Nucleophilic Alkoxylations of Unactivated Alkyl Olefins and α-Methyl Styrene by Photoredox Catalysis

Article abstract of DOI:10.1002/ejoc.202001533

N,N-diisobutylaminophenyl-phenothiazine is a strongly reducing catalyst that allows – for the first time – the photoredox catalytic addition of alcohols to alkyl olefins as non-activated substrates to products with Markovnikov orientation. The irradiation at 365 nm does not require any additional reagent. Using α-methyl styrene as activated substrate we additionally show that this photoredox catalytic method tolerates other functional groups, including allyl, alkynyl, cyanide, and even acid-labile Boc groups within the substrate scope.

Full text of DOI:10.1002/ejoc.202001533

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Nucleophilic alkoxylations of unactivated alkyl olefins and alpha-
methyl styrene by photoredox catalysis
Authors: Fabienne Seyfert, Mathis Mitha, and Hans-Achim
Wagenknecht
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001533
Link to VoR: https://doi.org/10.1002/ejoc.202001533
01/2020

10.1002/ejoc.202001533
European Journal of Organic Chemistry
COMMUNICATION
Nucleophilic alkoxylations of unactivated alkyl olefins and -
methyl styrene by photoredox catalysis
Fabienne Seyfert,[a] Mathis Mitha[a] and Hans-Achim Wagenknecht*[a]
[a]
M.Sc. Fabienne Seyfert, Prof. Hans-Achim Wagenknecht
Institute of Organic Chemistry
Karlsruhe Institute of Technology (KIT)
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
www.ioc.kit.edu/wagenknecht/
E-mail: Wagenknecht@kit.edu
Supporting information for this article is given via a link at the end of the document
Abstract: N,N-diisobutylaminophenyl-phenothiazine is a strongly
reducing catalyst that allows -for the first time- the photoredox
catalytic addition of alcohols to alkyl olefins as non-activated
substrates to products with Markovnikov orientation. The irradiation at
365 nm does not require any additional reagent. Using -methyl
styrene as activated substrate we additionally show that this
photoredox catalytic method tolerates other functional groups,
including allyl, alkynyl, cyanide and even acid-labile Boc groups within
the substrate scope.
acid-catalyzed addition, e.g. by heated ion exchange resin.[18]
Accordingly, these methods are not suited for the alkoxylation of
acid labile olefins as substrates or with acid labile alcohols. We
present herein the photoredox catalytic addition of alcohols to
unactivated alkyl olefins by the use of alkylated PPTs 1 and 2
(Figure 1). We demonstrate a broad substrate scope with respect
to the non-activated olefins 5-9 as substrates for methanol
addition. Using -methyl styrene (4) as activated substrate we
additionally show that this photoredox catalytic method tolerates
other functional groups in the alcohols that are added.
Photoredox catalysis is a recently established method of synthetic
organic chemistry that uses light, from the UV to the visible range,
to run reactions by alternative paths that are not tread by
conventional thermal reactions.[1] As
a result, photoredox
catalysis expand the current repertoire of organic reactions.[2]
Transition metal complexes, in particular with ruthenium, are
typically used as photoredox catalysts. With respect to the limited
availability and the rate of rare earth metals organic
chromophores provide important alternatives, as recently
demonstrated with e.g. eosin Y,[3] rhodamine 6G,[4] mesityl[5] and
aminoacridinium,[6]
naphthochromenones,[7]
4,6-
dicyanobenzenes, [8] and thioxanthones.[9] In contrast to transition
metal complexes, the versatility of organic chromophore is much
more restricted; there is not one single organic photoredox
catalyst for diverse photoredox catalytic transformations. It is
therefore important that organic chromophores can be modified to
adjust the photoredox properties to the given synthetic
problems.[9,10] N-phenylphenothiazines (PPT)[11] fulfil this
requirement because they can be modified by electron-donating
or -withdrawing groups either at the core or at the phenyl
substituent to vary the optoelectronic properties.[12] Other groups
used PPT for dehalogenations[13] and for ATRA (atom transfer
radical addition) polymerization.[14] We were able to activate inert
SF6 by PPT to yield pentafluorosulfanylated organic
compounds.[15] PPT can also be used for nucleophilic
Markovnikov-type addition of simple alcohols to activated olefins,
such as -phenyl and -methyl styrene (3 and 4).[16] The non-
photochemical version of this reaction is a key step in organic
chemistry; conventional methods are the two-step procedure
consisting of iodoalkoxylation using NIS and subsequent
reduction of the alkyl iodide in moderate yields[17] or the direct
Figure 1. N-phenylphenothiazines 1 and 2 and transition metal complexes as
photoredox catalysts, their redox potentials in relation to the redox potentials of
differently substituted olefin substrates, like activated -phenyl and -methyl
styrene (blue, 3 and 4) and unactivated alkyl olefins 5-9 (red), for nucleophilic
alkoxylation (R’’-OH) to products with Markovnikov selectivity 10-22, for R’ see
Figure 4. The image illustrates the photochemistry reactors.
1
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10.1002/ejoc.202001533
European Journal of Organic Chemistry
COMMUNICATION
The oxidation potentials Eox(X+·/X)=0.49 V-0.57 V (vs. SCE)
together with the singlet excited state energies E00=3.1-3.5 eV
give estimated excited state oxidation potentials Eox(X+·/X*)
between -2.5 V (for 1) and -2.9 V (for 2). -methyl styrene (4) is
an activated substrate due to the phenyl group whereas 2-
methylhept-1-ene (5), 2-methylhex-1-ene (6), methylenecyclo-
pentane (7), 1-methylcyclopent-1-ene (8) and 1-methylcyclohex-
1-ene (9) are only alkylated and therefore considered as non-
