Sequential MCR via Staudinger/Aza-Wittig versus Cycloaddition Reaction to Access Diversely Functionalized 1-Amino-1H-Imidazole-2(3H)-Thiones

Article abstract of DOI:10.3390/molecules24203785

A multicomponent reaction (MCR) strategy, alternative to the known cycloaddition reaction, towards variously substituted 1-amino-1H-imidazole-2(3H)-thione derivatives has been successfully developed. The novel approach involves α-halohydrazones whose azidation process followed by tandem Staudinger/aza-Wittig reaction with CS₂ in a sequential MCR regioselectively leads to the target compounds avoiding the formation of the regioisomer iminothiazoline heterocycle. The approach can be applied to a range of differently substituted α-halohydrazones bearing also electron-withdrawing groups confirming the wide scope and the substituent tolerance of the process for the synthesis of the target compounds. Interestingly, the concurrent presence of reactive functionalities in the scaffolds so obtained ensures post-modifications in view of N-bridgeheaded heterobicyclic structures.

Full text of DOI:10.3390/molecules24203785

molecules
Article
Sequential MCR via Staudinger/Aza-Wittig versus
Cycloaddition Reaction to Access Diversely
Functionalized 1-Amino-1H-Imidazole-2(3H)-Thiones
Cecilia Ciccolini, Giacomo Mari, Gianfranco Favi * , Fabio Mantellini, Lucia De Crescentini
and Stefania Santeusanio *
Department of Biomolecular Sciences, Section of Chemistry and Pharmaceutical Technologies, University of
Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino (PU), Italy; c.ciccolini@campus.uniurb.it (C.C.);
giacomo.mari@uniurb.it (G.M.); fabio.mantellini@uniurb.it (F.M.); lucia.decrescentini@uniurb.it (L.D.C.)
* Correspondence: gianfranco.favi@uniurb.it (G.F.); stefania.santeusanio@uniurb.it (S.S.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Wim Dehaen
Received: 25 September 2019; Accepted: 15 October 2019; Published: 21 October 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: A multicomponent reaction (MCR) strategy, alternative to the known cycloaddition reaction,
towards variously substituted 1-amino-1H-imidazole-2(3H)-thione derivatives has been successfully
developed. The novel approach involves α-halohydrazones whose azidation process followed by
tandem Staudinger/aza-Wittig reaction with CS2 in a sequential MCR regioselectively leads to the target
compounds avoiding the formation of the regioisomer iminothiazoline heterocycle. The approach can
be applied to a range of differently substituted α-halohydrazones bearing also electron-withdrawing
groups confirming the wide scope and the substituent tolerance of the process for the synthesis of the
target compounds. Interestingly, the concurrent presence of reactive functionalities in the scaffolds so
obtained ensures post-modifications in view of N-bridgeheaded heterobicyclic structures.
Keywords: multicomponent reaction; α-halohydrazones; Staudingerreaction; aza-Wittig; 1H-imidazole-
2(3H)-thione; 2H-imidazo[2,1-b][1,3,4]thiadiazine
1. Introduction
Imidazoles belong to an important class of heterocyclic compounds that play a crucial role in various
biochemical processes [1]. A lot of imidazole-based molecules have been shown bioactivities, [2] such as
antifungal, antiinflammatory, antihystamine, antihelmintic, analgesic, antineoplastic, antihypertensive
activity [3–7].
Among imidazole derivatives, imidazole-2-thiones have been associated to a special class of
biologically relevant thiourea derivatives [8] endowed with antithyroid [9], antiproliferative [10],
matrix metalloproteinases (MPP) inhibitory [11] properties and can be used as building blocks for the
synthesis of N-aminoimidazole with antiretroviral activity [12].
To date, the most widespread method used for the synthesis of N-substituted 1-amino-1H-imidazol-
2(3H)-thiones can be referred to the Schantl’s protocol, which consists of reacting
potassium thiocyanate and monosubstituted arylhydrazines in weak acidic medium (Scheme 1) [13
This multistep reaction is considered to proceed via the formation of conjugated azoalkenes, derived from
-thiocyanatohydrazones (Scheme 2) and dipolarophile isothiocyanic acid intermediate that in turn
α-haloketones with
–19].
α
D
undergo a [3+2] cycloaddition reaction providing substituted 1-arylamino-1H-imidazole-2(3H)-thione
scaffolds [20,21].
I
Molecules 2019, 24, 3785; doi:10.3390/molecules24203785
www.mdpi.com/journal/molecules

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Scheme 1. Schantl’s protocol for the synthesis of N-substituted 1-amino-1H-imidazole-2(3H)-thione
derivatives I.
Even if this method appears robust, it seems to suffer of some limitations in terms of insertion
of electron-withdrawing groups placed on the -halohydrazone precursors of conjugated azoalkene
intermediates. In this regard, for our research purposes, we tried to apply the Schantl’s method
reacting 2-chloro-N,N-dimethyl-3-oxobutanamide ( ), potassiun thiocyanate ( ) and tert-butyl
hydrazinecarboxylate ( ) in acetic acid to obtain the corresponding N-substituted 1-amino-1H-
imidazole-2(3H)-thione derivative but without success. As shown in Scheme 2, instead of the
α
A
B
C
I
cycloaddition, a 5-exo-dig cyclization reaction leading to 2-iminothiazole II took place. This evidence
is in agreement with the result obtained by Lagoja and coworkers where a pathway involving the key
α-thiocyanatohydrazone intermediate D is invoked [12].
Scheme 2. Pathway for the formation of 2-iminothiazoline heterocycle II.
The structure of the iminothiazoline II was confirmed by comparison of the spectral data of the
same compound obtained by means of a different procedure previously described by some of us that
foresees the conjugated hydrothiocyanation of the pertinent conjugated azoalkene in acidic medium
followed by intramolecular cyclization [22].
