Oxidative C-C bond cleavage of aldehydes via visible-light photoredox catalysis

Article abstract of DOI:10.1021/ol303437m

The visible-light mediated oxidative C-C bond cleavage of aldehydes has been achieved in good yields at ambient temperature and open to air using Ru(bpy)₃Cl₂ (bpy = 2,2′-bipyridine) as the photoredox catalyst. Moreover, we further demonstrated the application in a tandem Michael/oxidative C-C bond cleavage reaction.

Full text of DOI:10.1021/ol303437m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Oxidative CꢀC Bond Cleavage
of Aldehydes via Visible-Light
Photoredox Catalysis
Hongnan Sun,† Chao Yang,† Fei Gao,† Zhe Li,† and Wujiong Xia*,†,‡
State Key Lab of Urban Water Resource and Environment, the Academy of Fundamental
and Interdisciplinary Sciences, Harbin Institute of Technology, Harbin 150080, China,
and State Key Lab of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000,
China
xiawj@hit.edu.cn
Received December 16, 2012
ABSTRACT
The visible-light mediated oxidative CꢀC bond cleavage of aldehydes has been achieved in good yields at ambient temperature and open to air
using Ru(bpy)3Cl2 (bpy = 2,20-bipyridine) as the photoredox catalyst. Moreover, we further demonstrated the application in a tandem Michael/
oxidative CꢀC bond cleavage reaction.
Efficient and rapid CꢀC bond cleavage has been a clear
goal of synthetic organic and medicinal chemistry, and
accordingly, many research efforts have been focused on
developing new methodologies. In the case of cleaving the
CꢀC bond of aldehydes, however, very few procedures
with mild reaction conditions are available. One of the
most powerful methods is the oxidation of the enamines in
the presence of strong metal oxidants (Scheme 1, eq 1).1
However, these methods suffer from the drawbacks of
harsh reaction conditions, various byproducts and limita-
tion to the substrates. Recently, an elegant example from
Chi’s group reported the metal-free oxidative CꢀC bond
cleavage of aldehydes in the presence of 4-methoxyaniline
using molecular O2 as the oxidant, in which heating and
high pressure, for example, 10 atm of O2, were required to
achieve the corresponding chiral ketones (Scheme 1, eq 2).2
Nowadays, the field of organic photochemical reactions
experiences a veritable revival of activity in both academics
and industry. The contribution from Turro’s work on the
photooxidation of enecarbamates with singlet oxygen has
successfully demonstrated the efficiency of the organic
photochemical reaction in organic synthesis (Scheme 1,
eq 3). However, the generation of high-intensity UV light
requires specialized photoreactors, which limits their scal-
ability, and for photochemical reactions, selectivity re-
mains to be a challenging task in targeted synthesis. Hence,
the discovery of new processes to achieve CꢀC bond cleavage
of aldehydes through milder reaction conditions and more
environmentally friendly chemical synthesis is still appealing.
In recent years, research efforts have been focused on
harnessing visible light as a promoter in organic transfor-
mations owing to its natural abundance, renewability, and
ease of use. Due to the inability of many organic molecules
† Harbin Institute of Technology.
‡ Lanzhou University.
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r
10.1021/ol303437m
XXXX American Chemical Society

