Endo-Mode cyclizations of vinylogous N-acyliminium ions as a route to the synthesis of condensed thiazolidines

Article abstract of DOI:10.1016/j.tet.2011.10.011

endo-Mode cyclizations of vinylogous N-acyliminium ions incorporating heteroatom-based nucleophiles have been examined as a route to the synthesis of condensed thiazolidines. The scope of these reactions and stereochemical outcome are discussed and explained using quantum chemical calculations.

Full text of DOI:10.1016/j.tet.2011.10.011

Tetrahedron 67 (2011) 9541e9554
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endo-Mode cyclizations of vinylogous N-acyliminium ions as a route
to the synthesis of condensed thiazolidines
,
b
,
c
b
,b,c,
ꢀ a
*
ꢀ a
ꢀ a
Milovan Stojanovic , Rade Markovic , Erich Kleinpeter , Marija Baranac-Stojanovic
a Center for Chemistry ICTM, P.O. Box 473, 11000 Belgrade, Serbia
b
€
Chemisches Institut der Universitat Potsdam, Karl-Liebknecht Str. 24-25, D-14476 Potsdam (Golm), Germany
c Faculty of Chemistry, University of Belgrade, Studentski trg 16, P.O. Box 158, 11000 Belgrade, Serbia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 July 2011
Received in revised form 14 September 2011
Accepted 3 October 2011
Available online 10 October 2011
endo-Mode cyclizations of vinylogous N-acyliminium ions incorporating heteroatom-based nucleophiles
have been examined as a route to the synthesis of condensed thiazolidines. The scope of these reactions
and stereochemical outcome are discussed and explained using quantum chemical calculations.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Vinylogous N-acyliminium ion
endo-Mode cyclization
Condensed thiazolidines
Quantum chemical calculations
1. Introduction
Iminium ions have proven to be valuable intermediates in or-
ganic synthesis for the formation of carbonecarbon and carbone
heteroatom bonds. Indeed, the well-known Mannich reaction1
and its intramolecular variantdthe PicteteSpengler reaction,2
used for a long time as a-aminoalkylation reactions, are based on
the reactive iminium species. Iminium ion cyclizations have been
widely exploited as a powerful method for the construction of
a huge variety of heterocyclic systems.3 Diverse nucleophiles, such
Fig. 1. exo- and endo-Mode cyclizations.
as
p
-nucleophiles (aromatic rings, carbonecarbon double, and
Suitable structural variations in the iminium ion precursor, like
introduction of a second heteroatom, enlarges the scope of the
iminium ion methodology. For example, cyclizations involving
thiazolidine-based iminium ions can result in the formation of
a variety of derivatives of interesting pharmacological structure.6 In
addition, further desulfurization of thiazolidine-containing poly-
cycles is a valuable method for synthesis of various ring structures,
some of which are not easily accessible by other routes.6c,7
The iminium ions can be divided into two main categories:
N-alkyl-3a (R3, R4¼alkyl, aryl, Fig. 2) and N-acyliminium ions3b,c
(R3¼alkyl, aryl, R4¼COR, CO2R, SO2R, Fig. 2). Introduction of an
electron-withdrawing group on nitrogen leads to more electro-
philic iminium carbon, which makes N-acyliminium ions much
more reactive as electrophiles than simple N-alkyliminium ions. A
subtype of N-acyliminium ions with carbonecarbon double bond
conjugating an acyl group to nitrogen is referred to as vinylogous
N-acyliminium ions (Fig. 3). Literature covering this type of iminium
triple bonds),
s
-nucleophiles and heteroatom-based nucleophiles,
have been used to react with various acyclic and cyclic iminium
ions in both exo- and endo-mode cyclizations (Fig. 1). Heterocycles
produced via the addition of heteroatoms as nucleophiles onto the
iminium ions not only are well-known and important compounds,
particularly in the field of medicinal chemistry, but also represent
stable potential iminium ions equivalents due to reversibility of the
addition process. Despite the fact that, according to Baldwin’s
rules,4 5-endo-trig cyclizations are classified as ‘unfavoured’ for the
first-row elements,4b they can occur with iminium ions as reactive
species.3aec,h,j,5
* Corresponding author. Tel.: þ381 11 3336740; fax: þ381 11 2636061; e-mail
ꢀ
address: mbaranac@chem.bg.ac.rs (M. Baranac-Stojanovic).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.011

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M. Stojanovic et al. / Tetrahedron 67 (2011) 9541e9554
Table 1
ions is rather scarce, with just a few reports published thus far. It
has been shown that they can react with added nucleophiles,8 or
Comparison of synthesis of 4-oxothiazolidines 7 with and without solvent
initiate ring-closing reaction with
p
-nucleophile, such as an olefin9
or aromatic ring.10
Fig. 2. N-Alkyl and N-acyliminium ions.
Product
Reaction conditions and yielda (%)
7a-Z (R¼H)
EtOH, reflux, 5 h (67)
EtOH, reflux, 6 h (42)
No solvent, 75e80 ꢀC, 30 min (87)
No solvent, 75e80 ꢀC, 15 min (76)
7b-Z (R¼Me)
a
Yield of isolated products.
Fig. 3. Vinylogous N-acyliminium ions.
Table 2
N-Alkylation of 4-oxothiazolidines 7 with
a
,
u
-dibromides
In the course of our studies on the reactivity of 2-alkylidene-4-
oxothiazolidines we have observed that vinylogous N-acyliminium
ion 3 derived from compound 1 can undergo cyclization reaction in
a 5-exo mode giving rise to bicyclic product 5, albeit in low yield
(Scheme 1).11 The iminium ion 3 is formed from the hydroxy de-
rivative 2, produced by the regioselective reduction of one carbonyl
of the vinylogous imide function. The resistance of another car-
bonyl to reduction is considered to reside in its deactivation due to
the pushepull effect of the carbonecarbon double bond.12 Now, the
iminium function enhances the electrophilicity of the ester group
in 3 allowing its reduction to 4, even at rt.13 Subsequent 5-exo-trig
cyclization affords the cis-fused tetrahydrofurothiazolidine 5. This
finding prompted us to further explore the ability of these new
vinylogous N-acyliminium ions to participate in cyclization re-
actions with suitably positioned nucleophiles. We examined re-
actions with a range of heteroatom-based nucleophiles in both
endo- and exo-mode. Herein, we present the results of endo-mode
reactions together with quantum chemical calculations used to
rationalize the experimental observations.
R
n
Time (h)
Product 8a (%)
Dimer 9a (%)
H
Me
H
Me
H
Me
1
1
2
2
3
3
5
5
2
2.5
4
8a (72)
8b (82)
8c (70)
8d (70)
8e (83)
8f (80)
/
9a (6)
9b(18)
9c (21)
9d (4)
9e (7)
1.5
a
Yield of isolated products.
Scheme 1.
2. Results and discussion
4e5.4 molar excess of the alkylating agent to suppress the dia-
lkylating process and effect the best yields of 8.
2.1. Synthesis of 4-oxothiazolidines
The obtained alkyl bromides 8 were then converted into pre-
cursors possessing O, S, or N as a nucleophilic atom (Scheme 2 and
Table 3). Hydrolysis using 0.75 M DMF/H2O solution of HCl, based
on the method of Geluk and Schlatmann,17 afforded alcohols 11aee
in moderate to high yields (51e92%). The observed experimental
rates of hydrolysis (Scheme 2), which decrease in the order
(n¼1)>(n¼2)>(n¼3), points to the neighboring-group participa-
tion of carbonyl oxygen of the lactam group. When n¼1, formation
of a favorable five-membered cyclic intermediate 10 can facilitate
the hydrolytic reaction. When n¼2 and 3, the participation of car-
bonyl oxygen is diminished due to the greater loss of entropy ac-
companying the formation of six- and seven-membered rings,
resulting in much longer reaction times (n¼1 (3 h); n¼2 (19e21 h);
n¼3 (24 h)). Substrates 12aef containing sulfur as a nucleophile
were prepared in high yields (93e100%) by the reaction of bro-
mides 8 with KSAc in acetone, at rt.18 They were deprotected with
NaOEt/EtOH19 prior to the formation of iminium ions (see
Experimental section). Two type of precursors with nitrogen-based
Starting 4-oxothiazolidines 7 were prepared by the base-
catalyzed reaction of ethyl cyanoacetate and a-mercapto esters 6,
with a slight modification of our published procedure for the syn-
thesis of 4-oxothiazolidine compounds.14 In contrast to the pub-
lished procedure, these syntheses were run without solvent, which
resulted in significant shortening of the reaction time and increase
in the yields of the products (Table 1). The products were obtained
exclusively as Z isomers.15
2.2. Cyclization reactions
Preparation of precursors for the endo-mode cyclizations began
with the N-alkylation of 4-oxothiazolidines 7 with
a,u-dibro-
mides16 (Table 2). N-Bromoalkyl derivatives 8 were obtained along
with the dimeric products 9. Thus, it was necessary to employ

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M. Stojanovic et al. / Tetrahedron 67 (2011) 9541e9554
9543
the hydroxy derivatives 16 with NaBH4 in EtOH at 0 ꢀC, in the
presence of a catalytic amount of concd HCl. They were used
without isolation for the subsequent dehydration to the iminium
ions 17, which was achieved by the addition of 1 M HCl in EtOH.
Two type of products were formed from the iminium ions 17: bi-
cyclic derivatives 18 and thiazolines 19 (Scheme 3 and Table 4).
Each reaction yielded one of them as a sole product (in two cases,
however, a complex mixture was obtained; entries 2 and 14). The
products 19 arise from the C(5) deprotonation of the cationic in-
termediate 17 and they failed to participate in iminium ion cycli-
zation. In fact, the observed
b-elimination often occurs in the
cyclizations involving N-acyliminium ions, especially if they are
relatively sluggish because of a less reactive nucleophile or steric
hindrance. In many instances, particularly under protic acid con-
ditions, this side reaction is reversible. The reluctance of 19 to
participate in cyclization24 can be accounted for by the
development of a partial aromaticity in the thiazoline ring25
(Scheme 4).
The 5-endo-mode cyclization occurred only with sulfhydryl
group as a nucleophile, albeit in low yield (28e35%, Table 4, entries
6 and 7), but failed with both oxygen and nitrogen nucleophiles
(entries 1, 2, and 14). This is in consistence with Baldwin’s rules4
according to which 5-endo-mode cyclizations for the first-row el-
ements are unfavorable, but can occur with second-row elements,
i.e., sulfur.4b Though, 5-endo-mode cyclizations can be observed in
iminium ion chemistry, as already discussed in the introduction.
The formation of six-membered ring via a favorable 6-endo-mode
cyclization occurred for OH, SH, and NH2 nucleophiles in low to
good yields (36e66%, entries 3, 4, 8, 9, and 15), but failed with
NHBn; instead, stable thiazoline derivatives 19c and 19d were
formed (76e78%, entries 12 and 13). Cyclization to seven-
membered ring, although stereochemically allowed,4 was feasible
only for sulfur nucleophiles affording the bicyclic derivatives 18g
and 18h in moderate to good yields (57e69%, entries 10 and 11). In
the case of O and N nucleophiles the reaction resulted in formation
of thiazolines 19b and 19e in good yields (72e80%, entries 5
and 16).
In short, endo-mode cyclization was applicable to formation of
five- to seven-membered rings for sulfur nucleophiles. For hydroxy
and primary amino group it was restricted to the synthesis of (5,6)-
membered ring systems, i.e., closing of six-membered ring. In-
terestingly, NHBn did not cyclize to a favorable six-membered ring,
but gave thiazolines 19c and 19d.
The stereochemistry of bicyclic compounds 18b, 18d, 18f, and
18h was assigned by NOESY NMR techniques, where distinct NOEs
between H-4 and H-5 of the thiazolidine ring were observed for cis
isomers, and between He4 and C(5)eCH3 for trans isomers. Low to
moderate diastereoselectivity (Table 4, entries 4, 9, and 11) is
a consequence of the reversibility of the reaction and small energy
difference between the cis and trans isomers, i.e., thermodynamic
control. In the case of 18d, however, a kinetic control was observed
(entry 7). The free energies of the two diastereomers were pre-
dicted by DFT calculations at the B3LYP/6-31G(d) level of theory26
with inclusion of EtOH as a solvent27 (only relative energies are
Scheme 2. Reagents and conditions: (i) DMF/H2O (1:1, v/v), HCl,
(1.1e1.25 equiv), acetone, rt, 10e15 min; (iii) BnNH2 (5 equiv), Et3N (1.4 equiv), DMF, rt,
18 h; (iv) NaN3 (2e2.9 equiv), DMF, rt, 1e1.5 h; (v) Ph3P (1.5 equiv), MeOH, reflux, 1 h.
D; (ii) KSAc
Table 3
Yields of products 11e15
R
n
Producta (%)
R
n
Producta (%)
H
Me
H
Me
Me
H
Me
H
1
1
2
2
3
1
1
2
2
3
3
11a (66)
11b (72)
11c (92)
11d (62)
11e (51)
12a (98)
12b (100)
12c (95)
12d (94)
12e (93)
12f (98)
H
Me
H
H
H
H
H
H
2
2
1
2
3
1
2
3
13a (77)
13b (92)
14a (91)
14b (94)
14c (89)
15a (62)
15b (70)
15c (63)
Me
H
Me
a
Yield of isolated products.
nucleophiles were prepared. Compounds 13a,b, having a secondary
amino group as an internal nucleophile, were synthesized in good
to high yields (77e92%) from alkyl bromides 8 and benzylamine.20
Substrates 15aec, possessing a primary amino group were obtained
in two steps. First, bromides 8 were allowed to react with NaN3 in
DMF, at rt.21 Azides 14aec were isolated in high yields (89e94%)
and then subjected to reduction using Ph3P in MeOH at reflux22 to
give 15aec in moderate yields (62e70%).
With all precursors in hand, the next step was to examine imi-
nium ion-initiated reactions. Vinylogous N-acyliminium ions 17
were generated according to the procedure of Speckamp6b,23
(Scheme 3). Thus, the ring carbonyl group was reduced to give
Scheme 3. endo-Mode cyclizations of vinylogous N-acyliminium ions 17.

