Direct Synthesis of Polysubstituted Aldehydes via Visible-Light Catalysis

Article abstract of DOI:10.1002/anie.201712384

Aldehydes are among the most versatile functional groups for synthetic chemistry. However, access to polysubstituted alkyl aldehydes is very limited and requires lengthy synthetic routes that involve multiple-step functional-group conversion. This paper reports a one-step synthesis of polysubstituted aldehydes from readily available olefin substrates using visible-light photoredox catalysis. Despite a number of competing reaction pathways, commercial styrenes react with vinyl ethers selectively in the presence of an acridinium salt photooxidant and a disulfide hydrogen-atom-transfer catalyst under blue LED irradiation. Alkyl aldehydes with different substitution patterns are prepared in good yields. This strategy can be applied to structurally sophisticated substrates.

Full text of DOI:10.1002/anie.201712384

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Accepted Article
Title: Direct Synthesis of Polysubstituted Aldehydes via Visible-Light-
Catalysis
Authors: Fengjin Wu, Leifeng Wang, Jiean Chen, David A. Nicewicz,
and Yong Huang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712384
Angew. Chem. 10.1002/ange.201712384
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Angewandte Chemie International Edition
10.1002/anie.201712384
COMMUNICATION
Direct Synthesis of Polysubstituted Aldehydes via Visible-Light-
Catalysis
ǂ
ǂ
Fengjin Wu, Leifeng Wang, Jiean Chen,* David A. Nicewicz* and Yong Huang*
Dedication ((optional))
Abstract: Aldehydes are one of the most versatile functional groups
for synthetic chemistry. However, access to polysubstituted alkyl
aldehydes is very limited and requires lengthy synthetic routes that
involve multiple-step functional group interconversion. Herein, we
report a one-step synthesis of polysubstituted aldehydes from readily
available olefin substrates using visible light photoredox catalysis.
Despite a number of competing reaction pathways, commercial
styrenes react with vinyl ethers selectively in the presence of an
acridinium salt photooxidant and a disulfide hydrogen-atom-transfer
catalyst under blue LED irradiation. Alkyl aldehydes with different
substitution patterns are prepared in good yields. This strategy can be
applied to structurally sophisticated substrates.
Aldehydes represent a class of functional groups in organic
synthesis that provide a handle for a plethora of chemical
transformations. In addition to their high chemical reactivity
towards a very wide spectrum of nucleophiles, aldehydes are
integral substrates for reactions in the field of organocatalysis. A
Scheme 1. Approaches to Aldehyde Synthesis
large segment of organocatalytic reactions are based on the
unique reactivity of aldehydes employing a number of privileged
small molecule catalysts, for example, N-heterocyclic carbenes
availability of alkenes, the synthesis of aldehydes directly from
olefins would be a much more atom- and step-economic
alternative. In this fashion, terminal alkenes are mainly applied for
an anti-Markovnikov hydroformylation process and for the
fabrication of linear aldehydes (Scheme 1B).[
NHC)[1] and amines (iminium catalysis , enamine catalysis and
[2]
[3]
(
[
4]
[5]
associated SOMO and visible light catalysis ). Traditionally,
aldehydes are prepared by oxidation of alcohols or reduction of
carbonyl derivatives of higher oxidation states (esters, amide,
acids, acyl chlorides, etc.). Due to their high reactivity, direct
introduction of substituents on aldehyde substrates is very
challenging. As a result, substituents are installed prior to the
elaboration of the aldehyde functionality. Taking α,β-disubsituted
aldehydes for example, classical synthesis involves amidation,
7]
During the last decade, photoredox catalysis has emerged as
an alternative method for olefin activation. Significant progress
has been made by single electron oxidation of electron-rich olefins
using photooxidants and visible light.[8] The resulting radical
cation can be intercepted, regioselectively at the less substituted
carbon (anti-Markovnikov), by a number of nucleophiles including
alcohols, amines, acids, halogens and alkenes.[9] This polar
radical coupling mechanism provides excellent opportunities to
introduce substitution in a divergent fashion. Herein, we report a
robust synergistic catalyst system, consisting of an acridinium salt
as the photosensitizer (PS) and a disulfide as hydrogen-atom-
transfer (HAT) catalyst, for chemo- and regioselective coupling of
styrenes and vinyl ethers. This protocol represents a one-step
synthesis of polysubstituted aldehydes under mild conditions.
We recently reported a visible-light-mediated, chemo- and
regioselective [4+2] cycloaddition of two styrenes using the
Fukuzumi acridinium as a single-electron photooxidation catalyst.
