In Situ Formation of RSCl/ArSeCl and Their Application to the Synthesis of 4-Chalcogenylisocumarins/Pyrones from o-(1-Alkynyl)benzoates and (Z)-2-Alken-4-ynoates

Article abstract of DOI:10.1021/acs.orglett.9b01046

The reaction of diorganyl disulfides or diselenides with PhICl₂ in acetonitrile was found for the first time to lead to the in situ formation of organosulfenyl chloride or selenenyl chloride, which enables the regioselective intramolecular chalcogenylacyloxylation of alkynes resulting in the formation of 4-chalcogenylisocumarins/pyrones in good to excellent yields under metal-free conditions.

Full text of DOI:10.1021/acs.orglett.9b01046

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
In Situ Formation of RSCl/ArSeCl and Their Application to the
Synthesis of 4‑Chalcogenylisocumarins/Pyrones from o‑(1-
Alkynyl)benzoates and (Z)‑2-Alken-4-ynoates
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: The reaction of diorganyl disulfides or diselenides with
PhICl2 in acetonitrile was found for the first time to lead to the in situ
formation of organosulfenyl chloride or selenenyl chloride, which enables
the regioselective intramolecular chalcogenylacyloxylation of alkynes
resulting in the formation of 4-chalcogenylisocumarins/pyrones in good
to excellent yields under metal-free conditions.
Scheme 1. Existing Strategies for the Synthesis of 4-
Chalcogenylisocoumarins
rganosulfenyl chlorides or selenenyl chlorides are
Oversatile reagents in organic synthesis. They are
commonly used to install a chalcogenyl group into various
organic substrates, which can be further derivatized.1−10 In
addition, they have also been widely employed to conduct a
large range of synthetic transformations.11−16 Because of the
significant usefulness of these compounds, many methods for
their synthesis have been reported.17−26 Among these
approaches, the most general methods include passing chlorine
gas directly through a solution of thiophenol17 or disulfide/
diselenide,24 reacting diphenyl disulfide/diselenide with
sulfuryl chloride,18,22,23 and chlorinating thiophenol with
NCS.16,21,27 It is noteworthy that on many occasions, rather
than preparing these organochalcogenyl chloride reagents in
advance, protocols utilize in situ formation of such reactive
reagents, for example, from the reaction of the corresponding
thiol and N-chlorosuccinimide (NCS)16,21,27 or disulfide/
diselenide and SO2Cl2.19
Isocoumarins28−30 and pyrones,31,32 the core structures of
many naturally occurring compounds, have been found to
display a broad spectrum of biological activities including
antimicrobial,33−35 androgen-like,36 phytotoxic,37 antifun-
gal,38,39 and pheromonal40 effects. On the other hand, the
past decade has witnessed a growing interest in organo-
chalcogenide compounds, since the installation of chalcogen
functional groups into organic molecules can significantly
improve their physical and chemical features as well as enhance
their biological activities.41−46
In this regard, the development of new and efficient
protocols for the synthesis of chalcogen-substituted isocou-
marins or pyrones has received substantial attention during the
last decades.47−59 In 2011, Zeni’s group49 reported an FeCl3-
mediated cyclization of alkynylaryl esters with different
diorganyl dichalcogenides to afford 4-organochalcogenyl
isochromenones in good yields (Scheme 1, method a).
Furthermore, in 2014, Ding and co-workers55 reported
incorporation of the CF3S− group into the isocoumarin
scaffold through an electrophilic cyclization of o-(1-alkynyl)-
benzoates with trifluoromethanesulfanylamide in the presence
of BiCl3 and BF3·Et2O (Scheme 1, method b). However, these
two methods require the inevitable use of a stoichiometric
amount of the heavy metal for a complete reaction. Among the
synthetic approaches, the intramolecular electrophilic addition
of PhSeCl/PhSCl to o-(1-alkynyl)benzoates and (Z)-2-alken-
4-ynoates has been the most extensively explored method to
construct such types of interesting molecules. For example, in
Received: March 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01046
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2018, Billard58 realized the synthesis of fluoroalkylselenolated
isocoumarins using CF3SeCl or other fluorinated selenenyl
chlorides (Scheme 1, method c). In addition, Melen and
coauthors52 reported that the reaction of diynyl esters and
PhSeCl initially leads to the formation of isocoumarin and then
to a tetracyclic skeleton with an isocoumarin subunit fused to a
benzoselenopyran. Nevertheless, due to the unstable properties
of organosulfenyl chlorides or selenenyl chlorides which are
also costly and not easily available, both the synthesis and
application of these reagents are often troublesome and require
harsh conditions. Herein, we report a metal-free and atom-
economical protocol to the synthesis of 4-chalcogenyl
isocoumarins through regioselective intramolecular cyclization
of alkynes with organosulfenyl chlorides or selenenyl chlorides
generated in situ from unactivated disulfides or diselenides and
PhICl2, an easily prepared and nontoxic hypervalent iodine
reagent (Scheme 1, method d).
