Exo-Selective inverse-electron-demand hetero Diels-Alder reactions of norbornene with 5-benzylidine-2-arylimino-3-aryl-thiazolidine-4-thiones at room temperature

Article abstract of DOI:10.1016/j.tet.2012.11.085

2-Arylimino-3-aryl-thiazolidine-4-thiones were synthesized from the corresponding thiazolidine-4-ones using Lawesson's reagent (LR) and converted into 5-benzylidine-2-arylimino-3-aryl-thiazolidine-4-thiones by reaction with benzaldehyde, which were then used as heterodienes in the inverse-electron- demand hetero Diels-Alder cycloadditions with norbornene as a dienophile at 25 ^°C. The reactions with norbornene were found to proceed with 100% exo-selectivity as determined by NMR experiments. The hetero Diels-Alder reactions with axially chiral heterodienes with ΔG^#>116 kJ/mol showed kinetic atroposelectivities up to 11:1. However, the products were found to equilibrate, as revealed by the 97.1 kJ/mol barrier to hindered rotation of the most sterically hindered product, to produce 2:1 diastereoselectivities after the 24 h reaction time.

Full text of DOI:10.1016/j.tet.2012.11.085

Accepted Manuscript
Exo-selective Inverse-Electron-Demand Hetero Diels-Alder Reactions of Norbornene
with 5-benzylidine-2-arylimino-3-aryl-thiazolidine-4-thiones at Room Temperature
Sule Erol, Ilknur Dogan
PII:
S0040-4020(12)01803-0
10.1016/j.tet.2012.11.085
TET 23796
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 August 2012
Revised Date: 8 November 2012
Accepted Date: 26 November 2012
Please cite this article as: Erol S, Dogan I, Exo-selective Inverse-Electron-Demand Hetero Diels-
Alder Reactions of Norbornene with 5-benzylidine-2-arylimino-3-aryl-thiazolidine-4-thiones at Room
Temperature, Tetrahedron (2012), doi: 10.1016/j.tet.2012.11.085.
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ACCEPTED MANUSCRIPT
Exo-selective Inverse-Electron-Demand Hetero Diels-Alder Reactions of Norbornene
with 5-benzylidine-2-arylimino-3-aryl-thiazolidine-4-thiones at Room Temperature
Sule Erol and Ilknur Dogan*
Bogazici University, Chemistry Department, Bebek, 34342, İstanbul, Turkey
dogan@boun.edu.tr
ABSTRACT
2
-Arylimino-3-aryl-thiazolidine-4-thiones were synthesized from the corresponding
thiazolidine-4-ones using Lawesson’s reagent (LR) and converted into 5-benzylidine-2-
arylimino-3-aryl-thiazolidine-4-thiones by reaction with benzaldehyde, which were then used
as heterodienes in the inverse-electron-demand hetero Diels-Alder cycloadditions with
o
norbornene as a dienophile at 25 C. The reactions with norbornene were found to proceed
with 100% exo selectivity as determined by NMR experiments. The hetero Diels-Alder
#
reactions with axially chiral heterodienes with ꢀG > 116 kJ/mole showed kinetic
atroposelectivities up to 11:1. However, the products were found to equilibrate, as revealed by
the 97.1 kJ/mole barrier to hindered rotation of the most sterically hindered product, to
produce 2:1 diastereoselectivities after the 24 h reaction time.
Keywords: Inverse electron demand hetero Diels-Alder rearction, exo-selectivity, thiadiene,
norbornene, bioconjugation, atroposelectivity
*
Corresponding author: Tel.: +90-212-359-6620; Fax: +90-212-287-2467; Address: Bogazici
University, Chemistry Department, Bebek, 34342, Istanbul, Turkey
e-mail: dogan@boun.edu.tr

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1
. INTRODUCTION
The Diels-Alder reaction continues to occupy a central position in organic synthesis, the
stereocontrol of the reaction being an important issue. Various catalysts have been developed
1
,2
to control endo/exo and also the enantioselectivity of the reactions.
In fact, the
enantioselectivity has been successfully controlled by a variety of chiral catalysts or chiral
1
auxiliaries but the control of endo/exo-selectivity has proved more difficult. In recent years,
hetero Diels-Alder reactions received particular interest for their use in conjugation of several
3
4-8
polymeric materials and also in bioconjugation studies to modify and label several
biomolecules. For this purpose, chemical transformations which are mild and precise are
9
sought.
Norbornene has been introduced as a functional dienophile molecule into oligonucleotides
10
and into DNA which is conjugated to tetrazine dienes via a hetero Diels-Alder reaction. The
11,12
exo-selectivity of the norbornene ring in various addition reactions
has been known for
decades and a great deal of effort has been put into account for the origin of this controversial
1
3-19
selectivity.
In this work, we describe an inverse electron demand hetero Diels-Alder reaction of
norbornene with thiazolidine scaffold containing thiadienes 3a-3e. The reactions have been
o
found to proceed with complete exo-selectivity at 25 C in dichloromethane and in the
absence of any Lewis acid catalyst. This is the first statement of complete exo-selectivity of a
norbornene ring in an inverse electron demand hetero Diels-Alder reaction. The analogs of the
20-23
starting compounds are known to be pharmaceutical targets,
and thus the hetero Diels-
Alder synthesis described herein may be exploited for the bioconjugation of these potential

