Synthesis of thiazole derivatives bearing an incorporated Z-5-aminopent-3-enoic acid fragment

Article abstract of DOI:10.1016/j.tet.2013.06.060

Novel compounds bearing a joint thiazole and a Z-5-aminopent-3-enoic acid fragments have been synthesized from readily accessible 5-bromolevulinic esters through a sequence of nucleophilic substitution, bromination, Hantzsch-type heterocyclization and Gabriel-like deprotection reactions. A majority of these reactions proceed in ionic liquid media that enhances their efficiency and selectivity in comparison to the corresponding reactions in conventional organic solvents. The compounds have a significant pharmaceutical potential.

Full text of DOI:10.1016/j.tet.2013.06.060

Accepted Manuscript
Synthesis of thiazole derivatives bearing an incorporated Z-5-aminopent-3-enoic acid
fragment
Alexander G. Zavozin, Nikolai V. Ignat’ev, Michael Schulte, Sergei G. Zlotin
PII:
S0040-4020(13)01001-6
10.1016/j.tet.2013.06.060
TET 24536
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 April 2013
Revised Date: 7 June 2013
Accepted Date: 17 June 2013
Please cite this article as: Zavozin AG, Ignat’ev NV, Schulte M, Zlotin SG, Synthesis of thiazole
derivatives bearing an incorporated Z-5-aminopent-3-enoic acid fragment, Tetrahedron (2013), doi:
10.1016/j.tet.2013.06.060.
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ACCEPTED MANUSCRIPT
Graphical Abstract

ACCEPTED MANUSCRIPT
2
Synthesis of thiazole derivatives bearing an incorporated Z-5-
aminopent-3-enoic acid fragment
a
b
b
a,
Alexander G. Zavozin , Nikolai V. Ignat’ev , Michael Schulte , Sergei G. Zlotin *
a
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky
prosp., Moscow 119991, Russia
b
Merck KGaA, PC-RL, Frankfurter Strasse 250, D-64293 Darmstadt, Germany
*
Corresponding author: Tel.: +7(499)1371353, Fax: +7(499)1355328, E-mail: zlotin@ioc.ac.ru
Abstract: Novel compounds bearing a joint thiazole and a Z-5-aminopent-3-enoic acid fragments
have been synthesized from readily accessible 5-bromolevulinic esters through a sequence of
nucleophilic substitution, bromination, Hantzsch-type heterocyclization and Gabriel-like
deprotection reactions. A majority of these reactions proceed in ionic liquid media that enhances
their efficiency and selectivity in comparison to the corresponding reactions in conventional
organic solvents. The compounds have a significant pharmaceutical potential.
Key words: Thiazole derivatives, Z-5-aminopent-3-enoic acid, levulinic acid, Hantzsch reaction,
bromination reaction, ionic liquids.
1
. Introduction
5
-Aminopentanoic acid is an analog of γ-aminobutanoic acid (GABA), which plays a key role in
1
mammalians nervous system functioning. It interacts with GABA
A
-receptor as a moderately
2
3
active agonist and targets at the RDL (resistance to dieldrin) receptor. Z-5-Aminopent-3-enoic
4
A
acid acts also as a GABA -receptor agonist, being more active than 5-aminopentanoic acid.
5
Thiazole derivatives have found broad applications in drug design for inflammation,
6
7
8
9
hypertension, treatment of bacterial and HIV infections and some other diseases. Among
10
them, aminothiazoles are known as ligands for estrogen receptors and adenosine receptor
1
1
antagonists. It can be expected that functionalized compounds of the structure 1, in which the
thiazole moiety is incorporated into the Z-5-aminopent-3-enoic acid fragment (Figure 1), would
be capable to interact with different types of receptors responsible for the most essential
functions of living systems. This approach can be used to develop novel multi-target remedies.
To our best knowledge, the compounds described by general formula 1 have not been reported
so far.

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3
Figure 1. Target molecules 1 and key precursors 2.
2
. Results and discussion
-Phthalimido-4-oxopentanoic (levulinic) esters 2 bearing protected amino and carboxylic
5
groups along with the carbonyl group between carbon atoms C3 and C4 were chosen as key
precursors (Figure 1). It is worth mentioning that 5-phthalimido-levulinic acid 2 (R = H) itself
exhibits hypolipidemic activity and reduces serum triglyceride and cholesterol levels in CF
1
12
mice.
γ-Ketoesters 2 (R = Alk) are commonly synthesized by nucleophilic substitution of the
13a-d
bromine atom in 5-bromolevulinic esters 3 with potassium phthalimide 5 (Scheme 1).
However, it is hard to obtain pure terminal bromides 3; bromination of levulinic esters usually
13d, 14-16
affords a mixture of isomers 3 and 4 in varied ratios.
To simplify the experimental
procedure and to skip the separation of isomers 3 and 4 we decided to use a mixture of bromides
13d
3
and 4 (3:1, prepared by the known protocol ) directly in the reactions with potassium
phthalimide 5. We expected that less hindered terminal bromides 3 would react with 5 at higher
rates than isomeric bromides 4. Indeed, the reaction of bromides 3/4 mixture (R = Me or Et) with
imide 5 proceeds regioselectively resulting in the formation preferably of 5-phthalimido-4-
oxoesters 2a or 2b. Compounds 2a,b can be easily isolated from unreacted 3-bromolevulinates
4
a,b due to different solubility in diethyl ether. Pure phthalimide ketoesters 2a or 2b were
obtained in 50% yield (Scheme 1).
O
O
OR
N Cat
O
O
Levulinic esters
Cat = K (5), bmim (6)
Br+
[bmim]Cl, MeCN
rt
O
O
O
O
5
or 6
OR
OR
OR
N
DMF or MeCN,
rt, 20 h, 50-65%
Br
O
Br
O
O
O
3
4
2
: R=Me (a), Et (b)
Scheme 1. Synthesis of 5-(phthalimido)levulinates 2a,b.

