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Oxidative cleavage of ketoximes to ketones using
photoexcited nitroarenes†
Lucas T. Göttemann,‡ Stefan Wiesler‡ and Richmond Sarpong*

The methoxime group has emerged as a versatile directing group for a variety of C–H functionalizations.
Despite its importance as a powerful functional handle, conversion of methoximes to the parent ketone,
which is often desired, usually requires harsh and functional group intolerant reaction conditions.
Therefore, the application of methoximes and their subsequent conversion to the corresponding ketone
in a late-stage context can be problematic. Here, we present an alternative set of conditions to achieve

Received 12th October 2023
Accepted 17th November 2023

mild and functional group tolerant conversion of methoximes to the parent ketones using photoexcited
nitroarenes. The utility of this methodology is showcased in its application in the total synthesis of

DOI: 10.1039/d3sc05414d

cephanolide D. Furthermore, mechanistic insight into this transformation obtained using isotope labelingrsc.li/chemical-sciencestudies as well as the analysis of reaction byproducts is provided.

Introduction
The total synthesis of natural products continues to be an
exercise that highlights unaddressed gaps in synthetic methodology.1 In particular, the high density of functional groups incomplex natural products necessitates the development offunctional group tolerant methods that can eﬀect the selective
reaction of a targeted reactive group among many others.2
Recently, as a part of a total synthesis study of natural productsin the cephalotane family,3,4 we required a method that would
convert a methoxime to the corresponding ketone. Over the last
decade, methoximes have emerged as superior directing groups
for C–H functionalization.5–10 leading to value-added products
where a variety of groups are installed. Despite their importantrole in directing C–H functionalizations, methoximes, unlike Oacetyl oximes, are notoriously diﬃcult to convert to the parent
ketone, which is oen the desired functional group. The
conditions for the removal of methoximes are generally harshand, in some instances, can result in low yields (Scheme 1).
Therefore, the established conditions that are required forthe conversion of methoximes to ketones are incompatible witha wide range of functional groups, making their use in a latestage context challenging.11–15
In our synthesis of cephanolide D (Scheme 2), a methoxime(1) that was prepared from a precursor ketone, had served asa directing group to eﬀect carbomethoxylation at C15 giving riseto 2 through a palladated intermediate.16 However, myriad

attempts to convert the methoxime moiety in 2 back to the
ketone group, including using strongly acidic17 or reductive18
conditions, resulted in, among many other undesired
outcomes, elimination of the tertiary hydroxy group in 2 andsubsequent decarboxylation of the bridging lactone. The only
successful approach that was identied for removing themethoxime group in 2 was to eﬀect ozonolysis cleavage of theoxime19,20 followed by a reductive workup. Even in that case, thereaction proceeded capriciously and did not lead to fullconversion. Typically, reaction yields in the 35% range wererealized along with a signicant amount of recovered starting
material (64%).
The yield of the desired product dropped precipitously upon
prolonged exposure to ozone, likely due to competing oxidation
at other susceptible sites on the molecule including the arene21
and benzylic positions.22
While eﬀective, ozonolysis can be impractical, especially ona small scale where it is diﬃcult to determine the precise stoichiometry of ozone.23 Furthermore, the inhalation and explosivity hazards of ozone and ozonides,24 respectively, can maketheir use a signicant safety risk. As a result of these considerations, we sought to identify milder conditions that could be

Department of Chemistry, Latimer Hall, University of California, Berkeley, California
94720, USA. E-mail: rsarpong@berkeley.edu† Electronic supplementary information
https://doi.org/10.1039/d3sc05414d(ESI)

available.

See

DOI:

‡ These authors contributed equally.

© 2024 The Author(s). Published by the Royal Society of Chemistry

Known conditions for the cleavage of methoximes toketones and our approach.

Scheme 1

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Scheme 2

Ozonolytic cleavage of the cephanolide D methoxime.

employed as an alternative for the cleavage of oximes — ideally,in a practical, safe, stoichiometrically precise and functionalgroup tolerant fashion for applications in complex moleculesynthesis.
Recently, concurrent reports from the groups of Leonori25
and Parasram26 described the use of photoexcited nitroarenes tocleave alkenes (Scheme 3). Notably, a range of nitroarenes weresurveyed in these studies, whereby in some cases, the nature of
the nitroarene signicantly aﬀected the yield of the oxidative
cleavage product. Several functional groups were tolerated
under these oxidative cleavage conditions including oxidationsusceptible groups such as a sulde (see 4).27 These initialreports set the stage for additional developments such as thedihydroxylation of alkenes,28 hydroxylation of aliphatic
substrates,29 and the oxidation of aldehydes and aldimines tocarboxylic acids and amides, respectively.30 Furthermore, Li
recently reported a photoinduced cascade process between
nitroarenes and amines to form isoxazolidine derivatives.31