Upon blue-LED irradiation, the excited-state acridinium oxidizes
one of the styrenes to the corresponding radical cation, which is
trapped by the second styrene in solution to form tetralin scaffolds.
1
,4-cuprate addition, α-alkylation of the copper enolate, reduction
and oxidation (Scheme 1A).[6] The overall synthetic sequence is
five steps at minimum, permitting the α,β-unsaturated acid
starting material is commercially available. Considering the ready
[*]
F. Wu, Dr. L. Wang, Prof. Dr. J. Chen, Prof. Dr. D. A. Nicewicz, and
Prof. Dr. Y. Huang
Key Laboratory of Chemical Genomics, School of Chemical Biology
and Biotechnology, Peking University, Shenzhen Graduate School
Shenzhen, 518055 (China)
E-mail: chenja@pkusz.edu.cn, huangyong@pkusz.edu.cn
Dr. L. Wang
Shenzhen SynLED Technology Limited, 2-104, BIO-Incubator,
st
Gaoxin C, 1 Ave., Shenzhen Hi-Tech Industrial Park, Nanshan,
Shenzhen, 518057 (China)
Prof. Dr. D. A. Nicewicz
[
10]
Based on this finding, we proposed that the radical cation might
also be reactive toward ethyl vinyl ether (EVE). Instead of forming
the cyclic framework, an aldehyde product might be obtained by
elimination of ethylene prior to cyclization. This design has several
challenges: 1) selective oxidation between styrene and EVE; 2)
Department of Chemistry, University of North Carolina at Chapel Hill
Chapel Hill, NC 27599-3290 (USA)
E-mail: nicewicz@unc.edu
[‡
]
These authors contributed equally to this work.
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Angewandte Chemie International Edition
10.1002/anie.201712384
COMMUNICATION
undesired [2+2][11] and [4+2] cyclization of both the styrene and
EVE; 3) potential polymerization of either the styrene or EVE
under these oxidative conditions.[12]
We carried out a preliminary investigation of potential
reaction conditions using p-methoxystyrene and EVE as
substrates (Table 1). An initial survey of photosensitizers revealed
[
a] A 2 dram vial was charged with a photosensitizer (0.01 mmol, 5 mol%),
PhSSPh (0.04 mmol, 20 mol%), n-decane (0.2 mmol, internal standard), p-
methoxystyrene (0.2 mmol), EVE and 3 mL solvent. The reaction vessel was
placed in a 4x4 photoreactor (SynLED 16-A Discover 450 nm, designed
and manufactured by Shenzhen SynLED Tech. Ltd. See SI for details). The
yield of the aldehyde product was determined by GC. For entries 5-12, p-
methoxystyrene in 1 mL solvent was slowly added to the reaction mixture
over 20 hours with LED irradiation. [b] Isolated yield was measured. [c]
PhSSPh was omitted.
TM
that common transition metal photoredox-active complexes such
13]
as Ru(bpy)
3
Cl
2
and Ir[dF(CF
3
)ppy)
2
(dtbbpy)PF [
6
did not
promote this reaction. However, the desired aldehyde product
was observed when acridinium salts were employed. Interestingly,
the corresponding diethyl acetal was also formed alongside in
similar levels of conversion. Aqueous acidic workup led to
formation of the aldehyde in 12% yield using Acr-BF as the
4
photocatalyst. Not surprisingly, the [4+2] homodimerization of p-
methoxystyrene was the major side reaction. However, the
nucleophilicity of EVE towards the radical cation is not sufficient
to compete against styrene itself.[14] To address this
chemoselectivity issue, we hypothesized that higher
concentrations of EVE should promote the desired reactivity. As
predicted, slow addition of p-methoxystyrene over 20 hours
yielded 33% aldehyde 1 (entry 5). Increasing the equivalents of
EVE led to significantly improved yield (entries 5-7). Examination
of the reaction medium revealed that the transformation was best
accomplished in DCE as the solvent (entries 8-11). The HAT
cocatalyst, PhSSPh, is essential. Removing PhSSPh resulted in
no aldehyde formation.
With the optimized reaction conditions in hand, we
examined the reactivity of various substituted styrenes (Table 2).
Aldehydes with β- or/and γ-branches were constructed in
moderate to good yield with excellent chemo- and regioselectivity.