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4
Furthermore, we improved the yields of products 2a and 2b up to 65% by using reagent 6
with 1-butyl-3-methylimidazolim (bmim) cation instead of potassium phthalimide 5. The so far
1
7
unknown salt 6, which is a congener of an ionic liquid (IL), was prepared by an ion exchange
reaction between 5 and [bmim]Cl in anhydrous MeCN at ambient temperature. The reaction
appeared to be reversible, regardless of the 5 / [bmim]Cl ratio (1 : 1 or 2 : 1), the product 6
contains chloride originated from the salt [bmim]Cl. That was confirmed by microanalysis (Cl:
1
3
.00 %) and H NMR data (integral intensity of the signals is less than it should be for four
aromatic protons). The presence of chloride in reagent 6 does not hinder the reaction with
compounds 3. However it should be taken into account in order to calculate correctly the
required quantity of the reagents. Unlike potassium phthalimide 5, the compound 6 is readily
soluble in MeCN or DMF, that is beneficial for the reaction (Scheme 1) providing better yields
of phthalimide derivatives 2a or 2b.
The reaction of compounds 2a and 2b with bromine afforded 3-bromoderivatives 7a and
7
b correspondingly. The best results were obtained in the [bmim]BF – Et O (2 : 3, v/v) solvent
4 2
system in the presence of a catalytic amount of HBr. Under these conditions the reaction time
could be significantly reduced (40 h in Et O versus 0.5 h in the [bmim]BF – Et O system).
2
4
2
Furthermore, the ionic liquid [bmim]BF can be easily recovered and reused in the same reaction
4
without a reduction in yield (Scheme 2). Surprisingly, the bromination of ketoesters 2a and 2b
4 2
did not occur in pure ionic liquid [bmim]BF without the addition of Et O. Further research is
required to find out the reason for this unexpected result.
We found that bromine atom in bromoketones 7a,b could be easily substituted with various
nucleophiles. Sulfides 8a and 8b were obtained in 80-84% yields in reactions of the compounds
7
a or 7b with 5-methyl-1,3,4-thiadiazole-2-thiol. Intereaction of 7b with malononitrile proceeds
as a domino-reaction which includes nucleophilic substitution and intramolecular cyclization
resulting in the formation of furan derivative 9 in moderate yield of 33% (Scheme 2).

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5
Scheme 2. Synthesis and reactions of 3-bromo-4-keto-5-(phthalimido)valeric esters 7a,b.
By means of its reaction with thiourea 10a-h or thioamide 10i-l derivatives, bromoketone
b was converted into the corresponding thiazoles 11a-l (the Hantzsch reaction). To optimize the
7
reaction conditions we studied a model reaction of bromoketone 7b with phenylthiourea (10a) in
conventional organic solvents and in ionic liquid [bmim][BF
4
] (Table 1). The reaction did not
o
proceed by refluxing in EtOH for 5 h (Entry 1). However, the reaction in acetone (56 C, 5 h)
afforded the desired thiazole derivative 11a in 85% yield (Entry 2). A further improvement in the
o
yield of 11a (92%) was achieved in the IL medium (60 C, 5 h) (Entry 3). Various thiourea
derivatives 10b-h were involved in the reaction with bromoketone 7b in these conditions
(Entries 4-10). The corresponding thiazoles 11b-h were obtained in high yields (Entries 4-10).
Moreover, thioacetamide (10i) and thiobenzamides 10j-l are also reactive enough to be involved
in this reaction. Though a longer reaction time (12-15 h) was needed to reach reasonable yields
of alkyl- or aryl substituted isothiazoles 10j-l (Entries 11-14). The IL can be regenerated and
reused in the reaction between compounds 7b and 10g. Moreover, the yield of product 11g in the
second run was in 5% higher than in the first cycle, probably due to the presence of a minor
quantity of dissolved 11g in the recovered IL from the previous run. The synthesis of thiazoles

ACCEPTED MANUSCRIPT
6
from ordinary α-bromoketones and thiourea derivatives in the ionic liquid medium have been
9a
recently reported. However the reported protocol does not describe a treatment step essential
for product isolation. To our best knowledge, α-halogen ketones bearing other functional groups
have not been employed so far in the reactions with thiourea or thioamide derivatives in ionic
liquids.
2
a
Table 1. Synthesis of 2-R -5-ethoxycarbonylmethyl-4-phtalimidomethylthiazoles 11
2
o
Entry
Product 11
R
Yield, % (cycle) Mp, C
b
1
a
a
a
b
c
d
e
f
PhNH
PhNH
PhNH
0
-
c
2
85
144-146
144-146
182-184
94-95
3
4
5
6
7
8
9
92
NH
2
86
AllylNH
BnNH
89
87
119
4-MeC
6
H
4
NH
80
135-136
144-145
135-136
161-163
116-118
132-134
124-125
137-138
3-MeC H NH
95
6
4
g
h
i
2-MeOC
6
H
4
NH
76 (1), 81(2)
1
1
1
1
1
0
1
2
3
4
2-Pyridyl-NH
82
61
76
72
70
d
e
e
e
Me
Ph
j
k
l
4-FC
6 4
H
4-ClC H
6
4
a
Unless other conditions are pointed out, the reaction with 7b (0.30 g, 0.82 mmol) was carried
o
b
out with in [bmim]BF (1-2 mL) at 60 C for 5 h. The reaction was carried out by refluxing in
EtOH. The reaction was carried out by refluxing in acetone. The reaction was carried out for
1
4
c
d
e
5 h. The reaction was carried out for 12 h.
Phthalimido esters 11d,f,h,j were hydrolyzed to the target 2-(4-aminomethyl-thiazol-5-yl)
acetic acid derivatives 12a-d by a modified Gabriel protocol. Deprotection of the esters 11d,f,h,j
.
was achieved by refluxing in aqueous HCl. The generated amino acid hydrochlorides 12 HCl
were converted to the corresponding amino acids 12a-d by treatment with Na CO The amino
2
3
acids (12) are crystalline high-melting point compounds insoluble in most organic solvents. The

ACCEPTED MANUSCRIPT
7
1
13
structures and purity of the compounds 12 were confirmed by IR, H and C NMR
spectroscopy and HRMS spectrometry data.
3
. Conclusion
In summary, we have synthesized the previously unknown thiazole derivatives 12 bearing
the Z-5-aminopent-3-enoic acid structural fragment. The synthesis includes substitution of
bromine atom in 5-bromolevulinic esters 3 by means of the reaction with potassium or 1-butyl-3-
methylimidasolium phthalimides. The regioselective reaction of 2-phthalimido-4-oxoesters 2
with bromine followed by a Hantzsch-type substitution/heterocyclization domino reaction
sequence leads to the formation of the thiazole derivatives 11. The synthesis of the amino acids
1
2 was performed via a Gabriel-like deprotection of heterocycles 11. All reactions within this
protocol, with the exception of the last one, efficiently proceed in ionic liquid media. That
resulted in improved product yield and selectivity in comparison to the reactions in conventional
organic solvents. We believe that prepared thiazole derivatives 12 and their analogs may be
useful precursors in the development of novel multi-target remedies for various therapies.
4
4
. Experimental
.1. General
The IR spectra (KBr pellets) were recorded on a Bruker ALPHA-T spectrometer. Thin
layer chromatography was performed on TLC Silica gel 60 F254 (Merck) plates, visualization by
1
13
2
I or UV. The NMR spectra were recorded on a Bruker AM 300 ( H 300.13; C 75.47 MHz)
spectrometer. The chemical shifts are reported in ppm relative to tetramethylsilane. The mass
spectra were recorded on a Kratos MS-30 (UK) electron ionization spectrometer (EI = 70 eV).
The high resolution mass spectra (HRMS) were measured on a Bruker micrOTOF II
Electrospray Ionization (ESI) mass spectrometer. The measurements were done in a positive ion
mode (interface capillary voltage: 4500 V) or in a negative ion mode (3200 V); mass range from
m/z 50 to m/z 3000 Da; external or internal calibration was done with Electrospray Calibrant
Solution (Fluka). A syringe was used to inject a solution of the examined compound in
acetonitrile, methanol, or water (flow rate 3 µL/min). Nitrogen was applied as a dry carrier;
o
interface temperature was set at 180 C. Melting points were measured on a Boetius heating table.
For microanalyses a EURO Vector-3000 analyzer was used. The solvents were pre-purified. The
research-grade reagents were used as supplied by Merck.
4
.2. General procedure for the synthesis of alkyl 5-phthalimido-levulinates 2a and 2b

