A general synthesis of tetrahydropyrazolo[3,4-d]thiazoles

Article abstract of DOI:10.1016/j.tet.2013.04.002

A short three-step synthesis of tetrasubstituted 3,3a,5,6-tetrahydro-2H- pyrazolo[3,4-d]thiazoles has been worked out. This relatively unknown heterobicyclic system is assembled from two carbonyl compounds, an amine, a hydrazine, and mercaptoacetic acid e

Full text of DOI:10.1016/j.tet.2013.04.002

Accepted Manuscript
A general synthesis of tetrahydropyrazolo[3,4-d]thiazoles
Sophie Pelletier, Benjamin Pinson, Tomas Smejkal, Clemens Lamberth
PII:
S0040-4020(13)00514-0
10.1016/j.tet.2013.04.002
TET 24202
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 January 2013
Revised Date: 14 March 2013
Accepted Date: 1 April 2013
Please cite this article as: Pelletier S, Pinson B, Smejkal T, Lamberth C, A general synthesis of
tetrahydropyrazolo[3,4-d]thiazoles, Tetrahedron (2013), doi: 10.1016/j.tet.2013.04.002.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A general synthesis of tetrahydropyrazolo[3,4-d]thiazoles
Sophie Pelletiera, Benjamin Pinsona, Tomas Smejkala and Clemens Lambertha,
aSyngenta Crop Protection AG, Research Chemistry, Schaffhauserstr 101, CH-4332 Stein, Switzerland
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A short three-step synthesis of tetrasubstituted 3,3a,5,6-tetrahydro-2H-pyrazolo[3,4-d]thiazoles
has been worked out. This relatively unknown heterobicyclic system is assembled from two
carbonyl compounds, an amine, a hydrazine and mercaptoacetic acid ester. These versatile
starting materials allow the introduction of a broad range of alkyl, haloalkyl, cycloalkyl, aryl and
heteroaryl substituents into four different positions of the bicyclic scaffold. The efficiency of the
synthesis route is proven by the fact, that two of the three steps are a multicomponent reaction or
a cascade reaction respectively, and that it can further be shortened to two consecutive one-pot
processes.
Available online
Keywords:
tetrahydropyrazolothiazole
multicomponent reaction
cascade reaction
heterocycle
2009 Elsevier Ltd. All rights reserved.
heterocyclization
Corresponding author. Tel.: +41-62-866-0224; fax: +41-62-866-0860; e-mail: clemens.lamberth@syngenta.com

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered
A general synthesis of tetrahydropyrazolo
[3,4-d]thiazoles
Leave this area blank for abstract info.
Sophie Pelletier, Benjamin Pinson, Tomas Smejkal, Clemens Lamberth
Syngenta Crop Protection AG, Research Chemistry, Schaffhauserstr. 101, CH-4332 Stein, Switzerland
1)
2)
Lawesson's
reagent
Benzoic acid

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A general synthesis of tetrahydropyrazolo[3,4-d]thiazoles
Sophie Pelletiera, Benjamin Pinson, Tomas Smejkal and Clemens Lamberth
aSyngenta Crop Protection AG, Research Chemistry, Schaffhauserstr 101, CH-4332 Stein, Switzerland
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A short three-step synthesis of tetrasubstituted 3,3a,5,6-tetrahydro-2H-pyrazolo[3,4-d]thiazoles
has been worked out. This relatively unknown heterobicyclic system is assembled from two
carbonyl compounds, an amine, a hydrazine and mercaptoacetic acid ester. These versatile
starting materials allow the introduction of a broad range of alkyl, haloalkyl, cycloalkyl, aryl and
heteroaryl substituents into four different positions of the bicyclic scaffold. The efficiency of the
synthesis route is proven by the fact, that two of the three steps are a multicomponent reaction or
a cascade reaction respectively, and that it can further be shortened to two consecutive one-pot
processes.
Available online
Keywords:
tetrahydropyrazolothiazole
multicomponent reaction
cascade reaction
heterocycle
2009 Elsevier Ltd. All rights reserved.
heterocyclization
Corresponding author. Tel.: +41-62-866-0224; fax: +41-62-866-0860; e-mail: clemens.lamberth@syngenta.com

ACCEPTED MANUSCRIPT
1. Introduction
2. Results and discussion
Approximately 70% of all commercially available
agrochemicals and pharmaceuticals belong to the group of
heterocycles.1 Most of these active ingredients bear either one
or more heteromonocyclic scaffolds or a benzannulated bicyclic
core. There are only a few highly active compound classes
known, which contain a bicyclic scaffold made up of two
different heterocycles. Examples for such rare heterobicyclic
active ingredients are the cephalosporin antibiotics,2 such as
cefalexin (1), the imidazothiazole anthelminthics,3 such as
levamisole (2), and the triazolopyrimidine herbicides,4 such as
florasulam (3) (Figure 1).
We chose 3,3a,5,6-tetrahydro-2H-pyrazolo[3,4-d]thiazole as
the heterobicyclic scaffold of our model study for several
different reasons. First, only a few single examples of this ring
system have been described in the literature so far, always
without focusing on an optimized synthesis.9,10 Second, two
ring nitrogen and two ring carbon atoms are perfectly suited to
carry up to five different substituents, which could act as
potential pharmacophores. Third, according to the very limited
existing literature, it should be possible to assemble a
tetrasubstituted
tetrahydropyrazolo[3,4-d]thiazole
from
mercapoacetic acid, an amine, a hydrazine and two carbonyl
compounds. The abundant commercial availability of such
reagents should ensure the broad variability of the desired
substituents.
The synthesis of such tetrahydropyrazolo[3,4-d]thiazoles 8
has been described in two steps from thiazolidin-4-ones 5 via
Claisen condensation with an aldehyde to the arylidene
derivative 7 and subsequent ring condensation with a hydrazine
derivative to the target compound 8 (Scheme 1). The required
key intermediate 5 could usually be prepared by ring closure
either from an imine and mercaptoacetic acid 49 or from a
thiourea 6 and bromoacetic ester (towards 5’).10
1
2
cefalexin
levamisole
3
florasulam
4
5
Figure 1. Different heterobicyclic active ingredients.
BrCH2COOEt
Possible reasons for this obvious underrepresentation of
heterobicyclic compounds amongst the group of biologically
active compound classes are the lack of general reaction
methods, lengthy synthesis pathways, inavailability of complex
intermediates etc. On the other hand, a heterobicyclic scaffold
should be the ideal core of an active ingredient, because its
physico-chemical properties, influencing the uptake and
translocation of the pharmaceutical or agrochemical, can be
fine-tuned by the choice of the right heterocyclic rings and the
number of heteroatoms. And, in addition, a heterobicyclic
scaffold should be an appropriate core to link several
pharmacophoric substituents with the right exit-bond vectors
into the three-dimensional space for perfect binding at the
target-site of the enzyme. We decided to design a general
synthesis of a so far scarcely described heterobicyclic ring
system, which should fulfill two important criteria: 1. the
completion in only few steps from versatile starting materials;
and 2. the possibility to introduce a broad range of diverse
substituents. To keep the synthesis sequence as concise as
possible, we planned from the beginning the involvement of
special types of one-pot reactions. In the meantime,
multicomponent reactions5 and cascade reactions6 are well-
established as powerful tools for the rapid construction of
complex and structurally diverse compounds from relatively
simple building blocks. High atom-economy and chemical
efficiency are typical features of such one-pot reactions.
Because of the mentioned ubiquitous availability of
heterocyclic scaffolds in pharmaceuticals and agrochemicals,
the assembly of heterocycles via multicomponent7 or cascade8
reactions has been an especially emerging field of interest
recently. Therefore there is an existing arsenal of suitable
reactions to choose from, but also the possibility to add
completely novel reactions to this collection of known one-pot
transformations.
6
5'
5
R
O
1
1
1
O
O
5
R
R
R
N
H2N
N
H
R
4
R
N
N
N
N
3
R
4
R
3
H
3
R
R
4
2
R
S
2
R
2
R
R
S
S
5
7
8
Scheme 1. Known synthesis pathways to 3,3a,5,6-tetrahydro-2H-
pyrazolo[3,4-d]thiazoles 8.
We decided to start our general synthesis of
pyrazolothiazolidines via the mercaptoacetic acid route to a 4-
thiazolidinone 5. This would allow the introduction of a broader
varity of substituents between the two thiazolidinone
heteroatoms compared to the bromoacetic acid alternative.
Furthermore the synthesis of thiazolidinones 5 by one-pot
three-component condensation of an amine,
a carbonyl
compound and mercaptoactic acid 4 has been well described;
usually this multicomponent reaction is performed in the
presence of an acidic or desiccant reagent, such as zinc(II)
chloride,11 p-toluenesulfonic acid,12 lanthanum (III) triflate,13
sodium sulfate,14 dicyclohexylcarbodiimide,15 polyethylene
glycol,16 ionic liquid,17 ferrite,18 zeolite19 and baker’s yeast.20
We found out, that most of these conditions were not suitable
for a broadly applicable three-component condensation. In our
detailed optimization screening for this reaction we found, that
a diverse variety of carbonyl compounds and amines can be
transformed into 4-thiazolidinones 5 in the presence of benzoic
acid, a reagent, which had never been used in this reaction
before. Moreover, we replaced the mercaptoactic acid by its
ethyl ester 9. These two improvements allowed the synthesis of
thiazolidin-4-ones 5a-k with several different substituents in
positions 2 and 3 in 74% average yield (Scheme 2).

ACCEPTED MANUSCRIPT
9
7
8
22
21
20
23
17
1
6
2
Benzoic acid
15
KOtBu
toluene, RT
3 MS
14
10
18
19
toluene, 70-90
C
°
3
5
5
9
13
9
4
16
8
11
8
12
7
16
7
7c
6
5c
1
6
1
2
11
2
11
12
10
10
3
3
5
5
13
4
Scheme 3. Tert-butoxide mediated synthesis of 5-arylidene-thiazolidin-
4-one 7g.
4
15
14
12
5a-86%
5b-66%
5c-83%
5d-82%
As last step in our reaction sequence, we had foreseen the
condensation of the 5-arylidene-thiazolidin-4-ones 7 with
different
hydrazine
derivatives
to
the
desired
tetrahydropyrazolo[3,4-d]thiazoles 8. Unfortunately several
attempts with different basic reagents, such as piperidine,
pyridine, potassium tert-butoxide and sodium acetate did not
accomplish this ring closure reaction (Scheme 4). Therefore we
tried to enhance the activity of the thiazolidinone lactame
function. One obvious possibility was the conversion of the 4-
thiazolidinone 7 into a 4-thiazolidine-thione 11. Such a
transformation is easily possible with Lawesson’s reagent.27
5e-62%
5f-82%
5g-86%
5h-93%
5i-63%
5j-62%
5k-52%
8
Scheme 2. Benzoic acid mediated synthesis of thiazolidin-4-ones 5a-k.
7
Lawesson's
reagent
The reaction tolerates a wide variety of aldehydes: aliphatic
(both branched and linear, also the latter are lower yielding due
to the occurrence of aldol side reaction), aromatic (with
electron donating or electron withdrawing group around the
ring) and heteroaromatic. Similarly, the reaction performed
very well with a broad selection of amines: aliphatic (linear and
sterically hindered), aromatic and heteroaromatic. However, it
is worth mentioning that the reaction with poorly nucleophilic
amines such as anilines or amino-pyridines were found to
require longer reaction time and higher temperature to progress.
This observation indicated that the lactamization was the rate
determining step in the thiazolidin-4-one synthesis which was
confirmed by the isolation of intermediate 10 towards 5k
(Figure 2).
11
Scheme 4. Synthesis of tetrahydropyrazolo[3,4-d]thiazoles via 5-
arylidenethiazolidin-4-thiones.
A solvent screen was undertaken to probe the reactivity of
the resulting 5-arylidene-thiazolidin-4-thiones 11 with
methylhydrazine. Pleasingly the desired pyrazolothiazolidines 8
were obtained in all solvents, ranging from polar protic (entry
1) to apolar aprotic (entries 5, 6). as a mixture of two
diastereoiomers out of the four possible ones (Table 1).
Interestingly, the diastereomeric ratio was strongly influenced
by the nature of the solvent, and by using either methanol (entry
1) or heptane (entry 6), one could obtain one diastereoisomer or
the other preferentially.
10
Table 1- Solvent screen for synthesis of tetrahydropyrazolo[3,4-
d]thiazoles.
Figure 2.Intermediate 10
The next step in our planned synthesis pathway to
tetrahydropyrazolo[3,4-d]thiazoles was the aldol condensation
of an aldehyde to the methylene function in position 5 of the
thiazolidin-4-one. Such arylidenations have been achieved with
the aid of sodium acetate in acetic acid,21 sodium ethoxide,22
potassium
ethoxide,23
potassium tert-butoxide24
and
11j
8j-a
8j-b
montmorillonite.25 We found, that only potassium tert-butoxide
was effective enough to facilitate the aldol condensation at the
relatively unreactive methylene function of the thiazolidin-4-
one ring (Scheme 3). The newly formed Michael acceptor 7
was usually obtained as a 9:1 mixture of diastereoisomer.26
Entry
Solvent
MeOH
CH3CN
THF
CHCl3
Toluene
Heptane
Diastereomeric Ratio
1
2
3
4
5
6
1:2
3:1
2:1
1:1
1:1
5:1

