] Those include, for example, unsaturated alkene,
ketone and imine functionalities which are reduced to their
corresponding saturated products (Scheme 1A).[3] The use of
widely available hydrogen gas as cost-efficient reductant and
typically low catalyst loadings render this process economical and
efficient. In this regard, the development of enabling catalysts,
most frequently represented by phosphine-ligated late transition-
metals (e.g. Rh, Ru, Ir, Pd), has been crucial.[4] However, several
ubiquitous functional groups, like oximes, remain refractory to
hydrogenation using typical homogeneous catalysts. Oxime
substrates are less reactive, and when reactivity is observed,
over-reduction by cleavage of the rather labile N‒O bond
produces primary amine products instead of hydroxyl amines.[5]
This is in many instances not desirable, as the hydroxylamine
motif is valuable and present in many pharmaceuticals,
Scheme 1. Catalytic homogeneous hydrogenations of oximes to hydroxylamine
products.
Hence,
hydroxylamines via
a
generally applicable synthesis of N-alkyl-N-
catalytic chemoselective oxime
a
hydrogenation is highly desirable. To the best of our knowledge,
the two reported methods describing such a process, are both
limited regarding the oxime substrate substitution pattern
(Scheme 1B). In 2007, Kadyrov et al. reported a homogeneous
hydrogenation of β-oxime esters employing phosphine rhodium
and iridium catalysts under high pressure of hydrogen gas.[8] This
substrate type easily tautomerizes to 2,3-unsaturated esters,
1
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10.1002/anie.202103806
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RESEARCH ARTICLE
therefore the described oxime hydrogenation reaction may be
more appropriately described as a C=C double bond reduction. In
2014, Oestreich et al. disclosed a FLP-catalyzed hydrogenation
ligand exchange was detected with one equivalent of 2a instead,
which seemed to be a less competent ligand than 1a.
The dissociation of the diamine ligand of Ir1a or Ir1b should be
further enhanced during catalysis (significantly higher
concentration of acid relative to the iridium catalyst). In fact,
of oxime derivatives using
a tris(pentafluorophenyl)borane
catalyst.[9] This method is limited to oxime ethers bearing very
bulky O-substituents (tBu or Si(iPr)3) and requires high catalyst
loading of 5-10 mol%.
conducting the reduction of 1a with
1 mol% of 'naked'
Cp*Ir(H2O)3(SO4) complex afforded 2a in 90% yield (Scheme 2C).
The substrate ability of in situ chelation to iridium forming Ir2
seemed relevant. For instance, no reduced product 2b was
detected when acetophenone-derived oxime E-1b lacking the β-
hydroxyl group was subjected to identical hydrogenation
conditions. As well, adding catalytic amounts of 1a as ligand
proved ineffective. Having the aim to generalize the reduction of
oxime substrates without additional coordinating groups, we
decided to further investigate the importance of iridium chelation
with auxiliary ligands.
Very recently, we disclosed the development of cyclometalated
CpXIr(III) methanesulfonate complexes, and demonstrated their
efficiency in unique enantioselective hydrogenations of oximes to
hydroxylamines under acidic conditions.[10a,b] Herein we present a
full account on these developments leading to the discovery of an
active hydrogenation catalyst (Scheme 1C). Several novel
catalyst derivatives are disclosed and compared in terms of their
catalytic efficiency. In addition, we include an extended oxime
substrate scope, further expanding the generality of the method.
Finally, some insights on the reaction mechanism are provided in
order to foster understanding of this concept of “acid-assisted
ionic hydrogenation” with the goal to facilitate its application to
other classes of challenging substrates.
Results and Discussion
Our efforts were initiated by the hydrogenation of β-hydroxyl
acetone oxime ether 1a (a mixture of E and Z isomers) to access
2-(methoxyamino)propan-1-ol (2a)[10d] (Scheme 2A). Considering
the complete lack of activity and selectivity of several conventional
catalysts (Rh, Ru, Ir, Pt with phosphorous-based ligands) toward
oxime hydrogenation,[10c] we took inspiration in successful
heterogeneous variants using Pt/H2 with super-stoichiometric
amounts of acid.[11] We hypothesized that activation of the oxime
substrate by protonation could be essential for reactivity. Due to
the low basicity of oximes with a pKa that is approximately 5 units
lower than the one of imines,[12a-c] a much stronger Brønsted acid
would be required for protonation. Moreover, the strongly acidic
conditions would prevent the nitrogen lone pair of the formed
hydroxyl amine from coordination and eventually poisoning the
transition metal catalyst.
