Staudinger condensation for the preparation of thiohydantoins

Article abstract of DOI:10.1055/s-0033-1338592

An efficient one-pot, two-step sequence starting from azide derivatives is described: first, formation of iminophosphoranes (Staudinger reaction) and condensation with carbon disulfide to form nonisolated isothiocyanates; then, condensation with α-amino e

Full text of DOI:10.1055/s-0033-1338592

PAPER
▌1079
paper
Staudinger Condensation for the Preparation of Thiohydantoins
Staudinger Condensation for the Preparation of Thiohydantoins
Sandrine Gosling,a Chahrazade El Amri,b Arnaud Tatibouët*a
a
Institut de Chimie Organique et Analytique UMR 7311 – CNRS, Université d’Orléans, BP 6759, 45067 Orléans Cedex 2, France
Fax +33(2)38417281
b
GEMF UR4-UPMC, Université Pierre et Marie Curie Sorbonne Universités, case courrier 256, 7, quai St Bernard, 75252 Paris Cedex 05,
France
E-mail: arnaud.tatibouet@univ-orleans.fr
Received: 28.11.2013; Accepted after revision: 10.01.2014
to give the expected N-3-functionalized 2-thiohydantoins
Abstract: An efficient one-pot, two-step sequence starting from
2 (Scheme 1).
azide derivatives is described: first, formation of iminophospho-
ranes (Staudinger reaction) and condensation with carbon disulfide
to form nonisolated isothiocyanates; then, condensation with α-ami-
no esters to provide new N-3-substituted 2-thiohydantoins.
S
Et3N, THF
R1
Ph3P, CS2
reflux
N3
N
R1
NCS
N
H
R1
Key words: heterocycles, aza-Wittig reaction, Staudinger conden-
sation, amino acids, thiohydantoins
R2
THF, reflux
O
R2
H3N
Cl
CO2Me
1
2
2-Thiohydantoin heterocycles have proved to be flexible
tools to target various activities, somehow with controver-
sy as a ‘privileged scaffold’.1 Nonetheless, this heterocy-
cle has been described with activities for the treatment of
Scheme 1 Synthesis of N-3-functionalized 2-thiohydantoins 2 using
the one-pot Staudinger condensation reaction
prostate cancer,2 or as an antiangiogenic3 agent, as well as The sequence of reactions was first explored with glycine
for its inhibition of Cdc7 kinase4 or FGFR1 kinase.5 2- (R2 = H) and different primary 1a, 1b, 1e–j and secondary
Thiohydantoin is a simple molecular platform obtained 1c, 1d azides, obtained from carbohydrate structures [D-
through condensation of an amino acid with thiocyanate fructopyranose (for 1a), L-sorbofuranose (for 1b)], from
or isothiocyanate derivatives. In a previous paper, we glycerol carbonate (for 1e) and from thioethers (for 1f–j)
have described the synthesis of this small cycle using the (Figure 1).
Burgess-modified protocol of the Schlack–Kumpf reac-
tion, and explored its reactivity and selective functional-
N3
O
N3
O
ization.6 Numerous methods of 2-thiohydantoin
preparation have been described since the development of
the Schlack–Kumpf reaction.7 Of the mainly used proto-
cols for 2-thiohydantoin preparation, condensation of an
isothiocyanate with an α-amino acid derivative seems to
be the easiest approach.7,8 In light of previous publications
on heterocycle formation, our study was dedicated to a
more efficient protocol by condensing azido derivatives
with amino acid esters resulting in selectively functional-
ized thiohydantoins.9 It occurred to us that a direct con-
densation could be developed using the Staudinger
reaction without much handling of the isothiocyanate. To
our knowledge, only a unique example of the Staudinger
condensation of an α-azido ester with an isothiocyanate
has been previously described to generate in situ the
amine from azide.10 The approach to 2-thiohydantoin
scaffolds developed in this study has been elaborated us-
ing a tandem reaction of one-pot Staudinger reaction and
condensation with carbon disulfide, starting from azide
derivatives 1. Then, the resulting isothiocyanates, which
were not isolated, were reacted with α-amino acid esters
O
O
O
O
O
O
O
BnO
O
N3
OBn
BnO
O
OBn
1a
1b
1c
N3
N3
O
O
O
S
O
O
N3
OBz
O
OBz
OMe
1d
1e
1f
N3
N3
N3
N3
S
S
S
S
5
9
5
Me
1g
1h
1i
1j
Figure 1 Azide derivatives tested for 2-thiohydantoin formation
We succeeded in obtaining 2-thiohydantoins from carbo-
hydrate derivatives 1a, 1b and simple primary azides 1e–
j; however, this method seems to be inefficient with sec-
ondary azides 1c and 1d (Table 1, entries 3 and 4) proba-
SYNTHESIS 2014, 46, 1079–1084
Advanced online publication: 24.02.2014
DOI: 10.1055/s-0033-1338592; Art ID: SS-2013-T0768-OP
© Georg Thieme Verlag Stuttgart · New York
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0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1080
S. Gosling et al.
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bly because of the steric effects of the monosaccharidic hydantoins 2k, 2l and 2m using the optimized conditions
moiety hindering the cyclization step. In these cases, a (Table 2).
mixture of inseparable compounds was observed, using
classical purification techniques. Compounds 2a and 2b
D
H
1
S
NHBoc
2
were formed from the condensation of monosaccharidic
azides 1a and 1b with glycine in satisfactory yields of
71% and 45%, respectively (Table 1, entries 1 and 2).
Azide 1e derived from glycerol carbonate, being sensitive
to hydrolysis, allowed formation of thiohydantoin 2e in a
good yield of 68% (Table 1, entry 5), thus giving the pos-
sibility to obtain N-3-functionalized compounds with a
glycerol-type carbon chain. Very good yields, ranging
from 72% to 95%, were obtained for unhindered and reac-
tive azido sulfanes11 1f–j (Table 1, entries 6–10), regard-
less of the length of the carbon chain and the sulfur
substituent.
