Dialkyl Ether Formation at High-Valent Nickel

Article abstract of DOI:10.1021/jacs.0c07381

In this article, we investigated the I2-promoted cyclic dialkyl ether formation from 6-membered oxanickelacycles originally reported by Hillhouse. A detailed mechanistic investigation based on spectroscopic and crystallographic analysis revealed that a putative reductive elimination to forge C(sp3)-OC(sp3) using I2 might not be operative. We isolated a paramagnetic bimetallic NiIII intermediate featuring a unique Ni2(OR)2 (OR = alkoxide) diamond-like core complemented by a μ-iodo bridge between the two Ni centers, which remains stable at low temperatures, thus permitting its characterization by NMR, EPR, X-ray, and HRMS. At higher temperatures (>-10 °C), such bimetallic intermediate thermally decomposes to afford large amounts of elimination products together with iodoalkanols. Observation of the latter suggests that a C(sp3)-I bond reductive elimination occurs preferentially to any other challenging C-O bond reductive elimination. Formation of cyclized THF rings is then believed to occur through cyclization of an alcohol/alkoxide to the recently forged C(sp3)-I bond. The results of this article indicate that the use of F+ oxidants permits the challenging C(sp3)-OC(sp3) bond formation at a high-valent nickel center to proceed in good yields while minimizing deleterious elimination reactions. Preliminary investigations suggest the involvement of a high-valent bimetallic NiIII intermediate which rapidly extrudes the C-O bond product at remarkably low temperatures. The new set of conditions permitted the elusive synthesis of diethyl ether through reductive elimination, a remarkable feature currently beyond the scope of Ni.

Full text of DOI:10.1021/jacs.0c07381

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Dialkyl Ether Formation at High-Valent Nickel
Franck Le Vaillant, Edward J. Reijerse, Markus Leutzsch, and Josep Cornella*
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ABSTRACT: In this article, we investigated the I2-promoted cyclic
dialkyl ether formation from 6-membered oxanickelacycles originally
reported by Hillhouse. A detailed mechanistic investigation based on
spectroscopic and crystallographic analysis revealed that a putative
reductive elimination to forge C(sp3)−OC(sp3) using I2 might not be
operative. We isolated a paramagnetic bimetallic NiIII intermediate
featuring a unique Ni2(OR)2 (OR = alkoxide) diamond-like core
complemented by a μ-iodo bridge between the two Ni centers, which remains stable at low temperatures, thus permitting its
characterization by NMR, EPR, X-ray, and HRMS. At higher temperatures (>−10 °C), such bimetallic intermediate thermally
decomposes to afford large amounts of elimination products together with iodoalkanols. Observation of the latter suggests that a
C(sp3)−I bond reductive elimination occurs preferentially to any other challenging C−O bond reductive elimination. Formation of
cyclized THF rings is then believed to occur through cyclization of an alcohol/alkoxide to the recently forged C(sp3)−I bond. The
results of this article indicate that the use of F+ oxidants permits the challenging C(sp3)−OC(sp3) bond formation at a high-valent
nickel center to proceed in good yields while minimizing deleterious elimination reactions. Preliminary investigations suggest the
involvement of a high-valent bimetallic NiIII intermediate which rapidly extrudes the C−O bond product at remarkably low
temperatures. The new set of conditions permitted the elusive synthesis of diethyl ether through reductive elimination, a remarkable
feature currently beyond the scope of Ni.
Scheme 1. (A) Williamson Ether Synthesis (Advantages and
Pitfalls); (B) Existing Methods for C(sp2)−O Bond
Formation Using Ni Catalysts; (C) C(sp3)−O−C(sp3) Bond
Formation from High-Valent Ni
INTRODUCTION
■
Dialkyl ethers constitute one of the most valuable functional
groups, and their synthesis represents one of the oldest
strategies to build chemical complexity. As a result, formation
of C−O bonds through the union of two organic fragments has
prevailed one of the most powerful technologies, finding
application across the chemical sciences: from covalent
linkages and solid supports to crucial motifs in biologically
active compounds.1 From a synthetic point of view, formation
of the C−O bond has largely relied on the venerable
Williamson ether synthesis,2 which involves the union of an
alcohol and an alkyl halide through a SN2 reaction in the
presence of a strong base (Scheme 1A). The high practicality
and scalability of this transformation has placed it as a
cornerstone reaction in both academic and industrial settings.3
Yet, the nucleophilic mechanism of the reaction is in turn its
Achilles heel: the reaction efficiency is largely affected by the
competitive alkoxide- or base-promoted E1 and E2 processes
when secondary and tertiary alkyl halides are utilized. To
circumvent these limitations, organic chemists have devoted
their efforts in developing many strategies to produce highly
coveted etherselectrochemistry,4 organocatalysis,5 Lewis
acid/base catalysis,6 among others. Nevertheless, one of the
most promising alternatives in the literature to forge C−O
bonds relies on the mediation of transition metals. Exploiting
their redox properties, transition metal catalysis has been
demonstrated to be one of the pillars in the construction of
these linkages.7 For example, Chan-Lam or Ullmann couplings
Received: July 14, 2020
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A

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Scheme 2. I2-Promoted C(sp3)−O−C(sp3) Bond
