Ensembling three multicomponent reactions for the synthesis of a novel category of pseudo-peptides containing dithiocarbamate and N,X-heterocylic groups

Article abstract of DOI:10.1007/s00726-018-2661-0

Consecutive multicomponent reactions have been applied for the synthesis of novel pseudo-peptides bearing dithiocarbamate and N,X-heterocyclic groups (X = S, O) in only one structure. The first multicomponent reaction includes the synthesis of dithiocarbamates using an amine or amino acid, CS₂ and an electrophile. The second MCR is synthesis of Asinger imines using 2-chloroisobutyraldehyde, NaXH (X = S, O), ketone and ammonia. The final MCR is Ugi reaction to afford the corresponding three-dimensional pseudo-peptides. Various Asinger imines, carboxylic acids and isocyanides were applied in this protocol to provide diversities of pseudo-peptides in high to excellent yields.

Full text of DOI:10.1007/s00726-018-2661-0

Amino Acids
https://doi.org/10.1007/s00726-018-2661-0
ORIGINAL ARTICLE
Ensembling three multicomponent reactions for the synthesis
of a novel category of pseudo‑peptides containing dithiocarbamate
and N,X‑heterocylic groups
Maryam Khalesi1 · Azim Ziyaei Halimehjani1 · Max Franz2 · Marc Schmidtmann2 · Jürgen Martens2
Received: 7 March 2018 / Accepted: 1 October 2018
© Springer-Verlag GmbH Austria, part of Springer Nature 2018
Abstract
Consecutive multicomponent reactions have been applied for the synthesis of novel pseudo-peptides bearing dithiocarbamate
and N,X-heterocyclic groups (X=S, O) in only one structure. The frst multicomponent reaction includes the synthesis of
dithiocarbamates using an amine or amino acid, CS2 and an electrophile. The second MCR is synthesis of Asinger imines
using 2-chloroisobutyraldehyde, NaXH (X=S, O), ketone and ammonia. The fnal MCR is Ugi reaction to aford the cor-
responding three-dimensional pseudo-peptides. Various Asinger imines, carboxylic acids and isocyanides were applied in
this protocol to provide diversities of pseudo-peptides in high to excellent yields.
Keywords Consecutive multicomponent reaction · Pseudo-peptide · Dithiocarbamate · Asinger imine · Ugi reaction
Introduction
Multicomponent reactions (MCRs) are among the most
precious processes in organic chemistry due to their power-
ful characteristics such as high atom economy, high ef-
ciency and diversity-oriented synthesis. The Ugi four-com-
ponent reaction (Ugi-4CR) is undoubtedly one of the most
studied and used MCRs (Ugi et al. 1959; Trost 1991; Tietze
1996; Domling 2006; Herrera and Marques-Lopez 2015;
Zhu et al. 2015; Rotstein et al. 2014; Estevez et al. 2014;
Brauch et al. 2013). This reaction ofers a one-pot synthe-
sis of immensely functionalized α-acylaminocarboxamide
or pseudo-peptide, a construction found in many biologi-
cally active molecules (Keating and Armstrong 1995). In
the recent 20 years, the application of consecutive reac-
tions, especially the Ugi reaction, has widely expanded in
the drug industry and in research laboratories (Keating and
Armstrong 1995; Ugi 1962; Ugi et al. 2003).
Peptides are one of the most interesting classes of bioactive
molecules that represent a wide variety of biological activi-
ties such as anticancer and antimicrobial characteristics, but
they usually cannot be used for synthesizing efective medi-
cal drugs because they are rapidly changed or degenerated in
the body. To solve this issue, novel, stable and biologically
active pseudo-peptides have been synthesized. These new
derivatives can be utilized in drug design by ofering a wide
range of extremely specifed and safe drugs (Nielsen 2004).
Handling Editor: W. Maison.
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00726-018-2661-0) contains
supplementary material, which is available to authorized users.
The Asinger reaction was investigated for the frst time in
1956 by Friedrich Asinger (Asinger et al. 1964; Weber et al.
1992; Asinger and Ofermans 1967). The Asinger reaction
is a simple four-component reaction with efcient procedure
for the synthesis of 3-thiazolines and 3-oxazolines, which
are a group of bioactive heterocyclic compounds contain-
ing both sulfur (oxygen) and nitrogen in the ring. In recent
years, 3-thiazolines and 3-oxazolines have attracted a lot of
attention because the imine bond of these compounds can
be subjected to nucleophilic attack by various nucleophiles
* Azim Ziyaei Halimehjani
ziyaei@khu.ac.ir
* Jürgen Martens
juergen.martens@uni-oldenburg.de
1
Department of Organic Chemistry, Faculty of Chemistry,
Kharazmi University, P.O. Box 15719-14911, 49 Mofateh
Street, Tehran 31979-37551, Iran
2
Institut für Chemie (IfC), Carl von Ossietzky Universität
Oldenburg, P.O. Box 2503, 26111 Oldenburg, Germany
Vol.:(0123456789)
1 3

M. Khalesi et al.
(Martens et al. 1981; Stalling et al. 2013; Kröger et al.
