Regioselective synthesis of new 5-methyl-5H-pyrimido[4′,5′:4,5][1,3]thiazino [3,2-a]perimidines

Article abstract of DOI:10.1080/17415993.2017.1318877

A convenient and efficient regioselective synthesis of new pyrimido[4′,5′:4,5] [1,3]thiazino[3,2-a]perimidines is described through intermolecular heterocyclization of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine and 1H-perimidine-2(3H)-thione in short reaction times under mild conditions.

Full text of DOI:10.1080/17415993.2017.1318877

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
Regioselective synthesis of new 5-methyl-5H-
pyrimido[4′,5′:4,5][1,3]thiazino [3,2-a]perimidines
Neda Firoozi, Mehdi Bakavoli, Hossein Eshghi & Navid Ramezanian
To cite this article: Neda Firoozi, Mehdi Bakavoli, Hossein Eshghi & Navid Ramezanian (2017):
Regioselective synthesis of new 5-methyl-5H-pyrimido[4′,5′:4,5][1,3]thiazino [3,2-a]perimidines,
Journal of Sulfur Chemistry, DOI: 10.1080/17415993.2017.1318877
To link to this article: http://dx.doi.org/10.1080/17415993.2017.1318877
Published online: 06 May 2017.
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Date: 08 May 2017, At: 11:03

JOURNAL OF SULFUR CHEMISTRY, 2017
https://doi.org/10.1080/17415993.2017.1318877
Regioselective synthesis of new
ꢀ
ꢀ
5
[
-methyl-5H-pyrimido[4 ,5 :4,5][1,3]thiazino
3,2-a]perimidines
Neda Firoozi, Mehdi Bakavoli, Hossein Eshghi and Navid Ramezanian
Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
ABSTRACT
ARTICLE HISTORY
A convenient and efficient regioselective synthesis of new pyrimido
Received 3 April 2017
Accepted 8 April 2017
ꢀ ꢀ
[4 ,5 :4,5] [1,3]thiazino[3,2-a]perimidines is described through inter-
molecular heterocyclization of 2,4-dichloro-5-(chloromethyl)-6-
methylpyrimidine and 1H-perimidine-2(3H)-thione in short reaction
times under mild conditions.
KEYWORDS
2
,4-dichloro-5-
chloromethyl)-6-
(
methylpyrimidine;
perimidine-2-thione;
1,8-diaminonaphthalene;
pyrimidine;
pyrimido[1,3]thiazine
1. Introduction
Many heterocyclic compounds containing sulfur and nitrogen atoms are of great signifi-
cance to human life because of their roles in many natural products and biological processes
[
1–3]. Among these heterocycles, 1,3-thiazines are an important class of compounds with,
among others, antimicrobial [4], antitumor [5], antioxidant [6], calcium channel modula-
tors [7–11], antipyretic activities [12] and biological activities. Furthermore, 1,3-thiazines
have remarkable potential in various organic syntheses and transformations as reaction
intermediates [13,14].
Pyrimidines and fused pyrimidines also possess extensive antiviral, antitumor and
antimicrobial [15–19] biological activities.
Pyrimido[1,3]thiazines are also of great biological importance since they are considered
as being antibacterial, antiallergic, anti-inflammatory, antitumor, antipyretic and antiviral
agents as well as inhibitors of HIV-1 reverse transcriptase, phosphodiesterase and drugs
against parkinsonism [12,20–27]. Therefore, researchers over the years have paid special
attention to the study and syntheses of such compounds, and as a result, several methods
have been reported [28–31].
CONTACT Mehdi Bakavoli
mbakavoli@um.ac.ir, mbakavoli@yahoo.com
Department of Chemistry, Faculty of
Science, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran
©
2017 Informa UK Limited, trading as Taylor & Francis Group

