Base-promoted ring opening of 3-chlorooxindoles for the construction of 2-aminoarylthioates and their transformation to quinazolin-4(3: H)-ones

Article abstract of DOI:10.1039/c8nj00195b

An unprecedented methodology for the preparation of diverse S-alkyl 2-aminoarylthioates has been developed based on cesium carbonate-promoted direct ring opening of 3-chlorooxindoles with thiols. This novel protocol proceeds via cascade sulfenylation, aer

Full text of DOI:10.1039/c8nj00195b

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Base-promoted ring opening of 3-chlorooxindoles
for the construction of 2-aminoarylthioates and
their transformation to quinazolin-4(3H)-ones†
Cite this:DOI: 10.1039/c8nj00195b
Tej Narayan Poudel, ‡ Hari Datta Khanal ‡ and Yong Rok Lee
*
An unprecedented methodology for the preparation of diverse S-alkyl 2-aminoarylthioates has been
developed based on cesium carbonate-promoted direct ring opening of 3-chlorooxindoles with thiols.
This novel protocol proceeds via cascade sulfenylation, aerial oxidation, C2–C3 bond cleavage, and
decarboxylation. The resulting products from this transformation exhibit potential for application as
fluorescent sensors for the detection of Fe3+ ions. In addition, this methodology provides a concise
pathway for the construction of a variety of biologically interesting quinazolin-4(3H)-ones in good yields.
Received 12th January 2018,
Accepted 22nd February 2018
DOI: 10.1039/c8nj00195b
rsc.li/njc
Introduction
Thioesters are an important class of molecules that have been
applied in organic synthesis,1 bioorganic chemistry,2 industrial
chemistry,3 and medicinal chemistry.4 In addition, they have
been employed as useful intermediates in the synthesis of
various heterocycles,5 and have been used as efficient synthons
for a myriad of synthetic transformations, including acyl trans-
fer reactions,6 cross-coupling reactions,7 and functional group
transformations.8 Moreover, acetyl-CoA, a natural thioester,
plays an essential role in the metabolism of proteins, fatty
acids, carbohydrates, and lipids.9 As such, the synthesis of thioesters
Scheme 1 Representative methodologies for the preparation of thioesters.11–15
has attracted growing attention in the synthetic community, for the preparation of thioesters include the palladium-catalyzed
and the development of a facile and efficient methodology for thiocarbonylation of aryl halides with CO and thiols (method c),13
the preparation of their analogues is of particular interest.
and the metal-free C–H functionalization of methyl arenes with
In particular, 2-aminoarylthioates have been used in the disulfides (method d).14 In addition, the palladium-catalyzed
preparation of various catalysts. For example, Pd- or Cu-S-propyl- thiocarbonylation of styrene derivatives with CO and thiols has
2-aminobenzothioates immobilized on Fe3O4 nanoparticles, synthe- also been described (method e).15
sized from S-propyl-2-aminobenzothioates, exhibit promising
catalytic activities in Suzuki and Heck reactions10a and in the benzothioates, only a few methods using isatoic anhydrides
synthesis of polyhydroquinoline derivatives.10b
as the starting material have been developed, including the
In contrast, for the preparation of S-alkyl/aryl 2-amino-
Fueled by their importance and applicability, a number of tetrathiomolybdate- or sodium dithionite-mediated decarboxylation
synthetic approaches towards thioesters have been developed of isatoic anhydrides with thiols or disulfides (eqn (1), Scheme 2).16,17
in the past decade,11–15 with typical examples including the As such, a facile and novel route for the synthesis of diverse and
acid-catalyzed thioesterification of carboxylic acids (Scheme 1, functionalized 2-aminobenzothioates is highly desirable. In
path a)11 and the Fe-catalyzed thioesterification of carboxylic this context, we wished to examine reactions based on the char-
acid derivatives with thiols (path b).12 Other typical approaches acteristic reactivity of 3-chlorooxindoles. Recently, 3-chloro-
oxindole scaffolds have emerged as versatile precursors for
the synthesis of spirocyclopropyloxindoles18 and 3-alkyl/aryl
School of Chemical Engineering, Yeungnam University, Gyeongsan, 712-749,
thiooxindoles.19 Although the base-catalyzed nucleophilic sub-
Republic of Korea. E-mail: yrlee@yu.ac.kr; Fax: +82-53-810-4631;
stitution of 3-chlorooxindoles with thiols has been demonstrated to
Tel: +82-53-810-2529
produce 3-alkyl thiooxindoles, the synthesis of S-alkyl 2-aminobenzo-
thioates starting from 3-chlorooxindoles has not yet been reported.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8nj00195b
‡ T. N. P. and H. D. K. contributed equally to this work.