2015a, b; Stalling and Martens 2013; Franz et al. 2017).
Introduction of dithiocarbamate groups in the struc-
ture of various types of organic and inorganic compounds
is well established for the synthesis of novel biologically
active compounds (Csomos et al. 2006; Cao et al. 2005,
2006; Huang et al. 2009; Bacharaju et al. 2012; Zou et al.
2014; Jiao et al. 2016). Compounds containing the dithi-
ocarbamate functionality have shown various biological
activities such as antitumor, anticancer, or antibacterial
in medicine (Aboul-Fadl and El-Shorbagi 1996; Cascio
et al. 1996; Imamura et al. 2001; Scozzafava et al. 2000;
Hou et al. 2006), as pesticides, fungicides, or herbicides in
agriculture (Marinovich et al. 2002; Malik and Rao 2000),
as radiopharmaceutical agents for biological sensing and
imaging (Berry et al. 2012), as mono- and bidentate ligands
in coordination chemistry (Macias et al. 2002; Ziyaei Hal-
imehjani et al. 2011), as polymerization agents (Lai and
Shea 2006; Bathfeld et al. 2006), and as intermediate in
synthetic organic chemistry (Maddani and Prabhu 2007;
Das et al. 2008; Wong and Dolman 2007; Guillaneuf et al.
2008; Ziyaei Halimehjani et al. 2009, 2016; McMaster et al.
2012; Ziyaei Halimehjani and Airamlounezhad 2014; Ziyaei
Halimehjani and Hosseinkhany 2015; Ziyaei Halimehjani
and Lotf Nosood 2017). Due to the extensive application
of these compounds in various branches of science, syn-
thesis of novel dithiocarbamates with diferent substitution
pattern is still interesting. Recently, we have developed a
one-pot four-component reaction for the synthesis of dithi-
ocarbamates using carbon disulfde, cyclic imines, acid
chlorides, and commercially available primary or second-
ary amines (Scheme 1a) (Schlüter et al. 2016). In addition,
novel categories of pseudo-peptides containing dithiocar-
bamate motif were synthesized in our group via classical
Ugi-4CRs (Scheme 1a) (Ziyaei Halimehjani et al. 2013).
In continuation of these works, here we wished to combine
our previous fnding in CS2-MCRs with our expertise using
heterocyclic imines (3-thiazolines and 3-oxazolines) in
(a)
(b)
Scheme 1 Published and proposed MCRs for the synthesis of dithiocarbamates
1 3

Ensembling three multicomponent reactions for the synthesis of a novel category of…
consecutive MCRs for the synthesis of a new category of
pseudo-peptides containing dithiocarbamate and N,X-hetero-
cyclic groups (X=S, O) in a single structure (Scheme 1b, c).
The prepared acid derivatives 1–2 and Asinger imines
3–4 were applied in the next multicomponent reaction
(Schemes 3, 4). For this purpose, an equivalent of an acid, an
Asinger imine and an isocyanide were reacted in MeOH at
room temperature to aford the corresponding Ugi adducts 6.
Under Ugi-3CRs, various bis-amides were obtained eas-
ily with high yields. Carboxylic acids 1–2 derived from
glycine or secondary amines were applied successfully in
this protocol. Also, the diversities of isocyanides 5 includ-
ing cyclohexyl isocyanide, butyl isocyanide, benzyl isocya-
nide, 4-chlorophenyl isocyanide, p-toluenesulfonylmethyl
isocyanide and methyl isocyanoacetate were used to give
the diversities of Ugi adducts 6 with a high degree of func-
tionalization in high yields (Fig. 1).
Results and discussion
To expand our research work in multicomponent reactions,
here we report the use of the Ugi reaction for the synthe-
sis of new pseudo-peptides containing dithiocarbamate
and N,X-heterocyclic groups in a single structure. First of
all, multicomponent reactions were used for the synthe-
sis of two categories of acid derivatives 1 and 2 bearing a
dithiocarbamate motif. The frst category 1 was produced
via the one-pot three-component reaction of a secondary
amine, carbon disulfde and chloroacetic acid (Scheme 2a).