ACCEPTED MANUSCRIPT
To optimize the synthesis route to only three steps, we went
back to the products of the first step, the thiazolidin-4-ones 6
and converted them with Lawesson’s reagent into the
corresponding thiono derivatives 12 (Scheme 5). These
intermediates could then be converted in a one-pot two-step
sequence via the 5-arylidenethiazolidin-4-thiones 11 into the
tetrasubstituted bicyclic tetrahydropyrazolo[3,4-d]thiazoles 8.
1)
2)
benzoic acid
toluene, 70 o
C
Lawesson's reagent
100 o
C
9
12i
O
3)
1)
R4
H
R1
R3
R1
R3
R1
R3
KOtBu, RT
toluene
R5
65 oC
O
Lawesson's
reagent
S
R5
N
N
N
tBuOK, toluene, RT
4)
N
N
R4
dioxane
R2
S
R2
R2
S
5
S
2)
100 o
C
H2
N N
12a-k,
8
65 o
C
H
80% yield
in average
8j
9
Scheme 6: Two consecutive one-pot processes
8
2
7
N
N
N
6
20
N1
N
N
O
N
N
N
11
10
15
14
5
3
13
S
S
S
16
4
N
12
19
Conclusion
17
8a-46%
8b-15%
8c-14%
18
F
F
F
A general synthesis of 3,3a,5,6-tetrahydropyrazolo[3,4-
d]thiazoles 8 has been achieved, in which this heterobicyclic
scaffold is assembled in only three steps from two carbonyl
compounds, an amine, a hydrazine and ethyl thioglycolate 9.
Each of the three steps is optimized for the highest variability
of the applied reagents. Several improvements of literature-
known procedures have been found, e.g. the application of
mercaptoacetic acid esters as starting material and of benzoic
acid as acidic reagent in the synthesis of thiazolidin-4-ones as
well as the use of thiazolidin-4-thiones instead of thiazolidin-4-
ones in the ring condensation to the desired
tetrahydropyrazolo[3,4-d]thiazoles. We are confident, that such
learnings from our route optimization can be applied to the
synthesis of other heterobicyclic systems.
F
F
N
N
N
N
N
N
N
Cl
N
N
N
Cl
S
S
S
F
F
8d-42%
8e-4%
8f-43%
F
F
F
F
F
F
F
F
F
F
N
N
N
N
N
N
N
N
N
S
S
S
Cl
Cl
N
8i-38%
8g-57%
8h-48%
F
F
F
F
Cl
N
N
N
N
N
N
N
N
N
S
S
S
O
O
F
F
8j-30%
8k-32%
8l-20%
N
N
N
N
S
Cl
8m-3%
Scheme 5. Concise approach from thiazolidinthi-4-ones to
tetrahydropyrazolo[3,4-d]thiazoles.
The whole new reaction sequence to tetrahydropyrazolo[3,4-
d]thiazoles contains only three steps, two of which allow the
conversion of three different chemicals to a new reaction
product. The aldehydes, ketones and amines are broadly
variable, which results in diverse range of different substitution
pattern in the final products 8. 8e, for instance, bears an alkyl, a
cycloalkyl, an aryl and a heteroaryl substituent.
Furthermore, it is possible to reduce this synthesis to two
consecutive one-pot processes, by adding the Lawesson’s
reagent upon formation of the thiazolidinone. The reaction is
not as clean as the stepwise process but the desired product is
obtained in 50 to 60% overall yield (Scheme 6). With this two-
step procedure our tetrahydropyrazolo[3,4-d]thiazole synthesis
lines up with some recently published great examples, which
reported the efficient synthesis of other heterobicyclic
compounds in just two steps by multicomponent-cascade
reaction sequences.28

ACCEPTED MANUSCRIPT
Experimental section
4.2.1. 3-Isobutyl-2-isopropyl-thiazolidin-4-one (5a). Prepared
according to the general procedure A with ethyl thioglycolate
(5.0 g), isopropylamine and isobutyraldehyde. After stirring at
70 °C for 18h, 5a (8.4 g, 86%) was isolated by flash column
chromatography (heptane / ethyl acetate gradient from pure
heptane to Hept/EtOAc 3:1, Rf = 0.47 in Hept/EtOAc 2:1) as a
4.1. General experimental
All reactions were performed in degassed but not anhydrous
solvent unless otherwise stated and under
a nitrogen
1
yellow oil. IR (cm-1) υmax 1669 (C=O), 1412, 1274. H NMR
atmosphere (balloon). For reactions conducted under anhydrous
conditions glassware was dried in an oven at 100 °C and purged
with nitrogen. Bulk solutions were evaporated under reduced
pressure using a Büchi rotary evaporator. Reagents used were
obtained from commercial suppliers and used without further
purification. Column chromatography was carried out using
RediSep 4-12-24-40-80-120-330 g; Si60 (35-70 µm). All
(400 MHz, CHLOROFORM-d) δ ppm 4.67 (dd, 1H, J = 3.0
Hz, J =2.0 Hz, H-5), 3.62 (dd, 1H, J = 14.0 Hz, J = 10.0 Hz,
H-6), 3.50 (br. s, 2H, H-3), 2.70 (dd, 1H, J = 14.0 Hz, J = 6.0
Hz, H-6’), 2.19-2.31 (m, 1H, H-7), 1.92-2.03 (m, 1H, H-10),
0.95 (dd, 6H, J = 6.5 Hz, J = 2.5 Hz, H-8 and H-9), 0.88 (d,
3H, J = 6.5 Hz, H-11 or H-12), 0.84 (d, 3H, J = 6.5 Hz, H-12
or H-11). 13C NMR (101 MHz, CHLOROFORM-d) δ ppm
171.5 (C-2), 67.7 (C-5), 49.6 (C-6), 32.4 (C-3), 30.3 (C-10),
26.1 (C-7), 20.4 (C-8 or C-9), 19.7 (C-11 or C-12), 18.7 (C-9 or
C-8), 13.6 (C-12 or C-11). m/z (ES+) 202 ([M+H]+, 100%).
reactions were monitored by thin‐layer chromatography (TLC)
4.2.2.
1-Isobutyl-4-thia-1-azaspiro[4.5]decan-2-one
(5b).
Prepared according to the general procedure A with ethyl
thioglycolate (1.0 g), isopropylamine and cycohexanone. After
stirring at 70 °C for 48h, 5b (1.5 g, 66%) was isolated by flash
column chromatography (heptane / ethyl acetate gradient from
pure heptane to Hept/EtOAc 1:3, Rf = 0.30 in Hept/EtOAc 2:1)
as a light yellow oil. IR (cm-1) υmax 1670 (C=O), 1397. 1H
NMR (400 MHz, CHLOROFORM-d) δ ppm 3.49 (s, 2H, H-3),
3.07 (d, 2H, J = 7.5 Hz, H-6), 1.98-2.11 (m, 1H, H-7), 1.57-
1.71 (m, 10H, H-10, H-11, H-12, H-13 and H-14), 0.91 (d, 6H,
when practical, using Macherey-Nagel SIL G-25 / UV254 treated
silica which were revealed by UV light (250 nm) or by staining
with aqueous basic potassium permanganate solutions. Low
resolution mass spectrometry was recorded on Waters UPLC-
DAD-SQD/MS (ionization: ElectroSpray +/-, column: Acquity
UPLC HSS T3 2.1X30 mm – 1.8 µm, mobile phase A (water +
5% MeOH + 0.05% formic acid) and B (Acetonitrile + 0.05%
formic acid) and detection total absorbance 210-400 nm). All
1H and 13C NMR spectra were recorded using a Bruker 400
MHz and are quoted in ppm. Unless otherwise stated all
experiments were carried out using CDCl3 as solvent. Chemical
shifts (δ) are given in parts per million (ppm), and coupling
constants (J) are given in Hertz (Hz). The 1H NMR spectra are
reported as follows: ppm (multiplicity, number of protons,
J
=
7.0 Hz, H-8 and H-9). 13C NMR (101 MHz,
CHLOROFORM-d) δ ppm 171.9 (C-2), 74.3 (C-5), 49.4 (C-6),
38.2 (2C, CH2), 31.4 (C-3), 28.4 (C-7), 24.6 (CH2), 23.6 (2C,
CH2), 20.3 (C-8 and C-9). m/z (ES+) 228 ([M+H]+, 100%).
4.2.3. 3-Isobutyl-2-(2-methoxyphenyl)thiazolidin-4-one (5c).
Prepared according to the general procedure A with ethyl
thioglycolate (3.0 g), isopropylamine and o-anisaldehyde. After
stirring at 70 °C for 18h, 5c (6.5 g, 83%) was isolated by flash
column chromatography (heptane / ethyl acetate gradient from
pure heptane to Hept/EtOAc 4:1, Rf = 0.20 in Hept/EtOAc 4:1)
as a light yellow oil. IR (cm-1) υmax 1675 (C=O), 1489, 1408,
1242, 754. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm
7.34 (td, 1H, J = 8.0 Hz, J = 1.5 Hz, H-Ar), 7.09 (dd, 1H, J =
7.5 Hz, J = 1.5 Hz, H-Ar), 6.90-7.03 (m, 2H, H-Ar), 5.99 (d,
1H, J = 1.5 Hz, H-5), 3.90 (s, 3H, H-16), 3.76 (dd, 1H, J = 15.0
Hz, J = 1.5 Hz, H-3), 3.56-3.69 (m, 2H, H-3’ and H-6), 2.50
(dd, 1H, J = 13.5 Hz, J = 6.0 Hz, H-6’), 1.88-2.09 (m, 1H, H-7),
0.90 (d, 3H, J = 7.0 Hz, H-8 or H-9), 0.89 (d, 3H, J = 7.0 Hz,
H-9 or H-8). 13C NMR (101 MHz, CHLOROFORM-d) δ ppm
172.3 (C-2), 156.8 (C-11), 129.7 (CAr), 127.9 (C-10), 126.1
(CAr), 120.9 (CAr), 111.0 (CAr), 58.2 (C-5), 55.6 (C-16), 50.3 (C-
6), 32.5 (C-3), 26.4 (C-7), 20.3 (C-8 or C-9), 19.8 (C-9 or C-8).
m/z (ES+) 266 ([M+H]+, 100%).
coupling constants and assignment). Two‐dimensional (COSY,
HMQC, HMBC) NMR spectroscopy were used to assist the
1
assignment of signals in the H and 13C NMR spectra (s =
singlet, br s = broad singlet, d = doublet, br d = broad doublet, t
= triplet, q = quartet, m = multiplet, quin = quintet, sept =
septuplet, dd = doublet of doublet, dt = doublet of triplet, td =
triplet of doublet, dq = doublet of quadruplet, ddd = doublet of
doublet of doublet).
4.2. Preparation of thiazolidinones 5a-k
General procedure A: a round‐bottom flask, equipped with a
4.2.4. 2-(3-Chlorophenyl)-3-cyclopropyl-thiazolidin-4-one
(5d). Prepared according to the general procedure A with ethyl
thioglycolate
(3.0
g),
cyclopropylamine
and
m-
rubber seal and a magnetic stirrer bar, was charged with ethyl
thioglycolate 9 (1.0 eq.), benzoic acid (1.5 eq.) and toluene
(0.6mol/L). Then, amine (1.5 eq.) and aldehyde/ketone (1.5 eq.)
were added. The reaction was stirred at 70 °C to 90 °C under a
N2 atmosphere. Upon completion (monitored by 1H NMR
spectroscopy and TLC) the reaction mixture was concentrated
under vacuum and the crude residue was dissolved in DCM and
washed twice with 1M aqueous K2CO3. The combined aqueous
layers were re-extracted once with DCM and the combined
organic layers were dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude product was
purified by FCC.
chlorobenzaldehyde. After stirring at 70 °C for 18h, 5d (6.1 g,
82%) was isolated by flash column chromatography (heptane /
ethyl acetate gradient from pure heptane to Hept/EtOAc 3:2, Rf
= 0.53 in Hept/EtOAc 1:1) as an orange oil. IR (cm-1) υmax 1675
1
(C=O), 1391 (C=C), 1359, 683 (C=CAr). H NMR (400 MHz,
CHLOROFORM-d) δ ppm 7.30-7.35 (m, 3H, H-Ar), 7.18-7.22
(m, 1H, H-Ar), 5.44 (s, 1H, H-5), 3.83 (d, 1H, J = 15.5 Hz, H-
3), 3.65 (d, 1H, J = 15.5 Hz, H-3’), 2.23-2.32 (m, 1H, H-6),
0.80-1.01 (m, 2H, H-7 or H-8), 0.52-0.64 (m, 2H, H-8 or H-7).
13C NMR (101 MHz, CHLOROFORM-d) δ ppm 172.1 (C-2),
142.8 (C-9), 135.0 (C-11), 130.3 (C-Ar), 129.1 (C-Ar), 126.6
(C-Ar), 124.6 (C-Ar), 63.9 (C-5), 33.1 (C-3), 26.1 (C-6), 7.7
(C-7 or C-8), 5.1 (C-8 or C-7). m/z (ES+) 254 ([M+H]+,
100%).

