Photocatalytic, Phosphoranyl Radical-Mediated N-O Cleavage of Strained Cycloketone Oximes

Article abstract of DOI:10.1021/acs.orglett.9b00651

A photoinduced, phosphoranyl radical-mediated protocol for the direct N-O cleavage of strained cycloketone oximes via a polar/SET crossover process was developed for the first time. This visible-light-driven direct N-O activation mode for oxime offers beneficial features such as streamlined synthetic process and versatile photochemical reactivities. Consequently, the alkenes and α-trifluoromethyl alkenes with varied electronic and structural features acted as competent radical receptors in this protocol, enabling facile accesses to a range of elongated cyano and/or gem-difluoroalkene-bearing compounds.

Full text of DOI:10.1021/acs.orglett.9b00651

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photocatalytic, Phosphoranyl Radical-Mediated N−O Cleavage of
Strained Cycloketone Oximes
Peng-Ju Xia,† Zhi-Peng Ye,† Yuan-Zhuo Hu,† Dan Song,† Hao-Yue Xiang,*,† Xiao-Qing Chen,*,†,§
and Hua Yang*,†,§
†College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, P. R. China
§Key Laboratory of Hunan Province for Water Environment and Agriculture Product Safety, Central South University, Changsha
410083, P. R. China
S
* Supporting Information
ABSTRACT: A photoinduced, phosphoranyl radical-mediated
protocol for the direct N−O cleavage of strained cycloketone
oximes via a polar/SET crossover process was developed for the first
time. This visible-light-driven direct N−O activation mode for oxime
offers beneficial features such as streamlined synthetic process and
versatile photochemical reactivities. Consequently, the alkenes and
α-trifluoromethyl alkenes with varied electronic and structural
features acted as competent radical receptors in this protocol,
enabling facile accesses to a range of elongated cyano and/or gem-
difluoroalkene-bearing compounds.
Essentially, there are general two distinct mechanistic
pathways depending on the redox potentials of substrates
(Scheme 1a). A few elegant reductive approaches by employing
redox-active cyclic oxime esters have been well-established by
Xiao,7a−c Chen,7a−bc and Zhou.7d An impressive range of π-
acceptors encompassing styrenes, alkynes, silyl enol ethers, and
ree radical chemistry plays a vital role in producing
Fmolecules with structural complexity and diversity, which
always takes a backseat to the classical two-electron-involved
methodologies.1 Development of efficient methods for generat-
ing free radicals in a convenient manner is of continuous interest.
Over the past decade, visible-light photoredox catalysis, serving
as a powerful tool, has witnessed rapid advancements in
generating an array of carbon-centered radicals (CCRs)2 and
nitrogen-centered radicals (NCRs).3 The visible-light photo-
redox catalysis with overwhelming priorities stimulates the
extensive exploitation and breaks through the limit of competent
radical precursors in numerous important transformations.
Further, it enables facile carbon−carbon bond (C−C) and
carbon−heteroatom (C−X) bond-forming.
Scheme 1. Photocatalytic Iminyl Radical Formation and
Radical Transposition for Strained Cycloketone Oximes
In recent years, hydroxylamine derivatives have been actively
utilized in the generation of NCRs, especially in the domain of
visible-light photoredox catalysis.3c Specific interests have been
attracted to cyclobutanone oximes and their derivatives because
they are valuable and versatile intermediates in organic
synthesis.4 Noticeably, cyclobutanone oxime derivatives are
capable of generating iminyl radicals through a photocatalytic
single-electron transfer, which are prone to undergoing a β-
fragmentation radical transposition process. This process,
resembling the classical Norrish type-1 reactivity, can deliver
highly reactive open-shell carbon radicals (γ-cyanoalkyl
radicals).5 Indeed, cyanoalkyl scaffolds are a class of valuable
building blocks owing to their versatility in the conversion into
other functional groups, which are frequently encountered in
many pharmaceuticals.6 Following this line, an array of valuable
transformations based on the photocatalytic ring-opening of
cyclic oxime derivatives has been established.7,8
