Disulfides as Sulfonylating Precursors for the Synthesis of Sulfone-Containing Oxindoles

Article abstract of DOI:10.1002/adsc.201600200

The first facile one-pot synthesis of sulfone-containing oxindoles with easily accessible disulfides as the sulfonylating precursors is described. This reaction occurs smoothly under transition metal-free conditions and shows excellent functional group tolerance, allowing the facile and efficient green synthesis of various sulfone-containing oxindoles in aqueous solution. Preliminary mechanistic studies reveal that both water (H₂O) and potassium persulfate (K₂S₂O₈) can be the oxygen source of the sulfone groups in the products. (Figure presented.).

Full text of DOI:10.1002/adsc.201600200

UPDATES
DOI: 10.1002/adsc.201600200
Disulfides as Sulfonylating Precursors for the Synthesis of
Sulfone-Containing Oxindoles
Ming-Zhong Zhang,a,b Peng-Yi Ji,a Yu-Feng Liu,a Jing-Wen Xu,a
and Can-Cheng Guoa,*
a
State Key Laboratory of Chemo/Biosensing and Chemometrics, Advanced Catalytic Engineering Research Center of the
Ministry of Education, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, Peopleꢀs
Republic of China
E-mail: ccguo@hnu.edu.cn
b
School of Chemistry and Chemical Engineering, Yangtze Normal University, Chongqing 408100, Peopleꢀs Republic of
China
Received: February 18, 2016; Revised: May 2, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600200.
Abstract: The first facile one-pot synthesis of sul-
fone-containing oxindoles with easily accessible di-
sulfides as the sulfonylating precursors is described.
This reaction occurs smoothly under transition
metal-free conditions and shows excellent function-
al group tolerance, allowing the facile and efficient
green synthesis of various sulfone-containing oxin-
doles in aqueous solution. Preliminary mechanistic
studies reveal that both water (H2O) and potassium
persulfate (K2S2O8) can be the oxygen source of the
sulfone groups in the products.
ration of the starting materials.[8] The C H functional-
ization/cyclization of alkenes[9] has been used to in-
stall the valuable sulfonyl moieties onto unsaturated
hydrocarbon skeletons. With this strategy, various sul-
fonylating agents, such as sulfonylhydrazides,[10,11] sul-
finic acids,[7,12,13,14] and arylsulfinic acid sodium salts,[15]
have been employed to react with activated alkenes
to produce sulfonated oxindoles. However, these reac-
tions usually require toxic metal reagents or precious
photocatalysts and show low atom-efficiency, which
greatly restrict their applications in the fields of syn-
thetic chemistry and pharmaceutical industry. Thus, it
is important to develop more efficient and greener
protocols for the synthesis of sulfone-containing oxin-
doles.
À
Keywords: cyclization; hydrolysis; oxidation; radi-
cal reactions; synthetic methods
Disulfides are widely used as the thioether reagents
À
in transition metal-catalyzed C S bond-forming reac-
tions because they are readily available, easy-to-
handle, and have low-toxicity properties.[16,17] Howev-
er, the use of disulfides as the sulfonylating reagents
Introduction
Since the discovery of the first sulfonamide antibiotics has been less reported. Previous works mainly fo-
in the 1930s, sulfone-containing drugs have attracted cused on the oxyhalogenation of disulfides to produce
much attention.[1] Particularly in 1990, Gans devel- sulfonyl halides by using a variety of oxidative halo-
oped the tricyclic class prostaglandin inhibitor DuP- genation systems (Scheme 1a).[18] Bischoff and Bahra-
697.[2] Other precious sulfone compounds such as mi improved the procedure and achieved the one-pot
HIV-1 protease inhibitors,[3] matrix metalloproteinase conversion of disulfides to sulfonic acid derivatives
inhibitor SC-78080/SD-2590[4] and b2 adrenoceptor ag- via in situ generation of sulfonyl chlorides
onist[5] have also been discovered successively (Scheme 1b).[19] Johnson et al. employed disulfides as
(Figure 1).
sulfonylating reagents in the total synthesis of 5-HT6
Today, sulfone-containing scaffolds commonly receptor antagonists (Scheme 1c).[20] To the best of
occur in bioactive molecules and drugs.[6] Among our knowledge, the use of disulfides as sulfonylation
them, the sulfonated oxindoles are very important precursors for the synthesis of high-value sulfone-con-
due to their potential roles in structural library design taining oxindoles has never been reported. Herein,
and new drug discovery.[7] A traditional procedure for we communicate a highly efficient K2S2O8-mediated,
their preparation depends on the transformation of one-pot reaction of arylacrylamides with disulfides
halooxindoles, suffering from difficulty for the prepa- (Scheme 1d). This transformation is operationally
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Figure 1. Representative sulfone-containing drugs.