ACCEPTED MANUSCRIPT
8
Method A. Potassium phthalimide 5 (1.15 g, 6.21 mmol) was slowly added (10-15 min) to a
stirred solution of isomeric bromides 3 and 4 (6:4) (10.0 mmol) in dry DMF (8 mL) cooled with
ice-bath. The reaction mixture was kept stirred at ambient temperature for 20 h. Then water (50
mL) was added to the mixture. The precipitate was filtered off, washed successively with water
(
10 mL) and dried on air. The solid was dissolved in chloroform (10 mL), the insoluble fraction
phthalimide) was filtered off and the filtrate was rotary-evaporated. The residue was subjected
(
to flash chromatography (silica gel, 66% benzene/EtOAc) to afford 5-phthalimido-levulinates 2a
or 2b.
Method B. A solution of the mixture 6 / [bmim]Cl (3 : 1) (2.80 g) in MeCN (10 mL) was
dropwise added to a stirred solution of isomeric bromides 3 and 4 (6:4) (10.0 mmol) in MeCN
(
10 mL) cooled with ice-bath. The reaction mixture was kept stirred at ambient temperature for
0 h. The solvent was evaporated under reduced pressure (10 Torr) and water (50 mL) was
added to the residue. Products 2a or 2b were isolated as described above.
2
4
.2.1. Methyl 5-(1,3-dioxoisoindolin-2-yl)-4-oxopentanoate (2a) (0.83 g, 50%) (Method A) or
о
13a
o
(
1.00 g, 60%) (Method B) as a white solid, m.p. 94-95 С (n-hexane/EtOAc) (lit. m.p. 97 C);
R (75% benzene/EtOAc) 0.52; δ (CDCl ) 7.90-7.70 (4H, m), 4.56 (2H, s), 3.69 (3H, s), 2.86
f
H
3
(
3H, t, J 6.60 Hz), 2.66 (2H, t J 6.60 Hz).
4
.2.2. Ethyl 5-(1,3-dioxoisoindolin-2-yl)-4-oxopentanoate (2b) (0.90 g, 52%) (Method A) or
о
13b
(
1.13 g, 65%) (Method B) as a white solid, m.p. 81-82 С (n-hexane/EtOAc) (lit. m.p. 74-75
o
C); R
f
(75% benzene/EtOAc) 0.63; δ
H
(CDCl
3
) 7.90-7.70 (4H, m), 4.55 (2H, s), 4.12 (2H, q J
1
7
.34 Hz), 2.85 (2H, t J 6.60 Hz), 2.65 (2H, t J 6.60 Hz), 1.26 (3H, t J 7.70 Hz). The H NMR
18,19
characteristics of 2a and 2b are in agreement with reported data.
4
.3. Preparation of the [bmim]phthalimide (6) – [bmim]Cl (3:1) mixed salts system
Potassium phthalimide 5 (4.45 g, 24.0 mmol) was slowly added to a stirred solution of [bmim]Cl
4.20 g, 24.0 mmol) in dry MeCN (20 mL) at RT. The reaction mixture was stirred for 12 h at
(
ambient temperature. The colorless precipitate was filtered off and washed with MeCN (5 mL).
o
The filtrate was evaporated at 60 С under reduced pressure (10 torr) to afford the
[
bmim]phthalimide (6) – [bmim]Cl (3 : 1) mixed salts system (6.25 g, 91 %) as an yellow oil; δH
DMSO-d ) 9.42 (1H, s), 7.83 (1H, s), 7.75 (1H, s), 7.42-7.30 (3H, m, Ph), 4.18 (2H, t, J 7.2 Hz),
.88 (3H, s), 1.75 (2H, quintet, J 7.2 Hz), 1.24 (2H, sextet, J 7.2 Hz), 0.88 (3H, t, J 7.2 Hz); δ
DMSO-d ) 185.1, 139.2, 137.0, 130.2 (2C), 123.5, 122.2, 119.4 (2C), 48.4, 35.6, 31.4, 18.7,
(
6
3
C
(
6

ACCEPTED MANUSCRIPT
9
+
1
8 15 2
3.1; HRMS: MH - Pht, found: 139.1236. C H N requires 139.1230. The same mixed salt
was obtained in the experiment where potassium phthalimide 5 (4.45 g, 24.0 mmol) was used in
double excess to [bmim]Cl (2.10 g, 12.0 mmol). The product (mixed salt) was used in further
experiments without purification.
4
7
.4. General procedure for the synthesis of alkyl 3-bromo-5-phthalimido-levulinates 7a and
b
Bromine (0.11 mL, 2.20 mmol) was added to a stirred suspension of alkyl 5-phthalimido-
levulinates 2a or 2b (2.0 mmol), [bmim]BF (2.0 g) in Et O (2 mL) with 2 drops of HBr. The
reaction mixture was refluxed for 30 min (without Еt O the reaction did not proceed), cooled
down to RT and extracted with diethyl ether (3×20 mL). The combined extracts were washed
successively with aqueous NaHCO (15 mL), H O (15 mL) and dried over anhydrous Na SO
4
2
2
3
2
2
4
.
The solvent was evaporated under reduced pressure (10 torr). The residue was triturated with n-
hexane (20 mL), the precipitate was filtered and dried on air to afford alkyl 3-bromo-5-
phthalimido-levulinates 7a or 7b.
4
.4.1. Methyl 3-bromo-5-(1,3-dioxoisoindolin-2-yl)-4-oxopentanoate (7a) (0.53 g, 75%) as a
colourless crystals, m.p. 120-121 °C; [Found: C, 47.34; H, 3.41; Br, 22.58; N, 3.90.
(354.16) requires C, 47.48; H, 3.42; Br, 22.56; N, 3.95%]; R (75%
) 7.88-7.72
5), 4.82 (1H, t, J 7.3 Hz, 3H), 4.68 (1H, d, J 17.9 Hz, H 5),
C
14
H
12BrNO
5
f
-1
benzene/EtOAc) 0.70; νmax 1774, 1738, 1721, 1415, 725 (CHBr) cm ; δ
H 3
(CDCl
(4H, m), 5.08 (1H, d, J 17.9 Hz, H
b
a
3
1
3
.73 (3H, s), 3.34 (1H, dd, J 17.3, 8.1 Hz, H
b
2), 3.00 (1H, dd, J 17.3, 6.2 Hz, H
a
2); δ
C
3
(CDCl )
+
95.8, 169.9, 167.4, 134.3 (2C), 132.1, 123.7 (2C), 52.4, 44.3, 41.8, 38.2; HRMS: MNa , found
5
75.9794. C14H12BrNO requires 375.9791.
4
.4.2. Ethyl 3-bromo-5-(1,3-dioxoisoindolin-2-yl)-4-oxopentanoate (7b) (0.59 g, 80%) as a
colourless crystals, m.p. 97-99 °C; [Found: C, 49.19; H, 3.75; Br, 21.74; N, 3.82. C15H14BrNO
5
(
368.18) requires C, 48.93; H, 3.83; Br, 21.70; N, 3.80%]; R (75% benzene/EtOAc) 0.74; νmax
f
-
1
1
4
777, 1720, 1419, 716 (CHBr) cm ; δ
H
(CDCl
3
b
) 7.88-7.72 (4H, m), 5.08 (1H, d, J 17.9 Hz, H 5),
a 2
.82 (1H, t, J 7.3 Hz, H3), 4.70 (1H, d, J 17.9 Hz, H 5), 4.18 (2H, q, J 7.0 Hz, OCH ), 3.34 (1H,
dd, J 17.3, 8.1 Hz, H 2), 3.00 (1H, dd, J 17.3, 6.2 Hz, H 2), 1.26 (3H, t J 7.3 Hz, Me); δ
C
b
a
(CDCl
3
) 195.7, 169.4, 167.4, 134.3 (2C), 132.1, 123.7 (2C), 61.5, 44.3, 41.9, 38.5, 14.1; HRMS:
+
+
MH , found 368.0125, MNa , found 389.9939. C15
H
14BrNO
5
requires 368.0128 and 389.9948.