Received: February 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00651
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Letter
a
isonitriles is competent to trap the resulting γ-nitrile radicals. In
contrast, only rare success on the SET oxidation generating γ-
nitrile radicals was documented. Leonori and coauthors8
strategically introduced α-imino-oxy acids as efficient and easily
accessible iminyl radical precursors, which were oxidized by a
photoexcited organic sensitizer to the corresponding nitrile
radicals. Despite all of these advancements, the implementation
of the parent oximes has been considerably overlooked as the
introduction of electrophores onto the oxygen atom of cyclic
oximes was necessitated to manipulate the redox potentials in all
the previous cases. Up to now, to our knowledge, only one
exclusive example has been reported by Weinreb and coauthors
to employ an oxime for the generation of iminyl radical, in which
ultralow temperature was requisite.9 However, the photoredox
generation of iminyl radicals from strained cycloketone oximes
under mild conditions has never been harnessed because of the
unwanted, competitive O−H bond dissociation in oxime
moiety.10
Table 1. Optimization of the Reaction Conditions
b
entry
variation from the “standard conditions”
yield (%)
1
none
98
43
67
0
trace
45
trace
92
0
2
under air atmosphere
3
4
5
6
without Na2CO3
MesAcr+ClO4− instead of [Ir(dFCF3ppy)2dtbbpy]PF6
Ru(bpy)3PF6 instead of [Ir(dFCF3ppy)2dtbbpy]PF6
n-Bu3P instead of PPh3
7
8
9
MeCN instead of CH2Cl2 as the solvent
10 equiv of H2O in 2 mL of CH2Cl2
no PPh3
10
11
no light
no photocatalyst
0
0
a
Standard conditions: oxime 1a (0.6 mmol, 3 equiv), 1,1-diphenyl-
The synthetic potentials of phosphoranyl radicals in C−O
bond cleavage via β-scission were initially recognized in the early
1970s when Bentrude and coauthors detected these radicals as
intermediates by ESR spectroscopy.11 However, synthetic
applications of this strategy for direct deoxygenation remain a
great challenge owing to forcing conditions and limited
functional group tolerance. Encouragingly, this situation
changed dramatically very recently as pioneering independent
works from Xie,12 Zhu,12b Doyle,13 and Rovis13 realized the
direct C−O bond activation via photoredox catalysis with
phosphoranyl radicals. More recently, the radical deoxygenation
of N-hydroxyphthalimide promoted by a phosphite to access
phthalimidyl radicals has also been achieved by Schmidt and
coauthors.14 Inspired by these previous elegant works, we
questioned if the photocatalytic direct N−O cleavage of oxime
could be accomplished via the polar/SET crossover process
between phosphoranyl radical and oxime, which might provide a
unique solution for this everlasting challenge (Scheme 1b). In
this work, we successfully achieved the first photoredox-
catalyzed direct N−O bond activation of strained cycloketone
oximes via the PPh3 radical-mediated strategy, enabling a facile
access to a series of the elongated 1,1-diarylmethanenitriles and
alkyl nitriles (Scheme 1c). More importantly, this innovative
pathway for directly activating N−O bond of oxime offers new
avenues for synthetic methodology development. Mechanisti-
cally, the reductive quenching pathway rendered this developed
protocol amenable to broader substrate scope with varied
electronic features.
ethylene 2a (0.2 mmol, 1 equiv), PPh3 (0.72 mmol, 3.6 equiv),
Na2CO3 (0.3 mmol, 1.5 equiv), [Ir(dFCF3ppy)2dtbbpy]PF6 (2 mmol
%), CH2Cl2 (2 mL), 30 W blue LED, argon atmosphere, rt, 5 days.
b
Yield of isolated product.
H2O has a negligible effect on the reaction (entry 8). As
predicted, light, photocatalyst, and phosphine were indispen-
sable for this transformation (entries 9−11).
Having established the optimal conditions for this photo-
redox-catalyzed transformation, the substrate scope and
limitations were subsequently explored. As summarized in
Scheme 2, the substitution patterns on the cyclobutanone
a
Scheme 2. Scope With Respect to Oximes
We initiated our investigations by monitoring the reaction of
cyclobutanone oxime (1a) with 1,1-diphenylethylene (2a) in
the presence of photocatalyst and phosphine (Table 1). Unless
otherwise noted, all the experiments were conducted at room
temperature in CH2Cl2 under irradiation of 30 W blue LED.
