Polysubstituted fused ring bicyclic thiohydantoins from aminocarbo-N-thioylpyrrolidines derived from azomethine ylide 1,3-dipolar cycloadditions

Article abstract of DOI:10.3987/COM-11-12276

Highly substituted bicyclic thiohydantoins fused to pyrrolidines were prepared from aminocarbo-N-thioylpyrrolidines derived from a-amino acid esters via imine azomethine ylide 1,3-dipolar cycloadditions and subsequent reaction with aroylisothiocyanates. Aminocarbo-N-thioylpyrrolidines efficiently undergo cyclisation in the presence of sodium methoxide to form bicyclic N-substituted thiohydantoins with concomitant cleavage of the N-acyl group in good to excellent yield. And also some interesting both regiospecific and stereospecific rearrangement to the bicyclic fused thiocarbamoil pyrrolidine and bicyclic thiohydantoin were observed.

Full text of DOI:10.3987/COM-11-12276

HETEROCYCLES, Vol. 83, No. 9, 2011
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HETEROCYCLES, Vol. 83, No. 9, 2011, pp. 2091 - 2114. © The Japan Institute of Heterocyclic Chemistry
Received, 7th June, 2011, Accepted, 15th July, 2011, Published online, 22nd July, 2011
DOI: 10.3987/COM-11-12276
POLYSUBSTITUTED FUSED RING BICYCLIC THIOHYDANTOINS
FROM AMINOCARBO-N-THIOYLPYRROLIDINES DERIVED FROM
AZOMETHINE YLIDE 1,3-DIPOLAR CYCLOADDITIONS
Yahya Nural,a H. Ali Döndaş,a,b* Ronald Grigg,c and Ertan Şahind
a
Department of Chemistry, Faculty of Pharmacy, Mersin University, 33160,
Mersin, Turkey
b
Advanced Technology Education, Research and Application Centre, 33342,
Mersin, Turkey
c MIDAS Centre, School of Chemistry, Leeds University, Leeds LS2 9JT, UK
d
Department of Chemistry, Faculty of Science, Atatürk University, 25240,
Erzurum, Turkey
Abstract – Highly substituted bicyclic thiohydantoins fused to pyrrolidines were
prepared from aminocarbo-N-thioylpyrrolidines derived from α-amino acid esters
via imine azomethine ylide 1,3-dipolar cycloadditions and subsequent reaction
with aroylisothiocyanates. Aminocarbo-N-thioylpyrrolidines efficiently undergo
cyclisation in the presence of sodium methoxide to form bicyclic N-substituted
thiohydantoins with concomitant cleavage of the N-acyl group in good to
excellent yield. And also some interesting both regiospecific and stereospecific
rearrangement to the bicyclic fused thiocarbamoil pyrrolidine and bicyclic
thiohydantoin were observed.
INTRODUCTION
Thiohydantoins1,2 have found both pharmaceutical and agricultural applications,3 due to their
antimicrobial4,5 antiviral,6,7 anti-inflammatory,8 antitumor,8,9 antiandrogenic10 and anticonvulsant11
properties. Further applications include hypolipidemic agents,12 glycosidase,13 glycogen
phosphorylase14,15 and fatty acid amide hydrolase inhibitors.16-18 Recently some diaryl thiohydantoin
RD162 and MDV3100 have shown activity for treatment of prostate cancer.19 2-Thiohydantoins are also
useful intermediates in the synthesis of natural products such as dispacamide,20 leucettamine B,21
polyandrocarpamines A and B22 and aplysinopsins analogues.23 The chemistry of thiohydantoins has been
extensively studied.24-38

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HETEROCYCLES, Vol. 83, No. 9, 2011
Pyrrolidines and their derivatives are also an important class of heterocyclic compounds and are present
in many bioactive compounds such as lisinopril,39 ceronapril40,41 and meropenem.42 Grigg et al have
reported a range of thermal and metal catalyzed azomethine ylide 1,3-dipolar cycloaddition cascade
reactions furnishing pyrrolidines.43-48 This cascade chemistry has provided interalia a series of
spirobenzodiazepines related to MK-329,47 nikkomycin analogues,49 peptidomimetics,45 pyrrolidine
ß-lactam analogues50 and fused and bridged ring pyrrolidine derivatives.50-55
Thus the combination of pyrrolidines and 2-thiohydantoins into a new fused ring system was attractive. In
previous work,56-58 we have reported the synthesis, structure determination and antimicrobial activity of
novel benzoylaminocarbo-N-thioylpyrrolidines and their metal complexes. In this study, a series of
polysubstituted bicyclic thiohydantoins fused to pyrrolidines are reported.
RESULTS AND DISCUSSION
The aroylaminocarbo-N-thioylpyrrolidines 1a,b and 1d-g were prepared from the corresponding
pyrrolidines which, in turns were derived from α-amino acid esters via imine-azomethine ylide
1,3-dipolar cycloaddition and aroylisothiocyanates as previously described.56-59 The novel
aroylaminocarbo-N-thioylpyrrolidine derivatives 1c, 1h-j were similarly prepared, but in the case of 1h it
was necessary to reflux for 9 h. Cyclization of aroylaminocarbo-N-thioylpyrrolidines in the presence of
sodium methoxide in refluxing dry MeOH for 18-36 h gave the thiohydantoin-pyrrolidine-fused ring
systems 2a-j and cleavage of the aroyl group at nitrogen afforded the desired trans- and cis-fused bicyclic
thiohydantoins 3a-j (Scheme 1) in 72-93% yield (Table 1). The byproduct methyl benzoate derivatives 4
were also detected and confirmed after flash column chromatography. Compounds 3a-j were obtained as
mixture of trans- and cis-isomers assigned according to positions of the functional group at C-5 and C-6.
Column chromatography on silica gel and crystallization allowed the separation and isolation of the
1
isomers in most case. Compounds 3a-j were characterized by H NMR, 13C NMR, FT-IR, MS and
microanalysis. The structural assignment of the trans- and cis-isomers 3a-j is based on the H5 - H6
vicinal coupling constants (3JH-H) and X-ray crystal structures of cis-3a, trans-3a and cis-3j. The vicinal
coupling constant for cis-3a is 9.24 Hz and trans-3a is 4.02 Hz. Similarly, the vicinal coupling constant
for cis-3c is 8.16 Hz, trans-3c is 5.88 Hz, cis-3h is 8.16 Hz, trans-3h is 6.75 Hz, cis-3i is 6.47 Hz and
trans-3i is 3.6 Hz (see experimental). Additionally, the structures of (5R,6S,7aS)-methyl
hexahydro-7a-methyl-5-(naphthalen-2-yl)-1-oxo-3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-carboxylate cis-
3a, (5R,6R,7aS)-methyl hexahydro-7a-methyl-5-(naphthalen-2-yl)-1-oxo-3-thioxo-1H-pyrrolo[1,2-c]-
imidazole-6-carboxylate
trans-3a
and
(5S,6R,7aR)-methyl
7a-benzyl-hexahydro-1-oxo-5-
(pyridin-3-yl)-3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-carboxylate cis-3j were confirmed by X-ray crystal
structures (Figures 1-3).

HETEROCYCLES, Vol. 83, No. 9, 2011
2093
X
O
2
R1
R1
O
X
CO2Me
CO2Me
NaOMe
R1
7
5
1
H
N
7a
R2
NH
6
O
N
N
3
N
MeOH
reflux
18-36 h
X
N
S
R2
O
S
R3
S
R3
R2
R3
1
3
4
2
1
1
R2= CO2Me,
R2= CO2Me,
R3= 2-naphthyl
1a.
R = Me,
R2= CO2Me,
R2= CO2Me,
R2=phenylsulfonyl,
R2=CO2Me,
R3= 2-naphthyl,
X= H
3a.
R = Me,
1b. R1= Ph,
R3= 4-chlorophenyl, X= OMe
R3= 4-chlorophenyl, X= H
3b. R1= Ph,
3c. R1= Ph,
R3= 4-chlorophenyl
1
R = Ph,
R2=phenylsulfonyl,
R2=CO2Me,
R3= 4-chlorophenyl
R3= Ph
R3= 2-naphthyl
R3= 4-methoxyphenyl
R3= Ph
1c.
1d. R1= Ph,
R3= Ph,
R3= 2-naphthyl,
R3= 4-methoxyphenyl, X= H
R3= Ph,
X= H
X= H
3d.
R1= Ph,
1e. R1= Ph,
R2= CO2Me,
R2= CO2Me,
3e. R1= Ph,
R2= CO2Me,
R2= CO2Me,
R2 = CO2Me,
1
1
1f.
R = PhCH2,
3f.
R = PhCH2,
1g. R1= PhCH2,
R2 = CO2Me,
X= H
X= H
X= H
X= H
3g. R1= PhCH2,
1
2
R = (1H-indol-3-yl)CH2, R = phenylsulf onyl, R3= Ph,
3h. R1= (1H-indol-3-yl)CH2, R2= phenylsulf onyl, R3= Ph
1h.
1i. R1 = PhCH2,
1j. R1= PhCH2,
R2= methylsulfonyl, R3= Ph,
R2=CO2Me, R3= pyridin-3-yl,
3i.
R
1 = PhCH2,
3j. R1= PhCH2,
R2= methylsulfonyl, R3= Ph
R2=CO2Me,
R3= pyridin-3-yl
Scheme 1
Table 1. Fused thiohydantoin derivatives
Compound R1
R2
R3
cis:trans*
Yield (%)
3a
3b
3c
-Me
-CO2Me
55:45
67:33
80:20
85
Cl
Cl
-CO2Me
78
93
O
O
S
3d
3e
3f
-CO2Me
-CO2Me
-CO2Me
-CO2Me
54:46
50:50
67:33
75:25
50:50
85
89
81
83
74
OMe
3g
3h
O
O
S
N
H
O
O
S
3i
3j
85:15
75:25
72
91
Me
N
-CO2Me
*cis:trans stereochemistry was asigned at C-5 and C-6 by vicinal coupling constants 3JH-H and X-ray crystal structures
(Figures 1-3)

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HETEROCYCLES, Vol. 83, No. 9, 2011
Figure 2. An ORTEP drawing of the molecule
Figure 1. An ORTEP drawing of the molecule
trans-3a. Displacement ellipsoids are drawn at the
40% probability level. For the clarity solvent
acetonitrile was not shown in the Figure
cis-3a. Displacement ellipsoids are drawn at the
40% probability level
Figure 3. An ORTEP drawing of the molecule cis-3j with two molecules in the asymmetric unit
(racemates of the same compound). Displacement ellipsoids are drawn at the 40% probability level
When the bicyclic aroylaminocarbo-N-thioylpyrrolidine (5), prepared according to modification of the
literature methods,56-60 was reacted with sodium methoxide under same reaction conditions (MeOH,