B
N
5
3
2'
C
N
4
A
H
N
4-MeOC6H4S
1'
H
O
2k, 97%
S
N
N
4-MeOC6H4S
2m, 93%
O
H
S
N
Ph
N
4-MeOC6H4S
2l, 98%
O
Figure 2 N-3- and C-5-functionalized 2-thiohydantoins obtained
Table 1 N-3-Functionalized 2-Thiohydantoins Obtained with Vari-
with different amino acids
ous Azides
Entry
Starting azide 1
Thiohydantoin 2 Yield (%)
Table 2 S-Benzylation of N-3- and C-5-Functionalized 2-Thiohy-
dantoins
1
2
1a
1b
1c
1d
1e
1f
2a
71
45
–
BnBr (1.2 equiv)
NaHCO3 (1 equiv)
TBAI (1.2 equiv)
S
SBn
N
2b
R1
O
R1
O
N
N
N
H
3
mixture
mixture
2e
CH2Cl2, r.t., 48 h
R2
R2
4
–
2
3
5
68
95
81
86
85
72
Entry
Starting thiohydantoin, R2
Product
Yield (%)
6
2f
1
2
3
4
2f, H
3f
3k
3l
69
53a
66
–
7
1g
1h
1i
2g
2k, (CH2)4NHBoc
2l, Bn
8
2h
9
2i
b
2m, 1H-indol-3-ylmethyl
–
10
1j
2j
a NaH used as base.
b Starting material was recovered.
The formation of 2-thiohydantoin 2f in 95% yield from
(2-azidoethyl)(4-methoxyphenyl)sulfane (1f) allowed us
to use 1f as a model to examine the one-pot Staudinger
condensation reaction with different L-amino acids (L-ly-
sine, L-phenylalanine, L-tryptophane) in order to also
functionalize the C-5 position of the cycle. Under the con-
ditions used previously, we succeeded in obtaining the N-
3- and C-5-functionalized 2-thiohydantoins 2k, 2l and 2m
as racemic mixtures, in excellent yields (Figure 2).
Optimized conditions can be applied to 2-thiohydantoin 2l
but cannot be used with the base-sensitive moieties of
compounds 2k and 2m. The L-lysine derivative, thiohy-
dantoin 2k, was successfully S-benzylated with sodium
hydride as base, whereas the various conditions explored
did not lead to the desired trisubstituted L-tryptophane de-
rivative, regardless of the alkylation conditions used.
In order to access a trisubstituted thio-heterocycle, a se-
lective thioalkylation was undertaken with thiohydantoin
2f using triethylamine and benzyl bromide.6 Under these
conditions, only a part of the starting material was con-
verted into a mixture of unidentified compounds. There-
fore, modifications of the base and the solvent were
performed. The best yield of 69% for 3f was obtained at
room temperature using benzyl bromide, sodium bicar-
bonate and tetrabutylammonium iodide in dichlorometh-
ane, with a decrease in the reaction time from 72 to 48
hours. Selective S-benzylation was then applied to 2-thio-
Having in hand this panel of heterocycles, we were eager
to test their biological potential. The antiangiogenic activ-
ity of 2-thiohydantoin derivatives such as 5,5-diphenyl-2-
thiohydantoin (DPTH) has already been described.12
Thus, we examined the anticancer potential of the novel 2-
thiohydantoin compounds by investigating the cytotoxic
effect on HeLa tumor cells. All 2-thiohydantoins synthe-
sized were first tested at 100 μM. A compound was con-
sidered to be cytotoxic while involving less than 50% of
living cells; EC50 values were then measured for nine
compounds (Table 3) using an XTT assay (see the exper-
imental section).
Synthesis 2014, 46, 1079–1084
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Staudinger Condensation for the Preparation of Thiohydantoins
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and by staining either with 1% aq KMnO4 or with 5% phosphomo-
lybdic acid followed by heating. Flash column chromatography was
carried out using Merck silica gel 60N (spherical, neutral, 40–63
μm) under N2 pressure. NMR spectra were recorded on a 400 MHz
Bruker Avance 2 spectrometer using TMS as the internal standard.
Chemical shifts are reported in parts per million (ppm, δ units).
Coupling constants (J) are expressed in hertz (Hz), and splitting pat-
terns are designated as br (broad), s (singlet), d (doublet), t (triplet),
q (quartet) and m (multiplet). Atom numbering is indicated on com-
pound 2k in Figure 2, following the nomenclature of thiohydantoin
and alkylthiohydantoins. High-resolution mass spectra (HRMS)
were recorded with a TOF spectrometer in electrospray ionization
(ESI) mode or in chemical ionization (CI) mode. IR spectra were re-
corded on a Thermo-Nicolet AVATAR 320 AEK0200713 spec-
trometer. Melting points were measured using a Thermo Scientific
9200 capillary apparatus and are uncorrected. Optical rotations
were recorded at 20 °C using a Perkin Elmer 341 polarimeter (path
length = 1 dm).