Formation: (A) Hillhouse’s Seminal Work with Bipyridine
Oxanickelacycles; (B) Love’s Example Using Strained
Oxanickelacycle with Bidentate Phosphine
have experienced great success and found broad application for
the synthesis of a myriad of highly relevant ethers.8 Despite the
advantages associated with these methods, they have been
largely dominated by linkages such as C(sp2)−O−C(sp2) and
C(sp2)−O−C(sp3). In addition, Pd catalysis has also
experienced tremendous development in this front, providing
catalytic methods for C(sp2)−O bond formation.9−11 Yet, Pd
complexes that permit construction of dialkylethers (C(sp3)−
O−C(sp3)) through reductive elimination still present severe
challenges.12 A remarkable example of the formation of cyclic
ethers is the Co-catalyzed radical cyclization of alkenols from
Mukaiyama,13 which has found ample success in various
synthetic endeavors.13c
Other first-row transition metals (Cu, Fe, Ni)14,15 have also
been demonstrated to excel as catalysts in various C−O
coupling strategies.16 In particular, Ni-catalyzed transforma-
tions have gained tremendous momentum for their enormous
capabilities in forging C−heteroatom bonds.17 A seminal work
by Hartwig described the possibility to forge C(sp2)−O−
C(sp3) bonds using Ni(COD)2 and dppf as the optimal
catalytic system.18 Encompassing Hartwig’s precedent, Stra-
diotto described a general C(sp2)−O bond formation from
L2NiII complexes capitalizing on a newly designed set of
phosphine-based ligands (L = CyPAd-DalPhos)19 (Scheme
1B). More recently, methods that replace the phosphine by
simple diamine ligands have been reported, which rely on
access to high-valent20 or high-energy21 Ni complexes through
light irradiation, which rapidly forge the C(sp2)−O bond.
Mechanistic investigations on these latter approaches revealed
that C(sp2)−O bond formation can proceed either via a NiIII
intermediate or via an excited NiII complex after energy
transfer (Scheme 1B).22 In 2020, Ackermann and co-workers
developed a nickel-catalyzed electrochemical C(sp2)−H
alkoxylation, which proceeds through a NiIII intermediate.23
Recently, Nocera reported a NiI-catalyzed etherification
protocol that mimics the reactivity of photoredox-catalyzed
couplings without the use of a light source or photocatalyst.24
Similarly to the metallaphotoredox protocols, it is believed that
the high oxidation state of the NiIII intermediate provides the
necessary driving force to undergo C(sp2)−O bond linkage
upon reductive elimination. Whereas realization of C(sp2)−
O−C(sp3) through reductive elimination at a Ni center is well
precedented and studied,25 a fundamental mechanistic under-
standing of the analogous process to forge dialkyl ethers
through C(sp3)−OC(sp3) reductive elimination still remains
elusive with virtually no systematic studies on their feasibility
(Scheme 1C).26
In the 1990s, Hillhouse provided one of the first examples of
C(sp3)−O−C(sp3) bond formation from well-defined oxanick-
elacycles (1a−e) bearing bipyridine ligands and using
stoichiometric I2 as oxidant (Scheme 2A).27 In these seminal
reports, involvement of high-valent nickel species such as
NiIII−I or NiIV−I complexes was suggested; yet, minimal
evidence was provided, and such intermediates remained
purely speculative. Interestingly, when I2 was replaced by other
oxidants such as O2 or ferrocenium (Fc+) the C(sp3)−
OC(sp3) bond formation was not observed.27d In addition,
higher yields were obtained for those complexes where β-
hydride elimination is hampered by the limited conformations
of the oxanickelacycles (Scheme 2A). As a result, formation of
the C(sp3)−OC(sp3) bond was limited to cyclic products, as
exemplified by the incapacity of 1f to deliver the corresponding
acyclic dialkyl ether.27b On the basis of these early results, Love
and co-workers capitalized on the I2-promoted C−O bond
formation and applied it to the oxanickelacyclobutane 1g
bearing a 1,2-bis(di-tert-butylphosphino)ethane (dtbpe) as the
ligand (Scheme 2B).28 The authors observed rapid and clean
formation of the corresponding epoxide in good yield along
with almost quantitative formation of the corresponding
(dtbpe)NiI2 (3). In this case, deleterious β-hydride elimination
is not operative due to the presence of a ketone. To the best of
our knowledge, these reports represent solitary examples
present in the literature regarding formation of dialkyl ethers
from well-defined organometallic species. Despite the powerful
reactivity observed, no evidence of the intermediates involved
has been reported. Yet, fundamental understanding of the key
parameters that govern this particular transformation would
provide tremendous insights for the design of future catalytic
C(sp3)−O−C(sp3) ether syntheses. Herein, we report a
comprehensive mechanistic study on the transformation
originally described by Hillhouse: characterization of the
reaction intermediates revealed formation of a robust and
paramagnetic NiIII dimer, which thermally decomposes to
afford primarily elimination products. Additional mechanistic
data suggests that direct C(sp3)−OC(sp3) reductive elimi-
nation from such NiIII intermediate to forge simple THF rings
is highly unlikely. On the contrary, experimental evidence
supports an alternative mechanism based on a preferential
C(sp3)−I reductive elimination followed by an intramolecular
SN2 reaction. Yet, all of these drawbacks were overridden by
the replacement of I2 by fluorine-containing oxidants which
prevent not only competitive C−X reductive elimination but
also deleterious elimination side reactions. In this manner, high
yields of the cyclized tetrahydrofurans were obtained.
