1-(Methyldithiocarbonyl)imidazole as thiocarbonyl transfer reagent: A facile one-pot three-component synthesis of 3,5- and 1,3,5-substituted-2- thiohydantoins

Article abstract of DOI:10.1055/s-2007-967987

An efficient three-component one-pot synthesis of 3,5-and 1,3,5-substituted 2-thiohydantoins employing easily accessible amino acid esters, primary amines and 1-(methyldithiocarbonyl)imidazole as thiocarbonyl transfer reagent has been reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-967987

LETTER
251
1-(Methyldithiocarbonyl)imidazole as Thiocarbonyl Transfer Reagent:
A Facile One-Pot Three-Component Synthesis of 3,5- and 1,3,5-Substituted-
2-Thiohydantoins
Synthesis of 3,5-
a
.
nd 1,3,5-Sub
S
stituted-2-Thi
.ohydantoinsM. Sundaram, C. Venkatesh, H. Ila,* H. Junjappa
Department of Chemistry, Indian Institute of Technology, Kanpur-208016, India
Fax +91(512)2597436; fax +91(512)2590260; E-mail: hila@iitk.ac.in
Received 7 September 2006
S
+ Cl–
NH3
Abstract: An efficient three-component one-pot synthesis of 3,5-
and 1,3,5-substituted 2-thiohydantoins employing easily accessible
amino acid esters, primary amines and 1-(methyldithiocarbonyl)im-
idazole as thiocarbonyl transfer reagent has been reported.
S
R1
EtO
O
N
NH
R2
a or b
NH2
N
N
+
R1NH2
+
SMe
R2
O
1
2
4
3
Key words: thiohydantoins, multicomponent reactions, fused thio-
hydantoins, imidazole dithioate, amino acids
NH2
NH2
NH2
NH2
amines:
MeO
O
NH2
R
Hydantoins and their 2-thio analogues represent an impor-
tant class of heterocycles displaying a broad range of
biological (anticonvulsant, antiarrythmic, antimuscarine,
antineuralgic, anticancer) activities.1 Derivatives of 2-
thiohydantoins also play an important role in organic syn-
thesis, especially as starting materials for the preparation
of synthetic intermediates with wide range of applications
as therapeutics2 as well as fungicides and herbicides.3
They have also been used widely for the sequence analy-
sis of polypeptides and proteins (Edman degradation).4
These compounds are usually prepared by reaction of
amino acids or amino acid esters with an isothiocyanate.5
A few of the 2-thiohydantoins have been synthesized by
reaction of amino acids with dithiocarbamate esters.6 We
have recently7 reported synthetic application of 1-(meth-
yldithiocarbonyl)imidazole as a useful thiocarbonyl
transfer reagent8 for the synthesis of symmetrical and un-
symmetrical mono-, di- and trisubstituted thioureas and
dithiocarbamates under mild and simple non-hazardous
reaction conditions. In the present communication, we
wish to report further application of this reagent for the ef-
ficient synthesis of a broad range of 3,5- and 1,3,5-sub-
stituted-2-thiohydantoins by its reaction with amino acid
esters and amines in a three-component one-pot process.
NH2
MeO
N
R = H, OMe
H
EtO
NH2
EtO
NH2
EtO
NH2
amino acid esters:
O
Me
O
O
NH2
EtO
NH2
CO2Et
O
N
H
Scheme 1 Synthesis of 3,5-substituted 2-thiohydantoins 4.
