Polarity-Reversed Allylations of Aldehydes, Ketones, and Imines Enabled by Hantzsch Ester in Photoredox Catalysis

Article abstract of DOI:10.1002/anie.201607813

The polarity reversal (umpolung) reaction is an invaluable tool for reversing the chemical reactivity of carbonyl and iminyl groups, which subsequent cross-coupling reactions to form C?C bonds offers a unique perspective in synthetic planning and implementation. Reported herein is the first visible-light-induced polarity-reversed allylation and intermolecular Michael addition reaction of aldehydes, ketones, and imines. This chemoselective reaction has broad substrate scope and the engagement of alkyl imines is reported for the first time. The mechanistic investigations indicate the formation of ketyl (or α-aminoalkyl) radicals from single-electron reduction, where the Hantzsch ester is crucial as the electron/proton donor and the activator.

Full text of DOI:10.1002/anie.201607813

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201607813
German Edition: DOI: 10.1002/ange.201607813
Photochemistry
Polarity-Reversed Allylations of Aldehydes, Ketones, and Imines
Enabled by Hantzsch Ester in Photoredox Catalysis
Li Qi and Yiyun Chen*
Abstract: The polarity reversal (umpolung) reaction is an
invaluable tool for reversing the chemical reactivity of
carbonyl and iminyl groups, which subsequent cross-coupling
reactions to form CÀC bonds offers a unique perspective in
widely used, these reductants are water- or air-sensitive, and
are incompatible with many sensitive functional groups,
which limits their use in increasingly demanding modern
[4]
organic synthesis and chemical biology studies. Recently,
the generation of either ketyl or a-aminoalkyl radicals by
photoredox catalysis under mild reaction conditions has been
synthetic planning and implementation. Reported herein is the
first visible-light-induced polarity-reversed allylation and
intermolecular Michael addition reaction of aldehydes,
ketones, and imines. This chemoselective reaction has broad
substrate scope and the engagement of alkyl imines is reported
for the first time. The mechanistic investigations indicate the
formation of ketyl (or a-aminoalkyl) radicals from single-
electron reduction, where the Hantzsch ester is crucial as the
electron/proton donor and the activator.
[
5,6]
reported.
However, current applications of visible-light-
induced ketyl or a-aminoalkyl radicals in intermolecular
cross-coupling reactions are limited to radical–radical cou-
pling reactions, and their use in intermolecular radical
[
5,6]
addition reactions is unknown.
In addition, the reduc-
tion-resistant alkyl imines (alkyl aldehydes derived imines,
0
E
< À3.0 V vs. SCE in MeCN) do not react under current
[7]
1
/2
photoredox methods (Scheme 1b).
T
he carbon–heteroatom double bond (such as the carbonyl
Homoallylic alcohols and amines are pivotal building
blocks in organic synthesis, and their traditional syntheses rely
on nucleophilic allylations. In contrast, the polarity-reversed
or the iminyl group) is a valuable synthon for building new
[1]
[8]
carbon–carbon bonds by additive cross-coupling reactions.
As both the carbonyl and iminyl groups are polarized and
electrophilic, they can easily undergo nucleophilic addition
reactions to construct b-functionalized alcohols and amines,
allylation of aldehydes, ketones, and imines using ketyl (or a-
aminoalkyl) radical is unknown, which would introduce
a unique perspective in retrosynthetic analysis and imple-
mentations. Herein we report the first visible-light-induced
polarity-reversed allylation and intermolecular Michael addi-
tion reactions of aldehydes, ketones, and imines, and it is also
applicable to alkyl imines for the first time.
[2]
respectively (Scheme 1a). In contrast, its engagement as the
nucleophilic equivalent (the ketyl or the a-aminoalkyl
radical) requires the use of strong reductants, such as an
[
3]
alkali metal, or titanium and samarium reagents. While
We started our investigation with the readily available p-
methylbenzaldehyde (1) and the allyl sulfone 2 as substrates.
0
II/I
Using [Ru(bpy) ](PF ) (E
= À1.33 V vs. SCE in MeCN )
under blue LED (lmax = 468 Æ 25 nm) irradiation, the
homoallylic alcohol 3 was obtained in 63% yield with the
3
6
2
1/2
[
9]
[
10]
Hantzsch ester as a reductant (Table 1, entry 1). The use of
the iridium-based photocatalyst [Ir(dtbbpy)(ppy) ]PF
2
6
0
III/II
(E
= À1.51 V vs. SCE in MeCN) accelerates the reac-
1
/2
[11]
tion to three hours with 80% yield (entry 2). The addition
of diisopropylethylamine further improves the reaction to
9
0% yield (entry 3). However, the use of diisopropylethyl-
amine alone yields the allylation adduct 3 in merely 28%
yield (entry 4). Notably, the addition of water or exposure to
[
3]
air does not affect the reaction (entries 5 and 6). The
photocatalyst, light, and reductants are all critical for the
reaction (entries 7–9).
