Synthesis of thiazolidinimines/thiazinan-2-imines via three-component coupling of amines, vic-dihalides and isothiocyanates under metal-free conditions

Article abstract of DOI:10.1080/00397911.2021.1880594

An expeditious approach for the synthesis of thiazolidin-2-imines and 1,3-thiazinan-2-imines through three-components coupling (TCC) of amines, isothiocynates and dihalides under metal-free conditions has been described. Dichloroethane (DCE) employed as two carbon (C2) source for the annulation and obtained saturated five membered heterocycles.With 1,3-dibromopropane, six membered heterocycles were obtained in good yields. The metal-free, broad substrate scope, functional group tolerance and applicability at gram scale synthesis are the advantages of the present protocol.

Full text of DOI:10.1080/00397911.2021.1880594

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis of thiazolidinimines/thiazinan-2-imines
via three-component coupling of amines, vic-
dihalides and isothiocyanates under metal-free
conditions
Rahul Kumar, Abhisek Joshi, Deepa Rawat & Subbarayappa Adimurthy
To cite this article: Rahul Kumar, Abhisek Joshi, Deepa Rawat & Subbarayappa Adimurthy
(
2021) Synthesis of thiazolidinimines/thiazinan-2-imines via three-component coupling of amines,
vic-dihalides and isothiocyanates under metal-free conditions, Synthetic Communications, 51:9,
340-1352, DOI: 10.1080/00397911.2021.1880594
1
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https://doi.org/10.1080/00397911.2021.1880594
Synthesis of thiazolidinimines/thiazinan-2-imines via
three-component coupling of amines, vic-dihalides and
isothiocyanates under metal-free conditions
a,b
a,b
a,b
a,b
Rahul Kumar , Abhisek Joshi , Deepa Rawat , and Subbarayappa Adimurthy
a
b
Academy of Scientific and Innovative Research, Ghaziabad, India; CSIR–Central Salt and Marine
Chemicals Research Institute, Bhavnagar, India
ABSTRACT
ARTICLE HISTORY
An expeditious approach for the synthesis of thiazolidin-2-imines
and 1,3-thiazinan-2-imines through three-components coupling (TCC)
of amines, isothiocynates and dihalides under metal-free conditions
has been described. Dichloroethane (DCE) employed as two carbon
Received 10 August 2020
KEYWORDS
Amines; dihalides;
isothiocyanates; thiazinan-2-
imines; thiazolidinimines
(
C2) source for the annulation and obtained saturated five mem-
bered heterocycles.With 1,3-dibromopropane, six membered hetero-
cycles were obtained in good yields. The metal-free, broad substrate
scope, functional group tolerance and applicability at gram scale
synthesis are the advantages of the present protocol.
GRAPHICAL ABSTRACT
Non-aromatic nitrogen and sulfur-containing heterocycles are privileged scaffolds found
[
1,2]
in a wide range of pharmaceutical drugs and natural products.
The pharmaceutical
industry continues to require methodologies that address the key synthetic challenges
such as synthesis of small aliphatic heterocycles and the installation of desired moiety
[
3]
through late stage functionalization. The concept of introducing a functional handle
to the aliphatic heterocyclic system is a powerful way of synthesizing molecules with
increased biological activity or suitable for subsequent derivatization. thiazolidin-2-
imines/1,3-thiazinan-2-imines moieties are found in several biologically active com-
[
4]
[5]
[6–7]
[8]
[9]
pounds and exhibit antiviral, anticancer,
anti-tubercular, and antimicrobial
CONTACT Subbarayappa Adimurthy
adimurthy@csmcri.res.in
CSIR–Central Salt and Marine Chemicals Research
Institute, Bhavnagar, Gujarat 364002, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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Figure 1. Representative biologically active molecules containing 2-iminothiazolidin motifs.
activities. For example, molecule A (Figure 1) known to exhibit pronounced anticonvul-
[
10]
[11]
sant activity,
molecules B is a selective GSK-3b inhibitor,
molecules C and D
[
12]
[13]
exhibited antiproliferative activity,
and molecule E as hCA inhibitor (Figure 1).
Due to the synthetic and bio-importance of 5-membered heterocycles such as thiazo-
lidin-2-imines and their analogues, much attention has been paid on the development
of related methodologies.
A well-established route to access substituted thiazolidin-2-imines are through the
[
14–21]
[22]
[23]
ring opening of aziridines,
epoxides
and others
using a wide range of cata-
lytic systems. Despite the significance of these methods, it is desirable to develop new
methods to access thiazolidin-2-imines for late stage functionalization, hence it is a chal-
lenging task to the synthetic chemists.
To our knowledge, 1,2-dichloroethane has rarely been utilized as two carbon source
[
24,25]
in the synthesis of thiazolidin-2-imines.
Herein we describe a protocol for the
highly selective one pot synthesis of 2- thiazolidinimines from readily available amines,
isothiocyanates and 1,2-dichloroethane as C source under transition metal-free condi-
2
tions (Scheme 1d). Furthermore, this synthetic protocol was successfully extended to
1,3-thiazinan-2-imine to obtain six membered analogues.
Results and discussion
Our initial efforts were focused on the optimization of the reaction conditions with anil-
ine 1a and phenyl isothiocyanate 2a as model substrates. When these substrates were
reacted using 0.5 equivalents of sodium hydroxide in 1,2- dichloroethane DCE (3a) at
ꢀ
1
20 C in a sealed tube for 24 hours, 36% yield of the desired product 4a was obtained
(Table 1, entry 1). The structure of product 4a was further confirmed by the single

