Synthesis and pharmacological evaluation of 4-iminothiazolidinones for inhibition of pi3 kinase

Article abstract of DOI:10.1071/CH12140

The thiazolidinedione, compound 1, has previously shown pan-inhibition of the phosphoinositide 3-kinase (PI3K) class I isoforms. We hypothesized the derivatization of the thiazolidinedione core of compound 1 could introduce isoform selectivity. We report

Full text of DOI:10.1071/CH12140

CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
http://dx.doi.org/10.1071/CH12140
Synthesis and Pharmacological Evaluation
of 4-Iminothiazolidinones for Inhibition
of PI3 Kinase
A
B
A
Jo-Anne Pinson, Oleg Schmidt-Kittler, Mark Frazzetto,
A
A
B
B
Joyce Zheng, Ian G. Jennings, Kenneth W. Kinzler, Bert Vogelstein,
David K. Chalmers, and Philip E. Thompson
A
A C
,
A
Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical
Sciences, Monash Institute of Pharmaceutical Sciences, Monash University
(Parkville Campus), Parkville, Vic. 3052, Australia.
B
The Ludwig Center for Cancer Genetics and Therapeutics, The Howard Hughes
Medical Institute and The Johns Hopkins Kimmel Cancer Center,
Baltimore, MD 21231, USA.
C
Corresponding author. Email: philip.thompson@monash.edu
The thiazolidinedione, compound 1, has previously shown pan-inhibition of the phosphoinositide 3-kinase (PI3K) class I
isoforms. We hypothesized the derivatization of the thiazolidinedione core of compound 1 could introduce isoform
selectivity. We report the synthesis, characterization, and inhibitory activity of a novel series of 4-iminothiazolidin-2-ones
for inhibition of the class I PI3K isoforms. Their synthesis was successfully achieved by multiple pathways described in
this paper. Initial in vitro data of 28 analogues demonstrated poor inhibition of all class I PI3K isoforms. However,
we identified an alternate target, the phosphodiesterases, and present preliminary screening results showing improved
inhibitory activity.
Manuscript received: 7 March 2012.
Manuscript accepted: 18 April 2012.
Published online: 10 July 2012.
selectivity.[6,7] We prepared a series of 5-arylidene-4-
substituted iminothiazolidin-2-ones (Table 1) by multiple
pathways described further. Although each pathway proved
successful, we found that certain pathways produced trace
amounts of a biologically active impurity giving false posi-
tives in screening assays.[8] While the majority of compounds
assayed were inactive against PI3K, inhibitory activity was
observed for an alternate enzyme family, the phosphodies-
terases (PDEs).
Introduction
The thiazolidinediones (TZDs) are one of the most widely
examined compound classes in medicinal chemistry. Several
representatives have been used clinically while analogous
compound families such as the rhodanines (2-thioTZD) and
2-iminothiazolidin-4-ones have been extensively studied in
medicinal chemistry programs. In contrast, there has been
very little research reported of the synthesis or biology of
4-iminothiazolidin-2-ones. Their first reported synthesis was in
the 1960s (Fig. 1, structures I–III).[1–3] The body of published
literature currently is encompassed in just 30 research articles.
These, together with 10 other patents, embody 262 analogues of
this structural class with a further 800 compounds commercially
available. Biological applications for these compounds include
a report by Kim et al. of the modest inhibition of GSK-3b by
compound V,[4] and compound VII was described in a com-
pound library of potential antimalarial leads.[5]
Chemistry
The synthesis of arylidene-4-iminothiazolidin-2-ones was
achieved from commercially available thiazolidinedione 1 by
several possible routes shown in Scheme 1, using thionation,
Knoevenagel condensation, and amine displacement reactions
in any of three sequences.
The thiazolidinedione 2 is a potent inhibitor of phos-
phoinositide 3-kinase (PI3K). Our previously reported eval-
uation of the inhibition of PI3K by thiazolidinedione and
rhodanine derivatives suggested that elaboration through the
4-position might provide for interaction with non-conserved
residues of the binding site and thus induce PI3K isoform
When following the general route of Komaritsa and
Plevichuk,[1,3] (1 - 3 - 6- 7), treatment of thiazolidinedione
1 with phosphorus pentasulfide gave isorhodanine 3 in 56 %
yield after recrystallization from 1,2-dichloroethane.[1,9]
A
single carbonyl peak was observed in the isorhodanine IR
spectrum at 1700 cmꢀ1, consistent with the literature value.[9]
Journal compilation Ó CSIRO 2012
www.publish.csiro.au/journals/ajc

B
J.-A. Pinson et al.
OH
NH
NH
N
N
N
S
NH
NH
NH
S
S
O
S
O
O
O
IV
I
III
II
N
Cl
N
N
NH
O
S
NH
O
NH
N
S
S
O
O
VII
VI
Fig. 1. Literature examples of 4-iminothiazolidin-2-ones.
V
Treatment of isorhodanine 3 with various amines gave the
small component in the mass spectrum (m/z 279.9279, 7 %).
We identified compound 2 as the contaminant in the products 7e
and 7f, by the match of high-performance liquid chromatogra-
corresponding 4-iminothiazolidin-2-ones 6a–6f in good yields
and purity, with products precipitating from the reaction mixture
and then collected by filtration. The products were reacted on
directly without further purification.
Compounds 6a–6f were treated with piperonal under Knoe-
venagel conditions to give the arylidene substituted compounds
7a–7f. The desired products precipitated from the acetic acid
solvent upon cooling to give excellent yields and high purity. In
samples 7e and 7f a trace contaminant was observed at a
retention time of 8.9 min (Fig. 2). Although apparently negligi-
ble, the nature and importance of this contaminant was indeed
significant as discussed later.
An alternate synthesis of 4-iminothiazolidin-2-ones by
pathway 1 - 3 - 4 - 5 - 7 proved most satisfactory.
Condensation of piperonal with isorhodanine 3 to compound 4
(Scheme 1) gave a quantitative yield. The critical synthetic step
proved to be the S-methylation of precursor 4 to give the
intermediate compound 5 in 87 % yield after precipitation from
ethyl acetate. Compound 5 was an excellent substrate for
substitution reactions with amines such as n-pentylamine
affording the crystalline product 7f in 42 % yield. In this case,
no sign of the contaminant described above was observed.
