Visible-Light Photoredox-Catalyzed Hydroalkoxymethylation of Activated Alkenes Using α-Silyl Ethers as Alkoxymethyl Radical Equivalents

Article abstract of DOI:10.1021/acs.orglett.8b02721

A new neutral silicon-based traceless activation group (TAG) for visible-light photoredox-catalyzed hydroalkoxymethylation of alkenes is presented. This reaction involves in-situ-generated alkoxymethyl radical via single electron oxidation (SET) of α-TMS-substituted ethers, followed by subsequent conjugate addition to activated alkenes. Various functional groups were tolerated both under mild metal and metal-free conditions to provide good to excellent yields. Furthermore, the addition products were transformed to valuable synthetic building blocks, such as carboxylic acids,-butyrolactones, and complex aryl alkyl ethers.

Full text of DOI:10.1021/acs.orglett.8b02721

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light Photoredox-Catalyzed Hydroalkoxymethylation of
Activated Alkenes Using α‑Silyl Ethers as Alkoxymethyl Radical
Equivalents
Nilufa Khatun, Myeong Jun Kim, and Sang Kook Woo*
Department of Chemistry, University of Ulsan, 93 Daehak-Ro, Nam-Gu, Ulsan 44610, Korea
S
* Supporting Information
ABSTRACT: A new neutral silicon-based traceless activation group (TAG) for visible-light photoredox-catalyzed
hydroalkoxymethylation of alkenes is presented. This reaction involves in-situ-generated alkoxymethyl radical via single
electron oxidation (SET) of α-TMS-substituted ethers, followed by subsequent conjugate addition to activated alkenes. Various
functional groups were tolerated both under mild metal and metal-free conditions to provide good to excellent yields.
Furthermore, the addition products were transformed to valuable synthetic building blocks, such as carboxylic acids, γ-
butyrolactones, and complex aryl alkyl ethers.
α-Alkoxyalkyl radicals are useful reaction intermediates in C−
C bond forming reactions for functionalization of ethers,1
which represent an important structural motif in many
solvents, natural products, and pharmaceuticals. Since α-
oxyalkyl radicals act as nucleophiles2 with electrophiles such as
alkenes, alkynes, imines, and aldehydes, many methods
utilizing such species have been developed, because of their
significant importance. An efficient strategy for the generation
of α-alkoxyalkyl radicals is direct C−H activation of the α-
hydrogen in ethers. Conventional research has focused on the
generation of α-alkoxyalkyl radicals by radical initiators,
oxidants, γ-ray irradiation, or electrochemical promotion;3
however, these methods use stoichiometric oxidants and high-
energy light sources. To overcome these problems, suitable
alternative protocols are in high demand and are desirable for
synthetic organic chemists. Recently, visible-light photoredox
catalysis has been a useful tool for many organic trans-
formations,4 in particular in the field of single-electron redox
chemistry. However, the direct single electron oxidation of
ethers by visible-light photoredox catalysis remains difficult,
because of the higher oxidation potential of the corresponding
ethers (e.g., Eo1/x2 > +2.4 V vs SCE for THF, THP, and Et2O).5
Recently, this problem was solved by merging photoredox
catalysts with hydrogen atom transfer (HAT) reagents such as
thiols and persulfate.5c,6 Although these methods can directly
generate α-alkoxyalkyl radicals, they are limited by the need of
an excess of ether. Alternatively, the introduction of a traceless
activation group (TAG) at the α-carbon of an ether can
significantly decrease the oxidation potential necessary to
achieve direct and selective oxidation of ethers by photoredox
catalysis without any co-catalyst. Recently, potassium trifluor-
oborates,7 in-situ-generated carboxylates,8 and hypervalent
silicon anions9 have been developed as traceless activation
groups of ethers for oxidative generation of α-oxyalkyl radicals
via photoinduced electron transfer (PET), as shown in Scheme
1. Although these TAGs for ethers assist in the generation of α-
Scheme 1. Oxidative Generation of α-Oxyalkyl Radical via
PET
Received: August 24, 2018
© XXXX American Chemical Society
A
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a
oxyalkyl radicals and then react with electrophiles to form new
C−C bonds, they are in salt form or in-situ-generated by
stoichiometric base additives.
