Efficient synthesis of 4-sulfanylcoumarins from 3-bromo-coumarins: Via a highly selective DABCO-mediated one-pot thia-Michael addition/elimination process

Article abstract of DOI:10.1039/c9ra09545d

A facile and efficient protocol for the highly selective direct sulfanylation of 3-bromocoumarins under DABCO promotion, was developed. The transformation took place with aromatic and aliphatic thiols as well as with α,ω-dithiols, affording the expected products in very good to excellent yields. Simple and convenient ways to access 4-((ω-mercaptoalkyl) thio)coumarins and the dimeric 4,4′-(alkane-1,4-diylbis(sulfanediyl))bis(coumarins) were also devised with the use of α,ω-alkanedithiols in different ratios with regards to the starting 3-bromocoumarin. The transformation seems to proceed through the DABCO-mediated thia-Michael stereoselective addition of the thiolate anion to the α,β-unsaturated carbonyl system of the coumarin, followed by a DABCO-assisted stereoselective dehydrobromination of the resulting α-bromo carbonyl intermediate.

Full text of DOI:10.1039/c9ra09545d

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Efficient synthesis of 4-sulfanylcoumarins from 3-
bromo-coumarins via a highly selective DABCO-
mediated one-pot thia-Michael addition/
elimination process†
Cite this: RSC Adv., 2020, 10, 482
b
Vitor B. Mostardeiro,a Marina C. Dilelio,a Teodoro S. Kaufman
*
a
*
and Claudio C. Silveira
A facile and efficient protocol for the highly selective direct sulfanylation of 3-bromocoumarins under
DABCO promotion, was developed. The transformation took place with aromatic and aliphatic thiols as
well as with a,u-dithiols, affording the expected products in very good to excellent yields. Simple and
convenient ways to access 4-((u-mercaptoalkyl) thio)coumarins and the dimeric 4,40-(alkane-1,4-
diylbis(sulfanediyl))bis(coumarins) were also devised with the use of a,u-alkanedithiols in different ratios
with regards to the starting 3-bromocoumarin. The transformation seems to proceed through the
DABCO-mediated thia-Michael stereoselective addition of the thiolate anion to the a,b-unsaturated
carbonyl system of the coumarin, followed by a DABCO-assisted stereoselective dehydrobromination of
the resulting a-bromo carbonyl intermediate.
Received 15th November 2019
Accepted 18th December 2019
DOI: 10.1039/c9ra09545d
rsc.li/rsc-advances
the benzodiazepine receptors4c and the incorporation of DIG-11-
dUTP to BS-C-1 cells modied/infected with vaccinia virus,5a as
Introduction
well as inhibition of interleukin 2 (ref. 5b) and the TNF-
a induced expression of ICAM-1 (VII).5c 4-Sulfanylcoumarins
like VIII and IX6a–c have been tested as cytotoxic and anti-
proliferative agents and some of them proved to be interestingly
bioactive.6a,b Others displayed anti-Hepatitis C virus activity
(Fig. 1).6d
Despite the importance and usefulness of the 4-sulfanyl
coumarins, methods for accessing these compounds are scarce,
suffer from multiple synthetic steps and harsh reaction condi-
tions, in addition, the available methodologies oen use toxic
agents and high temperatures, and also display poor substit-
uent tolerance.
They mainly comprise formation of the C–S bond by 4-sul-
fanylation through nucleophilic vinylic substitution of suitable
4-substituted heterocyclic precursors, such as 4-hydrox-
ycoumarins,7a and their sulfonates,7b–d 4-halocoumarins8 and 4-
bromomethyl coumarins.9a,b An oxidative cross-coupling on 3-
aminocoumarin has been reported as an alternative.9c
In addition, elemental sulfur, inorganic suldes, KSCN, CS2
and thiourea have also served as sources of the sulfur
atom,6c,8b,10 whereas the alkylation of the resulting 4-mercapto-
coumarins11 and their arylation through the use of electro-
chemical means12 have been disclosed as other options.
An exhaustive literature search revealed that there are also
few and scattered cases related to the use of 3-bromocoumarins
as starting materials;13 however, their use seems discouraging,
since the transformations proceed under rather harsh
The coumarin core is a privileged scaffold and a ubiquitous
heterocyclic structure among natural products, bioactive
synthetic compounds and technologically interesting materials.
The introduction of sulfur as a heteroatom in many molecules
has been demonstrated to be an effective method for changing
their characteristics, by endowing them with new properties
useful for materials science or conveying signicant biological
activity.1
The 4-sulfanylcoumarin core is found in many relevant
natural products, such as in the cytotoxic pheofungins (Ia–d),
the tricyclic lactone iotrochotazine A (II), a chemical probe to
study Parkinson's disease and other heterocycles, like IIIa–d.2
They are also interesting structural motifs in the area of func-
tional materials, as exemplied by the selective uorescent
probes IV and V.3 It is also known that upon reaction with
glutathione, compound IV affords the 4-thiocoumarin
adduct VI.