HETEROCYCLES, Vol. 83, No. 9, 2011
2095
reflux for 36 h) it afforded a mixture of 6 (49%) and 7 (24%) with new functional moieties at C-6 and C-7
(Scheme 2). When the same reaction was carried out at room temperature (MeOH for 36 h), only 7 was
obtained in 83% yield. It can be concluded that the reaction is temperature dependent and for
confirmation of the reaction mechanism of 7, the bicyclic pyrrolidine (8) was reacted with sodium
methoxide in MeOH at reflux for 36 h. This resulted in rearrangement to the bicyclic pyrrolidine (9) in
85% yield (Scheme 3). The rearrangement was both regiospecific and stereospecific (Scheme 3). The
driving force for the epimerisation step is to locate the amide and indole groups on the less sterically
strained exo-face of the fused ring system (Schemes 4, 5). The structures of 6, 7 and 9 were determined
on the basis 1H NMR, 13C NMR, FT-IR, MS and microanalysis. The stereochemistry was unambiguously
determined for 6 and 7 by X-ray crystal analysis (Figures 4, 5).
NH
NH
O
Ph
Ph
S
7
8
MeO2C
O
O
N
CO2Et
H
H
H
2
3
3a
1
N
NH2
NaOMe
H
O
7
1
3
H
N
7a
6a
6
Ph
2
NH
Ph
N
N
MeO2C
5
MeOH
N
4
6
reflux, 36 h
5
S
O
NH
N
O
Ph
O
Ph
S
Ph
6
7
5
Scheme 2
NH
Ph
MeO2C
O
CO2Et
NH
H
H
2
3
3a
1
NH
H
O
NaOMe
6a
Ph
N
7
MeOH
reflux, 36 h
4
6
5
N
NH
O
O
Ph
Ph
8
9
Scheme 3

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HETEROCYCLES, Vol. 83, No. 9, 2011
Figure 4. An ORTEP drawing of the molecule 6. Figure 5. An ORTEP drawing of the molecule 7.
Displacement ellipsoids are drawn at the 40% Displacement ellipsoids are drawn at the 30%
probability level. For the clarity disordered crystal probability level
water was not shown in the Figure
R
R
R
O
O
O
O
OEt
Ph
O
Ph
Ph
CO2Et
OEt
N
N
N
H
H
N
H
Ph
N
A
Ph
N
A
N
Ph
B
N
A
N
O
S
MeO
MeO
S
O
O
S
MeO
O
Ph
Ph
Ph
O
O
5
O
R
Ph
HN
O
O
Ph
R
R
Ph
O
O
N
O
N
H
A
H
H
O
H
MeO
MeO
H
MeO
epimerisation
A
N
A
NH
NH
N
MeO
N
N
O
O
Ph
S
Ph
Ph
S
S
6
Scheme 4. Mechanism of rearrangement of 5 to 6

HETEROCYCLES, Vol. 83, No. 9, 2011
2097
Ph
R
R
Ph
O
O
N
N
R
O
CO2Et
O
OEt
OEt
Ph
O
H
N
H
H
Ph
N
Ph
N
N
Ph
B
A
N
A
N
A
N
MeO
MeO
O
S
O
S
S
O
MeO
O
Ph
Ph
Ph
O
O
5
Ph
Ph
Ph
O
O
O
N
N
N
R
R
R
O
O
O
NH2
S
NH2
NH
S
MeO
epimerisation
H
H
A
N
MeO
N
A
N
A
S
MeO
MeO
H
O
Ph
Ph
Ph
O
O
7
Scheme 5. Mechanism of rearrangement of 5 to 7
In conclusion, an efficient short synthesis of highly substituted bicyclic thiohydantoins fused to
pyrrolidines, having further modificable groups, has been achieved from aminocarbo-N-thioylpyrrolidines.
Some interesting regiospecific and stereospecific rearrangements to the bicyclic pyrrolidines and
thiocarbamoil pyrrolidine were also observed.
Other chiral versions of these processes and their metal complexes, which can be used as chiral catalysts,
are under investigation.
EXPERIMENTAL
IR spectra were recorded on Varian Scimitar Series 1000 FT-IR spectrophotometer, using horizontal ATR.
Nuclear magnetic resonance spectra and decoupling experiments were determined at 400 MHz on a
Bruker Ultrashield Plus Biospin GmbH and 300 MHz on a Bruker Ultrashield TM spectrometers as
specified. Chemical shifts are given in parts per million () downfield from tetramethylsilane as internal
standard. Spectra were determined in deuteriochloroform except where otherwise stated. The following
abbreviations are used; s =singlet, d =doublet, t =triplet, q = quartet, m =multiplet, br =broad, brd =broad
doublet and brs= broad singlet. Flash column chromatography was performed using silica gel 60
(230-400 mesh). Kieselgel columns were packed with silica gel GF254 (Merck 7730). Melting points
were determined on Stuart SMP3 hot stage apparatus and are uncorrected. Microanalyses were obtained
using a Carlo - Erba Model 1106 instrument. Mass spectra were recorded at Agilent LC/MSD mass
spectrometer or Agilent 6460 Triple Quad LC/MS/MS mass spectrometer. The X-ray crystal structure

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HETEROCYCLES, Vol. 83, No. 9, 2011
data were collected on Rigaku R-Axis Rapid-S model X-ray diffractometer.
General Procedures for the Preparation of Pyrrolidines. The known pyrrolidine derivatives, dimethyl
2-methyl-5-(naphthalen-2-yl)pyrrolidine-2,4-dicarboxylate,61 dimethyl 5-(4-chlorophenyl)-2-phenyl-
pyrrolidine-2,4-dicarboxylate,62 dimethyl 2,5-diphenylpyrrolidine-2,4-dicarboxylate,56,62,63 dimethyl
5-(naphthalen-2-yl)-2-phenylpyrrolidine-2,4-dicarboxylate,64 dimethyl 2-benzyl-5-(4-methoxyphenyl)-
pyrrolidine-2,4-dicarboxylate,61 dimethyl 2-benzyl-5-phenylpyrrolidine-2,4-dicarboxylate,56 and methyl
2-((1H-indol-3-yl)methyl)-5-phenyl-4-(phenylsulfonyl)pyrrolidine-2-carboxylate59 and 8,59 were prepared
according to literature methods and an analogues method was used for the phenylsulfonyl adducts and the
novel methyl 5-(4-chlorophenyl)-2-phenyl-4-(phenylsulfonyl)pyrrolidine-2-carboxylate, methyl 2-benzyl-
4-(methylsulfonyl)-5-phenyl pyrrolidine-2-carboxylate and dimethyl 2-benzyl-5-(pyridin-3-yl)-
pyrrolidine-2,4-dicarboxylate were similarly prepared as noted below.
Methyl 5-(4-chlorophenyl)-2-phenyl-4-(phenylsulfonyl)pyrrolidine-2-carboxylate. Prepared by
adaption of literature procedures.52 After a reaction time of 26 h and work up the product (0.42 g, 92%)
1
crystallised from Et2O:hexane as colourless prisms: mp 146-148 ºC. H NMR (300 MHz, CDCl3): δ =
7.71-7.09 (m, 14H, Ar-H), 4.50 (d, 1H, J = 6.51 Hz, 5-H), 3.99-3.94 (m, 1H, 4-H), 3.81 (s, 3H, OCH3),
3.61 (dd, 1H, J = 14.64, 5.19 Hz, 3-H), 2.88 (dd, 1H, J = 14.64, 8.01 Hz, 3-H'). 13C NMR (75 MHz,
CDCl3): δ = 173.26 (C=O), 141.70, 139,03, 134.20, 133,68, 133,02, 129.28 (2 x C), 128.90 (2 x C),
128.67 (2 x C), 128.10 (2 x C), 127.99, 127.65 (2 x C), 126,18 (2 x C), 70.51, 67.37, 62.74, 53.24, 39.39.
IR (cm-1): νmax 3314, 3071, 3035, 2960, 1727, 1598, 1492, 1446, 1301, 1257, 1208, 1144, 1085, 1010,
816, 729, 691. MS (ES, M+H+): m/z 456.1 (M+H+, 100), 458.1 (M+H+, 45). Anal. Calcd for
C24H22ClNO4S: C, 63.20; H, 4.85; N, 3.05; S, 7.05. Found: C, 62.85; H, 4.90; N, 3.15; S, 7.15.
Methyl 2-benzyl-4-(methylsulfonyl)-5-phenylpyrrolidine-2-carboxylate. Prepared by adaption of
literature procedures.52 After a reaction time of 28 h and work up the product (0.28 g, 75%) crystallised
1
from Et2O:hexane as colourless prisms: mp 134-136 ºC. H NMR (300 MHz, CDCl3): δ = 7.47-7.26 (m,
10H, Ar-H), 4.62 (d, 1H, J = 6.21 Hz, 5-H), 3.78 (s, 3H, OCH3), 3.57-3.51 (m, 1H, 4-H), 3.19 (dd, 1H, J =
15.03, 4.56 Hz, 3-H), 3.16 (d, 1H, J = 13.2 Hz, 6-H), 3.05 (d, 1H, J = 13.17 Hz, 6-H'), 2.53 (dd, 1H, J =
15.03, 8.28 Hz, 3-H'), 2.01 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): δ = 174.36 (C=O), 136.15 (2 x C),
130.22 (2 x C), 128.72 (2 x C), 128.59, 128.29 (2 x C), 127.99 (2 x C), 127.15, 68.94, 67.53, 63.43, 52.61,
45.62, 40.33, 35,57. IR (cm-1): νmax 3308, 3017, 2964, 1735, 1596, 1495, 1459, 1428, 1301, 1273, 1211,
1132, 1075, 1048, 748, 704. MS (ES, M+H+): m/z 374.1(M+H+, 100). Anal. Calcd for
C20H23NO4S.0.25H2O: C, 63.60; H, 6.20; N, 3.70; S, 8.50. Found: C, 63.75; H, 6.20; N, 3.80; S, 8.55.
Dimethyl 2-benzyl-5-(pyridin-3-yl)pyrrolidine-2,4-dicarboxylate. Prepared by adaption of literature
procedures.52 After a reaction time of 24 h and work up the product (0.33 g, 94%) crystallised from
1
Et2O:hexane as colourless prisms: mp 102-104 ºC. H NMR (300 MHz, CDCl3): δ = 8.52-8.49 (m, 2H,