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Table 1 Optimization of the reaction conditions for the formation of 3aa
Entry
Base
Solvent
Condition
Yieldb (%)
1
2
3
4
5
6
—
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
DCE
14 h, reflux
14 h, rt
14 h, rt
14 h, rt
12 h, rt
14 h, rt
12 h, rt
12 h, rt
12 h, rt
12 h, rt
12 h, rt
12 h, rt
—
—
—
10
15
Trace
72
60
45
—
Na2CO3
NaOMe
K2CO3
DBU
Scheme 2 Proposed strategies for the preparation of 2-aminobenzo-
thioates and quinazolin-4(3H)-ones.
TEA
7
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
8c
9
Thus, in our continued efforts into the development of novel
synthetic methodologies towards sulfur-containing organic
compounds,20 we herein report the development of a unique
one-pot synthesis of biologically interesting S-alkyl 2-amino-
benzothioates via the cesium carbonate-promoted direct ring
opening of 3-chlorooxindoles with thiols (eqn (2), Scheme 2). In
contrast to the reported methodologies for S-alkyl/aryl 2-amino-
benzothioates using isatoic anhydrides, this paper contains
interesting work in activation of 3-chloroxindoles by base and
oxygen through the direct ring opening of 3-chlorooxindoles. In
addition, this paper also presents the utility of the synthesized
2-aminoarylthioates as efficient fluorescent sensors for the
detection of Fe3+ ions. Furthermore, to demonstrate the potential
application of this protocol, we also report the unprecedented
copper-catalyzed reactions of the prepared compounds with
isocyanides to produce a range of quinazolin-4(3H)-ones.
10
11
12
THF
DMSO
10
20
a
Reaction conditions: a mixture of 1a (0.5 mmol), 2a (0.5 mmol), and
base (1 equiv.) in the desired solvent (5 mL) was stirred under air.
b
c
Isolated yield after column chromatography. 0.5 equiv. of base was
employed.
d = 5.70 ppm corresponding to the amine protons, while signals
corresponding to the methylene and methyl moieties of the
thioethyl group were observed as a quartet at d 2.93 ppm ( J = 7.5 Hz)
and a triplet at 1.25 ppm ( J = 7.2 Hz), respectively. In addition, the
13C NMR spectrum of 3a contained a signal corresponding
to the newly formed carbonyl carbon of the thioester moiety
at d = 193.32 ppm.
With the optimized conditions in hand, the generality and
scope of this process were assessed using a range of 3-chloro-
oxindoles 1a–1e and various alkyl thiols 2a–2e (Table 2). More
specifically, the reactions of 1a with n-propyl-, n-butyl-, i-propyl-,
Results and discussion
Initially, 3-chlorooxindole (1a) was reacted with ethyl mercaptan and t-butyl thiols at room temperature over 10–12 h afforded
(2a) in the presence of different bases and solvents to optimize products 3b–3e in 75, 71, 70, and 52% yields, respectively. In
the conditions for this model reaction (Table 1). Treatment of 1a addition, the treatment of 3-chloro-5-methoxyoxindole (1b),
(0.5 mmol) with 2a (0.5 mmol) in the absence of base in which contains the electron-donating 5-OMe group, with alkyl
acetonitrile under reflux for 14 h failed to provide the desired thiols 2a, 2c, and 2d provided products 3f–3h in yields of
product (entry 1, Table 1). Similar results were obtained using 54–72%. The reactions of 3-chlorooxindoles bearing electron-
Na2CO3 (1 equiv.) and NaOMe (1 equiv.) as bases (entries 2 and 3). withdrawing groups were also successful. For example, the
However, in the presence of K2CO3 (1 equiv.), the desired product reactions of 3,5-dichlorooxindole (1c) with 2a, 2b, 2d, and 2e
3a was formed in 10% yield (entry 4). When the reaction was furnished the desired products 3i–3l in 50–72% yields, while the
carried out using the organic base DBU (1,8-diazabicyclo[5.4.0]- reactions of 3-chloro-5-fluorooxindole (1d) with 2a–2c gave the
undec-7-ene, 1 equiv.), 3a was isolated in 15% yield (entry 5), desired products 3m–3o in 74, 70, and 68% yields, respectively.
