Accelerated Discovery in Photocatalysis by a Combined Screening Approach Involving MS Tags

Article abstract of DOI:10.1021/acs.orglett.9b03936

Herein we report on the development of an MS tag screening strategy that accelerates the discovery of photocatalytic reactions. By efficiently combining mechanism- and reaction-based screening dimensions, the respective advantages of each strategy were re

Full text of DOI:10.1021/acs.orglett.9b03936

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Accelerated Discovery in Photocatalysis by a Combined Screening
Approach Involving MS Tags
Michael Teders,† Sabrina Bernard,‡ Karin Gottschalk,† J. Luca Schwarz,† Eric A. Standley,†
,‡
Elodie Decuypere,‡ Constantin G. Daniliuc,† Davide Audisio,‡ Frederic Taran,*
́
́
and Frank Glorius*,†
†
̈
̈
̈
̈
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstraße 40, 48149 Munster, Germany
‡
́
Service de Chimie Bio-organique et Marquage, DRF-JOLIOT-SCBM, CEA, Universite Paris-Saclay, 91191 Gif-sur-Yvette, France
S
* Supporting Information
ABSTRACT: Herein we report on the development of an MS tag screening strategy that accelerates the discovery of
photocatalytic reactions. By efficiently combining mechanism- and reaction-based screening dimensions, the respective
advantages of each strategy were retained, whereas the drawbacks inherent to each screening approach could be eliminated.
Applying this approach led to the discovery of a mild photosensitized decarboxylative hydrazide synthesis from mesoionic
sydnones and carboxylic acids as starting materials.
he development of new transformations and the
catalytic reactions: Detectable amounts of product have to be
formed, requiring the matching of diverse reaction parameters.
For this purpose, a large number of parameters must be varied,
which leads to time-consuming and, in the end, costly
protocols with an overall limited hit rate.
Timprovement of existing methodologies toward “greener”
alternatives are central tasks of many research programs
throughout organic chemistry.1 In this regard, catalysis has
revolutionized the way valuable molecular scaffolds are
constructed under mild conditions and even enabled the
identification of numerous breakthroughs and unknown
reactivity modes.2 Many discoveries derive from an in-depth
understanding of well-established reactions and their under-
lying mechanisms, consecutively enabling the transfer of this
gained knowledge to new classes of suitable catalysts and
substrates. Whereas this “rational-design” approach has led to
many beautiful transformations,3 the breakthrough discovery
potential is limited. The exploration of new reactivity modes is
often enabled by utilizing discovery-oriented screening
approaches4 because they allow a broader and systematic
evaluation of chemical space.5 These discovery-oriented
screening methodologies contribute to a deep understanding
of the underlying reactivity principles, which can ultimately be
used in “comprehension-guided” rational-design approaches.6
A prominent strategy for the discovery of new transformations
are reaction-based screening approaches, where the formation
of a new reaction product is usually identified by GC− or LC−
MS analysis (Scheme 1a).7 Hereby, preselected substrates,
catalysts, or reaction conditions are screened in a systematic
fashion. Whereas the setup required for such a screening
approach is readily available and automatization is possible,8
this concept has one inherent drawback with respect to
In mechanism-based discovery-oriented screening ap-
proaches, one single step out of the whole catalytic cycle is
evaluated by means of a suitable analytical tool, for example,
mass spectrometry,9 cyclic voltammetry,10 or luminescence
spectroscopy.6,11 Such approaches therefore identify classes of
substrates that interact with a catalyst and provide useful
mechanistic insights (Scheme 1b). However, because this
approach covers only one step of what is often a complex
catalytic cycle, the development of a transformation requires
either significant postscreening or rational reaction design.
Recently, we reported on a screening strategy in the research
field of visible-light photocatalysis that merges mechanism- and
reaction-based screening approaches.12,13 The appropriate
combination of these two 1D screening approaches retains
their respective advantages in terms of breakthrough discovery
potential while eliminating the drawbacks inherent to each
approach, which is well demonstrated by our discovery of two
unexpected uphill energy-transfer reactions.