Table 3 Cytotoxicity of Thiohydantoins
Entry
Thiohydantoin
EC50 (μM)
1
2
3
4
5
6
7
8
9
2b
2h
2j
38 ± 6
18 ± 3
10 ± 2
42 ± 6
32 ± 5
17 ± 3
42 ± 6
29 ± 4
8 ± 1
2k
2l
2m
3f
3k
3l
N-3- and C-5-Substituted 2-Thioxoimidazolidin-4-ones 2;
General Procedure
Into a round-bottom flask, the azide derivative 1 (1 mmol, 1 equiv)
was introduced in THF (1 mL) at r.t. Ph3P (2 mmol, 2 equiv) and
CS2 (10 mmol, 10 equiv) were added and the solution was refluxed
until formation of the isothiocyanate, as monitored by TLC. The
mixture was concentrated under reduced pressure, after which an
amino acid methyl ester (1 mmol, 1 equiv) and Et3N (8 mmol, 8
equiv) were added in THF (1 mL). The solution was refluxed until
No cytotoxicity was observed for hydrophobic N-3-func-
tionalized 2-thiohydantoins 2f, 2g and 2i. Nevertheless, an
increase in the length of the carbon chain bearing a termi-
nal phenyl group induces cytotoxicity of 18 μM for com-
pound 2h and 10 μM for thiohydantoin 2j (Table 3, entries
2 and 3). This shows that the carbon chain length is the de- the transformation of the isothiocyanate, as monitored by TLC. The
mixture was concentrated under reduced pressure, then purified by
column chromatography on silica gel.
terminant for the cytotoxicity. Hydrophilic N-3-substitut-
ed 2-thiohydantoins 2a and 2e were not found to be
cytotoxic, except for compound 2b that showed an EC50
of 38 μM (Table 3, entry 1). On the other hand, all C-5-
substituted compounds 2k–m, 3k and 3l were found to be
cytotoxic (Table 3, entries 4–6, 8 and 9), with a quite in-
teresting EC50 range from 8 μM to 42 μM. Finally, we ob-
served that S-benzylation increased the cytotoxicity: 2f
was not cytotoxic while 3f has an EC50 of 42 μM (Table 3,
entry 7), the EC50 of the L-lysine derivative 2k decreased
from 42 μM to 29 μM for 3k (Table 3, entries 4 and 8) and
the cytotoxicity of compound 2l was multiplied by four
for 3l (Table 3, entries 5 and 9). These measurements re-
veal that potentially more cytotoxic structures would bear
a long carbon chain terminated by a phenyl group at the
N-3 position and would be C-5 substituted and S-2 ben-
zylated. Interestingly, compounds 2a, 2f and 2g do not
present cytotoxic effects on HeLa cancer cells.
1-Deoxy-2,3:4,5-di-O-isopropylidene-1-(5-oxo-2-thioxoimid-
azolidin-1-yl)-β-D-fructopyranose (2a)
1-Azido-1-deoxy-2,3:4,5-di-O-isopropylidene-β-D-fructopyranose
(1a; 100 mg, 0.35 mmol, 1 equiv) was used to prepare 2a. Purifica-
tion by flash chromatography on silica gel (PE–EtOAc, 1:1) afford-
ed compound 2a as a white solid; yield: 89.2 mg (71%).
20
Mp 210–211 °C (dec); [α]D –10 (c 0.85, CHCl3); Rf = 0.20 (PE–
EtOAc, 1:1).
IR (neat): 3293 (NH), 1748 (C=O), 1510 (N–C=S), 1250 (C–N),
1065 cm–1 (C–O).
1H NMR (400 MHz, CDCl3): δ = 7.70 (br, 1 H, NH), 4.81 (d,
J
3′,4′ = 2.7 Hz, 1 H, H-3′), 4.56 (dd, J4′,5′ = 7.8 Hz, 1 H, H-4′), 4.18
(d, J1′a,1′b = 14.3 Hz, 1 H, H-1′b), 4.17 (dd, J4′,5′ = 7.8 Hz, J6′b,5′ = 2.0
Hz, 1 H, H-5′), 4.13 (d, 1 H, H-1′a), 4.10 (s, 2 H, H-5), 3.83 (dd,
J6′a,6′b = 13.0 Hz, 1 H, H-6′b), 3.72 (d, 1 H, H-6′a), 1.50 (s, 3 H,
CH3), 1.47 (s, 3 H, CH3), 1.34 (s, 3 H, CH3), 1.33 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 185.4 (C-2), 171.7 (C-4), 109.0,
108.5 (Cq, i-Pr), 103.0 (C-2′), 71.6 (C-3′), 70.5 (C-4′), 70.3 (C-5′),
61.6 (C-6′), 48.3 (C-5), 46.6 (C-1′), 26.1, 25.8, 25.0, 24.1 (4 × CH3).
In summary, we have explored an efficient approach to
the synthesis of substituted thiohydantoins using a two-
step sequence, without any intermediate purification step.
The method proved effective on primary, nonhindered
azides. Preliminary biological screening showed signifi-
cant cytotoxicity of the resulting heterocycles, an aspect
which is currently under biological study.
ESI-HRMS: m/z [M + Na]+ calcd for C15H22N2NaO6S: 381.1096;
found: 381.1098.
4,6-Di-O-benzyl-1-deoxy-2,3-O-isopropylidene-1-(5-oxo-2-
thioxoimidazolidin-1-yl)-α-L-sorbofuranose (2b)
1-Azido-4,6-di-O-benzyl-1-deoxy-2,3-O-isopropylidene-α-L-sor-
bofuranose (1b; 100 mg, 0.24 mmol, 1 equiv) was used to prepare
2b. Flash chromatographic purification (PE–EtOAc, 7:3) afforded
compound 2b as a yellow oil; yield: 52.8 mg (45%).
The reactions requiring anhydrous conditions were performed in
oven-dried glassware with anhydrous solvents under argon atmo-
sphere. CH2Cl2 was distilled over P2O5. THF was distilled in the
presence of sodium/benzophenone. Toluene was distilled over
CaH2. DMF (HPLC) was dried over 4-Å MS and MeOH (HPLC)
over 3-Å MS. Most reagents were used as obtained from commer-
cial suppliers (Acros, Aldrich, Lancaster or Apollo). Analytical
TLC was performed on Merck silica gel 60 F254 precoated plates.
Visualization of the compounds was made with UV light (254 nm)
[α]D20 +32 (c 0.83, CHCl3); Rf = 0.67 (PE–EtOAc, 1:1).
