Synthesis of functionalized benzo[1,3]dioxin-4-ones from salicylic acid and acetylenic esters and their direct amidation

Article abstract of DOI:10.1039/d1ra05032j

Direct synthesis of 4H-benzo[d][1,3]dioxin-4-one derivatives from salicylic acids and acetylenic esters (both mono- and disubstituted) has been described. The reaction is mediated by CuI and NaHCO₃in acetonitrile. Room temperature amidation of

Full text of DOI:10.1039/d1ra05032j

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Synthesis of functionalized benzo[1,3]dioxin-4-
ones from salicylic acid and acetylenic esters and
their direct amidation†
Cite this: RSC Adv., 2021, 11, 24570
Rasmi P. Bhaskaran,
Kalinga H. Nayak
and Beneesh P. Babu
*
Received 29th June 2021
Accepted 7th July 2021
Direct synthesis of 4H-benzo[d][1,3]dioxin-4-one derivatives from salicylic acids and acetylenic esters (both
mono- and disubstituted) has been described. The reaction is mediated by CuI and NaHCO in acetonitrile.
3
DOI: 10.1039/d1ra05032j
Room temperature amidation of the synthesized 1,3-benzodioxinones with primary amines readily afforded
rsc.li/rsc-advances
the corresponding salicylamides in moderate to good yields.
Heterocycles and their derivatives play a pivotal role in natural dichloromethane as the methylene donor was reported by
products and synthetic organic chemistry. Isolation, bio and Xiuling Cui under catalyst-free condition using potassium
8
chemical synthesis, and investigation of pharmacological and phosphate. Later, Liu et al. developed a Cu(OAc) catalyzed
2
9
biological properties of diverse heterocycles have attracted both approach based on ortho-halobenzoic acid, KOH, and NaHCO3.
organic and medicinal chemists. It is a highly vibrant and ever- Morpholine catalyzed conversion of salicylic acid to the ben-
1
expanding eld of research. Besides, heterocycle scaffolds zodioxinone scaffold was reported by Qiu and co-workers
10
contribute signicantly towards the development of novel treating with ynones. In 2017, Kawatsura et al. reported the
organic materials for luminescent applications due to their synthesis of 1,3-oxathiine derivatives via an iron-catalyzed
unique photophysical properties, which can be tuned to suit intermolecular reaction between thiosalicylic acid and
2
11
diverse applications. Benzodioxans are oxygen-based isomeric internal alkynes. Very recently, Muthusamy et al. reported
heterocycles with various applications in medicinal, agricul- a catalyst-free synthesis of 1,3-oxathiine derivatives by treating
tural, and synthetic chemistry. Among the isomeric benzo-
dioxans, 1,3-benzodioxane and its derivatives are used in
3
medicinal and agrochemicals chemistry research. In addition,
they are potential synthetic intermediates in multistep organic
4
synthesis. Among the various 1,3-benzodioxane derivatives,
4H-benzo[d][1,3]dioxin-4-one has been identied as an active
core in many biologically active molecules such as nucleoside
base transport inhibitor, topoisomerase I inhibitor, anti-
plasmodial and cytotoxic drugs, etc., and its thio derivatives nd
applications as an insecticide, crop protection agents, and
5
fungicides. Few examples have been shown in Fig. 1.
Salicylic acid and its derivatives are widely used to access the
4
H-benzo[d][1,3]dioxin-4-one scaffolds, and several approaches
6
have been reported in the literature. In a similar line, reports in
which thiosalicylic acid yielding the corresponding benzo-1,3-
oxathiine derivatives are also reported. For example, conver-
7
sion of salicylic acid to benzo[d][1,3]dioxin-4-ones using
Department of Chemistry, National Institute of Technology Karnataka – NITK,
Surathkal 575025, Mangalore, India. E-mail: pbbeneesh@nitk.edu.in; Tel:
+
91-824-2473219
†
Electronic supplementary information (ESI) available: General experimental
1
13
information and procedure, full characterization data and spectra ( H and
C
NMR) of all the products are available. CCDC 2084126. For ESI and
crystallographic data in CIF or other electronic format see DOI:
Fig. 1 Bioactive molecules with 1,3-benzodioxinone or benzox-
athiinone core.
1
0.1039/d1ra05032j
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thiosalicylic acid and substituted propargylic alcohols. Due to [1,3]dioxin-4-one with moderate conversion. NaHCO
3
(1.2
our continued interest in the development of novel and modi- equiv.) was proved to be the best base for the reaction, yielding
13