The second category of acid derivatives 2 was prepared via
the one-pot three-component reaction of glycine, carbon
disulfde and benzyl bromide in the presence of sodium
hydroxide (Scheme 2b). Then, two diferent types of cyclic
imines (3-thiazolines and 3-oxazolines) were synthesized
as precursors for the further reaction steps. As example, the
fve-membered 2,5-dihydro-1,3-thiazoles 3 and 2,5-dihydro-
1,3-oxazole 4 were prepared by modifed Asinger reaction
via reaction of an α-chloro aldehyde with a second variable
carbonyl compound, NH3, and NaSH or H2O in CH2Cl2.
In addition, with this protocol, both thiazolidine and
oxazolidine heterocycles can be simply introduced in the
skeleton of Ugi adducts to provide a novel category of three-
dimensional pseudo-peptides 6.
The structures of products 6a–n were confrmed by IR, 1H
and 13C NMR and HRMS analysis. The IR spectra of the prod-
ucts show characteristic absorbance bands at 3200–3500 cm−1
for the N–H bond stretching vibration and at 1650–1750 cm−1
for the carbonyls of the amide groups. The 1H NMR spectra
of the products show a characteristic peak at 6–7 ppm for the
amide hydrogen and a singlet peak at 4.4–5.0 ppm for the CH
group in the thiazolidine and oxazolidine ring. 13C peaks of
Scheme 2 a One-pot three-
component route for synthesis
of dithiocarbamates 1 contain-
(a)
ing a carboxylic acid group. b
Synthesis of dithiocarbamate
2 from glycine. c Modi-
fed Asinger reaction for the
synthesis of 3-thiazolines 3 and
3-oxazolines 4
(b)
(c)
Scheme 3 Synthetic strategy
ensembling three MCRs
1 3

M. Khalesi et al.
Scheme 4 U-3CRs for the synthesis of novel pseudo-peptides 6
the carbons in amide moieties were observed around 166 and
169 ppm in 13C NMR spectra. Also, the peaks at 192–198 ppm
were assigned to the carbon of the dithiocarbamate group. In
addition, the structure of compound 6f was confrmed by sin-
gle crystal X-ray difraction and ORTEP representations are
shown in Fig. 2 (CCDC 1824814); for details of the crystal
structure data and refnement of 6f see the Supporting Infor-
mation). X-ray analysis shows planar geometry for the dithi-
ocarbamoyl moiety.
performed on Macherey–Nagel SiO2 F254 plates on alu-
minum sheets. Melting points were obtained on a melt-
ing apparatus of Laboratory Devices and are uncorrected.
IR spectra were recorded on a Bruker Tensor 27 spec-
trometer equipped with a “Golden Gate” diamond-ATR
1
(attenuated total refection) unit. H and 13C NMR spec-
tra of isolated products were recorded on a Bruker AMX
1
R500 (measuring frequency: H NMR = 500.1 MHz,
13C NMR = 125.8 MHz) or a Bruker Avance III 500
(measuring frequency: 1H NMR = 499.9 MHz, 13C
NMR=125.7 MHz) in CDCl3 solution. Mass spectra were
obtained on a Waters Q-TOF Premier (ESI) spectrometer.
Asinger or modifed Asinger reaction was applied for
the synthesis of N,X-cyclic imines according to previous
reports (Asinger et al. 1964; Weber et al. 1992; Asinger
and Ofermans 1967).
Conclusion
In conclusion, Ugi reaction was applied for the synthesis
of a novel category of pseudo-peptides containing glycine,
dithiocarbamate, and N,X-heterocycles via consecutive
multicomponent reactions. This protocol provides a novel
category of three-dimensional pseudo-peptides as potential
biologically active compounds. The presence of various
functional groups such as amide, dithiocarbamate and N,X-
heterocycle together in a single structure may have synergic
efects to provide a new family of compounds with interest-
ing biological activities in the pharmaceutical industry. The
dithiocarbamates were applied extensively for the protection
of the amino groups in amino acids for peptide synthesis. So,
by simple deprotection, the amino group can be furnished in
the structure of Ugi adducts for further applications.
General procedure for the synthesis of acid deriva-
tives bearing the dithiocarbamate group
(a) Using amino acid for the synthesis of acid derivatives
In a 25 mL round bottom fask equipped with a magnetic
stir bar in an ice bath, sodium hydroxide (10 mmol), glycine
(5 mmol) and MeOH (8 mL) were added. The mixture was
stirred for 0.5 h. Then, carbon disulfde (6 mmol) was added
and the mixture was stirred for 1 h. Then, benzyl chloride
(4.5 mmol) was added to the reaction mixture at room tem-
perature and the mixture was stirred for 24 h. Finally, water
(15–20 mL) was added to the reaction mixture and the pH
of the reaction was adjusted to 5 by adding hydrogen chlo-
ride to the reaction. The reaction mixture was fltered and
the precipitate was washed with water and petroleum ether.
