Regio-controlled nucleophilic attack of 3-thiaisatoic anhydride by α-amino acids: One-pot synthesis of 3-(2-Thienyl)imidazolidine-2,4-dione and 3,4-substituted thieno[2,3-][1,4]diazepine-2,5-dione analogues

Article abstract of DOI:10.1055/s-0028-1083320

Convenient syntheses of optically pure 3-(2-thienyl)imi- dazolidine-2,4-dione (35-63% yields) and 3,4-dihydro-1H- thieno[2,3-e][1,4] diazepine-2,5-dione (35-81% yields) analogues are described. The regioselective ring opening of 1H-thieno[2,3- d][1,3]oxaz

Full text of DOI:10.1055/s-0028-1083320

PAPER
389
Regio-Controlled Nucleophilic Attack of 3-Thiaisatoic Anhydride by a-Amino
Acids: One-Pot Synthesis of 3-(2-Thienyl)imidazolidine-2,4-dione and
3,4-Substituted Thieno[2,3-e][1,4]diazepine-2,5-dione Analogues
O
ne-Pot Synthesis
a
of
T
hienyl
n
imidazolidin
n
Institut des Biomolécules Max-Mousseron (IBMM), UMR 5247, Universités Montpellier I et II,
UFR des Sciences Pharmaceutiques et Biologiques, 15 Avenue Charles Flahault, 34093 Montpellier, France
Fax +33(4)67548654; E-mail: vincent.lisowski@univ-montp1.fr
Received 4 August 2008
Abstract: Convenient syntheses of optically pure 3-(2-thienyl)imi-
HO
O
O
HN
O
H
N
dazolidine-2,4-dione (35–63% yields) and 3,4-dihydro-1H-
thieno[2,3-e][1,4]diazepine-2,5-dione (35–81% yields) analogues
are described. The regioselective ring opening of 1H-thieno[2,3-
d][1,3]oxazine-2,4-dione (3-thiaisatoic anhydride), using inexpen-
sive natural and synthetic a-amino acids under aqueous conditions,
has been investigated to afford two libraries in a one-pot process.
N
N
CN
CF3
NO2
nilutamide
O
1
Key words: thiaisatoic anhydride, 3-(2-thienyl)imidazolidine-2,4-
dione, thieno[2,3-e][1,4]diazepine-2,5-dione, diazepine, oxazinedi-
one
= 2-thiaisatoic
anhydride (2)
H
S
S
where
Ar
N
O
The androgen receptor (AR), a member of the steroid and
nuclear receptor superfamily, constitutes an important tar-
get in medicinal chemistry.1 Among non-steroidal AR
ligands, the hydantoin scaffold2,3 was found to be useful in
the design of various antagonists such as nilutamide,4
which is currently involved in the management of prostate
cancer (Figure 1). More recently, this antiandrogen was
chemically modified, leading to the discovery of novel se-
lective androgen receptor modulators (SARMs) such as
N-arylbicyclohydantoins 1 (Figure 1).5 These anabolic
SARMs are presently under clinical trials for the treat-
ment of muscle wasting, the hypogonadism of aging, os-
teoporosis and female sexual dysfunction.6 In conjunction
with our ongoing interest in the reactivity of ring-fused
oxazinediones and our library screening program, we
have recently reported an efficient chemical process for
the generation of a series of optically pure hydantoin
= 3-thiaisatoic
anhydride (3)
Ar
:
O
= isatoic
anhydride (4)
O
Figure 1 Representative chemical structures
the isomeric thieno[2,3-d][1,3]oxazinedione 3 (Figure 1)
to generate potential hydantoin-based SARMs.
This previously described14 3-thiaisatoic anhydride 3, has
already been used as the key intermediate in the synthesis
of thienopyridinones,15–18 thienopyrimidinediones,19
thienoimidazolones20 and tricyclic pyrrolothienodiaze-
pines.21 In the case of this study, the anhydride 3 was pre-
pared using a three-step process from 2,5-dihydroxy-1,4-
dithiane and ethylcyanoacetate.16,22 The first part of this
work was dedicated to demonstrating that regioselective
ring opening of this anhydride by a-amino acids could be
performed. Relying on our precedent studies of the iso-
meric anhydride 2,13 our primary assays were carried in
neutral water with 1000 mol% of alanine (R1 = H and
R2 = CH3; Scheme 1) and monitored by LC-MS at 214
nm. From room temperature to 50 °C, no conversion of
the starting material was observed after 48 hours of stir-
ring. At higher temperatures (50–100 °C), progressive
amounts of hydrolyzed products were observed (5% at
50 °C rising to 35% at 100 °C), with concomitant but less
significant formation of the expected amide 5. This pre-
liminary result seemed to prove that 3-thiaisatoic anhy-
dride 3 was more stable than its isomeric counterpart 2.
