Stereoselective synthesis of (E)-halomethylidene[1,3]thiazolo[3,2-a] thieno[3,2-e] pyrimidinium and analogous [1,3]oxazolo[3,2-a] thieno[3,2-e]pyrimidinium halides starting from 3-N-substituted 2-propargylthio(oxy)thieno[2,3-d] pyrimidin-4-ones

Article abstract of DOI:10.1515/hc-2013-0036

A convenient procedure for the stereoselective synthesis of [1,3]thiazolo[3,2-a]thieno[3,2-e]pyrimidinium halides and analogous [1,3]oxazolo[3,2-a] thieno[3,2-e]pyrimidinium halides 5 and 6 is reported. 2-Propargylthio-3-R-thieno[2,3-d]pyrimidin-4-ones and 2-propargyloxy-3-R- thieno[2,3-d]pyrimidin-4-ones were treated with bromine or iodine in AcOH to afford (E)-halomethylidene[1,3]thiazolo[3,2-a]thieno[3,2-e]pyrimidinium and (E)-halomethylidene-[1,3]oxazolo[3,2-a]thieno[3,2-e] pyrimidinium halides, respectively.

Full text of DOI:10.1515/hc-2013-0036

ꢁꢁꢁꢂ
DOI 10.1515/hc-2013-0036ꢀ ꢀHeterocycl. Commun. 2013; 19(3): 189–193
Marina Slivka, Andrej Krivovjaz, Mikhailo Slivka* and Vasil Lendel
Stereoselective synthesis of (E)-halomethyl-
idene[1,3]thiazolo[3,2-a]thieno[3,2-e]
pyrimidinium and analogous [1,3]oxazolo[3,2-a]
thieno[3,2-e]pyrimidinium halides starting from
3-N-substituted 2-propargylthio(oxy)thieno[2,3-d]
pyrimidin-4-ones
Abstract: A convenient procedure for the stereoselec- condensed compound by introducing an additional ring
tive synthesis of [1,3]thiazolo[3,2-a]thieno[3,2-e]pyrimi- to the thieno[2,3-d]pyrimidine system. In recent years,
dinium halides and analogous [1,3]oxazolo[3,2-a] heteroannulation processes based on electrophilic halo-
thieno[3,2-e]pyrimidinium halides 5 and 6 is reported. cyclization has proved to be useful in producing various
2-Propargylthio-3-R-thieno[2,3-d]pyrimidin-4-ones
and condensed heterocycles such as imidazothiazole [16],
2-propargyloxy-3-R-thieno[2,3-d]pyrimidin-4-ones were thiazoloquinoline [17], thiazolopyrazolopyrimidine [18],
treated with bromine or iodine in AcOH to afford (E)-halo- thiazolotriazole [19–23], and thiazolo(oxazolo-)-thieno-
methylidene[1,3]thiazolo[3,2-a]thieno[3,2-e]pyrimidinium pyrimidine [24–27]. It has been shown [28] that most
and (E)-halomethylidene-[1,3]oxazolo[3,2-a]thieno[3,2-e] halocyclization processes are stereo- and regioselective
pyrimidinium halides, respectively.
and are efficient. In this report, we describe the reactiv-
ity of 3-substituted 2-propargylthio(oxy)-thieno[2,3-d]
Keywords: electrophilic halocyclization; [1,3]oxazolo[3,2- pyrimidin-4-ones in a series of halocyclization reactions
a]thieno[3,2-e]pyrimidinium halides; [1,3]thiazolo[3,2-a] with bromine or iodine.
thieno[3,2-e]pyrimidinium halides; stereoselective synthesis.
*Corresponding author: Mikhailo Slivka, Laboratory of Organic
Chemistry, Uzhgorod National University, 88000 Uzhgorod,
Results and discussion
Ukraine, e-mail: mikhailslivka@gmail.com
Marina Slivka, Andrej Krivovjaz and Vasil Lendel: Laboratory of
We have recently described [25] the regioselective halo-
Organic Chemistry, Uzhgorod National University, 88000 Uzhgorod,
Ukraine
cyclization of 2-allyloxythieno[2,3-d]pyrimidines leading
to oxazolothienopyrimidine derivatives. In this context,
and considering that the presence of a halomethylidene
moiety in the final polycyclic ensemble could be of interest
for further functionalization, we wish to report our results
on the halocyclization of 2-propargylthio(oxy)-thieno[2,3-
Introduction
A literature survey revealed that thieno[2,3-d]pyrimidines d]pyrimidin-4-ones 3 and 4 upon treatment with bromine
are valuable starting materials in organic synthesis [1–4] and iodine.