Table 1. Optimization of the Reaction Conditions
Therefore, the development of neutral TAGs is still needed.
Neutral alkylsilane10 at the α-carbon of ethers also decreases
the oxidation potential by stabilization of the cation radical
intermediate by overlap of the filled C−Si bond with the half-
vacant 2p orbital of the oxygen (β-silicon effect).5a In addition,
α-silyl-substituted ethers are easily synthesizable, inexpensive,
and easy to handle. Indeed, we became interested in utilizing
alkylsilane as a neutral TAG for ether functionalization. In
1998, the Steckhan group first reported an ultraviolet (UV)-
light-mediated generation of α-alkoxymethyl radical from α-
silyl ethers using 9,10-anthracenedicarbonitrile and biphenyl as
photoredox catalysts and its coupling with electron-deficient
alkenes (see Scheme 1a).11 Although this result provided a
new concept for neutral silane TAGs, the reaction suffered
from poor yields, limited substrate scope, and the requirement
of a high-energy source (UV range). More recently, Bode and
co-workers developed a new synthetic method for producing
N-heterocycles by in situ generation of α-alkoxymethyl radicals
via oxidative single-electron oxidation, followed by rapid
desilylation and subsequent intramolecular cyclization using
2,4,6-triphenylpyrylium tetrafluoroborate (TPP) as a photo-
redox catalyst (Scheme 1b).12 To the best of our knowledge,
the formation of α-alkoxymethyl radicals from TMS-modified
ethers by visible-light-mediated photoredox catalysis and its
subsequent intermolecular coupling with activated alkenes has
not been described. Herein, we report the visible-light
photoredox-catalyzed hydroalkoxymethylation of activated
alkenes using α-TMS-substituted ethers as α-alkoxymethyl
radical equivalents (see Scheme 1c).
b
2a
yield
entry
catalyst (mol %)
(equiv)
solvent (0.1 M)
MeCN
EtOAc
DMF
EtOH
MeOH
MeOH
MeOH/Acetone
(1:1)
MeOH/EtOAc (1:1)
MeOH/MeCN
(1:1)
MeOH/MeCN (1:1)
MeOH/MeCN (1:1)
MeOH/MeCN (1:1)
MeOH/MeCN (1:1)
(%)
1
2
3
4
5
6
7
Acr+-Mes (1.0)
Acr+-Mes (1.0)
Acr+-Mes (1.0)
Acr+-Mes (1.0)
Acr+-Mes (1.0)
Acr+-Mes (2.0)
Acr+-Mes (1.0)
2.0
2.0
2.0
2.0
2.0
2.0
2.0
9
41
29
53
64
66
65
8
9
Acr+-Mes (1.0)
Acr+-Mes (1.0)
2.0
2.0
76
c
82 (n.r.)