ACCEPTED MANUSCRIPT
1
0
4
.4.3. Recycling procedure. To ionic liquid remained after extraction of the reaction mixture
2 2 2
with Et O a fresh portions of 2b (0.58 g, 2.0 mmol), Et O (2 mL), HBr (2 drops) and Br (0.11
mL, 2.2 mmol) were added and the reaction was re-performed as described above to afford (0.64
g, 87%) of bromoketone 7b.
4
.5. General procedure for the synthesis of sulfides 8a and 8b
A mixture of alkyl 3-bromo-5-phthalimido-levulinate 7a or 7b (1.0 mmol), 5-methyl-1,3,4-
thiadiazole-2-thiol (0.13 g, 1.0 mmol), NaHCO (0.21 g, 2.5 mmol) and acetone (10 mL) was
3
stirred at RT for 48 h (TLC control). The solvent was evaporated in vacuo and water (30 mL)
was added to the residue. The precipitate was filtered and washed successively with water (5
mL) and n-hexane (5 mL) to afford corresponding sulfide 8a or 8b.
4
.5.1.
Methyl
5-(1,3-dioxoisoindolin-2-yl)-3-(5-methyl-1,3,4-thiadiazol-2-ylthio)-4-
о
oxopentanoate (8a) (0.32 g, 80%) as a light-brown powder, m.p. 140-141 С (n-hexane/EtOAc);
[
15 3 5 2
Found: C, 50.27; H, 3.58; N, 10.35; S, 15.64. C17H N O S (405.45) requires C, 50.36; H, 3.73;
-1
N, 10.36; S, 15.82%]; R
f
(66% benzene/EtOAc) 0.33; νmax 2956, 1776, 1721, 1405, 728 cm ; δ
H
(
CDCl ) 7.86-7.70 (4H, m), 5.11 (1H, t, J 4.7 Hz, H3), 5.05 (1H, d, J 17.9 Hz, H 5), 4.82 (1H, d,
3
b
J 17.9 Hz, H
a
b
5), 3.73 (3H, s), 3.20 (1H, dd, J 17.4, 8.1 Hz, H 2), 3.04 (1H, dd, J 17.4, 6.6 Hz,
H
a
2), 2.74 (3H, s); δ
6.8, 44.8, 34.9, 15.3; HRMS: MH , found 406.0529, MNa , found: 428.0347. C17
requires 406.0526 and 428.0345.
C 3
(CDCl ) 197.2, 169.9, 166.8, 166.4, 133.6 (2C), 131.6, 123.1 (2C), 51.8,
+
+
4
15 3 5 2
H N O S
4
.5.2. Ethyl 5-(1,3-dioxoisoindolin-2-yl)-3-(5-methyl-1,3,4-thiadiazol-2-ylthio)-4-oxopentanoate
o
(
8b) (0.35 g, 84%) as a light-yellow powder, m.p. 117-119 C (n-hexane/EtOAc); [Found: C,
5
1.62; H, 4.20; N, 10.03; S, 15.28. C H N O S (419.48) requires C, 51.54; H, 4.08; N, 10.02;
18 17 3 5 2
-1
S, 15.29%]; R
f
(66% benzene/EtOAc) 0.42; νmax 2993, 1776, 1725, 1414, 732 cm ; δ
H 3
(CDCl )
7
.84-7.68 (4H, m), 5.09 (1H, t, J 4.8 Hz, H3), 5.04 (1H, d, J 18.1 Hz, H 5), 4.79 (1H, d, J 18.1
b
Hz, H 5), 4.15 (2H, q, J 7.1 Hz), 3.16 (1H, dd, J 17.4, 8.3 Hz, H 2), 3.01 (1H, dd, J 17.4, 5.3 Hz,
a
b
H
a
2), 2.73 (1H, s), 1.24 (3H, t, J 7.1 Hz); δ
C
(CDCl
3
) 197.7, 170.0, 167.4, 167.0, 161.8, 134.1
+
+
(
2C), 132.1, 123.6 (2C), 61.5, 47.4, 45.4, 35.7, 15.8, 14.1; HRMS: MH , found 420.0672, MNa ,
found: 442.0497. C H N O S requires 420.0682 and 442.0502.
1
8
17
3
5 2
4
.6. Synthesis of ethyl 2-(5-amino-4-cyano-2-((1,3-dioxoisoindolin-2-yl)methyl)fur-3-
yl)acetate (9)