Experimental
Materials and methods
Column chromatographic purifcation was carried out
using SiO2 (0.040–0.060 mm, type KG 60). TLC was
1 3

Ensembling three multicomponent reactions for the synthesis of a novel category of…
Fig. 1 Diversity in the synthesis of pseudo-peptides. a Isolated yield
(b) Using chloroacetic acid for the synthesis of acid deriva‑
tives
General procedure for the synthesis of Ugi adducts
A solution of an acid derivative (1 mmol) and an N,X-
heterocyclic imine (1 mmol) in MeOH (5 mL) was stirred
for 0.5 h at room temperature. Then, isocyanide (1 mmol)
was added to the reaction mixture at the same tempera-
ture. The reaction progress was monitored by TLC. After
24 h, the precipitate was fltered and purifed by column
chromatography using petroleum ether and ethyl acetate
mixture as eluent (SiO2, PE/EtOAc; 3:1 V/V). All com-
pounds were characterized using IR, 1H NMR, 13C NMR
and HRMS analysis.
In a 25 mL round bottom fask equipped with a magnetic
stir bar in an ice bath, a secondary amine (5 mmol), DMF
(5 mL) and carbon disulfde (6 mmol) were added. The mix-
ture was stirred for 1 h. Then chloroacetic acid (5 mmol)
was added to reaction mixture at room temperature and the
mixture was stirred for 12 h. Finally, water (15–20 mL)
was added to the reaction mixture and the precipitate was
collected and washed with petroleum ether for more puri-
fcation. All acids were characterized based on their IR, 1H
NMR and 13C NMR techniques.
1 3

M. Khalesi et al.
694, 665, 645, 617, 598 cm−1; HRMS (ESI-TOF) calcd for
C24H35N3O2S3 [M+Na]+ 516.1789; found: 516.1776.
Benzyl {2‑[3‑(cyclohexylcarbamoyl)‑2,2‑dime‑
thyl‑1‑thia‑4‑azaspiro[4.5]decan‑4‑yl)]‑2‑oxoethyl} carba‑
modithioate (6c)
White powder (yield, 320 mg, 60%); mp 185–186 °C;
1H NMR (500 MHz, CDCl3) δ 8.06 (t, J = 3.8 Hz, 1H),
7.39–7.26 (m, 5H), 6.42 (d, J=8.2 Hz, 1H), 4.53–4.47 (m,
3H), 4.35–4.30 (m, 2H), 3.83 (m, 1H), 3.07–3.00 (m, 2H),
2.12–1.61 (m, 13H), 1.45 (s, 3H), 1.43–1.18 (m, 8H) ppm;
13C NMR (126 MHz, CDCl3) δ 196.7, 167.5, 165.9, 136.1,
129.0, 128.6, 127.5, 82.3, 76.2, 51.0, 49.6, 48.7, 39.9, 36.9,
36.8, 34.0, 32.9, 25.7, 25.4, 24.9, 24.7, 24.4 ppm; IR (ATR)
ν 3325, 3088, 2930, 2849, 1675, 1650, 1604, 1517, 1489,
1454, 1396, 1367, 1336, 1311, 1276, 1243, 1226, 1202,
1164, 1134, 1076, 1043, 983, 965, 936, 902, 865, 831, 810,
779, 766, 721, 702, 674, 651, 630, 589 cm−1; HRMS (ESI-
TOF) calcd for C27H39N3O2S3 [M+Na]+ 556.2102; found:
556.2108.
