An efficient approach to 3-thioether-functionalized 2,3-dihydrobenzofurans via a metal-free intramolecular radical cyclization/thiolation cascade reaction

Article abstract of DOI:10.1080/00397911.2021.1927098

A diverse series of 3-thioether-functionalized 2,3-dihydrobenzofurans were prepared by an intramolecular radical cyclization/thiolation cascade reaction of alkenyl-tethered arenediazonium salts with thiophenols under transition-metal-free conditions. The

Full text of DOI:10.1080/00397911.2021.1927098

Synthetic Communications
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An efficient approach to 3-thioether-functionalized
2,3-dihydrobenzofurans via a metal-free
intramolecular radical cyclization/thiolation
cascade reaction
Tingting Chen, Renhua Zheng & Jingmiao Yu
To cite this article: Tingting Chen, Renhua Zheng & Jingmiao Yu (2021) An efficient approach
to 3-thioether-functionalized 2,3-dihydrobenzofurans via a metal-free intramolecular radical
cyclization/thiolation cascade reaction, Synthetic Communications, 51:14, 2204-2212, DOI:
10.1080/00397911.2021.1927098
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https://doi.org/10.1080/00397911.2021.1927098
An efficient approach to 3-thioether-functionalized 2,3-
dihydrobenzofurans via a metal-free intramolecular radical
cyclization/thiolation cascade reaction
a
a
a,b
Tingting Chen , Renhua Zheng , and Jingmiao Yu
a
School of Pharmaceutical and Materials Engineering, Taizhou University, Taizhou, People’s Republic of
b
China; Institute for Advanced Studies, Taizhou University, Taizhou, People’s Republic of China
ABSTRACT
ARTICLE HISTORY
A diverse series of 3-thioether-functionalized 2,3-dihydrobenzofurans
were prepared by an intramolecular radical cyclization/thiolation cas-
cade reaction of alkenyl-tethered arenediazonium salts with thiophe-
nols under transition-metal-free conditions. The mild and practical
reaction conditions tolerated various functional groups and afforded
the corresponding 2,3-dihydrobenzofurans in moderate to good
yields.
Received 30 March 2021
KEYWORDS
Cyclization; dihydrobenzo-
furans; diazonium
salts; phenthiols
GRAPHICAL ABSTRACT
Introduction
The structural motifs of 2,3-Dihydrobenzofurans are important in a large number of
[
1]
natural products, bioactive molecules and pharmaceuticals (Fig. 1). These compounds
exhibit a wide range of important biological activities, such as antitubercular, antimalar-
ial, anti-cancer, antinociceptive, anti-inflammatory, antifungal and antibacterial activ-
[
2]
ities. Owing to the significant importance of these structural motifs, enormous efforts
have been devoted to developing transformations to synthesize the 2,3-dihydrobenzofur-
[
3]
ans and considerable attention has been focused on the intramolecular cyclization
using arenediazonium salts with olefins for the construction of the desired hetero-
[
4]
[5]
cycles. For example, Correia and co-workers reported the first intramolecular Heck
reaction of o-(allyloxy) arenediazonium salts in the synthesis of dihydrobenzofuran
acetic acid derivatives.
Meanwhile, Aryl diazonium salts are valuable precursors of highly active aryl radi-
[
6]
[7]
cals, which can undergo Meerwein reactions with olefins, in the presence of suitable
[
8]
reducing agents. Meijis and co-workers
developed the pioneering work on the
rapid and regioselective cyclization in the exo-mode of aryl diazonium salts with
CONTACT Jingmiao Yu
yujm@tzc.edu.cn
Institute for Advanced Studies, Taizhou University, 1139, Shifu Avenue,
Taizhou 318000, People’s Republic of China.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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2205
ortho-substituents containing double bonds in the 5,6 positions relative to the radical
center catalyzed by cooper salts, or with UV-light irradiation in the presence of
[
9]
[10]
Bu SnH. Then FeSO , TBAI
were successfully employed as the reducing agents for
3
4
[
11]
the construction of the functionalized 2,3-dihydrobenzofurans. Wu and co-workers
disclosed an electrostatic interaction between the aryldiazonium salt with DABSO and
the generated aryl radicals was also applied to the formation of 3-sulfonyl methyl 2,3-
[
12]
[13]
dihydrobenzofurans.
Polyzos and co-workers
described the annulative carbonyla-
tion of alkenyl-tethered arenediazonium salts mediated by visible-light photocatalysis in
continuous flow.
Aromatic thioethers are present in numerous bioactive molecules, materials and fine
[
14]
chemicals.
Therefore, various synthetic procedures have been reported for the con-
[
15]
struction of aromatic thioethers.
Due to the biological importance of 2,3-dihydroben-
zofurans and aromatic thioethers, there is an intense demand for the development of
convenient pathways for the synthesis of thioether-functionalized 2,3-dihydrobenzofur-
[
16]
ans. Nakada and co-workers
struction of the desired 2,3-dihydrobenzofurans. It was found that the use of
IPr)Pd(allyl)Cl and a TIPS thioether was key to obtaining the alkyl aryl sulfides in high
disclosed a Pd-catalyzed carbothiolation for the con-
(
yield. Stimulated by this work, we embarked a program on radical cyclization/thiolation
cascade reaction using arenediazonium salts and thiophenols as starting materials. One
advantage over the existing method is that with the radical approach it should be pos-
sible to conduct under transition-metal-free conditions (Scheme 1).
Results and discussion
Initially, o-(allyloxy) benzenediazonium tetrafluoroborate 1a and p-Toluenethiol 2a were
chosen as model substrates to explore and optimize the experimental conditions.
Figure 1. Representative natural products possessing a 2,3-dihydrobenzofuran core.

