Catalyst-free synthesis of 3,1-benzoxathiin-4-ones/1,3-benzodioxin-4-ones

Article abstract of DOI:10.1039/d0ob02543g

An unambiguous and precise method for the synthesis of 3,1-benzoxathiin-4-ones/1,3-benzodioxin-4-ones by the reaction of propargylic alcohols and salicylic/thiosalicylic acids under a catalyst-free and open-air atmosphere is described. This strategy is found to be quite general using various 2-mercapto and 2-hydroxybenzoic acids providing benzoxathiinones/benzodioxinones in good yields.

Full text of DOI:10.1039/d0ob02543g

Organic &
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Catalyst-free synthesis of 3,1-benzoxathiin-
4-ones/1,3-benzodioxin-4-ones†
Cite this: Org. Biomol. Chem., 2021,
19, 1508
Sengodagounder Muthusamy, *a Muthukumar Malarvizhi a and
Received 20th December 2020,
Accepted 26th January 2021
b
Eringathodi Suresh
DOI: 10.1039/d0ob02543g
rsc.li/obc
An unambiguous and precise method for the synthesis of 3,1-ben-
However, benzo[d][1,3]dioxin-4-ones play an important role
zoxathiin-4-ones/1,3-benzodioxin-4-ones by the reaction of pro- in natural products; maldoxin6,7 and drug research; nucleoside
pargylic alcohols and salicylic/thiosalicylic acids under a catalyst- base transporter inhibitors,8 and antiplasmoidal and cyto-
free and open-air atmosphere is described. This strategy is found toxicity9 topoisomerase I inhibitors10 (Fig. 1). These com-
to be quite general using various 2-mercapto and 2-hydroxyben- pounds act as potential intermediates and could be converted
zoic acids providing benzoxathiinones/benzodioxinones in good into flavones, aurones and phloroglucinols.11 Benzodioxinones
yields.
have been useful for the synthesis of chromones via nickel
catalyzed cycloaddition with alkynes12 and they act as photoi-
nitiators for free radical polymerization13 and undergo photo-
lytic reactions with alcohols to form salicylate derivatives.14
Natural products possessing a rare 1,3-benzodioxin-4-one
Heterocycles form the largest classical division of organic
chemistry and are of massive importance biologically and
industrially. One of the striking structural features1 inherent to
heterocycles, which continue to be exploited to great advantage
by the drug industry, lies in their ability to manifest substitu-
ents around a core scaffold in a defined three-dimensional rep-
resentation. Among them, sulfur- and oxygen-containing
heterocyclic compounds have attracted the interest of research-
ers through decades of historical development of organic syn-
thesis.2 The relevance of heterocycles having oxygen and sulfur
atoms comes from the significant changes in the cyclic mole-
cular structure caused by the difference in the electronic con-
figuration, unshared pair of electrons and ultimately the
electronegativity between the heteroatom and carbon.3
3,1-Benzoxathiin-4-ones are typically derived from the reac-
tion of 2-mercaptobenzoic acid and the significance of this
class of molecules gets further impetus due to their involve-
ment as intermediates in the synthesis of biologically active
scaffolds. The synthesis and reactivity of benzoxathiin-4-ones
have not been extensively studied so far as only a few reports
are available for the synthesis of 3,1-benzoxathiin-4-ones.4
Noticeably, 3,1-benzoxathiin-4-ones have been known as insec-
ticides,5a crop protection agents5b and fungicides5c (Fig. 1).
aSchool of Chemistry, Bharathidasan University, Tiruchirappalli-620 024, India.
E-mail: muthu@bdu.ac.in; Tel: +91-431-2407053
bAnalytical Discipline and Centralized Instrumentation Facility, Central Salt &
Marine Chemicals Research Institute, Bhavnagar-364 002, India
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra.
CCDC 2044131 and 2044132. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/d0ob02543g
Fig. 1 Bioactive molecules possessing 3,1-benzoxathiin-4-ones/1,3-
benzodioxin-4-ones.
