A rapid and efficient protocol for the synthesis of novel nitrothiazolo[3,2-c]pyrimidines via microwave-mediated Mannich cyclisation

Article abstract of DOI:10.1016/j.tet.2014.02.003

Several 6-substituted-8-nitrothiazolo[3,2-c]pyrimidine derivatives have been obtained very efficiently by a multicomponent cyclisation of 2-(nitromethylene)thiazolidine, formaldehyde and various aliphatic or aromatic amines in water, using both microwave

Full text of DOI:10.1016/j.tet.2014.02.003

Tetrahedron 70 (2014) 2122e2128
Contents lists available at ScienceDirect
Tetrahedron
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A rapid and efficient protocol for the synthesis of novel nitrothiazolo
[3,2-c]pyrimidines via microwave-mediated Mannich cyclisation
,
a
a
b
Muhammet Yıldırım a , Derya C¸ elikel , Yas¸ ar Durust , David W. Knight ,
*
€ €
Benson M. Kariuki b
a
_
Department of Chemistry, Faculty of Arts and Sciences, Abant Izzet Baysal University, TR-14280 Bolu, Turkey
b School of Chemistry, Cardiff University, Main College, Cardiff CF10 3AT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Several 6-substituted-8-nitrothiazolo[3,2-c]pyrimidine derivatives have been obtained very efficiently by
a multicomponent cyclisation of 2-(nitromethylene)thiazolidine, formaldehyde and various aliphatic or
aromatic amines in water, using both microwave irradiation and conventional heating. Reaction yields
were considerably higher and the reaction times very much reduced using microwave heating when
compared to conventional heating, resulting in the definition of a rapid and efficient synthetic protocol.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 12 December 2013
Received in revised form 20 January 2014
Accepted 3 February 2014
Available online 7 February 2014
Keywords:
Nitroenamine
One-pot reaction
Multicomponent
Mannich
Microwave heating
1. Introduction
piperidones have been reported.22e24 Among these compounds,
thiazolopyrimidines, which can act as purine antagonists, are
Microwave energy was first introduced for the heating of food
products. However, in the 1980s, microwave heating was found to
significantly accelerate many organic transformations.1,2 For such
microwave-induced organic syntheses, many reaction media and
conditions have been employed, including neat reactions or re-
actions in the presence of a phase transfer catalyst (e.g., alumina,
clayfen, Aliquat 336),3e5 under an open atmosphere, in a closed-
cup6e9 or under pressure,10,11 in water, ionic liquids or various or-
ganic solvents. In the last decade, the number of microwave-
assisted organic reactions has increased exponentially due to the
many advantages associated with its use, the most important of
which are arguably greater speed and enhanced efficiency.
The Mannich reaction is an important part of many multicom-
ponent reactions in synthetic chemistry and there are many useful
applications including the Betti, PicteteSpengler and Kabach-
nikeFields reactions.12,13 In these, a variety of monocyclic and fused
heterocyclic compounds such as triazolothiadiazole, pyrroloqui-
noline, benzimidazole, oxadiazole, naphthopyran, piperidone and
pyrimidine rings can be obtained in various ways.14e21
known to have potential biological importance, as these can act as
purine antagonists. They are formed by combining thiazole and
pyrimidine rings at differing positions (Fig. 1).
N
N
N
N
N
N
S
S
S
N
Thiazolo
[4,5-d]pyrimidine
Thiazolo
[3,2-a]pyrimidine
Thiazolo
[3,2-c]pyrimidine
Fig. 1. Main structures of thiazolopyrimidines.
Thiazolo[4,5-d]pyrimidines can be obtained by attaching a py-
rimidine ring to a thiazole ring (azine method), or by formation of
a pyrimidine from a substituted thiazole-containing compound.
Many examples of thiazolo[3,2-a]pyrimidines can be found in the
recent literature, which have been prepared by reactions of enones
with 2-aminothiazoles in hot ethanol, or by reaction of dihy-
Some examples of Mannich-type multicomponent reactions
using enamines for the preparation of tetrahydropyrimidines and
dropyrimidine-2-thiones with
a-bromo-phenylacetaldehyde in
acetonitrile.25e27 Compounds having a thiazolo[3,2-a]-pyrimidine
ring have shown a wide variety of biological activities (e.g., anti-
tuberculotic, anti-tumour, bronchodilators, central nervous system
* Corresponding author. Tel.: þ90 374 254 1000; fax: þ90 374 253 4642; e-mail
addresses: muhammetyildirim@ibu.edu.tr, mammy25@hotmail.com (M. Yıldırım).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.003

M. Yıldırım et al. / Tetrahedron 70 (2014) 2122e2128
2123
(CNS) depressants, analgesic, anti-human immunodeficiency virus
(HIV)-1, anti-inflammatory, anti-microbial, anti-diuretic and CNS-
active agents)28e35 (Fig. 2). It occurred to us that an efficient syn-
thetic approach to these highly bioactive molecules could feature
a multicomponent reaction, which employs sequential inter- and
intra-molecular enamineeimine Mannich condensations. We rea-
soned that this might require an initial thiazolidine having a highly
reactive enamine function, which would encourage a second imine
formation step prior to closure of the dihydropyrimidine ring (see
mechanistic rationale below). After a number of trials, we discov-
ered that highly reactive 2-(nitromethylene)thiazolidine provided
the desired reactivity, in combination with 2 equiv of formaldehyde
and a variety of primary amines, resulting in the definition of the
scope and limitations of a new approach to reduced thiazolo[3,2-c]
of the product under MW conditions. However, we found that there
were, at best, only very slight beneficial effects associated with
adding the clays (Montmorillonite KSF and K10) and the total yields
were found as low to moderate (Table 1, entry 1e6). We modified
the MW conditions by not using any heterogeneous catalysts and
also did not add any solvent. The yield of the reaction was thus
improved to moderate levels; however, more significantly, the re-
action time for complete consumption of starting materials was
lowered from 2 h with conventional heating to a remarkable 5 min
using MW irradiation (Table 1, entry 7). When more polar solvents
such as ethanol or acetonitrile were used, a small increment was
observed in terms of reaction yields, but there was no significant
change in reaction times for either conventional or MW heating
(Table 1, entry 8). Finally, water was used as solvent in this model
reaction, since it has a high dielectric constant, and is suitable for
microwave-mediated reactions. We were pleased to find that the
best results were obtained for the reaction in water without any
catalyst at reflux temperature for conventional heating or around
90 ꢀC for MW heating (Table 1, entry 9). Of course, this was very
convenient as the formaldehyde could simply be added as formalin.
