Intramolecular cyclization of Mannich reaction for synthesis of pyrimido[2,1-b]-1,3,5-tiadiazines

Article abstract of DOI:10.1002/jhet.471

Reaction of 6-aryl-5-cyano-2-mercapto-3,4-dihydropyrimidin-4-ones with formaldehyde and primary amines in suitable solvent via a double Mannich reaction gave the corresponding 8-aryl-7-cyano-3-N-substituted-pyrimido[2,1-b]- 1,3,5-thiadiazin-6-ones rather

Full text of DOI:10.1002/jhet.471

1294
Intramolecular Cyclization of Mannich Reaction for Synthesis of
Pyrimido[2,1-b]-1,3,5-tiadiazines
Vol 47
Hassan A. H. El-Sherief,* Zeinab A. Hozien, Ahmed F. M. El-Mahdy,
and Abdelwarth A. O. Sarhan
Chemistry Department, Faculty of Science, Assuit University, Assuit, 71516, Egypt
*E-mail: dr_Hassanahmed@yahoo.com
Received December 28, 2009
DOI 10.1002/jhet.471
Published online 20 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
Reaction of 6-aryl-5-cyano-2-mercapto-3,4-dihydropyrimidin-4-ones with formaldehyde and primary
amines in suitable solvent via a double Mannich reaction gave the corresponding 8-aryl-7-cyano-3-N-
substituted-pyrimido[2,1-b]-1,3,5-thiadiazin-6-ones rather than the isomeric products 6-aryl-7-cyano-3-
N-substituted-pyrimido[2,1-b]-1,3,5-thiadiazin-8-ones. The cyclization method was found to be the most
favored for the formation of the linear products rather than the angular isomers. This was confirmed not
only by using spectral analysis and molecular mechanical calculations but also by X-ray single crystal
structure determination.
J. Heterocyclic Chem., 47, 1294 (2010).
INTRODUCTION
[13], Triazolothiadiazines [13,15], and thiadiazinobenzi-
midazoles [14] were also obtained in high-yields using
double or triple Mannich reaction in one pot reaction.
We have recently described that similar compounds
could be synthesized via modification of Mannich reac-
tion using di-functional compounds [13–15]. We found
that the cyclization reactions to form the corresponding
thiadiazines 1 are different from that reported by Wang
and co-workers [16]. They suggested that the thiadiazine
derivatives 2 were formed rather than the isomeric
derivatives 1.
In our laboratory, we investigated the Mannich reac-
tion of polyfunctional heterocyclic compounds like
5-mercaptotriazoles, 5-aminopyrazoles, and 2-mercapto-
benzimidazoles, which gave the corresponding 1,2,4-tri-
azolo[3,2-b]-1,3,5-thiadiazines 1, pyrazolo[3,4-d]pyrimi-
dines 3, and 1,3,5-thiadiazino[3,2-a]benzimidazoles 4,
respectively in high-yield [13–15] (Fig. 2).
Although a few publications have been appeared since
last 12 years describing the synthesis of 1,3,5-thiadia-
zines but literature survey on this class of heterocyclic
system showed that 1,3,5-thiadiazines and its fused het-
erocycles possess a broad spectrum of biological interest
[1]. It was found that functionalized thiadiazines have
insecticidal [2], antibacterial [3], herbicidal [4], and fun-
gicidal [5] effects. The broad biological activities of py-
rimidine [6–12] and fused pyrimidine derivatives,
prompted us to synthesize new derivative of pyrimidines
fused heterocycles. During last decade, we were investi-
gating the behavior of Mannich reaction toward the mul-
tifunctional heterocyclic compounds such as 5-mer-
capto-3-aryl-1,2,4-triazole (Fig. 1). We investigated this
reaction in acidic, basic, and neutral mediums, and we
concluded that in all cases only one isomeric product 1
was isolated, rather than the other isomeric products 2
[13–15].
Those findings encouraged us to investigate continu-
ally the use of functionality factor and the reaction me-
dium. One of the advantages of this reaction is a wide
variety to synthesize a number of varieties of poly heter-
ocyclic compounds in one pot reaction which is difficult
to obtain by another procedure. Pyrazolothiadiazines
RESULTS AND DISCUSSION
In this study, we focused on the susceptibility and se-
lectivity of the cyclization of 6-aryl-5-cyano-2-thioxo-
1,2,3,4-tetrahydropyrimidin-4-one (5a–d) towards the
double Mannich reaction. On treatment of the poly
C
V
2010 HeteroCorporation

November 2010
Intramolecular Cyclization of Mannich Reaction for Synthesis of
Pyrimido[2,1-b]-1,3,5-thiadiazines
1295
Scheme 1. Synthesis of pyrimido[2,1-b]-1,3,5-thiadiazines 6–9.