although only a trace amount of 3a was obtained in the presence Similarly, a 78% yield of 3p was obtained in the reaction of 1e,
of trimethylamine (TEA) (entry 6). In addition, when Cs2CO3 which bears a strongly electron-withdrawing nitro group. These
(1 equiv.) was employed for the reaction in acetonitrile at room results therefore indicate that a slight decrease in yield was
temperature over 12 h, the yield of 3a increased significantly to observed upon increasing the length or branching degree of the
72% (entry 7). Decreasing the base loading to 0.5 equiv. had a thiol carbon chain.
detrimental effect on the reaction yield (entry 8). The use of
To further demonstrate the utility and versatility of this
various nonpolar and polar solvents were also examined, protocol, we examined the reactions of 3-chlorooxindoles with
although lower yields of 3a were obtained in all cases where thiols bearing a cyclic moiety (Table 3). In this case, the
toluene, 1,2-dichloroethane, tetrahydrofuran, or dimethyl sulf- reactions of 1a with cyclopentanethiol (2f) and cyclohexanethiol
oxide were employed (entries 9–12). Following its successful (2g) in the presence of Cs2CO3 (1 equiv.) in acetonitrile at room
synthesis, the structure of compound 3a was confirmed by temperature over 10 h provided products 4a and 4b in 62 and
NMR analysis and comparison with the literature data.21 More 60% yields, respectively. Further reaction of 1b with 2f gave 4c
1
specifically, the H NMR spectrum of 3a exhibited a singlet at in 65% yield, and the combination of 1c or 1d with 2f or 2g
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Table 2 Reaction of 3-chlorooxindoles 1a–1e with thiols 2a–2e for the
synthesis of S-alkyl 2-aminobenzothioates 3b–3p
Table 4 Reaction of 3-chlorooxindoles 1a–1d with benzyl thiols 2h–2k
for the synthesis of S-benzyl 2-aminobenzothioates 5a–5i
(2h) under the optimized reaction conditions provided product 5a
in a 68% yield. Similarly, when benzyl mercaptans 2i, 2j, and 2k
bearing electron-donating or electron-withdrawing groups at the
2- and 4-positions of the benzene ring were employed, products
5b–5d were obtained in yields of 70, 65, and 58%, respectively.
In addition, the reaction of 1b with 2h afforded 5e in 60% yield,
and the combination of 1c or 1d with 2h, 2i, or 2k provided the
desired products 5f–5i in yields of 65–70%. However, our
attempt to synthesize S-aryl 2-aminobenzothioates using aryl
thiols was not successful. Instead, only the starting materials
were recovered.
Table 3 Reaction of 3-chlorooxindoles 1a–1d with thiols 2f–2g bearing a
cyclic moiety for the synthesis of S-cycloalkyl 2-aminobenzothioates 4a–4g
To elucidate the reaction mechanism, a number of control
experiments were performed (Scheme 3). Initially, the reaction
of 1a with 2a under standard reaction conditions under an inert
atmosphere (Ar gas) provided both 6 (32%) and 3a (trace)
(eqn (1), Scheme 3). Subsequent treatment of 3-(ethylthio)indolin-
2-one (6) with 1 equiv. of Cs2CO3 in acetonitrile at room temperature
over 10 h under air provided 3a in 78% yield (eqn (2), Scheme 3).
afforded 4d–4g in 60–70% yields. These reactions therefore
provide a rapid synthetic route for the preparation of diverse
S-cycloalkyl 2-aminobenzothioates in moderate to good yields.
Encouraged by these results, we then explored the reactions
of 3-chlorooxindoles 1a–1d with benzyl mercaptans 2h–2k
(Table 4). In this case, the reaction of 1a with phenylmethanethiol
Scheme 3 Control experiments carried out to elucidate the reaction
mechanism.
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Scheme 4 Plausible reaction mechanism for the formation of 3a.
However, when the N-protected 3-chloro-1-methylindolin-2-one (1f)
was reacted with ethanethiol (2a) under standard conditions, the
formation of 3q was unsuccessful (eqn (3), Scheme 3). These results
indicate that 3-(ethylthio)indolin-2-one (6) is the key intermediate,
with aerial oxidation being a possible pathway for the reaction.
Based on the products obtained from the above control
experiments, a plausible mechanistic pathway for the formation
of 3a is depicted in Scheme 4. More specifically, nucleophilic
substitution between 2a and 1a in presence of Cs2CO3 gives
intermediate 6. Under basic conditions, the reaction of 6 with
O2 generates peroxide intermediate 7,22 which then undergoes
dehydration with concomitant cleavage of the C2–C3 bond to
form isocyanate derivative 8.23 Nucleophilic attack of 8 by water
followed by decarboxylation then yields the final product 3a via
intermediate 9. However, in the case of 1f, it is not possible to
generate isocyanate intermediate 8 via C2–C3 cleavage, leading
to the product 3q (Scheme 3, eqn (3)).