RESULTS AND DISCUSSION
■
Initially, we considered that oxanickelacyles 1a and 1b
provided an excellent platform to investigate an oxidative
C(sp3)−OC(sp3) bond formation (Scheme 3). Both com-
plexes represent challenging substrates to undergo intra-
molecular C−O bond formation (Scheme 2A) due to the
dynamic behavior of the alkoxide anion as a result of the
fluxionality of the alkyl backbone. Subsequently, diverse
B
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Scheme 3. Synthetic Route to Oxanickelacyclohexanes31
a
Figure 1. Cyclic voltammogram of 1b (1.0 mM) in CD3CN, recorded
versus Ag/AgNO3 electrode, using n-Bu4NPF6 (0.2 M) as electrolyte,
under argon, with a scan rate of 100 mV·s−1. Potentials are then
converted to the Fc/Fc+ couple.31
This yield comprises a mixture of 85:15 of 1b and 1b-isomer.
conformations of the CH and CH2 groups can be adopted
which could lead to unproductive β-hydride elimination or
simple E2. With these potential drawbacks in mind, we set out
to synthesize nickelacyclopentanes 4a and 4b as described in
the literature:27,29 the corresponding 1,4-alkyldibromides (1.0
equiv) were reacted with an excess of Ni(COD)2 (2.0 equiv)
and bipyridine (bipy, 4.0 equiv) at −78 °C in THF. After
warming up to 25 °C, the mixture is filtered and the dark-green
complexes 4a and 4b are obtained in 69% and 50% yield,
respectively (step 1, Scheme 3). Subsequently, 4a and 4b were
subjected to O-atom insertion using N2O following Hillhouse’s
procedure.27 After exposing 4a and 4b to N2O atmosphere (1
atm) in THF, oxanickelacyclohexane complexes 1a and 1b
were obtained as deep purple solids in 53% and 75% yield,
respectively (step 2, Scheme 3). It is important to mention that
to access high-purity 1a and 1b, further filtration is required
through Avicel30 in order to remove some colloidal nickel
particles.31 Complexes 1a and 1b exhibit remarkable stability
in the solid state and can be stored in the freezer of the
glovebox. Yet, solutions of 1a and 1b slowly degrade, probably
through decoordination of the alkoxide ligand, which
complicates purification. Indeed, purities that ranged from
85% to 93% could be achieved for 1a and 1b after a series of
crystallizations and filtrations. Such NiII complexes are square
planar and easily characterized by NMR in the diamagnetic
region.31 Whereas 1a offers inherent symmetry, 1b is not
symmetric and different products can arise in the O-atom
insertion step (step 2, Scheme 3). Compound 1b has both a 1°
and 2° carbons, and the selectivity for the O insertion was
found to be 85:15, favoring isomer 1b over 1b-isomer.32
However, considering that the reductive elimination of both
isomers would lead to the same THF product 2b, no further
separation was attempted. For clarity, only structure 1b will be
used in the following schemes.
On the basis of the oxidation potential obtained for 1b
(E1/2(NiII/NiIII) = −0.70 V, E1/2(NiIII/NiIV) = +0.31 V vs Fc/
Fc+ in CD3CN), it is reasonable to propose that oxidation of
this complex to the corresponding NiIII should be feasible
using Fc+ or O2.27d However, Hillhouse already noticed that
Fc+ and O2 did not lead to any C−O bond formation in good
yield. Indeed, when 1b was oxidized with FcBF4, mainly the
elimination product was obtained (6b) with only trace
amounts of C(sp3)−OC(sp3) bond formation (Scheme 4).
Scheme 4. Attempts to C−O Bond Formation after One-
Electron Oxidation of 1b To Access High-Valent NiIII
Other single-electron oxidants were tested, such as photo-
catalyst 4CzIPN (2,4,5,6-tetra(9H-carbazol-9-yl)-
isophthalonitrile (5),35 which would also lead to cationic
NiIII intermediates. Yet, no desired THF ring 2b could be
detected in the crude mixture. These results suggest that a
C(sp3)−OC(sp3) reductive elimination from cationic NiIII
intermediates is unlikely (vide infra).
