Metal- and Catalyst-Free One-Pot Cascade Coupling of α-Enolic Dithioesters with in situ Generated 4-Chloro-3-formylcoumarin: Access to Thioxothiopyrano[3,2-c]chromen-5(2H)-ones

Article abstract of DOI:10.1002/adsc.201901180

An efficient and viable one-pot protocol for the synthesis of a specific class of 2-thioxothiopyrano[3,2-c] chromen-5(2H)-ones has been devised by the cross-coupling of 4-hydroxycoumarin and α-enolic dithioesters under metal- and additive-free conditions in open air. The reaction proceeds via in situ generation of 4-chloro-3-formylcoumarin followed by consecutive Michael-type addition/intramolecular cyclization/ elimination cascade, enabling the creation of thiopyran-2-thione ring over coumarin framework through successive formation of C?C and C?S bonds. Remarkably, the benign conditions, atom-economy, and quantifying forbearance of a wide horizon of functional groups are added characteristics to this strategy. (Figure presented.).

Full text of DOI:10.1002/adsc.201901180

Title: Metal- and Catalyst-Free One-Pot Cascade Coupling of α-Enolic
Dithioesters with in situ Generated 4-Chloro-3-formylcoumarin:
Access to Thioxothiopyrano[3,2-c]chromen-5(2H)-ones
Authors: Dhananjay Yadav, Monish Ansari, Mitilesh Kumar, and MAYA
SINGH
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901180
Link to VoR: http://dx.doi.org/10.1002/adsc.201901180

10.1002/adsc.201901180
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Metal- and Catalyst-Free One-Pot Cascade Coupling of -
Enolic Dithioesters with in situ Generated 4-Chloro-3-
formylcoumarin: Access to Thioxothiopyrano[3,2-c]chromen-
5(2H)-ones
Dhananjay Yadav, Monish A. Ansari, Mitilesh Kumar and Maya Shankar Singh*
Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India
mayashankarbhu@gmail.com; mssingh@bhu.ac.in
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
The present popularity of the modified annulated
synthesis of a specific class of 2-thioxothiopyrano[3,2-c] coumarin derivatives is mainly due to their close
Abstract. An efficient and viable one-pot protocol for the
chromen-5(2H)-ones has been devised by the cross-
coupling of 4-hydroxycoumarin and -enolic dithioesters
under metal- and additive-free conditions in open air. The
reaction proceeds via in situ generation of 4-chloro-3-
formylcoumarin followed by consecutive Michael-type
addition/intramolecular cyclization/ elimination cascade,
enabling the creation of thiopyran-2-thione ring over
coumarin framework through successive formation of CC
and CS bonds. Remarkably, the benign conditions, atom-
economy, and quantifying forbearance of a wide horizon of
functional groups are added characteristics to this strategy.
structural relationship to some clinically important
molecules, which could open the door to many
challenges both in the areas of synthetic organic and
medicinal chemistry. Therefore, much attention has
been
paid
towards
the
synthesis
of
substituted/annulated coumarins.[9]
In spite of a wide range of literature reports
towards the synthesis of coumarin derivatives, it is
still highly desirable to explore operationally simple,
efficient and widely applicable approach to the
synthesis of annulated coumarins. Thiopyrano-fused
coumarins have been synthesized via sigmatropic
Keywords: -Enolic dithioesters; Coumarin; 4-Chloro-3-
formylcoumarin; Heteroannulation; Thiopyran annulated
coumarin
rearrangement[10a]
and
thio
Claisen-type
rearrangement.[10b] To the best of our knowledge, no
report on the synthesis of 2-thioxothiopyrano fused
coumarins utilizing -enolic dithioesters is known to
date (Scheme 1). For the success of any protocol, the
choice of substrate and reagent is highly vital and
dominant factor. The inherent synthetic tunability of
substrates makes them highly attractive in synthesis.
One such simple molecule is -enolic dithioester,
which bears both nucleophilic and electrophilic
centers. -Enolic dithioesters have become without
doubt one of the most exciting and popular species in
organic synthesis due to the ease of their preparation
and modularity in stereoelectronic properties.
