An efficient one-pot multicomponent approach to 5-amino-7-aryl-8- nitrothiazolo[3,2-a]pyridines

Article abstract of DOI:10.1016/j.tet.2011.10.005

A series of thiazolo[3,2-a]pyridines have been prepared using a multicomponent reaction between aromatic aldehydes, 2-nitromethylenethiazolidine and nitriles containing an active methylene group (malononitrile, ethyl 2-cyanoacetate and 2-phenylsulfonylace

Full text of DOI:10.1016/j.tet.2011.10.005

Tetrahedron 67 (2011) 9522e9528
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient one-pot multicomponent approach to 5-amino-7-aryl-8-nitrothiazolo
[3,2-a]pyridines
,
b
a
a
c
,
c
Cevher Altug a , Alan K. Burnett , Esra Caner , Yas¸ ar Durust , Mark C. Elliott , Roger P.J. Glanville ,
*
*
€ €
Carol Guy b, Andrew D. Westwell d
a
_
Department of Chemistry, Abant Izzet Baysal University, TR-14280 Bolu, Turkey
b Department of Medical Genetics, Haematology and Pathology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, Wales, UK
c School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, UK
d Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, Wales, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 August 2011
Received in revised form 20 September 2011
Accepted 3 October 2011
Available online 8 October 2011
A series of thiazolo[3,2-a]pyridines have been prepared using a multicomponent reaction between ar-
omatic aldehydes, 2-nitromethylenethiazolidine and nitriles containing an active methylene group
(malononitrile, ethyl 2-cyanoacetate and 2-phenylsulfonylacetonitrile) in the presence of Et3N under
mild conditions with high yields. One of the compounds shows promising anticancer activity across
a range of cancer cell lines.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reactions
Heterocycles
Pyridine
Thiazoline
Knoevenagel reaction
Nitrile
1. Introduction
malononitrile, as a representative active methylene compound, were
investigated first. The reaction of 2-nitromethylenethiazoline with
Multicomponent reactions (MCRs) have found increasing ap-
plication for the synthesis of libraries of complex pharmacologi-
cally important structures with multiple points of diversity in
a small number of steps.1 Among these structures, thiazolopyridine
compounds have been studied2 due to their importance in a num-
ber of biologically relevant areas, including cytotoxicity,3 antimi-
malononitrile and a broad range of aldehydes was carried out in dry
acetonitrile with triethylamine at room temperature. Typically
0.5 equiv of triethylamine was used, although smaller quantities can
be used with little reduction in yield. After 3 h, reactions were com-
plete (TLC analysis) in all cases, with excellent yields being obtained
with aldehydes possessing electron-withdrawing and electron-
donating substituents, as well as those with ortho substituents
(Table 1).
crobial activity,4
activity.6
a
-glucosidase inhibition5 and hypolipemic
Heterocyclic enamines, including 2-methylenethiazolines, have
a great deal of synthetic utility, particularlyas bis-nucleophiles for the
construction of more complex heterocyclic arrays.7 However, while
such compounds containing electron-withdrawing groups such as
esters are common, the reactions of 2-nitromethylenethiazolidine
have rarely been investigated.8e10
The identity of these compounds is fully supported by the
spectroscopic data obtained. Compound 4g, with two ortho sub-
stituents, showed hindered rotation of the aryl ring, with all 14
carbon atoms giving distinct resonances in the 13C NMR spectrum,
as well as distinct 1H peaks for the 3 hydrogen atoms on the aro-
matic ring. As an additional complication, these compounds are
only fully soluble in DMSO. Running the 1H NMR spectra in DMSO-
d6 gave good results, although the peak due to adventitious water
in the DMSO invariably obscured the CH2S resonance. In the 13C
NMR spectrum, the methine resonance (C-7) in some instances
overlapped with the deuterated solvent peak, although careful
examination of the DEPT spectra allowed unambiguous assign-
ment. The same products were formed, albeit in much lower yield
and purity, with aliphatic aldehydes.
We now report that the reaction of 2-nitromethylenethiazolidine11
with a range of aldehydes and active methylene compounds provides
access to a library of thiazolo[3,2-a]pyridines. The reactions of
* Corresponding authors. Tel.: þ90 3742541000 1252; fax: þ90 3742534642
(C.A.); tel.: þ44 (0)2920874686; fax: þ44 (0)2920874030 (M.C.E.); e-mail
addresses: altug_c@ibu.edu.tr (C. Altug), elliottmc@cardiff.ac.uk (M.C. Elliott).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.005

C. Altug et al. / Tetrahedron 67 (2011) 9522e9528
9523
compared to the experiments in Table 1, the reactions with malo-
nonitrile were not closely monitored, and it is likely that they were
also complete within 1 h. The reactions can also be carried out
under solvent-free conditions by simply grinding the reagents to-
gether for 10 min in a mortar, making this a particularly attractive
protocol.
Reactions with 2-phenylsulfonylacetonitrile also gave a similar
outcome, although in this case the spectra were complicated by the
presence of enamine and imine tautomers 10 and 11. As shown in
Table 3, the relative proportions of the tautomers are close to 1:1
with the exception of 10e/11e. The ratios observed vary only
slightly when the spectra are re-run on a different sample from the
same batch of compound, so we are confident that compound 10e/
11e is a genuine anomaly.
It is tempting to attribute the dramatically different ratio of
compounds 10e/11e to steric hindrance, although one might have
then expected that the imine tautomer would permit the phe-
nylsulfonyl group to position itself further from the 2,6-
dichlorophenyl ring. It would appear that the imine tautomer is
present in each case as a single diastereoisomer. In order to un-
derstand this process, calculations were carried out on com-
pounds 10a, 11a, 10e and 11e. The minimum energy
conformations of these four compounds were located using
Spartan 1012 at the AM1 semi-empirical level. These conforma-
tions were then minimised at the HartreeeFock level using the 3-
21G basis set. The first observation is that the HeCeCeH dihedral
angle defining the imine stereochemistry is 74.3ꢀ and 85.6ꢀ in
compounds 11a and 11e, respectively. This is suggestive of trans
stereochemistry based on the apparent lack of coupling between
these hydrogen atoms.
Table 1
Reactions of 2-nitromethylenethiazoline with malononitrile and aldehydes
3
R
CHO
R
Et N
3
CN
O N
2
CN
NH
O N
2
CH CN
3
CN
reflux, 3 h
N
S
NH
2
S
2
1
4
Compound
R
Yield/%
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
4-FC6H4
4-ClC6H4
4-BrC6H4
95
90
94
79
93
99
97
97
82
99
90
2-FC6H4
2,4-Cl2C6H3
2,6-Cl2C6H3
2-BrC6H4
2-HOe5-BrC6H3
4-O2NC6H4
4-Me2NC6H4
4j
4k
This reaction presumably proceeds by an initial Knoevenagel
condensation of the aldehyde and active methylene compound
followed by conjugate addition of the enamine and cyclisation
(Scheme 1).