Figure 1. 1,2,4-Triazolo[3,2-b]-1,3,5-thiadiazines 1 and 2.
functional compounds 5a–d with one equivalent of vari-
ant primary aliphatic and aromatic amines with excess
of formaldehyde (37%) in ethanol, ethanol/dioxane and
ethanol/acetic acid at room temperature the reaction
might proceed to afforded the corresponding 8-aryl-7-
cyano-3-N-substituted-pyrimido[2,1-b]-1,3,5-thiadiazin-
6-ones (6–9) or the other isomeric products 6-aryl-7-
cyano-3-N-substituted-pyrimido[2,1-b]-1,3,5-thiadiazin-
8-ones (10–13) or possible a mixture of both isomeric
products. However, based on TLC the reaction gave
only single isolable products 6–9 in high-yields,
(Scheme 1).
tion was supported by the molecular mechanics calcula-
tions–MMXE, which showed that tautomer A is more
stable than B. If double Mannich reaction occurred with
tautomer A the product will be the isomeric compounds
6–9, whereas, the isomeric products 10–13 could be
obtained in case of the existence of the tautomer B in
the reaction medium (Figure 3).
The IR spectra of the products lacked the NH absorp-
tion peaks and showed the CBN and C¼¼O peaks at
2220–2240 and 1650–1700 cmꢀ1, respectively, whereas
1
the H-NMR spectra of the reaction products were char-
acterized by the appearance of two signals at d 5.9–4.8
and 6.1–5.0 attributed to the two methylene groups
SCH2N and NCH2N respectively in addition to the other
protons at the expected chemical shifts. The Mass spec-
tra of the synthesized compounds showed the expected
molecular ion peaks and its CHNS analysis were found
to be in agreement with the calculated ones. All these
data presented here can’t confirm which one of these
isomers, 6–9 and 10–13 is formed.
We need a solid argument to prove whether the iso-
meric products formed 6–9 or 10–13. This directed us to
think about the tautomerism of compound 5a–d, whether
their structure existed in the form A or B. For example
compound 5a (R ¼ Ph) is in equilibrium with the two
forms A and B as shown in Figure 3.
Mechanistically, the formation of the cyclized com-
pounds could be explained either by the addition of SH
(route a) or NH (route b) group to the formed imines,
which resulted from the condensation of formaldehyde
with primary amine, (Scheme 2; Table 1). Based on
both molecular modeling study and X-ray analysis of 6h
(Figures 4 and 5), the structure of the reaction product
was assigned as the isomeric products 6–9 of lower
energy rather than the isomeric products 10–13. The for-
mation of single product only indicates that the reaction
is proceeded regioselectively. Recently, similar results
were obtained by Dotsenko et al [17].
X-ray analysis of compound 6h (Ar ¼ C6H5, R ¼
C6H4CH3-p) C20H16N4OS VA/01/890 P21/c 150K IPDS,
˚
Bond Distances (Angstroms) (see Table 2–4).
Based on resonance effect, the tautomer A is more
favorable than B as both the CN and CO groups are
conjugated with the diene system. Further, this assump-
BIOLOGICAL ACTIVITY
The antimicrobial activity of some synthesized com-
pounds were determined by the usual disk assay [18] at
Figure 2. Pyrazolo[3,4-d]pyrimidines
a]benzimidazoles 4.
3 and 1,3,5-thiadiazino[3,2-
Figure 3. Tautomerism of the thiouracil derivative.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1296
H. A. H. El-Sherief, Z. A. Hozien, A. F. M. El-Mahdy, and A. A. O. Sarhan
Vol 47
Scheme 2. The suggested mechanism of formation of the isomers 6–9.
a concentration of (10ꢀ3 mol) per disk Inhibition zones
in (cm) around filter paper disks (3 mm in diameter)
were measured and the average of these reading was
considered. From the antimicrobial used such as: a, Ba-
cillus cereus; b, E. coli.