1
342
R. KUMAR ET AL.
Scheme 1. Representative strategies on the synthesis of thiazolidin-2-imines
crystal XRD analysis. In this reaction DCE plays a dual role, as two carbon source and
as a solvent. The coupling reaction proceeded at a marginal improvement in yield with
NaOt-Bu and KOt-Bu as bases under the same conditions (entries 2 and 3). Use of
other bases (CsF, DBU, Et N) no improvement in yield was observed (entries 4–6). A
3
significant enhancement in yield (51–75%) was observed by conducting the reaction
with carbonates (CaCO , K CO , Cs CO , Na CO ) and KF as base (entries 7–11).
3
2
3
2
3
2
3
Further improvement in yield (82%) was observed with NaHCO as base (entry 12). A
3
comparable yield (74%) of 4a was obtained with 1,2-dibromoethane (3 b) as two carbon
sources instead of DCE (entry 13), Further attempts to improve the yield, the amount
of NaHCO3 and phenyl isothiocyanate 2a were increased (entries 14–18), but no
enhancement in yield was observed. While reducing the reaction temperature (from
ꢀ
1
20 C to r.t.) and time, the yield of 4a was dropped (entries 19–22), and no reaction
was observed without base (entry 23). To check the effect of KI as facilitating agent, the
reaction was carries out by the addition of KI (0.5 mmol), the desired product yield was
declined to 70% (entry 24). Hence the optimum conditions were set as entry 12,
Table 1, to study the further scope with both aromatic and aliphatic amines and as well
as different isothiocyanates.
The one-pot three-component procedure was ratified to be very general in preparing
various thiazolidin-2-imines products. First, phenyl isothiocyanate 2a was reacted with
various aromatic anilines (Scheme 2). Anilines having electron donating groups such as
methoxy, isopropyl, t-butyl, substituents reacted well with 2a and 3a under the opti-
mized conditions and afford the desired products (4b–4d) in moderate to good yields.

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a
Table 1. Optimization of the reaction conditions.
a
b
Reaction conditions: 1a (1 mmol) and 2a (1 mmol) base (0.5 mmol), solvent (1.0 mL), 24 h. Yield of the isolated prod-
uct. Reaction time 12 h. Reaction with addition of KI (0.5 mmol). nr: no reaction.
c
d
The reaction of fluoro and trifluoromethyl substituted phenyl isothiocyanates with dif-
ferent anilines were well tolerated under the optimal reaction conditions and yield the
desired products (4e–4g) in moderate yields. Notably, aliphatic isothiocyanates such as
cyclohexylisothiocyanate, ethylisothiocyanate, benzylisothiocyanate, and 1-adamantyl
isothiocyanate were reacted smoothly with various substituted anilines as well as thio-
phen-2-ylmethanamine under these conditions and afforded moderate yields (40–65%)
of desired products 4h–4p. Further thiophen-2-ylmethanamine, furan-2-ylmethanamine
and methoxy benzyl amines were reacted with arylisothiocyanate and obtained moderate
to good yields (62–74%) of corresponding products 4q–4s. Further the reaction of ortho
substituted phenyl isothiocyanates having electron withdrawing and electron donating
groups (chloro, methyl) reacted well with aniline and afford the desired products 4t and

