Visible-Light Photoredox-Catalyzed α-Regioselective Conjugate Addition of Allyl Groups to Activated Alkenes

Article abstract of DOI:10.1002/adsc.202000445

The α-regioselective conjugate addition of allyl groups to activated alkenes is a poorly explored area of research. Herein, we report an α-adduct and (E)-isomer selective conjugate addition of allylsilanes to activated alkenes by visible-light photoredox catalysis. The reaction involves allylic radicals that can be generated from allylsilanes through a photoinduced single-electron transfer mechanism. (Figure presented.).

Full text of DOI:10.1002/adsc.202000445

Title: Visible-Light Photoredox-Catalyzed α-Regioselective Conjugate
Addition of Allyl Groups to Activated Alkenes
Authors: Arjun Gontala and Sang Kook Woo
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10.1002/adsc.202000445
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Visible-Light Photoredox-Catalyzed α-Regioselective Conjugate
Addition of Allyl Groups to Activated Alkenes
Arjun Gontalaa and Sang Kook Wooa,*
a
Department of Chemistry, University of Ulsan, 93 Daehak-Ro, Nam-Gu, Ulsan 44610, Korea.
E-mail: woosk@ulsan.ac.kr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
reaction mechanism involves
a
carbocation
Abstract. The α-regioselective conjugate addition of
allyl groups to activated alkenes is a poorly explored area
of research. Herein, we report an α-adduct and (E)-isomer
selective conjugate addition of allylsilanes to activated
alkenes by visible-light photoredox catalysis. The
reaction involves allylic radicals that can be generated
from allylsilanes through a photoinduced single-electron
transfer mechanism.
intermediate that is stabilized by β-silicon effect[7] as
the driving force. The selective 1,4-addition of
allylsilanes with high γ-addition and anti-selectivity
has been reported.[6a, c, d, 8] In addition, allylsilanes are
used as allylic radicals precursors for radical-mediated
allylations. From allylsilanes, which have lower
oxidation potentials than alkenes owing to the β-
silicon effect,[7] allylic radicals are generated by
Keywords: photoredox catalysis; allylation; allylsilane;
conjugate addition; α-regioselectivity
photoinduced
single-electron
oxidation
and
desilylation. Mariano et al.[9] and Mizuno et al.[5]
reported the generation of allylic radicals from
allylsilanes by single-electron transfer (SET) using
UV irradiation in the presence of an organic
photosensitizer or donor–acceptor interaction.
Interestingly, this radical-mediated conjugate addition
provided α-adducts as the major product, which is the
reverse regioselectivity to that observed in the
Hosomi–Sakurai reaction (Scheme 1 b).
Carbon–carbon bond formation is essential for the
construction of organic compounds such as natural
products, pharmaceuticals, agrochemicals, and
organic materials. Allylation is one of the most
important methods for C–C bond formation in organic
synthesis, mainly owing to its regioselectivity,
stereoselectivity, and good functional-group tolerance
and the easy transformation of allyl moieties into
various functional groups.[1] Especially, carbonyl
allylation has been well developed using a variety of
allylic metal reagents and catalysts, with good
regioselectivity,
diastereoselectivity,
and
enantioselectivity being achieved.[1a-c, 1f] However, the
allylation of α,β-unsaturated carbonyl, nitro, and
nitrile compounds with allylic metals presents more
complex regioselectivity and stereoselectivity issues.
Thus, the selectivity of 1,2-addition and 1,4-addition
processes is highly dependent on allylic metals and
substrates.[2] To date, research on conjugate addition
has mainly focused on γ-addition with controlled
enantioselectivity[3] or diastereoselectivity[4] (Scheme
1 a). The selective α-addition in the conjugate addition
of allyl groups has been rarely reported,[5] and remains
a challenging subject. Therefore, we focused on
developing a highly α-regioselective allylation in
conjugate addition processes.
Allylsilanes are useful allylation reagents because
of their thermal stability, inertness in oxygen and water,
and good reactivity. The Hosomi–Sakurai reaction is a
representative allylation using allylsilanes,[6] whose
Scheme 1. Conjugate addition of allylic groups to activated
alkenes
1
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10.1002/adsc.202000445
Advanced Synthesis & Catalysis
This α-selectivity is due to steric effects during the
radical addition to activated alkenes. We were inspired
by this allylic radical reaction for the development of
an α-selective conjugate allylation. Although Mizuno
and coworkers developed α-regioselective conjugate
allylation using allylsilanes, this reaction was realized
using a high photosensitizer loading and high-energy
source (300-W Hg lamp, λ > 280 nm), and only one
example with moderate selectivity (5:1) was reported.