After determining that the most suitable solvent was water, and
optimising the reaction conditions for the preparation of 6a, a va-
riety of amines 4 having alkyl or aryl substituents were reacted
with formaldehyde 5 and 2-(nitromethylene)thiazolidine 3.
Under the optimal conditions, we produced novel 6-
substituted-8-nitro-3,5,6,7-tetrahydro-2H-thiazolo[3,2-c]pyrimi-
dine derivatives in good to excellent yields (65e100%). An espe-
cially important outcome in terms of reaction yields was that at
least 50% higher yields were often obtained under MW conditions
when compared with conventional heating and the reaction times
were reduced to minutes from several hours (Table 2). On the other
hand, the experiments showed that no cyclisation occurred with
many heterocyclic (especially N-containing) amines or examples,
which were sterically hindered (Table 2, entries 16e23) under ei-
ther conventional heating or MW irradiation. Even when the re-
action times were extended to 16 h (conventional) or 3e6 min
(MW), no Mannich cyclisation products were observed or isolated.
These results strongly suggest that if the amine 4 is insufficiently
nucleophilic, for whatever reason, to allow formation of an imine as
a first step, or subsequently an iminium ion at a later stage with
formaldehyde (see Scheme 2 below) then the sequence will fail and
only a few by-products will be obtained (Fig. 3).
pyrimidines. Herein, we provide
methodology.
a
full description of this
F
O
Cl
Cl
N
O
N
S
N
N
O
O
N
N
S
O
N
S
Anti-HIV-1 derivative
Anti-malarial derivative
Setoperone (antidepressant drug)
O
N
N
N
O
F
S
N
S
Analgesic derivative
Anti-cancer derivative
Fig. 2. Different thiazolo[3,2-a]pyrimidine derivatives having diverse biological ac-
tivities (drugs or proved activity).
Initially, this one-pot three-component Mannich sequence was
carried out using conventional heating, but later work revealed that
the use of microwave activation both improved the product yields
and greatly reduced the reaction times. The resulting optimised
method is simple, environmentally friendly and highly efficient.
Novel thiazolo[3,2-c]pyrimidine derivatives have been prepared
by this method in excellent yields and we believed that these and
related structures may well possess biological activities as they are
structurally similar to known bioactive thiazolo[3,2-a]pyrimidines
(Fig. 2).
However, the number of unsuccessful cyclisations is limited
when compared with the number of successful examples (Table 2,
entries 1e15). Based on these successful results, we can say that this
Mannich-based three multicomponent cyclisation method was
suitable for the efficient and green production of 6-substituted-8-
nitro-3,5,6,7-tetrahydro-2H-thiazolo[3,2-c]pyrimidines.
2. Results and discussion
In order to expand the scope of this efficient microwave-
mediated protocol, amines 4 were substituted by a diamine, 4,40-
oxydianiline 4ax, which was reacted with 2 equiv of nitroenamine 3
and 4 equiv of formaldehyde 5 under both heating conditions
(Scheme 1). The expected bicyclic product 6ax was obtained in
quantitative yield without any need for chromatographic separa-
tion, as it directly precipitated out of the cooled solution and only
required washing and drying to secure the pure product. This result
indicates that many other bis-amines could be used in this meth-
odology leading to many types of bicyclic thiazolo[3,2-c]pyrimi-
dines in a highly efficient manner. In addition, the microwave
cyclisation protocol is especially ‘green’ and effective since no or-
ganic solvent or purification material is used.
The starting material, 2-(nitromethylene)thiazolidine 3, was
easily and efficiently obtained by heating 1,1-bis(methylthio)-2-
nitroethylene 1 and 2-aminoethanethiol 2 together in ethanol at
reflux.36 However, in the present work, we found that the nitro-
enamine 3 could also be obtained under microwave conditions
with a considerably shorter reaction time (20 min) when compared
with the reported method (30 h).
In our initial optimisation experiments, microwave irradiation
(MW) was compared with conventional heating with or without
additives using, as a model reaction, the combination of 2-(nitro-
methylene)thiazolidine,
phenylethylamine. These preliminary results are presented in
Table 1.
formaldehyde
and
(R)-(þ)-1-
The structures of all new compounds 6aeax were fully sup-
ported by means of IR, 1H NMR, 13C NMR and HRMS measurements.
