Chain propagation determines the chemo- And regioselectivity of alkyl radical additions to C-O: Vs. C-C double bonds

Article abstract of DOI:10.1039/c9sc04846d

Investigations into the selectivity of intermolecular alkyl radical additions to C-O- vs. C-C-double bonds in α,β-unsaturated carbonyl compounds are described. Therefore, a photoredox-initiated radical chain reaction is explored, where the activation of the carbonyl-group through an in situ generated Lewis acid-originating from the substrate-enables the formation of either C-O or the C-C-addition products. α,β-Unsaturated aldehydes form selectively 1,2-, while esters and ketones form the corresponding 1,4-addition products exclusively. Computational studies lead to reason that this chemo- and regioselectivity is determined by the consecutive step, i.e. an electron transfer, after reversible radical addition, which eventually propagates the radical chain.

Full text of DOI:10.1039/c9sc04846d

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DOI: 10.1039/C9SC04846D
ARTICLE
Chain propagation determines the chemo- and regioselectivity of
alkyl radical additions to C–O vs. C–C double bonds
b
Tiffany O. Paulisch,a† Felix Strieth-Kalthoff,a† Christian Henkel,b Lena Pitzer,a Dirk M. Guldi and
Received 00th January 20xx,
Accepted 00th January 20xx
Frank Glorius *a
DOI: 10.1039/x0xx00000x
Investigations into the selectivity of intermolecular alkyl radical additions to C–O- vs. C–C-double bonds in α,β-unsaturated
carbonyl compounds are described. Therefore, a photoredox-initiated radical chain reaction is explored, where the
activation of the carbonyl-group through an in situ generated Lewis-acid – originating from the substrate – enables the
formation of either C–O or the C–C-addition products. α,β-Unsaturated aldehydes form selectively 1,2-, while esters and
ketones form the corresponding 1,4-addition products exclusively. Computational studies lead to reason that this chemo-
and regioselectivity is determined by the consecutive step, i.e. an electron transfer, after reversible radical addition, which
eventually propargates the radical chain.
as pyridine often yields a mixture of 2- and 4-substitution. In
such systems, as well as e. g. for benzene rings or asymmetrical
dienes, it remains challenging to predict the site selectivity of
Introduction
Radical chemistry has been investigated for decades and, owing
to the high reactivity of open-shell species, represents a
complementary approach to classical closed-shell chemistry
towards the synthesis of organic molecules.1 Considering that
the selectivity of radical reactions is essential for targeted
synthesis,2 numerous attempts to control these highly reactive
intermediates have been made.3 Especially recent advances in
controlled radical generation by means of photoredox catalysis
have further expanded the field of selective radical reactions.4
Owing to their high reactivity, radicals usually undergo only low
activation barrier pathways. Selective radical reactions are
therefore often enabled by rapid, innate chains (usually
requiring fast and exothermic steps) or efficient
transformations to long-lived (non-radical) intermediates (i. e.
radical-polar crossover). To enable efficient chains, a polarity
match of radical and reaction partner has to be given, otherwise
non-productive side reactions with lower activation barriers will
be the preferred pathways for these “impatient”
intermediates.5
the radical addition of a given radical. (see Figure 1).8
Radical additions to different extended -systems 8
OMe
S
N
N
Modes of selectivity control
Electron transfer (This work)
Radical addition (Common)
selective
x
electron
transfer
x


reversible addition
+
irreversible consecutive step
irreversible addition
This work
[Si]
[Si]
Amongst the elementary steps within radical chain reactions,
radical additions to different π-bonds,6 which represent an
efficient means to C–C bond formation, are quite well
understood. 7 In principle, selectivity in radical additions for two
competitive reaction steps is determined by the difference in
activation barriers: This kinetic control is usually governed by a
k1
O
O
(1,4)
R
X
R
X
[Si]
O
if k1  k2
R
X
[Si]
X
[Si]
O
O
k2
(1,2)
X
R
R
polarity match between an electrophilc radical and
a
if k1  k2
nucleophilc double bond, or vice versa. It is, however, rather
challenging to control such a selectivity, when multiple addition
sites with matching polarity and, in turn, similarly low barriers
are available. As an example, the classical Minisci-type addition
of nucleophilic radicals to electron-deficient heterocycles such
Figure 1: Radical additions to π-systems with indication where the addition can
take place. Selectivity of product formation governed in the radical addition or a
consecutive electron transfer step. This work: Radical addition to α,β-unsaturated
carbonyls shows 1,4- (blue) for R = OMe, Me and 1,2-(red) addition product for R
= H. k: rate constant.
a. Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut,
Corrensstraße 40, 48149 Münster, Germany.
b. Friedrich-Alexander-Universität Erlangen-Nürnberg, Departement of Chemistry
and Pharmacy, Egerlandstraße 3, 91058 Erlangen, Germany
† These authors contributed equally.
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ARTICLE
Journal Name
A Reaction conditions
View Article Online
DOI: 10.1039/C9SC04846D
OSiMe3
O
O
R
O
OH
1) [Ir(dF-CF3-ppy)2(dtbpy)]PF6 (PC-1, 1.0 mol%)
O
+
MeO
MeO
R
MeO
MeCN (0.1 M), h (455 nm, 5 W), 16 h
R
2) TBAF or water
1
2
3
4
or
B Proposed reaction mechanism
C Mechanistic studies


Stern-Volmer luminescence quenching
OSiMe3
MeO
O
 1 as only quenching component
R
ns-TAS
2
1
E1calc= +0.46 V vs. SCE
[IrIII]*
O
SiMe3
R
OSiMe3
O
kET = (1.25 ± 0.02) × 109 L mol-1 s-1
Photo
+
MeO
initiation
MeO
[IrIII
]
[IrII]
Radical chain
(Hole catalysis)
A
B
C
D
 = 15.6

Control reactions
O
OSiMe3
R
R
OSiMe3
O
R = OMe R = Me R = H
MeO
MeO
as above
no PC
(1,4)
(1,4)
(1,2)
O
OSiMe3
–
–
–
–
–
–
MeO
R
E3
E4
or
no hv
D3
add. of TMSOTf
–
(1,4)
(1,4)
H2O or
TBAF
or
1

TEMPO trapping
R
OSiMe3
O
O
O
O
MeO
OMe
MeO
MeO
O
O
R
OH
O
TEMPO
TEMPO
D4
MeO
R
MeO


Deuterium incorporation experiments
DFT calculations of redox potentials
ED calc= +0.96 – +1.63 V vs. SCE
3
4
or
Figure 2: A) Reaction conditions: Silyl ketene acetal 1, Michael acceptor 2, PC-1, MeCN, 455 nm LEDs, workup with H2O or TBAF. B) Proposed reaction mechanism for
the reaction of silyl ketene acetals 1 with Michael acceptors 2 in a 1,2- or 1,4-fashion. C) Stern-Volmer luminescence quenching studies and ns-transient absorption
spectroscopy suggest a reductive quenching by silyl ketene acetal 1. Control reactions investigating a competing Lewis-acid catalysed pathway. TEMPO trapping
experiments hint towards the presence of intermediary radical species. Deuterium incorporation experiments exclude HAT from solvent molecules. DFT-computed
redox potentials substantiate the proposed chain propagation steps.
Building on our recent study on the radical addition to
carbonyls, in which aromatic aldehydes and ketones act as
radical acceptors for alkyl radicals under BrØnsted acid
Results and discussion
activation, we investigated the selectivity of the radical addition
to the C–O vs. C–C double bond in Michael acceptors.9
To investigate the selectivity of the radical addition to C–O vs.
C–C double bonds, Michael acceptors were chosen as radical
acceptors. To enable an overall redox-neutral transformation,
silyl ketene acetals were applied as radical precursors. In
combination with an oxidizing photoredox catalyst, these
substrates form amphiphilic alkyl radicals12 after single electron
oxidation, which subsequently can add to π-bonds.