HETEROCYCLES, Vol. 83, No. 9, 2011
2099
Ar-H), 7.73-7.69 (m, 1H, Ar-H), 7.34-7.24 (m, 6H, Ar-H), 4.59 (d, 1H, J = 7.8 Hz, 5-H), 3.79 (s, 3H,
OCH3), 3.30-3.23 (m, 1H, 4-H), 3.24 (s, 3H, OCH3), 3.17 (d, 1H, J = 13.14 Hz, 6-H), 2.97 (d, 1H, J =
13.14 Hz, 6-H'), 2.78 (dd, 1H, J = 13.74, 5.94 Hz, 3-H), 2.26 (dd, 1H, J = 13.74, 7.56 Hz, 3-H'). 13C NMR
(75 MHz, CDCl3): δ = 175.47 (C=O), 172.42 (C=O), 148.70, 148.66, 136.57, 135.81, 134.61, 130.06 (2 x
C), 128.27(2 x C), 127.01, 123.24, 70.23, 62.24, 52.38, 51.42, 49.53, 45.65, 38.01. IR (cm-1): νmax 3358,
3024, 2945, 1738, 1574, 1492, 1433, 1262, 1183, 1098, 1037, 752, 706. MS (ES, M+H+): m/z 355.2
(M+H+, 35). Anal. Calcd for C20H22N2O4: C, 67.75; H, 6.25; N, 7.90. Found: C, 67.30; H, 6.20; N, 7.90.
General Procedures for the Preparation of Aroylaminocarbo-N-thioylpyrrolidines (1a-j, 5). The
known aroylaminocarbo-N-thioylpyrrolidines (1a,b,e),60 (1d,g),56-58 (f)58 were prepared according to
literature procedure from the corresponding pyrrolidines and subsequent reaction with
aroylisothiocyanates as previously described. The novel methyl 1-((benzamido)carbo-N-thioly)-5-(4-
chlorophenyl)-2-phenyl-4-(phenylsulfonyl)pyrrolidine-2-carboxylate (1c), Methyl 2-((1H-indol-3-yl)-
methyl)-1-((benzamido)carbo-N-thioly)-5-phenyl-4-(phenylsulfonyl)pyrrolidine-2-car-boxylate
(1h),
methyl 1-((benzamido)carbo-N-thioly)-2-benzyl-4-(methylsulfonyl)-5-phenyl pyrrolidine- 2-carboxylate
(1i), Dimethyl 1-((benzamido)carbo-N-thioly)-2-benzyl-5-(pyridin-3-yl)pyrrolidine-2,4-dicarboxylate (1j)
and Ethyl 1-((1H-indol-3-yl)methyl)-2-((benzamido)carbo-N-thioly)octahydro-4,6-dioxo-3,5-diphenyl-
pyrrolo[3,4-c]pyrrole-1-carboxylate (5) were similarly prepared. In the case of 1h and 5 the reactions
carried out in refluxing acetonitrile for 9 h.
Methyl 1-((benzamido)carbo-N-thioly)-5-(4-chlorophenyl)-2-phenyl-4-(phenylsulfonyl)pyrrolidine-
2-carboxylate (1c). After a reaction time of 8 h and work up the product (0.72 g, 95%) crystallised from
1
Et2O:hexane as pale yellow prisms as a 1:3 rotamer mixture: mp 163-165 ºC. H NMR (300 MHz,
CDCl3): δ = 7.76 (brs, 1H, NH major rotamer), 7.70-6.99 (m, 38H, Ar-H major and minor rotamers), 7.66
(brs, 1H, NH minor rotamer), 6.02 (d, 1H, J = 8.76 Hz, 5-H major rotamer), 5.98 (d, 1H, J = 8.52 Hz, 5-H
minor rotamer), 4.02-3.90 (m, 2H, 4-H major and minor rotamers), 3.87 (s 3H, OCH3 major rotamer) 3.63
(s 3H, OCH3 minor rotamer) 3.46 (dd 1H, J = 13.71, 12 Hz, 3-H major rotamer), 3.31 (dd 1H, J = 13.71,
11.58, Hz 3-H minor rotamer), 2.95 (dd 1H, J = 15.15 Hz, 8.37 Hz, 3-H' minor rotamer), 2.68 (dt 1H, J =
12, 5.34, Hz, 3-H' major rotamer). 13C NMR (75 MHz, CDCl3): δ = 187.39 (C=S minor rotamer), 180.03
(C=S major rotamer), 172.63 (C=O minor rotamer), 170.78 (C=O minor rotamer), 169.60 (C=O major
rotamer), 164.54 (C=O major rotamer), 137.46, 137.37, 135.13, 134.01, 133.81, 133.49, 133.42, 133.28,
133.12, 133.03, 131.98, 130.58, 129.81, 129.46, 129.14 (3 x C), 129.06 (2 x C), 129.03 (2 x C), 128.93,
128.84 (3 x C), 128.40, 128.32 (3 x C), 128.29 (3 x C), 128.24 (4 x C), 128.21 (4 x C), 128.10, 127.77 (2
x C), 127.44 (2 x C), 127.30, 127.17, 125.06, 78.08, 74.89, 65.97, 64.95, 64.82, 64.47, 53.40, 53.31,
41.70, 41.63. IR (cm-1): νmax 3218, 3057, 2956, 1720, 1710, 1589, 1526, 1491, 1448, 1293, 1216, 1182,
1141, 740, 706, 686. MS (ESI, M-H+): m/z 616.9(M-H+, 100), 618.8(M-H+, 45). Anal. Calcd for

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HETEROCYCLES, Vol. 83, No. 9, 2011
C32H27ClN2O5S2: C, 62.10; H, 4.40; N, 4.50; S, 10.35. Found: C, 62.05; H, 4.45; N, 4.65; S, 10.70.
Methyl 2-((1H-indol-3-yl)methyl)-1-((benzamido)carbo-N-thioly)-5-phenyl-4-(phenylsulfonyl)-
pyrrolidine-2-carboxylate (1h). After a reaction time of 9 h and work up the product (0.68 g, 88%)
1
crystallised from Et2O:hexane as pale yellow prisms as a 1:3 rotamer mixture: mp 158-160 ºC. H NMR
(300 MHz, CDCl3): δ = 8.47 (brs, 1H, NH major rotamer), 8.41 (brs, 1H, NH minor rotamer), 8.17-6.79
(m, 42H, Ar-H, NH major and minor rotamers), 5.58 (d, 1H, J = 8.31 Hz, 5-H minor rotamer), 5.50 (d, 1H,
J = 8.61 Hz, 5-H major rotamer), 4.65 (d, 1H, J = 15.42 Hz, 6-H major rotamer), 4.23 (d, 1H, J = 15.18
Hz, 6-H minor rotamer), 3.98 (s 3H, OCH3 major rotamer) 3.84 (s 3H, OCH3 minor rotamer) 3.65 (d, 1H,
J = 15.12 Hz, 6-H' minor rotamer), 3.51 (d, 1H, J = 15.36 Hz, 6-H' major rotamer), 3.13-2.99 (m 4H, 4-H,
13
3-H major and minor rotamers), 2.29-2.17 (m 2H, 3-H' major and minor rotamers). C NMR (75 MHz,
CDCl3): δ = 186.26 (C=S minor rotamer), 177.89 (C=S major rotamer), 172.82 (C=O minor rotamer),
172.32 (C=O minor rotamer), 171.37 (C=O major rotamer), 164.26 (C=O major rotamer), 138.69, 138.30,
135.62, 134.56, 134.38, 133.61, 133.40, 133.22 (2 x C), 132.93, 132.58 (2 x C), 129.37 (2 x C), 129.31 (3
x C), 129.22 (4 x C), 129.17 (2 x C), 129.05 (2 x C), 128.76 (2 x C), 128.66 (2 x C), 128.58 (2 x C),
128.27, 127.74 (2 x C), 127.62 (3 x C), 127.49 (2 x C), 127.34 (2 x C), 125.12, 123.71, 122.51, 122.24,
120.84, 120.61, 117.62, 117.53, 111.43, 109.66, 109.18, 75.52, 73.03, 67.40, 66.83, 63.44, 62.33, 53.05
(2 x C), 37.62, 37.12, 26.62, 22.67. IR (cm-1): νmax 3379, 3343, 3060, 3040, 2946, 2844, 1727, 1682, 1599,
1511, 1485, 1447, 1395, 1340, 1303, 1232, 1193, 1147, 742, 697. MS (ESI, M-H+): m/z 635.9(M-H+,
100). Anal. Calcd for C35H31N3O5S2: C, 65.90; H, 4.90; N, 6.60; S, 10.05. Found: C, 65.60; H, 5.10; N,
6.45; S, 9.95.
Methyl
1-((benzamido)carbo-N-thioly)-2-benzyl-4-(methylsulfonyl)-5-phenylpyrrolidine-2-
carboxylate (1i). After a reaction time of 7 h and work up the product (0.55 g, 84%) crystallised from
1
Et2O:hexane as pale yellow prisms as a 1:2 rotamer mixture: mp 167-169 ºC. H NMR (300 MHz,
CDCl3): δ = 8.18 (brs, 1H, NH major rotamer), 8.15-7.12 (m, 30H, Ar-H major and minor rotamers), 7.95
(brs, 1H, NH minor rotamer), 5.43 (d, 1H, J = 8.76 Hz, 5-H minor rotamer), 5.39 (d, 1H, J = 8.73 Hz, 5-H
major rotamer), 4.67 (d, 1H, J = 14.46 Hz, 6-H major rotamer), 4.30 (d, 1H, J = 14.13 Hz, 6-H minor
rotamer), 3.97 (s 3H, OCH3 major rotamer) 3.86 (s 3H, OCH3 minor rotamer) 3.55 (d, 1H, J = 14.13 Hz,
6H' minor rotamer), 3.43 (d, 1H, J = 14.46 Hz, 6-H' major rotamer), 2.93 (m 2H, 4-H major and minor
rotamers), 2.78-2.62 (m 4H, 3-H, 3-H’ major and minor rotamers), 2.04 (s 3H, CH3 major rotamer) 1.90
13
(s 3H, CH3 minor rotamer). C NMR (75 MHz, CDCl3): δ = 186.84 (C=S major rotamer), 178.17 (C=S
minor rotamer), 172.71 (C=O major rotamer), 172.61 (C=O major rotamer), 171.35 (C=O minor rotamer),
163.95 (C=O minor rotamer), 135.96, 135.91, 134.58, 133.98, 133.74, 133.11, 132.92 (2 x C), 132.60,
130.63 (2 x C), 130.01 (2 x C), 129.70, 129.56 (2 x C), 129.37 (3 x C), 129.25 (2 x C), 129.14 (2 x C),
129.05 (2 x C), 128.65 (2 x C), 128.60 (2 x C), 128.54, 128.32, 128.28 (2 x C), 128.17, 127.59 (2 x C),
74.77, 72.04, 66.39, 55.83, 63.55, 63.12, 53.32, 53.23, 41.53, 39.31, 38.48, 37.04, 36.84, 36.11. IR (cm-1):

