Redox-Neutral Dual Functionalization of Electron-Deficient Alkenes

Article abstract of DOI:10.1002/chem.201701589

Visible-light photoredox catalysis has been utilized in a new multicomponent reaction forming β-functionalized δ-diketones under mild conditions in an operationally convenient manner. Single-electron reduction of in situ generated carboxylic acid derivatives forms acyl radicals that react further via 1,2-acylalkylation of olefins in an intermolecular, three-components cascade reaction, giving valuable synthetic entities from readily available starting materials. A diverse set of substrates has been used, demonstrating robust methodology with broad substrate scope.

Full text of DOI:10.1002/chem.201701589

A Journal of
Accepted Article
Title: Redox Neutral Dual Functionalization of Electron Deficient
Alkenes
Authors: Fredrik Pettersson, Giulia Bergonzini, Carlo Cassani, and
Carl-Johan Wallentin
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Photoredox Catalysis
Redox Neutral Dual Functionalization of Electron Deficient
Alkenes
Fredrik Pettersson, Giulia Bergonzini, Carlo Cassani, and Carl-Johan Wallentin*
Abstract: Visible-light photoredox catalysis has been utilized in a
novel multicomponent reaction forming -functionalized -diketones
under mild conditions in an operationally convenient manner. Single-
electron reduction of in situ generated carboxylic acid derivatives
forms acyl radicals that react further via 1,2-acylalkylation of olefins
in an intermolecular, three components cascade reaction, yielding
valuable synthetic entities from readily available starting materials. A
diverse set of substrates have been used, demonstrating robust
methodology with broad substrate scope.
we envisioned that MCRs could be engaged in a radical context
under redox neutral conditions.
Electron rich acyl radicals have a pronounced reactivity
preference towards electron-deficient alkenes, a property that
can be exploited in a multicomponent setting by achieving
selectivity towards electron-poor coupling partners in the
presence of electron-rich olefins. Strategically, such
a
combination of coupling partners would provide access to the
synthetically challenging 1,2-dicarbofunctionalization of alkenes
(Figure 1c).
In recent years synthetic chemistry has evolved at such a pace
that molecular complexity can be rapidly achieved with high
selectivity. One of the most efficient methods to construct
molecular complexity is by utilizing multicomponent reactions
(MCRs) and cascade type transformations.[1] MCRs are
convergent reactions in which three or more starting materials
are reacted together to form a single product with high atom
efficiency.[1a] As opposed to the classical sequential synthetic
approach to construct complex molecules, MCRs enable the
assembly of complex molecules in a single operation. The
product is formed via a cascade of elementary chemical
reactions through a series of reaction equilibria, ideally ending in
an irreversible step to afford the desired product. MCRs have
become a very popular tool in many areas of applied chemistry
due to its labor efficient way to access a vast array of structural
space. [1e, f]
Recently, visible-light mediated photoredox catalysis has
emerged as
a competitive method for functional group
interconversions generating reactive radical intermediates under
mild and environmentally benign conditions.[2] Contributions to
this field from our group include the formation of acyl radicals via
single-electron reduction of aromatic carboxylic acid derivatives
(Figure 1b).[3] This approach combines the benefits of using
readily available and inexpensive starting materials with a
synthetic method that extends beyond the existing routes to
access acyl radicals.[4] Mixed anhydride intermediates, formed in
situ from simple carboxylic acids by reaction with dimethyl
dicarbonate (DMDC) have proven to be efficient oxidative
quenchers of the excited state of the photocatalyst fac-Ir(ppy)3 to
generate the desired acyl radical species, along with CO2 and
methanoate as the only byproducts.[3b]
Figure 1. a) Tin enolate mediated carbonylative coupling reaction. b)
Acylarylation of N-aryl acrylamides by means of visible-light photoredox
catalysis. c) Photoredox-catalyzed intermolecular three component synthesis
of -functionalized -diketones.
