Generation of 4-iodoisocoumarins through a TBAI-mediated oxidative cyclization of 2-alkynoates

Article abstract of DOI:10.1080/00397911.2018.1465094

A tetra-butylammonium iodide (TBAI)-mediated oxidative iodocyclization of 2-alkynoates for the synthesis of various 4-iodoisocoumarin is described herein, and the reaction is highly efficient and shows broad functional group tolerance. This newly develope

Full text of DOI:10.1080/00397911.2018.1465094

Synthetic Communications
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Generation of 4-iodoisocoumarins through a TBAI-
mediated oxidative cyclization of 2-alkynoates
Jin Luo, M. He, P. Chen & J. Li
To cite this article: Jin Luo, M. He, P. Chen & J. Li (2018): Generation of 4-iodoisocoumarins
through a TBAI-mediated oxidative cyclization of 2-alkynoates, Synthetic Communications, DOI:
10.1080/00397911.2018.1465094
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https://doi.org/10.1080/00397911.2018.1465094
Generation of 4-iodoisocoumarins through a TBAI-mediated
oxidative cyclization of 2-alkynoates
Jin Luoa, M. Heb, P. Chena and J. Lia
b
aAnalytical and Testing Center, Jiangxi Normal University, Nanchang, Jiangxi, China; College of
Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi, China
ABSTRACT
ARTICLE HISTORY
Received 16 November 2017
A tetra-butylammonium iodide (TBAI)-mediated oxidative iodocycliza-
tion of 2-alkynoates for the synthesis of various 4-iodoisocoumarin is
described herein, and the reaction is highly efficient and shows
broad functional group tolerance. This newly developed reaction
uses a mixture of water and DCE as co-solvent, and avoids the use of
iodine as iodine source for the electrophilic halocyclization.
KEYWORDS
2-Alkynoate;
4-iodoisocoumarin;
electrophilic
iodocyclization; Oxone
GRAPHICAL ABSTRACT
Introduction
Isocoumarin is one of the most important privileged structural cores due to its ubiquity in
natural products.[1] Many synthetic compounds with the isocoumarin skeleton exhibited
important biological activities.[2] Accordingly, tremendous efforts have been directed
toward its direct preparation to ultimately construct a library of structurally complex and
functionally diverse compounds for bioactivity assays by high-throughput screening. To the
best of our knowledge, 2-alkynoates are a versatile synthon for preparing the isocoumarin
core.[3] Various transition metals and Lewis acids have been used to promote the 6-endo
cyclization of 2-alkynoates for the synthesis of isocoumarin derivatives.[4] Subsequently, the
halo substituent (such as bromo or iodo) was installed at the C4-position of the isocou-
marin core by an electrophilic 6-endo cyclization. It was important that this reactive
substituent was introduced since the halo group can be converted into other building
blocks through classical coupling reaction combined and other transformations.
An initial precedent involving the electrophilic cyclization of 2-alkynoates was reported
by Oliver and Grandour.[5] According to their findings, bromine could trigger the
CONTACT Jin Luo
jinluo@jxnu.edu.cn
Analytical and Testing Center, Jiangxi Normal University, Nanchang,
Jiangxi, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis

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J. LUO ET AL.
Scheme 1. Proposed route for the synthesis of 4-iodoisocoumarin via iodide-mediated cyclization of
2-alkynoates.
electrophilic cyclization of 2-alkynoate to generate 4-bromoisocoumarins. However, the
versatility of this method and the generality of this electrophilic bromocyclization were
poor. Larock et al.[6] as well as other research groups were inspired by the reaction effi-
ciency of electrophilic halocyclization of 2-alkynoates. To date, various electrophiles
including Br2, I2, NIS and ICl, etc. have been developed. As presented in Scheme 1a, the
I2-mediated cyclization proceeded smoothly, and the corresponding 4-iodoisocoumarins
were generated in good yields. Generally, the I2-promoted electrophilic iodocyclization of
2-alkynoate required the use of an organic solvent. Moreover, after completion of the
reaction, Na2S2O3 was needed to remove the excess I2, which makes the workup proced-
ure relatively inconvenient. Inspired by the precedent mentioned above, we were inspired
to explore a simple alternative for the synthesis of 4-iodoisocoumarin. The protocol devel-
oped herein employed a solvent and iodine source that are more eco-friendly. In addition,
the reactions delivered the final products with a simple workup procedure. Thus, we have
developed an iodide-mediated oxidative cyclization of 2-alkynoates for the synthesis of
4-iodoisocoumarin derivatives.
Results and discussion
As illustrated in Scheme 1b, an iodide salt was oxidized in situ to the corresponding
hypervalent iodine by an inorganic salt,[7] which could go on to promote the electrophilic
iodocyclization. Notably, the iodide-mediated oxidative cyclization avoids the use of
elemental iodine. In addition, thanks to its high solubility in water, iodide and the oxi-
dant inorganic salt can be directly by extraction, which simplifies the workup procedure.
Encouraged by the above results, we started to explore this proposed transformations.
Initially, the reaction of 2-alkynoate 1a was selected as a model reaction. Considering
that an ammonium salt could improve the solubility of 1a in water, tetra-butylammonium
iodide (TBAI) was employed as the iodine source. The factors influencing the reaction