and exhibit a broad range of biological activities [5, 6],
The starting compounds 3 and 4 were conveniently
including anti-inflammatory, analgesic [6], and neuro- obtained by reaction of the corresponding thieno[2,3-d]
tropic properties [7]. They are also useful as kinase inhibi- pyrimidines 1, 2 with propargyl bromide in EtOH in the
tors [8, 9], monocarboxylate transporter 1 inhibitors [10], presence of sodium hydroxide (Scheme 1).
various receptor antagonists [11], immunomodulators
The (thio)ethers 3, 4 were allowed to react with
[12], and agents for therapy of cerebral ischemia [13], bromine and iodine in glacial acetic acid. This procedure
malaria [14], and Alzheimer’s disease [15]. Considering provides a convenient access to (E)-halomethylidene sub-
these observations, it was envisaged to synthesize a new stituted thiazolothienopyrimidinium halides 5a–e, 6b–e

ꢁꢁꢁꢂ
190ꢀ ꢀM. Slivka et al.: (E)-Halomethylidene[1,3]thiazolo(oxazolo-)[3,2-a]thieno[3,2-e]pyrimidinium halides
R1
O
O
R1
Br
cyclization with the involvement of the pyrimidine nitro-
gen to give the corresponding salt 5 or 6.
R3
X
R3
X
C
CH
N
N
R2
R2
NaOH, EtOH
The structural assignments of the products 3–6
were based on elemental analysis, IR and NMR data.
S
S
N
H
N
C
1
1a-e, 2
3a-e, 4
CH
For example, H NMR spectra of bromide salts 5 lack
the signals of the propargyl moiety. The signal of C(7)H2
protons appears as a broad singlet at 4.34 ppm (for 5a)
and 5.01 ppm (for 5f), whereas the signal of exocyclic
methylidene proton is markedly downshifted and appears
as a singlet at 7.28 ppm (for 5a) and 7.45 ppm (for 5f).
The downfield shift is most likely the result of a
deshielding field effect of the positively charged nitrogen
atom which is syn-periplanar to HCHal proton. In the IR
spectra of salts 5 and 6, a bathochromic shift is observed
for C=O and C=N+ bands in comparison to the spectra of
the substrates, which confirms the presence of a positively
1
1a 3a
,
: R = R2 = R3 = Me , X = S
1b, 3b: R1 + R2 = -(CH2)4-, R3 = Me, X = S
1
2
: R = R = Me , R3 = Ph, X = S
1c 3c
,
1d, 3d: R1 + R2 = -(CH2)3-, R3 = Ph, X = S
1
: R + R2 = -(CH2)4-, R3 = Ph, X = S
1e 3e
,
2, 4: R1 + R2 = -(CH2)4-, R3 = Ph, X = O
Scheme 1ꢀ
and oxazolothienopyrimidinium halides 5f, 6f (Scheme 2). charged nitrogen in the molecule [27]. The ionic nature of
In most cases, the crude products were pure enough products was confirmed by titration of the halide ion using
for analytical purposes or could be easily purified by equimolar quantities of AgBF4. The halocyclization reac-
crystallization.
tion of compounds 3 and 4 proved to be stereoselective.
The plausible mechanism for the formation of the The suggested (E)-configuration of the halomethylidene
thiazole (oxazole) ring is shown in Scheme 3. The cycliza- moiety is consistent with the results of the 2D-NOESY
tion reactions are believed to proceed through activation experiment [29] which revealed no cross-peaks between
of the carbon-carbon triple bond by coordination to Hal+. the exocyclic methylidene protons and cyclic methylene
The resultant complex A or B undergoes intramolecular protons.