The majority of published photoredox mediated MCRs rely on
radical polar crossover transformations in which free radical-
based bond formations are combined with nucleophilic trapping
of an intermediate carbocation, typically by a solvent or co-
solvent.[5] Photoredox mediated MCRs where two or more C‒C
bonds are formed in a pure radical fashion remain relatively
unexplored.[6] Moreover, MCRs based on classical free radical
chemistry are typically characterized by the need of external
oxidants, UV irradiation, high CO pressure, high temperature or
tin-, borane or lead-based reagents as well as stannylated and
silylated phosphanes as precursors.[7] Herein, we report the first
redox-neutral approach for the mild visible-light mediated
Capitalizing on this mild way to access acyl radical intermediates,
[*] Dr. F. Pettersson[+], Dr. C. Cassani, Dr. C.-J. Wallentin
Department of Chemistry and Molecular Biology,
Gothenburg University
41296 Gothenburg (Sweden)
E-mail: carl.wallentin@chem.gu.se
Dr. G. Bergonzini[+]
Cardiovascular and Metabolic Diseases,
Innovative Medicines and Early Development Biotech Unit,
AstraZeneca, Pepparedsleden 1, 43183 Mölndal (Sweden)
[+] These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document
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multicomponent 1,2-acylalkylation of alkenes giving convenient
formation of the desired product (Entries 14-16 in Table S1,
Supporting Information), observations that validated our
mechanistic rational. With optimized reaction conditions in hands,
the scope of the reaction in terms of structural diversity of all
components was examined. As shown in Table 1, the reaction
proceeds in modest to excellent yields (4a-n, Table 1) for a wide
range of mono- or disubstituted benzoic acids (1a-l, Table S2,
Supporting Information) as well heteroaromatic substrates such
as 5-methylthiophene-2-carboxylic acid and 2-furoic acid (1m-n,
Table S2, Supporting Information). In general, unfunctionalized
and electron-rich carboxylic acids provided higher yields as
compared to their electron-deficient counterparts (e.g. 4a and
4c). However, the inclusion of strongly electron-withdrawing
groups, such as trifluoromethyl or nitro moieties, at the para-
position of the carboxylic acid resulted in very low yields (≤10%).
For these substrates the background reaction (i.e. the
conversion of the acid into the corresponding unreactive methyl
esters) was evidently faster than the redox chemistry (Table S2
and NMR spectra, Supporting Information).[8] Notably, carboxylic
acids bearing free hydroxy or amino groups (1e and 1l, Table S2,
Supporting Information) smoothly furnished the corresponding
carbonate and carbamate derivatives without affecting the yields
in a deleterious way (4e and 4l, Table 1).
access to -functionalized -diketones (Figure 1c).
Preliminary studies of the three component reaction were
investigated using benzoic acid 1a, methyl acrylate 2a and tert-
butyldimethyl((1-phenylvinyl)oxy)silane 3a as the acyl radical
precursor, electron-deficient and electron-rich coupling partners,
respectively. In addition to the specified substrates, fac-Ir(ppy)3,
DMDC, and 2,6-lutidine were added to the protocol and the
reaction was conducted under visible-light irradiation (Table S1,
Supporting Information). The choice of the photocatalyst was
based on previous studies which demonstrated that fac-Ir(ppy)3
is capable of reducing mixed anhydride I to the corresponding
acyl radical species III as depicted in Figure 2.[3b] To our delight,
initial experiments validated our approach and provided the
corresponding product 4a in
a modest yield (Table S1,
Supporting Information). Subsequent optimizations revealed that
employing 3 as the limiting reagent in combination with a
catalyst loading of 2-5 mol % provided robust and optimal
conditions for the transformation.
Table 1. Scope of the carboxylic acids 1 and electron-rich olefins 3[a]
Table 2. Scope of the electron-poor olefins 2[a]
[a] Reaction performed using 2-5 mol% of fac-Ir(ppy)3, 0.5 equiv of 2,6-lutidine, 3
equiv of DMDC, 2 equiv of 1, 2 equiv of 2 and 1 equiv of 3 on a 0.2 mmol scale
(detailed description in Supporting Information). Isolated yields.
The scope of the reaction was further explored with regards to
the olefin substrates 2 and 3 (Table 1 and 2). p-Anisic acid (1c)
and methyl acrylate (2a) together with various electron-rich
olefins (3c-f, Table S3, Supporting Information), yielded the
desired products in generally good yields (4o-t, Table 1). The
reaction appears to tolerate both mono- and disubstituted aryls
as well as heteroaromatic derivates of the silylenolether 3, while
possible limitations include strongly electron deficient aryl
groups (trifluromethyl (4ad), Table S3, Supporting Information)
or non-aromatic silylenolethers (t-butyl (4ae), Table S3,
Supporting Information). In a similar manner, different electron-
poor olefins with a number of electron-withdrawing groups (2b-h,
Table S4 Supporting Information) were evaluated as coupling
[a] Reaction performed using 2-5 mol% of fac-Ir(ppy)3, 0.5 equiv of 2,6-lutidine, 3
equiv of DMDC, 2 equiv of 1, 2 equiv of 2a and 1 equiv of 3 on a 0.2 mmol scale
(detailed description in the Supporting Information). Isolated yields.
