Additions of Aldehyde-Derived Radicals and Nucleophilic N-Alkylindoles to Styrenes by Photoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.0c01182

The consecutive addition of acyl radicals and N-alkylindole nucleophiles to styrenes was established, as well as some additional radical-nucleophile combinations. Both aryl and aliphatic aldehydes give reasonable yields. The reaction proceeds best for α-substituted styrenes, effectively creating a quaternary all-carbon center. Some iridium-based photoredox systems are catalytically active; furthermore, a base is needed in this transformation. Radicals are formed by reductive perester cleavage and hydrogen atom transfer.

Full text of DOI:10.1021/acs.orglett.0c01182

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Letter
Additions of Aldehyde-Derived Radicals and Nucleophilic
N‑Alkylindoles to Styrenes by Photoredox Catalysis
Marcel Lux and Martin Klussmann*
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ABSTRACT: The consecutive addition of acyl radicals and N-
alkylindole nucleophiles to styrenes was established, as well as some
additional radical−nucleophile combinations. Both aryl and aliphatic
aldehydes give reasonable yields. The reaction proceeds best for α-
substituted styrenes, effectively creating a quaternary all-carbon
center. Some iridium-based photoredox systems are catalytically
active; furthermore, a base is needed in this transformation. Radicals
are formed by reductive perester cleavage and hydrogen atom transfer.
he consecutive addition of a radical and a nucleophile to
Such β-indolyl ketones can be synthesized by conjugate
Tthe CC bond of an olefin is an interesting method of addition of indoles to α,β-enones by Lewis acid catalysis, but
these methods rarely provide access to quaternary centers.4
olefin difunctionalization, as it allows the introduction of two
complementary reagents in a single step.1 To accomplish this
There are a few examples of adding indoles as nucleophiles
in radical difunctionalization reactions. A trifluoromethyl-
arylation of styrenes with a ruthenium-based photoredox
system and Umemoto’s reagent as the radical source can utilize
indoles.5 Benzylic radicals generated from pyridinium salts6
and ether radicals generated by HAT3f have been added
together with indole nucleophiles. Using Ag2CO3 as an
oxidant, α-bromoesters could be used as radical precursors
together with N-methylindoles.7 Variations of this method can
also be performed by applying iridium-based photoredox
catalysis.8 N-Methylindoles can also be used as nucleophiles
together with aryl radicals made from diazonium salts by
photoredox catalysis9 and with cyanomethyl radicals made
with Ag2CO3 as the oxidant at increased temperatures.10
Acyl radicals are generated in various fashions, including
HAT from aldehydes.11,12 Decarbonylation can take place,
especially at elevated temperatures and in the case of branched
alkyl aldehydes, generating alkyl radicals. Seminal examples of
applying acyl radicals in intermolecular difunctionalization
reactions of olefins are an autoxidative addition to acrylate
derivatives and an iron-catalyzed reaction forming peroxyke-
tones.13 In photocatalytic intermolecular difunctionalization
reactions, acyl radicals generated by HAT have so far been
used only for the generation of α-epoxy-ketones.14 Two
examples involving acyl radicals in difunctionalization reactions
type of reaction, an oxidation by electron transfer (ET) has to
convert the initially formed radical intermediate (1) to the
corresponding carbocation [2 (Scheme 1)].
Scheme 1. Reaction Path for Introduction of a Nucleophile
into a Radical Styrene Difunctionalization Involving
Hydrogen Atom Transfer (HAT)
A widely used technique for generating different kinds of
radicals is hydrogen atom transfer (HAT) from the substrate
(3) to an oxyl radical, which can be formed from peroxides.2
However, intermolecular difunctionalization reactions applying
HAT-derived radicals together with a nucleophile represent a
rather poorly developed branch among radical reactions.3 This
attracted our attention, as we wanted to contribute to the
portfolio of this method. We aimed for a catalytic system that
merges a reductive peroxide cleavage with the oxidation of the
intermediary olefin-radical adduct 1 to the corresponding
carbocation 2. Herein, we present a photoredox method of
olefin difunctionalization by addition of radicals formed by
HAT together with nucleophiles to styrenes, generating
products of type 4, especially β-indolyl ketones (Scheme 1).