HETEROCYCLES, Vol. 83, No. 9, 2011
2101
νmax 3341, 3060, 3027, 2957, 2919, 1728, 1683, 1602, 1564, 1493, 1451, 1374, 1353, 1248, 1156, 1126,
1086, 734, 701. MS (ESI, M-H+): m/z 534.9(M-H+, 100). Anal. Calcd for C28H28N2O5S2: C, 62.65; H,
5.25; N, 5.20; S,11.95. Found: C, 62.35; H, 5.35; N, 5.20; S, 12.25.
Dimethyl
1-((benzamido)carbo-N-thioly)-2-benzyl-5-(pyridin-3-yl)pyrrolidine-2,4-dicarboxylate
(1j). After a reaction time of 7 h and work up the product (0.53 g, 84%) crystallised from Et2O:hexane as
pale yellow prisms as a 1:3 rotamer mixture: mp 177-179 ºC. 1H NMR (300 MHz, CDCl3): δ = 8.66 (brs,
1H, NH major rotamer), 8.50-8.46 (m, 2H, Ar-H major and minor rotamers), 8.40 (brs, 1H, NH minor
rotamer), 8.17-7.21 (m, 26H, Ar-H major and minor rotamers), 5.51 (d, 1H, J = 9.57 Hz, 5-H minor
rotamer), 5.31 (d, 1H, J = 6.12 Hz, 5-H major rotamer), 4.53 (d, 1H, J = 14.04 Hz, 6-H minor rotamer),
4.22 (d, 1H, J = 13.5 Hz, 6-H major rotamer), 3.95 (s 3H, OCH3 minor rotamer) 3.84 (s 3H, OCH3 major
rotamer) 3.48 (d, 1H, J = 14.07 Hz, 6-H' major rotamer), 3.40 (d, 1H, J = 14.58 Hz, 6-H' minor rotamer),
3.19 (s 6H, OCH3 major and minor rotamers), 3.14-2.97 (m 2H, 4-H major and minor rotamers),
13
2.46-2.37 (m 2H, 3-H, 3-H' major rotamer), 2.36-2.28 (m 2H, 3-H, 3-H' minor rotamer). C NMR (100
MHz, CDCl3): δ= 173.37 (C=S major rotamer), 171.90 (C=S minor rotamer), 169.43 (4 x C=O major and
minor rotamers), 169.19 (2 x C=O major and minor rotamers), 150.29, 149.44, 148.96, 148.41, 136.24,
135.99, 135.34, 134.87, 133.66, 133.31, 133.10, 133.07, 132.43, 132.00, 130.92, 130.10 (3 x C), 129.25
(3 x C), 129.03 (3 x C), 128.75, 128.61 (3 x C), 127.82 (2 x C), 127.66, 127.40, 123.57, 123.04, 73.22,
66.03, 65.62, 53.28, 53.05, 51.82 (2 x C), 51.72, 46.68, 45.23, 41.50, 36.71 (2 x C), 35.80. IR (cm-1): νmax
3161, 2950, 1750, 1675, 1587, 1520, 1436, 1406 1367, 1280, 1238, 1192, 1101, 741, 706. MS (ESI,
M-H+): m/z 515.9 (M-H+, 100). Anal. Calcd for C28H27N3O5S2.0.5 H2O: C, 63.80; H, 5.30; N, 8.10; S,
6.20. Found: C, 63.85; H, 5.30; N, 7.85; S, 6.05.
Ethyl 1-((1H-indol-3-yl)methyl)-2-((benzamido)carbo-N-thioly)octahydro-4,6-dioxo-3,5-diphenyl-
pyrrol[3,4-c]pyrrole-1-carboxylate (5). After a reaction time of 9 h and work up the product (0.69 g,
1
86%) crystallised from Et2O:hexane as pale yellow prisms as a 1:2 rotamer mixture: mp 151-154 ºC. H
NMR (300 MHz, CDCl3): δ = 8.52 (brs, 1H, NH minor rotamer), 8.43 (brs, 1H, NH major rotamer),
8.25-6.43 (m, 42H, Ar-H, NH major and minor rotamers), 5.70 (d, 1H, J = 11.34 Hz, 3-H minor rotamer),
5.63 (d, 1H, J = 11.07 Hz, 3-H major rotamer), 4.55-4.26 (m, 6H, CH2CH3, 3a-H major and minor
rotamers), 4.07-3.82 (m, 4H, 7-H, 7-H' major and minor rotamers), 2.88 (dd, 1H, J = 10.56, 10.26 Hz,
6a-H minor izomer), 2.61 (dd, 1H, J = 11.07, 9.90 Hz 6a-H major rotomer), 1.58-1.28 (m, 6H, CH2CH3
major and minor rotamers). 13C NMR (100 MHz, CDCl3): δ = 187.16 (C=S major rotamer), 178.47 (C=S
minor rotamer), 172.95 (C=O major rotamer), 172.75 (C=O minor rotamer), 172.44 (C=O major rotamer),
172.10 (C=O minor rotamer), 171.95 (C=O major rotamer), 169.58 (C=O major rotamer), 167.68 (C=O
minor rotamer), 163.99 (C=O minor rotamer), 136.48, 136.09, 135.90, 135.87, 133.76, 133.10, 132.90,
130.86, 130.48, 129.19 (3 x C), 128.97 (4 x C), 128.91 (4 x C), 128.66 (6 x C), 128.46, 128.31 (2 x C),
127.85, 127.52 (3 x C), 125.90 (4 x C), 125.87 (4 x C), 124.28, 122.83, 122.46, 120.66, 120.41, 118.03,

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HETEROCYCLES, Vol. 83, No. 9, 2011
117.94, 111.91, 111.80, 108.93, 108.41, 76.07, 69.58, 69.04, 62.49, 54.42, 52.83, 49.45, 48.01, 33.04,
31.61, 22.71, 22.67, 14.15, 13.97. IR (cm-1): νmax 3383, 3063, 2922, 2852, 1736, 1711, 1596, 1562, 1494,
1451, 1368, 1241, 1197, 1168, 740, 711, 693. MS (ESI, M-H+): m/z 654.9 (M-H+, 100). Anal. Calcd for
C38H32N4O5S: C, 69.50; H, 4.90; N, 8.55; S,4.90. Found: C, 69.95; H, 5.15; N, 8.60; S, 4.55.
General Procedures for the Preparation of Thiohydantoins (3a-j). To a stirred solution of
aroylaminocarbo-N-thioylpyrrolidines (1 mmol) in dry MeOH (30 mL) was added a solution of sodium
methoxide (0,057 g, 1.05 mmol) in dry MeOH (20 mL) over 5 min. and the mixture stirred at reflux
temperature for 18-36 h. After completion of the reaction, the solvent was evaporated under reduced
pressure, quenched with saturated aqueous ammonium chloride and extracted with CH2Cl2. The
combined organic layers were dried (MgSO4), filtered, evaporated under reduced pressure and the
mixture was purified by column chromatography (Et2O:hexane) to afford bicyclic thiohydantoins 3 as a
mixture of trans- and cis-isomers together with benzoate byproduct.
Methyl
hexahydro-7a-methyl-5-(naphthalen-2-yl)-1-oxo-3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-
carboxylate (3a). After completion of the reaction (20 h), the product were obtained as a 55/45 mixture
of cis- and trans-isomers which were seperated by column chromatography (Et2O:hexane, 1:3) to afford
the products (0.30 g, 85%) as colourless prisms.
(5R,6S,7aS)-Methyl
hexahydro-7a-methyl-5-(naphthalen-2-yl)-1-oxo-3-thioxo-1H-pyrrolo[1,2-c]-
imidazole-6-carboxylate (cis-3a). The product crystallized from Et2O as colourless prisms; mp 271-273
1
ºC (decomp.). H NMR (300 MHz, CDCl3): δ = 8.03 (brs, 1H, NH), 7.83-7.76 (m, 4H, Ar-H), 7.57-7.46
(m, 2H, Ar-H), 7.09 (brs, 1H, Ar-H), 5.52 (d, 1H, J = 9.24 Hz, 5-H), 4.15-4.05 (m, 1H, 6-H), 3.12 (s, 3H,
OCH3), 2.92 (dd, 1H, J = 12.99, 12.96 Hz, 7-H), 2.19 (dd, 1H, J = 12.96, 6.27 Hz, 7-H'), 1.74 (s, 3H,
13
CH3). C NMR (75 MHz, CDCl3): δ= 180.90 (C=S), 177.44 (C=O), 169.94 (C=O), 133.28, 132.86 (2 x
C), 128.40, 127.84 (2 x C), 127.36, 126.49 (3 x C), 72.52, 63.62, 51.58 (2 x C), 31.12, 25.10. IR (cm-1):
ν
max 3098, 2945, 1750, 1731, 1703, 1602, 1508, 1471, 1365, 1222, 1198, 753, 728, 683. MS (ESI, M-H+):
m/z 353.0 (M-H+, 100). Anal. Calcd for C19H18N2O3S.0.25H2O: C, 63.60; H, 5.00; N, 7.80; S, 8.90.
Found: C, 63.80; H, 5.15; N, 7.95; S, 9.15.
(5R,6R,7aS)-Methyl
hexahydro-7a-methyl-5-(naphthalen-2-yl)-1-oxo-3-thioxo-1H-pyrrolo[1,2-c]-
imidazole-6-carboxylate (trans-3a). The product crystallized from Et2O:acetonitrile as colourless
1
prisms; mp 216-218 ºC. H NMR (300 MHz, CDCl3): δ = 8.21 (brs, 1H, NH), 7.88-7.77 (m, 4H, Ar-H),
7.55-7.48 (m, 2H, Ar-H), 7.22 (brs, 1H, Ar-H), 5.66 (d, 1H, J = 4.02 Hz, 5-H), 3.81 (s, 3H, OCH3),
3.55-3.49 (m, 1H, 6-H), 2.74 (dd, 1H, J = 13.44, 10.38 Hz, 7-H), 2.54 (dd, 1H, J = 13.41, 2.07 Hz, 7-H'),
1.65 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): δ = 177.54 (C=S), 175.37 (C=O), 172.90 (C=O), 133.90,
133.14, 133.09, 128.68, 128.12 (2 x C), 127.78 (2 x C), 126.58, 126.56, 73.66, 64.48, 55.11, 53.02, 33.59,
23.87. IR (cm-1): νmax 3056, 2803, 1751, 1729, 1602, 1502, 1414, 1351, 1214, 1193, 746, 653. MS (ESI,