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M. Stojanovic et al. / Tetrahedron 67 (2011) 9541e9554
9544
Table 4
Yields of products 18 and 19 obtained from vinylogous N-acyliminium ions 17
Entry
Substrate
R
n
X
Product 18a (%)
Ratio trans/cis expb
(calcd)c
Relative free energyd
(kcal/mol) trans/cis
Product 19 (%)a
19a (63)
1
2
3
4
5
6
7
8
11a
11b
11c
11d
11e
12a
12b
12c
12d
12e
12f
13a
13b
15a
15b
15c
H
Me
H
Me
Me
H
Me
H
Me
H
Me
H
Me
H
H
1
1
2
2
3
1
1
2
2
3
3
2
2
1
2
3
O
O
O
O
O
S
S
S
S
S
S
NBn
NBn
NH
NH
NH
Complex mixture
18a (36)
18b (63)
75/25 (79/21)
0/0.79
19b (80)
18c (28)
18d (35)
18e (66)
18f (60)
18g (57)
18h (69)
15/85 (93/7)
56/44 (86/14)
78/22 (86/14)
0/1.49
0/1.1
9
10
11
12
13
14
15
16
0/1.08
19c (76)
19d (78)
Complex mixture
18i (62)
H
19e (72)
a
Yield of isolated products.
Determined by an integration of the corresponding signals in 1H NMR spectra.
Calculated ratio based on free energy difference (obtained at the B3LYP/6-31G(d) level in EtOH) between cis and trans isomers.
Based on the optimized structures at the B3LYP/6-31G(d) level of theory in EtOH.
b
c
d
conformation and five-membered ring envelope conformation. In
all derivatives conformation of the thiazolidine ring is half-chair
with S(1)eC(2)eN(3) in one plane. The position of C(5)eCH3 is
pseudoequatorial in (5,6)- and (5,7)-membered ring systems, but
pseudoaxial in (5,5)-membered system. It is apparent that in both
(5,6)- and (5,7)-membered systems the nitrogen lone pair proves to
be a p-like orbital more or less in-plane with the breaking C(4)eX
bond and thus facilitating the formation of the iminium ion. In
(5,5)-membered molecule, the nitrogen lone pair orbital and the
breaking bond lie in different planes making it much less prone to
equilibration.
Next, we turned our attention to computational methods to
rationalize why some substrates did not cyclize, but gave thiazo-
lines instead. We envisioned the reaction to occur in the following
sequence (Scheme 7): (i) formation of an iminium ion 17 existing in
equilibrium with the covalent adduct 20,28 (ii) approach of a nu-
cleophile to a reactive center (conformations 17b and 20b), and (iii)
formation of products 18 or 19 where EtOH acts as a base
abstracting proton either from the heteroatom, which leads to the
cyclization or from C(5) of the thiazolidine ring leading to the
elimination.
First we sought for activation parameters for the cyclization and
elimination processes. To do this, iminium ion structures 17b were
optimized at the B3LYP/6-31G(d) level.26 Then EtOH was added and
supramolecules 21 and 2231 (Fig. 5) were optimized using the same
method and basis set. Transition state geometries were found by
the ‘reaction coordinate method’.32 In this method, one parameter,
chosen as a reaction coordinate, is constrained for the appropriate
degree of freedom while all other variables are freely optimized. In
the studied reactions, the reaction coordinate was taken to be the
distance between the hydrogen and heteroatom in 21 (HeX) and
hydrogen and C(5) of the thiazolidine ring in 22 (HeC(5)) and the
reaction path was calculated by the successive increase in this
distance. In the case of substrates containing amino groups as nu-
cleophiles the reaction path was calculated by successive decrease
in the distance between nitrogen and iminium carbon, without the
added EtOH molecule.
Scheme 4. Resonance structures of thiazoline derivatives 19.
given in Table 4). The calculated isomer ratio, based on these en-
ergies, is given along with the experimentally observed ratio. In
general, iminium ions are supposed to exist in equilibrium with
a covalent adduct, the structure of which depends on the type of
nucleophiles present in solution (Scheme 5). This type of equilib-
rium has been experimentally proved by Yamamoto et al. in their
studies of the reaction of a
-alkoxy carbamates with Lewis acids.28
In the case of our reactions run in the nucleophilic solvent EtOH,
the covalent species are, most probably, 4-ethoxy derivatives 20,29
enriched in the thermodynamically more stable trans isomer
(Scheme 6). For example, the calculated energy difference between
cis and trans 20 (X¼S, n¼1) amounts 1.85 kcal/mol, which corre-
sponds to a trans/cis ratio 96/4. Nucleophile attacks the iminium
carbon from the side opposite to the ethoxy group, which leads to
formation of a cis/trans mixture of bicyclic products 18 enriched in
thermodynamically less stable cis isomer. Obviously, this attack is
reversible process so that the two isomers equilibrate via iminium
ion 17 as an intermediate (Scheme 6). Judging from the isolated
isomer ratio for 18b, 18f, and 18h (Table 4) the reaction times
(30 min, 90 min, and 45 min for the reduction step for 18b, 18f, and
18h, respectively, and 1 h for the treatment with HCl) were in-
sufficient for complete equilibration. In the case of 18d the major
isomer isolated was the higher energy cis isomer, even after a total
of 2 h (1 h for reduction and 1 h for the treatment with HCl). Ap-
parently, this (5,5)-membered ring system equilibrated with the
slowest rate.30
Activation free energies (DGact), presented in Table 5, were cal-
Scheme 5. Equilibrium between an iminium ion and covalent adduct in solution.
culated from the difference in energies of the transition states and
starting supramolecular geometries. The activation barriers for
the cyclization of intermediates 21def incorporating sulfur nucle-
ophiles (8.87e9.32 kcal/mol) compared to the barrier for the
elimination reaction (13.08 kcal/mol) are in agreement with the
The reason for different rates of equilibration lies in stereo-
electronic factors. Most stable conformations of cis-18b, cis-18d, cis-
18f, and cis-18h are shown in Fig. 4. Six-membered ring adopts
chair
conformation,
seven-membered
ring
twist-chair

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M. Stojanovic et al. / Tetrahedron 67 (2011) 9541e9554
9545
Scheme 6. Formation and equilibration of cis and trans stereoisomers of 18b, 18d, 18f, and 18h.
Fig. 4. Most stable conformations of cis isomers of 18b, 18d, 18f, and 18h.
Scheme 7.
observed experimental data: all precursors cyclized to the expected
bicyclic products (Table 4). The barrier for the formation of five-
membered ring with oxygen nucleophile (intermediate 21a,
Table 5) is much higher than the barrier for the b-elimination, thus
explaining the thiazoline formation from the precursor 11a
(Table 4, entry 1). The activation free energy found for closing of
six- and seven-membered rings from intermediates 21b and 21c,
incorporating OH nucleophile, are quite similar and lower than the
Fig. 5. Initial supramolecular structures used for the calculation of activation
parameters.
energy required for the
b-elimination. However, six-membered

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M. Stojanovic et al. / Tetrahedron 67 (2011) 9541e9554
9546
carbon12 and positively charged hydrogen, and
p
/
sꢁNeH orbital
Table 5
The activation free energy for the cyclization stepa,b
interactions, as shown by the second order perturbation theory
analysis of Fock matrix in NBO basis33 (Table 6). Further, the sol-
vation effect was simulated34 by considering that zigzag confor-
mations are stabilized by three hydrogen bonds with the solvent,
while the reactive conformations 20b have two such interactions,
the third remained the above mentioned ]C/HeNþ interaction.
Consequently, the energy difference between the two conforma-
tions should be the difference in one ]C/HeNþ interaction and
O/HeNþ hydrogen bond (DDHEtOH in Table 6; the energy of one
hydrogen bond was estimated to be ꢂ17.26 kcal/mol, see
Computational details). As expected, the zigzag conformations are
now preferred and the smallest energy difference was found for
15b, the only precursor, which was able to cyclize affording the
bicyclic product 18i.
Starting structure
R
n
X
DGact
21a
21b
21c
21d
21e
21f
21g
21h
21i
21j
22
H
H
Me
H
H
H
H
H
H
H
1
2
3
1
2
3
1
2
2
3
O
O
O
S
S
S
NH
NH
NBn
NH
18.47
10.62
10.79
9.32
8.93
8.87
3.42
0.00c
0.00c
3.99
13.08
a
Obtained at the B3LYP/6-31G(d) level in gas phase.
Values are in kcal/mol.
Optimization of iminium ion structures 17b resulted in cyclic products.
b
c
3. Conclusions
ring was formed, but seven-membered was not (Table 4, entries
3e5). This fact is accounted for by the total higher entropy loss
accompanying the formation of seven-membered ring from the
open-chain intermediates 17a/20a (Scheme 7), having a higher
degree of freedom of internal rotation around single bonds than the
In summary, we have shown that endo-mode cyclizations of
vinylogous N-acyliminium ions, possessing O, S, and N as internal
nucleophiles, can be applied for the synthesis of thiazolidine-fused
heterocycles. While the cyclization to form five- to seven-
membered rings was feasible for SH as a nucleophile, it was re-
stricted to closing of six-membered ring with OH and NH2. The
attempted 5- and 7-endo cyclizations with these nucleophiles
ended in the formation of thiazoline derivatives, which was also the
case using NHBn nucleophile in 6-endo cyclization.
cyclic product, thus making the b-elimination more feasible. For all
intermediates with nitrogen nucleophiles 21gej the estimated
barriers, based on the NH2/NBn approach to the iminium carbon,
are quite low (0e3.99 kcal/mol). Yet, only 15b cyclized to the (5,6)-
membered 18i (Table 4, entries 12e16).
Assuming that amino species are protonated under the acidic
reaction conditions and that the deprotonation, leading to the
formation of the expected cyclization products, occurs near the
reaction center just before the generation of the iminium ion, we
next examined the energy difference between the protonated zig-
zag conformation 20a and reactive conformation 20b (Scheme 7) of
amino precursors 13a and 15aec. In the gas phase, the reactive
conformations 20b of all compounds were found to be energetically
much more favored than the corresponding zigzag conformations
20a (DDHgas phase in Table 6). This is due to the existence of an at-
tractive, non-bonded ]C/HeNþ interaction between the exo-
cyclic carbon of the CC double bond and protonated amino group,
The observed trend was rationalized by quantum chemical
calculations of activation energy for cyclization versus b-elimina-
tion of the intermediate iminium ions. The activation free energy,
predicted at the B3LYP/6-31G(d) level, needed for the formation of
the oxazolidine-fused ring (18.47 kcal/mol) was found to be higher
than the energy required for thiazoline formation (13.08 kcal/mol).
While all other barriers are lower than the b-elimination barrier
(more so for sulfur, 8.87e9.32 kcal/mol, than for oxygen nucleo-
philes, 10.62e10.79 kcal/mol), the fact that oxazepine-fused het-
erocycle was not formed is accounted for by the total higher
entropy loss accompanying the closing of seven-membered ring. In
the case of precursors containing N-nucleophiles the calculated
activation barriers were very low (0e3.99 kcal/mol), yet only 6-
endo cyclization with NH2 took place. This fact was rationalized by
computing the energy difference between the zigzag 20a and re-
active conformation 20b of protonated amino-containing 4-ethoxy
intermediates. The reactive conformation 20b, in which N-nucleo-
philic group is placed close to the reactive center, is stabilized by
non-bonded ]C/HeNþ interaction between the exocyclic carbon
of the CC double bond and protonated amino group. The strongest
stabilization was found for the intermediate derived from 15b,
which was the only precursor able to cyclize.
The stereochemical outcome of cyclization reactions was found
to originate from thermodynamic control and small energy differ-
ence between the cis and trans isomers of 18b, 18f, and 18h. In the
case of 18d, however, a kinetic control was observed. The rate of
equilibration of two isomers was dictated by stereoelectronic fac-
tors. The most favorable alignment of nitrogen p-like lone pair and
breaking CeX bond was achieved in (5,6)- and (5,7)-membered
ꢁ
evident from the C/H distances (dC/H (A) in Table 6, Fig. 6), which
are considerably shorter than the sum of Van der Waals radii
ꢁ
(2.9 A). The nature of the interaction is dual. It involves an elec-
trostatic attraction between the negatively charged exocyclic
Table 6
Enthalpy difference between reactive conformation 20b and the zigzag conforma-
tion 20a of precursors 13a and 15aec in the gas phase and by simulating solvation
effects, C/H distance and hyperconjugation energy
a
a
a,b
p
/ Þ
sꢁNeH
ꢁ
Substrate
DDHgas phase
DDHEtOH
dC/H (A)
E ð
13a
15a
15b
15c
ꢂ10.61
ꢂ8.00
6.65
9.26
2.81
8.19
2.01
2.40
1.82
2.50
14.39
11.31
25.58
2.18
ꢂ14.45
ꢂ9.07
a
Values are in kcal/mol.
b
Obtained by NBO analysis.
Fig. 6. Reactive conformations 20b of amino-containing intermediates 13a and 15aec.