R1
R1
S
O
N
O
N
R3
R3
I
N
N
R2
R2
AcOH
AcOH
Br
3a-e, 4
l2
Br2
S
3 h, 10°C
X
48 h, 20°C
X
H
C
H C
Br
5a c d e f
I
3a, 5a: R1 = R2 = R3 = Me, X = S
3b, 6b
3c , 5c, 6c: R1 = R2 = Me, R3 = Ph, X = S
6b c e f
, , ,
, , , ,
1
: R + R2 = -(CH2)4-, R3 = Me, X = S
1
: R + R2 = -(CH2)3-, R3 = Ph, X = S
3d, 5d
: R + R2 = -(CH2)4-, R3 = Ph, X = S
1
3e , 5e, 6e
1
: R + R2 = -(CH2)4-, R3 = Ph, X = O
4, 5f, 6f
Scheme 2ꢀ
R1
R1
O
O
R3
X
R3
N
N
R2
R2
Hal2
Hal
X
3, 4
S
S
5, 6
N
N
Hal
CH2
CH2
C
HC
C
HC
A
B
Hal
Hal
Scheme 3ꢀ

ꢂꢁꢁꢁ
M. Slivka et al.: (E)-Halomethylidene[1,3]thiazolo(oxazolo-)[3,2-a]thieno[3,2-e]pyrimidinium halidesꢀ
ꢀ191
(m, 3H, C6H5), 7.37 (m, 2H, C6H5), 3.91 (d, 2H, J = 2.4 Hz, CH2), 3.06 (bs,
1H, CH), 2.34, 2.36 (2s, 3H each, 2CH3). Anal. Calcd for С17H14N2OS2: C,
62.55; H, 4.32; N, 8.58; S, 19.64. Found: C, 62.52; H, 4.20; N, 8.57; S, 19.59.
Conclusions
(E)-Halomethylidene-[1,3]thiazolo[3,2-a]thieno[3,2-e]
pyrimidinium and (E)-halomethylidene-[1,3]oxazolo[3,2-a]
thieno[3,2-e]pyrimidinium halides 5, 6 were obtained by
stereoselective halocyclization of 2-propargylthio-thieno-
[2,3-d]pyrimidin-4-ones and 2-propargyloxy-3-thieno[2,3-d]
pyrimidin-4-ones 3 and 4. The method is experimentally
simple and efficient.
3-Phenyl-2-(prop-2-yn-1-ylsulfanyl)-3,5,6,7-tetrahydro-4H-cyclo-
penta[4,5]thieno[2,3-d]pyrimidin-4-one (3d)ꢀYield 4.20 g (62%);
1
colorless crystals; mp 249°C; IR: ν 1660 (C=O), 1580 (C=N+) cm-1; H
NMR (300 MHz, (CD3)2SO): δ 7.43–7.57 (m, 5H, C6H5), 3.92 (d, 2H, J =
2.4 Hz, CH2), 3.18 (bs, 1H, CH), 2.90 (m, 4H, 2CH2), 2.39 (m, 2H, CH2).
Anal. Calcd for С18H14N2OS2: C, 63.88; H, 4.17; N, 8.28; S, 18.95. Found:
C, 63.71; H, 4.21; N, 8.20; S, 18.88.
3-Phenyl-2-(prop-2-yn-1-ylthio)-5,6,7,8-tetrahydro[1]benzo-
thieno[2,3-d]pyrimidin-4(3H)-one (3e)ꢀYield 4.65 g (66%); color-
1
less crystals; mp 208°C; IR: ν 1680 (C=O), 1585 (C=N+) cm-1; H NMR
Experimental
(300 MHz, (CD3)2SO): δ 7.56 (m, 3H, C6H5), 7.41 (m, 2H, C6H5), 3.96 (d,
2H, J = 2.4 Hz, CH2), 3.17 (bs, 1H, CH), 2.77 (m, 4H, 2CH2), 1.77 (m, 4H,
2CH2). Anal. Calcd for С19H16N2OS2: C, 64.75; H, 4.58; N, 7.95; S, 18.19.
Found: C, 64.67; H, 4.51; N, 7.93; S, 18.02.
Infrared spectra were recorded on a Pye-Unicam SP3–300 spectrom-
eter using KBr pellets. 2D-NOESY experiments were carried out for
compounds 5e, 6e, 6f in CDCl3 on a Varian Mercury-400 instrument.
Elemental analyses were performed at the microanalytical unit of the
Institute of Organic Chemistry National Academy of Science (Kiev,
Ukraine). Melting points were determined using a Koefler block in-
strument. All reagents were obtained from commercial suppliers and
used without any further purification. Dry solvents were prepared ac-
cording to standard methods.
3-Phenyl-2-(prop-2-yn-1-yloxy)-5,6,7,8-tetrahydro[1]benzo-
thieno[2,3-d]pyrimidin-4(3H)-one (4)ꢀYield 5.85 g (87%); color-
1
less crystals; mp 189°C; IR: ν 1700 (C=O), 1590 (C=N+) cm-1; H NMR
(300 MHz, (CD3)2SO): δ 7.27–7.55 (m, 5H, C6H5), 4.77 (d, 2H, J = 2.4 Hz,
CH2), 3.49 (t, 1H, J = 2.4 Hz, CH), 2.75 (m, 4H, 2CH2), 1.79 (m, 4H, 2CH2).