Received: November 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03936
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Scheme 1. Principles of (a) Reaction- and (b) Mechanism-Based Discovery-Oriented Screening Approaches and (c) a
Conceptual Sketch of the Combined Mechanism- and MS Tag Reaction-Based Screening Approach (This Work) for
a
Accelerated and Highly Efficient Discovery in Photocatalysis
a
Cat, catalyst; Sub, substrate; Q, quencher; PC, photocatalyst.
Scheme 2. Workflow Diagram Illustrating the Conceptual Approach of the Combined Mechanism- and Reaction-Based
a
Screening Strategy That Lead to the Discovery of a Photosensitized Decarboxylative Hydrazide Synthesis
a
Installation of a phosphorus-based MS tag into a previously discovered sydnone quencher renders the second screening step highly efficient with
respect to the required catalyst, reagent, and solvent quantities. Values in yellow or green circles represent quenching fractions of the respective
substrate with [Ir−F] as a photocatalyst. PC, photocatalyst; Q, quencher; R, reagent; MeCN, acetonitrile.
Although this concept bears enormous potential for the
discovery of (new) reactions and reactivity modes, it still
suffers from three major limitations:
quenching might eliminate the previously mentioned dis-
advantages (Scheme 1c).14 The installed MS tag would allow
an intuitive and quick analysis of the reaction outcome using
electrospray ionization mass spectrometry (ESI−MS). Fur-
thermore, because of the extremely low detection limits that
this analytical technique possesses, the required quantities of
reagents, catalysts, and solvents would be significantly
decreased. A significant drawback of such a technique,
however, is the need for the covalent installation of a suitable
MS tag and the need to investigate the properties of the tagged
compound. In this context, also the full automatization of such
a screening approach is hardly possible.
(1) The GC−MS analysis of each reaction mixture is time-
consuming.
(2) The identification of polar reaction products by GC−
MS is not possible.
(3) Overall high quantities of reagents, catalysts, and
solvents are required due to the analytical limit-of-
detection.
We envisioned that the covalent installation of a suitable MS
tag onto a lead substrate previously identified by luminescence
B
DOI: 10.1021/acs.orglett.9b03936
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Organic Letters
Letter
We started our conceptual study by investigating the
interaction of 25 randomly selected potential quenchers,
featuring diverse functional groups, using [Ir(dF(CF3)-
ppy)2(dtbbpy)](PF6) ([Ir−F], dF(CF3)ppy = 2-(2,4-difluor-
ophenyl)-3-trifluoromethylpyridine, dtbbpy = 4,4′-di-tert-
butyl-2,2′-bipyridine) as a photocatalyst in the first mecha-
nism-based luminescence quenching screening dimension
(Scheme 2). The photocatalyst [Ir−F] was selected due to
its high excited-state redox potentials (E(MIII*/MII) = +1.15 V
vs Fc/Fc+ and E(MIII/MIV*) = −1.16 V vs Fc/Fc+)15 and its
Figure 1. Crystal structure of N,N-diacylhydrazide 3a. Thermal
ellipsoids are shown with 30% probability.
high triplet excited-state energy (ET = 61.82
0.30 kcal/
mol),13 thus covering both the electron-transfer (ET) and
energy-transfer (EnT) domains of chemical space. Among the
25 screened substrates, we identified 6 new quenchers (Q3,
Q10, Q14, Q22, Q23, and 1(Q20)) characterized by a
significant quenching fraction. Among them, phenylsydnone 1
was identified to strongly interact with photoexcited [Ir−F].
