Axially chiral pyridine compounds: Synthesis, chiral separations and determination of protonation dependent barriers to hindered rotation

Article abstract of DOI:10.1016/j.tetasy.2014.01.012

Axially chiral enantiomeric 2-pyridylimino-3-pyridyl-thiazolidine-4-ones and -thiones have been synthesized and their rotational barriers around the N-3C_(pyridyl) bond have been determined by variable temperature NMR or by thermal racemization of the micropreparatively resolved enantiomers. Rotational barriers of the unprotonated compounds ranged from 46 to 116 kJ/mol, depending on the substituent on the N-3-pyridyl ring and on the exocyclic oxygen or sulfur atoms of the thiazolidine ring. Protonation of the pyridine nitrogens by TFA caused a decrease in the barrier to the rotation by stabilizing the transition state of the rotations via hydrogen bonding interactions.

Full text of DOI:10.1016/j.tetasy.2014.01.012

Tetrahedron: Asymmetry 25 (2014) 449–456
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Axially chiral pyridine compounds: synthesis, chiral separations
and determination of protonation dependent barriers
to hindered rotation
⇑
Furkan Halis Isikgor, Sule Erol, Ilknur Dogan
_
Bog˘aziçi University, Chemistry Department, Bebek, 34342 Istanbul, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 December 2013
Accepted 22 January 2014
Axially chiral enantiomeric 2-pyridylimino-3-pyridyl-thiazolidine-4-ones and -thiones have been syn-
thesized and their rotational barriers around the N-3AC(pyridyl) bond have been determined by variable
temperature NMR or by thermal racemization of the micropreparatively resolved enantiomers. Rotational
barriers of the unprotonated compounds ranged from 46 to 116 kJ/mol, depending on the substituent on
the N-3-pyridyl ring and on the exocyclic oxygen or sulfur atoms of the thiazolidine ring. Protonation of
the pyridine nitrogens by TFA caused a decrease in the barrier to the rotation by stabilizing the transition
state of the rotations via hydrogen bonding interactions.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
and -thiones (Scheme 1) as potential organocatalysts. The chiral
separations of the atropisomeric derivatives and the protonation
2-Pyridylimino-3-pyridyl-thiazolidine-4-ones and -thiones 1–4
(Scheme 1) are structurally interesting compounds that possess an
amidine scaffold conjugated to a pyridine ring. The compounds
also have nitrogen, oxygen, and sulfur heteroatoms in their struc-
tures to ligate transition metals in different coordination
modes.1–10 These compounds are axially chiral due to hindered
rotation around the N-3AC(pyridyl) bond and may be atropisomer-
ic11 depending on the substituents at the C-3 position of the
N-3-pyridyl ring and on the exocyclic atoms of the thiazolidinone
ring. Axially chiral bidentate compounds, which have high enough
rotational barriers to allow their isolation as enantiopure
compounds,12 are of great importance due to their use as asym-
metric ligands and catalysts13 in the production of a variety of
pharmaceuticals, agrochemicals, flavors, and fragrances.14 Chiral
amidine-based catalysts have also proven to be useful in various
asymmetric syntheses, including enantioselective acyl trans-
fers,15,16 allylic substitutions,17 and nitroalkane alkylations.18
Compounds containing a pyridyl structure are well known to
possess a wide range of biological and pharmacological activities.19
Compounds with a 2-imino-thiazolidine-4-one scaffold have also
been reported as biologically important compounds.20,21 Herein
we report the synthesis of some novel chromatographically resolv-
able axially chiral 2-pyridylimino-3-pyridyl-thiazolidine-4-ones
dependent rotational barrier determinations have also been
reported.
2. Results and discussion
The 2-pyridylimino-3-pyridyl-thiazolidine-4-ones 1 and 2 were
synthesized by the reaction of the corresponding N,N0-diarylthiou-
reas and a-bromoacetic acid (Scheme 1). This included a facile two
step synthesis from the corresponding amino pyridine. The 2-pyr-
idylimino-3-pyridyl-thiazolidine-4-thiones 3 and 4 were synthe-
sized by the reaction of 1 and 2 with Lawesson’s reagent22
(Scheme 1). Conversion of the carbonyl group into thiocarbonyl
was monitored by the disappearance of the IR and 13C NMR
carbonyl peaks and the appearance of the corresponding thiocar-
bonyl peaks.