3
R
CHO
In both cases the enamine tautomer 10 is calculated to be more
stable. In the case of 10a/11a the difference is 22.5 kJ molꢁ1, while in
the case of 10e/11e the difference is 30.6 kJ molꢁ1. Therefore, while
the calculations are unable to reproduce the similar levels of sta-
bility for the tautomers 10a and 11a, they do show that the pref-
erence for the enamine tautomer in 10e/11e should be more
pronounced compared to 10a/11a, as observed. It is clear from the
structures (Fig. 1) that the 2,6-dichlorophenyl ring in compounds
10e and 11e must be perpendicular to the dihydropyridine ring as
a result of the bulk of the chlorine atoms. This results in destabi-
lisation of the imine tautomer, since the methine hydrogen at po-
R
R
CN
CN
CN
CN
O N
2
CN
CN
2
NH
S
2
5
4
Scheme 1. Likely sequence of steps for the formation of compounds 4.
ꢀ
sition 7 is pushed closer to the sulfone (H7/O¼2.360 A in
ꢀ
compound 11a; 2.254 A in compound 11e).
The reaction also works with ethyl 2-cyanoacetate, with three
representative examples being shown in Table 2. In this case, the
intermediate could cyclise onto either the nitrile or the ester; only
the products (7) of cyclisation onto the nitrile were observed. Al-
though these reactions were carried out for a shorter time
As with the previous case, compound 10e showed hindered
rotation of the 2,6-dichlorophenyl ring, with the 13C resonances for
the methine carbon atoms in this ring being broadened and the
quaternary carbons not readily distinguished.
Table 2
Reactions of 2-nitromethylenethiazoline with ethyl 2-cyanoacetate and aldehydes
3
R
CHO
R
R
Et N
3
CO Et
2
CN
O
O N
CO Et
O N
2
O N
2
2
2
not
CH CN
3
CN
reflux, 1 h
N
N
NH
2
S
NH
S
S
6
1
7
8
Compound
R
Yield/%a
7a
7b
7c
4-ClC6H4
4-BrC6H4
4-NO2C6H4
78 (88)
73
70 (79)
a
Yields in parentheses refer to reactions carried out under solvent-free conditions grinding with a pestle in a mortar.

9524
C. Altug et al. / Tetrahedron 67 (2011) 9522e9528
Table 3
Reaction of 2-nitromethylenethiazoline with 2-phenylsulfonylacetonitrile and aldehydes
3
R
CHO
R
R
Et N
3
SO Ph
2
O N
2
SO Ph
2
O N
2
SO Ph
2
O N
2
+
CH CN
3
CN
reflux, 1 h
N
NH
2
N
NH
S
NH
S
S
9
1
10
11
Compound
R
Ratio 10/11
Yield/%
10a/11a
10b/11b
10c/11c
10d/11d
10e/11e
10f/11f
C6H5
4-FC6H4
4-ClC6H4
4-BrC6H4
2,6-Cl2C6H3
4-NO2C6H4
1:1.35
1.25:1
1:1.5
1.4:1
5:1
77
80
80
63
83
76
1.4:1
Fig. 1. Lowest energy conformations and calculated gas phase heats of formation (Hartrees) of 10a, 11a, 10e, 11e (HF 3-21G).
2. Biological evaluation
Melting points were determined on a MELTEMP apparatus and
uncorrected. TLC was done using precoated plates with fluorescent
indicator (Merck 5735). Solutions of permanganate and PMBA were
used for visualisation of the TLC spots.
New compounds were subjected to in vitro anticancer evalua-
tion using the MTT assay in four human cancer cell lines repre-
sentative of major cancer sub-typesdPC3 (prostate), LoVo
(colorectal), MCF-7 (breast) and A549 (non-small cell lung). GI50
values (50% growth inhibitory concentrations) are presented in
Table 4. In general the compounds were found to be fairly inactive,
however the low micromolar GI50 values for compound 4h in three
cell lines (PC3, LoVo and MCF-7) are encouraging and provide
a starting point for optimisation of anticancer activity.
Table 4
Activity of 5-amino-7-aryl-8-nitrothiazolo[3,2-a]pyridines against human breast
cancer cell linesa
GI50 values (
Compound
m
M)b in cell linesc
PC3
LoVo
MCF-7
A549
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
7a
7b
7c
10a/11a
10b/11b
10c/11c
10d/11d
10e/11e
10f/11f
>100
>100
>100
>100
>100
>100
95
>100
>100
>100
>100
>100
>100
50
>100
>100
>100
>100
>100
>100
>100
24
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
3. Conclusion
In conclusion, we have accomplished a very efficient synthesis
of the new nitrothiazolo[3,2-a]pyridines using an efficient multi-
component coupling reaction. One of the compounds prepared
shows promising anticancer activity in a range of cell lines.
25
21
15
>100
>100
>100
>100
12
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
61
>100
>100
>100
>100
>100
17
4. Experimental section
4.1. General
2-Nitromethylenethiazolidine was prepared according to a lit-
erature procedure.9 Infrared spectra were recorded on a SHIMADZU
FTIR-8400S instrument (KBr disc). Mass spectra were recorded on
a Fisons VG Platform II spectrometer and on a Micromass Q-TOF
Micro spectrometer. NMR spectra were recorded on a Bruker DPX
400 spectrometer operating at 400 MHz for 1H and at 100 MHz for
13C at 25 ꢀC. All chemical shifts are reported in parts per million
downfield from TMS. Coupling constants (J) are reported in hertz.
33
a
Determined by MTT assay (96 h drug exposure), see Biological, Experimental for
details.
b
c
Compounds tested in triplicate, data expressed as mean values.
Cancer cell line origin: PC-3 (prostate), LoVo (colorectal), MCF-7 (breast), A549
(non-small cell lung).

C. Altug et al. / Tetrahedron 67 (2011) 9522e9528
9525
4.2. General reaction procedure for preparation of thiazolo
[3,2-a]pyridines
(C), 120.1 (C), 61.6 (C), 51.2 (CH2), 40.7 (CH) and 27.9 (CH2); m/z (TOF
ESꢁ) 379 (MꢁHþ, 100%) and 377 (95).
Aromatic
aldehyde
(1 mmol,
1.0 equiv),
2-
nitromethylenethiazolidine (1 mmol, 1 equiv, 146 mg) and appro-
priate nitrile (1 mmol, 1.0 equiv) were mixed in MeCN (10 mL) in
a round-bottomed flask and the reaction mixture was stirred and
heated until all reactants dissolved. Triethylamine (50 mg,
0.5 mmol) was added and the reaction mixture heated under reflux
for 1e3 h (see Tables 1e3). After cooling, the solvent was removed
under reduced pressure and the residue recrystallised from hex-
ane/ethyl acetate mixtures to give the pure products with data
given below.