To gain further insight into the C−O bond-forming event,
the reaction reported by Hillhouse and co-workers was
repeated: complex 1b (1.0 equiv) was reacted with I2 (1.1
equiv) in CD2Cl2 at 25 °C.36 To our surprise, upon addition of
I2 to a solution of 1b, the color of the reaction mixture quickly
changed from deep purple to orange. After 20 min of stirring at
25 °C, brown solids precipitated from the solution. At this
point, the solids were filtered off and the filtrate was analyzed
by 1H NMR and GC-MS. Surprisingly, the desired cyclic ether
2b was not observed (Scheme 5A). On the other hand,
significant amounts of pent-4-en-2-ol (6b, 45%) were obtained,
presumably through side-elimination reactions. More impor-
tantly, peaks relative to 5-iodopentan-2-ol (7b, 10%) were
detected and successfully assigned.31 The presence of 7b was
further confirmed by GC-MS. After solubilizing the solids,
With these complexes in hand, cyclic voltammetry studies
were performed in order to gain insight into their redox
properties. As shown in Figure 1, the cyclic voltammogram of
complex 1b in CD3CN revealed two oxidative waves at −0.70
and +0.31 V against Fc/Fc+. Interestingly, the first oxidative
wave is not reversible, whereas the second wave is quasi-
reversible. On the basis of other similar CVs for well-defined
cyclic (bipy)NiII(alkyl)(aryl) and (terpy)NiII(C4F8) com-
plexes,33 we tentatively assigned the redox potentials to the
corresponding single-electron oxidation NiII/NiIII and NiIII/
NiIV couples, respectively. It is worth pointing out that the low
values for both processes manifest the facility of 1b to access
high-valent Ni intermediates.34
1
analysis by H NMR revealed a set of broad paramagnetic
peaks, suggesting the presence of ligated bipy−Ni species.
HRMS analysis of the solid indicated that a possible structure
could be (bipy)NiI2,28 although dimeric compounds could not
be ruled out.37 Slow crystallization in CD2Cl2 at −20 °C led to
crystals suitable for X-ray analysis, which unequivocally
C
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Scheme 5. (A) Hillhouse I2-Promoted C(sp3)−O−C(sp3) Bond Formation Reaction (Analysis of the Fate of the Organic and
a
Inorganic Compounds); (B) X-ray Structure of Complex 8;31 (C) NiIII Bimetallic Intermediate 9a−b; (D) H NMR of
1
b
Paramagnetic Complex 9a31
a
Disordered iodine atoms are omitted for clarity. Selected distances (Angstroms): Ni1−I1 = N2−I2 = 2.78; Ni1−I2 = Ni2−I1 = 2.83; Ni1−N1 =
b
Ni1−N2 = 2.07. Selected angles (degrees): I1−Ni−I2 = 89.2; Ni1−I1−Ni2 = 94.2. Insets correspond to peaks at 237, −98, and −930 ppm.
confirmed formation of a polymeric (bipy)NiI2 (8) consisting
of octahedral Ni complexes linked together by μ-iodo bridges
(Scheme 5B).
Considering the redox potential of iodine (E1/2(I2/I2−•) =
+0.21 V vs Fc+/Fc),38 it is reasonable to assume formation of a
high-valent nickel NiIII−I complex upon mixing 1a and 1b with
I2. However, similarly to the case of Fc+, formation of NiIV is
highly unlikely. To investigate whether NiIII−I intermediates
are formed in the reaction system, we decided to monitor the
1
reaction by H NMR at low temperature. Upon adding a cold
solution of I2 (1.1 equiv) to a solution of 1a in a J-Young tube
Figure 2. X-ray structure of compound 9a.31 Hydrogen atoms and
disordered iodide atoms in I3 counterion are omitted for clarity.
Selected distances (Angstroms): Ni1−Ni2 = 2.84; Ni1−I1 = Ni2−I1
at −90 °C, a rapid color change was observed from deep
−
purple to deep orange (Scheme 5C). Complete conversion of
1
1a to a new set of well-defined signals was observed. The H
= 2.92; Ni1−O1 = Ni1−O2 = Ni2−O1 = Ni2−O2 = 2.00; Ni1−N1 =
NMR spectrum at −90 °C exhibits peaks ranging from −930
to +237 ppm, pointing to a paramagnetic complex (Scheme
5D).31 Upon storing a concentrated solution at −35 °C, good-
quality crystals formed. X-ray analysis unambiguously
determined that the intermediate consisted of a symmetric
cationic NiIII bimetallic complex (9a). This complex represents
a unique and unprecedented structure of a dinuclear NiIII with
several structural and electronic interesting features (Figure 2).
First, 9a contains two NiIII atoms in an octahedral arrangement
with a large Ni−Ni distance of 2.84 Å, thus suggesting no
metal−metal interaction.39 In addition, 9a features a rather
unique μ-iodo bridge unifying both Ni atoms with a highly
strained Ni1−I1−Ni2 angle of 58.07°. As a result, the I is
bridging both NiIII centers through an elongated Ni−I bond
(Ni1−I1 = Ni2−I1, 2.92 Å). It is important to mention that
NiIII dimers with one bridging halogen atom have been
recently proposed as intermediates in C(sp2)−X (X = Br, Cl, I)
bond formation.39a,40 However, the most striking feature of 9a
is the diamond-like core formed by the Ni atoms and the
alkoxide ligands. Two μ2-bridging alkoxide anions join the two
Ni centers in a highly symmetric environment (Ni1−O1 =
Ni1−O2 = Ni2−O1 = Ni2−O2, 2.00 Å) with angles of Ni1−
O1−Ni2 = 92.72° and O1−Ni1−O2 = 79.57°. The Ni−O
distances for 9a are in the range of other bis(μ2-oxide)-
1.99; Ni1−N2 = 2.05; Ni1−C1 = 2.013. Selected angles (degrees):
Ni1−I1−Ni2 = 58.07; Ni1−O1−Ni2 = 92.72; O1−Ni1−O2 = 79.57.
bridging NiIII complexes known in the literature.41 The
complex is complemented by the bipyridine ligands with
similar Ni−N distances for both N (Ni1−N1, 1.99 Å; Ni1−
N2, 2.05 Å). Finally, the remaining position of the octahedron
is occupied by the alkyl residue with Ni−C(sp3) distances
resembling those reported for other NiIII−C(sp3) bonds
(Ni1−C1, 2.013 Å).42 A parallel behavior was observed
when complex 1b was reacted with I2. However, attempts to
obtain crystals of the NiIII intermediate were unsuccessful.