IR (neat): 3290 (NH), 1750 (C=O), 1511 (N–C=S), 1347–1256 (C–
N), 1063 cm–1 (C–O).
1H NMR (400 MHz, CDCl3): δ = 7.35–7.29 (m, 10 H, H-Ph), 6.60
(br s, 1 H, NH), 5.28 (s, 1 H, H-3′), 4.64 (d, J = 12.0 Hz, 1 H, Ha,
CH2Ph), 4.58 (d, J1′a,1′b = 10.7 Hz, 1 H, H-1′b), 4.55 (d, 1 H, Hb,
CH2Ph), 4.44–4.40 (m, 1 H, H-5′), 4.40 (d, 1 H, H-1′a), 4.33 (d,
© Georg Thieme Verlag Stuttgart · New York
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S. Gosling et al.
PAPER
J = 14.3 Hz, 1 H, Hb, CH2Ph), 4.23 (d, 1 H, Ha, CH2Ph), 3.92 (d,
J4′,5′ = 3.1 Hz, 1 H, H-4′), 3.75 (dd, J6′a,6′b = 9.8 Hz, J6′b,5′ = 6.7 Hz, 1
H, H-6′b), 3.69 (dd, J6′a,5′ = 5.9 Hz, 1 H, H-6′a), 3.47 (d, J5a,5b = 19.0
Hz, 1 H, H-5b), 3.31 (d, 1 H, H-5a), 1.49 (s, 3 H, CH3), 1.44 (s, 3 H,
CH3).
13C NMR (100 MHz, CDCl3): δ = 185.1 (C-2), 171.0 (C-4), 138.1,
137.8 (Cq, Ph), 128.3, 128.3, 128.1, 128.0, 127.8, 127.6 (CH, Ph),
113.5, 111.4 (Cq, C-2′ and i-Pr), 82.6 (C-3′), 82.1 (C-4′), 79.6 (C-
5′), 73.5 (CH2Ph), 72.6 (CH2Ph), 67.2 (C-6′), 48.0 (C-5), 44.5 (C-
1′), 26.9, 26.3 (2 × CH3).
13C NMR (100 MHz, CDCl3): δ = 184.4 (C-2), 171.3 (C-4), 134.9
(Cq, Ph), 129.3, 129.0, 126.3 (CH, Ph), 48.3 (C-5), 40.8 (C-1′), 30.3
(C-2′).
ESI-HRMS: m/z [M + Na]+ calcd for C11H12N2NaOS2: 275.0289;
found: 275.0302.
3-[6-(Phenylsulfanyl)hexyl]-2-thioxoimidazolidin-4-one (2h)
(6-Azidohexyl)(phenyl)sulfane (1h; 200 mg, 0.85 mmol, 1 equiv)
was used to prepare 2h. Purification by flash chromatography on
silica gel (PE–EtOAc, 8:2) afforded compound 2h as a yellow solid;
yield: 225 mg (86%).
ESI-HRMS: m/z [M + Na]+ calcd for C26H30N2NaO6S: 521.1722;
found: 521.1729.
Mp 89–90 °C; Rf = 0.39 (PE–EtOAc, 1:1).
IR (neat): 3281 (NH), 1733 (C=O), 1514 (N–C=S), 1345–1134
cm–1 (C–N).
1H NMR (400 MHz, CDCl3): δ = 7.47 (br s, 1 H, NH), 7.33–7.14
(m, 5 H, H-Ph), 4.04 (s, 2 H, H-5), 3.79 (t, J1′,2′ = 7.4 Hz, 2 H, H-1′),
2.91 (t, J5′,6′ = 7.4 Hz, 2 H, H-6′), 1.72–1.62 (m, 4 H, H-2′ and H-5′),
1.51–1.44 (m, 2 H, H-4′), 1.39–1.31 (m, 2 H, H-3′).
3-[(2-Oxo-1,3-dioxolan-4-yl)methyl]-2-thioxoimidazolidin-4-
one (2e)
4-(Azidomethyl)-1,3-dioxolan-2-one13 (1e; 100 mg, 0.70 mmol, 1
equiv) was used to prepare 2e. Purification by flash chromatogra-
phy on silica gel (PE–EtOAc, 3:7) afforded compound 2e as a white
solid; yield: 103 mg (68%).
13C NMR (100 MHz, CDCl3): δ = 185.1 (C-2), 171.5 (C-4), 136.8
(Cq, Ph), 128.8, 128.8, 125.7 (CH, Ph), 48.3 (C-5), 41.2 (C-1′), 33.4
(C-6′), 28.9 (C-5′), 28.3 (C-4′), 27.4 (C-2′), 26.2 (C-3′).
ESI-HRMS: m/z [M + Na]+ calcd for C15H20N2NaOS2: 331.0915;
found: 331.0928.
Mp 150–151 °C (dec); Rf = 0.23 (PE–EtOAc, 3:7).
IR (neat): 3337 (NH), 1765 (C=O), 1733 (O–C=O), 1511 (N–C=S),
1180 (C–N), 1081 cm–1 (C–O).
1H NMR (400 MHz, DMSO-d6): δ = 10.35 (br s, 1 H, NH), 5.07–
5.00 (m, 1 H, H-2′), 4.56 (t, J1′b,1′a = J1′b,2′ = 8.3 Hz, 1 H, H-1′b), 4.38
(dd, J1′a,2′ = 6.0 Hz, 1 H, H-1′a), 4.17 (s, 2 H, H-5), 4.08 (dd,
3-[6-(Methylsulfanyl)hexyl]-2-thioxoimidazolidin-4-one (2i)
(6-Azidohexyl)(methyl)sulfane (1i; 200 mg, 1.15 mmol, 1 equiv)
was used to prepare 2i. Purification by flash chromatography on sil-
ica gel (PE–EtOAc, 8:2) afforded compound 2i as a yellow solid;
yield: 241 mg (85%).