Also, the structures of 6g and chiral, non-racemic products 6a and
6b were further elucidated by X-ray crystallographic analysis;37 the
full datasets have been deposited at the Cambridge X-ray database
(R)-(þ)-1-Phenylethylamine 4a was reacted with equivalent
quantities of the nitroenamine 3, but varying stoichiometries of
formaldehyde 5. Several solvents and two heterogeneous catalysts
have been tried in order to understand their effect on the formation

2124
M. Yıldırım et al. / Tetrahedron 70 (2014) 2122e2128
Table 1
Optimisation of reaction conditions to yield compound 6a
NH2
O2N
O2N
reaction conditions
N
H
O
+
+
S
or MW
S
N
NH
H
3
4a
5
6a
Entry
Reaction conditions
Additivea
Time
Yield (%)
D
(h)
MW (min)
D
MW
1
2
3
4
5
6
7
8
9
EtOH, 3 (1 equiv), 4a (1 equiv), 5 (1.5 equiv)
1
1
2
2
1
2
d
d
d
5
3
4
2
5
3
2
4
3
3
4
3
6
4
5
5
5
32
25
45
40
24
49
66
68
92
40
36
52
34
32
63
73
76
100
Toluene, 3 (1 equiv), 4a (1 equiv), 5 (1.5 equiv)
CH3CN, 3 (1 equiv), 4a (1 equiv), 5 (1.5 equiv)
Neat, 3 (1 equiv), 4a (1 equiv), 5 (3.0 equiv)b
CH2Cl2, 3 (1 equiv), 4a (1 equiv), 5 (2.0 equiv)
H2O, 3 (1 equiv), 4a (1 equiv), 5 (1.0 equiv)
Neat, 3 (1 equiv), 4a (1 equiv), 5 (2.5 equiv)b
EtOH, 3 (1 equiv), 4a (1 equiv), 5 (2.0 equiv)
H2O, 3 (1 equiv), 4a (1 equiv), 5 (2.0 equiv)
2.5
a
(1): Montmorillonite KSF; (2): Montmorillonite K10, were used (0.5e1.0 g) during MW heating only; The reactions were performed at reflux temperature of the solvents
specified.
b
The reactions were carried out at 90 ꢀC.
Table 2
Reaction conditions and yields of title compounds 6(aez)
O2N
R
O2N
N
1 equiv.3 and4
2 equiv.5, H2O
O
R
+
+
H2N
S
NH
N
S
H
H
3
4
5
6
Entry
Compound
R
CHa
Yieldc
(%)
MWb
Yieldc
(%)
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
(R)-(þ)-1-Phenylethyl
2.5h
2.5h
2h
92
70
94
41
35
82
65
77
70
63
78
70
42
58
32
NR
NR
NR
NR
NR
NR
NR
NR
5 min
4 min
4 min
4 min
4 min
4 min
4 min
4 min
4 min
4 min
4 min
4 min
7 min
4 min
4 min
4 min
6 min
4 min
6 min
6 min
4 min
3 min
5 min
100
95
100
65
65
100
95
98
80
80
100
100
72
76
55
NR
NR
NR
NR
NR
NR
NR
NR
(R)-(þ)-1-Phenylpropyl
(S)-(ꢁ)-1-Phenylpropyl
Butyl
3h
Propyl
Cyclohexyl
Benzyl
3-Trifluoromethylbenzyl
2-Methylthienyl
4-Chlorobenzyl
Isopropyl
3.5h
2.5h
4h
5h
4h
4h
3.5h
3h
6h
5h
6h
3h
4h
5h
4h
8h
3h
8h
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
6j
6k
6l
Diphenyl
6m
6n
6o
6p
6r
6s
6t
6u
6v
6y
6z
Benzo[d][1,3]dioxol-5-yl
4-Fluorophenyl
p-Tolyl
2-Thiazoyl
2-Mercaptobenzo[d]imidazol-5-yl
2-(1-Piperazinyl)ethyl
1,2,4-Triazoyl
6-Methylpyridyl
6-nitroquinolin-5-yl
1-Naphthyl
2,6-Dichloro-4-nitrophenyl
16h
a
Reactants of 0.5 mmol in 20 mL of water at reflux.
Reactants of 0.5 mmol in 2 mL of water at 90 ꢀC.
Total yields after column chromatographic separation.
b
c
(95%)
O2N
O
O
O
H2O,2.5h, reflux
NO2
O2N
+
+
S
NH
N
N
H
H
or
H2N
NH2
H2O,MW,90°C,3 min
(100%)
3
N
4ax
(1 eq.)
N
5
S
S
6ax
(2 eq.)
(4 eq.)
Scheme 1. Synthesis of bicyclic thiazolo[3,2-c]pyrimidine derivative 6ax.

M. Yıldırım et al. / Tetrahedron 70 (2014) 2122e2128
2125
H
N
MW
H
O
imine
H
NH2
R
R
OH
formation
-H2O
H
H
5
4
H
R
H
NO2
N
O2N
R
MW
N
Mannich
reaction
H
H
H
S
O
N
-H2O
H
S
N
3
OH2
O2N
R
H
R
N
O2N
Mannich
N
N
H
S
cyclisation
S
N
6
H
Scheme 2. Proposed microwave-mediated mechanism for the formation of derivatives 6.
O2N
S
R
O2N
N
O
R
+
+
H2N
NH
N
X
S
H
H
conventional or MW
3
4p-z
6
R
S
N
N
N
N
N
SH
N
N
N
NH
H
Cl
N
O2N
Cl
NO2
Fig. 3. Unreactive heterocyclic or bulky amine derivatives 4pez as Mannich substrate.
with reference numbers CCDC 968252, 968253 and 968251, re-
spectively (Figs. 4 and 5).