2
206
T. CHEN ET AL.
[
10]
Initially, according to Studer’s work,
tion was performed at room temperature overnight under a nitrogen atmosphere (Table
, entry 1). It was disappointing only a trace amount of the expected 3-thioether-func-
TBAI was utilized as an additive and the reac-
1
tionalized 2,3-dihydrobenzofurans 3a was detected and the corresponding diaryl disul-
fide was isolate as the main product. Then Et N was employed instead of TBAI and the
3
desired product 3-((p-tolylthio)methyl)-2,3-dihydrobenzofuran 3a was obtained in 56%
yield (Table 1, entry 2). Encouraged by this result, a number of bases were subsequently
studied to improve the reaction yields (Table 1, entries 3–7) and DABCO proved to be
best with 79% yield. Decreasing the amount of DABCO from 1.5 equiv. to 1.0 equiv.
gave an inferior result (Table 1, entry 8). A slight increase in yield was obtained when
the amount of DABCO was increased to 2.0 equiv. or the temperature was raised to
Scheme 1. (a, b) Strategies to 3-thioether-2,3-dihydrobenzofunans.
a
Table 1. Optimization of conditions.
b
Entry
Additive (equiv.)
TBAI (1.5)
Et N (1.5)
DBU (1.5)
DABCO (1.5)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
Trace
56
73
79
21
36
30
46
80
82
67
70
51
64
29
3
Na
NaOH (1.5)
Cs CO (1.5)
2 3
CO (1.5)
2
3
DABCO (1.0)
DABCO (2.0)
DABCO (1.5)
DABCO (1.5)
DABCO (1.5)
DABCO (1.5)
DABCO (1.5)
DABCO (1.5)
9
c
10
11
12
13
14
15
a
DCM
MeOH
DMF
d
MeCN
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol) and additive (0.3 mmol) in solvent (2.0 mL) at room temperature for
2 h under N ; isolated yield; reaction was conducted at 40 C; reaction was conducted under air atmosphere.
b
c
ꢀ
d
1
2

