Synthesis of Spiro[benzofuran-2,2'-benzo[b]thiophene]-3,3'-diones via PIDA/CuBr-Mediated Spirocyclization

Article abstract of DOI:10.1002/ejoc.202001001

A phenyliodine(III) diacetate (PIDA)/CuBr-mediated construction of the novel 3H,3'H-spiro[benzofuran-2,2'-benzo[b]thiophene]-3,3'-dione skeleton was realized from the reaction of (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-(2-halogenphenyl)prop-2-en-1-ones with p

Full text of DOI:10.1002/ejoc.202001001

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Synthesis of Spiro[benzofuran-2,2’-benzo[b]thiophene]-3,3’-
diones via PIDA/CuBr-Mediated Spirocyclization
Authors: Xuemin Li, Huiyuan Liang, Yaxin O Yang, Xi Wang, Jingran
Zhang, Donghua Wang, Fengxia Sun, and Yunfei Du
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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to this Accepted Article as a result of editing. Readers should obtain
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001001
Link to VoR: https://doi.org/10.1002/ejoc.202001001
0
1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202001001
FULL PAPER
Synthesis of Spiro[benzofuran-2,2’-benzo[b]thiophene]-3,3’-
diones via PIDA/CuBr-Mediated Spirocyclization
Xuemin Li,[a][d] Huiyuan Liang,[a][d] Yaxin O Yang, Xi Wang, Jingran Zhang, Donghua Wang,
[a]
[a]
[a]
[a]
[
c]
,[a][b]
Fengxia Sun, Yunfei Du*
Abstract:
A
phenyliodine(III) diacetate (PIDA)/CuBr-mediated
of the novel 3H,3'H-spiro[benzofuran-2,2'-
protect the liver, reduce inflammation, analgesia, sedation,
reduce blood lipid, hypoglycemic, hypotensive, anti-
arteriosclerosis, anti-convulsion, anti-epilepsy, vasodilation, but
also inhibit platelet aggregation.[8b]
construction
benzo[b]thiophene]-3,3'-dione skeleton was realized from the
reaction of (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-(2-
halogenphenyl)prop-2-en-1-ones with potassium ethylxanthate in the
presence of 1,10-phen. The reaction sequence was postulated to
encompass a PIDA-mediated oxidative C-O bond formation followed
by a CuBr-mediated spirocyclization step.
As the spiroheterocycles bearing S-atom in their spiro-ring
system are an important class of compounds, much effort has
been devoted to the assembly of this special type of heterocyclic
skeleton.[7] Literature survey reveals that the predominant
existing strategies adopted for the construction of this S-
containing spiroheterocyclic compounds include the 1,3-dipolar
cycloaddition reactions,[
cycloaddition reaction
irradiation[7j] and catalytic synthesis.
7a-b]
radical cycloaddition reactions,
[7c]
Introduction
catalyst,[7d-i]
without
microwave
[7k-n]
For instances,
Spiroheterocycles are a class of special spirocyclic compounds
containing heteroatoms such as nitrogen, sulfur, and/or oxygen
in the spiro ring systems. Due to their particular structure, they
have been found to possess the advantageous features of good
[
1]
stereoselectivity and versatile biological properties,
which
[2]
[3]
enable them to find wide application in medicines, pesticides,
dyes,[4] materials[5] and other fields. Although numerous
spiroheterocyclic compounds have been documented so far, the
majority of them possess N-atom and/or O-atom within the spiro-
ring skeletons,[6] while the S-containing spiroheterocycles are
relatively less explored.[7] However, this outcome does not
devalue the importance of S-containing spiroheterocycles, as
some of them have been found to display various biological
activities.[8] For examples, spirothiosteroids (A, Figure 1) can be
used as progesterone receptors to mimic some of the
Figure 1. Representative sulfur-containing spiroheterocyclic compounds with
application values.
Kochikyan[7f] disclosed an elegant synthesis of spiroheterocyclic
compounds from ethyl 5-alkoxymethyl-2-oxotetrahydrofuran-3-
carboxylates which reacted with bromine and substituted
thioureas (Scheme 1a). In 2019, Behera et. al.[7h] reported that
thiadiazolo[3,2-c] thiazolines were prepared from the reaction of
hydrazine intermediates with thioglycolc acid methanol in DMF
at high temperature (Scheme 1b). Kawada and co-workers[
synthesized spirobenzothiophene compounds by heating 2-(5-
[
8a]
physiological effects of progesterone.