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M. Stojanovic et al. / Tetrahedron 67 (2011) 9541e9554
9547
systems, which equilibrated more rapidly than (5,5)-membered
system.
5.2.1. (Z)-Ethyl 2-(4-oxothiazolidin-2-ylidene)acetate (7a). Compound
7a was obtained from ethyl cyanoacetate (5.31 g, 47.0 mmol), ethyl
mercaptoacetate (6.25 g, 52.0 mmol) and K2CO3 (450 mg; 3.26 mmol)
according to general procedure (reaction time 30 min), as a white
solid (7.70 g; 87%), mp 152e153 ꢀC (lit.36 154e155 ꢀC); Rf¼0.52
4. Computational details
(toluene/ethyl acetate 7:3); 1H NMR37 (200 MHz, DMSO-d6):
d 1.18 (t,
Ab initio MO calculations and the Natural Bond Orbital (NBO)
Population Analysis33 were done using Gaussian 03 program
package.35 Geometries of intermediates and products were fully
optimized at the B3LYP/6-31G(d) level26 and the minimum energy
structures confirmed by all positive vibrational force constants. The
J¼7.2 Hz, 3H, CH3), 3.78 (s, 2H, CH2S), 4.06 (q, J¼7.2 Hz, 2H, CH2O),
5.44 (s, 1H, ]CH), 11.58 (br s, 1H, NH); 13C NMR (50 MHz, DMSO-d6):
d
14.6 (CH3), 32.6 (CH2S), 59.2 (CH2O), 88.6 (]CH), 159.2 (C]), 167.3
(COester), 174.5 (COlactam); IR (KBr):
n
¼3246, 1722, 1660, 1151 cmꢂ1
.
solvent effects (EtOH
3
¼24.55) were included in the calculations by
the SCRF theory using IEFPCM model.27 Transition state structures
were found by the ‘reaction coordinate method’.32 In this method,
one parameter, chosen as a reaction coordinate, is constrained for
the appropriate degree of freedom while all other variables are
freely optimized. Initial supramolecular structures, consisting of an
iminium ion and suitably placed EtOH, were fully optimized at the
same level of theory. The reaction coordinate was taken to be the
distance between the hydrogen and heteroatom in 21 (HeX) and
hydrogen and C(5) of the thiazolidine ring in 22 (HeC(5)) and the
reaction path was calculated by the successive increase in this
5.2.2. (Z)-Ethyl
2-(5-methyl-4-oxothiazolidin-2-ylidene)acetate
(7b). Compound 7b was obtained from ethyl cyanoacetate (1.59 g,
14.1 mmol), ethyl 2-mercaptopropionate (1.99 g, 14.8 mmol), and
K2CO3 (94.5 mg; 0.68 mmol) according to general procedure (re-
action time 15 min), as a white solid (2.17 g; 76%), mp 120e121 ꢀC
(lit.36 123 ꢀC); Rf¼0.48; 0.73 (toluene/ethyl acetate 7:3; two spots
due to Z/E isomerization);15 1H NMR (200 MHz, CDCl3):
d 1.28 (t,
J¼7.0 Hz, 3H, CH3CH2), 1.63 (d, J¼7.0 Hz, 3H, CH3CH), 3.97 (q,
J¼7.0 Hz, 1H, CHS), 4.20 (q, J¼7.0 Hz, 2H, CH2O), 5.64 (s, 1H, ]CH),
9.62 (br s, 1H, NH); 13C NMR (50 MHz, CDCl3):
d 14.3 (CH3CH2), 18.8
(CH3CH), 41.8 (CHS), 60.1 (CH2O), 91.3 (]CH), 154.6 (C]), 167.9
(COester), 178.2 (COlactam); IR (KBr):
ꢁ
distance (for 0.01, 0.02 or 0.05 A, depending on the reaction). In the
n
¼3156, 1726, 1657, 1164 cmꢂ1
.
case of substrates containing amino groups as internal nucleophiles
the conformations 17b were optimized and the reaction path cal-
culated by the successive decrease in the distance between the
5.3. General procedure for synthesis of N-bromoalkyl
derivatives 8
ꢁ
nitrogen and iminium carbon (for 0.1 A). The transition state
structures were verified by having only one negative frequency. The
activation parameters were calculated from the difference in en-
ergies of the transition state structures and the initial supra-
molecules. Energy of one O/HeN hydrogen bond (formed
between EtOH and an ammonium group, ꢂ17.26 kcal/mol) was
estimated by first optimizing the zigzag conformation 17a (Scheme
7) with three hydrogen-bonded EtOH molecules. Then, from the
obtained energy, the energy of free 17a and energy of three EtOH
molecules were subtracted and divided by three.
An alkylating agent was added to a stirred mixture of 4-
oxothiazolidine 7 and K2CO3 in DMF, and stirring was continued
at rt until the disappearance of the starting material (TLC). The
reaction mixture was then diluted with CH2Cl2 (10e15 mL), washed
with water (3ꢃ10 mL), saturated aq NaCl (1ꢃ10 mL), and dried over
Na2SO4. After evaporation of the solvent, the crude product was
purified by column chromatography.
5.3.1. (Z)-Ethyl 2-(3-(2-bromoethyl)-4-oxothiazolidin-2-ylidene)ace-
tate (8a). Compound 8a was obtained from 7a (222 mg;
1.18 mmol), K2CO3 (170 mg; 1.23 mmol; 1.04 equiv), 1,2-
dibromoethane (1.00 g; 5.33 mmol; 4.5 equiv) in DMF (2.5 mL)
according to general procedure (reaction time 5 h, TLC: petro-
lether/ethyl acetate 4:1). Column chromatography (eluent: gradi-
ent petrolether/ethyl acetate 100:0 to 60:40) gave pure 8a, as
a white solid (250 mg; 72%), mp 106e107 ꢀC; Rf¼0.47 (petrolether/
5. Experimental
5.1. General
Melting points were determined on a Stuart SMP10 apparatus
and are uncorrected. The IR spectra were recorded on a Per-
kineElmer FT-IR 1725X spectrophotometer and are reported as
wave numbers (cmꢂ1). The NMR spectra were recorded on a Varian
Gemini 2000 spectrometer (1H at 200 MHz, 13C at 50.3 MHz) and on
a Bruker Ultrashield Advance III (1H at 500.26 MHz, 13C at
125.79 MHz) in DMSO-d6 or CDCl3. Chemical shifts are reported in
ethyl acetate 4:1); 1H NMR (200 MHz, CDCl3):
d
1.31 (t, J¼7.4 Hz,
3H, CH3), 3.47 (t, J¼7.6 Hz, 2H, CH2Br), 3.74 (s, 2H, CH2S) 4.07 (t,
J¼7.6 Hz, 2H, NCH2), 4.22 (q, J¼7.4 Hz, 2H, CH2O), 5.53 (s, 1H, ]
CH); 13C NMR (50 MHz, CDCl3):
d 14.3 (CH3), 25.0 (CH2Br), 31.5
(CH2S), 44.3 (NCH2), 60.2 (CH2O), 90.7 (]CH), 157.2 (C]), 167.4
parts per million (ppm) on the
d scale from TMS as an internal
(COester), 172.2 (COlactam); IR (KBr):
n
¼1719, 1680, 1562, 1182,
1137 cmꢂ1; HRMS: calcd for C9H13BrNO3S [MþH]þ 293.9794,
standard. Elemental analyses were performed at the microanalysis
laboratory at the Centre for Chemistry ICTM. HRMS was carried out
on 6210 TOF LC/MS coupled with HPLC 1200 Series Agilent Tech-
nologies. Thin-layer chromatography (TLC) was carried out on
Kieselgel G nach Stahl and spots were visualized by iodine or by
50% H2SO4. Column chromatography was carried out on SiO2 (silica
found 293.9798.
5.3.2. (Z)-Ethyl 2-(3-(2-bromoethyl)-5-methyl-4-oxothiazolidin-2-
ylidene)acetate (8b). Compound 8b was obtained from 7b
(242 mg; 1.20 mmol), K2CO3 (176 mg; 1.27 mmol; 1.06 equiv), 1,2-
dibromoethane (894 mg; 4.76 mmol; 4.0 equiv) in DMF (3.0 mL)
according to general procedure (reaction time 5 h, TLC: petrolether/
ethyl acetate 4:1). Column chromatography (eluent: gradient pet-
rolether/ethyl acetate 100:0 to 70:30) gave pure 8b, as a white solid
(306 mg; 82%), mp 105e106 ꢀC; Rf¼0.78 (petrolether/ethyl acetate
ꢁ
gel 60 A, 12e26, ICN Biomedicals). All solvents were distilled before
use. DMF was distilled over CaH2.
5.2. General procedure for synthesis of 4-oxothiazolidines 7
A mixture of ethyl cyanoacetate (1 equiv),
a-mercapto ester
3:2); 1H NMR (200 MHz, CDCl3):
d
1.31 (t, J¼7.2 Hz, 3H, CH3CH2),
(1.05 equiv), and K2CO3 (0.05 equiv) was heated with stirring at the
temperature of an oil bath of 75e80 ꢀC for 15e30 min (see below)
and then cooled to rt. After adding of water/EtOH 7/3 (v/v) to the
solidified reaction mixture stirring was continued for 1 h at rt.
Filtration gave pure products 7.
1.63 (d, J¼7.0 Hz, 3H, CH3CH), 3.47 (t, J¼7.4 Hz, 2H, CH2Br), 3.92 (q,
J¼7.0 Hz, 1H, CHS), 4.06 (t, J¼7.4 Hz, 2H, NCH2), 4.22 (q, J¼7.2 Hz,
2H, CH2O), 5.51 (s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
d 14.3
(CH3CH2), 19.1 (CH3CH), 25.2 (CH2Br), 40.3 (CHS), 44.2 (NCH2), 60.2
(CH2O), 90.2 (]CH), 155.9 (C]), 167.4 (COester), 175.4 (COlactam); IR

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M. Stojanovic et al. / Tetrahedron 67 (2011) 9541e9554
9548
(KBr):
n
¼1719, 1683, 1586, 1304, 1179, 1143 cmꢂ1; Anal. Calcd for
1146 cmꢂ1; HRMS: calcd for C11H17BrNO3S [MþH]þ 322.0107,
C10H14BrNO3S (308.19): C, 38.97; H, 4.58; N, 4.54; S, 10.40, found: C,
39.27; H, 4.41; N, 4.62; S, 10.61.
found 322.0096.
5.3.7. (2Z,20Z)-Diethyl 2,20-(3,30-(propane-1,3-diyl)bis(5-methyl-4-
oxothiazolidin-3-yl-2-ylidene))diacetate (9c). Compound 9c was
obtained as a by-product in the N-alkylation of 7b with 1,3-
dibromopropane, as a white solid (47.0 mg; 21%), mp 141e142 ꢀC;
Rf¼0.16 (petrolether/ethyl acetate 4:1); 1H NMR (200 MHz, CDCl3):
5.3.3. (2Z,20Z)-Diethyl 2,20-(3,30-(ethane-1,2-diyl)bis(5-methyl-4-
oxothiazolidin-3-yl-2-ylidene))diacetate (9a). Compound 9a was
obtained as a by-product in the N-alkylation of 7b with 1,2-
dibromoethane, as a white solid (15.4 mg; 6%), mp 186e188 ꢀC;
Rf¼0.52 (petrolether/ethyl acetate 3:2); 1H NMR (200 MHz, CDCl3):
d
1.30 (t, J¼7.2 Hz, 6H, 2ꢃ CH3CH2), 1.62 (d, J¼7.0 Hz, 6H, 2 x CH3CH),
d
1.29 (t, J¼7.2 Hz, 6H, 2ꢃ CH3CH2),1.58 (d, J¼7.0 Hz, 6H, 2ꢃ CH3CH),
1.89e2.02 (m, 4H, 2ꢃ CH2CH2CH2), 3.72 (t, J¼7.2 Hz, 4H, 2ꢃ NCH2),
3.92 (q, J¼7.0 Hz, 2H, 2ꢃ CHS), 4.20 (q, J¼7.2 Hz, 4H, 2ꢃ CH2O), 5.42
3.89e4.10 (m, 4H, 2ꢃ NCH2), 3.84 (q, J¼7.0 Hz, 1H, CHS), 3.85 (q,
J¼7.0 Hz, 1H, CHS), 4.21 (q, J¼7.2 Hz, 4H, 2ꢃ CH2O), 5.49 (s, 1H, ]
(s, 2H, 2ꢃ ]CH); 13C NMR (50 MHz, CDCl3):
d 14.3 (CH3CH2), 19.0
(CH3CH), 24.0 (CH2CH2CH2), 40.3 (CHS), 40.7 (NCH2), 60.0 (CH2O),
90.0 (]CH), 156.1 (C]), 167.4 (COester), 175.6 (COlactam); IR (KBr):
CH), 5.50 (s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
d
14.4 (CH3CH2),
18.5 (CH3CH), 40.1 (CHS), 40.1 (NCH2), 60.1 (CH2O), 89.6 (]CH),
156.5 (C]), 167.3 (COester), 176.1 (COlactam); IR (KBr):
n
¼1715, 1686,
n
¼1694, 1575, 1312, 1173 cmꢂ1; HRMS: calcd for C19H27N2O6S2
1570, 1292, 1150 cmꢂ1; HRMS: calcd for C18H25N2O6S2 [MþH]þ
[MþH]þ 443.1305, found 443.1294.
429.1148, found 429.1140.
5.3.8. (Z)-Ethyl 2-(3-(4-bromobutyl)-4-oxothiazolidin-2-ylidene)ac-
etate (8e). Compound 8e was obtained from 7a (203 mg;
1.09 mmol), K2CO3 (160 mg; 1.23 mmol; 1.13 equiv), 1,4-
dibromobutane (1.18 g; 5.44 mmol; 5.4 equiv) in DMF (2.5 mL)
according to general procedure (reaction time 4 h, TLC: petro-
lether/ethyl acetate 3:2). Column chromatography (eluent: gra-
dient petrolether/ethyl acetate 100:0 to 60:40) gave pure 8e, as
a white solid (289 mg; 83%), mp 76e77 ꢀC; Rf¼0.71 (petrolether/
5.3.4. (Z)-Ethyl 2-(3-(3-bromopropyl)-4-oxothiazolidin-2-ylidene)
acetate (8c). Compound 8c was obtained from 7a (218 mg;
1.16 mmol), K2CO3 (169 mg; 1.22 mmol; 1.05 equiv), 1,3-
dibromopropane (1.19 g; 5.88 mmol; 5.1 equiv) in DMF (3.0 mL)
according to general procedure (reaction time 2 h, TLC: toluene/
ethyl acetate 7:3). Column chromatography (eluent: gradient tol-
uene/ethyl acetate 100:0 to 70:30) gave pure 8c, as a white solid
(250 mg; 70%), mp 74e75 ꢀC; Rf¼0.36 (petrolether/ethyl acetate
ethyl acetate 3:2); 1H NMR (200 MHz, CDCl3):
d
1.31 (t, J¼7.2 Hz,
4:1); 1H NMR (200 MHz, CDCl3):
d
1.31 (t, J¼7.4 Hz, 3H, CH3),
3H, CH3), 1.71e1.96 (m, 4H, CH2CH2CH2CH2), 3.44 (t, J¼6.2 Hz, 2H,
CH2Br), 3.71 (t, J¼7.0 Hz, 2H, NCH2), 3.72 (s, 2H, CH2S), 4.22 (q,
J¼7.2 Hz, 2H, CH2O), 5.51 (s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
2.12e2.25 (m, 2H, CH2CH2CH2), 3.43 (t, J¼6.6 Hz, 2H, CH2Br), 3.72 (s,
2H, CH2S), 3.83 (t, J¼7.4 Hz, 2H, NCH2), 4.22 (q, J¼7.4 Hz, 2H, CH2O),
5.58 (s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
d
14.4 (CH3), 29.3
d 14.3 (CH3), 25.0 (CH2CH2Br), 29.5 (NCH2CH2), 31.7 (CH2S), 32.5
(CH2CH2CH2), 29.6 (CH2Br), 31.6 (CH2S), 42.2 (NCH2), 60.1 (CH2O),
90.6 (]CH), 157.60 (C]), 167.6 (COester), 172.5 (COlactam); IR (KBr):
(CH2Br), 42.5 (NCH2), 60.1 (CH2O), 90.6 (]CH), 157.8 (C]), 167.6
(COester), 172.4 (COlactam); IR (KBr):
n
¼1710, 1672, 1560, 1177, 1136,
n
¼1723,1679,1567,1180,1144 cmꢂ1; HRMS: calcd for C10H15BrNO3S
1040 cmꢂ1; HRMS: calcd for C11H17BrNO3S [MþH]þ 322.0107,
[MþH]þ 307.9950, found 307.9949.
found 322.0097.
5.3.5. (2Z,20Z)-Diethyl 2,20-(3,30-(propane-1,3-diyl)bis(4-
oxothiazolidin-3-yl-2-ylidene))diacetate (9b). Compound 9b was
obtained as a by-product in the N-alkylation of 7a with 1,3-
5.3.9. (2Z,20Z)-Diethyl 2,20-(3,30-(butane-1,4-diyl)bis(4-
oxothiazolidin-3-yl-2-ylidene))diacetate (9d). Compound 9d was
obtained as a by-product in the N-alkylation of 7a with 1,4-
dibromobutane, as a white solid (15.7 mg; 4%), mp 186e187 ꢀC;
Rf¼0.42 (petrolether/ethyl acetate 3:2); 1H NMR (200 MHz, CDCl3):
dibromopropane, as
a
white solid (44.4 mg; 18%), mp
159e160 ꢀC; Rf¼0.22 (petrolether/ethyl acetate 4:1); 1H NMR
(200 MHz, CDCl3):
d
1.30 (t, J¼7.0 Hz, 6H, 2ꢃ CH3),1.90e2.05 (m, 2H,
d
1.31 (t, J¼7.0 Hz, 6H, 2ꢃ CH3), 1.65 (m, 4H, CH2CH2CH2CH2), 3.70
CH2CH2CH2), 3.73 (t, J¼7.2 Hz, 4H, 2ꢃ NCH2), 3.73 (s, 4H, 2ꢃ CH2S),
(m, 4H, 2ꢃ CH2S), 3.72 (s, 4H, 2ꢃ NCH2), 4.22 (q, J¼7.0 Hz, 4H, 2ꢃ
4.21 (q, J¼7.0 Hz, 4H, 2ꢃ CH2O), 5.44 (s, 2H, 2ꢃ ]CH); 13C NMR
CH2O), 5.48 (s, 2H, 2ꢃ ]CH); 13C NMR (50 MHz, CDCl3):
d 14.4
(50 MHz, CDCl3):
d
14.3 (CH3), 23.7 (CH2CH2CH2), 31.6 (CH2S), 40.6
(CH3), 23.6 (CH2CH2CH2CH2), 31.7 (CH2S), 42.7 (NCH2), 60.1 (CH2O),
90.6 (]CH), 157.8 (C]), 167.6 (COester), 172.6 (COlactam); IR (KBr):
(NCH2), 60.1 (CH2O), 90.4 (]CH), 157.5 (C]), 167.4 (COester), 172.4
(COlactam); IR (KBr):
n
¼1717, 1684, 1571, 1171 cmꢂ1; HRMS: calcd for
n
¼1713, 1683, 1562, 1141, 1041 cmꢂ1; HRMS: calcd for C18H25N2O6S2
C17H23N2O6S2 [MþH]þ 415.0992, found 415.0983.
[MþH]þ 429.1148, found 429.1141.
5.3.6. (Z)-Ethyl 2-(3-(3-bromopropyl)-5-methyl-4-oxothiazolidin-2-
ylidene)acetate (8d). Compound 8d was obtained from 7b
(208 mg; 1.03 mmol), K2CO3 (150 mg; 1.08 mmol; 1 equiv), 1,3-
dibromopropane (1.03 g; 5.1 mmol; 4.9 equiv) in DMF (3.0 mL)
according to general procedure (reaction time 2.5 h, TLC: petro-
lether/ethyl acetate 4:1). Column chromatography (eluent: gra-
dient petrolether/ethyl acetate 100:0 to 60:40) gave pure 8d, as
a white solid (234 mg; 70%), mp 101e102 ꢀC; Rf¼0.61 (petro-
5.3.10. (Z)-Ethyl 2-(3-(4-bromobutyl)-5-methyl-4-oxothiazolidin-2-
ylidene)acetate (8f). Compound 8f was obtained from 7b
(205 mg; 1.02 mmol), K2CO3 (149 mg; 1.08 mmol; 1.06 equiv), 1,4-
dibromobutane (1.08 g; 5.44 mmol; 5 equiv) in DMF (2.0 mL)
according to general procedure (reaction time 1.5 h, TLC: petro-
lether/ethyl acetate 4:1). Column chromatography (eluent: gradi-
ent petrolether/ethyl acetate 100:0 to 60:40) gave pure 8f, as
a white solid (273 mg; 80%), mp 77e78 ꢀC; Rf¼0.51 (petrolether/
lether/ethyl acetate 4:1); 1H NMR (200 MHz, CDCl3):
d
1.31 (t,
ethyl acetate 4:1); 1H NMR (200 MHz, CDCl3):
d
1.31 (t, J¼7.2 Hz, 3H,
J¼7.2 Hz, 3H, CH3CH2), 1.61 (d, J¼7.2 Hz, 3H, CH3CH), 2.12e2.25
(m, 2H, CH2CH2CH2), 3.42 (t, J¼6.4 Hz, 2H, CH2Br), 3.83 (t,
J¼7.4 Hz, 2H, NCH2), 3.90 (q, J¼7.2 Hz, 1H, CHS), 4.22 (q, J¼7.2 Hz,
CH3CH2), 1.61 (d, J¼7.2 Hz, 3H, CH3CH), 1.71e1.96 (m, 4H,
CH2CH2CH2CH2), 3.44 (t, J¼6.2 Hz, 2H, CH2Br), 3.71 (t, J¼6.8 Hz, 2H,
NCH2), 3.94 (q, J¼7.2 Hz, 1H, CHS), 4.21 (q, J¼7.2 Hz, 2H, CH2O), 5.49
2H, CH2O), 5.56 (s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
d
14.4
(s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
d 14.4 (CH3CH2), 19.2
(CH3CH2), 19.0 (CH3CH), 29.4 (CH2CH2CH2), 29.6 (CH2Br), 40.3
(CHS), 42.2 (NCH2), 60.1 (CH2O), 90.1 (]CH), 156.3 (C]), 167.6
(CH3CH), 25.1 (CH2CH2Br), 29.5 (NCH2CH2), 32.5 (CH2Br), 40.4
(CHS), 42.5 (NCH2), 60.1 (CH2O), 90.2 (]CH), 156.5 (C]), 167.6
(COester), 175.7 (COlactam); IR (KBr):
n
¼1715, 1689, 1574, 1309, 1173,
(COester), 175.8 (COlactam); IR (KBr):
n
¼1712, 1684, 1568, 1312, 1179,