Anal. Calcd for С19H16N2O2S: C, 67.84; H, 4.79; N, 8.33; S, 9.53. Found:
C, 67.87; H, 4.73; N, 8.12; S, 9.55.
General procedure for 3-substituted 2-prop-
2-yn-1-ylthio(oxy)-thieno[2,3-d]pyrimidin-
4-ones 3a–e and 4
The starting thieno[2,3-d]pyrimidine 1a–e, 2 [27] (20 mmol) was dis-
solved in 200 mL of ethanol (96%) containing sodium hydroxide
(20 mmol) by heating. Propargyl bromide (25 mmol) was added to
the cooled solution and the reaction mixture was heated for 1 h at
80°C. Then the mixture was allowed to cool to room temperature and
the resultant solid product was filtered off, and washed with ethanol
(20 mL) and warm water (50 mL). The pure product was obtained by
crystallization from glacial acetic acid.
General procedure for (E)-bromomethyl-
idene-[1,3]thiazolo(oxazolo-)[3,2-a]thieno
[3,2-e]pyrimidinium bromides 5a and 5c–f
A solution of bromine (1.76 g, 11 mmol) in glacial acetic acid (10 mL)
was added dropwise within 30 min to a cooled (15°C) and vigorously
stirred solution of compound 3 or 4 (5 mmol) in glacial acetic acid
(150 mL). The temperature of the mixture was kept below 15°C while
stirring was continued for 3 h. The resultant precipitate was collected
by filtration and suspended in acetone (50 mL). The mixture was
stirred for 30 min, filtered, and the solid material was washed with
warm acetic acid (50 mL) to give pure compounds 5a–e. Compound
5f was additionally crystallized from dimethylformamide (DMF).
3,5,6-Trimethyl-2-(prop-2-yn-1-ylthio)thieno[2,3-d]pyrimidin-
4(3H)-one (3a)ꢀYield 3.60 g (68%); colorless crystals; mp 199°C; IR:
ν 1675 (C=O), 1580 (C=N+) cm-1; 1H NMR (300 MHz, (CD3)2SO): δ 4.07 (d,
2H, J = 2.4 Hz, CH2), 3.44 (s, 3H, CH3), 3.22 (bs, 1H, CH), 2.33, 2.37 (2s,
3H each, 2CH3). Anal. Calcd for С12H12N2OS2: C, 54.52; H, 4.58; N, 10.60;
S, 24.25. Found: C, 54.48; H, 4.51; N, 10.60; S, 24.12.
(8E)-8-(Bromomethylidene)-2,3,5-trimethyl-4-oxo-4,5,7,8-
tetrahydro[1,3]thiazolo[3,2-a]thieno[3,2-e]pyrimidin-9-ium
bromide (5a)ꢀYield 1.24 g (67%); colorless crystals; mp 217–218°C;
IR: ν 1730 (C=O), 1605 (C=N+) cm-1; 1H NMR (300 MHz, (CD3)2SO): δ 7.29
(s, 1Н, =СНBr), 4.34 (s, 2H, CH2), 3.21 (s, 3H, CH3), 2.33 (s, 6H, 2CH3).
Anal. Calcd for С12H12Br2N2OS2: C, 33.98; H, 2.85; N, 6.60; Br, 37.88.
Found: C, 34.66; H, 2.77; N, 6.52; Br, 37.65.
3-Methyl-2-(prop-2-yn-1-ylthio)-5,6,7,8-tetrahydro[1]benzo-
thieno[2,3-d]pyrimidin-4(3H)-one (3b)ꢀYield 4.30 g (74%); color-
1
less crystals; mp 179°C; IR: ν 1690 (C=O), 1585 (C=N+) cm-1; H NMR
(300 MHz, (CD3)2SO): δ 4.06 (d, 2H, J = 2.4 Hz, CH2), 3.42 (s, 3H, CH3),
3.23 (bs, 1H, CH), 2.70, 2.83 (2m, 2H each, 2CH2), 1.76 (m, 4H, 2CH2).
Anal. Calcd for С14H14N2OS2: C, 57.90; H, 4.86; N, 9.65; S, 22.08. Found:
C, 58.01; H, 4.81; N, 9.78; S, 22.00.