Reagents and conditions: a) Et3N, EtOH, D, 7–8 h; b) K2CO3, MeCN,
D, 7–8 h.
sponding free alanine, benzylamine and 1-(methyldithio-
carbonyl)imidazole resulted in the formation of only 1,3-
dibenzylthiourea and no trace of thiohydantoin 4a was
obtained. The reaction was equally facile in the presence
of K2CO3 as base in acetonitrile yielding 4a in comparable
yield (85%). The versatility of the protocol was further
demonstrated by the preparation of a library of 20 distinct
thiohydantoins with two points of diversity starting from
various primary amines and amino acid esters as shown in
Scheme 1 and Figure 1. In general, yields of the thio-
hydantoins were excellent, ranging between 87–97%. The
reaction scope of this methodology was further elaborated
by preparation of nine thiohydantoins 7a–i with a three-
point diversity backbone from N-substituted amino acid
esters by using three amino acid esters (R2 = benzyl, iso-
propyl, methyl), three aldehydes (R3 = 4-methoxyphenyl,
2-furyl and 2-thienyl) and four amines [R1 = benzyl, n-
butyl, 2-furylmethyl, 3-(indolyl)ethyl; Scheme 2]. Vari-
ous N-substituted amino acid esters 6 were prepared by
reductive N-alkylation with various aldehydes in the
presence of sodium triacetoxyborohydride.5b When
equimolar quantities of N-substituted amino acid ester 6a
(R2 = PhCH2, R3 = 4-MeOC6H4), 2-furfurylamine and 1-
(methyldithiocarbonyl)imidazole (3) were reacted in re-
fluxing ethanol in the presence of triethylamine under the
1-(Methyldithiocarbonyl)imidazole (3) was prepared ac-
cording to our earlier reported procedure7 by treatment of
imidazole with carbon disulfide in the presence of sodium
hydride as base followed by alkylation with methyl io-
dide. In a typical experiment,9 when equimolar quantities
of alanine ethyl ester hydrochloride, benzylamine and 1-
(methyldithiocarbonyl)imidazole were refluxed in etha-
nol (7–8 h) in the presence of triethylamine, the corre-
sponding (S)-3-benzyl-5-methyl-2-thiohydantoin (4a)
was obtained in 87% yield, whereas the use of corre-
SYNLETT 2007, No. 2, pp 0251–0254
0
1.
0
2.
2
0
0
7
Advanced online publication: 24.01.2007
DOI: 10.1055/s-2007-967987; Art ID: D26406ST
© Georg Thieme Verlag Stuttgart · New York

252
G. S. M. Sundaram et al.
LETTER
O
S
S
S
S
S
S
MeO
HN
N
NH
N
NH
N
NH
N
NH
N
NH
N
NH
O
O
O
O
O
O
4a, 87%
4b, 89%
4c, 96%
4d, 87%
4e, 87%
4f, 92%
MeO
MeO
S
S
S
S
S
MeO
HN
N
NH
N
NH
N
NH
N
NH
N
NH
O
O
O
O
O
4g, 89%
4i,89%
4j, 88%
4k, 97%
4h, 87%
MeO
S
O
S
S
S
S
O
MeO
N
NH
N
NH
N
NH
N
NH
N
NH
O
O
O
O
O
4l, 97%
4m, 93%
4n, 89%
4o, 94%
4p, 90%
S
S
S
S
MeO
HN
N
NH
N
NH
N
O
NH
N
NH
O
O
O
NH
NH
4q, 88%
4r, 94%
4s, 93%
4t, 91%
NH
Figure 1 Synthesis of substituted 2-thiohydantoins 4a–t with two points of diversity
S
earlier-described conditions, the desired 1,3,5-trisubstitut-
ed 2-thiohydantoin 7a was obtained only in 57% yield
S
EtO
O
NH2
EtOH
R1NH2
+
R1
N
N
SMe
N
H
SMe
R3
along with the formation of thiourea 8 in 32% yield. On
the other hand, prior generation of dithiocarbamate 5a
[R1 = 2-(furyl)methyl] by reaction of 2-furfurylamine and
3 followed by sequential addition of N-substituted amino
acid ester 6a in the presence of triethylamine as base in re-
fluxing ethanol afforded the corresponding (S)-5-benzyl-
3-(2-furfuryl)-1-(4-methoxybenzyl)-2-thiohydantoin (7a)
in 84% yield (Figure 2).10 These observations can be ex-
plained in terms of higher reactivity of primary amines to-
wards 3 in comparison to N-substituted amino acid esters
6 yielding dithiocarbamate 5 as initial sole intermediate.
