KIO3-Catalyzed Domino C(sp2)?H Bond Sulfenylation and C?N Bond Oxygenation of Enaminones toward the Synthesis of 3-Sulfenylated Chromones

Article abstract of DOI:10.1002/cctc.201601273

With 2-hydroxyphenyl-functionalized enaminones and thiophenols as the starting materials, the facile synthesis of 3-sulfenylated chromones has been realized through a KIO₃-catalyzed domino reaction of C?H sulfenylation and subsequent C?N-cleavage-based C?O bond formation. The reaction was performed under transition-metal-free conditions in ethyl lactate, a bioavailable ecofriendly medium.

Full text of DOI:10.1002/cctc.201601273

Accepted Article
Title: KIO3-catalyzed domino C(sp2)-H bond sulfenylation and C-N
bond oxygenation of enaminones toward the synthesis of 3-
sulfenylated chromones
Authors: Shanshan Zhong, Yunyun Liu, Xiaoji Cao, and Jie-Ping Wan
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10.1002/cctc.201601273
ChemCatChem
FULL PAPER
KIO3-catalyzed domino C(sp2)-H bond sulfenylation and C-N bond
oxygenation of enaminones toward the synthesis of 3-
sulfenylated chromones
Shanshan Zhong,[b] Yunyun Liu, Xiaoji Cao,[b] and Jie-Ping Wan*[a]
Abstract: Starting from 2-hydroxyphenyl functionalized enaminones
and thiophenols, the facile synthesis of 3-sulfenylated chromones
has been realized via KIO3-catalyzed domino C-H bond sulfenylation
and the subsequent C-N cleavage-based C-O bond formation in the
bio-available green medium ethyl lactate (EL).
derivatives consist of two main prototypes: a) the direct
elaboration of naturally or commercially available chromones;[5]
b) domino reactions involving the construction of chromone ring
and other bond transformation.[6] The former one, while
theoretically simpler, suffers from the high cost and limited
diversity of chromone substrates. On the other hand, as for the
synthetic tactics involving the in situ chromone ring construction,
the known reaction models are yet rather limited, especially in
the synthesis of 3-substituted chromones since most known
routes provide 2-substituted products (A, Scheme 1).[7]
Introduction
Chromone heterocycle is a featured backbone in a huge number
of valuable natural products and pharmaceuticals (Fig. 1).[1] This
moiety is also crucial for the biological activities and functions of
many complex molecules.[2] Moreover, the presence of the
conjugate enone fragment and the reactive fused phenyl ring in
the structure of chromones make them attractive as synthons in
the generation of more structurally sophisticated organic
Scheme 1 C(sp2)-H sulfenylation and related chromone synthesis
Rather recently, we have successfully identified
a novel
transition metal-free catalytic protocol for the α-C(sp2)-H
sulfenylation reactions of β-enaminones for the synthesis of poly
functionalized alknenes (B, Scheme 1),[8] which has also been
gracefully complemented by other groups.[9] On the basis of our
longstanding efforts in designing practical synthesis by making
use of the combinatorial bond transformations of enaminones[10]
as well as the elegant and versatile known synthesis based on
the enaminone C-H functionalization,[11] we envision that
combining the C(sp2)-H sulfenylation and the C-N bond
oxygenation with o-hydroxylphenyl functionalized enaminones
would be a potentially applicable approach for the synthesis of
3-thiolated chromones. Herein, we report our work on this
interesting new methodology toward 3-sulfenylated chromone
synthesis under environmentally benign conditions consist of
KIO3 catalyst and green bio-based medium ethyl lactate (C,
Scheme 1).[12]
F igure 1 Several chromone-based natural products
products by means of various efficient organic transformations.[3]
During the past decade, the synthesis of chromones has drawn
extensive interest and won significant advances.[4] Presently, the
available pathways toward the synthesis of chromone
[a]
[b]
S. Zhong, Prof. Dr. Y. Liu and Prof. Dr. J.-P. Wan
College of Chemistry and Chemical Engineering
Jiangxi Normal University
Nanchang 330022, P.R. China
E-mail: wanjieping@jxnu.edu.cn
Prof. Dr. X. Cao
Research Center of Analysis and Measurement
Zhejiang University of Technology
18 Chaowang Road, Hangzhou, Zhejiang 310014, P.R. China
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Results and Discussion
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Originally, the reaction of enaminone 1a and p-methyl thiophenol
2a was conducted in the presence of different catalysts or
catalyst-free condition in ethyl lactate (EL). The results showed
that iodine-containing species, including KI, I2, KIO3 and
PhI(OAc)2 were capable of catalyzing the reaction to afford
sulfenylated chromone 3a, while blank entry and entry with
TBHP didn’t provide the product (entries 1-6, Table 1). In
subsequent examination, reactions performed in different media
such as DMF, toluene, MeCN, EtOH and water proved that none
of these candidates was better than EL (entries 7-11, Table 1).
