Metal-Free Radical Annulation of Oxygen-Containing 1,7-Enynes: Configuration-Selective Synthesis of (E)-3-((Arylsulfonyl)methyl)-4-Substituted Arylidenechromene Derivatives

Article abstract of DOI:10.1021/acs.orglett.0c03946

A novel strategy for the synthesis of (E)-3-((arylsulfonyl)methyl)-4-substituted benzylidenechromene derivatives via a metal-free radical annulation reaction of oxygen-containing 1,7-enynes with thiosulfonates has been developed. The reaction shows broad substrate scope, wide functional group tolerance, and moderate to excellent yields. Moreover, thiosulfonates were well driven to achieve the bifunctionalization reaction of oxo-1,7-enynes which derived from aliphatic alkynes. In addition, the (E)-configuration of the products was highly controlled by the structure of 1,7-enyne.

Full text of DOI:10.1021/acs.orglett.0c03946

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Letter
Metal-Free Radical Annulation of Oxygen-Containing 1,7-Enynes:
Configuration-Selective Synthesis of (E)‑3-((Arylsulfonyl)methyl)-4-
Substituted Arylidenechromene Derivatives
Kaimin Mao, Mouwang Bian, Lei Dai, Jinghang Zhang, Qiuyu Yu, Chang Wang,* and Liangce Rong*
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ABSTRACT: A novel strategy for the synthesis of (E)-3-((arylsulfonyl)-
methyl)-4-substituted benzylidenechromene derivatives via a metal-free radical
annulation reaction of oxygen-containing 1,7-enynes with thiosulfonates has
been developed. The reaction shows broad substrate scope, wide functional
group tolerance, and moderate to excellent yields. Moreover, thiosulfonates
were well driven to achieve the bifunctionalization reaction of oxo-1,7-enynes
which derived from aliphatic alkynes. In addition, the (E)-configuration of the products was highly controlled by the structure of 1,7-
enyne.
hromene and its derivatives are the privileged scaffolds
azo-heterocyclic polycyclic compounds17 (Scheme 1, previous
work). In contrast, the radical reaction of oxygen-containing
C
widely present in many natural products1 (Figure 1,
Scheme 1. Radical Annulation Strategies of 1,7-Enyne
Figure 1. Bioactive molecule bearing chromene motif.
vitamin E2) and significant bioactive molecules (Figure 1,
englitazone,3 catechin,4 equol5) with a range of biological
activities, including antimicrobial,6 antiviral,7 mutagenicity,8
antiproliferative,9 sex hormone,10 antitubercular,11 anti-
cancer,12 anti-HIV,13 etc. Because of their widespread
applications and important biological activities, many synthetic
routes of chromene derivatives have been reported over the
past decades.14 Although numerous synthetic methods have
been well developed, exploring a novel strategy for
construction of chromene derivative which remains in high
demand.
1,7-enyne was relatively less studied, although sporadic
reactions could be found in the study of nitrogen-containing
1,7-enyne, which is merely a supplementary reaction of the
reported work. Therefore, the study of oxygen-containing 1,7-
enynes is an interesting work.
The 1,n-enyne annulation reaction is one of the most
important and efficient methodologies for the synthesis of
small molecules with structural diversity and complexity15 in
which the nitrogen-containing 1,7-enyne radical cascade
reaction is one of the most widely studied precursors for
constructing diverse organic compounds with many different
structures. For example, nitrogen-containing 1,7-enynes were
efficient substrates for obtaining quinolin-2(1H)-ones16 and
Received: November 29, 2020
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© XXXX American Chemical Society
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A

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Synthesis of organic sulfone derivatives is a hot topic in
organic chemistry because of their obvious bioactivities, such
as anticancer, anti-HIV, and antibacterial18 and their
application in therapy for some diseases.19 Herein, we report
a radical-based tandem annulation of oxygen-containing 1,7-
enynes and thiosulfonates to afford chromene derivatives
bearing a sulfone skeleton (Scheme 1, this work).
At the beginning of this study, we attempted to apply the
successful radical reaction cases of different sulfur reagents
(such as PhSO2H,20 PhSO2Na,21 PhSO2NHNH2,22
PhSO2Cl,23 PhSSPh,24 and PHSH25) with nitrogen-containing
1,7-enyne to achieve this synthetic strategy; however, to our
disappointment, the reaction results were very inferior and
none of products were obtained. This may be due to the
different electronic properties of the alkene in the two kinds of
1,7-enynes. The double bond in nitrogen-containing 1,7-enyne
is electrophilic, while that in oxygen-containing 1,7-enyne is
nucleophilic.
result, we next screened other solvents such as ethyl acetate
(EA), MeCN, dichloromethane (DCM), dichloroethane
(DCE), 1,4-dioxane, and EtOH (Table 1, entries 2−7),
which revealed that EtOH could give the best yield (entry 7).