Received: April 2, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01182
© XXXX American Chemical Society
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a
with radicals and nucleophiles have been reported: an
alkylation−azidation of styrenes at 110 °C15 and an
acylation−imidation using specially designed precursor sub-
strates that deliver both the radicals and the nucleophiles upon
photocatalytic activation.16
Scheme 3. Application of Various Aldehydes
We believed a peroxyester would be most suitable as the oxyl
radical precursor, which could be reductively cleaved by ET
from a photocatalyst, which would in turn oxidize the radical
intermediate. For example, Knowles et al. exploited tert-butyl
perbenzoate (TBPB) in a dehydrogenative synthesis of
elbasvir, using an iridium photocatalyst.17 On the basis of
the redox potentials of the widely used photocatalyst tris(2-
phenylpyridinato-C2,N)iridium(III) [Ir(ppy)3] and TBPB
[photoexcited Ir(ppy)3*; E1/2 = −1.73 V,18 and E1/2 = −1.40
V19; all potentials given vs SCE], we made a working model for
the reaction mechanism (Scheme 2). After irradiation, an ET
Scheme 2. Rationalization of Product Formation
a
Conditions: olefin (0.5 mmol, 1 equiv), TBPB (2 equiv), Ir(ppy)3
(0.4 mol %), aldehyde (5 equiv), N-methylindole (3 equiv), NaHCO3
(2 equiv), MeCN (5 mL), white LED light, 65 °C, 12 h.
occurs from the photoexcited Ir(III) species to TBPB, forming
Ir(IV), benzoate, and a tert-butoxyl radical. The latter is a good
acceptor in HAT reactions,2 thus forming radicals from
suitable substrates. These radicals add to styrene derivatives,
forming intermediate 1′ (compare to PhC·HCH3, for which
E1/2 = 0.37 V20), which can reduce Ir(IV) (E1/2 = 0.77 V18)
back to Ir(III) by ET. The carbocation intermediate 2′ thus
formed can react with nucleophiles to yield the final products.
We found that with the combination of Ir(ppy)3 and TBPB
in acetonitrile, acyl radicals and N-methylindole add to α-
methylstyrene if irradiated with white light-emitting diodes
(LEDs) (Scheme 3a). Addition of a base is necessary, and we
found NaHCO3 to give best results. The reaction mixture is
heated to 65 °C by the LEDs. For a detailed evaluation of
reaction conditions, see the Supporting Information.
In general, substituted benzaldehydes performed well in this
method and the corresponding products (4a−4j) were isolated
in yields between 31% and 78%. There is no clear substituent
effect on the product yields; the highest were obtained with p-
methylsulfide and p-methoxy substituents (4i, 71%; 4h, 78%),
but an electron-withdrawing substituent like CF3 also gave a
reasonably high yield of 60% (4g). Benzaldehydes bearing an
ortho substituent did not provide the desired products.
Heteroaromatic 2-thiophenecarboxaldehyde is also quite
suitable (4k, 75%), as are primary and secondary aliphatic
aldehydes (4l−4n). In contrast, tertiary pivaldehyde led to the
decarbonylated product 5. This can be understood by the well-
known decarbonylation of acyl radicals, giving a stabilized tert-
butyl radical, which then added to the olefin (Scheme 3b).