ACCEPTED MANUSCRIPT
1
1
Dicyanomethane (0.046 g, 0.70 mmol) and 7a (0.25 g, 0.68 mmol) were slowly added to a
stirred solution of Na (0.016 g) in abs. EtOH (1 mL) at RT. The resulting suspension was stirred
o
at 90 C for 2.5 h, cooled to ambient temperature, diluted with water (30 mL) and extracted with
4
EtOAc (3 x 15 ml). Combined extracts were dried over anhydrous MgSO and evaporated under
reduced pressure (10 Torr). The residue was purified by column chromatography (silica gel, 66%
o
benzene/EtOAc) to afford compound 9 (0.08 g, 33%) as a colourless crystals, m.p. 181-183 C;
-1
R
f
(75% benzene/EtOAc) 0.30; νmax 3356 (NH
2 2
), 2217 (CN), 1776, 1724, 1657 (NH ) cm ;
δ (CDCl ) 7.88-7.72 (4H, m), 4.90 (2H, s, NH ), 4.70 (2H, s), 4.20 (2H, q, J 7.0 Hz), 3.66 (2H,
H
3
2
s), 1.30 (3H, t, J 7.0 Hz); δ
C
(CDCl
22.8 (2C), 116.6, 114.7, 60.6, 31.4, 29.3, 13.6; HRMS: MH , found 354.1081, MNa , found:
76.0902. C H N O requires 354.1084 and 376.0904.
3 6
/DMSO-d ) 169.3, 166.9, 162.6, 135.6, 133.8 (2C), 131.4,
+
+
1
3
18
15
3
5
4
.7. General procedure for the synthesis of thiazole derivatives 11
A mixture of ethyl 3-bromo-5-phthalimidolevulinate 7b (0.30 g, 0.82 mmol) and thiourea or
thioamide 10 (0.82 mmol) in [bmim]BF (1-2 mL) was stirred at 60 °C for the time given in the
Table 1. After the reaction completion (TLC monitoring), the reaction mixture was diluted with
Na CO 20% aqueous solution (20 mL). Precipitated products 11a-c,e,g,i-l were filtered and
washed successively with water (2×5 mL) and cold Et O (2 mL) and crystallized from CHCl /n-
hexane or EtOAc/n-hexane solvent mixture. Oily products 11d,f,h were extracted with EtOAc
3×10 mL), the combined organic layers were concentrated in vacuo and the residue was purified
by column chromatography (silica gel, 75% benzene/EtOAc) to afford thiazoles 11 (d,f,h).
For recovering of ionic liquid the basic aqueous solution of [bmim]BF was evaporated to
a half of the volume and extracted with CH Cl (3×6 mL). The combined organic extracts were
4
2
3
2
3
(
4
2
2
dried over anhydrous MgSO and evaporated under reduced pressure (10 Torr). The remaining
4
IL was dried at 80 °C for 0.5 h (10 Torr) and could be further reused in the reactions described
above.
4
.7.1. Ethyl 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-2-(phenylamino)thiazol-5-yl) acetate (11a)
as a light-yellow crystals, m.p. 144-146 °C (CHCl /hexane); [Found: C, 62.74; H, 4.58; N, 9.93;
S, 7.73. C H N O S (421.45) requires C, 62.69; H, 4.54; N, 9.97; S, 7.61%]; R (75%
3
22
19
3
4
f
-1
benzene/EtOAc) 0.68; νmax 3308, 1769, 1733, 1708, 1528, 1395, 1187, 747, 713 cm ; δ
H
(
CDCl ) 7.85-7.68 (4H, m), 7.40-7.20 (5H, m), 7.00 (1H, t, J 6.8 Hz), 4.77 (2H, s), 4.18 (2H, q, J
3

ACCEPTED MANUSCRIPT
1
2
7
1
.1 Hz), 3.96 (2H, s), 1.28 (t, 3H, J 7.1 Hz); δ
C 3
(CDCl ) 170.3, 167.9, 163.5, 142.5, 140.0,
34.0 (2C), 132.3, 129.4 (2C), 123.4 (2C), 123.2, 118.3 (2C), 115.3, 61.5, 35.1, 31.8, 14.2.
4
.7.2. Ethyl 2-(2-Amino-4-(1,3-dioxoisoindolin-2-yl)methylthiazol-5yl) acetate (11b) as a light-
yellow crystals, m.p. 182-184 °C; [Found: C, 55.41; H, 4.29; N, 11.89; S, 9.08. C16
345.36) requires C, 55.64; H, 4.38; N, 12.17; S, 9.28%]; R (25% benzene/EtOAc ) 0.46; νmax
410 (NH ), 1766, 1729, 1710, 1633, 1531, 1395, 1180, 717 cm ; δ (DMSO-d ) 7.95-7.75 (4H,
15 3 4
H N O S
(
f
-1
3
2
H
6
m) 6.81 (2H, s, NH
DMSO-d ) 170.1, 167.2, 166.7 (2C), 142.6, 134.4 (2C), 131.5 (2C), 123.0 (2C), 112.1, 60.4,
5.0, 30.9, 13.9.
2 C
), 4.51 (2H, s), 4.08 (2H, q, J 6.8 Hz), 3.80 (2H, s), 1.18 (3H, t, J 6.8 Hz); δ
(
6
3
4
.7.3. Ethyl 2-(2-allylamino-4-((1,3-dioxoisoindolin-2-yl)methyl)thiazol-5-yl) acetate (11c). as a
colourless crystals, m.p. 94-95 °C (CHCl /n-hexane); [Found: C, 59.28; H, 5.10; N, 11.21; S,
3
8
.19. C19
19 3 4 f
H N O S (385.42) requires C, 59.21; H, 4.97; N, 10.90; S, 8.32%]; R (75%
benzene/EtOAc) 0.40; νmax 3313, 2982, 1767, 1740, 1711, 1545, 1403, 1336, 1193, 1173, 716
-1
cm ; δ
H 3
(CDCl ) 7.85-7.68 (4H, m), 5.93-5.78 (1H, m, CH), 5.25 (1H, d, J 17.0 Hz, NH), 5.14
(
2H, d, J 9.8 Hz, CH =CH), 4.68 (2H, s), 4.15 (2H, q, J 7.2 Hz), 3.91 (2H, s), 3.78 (2H, t, J 6.8
2
Hz, CH
2
C 3
NH), 1.27 (3H, t, J 7.2 Hz); δ (CDCl ) 170.5, 168.0 (2C), 167.8, 143.6, 133.8 (2C),
1
33.6, 132.3 (2C), 123.3 (2C), 117.2, 114.6, 61.2, 48.2, 35.4, 31.9, 14.2.
4
.7.4. Ethyl 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-2-((phenylmethyl)amino)thiazol-5-yl) acetate
(
11d) as a colourless crystals, m.p. 119 °C (n-hexane/EtOAc); [Found: C, 63.42; H, 4.83; N,
.63; S, 7.30. C23 S (435.48) requires C, 63.43; H, 4.86; N, 9.65; S, 7.36.%]; R (75%
benzene/EtOAc) 0.58; νmax 3215 (NH), 1772, 1716, 1578, 1395, 1202, 714 cm ; δ (CDCl )
9
H
21
3
N O
4
f
-1
H
3
7
.92-7.68 (4H, m), 7.40-7.20 (5H, m), 5.38 (1H, br s), 4.72 (2H, s), 4.35 (2H, d, J 6.4 Hz), 4.18
(
2H, q, J 6.8 Hz), 3.90 (2H, s), 1.25 (3H, t, J 6.8 Hz); δ (CDCl ) 170.6, 167.9, 162.5, 143.7,
C
3
1
3
37.6, 133.8 (2C), 132.3, 128.6 (2C), 127.8, 127.7 (2C), 123.3 (2C), 114.6, 61.3, 49.8, 35.4,
1.9, 14.2.
4
.7.5. Ethyl 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-2-((4-methylphenyl)amino)thiazol-5-yl)
acetate (11e) as a light-yellow crystals, m.p. 135-136 °C (CHCl
3
/n-hexane); [Found: C, 63.46;
H, 4.82; N, 9.70; S, 7.38. C H N O S (435.48) requires C, 63.43; H, 4.86; N, 9.65; S, 7,36%];
2
3
21
3
4
-1
R
f
(75% benzene/EtOAc) 0.66; νmax 3359, 1770, 1732, 1710, 1530, 1393, 1188, 713 cm ; δ
H
(
CDCl ) 7.88-7.66 (4H, m), 7.14-7.02 (5H, m), 4.75 (2H, s), 4.18 (2H, q, J 5.9 Hz), 3.92 (2H, s),
3

