π-Annulation reactions of 4-thiazolidinone enaminones in the synthesis of fused bi- and tri-cyclic compounds

Article abstract of DOI:10.1016/j.tet.2012.09.080

The α-C position in 4-oxo thiazolidinones functions as one of the three possible nucleophilic sites in these molecules. We used the inherent reactivity of α-C of the exocyclic double bond (a so called push pull system) to obtain bicyclic fused thiazolidin

Full text of DOI:10.1016/j.tet.2012.09.080

Tetrahedron 68 (2012) 9556e9565
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p
-Annulation reactions of 4-thiazolidinone enaminones in the synthesis of fused
bi- and tri-cyclic compounds
,
a
,
*
ꢀ ꢁ a
ꢀ
ꢀ ꢁ b
ꢁ c
*
Bojan P. Bondzic , Zdravko Dzambaski , Aleksandra M. Bondzic , Rade Markovic
a Center for Chemistry ICTM, University of Belgrade, P.O. Box 815, 11000 Belgrade, Serbia
b Vinca Institute of Nuclear Sciences, University of Belgrade, Belgrade, Serbia
c Faculty of Chemistry, University of Belgrade, Studentski trg 16, P.O. Box 16, 11001 Belgrade, Serbia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 May 2012
Received in revised form 28 August 2012
Accepted 17 September 2012
Available online 23 September 2012
The
molecules. We used the inherent reactivity of
system) to obtain bicyclic fused thiazolidinones via
conditions to selectively activate this position and secondary nitrogen towards N,
found. Furthermore, the intramolecular vinylogous iminium ion 6-exo-trig cyclization was used to access
a
-C position in 4-oxo thiazolidinones functions as one of the three possible nucleophilic sites in these
-C of the exocyclic double bond (a so called push pull
-annulation cyclization. Appropriate reaction
-annulation were
a
p
p
fused bicyclic precursors for the
stereoselectively.
p
-annulation in order to obtain the novel tricyclic structures
Keywords:
Thiazolidinones
Ó 2012 Elsevier Ltd. All rights reserved.
p-Annulation
Iminium cyclizations
Enaminones
Pushepull olefins
1. Introduction
and N-acylation.3 Annulations of heterocyclic ketene aminals of
type 1 in reactions with bis electrophiles (Eq. 1, Fig. 1), such as
a
,
b
b
-
-
Compounds of type 1, which contain the
b-enamino moiety
unsaturated carbonyl compounds (acid derivatives, aldehydes),
(Fig. 1) possess highly polarized double bonds with the increased
electron density at the -carbon atom (so called ‘pushepull’ effect).
Accordingly, the nucleophilicity of heterocyclic -enamines is en-
ketoesters and derivatives,4 and dihaloalkanes5 are known to pro-
a
ceed efficiently and under mild reaction conditions. We turned our
attention to the N,p-annulation reactions of this type with com-
b
hanced, allowing the introduction of various electrophiles at
a
-
pounds 2 (4-thiazolidinones).6 Their polyfunctional nature, the
stereogenic centre at the C-5 position of the thiazolidine ring, the
cis-configured eSeC]CeC]O moiety and the Z/E geometry of the
exocyclic C]C bond with incorporated electron-donors and
electron-acceptors, are essential structural features of these com-
pounds. There is considerable interest in synthetically and naturally
occurring thiazolidinones of this type due to their broad range of
biological activity. Among others they are active as aldosereductase
inhibitors,7 anticonvulsants,8 antibacterials,9 anticancer agents,10
SHP-2 inhibitors,11 antitusics,12 antiinflamatory agents,13 calcium
channel blockers,14 dipeptidylpeptidase IV inhibitors,15 etc.16
However, to the best of our knowledge few reactions are pub-
lished where 4-oxo thiazolidinones of type 2 were functionalized at
position.1 One of the most interesting features of these heterocyclic
enamines is their ambident nucleophilicity; nucleophilic reactions
can take place at the site of enaminic
a-carbon and/or the sec-
ondary amino nitrogen. Hence, the secondary amino group in the
molecule can also participate in reactions, such as N-alkylation2
X
X
S
X
α
EWG
EWG
EWG
1
EWG
n
( )
β
O
α
N
H
α
N
N
N
H
H
2
1
n
X = N, C, O, S
EWG = CO2Et, CN, COPh, CONHPh
a
-position of the enamine fragment.17 One of the reasons lies in the
regioselectivity problems imposed by the nucleophilic nature of the
position C-5, adjacent to the 4-oxo group.18 This position represents
another nucleophilic site in addition to the secondary nitrogen and
Fig. 1. Structures and reactivities of parent compounds.
a
-carbon of the exocyclic double bond. In addition, the 4-oxo group
lowers the electron density at the -carbon and hence, the re-
activity of this position towards electrophiles is decreased. Since
* Corresponding authors. Tel.: þ381 11 3336 741; fax: þ381 11 636 061; e-mail
a
ꢀ ꢁ
addresses: bbondzic@chem.bg.ac.rs (B.P. Bondzic), markovic@helix.chem.bg.ac.rs
ꢁ
(R. Markovic).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.080

ꢀ ꢁ
B.P. Bondzic et al. / Tetrahedron 68 (2012) 9556e9565
9557
the chemical shifts of both dH and dC approximately reflect the
electron density at the -carbon, they can be used as a parameter to
correlate the nucleophilicity of this nuclei.4a,19 In the presence of
a 4-oxo group chemical shifts of the vinyl proton and the -carbon
tested. In the presence of 2 equiv of pyridine the reaction pro-
ceeds similarly as without additive and 40% of the product was
isolated (Table 1, entry 6). The reaction proceeds in the presence
of 2 equiv NaH. After heating at 80 ꢀC for 30 h the substrate was
fully consumed and product was isolated in 35% yield (Table 1,
entry 7).
a
a
are shifted downfield, i.e., electron density at
a-C and reactivity
towards electrophiles is decreased compared to compounds 1.20
In this case, in addition to desired product, multiple unidentified
products were observed. The best results were obtained in the
presence of 30 mol % KI as an additive when 65% of the product was
isolated after 40 h of reaction at 120 ꢀC (Table 1, entry 8). After
optimal conditions were found the generality of the reaction was
investigated and results are summarized in Table 2. As already
discussed when R1¼Me and EWG¼ethoxycarbonyl, the desired
product was obtained in 65% yield after 40 h of the reaction (Table
2. Results and discussion
In accordance with Eq.1 (Fig.1) we first attempted bis-alkylation
of compound 2a (EWG¼CO2Et) with 1,3-dibromopropane in the
presence of the strong base (NaH, 3 equiv). However, mixtures of
products of C-5 alkylation and N-alkylation were obtained. No al-
kylation at a-C atom has been observed.
Alkylation of imidazoline enaminoesters of type 1 in the pres-
ence of the same biselectrophile and the strong base lead to sub-
sequent a
-C and N-alkylations leading to a ring closure.5 Hence, we
Table 2
Generality of the cyclization reactiona
envisaged using compounds 3, possessing an internal electrophile
attached by a tether to the secondary nitrogen, as the precursor for
the synthesis of fused bicyclic systems (Scheme 1). The use of
a weak base, K2CO3, was crucial for the regioselective alkylation
reaction of 2 to form the exclusively N-alkylated products 3, in the
presence of 1.1 equiv of base and 5 equiv of biselectrophile. Based
on previous reports,21 N-alkylated test substrate 3a was submitted
Entry
1
Product
Solvent
DMF
Time/h
40
Yield/% b
65
to
p-annulation reaction in refluxing CH3CN without any base or
additive.
R
S
R
R
Br
Br
S
N
S
EWG
EWG
Br
n
EWG
O
O
N
O
N
H
2
2
3
4
5
6
DMF
DMF
DMF
DMF
DMF
48
30
48
48
48
52
63
64
70
56
n
n
4
3
R = H, Me, CH2CO2Et
EWG = CO2Et, COPh, CN, etc.
Scheme 1. Envisaged reaction pathway for the synthesis of fused thiazolidinones.
However, no reaction even after prolonged heating was ob-
served under these reaction conditions (Table 1, entry 1). The
same reaction run in refluxing toluene, EtOH or CHCl3 also gave
no product (Table 1, entries 2e4). However, heating in DMF at
elevated temperature (120 ꢀC) gave the desired product in 45%
yield alongside the product of hydrolysis of Br group to a formic
ester (Table 1, entry 5). To prevent this side reaction and increase
the yield of desired product several additives and bases were
Table 1
Reaction conditions screening
7
8
DMF
36
75
67
Entry
Solvent
Additive
T [ꢀC]
Time [h]
Yieldd [%]
1
2
3
4
5
6
7
8
CH3CN
Toluene
EtOH
CHCl3
DMF
DMF
DMF
DMF
None
None
None
None
None
Pyridinea
NaHb
KIc
80
110
80
48
72
48
48
48
48
30
40
/
/
DMF
DMF
48
48
<5
/
45
40
35
65
80
120
120
80
9
/
120
a
Pyridine (2 equiv) was used.
NaH (2 equiv) was used.
KI (30 mol %) was used.
b
c
a
Unless otherwise shown, reaction conditions: substrate
(30 mol %), DMF (0.5 mL) at 120 ꢀC for designated time.
3
(0.5 mmol), KI
d
b
Isolated yield of the product after column chromatography.
Isolated yield of the product after column chromatography.

ꢀ ꢁ
B.P. Bondzic et al. / Tetrahedron 68 (2012) 9556e9565
9558
2, entry 1). Substrate 3b having COPh as the EWG, was sluggish to
react and took a bit longer time to complete yielding 52% of the
desired product after 48 h of reaction. In addition, bromine was
hydrolyzed to formic ester, which most probably came from the
intramolecular cyclization to give the compounds 8. Compound 9
should be obtained under optimized -annulation conditions from 8.
p
To test this, regioselective Michael addition of thiazolidinone sub-
strates 3 to acrolein was used to access the C-5 functionalized com-
pounds 10 (Table 3). Reduction of aldehydes 10aed yields the
hydroxyethyl group at C-5 as an internal nucleophile. Next, lactam
reduction and acid promoted imine formation followed by sub-
sequentintramolecularadditionofhydroxyethyl grouptoimine takes
place to close the tetrahydropyran ring and give compound 11aed.
The synthetic utility of vinylogous iminium ions of this type for ring
closure reactions had previously been examined by our group.23
solvent (Table 2, entry 2). Based on the NMR shift of its a-proton, 3b
should be the least reactive substrate (see Supplementary data),
which indeed correlated with the chemical yield of the reaction.
When EWG was a phenyl- or phenylethyl-amide the desired
products were isolated in good yields of 63% and 64%, respectively
(Table 2, entries 3 and 4). The reaction with the former substrate
was faster and was finished within 30 h. Starting materials without
a substituent at C-5 and with CO2Et or COPh as the EWG gave the
desired products in good to moderate yields of 70% and 56%, re-
spectively (Table 2, entries 5 and 6). Finally when R1 was CH2CO2Et
group and the EWG was CO2Et (3g) or COPh (3h) good yields of 75%
and 67% were obtained, respectively. Again, reaction with substrate
3g was faster and finished within 36 h while substrate 3h took
longer time and was finished within 48 h. Slightly better yields
than in previous cases may be due to the increased lipophilicity of
obtained compounds and easier isolation on the silica gel columns.