Compared to benzaldehydes, aliphatic aldehydes led to lower
product yields (34−55%), presumably due to more reactive
radicals.
the reaction with N-methylindoles and benzaldehyde (Scheme
4). Electron-donating or neutral substituents on the styrenes
give good yields (6a−6c), but electron-withdrawing sub-
stituents lead to significantly reduced yields (6d−6f). This is in
line with the assumed carbocation intermediate 2, which would
be stabilized least in the case of a p-CN substituent and which
in turn gives the lowest product yield (6f, 12%). Accordingly,
1,1-diphenyl ethylene would lead to a highly stabilized
carbocation and the corresponding product is indeed formed
in good yield (7a, 63%). X-ray crystal analysis of 7a confirmed
the products’ general structure (see the Supporting Informa-
tion). With α-cyclopropyl styrene, the corresponding product
7b was isolated in only 26% yield, indicating that carbocation
formation competes with ring opening of the radical
intermediate.
Plain styrene and β-substituted styrenes did not give the
desired product with benzaldehyde, which can be explained by
the lower degree of stabilization of a secondary carbocation
that would be formed in this case. Nevertheless, we could form
indolyl ketone 8 from p-methoxybenzaldehyde and p-
methoxystyrene, which would react via a secondary cation
that is stabilized by the electron-donating substituent. Using
pivaldehyde and styrene, the product (9) could be formed, by
decarbonylation of the initially formed acyl radical, as shown in
Scheme 3b. In contrast, pivaldehyde did not form the
analogous product with 1,1-diphenyl ethylene as olefin,
possibly due to steric hindrance (see the Supporting
Information for a summary of unsuccessful substrate
combinations).
Besides checking the aldehydes’ influence on product
formation, we examined para-substituted α-methylstyrenes in
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a
Scheme 4. Application of Various Styrenes and Indoles
Scheme 5. Alkyl Nitrile Solvent as a Nucleophile
a
Conditions: olefin (0.5 mmol, 1 equiv), TBPB (2 equiv), Ir(ppy)3
(0.4 mol %), aldehyde (5 equiv), N-methylindole (3 equiv), NaHCO3
(2 equiv), MeCN (5 mL), white LED light, 65 °C, 12 h.
In addition, different nucleophiles were evaluated in the
reaction of α-methylstyrenes with benzaldehyde. Other
electron-rich arenes like methoxy-substituted benzenes and
thiophene were not applicable, and neither were alcohols even
when used as the solvent. Surprisingly, even slight variations of
the indole such as plain indole or N-carbamate-protected
indole were unsuccessful (see the Supporting Information for
an overview). However, the reaction works well with some N-
alkyl indoles like 5-methyl- and 5-bromo-N-methylindole (10a
and 10b, respectively) and N-benzyl indole (10c), as well as
with benzotriazole (10d).
a
Conditions: olefin (0.5 mmol, 1 equiv), TBPB (2 equiv), Ir(ppy)3 (2
mol %), aldehyde (5 equiv), alkyl nitrile (5 mL), white LED light, 65
°C, 20 h. On a 0.1 mmol scale.
b
Reactions without addition of indole showed that the
solvent acetonitrile could act as a nucleophile (Scheme 5).
Interestingly, an N-acyl benzamide was formed, in contrast to
an N-acetamide as in a conventional Ritter reaction. This can
be explained by attack of acetonitrile on the intermediate
carbocation 2′, giving a nitrilium ion, which is attacked by
benzoate, giving an imidate that forms the final imide product
11 in a Mumm rearrangement (Scheme 5a).21 Similar imide
formations had been observed in intra- and intermolecular
reactions.16,22
Electron-rich aldehydes worked well in this reaction,
providing the keto-imides 11a and 11c as well as the imide
11b via decarbonylation from pivaldehyde (Scheme 5b). Also
omitting the aldehyde showed that solvent-derived radicals
could also become involved, leading to nitrile products from
propionitrile and isobutyronitrile (11d and 11e, respectively)
(Scheme 5c). In the case of acetonitrile as the solvent, we
could isolate the corresponding nitrile 11f and products 11g
and 11h (Scheme 5d). The latter two indicate that radicals
formed from the peroxide had become incorporated. Product
11g indicates addition of a tert-butoxyl radical, and 11h
addition of a methyl radical, which is known to form from tert-
butoxyl radicals by β-scission.23 In general, the imides were
obtained in medium yields and only from styrene. With α-
methylstyrene, no imide products were formed, possibly due to
the low nucleophilicity of acetonitrile.