Results and discussion
On the basis of the alkene oxidative cleavage reports from
Leonori and Parasram, we envisioned a cleavage of oximes
using photoexcited nitroarenes that might proceed through ananalogous mechanism. However, we anticipated that thistransformation was likely to be challenging due to the signicantly diﬀerent properties of the oxime double bond compared
to a C–C double bond. We envisioned that for cyclohexanonederived ketoxime 8 (Scheme 4), reaction with a photoexcited
nitroarene32 might result in the formation of an exciplex (see 9),
which upon cycloaddition would yield photoadduct 10. Several
scenarios could then be envisioned for the fate of photoadduct

Scheme 3

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Scheme 4 Possible fragmentation pathways for 10 in the oxidative

cleavage.

10 (Scheme 4). In the fragmentation A pathway, the anticipatedketone product (i.e., cyclohexanone, 11) could form directly
along with byproduct 12, shown as its diradical and ylide
resonance forms, which is expected to be a transient species.
Alternatively, in fragmentation B, aza-carbonyl ylide 13 andalkyl nitrite 14 would be the anticipated products. Again, azacarbonyl ylide 13 would be expected to be short-lived. In the
fragmentation C pathway, direct formation of the ketone would
be accompanied by alkyl nitrite 14 and aryl nitrene 15 as
byproducts. Here, nitrene 15 would be expected to be eeting.
We reasoned that because a reactive intermediate would beformed in each of the fragmentation scenarios from photoadduct 10, a trapping agent should be introduced to quench thereactive byproducts. We rationalized that water would be ideal
for these purposes. In the fragmentation A pathway, 12 would
be expected to hydrolyze to alkyl nitrite 14 and an aryl hydroxylamine. The formation of an aryl hydroxylamine byproductwould also be expected from the hydrolysis of aza-carbonyl ylide
13 (fragmentation B) and upon reaction of nitrene 15 with water
through an OH-insertion.
On the basis of this rationalization, we embarked on a surveyof conditions to eﬀect the photoexcited nitroarene-mediatedoxidative cleavage of oximes using tetralone methoxime 16(which we envisioned to be a suitable model substrate for our
cephanolide D synthesis). In addition to varying reaction
conditions (i.e., irradiation wavelength and duration, temperature, and solvent), we also tested several nitroarenes in our
optimization studies (see the ESI† for details). Of note, in thecases where incomplete cleavage of the starting oxime wasobserved, a side-product observed in the mixture was the oxime
diastereomer (Z-isomer), which presumably arises from photoisomerization under the reaction conditions.33 With an initial

Pioneering work by Leonori and Parasram.

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set of eﬀective conditions in hand (see conditions in entry 1,
Table 1), we began to examine the scope of this reaction.
Unfortunately, these conditions turned out not to be generalizable and we observed low yields for additional substrates
that were tested such as acetophenone-derived oxime 17 (20%yield, entry 1), necessitating a second round of optimization forless reactive compounds. We chose acetophenone methoxime(17) as the substrate for this ne-tuning to achieve more broadly
applicable conditions (see the ESI† for the full screening table).
We retained the solvent mixture (4 : 1 MeCN : H2O), which wasshown to be signicantly superior to other solvent mixtures
used in our initial screening. We started by testing lower
wavelength irradiation. LEDs centered at 390 nm showed an
immediate improvement and resulted in a signicant reductionof side reactions (entries 1–3). We then screened several nitroarenes and observed improved yields using nitroarenes N2 andN1, which possess more electrophilic character in their excitedstates as compared to N3 (entries 3–5).25 Increasing the nitroarene equivalents and using a setup with Kessil lamps insteadof a photoreactor34 (see pictures in the ESI†) led to signicantly
higher yields (entries 5–7). Overall, the optimized conditions
that we identied from these two surveys using tetralone
methoxime (16) and acetophenone methoxime (17) are: using
nitroarene N1 (3 equiv) in a 4 : 1 mixture of acetonitrile andwater with irradiation using LEDs centered at 390 nm at 40 °C(the measured temperature of our setup using a household fan
for cooling) for 48 h (Table 1, entry 7). Finally, as shown in entry
8, in the absence of the nitroarene, the starting oxime isrecovered in 90% yield along with 7% of the isomerized oxime.
We then investigated the scope of the reaction to test thefunctional group tolerance of our method and its eﬃcacy.

