Synthesis of thiazolidin-4-ones via [3+2] cycloaddition of in situ generated aza-oxyallylic cations with isothiocyanates

Article abstract of DOI:10.1016/j.tetlet.2017.10.004

A highly efficient one-pot synthesis of thiazolidin-4-ones via [3+2] cycloaddition of aza-oxyallylic cations with isothiocyanates is developed. The aza-oxyallyic cations were generated in situ in the present of a base. This cycloaddition reaction allows t

Full text of DOI:10.1016/j.tetlet.2017.10.004

Tetrahedron Letters xxx (2017) xxx–xxx
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Tetrahedron Letters
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Synthesis of thiazolidin-4-ones via [3+2] cycloaddition of in situ
generated aza-oxyallylic cations with isothiocyanates
Gangqiang Wang a,1, Sen Zhao a,1, Rongxing Chen a, Liangfeng Yang a, Jian Wang a, Haibing Guo a,
Minghu Wu a, Justin Domena b, Yalan Xing b, , Shaofa Sun a,
⇑
⇑
a Non-power Nuclear Technology Collaborative Innovation Center, School of Nuclear Technology and Chemistry & Biology, Hubei University of Science and Technology,
Xianning 437100, China
b Department of Chemistry, William Paterson University of New Jersey, 300 Pompton Road, Wayne, NJ 07470, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient one-pot synthesis of thiazolidin-4-ones via [3+2] cycloaddition of aza-oxyallylic cations
with isothiocyanates is developed. The aza-oxyallyic cations were generated in situ in the present of a
base. This cycloaddition reaction allows the rapid access to a variety of thiazolidin-4-one derivatives in
mild conditions, good yield, and excellent functional group compatibility.
Received 25 August 2017
Accepted 2 October 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Cycloaddition
Aza-oxyallylic cation
One-pot
Heterocycles
Isothiocyanates
Introduction
2H-pyrrol-2-one derivatives via [3+2] cycloaddition of aza-oxyal-
lylic cations and alkynes.7 On the other hand, isothiocyanates have
Thiazolidin-4-ones are unique heterocyclic structural motifs
which have been identified with a wide range of biological activi-
ties, such as cardiovascular,1 hypnotic,2 and anticancer activities3
(Fig. 1). These important biological activities and intriguing hetero-
cyclic structures attracted noticeable attention from the synthetic
community, which led to the development of efficient methods
for the synthesis of thiazolidin-4-one derivatives.4
During our continuous effort of developing efficient syntheses
of bio-active heterocyclic compounds, we decided to take advan-
tage of the [3+2] cycloaddition reaction of aza-oxyallylic cations
to access thiazolidin-4-ones. After Jeffrey first reported the applica-
tion of the aza-oxyallylic cation in [4+3] cycloaddition reactions,
many research groups began to utilize aza-oxyallylic cations as
the unique synthon for cycloaddition reactions in order to prepare
heterocyclic molecules (Scheme 1). For instance, Lin and co-work-
ers described a [3+3] cycloaddition of aza-oxyallylic cations with
2-alkenylindoles for the preparation of carbolinones.5 In 2016, Jef-
frey reported a synthesis of 4-oxazolidinone by [3+2] cycloaddition
of aza-oxyallylic cations with carbonyl compounds.6 Very recently,
we communicated an efficient one-pot synthesis of 1,3-dihydro-
been extensively used in the [3+2] cycloaddition of aziridines for
the synthesis of heterocycles.8 Thiazolidin-4-ones derivatives have
been prepared by [3+2] cycloaddition reaction previously9 While
we are preparing our manuscript, a report of base-promoted [3
+2] cycloaddtion of azaoxyallyl cations with isothiocyanates
appeared in the literature using hexafluoro-2-propyl alcohol (HFIP)
as the solvent.10 Herein, we present our study on the [3+2]
cycloaddition of in situ generated aza-oxyallylic cations and isoth-
iocyanates for the synthesis of thiazolidine-4-one derivatives. It is
worth to mention that our work illustrated many examples with
mono-substituted haloamides while the previous publications
focus on germinal dimethyl-substituted haloamides.
Results/Discussion
We started our investigation for the optimal reaction conditions
by choosing
the model substrate (Table 1). First, Na2CO3 was utilized as the
base to produce aza-oxyallylic cations from -Bromoamide 1a.
a-Bromoamide 1a and isothiocyanatobenzene 2a as
a
The corresponding aza-oxyallyic cation was expected to react with
2a for the [3+2] cycloaddition. To our delight, CH3CN was identified
to be the best solvent (entry 1) which gave 93% yield of the desired
[3+2] cycloaddition product 3a. Other solvents including Toluene,
Hexafluoroisopropanol (HFIP), CH2Cl2, DMF, CH3OH, and THF all
⇑
Corresponding authors.
E-mail address: xingy@wpunj.edu (Y. Xing).
These authors contributed equally to this work
1
https://doi.org/10.1016/j.tetlet.2017.10.004
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
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G. Wang et al. / Tetrahedron Letters xxx (2017) xxx–xxx
