Transition-metal-free sulfonylations of methylthiolated alkynones to synthesize 3-sulfonylated thioflavones

Article abstract of DOI:10.1039/d0nj03386c

A set of transition-metal-free NaI/TBHP-mediated sulfonylation cyclization reactions of methylthiolated alkynones with sulfonyl hydrazides was developed, by which various 3-sulfonylated thioflavones were prepared under mild reaction conditions. The features of this procedure included metal-free reaction conditions, ease of reagent handling, short reaction times, and a broad functional group tolerance.

Full text of DOI:10.1039/d0nj03386c

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DOI: 10.1039/D0NJ03386C
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Transition-Metal-Free Sulfonylation of Methylthiolated Alkynones
to Synthesize 3-Sulfonylated Thioflavones
Zhi-Wen Feng,a,# Jing Li,a,# Yu-Qin Jiang,a Yu Tian,a Gui-Qing Xu,a Xin Shi,a Qing-Jie Ding,a Wei Li,a
Received 00th January 20xx,
Accepted 00th January 20xx
Chun-Hua Ma,a* and Bing Yub*
DOI: 10.1039/x0xx00000x
A
transition-metal-free
NaI/TBHP-mediated
sulfonylation
cyclization reaction of methylthiolated alkynones with sulfonyl
hydrazides was developed, by which various 3-sulfonylated
thioflavones were prepared under mild reactions. The features of
this procedure include metal-free reaction conditions, the ease of
reagent handling, short reaction time, and a broad functional group
tolerance.
Thioflavone is one of the most important frameworks that
widely spread in numerous natural products, pharmaceuticals
and functional materials.1 In the past decades, thioflavones
have gained tremendous attention because of their intriguing
bioactivities in antibacterial, antitumor as well as anti-
malarial, etc (Scheme 1).2 Furthermore, thioflavones and
their oxidized sulfone derivatives exhibit extraordinary
promising applications in medicinally relevant molecules and
advanced materials, such as anti-infective agents and
photolabile protecting groups.3 Nowadays, the development
of novel and straightforward synthetic methods to access
structurally diverse thioflavones is highly desirable.
Due to the importance of organic sulfur compounds, the
development of efficient methods for the construction of C-S
bond has gained huge attention.4 Particularly, it is well known
that sulfones display various unique biological and
pharmaceutical activities and are therefore of great
importance in the development of drugs and agrochemicals.5
Moreover, sulfones are versatile synthetic intermediates in
organic synthesis, which can undergo interesting conversions,
such as Julia olefination and Ramberg-Bäcklund reaction.6
Therefore, enormous efforts have been devoted to the
development of novel and facile methods to introduce the
sulfonyl group into organic frameworks in recent years.7
Scheme 1. Examples of thioflavones
Over the past decades, sulfonyl hydrazides, as readily
accessible compounds, have been employed as sulfonyl radical
precursors to access
a number of sulfonyl-substituted
heterocycles and carbocycles via sulfonyl radical-initiated
reactions.8 As our ongoing interest in radical reaction and
sustainable chemistry,9 we herein disclosed a transition-metal-
free NaI/TBHP-mediated sulfonylation of methylthiolated
alkynones with sulfonyl hydrazides to access 3-sulfonylated
thioflavones under mild reaction conditions (Scheme 2). It
should be noted that although the cascade cyclization reaction
of methylthiolated alkynones has been realized recently,10 the
development of efficient protocols for the transformation of
methylthiolated alkynones in a short time is still desired.
Scheme 2. Preparation of 3-sulfonylated thioflavones
The exploratory study was initiated by using methylthiolated
alkynone (1a) and TsNHNH2 (2a) as model substrates to
optimize the reaction conditions (Table 1). Fortunately, when
the model reaction was treated with KI (1 equiv) and TBHP (3
equiv) in MeOH, the desired product 3a was obtained in an
isolated yield of 43% (entry 1). Encouraged by this exciting
result, other iodide reagents, including NH4I, TBAI, NaI, and
I2, were also tested to improve the reaction efficiency (entries
a. Collaborative Innovation Centre of Henan Province for Green Manufacturing of
Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry
of Education, Henan Engineering Research Centre of Chiral Hydroxyl
Pharmaceutical, Henan Engineering Laboratory of Chemical Pharmaceutical and
Biomedical Materials, School of Chemistry and Chemical Engineering, Henan
Normal University, Xinxiang 453007, China. E-mail: xiaoma3625@126.com
b. Green Catalysis Centre, College of Chemistry, Zhengzhou University. Zhengzhou 2-5). It was pleased to see that when NaI was employed, the
450001, China. E-mail: bingyu@zzu.edu.cn
product 3a was obtained in highest yield (69%, entry 5). Then
the NaI loading was screened, suggested that the stoichiometric
amount of NaI was necessary (entries 5-7). Afterward, various
# Zhi-Wen Feng and Jing Li contributed equally.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here.]. See DOI: 10.1039/x0xx00000x
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oxidants like K2S2O8, H2O2, DTBP, and BPO were further reaction conditions were thus established as follVoiewwsA:rti1clae O(n0li.n2e
investigated for the model reaction, and the results showed that mmol), 2a (3 equiv), NaI (1 equiv) and TBHP.10(239equivJ0) were
DOI: 10 /D0N 3386C
TBHP was still the best choice for this transformation (entries stirred in mixed solvent of MeOH/H2O (v/v = 5/1) at 70 oC for
8-11). Subsequently, the amount of TBHP as an oxidant was 2 h.