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M. Stojanovic et al. / Tetrahedron 67 (2011) 9541e9554
9549
1141 cmꢂ1; HRMS: calcd for C12H19BrNO3S [MþH]þ 336.0264,
(33.4 mg; 92%), mp 94e95 ꢀC; Rf¼0.28 (toluene/ethyl acetate 7:3);
found 336.0252.
1H NMR (200 MHz, CDCl3):
d
1.30 (t, J¼7.4 Hz, 3H, CH3), 1.79e1.91
(m, 2H, CH2CH2CH2), 3.61 (t, J¼6.0 Hz, 2H, CH2OH), 3.75 (s, 2H,
CH2S), 3.84 (t, J¼6.4 Hz, 2H, NCH2), 4.21 (q, J¼7.4 Hz, 2H, CH2O),
5.3.11. (2Z,20Z)-Diethyl 2,20-(3,30-(butane-1,4-diyl)bis(5-methyl-4-
oxothiazolidin-3-yl-2-ylidene))diacetate (9e). Compound 9e was
obtained as a by-product in the N-alkylation of 7b with 1,4-
dibromobutane, as a white solid (16.9 mg; 7%), mp 155e156 ꢀC;
Rf¼0.18 (petrolether/ethyl acetate 4:1); 1H NMR (200 MHz, CDCl3):
5.59 (s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
d 14.3 (CH3), 29.0
(CH2CH2CH2), 31.7 (CH2S), 40.2 (NCH2), 58.7 (CH2OH), 60.1 (CH2O),
90.9 (]CH), 157.7 (C]), 167.7 (COester), 173.4 (COlactam); IR (KBr):
n
¼3446, 1684, 1564, 1369, 1155, 1043 cmꢂ1; HRMS: calcd for
d
1.31 (t, J¼7.1 Hz, 6H, 2ꢃ CH3CH2), 1.61 (d, J¼7.4 Hz, 6H, 2ꢃ CH3CH),
C10H16BrNO4S [MþH]þ 246.0795, found 246.0802.
1.64 (m, 4H, CH2CH2CH2CH2), 3.67e3.75 (m, 4H, 2ꢃ NCH2), 3.90 (q,
J¼7.4 Hz, 2H, 2ꢃ CHS), 4.22 (q, J¼7.1 Hz, 4H, 2ꢃ CH2O), 5.47 (s, 2H,
5.4.4. (Z)-Ethyl 2-(3-(3-hydroxypropyl)-5-methyl-4-oxothiazolidin-
2-ylidene)acetate (11d). Compound 11d was prepared from 8d
(100 mg; 0.31 mmol) in 3 mL DMF/H2O 1:1 (v/v) to which 200 mL
2ꢃ ]CH); 13C NMR (50 MHz, CDCl3):
d
14.4 (CH3CH2), 19.1 (CH3CH),
23.6 (CH2CH2CH2CH2), 40.4 (CHS), 42.7 (NCH2), 60.1 (CH2O), 90.1
(]CH),156.4 (C]),167.6 (COester),175.8 (COlactam); IR (KBr):
n
¼1711,
concd HCl was added, according to general procedure (reaction
time 19 h, TLC: petrolether/ethyl acetate 3:2). Column chroma-
tography (eluent: gradient petrolether/ethyl acetate 80:20 to
50:50) gave pure 11d, as a white solid (50.2 mg; 62%), mp
104e105 ꢀC; Rf¼0.26 (petrolether/ethyl acetate 3:2); 1H NMR
1687, 1567, 1311, 1180, 1145 cmꢂ1; HRMS: calcd for C20H29N2O6S2
[MþH]þ 457.1462, found 457.1456.
5.4. General procedure for synthesis of alcohols 11
(200 MHz, CDCl3):
d
1.30 (t, J¼7.2 Hz, 3H, CH3CH2), 1.62 (d, J¼7.2 Hz,
A solution of bromide 8 in 0.75 M HCl in DMF/H2O (1:1 v/v) was
heated at the temperature of an oil bath of 100 ꢀC until the disap-
pearance of the starting material (TLC). The reaction mixture was
then diluted with CHCl3 (10 mL), washed with water (3ꢃ10 mL), 5%
aq NaHCO3 (1ꢃ10 mL), saturated aq NaCl (1ꢃ10 mL) and dried over
Na2SO4. After evaporation of the solvent, the crude product was
purified by stirring with n-hexane for 2 h at rt, or by column
chromatography.
3H, CH3CH), 1.79e1.91 (m, 2H, CH2CH2CH2), 2.58 (br s, 1H, OH), 3.59
(t, J¼5.0 Hz, 2H, CH2OH), 3.84 (dd, J1¼11.2 Hz, J2¼6.8 Hz, 2H, NCH2),
3.94 (q, J¼7.2 Hz, 1H, CHS), 4.21 (q, J¼7.2 Hz, 2H, CH2O), 5.57 (s, 1H,
]CH); 13C NMR (50 MHz, CDCl3):
d 14.3 (CH3CH2), 19.2 (CH3CH),
29.0 (CH2CH2CH2), 40.1 (CHS), 40.5 (NCH2), 58.6 (CH2OH), 60.1
(CH2O), 90.6 (]CH), 156.3 (C]), 167.6 (COester), 176.9 (COlactam); IR
(KBr):
n
¼3511, 1716, 1671, 1565, 1311, 1192, 1162 cmꢂ1; HRMS: calcd
for C11H18NO4S [MþH]þ 260.0951, found 260.0943.
5.4.1. (Z)-Ethyl
acetate (11a). Compound 11a was prepared from 8a (39.8 mg;
0.13 mmol) in 3 mL DMF/H2O 1:1 (v/v) to which 200 L concd HCl
2-(3-(2-hydroxyethyl)-4-oxothiazolidin-2-ylidene)
5.4.5. (Z)-Ethyl 2-(3-(4-hydroxybutyl)-5-methyl-4-oxothiazolidin-2-
ylidene)acetate (11e). Compound 11e was prepared from 8f
(93.1 mg; 0.28 mmol) in 3 mL DMF/H2O 1:1 (v/v) to which 200 mL
m
was added, according to general procedure (reaction time 3 h, TLC:
toluene/ethyl acetate 7:3). Column chromatography (eluent: gra-
dient petrolether/ethyl acetate 100:0 to 50:50) gave pure 11a, as
a white solid (20.5 mg; 66%), mp 107e108 ꢀC; Rf¼0.23 (toluene/
concd HCl was added, according to general procedure (reaction
time 24 h, TLC: petrolether/ethyl acetate 3:2). Column chroma-
tography (eluent: gradient petrolether/ethyl acetate 100:0 to
40:60) gave pure 11e, as a colorless oil (38.7 mg; 51%); Rf¼0.21
ethyl acetate 7:3); 1H NMR (200 MHz, CDCl3):
d
1.29 (t, J¼7.2 Hz, 3H,
(petrolether/ethyl acetate 3:2); 1H NMR (200 MHz, CDCl3):
d 1.30 (t,
CH3), 2.40 (br s, 1H, OH), 3.75 (s, 2H, CH2S), 3.82e3.90 (m, 4H,
J¼7.2 Hz, 3H, CH3CH2), 1.60 (d, J¼7.2 Hz, 3H, CH3CH), 1.51e1.77 (m,
4H, CH2CH2CH2CH2), 1.80 (s, 1H, OH), 3.69 (t, J¼6.0 Hz, 2H, CH2OH),
3.72 (t, J¼6.4 Hz, 2H, NCH2), 3.89 (q, J¼7.2 Hz, 1H, CH3CH), 4.21 (q,
J¼7.2 Hz, 2H, CH2O), 5.51 (s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
CH2CH2), 4.20 (q, J¼7.2 Hz, 2H, CH2O), 5.60 (s, 1H, ]CH); 13C NMR
(50 MHz, CDCl3):
d 14.3 (CH3), 31.7 (CH2S), 45.7 (NCH2), 59.0
(CH2OH), 60.1 (CH2O), 90.8 (]CH), 158.2 (C]), 167.8 (COester), 173.4
(COlactam); IR (KBr):
n
¼3497, 1703, 1678, 1569, 1368, 1167 cmꢂ1
;
d 14.4 (CH3CH2), 19.1 (CH3CH), 23.1 (CH2CH2Br), 29.4 (NCH2CH2),
HRMS: calcd for C9H14NO4S [MþH]þ 232.0638, found 232.0644.
40.4 (CHS), 43.3 (NCH2), 60.0 (CH2O), 62.0 (CH2OH), 90.1 (]CH),
156.1 (C]), 167.7 (COester), 175.8 (COlactam); IR (KBr):
n
¼3399, 1716,
5.4.2. (Z)-Ethyl 2-(3-(2-hydroxyethyl)-5-methyl-4-oxothiazolidin-2-
ylidene)acetate (11b). Compound 11b was prepared from 8b
1689, 1570, 1310, 1150 cmꢂ1; HRMS: calcd for C12H20NO4S [MþH]þ
274.1108, found 274.1095.
(100 mg; 0.33 mmol) in 3 mL DMF/H2O 1:1 (v/v) to which 200 mL
concd HCl was added, according to general procedure (reaction
time 3 h, TLC: petrolether/ethyl acetate 3:2). Column chromatog-
raphy (eluent: gradient petrolether/ethyl acetate 100:0 to 60:40)
gave pure 11b, as a white solid (59.7 mg; 72%), mp 93e94 ꢀC;
Rf¼0.27 (petrolether/ethyl acetate 3:2); 1H NMR (200 MHz, CDCl3):
5.5. General procedure for synthesis of S-acyl derivatives 12
A solution of bromide 8 and KSAc in dry acetone was stirred at rt
until the disappearance of the starting material (TLC). The reaction
mixture was then diluted with CH2Cl2 (10e15 mL), washed with
water (3ꢃ10 mL), saturated aq NaCl (1ꢃ10 mL), and dried over
Na2SO4. Evaporation of the solvent gave pure products.
d
1.29 (t, J¼7.2 Hz, 3H, CH3CH2), 1.62 (d, J¼7.2 Hz, 3H, CH3CH), 1.93
(br s, 1H, OH), 3.80e3.92 (m, 4H, CH2CH2), 3.94 (q, J¼7.2 Hz, 1H,
CHS), 4.21 (q, J¼7.2 Hz, 2H, CH2O), 5.58 (s, 1H, ]CH); 13C NMR
(50 MHz, CDCl3):
d
14.4 (CH3CH2), 19.1 (CH3CH), 40.4 (CHS), 45.7
5.5.1. (Z)-Ethyl 2-(3-(2-(acetylthio)ethyl)-4-oxothiazolidin-2-
ylidene)acetate (12a). Compound 12a was obtained from 8a
(66.6 mg; 0.23 mmol) and KSAc (29.4 mg; 0.33 mmol; 1.1 equiv) in
acetone (2.0 mL) according to general procedure (reaction time
15 min, TLC: petrolether/ethyl acetate 4:1) as a white solid
(64.5 mg; 98%), mp 120e121 ꢀC; Rf¼0.14 (petrolether/ethyl acetate
(NCH2), 59.2 (CH2OH), 60.1 (CH2O), 90.4 (]CH), 156.8 (C]), 167.7
(COester), 176.7 (COlactam); IR (KBr):
n
¼3451, 1706, 1682, 1568, 1306,
1160, 1041 cmꢂ1; HRMS: calcd for C10H16NO4S [MþH]þ 246.0795,
found 246.0785.
5.4.3. (Z)-Ethyl 2-(3-(3-hydroxypropyl)-4-oxothiazolidin-2-ylidene)
acetate (11c). Compound 11c was prepared from 8c (45.7 mg;
0.15 mmol) in 3 mL DMF/H2O 1:1 (v/v) to which 200 mL concd HCl
was added, according to general procedure (reaction time 21 h, TLC:
toluene/ethyl acetate 7:3). The crude product was purified by stir-
ring with n-hexane. Filtration gave pure 11c as a white solid
4:1); 1H NMR (200 MHz, CDCl3):
d
1.32 (t, J¼7.0 Hz, 3H, CH3), 2.38 (s,
3H, CH3COS), 3.00e3.08 (m, 2H, CH2SCO), 3.79e3.86 (m, 2H, NCH2),
3.72 (s, 2H, CH2S), 4.23 (q, J¼7.0 Hz, 2H, CH2O), 5.90 (s, 1H, ]CH);
13C NMR (50 MHz, CDCl3):
d 14.4 (CH3), 25.3 (CH2SCO), 30.5
(CH3COS), 31.6 (CH2S), 42.2 (NCH2), 60.1 (CH2O), 91.2 (]CH), 157.2
(C]), 167.8 (COester), 172.3 (COlactam), 195.5 (COS); IR (KBr):
¼1719,
n