We turned our attention to Cp*Ir(III) diamine complexes,
exemplified by Ir1a, which were previously successful for ketone
and imine hydrogenations in acidic media.[13] Pleasingly, treating
1a with 1 mol% of Ir1a, 1.5 equivalents of methanesulfonic acid
(MsOH) and 50 bar of H2 pressure in trifluoroethanol (TFE)
afforded desired methoxyamine 2a in quantitative yield at room
temperature (Scheme 2A). In stark contrast, only trace amounts
of 2a were detected in the absence of MsOH. In fact, at least
stoichiometric amounts of acid with respect to the oxime substrate
is required for complete conversion (vide infra). A striking
observation was the lack of any enantioselectivity in the reaction.
This prompted us to investigate the role of the chiral N,N-diamine
ligand. We thus conducted stoichiometric proton and 19F-NMR
studies in CD3OD using complex Ir1b,[13d] bearing a fluorinated
sulfonamide moiety as beacon (Scheme 2B) (see SI for full
details). After addition of one equivalent of MsOH, partial
dissociation of diamine ligand 3 from the iridium center was
observed. Decomposition of Ir1b was further enhanced upon
addition of one equivalent of β-hydroxyl oxime substrate 1a,
presumably forming the N,O-ligated complex Ir2. No similar
Scheme 2. Preliminary catalyst identification and reactivity studies. General
conditions: 2 mmol 1, 3 mmol MsOH, 20 µmol [Ir] in TFE (2 mL) at 23 °C for
3 h; yield of 2 determined by 1H-NMR using 1,3,5-trimethoxybenzene as
internal standard, and equals the conversion of the oxime starting material.
Synthesis of the catalyst library
Concerning the design aspects, we targeted half sandwich Ir(III)
complexes having a stable capping Cp* ligand, a lower aryl
ketimine C,N-chelating unit, and a displaceable (pseudo)halide
ligand (Scheme 3). These well-defined iridacycles have been
shown by Xiao and others to be effective catalysts for related
imine
dehydrogenation
hydrogenation,
other
catalytic
oxidations,
hydrogenations,
and hydro-
reactions,
functionalization reactions.[14] To test them towards oxime
hydrogenations, a series of complexes Ir4a-Ir4h were prepared
by cyclometalation of different iminoarenes 4a-4h with [Cp*IrCl2]2,
using a slightly modified version of the method originally reported
2
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10.1002/anie.202103806
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RESEARCH ARTICLE
by Davies.[15a,b] In a second step, methanesulfonate containing
derivatives Ir4a-Ir4h were accessed from Ir3a-Ir3h by salt
metathesis with silver methanesulfonate. Conveniently, all shown
high oxidation state 18-electron iridium(III) complexes were stable
to air and moisture, hence their handling and storage does not
require the use of sophisticated equipment.
2) the N-donor functionality; 3) the metalated aromatic ring.
Regarding the pendant imine C-substituent, removal of the methyl
substituent of Ir4a to generate p-methoxybenzaldehyde derivative
Ir4b is detrimental (entries 7 vs 8). In contrast, Ir4c featuring a
novel benzophenone-derived scaffold performed better (entries 7
vs 9). We rationalize this by the increased stability of the higher
substituted ketimine ligands. The geometry of their chelate (e.g.
bite angle) appeared to have less impact in catalytic performance.
For instance, Ir4d having a more rigid cyclic tetralone-derived
backbone displayed marginally superior activity than Ir4a (entries
7 vs 10). Therefore, the simpler acetophenone backbone of the
later was deemed as the best compromise for subsequent studies.
Table 1. Reaction optimization and catalyst screening studies.[a]
Entry
1
Complex
Ir4a
mol% Cat.
1.0
Solvent
TFE
% Yield[b]
>99
>99
>99
91
2
Ir4a
1.0
iPrOH
3
Ir4a
0.5
iPrOH
4
Ir4a
0.5
2-MeTHF
toluene
OC(OMe)2
iPrOH
5
Ir4a
0.5
95
Scheme 3. General synthesis of the cyclometalated Cp*M(III) complexes (M =
Rh, Ir) used for this study. Overall isolated yields are shown for each complex.