Inspired by our previous experience [23], and in order to perform a complete regioselective-oriented
method for the desired 1-amino-1H-imidazole-2(3H)-thiones
avoids the use of bidentate-nucleophilic reagents such as the potassium thiocyanate. In the construction
of , three strategic disconnections between the N1-C2, C2-N3 and N3-C4 were hypothesized (Scheme 3).
I, we have planned a different strategy that
I

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Scheme 3. Our hypothesized disconnection of 1-amino-1H-imidazole-2(3H)-thione I derivatives.
We reasoned that the azidation process of the pertinent -halohydrazone derivative followed by
α
tandem Staudinger/aza-Wittig reaction with CS2 could have been a successful route [24,25].
2. Results and Discussion
To validate our hypothesis we began to explore the process step by step. Thus,
derivative 1a 26 30] (2.0 mmol) dissolved in THF (9.0 mL) subjected to -azidation using an ice-cooled
aqueous solution of NaN3 [31] (2.0 mmol/1.0 mL) under magnetic stirring at room temperature.
After the evaporation of the solvent and an appropriate extraction, the -azidohydrazone derivative
α-chlorohydrazone
[
–
α
α
2a was obtained in 70% yield. In the next step, the addition of a stoichiometric amount of PPh3 to 2a
(1.0 mmol) dissolved in CH2Cl2 (5.0 mL) furnished the iminophosphorane derivative 3a by precipitation
from the reaction medium (66%). Then, 3a (0.65 mmol) was dissolved in 5.0 mL of THF/MeOH mixture
(4:1) and treated with an excess of CS2 at reflux to afford, after column chromatography purification,
the corresponding N-substituted 1-amino-2,3-dihydro-1H-imidazole-2-thione derivative 5a (53%)
arising from intramolecular cyclization of the α-isothiocyanate hydrazone intermediate 4a (Scheme 4).
Scheme 4. Step-by-step synthetic pathway for N-substituted 1-amino-2,3-dihydro-1H-imidazole-2-
thione derivative 5a.
Motivated by this result, we aimed to develop a one-pot sequential multicomponent reaction
(MCR) [32–35] as alternative method for regioselective synthesis of a new series of imidazole-2-
thione-containing structures as suitable precursors for drug-like compounds [36].
Hence, our new approach to N-substituted 1-amino-1H-imidazole-2(3H)-thiones 5a–k (53%–85%)
is depicted in Scheme 5. The whole process that permits the formation of the desired heterocycle can
be easily checked by the complete disappearance of the pertinent -azidohydrazone derivative and by
α
the observation of Ph3P=S as byproduct (thin-layer chromatography (TLC) check, see Experimental
Section). It is to be noted that for 5a, the efficiency of the reaction benefits by this latter protocol
increasing the overall yield from 25% (obtained employing the step-by-step procedure) to 79% (Table 1).
Moreover, the implemented strategy broadens the substitution patterns at the amino-N1 and at C4 of the

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heterocycle skeleton with electron-withdrawing groups (5a–e) and tolerates the aromatic (amino-N1)
and aliphatic (C4) groups, as for 5j [15,17,18] (Table 1).
Scheme 5. New multicomponent reaction (MCR) method for N-substituted 1-amino-2,3-dihydro-1H-
imidazole-2-thione derivatives 5a–k.
Table 1. Substrate scope of the MCR synthetic pathway for N-substituted 1-amino-2,3-dihydro-1H-
imidazole-2-thione derivatives 5a–k.
One-Pot MCR
Entry
α-Halohydrazone 1
Yield (%) a, b
5
R1
R2
R3
X
CO2But
CONHPh
CO2But
CO2But
CO2But
CO2But
CONHPh
COPh
25 a; 79 b
53 b
1
2
3
4
5
1a
1b
1c
1d
1e
1f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
CON(Me)2
CON(Me)2
CON(Et)2
H
CONH2
CONHPh
H
Cl
Cl
Br
Cl
Br
Br
Cl
Cl
Cl
Cl
Br
5a
5b
5c
5d
5e
5f
5g
5h
5i
72 b
69 b
58 b
67 b
6
82 b
7
8
9
1g
1h
1i
59 b
H
Me
Me
H
CONHPh
4-NO2-Ph
CO2But
85 b
84 b
10
11
1j
1k
5j
5k
66 b
a
b
Overall yield of isolated product 5a from the step-by-step reaction based on 1a
; Overall yield of isolated products
5a–k from one-pot MCR based on 1a–k.
These results not only lie in the wide scenario of the heterocyclic scaffolds obtainable through
tandem Staudinger/aza-Wittig sequence [24 25 37 41], but the concurrent presence of reactive
functionalities in the target compounds 5a ensures post-modifications in view of heterobicyclic
,
, –
–
k
structures. In fact, the tautomerism thionoamide/thioloimide permits the introduction of a further
element of diversity at the sulfur atom producing imidazole derivatives suitable to be combined with the
useful 1-amino-Boc protected group [42] directly installed by this approach, as for 5a
example, 5c (1.0 mmol) solved in acetone (10.0 mL), were reacted with 2-bromo-1-phenylethanone
6a) (1.0 mmol), 1-chloropropan-2-one) (6b) (1.0 mmol), and ethyl 2-bromoacetate (6c) (1.0 mmol),
respectively, in the presence of K2CO3 (1.0 mmol). After the removal of solvent followed by
extraction, the corresponding -(imidazol-2-ylthio) carbonyl compounds 7a were obtained as
, 5c–f, 5k. Thus, as an
,d,f
(
α
–c
solid after column chromatography purification (84%–93%) (Scheme 6). The subsequent cleavage
of the Boc-protecting group under homogeneous [43] or heterogeneous acidic conditions [44] was
able to produce free amino function available to interact with the carbonyl appendage in 2-position
of the ring, affording new 2H-imidazo [2,1-b][1,3,4]thiadiazine derivatives 8a,b by condensation
or 2H-imidazo[2,1-b][1,3,4]thiadiazinone derivative 8c by acylic nucleophilic substitution process
(Scheme 6, Table 2).