Surprisingly, the starting material having nitrile group as EWG (3i)
did not undergo this reaction at all and starting material was re-
covered (Table 2, entry 9). All attempts to cyclize five and seven
membered rings from appropriate substrates failed under the ap-
plied reaction conditions. It was only possible to synthesize six
membered fused thiazolidinones as shown above.
Table 3
Synthesis of the cyclization precursors 11
It is important to note the significance of the sulfur atom in this
structural motif. Compound 5 (Fig. 2) obtained after mCPBA oxi-
dation of starting material 3a was totally unreactive in this type of
cyclization under the applied reaction conditions.
Entry Product Yielda
[%]
Product
Time Yielda cis/transb
[h]
[%]
Me
O
O
S
CO2Et
Br
N
1
2
3
10a
10b
10c
56
54
73
2
83
>99/1
>99/1
>99/1
5
Fig. 2. Structure of oxidized N-alkylthiazolidinone 5.
Oxidation decreased the electron-donating ability of sulfur
hence decreasing the reactivity of the a-C atom towards electro-
philes.22 To further explore this type of cyclization on more com-
plex system and in order to increase the reactivity of parent
2
3
85
70
compounds towards the
p-annulation reaction, we envisaged the
following reaction pathway as shown in Scheme 2.
R
R
R
S
R1
Br
1
S
S
β
α
R1
Br
a
b
n
n
R
O
Nu
O
N
Nu
N
N
H
Br
n
3
n
6
n
7
R
S
R
c
n
S
R1
Br
n
d
R1
n
N
N
4
10d
57
2
78
>99/1
H
H
n
9
8
a) C-5 functionalization; b) reduction, iminium ion formation;
c) cyclization; d) π-annulation
a
Isolated yield of the product after column chromatography.
b
Determined by the 1H NMR spectroscopy of the crude reaction mixture.
Scheme 2. Envisaged reaction scheme for the synthesis of tricyclic compounds.
The Michael addition to acrolein proceeded with moderate to
To increase the reactivity we planned to transform the poor elec-
tron donor lactam into a more electron rich moiety. Appropriate setof
reactions had to be chosen to give the access to cyclization precursor
6, which upon reduction to intermediate iminium 7 undergoes
good yields of 54e73% for all substrates 3aec, i (Table 3, entries
1e4). The crucial feature of the Michael addition was the use of
a catalytic amount of K2CO3 (0.1 equiv), higher or lower loadings led

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B.P. Bondzic et al. / Tetrahedron 68 (2012) 9556e9565
9559
to decreased yields of Michael adducts while the use of stronger
bases, such as NaH or KOH led to mixtures of inseparable products.
Unlike the case with heterocyclic ketene aminals of type 1,5 Michael
addition at C-5 is the only reaction pathway observed with our
the product in 75% yield. When EWG was COPh group or N-phe-
nylamide reactions were finished in 20 h and 16 h, respectively
(Table 4, entries 2 and 3) yielding 74% and 71% yield of the desired
product after the column chromatography. With the substrate 11d
having a nitrile moiety as its EWG the reaction proceeds very effi-
ciently to yield 83% of the desired cyclization product (Table 4,
entry 4), in this case reaction was finished within only 12 h.
Noteworthy, while the substrate 3i (Table 2, entry 9) with CN group
as the EWG was unreactive in this type of cyclization, after it was
transformed into fused thiazolidine 11d it became sufficiently re-
molecules in the presence of the a,b-unsaturated compound and
base. It is important to note that substrates without substituent at
position C-5 gave products of double Michael addition. On the other
hand, with the substrates having CH2CO2Et group at position C-5
Michael addition proceeds efficiently but reduction gives mixtures
of compounds as the ester group is reduced under the reaction
conditions. The 5-Me substituted thiazolidinones proved to be the
substrates of choice for this investigation. For the second step, i.e.,
reduction of 10 and subsequent 6-exo-trig cyclization of vinylogous
N-acyliminium ion to give 11, previously optimized conditions were
used.23a The vinylogous N-acyliminium ion 7, generated from 6,
was trapped by O-nucleophile to give energetically preferred24 cis-
fused bicyclic derivatives 11. Reduction of aldehydes 10aed is fin-
ished within approximately 1 h in the presence of large excess of
NaBH4 (10 equiv), while reduction of lactam requires adding dilute
HCl into the reaction mixture.
active for p-annulation to take place. Cyclization to five and seven
membered rings was attempted with appropriate substrates as
well, however, without success under the applied reaction
conditions.
3. Conclusions
In conclusion we have described an easy and efficient route for
the synthesis of bi- and tri-cyclic fused thiazolidinones and thia-
zolidines, respectively using
p-annulation reaction as a key step.
After completion of the reduction, addition of concentrated HCl
in the same reaction flask dehydrates hemiaminal to the imine and
promotes cyclization to a fused thiazolidino tetrahydopyrane ring
system 11aed. With all substrates reactions proceeded efficiently
and products 11aed were obtained in very good 70e85% yields as
exclusively cis adducts (Table 3).23 After the synthesis of precursors
Using the so called ‘pushepull’ character of the starting materials
as the basis for this type of reactivity we managed to synthesize
a variety of compounds. Experimental data have shown that 4-oxo
thiazolidinones of type 2 with exocyclic enamine fragment are less
reactive towards a-C functionalizations compared to compounds
of type 1. The control of regioselectivity in alkylation and Michael
additions has been successfully achieved by the appropriate choice
of reaction conditions. We have also demonstrated the ability of
vinylogous N-acyliminium ions of type 7 possessing the hydrox-
yethyl group as an internal nucleophile to participate in a hetero-
cyclization reaction, that is, as one would anticipate, strongly
driven by the presence of various electron-withdrawing groups at
11aed, previously optimized conditions were applied for the
p-
annulation reaction in order to obtain the fused tricyclic (6, 5, 6)-
membered systems. Indeed, in these cases with more reactive
substrates, a temperature of 100 ꢀC was sufficient for reaction to
proceed to completion (Table 4). When EWG was CO2Et (Table 4,
entry 1) the reaction proceeded smoothly at 100 ꢀC for 16 h to yield
the
a
-position of the C]C bond. These substrates were success-
-annulation reaction to yield novel and syn-
fully submitted to
p
thetically interesting fused tricyclic structures of potential
biological activity.
Table 4
Generality of the cyclization reactiona
4. Experimental section
4.1. General
All reactions were carried out under normal atmosphere and
monitored by thin layer chromatography using Merck 60 F254
precoated silica gel plates (0.25 mm thickness). FT-IR spectra were
Entry
1
Product
Solvent
DMF
Time [h]
16
Yieldb [%]
75
cis/transc
recorded on a PerkineElmer FT-IR 1725X spectrometer. 1H and 13
C
NMR spectra were recorded on a Varian Gemini 2000 instrument
(1H at 200 MHz, 13C at 50.3 MHz) and Brucker AM400 (400 MHz)
99/1
instrument. Data for 1H NMR are reported as chemical shift
d (parts
per million) downfield from TMS as an internal standard, multi-
plicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br
s¼broad singlet), coupling constant (hertz), integration and as-
signment. Data for 13C NMR are reported as chemical shift. High-
resolution mass spectral analyses (HRMS) were carried out using
a MS system consisted of 6210 Time-of-Flight LC/MS (G1969A,
Agilent Technologies), samples dissolved in mobile phase were
introduced via 1200 Series HPLC system (Agilent Technologies).
Melting points (mp) were determined on a Stuart SMP10 in-
strument and are uncorrected. Flash column chromatography was
2
3
DMF
DMF
DMF
20
16
12
74
71
83
99/1
99/1
99/1
ꢂ
performed on silica gel (60 A, 12e26, ICN Biomedical).
4
4.2. General procedure for the N-alkylation of 4-
oxothiazolidine derivatives
a
Unless otherwise shown, reaction conditions: substrate 11 (0.5 mmol), KI
To a stirred solution of 4-oxothiazolidine derivative (1) (2 mmol)
in a dry DMF (4e5 mL) was added anhydrous K2CO3 (2.1 mmol). The
mixture was stirred for 1 h at room temperature and excess of 1,3-
(30 mol %), DMF (0.5 mL) at 100 ꢀC for designated time.
b
Isolated yield of the product after column chromatography.
c
Determined by 1H spectroscopy of the crude mixture.

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B.P. Bondzic et al. / Tetrahedron 68 (2012) 9556e9565
9560
dibromopropane (10 mmol) was then added in one portion. The
progress of reaction was followed by TLC. The reaction mixture was
stirred for additional 2e4 h, and the reaction mixture was neutral-
ized with satd NH4Cl solution. The aqueous phase was extracted
with chloroform (3ꢁ) and the organic layer was washed with water
(3ꢁ) and brine solution (1ꢁ) and dried over Na2SO4. The solvent was
removed under reduced pressure and the crude product was puri-
fied by column chromatography (silica-gel, hexane/ethyl acetate
gradient) to afford 3-bromopropyl-4-oxothiazolidine derivative.
followed with (Z)-2-(5-methyl-4-oxothiazolidin-2-ylidene)-N-
phenethylacetamide (552 mg, 2.00 mmol), K2CO3 (290 mg,
2.10 mmol) and 1,3-dibromopropane (2.01 g, 1.01 mL, 10.00 mmol).
Flash column chromatography (Hexane/EtOAc gradient: 0%e30%
EtOAc) of the crude mixture gave the title compound (556 mg, 70%)
as yellowish crystals. Mp 107e109 ꢀC; 1H NMR (500 MHz, CDCl3)
d
7.34e7.16 (m, 5H, Ph), 5.54 (s, 1H, NH), 5.47 (s, 1H, ]CH), 3.83 (q,
J¼7.2 Hz, 1H, CH), 3.77 (t, J¼7.2 Hz, 2H, NCH2), 3.64e3.52 (m, 2H,
NHCH2), 3.41 (t, J¼6.3 Hz, 2H, CH2Br), 2.86 (t, J¼7.0 Hz, 2H, CH2Ph),
2.19e2.11 (m, 2H, CH2), 1.58 (d, J¼7.2 Hz, 3H, CH3); 13C NMR
(126 MHz, CDCl3) 175.7 (COlactam), 166.7 (COamide), 152.6 (]C(C2)),
138.9 (C1-Ph), 128.7 (m-Ph), 128.6 (o-Ph), 126.4 (p-Ph), 92.2 (]
CH(C20)), 41.9 (NCH2), 40.6 and 40.1 (CH and NHCH2), 35.9 (CH2Ph),
4.2.1. (Z)-Ethyl 2-(3-(3-bromopropyl)-5-methyl-4-oxothiazolidin-2-
ylidene)acetate (3a). The general procedure was followed with (Z)-
ethyl 2-(5-methyl-4-oxothiazolidin-2-ylidene)acetate (402 mg,
2.00 mmol), K2CO3 (290 mg, 2.10 mmol) and 1,3-dibromopropane
(2.01 g, 1.01 mL, 10.00 mmol). Flash column chromatography (Hex-
ane/EtOAc gradient: 0%e30% EtOAc) of the crude mixture gave the
title compound (458 mg, 72%) as white crystals. Mp 106e107 ꢀC; 1H
30.2 and 29.5 (CH2Br and CH2), 19.1 (CH3); IR (neat): n
[cmꢂ1] 3306,
3062, 3029, 2932, 2868, 1712, 1644, 1575, 1451, 1406, 1327, 1232,
1203, 1152, 741; HRMS: m/z (ESI) calcd for [C17H22BrN2O2S]
(MþHþ): 397.0580, found 395.0577.
