Alkoxyl Radicals Generated under Photoredox Catalysis: A Strategy for anti-Markovnikov Alkoxylation Reactions

Article abstract of DOI:10.1002/anie.201806522

Reported herein is a novel photoredox-catalyzed approach for ether synthesis and it involves alkoxyl radicals generated from N-alkoxypyridinium salts. A wide range of alkenes are smoothly difunctionalized in an anti-Markovnikov fashion, affording various functionalized alkyl alkyl ethers. Notably, this mild process tolerates a number of functional groups and is efficiently carried out under both batch and flow conditions. Importantly, electron paramagnetic resonance (EPR) experiments by spin trapping were carried out to characterize the radical intermediates involved in this radical/cationic process.

Full text of DOI:10.1002/anie.201806522

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Accepted Article
Title: Alkoxyl Radicals Generated under Photoredox Catalysis: An
Efficient Strategy for anti-Markovnikov alkoxylation reactions
Authors: Anne-Laure Barthelemy, Béatrice Tuccio, Emmanuel Magnier,
and Guillaume Dagousset
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201806522
Angew. Chem. 10.1002/ange.201806522
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Alkoxyl Radicals Generated under Photoredox Catalysis: A
Strategy for anti-Markovnikov alkoxylation reactions
Anne-Laure Barthelemy,[a] Béatrice Tuccio,[b] Emmanuel Magnier[a] and Guillaume Dagousset*[a]
Abstract: We report herein a novel photoredox-catalyzed approach
for ether synthesis, involving alkoxyl radicals generated from N-
alkoxypyridinium salts. A wide range of alkenes are smoothly
difunctionalized in an anti-Markovnikov fashion, affording various
functionalized alkyl alkyl ethers. Notably, this mild process tolerates
a large number of functional groups and is efficiently carried out
under batch and flow conditions. Importantly, electron paramagnetic
resonance (EPR) experiments by spin trapping are carried out in
order to characterize the radical intermediates involved in this
radical/cationic process.
Alkoxyl radicals (RO·) are versatile intermediates, which not only
play a pivotal role in many biological processes but also are key
chemical species in a wide variety of organic transformations.[1]
Many strategies have been reported these last decades to
generate these highly reactive species, using a wide number of
RO· precursors such as nitrites,[2] hypohalites,[3] peroxides,[4]
[6]
sulfenyl ethers,[5] N-alkoxypyridine-2-thiones
or N-
alkoxyphthalimides.[7] However, these sources of alkoxyl radicals
suffer from several major limitations: they are either
toxic/unstable, or require the use of stoichiometric amounts of
radical initiators (typically Bu3SnH/AIBN mixture), or need harsh
reaction conditions (UV light irradiation, high temperatures)
which are incompatible with many sensitive functional groups.
To circumvent these issues, photoredox catalysis has very
recently been used as a powerful and eco-friendly means to
generate alkoxyl radicals.[8,9] Notably, the groups of Chen[10] and
Meggers[11] reported the use of N-alkoxyphthalimides for
selective C(sp3)–H functionalization thanks to the ability of RO·
radicals to perform 1,5-hydrogen atom transfer (HAT). A similar
1,5-HAT reactivity was later exploited by Zuo and co-workers for
the -selective functionalization of alkanols (Scheme 1a).[12]
Furthermore, the intermolecular HAT reactivity of alkoxyl radicals
was used by Lakhdar and co-workers for the P–H
functionalization of phosphine oxides (Scheme 1b).[13] In addition,
the propensity of RO· radicals to easily undergo -fragmentation
was also exploited by the groups of Chen,[14] Knowles,[15] and
Zuo[16] who reported efficient C–C bond cleavage and further
functionalization of the resulting C-centered radical (Scheme 1c).
It is worth noting that in all these examples, N-
alkoxyphthalimides or alcohols have all been specifically
designed. Indeed, the RO· radical intermediate reacts only via
1,5-HAT or -fragmentation because of its predisposition to
generate a highly stabilized C–centered radical (either a radical
in  position to an heteroatom, or a benzylic radical, or a tertiary
radical). For other less specific RO· radicals, we envisioned that
they could be trapped in an intermolecular manner by an
appropriate radical scavenger, such as an alkene, before any
Scheme 1. Different reactivities of alkoxyl radicals generated under
photoredox catalysis. NPhth = phthalimido.
