Convenient Synthesis of Thiohydantoins, Imidazole-2-thiones and Imidazo[2,1-b]thiazol-4-iums from Polymer-Supported α-Acylamino Ketones

Article abstract of DOI:10.3390/molecules23040976

The preparation of 5-methylene-thiohydantoins using solid-phase synthesis is reported in this paper. After sulfonylation of immobilized Ser (t-Bu)-OH with 4-nitrobenzenesulfonyl chloride followed by alkylation with various bromoketones, the 4-Nos group was removed and the resulting polymer-supported α-acylamino ketones reacted with Fmoc-isothiocyanate. Cleavage of the Fmoc protecting group was followed by the spontaneous cyclative cleavage releasing the 5-methylene-thiohydantoin derivatives from the polymer support. Reduction with triethylsilane (TES) yielded the corresponding 5-methyl-thiohydantoins. When Fmoc-isothiocyanate was replaced with alkyl isothiocyanates, the trifluoroacetic acid (TFA) mediated cleavage from the polymer support, which was followed by the cyclization reaction and the imidazo[2,1-b]thiazol-4-iums were obtained. Their conversion in deuterated dimethylsulfoxide led to imidazole-2-thiones.

Full text of DOI:10.3390/molecules23040976

molecules
Article
Convenient Synthesis of Thiohydantoins,
Imidazole-2-thiones and Imidazo[2,1-b]thiazol-4-iums
from Polymer-Supported α-Acylamino Ketones
Petra Králová 1 , Michal Malo nˇ , Hiroyuki Koshino 3 and Miroslav Soural 4,*
ID
2
ID
1
Department of Organic Chemistry, Faculty of Science, Palacký University, 17. Listopadu 12, 771 46 Olomouc,
Czech Republic; petra.kralova@upol.cz
JEOL Ltd., Musashino 3-1-2, Akishima, Tokyo 196-8558, Japan; mmichal@jeol.co.jp
RIKEN Center for Sustainable Resource Science, Hirosawa 2-1, Wako, Saitama 351-0198, Japan;
2
3
koshino@riken.jp
4
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University,
Hnevotinska 5, 779 00 Olomouc, Czech Republic
*
Correspondence: miroslav.soural@upol.cz; Tel.: +420-585632196
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 10 April 2018; Accepted: 20 April 2018; Published: 23 April 2018
Abstract: The preparation of 5-methylene-thiohydantoins using solid-phase synthesis is reported
in this paper. After sulfonylation of immobilized Ser (t-Bu)-OH with 4-nitrobenzenesulfonyl
chloride followed by alkylation with various bromoketones, the 4-Nos group was removed and
the resulting polymer-supported
of the Fmoc protecting group was followed by the spontaneous cyclative cleavage releasing the
-methylene-thiohydantoin derivatives from the polymer support. Reduction with triethylsilane
TES) yielded the corresponding 5-methyl-thiohydantoins. When Fmoc-isothiocyanate was replaced
α-acylamino ketones reacted with Fmoc-isothiocyanate. Cleavage
5
(
with alkyl isothiocyanates, the trifluoroacetic acid (TFA) mediated cleavage from the polymer support,
which was followed by the cyclization reaction and the imidazo[2,1-b]thiazol-4-iums were obtained.
Their conversion in deuterated dimethylsulfoxide led to imidazole-2-thiones.
Keywords: heterocycle; thiohydantoin; imidazole; serine; bromoketone; solid-phase synthesis
1
. Introduction
The reaction of polymer-supported 2- or 4-nitrobenzensulfonamides with
the simple production of many different heterocycles using the concept of diversity-oriented
synthesis [ ]. Recently, this chemistry was used to prepare morpholines and thiomorpholines from
polymer-supported serine and cysteine via the corresponding -acylamino ketones [ ]. In addition,
II [7 + 6] or pyrazino-oxazines III [6 + 6] were obtained via
-acylamino ketones with different reagents (see Scheme 1) [ ].
α-haloketones allows
1
α
2–4
fused benzodiazepine-oxazines
the acylation or sulfonylation of
I,
α
5–7
As a continuation of our ongoing research in the field of solid-phase syntheses of pharmacologically
promising heterocycles, we suggested the application of immobilized -acylamino ketones for
α
preparing novel fused [5 + 6] heterocycles bearing a thiohydantoin scaffold. 2-Thiohydantoins
are present in the structure of many natural and synthetic compounds that can serve as
antiandrogens [
possess antimycobacterial [12], anti-inflammatory [13], anticonvulsant [14
and anti-tumour properties [17 18]. A variety of approaches for accessing 2-thiohydantoins using both
traditional solution-phase synthesis [10 19 22] and solid-phase synthesis [23 26] have been reported.
8], immunomodulators [9], or agricultural agents [10
,
11]. These derivatives also
,15], antiarrhythmic [16],
,
,
–
–
In contrast, 2-thiohydantoins fused with morpholine or oxazine scaffolds and structurally related
compounds have rarely been studied. Inspired by these findings, we attempted a simple synthesis to
Molecules 2018, 23, 976; doi:10.3390/molecules23040976
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prepare the desired heterocycles from polymer-supported
α
-acylamino ketones. The actual course of
reaction based on careful structural elucidation of isolated products is reported in this paper.
Scheme 1. Previous applications of serine-based immobilized α-acylamino ketones and the proposed
[5 + 6] heterocyclic scaffold.
2
. Results
The proposed synthetic pathway (see Scheme 2) was tested with 2-bromo-1-phenylethan-1-one
and Fmoc-isothiocyanate as representative substrates. First, -acylamino ketone {1} (Chemset
Numbering System is used hereafter) was synthetized in four steps from Wang resin-supported
Fmoc-Ser(t-Bu)-OH based on previously reported procedures. [ ] Reaction with Fmoc-NCS yielded
the corresponding Fmoc-thiourea {1,1}. After cleaving the Fmoc-protecting group, liberated thiourea
{1,1} underwent spontaneous cyclative cleavage, which released 2-thiohydantoin intermediate {1,1}
from the polymer matrix. The cleavage cocktail (DMF/piperidine) was freeze dried and the residual
compound {1,1} was subjected to TFA cyclization. However, the previously reported formation of the
oxazine scaffold 5{1,1} [7] was not observed and 5-methylidene-thiohydantoin 6{1,1} was obtained in
0% crude purity (measured by LC-UV traces at 205–400 nm) as a result of the t-Bu protecting group
cleavage and dehydration. We also tested TFA/TES reduction of the methylidene derivative {1,1},
which was reported earlier to reduce dihydroxazines [ ]. This provided 5-methyl-thiohydantoin {1,1}
α
1
2
2
3
3
4
8
6
2
7
in excellent crude purity (85%) and had an overall yield of 19%. Similar results were obtained for other
1
5-methyl-thiohydantoins
7
{R ,1}, which were obtained in crude purities of 71% to 85% and overall
yields of 15% to 19% (see Table 1).