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M. Stojanovic et al. / Tetrahedron 67 (2011) 9541e9554
9550
1686, 1561, 1189, 1141 cmꢂ1; HRMS: calcd for C11H16NO4S2 [MþH]þ
(C]), 167.7 (COester), 172.4 (COlactam), 195.7 (COS); IR (KBr):
n
¼1718,
290.0515, found 290.0505.
1687, 1570, 1358, 1177, 1140 cmꢂ1; HRMS: calcd for C13H20NO4S2
[MþH]þ 318.0828, found 318.0822.
5.5.2. (Z)-Ethyl 2-(3-(2-(acetylthio)ethyl)-5-methyl-4-
oxothiazolidin-2-ylidene)acetate (12b). Compound 12b was ob-
tained from 8b (92.8 mg; 0.31 mmol) and KSAc (43.0 mg;
0.38 mmol; 1.2 equiv) in acetone (2.0 mL) according to general
procedure (reaction time 15 min, TLC: petrolether/ethyl acetate
4:1) as a white solid (93.0 mg; 100%), mp 85e86 ꢀC; Rf¼0.26
5.5.6. (Z)-Ethyl 2-(3-(4-(acetylthio)butyl)-5-methyl-4-
oxothiazolidin-2-ylidene)acetate (12f). Compound 12f was ob-
tained from 8f (101 mg; 0.3 mmol) and KSAc (42.4 mg; 0.37 mmol;
1.2 equiv) in acetone (3.0 mL) according to general procedure (re-
action time 10 min, TLC: petrolether/ethyl acetate 4:1) as a colorless
oil (98.1 mg; 98%); Rf¼0.56 (petrolether/ethyl acetate 4:1); 1H NMR
(petrolether/ethyl acetate 4:1); 1H NMR (200 MHz, CDCl3):
d 1.31 (t,
J¼7.2 Hz, 3H, CH3CH2), 1.61 (d, J¼7.3 Hz, 3H, CH3CH), 2.38 (s, 3H,
CH3COS), 3.01e3.08 (m, 2H, CH2SCO), 3.79e3.86 (m, 2H, NCH2),
3.90 (q, J¼7.3 Hz, 1H, CHS), 4.23 (q, J¼7.2 Hz, 2H, CH2O), 5.86 (s, 1H,
(200 MHz, CDCl3):
d
1.31 (t, J¼7.2 Hz, 3H, CH3CH2), 1.60 (d, J¼7.2 Hz,
3H, CH3CH), 1.59e1.73 (m, 4H, CH2CH2CH2CH2), 2.33 (s, 3H,
CH3COS), 2.90 (t, J¼6.8 Hz, 2H, CH2SCO), 3.67 (t, J¼7.0 Hz, 2H,
NCH2), 3.89 (q, J¼7.2 Hz, 1H, CHS), 4.21 (q, J¼7.2 Hz, 2H, CH2O), 5.46
]CH); 13C NMR (50 MHz, CDCl3):
d 14.4 (CH3CH2), 19.0 (CH3CH),
25.4 (CH2SCO), 30.5 (CH3COS), 40.3 (CHS), 42.2 (NCH2), 60.1 (CH2O),
90.7 (]CH), 155.9 (C]), 167.8 (COester), 175.5 (COlactam), 195.5
(s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
d 14.4 (CH3CH2), 19.1
(CH3CH), 25.4 (CH2CH2S), 26.7 (CH2SCO), 28.2 (NCH2CH2), 30.6
(CH3COS), 40.4 (CHS), 42.2 (NCH2), 60.0 (CH2O), 90.0 (]CH), 156.5
(COS); IR (KBr):
n
¼1724, 1686, 1573,1310, 1149 cmꢂ1; Anal. Calcd for
C12H17NO4S2: C, 47.50; H, 5.65; N, 4.62; S, 21.14, found: C, 47.17; H,
5.69; N, 4.63; S, 20.83.
(C]), 167.6 (COester), 175.6 (COlactam), 195.6 (COS); IR (KBr):
n
¼1715,
1687, 1570, 1176, 1141 cmꢂ1; HRMS: calcd for C14H22NO4S2 [MþH]þ
332.0985, found 332.0981.
5.5.3. (Z)-Ethyl 2-(3-(3-(acetylthio)propyl)-4-oxothiazolidin-2-
ylidene)acetate (12c). Compound 12c was obtained from 8c
(61.7 mg; 0.2 mmol) and KSAc (28.7 mg; 0.25 mmol; 1.25 equiv) in
acetone (2.0 mL) according to general procedure (reaction time
15 min, TLC: toluene/ethyl acetate 4:1) as a white solid (57.9 mg;
95%), mp 105e106 ꢀC; Rf¼0.36 (petrolether/ethyl acetate 4:1); 1H
5.6. General procedure for synthesis of secondary amines 13
A solution of bromide 8, benzylamine and Et3N in DMF was
stirred at rt until the disappearance of the starting material (TLC).
The reaction mixture was then diluted with CH2Cl2 (15 mL), washed
with water (3ꢃ10 mL), saturated aq NaCl (1ꢃ10 mL), and dried over
Na2SO4. After evaporation of the solvent, the crude product was
purified by column chromatography.
NMR (200 MHz, CDCl3):
d
1.30 (t, J¼7.2 Hz, 3H, CH3), 1.83e1.98 (m,
2H, CH2CH2CH2), 2.36 (s, 3H, CH3COS), 2.90 (t, J¼7.0 Hz, 3H,
CH2SCO), 3.71 (s, 2H, CH2S), 3.73 (t, J¼7.4 Hz, 2H, NCH2), 4.21 (q,
J¼7.2 Hz, 2H, CH2O), 5.50 (s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
d
14.3 (CH3), 26.1 (CH2SCO), 26.4 (CH2CH2CH2), 30.5 (CH3COS), 31.6
5.6.1. (Z)-Ethyl 2-(3-(3-(benzylamino)propyl)-4-oxothiazolidin-2-
ylidene)acetate (13a). Compound 13a was obtained from 8c
(77.3 mg; 0.25 mmol), benzylamine (137 mg; 1.28 mmol; 5.1 equiv),
and Et3N (36.0 mg; 0.36 mmol; 1.4 equiv) in DMF (3.0 mL)
according to general procedure (reaction time 18 h, TLC: toluene/
ethyl acetate 4:1). Column chromatography (eluent: gradient pet-
rolether/ethyl acetate 100:0 to 20:80) gave pure 13a, as a colorless
oil (64.6 mg; 77%); Rf¼0.37 (ethyl acetate); 1H NMR (200 MHz,
(CH2S), 42.2 (NCH2), 60.0 (CH2O), 90.5 (]CH), 157.7 (C]), 167.6
(COester), 172.4 (COlactam), 195.2 (COS); IR (KBr):
n
¼1721, 1682, 1566,
1358, 1142 cmꢂ1; HRMS: calcd for C12H18NO4S2 [MþH]þ 304.0672,
found 304.0663.
5.5.4. (Z)-Ethyl 2-(3-(3-(acetylthio)propyl)-5-methyl-4-
oxothiazolidin-2-ylidene)acetate (12d). Compound 12d was ob-
tained from 8d (100 mg; 0.31 mmol) and KSAc (43.4 mg;
0.38 mmol; 1.2 equiv) in acetone (2.0 mL) according to general
procedure (reaction time 10 min, TLC: petrolether/ethyl acetate
4:1) as a white solid (92.0 mg; 94%), mp 63e64 ꢀC; Rf¼0.41 (pet-
CDCl3):
d
1.28 (t, J¼7.2 Hz, 3H, CH3), 1.72e1.86 (m, 2H, CH2CH2CH2),
2.64 (t, J¼6.8 Hz, 2H, CH2NHBn), 3.66 (s, 2H, CH2Ph), 3.76 (s, 2H,
CH2S), 3.77 (t, J¼7.0 Hz, 2H, NCH2), 4.20 (q, J¼7.2 Hz, 2H, CH2O), 5.62
(s, 1H, ]CH), 7.23e7.34 (m, 5H, Ph); 13C NMR (50 MHz, CDCl3):
rolether/ethyl acetate 4:1); 1H NMR (200 MHz, CDCl3):
d
1.27 (t,
d 14.3 (CH3), 26.7 (CH2CH2CH2), 31.6 (CH2S), 41.4 (NCH2), 45.9
J¼7.0 Hz, 3H, CH3CH2), 1.58 (d, J¼7.2 Hz, 3H, CH3CH), 1.80e1.95 (m,
2H, CH2CH2CH2), 2.33 (s, 3H, CH3COS), 2.86 (t, J¼7.0 Hz, 2H,
CH2SCO), 3.70 (t, J¼7.2 Hz, 2H, NCH2), 3.86 (q, J¼7.2 Hz, 1H, CHS),
4.18 (q, J¼7.0 Hz, 2H, CH2O), 5.45 (s, 1H, ]CH); 13C NMR (50 MHz,
(CH2NHBn), 53.8 (CH2Ph), 59.9 (CH2O), 90.6 (]CH), 126.9 (p-Ph),
128.1 (o-Ph), 128.3 (m-Ph), 140.0 (C1Ph), 158.0 (C]), 167.7 (COester),
172.5 (COlactam); IR (KBr):
n
¼3313, 3027, 1716, 1684, 1568, 1308,
1156, 739, 700 cmꢂ1; HRMS: calcd for C17H23N2O3S [MþH]þ
CDCl3):
d
14.4 (CH3CH2), 19.0 (CH3CH), 26.2 (CH2SCO), 26.5
355.1424, found 355.1426.
(CH2CH2CH2), 30.6 (CH3COS), 40.3 (CHS), 42.2 (NCH2), 60.0 (CH2O),
90.1 (]CH),156.4 (C]),167.6 (COester),175.7 (COlactam),195.3 (COS);
5.6.2. (Z)-Ethyl 2-(3-(3-(benzylamino)propyl)-5-methyl-4-
oxothiazolidin-2-ylidene)acetate (13b). Compound 13b was ob-
tained from 8d (48.8 mg; 0.15 mmol), benzylamine (78.4 mg;
0.73 mmol; 4.9 equiv), and Et3N (21.6 mg; 0.21 mmol; 1.4 equiv) in
DMF (3.0 mL) according to general procedure (reaction time 18 h,
TLC: toluene/ethyl acetate 4:1). Column chromatography (eluent:
gradient petrolether/ethyl acetate 40:60 to 20:80) gave pure 13b, as
a colorless oil (48.6 mg; 92%); Rf¼0.46 (ethyl acetate); 1H NMR
IR (KBr):
n
¼1708, 1680, 1563, 1359, 1178, 1144 cmꢂ1; Anal. Calcd for
C13H19NO4S2: C, 49.19; H, 6.03; N, 4.41; S, 20.20, found: C, 48.89; H,
5.86; N, 4.39; S, 20.33.
5.5.5. (Z)-Ethyl 2-(3-(4-(acetylthio)butyl)-4-oxothiazolidin-2-
ylidene)acetate (12e). Compound 12e was obtained from 8e
(68.1 mg; 0.21 mmol) and KSAc (25.6 mg; 0.22 mmol; 1.05 equiv) in
acetone (2.0 mL) according to general procedure (reaction time
15 min, TLC: petrolether/ethyl acetate 4:1) as a colorless oil
(62.0 mg; 93%); Rf¼0.47 (petrolether/ethyl acetate 4:1); 1H NMR
(200 MHz, CDCl3):
d
1.29 (t, J¼7.2 Hz, 3H, CH3CH2), 1.58 (d, J¼7.3 Hz,
3H, CH3CH), 1.73e1.87 (m, 2H, CH2CH2CH2), 2.62 (t, J¼6.6 Hz, 2H,
CH2NHBn), 3.76 (s, 2H, CH2Ph), 3.77 (t, J¼7.0 Hz, 2H, NCH2), 3.86 (q,
J¼7.3 Hz, 1H, CHS), 4.20 (q, J¼7.2 Hz, 2H, CH2O), 5.60 (s, 1H, ]CH),
(200 MHz, CDCl3):
d
1.31 (t, J¼7.0 Hz, 3H, CH3), 1.57e1.74 (m, 4H,
CH2CH2CH2CH2), 2.34 (s, 3H, CH3COS), 2.90 (t, J¼6.8 Hz, 2H,
CH2SCO), 3.67 (t, J¼7.2 Hz, 2H, NCH2), 3.71 (s, 2H, CH2S), 4.22 (q,
J¼7.0 Hz, 2H, CH2O), 5.48 (s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
7.22e7.34 (m, 5H, Ph); 13C NMR (50 MHz, CDCl3):
d 14.4 (CH3CH2),
19.1 (CH3CH), 26.8 (CH2CH2CH2), 40.4 (CHS), 41.4 (NCH2), 45.8
(CH2NHBn), 53.9 (CH2Ph), 60.0 (CH2O), 90.2 (]CH), 127.0 (p-Ph),
128.2 (o-Ph), 128.4 (m-Ph), 140.0 (C1Ph), 156.6 (C]), 167.8 (COester),
d
14.3 (CH3), 25.3 (CH2CH2S), 26.7 (CH2SCO), 28.2 (NCH2CH2), 30.6
(CH3COS), 31.7 (CH2S), 42.9 (NCH2), 60.0 (CH2O), 90.4 (]CH), 157.9
175.9 (COlactam); IR (KBr):
n
¼3314, 3063, 3028, 1642, 1524, 1456,