ACCEPTED MANUSCRIPT
1H, J = 8.0 Hz, J = 5.0 Hz, H-12), 5.82 (s, 1H, H-5), 4.50 (dq,
4.2.5.
Prepared according to the general procedure A with ethyl
thioglycolate (5.0 g), cyclopropylamine and 3-
3-Cyclopropyl-2-(3-pyridyl)thiazolidin-4-one
(5e)
1H, J = 15.0 Hz, J = 9.5 Hz, H-6), 3.86 (s, 2H, H-3), 3.05 (dq,
1H, J = 15.0 Hz, J = 8.0 Hz, H-6’). 13C NMR (101 MHz,
CHLOROFORM-d) δ ppm 171.5 (C-2), 151.3 (C-9), 149.1 (C-
11), 135.1 (C-13), 133.5 (C-8), 124.1 (C-12), 123.5 (q, J =
283.0 Hz, C-7), 60.8 (C-5), 43.2 (q, J = 34.5 Hz, C-6), 32.0 (C-
3). m/z (ES+) 263 ([M+H]+, 100%).
pyridincarboxaldehyde. After stirring at 70 °C for 18h, 5e (6.7
g, 62%) was isolated by flash column chromatography (heptane
/ ethyl acetate gradient from pure heptane to Hept/EtOAc 1:4,
Rf = 0.03 in Hept/EtOAc 1:2) as a light yellow oil. IR (cm-1)
1
υmax 1673 (C=O), 1392 (C=C), 1357, 1025, 710 (C=CAr). H
4.2.9.
3-(4-Fluorophenyl)-2-(2-methoxyphenyl)thiazolidin-4-
NMR (400 MHz, CHLOROFORM-d) δ ppm 8.62 (dd, 1H, J =
5.0 Hz, J = 2.0 Hz, H-12), 8.59 (d, 1H, J = 2.0 Hz, H-10), 7.71
(dt, 1H, J = 8.0 Hz, J = 2.0 Hz, H-14), 7.36 (dd, 1H, J = 8.0 Hz,
J = 5.0 Hz, H-13), 5.52 (d, 1H, J = 1.0 Hz, H-5), 3.84 (app. dd,
1H, J = 16.5 Hz, J = 1.0 Hz, H-3), 3.69 (d, 1H, J = 16.5 Hz, H-
3’), 2.21 (m, 1H, H-6), 0.82-1.04 (m, 2H, H-7 or H-8), 0.51-
0.71 (m, 2H, H-8 or H-7). 13C NMR (101 MHz,
CHLOROFORM-d) δ ppm 171.9 (C-2), 150.4 (C-12), 148.4
(C-10), 136.2 (C-9), 134.3 (C-14), 124.0 (C-13), 62.2 (C-5),
33.2 (C-3), 26.0 (C-6), 7.8 (C-7 or C-8), 5.1 (C-8 or C-7). m/z
(ES+) 221 ([M+H]+, 100%).
one (5i). Prepared according to the general procedure A with
ethyl thioglycolate (15.0 g), p-fluoroaniline and o-anisaldehyde.
After stirring at 70 °C for 48h, 5i (28.2 g, 63%) was isolated by
flash column chromatography (heptane / ethyl acetate gradient
from pure heptane to Hept/EtOAc 3:1, Rf
= 0.10 in
Hept/EtOAc 4:1) as a yellow oil. IR (cm-1) υmax 1682 (C=O),
1
1506, 1240, 1218, 1266, 835, 752, 733. H NMR (400 MHz,
CHLOROFORM-d) δ ppm 7.23-7.29 (m, 3H, H-8, H-10 and H-
15 or H-17), 7.19 (dd, J = 7.5 and 1.5 Hz, 1H, H-17 or H-15),
6.94-7.01 (m, 2H, H-7 and H-11), 6.90 (d, J = 2.5 Hz, 1H, H-
14), 6.87 (t, J = 4.5 Hz, 1H, H-16), 6.38 (br. s, 1H, H-5), 3.95
(dd, J = 15.5 Hz, J = 1.5 Hz, 1H, H-3), 3.87 (s, 3H, H-18), 3.78
4.2.6. 2-(3-Chlorophenyl)-3-(2,2,2-trifluoroethyl)thiazolidin-4-
one (5f). Prepared according to the general procedure A with
ethyl thioglycolate (3.0 g), 2,2,2-trifluoroethylamine and m-
chlorobenzaldehyde. After stirring at 70 °C for 18h, 5f (7.1 g,
82%) was isolated by flash column chromatography (heptane /
ethyl acetate gradient from pure heptane to Hept/EtOAc 3:2, Rf
= 0.82 in Hept/EtOAc 1:1) as a yellow oil. IR (cm-1) υmax 1685
(C=O), 1396 (C=C), 1266, 1158, 1138, 707 (CF3), 683 (C=CAr).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.37-7.41 (m,
2H, H-12 and H-13), 7.31-7.33 (m, 1H, H-9), 7.21 (dt, 1H, J =
7.0 Hz, J = 2.0 Hz, H-11), 5.76 (s, 1H, H-5), 4.51 (dq, 1H, J =
15.0 Hz, J = 9.5 Hz, H-6), 3.83 (s, 2H, H-3), 3.07 (dq, 1H, J =
(d, J =
15.5 Hz, 1H, H-3’). 13C NMR (101 MHz,
CHLOROFORM-d) δ ppm 171.6 (C-2), 160.8 (d, J = 248.5 Hz,
C-9), 156.6 (C-13), 133.9 (d, J = 4.0 Hz, C-6), 129.9 (CAr),
127.6 (C-12), 126.9 (CAr), 126.6 (d, J = 8.0 Hz, C-7 and C-11),
120.8 (CAr), 115.8 (d, J = 23.0 Hz, C-8 and C-10), 111.1 (CAr),
60.5 (C-5), 55.6 (C-18), 33.3 (C-3). m/z (ES+) 304 ([M+H]+,
100%).
4.2.10. 3-(4-Chlorophenyl)-2-isobutyl-thiazolidin-4-one (5j).
Prepared according to the general procedure A with ethyl
thioglycolate (2.0 g), p-chloroaniline and isobutyraldehyde.
After stirring at 70 °C for 48h, 5j (3.3 g, 62%) was isolated by
flash column chromatography (heptane / ethyl acetate gradient
15.0 Hz,
J =
8.5 Hz, H-6’). 13C NMR (101 MHz,
CHLOROFORM-d) δ ppm 171.6 (C-2), 140.0 (Cquat), 135.4
(Cquat), 130.6 (C-12 or C-13), 123.0 (C-13 or C-12), 127.4 (C-
9), 125.5 (C-11), 123.9 (q, J = 282.0 Hz, C-7), 62.4 (C-5), 43.2
(q, J = 34.5 Hz, C-6), 31.9 (C-3). m/z (ES+) 296 ([M+H]+,
100%).
from pure heptane to Hept/EtOAc 3:1, Rf = 0.43 in
Hept/EtOAc 4:1) as a yellow oil. IR (cm-1) υmax 1683 (C=O),
1491, 1387, 1349, 1089, 826. 1H NMR (400 MHz,
CHLOROFORM-d) δ ppm 7.39-7.45 (m, 2H, H-7 and H-11),
7.21-7.26 (m, 2H, H-8 and H-10), 5.14 (ddd, 1H, J = 9.5, 4.0
and 1.0 Hz, H-5), 3.77 (dd, 1H, J = 15.5 Hz, J = 1.0 Hz, H-3),
3.70 (d, 1H, J = 15.5 Hz, H-3’), 1.72-1.83 (m, 1H, H-13), 1.52-
1.66 (m, 2H, H-12), 0.91 (d, 3H, J = 6.5 Hz, H-14 or H-15),
0.85 (d, 3H, J = 6.5 Hz, H-15 or H-14). 13C NMR (101 MHz,
CHLOROFORM-d) δ ppm 170.7 (C-2), 136.0 (C-9), 133.2 (C-
6), 129.7 (C-7 and C-11), 127.5 (C-8 and C-10), 62.4 (C-5) ,
45.2 (C-12), 32.4 (C-3), 24.9 (C-13), 23.7 (C-14 or C-15), 21.1
(C-15 or C-14). m/z (ES+) 270 ([M+H]+, 100%).
4.2.7. 2-(4-Chlorophenyl)-3-(2,2,2-trifluoroethyl)thiazolidin-4-
one (5g). Prepared according to the general procedure A with
ethyl thioglycolate (3.0 g), 2,2,2-trifluoroethylamine and p-
chlorobenzaldehyde. After stirring at 70 °C for 18h, 5g (7.5 g,
86%) was isolated by flash column chromatography (heptane /
ethyl acetate gradient from pure heptane to Hept/EtOAc 3:2, Rf
= 0.82 in Hept/EtOAc 1:1) as a yellow oil. IR (cm-1) υmax 1686
(C=O), 1394 (C=C), 1264, 1154, 1136, 709 (CF3), 683 (C=CAr).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.42 (d, 2H, J
= 8.5 Hz, H-10 and H-12), 7.28 (d, 2H, J = 8.5 Hz, H-9 and H-
13), 5.78 (s, 1H, H-5), 4.49 (dq, 1H, J = 15.5 Hz, J = 9.5 Hz, H-
6), 3.83 (s, 2H, H-3), 3.05 (dq, 1H, J = 15.5 Hz, J = 8.5 Hz, H-
6’). 13C NMR (101 MHz, CHLOROFORM-d) δ ppm 171.6 (C-
2), 136.1 (C-8 or C-11), 135.8 (C-11 or C-8), 129.7 (C-10 and
C-12), 128.9 (C-9 and C-13), 123.8 (q, J = 282.0 Hz, C-7), 62.5
(C-5), 43.1 (q, J = 34.5 Hz, C-6), 32.1 (C-3). m/z (ES+) 296
([M+H]+, 100%).
4.2.11. 2-(4-Chlorophenyl)-3-(3-pyridyl)thiazolidin-4-one (5k).
Prepared according to the general procedure A with ethyl
thioglycolate
(3.0
g),
3-aminopyridine
and
p-
chlorobenzaldehyde. After stirring at 90 °C for 4 days, 6k (4.4
g, 52%) was isolated by flash column chromatography (heptane
/ ethyl acetate gradient from pure heptane to pure EtOAc, Rf =
0.15 in Hept/EtOAc 1:1) as a yellow oil. IR (cm-1) υmax 1684
(C=O), 1480, 1369, 1088, 1013, 706. 1H NMR (400 MHz,
CHLOROFORM-d) δ ppm 8.45 (br. d, 1H, J = 2.0 Hz, H-7),
8.43 (dd, 1H, J = 5.0 Hz, J = 1.5 Hz, H-9), 7.59 (ddd, 1H, J =
8.0 Hz, J = 2.5 Hz, J = 1.5 Hz, H-11), 7.23-7.31 (m, 5H, H-13,
H-14, H-16, H-17 and H-10), 6.13 (s, 1H, H-5), 3.99 (d, 1H, J =
16.0 Hz, H-3), 3.91 (d, 1H, J = 16.0 Hz, H-3’). 13C NMR (101
MHz, CHLOROFORM-d) δ ppm 171.1 (C-2), 148.0 (C-9),
146.2 (C-7), 137.1 (Cquat), 135.2 (Cquat), 134.1 (Cquat), 132.8
(C-11), 129.4 (C-14 and C-16), 128.4 (C-13 and C-17), 123.7
(C-10), 64.4 (C-5), 33.2 (C-3). m/z (ES+) 291 ([M+H]+,
100%).
4.2.8. 2-(3-Pyridyl)-3-(2,2,2-trifluoroethyl)thiazolidin-4-one
(5h). Prepared according to the general procedure A with ethyl
thioglycolate (3.0 g), 2,2,2-trifluoroethylamine and 3-
pyridinecarboxaldehyde. After stirring at 70 °C for 18h, 5h (7.2
g, 93%) was isolated by flash column chromatography (heptane
/ ethyl acetate gradient from pure heptane to Hept/EtOAc 1:4,
Rf = 0.19 in Hept/EtOAc 2:1) as a yellow oil. IR (cm-1) υmax
1693 (C=O), 1396 (C=C), 1264, 1153, 1135, 711 (CF3), 639
1
(C=CAr). H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.69
(dd, 1H, J = 5.0 Hz, J = 2.0 Hz, H-9), 8.60 (d, 1H, J = 2.0 Hz,
H-11), 7.70 (dt, 1H, J = 8.0 Hz, J = 2.0 Hz, H-13), 7.41 (dd,
4.3. Preparation of thiazolidinthiones 12a-k