Fig. 2 ORTEP representations of compound 6f with thermal ellip-
soids at 50% probability. Hydrogen atoms (exception: hydrogen
atoms at stereogenic center and amide group) and opposite enan-
tiomer are omitted for clarity. The atom numbering does not follow
IUPAC nomenclature
2‑[4‑(Cyclohexylcarbamoyl)‑2,2,5,5‑tetramethylthiazoli‑
din‑3‑yl]‑2‑oxoethyl pyrrolidine‑1‑carbodithioate (6a):
2‑[3‑(Cyclohexylcarbamoyl)‑2,2‑dime‑
thyl‑1‑thia‑4‑azaspiro[4.5]decan‑4‑yl] ‑2‑oxoethyl pyrroli‑
dine‑1‑carbodithioate (6d)
White crystalline solid (yield, 352 mg, 77%); mp: 77–78 °C;
1H NMR (500 MHz, CDCl3) δ 6.41 (d, J = 8.1 Hz, 1H),
4.84 (s, 1H), 4.40 (d, J=16.0 Hz, 1H), 3.92–3.64 (m, 6H),
2.13–2.09 (m, 2H), 2.03 (s, 3H), 2.03–1.93 (m, 7H), 1.78
(s, 3H), 1.74–1.68 (m, 2H), 1.44 (s, 3H), 1.43–1.22 (m, 6H)
ppm; 13C NMR (126 MHz, CDCl3) δ 191.3, 168.6, 166.3,
77.9, 74.2, 55.2, 50.8, 50.2, 48.4, 41.7, 33.8, 32.8, 31.3,
29.6, 26.1, 25.4, 24.7, 24.5, 24.3 ppm; IR (ATR): ν 3308,
2928, 2855, 2196, 2184, 2161, 1651, 1538, 1434, 1367,
1249, 1220, 1161, 1133, 1009, 956, 891, 874, 846, 808, 766,
691, 655, 634, 613, 601 cm−1; HRMS (ESI-TOF) calcd for
C21H35N3O2S3 [M+Na]+ 480.1789; found: 480.1798.
White crystalline solid (yield, 328 mg, 66%); mp 86–87 °C;
1H NMR (500 MHz, CDCl3) δ 6.37 (d, J=8.2 Hz, 1H), 4.76
(s, 1H), 4.29 (d, J = 16 Hz, 1H), 3.83–3.58 (m, 6H), 3.08
(m, 1H), 2.98 (m, 1H), 2.05–1.08 (m, 28H) ppm; 13C NMR
(126 MHz, CDCl3) δ 191.3, 168.6, 166.4, 82.1, 77.8, 55.2,
50.8, 49.4, 48.5, 42.4, 37.5, 36.1, 34.0, 32.8, 32.8, 26.1,
25.9, 25.6, 25.4, 25.4, 25.0, 24.6, 24.5, 24.3 ppm; IR (ATR)
ν 3291, 2926, 2853, 2165, 1650, 1534, 1434, 1389, 1352,
1250, 1219, 1184, 1158, 1132, 1042, 1008, 956, 879, 867,
845, 803, 769, 692, 640, 623, 594, 584 cm−1; HRMS (ESI-
TOF) calcd for C24H39N3O2S3 [M+Na]+ 520.2102; found:
520.2090.
Benzyl {2‑[4‑(cyclohexylcarbamoyl)‑2,2,5,5‑tetramethylthi‑
2‑[4‑(Cyclohexylcarbamoyl)‑2,2,5,5‑tetramethylthiazoli‑
azolidin‑3‑yl]‑2‑oxoethyl} carbamodithioate (6b)
din‑3‑yl]‑2‑oxoethyl morpholine‑4‑carbodithioate (6e)
Brown powder (yield, 444 mg, 90%); mp 159–160 °C;
1H NMR (500 MHz, CDCl3) δ 8.07 (t, J = 3.9 Hz, 1H),
7.39–7.27 (m, 5H), 6.51 (d, J=8.2 Hz, 1H), 4.56–4.48 (m,
3H), 4.36–4.27 (m, 2H), 3.83 (m, 1H), 2.04 (s, 3H), 2.00 (s,
3H), 1.97–1.91 (m, 2H), 1.76–1.58 (m, 5H), 1.46 (s, 3H),
1.44–1.19 (m, 6H) ppm. 13C NMR (126 MHz, CDCl3) δ
196.8, 167.5, 165.7, 136.2, 129.0, 128.5, 127.4, 76.3, 74.5,
50.5, 48.6, 39.9, 33.8, 33.0, 32.9, 31.6, 28.9, 25.4, 24.7,
24.6 ppm; IR (ATR) ν 3261, 3161, 2987, 2926, 2854, 1673,
1540, 1495, 1449, 1395, 1366, 1297, 1263, 1251, 1230,
1164, 1134, 1104, 1029, 990, 953, 891, 798, 771, 712,
Cream powder (yield, 284 mg, 60%); mp 138–139 °C; 1H
NMR (500 MHz, CDCl3) δ 6.41 (d, J = 8.2 Hz, 1H), 4.73
(s, 1H), 4.28 (d, J = 16.2 Hz, 1H), 4.21–4.17 (brs, 2H),
3.91–3.87 (brs, 2H), 3.80–3.66 (m, 6H), 1.93 (s, 3H),
1.90–1.83 (m, 4H), 1.69 (s, 3H), 1.67–1.51 (m, 3H), 1.37 (s,
3H), 1.35–1.09 (m, 6H) ppm; 13C NMR (126 MHz, CDCl3)
δ 196.2, 168.6, 165.9, 78.0, 74.2, 66.1, 65.8, 51.4, 50.6, 50.2,
48.4, 41.9, 33.8, 32.8, 31.2, 29.5, 25.4, 24.7, 24.6, 24.5,
24.5 ppm; IR (ATR) ν 3306, 2929, 2851, 1974, 1651, 1538,
1450, 1420, 1355, 1299, 1268, 1227, 1164, 1112, 1065,
1028, 996, 891, 867, 806, 652, 630, 613, 581 cm−1; HRMS
1 3

Ensembling three multicomponent reactions for the synthesis of a novel category of…
(ESI-TOF) calcd for C21H35N3O3S3 [M + Na]+ 496.1738;
found: 496.1737.