In addition, 4-thiocoumarins have ample applications in
medicinal chemistry, exhibiting a wide range of biological and
pharmacological activities. These include inhibition of vitamin
K epoxide reductase4a and pyruvate kinase M2,4b to inhibition of
a
´
Departamento de Quımica, Universidade Federal de Santa Maria, Santa Maria, RS,
97105-900, Brazil. E-mail: silveira@quimica.ufsm.br
b
´
Instituto de Quımica Rosario (IQUIR, CONICET-UNR), Suipacha 531, 2000 Rosario,
Argentina
† Electronic supplementary information (ESI) available: NMR spectra of the nal
products. See DOI: 10.1039/c9ra09545d
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Scheme 1 Proposed DABCO-promoted approach for the sulfanyla-
tion of 1 toward 4-organyl sulfanyl-coumarin derivatives (3).
bromo-decarboxylation of 6-chlorocoumarin-3-carboxylic acid
with NBS.19
At the outset of our debromosulfanylation studies, we
employed the reaction between 3-bromocoumarin (1a) and 4-
chlorobenzenethiol (2b) as model system.
Therefore, with the intention of developing a more efficient
and selective protocol, we tested a small set of bases as
promoters, including inorganic (KOH,20a K2CO3 (ref. 20b and c))
and organic (pyridine,13b,c DMAP, Et3N,13a,20d DBU20e and DAB-
CO20f) examples, under different reaction conditions (Table 1).
At rst, the transformations were performed at room
temperature and monitored by GC/MS. Under these conditions,
a white precipitate began to form aer ca. 10 min and the
Table 1 Optimization of the reaction conditionsa
Fig.
1 Examples of relevant coumarin derivatives carrying C4–S
bonds.
conditions and with low selectivity, resulting in poor to
moderate product yields and/or giving mixtures of the isomeric
3- and 4-sulfanyl coumarins. These characteristics seriously
limit their general applicability.
We have reported the synthesis of different compounds
through functional group transposition,14 such as between C-3
and C-4 among tetrahydroisoquinoline derivatives and have
disclosed a vinylic nucleophilic substitution approach toward
the synthesis of 4-aryl- and 4-benzyl-selanylcoumarins.15
To the best of our knowledge, despite some scattered
precedents,13 there have been no systematic studies of the
functional transposition of 3-bromocoumarins toward their
corresponding 4-sulfanyl congeners. Therefore, due to our
continued interest in the preparation of new coumarin deriva-
tives,15,16 herein we report a facile and metal-free, selective direct
4-sulfanylation of 3-bromocoumarins (1) with aromatic and
aliphatic thiols (2), under DABCO promotion. The trans-
formations resulted in the synthesis of diverse novel 4-
organylsulfanyl-coumarins (3), as shown in Scheme 1.
Temp.
Entry no.
Base
(ꢀC)
Yieldb (%)
82
(3b : 4b)c
1
2
3
4
5
6
7
8
K2CO3
K2CO3
KOH
Pyridine
Pyridine
DMAP
DMAP
Et3N
Et3N
DBU
DBU
DABCO
DABCO
r.t
70
r.t
r.t.
70
r.t.
70
r.t.
60
r.t
70
r.t
70
46 : 54
28 : 72d
35 : 65
—
d
—
68
e
—
f
—
—
44
74
71
96 : 4
92 : 8
64 : 36
63 : 37d
66 : 34
66 : 34d
97 : 3
100 : 0
d
9
—
10
11
12
13
82
d
—
72
86
a
Reaction conditions: 3-bromocoumarin (1a,
1
mmol), p-
Results and discussion
chlorothiophenol (2b, 1.5 mmol), THF (5 mL), base (1.5 mmol), 2 h.
Isolated yields by column chromatography. Determined by GC/MS.
b
d
c
The required 3-bromocoumarin17 starting materials 1a (R ¼ H)
and 1c (R ¼ 8-Me) were conveniently obtained by bromination
of the corresponding coumarins with the HBr/oxone reagent
system,18 whereas the derivative 1b (R ¼ 6-Cl) was prepared by
The yield was not determined; only the isomer ratio was estimated
e
by GC. No precipitate was formed aer 3 h at room temperature.
f
No precipitate was formed aer 3 h. The GC-MS analysis of the
crude mixture revealed the formation of the disulde, coumarin and 1a.
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obtention of mixtures of C-3 and C-4 isomers was consistently an improved 86% yield (entry 13). Interestingly, to the best of
observed in the presence of the tested promoters, except our knowledge, despite the use of DABCO as a promoter of
pyridine.
a similar transformation has been recorded,20f this is the rst
The 1H NMR and GC/MS analyses of the products revealed that time the reaction is explored under DMAP assistance. The
the C-3 isomer (4b) prevailed in case of the inorganic bases K2CO3 differences between DABCO and DMAP as organocatalysts have
(46 : 54, entry 1) and KOH (35 : 65, entry 3), whereas the opposite been examined.21a
was detected for the organic promoters Et3N (64 : 36, entry 8) and
The 1H NMR signals of the vinylic protons of the starting
DBU (66 : 34, entry 10); however, when pyridine (1.5 equiv.) was material and product where compared with those of the
employed as base, the expected reaction product was not observ- unsubstituted coumarin (dH-3 6.43 ppm, doublet; dH-4 7.72 ppm,
ed13b,c even under the heating condition (entries 4 and 5). Instead, doublet), and taken as the diagnostic signals of this outcome.
