Umpolung cyclization reaction of: N -cinnamoylthioureas in the presence of DBU

Article abstract of DOI:10.1039/c8ob02066c

A novel regioselective cyclization reaction of N-cinnamoylthioureas leading to six- or five-membered heterocyclic compounds was developed. N-Cinnamoylthioureas in the presence of trifluoroacetic acid (TFA) underwent the well-established intramolecular cycloaddition reaction to give 2-imino-2,3,5,6-tetrahydro-4H-1,3-thiazin-4-ones in good yields. On the other hand, the reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) proceeded in an unprecedented umpolung cyclization fashion to afford five-membered 2-imino-1,3-thiazolidin-4-ones and/or 2-thioxoimidazolidine-4-ones. The reaction was considered to occur via a cycloadduct of DBU with the cinnamoyl moiety followed by intramolecular attack of the thiourea group.

Full text of DOI:10.1039/c8ob02066c

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Biomolecular Chemistry
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Umpolung cyclization reaction of
N-cinnamoylthioureas in the presence of DBU†
Cite this: Org. Biomol. Chem., 2018,
16, 7910
Rei Saito,a Naohiro Uemura,a Hiroki Ishikawa,a Akina Magara,a Yasushi Yoshida,
a,b
a,b
Takashi Mino, a,b Yoshio Kasashimac and Masami Sakamoto
*
A novel regioselective cyclization reaction of N-cinnamoylthioureas leading to six- or five-membered
heterocyclic compounds was developed. N-Cinnamoylthioureas in the presence of trifluoroacetic acid
(TFA) underwent the well-established intramolecular cycloaddition reaction to give 2-imino-2,3,5,6-tetra-
hydro-4H-1,3-thiazin-4-ones in good yields. On the other hand, the reaction with 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU) proceeded in an unprecedented “umpolung” cyclization fashion to afford five-mem-
bered 2-imino-1,3-thiazolidin-4-ones and/or 2-thioxoimidazolidine-4-ones. The reaction was con-
sidered to occur via a cycloadduct of DBU with the cinnamoyl moiety followed by intramolecular attack
of the thiourea group.
Received 23rd August 2018,
Accepted 3rd October 2018
DOI: 10.1039/c8ob02066c
rsc.li/obc
ing research area in organic and pharmaceutical chemistry. All
these heterocycles were usually provided by cyclization reac-
Introduction
Heterocyclic compounds containing heteroatoms such as tions of thioureas with acid derivatives, and suitable methods
nitrogen and sulfur in the skeleton are present in many for each substituent were adopted.13,14 If we can generate
natural products and are widely used as medical pesticides these heterocycles from the same starting materials by chan-
and functional materials. For example, six-membered imino- ging the reaction conditions or catalysts, this methodology will
thiazinone (iminothiazinanone) (I, Scheme 1) is a substrate become a facile and useful synthetic process leading to diverse
attracting attention as
a
novel therapeutic agent that heterocycles.
We have developed a facile intramolecular cyclization of
stops or slows the progression of Parkinson’s disease.1
Thioxopyrimidinones (II) are utilized as anti-allergic and N-cinnamoylthioureas leading to six-membered heterocycles,
anti-cancer agents.2 2-Iminothiazolidin-4-ones (III) and their iminothiazinone I, under acidic conditions. Furthermore, we
derivatives display a broad spectrum of biological activities3 and found an unprecedented “umpolung” cyclization reaction
exhibit pharmaceutical activities as a sphingosine-1-phosphate leading to five-membered heterocycles, iminothiazolidinones
receptor agonist4 and a preferential hCA inhibitor,5 pro- III and thiohydantoins IV, by using 1,8-diazabicyclo[5.4.0]
nounced anticonvulsant activity6 as a selective GSK-3β inhibi- undec-7-ene (DBU) as a basic catalyst. The “umpolung” reac-
tor,7 and antiproliferative activity against cancer cell lines.8 tion has been proposed for acyl anion equivalents, and many
Thiohydantoin (2-thioxoimidazolidin-4-one) analogues (IV) display fine examples using 1,3-thiazines,15 thiazolium ions,16 the
a range of biological activities, such as antimycobacterial,9 benzoin reaction,17 and ketimines18 have been reported.
antiviral,10 NADPH oxidase inhibition11 and antitumor pro- Furthermore, the Morita–Baylis–Hillman reaction initiated
perties.12 Therefore, the development of efficient and practical with the conjugate addition of a Brønsted base to enones is
methods for the synthesis of such heterocycles is an interest- also a representative “umpolung” reaction.19 Recently, the reac-
tion was applied to the intramolecular cyclization of alkyl-
aDepartment of Applied Chemistry and Biotechnology, Graduate School of
Engineering, Chiba University, Yayoi-cho, Inage-ku, Chiba, 263-8522 Japan.
E-mail: sakamotom@faculty.chiba-u.jp
bMolecular Chirality Research Center, Chiba University, Yayoi-cho, Inage-ku, Chiba,
263-8522 Japan
cEducation Center, Faculty of Creative Engineering, Chiba Institute of Technology,
Shibazono, Narashino, Chiba 275-0023, Japan
†Electronic supplementary information (ESI) available: X-ray crystallographic
data, NMR spectra. CCDC 1859352, 1859353, 1859354, 1859407, 1859355,
1859357, and 1859359. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c8ob02066c
Scheme 1 Various heterocyclic compounds with high pharmaceutical
activities.
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imines using a Brønsted base.20 These various types of “umpo-
lung” reactions have expanded the range of organic syntheses.
We have now discovered a novel example of an intramolecular
“umpolung”
cyclization
leading
to
five-membered
heterocycles.
Results and discussion
Previously, Britsun et al. reported that the reaction of N,N′-
diphenylthiourea with cinnamoyl chloride in acetone without
a base gave an iminothiazinone.13 In the presence of potass-
ium carbonate, however, cinnamanilide was the sole product
(Scheme 2). In these reactions, the intermediacy of
N-cinnamoylthiourea was suggested based on the decompo-
sition to the anilide.
We synthesized a variety of N-cinnamoylthioureas 1a–j and
investigated their cyclizations under both acidic and basic con-
ditions. N-Cinnamoylthioureas 1a–j were easily produced by
acylation of the corresponding thioureas using cinnamoyl
chloride and triethylamine in the presence of molecular sieves
(4 Å) (Scheme 3). When unsymmetrical thioureas were used,
selective acylation took place on the nitrogen atoms of the
anilide moieties leading to 1f–j in moderate yields. In these
cases, the formation of diacylated thioureas as by-products
caused a decrease in the chemical yields.
Scheme 4 Cyclization of N-cinnamoylthioureas 1a–1j under acidic
conditions. A dried toluene (2.0 mL) solution of 1 (0.400 mmol) and TFA
(4.00 mmol) was stirred at room temperature for 0.5 hours.
room temperature in the presence of trifluoroacetic acid. The
starting materials disappeared after 0.5 h. An efficient and
product-selective reaction was promoted, and the intra-
molecular cycloaddition product 2a by C–S bond formation
was obtained in 97% yield. Similar cycloadditions occurred in
other substrates 1b–1j leading to iminothiazinones 2b–2j in
good yields. In all cases, other isomers, such as thioxopyrimi-
dinones 2′ formed by C–N bond formation, could not be
observed under acidic conditions. The structures of the pro-
ducts were determined spectroscopically. Additionally, the
structures of 2h, 2i, and 2j were unequivocally established by
single crystal X-ray structure analysis (Fig. S1–S3†).
In the crystallographic analysis of 2h, the imide group
adopts an almost planar conformation owing to the strong
conjugation between the imino group and both the nitrogen
and sulfur atoms, and the two phenyl rings are in an almost
perpendicular conformation relative to the thiazinone ring
(Fig. S1†). Bond lengths are also shown in the figure. The
sulfur atom is conjugated with the imino group, thus this C–S
bond is shorter than the other C–S bond. The alkyl substituent
on the imino-nitrogen atom is placed in the Z configuration
oriented toward the sulfur atom to avoid steric interaction with
the phenyl ring on the nitrogen atom. Other iminothiazinones
2i and 2j adopted similar conformations to 2h in the crystal
lattice (Fig. S2 & S3†).