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drug molecules. The work may also contribute to understanding of the electronic influences
1
4,18
that are thought to be inherent in norbornyl frame works
on this stereoselectivity.
by initiating theoretical studies
Among the heterodienes used, the compounds 3b-3e and their precursors 2b-2e (Scheme 1)
2
are axially chiral due to hindered rotation about N3 -Caryl bond. The barrier to hindered
(sp )
rotation of the smallest o-aryl substituent bearing compound 2b, which is expected to be
similar to that of 3b, and that of cycloadduct 4e have been determined. Atroposelectivities of
the reactions have also been investigated.
Scheme 1. Synthesis of compounds 2a-2e and 3a-3e
H
H
H
H
S1
2
R2
S1
5
R2
5
2
4
4
3
3
N
S
N
O
LR
toluene, reflux
R1
R1
N
R1
N
R1
1
2
1
1
1
1
a. R = R = H
1
2
2
a. R = R = H
1
2
b. R = OCH , R = H
1
2
3
2b. R = OCH , R = H
3
1
2
c. R = CH , R = H
d. R = R = benzo
e. R = Br, R = H
1
2
R2
3
R2
2c. R = CH , R = H
3
1
2
1
2
PhCHO
CH CO Na,
CH CO H
2
2
d. R = R = benzo
1
2
1
1
2
3
2
e. R = Br, R = H
3
2
Ph
Ph
H
H
S1
2
5
4
R2
S1 5
R2
2
4
3
3
N
S
N
S
R1
N
R1
N
R1
R1
1
2
3
3
a. R = R = H
1
2
b. R = OCH , R = H
3
R2 3c. R = CH , R = H
1
2
R2
3
1
2
3
3
d. R = R = benzo
P
M
1
2
e. R = Br, R = H

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2
2
. RESULTS AND DISCUSSION
.1. Synthesis of 2-arylimino-3-aryl-thiazolidine-4-thiones.
24
The thionation reaction of 2-arylimino-3-aryl-thiazolidine-4-ones (1a-1e) with Lawesson’s
reagent gave the corresponding thiazolidine-4-thiones (2a-2e). The formation of the
thiocarbonyl group in compounds 2a-2e were confirmed by the disappearance of the carbonyl
13
peak and the appearance of the thiocarbonyl peak in the C NMR spectra (See supporting
information). Subsequently, compounds 2a-2e were converted into the corresponding 5-
benzylidine-2-arylimino-3-aryl-thiazolidine-4-thiones (3a-3e). The formation of the 5-
benzylidine bond in compounds 3a-3e was shown by the disappearance of the protons at C-5
1
of the precursor compounds in the H-NMR spectra.
2
In compounds 2b-2e and 3b-3e , the rotation about the N3(sp )-Caryl bond is sterically restricted
due to the presence of the exocyclic thiocarbonyl or the aryl imino group on the heterocyclic
3
ring and the ortho substituent on the N -aryl ring. Thus, partial rotation about this bond gives
rise to M and P enantiomers. The chiral nature of 2b-2e was revealed by the diastereotopicity
1
of the protons on C-5 which gave rise to an AB type splitting pattern in the H-NMR spectra
(Figure 1).

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diastereotopic protons
H
H
S1 5
2
4
3
N
S
N
H3CO
OCH3
4.50
4.4
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
1
Figure 1. The 400 MHz H NMR spectrum of compound 2b in CDCl
3
2
.2. Inverse-Electron-Demand Hetero Diels-Alder Reactions.
o
Hetero-Diels-Alder reactions were carried out in dichloromethane at 25 C for 24 h. The
heterodiene of the reaction, which is a thione at C-4 conjugated to the 5-benzylidene (3a-3e),
is a highly electron deficient system and was expected to react with electron rich norbornene
in an inverse-electron-demand hetero Diels-Alder reaction (Scheme 2).
Scheme 2. Inverse-Electron-Demand Hetero Diels-Alder reactions of 3a-3e with norbornene

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Initially, the hetero Diels-Alder reaction of the ortho-unsubstituted compound 3a, which lacks
a chiral axis, with norbornene was investigated. The adduct 4a (Scheme 2) was observed as a
1
single diastereomer, which was as expected, shown to be an enantiomeric pair by H NMR in
the presence of chiral auxiliary S-(+)-1-(9-antryl)-2,2,2-trifluoro ethanol (S-TFAE) (Figure 2).
1
The adduct 4a gave doublets at 3.14 and 2.56 ppm in the H NMR spectrum for the protons
on C-9 and C-2, respectively (Figure 2). However, in the presence of (S)-TFAE these signals
appeared as two doublets (Figure 2), which confirmed the presence of one enantiomeric pair
S,R,R and R,S,S, the configurations referring to C-9, C-10, C-2, respectively (Figure 3a).
Thus, the approach of norbornene from the upper face of the heterodiene produced the S,R,R
enantiomer by pushing the phenyl group down and putting it to an equatorial position in the
20, 25
boat conformation
of the dihydrothiopyrane formed (Figure 3). The equatorial position of
2
6
the phenyl was proven by the observation of diaxial 10.8 Hz coupling of hydrogens at C-9
and C-10 of the dihydrothiopyrane ring. The approach of norbornene from the lower face of
the heterodiene also puts the phenyl to the equatorial position, forming its enantiomer, R,S,S.
The R,R,R and S,S,S isomers of adduct 4a where the phenyl group would have been at the
axial position were not produced at all. The hetero Diels-Alder reaction was found to proceed
with 100% exo stereoselectivity of the norbornene ring (Figure 3b).