Fig. 5. X-ray crystal structures of 6b and 6g.
forms between the primary amine 4 and formaldehyde 5. This then
undergoes thermally induced condensation with the nitroenamine
3 to give a
b-amino-substituted nitroimine (or nitroenamine),
Fig. 4. X-ray crystal structure of 6a.
which is the precursor of an iminium ion, following a second
condensation with formaldehyde. Finally, an internal cyclisation of
this iminium ion with the thiazoline C]N group results in
Given that the Mannich cyclisation takes place by imine for-
mation, we can describe a mechanism in which first such an imine

2126
M. Yıldırım et al. / Tetrahedron 70 (2014) 2122e2128
formation of the 6-substituted-8-nitro-3,5,6,7-tetrahydro-2H-
thiazolo[3,2-c]pyrimidine products (Scheme 2).
reaction progress was followed by TLC every 2 min and upon
completion, reaction was stopped by cooling the microwave system
to 50 ꢀC by external vacuum system. The same work-up procedure
as in the conventional heating reactions was applied and products 6
were isolated in a pure state.
3. Conclusion
We have developed a new, efficient and environmentally friendly
approach to the synthesis of novel thiazolo[3,2-c]pyrimidines using
Mannich reactions under microwave irradiation. This method is very
effective for accessing such heterocycles having a diverse range of
substituents. The protocol is an example of green chemistry since
water is used as the solvent and often no other (organic) solvent is
required at any stage. We also believe that this efficient microwave
synthesis of thiazolo[3,2-c]pyrimidines is remarkable in terms of
microwave-based synthetic chemistry and will be a new example in
this area. First and foremost, this new series of thiazolo[3,2-c]py-
rimidines might display some important and diverse biological ac-
tivities; screening is in progress for potential anticancer activities on
MCF-7 cell lines in cooperation with our pharmacological laborato-
ries and any positive results will be reported elsewhere.
4.2.1. (R)-(þ)-8-Nitro-6-(1-phenylethyl)-3,5,6,7-tetrahydro-2H-thia-
zolo[3,2-c]pyrimidine (6a). Flash chromatography (50% hexane/
EtOAc) afforded yellow crystals (135 mg, 100% with MW; 124 mg,
92% with conv. heating). Mp 156e157 ꢀC; Rf (50% hexane/EtOAc)
0.60; [
a]
20 þ24.3 (c 1.0, CHCl3); nmax (KBr) 3026 (arom. CeH), 2972
D
(CeH), 2854, 1552 (C]CeNO2), 1452, 1350, 1253, 1190, 1149, 1020,
748, 702 cmꢁ1
; dH (400 MHz, CDCl3) 7.27e7.36 (5H, m, Ph), 4.20
(1H, d, J 12.0 Hz), 4.12 (1H, d, J 16.4 Hz), 3.95(2H, dd, J 18.8, 12.4 Hz),
3.67e3.74 (2H, m), 3.59 (1H, quartet, J 8.7 Hz), 3.15 (2H, t, J 7.6 Hz),
1.42 (3H, d, J 6.4 Hz); dC (100 MHz, CDCl3) 21.7, 28.1, 46.4, 54.1, 59.5,
65.2, 115.1, 127.4, 128.0, 129.0, 143.4, 162.2; m/z (TOF-MS ESþ) 292
(100, MHþ), 291 (1), 235 (3), 134 (3%); HRMS (TOF-MS ESþ): MHþ,
found 292.1120. C14H18N3O2S requires 292.1120.
4. Experimental
4.1. General
4.2.2. (R)-(þ)-8-Nitro-6-(1-phenylpropyl)-3,5,6,7-tetrahydro-2H-
thiazolo[3,2-c]pyrimidine (6b). Flash chromatography (33% hexane/
EtOAc) afforded yellow crystals (144 mg, 95% with MW; 106 mg
with conv. heating). Mp 184e185 ꢀC; Rf (50% hexane/EtOAc) 0.55;
1H and 13C NMR spectra were recorded on VARIAN spectrome-
ters (400 MHz for proton and 100 MHz for carbon) and all chemical
[a
]
þ33.5 (c 1.0, CHCl3); nmax (KBr) 3026 (arom. CeH), 2964
20
D
(CeH), 2874, 1552 (C]CeNO2), 1483, 1352, 1257, 1180, 1147, 1091,
shifts (
d
) are reported in parts per million (ppm) downfield from
956, 916, 868, 743, 704 cmꢁ1
;
dH (400 MHz, CDCl3) 7.23e7.36 (5H,
TMS; J values are given in hertz (Hz). IR spectra were recorded on
a SHIMADZU FTIR-8400S instrument (KBr pellet or NaCl discs).
High resolution mass spectra were run on a Waters Lct Premier XE
oa-TOF Mass Spectrometer. Single crystal X-ray diffraction mea-
surements were run on an EnrafeNonius CAD-4 Diffractometer.
Specific rotations were run by a Rudolph Research Analytical
Autopol I Automatic polarimeter. A single-mode Microwave reactor
(CEM Discover Explorer SP) was used for microwave-mediated
reactions. Melting points were determined on a MELTEMP appa-
ratus and are uncorrected. TLC was carried out using precoated
plates with fluorescent indicator (Merck 5735) for monitoring the
reactions. Column chromatographic separations were performed
on silica gel (200e300 mesh). Staining solutions of permanganate,
phosphomolybdic acid and iodine were used for visualisation of the
spots.
m, Ph), 4.18 (1H, dd, J 16.0, 1.2 Hz), 4.16 (1H, d, J 12.0 Hz), 3.95 (2H,
dd, J 14.0, 1.6 Hz), 3.64 (1H, dt, J 10.8, 8.0 Hz), 3.50 (1H, dt, J 10.4,
8.0), 3.45 (1H, q, J 4.6 Hz), 3.10 (2H, t, J 8.0 Hz), 1.96e2.00 (1H, m),
1.69e1.80 (1H, m), 0.67 (3H, t, J 7.4 Hz); dC (100 MHz, CDCl3) 10.8,
26.9, 28.0, 46.3, 54.0, 65.4, 66.3, 115.2, 128.1, 128.4, 128.8, 140.7,
162.1; m/z (TOF-MS ESþ) 305 (100, MHþ), 243 (1), 159 (2), 148 (5),
119 (2%); HRMS (TOF-MS ESþ): MHþ, found 306.1276. C15H20N3O2S
requires 306.1268.