ACCEPTED MANUSCRIPT
1
3
2
1
.28 (3H, s), 1.27 (3H, t, J 6.6 Hz); δ
C 3
(CDCl ) 170.4, 167.9, 163.9, 143.4, 137.8, 133.9 (2C),
32.8, 132.3, 129.9 (2C), 123.3 (2C), 118.8 (2C), 115.0, 61.4, 35.3, 31.8, 20.8, 14.2.
4
.7.6. Ethyl 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-2-((3-methylphenyl)amino)thiazol-5-yl)
°
acetate (11f) as a light-yellow crystals, m.p. 144-145 C (CHCl
3
/n-hexane); [Found: C, 63.40; H,
4
.80; N, 9.63; S, 7.31. C H N O S (435.48) requires C, 63.43; H, 4.86; N, 9.65; S, 7.36%]; R
23 21 3 4
f
-1
(
75% benzene/EtOAc) 0.62; νmax 3344, 1769, 1737, 1710, 1525, 1393, 1182, 713 cm ; δ
H
(CDCl
3
) 7.85-7.66 (4H, m), 7.15 (2H, t, J 6.8 Hz), 7.04 (1H, s), 6.98 (1H, d, J 7.6 Hz), 6.80 (1H,
d, J 7.2 Hz), 4.76 (2H, s), 4.18 (2H, q J 7.0 Hz), 3.94 (2H, s), 2.29 (3H, s), 1.28 (3H, t, J 7.0 Hz);
δ (CDCl ) 170.4, 167.9, 163.2, 143.4, 140.2, 139.4, 133.9 (2C), 132.3, 129.2, 123.8, 123.4 (2C),
C
3
+
1
18.8, 115.3, 115.2, 61.4, 35.4, 31.8, 21.5, 14.2; HRMS: MH , found 436.1319. C23
21 3 4
H N O S
requires 436.1326.
4
.7.7. Ethyl 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-2-((2-methoxyphenyl)amino)thiazol-5-yl)
°
acetate (11g) as a colourless crystals, m.p. 135-136 C (n-hexane/EtOAc); [Found: C, 61.29; H,
4
.51; N, 9.31; S, 7.15. C23
H
21
N
3
O
5
S (451.48) requires C, 61.18; H, 4.69; N, 9.31; S, 7.10%]; R
f
-1
(
75% benzene/EtOAc) 0.69; νmax 3335, 1772, 1720, 1542, 1392, 1248, 711 cm ; δ
H
(CDCl
3
)
7
.90-7.60 (6H, m), 6.98-6.78 (3H, m), 4.80 (2H, s), 4.20 (2H, q, J 7.0 Hz), 3.95 (2H, s), 3.80
(CDCl ) 170.4, 167.9, 162.2, 147.5, 143.5, 133.9 (2C), 132.4,
(3H, s), 1.25 (3H, t, J 7.0 Hz); δ
C
3
1
29.9, 123.4 (2C), 121.9, 121.1, 116.2, 115.4, 110.2, 61.4, 55.7, 35.4, 31.9, 14.2.
4
.7.8. Ethyl 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-2-(2-pyridinylamino)thiazol-5-yl) acetate
°
(
11h) as a light-yellow crystals, m.p. 161-163 C; [Found: C, 59.65; H, 4.21; N, 13.32; S, 7.65.
C
21
H
18
N
4
O
4
S (422.44) requires C, 59.70; H, 4.29; N, 13.26; S, 7.59%]; R
.51; νmax 3296, 1769, 1734, 1711, 1532, 1480 (2-Pyridyl), 1395, 1194, 768, 714 cm ; δ
CDCl ) 8.35-8.20 (2H, br d, J 4.1 Hz), 7.85-7.67 (4H, m), 7.52 (1H, t, J 7.1 Hz), 6.82 (1H, t, J
f
(75% benzene/EtOAc)
-1
0
H
(
3
6
7
.0 Hz), 6.68 (1H, d, J 8.3 Hz), 4.80 (2H, s), 4.18 (2H, q, J 7.1 Hz), 3.96 (2H, s), 1.25 (3H, t, J
.1 Hz); δ
C
(CDCl
3
) 170.6, 168.0, 158.5, 151.3, 146.9, 142.0, 137.7, 133.9 (2C), 132.3, 123.3
+
(
2C), 118.5, 116.3, 110.2, 61.3, 35.4, 31.7, 14.2; HRMS: MH , found 423.1144. C H N O S
21
18
4
4
requires 423.1122.
4
.7.9. Ethyl 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-2-methylthiazol-5-yl) acetate (11i) as a
°
16 2 4
colourless crystals, m.p. 116-118 C; [Found: C, 58.97; H, 4.69; N, 8.27; S, 9.58. C17H N O S
(344.38) requires C, 59.29; H, 4.68; N, 8.14; S, 9.31%] R
f
(75% benzene/EtOAc) 0.53; νmax 2953
-1
(CH
3
ring), 1766, 1734, 1708, 1394, 1186, 718 cm ; δ
H
(CDCl ) 7.86-7.70 (4H, m), 4.88 (2H, s),
3