When β-substituted styrene derivatives were used, the
corresponding β-branched aldehydes were isolated. We
hypothesize that the exclusive anti-Markovnikov addition of EVE
to the styrene radical cation is controlled by the formation of the
more stable benzylic radical intermediate. It is worth noting that
for these substrates, electron-donating groups are not required for
the arene. β-Substituted styrenes are far more stable than their
non-substituted analogues and are less prone to [2+2] and [4+2]-
type homodimerizations (products 5-13). The olefin geometry for
β-substituted styrenes has a minor impact on the reaction yield,
with the cis-isomers delivering slightly higher yield. Nevertheless,
comparable conversions were observed when a mixture of
cis/trans isomers was used. Functional groups labile to transition
metals, such as acetylene and halides, are well tolerated.
Table 1. Condition survey for the aldehyde formation.[a]
Table 2. The substrate scope of styrenes.[a]
entry
photosensitizer
Ru(bpy) Cl
Ir[dF(CF )ppy) (dtbbpy)PF
solvent
DCE
EVE (eq.)
yield (%)
1
2
3
4
5
6
7
8
9
3
2
1
1
1
1
1
3
5
5
5
5
5
5
0
0
3
2
6
DCE
Acr-Cl
Acr-BF
Acr-BF
Acr-BF
DCE
0
4
4
4
DCE
12
33
68
80[b]
72
20
0
DCE
DCE
Acr-BF
4
DCE
[
a] The numbers in the parentheses are yields using the corresponding cis-
Acr-BF
Acr-BF
Acr-BF
Acr-BF
Acr-BF
4
DCM
MeCN
toluene
DMF
DCE
styrenes.
4
Cyclic alkene substrates perform exceedingly well and lead to
products with a β-ring moiety, which belongs to a class of
challenging aldehydes for conventional methods (products 14-16).
1
0
1
4
4
4
[
15]
1
0
1,4-Divinylbenzene was effectively transformed to the
dialdehyde product (17). The use of methyl demonstrating the
tolerance of the reaction conditions on trisubstituted styrenes.
1
2[c]
0
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COMMUNICATION
When arylcyclohexenes were subjected stillbene afforded
intended adduct 18 in good yield (65%), to the catalytic conditions,
the desired aldehydes were isolated in 45% and 46% yield,
respectively (products 19 and 20). The diastereoselectivity is 9:1
for both substrates indicating a stereoselective hydrogen-atom-
transfer process for this substrate. A major side reaction was
corresponding benzofuranyl aldehyde 34 in 67% and 3:1 dr,
despite containing a highly electron-rich heteroaryl group. Then
an α,β-disubstituted styrene was further utilized to construct α/β/γ-
trisubstituted aldehyde 35 straightforward, which couldn’t be
synthesized through traditional approach. Several natural product
derived styrene substrates were tested. This visible-light-
determined to be the [4+2] cycloaddition (compounds 19’ and 20’), mediated process is also amenable to late-stage functionalization
likely due to capture of the incipient oxocarbenium ion in a Friedel-
Crafts-type cyclization.
of structurally sophisticated molecules. The rapid introduction of
branched aldehyde functionality significantly widens
a
The reaction was further evaluated using 2-substituted
VEEs in conjunction with a more diverse pool of styrenes (Table
accessibility to novel derivatives of these biologically relevant
scaffolds.
3
). The use of 2-substituted EVEs would allow us to prepare
aldehydes with an α-branch. Similarly as β-substituted styrenes,
-substituted EVEs are more stable under visible-light-catalysis
For most substrates, the corresponding acetals are formed in
significant quantities. Although they can be converted back to the
aldehyde products by acidic workup using HCl and water, we
were intrigued by the acetal formation. Undoubtedly, the second
ethoxy group arises from another molecule of EVE. Upon
nucleophilic addition of EVE to the styrene radical cation, an
oxonium intermediate would be formed. If ethanol is present,
acetal formation prior to ethylene elimination is likely responsible
for this side product. In order to confirm that, methanol was added
to the standard reaction conditions (Scheme 2A). Although
alcoholic co-solvent inhibits this reaction, addition of 1 equivalent
methanol did lead to the desired aldehyde and its diethyl acetal in
18% combined yield. The O-methyl-O-ethyl acetal was isolated in
21% yield. This result strongly supports the alcohol trapping
mechanism for the acetal formation. Considering EVE is itself
highly volatile, we used the vinyl ether with a C18 alkyl chain to
identify the detailed product composition (Scheme 2B). The
reaction using this vinyl ether reacted smoothly with p-
methoxystyrene to deliver the desired aldehyde and di-n-
octadecyl acetal products in 30% and 14% yield, respectively.
