Cs2CO3-promoted methylene insertion into disulfide bonds using acetone as a methylene source

Article abstract of DOI:10.1039/c8ob00877a

An efficient halogen-free Cs₂CO₃-promoted methylene insertion into disulfide bonds has been achieved using acetone as a methylene source under mild conditions. This method provides a convenient and practical route to dithioacetals in up to 96% yield with good functional group compatibility.

Full text of DOI:10.1039/c8ob00877a

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Cs2CO3‐promoted methylene insertion into disulfide bonds using
acetone as a methylene source†
Qian Chen,*a,b Guodian Yu,a Xiaofeng Wang,a Yulin Huang,a Yan Yana and Yanping Huoa
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient halogen‐free Cs2CO3‐promoted methylene insertion reduction for the formation of nucleophilic thiols. Therefore,
into disulfide bonds has been achieved using acetone as a the development of efficient methods for the preparation of
methylene source under mild conditions. This method provides a important dithioacetals is still of great interest.
convenient and practical route to dithioacetals in up to 96% yield
with good functional group compatibility.
Most recently, our group achieved the halogen‐ and metal‐
free construction of carbon sulfur, phosphorus sulfur, and
sulfone sulfur bonds via an addition of nucleophiles or sulfonyl
−
−
−
radicals to disulfide intermediates.11 During our studies on the
Cs2CO3‐promoted aerobic oxidative cross‐dehydrogenative
coupling of thiophenols with carbonyl compounds,11a trace
amounts of bis(arylthio)methanes were occasionally observed
when acetone was used as the solvent. Thus, we became
interested in investigating the formation of dithioacetals
through the reaction of disulfides with acetone in the presence
of Cs2CO3 under air atmosphere. Herein, we report a
convenient halogen‐free synthesis of dithioacetals via the
methylene insertion into disulfide bonds using acetone as a
methylene source under mild conditions (Scheme 1e).
Dithioacetals have been widely utilized in organic synthesis as
sulfur‐stabilized carbanions, which can react with various
electrophiles such as alkyl halides, epoxides, ketones and
aldehydes.1 In addition, the oxidation of dithioacetals can
efficiently produce important active methylene compounds
including sulfones and sulfoxides.2 On the other hand,
bis(arylthio)methane ligands have attracted significant
attention due to their potent applications in metal‐organic
coordination polymers.3 Notably, the conversion of the
disulfide bond of the important peptide hormone oxytocin into
highly stable dithioacetal annihilates the reductive lability and
increases the serum, pH and temperature stability, together
with unchanged biological activities.4 A variety of synthetic
methods to access dithioacetals have been well documented.5
Previous studies on the synthesis of dithiomethanes, the
simplest dithioacetals, mainly relied on the insertion of
methylene into disulfide bonds using diazomethane,6 sulfur
ylides,7 or zinc carbenoids8 as the methylene source (Scheme
1a−c). However, these protocols afforded the corresponding
dithioacetals in poor yields. Recently, Pace and co‐workers
developed an efficient homologation of disulfides to
dithioacetals via an addition of lithium carbenoids to disulfides
(Scheme 1c), while moisture‐sensitive reagents and low
temperature (‐78 oC) were necessarily required.9 It is
noteworthy that methylene halides were used for the
methylene insertion into disulfide bonds of peptides (Scheme
1d).4,10 However, this approach requires a prior disulfide bond
a. School of Chemical Engineering and Light Industry, Guangdong University of
Technology, Guangzhou 510006, China. E‐mail: qianchen@gdut.edu.cn
b. Key Laboratory of Functional Molecular Engineering of Guangdong Province,
South China University of Technology, Guangzhou 510640, China.
†Electronic Supplementary Information (ESI) available. See DOI: 10.1039/
x0xx00000x
Scheme 1 Synthesis of dithioacetals from disulfides.
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Table 1 Optimization of reaction conditionsa,b
Table 2 Scope of disulfidesa,b
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DOI: 10.1039/C8OB00877A
Entry Base
T (oC)
Time
Yield of 2a (%)
1
Cs2CO3
Rt
4 d
71
75
30
70
9
2
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
NaHCO3
K3PO4
40
40
40
40
40
40
40
40
40
40
40
40
40
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
3c
4
5
6
7
8
9
10
11d
12e
13e,f
14e,g
6
54
58
0
31
42
97
83
71
CsF
NaOAc
CsOAc
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
a
Reaction conditions: 1a (0.2 mmol), base (0.4 mmol), 18‐crown‐6
(0.4 mmol), anhydrous acetone (2 mL), open air. b Yield based on 1a
was determined by H NMR analysis of crude products using an
internal standard. The reaction was carried out under N2.