6
Ir4a
0.5
97
7
Ir4a
0.1
45
Reaction
development
and
structure-performance
8
Ir4b
Ir4c
0.1
iPrOH
13
relationship studies of the C,N-ligands
9
0.1
iPrOH
61
Continuing with our studies towards the reduction of oxime E-1b,
we investigated cyclometalated Cp*Ir(III) complexes Ir4 as
catalysts in the transformation (Table 1). Previous studies
regarding imine hydrogenations had shown that complexes
bearing alkoxy-substituted aryl ketimine chelates, such as the p-
10
11
12
13
14
15
Ir4d
Ir4e
0.1
iPrOH
48
0.1
iPrOH
32
Ir4f
0.1
iPrOH
55
methoxyacetophenone-derived
4a,
displayed the
best
activities.[14c,e] To our delight, 2b was quantitatively formed after
exposure of 1b to 1 mol% of Ir4a, 1.5 equivalents of MsOH and
50 bar of H2 pressure in TFE as solvent (entry 1). Most remarkably,
the transformation proceeded without detectable cleavage of the
N-O bond. Having identified a performing catalyst class, other
solvents were tested in the reaction. At an even lower 0.5 mol%
catalyst loading, a quantitative yield of 2b was maintained in
cheaper and more sustainable iPrOH, (entries 2 and 3). Aprotic
solvents, such as 2-MeTHF, toluene, or dimethyl carbonate, are
also suitable, reaching excellent levels of reactivity (>90% yield)
(entries 4-6). Nevertheless, simple alcoholic solvents are in
general superior. Using as low as 0.1 mol% of Ir4a in iPrOH
afforded 2b in 45 % yield (450 TON) (entry 7). This reaction set-
up was considered optimal for testing and comparing the catalytic
efficiency of different complexes Ir4a-Ir4h. The results are
summarized in entries 8-14 of Table 1. To gain insights into the
ligand structure-performance relationship, stereoelectronic
modifications were performed at three different subunits of the
aryl-imine ligand architecture: 1) the pendant imine C-substituent;
Ir4g
Ir4h
Rh4a
0.1
iPrOH
61
0.1
iPrOH
28
1.0
iPrOH
<5
[a] Conditions: 0.30 mmol 1, 0.45 mmol MsOH, indicated loading of complex
in solvent (0.3 mL) at 23 °C for 3 h (entries 1-6) or 16 h (entries 7-14); [b] yield
determined by 1H-NMR using 1,3,5-trimethoxybenzene as internal standard,
being equal to the conversion of the oxime starting material unless otherwise
stated.
The stereoelectronic properties of the metalated aromatic ring are
expected to have a major impact on the catalyst performance, in
terms of iridacycle stability and Ir-hydride nucleophilicity.[15d] In our
preceding publication we found that ortho alkoxy substituents had
a positive influence.[10a] Alkoxy and fluoro groups placed ortho to
the metalated carbon may provide extra stabilization to the
carbon-metal bond.[16] Being aware that ortho-alkoxy
acetophenone-derived ligands present regioselectivity issues in
their complexation to iridium,[14e,15b] we explored Ir4f having a
3
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10.1002/anie.202103806
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RESEARCH ARTICLE
symmetrical 3,5-dimethoxy substitution. Pleasingly, it showed
improved catalytic activity compared to the 4-methoxy analogue
Ir4a (entries 7 vs12). In contrast, the 3,5-difluoro derivative Ir4e
was less efficient (entries 11 vs 12). Some variations of the
privileged N-aryl imine ligand moiety[14a] were also feasible. For
Complex dIr-C1 (Å)
dCp*-Ir (Å)
1.839
1.825
1.837
1.824
1.812
1.811
dIr-N (Å)
2.096
2.074
2.079
2.095
2.100
2.090
θC1-Ir-N (°)
77.43
76.65
76.87
77.67
78.13
78.11
Ir3c
Ir3e
Ir3f
2.035
2.032
2.048
2.021
2.048
2.041
instance, complex Ir4g bearing
a 2-aryl pyridine ligand
outperformed the N-aryl ketimine-derived standard Ir4a (entries 7
vs 13). The dihydropyrrole analogue Ir4h was as well active
(entries 7 vs. 14), opening new possibilities for C,N-ligand design.