Reaction of 5a with N-substituted amino acid ester 6a
affords the thiohydantoin 7a whereas its reaction with re-
maining primary amine (furfuryl amine) in the reaction
mixture furnishes the thiourea 8 as the side product. These
reaction conditions were subsequently followed for the
synthesis of trisubstituted thiohydantoins 7b–i in a two-
step one-pot process (Scheme 2, Figure 2).
∆
R2
2
5
3
1
R3CHO
S
EtO
NH
R2
R1
N
N
NaBH(OAc)3
CH2Cl2, 0 °C to r.t.
R3
Et3N
EtOH, ∆
O
6
R2
O
7
S
R1 = PhCH2; 2-(furyl)methyl; 3-(indolyl)ethyl
O
O
R2 = PhCH2; Me; i-Pr
3 = 4-MeOC6H4; 2-furyl; 2-thienyl
N
H
N
H
R
8
Scheme 2 Synthesis of 1,3,5-trisubstituted 2-thiohydantoins 7
5b (R1 = benzyl) by reaction of benzylamine with 3 in re-
fluxing methanol followed by addition of L-proline ester
hydrochloride and triethylamine furnished the fused thio-
hydantoin 10a in 92% yield (Scheme 3). The other N-sub-
stituted fused thiohydantoins 10b–c were also obtained in
good yields following a similar sequential three-compo-
nent one-pot procedure (Scheme 3).
Finally, we have also explored the cyclization of L-proline
ester hydrochloride 9 to fused thiohydantoin derivatives
10 (Scheme 3). When the L-proline ester hydrochloride 9,
benzylamine and 1-(methyldithiocarbonyl)imidazole (3)
were refluxed together in methanol in the presence of tri-
ethylamine, the only product isolated was dibenzylthio-
urea formed in 89% yield along with the trace amount of
10a (3%). However, prior generation of dithiocarbamate
In conclusion, we have developed an efficient three-com-
ponent two-step one-pot synthesis of substituted thio-
hydantoins using 1-(methyldithiocarbonyl)imidazole as
thiocarbonyl transfer agent. The product thiohydantoins
contain two or three valuable substituents allowing for
considerable molecular diversity. All the three building
Synlett 2007, No. 2, 251–254 © Thieme Stuttgart · New York

LETTER
Synthesis of 3,5- and 1,3,5-Substituted-2-Thiohydantoins
253
OMe
OMe
blocks, i.e. amino acid esters, primary amines and 1-
(methyldithiocarbonyl)imidazole are easily available,
besides the method does not require the less readily
available isothiocyanates, which are commonly employed
in standard preparation of thiohydantoins.5 We believe
that dithiocarbamates such as 5 are masked isothiocyanate
synthons and react with amines by elimination–addition
mechanism.8 The method is also amenable to solid-phase
synthesis of thiohydantoins which is underway in our
laboratory.
O
S
S
N
N
N
N
O
O
7a, 84%
7b, 89%
OMe
S
O
All the newly synthesized thiohydantoins are found to be
optically active as evidenced by their optical rotation.11 A
study of the enantiomeric purity12 of few thiohydantoins
(4a,f,g, 7c,f, 10a) revealed that the reaction gives enantio-
merically pure (>95% ee) thiohydantoins in some cases
(4g, 7f, 10a), whereas racemization was observed in
others (4a,f, 7c), thus reducing the enantiomeric excess to
55–65%.
S
HN
N
N
N
N
O
O
7c, 91%
7d, 87%
S
O
S
O
HN
N
N
N
N
Acknowledgment
O
O
We thank CSIR, New Delhi for financial support.