Anhydrous acetone (1 mL) was used. Anhydrous acetone (3 mL)
1
c
d
e
f
was used. Cs2CO3 (0.3 mmol) and 18‐crown‐6 (0.3 mmol) were
introduced. g Cs2CO3 (0.2 mmol) and 18‐crown‐6 (0.2 mmol) were
introduced.
In order to improve the yields of dithioacetals, 18‐crown‐6
as a phase‐transfer catalyst was employed for increasing the
solubilities of inorganic bases in acetone. The reaction
conditions were tested by using a model reaction of diphenyl
disulfide 1a (0.2 mmol) with acetone (2 mL) in the presence of
an inorganic base (2 equiv) and 18‐crown‐6 (2 equiv) under air
atmosphere, and the results were shown in Table 1. We first
carried out the reaction of 1a with acetone at room
temperature using Cs2CO3 as the base (entry 1). To our delight,
the desired bis(phenylthio)methane 2a was obtained in 71%
yield, while the reaction proceeded very slowly (4 days). When
a Reaction conditions: 1 (0.4 mmol), Cs2CO3 (0.8 mmol), 18‐crown‐6
o
b
(0.8 mmol), anhydrous acetone (6 mL), open air, 40 C, 24 h.
c
Isolated yield based on 1. The reaction was performed in a 9.2
mmol scale for 36 h.
To investigate the scope of the methylene insertion protocol,
we applied the optimized conditions to the reaction of a
variety of disulfides with acetone, and the results are
illustrated in Table 2. Pleasingly, the results showed that diaryl
disulfide substrates bearing different groups such as electron‐
donating groups (Me, Et, t‐Bu and OMe) and electron‐
withdrawing groups (Br, Cl, F and NO2) at the para, meta or
ortho or at both positions of aromatic rings, as well as 2,2'‐
dinaphthyl disulfide, were well‐tolerated. The desired
o
the temperature was set at 40 C, the reaction proceeded
smoothly to afford 2a in 75% yield within 24 h (entry 2). When
the reaction was performed under N2, the yield of 2a
significantly decreased (entry 3), suggesting that an aerobic
oxidation might be involved in the reaction. We then turned to
screen inorganic bases including other cesium salts (entries
bis(arylthio)methanes 2a
moderate to excellent yields (50
−
2s and 2u−2w were isolated in
96%), indicating that the
−
electronic effects were not evident in this reaction. When the
substrate bearing methyl groups at both ortho positions was
examined, only trace amounts of the corresponding product 2t
were observed probably due to the steric hindrance of ortho‐
substituents. In addition, the reaction of di(2‐thienyl) disulfide
with acetone was also carried out, leading to the formation of
the desired 2x in 60% yield. However, the methylene insertion
into dibenzyl disulfide give 2y in only 36% yield, and didecyl
disulfide failed to give the desired 2z. The scale‐up of the
reaction of 1a with acetone was also attempted. When we
increased the scale of the reaction from 0.4 to 9.2 mmol, 2a
was isolated in moderate yield (1.23 g, 57% yield).
4−10), and found that Cs2CO3 was the optimal base. The use of
1 mL of acetone gave 2a in a low yield of only 42% (entry 11),
while the use of more acetone (3 mL) significantly increased
the yield further to 97% (entry 12). We then turned to the
decrease of Cs2CO3 and 18‐crown‐6 amounts, and the yield of
2a was suppressed (entries 13 and 14). In addition, the use of
DMSO, DMA, CH3NO2, CH3CN or ethyl acetate instead of
acetone failed to give 2a. Other ketones were then tested as
the methylene sources. However, the use of tert‐butyl methyl
ketone gave 2a in only 43% yield, and acetophenone and 3‐
pentanone gave α‐sulfenylated ketones.
2 | J. Name., 2012, 00, 1‐3
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Cs2CO3 (2 equiv)
18-crown-6 (2 equiv)
acetone-d6, air, 40 oC, 24 h
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DOI: 10.1039/C8OB00877A
H
D
(a)
PhS SPh
PhS
SPh
1a
2a-d, 92% (100% D)
Cs2CO3 (2 equiv)
18-crown-6 (2 equiv)
H
D
1a
(b)
(c)
PhS
SPh
D2O (5 equiv)
acetone, air, 40 oC, 24 h
2a-d, 90% (100% D)
Cs2CO3 (2 equiv)
18-crown-6 (2 equiv)
acetone, air, 40 oC, 1 h
O
O
SPh
SPh
1a
2a
+
+
SPh
4%
3a, 7%
4a, 17%
Cs2CO3 (2 equiv)
18-crown-6 (2 equiv)
acetone, air, 40 oC, 24 h
O
Scheme 4 Attempts at unsymmetric disulfides.