Related rhodium complexes are also known to engage in
hydrogenations.[17] However, rhodacycle Rh4a was totally
ineffective towards the reduction of 1b (entry 15). Presumably,
cyclometalated Cp*Rh(III) complexes are less stable than their
iridium congeners towards proto-demetallation due to the weaker
Rh-carbon bond.[18a] Additionally, Cp*Rh(III) hydrides may be
more prone to decompose via reductive elimination
processes.[18b-e]
Ir4a
Ir4b
Ir4d
Figure 1. ORTEP representations of selected iridium complexes and key
parameters (d = distance, θ = angle). Thermal ellipsoids are at 50% probability
and hydrogen atoms are omitted for clarity.[23]
Substrate scope of the reductions and functional group
compatibility
Solid state structure and key parameters for the iridium
complexes
We next evaluated the generality of the reduction process. Using
the optimized reaction conditions and catalyst Ir4a, a large array
of oximes 1 were reduced to the corresponding N-hydroxy or N-
alkoxyamines 2 in excellent yields (Scheme 4). Noteworthy, the
E/Z-stereochemistry of the substrate is inconsequential for the
reaction performance.[19,10a] We first evaluated N-alkoxy
We obtained X-ray quality single crystals for a variety of chloride
complexes Ir3 and methanesulfonates Ir4 by slow diffusion of a
nonsolvent to the respective solutions of the iridium complexes at
ambient temperature (see SI for experimental details). X-Ray
crystallographic analysis provided insights into their molecular
geometry in the solid state and selected parameters were
compared (Figure 1). All feature a ‘piano-stool’ shape with a
distorted pseudo-tetrahedral geometry around the iridium center
and are in full accordance with related Ir-complexes.[15a-c] Despite
different electronic and substitution pattern of the chelating C,N-
ligand, only very small differences in the bond distances C1-Ir, N-
Ir and angles are observed. Nevertheless, the systematic
collection of the complexes structural parameters might set the
basis for a correlation to their reactivity. Our studies may serve as
a guide for the development of even more active iridium
complexes in the future.
derivatives of relevant α-alkyl benzylamines (R1 = Ar, R2
=
alkyl).[20a-c] Regarding the oxime O-substitution pattern, different
bulk defined as 1o, 2o or 3o alkyl ethers (1b-1e) reacted smoothly
and were reduced in virtually quantitative yields. Remarkably,
unsubstituted oximes reacted equally well and gave
corresponding hydroxylamines (2f, 2pc) without any detectable
N-O bond cleavage. Benzyl ethers (2c, 2pd) proved to be stable
towards hydrogenolytic cleavage of the benzyl group. Products
having different p-substituted aryl units, such as 2b (p-OMe), 2ga
(p-Me), and 2gb (p-F), were accessed in excellent yields. The o-
CH3Ph analogue 1gc reacted more sluggishly due to steric
hindrance close to the reaction site. A similar behaviour was
observed for products 2i and 2j bearing bulkier 2o alkyl
substituents. In these cases, simply replacing iPrOH by MeOH as
solvent increased the yields. The use of triflic acid was found to
be beneficial for less basic oxime 1ib. Noteworthy, the nitro group
of 2j remained fully intact and was not reduced, showcasing the
unique chemo-selectivity of this hydrogenation protocol.
Heterocyclic benzoxazine scaffolds 2ka and 2kb were accessed
in quantitative yield. Ferrocene- and benzothiophene-containing
products 2h and 2l were obtained in excellent yield. The latter is
the immediate precursor for the synthesis of the marketed anti-
asthma drug Zileuton.[20c] Additionally, hydrogenation of
biologically active Fluvoxamine[20d] (protected as its N’-
phthalimido derivative) afforded reduced variant 2m. We next
targeted substrates with additional substitutions (R1 and R2) at the
oxime Csp2 atom. For instance, a linear N-benzylamine product
2n (R2 = H) was formed by reduction of its aldoxime precursor.
Moreover, a diaryl ketoxime (R1, R2 = aryl) was also hydrogenated
to corresponding α,α-diarylamine 2o, albeit in reduced yield.
