Metal-free Synthesis of Spiro-2,2′-benzo[b]furan-3,3′-ones via PhI(OAc)2-Mediated Cascade Spirocyclization

Article abstract of DOI:10.1002/adsc.201900652

Treating the benzyl protected 3-hydroxy-1,3-bis(2-hydroxyphenyl)prop-2-en-1-ones solely with PhI(OAc)₂ (PIDA) in DCE at room temperature readily furnished the seldom studied spiro-2,2′-benzo[b]furan-3,3′-ones in satisfactory to excellent yields. The hypervalent iodine reagent enables the metal-free cascade spirocyclization resulting in the dual oxidative C?O bond formation. (Figure presented.).

Full text of DOI:10.1002/adsc.201900652

Title: Metal-free Synthesis of Spiro-2,2’-benzo[b]furan-3,3’-ones via
PhI(OAc)2-Mediated Cascade Spirocyclization
Authors: Yunfei Du, Qingyu Xing, Huiyuan Liang, Mingmai Bao,
Xuemin Li, Jingran Zhang, Tianhao Bi, Yilin Zhang, and Jun
Xu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900652
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10.1002/adsc.201900652
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Metal-free Synthesis of Spiro-2,2’-benzo[b]furan-3,3’-ones via
PhI(OAc)2-Mediated Cascade Spirocyclization
Qingyu Xing,a,d Huiyuan Liang,a,d Mingmai Bao,a Xuemin Li,a Jingran Zhang,a Tianhao
Bi,a Yilin Zhang,c Jun Xu,a Yunfei Du,*,a, b and Kang Zhao*,a
a.
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and
Technology, Tianjin University, Tianjin 300072, China. Address here. E-mail: duyunfeier@tju.edu.cn;
kangzhao@tju.edu.cn
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
b.
c.
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506-6045,
United States
Q.X. and H.L. contributed equally.
d.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
known in which I(III) reagents facilitates double-
bond activation and subsequent nucleophilic
addition.[6] In addition to these examples, notable
progress on oxylactonization employing I(III)
reagent has also been reported in recent years.[7]
On the other hand, hypervalent iodine (III)
reagents have also been investigated for its
application in a series of cascade reactions
including C-C,[8] C-O,[9] C-N[10] bond formations.
However, to the best of our knowledge, I(III)-
mediated spirocyclization reactions involving
dual C-O bond formation have been least
explored.
Abstract: Treating the benzyl protected 3-hydroxy-1,3-
bis(2-hydroxyphenyl)prop-2-en-1-ones solely with
PhI(OAc)2 (PIDA) in DCE at room temperature readily
furnished the seldom studied spiro-2,2’-benzo[b]furan-3,3’-
ones in satisfactory to excellent yields. The hypervalent
iodine reagent enables the metal-free cascade
spirocyclization resulting in the dual oxidative C-O bond
formation.
Keywords: Metal-free synthesis; PIDA; Spirocyclization;
Cascade reaction; Spirobenzofuran
In the past several decades, hypervalent iodine
reagents(III) have been widely applied in a
plethora of oxidative coupling reactions.[1]
Remarkably, the hypervalent iodine reagents(III)
induced
C-O
bond
formation
through
dearomatization have received significant
attention as a powerful method to access complex
molecules.[2-3] On the other hand, a limited
number of studies were reported on I(III)
mediated C-O bond formation between carbon
and hydroxyl group without dearomatization. For
example, PIDA/I2 system was applied in Suarez
type cross coupling via photochemical reaction
involving a 1,5-hydrogen transfer in free radical
system.[4a] Kita has reported an oxidative lactone
formation via
a
similar C-H abstraction
strategy.[4b] Besides, several studies have focused
on the synthesis of benzo[b]furan-3-ones from o-
hydroxyacetophenones through I(III)-mediated
intramolecular cyclization that enables the
coupling of hydroxyl group and α-carbon of the
electron-withdrawing moiety.[5] Furthermore,
oxidative cyclization of Schiff base has been
Scheme 1 Construction of Benzo[b]furan-3-one Skeleton
via I(III)-Mediated O-O Bond Formation.
1
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10.1002/adsc.201900652
Advanced Synthesis & Catalysis
a All the reaction carried out with substrate 1a or 1a
’
(0.5 mmol), solvent (8 mL) at rt for 1 h, unless
otherwise stated. b Isolated yield..
benzo[b]furan-3-one derivatives via cascade
oxidation (Scheme 1b). Both of the
transformations above comprise intramolecular
and sequentially intermolecular C-O bond
formations, allowing for the construction of the
benzo[b]furan-3-one derivatives in a cascade
protocol. In 1990, Prakash reported[5g] that the
reaction
of
1-(2-hydroxyphenyl)-3-
phenylpropane-1,3-dione with PIDA and KOH in
methanol afforded 2-benzoylbenzofuran-3(2H)-
one via an intramoleculuar oxidative C-O bond
formation (Scheme 1c).