Subsequently, we investigated the different oxidants (Table 1,
entries 8−12), which depicted that their activities were lower
than that of TBHP. The temperature was evaluated in the
model reaction, and it was found that the yields were not
improved by elevating the temperature (entry 14), while lower
temperature (entry 13) inevitably reduced the reaction yield.
Then, the loading of TBHP was also carefully tested in model
reaction. The results showed that the yield remained
unchanged when the loading of TBHP decreased from 3 to
1 equiv (entries 15 and 16). However, when the loading of
TBHP was 0.5 equiv of 1a, the yield of the reaction decreased
significantly. Thus, 1 equiv of TBHP was sufficient to ensure a
successful reaction. Finally, we found that TBHP was essential
to the reaction, and without it the reaction did not proceed at
all (entry 18). The optimal reaction conditions was pointed
out as follows: the mixture of 1-((2-methylallyl)oxy)-2-
(arylethynyl)benzene (0.2 mmol), thiosulfonates (0.2 mmol),
and TBHP (1 equiv, 0.2 mmol) was stirred in EtOH (2.5 mL)
at 80 °C (oil bath temperature) under a nitrogen atmosphere
for 10 h.
Recently, thiosulfonate has been proven as an effective
radical precursor and successfully used in radical reactions.26
Herein, the 1-(allyloxy)-2-(phenylethynyl)benzene 1a and S-
phenyl benzenesulfonothioate 2a were chosen as the starting
materials to screen the optimized reaction conditions (Table
1). Gratifyingly, when 1a was treated with an equivalent
Under establishing the optimal reaction conditions, we
began to survey this radical-based tandem cyclization of 1-
(allyloxy)-2-(arylethynyl)benzene and thiosulfonate (Scheme
2). First, the reaction of 1-(allyloxy)-2-(phenylethynyl)-
benzene and thiosulfonate 2 with different substituent groups
was investigated, and all of the reactions were carried out to
give compounds 3a−3h in moderate to good yields, which
indicated that the substituent properties of thiosulfonate have
a
Table 1. Screening of the Reaction Conditions
b
c
entry
oxidant (equiv)
solvent
DMF
EA
CH3CN
DCM
DCE
1,4-dioxane
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
ratio (3a/3a’)
3a (yield )
1
2
3
4
5
6
7
8
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
H2O2 (3)
DTBP (3)
TBPB (3)
K2S2O8 (3)
BPO (3)
>20:1
51
NR
a
d
Scheme 2. Scope for the Synthesis of Compound 3
NR
trace
trace
52
70
26
43
40
34
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
9
10
11
12
13
14
15
16
17
18
25
55
70
e
TBHP (3)
TBHP (3)
TBHP (2)
TBHP (1)
TBHP (0.5)
f
69
70
53
NR
a
Reaction conditions: Unless otherwise noted, 1a (0.2 mmol), 2a (0.2
mmol), and oxidant in solvent (2.5 mL), reaction at 80 °C for 10 h
b
(monitored by TLC) under nitrogen atmosphere. Ratio of E/Z (3a/
c
d
3a’) isomers was detected by 1H NMR. Isolated yields. No reaction.
Under 60 °C. Under 90 °C.
e
f
amount 2a in the presence of 3 equiv of tert-butyl
hydroperoxide (TBHP) as oxidant in dimethyl formamide
(DMF) at 80 °C under N2 environment for 10 h, the desired
product 4-benzylidene-3-((phenylsulfonyl)methyl)chromene
3a was obtained in a moderate yield 51% along with excellent
E/Z ratios (the ratio of E/Z (3a/3a′, > 20:1) isomers was
a
Conditions: 1 (0.2 mmol), 2 (0.2 mmol), TBHP (1 equiv, 0.2
mmol), EtOH (2.5 mL), 80 °C (oil bath temperature), under a
nitrogen atmosphere for 10 h. Isolated yield.