This observation prompted us to envisage the use of diox-
ane, tetrahydrofuran or N,N-dimethylformamide as organ-
ic solvents. Unfortunately, only ureido-diacid 7 (20%)
was formed, with residual starting material (80%) and no
derivatives from thieno[3,2-d][1,3]oxazinedione
2
(Figure 1).7 In contrast to isatoic anhydride 4 (Figure 1),
for which the nucleophilic attack only takes place on the
carboxylic carbonyl,8 its five-membered fused analogues
such as pyrazole,9 furan10,11 or thiophene12 display a dif-
ferent reactivity occurring mainly at their carbamic carbo-
nyl. Alternatively, we demonstrated that ring opening of
the cyclic anhydride of 3-aminothenoic acid 2 by natural
amino acids can be regiocontrolled in protic conditions to-
wards either the diazepine13 or the hydantoin7 scaffolds, in
neutral or basic medium, respectively. In these biological
and chemical contexts, we now report a reactivity study of
SYNTHESIS 2009, No. 3, pp 0389–0394
x
x
.
x
x
.2
0
0
9
Advanced online publication: 09.01.2009
DOI: 10.1055/s-0028-1083320; Art ID: P09508SS
© Georg Thieme Verlag Stuttgart · New York

390
Y. Brouillette et al.
PAPER
Table 1 Synthesis of 3,4-Dihydro-1H-thieno[2,3-e][1,4]diazepine-
2,5-dione Analogues 6a–e
hydrolyzed products after stirring for two hours at reflux.
By using a water–dioxane (1:1) mixture, as previously de-
scribed for access to the pyrrolothienodiazepine scaf-
fold,21 no selectivity was observed (35% ureido-diacid 7,
40% amide 5, 35% hydrolyzed products) and similar re-
sults were obtained with other N-unsubstituted a-amino
acids (R1 = H). On the other hand, when alanine was re-
placed by its N-alkylated analogue (R1 = R2 = CH3), the
reaction in water after one hour at reflux, allowed a quan-
titative and chemo-selective ring opening at the carboxyl-
ic carbonyl. Interestingly, it was observed that extended
heating allowed direct cyclocondensation in a one-pot
process (Scheme 1). Therefore, N-benzylglycine, sar-
cosine, pipecolic acid and 3-hydroxyproline were also
submitted to the same protic neutral conditions to form the
corresponding optically pure thienodiazepines 6a–e in
yields of 35–81% (Table 1). Even though the reaction
with acyclic natural a-amino acids was not regioselective
for ring opening at the carboxylic carbonyl, it appears that
the nucleophilic character of N-alkylated a-amino acid
plays an essential role in the kinetics of this opening ver-
sus hydrolysis under neutral aqueous conditions. More-
over, due to partial cis/trans geometry induced by N-
alkylation of the amide bond (R1 ≠ H), the classical in-
tramolecular ring closure to afford diazepines under acid-
ic conditions (AcOH) was overcome by an additional one
hour reflux in water.
Product
Structure
Yield (%)
O
HN
S
6a
81
N
Me
O
O
HN
S
6b
6c
6d
75
80
63
N
O
O
HN
S
N
Me
O
O
HN
S
N
O
O
OH
HN
S
6e
35
O
H
N
N
S
O
O
O
Therefore, in order to develop access to the hydantoin
scaffold, 3-thiaisatoic anhydride 3 was submitted to nu-
cleophilic attack of natural and synthetic a-amino acids
under basic conditions. It was found that addition of tri-
ethylamine in water was required to allow ring opening by
a-amino acids at room temperature. Under these condi-
tions, totally opposite reactivity was observed, which led
to ureido-diacids 7 (Scheme 1), as previously reported
with isomer 2.7 This result is in accordance with the exist-
ence of a putative highly reactive isocyanate intermediate,
for which the formation could be subordinated to ioniza-
tion of oxazine 3 under basic conditions, directing the nu-
cleophilic attack towards the carbamic carbonyl.23
Moreover, under such conditions, quantitative transfor-
mation was observed in one hour at room temperature ver-
sus five minutes for the anhydride 2, confirming the
higher stability of this isomer, as also observed in the di-