4, 8-Diaza-1-thia-
spiro[4.5]decane-3-carbox-ylic acid derivatives (B, Figure 1),
also a class of S-containing spiroheterocycle, can not only
7i]
oxo-1,3-oxathiolan-4-yl) benzoic acid with acetic anhydride in
triethylamine (Scheme 1c). Yus and co-workers[7k] realized
[
a]
X. Li, H. Liang, Y. O Yang, X. Wang, J. Zhang, Prof. Dr. D. Wang,
Prof. Dr. Y. Du,
School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin 300072, China
Tel: +86-22-27406121
E-mail: duyunfeier@tju.edu.cn
synthesis of 1-thiaspiro[4.5]decane via a Hg(OAc)
2
-mediated
H (Scheme 1d). Glorius,
converted benzothiophene
3 2
spirolization of hydroxythiol in CF CO
[7l]
Neugebauer and co-workers
derivatives to
a class of scarcely explored S-containing
[
b]
c]
Prof. Dr. Y. Du,
spiroheterocycles through an enantioselective NHC-catalyzed
intramolecular hydroacylation/dearomatization transformation
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Tianjin 300072, China
Prof. Dr. F. Sun,
College of Chemical and Pharmaceutical Engineering, Hebei
University of Science and Technology; Hebei Research Center of
Pharmaceutical and Chemical Engineering, Shijiazhuang 050018,
China
[
(
Scheme 1e). Although the above approaches have been
reported, the overall number of these methods for construction
of the S-containing spiroheterocyclic skeleton are relatively
limited. Furthermore, all these existing methods utilize the
Scontaining substrates, which are somewhat not readily
accessible, as the starting materials. In these regards, the
development of novel strategy for synthesis of S-containing
spiroheterocycles, by introducing the S-atom from the readily
[d]
X.L. and H.L. contributed equally.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/ chem.201xxxxxx
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202001001
FULL PAPER
available S-source, should be highly desirable. In this
communication, we reported an alternative method for the
construction of 3H,3'H-spiro[benzofuran-2,2'-benzo[b]thiophene]-
3,3'-dione compound, an analogue of the previously reported
spiro-2,2'-benzo[b]furan-3,3'-one compound.
3
,3'-dione skeleton via PIDA/CuBr-mediated intramolecular
spirolization of (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-(2-
iodophenyl)prop-2-en-1-ones, using potassium ethyl xanthate
Table 1. Optimization of the Reaction Conditions. [a]
[
9]
as S-source to introduce S-atom into the spiroheterocyclic
product (Scheme 1f).
Temp
Yield
(%)[b]
Entry
Oxidant
Catalyst
S Reagent
Ligand
o
(
C)
1
2
3
4
5
6
7
8
9
Cu(OTf)
PIDA
PIDA
PIDA
PIDA
PIFA
TBHP
PhIO
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
2
none
Cu(OTf)
CuI
KSC(S)OEt
KSC(S)OEt
KSC(S)OEt
KSC(S)OEt
KSC(S)OEt
KSC(S)OEt
KSC(S)OEt
KSC(S)OEt
KSCN
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
A
80
80
80
80
80
80
80
80
80
80
80
100
60
40
rt
NR
31
2
32
CuSCN
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
38
43
NR
37
24
NR
NR
NR
63
10
11
12
13
14
15
16
17
18
S
K
8
2
S
KSC(S)OEt
KSC(S)OEt
KSC(S)OEt
KSC(S)OEt
KSC(S)OEt
KSC(S)OEt
KSC(S)OEt
40
27
NR
68
80
80
80
B
43
C
43
[
1
a] Reaction conditions: 1a (1.0 mmol), oxidant (3 mmol), catalyst (0.2 mmol),
,10-phen (0.2 mmol) and S reagent (2 mmol) in DMSO (4 mL). [b] Isolated
yield. NR = no reaction occurred.
Scheme 1. General Methods for Synthesis of S-Containing
Spiroheterocycles.