product (Table 1, entries 2−6). Next, a series of solvents
including methanol, EtOAc, dioxane, toluene, DMF, THF, and
DCE were surveyed; however, none of them provided superior
results to MeCN (Table 1, entries 7−13). It was gratifying to
find that when the loading of PhICl2 was reduced from 1.0 to
0.7 equiv, an increase in yield was observed (Table 1, entries
14−16). Further reduction of the oxidant loading to 0.6 or 0.5
equiv proved to be inefficient (Table 1, entries 17 and 18). It is
noteworthy that all of the reactions were carried out at rt and
under air atmosphere. Finally, the optimized conditions were
confirmed to be 1.0 equiv of 2-alkynoate 1a, 0.7 equiv of
PhICl2, and 0.5 equiv of PhSSPh in CH3CN at rt (Table 1,
entry 16).
With the optimal reaction conditions established, we next
examined the scope of the reaction by subjecting various o-
alkynylbenzoate derivatives 1 to the standard conditions
(Scheme 2). The effect of different substituents R1 was first
Utilization of sulfenyl chlorides generated in situ from the
reaction of RSSR/ArSeSeAr and PhICl2 is of general
significance since it avoids the direct use of moisture-sensitive
RSCl/ArSeCl. Screening of the reaction conditions was
initiated by reacting o-alkynylbenzoates 1a with sulfenyl
chlorides formed in situ by the above one-pot protocol.
Considering both the two phenylthio moieties in diphenyl
disulfide (PhSSPh)60 could be incorporated into the final
product, 0.5 equiv of diphenyl disulfide was introduced into
the reaction system. To our delight, when a mixture of 1a (0.5
mmol) with PhICl2 (1.0 equiv) and diphenyl disulfide (0.5
equiv) in MeCN (5 mL) was stirred at rt, 2a was obtained in a
yield of 79% (Table 1, entry 1). In order to further improve the
outcome of the reaction, other parameters including oxidant,
solvent, and oxidant loading were screened. All attempts to
perform the reaction with other oxidants including PIDA,
PIFA, DDQ, Oxone, and m-CPBA failed to give the desired
Scheme 2. PhICl2/PhSSPh-Mediated Synthesis of
Sulfenylated Isocoumarins
a
a
Table 1. Optimization of Reaction Conditions
b
entry
oxidant (equiv)
solvent
yield (%)
1
2
3
4
5
6
7
8
PhICl2 (1.0)
PIDA (1.0)
PIFA (1.0)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
MeOH
EtOAc
dioxane
toluene
DMF
79
ND
ND
ND
ND
ND
65
72
ND
67
45
15
75
84
90
96
89
80
DDQ (1.0)
oxone (1.0)
mCPBA (1.0)
PhICl2 (1.0)
PhICl2 (1.0)
PhICl2 (1.0)
PhICl2 (1.0)
PhICl2 (1.0)
PhICl2 (1.0)
PhICl2 (1.0)
PhICl2 (0.9)
PhICl2 (0.8)
PhICl2 (0.7)
PhICl2 (0.6)
PhICl2 (0.5)
a
Reaction conditions: 1 (1.0 mmol), PhSSPh (0.5 mmol), and PhICl2
(0.7 mmol) in CH3CN (10 mL) for 30 min, isolated yields.
9
10
11
12
13
14
15
16
17
18
explored. Substrates with either an electron-donating methyl
group or electron-withdrawing groups including F, Cl, and
NO2 substituted on the aromatic ring of the o-alkynylbenzoate
1 all reacted smoothly with PhSSPh under the optimized
conditions, giving the corresponding products 2a−g in good to
excellent yields. Next, substitution of the alkyne motif R2 was
also investigated. To our delight, the reaction worked well with
both aryl- and alkyl-substituted functional groups to generate
the cyclized products 2h−p in yields of 70−90%. Interestingly,
the electronic nature of these substituents or steric effects did
not have an obvious impact on the outcome of the reaction.
THF
DCE
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
a
Reaction conditions: 1a (0.5 mmol), PhSSPh (0.25 mmol), and
b
oxidant in solvent (5 mL) for 30 min. Isolated yields.
B
DOI: 10.1021/acs.orglett.9b01046
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
For instance, when the alkyne motif was substituted by either
electron-rich/electron-poor phenyl rings with diversely sub-
stituted groups including CO2Me, NO2, Cl, OMe, and Me or
the sterically hindered o-iPr-substituted aryl ring, products 2h−
m were obtained in good to excellent yields. Substrates with a
naphthalene or thiophene ring linked to the alkyne moiety also
proved to be well tolerated, providing the corresponding
products in relatively higher yields of 84% and 91%,
respectively. Most strikingly, it was found that the method
could be further applied to the synthesis of 3-alkyl-substituted
isocoumarins. When 2-alkynylbenzoate with a t/n-butyl R2
group was applied, product 2p/2q was obtained in a yield of
81% and 80%. Interestingly, a substrate bearing a cyclopropyl
group attached to the triple bond was effective as well under
the standard conditions, affording the desired product 2r in
70% yield. Furthermore, substrates bearing a TMS R2 group
(1s) or methoxycarbonyl R2 group (1t) were also converted to
the product 2s and 2t in 72% and 68% yield, respectively.
