N-Ammonium Ylide Mediators for Electrochemical C-H Oxidation

Article abstract of DOI:10.1021/jacs.1c03780

The site-specific oxidation of strong C(sp3)-H bonds is of uncontested utility in organic synthesis. From simplifying access to metabolites and late-stage diversification of lead compounds to truncating retrosynthetic plans, there is a growing need for new reagents and methods for achieving such a transformation in both academic and industrial circles. One main drawback of current chemical reagents is the lack of diversity with regard to structure and reactivity that prevents a combinatorial approach for rapid screening to be employed. In that regard, directed evolution still holds the greatest promise for achieving complex C-H oxidations in a variety of complex settings. Herein we present a rationally designed platform that provides a step toward this challenge using N-ammonium ylides as electrochemically driven oxidants for site-specific, chemoselective C(sp3)-H oxidation. By taking a first-principles approach guided by computation, these new mediators were identified and rapidly expanded into a library using ubiquitous building blocks and trivial synthesis techniques. The ylide-based approach to C-H oxidation exhibits tunable selectivity that is often exclusive to this class of oxidants and can be applied to real-world problems in the agricultural and pharmaceutical sectors.

Full text of DOI:10.1021/jacs.1c03780

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N‑Ammonium Ylide Mediators for Electrochemical C−H Oxidation
Masato Saito,† Yu Kawamata,*,† Michael Meanwell,‡ Rafael Navratil,‡ Debora Chiodi,‡ Ethan Carlson,
Pengfei Hu, Longrui Chen, Sagar Udyavara, Cian Kingston, Mayank Tanwar, Sameer Tyagi,
Bruce P. McKillican, Moses G. Gichinga, Michael A. Schmidt, Martin D. Eastgate,
Massimiliano Lamberto, Chi He, Tianhua Tang, Christian A. Malapit, Matthew S. Sigman,
Shelley D. Minteer, Matthew Neurock,* and Phil S. Baran*
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ABSTRACT: The site-specific oxidation of strong C(sp3)−H bonds is of uncontested utility in organic synthesis. From simplifying
access to metabolites and late-stage diversification of lead compounds to truncating retrosynthetic plans, there is a growing need for
new reagents and methods for achieving such a transformation in both academic and industrial circles. One main drawback of
current chemical reagents is the lack of diversity with regard to structure and reactivity that prevents a combinatorial approach for
rapid screening to be employed. In that regard, directed evolution still holds the greatest promise for achieving complex C−H
oxidations in a variety of complex settings. Herein we present a rationally designed platform that provides a step toward this
challenge using N-ammonium ylides as electrochemically driven oxidants for site-specific, chemoselective C(sp3)−H oxidation. By
taking a first-principles approach guided by computation, these new mediators were identified and rapidly expanded into a library
using ubiquitous building blocks and trivial synthesis techniques. The ylide-based approach to C−H oxidation exhibits tunable
selectivity that is often exclusive to this class of oxidants and can be applied to real-world problems in the agricultural and
pharmaceutical sectors.
been described for the direct conversion of C(sp3)−H to C−O
INTRODUCTION
■
bonds. Among the tactics explored, direct hydrogen abstraction
The area of C−H oxidation has experienced a dramatic
by reactive radicals4,8,9 (including metal-oxo10 and dioxirane11
increase in attention from the organic chemistry community
stemming from a strategic simplification of retrosynthesis1 and
species that are known to generate reactive radicals transiently)
a desire for late-stage functionalization in discovery settings,2
has been established as an effective approach for this purpose
and as a means to access valuable metabolites.3 Methods to
(Figure 1A). The mainstream approach for metabolite
synthesis/late-stage oxidation involves a combination of trial-
achieve such functionalizations, specifically C(sp3)−H to C−
O, have a rich history in organic synthesis.4 In an industrial
and-error together with a careful evaluation of critical chemical
features such as sterics and electronics to control innate
setting, biochemical approaches are the most oft-applied
methods of achieving such transformations in a chemo- and
Received: April 9, 2021
Published: May 13, 2021
position-selective manner using a toolkit of CYP enzymes or
whole-cell approaches (Figure 1A).5 These methods are
popular due to their mild nature, catalyst-controlled selectivity
(rather than substrate control), and ability to tune and
modulate selectivity through directed evolution.6,7 In an effort
to emulate these features, a myriad of reactive species have
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Figure 1. Overview of known reactive species for strong C(sp3)−H bond oxidation, current state of the art in metabolite synthesis, and challenges
for further innovation. (A) Summary of representative reactive species or precursors that were previously used for C(sp3)−H oxidation. (B)
Sophisticated reactive species are used in recent examples for metabolite synthesis, illustrating the potential of simple and tunable mediators to
enable access to various metabolites. (C) Our attempt to develop tunable quinuclidine-based mediators was concluded to be difficult due to
synthetic inefficiency for analog preparation and unsatisfactory change in reactivity/selectivity.