4.7. 5-Amino-7-(2-fluorophenyl)-8-nitro-3,7-dihydro-2H-
thiazolo[3,2-a]pyridine-6-carbonitrile (4e)
Obtained as a yellow solid (297 mg, 93%), mp 230 ꢀC (dec).
Found: (MꢁH)ꢁ, 317.0495. C14H10N4O2SF requires M, 317.0509; nmax
(KBr) 3431 (NH2), 2187 (CN) and 1659 (C]C) cmꢁ1
; dH (400 MHz;
DMSO-d6) 7.30e7.20 (2H, m, aromatic CH), 7.17e7.11 (2H, m, aro-
matic CH), 6.62 (2H, br s, NH2), 5.10 (1H, s, CHAr), 4.27 (2H, app. t, J
7.7, CH2N) and 3.45e3.30 (2H, m, obscured by water in DMSO,
CH2S); dC (100 MHz; DMSO-d6) 159.7 (d, 1JC,F 245.7, CeF), 158.1 (C),
2
3
4.3. 5-Amino-8-nitro-7-phenyl-3,7-dihydro-2H-thiazolo[3,2-
a]pyridine-6-carbonitrile (4a)
149.4 (C), 130.7 (d, JCeF 13.1, C), 129.5 (d, JCeF 4.1, CH meta to F),
3
4
129.1 (d, JCeF 8.3, CH meta to F), 124.8 (d, JCeF 3.3, CH para to F),
120.8 (C), 120.2 (C), 115.5 (d, 2JCeF 21.2, CH ortho to F), 60.7 (C), 51.2
(CH2), 35.2 (CH) and 27.9 (CH2); m/z (TOF ESꢁ) 353 (Mþ35Cl, 45%)
and 317 (MꢁH, 100).
Obtained as an orange solid (285 mg, 95%), mp 198e199 ꢀC.
Found: Mþ, 300.0685. C14H12N4O2S requires M, 300.0681; nmax
(KBr) 3345 (NH2), 2184 (CN) and 1658 (C]C) cmꢁ1
; dH (400 MHz;
DMSO-d6) 7.31 (2H, app. t, J 7.3, aromatic CH), 7.22 (1H, t, J 7.3, ar-
omatic CH), 7.19 (2H, d, J 7.0, aromatic CH), 6.57 (2H, br s, NH2), 4.77
(1H, s, CHPh), 4.34e4.18 (2H, m, CH2N) and 3.41e3.30 (2H, m, ob-
scured by water in DMSO, CH2S); dC (100 MHz; DMSO-d6) 157.9 (C),
149.6 (C), 144.5 (C), 128.9 (CH), 127.5 (CH), 127.4 (CH), 127.3 (C),
120.8 (C), 62.5 (C), 51.6 (CH2), 41.4 (CH) and 28.3 (CH2); m/z (TOF
EIþ) 300 (Mþ, 20%), 267 (60), 233 (100) and 223 (90).
4.8. 5-Amino-7-(2,4-dichlorophenyl)-8-nitro-3,7-dihydro-2H-
thiazolo[3,2-a]pyridine-6-carbonitrile (4f)
Obtained as a yellow solid (363 mg, 99%), mp 263e264 ꢀC.
Found: (MꢁH)ꢁ, 366.9829. C14H9N4O235Cl2S requires M, 366.9823;
nmax (KBr) 3396 (NH2), 2191 (CN) and 1658 (C]C) cmꢁ1
; dH
(400 MHz; DMSO-d6) 7.55 (1H, d, J 1.6, aromatic CH), 7.37 (1H, dd, J
8.3, 1.6, aromatic CH), 7.33 (1H, d, J 8.3, aromatic CH), 6.65 (2H, br s,
NH2), 5.30 (1H, s, CHAr), 4.28 (2H, app. t, J 7.6, CH2N) and 3.4e3.3
(2H, m, CH2S); dC (100 MHz; DMSO-d6) 158.6 (C), 149.5 (C), 140.3
(C), 132.8 (C), 132.2 (C), 131.3 (CH), 128.8 (CH), 127.9 (CH), 120.9 (C),
119.8 (C), 60.2 (C), 51.2 (CH2), 38.1 (CH) and 27.9 (CH2); m/z (TOF
ESꢁ) 371 (M, 14), 369 (M, 70) and 367 (M, 100).
4.4. 5-Amino-7-(4-fluorophenyl)-8-nitro-3,7-dihydro-2H-
thiazolo[3,2-a]pyridine-6-carbonitrile (4b)
Obtained as a yellow solid (287 mg, 90%), mp 232e233 ꢀC.
Found: (MꢁH)ꢁ, 317.0511. C14H10N4O2SF requires M, 317.0509; nmax
(KBr) 3433 (NH2), 2195 (CN) and 1659 (C]C) cmꢁ1
; dH (400 MHz;
DMSO-d6) 7.28e7.22 (2H, m, aromatic CH), 7.16e7.10 (2H, m, aro-
matic CH), 6.60 (2H, br s, NH2), 4.80 (1H, s, CHAr), 4.34e4.42 (2H, m,
CH2N) and 3.44e3.32 (2H, m, obscured by water in DMSO, CH2S); dC
(100 MHz; DMSO-d6) 161.2 (d, 1JCeF 241.3, CeF), 157.6 (C), 149.2 (C),
140.3 (d, 4JCeF 3.0, C para to F),129.0 (d, 3JCeF 8.2, CH meta to F),121.8
(C), 120.3 (C), 115.2 (d, 2JCeF 21.2, CH ortho to F), 61.9 (C), 51.2 (CH2),
40.4 (CH) and 27.9 (CH2); m/z (TOF ESꢁ) 317 (MꢁH, 100%).
4.9. 5-Amino-7-(2,6-dichlorophenyl)-8-nitro-3,7-dihydro-2H-
thiazolo[3,2-a]pyridine-6-carbonitrile (4g)
Obtained as an orange solid (356 mg, 97%), mp 279e281 ꢀC.
Found: (MꢁH)ꢁ, 366.9810. C14H9N4O235Cl2S requires M, 366.9823;
nmax (KBr) 3466 (NH2), 2180 (CN) and 1643 (C]C) cmꢁ1
; dH
4.5. 5-Amino-7-(4-chlorophenyl)-8-nitro-3,7-dihydro-2H-
thiazolo[3,2-a]pyridine-6-carbonitrile (4c)
(400 MHz; DMSO-d6) 7.46 (1H, d, J 7.0, aromatic CH), 7.39 (1H, d, J
7.4, aromatic CH), 7.27 (1H, app. t, J 7.7, aromatic CH), 6.69 (2H, br s,
NH2), 5.87 (1H, s, CHAr), 4.42e4.37 (1H, m, one of CH2N) and
4.25e4.17 (1H, m, one of CH2N) (CH2S peak obscured by broad
water peak from DMSO); dC (100 MHz; DMSO-d6) 160.2 (C), 150.8
(C), 136.2 (C), 136.0 (C), 134.8 (C), 130.9 (CH), 129.7 (CH), 129.0 (CH),
120.0 (C), 119.9 (C), 58.2 (C), 51.4 (CH2), 38.1 (CH) and 28.1 (CH2); m/
z (TOF ESꢁ) 371 (M, 10%), 369 (M, 47), 367 (M, 63) and 221 (100).