We set out to investigate the viability of the postulated
cascade oxidative C-O bond and C-S bond formations toward
synthesis of spiroheterocycle 2a by using (Z)-3-hydroxy-1-(2-
hydroxyphenyl)-3-(2-iodophenyl)prop-2-en-1-one 1a as subst-
Results and discussion
rate, potassium ethylxanthate as sulfur source, Cu(OTf)
2
as
Nowadays, transition metal-mediated coupling reaction between
aryl halides and S-containing alkyl thiol has become a powerful
copper oxidant and DMSO as solvent. However, to our
disappointment, no reaction occurred when the reaction mixture
was conducted at 80 oC for 24 h (Table 1, entry 1). To our
approach for the construction of aryl C(sp2)-S bond.[10] In our
previous work, we have realized the construction of spiro-2,2'-
delight, when PIDA was employed as an oxidant and Cu(OTf)
as catalyst, the desired 3H,3'H-spiro[benzofuran-2,2'-
2
benzo[b]furan-3,3'-one skeleton through
spirolization of benzyl protected
a
PIDA-mediated
a
3-hydroxy-1,3-bis(2-
benzo[b]thiophene]-3,3'-dione 2a was formed in 31% yield
(Table 1, entry 2). The structure of 2a was undoubtedly
confirmed by X-ray diffraction analysis.[13] The copper catalysts
including CuI, CuSCN and CuBr were further tested,[10l,14] and
the results showed that CuBr gave the best result (Table 1,
entries 3-5). With CuBr as the catalyst, several oxidants
including phenyliodine(III) bis(trifluoroacetate) (PIFA), tert-butyl
hydroperoxide (TBHP) and iodosobenzene (PhIO) were also
screened. However, none of these reagents outcompeted PIDA
hydroxyphenyl)prop-2-en-1-ones, during the process of which
dual intramolecular C-O bond forming reaction occurs.[11] In
continuation of our interest in the assemblage of
spiroheterocyclic framework,[6e-g,12] we were motivated to
investigate whether we could combine the strategy of transition-
2
metal mediated aryl C(sp )-S bond formation with that of the
PIDA-mediated C-O/C-S bond formation to produce the S-
containing
3H,3'H-spiro[benzofuran-2,2'-benzo[b]thioph-ene]-
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European Journal of Organic Chemistry
10.1002/ejoc.202001001
FULL PAPER
1
2
(
Table 1, entries 6-8). Further study on the other sulfur reagents
applicable to the substrates bearing both R and R substituents
concurrently, with the corresponding product achieved in
revealed that when potassium ethylxanthate was replaced by
2
KSCN, S and K S, no product formation was observed (Table 1, relatively lower yields (Table 2, 2e, 2i, 2p).
8
entries 9-11). Temperature optimization studies identified the
ideal temperature to be 80 oC (Table 1, entries 12-15). To our
delight, the yield of 2a increased when 1,10-phen[15] was
employed as an additive (Table 1, entry 16). We also studied the
other ligands including L-proline or picolinic acid, however, only
A control experiment was carried out to gain some insights on
the reaction mechanism. When compound 3a, in which there is
no iodo group substituted on the left pheny ring, was applied to
the standard conditions, benzofuran 4a was formed in 52% yield
(Scheme 2). Furthermore, when substrate 2a was subjected to
the standard conditions with the exclusion of PIDA, no thiolated
product 5a was found. These results might indicate that the
PIDA-mediated oxidative C-O bond formation occurred first
during the reaction process.
1, 10-phen gave the best result. (Table 1, entries 17-18). Based
on all the screening results, the optimal reaction conditions were
concluded to be 1 mmol of substrate 1a, 3 equiv of PIDA, 0.2
equiv of CuBr, 0.2 equiv of 1,10-phen, 2 equiv of KSC(S)OEt
o
with DMSO as solvent at 80 C.
Table 2. Study of Substrate Scope. [a,b]
Scheme 2. Control Experiments for Mechanistic Studies.
Based on the above results as well as the previous literature
reports,[17] we postulated a mechanistic pathway for this novel
cascade process for synthesizing 3H,3'H-spiro[benzofuran-2,2'-
benzo[b]thiophene]-3,3'-dione products (Scheme 3). First, the
enolic carbon in 1a nucleophilically attacked the iodine center of
PIDA to give the C-I intermediate A.[ Next, an intramolecular
C-O bond formation occurred in A to give benzofuran B, with the
release of one molecule of PhI and acetate. It is worth noting
that all of our attempts to isolate and characterize intermediate B
proved to be infertile. In the presence of copper(I) bromide, Cu
18]
2
was then inserted into the C(sp )-I bond, leading to the formation
[
a] Reaction conditions: 1 (1 mmol), PIDA (3 mmol), CuBr (0.2 mmol), 1,10-
o
phen (0.2 mmol) and KSC(S)OEt (2 mmol) in DMSO (4 mL) at 80 C. [b]
Isolated yield.
With the optimal conditions in hand, we came to explore the
generality and scope of this newly established spirolization
method. As indicated by the results in Scheme 2, substrates
bearing less reactive C-X bonds, such as C-Br, C-Cl, could
afford the desired product 2a in relatively lower yield. Further
study revealed that the substrates bearing either electron-
donating groups or electron-withdrawing groups could be
converted to the corresponding S-containing spiroheterocycles
in satisfactory to good yield. The method worked equally well for
1
2
the substrates bearing various R and R substituent on the two
phenyl rings. To be more specific, for substrates bearing R2
substituent (Me, OMe, F, Cl, Br), the reaction all delivered the
corresponding products in good yields (Table 2, 2b-d, 2f, 2j-m).
1
Scheme 3. Plausible Mechanism.