(8E)-8-(Bromomethylidene)-2,3-dimethyl-4-oxo-5-phenyl-
4,5,7,8-tetrahydro[1,3]-thiazolo[3,2-a]thieno[3,2-e]pyrimidin-
9-ium bromide (5c)ꢀYield 1.51 g (62%); colorless crystals; mp
1
224–225°C; IR: ν 1730 (C=O), 1610 (C=N+) cm-1; H NMR (300 MHz,
5,6-Dimethyl-3-phenyl-2-(prop-2-yn-1-ylthio)thieno[2,3-d]pyrimi- (CD3)2SO): δ 7.20–7.60 (m, 1Н, =СНBr, 5H, C6H5), 4.36 (s, 2H, CH2), 2.25,
din-4(3H)-one (3c)ꢀYield 4.64 g (71%); colorless crystals; mp 242°C; 2.27 (s, 3H each, 2CH3). Anal. Calcd for С17H14Br2N2OS2: C, 41.99; H,
IR: ν 1680 (C=O), 1580 (C=N+) cm-1; 1H NMR (300 MHz, (CD3)2SO): δ 7. 5 5 2.90; N, 5.76; Br, 32.87. Found: C, 41.85; H, 2.86; N, 5.68; Br, 32.88.

ꢁꢁꢁꢂ
192ꢀ ꢀM. Slivka et al.: (E)-Halomethylidene[1,3]thiazolo(oxazolo-)[3,2-a]thieno[3,2-e]pyrimidinium halides
(1E)-1-(Bromomethylidene)-5-oxo-4-phenyl-1,2,4,6,7,8-hexahy- (1E)-1-(Iodomethylidene)-4-methyl-5-oxo-1,2,4,5,6,7,8,9-octahy-
dro-5H-cyclopenta-[4,5]thieno[3,2-e][1,3]thiazolo[3,2-a]pyrimi- drobenzo[4,5]thieno[3,2-e][1,3]thiazolo[3,2-a]pyrimidin-11-ium
din-10-ium bromide (5d)ꢀYield 1.69 g (68%); colorless crystals; iodide (6b)ꢀYield 1.77 g (65%); light-brown crystals; mp 195–196°C;
mp 219–220°C; IR: ν 1730 (C=O), 1615 (C=N+) cm-1; 1H NMR (300 MHz, IR: ν 1725 (C=O), 1615 (C=N+) cm-1; 1H NMR (300 MHz, (CD3)2SO): δ 7.64
(CD3)2SO): δ 7.37–7.51 (m, 1Н, =СНBr, 5H, C6H5), 4.95 (s, 2H, CH2), 2.99
(s, 1Н, =СНI), 4.71 (s, 2H, CH2), 3.63 (s, 3H, 2CH3), 2.88, 2.92 (m, 2H
(m, 4H, 2CH2), 2.31 (m, 2H, CH2). Anal. Calcd for С18H14Br2N2OS2: C,
each, 2CH2), 1.85 (m, 4H, 2CH2). Anal. Calcd for С14H14I2N2OS2: C, 30.90;
43.39; H, 2.83; N, 5.62; Br, 32.07. Found: C, 43.15; H, 2.69; N, 5.58; Br, H, 2.59; N, 5.15; I, 46.64. Found: C, 30.69; H, 2.55; N, 5.02; I, 46.89.
32.23.
(8E)-8-(Iodomethylidene)-2,3-dimethyl-4-oxo-5-phenyl-4,5,7,8-
(1E)-1-(Bromomethylidene)-5-oxo-4-phenyl-1,2,4,5,6,7,8,9-oc-
tahydrobenzo[4,5]-thieno[3,2-e][1,3]thiazolo[3,2-a]pyrimidin-
tetrahydro[1,3]thiazolo-[3,2-a]thieno[3,2-e]pyrimidin-9-ium io-
dide (6c)ꢀYield 2.03 g (70%); light-brown crystals; mp 251–252°C;
11-ium bromide (5e)ꢀYield 1.64 g (64%); colorless crystals; mp IR: ν 1730 (C=O), 1615 (C=N+) cm-1; 1H NMR (300 MHz, (CD3)2SO):
246–247°C; IR: ν 1730 (C=O), 1615 (C=N+) cm-1; H NMR (300 MHz, δ 7.62–7.75 (m, 1Н, =СНI, 5H, C6H5), 4.56 (s, 2H, CH2), 2.51, 2.53 (s, 3H
1
(CD3)2SO): δ 7.19–7.52 (m, 1Н, =СНBr, 5H, C6H5), 4.84 (s, 2H, CH2), 2.69 each, 2CH3). Anal. Calcd for С17H14I2N2OS2: C, 35.19; H, 2.43; N, 4.83; I,
(m, 4H, 2CH2), 1.75 (m, 4H, 2CH2). Anal. Calcd for С19H16Br2N2OS2: C,
44.55; H, 3.15; N, 5.47; Br, 31.20. Found: C, 44.28; H, 3.11; N, 5.41; Br,
31.33.