Obtained as an orange solid (315 mg, 94%), mp 213e215 ꢀC.
Found: (Mꢁ2H)þ, 332.0137. C14H9N4O2S35Cl requires M, 332.0135;
nmax (KBr) 3439 (NH2), 2189 (CN) and 1649 (C]C) cmꢁ1
; dH
(400 MHz; DMSO-d6) 7.37 (2H, d, J 8.4, aromatic CH), 7.23 (2H, d, J
8.4, aromatic CH), 6.62 (2H, br s, NH2),4.80 (1H, s, CHAr), 4.33e4.19
(2H, m, CH2N) and 3.40e3.10 (2H, m, obscured by water in DMSO,
CH2S); dC (100 MHz; DMSO-d6) 158.2 (C), 149.6 (C), 143.5 (C), 132.0
(C), 129.4 (CH), 128.9 (CH), 122.0 (C), 120.7 (C), 62.1 (C), 51.6 (CH2),
41.0 (CH) and 28.3 (CH2); m/z (TOF EIþ) 334 (Mþ, 28%), 332 (Mþ, 86),
267 (60) and 84 (100).
4.10. 5-Amino-7-(2-bromophenyl)-8-nitro-3,7-dihydro-2H-
thiazolo[3,2-a]pyridine-6-carbonitrile (4h)
Obtained as a yellow solid (368 mg, 97%), mp 242e244 ꢀC.
Found: (MꢁH)þ, 376.9713. C14H10N4O2S79Br requires M, 376.9708;
4.6. 5-Amino-7-(4-bromophenyl)-8-nitro-3,7-dihydro-2H-
thiazolo[3,2-a]pyridine-6-carbonitrile (4d)
nmax (KBr) 3446 (NH2), 2185 (CN) and 1649 (C]C) cmꢁ1
; dH
(400 MHz; DMSO-d6) 7.55 (1H, d, J 7.9, aromatic CH), 7.30 (1H, app.
t, J 7.4, aromatic CH), 7.27 (1H, dd, J 7.7, 1.5, aromatic CH), 7.16 (1H,
app. td, J 7.6, 1.5, aromatic CH), 6.60 (2H, br s, NH2), 5.31 (1H, s,
CHAr), 4.28 (2H, app. t, J 7.7, CH2N) and 3.45e3.20 (2H, m, obscured
by water in DMSO, CH2S); dC (100 MHz; DMSO-d6) 158.3 (C), 149.4
(C), 142.8 (C), 132.7 (CH), 130.0 (CH), 128.9 (CH), 128.3 (CH), 122.3
(C), 121.5 (C), 119.8 (C), 60.9 (C), 51.1 (CH2), 40.6 (CH) and 27.8 (CH2);
m/z (TOF ESꢁ) 379 (MꢁHþ, 100) and 377 (97).
Obtained as a yellow solid (299 mg, 79%), mp 240 ꢀC (dec).
Found: (MꢁH)þ, 376.9694. C14H10N4O2S79Br requires M, 376.9708;
nmax (KBr) 3416 (NH2), 2193 (CN) and 1640 (C]C) cmꢁ1
; dH
(400 MHz; DMSO-d6) 7.50 (2H, d, J 8.4, aromatic CH), 7.16 (2H, d, J
8.4, aromatic CH), 6.62 (2H, br s, NH2), 4.78 (1H, s CHAr), 4.33e4.17
(2H, m, CH2N), 3.40e3.30 (2H, m, CH2S); dC (100 MHz; DMSO-d6)
157.8 (C), 149.2 (C), 143.5 (C), 131.4 (CH), 129.3 (CH), 121.5 (C), 120.3

9526
C. Altug et al. / Tetrahedron 67 (2011) 9522e9528
4.11. 5-Amino-7-(5-bromo-2-hydroxyphenyl)-8-nitro-3,7-
dihydro-2H-thiazolo[3,2-a]pyridine-6-carbonitrile (4i)
(1H, m, one of CH2N), 4.20e4.03 (3H, m, one of CH2N and OCH2),
3.48e3.20 (2H, m, CH2S) and 1.19 (3H, t, J 7.1, CH3); dC (100 MHz;
CDCl3) 169.0 (C), 154.6 (C), 150.0 (C), 143.7 (C), 131.2 (CH), 130.0
(CH), 125.8 (C), 120.6 (C), 84.1 (C), 60.1 (CH2), 49.9 (CH2), 39.2 (CH),
28.3 (CH2) and 14.4 (CH3); m/z (TOF ESꢁ) 426 (MꢁH, 100%) and 424
(MꢁH, 97).
Obtained as a yellow solid (325 mg, 82%), mp 210 ꢀC (dec).
Found: (MꢁH)ꢁ, 392.9674. C14H10N4O3S79Br requires M, 392.9657;
nmax (KBr) 3471 (NH2), 2191 (CN) and 1649 (C]C) cmꢁ1
; dH
(400 MHz; DMSO-d6) 9.86 (1H, s, OH), 7.19 (1H, dd, J 8.6, 2.5, aro-
matic CH), 7.11 (1H, d, J 2.5, aromatic CH), 6.71 (1H, d, J 8.6, aromatic
CH), 6.48 (2H, br s, NH2), 5.00 (1H, s, CHAr), 4.39e4.31 (1H, app. td, J
10.7, 7.8, one of CH2N), 4.18e4.11 (1H, app. td, J 10.7, 7.7, one of
CH2N) and 3.40e3.30 (2H, m, obscured by water in DMSO, CH2S); dC
(100 MHz; DMSO-d6) 158.2 (C), 154.6 (C), 149.7 (C), 132.0 (C), 131.2
(CH), 130.5 (CH), 120.9 (C), 120.4 (C), 117.8 (CH), 109.9 (C), 60.7 (C),
51.1 (CH2), 36.6 (CH) and 27.8 (CH2); m/z (TOF ESꢁ) 395 (M, 100),
393 (M, 100), 249 (81) and 247 (84).
4.16. Ethyl 5-amino-8-nitro-7-(4-nitrophenyl)-3,7-dihydro-
2H-thiazolo[3,2-a]pyridine-6-carboxylate (7c)
Obtained as a yellow solid (275 mg, 70%), mp 145 ꢀC (dec).