Several oximes having aliphatic substituents R1 and R2 were
smoothly hydrogenated to give medium and small cycloalkane-
containing N-alkoxy amines 2pa-2pe. Bulkier α-alkyl oximes 1q
and 1r were reduced as well. The method is suitable to access N-
alkoxy derivatives of amphetamine 2s[20e] as well as 1,2-amino
alcohols 2a.
4
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Scheme 4. Substrate scope of the hydrogenation process. Reaction conditions: 0.30 mmol 1, 0.45 mmol MsOH, 3 µmol Ir4a in iPrOH (0.3 mL) at 23 °C for 16 h.
[a] Yields determined by 1H-NMR using 1,3,5-trimethoxybenzene as internal standard; in all entries the yield equals the conversion of the oxime starting material.
[b] isolated yield. [c] in MeOH. [d] with triflic acid. [e] The crude product was N-benzoylated prior to isolation.
Notably, the dimethoxy acetal moiety of 2t remained intact during
the acidic reduction conditions. The use of anhydrous methanol
was needed to prevent hydrolysis. Oximes with adjacent
carboxylic acids or esters (R2 = CO2X) were suitable substrates
and smoothly hydrogenated in excellent yields. This enables a
convenient access to relevant N-hydroxy or N-alkoxy derivatives
of α-amino acids (2ua-2ud).[20f,g] Finally, N-hydroxyl norephedrine
2ue[20e] was obtained quantitatively from 1ue. Notably the double
reduction of α-keto oxime precursor 1ue proceeded in a highly
diastereoselective fashion and only a single diastereoisomer was
observed. Surprisingly few substrates were refractory to the
standard hydrogenation conditions. For instance, O-phenyl
substitution of 1v might provide extra stabilization to the oxime
C=N double bond by conjugation hampering reaction. 4,5-
Dihydroisoxazole 1w was not reduced, presumably due to high
steric congestion at the reactive site. Counterintuitively, a CF3
substituent in 1x which enhances the electrophilicity of the Csp2
center towards hydride attack, was detrimental. In this case, the
further reduced basicity of the oxime impedes its activation by N-
protonation. A similar effect may be responsible for pyridyl-
bearing oxime 1y, which did not react even in the presence of an
extra equivalent of acid to blunt the coordinating ability of the
pyridine ring. The pairing of tBu/Ph substitution (1z) proved to be
beyond the tolerance limit of catalyst Ir4a. Comparatively, a
sterically leaner chiral catalyst[10a] was able to reduce 1z in 90%
yield under otherwise identical reaction conditions.
Subsequently, the functional group tolerability was further
checked by selected additive tests using the reduction of oxime
1b using catalyst Ir4a (Scheme 5).[10a, 21] With the substrate scope
studies, these provide the full picture of the exquisite functional
group compatibility displayed by this acidic hydrogenation
protocol. The best scenario for which additive 5 is fully recovered
and 1b is quantitatively converted to 2b was observed for a host
of functional groups. These include aniline 5a, benzofuran 5b,
styrene 5c, N,N-dimethylbenzamide 5d, phosphine oxide 5e, and
phenyl boronic ester 5f. The addition of a ketone (5g), imine (5h)
or quinoline (5i) did not interfere with the reduction, allowing the
quantitative formation of 2b. However, these additives were
reduced
to
their
respective
alcohol,
amine
and
tetrahydroquinoline products 6g-6i. Pyridine (5j) or benzonitrile
additives (5k) remained intact but slow down the reduction of 1b.
This can be attributed to their coordinating properties to the
iridium center through their basic nitrogen atom. Similarly, halide
impurities poison the catalyst (vide infra). This might explain the
partial reduction of 1b in the presence of unpurified iodobenzene
5l. Lewis basic Ph3P (5n) and sulfoxide 5o remain stable but
suppress catalysis. Internal alkyne 5m disappears to a complex
mixture of products and prevents oxime reduction.