azepine pathway. To validate the method, acyclic, cyclic,
a-disubstituted and N-alkylated a-amino acids were ex-
amined in order to provide only the corresponding ureido-
diacids 7. Ascertained by LC-MS, once all the starting
material was consumed, the subsequent cyclocondensa-
tion was performed by addition of 10% aqueous hydro-
chloric acid, DMF and conventional heating at reflux for
18 to 48 hours. In this reaction, the hydantoins 8 were pre-
dominantly formed with residual persistence (~10%) of
their non-decarboxylated analogues (such as 9c,
3
R2
R1HN
H2O
CO2H
Et3N
r.t., 1 h
reflux
1 h
NH2
R1
CO2
R2
2 Et3NH
–
S
N
O
HN
S
O
N
CO2H
R1
–
CO2
R2
5
7
HCl 10%, DMF
reflux, 18–48 h
reflux
1 h
R1
O
N
R2
R2
HN
O
S
N
N
R1
S
O
O
6
8
Scheme 1 Synthesis of 3,4-dihydro-1H-thieno[2,3-e][1,4]diaze-
pine-2,5-dione (6) and 3-(2-thienyl)imidazolidine-2,4-dione (8) ana-
logues
Synthesis 2009, No. 3, 389–394 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Thienylimidazolidines
391
Table 2 Synthesis of 3-(2-Thienyl)imidazolidine-2,4-dione Analogues 8 and 9
Product
Structure
Yield (%)
Product
Structure
Yield (%)
H
H
N
O
N
O
8a
55
8g
54
56
37
N
N
S
O
O
O
S
O
O
O
OH
H
H
N
O
N
O
8b
8c
36
51
8h
8i
N
N
S
S
H
H
N
O
N
O
SMe
N
N
S
S
Me
H
O
N
O
N
N
O
8d
37
8j
55
OH
N
N
S
O
O
O
S
O
H
N
O
O
8e
8f
45
53
8k
8l
63
35
N
N
N
N
N
S
S
O
O
O
H
H
N
N
O
O
OH
N
S
S
H
N
O
9c
10
S
CO2H
Table 2).24 In comparison with 2-thiaisatoic anhydride 2, ries of five 3,4-dihydro-1H-thieno[2,3-e][1,4]diazepine-
decarboxylation at the b-position of the thiophene ring 2,5-dione analogues 6 was synthesized in 35–81% yields
was slower. When cyclization occurs faster than the de- through treatment of 1H-thieno[2,3-d][1,3]oxazine-2,4-
carboxylation, it is no longer possible to decarboxylate the dione (3) with N-substituted a-amino acids under neutral
hydantoin formed. Prolonged heating, microwave irradia- conditions. Hence, a library of twelve optically pure 3-(2-
tion and classical decarboxylative conditions, such as cop- thienyl)imidazolidine-2,4-dione derivatives 8 was also
per catalysis in quinoline,25,26 were all ineffective. synthesized in 35–63% yields from the same precursor
Nevertheless, this by-product could be easily removed by with natural and synthetic a-amino acids in a one-pot pro-
alkaline aqueous washing (when R2 is not an acid-contain- cedure. This versatile reactivity of thiaisatoic anhydride
ing side chain) to provide the expected optically pure hy- prompts us to apply this convenient methodology to the
dantoins 8 in 35–63% yields (Table 2).
design of potential SARMS, comparable to compound 8l.
Even though 3-thiaisatoic anhydride 3 is more stable than
its 2-thiaisatoic anhydride isomer 2, in the presence of a-
amino acids it still proved to be a flexible intermediate in
the synthesis of valuable heterocycles. To this end, a se-
Starting materials and solvents were obtained commercially and
used as received. Melting points were determined in open capil-
laries and are uncorrected. Optical rotations were measured on a
Perkin–Elmer polarimeter 341 using a 100 mm path-length cell at
Synthesis 2009, No. 3, 389–394 © Thieme Stuttgart · New York

392
Y. Brouillette et al.
PAPER
7,8,9,9a-Tetrahydropyrido[1,2-a]thieno[2,3-e][1,4]diazepine-
4,10(6H, 11H)dione (6d)
Yield: 63% (from a racemic mixture of piperidine-2-carboxylic ac-
id); white solid; mp 170–172 °C; tR = 1.49 min (method A).
1H NMR (DMSO-d6): d (mixture of two conformers) = 11.13 (s,
1 H), 7.12 (d, J = 5.7 Hz, 1 H), 7.09 (d, J = 5.7 Hz, 1 H), 4.23 (m,
2 H), 2.82 (m, 1 H), 2.07 (m, 1 H), 1.62 (m, 5 H).
13C NMR (DMSO-d6): d (conformer A) = 169.6, 163.8, 143.8,
126.8, 123.9, 117.8, 51.8, 39.1, 22.5, 22.1, 18.3; d (conformer B) =
171.6, 162.4, 152.0, 137.0, 127.5, 125.7, 56.8, 39.1, 26.6, 24.6,
22.0.