Found: (MꢁH)ꢁ, 391.0699. C16H15O6N4S requires M, 391.0712; nmax
(KBr) 3425 (NH2), 1665 (CO) and 1630 (C]C) cmꢁ1
; dH (400 MHz;
DMSO-d6) 8.10 (2H, d, J 8.3, aromatic CH), 7.40 (2H, d, J 8.5, aromatic
CH), 6.60 (2H, br s, NH2), 5.40 (1H, s, CHAr), 4.41e4.29 (1H, m, one
of CH2N), 4.16e4.02 (3H, m, one of CH2N and OCH2), 3.55e3.29 (2H,
m, CH2S) and 1.18 (3H, t, J 7.1, CH3); dC (100 MHz; CDCl3) 168.7 (C),
155.3 (C), 151.9 (C), 150.2 (C), 146.9 (C), 129.3 (CH), 125.1 (C), 123.5
(CH), 83.3 (C), 60.2 (CH2), 50.1 (CH2), 39.9 (CH), 28.4 (CH2) and 14.4
(CH3); m/z (TOF ESꢁ) 393 (MꢁH, 100%).
4.12. 5-Amino-8-nitro-7-(4-nitrophenyl)-3,7-dihydro-2H-
thiazolo[3,2-a]pyridine-6-carbonitrile (4j)
Obtained as a yellow solid (342 mg, 99%), mp 214 ꢀC (dec).
Found: (MꢁH)ꢁ, 344.0455. C14H10N5O4S requires M, 344.0454; nmax
(KBr) 3331 (NH2), 2187 (CN) and 1661 (C]C) cmꢁ1
;
dH (400 MHz;
4.17. 8-Nitro-7-phenyl-6-(phenylsulfonyl)-3,7-dihydro-2H-
thiazolo[3,2-a]pyridin-5-amine (10a) and 8-nitro-7-phenyl-6-
(phenylsulfonyl)-6,7-dihydro-2H-thiazolo[3,2-a]pyridin-
5(3H)-imine (11a)
DMSO-d6) 8.19 (2H, d, J 8.5, aromatic CH), 7.51 (2H, d, J 8.5, aromatic
CH), 6.72 (2H, br s, NH2), 4.98 (1H, s, CHAr), 4.35e4.20 (2H, m,
CH2N) and 3.50e3.33 (2H, m, obscured by water in DMSO, CH2S); dC
(100 MHz; DMSO-d6) 158.4 (C), 151.4 (C), 149.4 (C), 146.6 (C), 128.4
(CH), 123.9 (CH), 121.0 (C), 120.1 (C), 60.8 (C), 51.3 (CH2), 40.0 (CH),
28.0 (CH2); m/z (TOF ESꢁ) 407 (MþCH3CNþNaꢁH, 60%) and 344
(MꢁH, 100%).
Obtained as a pale yellow solid (320 mg, 77%, 1:1.35 mixture of
10a/11a according to 1H NMR spectroscopic data), mp 227e230 ꢀC.
Found: (MꢁH)ꢁ, 414.0569. C19H16O4N3S2 requires M, 414.0582;
nmax (KBr) 3298 (NH2), 1636 (C]C), 1555, 1445, 1381, 1211 and
4.13. 5-Amino-7-(4-(dimethylamino)phenyl)-8-nitro-3,7-
1138 cmꢁ1
; dH (400 MHz; DMSO-d6) 9.70 (1H of 11a, s, NH),
dihydro-2H-thiazolo[3,2-a]pyridine-6-carbonitrile (4k)
7.87e7.77 (3H of 11a, m, aromatic CH of SO2Ph), 7.68 (2H of 11a,
app. dd, J 8.3, 7.3, aromatic CH of SO2Ph), 7.64 (2H of 10a, d, J 7.2,
aromatic CH of SO2Ph), 7.52 (1H of 10a, app. t, J 7.4, aromatic CH of
SO2Ph), 7.40 (2H of 10a, app. t, J 7.7, aromatic CH of SO2Ph),
7.35e7.23 (3H of 11a, m, aromatic CH), 7.18e7.08 (5H of 10a, m,
aromatic CH), 6.96 (2H of 11a, app. d, J 7.0, aromatic CH), 6.92 (2H of
10a, br s, NH2), 5.10 (1H of 10a, s, CHPh), 4.92 (1H of 11a, s, CHPh),
4.91 (1H of 11a, s, CHSO2Ph), 4.41 (1H of 11a, ddd, J 11.8, 8.7, 3.3, one
of CH2N), 4.35e4.23 (2H of 10a, m, CH2N), 4.13 (1H of 11a, app. td, J
11.4, 8.5, one of CH2N), 3.37 (2H of 10a, app. t, J 7.6, CH2S), 3.33e3.27
(1H of 11a, m, one of CH2S) and 3.09 (1H of 11a, app. td, J 11.1, 8.8,
one of CH2S); dC (100 MHz; DMSO-d6) 159.7 (C, 11a), 157.1 (C, 10a),
149.6 (C, 11a), 147.7 (C, 10a), 143.6 (C, 11a), 143.5 (C, 10a), 138.6 (C,
11a), 135.7 (C, 11a), 135.3 (CH, 11a), 132.4 (CH, 10a), 129.7 (CH, 10a),
129.4 (CH, 11a), 129.0 (CH, 10a), 128.6 (CH, 11a), 128.1 (CH, 10a),
128.1 (CH, 11a), 127.7 (CH, 11a), 126.8 (CH, 10a), 126.6 (CH, 11a),
125.7 (CH, 10a), 123.7 (C, 10a), 119.6 (C, 11a), 86.3 (C, 10a), 69.9 (CH,
11a), 51.5 (CH2, 11a), 51.0 (CH2, 10a), 40.2 (CH, 11a), 39.9 (CH, 10a),
28.2 (CH2, 10a) and 27.8 (CH2, 11a); m/z (TOF ESꢁ) 414 (MꢁH, 100%)
and 340 (21).
Obtained as a brick-red solid (308 mg, 90%), mp 226 ꢀC (dec).
Found: (MꢁH)ꢁ, 342.1018. C16H16N5O2S requires M, 342.1025; nmax
(KBr) 3343 (NH2), 2184 (CN) and 1649 (C]C) cmꢁ1
; dH (400 MHz;
DMSO-d6) 6.98 (2H, d, J 8.7, aromatic CH), 6.64 (2H, d, J 8.7, aromatic
CH), 6.48 (2H, br s, NH2), 4.64 (1H, s, CHAr), 4.30e4.19 (2H, m,
CH2N), 3.40e3.30 (2H, m, obscured by water in DMSO, CH2S) and
2.85 (6H, s, NMe2); dC (100 MHz; DMSO-d6) 157.0 (C), 149.8 (C),
149.1 (C), 131.9 (C), 127.9 (CH), 122.8 (C), 120.8 (C), 112.6 (CH), 63.1
(C), 51.3 (CH), 40.4 (2ꢂCH3), 40.2 (CH) and 28.1 (CH2); m/z (TOF ESꢁ)
342 (MꢁH, 100%).