Within these compounds, the rotation around the N-3AC(pyridyl)
bond is restricted due to the steric interactions between the R1
substituent, the lone pair electrons of Nc, and the exocyclic oxygen
or sulfur atoms (Scheme 1). The restricted rotation results in the
formation of the thermally interconvertible M and P enantiomers
(Scheme 1, Table 1).
In compounds 1–4, the lone pair on N-3 cannot delocalize with
the pyridine ring bonded to N-3 because of the nonplanar ground
states. However, these electrons on N-3 can be donated to the pyr-
idine ring on the imino group via the resonance structure shown in
Scheme 2. As a result, the 1H NMR signals of the pyridine ring on
⇑
Corresponding author. Tel.: +90 2123596620; fax: +90 212 287 2467.
E-mail address: dogan@boun.edu.tr (I. Dogan).
http://dx.doi.org/10.1016/j.tetasy.2014.01.012
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

450
F. H. Isikgor et al. / Tetrahedron: Asymmetry 25 (2014) 449–456
R1
S
Na
Nb
Nc
S
N3
R1
R1
compound 3: R1 = H
compound 4: R1 = CH3
N
R1 = H or CH3
CS2
NH2
Lawesson's reagent
toluene
reflux
pyridine
reflux
R1
S
R1
R1
Na
Nb
Nc
O
N3
S
2-bromoacetic acid
R1
EtOH
reflux
N
N
H
N
H
N
1,3-di(pyridin-2-yl)thiourea: R1 = H 1a
1,3-bis(3-methylpyridin-2-yl)thiourea: R1 = CH3 2a
compound : R1 = H
1
2
compound : R1 = CH3
Scheme 1. Synthesis of the axially chiral 2-pyridylimino-3-pyridyl-thiazolidine-4-ones and -thiones 1–4.
Table 1
interconvertible enantiomers of compounds 1 and 3 could not be
resolved due to fast rotation around the N-3AC(pyridyl) bond (Fig. 1).
Due to the axial chirality of 1–4, the hydrogen atoms at the C-5
position of the thiazolidine ring are diastereotopic and are ex-
pected to give an AB type splitting pattern. AB splittings for 1
and 3 were not observed at 24 °C (NMR probe temperature) due
to a fast rotation (Fig. 2), but could be observed at lower tempera-
tures (Fig. 3).
Chemical shift values of the protons at the C-5 position
Compounds
NMR solvents
CHCl3-d1 (ppm)
Toluene-d8 (ppm)
TFA-d1 (ppm)
1a
2
m
m
= 3.88b
= 3.96c
m
= 2.95b
m
= 4.53b
m
m
1 = 3.08
2 = 3.00
m
m
1 = 4.62
2 = 4.56
3d
4e
m
m
= 4.41b
= 4.42c
m
= 3.68b
m
= 4.93b
In order to determine the racemization barriers for 1 and 3, var-
iable temperature 1H NMR experiments at lower temperatures
were carried out.23 The barriers were determined on the basis of
coalescence temperatures.24 The coalescence temperature was
found to be ꢀ50 °C for compound 1 (Fig. 3). However, spectra could
not be taken at lower temperatures due to solubility problems and
the barrier to rotation for this compound has been estimated to be
between 46 and 48 kJ/mol by taking possible minimum and max-
imum values of the chemical shift difference between the two C-
5 protons at ꢀ50 °C. The rotational barrier of compound 3 was
found as 57 kJ/mol by temperature dependent NMR24 (Fig. 3).
Since the two enantiomers of 2 and 4 were separable upon HPLC
at column temperature of 7 °C, the determination of the rotational
barrier to the hindered rotation for these compounds was carried
out by thermally interconverting the micropreparatively separated
enantiomer to its counterpart. For this process, the enantiomers of
2 and 4 were separated micropreparatively by HPLC on Chiralpak
AD and Chiralpak IC columns, respectively. The mobile solvent
was evaporated immediately and the process was repeated succes-
sively until 0.2 mg of each isomer was collected. Next, one of the
m
m
1 = 3.74
2 = 3.63
m
m
1 = 4.90
2 = 4.87
a
The corresponding chemical shift value in DMF-d7:
Due to rapid rotation around the N-3-pyridyl bond, AB type splitting of the
m
= 4.34 ppm.
b
protons at the C-5 position could not be observed.
c
AB type splitting of the protons at the C-5 position could not be observed.