Table 1
Optimization of reaction conditions.a
Entry
Base
Na2CO3
Solvent
T/h
T/°C
Yieldb
1
2
3
4
5
6
7
8
CH3CN
Tol
HFIP
DCM
DMF
4
4
4
4
4
4
4
4
4
4
4
4
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
93%
<5%
65%
<5%
67%
15%
13%
76%
73%
81%
11%
43%
Fig. 1. Bioactive thiazolidin-4-ones.
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Cs2CO3
TEA
CH3OH
THF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
10
11
12
K2CO3
NaOAc
NaOH
a
Reaction condition: 1a (1.0 mmol), 2a (1.0 mmol), base (2.0 equiv.) in solvent
(2 mL) for 4 h at room temperature.
b
Isolated yields.
Scheme 1. Previous work.
gave less yields (entries 2–7). Next, different bases such as Cs2CO3,
triethylamine, K2CO3, NaOAc, NaOH were screened. It was found
that all other bases gave less yield than Na2CO3 (entries 8–12) in
the presence of the optical solvent CH3CN. This efficient cycloaddi-
tion reaction was conducted at a mild condition at room tempera-
ture within short reaction time (4 h).
With the optimal conditions in hand, we began our study on the
substrate scope and limitations of this reaction. As shown in
Scheme 2,
a-Bromoamide 1a was utilized as the aza-oxyallylic
cation donor. Concurrently, a variety of substituted aromatic and
aliphatic thiocyanates were tested under the optimal [3+2]
cycloaddition reaction conditions. Substituted isothiocyanatoben-
zene bearing either electron withdrawing or electron donating
groups on the phenyl ring all gave good to excellent yields (entries
3a–l). It is noticeable that strong electron withdrawing groups on
the phenyl ring slightly decrease the yields of this reaction (entry
3j and 3k). Steric effect were also observed toinfluence the yields
of the reaction. For example, ortho-substituted isothiocyanatoben-
zenes (entries 3b and 3c) showed lower yields than the corre-
sponding meta- or para-substituted ones (entries 3b, 3e, 3h, 3c,
3d, and 3f). Additionally, the [3+2] cycloaddition reaction of thio-
cyanate with heteroaromatic substitute pyridine (entry 3m) pro-
ceeded in good yield (89%). Several alkyl substituted thiocyanates
Scheme 2. Substrate scope of isothiocyanates.
were also found to generate the [3+2] cycloaddition products in
good yields (entries 3n–q).
To confirm the structure of the thiazolidin-4-one product of this
[3+2] cycloaddition reaction, we successfully obtained the X-ray
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G. Wang et al. / Tetrahedron Letters xxx (2017) xxx–xxx
3
ucts in good to excellent yields (Scheme 3, 3a, 3r, and 3s). When
-bromoamide with ethyl substitution was employed, cycloaddi-
a
tion products were also obtained in 90% yield (3t). However, the
reaction yield dropped to 65% when N-substitution was changed
from OBn to OMe group (3u).
To demonstrate the broad application of this reaction in hetero-
cyclic structure syntheses, we explored the NAO bond cleavage to
remove the OBn group. Based on a literature procedure,6 the
NAOBn bond of 3a was cleaved by SmI2 to provide 2-aminothia-
zolone derivative 4 in good yield (Scheme 4). 2-Aminothiazolone
core structure, which exhibits a wide range of biological activi-
ties,12 is a well exploited pharmacophore in medicinal chemistry.13
Our [3+2] cycloaddition followed by SmI2 deprotection can serve as
an efficient method to access these 2-aminothiazolone derivatives.
A plausible mechanism was proposed for this interesting [3+2]
cycloaddition (Scheme 5). First, when a base was used, the aza-
oxyallylic cation was generated. The dipolarphile thiocyanate
reacts with the azaoxyllyic cation to produce the [3+2] cycloaddi-
tion product. The excellent regioselectivity of this reaction can be
explained by the electronic property of isothiocyanates.8 The
nucleophilicity of sulphur and electrophilicity of carbon of isoth-
icyantate determined the regioselectivity of this [3+2]
cycloaddition.
Fig. 2. X-ray structure of 3n.
Conclusion
In conclusion, we have developed an efficient and facile synthe-
sis of thiazolidin-4-ones from [3+2] cycloaddition of in situ gener-
ated aza-oxyallylic cations and isothiocyanates. This one-pot
reaction offers a unique approach to access bio-active thia-
zoidine-4-ones motifs in both good yield and mild conditions.
Acknowledgments
This work was supported by University and Education Depart-
ment of Hubei Province Science and Technology Research Project
(Nos. Q20162803). The authors are also grateful to National Natu-
ral Science Foundation (21602053). This research was supported
by a grant from the Center for Research, College of Science and
Health, William Paterson University of New Jersey. The authors
are also grateful to the ART program, College of Science and Health,
and Chemistry Department of William Paterson.
Scheme 3. Substrate scope of a-haloamide.
Scheme 4. NAO bond cleavage.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2017.10.004.
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