1
344
R. KUMAR ET AL.
a
a
Scheme 2. Scope of isothiocyanate with anilines and benzylamines . Reaction conditions: 1a
ꢀ
(
1 mmol) and 2a (1 mmol), NaHCO (0.5 mmol) in 3a (1 mL), at 120 C, 24 h, yield of the isolated prod-
3
b
c
uct. Yield with 1.023 g scale (11.0 mmol). Yields obtained from 1,2-dibromoethane.
4u in moderate to good yields (65% and 70%). Reaction of phenyl isothiocyanates
which contain both methyl and floro groups with aniline also gave the desired product
(4v) in 69% yield.
The successful transformation on the synthesis of various thiazolidin-2-imines under
metal-free conditions prompted us to further investigate the generality of the method
toward aliphatic amine substrates. Thus, different alkyl amines 5 were reacted with dif-
ferent isothiocyanates for the syntheses of alkyl-aryl thiazolidin-2-imines 6 (Scheme 3).
Reaction of phenyl isothiocyanate 2a with aliphatic amines such as long chain (up to
C18), branched, cyclic, and bicyclic amines in 1,2-dichloroethane DCE (3a) were per-
formed under the optimized conditions and the desired (Z)-N-phenyl-3-alkylthiazolidin-
2-imine products 6a–6k were obtained in good yields (66–81%). It is important to note
that, aryl, alkyl and cyclic isothiocyanates were also reactive with different aliphatic
amines under the optimized conditions and produced the corresponding products 6l–6t
in good yields (80%). Further the reaction of ortho substituted phenyl isothiocyanates
having electron withdrawing and electron donating groups (chloro, methyl) reacted

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a
a
Scheme 3. Scope of aliphatic amines . Reaction conditions: 5a (1 mmol) and 2a (1 mmol), NaHCO
(
3
ꢀ
b
0.5 mmol), 3a 1.0 mL at 120 C, 24 h, yield of the isolated product. Yield with 0.957 g
scale (11.0 mmol).
with pentylamine and afford the desired products(6u–6w) in moderate to good yields
(70%ꢁ 80%).
This method is not limited to the use of 1,2-dichloroethane as two carbon sources
products of Schemes 1 and 2); 1,3-dibromo propane 7a also participates in the three-
(
component coupling reactions, providing very good yields of the desired 1,3-thiazinan-
2-imines (Scheme 4). We have examined the reactivity of 7a with phenyl isothiocyanate
2
a and different amines under the set of optimized conditions. Anilines having
various electron donating groups (ethyl, isopropyl and tert-butyl) proceeded
smoothly and afford the desired diaryl-1,3-thiazinan-2-imines 8a2d in good yields
(58–67%). Pentafluoro aniline gave the desired product 8e in moderate (56%) yield.
Naphthalen-1-amine was also reactive and gave (Z)-3-(naphthalen-1-yl)-N-phenyl-1,3-
thiazinan-2-imine 8f in 61% yield. The reaction of 7a and 2a was also compatible with
thiophen-2- ylmethanamine and aliphatic amines under the optimized conditions and
provided the corresponding products 8g–8i in 59–69% yields. The reaction of trifluoro-
methyl phenylisothiocyanates with aniline under the optimal reaction conditions also
provided the desired product (8j) in moderate yields. Good yields of desired products
8
k and 8l were obtained by the reaction of 1-fluoro-4-isothiocyanatobenzene with both
aniline as well as pentylamine. Similarly, various aliphatic isothiocyanates (such as cyc-
lic, bicyclic and ethyl) reacted well with a range of aliphatic amines (C –C ) and
5
18
afforded the corresponding products 8m–8q in good yields (62–85%). Also