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Table 1 Survey of reaction conditions for 3,1-benzoxathiin-4-ones
(3a)a,b
scaffold, synnemadoxins A & B (Fig. 1), were isolated from the
Synnemapestaloides species and evaluated for their anti-
microbial, antifungal and antibiotic activities.15
Nishina and co-workers developed16 the synthesis of ben-
zoxathiinones through regioselective hydrothiolation of
alkynes with a palladium catalyst (Scheme 1). Kawatsura and
co-workers demonstrated17 the iron-catalyzed intermolecular
coupling of alkynes with thiosalicylic acid for the synthesis of
3,1-benzoxathiinone derivatives through intermolecular hydro-
thiolation and sequential intramolecular cyclization. Both
terminal and substituted ynones have been used to prepare
4H-benzo[d][1,3]dioxin-4-ones in the presence of a base, tri-
ethylamine18 or morpholine.19 The preparation of benzoxathii-
nones and benzodioxinones involving strong acidic/basic con-
ditions, transition metal catalysts, toxic reagents, and high
cost and also existing as intermediates in some cases have
severe drawbacks for industrial applications. In continuation
of our effort20 to explore the chemistry of propargyl alcohols,
we herein report a method for the synthesis of 3,1-benzox-
athiin-4-ones/1,3-benzodioxin-4-ones from the reaction of pro-
pargylic alcohols and salicylic acids without any catalyst under
open-air atmosphere.
Entry Catalyst
Solvent
T (°C)
t (h) Yield (%) 3a b
1
2
3
4
5
6
7
8
FeCl3
Cu(OAc)2
Pd(OAc)2
Pd(OAc)2
Fe(acac)2
Cu(acac)2
AgNO3
PdCl2(PPh3)2
Pd(dba)2
NiCl2
—
—
—
—
—
—
—
—
—
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
1,4-Dioxane Reflux 12
DMF
Benzene
H2O
C6H5F
Rt
Rt
Rt
12
12
12
45
40
78
82
43
51
61
52
46
21
86
Trace
25
31
48
nrc
23
51
41
46
Reflux 12
Reflux 12
Reflux 12
Reflux 12
Reflux 24
Reflux 16
Reflux 15
Reflux 12
Reflux 12
9
10
11
12
13
14
15
16
17
18
19
20
Reflux 12
Reflux 12
Reflux 12
Reflux 12
Reflux 12
Reflux 12
Reflux 12
Our initial investigation began with the examination of
different catalysts and reaction conditions for the reaction of
thiosalicylic acid 1 with propargylic alcohol 2a (Table 1). A
wide variety of transition metals promoted the hydrothiola-
tion/intramolecular cyclization sequence. To achieve this, the
C6H5Cl
o-Xylene
m-Xylene
—
Entry 11 is the optimized best reaction conditions for this
transformation. a Reaction conditions: Reaction of thiosalicylic acid 1
and propargylic alcohol 2a was carried out in 10 mL of solvent under
open-air atmosphere. b Yield of the isolated product after column
chromatography. c nr = no reaction.
reaction of an equimolar amount of thiosalicylic acid 1, pro-
pargylic alcohol 2a and 5 mol% of FeCl3 in toluene at room
temperature for 12 h resulted in the formation of benzox-
athiin-4-one 3a in 45% isolated yield (Table 1, entry 1). The
structure of compound 3a was confirmed using IR, NMR and
HRMS analyses. A low product yield was observed when the
reaction was performed in the presence of Cu(OAc)2 as a cata-
lyst at room temperature (Table 1, entry 2). The reaction was
repeated in toluene in the presence of 5 mol% Pd(OAc)2 as a
catalyst at room temperature to provide 78% yield of 3a
(Table 1, entry 3). The above reaction was performed under
reflux conditions to obtain 3a in 82% yield (Table 1, entry 4).
Then, common metal catalysts, Fe(acac)2, Cu(acac)2, AgNO3,
PdCl2(PPh3)2, Pd(dpa)2 and NiCl2, were also investigated with
varying reaction times (Table 1, entries 5–10), but a low yield
of product 3a was obtained. On the other hand, the reaction
was performed without adding a catalyst under reflux con-
ditions for 12 h to afford 3a in 86% yield (Table 1, entry 11).
Besides, the screening of numerous solvents was incompatible
for the synthesis of the desired product 3a (Table 1, entries
12–20). Finally, the optimized reaction conditions were found
to be as follows: no catalyst and use of toluene under reflux
conditions under open-air atmosphere for the formation of 3a
(Table 1, entry 11).