43.74. Found: C, 35.04; H, 2.40; N, 4.77; I, 43.91.
(1E)-1-(Iodomethylidene)-5-oxo-4-phenyl-1,2,4,5,6,7,8,9-octahy-
drobenzo[4,5]thieno[3,2-e][1,3]thiazolo[3,2-a]pyrimidin-11-ium
iodide (6e)ꢀYield 2.15 g (71%); light-brown crystals; mp 230°C; IR:
(1E)-1-(Bromomethylidene)-5-oxo-4-phenyl-1,2,4,5,6,7,8,9-oc-
tahydrobenzo[4,5]-thieno[3,2-e][1,3]oxazolo[3,2-a]pyrimidin-
11-ium bromide (5f)ꢀYield 1.79 g (72%); colorless crystals; mp
1
ν 1730 (C=O), 1615 (C=N+) cm-1; H NMR (300 MHz, (CD3)2SO): δ 7.6 2–
7.79 (m, 1Н, =СНI, 5H, C6H5), 4.57 (s, 2H, CH2), 2.87 (m, 4H, 2CH2), 1.82
(m, 4H, 2CH2). Anal. Calcd for С19H16I2N2OS2: C, 37.64; H, 2.66; N, 4.62;
I, 41.86. Found: C, 37.53; H, 2.61; N, 4.51; I, 42.02.
1
284–285°C; IR: ν 1740 (C=O), 1625 (C=N+) cm-1; H NMR (300 MHz,
(CD3)2SO): δ 7.52 (m, 3H, C6H5), 7.45 (s, 1Н, =СНBr), 7.30 (m, 2Н, C6H5),
5.01 (s, 2H, CH2), 2.82 (m, 4H, 2CH2), 1.84 (m, 4H, 2CH2). Anal. Calcd
for С19H16Br2N2O2S: C, 45.99; H, 3.25; N, 5.65; Br, 32.21. Found: C, 45.90;
H, 3.21; N, 5.59; Br, 32.45.
(1E)-1-(Iodomethylidene)-5-oxo-4-phenyl-1,2,4,5,6,7,8,9-octahy-
drobenzo[4,5]thieno[3,2-e][1,3]oxazolo[3,2-a]pyrimidin-11-ium
iodide (6f)ꢀYield 2.21 g (75%); yellow crystals; mp 274–275°C; IR:
1
ν 1740 (C=O), 1625 (C=N+) cm-1; H NMR (300 MHz, (CD3)2SO): δ 7.6 7
(s, 1Н, =СНI), 7.48 (m, 3H, C6H5), 7.22 (m, 2Н, C6H5), 4.72 (s, 2H, CH2),
2.74 (m, 4H, 2CH2), 1.77 (m, 4H, 2CH2). Anal. Calcd for С19H16I2N2O2S:
C, 38.67; H, 2.73; N, 4.75; I, 43.00. Found: C, 38.55; H, 2.70; N, 4.68;
I, 43.88.
General procedure for (E)-iodometh-
ylidene-[1,3]thiazolo(oxazolo)[3,2-a]
thieno[3,2-e]pyrimidinium iodides (6b–f)
A solution of iodine (2.79 g, 11 mmol) in glacial acetic acid (150 mL)
was added dropwise within 30 min to the cooled (room tempera-
ture) and vigorously stirred solution of compound 3 or 4 (5 mmol)
in glacial acetic acid (150 mL). Stirring was then continued for 72 h.
The precipitate was collected by filtration and washed with warm
acetic acid (50 mL) to give pure compound 6b,c,e. Compound 6f was
additionally purified by crystallization from DMF.
Acknowledgments: This work was supported by the
Department of Education and Science (DES) of Ukraine
(Project GR-0109U000899).
Received March 8, 2013; accepted April 24, 2013; previously
published online May 25, 2013
References
[1] Varvounis, G.; Giannopoulos, T. Synthesis, chemical and
biological properties of thieno[2,3-d]pyrimidines. Adv.
Heterocycl. Chem. 1996, 66, 193–283.
[2] Ibrahim Yelia, A.; Elway Ahmed, H. M.; Kadry Azza, M.
Thienopyrimidines: synthesis, reaction and biological activity.