[O2]•‑. With our continuous investigations on photochemical
reactions,9 we envisioned that the resulted [O2]•‑ could act as
an oxidant to selectively cleave CꢀC bond of the enamines
formed in situ from aldehydes and secondary amines enabled
by photoredox catalysts (Scheme 1, eq 3). Herein we report
what we have achieved on the realization of the strategy for
the direct oxidative cleavage of CꢀC bond to ketones using
visible-light irradiation and air as the source of the oxidant.
This new photocatalytic approach is particularly attractive
because mild reaction conditions, such as visible light, open to
air, and ambient temperature are involved.
Scheme 1. Oxidative CꢀC Bond Cleavage Reactions
Our initial investigation was carried out on the reaction
of 1a with 1 equiv piperidine in the presence of 5 mol %
Ru(bpy)3Cl2 in CH3CN under irradiation with a 15 W
fluorescent light bulb. To our delight, the desired CꢀC
cleavage product 2a was obtained in 29% yield after
irradiation for 2 h (Table 1, entry 1). Such a result, to the
best of our knowledge, presents the first example of
oxidative decarbonylation using a visible-light photocata-
lytic strategy and encourages us to explore the optimal
reaction conditions. Therefore 3 equiv piperidine and same
reaction time were employed which led to the yield in-
creased to 86% (Table 1, entry 2). If the reaction time was
prolonged to 5 h, excellent yield of 95% was obtained
(Table 1, entry 6). Further studies indicated that second
amine had a significant effect on the reaction efficiency
(Table 1, entries 5ꢀ11). Among all tested amines, piper-
idine showed the best transformation to product 2a.
The reaction proceeded equally well in DMF, CH3CN
and CH3OH (Table 1, entries 3, 4, 6 and 7) producing the
3
to absorb visible light, Photocatalysts such as Ru(bpy)3Cl2
were employed through electron-transfer processes to sensi-
tize organic molecules to carry out required photochemical
reactions. Since the pioneering work from the groups of
MacMillan,4 Stephenson,5 Yoon6 and others7 demonstrated
the utility of Ru(bpy)3Cl2 and its application to various
visible light induced synthetic transformations, the applica-
tion of visible light photoredox catalysis has emerged as a
growing field in organic chemistry and successfully applied in
a variety of reactions.8 Among these advances, air was usually
employed as an oxidant to regenerate Ru2þ from Ruþ in the
reductive quenching cycle and result in the formation of
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CH3CN).
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Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of the Photocatalytic Oxidative Cleavage
Conditions for Aldehyde 1aa
Table 2. Scope of the Photocatalytic Oxidative Cleavage
Conditions.a
entry
amine
solvent time (h) yield (%)b
1c
2
3
4
5
6
7
8
9
piperidine
piperidine
piperidine
piperidine
CH3CN
CH3CN
CH3OH
DMF
2
2
5
5
5
5
5
5
5
5
5
29
86
89
94
33
95
93
60
35
79
65
diisopropylamine
piperidine
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
pyrrolidine
morpholine
N-methylaniline
10 4-methoxy-N-methylaniline CH3CN
11 dibenzylamine CH3CN
a Reaction conditions: 1a (0.1 mmol, 0.1 M in solvent), amine
(0.3 mmol), Ru(bpy)3Cl2 (0.005 mmol), irradiation with a 15 W fluo-
rescent light bulb under air at 25 °C. b Determined by GC. c Piperidine
(1 equiv) was used in the reaction.
product in excellent yields. In addition, the reaction de-
gassed with N2 resulted in a a trace amount of product,
indicating that the oxygen plays an important role in the
reaction. Notably, exclusion of any of the reaction com-
ponents, including photocatalyst, the light source and
amine, did not afford the desired product 2a.
The scope of the reaction was examined by employing
a variety of aldehydes to the optimal reaction conditions.
As summarized in Table 2, the aldehydes were smoothly
oxidized to the corresponding ketones in good to excellent
yields. Among them the R-aryl aldehydes were effectively
converted to phenyl ketones (Table 2, entries 1ꢀ7). Inter-
estingly, more thermodynamically stable R,β-unsaturated
ketone was obtained from the reaction of γ,δ-unsaturated
aldehyde after decarbonylation and sequential CꢀC double
bond shifting (Table 2, entry 6). Moreover, the optically
pure ketone could be obtained from the diastereomers
without apparent erosion on the chiral center of the ketone
product under irradiation (Table 2, entry 7). Notably, the
substrate with an amino group also afforded the corre-
sponding product in acceptable yield (Table 2, entry 8). The
phenyl substituted olefin was isomerized to afford the
mixture of (E) and (Z)-olefins when subjected to the
reaction conditions. No further reaction was observed
albeit irradiation was for a longer time, which indicates
that the R-hydrogen of the aldehyde plays a crucial role in
the reaction (Table 2, entry 9). In addition, cyclic or alkyl
aldehydes were also tolerated under the reaction condi-
tions and as high as 83% yield was obtained (Table 2,
entries 10 and 11).
a Reaction conditions: 1(0.1 mmol, 0.1 M in CH3CN), piperidine
(0.3 mmol), Ru(bpy)3Cl2 (0.005 mmol), irradiation with a 15 W fluo-
rescent light bulb under air at 25 °C. b Determined by GC unless otherwise
noted. c Isolated yield in parentheses. d iPr2NH used instead of piperidine.
quenching process. Ruþ was oxidized by the oxygen of
air to regenerate Ru2þ and form [O2]•‑ which was reacted
with B to yield the final product.
To add more credence to the existence of intermediate B,
a control experiment was conducted by addition of 0.5
equiv 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO) to a
mixture of 1i, 3 equiv piperidine and 5 mol % Ru(bpy)3Cl2
to capture the radical generated in the reaction.10 The
above mixture was then irradiated with a 15 W fluorescent
light bulb in CH3CN (Scheme 3). Indeed, the R-oxyami-
nated aldehyde product 4i was isolated and characterized
by NMR spectra, along with which formamide 3i and
Accordingly, a tentative mechanism for this novel cata-
lytic cycle was proposed in Scheme 2. The enamine A
formed in situ from aldehyde 1 and secondary amine was
oxidized to cation radical B through the reductive
(10) Koike, T.; Akita, M. Chem. Lett. 2009, 38, 166.
Org. Lett., Vol. XX, No. XX, XXXX
C