However, a longer time (24 h) was required for a complete
reaction of substrate 1t. It is worth noting that the method was
also applicable to a terminal alkyne. When substrate 1u was
subjected to the standard conditions, the corresponding
cyclized product was obtained in an acceptable 52% yield. In
addition to methyl benzoate substrates, the other substrates
bearing ethyl, tert-butyl, and benzyl esters were all tested, and
the desired product was obtained in yields of 92%, 89%, and
90%, respectively.
was amenable to introduction of selenyl groups. To our
delight, the reaction of 2aa−ad with diphenyl diselenide
proceeded smoothly to provide the 4-selenylated products in
yields of 80−94%. Substrates bearing either an electron-
donating or electron-withdrawing substituent on the aromatic
ring of the o-alkynylbenzoate 1 as well as both phenyl and n-
butyl substituents attached to the alkyne moiety were
investigated, and they all provided the corresponding cyclized
products with good results. One might envisage that the
method could be extended to install a tert-butoxy group into
the isocoumarin skeleton by using DTBP and PhICl2.
However, the reaction of 1a with DTBP (0.5 equiv) and
PhICl2 (0.7 equiv) in MeCN at rt to 60 °C afforded 4-
chloroisocoumarin as the sole product.61
To further investigate whether the phenyl ring in the
substrate was indispensable for this transformation, we
subjected (Z)-2-alken-4-ynoate derivatives to the standard
conditions (Scheme 4). It was found that (Z)-2-alken-4-
Scheme 4. Synthesis of Sulfenylated Pyrones Using Various
a
Substrates
Next, we turned our attention to investigate the scope of
diorganyl dichalcogenides agents (Scheme 3). In general,
Scheme 3. Synthesis of Chalcogenyl Isocoumarins Using
Various Dichalcogenide Agents
a
a
Reaction conditions: 1 (1.0 mmol), PhSSPh (0.5 mmol), and PhICl2
(0.7 mmol) in CH3CN (10 mL) for 30 min, isolated yields.
ynoates bearing both a substituted phenyl group or an alkyl
group on the acetylene moiety reacted well to produce the
corresponding pyrones 4a−d in good yields.
To clarify the mechanism of this process, two control
experiments were conducted, and the following results were
achieved: (1) When PhICl2 and diphenyl diselenide reacted at
rt for 20 min in the absence of starting alkynyl aryl ester 1a, a
red solid formed that was characterized as PhSeCl. This
observation indicates that the pathway is consistent with the
typical mechanism involving electrophilic cyclization with
PhSeCl as the electrophilic source (Scheme 5a). (2) The
Scheme 5. Control Experiments
a
Reaction conditions: 1 (1.0 mmol), PhSSPh (0.5 mmol), and PhICl2
(0.7 mmol) in CH3CN (10 mL) for 30 min, isolated yields.
diphenyl disulfide reagents bearing an electron-donating
methyl group or electron-withdrawing chloro substituent on
the aromatic ring as well as the dichloro-substituted diphenyl
disulfide were all applicable for this conversion, with the
corresponding 6-exo-trig cyclization products 2v−x obtained in
76−90% yields. Additionally, dialkyl disulfides also served as
suitable reaction partners with o-alkynylbenzoates 1, giving the
sulfenylated products 2y and 2z in good yields. Finally, we
examined diselenide reagents to explore whether this strategy
resulting PhSeCl solid was further used to react with the
starting alkynyl aryl ester 1a, and the desired product was
obtained in a yield of 88% (Scheme 5b). Compared with the
previous methods,16,19,21,27,49 the in situ generation of
organosulfenyl chlorides or selenenyl chlorides was achieved
from easy-to-handle starting materials under mild conditions
by this method.
Based on the experimental results and previous litera-
ture,49,59 we propose that the reaction initially involves PhSCl
C
DOI: 10.1021/acs.orglett.9b01046
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01046.
(27) Yadav, J. S.; Subba Reddy, B. V.; Jain, R.; Baishya, G.
Experimental procedures; compound characterization
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AUTHOR INFORMATION
Corresponding Author
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*Tel: +86-22-27406121. E-mail: duyunfeier@tju.edu.cn.
ORCID
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Yunfei Du: 0000-0002-0213-2854
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We acknowledge the National Natural Science Foundation of
China (No. 21472136) for financial support.
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