A Photochemical Organocatalytic Strategy for the α-Alkylation of Ketones by using Radicals

Article abstract of DOI:10.1002/anie.201915814

Reported herein is a visible-light-mediated radical approach to the α-alkylation of ketones. This method exploits the ability of a nucleophilic organocatalyst to generate radicals upon S_N2-based activation of alkyl halides and blue light irradiation. The resulting open-shell intermediates are then intercepted by weakly nucleophilic silyl enol ethers, which would be unable to directly attack the alkyl halides through a traditional two-electron path. The mild reaction conditions allowed functionalization of the α position of ketones with functional groups that are not compatible with classical anionic strategies. In addition, the redox-neutral nature of this process makes it compatible with a cinchona-based primary amine catalyst, which was used to develop a rare example of enantioselective organocatalytic radical α-alkylation of ketones.

Full text of DOI:10.1002/anie.201915814

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Accepted Article
Title: A Photochemical Organocatalytic Strategy for the α-Alkylation of
Ketones using Radicals
Authors: Paolo Melchiorre, Davide Spinnato, Bertrand Schweitzer-
Chaput, Giulio Goti, and Maksim Ošeka
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915814
Angew. Chem. 10.1002/ange.201915814
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10.1002/anie.201915814
Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Radical Chemistry
A Photochemical Organocatalytic Strategy for the α-Alkylation of
Ketones using Radicals**
Davide Spinnato,‡ Bertrand Schweitzer-Chaput,‡ Giulio Goti, Maksim Ošeka, and Paolo Melchiorre*
In memory of Professor Dieter Enders
Abstract: Reported herein is a visible-light-mediated radical
approach to the α-alkylation of ketones. This method exploits the
ability of a nucleophilic organocatalyst to generate radicals upon
SN2-based activation of alkyl halides and blue light irradiation. The
resulting open-shell intermediates are then intercepted by weakly
nucleophilic silyl enol ethers, which would be unable to directly
attack the alkyl halides through a traditional two-electron path. The
method’s mild reaction conditions allowed us to functionalize the α
position of ketones with functional groups that are not compatible
with classical anionic strategies. In addition, the redox-neutral
nature of this process makes it compatible with a cinchona-based
primary amine catalyst, which was used to develop a rare example of
enantioselective organocatalytic radical α-alkylation of ketones.
effective reactions with the weakly nucleophilic silyl enol ethers 1
(Figure 1b). Moving from a two-electron logic to a radical reactivity
pattern could therefore provide the desired degree of chemoselectivity
and functional group tolerance to the α-alkylation of ketones.
However, this would require effective strategies to generate alkyl
halide-derived radicals. To date, the few reported protocols are
limited to the use of specific radical precursors that can be easily
activated by initiators or through single-electron transfer (SET)
processes, including perfluoralkyl iodides,[8] α-bromo ketones and
esters,[9] and N-(acyloxy)-phthalimide derivatives.[10] In addition,
redox-based strategies (e.g. photoredox catalysis)[11] offer an
additional challenge since the low oxidation potentials of silyl enol
ethers[12] make them prone to degradation upon SET oxidation.
Our laboratory recently reported a unique photochemical catalytic
radical generation strategy, which is not reliant on the redox
properties of the substrates.[13] This method exploits the ability of a
highly nucleophilic[14] dithiocarbonyl anion organocatalyst A to
generate radicals upon blue light irradiation and SN2-based activation
of substrates (including alkyl chlorides and mesylates), which would
be inert to classical radical-generating strategies (Figure 1c). Here,
we demonstrate how this catalytic platform can provide a general
radical approach for the α-alkylation of ketones using silyl enol ethers.
This approach synthetically complements and enriches traditional
two-electron strategies. This is because the method’s mild reaction
conditions and functional group tolerance allowed us to functionalize
the α position of ketones with moieties that are incompatible with
classical anionic processes.