HAT or -fragmentation processes occurred (Scheme 1d). If
such type of reactivity has been reported for other oxygen-
centered radicals such as nitroxide radicals,[17] to the best of our
knowledge in the case of alkoxyl radicals, it has not been used
in preparative and synthetically useful organic synthesis.[3,4,18]
We wish to report herein the first efficient synthesis of ethers
involving alkoxyl radicals generated under photoredox catalysis.
This method is of high interest, as it will lead to the preparation
of functionalized ethers with anti-Markovnikov regioselectivity,
which is currently a significant challenge in organic chemistry.[19]
We first chose to focus on the hydroxyalkoxylation of alkenes as
a model reaction (Table 1). Such photoredox-catalyzed three-
component difunctionalization reactions are indeed of high
interest and enable the one-pot synthesis of adducts of great
diversity and complexity from readily available building blocks.[20]
Moreover, compared to the well-known dihydroxylation of
olefins,[21] such hydroxyalkoxylation process usually requires a
two-step protocol, as one-pot procedures generally lead to poor
chemo- and/or regioselectivities.[22] To this end, we started
screening potential sources of methoxyl radical in the presence
of the strongly reducing photocatalyst fac-Ir(ppy)3 2a. When
alkene 1a was treated with 2 mol% of 2a and with N-
methoxyphthalimide 3a as a potential source of MeO· radical, no
desired product 4a could be detected (entry 1). We then decided
to turn our attention to N-alkoxypyridinium salts.[13] These
reagents are efficiently prepared in gram-scale from the
corresponding readily available pyridine N-oxides (see the
[a]
[b]
A.-L. Barthelemy, Dr. E. Magnier, Dr. G. Dagousset,
Institut Lavoisier de Versailles, UMR 8180, Université de Versailles-
Saint-Quentin 78035 Versailles Cedex, France
Fax: (+) 33 1 39254452
Dr. B. Tuccio
Aix-Marseille Université-CNRS, Institut de Chimie Radicalaire, UMR
7273, F-13397 Marseille Cedex 20, France
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Table 1. Survey of reaction conditions for the photoredox-catalyzed
hydroxyalkoxylation of alkene 1a.
base was not required to achieve complete conversion, pointing
out the high efficiency of this continuous-flow process.
With these optimized conditions in hand, the scope of this novel
photocatalyzed hydroxyalkoxylation was next investigated in
batch and in continuous flow and the results are summarized in
Scheme 2. A wide range of styrene derivatives were well
tolerated. Notably, various functionalities, such as halogens,
ethers, thioethers, amides, carbamates, or boronic esters, were
compatible with the mild reaction conditions, affording the
corresponding hydroxymethoxylated compounds 4a-4m in 50-
83% yield.[24] Vinyl-substituted heteroarenes 1n-o also reacted
smoothly during this photocatalyzed process. Interestingly, this
three-component reaction was successfully broadened to - and
-substituted styrenes 1p-r, providing the corresponding
alkoxylated alcohols 4p-r in up to 72% yield. A key feature of
photoredox-catalyzed transformations consists of the late-stage
functionalization of complex small molecules, which is a very
important tool in modern drug discovery. To this end, proline-
derived alkene 1s was also smoothly converted into highly
functionalized adduct 4s in 71% yield. In addition, a gram-scale
experiment was performed for the synthesis of adduct 4i without
any decrease in yield, showing the practicity and efficiency of
continuous-flow techniques.
Entry
MeO· source
Additive
Yield [%][a,b]
none
0
1
3a
none
24
2
3b
CsF
37
3
3b
2,6-lutidine
NaH2PO4·2H2O
NaH2PO4·2H2O
NaH2PO4·2H2O
NaH2PO4·2H2O
NaH2PO4·2H2O
none
32
4
3b
40
5
3b
44
6
3ca
3ca
3ca
3ca
3ca
3ca
3ca
7[c]
8[d]
9[c,e]
10[g]
11[c,h]
12[c,i]
60
50
67 (65)[f]
(64)[f]
0
NaH2PO4·2H2O
NaH2PO4·2H2O
Although our attempts to synthesize tertiary N-alkoxypyridinium
salts (e.g. R = t-Bu, Scheme 3) were all unsuccessful, it is worth
noting that other N-alkoxypyridinium salts 3cb-3cl derived from
primary or secondary alkoxy groups with various functionalities
(halogen, azido, cyano, ester, trifluoromethyl, sulfonyl) were also
suitable partners and led to the desired adducts 4t-4ad in good
yields (Scheme 3). In particular, N-alkoxypyridinium 3cj bearing
an alkyne moiety was successfully employed to afford the
0
[a] General conditions: 1a (0.10 mmol), 3 (0.20 mmol), 2a (0.02 equiv) in 1
mL of wet acetone irradiated at RT for 24 h. [b]Yields determined by 1H NMR
spectroscopy using mesitylene as an internal standard. [c] With 0.20 mmol
of 1a and 0.10 mmol of 3 for 36 h. [d] With 0.15 mmol of 1a and 0.10 mmol
of 3 for 36 h. [e] With 1 mol% of 2a. [f] Yields referred to chromatographically
pure product in parentheses. [g] Using flow conditions, with 3 mol% of 2a.
