Carbonylation of Alkyl Radicals Derived from Organosilicates through Visible-Light Photoredox Catalysis

Article abstract of DOI:10.1002/anie.201811858

Primary, secondary, and tertiary alkyl radicals formed by the photocatalyzed oxidation of organosilicates underwent efficient carbonylation with carbon monoxide (CO) to give a variety of unsymmetrical ketones. This study introduces the possibility of radi

Full text of DOI:10.1002/anie.201811858

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Accepted Article
Title: Alkyl Radical Carbonylation Using Organosilicates via Visible-
Light Photoredox Catalysis
Authors: Alex Cartier, Etienne Levernier, Vincent Corcé, Takahide
Fukuyama, Anne-Lise Dhimane, Cyril Ollivier, Ilhyong Ryu,
and Louis Fensterbank
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201811858
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10.1002/anie.201811858
Angewandte Chemie International Edition
COMMUNICATION
Alkyl Radical Carbonylation Using Organosilicates via Visible-
Light Photoredox Catalysis
[a]
Alex Cartier,‡ Etienne Levernier,‡ [b] Vincent Corcé,[b] Takahide Fukuyama,*[a] Anne-Lise Dhimane,[b]
Cyril Ollivier,*[b] Ilhyong Ryu,*[a][c] and Louis Fensterbank*[b]
carbonylation reactions.[15] In those studies organic halides,
Abstract: Primary, secondary and tertiary alkyl radicals, formed by
photocatalyzed oxidation of organosilicates, can be involved
efficiently in radical carbonylation with carbon monoxide (CO), which
leads to a variety of unsymmetrical ketones. This work constitutes the
first example of radical carbonylation under a photooxidative regime.
chalcogenides, and unsaturated C-C bonds were generally used
as the starting radical sources. Recently, several groups have
applied aryl radical carbonylation to successful photoredox
conditions, that follow a reductive photoredox pathway using aryl
diazonium salts as aryl radical precursors. For example, Gu,
Jacobi Von Wangelin, and Xiao independently reported that
ketones and esters can be formed via the photoredox
Visible-light photoredox catalysis now holds a privileged
position in modern radical chemistry.[1,2] Several families of alkyl
carbonylation of an aryl ring by using CO either in the presence
radical
precursors,
such
as
alkylcarboxylates,[3]
[16]
of eosin Y
A).[17,18]
or fluorescein as a photocatalyst (Scheme 1, type
alkyltrifluoroborates,[4] and alkylsulfinate salts[5] are known to use
visible light irradiation to promote the efficient formation of alkyl
radical species under photooxidation conditions. Recently, alkyl
bis(catecholato)silicates[6] were introduced by the Paris group[7]
and later by Molander[8] and others[9] to allow for the smooth
generation of a variety of alkyl radicals that includes unstabilized
primary radicals, and this enhancement applies to visible light
photoredox-catalyzed conditions with Ru(II) or Ir(III) salts and
even with organic dye 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyano-
benzene (4CzIPN).[7b, 10] The generated alkyl radical species can
be promptly trapped by several activated alkenes, allylsulfone,[7b,
7c] and imines.[11]
Radical multicomponent processes are in great demand as
they allow the reduction of a number of steps in order to obtain
the targeted compounds.[12] In this regard, carbon monoxide (CO)
is effective as a donor/acceptor type radical C1 synthon similar to
isonitriles.[13,14] Carbonylative couplings for the formation of
ketones or esters by radical carbonylations have been extensively
investigated by the Osaka group[15] which include photo-induced
Scheme 1. Photoredox catalysed radical carbonylation under photoreductive
conditions (previous work) and under photooxidative conditions (this work).
Ryu and co-workers previously reported three component
types of unsymmetrical ketone synthesis for which alkyl halides,
CO, and alkenes were reacted typically using tributyltin hydride[19]
‡
[a]
[b]
A. Cartier,[ ] Prof. T. Fukuyama, Prof. I. Ryu
Department of Chemistry, Graduate School of Science
Osaka Prefecture University
or tris(trimethylsilyl)silane[20] as
a
radical mediator.[21] We
Sakai, Osaka 599-8531, Japan
E-mail: fukuyama@c.s.osakafu-u.ac.jp
ryu@c.s.osakafu-u.ac.jp
E. Levernier,[ ] Dr. A.-L. Dhimane, Dr. V. Corcé, Dr. C. Ollivier,
Prof. L. Fensterbank
Sorbonne Université, CNRS
Institut Parisien de Chimie Moléculaire
4 Place Jussieu, CC 229, F-75252 Paris Cedex 05, France
E-mail: cyril.ollivier@sorbonne-universite.fr
louis.fensterbank@sorbonne-universite.fr
Prof. I. Ryu
Department of Applied Chemistry
National Chiao Tung University
Hsinchu, Taiwan
considered the use alkyl bis(catecholato)silicates as new
substrates in this reaction. These are easily prepared from the
corresponding alkoxysilanes and trichlorosilanes in a one-pot
reaction (see supporting information for more details). They can
be conserved weeks on the bench in contact with ambient air.[7-9]
They also exhibit relatively low oxidation potentials ( < 1 V vs.
