Synthesis of 4-chloroisocoumarins via intramolecular halolactonization of o-alkynylbenzoates: PhICl2-mediated C-O/C-Cl bond formation

Article abstract of DOI:10.1021/acs.orglett.9b00047

A series of 4-chloroisocoumarins were conveniently synthesized from o-alkynylbenzoates via PhICl₂-mediated intramolecular cyclization under metal-free conditions. PhICl₂ plays the role of both the oxidant and the chlorine source to e

Full text of DOI:10.1021/acs.orglett.9b00047

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 4‑Chloroisocoumarins via Intramolecular
Halolactonization of o‑Alkynylbenzoates: PhICl2‑Mediated C−O/C−
Cl Bond Formation
Linlin Xing,† Yong Zhang,† Bing Li,† and Yunfei Du*,†,‡
†Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin 300072, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
S
* Supporting Information
ABSTRACT: A series of 4-chloroisocoumarins were conveniently
synthesized from o-alkynylbenzoates via PhICl2-mediated intramolecu-
lar cyclization under metal-free conditions. PhICl2 plays the role of both
the oxidant and the chlorine source to enable oxidative C−O bond
formation and introduction of the chlorine atom. The utility and
practicability of this protocol have been exemplified by virtue of mild
reaction conditions, high-yielding products, simplified purification, and
gram-scale synthesis.
presence of a halogen atom at position 4 allows for further
functionalization.31−45 The predominant synthetic method
used for the generation of 4-haloisocoumarins is the electro-
philic cyclization of o-alkynylbenzoates using various electro-
philes, including Br2,31,34 I2,32,35−37 ICl,35−37,42 NBS,43 and
NIS.45 However, these methods are applicable only to the
preparation of 4-iodo/bromoisocoumarins, and the synthesis
of 4-chloroisocoumarins relies predominantly on the applica-
tion of transition metal-mediated approaches.33,35,38−40,44 For
example, Lisowski described a Cy2NH·HCl-promoted cycliza-
tion of o-alkynylbenzoates with CuCl2 to give 4-chloroisocou-
marins (Scheme 1, method a).35 Similarly, Miyata reported the
halocyclization of o-alkynylbenzoates using CuCl2/NCS
(Scheme 1, method b).39 However, these methods suffer
from the inevitable use of a stoichiometric amount of the
transition metal. Most recently, Li developed an alternative
route to the construction of 4-chloroisocoumarins from phenyl
2-(2-phenylethynyl)benzoate using TBAC and oxone.41
However, only one example was given, and the versatility
and generality of this electrophilic chlorocyclization approach
were unexplored. Furthermore, when the most simple ester
substrate, methyl o-alkynylbenzoate, was subjected to the
standard conditions, a diketone, rather than the 4-chloroiso-
coumarin product, was obtained. In this work, we reported an
alternative approach for convenient and efficient construction
of the biologically interesting 4-chloroisocoumarin skeleton
using PhICl2 as both the oxidant and the chlorine source.
(Dichloroiodo)arenes, hypervalent iodine reagents widely
used in organic synthesis, are often used as a replacement for
gaseous chlorine, which is a toxic gas and is hard to handle in
socoumarins, one class of privileged heterocyclic scaffolds,
Iare featured as the core structures of many naturally
occurring compounds.1−6 A large number of natural products
containing the isocoumarin skeleton have been found to
display a broad spectrum of biological activities.7−16 For
example, compound I can be used as a potent irreversible
inhibitor of blood coagulation enzymes,12 3-(2-bromoethoxy)-
isocoumarin (II) has been investigated as an inhibitor of
human leukocyte elastase,13 cercophorin A (III) was studied as
an antifungal agent,14 LGK 2 (IV) has been used as a β-
amyloid peptide production inhibitor,15 and 7-hydroxy-3-(4-
hydroxyphenyl)isocoumarin (V) was investigated as a selective
estrogen receptor β ligand.16 Because of the pharmaceutical
importance of isocoumarin compounds, there has been
growing interest in the development of efficient strategies for
their synthesis (Figure 1).17−30
Among the synthetic approaches, the synthesis of 4-
haloisocoumarins has received considerable attention as these
molecules possess interesting biological activities and the
Figure 1. Representative naturally occurring and pharmaceutically
active isocoumarins.
Received: January 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00047
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Organic Letters
Letter
a
Scheme 1. Existing Strategies for the Synthesis of 4-
Chloroisocoumarins
Table 1. Optimization of Reaction Conditions
b
entry
oxidant
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
PhICl2
CH3CN
CH3CN
DCE
EtOAc
THF
rt
60
60
60
60
60
60
60
60
70
80
70
70
70
ND
92
88
ND
ND
ND
<5
ND
10
96
90
36
33
DMF
toluene
dioxane
CHCl3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
10
11
12
13
14
c
PIDA
most cases. Because of desirable properties such as their ease of
handling, ready availability, nontoxicity, and environmentally
benign properties, (dichloroiodo)arenes have found broad
synthetic application as reagents for both chlorination and
oxidation reactions.46−50 For example, (dichloroiodo)arenes
have been applied to the typical chlorination of alkanes or
alkenes, substitutive chlorination at the sp3 carbon of various
organic substrates, including alkanes, ethers, esters, thioethers,
ketones, and sulfoxides, and chlorination of a variety of organic
compounds containing heteroatoms such as sulfur, phospho-
rus, selenium, arsenic, antimony, and some metals.47 However,
to the best of our knowledge, the application of
(dichloroiodo)benzene (PhICl2) to the synthesis of chloro-
substituted isocoumarins has not yet been explored. In this
regard, we were interested in determining whether o-
alkynylbenzoates could be converted to 4-chloroisocoumarins
via a PhICl2-mediated intramolecular cyclization/chlorination
process.