NMR (500 MHz, CDCl3)
d
5.55 (s, 1H, ]CH), 4.22 (q, J¼7.1 Hz, 2H,
OCH2), 3.89 (q, J¼7.2 Hz,1H, CH), 3.82 (t, J¼6.4 Hz, 2H, NCH2), 3.41 (t,
J¼6.4 Hz, 2H, CH2Br), 2.18 (tt, J¼6.4, 6.4 Hz, 2H, CH2),1.61 (d, J¼7.2 Hz,
3H, CH3CH), 1.30 (t, J¼7.1 Hz, 3H, CH3); 13C NMR (126 MHz, CDCl3)
4.2.5. (Z)-Ethyl 2-(3-(3-bromopropyl)-4-oxothiazolidin-2-ylidene)
acetate (3e). The general procedure was followed with (Z)-ethyl 2-
(4-oxothiazolidin-2-ylidene)acetate (374 mg, 2.00 mmol), K2CO3
(290 mg, 2.10 mmol) and 1,3-dibromopropane (2.01 g, 1.01 mL,
10 mmol). Flash column chromatography (Hexane/EtOAc gradient:
0%e30% EtOAc) of the crude mixture gave the title compound
(579 mg, 94%) as white crystals. Mp 78e80 ꢀC; 1H NMR (200 MHz,
d
175.7 (COlactam), 167.6 (COester), 156.2 (]C(C2)), 90.2 (]CH(C20)),
60.1 (OCH2), 42.3 (NCH2), 40.3 (CH), 29.6 (CH2Br), 29.4 (CH2), 19.1
(CH3CH), 14.4 (CH3CH2); IR (neat):
n
[cmꢂ1] 2979, 2932, 2870, 1713,
1687, 1574, 1453, 1408, 1349, 1307, 1172, 1144, 1091; HRMS: m/z (ESI)
calcd for ½C11H1779BrNO3Sꢃ (MþHþ): 322.0107, found 322.0106.
CDCl3)
d
5.57 (s, 1H, ]CH), 4.22 (q, J¼7.1 Hz, 2H, OCH2), 3.83 (t,
J¼7.1 Hz, 2H, NCH2), 3.72 (s, 2H, CH2(C5)), 3.43 (t, J¼6.4 Hz, 2H,
4.2.2. (Z)-3-(3-Bromopropyl)-5-methyl-2-(2-oxo-2-phenyl
ethyl-
CH2Br), 2.30e2.08 (m, 2H, CH2), 1.31 (t, J¼7.1 Hz, 3H, CH3); 13C NMR
idene) thiazolidin-4-one (3b). The general procedure was followed
with (Z)-5-methyl-2-(2-oxo-2-phenylethylidene)thiazolidin-4-one
(466 mg, 2.00 mmol), K2CO3 (290 mg, 2.10 mmol) and 1,3-
dibromopropane (2.01 g, 1.01 mL, 10 mmol). Flash column chroma-
tography (Hexane/EtOAc gradient: 0%e30% EtOAc) of the crude
mixture gave the title compound (390 mg, 55%) as grayish crystals.
(50 MHz, CDCl3) d 172.5 (COlactam), 167.6 (COester), 157.6 (]C(C2)),
90.6 (]CH(C20)), 60.1 (OCH2), 42.2 (NCH2), 31.6 (CH2(C5)), 29.6
(CH2Br), 29.3 (CH2), 14.3 (CH3); IR (neat):
n
[cmꢂ1] 2981, 2935, 1717,
1677, 1561, 1448, 1362, 1341, 1272, 1235, 1173, 1140, 1045, 793;
HRMS: m/z (ESI) calcd for ½C10H1579BrNO3Sꢃ (MþHþ): 307.9950,
found 307.9961.
Mp126e127 ꢀC;1HNMR (500 MHz, CDCl3)
d 8.00e7.95 (m, 2H, o-Ph),
7.58e7.51 (m, 1H, p-Ph), 7.50e7.43 (m, 2H, m-Ph), 6.87 (s, 1H, ]CH),
3.99 (t, J¼7.5 Hz, 2H, NCH2), 3.88 (q, J¼7.3 Hz, 2H, CH), 3.50 (t,
J¼6.1 Hz, 2H, CH2Br), 2.27 (tt, J¼7.5, 6.1 Hz, 2H, CH2),1.64 (d, J¼7.3 Hz,
4.2.6. (Z)-3-(3-Bromopropyl)-2-(2-oxo-2-phenylethylidene)-thiazo-
lidin-4-one (3f). The general procedure was followed with (Z)-2-(2-
oxo-2-phenylethylidene)thiazolidin-4-one (438 mg, 2.00 mmol),
K2CO3 (290 mg, 2.10 mmol) and 1,3-dibromopropane (2.01 g,
1.01 mL, 10 mmol). Flash column chromatography (Hexane/EtOAc
gradient: 0%e30% EtOAc) of the crude mixture gave the title com-
pound (395 mg, 58%) as yellow crystals. Mp 125e126 ꢀC; 1H NMR
3H, CH3); 13C NMR (126 MHz, CDCl3)
d 188.6 (COketone), 176.2 (COlac-
tam), 159.4 (]C(C2)), 138.4 (C1-Ph), 132.2 (p-Ph), 128.6 (m-Ph), 127.6
(o-Ph), 95.3 (]CH(C20)), 42.3 (NCH2), 40.1 (CH), 30.3 and 29.5 (CH2Br
and CH2), 18.7 (CH3); IR (neat): n
[cmꢂ1] 3057, 2928, 2364,1716,1631,
1576,1515,1451,1346,1229,1151,1055, 764; HRMS: m/z (ESI) calcd for
(500 MHz, CDCl3) d 8.02e7.93 (m, 2H, o-Ph), 7.57e7.51 (m, 1H, p-
½C15H1779BrNO2Sꢃ (MþHþ): 354.0158, found 354.0149.
Ph), 7.50e7.44 (m, 2H, m-Ph), 6.89 (s, 1H, ]CH), 3.99 (t, J¼7.0 Hz,
2H, NCH2), 3.72 (s, 2H, CH2(C5)), 3.51 (t, J¼6.1 Hz, 2H, CH2Br), 2.27
4.2.3. (Z)-2-(3-(3-Bromopropyl)-5-methyl-4-oxothiazolidin-2-yli-
dene)-N-phenylacetamide (3c). The general procedure was fol-
(tt, J¼7.0, 6.1 Hz, 2H, CH2); 13C NMR (126 MHz, CDCl3)
d 188.8
(COketone), 173.1 (COlactam), 160.9 (]C(C2)), 138.4 (C1-Ph), 132.5 (p-
lowed
with
(Z)-2-(5-methyl-4-oxothiazolidin-2-ylidene)-N-
Ph), 128.8 (m-Ph), 127.7 (o-Ph), 95.8 (]CH(C20)), 42.4 (NCH2), 31.8
phenylacetamide (498 mg, 2.00 mmol), K2CO3 (290 mg, 2.10 mmol)
and 1,3-dibromopropane (2.01 g, 1.01 mL, 10 mmol). Flash column
chromatography (Hexane/EtOAc gradient: 0%e50% EtOAc) of the
crude mixture gave the title compound (532 mg, 72%) as yellowish
(CH2(C5)), 30.5 and 29.6 (CH2Br and CH2); IR (neat): n
[cmꢂ1] 3061,
2964, 2927, 2856,1711, 1627,1574,1521,1347,1229,1185,1149,1082,
1058; HRMS: m/z (ESI) calcd for ½C14H1579BrNO2Sꢃ (MþHþ):
314.0001, found 314.0010.
crystals. Mp 112e114 ꢀC; 1H NMR (200 MHz, CDCl3)
d 7.62 (s, 1H,
NH), 7.53 (d, J¼8.0 Hz, 2H, o-Ph), 7.29 (t, J¼7.9 Hz, 2H, m-Ph), 7.08 (t,
J¼7.3 Hz, 1H, p-Ph), 5.75 (s, 1H, ]CH), 3.83 (t, J¼7.0 Hz, 2H, NCH2),
3.81 (q, J¼7.2 Hz, 1H, CH), 3.41 (t, J¼6.3 Hz, 2H, CH2Br), 2.33e2.07
(m, 2H, CH2), 1.58 (d, J¼7.2 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3)
4.2.7. (Z)-Ethyl-2-(3-(3-bromopropyl)-2-(2-ethoxy-2-oxo
ethyl-
idene)-4-oxothiazolidin-5-yl)acetate (3g). The general procedure
was followed with (Z)-ethyl 2-(5-(2-ethoxy-2-oxoethyl)-4-
oxothiazolidin-2-ylidene)acetate (546 mg, 2.00 mmol), K2CO3
(290 mg, 2.10 mmol) and 1,3-dibromopropane (2.01 g, 1.01 mL,
10 mmol). Flash column chromatography (Hexane/EtOAc gradient:
0%e30% EtOAc) of the crude mixture gave the title compound
(573 mg, 73%) as white crystals. Mp 88e90 ꢀC; 1H NMR (500 MHz,
d
175.7 (COlactam), 165.3 (COamide), 154.3 (]C(C2)), 138.1 (C1-Ph),
128.9 (m-Ph), 124.1 (p-Ph), 119.8 (o-Ph), 92.6 (]CH(C20)), 42.1
(NCH2), 40.1 (CH), 30.1 and 29.5 (CH2Br and CH2), 19.0 (CH3); IR
(neat):
n
[cmꢂ1] 3306, 3062, 3029, 2932, 2868, 1712, 1644, 1575,
1451, 1406, 1327, 1232, 1203, 1152, 741; HRMS: m/z (ESI) calcd for
CDCl3)
d
5.57 (s, 1H, ]CH), 4.21 (q, J¼7.1 Hz, 2H, OCH2), 4.19e4.12
½C17H2279BrN2O2Sꢃ (MþHþ): 397.0580, found 395.0577.