the disulde related to 2b, coumarin and 1a was the detected
The H-4 resonance of 1a was observed as a highly deshielded
products when the reaction was executed at 70 ꢀC. It is worth singlet resonating at d 8.11 ppm, whereas the product exhibited
noting that a similar process was reported to proceed at 140 ꢀC in a considerably more shielded singlet at d 5.62 ppm, consistent
reuxing pyridine, employed both, as solvent and base.13b–d
with structure 3b. The reason for this upeld shi could only be
Gratifyingly, however, although not fully suppressing the assigned to H-3 in the presence of an adjacent sulfur-containing
formation of the undesired C-3 isomer, the use of DMAP (96 : 4, group, due to its electron-donating character.
entry 8) and DABCO (97 : 3, entry 12) resulted in a comparatively
larger preference for the expected C-4 isomer 3b, with the latter with the different bases other than DABCO, it was concluded
affording higher product yields.
that use of the latter in THF at 70 ꢀC was the best choice for the
Since only mixtures of C-3 and C-4 isomers were observed
Therefore, the performances of the reactions with these proposed transformation. Once suitably optimized conditions
bases were examined at higher temperatures, where formation were obtained, the scope of the reaction was examined with four
of a white precipitate was observed almost immediately; different 4-substituted thiophenols (2a–d) and three coumarins
however, these also furnished mixtures of isomers (entries 2, 9 (1a–c).
and 11). Aer some trial and error experiments, it was observed
As shown in Table 2, the use of DABCO as promoter
that heating a mixture of 1a, the thiol 2b and DMAP gave a 92 : 8 systematically resulted in the expected 4-substituted heterocy-
mixture of 3b and 4b in a satisfactory 74% overall yield (entry 7). cles (3a–l) in consistently high yields (71–97%).
ꢀ
Luckily, however, the use of DABCO in THF at 70 C, led to
From the analysis of these results, no clear trend emerged
the exclusive formation of 3b, the product substituted at C-4, in with regards to the effect of the substituents of both reaction
Table 2 Synthesis of 4-arylthiocoumarinsa
Entry no.
Coumarin no.
R1
R2
Thiophenol no.
R3
Product no.
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
H
H
H
H
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
H
Cl
Me
OMe
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
90
86
84
90
78
97
84
79
80
78
71
87
Cl
Me
OMe
H
Cl
Me
OMe
9
10
11
12
3j
3k
3l
a
Reaction conditions: 3-bromocoumarin (0.5 mmol), arenethiol (2, 0.75 mmol), THF (5 mL), DABCO (1.0 equiv.), 2 h. b Isolated yields by column
chromatography.
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components on the performance of the transformation. (alkane-a,u-diylbis(sulfanediyl))bis(coumarins). As shown in
However, it was observed that electron-donating and electron- Table 4, under our optimized conditions, the corresponding
withdrawing substituents on the thiol side were well tolerated. reactions of 1a with 5c and 5d gave good yields of the expected
Furthermore, the data revealed that the more acidic 4-chloro products 7a and 7b, respectively. Sadly, however, when analo-
thiophenol (2b, pKa ¼ 5.46)21b performed better with 6-chlor- gous transformations were attempted with the more reactive
ocoumarin (1b) than with its congeners, the heterocycles 1a and 1,2-ethanedithiol (5a) and 1,3-propanedithiol (5b), they met
1c (entry 6 vs. entries 2 and 10). Analogously, the less acidic 4- with failure, giving insoluble white solids, which could not be
methoxythiophenol (2d, pKa ¼ 6.21) gave better results in the analyzed by NMR.
presence of the coumarins 1a and 1c than with 1b (entries 4 and
12 vs. entry 8).
Noteworthy, compounds such as 7a and 7b are very rare. A
related 4,40-sulfanediyl-biscoumarin was prepared as a side
Taking advantage of the good performance of the trans- product of the reaction of 4-mercaptocoumarin with
formation when arenethiols were employed, and in order to diphenylketene.22
expand its scope, the reaction was also carried out with a,u-
On the other hand, their synthesis complements earlier work
dithiols (5a,d). Rewardingly, it was observed (Table 3) that in the by Drozd and coworkers who prepared analogous heterocycles
presence of the a,u-dithiols in excess, the reaction furnished in a more cumbersome way, by vinylic substitution on 3-nitro-4-
the expected 4-((u-mercaptoalkyl)thio)coumarins 6a,d.
halocoumarins.23
Thus, in the presence of 3.0 equiv. of the dithiols with three
Further, these authors also found out that the presence of
(5b) and six (5d) carbon atoms and 1.5 equiv. of the dithiol with a good leaving group on C-3 enables short chain dithiols to
ve carbon atoms (5c), the coumarin 1a afforded good yields of displace the leaving group, resulting in intramolecular cycliza-
the expected coumarin thiols 6b–d (71–79%, entries 2–4), with tion, to afford tricyclic products which carry 1, n + 2 dithiane
slightly decreased with the increase of the chain length. Con- motifs (n ¼ number of carbon atoms of the a,u-dithiol), and
trastingly, however, only a meagre 39% yield of 6a was isolated bear sulfur atoms attached to both positions, C-3 and C-4. In
(entry 1), despite the use of 3.0 equiv. of the more reactive 1,2- addition, they discovered that 4-((u-mercaptoalkyl)thio)
ethanedithiol (5a).