While R substituent, being either the electron-donating (Me) or
the electron-withdrawing (Cl, Br) groups, could be well tolerated,
with the corresponding products in most cases obtained in good
yields (Table 2, 2g-h, 2n-o, 2q).[16] The method was also
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European Journal of Organic Chemistry
10.1002/ejoc.202001001
FULL PAPER
of a benzofuran-copper(III) complex C. Followed by its reaction
with potassium ethylxanthate, copper(III) intermediate D was
formed. Next, reductive elimination of CuBr from D afforded
intermediate E, which reacted with the second molecule of PIDA
to give the C-I intermediate F. After that, an intramolecular S-C
bond formation occurred in F to give the sulfonium G, with the
release of PhI and acetate. Finally, the reaction of intermediate
G with another molecule of ethylxanthate gave rise to the title
product, with the formation of bis(ethoxythiocarbony)sulfide[19] as
a byproduct.
8.47 (d, J = 7.9 Hz, 1H), 8.15 (d, J = 2.7 Hz, 1H), 7.82 – 7.76 (m, 1H),
7
.75 – 7.68 (m, 2H), 7.59 (d, J = 8.8 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H). 13C
NMR (150 MHz, CDCl
28.4, 128.0, 126.8, 126.2, 124.6, 121.3, 116.1, 115.6, 100.1. HRMS
ESI) m/z calcd for
79BrlNaO S+ [M Na+] 368.9191, found
3
) δ 192.8, 192.6, 171.3, 150.4, 141.4, 137.6,
1
(
C
H
15 7
3
+
368.9198.
5'-Methyl-3H,3'H-spiro[benzo[b]thiophene-2,2'-benzofuran]-3,3'-
dione (2d): Following the general procedure for preparation of 2, 2d was
purified by silica gel chromatography (10% EtOAc/PE). Yield: 339 mg,
80%, an orange solid, mp. 210 - 212 oC. 1H NMR (600 MHz, CDCl
7
(
) δ
.80 (dd, J = 7.7, 0.6 Hz, 1H), 7.66 (td, J = 8.1, 1.3 Hz, 1H), 7.57 – 7.53
m, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.33 – 7.29 (m, 1H), 7.18 (d, J = 8.4 Hz,
3
1
1
H), 2.42 (s, 3H). 13C NMR (150 MHz, CDCl
50.6, 140.2, 137.2, 133.3, 128.2, 127.2, 126.0, 124.9, 124.6, 119.5,
3
) δ 193.9, 193.6, 171.0,
Conclusion
1
C
13.4, 95.5, 77.3, 77.0, 76.8, 20.7. HRMS (ESI) m/z calcd for
H10NaO S [M + Na ] 305.0243, found 305.0246.
16 3
In conclusion, we have presented
a
PIDA/CuBr-mediated
+
+
spirocyclization reaction involving an intramolecular oxidative C-
O bond formation step followed by C-S bond formation process,
enabling a convenient synthesis of 3H,3'H-spiro[benzofuran-2,2'-
benzo[b]thiophene]-3,3'-dione in satisfactory to good yield. This
could represent an alternative strategy for the assemblage of S-
containing spiroheterocycles, which features a cascade process
introducing S-atom from the readily available potassium
ethylxanthate at late stage, rather than utilizing the S-containing
substrate. Further studies on the reaction mechanism are still in
progress in our lab.
6-Fluoro-3H,3'H-spiro[benzo[b]thiophene-2,2'-benzofuran]-3,3'-dione
(2e): Following the general procedure for preparation of 2, 2e was
purified by silica gel chromatography (10% EtOAc/PE). Yield: 390 mg,
8
7
1
8
1
1
2%, an orange solid, mp. 207 - 208 oC. 1H NMR (400 MHz, CDCl
) δ
3
.69 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.8, 2.3 Hz, 1H), 7.61 – 7.57 (m,
H), 7.47 (dd, J = 8.1, 1.4 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.21 (d, J =
.8 Hz, 1H), 2.38 (s, 3H).13C NMR (100 MHz, CDCl
70.8, 147.2, 138.7, 138.7, 136.5, 129.0, 128.3, 127.0, 124.8, 124.3,
S+ [M +
20.8, 115.1, 96.3, 20.7. HRMS (ESI) m/z calcd for C16 ClNaO
] 338.9853 found 338.9855.