ACCEPTED MANUSCRIPT
General procedure B: a one-necked flask, equipped with a
and H-13), 7.23-7.66 (m, 1H, H-10), 7.08-7.19 (m, 1H, H-14),
5.83 (d, 1H, J = 2.0 Hz, H-5), 4.45 (app. ddd, 1H, J = 16.5 Hz,
J = 2.0 Hz, J = 1.0 Hz, H-3), 4.29 (d, 1H, J 16.5 Hz, H-3’),
2.65-2.75 (m, 1H, H-6), 1.07-1.18 (m, 1H, H-7 or H-8), 0.87-
0.98 (m, 1H, H-7 or H-8), 0.70-0.83 (m, 2H, H-8 or H-7). 13C
NMR (101 MHz, CHLOROFORM-d) δ ppm 199.9 (C-2),
142.0 (C-9), 135.2 (C-11), 130.6 (C-13), 129.3 (C-12), 126.4
(C-10), 124.3 (C-14), 73.0 (C-5), 46.0 (C-3), 31.9 (C-6), 9.4 (C-
7 or C-8), 7.3 (C-8 or C-7). m/z (ES+) 270 ([M+H]+, 100%),
HRMS (ES+) exact mass calculated for [M+H] (C12H13NClS2+)
requires m/z 270.0172, found m/z 270.0171.
magnetic stirrer bar was charged with thiazolidinone 5 (1.0 eq.),
Lawesson’s reagent (0.6 eq.) and 1,4-dioxane (0.5 mol/L). The
reaction was stirred at 100 °C overnight. Upon completion
(monitored by LCMS), 1,4-dioxane was removed under
vacuum and the crude product was purified by FCC.
4.3.1.
3-Isobutyl-2-isopropyl-thiazolidin-4-thione
(12a).
Prepared according to the general procedure B with ethyl 3-
isobutyl-2-isopropyl-thiazolidin-4-one 5a (1.0 g). 12a (1.0 g,
90%) was isolated by flash column chromatography (heptane /
ethyl acetate gradient from pure heptane to pure EtOAc, Rf =
0.86 in Hept/EtOAc 1:1) as an orange oil. IR (cm-1) υmax 1461,
1386, 1216, 1136 (C=S), 1092. 1H NMR (400 MHz,
CHLOROFORM-d) δ ppm 5.07 (br. s, 1H, H-5), 4.42 (dd, 1H,
J = 13.5 Hz, J = 8.5 Hz, H-6’), 4.17 (br. s, 2H, H-3), 2.94 (dd,
1H, J = 13.5 Hz, J = 7.0 Hz, H-6), 2.34-2.43 (m, 1H, H-10),
2.23-2.33 (m, 1H, H-7), 1.1 (t, 6H, J = 7.0 Hz, H-9 or H-8 and
H-12 or H-11), 0.94 (d, 3H, J = 7.0 Hz, H-8 or H-9), 0.84 (d,
3H, J = 7.0 Hz, H-11 or H-12). 13C NMR (101 MHz,
CHLOROFORM-d) δ ppm 197.4 (C-2), 78.0 (C-5), 54.9 (C-6),
45.7 (C-3), 31.4 (C-7), 26.0 (C-10), 20.4 (C-8 or C-9), 19.8 (C-
11 or C-12), 19.3 (C-11 or C-12), 14.0 (C-8 or C-9). m/z (ES+)
217 ([M+H]+, 100%).
4.3.5. 3-Cyclopropyl-2-(3-pyridyl)thiazolidin-4-thione (12e).
Prepared according to the general procedure B with 3-
cyclopropyl-2-(3-pyridyl)thiazolidin-4-one 5e (0.8 g). 12e (0.3
g, 40%) was isolated by flash column chromatography (heptane
/ ethyl acetate gradient from pure heptane to Hept/EtOAc 1:4,
Rf = 0.27 in Hept/EtOAc 1:1) as an orange oil. IR (cm-1) υmax
1442, 1403, 1271, 1132 (C=S), 1027. 1H NMR (400 MHz,
CHLOROFORM-d) δ ppm 8.62 (br. d, 1H, J = 2.5 Hz, H-12),
8.58 (br. s, 1H, H-10), 7.63 (dt, 1H, J = 8.0 Hz, J = 1.5 Hz, H-
14), 7.38 (dd, 1H, J = 8.0 Hz, J = 5.5 Hz, H-13), 5.91 (d, 1H, J
= 2.0 Hz, H-5), 4.46 (app. ddd, 1H, J = 17.0 Hz, J = 2.0 Hz, J =
1.0 Hz, H-3’), 4.31 (d, 1H, J = 17.0 Hz, H-3), 2.62 (app. dt, 1H,
J = 11.5 Hz, J = 5.5 Hz, H-6), 1.09-1.19 (m, 1H, H-8 or H-7),
0.90-0.99 (m, 1H, H-8 or H-7), 0.74-0.82 (m, 2H, H-7 or H-8).
13C NMR (101 MHz, CHLOROFORM-d) δ ppm 199.8 (C-2),
150.5 (C-12), 147.9 (C-10), 135.7 (C-9), 133.9 (C-14), 124.2
(C-13), 71.2 (C-5), 40.1 (C-3), 31.8 (C-6), 9.6 (C-7 or C-8), 7.4
(C-8 or C-7). m/z (ES+) 237 ([M+H]+, 100%).
4.3.2. 1-Isobutyl-4-thia-1-azaspiro[4.5]decan-2-thione (12b).
Prepared according to the general procedure B with 1-isobutyl-
4-thia-1-azaspiro[4.5]decan-2-one 5b (0.9 g). 12b (0.9 g, 86%)
was isolated by flash column chromatography (heptane / ethyl
acetate gradient from pure heptane to Hept/EtOAc 1:1, Rf =
0.65 in Hept/EtOAc 2:1) as a red oil. IR (cm-1) υmax 1462, 1385,
1181, 1148, 1130 (C=S), 1107. 1H NMR (400 MHz,
CHLOROFORM-d) δ ppm 4.08 (s, 2H, H-3), 3.53 (d, 2H, J =
8.0 Hz, H-6), 2.30-2.52 (m, 1H, H-7), 1.69-1.91 (m, 6H, H-11,
H-12 and H-13), 1.47-1.68 (m, 4H, H-10 and H-14), 0.90 (d,
6H, J = 7.0 Hz, H-9 and H-8).13C NMR (101 MHz,
CHLOROFORM-d) δ ppm 198.4 (C-2), 84.9 (C-5), 54.0 (C-6),
43.4 (C-3), 37.5 (C-11 and C-13), 27.4 (C-7), 24.6 (C-12), 24.3
(C-10 and C-14), 20.5 (C-8 and C-9). m/z (ES+) 244 ([M+H]+,
100%), HRMS (ES+) exact mass calculated for [M+H]
(C12H22NS2+) requires m/z 244.1188, found m/z 244.1186.
4.3.6. 2-(3-Chlorophenyl)-3-(2,2,2-trifluoroethyl)thiazolidin-4-
thione (12f). Prepared according to the general procedure B
with 2-(3-chlorophenyl)-3-(2,2,2-trifluoroethyl)thiazolidin-4-
one 5f (2.4 g). 12f (1.9 g, 77%) was isolated by flash column
chromatography (heptane / ethyl acetate gradient from pure
heptane to Hept/EtOAc 3:1, Rf = 0.88 in Hept/EtOAc 1:1) as an
orange oil. IR (cm-1) υmax 1450, 1402, 1260, 1134 (C=S), 1109,
1
1079. H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.29-
7.37 (m, 2H, H-11 and H-12), 7.18-7.23 (m, 1H, H-9), 7.09 (dt,
1H, J = 17.0 Hz, J = 2.0 Hz, H-13), 6.02 (s, 1H, H-5), 5.30 (dq,
1H, J = 15.0 Hz, J = 9.5 Hz, H-6), 4.38 (app. ddd, 1H, J = 17.0
Hz, J = 2.0 Hz, J = 1.0 Hz, H-3), 4.32 (dd, 1H, J = 17.0 Hz, J =
1.0 Hz Hz, J = H-3’), 3.20-3.33 (m, 1H, H-6’). 13C NMR (101
MHz, CHLOROFORM-d) δ ppm 201.3 (C-2), 139.2 (C-8),
135.6 (C-10), 130.9 (C-11 or C-12), 130.3 (C-12 or C-11),
127.5 (C-9), 125.5 (C-13), 124.5 (q, J = 280.0 Hz, C-7), 72.0
(C-5), 47.3 (q, J = 34.0 Hz, C-6), 45.0 (C-3). m/z (ES+) 312
([M+H]+, 100%), HRMS (ES+) exact mass calculated for
[M+H] (C11H10NClF3S2+) requires m/z 311.9890, found m/z
311.9890.
4.3.3.
3-Isobutyl-2-(2-methoxyphenyl)thiazolidin-4-thione
(12c). Prepared according to the general procedure B with ethyl
3-isobutyl-2-(2-methoxyphenyl)thiazolidin-4-one 5c (2.5 g).
12c (2.6 g, 99%) was isolated by flash column chromatography
(heptane / ethyl acetate gradient from pure heptane to
Hept/EtOAc 1:4, Rf = 0.55 in Hept/EtOAc 2:1) as an orange
1
oil. IR (cm-1) υmax 1459, 1240, 1137 (C=S), 1105. H NMR
(400 MHz, CHLOROFORM-d) δ ppm 7.30-7.38 (m, 1H, HAr),
6.92-7.00 (m, 3H, HAr), 6.38 (d, 1H, J = 2.0 Hz, H-5), 4.07-4.58
(m, 3H, H-3 and H-6), 3.89 (s, 3H, H-16), 2.71 (dd, 1H, J =
13.0 Hz, 7.0 Hz, H-6’), 1.93-2.42 (m, 1H, H-7), 0.97 (d, 3H, J =
7.0 Hz, H-8 or H-9), 0.94 (d, 3H, J = 7.0 Hz, H-9 or H-8). 13C
NMR (101 MHz, CHLOROFORM-d) δ ppm 198.7 (C-2),
156.5 (C-11), 130.1 (CAr), 126.8 (C-10), 126.0 (CAr), 121.0
(CAr), 111.1 (CAr), 68.2 (C-5), 55.7 (C-16), 55.6 (C-6), 45.4 (C-
3), 26.2 (C-7), 20.3 (C-8 or C-9), 19.9 (C-9 or C-8). m/z (ES+)
282 ([M+H]+, 100%), HRMS (ES+) exact mass calculated for
[M+H] (C14H20ONS2+) requires m/z 282.0980, found m/z
282.0982.
4.3.7. 2-(4-Chlorophenyl)-3-(2,2,2-trifluoroethyl)thiazolidin-4-
thione (12g). Prepared according to the general procedure B
with 2-(4-chlorophenyl)-3-(2,2,2-trifluoroethyl)thiazolidin-4-
one 5g (2.8 g). 12g (2.6 g, 89%) was isolated by flash column
chromatography (heptane / ethyl acetate gradient from pure
heptane to Hept/EtOAc 1:1, Rf = 0.91 in Hept/EtOAc 1:1) as an
orange oil. IR (cm-1) υmax 1446, 1401, 1258, 1134 (C=S), 1108,
1
1089. H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.31-
7.39 (m, 2H, H-10 and H-12), 7.15-7.21 (m, 2H, H-9 and H-
13), 6.04 (s, 1H, H-5), 5.28 (dq, 1H, J = 15.0 Hz, J = 9.5 Hz, H-
6), 4.37 (app. ddd, 1H, J =17.0 Hz, J = 2.0 Hz, J = 0.5 Hz, H-
3), 4.31 (dd, 1H, J = 17.0 Hz, J = 1.0 Hz, H-3’), 3.24 (dq, 1H, J
= 15.0 Hz, J = 8.0 Hz, H-6’). 13C NMR (101 MHz,
CHLOROFORM-d) δ ppm 201.3 (C-2), 136.2 (C-11), 135.5
(C-8), 129.8 (C-10 and C-12), 128.9 (C-9 and C-13), 123.5 (q, J
280.0 Hz, C-7), 72.0 (C-5), 47.2 (q, J 34.0 Hz, C-6), 45.0 (C-3).
m/z (ES+) 312 ([M+H]+, 100%), HRMS (ES+) exact mass
4.3.4. 2-(3-Chlorophenyl)-3-cyclopropyl-thiazolidin-4-thione
(12d). Prepared according to the general procedure B with 2-(3-
chlorophenyl)-3-cyclopropyl-thiazolidin-4-one 5d (3.9 g). 12d
(3.8 g, 92%) was isolated by flash column chromatography
(heptane / ethyl acetate gradient from pure heptane to
Hept/EtOAc 1:4, Rf = 0.89 in Hept/EtOAc 2:1) as a yellow oil.
1
IR (cm-1) υmax 1444, 1404, 1277, 1131 (C=S), 1079. H NMR
(400 MHz, CHLOROFORM-d) δ ppm 7.33-7.36 (m, 2H, H-12