SCE). Herein we report the first example of oxidative
photocatalyzed carbonylative coupling reaction, as a novel three-
component carbonylation route to unsymmetrical ketones under
mild visible-light photoredox conditions that require no traditional
radical mediators (Scheme 1, type B). As ketones are ubiquitous
and important in organic chemistry due to their polyvalent
reactivity, the development of new methods for their synthesis is
still very useful for chemists. [22]
‡
[c]
E-mail: ryu@c.s.osakafu-u.ac.jp
These authors contributed equally to this work.
‡
[ ]
Supporting information for this article is given via a link at the end
of the document.((Please delete this text if not appropriate))
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10.1002/anie.201811858
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COMMUNICATION
Table 1: Optimization of the reaction conditions [a]
cases, the ratio remained excellent (97 : 3). When the reaction
was carried out with 0.09 M of 2a, we observed an increased yield
of product 3a to 71% with a slightly decreased ratio of 94 : 6 (Table
1, entry 6). Since the reaction of entry 6 remained slow, we
extended the reaction time for 48 h, which gave 3a in an 85%
isolated yield (Table 1, entry 7).
Entry
Catalyst
[2a] [M]
Time (h)
Yield 3a[b]
Ratio 3a : 4a[d]
1
2
3
4
[Ir][e]
0.15
0.15
0.15
0.02
24
24
24
24
58%
69%
13%[c]
49%
92 : 8
93 : 7
75 : 25
97 : 3
4CzIPN[f]
none
4CzIPN[f]
5
6
7
4CzIPN[f]
4CzIPN[f]
4CzIPN[f]
0.04
0.09
0.09
24
24
48
65%
71%
85%
97 : 3
94 : 6
95 : 5
[a] Conditions: potassium [18-Crown-6] bis(catecholato)-cyclohexylsilicate
(1a, 0.3 mmol, 1 equiv), dimethylmaleate (2a, 2 equiv), photocatalyst (1-2
mol%), KH2PO4 (0.36 mmol), CO (80 atm), DMF (10-3 mL), irradiation by
blue LED lamp (425 nm) for 24-48 h. [b] isolated yield. [c] determined by 1H
NMR. [d] determined by GC of the crude mixture. [e]
[Ir(dF(CF3)ppy)2(bpy)](PF6), 2 mol%. [f] 1 mol%.
As a model, we first chose to test a three-component
coupling reaction comprised of cyclohexyl bis(cathecolato)
silicate (1a), CO, and dimethylmaleate (2a). The experiment was
carried out in a stainless-steel autoclave equipped with two quartz
glass windows that served as a pressure-durable apparatus
during light irradiation (15 W blue LED, see the supporting
information for details). The results are summarized in Table 1.
When a solution of 1a, 2a, [Ir(dF(CF3)ppy)2(bpy)](PF6) (1 mol%),
and KH2PO4 (1.2 equiv) in DMF was irradiated for 24 hours under
a CO pressure of 80 atm, the desired reaction proceeded to give
the anticipated unsymmetrical ketone 3a in a 58% yield after
isolation by flash chromatography on silica gel (Table 1, entry 1).
The non-carbonylated product 4a was the only by-product of the
reaction, and was present in only a small amount (3a : 4a = 92 :
8). To insure effective photoredox catalysis, we used an organic
dye, 1,2,3,5-tetrakis-(carbazole-yl)-4-dicyanobenzene (4CzIPN),
with a long excited state lifetime (5.1 s).[23,7c] It also displays
interesting photoredox properties (E1/2 (4CzIPN*/[4CzIPN]-) =
+1.59 V vs. SCE and E1/2 (4CzIPN/[4CzIPN]-) = -1.21 V vs.