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Table 1. Initial studies for the synthesis of 4-iodoisocoumarin via iodide salt-mediated cyclization of 2-alkynoate 1aa.
Entry
Oxidant
Solvent
Temp. (ꢁC)
Yield (%)b
1
/
H2O
H2O
H2O
H2O
H2O
H2O
H2O
80
80
80
80
80
100
60
80
80
80
80
80
N.R.
12
35
67
63
65
59
79
66
83
88
83
2
Cu(OAc)2
CAN
3c
4
Oxone
K2S2O8
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
Oxone
5
6
7
8
H2O:DCE (v/v, 1:1)
H2O:THF (v/v, 1:1)
H2O:DCE (v/v, 2:1)
H2O:DCE (v/v, 4:1)
H2O:DCE (v/v, 10:1)
9
10
11
12
aReaction conditions: 1a (0.2 mmol), 2a (1.5 equiv), oxidant (2.0 equiv), 8 h.
bIsolated yield based on 2-alkynoate 1a.
cCAN ¼ Ce(NH4)2(NO3)6; THF ¼ tetrahydrofuran; DCE ¼ 1,2-dichloroethane; N.R. ¼ no reaction.
outcome, including the oxidant, solvent and temperature, were evaluated. The results
from the oxidant screening suggested that an oxidant was required and Oxone (the triple
salt: KHSO5ꢀKHSO4ꢀK2SO4) was the best choice as it provided 4-iodoisocoumarin in 67%
yield (entries 1–5, Table 1). Other inorganic salt oxidants such as Cu(OAc)2, CAN and
K2S2O8 gave inferior results. Interestingly, the combination of an ammonium halide salt
with an oxidant has been employed in halohydrations of alkynes, dihalohydrations of
alkynes and diketonizations of alkynes. These findings indicated that water was pivotal for
the reaction and likely influenced the reaction pathway.[8]
The reaction temperature was screened as well. The results showed that increasing the
reaction temperature to 100 ꢁC impacted the reaction only slightly, and a similar yield of
the final product was observed (entry 6, Table 1). Decreasing the temperature negatively
impacted the reaction outcome (entry 7, Table 1). In the above experiments, we found
that the starting material (2-alkynoate 1a) was not completely consumed likely due to
the poor solubility of 1a in water. Consequently, we turned our attention to the use of
an organic solvent as a co-solvent with water. To our delight, the use of a co-solvent
(H2O:DCE, v/v ¼ 1:1) greatly improved the reaction efficiency, leading to the formation
of 4-iodoisocoumarin 3a in 79% isolated yield (entry 8, Table 1). Encouraged by this
result, other co-solvents and various ratios of water and DCE were examined accord-
ingly. Fortunately, the use of a mixture of co-solvent H2O:DCE (v/v ¼ 4:1) was the best
choice, producing the final molecule 4-iodoisocoumarin 3a in 88% yield (entry 11,
Table 1). The improvement of the reaction efficiency was attributed to the improved
solubility of 1a in the solvent system. Decreasing the percentage of DCE in the solvent
system did not offer a better yield (entry 12, Table 1).
With the optimal reaction conditions in hand, we then examined the substrate scope of
this transformation. The results are illustrated in Table 2. A series of 4-iodoisocoumarin

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J. LUO ET AL.
Table 2. The synthesis of 4-iodoisocoumarin via TBAI-mediated cyclization of 2-alkynoates 1a.
aIsolated yield based on 2-alkynoates 1.
derivatives 3 were constructed as expected. For example, the substrates with methyl and
bromo substituents were compatible with the reaction conditions, producing the corre-
sponding 4-iodoisocoumarin derivatives 3b in 85% yield and 3c in 76% yield, respectively.
The pyridine-substituted alkynoate was also tolerated, and the corresponding product 3d
was obtained in 64% yield. In addition, the variation of substituent at the R2 position was
also explored. The reactions of diverse aryl-, 1-naphthyl-, and alkyl-substituted alkynoates
proceeded smoothly and afforded corresponding 4-iodoisocoumarins 3e–3j in 65–84%
yields. For instance, the substrates with 1-naphthyl moieties at the R2-position was well-
tolerated, generating corresponding product 3e in 75% yield. Meanwhile, the reaction of
the 2-thiothenyl-substituted substrate gave 4-iodo-3-(2-thiothenyl) isocoumarin 3h in 68%