Further investigation on the effect of catalyst loading and
reaction temperature finally confirmed that 30 mol% KIO3 and 60
oC were optimal reaction parameters, respectively (entries 12-16,
Table 1).
(see 3a-3g, Table 1). Besides the generally good results
employing conventional thiophenols, a notable point was that
heteroaryl thiols also exhibited satisfactory tolerance to the
synthetic protocol (3f, 3g, Table 2). On the other hand, the
strong electron withdrawing substitution on the enaminone was
found to be negative by providing corresponding product with
lower yield (3z, Table 2). No expect product was observed in the
entry employing alkyl thiol such as propane-1-thiol.
Table 2 Scope of the transition metal-free domino reactions toward chromone
synthesis.[a]
Table 1 Optimization of reaction conditions.[a]
Enaminone
Ar
Product
Yield (%)[b]
3a
3b
3c
3d
3e
3f
85
85
83
88
80
81
p-tolyl
p-i-PrC6H4
p-MeOC6H4
p-ClC6H4
o-tolyl
Entry
1
Catalyst
-
Solvent
EL
T (oC)
90
Yield (%)[b]
nr
benzothiazole-2-yl
1a
3g
80
2
KI
EL
90
77
3
I2
EL
90
71
Ph
p-tolyl
p-i-PrC6H4
p-MeOC6H4
p-ClC6H4
o-tolyl
3h
3i
3j
3k
3l
3m
80(66)[c]
83
80
83
86
78
4
KIO3
PhI(OAc)2
TBHP
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
KIO3
EL
90
82
5
EL
90
15
1b
6
EL
90
trace
80
7
DMF
toluene
MeCN
EtOH
H2O
EL
90
Ph
p-tolyl
p-i-PrC6H4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
3n
3o
3p
3q
3r
84
81
82
85
78
80
8
90
12
9
reflux
reflux
90
35
1c
3s
10
11
12[c]
13[d]
14[c]
15[c]
16[c]
22
35
Ph
p-tolyl
p-i-PrC6H4
3t
3u
3v
80
77
76
90
84
1d
1e
1f
EL
90
80
EL
70
84
p-tolyl
p-i-PrC6H4
p-MeOC6H4
3w
3x
3y
80
79
82
EL
60
85
EL
50
80
[a]General conditions: 1a (0.3 mmol), 2a (0.36 mmol), catalyst (0.15 mmol) in
1.5mL solvent, stirred for 8 h. [b]Yield of isolated product. [c]Catalyst (0.09
mmol). [d]Catalyst (0.06 mmol).
p-tolyl
3z
76
In the section of scope examination,
a broad array of
[a]General conditions: enaminone 1 (0.3 mmol), thiol 2 (0.36 mmol) and KIO3
(0.09 mmol) in 1.5 mL EL, stirred at 90 oC for 8 h; [b]Yield of isolated product
based on 1. [c]The yield in the parenthesis was acquired by employing 1,2-
diphenyldisulfide as thio source at 80 oC.
thiophenols 2 as well as various enaminones 1 were employed,
respectively, and afforded successfully diverse 3-thiolated
chromone products 3 (Table 2). For the thiophenol component,
similar yields of products were provided when different
thiophenols was subjected to react with one same enaminone
Notably, following the successful synthesis of 3-sulfenylated
chromones via this domino reactions, the synthesis of equivalent
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10.1002/cctc.201601273
ChemCatChem
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3-phenylselanylated chromones 5 were also found practical by
simply employing benzeneselenol 4 as substrate under the
standard reaction condition (Scheme 2)
The 3-thiolated chromone is finally generated via the elimination
of dimethylamine on 9.