l = 589 nm (Sodium D line) in low concentrations due to colored
solutions. Mass spectral data, HRMS/LRMS were obtained by ESI-
Q or Q-TOF analyses. 1H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were recorded at r.t. in DMSO-d6. Chemical shifts (d) are re-
ported in parts per million (ppm) downfield/upfield from residual
DMSO (d = 2.50 and 39.5 ppm) or residual CHCl3 (d = 7.26 and
77.2 ppm); coupling constants (J) are reported in hertz (Hz). The
quaternary carbon of the thiophene ring emits a very weak signal on
the 13C NMR spectrum in comparison to all other signals of the mol-
ecule. HPLC analyses were performed on Merck Chromolith Flash
RP18e (5 mm, 225 × 4.6 mm) analytical reversed-phase column us-
ing a flow rate of 3.0 mL/min, and gradients of eluents A:B,
100:0→0:100 [eluents: A (H2O + 0.1% TFA) and B (MeCN + 0.1%
TFA)] over 5 min (method A). Retention times (tR) are reported as:
tR (min) and elution conditions. HPLC preparative purification was
performed on Chromolith SemiPrep RP-18 (5 mm, 100 × 10 mm)
semi-preparative column, using a flow rate of 15 mL/min and gra-
dient of 100:0→0:100, A:B over 40 min (method B). Analytical
thin-layer chromatography (TLC) was performed using aluminum-
backed silica gel plates coated with a 0.2 mm thickness of silica gel.
HRMS: m/z [M + H+] calcd for C11H13N2O2S: 237.069; found:
237.0668.
(8S,8aS)-8-Hydroxy-6,7,8,8a-tetrahydro-4H-pyrrolo[1,2-
a]thieno[2,3-e][1,4]diazepine-4,9(10H)-dione (6e)
Yield: 35%; white solid; mp >200 °C; [a]D20 +200.8(c 0.2, DMSO);
tR = 0.82 min (method A).
1H NMR (DMSO-d6): d = 11.27 (br s, 1 H), 7.12 (m, 2 H), 5.23 (s,
1 H), 4.75 (s, 1 H), 3.94 (s, 1 H), 3.56 (m, 2 H), 1.91 (m, 2 H).
13C NMR (DMSO-d6): d = 168.5, 161.6, 143.5, 126.4, 124.1, 117.9,
70.4, 65.4, 44.6, 31.7.
HRMS: m/z [M + H+] calcd for C10H11N2O3S: 239.0490; found:
239.0477.
3,4-Dihydro-1H-thieno[2,3-e][1,4]diazepine-2,5-dione Ana-
logues (6); General Procedure
A suspension of 1H-thieno[2,3-d][1,3]oxazine-2,4-dione (3; 0.300
g, 1.80 mmol) and the corresponding a-amino acid (4.50 mmol) in
H2O (15 mL) was stirred under reflux for 1–2 h. The resulting sus-
pension was filtered over a frit and partitioned between H2O (15
mL) and EtOAc (15 mL). The aqueous phase was extracted with
EtOAc (3 × 20 mL) and the combined organic layers were washed
with brine (2 × 20 mL), dried over Na2SO4, filtered, evaporated and
purified by flash chromatography27 to afford the corresponding di-
azepinedione 6, which was stored in a stoppered flask.
3-(Thien-3-yl)imidazolidine-2,4-diones (8); General Procedure
Et3N (0.72 mmol) was added to a stirring suspension of 1H-
thieno[2,3-d][1,3]oxazine-2,4-dione (3; 0.100 g, 0.60 mmol) and
the corresponding a-amino acid (0.66 mmol) in H2O (4 mL). The
suspension was stirred at r.t. for 1 h until homogeneity. HCl (10%,
2 mL) was added until pH 1. Drops of DMF were added until the
solution became homogenous. The reaction was stirred under reflux
for 18–48 h, then the resulting solution was partitioned between
H2O (10 mL) and EtOAc (10 mL). The aqueous phase was extracted
with EtOAc (3 × 10 mL) and the combined organic layers were
washed with NaHCO3 (10%, 3 × 10 mL; except for 8j) and brine
(2 × 10 mL), dried over Na2SO4, filtered, evaporated and purified
by reverse-phase preparative HPLC to afford the corresponding im-
idazolidinedione 8, which were stored in stoppered flasks.
3,4-Dihydro-4-methyl-1H-thieno[2,3-e][1,4]diazepine-2,5-di-
one (6a)
Yield: 81%; brown solid; mp 170 °C (dec); tR = 1.08 min (method
A).
1H NMR (DMSO-d6): d = 11.19 (s, 1 H), 7.09 (s, 2 H), 3.93 (s, 2 H),
3.04 (s, 3 H).
13C NMR (DMSO-d6): d = 168.3, 163.3, 144.0, 127.2, 123.2, 117.6,
53.0, 35.6.
HRMS: m/z [M + H+] calcd for C8H9N2O2S: 197.0385; found:
197.0381.
