Photoredox β-thiol-α-carbonylation of enones accompanied by unexpected Csp2-C(CO) bond cleavage

Article abstract of DOI:10.1039/d0ob01349h

An olefinic difunctionalization method of enones was presented hereviaaerobic visible-light catalysis. A novel reactivity was showcased in conjunction with the selective Csp²-C(CO) bond activation of enones, which provided a convenient method for the preparation of various β-thiolated-α-functionalized compounds. Moreover, the preliminary investigation of the mechanism indicated that a β-peroxysulfide intermediate was formed under the promotion of visible light under an oxygen atmosphere, which finally induced the unexpected C-C bond cleavage.

Full text of DOI:10.1039/d0ob01349h

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Photoredox β-thiol-α-carbonylation of enones accompanied by
unexpected Csp2-C(CO) bond Cleavage
Rui Maa, Jie Feng,a Kuili Zhanga, Beichen Zhanga and Ding Dua*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An olefinic difunctionalization method of enones was presented ring compounds.8b,8d-8f Besides that, radical reactions via
here via aerobic visible-light catalysis. A novel reactivity was hydrogen atom transfer (HAT) or proton-coupled electron
showcased in conjunction with the selective Csp2-C(CO) bond transfer (PCET) strategies are always employed to promote the
activation of enones, which provided a convenient method for C−C bond cleavage (Scheme 1a).8a,8g Although great pioneering
preparation of various -thiolated-α-functionalized compounds. works have been made in this field, activation of specific C-C
Moreover, preliminary mechanism investigation indicated that a bonds remains largely underexplored. In Particular, for enone
-peroxysulfides intermediate was formed under the promotion substrates, most previous literatures focused on olefinic
of visible light under oxygen atmosphere, which finally induced difunctionalizations. Selective Csp2-C(CO) σ-bond cleavage of
the unexpected C-C bond cleavage.
enones are rarely reported due to the existence of vinylogous
reactivity and conjugated structure.9 Therefore, a general
solution to the challenging Csp2-C(CO) σ-bond activation of
enones for further constructing functionalized molecules
would be meaningful. Herein, we wished to report a visible-
light and oxygen promoted method for -thiol-α-carbonylation
of enones accompanied by selective Csp3-C(CO) σ-bond
cleavage (Scheme 1c).
Olefin difunctionalization has been drawing much attention in
the field of synthetic methodology, as it provides
a
synthetically useful route to introduce two functionalized
substituents simultaneously1. Among them, α,-vicinal
difunctionalization of activated olefins, typically like enones (or
enals), is a standard tactic in organic synthesis, which is utilized
for multicomponent assembly of synthetic fragments in one
single step.2 Enones are well known as excellent Michael
acceptors,3 however, great advances have been achieved for
a) Known photoredox C-C activation substrates
R2
R
?
OH
R'
FG
N
O
R
R'
R
R1
R3
R'
( )n
radical-pathway
or
transition-metal-catalyzed
R
(
difunctionalizations of enones, such as halofunctionalization,2b
acyl-azidation,4 hydroxysulfenylation5 etc.,6 affording various
α,-difunctionalized ketones (Scheme 1b).
)
( )n
( )n
n
O
b) Difunctionalisation of enones
R2
R2
E
or
E
Nu
Nu
R1
R3
R1
R3
Meantime, the C-C bond activation and subsequent
functionalization are particularly important in simplifying the
synthetic routes for assembling complex molecules and
constructing functionalized compounds from readily-available
starting materials.7 In recent years, photo-redox C-C bond
activation reactions have emerged as a versatile and powerful
method, enabling the construction of targeted product under
ambient conditions.8 Until now, one of the common photo-
redox strategies to facilitate C-C bond activation is the
utilization of strained molecules, typically like 3-5 membered
Nu
O
O
c) This work
O
R2
R2
OOH
R3
R4SH
fac-Ir(ppy)3
O2, Blue LEDs
R1
homolysis
R1
R2
R1
R3
C-C,O-O cleavage
SR4
SR4
O
O
Scheme 1. Enone difunctionalization and overview of this work
At the start of this work, the model reaction of thiophenol
1a with benzalacetophenone 2a was carried out under oxygen
atmosphere (Figure 1). To our interest, unexpected -
thiolative-α-aldehyde 3a was monitored in less than 10% yield
(Figure 1, column 2, blue). As a comparison, no product 3a was
observed under argon conditions (Figure 1, column 1, blue).
