Resolving a Reactive Organometallic Intermediate from Dynamic Directing Group Systems by Selective C?H Activation

Article abstract of DOI:10.1002/chem.201705273

Catalyst discovery from systems of potential precursors is a challenging endeavor. Herein, a new strategy applying dynamic chemistry to the identification of catalyst precursors from C?H activation of imines is proposed and evaluated. Using hydroacylation of imines as a model reaction, the selection of an organometallic reactive intermediate from a dynamic imine system, involving many potential directing group/metal entities, is demonstrated. The identity of the amplified reaction intermediate with the best directing group could be resolved in situ by ESI-MS, and coupling of the procedure to an iterative deconvolution protocol generated a system with high screening efficiency.

Full text of DOI:10.1002/chem.201705273

A Journal of
Accepted Article
Title: Resolving a Reactive Organometallic Intermediate from Dynamic
Directing Group Systems by Selective C-H Activation
Authors: Fredrik Schaufelberger, Brian J. J. Timmer, and Olof
Ramström
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To be cited as: Chem. Eur. J. 10.1002/chem.201705273
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Resolving a Reactive Organometallic Intermediate from Dynamic
Directing Group Systems by Selective C-H Activation
Fredrik Schaufelberger,[a] Brian J.J. Timmer,[a] and Olof Ramström*[a][b]
Abstract: Catalyst discovery from systems of potential precursors is
a challenging endeavor. Herein, a new strategy applying dynamic
chemistry to the identification of catalyst precursors from C-H
activation of imines is proposed and evaluated. Using hydroacylation
of imines as a model reaction, the selection of an organometallic
reactive intermediate from a dynamic imine system, involving many
potential directing group/metal entities, is demonstrated. The identity
of the amplified reaction intermediate with the best directing group
could be resolved in situ via ESI-MS, and coupling of the procedure
to an iterative deconvolution protocol generated a system with high
screening efficiency.
efficient identification of a reactive metal-substrate intermediate.
The approach relies on dynamic systemic resolution (DSR),[6]
applying
kinetically
controlled
resolution
steps
to
thermodynamically controlled systems, targeting
a
metal-
substrate complex that provides information as to which
metal/substrate combination is able to efficiently initiate a catalytic
cycle. Metals, acids and directing groups (DGs) were screened in
a
model system of selective C-H activation reactions by
interruption of the catalytic cycle to amplify the reactive
intermediate (Figure 1). This enabled in situ identification of the
active complex with the corresponding directing group and metal
using ESI-MS. We furthermore demonstrate the coupling of this
method to an iterative deconvolution protocol to provide efficient
screening of reaction parameters.
Much effort in synthetic organic chemistry is dedicated to the
search for new catalytic systems, often discovered through time-
consuming single catalyst screening. To accelerate the discovery
of novel catalysts, constitutional dynamic chemistry has emerged
as a promising concept.[1] Reversible covalent bonds are in this
case utilized to allow the thermodynamic or kinetic adaptation of
dynamic systems in response to applied selection pressures,
resulting in amplification of the systemic constituents that best
adapt to the given settings. In principle, this approach of
simultaneously generating and evaluating multiple catalysts in
one-pot is ideal for abbreviating discovery times, and the
requirement for all catalyst candidates to be synthesized, purified,
characterized and evaluated individually is circumvented.[2] This
concept has previously been explored by us,[3] and others,[4]
showing that catalysts can be rapidly identified using dynamic
deconvolution, self-resolved from dynamic systems, or amplified
from binding to transition state analogues.
The direct identification of optimal catalyst-substrate species,
which act as reactive intermediates in the catalyzed
transformations, is in this context especially attractive. In situ
detection of such intermediates, generated from dynamic systems
involving many potential catalysts and substrates, thus provides
information of the properties of the catalyst-substrate entity
required for achieving catalytic activation.[2g, 5]
Figure 1. DG-based C-H activation of imines with metal catalyst.
DG-controlled C-H functionalization is a versatile and powerful
strategy for synthesis of a range of complex molecular targets.[7]
However, many studies have shown that even small changes in
sterics or electronics of the DGs can lead to significant activity
differences.[8] Also, the need to attach and detach the DG from
the substrate constitutes a significant drawback. In the present
study, it was hypothesized that transiently formed DGs based on
dynamic covalent bonds can bypass such limitations,[9] enabling
catalytic DGs with sufficiently rapid dynamic exchange processes.