We first examined the intramolecular cycloaddition of 1
leading to iminothiazinones (I) or thioxopyrimidinones (II)
under acidic conditions (Scheme 4). N-Cinnamoyl-N,N′-di-
methylthiourea 1a was dissolved in toluene and stirred at
Next, we examined the reaction of 1a–j in the presence of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (Scheme 5). When
the reaction was run in toluene at room temperature in the
presence of DBU and molecular sieves (4 Å), unprecedented
“umpolung” reaction products were obtained. When 1a was
reacted at rt for 0.5 h until the starting material disappeared,
Scheme 2 Reaction of N,N’-diphenylthiourea with cinnamoyl chloride.
Scheme 5 “Umpolung” cyclization reaction of 1a–j in the presence of
Scheme 3 Synthesis of various N-cinnamoylthioureas 1a–1j.
DBU.
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Table 1 Cyclization reaction of 1a–j in the presence of DBU and mole-
stable than 1, because the deprotonated amidate anion from 1′
can delocalize through the aryl group, whereas the anion
cannot conjugate with the alkyl group. This fast rearrangement
occurred before cyclization to form 3 and 4 in the case of
1f–1j.
In the case of the reaction using 1i, cinnamanilide was
obtained by decomposition of 1i before acyl transformation.
The steric hindrance of the isopropyl group prevented effective
transformation of the cinnamoyl group (Table 1, entry 9).
The second phenomenon is the reaction mechanism. The
α-position of the cinnamoyl group reacted with the nitrogen or
sulfur atom of the thiourea group. Michael additions typically
occur at the β-position of α,β-unsaturated groups, and six-
membered heterocycles 2 or 2′ should be formed as in the case
of the reaction under acidic conditions.
cular sievesa
Entry
Urea 1
R1
R2
Yield of 3 (%)
Yield of 4 (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Me
Et
n-Pr
i-Pr
Bn
Me
Et
n-Pr
i-Pr
Bn
Me
Et
81
75
70
77
51
10
3
6
3
11
0
0
0
8
0
65
71
57
32b
66
n-Pr
i-Pr
Bn
Ph
Ph
Ph
Ph
Ph
10
1j
a A dried toluene (8.0 mL) solution of 1 (1.20 mmol) and DBU
(0.600 mmol) was stirred at room temperature for 0.5 hours in the
presence of molecular sieves (4 Å, 1.5 g). b Cinnamanilide was obtained
in 50% yield.
Next we examined the reaction by changing bases and
the effect of molecular sieves (Scheme 7 and Table 2). Other
bases such as triethylamine, 4-(N,N-dimethylamino)pyridine
(DMAP), or 1,4-diazabicyclo[2.2.2]octane (DABCO) were inert in
this cyclization (Table 2, entries 1–3). On the other hand, the
use of 1,8-diazabicyclo[4.3.0]nona-7-ene (DBN) or 1,5,7-triaza-
bicyclo[4.4.0]dec-5-ene (TBD) also worked as in the case of the
reaction with DBU (Table 2, entries 4 and 5). This “umpolung”
cyclization reaction is peculiar for DBU, DBN and TBD.
The conjugate addition of DBU to enones is supported by
the well-known reaction mechanism for the Morita–Baylis–
Hillman reaction.19 Furthermore, the addition of DBU to cou-
marins, tetrazines and hydroxyalkynoates leading to cycliza-
five-membered thiohydantoin 3a was obtained in 81% yield
(Table 1, entry 1). Cyclization of other N-acylthioureas 1b–1e
also proceeded efficiently and gave the corresponding thiohy-
dantoins 3b–3e (entries 2–5). In the case of the reaction of 1d,
a small amount of 4d was also produced in 8% yield (entry 4).
When asymmetrically substituted N-alkyl-N′-cinnamoyl-N′-
phenylthioureas 1f–1j were used for the reaction, the major
products changed and iminothiazolidinones 4f–4j were
obtained, accompanied by a small amount of 3 (entries 6–10).
The structures of all these materials were determined spec-
troscopically. Additionally, the structures of 3i, 3j and 4g were
unequivocally established by single crystal X-ray analysis
(Fig. S4–S6†). Both thiohydantoins and iminothiazolidinones
adopted planar conformations. The substituent on the imino-
nitrogen atom of 4g was inclined toward the sulfur atom owing
to the steric interaction as in the cases of iminothiazinones 2.
As can be seen from the molecular structures, three unique
phenomena were promoted in this cyclization using DBU. The
first is that the rearrangement of the cinnamoyl group
occurred before the cyclization reaction in the case of the phe-
nylthioureas (Scheme 6). Although it cannot be distinguished
in the case of 1a–e, it is clear that the cinnamoyl group
rearranged from the nitrogen atom substituted R2 (Ph) group
to the other nitrogen atom substituted by the alkyl group in
the cases of 1f–j, whereas the rearrangement did not take place
in the cyclization under acidic conditions as shown in
Scheme 4. Rearrangement of the acyl group for N-acylthioureas
is well-known for arylthioureas under thermal or basic con-
ditions.21 Under basic conditions, it seems that 1′ is more
Scheme 7 Cyclization reaction of 1b and 1c in the presence of a variety
of bases with or without molecular sieves.
Table 2 Cyclization reaction of 1b and 1c in the presence of a variety
of bases with or without molecular sievesa
Entry Urea 1 Solvent
Base
Yield of 3 (%) Yield of 5 (%)
1b,c
2b,d
3b,e
4b, f
5b,g
6c,h
7c,h
8c,h
9c,h
1b
1b
1b
1b
1b
1b
1b
1b
1c
Toluene Et3N
Toluene DMAP
Toluene DABCO
Toluene DBN
Toluene TBD
Toluene DBU
0
0
0
74
46
21
10
0
0
0
0
0
0
10
61
87
12
CH2Cl2
THF
DBU
DBU
Toluene DBU
59
a Each solvent (8.0 mL) containing
1
(1.20 mmol) and a base
(0.600 mmol) was stirred with or without molecular sieves (4 Å, 1.5 g)
at room temperature for 0.5 h. b The reaction was conducted with
molecular sieves. c Et3N was used as a base. d DMAP was used as a
base. e DABCO was used as a base. f DBN was used as a base. g TBD was
used as a base. h The reaction was conducted without molecular sieves
in the presence of DBU (1.50 mmol).
Scheme 6 Rearrangement of N-cinnamoylthioureas 1f–1j under basic
conditions.
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Scheme 8 Mechanism for the formation of five-membered hetero-
cycles 3 and 4 in the presence of DBU.
tion products has also been reported.22 While the cyclo-
addition of DBU with cinnamic acid derivatives is not unpre-
cedented, a mechanism involving an intermediacy of a DBU
adduct is advocated to explain this mysterious phenomenon
(Scheme 8). The DBU undergoes cycloaddition to the enone
group to form intermediate A or A′. Attack of the nitrogen
atom affords 3, and reaction with the sulfur atom gives 4. The
difference is reasonably understood in terms of the electron
density of the sulfur atoms due to the substituents on the
nitrogen atom, regardless of the alkyl or aryl group. Cleavage
of the C–O bond followed by the elimination of DBU from the
strained fused molecule aids in the addition of the sulfur or
the nitrogen atom of the thiourea group. Unfortunately, no
reaction intermediates were detected when the reaction was
monitored by NMR spectroscopy.
Scheme 9 Plausible mechanism for the formation of 5 in the presence
of DBU in a water-containing solvent.