Bimetallic complexes 9a and 9b were further characterized by
HRMS both in ESI+ and in ESI− modes.31 Finally, due to the
paramagnetic nature of complexes 9a and 9b, further structural
and electronic characterization was attempted by electron
paramagnetic resonance (EPR).
The EPR spectra of complexes 9a and 9b were recorded at
the X-band, 30 K, and are depicted in Figure 3. As expected,
the EPR spectra of 9a and 9b are very similar but show subtle
differences in line splitting and intensity ratio between the
different spectral features. The multiple line splitting suggests
an electron−electron spin−spin interaction between the two
NiIII centers. This means that the dimer structure found in the
D
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preferential formation of 6b and 7b led us to consider that the
C(sp3)−OC(sp3) bond formation pathway accounting for the
ca. 10−14% yield of 2b may arise from a slow intramolecular
cyclization of the iodoalkoxide/iodoalcohol in a SN2 fashion.46
Indeed, after 48 h of reaction time in the NMR tube without
stirring, the iodoalcohol formed initially slowly evolves to form
2b (Scheme 6).31 It is well established that 5-iodoalkoxides can
Scheme 6. Thermal Decomposition of Complex 9b and
Hypothetical SN2 Reaction from 7b
Figure 3. X-band EPR (9.623 GHz) of complexes 9a and 9b recorded
at 30 K (blue traces).31 Experimental parameters: 1 mW, 100 kHz, 7.5
G field modulation. Red traces represent the Easyspin43 (esfit)
simulation with the following parameters: g(9a) = (2.081, 2.155,
2.279); g(9b) = (2.084, 2.144, 2.287). Dipolar interaction D(9b) =
517 MHz; D(9a) = 550 MHz. J coupling < 50 MHz.
undergo intramolecular 5-exo-tet cyclization to afford cyclic
ethers.47 This experimental evidence supports the lack of
reactivity when attempting formation of open-chain ethers
such as Et2O (2f) due to the much slower rates for
intermolecular SN2 reactions.48
solid state (Figure 2) is retained in solution for both
complexes. Making use of the symmetry properties of the
dimer complex,31 we were able to simulate the EPR spectra as
shown in Figure 3. The g-matrix principal values obtained for
9a (2.081, 2.155, 2.279) and 9b (2.084, 2.144, 2.287) are
similar to what has been observed for a similar N,N-ligand-
coordinated NiIII monomer complex (2.03, 2.14, 2.20).40 The
magnetic interaction between the two NiIII centers is
dominated by the dipolar contribution found to be (0.9, 1.1,
−2)*550 MHz for 9a and (0.9, 1.1, −2)*517 MHz for 9b. The
J coupling between the two NiIII centers is very small (50
MHz), and its effect on the EPR is only visible as a small
splitting at the center of the spectrum. As confirmed by DFT
analysis,31 the two NiIII centers effectively behave as isolated S
= 1/2 systems. This is in agreement with NMR analysis,
estimating the magnetic susceptibility of the dimer complex
using the Evans method to be S = 1/2 for each NiIII center.31
Having identified and characterized 9, we set out to explore
its reactivity. Upon slowly warming solutions of 9a and 9b in
CD2Cl2 from −90 to 25 °C, several interesting observations
were made. First, the chemical shifts of complexes 9a and 9b
are highly dependent on the temperature, which further
confirms the paramagnetic nature of 9.31 Moreover, 9a and 9b
have a remarkable stability across a wide range of temperatures,
from −90 to −10 °C. Beyond −10 °C, rapid evolution of 9a
and 9b to terminal alkenes 6a and 6b and iodoalcohols 7a and
7b is observed. While traces of THF could be detected in the
case of 9a, no detectable amount of the C(sp3)−OC(sp3)
bond formation product 2b was observed for 9b.44 This last
observation indicates that the C(sp3)−I reductive elimination
is kinetically more favorable to any other C−O bond-forming
event at Ni. Whereas such C(sp3)−I bond formation proceeds
via a reductive elimination from NiIII−I or direct attack of the I
counterion to the Ni−C(sp3) bond in a SN2 fashion is
currently unknown.42,45 However, a similar system was
recently reported by Diao, suggesting that C(sp3)−I bond
formation could proceed through monomeric square pyramid
NiIII complexes.40 Hence, it is plausible to think that after
dissociation of 9a and 9b, a similar process could be operative.
The absence of 2b upon warming 9b to 25 °C together with
rapid consumption of oxanickelacycle 1b at −90 °C toward
With these results in hand, we addressed such a defying and
elusive reductive elimination. It was clear that other oxidants
that enable access to high-valent Ni species should be
scrutinized.49 When I2 was replaced by Umemoto’s reagent
(S-(trifluoromethyl)dibenzothiophenium triflate, TDTT,
10a),33a a low yield of 2b was observed (10%). A reduced
amount of side product 6b was obtained when CD3CN was
used instead. During monitoring studies at variable temper-
atures, HCF3 (boiling point = −82.1 °C) was detected.