Table 1

Importantly, we selected substrates featuring groups that areoen encountered in more complex settings (e.g., in total
synthesis), where existing methods for converting methoximes
to ketones have not been as eﬀective. As shown in Fig. 1, a rangeof benzylic ketoximes are eﬀectively cleaved under the conditions we have identied to aﬀord the corresponding ketones.35
Of note, sterically encumbered methoximes can be cleaved (see34) and oxidatively sensitive groups such as a thiomethyl group(45), which is oxidized to the sulfone under ozonolysis conditions (see the ESI†), are tolerated to some extent, emphasizing
the complementarity of the current method to existing
methods. Furthermore, tetralone, acetophenone, benzosuberone, and chromanone derived oximes all participate faithfullyin this oxidative cleavage reaction. In addition, free oximes (see39), acetylated oximes (see 40) and hydrazones (41) all undergo
oxidative cleavage to the corresponding ketones under theconditions that we have identied. In general, we have foundthat substrates that proceed in low conversion, but high massbalance, can be further converted to the product over an
extended reaction time, but the reaction rate decreases noticeably. In cases where poor mass balance was observed, longer
wavelength irradiation (using LEDs centered at 420 nm) wasbenecial to the reaction outcome. This is likely due reactivity ofintermediates at the shorter wavelengths that were previously
employed, which led to undened side reactions. Mainly, theyields improved by irradiation at longer wavelengths for
substrates with benzylic C–H groups that are known to undergo
benzylic oxidation reactions. Albeit proceeding with lower massbalance upon irradiation at 420 nm over a prolonged period, we
did not observe signicant benzylic C–H hydroxylation products
under these conditions.

Optimization of the reaction conditions for methoxime 17

Entry

Wavelength

Nitroarene

Solvent

Timeb

Yield 17 : 18 : 19

1
2
3
4
5
6
7c
8

420 nm405 nm390 nm390 nm390 nm390 nm390 nm390 nmN3 (1.5 equiv)
N3 (1.5 equiv)
N3 (1.5 equiv)
N2 (1.5 equiv)
N1 (1.5 equiv)
N1 (3.0 equiv)
N1 (3.0 equiv)—

MeCN/H2O 4 : 1
MeCN/H2O 4 : 1
MeCN/H2O 4 : 1
MeCN/H2O 4 : 1
MeCN/H2O 4 : 1
MeCN/H2O 4 : 1
MeCN/H2O 4 : 1
MeCN/H2O 4 : 1

48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h

6%/70%/20%
7%/65%/23%
10%/58%/29%
14%/33%/47%
7%/21%/65%<5%/17%/74%–/trace/95%
90%/7%/–a
A reaction time of 48 h is consistent with values reported for photochemical reactions with nitroarenes.25,26 b The reactions were carried out ina photoreactor.28 A reaction time of 48 h is consistent with values reported for photochemical reactions with nitroarenes.25,26 c The reaction was
carried out using Kessil lamps (distance to LED = 3 cm).

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Scope of benzylic methoxime cleavage. aRSM = recovered starting material. The RSM is a combined yield of oxime diastereomers. bIrradiation was conducted at 420 nm using nitroarene N3 for 48 h. cThe reaction was irradiated for 96 h.
Fig. 1

However, the reaction does not tolerate alkenes, which arecleaved under the reaction conditions. For example, a,b-unsaturated oxime 50 leads to benzaldehyde (51) as the main detected product (Scheme 5A). Similarly, we found that acyloin
derived methoxime 52 undergoes C–C bond cleavage under thereaction conditions to give acetophenone (Scheme 5B).
Of note, ozonolysis of 52 also results in the formation ofacetophenone (19). Furthermore, we observed that substrates
with free alcohol groups as well as amines were not tolerated

Methoxime cleavage of aliphatic compounds. aRSM = recovered starting material. The RSM is a combined yield of oxime
diastereomers.
Fig. 2The photoexcited nitroarene oxidative cleavage of a series ofaliphatic methoximes was also investigated (Fig. 2). The reaction was found to work well for several aliphatic ketoximes
including cyclic and sterically encumbered as well as acyclic
substrates (see 46–49).
Scheme 5

216 | Chem. Sci., 2024, 15, 213–219

Limitations and side reactions.