(m, 3H, OCH2 and CHxS), 3.84 (m, 2H, NCH2), 3.44 (t, J¼6.5 Hz, 2H,
CH2Br), 3.10 (dd, J¼17.4, 3.9 Hz, 1H, CHAHBCOO), 2.94 (dd, J¼17.4,
8.0 Hz, 1H, CHAHBCOO), 2.24e2.18 (m, 2H, CH2CH2Br), 1.30 (t,
J¼7.1 Hz, 3H, CH3), 1.26 (t, J¼7.1 Hz, 3H, CH3); 13C NMR (126 MHz,
4.2.4. (Z)-2-(3-(3-Bromopropyl)-5-methyl-4-oxothiazolidin-2-
ylidene)-N-phenethylacetamide (3d). The general procedure was

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9561
CDCl3)
d
174.1 (COlactam), 169.6 (COester), 167.6 (COester), 156.5 (]
J¼7.0 Hz, 2H, OCH2), 3.88 (q, J¼7.1 Hz, 1H, CH), 3.79e3.47 (m, 2H,
NCH2), 2.49 (t, J¼6.0 Hz, 2H, CH2C]), 2.08e1.78 (m, 2H, CH2), 1.60
(d, J¼7.1 Hz, 3H, CH3CH), 1.31 (t, J¼7.0 Hz, 3H, CH3); 13C NMR
C(C2)), 90.6 (]CH(C20)), 61.4 (OCH2), 60.1 (OCH2), 42.3 (NCH2), 41.5
(CH(C5)), 37.3 (CH2COO), 29.8 (CH2Br), 29.3 (CH2), 14.4 (CH3), 14.1
(CH3); IR (neat):
n
[cmꢂ1] 2980, 1721, 1686, 1572, 1449, 1371, 1344,
(50 MHz, CDCl3) d 174.9 (COlactam), 167.5 (COester), 148.6 (]C(C2)),
1307, 1239, 1178, 1139, 1040; HRMS: m/z (ESI) calcd for
100.5 (]C(C20)), 60.3 (OCH2), 42.2 (NCH2), 41.1 (CH), 23.0 (CH2C]),
½C14H2179BrNO5Sꢃ (MþHþ): 394.0318, found 394.0336.
19.9 (CH2), 19.0 (CH3CH), 14.4 (CH3); IR (neat):
n
[cmꢂ1] 3401, 2978,
2901, 1709, 1682, 1577, 1448, 1385, 1364, 1309, 1271, 1175, 11,360,
1025; HRMS: m/z (ESI) calcd for [C11H16NO3S] (MþHþ): 242.0845,
found 242.0845.
4.2.8. (Z)-Ethyl 2-(3-(3-bromopropyl)-4-oxo-2-(2-oxo-2-phenyl eth-
ylidene)thiazolidin-5-yl)acetate (3h). The general procedure was
followed with (Z)-ethyl 2-(4-oxo-2-(2-oxo-2-phenylethylidene)
thiazolidin-5-yl)acetate (610 mg, 2.00 mmol), K2CO3 (290 mg,
2.10 mmol) and 1,3-dibromopropane (2.01 g, 1.01 mL, 10 mmol).
Flash column chromatography (Hexane/EtOAc gradient: 0%e30%
EtOAc) of the crude mixture gave the title compound (537 mg, 63%)
4.3.2. 8-Benzoyl-2-methyl-6,7-dihydro-2H-thiazolo[3,2-a]pyridin-
3(5H)-one (4b). The general procedure was followed with (Z)-3-(3-
bromopropyl)-5-methyl-2-(2-oxo-2-phenyl ethylidene) thiazoli-
din-4-one (50 mg, 0.14 mmol) and KI (7.0 mg, 30 mol %). Flash
column chromatography (Hexane/EtOAc gradient: 0%e30% EtOAc)
of the crude mixture gave the title compound (20 mg, 52%) as
brownish crystals. Mp 93e95 ꢀC; 1H NMR (500 MHz, CDCl3)
as yellow crystals. Mp 100e101 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.97
(d, J¼7.3 Hz, 2H, o-Ph), 7.57e7.41 (m, 3H, m- and p-Ph), 6.88 (s, 1H,
]CH), 4.23e4.08 (m, 3H, OCH2 and CHxS), 4.07e3.90 (m, 2H),
3.56e3.48 (m, 2H, CH2Br), 3.10 (dd, J¼17.5, 4.0 Hz, 1H, CHAHBCOO),
3.00 (dd, J¼17.5, 7.5 Hz, 1H, CHAHBCOO), 2.37e2.21 (m, 2H,
CH2CH2Br), 1.25 (t, J¼7.1 Hz, 3H, CH3); 13C NMR (126 MHz, CDCl3)
d
7.56e7.50 (m, 2H, o-Ph), 7.49e7.39 (m, 3H, m- and p-Ph), 3.87 (q,
J¼7.3 Hz, 1H, CH), 3.73e3.70 (m, 2H, NCH2), 2.63 (m, 2H, CH2C]),
1.92e1.85 (m, 2H, CH2), 1.63 (d, J¼7.3 Hz, 3H, CH3); 13C NMR
d
188.4 (COketone), 174.5 (COlactam), 169.5 (COester), 159.6 (]C(C2)),
(126 MHz, CDCl3) d 194.2 (COketone), 175.6 (COlactam), 153.1 (]
138.1 (C1-Ph), 132.1 (p-Ph), 128.5 (m-Ph), 127.5 (o-Ph), 95.4 (]
C(C2)), 139.8 (C1-Ph), 130.5 (p-Ph), 128.1 (m-Ph), 127.4 (o-Ph), 107.6
CH(C20)), 61.3 (OCH2), 42.3 (NCH2), 41.1 (CH(C5)), 36.8 (CH2COO),
(]C(C20)), 42.7 (NCH2), 40.9 (CH), 26.7 (CH2C]), 20.6 (CH2), 18.5
30.5 (CH2Br), 29.3 (CH2), 14.0 (CH3); IR (neat):
n
[cmꢂ1] 3057, 2981,
(CH3); IR (neat): n
[cmꢂ1] 2932, 1710, 1622, 1575, 1500, 1385, 1320,
1721, 1628, 1574, 1511, 1350, 1227, 1186, 1149, 1058, 762; HRMS: m/z
(ESI) calcd for ½C18H2179BrNO4Sꢃ (MþHþ): 426.0369, found
426.0373.
1280, 1192, 993, 734; HRMS: m/z (ESI) calcd for [C12H16NO2S]
(MþHþ): 274.0896, found 274.0898.
4.3.3. 2-Methyl-3-oxo-N-phenyl-3,5,6,7-tetrahydro-2H-thiazolo [3,2-a]
4.2.9. (Z)-2-(3-(3-Bromopropyl)-5-methyl-4-oxothiazolidin-2-
ylidene)acetonitrile (3i). The general procedure was followed with
(Z)-2-(5-methyl-4-oxothiazolidin-2-ylidene)acetonitrile (308 mg,
2.00 mmol), K2CO3 (290 mg, 2.10 mmol) and 1,3-dibromopropane
(2.01 g, 1.01 mL, 10 mmol). Flash column chromatography (Hex-
ane/EtOAc gradient: 0%e30% EtOAc) of the crude mixture gave the
title compound (380 mg, 69%) as white crystals. Mp 92e96 ꢀC; 1H
pyridine-8-carboxamide (4c). The general procedure was followed
with
(Z)-2-(3-(3-bromopropyl)-5-methyl-4-oxothiazolidin-2-ylid-
ene)-N-phenylacetamide (50 mg, 0.13 mmol) and KI (7.0 mg,
30 mol %). Flash column chromatography (Hexane/EtOAc gradient:
0%e50% EtOAc) of the crude mixture gave the title compound (26 mg,
68%) as yellow crystals. Mp 93e94 ꢀC; 1H NMR (200 MHz, CDCl3)
d
7.53 (d, J¼8.0 Hz, 2H, o-Ph), 7.30 (t, 2H, m-Ph), 7.28 (s,1H, NH) 7.08 (t,
NMR (500 MHz, CDCl3)
d
4.88 (s, 1H, ]CH), 4.13 (q, J¼7.2 Hz, 1H,
J¼7.3 Hz, 1H, p-Ph), 3.83 (q, J¼7.2 Hz, 1H, CH), 3.75e3.58 (m, 2H,
NCH2), 2.52 (t, J¼6.1 Hz, 2H, CH2C]), 2.04e1.88 (m, 2H, CH2), 1.57 (d,
CH), 3.79 (t, J¼6.2 Hz, 2H, NCH2), 3.42 (t, J¼6.2 Hz, 2H, CH2Br), 2.16
(tt, J¼6.2, 6.2 Hz, 2H, CH2), 1.67 (d, J¼7.2 Hz, 3H, CH3); 13C NMR
J¼7.2 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3)
d 174.5 (COlactam), 165.5
(126 MHz, CDCl3)
d
174.6 (CO), 158.1 (]C(C2)), 116.4 (CN), 68.2 (]
(COamide), 147.7 (]C(C2)), 137.7 (C1-Ph), 128.8 (m-Ph), 124.1 (p-Ph),
CH(C20)), 42.1 and 42.0 (NCH2 and CH), 29.6 and 29.3 (CH2Br and
120.3 (o-Ph), 100.6 (]C(C20)), 41.5 (NCH2), 40.9 (CH), 23.1 (CH2C]),
CH2), 19.2 (CH3); IR (neat):
n
[cmꢂ1] 3416, 3079, 2994, 2948, 2203,
20.1 (CH2),18.8 (CH3); IR (neat): n
[cmꢂ1] 3363, 3057, 2932,1704,1649,
1719,1584, 1486, 1402,1315,1249, 1117, 1003; HRMS: m/z (ESI) calcd
for ½C9H1279BrN2OSꢃ (MþHþ): 274. 9854, found 274.9850.
1598, 1565, 1530, 1440, 1390, 1321, 1254, 1188; HRMS: m/z (ESI) calcd
for [C15H17N2O2S] (MþHþ): 289.1005, found 289.1005.
4.3. General procedure for the
p
-annulation reaction
4.3.4. 2-Methyl-3-oxo-N-phenethyl-3,5,6,7-tetrahydro-2H-thiazolo
[3,2-a]pyridine-8-carboxamide (4d). The general procedure was fol-
lowed with (Z)-2-(3-(3-bromopropyl)-5-methyl-4-oxothiazolidin-2-
ylidene)-N-phenethylacetamide (50 mg, 0.13 mmol) and KI (7.0 mg,
30 mol %). Flash column chromatography (Hexane/EtOAc gradient:
0%e50% EtOAc) of the crude mixture gave the title compound
(25 mg, 64%) as whitish crystals. Mp 86e88 ꢀC; 1H NMR (500 MHz,
To a solution of 3-bromopropyl-4-oxothiazolidinone derivative
(50 mg, 1 equiv) in a dry DMF (0.2 M) was added KI (0.3 equiv) and
the solution was stirred at 120 ꢀC under argon atmosphere. The
progress of reaction was followed by TLC. The reaction mixture was
stirred until completion, and the reaction mixture was diluted
with satd NH4Cl solution. The aqueous phase was extracted
with chloroform (3ꢁ) and the organic layer was washed with water
(3ꢁ) and brine solution (1ꢁ) and dried over Na2SO4. The solvent
was removed under reduced pressure and the crude product
was purified by column chromatography (silica-gel, hexane/
ethyl acetate gradient) to afford 3-bromopropyl-4-oxothiazolidine
derivative.