1
346
R. KUMAR ET AL.
a
a
Scheme 4. Synthesis and scope of 1,3-thiazinan-2-imines . Reaction conditions: 5a (1 mmol) and 2a
ꢀ
(
1 mmol), NaHCO (0.5 mmol) in 7a 1 mL solvent at 120 C, 24 h.
3
isothiocyanates having activating groups (methyl and tert-butyl) proceeded smoothly
and afford the desired products 8r and 8s in 70% and 72% yields. To further expand
the scope of the present three-component strategy, we tested (1,2-dibromoethyl)ben-
zenes 9 as the dihalide source in dichlorobenzene as solvent under the optimized condi-
tions, surprisingly we observed the regioselective annulated product 10 over the other
product 11 (Scheme 5). Aniline as well as aliphatic amines 5 and phenylisothiocyanate
2
a were reacted smoothly with 1,2-dibromoethyl)benzene derivatives 9 and afford the
desired products 10a2f in moderate to good yield (50–75%). The regioselective annula-
tion of dibromo styrenes under the present conditions has been further confirmed by
XRD analysis of the product 10e. The reaction of 1a and 2a with 1-(1,2-dibromoethyl)
naphthalene and 1,2-dibromooctane under the same conditions gave the desired prod-
ucts 10g and 10h in 61% and 62% yields respectively. Also, the reaction was performed
with ethyl isothiocyanate with aniline and 1,2-dibromoethyl) benzene, the desired annu-
lated product 10i was obtained in 58% yield. However, the present conditions are not
suitable to yield the desired products (10j and 10k) when cyclic and internal dibromo
derivatives were employed.
To gain insights into the reaction mechanism, selective control experiments were per-
formed (Scheme 6). The reaction of 1a and 2a was subjected to the optimized condi-
tions along with radical scavengers (TEMPO, BHT, and benzoquinone) to know the
reaction pathway. Under these conditions, the desired product 4a was isolated in 55%,
58% and 60% yield “respectively” (Scheme 6a). These reactions suggest that, the present
transformation may proceed through the ionic path. The reaction of 1a and 2a was

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a
a
Scheme 5. Synthesis and scope of 1,3-thiazinan-2-imines . Reaction conditions: 5 (1 mmol) and 2
ꢀ
(
1 mmol), NaHCO (0.5 mmol), 9 (1.0 mmol), 1,2-dichlorobenzene (1.0 mL) at 120 C, 24 h, yield of the
3
b
isolated product. Yield with 1.023 g scale (11.0 mmol). CCDC for 10e: 1959624.
subjected with b-bromo/nitro styrene 11 under the optimized conditions in 1,2-dichlor-
obenzene, and obtained the product (Z)-N,3,5-triphenylthiazol-2(3H)-imine 12 in 56%
and 30% yield (Scheme 6b). Further 1a and 2a was subjected with a-substituted styrene
1
3, 15 and styrene and 16 with the above conditions, in these cases no reaction was
observed (Scheme 6c–e). These reactions indicate that b-substituted styrenes react with
a and 2a, but a-substituted styrenes do not react under these conditions. No reaction
1
was observed with ethylbenzene 17 under the same conditions (Scheme 6f). Also the
reaction was performed with (2-bromoethyl)benzene 18 and (1-bromoethyl)benzene 20
there were no desired products were obtained only 1,3-diphenylthiourea 19 products
was observed (Scheme 6g–h) with yield (70-75%). From the above reactions it suggests
that it is essential to have the leaving group at b-position and hydride at a-position of
styrenes for the cyclization to yield the expected products. When the reaction was per-
ꢀ
formed at room temperature and at 60 C, the desired product was obtained in trace at
ꢀ
r.t, and 40% yield at 60 C along with 47% yield of undesired product 1,3-diphenylth-
iourea 19 was observed (Scheme 6i).