HETEROCYCLES, Vol. 83, No. 9, 2011
2103
M-H+): m/z 352.9 (M-H+, 100). Anal. Calcd for C19H18N2O3S: C, 64.40; H, 5.10; N, 7.90; S, 9.05. Found:
C, 64.00; H, 5.10; N, 7.80; S, 9.35.
Methyl
5-(4-chlorophenyl)hexahydro-1-oxo-7a-phenyl-3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-
carboxylate (3b). After completion of the reaction (28 h), the product were obtained as a 67/33 mixture
of cis- and trans-isomers and seperated by column chromatography (Et2O:hexane, 1:3). The product
(0.31 g, 78%) was as an amorphous colourless solid.
(5R,6S,7aR)-Methyl
5-(4-chlorophenyl)hexahydro-1-oxo-7a-phenyl-3-thioxo-1H-pyrrolo[1,2-c]-
imidazole-6-carboxylate (cis-3b). The product crystallized from Et2O as colourless prisms; mp 243-245
ºC (decomp.). 1H NMR (300 MHz, CDCl3): δ = 8.14 (brs, 1H, NH), 7.61-7.08 (m, 9H, Ar-H), 5.42 (d, 1H,
J = 9.24 Hz, 5-H), 3.68-3.58 (m, 1H, 6-H), 3.27 (s, 3H, OCH3), 3.05 (dd, 1H, J = 12.9, 12.93 Hz, 7-H),
2.59 (dd, 1H, J = 12.72, 5.82 Hz, 7-H'). 13C NMR (75 MHz, CDCl3): δ = 178.98 (C=S), 172.77 (C=O),
168.77 (C=O), 137.20, 134.59, 132.24, 129.41 (3 x C), 128.53 (3 x C), 124.88 (3 x C), 77.51, 63.13,
51.90, 51.18, 34.22. IR (cm-1): νmax 3213, 2973, 2902, 1727, 1597, 1491, 1468, 1363, 1209, 1151, 724,
698. MS (ESI, M-H+): m/z 398.8 (M-H+, 100), 400.9(M-H+, 40). Anal. Calcd for C20H17N2O3SCl: C,
59.90; H, 4.25; N, 7.00; S, 8.00. Found: C, 59.60; H, 4.30; N, 6.95; S, 8.20.
(5R,6R,7aR)-Methyl
5-(4-chlorophenyl)hexahydro-1-oxo-7a-phenyl-3-thioxo-1H-pyrrolo[1,2-c]-
imidazole-6-carboxylate (trans-3b). The product was an amorphous colourless solid; mp 192-194 ºC. 1H
NMR (300 MHz, CDCl3): δ = 8.15 (brs, 1H, NH), 7.60-7.18 (m, 9H, Ar-H), 5.77 (d, 1H, J = 2.07 Hz,
5-H), 3.27-3.21 (m, 1H, 6-H), 3.21 (s, 3H, OCH3), 3.27-3.11 (m, 1H, 7-H), 2.91 (dd, 1H, J = 13.05, 8.55
Hz, 7-H'). 13C NMR (75 MHz, CDCl3): δ = 178.49 (C=S), 172.80 (C=O), 170.82 (C=O), 135.9, 135.76,
134.27, 129.41, 129.31, 129.11 (2 x C), 128.95 (2 x C), 128.52, 125.56 (2 x C), 78.41, 63.36, 55.46, 52.39,
35.00. IR (cm-1): νmax 3266, 3069, 2937, 1743, 1597, 1459, 1354, 1254, 1196, 745, 698. MS (ESI, M-H+):
m/z 398.9 (M-H+, 100), 400.9(M-H+, 40). Anal. Calcd for C20H17N2O3SCl: C, 59.90; H, 4.25; N, 7.00; S,
8.00. Found: C, 60.05; H, 4.35; N, 7.05; S, 8.20.
5-(4-Chlorophenyl)hexahydro-7a-phenyl-6-(phenylsulfonyl)-3-thioxopyrrolo[1,2-c]imidazol-1-one
(3c). After completion of the reaction (36 h), the product were obtained as a mixture of cis- and
trans-isomers in 80/20 ration and isolated by column chromatography (Et2O:hexane, 1:3). The product
(0.45 g, 93%) was as an amorphous colourless solid.
(5S,6S,7aR)-5-(4-Chlorophenyl)hexahydro-7a-phenyl-6-(phenylsulfonyl)-3-thioxopyrrolo[1,2-c]-
imidazol-1-one (cis-3c). The product crystallized from Et2O as colourless prisms; mp 219-221 ºC
(decomp.). 1H NMR (300 MHz, CDCl3): δ = 8.37 (brs, 1H, NH), 7.74-6.94 (m, 14H, Ar-H), 5.50 (d, 1H, J
= 8.16 Hz, 5-H), 4.27-4.18 (m, 1H, 6-H), 3.06 (dd, 1H, J = 13.14, 12.09 Hz, 7-H), 2.81 (dd, 1H, J = 11.91,
13
5.25 Hz, 7-H'). C NMR (75 MHz, CDCl3): δ = 178.82 (C=S), 172.49 (C=O), 137.17, 136.52, 135.22,
133.98, 129.87, 129.63 (3 x C), 129.44, 129.15 (3 x C), 128.35, 128.22 (3 x C), 124.85 (2 x C), 76.33,
68.69, 62.70, 34.57. IR (cm-1): νmax 3202, 3062, 2922, 1751, 1592, 1491, 1443, 1368, 1215, 1137, 750,

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HETEROCYCLES, Vol. 83, No. 9, 2011
688. MS (ESI, M-H+): m/z 480.8 (M-H+, 100), 482.8(M-H+, 40).
(5S,6R,7aR)-5-(4-Chlorophenyl)hexahydro-7a-phenyl-6-(phenylsulfonyl)-3-thioxopyrrolo[1,2-c]-
1
imidazol-1-one (trans-3c). Obtained as an amorphous colourless solid; mp 168-170 ºC. H NMR (300
MHz, CDCl3): δ = 8.29 (brs, 1H, NH), 7.61-6.88 (m, 14H, Ar-H), 5.25 (d, 1H, J = 5.88 Hz, 5-H),
4.19-4.12 (m, 1H, 6-H), 3.26-3.08 (m, 2H, 7-H ve 7-H'). 13C NMR (75 MHz, CDCl3): δ = 178.48 (C=S),
173.13 (C=O), 137.14, 136.53, 134.93, 134.39, 132.55, 129.47 (3 x C), 129.32 (3 x C), 128.81 (2 x C),
128.54 (3 x C), 125.09 (2 x C), 77.75, 73.81, 63.68, 33.42. IR (cm-1): νmax 3221, 3060, 2957, 1720, 1592,
1491, 1448, 1293, 1218, 1184, 737, 687. MS (ESI, M-H+): m/z 480.8 (M-H+, 100), 482.8 (M-H+, 35).
Anal. Calcd for C24H19ClN2O3S2 : C, 59.70; H, 3.95; N, 5.80; S, 13.30. Found: C, 59.75; H, 4.15; N, 6.65;
S, 13.15.
Methyl hexahydro-1-oxo-5,7a-diphenyl-3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-carboxylate (3d).
After completion of the reaction (24 h), the product were obtained as a 54/46 mixture of cis- and
trans-isomers and isolated by column chromatography (Et2O:hexane, 1:2). The product (0.31 g, 85%)
was as an amorphous colourless solid.
(5R,6S,7aR)-Methyl
hexahydro-1-oxo-5,7a-diphenyl-3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-
carboxylate (cis-3d). The product crystallized from Et2O as colourless prisms; mp 199-201 ºC. 1H NMR
(300 MHz, CDCl3): δ = 8.23 (brs, 1H, NH), 7.62-7.32 (m, 8H, Ar-H), 7.15 (brs, 2H, Ar-H), 5.44 (d, 1H, J
= 9.18 Hz, 5-H), 3.68-3.58 (m, 1H, 6-H), 3.22 (s, 3H, OCH3), 3.10 (dd 1H, J = 12.93, 12.84 Hz, 7-H),
2.58 (dd, 1H, J = 12.66, 5.76 Hz, 7-H'). 13C NMR (75 MHz, CDCl3): δ = 179.22 (C=S), 173.06 (C=O),
168.96 (C=O), 137.43, 133.66, 129.36 (3 x C), 128.69, 128.24 (3 x C), 124.94 (3 x C), 77.59, 63.85,
51.73, 51.29, 34.14. IR (cm-1): νmax 3190, 3072, 2937, 1722, 1600, 1468, 1444, 1378, 1229, 1198, 725,
697. MS (ES, M+H+): m/z 367.3 (M+H+, 100). Anal. Calcd for C20H18N2O3S: C, 65.55; H, 4.95; N, 7.65;
S, 8.75. Found: C, 65.90; H, 5.00; N, 7.70; S, 9.05.
(5R,6R,7aR)-Methyl
hexahydro-1-oxo-5,7a-diphenyl-3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-
carboxylate (trans-3d). Crystallisation gave trans-isomer together with trace cis-isomer as an amorphous
colourless solid; mp 189-191 ºC. 1H NMR (300 MHz, CDCl3): δ = 7.97 (brs, 1H, NH), 7.63-7.25 (m, 10H,
Ar-H), 5.80 (d, 1H, J = 1.92 Hz, 5-H), 3.75-3.59 (m, 1H, 6-H), 3.28 (brd, 1H, J = 9.06 Hz, 7-H), 3.21 (s,
13
3H, OCH3), 2.96 (dd, 1H, J = 12.99, 8.46 Hz, 7-H'). C NMR (CDCl3) (75 MHz): δ = 178.71 (C=S),
171.05 (C=O), 168.96 (C=O), 137.38, 136.21, 129.35 (2 x C), 129.22, 128.90 (3 x C), 128.40, 125.62 (3 x
C), 78.50, 63.85, 55.59, 52.30, 34. 94. IR (cm-1): νmax 3213, 2950, 1725, 1599, 1478, 1444, 1383, 1248,
1210, 723, 696. MS (ES, M+H+): m/z 367.2 (M+H+, 100). Anal. Calcd for C20H18N2O3S: C, 65.55; H,
4.95; N, 7.65; S, 8.75. Found: C, 65.25; H, 5.05; N, 7.55; S, 8.85.
Methyl hexahydro-5-(naphthalen-2-yl)-1-oxo-7a-phenyl-3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-
carboxylate (3e). After completion of the reaction (21 h), the product were obtained as a 50/50 mixture
of cis- and trans-isomers and isolated by column chromatography (Et2O:hexane, 1:2) which afforded the