5
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Scheme 5. Further functional group compatibility of the oxime hydrogenation by additive tests. Reaction conditions: 0.1 mmol E-1b, 1 equiv. additive 5, 1 mol%
Ir4a, 50 bar H2, 1.5 equiv. MsOH, 0.5 M in iPrOH, 23 °C, 20 h. [a]Yield determined by 1H-NMR using 1,3,5-trimethoxybenzene as the internal standard; for all cases
the yield of 2b is virtually identical to the consumption of 1b; [b]with 2.5 equiv. MsOH
We thus hypothesized that a weakly coordinating anion, such as
methanesulfonate, was essential to spontaneously dissociate
from 18-electron iridium complex Ir4a, allowing dihydrogen
Mechanistic insight of the reduction
coordination and subsequent formation of the active hydride
species Ir5a. We validated this hypothesis in the catalytic
hydrogenation of 1b (Table 2, entries 1-4). Negligible catalytic
activity was observed for chloride complex Ir3a (entry 1). In
contrast, using Ir4a and Ir6a bearing weakly basic O-binding
methanesulfonate or trifluoroacetate counter ions, led to
quantitative formation of product 2b (entries 2-3). Likewise,
excellent reactivity was observed with the cationic complex Ir7a,
Having developed Cp*Ir(III) complexes that are highly efficient
catalysts for selective oxime hydrogenations in the presence of a
strong acid, several parts of their mode of operation remained
uncertain. This knowledge might be of help in the design of
improved second-generation catalysts. In principle, catalytic
hydrogenations can be formally dissected into two core
mechanistic events: the hydride formation by dihydrogen
22h]
activation and the subsequent hydride transfer.[3a,
In this
featuring a non-coordinating tetrafluoroborate counteranion (entry
4). The results imply that any chloride impurities present in the
reaction media have the capability to poison the catalyst.[3a] To
maximize catalyst efficiencies, brine-wash work-up procedures
without additional substrate purification steps should be avoided,
and low chloride source of MsOH should be preferred. The
hydrogen pressure is a relevant factor (entries 2, 5-7). Oxime 1b
is completely reduced after 3 h at 10 bar of hydrogen gas (using
1 mol% Ir4a). Almost no difference is found with higher pressures.
Under identical conditions, using just a balloon of hydrogen
reduced the reactivity and gave 66% yield in the same time frame
(entry 6). This outlines the feasibility of conducting oxime
hydrogenations at convenient atmospheric pressure if the
maximum catalytic efficiency is not a top priority. From the
mechanistic standpoint, H2 is likely to become involved in the rate-
determining step (RDS) of the hydrogenation somewhere below
10 bar. At higher pressures, the hydride transfer presumably
becomes the RDS. A control experiment showed the formation of
just traces amounts of 2b in the absence of H2 gas (entry 7),
indicating a very weak background reactivity via hydrogen
transfer from iPrOH.[22a]
respect, we attempted the stoichiometric formation of the active
iridium hydride species Ir5a (Scheme 6). Xiao et al. described a
synthesis from chloride Ir3a with the hydride originating from
triethylammonium formate.[15c] Subsequent isolation and X-Ray
analysis provided solid evidence of its identity, and 1H-NMR
analysis in CD2Cl2 revealed a hydride peak at -16.19 ppm. In a
NMR tube,
we
observed
complete conversion of
methanesulfonate complex Ir4a to Ir5a after 16 h with one
atmosphere of hydrogen gas using d8-THF as the solvent. The
characteristic hydride peak at -16.02 ppm was detected.
Equimolar amounts of triethylamine were needed to quench the
MsOH byproduct driving the reaction to completion (see SI for full
details). In contrast, chloride bearing complex Ir3a was not
competent to form Ir5a under the same reaction conditions.
Scheme 6. Stoichiometric iridium hydride formation.
6
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Table 2. Influence of anionic ligand (X) and hydrogen pressure on the oxime
reduction.[a]
Entry
1
[Ir]
3a
4a
6a
7a
4a
4a
4a
X
H2 pressure
50 bar
50 bar
50 bar
50 bar
10 bar
1 bar
Yield (%)[b]
Cl-
<5
>99
99
2
MsO-
TFA-
3
- [c]
4
BF4
95
5[d]
6[d]
7[d]
MsO-
MsO-
MsO-
>99
66
Figure 2. Influence of the acid concentration in the reaction rate. Conditions:
0.3 mmol 1a, 0.23 / 0.45 / 0.90 mmol MsOH, 0.25 mol% Ir4a, 50 bar H2 in
iPrOH (0.3 mL) at 23 °C; yield of 2b determined by 1H-NMR using 1,3,5-
trimethoxybenzene as internal standard, being equal to the conversion of 1b.