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Table 1. List of prepared compounds.
Crude
Final Purity
(%)
OverallVield
(%) c
Ratio 8:9
Ratio 8:9 after
Heating (%)
Cmpd
R1
R2
Purity (%) a
b
At rt (%) c
c,d
6{1,1}
6{4,1}
6{5,1}
6{6,1}
6{7,1}
7{1,1}
7{6,1}
7{7,1}
8{1,2}
8{1,3}
8{1,4}
8{2,2}
8{2,5}
8{3,3}
8{3,4}
8{3,6}
8{4,4}
8{4,5}
8{5,2}
8{5,3}
8{5,6}
8{7,2}
8{7,3}
8{7,6}
Ph
4-F-Ph
4-Br-Ph
H
H
H
H
H
H
H
H
Bn
allyl
Et
Bn
80
69
75
68
85
85
71
72
80
90
91
96
77
87
92
95
85
70
91
69
90
97
83
95
99
98
97
98
97
99
98
99
98
98
99
99
99
99
99
99
99
99
98
99
98
98
98
98
11
11
7
8
8
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
4-NH
2
-3,5-diClPh
3-thiophenyl
Ph
4-Br-Ph
3-thiophenyl
Ph
19
16
15
53
34
23
38
49
32
59
39
57
19
28
18
17
26
24
39
93:7
100:0
45:55 e
97:3
100:0
84:16
100:0
60:40 e
100:0
8:92 e
98:2
100:0
88:12
97:3
89:11
82:18
0:100
8:92
11:89
3:97
NT
3:97
13:87
0:100
16:84
8:92
9:91
29:71
0:100
0:100
0:100
82:18
Ph
Ph
4-Me-Ph
4-Me-Ph
4-MeO-Ph
4-MeO-Ph
4-MeO-Ph
4-F-Ph
4-F-Ph
4-Br-Ph
4-Br-Ph
4-Br-Ph
cyclohexylmethyl
allyl
Et
2-(4-morpholino)ethyl
Et
cyclohexylmethyl
Bn
allyl
2-(4-morpholino)ethyl
Bn
3-thiophenyl
3-thiophenyl
3-thiophenyl
allyl
2-(4-morpholino)ethyl
a
b
Overall purity after the entire reaction sequence calculated from HPLC-UV (205–400 nm); HPLC-UV after
c
1
d
purification (205–400 nm); Calculated from the H-NMR spectrum of the purified product; Sample heated at
1
◦
◦
e
20 C for 30 min and measured after cooling to 27 C; Sample was shortly heated prior to NMR analysis to
dissolve, NT—not tested.
Scheme 2. Synthesis of 5-methylidene and 5-methyl-thiohydantoins. Reagents and conditions:
(
i) Fmoc-NCS, anhydrous THF, 2 h, rt; (ii) 35% piperidine/DMF, 24 h, rt (or 10% piperidine/DMF for
◦
derivative 2{4,1}); (iii) neat TFA, 20 h, 35 C; (iv) TFA/TES/DCM (5:3:5), 24 h, rt.