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2105
product (0.37 g, 89%) as an amorphous colourless solid.
(5R,6S,7aR)-Methyl hexahydro-5-(naphthalen-2-yl)-1-oxo-7a-phenyl-3-thioxo-1H-pyrrolo[1,2-c]-
imidazole-6-carboxylate (cis-3e). The product crystallized from Et2O as colourless prisms; mp 139-141
1
ºC (decomp.). H NMR (300 MHz, CDCl3): δ = 7.93 (brs, 1H, NH), 7.85-7.81 (m, 4H, Ar-H), 7.66-7.62
(m, 3H, Ar-H), 7.56-7.43 (m, 5H, Ar-H), 5.63 (d, 1H, J = 9.21 Hz, 5-H), 3.79-3.66 (m, 1H, 6-H), 3.22 (dd,
1H, J = 12.93, 12.84 Hz, 7-H), 3.10 (s, 3H, OCH3), 2.64 (dd, 1H, J = 12.66, 5.76 Hz, 7-H'). 13C NMR (75
MHz, DMSO-d6): δ = 181.04 (C=S), 174.74 (C=O), 169.26 (C=O), 138.51, 132.96, 132.91, 132.76,
129.61 (3 x C), 129.37, 128.46, 127.89, 127.48, 126.60, 126.53, 125.35 (3 x C), 77.37, 63.07, 51.68,
51.65, 33.28. IR (cm-1): νmax 3200, 3056, 2954, 1746, 1701, 1599, 1461, 1439, 1362, 1208, 1140, 721,
697. MS (ESI, M-H+): m/z 414.9 (M-H+, 100). Anal. Calcd for C24H20N2O3S.0.5H2O: C, 67.75; H, 4.95;
N, 6.60; S, 7.55. Found: C, 68.25; H, 4.90; N, 6.60; S, 7.50.
(5R,6R,7aR)-Methyl
hexahydro-5-(naphthalen-2-yl)-1-oxo-7a-phenyl-3-thioxo-1H-pyrrolo[1,2-c]-
imidazole-6-carboxylate (trans-3e). Crystallisation gave trans-isomer together with trace cis-isomer as
1
an amorphous colourless solid; mp 236-238 ºC (decomp.). H NMR (300 MHz, acetone-d6): 10.50 (brs,
1H, NH), 8.03-7.35 (m, 12H, Ar-H), 5.87 (d, 1H, J = 2.13 Hz, 5-H), 3.77-3.68 (m, 1H, 6-H), 3.32-3.12 (m,
13
2H, 7-H, 7-H'), 3.22 (s, 3H, OCH3). C NMR (75 MHz, DMSO-d6): δ = 181.04 (C=S), 174.75 (C=O),
169.26 (C=O), 137.45, 135.77, 133.23, 133.02 (2 x C), 129.60, 129.26 (3 x C), 129.20, 128.42, 127.95 (2
x C), 125.68 (3 x C), 78.26, 64.02, 55.49, 52.38, 34.44. IR (cm-1): νmax 3198, 3054, 2945, 1757, 1723,
1598, 1508, 1461, 1364, 1208, 1153, 723, 695. MS (ESI, M-H+): m/z 414.9 (M-H+, 100). Anal. Calcd for
C24H20N2O3S.0.5H2O: C, 67.75; H, 4.95; N, 6.60; S, 7.55. Found: C, 67.80; H, 4.85; N, 6.60; S, 7.55.
Methyl
7a-benzyl-hexahydro-5-(4-methoxyphenyl)-1-oxo-3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-
carboxylate (3f). After completion of the reaction (18 h), the product were obtained as a 67/33 mixture of
cis- and trans-isomers and isolated by column chromatography (Et2O:hexane, 1:2) which afforded the
product (0.33 g, 81%) as an amorphous colourless solid.
(5R,6S,7aR)-Methyl 7a-benzyl-hexahydro-5-(4-methoxyphenyl)-1-oxo-3-thioxo-1H-pyrrolo[1,2-c]-
imidazole-6-carboxylate (cis-3f). The product crystallized from Et2O as colourless prisms; mp 191-193
ºC. 1H NMR (300 MHz, CDCl3): δ = 7.82 (brs, 1H, NH), 7.37-6.79 (m, 9H, Ar-H), 5.27 (d, 1H, J = 9.33
Hz, 5-H), 3.78 (s, 3H, OCH3), 3.73-3.65 (m, 1H, 6-H), 3.25 (s, 3H, OCH3), 3.24 (d, 1H, J = 13.50 Hz,
8-H) 3.15 (d, 1H, J = 13.47 Hz, 8-H') 2.88 (dd, 1H, J = 13.05, 13.02 Hz, 7-H), 2.26 (dd, 1H, J = 13.17,
13
6.57 Hz, 7-H'). C NMR (75 MHz, CDCl3): δ = 179.60 (C=S), 174.49 (C=O), 169.33 (C=O), 159.48,
133.20, 129.89, 128.80 (3 x C), 128.10 (2 x C), 126.26, 113.41 (3 x C), 76.61, 64.27, 55.13, 51.84, 51.51,
44.45, 30.84. IR (cm-1): νmax 3137, 3038, 2938, 2838, 1737, 1612, 1514, 1454, 1351, 1240, 1197, 742,
700. MS (ESI, M-H+): m/z 409.0 (M-H+, 100). Anal. Calcd for C22H22N2O4S : C, 64.35; H, 5.40; N, 6.80;
S, 7.80. Found: C, 64.30; H, 5.40; N, 6.85; S, 8.05.
(5R,6S,7aR)-Methyl 7a-benzyl-hexahydro-5-(4-methoxyphenyl)-1-oxo-3-thioxo-1H-pyrrolo[1,2-c]-

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imidazole-6-carboxylate (trans-3f). Crystallisation gave trans-isomer together with trace cis-isomer as
an amorphous colourless solid; mp 129-131 ºC. 1H NMR (300 MHz, CDCl3): δ = 7.75 (brs, 1H, NH),
7.39-6.78 (m, 9H, Ar-H), 5.50 (d, 1H, J = 4.53 Hz, 5-H), 3.81 (s, 3H, OCH3), 3.53-3.47 (m, 1H, 6-H),
3.26-3.13 (m, 2H, 8-H, 8-H') 3.15 (s, 3H, OCH3), 2.76 (dd, 1H, J = 13.59, 10.5 Hz, 7-H), 2.58 (dd, 1H, J
= 13.59 Hz, 2.67 Hz, 7-H'). 13C NMR (75 MHz, CDCl3): δ = 180.32 (C=S), 175.28 (C=O), 173.00 (C=O),
158.95, 133.75, 130.14, 130.00, 129.21, 128.31, 128.02, 127.45, 127.29, 112.97 (3 x C), 76.92, 64.01,
54.90, 54.68, 52.68, 42.54, 33.05. IR (cm-1): νmax 3158, 3046, 2943, 2840, 1736, 1612, 1514, 1454, 1347,
1227, 1198, 747, 699. MS (ESI, M-H+): m/z 409.0 (M-H+, 100). Anal. Calcd for C22H22N2O4S: C, 64.35;
H, 5.40; N, 6.80; S, 7.80. Found: C, 64.70; H, 5.80; N, 6.40; S, 7.30.
Methyl
7a-benzyl-hexahydro-1-oxo-5-phenyl-3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-carboxylate
(3g). After completion of the reaction (24 h), the product were obtained as a 75/25 mixture of cis- and
trans-isomers and seperated by column chromatography (Et2O:hexane, 1:2) which afforded the product
(0.315 g, 83%) as an amorphous colourless solid.
(5R,6S,7aR)-Methyl 7a-benzyl-hexahydro-1-oxo-5-phenyl-3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-
carboxylate (cis-3g). The product crystallized from Et2O as colourless prisms; mp 202-204 ºC. 1H NMR
(300 MHz, CDCl3): δ= 8.03 (brs, 1H, NH), 7.3-7.02 (m, 10H, Ar-H), 5.30 (d, 1H, J = 9.36 Hz, 5-H),
3.77-3.67 (m, 1H, 6-H), 3.26 (d, 1H, J = 13.5 Hz, 8-H) 3.20 (s, 3H, OCH3), 3.17 (d, 1H, J = 13.59 Hz,
8-H') 2.91 (dd, 1H, J = 13.11, 13,02 Hz, 7-H), 2.27 (dd, 1H, J = 13.23, 6.57 Hz, 7-H'). 13C NMR (75 MHz,
CDCl3): δ = 179.70 (C=S), 174.62 (C=O), 169.25 (C=O), 134.15, 133.22, 129.91 (3 x C), 128.82 (3 x C),
128.54, 128.10 (3 x C), 77.13, 64.68, 51.77, 51.56, 44.51, 30.83. IR (cm-1): νmax 3156, 3045, 2948, 1738,
1599, 1454, 1349, 1227, 1197, 737, 697. MS (ESI, M-H+): m/z 378.9 (M-H+, 100). Anal. Calcd for
C21H20N2O3S.0.25H2O: C, 65.55; H, 5.35; N, 7.30; S, 8.30. Found: C, 65.80; H, 5.30; N, 7.20; S, 8.35.
(5R,6R,7aR)-Methyl 7a-benzyl-hexahydro-1-oxo-5-phenyl-3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-
carboxylate (trans-3g). Crystallisation gave trans-isomer together with trace cis-isomer as an amorphous
colourless solid; mp 183-185 ºC. 1H NMR (300 MHz, CDCl3): δ = 7.90 (brs, 1H, NH), 7.39-7.01 (m, 10H,
Ar-H), 5.58 (d, 1H, J = 3.99 Hz, 5-H), 3.83 (s, 3H, OCH3), 3.54-3.49 (m, 1H, 6-H), 3.27-3.10 (m, 2H, 8-H,
8-H'), 2.77 (dd, 1H, J = 13.59 Hz, 10.35 Hz, 7-H), 2.62 (dd, 1H, J = 13.59 Hz, 2.19 Hz, 7-H'). 13C NMR
(75 MHz, CDCl3): δ = 178.34 (C=S), 174.22 (C=O), 173.03 (C=O), 136.72, 132.99, 128.91 (3 x C),
128.78 (2 x C), 128.57 (2 x C), 127.92 (3 x C), 77.92, 64.64, 55.07, 53.07, 42.99, 33.24. IR (cm-1): νmax
3238, 3035, 2954, 2924, 1728, 1616, 1452, 1351, 1204,1176, 736, 697. MS (ESI, M-H+): m/z 378.9
(M-H+, 100). Anal. Calcd for C21H20N2O3S.0.25H2O: C, 65.55; H, 5.35; N, 7.30; S, 8.30. Found: C,
65.50; H, 5.20; N, 7.25; S, 8.55.
7a-((1H-Indol-3-yl)methyl)hexahydro-5-phenyl-6-(phenylsulfonyl)-3-thioxopyrrolo[1,2-c]imidazol-
1-one (3h). After completion of the reaction (24 h), the product were obtained as a 50/50 mixture of cis-
and trans-isomers and seperated by column chromatography (Et2O:hexane, 1:3) which afforded the