ACCEPTED MANUSCRIPT
1
4
4
1
C 3
.20 (2H, q, J 6.8 Hz), 4.04 (2H, s), 2.60 (3H, s), 1.26 (3H, t, J 6.8 Hz); δ (CDCl ) 170.0,
67.8, 164.7, 147.2, 133.9 (2C), 132.2, 126.7, 123.4 (2C), 61.4, 35.3, 31.9, 19.2, 14.1; HRMS:
+
MH , found 345.0902. C17
H
16
N
2
O
4
S requires 345.0904.
4
.7.10. Ethyl 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-2-phenylthiazol-5-yl) acetate (11j) as a
°
colourless crystals, m.p. 132-134 C (CHCl /n-hexane); [Found: C, 64.91; H, 4.38; N, 6.88; S,
3
7
.95. C22
H
18
N
2
O
4
S (406.45) requires C, 65.01; H, 4.46; N, 6.89; S, 7.89%]; R
f
(85% n-
-1
hexane/EtOAc) 0.48; νmax 1778, 1770, 1720, 1392, 1190, 716 cm ; δ (CDCl ) 7.95-7.64 (6H,
H
3
m), 7.45-7.30 (3H, m), 4.96 (2H, s), 4.20 (2H, q, J 6.8 Hz), 4.10 (2H, s), 1.27 (3H, t, J 6.8 Hz);
δ (CDCl ) 169.9, 167.9, 166.4, 148.7, 134.0 (2C), 133.4, 132.3, 129.9, 128.8 (2C), 127.1, 126.4
C
3
+
(
18 2 4
2C), 123.4 (2C), 61.6, 35.6, 32.1, 14.2; HRMS: MH , found 407.1060. C22H N O S requires
4
07.1060.
4
.7.11. Ethyl 2-(4-((1,3-dioxoisoindolin-2-yl)methyl)-2-(4-fluorophenyl)thiazol-5-yl) acetate
°
(
11k) as a colourless crystals, m.p. 124-125 C (n-hexane/EtOAc); R
f
(85% n-hexane/EtOAc)
-1
0
.50; νmax 1769, 1731, 1716, 1395, 1189, 718 cm ; δ
H
(CDCl
3
) 7.91-7.66 (6H, m), 7.10-7.00
(
2H, m), 4.95 (2H, s), 4.20 (2H, q, J 7.0 Hz), 4.10 (2H, s), 1.28 (t, 3H, J 7.0 Hz); δ (CDCl )
C 3
1
69.9, 167.9, 165.4 (1C, d, JC,F 18.1 Hz), 162.2, 148.7, 134.0 (2C), 132.3, 129.8, 128.3 (1C, d,
+
J
C,F 8.3 Hz), 127.2, 123.4 (2C), 115.8 (1C, d, JC,F 22.6 Hz), 61.7, 35.5, 32.1, 14.2; HRMS: MH ,
2 4
found 425.0964. C22H17FN O S requires 425.0966.
4
.7.12. Ethyl 2-(2-(4-chlorophenyl)-4-((1,3-dioxoisoindolin-2-yl)metyl)thiazol-5-yl) acetate (11l)
°
as a colourless crystals, m.p. 137-138 C (CHCl
3
/n-hexane); R
(CDCl ) 7.95-7.65 (6H, m), 7.40-7.28 (2H, m), 4.96
2H, s), 4.22 (2H, q, J 6.8 Hz), 4.12 (2H, s), 1.30 (3H, t, J 6.8 Hz); δ (CDCl ) 169.9, 167.9,
64.4, 148.9, 135.9, 134.0 (2C), 132.3, 132.0, 129.0 (2C), 127.7 (2C), 127.5, 123.5 (2C), 61.7,
f
(85% n-hexane/EtOAc) 0.52; νmax
-1
1
768, 1733, 1716, 1396, 1194, 717 cm ; δ
H
3
(
C
3
1
3
+
2 4
5.6, 32.2, 14.2; HRMS: MH , found 441.0663. C22H17ClN O S requires 441.0670.
4
.8. General procedure for the synthesis of amino acids 12
A mixture of compound 11 (0.69 mmol) in 12% HCl (6 mL) was refluxed for 6 h and cooled to
.
ambient temperature. A solid mixture of hydrochloride 12 HCl and phthalic acid was filtered off
2 3
and washed with cold water (2 × 5 mL). The aqueous Na CO was added to combined mother
liquid to adjust pH 7.0. The precipitate was filtered and washed successively with water (5 mL)
and acetone (5 mL) to afford crude amino acid 12. The latter (0.10 g) was suspended in water

ACCEPTED MANUSCRIPT
1
5
2 3
(10 mL), the suspension was treated with Na CO and pH value was adjust to 7.0 by the
addition of AcOH. The precipitate was filtered and washed successively with water (5 mL) and
acetone (5 mL) to afford corresponding amino acid 12.
4
.8.1. 2-(4-Aminomethyl-2-((phenylmethyl)amino)thiazol-5-yl) acetic acid (12а) (0.17 g, 89%) as
°
a colourless crystals, m.p. 220-225 C (dec.); ν 3410-2170, 1655, 1554, 1369, 1279, 757, 702
max
-1
cm ; δ
H
(DMSO-d
6
3
/CF CO
2
H 2.5/1) 10.36 (1H, br s), 8.28-8.10 (3H, m), 7.40-7.20 (5H, m),
4
1
.52 (2H, s), 3.98 (2H, s), 3.81 (2H, s); δ
C
(DMSO-d /CF CO H 2.5/1) 171.9, 168.8, 136.4,
6
3
2
31.1, 129.6 (2C), 128.9, 128.6 (2C), 119.2, 49.9, 34.4, 31.7; MS 259 [M-H O] for
2
+
C
13
H
15
N
3
O
2
S; HRMS: MH , calcd: 278.0958; found: 278.0952.
4
.8.2. 2-(4-Aminomethyl-2-((3-methylphenyl)amino)thiazol-5-yl) acetic acid (12b) (0.18 g, 95%)
°
as a colourless crystals, m.p. 210-212 C (dec) (H
2
O); νmax 3500-2300, 1687, 1623, 1576, 1553,
-1
6
99, 681 cm ; δ
H 6
(DMSO-d ) 10.20 (1H, s), 8.70-8.20 (2H, br s), 7.60 (1H, s), 7.40 (1H, s), 7.18
(
1H, s), 6.72 (1H, s), 3.90 (2H, s), 3.72 (2H, s), 2.26 (3H, s); MS 259 [M-H O] for C H N O S;
2
13 15
3
2
+
HRMS: MH , calcd: 278.0958; found: 278.0952.
4
.8.3. 2-(4-Aminomethyl-2-((2-pyridyl)amino)thiazol-5-yl) acetic acid (12c) (0.14 g, 75%) as a
°
light-yellow crystals, m.p.>300 C (dec) (MeOH/H
2
O); νmax 3500-2400, 1616, 1603, 1543, 1413,
-
1
1
7
375, 1091, 765, 686 cm ; δ
H
(DMSO-d
6
/CF
3
CO
2
H) 8.41-8,25 (4H, m), 8.12 (1H, t, J 7.3 Hz),
2 12 4 2
.40-7.20 (2H, m), 4.12-4.00 (2H, m), 3.86 (2H, s); MS 246 [M-H O] for C11H N O S; HRMS:
+
MH , calcd: 265.0754; found: 265.0760.
4
.8.4. 2-(4-Aminomethyl-2-phenylthiazol-5-yl)acetic acid (12d) (0.12 g, 70%) as a colourless
°
-1
crystals, m.p. 210-213 C (dec) (H
2
O); νmax 3500-2400, 1622, 1555, 1378, 1368, 758, 689 cm ;
δ (DMSO-d /CF CO H) 8.38-8.11 (3H, br s), 7.98-7.80 (2H, br s), 7.50-7.30 (3H, br s), 4.12
H
6
3
2
(
(
2H, s), 3.95 (2H, s); δ
C
(DMSO-d
6
/CF
3
2
CO H) 171.7, 166.6, 147.1, 133.5, 130.9, 129.8, 129.7
+
2C), 126.6 (2C), 37.2, 31.8; HRMS: MH , calcd for C12
H
12
N
2
O
2
S: 249.0692; found: 249.0698.
Acknowledgements
This work was supported by Merck KGaA, Darmstadt, Germany.
Supplementary data
Supplementary data for this paper can be found in the online version at doi:XXX