Gratifyingly, upon optimization of the reaction conditions (see
Table S1 in Supporting Information), 1,1-diarylmethanenitrile
3a was furnished in a nearly quantitative yield (entry 1). Inert
atmosphere and base were beneficial for this photoredox-
catalyzed transformation (entries 2 and 3). Among the screened
catalysts, [Ir(dFCF3ppy)2dtbbpy]PF6 was proven to be the best
a
Standard conditions: oximes 1 (0.6 mmol, 3 equiv), alkene 2a (0.2
mmol, 1 equiv), PPh3 (0.72 mmol, 3.6 equiv), Na2CO3 (0.3 mmol,
1.5 equiv), [Ir(dFCF3ppy)2dtbbpy]PF6 (2 mmol %), CH2Cl2 (2 mL),
30 W blue LED, argon atmosphere, rt, 5 days. Yield of isolated
product.
choice, whereas MesAcr+ClO4 and Ru(bpy)3PF6 were
−
oximes were first varied and investigated, which were generally
tolerated well in the reaction. Substituted oximes 1b−1d bearing
various functional groups such as carboxylate and naphthyl are
amenable substrates, affording the desired products 3b−3d in
good to excellent yields. Notably, this reaction system was also
suitable for oxetan-3-one oxime and N-substituted azetidinone
ineffective in the reaction (entries 4 and 5). Use of n-Bu3P in
place of PPh3 resulted in a less efficient reaction (entry 6).
Screening of solvents revealed that CH2Cl2 was the optimal
solvent, and only trace amount of the desired product 3a was
obtained in MeCN (entry 7). Further exploration showed that
B
DOI: 10.1021/acs.orglett.9b00651
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Letter
a
oximes, delivering the corresponding ether 3e and amines 3f and
3g in excellent yields.
Scheme 4. Scope with Respect to α-trifluoromethyl Alkenes
Author: Encouraged by the above results, we continued to
investigate the substrate generality with a range of 1,1-
disubstituted alkenes under the standard conditions. As shown
in Scheme 3, the substitution patterns and electronic character-
a
Scheme 3. Scope with Respect to Alkenes
a
Standard conditions: oxime 1a (0.6 mmol, 3 equiv), alkenes 5 (0.2
mmol, 1 equiv), PPh3 (0.72 mmol, 3.6 equiv), Na2CO3 (0.3 mmol,
1.5 equiv), [Ir(dFCF3ppy)2dtbbpy]PF6 (2 mmol %), CH2Cl2 (2 mL),
30 W blue LED, argon atmosphere, rt, 5 days. Yield of isolated
b
product. Performed at 4 mmol scale of 5a.
a
Standard conditions: oxime 1a (0.6 mmol, 3 equiv), alkenes 2 (0.2
mmol, 1 equiv), PPh3 (0.72 mmol, 3.6 equiv), Na2CO3 (0.3 mmol,
1.5 equiv), [Ir(dFCF3ppy)2dtbbpy]PF6 (2 mmol %), CH2Cl2 (2 mL),
30 W blue LED, argon atmosphere, rt, 5 days. Yield of isolated
product.
corresponding gem-difluorostyrenes 6b−6h in moderate yields.
Additionally, CF3-naphthalene worked well and gave difluoro-
naphthalene 6i. Moreover, gem-difluoroalkene moiety is known
to serve as a carbonyl bioisostere with less susceptibility and a
versatile precursor for the synthesis of fluorine-containing
molecules; these results are thus of particular significance for
drug discovery. Noticing mildness of the reaction conditions, we
were devoted to exploiting the practicality and scalability of this
protocol. The title reaction for oxime 1a with 5a was performed
at gram-scale under the standard reaction conditions, which
proceeded smoothly to give the corresponding product 6a in
58% yield without any loss of efficiency. As expected, the desired
product 6a bearing a gem-difluoroalkene moiety can be readily
transformed into highly functionalized alkyl derivative 8.
Inevitably, at the current stage, there are still some limitations
for some special reaction partners, as listed in the Supporting
Information.
To gain mechanistic insights into the process, several control
experiments were carried out (Scheme 5). The radical inhibition
experiments were conducted by adding 2,2,6,6-tetramethyl-1-
piperdinyloxy (TEMPO) or dibenzoyl peroxide (BPO) under
the standard reaction conditions, and the reactions were
significantly inhibited (Scheme 5a). These results indicated
that a free-radical pathway was probably involved in this
photocatalytic transformation. Moreover, the isolation of
byproduct 7 suggested the radical transposition in the cascade
process of N−O and C−C cleavage of oxime (Scheme 5b).
Further deuterium-labeling experiment by adding D2O was
performed, but no deuterated product was detected (Scheme
5c). Thus, water seems impossible to be the proton source for
this transformation. Presumably, excess free oxime served as the
major proton source (see Supporting Information). The
corresponding Stern−Volmer studies further reveals that
istics of 1,1-diphenylenes have slight effects on their reaction
efficiency, with the desired products 4a−4i being obtained in
excellent yields. The fluorene analogue 2j also proceeded
smoothly to give the corresponding product 4j in 92% yield.