Scheme 2 Synthesis of 3-phenylselanylated chromones
To investigate the possible process of the reaction, several
control experiments were designed. As outlined in Scheme 3,
the first examination by subjecting only enaminone 1b to the
standard reaction condition afforded no reaction (Eq 1, Scheme
3), indicating that the C-N bond oxygenation was not practical in
the absence of thiol component. In addition, the entry directly
employing chromone 6 and thiophenol 2a with standard reaction
condition was found to be incapable of yielding target product 3i,
either (Eq 2, Scheme 3). The outcome also support that the
annulation to chromone was not the initial step in the reaction.
The attempts in isolating the sulfenylated acyclic product from
the C-H sulfenylation of enaminone 1b under the standard
reaction conditions was not successful because of this
intermediate may quickly undergo subsequent annulation to final
product (see also Scheme 4). Additional experiment in the
presence of TEMPO gave 3i with 78% yield (Eq 3, Scheme 3),
demonstrating that the reaction might not involve radical
intermediates, which was in agreement with the case in previous
work.[8]
Scheme 4 The proposed reaction mechanism
Conclusions
Conclusively, by employing a transition metal-free C(sp2)-H
sulfenylation as key transformation, we have designed
a
practical domino synthetic method towards the synthesis of 3-
sulfenylated chromones. With only KIO3 as catalyst, the reaction
proceeds well in green solvent EL under mild heating to afford a
broad array of 3-sulfenylated chromones. The features of
sustainable green catalytic conditions as well as the easy
availability of starting materials ensure the usefulness of the
present method in the synthesis of these useful heterocyclic
products.
Experimental Section
General procedure for the synthesis of 3 and 5
To a round-bottom flask (10 ml) were added enaminone 1 (0.3 mmol),
thiol 2/benzeneselenol 4 (0.36 mmol), KIO3 (0.09mmol) and ethyl lactate
(1.5 mL). Then the resulting mixture was heated up to 60 oC, and stirred
at the same temperature for 8 hours (TLC). After cooling down to room
temperature, 5 mL of water was added, and the resulting mixture was
extracted with ethyl acetate (3 × 8 mL). The organic phases were
collected and washed with small amount of water for three times. After
drying with anhydrous Na2SO4, the solid was filtered. The solvent was
then removed under reduced pressure from the solution, and the
resulting residue was subjected to flash silica gel column
chromatography to provide pure products with the elution of mixed
petroleum ether/ethyl acetate (v/v = 10:1).
Scheme 3 Control experiments
Acknowledgements
This work is financially supported by the National Natural
Science Foundation of China (21562025) and the Natural
Science Foundation of Jiangxi Province (20161ACB21010).
Based on the results from these control experiments, a concise
reaction mechanism is proposed (Scheme 4). As mentioned in
previous work,8 the reaction between enaminone
1 and
thiophenol first takes place to provide sulfenylated enaminone 7.
Consequently, the fast annulation based on the tautomeric
intermediate 8 facilitates the formation of intermediate 9 via
intramolecular addition of the hydroxyl to the imine fragment.
Keywords: Enaminone • domino • C-H sulfenylation • annulation
• chromones
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Entry for the Table of Contents
FULL PAPER
Chromone synthesis
Shanshan Zhong, Yunyun Liu, Xiaoji
Cao and Jie-Ping Wan*
Page No. – Page No.
KIO3-catalyzed domino C(sp2)-H bond
sulfenylation and C-N bond
oxygenation of enaminones toward
the synthesis of 3-sulfenylated
chromones
Text for Table of Contents
The domino C-H sulfenylation and C-N cleavage-based annulation of enaminones lead to the concise construction of 3-
sulfenylated chromones under transition metal-free condition.
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