7e, 81%
7f, 82%
References and Notes
O
S
S
(1) Selected references: (a) Brouillete, W. J.; Jestkov, V. P.;
Brown, M. L.; Akhtar, M. S.; DeLorey, T. M.; Brown, G. B.
J. Med. Chem. 1994, 37, 3289. (b) Nefzi, A.; Giulianotti,
M.; Truong, L.; Rattan, S.; Ostresh, J. M.; Houghten, R. A.
J. Comput. Chem. 2002, 4, 175; and references therein.
(c) Chazeau, V.; Cussac, M.; Boucherle, A. Eur. J. Med.
Chem. 1992, 27, 839. (d) Scicinski, J. J.; Barker, M. D.;
Murray, P. J.; Jarvie, E. M. Bioorg. Med. Chem. Lett. 1998,
8, 3609. (e) He, S.; Kuang, R.; Venkatraman, R.; Tu, J.;
Truong, T. M.; Chan, H. T.; Groutas, W. C. Bioorg. Med.
Chem. 2000, 8, 1713. (f) Zhang, D.; Xing, X.; Cuny, G. D. J.
Org. Chem. 2006, 71, 1750. (g) Reyes, S.; Burgess, K. J.
Org. Chem. 2006, 71, 2507.
S
S
N
N
N
N
O
Me
O
Me
7h, 83%
7g, 85%
S
S
HN
N
N
O
Me
(2) Cherouvrier, J.-P.; Carreaux, F.; Bazureau, J. P. Tetrahedron
Lett. 2002, 8745; and references therein.
7i, 86%
Figure 2 Synthesis of 1,3,5-trisubstituted 2-thiohydantoins 7a–i
with three points of diversity
(3) (a) Cremlyn, R. J.; Elias, R. S.; Geoghagan, M. J. A.;
Braunholtz, J. L. Br. Patent 967166, 1964; Chem. Abstr.
1965, 62, 7768g. (b) Mizuno, T.; Kino, T.; Ito, T.; Miyata,
T. Synth. Commun. 2000, 30, 1675. (c) Mappes, C. J.;
Pommer, E.-H.; Rentzea, C.; Zeeh, B. US 4 198 423, 1980;
Chem. Abstr. 1980, 93, 71784.
(4) (a) Edman, P. Acta Chem. Scand. 1950, 4, 283. (b) Edman,
P.; Begg, G. Eur. J. Biochem. 1967, 1, 80. (c) Evindar, G.;
Batey, R. A. Org. Lett. 2003, 5, 1201.
(5) (a) Lin, M.-J.; Sun, C.-M. Tetrahedron Lett. 2003, 44, 8739.
(b) Mui, M.; Ganesan, A. J. Org. Chem. 1997, 62, 3230.
(c) Zhang, W.; Lu, Y. Org. Lett. 2003, 5, 2555; and
references therein. (d) Matthews, J.; Rivero, R. A. J. Org.
Chem. 1997, 62, 6090. (e) Wu, S.; Janusz, J. M.
Tetrahedron Lett. 2000, 41, 1165. (f) Lopez, A.; Trigo, G.
G. Adv. Heterocycl. Chem. 1985, 38, 177.
(6) Blotny, G. Synthesis 1983, 391.
(7) Mohanta, P. K.; Dhar, S.; Samal, S. K.; Ila, H.; Junjappa, H.
Tetrahedron 2000, 56, 629.