ACCEPTED MANUSCRIPT
1
6
References and notes
1
. (a) Goodman and Gilman's the Pharmacological Basis of Therapeutics. (Eds J. G. Hardman,
L. E. Limbird, A. G. Gilman). (New York: McGraw-Hill, 2001); (b) Basic Neurochemistry:
Molecular, Cellular and Medical Aspects (Eds G. J. Siegel, R. W. Alberts, S. Brady, D.
Price). (Boston, MA: Academic Press, Elsevier, 2006).
2
3
4
. Kerr, D.I.B.; Ong, J. Br. J. Pharmacol., 1984, 83, 169-174.
. McGonigle, I.; Lummis, S.C.R. Biochemistry, 2010, 49, 2897-2902.
. Allan, R.D.; Dickenson, H.W.; Johnston, G.A.R.; Kazlauskas, R.;Tran, H.W. Austr. J.
Chem., 1985, 38, 1651-1656.
5
6
. Haviv, F.; Ratajczyk, J. D.; DeNet, R. W.; Kerdesky, F. A.; Walters, R. L.; Schmidt, S. P.;
Holms, J. H.; Young, P. R.; Carter, G. W. J. Med. Chem. 1988, 31, 1719-1728.
. Patt, W. C.; Hamilton, H. W.; Taylor, M. D.; Ryan, M. J.; Taylor, D. G., Jr.; Connolly, C. J.
C.; Doherty, A. M.; Klutchko, S. R.; Sircar, I.; Steinbaugh, B. A.; Batley, B. L.; Painchaud,
C. A.; Rapundalo, S. T.; Michniewicz, B. M.; Olson, S. C. J. J. Med. Chem. 1992, 35, 2562-
2
572.
7
8
. Tsuji, K.; Ishikawa, H. Bioorg. Med. Chem. Lett. 1994, 4, 1601-1606.
. Bell, F. W.; Cantrell, A. S.; Hoegberg, M.; Jaskunas, S. R.; Johansson, N. G.; Jordon, C. L.;
Kinnick, M. D.; Lind, P.; Morin, J. M., Jr.; Noreen, R.; Oberg, B.; Palkowitz, J. A.; Parrish,
C. A.; Pranc, P.; Sahlberg, C.; Ternansky, R. J.; Vasileff, R. T.; Vrang, L.; West, S. J.;
Zhang, H.; Zhou, X.-X. J. Med. Chem. 1995, 38, 4929-4936.
9
. (a) Potevar, T. M.; Ingale S.A.; Srinivasan, K. V. Tetrahedron, 2007,63, 11066-11069.; (b)
Aoyama, T.; Murata, S.; Arai, I.; Araki, N.; Takido, T.; Suzuki, Y.; Kodomari, M.
Tetrahedron, 2006, 62, 3201-3213.(c) Pumpor, K.; Windeisen, E.; Burger, K. J. Heterocyclic
Chem.,2003, 40, 435-442.
1
1
0. Fink, B.A.; Mortensen, D.S.; Stauffer, S.R.; Aron, Z.D.; Katzenellenbogen, J.A. Chem. Biol.
1
999, 6, 205-219.
1. Van Muijlwijk-Koezen, J.E.; Timmerman, H.; Vollinga, R.C.; Von Drabbe Kunzel, J.F.; De
Groote, M.; Visser, S.; Ijzerman, A.P. J. Med. Chem. 2001, 44, 749-762.
1
1
2. Chapman, Jr., J.M.; Cocolas, G.H.; Hall, I.H. J. Med. Chem., 1983, 26, 243-246.
3. (a) Pichat, L.; Hucleux, M.; Herbert, M. Bull. Soc. Chim. France, 1956, 1750-1751; (b)
Rykowski, Z.; Burak, K.; Chabudzinski, Z. Roczniki Chemii, 1977, 51, 1675-1678; (c)
Zavyаlov, S.I.; Zavozin, A.G. Russ. Chem. Bull. 1987, 36, 1663-1666; (d) Zavyаlov, S.I.;
Kravchenko, N.E.; Ezhova, G.I.; Kulikova, L.B.; Zavozin, A.G.; Dorofeeva, O.V. Pharm.
Chem. J. 2007, 41, 105-108.
,
1
4. Zavozin, A.G.; Kravchenko, N.E.; Ignat ev, N.V.; Zlotin, S.G. Tetrahedron Letters, 2010, 51,
5
45-547.
1
1
1
5. MacDonald, S.F. Can. J. Chem.,1974, 52, 3257-3258.
6. Sorg, A.; Siegel, K.;Bruckner, R. Chem. Eur. J.,2005, 11, 1610-1624.
7. (a) Ionic Liquids in Synthesis, 2nd ed., (eds. P. Wasserscheid, T. Welton), Wiley-VCH,
Weinheim, Germany, 2008. (b) Zlotin, S.G.; Makhova, N.N. Mendeleev Commun., 2010, 20
(2), 63-71; (c) Zlotin, S.G. Makhova, N.N. Russ. Chem. Rev., 2010, 79 (7) 543–583.
1
8. Wang, J.; Scott, A.I. Tetrahedron Let., 1997, 38, 739-740.

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9. Iida, K.; Tokiwa, S.; Ishii, T.; Kajiwara, M. J. Label. Compd. Radiopharm., 2002, 45, 569-
5
76.

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Supporting Information
Synthesis of thiazole derivatives bearing incorporated Z-5-aminopent-3-
enoic acid fragment
a
b
b
a
Alexander G. Zavozin , Nikolai V. Ignat’ev , Michael Schulte , Sergei G. Zlotin
a
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp.,
Moscow 119991, Russia
b
Merck KGaA, PC-RL, Frankfurter Strasse 250, D-64293 Darmstadt, Germany
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13
H NMR, C NMR and mass spectra of synthesized compounds

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Figure 1. H NMR spectra of 2a

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Figure 2. H NMR spectra of 2b

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Figure 3. H NMR spectra of salt 6

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Figure 4. C NMR spectra of salt 6

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Figure 5. H NMR spectra of 7a

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Figure 6. C NMR spectra of 7a

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Figure 7. H NMR spectra of 7b

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Figure 8. C NMR spectra of 7b

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Figure 9. H NMR spectra of 8a

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Figure 10 C NMR spectra of 8a

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Figure 11. H NMR spectra of 8b