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M. Stojanovic et al. / Tetrahedron 67 (2011) 9541e9554
9551
1380, 1166, 1140, 741, 700 cmꢂ1; HRMS: calcd for C18H25N2O3S
0.23 mmol) and Ph3P (90.5 mg; 0.34 mmol; 1.5 equiv) in MeOH
(5.0 mL) according to general procedure (reaction time 1 h, TLC:
toluene/ethyl acetate 7:3) as a colorless oil (32.7 mg; 62%); Rf¼0.38
[MþH]þ 349.1580, found 349.1581.
5.7. General procedure for synthesis of azides 14
(ethyl acetate/MeOH 1:1); 1H NMR (200 MHz, CDCl3):
d 1.30 (t,
J¼7.2 Hz, 3H, CH3), 2.11 (br s, 2H, NH2), 2.96 (t, J¼6.8 Hz, 2H,
CH2NH2), 3.74 (s, 2H, CH2S), 3.76 (t, J¼6.8 Hz, 2H, NCH2), 4.21 (q,
J¼7.2 Hz, 2H, CH2O), 5.55 (s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
A solution of bromide 8 and NaN3 in DMF was stirred at rt until
the disappearance of the starting material (TLC). The reaction
mixture was then diluted with CHCl3 (10e15 mL), washed with
water (3ꢃ10 mL), saturated aq NaCl (1ꢃ10 mL), and dried over
Na2SO4. Evaporation of the solvent gave pure products.
d
14.3 (CH3), 31.7 (CH2S), 38.6 (CH2NH2), 46.0 (NCH2), 60.0 (CH2O),
90.6 (]CH), 158.0 (C]), 167.7 (COester), 172.9 (COlactam); IR (KBr):
n
¼3367, 1717, 1683, 1568, 1142 cmꢂ1; HRMS: calcd for C9H15N2O3S
[MþH]þ 231.0798, found 231.0818.
5.7.1. (Z)-Ethyl 2-(3-(2-azidoethyl)-4-oxothiazolidin-2-ylidene)ace-
tate (14a). Compound 14a was obtained from 8a (128 mg;
0.43 mmol) and NaN3 (56.0 mg; 0.86 mmol; 2 equiv) in DMF
(3.0 mL) according to general procedure (reaction time 1 h, TLC:
toluene/ethyl acetate 7:3) as a white solid (101 mg; 91%), mp
90e91 ꢀC; Rf¼0.61 (toluene/ethyl acetate 7:3); 1H NMR (200 MHz,
5.8.2. (Z)-Ethyl
2-(3-(3-aminopropyl)-4-oxothiazolidin-2-ylidene)
acetate (15b). Compound 15b was obtained from 14b (33.6 mg;
0.12 mmol) and Ph3P (49.0 mg; 0.19 mmol; 1.5 equiv) in MeOH
(5.0 mL) according to general procedure (reaction time 1 h, TLC:
toluene/ethyl acetate 7:3) as a pale pink solid (20.6 mg; 70%), mp
158e159 ꢀC; Rf¼0.32 (ethyl acetate/MeOH 1:1); 1H NMR (200 MHz,
CDCl3):
d
1.31 (t, 3H, J¼7.2 Hz, CH3), 3.55 (t, J¼6.2 Hz, 2H, CH2N3),
3.75 (s, 2H, CH2S), 3.88 (t, J¼6.2 Hz, 2H, NCH2), 4.22 (q, J¼7.2 Hz, 2H,
CH2O), 5.55 (s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
14.3 (CH3),
31.5 (CH2S), 42.3 (NCH2), 47.3 (CH2N3), 60.2 (CH2O), 90.7 (]CH),
CDCl3):
d
1.29 (t, J¼7.2 Hz, 3H, CH3), 1.86e1.97 (m, 2H, CH2CH2CH2),
d
3.47e3.56 (m, 4H, CH2CH2CH2), 3.75 (br s, 2H, NH2), 3.81 (s, 2H,
CH2S), 4.19 (q, J¼7.2 Hz, 2H, CH2O), 5.21 (s, 1H, ]CH); 13C NMR
157.5 (C]), 167.5 (COester), 172.5 (COlactam); IR (KBr):
n
¼2106, 1720,
(50 MHz, CDCl3): d 14.4 (CH3), 19.3 (CH2CH2CH2), 32.5 (CH2S), 43.3
1682, 1571, 1157 cmꢂ1; HRMS: calcd for C9H13N4O3S [MþH]þ
(CH2NH2), 44.6 (NCH2), 59.7 (CH2O), 85.4 (]CH), 154.5 (C]), 160.6
257.0703, found 257.0705.
(COester), 168.3 (COlactam); IR (KBr):
n
¼3425, 3276, 1716, 1674, 1582,
1165 cmꢂ1; HRMS: calcd for C10H17N2O3S [MþH]þ 245.0954, found
5.7.2. (Z)-Ethyl 2-(3-(3-azidopropyl)-4-oxothiazolidin-2-ylidene)ac-
etate (14b). Compound 14b was obtained from 8c (41.7 mg;
0.14 mmol) and NaN3 (26.4 mg; 0.41 mmol; 2.9 equiv) in DMF
(2.0 mL) according to general procedure (reaction time 1 h, TLC:
toluene/ethyl acetate 7:3) as a colorless oil (34.5 mg; 94%); Rf¼0.68
245.0959.
5.8.3. (Z)-Ethyl 2-(3-(4-aminobutyl)-4-oxothiazolidin-2-ylidene)ac-
etate (15c). Compound 15c was obtained from 14c (77.1 mg;
0.27 mmol) and Ph3P (107 mg; 0.41 mmol; 1.5 equiv) in MeOH
(5.0 mL) according to general procedure (reaction time 1 h, TLC:
toluene/ethyl acetate 7:3) as a colorless oil (44.2 mg; 63%); Rf¼0.40
(toluene/ethyl acetate 7:3); 1H NMR (200 MHz, CDCl3):
d 1.31 (t,
J¼7.0 Hz, 3H, CH3), 1.81e1.95 (m, 2H, CH2CH2CH2), 3.40 (t, J¼6.0 Hz,
2H, CH2N3), 3.73 (s, 2H, CH2S), 3.77 (t, J¼6.8 Hz, 2H, NCH2), 4.22 (q,
J¼7.0 Hz, 2H, CH2O), 5.53 (s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
(ethyl acetate/MeOH 1:1); 1H NMR (200 MHz, CDCl3):
d 1.30 (t,
J¼7.2 Hz, 3H, CH3),1.44e1.55 (m, 2H, CH2CH2NH2) 1.56e1.74 (m, 2H,
NCH2CH2), 1.89 (br s, 2H, NH2), 2.74 (t, J¼7.0 Hz, 2H, CH2NH2), 3.69
(t, J¼7.2 Hz, 2H, NCH2), 3.71 (s, 2H, CH2S), 4.21 (q, J¼7.2 Hz, 2H,
d
14.3 (CH3), 25.9 (CH2CH2CH2), 31.6 (CH2S), 40.8 (NCH2), 48.7
(CH2N3), 60.1 (CH2O), 90.5 (]CH), 157.6 (C]), 167.6 (COester), 172.4
(COlactam); IR (KBr):
n
¼2098, 1717, 1683, 1570, 1153 cmꢂ1; HRMS:
CH2O), 5.51 (s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
d 14.4 (CH3),
calcd for C10H15N4O3S [MþH]þ 271. 0859, found 271.0854.
23.7 (NCH2CH2), 30.3 (CH2CH2NH2), 31.6 (CH2S), 41.4 (CH2NH2),
43.2 (NCH2), 59.9 (CH2O), 90.4 (]CH), 157.9 (C]), 167.6 (COester),
5.7.3. (Z)-Ethyl 2-(3-(4-azidobutyl)-4-oxothiazolidin-2-ylidene)ace-
tate (14c). Compound 14c was obtained from 8e (131 mg;
0.4 mmol) and NaN3 (53.0 mg; 0.81 mmol; 2 equiv) in DMF (3.0 mL)
according to general procedure (reaction time 1.5 h, TLC: toluene/
ethyl acetate 7:3) as a colorless oil (103 mg; 89%); Rf¼0.61 (toluene/
172.4 (COlactam); IR (KBr):
n
¼3400, 1716, 1683, 1568, 1158 cmꢂ1
;
HRMS: calcd for C11H19N2O3S [MþH]þ 259.1111, found 259.1110.
5.9. Deprotection of S-acyl derivatives 12 prior to the
generation of an iminium ion
ethyl acetate 7:3); 1H NMR (200 MHz, CDCl3):
d
1.31 (t, J¼7.2 Hz, 3H,
CH3), 1.54e1.80 (m, 4H, CH2CH2CH2CH2), 3.35 (t, J¼6.2 Hz, 2H,
CH2N3), 3.72 (s, 2H, CH2S), 3.70 (t, J¼7.0 Hz, 2H, NCH2), 4.22 (q,
J¼7.2 Hz, 2H, CH2O), 5.50 (s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
S-Acyl derivatives 12 were deprotected by 0.2 M NaOEt/EtOH
(1 equiv of NaOEt) at rt for 15 min (TLC: toluene/ethyl acetate 4:1)
and used, without isolation, for the formation of an iminium ion.
d
14.3 (CH3), 23.7 (NCH2CH2), 26.0 (CH2CH2N3), 31.6 (CH2S), 42.8
(NCH2), 50.7 (CH2N3), 60.1 (CH2O), 90.5 (]CH), 157.7 (C]), 167.6
5.10. General procedure for generation of an iminium ion and
work-up of reaction mixture
(COester), 172.4 (COlactam); IR (KBr):
n
¼2097, 1718, 1684, 1568,
1151 cmꢂ1; HRMS: calcd for C11H17N4O3S [MþH]þ 285.1016, found
285.1017.
To a mixture of a substrate and NaBH4 in abs EtOH at 0 ꢀC three
drops of 0.4 M aq HCl were added every 10e15 min until the
completion of the reduction (TLC). The reaction mixture was then
acidified by dropwise addition of 1 M ethanolic HCl (until H2 evo-
lution had ceased) and stirring was continued for 30 min at 0 ꢀC.
After dilution with water stirring was continued at rt for additional
30 min. The reaction mixture was then neutralized with NaHCO3,
extracted with CH2Cl2 (3ꢃ10 mL) and dried over Na2SO4. Evapo-
ration of the solvent gave crude products, which were purified by
column chromatography.
5.8. General procedure for synthesis of amines 15
A solution of azide 14 and Ph3P in MeOH was refluxed until the
disappearance of the starting material (TLC). The reaction mixture
was then diluted with CH2Cl2 (15 mL), a few drops of concd HCl
were added and it was extracted with water (3ꢃ10 mL). The water
layer was neutralized with Na2CO3, extracted with CH2Cl2
(3ꢃ10 mL) and dried over Na2SO4. Evaporation of the solvent gave
pure products.
5.10.1. (Z)-Ethyl
(tetrahydrothiazolo[4,3-b][1,3]oxazin-6(2H)-yli-
5.8.1. (Z)-Ethyl 2-(3-(2-aminoethyl)-4-oxothiazolidin-2-ylidene)ace-
dene)acetate (18a). Compound 18a was obtained from 11c
tate (15a). Compound 15a was obtained from 14a (59.5 mg;
(40.0 mg; 0.16 mmol) and NaBH4 (82.3 mg; 2.2 mmol; 13.6 equiv) in