Table 1. Optimization of the reaction conditions.[a]
Entry Oxidant [equiv.] Solvent
T [8C] Yield [%][b]
1
2
3
4
K2S2O8 (2.0)
none
CH3CN/H2O 80
73
0
79
86
88
85
79
71
CH3CN/H2O 80
CH3CN/H2O 80
CH3CN/H2O 80
CH3CN/H2O 80
CH3CN/H2O 80
CH3CN/H2O 80
CH3CN/H2O 80
K2S2O8 (2.5)
K2S2O8 (3.0)
K2S2O8 (3.5)
K2S2O8 (3.0)
K2S2O8 (3.0)
Na2S2O8 (3.0)
5
6[c]
7[d]
8
9
(NH4)2S2O8 (3.0) CH3CN/H2O 80
76
10
11
12
13
14
15
16
17
18
19
oxone (3.0)
K2S2O8 (3.0)
K2S2O8 (3.0)
K2S2O8 (3.0)
K2S2O8 (3.0)
K2S2O8 (3.0)
K2S2O8 (3.0)
K2S2O8 (3.0)
K2S2O8 (3.0)
K2S2O8 (3.0)
K2S2O8 (3.0)
K2S2O8 (3.0)
CH3CN/H2O 80
CH3CN/H2O 60
CH3CN/H2O 100
trace
65
78
16
40
trace
trace
37
0
0
DMF/H2O
80
DMSO/H2O 80
DCE/H2O
CH3CN
H2O
DMSO
DMF
80
80
80
80
80
80
Scheme 1. Disulfides as sulfonylating precursors in synthetic
chemistry.
simple, functional group tolerant, and represents the 20
DCE
trace
57
21[e]
CH3CN/H2O 80
first example on the synthesis of sulfone-containing
oxindoles using disulfides as the sulfonylating re-
agents.
[a]
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol,
1.5 equiv.), and solvent (v:v, 1:1; 2 mL) under an N2 at-
mosphere for 24 h.
Isolated yields based on 1a.
2a (0.4 mmol, 2.0 equiv.).
[b]
[c]
[d]
[e]
Results and Discussion
2a (0.2 mmol, 1.0 equiv.).
Under an air atmosphere.
We chose N-arylacrylamide (1a) and diphenyl disul-
fide (2a) as the model substrates to optimize the con-
ditions for this reaction, and the obtained results are
summarized in Table 1. By using 2.0 equiv. of K2S2O8 vent, the mixture of 1a and 2a was heated at 808C
as the oxidant and CH3CN/H2O (v/v, 1:1) as the sol- under an N2 atmosphere for 24 h, the corresopnding
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sulfonated oxindole (3a) was produced in 73% yield seen when the reaction was carried out under an air
(entry 1). No reaction was observed in the absence of atmosphere (entry 21).
K2S2O8 (entry 2). A good yield (86%) was afforded
Under the optimized reaction conditions, the cycli-
by increasing the amount of K2S2O8 to 3.0 equiv. (en- zation reactions of diphenyl disulfide with various N-
tries 3 and 4); however further increasing the amount arylacrylamides were explored. As shown in
of K2S2O8 did not improve the reaction efficiency Scheme 2, except for a para-NO2 substituted amide
drastically (entry 5). Under similar reaction condi- (3g), a variety of amides bearing functional groups at
tions, the reaction gave the highest yield with the para-position of the phenyl ring were applicable
1.5 equiv. of 2a (entry 4 vs. entries 6 and 7). Other in- to this reaction, affording the desired products in
organic oxidants like Na2S2O8, (NH4)2S2O8, and oxone good to excellent yields (3b–3f, 3h, and 3i). Particular-
were tested, and K2S2O8 was found to be the best ly noteworthy was that halogen atoms (F, Cl, Br, and
choice (entry 4 vs. entries 8–10). By further screening I) were well tolerated under the reaction conditions,
the reaction temperatures (entries 11 and 12) and sol- facilitating further functionalization of the products
vents (entries 13–20), it turned out that the highest by transition metal-catalyzed cross-coupling reactions.
yield was provided when the reaction was performed The sterically congested ortho-substituted N-arylacryl-
in CH3CN/H2O at 808C. Dioxygen seemed to be det-
ACHTUNGTRENaNGNU mides also showed reactivity in this reaction with
rimental to the reaction since a decreased yield was synthetically useful yields (3j and 3k). Interestingly,
Scheme 2. Scope of disulfides. Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), K2S2O8 (3.0 equiv.), and CH3CN/H2O (1:1,
2 mL) at 808C under an N2 atmosphere for 24 h; Isolated yields based on 1.