selectivity. This is illustrated in Figure 1B with three different
commercially used pharmaceuticals (1,12,13 314, and 415) and
one agrochemical (2).16 With the native metabolic sites
highlighted in red,17−20 one observes similar selectivities using
metal-oxo species that can be tuned to some extent using
engineered enzymes such as 5 for the oxidation of buspirone
(1). Although the screening of chemical reagents such as 5−8
on these commercial products (1−4) can also furnish natural
metabolites, this trial-and-error approach is limited. Each
reagent or catalyst requires a separate laborious synthesis that
makes rapid tunability challenging. In contrast, the extra-
ordinary utility of directed evolution approaches is a
consequence of the sheer number of enzymatic catalysts that
can be empirically screened (hundreds to millions). Our
attempts to improve electrochemical C−H oxidation using
quinuclidine 11 as the hydrogen atom transfer (HAT)-based
mediator (Figure 1C) was emblematic of this problem.21 Thus,
several analogs of quinuclidine (12−17) were either prepared
(4−6 steps)22 or purchased, yet no improvement in efficiency
or selectivity was observed in the oxidation of sclareolide 9.
Each designed quinuclidine analog generally required a de novo
total synthesis requiring weeks or months of effort. To even
begin to compete with any biochemical approach, a
combinatorial array of simple, tunable, and easily accessed
mediators/reagents/catalysts is needed so that synthesis is no
longer a bottleneck. Herein we present such an approach using
a new class of mediators that have rarely been employed in
organic synthesis: N-alkyl ammonium ylides. These mediators,
designed based on first principles and triaged through in silico
screening, form the basis of a simple chemical approach to C−
H oxidation as they are easily prepared, stable, and modular
and exhibit unique selectivity.
RESULTS AND DISCUSSION
■
This study was launched with a structure-agnostic approach
guided by a postulated mechanism. As such, instead of starting
with a plausible mediator structure, the desired catalytic cycle
was modeled, and thermodynamic descriptors were evaluated
computationally. To perform such an in silico screen logically,
parameters were chosen to evaluate reactive radicals based on
the cycle depicted in Figure 2A. This general catalytic cycle
was modeled from the mechanism of quinuclidine-mediated
C−H oxidation21 and consists of three elementary steps: (1)
hydrogen abstraction by the reactive mediator-centered radical
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Figure 2. Design, proof of concept, and library construction of new electrochemical mediator N-ammonium ylides (A). Design of ideal catalytic
cycle and evaluation of thermodynamic parameters (Eox, ΔGH‑bind, DPFE) of reactive species in order to perform in silico screening logically and
efficiently. (B) Preliminary results to confirm predicted parameters, which were proven to be in good agreement with experimental results. (C).
a
Synthesis of N-ammonium ylides, their unparalleled diversity, and their unique tunability to rapidly modulate their reactivity/selectivity. Possible
chemical space constructed by 2419 acids is shown in gray, screened mediators are highlighted in orange, and Y2−Y7 are highlighted in blue.
c
d
bReference 34. Product distribution was too complex to analyze. Reference 42.