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Scheme 6. Synthetic approach to 2H-imidazo[2,1-b][1,3,4]thiadiazine derivatives.
Table 2. Substrate scope of the reaction between 1-amino-2,3-dihydro-1H-imidazole-2-thione derivatives
5 with α-haloketones 6a,b or α-haloester 6c.
5
6
7
Yield (%) a
8
Yield (%) b
R2
Me
Me
Me
R3
X
R4
Ph
Me
OEt
5c
5d
5f
CON(Et)2
H
CONHPh
6a
6b
6c
Br
Cl
Br
7a
7b
7c
84
93
92
8a
8b
8c
82
65
74
a
Yield of isolated product 7a–c based on 6a–c; b Yield of isolated product 8a–c based on 7a–c.
It is worthwhile to note that the proposed synthetic pathway can offer an alternative method for
obtaining 2H-imidazo[2,1-b][1,3,4]thiadiazine derivatives with respect to the ring transformation
of -(oxazol-2-ylthio) ketones on treatment with hydrazine hydrate 10 45], together with the
8
α
9
[
possibility of wide diversification of the substituents at the different positions of the N-bridgeheaded
heterobicyclic structures. As depicted in Scheme 7, a different disconnection for the assembly of the
2H-imidazo[2,1-b][1,3,4]thiadiazine scaffold can be envisaged.
Scheme 7. Different synthetic approaches to 2H-imidazo[2,1-b][1,3,4]thiadiazine derivatives.

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3. Experimental Section
3.1. General
All the commercially available reagents and solvents were used without further purification.
-Halohydrazones 1a were synthesized by known procedures [26 30]. Chromatographic purification
of compounds was carried out on silica gel (60–200 m). Thin-layer chromatography (TLC) analysis
α
–k
–
µ
was performed on pre-loaded (0.25 mm) glass supported silica gel plates (Silica gel 60, F254, Merck;
Darmstadt, Germany); compounds were visualized by exposure to UV light. Melting points (Mp) were
determined in open capillary tubes and are uncorrected.
1
◦
All H NMR and 13C NMR spectra were recorded at 400 and 100 MHz, respectively at 25 C
on a Bruker Ultrashield 400 spectrometer (Bruker, Billerica, MA, USA). Proton and carbon spectra
were referenced internally to residual solvent signals as follows:
δ
= 2.50 ppm for proton (middle
= 7.27 ppm for proton and
peak) and = 39.50 ppm for carbon (middle peak) in DMSO-d6 and
δ
δ
δ = 77.00 ppm for carbon (middle peak) in CDCl3. The following abbreviations are used to describe
peak patterns where appropriate: s = singlet, d = doublet, t = triplet q = quartet, m = multiplet and
br = broad signal. All coupling constants (J) are given in Hz. Copies of 1H-NMR and 13C-NMR spectra
of compounds II, 2a, 3a, 5a–k, 7a–c, and 8a–c are in Supplementary Materials. FT-IR spectra were
measured as Nujol mulls using a Nicolet Impact 400 (Thermo Scientific, Madison, WI, USA). Mass
spectra were obtained by ESI-MS analyses performed on Thermo Scientific LCQ Fleet Ion Trap LC/MS
and Xcalibur data System. High-resolution mass spectra (HRMS) were determined with ESI resource
on a Waters Micromass QTOF instrument (Waters, Milford, MA, USA). Elemental analyses were within
±0.4 of the theoretical values (C, H, N).
3.2. Step-By-Step Synthetic Method for 5a
3.2.1. Synthesis of tert-butyl 2-(3-azido-4-(dimethylamino)-4-oxobutan-2-ylidene)
hydrazinecarboxylate (2a)
To the α-halohydrazone 1a (555.5 mg, 2.0 mmol) solved in THF (9.0 mL), an ice-cooled aqueous
solution (1.0 mL, T = 4 ◦C) of NaN3 (2.0 mmol, 130.02 mg) was added. The reaction mixture was stirred
at room temperature until the disappearance of the starting 1a (TLC check). THF was removed under
reduced pressure and the residue was diluted with water and extracted with CH2Cl2 (3 × 15.0 mL).
The combined organic layers were dried over anhydrous NaSO4 and concentrated under reduced
pressure. The crude reaction was purified by crystallization from Et2O affording the
2a. Yield 70.0% (398.0 mg) as a white solid; Mp 120–124 ◦C (dec); 1H-NMR, 400 MHz, DMSO-d6)
(s, 9H, OBut), 1.84 (s, 3H, CH3), 2.86 (s, 3H, NCH3), 2.92 (s, 3H, NCH3), 4.99 (s, 1H, CH), 9.82 (br s, 1H,
NH, D2O exch.); 13C-NMR (100 MHz, DMSO-d6)
13.8, 28.0, 35.5, 36.6, 64.6, 79.5, 146.2, 152.9, 166.5; IR
(Nujol,
, cm−1): 3239, 3150, 2982, 2172, 2098, 1706, 1686, 1664; MS m/z (ESI): 285.07 (M + H)+; anal.
α
-azido derivative
δ
1.44
δ
ν
calcd. for C11H20N6O3 (284.31): 46.47; H, 7.09; N, 29.56; found: C, 46.36; H, 7.15; N, 29.65.