J3′a,3′b = 14.4 Hz, J3′b,2′ = 7.2 Hz, 1 H, H-3′b), 3.94 (dd, J3′a,2′ = 5.1
Hz, 1 H, H-3′a).
13C NMR (100 MHz, DMSO-d6): δ = 182.8 (C-2), 172.7 (C-4),
154.2 (O–C=O), 73.4 (C-2′), 67.4 (C-1′), 48.4 (C-5), 41.9 (C-3′).
ESI-HRMS: m/z [M + Na]+ calcd for C7H8N2NaO4S: 239.0102;
Mp 64–65 °C; Rf = 0.39 (PE–EtOAc, 1:1).
found: 239.0103.
IR (neat): 3275 (NH), 1710 (C=O), 1504 (N–C=S), 1348–1131
cm–1 (C–N).
1H NMR (400 MHz, CDCl3): δ = 7.53 (br s, 1 H, NH), 4.06 (s, 2 H,
H-5), 3.79 (t, J1′,2′ = 7.4 Hz, 2 H, H-1′), 2.47 (t, J5′,6′ = 7.4 Hz, 2 H,
H-6′), 2.08 (s, 3 H, SCH3), 1.71–1.65 (m, 2 H, H-2′), 1.63–1.55 (m,
2 H, H-5′), 1.46–1.38 (m, 2 H, H-4′), 1.36–1.31 (m, 2 H, H-3′).
13C NMR (100 MHz, CDCl3): δ = 185.1 (C-2), 171.5 (C-4), 48.4
(C-5), 41.2 (C-1′), 34.1 (C-6′), 28.9 (C-5′), 28.2 (C-4′), 27.4 (C-2′),
26.3 (C-3′), 15.5 (CH3).
3-[2-(4-Methoxyphenylsulfanyl)ethyl]-2-thioxoimidazolidin-4-
one (2f)
(2-Azidoethyl)(4-methoxyphenyl)sulfane (1f; 3.30 g, 15.8 mmol, 1
equiv) was used to prepare 2f. Flash chromatographic purification
(PE–EtOAc, 1:1) afforded compound 2f as a yellow solid; yield:
4.22 g (95%).
Mp 114–115 °C; Rf = 0.21 (PE–EtOAc, 1:1).
IR (neat): 3311 (NH), 1746 (C=O), 1514–1494 (N–C=S), 1230–
1145 cm–1 (C–O or C–N).
ESI-HRMS: m/z [M + Na]+ calcd for C10H18N2NaOS2: 269.0758;
found: 269.0766.
1H NMR (400 MHz, CDCl3): δ = 7.43 (d, Jm,o = 8.8 Hz, 2 H,
MeOC6H4-Hortho), 6.85 (d, 2 H, MeOC6H4-Hmeta), 4.00 (t, J1′,2′ = 7.1
Hz, 2 H, H-1′), 3.97 (s, 2 H, H-5), 3.79 (s, 3 H, OCH3), 3.16 (t, 2 H,
H-2′).
13C NMR (100 MHz, CDCl3): δ = 184.5 (C-2), 171.2 (C-4), 159.1
(Cpara), 133.1 (Cortho), 125.0 (CSipso), 114.6 (Cmeta), 55.3 (OCH3),
48.3 (C-5), 40.9 (C-1′), 32.2 (C-2′).
3-[10-(Phenylsulfanyl)decyl]-2-thioxoimidazolidin-4-one (2j)
(10-Azidodecyl)(phenyl)sulfane (1j; 200 mg, 0.69 mmol, 1 equiv)
was used to prepare 2j. Purification by flash chromatography on sil-
ica gel (PE–EtOAc, 8:2) afforded compound 2j as a white solid;
yield: 180 mg (72%).
Mp 89–90 °C; Rf = 0.50 (PE–EtOAc, 1:1).
ESI-HRMS: m/z [M + Na]+ calcd for C12H14N2NaO2S2: 305.0394;
found: 305.0409.
IR (neat): 3153 (NH), 1741 (C=O), 1535 (N–C=S), 1346–1133
cm–1 (C–N).
1H NMR (400 MHz, CDCl3): δ = 7.33–7.25 (m, 5 H, H-Ph and NH),
7.18–7.13 (m, 1 H, H-Ph), 4.05 (s, 2 H, H-5), 3.79 (t, J1′,2′ = 7.5 Hz,
2 H, H-1′), 2.91 (t, J9′,10′ = 7.5 Hz, 2 H, H-10′), 1.68–1.66 (m, 2 H,
H-2′), 1.64–1.60 (m, 2 H, H-9′), 1.43–1.37 (m, 2 H, H-8′), 1.31–1.27
(m, 10 H, H-3′, H-4′, H-5′, H-6′ and H-7′).
3-[2-(Phenylsulfanyl)ethyl]-2-thioxoimidazolidin-4-one (2g)
(2-Azidoethyl)(phenyl)sulfane (1g; 200 mg, 1.12 mmol, 1 equiv)
was used to prepare 2g. Purification by flash chromatography on sil-
ica gel (PE–EtOAc, 8:2) afforded compound 2g as a yellow solid;
yield: 229 mg (81%).
Mp 131–132 °C; Rf = 0.15 (PE–EtOAc, 1:1).
13C NMR (100 MHz, CDCl3): δ = 185.2 (C-2), 171.5 (C-4), 137.0
(Cq, Ph), 128.8, 128.8, 125.6 (CH, Ph), 48.3 (C-5), 41.4 (C-1′), 33.5
(C-10′), 29.3 (2 × CH2), 29.1 (2 × CH2), 29.1 (C-9′), 28.8 (C-8′),
27.5 (C-2′), 26.7 (CH2).