SCE),[24] so that this photocatalyst has proven useful for the
photooxidation of alkyl bis(catecholato)silicates.[7b,10e] To our
delight, using this organic dye we obtained a better yield of 69%
with similar ratios of 3a and 4a (93 : 7) (Table 1, entry 2). When
the reaction was tested without the use of a photocatalyst, the
yield dropped dramatically to 13% (Table 1, entry 3), which
suggested the necessity of a photocatalyst. Next, we decreased
the concentration of 2a from 0.15 M to 0.02 and 0.04 M. At a lower
concentration (0.02 M), the reaction became sluggish and the
yield of 3a was decreased to 49% (Table 1, entry 4). With 2a at
0.04 M, the yield reached 65% (Table 1, entry 5). In these two
Scheme 2. Scope of the substrates for the three-component reaction leading
to unsymmetrical ketones 3
We applied these optimized conditions to the three-
component synthesis of a series of unsymmetrical ketones 3,
using a variety of alkyl bis(cathecolato)silicates as substrates
(Scheme 2). The carbonylation of the cyclopentyl derivative
worked well and led to the corresponding unsymmetrical ketone
3b in a 68% yield. Primary radicals furnished good yields,
irrespective of the use of a linear alkyl (3c, 70%) or a branched
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alkyl (3d, 65%). The reaction of a tertiary alkylsilicate also gave
ketone 3e in a 67% yield. Interestingly, the reaction was
compatible with a rather sensitive level of functionality, such as
with an oxirane, and gave the desired product 3f in a 79% yield.
Product 3g with an oxabicycloheptyl moiety was obtained in an
80% yield, albeit with an extended reaction time of 72 hours. The
carbonylated adduct 3h, bearing an acetate, appeared unstable
and could not be isolated, although it was identified by 1H NMR in
the crude reaction mixture (50%). The use of the 5-hexenyl
derivative 1i was expected to provide insight into the rate of
carbonylation under these conditions. Interestingly, under the
employed conditions, we obtained an almost equimolar mixture of
uncyclized 3i and cyclized 3i’ in a 34% yield, with a crude NMR
chart that suggested other by-products had formed via
carbonylation.[25]
We proposed the overall mechanism illustrated in Scheme 3.
In the first step, the photocatalyst is excited under visible-light
irradiation. A SET oxidation of the alkyl bis(catecholato)silicate 1
by the excited *4CzIPN,[10] leads to the reduced species [4CzIPN].-
and to the formation of the alkyl radical A via homolytic cleavage
of the C-Si bond of the silicate radical.[7-9] Alkyl radical A reacts
with CO to form the acyl radical B,[14] which adds to the acceptor
alkene 2 to provide adduct radical C. The latter would be reduced
by [4CzIPN].- to afford the stabilized carbanionic species D and
regenerate the photocatalyst in its ground state, thus closing the
catalytic cycle and ensuring its propagation. Finally, protonation
of D by KH2PO4 yields the final product 3.
To support this hypothetical mechanism, we conducted
several experiments (see the supporting information for details).
Fluorescent quenching studies of *4CzIPN by silicate 1a in the
absence of CO showed a decrease of the fluorescent intensity
upon gradual addition of 1a. The quenching rate constant kq from
the Stern-Volmer equation was determined to be 1.37 x 108 mol-
1·L·s-1 (in DMF), a value consistent with another determination in
DMSO (kq = 2.5 x107 M-1·s-1) by Molander.[27] Based on the redox
Next, we investigated the compatibility of a variety of activated
alkenes as radical acceptors (2a-k) by using the three-component
transformation (Scheme 2). 1,4-Dicarbonyl derivatives still remain
challenging to access.[26] Gratifyingly, methyl vinyl ketone 2b was
successfully used in the three-component reaction with CO and
bis(catecholato-cyclo-hexyl)silicate 1a to give the corresponding
1,4-diketone 3j in 80% yield. By contrast, the reaction of
vinylsulfone 2c, and methyl acrylate 2d gave the carbonylation
products 3k and 3l in rather moderate yields (42 and 34%,
respectively). When we used acrylonitrile, the expected product
3m was obtained in an excellent yield of 81%. The compound 3n,
obtained from the N,N-dimethylacrylamide 2f, was isolated in a
60% yield. Cyclopentenone 2g led to the formation of diketone 3o
in a 53% yield. Interestingly, -alkyl-substituted, -unsaturated
carbonyl compounds capably underwent the present
transformation. Thus, methyl crotonate 2h gave the
corresponding 4-keto ester 3p in a 78% yield. The reaction of
diethyl 2-ethylidenemalonate 2i gave the expected product 3q in
an 89% yield. The reaction of butyl methacrylate 2j gave the
corresponding 4-keto ester 3r in a 54% yield. The reaction of 1a
with CO in the presence of disulfonylethene 2k, gave non-
carbonylated adduct 4s in a 76% yield. Disulfonylethylene 2k is
such a good radical acceptor that a direct addition of a cyclohexyl
radical proceeded.