2
N. FIROOZI ET AL.
The diverse pharmacological and biological activities of these derivatives have encour-
aged us to develop a simple and efficient method for the synthesis of new fused
pyrimido[1,3]thiazines.
2. Result and discussion
Our approach to the synthesis of fused pyrimido[1,3]thiazines is based upon a sim-
ple two-step intermolecular S Ar reaction between 2,4-dichloro-5-(chloromethyl)-6-
N
methylpyrimidine and perimidine-2-thione. The synthetic strategy to assemble the desired
ꢀ
ꢀ
2
-substituted-4-methyl-5H-pyrimido[4 ,5 :4,5][1,3]thiazino[3,2-a]perimidines 7 is shown
in Scheme 1. Direct transformation of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine
into new pyrimido[1,3]thiazino[3,2-a]perimidines 7a–i has been achieved through
condensation with perimidine-2-thione in DMF at room temperature (Scheme 1).
,4-Dichloro-5-(chloromethyl)-6-methylpyrimidine 3 as the key intermediate could be
easily prepared by reaction of 6-methyluracil and formaldehyde in 10% aqueous NaOH
3
2
with subsequent chlorination in boiling POCl under basic condition as described in our
3
previously published method [32,33]. Furthermore, perimidine-2-thione was synthesized
in good yield from the reaction of 1,8-diaminonaphthalene and carbon disulfide, following
a known procedure [34].
Scheme 1. Synthetic route for the synthesis of compounds (7 a–i).

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3
Figure 1. (Left) H-H COZY and (Right) H-H NOESY spectra of compound 7f.
Herein, both 4-Cl and the chloromethyl group on the pyrimidine core 3 were substituted
by nitrogen and sulfur groups of perimidine-2-thione, respectively, during the ring closure.
ꢀ
As depicted in Scheme 1, the formation of two different regioisomeric products 6 and 6 are
possible. The choice between the two regioisomers is based upon the greater reactivity of
the chloromethyl group compared to 4-Cl toward nucleophilic displacement [35,36] with
the thiol group of the perimidine-2-thione 5 [35,37–39] to give the regioisomer 6 after ring
closure as the sole product. This two-step process was very fast, and the desired products
7
a–i were obtained in moderate to high yield.
The reaction of the synthesized compound 6 with various primary and sec-amines led
to the substitution of the 2-Cl atom of pyrimidine to give the derivatives of a new ring sys-
ꢀ
ꢀ
tem 7a–i. The structures of the pyrimido[4 ,5 :4,5] [1,3]thiazino[3,2-a]perimidines 7a–i
1
were established by spectral and elemental analysis. The H NMR spectrum of product
7
f, as an example, showed four multiple signals at 1.89, 1.67, 1.62 and 1.18 ppm due to
the methylene protons of the cyclohexylamine ring, a singlet signal at 2.35 ppm indicat-
ing the methyl group on the pyrimidine ring and two singlet signals at δ 3.0 and 4.90 ppm
attributed to the CH S hydrogens of the thiazine ring and NH of cyclohexylamine, respec-
2
1
3
tively. The C NMR spectrum clearly showed six signals at 21.7, 23.7, 24.8, 25.6, 33.2 and
9.7 ppm for the aliphatic carbons of compound 7f and 13 signals for its unsaturated car-
bons appearing at 116.0, 121.9, 122.0, 122.4, 125.8, 128.0, 134.3, 134.5, 139.6, 156.0, 159.1,
4
1
59.8 and 164.5 ppm. In the IR spectrum, the presence of the stretching vibration bands
−
1
of CH , C−C and C−N at 2934, 2854, 1601 and 1549 cm , respectively, confirmed the
2
desired structure 7f.
Further confirmation for structure 7f came from 2D NMR studies as shown in Figure 1.
1
1
The absence of H– H COSY correlation between the CH moiety of the thiazine ring at
2
3
.80 ppm and aromatic proton, and the lack of interaction between them in the NOESY
spectrum clearly show the formation of 7f from regioisomer 6.
3
. Conclusion
In conclusion, we have described the regioselective synthesis of new pyrimido[4 ,5 :4,5]
1,3]thiazino[3,2-a]perimidines under mild conditions. This process proceeded upon the
ꢀ
ꢀ
[