(8) For other thiocarbonyl transfer reagents, see: (a) Katritzky,
A. R.; Ledoux, S.; Witek, R. M.; Nair, S. K. J. Org. Chem.
2004, 69, 2976; and references therein. (b) Katritzky, A. R.;
Witek, R. M.; Rodriguez-Garcia, V.; Mohapatra, P. P.;
S
S
MeOH, ∆
R1NH2
R1
N
N
+
SMe
O
N
SMe
H
2
3
5
OMe
+
N
Cl–
Et3N
N
R1
O
H
H
N
MeOH, ∆
9
S
10
O
Me
O
O
O
N
N
N
N
N
N
S
S
S
10c, 87%
10a, 92%
10b, 89%
Scheme 3 Synthesis of N-substituted fused 3-thiohydantoins 10
Synlett 2007, No. 2, 251–254 © Thieme Stuttgart · New York

254
G. S. M. Sundaram et al.
LETTER
Rogers, J. W.; Cusido, J.; Abdel-Fattah, A. A. A.; Steel, P. J.
(S)-5-Benzyl-3-[2-(1H-indol-3-yl)ethyl]-1-(4-
J. Org. Chem. 2005, 70, 7866.
(9) General Procedure for the Preparation of 3,5-
Substituted 2-Thiohydantoins 4.
methoxybenzyl)-2-thioxoimidazolidin-4-one (7c).
Yield 91% (0.85 g); yellow solid; mp 170–171 °C; Rf = 0.56
(5:1 hexane–EtOAc). IR (KBr): 3404, 2927, 1750, 1473,
1350, 1263, 739 cm–1. [a]D25 –13.1 (c 0.1, CHCl3). 1H NMR
(400 MHz, CDCl3): d = 2.69–2.83 (m, 2 H), 2.92 (dd,
J = 14.52, 5.40 Hz, 1 H), 3.12 (dd, J = 14.54, 4.40 Hz, 1 H),
3.77 (s, 3 H), 3.92–3.98 (m, 2 H), 4.00 (t, J = 4.64 Hz, 1 H),
4.15 (d, J = 14.88 Hz, 1 H), 5.87 (d, J = 14.88 Hz, 1 H), 6.81
(d, J = 8.52 Hz, 2 H), 6.98 (d, J = 1.96 Hz, 1 H), 7.05 (d,
J = 7.46 Hz, 2 H), 7.07 (dd, J = 5.60, 2.20 Hz, 2 H), 7.10 (t,
J = 7.84 Hz, 1 H), 7.17 (t, J = 8.08 Hz, 1 H), 7.24 (t, J = 7.32
Hz, 3 H), 7.31 (d, J = 7.56 Hz, 1 H), 7.74 (d, J = 7.80 Hz, 1
H), 8.0 (br s, 1 H). 13C NMR (100 MHz, CDCl3): d = 22.9,
35.1, 42.3, 47.7, 55.2, 61.1, 111.0, 112.2, 114.2, 119.0,
119.4, 121.9, 122.1, 126.8, 127.4, 127.5, 128.6, 129.3,
129.6, 133.9, 136.0, 159.4, 172.7, 182.6. MS-FAB: m/z
(%) = 470 (50) [M + 1], 121 (65). ESI-HRMS: m/z calcd for
C28H27N3O2SNa: 492.1722 [M + Na]+; found: 492.1762.
(S)-1-Furan-2-ylmethyl-3-[2-(1H-indol-3-yl)ethyl]-5-
isopropyl-2-thioxoimidazolidin-4-one (7f).