3-(2-Thienyl)imidazolidine-2,4-dione (8a)
Yield: 55%; brown solid; mp 130–134 °C; tR = 1.03 min (method
A).
4-Benzyl-3,4-dihydro-1H-thieno[2,3-e][1,4]diazepine-2,5-dione
(6b)
1H NMR (DMSO-d6): d = 8.49 (s, 1 H), 7.40 (dd, J = 3.8, 1.4 Hz,
1 H), 7.36 (dd, J = 5.5, 1.4 Hz, 1 H), 7.02 (dd, J = 5.5, 3.8 Hz, 1 H),
4.08 (d, J = 0.9 Hz, 2 H).
13C NMR (DMSO-d6): d = 169.8, 155.3, 132.8, 124.8, 121.7, 119.3,
45.6.
HRMS: m/z [M + H+] calcd for C7H7N2O2S: 183.0150; found:
183.0147.
Yield: 75%; black solid; mp 145–148 °C; tR = 1.78 min (method A).
1H NMR (DMSO-d6): d = 11.19 (s, 1 H), 7.30 (m, 5 H), 7.14 (m,
2 H), 4.70 (s, 2 H), 3.94 (s, 2 H).
13C NMR (DMSO-d6): d = 168.3, 163.3, 144.4, 137.2, 128.5, 127.6,
127.4, 127.3, 122.7, 117.6, 51.7, 51.0.
HRMS: m/z [M + H+] calcd for C14H13N2O2S: 273.0698; found:
273.0674.
(S)-5-Methyl-3-(2-thienyl)imidazolidine-2,4-dione (8b)
Yield: 36%; brown solid; mp 99–102 °C; [a]D –4.2 (c 0.1,
DMSO); tR = 1.31 min (method A).
1H NMR (DMSO-d6): d = 8.66 (s, 1 H), 7.40 (d, J = 3.4 Hz, 1 H),
7.36 (d, J = 5.4 Hz, 1 H), 7.02 (dd, J = 5.1, 4.0 Hz, 1 H), 4.28 (q,
J = 6.9 Hz, 1 H), 1.34 (d, J = 6.9 Hz, 3 H).
13C NMR (DMSO-d6): d = 173.1, 154.6, 133.2, 125.2, 122.1, 119.6,
52.2, 17.4.
20
(S)-3,4-Dihydro-3,4-dimethyl-1H-thieno[2,3-e][1,4]diazepine-
2,5-dione (6c)
Yield: 80%; light-beige solid; mp 180 °C (dec); [a]D +314.2 (c
0.1, DMSO); tR = 1.18 min (method A).
1H NMR (DMSO-d6): d = 11.15 (s, 1 H), 7.09 (d, J = 0.6 Hz, 2 H),
4.24 (q, J = 7.0 Hz, 1 H), 2.89 (s, 3 H), 1.33 (d, J = 6.9 Hz, 3 H).
13C NMR (DMSO-d6): d = 169.4, 163.6, 143.4, 127.0, 124.3, 117.7,
52.4 (br s), 28.7 (br s), 12.4.
20
HRMS: m/z [M + H+] calcd for C8H9N2O2S: 197.0306; found:
197.0316.
HRMS: m/z [M + H+] calcd for C9H11N2O2S: 211.0541; found:
211.0527.
Synthesis 2009, No. 3, 389–394 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of Thienylimidazolidines
393
5,5-Dimethyl-3-(2-thienyl)imidazolidine-2,4-dione (8c)
Yield: 51%; beige solid (soluble in Et2O); mp 100–102 °C; tR = 1.53
min (method A).
1H NMR (CDCl3): d = 7.51 (dd, J = 3.8, 1.3 Hz, 1 H), 7.16 (dd,
J = 5.5, 1.3 Hz, 1 H), 7.00 (dd, J = 5.5, 3.9 Hz, 1 H), 6.36 (br s,
1 H), 1.54 (s, 6 H).
1H NMR (DMSO-d6): d = 8.71 (s, 1 H), 7.41 (dd, J = 3.8, 1.2 Hz,
1 H), 7.34 (dd, J = 5.4, 1.2 Hz, 1 H), 7.01 (dd, J = 5.4, 3.9 Hz, 1 H),
5.07 (d, J = 5.8 Hz, 1 H), 4.11 (s, 1 H), 4.05 (m, 1 H), 1.20 (d,
J = 6.6 Hz, 3 H).
13C NMR (DMSO-d6): d = 170.8, 155.2, 132.8, 124.8, 121.3, 118.6,
65.4, 62.2, 20.2.
13C NMR (CDCl3): d = 174.7, 154.3, 131.1, 125.2, 121.8, 120.1,
58.6, 25.4.