See the Supporting Information for more details. [h] In the dark. [i] Without
2a.
Supporting Information for the synthesis of a variety of N-
alkoxypyridinium salts bearing various electron-donating or
withdrawing groups). To our delight, when N-methoxypyridinium
salt 3b was tested, the expected three-component adduct 4a
was obtained in 24% NMR yield with perfect anti-Markovnikov-
type regioselectivity after 24 h of irradiation with blue LEDs
(entry 2), albeit with incomplete conversion. Encouraged by this
promising result, the reaction conditions were next optimized
(entries 3-9, see the Supporting Information for more details).
Notably, the addition of a base such as NaH2PO4 enabled the
reaction to go to completion within 36 h, probably by assisting
the nucleophilic attack of water. Furthermore, the yield was
improved by using 4-cyano substituted N-methoxypyridinium salt
3ca, and the hydroxymethoxylated product 4a was isolated in
65% yield (entry 9). In addition, in order to accelerate this
alkoxylation process, we also optimized this novel reaction with
the use of continuous-flow techniques, which are perfectly well
adapted to photochemical transformations: indeed, they provide
a more homogeneous irradiation of the reaction mixture,
enhanced mass transfer characteristics, and allow performing
scale-up experiments.[23] Under slightly modified reaction
conditions (entry 10), we were pleased to see that the
hydroxyalkoxylation of 1a could be carried out with a residence
time of 1 h at 25 °C (see the Supporting Information for more
details). Remarkably, under these conditions, the assistance of a
Scheme 2. Scope of alkenes. Yields referred to chromatographically pure
product. [a] Batch conditions: alkene 1 (0.2 mmol), 3ca (0.1 mmol), 2a (1
mol%), NaH2PO4·2H2O (0.1 mmol) in wet acetone (1 mL) irradiated with blue
LEDs at RT for 36 h. [b] Flow conditions: alkene 1 (0.2 mmol), 3ca (0.1 mmol),
2a (3 mol%), in acetone/CH2Cl2 mixture (5:1, 2 mL) irradiated with blue LEDs
with a flow rate of 0.15 mL.min-1 at 25°C. [c] With 4 mmol of 3ca. [d]
d.r. = 1.7:1. [e] d.r. = 2:1. d.r. = diastereomeric ratio.
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Scheme 3. Scope of N-alkoxypyridinium salts. Yields referred to
chromatographically pure product. See Scheme 2 for conditions [a] and [b]. [c]
Reaction performed without alkene 1l. [d] d.r. = 1.1:1. [e] d.r. = 2.3:1. X = BF4
or OTf.
corresponding compound 4aa, pointing out the high
chemoselectivity of this photoredox-catalyzed three-component
process. Finally, this hydroxyalkoxylation process was also
readily carried out in an intramolecular fashion with N-
alkoxypyridinium salts 3cm-3cn, providing the corresponding
cyclic ethers 4ae-4af in good yields.
Scheme 4. Dialkoxylation and aminoalkoxylation. See the Supporting
Information for details. Yields referred to chromatographically pure product.
following control experiments were performed. No reaction took
place in the absence of irradiation and/or fac-Ir(ppy)3 2a (see
Table 1, entries 11-12). Moreover, the formation of 4-6 was
inhibited in the presence of radical scavengers such as TEMPO
((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) or O2, suggesting that a
radical process is involved in this reaction. Furthermore, when
N-alkoxypyridinium salts 3co and 3cp were subjected to the
optimal reaction conditions, benzaldehyde and compound 7
were isolated as major products, respectively (Scheme 5a).