Adv. Heterocycl. Chem. 1996, 65, 235–281.
[3] Russo, F.; Santagati, A.; Santagati, M.; Caruso, A.; Leone, M. G.;
Felice, A.; Amico-Roxas, M. Studies on annelated thiazolopy-
rimidines. IV. Synthesis and pharmacological properties of
thiazolothienopyrimidine derivatives. Eur. J. Med. Chem. 1989,
24, 91–95.
[4] Litvinov, V. P. Thienopyrimidines: synthesis, properties, and
biological activity. Russ. Chem. Bull. 2004, 53, 487–516.
[5] Wardakhan, W. W.; Shams, H. Z.; Moustafa, H. E. Synthesis of
polyfunctionally substituted thiophene, thieno[2,3-b]pyridine
and thieno[2,3-d]pyrimidine derivatives. Phosphorus Sulfur
Silicon 2005, 180, 1815–1827.
[6] Alagarsamya, V.; Meena, S.; Ramseshu, K. V.; Solomon, V. R.;
Thirumurugan, K.; Dhanabal, K.; Murugan, M. Synthesis,
analgesic, anti-inflammatory, ulcerogenic index and
antibacterial activities of novel 2-methylthio-3-substituted-
5,6,7,8-tetrahydrobenzo(b)thieno[2,3-d]pyrimidin-4(3H)-ones.
Eur. J. Med. Chem. 2006, 41, 1293–1300.
[7] Oganisyan, A. S.; Noravyan, A. S.; Dzhagatspanyan, I. A.;
Akopyan, A. G. Condensed thienopyrimidine derivatives.
Part 20: synthesis and neurotropic activity of a series of new
pyrano[4′,3′:4,5]thieno[3,2-e]imidazolidino[2,1-b]pyrimidines.
Pharm. Chem. J. 2001, 35, 650–652.
[8] Barnes, D. M.; Haight, A. R.; Hameury, T.; McLaughlin, M. A.,
Mei, J.; Tedrow, J. S.; Toma, J. D. R. New conditions for the

ꢂꢁꢁꢁ
M. Slivka et al.: (E)-Halomethylidene[1,3]thiazolo(oxazolo-)[3,2-a]thieno[3,2-e]pyrimidinium halidesꢀ
ꢀ193
synthesis of thiophenes via the Knoevenagel/Gewald
reaction sequence. Application to the synthesis of a
multitargeted kinase inhibitor. Tetrahedron 2006, 62,
11311–11319.
[18] Onysko, M. Y.; Svalyavin, O. V.; Lendel, V. G. Synthesis and
halogenation of allylthioethers of pyrazolo[3,4-d]pyrimidine.
Chem. Heterocycl. Comp. 2007, 43, 496–498.
[19] Usenko, R. M.; Slivka, M. V.; Lendel, V. G. Electrophilic
heterocyclization of 4,5-disubstituted 3-allylthio-4H-1,2,4-
triazoles by the action of halogens. Chem. Heterocycl. Comp.
2011, 47, 1029–1036.
[20] Khripak, S. M.; Slivka, M. V.; Vilkov, R. V.; Usenko, R. N.;
Lendel, V. G. Regioselectivity of the monohalogenation of
4-allyl-3-allylamino-1,2,4-triazole-5-thione. Chem. Heterocycl.
Comp. 2007, 43, 781–785.
[21] Shmygarev, V. I.; Kim, D. G. Study of the products of iodocy-
clization of 4-allyl-5-phenyl-1,2,4-triazole-3-thione. Chem.
Heterocycl. Comp. 2004, 40, 1077–1082.
[22] Slivka, M. V.; Khripak, S. M.; Britsun, V. N.; Staninets, V. I.
Synthesis of 3-substituted 1,2,4-triazolo[3,4-b]thiazolium
halides. Russ. J. Org. Chem. 2000, 36, 1033–1038.
[23] Ernst, S.; Jelonek, S.; Sieler, J.; Schulze, K. 4-Methallyl
substituted 1,2,4-triazoline-3-thiones as a source of
N-bridgehead heterocycles. Tetrahedron 1996, 52, 791–798.
[24] Nesterenko, A. M.; Vaśkevich, R. I.; Zborovskii, Y. L.; Staninets,
V. I. Reactions of 3-allyl-4-oxothieno[2,3-d]pyrimidin-2-yl
disulfides with iodine. Russ. Chem. Bull. 2005, 54, 2582–2585.