Hydroacylation of aromatic imines with alkenes was chosen
as a model reaction for the system,[10] projected to involve initial
establishment of
a
transient DG via acid-catalyzed
This challenge has been addressed in the present
investigation, where we describe a dynamic chemistry strategy for
transimination.[11] The metal would subsequently coordinate to the
DG and insert into the aldimine C-H bond via oxidative addition,
generating a metal hydride intermediate. The rate-determining
step in the catalytic cycle has been proposed to occur after the
formation of the intermediate, enabling identification of this
species in the process. This type of intermediate has also been
observed with several different metals and DGs, for this and
similar reactions, and was thus considered suitable for the proof-
of-concept system.[12]
[a]
[b]
Dr. F. Schaufelberger, Dr. B.J.J. Timmer, Prof. Dr. Olof Ramström
Department of Chemistry
KTH - Royal Institute of Technology
Teknikringen 36, S-10044 Stockholm, Sweden
E-mail: ramstrom@kth.se
Prof. Dr. O. Ramstrom
Department of Chemistry,
University of Massachusetts Lowell
1 University Ave., Lowell, MA 01854, USA
E-mail: olof_ramstrom@uml.edu
The overall hydroacylation process is outlined in Figure 2,
indicating the imine exchange and the proposed detectable
intermediate. In addition to being identifiable, the intermediate
Supporting information for this article is given via a link at the end of
the document.
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should also be compatible with the conditions of the dynamic
process, including the different amines.
explored, but well-working approaches towards structured
deconvolution strategies of such mixtures have only recently been
proposed.[2a, 14] In the present study, a multi-parameter, iterative
deconvolution strategy was used.[2a] The investigated reagents,
eight metal catalysts and eight acids (Figure 3), were divided into
pools, which were evaluated pairwise, followed by selection of the
best-performing combination and further division into smaller
pools until a hit was found. The metals were selected to
encompass both known, working catalysts (IrI, RhI, Pt0, RuII) as
well as controls (MnII, ZnII, NiII, CuI).[12d, 12e, 15] Likewise, the acids
were chosen to obtain a wide spread in pKa, steric bulk and ability
for complementary non-covalent interactions (cf. Supporting
Information). For analysis, the expected hydride formation was
targeted, since initial experiments following the consumption of
the starting materials revealed that only this key product was
formed. Thus, the large upfield NMR spectral shift of the imine
proton upon transformation into a heavily shielded hydride (typical
signals at 0 to -25 ppm), was followed.
The metals and acids were thus separated into pools of four,
and the dynamic DG system was subjected to each metal/acid
mixture (Figure 3). The alkene substrate was omitted to maximize
amplification by preventing catalytic turnover. A short reaction
time (30 min) at 80 °C in deoxygenated toluene, with added 4 Å
MS to keep the system moisture-free, was found to produce a
small amount of a new organometallic hydridic species, as
evidenced by the appearance of a quartet at -11.2 ppm in the 1H
NMR spectrum (Round 1). No new major signals appeared in the
indicative regions of the spectrum, other than amine-containing
compound signal shifts due to metal complexation. The hydride
peak could be observed in the two pools containing Ru, Rh, Ni
and Ir. Furthermore, one acid combination proved slightly superior
to the other, leading to the selection of this pool and dividing the
metals and acids into four new pools each containing two species
of each type (Round 2). From this round, the hydridic species
could only be observed in pools with Rh and Ru. Further selection
of the best acid combination and a final pool split (Round 3)
allowed assignment of the key metal as Rh (M7) and the optimum
acid as benzoic acid (B2). As a control, omitting the acid led to
complete loss of activity in the system.
Figure 2. General scheme of dynamic directing group-controlled hydroacylation
process.
To evaluate this, a dynamic imine system utilizing acid-catalyzed
transimination was first constructed (Figure 3, top). Imine A1 did
not contain a functional DG, but all auxiliary amines 2-7 were
selected to contain well-established DGs previously used for C-H
functionalization processes.[8a, 9a, 13] Based on these structures,
imines A2-A7 formed transiently and under thermodynamic
control in the dynamic system.
Next, the dynamic imine system was applied to a mixture of
metals and acid co-catalysts to evaluate the feasibility of the DSR
methodology. The use of mixtures of metals and additives in so-
called “shotgun” approaches to catalyst screening have been
Figure 3. DSR of DG system with coupled iterative deconvolution. Numbers in boxes indicate concentration (mM, average values from duplicate experiments) of
metal hydride species at -11.2 ppm. Concentrations determined by 1H-NMR spectroscopy with PhSiMe3 as internal standard. Conditions: Imine A1 (0.03 mmol),
amines 2-7 (0.015 mmol each), acids (3.0 μmol total), toluene (0.60 ml), 80 °C, Ar, 1 h, then metals (0.015 mmol each), 4 Å MS (20 mg), 80 °C, 30 min.