10 Acr+-Mes (0.5)
11 Acr+-Mes (1.0)
12 Acr+-Mes (1.0)
13 Ru(bpz)3(PF6)2
(1.0)
2.0
1.5
1.2
2.0
58
68
50
96
In our initial study, PMPOCH2TMS 1a was chosen as an α-
alkoxymethyl radical surrogate. By the above-mentioned β-
silicon effect, the oxidation potential of PMPOCH2TMS 1a
was measured as +1.1 V vs SCE in MeCN, which is lower than
the corresponding alkyl ether. We expected the high
oxidization ability of photoredox catalyst (E1/2red (PC*/
PC• −) > +1.1 V vs SCE) would be necessary to oxidize
PMPOCH2TMS 1a.13 First, we focused on metal-free
conditions, because they have advantages over transition-
metal conditions (e.g., residual metal problems, price, etc.).4e,f
The reaction of PMPOCH2TMS 1a with benzalmalononitrile
2a was first performed in MeCN using 1 mol % organic
photoredox catalyst under irradiation with 6 W blue LEDs. As
expected, the desired hydroalkoxymethylation product 3a was
obtained in 9% yield, using Fukuzumi acridinium salt (Acr+-
Mes)14 with strong oxidizing power (Table 1, entry 1), while
other organic photocatalysts with weaker oxidizing power did
not react (see details in the Supporting Information). We
investigated further to optimize the reaction conditions,
keeping other parameters unchanged. The influence of solvent
on the reaction efficiency was significant. Especially, a MeOH/
CH3CN co-solvent provided an excellent yield of 3a in 82%
yield (Table 1, entry 9). In addition, when the amount of
benzalmalononitrile 2a and the catalyst loading were reduced,
the yields were unfortunately reduced (Table 1, entries 10−
12). After a thorough screening of the reaction conditions, the
best result was achieved by reaction of PMPOCH2TMS 1a and
2.0 equivalents of benzalmalononitrile in the presence of 1.0
mol % of Acr+-Mes in CH3CN/MeOH at room temperature,
being irradiated with 6 W blue LEDs under an argon
atmosphere to furnish the desired product 3a in 82% yield
14 Ru(bpz)3(PF6)2
(1.0)
15 Ru(bpz)3(PF6)2
(1.0)
16 Ru(bpz)3(PF6)2
(0.5)
1.5
1.2
1.2
MeOH/MeCN (1:1)
93
94 (n.r.)
88
c
MeOH/MeCN
(1:1)
MeOH/MeCN (1:1)
a
Reaction conditions: 1a (0.2 mmol), 2a (quantity noted), catalyst
(quantity noted), solvent (0.1 M) with 6 W blue LEDs irradiation at
room temperature for 24 h under argon in pressure tubes. Isolated
yield by flash column chromatography. In the absence of light source
b
c
or photocatalyst. n.r. = no reaction.
(Table 1, entry 9). Next, we expanded our research to find
transition-metal-based photocatalysts to perform the same
transformation. Transition-metal-based catalysts such as fac-
Ir(ppy)3, Ir(ppy)2(dtb-bpy)PF6, Ir(dF-CF3ppy)2(dtb-bpy)PF6,
Ru(bpy)3Cl2, and Ru(bpz)3(PF6)2 were tested to perform the
hydroalkoxymethylation.
Surprisingly, coupling product 3a was obtained in
quantitative yield in the presence of Ru(bpz)3(PF6)2, while
other metal-based photocatalysts did not facilitate the reaction
(Table 1, entry 13; see the Supporting Information). The
amount of alkene 2a was decreased, resulting in a slight
decrease in yield to 94%, still an excellent result (Table 1,
entries 14 and 15). Ultimately, reaction of PMPOCH2TMS 1a
with 1.2 equivalents of benzalmalononitrile 2a utilizing 1.0
mol % Ru(bpz)3(PF6)2 was chosen as the transition-metal-
based optimized conditions (Table 1, entry 15). It is notable
that either in the absence of light or the photocatalyst under
both catalytic conditions, the formation of product 3a was not
B
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Letter
observed, which strongly supports the role of visible light in
this reaction (Table 1, entries 9 and 15). We developed
organic and metal-based photoredox catalyst systems for the
hydroalkoxymethylation of alkene. Therefore, we explored
various substrates using both catalysts for hydroalkoxymethy-
lations.
diastereomeric ratio (dr). Next, we expanded the substrate
with various aryloxymethylsilanes 1 that have substituted H,
Br, I, COMe, NO2 in the aryl group, instead of a methoxy
group to examine the electronic effect for desilylative coupling.
