Facile synthesis of halogenated spiroketals via a tandem iodocyclization

Article abstract of DOI:10.1021/ol500741a

A strategy for the synthesis of spiroketal compounds through a tandem iodocyclization of 1-(2-ethynylphenyl)-4-hydroxybut-2-yn-1-one derivatives is presented. This reaction could proceed under very mild conditions in a short time and avoid the use of expensive and toxic metal catalysts. Moreover, the resulting halides can be further exploited by subsequent palladium-catalyzed coupling reactions, which act as the important intermediates for building other valuable compounds.

Full text of DOI:10.1021/ol500741a

Letter
pubs.acs.org/OrgLett
Facile Synthesis of Halogenated Spiroketals via a Tandem
Iodocyclization
Jia Wang,† Hai-Tao Zhu,† Ying-Xiu Li,† Li-Jing Wang,† Yi-Feng Qiu,† Zi-Hang Qiu,† Mei-jin Zhong,†
Xue-Yuan Liu,† and Yong-Min Liang*,†,‡
†State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P.R. China
‡State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Science, Lanzhou, 730000,
P.R. China
S
* Supporting Information
ABSTRACT: A strategy for the synthesis of spiroketal compounds
through a tandem iodocyclization of 1-(2-ethynylphenyl)-4-hydroxybut-
2-yn-1-one derivatives is presented. This reaction could proceed under
very mild conditions in a short time and avoid the use of expensive and
toxic metal catalysts. Moreover, the resulting halides can be further
exploited by subsequent palladium-catalyzed coupling reactions, which
act as the important intermediates for building other valuable
compounds.
Scheme 1. Electrophilic Ketalization
xcellent alkynophilicity of iodine cations as reactive
Eintermediates has been proven to be one of the most
interesting subjects in organic chemistry1 and has been widely
used for the preparation of iodocyclization.2 Indeed, a series of
intramolecular iodine-induced cyclization reactions of carbon-
centered or heteroatom nucleophiles with alkynes have been
reported to construct carbocycles3 and heterocycles.4 Never-
theless, only a few examples of sequential tandem iodospir-
oketalization of alkynes have been reported until now.5
Furthermore, spiroketals are ubiquitous structural units in
numerous biologically significant natural products,6 which
essentially contribute to bioactivity and represent a privileged
scaffold in drug discovery.7 As a result of their remarkable and
diverse biological activities,8 spiroketals have been the focus of
considerable attention for synthetic organic chemists as well as
pharmaceutical chemists.9 Thus, much attention has been given
to the development of new methods for the synthesis of
spiroketals. However, many traditional approaches to spiroke-
tals are still limited to metal-mediated10 or acid-catalyzed11
strategies. Therefore, seeking alternative methods for the
construction of spiroketals is indeed desirable.
In 2003, the Barluenga group described an interesting
transformation of o-alkynyl aldehydes with intermolecular
nucleophiles to iodoisochromenes utilizing bis(pyridine)
iodonium tetrafluoroborate (IPy2BF4)12 (Scheme 1a). After-
ward, Larock and co-workers reported another analogous
electrophilic cyclization promoted by molecular iodine.13 These
reactions are generally believed to proceed through a stepwise
mechanism. In the presence of I2, the oxygen of the carbonyl
group attacks the alkyne group activated by the iodine cation to
form the intermediate C, which is immediately trapped by the
nucleophile to give the product D. Encouraged by these
achievements and in the context of our ongoing interest to the
electrophilic cyclization of alkynols,14 we envisioned that the
substrates 1 containing propargylic alcohol could undergo the
cyclization of the carbonyl group to form the intermediate E
with an alkynol moiety, which could tandemly cyclize to give
the halogenated spiroketals 2 (Scheme 1b). Herein, we report a
concise and effective method for the synthesis of a variety of
spiroketals via sequential tandem iodocyclization.
At the onset of our investigation, we examined the reaction
of 4-hydroxy-1-(2-((4-methoxyphenyl)ethynyl)phenyl)-4-
methylpent-2-yn-1-one (1a) with 2 equiv of I2 in CH3CN at
room temperature. To our delight, the desired product 3,4,4′-
triiodo-3′-(4-methoxyphenyl)-5,5-dimethyl-5H-spiro[furan-
2,1′-isochromene] (2a) was isolated in 57% yield after 0.5 h
Received: March 10, 2014
Published: April 4, 2014
© 2014 American Chemical Society
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Letter
a
(Table 1, entry 1). An increase in the amount of I2 to 3 equiv
afforded 2a in 87% yield. However, further increasing the
Table 2. Synthesis of Triiodinated Spiroketals 2 and 2′
Table 1. Optimization of the Electrophilic Spiroketalization
of 4-Hydroxy-1-(2-((4-methoxyphenyl)ethynyl)phenyl)-4-
a
methylpent-2-yn-1-one
b
entry
solvent
I2 (equiv) base (1.0 equiv) time (h) yield (%)
1
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
THF
2.0
3.0
3.5
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
K2CO3
K2CO3
K2CO3
Na2CO3
K3PO4
KOH
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
57
87
83
85
84
65
83
84
52
46
86
2
3
4
5
6
7
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
8
9
CH3COCH3
CH3NO2
CH3CN
10
11
a
All reactions were run under the following conditions, unless
otherwise indicated: 0.20 mmol of 1a, 3.0 equiv of I2, and 1.0 equiv of
b
base in 4 mL of solvent were stirred at room temperature. Yield of
isolated product.
amount of I2 (3.5 equiv) gave a slightly lower yield of 2a (entry
3). After screening a series of bases, such as K2CO3, Na2CO3,
K3PO4, and KOH, we found that K2CO3 was the best
compared with the others (entries 2 and 4−6). In the
meantime, the study of solvent influence showed that none
of CH2Cl2, THF, CH3COCH3, and CH3NO2 could give a
superior yield (entries 7−10). In adition, prolonging the