ACCEPTED MANUSCRIPT
calculated for [M+H] (C11H10NClF3S2+) requires m/z 311.9890,
found m/z 311.9887.
(heptane / ethyl acetate gradient from pure heptane to
Hept/EtOAc 1:1, Rf = 0.51 in Hept/EtOAc 1:1) as a yellow oil.
1
IR (cm-1) υmax 1435, 1396, 1190, 1148, 1140 (C=S), 1104. H
4.3.8. 2-(3-Pyridyl)-3-(2,2,2-trifluoroethyl)thiazolidin-4-thione
(12h). Prepared according to the general procedure B with 2-(3-
pyridyl)-3-(2,2,2-trifluoroethyl)thiazolidin-4-one 5h (5.5 g).
12h (2.1 g, 36%) was isolated by flash column chromatography
(heptane / ethyl acetate gradient from pure heptane to
Hept/EtOAc 1:3, Rf = 0.53 in Hept/EtOAc 2:1) as an orange
oil. IR (cm-1) υmax 1449, 1402, 1259, 1136 (C=S), 1108. 1H
NMR (400 MHz, CHLOROFORM-d) δ ppm 8.62 (dd, 1H, J =
5.0 Hz, J = 2.0 Hz, H-11), 8.51 (d, 1H, J = 2.0 Hz, H-9), 7.59
(dt, 1H, J = 8.0 Hz, J = 2.0 Hz, H-13), 7.34 (dd, 1H, J = 8.0 Hz,
J = 5.0 Hz, H-12), 6.10 (s, 1H, H-5), 4.37-4.43 (m, 1H, H-6),
4.40 (app. ddd, 1H, J = 17.0 Hz, J = 1.5 Hz, J = 1.0 Hz, H-3),
4.34 (dd, 1H, J = 17.0 Hz, J = 1.0 Hz, H-3’), 3.15-3.36 (m, 1H,
H-6’). 13C NMR (101 MHz, CHLOROFORM-d) δ ppm 201.3
(C-2), 151.5 (C-11), 149.0 (C-9), 135.1 (C-13), 133.0 (C-8),
124.4 (C-12), 123.5 (q, J = 281 Hz, C-7), 70.2 (C-5), 47.3 (q, J
= 34 Hz, C-6), 45.0 (C-3). m/z (ES+) 279 ([M+H]+, 100%),
HRMS (ES+) exact mass calculated for [M+H]
(C10H10N2F3S2+) requires m/z 279.0232, found m/z 279.0227.
NMR (400 MHz, CHLOROFORM-d) δ ppm 8.45 (br. d, 1H, J
= 4.0 Hz, H-9), 8.36 (br. s, 1H, H-7), 7.40 (d, 1H, J = 8.0 Hz,
H-11), 7.23-7.32 (m, 5H, H-10, H-13, H-14, H-16 and H-17),
6.27 (s, 1H, H-5), 4.63 (dd, 1H, J = 17.5 Hz, J = 2.0 Hz, H-3),
4.54 (d, 1H, J = 17.5 Hz, H-3’). 13C NMR (101 MHz,
CHLOROFORM-d) δ ppm 200.6 (C-2), 149.5 (C-9), 148.5 (C-
7), 136.6 (Cquat), 135.9 (Cquat), 135.8 (Cquat), 135.5 (C-11),
129.4 (C-13 and C-17 or C-14 and C-16), 129.2 (C-13 and C-17
or C-14 and C-16), 123.9 (C-10), 75.4 (C-5), 46.2 (C-3). m/z
(ES+) 307 ([M+H]+, 100%).
4.4. Preparation of pyrazolothiazoles 8a-k
General procedure C: a dried one-necked flask, equipped with
a magnetic stirrer bar, was charged with thiazolidinethione 12
(1.0 eq.), an aldehyde (1.1 eq.) and dry toluene (0.1 mol/L).
t
Then, potassium butoxide (1.1 eq.) was added dropwise. After
stirring for 5 min under nitrogen, 3Å molecular sieves were
added to the reaction. The mixture was left under a nitrogen
atmosphere and stirred at RT until completion (monitored by
LCMS, usually 30 min). Then, methylhydrazine (10.0 eq) was
added and the reaction was stirred at 65 °C overnight. The
toluene was removed under vacuum and the crude product was
purified by FCC.
4.3.9.
3-(4-Fluorophenyl)-2-(2-methoxyphenyl)thiazolidin-4-
thione (12i). Prepared according to the general procedure B
with 3-(4-fluorophenyl)-2-(2-methoxyphenyl)thiazolidin-4-one
5i (1.2 g). 12i (1.2 g, 96%) was isolated by flash column
chromatography (heptane / ethyl acetate gradient from pure
heptane to Hept/EtOAc 3:1, Rf = 0.69 in Hept/EtOAc 1:1) as an
orange oil. IR (cm-1) υmax 1505, 1434, 1243, 1136 (C=S), 1048.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.17-7.24 (m,
2H, H-15 and H-17), 7.02-7.08 (m, 2H, H-7 and H-11), 6.89-
6.96 (m, 2H, H-8 and H-10), 6.86 (t, 1H, J = 7.5 Hz, H-16),
6.76 (d, 1H, J = 8.5 Hz, H-14), 6.54 (br. s, 1H, H-5), 4.51 (dd,
1H, J =16.5 Hz, J = 2.0 Hz, H-3), 4.38 (d, 1H, J = 16.5 Hz, H-
3’), 3.70 (s, 3H, H-18). 13C NMR (101 MHz, CHLOROFORM-
d) δ ppm 200.4 (C-2), 161.9 (d, J = 247.0 Hz, C-9), 156.7 (C-
13), 136.0 (d, J = 4.0 Hz, C-6), 130.6 (C-15), 129.1 (C-7 or C-
11), 129.0 (C-11 or C-7), 128.1 (C-17), 126.1 (C-12), 120.9 (C-
16), 116.4 (C-8 or C-10), 116.2 (C-10 or C-8), 111.2 (C-14),
71.2 (C-5), 55.6 (C-18), 46.5 (C-3). m/z (ES+) 320 ([M+H]+,
100%), HRMS (ES+) exact mass calculated for [M+H]
(C16H15ONClFS2+) requires m/z 320.0574, found m/z
320.0571.
4.4.1. 6-Isobutyl-5-isopropyl-2-methyl-3-(3-pyridyl)-3,3a,5,6a-
tetrahydro-1H-pyrazolo[3,4-d]thiazole
(8a).
Prepared
according to the general procedure C with 3-isobutyl-2-
isopropyl-thiazolidin-4-thione 12a (335 mg) and 3-
pyridinecarboxaldehyde. 8a (225 mg, 46 %) was isolated by
flash column chromatography (cyclohexane / EtOAc gradient
from pure cyclohexane to pure EtOAc, Rf = 0.1 in EtOAc) as a
yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm
8.64 (d, 1H, J = 2.0 Hz, H-15), 8.58 (dd, 1H, J = 8.0 Hz, J = 2.0
Hz, H-17), 7.84 (dt, 1H, J = 8.0 Hz, J = 2.0 Hz, H-19), 7.30
(dd, 1H, J = 8.0 Hz, J = 6.0 Hz, H-18), 4.77 (br. d, 1H, J = 3.5
Hz, H-5), 4.65 (d, 1H, J = 11.5 Hz, H-3), 3.77 (d, 1H, J = 11.5
Hz, H-13), 3.18 (dd, 1H, J = 13.5 Hz, J = 7.0 Hz, H-6’), 2.96
(dd, 1H, J = 13.5 Hz, J = 8.0 Hz, H-6), 2.58 (s, 3H, H-20),
2.14-2.24 (m, 1H, H-7), 2.05-2.13 (m, 1H, H-10), 0.93-0.99 (m,
9H, H-8 and H-9, H-12 or H-11), 0.88 (d, 3H, J = 7.0 Hz, H-11
or H-12). 13C NMR (101 MHz, CHLOROFORM-d) δ ppm
163.3 (C-2), 149.8 (C-17), 149.3 (C-15), 134.8 (C-19), 133.3
(C-14), 123.6 (C-18), 81.7 (C-5), 81.43 (C-13), 58.6 (C-3), 55.8
(C-6), 44.0 (C-20), 33.57 (C-10), 27.0 (C-7), 20.3 (C-8 or C-9),
20.2 (C-9 or C-8), 19.5 (C-11 or C-12), 15.0 (C-12 or C-11).
m/z (ES+) 319 ([M+H]+, 100%).
4.3.10.
3-(4-Chlorophenyl)-2-isobutyl-thiazolidin-4-thione
(12j). Prepared according to the general procedure B with 3-(4-
chlorophenyl)-2-isobutylthiazolidin-4-one 5j (0.8 g). 12j (0.7 g,
83%) was isolated by flash column chromatography (heptane /
ethyl acetate gradient from pure heptane to Hept/EtOAc 1:1, Rf
= 0.60 in Hept/EtOAc 2:1) as a yellow oil. IR (cm-1) υmax 1488,
1435, 1140 (C=S), 1089. 1H NMR (400 MHz,
CHLOROFORM-d) δ ppm 7.38-7.44 (m, 2H, HAr), 7.11-7.16
(m, 2H, HAr), 5.24 (app. ddt, 1H, J = 11.0 Hz, J = 2.0 Hz, J =
1.0 Hz, H-5), 4.29 (dd, 1H, J = 16.0 Hz, J = 2.0 Hz, H-3), 4.24
(dd, 1H, J = 16.0 Hz, J = 1.0 Hz, H-3’), 1.65-1.74 (m, 1H, H-
13), 1.57-1.65 (m, 1H, H-12), 1.45-1.54 (m, 1H, H-12’), 0.84
(d, 3H, J = 7.0 Hz, H-14 or H-15), 0.73 (d, 3H, J = 7.0 Hz, H-
15 or H-14). 13C NMR (101 MHz, CHLOROFORM-d) δ ppm
199.6 (C-2), 138.3 (Cquat), 134.8 (Cquat), 130.1 (2xCAr), 128.9
(2xCAr), 73.2 (C-5), 45.1 (C-3), 44.7 (C-12), 25.6 (C-13), 23.6
(C-14), 20.8 (C-15). m/z (ES+) 286 ([M+H]+, 100%), HRMS
(ES+) exact mass calculated for [M+H] (C13H17NClS2+)
requires m/z 286.0485, found m/z 286.0487.
4.4.2.
3-(4-Fluorophenyl)-6-isobutyl-2-methyl-spiro[3,3a-
(8b).
dihydropyrazolo[3,4-d]thiazole-5,1'-cyclohexane]
Prepared according to the general procedure C with 1-isobutyl-
4-thia-1-azaspiro[4.5]decan-2-thione 12b (170 mg) and p-
fluorobenzaldehyde. 8b (38 mg, 15 %) was isolated by flash
column chromatography (heptane / EtOAc gradient from pure
heptane to hept/EtOAc 2:1, Rf = 0.1 in EtOAc) as a light
yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm
7.19-7.29 (m, 2H, H-17 and H-21), 6.77-6.88 (m, 2H, H-18 and
H-20), 4.36 (d, 1H, J = 11.5 Hz, H-3), 3.43 (d, 1H, J = 11.5 Hz,
H-15), 2.96 (dd, 1H, J = 13.5, 6.5 Hz, H-6), 2.56 (dd, 1H, J =
13.5 Hz, J = 8.5 Hz, H-6’), 2.36 (s, 3H, H-22), 1.97-2.05 (m,
1H, H-7), 1.13-1.81 (m, 10H, H-10, H-11, H12, H-13 and H-
14), 0.74 (d, 3H, J = 6.5 Hz, H-8 or H-9), 0.69 (d, 3H, J = 6.5
Hz, H-9 or H-8).13C NMR (101 MHz, CHLOROFORM-d) δ
ppm 162.5 (d, J = 245.0 Hz, C-19), 161.8 (C-2), 133.2 (d, J =
3.0 Hz, C-16), 129.0 (d, J = 8.0 Hz, C-17 and C-21), 115.5 (d, J
4.3.11.
2-(4-Chlorophenyl)-3-(3-pyridyl)thiazolidin-4-thione
(12k). Prepared according to the general procedure B with 3-(4-
chlorophenyl)-3-(3-pyridyl)thiazolidin-4-one 5k (1.0 g). 12k
(0.9 g, 86%) was isolated by flash column chromatography

ACCEPTED MANUSCRIPT
= 22.0 Hz, C-18 and C-20), 85.6 (C-5), 82.7 (C-15), 55.9 (C-3),
8 or C-7). m/z (ES+) 388 ([M+H]+, 100%), HRMS (ES+) exact
mass calculated for [M+H] (C20H20ClFN3S+) requires m/z
388.1045, found m/z 388.1046.
51.1 (C-6), 43.8 (C-22), 39.5 (CH2), 37.7 (CH2), 26.6 (C-7),
24.9 (CH2), 24.7 (CH2), 23.7 (CH2), 20.3 (C-8 or C-9), 20.2 (C-
9 or C-8). m/z (ES+) 362 ([M+H]+, 100%), HRMS (ES+) exact
mass calculated for [M+H] (C20H29FN3S+) requires m/z
362.2061, found m/z 362.2057.
1
Minor Diastereoisomer: (selected data) H NMR (400 MHz,
CHLOROFORM-d) δ ppm 7.40-7.44 (m, 2H, H-17 and H-21),
7.24-7.29 (m, 3H, HAr), 7.13-7.18 (m, 1H, HAr), 7.00-7.06 (m,
2H, H-18 and H-20), 5.73 (s, 1H, H-5), 4.84 (d, 1H, J = 12.0
Hz, H-3), 3.89 (d, 1H, J = 12.0 Hz, H-15), 2.67 (s, 3H, H-22),
2.52-2.58 (m, 1H, H-6), 0.71-0.92 (m, 2H, H-7 or H-8), 0.37-
0.47 (m, 1H, H-8 or H-7), 0.20-0.30 (m, 1H, H-8 or H-7). m/z
(ES+) 388 ([M+H]+, 100%), HRMS (ES+) exact mass
calculated for [M+H] (C20H20ClFN3S+) requires m/z 388.1045,
found m/z 388.1050.
4.3.3.
3-(4-Fluorophenyl)-6-isobutyl-5-(2-methoxyphenyl)-2-
methyl-3a,5-dihydro-3H-pyrazolo[3,4-d]thiazole (8c). Prepared
according to the general procedure C with 3-isobutyl-2-(2-
methoxyphenyl)thiazolidin-4-thione 12c (150 mg) and p-
fluorobenzaldehyde. 8c (30 mg, 14 %) was isolated by flash
column chromatography (heptane / EtOAc gradient from pure
heptane to hept/EtOAc 2:1) as a light yellow oil as a 1: 0.7
mixture of diastereoisomers.
4.3.5.
6-Cyclopropyl-3-(4-fluorophenyl)-2-methyl-5-(3-
(8e).
pyridyl)-3a,5-dihydro-3H-pyrazolo[3,4-d]thiazole
Major
diastereoisomer:
1H
NMR
(400
MHz,
Prepared according to the general procedure C with 3-
cyclopropyl-2-(3-pyridyl)thiazolidin-4-thione 12e (343 mg) and
p-fluorobenzaldehyde. 8e (20 mg, 4 %) was isolated by flash
column chromatography (Heptane/EtOAc gradient from pure
heptane to pure EtOAc, Rf = 0.1 in EtOAc) as a light yellow
oil. Major diastereoisomer: 1H NMR (400 MHz,
CHLOROFORM-d) δ ppm 8.66 (d, 1H, J = 2.0 Hz, H-10), 8.61
(dd, 1H, J = 5.0 Hz Hz, J = 2.0 Hz, H-12), 7.91 (dt, 1H, J = 8.0
Hz, J = 2.0 Hz, H-14), 7.42-7.48 (m, 2H, H-17 and H-21), 7.28-
7.31 (m, 1H, H-13), 7.03-7.10 (m, 2H, H-18 and H-20), 5.83 (s,
1H, H-5), 4.69 (d, 1H, J = 11.5 Hz, H-3), 3.92 (d, 1H, J = 11.5
Hz, H-15), 2.66 (s, 3H, H-22), 2.05-2.11 (m, 1H, H-6), 0.82-
0.91 (m, 2H, H-7 or H-8), 0.50-0.58 (m, 1H, H-8 or H-7), 0.37-
0.47 (m, 1H, H-8 or H-7). 13C NMR (101 MHz,
CHLOROFORM-d) δ ppm 162.9 (d, J = 247.0 Hz, C-19),
161.4 (C-2), 150.8 (C-12), 149.7 (C-10), 136.2 (C-9), 136.1 (C-
14), 132.7 (C-16), 129.3 (d, J = 16.0 Hz, C-17 and C-21), 123.9
(C-13 ), 115.9 (d, J = 20.0 Hz, C-18 and C-20), 83.1 (C-15),
71.2 (C-5), 59.0 (C-3), 44.0 (C-22), 25.8 (C-6), 8.5 (C-7 or C-
8), 6.5 (C-8 or C-7). m/z (ES+) 355 ([M+H]+, 100%).
CHLOROFORM-d) δ ppm 7.20-7.43 (m, 4H, HAr), 6.73-7.03
(m, 4H, HAr), 6.04 (s, 1H, H-5), 4.66 (d, 1H, J = 11.5 Hz, H-3),
3.67-3.87 (m, 4H, H-16 and H-17), 3.14 (dd, 1H, J = 14.0 Hz, J
= 8.0 Hz, H-6), 2.92 (dd, 1H, J = 14.0 Hz, J = 7.5 Hz, H-6’),
2.55 (s, 3H, H-24), 1.93-2.05 (m, 1H, H-7), 0.86 (d, 3H, J = 6.5
Hz, H-8 or H-9), 0.85 (d, 3H, J = 6.5 Hz, H-9 or H-8).13C NMR
(101 MHz, CHLOROFORM-d) δ ppm 163.7 (C-2), 162.6 (d, J
= 245.0 Hz, C-21), 160.8 (C-15), 133.1 (d, J = 3.0 Hz, C-18),
130.6 (C-10), 129.3 (CAr), 129.0 (d, J = 8.0 Hz, C-19 and C-
23), 125.5 (CAr ), 120.5 (CAr ), 115.6 (d, J = 22.0 Hz, C-20 and
C-22), 110.6 (CAr ), 82.3 (C-17), 69.2 (C-5), 57.9 (C-3), 55.4
(C-16), 54.7 (C-6), 44.0 (C-24), 26.7 (C-7), 20.3 (C-8 or C-9),
20.2 (C-9 or C-8). m/z (ES+) 400 ([M+H]+, 100%), HRMS
(ES+) exact mass calculated for [M+H] (C22H27FN3S+) requires
m/z 400.1853, found m/z 400.1849.
Minor
diastereoisomer:
1H
NMR
(400
MHz,
CHLOROFORM-d) δ ppm 7.20-7.43 (m, 4H, HAr), 6.73-7.03
(m, 4H, HAr), 6.04 (s, 1H, H-5), 4.72 (d, 1H, J = 12.0 Hz, H-3),
3.67-3.87 (m, 4H, H-16 and H-17), 3.15 (dd, 1H, J = 14.0, 8.5
Hz, H-6), 2.42 (dd, 1H, J = 14.0 Hz, J = 7.0 Hz, H-6’), 2.56 (s,
3H, H-24), 1.77-1.89 (m, 1H, H-7), 0.79 (d, 3H, J = 6.5 Hz, H-
8 or H-9), 0.70 (d, 3H, J = 6.5 Hz, H-9 or H-8).13C NMR (101
MHz, CHLOROFORM-d) δ ppm 163.7 (C-2), 162.6 (d, J =
245.0 Hz, C-21), 160.8 (C-15), 133.0 (d, J = 3.0 Hz, C-18),
130.7 (C-10), 129.4 (CAr), 129.2 (d, J = 8.0 Hz, C-19 and C-
23), 126.0 (CAr ), 121.0 (CAr ), 115.7 (d, J = 22.0 Hz, C-20 and
C-22), 111.6 (CAr ), 82.0 (C-17), 69.2 (C-5), 58.0 (C-3), 55.6
(C-16), 51.8 (C-6), 43.9 (C-24), 26.4 (C-7), 20.1 (C-8 or C-9),
19.8 (C-9 or C-8). m/z (ES+) 400 ([M+H]+, 100%), HRMS
(ES+) exact mass calculated for [M+H] (C22H27FN3S+) requires
m/z 400.1853, found m/z 400.1848.
Minor
diastereoisomer:
1H
NMR
(400
MHz,
CHLOROFORM-d) δ ppm 8.52-8.54 (m, 2H, H-10 and H-12),
7.63 (dt, 1H, J = 8.0 Hz, J = 2.0 Hz, H-14), 7.37-7.42 (m, 2H,
H-17 and H-21), 7.21-7.25 (m, 1H, H-13), 7.01-7.05 (m, 2H, H-
18 and H-20), 5.74 (s, 1H, H-5), 4.83 (d, 1H, J = 11.0 Hz, H-3),
3.88 (d, 1H, J = 11.0 Hz, H-15), 2.66 (s, 3H, H-22), 2.50-2.57
(m, 1H, H-6), 0.80-0.89 (m, 1H, H-7 or H-8), 0.70-0.78 (m, 1H,
H-7 or H-8), 0.35-0.42 (m, 1H, H-8 or H-7), 0.07-0.15 (m, 1H,
H-8 or H-7). 13C NMR (101 MHz, CHLOROFORM-d) δ ppm
163.7 (C-2), 162.9 (d, J = 247.0 Hz, C-19), 150.1 (C-12), 148.2
(C-10), 134.5 (C-9), 134.5 (C-14), 132.8 (C-16), 129.2 (d, J =
16.0 Hz, C-17 and C-21), 123.8 (C-13 ), 115.8 (d, J = 20.0 Hz,
C-18 and C-20), 83.6 (C-15), 72.2 (C-5), 58.0 (C-3), 44.1 (C-
22), 28.7 (C-6), 6.3 (C-7 or C-8), 5.5 (C-8 or C-7).
4.3.4. 5-(3-Chlorophenyl)-6-cyclopropyl-3-(4-fluorophenyl)-2-
methyl-3a,5-dihydro-3H-pyrazolo[3,4-d]thiazole (8d). Prepared
according to the general procedure C with 2-(3-chlorophenyl)-
3-cyclopropyl-thiazolidin-4-thione 12d (209 mg) and p-
fluorobenzaldehyde. 8d (126 mg, 42 %) was isolated by flash
column chromatography (heptane / EtOAc gradient from pure
heptane to pure EtOAc) as a light yellow oil.
4.3.6.
5-(3-Chlorophenyl)-3-(4-fluorophenyl)-2-methyl-6-
(2,2,2-trifluoroethyl)-3a,5-dihydro-3H-pyrazolo[3,4-d]thiazole
(8f). Prepared according to the general procedure C with 2-(3-
chlorophenyl)-3-(2,2,2trifluoroethyl)thiazolidin-4-thione
12f
(226 mg) and p-fluorobenzaldehyde. 8f (134 mg, 43 %) was
isolated by flash column chromatography (heptane / EtOAc
gradient from pure heptane to pure EtOAc, Rf = 0.1 in EtOAc)
as a light yellow oil.
Major
diastereoisomer:
1H
NMR
(400
MHz,
CHLOROFORM-d) δ ppm 7.47-7.50 (m, 1H, HAr), 7.41-7.46
(m, 2H, H-17 and H-21), 7.36-7.40 (m, 1H, HAr), 7.32-7.36 (m,
2H, HAr), 7.07-7.08 (m, 2H, H-18 and H-20), 5.78 (s, 1H, H-5),
4.68 (d, 1H, J = 12.0 Hz, H-3), 3.93 (d, 1H, J = 12.0 Hz, H-15),
2.69 (s, 3H, H-22), 2.11-2.20 (m, 1H, H-6), 0.81-0.97 (m, 2H,
H-7 or H-8), 0.46-0.64 (m, 1H, H-8 or H-7), 0.36-0.46 (m, 1H,
H-8 or H-7). 13C NMR (101 MHz, CHLOROFORM-d) δ ppm
162.7 (d, J = 245.0 Hz, C-21), 161.4 (C-2), 141.6 (C-13), 134.6
(C-10), 132.7 (d, J = 3.0 Hz, C-16), 130.0 (CAr), 129.2 (d, J =
16.0 Hz, C-17 and C-21), 129.1 (CAr ), 128.3 (CAr ), 126.4 (CAr
), 115.7 (d, J = 20.0 Hz, C-18 and C-20), 82.9 (C-15), 73.0 (C-
5), 58.8 (C-3), 43.8 (C-22), 25.6 (C-6), 8.1 (C-7 or C-8), 6.3 (C-
Major
diastereoisomer:
1H
NMR
(400
MHz,
CHLOROFORM-d) δ ppm 7.22-7.29 (m, 3H, H-16, H-20 and
HAr), 7.10-7.20 (m, 3H, HAr), 6.82-6.89 (m, 2H, H-17 and H-
19), 5.87 (s, 1H, H-5), 4.63 (d, 1H, J = 12.0 Hz, H-3), 3.93 (dq,
1H, J = 16.0 Hz, J = 9.0 Hz, H-6), 3.76 (d, 1H, J = 12.0 Hz, H-
14), 2.86-3.01 (m, 1H, H-6’), 2.43 (s, 3H, H-21). 13C NMR
(101 MHz, CHLOROFORM-d) δ ppm 162.8 (d, J = 250.0 Hz,
C-18), 160.8 (C-2), 138.1 (C-8 or C-12), 135.3 (C-12 or C-8),
132.3 (d, J = 3.0 Hz, C-15), 130.5 (CAr), 130.4 (CAr), 129.2 (d, J
= 8.0 Hz, C-16 and C-20), 128.8 (CAr ), 127.1 (CAr ), 124.1 (q, J