CDCl3)
d
7.31 (t, J¼7.3 Hz, 2H, m-Ph), 7.26e7.17 (m, 3H, o- and p-Ph),
5.51 (s, 1H), 3.82 (q, J¼7.2 Hz, 1H, CH), 3.70e3.52 (m, 4H, NCH2 and
NHCH2), 2.86 (t, J¼7.0 Hz, 2H, CH2Ph), 2.24 (t, J¼6.2 Hz, 2H, CH2C]),
2.01e1.86 (m, 2H, CH2), 1.58 (d, J¼7.2 Hz, 3H, CH3); 13C NMR
(126 MHz, CDCl3)
d 174.9 (COlactam), 167.2 (COamide), 145.9 (]C(C2)),
139.0 (C1-Ph), 128.7 (m-Ph), 128.6 (o-Ph), 126.5 (p-Ph), 100.5 (]
C(C20)), 41.5 (NCH2), 40.9 and 40.6 (CH and NHCH2), 35.9 (CH2Ph),
22.9 (CH2C]), 20.1 (CH2), 19.0 (CH3); IR (neat): n
[cmꢂ1] 3367, 2930,
4.3.1. Ethyl
2-methyl-3-oxo-3,5,6,7-tetrahydro-2H-thiazolo[3,2-a]
1702, 1638, 1567, 1530, 1450, 1390, 1288, 1193; HRMS: m/z (ESI) calcd
pyridine-8-carboxylate (4a). The general procedure was followed
with (Z)-ethyl 2-(3-(3-bromopropyl)-5-methyl-4-oxothiazolidin-2-
ylidene)acetate (50 mg, 0.15 mmol) and KI (7.50 mg, 30 mol %).
Flash column chromatography (Hexane/EtOAc gradient: 0%e30%
EtOAc) of the crude mixture gave the title compound (24 mg, 65%)
for [C17H21N2O2S] (MþHþ): 317.1318, found 317.1326.
4.3.5. Ethyl 3-oxo-3,5,6,7-tetrahydro-2H-thiazolo[3,2-a]pyridine-8-
carboxylate (4e). The general procedure was followed with (Z)-
ethyl
2-(3-(3-bromopropyl)-4-oxothiazolidin-2-ylidene)acetate
as white crystals. Mp 70e71 ꢀC; 1H NMR (200 MHz, CDCl3)
d 4.24 (q,
(50 mg, 0.16 mmol) and KI (8.0 mg, 30 mol %). Flash column

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B.P. Bondzic et al. / Tetrahedron 68 (2012) 9556e9565
9562
chromatography (Hexane/EtOAc gradient: 0%e30% EtOAc) of the
HRMS: m/z (ESI) calcd for [C18H20NO4S] (MþHþ): 346.1108, found
crude mixture gave the title compound (26 mg, 70%) as white
346.1094.
crystals. Mp 89e90 ꢀC; 1H NMR (200 MHz, CDCl3) 1H NMR
d 4.21
(q, J¼7.1 Hz, 2H, OCH2), 3.70 (s, 2H, CH2(C5)), 3.66 (t, J¼6.2 Hz,
2H, NCH2), 2.45 (t, J¼6.1 Hz, 2H, CH2C]), 1.85 (tt, J¼6.2, 6.1 Hz,
2H, CH2), 1.28 (t, J¼7.1 Hz, 3H, CH3); 13C NMR (50 MHz, CDCl3)
171.8 (COlactam), 167.5 (COester), 149.9 (]C(C2)), 100.8 (]C(C20)),
60.2 (OCH2), 42.0 (NCH2), 32.3 (CH2(C5)), 22.8 (CH2C]), 19.8
4.4. General procedure for the Michael addition to acrolein
To a stirred solution of 3-bromopropyl-4-oxothiazolidine de-
rivative (1 equiv) in a dry DMF (0.2 M) was added anhydrous K2CO3
(0.1 equiv). The mixture was stirred for 30 min at room tempera-
ture and excess of acrolein (1.2 equiv) was then added in one por-
tion. The progress of reaction was followed by TLC. The reaction
mixture was stirred for an additional 2e4 h, and the reaction
mixture was neutralized with satd NH4Cl solution. The aqueous
phase was extracted with chloroform (3ꢁ) and the organic layer
was washed with water (3ꢁ) and brine solution (1ꢁ) and dried over
Na2SO4. The solvent was removed under reduced pressure and the
crude product was purified by column chromatography (silica-gel,
hexane/ethyl acetate gradient) to afford Michael adducts.
(CH2), 14.3 (CH3); IR (neat):
n
[cmꢂ1] 2979, 2927, 2857, 1705,
1676, 1568, 1474, 1388, 1360, 1310, 1273, 1175, 1138, 1067; HRMS:
m/z (ESI) calcd for [C10H14NO3S] (MþHþ): 228.0689, found
228.0683.
4.3.6. 8-Benzoyl-6,7-dihydro-2H-thiazolo[3,2-a]pyridin-3(5H)-one
(4f). The general procedure was followed with (Z)-3-(3-
bromopropyl)-2-(2-oxo-2-phenylethylidene)thiazolidin-4-one
(50 mg, 0.15 mmol) and KI (7.50 mg, 30 mol %). Flash column
chromatography (Hexane/EtOAc gradient: 0%e30% EtOAc) of the
crude mixture gave the title compound (21 mg, 56%) as yellowish
4.4.1. (Z)-Ethyl 2-(3-(3-bromopropyl)-5-methyl-4-oxo-5-(3-
oxopropyl)thiazolidin-2-ylidene)acetate (10a). The general pro-
cedure was followed with (Z)-ethyl 2-(3-(3-bromopropyl)-5-
methyl-4-oxothiazolidin-2-ylidene)acetate (200 mg, 0.62 mmol),
crystals. Mp 65e66 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.56e7.52 (m,
2H, o-Ph), 7.50e7.41 (m, 3H, m- and p-Ph), 3.73 (t, J¼6.0 Hz, 2H,
NCH2), 3.69 (s, 2H, CH2(C5)), 2.63 (t, J¼5.9 Hz, 2H, CH2C]), 1.89 (tt,
J¼6.0, 5.9 Hz, 2H, CH2); 13C NMR (126 MHz, CDCl3) 194.1 (COketone),
172.4 (COlactam), 154.6 (]C(C2)), 139.7 (C1-Ph), 130.6 (p-Ph), 128.2
(m-Ph), 127.4 (o-Ph), 108.1 (]C(C20)), 42.6 (NCH2), 32.4 (CH2(C5)),
K2CO3 (9.0 mg, 0.06 mmol) and acrolein (50
mL, 0.74 mmol). Re-
action was stirred at room temperature for 2.5 h. Flash column
chromatography (Hexane/EtOAc gradient: 0%e30% EtOAc) of the
crude mixture gave the title compound (130 mg, 56%) as viscous
26.6 (CH2C]), 20.6 (CH2); IR (neat):
n
[cmꢂ1] 3401, 3058, 2930,
1714, 1622, 1575, 1504, 1382, 1322, 1279, 1258, 1190, 987, 881;
HRMS: m/z (ESI) calcd for [C14H14NO2S] (MþHþ): 260.0740, found
260.0739.
liquid. 1H NMR (500 MHz, CDCl3)
d
9.70 (t, J¼1.0 Hz, 1H, CHO), 5.56
(s, 1H, ]CH), 4.19 (q, J¼7.1 Hz, 2H, OCH2), 3.80 (t, J¼6.4 Hz, 2H,
NCH2), 3.39 (t, J¼6.4 Hz, 2H, CH2Br), 2.61 (dddd, J¼17.7, 9.9, 5.5,
1.0 Hz, 1H, CHHCHO), 2.39 (dddd, J¼17.7, 9.9, 5.1, 1.0 Hz, 1H,
CHHCHO), 2.26e2.07 (m, 4H, CCH2CH2 and CH2), 1.60 (s, 3H, CH3C),
4.3.7. Ethyl 2-(2-ethoxy-2-oxoethyl)-3-oxo-3,5,6,7-tetrahydro-2H-
thiazolo[3,2-a]pyridine-8-carboxylate (4g). The general procedure
was followed with (Z)-ethyl 2-(3-(3-bromopropyl)-2-(2-ethoxy-2-
oxoethylidene)-4-oxothiazolidin-5-yl)acetate (50 mg, 0.13 mmol)
and KI (6.40 mg, 30 mol %). Flash column chromatography (Hexane/
EtOAc gradient: 0%e30% EtOAc) of the crude mixture gave the title
compound (30 mg, 75%) as viscous liquid. 1H NMR (500 MHz,
1.28 (t, J¼7.1 Hz, 3H, CH3); 13C NMR (126 MHz, CDCl3)
d 199.9 (CHO),
177.1 (COlactam), 167.6 (COester), 154.6 (]C(C2)), 90.7 (]CH(C20)),
60.3 (OCH2), 52.7 (C(C5)), 42.5 (NCH2), 39.6 (CH2CHO), 32.4 (C(5)
CH2), 29.6 (CH2Br), 27.2 (CH3C), 14.5 (CH3); IR (neat): n
[cmꢂ1] 3429,
2977, 2730, 1717, 1688, 1572, 1451, 1308, 1177, 1136; HRMS: m/z (ESI)
calcd for ½C14H2179BrNO4Sꢃ (MþHþ): 378.0369, found 378.0365.
CDCl3)
d
4.24 (q, J¼7.1 Hz, 2H, OCH2), 4.21e4.15 (m, 3H, OCH2 and
CHxS), 3.72 (ddd, J¼13.5, 7.5, 4.0 Hz, 1H, NCHH), 3.62 (ddd, J¼13.0,
8.0, 4.0 Hz,1H, NCHH), 3.15 (dd, J¼17.3, 3.9 Hz,1H, CHAHBCOO), 2.85
(dd, J¼17.4, 9.0 Hz, 1H, CHAHBCOO), 2.50 (dd, J¼12.2, 6.3 Hz, 2H,
CH2C]), 2.00e1.79 (m, 2H, CH2CH2C]), 1.31 (t, J¼7.1 Hz, 3H, CH3),
1.26 (t, J¼7.1 Hz, 3H, CH3); 13C NMR (126 MHz, CDCl3) 173.0
(COlactam), 170.0 (COester), 167.4 (COester), 148.7 (]C(C2)), 100.9 (]
C(C20)), 61.3 (OCH2), 60.3 (OCH2), 42.3 and 42.2 (CH and NCH2), 37.8
(CH2COO), 23.0 (CH2C]), 19.9 (CH2CH2C]), 14.4 (CH3), 14.1 (CH3);
4.4.2. (Z)-3-(3-(3-Bromopropyl)-5-methyl-4-oxo-2-(2-oxo-2-
phenylethylidene)thiazolidin-5-yl)propanal (10b). The general pro-
cedure was followed with (Z)-3-(3-bromopropyl)-5-methyl-2-(2-
oxo-2-phenylethylidene)thiazolidin-4-one (285 mg, 0.80 mmol),
K2CO3 (11.0 mg, 0.08 mmol) and acrolein (64 mL, 0.96 mmol). Re-
action was stirred at room temperature for 2 h. Flash column
chromatography (Hexane/EtOAc gradient: 0%e30% EtOAc) of the
crude mixture gave the title compound (179 mg, 54%) as viscous
IR (neat):
n
[cmꢂ1] 2983, 1735, 1712, 1685, 1580, 1382, 1309, 1274,
liquid. 1H NMR (500 MHz, CDCl3)
d
9.73 (t, J¼1.0 Hz, 1H, CHO),
1179, 1132; HRMS: m/z (ESI) calcd for [C14H20NO5S] (MþHþ):
8.00e7.94 (m, 2H, o-Ph), 7.58e7.52 (m, 1H, p-Ph), 7.50e7.43 (m, 2H,
m-Ph), 6.91 (s, 1H, ]CH), 4.00 (t, J¼7.6 Hz, 2H, NCH2), 3.56e3.46
(m, 2H, CH2Br), 2.66 (dddd, J¼17.7, 9.8, 5.2, 1.0 Hz, 1H, CHHCHO),
2.41 (dddd, J¼17.7, 9.8, 5.2, 1.0 Hz, 1H, CHHCHO), 2.30e2.22 (m, 3H,
CH2 and CCHH), 2.22e2.12 (m, 1H, CCHH), 1.65 (s, 3H, CH3); 13C
314.1057, found 314.1059.