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1
1
Figure 2. (a) H NMR spectrum of compound 4a in CDCl
3
(b) H NMR signals of protons
on C-9 and C-2 of 4a in the presence of (S)-TFAE.
Ph
H
10
R
11
H
Ph 11
10 12
12
1413
(a)
9
9
S
R
1
H
4
S
S
13
S
S
6
H
7
8
R
7 8
3
3
6
4
4
5
S 2
1
5
N
S 2
H 1
N
H
N
N
S,R,R
R,S,S
(b)
S,R,R
R,S,S
Figure 3. (a) S,R,R and R,S,S isomers of adduct 4a (b) the 3D structural representation of
[
a]
S,R,R and R,S,S isomers of the adduct 4a .
[a]
drawn in ChemOffice 10.0 for the visualization of the stereoisomers.

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2
.3. Barriers to Rotation.
The compounds 2b-2e and 3b-3e exist as racemates of interconvertible enantiomers M and P,
2
and barriers to rotation about the N3(sp )-Caryl bond can be determined by thermal
24
racemization of the micropreparatively separated enantiomers.
Enantiomers of 2b were separated micropreparatively on Chiralpak IC (eluent:hexane:2-
propanol (70:30, v/v)). The separated enantiomers were then subjected to thermal
racemization in toluene at 333 K to find out the rotational barrier (Figure 4). The thermal
racemization was done in the following way: micropreparatively resolved enantiomer was
dissolved in toluene, the solution was kept in a constant temperature bath (333 K), and the
conversion of the enantiomer to its counterpart was followed by enantioselective HPLC until
equilibrium. The ratios of the enantiomers (Figure 4a) were found by integration of the UV
peaks (λ= 254 nm) on the chromatogram. A plot of ln([M] - [M] ) / [M] - [M] ) versus time
eq 0 eq
(Figure 4b) gave first-order rate constant for the interconversion, and substitution of the rate
#
constant into the Eyring equation ∆G = RTln(k
b
T/kh) provided the barrier to rotation. The
barrier was found to be 115.9 ± 0.7 kJ/mole which is about 18 kJ/mole higher than the
24
rotational barrier of its oxygen analog 1b that has been previously reported. The
replacement of the oxygen by a sulfur atom, as expected, increased the barrier making the
2
rotation about N3 -aryl bond more hindered.
(sp )
Although the enantiomers of compound 3b and 3e could be resolved micropreparatively by
enantioselective HPLC (Figure 5), the rotational barrier could not be determined because the
compounds were found to decompose during the thermal racemization process at 333 K and
also at 313 K in toluene. However, based on our previous work on 2-arylimino-3-aryl-

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2
4
thiazolidine-4-ones where we showed that 5-benzylidine derivatization gave rise to an
increase of only 2-3 kJ/mol, barrier to rotation of compound 3b would be expected to be
slightly higher than that of 2b. The compounds 2c-2e and 3c-3d were not seperable by HPLC
with a chiral stationary phase, but their rotational barriers are expected to be higher than that
of the smallest substituent bearing 2b (115.9 kJ/mole).
Figure 4 (a) The HPLC chromatograms taken to follow the thermal racemization process of
the micropreparatively resolved enantiomer of compound 2b at 333 K (column: Chiralpak
IC (eluent : hexane : 2-propanol (70:30, v/v); flow rate: 0.5 mL/min; retention times: t
min, t , 39.3 min; column temperature: 280 K). (b) The plot of ln(([M] - [M]eq/[M] - [M]eq))
versus time at 333 K. The slope equals to 2k, the rate constant for the racemization,
1
, 26.6
2
0
-6
-1
k=4.5x10 s .

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Figure 5. The enantiomers of 3b which were separated by enantioselective HPLC on
Chiralpak IC column (eluent:hexane:2-propanol (70:30, v/v), flow rate:0.7 mL/min, α=1.81)
The rotational barrier of the adduct 4e bearing the largest ortho substituent was determined as
o
9
7.1 ± 0.7 kJ/mole at 25 C which corresponds to a half life of 4.81 h. The barrier obtained is
much smaller than the starting materials.
2
.4. Atroposelectivity of the Hetero Diels-Alder Reactions.
The hetero Diels-Alder reactions of the axially chiral compounds 3b-3e were also investigated
in order to see the effect of the chiral axis on the facial selectivity of the dienophile. Due to
the presence of three stereogenic centers and one chiral axis in the adducts 4b-4e, the number
of possible isomers is 16 and since the configuration of norbornene is retained in the product,
1
eight stereoisomers may be expected. In the H NMR spectrum of the cycloadduct 4b, two
sets of signals were observed for the two diastereomeric pairs (four stereoisomers) (Figure 6).