Introduction
T
he α-alkylation of ketones is a fundamental C-C bond forming
process.[1] Classically, it is accomplished by means of highly
nucleophilic alkali metal enolates, generated via deprotonation of the
corresponding ketones, which can react with alkyl halides through a
SN2 manifold (Figure 1a).[2] This two-electron, anionic strategy has
found extensive use in synthesis. However, it also brings about some
chemoselectivity issues, since the strongly basic and nucleophilic
nature of the metal enolates limits the range of functional groups that
can be tolerated. Milder alternatives, which avoid the use of strongly
basic metal enolates, are therefore highly sought-after. Silyl enol
ethers are stable enolate equivalents, which are easy to synthesize and
to handle.[3] They have been extensively used in nucleophilic addition
chemistry (aldol, Michael, and Mannich-type processes).[4] However,
their poor nucleophilicity[5] makes them unsuitable for alkylation
reactions with alkyl halides via a SN2 manifold (Figure 1a, right
arrow). The literature contains only a few reports of silyl enol ether
alkylation, generally limited to SN1-type substitution processes.[6]
In principle, the high reactivity of open-shell intermediates, which
can easily engage in C-C bond forming processes,[7] could be used for
[]
Prof. Dr. P. Melchiorre
ICREA – Passeig Lluís Companys 23, 08010 Barcelona, Spain
Dr. B. Schweitzer-Chaput, Dr. G. Goti, Dr. M. Ošeka, D. Spinnato,
and Prof. Dr. P. Melchiorre
ICIQ - Institute of Chemical Research of Catalonia
the Barcelona Institute of Science and Technology,
Avenida Països Catalans 16 – 43007, Tarragona, Spain
E-mail: pmelchiorre@iciq.es
Figure 1. (a) Traditional strategies for the α-alkylation of ketones using enolate
equivalents via anionic pathways. (b) Radical approach to the alkylation of silyl
enol ethers 1. (c) The presented photochemical strategy uses a nucleophilic
catalyst A and visible light to generate radicals from redox-inert alkyl
Homepage: http://www.iciq.org/research/research_group/prof-paolo-
melchiorre/
[‡]
These authors contributed equally to this work.
electrophiles, which are then trapped by weakly nucleophilic silyl enol ethers.
[]
Financial support was provided by MICIU (CTQ2016-75520-P), the
AGAUR (Grant 2017 SGR 981), and the European Research
Council (ERC-2015-CoG 681840 - CATA-LUX). We thank Dr.
Matthew A. Horwitz for the synthesis of complex starting materials.
1
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10.1002/anie.201915814
Angewandte Chemie International Edition
Results and Discussion
perform the model reaction using classical enolate chemistry, e.g.
treating acetophenone with strong bases, met with failure (see Table
S2 in the Supporting Information). Finally, we demonstrated that the
strongly reducing fac-Ir(ppy)3 photoredox catalyst provided vastly
inferior results (entry 10), presumably because of a difficult
generation of the reactive radical from 2a.
We commenced our studies by evaluating the alkylation of
acetophenone-derived silyl enol ether 1, using the commercially
available chloroacetonitrile 2a as the radical precursor (Table 1). The
experiments were conducted at 25 ºC in acetonitrile, using a blue LED
strip emitting at 465 nm, 10 mol% of the dithiocarbonyl anion catalyst
A, adorned with an indole chromophoric unit, and a slight excess of
1 (1.5 equiv.). When using the trimethylsilyl derivative 1a, these
conditions furnished the desired ketone product 3a in good yield
along with traces of the silyl derivative 4 (entry 1). The use of
different silyl protecting groups, including tert-butyldimethylsilyl
(TBS) and triisopropylsilyl (TIPS), provided better chemical yields
while selectively favoring the formation of the O-silylated adduct 4
(entries 2 and 3, respectively). Considering the cost of the silyl enol
ethers and the efficiency of the reaction, we continued our
investigations with the TBS derivative 1b. Adding water to the
reaction mixture allowed us to directly achieve ketone 3a as the major
product (entry 4). However, since this hydrolysis step was not
uniformly effective for all the silyl enol ethers evaluated, we treated
the crude mixture with trifluoroacetic acid or tetrabutylammonium
fluoride (TBAF), which quantitatively and consistently led to
complete conversion of 4 into the target product 3a (entry 5).
Effective hydrolysis can be also achieved in the presence of acids,
since methanesulfonic acid or HCl in H2O (4 equiv., entry 6) afforded
3a in high yields.
Using the optimized conditions described in Table 1, entry 5, we
tested the generality of the photochemical organocatalytic α-
alkylation process (Figure 2). We first evaluated the scope of the
carbon radicals that could be intercepted by the silyl enol ether 1b. A
large variety of electrophilic primary radicals afforded the
corresponding α-alkylated ketones in good yields (3a, 3e, 3h).