3.2.2. Synthesis of tert-butyl 2-(4-(dimethylamino)-4-oxo-3-((triphenylphosphoranylidene)amino)
butan-2-ylidene)hydrazinecarboxylate (3a)
1.0 Mmol of 2a (284.31 mg) was solved in CH2Cl2 (5.0 mL). The reaction flask was then immersed in
an ice bath (T = 0 ◦C), and a cooled solution of PPh3 (262.3 mg, 1.0 mmol) in CH2Cl2 (1.0 mL) was added
dropwise. The reaction was brought back to room temperature and stirred until the disappearance
of organic azide 2a (monitored by TLC). The formation of phosphazene 3a was accompanied by the
development of N2. After partial removal of the solvent under reduced pressure, 3a was isolated by
precipitation from a solution of CH2Cl2/EtOAc as white powder; yield 66% (342.3 mg); Mp 127–131 ◦C
1
(dec.); H-NMR (400 MHz, DMSO-d6)
δ
1.42 (s, 9H, OBut), 1.81 (s, 3H, CH3), 2.59 (s, 3H, NCH3),
2.73 (s, 3H, NCH3), 4.62 (t, JH-P = 9.2 Hz, 1H, CH), 7.57–7.90 (m, 15H, Ar), 9.64 (s, 1H, NH, D2O
exch.) ppm; 13C-NMR (100 MHz, DMSO-d6) 13.0, 28.0, 35.6, 36.1, 59.3, 79.5, 120.9 (1JC-P = 102.0 Hz),
δ

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129.7 (2JC-P = 14.0 Hz), 133.7 (3JC-P = 11.0 Hz), 133.8 (3J-CP = 12.0 Hz), 134.9 (4JC-P = 2.0 Hz), 150.7,
167.0 ppm; IR (Nujol,
, cm−1): 3543, 3377, 3211, 1722, 1664; MS m/z (ESI): 519.31 (M + H)+; anal. calcd.
ν
for C29H35N4O3P (518.59): C, 67.17; H, 6.80; N, 10.80; found: C, 67.31; H, 6.86; N, 10.72.
3.2.3. Synthesis of tert-butyl (4-(dimethylcarbamoyl)-5-methyl-2-thioxo-2,3-dihydro-1H-imidazol-1-
yl)carbamate (5a)
0.65 Mmol of 3a (337.0 mg,) was solved in a mixture of THF:MeOH (4:1, 5.0 mL) heating. Then,
0.5 mL of CS2 was added and the reaction was refluxed. The end of the reaction was defined (4.0 h)
by the disappearance of 3a together with the formation of Ph3P=S as byproduct (monitored by TLC).
After removal of the reaction solvents under reduced pressure, a first crop of 5a was obtained as white
powder from a solution of THF/light petroleum ether. A further amount was be gained by column
chromatography eluting with CH2Cl2/EtOAc mixtures. White powder from THF/light petroleum ether;
yield 53% (103.4 mg); Mp 172–173 ◦C (dec.); 1H-NMR (400 MHz, DMSO-d6,)
OBut), 1.99 (s, 3H, CH3), 2.94 [s, 6H, N(CH3)2], 9.69 and 10.15 (2 br s, 1H, NH, D2O exch.), 12.50 (br s,
1H, NH, D2O exch.) ppm; 13C-NMR (100 MHz, DMSO-d6)
8.9, 27.6, 27.8, 35.9, 80.8, 116.2, 128.2, 153.8,
160.2, 162.9 ppm; IR (Nujol,
, cm−1): 3188, 3115, 1741, 1645, 1607; MS m/z (ESI): 301.15 (M + H)+; calcd.
δ 1.32 and 1.45 (2 s, 9H,
δ
ν
for C12H20N4O3S (300.38): C, 47.98; H, 6.71; N, 18.65; found: C, 48.11; H, 6.63; N, 18.57. The partition
of some signals here, as well as in the following cases, is due to the N1-amide rotameric effect [46].
3.3. Typical MCR Procedure for the Synthesis of N-Substituted 1-Amino-1H-Imidazole-2(3H)-Thione
Derivatives 5a–k
To a round flask equipped with a magnetic stirring bar containing ice-cooled solution of NaN3
(1.0 mmol, 65.01 mg) dissolved in 0.5 mL of H2O, the corresponding
dissolved in THF (4.5 mL) was added. The mixture was stirred at room temperature until the
disappearance of (monitored by TLC). Upon completion, Na2SO4 (0.5 g), a solution of PPh3 (1.1 mmol,
288.5 mg) in THF (1.0 mL) and CS2 (1.0 mL) were added in sequence, and the mixture was refluxed for
the appropriate reaction time (3.0–20.0 h). The formation of the final products 5a was revealed by
the complete disappearance of the spot corresponding to the -azidohydrazone 2a as well as the
α-halohydrazone 1a–k (1.0 mmol)
1
–k
α
–k
detection of the byproduct Ph3P=S. The Na2SO4 was filtered in vacuo and washed with THF (10.0 mL).
The filtrate was concentrated under reduced pressure and the residue was purified by crystallization
and/or by chromatography eluting with cyclohexane:EtOAc or CH2Cl2:EtOAc mixtures. The resulting
products 5a–k were isolated by crystallization from the specific solvents (see below). According to this
procedure, 5a was obtained in 79% (237.3 mg).