4
N. FIROOZI ET AL.
intermolecular cyclization reaction of 2,4-dichloro-5-(chloromethyl)- 6-methylpyrimidine
and 1H-perimidine-2(3H)-thione in two steps. Subsequent treatment of the latter com-
pound with primary and secondary amines gave the substituted compounds 7a–i in
moderate to high yield.
4. Experimental
Melting points were recorded on an Electrothermal type 9100 melting point apparatus.
The IR spectra were obtained on Avatar 370 FT-IR Thermo Nicolet and only noteworthy
1
13
absorptions were listed. The H NMR (300 MHz) and the C NMR (75 MHz) spectra were
recorded on a Bruker Avance DRX-300 Fourier transform spectrometer. Chemical shifts
were reported in ppm downfield from TMS as internal standard. The mass spectra were
scanned on a Varian Mat CH-7 at 70 eV. Elemental analysis was performed on a Thermo
Finnigan Flash EA microanalyzer.
ꢀ
ꢀ
4
.1. Synthesis of 2-chloro-4-methyl-5H-pyrimido[4 ,5 :4,5][1,3]thiazino
[3,2-a]perimidine (6)
A solution of 1H-perimidine-2(3H)-thione (5) (1 mmol, 0.20 g) in DMF (1 mL) was added
dropwise to a solution of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine (3) (1 mmol,
0
5
.21 g) and K CO (2 mmol, 0.28 g) in DMF (5 mL). The resulting mixture was stirred for
h, then water (10 mL) was added and the mixture was extracted with EtOAc (3× 10 mL).
2 3
The combined organic solvents were dried over anhydrous sodium sulfate and concen-
trated. The resulting solid was purified using silica gel column chromatography with
hexane-ethyl acetate (1:1) as the eluent. Yield 74%; yellow powder, m.p.: 160–162°C; H
1
NMR (300 MHz, DMSO) δ 7.52–7.39 (m, 2H), 7.39–7.29 (m, 2H), 7.27–7.24 (m, 1H), 6.87
1
3
(
1
1
d, J = 7.1, 1H 1H), 4.28 (s, 2H), 2.58 (s, 3H); C NMR (75 MHz, DMSO): 22.8, 30.2,
05.0, 113.4, 116.6, 119.4, 122.7, 127.1, 128.7, 134.4, 135.7, 138.9, 155.3, 157.1, 159.7, 167.7,
73.3; IR (KBr disc) ν = 2958, 2925, 2856, 1727, 1642.
ꢀ
ꢀ
4
.2. Synthesis of 2-substituted-4-methyl-5H-pyrimido[4 ,5 :4,5][1,3]thiazino[3,2-
a]perimidine (7a–i)
The appropriate primary and secondary amine (5 mmol) was added dropwise to a stirred
ꢀ
ꢀ
solution of 2-chloro-4-methyl-5H-pyrimido[4 ,5 :4,5][1,3]thiazino[3,2-a]perimidine (6)
1 mmol, 0.33 g) in EtOH (10 mL) and the solution was heated to reflux for 1 h. The sol-
(
vent was evaporated and the crude product was purified by column chromatography on
silica gel (eluent: n-hexane/ethyl acetate 2:1) and recrystallized from boiling ethanol to give
2
ꢀ
ꢀ
-substituted-4-methyl-5H-pyrimido[4 ,5 :4,5][1,3]thiazino[3,2-a]perimidines (7a–i).
ꢀ
ꢀ
4
.3. 4-Methyl-2-(pyrrolidin-1-yl)-5H-pyrimido[4 ,5 :4,5][1,3]thiazino[3,2-
a]perimidine (7a)
Yellow powder, m.p.: 185–187°C; yield: 0.30 g (80%). IR (KBr disc) ν = 2949, 2921,
−1 1
1597, 1565 cm
H NMR (300 MHz, CDCl ) δ 7.39–7.32 (m, 1H), 7.32–7.29 (m, 3H),
. 3
7
.27–7.21 (m, 1H), 6.91 (dd, J = 6.2, 2.1 Hz, 1H), 3.91 (s, 2H), 2.48 (s, 3H), 1.97–1.93 (m,