Therefore, the development of an α-selective
conjugate allylation that proceeds under mild reaction
conditions with high regioselectivity and good
functional-group tolerance is required.
Table 1. Optimization of the reaction conditionsa
Recently, visible-light photoredox catalysis has
emerged as
a
powerful tool in chemical
transformations.[10] Wu and Glorius groups reported an
efficient allylation using allylic radicals that are
generated in situ from electron-rich alkenes by a
visible photoredox-catalyzed oxidation/deprotonation
process.[11] However, this reaction is limited to
electron-rich alkenes. Previously, we developed a
neutral silicon-based traceless activation group to
generate stabilized radicals by photoinduced SET, and
applied it in the visible-light photoredox-catalyzed
Giese reaction of stabilized radicals with alkenes.[12]
Following this, we expanded the use of our recently
developed silicon-activation groups to the formation
of allylic radicals. Although Wu and coworkers
recently reported visible-light photoredox-catalyzed
allylation of activated alkenes using allylsilanes, they
did not deal with regioselective and stereoselective
allylation and reported only reactions with
unsubstituted allylsilane.[13] Herein, we report an α-
adduct and (E)-isomer selective conjugate addition of
allylsilanes to activated alkenes by metal-free visible-
light photoredox catalysis.
a)Reaction conditions: 1a, 2a, catalyst, solvent with 10
W blue LEDs (452 nm) irradiation at room
temperature under argon atmosphere in pressure tube.
1
b)Yield determined by H NMR (internal standard:
methyl benzoate). c)Isolated yield, >20:1 α:γ, 16:1 E:Z.
d)Under air atmosphere. Acr+-Mes (9-mesityl-10-
methylacridinium perchlorate), nd = not detected.
Allyltrimethylsilanes are good precursors of
allylic radicals. They can be easily prepared from
allylic alcohols and stand out as the most atom
economic allylic radical surrogates among the
allylsilane family. We commenced the investigation of
the photoredox-catalyzed allylation by using n-pentyl-
We then proceeded to further optimize the reaction
conditions by using Fukuzumi acridinium salt as a
photocatalyst and surveyed the catalyst loading and
solvents (Table 1, entries 5–8, see SI for details);
however, no significant improvement in yield was
observed. We found 100% conversion of
allyltrimethylsilane 1a into the corresponding
allylation products and byproducts, the latter mixtures
of alkenes being generated by the protonation of the
allylic radical. Therefore, we changed the ratio of
allyltrimethylsilane 1a and benzalmalononitrile 2a
from 1:2 to 2:1 to improve the yield. Further test of
solvents and reaction time resulted in the 1:1 mixture
of MeOH and DCE with long reaction times providing
the best yield (Table 1, entry 10). However, the
reaction time of 60 h was inefficient. Upon increasing
the amount of 1a to 3 equiv, the reaction time
decreased dramatically to 32 h, with a modest increase
in yield (Table 1, entry 11). We performed a control
experiment in the absence of photocatalyst and light to
check the dependency of the reaction on both
parameters. In either case, the desired product was not
observed, which strongly indicates that the presence of
light and a photocatalyst is required for the reaction to
occur.
substituted
allyltrimethylsilane
1a
and
benzalmalononitrile 2a as model substrates in
MeOH:MeCN (1:1) under irradiation with 10 W blue
LEDs. The oxidation potential of allylsilane 1a was
measured by cyclic voltammetry (+1.39 V vs SCE in
MeCN). Therefore, photocatalysts having high
oxidation power were investigated in the initial study
(Table 1, entries 1–4). The desired allylation product
was obtained in 29% yield when using
Ir(dF(CF3)ppy)2(dtbpy)PF6 (Table 1, entry 3) and in
56% yield with Fukuzumi acridinium salt (Acr+-Mes)
(Table 1, entry 4). We found that the α-adduct (α:γ =
>20:1) and (E)-isomer was the major product. This
enhanced regioselectivity compared to Mizuno’s
allylation (α:γ = 5:1) is most likely due to mechanistic
differences. Thus, Mizuno’s group proposed a radical
coupling mechanism of allylic radicals with anion
radicals of benzalmalononitrile, whereas a radical
addition mechanism of allylic radicals to
benzalmalononitrile is more likely in our case.