[25] Khripak, S. M.; Plesha, M. V.; Slivka, M. V.; Yakubets, V. I.;
Krivovyaz, A. A. Synthesis and reactivity of 1-bromomethyl-
5-oxo-4-phenyl-1,2,4,5,6,7,8,9-octahydrobenzo[4,5]thieno
[3,2-e][1,3]oxazolo[3,2-e]pyrimidin-11-ium bromides. Russ. J.
Org. Chem. 2004, 40, 1705–1706.
[26] Wippich, P.; Gutschow, M.; Leistner, S. Regioselective
preparation of 1-(bromomethyl)-5H-thiazolo[3,2-a]
quinazolin-5-ones and analogous 5H-thieno[3,2-e]thiazolo[3,2-
a]-pyrimidin-5-ones. Synthesis 2000, 5, 714–720.
[27] Khripak, S. M.; Yakubets, V. I.; Migalina, Y. V.; Koźmin, A. S.;
Zefirov, N. S. Thiazolo(oxazolo)thieno[b]pyrimidines.
Preparation from 2-allylthio(oxy)thieno[2,3-d]pyrimidines
and hydrolysis. Khim. Geterotsikl. Soedin. 1989, 25, 347–352.
[28] Godoi, B.; Schumacher, R. F.; Zeni, G. Synthesis of
heterocycles via electrophilic cyclization of alkynes containing
heteroatom. Chem. Rev. 2011, 111, 2937–2980.
[9] Munchhof, M. J.; Beebe, J. S.; Casavant, B. A.; Cooper, B. A.;
Doty, J. L.; Higdon, R. C.; Hillerman, S. M.; Soderstron, C. I.;
Knauth, E. A.; Marx, M. A.; et al. Design and SAR of
thienopyrimidine and thienopyridine inhibitors of
VEGFR-2 kinase activity. Bioorg. Med. Chem. Lett. 2004, 14,
21–24.
[10] Devinyak, O. T.; Slivka, M. V.; Slivka, M. V.; Vais, V. M.; Lendel,
V. G. Quantitative structure-activity relationship study and
directed synthesis of thieno[2,3-d]pyrimidine-2,4-diones as
monocarboxylate transporter 1 inhibitors. Med. Chem. Res.
2012, 21, 2263–2272.
[11] Betz, S. F.; Zhu, Y.; Chen, C.; Struthers, R. S. Non-peptide
gonadotropin-releasing hormone receptor antagonists. J. Med.
Chem. 2008, 51, 3331–3348.
[12] Guile, S. D.; Bantick, J. R.; Cheshire, D. R.; Cooper, M. E.;
Davis, A. M.; Donald, D. K.; Evans, R.; Eyssade, C.; Ferguson,
D. D.; Hill, S.; et al. Potent blockers of the monocarboxylate
transporter MCT1: novel immunomodulatory compounds.
Bioorg. Med. Chem. Lett. 2006, 16, 2260–2265.
[13] Nomoto, Y.; Takai, H.; Ohno, T.; Kuba, K. Studies in cardiotonic
agents. Potent cardiotonic agent KF 15232 with myofibrillar
Ca2+ sensitizing effect VII. Chem. Pharm. Bull. 1991, 39,
900–910.
[14] Hozein, Z. A.; Abdel-Wahab, A. A.; Hassan, K. M.; Atta, F. M.;
Ahmed S. A. Synthesis and application of some new
tienopyrimidine derivatives as antimicrobial agents.
Synth. Commun. 1996, 26, 3733–3755.
[15] Hozein, Z. A.; Abdel-Wahab, A. A.; Hassan, K. M.; Atta, F. M.;
Ahmed, S. A. Synthesis of some active biological agents from
thieno[2,3-d]pyrimidine derivatives. Die Pharmazie 1997, 52,
753–758.
[16] Jasiński, M.; Mlostoń, G.; Heimgartner, H. Synthesis of
2,3-dihydroimidazo[2,1-b]thiazole derivatives via cyclization
of N-allylimidazoline-2-thiones. J. Heterocycl. Chem. 2010, 47,
1287–1293.
[17] Onysko, M. Y.; Lendel, V. G. Haloheterocyclization of
2-methallyl(propargyl)-thioquinoline-3-carbaldehydes. Chem.
Heterocycl. Comp. 2009, 45, 853–855.
[29] Neuhaus, D.; Williamson, M. The Nuclear Overhauser Effect
in Structural and Conformational Analysis; Wiley-VCH:
Weinheim, 1989.

Copyright of Heterocyclic Communications is the property of De Gruyter and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.