The corresponding chemical shift value in benzene-d6:
d
m
= 3.40 ppm.
The corresponding chemical shift values in benzene-d6: 1 = 3.42 ppm and
2 = 3.30 ppm.
e
m
m
the imino group are more shielded than those of the N-3-pyridine
ring, thus enabling the appearance of the aromatic protons of the
two pyridyl rings separately (Table 2). The 2D-NOESY spectra of
these compounds did not show any crosspeaks between the two
well resolved pyridine ring 1H NMR signals. Based on this observa-
tion, the imino bond is assumed to have a Z-configuration.
Analytical resolutions for the isomers of 1–4 were attempted by
enantioselective HPLC. The enantiomers of compounds 2 and 4
could be resolved by HPLC on Chiralpak AD and Chiralpak IB
columns, respectively (Fig. 1). On the other hand, the thermally
enantiomers was dissolved in approximately 200
ll of HPLC sol-
vent and 40 l of this solution was injected into the column to
l
'
H3
determine the initial concentration. The solution was kept in an
oil bath at a constant temperature and the thermal racemization
process was followed by HPLC analysis at certain time intervals
(Fig. 4a). Integration of the UV peaks (k = 254 nm) on the chro-
matogram yielded the ratio of the enantiomers.
'
R1
N
H2
R1'
N
S
S
-
N
..
'
+
H1
N
X
X
a
b
N
a
b
N
3
3
..
..
R1
R1
X = O, S
1 = H4 or CH3
R1' = H4' or CH3
N
c
N
c
A plot of lnð½Mꢁ ꢀ ½MꢁeqÞ=½Mꢁ0 ꢀ ½MꢁeqÞ versus time (Fig. 4b) gave
the first order rate constants for thermal interconversion of the
compounds.25 Substitution of the rate constant into the Eyring
R
H1
H3
H2
and P
equation
D
G# = RTln(kb T/k h) provided the rotational barriers as
and P
102.1 and 115.7 kJ/mol, respectively. For compounds 1–4, the dy-
Scheme 2. The resonance structure of the compounds 1–4.
namic NMR or HPLC conditions are summarized in Table 3.

F. H. Isikgor et al. / Tetrahedron: Asymmetry 25 (2014) 449–456
451
Table 2
Chemical shift valuesa of the aromatic and R1 protons of 1–4
Compounds
NMR solvents
CHCl3-d1
Toluene-d8
TFA-d1
1
2
3
4
H1 = 8.64
H2 = 7.36
H3 = 7.85
H4 = 7.33
H01 = 8.36
H02 = 6.95
H03 = 7.54
H04 = 6.89
H1 = 8.35
H2 = 6.59
H3 = (ꢀ)b
H4 = 6.86
H01 = 8.27
H02 = 6.42
H03 = (ꢀ)b
H04 = 6.78
H1 = 9.06
H2 = 8.26
H3 = 8.91
H4 = 8.39
H01 = 8.60c
H02 = 7.80
H03 = 8.60c
H04 = 7.90
H
1 = 8.51
H01 = 8.25
H02 = 6.93
H03 = 7.42
CH03 = 1.93
H1 = 8.28
H2 = 6.66
H3 = (ꢀ)b
CH3 = 1.99
H01 = 8.18
H02 = 6.48
H03 = 6.91
CH03 = 1.84
H1 = 8.97
H2 = 8.22
H3 = 8.42c
CH3 = 2.70
H01 = 8.79
H02 = 7.71
H03 = 8.42c
CH03 = 2.47
H2 = 7.35
H3 = 7.72
CH3 = 2.29
H
1 = 8.68
H01 = 8.39
H02 = 6.96
H03 = 7.54
H04 = 6.89
H1 = 8.37
H2 = 6.64
H3 = (ꢀ)b
H4 = 6.81
H01 = 8.25
H02 = 6.43
H03 = (ꢀ)b
H04 = 6.74
H1 = 9.18
H2 = 8.38c
H3 = 9.00
H4 = 8.38c
H01 = 8.58
H02 = 7.82
H03 = 8.65
H04 = 7.97
H2 = 7.39
H3 = 7.89
H4 = 7.29
H
1 = 8.49
H01 = 8.22
H02 = 6.89
H03 = 7.36
CH03 = 1.83
H1 = 8.28
H2 = 6.67
H3 = (ꢀ)b
CH3 = 1.94
H01 = 8.16
H02 = 6.45
H03 = 6.87
CH03 = 1.77
H1 = 9.00
H2 = 8.24
H3 = 8.43c
CH3 = 2.66
H01 = 8.80
H02 = 7.72
H03 = 8.43c
CH03 = 2.48
H2 = 7.30
H3 = 7.69
CH3 = 2.17
a
b
c
Chemical shift values are in parts per million (ppm) relative to tetramethylsilane.