Twenty-two compounds 7e–7z were prepared by the thio-
methyl intermediate 5 in 16–100 % yield as a precipitate from
EtOH, shown in Table 2. Full details of the synthesis of all
analogues are provided in the Supplementary material. We were
also able to utilize a solid phase adaptation of the method to
afford the carboxylic acid derivatives 7aa and 7ab (Scheme 2).
We also commenced the third possible route (1 - 2 - 4)
shown in Scheme 1.[3] It was abandoned due to difficult isolation
of compound 4 from the precursor 2 despite attempts at
purification. However, the investigation of this reaction led us
to identify the contaminant found in 7e and 7f described above,
as compound 2. Moreover, compound 2 was sometimes found as
a by-product of the synthesis of compound 4 from isorhodanine
3. In the worst case, the base peak (electrospray ionization time-
of-flight mass spectrometry, ESI-TOF MS) for the desired
material (m/z 263.9733) was accompanied by another for
compound 4 (m/z 247.9996, 55 %). It should also be noted that
the corresponding thiorhodanine product was also identified as a
1
phy (HPLC) retention, parent MS adduct, and H NMR spec-
trum. The specific alkene d7.72 and aromatic proton d7.17–7.11
NMR signals were shown to match the authentic material
compound 2.
We investigated the purity of the isorhodanine 3 samples,
by IR and NMR spectroscopy, and attribute the contamination
to trace thiazolidinedione 1, either retained in the second crop
from the recrystallization of 3 or obtained upon storage, and
carried through subsequent synthetic steps. The IR and NMR
spectra of the various samples of isorhodanine 3 showed the
apparent heterogeneity from isolation or storage. The pres-
ence of thiazolidinedione in samples was apparent as a
shoulder at 1730 cmꢀ1 in the carbonyl stretching region,
whereas isorhodanine absorbs at 1700 cmꢀ1 [9] The 1H
.
NMR spectrum shows a resonance for the methylene protons
at d4.1 corresponding to the thiazolidinedione as compared to
d4.6 for isorhodanine.
From the perspective of our research this was an important
result as compound 2 is a potent PI3K inhibitor (IC50 v.
PI3Ka ¼ 50 ꢁ 10ꢀ9 M). Compounds 7e and 7f initially showed
significant (IC50 , 5 ꢁ 10ꢀ6 M) inhibitory activity at PI3K iso-
forms due entirely to the residual contaminant 2 in the sample.
We found that the same compounds synthesized by compound 5
as a key intermediate showed no inhibition of PI3K.
Results and Discussion
Of the 28 compounds synthesized, we found only two displayed
modest inhibition of PI3K isoforms. Therefore, modification at
the 4-position of the thiazolidinedione group severely disrupted
enzyme-inhibitor binding. Even the very small N-methyl sub-
stitution effectively abolished the activity of 7x (IC50 . 90 ꢁ
10ꢀ6 M, Table 2). The exceptions were the amino acid
derivatized analogues: 7aa (Gly) and 7ab (L-Trp) amino
acid derivatives. These showed modest inhibition against
certain PI3K isoforms with an IC50 range of 10–20 ꢁ 10ꢀ6 M
(Table 2).

4-Iminothiazolidin-2-ones for PI3K and PDE Inhibition
C
Table 1. (Continued)
Yield [%]
Table 1. Synthesized 4-iminothiazolidin-2-ones
n.d., not determined
Number
R
Mp [8C]
R
N
O
N
7u
35
223–225
NH
S
O
O
7v
41
23
226–228
210
Number
R
Yield [%]
Mp [8C]
OH
7w
7a
7b
-Ph
100
97
268–270
221–223
-PhCH2
7x
7y
-Me
-Et
74
59
285
230
7c
67
213–215
7z
34
228–230
OH
7d
89
268
7aa
7ab
-L-Ala(OH)
-L-Trp(OH)
51
51
233
n.d.
OH
7e
73
269
7f
42
20
262–265
232–235
108–110
O
7 g
7h
N
With the compounds in hand we were able to investigate their
activity at other targets. Previously, Irvine et al. has described
inhibition of PDE4 by arylidene rhodanine derivatives, so a
sample set of 4-iminothiazolidin-2-ones were screened against
both PDE4 and PDE2.[10] We tested compounds 7p, 7x, and 7z.
Compounds 7x and 7z were virtually inactive, while the
compound 7p showed robust inhibition of PDE2 and PDE4 with
IC50 values4.7 ꢁ 10ꢀ6 and5.1 ꢁ 10ꢀ6 M.Thiscompoundshowed
no inhibition of PI3K isoforms. The activity of the analogue
bearing the catechol ether moiety characteristic of PDE inhibi-
tors suggests that the 3,4-dimethoxybenzyliminothiazolidinone
portion is the key pharmacophore for this activity.[10] This is
the first description of PDE inhibition by this compound class.
As a derivation of the privileged thiazolidinedione structure,
these compounds warrant broader investigation as bioactive
ligands.
This work also provides a significant warning to the
screening of compounds en masse without thorough consider-
ation of compound purity. Commercial compound libraries are
typically sold with purities advertised as .90 % by HPLC and
NMR analysis. A library of compounds derived by our first
method could easily fall within such specifications.[8] Gonzalez
and Polli report an impurity of less than 2.5 % is a reasonable
target, provided the impurity is less than 10-fold more potent
than the test compound.[11] Fortunately for this work, the
possible formation and activity of this impurity was recog-
nized, which led to the adoption of a more suitable synthetic
pathway.
N
N
100
7i
7j
L-Trp(OMe)
8
89
N
N
17
169
O
N
7k
7l
16
38
213–215
195–198
O
O
O
OH
7m
7n
7o
100
50
249
94
D-Trp(OH)
NO2
77
248
N
N
H
O
O
7p
87
268
O
7q
7r
57
51
244
O
215–217
The related rhodanine class has been identified as a group of
Pan-Assay Interference compounds (PAINS) and it is within the
realms of possibility that this class might also deliver ‘nuisance’
compounds.[8] Our work does not have the scope to confirm or
deny this possibility, which would require a broad suite of
screening, stability, and/or reactivity assays. However, we can
confirm that active trace impurities, another characteristic of
PAINS, may need to be considered when preparing compounds
of this class. Our description of the outcomes of these syntheses
will hopefully assist in future analyses.
7s
7t
42
56
212–214
H
N
248–251
(Continued)

D
J.-A. Pinson et al.