The same intermediate A (A′) can be proposed for the for-
mation of 5 as shown in Scheme 9. Addition of water gives the
ring-opened product B, which is followed by proton transfer
leading to C. Elimination of hydrogenated DBU gives D, which
is transformed to α-oxoamide derivative E. Finally, inter-
molecular attack of the nitrogen atom leads to aminal com-
pound 5. In this reaction, DBU functions as a dehydrogenating
reagent, which is known to occur in some cases.23
The third phenomenon is that the apparent product selecti-
vity depends on the substituents. N,N′-Dialkyl derivatives (1a–
1e) selectively gave thiohydantoins that were formed by N–C
bond formation between the nitrogen atom and the α-position
of the cinnamoyl group. On the other hand, unsymmetrical
Conclusions
derivatives (1f–1j) formed S–C bonds leading to iminothiazoli- We provided a facile synthetic methodology for five- and six-
dinones (4f–4j) as major products. This difference is reason- membered heterocycles from easily available N-acylthioureas
able in terms of the electron density of the sulfur atoms. In under acidic or basic conditions. All derivatives of these
1a–1e, the electron-donating properties of the alkyl group heterocycles are well known for various high pharmaceutical
make the electron density of the nitrogen atoms high. On the activities. The reaction in the presence of trifluoroacetic acid
other hand, in N-phenyl derivatives 1f′–1j′, lone pair electrons gives six-membered 2-imino-1,3-thiazin-4-ones in good yields
conjugated with the phenyl group lower the nucleophilicity of regardless of the substituents on the nitrogen atoms. On the
the nitrogen atoms compared to those of 1a–1e, resulting in other hand, the reaction of N-acylthioureas with DBU pro-
S–C bond formation.
moted unprecedented “umpolung” reaction pathways leading
We also examined the reaction with DBU without molecular to five-membered thiohydantoins from N-cinnamoyl-N,N′-di-
sieves (Table 2, entries 6–9). When 1b was stirred with an alkylthioureas and 2-imino-1,3-thiazolidin-4-ones from N-alkyl-
excess amount of DBU in toluene, the yield of 3b decreased N′-cinnamoyl-N′-phenylthioureas. A novel reaction mechanism
and unexpected 5b was formed (Scheme 7 and Table 2, involving the cycloaddition of DBU with the cinnamoyl group
entry 6). The amount of water included in the solvent deter- was proposed. Furthermore, the reaction in the presence of
mined the reaction pathways. The use of CH2Cl2 increased the DBU in a water-containing solvent gave oxygenated 5-hydroxy-
yield of 5b to 61% (entry 7). The reaction in THF predomi- thiohydantoin derivatives, in which the same DBU adduct was
nantly gave 5b in 87% yield (entry 8). The unexpected oxy- proposed as an intermediate in the mechanistic pathway.
genated chemical structure of 5c, obtained as a minor product Formation of this adduct was followed by the attack of a water
from the reaction of 1c in toluene without molecular sieves molecule and the elimination of reduced DBU. Although
(entry 9), was determined by single crystal X-ray structure ana- unique heterocycles were obtained, the reaction mechanisms
lysis (Fig. S7†).
are unprecedented and are yet to be confirmed. However, in
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the reaction in the presence of a base, it is undeniable that the 7.53–7.57 (m, 2H), 7.79 (d, J = 15.2 Hz, 1H); 13C NMR (CDCl3)
reaction proceeds at a position that cannot be predicted in the δ 11.0, 11.7, 21.3, 23.1, 48.9, 50.9, 119.0, 128.2, 129.0, 130.7,
usual electronic state. We are continuing to explore the reac- 134.3, 145.2, 146.3, 170.1, 183.9; IR (cm−1, KBr) 3170 (NH),
tion mechanism and the generality of the reaction.
1647 (CvO); HRMS (ESI-MS) m/z calcd for C16H22N2OS + H
291.1526, found 291.1525.
N-Cinnamoyl-N,N′-diisopropylthiourea (1d). Yield: 96%;
1
colorless needles; m.p. 160–161 °C; H NMR (CDCl3) δ 1.37 (d,
Experimental section
General information
J = 6.8 Hz, 6H), 1.40 (d, J = 6.8 Hz, 6H), 4.61 (sept, J = 6.8 Hz,
1H), 4.70–4.74 (m, 1H), 6.66 (d, J = 15.5 Hz, 1H), 7.26–7.30 (m,
NMR spectra were recorded in CDCl3 solutions on Bruker 300 5H), 7.54 (d, J = 15.5 Hz, 1H), 8.33 (s, 1H); 13C NMR (CDCl3)
and 400 spectrometers for H- and 13C-NMR. Chemical shifts δ 20.3, 20.8, 48.3, 48.4, 118.9, 127.8, 128.8, 129.8, 134.4, 142.7,
1
are reported in parts per million (ppm) relative to TMS as an 164.0, 182.5; IR (cm−1, KBr) 3191 (NH), 1639 (CvO); HRMS
internal standard. IR spectra were recorded on a JASCO FT/ (ESI-MS) m/z calcd for C16H22N2OS + H 291.1526, found
IR-230 spectrometer. High-resolution mass spectra (HRMS) 291 1520.
were performed on an Orbitrap ThermoFisher Exactive ion
N-Cinnamoyl-N,N′-dibenzylthiourea (1e). Yield: 84%; color-
1
trap mass spectrometer. X-ray single crystallographic analysis less powder; m.p. 113–115 °C; H NMR (CDCl3) δ 4.93 (d, J =
was conducted using a SMART APEX II (Bruker AXS) and APEX 4.9 Hz, 2H), 5.86 (s, 2H), 6.77 (d, J = 15.3 Hz, 1H), 7.23–7.45
II ULTRA (Bruker AXS). Commercially available reagents and (m, 15H), 7.69 (d, J = 15.3 Hz, 1H); 13C NMR (CDCl3) δ 51.6,
solvents were used without further purification.
53.0, 119.4, 126.0, 127.4, 127.5, 127.8, 128.0, 128.2, 128.9,
Synthesis of N-cinnamoyl-N,N′-dimethylthiourea (1a). N,N′- 128.9, 130.7, 134.2, 136.4, 137.4, 146.6, 170.7, 184.8; IR (cm−1
,
Dimethylthiourea (0.890 g, 8.56 mmol) and triethylamine KBr) 3207 (NH), 1644 (CvO); HRMS (ESI-MS) m/z calcd for
(1.30 g, 12.9 mmol) were added to a THF (20.0 mL) solution C24H22N2OS + Na 409.1345, found 409.1340.
containing cinnamoyl chloride (1.70 g, 10.2 mmol) and mole-
N-Cinnamoyl-N-phenyl-N′-methylthiourea (1f).24 Yield: 62%;
cular sieves (4 Å, 1.50 g) and the reaction mixture was stirred at yellow needles; m.p. 127–129 °C; 1H NMR (CDCl3) δ 3.26 (d, J =
room temperature for 3 hours. After the disappearance of N,N′- 4.8 Hz, 3H), 6.09 (d, J = 15.5 Hz, 1H), 7.20–7.37 (m, 8H),
dimethylthiourea was confirmed by TLC, the solvent was 7.48–7.52 (m, 3H), 7.70 (d, J = 15.5 Hz, 1H); 13C NMR (CDCl3)
removed under reduced pressure, and the residual mixture was δ 33.1, 119.5, 128.2, 128.8, 129.0, 129.3, 130.2, 130.6, 134.1,
dissolved in ethyl acetate and extracted with an acid and base. 141.2, 145.4, 169.3, 185.2; IR (cm−1, KBr) 3214 (NH), 1658
After removing the solvent again under reduced pressure, the (CvO).
obtained residue was separated by silica gel column chromato-
N-Cinnamoyl-N-phenyl-N′-ethylthiourea (1g). Yield: 68%;
1
graphy using a mixed solvent of ethyl acetate–hexane (1 : 4) to yellow needles; m.p. 105–106 °C; H NMR (CDCl3) δ 1.37 (t, J =
afford N-cinnamoyl-N,N′-dimethylthiourea (1a) (0.880 g, 7.3 Hz, 3H), 3.74 (qd, J = 7.3, 4.9 Hz, 2H), 6.08 (d, J = 15.4 Hz,
3.76 mmol, 44%). The obtained crystals were recrystallized 1H), 7.20–7.36 (m, 8H), 7.47–7.55 (m, 3H), 7.69 (d, J = 15.4 Hz,
from a mixed solvent of chloroform and hexane. The other 1H); 13C NMR (CDCl3) δ 13.4, 41.6, 119.7, 128.3, 128.9, 129.0,
cinnamoylthioureas (1b–1j) were synthesized in the same 129.3, 130.3, 130.7, 134.1, 141.1, 145.3, 169.4, 183.9; IR (cm−1
,
manner.
KBr) 3278 (NH), 1655 (CvO); HRMS (ESI-MS) m/z calcd for
N-Cinnamoyl-N,N′-dimethylthiourea (1a).24 Yield: 63%; C18H18N2OS + Na 333.1032, found 333.1027.
colorless needles; m.p. 120–122 °C; 1H NMR (CDCl3) δ 3.22
N-Cinnamoyl-N-phenyl-N′-propylthiourea (1h). Yield: 38%;
1
(d, J = 4.5 Hz, 3H), 3.85 (s, 3H), 6.93 (d, J = 15.3 Hz, 1H), yellow needles; m.p. 109–110 °C; H NMR (CDCl3) δ 1.07 (t, J =
7.38–7.45 (m, 3H), 7.54–7.59 (m, 2H), 7.76 (d, J = 15.3 Hz, 1H); 7.3 Hz, 3H), 1.79 (sex, J = 7.3 Hz, 2H), 3.68 (td, J = 7.3, 4.9 Hz,
13C NMR (CDCl3) δ 33.4, 38.6, 118.9, 128.3, 129.0, 130.9, 134.2, 2H), 6.08 (d, J = 15.5 Hz, 1H), 7.20–7.37 (m, 8H), 7.48–7.55 (m,
146.3, 170.3, 185.3; IR (cm−1, KBr) 3127 (N–H), 1648 (CvO).