1
b
detected by H NMR) (Table1, entry 1). Encouraged by this
B
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a
little influence on the reaction. Second, we inspected different
alkyls (such as methyl, ethyl, n-propyl, and n-butyl) on the
aromatic ring at the terminal alkyne (R2), and the reactions
were also performed successfully with corresponding products
3i−3y in good yields. In addition, the reaction revealed that
1,7-enyne with a methoxy or ethoxy group was more suitable
for this synthesis process and the higher yields could be
obtained (3z, 3aa−3ae). However, when a halogen atom
(Cl−) was present on the aromatic ring of 1,7-enyne, the yields
of the products were lower than those of alkyl and alkoxy (3f−
3aj). While 1,7-enyne has a stronger electron-withdrawing
group, the reaction failed completely (3ak−3an), which
indicates that the substituent properties on 1,7-enyne had a
greater influence on the reaction. Due to the steric hindrance,
the products are mainly (E)-isomer, indicating that the
reaction has excellent configurational selectivity. The X-crystal
diffraction analysis of 3c further confirmed this conclusion.
Subsequently, we investigated the substitution effect on the
aromatic ring at phenol (R1) (Scheme 3). When R1 was a
Scheme 4. Scope for the Synthesis of Compound 6
a
Scheme 3. Scope for the Synthesis of Compound 4
a
Condition: 5 (0.2 mmol), 2 (0.2 mmol), TBHP (1 equiv, 0.2 mmol),
EtOH (2.5 mL), 80 °C (oil bath temperature), under a nitrogen
b
atmosphere for 10 h. Isolated yield.
reported reactions proceeded well, which given the corre-
sponding products with favorable yields (6k−6p). In addition,
when R1 was a methyl, the explored reactions were afforded
the corresponding products in excellent yields (6q−6t) (up to
91%). Consistent with the result of product 3, the reaction
failed when R2 was a strongly electron-withdrawing group
(NO2−, −CN, and MeCO−) (6u−6x). Interestingly, because
of the steric hindrance effect of methyl, the structure 6 was
confirmed as an (E)-isomer by the X-ray crystal diffraction of
6p. Therefore, this indicated that the configuration of the
products was highly controlled by the structure of 1,7-enyne.
Strangely, when substrate 7 is derived from aliphatic alkynes,
the obtained product 8 is only the vicinal thiosulfonylation27 of
7 and thiosulfonate (Scheme 5), which may be due to the
difference in the electronic effects of the alkyl group from the
aryl group. This can be demonstrated by 8g, indicating that
allyl is not involved in the reaction. In addition, the
selenosulfonate can also be used in this reaction to give
product 8h with good yield.
The gram scale reaction was also verified. When 1a (1.0 g,
4.3 mmol) reacted with 2a (1.07 g, 4.3 mmol) under standard
conditions, the desired product 3a could be obtained with 73%
yield (1.18 g). Moreover, the obtained compound 3 can be
further applied to the Julia−Kosinski-type reaction to give β-
alcohol derivatives (Scheme 6).
In order to understand the mechanism of the reaction, the
control reaction of 1a and 2a was investigated under the
standard conditions with the typical radical scavengers
TEMPO (3 equiv) and BHT (3 equiv), respectively, and the
a
Conditions: 1′ (0.2 mmol), 2 (0.2 mmol), TBHP (1 equiv, 0.2
mmol), EtOH (2.5 mL), 80 °C (oil bath temperature), under a
nitrogen atmosphere for 10 h. Isolated yield.
b
methyl, the 1,7-enyne could effectively react with thiosulfonate
bearing different groups (Me−, F−, Cl−) to give the
corresponding products (4a−4d) in good yield. We further
found that R2 was an electron-donating group (Me−, Et−) or a
weak electron-donating group (F−), the reactions were all
carried out smoothly to afford compounds (4e−4l) with
satisfactory yields. When R1 was a chlorine group (Cl−), the
yield of the reaction decreased significantly (4m−4s),
indicating that the substituents on 1,7-enyne had a great
influence on the reaction.
Next, a series of oxygen-containing 1,7-enyne 1-((2-
methylallyl)oxy)-2-(arylethynyl)benzene 5 was also studied
with thiosulfonate 2 to investigate the scope of the annulation
reaction (Scheme 4). At first, 1-((2-methylallyl)oxy)-2-
(phenylethynyl)benzene could react well with different
thiosulfonates to give 6a−6d in good yields. When R2 was a
electron-donating group (Me−, Et−, Pr−, MeO−, and EtO−),
which all could tolerate the screened conditions, providing the
corresponding compounds with high yields (6e−6j). In
addition, when R2 was a halogen atom (F−, Cl−), the
C
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a
Scheme 5. Reactions of Compound 7
Scheme 7. Control Experiments
a
Condition: 7 (0.2 mmol), 2 (0.2 mmol), TBHP (1 equiv, 0.2 mmol),
EtOH (2.5 mL), 80 °C (oil bath temperature), under a nitrogen
b
atmosphere for 10 h. Isolated yield.