2
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10.1002/adsc.202000445
Advanced Synthesis & Catalysis
Table 2. Substrate scope, gram-scale reaction, and dehomologation of the allylation producta
a)Reaction conditions: Table 1, entry 11, Isolated yield.
With the optimized conditions, we investigated
the scope of several arylidene and alkylidene
malononitriles (Table 2). Arylidene malononitriles
(2a–2n) bearing electron-withdrawing and electron-
donating substituents performed well in the reaction,
providing good to moderate yields with high
regioselectivities and stereoselectivities (α:γ = 9:1 ~
>50:1, E:Z = 7:1 ~ >50:1) (3a–n). A variety of
functional groups were tolerated in the arylidene
malononitrile substrates; methyl, tert-butyl, and
phenyl substitutions delivered good yields with
excellent regioselectivities and stereoselectivities (3b–
3d, α:γ = >20:1, E:Z = 10:1 ~ >50:1). Photolabile
halogen functional groups such as bromo, chloro (3e,
3f), and strong electron-withdrawing groups (3h–3i)
were well tolerated under the developed reaction
conditions and afforded good to excellent
regioselectivities and stereoselectivities. Allylation
with arylidene malononitriles containing ortho-, meta-,
and para-substituted methoxy functional groups
performed well, with the meta-methoxy-substituted
benzalmalononitrile producing the best result, whereas
ortho- and para-methoxy substituents gave moderate
yields and good selectivity. These results show that the
presence of an electron-donating group in ortho and
para position positions of arylidene malononitriles
decreases the reactivity. Arylidene malononitriles
containing disubstituted and trisubstituted arenes also
underwent the reaction, and gave the desired product
3
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10.1002/adsc.202000445
Advanced Synthesis & Catalysis
in moderate to good yields with exclusive formation of
the α-adduct. Moreover, alkylidene malononitriles
(2o–2r) reacted to provide the desired allylation
products in good yields and high regioselectivities
(3o–3r). In general, arylidene and alkylidene
malononitriles bearing bulky substituents showed
excellent regioselectivities. We next explored a variety
of allylsilanes (1b–1g) to evaluate the generality of the
allylation reaction. The allylation of various silanes
(1b–1g) with benzalmalononitrile 2a provided the
desired product with moderate to good yields and good
regioselectivities. Although allyltrimethylsilane 1b
has a high oxidation potential (E = 1.61 V vs. SCE),
Fukuzumi salt (Acr+-Mes), having an oxidation
potential E = 2.06 V vs SCE, was able to oxidize 1b to
generate the allylic radical. Methallyltrimethylsilane
1c was more efficient as an allyl radical source than
allyltrimethylsilane 1b, providing good yields. In
addition, we performed a gram-scale reaction of 1c
with 2a to investigate the possibility of a scale-up. The
scale-up reaction required high-power blue LEDs (40
W) and longer reaction times (72 h) and resulted in a
slight decrease in the yield of allylation product 3t.
The malononitrile group in 3t was transformed into
esters (4a, 4b) by oxidative dehomologation.[11a,14]
Cyclohexyl-substituted allylsilane 2d provided the
corresponding coupling product 3u with excellent
yield and regioselectivity. Phenyl- and benzyl-
protected alcohols in allylsilanes were tolerated in the
present reaction conditions. Unfortunately, we have
not been able to expand on allylation with less
activated alkenes such as acrylonitrile and methyl
acrylate under optimized conditions.
Because we considered that the occurrence of a
radical mechanism is important to achieve an α-
addition selective allylation, we decided to confirm
that allylsilanes were oxidized by the photocatalyst,
and that the allyl radical intermediates were produced
under the reaction conditions. We determined the
oxidation potential of allylsilanes by cyclic
voltammetry. The measured oxidation potential was
less than 1.6 V, which means that the excited
photocatalyst (Acr+-Mes*) can oxidize allylsilanes. In
addition, Stern–Volmer fluorescence quenching
experiments were conducted with allylsilane 1a and
benzalmalononitrile 2a. It was found that only
allylsilane 1a quenched the excited photocatalyst,
whereas benzalamalononitrile 2a did not (detailed in
SI). This result reveals that a SET mechanism between
allylsilane 1a and the photocatalyst occurs under blue
LEDs irradiation. We were able to isolate an allylic
radical–TEMPO complex (α:γ = ~1:1, E:Z = > 20:1)
in a radical trapping experiment using TEMPO. This
result provides strong evidence that the photocatalyzed
allylation involved an allylic radical intermediate
(Scheme 2 a).