Irradiating silyl ketene acetal 1 in the presence of the
photocatalyst [Ir(dF-CF3-ppy)2(dtbpy)]PF6 (PC-1) and different
Michael acceptors 2, an unexpected chemoselectivity switch
was observed: Whereas the addition to α,β-unsaturated esters
and ketones afforded the Giese-type 1,4-addition product, the
reaction of α,β-unsaturated aldehydes selectively formed allylic
alcohols as products of a formal 1,2-addition. To rationalize this
switch in reactivity, experimental and computational
mechanistic analyses were conducted.
In these systems (see Figure 1), which exhibit two electrophilic
addition sites, perfect regio- and chemoselectivity of alkyl
radical additions was observed. We hypothesized that this
selectivity is not determined by the addition itself, but by the
consecutive electron transfer. Interestingly, this concept of
radical selectivity control through consecutive steps has only
been rarely applied, e. g. for controlling a radical metalation
through a consecutive favoured/disfavoured cyclization,10 or to
direct a reversible radical cyclization by selective radical-polar
crossover.11 To the best of our knowledge, using electron
transfer steps for controlling the selectivity of radical chain
reactions has remained, to this date, elusive.
2 | J. Name., 2012, 00, 1-3
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M
echanistic Studies
to the Lewis-acid activated α,β-unsaturated carbonyl C to yield
View Article Online
DOI: 10.1039/C9SC04846D
As a first model system the reaction between trimethyl silyl radical cation D.16 Intermediate D is readily reduced by the
ketene acetal (1a) and methyl acrylate (2a) was investigated in excess of silyl ketene acetal 1,17 which closes the radical chain
detail. In the absence of either light or photocatalyst, no cycle and yields intermediate E. Removal of the trimethylsilyl
product was detected, which corroborates a photochemical group by aqueous or fluoride workup leads to the final product.
reaction pathway. In steady-state absorption measurements, Additional support for such a reaction mechanism came from
the photocatalyst was confirmed to be the only visible-light- further mechanistic experiments (see SI for further details):
absorbing component in the reaction mixture. Stern-Volmer Upon addition of TEMPO to the reaction mixture, TEMPO
analysis and nanosecond-transient absorption spectroscopy adducts of intermediates B and D could be detected, while
(ns-TAS) suggest an effective quenching of the electronically intermediate
E was identified by means of ESI-MS.
exited state of PC-1 by silyl ketene acetal 1. Upon irradiation Furthermore, experiments using deuterated reaction solvent
PC-1 gives rise to a MLCT triplet state featuring a 2.49 ± 0.06 μs excluded the possibility of a hydrogen atom transfer (HAT)
lifetime. In ns-TAS experiments, the latter is effectively event from a solvent molecule. Overall, the thermodynamic
quenched when silyl ketene acetal 1 is added and gives rise to feasibility of the chain propagation step was supported by the
newly developing transient absorption features. A comparison calculated redox potentials, which underline that oxidation of
with the spectro-electrochemical measurements (see SI for silyl ketene acetal 1 by intermediate D is feasible (E1= +0.46 V
further details) infers the reduction of PC-1 to afford PC-1•-.13 vs. SCE, ED= +0.96 V vs SCE).18
The underlying electron transfer from the silyl ketene acetal 1 For α,β-unsaturated aldehydes the observed 1,2-addition can
to photoexcited catalyst PC-1 occurs with diffusion-controlled be rationalized by an analogous hole catalysis mechanism (ED=
dynamics: kET = (1.25 ± 0.02) 109 L mol−1 s−1. A high quantum +1.63 V vs. SCE). Here, photocatalyst and light are required for
yield (φ = 15.6) suggests that this quenching step initiates an the reaction to proceed as well. Notably, the addition of
efficient chain reaction.14 Considering that the addition of TMSOTf (without irradiation) leads to exclusive formation of the
TMSOTf (without irradiation) did not lead to product formation 1,4-addition product. Since no 1,2-addition product was
a
radical pathway rather than
a
Lewis-acid mediated observed under these Lewis-acid conditions, a radical pathway
rather than a Lewis-acid mediated mechanism is likely to be
mechanism is likely to be operative.