However, to our best knowledge, there is no
report describing the intramolecular dual C-O
bond formation leading to the construction of
spiroheterocyclic scaffold with hypervalent
iodine reagents. Herein, we report a cascade
reaction starting from the protected 3-hydroxy-
Scheme 2 Examples of Natural Products and Bioactive
Compounds Containing Benzo[b]furan-3-one.
Benzo[b]furan-3-one is an important heterocyclic
skeleton found in a broad variety of natural
products[11], such as sulphuretin[11a] and VC-15B,[11d]
and pharmaceutical bioactive compounds,[12] such as
a PIM1 inhibitor reported by Nagano group (Scheme
2). [12a]
1,3-bis(2-hydroxyaryl)prop-2-en-1-ones
1
and
PIDA, which produces spiro-2,2’-benzo[b]furan-
3,3’-one[14] species in high yields via an
intramolecular dual C-O bond formation (Scheme
1d).[5h]
One of the most conventional approach to
benzo[b]furan-3-one involves halogenation of α-
In continuation of our interest in the
construction of spiroheterocyclic framework,[15]
we initially investigated the viability of dual
hydroxyl
acetophone
followed
by
an
intramolecular SN2 reaction.[13] Moreover, another
general approach assembling benzo[b]furan-3-
ones makes use of hypervalent iodine reagent as
oxidant and this approach is widely utilized for its
merit of requiring no functionalization on the α-
oxidative
spiroheterocycle 2a starting from 1,3-bis(2-
hydroxyphenyl)propane-1,3-dione 1a’.
C-O
bond
formation
toward
Fortunately, when 1a’ was treated with PIDA in
DMF at room temperature, spiro-product 2a
could be obtained in only 31% yield (Table 1,
entry 1) with the generation of some unidentified
byproducts. We tentatively propose that the
concurrent presence of two hydroxyl groups in
the substrate facilitates the over-oxidation by the
hypervalent iodine oxidant. Due to the fact that
the reaction yield could not be improved after
various attempts, we started to conceive whether
1a, the precursor of 1a’, could also achieve this
hydroxyl
acetophenones.
For
examples,
Musallam and co-workers[5a] achieved 20% yield
of 2, 2-dimethoxyl-benzo[b]furan-3-one using
PIDA under basic conditions (Scheme 1a). In
2009, Fan reported[5b] a PIDA-mediated synthesis
of
Table 1. Optimization of the Reaction Conditions.a
PIDA-mediated
spiroheterocyclization
transformation, as the oxonium intermediate
generated may act as the reactive center for
removal of the benzyl group. On the other hand,
one less free phenolic hydroxyl group is believed
to be beneficial for eliminating some undesired
byproducts from over-oxidation. To our delight,
when 1a was treated with 3 equivalents of PIDA
in DMF, product 2a was obtained in 49% yield
(Table 1, entry 2). Further screening of solvents
indicated that when DCE was used as solvent,
product 2a was obtained in a nearly quantitative
yield (Table 1, entries 3-6). It was found that
reducing the amount of PIDA from 3 equivalents
to 2.5 and 2.0 equivalents, the yield of product 2a
decreased to 87% and 77%, respectively (Table 1,
Entry
Substrate
Oxidant (equiv)
Solvent
Yield(%)b
1
2
3
4
5
6
7
8
1a’
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
PIDA (3.0)
PIDA (3.0)
PIDA (3.0)
PIDA (3.0)
PIDA (3.0)
PIDA (3.0)
PIDA (2.5)
PIDA (2.0)
I2 (3.0)
DMF
DMF
AcOH
EtOAc
MeOH
DCE
DCE
DCE
DCE
DCE
31
49
ND
33
10
99
87
77
ND
ND
92
9
10
11
mCPBA (3.0)
PhIO (3.0)
DCE
2
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10.1002/adsc.201900652
Advanced Synthesis & Catalysis
entries 7-8). The other commonly used oxidants
including I2 and mCPBA were also examined and
it was found that the reaction gave no desired
bearing the electron-donating methyl group
(substrates 1b (R1 = H, R2 = Me)), the electron-
withdrawing fluoro (substrates 1e
1s) on B ring, the
PhIO afforded the desired product 2a in a slightly spirocyclic products could also be obtained in
, 1j) and chloro
product in each case (Table 1, entries 9-10), while group (substrates 1c
,
lower yield (Table 1, entry 11).
good to excellent yields. The substrate bearing
bromo substituent on ring B delivered the desired
products in satisfactory to excellent yield
(substrates 1d (R1 = H, R2 = Br) and 1o-p).