So, oxygen was crucial to this transformation. The addition of
photo catalyst fac-Ir(ppy)3 and conducting the reaction under
a. State Key Laboratory of Natural Medicines, Department of Organic Chemistry,
China Pharmaceutical University, No. 24 Tongjiaxiang Road, Nanjing, 210009,
P.R. China. E-mail: ddmn9999@ cpu.edu.cn
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Journal Name
white LEDs irritation significantly improved the yield of 3a could be obtained with toluene and dichloromethane (Table 1,
View Article Online
DOI: 10.1039/D0OB01349H
(Figure 1, column 3, blue).
entries 8 and 9). When protic solvent MeOH was used, only
hydrothiolation byproduct was obtained (Table 1, entry 10) .
Encouraged by these results, great interests have been
aroused to understand the possible mechanism involved.
Thiophenol is known to be “ auto-oxidized ” to form
mercapto radical under aerobic conditions.10 Alternatively,
mercapto radical can also be initiated via photo-redox
catalysis.11 Radical inhibitors TEMPO and BHT were then added
to the model reaction, respectively. As a result, product 3a was
not observed for both two reagents (Scheme 2a). After that, a
photo “on-off” experiment was conducted (Scheme 2b).
Model reaction with photocatalyst was firstly treated under
Blue LEDs irradiation for 30 mins and then without the light
irradiation for another 210 mins, and 23% yield was obtained.
Reversely, if the reaction was irradiated for the last 30 mins,
the yield would drop to 17%. As a comparison, when model
reaction was irradiated at both the first and last 30 mins, 40%
yield was obtained. It indicated that photocatalyst along with
Blue LEDs was the main driving force to this reaction. Actually,
in this reaction, thiophenol 1a would be quickly transformed to
disulfides 1a’ in the presence of oxygen (Figure 1, column 2,
grey). While, in the presence of photocatalyst and light
irradiation, the formed disulfides 1a’ can relay generating the
product 3a (Scheme 2c).
4-ClPhS
4-ClPhS
Ph
O
1a
4-ClPhSH
O2
H
+
+
Ph
O
Ph
with or without
photo conditions
O
3a'
3a
Ph
Ph
2a
(4-ClPhS)2
1a'
Figure 1. Primary reaction condition screening for -thiol-α-
carbonylation of enone 2a. Reaction conditions: 4-
chlorothiophenol (0.4 mmol), chalcone (0.2 mmol),
photocatalyst (0.004 mmol), O2 balloon, 23W white LEDs,
solvent 4 mL, RT, 4 h. Yield was determined by 1H NMR.
Next, Different photo-catalysts and light irradiations were
screened successively (Table 1, entries 1-7). The NMR yield
could boost to 82% using fac-Ir(ppy)3 as photo-catalyst under
blue LED irradiation (Table 1, entry 7). Other photocatalysts
were inferior to fac-Ir(ppy)3 (Table 1, entries 2-6). Further
screening of the light wavelength identified the blue LEDs as
the best light source (Table 1, entry 7). Next, solvent effect
proved to be crucial for the observed reactivity, and CH3CN
emerged as the best choice (Table 1, entry 7). Moderate yields
a)
Addition of radical inhibitors
fac-Ir(ppy)3, Blue LED
O2,CH3CN
1a
3a
0%
2a
+
TEMPO (2 equiv)
or BHT (2 equiv)
b) Photo "on-off" experiment: yellow-on; grey-off
fac-Ir(ppy)3, Blue LED
O2,CH3CN
1a
2a
3a
+
210 min
87%
23%
40%
17%
210 min
180 min
210 min
30 min
30 min
Table
1
Optimal condition screening for β-thiol-α-
30 min
30 min
carbonylation of enone 2a[a]
4-ClPhS
O
c) The reaction of disulfide 1a' with enone 2a
H
4-ClPhSH
1a
+
Ph
fac-Ir(ppy)3, Blue LED
Ph
Ph
O
3a
2a
O2,CH3CN
3a
2a
1a'
+
35%
Entry PC*
Light/LEDs
Solvent Yield/%[b]
d) Hydroxysulfenylation of olefins
1
2
3
4
5
6
fac-Ir(ppy)3 White LED
Ru(bpy)3Cl3 White LED
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
68
0
Trace
0
Trace
30
R2
OH
R2
O
R3SH
O2
[H]
R1
R1
R1
R2
OH
Eosin Y
Eosin B
ACR-Mes
Methylene
Blue
Green LED
Blue LED
Blue LED
Blue LED
SR3
SR3
e) Wang's method for sulfur-mediated olefin cleavage
OH
R1CHO
O
O O
R3SH
O2
-R3SH
R1
R1
+
R2
R2
R1
R2
R2CHO
SR3
7
8
9
10
fac-Ir(ppy)3 Blue LED
fac-Ir(ppy)3 Blue LED
fac-Ir(ppy)3 Blue LED
fac-Ir(ppy)3 Blue LED
fac-Ir(ppy)3 Blue LED
CH3CN
Toluene 54
DCM
MeOH
THF
82
Scheme 2. Control experiments and relative literature reports
In classic enone hydrothiolation reactions, mercapto radical
was added to -position of enone to get Michael-addition
product. In this work, similar pathway may occur with
mercapto radicals adding to enones. Meantime, in some
50
Trace
17
11
[a]Reaction conditions: 4-chlorothiophenol 1a (0.4 mmol),
chalcone 2a (0.2 mmol), photocatalyst (0.004 mmol), O2
balloon, light, solvent (4 mL), RT, 4 h. [b] Yield was determined
by 1H NMR using mesitylene as internal standard.