product 2i were also detected by GC-MS due to that only
0.5 equiv TEMPO was applied.
cleavage reaction. As expected, product 6a was obtained
directly from the starting material 5a in 33% isolated yield.
The scope of the reaction was examined by subjecting the
compounds substituted with electron donating and/or
withdrawing groups at the different positions on the
phenyl groups to the reaction condtions, and the corre-
sponding products were obtained in 20ꢀ33% yield
(Scheme 4aꢀe). To the best of our knowledge, the result
represents the first example of such a Michael/Oxidative
CꢀC bond cleavage tandem reaction and provides a novel
access to the synthesis of cyclopentanone derivatives.
Scheme 2. Proposed Mechanism
Scheme 4. Tandem Michael/Oxidative CꢀC Bond Cleavage
Reaction
Scheme 3. Control Experiment with TEMPO
In conclusion, we have developed a visible-light induced
photocatalytic reaction for oxidative CꢀC bond cleavage
of aldehydes using air as the oxidant. Compared with the
previous procedures, this reaction was conducted in the
milder conditions, such as room temperature, open air, and
compatible with a wider range of substrates. More impor-
tantly, the photocatalytic reaction was first applied in a
tandem Michael/oxidative CꢀC bond cleavage process
through the use of amine as both the catalyst and reactant.
Tofurther investigate the applicability of thisprotocol in
organic synthesis, the formyl enone 5a prepared from 1,6-
hexanediol11 was treated with 3 equiv iPr2NH and 5 mol %
Ru(bpy)3Cl2 under irradiation with a 15 W fluorescent
light bulb. We envisioned that the secondary amine could
act both as the catalyst and reductive quencher to realize
a tandem reaction in which the cyclopentyl aldehyde 7
could be generated from iPr2NH catalyzed intramolecular
Michael reaction, which was sequentially transformed to
the cylclopentanone 6a through an oxidative CꢀC bond
Acknowledgment. We are grateful for the financial
supports from China NSFC (Nos. 21272047, 21002018
and 21072038) and ZJNSF (No. LY12B02009).
Supporting Information Available. Supplementary de-
tails. This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui, R.;
Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028.
The authors declare no competing financial interest.
D
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