1H NMR signal of the proton is under the corresponding solvent peak.
The corresponding peak overlaps with other aromatic peaks.
rt = 34.5
r t= 48.3
rt = 60.1
Compound 1a
Compound 2b
rt = 20.4
rt = 41.0
rt = 42.6
Compound 4d
Compound 3c
rt: retention times (min)
a: Column: Chiralpak AD, Eluent (v/v): hexane/2-propanol (50/50), Flow rate (ml/min): 0.6.
b: Column: Chiralpak AD, Eluent (v/v): hexane/2-propanol (90/10), Flow rate (ml/min): 0.6, Separation factor
between enantiomeric pairs (α): 1.27.
c: Column: Chiralpak IB, Eluent (v/v): hexane/2-propanol (70/30), Flow rate (ml/min): 0.4.
d: Column: Chiralpak IC, Eluent (v/v): hexane/2-propanol (70/30), Flow rate (ml/min): 0.6, Separation factor
between enantiomeric pairs (α): 2.43.
Figure 1. The HPLC chromatograms of 1–4.
For compound 2, the rotational barrier was also determined un-
under acidic conditions indicated that the planar transition state
for rotation is exceptionally stabilized. This is possible by intramo-
lecular H-bonding interactions between the protonated pyridine
and the carbonyl oxygen or imine nitrogen of the thiazolidine-4-
one ring in the planar transition state via the formation a 6-mem-
bered ring (Fig. 5c). Rousell et al. have shown for structurally related
axially chiral compounds that28 (Fig. 6) H-bonding to a carbonyl
during the transition state for rotation decreases the barrier by
23.2 kJ/mol (Fig. 6). Considering a hydrogen bonding interaction of
a comparable strength in protonated 2, the barrier to rotation was
lowered to 78.9 kJ/mol, which would cause an immediate racemiza-
tion (t1/2 = 7.5 s). Such stabilizations of transition states have also
been observed29 by Rebek et al. during an acid catalyzed racemiza-
tion of bipyridyl derivatives. The determination of the catalytic
der acidic conditions where the micropreparatively separated
enantiomer was dissolved in chloroform containing 0.4% TFA and
the thermal racemization was followed by HPLC on a Chiralpak
IB column. It was observed that under this acidic medium, the
micropreparatively separated enantiomer immediately intercon-
verted into its counterpart (Fig. 5a).
The axially chiral compound 2 racemizes by partial rotation
about the N-3AC(pyridyl) chiral axis via a planar transition state.26
The excess acid present in the medium is expected to protonate
the nitrogens of the N-3-pyridine and the imino-pyridine of the mol-
ecule (Fig. 5c). The imine nitrogen has been shown to remain
unprotonated in structurally related compounds in TFA.27 The
observation that the rotational barrier is dramatically lowered

452
F. H. Isikgor et al. / Tetrahedron: Asymmetry 25 (2014) 449–456
CHCl3-d1
toluene-d8
TFA-d1
CHCl3-d1
toluene-d8
TFA-d1
Compound 1
Compound 2
CHCl3-d1
toluene-d8
TFA-d1
CHCl3-d1
toluene-d8
TFA-d1
Compound 3
Compound 4
Figure 2. The 1H NMR signals of the protons at the C-5 position of compounds 1–4 in different solvents.
