Facile synthesis of 2-iodo-spiro[indene-1,1′-isobenzofuran]-3′- ones via iodine-promoted cascade cyclization

Article abstract of DOI:10.1039/c2cc36127b

A novel and efficient synthetic approach to substituted 2-iodo-spiro[indene-1,1′-isobenzofuran]-3′-ones has been developed via an iodine-promoted cascade cyclization of 2-(3-hydroxy-3,3-diarylprop-1-yn- 1-yl)benzoates. This sequential cascade process is concisely conducted at room temperature. Subsequent palladium-catalyzed Sonogashira, Suzuki, and Heck reactions of the resulting iodides proceed smoothly in good yields.

Full text of DOI:10.1039/c2cc36127b

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COMMUNICATION
Facile synthesis of 2-iodo-spiro[indene-1,10-isobenzofuran]-30-ones via
iodine-promoted cascade cyclizationw
Hai-Tao Zhu, Xue Dong, Li-Jing Wang, Mei-Jin Zhong, Xue-Yuan Liu and
Yong-Min Liang*
Received 12th June 2012, Accepted 13th September 2012
DOI: 10.1039/c2cc36127b
A novel and efficient synthetic approach to substituted 2-iodo-
spiro[indene-1,10-isobenzofuran]-30-ones has been developed via
an iodine-promoted cascade cyclization of 2-(3-hydroxy-3,3-
diarylprop-1-yn-1-yl)benzoates. This sequential cascade process is
concisely conducted at room temperature. Subsequent palladium-
catalyzed Sonogashira, Suzuki, and Heck reactions of the resulting
iodides proceed smoothly in good yields.
The electrophilic cyclization of alkenes, alkynes and allenes was
Scheme 1 Iodine-promoted cascade carbocyclization.
studied in detail by Larock, Barluenga, Ma and others.1–18 It has
been proved to be a useful method for the construction of
carbocyclic and heterocyclic compounds. Due to the excellent
alkynophilicity and alkenophilicity of iodine, much attention has
been paid to iodine-based unsaturated hydrocarbon activation as
an attractive protocol for developing new and efficient iodocycliza-
tions.11–13 Many important carbocycles and heterocycles,
such as furans,1 benzofurans,2 furanones,3 pyrroles,4 indoles,5 iso-
quinolines,6 quinolines,7 benzothiophenes,8 phosphaisocoumarins,9
naphthols,10 naphthalenes,11 indenes,12 benzenes,13 cyclopentenes,14
chromans,15 isochromenes,16 chromenes,17 and thiochromenes,18
have been produced by this protocol. However, there is no
successful example of the preparation of spirocyclic compounds by
the iodine-mediated cascade cyclization. Spirocycles as key struc-
tural subunits are prevalent in numerous natural products and play
an important role in pharmaceutical chemistry.19 Therefore, the
development of efficient methods for the construction of spirocyclic
ring systems in a one-pot manner based on iodocyclization
reactions is necessary.
polycyclic compounds might be achieved, in which the allene
cation intermediate could be captured by the oxygen of the
carbonyl group instead of the iodine anion and then cyclized
to give another ring (Scheme 1b). Herein, we report an efficient
and concise method for the highly regioselective synthesis of
substituted 2-iodo-spiro[indene-1,10-isobenzofuran]-30-ones via
a cascade iodocyclization of benzyl-2-(3-hydroxy-3,3-diaryl-
prop-1-yn-1-yl)benzoates under mild conditions.
After optimizing the reaction conditions, we employed 1.0
equivalent of benzyl-2-(3-hydroxy-3,3-diphenylprop-1-yn-1-yl)-
benzoate 1a and 2.0 equivalents of I2, in anhydrous ClCH2CH2Cl,
at room temperature (see Table S1, ESIw).
With the optimized conditions in hand, various 2-(3-hydroxy-
3,3-diphenylprop-1-yn-1-yl)benzoate derivatives were subjected to
the standard reaction conditions, as depicted in Table 1. We first
investigated the reactions of substrates 1b–d with methyl, ethyl and
isopropyl substituents under the optimized conditions; however,
the desired product 2a was not obtained. Increasing the tempera-
ture to 80 1C, we were pleased to find that these substrates
produced the desired product 2a smoothly in moderate to good
yields (Table 1, entries 2–4). The structure of the representative
product 2a was determined by X-ray crystallographic analysis.21
The reaction of substrate 1e with a t-butyl substituent afforded the
mixture at room temperature (entry 5). However, when the
temperature was decreased to 0 1C, an 80% yield of 2a was
obtained. Subsequently, we examined the electronic effects of the
substituents on R2 and R3 of the aromatic ring. It was found that
an electron-withdrawing (F) substituent on the aryl group afforded
the corresponding product 2i in 81% yield (entry 9). However, an
electron-donating (OMe) substituent on the aryl group only
resulted in a moderate yield (59%) of the product 2g (entry 7).