Furthermore, replacing the benzyloxy group on
the ring A with a methoxy or an isopropyloxy
group, the corresponding substrates 1t (PG = Me)
With the optimal conditions (Table 1, entry 6) in
hand,[16] we came to explore the generality and scope
of this newly established method. As indicated by the
results in Table 2, the substrates bearing either
electron-donating groups or electron-withdrawing
groups can be transformed to the corresponding
spiroheterocycles under the reaction conditions. The
method worked equally well for the substrates
bearing various substituent on both ring A and ring B
concurrently. Specifically, when ring A bears the
electron-donating benzyloxy (substrates 1f-h and 1o),
methyl (substrates 1m (R1 = Me, R2 = H), 1n and 1r),
or the electron-withdrawing bromo group (substrates
1i (R1 = Br, R2 = H), 1k-l and 1p-q), the
corresponding spirocyclic products could be obtained
in nearly quantitative yields. For the substrates
i
and 1u (PG= Pr) also furnished the same product
2a, but in a much lower yield in each case. It is
worthy to note that when 1 gram of substrate 1a
was subjected to the reaction conditions, product
2a could be isolated in 95% yield, indicating that
the method is applicable for the gram-scale
synthesis.
Results of our control experiments suggested
that the reaction happens between an enol with
the hypervalent iodine center. According to the
previous reported work,[17] there are two plausible
attack modes on the iodine center. First, the
enolic carbon attack the iodine center gave the C-
I type intermediate followed by 5-exo-tet type
cyclization. Second, the enolic oxygen attack
gave the C-I or O-I type intermediate followed by
5-endo-trig type cyclization. On the basis of the
previous computational studies reported by
Legault[17e] and the low-temperature NMR study
on the O-I type intermediate reported by
Szpilman,[17d] we propose that the reaction might
undergo the O-I intermediate.
Table 2. PIDA-Mediated Synthesis of Spiro-2,2’-
benzo[b]furan-3,3’-ones.a, b
Based on the results from the control experiments
as well as the previous literatures,[15a,17] we proposed
a plausible mechanism for this spirocyclization
reaction. First, the enolic oxygen in 1a
nucleophilically attack the iodine center of PIDA to
give intermediate A,[18] with the release of one
molecule of AcOH. Next, an intramolecular
cyclization occurred in A which realized the
oxidative formation of the first C-O bond, with the
loss of one PhI and acetate anion. It is worth noting
that all of our attempts to isolate and characterize
intermediate B[19] were unsuccessful, as the use of
less PIDA only led to the final products and some of
the unconsumed starting materials in all cases. Next,
the enol form of B was tautomerized into C, which
reacted with PIDA to give intermediate D.[18] Then D
underwent cyclization to realize the oxidative
formation of the second C-O bond, which gave the
oxonium ion intermediate E. Ultimately, the
nucleophilic attack of acetate anion on the benzylic
carbon led to the removal of the benzyl group,
affording the title product 2a (Scheme 3). The
formation of the byproduct, namely, benzyl acetate
could be detected in all cases.
aAll reactions were carried out with substrate 1 (0.5
mmol) and PIDA (1.5 mmol) in DCE at rt for 1 h.
c
d
bIsolated yield. Carried out at 1-gram scale. The
structure of 2l was confirmed by X-crystal analysis.
3
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10.1002/adsc.201900652
Advanced Synthesis & Catalysis
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We acknowledge the National Natural Science Foundation of
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similar spirofurooxindole
B
via PIDA-mediated
oxidative cyclization of 3-(2-hydroxyphenyl)-3-oxo-N-
phenyl propanamides, see ref 15.
[20] For crystallographic data of compound 12, see
Supporting Information. CCDC-1907783 contains the
supplementary crystallographic data for compound 12.
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[21] Our preliminary investigation on the enantioselective
version of the reaction by using a chiral hyervalent
iodine reagent proved to be unsuccessful. For details,
see SI.
[15] a) J. Wang, Y. Yuan, R. Xiong, D. Zhang-Negrerie, Y.
Du, K. Zhao. Org. Lett. 2012, 14, 2210. b) X. Zhang,
W. Hou, D. Zhang-Negrerie, K. Zhao, Y. Du. Org. Lett.
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[22] For crystallographic data of compound 2l, see
Supporting Information. CCDC-1895335 contains the
supplementary crystallographic data for compound 2l.
5
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10.1002/adsc.201900652
Advanced Synthesis & Catalysis
COMMUNICATION
Metal-free Synthesis of Spiro-2,2’-benzo[b]furan-
3,3’-ones via PhI(OAc)2-Mediated Cascade
Spirocyclization
Adv. Synth. Catal. Year, Volume, Page – Page
Qingyu Xing,a,d Huiyuan Liang,a,d Mingmai Bao,a
Xuemin Li,a Jingran Zhang,a Tianhao Bi,a Yilin Zhang,c
Jun Xu,a Yunfei Du,*,a, b and Kang Zhao*,a
6
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