With these results in hand, we propose the following general operative under the standard reaction conditions. For α,β-
mechanism (see Figure 2): Silyl ketene acetal 1 is oxidized by unsaturated ketones, however,
a competing Lewis-acid
photocatalyst PC-1. The resulting radical cation A then mediated chain reaction could not be fully excluded.19
fragments to the respective α-carbonyl radical B,15 which adds
B
1,2 vs. 1,4-Addition to -unsaturated esters
A
1,2 vs. 1,4-Addition to -unsaturated aldehydes
 G [kcal mol-1
]
G [kcal mol-1
]

(45.6)
TMS
O
Ph
MeO2
H
C
(35.3)
(13.7)
(7.7)
(12.2)
TS C-D4
(9.1)
(29.4)
(27.9)
MeO2
C
TMS
OMe
O
(5.1)
O
(3.9)
(1.9)
TMS
H
Ph
TMS
Ph
O
(21.0)
(0.0)
TS C-D3
O
H
TS C-D3
Ph
MeO2
H
Ph
C
(12.4)
O
MeO2
C
TMS
OMe
(8.4)
Ph
TMS
OMe
(-14.5)
(7.1)
(1.0)
O
Ph
(-19.2)
O
TS C-D4
TMS
H
(0.0)
MeO2
C
TMS
OMe
O
O
Ph
MeO2
Ph
OMe
Ph
C
MeO2C
MeO2C
TMS+
e-
e-
TMS+
C
D
2
E
C
D
2
E
Radical
addition
Electron
transfer
Radical
addition
Electron
transfer
Figure 3: A) 1,2-(red) vs. 1,4-(grey) radical addition to α,β-unsaturated aldehydes B) 1,2-(grey) vs. 1,4-(blue) radical addition to α,β-unsaturated esters and the
subsequent electron transfer step towards product E. Calculated for cinnamaldehyde and methyl cinnamate with trimethyl silyl ketene acetal (B3LYP-D3 / def2-
TZVPP / CPCM(MeCN)).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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To understand the difference in behaviour of α,β-unsaturated is the selectivity determining step, which accountVsiefwoArrttichleeO1n,li2ne-
aldehydes and esters, a computational analysis of the proposed over 1,4-preference. This conclusion is iDnOaI:g1r0e.1e0m39e/nCt9SwCi0t4h84th6De
radical chain processes was conducted. Density functional computed redox potentials, since the 1,2-addition product (ED =
theory calculations were performed at the B3LYP-D3 / def2- +1.63 V vs. SCE) shows a higher oxidation potential than the 1,4-
TZVPP / CPCM(MeCN) level. Activation barriers for the electron addition product (ED = +1.21 V vs. SCE) and therefore undergoes
transfer steps were estimated using the four-point a faster electron transfer.
approximation to Marcus-Hush theory (see SI for further For α,β-unsaturated esters, a different selectivity is observed
details).20 Although not widely established, this method was (see Figure 3B). Here, a rather high activation barrier is
applied to different cases in organic chemistry to estimate calculated for the 1,2-radical addition (ΔG‡ = 26.9 kcal mol-1),
electron transfer barriers.21 Therefore, we believe that this which renders the reaction less favourable compared to the 1,4-
methodology should result in reasonable estimation to the addition product (ΔG‡ = 12.6 kcal mol-1). Furthermore, the
electron transfer activation barrier (see Figure 3).