This might be due to the decreased electrophilicity of the allenolic
cation intermediate in the latter case. The reaction could tolerate
Recently, our group have successfully reported a novel and
concise iodocyclization of allenes generated in situ from simple
propargylic alcohols (Scheme 1a).20 In the presence of iodine,
substrate A lost a hydroxyl group and then rearranged to the
intermediate allene cation B. Subsequently, B reacted with an
iodide anion to give C. Finally, C was activated by an iodine
cation and then cyclized to give the carbocycles D.
Encouraged by this achievement, we envisioned that a
sequential cascade iodocyclization of propargylic alcohols to
State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, Lanzhou 730000, China. E-mail: liangym@lzu.edu.cn;
Fax: +86-931-8912582; Tel: +86-931-8912582
w Electronic supplementary information (ESI) available. CCDC
861376 (2a) and 893622 (3zb). For ESI and crystallographic data in
CIF or electronic format see DOI: 10.1039/c2cc36127b
c
10748 Chem. Commun., 2012, 48, 10748–10750
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Table 1 Synthesis of 2-iodo-spiro[indene-1,10-isobenzofuran]-30-ones
Table 2 Cascade electrophilic cyclization of benzyl-2-(3-hydroxy-3-
arylbut-1-yn-1-yl)benzoates 1a
a
2 and 20
Product/yieldb (%)
Entry
Substrate
R
Yieldb
Product (%)
Entry Substrate (R1, R2, R3, R4)
1
2
3
4
5
6
1v
H
2v/59
—
—
3v/9
1w
1x
1y
1z
4-OMe
3-OMe
2-OMe
2-Cl
1
2
3
4
5
6
7
8
R1 = Bn, R2 = R3 = H, R4 = H 1a
R1 = Me, R2 = R3 = H, R4 = H 1b
R1 = Et, R2 = R3 = H, R4 = H 1c
R1 = i-Pr, R2 = R3 = H, R4 = H 1d
R1 = t-Bu, R2 = R3 = H, R4 = H 1e
R1 = Bn, R2 = R3 = Me, R4 = H 1f
R1 = Bn, R2 = R3 = MeO, R4 = H 1g
R1 = Bn, R2 = R3 = Cl, R4 = H 1h
R1 = Bn, R2 = R3 = F, R4 = H 1i
R1 = Bn, R2 = R3 = H, R4 = 5-Me 1j
2a
2a
2a
2a
2a
2f
2g
2h
2i
88
70c
68c
80c
80d
49
59
72
81
84
84
72
84
79
80
73
81
—
2z/54
—
3y/20
3z/6
3za/86
1za
4-Cl
7
8
a
3zb/42
3zc/65
9
10
11
12
13
14
15
16
17
2j
R1 = Bn, R2 = R3 = H, R4 = 5-MeO 1k 2k
R1 = Bn, R2 = R3 = H, R4 = 5-Cl 1l
R1 = Bn, R2 = R3 = H, R4 = 5-F 1m
2l
2m
All reactions were run under the following conditions, unless otherwise
indicated: 0.2 mmol of 1 with 2.0 equivalents of I2 in 4 mL anhydrous
b
ClCH2CH2Cl at room temperature. Isolated yield.
R1 = Bn, R2 = R3 = H, R4 = 5-NO2 1n 2n
R1 = Bn, R2 = R3 = H, R4 = 4-Cl 1o
R1 = Bn, R2 = R3 = H, R4 = 6-Cl 1p
R1 = Bn, R2 = R3 = H, R4 = 4-F 1q
R1 = Bn, R2 = R3 = H,
R4 = 4,5-Dimethoxyl 1r
2o
2p
2q
yield (Table 2, entry 1). Similarly, the iodocyclization of o-chloro-
substituted reactant 1z could afford the corresponding spirocycle 2z
in 54% yield and 3z in 6% yield (entry 5). Unfortunately, attempts
to use substrates 1w–y and 1za proved to be unsuccessful for
the construction of spirocycles, possibly because of unfavorable
electronic factors (entries 2–4 and 6). Two similar substrates, 1zb
with a methyl substituent and 1zc with a benzyl substituent
afforded two different products 3zb and 3zc under the same
conditions (entries 7 and 8). The X-ray crystal structure of 3zb21
confirmed that the cyclization was 6-endo-trig type, so we inferred
that the cyclization of 1zc was 5-exo-trig type. The structures of 3v,
3y, 3z and 3za were assigned in analogy to 3zc.