EXPERIMENTAL
Melting points were determined using Gallen Camp melting
point apparatus and are uncorrected. The IR-spectra were
measured on a Shimatzu-470 spectrometer using KBr tech-
nique (m cmꢀ1). The 1H-NMR spectra were measured on a
Varian EM-390,90MHz spectrometer (Spectral Unit, Assuit
University, Egypt) and dx 500.13 MHz spectrometer (Depart-
ment of Physical Chemistry, Geneva) using CDCl3, DMSO- d6
as a solvent and TMS was used as internal standard, d ppm.
The 13C-NMR spectra were measured on dx 125.77 MHz spec-
trometer. The mass spectra were recorded on Jeol-Jms-600H
spectrometer using the direct inlet system. The elemental anal-
yses were performed using Perkin-Elmer elemental analyzer
240-C and the X-ray diffraction analysis from faculty of sci-
ence, Geneva University.
General procedures for synthesis of 8-Arylpyrimido[2,1-
b]-1,3,5-thiadiazine derivatives. A mixture of 5-Cyano-4-
oxo-6-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine (1.0 mmole),
primary amines (1.1 mmole) and formaldehyde (2 mL) was
stirred in appropriate solvent (20 mL) at room temperature for
2–3 h. The resulting precipitate was collected by filtration,
washed with water several times and dried well. The crude
product was crystallized from the proper solvent to give the
þVe
Diameter of
inhibitor
(cm)
ꢀVe
Diameter of
inhibitor
(cm)
Compound bacterial
no.
bacterial
E. Coli
Bacillus
6a
6f
6h
7c
7i
7k
8b
8d
9e
9g
þ
þ
þ
þ
þ
ꢀ
þ
þ
ꢀ
ꢀ
ꢀ
þ
0.6
1
þ
þ
þ
þ
þ
þ
þ
þ
þ
þ
ꢀ
þ
1.5
2
0.2
0.7
0.3
ꢀ
0.9
1
1
0.8
2
2.2
1
0.7
0.5
ꢀ
ꢀ
0.9
ꢀ
DMSO
CHL
ꢀ
4
3.2
CHL, chloramphenicol as standard.
corresponding
derivatives.
8-phenyl-pyrimido[2,1-b]-1,3,5-thiadiazine
8-phenylpyrimido [2,1-b]-1,3,5-thiadiazine derivatives (6a-
k). These compounds were obtained according to general
method using ethanol as solvent.
7-Cyano-3-ethyl-8-phenyl-3,4-dihydro-2H-pyrimido[2,1-b]-
1,3,5-thiadiazin-6-one (6a). This compound was obtained as
The antimicrobial activity study revealed that all com-
pounds screened showed moderate to weak antimicrobial
activity, except compounds 6f, 8b, and 8d have good
effect.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Intramolecular Cyclization of Mannich Reaction for Synthesis of
Pyrimido[2,1-b]-1,3,5-thiadiazines
1297
Table 1
Heat of formations based on the molecular mechanics calculation (MMXE) of compounds 6–13.
No.
HF
No.
HF
No.
HF
No.
HF
6a
6b
6c
6d
6e
6f
6g
6h
6i
7a
7b
7c
7d
7e
7f
87.700
71.456
10a
10b
10c
10d
10e
10f
10g
10h
10i
11a
11b
11c
11d
11e
11f
94.335
80.758
7i
7j
80.360
110.106
136.573
89.755
11i
11j
90.103
120.492
147.192
100.910
87.456
124.489
117.719
129.488
116.817
87.322
134.379
127.728
139.751
126.548
96.342
7k
8a
8b
8c
8d
8e
9a
9b
9c
9d
9e
9f
11k
12a
12b
12c
12d
12e
13a
13b
13c
13d
13e
13f
76.137
79.074
121.659
129.529
69.418
89.953
138.179
140.051
77.689
116.841
143.271
78.220
64.609
67.551
126.789
152.725
88.028
74.510
77.080
55.812
56.745
64.038
67.415
102.831
108.786
102.033
113.843
101.168
113.416
119.086
110.748
122.864
110.01
111.687
117.747
110.986
122.764
110.371
124.945
127.917
121.719
133.586
120.005
9g
9h
13g
13h
7g
7h
11g
11h
HF, heat of formation (kcal/mol).
colorless crystals from ethanol, yield (0.25 g, 84 %). Mp 148–
150ꢁC. IR (KBr): 3050, 2995, 2200, 1660, 1520, 1470 cmꢀ1
7-Cyano-3-isobutyl-8-phenyl-3,4-dihydro-2H-pyrimido[2,1-b]-
1,3,5-thiadiazin-6-one (6c). This compound was obtained as
colorless crystals from ethanol, yield (0.15 g, 64%). Mp 156–
158ꢁC. IR (KBr): 3080, 2995–2800, 2200, 1680, 1590, 1520
.