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1
Figure 6. The partial H NMR spectrum of the adduct 4b in CDCl
3
1
Based on a diaxial 10.4 Hz H NMR coupling constant between protons on C-9 and C-10,
which pointed to an equatorial orientation of the phenyl group, we assigned stereochemistries
as M,R,R,S and P,S,S,R to the major products and P,R,R,S and M,S,S,R to minor products
(Figure 7). After 24 h reaction time, the ratio of diastereomeric pairs of the product was found
to be 2:1.
3
The hetero Diels-Alder reactions of 3c-3e, which possessed larger ortho substituents –CH ,
benzo and –Br were carried out with the expectation of obtaining higher atroposelectivities.
However, the atroposelectivities observed at the end of the 24 h reaction time were found
again as 2:1 in yielding compounds 4c-4e. Based on the 97.1 kJ/mole barrier to rotation of 4e,
this result was interpreted to be a consequence of an internal rotation in the products 4c-4e
which produced the thermodynamic products within 24 h. Such diastereoselectivities have
also been observed during the Diels-Alder reactions of an axially chiral maleimide with
27
several dienes. To be able to find out the kinetic atroposelectivities, samples were taken
from the reaction mixture at the end of 90 min reaction time and analyzed by HPLC for the
major:minor isomer ratios. The atroposelectivities of the reactions determined in this way

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were found to be 6:1, 5:1, and 11:1 for 4c, 4d and 4e, respectively (Figure 8). The largest
ortho-Br, as expected, gave the best kinetic atroposelectivity while the ortho-CH and the
3
naphthyl group resulted in close selectivities. The initial atroposelectivities apparently
3
decreased on standing for 24 h due to rotation around the N -Caryl bond in products 4c-4e. The
o
final atroposelectivities (after 24 h at 25 C) are thermodynamic and result from relatively
rapid equilibration by N -C bond rotation in adducts 4c-4e. In addition, the reactions again
3
aryl
did not produce any endo-products.
enantiomers
H
H
S
R
R
S
S
S
H
H
S
R
N
S
H
N
S
H
N
N
H3CO
H3CO
OCH3
OCH3
diastereomers
M,S,R,R
major
P,R,S,S
major
diastereomers
H
H
S
R
R
R
S
S
S
H
H
S
N
S
H
N
S
H
N
N
H3CO
H3CO
OCH3
OCH3
P,S,R,R
M,R,S,S
minor
enantiomers
minor
Figure 7. Four stereoisomers of the adduct 4b obtained from hetero Diels-Alder reaction of
compound 3b with norbornene.

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3
c
3
e
4
d
4
c
4
e
4c
4d
4e
Figure 8. The HPLC chromatograms taken after 90 min (major:minor: 6:1, 5:1 and 11:1
for 4c, 4d and 4e, respectively)
5
. CONCLUSION
In the work described here, the carbonyl functionality of 2-arylimino-3-aryl-thiazolidine-4-
ones (1a-1e) has been converted into a thiocarbonyl group. The resulting 2-arylimino-3-aryl-
thiazolidine-4-thiones (2a-2e) have then been converted into the corresponding 5-benzylidene
derivatives (3a- 3e). The compounds 2b-2e and 3b-3e are axially chiral and energy barrier to
rotation of 2b has been determined as 115.9 kJ/mole by the thermal racemization of
enantiomers. The 5-benzylidene-2-arylimino-3-aryl-thiazolidine-4-thiones (3a-3e) have been
used as heterodienes in the inverse-electron-demand hetero Diels-Alder reaction with
o
norbornene as a dienophile in dichloromethane at 25 C. The hetero Diels-Alder reactions
were shown to proceed with complete exo selectivity with norbornene as the dienophile. In
addition, the barrier of axially chiral cycloadduct 4e was determined as 97.1 kJ/mole by
following the thermal atropisomerization of enantiomeric pairs. As a result of the relatively

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low barrier reactions of the axially chiral heterodienes were found to result in a 2:1
thermodynamic diastereoselectivity in formation of products 4b-4e.
The inverse-electron demand nature of the reaction that proceeded with 100% exo-selectivity
may help to interpret the electronic influences that are thought be inherent in the norbornane
1
4,18
ring.
The hetero Diels-Alder reaction with norbornene can also be useful in
4
-8
3
bioconjugation and other conjugation studies because the reaction is run under mild
o
conditions (25 C) and in the absence of a Lewis acid or any other additive. Moreover, now
that the reaction is under 100% diastereoselective control by the substrate, it is ideally suited
for further elaborations for enantioselective syntheses.
Experimental Section
General Methods
1
13
H and C nuclear magnetic resonance (NMR) spectra of all compounds were recorded on a
Varian-Mercury VX-400MHz-BB. IR spectra of all compounds were recorded on Thermo
Nicolet 380 FT-IR spectrometer. Liquid chromatography analyses with ultraviolet (UV)
detector (λ = 254 nm) were performed using CHIRALPAK IC column (partical size, 5 mm;
2
column size, 250 x 4.6 mm ). Elemental analyses were performed on Thermo Scientific Flash
EA 1112 analyzer. Melting points were recorded using Electrothermal 9100 melting point
apparatus.
General Procedure for the Preparation of Compounds 2a-2e. 2-arylimino-3-aryl-
24
thiazolidine-4-thiones (2a-2e) were synthesized from 2-arylimino-3-aryl-thiazolidine-4-ones