N,N,5-trimethyl-1-(3-phenylureido)-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxamide(5b): Yield53%(169.3mg),
pink powder from CH2Cl2/Et2O; Mp 247–248 ◦C (dec.); 1H-NMR (400 MHz, DMSO-d6)
δ
2.06 (s, 3H,
CH3), 2.97 [s, 6H, N(CH3)2], 7.01 (t, J = 8.0 Hz, 1H, Ar), 7.29 (t, J = 8.0 Hz, 2H, Ar), 7.46 (d, J = 8.0 Hz
2H, Ar), 9.00 (s, 1H, NH, D2O exch.), 9.33 (br s, 1H, NH, D2O exch.), 12.56 (s, 1H, NH, D2O exch.)
ppm; 13C-NMR (100 MHz, DMSO-d6)
9.3, 36.8, 116.1, 118.3, 122.3, 128.7, 129.0, 139.1, 153.6, 160.3,
162.6 ppm; IR (Nujol,
, cm−1): 3323, 3248, 3195, 3136, 1713, 1638, 1605; MS m/z (ESI): 320.40 (M + H)+;
,
δ
ν
calcd. for; C14H17N5O2S (319.38): C, 52.65; H, 5.37; N, 21.93; calcd. for; C14H17N5O2S (319.38): C,
52.65; H, 5.37; N, 21.93; found: C, 52.79; H, 5.44; N, 21.84.
tert-Butyl (4-(diethylcarbamoyl)-5-methyl-2-thioxo-2,3-dihydro-1H-imidazol-1-yl)carbamate (5c): Yield 72%
(236.3 mg), white powder from EtOAc/THF/light petroleum ether; Mp 168–169 ◦C (dec.); 1H-NMR
(400 MHz, DMSO-d6)
3H, CH3), 3.26–3.37 (m, 4H, 2xNCH2CH3), 9.68 and 10.07 (2 br s, 1H, NH, D2O exch.), 12.49 (br s, 1H,
NH, D2O exch.) ppm; 13C-NMR (100 MHz, DMSO-d6)
8.6, 13.4, 27.5, 27.8, 34.8, 80.6, 117.0, 126.6,
153.8, 159.8, 162.7 ppm; IR (Nujol,
, cm−1): 3169, 3120, 1748, 1642, 1634; MS m/z (ESI): 329.23 (M +
H)+;calcd. for C14H24N4O3S (328.16): C, 51.20; H, 7.37; N, 17.06; found: C, 51.09; H, 7.42; N, 16.95.
δ
1.06–1.10 (m, 6H, 2xNCH2CH3), 1.32 and 1.45 (2s, 9H, OBut), 1.94 and 1.97 (2s,
δ
ν

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tert-Butyl (5-methyl-2-thioxo-2,3-dihydro-1H-imidazol-1-yl)carbamate (5d): Yield 69% (158.1 mg), white
powder from EtOAc/THF/light petroleum ether; Mp 168–169 ◦C (dec.); 1H-NMR (400 MHz, DMSO-d6)
δ
1.32 and 1.45 (2s, 9H, OBut), 1.93 (s, 3H, CH3), 6.60 (s, 1H, CH), 9.51 and 9.94 (2 br s, 1H, NH, D2O
exch.), 11.97 (br s, 1H, NH, D2O exch.) ppm; 13C-NMR (100 MHz, DMSO-d6)
126.9, 153.9, 162.4 ppm; IR (Nujol,
+ H)+; calcd. for C9H15N3O2S (229.09): C, 47.14; H, 6.59; N, 18.33; found: C, 47.01; H, 6.65; N, 18.41.
δ
8.9, 27.9, 80.5, 108.9,
ν
, cm−1): 3271, 3144, 3098, 1744, 1732, 1640; MS m/z (ESI): 229.96 (M
tert-Butyl (4-carbamoyl-5-methyl-2-thioxo-2,3-dihydro-1H-imidazol-1-yl)carbamate (5e): Yield 58% (157.8 mg),
white powder from CH2Cl2/light petroleum ether; Mp 270 ◦C (dec.); 1H-NMR (400 MHz, DMSO-d6)
δ
1.32 and 1.45 (2s, 9H, OBut), 2.23 and 2.26 (2s, 3H, CH3), 7.23 and 7.53 (2 br s, 2H, NH2, D2O exch.), 9.71
and 10.17 (2s, 1H, NH, D2O exch.), 12.42 (s, 1H, NH, D2O exch.) ppm; 13C NMR (100 MHz, DMSO-d6)
δ
8.9, 10.1, 27.6, 27.8, 80.9, 115.8, 133.1, 153.7, 159.6, 162.9 ppm; IR (Nujol, ν
, cm−1): 3395, 3354, 3182,
3137, 1754, 1717, 1676, 1594; MS m/z (ESI): 273.04 (M + H)+; calcd. for C10H16N4O3S (272.09): C, 44.10;
H, 5.92; N, 20.57; found: C, 44.23; H, 5.96; N, 20.45.
tert-Butyl (5-methyl-4-(phenylcarbamoyl)-2-thioxo-2,3-dihydro-1H-imidazol-1-yl)carbamate (5f): Yield 67%
(233.2 mg), white powder from EtOAc; Mp 170–171 ◦C (dec.); 1H-NMR (400 MHz, DMSO-d6)
δ 1.34
and 1.46 (2s, 9H, OBut), 2.28 (s, 3H, CH3), 7.11 (t, J = 8.0 Hz, 1H, Ar), 7.35 (t, J = 8.0 Hz, 2H, Ar), 7.65 (d,
J = 8.0 Hz, 2H, Ar), 9.68 (s, 1H, NH, D2O exch.), 10.28 (s, 1H, NH, D2O exch.), 12.69 (s, 1H, NH, D2O
exch.) ppm; 13C-NMR (100 MHz, DMSO-d6)
δ 9.2, 27.8, 81.0, 116.0, 119.7, 123.8, 128.8, 133.9, 138.4,
153.7, 156.3, 163.2 ppm; IR (Nujol, ν
, cm−1): 3375, 3243, 3066, 1752, 1659, 1630, 1598, 1545; MS m/z (ESI):
349.22 (M + H)+; calcd. for C16H20N4O3S (348.13): C, 55.16; H, 5.79; N, 16.08; found: C, 55.01; H, 5.72;
N, 16.16.