4.2.3. (S)-(ꢁ)-8-Nitro-6-(1-phenylpropyl)-3,5,6,7-tetrahydro-2H-
thiazolo[3,2-c]pyrimidine (6c). Flash chromatography (33% hexane/
EtOAc) afforded yellow crystals (79 mg, 100% with MW; 143 mg,
94% with conv. heating). Mp 187e188 ꢀC; Rf (50% hexane/EtOAc)
0.45; [
a
]
20 ꢁ32.8 (c 1.0, CHCl3); nmax (KBr) 3030 (arom. CeH), 2962
D
(CeH), 2850, 1550 (C]CeNO2), 1481, 1383, 1253, 1176, 1150, 1012,
740, 703 cmꢁ1
; dH (400 MHz, CDCl3) 7.23e7.36 (5H, m, Ph), 4.16 (2H,
4.2. Synthesis of thiazolo[3,2-c] pyrimidines (6)
dd, J 16.4, 8.4 Hz), 3.96 (2H, dd, J 13.2, 2.4 Hz), 3.64 (1H, dt, J 10.8,
8.0 Hz), 3.51 (1H, dt, J 10.8, 8.0 Hz), 3.44 (1H, dd, J 9.6, 4.4 Hz), 3.10
(1H, t, J 8.0 Hz), 1.94e2.01 (1H, m), 1.69e1.80 (1H, m), 0.67 (3H, t, J
7.2 Hz); dC (100 MHz, CDCl3) 10.5, 26.7, 27.8, 46.1, 53.7, 65.1, 66.1,
114.9, 127.8, 128.1, 128.6, 140.4, 161.8; m/z (TOF-MS ESþ) 306 (100,
MHþ), 297 (5), 148 (5%); HRMS (TOF-MS ESþ): MHþ, found
306.1256. C15H20N3O2S requires 306.1276.
General procedure (conventional heating)
2-(Nitromethylene)thiazolidine 3 (0.5 mmol, 1.0 equiv) and
a primary amine 4 (0.5 mmol, 1.0 equiv) were dissolved in water
(20 mL) and the resulting suspension was stirred for 5 min.
Formaldehyde 5 (37% v/v solution in water, 1.0 mmol, 2.0 equiv)
was added dropwise by syringe and the resulting mixture was
refluxed for 2e6 h under an argon atmosphere. The reaction
progress was followed by TLC and upon completion, the reaction
mixture was cooled to ambient temperature. The resulting pre-
cipitate was filtered off using a sintered funnel and washed with
water (2ꢂ10 mL). After drying, the crude products were purified by
flash column chromatography on silica gel, using the mixtures of
EtOAc and hexanes specified, to afford the title compound 6 in
a pure state.
4.2.4. 6-Butyl-8-nitro-3,5,6,7-tetrahydro-2H-thiazolo[3,2-c]pyrimi-
dine (6d). Flash chromatography (25% hexane/EtOAc) afforded
a yellow powder (78 mg, 65% with MW; 49 mg with conv. heating).
Mp 124e125 ꢀC; Rf (50% hexane/EtOAc) 0.40; nmax (KBr) 2949, 2926
(CeH), 2854, 1552 (C]CeNO2), 1462, 1359, 1280, 1188, 1151, 1128,
1018, 985, 958, 744, 665, 607 cmꢁ1
; dH (400 MHz, CDCl3) 4.15 (2H,
s), 3.89 (2H, s), 3.81 (2H, t, J 8.0 Hz), 3.19 (2H, t, J 8.0 Hz), 2.54 (2H, t, J
7.4 Hz), 1.51 (2H, p, J 7.4 Hz), 1.35 (2H, sextet, J 7.6 Hz), 0.92 (3H, t, J
7.2 Hz); dC (100 MHz, CDCl3) 14.1, 20.5, 28.0, 30.2, 48.3, 53.1, 54.3,
67.7,115.1,162.1; m/z (TOF-MS ESþ) 244 (100, MHþ), 228 (1),159 (8),
61 (1%); HRMS (TOF-MS ESþ): MHþ, found 244.1125. C10H18N3O2S
requires 244.1120.
General procedure (microwave heating)
2-(Nitromethylene)thiazolidine 3 (0.5 or 0.25 mmol, 1.0 equiv),
a primary amine 4 (0.5 or 0.25 mmol,1.0 equiv) and formaldehyde 5
(37% v/v solution in water,1.0 or 0.5 mmol, 2.0 equiv) were mixed in
water (2 mL) and the resulting suspension was pre-stirred for 1 min
in a microwave reactor prior to reaction. Then the reaction mixture
was heated at exactly 90 ꢀC in the dynamic mode for 4e6 min. The
4.2.5. 8-Nitro-6-propyl-3,5,6,7-tetrahydro-2H-thiazolo[3,2-c]pyrimi-
dine (6e). Flash chromatography (25% hexane/EtOAc) afforded

M. Yıldırım et al. / Tetrahedron 70 (2014) 2122e2128
2127
a yellow solid (38 mg, 65% with MW; (0.5 mmol) 40 mg, 35% with
conv. heating). Mp 132e133 ꢀC; Rf (50% hexane/EtOAc) 0.30; nmax
(KBr) 2960 (CeH), 2933, 2874, 1550 (C]CeNO2), 1383, 1359, 1249,
(KBr) 2922 (CeH), 2852, 1552 (C]CeNO2), 1481, 1450, 1350, 1251,
1188, 1143, 1014, 802, 665 cmꢁ1
dH (400 MHz, CDCl3) 7.32 (2H, d, J
;
8.8 Hz), 7.26 (2H, d, J 8.8 Hz), 4.10 (2H, s), 3.92 (2H, s), 3.75 (2H, t, J
7.6 Hz), 3.70 (2H, s), 3.20 (2H, t, J 7.6 Hz); dC (100 MHz, CDCl3) 28.0,
48.6, 54.2, 56.8, 66.4, 115.0, 129.1, 130.4, 133.8, 135.8, 161.6; m/z
(TOF-MS ESþ) 312 (100, MHþ), 257 (3), 230 (3), 156 (2%); HRMS
(TOF-MS ESþ): MHþ, found 312.0563. C13H15ClN3O2S requires
312.0574.