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Table 3. Coupling reactions of 4-iodoisocoumarinsa.
aIsolated yield based on isocoumarin 3a.
yield. From the screening results of various substrates with aryl substituents at R2, it
seemed that electron-rich aryl substituents was favorable for the reaction. The reaction of
the substrate with a 4-methylaryl substituent at R2 produced 4-iodoisocoumarin 3f in
84% yield, while the reaction of the substrate with a 4-chloroaryl substituent at R2 pro-
vided corresponding 4-iodoisocoumarin 3g in just 71% yield. The substrates with the sub-
stituent cyclopropyl or n-butyl substituents at R2 were compatible with the reaction
conditions, and corresponding 4-iodoisocoumarin derivatives 3i and 3j were generated in
good yields. Additionally, tetra-butylammonium bromide (TBAB) and tetra-butylammo-
nium chloride (TBAC) were good halo sources, providing 4-bromoisocoumarin 3k in
81% yield and 4-chloroisocoumrain 3l in 72% yield, respectively, under the standard con-
ditions, respectively. To our surprise, the reaction of methyl 2-alkynoate 1m under the
standard conditions did not gave rise to the corresponding isocoumarin derivative. A dis-
tinctive compound benzil-o-carboxylate 3m was observed in 72% yield. This unexpected
product inspired us to delve deeper into the relevant literature. To our delight, Qiu
et al.[8] observed the similar results, which they attributed to a change in the reaction
pathway due to the use of water as a co-solvent.
Finally, derivatization of 4-iodoisocoumarin was explored in this study. The results are
shown in Table 3. Delightfully, both the Suzuki coupling and Sonogashira coupling reac-
tions of 4-iodoisocoumarin 3a provided the corresponding products 4 and 5 in good yields.
Conclusions
In conclusion, we have developed an alternative route for the generation of 4-iodoiso-
coumarins from 2-alkynaotes. The reaction proceeded smoothly in the presence of TBAI
and Oxone, and an array of 4-iodoisocoumarins were generated with high reaction effi-
ciency and excellent functional group tolerance. The reaction developed herein used a
co-solvent system of water and DCE, and avoided the use of elemental iodine as iodine
source for the electrophilic halocyclization.

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J. LUO ET AL.
Experimental
Unless otherwise stated, all commercial reagents and solvents were used without add-
itional purification. All solvents were dried and distilled according to standard proce-
dures. Flash column chromatography was performed using silica gel (60 Å pore size,
32–63 lm, standard grade). Analytical thin–layer chromatography was performed using
glass plates pre-coated with 0.25 mm 230–400 mesh silica gel impregnated with a fluor-
escent indicator (254 nm). Thin-layer chromatography plates were visualized by exposure
to ultraviolet light. Organic solutions were concentrated on rotary evaporators at
ꢂ20 Torr (house vacuum) at 25–35 ꢁC. Commercial reagents and solvents were used as
received. Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker 400
spectrometer with CDCl3 as the solvent at 400 (1H) and 101 MHz (13C). LC-MS spectra
were acquired on a 1100LC/MSD Trap spectrometer. Elementary analyses were con-
ducted on a Vario EL III elemental analysis instrument. The supplemental materials
contains sample 1H and 13C NMR for products 3–5, together with full characteriza-
tion data.
General procedure
2-Alkynoate 1, TBAI (1.5 equiv), and Oxone (2.0 equiv) were added to a test tube, and
the co-solvent system DCE:H2O (3 mL, v/v ¼ 1:4) was then added. The mixture
was stirred at 80 ꢁC. After completion of the reaction, the mixture was cooled to
room temperature, and ethyl acetate (3.5 mL) was added. Extraction, drying of the
organic layer, concentration and flash column chromatography provided the desired
4-iodoisocoumarin 3.
Funding
We thank the Natural Science Foundation of Jiangxi Province in China [No. 20161BAB213072]
and the Scientific Research Fund of Jiangxi Provincial Education Department in China [No.
GJJ150326] for their financial support.
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