4.3.8. Ethyl 2-(8-benzoyl-3-oxo-3,5,6,7-tetrahydro-2H-thiazolo[3,2-
a]pyridin-2-yl)acetate (4h). The general procedure was followed
with (Z)-ethyl 2-(3-(3-bromopropyl)-4-oxo-2-(2-oxo-2-phenyl-
ethylidene)thiazolidin-5-yl)acetate (50 mg, 0.12 mmol) and KI
(6.0 mg, 30 mol %). Flash column chromatography (Hexane/EtOAc
gradient: 0%e30% EtOAc) of the crude mixture gave the title com-
pound (27 mg, 67%) as yellow crystals. Mp 94e95 ꢀC; 1H NMR
NMR (126 MHz, CDCl3)
d 199.8 (CHO), 188.6 (COketone), 177.5
(COlactm), 157.5 (]C(C2)), 138.2 (C1-Ph), 132.4 (p-Ph), 128.6 (m-Ph),
127.6 (o-Ph), 95.5 (]CH(C20)), 51.9 (C(C5)), 42.3 (NCH2), 39.4
(CH2CHO), 32.1 (C(5)CH2), 30.2 (CH2), 29.6 (CH2Br), 26.7 (CH3); IR
(neat): n
[cmꢂ1] 2972, 1718, 1633, 1516, 1449, 1345, 1229, 1144, 1057,
(200 MHz, CDCl3)
d
8.04e7.92 (m, 2H, o-Ph), 7.55e7.38 (m, 3H, m- and
767; HRMS: m/z (ESI) calcd for ½C19H2179BrNO3Sꢃ (MþHþ):
p-Ph), 4.24e4.08 (m, 3H, OCH2 and CH), 4.01 (td, J¼7.0, 5.0 Hz, 2H,
NCH2), 3.53 (t, J¼6.0 Hz, 2H, CH2C]), 3.11e3.01 (m, 2H, CH2COO),
2.39e2.21 (m, 2H, CH2CH2C]), 1.25 (t, J¼7.1 Hz, 3H, CH3); 13C NMR
(50 MHz, CDCl3) 188.6 (COketone),174.7 (COlactam),169.6 (COester),159.8
(]C(C2)), 138.2 (C1-Ph), 132.3 (p-Ph), 128.6 (m-Ph), 127.6 (o-Ph), 95.5
(]C(C20)), 61.4 (OCH2), 42.3 and 41.1 (CH and NCH2), 36.8 (CH2COO),
410.0420, found 410.0408.
4.4.3. (Z)-2-(3-(3-Bromopropyl)-5-methyl-4-oxo-5-(3-oxo propyl)
thiazolidin-2-ylidene)-N-phenylacetamide (10c). The general pro-
cedure was followed with (Z)-2-(3-(3-bromopropyl)-5-methyl-4-
oxothiazolidin-2-ylidene)-N-phenylacetamide (210 mg, 0.57 mmol),
27.0 (CH2C]), 21.2 (CH2CH2C]), 14.0 (CH3); IR (neat):
n
[cmꢂ1] 3433,
K2CO3 (8.0 mg, 0.06 mmol) and acrolein (45
mL, 0.68 mmol). Reaction
3059, 2980, 1724, 1631, 1575, 1514, 1347, 1276, 1225, 1189, 1055, 764;
was stirred at room temperature for
4
h. Flash column

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B.P. Bondzic et al. / Tetrahedron 68 (2012) 9556e9565
9563
chromatography (Hexane/EtOAc gradient: 0%e50% EtOAc) of the
(OCH2), 49.4 (CH3C), 45.1 (NCH2), 31.6 (CH2Br), 30.7 (CH2C(C5)), 29.8
crude mixture gave the title compound (138 mg, 57%) as viscous
(CH2CH2Br), 29.0 (CH3C), 21.1 (CH2CH2C(C5)), 14.6 (CH3); IR (neat): n
liquid. 1H NMR (500 MHz, CDCl3)
d
9.70 (s, 1H, CHO), 7.56 (br m, 3H,
[cmꢂ1] 3490, 2955, 1723, 1674, 1553, 1461, 1373, 1233, 1162, 1136,
1069, 1033, 907; HRMS: m/z (ESI) calcd for ½C14H2379BrNO3Sꢃ
(MþHþ): 364.0582, found 364.0587.
NH and o-Ph), 7.29 (t, J¼7.9 Hz, 2H, m-Ph), 7.06 (t, J¼7.2 Hz,1H, p-Ph),
5.84 (s, 1H, ]CH), 3.79 (t, J¼7.3 Hz, 2H, NCH2), 3.41 (t, J¼6.3 Hz, 2H,
CH2Br), 2.63 (dddd, J¼17.6, 9.9, 5.2, 0.9 Hz, 1H, CHHCHO), 2.41e2.31
(m, 1H, CHHCHO), 2.25e1.96 (m, 4H, CH2 and C(5)CH2), 1.59 (s, 3H,
CH3); 13C NMR (126 MHz, CDCl3) 200.0 (CHO), 176.9 (COlactm), 165.0
(COamide), 152.6 (]C(C2)), 138.0 (C1-Ph), 128.9 (m-Ph), 124.1 (p-Ph),
119.7 (o-Ph), 92.9 (]CH(C20)), 52.1 (C(C5)), 42.2 (NCH2), 39.5
(CH2CHO), 32.3 (C(5)CH2), 30.1 and 29.6 (CH2Br and CH2), 26.9 (CH3);
4.5.2. (Z)-2-((7aS)-3-(3-Bromopropyl)-7a-methylhexahydro-2H-pyr-
ano[2,3-d]thiazol-2-ylidene)-1-phenylethanone (11b). The general
procedure was followed with (Z)-3-(3-(3-bromopropyl)-5-methyl-4-
oxo-2-(2-oxo-2-phenylethylidene)thiazolidin-5-yl) propanal (160
mg, 0.39 mmol), NaBH4 (148 mg, 3.9 mmol). Reaction was stirred at
0 ꢀC for 2 h. Flash column chromatography (Hexane/EtOAc gradient:
0%e30% EtOAc) of the crude mixture gave the title compound
(131 mg, 85%) as a viscous liquid. 1H NMR (500 MHz, CDCl3)
IR(neat): n
[cmꢂ1] 3317, 3135, 3062, 2929,1715,1658,1598,1570,1497,
1444, 1406, 1330, 1247, 1181, 1139, 757; HRMS: m/z (ESI) calcd for
½C18H2279BrN2O3Sꢃ (MþHþ): 425.0529, found 425.0520.
d
7.96e7.90 (m, 2H, o-Ph), 7.49e7.37 (m, 3H, m- and p-Ph), 6.32 (s,1H,
4.4.4. (Z)-2-(3-(3-Bromopropyl)-4-oxo-5-(3-oxopropyl) thiazolidin-2-
ylidene)acetonitrile (10d). The general procedure was followed with
(Z)-2-(3-(3-bromopropyl)-5-methyl-4-oxothiazolidin-2-ylidene)ace-
tonitrile (307 mg, 1.12 mmol), K2CO3 (16.0 mg, 0.08 mmol) and acro-
lein (89 mL, 1.34 mmol). Reaction was stirred at room temperature
for 2.5 h. Flash column chromatography (Hexane/EtOAc gradient:
]CH), 4.62 (s, 1H, OCHN), 3.90e3.82 (m, 1H, CHHO), 3.78e3.63 (m,
2H, NCH2), 3.57e3.47 (m, 2H, CH2Br), 3.43 (td, J¼11.3, 2.6 Hz, 1H,
CHHO), 2.41e2.20 (m, 2H, CH2CH2Br), 2.17e2.10 (m, 1H, CHHC(C5)),
2.04e1.91 (m, 1H, CHHCH2C(C5)), 1.77 (ddd, J¼14.7, 11.9, 4.6 Hz, 1H,
CHHC(C5)), 1.56 (ddt, J¼13.9, 7.1, 3.4 Hz, 1H, CHHCH2C(C5)), 1.45 (s,
3H, CH3); 13C NMR (126 MHz, CDCl3)
d 187.1 (CO), 166.1 (), 139.7 (C1-
0%e30% EtOAc) of the crude mixture gave the title compound
Ph), 131.1 (p-Ph), 128.2 (m-Ph), 127.4 (o-Ph), 96.3 (OCHN), 90.0 (]
(272 mg, 73%) as viscous liquid.1H NMR (500 MHz, CDCl3)
d 9.75 (s,1H,
CH(C20)), 63.7 (OCH2), 49.1 (CH3C), 45.4 (NCH2), 31.4 (CH2C(C5)), 30.8
CHO), 4.93 (s,1H, ]CH), 3.80 (t, J¼7.2 Hz, 2H, NCH2), 3.43 (t, J¼7.2 Hz,
2H, CH2Br), 2.65 (dddd, J¼17.8, 9.5, 5.4, 0.9 Hz, 1H, CHHCHO), 2.41
(dddd, J¼17.8, 9.9, 5.6, 1.1 Hz, 1H, CHHCHO), 2.29 (ddd, J¼15.0, 9.5,
5.6 Hz,1H, CCHH), 2.25e2.11 (m, 3H, CCHH and CH2),1.69 (s, 3H, CH3);
(CH2Br), 30.1 (CH2CH2Br), 28.7 (CH3), 21.1 (CH2CH2C(C5)); IR (neat): n
[cmꢂ1] 2960, 2856, 1615, 1573, 1505, 1462, 1368, 1227, 1206, 1070,
1031, 1002, 751; HRMS: m/z (ESI) calcd for ½C18H2379BrNO2Sꢃ
(MþHþ): 396.0627, found 396.0620.
13C NMR (126 MHz, CDCl3)
d 199.3 (CHO), 176.1 (COlactm), 156.5 (]
C(C2), 116.3 (CN), 68.6 (]CH(C20)), 55.8 (C(C5)), 42.0 (NCH2), 39.4
(CH2CHO), 32.3 (C(5)CH2), 29.5 and 29.3 (CH2Br and CH2, 27.1 (CH3); IR
4.5.3. (Z)-2-((7aS)-3-(3-Bromopropyl)-7a-methylhexahydro-2H-pyr-
ano[2,3-d]thiazol-2-ylidene)-N-phenylacetamide (11c). The general
procedure was followed with (Z)-2-(3-(3-bromopropyl)-5-methyl-
4-oxo-5-(3-oxopropyl)thiazolidin-2-ylidene)-N-phenyl acetamide
(148 mg, 0.35 mmol), NaBH4 (131 mg, 3.46 mmol). Reaction was
stirred at 0 ꢀC for 3 h. Flash column chromatography (Hexane/EtOAc
gradient: 0%e50% EtOAc) of the crude mixture gave the title com-
pound (100 mg, 70%) as viscous liquid. 1H NMR (500 MHz, CDCl3)
(neat): n
[cmꢂ1] 3070, 2933, 2207, 1722, 1587, 1452, 1387, 1239, 1146;
HRMS: m/z (ESI) calcd for ½C12H1679BrN2O2Sꢃ (MþHþ): 331.0110,
found 331.0104.