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Scheme 2. Scope of thiophenols. Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol) and DABCO
(
0.3 mmol) in MeCN (2.0 mL) at room temperture for 12 h under N ; isolated yield.
2
ꢀ
4
0 C (Table 1, entries 9–10). However, given the economic and environmental factors,
the radical cyclization/thiolation cascade reaction was conducted promoted by 1.5 equiv.
DABCO at room temperature. Subsequently, to further explore this reaction, a variety
of solvents were screened. Screening revealed that other solvents, such as DCE, DCM,
MeOH and DMF, did not provide any better results than MeCN (Table 1, entries
11–14). Moreover, when the reaction was conducted in air, the yield of 3a decreased
dramatically.
After the establishment of the optimal reaction conditions, the scope of thiophe-
nols for the DABCO-promoted intramolecular radical cyclization/thiolation cascade
reaction was explored (Scheme 2). Initially, a range of para-substituted thiophenols
were examined under the optimal conditions in order to study the electronic
substituent effect. To our delight, it was observed that both electron-rich and
electron-deficient thiophenols could react smoothly and afford the corresponding

2
208
T. CHEN ET AL.
2
,3-dihydrobenzofurans 3a–3e in up to 83% yields, although the reactivity of the thi-
ophenols with electron-donating groups was superior to that with electron-withdraw-
ing groups.
The sterically hindered thiophenol (2-methylbenzenethiol 2g) could also be used as
starting materials for the preparation of 2,3-dihydrobenzofurans 3g with satisfactory
yield, indicating that steric effects had a slight effect on the yields of the intramolecular
radical cyclization/thiolation cascade reaction (products 3a, 3f and 3g). Besides, naph-
thalene-2-thiol was employed and gave product 3h in 75% yield. To further demon-
strated the generality of the reaction, the heteroaromatic thiols pyridine-2-thiol 2i
and benzo[d]thiazole-2-thiol 2j were investigated and resulted the corresponding
2,3-dihydrobenzofunans 3i and 3j in 65% and 72% yields, respectively.
After the scope of thiophenols was examined, a series of arenediazonium tetrafluoro-
borate salts were investigated (Scheme 3). The electronic and steric variations in the aryl
moiety of benzenediazonium tetrafluoroborates were also tested. Both donating and elec-
tron-withdrawing substituents afforded the desired radical cyclization/thiolation products
in moderate to good yields (3k–3p). Remarkably, halogen atoms (Cl and Br groups)
were found to be compatible with this transformation, affording 2,3-dihydrobenzofunans
3
o and 3p in good yields, without the competing products between aryl halides with
Scheme 3. Scope of alkenyl-tethered arenediazonium salts. Reaction conditions: 1 (0.2 mmol), 2a
0.3 mmol) and DABCO (0.3 mmol) in MeCN (2.0 mL) at room temperature for 12 h under N ; iso-
(
2
lated yield.