4.14. Ethyl 5-amino-7-(4-chlorophenyl)-8-nitro-3,7-dihydro-
2H-thiazolo[3,2-a]pyridine-6-carboxylate (7a)
Obtained as an orange solid (295 mg, 78%), mp 214e216 ꢀC.
Found: (MꢁH)ꢁ, 380.0486. C16H15O4N3S35Cl requires M, 380.0472;
nmax (KBr) 3420 (NH2), 1667 (CO) and 1632 (C]C) cmꢁ1
; dH
(400 MHz; DMSO-d6) 7.27 (4H, app. s, aromatic CH), 6.57 (2H, br s,
NH2), 5.36 (1H, s, CHAr), 4.41e4.32 (1H, m, one of CH2N), 4.17e4.08
(3H, m, one of CH2N and OCH2), 3.43e3.35 (2H, m, CH2S) and 1.25
(3H, t, J 8.5, CH3); dC (100 MHz; CDCl3) 169.0 (C), 154.9 (C), 149.9 (C),
143.1 (C), 132.4 (C), 129.7 (CH), 128.2 (CH), 125.7 (C), 84.0 (C), 60.1
(CH2), 49.9 (CH2), 39.1 (CH), 28.3 (CH2) and 14.4 (CH3); m/z (TOF
ESꢁ) 382 (MꢁH, 40%) and 380 (MꢁH, 100).
4.18. 7-(4-Fluorophenyl)-8-nitro-6-(phenylsulfonyl)-3,7-
dihydro-2H-thiazolo[3,2-a]pyridin-5-amine (10b) and 7-(4-
fluorophenyl)-8-nitro-6-(phenylsulfonyl)-6,7-dihydro-2H-
thiazolo[3,2-a]pyridin-5(3H)-imine (11b)
Obtained as a pale yellow solid (345 mg, 80%, 1.25:1 mixture of
10b/11b according to 1H NMR spectroscopic data), mp 243e244 ꢀC.
Found: (MꢁH)ꢁ, 432.0497. C19H16O4N3S2F requires M, 432.0488;
nmax (KBr) 3293 (NH2), 1638 (C]C), 1562, 1449, 1379, 1215 and
4.15. Ethyl 5-amino-7-(4-bromophenyl)-8-nitro-3,7-dihydro-
2H-thiazolo[3,2-a]pyridine-6-carboxylate (7b)
Obtained as an orange solid (310 mg, 73%), mp 213e214 ꢀC.
Found: (MꢁH)ꢁ, 423.9980. C16H15N3O4S79Br requires M, 423.9967;
1138 cmꢁ1
; dH (400 MHz; DMSO-d6) 9.69 (1H of 11b, s, NH),
7.85e7.77 (3H of 11b, m, aromatic CH of SO2Ph), 7.71e7.62 (2H of
10b and 2H of 11b, m, aromatic CH of SO2Ph), 7.53 (1H of 10b, app. t,
J 7.4, aromatic CH of SO2Ph), 7.41 (2H of 10b, app. t, J 7.7, aromatic CH
of SO2Ph), 7.19e7.12 (4H of 10b, m, aromatic CH of AreF), 7.05e7.00
nmax (KBr) 3416 (NH2), 1667 (CO) and 1632 (C]C) cmꢁ1
; dH
(400 MHz; DMSO-d6) 7.34 (2H, d, J 8.5, aromatic CH), 7.15 (2H, d, J
8.5, aromatic CH), 6.50 (2H, br s, NH2), 5.31 (1H, s, CHAr), 4.35e4.24

C. Altug et al. / Tetrahedron 67 (2011) 9522e9528
9527
(2H of 11b, m, aromatic CH of AreF), 6.98e6.91 (2H of 11b, m, ar-
omatic CH of AreF), 6.95 (2H of 10b, br s, NH2), 5.08 (1H of 10b, s,
CHAr), 4.92 (2H of 11b, app. s, CHAr, CHSO2Ph), 4.40 (1H of 11b, ddd,
J 11.9, 7.0, 2.7, one of CH2N), 4.34e4.24 (2H of 10b, m, CH2N), 4.14
(1H of 11b, app. td, J 11.3, 8.5, one of CH2N), 3.37 (2H of 10b, app. t, J
7.6, CH2S), 3.35e3.27 (1H of 11b, m, one of CH2S) and 3.08 (1H of
11b, app. td, J 11.1, 8.8, one of CH2S); dC (100 MHz; DMSO-d6) 161.6
CHAr), 4.94 (1H of 11d, s, CHAr), 4.91 (1H of 11d, s, CHSO2Ph), 4.39
(1H of 11d, ddd, J 11.2, 7.2, 2.9, one of CH2N), 4.34e4.25 (2H of 10d,
m, CH2N), 4.13 (1H of 11d, app. td, J 11.5, 8.5, one of CH2N), 3.38 (2H
of 10d, app. t, J 7.7, CH2S), 3.35e3.28 (1H of 11d, m, one of CH2S) and
3.09 (1H of 11d, app. td, J 11.1, 8.8, one of CH2S); dC (100 MHz;
DMSO-d6) 160.0 (C, 11d), 157.3 (C, 10d), 149.5 (C, 11d), 147.7 (C, 10d),
143.4 (C, 10d), 143.0 (C, 11d), 137.9 (C, 11d), 135.6 (CH, 11d), 135.4 (C,
10d), 132.4 (CH, 11d), 132.2 (CH, 10d), 130.9 (CH, 10d), 130.1 (CH,
10d), 129.7 (CH, 11d), 129.0 (CH, 10d), 128.9 (CH, 11d), 128.6 (CH,
11d), 125.7 (CH, 10d), 123.1 (C, 10d), 121.2 (C, 11d), 119.9 (C, 10d),
119.1 (C, 11d), 85.7 (C, 10d), 69.6 (CH, 11d), 51.5 (CH2, 11d), 51.0 (CH2,
10d), 48.6 (CH, 10d), 39.6 (CH, 11d), 28.2 (CH2, 10d) and 27.8 (CH2,
11d); m/z (TOF ESꢁ) 494 (MꢁHþ, 48%), 492 (50), 339 (100), 325 (70),
311 (60) and 265 (75).
1
(d, 1JCeF 244.3, CeF, 11b), 161.0 (d, JCeF 242.8, CeF, 10b), 157.1 (C,
10b), 149.6 (C, 11b), 147.7 (C, 10b), 143.5 (C, 10b), 139.8 (d, 4JCeF 3.2, C
4
para to F, 11b), 135.6 (C, 10b), 135.3 (CH, 11b), 134.7 (d, JCeF 3.0, C
para to F, 11b),132.4 (CH,11b),129. 7 (CH,10b),129.7 (d, 3JCeF 7.6, CH
3
meta to F, 11b), 128.9 (CH, 10b), 128.8 (d, JCeF 8.6, CH meta to F),
128.6 (C, 11b), 125.7 (CH, 10b), 123.4 (C, 10b), 119.5 (C, 11b), 116.1 (d,
2JCeF 21.7, CH ortho to F, 11b), 114.7 (d, 2JCeF 21.3, CH ortho to F, 10b),
86.1 (C, 10b), 69.8 (CH, 11b), 51.5 (CH2, 11b), 51.0 (CH2, 10b), 40.0
(CH, 10b), 39.87 (CH, 11b), 28.2 (CH2, 10b) and 27.8 (CH2, 11b); m/z
(TOF ESꢁ) 432 (MꢁH, 100%) and 180 (56).