Scheme 1 Synthesis of 3,1-benzoxathiin-4-ones/1,3-benzodioxin-4-
ones.
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With the optimized reaction conditions, we eventually groups at the R2 position of propargylic alcohol, and the
tested the substrate array for the synthesis of 1,3-benzoxathiin- needed product 3h was formed in good yield. The alkyl substi-
4-ones 3a–k using thiosalicylic acid 1 and propargylic alcohols tuent at the R2 position in propargylic alcohol was also found
2a–k as illustrated in Table 2. Various propargylic alcohols to yield 79% of product 3i. Furthermore, t-butyl and pentoxy
reacted with thiosalicylic acid to give 3,1-benzoxathiin-4-ones phenyl substituted groups at the R2 position of propargylic
3a–k in good yields. The electron-withdrawing and -donating alcohols enabled excellent yields of 3,1-benzoxathiin-4-ones
groups present on the propargylic alcohol were well tolerated 3j–k. The product 3e was re-crystallized using hexane/EtOAc as
to afford the desired 3,1-benzoxathiin-4-ones 3b–e in good colourless crystals and single-crystal X-ray analysis was per-
yields. Fluorenyl propargylic alcohol also reacted efficiently to formed21 to unambiguously confirm the proposed structure
provide 3f. The scope of R2 as p-MeC6H4 in propargylic alcohol and its solid-state structure shows C–H⋯O, C–H⋯F and C–
to provide 3g in 91% yield was also determined. Furthermore, H⋯π interactions. Regrettably, the desired product was not
the scope of this reaction was tested with cyclopropyl and alkyl formed when using 2-mercaptonicotinic and 3-mercaptopicoli-
nic acids and this may be due to the presence of tautomerism
and the involvement of the pyridine ring during the course of
the reaction.
Table 2 Catalyst free synthesis of 3,1-benzoxathiin-4-ones (3)a
This protocol was further extended to salicylic acid 4a with
propargylic alcohol 2a in a similar manner to yield product 5a
in 70% yield and product 6a in 30% yield via a Meyer–Schuster
rearrangement (Table 3, entry 1). This may be due to the lower
nucleophilicity of oxygen in salicylic acid 4 than sulphur in
thiosalicylic acid 1. In order to avoid the byproduct 6a, the
screening of various solvents was performed but it was
unsuited for this transformation (Table 3, entries 2–5).
Furthermore, the flow rate of propargyl alcohol 2a was con-
trolled using a syringe pump, and it was helpful in minimizing
the product 6a via a Meyer–Schuster rearrangement (Table 3,
entries 6–8). The addition of propargyl alcohol 2a was carried
out with a 0.2 mL h−1 flow rate using a syringe pump to
provide more than 99% yield of product 5a with a trace
amount of 6a based on HPLC (Table 3, entry 8). With the
above information in hand, the optimized reaction conditions
of 1,3-benzodioxinones were found to be the controlled
addition (0.2 mL h−1) of propargyl alcohol 2a into salicylic acid
Table 3 Survey of reaction conditions for 1,3-benzodioxin-4-ones (5a)a
Entry Solvent
Flow-rate of 2a (mL h−1
)
t (h) Yield (%) 5a/6a b
1
2
3
4
5
6
7
8
Toluene
p-Xylene
Benzene
DMF
—
—
—
—
—
1
12
12
12
12
12
5
70/30
15/57
—/69
nrc
DMSO
nrc
Toluene
Toluene
Toluene
92/8
98/2
99/—
0.4
0.2
8
10
Entry
8 is the optimized best reaction conditions for this
a Reaction conditions: Reactions of thiosalicylic acid 1 (1.0 equiv.) and transformation. a Reaction conditions: Reaction of equimolar amounts
propargylic alcohols 2a–k (1.0 equiv.) were carried out in 10 ml of of salicylic acid 4a and propargylic alcohol 2a was carried out in 10 mL
toluene under reflux conditions under open-air atmosphere for 12 h. of solvent under reflux conditions under open-air atmosphere. b Yield
b Yield of the isolated product after column chromatography.
of the product based on HPLC. c nr = no reaction.