Moreover, this strategy was applicable as well to the olefin
containing heterocycle 2k. In the case of olefin with electron-
withdrawing group attached 2l, an excellent yield was also
secured, further expanding the practical range of substrates.
Interestingly, when electron-rich olefins 2m and 2n were
employed, a Heck-type pathway occurred, and C−C double
bond remained predominant with a reactivity ratio (rr) of 6:1,
leading to alkenyl nitriles 4m and 4n in good to excellent yields.
Presumably, the difference in the product structures stemmed
from the relatively higher reductive potential of the
intermediates for these electron-rich olefins, slowing down the
single electron reduction step and facilitating the ultimate
elimination process.
Mechanistically, we speculated that α-trifluoromethyl al-
kenes15 should be amenable to this developed platform to give
functionalized 1,1-difluoroalkenes as the ultimate reductive
quenching step in the reaction could be facilitated by E1cB-type
fluoride elimination via a radical-polar crossover pathway. We
began this part of the investigations by examining the reaction of
cyclobutanone oxime 1a with α-trifluoromethylstyrene 5a
(Scheme 4). Satisfyingly, the desired product gem-difluoroal-
kene 6a was obtained in a moderate yield under the standard
conditions. Otherwise, a range of CF3-styrenes bearing various
substitutents was also suitable as reaction partners, giving the
C
DOI: 10.1021/acs.orglett.9b00651
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Letter
radical species from strained cycloketone oximes has been
established for the first time. This photocatalytic phosphoranyl
radical-mediated approach significantly avoids the voltage-
directed derivatizations of oximes and expands the functional
group tolerance. By fully taking advantage of the activation mode
in the iminyl radical formation, alkenes and α-trifluoromethyl
alkenes with varied electronic and structural features worked as
effective radical receptors, readily affording a range of elongated
functionalized cyano compounds and cyano difluorostyrenes.
The versatility and scalability of this transformation would
greatly broaden synthetic utilizations of oximes in the domain of
photochemistry. More importantly, this photoredox-catalyzed
phosphoranyl radical-mediated pathway offers a new dimen-
sionality for N−O bond activation
Scheme 5. Control Experiments
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00651.
■
photoexcited Ir(dF(CF3)ppy)2(dtbbpy)]PF6 was quenched by
triphenylphosphine (see Supporting Information). Additionally,
the quantum yields for the synthesis of 3a and 6a in this reaction
system were also measured to be 0.53 and 0.25, respectively,
suggesting that a long-chain progress is unlikely to be involved
(see Supporting Information).
On the basis of the above-mentioned results and the redox
potentials of the involved species, a possible photoredox cycle is
proposed in Scheme 6. Initially, the excitation of the
S
Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Scheme 6. Plausible Mechanistic Pathways
*E-mail: xianghaoyue@csu.edu.cn.
*E-mail: xqchen@csu.edu.cn.
*E-mail: hyangchem@csu.edu.cn.
ORCID
Hao-Yue Xiang: 0000-0002-7404-4247
Xiao-Qing Chen: 0000-0002-8768-8965
Hua Yang: 0000-0002-5518-5255
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (Grants
21576296, 21776318, 21676302, and 81703365), Natural
Science Foundation of Hunan Province (Grant 2017JJ3401),
and Central South University.
photocatalyst resulted in the excited *Ir(dF(CF3)-
16
ppy)2(dtbbpy)]PF6 [E1/2 (*IrIII/IrII) = +1.21 V vs SCE],
red
17
red
which was quenched by Ph3P (E1/2 = +0.98 V vs SCE) to
generate IrII and triphenylphosphine radical cation. Subse-
quently, in the presence of Na2CO3, a polar/SET crossover
process followed by the β-scission occurred sequentially to
undergo the proposed radical deoxygenation, generating the key
iminyl radical B. A facile radical transposition through a strain-
relieved C−C single bond cleavage delivered a cyanoalkyl radical
species C. This highly reactive CCR immediately was rapidly
captured by the alkenes to generate radical species D, which was
then quickly reduced by IrII to form carbanion intermediate E
with the concurrent regeneration of photocatalyst,18 thus
completing the photocatalytic cycle. As for regular alkenes,
direct protonation of intermediate D yielded the corresponding
1,1-diarylmethanenitriles or alkyl nitriles 4. Otherwise, in the
case of CF3-styrene carbanions, a β-fluoride elimination of
intermediate E ultimately afforded the corresponding gem-
difluoroalkenes 6.
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DOI: 10.1021/acs.orglett.9b00651
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