ACCEPTED MANUSCRIPT
= 279.0 Hz, C-7), 115.7 (d, J = 21.0 Hz, C-17 and C-19), 82.4
Hz, J 2.0 Hz, H-13), 7.41-7.52 (m, 3H, H-12, H-16 and H-20),
7.03-7.13 (m, 2H, H-17 and H-19), 6.17 (s, 1H, H-5), 4.88 (d,
1H, J = 12.0 Hz, H-3), 4.10-4.26 (m, 1H, H-6), 3.94-4.06 (m,
1H, H-14), 3.04-3.19 (m, 1H, H-6’), 2.66 (s, 3H, H-21). 13C
NMR (101 MHz, CHLOROFORM-d) δ ppm 162.7 (d, J =
250.0 Hz, C-18), 160.7 (C-2), 151.6 (C-11), 150.3 (C-9), 136.5
(C-13), 135.9 (C-8), 132.1 (d, J = 3.0 Hz, C-15), 129.2 (d, J =
8.0 Hz, C-16 and C-20), 124.1 (C-12), 124.1 (q, = J 279.0 Hz,
C-7), 115.8 (d, J = 22.0 Hz, C-17 and C-19), 82.5 (C-14), 71.5
(C-5), 57.9 (C-3), 44.2 (q, J = 35.0 Hz, C-6), 43.5 (C-21). m/z
(ES+) 383 ([M+H]+, 100%), HRMS (ES+) exact mass
calculated for [M+H] (C18H17F4N4S+) requires m/z 397.1104,
found m/z 397.1103.
(C-14), 73.4 (C-5), 57.8 (C-3), 44.4 (q, J = 35.0 Hz, C-6), 43.5
(C-21). m/z (ES+) 430 ([M+H]+, 100%), HRMS (ES+) exact
mass calculated for [M+H] (C19H17ClF4N3S+) requires m/z
430.0762, found m/z 430.0763.
Minor
diastereoisomer:
1H
NMR
(400
MHz,
CHLOROFORM-d) δ ppm 7.32-7.39 (m, 2H, H-16 and H-20),
7.18-7.23 (m, 3H, HAr), 7.02-7.12 (m, 1H, HAr), 6.92-7.00 (m,
2H, H-17 and H-19), 5.72 (s, 1H, H-5), 4.79 (d, 1H, J = 11.5
Hz, H-3), 3.89 (d, 1H, J = 11.5 Hz, H-14), 3.74-3.84 (m, 2H, H-
6), 2.57 (s, 3H, H-21). 13C NMR (101 MHz, CHLOROFORM-
d) δ ppm 162.8 (d, J = 250.0 Hz, C-18), 161.2 (C-2), 142.2 (C-8
or C-12), 135.0 (C-12 or C-8), 132.3 (d, J = 3.0 Hz, C-15),
130.3 (CAr), 129.1 (d, J = 6.0 Hz, C-16 and C-20), 129.0 (CAr),
126.2 (CAr ), 124.2 (CAr ), 124.0 (q, J = 279.0 Hz, C-7), 115.8
(d, J = 22.0 Hz, C-17 and C-19), 83.4 (C-14), 74.0 (C-5), 56.9
(C-3), 48.2 (q, J = 35.0 Hz, C-6), 43.7 (C-21). m/z (ES+) 430
([M+H]+, 100%), HRMS (ES+) exact mass calculated for
[M+H] (C19H17ClF4N3S+) requires m/z 430.0762, found m/z
430.0762.
Minor
diastereoisomer:
1H
NMR
(400
MHz,
CHLOROFORM-d) δ ppm 8.59 (dd, 1H, J = 5.0 Hz, J = 2.0
Hz, H-11), 8.55 (d, 1H, J = 2.0 Hz, H-9), 7.70 (dt, 1H, J = 8.0
Hz, J = 2.0 Hz, H-13), 7.41-7.52 (m, 2H, H-16 and H-20), 7.34
(dd, 1H, J = 8.0 Hz, J 5.0 Hz, H-12), 7.03-7.13 (m, 2H, H-17
and H-19), 5.84 (s, 1H, H-5), 4.90 (d, 1H, J = 11.5 Hz, H-3),
3.94-4.06 (m, 2H, H-6 and H-14), 3.72-3.85 (m, 1H, H-6’),
2.66 (s, 3H, H-21). 13C NMR (101 MHz, CHLOROFORM-d) δ
ppm 162.7 (d, J = 250.0 Hz, C-18), 160.7 (C-2), 150.3 (C-11),
147.7 (C-9), 134.0 (C-13), 135.9 (C-8), 132.1 (d, J = 3.0 Hz, C-
15), 129.1 (d, J 8.0 = Hz, C-16 and C-20), 123.8 (C-12), 124.1
(q, J = 279.0 Hz, C-7), 115.7 (d, J = 22.0 Hz, C-17 and C-19),
83.6 (C-14), 72.7 (C-5), 57.0 (C-3), 48.5 (q, J =35.0 Hz, C-6),
43.5 (C-21). m/z (ES+) 383 ([M+H]+, 100%), HRMS (ES+)
exact mass calculated for [M+H] (C18H17F4N4S+) requires m/z
397.1104, found m/z 397.1101.
4.3.7.
5-(4-Chlorophenyl)-3-isobutyl-2-methyl-6-(2,2,2-
trifluoroethyl)-3a,5-dihydro-3H-pyrazolo[3,4-d]thiazole (8g).
Prepared according to the general procedure C with 3-(3-
chlorophenyl)-3-(2,2,2trifluoroethyl)thiazolidin-4-thione 12g
(209 mg) and isobutyraldehyde. 8g (150 mg, 57%) was isolated
by flash column chromatography (heptane / EtOAc gradient
from pure heptane to pure EtOAc, Rf = 0.1 in EtOAc) as a light
yellow oil.
Major
diastereoisomer:
1H
NMR
(400
MHz,
CHLOROFORM-d) δ ppm 7.30-7.56 (m, 4H, H-9, H-10, H-12
and H-13), 6.11 (s, 1H, H-5), 4.45 (d, 1H, J = 12.0 Hz, H-3),
4.08 (dq, 1H, J = 15.5 Hz, J = 9.5 Hz, H-6), 2.97-3.16 (m, 2H,
H-6’ and H-14), 2.72 (s, 3H, H-19), 1.49-1.74 (m, 3H, H-15
and H-16), 0.98 (d, 3H, J = 6.0 Hz, H-17 or H-18), 0.89 (d, 3H,
4.3.9. 5-(4-chlorophenyl)-3-(4-fluorophenyl)-2-methyl-6-(2,2,2-
trifluoroethyl)-3a,5-dihydro-3H-pyrazolo[3,4-d]thiazole (1H).
Prepared according to the general procedure C with 3-(3-
chlorophenyl)-3-(2,2,2trifluoroethyl)thiazolidin-4-thione 12g
(220 mg) and p-fluorobenzaldehyde. 8i (115 mg, 38 %) was
isolated by flash column chromatography (heptane / EtOAc
gradient from pure heptane to pure EtOAc, Rf = 0.1 in EtOAc)
as a light yellow oil.
J
=
6.0 Hz, H-18 or H-17). 13C NMR (101 MHz,
CHLOROFORM-d) δ ppm 161.5 (C-2), 136.0 (C-11), 134.8
(C-8), 130.3 (C-10 and C-12), 129.5 (C-9 and C-13), 124.0 (q, J
= 270.0 Hz, C-7), 77.9 (C-14), 73.4 (C-5), 54.8 (C-3), 44.1 (q, J
= 35.0 Hz, C-6), 43.8 (C-19), 40.2 (C-15), 27.2 (C-16), 24.2 (C-
17 or C-18), 21.8 (C-18 or C-17). m/z (ES+) 392 ([M+H]+,
100%), HRMS (ES+) exact mass calculated for [M+H]
(C17H22ClF3N3S+) requires m/z 392.1170, found m/z 392.1167.
Major
diastereoisomer:
1H
NMR
(400
MHz,
CHLOROFORM-d) δ ppm 7.22-7.28 (m, 2H, H-16 and H-20),
7.20 (app. d, 4H, J = 2.5 Hz, H-9, H-10, H-12 and H-13), 6.81-
6.88 (m, 2H, H-17 and H-19), 5.90 (s, 1H, H-5), 4.63 (d, 1H, J
= 12.0 Hz, H-3), 3.91 (dq, 1H, J = 15.5 Hz, J = 9.5 Hz, H-6),
3.74 (d, 1H, J = 12.0 Hz, H-14), 2.82-3.00 (m, 1H, H-6’), 2.43
(s, 3H, H-21). 13C NMR (101 MHz, CHLOROFORM-d) δ ppm
162.8 (d, J = 245.0 Hz, C-18), 161.0 (C-2), 136.2 (C-8 or C-
11), 134.3 (C-11 or C-8), 132.2 (d, J = 4.0 Hz, C-15), 130.3 (C-
9 and C-13), 129.5 (C-10 and C-12), 129.2 (d, J = 8.0 Hz, C-16
and C-20), 124.0 (q, J = 279.0 Hz, C-7), 115.8 (d, J = 21.0 Hz,
C-17 and C-19), 82.4 (C-14), 73.5 (C-5), 57.8 (C-3), 44.3 (q, J
= 34.0 Hz, C-6), 43.5 (C-21). m/z (ES+) 430 ([M+H]+, 100%),
HRMS (ES+) exact mass calculated for [M+H]
(C19H17ClF4N3S+) requires m/z 430.0762, found m/z 430.0766.
Minor
diastereoisomer:
1H
NMR
(400
MHz,
CHLOROFORM-d) δ ppm 7.33-7.44 (m, 2H, HAr), 7.20-7.25
(m, 2H, HAr), 5.76 (s, 1H, H-5), 4.48 (d, 1H, J = 12.0 Hz, H-3),
3.73-3.92 (m, 2H, H-6), 2.97-3.10 (m, 1H, H-14), 2.72 (s, 3H,
H-19), 1.49-1.73 (m, 3H, H-15 and H-16), 0.93 (d, 3H, J = 6.0
Hz, H-17 or H-18), 0.87 (d, 3H, J = 6.0 Hz, H-18 or H-17). 13C
NMR (101 MHz, CHLOROFORM-d) δ ppm 161.5 (C-2),
138.8 (C-11), 134.5 (C-8), 129.1 (C-10 and C-12), 127.2 (C-9
and C-13), 124.0 (q, J = 270.0 Hz, C-7), 79.0 (C-14), 74.1 (C-
5), 53.6 (C-3), 44.5 (q, J = 35.0 Hz, C-6), 43.9 (C-19), 40.3 (C-
15), 27.2 (C-16), 24.1 (C-17 or C-18), 21.6 (C-18 or C-17). m/z
(ES+) 392 ([M+H]+, 100%), HRMS (ES+) exact mass
calculated for [M+H] (C17H22ClF3N3S+) requires m/z 392.1170,
found m/z 392.1170.
Minor
diastereoisomer:
1H
NMR
(400
MHz,
CHLOROFORM-d) δ ppm 7.40-7.47 (m, 2H, H-16 and H-20),
7.32-7.38 (m, 2H, H-10 and H-12), 7.22-7.26 (m, 2H, H-9 and
H-13), 7.01-7.09 (m, 2H, H-17 and H-19), 5.80 (s, 1H, H-5),
4.87 (d, 1H, J = 12.0 Hz, H-3), 3.96 (d, 1H, J = 12.0 Hz, H-14),
3.77-3.94 (m, 2H, H-6), 2.65 (s, 3H, H-21). 13C NMR (101
MHz, CHLOROFORM-d) δ ppm 162.8 (d, J = 245.0 Hz, C-
18), 161.3 (C-2), 138.2 (C-8 or C-11), 134.8 (C-11 or C-8),
132.3 (d, J = 3.0 = Hz, C-15), 129.2 (C-10 and C-12), 129.1 (d,
J = 8.0 = Hz, C-16 and C-20), 127.5 (C-9 and C-13), 123.9 (q, J
= 280.0 Hz, C-7), 115.8 (d, J = 21.0 Hz, C-17 and C-19), 83.5
(C-14), 74.1 (C-5), 56.9 (C-3), 48.5 (q, J = 35.0 Hz, C-6), 43.7
(C-21). m/z (ES+) 430 ([M+H]+, 100%), HRMS (ES+) exact
mass calculated for [M+H] (C19H17ClF4N3S+) requires m/z
430.0762, found m/z 430.0764.
4.3.8.
3-(4-Fluorophenyl)-2-methyl-5-(3-pyridyl)-6-(2,2,2-
trifluoroethyl)-3a,5-dihydro-3H-pyrazolo[3,4-d]thiazole (8h).
Prepared according to the general procedure C with 2-(3-
pyridyl)-3-(2,2,2trifluoroethyl)thiazolidin-4-thione 12h (210
mg) and p-fluorobenzaldehyde. 8h (138 mg, 48 %) was isolated
by flash column chromatography (heptane / EtOAc gradient
from pure heptane to pure EtOAc, Rf = 0.1 in EtOAc) as a light
yellow oil.
Major
diastereoisomer:
1H
NMR
(400
MHz,
CHLOROFORM-d) δ ppm 8.72 (dd, 1H, J = 5.0 Hz, J = 2.0
Hz, H-11), 8.69 (d, 1H, J = 2.0 Hz, H-9), 7.87 (dt, 1H, J = 8.0