lower activation barrier of the electron transfer for the 1,4-
For α,β-unsaturated aldehydes (see Figure 3A), a highly addition product compared to the 1,2-addition product,
oxidizing radical cation D4 can be formed via a reversible radical additionally accounts for the selectivity towards the 1,4-
C–O addition, which can undergo a fast electron transfer as addition. We reason that also here the observed selectivity is
consecutive reaction. Crucial for the selectivity is the electron determined by the final chain-propagating electron transfer
transfer barrier, which is seemingly lower for the 1,2-addition step. Both computed reaction profiles are in good agreement
product (ΔG‡ = 3.8 kcal mol-1) than for the respective 1,4- with the experimental observation and support our hypothesis
addition product (ΔG‡ = 11.8 kcal mol-1). As such, we propose of selectivity control through the consecutive step.22
that, in a Curtin-Hammett-type scenario, the electron transfer
Reaction scope
OSiMe3
O
O
O
R
OH
PC-1
( , 1.0 mol%)
1) [Ir(dF-CF3-ppy)2(dtbpy)]PF6
O
+
or
MeO
MeO
R
MeO
R
MeCN (0.1 M), h (455 nm, 5 W), 16 h
2) TBAF or water
1
2
3
4
Esters
O
O
O
O
O
O
O
O
O
O
O
O
MeO
O
OtBu
MeO
EtO
OMe
OMe
MeO
MeO
OMe
OMe
MeO
OMe
OMe
MeO
F
a3a,
a3b
a3c
a3d
a3e
, 93%
81%
, 92%
, 72%
, 41%
O
O
O
O
O
O
O
R
MeO
OMe
MeO
O
O
N
MeO
OEt
OMe
3k
R = H, , 57%
b3g
b3f
, 85%
b3h
b3i
, 48%
, 75%
, 75%
3l
R = m-CF3, , 58%
Ketones
OMe
CF3
O
O
O
O
O
O
O
O
O
O
O
MeO
MeO
MeO
MeO
MeO
MeO
MeO
c3m
a,c3n
c3o
, 58%
c3p, 44%
c3q, 43%
, 90%
, 93%
Aldehydes
O
OH
O
OH
O
OH
O
OH
O
OH
MeO
MeO
MeO
Ph
MeO
C5H11
R
4d
R = p-Me, , 65%
4e
R = p-F, , 70%
4g
, 48%
OH
4a
4b
, 90%
4c
, 65%
, 92%
OH
4f
R = p-Cl, , 45%
O
OH
O
OH
O
O
OH OMe
O
MeO
MeO
MeO
MeO
Ph
O
COOMe
c4h
c4i
c4k
c4l
c4m
, 65%
, 79%
, 93%
, 91%
, 46%
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Figure 4: Scope of the 1,4-radical addition to α,β-unsaturated esters and ketones and the 1,2-radical addition to aldehydes. Standard conditions: Michael acceptor (2, 0.4 mmol),
View Article Online
DOI: 10.1039/C9SC04846D
silyl ketene acetal (1, 0.6 mmol), PC-1 (0.004 mmol), MeCN (0.1 M), 16 h, 455 nm LEDs, workup with TBAF. a) Workup with aq. HCl, 0.5 mmol scale, 1 (3.0 equiv.). b) Pre-formation
of 1 without purification and subsequent coupling, 0.5 mmol scale. c) Addition of TMSOTf (in the absence of light) showed product formation.
Reaction Scope
We thank Frederik Sandfort, Dr. Eloisa Serrano and Dr. Michael
With these mechanistic insights in hand, we sought to James for helpful discussions. Financial support by Deutsche
investigate the applicability of this protocol to functionalize Forschungsgemeinschaft (SPP2102; FSK, CH) is gratefully
aldehydes in 1,2- as well as esters and ketones in 1,4-fashion. acknowledged.
The reaction was applied to several different silyl ketene acetals
and Michael acceptors. As standard conditions, a solution of
Michael acceptor 2 (1 eq.), silyl ketene acetal 1 (1.5 eq.) and
Notes and references
PC-1 (1 mol%) in MeCN (0.1 M) was irradiated with 455 nm LEDs
for 16 h (see Figure 4).
1
a) D. P. Curran, Synthesis, 1988, 6, 417; b) D. P. Curran,
Synthesis, 1988, 7, 489; c) B. Giese, Angew. Chem. Int. Ed.
Engl., 1985, 24, 553.
Applying these conditions, esters and ketones showed high
regio- and chemoselectivity towards the 1,4-addition product.