3
) δ 192.9, 192.9,
H
9
3
+
Na
6'-Methoxy-3H,3'H-spiro[benzo[b]thiophene-2,2'-benzofuran]-3,3'-
dione (2f): Following the general procedure for preparation of 2, 2f was
Experimental Section
purified by silica gel chromatography (10% EtOAc/PE). Yield: 295 mg,
6
6%, an orange solid, Decomposition > 300 oC. 1H NMR (400 MHz,
General Procedure for the synthesis of compound 2: To
suspension of substrate 1 (1.5 mmol), xanthate (3 mmol), CuBr (0.3
mmol), 1, 10-phen (0.3 mmol) in DMSO (5 mL) was added PIDA (4.5
mmol) portionwise at 80 oC. The resulting mixture was kept at the same
a
CDCl
J = 8.0 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 6.74 (dd, J = 8.7, 2.0 Hz, 1H),
6.67 (d, J = 2.0 Hz, 1H), 3.92 (s, 3H). 13C NMR (100 MHz, CDCl
) δ
3
) δ 7.78 (d, J = 7.4 Hz, 1H), 7.64 (dd, J = 10.0, 4.9 Hz, 2H), 7.45 (d,
3
1
1
C
93.7, 191.1, 175.1, 169.1, 150.6, 137.2, 128.1, 127.2, 126.6, 126.0,
temperature until TLC indicated the total consumption of substrate 1.
24.6, 113.1, 112.5, 96.8, 96.1, 56.2. HRMS (ESI) m/z calcd for
Then H
with DCM (3 x 30 mL). The organic phase was washed with sat. NaCl,
dried with anhy. Na SO . The solvent was removed and the residue was
2
O (30 mL) was added and the reaction mixture was extracted
+
+
16 4
H10NaO S [M + Na ] 321.0192, found 321.0195.
2
4
5-Bromo-3H,3'H-spiro[benzo[b]thiophene-2,2'-benzofuran]-3,3'-
purified by flash column chromatography on silica gel to afford the
dione (2g): Following the general procedure for preparation of 2, 2g was
desired compound 2.
purified by silica gel chromatography (10% EtOAc/PE). Yield: 380 mg,
7
7
7
3%, an orange solid, mp. 147 - 149 oC. 1H NMR (600 MHz, CDCl
3
) δ
.89 (d, J = 2.0 Hz, 1H), 7.77 – 7.72 (m, 3H), 7.35 (d, J = 8.4 Hz, 1H),
.27 (s, 1H), 7.22 (dd, J = 11.4, 4.0 Hz, 1H). 13C NMR (150 MHz, CDCl
3
H,3'H-Spiro[benzo[b]thiophene-2,2'-benzofuran]-3,3'-dione
(2a):
Following the general procedure for preparation of 2, 2a was purified by
silica gel chromatography (10% EtOAc/PE). Yield: 274 mg, 68%, an
3
)
o
1
δ 193.2, 192.3, 172.4, 149.3, 139.8, 139.1, 130.6, 128.8, 125.8, 125.7,
orange solid, mp. 145 - 146 C. H NMR (600 MHz, CDCl
3
) δ 7.78 (d, J =
.7 Hz, 1H), 7.76 – 7.69 (m, 2H), 7.67 – 7.62 (m, 1H), 7.46 (d, J = 8.0 Hz,
H), 7.30 (d, J = 7.3 Hz, 1H), 7.29 – 7.26 (m, 1H), 7.21 (t, J = 7.4 Hz,
H). 13C NMR (150 MHz, CDCl ) δ 160.1, 154.7, 148.3, 142.9, 142.6,
38.4, 129.6, 128.8, 127.7, 127.6, 127.1, 126.8, 123.5, 122.5, 113.7,
123.6, 119.8, 119.3, 113.9, 95.4, 77.2, 77.0, 76.8. HRMS (ESI) m/z calcd
7
1
1
1
79BrNaO
S [M + Na ] 368.9191, found 368.9193.
+
+
for C15
H
7
3
3
5-Methyl-3H,3'H-spiro[benzo[b]thiophene-2,2'-benzofuran]-3,3'-dione
+
+
(2h): Following the general procedure for preparation of 2, 2h was
112.0, 91.6. HRMS (ESI) m/z calcd for C15
H NaO
8
3
S [M + Na ] 291.0086,
purified by silica gel chromatography (10% EtOAc/PE). Yield: 330 mg,
found 291.0089.
7
8%, an orange solid, mp. 168 - 170 oC. 1H NMR (600 MHz, CDCl
3
) δ
7
.75 – 7.68 (m, 1H), 7.59 (s, 0H), 7.47 (dd, J = 8.1, 1.4 Hz, 1H), 7.34 (d,
5
-Methyl-3H,3'H-2,2'-spiro[b][benzofuran]-3,3'-dione (2b): Following
J = 8.1 Hz, 0H), 7.25 (s, 0H), 7.20 (t, J = 7.5 Hz, 1H), 2.38 (s, 2H). 13C
the general procedure for preparation of 2, 2b was purified by silica gel
chromatography (10% EtOAc/PE). Yield: 479 mg, 79%, an orange solid,
Decomposition > 300 oC. 1H NMR (400 MHz, CDCl
Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.68 – 7.60 (m, 2H), 7.46 (d, J = 8.0
Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H). 13C NMR (100
NMR (150 MHz, CDCl
136.3, 128.2, 127.3, 125.6, 124.3, 123.4, 119.6, 113.9, 95.6, 77.3, 77.1,
3
) δ 194.0, 193.5, 172.5, 147.4, 138.9, 138.6,
3
) δ 7.78 (d, J = 7.5
+
+
76.9, 20.7. HRMS (ESI) m/z calcd for C16
H10NaO S [M + Na ] 305.0243,
3
found 305.0248.