At the outset of the study, 2-alkynoate 1a was used as a
model substrate to test the feasibility of the proposed
transformation. No reaction occurred when substrate 1a was
treated with 1.2 equiv of PhICl2 in CH3CN at room
temperature. To our delight, the cyclization successfully
produced 2a in 92% yield when the reaction temperature
was increased to 60 °C (Table 1, entry 2). Solvent screening
showed that CH3CN was the most favorable solvent in
comparison to DCE, ethyl acetate, DMF, toluene, dioxane,
CHCl3, and THF (Table 1, entries 2−9, respectively). As a
result of the adjustment of the temperature from 60 to 70 °C,
the yield of product 2a was improved from 92% to 96%, while
further increasing the temperature to 80 °C was not beneficial
to the outcome of the reaction (Table 1, entries 2, 10, and 11).
Furthermore, we also investigated the reaction using PIFA or
PIDA as the oxidant and FeCl3 as a chlorine source. To our
disappointment, neither of these reagents was found to be
superior to the current approach using PhICl2 as both the
oxidant and the chlorine source. NCS was also investigated and
was found not to mediate the reaction, which indicated that
PhICl2 cannot be replaced by the commonly used NCS for this
transformation. On the basis of the screening results, optimized
conditions were concluded to be 1.0 equiv of 2-alkynoate 1a
and 1.2 equiv of PhICl2 in CH3CN at 70 °C (Table 1, entry
10).
c
PIFA
NCS
ND
a
Reaction conditions: 1a (0.5 mmol) and oxidant (0.6 mmol) in
b
c
solvent (5 mL) for 15 min. Isolated yields. Using FeCl3 (0.6 mmol)
as the chlorine source.
approach. Substituent effects of R1 and R2 were studied to
probe the scope and limitations of this method. Substrates
bearing either an electron-withdrawing group (R1 = F, Cl, or
NO2) or an electron-donating group (R1 = Me) at position 5
were converted to the desired cyclized products in satisfactory
to excellent yields (Scheme 2, 2b−e). It is worth noting that
reaction of the substrate when R1 is the strongly electron-
withdrawing NO2 group required a larger dosage of oxidant
and a longer reaction time (Scheme 2, 2b). Likewise,
substrates bearing either a F or Cl substituent at position 4
gave the corresponding products in satisfactory yields (Scheme
2, 2f and 2g).
Investigation of the substituent effect of the alkyne motif
showed that the reactions of diversely substituted phenyl-, 2-
naphthyl-, 2-thienyl, and alkyl-substituted alkynoates pro-
ceeded smoothly to afford the corresponding 4-chloroisocou-
marins 2h−r in 41−96% yields. For instance, substrates with
different phenyl-substituted R2 groups were well tolerated and
generated the corresponding products 2h−n in excellent
yields, regardless of the nature of the substituents on the
phenyl ring. Meanwhile, the reaction of 2-naphthyl- and 2-
thienyl-substituted substrates also gave the corresponding
isocoumarins 2o and 2p in 84% and 83% yields, respectively.
Most strikingly, it was found that the method could be further
extended to the preparation of 3-alkyl-substituted cyclized
products such as 3-tert-butyl 4-chloroisocoumarin 2q and 3-
cyclopropyl 4-chloroisocoumarin 2r. Furthermore, the method
could also be applied to the cyclization/chlorination of (Z)-
methyl 5-phenylpent-2-en-4-ynoate, with the desired product
2s achieved in satisfactory yield. Unfortunately, the reaction
involving a substrate bearing an n-butyl R2 group gave a
complex mixture, and no desired cyclized product was isolated
and/or observed (Scheme 2, 2t). It is noteworthy that most of
the reactions proceeded rapidly and were completed within 15
min. Furthermore, the desired products could be crystallized
from the reaction mixture in relatively high yields, which
dramatically simplified purification.
Under the optimized conditions, a series of 4-chloroisocou-
marin derivatives were prepared by this newly established
B
DOI: 10.1021/acs.orglett.9b00047
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Letter
a
4a,b). It is noteworthy that for the reaction of substrates 1d,
the formation of BnCl could be detected, which provided
evidence for the mechanistic pathway of this transformation.