4.21. 8-Nitro-7-(2,6-dichlorophenyl)-6-(phenylsulfonyl)-3,7-
dihydro-2H-thiazolo[3,2-a]pyridin-5-amine (10e) and 7-(2,6-
dichlorophenyl)-8-nitro-6-(phenylsulfonyl)-6,7-dihydro-2H-
thiazolo[3,2-a]pyridin-5(3H)-imine (11e)
4.19. 7-(4-Chlorophenyl)-8-nitro-6-(phenylsulfonyl)-3,7-
dihydro-2H-thiazolo[3,2-a]pyridin-5-amine (10c) and 7-(4-
chlorophenyl)-8-nitro-6-(phenylsulfonyl)-6,7-dihydro-2H-
thiazolo[3,2-a]pyridin-5(3H)-imine (11c)
Obtained as an orange solid (0.5 mmol scale, 200 mg, 83%, 5:1
mixture of 10e/11e according to 1H NMR spectroscopic data), mp
271e273 ꢀC. Found: (MꢁH)þ, 481.9816; C19H14O4N3S235Cl2 requires
M, 481.9803; nmax (KBr) 3443, 3339, 1639, 1444, 1296, 1246, 1230
Obtained as a pale yellow solid (360 mg, 80%, 1:1.5 mixture of
10c/11c according to 1H NMR spectroscopic data), mp 246e247 ꢀC.
Found: (MꢁH)ꢁ, 448.0183. C19H16O4N3S235Cl requires M, 448.0193;
nmax (KBr) 3293 (NH2), 1638 (C]C), 1557, 1447, 1383, 1219 and
and 1138 cmꢁ1
; dH (400 MHz; DMSO-d6) (data for 10e only) 7.66
(2H, app. d, J 7.5, aromatic CH of SO2Ph), 7.52 (1H, app. t, J 7.4,
aromatic CH of SO2Ph), 7.42 (2H, app. t, J 7.7, aromatic CH of
SO2Ph), 7.36e7.27 (1H, m, aromatic CH of AreCl2), 7.20 (2H, br s,
NH2), 7.12e7.05 (2H, m, aromatic CH of AreCl2), 5.91 (1H, s, CHAr),
4.54 (1H, app. td, J 11.6, 7.3, one of CH2N), 4.23 (1H, app. td, J 10.5,
8.2, one of CH2N) and 3.37e3.27 (2H, m, CH2S); dC (100 MHz;
DMSO-d6) (data for 10e only, quaternary carbon atoms of 2,6-
dichlorophenyl not observed due to hindered rotation) 159.1 (C),
148.8 (C), 143.2 (C), 132.4 (CH), 129.8 (CH), 128.9 (CH), 128.8 (CH),
125.20 (CH), 120.0 (C), 82.2 (C), 50.9 (CH2), 37.2 (CH), 27.5 (CH2);
m/z (TOF ESꢁ) 486 (MꢁH, 23%), 484 (MꢁH, 64) and 482 (MꢁHþ,
100).
1138 cmꢁ1
; dH (400 MHz; DMSO-d6) 9.68 (1H of 11c, s, NH),
7.85e7.77 (3H of 11c, m, aromatic CH of SO2Ph), 7.71e7.64 (2H of
10c and 2H of 11c, m, aromatic CH of SO2Ph), 7.54 (1H of 10c, app.
t, J 7.4, aromatic CH of SO2Ph), 7.42 (2H of 10c, app. t, J 7.8, aro-
matic CH of SO2Ph), 7.38 (2H of 11c, d, J 8.5, aromatic CH of AreCl),
7.20 (2H of 10c, d, J 8.6, aromatic CH of AreCl), 7.15 (2H of 10c, d, J
8.6, aromatic CH of AreCl), 6.99e7.03 (2H of 11c, d, J 8.5, aromatic
CH of AreCl), 6.97 (2H of 10c, br s, NH2), 5.06 (1H of 10c, s, CHAr),
4.93 (1H of 11c, s, CHAr), 4.92 (1H of 11c, s, CHSO2Ph), 4.39 (1H of
11c, ddd, J 11.9, 8.7, 3.3, one of CH2N), 4.33e4.25 (2H of 10c, m,
CH2N), 4.13 (1H of 11c, app. td, J 11.4, 8.6, one of CH2N), 3.37 (2H of
10c, app. t, J 7.6, CH2S), 3.34e3.26 (1H of 11c, m, one of CH2S) and
3.09 (1H of 11c, app. td, J 11.1, 8.8, CH2S); dC (100 MHz; DMSO-d6)
159.9 (C, 10c), 157.3 (C, 11c), 149.5 (C, 10c), 147.7 (C, 11c), 143.4 (C,
11c), 142.6 (C, 11c), 137.5 (C, 10c), 135.6 (C, 10c), 135.4 (CH, 10c),
132.7 (C, 10c), 132.4 (CH, 11c), 131.4 (C, 11c), 129.7 (CH, 10c), 129.7
(CH, 11c), 129.3 (CH, 10c), 129.0 (CH, 11c), 128.6 (CH, 10c), 128.6
(CH, 10c), 127.9 (CH, 11c), 125.7 (CH, 11c), 123.1 (C, 11c), 119.2 (C,
10c), 85.5 (C, 10c), 69.6 (CH, 11c), 51.5 (CH2, 11c), 51.0 (CH2, 10c),
39.2 (CH, 10c), 39.0 (CH, 11c), 28.2 (CH2, 10c) and 27.8 (CH2, 11c);
m/z (TOF ESꢁ) 450 (MꢁH, 42%), 448 (MꢁH, 100), 341 (48), 339 (95)
and 163 (55).
4.22. 8-Nitro-7-(4-nitrophenyl)-6-(phenylsulfonyl)-3,7-dihydro-
2H-thiazolo[3,2-a]pyridin-5-amine (10f) and 8-nitro-7-(4-
nitrophenyl)-6-(phenylsulfonyl)-6,7-dihydro-2H-thiazolo[3,2-
a]pyridin-5(3H)-imine (11f)
Obtained as light brown crystals (350 mg, 76%, 1.4:1 mixture of
1
10f/11f according to H NMR spectroscopic data), mp 184e186 ꢀC.