According to our observations and previous reports,11,12
plausible reaction mechanism is outlined in Scheme 3. Initially,
acetone reacts with Cs2CO3 to form cesium enolate. The
SPh
(d)
(e)
PhS
SPh
2a, 95%
4a
SPh
a
Cs2CO3 (2 equiv)
R
R
18-crown-6 (2 equiv)
SH
R
acetone, air, 40 oC, 24 h
S
S
nucleophilic attack of the in situ generated enolate on
affords α‐monosulfenylated acetone and cesium arylthiolate,
which is recombined to disulfide
by O2.12 α,α‐Disulfenylated
acetone is generated by the second sulfenylation of in the
presence of Cs2CO3. The intermediate then reacts with
hydroxide ions under hygroscopic alkaline conditions to form
the unstable intermediate . Finally, the decarboxylation of
and a subsequent protonation give the desired dithioacetal
1 then
5
2b, R = Me, 72%
2f, R = Br, 80%
2i, R = NO2, 83%
3
1
4
3
Scheme 2 Mechanistic studies.
4
To gain more insight into the mechanism of this reaction, a
couple of control experiments were then conducted (Scheme
2). In order to elucidate the hydrogen source of dithioacetals
6
6
2.
2
,
The low yield of the reaction under N2 (Table 1, entry 3)
indicated that the in situ cesium benzenethiolate failed to form
disulfide 1a in the absence of O2, which is in good agreement
with the proposed mechanism. To further elucidate the
mechanism, we then carried out the methylene insertion into
unsymmetric disulfides under the standard conditions (Scheme
4). The reaction of unsymmetric diaryl disulfide 1bi smoothly
gave 2b and 2i in high yields, while the reaction of
unsymmetric ArS‐S‐alkyl 1bz gave the only product 2b in good
yield. However, unsymmetric dithioacetals were not detected
in both reactions. These observations clearly indicated that the
we carried out deuterium labeling studies. When the reaction
was performed in deuterated acetone under the standard
conditions, monodeuterated 2a‐d was formed in 92% yield
with 100% D incorporation at the methylene group (Scheme
2a). The same results were observed when the reaction was
performed in non‐deuterated acetone with the addition of 5
equiv of D2O (Scheme 2b). These observations clearly indicated
that trace amounts of water in hygroscopic Cs2CO3 served as
one proton source, and acetone provided the other proton of
the methylene group. Our attention turned next to an
investigation of key reaction intermediates. When the reaction
was conducted under the same conditions for only 1 hour
(Scheme 2c), trace amounts of 2a were detected, together
with α‐monosulfenylated acetone 3a and α,α‐disulfenylated
acetone 4a in 7% and 17% yield, respectively. Furthermore,
the reaction of 4a under the standard conditions smoothly led
to the formation of 2a in excellent yield (Scheme 2d). These
results demonstrated that both 3a and 4a might be the
reaction intermediates. On the other hand, the use of
enolates of acetone and
3 selectively attacked the relatively
electron‐deficient sulfur atom in disulfide bonds to afford the
first symmetric dithioacetals, and the regenerated diaryl
disulfides gave the second symmetric products, while the
regenerated dialkyl disulfides failed to give the products. These
experimental results provided further support for the
proposed mechanism.
In summary, we have developed the Cs2CO3‐promoted
methylene insertion into disulfide bonds using acetone as a
methylene source, which provides a convenient, practical and
economical protocol for the synthesis of dithioacetals with
good functional group compatibility. It is noteworthy that the
important dithioacetals were obtained in moderate to
excellent yields under very mild and environmentally friendly
conditions. We envision that the reaction mode outlined here
will have potential applications in organic synthesis.
thiophenols
5 instead of disulfides also afforded the desired 2
in good yields (Scheme 2e), suggesting that the autoxidation of
thiols under the reaction conditions might form disulfides.
Conflicts of interest
There are no conflicts of interest to declare.
Scheme 3 Proposed mechanism.
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Journal Name
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Cs2CO3-promoted methylene insertion into disulfide bonds using
acetone as a methylene source
Qian Chen, Guodian Yu, Xiaofeng Wang, Yulin Huang, Yan Yan and Yanping Huo
A practical route to dithioacetals has been achieved via methylene insertion into
disulfide bonds using acetone as a methylene source.