examined. As it can be seen, the yield of 3a increased from 66%
With the optimized reaction conditions established, the
to 77% as the amount of TBHP increased from 1 to 2 equiv
substrate scope of this transition-metal-free sulfonylation
(entries 12 and 13), and decreased from 77% to 69% as the
reaction was further evaluated by using various
amount continuously increased from 2 to 3 equiv. (entries 13
methylthiolated alkynones
1 and sulfonyl hydrazides 2. As it
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vs 5). For further optimization, a range of solvents, including
DMSO, CH3CN, EtOH, DMF, DCE, 1,4-dioxane, THF, H2O,
and methanol aqueous solution were evaluated (entries 14-24).
The results showed that the mixed solvent MeOH/H2O (v/v =
5/1) was the most efficient and provide the desired product 3a
in 79% yield (entry 24). Furthermore, when the amount of 2a
was increased to 3 equiv, we were delighted to obtain the
product 3a in yield of 85% (entry 25). When the reaction was
conducted in the absence of NaI or TBHP, no desired product
was observed (entries 26-27), demonstrating that this reaction
is initiated by the NaI/TBHP system. Overall, the optimal
can be seen in Table 2, numerous methylthiolated alkynones
1
,
including those attached with electron-donating and electron-
withdrawing groups at different position of the phenyl ring,
reacted smoothly with TsNHNH2 (2a) to afford the desired
products 3a-m in good to excellent yields. The presence of
electron-withdrawing and electron-donating groups has no
significant impact on the reaction efficiency under the optimal
conditions. Notably, the trifluoromethyl group (CF3), as
versatile structural units widespread in pharmaceuticals and
Table 2. Substrate scope for 3-sulfonylated thioflavones
Table 1. Optimization of reaction conditions a
Oxidant
(equiv)
Yield
(%)
43
Entry
[I] (equiv)
Solvent
1
2
KI (1)
NH4I (1)
TBAI (1)
I2 (1)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
K2S2O8 (3)
H2O2 (3)
DTBP (3)
BPO (3)
MeOH
MeOH
59
3
4
5
MeOH
MeOH
MeOH
63
35
69
NaI (1)
NaI (0.25)
NaI (0.1)
NaI (1)
NaI (1)
NaI (1)
NaI (1)
NaI (1)
NaI (1)
NaI (1)
NaI (1)
NaI (1)
NaI (1)
NaI (1)
NaI (1)
NaI (1)
NaI (1)
NaI (1)
NaI (1)
NaI (1)
NaI (1)
---
6
7
8
MeOH
MeOH
MeOH
41
25
65
9
MeOH
MeOH
MeOH
23
N.D.
45
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24
25b
26b
27b
TBHP (1)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
---
MeOH
MeOH
DMSO
66
77
6
CH3CN
EtOH
DMF
36
62
N.D.
N.D.
39
DCE
1,4-Dioxane
THF
57
H2O
44
54
63
MeOH/H2O = 1/1
MeOH/H2O = 3/1
MeOH/H2O = 5/1
MeOH/H2O = 5/1
MeOH/H2O = 5/1
MeOH/H2O = 5/1
79
85
N.D.
N.D.
NaI (1)
a
Reaction conditions: 1a (0.2 mmol), 2a (2 equiv), catalyst, oxidant,
solvent (2 mL), 70 oC, 2 h. TBHP = tert-butyl hydroperoxide (70% aqueous
solution), DTBP = di-tert-butyl peroxide, BPO = benzoyl peroxide, DCE =
1,2-dichloroethane. Isolated yields were given based on 1a.
b 2a (3 equiv)
a Reaction conditions: 1 (0.2 mmol), 2 (3 equiv), NaI (1 equiv), TBHP (2 equiv),
MeOH/H2O (v/v = 5/1, 2 mL), 70 oC, 2 h. Isolated yields were given based on 1.
was employed.