Formation of fluoroform suggests the involvement of CF3−
Ni−H intermediates and points to alkenol 6b being formed
through β-hydride elimination pathways. In addition to alkenol
6b and HCF3, other byproducts containing C(sp3)−CF3 were
also identified by 19F NMR, which was consistent with
formation of high-valent Ni intermediates.50 Despite the low
yields, to the best of our knowledge, this challenging C(sp3)−
CF3 bond formation is unprecedented at a Ni center.51 At this
point, it was quite evident that competitive C(sp3)−X
reductive eliminations (X = I, CF3) should be suppressed if
the challenging C(sp3)−O−C(sp3) is to be achieved. Hence,
we speculated that the presence of F ligands in the
coordination sphere of a high-valent Ni intermediate would
dramatically reduce the observed side reactions due to the high
kinetic barrier to forge C(sp3)−F bonds.52 When 1b was mixed
with 1.05 equiv of XeF2 in CD2Cl2 or CD3CN, immediate
reaction took place and the desired ether 2b was observed as
the major product in 60% or 47% yield, respectively.50a,52f,53
Interestingly, formation of 6b remained minor in CD2Cl2 and
could be largely suppressed in CD3CN (8%). It is important to
mention that products derived from a putative C(sp3)−F
reductive elimination were only observed in trace amounts.31
In this line, when XeF2 was replaced by SelectFluor (10c) in
CD3CN a similar outcome was obtained with a 45% yield of 2b
along with a minimal amount of 6b (10%). We then
investigated several commercially available substituted 1-
fluoro-pyridinium salts (10d−f) as they have increased
solubility in CH3CN.54 Using 10d, 45% 2b and <5% 6b
were obtained. Gratifyingly, when using NFTPB (10e, N-
fluoro-2,4,6-trimethylpyridinium tetrafluoroborate) and
NFTPT (10f, N-fluoro-2,4,6-trimethylpyridinium triflate) an
E
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increase in the yield of 2b was observed (61% and 63%,
respectively). Notice that when using BF4 as counterion,
formation of 6b could be minimized to a residual 8%. As
expected, 2a was also obtained in a satisfactory 56% and 63%
yield when using 10e and 10f, respectively (Scheme 7B).
filtration (87%), the deep green solid 11 is subjected to N2O
atmosphere at 25 °C, allowing smooth O insertion into the
Ni−C(sp3) bond,27a,b leading to (bipy)Ni(Et)(OEt) (1f) in
63% yield. At this point, 1f was subjected to our optimized
oxidation conditions using 10f in CD3CN at 25 °C (Scheme
8B). Gratifyingly, rapid formation of Et2O (2f) was observed in
20% yield at 25 °C. A similar result was obtained using 10e.
Formation of 2f from 1f represents a unique example of
C(sp3)−OC(sp3) bond formation and contrasts with the
results obtained from Hillhouse, where C(sp3)−OC(sp3) bond
formation from acyclic NiII complexes could not be achieved
(see Scheme 2A). This unprecedented result for unbiased,
acyclic substrates combined with the use of simple pyridinium
salt 10e and 10f as a mild oxidant provides an interesting
proof-of-concept for the development of new strategies based
on Ni and may open the door to new avenues for catalytic
dialkyl ether syntheses in the future.
Scheme 7. (A) Screening of Oxidants for the Oxidatively
a
Induced C(sp3)−OC(sp3) Bond Formation; (B)
Application to the Synthesis of THF
Successful formation of C(sp3)−O−C(sp3) bonds using N-
fluoropyridinium reagents posed the question of what is the
exact nature of the high-valent Ni species involved in the
process. On the basis of the CV results for 2b (Figure 1)
together with the oxidation results using Fc+, O2, and 4CzIPN
photocatalyst (Scheme 4),27 it is evident that access to NiIII
species is facile;49 yet, cationic NiIII are not capable of C−O
bond formation due to fast elimination side reactions. It is
important to point out that owing to the extremely fast
reaction rates for C−O bond formation, mechanistic
investigations on this particular system pose an experimental
challenge. Indeed, 1a, 1b, 10e, and 10f react at −90 °C in <1
min, and no Ni intermediates could be detected spectroscopi-
cally (1H and 19F NMR). Attempts to stabilize high-valent Ni
species using tripodal ligands (tris(pyrazolyl)borate56 or
tris(pyridyl)methane)33a,49 resulted in degradation or failed
to incorporate O to the NiII−C(sp3) bond. To our delight
however, a signal could be detected by EPR from reaction of
1b with 10f. Such species were very short lived, but a sufficient
amount could be trapped after rapid (1 s) mixing at −95 °C
(melting point of PhMe) and subsequent freezing in liquid N2
(Scheme 9A). The EPR spectrum showed multiple splitting
features consistent with a NiIII dimer species (int-I, Scheme
9B). The width of the spectrum, however, is reduced with
respect to that of 9a and 9b, suggesting a reduction in the
dipolar interaction between the two NiIII centers. Indeed,
spectral fits resulted in a smaller value (299 vs 517 and 550
MHz), whereas the g-tensor only differed slightly.31 It is
important to point out that although the fitting parameters for
int-I are probably not unique due to the few spectral features
and large number of free parameters, the current fits would be
consistent with a NiIII dimer with symmetry properties
resembling 9a.57 Additional information about the putative
intermediates was provided by mass spectrometry analysis.