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the N-ethyl-substituted substrate with a meta methyl
group on the phenyl ring could also be cyclized to
produce the corresponding products in good yield al-
though with inevitable regioisomers (3l/3l’ in a ratio
of 1:2). The N-benzyl and tetrahydroquinoline deriva-
tives could also afford the desired oxindoles 3m and
3n in 92% and 77% yields, respectively. Subsequently,
the substituent effect at the a-position (R3) of the ac-
rylamide moiety was evaluated. It was found that
except for 3o (R3 =H), other monosubstituted olefins
with CH2OH, CH2OAc, and 1,3-dioxoisoindolin-2-yl
Scheme 4. Gram-scale reaction.
all proved to be good substrates (3p–3r). However, on isolated yield, clearly demonstrating the preparative
switching the heteroatoms from N to O in the frame- practicality of this novel one-pot protocol.
work of the activated alkenes, no desired products
were observed under similar reaction conditions (3s tion, several control experiments were carried out as
and 3t). described in Scheme 5. On addition of 2 equiv. of rad-
Then, we explored the scope of disulfides ical scavenger 2,6-di-tert-butyl-4-methylphenol
To understand the mechanism of this transforma-
(Scheme 3). Derivatives with Me, OMe, and Cl (BHT), only a trace amount of 3a was generated
groups at the para-position of the benzene ring pro- under similar reaction conditions. Moreover, replacing
duced the desired products in excellent yields (3u– BHT
with
2,2,6,6-tetramethyl-1-piperidinyloxy
3w). However, an NO2 substituent at the para-posi- (TEMPO) or hydroquinone completely inhibited this
tion leads to a dramatic decrease of the reaction effi- reaction [Eq. (1)]. These results indicated that the re-
ciency (3x). Interestingly, when the NO2 group is action should be a radical process. Interestingly, when
placed at the meta-position, the reaction proceeded anhydrous CH3CN and H218O were used as the sol-
smoothly and afforded the corresponding product in vent, a mixture of 3a and 18O-labeled products
good yield (3y). To our delight, this protocol is also (3a-18O-1 and 3a-18O-2) was obtained as determined
1
applicable to diheteroaryl disulfides and dicycloalkyl by LC, LR-MS and H NMR analyses (for details, see
disulfides. For example, 2,2’-dipyridyl disulfide, 2,2’-di- the Supporting Information) [Eq. (2)], implying that
thienyl disulfide, dicyclopropyl disulfide and dicyclo- both H2O and K2S2O8 could be the source of the
hexyl disulfide were converted to the corresponding oxygen atom of the final products. In addition, when
products in yields ranging from 19% to 61% (3z–3ac). the reaction was carried out under an O2 atmosphere,
This reaction could also be performed on a gram no 3a was produced, which might rule out the possi-
scale. As shown in Scheme 4, treatment of 1.05 g bility of O2 (from the solvent) as an oxygen source in
(6 mmol) of N-arylacrylamide 1a with 1.5 equiv. di- this reaction [Eq. (3)].
phenyl disulfide 2a under the optimized reaction con-
It should be noted that in addition to the desired
ditions afforded the corresponding 3a (1.36 g) in 72% product 3a, the reaction of N-arylacrylamide 1a and
Scheme 3. Scope of disulfides. Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), K2S2O8 (3.0 equiv.), and CH3CN/H2O (1:1,
2 mL) at 808C under an N2 atmosphere for 24 h; Isolated yields based on 1a.