ed synthetic routes to heterocycles, we herein report 55% of the product 3aa (Table 1, entry 5). We further studied the
a modied route to synthesize benzo[d][1,3]dioxin-4-ones from effect of different metal salts such as CuI, Pd(OAc) , CuCl, FeCl ,
2
3
2 2
salicylic acid and acetylenic esters. To the best of our knowl- NiCl , and MnCl in the reaction. Among the various metal salts
edge, this is the rst report on the synthesis of benzo[d][1,3] screened, CuI showed a remarkable inuence on the outcome of
dioxin-4-ones from salicylic acid and acetylenic esters though the reaction as summarized in Table 1. Stoichiometric CuI (1
3
the corresponding benzo-1,3-oxathiine route has already been equiv.) as an additive in presence of NaHCO (1.2 equiv.) base
11
documented. Interestingly, both mono- and disubstituted enhanced the yield of the nal benzo[d][1,3]dioxin-4-one
acetylenic esters were equally effective in the reaction. The derivative to 88% in 24 h (entry 8). We noticed that the pres-
benzo[d][1,3]dioxin-4-ones derivatives synthesized further ence of both NaHCO and CuI was crucial for the reaction as
3
readily converted to amides when treated with primary amines withdrawal of any one of the reagents affected the overall
at room temperature.
conversion (entries 5 and 9). Acetonitrile was nalized as the
From the literature, we understand that the reaction between best solvent for the reaction aer screening various solvents.
salicylic acid and acetylenic esters is not yet explored in detail THF and 1,2-DCE yielded the product in trace amount while
though the analogous thiosalicylic acid-based methods have methanol and DMSO failed to promote the reaction. In short,
been well documented. We started our investigations using the aer a series of optimization experiments, we identied the best
salicylic acid 1a and dimethyl acetylenedicarboxylate (DMAD) reaction condition for the synthesis of 3aa as treating 1a and 2a
2
a as the model substrates and the reaction optimization in acetonitrile in presence of CuI (1 equiv.) and NaHCO (1.2
3
ꢀ
observations of the pilot experiment are summarized in Table 1. equiv.) at 80 C for 24 h.
Stirring 1a (0.6 mmol) and 2a (0.5 mmol) together in a Schlenk
With the optimized reaction conditions in hand, we subse-
tube using acetonitrile (2 ml) as the solvent resulted in no quently explored the substrate scope of the reaction using
ꢀ
characteristic reaction at room temperature as well as at 80 C. various 2-hydroxy aromatic acids and acetylenic esters. Inter-
We further introduced a base into the reaction medium. Both estingly, both disubstituted acetylenic esters – such as DMAD 2a
organic and inorganic bases were screened to identify the best and diethyl acetylenedicarboxylate 2b – and monosubstituted
condition. Organic bases such as pyridine and DABCO failed to acetylenic esters – such as methyl propiolate 2c and ethyl pro-
afford the expected product under hot conditions. Interestingly, piolate 2d – were equally effective in the optimized conditions
inorganic bases succeeded in yielding the expected benzo[d] affording the benzo[d][1,3]dioxin-4-one derivatives in moderate
a
Table 1 Optimization of the reaction conditions
ꢀ
b
S. no.
Base
Additive
Solvent
T ( C)
Yield (%)
c
1
2
3
4
5
6
7
8
9
Pyridine 10 mol%
DABCO 10 mol%
—
—
—
—
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
80
80
80
80
80
80
80
80
80
80
60
60
100
80
80
80
80
nr
nr
Trace
40
55
<60
45
88
30
Trace
nr
Trace
Sluggish reaction
nr
Trace
nr
K CO
2 3
20 mol%
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
—
3
3
3
3
3
20 mol%
1.2 equiv.
1.2 equiv.
1.2 equiv.
1.2 equiv.
—
CuI 20 mol%
Pd(OAc)
2
10 mol%
CuI 1 equiv.
CuI 1 equiv.
CuI 1 equiv.
CuI 1 equiv.
CuI 1 equiv.
CuI 1 equiv.
FeCl
CuCl 1 equiv.
NiCl 1 equiv.
MnCl 1 equiv.
10
11
12
13
14
15
16
17
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
NaHCO
3
3
3
3
3
3
3
3
1.2 equiv.
1.2 equiv.
1.2 equiv.
1.2 equiv.
1.2 equiv.
1.2 equiv.
1.2 equiv.
1.2 equiv.
1,2-DCE
CH OH
3
THF
DMSO
3
1 equiv.
CH
CH
CH
CH
3
3
3
3
CN
CN
CN
CN
2
2
nr