HRMS: m/z [M + H+] calcd for C9H11N2O3S: 227.0490; found:
227.0487.
HRMS: m/z [M + H+] calcd for C9H11N2O2S: 211.0541; found:
211.0521.
(S)-5-[2-(Methylthio)ethyl]-3-(2-thienyl)imidazolidine-2,4-di-
one (8i)
Yield: 37%; beige solid; mp 90–94 °C; tR = 1.86 min (method A).
1-Methyl-3-(2-thienyl)imidazolidine-2,4-dione (8d)
Yield: 37%; brown solid; mp 109 °C; tR = 1.22 min (method A).
1H NMR (DMSO-d6): d = 7.38 (s, 2 H), 7.02 (s, 1 H), 4.12 (s, 2 H),
2.93 (s, 3 H).
13C NMR (DMSO-d6): d = 168.1, 154.4, 132.8, 124.9, 121.8, 119.4,
51.0, 29.5.
HRMS: m/z [M + H+] calcd for C8H9N2O2S: 197.0385; found:
197.0386.
1H NMR (DMSO-d6): d = 8.75 (s, 1 H), 7.40 (dd, J = 3.7, 1.0 Hz,
1 H), 7.36 (dd, J = 5.5, 1.0 Hz, 1 H), 7.01 (dd, J = 5.4, 3.9 Hz, 1 H),
4.35 (t, J = 6.1 Hz, 1 H), 2.60 (t, J = 7.3 Hz, 2 H), 2.05 (s, 5 H).
13C NMR (DMSO-d6): d = 171.9, 154.5, 132.7, 124.8, 121.8, 119.3,
54.8, 30.4, 28.7, 14.4.
HRMS: m/z [M + H+] calcd for C10H13N2O2S2: 257.0418; found:
257.0421.
3-[(S)-2,5-Dioxo-1-(2-thienyl)imidazolidin-4-yl]propanoic Acid
(S)-Tetrahydro-2-(2-thienyl)-2H-pyrrolo[1,2-e]imidazole-1,3-
dione (8e)
(8j)
20
Yield: 55%; brown solid; mp 124 °C; [a]D –5.1 (c 0.1, DMSO);
tR = 1.34 min (method A).
Yield: 45%; grey solid; mp 81–84 °C; [a]D20 –8.1 (c 0.1, DMSO);
tR = 1.64 min (method A).
1H NMR (DMSO-d6): d = 12.28 (br s, 1 H), 8.75 (s, 1 H), 7.40 (dd,
J = 3.8, 1.4 Hz, 1 H), 7.36 (dd, J = 5.5, 1.4 Hz, 1 H), 7.01 (dd,
J = 5.5, 3.8 Hz, 1 H), 4.27 (t, J = 6.0 Hz, 1 H), 2.40 (t, J = 7.6 Hz,
2 H), 2.05 (m, 1 H), 1.85 (m, 1 H).
13C NMR (DMSO-d6): d = 173.5, 171.8, 154.4, 132.6, 124.9, 121.8,
119.4, 55.2, 29.1, 26.8.
1H NMR (DMSO-d6–D2O, 9:1): d = 7.34 (dd, J = 5.5, 1.3 Hz, 1 H),
7.25 (dd, J = 3.8, 1.3 Hz, 1 H), 7.01 (dd, J = 5.5, 3.8 Hz, 1 H), 4.32
(dd, J = 9.4, 7.4 Hz, 1 H), 3.50 (m, 1 H), 3.24 (m, 1 H), 2.06 (m,
3 H), 1.85 (m, 1 H).
13C NMR (DMSO-d6): d = 171.8, 157.9, 133.0, 125.3, 122.5, 120.2,
62.9, 45.8, 26.9, 26.9.
HRMS: m/z [M + H+] calcd for C10H11N2O4S: 255.0361; found:
255.0372.
HRMS: m/z [M + H+] calcd for C10H11N2O2S: 223.0541; found:
223.0548.
(S)-5-[(1H-indol-3-yl)methyl]-3-(2-thienyl)imidazolidine-2,4-
(S)-5-Isopropyl-3-(2-thienyl)imidazolidine-2,4-dione (8f)
Yield: 53%; brown solid; mp 93–95 °C; [a]D –62.1 (c 0.1,
DMSO); tR = 1.88 min (method A).
1H NMR (DMSO-d6): d = 8.74 (s, 1 H), 7.40 (d, J = 3.3 Hz, 1 H),
7.37 (d, J = 5.5 Hz, 1 H), 7.02 (dd, J = 5.4, 3.5 Hz, 1 H), 4.17 (d,
J = 2.9 Hz, 1 H), 2.13 (m, 1 H), 1.00 (d, J = 6.9 Hz, 3 H), 0.84 (d,
J = 6.7 Hz, 3 H).