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To test the applicability of the reaction sequence for N-substituted derivatives, we subsequently
replaced Fmoc-NCS with alkyl-isothiocyanates. The reaction of
yielded the corresponding N-benzyl-thiourea
the immobilized N-benzyl-thiourea
1
{1} with benzyl-isothiocyanate
1
2
{1,2} (see Scheme 3). In contrast to intermediates
{1,2} did not undergo the cyclative cleavage and trifluoroacetic
3{R ,1},
2
acid (TFA) was used to release the compound from the resin. Further exposure to TFA under an elevated
temperature led to a cyclization reaction. Although the mass spectrometry data corresponded to
the expected thiohydantoin-dihydrooxazine derivative (see Scheme 3), the careful structural NMR
elucidation of the isolated compound revealed that the scaffold was not formed. The cyclization
to imidazole-2-thione took place followed by the dehydration and ring closure, which yielded
an imidazo[2,1-b]thiazol-4-ium derivative
purity of 80% and overall yield of 53% (after semipreparative HPLC purification).
We further tested how applicable the reaction sequence is for various -bromoketones and
8{1,2}. The product was obtained in an overall crude
α
isothiocyanates. Structurally diverse building blocks (see Figure 1) with electron-donating and
1
electron-withdrawing substituents were successfully used to prepare key intermediates
2
{R ,2
−
6}.
The reaction time was dependent on the reactivity of the used isothiocyanate. For instance, in the case
1
of resin-bound compounds
2
{R ,2}, which were prepared from benzyl isothiocyanate, the formation
of the corresponding thioureas was relatively fast and the reaction time was only 20 h. However,
the reaction with cyclohexylmethyl isothiocyanate required noticeably longer to reach quantitative
conversion (see supplementary materials for more details). The subsequent TFA-mediated cyclization
1
was also dependent on the type of N-substituent, and for allyl derivatives
8
{R ,3}, the reaction time had
to be extended from 20 h to 48 h. In total, 16 final compounds were synthesized by combining different
-bromoketones and isothiocyanates (see Table 1 for the list of products). The desired products were
α
obtained and they had very good to excellent overall crude purities of 69% to 97% and good overall
yields of 17% to 59%.
Scheme 3. Synthesis and applicability of N-substituted immobilized thioureas. Reagents and
2
1
conditions: (i) R -NCS, anhydrous THF, 44 h, rt (or 20 h for derivatives 2{R ,2} and 64 h for derivatives
2
1
◦
1
{R ,5}); (ii) (a) neat TFA, 80 C, 20 h (or 48 h for derivatives 2{R ,3}), (b) evaporation of TFA,
(c) reverse-phase HPLC purification using ammonium acetate buffer, (d) freeze-drying.