activated substrates. This difference is documented by their
reduction potentials; the potential of 4 lies in the range between
that of -phenyl styrene (3), Ered(S/S-·)=-2.3 V, and that of styrene,
Ered(S/S-·)=-2.6 V,[19] whereas the potential of alkyl olefins, like 5-
9, is found at approximately Ered(S/S-·)=-3.0 V.[20] After excitation
of 1 or 2 as photoredox catalyst an electron is transferred onto the
substrate (5 representatively shown as substrate in Figure 2) if
the oxidation potential in the excited state is sufficiently high. The
driving force G of this critical electron transfer process can be
estimated according to Rehm-Weller G=Eox-Ered-E00 (lacking the
Coulomb interaction energy Ec). For the photoredox catalysts 1
and 2 the G values lie in the range between -0.5 eV and ±0.0 eV,
predicting an exergonic electron transfer with substrate 4, but
borderline cases for the less activated substrates 5-9. The radical
anion 5-· that is formed after the photoinduced electron transfer
gets instantaneously protonated to the neutral radical 5·. Back
electron transfer to the photoredox catalysts converts the
substrate into an electrophile which subsequently reacts with
alcohols (R’-OH, like MeOH) as nucleophiles to the final addition
product 10. We studied this mechanism in our previous
publications. [15,16] Additionally, the steric hindrance of the alcohols
strongly influences yields (vide infra) and thereby supports the
nucleophilic attack onto the cation 5+.
comparison to Eox(X+·/X*)=-2.5 V for 1. Using a catalyst loading of
5 mol% 2, the products 10-14 were formed in yields of 12 - 68%.
The yields could not be simply increased by a higher catalyst
loading of 10 mol% 2. The best yields of 46% and 68% were
obtained for products 10 and 11, respectively, after an extended
irradiation time of 185 h. Obviously, these are extremely long
irradiation times, but these example should be considered as
proof-of-principle, since is very remarkable that terminal alkyl
olefins can indeed be converted by such simple photoredox
catalysis.
Figure 3. Substrate scope 5-9 and yields of products 10-14 after photoredox
catalytic methoxylation by N-phenylphenothiazines 1 and 2; a10 mol%; b5 mol%.
For irradiation times, see Table 1. The yields were determined by GC.
Table 1. Screening of reaction conditions for methoxylation of alkenes 5-9 to
products 10-24, 35 °C, MeOH, 365 nm LEDs. The yields were determined via
GC.
catalyst
mol%
substrate
t/h
product
yield/%
1
2
2
1
2
2
1
2
2
1
2
2
1
2
5
5
5
5
5
6
6
6
7
7
7
8
8
8
9
9
65
185
185
65
10
10
10
11
11
11
12
12
12
13
13
13
14
14
26
46
24
6
2
5
10
5
65
14
68
12
12
20
12
17
20
5
185
65
5
10
10
5
65
185
65
10
5
65
185
65
Figure 2. Proposed mechanism for photoredox catalyzed addition of alcohols
(ROH) to alkenes, like the non-activated alkene 5, ET=electron transfer,
irradiation by 365 nm LED.
5
5
185
32
Furthermore, there is no need for any additive, in particular no
trimethylamine as electron shuttle for efficient back electron
transfer.[21] This is an important feature of our photoredox catalytic
method. Thus, a broad variety of different functional groups
should be tolerated that are typically not stable during
conventional reaction conditions for alcohol additions to
olefins.[17,18] To widen the substrate scope not only with respect to
the olefins but also with respect to the alcohols we applied the
activated substrate 4 for the photoredox catalytic alkoxylation with
In control experiments without the addition of a catalyst or without
irradiation no products could be isolated. The substrates 5-9 were
irradiated at 365 nm in the presence of methanol and the
respective photoredox catalyst 1 or 2 (10 or 5 mol%). In general,
the use of photoredox catalyst 2 gives higher yields of products
10-14 than catalyst 1, also with higher catalyst loadings of 10
mol% (Figure 3). This difference can be attributed to the much
stronger excited state redox potential of 2, Eox(X+·/X*)=-2.9 V, in
2
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10.1002/ejoc.202001533
European Journal of Organic Chemistry
COMMUNICATION
a broad range of different alcohols (Figure 4). Remarkably,
alcohols with allyl, alkynyl and cyanide groups are converted to
products 18, 20 and 21 in excellent yields of 66 - 98%. Even the
Boc protecting group is tolerated, both as part of the alcohol
yielding product 22 or as part of the olefin substrate 23. The
photoredox catalyzed conversion of 4 with 3-(Boc-amino)1-
propanol gives product 22 in 85% yield. The methoxylation of the
Boc-protected substrate 23 gives product 24 in 80% yield. These
results show that this type of photocatalysis is also well suited for
alkoxylation of acid labile substrates and for peptide chemistry
based on Boc-protected building blocks.
level of sustainability is achieved by the use of light and the use
of an organic chromophore as photoredox catalyst.
Acknowledgements
This work was financially supported by the Deutsche
Forschungsgemeinschaft (DFG, grant Wa 1386/16-2) and
the Karlsruhe Institute of Technology (KIT).
Keywords: phenothiazine • chromophore • photocatalysis •
energy transfer • radical
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3
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10.1002/ejoc.202001533
European Journal of Organic Chemistry
COMMUNICATION
4
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10.1002/ejoc.202001533
European Journal of Organic Chemistry
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Entry for the Table of Contents
Insert graphic for Table of Contents here.
The photoredox catalytic addition of alcohols to non-activated terminal alkyl olefins is obtained by the use of N,N-diisobutylamino-
phenylphenothiazine. Its excited state redox potential is sufficiently high to promote the photoreduction.
5
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