Visible light-mediated selective α-functionalization of 1,3-dicarbonyl compounds: Via disulfide induced aerobic oxidation

Article abstract of DOI:10.1039/c9cc06544j

A visible light-mediated α-functionalization of 1,3-dicarbonyl compounds with switchable selectivity induced by disulfide is disclosed. Upon irradiation with visible light, the metal- A nd base-free α-hydroxylation or α-hydroxymethylation reaction proceeded smoothly through a disulfide-catalyzed oxidation under mild conditions. The combination of a continuous-flow strategy could further improve the reaction efficiencies.

Full text of DOI:10.1039/c9cc06544j

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Visible light-mediated selective a-functionalization
of 1,3-dicarbonyl compounds via disulfide induced
aerobic oxidation†
Cite this: Chem. Commun., 2019,
55, 13008
Received 23rd August 2019,
Accepted 7th October 2019
Jingnan Zhao, Fan Yang, Zongyi Yu, Xiaofei Tang, Yufeng Wu, Cunfei Ma and
Qingwei Meng
*
DOI: 10.1039/c9cc06544j
rsc.li/chemcomm
A visible light-mediated a-functionalization of 1,3-dicarbonyl compounds
with switchable selectivity induced by disulfide is disclosed. Upon
irradiation with visible light, the metal- and base-free a-hydroxylation
or a-hydroxymethylation reaction proceeded smoothly through a
disulfide-catalyzed oxidation under mild conditions. The combination
of a continuous-flow strategy could further improve the reaction
efficiencies.
Direct C–C and C–O bond formation via a-functionalization of
1,3-dicarbonyl compounds provides a powerful synthetic strategy for
the construction of organic compounds.1a For many years, research
in this field has largely focused on the invention of new catalysts and
Scheme 1 Approaches to a-functionalization of 1,3-dicarbonyl compounds.
the optimization of their performance to achieve high conversions chemoselective transformations in the a-functionalization of
and/or selectivities.1b However, inspired by nature,2 chemists are 1,3-dicarbonyl compounds induced by disulfide (Scheme 1).
beginning to turn their attention to the development of a switchable
Initially, the visible light-mediated disulfide catalyzed hydroxy-
selectivity chemical process.3 Alternatively, metal-free visible lation protocol was probed with 1-indanone-derived b-keto ester
light-mediated aerobic oxidation is an appealing environ- (1a) as the model substrate. When diphenyl disulfide (2a)
mentally friendly method which has offered an attractive and was present, the reaction proceeded smoothly and formed the
energy-saving platform in comparison to the traditional oxidation desired a-hydroxylation product (3a) in 31% yield (Table 1,
processes. Although a significant number of transition-metal- entry 1). Notably, we observed none of the desired products in
catalyzed hydroxylation and hydroxymethylation reactions of the absence of disulfide or visible light (Table 1, entries 2 and
1,3-dicarbonyl compounds have been developed,4,5 practical and 3), demonstrating the requirement of both components in this
efficient a-functionalization with molecular oxygen as the terminal protocol. Various light sources were then applied to the model
oxidant and oxygen source are still desirable. Recently, the field of reaction. We chose a 10 W blue LED (450–455 nm) as the best
disulfide and thiol catalysis has grown rapidly,6 partly because light source. The substituent groups of the aromatic ring in the
these reagents can serve as a hydrogen-atom-transfer (HAT) disulfides could influence the reaction results (Table S2, entries
cocatalyst in photo-redox catalysis.7 Recently, disulfide-catalyzed 1–8, ESI†). When the para-positions of the disulfides contain
visible light-mediated oxidative cleavage of CQC bonds has been electron-withdrawing groups it will improve the yield; for
reported by Wang and their experimental and computational example, bis(4-fluorophenyl)disulfide (2d) could afford a better
studies suggested that an olefin-disulfide EDA complex exists.7p 56% yield (Table 1, entry 4). Unexpectedly, when the reaction
Therefore, as part of our studies on visible light-induced green proceeded in DMF (with 1a 0.025 M), 96% yield could be
chemical reactions and inspired by the reported results,7,8 we observed (Table 1, entry 6). We further investigated the applica-
audaciously envisioned visible light-mediated readily tunable and tion of this visible light-mediated disulfide-catalyzed activation
of molecular oxygen for aerobic dehydrogenation coupling
reactions. While examining the alkylation between b-keto esters
and olefins in the presence of 1a and 10 W blue LED irradia-
State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and
Technology, Dalian University of Technology, Dalian, 116024, P. R. China.
tion, we serendipitously discovered that the presence of styrene
E-mail: mengqw@dlut.edu.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9cc06544j
leads predominantly to the a-hydroxymethyl b-keto ester rather
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Table 1 Selected optimization of the reaction conditionsa
Scheme 2 Substrate scope of olefin.