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Chemical ScienceFig. 3 (A) Application of methoxime cleavage in bioactive andcomplex substrates. (B) Synthesis of cephanolide D (3). aRSM =recovered starting material. The RSM is a combined yield of oxime
diastereomers. bThe reaction was irradiated for 96 h.

under the reaction conditions, leading to a very low conversionof the starting material (see the ESI† for examples).
The oxime cleavage reaction has also been found to work wellin several complex substrates (Fig. 3). For example, naproxen
derived methylketone 53 is formed from the corresponding
methoxime using our standard photoexcited nitroarene oxidative
cleavage conditions in 21% yield (isolated along with 51% of themethoxime starting material). Cholestanone (54) is obtained in
31% yield (along with 52% of the methoxime starting material)
upon subjection to the cleavage conditions. Similar to substrate
34 the yield for methylketone 53 could be improved upon irradiation for 96 h (see Fig. 3A), however cholestanone derived
methoxime 54 suﬀered from solubility issues. On the other hand,the cleavage of the corresponding methoxime generated fromkobusone (55) gives 55 in 67% yield (along with 22% of themethoxime starting material). Finally, in the context of our
synthesis of cephanolide D, we subjected methoxime 56 36 to the
newly developed oxidative cleavage conditions (Fig. 3B). To ourdelight, our conditions were tolerated by the ester, lactone andeven the TMS group, giving rise to ketone 57 — showcasing theuse of photoexcited nitroarenes as an eﬀective alternative formethoxime cleavage in compounds bearing various reactive
groups.37 Cephanolide D (3) was then obtained from 57 in 93%
yield upon treatment with TBAF.
In order to test our hypothesis of a photoexcited nitroarene
mediated oxidative cleavage of methoximes to the corresponding ketones, a comprehensive photophysical study was carriedout. As a part of this investigation, the UV-vis data, including theabsorption maxima of all the methoxime starting materials,
ketone products, and nitroarenes at various concentrations
were obtained experimentally. Our observations indicated thatat a concentration of 50 mM, the methoximes, ketones, and© 2024 The Author(s). Published by the Royal Society of ChemistryFig. 4 (A). Absorption maximum for 17, 19 and N1 at 50 mM. (B) UV-vis
absorption spectra for 17 and 19 at 200 mM and N1 at 600 mM. C. UVvisible spectra for the reaction monitoring experiment indicating
redshift using 17 and N1 under standard reaction conditions and taking
aliquots at the indicated time.

Table 218

O incorporation experiments

nitroarenes do not absorb light centered at 390 nm. However, at
higher concentrations, which reect our reaction conditions(0.2 M), the nitroarenes strongly absorb whereas ketones canpartially absorb at 390 nm (Fig. 4B). These absorption prolesstrongly support the hypothesis that the reaction is mediated by

Scheme 6Preparation of 18O labelled nitroarene 18O-N4.

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Scheme 7 (A). Proposed mechanism of the oxidative cleavage. (B). Color change after 48 h reaction time. aByproducts were both detected by
GC-MS and 1H NMR.

photoexcited nitroarenes. Furthermore, our observations also
explain the relatively long reaction time of 48 h since the ketone,
formed over the course of the reaction (i.e., continuously
increasing concentration) partially absorbs light and reduces
the eﬃciency of the absorption of the nitroarene and therefore
reaction. This rationale is further supported by an increasing
redshi over the course of the 48 h reaction duration, whichsuggests that an inner lter eﬀect slows down the reaction.
To gain further insight into the proposed mechanism for thisoxime cleavage method, we have carried out a series of experiments using 18O-labeled nitroarene 18O-N4 and H218O (seeTable 2). 18O-Labeled nitroarene 18O-N4 was prepared bynitration of benzonitrile using 18O-labeled nitric acid andsulfuric acid analogous to the protocol of Wibaut (Scheme 6).38
In our mechanistic studies, we have found that subjecting
adamantanone methoxime (59) to our standard conditions using
the 18O-labeled 18O-N4 in a mixture of acetonitrile and 16O-labeledwater leads to a 6% 18O incorporation in the ketone product (entry1). The use of unlabeled (i.e., 16O) nitroarene N4 and 18O-labeledwater leads to a 69% incorporation of 18O in the ketone product(entry 2), suggesting a fast O-atom exchange in the ketone groupof adamantanone under the reaction conditions. The use of 18Olabeled nitroarene 18O-N4 and 18O-labeled water leads to the
ketone product in a slightly more isotopically enriched form (77%incorporation of 18O; entry 3) than in the case where only 18Olabeled water is used (i.e., entry 2). While strict conclusions as
to the source of 18O label in the observed products cannot be
drawn (i.e., the oxygen atom in the ketone product might arise
from the nitroarene or through fast exchange with water), theslight enrichment in 18O for the product under the conditions
where only 18O-N4 is used (entry 1), and also the higher enrichment for the case where 18O-N4 and H218O are used (compare
entry 3 to entry 2) may support the nitroarene, in addition to thewater co-solvent, as sources of the oxygen atom in the product.
These preliminary labeling studies support the proposed mechanism (Scheme 4) wherein a cycloaddition between the photoexcited nitroarene and oxime is proposed (see 9).