Sydnones are prominent compounds of the mesoionic family
and have been mainly studied for their cycloaddition reactivity
(noncatalyzed,16 copper-catalyzed,17 or light-induced18). To
the best of our knowledge, visible-light photocatalyzed
reactions involving mesoionic compounds have not been
reported. Consequently, the high degree of quenching of
phenylsydnone 1 prompted us to select it as lead compound
for the second MS tag reaction-based screening. Because of its
high chemical robustness, low reactivity, and excellent
ionization properties, a phosphorus-based MS tag was
covalently installed into the phenylsydnone scaffold in two
straightforward steps, yielding MS-tagged phenylsydnone
1tag.19 We then selected 96 diverse reactants covering chemical
space to discover new reactions by applying the second MS tag
reaction-based screening dimension. Using a 96-well plate with
the [Ir−F] photocatalyst, tagged 1tag, and the respective
reactant R1−R96 in each vial dissolved in a total reaction
volume of 200 μL of acetonitrile, we irradiated the reaction
mixtures using blue LEDs (λmax = 455 nm). After 24 h of
irradiation, the outcome of the reactions was investigated by
ESI−MS.20 By simply comparing the obtained spectra with
two reference spectra ((I) only 1tag and hν in MeCN; (II) [Ir−
F], 1tag, and hν in MeCN), additional peaks may indicate the
formation of a reaction product. In total, 17 out of 96
combinations gave rise to new ESI−MS peaks. Some of the
masses could be directly transformed into possible product
motifs using only the mass spectra.20 During the analysis of the
reaction-based screening results, we noticed a recurring pattern
of the formation of a new MS peak when a carboxylic acid
functionality was present within the reactant’s structure. To
verify and reproduce our screening results, we decided to run
this reaction on a 0.3 mmol scale using untagged 4-
fluorophenyl sydnone 1 in the presence of cyclohexanecarbox-
ylic acid 2a and [Ir−F] under otherwise unchanged screening
conditions. After the reaction and the subsequent purification
process, we identified diacylhydrazide 3a as the formed
reaction product, verified by nuclear magnetic resonance
(NMR) spectroscopy and by X-ray crystallography (see Figure
1).
photocatalyst, employing a catalyst loading of 2.5 mol %, and
increasing the equivalents of the carboxylic acid 2a21 while
using acetonitrile (0.1 M) as solvent.22 With the optimized
reaction conditions in hand, we next investigated the scope and
synthetic limitations of this decarboxylative hydrazide synthesis
(Scheme 3a). Performing the reaction on a 10-fold higher scale
worked well, delivering the product in 61% isolated yield. The
utilization of cyclic secondary carboxylic acids with five- or
three-membered ring systems was successful, delivering the
products in 49 or 46% yield, respectively (3b, 3c).23 When
acetic acid was used as a coupling partner, the desired product
3d could be obtained in a moderate yield of 51%. Benzoic or
phenylacetic acid could also be converted; however, the yield
decreased to 36 and 43% (3e and 3f). The incorporation of
fluorine substituents or alkyne moieties into the carboxylic acid
functionality was tolerated and provided the corresponding
products 3g and 3h in good yield (77−81%). Tertiary
carboxylic acids could also be employed, as shown by the
use of pivalic acid delivering hydrazide 3i in 45% yield.
Gratifyingly, the use of unsaturated fatty acids was also
possible, resulting in the formation of hydrazide 3j in 63%
yield. The up-scaling of this reaction resulted in a slightly
diminished yield of 55% (3.0 mmol scale). We next
investigated the scope with respect to modifications of the
sydnone’s aryl moiety. Diverse functional groups, such as
methoxy (3l), iodo (3m), acetyl (3n), or hydroxyl (3o)
substituents, were tolerated, delivering the hydrazide products
in good to excellent yields (67−78%, 3k−o). The replacement
of the phenyl group by a methyl group had no influence on the
reaction: Methyl hydrazide 3p could be isolated in 85% yield.
The reaction further tolerates the presence of alkyl or aryl
substituents at the C-4-position of the phenyl sydnone. The
hydrazide products 3q−s could be obtained in good yield
(78−82%). Besides, an inversion of regioselectivity is observed
for those latest examples. To further investigate the functional
group tolerance and the preservation of this photocatalytic
hydrazide synthesis, an additive-based robustness screen was
performed.24 The results are summarized in histograms
(Scheme 3b). We were delighted to see that in most cases
the yield of the product was not affected by the presence of an
additional additive, indicating an overall high robustness of the
transformation. With an average recovered additive yield of
76%, the reaction is furthermore characterized by an extremely
high functional group preservation.