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2107
product (0.37 g, 74%) as an amorphous colourless solid.
(5S,6S,7aS)-7a-((1H-Indol-3-yl)methyl)hexahydro-5-phenyl-6-(phenylsulfonyl)-3-thioxopyrrolo-
[1,2-c]imidazol-1-one (cis-3h). The product crystallized from Et2O as colourless prisms; mp: 259-262 ºC
(decomp). 1H NMR (300 MHz, acetone-d6): δ = 10.40 (brs, 1H, NH), 10.27 (brs, 1H, NH), 7.78-7.77 (m,
H, Ar-H), 7.60-7.51 (m, 3H, Ar-H), 7.43-7.40 (m, 3H, Ar-H), 7.25-7.10 (m, 5H, Ar-H), 7.02-6.97 (m, 3H,
Ar-H), 5.30 (d, 1H, J = 8.16 Hz, 5-H), 4.61-4.52 (m, 1H, 6-H), 3.46 (d, 1H, J = 14.31 Hz, 8-H), 3.40 (d,
13
1H, J = 14.43 Hz, 8-H'), 2.95-2.82 (m, 1H, 7-H), 2.43 (dd, 1H, J = 12.21 Hz, 5.88 Hz, 7-H'). C NMR
(100 MHz, DMSO-d6): δ = 179.46 (C=S), 175.79 (C=O), 137.25, 135.66, 134.28, 133.89, 129.41 (3 x C),
128.43 (3 x C), 127.92, 127.49, 127.28 (2 x C), 124.95, 120.82, 118.54, 118.36, 111.23, 106.51, 75.61,
71.63, 63.24, 32.15, 30.24. IR (cm-1): νmax 3402, 3389, 3062, 2955, 1922, 1727, 1582, 1448, 1358, 1210,
1146, 725, 689. MS (ESI, M+H+): m/z 502.3 (M+H+, 100).
(5S,6R,7aS)-7a-((1H-Indol-3-yl)methyl)hexahydro-5-phenyl-6-(phenylsulfonyl)-3-thioxopyrrolo-
[1,2-c]imidazol-1-one (trans-3h). Crystallisation gave trans-isomer together with trace cis-isomer as an
amorphous colourless solid; mp 228-230 ºC (decomp.). 1H NMR (300 MHz, acetone-d6): δ = 10.19 (brs,
1H, NH), 9.91 (brs, 1H, NH), 7.90-6.97 (m, 15H, Ar-H), 5.37 (d, 1H, J = 6.75 Hz, 5-H), 4.70-4.63 (m, 1H,
13
6-H), 3.52-3.37 (m, 2H, 8-H, 8-H'), 3.14-2.76 (m, 2H, 7-H, 7-H'). C NMR (100 MHz, DMSO-d6): δ=
181.26 (C=S), 175.74 (C=O), 138.44, 135.71, 133.93, 132.51, 129.25 (3 x C) 127.93 (3 x C), 127.76 (3 x
C), 127.16 (2 x C), 125.38, 120.87, 118.68, 118.34, 106.37, 74.87, 64.04, 63.28, 33.90, 30.01. IR (cm-1):
νmax 3358, 3280, 3062, 2933, 1753, 1584, 1450, 1374, 1206, 1143, 730, 691. MS (ESI, M+H+): m/z 502.3
(M+H+, 100). Anal. Calcd for C27H23N3O3S2.0.5H20 : C, 63.45; H, 4.70; N, 8.20; S, 12.55. Found: C,
63.10; H, 4.70; N, 8.00; S, 12.30.
7a-Benzylhexahydro-6-(methylsulfonyl)-5-phenyl-3-thioxopyrrolo[1,2-c]imidazol-1-one (3i). After
completion of the reaction (21 h), the product were obtained as a 85/15 mixture of cis- and trans-isomers
and seperated by column chromatography (Et2O:hexane, 1:3) which afforded the product (0.29 g, 72%)
as an amorphous colourless solid.
(5S,6S,7aS)-7a-Benzylhexahydro-6-(methylsulfonyl)-5-phenyl-3-thioxopyrrolo[1,2-c]imidazol-1-one
1
(cis-3i). The product crystallized from Et2O as colourless prisms; mp 151-153 ºC. H NMR (300 MHz,
CDCl3): δ = 7.44-7.14 (m, 11H, Ar-H and N-H), 5.44 (d, 1H, J = 6.47 Hz, 5-H), 4.19-4.12 (m, 1H, 6-H),
3.74 (d, 1H, J = 13.83 Hz, 8-H), 3.24 (d, 1H, J = 13.83 Hz, 8-H'), 2.94-2.80 (m, 2H, 7-H ve 7H'), 2.75 (s,
13
3H, SCH3). C NMR (75 MHz, CDCl3): δ = 177.51 (C=S), 173.60 (C=O), 133.70, 133.03, 129.88 (3 x
C), 129.75, 129.15 (2 x C), 128.60 (3 x C), 127.92 76.97, 72.39, 64.43, 42.64, 41.27, 30.45. IR (cm-1):
νmax 3239, 3022, 2955, 2924, 2866, 1742, 1603, 1452, 1378, 1240, 1200, 734, 697. MS (ESI, M-H+): m/z
398.9 (M-H+, 100). Anal. Calcd for C20H20N2O3S: C, 60.00; H, 5.05; N, 7.00; S, 16.00. Found: C, 59.65;
H, 5.15; N, 6.85; S, 16.20.
(5S,6R,7aS)-7a-Benzylhexahydro-6-(methylsulfonyl)-5-phenyl-3-thioxopyrrolo[1,2-c]imidazol-1-one

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(trans-3i). Crystallisation gave trans-isomer together with trace cis-isomer as an amorphous colourless
1
solid; mp 162-164 ºC. H NMR (300 MHz, CDCl3): δ = 7.95 (brs, 1H, NH), 7.44-7.13 (m, 10H, Ar-H),
5.44 (d, 1H, J = 3.6 Hz, 5-H), 3.98-3.85 (m, 1H, 6-H), 3.31 (d, 1H, J = 13.53 Hz, 8-H), 3.22 (d, 1H, J =
13.38 Hz, 8-H') 2.94-2.80 (m, 1H, 7-H), 2.59 (dd, 1H, J = 12.48 Hz, 5.82 Hz, 7-H'), 2.02 (s, 3H, SCH3).
13C NMR (75 MHz, CDCl3): δ = 180.26(C=S), 174.11(C=O), 132.69, 131.71, 129.96 (3 x C), 129.52,
129.96, 129.04(3 x C), 128.61, 128.48, 75.70, 68.30, 63.83, 45.16, 39.18, 30.27. IR (cm-1): νmax 3239,
3063, 3030, 2951, 2924, 1742, 1601 1452, 1384, 1240, 1200, 730, 698. MS (ESI, M-H+): m/z 401.1
(M+H+, 70). Anal. Calcd for C20H20N2O3S: C, 60.00; H, 5.05; N, 7.00; S, 16.00. Found: C, 60.05; H,
5.25; N, 6.65; S, 15.90.
Methyl
7a-benzylhexahydro-1-oxo-5-(pyridin-3-yl)-3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-
carboxylate (3j). After completion of the reaction (18 h), the product were obtained as a 75/25 mixture of
cis- and trans-isomers and seperated by column chromatography (Et2O:hexane, 1:3) which afforded the
product (0.35 g, 91%) as an amorphous colourless solid.
(5R,6S,7aR)-Methyl 7a-benzyl-hexahydro-1-oxo-5-(pyridin-3-yl)-3-thioxo-1H-pyrrolo[1,2-c]-
imidazole-6-carboxylate (Z-3j). The product crystallized from Et2O as colourless prisms; mp 236-238 ºC
(decomp). 1H NMR (300 MHz, DMSO-d6): δ = 11.45 (brs, 1H, NH), 8.39 (dd, 1H, J = 1.44 Hz, 1.44 Hz,
Ar-H), 8.27 (brs, 1H, Ar-H), 7.29-7.14 (m, 7H, Ar-H), 5.26 (d, 1H, J = 9.36 Hz, 5-H), 3.81-3.71 (m, 1H,
6-H), 3.13 (s, 3H, OCH3), 2.98 (brs, 2H, 8-H, 8-H') 2.69 (dd, 1H, J = 13.2, 12.9 Hz, 7-H), 2.19 (dd, 1H, J
= 13.2, 6.57 Hz, 7-H'). 13C NMR (75 MHz, DMSO-d6): δ = 181.12 (C=S), 175.63 (C=O), 169.78 (C=O),
148.87, 134.42, 131.30, 130.40 (3 x C), 128.40 (3 x C), 127.56, 123.10, 76.70, 61.29, 51.71, 51.35, 43.16,
31.17. IR (cm-1): νmax 3143, 3044, 2939, 1736, 1580, 1458, 1349, 1204, 1176, 737, 698. MS (ESI, M-H+):
m/z 379.9 (M-H+, 100). Anal. Calcd for C20H19N3O3S: C, 62.95; H, 5.00; N, 11.00; S, 8.40. Found: C,
62.90; H, 5.10; N, 10.80; S, 8.25.
(5R,6R,7aR)-Methyl
7a-benzylhexahydro-1-oxo-5-(pyridin-3-yl)-3-thioxo-1H-pyrrolo[1,2-c]-
imidazole-6-carboxylate (trans-3j). Crystallisation gave trans-isomer together with trace cis-isomer as
an amorphous colourless solid; mp 216-218 ºC (decomp). 1H NMR (400 MHz, DMSO-d6): δ = 11.27 (brs,
1H, NH), 8.59 (brd, 1H, J = 1.96 Hz, Ar-H), 8.46 (dd, 1H, J = 1.56, 1.52 Hz, Ar-H), 7.27-7.17 (m, 7H,
Ar-H), 5.45 (d, 1H, J = 6 Hz, 5-H), 3.81-3.68 (m, 1H, 6-H), 3.69 (s, 3H, OCH3), 3.39 (d, 1H, J = 4.05 Hz,
8-H), 3.37 (d, 1H, J = 4.05 Hz, 8-H'), 2.91 (dd, 1H, J = 13.16, 11 Hz, 7-H), 2.35 (dd, 1H, J = 13.2, 3.24
Hz, 7-H'). 13C NMR (100 MHz, DMSO-d6): δ = 179.64 (C=S), 174.95 (C=O), 172.57 (C=O), 148.54,
133.92, 131.91, 129.73 (3 x C), 127.91 (3 x C), 127.13, 122.87, 76.61, 60.64, 53.33, 52.46, 41.68, 32.59.
IR (cm-1): νmax 3030, 2950, 1735, 1598, 1443, 1359, 1204, 1180, 741, 702. MS (ESI, M-H+): m/z 379.9
(M-H+, 100).
Synthesis of compounds 6 and 7. To a stirred solution of aroylaminocarbo-N-thioylpyrrolidines (0.65 g,