M•, (2) deprotonation of protonated species MH to regenerate
the precursor to this radical M−, and (3) oxidative regeneration
of M•. Accordingly, three thermodynamic parameters were
chosen to estimate the efficacy of each elementary step:
hydrogen binding free energy (ΔGH‑bind), deprotonation free
energy (DPFE), and oxidation potential (Eox). The ideal
reactive radical needs to have a large negative ΔGH‑bind (kJ/
mol) to readily facilitate hydrogen abstraction, low DPFE (kJ/
mol) for mild deprotonation, and low Eox (V/SHE) for facile
oxidation. We initially evaluated the oxidation potentials (Eox)
and hydrogen binding energies (ΔGH‑bind) for numerous
potential mediator structural classes (11, 12, 18−24) using
first-principles density functional theory (DFT) calculations
along with chemical intuition and literature precedent23−27
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(see the Supporting Information (SI) for details regarding the
calculation methodology). This allows for a targeted search of
effective mediator candidates. Boundaries for furthering the
search (ΔGH‑bind ≤ −180 kJ/mol, Eox ≤ 1.7 V vs SHE) were set
based on the ΔGH‑bind for the quinuclidinium radical 11•
(ΔGH‑bind = −183 kJ/mol), which has shown demonstrated
reactivity for the desired transformation (Figure 2A), as well as
readily achievable oxidation potential within common solvent
electrochemical window (Eox ≤ 1.7 V). Within these
boundaries (highlighted in blue), three promising mediator
candidates (11•, 22•, 23•) were identified. For example, the
quinuclidine analog 12 (Figure 1C), which is not effective in
C−H oxidation, lies far outside the highlighted area. Among
these potential candidates, the imidazolium mediator 23 was
considered less attractive due to its high DPFE values (673 kJ/
mol, experimental pKa = 2328), making regeneration of such
species difficult under mild conditions. Quinuclidine scaffolds
based on 11 were excluded due to low tunability demonstrated
previously (Figure 1C). The result of this analysis thus led to
the identification of the N-ammonium amminium radical 22•
as a possible candidate for experimental study: it offers low
DPFE (600 kJ/mol), highly negative hydrogen binding energy
(ΔGH‑bind = −229 kJ/mol), moderate oxidation potentials (Eox
= 1.7 V vs SHE), and excellent tunability, as discussed below.
To our knowledge, N-ammonium ylides (the precursor to such
radicals) have not been studied in the realm of C−H
functionalization, with the closest example being a triazolium
betaine for activated C−H bond functionalization.29
The simple cyclic N-ammonium ylide Y1 was synthesized to
confirm these calculated results (Figure 2B). Indeed, the
measured oxidation potential matched with the calculated
value, and the predicted basicity (less basic than quinuclidine)
was experimentally confirmed (see SI for basicity study). Most
excitingly, it was experimentally proven that an N-ammonium
ylide can be effective for unactivated C−H bond oxidation.
This finding led to an extensive investigation of N-ammonium
ylides as a new class of tunable and easily accessed mediators
for electrochemical C−H bond oxidation. The simple, modular
gram-scale synthesis of N-ammonium ylide salts enabled rapid
construction of a library carrying various electron-withdrawing
groups (EWGs) and alkyl groups (R1, R2) (Figure 2C). Most
of the ylide salts are stable and handled without any precaution
to atmospheric oxygen and moisture. The free ylides can be
conveniently generated in situ with a mild base (NaHCO3) or
separately isolated and employed in the reaction. The
tunability of N-ammonium ylides is unparalleled in other
classes of reactive species; even if the EWG is limited to
carboxylic acids, more than 200 000 carboxylic acids are
commercially available, demonstrating a huge window of
structural variation. With a small library of ylides in hand (80
members), a reactivity screening was performed across the
entire library (see SI for details), leading to the identification of
ylides Y2−Y7 as better mediators than Y1 based on reactivity,
ease of preparation, and structural diversity. In particular, to
highlight the remarkable structural diversity, visualization of
the chemical space for readily available carboxylic acids, the
building unit for ylide mediators, was attempted.30 In order to
provide a reasonably sized dataset for the analysis of carboxylic
acid chemical space (see SI for details), the list of acids from a
Reaxys substructure search (>2.78 million) was filtered based
on commercial availability, functionality, and available data,
resulting in 2419 acids for which two- and three-dimensional
Mordred descriptors were calculated.31 Uniform Manifold
Approximation and Projection (UMAP), a non-linear
dimensionality reduction technique that preserves global
structure, was applied to the data to enable visualization of