reaction did not provide a better result (entry 11). With a series
of detailed investigations mentioned above, the combination of
1.0 equiv of 1a, 3.0 equiv of I2, and 1.0 equiv of K2CO3 in
CH3CN at room temperature are the optimum reaction
conditions.
After having established the optimized conditions for the
present reaction, various 1-(2-ethynylphenyl)-4-hydroxybut-2-
yn-1-one derivatives were subjected to the above conditions, as
summarized in Table 2. The reactions of substrates 1a and 1b
bearing electron-donating aromatic groups (R2) at the alkynyl
carbon resulted in the corresponding products 2a and 2b in
excellent yields, respectively. The structure of the representative
product 2a was determined by X-ray crystallographic analysis.
Unexpectedly, under the optimized conditions, the desired
products 2c and 2f appeared along with the byproducts 2′c and
2′f (entries 3 and 6). Meanwhile, the proportion of products 2c
and 2f decreased with the increase of electronegativity on the
substituent R3 group (entry 3 vs 6). Surprisingly, in the case of
4-NO2C6H4-substituted substrate 1g, the reaction gave a sole 5-
exo-dig cyclization product 2′g, rather than the six-membered
ring (entry 7). Fortunately, the presence of aliphatic group of
pentyl on R3 in substrate 1d was also tolerated, and the desired
product 2d was obtained in 75% yield (entry 4). However, the
substrate 1e only led to 2e in 36% yield. This might be due to
the weak nucleophilicity of the aliphatic acetylene. The
reactions also worked well with the substrates 1h−l with
a
All reactions were run under the following conditions, unless
otherwise indicated: 0.2 mmol of 1 with 3.0 equiv of I2 and 1.0 equiv
of K2CO3 in 4 mL of CH3CN at room temperature. Isolated yields.
b
electron-donating or electron-withdrawing substituents on R4,
furnishing the expected products 2h−l in good yields.
Remarkably, the electron-withdrawing substituents on the C-4
or C-5 position gave better yields than the electron-donating
ones (entries 8−12). This might be because the electron-
withdrawing substituents increased the activity of the alkyne
group. Subsequently, we examined the effect of substituents at
R1 and R2. In contrast, the substrates 1n, 1p, and 1q underwent
the cyclization to give the products in low yields, which might
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be due to the steric hindrance (entries 14, 16, and 17). It is
noteworthy that when the R1 or R2 changed to the cyclic
substituent, the corresponding products 2r−t were obtained in
good yields (entries 18−20). In addition, substrate 1v with a
butynol group gave the six-membered heterocyclic ring product
2v in 65% yield (entry 22).
To explore the scope of the iodine-containing electrophiles
as well as the mechanism of this electrophilic spiroketalization,
the reactions of 1-(2-ethynylphenyl)-4-hydroxybut-2-yn-1-one
derivatives with ICl and IBr were studied under the standard
reaction conditions, as depicted in Table 3. The product 2aa
reactive species A to give the intermediate B, which could
resonate with allene carbocation C. At the same time, the
halogen anion captured the allene carbocation to give the
halogenated intermediate D. Meanwhile, the intermediate D
coordinated with the excess iodide cation to gain the complex
E, which was attacked by the hydroxyl group and then released
the hydrogen cation in the presence of base to attain the
desired product 2.
As shown in Scheme 3, spiroketal compounds 2a and 2aa
can be further elaborated by using the Suzuki palladium-
Scheme 3. Palladium-Catalyzed Coupling Reactions
Table 3. Synthesis of Diiodinated Spiroketals with ICl and
IBr
a
b
entry
1
IX
product
yield (%)
1
2
3
4
5
6
7
8
9
10
1a
1b
1h
1j
ICl
ICl
ICl
ICl
ICl
ICl
ICl
IBr
IBr
IBr
2aa
2ba
2ha
2ja
63
83
70
60
92
80
73
76
60
43
1m
1o
1r
2ma
2oa
2ra
1b
1j
2bb
2jb
1o
2ob
catalyzed processes.15 The Suzuki coupling of 2a and 2aa
afforded the corresponding products 3a and 3aa in 90% and
75% yields, respectively.
a
All reactions were run under the following conditions, unless
otherwise indicated: 0.2 mmol of 1 with 3.0 equiv of IX and 1.0 equiv
of K2CO3 in 4 mL of CH3CN at room temperature. Isolated yields.
b
In conclusion, a new and mild protocol for the synthesis of
halogenated spiroketals has been established. This method adds
interest to this clean process and also relates to the
incorporation of iodine. Foremost, the resulting halogenated
spiroketals are readily elaborated to more products by using
known organopalladium chemistry which may be essential
intermediates for the synthesis of natural products. Further
studies on the synthesis of spiroketal compounds are underway.
was achieved in 63% yield (Table 3, entry 1). The structure of
the representative product 2aa was determined by X-ray
crystallographic analysis. Similarly, other typical substrates also
gave the corresponding chlorine-containing products in good
yields (Table 3, entries 2−7). Meanwhile, in the presence of
IBr, the desired products 2bb, 2ob, and 2jb were gained in
moderate to good yields (Table 3, entries 8−10).
On the basis of the above observations, a possible mechanism
is outlined in Scheme 2. The alkyne moiety was first activated
by iodide cation, and the oxygen of carbonyl group attacked the
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and spectral data for all new
compounds are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
Scheme 2. Proposed Reaction Mechanism
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: liangym@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (NSF-21072080
and NSF-21302076) and the National Basic Research Program
of China (973 Program) 2010CB833203 for financial support.
We also acknowledge support from the “111” Project.
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Letter
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