1H-NMR (90 MHz, CDCl3): d ¼ 1.1 (t, J ¼ 2.7 Hz, 3H,
NCH2CH3), 2.7 (q, J ¼ 2.7 Hz, 2H, NCH2CH3), 4.6 (s, 2H,
SCH2N), 4.9 (s, 2H, NCH2N), 7.0–8.1 ppm (m, 5H, arom-H).
Anal. Calcd for C15H14N4OS: C, 60.38; H, 4.73; N, 18.78;
S, 10.75. Found: C, 60.12; H, 4.60; N, 18.77; S, 10.76.
1
cmꢀ1. H-NMR (90 MHz, DMSO-d6): d ¼ 0.9 (d, J ¼ 2.4 Hz,
6H, CH (CH3)2), 1.8 (m, 1H, NCH2CH(CH3)2), 2.5 (d, J ¼
2.45 Hz, 2H, NCH2CH), 4.9 (s, 2H, SCH2N), 5.15 (s, NCH2N)
7.5–8.1 ppm (m, 4H, arom-H). Anal. Calcd for C17H18N4OS:
C, 62.55; H, 5.56; N, 17.16; S, 9.82. Found: C, 62.42; H, 5.49;
N, 17.10; S, 9.78.
3-Butyl-7-cyano-8-phenyl-3,4-dihydro-2H-pyrimido[2,1-b]-
1,3,5-thiadiazin-6-one (6b). This compound was obtained as
colorless crystals from ethanol, yield (0.23 g, 71%). Mp 155–
156ꢁC. IR (KBr): 3080, 2995–2850, 2200, 1670, 1530, 1460
3-Benzyl-7-cyano-8-phenyl-3,4-dihydro-2H-pyrimido[2,1-b]-
1,3,5-thiadiazin-6-one (6d). This compound was obtained as
cmꢀ1
.
1H-NMR (90 MHz, CDCl3): d ¼ 0.9 (t, J ¼ 1.8 Hz,
3H, CH2CH3), 1.4 (m, 2H, CH2CH3), 2.3 (m, 2H, NCH2CH2),
2.7 (t, J ¼ 2.25 Hz, 2H, NCH2CH2), 4.7 (s, 2H, SCH2N), 5.0
(s, NCH2N), 7.7–8.1 ppm (m, 5H, arom-H).
Anal. Calcd for C17H18N4OS: C, 62.55; H, 5.56; N, 17.16;
S, 9.82. Found: C, 62.45; H, 5.50; N, 17.12; S, 9.72.
Figure 4. Single crystal X-ray of compound 6h (Ar ¼ C6H5, R ¼
C6H4CH3-p).
Figure 5. Crystal structure of compound 6h (Ar ¼ C6H5, R ¼
C6H4CH3-p).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1298
H. A. H. El-Sherief, Z. A. Hozien, A. F. M. El-Mahdy, and A. A. O. Sarhan
Vol 47
Table 2
Table 3
˚
Bond distances (A) of compound 6h.
Bond angles (degrees) of compound 6h.