Fig. 1 The fluorescent spectra of a selection of the synthesized compounds
(0.001 M) measured in acetonitrile at room temperature, upon excitation at
360 nm.
In terms of the potential application of such compounds,
fluorescence sensing is of particular interest. Fluorescence
sensing is an effective method for the detection of metal ions
due to its high selectivity, sensitivity, efficiency, and ease of
operation,24 and to date, a number of heteroatom-containing
organic molecules have been employed for the fluorescence
sensing of metal ions. As an example of a metal whose detection is
of particular importance, iron is an essential trace element in the
human body due to its involvement in various biological functions,
such as oxygen transportation, oxygen metabolism, transcriptional
regulation, and electron transfer.25 Any alteration in the concen-
tration of iron can result in various complications and disorders,
such as anemia, Parkinson’s disease, and Alzheimer’s disease.26 As
such, the analysis of iron levels in environmental and biomedical
contexts is of significant importance.
Fig. 2 The fluorescent response of 3n (0.001 M) in the presence of
various metal ions (50 mM, lex = 360 nm) in acetonitrile.
In this context, the fluorescent properties of synthesized
compounds 3b, 3d, 3g, 3n, 4a, 5b, 5c, 5d, and 5h were
examined. Interestingly, compound 3n emitted the highest
fluorescence (Fig. 1), and so the fluorescence sensing ability
of compound 3n towards different metal ions (i.e., Co2+, Zn2+,
Cr3+, Na+, Hg2+, Cu2+, K+, and Fe3+) was then examined.
Indeed, as indicated in Fig. 2, 3n selectively sensed Fe3+ ions,
and so we moved on to examine the sensitivity of 3n towards
Fig. 3 Fluorescent titration response of 3n upon the addition of various
concentrations of Fe3+ (0–420 mM) in acetonitrile.
different concentrations of Fe3+ ions in acetonitrile (Fig. 3). then demonstrated between the maximum emission intensity
In this case, the fluorescent intensity of 3n decreased linearly upon (446 nm) and various Fe3+ concentrations (Fig. 4) based on the
increasing the concentration of Fe3+ ions. A linear relationship was linear correlation coefficient (R2 = 0.98). This linear quenching
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Scheme 5 Proposed mechanism for the formation of 11a.
copper-catalyzed radical reaction of 2-amino-N-phenylbenza-
nilide with dicumyl peroxide,30a and the microwave-mediated
reduction of nitro and azido arenes using Zn-HCOONH4.31a
Although several synthetic approaches to 2-unsubstituted qui-
nazolinones have been reported, the preparation of quinazolin-
4(3H)-ones from S-alkyl 2-aminobenzothioates has not yet been
examined.
Fig. 4 Stern–Volmer plot of the fluorescent intensity ratios (F0 ꢀ F)/F0 at
446 nm vs. the Fe3+ concentration (30–180 mM).
fluorescence of 3n can be attributed to coordination between the
Fe3+ ions and the lone pairs of electrons on the sulfur and nitrogen
(amine) atoms of S-propyl 2-amino-5-fluorobenzothioate.
Thus, we initially investigated the reactions of 3a with t-butyl
isocyanide (10a) and cyclohexyl isocyanide (10b) in the presence
of 10 mol% Cu(OTf)2 in toluene at 80 1C over 10–12 h, which
afforded products 11a and 11b in 86 and 82% yields, respectively.
Similarly, treatment of the methoxy-containing 3f with 10a
provided 11c in 83% yield, while 3i or 3m, which bear the
electron-withdrawing chloro- and fluoro- groups, respectively,
gave the desired products 11d–11g in yields of 70–80% upon
reaction with 10a and 10b. However, the reaction of 3p bearing
a strong electron withdrawing of the nitro group with t-butyl
isocyanide (10a) did not afford the desired product. These
results therefore confirm that such reactions constitute a rapid
and facile route to the preparation of diverse quinazolin-4(3H)-
ones in good yields.
The proposed mechanism for the formation of product 11a
is presented in Scheme 5. As indicated, in the presence of Cu(OTf)2,
isocyanide 10a produces copper isocyanide complex 10a0,32 which
reacts with 3a to give intermediate 12. Proton exchange of 12
generates the imine intermediate 13, which subsequently undergoes
intramolecular nucleophilic attack to the carbonyl carbon atom of
the thioester group to give the cyclic intermediate 14. Finally, the
elimination of ethanethiol from 14 gives the desired product 11a.