Substituents at the α-position (3b, 3c) and alkene functionalities
(3d) in the acceptor were well tolerated. Furthermore, diverse
secondary and tertiary silyl ketene acetals could be applied (3g-
i). For α,β-unsaturated ketones, 1,4-addition could be observed
exclusively, although full conversion could not be achieved in all
cases. This reaction was shown to be applicable for the
functionalization of cyclopentenone (3m) and chromone (3n) in
high yields. 4-Phenylbutenones (3o-r) could also be applied
leading to decent yields. Employed α,β-unsaturated aldehydes
could be functionalized with exclusive selectivity for the 1,2-
addition product. Aliphatic α,β-unsaturated aldehydes
underwent the transformation in good yields (4a-b). Moreover,
cinnamaldehydes with different substituents in the aromatic
ring and in α-position (4c-g) could be transformed in decent
yields. The same reaction conditions could be applied to
benzaldehydes (4h-l) in synthetically useful yields, while
tolerating double bonds or esters in the side chains.
2
3
a) B. M. Trost, Science, 1983, 219, 245; b) B. Giese, Angew.
Chem. Int. Ed. Engl., 1983, 22, 753.
a) S. Zhu, A. Das, L. Bui, H. Zhou, D. P. Curran, M. Rueping, J.
Am. Chem. Soc., 2013, 135, 1823; b) X. Liu, X. Ye, F. Bureš, H.
Liu, Z. Jiang, Angew. Chem. Int. Ed., 2015, 54, 11443; c) C.
Zhang, S. Li, F. Bureš, R. Lee, X. Ye, Z. Jiang, ACS Catal., 2016,
6, 6853; d) C. Yu, N. Iqbal, S. Park, E. J. Cho, Chem. Commun.,
2014, 50, 12884.
a) A. Albini, S. Protti, Photochemistry, Royal Society of
Chemistry, Cambridge, 2019; b) M. Silvi, C. Verrier, Y. P. Rey,
L. Buzzetti, P. Melchiorre, Nat. Chem., 2017, 9, 868; c) D. A.
Nicewicz, D. W. C. MacMillan, Science, 2008, 322, 77.
A. Studer, D. P. Curran, Angew. Chem. Int. Ed., 2016, 55, 58.
a) S. Wilsey, P. Dowd, K. N. Houk, J. Org. Chem., 1999, 64,
8801; b) L. Hernández-García, L. Quintero, M. Sánchez, F.
Sartillo-Piscil, J. Org. Chem., 2007, 72, 8196; c) J. Hartung, T.
Gottwald, K. Špehar, Synthesis, 2002, 11, 1469; d) G. Fuller, F.
F. Rust, J. Am. Chem. Soc., 1958, 80, 6148; e) H. Miyabe, M.
Ueda, T. Naito, Synlett, 2004, 7, 1140; f) G. K. Friestad,
Tetrahedron, 2001, 57, 5461; g) A. G. Fallis, I. M. Brinza,
Tetrahedron, 1997, 53, 17543; h) P. Devin, L. Fensterbank, M.
Malacria, Tetrahedron Lett., 1999, 40, 5511.
4
5
6
7
8
a) J. M. Tedder, J. C. Walton, Acc. Chem. Res., 1976, 9, 183; b)
F. De Vleeschouwer, P. Jaque, P. Geerlings, A. Toro-Labbé, F.
De Proft, J. Org. Chem., 2010, 75, 4964; c) H. Fischer, L.
Radom, Angew. Chem. Int. Ed., 2001, 40, 1340; d) B. Giese,
Angew. Chem. Int. Ed. Engl., 1983, 22, 753.