O
O
(a)
O
O
NH
NH
S
S
O
1
O
2
(b)
(b)
S
S
(a)
O
O
NH
O
NH
S
S
(c)
S
4
3
O
O
O
N
(d)
S
(d) or
(d, e)
R
R
O
N
5
N
(a)
O
O
NH
NH
O
S
S
O
6a–6f
7a–7ab
Scheme 1. Synthesis of 4-iminothiazolidin-2-ones. Reagents and conditions: (a) Piperonal (0.56 equiv), b-alanine
(1 equiv), CH3CO2H, reflux, 3 h, 100 %. (b) 1,4-Dioxane, P2S5 (0.36 equiv), reflux, 2.5 h, 56 %. (c) MeI (5 equiv),
N-methyl-2-pyrrolidinone, N,N-diisopropylethylamine (1.15 equiv), room temp., 2 h, 87 %. (d) NH2R (1–5 equiv),
MeOH or EtOH, reflux, 18 h, 100 %. (e) 1 N NaOH/ethanol (1 : 2, 7.5 mL), reflux, 5 h, 39 %.
the observed inhibition of PDE4 and PDE2 by one representa-
tive compound.
1.00
0.80
0.60
0.40
0.20
0
Experimental
General
All chemical reagents acquired from Sigma–Aldrich, Fluka,
Merck, BDH laboratories, CSL, Ajax Finechem, Merck Schu-
hardt, ChemSupply, Auspep, Prolabo, Lancaster, TCI, Matrix
Scientific, Boron Molecular, Alfa Aesar, Chem-Impex, and
May and Baker were used without further purification. 1H NMR
spectra were recorded with either a 300 MHz Varian widebore
NMR spectrometer or a 400 MHz Bruker Ultrashield-Avance
III NMR spectrometer. 13C NMR spectra were recorded with
either a 600 MHz Varian Oxford AS600-Unity Inova NMR
spectrometer or a 300 MHz Varian Widebore NMR spectro-
meter. Results were recorded as follows: chemical shift
values are expressed in d units acquired in either CDCl3
(7.26 ppm), (CD3)2SO (2.50 ppm) or CD3OD (3.31 ppm) as
references, multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼
quartet, m ¼ multiplet), integration and coupling constants (J)
are reported in Hertz. Infrared spectra were recorded on a
Scimitar Series Varian 800 FT-IR Spectrometer fitted with a
PIKE Technologies MIRacle ATR and running Varian’s
Resolutions software package version 4.0. Mass spectra were
acquired in the positive and negative mode using an atmospheric
pressure (ESI/atmospheric pressure chemical ionization, APCI)
ion source on a Micromass Platform II ESI/APCI single quad-
rupole mass spectrometer with sample management facilitated
by an Agilent 1100 series HPLC system using MassLynx version
3.5 software. High resolution MS analyses were collected on a
Waters Micromass LCT Premier XE Orthogonal Acceleration
Time-of -Flight Mass Spectrometer coupled to an Alliance 2795
Separation Module using MassLynx version 4.1 software.
Analytical reverse phase (RP)-HPLC was obtained on a Waters
8.00
10.00
12.00
14.00
16.00
Minutes
Fig. 2. Analytical high-performance liquid chromatography trace at
254 nm of compound 7f showing the impurity with retention time of
8.90 min.
Conclusion
In conclusion, we have established an expedient route to the
synthesis of 4-iminothiazolidin-2-ones with potential for
activity against a wide range of biological targets. While the
4-iminothiazolidin-2-ones were relatively poor inhibitors of the
class I PI3K isoforms, the class is worthy of evaluation against
the many other targets of thiazolidinediones, as exemplified by

4-Iminothiazolidin-2-ones for PI3K and PDE Inhibition
E
Table 2. Phosphoinositide 3-kinase (PI3K) and phosphodiesterase (PDE) inhibition by selected 4-iminothiazolidin-2-ones
n.d., not determined; IC50, half maximum inhibitory concentration
Compound
IC50 ꢁ 10ꢀ6 [M]
PI3Ka inhibition
PI3Kb inhibition
PI3Kg inhibition
PI3Kd inhibition
PDE2 inhibition
PDE4 inhibition
2
0.05
0.45
0.056
.100
90
0.6
0.15
.1
0.04
0.12
0.06
.100
.100
.100
14.5
11
n.d.
0.76
0.038
.100
.100
.100
62
n.d.
n.d.
n.d.
4.7
n.d.
n.d.
n.d.
5.1
4
5
7p
7x
7z
7aa
7ab
.100
.100
.100
94
.10
.10
n.d.
n.d.
.10
.10
n.d.
n.d.
.100
19
26
80
43
R
R
N
S
N
O
OH
WANG
O
O
O
O
(a)
O
(b)
N
O
O
O
NH
NH
S
S
S
O
O
O
5
7aa, 7ab
Scheme 2. Synthesis of 4-iminothiazolidin-2-one amino acids from Wang resin. Reagents and conditions: (a) DMF, piperidine
(20 %), Fmoc-R1-Wang resin. (ii) H2N-R1-Wang, DMF, 808C, overnight. (b) TFA (95 %), H2O (5 %), 51 %.
Millenium 2690 system, with UV detection at 254 nm, with
gradient elution through a Supelco C8 column (150 ꢁ 2.1 mm
ID) 80–20 % Buffer B (Buffer A: H2O, 0.1 % TFA; Buffer B:
80 % CH3CN, 0.1 % TFA, 19.9 % H2O or Buffer B: 80 %
product collected by filtration, washed with MeOH, then dried
to yield the product 6a. If solid not isolated, then product was
reacted on as an oil in crude form. The following substituted
4-iminothiazolidin-2-ones 6a–6d were prepared in this manner.
CH3OH, 0.1 % TFA, 19.9 % H2O) over 10 min at 1.0 mL minꢀ1
.
Preparative RP-HPLC was obtained on a Waters 600 HPLC
system, with UV detection at 254 nm with gradient elution
through a Phenomonex Luna C8 column (250 ꢁ 20 mm ID),
20–90 % Buffer B (Buffer A: H2O, 0.1 % TFA; Buffer B: 80 %
4-(Phenylimino)thiazolidin-2-one 6a
Off-white crystals (0.075 g, 51.9 %), mp 208–2118C (lit 221–
2228C).[1] dH (300.13 MHz, DMSO) 10.95 (br s, 1H, NH), 7.73
(d, J 8.3, 2H, ArH), 7.40 (t, J 7.5, 2H, ArH), 7.17 (t, J 7.4, 1H,
ArH), 4.52 (s, 2H, CH2). m/z (ESI, 20 V) 193.0 (100 %, Mþꢂ).