3
MHz, CDCl ) δ 192.8, 192.8, 170.8, 150.3, 138.8, 137.5, 129.1, 128.3,
5
'-Bromo-5-methyl-3H,3'H-spiro[benzo[b]thiophene-2,2'-
1
26.9, 126.3, 124.8, 124.6, 120.7, 115.2, 95.9. HRMS (ESI) m/z calcd for
35ClNaO +
+
benzofuran]-3,3'-dione (2i): Following the general procedure for
preparation of 2, 2i was purified by silica gel chromatography (10%
C H
15 7
3
S [M + Na ] 324.9697, found 324.9700.
EtOAc/PE). Yield: 314 mg, 58%, an orange solid, mp. 185 - 186 oC. 1
NMR (400 MHz, CDCl ) δ 7.85 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 8.8, 2.2
Hz, 1H), 7.59 (s, 1H), 7.52 – 7.46 (m, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.17
(d, J = 8.8 Hz, 1H), 2.39 (s, 3H). 13C NMR (150 MHz, CDCl
) δ 192.8,
H
5
'-Bromo-3H,3'H-spiro[benzo[b]thiophene-2,2'-benzofuran]-3,3'-
3
dione (2c): Following the general procedure for preparation of 2, 2c was
purified by silica gel chromatography (10% EtOAc/PE). Yield: 266 mg,
1%, an orange solid, mp. 225 - 227 oC. 1H NMR (600 MHz, CDCl
3
5
3
) δ
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European Journal of Organic Chemistry
10.1002/ejoc.202001001
FULL PAPER
1
1
C
92.7, 171.2, 147.2, 141.4, 138.7, 136.5, 128.3, 127.9, 127.0, 124.3,
5,5'-Dimethyl-3H,3'H-spiro[benzo[b]thiophene-2,2'-benzofuran]-3,3'-
dione (2p): Following the general procedure for preparation of 2, 2p was
purified by silica gel chromatography (10% EtOAc/PE). Yield: 320 mg,
21.3, 116.0, 115.5, 96.1, 20.7. HRMS (ESI) m/z calcd for
79BrNaO
+
+
16
H S [M + Na ] 382.9348, found 382.9348.
9 3
7
7
2%, an orange solid, mp. 235 - 237 oC. 1H NMR (600 MHz, CDCl
.58 (s, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.45 (dd, J = 8.1, 1.1 Hz, 1H), 7.33
3
) δ
5
'-Fluoro-3H,3'H-spiro[benzo[b]thiophene-2,2'-benzofuran]-3,3'-
(
d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 2.38 (d, J = 7.2 Hz, 6H). 13C
) δ 194.0, 193.6, 171.0, 147.4, 140.1, 138.5,
136.2, 133.2, 128.2, 127.3, 124.9, 124.2, 119.5, 113.4, 95.9, 77.3, 77.0,
dione (2j): Following the general procedure for preparation of 2, 2j was
purified by silica gel chromatography (10% EtOAc/PE). Yield: 391 mg,
NMR (150 MHz, CDCl
3
1%, an orange solid, mp. 201 - 203 oC. 1H NMR (400 MHz, CDCl
7
9
3
) δ
.78 (dd, J = 7.7, 0.7 Hz, 1H), 7.69 – 7.62 (m, 1H), 7.45 (dt, J = 8.7, 3.1
7
3
6.8, 20.7, 20.6. HRMS (ESI) m/z calcd for C17
19.0399, found 319.0403.