no H2
3
Considering all aspects, the following hydrogenation mechanism
can be suggested (Scheme 7). Initial dissociation of the
methanesulfonate counter ion from coordinatively saturated
complex [Ir-OMs] (likely favored in polar solvents) forms 16-
electron cationic complex [Ir]+. Dihydrogen η2-coordination to
iridium generates [IrH2]+ complex. This species has been
calculated to be super-acidic,[22d] even more acidic than MsOH,
thus favoring heterolytic splitting of H2 into iridium hydride species
[Ir-H] and MsOH. The conjugated base, in this case mesylate,
and protic solvents have been demonstrated to accelerate this
step.[22e] Separately, oxime substrate 1 is activated by protonation
with MsOH forming 1-H+ with enhanced electrophilicity. Next, the
uncoordinated 1-H+ is reduced by separately receiving a hydride
from [Ir-H] and subsequently a proton from MsOH. This outer-
[a] Conditions: 0.30 mmol 1b, 0.45 mmol MsOH, 0.75 µmol [Ir] in solvent (2
mL) at 23 °C for 3 h; [b] yield determined by 1H-NMR using 1,3,5-
trimethoxybenzene as internal standard, being equal to the conversion of the
oxime starting material unless otherwise stated; [c] as its mono acetonitrile
adduct, crystal structure included in the SI;[23] [d] With 1 mol% Ir.
We next investigated the effect of different amounts of the
Brønsted acid on the reaction rate (Figure 2). For instance, a run
with 0.25 mol% Ir4a and an excess of acid (1.5 equivalents MsOH
with respect to 1b), reached full conversion to product 2b within
30 minutes. A further increase of the acid concentration to 3.0
equivalents did not results in any increase of the reaction rate. In
contrast, reducing the amount of MsOH to 0.75 equivalents
caused a stall of the conversion of 1b at 70%. This observation is
fully consistent with a mandatory protonation of the oxime for
reaction. In case of substoichiometric amounts of acid, the more
basic alkoxy amine product scavenges all available protons
forming stable ammonium salts. The slightly slower initial reaction
rate (data point at 5 minute reaction time) might suggest that the
role of the Brønsted acid extends beyond oxime protonation, as
this process should be fast and near-quantitative with
methanesulfonic acid having a pKa of -1.9.[12d] For instance, it has
been proposed that the conjugated base may assist the
heterolytic cleavage of H2 into a hydride and a proton.[22b,c]
Separate studies of the impact of the acid strength on reactivity
revealed that TFA (pKa = 0.23)[12d] as the weakest acid still
allowing the process.[10a] Noteworthy, we have not found in any
case an induction period, indicating that dissociation of the
methanesulfonate ligand from the initial catalyst species is not the
RDS.
sphere
hydrogenation
mechanism
is
termed
ionic
hydrogenation.[22f-i] It has as well been proposed for related
catalytic imine hydrogenations.[14d, 22j, 22k] In the present case, the
hydride transfer from [Ir-H] to 1-H+ seems to be the rate-limiting
step of the catalytic cycle. Rapid N-protonation of alkoxy amine
product as the most basic entity in the reaction mixture occurs
rapidly by MsOH forming salt 2-H+. Outside the cycle, free base 2
is obtained upon basic work-up.
7
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10.1002/anie.202103806
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RESEARCH ARTICLE
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Conclusion
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complexes. These iridacycles are air and moisture stable and are
synthesized in
a simple and straight-forward manner. In
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This work was supported by EPFL and Syngenta. We thank Dr.
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Keywords: Homogeneous catalysis • Hydrogenation • Iridium •
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9
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RESEARCH ARTICLE
Entry for the Table of Contents
Half sandwich iridium(III) complexes are found to be efficient catalysts for homogeneous oxime hydrogenation to hydroxylamine
products. Only if equipped with an aryl imine ligand and operating under strong acidic conditions. Remarkably they do not
hydrogenolyse the fragile N-O bond. Experimental evidence suggests an unusual acid-assisted ionic hydrogenation mechanism which
may be applicable to the reduction of other challenging substrates.
10
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