Scheme 1. Nucleophilic and polarity-reversed allylation.
We further explored the mechanism of this novel polarity-
reversed allylation. The luminescence quenching experiments
indicate that either the diisopropylethylamine or the
[*] L. Qi, Prof. Dr. Y. Chen
Hantzsch ester quenches the photoexcited [Ir(dtbbpy)-
State Key Laboratory of Bioorganic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences
[12]
(
ppy) ]PF effectively, while both 1 and 2 are ineffective.
2 6
In the absence of 2, the pinacol-coupling adduct 5 (dl/meso =
.5:1) is obtained from the aldehyde 4 in 83% yield
(Scheme 2a). In contrast, in the absence of 1, little conversion
1
345 Lingling Road, Shanghai 200032 (China)
E-mail: yiyunchen@sioc.ac.cn
[
12]
of 2 was observed. These results collectively suggest the
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201607813.
formation of ketyl radicals in the photoredox reaction.
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Table 1: Optimization of the aldehyde allylation reaction.
reaction compared to the reaction without additives
squares), and the base (sodium carbonate; circles) deceler-
(
ates the reaction. While it is unclear at this point how the
Hantzsch ester activates the aldehyde, the Hantzsch ester
radical cation formed during the oxidation might activate the
aldehyde by the proton-coupled electron-transfer (PCET)
[
a]
[b]
[b]
[5,6,14]
Entry Reaction conditions
t [h] Conv. [%] Yield [%]
mechanism.
Based on mechanistic investigations above, we propose
1
2
3
4
5
6
7
8
9
[Ru(bpy) ](PF ) , HE
24
3
3
3
3
3
3
3
24
>95
>95
>95
30
>95
>95
<5
63
80 (73)
90 (84)
28
99
91
0
0
0
3
6 2
III
that [Ir(dtbbpy)(ppy) ]PF6 is photoexcited to Ir * and
[Ir(dtbbpy)(ppy) ]PF , HE
2
2
6
II
[Ir(dtbbpy)(ppy)
2
]PF
6
, HE, iPr
2
NEt
reduced by the Hantzsch ester to Ir (Scheme 3). The
resulting Ir intermediate reduces the aldehydes by single-
II
[Ir(dtbbpy)(ppy) ]PF , iPr NEt
2
6
2
entry 3, CH CN/H O
3
2
electron transfer with the activation from the Hantzsch ester
entry 3, air
[14]
radical cation. With the proton transfer from the Hantzsch
entry 3, no HE/iPr NEt
2
ester radical cation, the hydroxymethyl radical then adds
either to the allyl sulfone to obtain the homoallylic alcohol or
to the Michael acceptor to obtain the Michael addition
entry 3, no hn
entry 3, no [Ir]
<5
<5
[
(
(
a] Reaction conditions: 1 (0.10 mmol), 2 (0.30 mmol), photocatalyst
0.001 mmol), Hantzsch ester (HE, 0.15 mmol), and iPr NEt
0.20 mmol) in 1.0 mL dichloromethane under nitrogen with 468 nm
LED irradiation. [b] Conversions and yields were determined by H NMR
analysis. Yields of isolated products given within parentheses.
dtbbpy=4,4’-di-tert-butyl-2,2’-bipyridine, ppy=2-phenylpyridine.
[15]
adduct. In the photoredox system, the Hantzsch ester is
2
crucial as electron/proton donor, and also serves to activate
the aldehydes.
1
Scheme 3. Mechanistic proposal of the polarity-reversed allylation
reaction. EWG=electron-withdrawing group.
With the mild polarity-reversal reaction conditions in
[
16]
hand (entry 3 in Table 1), we explored the substrate scope
with respect to the aldehydes and ketones. Halogen substitu-
ents on the benzaldehydes did not affect the reaction, and
delivered the chloro- and bromo-substituted homoallylic
alcohols 6 and 7, respectively, in 72% yield (Scheme 4). The
bulky mesityl- and naphthyl-substituted aldehydes reacted
Scheme 2. Mechanistic investigations of the polarity-reversed allylation
reaction.