Encouraged by these results, the scope of this selective sul- running the transformation at low temperature.
fanylation was also explored in the presence of excess of the It was reported that a-bromo Michael acceptors such as
coumarins can be preferentially obtained (<40% yield) by
coumarin 1a, aiming to obtain the more challenging 4,40- ketones and esters, react with thiols to undergo ipso-
Table 3 Synthesis of 4-((u-mercaptoalkyl)thio)coumarinsa
Entry no.
1
a,u-Dithiol no.
a,u-Dithiol (equiv.)
n
Product
Product no.
Yieldb (%)
39
5a
3.0
2
6a
2
3
5b
5c
3.0
1.5
3
5
6b
6c
79
74
4
5d
3.0
6
6d
71
a
b
Reaction conditions: 3-bromocoumarin (1a, 1 mmol), a,u-dithiol, THF (5 mL), DABCO (1.5 equiv.), 2 h. Isolated yields by column
chromatography.
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Table 4 Synthesis of 4,40-(alkane-a,u-diylbis(sulfanediyl))bis(coumarins)
a,u-Dithiol
no.
Entry no.
1
n
Product
Product no.
Yielda (%)
86
5c
5
7a
2
5d
6
7b
65
a
Isolated yields by column chromatography, based on the a,u-dithiols. Excess 3-bromocoumarin 1a (3.0 equiv.) and DABCO (3.0 equiv.) were
employed.
substitution, furnishing the a-sulfanyl derivatives alone or in coumarin intermediate and returning the nucleophilic catalyst
mixtures with the corresponding dithiosubstituted com- DABCO to the reaction medium. If the transformation path
pounds.20c,24a,b Further, cyclic a-haloenones react with thiols takes the Route a, the structure of this intermediate is ii, which
providing mainly the a-sulfanyl derivatives,24c and a-haloenals can then undergo a base-mediated dehydrohalogenation to
derived from crotonaldehyde and cinnamaldehyde gave furnish the expected 4-sulfanylcoumarin 3.
moderate yield of the ipso-substitution product upon reaction
with butanethiol.24d,e
Some literature precedents suggest that, at least in the case
of the coumarins, both stages, the formation intermediate ii as
The actual case is different and, although the exact reaction well as its dehydrohalogenation, should be stereospecic
mechanism of the disclosed transformations remains processes, with the latter stage being an 1,2-anti-type elimi-
unknown, a good mechanistical picture can be drawn based on nation.25c In view of the observed results, it is most likely that
literature precedents.25a As shown in Scheme 2, it can be
assumed that the addition of DABCO effects deprotonation of
the acidic thiol moieties 2 and results in the formation of the
thiolate anions (2Sꢁ), which are stronger nucleophiles and can
react with the a,b-unsaturated carbonyl system of 1a.
In general, the a,b-unsaturated carbonyl system of couma-
rins is prone to undergo a Michael type (C-4) addition, and it
has been observed that the latter transformation takes place
preferentially in these heterocycles when they are 3,4-disubsti-
tuted with good leaving groups, such as halides and
sulfonates.7b,25b
This in sharp contrast with the reactivity of the neighbor C-3
position. It is known that in a,b-unsaturated carbonyl systems
like those of coumarins, when an halogen atom is placed at the
a-position to the carbonyl moiety (C-3), the activation of the a-
carbon atom is usually too low to afford a substitution product
via an addition–elimination mechanism. Therefore, all the
reactivity characteristics of the coumarin unsaturated system
strongly favor a C-4 attack.
Accordingly, the thiolate anions might trigger a thia-Michael
addition, where the incoming nucleophile becomes attached to
the b-end of the double bond (C-4) system, resulting in the
Scheme 2 Plausible reaction mechanism for the DABCO-promoted
enolate intermediate i. In turn, the latter may capture a proton
selective sulfanylation of 3-bromocoumarins to afford 4-sulfa-
nylcoumarins 3.
(from DABCOH+), furnishing a 3,4-disubstituted 3,4-dihydro
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the bulk of DABCO, a sterically hindered tertiary amine, may I2 or H2SO4/vanillin solution. The chromatographic purica-
play some key role in inducing the delivery of the proton to tions were carried out by column chromatography employing
intermediate i in an anti-fashion to the incoming sulfur reac- silica gel (230–400 mesh, 40–63 mm) and eluting with hexane–
tant, to selectively afford the intermediate ii.
EtOAc (10 : 1, v/v).
Notably, when the transformation of 1a with thiol 2b was
performed in the presence of a small amount of D2O (z0.1 mL),
it was observed that the product 3b exhibited deuteration on C-3
Equipment
(d 5.62 ppm),25c,d as stemmed from the reduction of its 1H NMR The melting points were taken on a MQAPF-301 melting point
resonance integral, clearly demonstrating the participation of apparatus and are reported uncorrected.
intermediates i and ii in the reaction. Furthermore, a GC/MS
analysis of the reaction products conrmed this observation, MHz NMR spectrometer, with the samples dissolved in CDCl3,
and indicated over 90% deuterium incorporation.
unless otherwise noted. The chemical shis are informed
The 1H and 13C NMR spectra were recorded on a Bruker 400
Interestingly, Nambara found out that the reaction between in ppm downeld from the signal of TMS, used as internal
thiophenol and 3-bromothiachromone-1,1-dioxide affords 2- standard, and the coupling constants (J) are expressed in Hertz
phenylsufanylthiachromone-1,1-dioxide. Despite the reaction (Hz).