˚
Distance (A)
˚
Distance (A)
Bond
SAC6
N1AC1
N2AC1
N2AC5
N3AC6
N4AC13
C2AC7
C3AC13
C7AC12
C9AC10
C11AC12
C14AC19
C16AC17
C17AC20
Bond
Angle
(degree)
Angle
(degree)
Bond
Bond
1.871(2)
1.313(2)
1.369(2)
1.505(2)
1.429(2)
1.159(3)
1.495(2)
1.425(3)
1.393(3)
1.381(3)
1.401(3)
1.402(2)
1.403(2)
1.511(3)
SAC1
OAC4
N1AC2
N2AC4
N3AC5
N3AC14
C2AC3
C3AC4
C7AC8
C8AC9
C10AC11
C14AC15
C15AC16
C17AC18
C18AC19
1.745(2)
1.228(2)
1.357(2)
1.405(2)
1.438(2)
1.433(3)
1.398(2)
1.460(2)
1.403(2)
1.392(3)
1.383(3)
1.396(3)
1.384(3)
1.378(3)
1.396(3)
C1ASAC6
102.49(8)
120.7(1)
118.1(1)
117.0(2)
113.1(1)
123.9(2)
114.5(1)
120.3(2)
113.7(1)
124.2(2)
111.1(1)
117.0(2)
118.9(2)
120.0(2)
120.3(2)
176.4(2)
122.2(2)
121.1(2)
116.9(2)
122.1(2)
119.8(2)
C1AN1AC2
C1AN2AC5
C5AN3AC6
C6AN3AC14
SAC1AN2
N1AC2AC3
C3AC2AC7
C2AC3AC13
OAC4AN2
119.8(1)
121.2(2)
110.9(1)
119.9(1)
122.9(1)
120.4(2)
125.1(2)
126.0(2)
121.2(2)
114.6(1)
113.3(1)
124.1(2)
120.5(2)
120.2(2)
120.0(2)
119.8(1)
117.9(2)
121.5(2)
121.0(2)
122.7(2)
C1AN2AC4
C4AN2AC5
C5AN3AC14
SAC1AN1
N1AC1AN2
N1AC2AC7
C2AC3AC4
C4AC3AC13
OAC4AC3
N2AC5AN3
C2AC7AC8
C8AC7AC12
C8AC9AC10
C10AC11AC12
N4AC13AC3
N3AC14AC19
C14AC15AC16
C16AC17AC18
C18AC17AC20
C14AC19AC18
N2AC4AC3
SAC6AN3
C2AC7AC12
C7AC8AC9
C9AC10AC11
C7AC12AC11
N3AC14AC15
C15AC14AC19
C15AC16AC17
C16AC17AC20
C17AC18AC19
colorless crystals from ethanol, yield (0.28 g, 77%). Mp 162–
164ꢁC. IR (KBr): 3080, 2985, 2200, 1685, 1590, 1520 cmꢀ1
.
1H-NMR (90 MHz, DMSO-d6): d ¼ 3.9 (s, 2H, NCH2Ph), 4.9
(s, 2H, SCH2N), 5.15 (s, 2H, NCH2N) 7.1–8.1 ppm (m, 10H,
arom-H).
Anal. Calcd for C20H16N4OS: C, 66.65; H, 4.47; N, 15.54;
S, 8.90. Found: C, 66.53; H, 4.41; N, 15.50; S, 8.80.
7-Cyano-3,8-diphenyl-3,4-dihydro-2H-pyrimido[2,1-b]-1,3,5-
thiadiazin-6-one (6e). This compound was obtained as color-
less crystals from ethanol, yield (0.27 g, 80%). Mp 214–
216ꢁC. IR (KBr): 3050, 2910, 2200, 1660, 1525, 1475 cmꢀ1
.
1H-NMR (90 MHz, DMSO-d6): d ¼ 5.0 (s, 2H, SCH2N), 5.2
Table 4
Dihedral angles (degrees).