When a low-temperature mixture of 1b and 10f was analyzed
by mass spectrometry, a m/z corresponding to int-I could be
detected. In addition, m/z consistent with structures such as
int-II (or 1b) and int-IV were also identified.58 Although the
nature of the exact species prior to reductive elimination still
remains elusive, several possibilities are envisaged. On one
hand, dissociation of int-I would afford int-II and int-III (path
a).59 An alternative pathway would involve a disproportiona-
tion of int-I into starting oxanickelacycle 1b and int-IV (path
c).60 Reductive elimination could then occur from either int-
III or int-IV. The high degree of elimination obtained in
Scheme 4 when using Fc+ or 4CzIPN would argue against path
a
Reaction conditions: oxanickelacycle 1b (1 equiv), oxidant 10 (1.05
equiv) in CD3CN or CD2Cl2 at 25 °C.
Having identified a set of conditions that enable formation
of cyclic C(sp3)−O−C(sp3) bonds at high-valent Ni centers,
we speculated that a similar pathway should be valid for
formation of acyclic ethers. In order to study this possibility, an
acyclic precursor was synthesized through a two-step sequence
(Scheme 8A). Following the protocol from Ikeda,55 we initially
synthesized (bipy)NiEt2 (11) by reacting bipy, Ni(acac)2, and
(EtO)AlEt2 in Et2O for 50 h at 25 °C. After isolation via
Scheme 8. (A) Synthesis of (bipy)NiEt2 11 and
(bipy)Ni(Et)(OEt) 1f; (B) Oxidatively Induced Synthesis
of Diethyl Ether from Nickel Complex 1f
a
b
a
Reaction conditions: (step 1) Ni(acac)2 (1 equiv), bipy (1 equiv)
Et2AlOEt (3 equiv) in Et2O, from −50 to 25 °C, 50 h, 11 87%
isolated yield; (step 2) 11 (1 equiv), N2O (1 atm) in THF at 25 °C,
b
1f 63% isolated yield. Reaction conditions: oxanickelacycle 1f (1
equiv), 10e and 10f (1.05 equiv) in CD3CN at 25 °C, 1 min. Yields
determined by H NMR using mesitylene as internal standard.
1
F
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a
by a μ-iodo bridge between the two Ni centers. The anionic
counterion of the complexes consists of the linear I3 , which
Scheme 9. (A) EPR of int-I at 20 K; (B) Mass
−
Spectrometry Results and Postulated Mechanistic Pathways
remains in the outer sphere of the robust bimetallic cation.
Thermal decomposition of 9 beyond −10 °C leads primarily to
elimination products (6). In addition, substantial amounts of
iodoalkanols (7) were detected through preferential C(sp3)−I
reductive elimination. The low yields obtained for 2a and 2b
are postulated to arise from an intramolecular SN2 reaction
from 7 over long periods of time. This manifests that the
original mechanistic picture for direct C(sp3)−OC(sp3) bond
formation through reductive elimination is extremely challeng-
ing for simple THF rings. Cyclic voltammetry studies as well as
a survey of oxidants identified the use of fluoropyridinium
reagents 10e and 10f as excellent candidates to afford good
yields of 2 while minimizing formation of elimination
byproducts (6). In addition, this new set of conditions was
successfully applied in the elusive synthesis of acyclic diethyl
ether (2f) from a well-defined NiII complex. Preliminary
mechanistic studies revealed that upon oxidation of 1 with 10,
a highly reactive intermediate could be detected in solution by
EPR and HRMS, which is consistent with a NiIII dimeric
structure (int-I). Efforts to fully characterize the high-valent
species involved after oxidation and prior to reductive
elimination are currently under investigation in our laboratory.
We believe the findings reported here open the door to new
avenues for Ni catalysis and could aid practitioners in the field
to unravel novel metal-catalyzed ether synthesis.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c07381.
■
sı
Experimental procedures and analytical data (1H, 19F,
and 13C NMR, EPR, X-ray, HRMS, CV) (PDF)
CIF file for compound 8, also available free of charge
from the www.ccdc.cam.ac.uk under CCDC number
2014828 (CIF)
a
Experimental conditions: Power = 2.0 mW, modulation (100 kHz)
amplitude 7.5 G. Dotted red trace represents the Easyspin43 (esfit)
simulation with parameters g = (2.103, 2.200, 2.227). Dipolar
interaction D(int-I) = 299 MHz. J coupling = 100 MHz.
CIF file for compound 9a, also available free of charge
from the www.ccdc.cam.ac.uk under CCDC number
2014830 (CIF)
CIF file for compound S1, also available free of charge
from the www.ccdc.cam.ac.uk under CCDC number
2014829 (CIF)
a as a major contributor. Moreover, another possible pathway
could involve direct reductive elimination from the dinuclear
complex int-I (path b), which has been postulated for certain
C−heteroatom and C−C bond-forming events.40,61 In an
attempt to discern between mechanistic pathways, we carried
out the oxidation of 1b with only 0.5 equiv of 10f. In this case,
one-half of the yield of 2b observed in Scheme 7A was
obtained (35−40%) without trace amounts of 6b.31 The
absence of elimination byproducts suggests that cationic NiIII
species might not be present and adds additional evidence
about path a not being operative. However, the variety of
pathways by which the C−O bond could be formed manifests
the need for further mechanistic investigations to fully
elucidate the nature of the intermediates involved.