1-(5-Methyl-2-thioxo-2,3-dihydro-1H-imidazol-1-yl)-3-phenylurea (5g): Yield 82% (203.4 mg), white powder
from THF/EtOAc; Mp 245–248 ◦C (dec.); 1H-NMR (400 MHz, DMSO-d6)
δ 2.01 (s, 3H, CH3), 6.64 (s,
1H, CH), 6.99 (t, J = 8.0 Hz, 1H, Ar), 7.28 (t, J = 8.0 Hz, 2H, Ar), 7.46 (d, J = 8.0 Hz, 2H, Ar), 8.91 (s, 1H,
NH, D2O exch.), 9.25 (s, 1H, NH, D2O exch.), 12.05 (s, 1H, NH, D2O exch.) ppm; 13C-NMR (100 MHz,
DMSO-d6) δ 9.1, 108.8, 118.3, 122.3, 127.6, 128.8, 139,1, 153.8, 161.9 ppm; IR (Nujol, ν
, cm−1): 3305, 3154,
3119, 3097, 1714, 1681, 1637, 1602; MS m/z (ESI): 249.07 (M + H)+; calcd. for C11H12N4OS (248.07): C,
53.21; H, 4.87; N, 22.56; found: C, 53.08; H, 4.94; N, 22.65.
N-(5-methyl-2-thioxoimidazolidin-1-yl)benzamide (5h): Yield 59% (137.6 mg) white powder from MeOH;
Mp 240–242 ◦C (dec.); 1H-NMR (400 MHz, DMSO-d6)
δ
1.97 (s, 3H, CH3), 6.72 (s, 1H, CH), 7.56 (t,
J = 8.0 Hz, 2H, Ar), 7.65 (t, J = 8.0 Hz, 1H, Ar), 7.99 (d, J = 8.0 Hz, 2H, Ar), 11.44 (s, 1H, NH, D2O exch.),
12.15 (s, 1H, NH, D2O exch.) ppm; 13C-NMR (100 MHz, DMSO-d6)
8.9, 109.3, 127.0, 127.7, 128.6,
δ
131.5, 132.5, 162.0, 165.4 ppm; IR (Nujol, ν
, cm−1): 3168, 3106, 1666, 1631; MS m/z (ESI): 234.04 (M +
H)+; calcd. for C11H11N3OS (233.29): C, 56.63; H, 4.75; N, 18.01; found: C, 56.76; H, 4.82; N, 17.89.
1-(4,5-Dimethyl-2.thioxo-2,3-dihydro-1H-imidazol-1-yl)-3-phenylurea (5i): Yield 85% (223.0 mg), white
powder from THF/Et2O; Mp 245–250 ◦C (dec.); 1H-NMR (400 MHz, DMSO-d6)
δ 1.94 (s, 3H, CH3),
1.99 (s, 3H, CH3), 6.99 (t, J = 8.0 Hz, 2H, Ar), 7.28 (t, J = 8.0 Hz, 1H, Ar), 7.46 (d, J = 8.0 Hz, 2H, Ar), 8.89
(s, 1H, NH, D2O exch.), 9.19 (s, 1H, NH, D2O exch.), 12.00 (s, 1H, NH, D2O exch.) ppm; 13C-NMR
(100 MHz, DMSO-d6) δ 7.8, 8.9, 116.6, 118.3, 122.2, 122.5, 128.7, 139.1, 153.9, 160.7 ppm; IR (Nujol, ν,
cm−1): 3271, 3172, 3095, 1719, 1691, 1665, 1603; MS m/z (ESI): 263.11 (M + H)+; calcd. for C12H14N4OS
(262.33): C, 54.94; H, 5.38; N, 21.36; found: C, 54.87; H, 5.46; N, 21.23.
4,5-Dimethyl-1-[(4-nitrophenyl)amino]-1H-imidazole-2(3H)-thione (5j): Yield 84% (222.0 mg), beige powder
from THF/EtOAc/Et2O; Mp 279–282 ◦C (dec.); 1H-NMR (400 MHz, DMSO-d6)
δ
1.90 (s, 3H, CH3), 2.03
(s, 3H, CH3), 6.59 (d, J = 8.0 Hz, 2H, Ar), 8.10 (d, J = 8.0 Hz, 2H, Ar), 10.09 (s, 1H, NH, D2O exch.),
12.19 (s, 1H, NH, D2O exch.) ppm; 13C-NMR (100 MHz, DMSO-d6)
7.6, 9.0, 111.3, 117.8, 121.7, 125.8,
139.3, 153.0, 160.8 ppm; IR (Nujol,
, cm−1): 3199, 3094, 1673, 1594; HRMS m/z calcd. for [M + H]+
C11H13N4O2S 265.0759; found 265.0774.
δ
ν

Molecules 2019, 24, 3785
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tert-Butyl (5-phenyl-2-thioxo-2,3-dihydro-1H-imidazol-1-yl)carbamate (5k): Yield 66% (192.3 mg), light
yellow powder from THF/EtOAc/light petroleum ether; Mp 172–174 ◦C (dec.); 1H-NMR (400 MHz,
DMSO-d6)
NH, D2O exch.), 12.51 (br s, 1H, NH, D2O exch.) ppm; 13C-NMR (100 MHz, DMSO-d6)
80.2, 80.5, 110.7, 110.8, 126.9, 127.0, 127.7, 127.9, 128.1, 128.5, 130.6, 130.8, 153.2, 153.9, 162.0, 164.2 ppm;
IR (Nujol,
, cm−1): 3275, 3120, 3093, 1726, 1618, 1600; MS m/z (ESI): 292.18 (M + H)+; calcd. for
δ
1.17 and 1.39 (2s, 9H, OBut), 7.18 (s, 1H, CH), 7.35–7.49 (m, 5H, Ar), 9.79 and 10.12 (2s, 1H,
δ
27.5, 27.9,
ν
C14H17N3O2S (291.37); C, 57.71; H, 5.88; N, 14.42; found: C, 57.83; H, 5.82; N, 14.37.