These results, especially the products shown in Scheme 5,
provide important information about the reaction’s mecha-
nism. They support the working model shown in Scheme 2,
especially the formation of a benzoate anion and a tert-butoxyl
radical, as well as an intermediate benzylic carbocation.
Further support for this mechanistic working model was
gained from the following observations. (a) No product was
formed in the presence of 1 equiv of the radical inhibitor BHT.
(b) Product formation essentially stopped when the light was
switched off, and no product was formed when Ir(ppy)3 was
substituted with the radical initiators benzoyl peroxide and
AIBN, supporting photocatalysis and rather discounting “smart
initiation”.24 (c) We observed a larger decrease in
luminescence with an increase in TBPB concentration,
supporting ET from IrIII* to the peroxide; analysis of the
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Stern−Volmer relationship25 indicated that more than one
quenching mode is operating (for experimental details and
extended mechanistic discussions, see the Supporting
Information).
ACKNOWLEDGMENTS
■
Support from the DFG (KL 2221/7-1 and Heisenberg
scholarship to M.K., KL 2221/4-2) and from the MPI fu
Kohlenforschung is gratefully acknowledged. The authors
̈
r
To date, it has been very common for methods of radical
difunctionalizations of olefins to have strong limitations. With
indoles as nucleophiles, the electronic properties of the
styrenes show an extraordinarily strong impact. Apart from
our work shown here (see 6f above), there is only one
procedure that could successfully apply a p-cyano-substituted
styrene.3d Most methods are limited to electron-rich styrenes,
which is not the case for difunctionalizations with other
nucleophiles. There is no simple rationalization of the substrate
limitations of such methods yet, hindered by a lack of
information. In the work presented here, we could not isolate
any characterizable products from reactions with incompatible
substrates. Clearly, there is room for future studies in this field.
In summary, we could show that styrene difunctionalization
reactions can be realized with a broad scope of aldehyde-
derived acyl radicals, in combination with the addition of
nucleophiles. This combination had previously not been
reported. We were able to show that various functional groups
on the styrene can be employed, forming quaternary all-carbon
centers upon addition of indoles and benzotriazole to the
benzylic position. The stabilization of the carbocation
intermediate is a key issue, reflected by the preference for α-
substituted styrenes in the case of heteroarene nucleophiles.
The case is opposite for alkyl nitriles, which provide imides
from α-unsubstituted styrenes only.
̈
̈
thank Jorg Rust and Conny Wirtz (both MPI fur
Kohlenforschung) for X-ray crystal analysis and NMR
measurements, respectively.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01182.
Experimental details, NMR spectra, crystallographic
data, and further mechanistic discussion (PDF)
Accession Codes
(10) Ouyang, X.-H.; Hu, M.; Song, R.-J.; Li, J.-H. Chem. Commun.
CCDC 1978887 contains the supplementary crystallographic
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data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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́
AUTHOR INFORMATION
■
Corresponding Author
Martin Klussmann − Max-Planck-Institut fu
̈
r Kohlenforschung,
45470 Mulheim an der Ruhr, Germany; orcid.org/0000-
̈
0002-9026-205X; Phone: +49 2083062453; Email: klusi@
mpi-muelheim.mpg.de
(16) Cheng, Y.-Y.; Lei, T.; Su, L.; Fan, X.; Chen, B.; Tung, C.-H.;
Wu, L.-Z. Org. Lett. 2019, 21, 8789.
Author
Marcel Lux − Max-Planck-Institut fu
Mulheim an der Ruhr, Germany
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r Kohlenforschung, 45470
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01182
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The authors declare no competing financial interest.
D
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