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Figure 1. List of successfully tested building blocks.
1
2
When semipreparative HPLC purified compounds
8
{R ,R } were submitted to NMR analysis in
deuterated DMSO. H-NMR spectra of some derivatives showed the presence of impurity in quantities
up to 18%. Compound {3,3}, which was synthesized from allyl isothiocyanate (16% of impurity
1
8
detected), was subjected to detailed NMR characterization. The data indicated ring opening may have
led to the formation of 9{3,3} as the corresponding impurity (see Figure 2).
Figure 2. Isomerization of imidazo[2,1-b]thiazol-4-iums to imidazole-2-thiones.
1
To prove the structure,
8
{3,3} was analyzed using gradual increase temperature H-NMR. Elevated
◦
temperatures led to a gradual increase in the content of the minor compound from 16% to 43% (80 C)
◦
◦
and 84% (100 C). A nearly full conversion (97%) to the side product was observed at 120 C. Cooling
the sample to room temperature did not change the content of the new product. HPLC-MS analysis of
the isolated compound confirmed its molecular weight was identical to that of the original product,
which supported the putative formation of compound
of both compounds ( {3,3} and {3,3}) using 2D experiments confirmed their structures by identifying
characteristic signals (see Figure 3).
In the case of compound
conversion to
to
9{3,3} (see Figure 2). Further NMR investigations
8
9
8
{1,2}, which was synthesized from benzyl isothiocyanate, the slow
◦
9
{1,2} was observed at 27 C in DMSO-d . The reaction quickly reached full conversion
6
9
{1,2} at a higher temperature (see Supporting Information for more details). In most cases, the
1
1
heating of derivatives
8{R ,2–6} for 30 min provided compounds
9{R ,2–6} as major products (71–100%
1
as measured by H NMR spectra; see Table 1). If the conversion to imidazole-2-thiones
9
was not
quantitative, heating for a longer time was also tested and the ratio remained unchanged, but slow
decomposition of products was observed. In just one case, heating of 8{7,6} did not change the initial
ratio of compounds even after a prolonged time of 17 h. In the cases of
8{1,4}, 8{3,6}, and 8{4,5},
the solubilities of the purified samples in DMSO-d at room temperature were limited. Therefore,
6

Molecules 2018, 23, 976
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◦
short heating to 50 C was necessary to dissolve the material for analysis. For this reason, the NMR
spectra of these products are significantly enriched in the compounds 9 (40% to 92%).
Figure 3. Characteristic signals of imidazo[2,1-b]thiazol-4-ium
8
{3,3} (highlighted in red) and
◦
◦
imidazole-2-thione
9{3,3} (highlighted in blue) (measured at 27 C and after heating to 140 C and
◦
cooling to 27 C, respectively).
3
. Conclusions
In conclusion, we have reported a convenient method for preparing novel thiohydantoins,
imidazole-2-thiones, and imidazo[2,1-b]thiazol-4-iums using a solid-phase synthesis technique.
Depending on the type of isothiocyanate and cleavage conditions used, different products were
obtained. In total, we synthetized and fully characterized more than 36 original compounds,
which were generally isolated and had very good overall purities and acceptable yields. The developed

Molecules 2018, 23, 976
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strategy can be combined with previously reported protocols to synthesize different heterocycles
starting from immobilized -acylamino ketones by using diversity-oriented reagent-based synthesis.
Derivatives and represent Michael acceptors and can be considered potential inhibitors of various
α
7
9
enzymes through the irreversible Michael addition reaction, which currently represents an area of
growing interest in the field of drug discovery and development [27–29].
Supplementary Materials: The following are available online: Experimental procedures and analytical data
of products.
Acknowledgments: The authors are grateful to project CZ.1.07/2.3.00/20.0009 from the European Social
Fund, the National Program of Sustainability (project LO1304), and an internal grant from Palacký University
(IGA_LF_2018_32 and IGA_PrF_2018_29).
Author Contributions: P.K. performed all synthetic experiments and characterization of compounds; M.M. and
H.K. analyzed NMR data and verified the target structures; M.S. supervised the project and wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest. The founding sponsors had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the
decision to publish the results.
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Sample Availability: Samples of the compounds are not available from the authors.
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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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