1186, 1130, 1018, 744, 665 cmꢁ1
; dH (400 MHz, CDCl3) 4.16 (2H, s),
3.89 (2H, s), 3.81 (2H, t, J 7.6 Hz), 3.19 (2H, t, J 8.0 Hz), 2.51 (2H, t, J
7.2 Hz), 1.55 (2H, p, J 7.6 Hz), 0.93 (3H, t, J 7.2 Hz); dC (100 MHz,
CDCl3) 11.6, 21.1, 27.8, 48.0, 54.1, 55.0, 67.6, 115.0, 161.4; m/z (TOF-
MS ESþ) 230 (100, MHþ), 159 (10%); HRMS (TOF-MS ESþ): MHþ,
found 230.0954.C9H16N3O2S requires 230.0963.
4.2.11. 6-Isopropyl-8-nitro-3,5,6,7-tetrahydro-2H-thiazolo[3,2-c]py-
rimidine (6k). Flash chromatography (33% hexane/EtOAc) afforded
a yellow solid (58 mg, 100% with MW; 89 mg, 78% with conv.
heating). Mp 128e129 ꢀC; Rf (33% hexane/EtOAc) 0.10e0.20; nmax
(KBr) 2970 (CeH), 2926, 2868, 1550 (C]CeNO2), 1460, 1377, 1278,
4.2.6. 6-Cyclohexyl-8-nitro-3,5,6,7-tetrahydro-2H-thiazolo[3,2-c]py-
rimidine (6f). Flash chromatography (33% hexane/EtOAc) afforded
a yellow solid (67.5 mg, 100% with MW; (0.5 mmol) 110 mg, 82%
with conv. heating). Mp 138e139 ꢀC; Rf (50% hexane/EtOAc) 0.30;
nmax (KBr) 2931 (CeH), 2856, 1550 (C]CeNO2), 1450, 1357, 1263,
1255, 1188, 1151, 1122, 1014, 748, 693 cmꢁ1
; dH (400 MHz, CDCl3)
1188, 1153, 1020, 738, 665 cmꢁ1
;
dH (400 MHz, CDCl3) 4.26 (2H, s),
4.23 (2H, s), 3.83 (2H, t, J 8.0 Hz), 3.75 (2H, s), 3.17 (2H, t, J 8.4 Hz),
2.80 (1H, septet, J 6.4 Hz), 1.00 (6H, d, J 6.0 Hz); dC (100 MHz, CDCl3)
21.1, 28.1, 45.5, 51.0, 54.3, 64.7, 114.7, 162.9; m/z (TOF-MS ESþ) 230
(100, MHþ), 188 (1), 159 (2%); HRMS (TOF-MS ESþ): MHþ, found
230.0957. C9H16N3O2S requires 230.0963.
4.00 (2H, s), 3.81 (2H, t, J 7.6 Hz), 3.19 (2H, t, J 7.6 Hz), 2.50e2.58 (1H,
m), 1.88e1.90 (2H, m), 1.78e1.81 (2H, m), 1.62 (1H, d, J 12.0 Hz),
1.12e1.31 (5H, m); dC (100 MHz, CDCl3) 25.5, 25.9, 28.1, 31.0, 45.5,
54.0, 59.7, 64.6, 116.0, 162.6; m/z (TOF-MS ESþ) 270 (100, MHþ), 218
(3), 112 (5%); HRMS (TOF-MS ESþ): MHþ, found 270.1260.
C
12H20N3O2S requires 270.1276.
4.2.12. 6-Benzhydryl-8-nitro-3,5,6,7-tetrahydro-2H-thiazolo[3,2-c]
pyrimidine (6l). Flash chromatography (33% hexane/EtOAc) affor-
ded yellow crystals (89 mg, 100% with MW; 123 mg, 70% with conv.
heating). Mp 184e185 ꢀC; Rf (EtOAc) 0.70e0.75; nmax (KBr) 3026
(arom. CeH), 2922 (CeH), 2856,1552 (C]CeNO2),1477,1448,1390,
4.2.7. 6-Benzyl-8-nitro-3,5,6,7-tetrahydro-2H-thiazolo[3,2-c]pyrimi-
dine (6g). Flash chromatography (33% hexane/EtOAc) afforded
a yellow powder (65 mg, 95% with MW; 90 mg, 65% with conv.
heating). Mp 132e133 ꢀC; Rf (50% hexane/EtOAc) 0.45; nmax (KBr)
3028 (arom. CeH), 2922 (CeH), 2854, 1554 (C]CeNO2), 1473,1350,
1356, 1253, 1192, 1145, 1020, 748, 707 cmꢁ1
; dH (400 MHz, CDCl3)
7.44 (4H, d, J 7.2 Hz), 7.29 (4H, t, J 7.2 Hz), 7.21 (2H, tt, J 7.2, 1.2 Hz),
4.67 (1H, s), 4.08 (2H, s), 3.77 (2H, s), 3.53 (2H, t, J 7.6 Hz), 3.19 (2H, t,
J 8.0 Hz); dC (100 MHz, CDCl3) 28.2, 46.9, 54.4, 64.8, 68.8, 113.5,
115.0, 128.1, 128.2, 129.4, 130.6, 142.4, 162.7; m/z (TOF-MS ESþ) 354
(100, MHþ), 278 (5), 258 (5), 250 (2),193 (5%); HRMS (TOF-MS ESþ):
MHþ, found 354.1262. C19H20N3O2S requires 354.1276.
