Transition-metal-free synthesis of 3-sulfenylated chromones via KIO3-catalyzed radical C(sp2)–H sulfenylation

Article abstract of DOI:10.3762/bjoc.13.199

The reactions between o-hydroxylphenyl-functionalized enaminones and sulfonyl hydrazines providing 3-sulfenylated chromones via domino chromone ring construction and C(sp²)–H bond sulfenylation have been achieved under transition-metal-free conditions by using KIO₃ as the only catalyst.

Full text of DOI:10.3762/bjoc.13.199

Transition-metal-free synthesis of 3-sulfenylated chromones
via KIO3-catalyzed radical C(sp2)–H sulfenylation
Yanhui Guo, Shanshan Zhong, Li Wei and Jie-Ping Wan*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 2017–2022.
College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang 330022, P.R. China
doi:10.3762/bjoc.13.199
Received: 20 June 2017
Email:
Accepted: 15 September 2017
Published: 27 September 2017
Jie-Ping Wan* - wanjieping@jxnu.edu.cn
* Corresponding author
Associate Editor: C. Stephenson
Keywords:
© 2017 Guo et al.; licensee Beilstein-Institut.
License and terms: see end of document.
C–H sulfenylation; chromones; domino reaction; free-radical;
transition-metal-free
Abstract
The reactions between o-hydroxylphenyl-functionalized enaminones and sulfonyl hydrazines providing 3-sulfenylated chromones
via domino chromone ring construction and C(sp2)–H bond sulfenylation have been achieved under transition-metal-free condi-
tions by using KIO3 as the only catalyst.
Introduction
The C–S bond-forming reactions occupy a significant position Recently, as a new trend, the transition-metal-free oxidative
in organic synthesis as they are the major route to install sulfur coupling has emerged as a powerful complementary tactic in
fragments to organic compounds. As prevalent substructures in C(sp2)–S bond forming reactions [16-27]. As a beneficial and
many natural products and biologically relevant organic mole- sustainable approach, such transition-metal-free cross coupling
cules, the C(sp2)–S bonds such as the C–S(sulfenyl) bond are transformations have been successfully employed in the synthe-
known to play crucial roles in determining the properties and bi- sis of many useful organic compounds elaborated with sulfenyl
ological functions of sulfur-containing compounds [1-3]. There- groups. For example, the 3-sulfenylated chromones, a class of
fore, research works in developing efficient and flexible meth- useful organic molecules with important biological profiles [28-
odologies to generate C(sp2)–S bonds have attracted sustain- 31] and extensive application in synthetic chemistry [32-37],
able interest throughout the advances of modern organic synthe- have been readily synthesized with several different transition-
sis. Presently, the most popular approaches in constructing a metal-free C–H cross-coupling approaches. Zhou and
C(sp2)–S bond are the transition-metal-catalyzed Ullmann C–S co-workers reported the NH4I-promoted synthesis of 3-sulfeny-
coupling reaction [4-8], Chan–Lam cross-coupling reaction lated chromones via the direct chromone C–H sulfenylation by
[9-12] as well as the transition-metal-catalyzed C–H bond acti- using different sulfur sources (A, Scheme 1) [38,39]. Recently,
vation [13-15].
our continuous efforts in exploring enaminone C(sp2)–H bond
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Beilstein J. Org. Chem. 2017, 13, 2017–2022.
Scheme 1: Methods on the synthesis of 3-sulfenylchromones.
sulfenylation [40,41] reactions have led us to establish the syn-
thesis of 3-sulfenylated chromones via KIO3-catalyzed tandem
reactions of o-hydroxylphenylenaminone and thiophenols via
tandem C–H sulfenylation and intramolecular C–N bond
oxygenation (B, Scheme 1) [42]. Subsequently, Braga et al. re-
ported a similar catalytic 3-sulfenylchromone synthesis by em-
ploying disfulfides as the sulfenyl sources (B, Scheme 1) [43].
Although the efficiency and application scope of the known
routes are fine, the cost and limited variation on chromone sub-
strates and/or the utility of the odorous thiophenols remain as
restrictions. In this regard, devising alternative synthetic
methods featuring simultaneously the advantages of easily vari-
able, low-cost substrates and operationally practical sulfur
sources is highly demanding. Herein, we report a new synthetic
protocol toward these compounds through the tandem reactions
between o-hydroxyphenylenaminones and sulfonyl hydrazines.
In this method, the construction of the target products is
furnished via the key C–H sulfenylation without using any tran-
sition metal catalyst or oxidative additive.
Table 1: Optimization of the reaction conditions for the synthesis of
sulfenylated chromonesa.
Entry
Catalyst Solvent
T (°C)
Yield (%)b
1
no
DMF
100
100
100
100
100
100
reflux
reflux
100
100
120
130
140
130
130
130
130
nr
2
KI
DMF
45
56
69
61
60
56
55
57
62
76
79
78
78
75
84
82
3
I2
DMF
4
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
DMF
5
DMSO
EL
6
7
EtOH
MeCN
1,4-dioxane
toluene
DMF
8
9
Results and Discussion
10
11
12
13
14c
15d
16e
17f
Initially, the reaction of enaminone 1a and sulfonyl hydrazine
2a was tentatively subjected to different iodine reagents or cata-
lyst-free conditions. The results indicated that no product was
observed in the reaction without catalyst (entry 1, Table 1), and
different types of iodine reagents such as KI, I2 or KIO3 could
all catalyze the domino reaction to provide product 3a, wherein
KIO3 displayed the highest catalytic activity (entries 2–4,
Table 1). On the other hand, in the reactions performed in dif-
ferent media, including DMSO, ethyl lactate (EL), EtOH,
MeCN, 1,4-dioxane and toluene, DMF was found as the most
proper medium (entries 4–10, Table 1). Notably, increasing the
reaction temperature to 130 °C promoted the production of 3a
DMF
DMF
DMF
DMF
DMF
DMF
aGeneral conditions: 1a (0.3 mmol), 2a (0.36 mmol), catalyst
(0.15 mmol) in 2 mL solvent, stirred for 12 h (nr = no reaction). bYield