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M. Stojanovic et al. / Tetrahedron 67 (2011) 9541e9554
9552
EtOH (6.0 mL) according to general procedure (reduction time
45 min, TLC: toluene/ethyl acetate 7:3). Column chromatography
(eluent: gradient petrolether/ethyl acetate 100:0 to 70:30) gave
pure 18a (13.4 mg; 36%) as a colorless oil; Rf¼0.64 (toluene/ethyl
(3.0 mL) according to general procedure (reduction time 1 h, TLC:
toluene/ethyl acetate 4:1). Column chromatography (eluent: gra-
dient petrolether/ethyl acetate 100:0 to 80:20) gave pure 18d
(22.0 mg; 35%; trans/cis 1:5.7) as a colorless oil; Rf¼0.58 (toluene/
acetate 7:3); 1H NMR (500 MHz, CDCl3):
d
1.27 (t, J¼7.0 Hz, 3H, CH3),
ethyl acetate 7:3); 1H NMR (500 MHz, CDCl3): cis isomer
d 1.26 (t,
1.44e1.47 (m, 1H, CH2CHHCH2), 1.95e2.05 (m, 1H, CH2CHHCH2),
2.98 (dd, J1¼12.0 Hz, J2¼3.5 Hz, 1H, CHHS), 3.24 (dd, J1¼12.0 Hz,
J2¼5.5 Hz, 1H, CHHS), 3.30 (dt, J1¼13.0 Hz, J2¼3.0 Hz, 1H,
OCHHCH2CH2N), 3.74e3.79 (m, 2H, OCHHCH2CHHN), 4.12e4.15 (m,
1H, CHHN), 4.16 (q, J¼7.0 Hz, 2H, CH2O), 5.03 (s, 1H, ]CH), 5.04 (dd,
J¼7.0 Hz, 3H, CH3CH2), 1.46 (d, J¼7.0 Hz, 3H, CH3CH), 3.05e3.07 (m,
1H, CHHS), 3.24e3.34 (m, 2H, CHHS and NCHH), 3.89 (dq, J1¼7.0 Hz,
J2¼5.5 Hz, 1H, CHS), 4.00e4.02 (m, 1H, NCHH), 4.15 (q, J¼7.0 Hz, 2H,
CH2O), 5.10 (s, 1H, ]CH), 5.28 (d, 1H, J¼5.5 Hz, SCHN), trans isomer
d
1.26 (t, J¼7.0 Hz, 3H, CH3CH2), 1.49 (d, J¼6.5 Hz, 3H, CH3CH),
J1¼5.5 Hz, J2¼3.5 Hz, 1H, OCHN); 13C NMR (125 MHz, CDCl3):
d
14.6
3.09e3.12 (m, 1H, CHHS), 3.15e3.20 (m, 1H, CHHS), 3.26e3.32 (m,
1H, NCHH), 3.66 (dq, J1¼6.5 Hz, J2¼5.5 Hz, 1H, CHS), 3.97 (ddd, 1H,
J1¼11.5 Hz, J2¼6.0 Hz, J3¼3.0 Hz NCHH), 4.15 (q, J¼7.0 Hz, 2H, CH2O),
4.89 (d, J¼5.5 Hz, 1H, SCHN), 5.07 (s, 1H, ]CH); 13C NMR (50 MHz,
(CH3), 23.2 (CH2CH2CH2), 32.8 (CH2S), 44.6 (NCH2), 59.2 (CH2O),
67.5 (CH2OCH), 82.4 (]CH), 92.5 (OCHN), 162.8 (C]), 169.0 (COes-
ter); IR (KBr):
n
¼1671, 1551, 1151, 1049 cmꢂ1; HRMS: calcd for
C10H16NO3S [MþH]þ 230.0845, found 230.0840.
CDCl3): cis isomer d 14.5 (CH3CH2), 17.0 (CH3CH), 31.0 (CH2S), 41.3
(CHS), 51.0 (NCH2), 59.4 (CH2O), 76.8 (SCHN), 84.8 (]CH), 163.8
(C]), 168.6 (CO), trans isomer 14.5 (CH3CH2), 20.1 (CH3CH), 32.0
(CH2S), 45.2 (CHS), 50.7 (NCH2), 59.4 (CH2O), 77.8 (SCHN), 84.4 (]
5.10.2. (Z)-Ethyl
(8-methyltetrahydrothiazolo[4,3-b][1,3]oxazin-
d
6(2H)-ylidene)acetate (18b). Compound 18b was obtained from 11d
(44.0 mg; 0.17 mmol) and NaBH4 (88.0 mg; 2.33 mmol; 13.7 equiv)
in EtOH (4.0 mL) according to general procedure (reduction time
30 min, TLC: toluene/ethyl acetate 3:2). Column chromatography
(eluent: gradient petrolether/ethyl acetate 100:0 to 50:50) gave
pure 18b (24.7 mg; 63%; trans/cis 3:1) as a colorless oil; Rf¼0.68
(petrolether/ethyl acetate 3:2); 1H NMR (500 MHz, CDCl3): cis
CH), 163.8 (C]), 168.6 (CO); IR (KBr, cis and trans isomer):
n
¼1674,
1556, 1454, 1329, 1144, 1090 cmꢂ1; HRMS: calcd for C10H16NO2S2
[MþH]þ 246.0617, found 246.0627.
5.10.5. (Z)-Ethyl (tetrahydrothiazolo[4,3-b][1,3]thiazin-6(2H)-ylidene)
acetate (18e). Compound 18e was obtained from 12c (50.5 mg;
0.17 mmol), deprotected prior to the addition of a reducing agent,
and NaBH4 (101 mg; 2.7 mmol; 15.9 equiv) in EtOH (5.0 mL)
according to general procedure (reduction time 45 min, TLC: tolu-
ene/ethyl acetate 7:3). Column chromatography (eluent: gradient
petrolether/ethyl acetate 100:0 to 80:20) gave pure 18e (27.4 mg;
66%) as a white solid, mp 108e109 ꢀC; Rf¼0.38 (petrolether/ethyl
isomer
d
1.26 (t, J¼7.0 Hz, 3H, CH3CH2), 1.35 (d, J¼7.0 Hz, 3H,
CH3CH), 1.46e1.50 (m, 1H, CH2CHHCH2), 1.95e2.04 (m, 1H,
CH2CHHCH2), 3.24 (dt, 1H, J1¼13.5 Hz, J2¼3.5 Hz, OCHHCH2CH2N),
3.59 (dq, J1¼7.0 Hz, J2¼5.5 Hz, 1H, CHS), 3.68e3.76 (m, 2H,
OCHHCH2CHHN), 4.12e4.19 (m, 1H, CHHN), 4.16 (q, J¼7.0 Hz, 2H,
CH2O), 4.79 (d, J¼5.5 Hz,1H, OCHN), 5.00 (s,1H, ]CH), trans isomer
d
1.26 (t, J¼7.0 Hz, 3H, CH3CH2), 1.38 (d, J¼7.0 Hz, 3H, CH3CH),
acetate 4:1); 1H NMR (200 MHz, CDCl3):
d
1.27 (t, J¼7.0 Hz, 3H, CH3),
1.46e1.50 (m, 1H, CH2CHHCH2), 1.95e2.04 (m, 1H, CH2CHHCH2),
3.22 (dt, J1¼13.0 Hz, J2¼3.5 Hz, 1H, OCHHCH2CH2N), 3.36 (dq,
J1¼7.0 Hz, J2¼4.0 Hz, 1H, CHS), 3.68e3.76 (m, 2H, OCHHCH2CHHN),
4.12e4.19 (m, 1H, CHHN), 4.16 (q, J¼7.0 Hz, 2H, CH2O), 4.55 (d,
J¼4.0 Hz, 1H, OCHN), 4.98 (s, 1H, ]CH); 13C NMR (50 MHz, CDCl3):
1.65e2.05 (m, 2H, CH2CH2CH2), 2.76e2.84 (m, 1H, SCHHCH2CH2N),
2.83 (dd, J1¼11.8 Hz, J2¼2.0 Hz, 1H, CHHS), 3.04e3.19 (m, 1H,
SCHHCH2CH2N), 3.19e3.34 (m, 1H, NCHH), 3.39 (dd, J1¼11.8 Hz,
J2¼7.0 Hz,1H, CHHS), 3.80e3.87 (m,1H, NCHH), 4.19 (q, J¼7.0 Hz, 2H,
CH2O), 5.05 (s, 1H, ]CH), 5.09 (dd, J1¼7.0 Hz, J2¼2.0 Hz, 1H, SCHN);
cis isomer
d
13.6 (CH3CH), 14.6 (CH3CH2), 23.0 (CH2CH2CH2), 40.7
13C NMR (50 MHz, CDCl3):
d 14.6 (CH3), 22.0 (CH2CH2CH2), 29.1
(CHS), 44.8 (NCH2), 59.2 (CH2O), 67.4 (CH2OCH), 82.4 (]CH), 93.3
(OCHN), 162.4 (C]), 169.0 (CO), trans isomer 14.5 (CH3CH2), 18.5
(CH3CH), 23.1 (CH2CH2CH2), 42.8 (CHS), 44.6 (NCH2), 59.2 (CH2O),
67.4 (CH2OCH), 82.1 (]CH), 98.1 (OCHN), 162.4 (C]), 169.0 (CO); IR
(SCH2CH2CH2N), 33.0 (CH2S), 46.8 (NCH2), 59.3 (CH2O), 67.5 (SCHN),
d
83.5 (]CH), 162.3 (C]), 168.9 (CO); IR (KBr):
n
¼1663, 1531, 1459,
1144, 1102 cmꢂ1; HRMS: calcd for C10H16NO2S2 [MþH]þ 246.0617,
found 246,0618.
(KBr, cis and trans isomer):
n
¼1674, 1553, 1455, 1371, 1151,
1050 cmꢂ1; HRMS: calcd for C11H18NO3S [MþH]þ 244.1002, found
5.10.6. (Z)-Ethyl (8-methyltetrahydrothiazolo[4,3-b][1,3]thiazin-6(2H)-
ylidene)acetate (18f). Compound 18f was obtained from 12d
(48.0 mg; 0.15 mmol), deprotected prior to the addition of a reducing
agent, and NaBH4 (100 mg; 2.64 mmol; 15.5 equiv) in EtOH (5.0 mL)
according to general procedure (reduction time 1.5 h, TLC: toluene/
ethyl acetate 4:1). Column chromatography (eluent: gradient pet-
rolether/ethyl acetate 100:0 to 70:30) gave pure 18f (23.4 mg; 60%;
trans/cis 1.3:1) as a colorless oil; Rf¼0.34; 0.42 (petrolether/ethyl
244.0997.
5.10.3. (Z)-Ethyl (tetrahydrothiazolo[4,3-b]thiazol-5-ylidene)acetate
(18c). Compound 18c was obtained from 12a (45.9 mg; 0.16 mmol),
deprotected prior to the addition of a reducing agent, and NaBH4
(92.0 mg; 2.4 mmol; 15.2 equiv) in EtOH (5.0 mL) according to
general procedure (reduction time 1 h, TLC: toluene/ethyl acetate
4:1). Column chromatography (eluent: gradient petrolether/ethyl
acetate 100:0 to 80:20) gave pure 18c (10.2 mg; 28%) as a colorless
oil; Rf¼0.61 (toluene/ethyl acetate 4:1); 1H NMR (200 MHz, CDCl3):
acetate 4:1); 1H NMR (500 MHz, CDCl3): cis isomer
d
1.27 (t, J¼7.0 Hz,
3H, CH3CH2), 1.38 (d, J¼7.0 Hz, 3H, CH3CH), 1.64e1.68 (m, 1H,
CH2CHHCH2), 1.86e1.96 (m, 1H, CH2CHHCH2), 2.84e2.87 (m, 1H,
CHHS), 2.99e3.05 (m, 1H, CHHS), 3.28e3.31 (m, 1H, NCHH),
3.79e3.90 (m, 2H, NCHH and CHS), 4.16 (q, J¼7.0 Hz, 2H, CH2O), 5.01
d
1.27 (t, J¼7.0 Hz, 3H, CH3), 3.08e3.36 (m, 3H, NCHHCH2S), 3.23 (dd,
J1¼11.6 Hz, J2¼4.0 Hz, 1H, CHHS), 3.51 (dd, J1¼11.6 Hz, J2¼6.2 Hz, 1H,
CHHS), 3.99e4.09 (m, 1H, NCHH), 4.17 (q, J¼7.0 Hz, 2H, CH2O), 5.16
(s, 1H, ]CH), 5.27 (dd, J1¼6.2 Hz, J2¼4.0 Hz, 1H, SCHN); 13C NMR
(s, 1H, ]CH), 5.09 (d, J¼6.0 Hz, 1H, SCHN), trans isomer
d 1.27 (t,
J¼7.0 Hz, 3H, CH3CH2), 1.43 (d, J¼7.0 Hz, 3H, CH3CH), 1.71e1.75 (m,
1H, CH2CHHCH2), 1.86e1.96 (m, 1H, CH2CHHCH2), 2.78e2.81 (m, 1H,
CHHS), 3.04e3.10 (m, 1H, CHHS), 3.18e3.26 (m, 2H, NCHH and CHS),
3.79e3.86 (m, 1H, NCHH), 4.16 (q, J¼7.0 Hz, 2H, CH2O), 4.75 (d,
J¼2.0 Hz,1H, SCHN), 5.00 (s,1H, ]CH); 13C NMR (50 MHz, CDCl3): cis
(50 MHz, CDCl3):
d 14.5 (CH3), 31.9 (CH2CH2S), 33.3 (CH2S), 51.2
(NCH2), 59.5 (CH2O), 71.3 (SCHN), 85.1 (]CH), 164.4 (C]), 168.7
(CO); IR (KBr):
n
¼1674, 1558, 1462, 1163, 1141, 1046 cmꢂ1; HRMS:
calcd for C9H14NO2S2 [MþH]þ 232.0460, found 232.0464.
isomer d 13.5 (CH3CH),14.6 (CH3CH2), 22.0 (CH2CH2CH2), 28.4 (CH2S),
5.10.4. (Z)-Ethyl (7-methyltetrahydrothiazolo[4,3-b]thiazol-5-
ylidene)acetate (18d). Compound 18d was obtained from 12b
(77.3 mg; 0.25 mmol), deprotected prior to the addition of a re-
ducing agent, and NaBH4 (130 mg; 3.4 mmol; 13.8 equiv) in EtOH
41.4 (CHS), 47.0 (NCH2), 59.2 (CH2O), 73.1 (SCHN), 83.3 (]CH), 162.7
(C]), 168.7 (CO), trans isomer 14.5 (CH3CH2), 21.3 (CH3CH), 22.4
(CH2CH2CH2), 29.0 (CH2S), 43.2 (CHS), 46.8 (NCH2), 59.2 (CH2O), 73.9
(SCHN), 83.0 (]CH), 162.2 (C]), 168.8 (CO); IR (KBr, cis and trans
d

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M. Stojanovic et al. / Tetrahedron 67 (2011) 9541e9554
9553
isomer):
n
¼1670, 1554, 1445, 1364, 1154, 1114 cmꢂ1; HRMS: calcd for
78.0 (NHCHN), 81.5 (]CH), 162.7 (C]), 169.2 (CO); IR (KBr):
C11H18NO2S2 [MþH]þ 260.0774, found 260.0771.
n
¼3288, 1666, 1554, 1456, 1368, 1176, 1147 cmꢂ1; HRMS: calcd for
C10H17N2O2S [MþH]þ 229.1005, found 229.1001.
5.10.7. (Z)-Ethyl (hexahydrothiazolo[4,3-b][1,3]thiazepin-7(2H)ylidene)
acetate (18g). Compound 18g was obtained from 12e (41.0 mg;
0.13 mmol), deprotected prior to the addition of a reducing agent, and
NaBH4 (82.0 mg; 2.2 mmol; 16.7 equiv) in EtOH (5.0 mL) according to
general procedure (reduction time 45 min, TLC: toluene/ethyl acetate
4:1). Column chromatography (eluent: gradient petrolether/ethyl
acetate 100:0 to 80:20) gave pure 18g (19.1 mg; 57%) as a white solid,
mp 85e87 ꢀC; Rf¼0.64 (petrolether/ethyl acetate 3:2); 1H NMR
5.10.10. (Z)-Ethyl 2-(3-(2-hydroxyethyl)thiazol-2(3H)-ylidene)ace-
tate (19a). Compound 19a was obtained from 11a (23.1 mg;
0.1 mmol) and NaBH4 (45.0 mg; 1.19 mmol; 11.9 equiv) in EtOH
(3.0 mL) according to general procedure (reduction time 2 h, TLC:
toluene/ethyl acetate 1:1). Column chromatography (eluent: gradient
toluene/ethyl acetate 100:0 to 30:70) gave pure 19a (13.5 mg; 63%) as
a white solid, mp 56e58 ꢀC; Rf¼0.22 (toluene/ethyl acetate 3:7); 1H
(200 MHz, CDCl3):
d
1.27 (t, J¼7.0 Hz, 3H, CH3), 1.73e2.06 (m, 4H,
NMR (200 MHz, CDCl3):
d
1.28 (t, J¼7.2 Hz, 3H, CH3), 3.84e3.95 (m,
CH2CH2CH2CH2), 2.69e2.74 (m, 2H, SCH2CH2CH2CH2N), 3.11 (dd,
J1¼11.8 Hz, J2¼4.8 Hz, 1H, CHHS), 3.48 (dd, J1¼11.8 Hz, J2¼7.0 Hz, 1H,
CHHS), 3.50e3.53 (m, 2H, NCH2), 4.16 (q, J¼7.0 Hz, 2H, CH2O), 4.93 (s,
1H, ]CH), 5.13 (dd, J1¼7.0 Hz, J2¼4.8 Hz, 1H, SCHN); 13C NMR
4H, CH2CH2), 4.16 (q, J¼7.2 Hz, 2H, CH2O), 5.01 (br s,1H, ]CH), 6.26(d,
J¼4.4 Hz,1H, ]CHS), 6.75(d, J¼4.4 Hz,1H, ]CHN); 13C NMR (50 MHz,
CDCl3): d 14.7 (CH3), 50.9 (NCH2), 58.8 (CH2OH), 59.0 (CH2O), 75.3 (]
CHCO2Et), 104.6 (]CHS), 129.7 (]CHN), 162.4 (C]), 169.1 (CO); IR
(50 MHz, CDCl3):
d
14.6 (CH3), 25.8 (SCH2CH2CH2CH2N), 29.8
(KBr):
n
¼3399, 3115, 1622, 1519, 1163 cmꢂ1; HRMS: calcd for
(SCH2CH2CH2CH2N), 31.7 (SCH2CH2CH2CH2N), 35.7 (CH2S), 47.4
(NCH2), 59.1 (CH2O), 69.7 (SCHN), 81.1 (]CH), 161.9 (C]), 167.0 (CO);
C9H14NO3S [MþH]þ 216.0689, found 216.0684.
IR (KBr):
n
¼1666, 1552, 1462, 1181, 1160 cmꢂ1; HRMS: calcd for
5.10.11. (Z)-Ethyl 2-(3-(4-hydroxybutyl)-5-methylthiazol-2(3H)-yli-
dene)acetate (19b). Compound 19b was obtained from 11e
(37.4 mg; 0.16 mmol) and NaBH4 (65.0 mg; 1.72 mmol; 12.3 equiv)
in EtOH (5.0 mL) according to general procedure (reduction time
30 min, TLC: petrolether/ethyl acetate 3:2). Column chromatogra-
phy (eluent: gradient petrolether/ethyl acetate 100:0 to 20:80)
gave pure 19b (28.0 mg; 80%) as a colorless oil; Rf¼0.31 (toluene/
C11H18NO2S2 [MþH]þ 260.0774, found 260.0765.
5.10.8. (Z)-Ethyl (9-methylhexahydrothiazolo[4,3-b][1,3]thiazepin-
7(2H)ylidene)acetate (18h). Compound 18h was obtained from 12f
(74.0 mg; 0.22 mmol), deprotected prior to the addition of a reducing
agent, and NaBH4 (144 mg; 3.8 mmol; 17.3 equiv) in EtOH (5.0 mL)
according to general procedure (reduction time 45 min, TLC: tolu-
ene/ethyl acetate 4:1). Column chromatography (eluent: gradient
petrolether/ethyl acetate 100:0 to 80:20) gave pure 18h (42.1 mg;
69%; trans/cis 3.5:1) as a light yellow oil; Rf¼0.44; 0.47 (petrolether/
ethyl acetate 3:7); 1H NMR (200 MHz, CDCl3):
d
1.28 (t, J¼7.2 Hz, 3H,
CH3CH2), 1.51e1.64 (m, 2H, NCH2CH2), 1.73e1.87 (m, 2H,
CH2CH2OH), 2.15 (d, J¼1.4 Hz, 3H, CH3C), 2.29 (br s, 1H, OH), 3.67 (t,
J¼6.4 Hz, 4H, CH2OH and NCH2), 4.17 (q, J¼7.2 Hz, 2H, CH2O), 4.96
(br s, 1H, ]CHCO2Et), 6.34 (d, J¼1.4 Hz, 1H, ]CHN); 13C NMR
ethyl acetate 4:1); 1H NMR (500 MHz, CDCl3): cis isomer
d 1.26 (t,
J¼7.0 Hz, 3H, CH3CH2), 1.44 (d, J¼7.0 Hz, 3H, CH3CH), 1.74e1.79 (m,
1H, SCH2CH2CHHCH2N), 1.86e2.00 (m, 2H, SCH2CHHCHHCH2N),
2.01e2.08 (m, 1H, SCH2CHHCH2CH2N), 2.62e2.79 (m, 2H, SCH2),
3.54e3.56 (m, 2H, NCH2), 3.87 (dq, J1¼7.0 Hz, J2¼6.0 Hz, 1H, CHS),
4.15 (q, J¼7.0 Hz, 2H, CH2O), 4.90 (s, 1H, ]CH), 5.02 (d, J¼6.0 Hz, 1H,
(50 MHz, CDCl3): d 11.9 (CH3C), 14.7 (CH3CH2), 24.0 (CH2CH2OH),
29.4 (NCH2CH2), 48.4 (NCH2), 58.8 (CH2O), 61.9 (CH2OH), 74.4 (]
CHCO2Et), 117.4 (]CHS), 124.6 (]CHN), 162.6 (C]), 169.0 (CO); IR
(KBr):
n
¼3399, 1635, 1522, 1171, 1141 cmꢂ1; HRMS: calcd for
C12H20NO3S [MþH]þ 258.1158, found 258.1157.
SCHN), trans isomer
d
1.26 (t, J¼7.0 Hz, 3H, CH3CH2),1.43 (d, J¼7.0 Hz,
3H, CH3CH), 1.74e1.79 (m, 1H, SCH2CH2CHHCH2N), 1.86e2.00 (m,
2H, SCH2CHHCHHCH2N), 2.01e2.08 (m, 1H, SCH2CHHCH2CH2N),
2.62e2.79 (m, 2H, SCH2), 3.47 (dq, J1¼7.0 Hz, J2¼6.0 Hz, 1H, CHS),
3.54e3.56 (m, 2H, NCH2), 4.15 (q, J¼7.0 Hz, 2H, CH2O), 4.60 (d,
J¼6.0 Hz,1H, SCHN), 4.91 (s,1H, ]CH); 13C NMR (50 MHz, CDCl3): cis
5.10.12. (Z)-Ethyl
2-(3-(3-(benzylamino)propyl)thiazol-2(3H)-yli-
dene)acetate (19c). Compound 19c was obtained from 13a (28.3 mg;
0.08 mmol) and NaBH4 (58.1 mg; 1.53 mmol; 18.1 equiv) in EtOH
(3.0 mL) according to general procedure (reduction time 1 h, TLC:
ethyl acetate/MeOH 1:1). Column chromatography (eluent: gradient
ethyl acetate/MeOH 100:0 to 70:30) gave pure 19c (20.6 mg; 76%) as
isomer d 14.6 (CH3CH2),15.5 (CH3CH), 25.2 (SCH2CH2CH2CH2N), 31.0
(SCH2CH2CH2CH2N), 32.0 (SCH2), 42.7 (CHS), 48.2 (NCH2), 59.0
(CH2O), 76.0 (SCHN), 81.6 (]CH), 161.5 (C]), 168.9 (CO), trans iso-
a
colorless oil; Rf¼0.53 (ethyl acetate/MeOH 1:1); 1H NMR
(200 MHz, CDCl3):
d
1.29 (t, J¼7.2 Hz, 3H, CH3), 1.82e1.95 (m, 2H,
mer
d
14.6 (CH3CH2), 19.5 (CH3CH), 26.1 (SCH2CH2CH2CH2N), 29.1
CH2CH2CH2), 2.64 (t, J¼6.6 Hz, 2H, CH2NHBn), 3.77 (s, 2H, CH2Ph),
3.84 (t, J¼6.8 Hz, 2H, NCH2), 4.20 (q, J¼7.2 Hz, 2H, CH2O), 5.09 (s,1H,
]CHCO2Et), 6.21 (d, J¼4.6 Hz, 1H, ]CHS), 6.60 (d, J¼4.6 Hz, 1H, ]
(SCH2CH2CH2CH2N), 31.3 (SCH2), 41.7 (CHS), 47.2 (NCH2), 59.0
(CH2O), 76.1 (SCHN), 80.3 (]CH), 161.5 (C]), 168.9 (CO); IR (KBr, cis
and trans isomer):
n
¼1665, 1538, 1449, 1342, 1150, 1127, 1044 cmꢂ1
;
CHN), 7.28e7.35 (m, 5H, Ph); 13C NMR (50 MHz, CDCl3):
d 15.0 (CH3),
HRMS: calcd for C12H20NO2S2 [MþH]þ 274.0935, found 274.0931.
27.1 (CH2CH2CH2), 45.4 (CH2NHBn), 46.2 (NCH2), 53.0 (CH2Ph), 58.2
(CH2O), 74.6 (]CHCO2Et), 104.7 (]CHS), 127.1 (p-Ph), 128.5 (o-Ph),
128.6 (m-Ph),130.5 (]CHN),140.2 (C1Ph),162.0 (C]),168.1 (CO); IR
5.10.9. (Z)-Ethyl (hexahydrothiazolo[3,4-a]pyrimidin-6-ylidene)ace-
tate (18i). Compound 18i was obtained from 15b (36.6 mg;
0.15 mmol) and NaBH4 (84.0 mg; 2.2 mmol; 14.8 equiv) in EtOH
(7.0 mL) according to general procedure (reduction time 1 h, TLC:
ethyl acetate/MeOH 1:1). Column chromatography (eluent: gradi-
ent ethyl acetate/MeOH 100:0 to 85:15) gave pure 18i (21.3 mg;
62%) as a light pink oil; Rf¼0.61 (ethyl acetate/MeOH 1:1); 1H NMR
(KBr):
n
¼3416, 1639, 1523, 1160, 1051, 764, 698 cmꢂ1; HRMS: calcd
for C17H23N2O2S [MþH]þ 319.1475, found 319.1471.
5.10.13. (Z)-Ethyl
2-(3-(3-(benzylamino)propyl)-5-methylthiazol-
2(3H)-ylidene)acetate (19d). Compound 19d was obtained from
13b (22.8 mg; 0.07 mmol) and NaBH4 (46.0 mg; 1.22 mmol;
18.7 equiv) in EtOH (2.0 mL) according to general procedure (re-
duction time 30 min, TLC: ethyl acetate). Column chromatography
(eluent: gradient petrolether/ethyl acetate 50:50 to 0:100) gave
pure 19d (16.9 mg; 78%) as a colorless oil; Rf¼0.36 (ethyl acetate/
(500 MHz, CDCl3):
d
1.26 (t, J¼7.0 Hz, 3H, CH3), 1.59e1.72 (m, 2H,
CH2CH2CH2), 2.07 (s, 1H, NH), 2.76 (dd, J1¼11.0 Hz, J2¼7.5 Hz, 1H,
CHHS), 2.83e2.89 (m, 1H, CHHNH), 3.10 (ddd, J1¼J2¼12.5 Hz,
J3¼3.5 Hz, 1H, CHHNH), 3.21e3.22 (m, 1H NCHH), 3.24 (dd,
J1¼11.0 Hz, J2¼6.5 Hz, 1H, CHHS), 3.74e3.77 (m, 1H NCHH), 4.15 (q,
J¼7.0 Hz, 2H, CH2O), 4.42 (dd, J1¼7.5 Hz, J2¼6.5 Hz, 1H, NHCHN),
EtOH 1:1); 1H NMR (200 MHz, CDCl3):
d
1.28 (t, J¼7.4 Hz, 3H,
CH3CH2), 1.77e1.90 (m, 2H, CH2CH2CH2), 2.11 (d, J¼1.4 Hz, 3H,
CH3C), 2.62 (t, J¼6.4 Hz, 2H, CH2NHBn), 3.74 (t, J¼6.8 Hz, 2H, NCH2),
3.77 (s, 2H, CH2Ph), 4.18 (q, J¼7.4 Hz, 2H, CH2O), 5.00 (s, 1H, ]CH),
4.96 (s, 1H, ]CH); 13C NMR (125 MHz, CDCl3):
d 14.6 (CH3), 20.6
(CH2CH2CH2), 32.7 (CH2S), 44.6 (CH2NH), 45.7 (NCH2), 59.2 (CH2O),