610, 571 cm−1; HRMS (ESI-TOF) calcd for C26H37N3O2S3
[M+Na]+ 542.1946; found: 542.2019.
Benzyl {2‑[4‑(butylcarbamoyl)‑2,2,5,5‑tetramethyloxazoli‑
din‑3‑yl]‑2‑oxoethyl}carbamodithioate (6i)
2‑[4‑(Cyclohexylcarbamoyl)‑2,2,5,5‑tetramethyloxazoli‑
din‑3‑yl]‑2‑oxoethyl piperidine‑1‑carbodithioate (6f)
Cream powder (yield, 300 mg, 66.6%); mp 126–127 °C;
1H NMR (500 MHz, CDCl3) δ 8.18 (t, J = 4.1 Hz, 1H),
7.38–7.26 (m, 5H), 6.24 (t, J=5.8 Hz, 1H), 4.61–4.40 (m,
3H), 4.22 (s, 1H), 4.10 (dd, J=17.6 and 3.9 Hz, 1H), 3.38
(m, 1H), 3.27 (m, 1H), 1.79 (s, 3H), 1.75 (s, 3H), 1.57–1.44
(m, 5H), 1.40–1.34 (m, 5H), 0.95 (t, J =7.3 Hz, 3H) ppm;
13C NMR (126 MHz, CDCl3) δ 197.4, 168.0, 164.6, 135.9,
129.0, 128.6, 127.5, 97.1, 81.4, 69.3, 49.6, 39.9, 39.7, 31.5,
30.7, 27.6, 27.0, 25.2, 20.1, 13.6 ppm; IR (ATR) ν 3282,
2990, 2956, 2868, 1680, 1651, 1560, 1495, 1477, 1445,
1407, 1370, 1343, 1264, 1197, 1154, 1009, 989, 947, 919,
879, 846, 782, 753, 712, 694, 667, 632, 602, 592, 580 cm−1;
HRMS (ESI-TOF) calcd for C22H33N3O3S2 [M + Na]+
474.1861; found: 474.1857.
Cream powder (yield, 241 mg, 53%); mp 203–204 °C; 1H
NMR (500 MHz, CDCl3) δ 5.90 (d, J=8.0 Hz, 1H), 4.58 (s,
1H), 4.30 (m, 1H), 4.17 (d, J=15.6 Hz, 1H), 4.07–3.89 (m,
2H), 3.82–3.74 (m, 2H), 3.57 (d, J=15.6 Hz, 1H), 1.91–1.87
(m, 2H), 1.6 z9 (s, 3H), 1.67–1.53 (m, 12H), 1.49 (s, 3H),
1.34–1.28 (m, 5H), 1.20–1.09 (m, 3H) ppm; 13C NMR
(126 MHz, CDCl3) δ 194.1, 167.9, 165.3, 96.7, 81.1, 70.7,
53.2, 51.8, 48.5, 40.9, 32.9, 30.6, 27.7, 27.3, 25.9, 25.9,
25.3, 25.2, 24.6, 24.0 ppm; IR (ATR) ν 3308, 3073, 2980,
2932, 2857, 2165, 2148, 2035, 1684, 1635, 1546, 1472,
1415, 1230, 1162, 1145, 1114, 1009, 975, 948, 894, 844,
807, 773, 725, 683, 631 cm−1; HRMS (ESI-TOF) calcd for
C22H37N3O3S2 [M+Na]+ 478.2174; found: 478.2153.