1
348
R. KUMAR ET AL.
Scheme 6. Control experiments.
Based on the control experiments and the literature reports [16,17] plausible reac-
tion mechanism has been proposed for the present transformation (Scheme 7).
Initially, the reaction of aniline 1a with phenylisothiocyanate 2a in presence of base
generates thiourea sulphonium ion intermediate A. The nucleophilic attack of A on

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Scheme 7. Plausible mechanism.
the secondary carbon of 3/9 generates more stable intermediate B (path a). The
dehydrohalogenation of B and followed by cyclization afford the desired product 4/
1
0. On the other hand, the attack of A on the primary carbon of 3/9 (path b), to
generate the intermediate C, and its subsequent dehydrohalogenation to yield the
product 11 was not observed.
Conclusions
In summary, we have developed a convenient method for the synthesis of thiazolidin-2-
imines/1,3-thiazinan-2-imines via three-component annulation reactions under
metal-free conditions. We have employed both dichloroethane, 1,2-dibromo-octane and
(1,2-dibromoethyl) benzenes as two carbon sources for the annulation reactions and
obtained the corresponding saturated five-membered heterocycles. Under the same con-
ditions, with 1,3-dibromopropane as dihalide source, the corresponding saturated six
membered heterocycles were obtained in good yields. These aliphatic heterocycles
enhance the drug discovery process through late stage functionalization. The method
works well with broad substrate scope with respect to both isothiocyanates (such as aro-
matic, aliphatic, cyclic) and amines such as aromatic, aliphatic, cyclic, adamantine
including thiophen-2-ylmethanamine and furan-2-ylmethanamine. To validate the feasi-
bility of the process for commercial applications, four products were synthesized at
1
1.0 mmol scale under the optimized conditions.
Experimental section
General
All commercially available chemicals and reagents were used without any further purifi-
1
13
cation unless otherwise indicated. H and C NMR spectra were recorded at 600, 500,
00 and 150, 125, 50 MHz, respectively. The spectra were recorded in CDCl as solvent.
2
3
Multiplicity was indicated as follows: s (singlet); d (doublet); t (triplet); m (multiplet);

1
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R. KUMAR ET AL.
dd (doublet of doublets), etc. and coupling constants (J) were given in Hz. Chemical
shifts are reported in ppm relative to TMS as an internal standard. The peaks around
1
13
delta values of H NMR (7.2), and C NMR (77.0) are correspond to deuterated solvent
chloroform respectively. Mass spectra were obtained using electron impact (EI) ioniza-
tion method. Progress of the reactions was monitored by thin layer chromatography
(TLC). All products were purified through column chromatography using silica gel
100–200 mesh size using hexane/ethyl acetate as eluent unless otherwise indicated.
General procedure for 4a
A clean washed boiling tube equipped with a magnetic stir bar was charged with aniline
1
a (0.0930 g, 1 mmol), phenyl isothiocyanates 2a (0.1350 g, 1 mmol), 0.5 mmol of
ꢀ
NaHCO and dichloroethane (1 mL), the above mixture was stirred for 24 h at 120 C
3
temperature. After completion of the reaction, the mixture was poured into 10 mL of
NaHCO solution. The product was extracted with ethyl acetate (10 mL ꢂ 3) and dried
3
with anhydrous Na SO . Removal of the solvent under reduced pressure, the left-out
2
4
residue was purified through column chromatography using silica gel (20% EtOAc/hex-
ane) to obtained (Z)-N,3-diphenylthiazolidin-2-imine 4a in 82% yield (0.2082 g).
Copies of NMR spectra for all compounds, HRMS spectra for new compounds and
melting points of solid compounds. This material is available free of charge via the
internet at Crystallographic data for compounds 4a (CCDC-1959623) and 10e (CCDC-
1959624) can be obtained free of charge from the Cam-bridge Crystallographic Data
Center via mail-to: www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
Authors are thankful to the “Analytical Discipline and Centralized Instrumental Facilities” for
providing instrumentation facilities.
Funding
CSIR-CSMCRI communication [No. 140/2019]. R. K is to AcSIR for his Ph.D. enrolment and
UGC, New Delhi for Senior Research Fellowship. S. A. is thankful to DST, Govt. India [EMR/
2
016/000010] for the research grants and CSIR-CSMCRI [MLP-027] for partial financial support.
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