4.5. General procedure for the iminium ion cyclization
To a solution of the Michael adduct in ethanol at 0 ꢀC under
argon atmosphere were added 10 equiv of NaBH4. During the next
2e3 h every 15 min were added three drops of 0.4 M HCl/EtOH
solution to the reaction mixture. After completion (TLC analysis)
reaction mixture was acidified with concentrated HCl until H2
evolution stopped and then stirred at 0 ꢀC for the next 15e30 min.
Then, reaction mixture was diluted with 15 mL of water, and stirred
for the next 15 min at room temperature. The aqueous phase was
extracted with chloroform (3ꢁ) and the collected organic layers
were washed with satd NaHCO3 solution and brine solution (1ꢁ)
and dried over Na2SO4. The solvent was removed under reduced
pressure and the crude product was purified by column chroma-
tography (silica-gel, hexane/ethyl acetate gradient) to afford 3-
bromopropyl-4-oxothiazolidine derivative.
d
7.53 (d, J¼7.8 Hz, 2H, o-Ph), 7.29e7.21 (m, 2H, m-Ph), 7.18 (br s, 1H,
NH), 7.00 (t, J¼7.4 Hz,1H, p-Ph), 5.17 (s,1H, ]CH), 4.52 (s,1H, OCHN),
3.88e3.81 (m, 1H, CH2CHHO), 3.59e3.42 (m, 4H, NCH2 and CH2Br),
3.40e3.38 (m, 1H, CH2CHHO), 2.30e2.21 (m, 1H, CHHCH2Br),
2.19e2.10 (m, 1H, CHHCH2Br), 2.09e2.03 (m, 1H, CHHC(C5)),
2.00e1.86 (m, 1H, CHHC(C5)), 1.74e1.68 (m, 1H, CHHCH2C(C5)),
1.52e1.45 (m, 1H, CHHCH2C(C5)), 1.41 (s, 3H, CH3); 13C NMR
(101 MHz, CDCl3) 166.5 (CO), 161.2 (]C(C2)), 139.2 (C1-Ph), 128.7
(m-Ph), 123.0 (p-Ph), 119.6 (o-Ph), 96.0 (OCHN), 85.5 (]CH(C20)),
63.9 (CH2CH2O), 49.1 (CH3C), 45.0 (NCH2), 31.6 (CH2C(C5)), 31.0
(CH2Br), 30.0 (CH2CH2Br), 29.0 (CH3C), 21.1 (CH2CH2C(C5)); IR (neat):
n
[cmꢂ1] 3183, 3124, 3051, 2961, 2869, 1683, 1599, 1550, 1469, 1442,
1325, 1246, 1175, 1029, 735; HRMS: m/z (ESI) calcd for
½C18H2479BrN2O2Sꢃ (MþHþ): 411.0736, found 411.0729.
4.5.1. (Z)-Ethyl-2-((7aS)-3-(3-bromopropyl)-7a-methyl
2H-pyrano[2,3-d]thiazol-2-ylidene)acetate (11a). The general pro-
cedure was followed with (Z)-ethyl 2-(3-(3-bromopropyl)-5-methyl-
hexahydro-
4.5.4. (Z)-2-((7aS)-3-(3-Bromopropyl)-7a-methylhexahydro-2H-
pyrano[2,3-d]thiazol-2-ylidene)acetonitrile (11d). The general pro-
cedure was followed with (Z)-2-(3-(3-bromopropyl)-5-methyl-4-
4-oxo-5-(3-oxopropyl)thiazolidin-2-ylidene)
acetate
(45 mg,
oxo-5-(3-oxopropyl)thiazolidin-2-ylidene)acetonitrile
(140 mg,
0.12 mmol), NaBH4 (45 mg, 1.19 mmol). Reaction was stirred at 0 ꢀC
for 2 h. Flash column chromatography (Hexane/EtOAc gradient: 0%e
30% EtOAc) of the crude mixture gave the title compound (36 mg,
0.42 mmol), NaBH4 (161 mg, 4.23 mmol). Reaction was stirred at
0 ꢀC for 2 h. Flash column chromatography (Hexane/EtOAc gradi-
ent: 0%e30% EtOAc) of the crude mixture gave the title compound
83%) as viscous liquid. 1H NMR (500 MHz, CDCl3)
d
5.00 (s,1H, ]CH),
(104 mg, 78%) as viscous liquid. 1H NMR (500 MHz, CDCl3)
d 4.59 (s,
4.56 (s, 1H, OCHN), 4.21e4.09 (m, 2H, OCH2), 3.86 (ddd, J¼11.5, 5.7,
3.3 Hz, 1H, CH2CHHO), 3.44e3.41 (m, 2H, CH2Br), 3.40e3.37 (m, 1H,
CH2CHHO) 3.31 (t, 2H, J¼7.2 Hz, NCH2), 2.11e2.06 (m,1H, CHHC(C5)),
1.94e1.79 (m, 3H, CH2CH2Br and CHHCH2C(C5)),1.76e1.70 (m, 1H,
CHHC(C5)), 1.55e1.47 (m, 1H, CHHCH2C(C5)), 1.44 (s, 3H, CCH3), 1.26
1H, OCHN), 4.19 (s, 1H, ]CH), 3.95e3.83 (m, 1H, CH2CHHO),
3.57e3.34 (m, 5H, CH2CHHO, NCH2 and CH2Br), 2.25e2.06 (m, 3H,
CH2CH2Br and CHHC(C5)), 1.91 (dtt, J¼11.8, 10.6, 4.0 Hz, 1H,
CHHCH2C(C5)), 1.79 (ddd, J¼14.8, 11.9, 4.3 Hz, 1H, CHHC(C5)),
1.62e1.52 (m, 1H, CHHCH2C(C5)), 1.49 (s, 3H, CH3); 13C NMR
(t, J¼7.1 Hz, 3H, CH3); 13C NMR (126 MHz, CDCl3)
d
168.7 (CO), 163.3
(126 MHz, CDCl3)
d 164.4 (]C(C2)), 120.2 (CN), 97.3 (OCHN), 64.0
(]C(C2)), 96.5 (OCHN), 82.7 (]CH(C20)), 63.9 (CH2CH2O), 59.2
(CH2CH2O), 59.3 (]CH(C20)), 51.7 (CH3C), 44.5 (NCH2), 31.7

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B.P. Bondzic et al. / Tetrahedron 68 (2012) 9556e9565
9564
(CH2C(C5)), 30.5 (CH2CH2Br), 29.7 (CH2Br), 28.7 (CH3C), 21.0
general procedure was followed with (Z)-2-((7aS)-3-(3-
bromopropyl)-7a-methylhexahydro-2H-pyrano[2,3-d]thiazol-2-
ylidene)-N-phenylacetamide (60 mg, 0.15 mmol) and KI (7.5 mg,
30 mol %). Reaction was stirred for 16 h at 100 ꢀC. Flash column
chromatography (Hexane/EtOAc gradient: 0%e50% EtOAc) of the
crude mixture gave the title compound (34 mg, 71%) as white
(CH2CH2C(C5)); IR (neat):
n
[cmꢂ1] 3067, 2963, 2858, 2192, 1572,
1454, 1397, 1073; HRMS: m/z (ESI) calcd for ½C12H1879BrN2OSꢃ
(MþHþ): 317.0318, found 317.0323.
4.6. General procedure for the tricycle synthesis
crystals. Mp 151e153 ꢀC; 1H NMR (500 MHz, CDCl3)
d 7.57e7.50 (m,
To a solution of a fused pyrano-thiazolidinine (1 equiv) in a dry
DMF (0.2 M) was added KI (0.3 equiv) and the solution was stirred
at 100 ꢀC under argon atmosphere. The progress of reaction was
followed by TLC. The reaction mixture was stirred until completion,
cooled to room temperature and diluted with satd NH4Cl solution.
The aqueous phase was extracted with chloroform (3ꢁ) and the
organic layer was washed with water (3ꢁ) and brine solution (1ꢁ)
and dried over Na2SO4. The solvent was removed under reduced
pressure and the crude product was purified by column chroma-
tography (silica-gel, hexane/ethyl acetate gradient) to afford 3-
bromopropyl-4-oxothiazolidine derivative.
2H, o-Ph), 7.30e7.22 (m, 2H, m-Ph), 7.04e6.98 (m, 2H, p-Ph and
NH), 4.42 (s, 1H, OCHN), 3.87e3.79 (m, 1H, CHHO), 3.41 (m, 2H,
CHHO and NCHH), 3.24 (dt, J¼10.4, 4.4 Hz, 1H, NCHH), 2.51e2.36
(m, 2H, CH2C]), 2.11e1.98 (m, 3H, CH2CH2C] and CHHC(C5)),
1.98e1.85 (m, 1H, CHHCH2C(C5)), 1.71 (ddd, J¼14.7, 11.1, 4.4 Hz, 1H,
CHHC(C5)), 1.53e1.47 (m, 1H, CHHCH2C(C5)), 1.43 (s, 3H, CH3); 13C
NMR (126 MHz, CDCl3) d 166.2 (CO), 155.5 (]C(C2)), 138.9 (C1-Ph),
128.6 (m-Ph), 123.0 (p-Ph), 119.8 (o-Ph), 95.9 (OCHN), 93.6 (]
CH(C20)), 63.4 (OCH2CH2), 48.4 (CH3C), 44.1 (NCH2), 32.0
(CH2C(C5)), 28.2 (CCH3), 22.4 (CH2CC]), 21.5 and 21.3
(CH2CH2C(C5) and CH2CH2C]); IR (neat):
n
[cmꢂ1] 3348, 3057,
2957, 2930, 2859, 1687, 1638, 1597, 1548, 1438, 1323, 1297, 1242,
1187, 1125, 1074, 1031; HRMS: m/z (ESI) calcd for [C18H23N2O2S]
(MþHþ): 331.1480, found 331.1487.