ꢀ
9554
M. Stojanovic et al. / Tetrahedron 67 (2011) 9541e9554
6.23 (d, J¼1.4 Hz, 1H, ]CHN), 7.25e7.33 (m, 5H, Ph); 13C NMR
ꢀ
ꢀ
11. (a) Markovic, R.; Baranac, M.; Steel, P.; Kleinpeter, E.; Stojanovic, M. Heterocycles
ꢀ
ꢀ
2005, 65, 2635; (b) Markovic, R.; Baranac, M.; Stojanovic, M. Synlett 2004, 1034.
12. For a selected literature on pushepull alkenes, see: (a) Rattananakin, P.; Pitt-
man, C. R., Jr.; Collier, W. E.; Saebø, S. Struct. Chem. 2007, 18, 399; (b) Kleinpeter,
E. J. Serb. Chem. Soc. 2006, 71, 1; (c) Kleinpeter, E.; Klod, S.; Rudorf, W.-D. J. Org.
(50 MHz, CDCl3):
d 11.9 (CH3C), 14.8 (CH3CH2), 27.5 (CH2CH2CH2),
45.5 (CH2NHBn), 46.1 (NCH2), 53.9 (CH2Ph), 58.7 (CH2O), 74.4 (]
CH), 117.1 (]CS), 124.8 (]CHN), 127.0 (p-Ph), 128.2 (o-Ph), 128.4
€
Chem. 2004, 69, 4317; (d) Sandstrom, J. Top. Stereochem. 1983, 14, 83.
(m-Ph), 140.2 (C1Ph), 162.6 (C]), 167.0 (CO); IR (KBr):
n
¼3310, 1641,
13. NaBH4 does not reduce esters under ambient conditions. Such reduction is
possible under reflux conditions or by enhancing its reactivity by the addition
of certain additives. For examples, with additives, see: (a) Periasami, M.;
Thirumalaikumar, M. J. Organomet. Chem. 2000, 609, 137; (b) Prasad, A. B. S.;
Kanth, J. V. B.; Periassamy, M. Tetrahedron 1992, 48, 4623; (c) Yamakawa, T.;
Masaki, M.; Nohira, H. Bull. Chem. Soc. Jpn. 1991, 64, 2730 For examples, of using
reflux temperature, see: (d) da Costa, J. C. S.; Pais, K. C.; Fernandes, E. L.; de
Oliveira, P. S. M.; Mendonc¸ a, J. S.; de Souza, M. V. N.; Peralta, M. A.; Vasconcelos,
T. R. A. Arkivoc 2006, i, 128; (e) Boechat, N.; da Costa, J. C. S.; Mendonc¸ a, J. S.; de
Oliveira, P. S. M.; de Souza, M. V. N. Tetrahedron Lett. 2004, 45, 6021; (f) Bachi,
M. O.; Breiman, R.; Meshulam, H. J. Org. Chem. 1983, 48, 1439 and Ref 11 in the
present paper. Reduction of an ester at rt is possible without any additive if
a substrate contains hydroxy or keto group in the vicinity of the ester function.
These groups can complex with NaBH4 thereby activating it. For examples, see:
(g) Patra, A.; Batra, S.; Bhaduri, A. P. Synlett 2003, 1611; (h) Kim, J.; De Castro, K.
A.; Lim, M.; Rhee, H. Tetrahedron 2010, 66, 3995.
1525, 1381, 1164, 1139, 737, 699 cmꢂ1; HRMS: calcd for C18H25N2O2S
[MþH]þ 333.1631, found 333,1627.
5.10.14. (Z)-Ethyl 2-(3-(4-aminobutyl)thiazol-2(3H)-ylidene)acetate
(19e). Compound 19e was obtained from 15c (38.9 mg; 0.15 mmol)
and NaBH4 (87.0 mg; 2.3 mmol; 14.4 equiv) in EtOH (3.5 mL)
according to general procedure (reduction time 30 min, TLC: ethyl
acetate/MeOH 4:1). Column chromatography (eluent: gradient
ethyl acetate/MeOH 100:0 to 0:100) gave pure 19e (27.8 mg; 72%) as
a
white solid; Rf¼0.08 (ethyl acetate/MeOH 1:1); 1H NMR
(200 MHz, DMSO-d6):
d
1.17 (t, J¼7.2 Hz, 3H, CH3), 1.32e1.51 (m, 2H,
CH2CH2NH2), 1.55e1.68 (m, 2H, NCH2CH2), 1.72 (s, 2H, NH2),
2.58e2.64 (t, 2H, CH2NH2), 3.79 (t, J¼6.8 Hz, 2H, NCH2), 4.01 (q,
J¼7.2 Hz, 2H, CH2O), 5.05 (br s, 1H, ]CHCO2Et), 6.57 (d, J¼4.4 Hz,
1H, ]CHS), 7.14 (d, J¼4.4 Hz,1H, ]CHN); 13C NMR (50 MHz, DMSO-
ꢀ
ꢀ
ꢂ
14. (a) Markovic, R.; Baranac, M.; Jovanovic, V.; Dzambaski, Z. J. Chem. Educ. 2004,
ꢀ
ꢂ
ꢀ
81, 1026; (b) Markovic, R.; Baranac, M.; Dzambaski, Z.; Stojanovic, M.; Steel, P. J.
Tetrahedron 2003, 59, 7803 The synthesis of 7a and 7b was not published
previously, by us.
15. For the determination of configuration around the carbonecarbon double bond
d6):
d 15.0 (CH3), 24.6 (NCH2CH2), 28.4 (CH2CH2NH2), 40.4
ꢀ
in these and similar compounds, and isomerization studies, see: (a) Markovic,
R.; Baranac, M.; Juranic, N.; Macura, S.; Cekic, I.; Minic, D. J. Mol. Struct. 2006,
800, 85; (b) Markovic, R.; Shirazi, A.; Dzambaski, Z.; Baranac, M.; Minic, D. J.
Phys. Org. Chem. 2004, 17, 118; (c) Markovic, R.; Dzambaski, Z.; Baranac, M.
Tetrahedron 2001, 57, 5833; (d) Markovic, R.; Baranac, M. Heterocycles 1998, 48,
893 and Ref 14 in the present paper.
(CH2NH2), 47.9 (NCH2), 58.0 (CH2O), 74.5 (]CHCO2Et), 104.6 (]
CHS), 130.5 (]CHN), 161.9 (C]), 168.0 (CO); HRMS: calcd for
C11H19N2O2S [MþH]þ 243.1167, found 243.1172.
ꢀ
ꢀ
ꢀ
ꢀ
ꢂ
ꢀ
ꢀ
ꢂ
ꢀ
ꢀ
16. Some endo-mode cyclizations have been communicated: Stojanovic, M.;
Acknowledgements
ꢀ
Markovic, R. Synlett 2009, 1997.
17. Geluk, H. V.; Schlatmann, J. L. M. A. Tetrahedron 1968, 24, 5361.
This work was supported by the Ministry of Science of the Re-
public of Serbia, Grant No. 142007 (to R.M.), and Deutscher Aka-
demischer Austauschdienst (DAAD)dproject ID: 504 252 70.
18. Zheng, T.-C.; Burkart, M.; Richardson, D. E. Tetrahedron Lett. 1999, 40, 603.
19. Van Maarseveen, J. H.; Scheeren, H. W.; Kruse, C. G. Tetrahedron 1993, 49, 2325.
20. Yu, M. S.; Lantos, I.; Peng, Z.-Q.; Yu, J.; Cacchio, T. Tetrahedron Lett. 2000, 41, 5647.
ꢀ
21. (a) Marco-Contelles, J.; Rodrígues-Fernandes, M. J. Org. Chem. 2001, 66, 3717; (b)
Alvarez, S. G.; Alvarez, M. T. Synthesis 1997, 413.
22. Pal, B.; Jaisankar, P.; Giri, V. S. Synth. Commun. 2004, 34, 1317.
23. Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N. Tetrahedron 1975, 31, 1437.
24. Similar dehydration, which slows down or completely blocks the cyclization,
has also been observed in reactions starting from imidazolidin-2-ones and
thiazolidin-2-ones as iminium ion precursors. For examples, see: (a) Liao, Z. K.;
Kohn, K. J. Org. Chem. 1984, 49, 4745; (b) Kohn, K.; Liao, Z. K. J. Org. Chem. 1982,
47, 2787 and Refs. 6b and 6c in the present paper.
25. Baranac-Stojanovic, M.; Kleinpeter, E. J. Org. Chem. 2011, 76, 3861.
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Phys. Rev. B: Condens. Matter 1988, 37, 785.
Supplementary data
X, Y, Z Coordinates of optimized structures of products, in-
termediates, ground states, and transition states. Supplementary
data associated with this article can be found in the online version
at doi:10.1016/j.tet.2011.10.011.
ꢀ
27. (a) Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J. Chem. Phys. Lett. 1996, 255, 327;
(b) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106, 5151.
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