Visible-Light-Promoted Catalytic Ring-Opening Isomerization of 1,2-Disubstituted Cyclopropanols to Linear Ketones

Article abstract of DOI:10.1002/ejoc.202000094

Isomerization to linear ketones is a valuable transformation of 1,2-disubstituted cyclopropanols proceeding through radical intermediates. Despite simplicity of this reaction, the known protocol required stoichiometric amounts of both an oxidant and a reducing agent. In this article, we report a catalytic isomerization of 1,2-disubstituted cyclopropanols to linear ketones enabled by the photoredox catalytic system consisting of an acridinium photocatalyst and diphenyl disulfide under irradiation with blue LEDs.

Full text of DOI:10.1002/ejoc.202000094

A Journal of
Accepted Article
Title: Visible-light-promoted catalytic ring-opening isomerization of 1,2-
disubstituted cyclopropanols to linear ketones
Authors: Marharyta Laktsevich-Iskryk, Nastassia Varabyeva, Volha
Kazlova, Vladimir Zhabinskii, Vladimir Khripach, and Alaksiej
L. Hurski
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000094
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000094
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European Journal of Organic Chemistry
10.1002/ejoc.202000094
COMMUNICATION
Visible-light-promoted catalytic ring-opening isomerization of 1,2-
disubstituted cyclopropanols to linear ketones
[a]
[a]
[a]
Marharyta V. Laktsevich-Iskryk, Nastassia A. Varabyeva, Volha V. Kazlova, Vladimir N.
[a]
[a]
[a]
Zhabinskii, Vladimir A. Khripach and Alaksiej L. Hurski*
Abstract: Isomerization to linear ketones is a valuable transformation
of 1,2-disubstituted cyclopropanols proceeding through radical
intermediates. Despite simplicity of this reaction, the known protocol
required stoichiometric amounts of both an oxidant and a reducing
agent. In this article, we report a catalytic isomerization of 1,2-
disubstituted cyclopropanols to linear ketones enabled by the
photoredox catalytic system consisting of an acridinium photocatalyst
and diphenyl disulfide under irradiation with blue LEDs.
Introduction
Ring-opening
functionalization
of
1,2-disubstituted
cyclopropanols is a versatile tool for the preparation of α- and β-
substituted ketones.[1] Generally, cleavage of the ring proceeds
under mild conditions, and regioselectivity of the reaction can be
controlled by choosing an appropriate reagent or catalyst.[1a-c, 1f]
While disconnection of C1-C3 bond is promoted by acids, bases
or transition metal catalysts,[2] cleavage of C1-C2 bond is
triggered by one-electron oxidation of 1 to form an unstable
oxycyclopropyl radical 2 (Scheme 1). [3-6] These species undergo
facile rearrangement to β-carbonyl radical 3, functionalization of
which with an appropriate reagent furnishes β-substituted ketone
[
3a-e]
4
. To generate intermediates 2, metal oxidants
or 4-hydroxy-
TEMPO[
3f]
were utilized. Moreover, several light-promoted
approaches were recently developed.[4-5] Chen[4a] found that
under visible light irradiation in the presence of a ruthenium
photocatalyst, the in situ formed cyclopropanol/benziodoxole
complex undergoes decomposition giving the oxygen-centered
radical. Zhu[ disclosed that cyclopropanols can be oxidized by
Ir species formed by the reaction of a photoexcited IrIII catalyst
with a persulfate salt. Examples of the direct electron transfer from
a cyclopropanol to a photoexcited catalyst were also reported.
Lectka[4c] developed UV-promoted 1,2,4,5-tetracyanobenzene
catalyzed radical ring-opening fluorination, and Melchiorre[4d]
showed that 1,2,2-trisubstituted cyclopropanols undergo one-
electron oxidation by the photoexcited iminium ions. In this article,
we report that organic acridinium photocatalysts irradiated with
blue LEDs also promotes the radical ring opening. We
successfully employed such a catalyst in the isomerizatiton of 1,2-
disubstituted cyclopropanols to linear ketones.
4b]
IV
Scheme 1. Radical ring-opening of cyclopropanols
Formation of linear ketones 4 (Z=H) is the simplest but a valuable
radical transformation of cyclopropanols 1, which was applied in
several total syntheses of natural products at the crucial stage of
subunits coupling.[7] In the synthesis of (+)-spirolaxine (10)
reported by Phillips,[7a] ester and alkene fragments 5 and 6 were
assembled by the Kulinkovich reaction to afford cyclopropanol 7,
which was further converted to the desired ketone 9 by means of
the radical ring-opening. Although formally this reaction is a
rearrangement, it proceeds through two separate stages, each of
which requires stoichiometric amounts of reagents, an oxidant
and an H-atom source, respectively.[ One more disadvantage
of the known protocol is a high toxicity of the reducing agent,
tributyltin hydride (8). Recently, Wallentin[8] and Nicewicz[9]
reported approaches for decarboxylation of aliphatic acids in
which one-electron oxidation and further H-atom transfer were
7a]
[
a]
Marharyta V. Laktsevich-Iskryk, Nastassia A. Varabyeva, Volha V.