may take place through an analogous mechanism, it is note-
The high-resolution mass spectral data were obtained on
worthy that the transformation was performed in KOH,20a which a LTQ Orbitrap Discovery mass spectrometer (Thermo Fisher
proved to give unsatisfactory results in the case of 1a. In addi- Scientic), using sodium formate as reference.
tion, a similar mechanism may be at the heart of a recently
3-Bromo-6-chlorocoumarin (1b).19 A stirred mixture of sali-
reported modication of Fiesselmann's thiophene synthesis.25e cylaldehyde (1.22 g, 10 mmol) and TsOH$H2O (3.8 g, 20 mmol)
Alternatively, the reaction could take place through Route in MeCN (100 mL) was treated with NCS (1.33 g, 10 mmol) and
b and proceed through the intermediacy of iii, which has the the system was stirred at room temperature for 4 h. The reaction
proper geometric array for an intramolecular attack by the was diluted with H2O (20 mL) and extracted with EtOAc (4 ꢂ 25
sulfur moiety of the sulfanyl group from behind to the bromine mL). The combined extracts were dried over MgSO4, concen-
atom, to furnish the episulfonium (thiiranium) ion interme- trated under reduced pressure. The residue was chromato-
diate iv.20e This step entails a 3-exo-tert process,24e which is graphed affording 4-chloro salicylaldehyde (1.29 g, 81%), as
favorable according to Baldwin's rules. In turn, the intermediate a white solid. 1H NMR d 10.9 (s, OH), 9.85 (s, 1H), 7.53 (d, J ¼ 2.6,
iv could suffer an attack of the base on the most acidic a- 1H), 7.47 (dd, J ¼ 2.6, 8.9, 1H) and 6.96 (d, J ¼ 8.9, 1H).28a
carbonyl hydrogen, resulting in opening of the strained epis- Without further purication, the aldehyde (3.13 g, 20 mmol)
ulfonium ion ring, to nally give the 3-sulfanylcoumarin 4.
was mixed with meldrum acid (2.88 g, 20 mmol) in H2O (100
The same outcome could be achieved by means of either mL) and the stirred reaction was warmed to 75 ꢀC for 2 h. Then,
a thiolate-mediated nucleophilic ring opening of intermediate the reaction was cooled to room temperature and the solid
iv, or a nucleophilic bromide substitution on intermediate iii, obtained was ltered employing a sintered glass funnel. The
followed in both cases by elimination of a molecule of thio- solid was washed with ice water (5 mL) and Et2O (5 mL) and
l,20e,24c,24e which would result in a formal ipso-substitution of the further dried under high vacuum to afford 6-chlorocoumarin-3-
1
halogen atom. This sequence of events is reminiscent of intra- carboxylic acid (3.57 g, 80%), as a white solid. H NMR d 10.01
cellular reactions of molecules containing the a-haloacryloyl (s, 1H), 8.64 (s, 1H), 7.73 (d, J ¼ 2.4, 1H), 7.63 (dd, J ¼ 2.5, 8.9,
motif with biological thiols in living organisms, which generate 1H), 7.35 (d, J ¼ 8.9, 1H).28b Next, the coumarin (0.898 g, 4
episulfonium ion intermediates; the latter are DNA-alkylating mmol) and LiOAc (0.397 g, 4.8 mmol) were dissolved in a MeCN/
agents and play a key role in processes of DNA-damaging and H2O mixture (10 : 1, v/v). Aer 5 minutes, the stirred reaction
cytotoxicity.26
was treated with NBS (0.748 g, 4.2 mmol) and allowed to further
Contrastingly, however, in the actual case and under DABCO stir overnight at room temperature. Then, the reaction was
promotion in reuxing THF, no 3-thio-substituted coumarin diluted with H2O (10 mL) and extracted with EtOAc (3 ꢂ 25 mL);
derivatives 4 were isolated in any of the studied cases. the combined organic phases were washed with brine (10 mL),
Furthermore, the high yields recorded in most of the examples dried over MgSO4 and concentrated under reduced pressure.
suggest that the reaction takes place exclusively through Route Chromatographic purication of the residue afforded 1b
a or that involvement of Route b, if any, should be minimal.
(0.838 g, 81%), as a white solid, mp 174 ꢀC (lit. 172–174 ꢀC). 1H
NMR d 8.02 (s, 1H), 7.51 (dd, J ¼ 2.4, 8.8, 1H), 7.44 (d, J ¼ 2.4,
1H), 7.29 (d, J ¼ 8.8, 1H).19
Experimental
General information
8-Methylcoumarin.28c Propiolic acid (1.26 g, 18 mmol) was
added to a stirred solution of ortho-cresol (1.62 g, 15 mmol) and
The solvents were puried and dried according to usual Ce(OTf)3 (0.587 g, 1 mmol) in MeSO3Hꢀ (15 mL) at room
procedures.27 The reagents for synthesis were obtained temperature. The system was heated at 90 C and stirred over-
commercially and were used as received, without further puri- night. Then, H2O (20 mL) was added and the product was
cation. The progress of the reactions was monitored by thin extracted with EtOAc (3 ꢂ 25 mL). The combined organic pha-
layer chromatography on silica gel GF254 plates. For detection of ses were washed with brine (10 mL), dried over MgSO4 and
the spots the plates were exposed to UV light (254 and 365 nm), concentrated under reduced pressure. Chromatography of the
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residue gave 8-methylcoumarin (0.721 g, 30%), as a white solid, 159.8, 159.0, 152.4, 137.8 (2C), 132.4, 124.2, 123.8, 118.1, 117.3,
mp 106 ꢀC (lit. 106–107 ꢀC). 1H NMR d 7.68 (d, J ¼ 9.5, 1H), 7.39– 116.5, 116.2 (2C), 108.3 and 55.7. HRMS: m/z calcd for
7.35 (m, 1H), 7.33–7.29 (1H), 7.17 (t, J ¼ 7.6, 1H), 6.40 (d, J ¼ 9.5,
C
16H13O3S [M + H]+: 285.0580; found: 285.0573.