Found: (MꢁH)ꢁ, 459.0414. C19H16N4O6S2 requires M, 459.0433;
nmax (KBr) 3289 (NH2), 1637 (C]C), 1559, 1443, 1383, 1219 and
1138 cmꢁ1
; dH (400 MHz; DMSO-d6) 9.69 (1H of 11f, s, NH), 8.18 (2H
of 11f, d, J 8.7, aromatic CH of AreNO2), 8.01 (2H of 10f, d, J 8.8,
aromatic CH of AreNO2), 7.86e7.80 (3H of 11f, m, aromatic CH of
SO2Ph), 7.73e7.67 (2H of 10f and 2H of 11f, m, aromatic CH of
SO2Ph), 7.54 (1H of 10f, app. t, J 7.4, aromatic CH of SO2Ph),
7.47e7.40 (4H of 10f, m, aromatic CH of AreNO2 and SO2Ph), 7.33
(2H of 11f, app. d, J 8.7, aromatic CH of AreNO2), 7.09 (2H of 10f, br s,
NH2), 5.19 (1H of 10f, s, CHAr), 5.09 (1H of 11f, s, CHAr), 5.03 (1H of
11f, s, CHSO2Ph), 4.41 (1H of 11f, ddd, J 12.0, 8.7, 3.4, one of CH2N),
4.37e4.30 (2H of 10f, m, CH2N), 4.17 (1H of 11f, app. td, J 11.4, 8.6,
one of CH2N), 3.40 (2H of 10f, app. t, J 7.7, CH2S), 3.38e3.31 (1H of
11f, m, one of CH2S) and 3.12 (1H of 11f, app. td, J 11.1, 8.9, one of
CH2S); dC (100 MHz; DMSO-d6) 160.4 (C, 11f), 157.9 (C, 10f), 150.9 (C,
10f),149.4 (C,11f),147.9 (C,10f),147.2 (C,11f),146.2 (C,10f),145.7 (C,
11f), 143.3 (C, 10f), 135.5 (CH, 11f), 132.5 (CH, 10f), 129.8 (CH, 11f),
129.2 (CH, 10f), 129.0 (CH, 10f), 128.6 (CH, 11f), 128.3 (CH, 11f), 125.7
(CH, 10f), 124.4 (CH, 11f), 123.2 (CH, 10f), 122.4 (C, 10f), 118.5 (C, 11f),
85.1 (C, 10f), 69.1 (CH, 11f), 51.6 (CH2, 11f), 51.1 (CH2, 10f), 40.1 (CH,
4.20. 7-(4-Bromophenyl)-8-nitro-6-(phenylsulfonyl)-3,7-
dihydro-2H-thiazolo[3,2-a]pyridin-5-amine (10d) and 7-(4-
bromophenyl)-8-nitro-6-(phenylsulfonyl)-6,7-dihydro-2H-
thiazolo[3,2-a]pyridin-5(3H)-imine (11d)
Obtained as a pale yellow solid (310 mg, 63%, 1.4:1 mixture of
10d/11d according to 1H NMR spectroscopic data), mp 243e245 ꢀC.
Found: (MꢁH)ꢁ, 491.9710. C19H16O4N3S729Br requires M, 491.9687;
nmax (KBr) 3293 (NH2), 1638 (C]C), 1555, 1447, 1383, 1219 and
1138 cmꢁ1
; dH (400 MHz; DMSO-d6) 9.69 (1H of 11d, s, NH),
7.87e7.70 (2H of 10d, m, aromatic CH of SO2Ph), 7.72e7.65 (5H of
11d, m, aromatic CH of SO2Ph), 7.58e7.50 (2H of 11d and 1H of 10d,
m, aromatic CH), 7.43 (2H of 10d, app. t, J 7.7, aromatic CH of SO2Ph),
7.34 (2H of 10d, app. d, J 8.4, aromatic CH of AreBr), 7.11 (2H of 10d,
app. d, J 8.4, aromatic CH of AreBr), 6.99 (2H of 10d, br s, NH2), 6.96
(2H of 11d, app. d, J 8.5, aromatic CH from AreBr), 5.05 (1H of 10d, s,

9528
C. Altug et al. / Tetrahedron 67 (2011) 9522e9528
10f), 39.6 (CH,11f), 28.2 (CH2,10f) and 27.9 (CH2,11f); m/z (TOF ESꢁ)
459 (MꢁH, 100%) and 339 (60).
software. DMSO concentration in the culture medium never
exceeded 0.2%.
Acknowledgements
4.23. General procedure for the preparation of thiazolopy-
ridines under solvent-free conditions
_
We are extremely grateful to the Abant Izzet Baysal University, Di-
rectorate of Research Projects Commission (BAP grant 2011.03.03.391).
2-Nitromethylenethiazolidine (0.5 mmol, 1 equiv), aromatic al-
dehyde (0.5 mmol, 1 equiv), ethyl cyanoacetate (0.5 mmol, 1 equiv)
and triethylamine (0.25 mmol, 0.5 equiv) were ground together for
10 min using a pestle and mortar at ambient temperature. The
mixture was then dissolved in ethyl acetate (25 mL) and the solu-
tion washed with water (3ꢂ15 mL). The organic solution was then
dried over magnesium sulfate and the solvent removed under re-
duced pressure. The crude product was recrystallised from hexane/
ethyl acetate mixtures to give the pure products with data as al-
ready reported.
Supplementary data
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2011.10.005.
References and notes
€
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The four human cancer cell lines useddA549 (lung), PC3
(prostate), LoVo (colorectal) and MCF-7 (breast)dare cell lines
representative of major cancer types and available from American
Type Culture Collection (http://www.atcc.org). All cancer cell lines
were cultured in DMEM (Dulbecco’s Modified Eagle Medium)
containing 10% heat inactivated foetal calf serum (FCS) (A549 and
MCF-7) or 10% FCS (LoVo and PC3). Cells were passaged routinely
and kept at 37 ꢀC and 5% CO2. Exponentially growing cells were
used in all experiments. Cell viability was measured using the
established MTT assay,13 a colorimetric assay that measures the
reduction of MTT tetrazolium dye to purple formazan in living cells.
Cells (3e10ꢂ103/well) were seeded into 96-well microtiter plates
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€ €
Sakurai, A.; Midorikawa, H. Synthesis 1981, 531e533; Altug, C.; Durust, Y.; Elliott,
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with the sulfur. For leading references see Rajappa, S.; Nagarajan, K.; Venka-
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12. Spartan 10; Wavefunction Inc. http://www.wavefun.com Conformational
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moved and replaced with 150
mL of media containing test com-
pounds at concentrations of 0.1, 1, 10 and 100
mM (diluted from
10 mM DMSO stock solution) for 96 h, in addition to media only
control. Following exposure to test compounds, media was again
removed and replaced with MTT solution in phenol red free RPMI
(0.5 mg/mL). Absorbance was measured at 540 nm using a micro-
plate reader spectrophotometer, and inhibition of proliferation was
assessed as the percentage reduction of absorbance of treated cells
versus control cultures. The concentration of compounds that de-
creased cell viability by 50% (IC50) was calculated using Calcusyn