a
All reactions were carried out in a Schlenk tube in 0.5 mmol scale. Reaction conditions: 1a (1.2 equiv.), 2a (1 equiv.), base (1.2 equiv.), additive (1
ꢀ
b
c
equiv.), solvent (2 ml), 24 h, 80 C. Isolated yield aer column chromatography is reported. nr: no reaction.
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a
Table 2 Synthesis of benzo[d][1,3]dioxin-4-ones
Scheme
1
Reaction between thiosalicylic acid and 3-
phenylpropiolonitrile.
under the optimized reaction conditions. Contrary to the ex-
pected 1,3-benzothiinone, the 1 : 2 adduct 2-cyano-1-
phenylvinyl(2-(2-cyano-1,2-diphenylvinyl)-thio)benzoate (4ee)
was obtained as the nal product (Scheme 1).
The 4H-benzo[d][1,3]dioxin-4-one derivatives are widely used
in synthetic organic chemistry as a versatile synthetic interme-
diate. A spectrum of compounds such as amide, ester, alcohol,
aldehyde etc. can be easily accessed from the 1,3-benzodiox-
14
inone derivatives. We were particularly interested in their
conversion to amides, because salicylamides are widely used in
15
medicinal chemistry as various receptor inhibitors. Keeping
this in mind, we treated the nal 1,3-benzodioxinones with
various amines expecting easy access to salicylamides.
16
Following the literature procedure of amide synthesis, we
treated 3aa and n-propylamine 5a in presence of DMAP
(10 mol%) and DBU (1 equiv.) in acetonitrile at room temper-
ature for 8 h. The reaction was successful and the expected
salicylamide was formed in good yield (Table 3). The strategy
was quite versatile and other primary amines such as iso-
propylamine 5b, benzylamine 5c and cyclohexylamine 5d
readily afforded the salicylamide in moderate to good yield. At
the same time, secondary amines such as diethylamine and
a
All reactions were carried out in a Schlenk tube. Reaction conditions:
1
a (1.2 equiv.), alkyne (1 equiv.), NaHCO
3
(1.2 equiv.), CuI (1 equiv.), diphenylamine were not very effective. 1,3-Benzodioxinones
ꢀ
acetonitrile (2 ml), 24 h, 80 C. Isolated yield aer column
chromatography is reported.
derived from both salicylic acid and 3-hydroxy-2-naphthoic acid
yielded the amide at room temperature. However, attempt to
a
Table 3 Synthesis of salicylamides from 1,3-benzodioxinones
to good yields (Table 2). Surprisingly, the hindered 3-phenyl-
propiolonitrile 2e in place of acetylenic esters also afforded the
expected product in 55% yield. However, ethyl phenyl-
propiolate, phenylacetylene and acetylenic ketone such as 4-
phenylbut-3-yn-2-one failed to yield the product. Apart from
salicylic acid, substituted salicylic acids – 4-methoxy derivative
1b and 4-bromo derivative 1c – were also used in the reaction.
The former afforded 36% of the nal product while the latter
yielded 69%. Electron decient 2-hydroxy-3-nitrobenzoic acid
and 3-hydroxypicolinic acid were not successful in the reaction
as the former yielded a sluggish reaction mixture while the
latter didn't react at all. Interestingly, the hindered 3-hydroxy-2-
naphthoic acid 1d reacted efficiently with both DMAD and ethyl
propiolate with good conversion. However, with thiosalicylic
acid 1e, conversion was moderate with DMAD and very low with
methyl propiolate.
a
Reaction conditions: 3 (1 equiv.), amine (1.1 equiv.), DMAP (10 mol%),
Surprisingly, an unexpected reactivity was observed when
DBU (1 equiv.), acetonitrile (4 ml) 8 h, rt. Isolated yield aer column
thiosalicylic acid is treated with 3-phenylpropiolonitrile 2e chromatography is reported.
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Award (IFA-13 CH-98). B. P. B., R. P. B., and K. H. N. thank NITK,
Surathkal for providing laboratory facility and research fellow-
ships for R. P. B. and K. H. N. The authors also thank NIIST-
CSIR Trivandrum, STIC-CUSAT Kochi, CIF-Manipal and NMR
Centre, Mangalore University for spectra.
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7
aa which was isolated, characterized and compared with the
18
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9
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