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4a in the absence of any catalyst in toluene under reflux con-
ditions under open-air atmosphere for the formation of 5a
(Table 3, entry 8). Furthermore, the scope of propargylic alco-
hols was tested using these optimized reaction conditions
(Table 4). Reactions of propargylic alcohols bearing either elec-
tron-donating or -withdrawing groups were performed for this
transformation to furnish products 5b–c. Furthermore, the
scope of salicylic acids for these reactions was examined.
Chloro-substituted salicylic acid worked well compared to
methyl-substituted salicylic acid with the reactions of pro-
pargylic alcohols under optimized conditions providing 5c–e
in good yields. The product 5a was re-crystallized using
hexane/EtOAc as colourless crystals and single-crystal X-ray
analysis was carried out21 to unambiguously confirm the pro-
posed structure and its solid-state structure shows three C–
H⋯O and two C–H⋯π interactions. Unfortunately, the reaction
was not successful when tertiary propargylic alcohols having
an unsymmetrical substituent, a heteroaryl substituent, term-
inal alkynes (R2 = H) or alkyl substituents at R1 and R2 posi-
tions were used. Primary or secondary propargylic alcohols
also failed to provide the desired product and it may be due to
the lower stability of carbocation intermediates formed.
Scheme 2 Control experiments.
However, the reaction of an equimolar amount of acid 1/4 and
α,β-unsaturated carbonyl compound 6a under the optimized
reaction conditions failed to give the desired products 3a/5a
(eqn (2), Scheme 2). Based on the above control experiments, it
is concluded that the reaction does not proceed via the Meyer–
Schuster rearrangement.
In order to gain insight into the reaction mechanism, a few
control experiments (Scheme 2) were performed. The reaction
of 1 equiv. of thiosalicylic acid 1 was carried out with 2 equiv.
of propargylic alcohol 2a to afford the corresponding 3,1-ben-
zoxathiin-4-one 3a (56% yield) with α,β-unsaturated carbonyl
compound 6a (41% yield) as a byproduct (eqn (1), Scheme 2).
Based on the product structure, we propose a plausible
mechanism for the formation of 3,1-benzoxathiin-4-ones 3/1,3-
benzodioxin-4-ones 5 (Scheme 3). The propargyl hydroxyl
group of substrate 2 initially generated propargylic cation A
under reflux conditions, which would undergo subsequent
tautomerism to generate the allenic cation B. The inter-
molecular nucleophilic attack of the alcoholic group in acid 1/
4 onto B affords intermediate C which on further cyclization
provides product 3/5.
Table 4 Catalyst free synthesis of 1,3-benzodioxin-4-ones (5)a
To demonstrate the consistency and practicality of the
present synthetic methodology, gram-scale experiments using
propargylic alcohol 2a and acid 1/4a were carried out to afford
the corresponding products 3a/5a in good yields (Scheme 4). It
a Reaction conditions: Controlled addition (0.2 mL h−1) of propargylic
alcohols 2a, b, and e (1.0 equiv.) into salicylic acids 4 (1.0 equiv.) in
10 ml of toluene at reflux conditions in an open-air atmosphere for
10 h. b Yield of the isolated product after column chromatography.
Scheme 3 The plausible mechanism for the synthesis of 3,1-benzox-
athiin-4-ones 3 and 1,3-benzodioxin-4-ones 5.
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HRMS facilities under the FIST program and the Alexander
von Humboldt Foundation, Germany, for FT-IR equipment
donation. M. M. thanks the University Grants Commission
(UGC) for a BSR fellowship.
Notes and references
Scheme 4 Gram scale preparation of 3,1-benzoxathiin-4-one 3a and
1,3-benzodioxin-4-one 5a.
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Scheme 5 Synthetic utility of compounds.
is worth mentioning that thiosalicylic/salicylic acid could be
easily handled as they are stable and show no changes of the
product 3/5 under open air over a period of a month at room
temperature.
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described. Studies of salicylic acids and propargylic alcohols
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athiine-4-ones/benzodioxin-4-ones in an easy manner. The
ready availability of substrates, broad scope and operational
simplicity of this process are beneficial for its large-scale appli-
cation. A study on the development of the related molecules is
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