To examine the potential application of the synthesized
S-alkyl 2-aminobenzothioates as versatile synthons in organic
transformations, their conversion to biologically interesting
quinazolin-4(3H)-ones was then examined (Table 5). Quinazolin-
4(3H)-ones are an important class of fused heterocyclic compounds
found in many natural products and pharmaceuticals.27 Indeed,
molecules bearing the quinazoline moiety exhibit a wide range
of biological activities, such as anti-inflammatory, anticonvulsant,
anticancer, antiulcer, antituberculosis, and hypolipidemic
activities.28 Owing to their biological and pharmaceutical impor-
tance, a number of synthetic approaches have been developed to
construct such quinazolin-4(3H)-ones.29–31 Among these approaches,
the most common methods for the preparation of 2-unsubstituted
quinazolinones involve the I2-catalyzed reaction of 2-amino-
benzamides with tetramethylethylenediamine (TMEDA),29a the
Table 5 Synthesis of quinazolin-4(3H)-ones 11a–11g by reaction of
synthetic S-alkyl 2-aminobenzothioates 3a, 3f, 3i, and 3m with isocyanides
10a and 10b
Conclusion
In summary, we developed a novel methodology for the synthesis
of diverse S-alkyl 2-aminobenzothioate derivatives via the cesium
carbonate-mediated direct ring opening of 3-chlorooxindoles with
a range of thiols. This novel process involves the cascade
sulfenylation of 3-chlorooxindoles, aerial oxidation, C2–C3 bond
cleavage, and decarboxylation. To demonstrate the utility of this
protocol, the prepared 2-aminobenzothioate derivatives were
utilized as fluorescent sensors for the detection of Fe3+ ions.
In addition, they were also employed as key intermediates in the
preparation of biologically important quinazolin-4(3H)-ones.
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Experimental section
Notes and references
General remarks
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3-Chlorooxindoles 1a–1e were prepared according to literature
procedures.33 All other reagents and solvents were purchased at
the highest commercial purity and were used without further
purification. All experiments were carried out under air, unless
stated otherwise. Merck precoated silica gel plates (Art. 5554)
treated with a fluorescent indicator were used for analytical thin
layer chromatography (TLC). Flash column chromatography was
performed using silica gel 9385 (Merck). Melting points are
uncorrected and were determined using Fisher-Johns Melting
Point Apparatus. 1H NMR and 13C NMR spectra were recorded
on Varian VNS or DPX (600 or 300 MHz and 150 or 75 MHz,
respectively) spectrometers in CDCl3 using d = 7.24 and 77.00 ppm
as the solvent chemical shifts. All chemical shifts (d) are expressed
in units of ppm and J values are given in Hz. Multiplicities
are abbreviated as follows: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet or overlap of nonequivalent resonances,
and dd = doublet of doublets. Infrared (IR) spectra were recorded
on a PerkinElmer Spectrum Twot IR spectrometer with frequencies
expressed in cmꢀ1, and high-resolution mass spectrometry (HRMS)
was carried out using a JEOL JMS-700 spectrometer at the Korea
Basic Science Institute.
General experimental procedure for the synthesis of S-alkyl
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2-aminobenzothioates (3, 4, and 5)
To a solution of the desired 3-chlorooxindole 1 (0.5 mmol) and
thiol 2 (0.5 mmol) in acetonitrile (5 mL) was added Cs2CO3
(1 equiv.). The reaction mixture was stirred at room temperature
until completion, as indicated by TLC. The volatiles were then
removed in vacuo and the residue was purified by silica gel
column chromatography (hexane: ethyl acetate = 10 : 1) to give
the desired product.
General experimental procedure for the synthesis of
quinazolin-4(3H)-ones (11)
To a solution of S-alkyl 2-aminobenzothioate 3a, 3f, 3i, or 3m
(0.27 mmol) and isocyanide 10a or 10b (0.27 mmol) in toluene
(3 mL), was added Cu(OTf)2 (10 mol%). The reaction mixture
was then stirred at 80 1C until completion, as indicated by TLC.
The volatiles were then removed in vacuo and the residue was
purified by silica gel column chromatography (hexane : ethyl
acetate = 5 : 1) to give the desired product.
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Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
This study was supported by the 2017 Yeungnam University 14 S. S. Badsara, Y.-C. Liu, P.-A. Hsieh, J.-W. Zeng, S.-Y. Lu,
Research Grant (217A345016).
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