Angle
Degree
Angle
Degree
0.7(2)
175.7(1)
ꢀ4.4(3)
ꢀ170.7(1)
10.1(2)
C6ASAC1AN1
C1ASAC6AN3
ꢀ176.1(1)
23.5(2)
ꢀ1.0(3)
175.5(2)
5.7(3)
C6ASAC1AN2
C2AN1AC1AS
C1AN1AC2AC3
C4AN2AC1AS
C5AN2AC1AS
C1AN2AC4AO
C5AN2AC4AO
C2AN1AC1AN2
C1AN1AC2AC7
C4AN2AC1AN1
C5AN2AC1AN1
C1AN2AC4AC3
C5AN2AC4AC3
C4AN2AC5AN3
C14AN3AC5AN2
C14AN3AC6AS
C5AN3AC14AC19
C6AN3AC14AC19
N1AC2AC3AC13
C7AC2AC3AC13
N1AC2AC7AC12
C3AC2AC7AC12
C2AC3AC4AN2
C13AC3AC4AN2
C12AC7AC8AC9
C8AC7AC12AC11
C8AC9AC10AC11
C10AC11AC12AC7
C19AC14AC15AC16
C15AC14AC19AC18
C15AC16AC17AC18
C16AC17AC18AC19
C17AC18AC19AC14
ꢀ173.5(2)
ꢀ4.7(2)
174.6(2)
135.1(2)
ꢀ70.1(2)
80.9(2)
141.0(2)
1.9(3)
175.1(2)
ꢀ5.6(3)
ꢀ45.6(2)
72.5(2)
C1AN2AC5AN3
C6AN3AC5AN2
C5AN3AC6AS
C5AN3AC14AC15
C6AN3AC14AC15
N1AC2AC3AC4
C7AC2AC3AC4
N1AC2AC7AC8
C3AC2AC7AC8
C2AC3AC4AO
C13AC3AC4AO
C2AC7AC8AC9
C2AC7AC12AC11
C7AC8AC9AC10
C9AC10AC11AC12
N3AC14AC15AC16
N3AC14AC19AC18
C14AC15AC16AC17
C15AC16AC17AC20
C20AC17AC18AC19
ꢀ60.4(2)
ꢀ41.7(2)
179.2(2)
5.0(3)
ꢀ174.9(2)
ꢀ18.9(2)
161.0(2)
179.8(2)
ꢀ0.1(3)
ꢀ177.8(2)
177.8(2)
ꢀ0.6(3)
1.0(3)
ꢀ175.1(2)
4.9(3)
161.2(2)
ꢀ18.9(3)
ꢀ0.4(3)
179.7(2)
2.1(3)
ꢀ2.1(3)
ꢀ0.9(3)
0.5(3)
ꢀ176.5(2)
175.5(2)
0.8(3)
0.9(3)
ꢀ1.8(3)
ꢀ1.7(3)
0.8(3)
178.9(2)
ꢀ179.8(2)
0.9(3)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Intramolecular Cyclization of Mannich Reaction for Synthesis of
Pyrimido[2,1-b]-1,3,5-thiadiazines
1299
(s, 2H, NCH2N), 6.6–7.3 ppm (m, 10H, arom-H). MS (EI,
70Ev): m/z ¼ (%) 345.98 [Mþ] (19.5), 285.9 (0.9), 212.91
(3.8), 211.05 (8.6), 180.02 (2.8), 178.0 (2.5), 176.0 (1.2),
169.0 (0.9), 165.0 (2.3), 158.0 (0.7), 154.93 (1.6), 153.93
(1.2), 152.98 (1.1), 149.94 (5.1), 145.94 (1.6), 145.02 (1.0),
142.03 (0.5), 140.99 (10.07), 134.06 (2.6), 133.01 (1.8),
129.06 (8.7), 128.0 (0.4), 127.0 (8.7), 122.0 (5.3), 199.0 (2.5),
118.05 (2.1), 117.04 (4.4), 107.03(2.7), 106 (42.9), 105 (100),
104.02 (93.6), 103 (2.7), 102.08 (0.5), 95.01 (2.1), 93.93 (0.7),
93.01 (4.2), 92.0 (5.3), 90.76 (16.8), 90.02 (3.9), 89.05 (6.0),
88.08 (2.6), 87 (2.2), 85.93 (15.8), 85.04 (1.2), 83.09 (1.8),
82.06 (2.1), 81.06 (1.0), 79.92 (1.1), 79.04 (6.9), 78.02 (13.1),
77.02 (46.2), 76.01 (3.8), 75.00 (4.9).
1H-NMR (90 MHz, DMSO-d6): d ¼ 2.1 (s, 3H, CH3), 5.3 (s,
2H, SCH2N), 5.5 (s, 2H, NCH2N), 7.0–7.8 ppm (m, 9H, arom-
H).
Anal. Calcd for C20H16N4OS: C, 66.65; H, 4.47; N, 15.54;
S, 8.90. Found: C, 66.50; H, 4.41; N, 15.50; S, 8.88.
7-Cyano-3-(2-naphthyl)-8-phenyl-3,4-dihydro-2H-pyrimido
[2,1-b]-1,3,5-thiadiazin-6-one (6k). This compound was
obtained as colorless crystals from ethanol, yield (0.38 g, 95
%). Mp 238–240ꢁC. IR (KBr): 3050, 2920, 2200, 1620, 1520,
1480 cmꢀ1
.
1H-NMR (90 MHz, DMSO-d6): d ¼ 5.7 (s, 2H,
SCH2N), 5.9 (s, 2H, NCH2N), 7.1–8.15 ppm (m, 12H, arom-
H).