JOURNAL OF SULFUR CHEMISTRY
5
4
1
H), 0.93–0.83 (m, 4H). 13C NMR (75 MHz, CDCl ): 21.9, 25.4, 29.7, 46.6, 105.9, 112.8,
15.7, 121.6, 121.8, 122.6, 125.8, 127.9, 134.5, 134.6, 139.9, 156.3, 158.4, 158.5, 160.0. MS
3
(m/z) 373 (M+). Anal. calcd for C H N S: S, 67.54; H, 5.13; N, 18.75; S, 8.58; found: C,
2
1
19
5
6
7.23; H, 5.03; N, 18.52; S, 8.21.
ꢀ
ꢀ
4
.4. 4-Methyl-2-(piperidin-1-yl)-5H-pyrimido[4 ,5 :4,5][1,3]thiazino[3,2-
a]perimidine (7b)
Yellow powder, m.p.: 176–179°C; yield: 0.29 g (74%). IR (KBr disc) ν 3002, 2929, 2851,
−
1 1
1
7
3
600, 1533 cm . H NMR (300 MHz, CDCl ) δ 7.28–7.25 (m, 1H), 7.21–7.20 (m, 1H),
3
.19–7.17 (m, 1H), 7.16–7.13 (m, 2H), 6.81 (dd, J = 6.2, 2.1 Hz, 1H), 3.80 (s, 2H),
1
3
.61–3.39 (m, 4H), 2.35 (s, 3H), 1.51 (dd, J = 27.2, 4.5 Hz, 6H). C NMR (75 MHz,
CDCl ): 22.0, 23.8, 24.8, 25.7, 44.7, 105.8, 112.6, 115.8, 121.6, 121.8, 122.6, 125.8, 127.9,
3
1
34.5, 134.6, 139.8, 156.3, 158.6, 159.4, 164.2. MS (m/z) 387 (M+). Anal. calcd for
C H N S: C, 68.19; H, 5.46; N, 18.07; S, 8.27; found: C, 68.03; H, 5.23; N, 17.93; S, 7.99.
2
2
21
5
ꢀ
ꢀ
4
.5. 4-Methyl-2-(4-methylpiperidin-1-yl)-5H-pyrimido[4 ,5 :4,5][1,3]thiazino[3,2-
a]perimidine (7c)
Yellow powder, m.p. 189–191°C; yield: 0.28 g (69%). IR (KBr disc) ν 2946, 2919, 2847,
−
1 1
1
600, 1533 cm . H NMR (300 MHz, CDCl ) δ 7.28–7.23 (m, 1H), 7.23–7.19 (m, 2H),
3
7
.16–7.13 (m, 1H), 6.81 (dd, J = 6.2, 2.0 Hz, 1H), 4.50 (d, J = 13.0 Hz, 2H, equatorial
hydrogens of CH –N), 3.80 (s, 2H, CH of thiazine), 2.72 (t, J = 11.9 Hz, 2H, hydrogens of
2
2
CH –N), 2.36 (s, 3H), 1.60–1.57 (m,3H, equatorial hydrogens of CH , CH of piperidine),
2
2
1
.14–0.94 (m, 2H, axial hydrogens of CH ), 0.87 (d, J = 6.2 Hz, 3H, CH of piperidine).
2
3
1
3
C NMR (75 MHz, CDCl ): 21.9, 22.0, 23.8, 31.3, 34.6, 44.1, 105.9, 112.6, 115.8, 121.6,
3
1
21.8, 122.6, 125.8, 127.9, 134.5, 134.6, 139.8, 156.2, 158.6, 159.4, 164.2. MS (m/z) 401
(
M+). Anal. calcd for C H N S: C, 68.80; H, 5.77; N, 17.44; S, 7.98; found: C, 68.67; H,
2
3
23
5
5
.54; N, 17.19; S, 7.52.
ꢀ
ꢀ
4
.6. 4-(4-methyl-5H-pyrimido[4 ,5 :4,5][1,3]thiazino[3,2-a]perimidin-2-
yl)morpholine (7d)
Yellow powder, m.p.: 150–152°C; yield: 0.32 g (82%). IR (KBr disc) ν = 2958, 2922, 2852,
−
1 1
1
7
2
1
599, 1540 cm . H NMR (300 MHz, CDCl ) δ 7.39–7.36 (m, 1H), 7.35–7.33 (m, 1H),
3
.32–7.30 (m, 1H), 7.27–7.24 (m, 1H), 7.26–7.22 (m, 1H), 6.92 (dd, J = 6.6, 1H), 3.91 (s,
H), 3.72 (m, 8H), 2.48 (s, 3H). 1 C NMR (75 MHz, CDCl ): 21.9, 29.7, 44.2, 66.7, 107.2,
3
3
12.6, 116.0, 121.8, 122.0, 122.5, 125.8, 128.0, 134.4, 134.5, 139.6, 155.9, 158.7, 159.5, 164.4.
MS (m/z) 389 (M+). Anal. calcd for C H N OS: C, 67.76; H, 4.92; N, 17.98; S, 8.23;
2
1
19
5
found: C, 64.65; H, 4.83; N, 17.63; S, 7.98.
ꢀ
ꢀ
4
.7. 4-Methyl-2-(4-phenylpiperazin-1-yl)-5H-pyrimido[4 ,5 :4,5][1,3]thiazino[3,2-
a]perimidine (7e)
Yellow powder, m.p.: 180–184°C; yield: 0.29 g (62%). IR (KBr disc) ν = 3165, 3055, 2921,
−
1 1
2
855, 1593, 1534 cm . H NMR (300 MHz, CDCl ) δ 7.43–7.29 (m, 2H), 7.22-7.19 (m,
3