3.4. General Procedure for the Synthesis of α-(Imidazol-2-Ylthio) Carbonyl Compounds 7a–c.
To a suspension of the N-Boc-protected 1-amino-1H-imidazole-2(3H)-thione derivatives 5c,d
,
f
(1.0 mmol) and K2CO3 (1.0 mmol, 138 mg) in 10.0 mL of acetone, the corresponding
α-halocarbonyl
derivative 6a (1.0 mmol) was added. The reaction mixture was kept under magnetic stirring at room
–c
temperature. Upon completion (monitored by TLC) the solvent was removed, and the crude reaction
mixture was quenched to neutrality with a solution of HCl 1N and extracted with EtOAc (30.0 mL). The
organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed in
vacuum and the crude extract was purified by crystallization or by column chromatography eluting
with cyclohexane:ethyl acetate mixtures to furnish 7a–c derivatives in good yields (84%–93%).
tert-Butyl (4-(diethylcarbamoyl)-5-methyl-2-((2-oxo-2-phenylethyl)thio)-1H-imidazol-1-yl)carbamate (7a):
Yield 84% (375.1 mg); white solid from Et2O; Mp 123–126 ◦C; 1H-NMR (400 MHz, CDCl3)
δ 1.14–1.23
(m, 6H, 2xNCH2CH3), 1.48 (s, 9H, OBut), 1.98 (s, 3H, CH3), 3.37–3.64 (m, 4H, 2xNCH2CH3), 4.50 (br s,
1H, SCHaHb), 4.69 (br s, 1H, SCHaHb), 7.46 (t, J = 8.0 Hz, 2H, Ar), 7.58 (t, J = 8.0 Hz, 1H, Ar), 7.97 (d,
J = 8.0 Hz, 2H, Ar), 9.45 (br s, 1H, NH, D2O exch.) ppm; 13C-NMR (100 MHz, CDCl3)
δ
8.7, 12.9, 14.5,
28.0, 40.6, 41.6, 43.4, 82.5, 128.4, 128.5, 128.7, 130.9, 133.7, 135.3, 135.4, 139.9, 153.8, 164.5, 193.7 ppm; IR
(Nujol,
, cm−1): 3114, 3059, 1741, 1726, 1700, 1681, 1597, 1584; MS m/z (ESI): 447.35 (M + H)+; calcd.
ν
for C22H30N4O4S (446.56): C, 59.17; H, 6.77; N, 12.55; found: C, 59.02; H, 6.84; N, 11.67.
tert-Butyl (5-methyl-2-((2-oxopropyl)thio)-1H-imidazol-1-yl)carbamate (7b): Yield 93% (265.4 mg); ocher
solid from EtOAc/cyclohexane; Mp 103–104 ◦C; 1H-NMR (400 MHz, CDCl3)
δ
1.50 (s, 9H, OBut), 2.14
(s, 3H, CH3), 2.24 (s, 3H, COCH3), 3.81 (br s, 1H, SCHaHb), 3.94 (br s, 1H, SCHaHb), 6.77 (s, 1H, CH),
8.26 (br s, 1H, NH, D2O exch.) ppm; 13C-NMR (100 MHz, CDCl3)
8.9, 28.0, 28.8, 44.8, 82.8, 125.1,
131.5, 139.5, 154.1, 203.5 ppm; IR (Nujol,
, cm−1): 3125, 1725, 1714; MS m/z (ESI): 286.17 (M + H)+;
δ
ν
calcd. for C12H19N3O3S (285.36): C, 50.51; H, 6.71; N, 14.73; found: C, 50.40; H, 6.78; N, 14.86.
Ethyl 2-((1-((tert-Butoxycarbonyl)amino)-5-methyl-4-(phenylcarbamoyl)-1H-imidazol-2-yl)thio)acetate (7c):
◦
1
Yield 92% (399.7 mg), white solid from EtOAc/cyclohexane; Mp 134–136 C; H-NMR (400 MHz,
CDCl3)
δ
1.27 (t, J = 8.0 Hz, 3H, OCH2CH3), 1.51 (s, 9H, OBut), 2.55 (s, 3H, CH3), 3.66 (d, J = 16.0 Hz,
1H, SCHaHb), 3.90 (d, J = 16.0 Hz, 1H, SCHaHb), 4.17–4.24 (m, 2H, OCH2CH3), 7.10 (t, J = 8.0 Hz, 1H,
Ar), 7.34 (t, J = 8.0 Hz, 2H, Ar), 7.67 (d, J = 8.0 Hz, 2H, Ar), 8.18 (br s, 1H, NH, D2O exch.), 8.96 (s, 1H,
NH, D2O exch.) ppm; 13C-NMR (100 MHz, CDCl3):
δ 9.4, 14.0, 28.0, 36.7, 62.7, 83.4, 119.5, 123.8, 128.9,
129.9, 137.3, 138.0, 139.0, 153.6, 160.6, 169.9 ppm; IR (Nujol, ν, cm−1): 3315, 3182, 1733, 1647, 1601; MS
m/z (ESI): 435.20 (M + H)+; calcd. for C20H26N4O5S (434.51): C, 55.28; H, 6.03; N, 12.89; found: C, 55.39;
H, 5.97; N, 12.81.