pioneering
work12
and
our
previous
work,13
hydroxysulfenylation of terminal olefins have proven to be an
efficient pathway to afford -hydroxysulfides (Scheme 2d).
2 | J. Name., 2012, 00, 1-3
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These processes were considered to undergo through - further protonated to give intermediate B, which undergoes
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DOI: 10.1039/D0OB01349H
peroxysulfide radical intermediates which were subsequently homolysis C-C and O-O bond cleavage to yield product 3a and
reduced to -hydroxysulfides. Likewise, for non-terminal some observed byproducts. As for the photo-redox cycle, Ir(III)
olefins, Wang group reported that similar β-peroxysulfide was activated under the visible light irritation, activated Ir(III)
intermediates could proceed olefinic C-C cleavage after the was reduced to Ir(II) with thiopheol. Last, intermediate D, the
abandon of the thiophenol part (Scheme 2e)12c. Therefore, it formed H2O2 or disulfides 1a’ may oxidize Ir(II) to regenerate
can be anticipated that β-benzoyl-β-hydroxysulfides A or β- the Ir(III) photocatlyst. Another byproduct 3a’ was supposed to
benzoyl-β-peroxysulfides B may be the potential reaction be generated through protonation of intermediate C.
intermediate in this process (Scheme 3).
2R4S
from Ir2+ to Ir3+
R4SSR4
PhCHO
PhCOOH
H2O2
observed
byproduct
Cl
Cl
O
Ph
R4SSR4
R4S
R4S
+ OH
+
O
S
O
S
C-C
O-O
cleavage
OH
O
O
Ph
Ph
Ph
Ph
Ph
B
BDE energy
271 kJ/mol
A
BDE energy
332 kJ/mol
Ph
R4
Ph
H
O
OH
OH
S
R4S
3a
R4
S
O
B
Scheme 3. Possible reaction intermediates and their C-C BDE
R4SH
product
+H+
energy
O
O
O
Ir3+
SET
Ph
Ph
Comparatively, -hydroperoxysulfide
B is a preferred
H
S
candidate as the calculated C-C BDE energy of -
hydroperoxysulfides is significantly weaker than its
counterpart  -hydroxysulfide A (271 KJ/mol vs 332 KJ/mol,
Scheme 3). Moreover, calculation using Gaussian 09 has been
made to further support the assumption. As illustrated in
Figure 2, the bold C-C bond of hydroperoxide B was extended
to 2.07 Å and the energy barrier was only 5.7 kcal/mol.
According to the calculation results, the homolytic C-C and O-O
cleavage of hydroperoxide may occur to give the product 3a,
hydroxyl radical and benzoyl radical. In this reaction, both
benzaldehyde and benzoic acid were observed. Benzaldehyde
may come from the protonation of benzoyl radical and benzoic
acid may come from the combination of hydroxyl radical with
benzoyl radical.