ACCEPTED MANUSCRIPT
4.3.10. 3,6-Bis(4-fluorophenyl)-5-(2-methoxyphenyl)-2-methyl-
3a,5-dihydro-3H-pyrazolo[3,4-d]thiazole (8j). Prepared
heptane to pure EtOAc, Rf = 0.1 in EtOAc) as a light yellow
oil.
according to the general procedure C with 3-(4-fluorophenyl)-
2-(2-methoxyphenyl)thiazolidin-4-thione 12i (200 mg) and p-
fluorobenzaldehyde. 8j (82 mg, 30 %) was isolated by flash
column chromatography (heptane / EtOAc gradient from pure
heptane to pure EtOAc, Rf = 0.1 in EtOAc) as a light yellow oil
(unseparable mixture of diastereoisomers).1H NMR (400 MHz,
CHLOROFORM-d) δ ppm 7.15-7.45 (m, 12H, HAr), 6.72-7.05
(m, 13H, H-5a and HAr), 6.60 (s, 1H, H-5b), 4.75 (d, 1H, J =
12.0 Hz, H-3a), 4.72 (d, 1H, J = 12.0 Hz, H-3b), 3.92 (d, 1H, J
= 12.0 Hz, H-14a), 3.91 (d, 1H, J = 12.0 Hz, H-14b), 3.83 (s,
6H, H-18), 3.91 (s, 6H, H-26). 13C NMR (101 MHz,
CHLOROFORM-d) δ ppm 162.7 (d, J = 245.0 Hz, Cquat-F),
162.6 (d, J = 245.0 Hz, Cquat-F), 159.3 (C-2a), 158.3 (C-2b),
156.2 (C-17b), 155.5 (C-17a), 136.1 (d, J = 2.0 Hz, C-6a),
136.0 (d, J = 2.0 Hz, C-6b), 132.7 (d, J = 3.0 Hz, C-20b), 132.5
(d, J = 3.0 Hz, C-20a), 129.8 (CAr), 129.6 (CAr), 129.1 (d, J =
8.0 Hz, C-21a and C-25a), 129.0 (d, J = 8.0 Hz, C-21b and C-
25b), 127.8 (C-12a), 127.4 (C-12b), 127.3 (CAr), 124.7 (CAr),
121.4 (CAr), 120.7 (CAr), 119.5 (d, J = 8.0 Hz, C-11a and C-7a),
119.4 (d, J = 8.0 Hz, C-11b and C-7b), 115.7 (d, J = 21.0 Hz,
CAr-CF), 115.6 (d, J = 21.0 Hz, CAr-CF), 115.3 (d, J = 21.0 Hz,
CAr-CF), 110.8 (CAr), 110.7 (CAr), 82.1 (C-14b), 80.8 (C-14a),
68.7 (C-5b), 66.9 (C-5a), 59.1 (C-3b), 58.4 (C-3a), 55.7 (C-
18b), 55.5 (C-18a), 43.9 (C-26a), 43.6 (C-26b). m/z (ES+) 438
([M+H]+, 100%), HRMS (ES+) exact mass calculated for
[M+H] (C24H22F2N3OS+) requires m/z 438.1446, found m/z
438.1442.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.39-7.49 (m,
4H, H-18, H-22 and HAr), 7.30-7.36 (m, 2H, HAr), 7.03-7.12 (m,
2H, H-19 and H-21), 5.68 (dd, 1H, J = 10.5 Hz, J = 3.0 Hz, H-
5), 4.67 (d, 1H, J = 12.0 Hz, H-3), 3.90 (d, 1H, J = 12.0 Hz, H-
16), 2.67 (s, 3H, H-23), 1.92-2.07 (m, 1H, H-12), 1.62-1.80 (m,
2H, H-12’ and H-13), 0.97 (d, 3H, J = 7.0 Hz, H-14 or H-15),
0.94 (d, 3H, J = 7.0 Hz, H-15 or H-14). 13C NMR (101 MHz,
CHLOROFORM-d) δ ppm 162.7 (d, J = 245.0 Hz, C-20),
157.4 (C-2), 138.2 (C-6), 132.6 (d, J = 3.0 Hz, C-17), 129.2 (d,
J = 11.0 Hz, C-18 and C-22), 129.1 (2xCAr), 128.2 (C-9), 121.0
(CAr), 115.7 (d, J = 20.0 Hz, C-19 and C-21), 82.3 (C-16), 7.06
(C-5), 58.3 (C-3), 44.1 (C-12), 43.6 (C-23), 25.2 (C-13), 23.8
(C-14 or C-15), 21.2 (C-15 or C-14). m/z (ES+) 404 ([M+H]+,
100%), HRMS (ES+) exact mass calculated for [M+H]
(C21H24ClFN3S+) requires m/z 404.1358, found m/z 404.1357.
4.3.13. 5-(4-Chlorophenyl)-3-isobutyl-2-methyl-6-(3-pyridyl)-
3a,5-dihydro-3H-pyrazolo[3,4-d]thiazole (8m).
Prepared according to the general procedure C with 2-(4-
chlorophenyl)-3-(3-pyridyl)thiazolidin-4-thione 13k (250 mg)
and isobutyraldehyde. 8m (10 mg, 3 %) was isolated by flash
column chromatography (heptane / EtOAc gradient from pure
heptane to pure EtOAc, Rf = 0.26 in Hept/EtOAc 1:1) as a light
yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm
8.50 (br. s, 1H, H-7), 8.22 (d, 1H, J = 1.5 Hz, H-9), 8.16 (dt,
1H, J = 8.5 and 1.5 Hz, H-11), 7.33 (d, 2H, J = 8.5 Hz, H-14
and H-16), 7.21-7.25 (m, 1H, H-10), 7.18 (d, 2H, J = 8.5 Hz, H-
13 and H-17), 6.42 (s, 1H, H-5), 4.53 (d, 1H, J = 11.0 Hz, H-3),
3.09 (td, 1H, J = 11.0 and 4.0 Hz, H-18), 2.81 (s, 3H, H-23),
1.57-1.69 (m, 2H, H-19), 1.44-1.52 (m, 1H, H-20), 0.93 (d, 3H,
J = 6.5 Hz, H-22 or H-21), 0.87 (d, 3H, J = 6.5 Hz, H-21 or H-
22). 13C NMR (101 MHz, CHLOROFORM-d) δ ppm 158.5 (C-
2), 149.0 (C-6), 143.4 (C-9), 138.8 (C-7), 138.5 (C-12), 134.4
(C-15), 129.5 (C-14 and C-16), 126.4 (C-13 and C-17), 124.9
(C-11), 123.8 (C-10), 76.7 (C-18), 72.1 (C-5), 54.7 (C-3), 43.9
(C-23), 40.1 (C-19), 27.2 (C-20), 22.4 (C-21 or C-22), 21.6 (C-
22 or C-21). m/z (ES+) 387 ([M+H]+, 100%).
4.3.11. 6-(4-Fluorophenyl)-3-isobutyl-5-(2-methoxyphenyl)-2-
methyl-3a,5-dihydro-3H-pyrazolo[3,4-d]thiazole (8k). Prepared
according to the general procedure C with 3-(4-fluorophenyl)-
2-(2-methoxyphenyl)thiazolidin-4-thione 12i (185 mg) and
isobutyraldehyde. 8k (74 mg, 32 %) was isolated by flash
column chromatography (heptane / EtOAc gradient from pure
heptane to Heptane/EtOAc 3:2, Rf = 0.49 in Hept/EtOAc 1:2)
as a light yellow oil.
Major
diastereoisomer:
1H
NMR
(400
MHz,
CHLOROFORM-d) δ ppm 7.17-7.49 (m, 4H, HAr), 6.77-7.13
(m, 5H, H-5 and HAr), 4.43 (d, 1H, J = 12.0 Hz, H-3), 3.91 (s,
3H, H-18), 3.01-3.15 (m, 1H, H-19), 2.82 (s, 3H, H-24), 1.48-
1.72 (m, 3H, H-20 and H-21), 0.80-1.02 (m, 6H, H-22 and H-
23). 13C NMR (101 MHz, CHLOROFORM-d) δ ppm 159.1 (C-
2), 157.9 (d, J = 240.0 Hz, C-9), 156.2 (C-13), 136.1 (d, J = 3.0
Hz, C-6), 129.7 (CAr), 128.6 (C-12), 127.4 (CAr), 121.4 (CAr),
119.4 (d, J = 8.0 Hz, C-11 and C-7), 115.2 (d, J = 22.0 Hz, C-8
and C-10), 110.7 (CAr), 77.6 (C-14), 66.9 (C-5), 56.0 (C-3),
55.8 (C-18), 43.8 (C-24), 40.4 (C-20), 27.2 (C-21), 24.2 (C-22
or C-23), 21.9 (C-23 or C-22). m/z (ES+) 400 ([M+H]+, 100%)
4.5. Preparation of 5-[(4-fluorophenyl)methylene]-3-
isobutyl-2-(2-methoxyphenyl)thiazolidin-4-one 7c : a dried
one-necked flask, equipped with a magnetic stirrer bar, was
charged with thiazolidinone 5c (1.0 g, 1.0 eq.), p-
fluorobenzaldehyde (0.4 mL, 1.1 eq.) and dry toluene (30 mL,
t
0.1 mol/L). Then, potassium butoxide (4.1 mL, 1.1 eq.) was
added dropwise. After stirring for 5 min under nitrogen, 3Å
molecular sieves were added to the reaction. The mixture was
left under a nitrogen atmosphere and stirred at RT until
completion (monitored by LCMS, usually 30 min). Then, the
solvent was removed under vacuum and the crude material was
purified by FCC (heptane / EtOAc gradient from pure heptane
to Heptane/EtOAc 2:1, Rf = 0.74 in Hept/EtOAc 1:1) giving
0.51g (37% yield) of desired product as a yellow oil.
Minor
diastereoisomer:
1H
NMR
(400
MHz,
CHLOROFORM-d) δ ppm 7.17-7.49 (m, 4H, HAr), 6.77-7.13
(m, 4H, HAr), 6.63 (s, 1H, H-5), 4.48 (d, 1H, J = 12.0 Hz, H-3),
3.93 (s, 3H, H-18), 3.01-3.15 (m, 1H, H-19), 2.80 (s, 3H, H-
24), 1.48-1.72 (m, 3H, H-20 and H-21), 0.80-1.02 (m, 6H, H-22
and H-23). 13C NMR (101 MHz, CHLOROFORM-d) δ ppm
162.0 (C-13), 159.1 (C-2), 157.9 (d, J = 240.0 Hz, C-9), 136.1
(d, J = 3.0 Hz, C-6), 129.4 (CAr), 128.1 (C-12), 127.3 (CAr),
120.7 (CAr), 119.5 (d, J = 8.0 Hz, C-11 and C-7), 115.5 (d, J =
22.0 Hz, C-8 and C-10), 110.8 (CAr), 77.6 (C-14), 66.8 (C-5),
56.0 (C-3), 55.6 (C-18), 44.0 (C-24), 40.2 (C-20), 27.1 (C-21),
24.2 (C-22 or C-23), 21.6 (C-23 or C-22).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51 (s, 1H,
H-17), 7.43-7.50 (m, 2H, H-19 and H-23 ), 7.31 (td, 1H, J = 8.0
Hz, J = 2.0 Hz, H-13), 7.01-7.12 (m, 3H, H-15, H-20 and H-
22), 6.88-6.99 (m, 2H, H-12 and H-14), 6.28 (s, 1H, H-5), 3.89
(s, 3H, H-16), 3.82 (dd, 1H, J = 14.0 Hz, J = 9.0 Hz, H-6), 2.67
(dd, 1H, J = 14.0 Hz, J = 6.0 Hz, H-6’), 1.95-2.08 (m, 1H, H-7),
0.92 (d, 3H, J = 6.5 Hz, H-8 or H-9), 0.91 (d, 3H, J = 6.5 Hz,
H-9 or H-8).13C NMR (101 MHz, CHLOROFORM-d) δ ppm
167.2 (C-2), 161.9 (d, J = 248.0 Hz, C-21), 157.1 (C-11), 131.7
(d, C-18), 131.1 (d, J = 8.0 Hz, C-19 and C-23), 130.1 (C-13),
126.5 (C-15), 126.3 (C-3), 125.9 (C-10), 124.0 (C-17), 121.2
(C-14), 115.6 (d, J = 21.0 Hz, C-20 and C-22), 111.0 (C-12),
56.8 (C-5), 55.7 (C-16), 50.7 (C-6), 26.6 (C-7), 20.3 (C-8 or C-
9), 19.8 (C-9 or C-8). m/z (ES+) 372 ([M+H]+, 100%).
4.3.12.
6-(4-Chlorophenyl)-3-(4-fluorophenyl)-5-isobutyl-2-
methyl-3a,5-dihydro-3H-pyrazolo[3,4-d]thiazole (8l) Prepared
according to the general procedure C with 3-(4-chlorophenyl)-
2-isobutyl-thiazolidin-4-thione 12j (200 mg) and p-
fluorobenzaldehyde. 8l (56 mg, 20 %) was isolated by flash
column chromatography (heptane / EtOAc gradient from pure