ACCEPTED MANUSCRIPT
(1a-1e) using Lawesson’s reagent (LR). A mixture of appropriate thiazolidine-4-one (1a-1e)
and Lawesson’s reagent was heated at reflux in dry toluene for 5 h. After cooling to room
temperature, the reaction mixture was washed successively with water, aq. Na CO solution
10%), then with water and dried with anhydrous MgSO . Toluene was removed under
2
3
(
4
reduced pressure and the residue was treated with petroleum ether. The precipitated solid was
isolated by filtration and recrystallized from a mixture of ethyl acetate and hexane (a
minimum amount of ethyl acetate was used to dissolve the crude product and then hexane was
added until the precipitation was observed).
2
-Phenylimino-3-phenyl-thiazolidine-4-thione (2a). The compound was synthesized
according to the general procedure using 1a (1.34 g, 5.00 mmol), Lawesson’s reagent (1.01 g,
1
2
.50 mmol) and dry toluene (35.0 mL). Yield: 0.920 g (65%), mp: 160-162 °C H NMR (400
1
3
3
MHz, CDCl ): δ 7.62-6.91 (m, 10H, Ar), 4.41 (s, 2H at C-5) ppm. C NMR (100 MHz,
CDCl
Calculated for C15
FTIR (neat) 1629, 1228 cm .
3
): δ 201.8, 159.6, 148.7, 138.3, 129.8, 129.6, 129.4, 128.5, 125.2, 120.6, 44.0 ppm.
12 2 2
H N S
: C, 63.35; H, 4.25; N,9.85,. Found: C, 62.96; H,4.42; N; 9.56.
-1
2
-(o-Methoxyphenyl)imino-3-(o-methoxyphenyl)-thiazolidine-4-thione
(2b).
The
compound was synthesized according to the general procedure using 1b (1.64 g, 5.00 mmol),
Lawesson’s reagent (1.01 g, 2.50 mmol) and dry toluene (35.0 mL). Yield: 1.42 g (83%), mp:
1
2
04-206 °C H NMR (400 MHz, CDCl ): δ 7.47-6.82 (m, 8H, Ar), 4.51 (1H at C-5, d, J = 18
3
13
Hz), 4.46 (1H at C-5, d, J=18 Hz), 3.88 (s, 3H, OCH ), 3.77 (s, 3H, OCH ) ppm. C NMR
3
3
(
100 MHz, CDCl
3
): δ 202.0, 159.9, 154.8, 150.5, 138.5, 131.3, 129.8, 126. 8, 125.9, 121.5,
21.3, 121.2, 113.1, 112.6, 56.2, 56.1, 43.9 ppm. Calculated for C17 : C, 59.28; H,
.68; N, 8.13. Found: C, 59.11; H, 4.64; N, 7.85. FTIR (neat) 1637, 1245 cm .
1
4
16 2 2 2
H N O S
-1

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2
-(o-Tolyl)imino-3-(o-tolyl)-thiazolidine-4-thione (2c). The compound was synthesized
according to the general procedure using 1c (0.750 g, 2.50 mmol), Lawesson’s reagent (0.510
1
g, 1.25 mmol) and dry toluene (20.0 mL). Yield: 0.420 g (53%), mp: 96-98 °C H NMR
(400MHz, CDCl
3
): δ 7.40-6.82 (m, 8H, Ar), 4.55 (1H at C-5, d, J = 2 Hz), 4.48 (1H at C-5, d,
13
J = 2 Hz), 3.25 (s, 3H, CH ), 3.06 (s, 3H, CH ) ppm. C NMR (100 MHz, CDCl ): δ 200.9,
3
3
3
1
1
6
58.2, 147.4, 137.4, 135.9, 131.6, 130.8, 130.0, 129.5, 128.3, 127.7, 126.7, 125.2, 119.1, 43.9,
7.9, 17.6 ppm. Calculated for C17 : C, 65.35; H, 5.16; N, 8.91. Found: C, 65.33; H,
.09; N, 8.97. FTIR (neat) 1628, 1229 cm .
16 2 2
H N S
-1
2
-(α-Naphthyl)imino-3-(α-naphthyl)-thiazolidine-4-thione (2d). The compound was
synthesized according to the general procedure using 1d (0.920 g, 2.50 mmol), Lawesson’s
reagent (0.510 g, 1.25 mmol) and dry toluene (20.0 mL). Yield: 0.590 g (61%), mp: 146-148
1
°
C H NMR (400 MHz, CDCl
3
): δ 8.04-6.91 (m, 14H, Ar), 4.68 (1H at C-5, d, J = 9.2 Hz),
1
3
4
1
1
7
.65 (1H at C-5, d, J = 9.2 Hz) ppm. C NMR (100 MHz, CDCl
43.3, 141.4, 138.2, 136.9, 135.8, 134.8, 133.7, 132.3, 132.1, 130.1, 129.8, 128.4, 128.2,
27.8, 127.2, 125.1, 122.5, 119.6, 42.2 ppm. Calculated for C23 : C, 71.84; H, 4.19; N,
.29. Found: C, 71.79; H, 4.30; N, 7.59. FTIR (neat) 1626, 1224 cm .
3
): δ 203.5, 154.1, 145.0,
16 2 2
H N S
-
1
2
-(o-Bromophenyl)imino-3-(o-bromophenyl)-thiazolidine-4-thione (2e). The compound
was synthesized according to the general procedure using 1e (1.07 g, 2.50 mmol), Lawesson’s
reagent (0.510 g, 1.25 mmol) and dry toluene (20.0 mL). Yield: 0.600 g (54%), mp: 46-48 °C
1
H NMR (400 MHz, CDCl
3
): δ 7.71-6.88 (m, 8H, Ar), 4.54 (1H at C-5, d, J = 10.4 Hz), 4.49
1
3
(
1H at C-5, d, J = 10.4 Hz) ppm. C NMR (100 MHz, CDCl ): δ 200.9, 154.2, 143.2, 137.5,
3