the chemical space (Figure 2C, UMAP).32,33 Qualitative
analysis indicated that the preliminary screening campaign
covered a large region of chemical space, but the possibilities
for further exploration are vast. In contrast, other species
known to be useful for direct C−H oxidation, such as
dioxirane, oxaziridine, quinuclidine, and iron-oxo complexes,
have much fewer derivatives reported in the literature to date
despite many decades of precedent (see SI for detailed
references used for counting derivatives). The tunable
selectivity of these mediators was vividly demonstrated in the
oxidation of sclareolide 9, in which the ratio of 2-oxo and 3-
oxo products could be varied from 2:1 to 25:1 simply by
changing substituents on the ylides. Moreover, these ylides
provided improved reactivity and differing site-selectivity in
C−H oxidation relative to other methods. For example,
isopregnanolone acetate (27) and menthol acetate (28) gave
poor conversion when quinuclidine was used as a mediator,
whereas ylides Y4 and Y7 afforded the oxidation products in
synthetically useful yields in these cases. Notably, site-
selectivity and reactivity for these substrates were either
superior (in the case of 27) or orthogonal (in the case of 28)
to known oxidation systems (Fe-,34 Ru-,35 and W-based,36
TFDO,37,38 and quinuclidine21), demonstrating that N-alkyl
ammonium ylides are a distinct class of reactive species with
high tunability. To aid the practitioner and understand the
contextual selectivity of ylides, all substrates in this study were
subjected to this comparative panel of oxidants.
Figure 3 illustrates the scope of ylide-mediated electro-
chemical C−H oxidation with a broad range of substrates and
unveils their unusual and often singularly selective nature. Y7
was found to be the most effective across various substrates; in
some cases Y4 and Y6 were found superior to Y7,
demonstrating rapid reaction optimization through this
combinatorial approach. Two general protocols were followed,
employing either hexafluoroisopropanol (HFIP)/CH3CN or
water/CH3CN solvent mixtures. The latter solvent combina-
tion often resulted in a cleaner reaction, albeit with slower
product formation. Although the oxidation of unactivated C−
H bonds is routinely carried out in the presence of a large
excess of substrates in the literature, all screening was
performed with the substrate as limiting agent, to accurately
represent real-world applications. Ylide-based C−H oxidations
generally fell into two categories: unique selectivity and
enhanced reactivity not readily achievable with other known
chemical oxidants (Class I), and selectivity in line with that
observed previously (Class II). In general, substrates falling
into Class I are more complex and likely better representations
of the types of molecules encountered in medicinal and natural
product chemistry. The ability of ylide mediators to oxidize
unactivated methylene positions in these settings, where all
other commonly employed chemical reagents fail, is notable
(e.g., 27, 29−32). This selectivity stems from a strong affinity
of the N-ammonium amidyl radical to hydrogen along with
steric guidance of such a radical, as corroborated by DFT
calculations which model the transition state of the oxidation
of 29 (see SI for details). The same calculations can rationalize
why quinuclidine has unique methine selectivity on the same
molecule. In fact, one of the only methine oxidations observed
in this work was on the isopropyl group of menthol acetate
(28). In this case, the methylene positions are less sterically
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Figure 3. Ylide-mediated electrochemical C(sp3)−H oxidation. See SI for the detailed conditions for each reaction. N.D. indicates that the product
distribution was too complex to analyze. RSM: recovered starting material (%). aCondition A was used. bCondition B was used. cRecovered starting
d
e
material was recycled once. See SI for detailed product distribution. Yield with flow system (ref 36).
accessible by the bulky ylide mediator, resulting in the tertiary
alcohol product derived from C1 oxidation. This result is
especially unusual given that, of the productive oxidants
screened, all favored C5 oxidation. Another unique attribute of
the ylide platform is its tendency to afford significant quantities
of secondary alcohol rather than ketone products (27, 32,
33).39 This stands in stark contrast to quinuclidine-mediated
electrochemical oxidation, where only ketone products were
observed. Although a precise reason for this observation
remains elusive, the literature supports a Russell-type
mechanism for disproportionation of the intermediate hydro-
peroxy radical, leading to carbonyl and alcohol products.24
Oxidation of an amide to an imide could also be achieved in
good yield relative to other chemical oxidants screened (34).