13C NMR (DMSO-d6): d = 171.4, 154.8, 132.5, 124.9, 121.8, 119.3,
61.1, 29.9, 18.4, 15.9.
dione (8k)
20
20
Yield: 63%; yellow solid; mp 66–69 °C; [a]D –66.2 (c 0.2,
DMSO); tR = 2.16 min (method A).
1H NMR (DMSO-d6): d = 10.89 (s, 1 H), 8.67 (s, 1 H), 7.57 (d,
J = 7.8 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.30 (dd, J = 5.5, 1.3 Hz,
1 H), 7.12 (d, J = 2.3 Hz, 1 H), 7.11 (dd, J = 3.8, 1.4 Hz, 1 H), 7.06
(t, J = 7.0 Hz, 1 H), 6.96 (t, J = 7.4 Hz, 1 H), 6.93 (dd, J = 5.5, 3.8
Hz, 1 H), 4.57 (t, J = 4.5 Hz, 1 H), 3.21 (dd, J = 4.6, 2.0 Hz, 2 H).
13C NMR (DMSO-d6): d = 171.9, 154.4, 135.9, 132.5, 127.4, 124.8,
124.2, 121.9, 120.9, 119.4, 118.5, 118.4, 111.3, 107.5, 56.8, 26.8.
HRMS: m/z [M + H+] calcd for C10H13N2O2S: 225.0698; found:
225.0698.
HRMS: m/z [M + H+] calcd for C16H14N3O2S: 312.0807; found:
312.0804.
(S)-5-Benzyl-3-(2-thienyl)imidazolidine-2,4-dione (8g)
Yield: 54%; brown solid; mp 114–115 °C; [a]D –69.1 (c 0.1,
DMSO); tR = 2.17 min (method A).
1H NMR (DMSO-d6): d = 8.71 (s, 1 H), 7.33–7.16 (m, 7 H), 6.96
(dd, J = 5.5, 3.8 Hz, 1 H), 4.58 (t, J = 4.9 Hz, 1 H), 3.06 (d, J = 4.9
Hz, 2 H).
13C NMR (DMSO-d6): d = 171.3, 154.2, 135.0, 129.6, 128.1, 128.0,
126.8, 124.8, 122.1, 119.8, 56.9, 36.6.
20
(7S,7aS)-Tetrahydro-7-hydroxy-2-(2-thienyl)-2H-pyrrolo[1,2-
e]imidazole-1,3-dione (8l)
Yield: 35%; white solid; mp 142–144 °C; [a]D +29.9 (c 0.1,
DMSO); tR = 1.24 min (method A).
1H NMR (DMSO-d6): d = 7.39 (dd, J = 5.5, 1.3 Hz, 1 H), 7.37 (dd,
J = 3.9, 1.3 Hz, 1 H), 7.03 (dd, J = 5.4, 3.9 Hz, 1 H), 5.57 (br s,
1 H), 4.43 (s, 2 H), 3.65 (q, J = 10.1 Hz, 1 H), 3.36 (t, J = 9.8 Hz,
1 H), 2.12 (m, 2 H).
20
HRMS: m/z [M + H+] calcd for C14H13N2O2S: 273.0698; found:
13C NMR (DMSO-d6): d = 168.6, 158.4, 132.5, 124.9, 121.9, 119.4,
273.0700.
69.0, 68.8, 43.4, 35.5.
(S)-5-[(R)-1-Hydroxyethyl]-3-(2-thienyl)imidazolidine-2,4-di-
one (8h)
HRMS: m/z [M + H+] calcd for C10H11N2O3S: 239.0490; found:
239.0477.
Yield: 56%; yellow solid; mp 122 °C; [a]D20 –93.3 (c 0.2, DMSO);
tR = 1.05 min (method A).
Synthesis 2009, No. 3, 389–394 © Thieme Stuttgart · New York

394
Y. Brouillette et al.
PAPER
(9) Elmahdi, O.; Lavergne, J. P.; Viallefont, P.; Akssira, M.;
Sedqui, A. Bull. Soc. Chim. Fr. 1995, 132, 675.
(10) Press, J. B.; Eudy, N. H.; Olagbemiro, T. O. J. Org. Chem.
1981, 46, 3853.
(11) Press, J. B.; Mcnally, J. J.; Keiser, J. A.; Offord, S. J.; Katz,
L. B.; Giardino, E.; Falotico, R.; Tobia, A. J. Eur. J. Med.
Chem. 1989, 24, 627.
(12) Le Foulon, F. X.; Braud, E.; Fabis, F.; Lancelot, J. C.; Rault,
S. J. Comb. Chem. 2005, 7, 253.
2-(4,4-Dimethyl-2,5-dioxoimidazolidin-1-yl)thiophene-3-car-
boxylic Acid (9)
Yield: 10%; beige solid; mp 115–118 °C; tR = 1.27 min (method A).