Anal. Calcd for C23H16N4OS: C, 69.68; H, 4.07; N, 14.13;
S, 8.09. Found: C, 69.58; H, 4.39; N, 14.08; S, 8.00.
8-(4-Chlorophenyl)-Pyrimido[2,1-b]-1,3,5-thiadiazine deriv-
atives (7a-k). These compounds were obtained according to
the general method using ethanol/dioxane in a ratio of 1:1
mixture as solvent.
Anal. Calcd for C19H14N4OS: C, 65.88; H, 4.07; N, 16.17;
S, 9.26. Found: C, 65.80; H, 4.00; N, 16.13; S, 9.15.
3-(4-Chlorophenyl)-7-cyano-8-phenyl-3,4-dihydro-2H-pyri-
mido[2,1-b]-1,3,5-thiadiazin-6-one (6f). This compound was
obtained as yellow crystals from ethanol, yield (0.34 g, 90%).
Mp 230–232ꢁC. IR (KBr): 3060, 2940, 2200, 1680, 1540, 1470
cmꢀ1. 1H-NMR (90 MHz, DMSO-d6): d ¼ 5.5 (s, 2H, SCH2N),
5.75 (s, 2H, NCH2N), 7.3–7.95 ppm (m, 9H, arom-H).
Anal. Calcd for C19H13ClN4OS: C, 59.92; H, 3.44; N,
14.71; S, 8.42. Found: C, 59.80; H, 3.41; N, 14.65; S, 8.40.
3-(4-Bromophenyl)-7-cyano-8-phenyl-3,4-dihydro-2H-pyri-
mido[2,1-b]-1,3,5-thiadiazin-6-one (6g). This compound was
obtained as green crystals from ethanol, yield (0.4 g, 95%).
Mp 242-244ꢁC. IR (KBr): 3010, 3000, 2200, 1640, 1520, 1490
8-(4-Chlorophenyl)-7-cyano-3-ethyl-3,4-dihydro-2H-pyrimido
[2,1-b]-1,3,5-thiadiazin-6-one (7a). This compound was
obtained as colorless crystals from ethanol, yield (0.32 g, 96
%). Mp 160–162ꢁC. IR (KBr): 3100, 2990, 2200, 1680, 1590,
1520 cmꢀ1
.
1H-NMR (90 MHz, CDCl3): d ¼ 1.3 (t, J ¼ 2.7
Hz, 3H, NCH2CH3), 2.9 (q, J ¼ 2.7 Hz, 2H, NCH2CH3), 4.9
(s, 2H, SCH2N), 5.2 (s, 2H, NCH2N), 7.55–8.1 ppm (m, 4H,
arom-H). MS (EI, 70 eV): m/z (%) ¼ 344.97 [Mþ þ2] (41.4),
332.97 [Mþ] (98.4), 33.98 (30.1), 332.01 (9.8), 330.96 (17.1),
318.05 (5.5), 316.04 (1.8), 299.01 (15.8), 277.93 (27.1),
276.95 (18.7), 275.93 (46.1), 265.92(16.8), 263.93 (27.0),
262.95 (10.4), 260.98 (10.6), 248.97 (17.8), 247.97 (12.8),
246.95 (25.9), 232.02 (11.6), 230.01 (10.5), 219.04 (14.1),
218.04 (10.8), 217.02 (24.5), 215.05 (10.1), 207.03 (10.0),
205.0 (14.4), 194.06 (11.9), 190.03 (12.4), 189.01(11.8),
187.03 (11.1), 185.06 (33.6), 183.04 (10.7), 176.05 (10.9),
130.05 (13.05), 129.05 (19.6), 128.06 (13.0), 127.03 (13.7),
125.2 (14.9), 117.98 (9.48), 116.99 (23.7), 112.99 (15.6),
110.98 (12.2), 110.01 (8.2), 108.98 (5.7), 107.98 (6.6), 106.98
(6.6).
cmꢀ1
.
1H-NMR (500 MHz, DMSO-d6): d ¼ 5.5 (s, 2H,
SCH2N), 5.7 (s, NCH2N), 7.1 (d, J ¼ 10 Hz, 2H, arom-H), 7.5
(m, 5H, arom-H), 7.7 ppm (d, J ¼ 5 Hz, 2H, arom-H). 13C-
NMR (125 MHz, DMSO-d6) d ¼ 166.0, 164.5, 159.5, 143.0,
134.5, 132.0, 131.5, 128.5, 118.5, 115.0, 114.0, 92.0, 60.0,
53.0.