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2109
1 mmol) in dry MeOH (30 mL) was added a solution of sodium methoxide (0,057 g, 1.05 mmol) in dry
MeOH (20 mL) over 5 min. and the mixture stirred at reflux temperature for 36 h. After completion of the
reaction, the solvent was evaporated under reduced pressure, quenched with saturated aqueous
ammonium chloride and extracted with CH2Cl2. The combined organic layers were dried (MgSO4),
filtered, evaporated under reduced pressure and the mixture was purified by column chromatography
(Et2O:hexane, 1:3) to afford bicyclic compounds 6 (0.26 g, 49%) and 7 (0.13 g, 24%). When the same
reaction was carried out at room temperature for 36 h, only compound 7 (0.445 g, 83%) was obtained.
(5R,6S,7S,7aS)-Methyl 7-(phenylcarbamoyl)-7a-((1H-indol-3-yl)methyl)hexahydro-1-oxo-5-phenyl-
3-thioxo-1H-pyrrolo[1,2-c]imidazole-6-carboxylate (6). The product crystallized from Et2O as
colourless prisms; mp 202-205 ºC (decomp.). 1H NMR (300 MHz, CDCl3): δ = 8.97 (brs, 1H, NH), 8.20
(brs, 1H, NH), 7.75-6.93 (m, 16H, NH, Ar-H), 5.40 (d, 1H, J = 9.63 Hz, 5-H), 4.42 (dd, 1H, J = 11.94,
9.66 Hz, 6-H), 4.19 (d, 1H, J = 11.97 Hz, 7-H), 3.60 (d, 1H, J = 14.58 Hz, 8-H), 3.38 (d, 1H, J = 14.61 Hz,
8-H'), 3.25(s, 3H, OCH3). 13C NMR (75 MHz, CDCl3): δ = 178.32 (C=S), 176.52 (C=O), 168.61 (C=O),
164.42 (C=O), 137.67, 135.83, 133.25, 129.22 (3 x C), 128.77, 128.17, 127.15 (2 x C), 124.82, 124.71,
122.53, 120.31, 119.87 (3 x C), 118.29, 111.37, 106.09, 75.34, 63.03, 53.43, 52.04, 48.02, 30.46. IR
(cm-1): νmax 3404, 3327, 3198, 3130, 2951, 2924, 1746, 1719, 1684, 1598, 1455, 1368, 1210, 1172, 745,
697. MS (ESI, M+H+): m/z 539.4 (M+H+, 100). Anal. Calcd for C30H26N4O4S: C, 66.90; H, 4.85; N,
10.40; S, 5.95. Found: C, 66.80; H, 5.10; N, 10.05; S, 5.85.
(2S,3S,3aS,6aR)-Methyl
6a-((1H-indol-3-yl)methyl)octahydro-4,6-dioxo-2,5-diphenyl-1-
thiocarbamoylpyrrolo[3,4-b]pyrrole-3-carboxylate (7). The product crystallized from Et2O as
1
colourless prisms; mp 234-236 ºC (decomp.). H NMR (400 MHz, DMSO-d6): δ = 11.11 (brs, 1H, NH),
11.10 (brs, 1H, NH), 10.61 (brs, 1H, NH), 7.70-7.05 (m, 15H, Ar-H), 5.28 (d, 1H, J = 7.80 Hz, 2-H), 3.94
(dd, 1H, J = 7.76, 4.16 Hz, 3-H), 3.81 (d, 1H, J = 4.16 Hz, 3a-H), 3.68 (s, 3H, OCH3), 3.53(d, 1H, J =
13
14.72 Hz, 7-H), 3.48 (d, 1H, J = 14.76 Hz, 7-H'). C NMR (100 MHz, DMSO-d6): δ = 178.30 (C=S),
174.19 (C=O), 171.36 (C=O), 169.59 (C=O), 138.36, 135.74, 135.07, 128.75 (3 x C), 128.08, 127.56 (2 x
C), 127.40, 125.35, 123.94, 120.97, 119.75 (3 x C), 118.67, 118.22, 111.32, 105.79, 79.35, 63.93, 58.98,
52.52, 52.17, 32.68. IR (cm-1): νmax 3323, 3208, 3062, 2964, 1759, 1706, 1667, 1596, 1539, 1445, 1394,
1210, 1187, 745, 730, 690. MS (ESI, M+H+): m/z 539.4 (M+H+, 100).
Synthesis of (2S,3S,3aS,6aR)-Methyl 6a-((1H-indol-3-yl)methyl)octahydro-4,6-dioxo-2,5-diphenyl-
pyrrolo[3,4-b]pyrrole-3-carboxylate (9). To a stirred solution of bicyclic pyrrolidine 8 (0,48 g, 1 mmol)
in dry MeOH (30 mL) was added a solution of sodium methoxide (0.057 g, 1.05 mmol) in dry MeOH (20
mL) over 5 min. and the mixture stirred and heated at reflux temperature for 36 h. After completion of the
reaction, the solvent was evaporated under reduced pressure, quenched with saturated aqueous
ammonium chloride and extracted with CH2Cl2. The combined organic layers were dried (MgSO4),

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HETEROCYCLES, Vol. 83, No. 9, 2011
filtered, evaporated under reduced pressure and the mixture was purified by column chromatography
(Et2O:hexane, 1:3) to afford 9. The product (0.41g, 85%) crystallised from Et2O:hexane as colourless
1
prisms; mp 122-124 ºC. H NMR (400 MHz, CDCl3): δ = 8.30 (brs, 1H, NH), 7.87 (d, 1H, J = 7.68,
Ar-H), 7.57-7.15 (m, 12H, Ar-H), 6.47 (m, 2H, Ar-H), 5.00 (d, 1H, J = 3.64 Hz, 2-H), 3.84 (d, 1H, J =
2.84 Hz, 3a-H), 3.81 (s, 3H, OCH3), 3.78 (d, 1H, J = 13.87 Hz, 7-H), 3.72 (t, 1H, 3-H), 3.47 (d, 1H, J =
13.87 Hz, 7-H'). 13C NMR (100 MHz, CDCl3): δ = 178.99 (C=O), 175.73 (C=O), 173.21 (C=O), 140.24,
136,00, 131.41, 128,86 (2 x C), 128.83 (2 x C), 128.60, 127.84, 127.52, 126.34 (2 x C), 126.09 (2 x C),
124.20, 122.50, 120.14, 119.05, 111.28, 109.14, 71.92, 66.14, 54.26, 52.74, 51.30, 30.36. IR (cm-1): νmax
3386, 3351, 3058, 3035, 2953, 2921, 1705, 1596, 1493, 1454, 1380, 1194, 1175, 1128, 1095, 1010, 737,
693. MS (ESI, M-H+): m/z 478.0 (M-H+, 100).
Crystallograpy
For the crystal structure determination, a single-crystal of the compounds cis-3a, trans-3a, cis-3j, 6 and 7
were used for data collection on a four-circle Rigaku R-AXIS RAPID-S diffractometer (equipped with a
two-dimensional area IP detector). The graphite-monochromatized Mo-Kα radiation (λ = 0.71073 Å) and
oscillation scans technique with ω = 5° for one image were used for data collection. The lattice
parameters were determined by the least-squares methods on the basis of all reflections with F2>2σ(F2).
Integration of the intensities, correction for Lorentz and polarization effects and cell refinement was
performed using CrystalClear (Rigaku/MSC Inc., 2005) software.65 The structures were solved by direct
methods using SHELXS-9766 and refined by a full-matrix least-squares procedure using the program
SHELXL-97.66 Hydrogen positions were found from difference Fourier maps and geometric calculations
and refined using a riding model. The final difference Fourier maps showed no peaks of chemical
significance. Crystallographic data for the compounds have been deposited at the Cambridge
Crystallographic Data Centre. Copies of the information may be obtained free of charge from The
Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk).
Crystal data for compound cis-3a. Compound cis-3a was crystallized by slow evaporation from an
Et2O solution at room temperature. C19H18N2O3S, crystal system, space group: monoclinic, P21/c;
(no:14); unit cell dimensions: a = 10.3012(10), b = 14.5412(8), c = 12.5644(11)Å,  = 90, β = 110.029(4),
 = 90º; volume: 1768.2(3) Å3; Z=4; calculated density: 1.331 g/cm3; absorption coefficient: 0.203 mm−1;
F(000): 744; θ-range for data collection 2.1–26.4º; refinement method: full-matrix least-square on F2;
data/parameters: 2244/227; goodness-of-fit on F2: 1.062; final R indices [I>2σ(I)]: R1 = 0.070, wR2 =
0.191; R indices (all data): R1 = 0.105, wR2 = 0.220; largest diff. peak and hole: 0.434 and -0.314 e Å−3;
CCDC : 818055.

HETEROCYCLES, Vol. 83, No. 9, 2011
2111
Crystal data for compound trans-3a. Compound trans-3a was crystallized by slow evaporation from an
Et2O-MeCN solution at room temperature. C19H18N2O3S.MeCN, crystal system, space group: monoclinic,
P21/c; (no:14); unit cell dimensions: a =18.6497(7), b =5.6334(3), c =20.7534(8)Å,  =90, β = 112.105(4),
=90º; volume: 2020.12(16) Å3; Z=4; calculated density: 1.30 g/cm3; absorption coefficient: 0.187 mm−1;
F(000): 832; θ-range for data collection 2.4–26.4º; refinement method: full-matrix least-square on F2;
data/parameters: 2389/257; goodness-of-fit on F2: 1.033; final R indices [I>2σ(I)]: R1 = 0.066, wR2 =
0.140; R indices (all data): R1 = 0.121, wR2 = 0.162; largest diff. peak and hole: 0.214 and -0.195 e Å−3;
CCDC: 818642.
Crystal data for compound cis-3j. Compound cis-3j was crystallized by slow evaporation from an Et2O
solution at room temperature. C20H19N3O3S, crystal system, space group: monoclinic, P21/a; (no:14); unit
cell dimensions: a = 19.7407(5), b=8.0998(2), c = 24.4643(6)Å,  = 90, β = 108.394(7),  = 90º; volume:
3711.88(16) Å3; Z = 8; calculated density: 1.365 g/cm3; absorption coefficient: 0.200 mm−1; F(000):
1600; θ-range for data collection 2.1–26.6º; refinement method: full-matrix least-square on F2;
data/parameters: 3698/487; goodness-of-fit on F2: 0.971; final R indices [I>2σ(I)]: R1 = 0.076, wR2 =
0.207; R indices (all data): R1 = 0.148, wR2 = 0.272; largest diff. peak and hole: 0.317 and -0.297 e Å−3;
CCDC: 817919.
Crystal data for compound 6. Compound 6 was crystallized by slow evaporation from an Et2O solution
at room temperature. C30H26N4O4S.H2O, crystal system, space group: triclinic, P-1; (no:2); unit cell
dimensions: a=11.1814(4), b=12.0039(5), c=13.9183(5)Å,  = 105.98(4), β = 103.04(7),  = 111.06(8)º;
volume: 1562.38(10) Å3; Z = 2; calculated density: 1.183 g/cm3; absorption coefficient: 0.145 mm−1;
F(000): 584; θ-range for data collection 2.1–26.4º; refinement method: full-matrix least-square on F2;
data/parameters: 3648/358; goodness-of-fit on F2: 1.062; final R indices [I>2σ(I)]: R1 = 0.081, wR2 =
0.244; R indices (all data): R1 = 0.123, wR2 = 0.292; largest diff. peak and hole: 0.587 and -0.262 e Å−3;
CCDC: 817634.
Crystal data for compound 7. Compound 7 was crystallized by slow evaporation from an Et2O solution
at room temperature. C30H26N4O4S, crystal system, space group: triclinic, P-1; (no:2); unit cell
dimensions: a = 11.4619(4), b = 11.5299(5), c = 11.6129(6)Å,  = 69.52(4), β = 71.23(3),  = 79.68(5)º;
volume: 1357.47(11) Å3; Z = 2; calculated density: 1.318 g/cm3; absorption coefficient: 0.162 mm−1;
F(000): 564; θ-range for data collection 2.3–26.4º; refinement method: full-matrix least-square on F2;
data/parameters: 3196/352; goodness-of-fit on F2: 1.026; final R indices [I>2σ(I)]: R1 = 0.062, wR2 =
0.132; R indices (all data): R1 = 0.115, wR2 = 0.157; largest diff. peak and hole: 0.191 and -0.189 e Å−3;
CCDC: 817614.
ACKNOWLEDGEMENTS
This work is a part of Yahya Nural PhD thesis and we thank to Mersin University (project grant

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BAP-SBE AKB (YN) 2009-3 DR for Yahya Nural) for financial support.
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