H12NaO
3
S+ [M + Na+]
Hz, 2H), 7.38 (dd, J = 6.5, 2.7 Hz, 1H), 7.33 – 7.27 (m, 1H), 7.24 (dd, J =
9
.0, 3.6 Hz, 1H). 13C NMR (150 MHz, CDCl
) δ 193.4, 193.4, 193.0,
3
1
68.7, 159.3, 157.7, 150.3, 137.4, 128.3, 127.0, 126.7, 126.5, 126.2,
7'-Methyl-3H,3'H-spiro[benzofuran-2,2'-benzo[b]thiophene]-3,3'-
dione （2q）: Following the general procedure for preparation of 2, 2q
was purified by silica gel chromatography (5% EtOAc/PE). Yield: 347 mg,
124.6, 120.2, 120.2, 115.1, 115.0, 110.7, 110.5, 96.1. HRMS (ESI) m/z
+
+
7 3
calcd for C15H FNaO S [M + Na ] 308.9992, found 308.9996.
o
1
8
(
2%, an orange solid, mp. 194-196 C. H NMR (400 MHz, CDCl
ddd, J = 8.6, 7.3, 3.7 Hz, 2H), 7.64 (d, J = 7.7 Hz, 1H), 7.46 (d, J = 7.4
Hz, 1H), 7.29 – 7.25 (m, 2H), 7.25 – 7.18 (m, 2H), 2.36 (s, 2H). 13C NMR
101 MHz, CDCl ) δ 194.0, 193.8, 172.6, 150.2, 138.9, 137.6, 133.9,
127.0, 126.3, 125.60, 125.57, 123.4, 119.6, 113.9, 18.7. HRMS (ESI) m/z
3
) δ 7.72
6'-Methyl-3H,3'H-spiro[benzo[b]thiophene-2,2'-benzofuran]-3,3'-
dione (2k): Following the general procedure for preparation of 2, 2k was
(
3
purified by silica gel chromatography (10% EtOAc/PE). Yield: 287 mg,
5%, an orange solid, mp. 163 - 164 oC. 1H NMR (400 MHz, CDCl
6
3
) δ
+
+
calcd for C16
H10NaO S [M + Na ] 305.0243, found 305.0245.
3
7.56 (dd, J = 7.7, 0.6 Hz, 1H), 7.42 (td, J = 8.0, 1.3 Hz, 1H), 7.34 – 7.29
(
1
1
m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.10 – 7.05 (m, 1H), 6.97 – 6.92 (m,
H), 2.18 (s, 3H). 13C NMR (101 MHz, CDCl
50.6, 140.2, 137.2, 133.3, 128.1, 127.2, 126.0, 124.9, 124.6, 119.5,
S+ [M + Na+]
General Procedure for the synthesis of compound 4a: To a
3
) δ 193.9, 193.6, 171.0,
suspension of substrate 3a (1.5 mmol), xanthate (3 mmol), CuBr (0.3
mmol), 1, 10-phen (0.3 mmol) in DMSO (5 mL) was added PIDA (4.5
mmol) portionwise at 80 oC. The resulting mixture was kept at the same
temperature until TLC indicated the total consumption of substrate 3a.
1
13.4, 95.5, 20.7. HRMS (ESI) m/z calcd for C16
H
10NaO
3
305.0243, found 305.0247.
Then H
with DCM (3 x 30 mL). The organic phase was washed with sat. NaCl,
dried with anhy. Na SO . The solvent was removed and the residue was
2
O (30 mL) was added and the reaction mixture was extracted
7
'-Bromo-5'-chloro-3H,3'H-spiro[benzo[b]thiophene-2,2'-
benzofuran]-3,3'-dione (2l): Following the general procedure for
preparation of 2, 2l was purified by silica gel chromatography (10%
EtOAc/PE). Yield: 349 mg, 61%, an orange solid, mp. 212 - 214 oC. 1
2
4
purified by flash column chromatography on silica gel to afford the
H
desired compound 4a.
NMR (600 MHz, CDCl
3
) δ 7.88 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 7.6 Hz,
H), 7.72 – 7.62 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H).
) δ 192.4, 192.2, 167.8, 150.2, 140.8, 137.7,
29.6, 128.5, 126.6, 126.4, 124.6, 123.7, 121.8, 107.6, 96.3, 77.3, 77.1,
1
1
3C NMR (150 MHz, CDCl
3
2-Benzoylbenzofuran-3(2H)-one (11): Following the general procedure
for preparation of 4, 11 was purified by silica gel chromatography (10%
1
7
4
6.8. HRMS (ESI) m/z calcd for
02.8802, found 402.8809.
C
H
15 6
81Br35ClNaO
3
S+ [M
+
Na+]
EtOAc/PE). Yield: 203 mg, 71%, a yellow solid, mp. 105 - 106 oC. 1
NMR (600 MHz, CDCl ) δ 7.97 (dd, J = 7.7, 4.8 Hz, 3H), 7.56 (t, J = 7.4
Hz, 1H), 7.52 (dd, J = 7.6, 1.6 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.44 (t, J
7.5 Hz, 1H), 7.15 (td, J = 7.7, 1.6 Hz, 1H), 6.57 (s, 1H). 13C NMR (150
H
3
=
6'-Fluoro-3H,3'H-spiro[benzo[b]thiophene-2,2'-benzofuran]-3,3'-
MHz, CDCl
3
) δ 195.7, 177.5, 162.5, 135.8, 133.7, 132.4, 128.8, 128.5,
dione (2m): Following the general procedure for preparation of 2, 2m
was purified by silica gel chromatography (10% EtOAc/PE). Yield: 271
+
1
26.8, 119.1, 119.0, 118.8, 92.3. HRMS (ESI) m/z calcd for C15H10NaO
3
+
o
1
[M + Na ] 261.0522, found 261.0527.