Dealkylation, a process that is often observed in drug
metabolism, was observed when imide formation was
structurally impossible (35).
Class II substrates are simpler systems that are often found
within the scope tables of other methodologies and provide a
good baseline comparison to existing protocols. In general,
ylides delivered similar site-selectivity to other systems
involving homolytic hydrogen abstraction. Namely, distal C−
H bonds that are more than two carbon atoms away from an
electron-withdrawing group are susceptible to oxidation, and
C−H bonds in cyclic structures are more reactive than acyclic
ones.40 The estrone derivative 44 did display some unique
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Figure 4. Practicality of ylide-mediated electrochemical C−H oxidation in various contexts and mechanistic study. (A) Ylide-mediated oxidation as
a uniquely effective approach for direct oxidation of P450 metabolic sites on Penconazole. (B) Short synthesis of a key intermediate for drug
metabolites without prefunctionalization. (C) Ten-gram-scale reaction was performed without the need of expensive reagents. (D) Intramolecular
C−H oxidation is directed and tolerates alkene. (E) 18O-labeled experiments to identify the source of oxygen in the products.
reactivity using Y7, as it cleanly furnished benzylic ketone
(C6), whereas other oxidants gave mixtures of overoxidized
products (C6 and C9) or the unusual olefin product (likely
stemming from dehydration of C9−OH). As mentioned above,
a subtle difference between ylides and other oxidants was
noticeable when a substrate contained a tertiary C−H bond
(37 and 38). Although low conversion or yield was indeed
observed in some cases, this appears to be the trend for all
oxidants screened and is a general challenge in this field.
Figure 4 depicts specific applications of the ylide platform
for the preparation of valuable metabolites and derivatives
thereof. For instance, Penconazole 45 (Figure 4A) is a widely
used fungicide with a primary metabolite profile in humans
stemming from enzymatic oxidation on the propyl chain.41
When this compound was subjected to ylide-mediated
electrochemical C−H oxidation (Y4), the propyl group was
successfully oxidized to afford the ketone products 46 in 26%
yield in a 2:1 ratio (the alcohol corresponding to 46a being the
natural metabolite).
Notably, other known oxidation conditions gave either poor
conversion or different oxidation products, again demonstrat-
ing the unique chemoselectivity of the ylide protocol in the
presence of the Lewis-basic triazole. In contrast, non-enzymatic
routes to such derivatives required a de novo total synthesis (6
steps each from 2,4-dichlorophenylacetic acid). Another
interesting application is the short synthesis of compound
50, which is a common intermediate for metabolites of
buspirone and tiospirone (Figure 4B).42 In this case the
remote oxidation of 52 to 53 was performed using Y7 without
affecting the alkyl bromide and imide functionality (the
starting material was recycled three times). The success of
this key oxidation allowed us to access 53 in two steps from
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readily available material as opposed to a known 8-step
synthesis from expensive, pre-oxidized 54.42
The reaction was also robust enough for preparative scale, as
demonstrated with the 10-g-scale oxidation of 41 in batch,
delivering a 40% yield of ketone 55 (Figure 4C). For this larger
scale run, a less expensive stainless steel cathode could be used
in place of the Ni plate.
Mechanistically, it is hypothesized that ylide mediators
achieve C−H oxidation through the canonical electrochemical
pathway outlined in Figure 2A (analogous to quinuclidine).