Under the metal-free conditions, similar and less-efficient
results were obtained. However, reactivity under the metal-
catalyzed conditions was reduced, because Ru(bpz)3(PF6)2 is a
weaker oxidant than Acr+-Mes in the excited state from visible-
light irradiation. Therefore, metal-based catalyst systems were
less efficient at oxidizing the electron-neutral and electron-poor
aryloxymethylsilanes (1b−1f). When the Ru(bpz)3(PF6)2
loading was increased, hydroalkoxymethylation of H and
halogen-substituted aryloxymethylsilanes (1b−1d) proceeded
smoothly, and the corresponding coupled product (3r−3t)
was obtained in good yield. However, strong electron-
withdrawing-group-substituted aryloxymethylsilanes (1f, 1e)
cannot oxidize via Ru(bpz)3(PF6)2. Hydroalkoxymethylation
of (methoxymethyl)trimethylsilane also proceeded under
metal-free conditions. This result shows that the develped
method proceeds in both aryl ether and alkyl ether.
Next, we explored the substrate scope of various primary α-
silyl ethers with activated alkenes (see Scheme 2). Under both
Scheme 2. Substrate Scope of Various Primary α-Silyl
a
Ethers with Activated Alkenes
In addition, we conducted further functionalization of 3t and
gram-scale synthesis of 3a. The 3t smoothly underwent Suzuki
coupling with arylboronic acids to provide moderate to good
yields of the corresponding products (4a−4c) (see Scheme
3).15 The 3a was obtained in 1.22 g, 83% (Acr+-Mes) and 1.42
Scheme 3. Further Functionalization of 3t
a
Reaction conditions as given in Table 1, entries 9 and 15; reported
yields are given for isolated material. bCatalyst (2 mol %). cAlkene 2o
(2.0 equiv). Catalyst (5 mol %). After 48 h. See the Supporting
Information for details.
d
e
g, 97% (Ru(bpz)3(PF6)2) yield (see details in the Supporting
Information). Unfortunately, we have not been able to expand
on hydroalkoxylmethylation with less-activated alkenes, such as
acrylonitrile, methyl acrylate, α,β-unsaturated ketone and
lactone, etc. under the optimized conditions.
Next, we examined secondary α-silyl ethers in this reaction.
TBS-protected secondary α-silyl ether 1e was treated with
various alkenes containing both electron-neutral, electron-
donating, and halogen substituents. As illustrated in Scheme 4,
all of the reactions provided moderate to good yields and ∼1:1
optimized conditions, PMPOCH2TMS 1a was added to a
diverse range of benzalmalononitrile derivatives (2a−2m) to
form aryl alkyl ethers (3a−3m) in good to excellent yields. In
particular, bulky tert-butyl, phenyl-substituted (2c, 2d), o-, m-,
and p-MeO substituted- (2i−2k), and 3,4-disubstituted- and
3,4,5-trisubstituted (2l, 2m) benzylidenemalononitriles were
not influenced by steric hindrance in the addition reaction.
Halogen-containing benzalmalononitrile derivatives (2e−
2g) gave slightly low yields with the exception of 4-
chlorobenzalmalononitrile 2e under metal-free conditions.
However, the corresponding products of these lower-yielding
reactions could be enhanced using Ru(bpz)3(PF6)2 as the
photoredox catalyst. We extended the substrate scope to
alkylidene malononitriles (2n−2p). Under metal-free con-
ditions, the alkylidene malononitriles were less efficient than
benzalmalononitrile derivatives for the photocatalyzed hydro-
alkoxymethylation reaction. As an alternative, Ru(bpz)3(PF6)2
was used as the photoredox catalyst, and the desired
corresponding products (3n−3p) were obtained in excellent
yields of 83%−96%. Instead of benzalmalononitrile derivatives,
other alkene types, such as methyl (E)-2-cyano-3-phenyl
acrylate 2q, smoothly coupled with PMPOCH2TMS 1a to
give the corresponding product 3q in 62% yield and ∼1:1
Scheme 4. Substrate Scope of Secondary α-Silyl Ethers with
a
Various Activated Alkenes
a
Reaction conditions as given in Table 1, entry 9. See the Supporting
Information for details.
C
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dr under the optimized conditions. Unfortunately, the
hydroalkoxylation of secondary α-silyl ethers with alkenes
was not efficient under metal-catalyzed conditions, presumably
because the TBS-protected α-silyl ether 1e has a higher
oxidation potential than PMPOCH2TMS 1a.