4.6.1. (4aS)-Ethyl-4a-methyl-2,3,4,4a,7,8,9,10a-octa hydro pyrano
[20,30:4,5]thiazolo[3,2-a]pyridine-6-carboxylate (12a). The general
procedure was followed with (Z)-ethyl 2-((7aS)-3-(3-bromopropyl)-
7a-methylhexahydro-2H-pyrano[2,3-d]thiazol-2-ylidene)
acetate
4.6.4. (4aS)-4a-Methyl-2,3,4,4a,7,8,9,10a-octahydropyrano [20,30:4,5]
thiazolo[3,2-a]pyridine-6-carbonitrile (12d). The general procedure
was followed with (Z)-2-((7aS)-3-(3-bromopropyl)-7a-methylhex-
(40 mg, 0.11 mmol) and KI (6.0 mg, 30 mol %). Reaction was stirred
for 16 h at 100 ꢀC. Flash column chromatography (Hexane/EtOAc
gradient: 0%e30% EtOAc) of the crude mixture gave the title com-
pound (23 mg, 75%) as white crystals. Mp 141e154 ꢀC; 1H NMR
ahydro-2H-pyrano[2,3-d]thiazol-2-ylidene)acetonitrile
(70 mg,
0.22 mmol) and KI (11.0 mg, 30 mol %). Reaction was stirred at
100 ꢀC for 12 h. Flash column chromatography (Hexane/EtOAc
gradient: 0%e30% EtOAc) of the crude mixture gave the title com-
pound (43 mg, 83%) as white crystals. Mp 145e146 ꢀC; 1H NMR
(500 MHz, CDCl3)
d
4.43 (s, 1H, OCHN), 4.16 (q, J¼7.1 Hz, 2H), 3.84
(dtd, J¼11.4, 4.0, 1.5 Hz, 1H, CH2CHHO), 3.45e3.35 (m, 2H, CH2CHHO
and NCHH), 3.26e3.18 (m, 1H, NCHH), 2.47e2.31 (m, 2H, CH2C]),
2.07 (dtd, J¼14.5, 4.3, 1.5 Hz, 1H, CHHC(C5)), 1.98e1.84 (m, 3H,
CH2CH2C(C5) and CHHCH2C]), 1.73 (ddd, J¼14.6, 11.1, 4.4 Hz, 1H,
CHHC(C5)),1.52 (dqd, J¼11.4, 4.4, 2.8 Hz,1H, CHHCH2C]),1.44 (s, 3H,
(500 MHz, CDCl3)
d 4.46 (s, 1H, OCHN), 3.90e3.85 (m, 1H,
CH2CHHO), 3.49e3.41 (m, 1H, NCHH), 3.41e3.34 (m, 1H, CH2CHHO),
3.27e3.19 (m, 1H, NCHH), 2.37e2.21 (m, 2H, CH2C]), 2.09 (dd,
J¼14.4, 3.5 Hz, 1H, CHHC(C5)), 1.96e1.84 (m, 3H, CH2CH2C(C5) and
CHHCH2C]), 1.79 (ddd, J¼15.0, 11.2, 4.1 Hz, 1H, CHHC(C5)),
1.59e1.52 (m, 1H, CHHCH2C]), 1.49 (s, 3H, CH3); 13C NMR
CCH3), 1.26 (t, J¼7.1 Hz, 3H, CH3); 13C NMR (126 MHz, CDCl3)
d 168.4
(CO), 156.2 (]C(C2)), 96.3 (OCHN), 93.0 (]C(C20)), 63.5 (OCH2CH2),
59.3 (OCH2), 48.7 (CH3C), 44.6 (NCH2), 32.2 (CH2C(C5)), 28.3 (CCH3),
22.1 (CH2CC]), 21.4 and 21.3 (CH2CH2C(C5) and CH2CH2C]), 14.7
(126 MHz, CDCl3)
d 156.6 (]C(C2)), 121.5 (CN), 96.6 (OCHN), 71.2
(CH3); IR (neat):
n
[cmꢂ1] 3498, 2950, 2855, 1699, 1557, 1448, 1372,
(]CH(C20)), 63.6 (CH2O), 51.6 (CCH3), 43.7 (NCH2), 32.4 (CH2C(C5)),
28.3 (CH3), 23.5 (CH2C]), 21.3 and 20.9 (CH2CH2C] and
1263, 1187, 1117, 1072; HRMS: m/z (ESI) calcd for [C14H22NO3S]
(MþHþ): 284.1315, found 284.1328.
CH2CH2C(C5)); IR (neat):
n
[cmꢂ1] 2964, 2918, 2875, 2845, 2173,
1580, 1456, 1348, 1248, 1185, 1027; HRMS: m/z (ESI) calcd for
4.6.2. ((4aS)-4a-Methyl-2,3,4,4a,7,8,9,10a-octa hydropyrano [20,30:4,5]
thiazolo[3,2-a]pyridin-6-yl)(phenyl)methanone (12b). The general
procedure was followed with (Z)-2-((7aS)-3-(3-bromopropyl)-7a-
methylhexahydro-2H-pyrano[2,3-d]thiazol-2-ylidene)-1-phenylet-
hanone (44 mg, 0.11 mmol) and KI (6.0 mg, 30 mol %). Reaction was
stirred for 20 h at 100 ꢀC. Flash column chromatography (Hexane/
EtOAc gradient: 0%e30% EtOAc) of the crude mixture gave the title
compound (26 mg, 74%) as brownish crystals. Mp 143e145 ꢀC; 1H
[C12H17N2OS] (MþHþ): 237.1056, found 237.1062.
4.7. Sulfoxide synthesis
4.7.1. (Z)-Ethyl-(3-(3-bromopropyl)-1,4-dioxothiazolidine-2-ylidene)
ethanoate (5). The title compound was obtained after mCPBA
(2 equiv) oxidation of 3a in DCM at 0 ꢀC for 1 h as a mixture of two
diastereomers in 85% yield, colourless oil; 1H NMR (CDCl3,
NMR (500 MHz, CDCl3) d 7.52e7.46 (m, 2H, o-Ph), 7.37e7.33 (m, 3H,
m- and p-Ph), 4.52 (s, 1H, OCHN), 3.89e3.81 (m, 1H, CHHO),
3.56e3.49 (m, 1H, CHHO), 3.45 (ddd, J¼11.5, 10.0, 2.9 Hz, 1H, NHH),
3.39e3.29 (m, 1H, NHH), 2.58e2.44 (m, 2H, CH2C]), 2.14e1.98 (m,
1H, CHHC(C5)), 2.01e1.90 (m, 1H, CHHCH2C(C5)), 1.90e1.83 (m, 2H,
CH2CH2C]), 1.75 (ddd, J¼14.6, 11.3, 4.5 Hz, 1H, CHHC(C5)), 1.60e1.53
(m, 1H, CHHCH2C(C5)), 1.46 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3)
500 MHz): diastereomer I (87%) d 5.85 (s, 1H, ]CH), 4.32 (q, 2H,
J¼7.0 Hz, OCH2), 3.91e3.85 (m, 1H, NCHaHb), 3.82e3.76 (m, 1H,
NCHaHb), 3.44e3.37 (m, 2H, CH2Br), 3.39 (q, 1H, J¼7.0 Hz, CH(C5)),
2.21e2.16 (m, 2H, CH2), 1.62 (d, 3H, J¼7.0 Hz, CH3CH), 1.35 (t, 3H,
J¼7.0 Hz, CH3CH2); diastereomer II (13%)
d 5.88 (s, 1H, ]CH), 4.32 (q,
2H, J¼7.0 Hz, OCH2), 3.85e3.91 (m, 1H, NCHaHb), 3.76e3.82 (m, 1H,
NCHaHb), 3.63 (q, 1H, J¼8.0 Hz, CH(C5)), 3.44e3.37 (m, 2H, CH2Br),
2.16e2.21 (m, 2H, CH2), 1.54 (d, 3H, J¼8.0 Hz, CH3CH),1.35 (t, 3H,
J¼7.0 Hz, CH3CH2); 13C NMR (CDCl3, 126 MHz): diastereomer I (87%)
d
191.6 (CO), 160.6 (]C(C2)), 141.3 (C1-Ph), 129.1 (p-Ph), 127.7 (m-
Ph), 127.3 (o-Ph), 101.4 (]CH(C20)), 96.1 (OCHN), 63.3 (OCH2CH2),
48.6 (CH3C), 45.2 (NCH2), 31.7 (CH2C(C5)), 28.1 (CCH3), 25.6
(CH2CC]), 21.8 and 21.3 (CH2CH2C(C5) and CH2CH2C]); IR (neat):
n
d 172.30 (COlactam), 164.62 (COester), 156.06 (]C(C2)), 100.82 (]
[cmꢂ1] 2957, 2858, 1601, 1492, 1463, 1404, 1274, 1189, 1075, 1034,
731; HRMS: m/z (ESI) calcd for [C18H22NO2S] (MþHþ): 316.1366,
found 316.1367.
CH(C20)), 61.43 (OCH2), 53.48 (CH(C5)), 41.94 (NCH2), 29.49 (CH2Br),
28.92 (CH2), 14.15 (CH3CH2), 6.62 (CH3CH); diastereomer II (13%)
d
172.30 (COlactam), 164.62 (COester), 156.06 (]C(C2)), 101.09 (]
CH(C20)), 61.43 (OCH2), 59.60 (CH(C5)), 41.94 (NCH2), 29.49 (CH2Br),
4.6.3. (4aS)-4a-Methyl-N-phenyl-2,3,4,4a,7,8,9,10a-octa hydro pyr-
28.92 (CH2), 14.15 (CH3CH2), 12.24 (CH3CH); IR (neat):
n
[cmꢂ1
]
;
ano[20,30:4,5]thiazolo[3,2-a]pyridine-6-carboxamide
(12c). The
2983, 2939, 1709, 1615, 1306, 1236, 1182, 1145, 1059, 838 cmꢂ1

ꢀ ꢁ
B.P. Bondzic et al. / Tetrahedron 68 (2012) 9556e9565
9565
HRMS: m/z (ESI) calcd for ½C11H1779BrNO4Sꢃ (MþNaþ): 338.0056,
10. (a) Chen, S.; Chen, L.; Le, N. T.; Zhao, C.; Sidduri, A.; Lou, J. P.; Michoud, C.;
Portland, L.; Jackson, N.; Liu, J.-J.; Konzelmann, F.; Chi, F.; Tovar, C.; Xiang, Q.;
Chen, Y.; Wen, Y.; Vassilev, L. T. Bioorg. Med. Chem. Lett. 2007, 17, 2134e2138; (b)
Gududuru, V.; Hurh, E.; Dalton, J. T.; Miller, D. D. Bioorg. Med. Chem. Lett. 2004,
14, 5289e5293.
found 338.0052.
Acknowledgements
11. Geronikaki, A.; Eleftheriou, P.; Vicini, P.; Alam, I.; Dixit, A.; Saxena, A. K. J. Med.
Chem. 2008, 51, 5221e5228.
This work was supported by the Ministry of Science of the Re-
public of Serbia (Grant No. 172020 to R.M.)
12. Gandolfi, C. A.; Di Domenico, R.; Spinelli, S.; Gallico, L.; Fiocchi, L.; Lotto, A.;
Menta, E.; Borghi, A.; Rosa, C. D.; Tognella, S. J. Med. Chem. 1995, 38, 508e525.
13. (a) Venable, J. D.; Ameriks, M. K.; Blevitt, J. M.; Thurmond, R. L.; Fung-Leung,
W.-P. Drug Discovery 2010, 4, 1e15; (b) Geronikaki, T. A.; Lagunin, A. A.;
Hadjipavlou-Litina, D. I.; Eleftheriou, P. T.; Filimonov, D. A.; Poroikov, V. V.;
Alam, I.; Saxena, A. K. J. Med. Chem. 2008, 51, 1601e1609.
Supplementary data
14. (a) Knutsen, L. J. S.; Hobbs, C. J.; Earnshaw, C. G.; Fiumana, A.; Gilbert, J.; Mellor,
S. L.; Radford, F.; Smith, N. J.; Birch, P. J.; Burley, J. R.; Ward, S. D. C.; James, I. F.
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Supplementary data for this article including full experimental
procedures, 1H- and 13C NMR traces and IR traces for all new
compounds. Supplementary data related to this article can be found
at http://dx.doi.org/10.1016/j.tet.2012.09.080.
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