ACCEPTED MANUSCRIPT
1
4
35.9, 134.8, 131.4, 130.1, 129.9, 127.4, 127.0, 125.2, 120.1, 43.7 ppm. C H Br N S : C,
15
10
2
2 2
-1
0.74; H, 2.28; N, 6.34. Found: C, 40.91; H, 2.38; N, 5.98. FTIR (neat) 1623, 1221 cm .
General Procedure for the Preparation of Compounds 3a-3e. 5-benzylidene-2-arylimino-
-aryl-thiazolidine-4-thiones (3a-e) were synthesized by heating at reflux the appropriate 2-
3
arylimino-3-arylthiazolidine-4-thiones (2a-e) with benzaldehyde in the presence of sodium
acetate and acetic acid for 5 h. The compounds were purified by recrystallization from a
mixture of ethyl acetate and hexane (a minimum amount of ethyl acetate was used to dissolve
the crude product and then hexane was added until the precipitation was observed).
5
-Benzylidine-2-phenylimino-3-phenyl-thiazolidine-4-thione (3a). The compound was
synthesized according to the general procedure using 2a (0.570 g, 2.00 mmol), benzaldehyde
(0.230 g, 2.20 mmol), sodium acetate (0.160 g, 2.20 mmol) and acetic acid (10.0 mL). Yield:
1
0
6
1
.49 g (66%), mp: 204-206 °C. H NMR (400 MHz, CDCl
3
): δ 8.27 (s, 1H, =CHPh), 7.61-
1
3
.82 (m, 15H, Ar) ppm. C NMR (100 MHz, CDCl ): δ 194.9, 155.9, 149.2, 138.6, 135.5,
3
30.5, 130.3, 129.8, 129.6, 129.5, 129.4, 129.3, 128.7, 125.3, 120.9 ppm. Calculated for
22 16 2 2
C H N S : C, 70.93; H, 4.33; N, 7.52. Found: C, 70.62; H, 4.15; N, 7.58. FTIR (neat) 1627,
-1
1
214 cm .
5
-Benzylidine-2-(o-methoxyphenyl)imino-3-(o-methoxyphenyl)-thiazolidine-4-thione
(3b). The compound was synthesized according to the general procedure using 2b (0.690 g,
2
.00 mmol), benzaldehyde (0.230 g 2.20 mmol), sodium acetate (0.160 g, 2.20 mmol) and
1
acetic acid (10.0 mL). Yield: 0.560 g (65%), mp: 140-142°C. H NMR (400 MHz, CDCl
3
): δ
8
3 3
.31 (s, 1H, =CHPh ), 7.8-6.89 (m, 13H, Ar). 3.91 (s, 3H, OCH ), 3.79 (s, 3H, OCH
) ppm.

ACCEPTED MANUSCRIPT
1
3
C NMR (100 MHz, CDCl ): δ 192.0, 153.3, 152.0, 147.7, 135.9, 131.8, 131.7, 128.4, 127.6,
3
1
27.1, 126.9, 126.0, 124.3, 123.1, 118.7, 118.6, 118,3, 110.1, 109.6, 109.6, 53.4, 53.2 ppm.
: C, 66.64; H, 4.66; N, 6.48. Found: C ,66.49; H, 4.42; N, 6.37.
Calculated for C24
20 2 2 2
H N O S
-1
FTIR (neat) 1642, 1250 cm .
5
-Benzylidine-2-(o-tolyl)imino-3-(o-tolyl)-thiazolidine-4-thione (3c). The compound was
synthesized according to the general procedure using 2c (0.310 g, 1.00 mmol), benzaldehyde
(0.120 g, 1.10 mmol), sodium acetate (0.800 g, 1.10 mmol) and acetic acid (10.0 mL). Yield:
1
0
6
1
1
.240 g (60%), mp: 126-128 °C. H NMR (400 MHz, CDCl
3
): δ 8.24 (s, 1H, =CHPh), 7.56-
13
3 3 3
.86 (m, 13H, Ar ), 2.29 (s, 3H, CH ), 2.10 (s, 3H, CH ) ppm. C NMR (100 MHz, CDCl ): δ
94.2, 154.3, 148.1, 137.8, 136.0, 135.2, 134.5, 131.6, 130.9, 130.6, 130.3, 130.1, 129.8,
29.4, 129.3, 128.4, 127.7, 126.9, 125.3, 119.8, 18.2, 18.1 ppm. Calculated for C H N S :
24
20
2 2
-1
C, 71.96; H, 5.03; N, 6.99. Found: C, 71.41; H, 5.89; N, 6.75. FTIR (neat) 1641, 1248 cm .
5
-Benzylidine-2-(α-naphthyl)imino-3-(α-naphthyl)-thiazolidine-4-thione
(3d)
The
compound was synthesized according to the general procedure using 2d (0.390 g, 1.00 mmol),
benzaldehyde (0.120 g, 1.10 mmol), sodium acetate (0.800 g, 1.10 mmol) and acetic acid
1
(
10.0 mL). Yield: 0.220 g (52%), mp: 186-188 °C. H NMR (400 MHz, CDCl
3
): δ 8.31 (s,
1
3
1
1
1
H, =CHPh), 8.10-7.09 (m, 19H, Ar) ppm. C NMR (100 MHz, CDCl
3
): δ 200.1, 158.1,
6.1, 143.2, 139.8, 137.5, 136.1, 131.1, 131.0, 130.2, 130.0, 127.5, 127.3, 126.9, 125.0, 120.1,
14.8 ppm. Calculated for C H N S : C, 76.24; H, 4.27; N, 5.93. Found: C, 76.45; H, 4.15;
30
20
2 2
-1
N, 5.89. FTIR (neat) 1630, 1250 cm .
5
-Benzylidine-2-(o-bromophenyl)imino-3-(o-bromophenyl)-thiazolidine-4-thione
(3e).
The compound was synthesized according to the general procedure using 2e (0.690 g, 1.00