Kazlova, Dr. Vladimir N. Zhabinskii, Prof. Vladimir A. Khripach,
Dr. Alaksiej L. Hurski
Institute of Bioorganic Chemistry, National Academy of Sciences of
Belarus, Kuprevich str. 5/2, Minsk 220141, Belarus
E-mail: ahurski@iboch.by
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European Journal of Organic Chemistry
10.1002/ejoc.202000094
COMMUNICATION
[
10]
performed by means of the photocatalytic system consisting of
an acridinium photocatlyst[11] and diaryldisulfide used as an H-
atom shuttle.[12] We found that these catalysts efficiently promote
radical isomerization of cyclopropanols to the linear ketones. The
reaction proceeds under mild conditions and various functional
groups are tolerated.
4
5
6
+
-
4
Without Mes-Acr-Ph BF
No reaction
Ru(bpy)
3
(BF
4
)
2
instead of Mes-Acr-
No reaction
+
-
Ph BF
4
5%[a] (30:70)
3
[
Ir{dF(CF
3
)ppy}
2
(dtbpy)]PF
6
instead of
+
-
42%[b][c] (81:19)
Mes-Acr-Ph BF
4
Results and Discussion
7
8
+
-
4
Eosin Y (16) instead of Mes-Acr-Ph BF
No reaction
(in acetone, white LEDs)
Our investigations started with an attempt to isomerize
cyclopropanol 11a to linear ketone 12a in the presence of
acridinium photocatalyst 14 and diphenyl disulfide under
irradiation with blue LEDs (Table 1). We were pleased to observe
smooth formation of product 12a in 75% yield and with a good
+
-
4
Mes-Acr-Me BF (15) instead of Mes-
9%[a] (88:12)
4
+
-
4
Acr-Ph BF (14)
9
1
1
53[a] % (90:10)
MeCN instead of DCE
90:10 regioselectivity. Without diphenyl disulfide, the yield of the
transformation was lower and the regioselectivity was reverse,
which indicated changing of the mechanism of isomeriation to
non-radical. In the absence of light or the photocatalyst, only
recovery of the starting material was observed. Metal-based
ruthenium and iridium photocatalysts, as well as an alternative
organophotocatalyst eosin Y (16) were not efficient. Surprisingly,
in the presence of the iridium photocatalyst, branched ketone 13a
became the major product. However, when the reaction was
carried out in the presence of 2,6-lutidine, the selectivity became
typical for the radical reactions. This result can be explained by
formation of trace amounts of acids in the course of the
reaction.[13] In the presence of methylacridinium catalyst 15, the
yield of ketone 12a was significantly lower, though the
regioselectivity was not distorted. Replacing the solvent with
acetonitrile or methanol reduced the yield. The regioselectivity of
the reaction in acetonitrile remained good, but dropped to 80:20
in methanol. In DMA only the starting material was recovered.
0
1
31%[b,d] (83:17)
No reaction
MeOH instead of DCE
DMA instead of DCE
[
a]isolated yield; [b]determined from 1H NMR spectrum of the reaction
mixture using CH Br as an internal standard; [c] 2,6-lutidine (0.1 equiv.) was
2
2
added to the reaction mixture [d]30% of the starting material was recovered
Table 1. Optimization of the reaction conditions
With the optimized conditions in hand, the scope of the
reaction was investigated (Table 2). Prepared by means of the
Kulinkovich or Simmons-Smith reaction,[14] cyclopropanols
generally underwent smooth regioselective isomerization even in
the presence of sensitive units. Non-functionalized 1,2-dialkyl
substituted cyclopropanols and the substrates bearing silyloxy
groups were transformed to the linear ketones 12a-f in good
yields independent on the steric volume of a substituent at C1 and
C2. The reaction tolerated bromide and trimethylsilyl substituents.
Products 12g and 12h were isolated in good 68% and 61% yields,
respectively. Dioxolane protecting group in 11i was stable under
the reaction conditions, but dimethylacetal unit in 11j underwent
partial deacetalyzation. Hence, an inseparable 83:17 mixture of
acetal 12j-1 and aldehyde 12j-2 was formed, though, in a good
overall yield. The alkenyl moiety in 11k and 11l were non-reactive
and the isomerization proceeded smoothly. Even though the β-
ketoradical intermediate generated from 11l could undergo
intramolecular cyclization to a cyclohexane derivative, only the
isomerization product 12l was isolated. Cyclopropanol 11m was
smoothly converted to ketone 12m in a high 85% yield.