Secondary radicals could also be generated and efficiently intercepted
by 1b, albeit, in some cases, there was a need to heating at 60 ºC
(adducts 3b-d, 3f-g). Benzylic radical precursors, bearing both
electron-rich and electron-poor aryl substituents, were also competent
substrates (products 3i-n). The strategy can be used to implement a
radical α-aminomethylation process, allowing the introduction of a
protected primary amine (3o) along with a trifluoromethyl moiety
(3p). The reaction could be performed on a gram scale without losing
efficiency (7.0 mmol scale, 3a obtained in 91% yield, 1.0 g).
We then evaluated the compatibility with unprotected polar
functional groups, which is an important criterion for assessing a
method’s potential applicability to complex molecule synthesis and
drug discovery.[15] Our approach displayed a good level of tolerance
towards heterocycles containing nitrogen, sulfur, and oxygen atoms
(3q-s). In addition, good tolerance was achieved for functional groups
that would be incompatible with classical anionic alkylation strategies
or Lewis acid activation, including unprotected alcohols (3t), amide
N-H bonds (3p), esters (3e and 3r), ketones (3g and 3h), enones (3t),
and aldehydes (3i). Finally, cortisone (3t) and chloramphenicol (3u)
derivatives could be used as radical precursors, highlighting the
potential of this method for complex molecule synthesis. As a
limitation of the system, alkyl bromides leading to non-stabilised
primary and secondary radicals and to tertiary radicals could not be
activated. A list of moderately successful and unsuccessful substrates
for this radical alkylation strategy is reported in Figure S4 of the
Supporting Information.
We then demonstrated that silyl enol ethers derived from aromatic
ketones could intercept the electrophilic radical generated from
chloroacetonitrile 2a. A variety of substitution patterns on the aryl
ring, with different electronic (4a-e) or steric profiles (4e, 4f), could
be easily accommodated. Importantly, easily oxidizable heterocyclic
substrates (4l-m) or nitrogen-containing heterocycles (4n-p) are
readily tolerated. A substrate derived from azaperone, containing an
aminopyridine and a piperazine moiety, could be alkylated in
moderate yield (4q). Cyclic and acyclic silyl enol ethers could also be
used in this radical alkylation process, leading to the corresponding
aliphatic ketones (5a-5g). Interestingly, selective alkylation at the
terminal position of a β-ketoester was achieved (5e), exploiting the
modularity of silyl enolate synthesis compared to classical alkali
metal enolates. Finally, O-O and N-O silyl ketene acetals were also
suitable substrates and afforded the corresponding α-alkylated esters
and amides in high yields (6a-6g). A chiral oxazolidinone could be
used to give moderate diastereoselectivity (6g). This strategy also
provides a tool for forging quaternary carbon centers using different
silyl enolates (4k, 5g, and 6e-f).
Table 1. Optimization studies and control experiments.[a]
entry
deviation
SiR3
1
[%] yield 3/4[b]
1
2
3
4
5
none
none
TMS
TBS
TIPS
TBS
TBS
a
b
c
b
b
71 / 5
7 / 93
none
<5 / >95
90 / 8
H2O (20 equiv.)
Work up: TFA or TBAF
91[c] / 0
Work up: CH3SO3H or
6
TBS
b
>95 / 0
HCl(aq)
7
8
9
no light
TBS
TBS
TBS
b
b
b
0
0
0
no catalyst A
TEMPO (1 equiv.)
fac-Ir(ppy)3 (1 mol%); no
catalyst A
10
TBS
b
5 / 40
[a] Reactions performed on a 0.2 mmol scale at 25 °C for 24 h using 0.4 mL of
CH3CN under illumination by blue LED strip (λmax = 465 nm, 14 W) and using
catalyst A (10 mol%), 1.5 equiv. of 1a, and 1.7 equiv. of lutidine. [b] Yield and
distribution of products 3 and 4 determined by 1H NMR analysis of the crude
mixture using trichloroethylene as the internal standard. [c] Yield of isolated 3a.
[d] After work up with TFA. TMS: trimethylsilyl, TBS: tert-butyldimethylsilyl, TIPS:
triisopropylsilyl, TFA: trifluoroacetic acid, TBAF: tetrabutyl ammonium fluoride.