CH3CN, 0.1 % TFA, 19.9 % H2O) over 15 min at 10 mL minꢀ1
.
Melting point determination was performed uncorrected using a
Mettler Toledo MP50 melting point apparatus.
(Z)-4-(Benzylimino)thiazolidin-2-one 6b
White crystals (0.036 g, 33.2 %). dH (300.13 MHz,
DMSO) 9.47 (br s, 1H, NH), 7.35 (m, 5H, ArH), 4.55 (d,
J 7.9, 2H, SCH2), 4.27 (s, 2H, ArCH2). m/z (ESI, 20 V) 207.1
(100 %, Mþꢂ).
General Procedure for the Preparation
of 4-Thioxothiazolidin-2-one (Isorhodanine)
To a mixture of P2S5 (1.4 g, 6.1 mmol, 1 equiv) in dry 1,4-
dioxane (10.0 mL) was added thiazolidinedione (2.0 g,
2.8 equiv), and the mixture heated to reflux for 3.5 h. The
mixture was cooled, the product collected by filtration, and
solvent removed under reduced pressure. The crude product was
crystallized from dichloroethane to yield the title compound as a
brown powder. The following compound 3 was prepared in this
manner.
(Z)-4-(sec-Butylimino)thiazolidin-2-one 6c
Yellow oil (0.088 g, 97.8 %), dH (300.13 MHz, CDCl3) 5.73
(br s, 1H, NH), 4.20 (m, 3H, NCH, SCH2), 1.65 (m, 2H,
CH2CH3), 1.27 (d, J 6.6, 3H, CHCH3), 0.97 (m, 3H, CH2CH3).
m/z (ESI, 20 V) 173.1 (100 %, Mþꢂ).
(Z)-4-(Bicyclo[2.2.1]heptan-7-ylimino)thiazolidin-
2-one 6d
4-Thioxothiazolidin-2-one 3
Light brown powder (1.5 g, 67.9 %), mp 151–1558C, also
160–58C; (lit. 145–508C, 158–1628C).[1,9] dH (300.13 MHz,
DMSO) 4.61 (s, 2H, CH2), m/z (ESI) 132.0 [M ꢀ H]ꢀ.
Orange crystals (0.045 g, 50.0 %), HPLC: purity .85 %,
6.28 min.
n
max/cmꢀ1 3347.3, 3112.7, 2950.2, 2910.7, 1701.0, 1464.9,
General Procedure for the Preparation of Benzodioxol
Thiazolidinediones and 4-Amino Substituted Benzodioxol
Thiazolidinediones (Knoevenagel Condensation)
1383.8, 1170.1, 1119.1, 1008.4, 786.0, 749.6, 705.4, 561.9.
General Procedure for the Preparation of Monosubstituted
4-Iminothiazolidin-2-ones
A mixture of piperonal (0.72 g, 4.79 mmol, 1 equiv), b-alanine
(0.76 g, 1.8–2 equiv), and isorhodanine 3 (1.14 g, 1.8–2 equiv) in
glacial acetic acid (20.0 mL) was heated to 1008C for 2–3 h. The
reaction mixture was cooled, the product was collected by
filtration, washed with acetic acid, and then water to yield the
To a solution of isorhodanine 3 (0.10 g, 0.75 mmol, 1 equiv) in
MeOH (1.0 mL) was added aniline (0.070 g, 1 equiv), and the
mixture was refluxed for 1.5 h. The mixture was cooled, the

F
J.-A. Pinson et al.
title compound as a yellow crystalline solid, unless otherwise
indicated. The following benzodioxol thiazolidinedione 2,
isorhodanine 4, and 4-amino substituted benzodioxol thiazoli-
dinediones 7a–7d were prepared in this manner.
(3 mL) was reacted with piperonal (0.018 g, 0.12 mmol) and
after filtering afforded brown crystals (0.055 g, 88.9 %). Mp
2688C (decomp.). dH (300.13 MHz, DMSO) 8.71 (d, J 5.3, 1H,
NH), 7.87 (s, 1H, CH), 7.07 (d, J 11.7, 3H, ArH), 6.12 (s, 2H,
CH2), 3.83 (s, 1H, NCH), 2.33 (s, 2H, CH2), 1.74 (m, 1H, CH),
1.63 (m, 2H, CH2), 1.49 (t, J 10.1, 2H, CH2), 1.20 (d, J 9.9, 3H,
CH, CH2). m/z (HR-ESI) Calc. for C18H18N2O3S, [M þ H]þ:
343.1111. Found 343.1122. HPLC purity 95 %, 11.41 min.
(Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)
thiazolidine-2,4-dione 2
Yellow powder (0.43 g, 99 %), mp 246–2498C (lit. 247–
2498C).[12] dH (300.13 MHz, DMSO) 12.5 (br s, 1H, NH), 7.71
(s, 1H, CH), 7.14 (m, 3H, ArH), 6.13 (s, 2H, CH2). m/z (ESI
20 V) 248.1 (100 %, Mꢀꢂ). HPLC purity .95 %.
General Procedure for the Preparation of (Z)-5-
(Benzo[d][1,3]dioxol-5-ylmethylene)-4-(methylthio)
thiazol-2(5H)-one 5
(Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-thioxothiazolidin-2-one 4
To a solution of 5-benzo[1,3]dioxol-5-ylmethylene-4-thioxo-
thiazolidin-2-one 4 (0.50 g, 1.9 mmol, 1 equiv) and N,N-
diisopropylethylamine (DIPEA, 0.27 g, 1.1 equiv) in N-methyl
2-pyrrolidinone (NMP, 20 mL) was added methyl iodide
(1.27 g, 5 equiv) in N-methyl 2-pyrrolidinone (2.5 mL). The
reaction mixture was stirred for 2 h at room temperature, diluted
with ethyl acetate (45 mL), washed with brine, and then water.
Solvent was removed to 50 % volume, resulting in the product 5
collected by filtration as a yellow solid. The following thio-
methyl benzodioxol 5 was prepared in this manner.
Red crystals (1.09 g, 100 %), Mp 2648C (dec.). dH
(300.13 MHz, DMSO) 13.9 (br s, 1H, NH), 8.04 (s, 1H, CH),
7.27 (d, J 8.1, 1H, ArH), 7.21 (s, 1H, ArH), 7.10 (d, J 8.2, 1H,
ArH), 6.15 (s, 2H, CH2). dC (75.5 MHz, DMSO) 195.14, 170.63,
150.02, 148.45, 136.43, 127.74, 127.63, 127.31, 109.46, 109.46,
102.33. m/z (ESI 20V) 264.1 (100 %, Mꢀꢂ). HPLC: purity
.99 %, 10.36 min.