24°C
24°C
-20°C
5°C
0 oC
-30 oC
-40 oC
-5°C
-50 oC
-15 °C
Compound 1
NMR solvent: DMF-d7
Compound 3
NMR solvent: Toluene-d8
Figure 3. Temperature dependent 1H NMR of the –CH2 protons of compounds 1 and 3.
activity by means of binding forces at the well defined transition
state has been considered important30 because of its influence on
topics such as enzyme binding31 and molecular rotors.32
When the same thermal racemization experiment in an acidic
medium is repeated with the resolved enantiomer of compound
4 at 32 °C, it was found that the compound racemized with a bar-
rier of 106.4 kJ/mol (Fig. 5b). The observed decrease of 9.3 kJ/mol is
indicative of a weaker H-bonding between the exocyclic sulfur
atom and the protonated pyridine (Fig. 5c). Rousell et al. observed
a decrease of 8.1 kJ/mol27 in the rotational barrier due to the
hydrogen bonding interactions of the hydroxyl group with the
thiocarbonyl in the transition state (Fig. 6).
Amidine conjugation in compounds 1–4 was expected to in-
crease the basicity of the imino pyridine ring (Scheme 2). For this
reason we hypothesized that compounds 1–4 may act as DMAP
analogs to catalyze the acylation reactions of alcohols (Fig. 7). The
acylation of 1-phenylethanol33 with acetic anhydride was found
to be slightly catalyzed in the presence of 10 mol % of racemic 2
(the reaction rate of the esterification was found to increase by
1.5 times based on the comparison of the 1H NMR integral of the

F. H. Isikgor et al. / Tetrahedron: Asymmetry 25 (2014) 449–456
453
a
b
Figure 4. (a) Interconversion of the micropreparatively separated enantiomer of compound 4 to its counterpart at 80 °C. (b) lnð½Mꢁ ꢀ ½MꢁeqÞ=½Mꢁ0 ꢀ ½MꢁeqÞ versus time graph.
Table 3
Dynamic NMR and HPLC conditions for compounds 1–4
Compound
Method
Temperature (°C)
k (Rate constant) (sꢀ1
)
Barrier to hindered rotation (kJ/mol)
1
2
3
4
Dynamic NMR
ꢀ50a
40
kc = (2.3–7.1) ꢂ 10ꢀ1b
46–48
102.1 0.7
57
Thermal racemization on HPLCc
Dynamic NMR
5.9 ꢂ 10ꢀ5d
5a
kc = 1.12 ꢂ 10ꢀ2b
5.5 ꢂ 10ꢀ5d
Thermal racemization on HPLCe
80
115.7 0.7
a
b
c
Coalescence temperature.
kc is the rate constant at coalescence temperature (Tc).
Thermal racemization was followed on a Chiralpak AD HPLC column: amylose tris (3,5-dimethylphenylcarbamate).
The first order rate constant for thermal interconversion.
Thermal racemization was followed on Chiralpak IC: cellulose tris (3,5-dichlorophenylcarbamate).
d
e
product peak to the remaining reactant in the presence and absence
of 10 mol % of 2, respectively) at room temperature. We are search-
ing for conditions that will increase the catalytic activity of 2 so that
compounds 1 and 2 by sulfur (compounds 3 and 4) caused an
increase of 11–14 kJ/mol in the rotational barriers. Methyl substi-
tution at the C-3 position of the N-3-pyridyl (compounds 2 and
4) caused an increase of approximately 57 kJ/mol in the rotational
barrier. Under acidic conditions (0.4% TFA), it was observed that
compound 2 immediately racemized and this observation indi-
cated that the planar transition state of rotation is exceptionally
stabilized by hydrogen bonding interactions either with the car-
bonyl oxygen or with the imino nitrogen (Fig. 5c). The rotational
barrier of compound 4 decreased by 9.3 kJ/mol under the same
acidic conditions via weaker H-bonding between the protonated
N-3-pyridine and the exocyclic sulfur atom. Research is currently
underway in our laboratories to determine if we can exploit the
chromatographically resolved thermally stable enantiomers of 2
as axially chiral acylation organocatalysts.