Control experiments performed in the absence of the
photocatalyst, DMDC or light irradiation did not result in the
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10.1002/chem.201701589
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partners together with benzoic acid (1a) or p-anisic acid (1c) and
silylenolethers 3a or 3b. Common acrylic derivatives were
compatible with the optimized conditions providing the
corresponding products in fair yields (4u-aa, Table 2). Taken
together, the protocol provides a novel entry to 1,2-acylalkylated
alkenes in the form of -functionalized -diketones. The protocol
demonstrates a relatively broad scope with respect to the
different substrates, with yields ranging from 58% to 99% for
each individual C–C bond forming reaction.
In order to demonstrate the robustness and thus synthetic
value of this photoredox-mediated multicomponent reaction, its
scalability was evaluated. Satisfyingly, the reaction was
successfully scaled-up to 1 mmol scale using p-anisic acid (1c),
methyl acrylate (2a) and tert-butyldimethyl((1-(5,6,7,8-
tetrahydronaphthalen-2-yl)vinyl)oxy)silane (3b), providing 4c in
very good yield (87ꢀ%). Furthermore, to illustrate the diverseness
of -diketones in synthetic elaborations, 4c was converted to a
trisubstituted pyridine and
a
trisubstituted cyclopentene
derivative in 46% and 48% yield, respectively, following
published literature procedures (Scheme 1).[9] It is worth noting
that these compounds were accordingly synthesized in two
steps from commercially available and structurally simple
starting materials.
Figure 2. Proposed mechanism.
A plausible catalytic cycle for the presented transformation
is proposed in Figure 2. Photoexcitation of fac-IrIII(ppy)3
(depicted as IrIII) under visible light, generates the strong
reductant fac-*IrIII(ppy)3.
Next, IV reacts selectively with the silylenolether 3 forming
intermediate V, which in turn is oxidized by fac-IrIV(ppy)3 to
provide intermediate VI while regenerating the ground-state of
the catalyst. Finally the elimination of TBS+ from VI forms the
desired product in an irreversible step.
In conclusion, a novel photoredox catalyzed multicomponent
reaction for the formation of variously -functionalized -
diketones under mild visible-light conditions is presented. The
use of simple carboxylic acids as acyl radical precursors
promoted by visible light, allowed the development of this
intermolecular cascade reaction, which combines three
compounds in a radical process. The overall reaction proceeds
in a redox neutral fashion avoiding the need for stoichiometric
amounts of external electron donors or oxidants. Furthermore,
the possibility of accessing a large variety of structures by the
straightforward derivatization of compound 4c showcases the
synthetic utility of the presented method. Exploration of the
reactivity of acyl radicals under photoredox catalyzed conditions
and exploitation of this chemistry in unprecedented
multicomponent reactions are currently under investigation in
our laboratory.
Acknowledgements
Scheme 1. Examples of accessible transformations of 1,5-diones: a) Mojr et
al.[10] b) Foster et al.[11] c) Wang et al.[12] d) Padmavathi et al.[13]
Transformations of 4c into cyclized compounds 5a and 5b following published
literature procedures.[9]
The authors thank the Olle Engkvist Byggmästare foundation,
the Wilhelm and Martina Lundgren research foundation, the Ollie
and Elof foundation, the Magnus Bergvall foundation, the
Adlerbertska foundation and the Swedish Research Council.
C.C. is grateful to the European Commission for a Marie
Skłodowska-Curie fellowship (H2020-MSCA-IF-2014 n: 660668).
We would also like to thank Dr. Cassandra L. Fleming for proof
reading the manuscript.
Single-electron reduction of mixed anhydride I (generated in situ
from carboxylic acid 1 in the presence of DMDC under basic
conditions) by fac-*IrIII(ppy)3 provides fac-IrIV(ppy)3 and radical
anion II that, after fragmentation, delivers acyl radical III along
with CO2 and methanoate. Subsequently, acyl radical III
undergoes selective radical addition to the electron-poor olefin 2
affording radical intermediate IV.
Keywords: photoredox catalysis • multicomponent reactions •
acyl radicals • carboxylic acids • cascade transformation
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Fredrik Pettersson, Giulia Bergonzini,
Carlo Cassani, and Carl-Johan
Wallentin*
Page No. – Page No.
Redox neutral dual functionalization
of electron deficient alkenes
A mild method for C‒C bond formation in multicomponent cascade type reactions:
Acyl radicals have been accessed from simple aromatic carboxylic acids under
visible-light photoredox catalysis. The method offers an atom efficient entry to
valuable synthetic entities from readily available starting materials without the need
of high-energy UV irradiation, stoichiometric oxidants, high CO pressure, or high
temperature.
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