These compounds are most probably resulting from 1,2-H shift
and -scission of the respective alkoxyl radical intermediates 8
and 9, which is once again in favour of a radical mechanism. In
addition, various spin trapping / electron paramagnetic
resonance (ST/EPR) experiments were carried out, and allowed
verifying the formation of RO· radicals without ambiguity (see
the Supporting Information for more details). Based on these
experiments, the most plausible mechanism is proposed in
Scheme 5b. First, N-alkoxypyridinium salt 3c (Ered (3ca) = –
0.47 V vs. SCE)[26] is reduced by the excited state of fac-Ir(ppy)3
2a (–1.73 V vs. SCE), generating RO· A. This radical can then
add onto alkene 1, leading to a carbon-centered radical B
stabilized in benzylic position. It is worth noting that alkyl
In order to demonstrate the versatility of this novel radical
approach towards ether synthesis, we next focused on
dialkoxylation of alkenes. To the best of our knowledge, in
previous reports on such transformation,[25] the alkoxyl source is
always an alcohol which is used as solvent. This leads to two
main drawbacks: i) Such processes have been mainly limited to
methoxy or ethoxy groups, and have not been extended to more
complex alkoxy groups; ii) three-component dialkoxylation
processes with two different alkoxy groups have not been
reported yet. Our method involving alkoxyl radicals under
photoredox catalysis would provide a solution to both these
limitations. Pleasingly, by adding an alcohol in the reaction
mixture, our methodology was successfully broadened to the
synthesis of a wide range of dialkoxylated adducts 5a-k bearing
various functional groups (Scheme 4). Once again, such
process was readily applied to the late-stage functionalization of
complex molecules such as cholesterol-derived alkene 1v,
without any degradation of its tri-substituted C–C double bond. It
is also worth noting that unsymmetrical regioisomers 5h and 5j
as well as regioisomers 5i and 5k were for the first time
efficiently prepared starting from the same substrate 1l.
substituted
alkenes,
such
as
6-phenyl-1-hexene
or
methylenecyclohexane, which are less capable of stabilizing
radical intermediates, were not suitable partners for this
transformation. Subsequently, SET oxidation of B by Ir(ppy)3
generates the corresponding carbocation C stabilized in benzylic
position. Final trapping with either water, alcohol or acetonitrile,
provides the corresponding products 4-6.
Finally, we decided to use acetonitrile as both the solvent and
the nucleophile, as it is known to easily trap carbocation
intermediates (Ritter-type reaction). To our delight, this
photoredox-catalyzed aminoalkoxylation reaction was efficiently
applied to functionalized alkenes, affording products 6a-d in
good yields.
+
In summary, we have developed a novel strategy for ether
To study the mechanism of these alkoxylation reactions, the
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[7]
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alkoxypyridinium salts under photoredox catalysis. Three new
types of difunctionalization of alkenes (hydroxyalkoxylation,
dialkoxylation, and aminoalkoxylation) with perfect anti-
Markovnikov-type regioselectivity have been successfully
developed, which tolerate a wide range of functional groups and
are amenable to gram scale synthesis thanks to continuous-flow
techniques. Other ether syntheses involving alkoxyl radicals are
currently under investigation in our laboratory and will be
reported in due course.
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Acknowledgements
ALB thanks the French Ministry of Research for a doctoral
fellowship. BT acknowledges NIEHS for providing free the
WINSIM software used to simulate all the EPR spectra. Labex
Charmmmat is gratefully acknowledged for the funding of the
continuous flow device.
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Keywords: alkoxyl radicals • photoredox catalysis • anti-
Markovnikov selectivity • ethers • alkoxypyridinium salts
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Anne-Laure Barthelemy,[a] Béatrice
Tuccio,[b] Emmanuel Magnier[a] and
Guillaume Dagousset*[a]
Page No. – Page No.
Alkoxyl Radicals Generated under
Photoredox Catalysis: A Strategy for
anti-Markovnikov alkoxylation
reactions
Alkoxyl radicals generated under visible light photoredox catalysis from N-
alkoxypyridinium salts were for the first time efficiently trapped by alkenes in an
intermolecular fashion, using either batch or flow conditions. This alkoxylation
strategy enabled the access to a wide variety of functionalized alkyl alkyl ethers,
thanks the difunctionalization of alkenes with perfect anti-Markovnikov selectivity.
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