potentials
differences
between
*4CzIPN
and silicate 1a (Eox
(E1/2
[10f]
(4CzIPN*/[4CzIPN]-) = +1.59 V vs. SCE)
= +0.69 V vs. SCE )[7c], a SET consisting in the reductive
quenching of the photoexited photocatalyst *4CzIPN by silicate
1a is presumably involved. This was confirmed by the reaction of
cyclohexylsilicate 1a with CO, in the presence of 2.2 equiv. of
TEMPO which led to the exclusive formation of the non-
carbonylated TEMPO adduct 5 in 77% yield, thus highlighting the
formation of radical intermediates of type A. A “light/dark”
experiment was also conducted in the absence of CO and it
appears that the product formation occurs only during periods of
light irradiation. This result might support the catalytic mechanism
shown in Scheme 3.[28] To ensure that no short radical chain
occurs, we measured quantum yields of the reaction of silicate 1a
with different acceptors in the presence of 4CzIPN. We obtained
a quantum yield of 0.066 in the conjugate addition with maleate
and 0.33 for the allylation reaction with 2-phenylallyl p-tolyl
sulfone with 4CzIPN. These findings show that the present
mechanism does not follow a radical chain pathway but most
likely a closed photoredox loop, as depicted in Scheme 3.
Scheme 4. Three-component reaction leading to unsaturated ketones 7
Next, we focused on the behavior of various silicates towards
carbonylative radical allylation with various allylsulfones (6a-b)
(Scheme 4), for which previous work used allyltin as a radical
acceptor.[19a] The reaction of 1a with CO and allylsulfone 6b,
Scheme 3. Proposed mechanism
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10.1002/anie.201811858
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2
3
For recent books, see: a) Chemical Photocatalysis, Eds. B. König,
DeGruyter Berlin, 2013; b) Photochemically generated intermediates in
Synthesis, Eds A. Albini, M. Fagnoni, Wiley, Hoboken, 2013; c) Visible
Light Photocatalysis in Organic Chemistry Stephenson, C.; Yoon, T.;
which bears a methoxycarbonyl group at the 2 position, returned
,-unsaturated ketone 7a in
a
66% yield. When
phenylallylsulfone 6b was reacted with cyclohexylsilicate 1a and
CO, it gave the expected enone 7b in a 60% yield. Primary
radicals are good substrates for the present radical allylation
regardless of whether it is a linear alkyl (7c, 58%), or a branched
alkyl (7d, 51%). The reaction with a tertiary alkylsilicate gave the
desired enone 7e in a 40% yield together with a non-carbonylated
addition product. These allylation reactions followed the pattern of
the mechanism reported in Scheme 3, in which the photocatalyst
was regenerated by a reduction of the phenylsulfonyl radical to a
phenylsulfinate anion.[7c] The ketones formed herein could be
useful scaffolds. For instance, 1,4 ketone 3j could be used
through a Paal-Knorr reaction for the synthesis of pyrroles or
thiophenes. These heteroaromatics can be found in many natural
products but also in biological active compounds such as HMG-
CoA reductase inhibitors and hepatitis C virus polymerase
inhibitors.[29]
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,
In summary, herein, we described an oxidative photoredox
catalysis combined with radical carbonylation chemistry, for the
first time. The present reaction protocol was based on the use of
an inexpensive organic dye, 4CzIPN, as a photocatalyst and on a
wide range of alkyl bis(catecholato)silicates that were used as
alkyl radical precursors under a CO atmosphere, which afforded
efficient access to a variety of functionalized unsymmetrical
ketones including ,-unsaturated ketones. These results
demonstrate the plausibility of other photocatalyzed radical
carbonylation reactions under oxidative regimes that we are now
exploring in our laboratory.
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Acknowledgements
This work was supported by the Grant-in-Aid for Scientific Research
(A) (No. 26248031) and (C) (No. 17K05866) from the JSPS, and
Scientific Research on Innovative Areas 2707: Middle molecular
strategy (No. 15H05850) from the MEXT. We thank Sorbonne
University, ANR-17-CE07-0018 HyperSilight (PhD grant to E.L.).
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Conflicts of interest
None to declare.
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Keywords: carbonylation • three-component reaction •
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28 For practical reasons, the “light/dark” experiment was conducted
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Alex Cartier, Etienne Levernier, Vincent
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and Louis Fensterbank*
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Primary, secondary and tertiary alkyl radicals, formed by photocatalyzed oxidation of
organosilicates, are involved in three-component reactions with carbon monoxide
(CO) and radical acceptors to provide unsymmetrical ketones. This work constitutes
the first example of radical carbonylation under a photooxidative regime and metal-
free conditions.
Radical Carbonylation of
Organosilicates by Visible-Light
Photoredox Catalysis
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