6-Chloro-4-(phenylthio)-2H-chromen-2-one (3e).29a Yellowish
1H) and 2.45 (s, 3H).
3-Bromocoumarin (1a) and 3-bromo-8-methylcoumarin solid (113 mg, 78%), mp 202–204 ꢀC. 1H NMR d 7.82 (d, J ¼ 2.4,
(1c).18 Oxone (7.4 g, 12 mmol) was added to a solution of the 1H), 7.62–7.49 (m, 6H), 7.30–7.27 (m, 1H) and 5.66 (s, 1H). 13C
corresponding coumarin (10 mmol) in CH2Cl2 (40 mL) and the NMR d 159.0, 156.9, 150.8, 136.2 (2C), 132.4, 131.2, 130.7 (2C),
system was treated dropwise with 48% HBr (2.5 mL, 22 mmol) 129.8, 125.8, 123.5, 119.0, 118.7 and 109.2.
dissolved in H2O (15 mL). The reaction was stirred at room
6-Chloro-4-((4-chlorophenyl)thio)-2H-chromen-2-one
(3f).
temperature for 4 h, when Et3N (8.7 mL) was added and then, it White solid (156 mg, 97%), mp 164–166 ꢀC. 1H NMR d 7.76 (d, J
was allowed to stir overnight. The reaction was diluted with H2O ¼ 2.4, 1H), 7.54–7.47 (m, 5H), 7.26 (d, J ¼ 8.8, 1H) and 5.63 (s,
(40 mL) and extracted with CH2Cl2 (3 ꢂ 25 mL). The combined 1H). 13C NMR d 158.6, 156.1, 150.7, 137.9, 137.3 (2C), 132.4,
organic layers were dried over MgSO4, concentrated under 130.9 (2C), 129.8, 124.2, 123.3, 118.7, 118.7 and 109.4. HRMS: m/
reduced pressure and chromatographically puried to afford 1a z calcd for C15H9O2SCl2 [M + H]+: 322.9695; found: 322.9687.
(R ¼ H; 1.88 g, 84%), as a white solid, mp 110 C (lit. 110–111
6-Chloro-4-(p-tolylthio)-2H-chromen-2-one (3g).7a White
ꢀ
ꢀC). 1H NMR d 8.11 (s, 1H), 7.60–7.55 (m, 1H), 7.49–7.45 (m, 1H) solid (127 mg, 84%), mp 190–191 ꢀC. 1H NMR d 7.82 (d, J ¼ 2.4,
and 7.37–7.29 (m, 2H). Compound 1c (R ¼ 8-Me) was obtained 1H), 7.51 (dd, J ¼ 8.8, 2.4, 1H), 7.48–7.42 (m, 2H), 7.35–7.30 (m,
in a similar fashion (1.62 g, 68%), as a yellowish solid, mp 2H), 7.27 (d, J ¼ 8.8, 1H), 5.65 (s, 1H), 2.44 (s, 3H). 13C NMR
1
ꢀ
ꢀ
128 C (lit. 127–129 C). H NMR d 8.07 (s, 1H), 7.41–7.38 (m, d 159.1, 157.4, 150.9, 141.9, 136.1 (2C), 132.3, 131.5 (2C), 129.8,
1H), 7.30–7.26 (m, 1H), 7.20 (t, J ¼ 7.6, 1H) and 2.46 (s, 3H).
123.5, 122.3, 119.1, 118.7, 109.2 and 21.5.
6-Chloro-4-((4-methoxyphenyl)thio)-2H-chromen-2-one (3h).
1
ꢀ
White solid (126 mg, 79%), mp 106–108 C. H NMR d 7.81 (s,
1H), 7.52–7.46 (m, 3H), 7.29–7.25 (m, 1H), 7.05–7.00 (m, 2H),
5.64 (s, 1H), 3.88 (s, 3H). 13C NMR d 162.1, 159.0, 157.8, 150.9,
General procedure for the 4-sulfanylation of 3-
bromocoumarins
The coumarin (0.5 mmol) was transferred to a 25 mL two- 137.8 (2C), 132.3, 129.8, 123.5, 119.1, 118.7, 116.3 (2C), 116.0,
necked round bottomed ask containing THF (3 mL) and the 109.0 and 55.7. HRMS: m/z calcd for C16H12O3SCl [M + H]+:
ꢀ
mixture was heated to 70 C. Then, the thiol (0.75 mmol) and 319.0190; found: 319.0185.