3H), 7.70 (d, J = 15.5 Hz, 1H); 13C NMR (CDCl3) δ11.7, 21.4,
N-Cinnamoyl-N,N′-diethylthiourea (1b). Yield: 72%; colorless 48.6, 119.7, 128.3, 128.9, 129.0, 129.3, 130.3, 130.7, 134.1,
powder; m.p. 139–140 °C; 1H NMR (CDCl3) δ 1.31 (t, J = 7.4 Hz, 141.1, 145.4, 169.4, 184.0; IR (cm−1, KBr) 3125 (NH), 1656
3H), 1.44 (t, J = 6.9 Hz, 3H), 3.70 (qd, J = 7.4, 4.9 Hz, 2H), 4.54 (CvO); HRMS (ESI-MS) m/z calcd for C19H20N2OS + Na
(q, J = 7.0 Hz, 2H), 6.95 (d, J = 15.3 Hz, 1H), 7.41–7.44 (m, 3H), 347.1189, found 347.1182.
7.54–7.58 (m, 2H), 7.79 (d, J = 15.3 Hz, 1H); 13C NMR (CDCl3)
N-Cinnamoyl-N-phenyl-N′-isopropylthiourea (1i). Yield: 49%;
δ 13.3, 15.1, 41.8, 44.5, 119.0, 128.2, 129.0, 130.7, 134.3, 146.4, yellow needles; m.p. 108–109 °C; 1H NMR (CDCl3) δ 1.37 (d, J =
170.0, 183.5; IR (cm−1, KBr) 3170 (NH), 1647 (CvO); HRMS 6.3 Hz, 6H), 4.50–4.66 (m, 1H), 6.07 (d, J = 15.4 Hz, 1H),
(ESI-MS) m/z calcd for C14H18N2OS + Na 285.1032, found 7.20–7.37 (m, 8H), 7.47–7.54 (m, 3H), 7.69 (d, J = 15.4 Hz, 1H);
285.1024.
13C NMR (CDCl3) δ 21.6, 48.4, 119.8, 128.2, 128.8, 129.2, 130.3,
N-Cinnamoyl-N,N′-dipropylthiourea (1c). Yield: 91%; color- 130.6, 134.1, 141.1, 145.3, 169.4, 182.6; IR (cm−1, KBr) 3198
less powder; m.p. 119–120 °C; 1H NMR (CDCl3) δ 1.01 (t, J = (NH), 1655 (CvO); HRMS (ESI-MS) m/z calcd for C19H20N2OS +
7.3 Hz, 3H), 1.02 (t, J = 7.6 Hz, 3H), 1.73 (sex, J = 7.3 Hz, 2H), Na 347.1189, found 347.1179.
1.87 (sext, J = 7.6 Hz, 2H), 3.64 (td, J = 7.3, 4.9 Hz, 2H),
N-Cinnamoyl-N-phenyl-N′-benzylthiourea (1j). Yield: 42%;
4.37–4.42 (m, 2H), 6.91 (d, J = 15.2 Hz, 1H), 7.26–7.46 (m, 3H), yellow needles; m.p. 147–148 °C; 1H NMR (CDCl3) δ 4.91 (d, J =
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4.8 Hz, 2H), 6.08 (d, J = 15.4 Hz, 1H), 7.18–7.76 (m, 15H), 7.68 7.20–7.40 (m, 15H); 13C NMR (CDCl3) δ 40.7, 42.5, 46.0, 54.1,
(d, J = 15.4 Hz, 1H); 13C NMR (CDCl3) δ 51.0, 119.4, 127.8, 126.6, 127.0, 127.3, 127.4, 128.2, 128.2, 128.5, 128.7, 129.1,
128.0, 128.3, 128.8, 129.0, 129.4, 130.2, 130.7, 134.0, 136.4, 137.1, 137.9, 139.6, 148.7, 169.0; IR (cm−1, KBr) 1678, 1617;
141.1, 145.6, 169.4, 184.2; IR (cm−1, KBr) 3200 (NH), 1655 HRMS (ESI-MS) m/z calcd for C24H22N2OS + H 387.1526, found
(CvO); HRMS (ESI-MS) m/z calcd for C23H20N2OS + H 387.1525.
373.1369, found 373.1369.
(Z)-2-(Methylimino)-3,6-diphenyl-1,3-thiazinan-4-one (2f).24
Cyclization reaction of 1a–1j in the presence of trifluoroace- Yield: 81%; colorless needles; m.p. 188–190 °C; 1H NMR
tic acid. N-Cinnamoyl-N,N′-dimethylthiourea (1a) (0.100 g, (CDCl3) δ 3.07 (s, 3H), 3.36–3.42 (m, 2H), 4.73 (dd, J = 9.3,
0.427 mmol) and trifluoroacetic acid (0.450 g, 3.95 mmol) 5.1 Hz, 1H), 7.14–7.17 (m, 2H), 7.34–7.48 (m, 8H); 13C NMR
were dissolved in toluene (2.0 mL) and the mixture was (CDCl3) δ 38.0, 41.0, 43.0, 127.3, 128.0, 128.7, 128.8, 129.1,
stirred at room temperature for 0.5 hours under an argon 129.2, 137.2, 138.6, 151.5, 169.1; IR (cm−1, KBr) 1681, 1611.
atmosphere. After the disappearance of 1a was confirmed by
(Z)-2-(Ethylimino)-3,6-diphenyl-1,3-thiazinan-4-one
(2g).
TLC, base extraction was carried out using aqueous sodium Yield: 76%; colorless needles; m.p. 168–169 °C; 1H NMR
bicarbonate. The solvent was removed under reduced pressure, (CDCl3) δ 1.06 (t, J = 7.2 Hz, 3H), 3.28–3.39 (m, 4H), 4.71 (dd,
and the residue was purified by silica gel column chromato- J = 9.6, 5.1 Hz, 1H), 7.13–7.16 (m, 2H), 7.32–7.51 (m, 8H); 13C
graphy using a mixed solvent of ethyl acetate–hexane (1 : 5) to NMR (CDCl3) δ 15.1, 41.1, 43.1, 45.6, 127.4, 127.7, 128.8, 128.9,
afford
N,N′-dimethyl-6-phenyl-2-iminotetrahydro-1,3-thiazin- 129.2, 137.4, 138.9, 148.8, 169.2; IR (cm−1, KBr) 1685, 1604;
4-one (2a) (0.097 g, 0.415 mmol, 97%). The obtained crystals HRMS (ESI-MS) m/z calcd for C18H18N2OS + H 311.1213, found
were recrystallized from a mixed solvent of chloroform and 311.1205.
hexane. Other 1,3-thiazin-4-ones (2b–2j) were synthesized in
(Z)-3,6-Diphenyl-2-(propylimino)-1,3-thiazinan-4-one
(2h).
the same manner.
Yield: 79%; colorless needles; m.p. 164–165 °C; 1H NMR
(Z)-3-Methyl-2-(methylimino)-6-phenyl-1,3-thiazinan-4-one (2a).24 (CDCl3) δ 0.76 (t, J = 7.1 Hz, 3H), 1.46 (sex, J = 7.1 Hz, 2H), 3.21
1
Yield: 97%; colorless needles; m.p. 87–89 °C; H NMR (CDCl3) (t, J = 7.1 Hz, 2H), 3.30–3.44 (m, 2H), 4.70 (dd, J = 9.6, 4.8 Hz,
δ 3.16 (s, 3H), 3.16–3.22 (m, 2H), 3.36 (s, 3H), 4.52 (dd, J = 1H), 7.13–7.16 (m, 2H), 7.31–7.45 (m, 8H); 13C NMR (CDCl3)
10.7, 4.4 Hz, 1H), 7.32–7.42 (m, 5H); 13C NMR (CDCl3) δ 31.0, δ 11.7, 23.5, 41.1, 43.1, 52.7, 127.3, 127.6, 128.7, 128.7, 128.8,
37.5, 40.6, 42.4, 127.3, 128.7, 129.1, 137.2, 151.0, 169.3; 129.2, 137.3, 138.8, 148.6, 169.2; IR (cm−1, KBr) 1685, 1600;
IR (cm−1, KBr) 1673, 1606.