ESI-HRMS: m/z [M + Na]+ calcd for C19H28N2NaOS2: 387.1541;
found: 387.1554.
IR (neat): 3280 (NH), 1730 (C=O), 1513 (N–C=S), 1343–1146 cm–
1 (C–N).
1H NMR (400 MHz, CDCl3): δ = 7.46–7.43 (m, 2 H, H-Ph), 7.41 (br
s, 1 H, NH), 7.32–7.18 (m, 3 H, H-Ph), 4.07 (t, J1′,2′ = 7.2 Hz, 2 H,
H-1′), 3.95 (s, 2 H, H-5), 3.27 (t, 2 H, H-2′).
Synthesis 2014, 46, 1079–1084
© Georg Thieme Verlag Stuttgart · New York

PAPER
Staudinger Condensation for the Preparation of Thiohydantoins
1083
5-[4-(tert-Butoxycarbonylamino)butyl]-3-[2-(4-methoxyphe-
nylsulfanyl)ethyl]-2-thioxoimidazolidin-4-one (2k)
J
Aa,Ab = 14.7 Hz, 1 H, H-Ab), 3.03 (dd, 1 H, H-Aa), 2.99–2.92 (m, 1
H, H-2′b), 2.90–2.83 (m, 1 H, H-2′a).
(2-Azidoethyl)(4-methoxyphenyl)sulfane (1f; 466 mg, 2.23 mmol,
1 equiv) and N-(tert-butoxycarbonyl)-L-lysine methyl ester12 (580
mg, 2.23 mmol, 1 equiv) were used to prepare 2k. Purification by
flash chromatography on silica gel (PE–EtOAc, 7:3) afforded com-
pound 2k as a translucent oil; yield: 978 mg (97%).
13C NMR (100 MHz, CDCl3): δ = 183.2 (C-2), 173.4 (C-4), 159.0
(Cpara), 136.2 (C-7aindole), 132.9 (Cortho), 126.6 (C-3aindole), 125.1
(CSipso), 123.2 (C-2indole), 122.7 (C-6indole), 120.1 (C-5indole), 118.4
(C-4indole), 114.6 (Cmeta), 111.4 (C-7indole), 108.8 (C-3indole), 59.8 (C-
5), 55.3 (OCH3), 40.5 (C-1′), 31.9 (C-2′), 27.7 (C-A).
ESI-HRMS: m/z [M + Na]+ calcd for C21H21N3NaO2S2: 434.0973;
found: 434.0986.
Rf = 0.30 (PE–EtOAc, 1:1).
IR (neat): 3271 (NH), 1744 (C=O, ring), 1684 (C=O, Boc), 1494–
1404 (N–C=S), 1242–1152 cm–1 (C–O or C–N).
S-Benzylated N-3- and C-5-Substituted 2-Thioxoimidazolidin-
4-ones 3; General Procedure
1H NMR (400 MHz, CDCl3): δ = 7.42 (d, Jo,m = 8.8 Hz, 2 H,
MeOC6H4-Hortho), 6.85 (d, 2 H, MeOC6H4-Hmeta), 4.61 (br s, 1 H,
NHBoc), 4.03–3.98 (m, 1 H, H-5), 3.97–3.95 (m, 2 H, H-1′), 3.79
(s, 3 H, OCH3), 3.15–3.12 (m, 2 H, H-2′), 3.12–3.08 (m, 2 H, H-D),
1.95–1.89 (m, 1 H, H-Ab), 1.78–1.69 (m, 1 H, H-Aa), 1.52–1.47 (m,
2 H, H-C), 1.44 (s, 9 H, t-Bu), 1.39–1.37 (m, 2 H, H-B).
13C NMR (100 MHz, CDCl3): δ = 183.5 (C-2), 174.0 (C-4), 159.1
(Cpara), 156.2 (C=O, Boc), 133.1 (Cmeta), 125.1 (CSipso), 114.6
(Cortho), 79.5 (Cq, t-Bu), 59.1 (C-5), 55.3 (OCH3), 40.5 (C-1′), 39.8
(C-D), 32.6 (C-2′), 30.6 (C-A), 29.5 (C-C), 28.4 (3 × CH3, t-Bu),
21.7 (C-B).
NaHCO3 (1 equiv), TBAI (1.2 equiv) and then BnBr (1.2 equiv)
were added to a solution of the 3-[2-(4-methoxyphenylsulfanyl)eth-
yl]-2-thioxoimidazolidin-4-one derivative 2 (1 equiv) in CH2Cl2 (10
mL) at r.t. The mixture was stirred for 48 h at r.t., after which the
solution was concentrated under reduced pressure. The crude prod-
uct was purified by column chromatography on silica gel.
2-(Benzylsulfanyl)-1-[2-(4-methoxyphenylsulfanyl)ethyl]-4,5-
dihydro-1H-imidazol-5-one (3f)
Compound 2f (3.0 g, 10.62 mmol) was used to prepare 3f. Purifica-
tion by flash chromatography on silica gel (PE–EtOAc, 7:3) afford-
ed the S-benzylated 2-thiohydantoin 3f as a yellow oil; yield: 2.745
g (69%).
ESI-HRMS: m/z [M + Na]+ calcd for C21H31N3NaO4S2: 476.1654;
found: 476.1660.
Rf = 0.37 (PE–EtOAc, 7:3).
IR (neat): 1729 (C=O), 1568–1493 (N–C=S), 1242–1140 cm–1 (C–
O or C–N).
5-Benzyl-3-[2-(4-methoxyphenylsulfanyl)ethyl]-2-thioxoimid-
azolidin-4-one (2l)
(2-Azidoethyl)(4-methoxyphenyl)sulfane (1f; 1.12 g, 5.37 mmol, 1
equiv) and L-phenylalanine methyl ester hydrochloride (1.16 g, 5.37
mmol, 1 equiv) were used to prepare 2l. Purification by flash chro-
matography on silica gel (PE–EtOAc, 8:2) afforded compound 2l as
a white solid; yield: 1.99 g (quantitative).