Substituted/annulated coumarins are important
synthetic targets for both the pharmaceutical
industries and academic laboratories. They have
always fascinated synthetic and medicinal chemists
because of their comprehensive pharmacological
profiles such as antiallergic, antibiotic, anticancerous,
antitumor, antidiabetic, anticoagulant, antioxidant and
antihypertensive
properties.[1-3]
Addition
of
heterocyclic moiety to coumarin nucleus enhances its
biological applications and therapeutic values.[4]
Coumarin fused heterocycles are present as core
structures in many natural products and biologically
active molecules such as alkaloids, tocopherols, and
flavonoids.[5] Pyrano-fused coumarins have been
explored for various biological properties like
antihypertensive, spasmolytic, and activity towards
potential cancer cells.[6] Furthermore, many of the
coumarin derivatives also found application as
insecticides[7a] and biodegradable chemicals[7b-g] for
agricultural industries. In addition to medicinal
applications, molecules bearing coumarin moiety
have been used as fluorescent probes for biothiols.[8]
Over the past decade, -enolic dithioesters having
multiple reactive centers not only received
considerable attention of synthetic chemists, but also
have been extensively exploited for the construction
of diverse heterocyclic scaffolds.[11] Inspired by
exceptional reactivity and in line with our long-
standing interest to construct diverse heterocyclic
frameworks employing-enolic dithioesters as a key
substrate,[12] we intended to react -enolic dithioester
with coumarin derivative with a vision to get
annulated coumarin framework. Herein, we report a
one-pot domino approach to assemble thioxopyrano
1
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10.1002/adsc.201901180
Advanced Synthesis & Catalysis
annulated coumarin derivatives from -enolic DMF could not provide better result (Table 1, entries
dithioester under metal- and additive-free conditions 9 and 10). Thus, the optimum condition for the
in open air (Scheme 1c).
reaction was achieved by employing 1a (0.25 mmol),
3a (0.25 mmol), POCl3-DMF mixture (6:6 equiv.) at
60 oC in open air (Table 1, entry 7).
With the established optimal conditions in hand
(Table 1, entry 7), we then set out to explore the
scope of this novel coupling reaction by allowing a
variety of structurally diverse -enolic dithioesters
bearing aryl, hetaryl, and extended aromatic
substituents at R moiety, and the results are
summarized in table 2. The influence of substituents
in the phenyl ring (R moiety) of -enolic dithioesters
3 was first investigated. The variants of the
substituents did not hamper the reaction process, and
proved to be the suitable substrates for this protocol to
access diverse thiopyran fused coumarin derivatives 4
in good yields. The diverse substituents like -OMe, -
Me, -Et, -Cl, -CF3, -F and -OCH2O- groups regardless
of their substitution patterns (ortho, meta, para) on
the phenyl ring (R moiety) were found to be well-
suited under the optimal reaction conditions affording
the corresponding products in high yields (Table 2,
4ab-4al), revealing no obvious electronic and steric
impact from the substituents. The introduction of
halogen moiety into target product is attractive
because of their potential towards cross-coupling for
further synthetic elaborations.
Scheme 1. Strategy for the synthesis of annulated
coumarins.
Table 1. Optimization of reaction conditions.a
To this end, to establish the viability of our new
concise approach, we intensively investigated the
model reaction of coumarin (1a) with methyl-3-
hydroxy-3-phenyl-prop-2-enedithioate (3a) in POCl3-
DMF mixture in open air, and the results are listed in
Table 1. Initially, we performed the test reaction of 1a
(0.25 mmol) in POCl3-DMF mixture (1:6 equiv.) at 0
oC for 30 minutes, followed by slow addition of
dithioester 3a (0.25 mmol) at room temperature. No
trace of the product was obtained even after 24 h of
stirring, and the substrates 1a and 3a remained
completely unconsumed (Table 1, entry 1). To check
the effect of temperature on the reaction, the test
reaction was carried out at higher temperatures (Table
1, entries 2-4). It has been observed that maximum
Entry Reagent
Temp Time Yieldb
(o C)
(h)
24
(%)
NR
1
POCl3-DMF (1:6)
rt
2
POCl3-DMF (1:6)
POCl3-DMF (1:6)
POCl3-DMF (1:6)
POCl3-DMF (2:6)
POCl3-DMF (4:6)
POCl3-DMF (6:6)
POCl3-DMF (8:6)
POCl3-DMF (6:4)
POCl3-DMF (6:8)
40
60
80
60
60
60
60
60
60
8
8
8
6
6
6
6
6
6
20
42
30
48
62
77
77
66
77
3
4
o
conversion occurred at 60 C, providing the desired
product 4aa in 42% yield within 8 h (Table 1, entry 3).