1251, 1188, 1143, 1024, 742, 700 cmꢁ1
; dH (400 MHz, CDCl3)
7.27e7.37 (5H, m, Ph), 4.10 (2H, s), 3.96 (2H, s), 3.75 (2H, t, J 8.4 Hz),
3.72 (2H, s), 3.20 (2H, t, J 7.8 Hz); dC (100 MHz, CDCl3) 28.1, 48.8,
54.2, 57.6, 66.3, 115.1, 128.1, 128.9, 129.2, 137.3, 161.6; m/z (TOF-MS
ESþ) 278 (100, MHþ), 276 (1), 228 (2), 120 (3%); HRMS (TOF-MS
ESþ): MHþ, found 278.0958. C13H16N3O2S requires 278.0963.
4.2.13. 6-(Benzo[d][1,3]dioxol-5-yl)-8-nitro-3,5,6,7-tetrahydro-2H-
thiazolo[3,2-c]pyrimidine (6m). Flash chromatography (33% hex-
ane/EtOAc) afforded yellow crystals (55 mg, 72% with MW; 64 mg,
42% with conv. heating). Mp 182e183 ꢀC; Rf (33% hexane/EtOAc)
0.40e0.50; nmax (KBr) 3015 (arom. CeH), 2928 (CeH), 2895, 1550
(C]CeNO2), 1483, 1382, 1357, 1246, 1197, 1149, 1120, 1031, 950, 748,
4.2.8. 8-Nitro-6-(3-(trifluoromethyl)benzyl)-3,5,6,7-tetrahydro-2H-
thiazolo[3,2-c]pyrimidine (6h). Flash chromatography (25% hexane/
EtOAc) afforded yellow crystals (84 mg, 98% with MW; 133 mg, 77%
with conv. heating). Mp 181e182 ꢀC; Rf (33% hexane/EtOAc) 0.50;
nmax (KBr) 2926 (CeH), 2856, 1552 (C]CeNO2), 1489, 1460, 1357,
1327, 1286, 1251, 1188, 1118, 1147, 1072, 987, 792, 700 cmꢁ1
;
dH
665 cmꢁ1
; dH (400 MHz, CDCl3) 6.77 (1H, d, J 5.6 Hz), 6.75 (1H, s),
(400 MHz, DMSO-d6) 7.72 (1H, s), 7.65 (2H, d, J 7.2 Hz), 7.59 (1H, t, J
7.6 Hz), 4.29 (2H, s), 3.85 (2H, t, J 8.0 Hz), 3.80 (2H, s), 3.74 (2H, s),
3.23 (2H, t, J 8.0 Hz); dC (100 MHz, DMSO-d6) 28.1, 47.9, 54.5, 56.3,
67.1, 112.8, 122.8, 124.0, 124.8, 125.5, 129.3, 132.5, 139.5, 161.5; m/z
(TOF-MS ESþ) 346 (100, MHþ), 254 (10), 246 (3), 145 (1%); HRMS
(TOF-MS ESþ): MHþ, found 346.0841. C14H15F3N3O2S requires
346.0837.
6.35 (1H, dd, J 8.0, 2.4 Hz), 5.92 (2H, s, eOeCH2eOe), 4.79 (2H, s),
4.32 (2H, s), 3.87 (2H, t, J 8.0 Hz), 3.16 (2H, t, J 8.4 Hz); dC (100 MHz,
CDCl3) 28.1, 48.0, 54.3, 65.3, 101.3, 101.6, 108.8, 110.3, 114.4, 142.6,
143.8, 148.7, 163.2; m/z (TOF-MS ESþ) 308 (100, MHþ), 255 (12), 235
(10), 227 (5), 150 (20%); HRMS (TOF-MS ESþ): MHþ, found
308.0693. C13H14N3O4S requires 308.0705.
4.2.14. 6-(4-Fluorophenyl)-8-nitro-3,5,6,7-tetrahydro-2H-thiazolo
[3,2-c]pyrimidine (6n). Flash chromatography (33% hexane/EtOAc)
afforded a pale orange solid. (50 mg, 76% with MW; 82 mg, 58%
with conv. heating). Mp 185e186 ꢀC; Rf (50% hexane/EtOAc)
0.35e0.40; nmax (KBr) 3015 (arom. CeH), 2924 (CeH), 2852, 1548
(C]CeNO2), 1508, 1356, 1280, 1251, 1201, 1147, 1122, 1068, 1006,
4.2.9. 8-Nitro-6-(thiophen-2-ylmethyl)-3,5,6,7-tetrahydro-2H-thia-
zolo[3,2-c]pyrimidine (6i). Flash chromatography (25e33% hexane/
EtOAc)afforded a yellow solid (56 mg, 80% with MW; 99 mg, 70%
with conv. heating). Mp 173e174 ꢀC; Rf (33% hexane/EtOAc) 0.40;
nmax (KBr) 3097 (arom. CeH), 2922 (CeH), 2854, 1550 (C]CeNO2),
1467, 1357, 1286, 1184, 1143, 1122, 1022, 977, 850, 742, 707 cmꢁ1
;
dH
746, 665 cmꢁ1
s), 4.14 (2H, s), 3.92 (2H, t, J 8.4 Hz), 3.19 (2H, t, J 8.0 Hz); dC
(100 MHz, CDCl3) 28.1, 47.7, 54.4, 64.8, 114.3, 116.3e116.5 ( -C to
-C to CeF, Jmeta¼10 Hz),
; dH (400 MHz, CDCl3) 7.04e7.13 (4H, m, Ph), 4.89 (2H,
(400 MHz, CDCl3) 7.29 (1H, dd, J 5.2, 1.6 Hz), 6.94e6.97(2H, m), 4.15
(2H, s), 4.00 (2H, s), 3.93 (2H, s), 3.76 (2H, t, J 7.6 Hz), 3.20 (2H, t, J
7.8 Hz); dC (100 MHz, CDCl3) 28.1, 48.5, 52.1, 54.2, 65.8, 114.9, 126.2,
127.0, 127.1, 140.6, 161.6; m/z (TOF-MS ESþ) 284 (100, MHþ), 231 (2),
159 (5%); HRMS (TOF-MS ESþ): MHþ, found 284.0525. C11H14N3O2S
requires 284.0527.