With the optimal conditions in hand, we sought to evaluate the
generality of these transformations. As highlighted in Table 2, a
wide range of 1,3-dicarbonyl substrates can be hydroxylated and
hydroxymethylated under the developed reaction conditions.
b-Keto esters and b-keto amides with electron-donating or
electron-withdrawing substituents (such as methyl or halides) on
the phenyl ring are hydroxylated in excellent efficiencies (3a, 3c–3h,
3l–3m and 3q, 68–98% yield). They could also effectively react with
styrene in the presence of 2a (5 mol%) under blue LED irradiation
to furnish hydroxymethylation products in good yield and selectivity
(4a, 4c–4g and 4k, 54–92% yield). The unsubstituted indanone
carboxylic methyl ester (1b) gave 3b in 63% yield and 4b in 89%
yield. However, a sharp decrease in the yields was observed when
electron-donating methoxyl groups were introduced into the aro-
matic ring of b-keto esters (3i–3k, 13–33% yield) while there was
slight fluctuation in the yields of hydromethylation products (4h–4j,
Yieldb [%]
Entry Alteration
3a
4a
1c
2
None
31
N.R.
N.R.
N.R.
No light (dark) or no air
No disulfide 2a
2d instead of 2a
3c
4d
5d
6
Trace N.R.
56
N.R.
N.R.
2d instead of 2a, DMF instead of PhMe 89
2d, DMF, 1a (0.025 M)
Styrene
Styrene; no light, no 2a or no air
96
N.R.
N.R.
N.R.
7e
8c,e
81f, 88g, 95h
N.R.
a
Unless otherwise noted, the reactions were carried out with 1a
(0.1 mmol), disulfide 2a (5 mol%), and 2.0 mL PhMe in a quartz tube
at room temperature under the irradiation of a 10 W blue LED for a given
b
time. Meanwhile, the solution was bubbled with an air pump. Yield
c
d
e
f
determined by 1H-NMR. 3 W white LED. 3 W blue LED. MeCN. 5a
g
h
(1.5 equiv.), 24 h. 5a (1.5 equiv.), O2 balloon, 24 h. 5a (10 equiv.), 4 h.
than the cross-dehydrogenative coupling product (Table 1, entry 7). 88–97% yield). After investigation of the b-keto esters, the scope of
As the amount of styrene 5a increased, the yield of the reaction is b-keto amides was then examined. We found that the yields of
increased while the reaction time is greatly shortened. We next hydroxylated and hydroxymethylated b-keto amides were related to
evaluated the activity of some commonly employed olefins and a the N-substituent groups (3o–3p and 3s–3t, 53–87% yield; 4l–4m and
variety of solvents for the hydroxymethylation of the 1-indanone- 4o–4r, 42–89% yield). Further substrate expansion to 1-tetralone-
derived b-keto ester 1a. Unfortunately, due to the basic reaction derived 1,3-dicarbonyl substrates and carbonyl compounds was
conditions in combination with the disulfide and visible light also investigated and the corresponding products were generated
irradiation, the hydroxylation product was observed (5o, 5p and effectively (3n, 3u and 4s–4t, 54–85% yield). Efforts were made to
5q). Therefore, we recognized that judicious selection of a styrene expand the species scope of the substrate. However, some other
would be necessary to suppress the formation of this unwanted 1,3-dione compounds such as open 1,3-dicarbonlyl compounds,
byproduct without obstructing the desired photocatalytic hydroxy- functionalized five-, six- and seven-membered keto ester derivatives
methylation reaction pathway. When the phenyl ring of the styrene and carbonyl compounds did not react under identical reaction
has a halogen substitution on the para- or meta-position, the conditions. To further expand the utility of the reactions, we directed
yields will fluctuate (5e–5j, 51–84% yield). When electron- our efforts toward achieving a continuous-flow process. The
donating methyl or methoxyl groups were introduced to the disulfide-catalyzed aerobic oxidations were amenable to scale-up to
para-position of the aromatic ring, lower yields were observed gram quantities using continuous-flow reactors (Table 2).