1H NMR (400 MHz, CDCl3): δ = 7.39–7.30 (m, 7 H, MeOC6H4-
Hortho, H-Ph), 6.81 (d, Jo,m = 8.8 Hz, 2 H, MeOC6H4-Hmeta), 4.37 (s,
2 H, SCH2Ph), 4.07 (s, 2 H, H-4), 3.77 (s, 3 H, OCH3), 3.63 (t,
J1′,2′ = 7.3 Hz, 2 H, H-1′), 3.01 (t, 2 H, H-2′).
13C NMR (100 MHz, CDCl3): δ = 179.7 (C-5), 162.5 (C-2), 159.3
(Cpara), 135.8 (Cq, Ph), 133.5 (Cortho), 129.1, 128.7, 127.8 (CH, Ph),
124.7 (CSipso), 114.7 (Cmeta), 58.9 (C-4), 55.3 (OCH3), 40.5 (C-1′),
34.4 (SCH2Ph), 33.4 (C-2′).
Mp 97–98 °C; Rf = 0.44 (PE–EtOAc, 1:1).
IR (neat): 3180 (NH), 1737 (C=O), 1573–1518 (N–C=S), 1240–
1176 cm–1 (C–O or C–N).
1H NMR (400 MHz, CDCl3): δ = 7.42 (d, Jo,m = 8.8 Hz, 2 H,
MeOC6H4-Hortho), 7.34–7.17 (m, 5 H, H-Ph), 6.86 (d, 2 H,
MeOC6H4-Hmeta), 4.24 (dd, JAb,5 = 3.8 Hz, JAa,5 = 8.9 Hz, 1 H, H-5),
3.91 (t, J1′,2′ = 7.2 Hz, 2 H, H-1′), 3.79 (s, 3 H, OCH3), 3.27 (dd,
JAa,Ab = 14.0 Hz, 1 H, H-Ab), 3.03–2.91 (m, 2 H, H-2′), 2.83 (dd, 1
H, H-Aa).
13C NMR (100 MHz, CDCl3): δ = 183.2 (C-2), 173.0 (C-4), 159.0
(Cpara), 134.6 (Cq, Ph), 132.9 (Cortho), 129.1, 129.0, 127.7 (CH, Ph),
125.0 (CSipso), 114.6 (Cmeta), 60.4 (C-5), 55.3 (OCH3), 40.7 (C-1′),
37.4 (C-A), 32.0 (C-2′).
ESI-HRMS: m/z [M + H]+ calcd for C19H21N2O2S2: 373.1044;
found: 373.1045.
2-(Benzylsulfanyl)-4-[4-(tert-butoxycarbonylamino)butyl]-1-[2-
(4-methoxyphenylsulfanyl)ethyl]-4,5-dihydro-1H-imidazol-5-
one (3k)
Compound 2k (0.1 g, 0.2 mmol) was used to prepare 3k, using 60%
NaH (6 mg, 0.2 mmol) instead of NaHCO3. Flash chromatographic
purification (PE–EtOAc, 1:1) afforded the S-benzylated 2-thiohy-
dantoin 3k as a translucent oil; yield: 90.0 mg (53%).
ESI-HRMS: m/z [M + Na]+ calcd for C19H20N2NaO2S2: 395.0864;
found: 395.0863.
Rf = 0.36 (PE–EtOAc, 1:1).
IR (neat): 3366 (NH), 1709 (C=O), 1567–1494 (N–C=S), 1243–
1169 cm–1 (C–O or C–N).
5-(1H-Indol-3-ylmethyl)-3-[2-(4-methoxyphenylsulfanyl)eth-
yl]-2-thioxoimidazolidin-4-one (2m)
1H NMR (400 MHz, CDCl3): δ = 7.37 (d, Jo,m = 8.8 Hz, 2 H,
MeOC6H4-Hortho), 7.38–7.27 (m, 5 H, H-Ph), 6.81 (d, 2 H,
MeOC6H4-Hmeta), 4.59 (br s, 1 H, NH), 4.40 (d, J = 13.2 Hz, 1 H,
Hb, SCH2), 4.33 (d, 1 H, Ha, SCH2), 3.98 (dd, J4,Aa = 7.3 Hz,
J4,Ab = 5.2 Hz, 1 H, H-4), 3.76 (s, 3 H, OCH3), 3.59 (t, J1′,2′ = 7.2 Hz,
2 H, H-1′), 3.11–3.09 (m, 2 H, H-D), 2.98 (t, 2 H, H-2′), 1.93–1.85
(m, 1 H, H-Ab), 1.68–1.59 (m, 1 H, H-Aa), 1.51–1.47 (m, 2 H, H-
C), 1.43 (s, 9 H, t-Bu), 1.40–1.36 (m, 2 H, H-B).
13C NMR (100 MHz, CDCl3): δ = 181.0 (C-5), 160.7 (C-2), 159.2
(Cpara), 155.9 (C=O, t-Bu), 135.9 (Cq, Ph), 133.5 (Cortho), 129.1,
128.6, 127.7 (CH, Ph), 124.6 (CSipso), 114.6 (Cmeta), 79.0 (Cq, t-Bu),
68.5 (C-4), 55.2 (OCH3), 40.2 (C-1′), 40.2 (C-D), 34.3 (SCH2Ph),
33.5 (C-2′), 31.0 (C-A), 29.7 (C-C), 28.4 (3 × CH3, t-Bu), 22.4 (C-
B).