(Z)-3-Ethyl-2-(ethylimino)-6-phenyl-1,3-thiazinan-4-one (2b). 325.1363.
HRMS (ESI-MS) m/z calcd for C19H20N2OS + H 325.1369, found
1
Yield: 95%; colorless needles; m.p. 64–65 °C; H NMR (CDCl3)
(Z)-2-(Isopropylimino)-3,6-diphenyl-1,3-thiazinan-4-one (2i).
δ 1.18 (t, J = 6.9 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H), 3.16 (t, J = Yield: 82%; colorless needles; m.p. 150–152 °C; 1H NMR
5.0 Hz, 2H), 3.27–3.45 (m, 2H), 4.02–4.19 (m, 2H), 4.47 (dd, J = (CDCl3) δ 0.96 (d, J = 6.2 Hz, 3H), 1.01 (d, J = 6.2 Hz, 3H),
9.6, 5.1 Hz, 1H), 7.30–7.41 (m, 5H); 13C NMR (CDCl3) δ 13.0, 3.28–3.43 (m, 2H), 3.64 (sept, J = 6.2 Hz, 1H), 4.69 (dd, J = 11.6,
15.8, 38.8, 40.6, 42.6, 45.3, 76.6, 77.0, 77.4, 127.3, 128.6, 129.1, 6.2 Hz, 1H), 7.08–7.14 (m, 2H), 7.29–7.57 (m, 8H); 13C NMR
137.5, 147.0, 168.7; IR (cm−1, KBr) 1680, 1591; HRMS (ESI-MS) (CDCl3) δ 23.0, 41.1, 43.2, 51.8, 127.3, 127.8, 128.6, 128.7,
m/z calcd for C14H18N2OS + H 263.1213, found 263.1208.
129.1, 137.4, 139.1, 146.3, 169.3; IR (cm−1, KBr) 1686, 1600;
(Z)-6-Phenyl-3-propyl-2-(propylimino)-1,3-thiazinan-4-one (2c). HRMS (ESI-MS) m/z calcd for C19H20N2OS + H 325.1369, found
1
Yield: 90%; colorless needles; m.p. 55–57 °C; H NMR (CDCl3) 325.1363.
δ0.90 (t, J = 7.4 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H), 1.56–1.72 (m,
(Z)-2-(Benzylimino)-3,6-diphenyl-1,3-thiazinan-4-one
(2j).
4H), 3.17 (t, J = 5.0 Hz, 2H), 3.25 (td, J = 6.8, 2.6 Hz, 2H), Yield: 72%; colorless needles; m.p. 201–202 °C; 1H NMR
3.95–4.10 (m, 2H), 4.48 (dd, J = 9.5, 5.3 Hz, 1H), 7.30–7.42 (m, (CDCl3) δ 3.34–3.48 (m, 2H), 4.51 (s, 2H), 4.75 (dd, J = 9.8,
5H); 13C NMR (CDCl3) δ 11.4, 12.0, 20.9, 24.0, 40.7, 42.7, 45.0, 4.7 Hz, 1H), 7.04–7.49 (m, 15H); 13C NMR (CDCl3) δ 41.3, 43.0,
52.4, 127.3, 128.6, 129.1, 137.5, 147.2, 168.9; IR (cm−1, KBr) 53.8, 126.4, 126.9, 127.4, 127.9, 128.1, 128.8, 129.0, 129.2, 137.1,
1684, 1607; HRMS (ESI-MS) m/z calcd for C16H22N2OS + H 138.7, 139.5, 150.2, 169.2; IR (cm−1, KBr) 1685, 1616; HRMS
291.1526, found 291.1521.
(Z)-3-Isopropyl-2-(isopropylimino)-6-phenyl-1,3-thiazinan-4-
(ESI-MS) m/z calcd for C23H20N2OS + H 373.1369, found 373.1366.
Cyclization of 1a–j in the presence of DBU. To a dried
one (2d). Yield: 82%; colorless needles; m.p. 85–87 °C; 1H toluene (8.0 mL) solution of N-cinnamoyl-N,N′-dimethyl-
NMR (CDCl3) δ 1.16 (d, J = 6.3 Hz, 6H), 1.40 (d, J = 6.8 Hz, 3H), thiourea (1a) (0.308 g, 1.32 mmol), DBU (0.100 g, 0.66 mmol)
1.46 (d, J = 6.8 Hz, 3H), 3.10 (d, J = 7.5 Hz, 2H), 3.67 (sept, J = was added and the mixture was stirred at room temperature
6.3 Hz, 1H), 4.43–4.54 (m, 1H), 4.99 (sept, J = 6.8 Hz, 1H), for 0.5 hours in the presence of molecular sieves (4 Å, 1.50 g).
7.28–7.39 (m, 5H); 13C NMR (CDCl3) δ 19.5, 20.6, 23.3, 23.3, After acid extraction and removal of the solvent under reduced
41.4, 43.8, 49.5, 51.8, 127.4, 128.4, 129.0, 137.7, 144.6, 169.6; pressure, the residue was purified by silica gel column chrom-
IR (cm−1, KBr) 1684, 1596; HRMS (ESI-MS) m/z calcd for atography using a mixed solvent of ethyl acetate–hexane (1 : 3)
C16H22N2OS + H 291.1526, found 291.1520.
to give N,N′-dimethyl-5-benzyl-2-thiohydantoin (3a) (81% yield,
(Z)-3-Benzyl-2-(benzylimino)-6-phenyl-1,3-thiazinan-4-one (2e). 0.249 g, 1.07 mmol). Other 5-benzyl-2-thiohydantoins (3b–3j)
Yield: 88%; colorless needles; m.p. 123–124 °C; 1H NMR and 5-benzyl-2-iminothiazolidin-4-ones (4f–4j) were syn-
(CDCl3) δ 3.20–3.31 (m, 2H), 4.46–4.59 (m, 3H), 5.38 (s, 2H), thesized by the same procedure.
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Cyclization of 1b in the presence of a variety of bases with δ 3.05 (dd, J = 14.4, 5.2 Hz, 1H), 3.20 (s, 3H), 3.25 (dd, J = 14.6,
molecular sieves. To a dried toluene (8.0 mL) solution of 4.1 Hz, 1H), 4.89 (dd, J = 5.2, 4.1 Hz, 1H), 6.91–6.96 (m, 2H),
N-cinnamoyl-N,N′-diethylthiourea (1b) (0.300 g, 1.15 mmol), 7.16–7.22 (m, 3H), 7.32–7.49 (m, 5H); 13C NMR (CDCl3) δ 28.2,
triethylamine (0.058 g, 0.573 mmol) was added and the 53.1, 64.7, 126.2, 127.4, 127.7, 128.4, 129.1, 129.4, 133.5, 136.5,
mixture was stirred at room temperature for 0.5 hours under 172.2, 182.1; IR (cm−1, KBr) 1750 (CvO); HRMS (ESI-MS) m/z
an argon atmosphere. After acid extraction and removal of the calcd for C17H16N2OS + H 297.1056, found 297.1057.
solvent under reduced pressure, the residue was analysed by
5-Benzyl-3-ethyl-1-phenyl-2-thioxoimidazolidin-4-one
(3g).
NMR spectroscopy. When trimethylamine, DMAP, or DABCO Yield: 3%; colorless prisms; m.p. 81–83 °C; 1H NMR (CDCl3)
was used as a base, starting materials were recovered. The use δ 1.00 (t, J = 7.1 Hz, 3H), 3.04 (dd, J = 14.4, 4.9 Hz, 1H), 3.25
of DBN and TBD gave 3b as summarized in Table 2.