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-(phenylimino)thiazolidin-2-one 7a
(Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-(methylthio)thiazol-2(5H)-one 5
A solution of (Z)-4-(phenylimino)thiazolidin-2-one 6a
(0.050 g, 0.26 mmol) in acetic acid (1 mL) was reacted with
piperonal (0.021 g, 0.13 mmol) and after filtering afforded a
yellow powder (0.057 g, 100 %). Mp 268–2708C. dH
(300.13 MHz, DMSO) 10.67 (br s, 1H, NH), 8.05 (s, 1H, CH),
7.76 (d, J 8.1, 2H, ArH), 7.44 (t, J 7.9, 2H, ArH), 7.15 (m, 4H,
ArH), 6.12 (s, 2H, CH2). m/z (ESI, 20V) 325.1 (100 %, Mþꢂ).
m/z (HR-ESI) Calc. for C17H12N2O3S, [M þ H]þ: 325.0647.
Found 325.0640. HPLC purity 90 %, 8.20 min.
Yellow powder, (0.49 g, 86.5 %). dH (300.13 MHz, DMSO)
7.81 (s, 1H, CH), 7.35 (dd, J 8.3, 1.6, 1H, ArH), 7.28 (d, J 1.6,
1H, ArH), 7.13 (d, J 8.2, 1H, ArH), 6.16 (s, 2H, CH2), 2.76
(s, 3H, SCH3). m/z (ESI 20 V) 280.2 (100 %, Mþꢂ). HPLC:
purity .98 %, 11.05 min.
General Procedure for the Preparation of 4-Substituted
Iminothiazolidin-2-ones
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-(benzylimino)thiazolidin-2-one 7b
To
a
solution of 5-benzo[1,3]dioxol-5-ylmethylene-4-
methylsulfanyl-thiazol-2-one 5 (0.030 g, 0.11 mmol, 1 equiv)
was added an amine such as cyclopentylamine (0. 079 g,
5 equiv) in EtOH (4.0–9.0 mL) and the mixture refluxed at 858C
for 19–64 h. After cooling, the organic layer was reduced to
50 %, the product was collected by filtration and washed with
chilled ethanol to yield the title compound as a yellow solid,
unless otherwise indicated. The following 4-substituted
iminothiazolidin-2-ones 7e–z were prepared in this manner.
A solution of (Z)-4-(benzylimino)thiazolidin-2-one 6b
(0.030 g, 0.15 mmol) in acetic acid (1 mL) was reacted with
piperonal (0.013 g, 0.09 mmol) and after filtering afforded green
crystals (0.029 g, 96.8 %). Mp 221–2238C. dH (300.13 MHz,
DMSO) 9.75 (br s, 1H, NH), 7.81 (s, 1H, CH), 7.37 (d, J 8.1, 3H,
ArH), 7.33 (s, 1H, ArH), 7.31 (dt, J 9.0, 4.5, 1H, ArH), 7.08
(s, 1H, ArH), 7.06 (d, J 11.0, 2H), 6.12 (s, 2H, CH2), 4.31 (t,
J 5.1, 2H, NCH2); m/z (ESI, 20V) 339.3 (100 %, Mþꢂ). HPLC
purity .94 %.
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-4-
((4-hydroxyphenethyl)imino)thiazolidin-2-one 7e
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-(sec-butylimino)thiazolidin-2-one 7c
Yellow powder (0.048 g, 72.5 %). Mp 2698C (decomp). dH
(300.13 MHz, DMSO) 9.35 (br s, 1H, NH), 9.19 (s, 1H, OH),
7.71 (s, 1H, CH), 7.06 (dd, J 8.1, 5.4, 5H, ArH), 6.70 (d, J 8.3,
2H, ArH), 6.12 (s, 2H, CH2), 3.64 (t, J 7.5, 2H, NCH2), 2.83 (t,
J 7.5, 2H, ArCH2). m/z (ESI, 20 V) 369.3 (100 %, Mþꢂ). m/z
(HR-ESI) Calc. for C19H16N2O4S, [M ꢀ H]ꢀ: 367.0758. Found
367.0737. HPLC purity .95 %, 9.51 min.
A solution of (Z)-4-(sec-butylimino)thiazolidin-2-one 6c
(0.080 g, 0.46 mmol) in acetic acid (1.5 mL) was reacted with
piperonal (0.040 g, 0.27 mmol) and after filtering afforded
yellow crystals (0.054 g, 66.9 %). Mp 213–2158C. dH
(300.13 MHz, DMSO) 8.93 (br s, 1H, NH), 7.80 (s, 1H, CH),
7.07 (d, J 9.9, 3H, ArH), 6.12 (s, 2H, CH2), 4.32 (m, 1H, NCH),
1.62 (m, 2H, CH2), 1.23 (d, J 6.6, 3H, CHCH3), 0.90 (t, J 7.4, 3H,
CH2CH3). m/z (ESI, 20 V) 305.1 (100 %, Mþꢂ). m/z (HR-ESI)
Calc. for C15H16N2O3S, [M þ H]þ 305.0960. Found 305.0955.
HPLC purity .96 %.
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-(cyclopentylimino)thiazolidin-2-one 7f
Yellow crystals (0.010 g, 41.9 %). Mp 262–2658C. dH
(300.13 MHz, DMSO) 9.00 (br s, 1H, NH), 7.80 (s, 1H, CH),
7.06 (d, J 10.8, 3H, ArH), 6.11 (s, 2H, CH2), 4.32 (s, 1H, NCH),
1.98 (m, 2H, CH2), 1.67 (m, 6H, CH2). dC (75.5 MHz, DMSO)
176.64, 172.37, 148.63, 148.06, 128.43, 127.40, 126.42, 125.39,
109.05, 108.25, 101.85, 56.37, 31.74, 23.68. m/z (ESI, 20 V)
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-4-
(bicyclo[2.2.1]heptan-7-ylimino)thiazolidin-2-one 7d
A solution of (Z)-4-(bicyclo[2.2.1]heptan-7-ylimino)
thiazolidin-2-one 6d (0.045 g, 0.21 mmol) in acetic acid

4-Iminothiazolidin-2-ones for PI3K and PDE Inhibition
G
317.1 (100 %, Mþꢂ). m/z (HR-ESI) Calc. for C16H16N2O3S,
[M þ H]þ: 317.0954. Found 317.0966. HPLC purity .99 %,
10.60 min.