(5b–5c, 44–63%). The yield declined to 43% when the Boc group
A series of control experiments were further carried out to
was on the para-position of the styrene and the yield slightly better understand the possible mechanism. When the trans-
fluctuated for the 3-methyl substituted styrene. 1,2-Disubstituted formation was performed under an N2 atmosphere, no antici-
olefins, such as b-nitrostyrene and b-methylstyrene, were also pated product 3a and 4a was obtained, confirming the crucial
examined; however, the desired hydroxymethylation product 4a role of O2 in the reaction (Schemes S3 and S4, ESI†). However,
was not formed after 24 h (Scheme 2). A series of control the model hydroxylation reaction worked very well even with
experiments omitting each individual reaction component high- the addition of one equivalent of TEMPO (2,2,6,6-tetramethyl-1-
lighted the importance of the disulfide, aromatic terminal piperidinyloxy, a well-known radical scavenger), and afforded
alkenyl derivatives and visible light for achieving this general product 3a in 89% yield. In contrast, when the singlet oxygen
hydroxymethylation reaction protocol accomplished by the oxi- quencher DABCO (1,4-diazabicyclo[2.2.2]octane) was added to
dative cleavage of CQC double bonds (Tables S4 and S5, ESI†). the hydroxylation reaction of 1a, the yield of product decreased
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Table 2 Switchable selectivity in the a-functionalization of 1,3-dicarbonyl
compoundsa
Scheme 3 Preliminary mechanistic investigations.
a
Isolated yields. b Reaction conditions: 1a (0.1 mmol), disulfide (5 mol%) a-H (–CH–) (d 3.76 ppm) as well as b-H (–CH2–) (d 3.35 ppm)
and DMF (4.0 mL) in a quartz tube at room temperature under irradiation of
a 10 W blue LED for a given time. In addition, the solution was bubbled
with an air pump for 12 h. Reaction conditions: 1a (0.1 mmol), disulfide
shifted upfield, which indicated that the electron density on the
c
substrate had increased. To better understand this photo-
chemical oxidation reaction and to elucidate the mechanism,
we also performed UV-Vis spectroscopic measurements on a
combination of 1a and 2a. Notably, we observed the formation
of a new peak (lmax = 410 nm) when 1a and 2a were combined; this
(5 mol%) and MeCN (2.0 mL) in a quartz tube at room temperature under
irradiation of a 10 W blue LED for a given time. In addition, the solution was
bubbled with an air pump for 24 h.
dramatically, affording product 3a in 47% yield, suggesting that peak is proposed to result from the absorption of disulfide–enol
a singlet oxygen process might be involved in the present complex (Scheme 3c). Meanwhile, the photographs of the reaction
reaction. To provide some insight into the plausible radical solution before and after blue LED irradiation indicated that an
mechanism for the hydroxymethylation reaction, TEMPO as a EDA complex might exist. In addition, fluorescence experiments
radical scavenger was subjected to our standard conditions. As were also conducted to prove the complexation between 1a and 2a
expected, the hydroxymethylation reaction was significantly (Scheme 3c). The emission intensity of PhSSPh dramatically
inhibited, and the system was prone to hydroxylation. In increased with the increasing amounts of 1a. This complex may
addition, the hydroxymethylation system in the presence of be photosensitive.
TEMPO afforded adducts 6 and 7 (Scheme 3a). These results
Based on the above results and considering previous studies, a
suggest that an alkyl intermediate might be involved in this preliminary mechanism is proposed in Scheme 4. (A) Irradiation of
transformation. We carried out NMR experiments to confirm the disulfide–enol complex I yields a photoexcited disulfide–enol
the formation of the disulfide–substrate enol complex. The complex I*, which then transferred energy to the triplet oxygen
1
1H NMR spectra are shown in Scheme 3b, and changes in the (3O2) to form reactive singlet oxygen (1O2). Then O2 reacts with
peaks and chemical shifts were observed at d 3.90–3.30 ppm as complex I to afford hydroxylation product 3.8 (B) Upon the addition
the ratio of disulfide to 1a increased. From Scheme 3b, the of a stoichiometric amount styrene, there is precedence for the
chemical shift of –COOCH3 (d 3.80 ppm, 3.86 ppm) from the disulfide to react with the styrene to form a disulfide–olefin
keto form and enol form of 1a shifted upfield, and the peak of complex II. The complex II would provide a S–S bond that is more
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U1608224, and 61633006) and the State Key Laboratory of Fine
Chemicals for their support.
Conflicts of interest
There are no conflicts to declare.
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thus the generated thiyl radical would add to styrene to give
intermediate 8. We believed that the key intermediate was the
dioxetane 10, which was formed from intermediate 9 by the
abstraction and substitution of the thiyl radical and alkyl
radical.7p Then enol-form 1 attacked dioxetane 10 to afford
benzaldehyde 11 and hydroxymethyl-adduct 4.9
In conclusion, a visible light-mediated switchable selective
a-functionalization of 1,3-dicarbonyl compounds using air as
the oxidant and an oxygen source induced by disulfide is disclosed
for the first time. Upon irradiation with visible light, the metal- and
base-free a-hydroxylation or a-hydroxymethylation reactions pro-
ceeded smoothly through a disulfide-catalyzed oxidation under mild
conditions. The combination of a continuous-flow strategy could
further improve the reaction efficiencies. The application of this
system to the synthesis of other compounds is currently underway in
our laboratory.
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