Further isolation revealed that n-octadecene was formed in 40%
yield. n-Octadecanol was isolated in 6% yield. These results
confirm that alkene elimination is the primary pathway for the
aldehyde formation, and the presence of n-octadecanol leads to
the acetal formation. Decomposition of vinyl ether via hydrolysis
and oligmerization, is likely the source of free n-octadecanol in the
reaction.
2
and tolerate a broader scope of styrenes. For example, styrene
with an electron-withdrawing ester group at the para-position
reacts smoothly with 1-propenyl ethyl ether to give the
corresponding α-methyl aldehyde 24 in 49% yield. This electron-
deficient styrene is rarely used in visible-light-photoredox
catalysis due to its high oxidation potential. To further challenge
the steric tolerance, β-substituted styrenes were employed to
form sterically demanding double branched C-C bonds. We were
pleased to find that the reactions procceded smoothly with a wide
range of styrenes and their analgoues. α,β-Disubstituted
aldehydes were prepared in moderate to good yield (products 25-
30).
Table 3. Synthesis of polysubstituted aldehydes.[a]
Scheme 2. Mechanistic experiments. (A) When the reaction between p-
methoxystyrene and EVE was carried out in the presence of 1 equivalent of
methanol, the aldehyde and the diethyl acetal were isolated in 18% combined
yield. The O-methyl-O-ethyl acetal was isolated in 21% yield. (B) When the
reaction between p-methoxystyrene and octadecyl vinyl ether was carried out
under the standard reaction conditions, the combined yield of aldehyde and
acetal was 44%. n-octadecene was obtained in 40% isolated yield. n-
octadecanol was isolated in 6% yield.
Unfortunately, little diastereoselectivity was observed. This
result is not surprising considering the similar size of both olefinic
carbons of 2-substituted EVEs. Endocyclic alkenes, such as
indene, benzocyclohexene and benzocycloheptene, react with 1-
propenyl ethyl ether smoothly (products 31-33). Heterocyclic
alkenes, propenyl benzofuran for instance, yielded the
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Angewandte Chemie International Edition
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COMMUNICATION
Based on these experimental inspiration, we propose the
following reaction mechanism (Scheme 3). The oxidation
potentials of both styrenes (+1.15 to +1.75 V vs SCE)[16a] and vinyl
ethers (+1.30 to +1.45 V vs SCE)[16b] are well within the reduction
potential of the singlet excited state of acrimidinium
This work is financially supported by the National Natural Science
Foundation of China (21572004, 21602007), the China
Postdoctoral Science Foundation (2017T100010), and Shenzhen
municipality (GRCK2017042414452296).
+
•
[8]
[
E*1/2(Acr /Acr )= +2.06 V]. Due to favorable π-π stacking, the
+
excited photosensitizer, Mes-Acr *, preferentially oxidizes the
Competing financial interests
styrene to generate the highly electrophilic radical cation I and

Mes-Acr . EVE is by far the most nucleophilic species in the
The authors declare no competing financial interests.
reaction and reacts with I to generate the oxonium radical II, which
has two forward pathways: β-elimination to give radical III and
trapping by ethanol, from photoinduced decomposition of EVE, to
give radical IV. PhSSPh acts as the oxidant to turn over the
Keywords: photocatalysis • H-atom transfer • styrene • radical
cation • aldehyde
-
photocatalyst. Its reduced form (PhS ), upon receiving a proton
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regenerated. Finally, acidic workup converts the acetal side
product to the aldehyde.
4

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The key C-C bond formation is accomplished by nucleophilic addition of EVE to
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6
In summary, we developed a highly efficient, one-step synthesis
of polysubstituted aldehyde using readily available styrenes and
vinyl ethers under visible-light-catalysis. Aldehydes with α-, α,β-,
β,γ-, and α,β,γ-branches are synthesized in good yield under very
mild, blue LED irradiation conditions. This method can stitch up to
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2
three branched sp carbons together in a single transformation.
The reaction features wide substrates scope and excellent
chemo-, regoselectivity and functional group tolerance. The
synergistic merging of acridinium photosensitizer and disulfide
HAT catalyst is essential for this transformation.
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Acknowledgements
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Angewandte Chemie International Edition
10.1002/anie.201712384
COMMUNICATION
COMMUNICATION
ǂ
ǂ
Fengjin Wu, Leifeng Wang, Jiean
Chen,* David A. Nicewicz* and Yong
Huang*
Direct Synthesis of Polysubstituted
Aldehydes via Visible-Light-Catalysis
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