2 | J. Name., 2012, 00, 1-3
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, which
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agrochemicals,11 can also be well tolerated in this reaction bond of 1a leads to the vinyl radical intermediVaiteew Article Online
system, offering the products 3i in excellent yield (89%). undergoes a 6-exo-trig cyclization withDOthI:
Afterward, a variety of sulfonyl hydrazides were investigated generate the aromatic ring, affording the final product
to further explore the limitations of the reactions (3n-y). with methyl radical. The methyl radical is further converted to
Different sulfonyl hydrazides bearing various groups, such as methane via H-abstraction.13
alkyl (–Me and –tBu), methoxyl as well as halide (–F, –Cl, –Br
and –I), exhibited good reactivities for the cyclization reaction
producing the desired products 3o-x in moderate to good yields
8
e –SMe moiety to
10.1039/D0NJ03386C
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3 along
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(46%–95%). 1-Naphthyl and 2-thienyl-based sulfonyl
hydrazides were also applicable for this transformation, and the
corresponding products 3x and 3y were isolated in 50% and 43%
yield, respectively. Unfortunately, the reaction using alkyl
sulfonyl hydrazide as substrate did not generate the
corresponding product (3z). Notably, the structure of 3a was
further confirmed by X-ray crystallography (CCDC 1953609).
The gram-scale reaction was also conducted based on the
model reaction (see the Supporting Information for details).
Unfortunately, only 33% yield of 3a was obtained, probably
due to the limitation of mass transfer. Furthermore, the
synthesized 3-sulfonylated thioflavone 3a could be converted
into β-carbonyl sulfone
5 in an isolated yield of 43% under
Scheme 5. Proposed mechanism
oxidative reaction conditions (Scheme 3, see the Supporting
Information for details).
Conclusions
In conclusion, we have disclosed a NaI/TBHP-mediated
transition-metal-free strategy for the synthesis of 3-
sulfonylated
thioflavones
from
easily
accessible
methylthiolated alkynones and sulfonyl hydrazides. The
features of this methodology include metal-free reaction
conditions, the ease of reagent handling, short reaction time,
and a broad functional group tolerance. The transformation of
the synthesized 3-sulfonylated thioflavone into β-carbonyl
sulfone suggested that 3-sulfonylated thioflavones could be
employed as useful building blocks in organic synthesis.
Further applications of this synthetic strategy and the biological
activities of 3-sulfonylated thioflavones are currently ongoing
in our laboratory.
Scheme 3. Transformation of 3a
To gain deep mechanistic insights into this transition-metal-
free sulfonylation of methylthiolated alkynones, several
control experiments were carried out. As it can be seen in
Scheme 4, the treatment of 1a with TsNHNH2 (2a) in the
presence of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or
BHT (2,6-di-tert-butyl-4-methylphenol), two well-known
radical scavengers, the reactions were severely inhibited,
suggesting that a radical pathway should be involved in the
reaction. Furthermore, when BHT was subjected to the reaction
system under standard conditions, the adduct
4 was
Conflicts of interest
There are no conflicts to declare.
successfully separated with 18% yield, demonstrating that a
sulfonyl radical was produced and participated in this reaction.
Acknowledgment
We acknowledge the financial support from the National Natural
Science Foundation of China (21971224), Key Research Projects
of Universities in Henan Province (20A150006, 20B350001), and
Postgraduate Education Reform Project of Henan Province
(2019SJGLX008Y, 2019SJGLX034Y).
Scheme 4. Control experiments
Notes and references
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Based on the results of control experiments and previous
reports,12 a plausible mechanism involved radical process is
proposed as shown in Scheme 5. Initially, the radicals t-
BuO
of iodide anion under 70 C. Then, the resultant radicals react
with sulfonyl hydrazide produce the sulfonyl diazene radical
, which is rapidly converted into sulfonyl radical by
to the C≡C
· and t-BuOO· are generated from TBHP in the presence
o
2
6
7
releasing N2. Subsequently, the addition of radical
7
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New Journal of Chemistry
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DOI: 10.1039/D0NJ03386C
Table of Contents
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Transition-Metal-Free Sulfonylation of Methylthiolated Alkynones to Synthesize 3-Sulfonylated
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Thioflavones
Zhi-Wen Feng,a,# Jing Li, a,# Yu-Qin Jiang,a Yu Tian,a Gui-Qing Xu,a Xin Shi,a Qing-Jie Ding,a Wei Li,a Chun-Hua
Ma,a* and Bing Yub*
O
S
O
S
O
S
R2
NaI/TBHP
R2SO NHNH
+
2
2
O
R1
MeOH/H2O = 5/1
70 °C, 2 h
R1
+ Transition-metal-free
+ Sulfonylation cyclization
+ Mild conditions
+ Short reaction time
A transition-metal-free NaI/TBHP-mediated sulfonylation cyclization reaction of methylthiolated
alkynones with sulfonyl hydrazides was developed, by which various 3-sulfonylated thioflavones were
prepared under mild reactions. The features of this procedure include metal-free reaction conditions,
the ease of reagent handling, short reaction time, and a broad functional group tolerance.