Conclusions
With this method, a radical alternative to the well-studied ionic
Mukaiyama-Michael/Aldol-reaction was developed.23 This
variant does not require any external Lewis-acid, allowing for
good functional group tolerance and for the generation of
quaternary carbon centers under mild reaction conditions. α,β-
Unsaturated esters and ketones show a high selectivity towards
the 1,4-addition products, while α,β-unsaturated aldehydes
form the 1,2-addition product exclusively. Computational
studies suggest that the high regio- and chemoselectivity of the
reaction is not determined by the radical addition itself, but by
the subsequent electron transfer step, which propagates the
radical chain. The control of regioselectivity of radical additions
a) Minisci, F., Galli, R., Cecere, M., Malatesta, V., Caronna, T.,
Tetrahedron Lett., 1968, 54, 5609; b) Gardini, G. P., Minisci, F.,
Ann. Chim. (Rome), 1970, 60, 746; c) Minisci, F., Galli, R.,
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through
a
consecutive step represents
a
previously
9
underestimated strategy which shows potential for further
reaction design towards switchable selective radical additions.
10 a) S. Mondal, R. K. Mohamed, M. Manoharan, H. Phan, I. V.
Alabugin, Org. Lett., 2013, 15, 5650; b) R. K. Mohamed, S.
Mondal, B. Gold, C. J. Evoniuk, T. Banerjee, K. Hanson, I. V.
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Conflicts of interest
There are no conflicts to declare.
11 A. Gansäuer, T. Lauterbach, D. Geich-Gimbel, Chem. Eur. J.,
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12 B. Giese, J. He, W. Mehl, Chem. Ber., 1988, 121, 2063.
Acknowledgements
This journal is © The Royal Society of Chemistry 20xx
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Chemical Science
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ARTICLE
Journal Name
13 D. M. Arias-Rotondo, J. K. McCusker, Chem. Soc. Rev., 2016,
45, 5803.
14 M. A. Cismesia, T. P. Yoon, Chem. Sci., 2015, 6, 5426.
15 The fragmentation of A can facilitate oxidation of the silyl
ketene acetal through equilibrium shift, see: M. A. Syroeshkin,
1,4-addition product formation, so that twVoiewcAormticlpeeOtnilninge
mechanisms are likely to be operative.
DOI: 10.1039/C9SC04846D
20 a) R. A. Marcus, Rev. Mod. Phys., 1993, 65, 599; b) O. López-
Estrada, H. G. Laguna, C. Barrueta-Flores, C. Amador-Bedolla,
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2017, 30, e3744.
16 DFT studies show that a radical addition to the Lewis-acid
activated α,β-unsaturated carbonyl (C) is kinetically and
thermodynamically more favored compared to the direct
addition to 1 (see SI for more detail).
17 Within the course of the chain propargation, radical cation A
is converted to radical cation D, which is a stronger oxidant
then A. In the context of Alabugin’s recent work, this could be
described as upconversion of an oxidant, see: M. A.
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22 It is important to consider that a certain amount of product
can be formed through the re-oxidation of the photocatalyst.
However, a quantum yield of 15.6 suggests an efficient chain,
the major amount of product should be formed through the
described hole catalytic cycle.
Syroeshkin, F. Kuriakose, E. A. Saverina, V. A. Timofeeva, M. P. 23 a) T. Mukaiyama, K. Narasaka, K. Banno, Chem. Lett., 1973, 2,
Egorov, I. V. Alabugin, Angew. Chem. Int. Ed., 2019, 58, 5532.
18 H. G. Roth, N. A. Romero, D. A. Nicewicz, Synlett, 2016, 27,
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19 Analogous to α,β-unsaturated aldehydes and esters, the hole
catalysis cycle is thermodynamically feasible for α,β-
unsaturated ketones (ED= +1.08 V vs. SCE). However, the
addition of TMSOTf in the absence of light led to significant
6 | J. Name., 2012, 00, 1-3
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Chemical Science
View Article Online
DOI: 10.1039/C9SC04846D
Reversible radical addition followed by an irreversible electron transfer leads to regio- and
chemoselective control of radical additions to π-systems
O
reversible
radical addition
X
O[Si]
O[Si]
X
or
Selectivity
R
[Si]
X
R
1,2-Addition
via
R
1,4-Addition
electron transfer
 photoredox initiated hole-catalysis
 in situ activation by Lewis acid
 chemo- & regioselective
determines 1,4 vs. 1,2 selectivity