Scheme 2. Halocyclization of Methyl o-Alkynylbenzoate
Scheme 4. Further Investigation of the Halocyclization of
Ethyl, Benzyl, and tert-Butyl o-Alkynylbenzoates
Because of the mild reaction conditions and convenience of
the procedure, we performed a scale-up experiment on
substrate 1a. It was found that the reaction of 2 g of substrate
1a afforded 1.63 g of 2a in 75% yield, indicating that a large-
scale synthesis of 4-chloroisocoumarin is practical using this
metal-free method. In addition, when the reaction mixture was
cooled, a simple filtration was sufficient to isolate 1a in the
form of needles, obviating the need for purification by silica gel
column chromatography.
One application of the 4-chloroisocoumarins obtained is to
convert them to other building blocks by known methods. For
example, reductive dechlorination of 4-chloroisocoumarin 2a
under conditions of Pd(PPh3)4, Et3SiH, and Et3N in DMF51,52
led to formation of the corresponding 4-unsubstituted
isocoumarin 4a in good yield. Furthermore, Suzuki−Miyaura
coupling of 2a with 4-methylbenzeneboronic acid in the
presence of a L/Pd catalyst system and CsF53 furnished 4-
arylisocoumarin 5a in 90% yield (Scheme 5).
a
Reaction conditions: 1 (1.0 mmol) and PhICl2 (1.2 mmol) in
solvent (8 mL) for 15 min, isolated yield from chromatography/
crystallization (yields in parentheses). Using 2.0 equiv of PhICl2, 1.5
h.
b
To our surprise, substrates bearing a MeO R1 substituent at
different positions of the aromatic ring gave different results
(Scheme 3). Substrate 1u with a MeO group at the para
Scheme 5. Further Derivatization of 4-Chloroisocoumarin
2a
Scheme 3. Halocyclization of Methyl o-Alkynylbenzoate
Bearing an OMe Substituent at Different Positions
A literature survey indicated that the PhICl2-mediated
reactions could use either a radical or an ionic pathway.47 In
this regard, we conducted a series of control experiments to
gain further insight into the reaction mechanism of this
transformation. When the radical scavengers, including
TEMPO, tert-butylhydroxytoluene (BHT), and 1,1-diphenyle-
thene, were introduced into the reaction mixture of substrate
1a, almost no desired product 2a was obtained in any case.
However, considering that PhICl2 could be consumed by the
radical scavenger47,54,55 and then the reaction could be
disabled, we postulated that an ionic pathway cannot be
completely ruled out. Our control experiment showed that
when methanol was used as the solvent for substrate 1a, the
reaction could not afford the desired product 2a at all. This
result might support an ionic mechanism for this reaction, as a
radical pathway generally should not be affected by the use of a
protic polar solvent. On the other hand, a radical-based
mechanism could be supported by a radical clock experiment
in which a cyclopropane-derived substrate would deliver a ring-
position of the methoxyl carbonyl substituent underwent the
halocyclization process smoothly, affording the desired product
2u in an 83% yield. However, substrate 1v with the MeO
substituent at the para position of the alkyne moiety reacted to
afford a mixture of the trans- and cis-dichloronated alkenes,
with no desired cyclized product formed at all.
To further investigate the halocyclization process, ethyl,
benzyl, and tert-butyl o-alkynylbenzoates were prepared and
subjected to the standard conditions. As expected, substrates
1b−d were compatible with the method, offering the desired
product 2a in 94%, 89%, and 93% yields, respectively (Scheme
C
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Letter
open product.56,57 However, for the reaction of substrate 1r
with a cyclopropyl substituent, we found that no ring-open
product could be observed.
which involves both C−Cl and C−O bond formation, has the
advantages of mild reaction conditions, simple operation, fast,
easy purification, large-scale preparation, and metal-free
features. Further investigation of the reaction mechanism is
still ongoing in our lab.
On the basis of these results, we tentatively proposed an
ionic pathway for this reaction.37,58 First, the alkyne triple
bond coordinates with PhICl2 to give intermediate A. Next, a
concerted process involving the nucleophilc attack of the
carbonyl oxygen atom of the ester group on the triple bond
and the triple bond on the iodine center to PhICl2 occurs
affording the oxonium ion intermediate B, with the formation
of a C−I bond and release of a chloride anion. Next, chloride
nucleophilically attacks the methyl carbon center in B, leading
to the formation of intermediate C. While in the case of tert-
butyl ester 1d, the removal of the tert-butyl group should occur
by an SN1 mechanistic pathway. Finally, reductive elimination
of PhI in C affords the title product (Scheme 6). We
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00047.
Experimental procedures and compound characteriza-
tion data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Scheme 6. Proposed Pathway for the Halocyclization of
Methyl o-Alkynylbenzoates
*Telephone: +86-22-27406121. E-mail: duyunfeier@tju.edu.
cn.
ORCID
Yunfei Du: 0000-0002-0213-2854
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the National Natural Science
Foundation of China (21472136) and the Tianjin Research
Program of Application Foundation and Advanced Technology
(15JCZDJC32900) for financial support.
tentatively proposed that the failure of substrate 1t might be
attributed to unstable intermediate B with an n-butyl R group,
which might easily undergo a β-H elimination to give some
unstable allene byproduct.
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