DABCO (0.5 mmol) were successively added (specic modica-
8-Methyl-4-(phenylthio)-2H-chromen-2-one (3i). White solid
tions to the amounts of the reagents of this protocol are given in (106 mg, 80%), mp 149–151 ꢀC. 1H NMR d 7.71 (d, J ¼ 8.0, 1H),
the tables). The reaction was monitored by TLC. Upon complete 7.62–7.49 (m, 5H), 7.42 (d, J ¼ 7.4, 1H), 7.21 (t, J ¼ 7.7, 1H), 5.64
consumption of the starting material, the reaction was diluted (s, 1H), 2.45 (s, 3H). 13C NMR d 159.8, 158.4, 150.8, 136.2 (2C),
with H2O (10 mL) and the products were extracted with EtOAc; 133.7, 130.9, 130.5 (2C), 126.8, 126.7, 123.8, 121.5, 117.7, 108.4
the combined organic extracts were washed with 10% w/v and 15.9. HRMS: m/z calcd for C16H13O2S [M + H]+: 269.0631;
Na2CO3 solution, dried over MgSO4 and concentrated under found: 269.0628.
reduced pressure. The residue was puried by column chro-
4-((4-Chlorophenyl)thio)-8-methyl-2H-chromen-2-one (3j).
matography. In the labelling experiment, D2O (0.1 mL) were White solid (118 mg, 78%), mp 160–162 ꢀC. 1H NMR d 7.69–7.64
mixed with the thiol and the coumarin, before adding DABCO. (m, 1H), 7.55–7.46 (m, 4H), 7.44–7.40 (m, 1H), 7.21 (t, J ¼ 7.7,
4-(Phenylthio)-2H-chromen-2-one (3a).7d,29a–c White solid 1H), 5.62 (s, 1H) and 2.45 (s, 3H). 13C NMR d 159.5, 157.7, 150.8,
1
ꢀ
(114 mg, 90%), mp 150–152 C. H NMR d 7.88–7.84 (m, 1H), 137.7, 137.4 (2C), 133.9, 130.8 (2C), 126.9, 125.2, 123.8, 121.4,
7.63–7.49 (m, 6H), 7.37–7.29 (m, 2H) and 5.64 (s, 1H). 13C NMR 117.6, 108.6 and 15.9. HRMS: m/z calcd for C16H12O2SCl [M +
d 159.7, 158.1, 152.3, 136.2 (2C), 132.4, 131.0, 130.6 (2C), 126.3, H]+: 303.0241; found: 303.0244.
124.3, 123.8, 117.9, 117.3 and 108.5.
8-Methyl-4-(p-tolylthio)-2H-chromen-2-one (3k). White solid
4-((4-Chlorophenyl)thio)-2H-chromen-2-one (3b).29a,c White (98 mg, 71%), mp 141–143 ꢀC. 1H NMR d 7.73–7.67 (m, 1H),
1
ꢀ
solid (124 mg, 86%), mp 103–104 C. H NMR d 7.83–7.79 (m, 7.48–7.43 (m, 2H), 7.43–7.39 (m, 1H), 7.33–7.29 (m, 2H), 7.21 (t, J
1H) 7.59–7.46 (m, 5H), 7.34–7.28 (m, 2H) and 5.62 (s, 1H). 13C ¼ 7.7, 1H), 5.62 (s, 1H), 2.45 (s, 3H) and 2.43 (s, 3H). 13C NMR
NMR d 159.3, 157.2, 152.3, 137.7, 137.4 (2C), 132.5, 130.8 (2C), d 159.8, 158.9, 150.8, 141.5, 136.1 (2C), 133.6, 131.3 (2C), 126.8,
124.8, 124.3, 123.7, 117.7, 117.3 and 108.7.
123.7, 123.1, 121.5, 117.8, 108.2, 21.5 and 15.9. HRMS: m/z calcd
4-(p-Tolylthio)-2H-chromen-2-one (3c).7a Yellowish solid for C17H15O2S [M + H]+: 283.0787; found: 283.0799.
(113 mg, 84%), mp 142–144 ꢀC. 1H NMR d 7.86 (dd, J ¼ 7.9, 1.5,
4-((4-Methoxyphenyl)thio)-8-methyl-2H-chromen-2-one (3l).
1H), 7.59–7.53 (m, 1H), 7.50–7.43 (m, 2H), 7.36–7.29 (m, 4H), White solid (129 mg, 87%), mp 199–201 ꢀC. 1H NMR d 7.72–7.69
5.63 (s, 1H) and 2.43 (s, 3H). 13C NMR d 159.7, 158.5, 152.4, (m, 1H), 7.52–7.46 (m, 2H), 7.44–7.39 (m, 1H), 7.21 (t, J ¼ 7.7,
141.6, 136.1 (2C), 132.3, 131.3 (2C), 124.2, 123.8, 122.7, 118.0, 1H), 7.04–7.00 (m, 2H), 5.61 (s, 1H), 3.88 (s, 3H) and 2.45 (s, 3H).
117.3, 108.3 and 21.5.
13C NMR d 161.9, 159.8, 159.3, 150.8, 137.8 (2C), 133.6, 126.7,
4-((4-Methoxyphenyl)thio)-2H-chromen-2-one (3d). White 123.7, 121.4, 117.7, 116.8, 116.2 (2C), 108.0, 55.6 and 15.9.