However, it is puzzling how the electron transfer occurs with
aldehydes. With the very low aldehyde reduction potentials
0
[13]
(E
= À2.28 V vs. SCE in MeCN for 1),
neither the
1
/2
0
IV/III*
photoexcited [Ir(dtbbpy)(ppy) ]PF
(III)* (E
1/2
=
2
6
À0.96 V vs. SCE in MeCN) nor the reductive [Ir(dtbbpy)-
0
III/II
(
ppy) ]PF (II) (E
1/2
= À1.51 V vs. SCE in MeCN) is
2
6
[11]
suitable for reduction.
Previous reports of visible-light-
induced ketyl radical formation uses Lewis acids or in situ
generated acids to facilitate the electron transfer, and those
reactions are enhanced by the addition of acids and inhibited
[
5,6]
by the addition of bases.
experiments with only the Hantzsch ester as a reductant
Scheme 2b). The acid (acetic acid; triangles) accelerates the
We then did the acid/base doping
Scheme 4. Substrate scope with respect to aldehydes and ketones.
Reaction conditions are those detailed in entry 3 of Table 1. Yield is
that of isolated product.
(
2
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smoothly to deliver 8 (75%) and 9 (73%), respectively.
Heterocycles are well tolerated to give the furan- and
thiophene-containing homoallylic alcohols 10 (65%) and 11
(
72%), respectively. This reaction works with arylketones to
give the homoallylic tertiary alcohols 12 (92%) and 13 (73%),
in which the allylic ether group is not affected. Ester- and
amide-substituted ketones selectively yielded the ketone
allylation adducts 14 and 15, respectively, without affecting
[
17]
Scheme 6. Three-component reaction of alkyl imines.
either the ester or the amide group. The ketyl radical can
engage in radical additions other than allylation as indicated
by the Michael addition adduct 16, which is effectively
obtained in 93% yield by reaction with vinyl sulfones.
We next tested the aryl imines in our reaction conditions,
as they were less studied in polarity reversal reactions because
isobutylaldehyde (30) and 4-tert-butylaniline (31) together
with 2 under the photoredox reaction conditions, and the
homoallylic amine 32 was obtained in 61% yield from the
[
1c,6]
[18]
of the low reactivity.
With the 4-tertbutylaniline-derived
three-component reaction.
The cyclopropyl-substituted
aryl imine, various substitutions including the methyl,
methoxy, and diethylamino, as well as the bromo group all
react well to give 17–20 in 53–91% yields (Scheme 5). The
aldehyde reacts without ring opening to give the homoallylic
[19]
amine 33 in 83% yield.
Isobutyl- or pentyl-substituted
aldehydes also reacted smoothly to yield 34 and 35, respec-
tively, in slightly decreased yields.
In conclusion, we have developed the first visible-light-
induced polarity-reversed allylation and intermolecular
Michael addition reactions of aldehydes, ketones, and
imines with an unprecedented broad substrate scope. The
Hantzsch ester is reported for the first time as the activator in
the photoredox catalytic system and enables the polarity
reversed allylation of alkyl imines. This unique reactivity of
the Hantzsch ester in photoredox catalysis and its application
for biomolecules are under investigation in our laboratory.
Acknowledgments
Financial support was provided by the National Basic
Research Program of China (2014CB910304) and the
National Natural Science Foundation of China (21272260,
2
1472230).
Keywords: allylic compounds · iridium · photoredox catalysis ·
radicals · umpolung
Scheme 5. Substrate scope of aryl imines. Reaction conditions are
those detailed in entry 3 of Table 1. Yield is that of isolated product.
Ar=4-tBuC H . Boc=tert-butoxycarbonyl.
6
4
propargyl ether group is tolerated to give 21 in 72% yield. 1-
Naphthylamine and various anilines reacted smoothly to give
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ketyl radical anion) adds to the allyl sulfone and Michael
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off light experiment, and the quantum yield of the reaction is 0.8.
The radical-chain mechanism is unlikely, however we cannot
exclude a possible radical-chain mechanism with very short
chain length. See the Supporting Information for details.
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Published online: && &&, &&&&
4
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Angew. Chem. Int. Ed. 2016, 55, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Photochemistry
Visible-light-induced polarity-reversed
allylation and intermolecular Michael
addition reactions of aldehydes, ketones,
and imines are reported. This chemo-
selective reaction has broad substrate
scope and the engagement of alkyl imines
by a three-component reaction is
reported for the first time. Mechanistic
investigations indicate the formation of
ketyl (or a-aminoalkyl) radicals from
single-electron reduction, wherein the
Hantzsch ester is crucial as the electron/
proton donor and the activator.
L. Qi, Y. Chen*
&&&& — &&&&
Polarity-Reversed Allylations of
Aldehydes, Ketones, and Imines Enabled
by Hantzsch Ester in Photoredox
Catalysis
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!