AUTHOR INFORMATION
Corresponding Author
■
Josep Cornella − Max-Planck-Institut fu
Mulheim an der Ruhr 45470, Germany; orcid.org/0000-
0003-4152-7098; Email: cornella@kofo.mpg.de
̈
r Kohlenforschung,
̈
Authors
Franck Le Vaillant − Max-Planck-Institut fu
Mulheim an der Ruhr 45470, Germany; orcid.org/0000-
0002-2723-1787
Edward J. Reijerse − Max-Planck-Institut fu
Energiekonversion, Mulheim an der Ruhr 45470, Germany;
orcid.org/0000-0001-9605-4510
Markus Leutzsch − Max-Planck-Institut fu
Mulheim an der Ruhr 45470, Germany; orcid.org/0000-
0001-8171-9399
̈
r Kohlenforschung,
̈
CONCLUSIONS
■
̈
r Chemische
In conclusion, we studied the seminal I2-promoted C−O bond
formation reported by Hillhouse toward formation of cyclic
ethers (2a and 2b). A detailed mechanistic investigation
revealed formation of 9a and 9b, an unprecedented NiIII
bimetallic structure as a cationic intermediate, which was
fully characterized by NMR, EPR, HRMS, and X-ray in the
case of 9a. These paramagnetic complexes feature a unique
Ni2(OR)2 (OR = alkoxide) diamond-like core complemented
̈
̈
r Kohlenforschung,
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c07381
G
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Article
D.; Fares, C.; List, B. Activation of olefins via asymmetric Brønsted
acid catalysis. Science 2018, 359, 1501. (f) Luo, C.; Bandar, J. S.
Superbase-Catalyzed anti-Markovnikov Alcohol Addition Reactions. J.
Am. Chem. Soc. 2018, 140, 3547. (g) Shigeno, M.; Hayashi, K.;
Nozawa-Kumada, K.; Kondo, Y. Phosphazene Base tBu-P4 Catalyzed
Methoxy−Alkoxy Exchange Reaction on (Hetero)Arenes to Aryl
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the Max-
Planck-Gesellschaft, Max-Planck-Institut fu
̈
r Kohlenforschung,
(7) (a) Vedernikov, A. N. C−O Reductive Elimination from High
Valent Pt and Pd Centers. In C-X Bond Formation. Topics in
Organometallic Chemistry; Vigalok, A., Ed.; Springer, Berlin,
Heidelberg, 2010; Vol. 31. (b) Stambuli, J. P. New Trends in
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Catalyzed Formation of C−O and C−S Bonds; Colacot, T. J., Eds.;
Royal Society of Chemistry: Cambridge, UK, 2014; Vol. 254.
(8) (a) Munir, I.; Zahoor, A. F.; Rasool, N.; Naqvi, S. A. R.; Zia, K.
M.; Ahmad, R. Synthetic applications and methodology development
of Chan−Lam coupling: a review. Mol. Diversity 2019, 23, 215.
(b) Qiao, J. X.; Lam, P. Y. S. In Boronic Acids:Preparation and
Applications in Organic Synthesis, Medicine and Materials; Hall, D. G.,
Ed.; Wiley-VCH: Weinheim, 2011; pp 315−361. (c) Sambiagio, C.;
Marsden, S. P.; Blacker, A. J.; McGowan, P. C. Copper catalysed
Ullmann type chemistry: from mechanistic aspects to modern
development. Chem. Soc. Rev. 2014, 43, 3525. (d) Monnier, F.;
Taillefer, M. Catalytic C−C, C−N, and C−O Ullmann-Type
Coupling Reactions. Angew. Chem., Int. Ed. 2009, 48, 6954.
and Fonds der Chemischen Industrie (VCI-FCI). F.L.V.
thanks the Swiss National Science Foundation for an Early
Mobility Postdoctoral Fellowship (Grant no. 184406). Sigrid
Lutz is acknowledged for help in the synthesis of (bipy)
Ni(Et)2. We thank M. Kochius for technical support with low-
temperature NMR measurements. The analytical departments
(X-ray crystallography, NMR spectroscopy, and Mass spec-
trometry) at the MPI fur Kohlenforschung are gratefully
̈
acknowledged for support in characterization of the com-
pounds. We thank Prof. Dr. T. Ritter for providing access to
the photoredox equipment in his laboratory. E.J.R. thanks
Frank Reikowski and Dr. Leonid Rapatskiy for technical
assistance with the EPR measurements. We thank Petra Hoefer
́
and Dr. Christophe Werle from the Max-Planck-Institut fur
̈
Chemische Energiekonversion (MPI-CEC) for assistance in
the cyclic voltammetry studies. We are thankful to Prof. Dr. A.
(9) For seminal Pd-catalyzed C(sp2)−O bond formation, see:
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Fu
̈
rstner for insightful discussions and generous support.
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