mg, 63%, an orange solid, mp. 156 - 158 C. H NMR (400 MHz, CDCl
δ 7.81 – 7.77 (m, 1H), 7.74 (ddd, J = 8.1, 5.7, 0.7 Hz, 1H), 7.69 – 7.60
m, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.33 – 7.27 (m, 1H), 6.93 (dd, J = 13.6,
3
)
(
5
1
1
C
.4 Hz, 2H).13C NMR (150 MHz, CDCl
3
) δ 193.4, 193.4, 193.0, 168.7,
59.3, 157.7, 150.3, 137.4, 128.3, 127.0, 126.7, 126.5, 126.2, 124.6,
20.2, 120.2, 115.1, 115.0, 110.7, 110.5, 96.1. HRMS (ESI) m/z calcd for
Acknowledgments
+
+
We acknowledge the National Natural Science Foundation of
China (#21472136) for financial support. We thank the
instrument analytical center of School of Pharmaceutical
Science and Technology at Tianjin University for providing the
analysis and Yan Gao and Dr Xiangyang Zhang for the helpful
discussion.
15
H FNaO S [M + Na ] 308.9992, found 308.9996.
7 3
6-Chloro-3H,3'H-spiro[benzo[b]thiophene-2,2'-benzofuran]-3,3'-
dione (2n): Following the general procedure for preparation of 2, 2n was
purified by silica gel chromatography (10% EtOAc/PE). Yield: 350 mg,
7
8
7%, an orange solid, mp. 234 - 236 oC. 1H NMR (400 MHz, DMSO) δ
.29 (d, J = 8.6 Hz, 1H), 8.11 (dd, J = 11.7, 4.8 Hz, 2H), 7.92 (d, J = 8.5
Hz, 1H), 7.79 (t, J = 7.4 Hz, 1H), 7.66 (dd, J = 8.6, 1.8 Hz, 1H), 7.58 (t, J
7.5 Hz, 1H). 13C NMR (150 MHz, CDCl
Keywords: PIDA • CuBr • potassium ethylxanthate • heterocycle
• spirocyclization
=
1
3
) δ 155.8, 155.1, 149.1, 139.5,
37.2, 130.7, 127.8, 125.8, 124.4, 123.8, 120.5, 118.4, 117.8, 113.5.
HRMS (ESI) m/z calcd for C15
H
7
35ClNaO
3
S+ [M + Na ] 324.9697, found
+
324.9698.
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7
7
1
8%, an orange solid, mp. 246 - 248 oC. 1H NMR (600 MHz, CDCl
) δ
3
.79 – 7.72 (m, 3H), 7.62 (dd, J = 8.4, 2.2 Hz, 1H), 7.42 (d, J = 8.4 Hz,
H), 7.28 (d, J = 8.3 Hz, 1H), 7.26 – 7.20 (m, 1H).13C NMR (150 MHz,
CDCl
3
) δ 193.3, 192.4, 172.4, 148.7, 139.2, 137.1, 133.7, 132.5, 128.5,
127.6, 125.7, 125.6, 123.6, 119.3, 113.9. HRMS (ESI) m/z calcd for
35ClNaO
+
+
C H S [M + Na ] 324.9697, found 324.9698.
15 7 3
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European Journal of Organic Chemistry
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This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202001001
FULL PAPER
FULL PAPER
Xuemin Li, Huiyuan Liang, Yaxin O
Yang, Xi Wang, Jingran Zhang,
Donghua Wang，Fengxia Sun, Yunfei
Du
A phenyliodine(III) diacetate (PIDA)/CuBr-mediated construction of the novel
Page No. – Page No.
3
H,3'H-spiro[benzofuran-2,2'-benzo[b]thiophene]-3,3'-dione skeleton was realized
Synthesis of Spiro[benzofuran-2,2'-
benzo[b]thiophene]-3,3'-diones via
PIDA/CuBr-Mediated Spirocyclization
from the reaction of (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-(2-halogenphenyl)prop-2-
en-1-ones with potassium ethylxanthate in the presence of 1,10-phen. The reaction
sequence was postulated to encompass a PIDA-mediated oxidative C-O bond
formation followed by a CuBr-mediated spirocyclization step.
*Heterocycle; Spirocyclization
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