ACCEPTED MANUSCRIPT
18. Sadashivaa, C. T.; Narendra, J. N.; Chandraa, S.; Kavithaa, C.
References and notes
V.; Thimmegowdab, A.; Subhashc, M. N.; Rangapaa, K. S. Eur.
J. Med. Chem. 2009, 44, 4848-4854.
19. Meshram, J.; Ali, P.; Tiwari, V. Green Chem. Lett. Rev. 2010, 3,
195-200.
1. Lamberth, C., Dinges, J. in Bioactive Heterocyclic Compound
Classes, Lamberth, C., Dinges, J. (Eds.), Wiley-VCH,
Weinheim, 2012, p. 3-20.
2. a) Zwanenburg, B.; Kemperman, G. J.; Zhu, J.; De Gelder, R.;
Dommerholt, F. J.; Titulaer, G. T. M.; Keltjens, R.; Klunder, A.
J. H. in Synthesis of β-Lactam Antibiotics, Bruggink, A. (Ed.),
Kluwer Academic Publishers, Dordrecht, 2001, pp. 56-101; b)
Pitlik, J. Bioorg. Med. Chem. 1995, 3, 1157-1181.
3. a) Amery, W. K. P.; Bruynseels, J. P. J. M. Int. J.
Immunopharmcol. 1992, 14, 481-486; b) Janssen, P. A. J. Prog.
Drug Res. 1976, 20, 347-383.
4. a) Johnson, T. C. in Bioactive Heterocyclic Compound Classes,
Lamberth, C., Dinges, J. (Eds.), Wiley-VCH, Weinheim, 2012,
p. 51-60; b) Johnson, T. C.; Mann, R. K.; Schmitzer, P. R.; Gast,
R. E.; deBoer, G. J. in Modern Crop Protection Compounds,
Krämer, W., Schirmer, U., Jeschke, P., Witschel, M. (Eds.),
Wiley-VCH, Weinheim, 2012, p. 99-117.
20. Pratap, U. R.; Jawale, D. V.; Bhosle, M. R.; Mane, R. A.
Tetrahedron Lett. 2011, 52, 1689-1691.
21. a) Srinivas, A.; Nagaraj, A.; Reddy, C. S. Eur. J. Med. Chem.
2010, 45, 2353-2358; b) Thadhaney, B.; Sharma, S.; Sharma, C.;
Talesara, G. L. J. Ind. Chem. Soc. 2009, 86, 1204-1213; c)
Reddy, C. S.; Srinivas, A.; Nagaraj, A. Chem. Pharm. Bull.
2009, 57, 685-693; d) Zhou, J.-F.; Sun, X.-J.; Zhu, F.-X.; Li, Y.-
L-; Gong, G.-X. Synth. Commun. 2008, 38, 4182-4187; e)
Merja, B. C.; Joshi, A. M.; Parikh, K. A.; Parikh, A. R. Ind. J.
Chem. 2004, 43B, 909-912.
22. a) Dua, R.; Sonwane, S. K.; Srivastava, S. K.; Srivastava, S. D.
J. Chem. Pharm. Res. 2010, 2, 415-423; b) Shashank, D.;
Vishawanth, T.; Arif, P. M:; Balasubramaniam, V.; Nagendra,
A.; Perumal, P.; Suthakaran, R. Int. J. ChemTech Res. 2009, 1,
1224-1231; c) Öcal, N.; Aydogan, F.; Yolacan, C.; Turgut, Z. J.
Heterocycl. Chem. 2003, 40, 721-724;
5. a) Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112,
3083-3135; b) Dömling, A. Chem. Rev. 2006, 106, 17; c)
Multicomponent Reactions, Zhu, J.; Bienayme, H. (Eds.),
Wiley-VCH, Weinheim, 2005; d) Hulme, C.; Gore, V. Curr.
Med. Chem. 2003, 10, 51.
23. Panda, S.; Dash, S. K. J. Chem. Pharm. Res. 2010, 2, 449-457.
24. Kaminskyy, D.; Khyluk, D.; Vasylenko, O.; Lesyk, R.
Tetrahedron Lett. 2012, 53, 557-559.
25. Arya, K.; Dandia, A. J. Fluorine Chem. 2007, 128, 224-231.
26. Russel, A. J.; Westwood, I. M.; Crawford, M. H. J.; Robinson,
J.; Kawamura, A.; Redfield, C.; Laurieri, N.; Lowe, E. D.;
Davies, S. G.; Sim, E. Bioorg. Med. Chem. 2009 17, 905-918; b)
Ohishi, Y.; Mukai, T.; Naghara, M.; Yajima, M.; Kajikawa, N.;
Miyahara, K.; Takeno, T. Chem. Pharm. Bull. 1990, 38, 1911-
1919; c) Li, Q.; Wu, J.; Zheng, H.; Liu, K.; Guo, T. L.; Eblen, S.
T.; Grant, S.; Zhang, S. Bioorg. Med. Chem. 2010, 20, 4526-
4530; d) Panda, S.; Dash, S. K. J. Chem. Pharm. Res. 2010, 2,
449-457; e) Eggers, K.; Fyles, T. M.; Montoya-Pelaez, P. J. J.
Org. Chem. 2001, 66, 2966-2977; f) Kaminskyy, D.; Khyluk,
D.; Vasylenko, O.; Lesyk, R. Tetrahedron Lett. 2012, 53, 557-
559
27. a) Pawelczyk, A.; Zaprutko, L. Flavour Fragr. J. 2011, 26, 101-
106; b) Vintonyak, V. V.; Warburg, K.; Kruse, H.; Grimme, S.;
Hübel, K.; Rauh, D.; Waldmann, H. Angew. Chem. Int. Ed.
2010, 49, 5902-5905; c) Metwally, N. H. Phosphorus Sulfur
Silicon 2008, 183, 34-43; d) Rao, A.; Carbone, A.; Chimirri, A.;
De Clercq, E.; Monforte, A. M.; Montforte, P.; Pannecouque,
C.; Zappala, M. Farmaco 2002, 57, 747-751.
6. a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions
in Organic Synthesis, Wiley-VCH, Weinheim, 2006; b)
Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.
Int. Ed. 2006, 45, 7134-7186; c) Pellisier, H. Tetrahedron 2006,
62, 2143-2173; d) Pellissier, H. Tetrahedron 2006, 62, 1619-
1665; e) Tietze, L. F. Chem. Rev. 1996, 96, 115-136.
7. a) Synthesis of Heterocycles via Multicomponent Reactions;
Top. Heterocycl. Chem. 2010, 23, Orru, R. V. A., Ruijter, E.
(Eds.), Springer, Berlin, 2010; b) Jiang, B.; Shi, F.; Tu, S.-J.
Curr. Org. Chem. 2010, 14, 357; c) Jiang, B.; Rajale, T.; Wever,
W.; Tu, S.-J.; Li, G. Chem. Asian J. 2010, 5, 2318; d)
Ivachtchenko, A. V.; Ivanenkov, Y. A.; Kysil, V. M:; Krasavin,
M. Y.; Ilyin, A. P. Russ. Chem. Rev. 2010, 79, 787, e)
Sunderhaus, J. D.; Martin, S. F. Chem. Eur. J. 2009, 15, 1300; f)
D’Souza, D. M.; Müller, T. J. J. Chem. Soc. Rev. 2007, 36,
1095; g) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471; h)
Zhu, J. Eur. J. Org. Chem. 2003, 1133.
8. a) Lu, L.-Q.; Chen, J.-R.; Xiao, W.-J. Acc. Chem. Res. 2012, 45,
1278-1293; b) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63,
5341-5378; c), Tietze, L. F.; Rackelmann, N. Pure Appl. Chem.
2004, 76, 1967-1983.
9. A) Sayed, H. H.; Morsy, E. M. H.; Kotb, E. R. Synth. Commun.
2010, 40, 2712-2722; b) Cherkupally, S. R.; Dasari, C. R.;
Vookanti, Y.; Adki, N. Org. Commun. 2010, 3, 57-69; c) Reddy,
C. S.; Srinivas, A.; Nagaraj, A. Chem. Pharm. Bull. 2009, 57,
685-693; d) Turgut, Z.; Yolacan, C.; Aydogan, F.; Bagdatli, E.;
Ocal, N. Molecules 2007, 12, 2151-2159; e) Abdel-Megid, M.;
Awas, M. A. A. Heterocycl. Commun. 2002, 8, 161-168; f) El-
Zohry, M. F.; Awad, I. M. A.; Abdel-Hafez, A. A. Arch. Pharm.
1993, 326, 115-118.
28. a) Xu, Z.; De Moliner, F.; Cappelli, A. P. ; Hulme, C. Angew.
Chem. Int. Ed. 2012, 51, 8037-8040 ; b) Ausmees, K. ; Kriis, K.;
Pehk, T.; Werner, F.; Järving, I.; Lopp, M.; Kanger, T. J. Org.
Chem. 2012, 77, 10680-10687.
10. a) Faidallah, H. M.; Khan, K. A.; Asiri, A. M. J. Fluorine Chem.
2011, 132, 131-137; b) Al-Saadi, M. S.; Rostom, S. A. F.;
Faidallah, H. M. Arch. Pharm. Chem. Life Sci. 2008, 341, 181-
190.
11. a) Shah, P. M.; Patel, M. P. Ind. J. Chem. 2011, 50B, 310-314;
b) Srinivas, A.; Nagaraj, A.; Reddy, C. S. J. Heterocycl. Chem.
2008, 45, 999-1003; c) Gurav, V. M.; Huge, K. G.; Kondaya, G.
C. J. Indian Chem. Soc. 2007, 84, 1174-1175; d) Desai, K. G.;
Desai, K. R. J. Sulfur Chem. 2006, 27, 315-328; e) Srivastava, S.
K.; Srivastava, S. L.; Srivastava, S. D. J. Ind. Chem. Soc. 2002,
77, 104-105.
12. Zhou, Z. Z.; Huang, W.; Ji, F. Q.; Ding. M. W.; Yang, G. F.
Heteroatom Chem. 2007, 18, 381-3989.
13. Bhatt, R. K.; Sharma, S.; Nath, M. Monatsh. Chem. 2012, 143,
309-316.
14. Sharma, R. C.; Kumar. D. J. Ind. Chem. Soc 2000, 77, 492-493.
15. a) Rawal, R. K.; Prabhakar, Y. S.; Katti, S. B.; De Clercq, E.
Biorog. Med. Chem. 2005, 13, 6771-6776; b) Srivastava, T.;
Haq, W.; Katti, S. B. Tetrahedron 2002, 58, 7619-7624.
16. Bhosle, M. R.; Mali, J. R.; Mulay, A. A.; Mane, R. A. Heteroat.
Chem. 2012, 23, 166-170.
17. a) Arya, K.; Rawat, D. S.; Dandia, A.; Sasai, H. J. Fluorine
Chem. 2012, 137, 117-122; b) Lingampalle, D.; Jawale, D.;
Waghmare, R.; Mane, R. Synth. Commun. 2010, 40, 2397-2401;
c) Yadav, A. K.; Kumar, M.; Yadav, T.; Jain, R. Tetrahedron
Lett. 2009, 50, 5031-5034; d) Zhang, X.; Li, X.; Li, D.; Qu, G.;
Wang, J.; Loiseau, P. M.; Fan, X. Bioorg. Med. Chem. Lett.
2009, 19, 6280-6283; e) Fraga-Dubreuil, J.; Bazureau, J. P.
Tetrahedron 2003, 59, 6121-6130.