3.5. General Procedure for the Synthesis of N-Bridgeheaded Heterobicyclic Derivatives 8a–c.
Derivative 7a,b (1.0 mmol) was solved in 5.0 mL of a solution of trifluoroacetic acid (TFA) and
CH2Cl2 (1:1). The reaction mixture was left at room temperature until the disappearance of the starting
7a
mixture was quenched to neutrality with a saturated solution of Na2CO3 and extracted with EtOAc
(20.0 mL 3). The combined organic layers were washed with brine and dried over anhydrous
Na2SO4. After the removal of the solvent, the crude extract was purified by crystallization or by
column chromatography eluting with cyclohexane/ethyl acetate mixtures to furnish 8a derivatives.
,b (TLC check). Then, the solvent was removed under reduced pressure and the crude reaction
×
,b

Molecules 2019, 24, 3785
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For obtaining 8c, the best condition found was to treat 7c (1.0 mmol) with Amberlyst 15H (500 mg) in
refluxing dioxane (15.0 mL) for 12.0 h. Upon completion (monitored by TLC) the resin was filtered off
in vacuo and washed with THF (20.0 mL). The filtrate was evaporated under reduced pressure and the
crude reaction mixture was purified by crystallization.
N,N-diethyl-6-methyl-3-phenyl-2H-imidazo[2,1-b][1,3,4]thiadiazine-7-carboxamide (8a): Yield 82% (269.3 mg)
white powder from EtOAc/cyclohexane; Mp 125–127 ◦C; 1H-NMR (400 MHz, CDCl3)
δ
1.22 (t, J = 8.0 Hz
6H, 2xNCH2CH3), 2.56 (s, 3H, CH3), 3.53 (br s, 2H, NCH2CH3), 3.74 (br s, 2H, NCH2CH3), 3.97 (s, 2H,
SCH2), 7.50–7.52 (m, 3H, Ar), 7.90 (d, J = 8.0 Hz, 2H, Ar) ppm; 13C-NMR (100 MHz, CDCl3)
9.7, 13.0,
, cm−1):
,
δ
14.5, 23.9, 40.3, 43.0, 127.0, 128.9, 129.7, 131.1, 131.3, 133.5, 134.2, 150.8, 164.1 ppm; IR (Nujol,
1611, 1574, 1562, 1557; MS m/z (ESI): 329.28 (M + H)+; calcd. for C17H20N4OS (328.43): C, 62.17; H, 6.14;
ν
N, 17.06; found: C, 62.04; H, 6.19; N, 17.15.
3,6-Dimethyl-2H-imidazo[2,1-b][1,3,4]thiadiazine (8b): Yield 65% (108.7 mg); white needles from CHCl3/
cyclohexane; Mp 57–58 ◦C; 1H-NMR (400 MHz, CDCl3)
δ
2.26 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.42 (s,
2H, SCH2), 6.70 (s, 1H, CH), ppm; 13C-NMR (100 MHz, CDCl3)
8.8, 23.5, 26.1, 123.7, 128.6, 130.1,
152.0 ppm; IR (Nujol,
, cm−1): 1640. 1582; MS m/z (ESI): 168.06 (M + H)+; calcd. for C7H9N3S (167.23):
δ
ν
C, 50.27; H, 5.42; N, 25.13; found: C, 50.39; H, 5.39 N, 25.06.
6-Methyl-3-oxo-N-phenyl-3,4-dihydro-2H-imidazo[2,1-b][1,3,4]thiadiazine-7-carboxamide (8c): Yield 74%
(213.3 mg), light yellow powder from EtOAc/light petroleum ether; Mp 229–232 ◦C; 1H-NMR (400 MHz,
DMSO-d6)
7.81 (d, J = 8.0 Hz, 2H, Ar), 9.80 (s, 1H, NH, D2O exch.), 12.27 (br s, 1H, NH, D2O exch.) ppm; 13C-NMR
(100 MHz, DMSO-d6): 9.2, 29.7, 119.8, 123.0, 128.3, 128.4, 130.6, 132.2, 138.8, 160.8, 164.6 ppm; IR
(Nujol,
, cm−1): 1679, 1666, 1595, 1582; MS m/z (ESI): 288.97 (M + H)+; calcd. for C13H12N4O2S
δ 2.53 (s, 3H, CH3), 3.81 (s, 2H, SCH2), 7.04 (t, J = 8.0 Hz, 1H, Ar), 7.29 (t, J = 8.0 Hz, 2H, Ar),
δ
ν
(288.32): C, 54.15; H, 4.20; N, 19.43; found: C, 54.08; H, 4.27; N, 19.31.
4. Conclusions
In conclusion, combining sequential azidation, Staudinger, and aza-Wittig reactions with CS2 on
α
-halohydrazones in a one-pot protocol, variously substituted 1-amino-1H-imidazole-2(3H)-thiones
are directly accessible in good yields and with complete control of regioselectivity. The method
is particularly attractive and advantageous for its mild conditions, operational simplicity, and its
efficiency as well as its robustness (wide substrate scope and tolerance of various functional groups)
and reliability. The concurrent presence of reactive appendages on the obtained scaffolds ensures
post-modifications toward N-bridgeheaded heterobicyclic structures.
Supplementary Materials: The following are available online: procedure followed for obtaining II; copies of
1H-NMR and 13C-NMR spectra of II 22]; copies of 1H-NMR and 13C-MNR spectra of all newly synthesized
[
compounds; copies of HMQC of compound 5a and 8c.
Author Contributions: C.C. performed all synthetic work in laboratory; G.M. designed the experiments; G.F.;
supervised the project, F.M. funding acquisition; L.D.C. validation; S.S.* conceived the synthetic route and wrote
the paper.
Funding: The authors declare no competing financial interest.
Acknowledgments: The authors gratefully thank Anna Maria Gioacchini and Samuele Lillini who competently
performed the mass spectra and the Department of Biomolecular Science of the University of Urbino for the
economical support.
Conflicts of Interest: There are no conflicts to declare.
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Sample Availability: Samples of the compounds 5a–k are available from the authors.
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