Benzyl {2‑[4‑(cyclohexylcarbamoyl)‑2,2,5,5‑tetramethylox‑
azolidin‑3‑yl]‑2‑oxoethyl)}carbamodithioate (6g)
2‑[4‑(Butylcarbamoyl)‑2,2,5,5‑tetramethyloxazoli‑
din‑3‑yl]‑2‑oxoethyl morpholine‑4‑carbodithioate (6j)
Cream powder (yield, 429 mg, 90%); mp 181 °C; 1H NMR
(500 MHz, CDCl3) δ 8.07 (brs, 1H), 7.32–7.21 (m, 5H), 5.97
(d, J=8.2 Hz, 1H), 4.48–4.45 (m, 2H), 4.35 (d, J=17.7 Hz,
1H), 4.09–4.05 (m, 2H), 3.79 (m, 1H), 1.94–1.86 (m, 2H),
1.74 (s, 3H), 1.70–1.55 (m, 6H), 1.45 (s, 3H), 1.35–1.28 (m,
5H), 1.22–1.08 (m, 3H) ppm; 13C NMR (126 MHz, CDCl3)
δ 197.2, 166.9, 164.5, 135.9, 129.0, 128.6, 127.5, 97.1, 81.3,
69.3, 49.6, 48.8, 39.9, 33.0, 30.7, 27.6, 26.9, 25.3, 25.0,
24.7 ppm; IR (ATR) ν 3269, 2983, 2935, 2853, 1659, 1645,
1548, 1495, 1444, 1416, 1371, 1320, 1264, 1252, 1197,
1148, 1119, 1093, 1072, 1017, 991, 945, 913, 891, 846, 770,
702, 665, 636, 599, 581 cm−1; HRMS (ESI-TOF) calcd for
C24H35N3O3S2 [M+Na]+ 500.2018; found: 500.2035.
Cream powder (yield, 241 mg, 56%); mp 130–132 °C; 1H
NMR (500 MHz, CDCl3) δ 6.05 (t, J=5.8 Hz, 1H), 4.6 (s,
1H), 4.27–3.80 (m, 5H), 3.72–3.67 (m, 5H), 3.33 (m, 1H),
3.21 (m, 1H), 1.68 (s, 3H), 1.67 (s, 3H), 1.50–1.44 (m, 5H),
1.33–1.27 (m, 5H), 0.88 (t, J=7.3 Hz, 3H) ppm; 13C NMR
(126 MHz, CDCl3) δ 196.1, 168.8, 164.9, 96.8, 81.2, 70.8,
66.1, 66.0, 51.5, 50.9, 40.8, 39.4, 31.5, 30.7, 27.8, 27.3, 25.3,
20.1, 13.6 ppm; IR (ATR) ν 3297, 2934, 2850, 1658, 1555,
1464, 1420, 1394, 1379, 1361, 1300, 1285, 1263, 1246,
1225, 1195, 1159, 1110, 1060, 1025, 1007, 992, 910, 878,
864, 842, 801,723, 698, 661, 617, 597, 571 cm−1; HRMS
(ESI-TOF) calcd for C19H33N3O4S2[M + Na]+ 454.1810;
found: 454.1807.
2‑[3‑(Benzylcarbamoyl)‑2,2‑dimethyl‑1‑thia‑4‑azaspiro[4.5]
2‑[4‑(Benzylcarbamoyl)‑2,2‑dimethyl‑1‑thia‑3‑azaspiro[4.5]
decan‑4‑yl]‑2‑oxoethyl morpholine‑4‑carbodithioate (6k)
decan‑3‑yl]‑2‑oxoethyl piperidine‑1‑carbodithioate (6h)
White crystalline solid (yield, 229 mg, 44%); mp
199–200 °C; 1H NMR (500 MHz, CDCl3) δ 7.37–7.28 (m,
5H), 6.88 (t, J = 5.7 Hz, 1H), 4.92 (s, 1H), 4.57–4.49 (m,
2H), 4.33 (d, J=16.2 Hz, 1H), 4.28 (brs, 2H), 3.98 (brs, 2H),
3.83–3.76 (m, 5H), 3.14–3.02 (m, 2H), 1.91–1.78 (m, 4H),
1.74 (s, 3H), 1.67–1.56 (m, 2H), 1.43 (s, 3H), 1.26–1.17
(m, 2H) ppm; 13C NMR (126 MHz, CDCl3) δ 196.3, 169.5,
166.0, 137.5, 128.8, 127.7, 127.7, 82.4, 76.8, 66.3, 66.1,
51.6, 50.8, 49.5, 43.8, 42.7, 37.5, 36.2, 34.0, 25.8, 25.5, 25.1,
24.4 ppm; IR (ATR) ν 3403, 2931, 2902, 2853, 2176, 1696,
1650, 1508, 1451, 1430, 1390, 1358, 1290, 1269, 1227,
1211, 1198, 1186, 1157, 1132, 1117, 1034, 1020, 998, 982,
Cream powder (yield, 228 mg, 44%); mp: 186–187 °C;
1H NMR (500 MHz, CDCl3) δ 7.32–7.23 (m, 5H), 6.75 (t,
J=5.7 Hz, 1H), 4.97 (s, 1H), 4.53–4.41 (m, 2H), 4.36–4.29
(m, 2H), 4.13–3.75 (m, 3H), 3.62 (d, J=15.9 Hz, 1H), 2.17
(m, 1H), 1.91 (s, 3H), 1.84–1.74 (m, 6H), 1.69–1.57 (m,
10H), 1.28–1.21 (m, 2H) ppm; 13C NMR (126 MHz, CDCl3)
δ 194.3, 169.4, 166.4, 137.5, 128.8, 127.8, 127.7, 73.4,
56.8, 53.3, 51.8, 43.8, 42.0, 40.1, 34.4, 31.6, 29.5, 25.9,
25.9, 25.3, 24.5, 24.1, 22.7, 21.7 ppm; IR (ATR) ν 3594,
3248, 3067, 2932, 2856, 1681, 1625, 1550, 1447, 1426,
1400, 1362, 1309, 1284, 1256, 1227, 1170, 1136, 1112,
1069, 1004, 981, 954, 895, 872, 855, 802, 737, 695, 638,
1 3