1H NMR (DMSO-d6): d = 8.61 (s, 1 H), 7.61 (d, J = 5.7 Hz, 1 H),
7.38 (d, J = 5.6 Hz, 1 H), 1.91 (s, 1 H), 1.39 (s, 6 H).
13C NMR (DMSO-d6): d = 176.1, 162.6, 153.4, 130.5, 127.7, 125.4,
125.4, 58.3, 24.4.
HRMS: m/z [M + H+] calcd for C10H11N2O4S: 255.0440; found:
255.0438.
(13) Brouillette, Y.; Lisowski, V.; Martinez, J. J. Org. Chem.
2007, 72, 2662.
(14) Baker, B. R.; Joseph, J. P.; Schaub, R. E.; Mcevoy, F. J.;
Williams, J. H. J. Org. Chem. 1953, 18, 138.
(15) Barker, J. M.; Huddleston, P. R.; Holmes, D. J. Chem. Res.,
Synop. 1986, 155.
Acknowledgment
This work was supported by grants from Société de Chimie Théra-
peutique (SCT) and the Laboratoires Servier. The authors thank Dr
Pascal Verdié and M. Pierre Sanchez for performing mass spectral
analyses. Y.B. thanks the Société de Chimie Thérapeutique and the
Laboratoires Servier for a doctoral scholarship
(16) Barker, J. M.; Huddleston, P. R.; Holmes, D. J. Chem. Res.,
Miniprint 1986, 1462.
(17) Barker, J. M.; Huddleston, P. R.; Holmes, D. J. Chem. Res.,
Synop. 1986, 328.
(18) Barker, J. M.; Huddleston, P. R.; Holmes, D. J. Chem. Res.,
Miniprint 1986, 2828.
(19) Ogawva, K.; Yamawaki, I.; Matsusita, Y. I.; Nomura, N.;
Kador, P. F.; Kinoshita, J. H. Eur. J. Med. Chem. 1993, 28,
769.
References
(1) Gao, W. Q.; Dalton, J. T. Drug Discovery Today 2007, 12,
241.
(20) Fabis, F.; Jolivet-Fouchet, S.; Rault, S. Tetrahedron 1999,
55, 6167.
(2) Lopez, C. A.; Trigo, G. G. Adv. Heterocycl. Chem. 1985, 38,
177.
(21) Jolivet-Fouchet, S.; Fabis, F.; Rault, S. Tetrahedron Lett.
1998, 39, 5369.
(3) Meusel, M.; Gutschow, M. Org. Prep. Proced. Int. 2004, 36,
391.
(22) Gutschow, M.; Kuerschner, L.; Neumann, U.; Pietsch, M.;
Loser, R.; Koglin, N.; Eger, K. J. Med. Chem. 1999, 42,
5437.
(23) Bunnett, J. F.; Naff, M. B. J. Am. Chem. Soc. 1966, 88, 4001.
(24) For example, in the case of the aminoisobutyric acid (AIB)
residue, the non-decarboxylated analogue 9c was isolated in
a large enough amount to allow for characterization by 1H
and 13C NMR spectroscopy. For more experimental data,
refer to the experimental section.
(25) Goossen, L. J.; Rodriguez, N.; Melzer, B.; Linder, C.; Deng,
G. J.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824.
(26) He, M. Q.; Zhang, F. X. J. Org. Chem. 2007, 72, 442.
(27) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
(4) Lamothe, M.; Lannuzel, M.; Perez, M. J. Comb. Chem.
2002, 4, 73.
(5) Hamann, L. G.; Manfredi, M. C.; Sun, C. Q.; Krystek, S. R.;
Huang, Y. T.; Bi, Y. Z.; Augeri, D. J.; Wang, T.; Zou, Y.;
Betebenner, D. A.; Fura, A.; Seethala, R.; Golla, R.; Kuhns,
J. E.; Lupisella, J. A.; Darienzo, C. J.; Custer, L. L.; Price, J.
L.; Johnson, J. M.; Biller, S. A.; Zahler, R.; Ostrowski, J.
Bioorg. Med. Chem. Lett. 2007, 17, 1860.
(6) Omwancha, J.; Brown, T. R. Curr. Opin. Invest. Drugs
2006, 7, 873.
(7) Brouillette, Y.; Lisowski, V.; Guillon, J.; Massip, S.;
Martinez, J. Tetrahedron 2007, 63, 7538.
(8) Coppola, G. M. Synthesis 1980, 505.
Synthesis 2009, No. 3, 389–394 © Thieme Stuttgart · New York