6
N. FIROOZI ET AL.
2
H), 7.19–7.17 (m, 2H), 7.09–7.03 (m, 1H), 6.91–6.78 (m, 4H), 3.86 (s, 2H), 2.41 (s, 3H).
1
3
C NMR (75 MHz, CDCl ): 21.9, 23.6, 43.4, 49.5, 104.8, 107.0, 112.7, 115.8, 119.4, 121.8,
3
1
21.9, 122.3, 125.9, 127.9, 128.0, 129.1, 134.3, 134.4, 135.2, 139.5, 158.6, 159.2, 164.4. MS
(
m/z) 464 (M+). Anal. calcd for C H N S: C, 69.80; H, 5.21; N, 18.09; S, 6.90; found: C,
2
7
24
6
6
9.48; H, 5.08; N, 17.83; S, 6.60.
ꢀ
ꢀ
4
.8. N-cyclohexyl-4-methyl-5H-pyrimido[4 ,5 :4,5][1,3]thiazino[3,2-a]perimidin-2-
amine (7f)
Yellow powder, m.p.: 200–203°C; yield: 0.36 g (88%). IR (KBr disc) ν = 3374, 3051, 2934,
−1 1
2
854, 1601, 1549 cm . H NMR (300 MHz, CDCl ) δ 7.30–7.26 (m, 1H), 7.24–7.19 (m,
3
2
(
H), 7.16–7.10 (m, 2H), 6.82 (dd, J = 6.4, 1.8 Hz, 1H), 4.90 (s, 1H, N–H), 3.80 (s, 2H), 2.35
s, 3H), 1.89–1.88 (m, 2H), 1.67–1.66 (m, 4H), 1.62–1.61 (m, 1H), 1.18–1.06 (m, 4H). 13
C
NMR (75 MHz, CDCl ): 21.7, 23.7, 24.8, 25.6, 33.2, 49.7, 116.0, 121.9, 122.0, 122.4, 125.8,
3
1
28.0, 134.3, 134.5, 139.6, 156.0, 159.1, 159.8, 164.5. MS (m/z) 401 (M+). Anal. calcd for
C H N S: C, 68.80; H, 5.77; N, 17.44; S, 7.98; found: C, 68.58; H, 5.67; N, 17.27; S, 7.77.
2
3
23
5
ꢀ
ꢀ
4
.9. N,4-dimethyl-5H-pyrimido[4 ,5 :4,5][1,3]thiazino[3,2-a]perimidin-2-
amine (7g)
Yellow powder, m.p.: 210–213°C; yield: 0.29 g (87%). IR (KBr disc) ν = 3278, 2953, 2924,
−1 1
2
853, 1629, 1601, 1540 cm . H NMR (300 MHz, CDCl ) δ 7.29–7.25 (m, 1H), 7.25–7.19
3
(
2
2
m, 2H), 7.19–7.14 (m, 2H), 6.82 (dd, J = 6.3, 1.4 Hz, 1H), 5.04 (s, 1H, N–H), 3.81 (s, 2H),
1
3
.81 (d, J = 3.7 Hz, 3H, CH –NH), 2.37 (s, 3H). C NMR (75 MHz, CDCl ):21.7, 23.7,
3
3
8.3, 107.6, 112.7, 116.0, 121.9, 122.0, 122.4, 125.9, 128.0, 134.5, 139.6, 155.9, 159.6, 161.6,
1