Next, we started optimizing the reaction parameters, such as
the nature of the photocatalyst, the irradiation wavelength, or
the solvent, using 4-fluorophenyl sydnone 1a and cyclo-
hexanecarboxylic acid 2a as benchmark reagents. Gratifyingly,
the yield of 3a could be increased from 13 to 67% by switching
to [Ru(bpz)3](PF6)2 ([Ru], bpz = 2,2′-bipyrazine) as the
The obtained N,N-diacylhydrazide product scaffold 3 is of
huge importance for many diverse applications in pesticide,25
materials,26 and pharmaceutical chemistry.27 Furthermore, the
products are important key intermediates for the synthesis of
numerous heterocycles.28 As shown in Scheme 4a, the
products can be easily transformed to chiral 1,2,4-triazolium
C
DOI: 10.1021/acs.orglett.9b03936
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Scheme 3. (a) Substrate Scope and (b) Additive-Based
Robustness Screen Results for the Photosensitized
Decarboxylative Hydrazide Synthesis
Scheme 4. (a) Product Diversification of the Reaction
Products To Access Chiral 1,2,4-Triazolium Salts as NHC
Precatalysts and (b) Proposed Energy-Transfer Mechanism
(Supported by Diverse Mechanistic Experiments) for the
a
a
Photosensitized Decarboxylative Hydrazide Synthesis
a
NHC, N-heterocyclic carbene. For the experimental procedure and
details of mechanistic experiments, see the Supporting Information.
mol).11a Triplet−triplet energy transfer from 3*[RuII] to
sydnone 1 (ET = 48.5 kcal/mol)18b recycles the [RuII]
ground-state photocatalyst. The sensitization of 1 promotes
the formation of Earl’s bicyclic lactone intermediate 5, which
yields diazirene 6 after decarboxylation. For unsubstituted
sydnones (R = H), IM1 is formed after the addition of the
carboxylic acid. The corresponding products 3a−p are
obtained after consecutive rearrangement. In the case of
sydnone substitution (R = aryl or alkyl), nitrilimine IM2 is
formed, which yields the corresponding products 3q−s after
carboxylic acid addition and rearrangement. A reaction
quantum yield of Φ = 0.59, UV−vis and Stern−Volmer
analysis, TEMPO-trapping experiments, as well as diverse
deuterium and 13C-labeling experiments support this mecha-
nistic hypothesis.30 Transient absorption studies to prove the
energy-transfer activation nature of 1 are currently being
investigated in our laboratories.
In conclusion, we have successfully developed a screening
methodology involving MS tags that allowed the accelerated
discovery of a photocatalytic reaction. By combining
mechanism- and reaction-based screening, the limitations of
each individual screening approach are eliminated while
establishing a highly efficient strategy potentially allowing the
discovery of ground-breaking photocatalytic reactions. Indeed,
the covalent installation of a suitable MS tag both facilitates the
identification of newly formed bond (dis)connections and
allows a significant reduction of the required amount of
reagents, catalysts, and solvents. Applying this approach
resulted in the discovery of a highly functional-group-tolerant
photosensitized decarboxylative hydrazide synthesis from
mesoionic sydnones and carboxylic acids as starting materials.
We are convinced that the application of combined screening
approaches will accelerate diverse ground-breaking discoveries,
a
[a] General conditions: 1a−s (0.3 mmol), 2 (6.0 mmol, 20.0 equiv),
[Ru] (2.5 mol %), MeCN (0.1 M), λmax = 455 nm, rt, 24 h. All stated
yields are isolated. [b] HPLC purification required. [c] Product
structure confirmed by X-ray analysis; see ref 20. [d] 40.0 equiv of
acetic acid used. [e] Robustness screen performed using 0.1 mmol of
1a; see the Supporting Information for the experimental details and
procedure.
salt N-heterocyclic carbene (NHC) precursors 4, which can be
used for enantioselective catalysis.29
The proposed mechanism of this transformation, which is in
accordance with diverse performed mechanistic experiments
(see the SI for further information) and literature reports on
the direct sensitization of mesoionic sydnones (λ < 300 nm)18,
is depicted in Scheme 4b. The [RuII] photocatalyst is excited
by visible light to its triplet excited state (ET = 48.4 kcal/
D
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03936.