5
o
Further higher temperature (80 C) made the reaction
messy, and reduced the yield of product 4aa to 30%
6
(Table 1, entry 4).
7
To improve the efficiency of the reaction, next we
o
assessed the amount of POCl3 at 60 C (Table 1,
8
entries 5-8). It was found that 6 equiv. of POCl3
drives the reaction smoothly furnishing the desired
product 4aa in 77% yield within 6 h (Table 1, entry 7).
Further increase in the amount of POCl3 (8 equiv.)
could not improve the result (Table 1, entry 8). Next,
we surveyed the amount of DMF. Lowering the
amount of DMF from 6 equivalents, decreased the
yield of the product, and increasing the amount of
9
10
a
Reaction conditions: 1a (0.25 mmol), 3a (0.25 mmol) in
open air. b Isolated yield. NR = No reaction reaction
2
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10.1002/adsc.201901180
Advanced Synthesis & Catalysis
Remarkably, -enolic dithioesters bearing
R
performed the reaction employing dithioesters derived
moiety as hetaryl groups such as 2-furyl and 2-thienyl from aliphatic ketones bearing R as methyl, isobutyl
were also well suited affording the corresponding and cyclopropyl groups. In all these cases, even a
products in 74% and 75% yield, respectively (Table 2, trace of the desired product was not obtained (Table 2,
4am and 4an). Further in a challenging case, in which 4ar, 4as and 4at), which limit the scope of the
R moiety as extended aromatic biphenyl group reaction to some extent. This could be due to less
provided the desired product 4ao in 56% yield. stability of aliphatic dithioesters than aromatic
Noticeably, even more challenging case where three dithioesters. Further to check the versatility of the
strong electron-donating methoxy groups at R moiety reaction, we surveyed the scope of substituted
was also found to be compatible for the formation of coumarins. Thus, we employed coumarins bearing
desired product 4ap in 80% yield. However, only a electron-donating and electron-withdrawing groups at
trace amount of product was observed on TLC plate phenyl ring under the standard condition, the
in case of R moiety as naphthyl group, which could corresponding products (Table 2, 4ba, 4bc, 4ca, 4da)
not be isolated 4aq.
were obtained in good yields, revealing synthetic
utility and broad scope of the reaction.
Table 2. Substrate scope.
To illustrate the practical application of this
protocol, we performed a gram-scale experiment with
1a (7 mmol) and 3a (7 mmol) under the standard
reaction conditions (Scheme 2). The desired product
3-benzoyl-2-thioxothiopyrano[3,2-c]chromen-5(2H)-
one (4aa) was obtained in 73% yield (1.79 g), which
is comparable to the small scale experiment. This
result suggests that the present method could be easily
adapted for a large-scale preparation.
Scheme 2. Gram-scale synthesis of 4aa.
To have deep insight into the mechanism for the
reaction, we performed some control experiments
(Scheme 3). In the absence of POCl3, under standard
condition, the desired product 4aa was not observed
even in trace (Scheme 3, eq.1). Similar result was
observed in the absence of DMF also (Scheme 3, eq.
2). Thus, use of only POCl3 or DMF alone could not
trigger the reaction, which shows that formylating
reagent (POCl3-DMF), which generates the reactive
species 4-chloro-3-formyl coumarin in situ, is
necessary for the reaction. During the course of the
reaction, we observed the formation of intermediate
4-chloro-3-formyl coumarin (2) on TLC plate.
Scheme 3. Control experiments.
The structural elucidation of all the newly
synthesized compounds 4 was determined by their
satisfactory spectral (1H and 13C NMR, and HRMS)
studies. Furthermore, the structure of one of the
representative compounds 4aa was unequivocally
We attempted the synthesis of -enolic
aryldithioesters from substituted acetophenones
bearing NO2, OH and NH2 groups, but could not get
the desired dithioesters. In addition, we also
3
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10.1002/adsc.201901180
Advanced Synthesis & Catalysis
confirmed by single crystal X-ray diffraction analysis thioxothiopyrano[3,2-c]chromen-5(2H)-ones by the
(Figure 1, see Supporting Information for details).[13]
reaction of coumarins with -enolic dithioesters via
consecutive CC and C(sp2)S bonds formation. The
reaction involves cross-coupling of -enolic
dithioesters with in situ generated 4-chloro-3-formyl
coumarin via Michael-type addition/intramolecular
cyclization/elimination cascade sequence. Thus, the
construction of thioxothiapyrano annulated coumarin
derivatives by this operationally simple protocol
expands the coumarin derivatives toolbox, which
could be of further biological significance. The clean
reaction profile, transition-metal-free conditions,
tolerance of wide functional groups, avoidance of
expensive/toxic reagents, and CH3Cl being only by-
product are additional attributes to this novel one-pot
strategy. This heteroannulation based platform
illustrates not only the synthesis of previously
inaccessible and synthetically demanding annulated
coumarins, but also enriches the chemistry of -
enolic dithioesters. The future portends even greater
and richer implementations of this unique synthon to
a vast range of other synthetic and material science
applications.