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In view of the wealth of literature precedence, identification of the
Rh species as the metal most proficient at performing the
oxidative addition step of the hydroacylation process was
unsurprising. Correspondingly, benzoic acid has also been
utilized as a highly efficient co-catalyst in a number of Rh-
catalyzed hydroacylations.[16]
system with lower free amine content, yet retaining the dynamic
properties of the exchange process. Indeed, C-H activation with
Rh(PPh3)3Cl from this system provided P2 as the sole new
product in a much-improved 81% yield over 30 min.
Given that the organometallic intermediates have high
molecular weights in comparison to the initial imines and DG-
bearing amines, ESI-MS was selected as a straightforward
methodology for identifying the key Rh-H containing species
observable from the system. Indeed, direct monitoring of the
reaction system involving species B2/M7 with ESI-MS in positive
mode allowed observation of the C-H activated product P2 with a
relatively strong [P2–H]+ signal (Figure S1). Furthermore, an
intense peak originating from the [P2–Cl]+ signal could be
observed. A very small concentration of potential product P3 was
otherwise the only additional organometallic intermediate
observable.
Since the ESI-MS signals of C-H activated intermediates have
the same mass as the unactivated metal-DG complexes, NMR
spectroscopy was also employed for complementary qualitative
analysis. Performing the reaction in toluene-d8 allowed for more
accurate 1H- and 31P-NMR analysis, indicating a process with
relatively low amounts of side products despite the complexity of
the system (Figures S2-S4). It was thus again evident that
essentially only one single new species was formed, and this
intermediate was assigned as product P2. These results show
that coupling of the DSR process to an iterative deconvolution
protocol allowed for efficient reaction parameter screening and in
situ identification of the optimal DG, metal and acid for inducing
oxidative addition. A total of 448 different reaction conditions were
thus screened with just twelve reactions.
Scheme 2. Conversion of intermediate P2 into hydroacylation product P-ket.
The presented selection strategy provided information on which
metal/DG combinations were capable of inducing the oxidative
addition step in the catalytic cycle. The overall hydroacylation
reaction was therefore carried out using the selected intermediate
to verify its function. It could thus be independently confirmed that
the amplified organometallic species P2 is indeed an intermediate
for a hydroacylation reaction.[17] When compound P2 was
synthesized separately (Scheme 2), and treated with 1-octene in
deoxygenated toluene at 130 °C, followed by hydrolysis with
aqueous HCl, the expected ketone was obtained in good overall
yield starting from imine A2.
Although the system was capable of selectively resolving
product P2 in the presence of close structural analogues, higher
concentrations of free amines were suspected to affect the
resolution efficiency. 1H-NMR monitoring of product P2 over time
indicated rapid C-H activation over the first 30 min, followed by a
short plateau, before the reaction intermediate started to
decompose (Figure S4). To test if the amine concentration was
detrimental to product stability, the size of the dynamic imine
system was increased and reduced by addition or removal of DG
components (Table S2). This resulted in a clear correlation
between total amine concentration and resolution efficiency.
Following these conclusions, a new approach to obtain higher
efficiency was devised (Scheme 1). All relevant DG-containing
free amines were thus condensed with slightly substoichiometric
amounts of benzaldehyde with 4 Å MS to obtain a dynamic imine
In summary, we have demonstrated a new strategy applying
dynamic chemistry to reactive organometallic intermediate
discovery. A dynamic systemic resolution process could be used
to amplify an intermediate in a catalytic cycle, and enabled direct
identification of active metal/directing groups in a complex system.
Furthermore, judicious coupling of this amplification method to an
iterative deconvolution protocol led to powerful resolving
efficiency in parameter space. The organometallic complex P2 is
by far the most intricate and reactive structure resolved from a
dynamic system. This study thus additionally demonstrates that
with appropriate optimization and choice of parameters, even
transient or metastable species can be resolved from dynamic
systems.
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Scheme 1. Direct condensation followed by selective C-H activation of dynamic directing group system.
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demonstration under grant agreement no 289033. FS thanks the
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Keywords: Dynamic chemistry • C-H activation • Catalysis •
Directing group • Systems chemistry
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Fredrik Schaufelberger, Brian J.J.
Timmer, and Olof Ramström*
Page No. – Page No.
Resolving a Reactive Organometallic
Intermediate from Dynamic Directing
Group Systems by Selective C-H
Activation
A new strategy applying dynamic chemistry to the selection of catalyst precursors
from C-H activation of imines is presented. Using hydroacylation as a model reaction,
the strategy enabled identification of an organometallic reactive intermediate from a
dynamic imine system, where the best directing group could be resolved in situ.
This article is protected by copyright. All rights reserved.