4-(((Z)-((Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
2-oxothiazolidin-4-ylidene)amino)methyl)
cyclohexanecarboxylic acid 7m
Yellow crystals (0.082 g, 100 %). Mp 2498C (decomp.). dH
(300.13 MHz, DMSO) 9.28 (br s, 1H, NH), 7.77 (s, 1H, CH),
7.07 (d, J 10.4, 3H, ArH), 6.13 (s, 2H, CH2), 4.32 (s, 1H, COCH),
3.45 (dd, J 6.9, 2.3, 2H NCH2), 2.15 (t, J 11.7, 1H, CHCH2), 1.86
(dd, J 36.8, 13.5, 4H, CH2), 1.66 (s, 1H, CH2), 1.30 (dd, J 24.9,
10.6, 2H, CH2), 1.02 (m, 1H, CH2). dC (75.5 MHz, DMSO)
190.51, 176.60, 173.26, 149.61, 149.10, 128.36, 127.16, 126.32,
125.46, 109.06, 108.24, 101.85, 50.52, 42.31, 36.33, 29.37,
28.16. m/z (HR-ESI) Calc. for C19H20N2O5S, [M þ H]þ:
389.1166. Found 389.1181. HPLC purity 95 %, 9.04 min.
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-4-
((3-morpholinopropyl)imino)thiazolidin-2-one 7g
Yellow powder (0.011 g, 20.3 %). Mp 232–2358C. dH
(300.13 MHz, DMSO) 8.21 (s, 1H, NH), 7.71 (s, 1H, CH),
7.06 (s, 1H, ArH), 7.04 (d, J 13.2, 2H, ArH), 6.13 (s, 2H,
CH2), 3.53 (s, 4H, OCH2), 2.31 (s, 4H, CH2), 1.76 (m, 2H, CH2).
m/z (HR-ESI) Calc. for C18H21N3O4S, [M þ H]þ: 376.1331.
Found 376.1329. HPLC purity .95 %, 8.80 min.
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-4-
((4-methylpiperazin-1-yl)imino)thiazolidin-2-one 7h
(R)-Methyl 2-((Z)-((Z)-5-(Benzo[d][1,3]dioxol-5-
ylmethylene)-2-oxothiazolidin-4-ylidene)amino)-
3-(1H-indol-2-yl)propanoate 7n
Yellow powder (0.060 g, 100 %). Mp 108–1108C. dH
(300.13 MHz, DMSO) 7.56 (s, 1H, CH), 7.03 (m, 3H, ArH),
6.09 (s, 2H, CH2), 3.03 (t, J 6.3, 2H, CH2), 2.97 (t, J 3.6, 6H,
CH2), 2.22 (s, 3H, NCH3). m/z (ESI, 20 V) 347.1 (100 %, Mþꢂ).
HPLC purity .94 %, 6.58 min.
Brown solid (0.040 g, 49.8 %). Mp 948C (decomp.). m/z (ESI,
20 V) 357.0 (100 %, Mþꢂ). HPLC purity 95 %, 10.58 min.
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-((2-((6-nitropyridin-3-yl)amino)ethyl)imino)
thiazolidin-2-one 7o
(S)-Methyl 2-((Z)-((Z)-5-(Benzo[d][1,3]dioxol-5-
ylmethylene)-2-oxothiazolidin-4-ylidene)amino)-
3-(1H-indol-2-yl)propanoate 7i
Yellow powder (0.057 g, 76.9 %). Mp 2488C (decomp.). dH
(300.13 MHz, DMSO) 9.40 (br s, 1H, NH), 8.92 (d, J 2.7, 1H,
ArH), 8.30 (s, 1H, ArH), 8.13 (d, J 9.7, 1H, ArH), 7.69 (s, 1H,
CH), 7.06 (m, 3H, ArH), 6.59 (d, J 9.4, 1H, ArH), 6.13 (s, 2H,
CH2), 3.69 (s, 4H, NCH2). m/z (HR-ESI) Calc. for
C18H15N5O5S, [M þ H]þ: 414.0867. Found 414.0887. HPLC
purity 90 %, 9.64 min.
Yellow powder (0.005 g, 7.8 %). Mp 898C (decomp). m/z
M
þꢂ). HPLC purity .99%,
(ESI, 20 V) 450.0 (100 %,
10.79 min.
(4Z,5Z)-4-((3-(1H-Imidazol-1-yl)propyl)imino)-5-(benzo
[d][1,3]dioxol-5-ylmethylene)thiazolidin-2-one 7j
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-((3,4-dimethoxybenzyl)imino)thiazolidin-2-one 7p
Yellow crystals (0.011 g, 16.6 %). Mp 1698C (decomp.). dH
(300.13 MHz, DMSO) 7.69 (d, J 8.3, 1H, ArH), 7.60 (s, 1H,
CH), 7.12 (m, 4H, ArH), 6.88 (d, J 8.8, 1H, ArH), 6.09 (s, 2H,
CH2), 4.02 (m, 2H, NCH2), 2.08 (m, 2H, NCH2), 1.76 (m, 2H,
CH2). m/z (ESI, 20 V) 357.0 (100 %, Mþꢂ). m/z (HR-ESI) Calc.
for C17H16N4O3S, [M þ H]þ: 357.1016. Found 357.1025.
HPLC purity .90 %, 6.30 min.