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Scheme 5. Experiments for mechanistic studies.
diphenyl disulfide 2a also gave a by-product S-phenyl Thus, it it would be reasonable to deduce that com-
benzenesulfonothioate (4) in 31% yield [Eq. (4); for pounds 4 and 5 were the plausible intermediates in
details, see the Supporting Information]. When the this reaction.
resulting by-product 4 was subjected to this reaction,
On the basis of the results described above and pre-
a 91% yield of 3a was obtained [Eq. (5)]. In addition, vious reports, a plausible mechanism is outlined in
the sulfur-containing oxindole (5)[21] could also be Scheme 6. The reaction is initiated by the oxidative
converted to the sulfone-containing oxindole 3a (the activation of disulfide 2a with persulfate via multiple
18O-labeled products were not observed in this case) processes.[22] The key intermediate thiosulfonate (4),
in good yield under similar reaction conditions [Eq. generated from the rearrangement of disulfoxide (7)
(6); for details, see the Supporting Information]. via concerted mechanisms,[22,23] could be isolated from
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Scheme 6. Proposed mechanism.
this reaction. In the absence of persulfate oxidant, the which was converted into an oxygen-centered radical
reaction of 1a with 4 progressed sluggishly; however (H) resonating with sulfonyl radical A via the single
a high yield of 3a was obtained by addition of 3 equiv. electron transfer (SET) and deprotonation process in
of persulfate oxidant [Scheme 5, Eq (5)]. It was de- the presence of persulfate.[29] The further reaction be-
duced that compound 4 was further oxidized to sulfi- tween A and 1a would lead to the selective formation
nyl sulfone (8), which could undergo spontaneous ho- of the final product.
À
molytic S S bond cleavage to yield a sulfonyl radical
(A) and a sulfinyl radical (9).[24] On the other hand,
sulfinyl radical intermediate 9 is also generated from Conclusions
À
the homolytic cleavage of the S S bond in disulfoxide
7.[22,25] The subsequent reaction between 9 and thiosul- In summary, we have developed a highly efficient and
finate intermediate (6) would generate the activated facile cascade cyclization of N-arylacrylamides with
radical (B) as well as thiosulfonate 4 via a similar oxi- disulfides under transition metal-free conditions. A
dative process again.[26] The addition of radical B to variety of sulfone-containing oxindoles are efficiently
N-arylacrylamide 1a would lead to the formation of prepared by using this novel one-pot protocol. Pre-
alkyl radical D, which underwent an intramolecular liminary mechanistic studies showed that this reaction
radical cyclization to form the aryl radical F.[21] Final- would be a radical process and the oxygen atoms in
ly, oxidation of F afforded the corresponding carbo- the products would originate from both H2O and
cation, followed by the loss of H+, thus producing the K2S2O8. Further studies on the mechanism and appli-
sulfur-containing oxindole 5.[27] The resulting 5 would cations are ongoing in our laboratory.
be rapidly oxidized to 3a by K2S2O8. In parallel, rever-
sible addition of sulfonyl radical A to the C=C double
bond[28] of 1a would lead to the formation of alkyl
radical C, which underwent radical cyclization to
afford the corresponding product 3a. Since 3a-18O-
1 as another main product was observed in our label-
ing experiment, we propose a plausible pathway. It
was deduced that the hydrolysis of disulfoxide
Experimental Section
Preparation of Substrates
Substrates 1a–r[30a,b] and substrates 1s and 1t[30c] were pre-
7[22,23a,b,c] would generate benzenesulfinic acid (G) pared according to the literature procedures.
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S. Wu, L.-M. Lin, M. Sun, Y.-S. Chao, C. Shih, S.-Y.
Wu, S.-L. Pan, M.-S. Hung, S.-H. Ueng, J. Med. Chem.
2016, 59, 419.
Typical Procedure for the Synthesis of Sulfone-
Containing Oxindoles
To a 25-mL Schlenk tube were added N-arylacrylamide
1 (0.2 mmol), disulfide 2 (0.3 mmol, 1.5 equiv.), K2S2O8
(0.6 mmol, 3.0 equiv.) and CH3CN/H2O (1:1, 2 mL). Then
the tube was charged with nitrogen, and the content was
stirred at 808C for 24 h until complete consumption of start-
ing material as monitored by TLC. After the reaction, the
resulting mixture was extracted with ethyl acetate (EtOAc).
The combined organic layers were dried over Na2SO4, fil-
tered, and concentrated in vacuum. The resulting residue
was purified by silica gel column chromatography (petrole-
um ether/ethyl acetate) to afford the desired product 3.
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À
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Acknowledgements
Financial support from the National Science Foundation of
China (No.21372068, 21572049) is gratefully acknowledged.
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ÞÞ
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UPDATES
Disulfides as Sulfonylating Precursors for the Synthesis of
Sulfone-Containing Oxindoles
9
Adv. Synth. Catal. 2016, 358, 1 – 9
Ming-Zhong Zhang, Peng-Yi Ji, Yu-Feng Liu, Jing-Wen Xu,
Can-Cheng Guo*
Adv. Synth. Catal. 0000, 000, 0 – 0
9
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!