Ph
Ph
R4
D
Ir2+
O2
Ph
*
Ir3+
3a'
O
S
R4
SET
observed
byproduct
Ph
R4SH
Ph
R4S
R
4
S
S
O
R4SH
R4
C
Ph
2a
R4 = 4-ClPh
O
Figure 3. Possible reaction mechanism
With the optimal conditions in hand and preliminary
understanding of the mechanism, the substrate scope was
then investigated. During the research, although the α-
thiolaldehyde 3a could be isolated via flash column separation,
3a was not stable under air atmosphere. It was difficult to
store the sample and take test. Therefore, an extra reduction
process with NaBH4 was conducted to yield more stable β-
hydroxysulfides 4 (Table 2). First, some commercially available
thiophenols bearing various substituents were used to react
with benzalacetophenone 2a. Thiophenols with substituents at
different positions showed good tolerance to give products 4a-
Cl
O
S
O
OH
e
in moderate to good yields (entries 1-5). However,
representative alkyl thiols were not suitable for this reaction as
hydrothiolation products 3f’ and 3g’ instead of the desired
products were obtained without NaBH4 reduction (entries 6
and 7). It may be explained that aliphatic thiols had higher S-H
bond BDE energy, which would be more difficult to be initiated
to form relative radicals. Meantime, competitive Michael
addition to enones was in priority because the aliphatic thiols
usually have higher nucleophilicity than thiophenols. As for
heterocyclic thiophenol (entry 8), only trace of starting
material was transformed to product. In terms of the enones
2, similar high yields were given when R3 was phenyl group or
Figure 2. Theoretical calculation for the possible reaction
intermediate B
Based on the above results, possible mechanism was shown
in Figure 3. Mercapto radical was generated by auto-oxidation
or photo oxidation of thiophenol 1a. Along with the reaction
process, the formed disulfide can be also transformed to
mercapto radical with aid of photo-redox catalytic cycle. -
Peroxysulfide radical intermediate D was then formed via the
addition of thiyl radical to enone 2a followed by capturing
oxygen under aerobic condition.12d Radical intermediate D was
steric 2-methoxyl phenyl group (entry 9). However,
a
significantly decreased yield was obtained when R3 was an
alkyl group (entry 10). -Unsaturated ester was also found
to be unsuitable due to the low conversion of the substrate
(entry 11). As the acyl group acts as a leaving group that has
no influence on the product structure, R3 was set as phenyl
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J. Name., 2013, 00, 1-3 | 3
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group in the following screening process. The reaction was
Journal Name
The present method also provided a convenienVtiepwaAtrhticwleaOynlitnoe
amenable to substituted benzalacetophenones, affording the synthesize various α-thiolaldehyde derivDaOtiIv:e10s.1(0S3c9h/eDm0OeB401).34F9oHr
corresponding products 4i-4o in the average yield of 80% example, one-pot condensation of 3a with 2,4-
(entries 12-18). Interestingly, 4-Br and 3-CN substituted dinitrophenylhydrazine afforded hydrazone 5 in overall 92%
substrates showed significantly decreased yields under the yield. Treatment of the reaction mixture with methyl Grignard
standard conditions, but replacement of benzalacetophenone regent can afforded higher order β-thiolative-α-alcohol 6.
with 2-methoxyl benzalacetophenone could increase the yields Sequential reduction and esterification of intermediate 3a in
of 4p and 4q to 69% and 76%, respectively (entries 19-22). one pot afforded product 7 in overall 73% yield. Notably,
Additionally, 2-naphthyl substituted substrate was also tested, additional separation process is not necessary for the above
and the desired product 4r was obtained in 68% yield (entry reactions. Additionally, treatment of 4a with a brominating
23). The product for the 4-pyridyl substrate can be tracked but reagent and a nucleophilic reagent also allows for the 1,2-
failed to be isolated due to the low transformation efficiency sulfur migration reaction. For instance, product 8 can be
and instability of product (entry 24). When 3-cyclohexyl-1- accessed with the addition of CBr4 and PPh3; dehydroxylated
phenylprop-2-en-1-one was used as the enone substrate, the amination product 9 was achieved in the presence of
desired product 4t was also obtained in a moderate yield CBr4/PPh3 and aniline. Thus, the developed method can serve
(entry
25).
Furthermore,
two
α-substituted as alternative access to α-thiolated derivatives, avoiding pre-
benzalacetophenones were tested. The reaction of α-methyl synthesis of unstable α-thiolaldehyde.
benzalacetophenone afforded desired product 3u in 60% yield
4-ClPhS
O
4-ClPhS
one-pot
-COPh
O2
O
without NaBH4 work-up (entry 26).