the chromatographically resolved34 enantiomer of
2 can be
exploited as an axially chiral asymmetric acylation catalyst.35
3. Conclusion
Herein chromatographically resolvable axially chiral enantio-
meric 2-pyridylimino-3-pyridyl-thiazolidine-4-ones and -thiones
have been synthesized and the rotational barriers of unprotonated
forms have been determined as 46–116 kJ/mol either by tempera-
ture dependent NMR or by thermal racemization of the resolved
enantiomers. The barrier of 1 was estimated to be between 46
and 48 kJ/mol. Replacement of the exocyclic oxygen atom in

454
F. H. Isikgor et al. / Tetrahedron: Asymmetry 25 (2014) 449–456
a
b
immediately after dissolving
the resolved enantiomer in an
acidic medium (0.4 % TFA)
resolved
enantiomer of
compound 2
at=14640 s
t=0 s
t=6060 s
t=9240 s
t=12120s
aAt a constant temperature of 32°C, compound 4 started to degrade in the presence of 0.4 % trifluoroacetic acid after
t=12120 s while rotational barrier of the compound was determined by taking the interconversion process up to that
time into consideration.
Decomposition products.
Energy
kJ/mol
Energy
kJ/mol
c
CH3
S
CH3
S
N
N
N
S
N
S
N
or
N
H3C
CH3
N
N
115.7
CH3
S
CH3
S
N
N
N
O
N
O
N
or
N
H3C
CH3
N
N
106.4
102.1
b
b
CH3
CH3
S
S
CH3
CH3
S
N
S
N
N
O
H
N
O
CH3
N
or
N
N
N
N
S
H
N
S
N
H3C
or
N
H
N
N
H3C
CH3
H
N
N
~79
CH3
S
CH3
CH3
S
CH3
S
S
N
N
N
N
N
O
N
S
N
O
N
N
S
N
N
N
H3C
H3C
H3C
H3C
N
N
N
N
P
compound 4
M
compound 2
M
P
Figure 5. (a) Immediate interconversion of the micropreparatively resolved first eluted enantiomer of 2 into its counterpart in an acidic medium (0.4% TFA) at 25 °C. (b)
Thermal racemization of the micropreparatively resolved first eluted enantiomer of 4 in CHCl3 containing 0.4% TFA at 32 °C. (c) Rotational energy barriers of the protonated
and unprotonated forms of compounds 2 and 4.

F. H. Isikgor et al. / Tetrahedron: Asymmetry 25 (2014) 449–456
455
S
S
acetate. After drying, the product was purified by recrystallization
from ethanol.
X
X
N
N
OCH3
OH
4.2.1. 3-(Pyridin-2-yl)-2-(pyridin-2-ylimino)thiazolidin-4-one 1
This compound was synthesized according to the general proce-
dure using 1.15 g (0.005 mol) 1,3-di(pyridin-2-yl)thiourea, 0.69 g
X=O ΔG≠= 110.5 kJ/mol28
X=S ΔG≠= 135.8kJ/mol28
ΔG≠= 87.3 kJ/mol28
ΔG≠= 127.7 kJ/mol28
(0.005 mol) of
a-bromoacetic acid, 0.49 g (0.006 mol) of sodium
acetate, and 30 ml of ethanol. Yield: 0.71 g (53%), mp:
210–212 °C. 1H NMR (400 MHz, CDCl3): d 8.64 (dd, 1H, H1,
J = 4.5 Hz), 8.36 (dd, 1H, H01, J = 4.9 Hz), 7.85 (m, 1H, H3), 7.54 (m,
1H, H03), 7.36 (m, 1H, H2), 7.33 (d, 1H, H4, J = 7.8 Hz), 6.95 (m, 1H,
H02), 6.89 (d, 1H, H04, J = 7.8 Hz), 3.88 (s, 2H, CH2) ppm. 13C NMR
(100 MHz, CDCl3): d 171.9, 157.9, 149.9, 148.9, 146.4, 138.5,
137.8, 124.2, 123.9, 121.2, 120.1, 33.9 ppm. HRMS (TOF MS ES+):
Calculated for C13H10N4O1S1H+: 271.0654; Found: 271.0650.