Figure 1. ORTEP diagram of compound 4aa (CCDC
1923182).
Based on our experimental observations, the
following plausible mechanism for the formation of
thiopyran annulated coumarins 4 has been suggested
(Scheme 4). The first step is supposed to be the
Vilsmeier-Haack formylation of 4-hydroxy-coumarin
1 to give 4-chloro-3-formyl coumarin 2, which has
been isolated and fully characterized. Thus, in situ
generated intermediate 2 undergoes Michael-type
addition with -carbon of dithioester 3 to form
Experimental Section
intermediate A. Intermediate
A
undergoes
intramolecular S-cyclization forming C(sp2)S bond
to give enolate ion intermediate B. The eliminated
The precursor 4-hydroxy-2H-chromen-2-one (1) and its
derivatives were synthesized by the reaction of 1-(2-
hydroxyphenyl)ethanone with dialkyl carbonate in the
presence of sodium hydride in accordance with the
literature reports.[14] The in situ generation of 4-chloro-2-
oxo-2H-chromene-3-carbaldehyde 2 has been done by
treating 4-hydroxy-2H-chromen-2-one with POCl3/DMF
mixture as formylating reagents under Vilsmeier
conditions.[15] α-Enolic dithioesters 3 are not commercially
sourced, and were synthesized in good yields following the
reported procedure.[16] To an ice-cooled stirred solution of
4-hydroxy-2H-chromen-2-one (1) (0.25 mmol, 1 equiv.) in
DMF (6 equiv.), POCl3 (6 equiv.) was added drop wise
over a period of 5 min. The reaction mixture was allowed
to stir at room temperature for 30 min. The temperature of
the reaction was increased to 60 0C followed by the
addition of α-enolic dithioester 3. The reaction mixture was
further stirred till the completion of the reaction. After
completion of the reaction (monitored by TLC), the
reaction mixture was diluted with 30 mL of ethyl acetate,
followed by washing with saturated NaHCO3 solution (2 ×
50 mL) to neutralize the acid formed during the course of
the reaction. The organic layer was dried over anhydrous
Na2SO4, and solvent was evaporated under reduced
pressure. The crude residue thus obtained was purified by
column chromatography over silica gel (100−200 mesh)
using hexane-ethyl acetate (9:1) as eluent to give the pure
products 4.
chloride ion from intermediate
B attacks on
intermediate C, enabling the cleavage of C(sp3)S
bond to form the desired annulated coumarin 4 by
elimination of methyl chloride. To authenticate the
reaction mechanism, we recorded HRMS of reaction
mixture. We did not observe any peak of eliminated
methyl chloride, which could be due to its gaseous
nature. Next, we performed the reaction with -enolic
dithioester bearing n-butyl group instead of methyl
group of thioalkyl, and recorded the HRMS of
reaction mixture. In this case, we found the desired
peak of butyl chloride suggesting the elimination of
alkyl chlorides during the course of the reaction (see
Supporting Information for details).
Acknowledgements
We gratefully acknowledge the financial support from the Science
and Engineering Research Board (SERB/EMR/2015/002482) and
the Council of Scientific and Industrial Research
(02(0263)/16/EMR-II), New Delhi. The authors ( D.Y., M.A.A.
and M.K.) are thankful to UGC and CSIR, New Delhi for research
fellowship.
Scheme 4. Plausible mechanism for the formation of
thiopyran annulated coumarins 4.
In summary, we have developed an efficient
domino protocol to access versatile tricyclic 2-
4
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10.1002/adsc.201901180
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
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6
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Adv. Synth. Catal. Year, Volume, Page – Page
Dhananjay Yadav, Monish A. Ansari, Mitilesh
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