Scheme 6. Gram-Scale Reaction and Further
Transformation
Figure 2. Proposed mechanism of the reaction.
hydrogen radical generated from EtOH to afford product 3
and simultaneously generated the radical EtO•, which
reparticipated in a new radical reaction process. However,
because of the steric hindrance, the intermediate E is not easy
to form, so the (Z)-isomer is not easy to be obtained. When 5
was involved in the reaction, the preferred intermediates F
could be effectively obtained so that it finally yielded the
product 6 with (E)-configuration. Similar to intermediate E,
the intermediate G is not easy to be generated, and its
corresponding (Z)-isomer is also difficult to be obtained.
In conclusion, we have successfully developed a metal-free
protocol for the preparation of chromene derivatives with
sulfone skeleton via a radical annulation reaction of oxygen-
containing 1,7-enynes with thiosulfonates. The 1,7-enynes and
thiosulfonates bearing a wide range of substituted groups were
well tolerated the screening condition to afford corresponding
products in moderate to good yields. In addition, the
bifunctionalization product was obtained from the reaction
of thiosulfonates and oxo-1,7-enynes which derived from
aliphatic alkynes. Moreover, the obtained products were (E)-
isomer, indicating that the reaction had an excellent
configuration selectivity. The obtained product 3 could further
apply to the Julia−Kosinski reaction.
reaction was strictly inhibited, which indicated this reaction
was a radical process. In order to further confirm the reaction
mode of thiosulfonates, the reaction of 5a and 2e was
investigated. It was found that only the 6a was obtained, while
the phenylthio group did not participate in the reaction. In
addition, under the reaction of 1d and 2c in ethanol-d6, the
source of hydrogen on the olefinic bond was confirmed from
the solvent ethanol (see the Supporting Information). The
results are shown in Scheme 7.
On the basis of the above experimental results and
literature,28 a possible mechanism was proposed in Figure 2.
First, TBHP produced the hydroxyl radical (OH•) and tert-
butoxy radical (tBuO•) by a homolysis reaction. Then, induced
by these two radicals, the ethoxy radical (EtO•) was generated
alongwith the release of a water and a tertiary butanol
molecule. Under the initiation of radical EtO•, a sulfonyl
radical B was formed with release of the A molecule.29 Second,
with the radical addition reaction between 1 and radical B, the
intermediate C was obtained. Subsequently, the preferred
intermediate D was formed by intramolecular radical addition
reaction of intermediate C. Finally, D combined with a
D
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Scientific Research Innovation Plan (KYCX20_2254), and
TAPP.
ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
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AUTHOR INFORMATION
Corresponding Authors
■
Chang Wang − Jiangsu Key Laboratory of Green Synthetic
Chemistry for Functional Materials, School of Chemistry and
Materials Science, Jiangsu Normal University, Xuzhou
221116, Jiangsu, P.R. China; Email: wangchangacdm@
jsnu.edu.cn
Liangce Rong − Jiangsu Key Laboratory of Green Synthetic
Chemistry for Functional Materials, School of Chemistry and
Materials Science, Jiangsu Normal University, Xuzhou
221116, Jiangsu, P.R. China; orcid.org/0000-0003-
0561-1137; Email: lcrong@jsnu.edu.cn
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Authors
Kaimin Mao − Jiangsu Key Laboratory of Green Synthetic
Chemistry for Functional Materials, School of Chemistry and
Materials Science, Jiangsu Normal University, Xuzhou
221116, Jiangsu, P.R. China
Mouwang Bian − Jiangsu Key Laboratory of Green Synthetic
Chemistry for Functional Materials, School of Chemistry and
Materials Science, Jiangsu Normal University, Xuzhou
221116, Jiangsu, P.R. China
Lei Dai − Jiangsu Key Laboratory of Green Synthetic
Chemistry for Functional Materials, School of Chemistry and
Materials Science, Jiangsu Normal University, Xuzhou
221116, Jiangsu, P.R. China
Jinghang Zhang − Jiangsu Key Laboratory of Green Synthetic
Chemistry for Functional Materials, School of Chemistry and
Materials Science, Jiangsu Normal University, Xuzhou
221116, Jiangsu, P.R. China
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Author Contributions
K.M. and M.B. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by the NSFC (21571087), the Natural
Science Foundation of the Jiangsu Higher Education
Institutions of China (18KJA150004), Jiangsu Graduate
E
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