1a
Ph
O
+
Ph
Ph
Ph
H
2a
3a
5-7
H
Table 2. Substrate scope for β-thiol-α-carbonylation of enone[a]
Cl
NO2
Cl
Cl
R4
R4
O
S
S
-COR3
O2
[H]
O2N
S
S
S
OH
R4SH
R1
R3
2
R1
O
+
R1
OH
N
O
Ph
R2
Ph
N
H
Ph
R2
1
3
4
R2
Me
H
O
6,
5,
70% dr = 1/1
7,
73%
92%
Entry
R4
R1
R2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
R3
Product
Yield/%
82
Cl
1
4-ClPh
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
3f’
3g’
4h
4a
4a
4a
4i
OH
8
Cl
4-ClPhS
Ph
S
CBr4
PPh3
2
3-MePh
76
CBr4/PPh3
4-ClPhNH2
NH
Ph
OH
S
3
2-CO2MePh
4-MePh
4-tBuPh
Cyclohexyl
n-Bu
62
Ph
Cl
4a
, 79%
9,
75%
4
68
Scheme 4. Functionalization of 3a to afford α-thiolated
5
80
6
30[b,c]
25[b,c]
trace
80
derivatives
7
Another feature of this photo-catalyzed protocol is the
opportunity for potential drug molecule skeleton synthesis
(Scheme 5). For example, starting from commercially available
5-bromothiophene-2-carbaldehyde, synthesis of PPAR
modulators molecule14could be easily accessed via sequential
aldol condensation, this developed photo-catalysis reaction
and Suzuki-Miyuara coupling to afford product 10 in 61% total
yield.
8
4-Pyridyl
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
9
2-OMePh
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Me
OMe
Ph
38
trace
74
4-FPh
4-MePh
4-tBuPh
4-ClPh
Ph
4j
82
Ph
4k
4l
80
Ph
84
Cl
3-MePh
3-ClPh
Ph
4m
4n
4o
4p
4p
4q
4q
4r
86
1. 4-ClPhSH
Ph
79
S
fac-Ir(ppy)3
Blue LEDs
CH3CN,O2
O
OH
S
2-ClPh
Ph
83
Br
PhB(OH)2
Ph
10% NaOH
S
4-BrPh
4-BrPh
3-CNPh
3-CNPh
2-naphthyl
4-Pyridyl
Cyclohexyl
Ph
Ph
13
CHO
Pd(PPh3)Cl2
K3PO4
2. NaBH4
PPAR modulator
analogue
2-OMePh
Ph
79
10,
61% total yield
within 3 steps
46
2-OMePh
Ph
76
68
Scheme 5. Synthesis of PPAR modulator analogue with the
Ph
4s
4t
trace
60
60[c]
developed method.
Ph
Ph
3u
In summary, a photoredox sulfenylcarbonylation method of
enones is reported. This method fulfills the simultaneous C-S
coupling, oxidation, C-O coupling and Csp2–C(CO) σ-bond
cleavage in one pot. Preliminary mechanistic studies indicate
the potential radical pathway and highlight the potential
homolytic C-C and O-O cleavage. Moreover, the procedure is
[a]
Reaction conditions: thiols (0.4 mmol), enones (0.2 mmol),
O2 balloon, photocatalyst (0.004 mmol), CH3CN (4 mL), blue
LED, RT, 4 h, followed by NaBH4 (0.6 mmol), isolated yield.
Yield of hydrothiolation product 3’. [c]Without NaBH4 workup.
[b]
4 | J. Name., 2012, 00, 1-3
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Wei, H. Wang, Y. Sun, Ti. Noi, X. Wang, Angew. Chem. Int. Ed.
attractive from the application perspective, as evidenced by
the ability for construction of various α-thiolated derivatives.
View Article Online
2017, 56, 832.
DOI: 10.1039/D0OB01349H
13 B. Zhang, T. Liu, Y. Bian, T. Lu., J. Feng, ACS Sustain. Chem.
Eng. 2018, 6, 2651.
14 N. B. Mantlo, X. Wang, G. Zhu, PCT Int. Appl., 2004,
2004063184.
Acknowledgements
This work is funded by the National Natural Science Foundation of
China (Nos. 21572270, 21702232), the “Double First-Class”
University Project (CPU2018GY02 and CPU2018GY35).
Conflicts of interest
There are no conflicts to declare
Notes and references
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DOI: 10.1039/D0OB01349H
O
fac-Ir(ppy)3
R1
R1
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R2
Blue LEDs
O2, CH3CN
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Ar
Ar
R1 = Ar, alkyl; R2 = Ar
Unexpected aerobic enone difunctionalization
Method for -thiolative--functions
Homolytic C-C and O-O cleavage