18
19
2r
99
R1 = Bn, R2 = H,
2s/20s =
R3 = MeO, R4 = H 1s
2.7/1.0 86e
2t/20t =
R1 = Bn, R2 = H,
20
21
R3 = Me, R4 = H 1t
3.5/1.0 85e
R1 = Bn, R2 = Cl, R3 = MeO, R4 = H 1u 2u
80
a
All reactions were run under the following conditions, unless otherwise
indicated: 0.2 mmol of 1 with 2.0 equivalents of I2 in 4 mL anhydrous
b
c
ClCH2CH2Cl at room temperature. Isolated yield. The reaction tem-
perature was 80 1C. d The reaction temperature was 0 1C. e An inseparable
mixture was obtained. This ratio is based on H1 NMR spectra.
As shown in Scheme 2, the iodospirocyclic compound 2a
produced by iodocyclization can be further elaborated by
using various palladium-catalyzed processes. For example,
the Sonagashira coupling,22 Heck coupling23 and Suzuki
coupling24 of 2-iodo-3-phenyl-30H-spiro[indene-1,10-isobenzo-
furan]-30-one 2a afforded the corresponding products 4a, 5a
and 6a in 74%, 96% and 99% yields, respectively.
various substituents at R4. The reactions of substrates 1j–q
bearing an electron-donating or an electron-withdrawing
substituent on the C-4,5,6 position of benzoate produced the
corresponding products 2j–q in good yields (entries 10–17).
Remarkably, when substrate 1r having dimethoxyl substituents on
the C-4,5 position of benzoate was used, the desired product 2r
was formed in excellent yield (entry 18). This might be because two
electron-donating (OMe) substituents increased the nucleophilicity
of the oxygen of the carbonyl group and enhanced the formation
of the allene intermediate. We also investigated the reaction of
substrates 1s–u with different substituents on the aryl group
(R2 a R3). The results indicated that this reaction showed certain
selectivity. Interestingly, compound 1u, bearing a chloro on R2
and a methoxyl on R3, afforded the exclusive product 2u (entry 21).
The structure of 2u was determined by analyzing the 1D NMR
and 2D NMR spectra (see the ESIw). Compound 1s, bearing a
methoxyl on R3, gave the inseparable mixture (2s and 20s) in
approximately a 2.7 : 1.0 ratio (entry 19). Compound 1t, bearing a
methyl on R3, gave a similar result (entry 20).
On the basis of the above observations, the working iodo-
cyclization mechanisms for the formation of the spirocycle 2
and the byproduct 3 are proposed as shown in Scheme 3.
Furthermore, to expand the scope of this reaction, we also
investigated the reaction of benzyl-2-(3-hydroxy-3-arylbut-1-yn-
1-yl)benzoates, 1v–za. It was found that, under the optimized
conditions, substrate 1v was also transformed into the desired
product 2v in 59% yield, but a byproduct 3v was produced in 9%
Scheme 2 Palladium-catalyzed coupling reactions.
Chem. Commun., 2012, 48, 10748–10750 10749
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Scheme 3 Proposed mechanism for the formation of 2 and 3.
Substrates 1 are transformed into 2 through the path a. Firstly, in
the presence of Lewis acidic iodine, propargylic alcohol 1 (R = Me
or Ph) is converted to the intermediate E through the elimination of
the hydroxyl group in an unstable hypoiodous acid (HOI) form.11b
The formed E could be resonated with allene carbocation F.
Nucleophilic attack by the oxygen of the carbonyl group on F is
followed by SN2 attack of the halide anion on the benzyl group to
give the benzyl halide and the allene G. Finally, electrophilic
addition of an adjacent phenyl group on iodonium led to the
formation of the spirocycle 2. According to the substrate survey
and literature processes, the formation of the byproduct 3 is by the
path b. Coordinated with the iodine cation, propargylic alcohol 1
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Electrophilic addition to enyne H led to the formation of
iodonium intermediate I. The 5-exo-trig cyclization by the
oxygen of the carbonyl group on the iodonium I is followed by
SN2 attack of the halide anion on the benzyl group to give the
benzyl halide and the byproduct 3.
In conclusion, we have developed an efficient approach for the
synthesis of substituted 2-iodo-3-phenyl-30H-spiro[indene-1,10-iso-
benzofuran]-30-ones in moderate to good yields from benzyl-2-
(3-hydroxy-3,3-diphenylprop-1-yn-1-yl)benzoate derivatives under
mild reaction conditions. The halogenated moiety can be readily
introduced into the spirocycle at a position not easily obtained
previously.
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We thank the National Science Foundation (NSF-21072080)
and the National Basic Research Program of China (973 Program)
2010CB833203 for financial support. We also acknowledge the
support by the ‘‘111’’ Project.
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10750 Chem. Commun., 2012, 48, 10748–10750
This journal is The Royal Society of Chemistry 2012