(dd, J = 14.4, 4.0 Hz, 1H), 3.76–3.90 (m, 2H), 4.86 (dd, J = 4.9,
5-Benzyl-1,3-dimethyl-2-thioxoimidazolidin-4-one (3a). Yield: 4.0 Hz, 1H), 6.96–6.99 (m, 2H), 7.17–7.52 (m, 8H); 13C NMR
1
81%; colorless prisms; m.p. 96–98 °C; H NMR (CDCl3) δ 3.08 (CDCl3) δ 12.4, 35.0, 36.8, 64.4, 126.2, 127.5, 127.7, 128.4,
(s, 3H), 3.16 (dd, J = 14.6, 5.4 Hz, 1H), 3.24 (s, 3H), 3.28 (dd, J = 129.1, 129.6, 133.3, 136.6, 171.9, 181.5; IR (cm−1, KBr) 1743
14.6, 4.6 Hz, 1H), 4.22 (t, J = 4.9 Hz, 1H), 7.02–7.32 (m, 5H); (CvO); HRMS (ESI-MS) m/z calcd for C18H18N2OS + Na
13C NMR (CDCl3) δ 28.0, 33.0, 35.7, 64.9, 127.6, 128.7, 129.0, 333.1032, found 333.1027.
133.9, 172.7, 183.1; IR (cm−1, neat) 1744 (CvO); HRMS
5-Benzyl-1-phenyl-3-propyl-2-thioxoimidazolidin-4-one (3h).
(ESI-MS) m/z calcd for C12H14N2OS + H 235.0900, found Yield: 6%; yellow oil; 1H NMR (CDCl3) δ 0.77 (t, J = 10.1 Hz,
235.0899. 3H), 1.40–1.53 (m, 2H), 3.04 (dd, J = 14.4, 4.8 Hz, 1H), 3.25 (dd,
5-Benzyl-1,3-diethyl-2-thioxoimidazolidin-4-one (3b). Yield: J = 14.4, 4.0 Hz, 1H), 3.64–3.81 (m, 2H), 4.87 (dd, J = 4.8,
1
75%; colorless prisms; m.p. 64–66 °C; H NMR (CDCl3) δ 0.83 4.0 Hz, 1H), 6.95–6.98 (m, 2H), 7.20–7.52 (m, 8H); 13C NMR
(t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H), 3.17 (dd, J = 14.6, (CDCl3) δ 11.1, 20.6, 34.9, 43.4, 64.4, 126.2, 127.5, 127.6, 128.4,
4.5 Hz, 1H), 3.25 (dd, J = 14.6, 4.5 Hz, 1H), 3.37 (sex, J = 7.2 Hz, 129.1, 129.7, 133.3, 136.6, 172.1, 182.0; IR (cm−1, neat) 1743
1H), 3.67 (q, J = 7.2 Hz, 1H), 3.67 (q, J = 7.2 Hz, 1H), 4.29 (t, J = (CvO); HRMS (ESI-MS) m/z calcd for C19H20N2OS + H
4.5 Hz, 1H), 4.47 (sex, J = 7.2 Hz, 1H), 7.08–7.29 (m, 5H); 13C NMR 325.1369, found 325.1365.
(CDCl3) δ 11.9, 12.3, 34.8, 36.4, 39.5, 61.3, 127.5, 128.5, 129.2,
133.4, 172.6, 181.7; IR (cm−1, KBr) 1737 (CvO); HRMS (ESI-MS) Yield: 3%; yellow oil; 1H NMR (CDCl3) δ 1.19 (d, J = 7.0 Hz,
m/z calcd for C14H18N2OS + Na 285.1032, found 285.1030. 3H), 1.42 (d, J = 7.0 Hz, 3H), 3.00 (dd, J = 14.4, 4.8 Hz, 1H),
5-Benzyl-3-isopropyl-1-phenyl-2-thioxoimidazolidin-4-one (3i).
5-Benzyl-1,3-dipropyl-2-thioxoimidazolidin-4-one (3c). Yield: 3.23 (dd, J = 14.4, 3.8 Hz, 1H), 4.77 (dd, J = 4.8, 3.8 Hz, 1H),
70%; yellow oil; 1H NMR (CDCl3) δ 0.69 (t, J = 7.4 Hz, 3H), 0.92 4.86 (sep, J = 7.0 Hz, 1H), 6.97–7.01 (m, 2H), 7.20–7.23 (m, 3H),
(t, J = 7.4 Hz, 3H), 1.21–1.38 (m, 2H), 1.57–1.75 (m, 2H), 7.34–7.52 (m, 5H); 13C NMR (CDCl3) δ 18.5, 18.9, 34.9, 48.2,
3.12–3.30 (m, 3H), 3.50–3.65 (m, 2H), 4.28 (t, J = 4.5 Hz, 1H), 63.9, 126.4, 127.5, 127.7, 128.3, 129.1, 129.8, 133.4, 137.0,
4.38 (ddd, J = 14.0, 9.3, 7.1 Hz, 1H), 7.08–7.30 (m, 5H); 13C 172.2, 182.3; IR (cm−1, neat) 1739 (CvO); HRMS (ESI-MS) m/z
NMR (CDCl3) δ 11.0, 11.1, 20.1, 20.5, 34.8, 43.1, 46.3, 61.9, calcd for C19H20N2OS + H 325.1369, found 325.1369.
127.5, 128.6, 129.2, 133.5, 172.8, 182.4; IR (cm−1, neat) 1741
(CvO); HRMS (ESI-MS) m/z calcd for C16H22N2OS + Na 11%; colorless powder; m.p. 126–127 °C; 1H NMR (CDCl3)
3,5-Dibenzyl-1-phenyl-2-thioxoimidazolidin-4-one (3j). Yield:
313.1345, found 313.1338.
δ 3.04 (dd, J = 14.5, 5.1 Hz, 1H), 3.28 (dd, J = 14.5, 4.0 Hz, 1H),
5-Benzyl-1,3-diisopropyl-2-thioxoimidazolidin-4-one
(3d). 4.92 (dd, J = 5.1, 4.0 Hz, 1H), 4.97 (d, J = 14.6 Hz, 1H), 5.04 (d,
Yield: 77%; colorless prisms; m.p. 73–74 °C; H NMR (CDCl3) J = 14.6 Hz, 1H), 6.86–6.90 (m, 2H), 7.07–7.49 (m, 13H); 13C
δ 0.92 (d, J = 6.8 Hz, 3H), 1.30 (d, J = 6.8 Hz, 3H), 1.37 (d, J = NMR (CDCl3) δ 34.7, 45.1, 64.4, 126.2, 127.4, 127.5, 127.7,
6.8 Hz, 3H), 1.54 (d, J = 6.6 Hz, 3H), 3.24 (d, J = 4.5 Hz, 2H), 128.3, 128.4, 128.5, 129.1, 129.6, 133.2, 135.3, 136.7, 172.0,
4.22 (t, J = 4.5 Hz, 1H), 4.72 (sept, J = 6.8, 1H), 5.01 (sept, J = 181.8; IR (cm−1, KBr) 1741 (CvO); HRMS (ESI-MS) m/z calcd
6.8, 1H), 7.16–7.30 (m, 5H); 13C NMR (CDCl3) δ 17.9, 19.1, for C23H20N2OS + H 373.1369, found 373.1373.
1
19.6, 21.7, 36.9, 47.5, 50.2, 60.2, 127.4, 128.4, 129.7, 133.6,
173.0, 183.3; IR (cm−1, KBr) 1735 (CvO); HRMS (ESI-MS) m/z (4d). Yield: 8%; yellow oil; 1H NMR (CDCl3) δ 1.09 (d, J =
calcd for C16H22N2OS + Na 313.1345, found 313.1335. 6.2 Hz, 3H), 1.10 (d, J = 6.2 Hz, 3H), 1.34 (d, J = 7.0 Hz, 6H),
(Z)-5-Benzyl-3-isopropyl-2-(isopropylimino)thiazolidin-4-one
1,3,5-Tribenzyl-2-thioxoimidazolidin-4-one (3e). Yield: 51%; 3.02 (dd, J = 13.9, 9.5 Hz, 1H), 3.32 (sept, J = 6.2 Hz, 1H), 3.47
1
yellow oil; H NMR (CDCl3) δ 3.12 (dd, J = 14.7, 4.6 Hz, 1H), (dd, J = 13.9, 3.6 Hz, 1H), 4.21 (dd, J = 9.5, 3.6 Hz, 1H), 4.66
3.23 (dd, J = 14.7, 4.6 Hz, 1H), 4.12 (t, J = 4.6 Hz, 1H), 4.27 (d, (sept, J = 7.0, 1H), 7.22–7.33 (m, 5H); 13C NMR (CDCl3) δ 18.6,
J = 15.0 Hz, 1H), 4.88 (d, J = 14.7 Hz, 1H), 4.96 (d, J = 14.7 Hz, 18.7, 39.0, 47.7, 49.3, 120.8, 124.3, 127.2, 129.1, 129.4, 136.0,
1H), 5.96 (d, J = 15.0 Hz, 1H), 6.99–7.37 (m, 15H); 13C NMR 148.4, 153.0, 173.8; IR (cm−1, neat) 1714, 1637; HRMS (ESI-MS)
(CDCl3) δ 34.8, 45.2, 48.5, 61.2, 127.4, 127.5, 128.0, 128.2, m/z calcd for C16H22N2OS + H 291.1526, found 291.1522.