Experimental details, characterization data, mechanistic
experiments, and copies of NMR spectra of new
compounds (PDF)
Accession Codes
CCDC 1867622−1867625 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
́
́
(6) (a) Hopkinson, M. N.; Gomez-Suarez, A.; Teders, M.; Sahoo, B.;
Glorius, F. Accelerated Discovery in Photocatalysis using a
Mechanism-Based Screening Method. Angew. Chem., Int. Ed. 2016,
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Kalthoff, F.; Gomez-Suarez, A.; Kleinmans, R.; Kahnt, A.;
Rentmeister, A.; Guldi, D.; Glorius, F. The Energy-Transfer-Enabled
Biocompatible Disulfide−Ene Reaction. Nat. Chem. 2018, 10, 981−
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AUTHOR INFORMATION
Corresponding Authors
■
(7) (a) McNally, A.; Prier, C. K.; MacMillan, D. W. C. Discovery of
an α-Amino C−H Arylation Reaction Using the Strategy of
Accelerated Serendipity. Science 2011, 334, 1114−1117. (b) Robbins,
D. W.; Hartwig, J. F. A Simple, Multidimensional Approach to High-
Throughput Discovery of Catalytic Reactions. Science 2011, 333,
1423−1427. (c) Troshin, K.; Hartwig, J. F. Snap Deconvolution: An
Informatics Approach to High-Throughput Discovery of Catalytic
Reactions. Science 2017, 357, 175−181.
*E-mail: frederic.taran@cea.fr (F.T.).
*E-mail: glorius@uni-muenster.de (F.G.).
ORCID
Eric A. Standley: 0000-0003-0680-6788
Davide Audisio: 0000-0002-6234-3610
(8) (a) Shevlin, M. Practical High-Throughput Experimentation for
Chemists. ACS Med. Chem. Lett. 2017, 8, 601−607. (b) Kuijpers, K.
́
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Frederic Taran: 0000-0001-5461-329X
Frank Glorius: 0000-0002-0648-956X
́
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P.; Bottecchia, C.; Cambie, D.; Drummen, K.; Konig, N. J.; Noel, T. A
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Quenching Studies and Stern-Volmer Analysis. Angew. Chem., Int.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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Catalyst Mixtures by Mass Spectrometric Monitoring of Catalytic
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We thank the Deutsche Forschungsgemeinschaft (Leibniz
Award), the Alexander von Humboldt Foundation (E.A.S.),
and SusChemSys 2.0 (M.T.) for generous financial support.
We are also grateful to T. Wagener, F. Strieth-Kalthoff, and L.
̈
̈
̈
Anhauser (all WWU Munster) for experimental support and
helpful discussions.
Mass-Labeling Strategy. J. Am. Chem. Soc. 2008, 130, 3234−3235.
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(19) Luminescence quenching analysis revealed a quenching fraction
of the phosphorus-based MS tag of F = 24%, most likely due to
reductive quenching of the excited-state [Ir-F] photocatalyst by the
iodide. Because this quenching fraction is low compared with the one
of the mesoionic sydnone 1, the influence of the background
quenching on the screening should be rather low. Details can be
found in the Supporting Information.
(20) See the Supporting Information for the experimental details
and procedure.
(21) After the reaction, 18.9 equiv of the carboxylic acid could be
recovered. Effectively 1.1 equiv of the carboxylic acid was therefore
consumed; see the Supporting Information for details.
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be found in the Supporting Information.
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F
DOI: 10.1021/acs.orglett.9b03936
Org. Lett. XXXX, XXX, XXX−XXX