a
CeF, Jortho¼22 Hz), 119.8e119.9
(b
145.13e145.15 (quarter. C in Ph ring, Jpara¼2.2 Hz), 158.5e158.9
(CeF carbon, J¼232 Hz), 163.3; m/z (TOF-MS ESþ) 282 (100, MHþ),
222 (35), 214 (12), 208 (3%); HRMS (TOF-MS ESþ): MHþ, found
282.0700. C12H13FN3O2S requires 282.0713.
4.2.10. 6-(4-Chlorobenzyl)-8-nitro-3,5,6,7-tetrahydro-2H-thiazolo
[3,2-c]pyrimidine (6j). Flash chromatography (25% hexane/EtOAc)
afforded a yellow solid (63 mg, 80% with MW; 98 mg, 63% with
conv. heating). Mp 174e175 ꢀC; Rf (33% hexane/EtOAc) 0.40; nmax
4.2.15. 8-Nitro-6-(4-methylphenyl)-3,5,6,7-tetrahydro-2H-thiazolo
[3,2-c]pyrimidine (6o). Flash chromatography (33% hexane/EtOAc)
afforded bright yellow crystals (35 mg, 55% with MW; 44 mg, 32%

2128
M. Yıldırım et al. / Tetrahedron 70 (2014) 2122e2128
with conv. heating). Mp 194e195 ꢀC; Rf (EtOAc) 0.55e0.45; nmax
(KBr) 3032 (arom. CeH), 2922 (CeH), 2856, 1550 (C]CeNO2), 1512,
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1450, 1356, 1278, 1251, 1201, 1145, 1124, 1070, 815, 748 cmꢁ1
; dH
8. Vallin, K. S. A.; Emilsson, P.; Larhed, M.; Hallberg, M. A. J. Org. Chem. 2002, 67,
6243e6246.
(400 MHz, CDCl3) 7.03 (2H, d, J 8.0 Hz), 6.88 (2H, d, J 8.4 Hz), 4.84
(2H, s), 4.36 (2H, s), 3.87 (2H, t, J 8.0 Hz), 3.13 (2H, t, J 8.0 Hz), 2.16
(3H, s); dC (100 MHz, CDCl3) 20.7, 28.1, 47.3, 54.4, 64.6, 114.4, 118.0,
130.4, 130.7, 146.1, 163.2; m/z (TOF-MS ESþ) 278 (100, MHþ), 207
(23), 173 (4), 143 (10), 122 (15%). HRMS (TOF-MS ESþ): MHþ, found
278.0956. C13H16N3O2S requires 278.0963.
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4.2.16. 6,60-(4,40-Oxybis(4,1-phenylene))bis(8-nitro-3,5,6,7-tetrahy-
dro-2H-thiazolo[3,2-c]pyrimidine) (6ax). Flash chromatography
(25% hexane/EtOAc) afforded bright yellow crystals. (135 mg, 100%
with MW; 256 mg, 95% with conv. heating). Mp 188 ꢀC (decomp.);
Rf (33% hexane/EtOAc) 0.20e0.30; nmax (KBr) 3053 (arom. CeH),
2987 (CeH), 2870, 1550 (C]CeNO2), 1502 (CeOeC), 1450, 1356,
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1263, 1203, 1149, 1122, 1068, 731, 665 cmꢁ1
; dH (400 MHz, CDCl3)
7.03 (2ꢂ2H, d, J 9.2 Hz), 6.89 (2ꢂ2H, d, J 8.8 Hz), 4.86 (2ꢂ2H, s), 4.40
(2ꢂ2H, s), 3.92 (2ꢂ2H, t, J 8.0 Hz), 3.20 (2ꢂ2H, t, J 8.0 Hz); dC
(100 MHz, CDCl3) 28.1, 47.9, 54.3, 64.6, 114.4, 119.7, 119.9, 144.3,
152.0, 163.3; m/z (TOF-MS ESþ) 541 (100, MHþ), 331 (45), 302 (15),
174 (5%); HRMS (TOF-MS ESþ): MHþ, found 541.1317. C24H25N6O5S2
requires 541.1328.
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We gratefully acknowledge the financial supports of Abant Izzet
Baysal University, Directorate of Research Projects Commission
(BAP grant no. 2013.03.03.600) and TUBITAK (Turkish Scientific and
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Cambridge Crystallographic Data Centre, 12 Union Road, GB-Cambridge
CB21EZ; fax: þ44 1223 336 033; or deposit@ccdc.cam.ac.uk.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.02.003.
References and notes
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