1
solid (128 mg, 90%), mp 154–156 C. H NMR d 7.88–7.83 (m, HRMS: m/z calcd for C17H15O3S [M + H]+: 299.0736; found:
ꢀ
1H), 7.59–7.53 (m, 1H), 7.52–7.47 (m, 2H), 7.36–7.29 (m, 2H), 299.0739.
7.05–7.00 (m, 2H), 5.62 (s, 1H) and 3.88 (s, 3H). 13C NMR d 161.9,
488 | RSC Adv., 2020, 10, 482–491
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following anti-elimination step and precludes thiirane forma-
tion, to afford only 4-substituted coumarins. This approach is
simple and metal-free; therefore, it may nd application in the
synthesis of other relevant compounds from the biological,
functional or structural points of view.
4-((2-Mercaptoethyl)thio)-2H-chromen-2-one (6a). White
1
solid (92 mg, 39%), mp 138–140 ꢀC. H NMR d 7.77–7.71 (m,
1H), 7.59–7.52 (m, 1H), 7.37–7.26 (m, 2H), 6.16 (s, 1H), 3.32–3.26
(m, 2H), 2.96–2.88 (m, 2H), 1.79 (t, J ¼ 8.4, 1H). 13C NMR d 159.3,
155.3, 152.4, 132.5, 124.3, 124.0, 118.2, 117.4, 107.2, 34.6 and
23.0. HRMS: m/z calcd for C11H11O2S2 [M + H]+: 239.0195;
found: 239.0198.
Conflicts of interest
4-((3-Mercaptopropyl)thio)-2H-chromen-2-one (6b). White
1
ꢀ
There are no conicts of interest to declare.
solid (99 mg, 79%), mp 79–81 C. H NMR d 7.73 (dd, J ¼ 8.0,
1.5, 1H), 7.56–7.51 (m, 1H), 7.35–7.31 (m, 1H), 7.30–7.24 (m,
1H), 3.18 (t, J ¼ 6.5, 2H), 2.75–2.70 (m, 2H), 2.14–2.08 (m, 2H)
and 1.45 (t, J ¼ 8.2, 1H). 13C NMR d 159.3, 156.0, 152.3, 132.3,
124.2, 124.0, 118.3, 117.4, 107.2, 31.6, 29.0 and 23.5. HRMS: m/z
calcd for C12H13O2S2 [M + H]+: 253.0351; found: 253.0345.
4-((5-Mercaptopentyl)thio)-2H-chromen-2-one (6c). White
solid (103 mg, 74%), mp 89–91 ꢀC. 1H NMR d 7.73 (dd, J ¼ 8.0,
1.5, 1H), 7.56–7.50 (m, 1H), 7.33–7.23 (m, 2H), 6.13 (s, 1H), 3.02
(t, J ¼ 7.3, 2H), 2.60–2.52 (m, 2H), 1.86–1.79 (m, 2H), 1.73–1.56
(m, 4H) and 1.37 (t, J ¼ 7.8, 1H). 13C NMR d 159.2, 156.4, 152.1,
132.1, 124.0, 123.8, 118.2, 117.1, 106.8, 33.3, 30.7, 27.6, 27.2 and
24.3. HRMS: m/z calcd for C14H17O2S2 [M + H]+: 281.0664;
found: 281.0674.
Acknowledgements
The authors are thankful to CNPq, CAPES and CONICET for
nancial support.
Notes and references
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15H19O2S2 [M + H]+: 295.0821; found: 295.0823.
4,40-(Pentane-1,5-diylbis(sulfanediyl))bis(2H-chromen-2-
one) (7a). White solid (364 mg, 86%), mp. 164–165 ꢀC. 1H NMR
d 7.74–7.70 (m, 2H), 7.56–7.50 (m, 2H), 7.32–7.23 (m, 4H), 6.14
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(2C), 30.6 (2C), 28.3 (2C) and 27.3 (1C). HRMS: m/z calcd for
C
23H21O4S2 [M + H]+: 425.0876; found: 425.0857.
4,40-(Hexane-1,6-diylbis(sulfanediyl))bis(2H-chromen-2-one)
(7b). White solid (247 mg, 65%), mp 185–187 ꢀC. 1H NMR d 7.68
(d, J ¼ 8.0, 1.4, 2H), 7.50–7.44 (m, 2H), 7.28–7.24 (m, 2H), 7.23–
7.17 (m, 2H), 6.08 (s, 2H), 2.97 (t, J ¼ 7.3, 4H), 1.83–1.74 (m, 4H)
and 1.55–1.49 (m, 4H). 13C NMR d 159.5 (2C), 156.6 (2C), 152.4
(2C), 132.3 (2C), 124.2 (2C), 124.0 (2C), 118.4 (2C), 117.4 (2C),
107.0 (2C), 30.8 (2C), 28.6 (2C) and 27.7 (2C). HRMS: m/z calcd
for C24H23O4S2 [M + H]+: 439.1032; found. 439.1036.
Conclusion
In conclusion, we have developed an efficient DABCO-promoted
approach for the direct 4-sulfanylation of 3-bromocoumarins, to
afford a ready access to different 4-organylsulfanyl-coumarin
derivatives in good yield. This methodology entails a one-pot
thia-Michael addition/dehydrobromination process and
results in a direct C–S bond formation.
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