218 | Chem. Sci., 2024, 15, 213–219

To gain further mechanistic insight, we sought to investigate
the fate of the oxime residue. Two chemical probes (60 and 61)
bearing a bulky, non-volatile, alkyl substituent (in place of themethyl group) were synthesized and subjected to our reaction
conditions (Scheme 7). Assuming the formation of cycloadduct62, fragmentation B pathway (vide supra) would give rise to azacarbonyl ylide 63 and transient adamantyl nitrite 64. Subsequently, aza-carbonyl ylide 63 could be trapped by water yielding
the desired ketone (19 or 32) as well as hydroxylamine 67, which
can then be envisioned to undergo NO mediated reduction toaniline 67.39,40 We assumed that the NO arises from the photochemical decomposition of alkyl nitrite 64, resulting in theformation of 1-adamantanol (65) and NO.41 Both 65 and 67 weredetected in the crude reaction mixture (using GC-MS and NMR;
see the ESI† for more details), providing additional support for
the fragmentation B pathway. Due to the reactive nature of theintermediates described, other concomitant decomposition
pathways of 62 are also plausible (e.g., via the fragmentation A
pathway), which would explain a partial incorporation of 18O
from the nitroarene as observed in the labeling experiments.

Conclusions
In summary, building on recent studies that describe the use ofphotoexcited nitroarenes to eﬀect oxidative cleavage of alkenes,
we report here the removal of oxime groups to aﬀord the corresponding ketones under a related set of conditions. The
substrate scope of the transformation is relatively broad but is
not tolerant of alkenes, which are cleaved under the reaction
conditions (consistent with the precedent of Leonori and Parasram). The success of the current studies enabled the application of this new protocol to a preparation of cephanolide Dfrom a precursor methoxime. While the mechanism of thereaction is yet to be fully elucidated, isotopic labelling studies
and the detection of several by-products support both the water
cosolvent and nitroarene as possible sources of the O-atom inthe ketone product that is obtained. Overall, this protocol oﬀers© 2024 The Author(s). Published by the Royal Society of ChemistryView Article Online

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an alternative to the strongly acidic or reductive conditions aswell as ozonolysis cleavage conditions that are usually employedin the conversion of ketoxime groups to ketones.

Author contributions
The project was conceived by S. W. The experimental work was
performed by L. G. and S.W. The initial dra was written by R. S.
with input from all authors. L. G., S. W. and R. S. were involvedin editing and nalizing the manuscript. R. S. supervised the
project and secured funding.

Conﬂicts of interest
There are no conicts to declare.

Acknowledgements
This work was supported by funding from the US National
Science Foundation (CHE-1700982). S.W. thanks the Deutsche
Forschungsgemeinscha (DFG, German Research Foundation,
WI 5665/1-1) for a postdoctoral scholarship. The authors are
grateful to Dr Hasan Celik and UC Berkeley's NMR facility in theCollege of Chemistry (CoC-NMR) for spectroscopic assistance.
Instruments in CoC-NMR are supported in part by NIH
S10OD024998. The authors thank Magan Powell (UC Berkeley)
for assistance with GC-MS.

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36 As we mentioned before, free alcohols react poorly and are
therefore a limitation of this method. For this reason we
decided to use the TMS protected methoxime 62 instead of
methoxime 10.
37 Subsequently, we removed the TMS group in 63 using TBAF
to yield cephanolide D (93% yield).
38 J. P. Wibaut and R. van Strik, Recueil, 1958, 77, 316–326.
39 E. Damiani, L. Greci and C. Rizzoli, J. Chem. Soc. Perkin
Trans., 2001, 2, 1139–1144.
40 H. Weber, A. Grzesiok, R. Sustmann and H.-G. Korth, Z.
Naturforsch., 1994, 49b, 1041–1050.
41 G. R. McMillan, J. Phys. Chem., 1963, 67, 931–932.

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