M. Khalesi et al.
913, 902, 880, 872, 865, 838, 797, 766, 732, 701, 686, 632,
595, 580 cm−1; HRMS (ESI-TOF) calcd for C25H35N3O3S3
[M+Na]+ 544.1738; found: 544.1737.
1137, 1084, 1042, 1002, 978, 925, 875, 852, 813, 742, 700,
670, 624, 609, 578 cm−1; HRMS (ESI-TOF) m/z: calcd for
C27H39N3O4S4 [M+Na]+ 620.1721; found: 620.1930.
Acknowledgements We are grateful to the Iran National Science Foun-
dation: INSF, Grant number 95829698, for supporting this work. We
also thank the research council of Kharazmi University (Grant num-
ber D/2056) for supporting this work. We are thankful to the central
analytic section of the University of Oldenburg for retrieving NMR
and MS data.
2‑{3‑[(4‑Chlorophenyl)carbamoyl]‑2,2‑dime‑
thyl‑1‑thia‑4‑azaspiro[4.5]decan‑4‑yl}‑2‑oxoethyl piperi‑
dine‑1‑carbodithioate (6l)
White solid (yield, 318 mg, 59%); mp 139–140 °C; 1H NMR
(500 MHz, CDCl3) δ 8.55 (s, 1H), 7.52 (d, J=8.8 Hz, 2H),
7.26 (d, J=8.3 Hz, 2H), 4.97 (s, 1H), 4.38 (d, J=15.8 Hz,
1H), 4.24 (brs, 1H), 4.12 (brs, 1H), 3.90–3.75 (m, 3H), 3.19
(m, 1H), 3.09 (m, 1H), 2.02 (m, 1H), 1.99–1.83 (m, 3H),
1.75 (s, 3H), 1.73–1.57 (m, 8H), 1.47 (s, 3H), 1.37–1.17
(m, 2H) ppm; 13C NMR (126 MHz, CDCl3) δ 194.2, 168.02,
166.7, 135.8, 129.9, 129.2, 121.2, 82.8, 78.5, 53.5, 51.9,
49.9, 43.1, 37.9, 36.4, 34.1, 26.1, 25.8, 25.5, 25.2, 24.6,
24.2 ppm; IR (ATR) ν 3277, 2934, 2856, 1700, 1625, 1597,
1535, 1491, 1430, 1398, 1352, 1244, 1130, 1009, 978, 829,
751 cm−1; HRMS (ESI-TOF) calcd for C25H34N3O2S3Cl
[M+Na]+ 562.1399; found: 562.1401.
Author contributions Conceived and designed the experiments: AZH;
JM. Performed the experiments and analyzed the data: MK; MF. X-ray
data: MS. Wrote the paper: AZH; JM; MK; MF.
Compliance with ethical standards
Conflict of interest The authors declare no confict of interest.
Ethical standard This article does not contain any studies with human
participants or animals performed by any of the authors.
Informed consent Informed consent was obtained from all individual
participants included in the study.
Methyl 2‑(2,2,5,5‑tetramethyl‑3‑(2‑((piperidine‑1‑carbono‑
thioyl)thio)acetyl)thiazolidine‑4‑carboxamido)acetate (6m)
References
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White solid (yield, 286 mg, 62%); mp 136–137 °C; H
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