Based on our control experiments and the
literature,[5,9] we propose the reaction mechanism
depicted in Scheme 2 b. Initially, the single-electron
oxidation of allylsilane 1a by excited Fukuzumi
acridium (Acr+-Mes*) generates an allylic cation
radical I, which is desilylated by a MeOH molecule to
produce allylic radical II. Substituted allylic radicals
are in equilibrium with (E)-isomer (E)-II and (Z)-
isomer (Z)-II, and (E)-II is the thermodynamically
predominant isomer.[15]
Scheme 2. Control experiments and proposed reaction mechanism
4
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10.1002/adsc.202000445
Advanced Synthesis & Catalysis
Gómez, F. Foubelo, Chem. Rev. 2011, 111, 7774-
7854; d) S. W. Kim, W. Zhang, M. J. Krische, Acc.
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The less hindered terminal position of (E)-II is then
added to benzalamalononitrile 2a to provide α-adduct
(E)-III as the major product. As minor products, α-
adduct (Z)-III and γ-adduct γ-III are generated from
(Z)-allylic radical (Z)-II, and by addition of allylic
radical II at the γ-position, respectively. Moreover,
allylic radicals II are converted into alkenes by the
proton source as byproducts, which were detected by
1H NMR spectroscopy. Adducts III are converted into
anion intermediate IV by single-electron reduction
from the reduced photocatalyst (Acr•-Mes), and the
photocatalyst is regenerated. Finally, the desired
product 3a is produced by the protonation of anion IV
by methanol. We confirmed the proton source by
performing an isotope labeling experiment using
deuterated methanol (CD3OD) (Scheme 2 a). In
addition, we performed on–off experiments and
determined quantum yield (Φ = 0.0077) to verify the
proposed mechanism (detailed in SI).[16]
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In conclusion, we have developed a visible-light
photoredox-catalyzed
regioselective
and
stereoselective allylation of activated alkenes. This
reaction proceeds under mild conditions, i.e., metal-
and additive-free photoredox catalysis at room
temperature and tolerates various functional groups.
Especially, this conjugate allylation provides high α-
regioselectivities and (E)-stereoselectivities and
moderate to good yields. The investigation of the
mechanism provides evidence for a photoinduced
allylic radical-mediated reaction mechanism. These
results present a new strategy for the α-allylation
reaction using allylsilanes.
Experimental Section
General procedure for conjugate addition of allylsilanes
1 to alkenes 2
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To a re-sealable pressure tube (13 × 100 mm) with a
magnetic stir bar was charged with 1 (0.6 mmol, 3.0 equiv),
2 (0.2 mmol, 1.0 equiv) and 9-mesityl-10-methylacridinium
perchlorate (Acr+-Mes) (0.82 mg, 0.002 mmol, 1.0 mol %)
under argon atmosphere. The reaction mixture was
dissolved by degassed methanol and DCE (1:1, 1 mL, 0.2 M
for 2). The mixture was irradiating with 2 × 5W blue LEDs
using our customized milligram scale reaction set up [as
shown in Figure S2 (a)] under constant stirring condition at
room temperature (20 ~ 30 o C) for 16 ~ 72 h. After finishing
the stipulated time, the solvent was removed under reduced
pressure and residue was purified by flash column
chromatography on silica gel to afford the corresponding
allylation product 3.
[10] a) T. P. Yoon, M. A. Ischay, J. N. Du, Nat. Chem.
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J. Xuan, W.-J. Xiao, Angew. Chem. Int. Ed. 2012, 51,
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M. Teders, L. Pitzer, F. Glorius, Chem. Soc. Rev.
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Acknowledgements
This work was supported by the National Research Foundation of
Korea (NRF-2019R1C1C1004015) grant funded by the Korea
government (MSIT).
[11] a) R. Zhou, H. Liu, H. Tao, X. Yu, J. Wu, Chem. Sci.
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Advanced Synthesis & Catalysis
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6
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10.1002/adsc.202000445
Advanced Synthesis & Catalysis
UPDATE
Visible-Light Photoredox-Catalyzed α-
Regioselective Conjugate Addition of Allyl Groups
to Activated Alkenes
Adv. Synth. Catal. Year, Volume, Page – Page
Arjun Gontalaa and Sang Kook Wooa,*
7
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