Yield 82% (0.62 g); white solid; mp 143–144 °C; Rf = 0.56
(5:1 hexane–EtOAc). IR (KBr): 3332, 1712, 1466, 1356,
1288, 1258, 1222, 1148, 1005, 747 cm–1. [a]D25 –17.2 (c 0.1,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 0.76 (d, J = 6.84
Hz, 3 H), 1.14 (d, J = 7.08 Hz, 3 H), 2.34–2.41 (m, 1 H),
3.05–3.17 (m, 2 H), 3.77 (d, J = 3.40 Hz, 1 H), 4.09 (t,
J = 8.32 Hz, 2 H), 4.42 (d, J = 15.60 Hz, 1 H), 5.67 (d,
J = 15.60 Hz, 1 H), 6.34 (dd, J = 3.12, 1.96 Hz, 1 H), 6.37 (d,
J = 3.16 Hz, 1 H), 7.07 (s, 1 H), 7.12 (dd, J = 7.08, 1.00 Hz,
1 H), 7.17 (dt, J = 7.94, 1.24 Hz, 1 H), 7.32 (d, J = 7.58 Hz,
1 H), 7.37 (d, J = 1.34 Hz, 1 H), 7.80 (d, J = 7.84 Hz, 1 H),
7.98 (br s, 1 H). 13C NMR (100 MHz, CDCl3): d = 15.6, 17.3,
23.5, 28.8, 41.1, 42.4, 65.8, 109.8, 110.6, 111.0, 112.2,
119.1, 119.4, 122.0, 122.2, 127.5, 136.1, 142.8, 148.5,
172.3, 182.7. MS-FAB: m/z (%) = 382 (100) [M + 1]. ESI-
HRMS: m/z calcd for C21H23N3O2SNa: 404.1409 [M + Na]+;
found: 404.1436.
A solution of L-amino acid ethyl ester hydrochloride salt 1
(2.0 mmol), amine 2 (2.0 mmol), 1-(methyldithio-
carbonyl)imidazole 3 (0.32 g, 2.0 mmol) and Et3N (0.58 mL,
4.2 mmol) in 15.0 mL of absolute EtOH was refluxed for 7–
8 h (monitored by TLC). The reaction mixture was cooled to
r.t. and concentrated under vacuo. The residue was dissolved
in CHCl3 (25 mL) and washed with H2O (2 × 20 mL), brine
(20 mL), dried (Na2SO4) and concentrated under reduced
pressure to afford the crude 4a–t, which were purified by
column chromatography over silica gel using hexane–
EtOAc as eluent. All the newly synthesized thiohydantoins
4a,b,e,f,h–t, 7a–i and 10a–c were characterized with the
help of spectral and analytical data.
(S)-3-Furan-2-ylmethyl-5-isobutyl-2-thioxo-
imidazolidin-4-one (4f).
Yield 92% (0.46 g); white solid; mp 132–133 °C; Rf = 0.73
(5:1 hexane–EtOAc). IR (KBr): 3185, 3004, 2958, 1754,
1527, 1430, 1342, 1169, 738 cm–1. [a]D25 –2.6 (c 0.5,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 0.92 (d, J = 2.44
Hz, 3 H), 0.93 (d, J = 2.44 Hz, 3 H), 1.52–1.59 (m, 1 H),
1.71–1.83 (m, 2 H), 4.12 (dd, J = 9.34, 2.72 Hz, 1 H), 4.93
(d, J = 15.12 Hz, 1 H), 4.98 (d, J = 15.12 Hz, 1 H, CH2), 6.27
(dd, J = 3.16, 1.96 Hz, 1 H), 6.35 (dd, J = 3.40 Hz, 1 H), 7.30
(d, J = 0.72 Hz, 1 H), 8.20 (br s, 1 H). 13C NMR (100 MHz,
CDCl3): d = 21.3, 22.9, 25.0, 37.4, 40.1, 57.9, 109.4, 110.3,
142.3, 148.5, 174.0, 182.9. MS-FAB: m/z (%) = 253 (100)
[M + 1]. ESI-HRMS: m/z calcd for C12H16N2O2SNa:
275.0830 [M + Na]+; found: 275.0838.
(S)-3-[2-(3,4-Dimethoxyphenyl)ethyl]-5-isopropyl-2-
thioxoimidazolidin-4-one (4i).