The intramolecular experiment outlined in Figure 4D using
ylide 56 demonstrates a clear directing effect that is unique to
this system, as most oxidants employed for C(sp3)−H
oxidation will engage an olefin preferentially (see 58). Further
evidence for this mechanism (see SI for an extensive
discussion) stems from the use of both labeled 18O2 and
H218O, showing conclusively that the source of oxygen is air
(Figure 4E).24
Debora Chiodi − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States;
orcid.org/0000-0002-9045-4932
Ethan Carlson − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States
Pengfei Hu − Department of Chemistry, The Scripps Research
Institute, La Jolla, California 92037, United States;
orcid.org/0000-0003-2915-4102
Longrui Chen − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States
Sagar Udyavara − Department of Chemical Engineering and
Materials Science, University of Minnesota, Minneapolis,
Minnesota 55455, United States; orcid.org/0000-0001-
8562-7790
Cian Kingston − Department of Chemistry, University of
Utah, Salt Lake City, Utah 84112, United States
Mayank Tanwar − Department of Chemical Engineering and
Materials Science, University of Minnesota, Minneapolis,
Minnesota 55455, United States
Sameer Tyagi − Product Metabolism and Analytical Science,
Syngenta Crop Protection, Greensboro, North Carolina
27409, United States
Bruce P. McKillican − Product Metabolism and Analytical
Science, Syngenta Crop Protection, Greensboro, North
Carolina 27409, United States
Moses G. Gichinga − Product Metabolism and Analytical
Science, Syngenta Crop Protection, Greensboro, North
Carolina 27409, United States
Michael A. Schmidt − Chemical Process Development, Bristol
Myers Squibb, New Brunswick, New Jersey 08903, United
States; orcid.org/0000-0002-4880-2083
Martin D. Eastgate − Chemical Process Development, Bristol
Myers Squibb, New Brunswick, New Jersey 08903, United
States; orcid.org/0000-0002-6487-3121
Massimiliano Lamberto − Department of Chemistry &
Physics, Monmouth University, West Long Branch, New
Jersey 07740, United States
Chi He − Department of Chemistry, The Scripps Research
Institute, La Jolla, California 92037, United States
Tianhua Tang − Department of Chemistry, University of
Utah, Salt Lake City, Utah 84112, United States
Christian A. Malapit − Department of Chemistry, University
of Utah, Salt Lake City, Utah 84112, United States;
orcid.org/0000-0002-8471-4208
Matthew S. Sigman − Department of Chemistry, University of
Utah, Salt Lake City, Utah 84112, United States
Shelley D. Minteer − Department of Chemistry, University of
Utah, Salt Lake City, Utah 84112, United States;
orcid.org/0000-0002-5788-2249
CONCLUSION
■
A new class of reactive radicals with tunable reactivity and
selectivity for unactivated C−H oxidation has been disclosed.
Although the reactions presented in this work were performed
under electrochemical conditions, the utility of N-ammonium
ylides may not be limited to electrochemical oxidation; it is
possible that such species can also be employed in other
(photo)chemical C−H functionalization processes under
suitable conditions. Since various ways to intercept the
resulting carbon radical after C−H abstraction are known,
the unique tunability of such ylides will have an impact on
various aspects of C−H functionalization chemistry.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03780.
■
sı
Experimental procedures, additional experimental data,
and details of the DFT calculations (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Yu Kawamata − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States;
orcid.org/0000-0002-5515-9612; Email: yukawama@
scripps.edu
Matthew Neurock − Department of Chemical Engineering
and Materials Science, University of Minnesota, Minneapolis,
Minnesota 55455, United States; Email: mneurock@
umn.edu
Phil S. Baran − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States;
orcid.org/0000-0001-9193-9053; Email: pbaran@
scripps.edu
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c03780
Author Contributions
†M.S. and Y.K. contributed equally to this work.
Author Contributions
Authors
‡M.M., R.N., and D.C. contributed equally to this work.
Masato Saito − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States
Michael Meanwell − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States
Rafael Navratil − Department of Chemistry, The Scripps
Research Institute, La Jolla, California 92037, United States;
orcid.org/0000-0003-3949-0185
Funding
Financial support for this work was provided by National
Science Foundation Center for Synthetic Organic Electro-
chemistry (CHE-2002158) and the National Institutes of
Health (grant number GM-118176). M.S. was supported by a
Postdoctoral Fellowship for Research Abroad (JSPS), R.N. was
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank D.-H. Huang and L. Pasternack (Scripps Research)
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