128.3, 128.8, 129.0, 129.2, 133.5, 134.7, 135.4, 172.6, 183.1; IR
(cm−1, neat) 1748 (CvO); HRMS (ESI-MS) m/z calcd for Yield: 65%; yellow oil; 1H NMR (CDCl3) δ 3.01 (dd, J = 14.1,
C24H22N2OS + Na 409.1345, found 409.1344. 10.0 Hz, 1H), 3.28 (s, 3H), 3.57 (dd, J = 14.1, 3.7 Hz, 1H), 4.33
(Z)-5-Benzyl-2-(methylimino)-3-phenylthiazolidin-4-one (4f).
5-Benzyl-3-methyl-1-phenyl-2-thioxoimidazolidin-4-one (3f). (dd, J = 10.0, 3.7 Hz, 1H), 6.88–6.91 (m, 2H), 7.08–7.33 (m, 8H);
1
Yield: 10%; colorless prisms; m.p. 91–92 °C; H NMR (CDCl3) 13C NMR (CDCl3) δ 29.5, 39.2, 50.3, 121.0, 124.5, 127.3, 128.6,
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129.0, 129.1, 136.4, 148.0, 153.9, 173.8; IR (cm−1, neat) 1720, 129.6, 131.7, 173.4, 180.6; IR (cm−1, KBr) 3283 (OH), 1719
1620; HRMS (ESI-MS) m/z calcd for C17H16N2OS + H 297.1056, (CvO); HRMS (ESI-MS) m/z calcd for C14H18N2O2S + H
found 297.1055.
279.1162, found 279.1159.
(Z)-5-Benzyl-2-(ethylimino)-3-phenylthiazolidin-4-one (4g).
5-Benzyl-5-hydroxy-1,3-diisopropyl-2-thioxoimidazolidin-4-one
Yield: 71%; colorless prisms; m.p. 64–65 °C; H NMR (CDCl3) (5c). Yield: 59%; colorless prisms; m.p. 90–92 °C; 1H-NMR
δ 1.21 (t, J = 7.1 Hz, 3H), 3.04 (dd, J = 14.1, 9.8 Hz, 1H), 3.51 δ 0.62 (t, J = 7.4 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H), 1.12 (sex, J =
(dd, J = 14.1, 3.7 Hz, 1H), 3.86 (q, J = 7.1 Hz, 1H), 3.86 (q, J = 7.5, 2H), 1.71–1.89 (m, 1H), 1.96–2.11 (m, 1H), 3.29 (q, J =
7.1 Hz, 1H), 4.31 (dd, J = 9.8, 3.7 Hz, 1H), 6.85–6.94 (m, 2H), 14.0 Hz, 2H), 3.33–3.59 (m, 3H), 4.09 (ddd, J = 13.6, 11.0, 5.0,
7.05–7.35 (m, 8H); 13C NMR (CDCl3) δ 12.5 38.1, 39.1, 50.0, 1H), 4.51 (s, 1H), 7.02–7.05 (m, 2H), 7.22–7.26 (m, 3H); 11.0,
120.9, 124.4, 127.3, 128.5, 129.1, 129.2, 136.2, 148.2, 153.1, 11.5, 20.5, 21.7, 40.8, 42.7, 45.6, 89.3, 127.8, 128.6, 129.6,
173.5; IR (cm−1, KBr) 1722, 1628; HRMS (ESI-MS) m/z calcd for 131.7, 173.6, 181.3; IR (cm−1, KBr) 3295 (OH), 1726 (CvO);
1
C18H18N2OS + Na 333.1032, found 311.1020.
HRMS (ESI-MS) m/z calcd for C16H22N2O2S + H 307.1475,
(Z)-5-Benzyl-3-phenyl-2-(propylimino)thiazolidin-4-one (4h). found 307.1472.
1
Yield: 57%; yellow oil; H-NMR δ 0.92 (t, J = 7.4 Hz, 3H), 1.68
Single crystal X-ray structure analysis of 2h (CCDC
(sex, J = 7.4 Hz, 2H), 3.03 (dd, J = 14.0, 9.7 Hz, 1H), 3.75 (dd, J = 1859352†). Colorless prisms (0.20 × 0.10 × 0.05 mm3), monocli-
14.0, 3.7 Hz, 1H), 3.77 (t, J = 7.4 Hz, 2H), 4.31 (dd, J = 9.7, nic space group P21/c, a = 12.8458(5) Å, b = 5.3427(2) Å, c =
3.7 Hz, 1H), 6.80–6.96 (m, 2H), 6.97–7.43 (m, 8H); 13C-NMR 24.6144(10) Å, β = 101.767(3)°, V = 1653.82(11) Å3, Z = 4,
δ 11.2, 20.5, 39.1, 50.0, 120.9, 124.4, 127.2, 128.5, 129.1, 129.2, λ (CuKα) = 1.54178 Å, ρ = 1.303 g cm−3, μ (CuKα) =
136.2, 148.2, 153.3, 173.8; IR (cm−1, neat) 1718, 1641; HRMS 1.776 mm−1, 10 898 reflections measured (T = 173 K, 3.514° <
(ESI-MS) m/z calcd for C19H20N2OS + H 325.1369, found θ < 68.341°), no. of independent data collected: 3012, no. of
325.1364.
independent data used for refinement: 2264 in the final
(Z)-5-Benzyl-2-(isopropylimino)-3-phenylthiazolidin-4-one (4i). least-squares refinement cycles on F2, the model converged
1
Yield: 32%; yellow oil; H-NMR δ 1.44 (d, J = 7.1 Hz, 6H), 3.07 at R1 = 0.0495, wR2 = 0.1324 [I > 2s(I)], R1 = 0.0696, wR2
=
(dd, J = 13.9, 9.0 Hz, 1H), 3.43 (dd, J = 13.9, 3.7 Hz, 1H), 4.23 0.1416 (all data), and GOF = 1.007, H-atom parameters
(dd, J = 9.0, 3.7 Hz, 1H), 4.792 (sept, J = 7.1, 1H), 6.84–6.87 (m, constrained.
2H), 7.04–7.40 (m, 8H). 13C-NMR δ 18.6, 18.7, 39.0, 47.7, 49.3,
Single crystal X-ray structure analysis of 2i (CCDC
120.8, 124.3, 127.2, 128.4, 129.1, 129.4, 136.0, 148.4, 153.0, 1859353†). Colorless prisms (0.20 × 0.05 × 0.05 mm3), monocli-
173.8; IR (cm−1, neat) 1716, 1631; HRMS (ESI-MS) m/z calcd for nic space group P21/c, a = 13.0104(7) Å, b = 5.4301(3) Å, c =
C19H20N2OS + H 325.1369, found 325.1370.
24.2997(15) Å, β = 101.772(4)°, V = 1680.61(17) Å3, Z = 4,
(Z)-5-Benzyl-2-(benzylimino)-3-phenylthiazolidin-4-one (4j). λ (CuKα) = 1.54178 Å, ρ = 1.282 g cm−3, μ (CuKα) =
Yield: 66%; colorless prisms; m.p. 81–82 °C; 1H-NMR δ 3.02 1.747 mm−1, 11 611 reflections measured (T = 173 K, 3.470° < θ
(dd, J = 14.0, 9.7 Hz, 1H), 3.52 (dd, J = 14.0, 3.7 Hz, 1H), 4.34 < 68.239°), no. of independent data collected: 3051, no. of
(dd, J = 9.7, 3.7 Hz, 1H), 4.98 (s, 1H), 4.99 (s, 1H), 6.85–7.16 independent data used for refinement: 2600 in the final least-
(m, 2H), 7.07–7.45 (m, 13H); 13C-NMR δ 39.0, 46.1, 50.0, 120.9, squares refinement cycles on F2, the model converged at R1 =
124.4, 127.2, 127.7, 128.4, 128.6, 128.8, 129.1, 135.8, 136.2, 0.0468, wR2 = 0.1307 [I > 2s(I)], R1 = 0.0545, wR2 = 0.1367 (all
148.0, 152.7, 173.6; IR (cm−1, KBr) 1716, 1644; HRMS (ESI-MS) data), and GOF = 1.029, H-atom parameters constrained.
m/z calcd for C23H20N2OS + Na 395.1189, found 395.1189.