Yield 89% (0.57 g); colorless solid; mp 114–115 °C; Rf =
0.76 (5:1 hexane–EtOAc). IR (KBr): 3188, 2949, 1747,
1515, 1441, 1350, 1269, 1152, 1028 cm–1. [a]D –5.4 (c 0.5,
25
CHCl3). 1H NMR (400 MHz, CDCl3): d = 0.82 (d, J = 6.84
Hz, 3 H), 1.01 (d, J = 7.08 Hz, 3 H), 2.13–2.24 (m, 1 H), 2.90
(t, J = 8.08 Hz, 2 H), 3.82 (s, 3 H), 3.86 (s, 3 H), 3.91 (dd,
J = 4.04, 1.20 Hz, 1 H), 3.94–4.08 (m, 2 H), 6.76 (s, 1 H),
6.78 (dd, J = 4.40, 1.72 Hz, 2 H), 7.72 (br s, 1 H). 13C NMR
(100 MHz, CDCl3): d = 16.1, 18.6, 30.6, 33.0, 42.1, 55.8,
64.4, 111.1, 112.0, 120.9, 130.1, 147.7, 148.7, 173.3, 184.1.
MS-FAB: m/z (%) = 323 (100) [M + 1]. ESI-HRMS: m/z
calcd for C16H22N2O3SNa: 345.1249 [M + Na]+; found:
345.1215.
(S)-2-Benzyl-3-thioxohexahydropyrrolo[1,2-c]imidazol-
1-one (10a).
Yield 92% (0.45 g); white solid; mp 80–81 °C; Rf = 0.70 (5:1
hexane–EtOAc). IR (KBr): 3055, 2971, 2932, 1741, 1457,
1346, 1246, 1263, 1222, 1167, 962 cm–1. [a]D25 –16.6 (c 0.1,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 1.55–1.63 (m, 1
H), 2.03–2.09 (m, 1 H), 2.11–2.22 (m, 2 H), 3.47 (ddd,
J = 11.78, 8.68, 3.16 Hz, 1 H), 3.83–3.90 (m, 1 H), 4.09 (dd,
J = 10.28, 6.84 Hz, 1 H), 4.83 (d, J = 14.64 Hz, 1 H), 4.93 (d,
J = 14.64 Hz, 1 H), 7.15–7.24 (m, 3 H), 7.34–7.36 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 26.6, 44.9, 48.2, 64.9,
127.7, 128.3, 128.5, 135.7, 173.3, 186.6. MS-FAB: m/z
(%) = 247 (100) [M + 1]. ESI-HRMS: m/z calcd for
C13H14N2OSNa: 269.0724 [M + Na]+; found: 269.0723.
(11) Optical rotation of 4o [a]D25 –46.7 (c 0.225, MeOH) was
compared with the reported value [a]D25 –40.5 (c 0.225,
MeOH). See: Poupaert, J. H.; Cavalier, R.; Claesen, M. H.;
Dumont, P. A. J. Med. Chem. 1975, 18, 1268.
(10) General Procedure for the Preparation of 1,3,5-
Trisubstituted 2-Thiohydantoins 7 and N-Substituted
Fused 3-Thiohydantoins 10.
A solution of appropriate amine 2 (2.0 mmol) and 1-(methyl-
dithiocarbonyl)imidazole (3, 0.32 g, 2.0 mmol) in 10 mL of
absolute EtOH (or MeOH) was refluxed for 30 min. After
the complete consumption of 3 (as shown by TLC), a
mixture of appropriate N-substituted amino ester 6 (2.0
mmol) or L-proline methyl ester hydrochloride 9 (0.33 g, 2.0
mmol) and Et3N (0.58 mL, 4.2 mmol) in 5 mL absolute
EtOH (or MeOH) was added and the reaction mixture was
further refluxed for 6–7 h (monitored by TLC). It was then
worked up and purified as described above to afford the
products 7a–i or 10a–c.
(12) The optical purity was determined by chiral HPLC
[Chiralcel OD column, hexane–2-PrOH, 9:1]; ee (%): 4a,
64; 4f, 58; 4g, 95; 7c, 58; 7f, >99; 10a, >99.
Synlett 2007, No. 2, 251–254 © Thieme Stuttgart · New York

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