Yellow powder (0.062 g, 86.9 %). Mp 2688C (decomp.). dH
(300.13 MHz, DMSO) 9.64 (br s, 1H, NH), 7.80 (s, 1H, CH),
7.07 (s, 2H, ArH), 7.03 (d, J 8.6, 2H, ArH), 6.93 (m, 2H, ArH),
6.11 (s, 2H, CH2), 4.63 (s, 2H, CH2), 3.76 (s, 3H, CH3), 3.74
(s, 3H, CH3). m/z (HR-ESI) Calc. for C20H18N2O5S, [M ꢀ H]ꢀ:
397.0864. Found 397.0873. HPLC purity 90 %, 9.75 min.
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-4-
((2-morpholinoethyl)imino)thiazolidin-2-one 7k
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-4-
((4-methoxyphenethyl)imino)thiazolidin-2-one 7q
Yellow crystals (0.011 g, 16.2 %). Mp 213–2158C. dH
(300.13 MHz, DMSO) 7.71 (s, 1H, CH), 7.06 (d, J 11.8, 3H,
ArH), 6.12 (s, 2H, CH2), 3.58 (m, 4H, OCH2), 2.57 (dt, J 18.5,
6.6, 2H, NCH2), 2.42 (t, J 4.5, 4H, NCH2), 2.30 (m, 2H, NCH2).
dC (75.5 MHz, DMSO) 176.80, 173.22, 148.84, 148.22, 128.35,
127.37, 126.37, 125.68, 109.24, 108.34, 102.03, 66.22, 56.48,
55.33, 41.67. m/z (HR-ESI) Calc. for C17H19N3O4S, [M þ H]þ:
362.1169. Found 362.1183. HPLC purity .90 %, 6.23 min.
Yellow powder (0.039 g, 57.4 %). Mp 2448C (decomp.). dH
(300.13 MHz, DMSO) 9.30 (br s, 1H, NH), 7.71 (s, 1H, CH),
7.17 (d, J 8.6, 2H, ArH), 7.05 (m, 3H, ArH), 6.87 (d, J 8.6, 2H,
ArH), 6.12 (s, 2H, CH2), 3.72 (s, 3H, CH3), 3.66 (t, J 7.5, 2H,
NCH2), 2.88 (t, J 7.4, 2H, CH2). m/z (HR-ESI) Calc. for
C20H18N2O4S, [M þ H]þ: 383.1060. Found 383.1050. HPLC
purity .99 %, 10.60 min.
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-((furan-2-ylmethyl)imino)thiazolidin-2-one 7r
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-4-
(((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)imino)
thiazolidin-2-one 7l
Yellow powder (0.030 g, 51.0 %). Mp 215–2178C. dH
(300.13 MHz, DMSO) 9.68 (br s, 1H, NH), 7.81 (s, 1H, CH),
7.66 (s, 1H, ArH), 7.06 (d, J 13.4, 3H, ArH), 6.45 (dd, J 5.3, 3.7,
2H, ArH), 6.13 (s, 2H, CH2), 4.72 (s, 2H, NCH2). m/z (HR-ESI)
Calc. for C16H12N2O4S, [M þ H]þ: 329.0591. Found 329.0606.
HPLC purity .99 %, 9.80 min.
Yellow crystals (0.025 g, 38.1 %). Mp 195–1988C. dH
(300.13 MHz, DMSO) 7.80 (s, 1H, CH), 7.07 (d, J 11.8, 3H,
ArH), 6.12 (s, 2H, CH2), 4.33 (t, J 5.7, 1H, OCH), 4.04 (t, J 8.4,
1H, OCH), 3.75 (t, J 8.4, 1H, OCH), 3.65 (t, J 5.1, 2H, NCH2),
1.37 (s, 3H, CH3), 1.26 (s, 3H, CH3). dC (75.5 MHz, DMSO)
176.86, 173.60, 148.89, 148.21, 128.29, 127.82, 126.04, 125.74,
109.22, 108.87, 108.33, 102.02, 73.35, 66.56, 47.32, 26.86,
25.36. m/z (HR-ESI) Calc. for C17H18N2O5S, [M þ H]þ:
363.1009. Found 363.1021. HPLC purity .95 %, 9.47 min.
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-(cyclohexylimino)thiazolidin-2-one 7s
Yellow crystals (0.025 g, 41.6 %). Mp 212–2148C. dH
(300.13 MHz, DMSO) 8.96 (br s, 1H, NH), 7.80 (s, 1H, CH),

H
J.-A. Pinson et al.
7.09 (d, J 10.6, 2H, ArH), 7.05 (s, 1H, ArH), 6.13 (s, 2H, CH2),
3.89 (s, 1H, NCH), 1.87 (dd, J 51.5, 10.7, 2H, CH2), 1.71 (dd,
J 40.8, 12.2, 2H, CH2), 1.36 (m, 4H, CH2), 1.18 (m, 2H, CH2).
m/z (HR-ESI) Calc. for C17H18N2O3S, [M þ H]þ: 331.1111.
Found 331.1095. HPLC purity .99 %, 10.37 min.
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-((2-hydroxypropyl)imino)thiazolidin-2-one 7z
Yellow crystals (0.020 g, 33.8 %). Mp 228–2308C
(decomp.). dH (300.13 MHz, DMSO) 9.35 (br s, 1H, NH), 7.82
(d, J 4.8, 1H, CH), 7.06 (dd, J 13.8, 4.4, 3H, ArH), 6.13 (d, J 4.4,
2H, CH2), 4.97 (s, 1H, OH), 3.91 (s, 1H, NCH), 3.42 (m, 2H,
NCH2), 1.10 (t, J 5.2, 3H, CHCH3). m/z (ESI) 307.3 [M þ H]þ.
m/z (HR-ESI) Calc. for C14H14N2O4S, [M þ H]þ: 307.0747.
Found 307.0750. HPLC purity .99 %, 7.80 min.
(4Z,5Z)-4-((2-(1H-Indol-3-yl)ethyl)imino)-5-(benzo[d]
[1,3]dioxol-5-ylmethylene)thiazolidin-2-one 7t
Yellow powder (0.039 g, 56.0 %). Mp 248–2518C. dH
(300.13 MHz, DMSO) 10.85 (br s, 1H, NH), 10.75 (s, 1H,
NH), 7.71 (s, 1H, CH), 7.59 (d, J 7.4, 1H, ArH), 7.51 (d, J 7.9,
1H, ArH), 7.34 (t, J 8.2, 1H, ArH), 7.21 (s, 1H, ArH), 7.05 (dq,
J 14.8, 7.4, 5H, ArH), 6.13 (s, 2H, CH2), 3.77 (t, J 7.4, 2H,
NCH2), 3.07 (t, J 7.4, 2H, CH2). m/z (HR-ESI) Calc. for
C21H17N3O3S, [M ꢀ H]ꢀ: 390.0918. Found 390.0937. HPLC
purity .99 %, 10.00 min.