A benefit of this protocol is that it can rely on radical precursors
2 bearing different leaving groups, including halides (Cl or Br) and
sulfonates (OMs or ONs). The choice of the leaving group can
therefore be dictated by its ease of access or compatibility with other
functional groups in a complex synthetic plan.
Control experiments confirmed that the alkylation reaction could
not proceed in the absence of light or catalyst A (entries 7 and 8). The
presence of a radical scavenger (TEMPO, 1 equiv.) completely
suppressed the reaction (entry 9), whereas traces of the cyanomethyl-
TEMPO adduct could be detected. Importantly, our attempts to
2
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10.1002/anie.201915814
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Figure 2. Reaction scope: reactions performed on 0.5 mmol scale using 1.5 equiv. of 1 and 1.0 mL of acetonitrile; yields of products refer to isolated material after
purification; the bold orange bond denotes the newly formed C-C bond. * Performed at 60 ºC. † Using dichloroethane as the solvent. ‡ Reaction time: 48 hours, # 3.0
equiv. of silyl enolate. TFA: trifluoroacetic acid, TBAF: tetrabutylammonium fluoride, Piv: tert-butylacyl, Ms: mesyl, Ns: nosyl.
To showcase the system’s synthetic utility, we used this strategy
for the stereoselective catalytic α-functionalization of ketones (Figure
3). While effective catalytic enantioselective methods are available,
they are limited to ionic chemistry.[16] The direct asymmetric α-
alkylation of ketones with radicals remains a difficult target.[17] This
is in contrast to the radical functionalization of aldehydes, where the
combination of enamine-mediated catalysis and photoredox catalysis
recently provided useful tools for designing asymmetric processes.[18]
The lack of application in the enamine-mediated functionalization of
ketones is ascribable to the peculiar structure of the cinchona-based
primary amine B.[19] This chiral amine is often the catalyst of choice
in ionic chemistry because it can trap different electrophiles with
consistently high stereocontrol upon activation of ketones via
enamine formation. However, catalyst B bears an easily oxidazable
tertiary amine moiety, which makes it incompatible with a
photoredox catalyst usually needed to generate the reactive open-shell
intermediate. In principle, the redox-neutral nature of our radical
generation strategy means that catalysts A and B could coexist. As
depicted in Figure 4, this possibility was translated into experimental
reality to develop an enantioselective direct radical α-alkylation of
cyclic ketones 7. The dithiocarbamate anion catalyst A effectively
activated chloride 2a toward radical formation, while the
hydroquinidine-derived amine B secured the formation of a chiral
enamine upon condensation with 7, which could easily trap the
radical. This photochemical strategy afforded the corresponding α-
cyanoalkylation products 8a-h.[20] While cyclohexanone derivatives
provided high stereocontrol (8a-g), a five-membered ring proved less
reactive and stereoselective (8h). Interestingly, acid-sensitive
functionalities, including an acetal or a Boc group, were tolerated well
(8e and 8f). This asymmetric alkylation could be extended to other
alkyl chloride radical precursors, since 2,4-dinitrobenzyl chloride and
phenacyl chloride afforded the corresponding alkylated products (8i
and 8j) with good results.
3
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10.1002/anie.201915814
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Figure 4. Proposed catalytic mechanism for the visible-light-driven radical
alkylation of silyl enol ethers; Z: chromophore.
Conclusion
Figure 3. Aminocatalytic enantioselective photochemical α-alkylation of cyclic
ketones with alkyl chloride-derived radicals. Reactions performed on a 0.2 mmol
scale; yields refer to isolated material. The reactivity was completely inhibited in
the absence of light. *Reaction performed at 25 ºC.
In summary, we have developed a visible-light-mediated
organocatalytic strategy for the radical α-alkylation of ketones using
silyl enol ethers, which synthetically complements traditional two-
electron strategies. The method’s mild reaction conditions and
functional group tolerance allowed us to install, at the ketones’ α
position, moieties not compatible with classical anionic processes. In
addition, the redox neutral conditions of this process make it tolerant
of a cinchona-based amine catalyst, which was used to develop an
enantioselective variant.