ACCEPTED MANUSCRIPT
mmol), benzaldehyde (0.120 g, 1.10 mmol), sodium acetate (0.440 g, 1.10 mmol) and acetic
1
acid (10.0 mL). Yield: 0.18 g (34%), mp: 88-90 °C. H NMR (400 MHz, CDCl ): δ 8.11 (s,
3
1
3
1
1
H, =CHPh), 7.89-6.99 (m, 13H, Ar ) ppm. C NMR (100 MHz, CDCl
48.0, 143.8, 137.4, 135.7, 131.0, 130.1, 129.8, 127.6, 127.5, 127.1, 125.0, 114.6 ppm.
: C, 49.83; H, 2.66; N, 5.28. Found: C, 49.98; H, 3.38; N, 4.99.
3
): δ 198.8, 158.5,
Calculated for C22
2 2 2
H14Br N S
-1
FTIR (neat) 1618, 1240 cm .
General Procedure for the Preparation of Compounds 4a-4e. A mixture of appropriate 5-
benzylidene-2-arylimino-3-aryl-thiazolidine-4-ones (3a-e) and norbornene was stirred for 24
o
h in CH
2
Cl
2
at 25 C. Then, CH
Cl
2 2
was evaporated. The precipitated crystals were
recrystallized from mixtures of ethyl acetate and hexane (a minimum amount of ethyl acetate
was used to dissolve the crude product and then hexane was added until the precipitation was
observed).
2
,10 4,8
9
-Phenyl-3,7-dithia-5-phenylazatetracyclo[9.2.1.0 .0 ]6-phenylimino-4(8)tetradecene
(4a). The compound was synthesized according to the general procedure using 3a (0.0380 g,
0
0
3
.100 mmol), norbornene (0.010 g, 0.110 mmol) and dichloromethane (5.00 mL). Yield:
1
.0340 g (73%), mp: 200-202 °C. H NMR (400 MHz, CDCl
3
): δ 7.52-6.87 (m, 15H, Ar),
.49 (d, 1H, J = 10.8 Hz, ArCH), 3.32 (d, 1H, J = 6.8 Hz, SCH), 2.26-1.07 (m, 9H, norbornyl
1
3
H’s) ppm. C NMR (100 MHz, CDCl
3
): δ 158.1, 151.6, 140.8, 137.1, 129.3, 129.2, 128.9,
28.8, 128.1, 127.9, 127.6, 127.0, 122.9, 121.6, 111.8, 58.6, 53.1, 47.6, 43.4, 41.4, 34.3, 29.7,
8.9 ppm. Calculated for C H N S : C,74.64; H,5.62; N,6.00. Found: C,74.29; H,5.64;
1
2
2
9
26
2 2
-1
N,5.75. FTIR (neat) 1605 cm .

ACCEPTED MANUSCRIPT
2
,10 4,8
9
-Phenyl-3,7-dithia-5-(o-methoxyphenyl)azatetracyclo[9.2.1.0 .0 ]6-(o-
methoxyphenyl)imino-4(8)tetradecene (4b). The compound was synthesized according to
the general procedure using 3b (0.0440 g, 0.100 mmol), norbornene (0.0100 g, 0.110 mmol)
1
and dichloromethane (5.00 mL). Yield: 0.042g (80%), mp: 90-92 °C. H NMR (400 MHz,
CDCl
3 3 3
): δ 7.61-6.64 (m, 26 H, Ar), 3.94 (s, 3H, OCH ), 3.87 (s, 3H, OCH ), 3.76 (s, 3H,
OCH ), 3.69 (s, 3H, OCH ), 3.50 (d, 1H, J = 10.4 Hz, ArCH), 3.43(d, 1H, J = 10.4 Hz,
3
3
ArCH), 3.31 (d, 1H, J = 6.8 Hz, SCH), 3.22 (d, 1H, J = 6.8 Hz, SCH), 2.16-1.01 (m, 18 H,
1
3
norbornyl H’s) ppm. C NMR (100 MHz, CDCl
3
): δ 154.9, 154.4, 150.8, 139.9, 134.2, 132.5,
1
1
1
4
7
30.1, 130.0, 129.9, 129.8, 129.7, 129.6, 129.4, 129.3, 129.2, 129.0, 128.8, 128.6, 128.5,
28.4, 128.3, 128.2, 128.0, 127.5, 127.1, 126.4, 126.0, 124.3, 124.2, 123.1, 123.0, 122.2,
22.1, 120.3, 120.2, 120.1, 111.6, 111.5, 111.4, 57.6, 55.1, 54.9, 54.8, 54.7, 51.9, 51.6, 50.4,
7.5, 46.5, 42.5, 42.4, 40.7, 40.3, 33.1, 29.1, 28.2, 23.6 ppm. Calculated for C H N O S : C,
3
1
30
2
2 2
-1
0.69; H, 5.74; N, 5.32. Found: C,70.93; H,5.48; N,5.52. FTIR (neat) 1641 cm .
2
,10 4,8
9
4
-Phenyl-3,7-dithia-5-(o-tolyl)azatetracyclo[9.2.1.0 .0 ]6-(o-tolyl)imino-
(8)tetradecene (4c). The compound was synthesized according to the general procedure
using 3c (0.0490 g, 0.100 mmol), norbornene (0.0100 g, 0.110 mmol) and dichloromethane
1
(
5.00 mL). Yield: 0.03g (61%), mp: 112-114 °C. H NMR (400 MHz, CDCl
3
): δ 7.65-6.55
(
m, 26 H, Ar), 3.39 (d, 1H, J = 10.2 Hz, ArCH), 3.37 (d, 1H, J = 10.2 Hz, ArCH), 3.29 d, 1H,
), 2.22 (s, 3H, CH ), 2.03
s, 3H, CH ), 1.99 (s, 3H, CH ), 2.26-0.79 (m, 18H, norbornyl H’s) ppm C NMR (100
J = 7.8 Hz, SCH) 3.24 (d, 1H, J = 7.8 Hz, SCH), 2.34 (s, 3H, CH
3
3
1
3
(
3
3
MHz, CDCl ): δ 155.0, 154.6, 150.8, 140.0, 134.3, 132.2, 130.0, 129.9, 129.8, 129.7, 129.6,
3
1
5
29.4, 128.0, 127.9, 127.8, 127.7, 127.6, 121.7, 121.6, 121.5, 111.8, 55.9, 55.8, 55.7, 52.1,
2.0, 50.4, 47.7, 46.3, 42.2, 40.1, 33.2, 28.6, 28.1,23.9, 15.1, 15.0, 14.9 ppm. Calculated for