Single crystal X-ray structure analysis of 2j (CCDC
Cyclization of 1b–c in the presence of DBU without mole- 1859354†). Colorless prisms (0.50 × 0.20 × 0.10 mm3), monocli-
cular sieves. To a toluene (8.0 mL) solution of N-cinnamoyl-N, nic space group P21/c, a = 13.613(2) Å, b = 5.3251(9) Å, c =
N′-diethylthiourea (1b) (0.314 g, 1.20 mmol), DBU (0.228 g, 26.026(4) Å, β = 95.958(3)°, V = 1876.4(6) Å3, Z = 4, λ (MoKα) =
1.50 mmol) was added and the mixture was stirred at room 0.71073 Å, ρ = 1.318 g cm−3, μ (MoKα) = 0.188 mm−1, 10 165
temperature for 0.5 hours under an argon atmosphere. After reflections measured (T = 173 K, 1.504° < θ < 27.502°), no. of
acid extraction and removal of the solvent under reduced independent data collected: 4244, no. of independent data
pressure, the residue was purified by silica gel column chrom- used for refinement: 2649 in the final least-squares refinement
atography using a mixed solvent of ethyl acetate–hexane (1 : 3) cycles on F2, the model converged at R1 = 0.0521, wR2 = 0.1235
to give N,N′-diethyl-5-benzyl-2-thiohydantoin (3b) (21% yield, [I > 2s(I)], R1 = 0.0974, wR2 = 0.1579 (all data), and GOF =
0.063 g, 0.24 mmol) and 5-benzyl-1,3-diethyl-5-hydroxy-2-thioxo- 0.966, H-atom parameters constrained.
imidazolidin-4-one (5b) (10% yield, 0.032 g, 0.115 mmol).
Single crystal X-ray structure analysis of 3i (CCDC
Another 5-benzyl-5-hydroxy-1,3-diisopropyl-2-thioxoimidazoli- 1859407†). Colorless prisms (0.30 × 0.20 × 0.10 mm3), monocli-
din-4-one (5c) was synthesized by the same procedure.
nic space group P21/c, a = 12.4130(15) Å, b = 17.816(2) Å, c =
5-Benzyl-1,3-diethyl-5-hydroxy-2-thioxoimidazolidin-4-one (5b). 7.9085(10) Å, β = 106.841(2)°, V = 1674.0(4) Å3, Z = 4, λ (MoKα)
1
Yield: 87%; colorless prisms; m.p. 144–146 °C; H-NMR δ 0.70 = 0.71073 Å, ρ = 1.287 g cm−3, μ (MoKα) = 0.199 mm−1, 9554
(t, J = 7.1 Hz, 3H), 1.43 (t, J = 7.1 Hz, 3H), 3.28 (q, J = 13.4 Hz, reflections measured (T = 173 K, 2.5558° < θ < 27.5219°), no. of
2H), 3.51 (sex, J = 7.1, 1H), 3.65 (sex, J = 7.1, 2H), 4.21 (sex, J = independent data collected: 3838, no. of independent data
7.1, 1H), 4.41 (s, 1H), 7.01–7.06 (m, 2H), 7.21–7.24 (m, 3H); used for refinement: 2379 in the final least-squares refinement
13C-NMR δ 12.2, 13.9, 35.9, 38.7, 40.9, 89.48, 127.8, 128.6, cycles on F2, the model converged at R1 = 0.0512, wR2 = 0.1170
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[I > 2s(I)], R1 = 0.0924, wR2 = 0.1447 (all data), and GOF =
0.929, H-atom parameters constrained.
2 S. A. Bahashwan, A. A. Fayed, M. A. Ramadan, A. E.-G.
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Single crystal X-ray structure analysis of 3j (CCDC
1859355†). Colorless prisms (0.50 × 0.50 × 0.10 mm3), triclinic
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ˉ
space group P1, a = 8.887(2) Å, b = 9.348(2) Å, c = 12.182(3) Å,
α = 80.025(3)°, β = 72.125(3)°, γ = 88.273(3)°, V = 948.3(4) Å3,
Z = 2, λ (MoKα) = 0.71073 Å, ρ = 1.304 g cm−3, μ (MoKα) =
0.186 mm−1, 5472 reflections measured (T = 173 K, 2.2128° < θ
< 27.5491°), no. of independent data collected: 4141, no. of
independent data used for refinement: 3585 in the final least-
squares refinement cycles on F2, the model converged at R1 =
0.0365 wR2 = 0.0914 [I > 2s(I)], R1 = 0.0429, wR2 = 0.0954 (all
data), and GOF = 1.065, H-atom parameters constrained.
Single crystal X-ray structure analysis of 4g (CCDC
1859357†). Colorless prisms (0.50 × 0.50 × 0.10 mm3), monocli-
nic space group C2/c, a = 34.665(4) Å, b = 6.9265(9) Å, c =
14.4146(18) Å, β = 113.1370(10)°, V = 3182.7(7) Å3, Z = 8,
λ (MoKα) = 0.71073 Å, ρ = 1.296 g cm−3, μ (MoKα) =
0.207 mm−1, 17 622 reflections measured (T = 173 K, 2.5558° <
θ < 27.5219°), no. of independent data collected: 3651, no. of
independent data used for refinement: 3146 in the final least-
squares refinement cycles on F2, the model converged at R1 =
0.0310, wR2 = 0.0789 [I > 2s(I)], R1 = 0.0380, wR2 = 0.0871 (all
data), and GOF = 1.042, H-atom parameters constrained.
Single crystal X-ray structure analysis of 5c (CCDC
1859359†). Colorless prisms (0.40 × 0.30 × 0.10 mm3), triclinic
ˉ
space group P1, a = 8.7745(14) Å, b = 9.4352(16) Å, c = 20.409(3)
Å, α = 93.504(2)°, β = 97.479(2)°, γ = 90.918(2)°, V = 1671.6(5)
Å3, Z = 4, λ (MoKα) = 0.71073 Å, ρ = 1.218 g cm−3, μ (MoKα) =
9 C. Kiec-Kononowicz and E. Szymanska, Il Farmaco, 2002,
57, 909–916.
0.200 mm−1, 9602 reflections measured (T = 173 K, 2.1632° < θ 10 A. I. Khodair, A. A. El-Barbary, Y. A. Abbas and D. R. Imam,
< 23.5028°), no. of independent data collected: 7319, no. of
Phosphorus, Sulfur Silicon Relat. Elem., 2001, 170, 261–278.
independent data used for refinement: 4764 in the final least- 11 Y. S. Bae, S. Choi, J. J. Park, J. H. Joo, M. Cui, H. Cho,
squares refinement cycles on F2, the model converged at R1 =
0.0538, wR2 = 0.1302 [I > 2s(I)], R1 = 0.0851, wR2 = 0.1602 (all
data), and GOF = 0.999, H-atom parameters constrained.
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Conflicts of interest
13 V. N. Britsun, A. N. Esipenko and M. O. Lozinskii,
Russ. J. Org. Chem., 2006, 42, 1719–1724; V. N. Britsun and
M. O. Lozinskii, Chem. Heterocycl. Compd., 2003, 39, 960–
964.
There are no conflicts to declare.
14 M. Urbano, M. Guerrero, S. Velaparthi, M. Crisp, P. Chase,
P. Hodder, M.-T. Schaeffer, S. Brown, H. Rosen and
E. Roberts, Bioorg. Med. Chem. Lett., 2011, 21, 6739–6745.
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Acknowledgements
This work was supported by a Grants-in-Aid for Scientific
Research (No. 17K19114, 26410124 and 16H04144) from the
Ministry of Education, Culture, Sports, Science and Technology
(MEXT) of the Japanese Government. Mr Uemura acknowledges
financial support from the Frontier Science Program of
Graduate School of Science and Engineering, Chiba University.
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