Figure 6. The rotational barriers of the structurally related ortho-OH versus ortho-
OCH3 compounds.28
4. Experimental
4.1. General procedure for the preparation of N,N0-diarylthiou-
reas
4.2.2. 3-(3-Methylpyridin-2-yl)-2-(3-methylpyridin-2-ylimino)
thiazolidin-4-one 2
The appropriate aniline derivative was dissolved in pyridine
after which CS2 was added. The mixture was refluxed overnight
under N2. Next, the solution was concentrated by evaporating the
solvent and then cooled to give a precipitate. The precipitated
product was isolated by vacuum filtration, stirred in water over-
night, and dried in vacuo. The crude N,N0-diarylthiourea was puri-
fied by recrystallization from ethanol.
This compound was synthesized according to the general proce-
dure using 1.29 g (0.005 mol) 1,3-bis(3-methylpyridin-2-yl)thio-
urea, 0.69 g (0.005 mol) of
a-bromoacetic acid, 0.49 g (0.006 mol)
of sodium acetate, and 30 ml of ethanol. Yield: 0.54 g (36%), mp:
134–136 °C. 1H NMR (400 MHz, CDCl3): d 8.51 (dd, 1H, H1,
J = 4.6 Hz), 8.25 (dd, 1H, H01, J = 4.6 Hz), 7.72 (m, 1H, H3), 7.42 (m,
1H, H03), 7.35 (dd, 1H, H2, J = 7.5 Hz), 6.93 (dd, 1H, H02, J = 7.7 Hz),
3.96 (s, 2H, CH2), 2.29 (s, 3H, CH3), 1.93 (s, 3H, CH03) ppm. 13C
NMR (100 MHz, CDCl3): d 170.5, 155.1, 147.3, 146.45 and 146.44
(partially coalesced), 142.7, 138.7, 137.4, 131.3, 128.4, 123.6,
119.2, 32.9, 16.0, 15.7 ppm. HRMS (TOF MS ES+): Calculated for
4.1.1. 1,3-Di(pyridin-2-yl)thiourea 1a36
This compound was synthesized according to the general proce-
dure using 4.71 g (0.05 mol) of 2-amino pyridine, 7.61 g (0.1 mol)
of carbon disulfide and 20 ml of pyridine. Yield: 3.33 g (58%),
mp: 156–158 °C. 1H NMR (400 MHz, CDCl3): d 14.31 (br s, 1H,
NH), 9.02 (br s, 1H, NH), 8.86 (br s, 1H), 8.39 (s, 2H), 7.71 (s, 2H),
7.06 (s, 2H), 6.87 (br s, 1H) ppm.
C15H14N4O1S1H+: 299.0967; Found: 299.0953.
4.3. General procedure for the preparation of compounds 3 and 4
The appropriate 2-arylimino-3-aryl-thiazolidine-4-one and
Lawesson’s reagent were refluxed for 6 h in dry toluene. The sol-
vent was then removed under reduced pressure. The crude product
was purified by column chromatography using silica gel.
4.1.2. 1,3-Bis(3-methylpyridin-2-yl)thiourea 2a
This compound was synthesized according to the general proce-
dure using 5.03 ml (0.05 mol) of 2-amino-picoline, 7.61 g (0.1 mol)
of carbon disulfide, and 20 ml of pyridine. Yield: 3.33 g (60%), mp:
166–169 °C. 1H NMR (400 MHz, CDCl3): d 13.78 (br s, 1H, NH), 8.42
(br s, 1H, NH), 8.09 (br s, 2H), 7.63 (br s, 1H), 7.54 (br s, 1H), 7.21
(br s, 1H), 6.95 (br s, 1H), 2.42 (br s, 3H, CH3), 2.35 (br s, 3H, CH3)
ppm. HRMS (TOF MS ES+): Calculated for C13H14N4S1H+: 259.1017;
Found: 259.1007.