ACCEPTED MANUSCRIPT
C H N S : C, 75.26; H, 6.11; N, 5.66. Found:C, 74.98; H, 6.49; N, 5.97. FTIR (neat) 1635
31
30
2 2
-1
cm
2
,10 4,8
9
4
-Phenyl-3,7-dithia-5-(α-naphthyl)azatetracyclo[9.2.1.0 .0 ]6-(α-naphthyl)imino-
(8)tetradecene (4d). The compound was synthesized according to the general procedure
using 3d (0.0560 g, 0.100 mmol), norbornene (0.0100 g, 0.110 mmol) and dichloromethane
1
(
5.00 mL). Yield: 0.0400 g (71%), mp: 92-94 °C. H NMR (400 MHz, CDCl
3
): δ 8.05-6.99
(m, 38 H, Ar), 3.54 (d, 1H, J = 10.2 Hz, ArCH), 3.51(d, 1H, J = 10.2 Hz, ArCH), 3.35(d, 1H,
1
3
J = 7.8 Hz, SCH), 3.21 (d, 1H, J = 7.8 Hz, SCH), 2.28-1.05 (m, 18H, norbornyl H’s) ppm. C
NMR (100 MHz, CDCl ): δ 156.2, 150.8, 142.2, 140.0, 136.2, 134.1, 132.2, 128.1, 128.0,
27.9, 127.8, 127.7, 121.2, 121.1, 121.0, 120.9, 119.0, 117.2, 114.0, 111.8, 58.0, 55.9, 55.8,
2.1, 51.9, 50.2, 47.8, 47.5, 44.2, 42.3, 42.1, 40.3, 40.2, 36.3, 36.2, 33.6, 33.5, 28.4, 28.0, 23.8
: C, 78.41; H, 5.34; N, 4.94. Found: C, 78.08; H, 5.68; N,
3
1
5
30 2 2
ppm. Calculated for C37H N S
-1
4
.66. FTIR (neat) 1612 cm .
2
,10 4,8
9
-Phenyl-3,7-dithia-5-(o-bromophenyl)azatetracyclo[9.2.1.0 .0 ]6-(o-
bromophenyl)imino-4(8)tetradecene (4e). The compound was synthesized according to the
general procedure using 3e (0.0620 g, 0.1 mmol), norbornene (0.010 g, 0.110 mmol) and
1
dichloromethane (5.00 mL). Yield: 0.0320 g (51%), mp: 78-80 °C. H NMR (400 MHz,
CDCl
3
): δ 7.71-6.70 (m, 26H, Ar), 3.46 (d, 1H, J = 10.2 Hz, ArCH), 3.38 (d, 1H, J = 10.2 Hz,
ArCH), 3.37 (d, 1H, J = 7.8 Hz, SCH), 3.25 (d, 1H, J = 7.8 Hz, SCH), 2.21-0.81 (m, 18H,
1
3
norbornyl H’s) ppm. C NMR (100 MHz, CDCl
3
): 159.1, 151,1 142.2, 140.1, 136.3, 134.2,
32.1, 128.0, 127.9, 127.7, 127.6, 118.8, 116.7, 114.1, 111.6, 57.8, 51.8, 50.1, 47.7, 46.5,
4.2, 40.0, 36.3, 33.2, 23.6 ppm. Calculated for C29 : C, 55.78; H, 3.87; N, 4.49.
1
4
H
2 2 2
24Br N S
-1
Found: C, 55.44; H, 4.12; N, 4.88. FTIR (neat) 1616 cm .

ACCEPTED MANUSCRIPT
Acknowledgements
This project has been supported by Boğaziçi University research fund (BAP) with project
numbers 09B506D and 10B05P6.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Ph
S1
2
5
PhCHO,
S1
H
5
Ar
CH3CO2
,
H
Ar
4
LR
3
4
S 1
2
5
3
N
S
N
O toluene, reflux
N
CH3CO2Na,
reflux
Ar
4
3
N
2
N
S
N
Ar
Ar
Ar
CH2Cl2,
2
5oC
Ph
H
S
H
Ar
N
S
H
N
1
00% exo-selectivity
Ar