64.4. MS (m/z) 333 (M+). Anal. calcd for C H N S: C, 64.84; H, 4.53; N, 21.01; S, 9.62;
1
8
15
5
found: C, 64.73; H, 4.12; N, 20.79; S, 9.18.
ꢀ
ꢀ
4
.10. N-ethyl-4-methyl-5H-pyrimido[4 ,5 :4,5][1,3]thiazino[3,2-a]perimidin-2-
amine (7h)
Yellow powder, m.p.: 220–224°C; yield: 0.28 g (80%). IR (KBr disc) ν = 3278, 2970, 2927,
−1 1
2
872, 1629, 1599, 1536 cm . H NMR (300 MHz, CDCl ) δ 7.39–7.36 (m,1H), 7.36–7.29
3
(
2
3
m, 2H), 7.29–7.23 (m, 2H), 6.92 (d, J = 5.2 Hz, 1H), 5.05 (s, 1H), 3.90 (s, 2H), 3.33 (m,
1
3
H), 2.46 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). C NMR (75 MHz, CDCl ):15.0, 21.7, 23.8,
3
6.2, 107.6, 112.7, 116.0, 121.8, 122.0, 122.4, 125.9, 128.0, 134.3, 134.5, 139.6, 156.0, 159.0,
1
60.4, 164.4. MS (m/z) 347 (M+). Anal. calcd for C H N S: C, 65.68; H, 4.93; N, 20.16;
1
9
17
5
S, 9.23; found: C, 65.24; H, 4.56; N, 20.02; S, 8.99.
ꢀ
ꢀ
4
.11. N-isopropyl-4-methyl-5H-pyrimido[4 ,5 :4,5][1,3]thiazino[3,2-a]perimidin-2-
amine (7i)
Yellow powder, m.p.: 198–200°C; yield: 0.24 g (66%). IR (KBr disc) ν = 3282, 2964, 2936,
−
1 1
2
876, 1635, 1598 cm . H NMR (300 MHz, CDCl ) δ 7.30–7.27 (m, 1H), 7.26–7.22
3
(
m, 2H), 7.17–7.16 (m, 1H), 7.13–7.12 (m, 1H), 6.82 (dd, J = 6.3, 1.9 Hz, 1H), 4.82 (d,
13
J = 7.1 Hz, 1H), 3.89 (m, 1H), 3.80 (s, 2H), 2.35 (s, 3H), 1.09 (d, J = 6.5 Hz, 6H).
C

JOURNAL OF SULFUR CHEMISTRY
7
NMR (75 MHz, CDCl ): 21.7, 22.9, 23.8, 42.8, 107.4, 112.6, 112.8, 116.0, 121.8, 122.0, 125.9,
3
1
28.0, 134.3, 134.5, 139.7, 156.0, 159.1, 159.0, 164.4. MS (m/z) 361 (M+). Anal. calcd for
C H N S: C, 66.46; H, 5.30; N, 19.38; S, 8.87; found: C, 66.18; H, 5.14; N, 19.12; S, 8.59.
2
0
19
5
Disclosure statement
No potential conflict of interest was reported by the authors.
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