of isolated product based on 1a. cThe loading of KIO3 = 0.3 mmol.
dThe loading of KIO3 = 0.09 mmol. eThe reaction time was 24 h. fThe
reaction time was 30 h.
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Beilstein J. Org. Chem. 2017, 13, 2017–2022.
with evidently higher yields (entries 11–13, Table 1). While To examine the scope of the reaction, enaminones 1 containing
varying the loading of KIO3 catalyst did not led to better results different functional groups as well as various sulfonyl
(entries 14 and 15, Table 1), prolonging the reaction time to 24 hydrazines 2 were subjected to the optimized standard reaction
h was found to be capable of further improving the yield of 3a conditions. As shown in Scheme 2, functional groups with dif-
(entries 16 and 17, Table 1).
ferent properties, including electron-withdrawing and electron-
Scheme 2: Scope of the 3-sulfenylated chromone synthesis. General conditions: 1 (0.3 mmol), 2 (0.36 mmol), KIO3 (0.15 mmol) in 2 mL DMF, stirred
at 130 °C for 24 h; yield of isolated product based on 1 are reported.
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Beilstein J. Org. Chem. 2017, 13, 2017–2022.
donating ones at the phenyl ring of the enaminones and the sul- standard conditions in the synthesis of products 3 was found to
fonyl hydrazines exhibited tolerance to the reaction conditions. provide chromone 5 with high yield (reaction 1, Scheme 3). In
The 3-sulfenylated products were obtained in generally good to addition, sulfonyl hydrazine 2b gave disulfide 6 under the same
excellent yields. A strong electron-withdrawing group such as a conditions (reaction 2, Scheme 3), suggesting that chromone 5
nitro group at the phenyl ring of the enaminone was found to and disulfide 6 might be key intermediates in the domino reac-
have a negative influence on the product yields (3d and 3l, tions. Moreover, the same reaction in the presence of TEMPO
Scheme 2). On the other hand, the substituent on the aryl frag- gave no formation of 6, indicating that a free radical intermedi-
ment of 2 also influenced the product yields. The main tenden- ate has also occurred in the generation of 6 (reaction 3,
cy was that a electron-withdrawing group on the aryl ring of the Scheme 3). The reactions of 5 with 6 and 2b were both found to
sulfonyl hydrazines and the group with ortho-steric hindrance yield the sulfenylated chromone 3i in excellent yield, respec-
gave the corresponding products with slightly lower yields than tively (reactions 4 and 5, Scheme 3). On the other hand, the
equivalent reactions using electron-donating-group-functionali- reaction of 5 and 6 in the presence of TEMPO, however,
zed arylsulfonyl hydrazines (3p, 3q and 3s, Scheme 2).
provides only with trace amounts of 3i, supporting that
products 3 are yielded via a free radical route (reaction 6,
On the basis of the results in hand, some control experiments Scheme 3). In addition, the control reaction of 1b and 2b
were also designed to probe the possible reaction mechanism. afforded also only trace amounts of product 3i in the presence
As outlined in Scheme 3, directly using enaminone 1b under of 1 equiv TEMPO (reaction 7, Scheme 3), further confirming
that a radical intermediate was generated during the reaction
process.
According to the results obtained in the control experiments, the
mechanism for this domino reaction is proposed (Scheme 4). As
one of the key steps, the reductive coupling of two sulfonyl
hydrazine molecules may first take place via the promotion of
IO3− to afford intermediate 7, and the IO4− generated therein
returns to IO3− in the presence of the simultaneously generated
hydrogen in this step. According to a known route [44,45], 7
can be further reduced to yield disulfide 6. The disulfide is
capable of either coupling chromone 5 to generate intermediate
10 by radical chain propagation (path a), or transforming into
sulfur radical 8 [46,47] which can be captured by the in situ
generated chromone 5 to yield radical intermediate 9 via revers-
ible addition to the double bond. The repeated coupling of 9
with radical 8 may also provide dithiolated intermediate 10
(path b). And the elimination of the α-hydrogen and β-sulfur
gives target product 3i and thiophenol 11. The thiophenol could
be easily reoxidized into disulfide 6 even under air atmosphere
[48,49], which enables the recycled production of sulfenylated
chromone. The present method involving the free radical path-
way is different from our previous work on synthesizing iden-
tical products via an ionic-based mechanism.
Conclusion
In conclusion, starting from o-hydroxyphenyl-functionalized
enaminones and sulfonyl hydrazines, we have successfully de-
veloped a flexible and facile method for the synthesis of
3-sulfenylated chromones via a transition-metal-free reaction
involving a C(sp2)–H bond sulfenylation. Besides the notable
feature of transition-metal-free operation, the present method
also displays advantages in using odourless sulfur sources, free
Scheme 3: Control experiments.
of any strong oxidants and neutral reaction conditions.
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Beilstein J. Org. Chem. 2017, 13, 2017–2022.
Scheme 4: The proposed reaction mechanism.
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Supporting Information
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doi:10.1002/anie.200804497
Supporting Information File 1
General experimental information, experimental details on
the synthesis of products 3; full characterization data as
well as 1H/13C NMR spectra of all products.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-199-S1.pdf]
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Acknowledgements
This work is financially supported by National Natural Science
Foundation of China (21562025), Natural Science Foundation
of Jiangxi Province (20161ACB21010), and the Science Fund
for Distinguished Young Scholars of Jiangxi Province
(20162BCB23023).
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