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Scheme 4. Construction of 3-thioether-benzofuran.
thiols being detected, thus enabling this methodology more useful for further transfor-
mations at the halogenated position. The use of o-methallyloxy benzenediazonium tetra-
fluoroborate 1q furnished the 3-methyl-3-((p-tolylthio)methyl)-2,3-dihydrobenzofuran 3q
in 68% yield successfully, forming a quaternary C centers at the C3 position. Besides, 4-
thioether-chromane 3r could be realized by 6-exo cyclization of 1-butenyloxy-tethered
arenediazonium tetrafluoroborate, in 80% yield.
To establish the scope of this transformation further, 2-propargyloxy substituted benzene-
diazonium tetrafluoroborate 4 was next investigated under optimal conditions. Gratifyingly,
the expectative product 3-thioether-benzofunan 5 was obtained in 57% yield (Scheme 4).
Control experiments were performed to understand the reaction mechanism. When
TEMPO was added into the reaction system of o-(allyloxy) benzenediazonium tetra-
fluoroborate 1a and p-toluenethiol 2a under standard reaction conditions (Scheme 5a),
the yield of product 3a was dramatically decreased. In addition, the cyclized alkoxy-
[
10b]
amine 6 was obtained in 81% isolated yield
mechanism proceeded through a radical pathway. Then, the reaction employed
.75 equiv. disulfide 7 as starting material was performed and the yield of the desired
. This result indicates that the reaction
0
product 3a decreased obviously, suggesting that the thiolate anion may play a crucial
role in this reaction system (Scheme 5b).
[
6a]
Consequently, based on experimental observations and the literature , a plausible
mechanism for this DABCO-promoted intramolecular radical cyclization/thiolation cas-
cade reaction was illustrated (Scheme 6). Initially, deprotonation of phenthiol 2 afforded
the thiolate anion A using DABCO as organic base. Then a very rapid bimolecular reac-
tion occurred between the diazonium cation 1 and the anion A, leading to the covalent
intermediate diazo sulfide B. Thermal homolysis of intermediate B produced the aryl
radical C, N and sulfenyl radical E. The former conducted an intramolecular addition
2
of the aromatic radical to the double bond in 5-exo mode rapidly and furnished the pri-
mary alkyl radical intermediate D, which would then react with sulfenyl radical E to
form the desired 3-thioether-functionalized 2,3-dihydrobenzofurans 3.
Experimental procedure
General procedure for the preparation of 3-thioether-functionalized 2,3-
dihydrobenzofurans
In a flame-dried Schlenk-tube, o-allyloxy benzenediazonium tetrafluoroborate 1
(0.2 mmol), thiophenols 2 (0.3 mmol, 1.5 equiv.) and DABCO (0.3 mmol, 1.5 equiv.) in
MeCN (2.0 mL) were reacted under nitrogen atmosphere. The mixture was stirred at
room temperature for 12 h. Upon completion, the solvent was evaporated and the

2
210
T. CHEN ET AL.
Scheme 5. (a, b) Control experiments.
Scheme 6. Plausible mechanism.
residue was purified directly by preparative TLC using petrol ether as the eluent to give
the corresponding product 3.
3
-((p-tolylthio)methyl)-2,3-dihydrobenzofuran (3a): colorless oil, 79% isolated yield,
1
H-NMR (400 MHz, Chloroform-d) d 7.31 (d, J ¼ 8.0 Hz, 2H), 7.25–7.21 (m, 1H),
7
1
2
1
2
.18–7.06 (m, 3H), 6.85 (t, J ¼ 7.4 Hz, 1H), 6.79 (d, J ¼ 8.0 Hz, 1H), 4.60 (t, J ¼ 9.0 Hz,
H), 4.43 (dd, J ¼ 9.2, 5.6 Hz, 1H), 3.66–3.54 (m, 1H), 3.27 (dd, J ¼ 13.0, 5.0 Hz, 1H),
13
.95 (dd, J ¼ 13.0, 9.7 Hz, 1H), 2.33 (s, 3H). C-NMR (100 MHz, CDCl ) d 160.04,
3
36.92, 131.61, 130.84, 129.93, 129.24, 128.84, 124.55, 120.51, 109.82, 76.13, 41.66, 39.63,
þ
þ
1.07. HRMS (ESI) calcd for C H OS (M þ H ): 257.0995, found: 257.0991.
1
6
17
Conclusion
In summary, a facile approach for 3-thioether-2,3-dihydrobenzofurans starting from o-
allyloxy) benzenediazonium salts and thiophenols promoted by DABCO was reported.
The reaction proceeded via an intramolecular radical cyclization/thiolation cascade
(

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reaction. The protocol displayed good functional group tolerance and afforded the
desired products in moderate to good yields.
1
13
The material including full experimental detail, H- and C-NMR spectra can be
found via the “Supplementary Content” section of this article’s webpage.
Acknowledgements
Our present work was financially supported by the Chemical Engineering & Technology of
Zhejiang Province First-Class Discipline (Taizhou University).
Funding
The present work was financially supported by the Chemical Engineering & Technology of
Zhejiang Province First-Class Discipline (Taizhou University).
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