General Procedure for the Preparation 4-Amino Acid
Substituted Benzodioxol Thiazolidin-2-ones
Fmoc-L-Ala-Wang resin (0.13 mg: loading 0.83 mmol gꢀ1) was
suspended in DMF (2.0 mL) for 10 min, and then excess solvent
was removed by filtration. The resin was treated with 20 %
piperidine (2.0 mL) for 5 min. Excess reagent was removed by
filtration. This process was repeated, and then L-Ala depro-
tected beads were thoroughly washed with DMF. Qualitative
deprotection was confirmed using the ninhydrin test. L-Ala
deprotected beads were taken up in DMF (5.0 mL), added to
5-benzo[1,3]dioxol-5-ylmethylene-4-methylsulfanyl-thiazol-2-
one 5 (0.060 g, 0.20 mmol), and the mixture heated to 808C for
19–23 h. The reaction mixture was cooled, the resin isolated by
filtration, washed thoroughly with DMF, MeOH, and ether and
then dried. The final product was cleaved from the resin in 95 %
TFA, 5 % H2O (3.0 mL) over 1.5 h, filtered, then the supernatant
diluted with acetonitrile/H2O (50 : 50, 50 mL), and placed on a
freezedrier overnight. Crystallization from ethanol afforded the
title compound as a brown powder unless otherwise stated. The
following 4-amino acid substituted benzodioxol thiazolidin-
2-ones 7aa–7ab were prepared in this manner.
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-((pyridin-2-ylmethyl)imino)thiazolidin-2-one 7u
Yellow crystals (0.021 g, 34.8 %). Mp 223–2258C. dH
(300.13 MHz, DMSO) 9.86 (br s, 1H, NH), 8.56 (d, J 4.4, 1H,
ArH), 7.88 (s, 1H, CH), 7.81 (td, J 7.7, 1.7, 1H, ArH), 7.41 (d,
J 7.7, 1H, ArH), 7.33 (m, 1H, ArH), 7.08 (d, J 11.5, 2H, ArH),
6.14 (s, 2H, CH2), 4.81 (s, 2H, NCH2). m/z (HR-ESI) Calc. for
C17H13N3O3S, [M þ H]þ: 340.0750. Found 340.0736. HPLC
purity .95 %, 6.45 min.
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-(phenethylimino)thiazolidin-2-one 7v
Yellow powder (0.026 g, 40.6 %). Mp 226–2288C. dH
(300.13 MHz, DMSO) 7.72 (s, 1H, CH), 7.25 (m, 5H, ArH),
7.06 (d, J 13.6, 3H, ArH), 6.13 (s, 2H, CH2), 3.72 (t, J 7.5, 2H,
NCH2), 2.96 (t, J 7.5, 2H, CH2). m/z (HR-ESI) Calc. for
C19H16N2O3S, [M þ H]þ: 353.0954. Found 353.0967. HPLC
purity .99 %, 11.12 min.
(S)-2-((Z)-((Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-2-
oxothiazolidin-4-ylidene)amino)propanoic Acid 7aa
A solution of (Z)-5-(benzo[d][1,3]dioxol-5-ylmethylene)-4-
(methylthio)thiazol-2(5H)-one (5) (0.060 g) in DMF reacted
with Wang-L-Ala-Fmoc (130 mg: loading 0.83 mmol gꢀ1) and
after workup afforded a brown powder (0.018 g, 51.0 %), mp
2338C (decomp.). m/z (ESI, 20 V) 321.3 (100 %, Mþꢂ). m/z
(HR-ESI) Calc. for C14H12N2O5S, [M þ H]þ: 321.0540. Found
321.0533. HPLC: purity .95 %, 8.20 min.
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-((3-hydroxypropyl)imino)thiazolidin-2-one 7w
Yellow crystals (0.010 g, 22.8 %). Mp 2108C (decomp.). dH
(300.13 MHz, DMSO) 9.30 (br s, 1H, NH), 7.74 (s, 1H, CH),
7.06 (m, 3H, ArH), 6.12 (s, 2H, CH2), 4.57 (s, 1H, OH), 3.51 (m,
4H, CH2), 1.77 (m, 2H, CH2CH2). m/z (ESI, 20V) 307.6 (40 %,
Mþꢂ). m/z (HR-ESI) Calc. for C14H14N2O4S, [M þ H]þ:
307.0747. Found 307.0755. HPLC purity .95 %, 7.65 min.
(S)-2-((Z)-((Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
2-oxothiazolidin-4-ylidene)amino)-3-(1H-indol-2-yl)
propanoic Acid 7ab
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-(methylimino)thiazolidin-2-one 7x
A solution of (Z)-5-(benzo[d][1,3]dioxol-5-ylmethylene)-4-
(methylthio)thiazol-2(5H)-one (5) (0.050 g) in DMF reacted
with Wang-L-Trp(tBu)-Fmoc (180 mg: loading 0.61 mmol gꢀ1
)
Yellow powder (0.042 g, 74.1 %). Mp 2858C (decomp.). dH
(300.13 MHz, DMSO) 9.35 (br s, 1H, NH), 7.68 (s, 1H, CH),
7.05 (m, 3H, ArH), 6.12 (s, 2H, CH2), 3.03 (d, J 4.4, 3H, NCH3).
m/z (ESI, 20 V) 263.3 (100 %, Mþꢂ). m/z (HR-ESI) Calc. for
C12H10N2O3S, [M ꢀ H]ꢀ: 261.0339. Found 261.0346. HPLC
purity .99 %, 8.25 min.
and after workup afforded a brown powder (0.025 g, 51.0 %).
m/z (HR-ESI) Calc. for C22H17N3O5S, [M þ H]þ: 436.0967.
Found 436.0962. HPLC: purity .98%, 9.80 min.
Acknowledgements
J-A.P. is a recipient of an Australian Postgraduate Award (APA) Scholar-
ship. This work was funded through the National Institutes of Health grants
CA43460 and CA62924, the Virginia and D.K. Ludwig Fund for Cancer
Research (USA), the Cancer Council Victoria no. 436708 and a National
Health and Medical Research Council grant no. 545943 (Australia).
(4Z,5Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-
4-(ethylimino)thiazolidin-2-one 7y
Yellow powder (0.035 g, 58.9 %). Mp 2308C (decomp.). dH
(300.13 MHz, DMSO) 9.40 (br s, 1H, NH), 7.78 (s, 1H, CH),
7.06 (d, J 13.0, 3H, ArH), 6.12 (s, 2H, CH2), 3.49 (m, 2H,
NCH2), 1.21 (t, J 7.2, 3H, CH2CH3). m/z (ESI, 20 V) 277.3
(100 %, Mþꢂ). m/z (HR-ESI) Calc. for C13H12N2O3S, [M þ H]þ:
277.0641. Found 277.0648. HPLC purity .99 %, 8.97 min.
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