4.3.1. 3-(Pyridin-2-yl)-2-(pyridin-2-ylimino)thiazolidine-4-thi-
one 3
This compound was synthesized according to the general
procedure using 0.423 g (1.57 mmol) of 3-(pyridin-2-yl)-2-
(pyridin-2-ylimino)thiazolidin-4-one 1, 0.317 g (0.785 mmol)
Lawesson’s reagent, and 30 ml of dry toluene. The crude product
was purified by column chromatography, using silica gel and
eluted with EtOAc/CH2Cl2 mixture (1/10). Yield: 0.13 g (30%),
mp: 134–136 °C. 1H NMR (400 MHz, CDCl3): d 8.68 (br s, 1H, H1),
8.39 (br s, 1H, H01), 7.89 (m, 1H, H3), 7.54 (m, 1H, H03), 7.39 (m,
1H, H2), 7.29 (d, 1H, H4, J = 7.4 Hz), 6.96 (m, 1H, H02), 6.89 (d, 1H,
H04, J = 7.4 Hz), 4.41 (s, 2H, CH2) ppm. 13C NMR (100 MHz, CDCl3):
d 202.2, 161.5, 157.3, 151.6, 150.2, 146.5, 138.8, 137.8, 124.4,
124.1, 121.9, 120.4, 46.2 ppm. HRMS (TOF MS ES+): Calculated
for C13H10N4S2H+: 287.0425; Found: 287.0425.
4.2. General procedure for the preparation of compounds 1 and 2
The appropriate N,N0-diarylthiourea and
a-bromoacetic acid or
2-bromo-propionic acid were refluxed for 4 h in absolute ethanol
in the presence of sodium acetate. At the end of this period, the
excess of ethanol was distilled off and the reaction mixture was
poured into cold water to give a precipitate, which was collected
and washed several times with hot water in order to remove unre-
acted
a
-bromoacetic acid/2-bromo-propionic acid and sodium
CH3
S
CH3
S
O
N
N
O
N
N
O
N
O
O
CH3
N
O
O
CH3
2
+
O
N
CH3
OH
N
2
Figure 7. The proposed mechanism for the acylation reaction with the catalysis of 2.

456
F. H. Isikgor et al. / Tetrahedron: Asymmetry 25 (2014) 449–456
T.; Takashiba, K.; Nabeshima, K.; Takagi, R.; Takatani, M.; Okamoto, T.;
Kinoshita, I.; Doe, M.; Hamazawa, A.; Morita, M.; Nishida, F.; Sakakibara, T.;
Orvig, C.; Yano, S. J. Org. Chem. 2001, 66, 3783–3789.
4.3.2. 3-(3-Methylpyridin-2-yl)-2-(3-methylpyridin-2-ylimino)
thiazolidine-4-thione 4
This compound was synthesized according to the general proce-
dure using 1.85 g (6.2 mmol) of 3-(3-methylpyridin-2-yl)-2-(3-
methylpyridin-2-ylimino)thiazolidin-4-one 2, 1.25 g (3.1 mmol)
of Lawesson reagent, and 15 ml of dry toluene. The crude product
was purified by column chromatography, using silica gel and
eluted with EtOAc/hexane mixture (1/5). Yield: 0.43 g (22%), mp:
169–171 °C. 1H NMR (400 MHz, CDCl3): d 8.49 (m, 1H, H1), 8.22
(m, 1H, H01), 7.69 (m, 1H, H3), 7.36 (m, 1H, H30 ), 7.30 (dd, 1H, H2,
J = 7.2 Hz), 6.89 (dd, 1H, H02, J = 7.2 Hz), 4.42 (s, 2H, CH2), 2.17 (s,
3H, CH3), 1.83 (s, 3H, CH03) ppm. 13C NMR (100 MHz, CDCl3): d
199.7, 158.4, 154.4, 149.9, 146.7, 142.9, 138.8, 137.5, 130.9,
129.1, 123.7, 119.5, 45.1, 15.7, 15.6 ppm. HRMS (TOF MS ES+): Cal-
culated for C15H14N4S2H+: 315.0738; Found: 315.0734.
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This project was supported by the Bog˘aziçi University research
fund (BAP) with project numbers 10B05P6 and 13B05P5.
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