entry
deviation from above
Yield of
2a+13a, %
12a:13a ratio)
1
(
1
2
3
75%[a] (93:7)
30%[a] (40:60)
none
Without PhSSPh
No light
No reaction
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European Journal of Organic Chemistry
10.1002/ejoc.202000094
COMMUNICATION
Remarkably, this isomerization carried out according to the
previously reported protocol[7a] resulted in formation of an
inseparable mixture of the desired product 12m and
corresponding enone (see SI for details). The photochemical
isomerization was mild enough for preparing ketone 12n, which
To get insight into the reaction mechanism, control experiments
were carried out. Existance of the intermediate β-ketoradicals in
the isomerization was proved by formation of cyclization product
bears
a stereocener next to the carbonyl group, in an
18 from cyclopropanol 11s (Scheme 2). Moreover, when the ring-
enantiomerically pure form. In the presence of
a
opening of 11a was run in the presence of TEMPO, significant
inhibition was observed and enone 19 was isolated in a low yield,
which, in turn, might suggest formation of TEMPO adduct 20. To
determine the source of H-atom at the final stage of the reaction,
deuterium studies were carried out. Before the ring opening, OH
group in cyclopropanol 11c was subjected to H-D exchange and
the deuterated substrate was engaged in the isomerization. After
the reaction, β-deuterated product d-12c was detected in the
reaction mixture. These studies suggested the mechanism
depicted in Scheme 2. The reaction starts with the single-electron
oxidation of cyclopropanol unit I by the photoexcited acridinium
catalyst. Then, radical-cation II undergoes deprotonation and the
formed oxycyclopropyl radical III rearranges to β-oxocarbonyl
radical IV. Its reaction with thiophenol leads to linear ketone unit
V.
thiophenyltetrazole moiety, the reaction did not reach completion
and the product was isolated in a 29% yield along with 44% of the
recovered starting material. The unprotected hydroxyl group in
11p was tolerated and we successfully obtained ketone 12p in a
moderate yield. Monosubstituted cyclopropanol 11q and 2-
phenylsubstituted cyclopropanol 11r were completely non-
reactive under the standard conditions. However, when the
intensity of the irradiation was increased, the desired products
12q and 12r were formed, though, in poor yields.
Table 2. Scope of the visible light-promoted isomerization of
1
,2-disubstituted cyclopropanols.[a]
+
-
[
a] Reaction conditions: cyclopropanol (0.17 mmol), Mes-Acr-Ph BF (14)
4
(
1
0.0085 mmol), PhSSPh (0.034 mmol), DCE (0.7 mL), blue LEDs 14.4W, rt,
2 h; [b] linear to branched isomer ratio (determined from H NMR spectra);
Scheme 2. Control experiments and plausible mechanism of the
reaction.
1
[
c] 2x20W blue LED sources were used.
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European Journal of Organic Chemistry
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COMMUNICATION
Zhabinskii, V. A. Khripach, Chem. Commun. 2018, 54, 2800-2803; d) I. Novikau, A.
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Conclusions
To conclude, we have successfully employed a photoredox
catalytic system consisting of an organic acridinium photocatalyst
and diphenyl disulfide in the isomerization of 1,2-disubstituted
cyclopropanols to linear ketones. The reaction conditions are mild
and neutral enough to tolerate sensitive functional groups,
including the stereocenter next to the carbonyl function. The
protocol does not require toxic reagents. Moreover, utilizing this
[
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9, 4179-4188.
method, we have successfully prepared ketone 12m, which could
not be prepared by the known[7a] approach.
[
[
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Experimental Section
General procedure for the visible-light-promoted ring-opening of 1,2-
disubstituted cyclopropanols:
Dry 1,2-dichloroethane (0.7 mL), was added to the 4 mL vial containing
cyclopropanol 11 (0.17 mmol, 1 equiv), 9-mesityl-10-phenylacridinium
tetrafluoroborate 14 (3.9 mg, 8.5 μmol, 5 mol%) and diphenyl disulfide (7.5
mg, 0.034 mmol, 20 mol%) under Ar atmosphere. The resulting mixture
was placed at a distance of about 5 cm from 450 nm LED strip and
irradiated with stirring at room temperature for 12 h. The solvent was
evaporated under reduced pressure and the residue was purified by
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column chromatography on silica gel (5-15% Et
2
O/PE).
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Acknowledgments
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We are grateful for the financial support from the National
academy of sciences of Belarusian (project 2019-27-120) and the
Belarusian Foundation for Fundamental Research (projects
X19PM-074, X20-054).
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Keywords: cyclopropanols • ring-opening • ketones •
photochemistry • radicals
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[13] We also tried to alter the selectivity of the acridinium-catalyzed isomerization in
the absence of PhSSPh (Table 1, entry 2) by addition of 2,6-lutidine, but under the
modified conditions, only recovery of the starting material was observed.
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European Journal of Organic Chemistry
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COMMUNICATION
Photocatalysis
Marharyta V. Laktsevich-Iskryk,
Nastassia A. Varabyeva, Volha V.
Kazlova, Vladimir N. Zhabinskii, Vladimir
A. Khripach, Alaksiej L. Hurski*
Page No. – Page No.
Visible-light-promoted catalytic ring-
opening isomerization of 1,2-
disubstituted cyclopropanols to
linear ketones
A visible-light-promoted acridinium-catalyzed radical isomerization of 1,2-disubstituted
cyclopropoanols to linear ketones is reported
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