(2-Azidoethyl)(4-methoxyphenyl)sulfane (1f; 150 mg, 0.72 mmol,
1 equiv) and L-tryptophane methyl ester hydrochloride (183 mg,
0.72 mmol, 1 equiv) were used to prepare 2m. Purification by flash
chromatography on silica gel (PE–EtOAc, 8:2) afforded compound
2m as a yellow solid; yield: 275 mg (93%).
Mp 61–62 °C; Rf = 0.50 (PE–EtOAc, 1:1).
IR (neat): 3184 (NH), 1738 (C=O), 1517–1493 (N–C=S), 1241–
1150 cm–1 (C–O or C–N).
1H NMR (400 MHz, CDCl3): δ = 8.15 (s, 1 H, NH), 7.58 (d,
J4,5 = 7.5 Hz, 1 H, H-4indole), 7.38 (d, Jo,m = 8.7 Hz, 2 H, MeOC6H4-
Hortho), 7.36 (d, J6,7 = 8.1 Hz, 1 H, H-7indole), 7.23 (br s, 1 H, NH),
7.23 (t, J5,6 = 8.1 Hz, 1 H, H-6indole), 7.15 (t, J5,4 = 7.5 Hz, 1 H, H-
5indole), 7.06 (d, J2,NH = 2.3 Hz, 1 H, H-2indole), 6.86 (d, 2 H,
ESI-HRMS: m/z [M + Na]+ calcd for C28H37N3NaO4S2: 566.2123;
found: 566.2123.
MeOC6H4-Hmeta), 4.29 (dd, JAb,5 = 3.8 Hz, JAa,5 = 9.0 Hz, 1 H, H-5),
3.90 (t, J1′,2′ = 7.2 Hz, 2 H, H-1′), 3.78 (s, 3 H, OCH3), 3.42 (dd,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1079–1084

1084
S. Gosling et al.
PAPER
4-Benzyl-2-(benzylsulfanyl)-1-[2-(4-methoxyphenylsulfa-
nyl)ethyl]-4,5-dihydro-1H-imidazol-5-one (3l)
Compound 2l (0.1 g, 0.27 mmol) was used to prepare 3l. Purifica-
tion by flash chromatography on silica gel (PE–EtOAc, 7:3) afford-
ed the S-benzylated 2-thiohydantoin 3l as a translucent oil; yield:
82.2 mg (66%).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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References
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Rf = 0.61 (PE–EtOAc, 6:4).
IR (neat): 1726 (C=O), 1566–1493 (N–C=S), 1244 cm–1 (C–O or
C–N).
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Jo,m = 8.7 Hz, 2 H, MeOC6H4-Hortho), 7.21–7.12 (m, 5 H, H-Ph),
6.81 (d, 2 H, MeOC6H4-Hmeta), 4.41 (d, J = 13.3 Hz, 1 H, Hb,
SCH2Ph), 4.31 (d, 1 H, Ha, SCH2Ph), 4.29 (dd, JAb,4 = 4.5 Hz,
JAa,4 = 6.3 Hz, 1 H, H-4), 3.76 (s, 3 H, OCH3), 3.52–3.45 (m, 1 H,
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H-1′b), 3.35–3.28 (m, 1 H, H-1′a), 3.25 (dd, JAa,Ab = 13.7 Hz, 1 H,
H-Ab), 3.01 (dd, 1 H, H-Aa), 2.64–2.51 (m, 2 H, H-2′).
13C NMR (100 MHz, CDCl3): δ = 181.0 (C-5), 161.0 (C-2), 159.2
(Cpara), 136.1, 135.9 (Cq, Ph), 133.2 (Cortho), 133.2, 129.8, 129.1,
128.6, 127.9, 127.7 (CH, Ph), 124.6 (CSipso), 114.6 (Cmeta), 69.3 (C-
4), 55.3 (OCH3), 40.0 (C-1′), 37.2 (C-A), 34.3 (SCH2Ph), 32.6 (C-
2′).
ESI-HRMS: m/z [M + H]+ calcd for C26H27N2O2S2: 463.1514;
found: 463.1519.
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Cytotoxicity Assay
HeLa cells (human cervical carcinoma) were a kind gift from S.
Lefebvre (Institut Jacques Monod, Paris). The cells were grown in
DMEM supplemented with 10% fetal bovine serum in a 5% CO2
humidified atmosphere (95% humidity). Confluent cells were col-
lected and then preincubated without inhibitor for 20 h (5 × 103
cells in 100 μL culture medium in 96-well plates). They were then
exposed for 48 h to increasing concentrations of compounds: 5–100
μM (final concentration of DMSO: 0.5% v/v). After removal of the
DMEM medium, an XTT solution was added to each well (100 μL
at 0.3 mg/mL containing 8.3 μM PMS) for 2 h. Absorbance was
measured using a BMG FLUOstar microplate reader at 485 nm. The
cytotoxicity activity of drugs is expressed as the concentration in-
hibiting cell growth by 50% (EC50) calculated from the survival
curves. The experimental data were fitted to the following equation,
where E is the survival percentage, C is the drug concentration, Emax
is the maximum drug effect, and n is the Hill constant, which de-
scribes the shape of the curve: E = (Emax × Cn)/(Cn + EC50n). EC50 is
the concentration that produces one half of the maximum effect.
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B. A. B.; Angeles Pradera, M.; Fernández de Córdoba, F. J.;
Gasch, C. Tetrahedron 2006, 62, 97. (d) Tardy, S.; Lobo
Vicente, J.; Tatibouët, A.; Dujardin, G.; Rollin, P. Synthesis
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(10) Fresneda, P. M.; Castaneda, M.; Sanz, M. A.; Bautista, D.;
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Acknowledgment
The authors thank the Université d’Orléans and the MESR for a fel-
lowship (S.G.) and the ANR for financial support of the project.
Synthesis 2014, 46, 1079–1084
© Georg Thieme Verlag Stuttgart · New York