The proposed catalytic cycle of the photochemical radical
alkylation of silyl enol ethers is outlined in Figure 4. The nucleophilic
catalyst A attacks[14] the alkyl halide 2 to form the photon-absorbing
intermediate I.[21] Blue light irradiation triggers the cleavage of the
weak C-S bond to generate a pair of radicals II and III.[22] The silyl
enol ether 1 is reactive enough to intercept the carbon-centered radical
II, leading to the α-oxo stabilized radical IV. SET between IV and
the sulfur-centered radical III regenerates catalyst A and forms the
oxocarbenium ion V, which can easily hydrolyze to afford the final
α-alkylation ketone 3.[23] To glean insights into the mechanism, we
measured the quantum yield (Φ) of the model reaction, which was
found to be as low as 0.05 (λ = 460 nm, using potassium ferrioxalate
as the actinometer, experiments performed both with a stoichiometric
amount of intermediate I and under catalytic conditions, see Section
E.5 in the Supporting Information for details). This result suggests
that a radical chain process, based on either a dithiocarbamate group
transfer manifold or a SET from radical IV to intermediate I, is highly
unlikely (see Section E.6 for these alternative mechanistic pathways).
Mechanistically, we also evaluated the possibility for the dimeric
adduct VI, arising from the self-reaction of the sulfur-centered radical
III, to be generated during the process (Figure 4). We indeed detected
intermediate VI under catalytic conditions. In addition, an authentic
sample of VI (5 mol%) catalyzed the model reaction when irradiated
with blue LEDs, affording product 3a in quantitative yield (no
reaction was observed in the dark). These observations suggest that
dimer VI is a photoactive species in equilibrium with the progenitor
radical III. This dimerization manifold confers a longer lifetime to
III,[24] facilitating the turnover of catalyst A (SET reduction from IV).
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: α-alkylation • enamines • photochemistry • radical
chemistry • silyl enolates
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Angewandte Chemie International Edition
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[22] With the aim to evaluate its direct implication within the mechanistic
path, we synthesized the adduct of type I by reacting equimolar
amounts of the dithiocarbonyl anion A and chloroacetonitrile 2a. 10
mol% of this type I intermediate could effectively promote the model
reaction (3a formed in 95% yield). In addition, light irradiation of
adduct I in the presence of TEMPO led to the formation of the
cyanomethyl-TEMPO adduct in 60% yield (see Section E4 in the
Supporting Information for details).
[10] The following protocols are effective for a wide scope of alkyl
electrophiles, since unstabilized primary radicals as well as secondary
and tertiary alkyl radicals can be successfully used. However, they are
limited to acetophenone-derived silyl enol ethers: a) W. Kong, C. Yu,
H. An, Q. Song, Org. Lett. 2018, 20, 349−352; b) M.-C. Fu, R. Shang,
B. Zhao, B. Wang, Y. Fu, Science 2019, 363, 1429–1434.
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[23] Cross-coupling of the α-oxo radical IV and the sulfur-centered radical
III cannot be excluded. This process would provide the exact same
product of the SET manifold proposed in Figure 4, since the ensuing
adduct would collapse to afford oxocarbenium ion V and catalyst A.
This alternative mechanistic pathway is detailed in Figure S21 of the
Supporting information.
[24] This dimerization behavior could infer a persistent radical character to
intermediate III, see: a) D. Leifert, A. Studer Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201903726; b) K. S. Focsaneanu, J. C. Scaiano,
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[14] For a study discussing the high nucleophilicity of dithiocarbonate and
dithiocarbamate anions of type A, see: X.-H. Duan, B. Maji, H. Mayr,
Org. Biomol. Chem. 2011, 9, 8046–8050.
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10.1002/anie.201915814
Angewandte Chemie International Edition
Radical Chemistry
Davide Spinnato, Bertrand Schweitzer-Chaput,
Giulio Goti, Maksim Ošeka, and Paolo Melchiorre*
__________ Page – Page
A Photochemical Organocatalytic Strategy for
the α-Alkylation of Ketones using Radicals
Radical time to alkylate ketones. We report a visible-light-mediated
radical approach that enables the α-alkylation of ketones using alkyl
electrophiles recalcitrant to traditional ionic pathways. The redox-neutral
nature of this process makes it compatible with a chiral amine catalyst,
which was used to develop a rare example of enantioselective
organocatalytic α-alkylation of cyclic ketones via a radical path.
6
This article is protected by copyright. All rights reserved.