Scheme 6. Control Experiments and Proposed Reaction
Mechanism
To demonstrate the efficacy of this protocol, the coupled
products 3 were converted to useful synthetic building blocks
(see Scheme 5). Carboxylic acid-containing aryl alkyl ethers
Scheme 5. Conversion of Ethers 3 to Useful Synthetic
Building Blocks
was confirmed by 1H NMR (Scheme 6a). In addition, we also
performed on−off experiments to verify the proposed SET
mechanism.
These results showed that sustained irradiation with visible
light is essential for hydroalkoxymethylation to occur (see
details in the Supporting Information).
(4a, 4s) were obtained after acidic hydrolysis and decarbox-
ylation in good yields. Notably, γ-butyrolactones,16 which are
very important synthetic core structures found in natural
products and pharmaceuticals, were prepared from ethers 3 by
acidic hydrolysis, decarboxylation, deprotection, and cycliza-
tion in good yields. The diastereomeric mixtures of ethers (3x,
3ac) were converted to predominantly anti γ-butyrolactones
(6x, 6ac) by kinetic resolution in the lactonization.
To gain insight into the reaction mechanism, control
reactions were performed under both catalyst conditions. In
the Stern−Volmer luminescence quenching experiment, the
excited state of the photoredox catalyst was quenched by
PMPOCH2TMS 1a but was not quenched by benzalmalono-
nitrile 2a.
In conclusion, we have developed a neutral silicon-based
TAG for visible-photoredox-catalyzed hydroalkoxymethylation
of alkenes. The addition reaction tolerates various functional
groups and provides good to excellent yields under both metal
and metal-free conditions. We proposed a reaction mechanism
that involves in-situ-generated alkoxymethyl radical via single
electron oxidation of α-TMS substituted ethers. Mechanistic
studies support a radical pathway for a plausible reaction
mechanism. Furthermore, the synthesized ether compounds
were further transformed to valuable synthetic building blocks
such as carboxylic acids, γ-butyrolactones, and complex aryl
alkyl ethers.
This result indicates that the SET mechanism between
PMPOCH2TMS 1a and the excited photoredox catalyst occurs
in the initial stage (as detailed in the Supporting Information).
Next, radical trapping experiments were undertaken. The
addition of TEMPO or γ-terpinene to the hydroalkoxymethy-
lation completely suppressed the reaction, indicating that the
reaction involves a radical process (Scheme 6a). Based on our
control experiments and the literature,5a,11,12 a plausible
mechanism has been postulated in Scheme 6b. Single-electron
oxidation of PMPOCH2TMS 1a by the excited photoredox
catalyst (PC*) produces cation radical species I, which rapidly
converts to α-alkoxymethyl radical II in a desilylation process
via solvent. This in-situ-generated α-alkoxymethyl radical II
couples with benzalmalonitrile 2a to generate stable α-cyano
radical III. Further single-electron transfer from the reduced
photoredox catalyst (PC• −) to its original state leads to the
formation of α-cyano anion IV. Subsequent protonation of α-
cyano anion IV with methanol provides the desired product
3a. Control experiments using CH3CN/CD3OD instead of
CH3CN/CH3OH as solvent were performed to confirm the
proposed mechanism. As a result of the experiment,
replacement of the hydrogen of product 3a with deuterium
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02721.
■
S
Electrochemical and photophysical measurements and
mechanism studies; experimental procedures; spectro-
scopic data for all new compounds (1H NMR, 13C
NMR, 19F NMR, IR, HRMS), including images of NMR
spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: woosk@ulsan.ac.kr.
ORCID
Sang Kook Woo: 0000-0002-8808-037X
Notes
The authors declare no competing financial interest.
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Letter
(12) Jackl, M. K.; Legnani, L.; Morandi, B.; Bode, J. W. Org. Lett.
2017, 19, 4696.
ACKNOWLEDGMENTS
■
This work was supported by the National Research
Foundation (No. NRF-2016R1D1A1B03934062) and the
Priority Research Centers Program (No. NRF-2009-
0093818) funded by the Ministry of Education of the Republic
of Korea.
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