Anal. Calcd for C19H13BrN4OS: C, 53.66; H, 3.08; N,
13.17; S, 7.54. Found: C, 53.55; H, 2.98; N, 13.12; S, 7.45.
7-Cyano-3-(4-tolyl)-8-phenyl-3,4-dihydro-2H-pyrimido[2,1-b]-
1,3,5-thiadiazin-6-one (6h). This compound was obtained as
colorless crystals from benzene, yield (0.31 g, 87 %). Mp
210–212ꢁC. IR (KBr): 3050, 2995, 2200, 1650, 1500, 1480
Anal. Calcd for C15H13ClN4OS: C, 54.13; H, 3.94; N,
16.83; S, 9.63. Found: C, 54.02; H, 3.90; N, 16.82; S, 9.58.
3-Butyl-8-(4-chlorophenyl)-7-cyano-3,4-dihydro-2H-pyrimido
[2,1-b]-1,3,5-thiadiazin-6-one (7b). This compound was
obtained as colorless crystals from ethanol, yield (0.33 g,
94%). Mp 186–188ꢁC. IR (KBr): 3050, 2990–2850, 2200,
1
cmꢀ1. H-NMR (90 MHz, CDCl3): d ¼ 2.3 (s, 3H, CH3), 5.3
(s, 2H, SCH2N), 5.7 (s, 2H, NCH2N), 7.1–7.9 ppm (m, 9H,
arom-H).
Anal. Calcd for C20H16N4OS: C, 66.65; H, 4.47; N, 15.54;
S, 8.90. Found: C, 66.45; H, 4.35; N, 15.50; S, 8.84.
7-Cyano-3-(4-methoxyphenyl)-8-phenyl-3,4-dihydro-2H-pyri-
mido[2,1-b]-1,3,5–thiadiazin-6-one (6i). This compound was
obtained as yellow crystals from (benzene/ cyclohexane), yield
(0.35 g, 94 %). Mp 174–176ꢁC. IR (KBr): 3080, 2995, 2200,
1
1680, 1590, 1520 cmꢀ1. H-NMR (90 MHz, CDCl3): d ¼ 1.0
(t, J ¼ 1.8 Hz, 3H, CH2CH3), 1.5 (m, 2H, CH2CH3), 1.7 (m,
2H, NCH2CH2), 2.9 (t, J ¼ 1.5 Hz, 2H, NCH2CH2), 4.8 (s,
2H, SCH2N), 5.2 (s, 2H, NCH2N), 7.5–8.1 ppm (m, 4H, arom-
H).
1600, 1530, 1480 cmꢀ1
.
1H-NMR (500 MHz, CDCl3): d ¼
3.74 (s, 3H, OCH3), 5.19 (s, 2H, SCH2N), 5.60 (s, 2H,
NCH2N), 6.85 (d, J ¼ 5.1 Hz, 2H, arom-H), 7.00 (d, J ¼ 7
Hz, 2H, arom-H), 7.44–7.52 (m, 3H, arom-H), 7.95 ppm (d, J
¼ 9 MHz 2H, arom-H). 13C-NMR (125 MHz, DMSO-d6): d ¼
166.36, 163.26, 159.66, 155.99, 136.51, 134.32, 132.06,
128.93, 119.10, 115.16, 115.06, 93.01, 61.80, 55.59, 52.26.
Anal. Calcd for C20H16N4O2S: C, 63.81; H, 4.28; N, 14.88;
S, 8.52. Found: C, 63.71; H, 4.14; N, 14.69; S, 8.49.
Anal. Calcd for C17H17ClN4OS: C, 56.58; H, 4.75; N,
15.53; S, 8.89. Found: C, 56.57; H, 4.70; N, 15.51; S, 8.86.
8-(4-Chlorophenyl)-7-cyano-3-isobutyl-3,4-dihydro-2H-pyri-
mido[2,1-b]-1,3,5–thiadiazin-6-one (7c). This compound was
obtained as colorless crystals from ethanol, yield (0.23 g,
64%). Mp 198–200ꢁC. IR (KBr): 3060, 2985–2800, 2200,
1680, 1590, 1520 cmꢀ1
.
1.0 (d, 1.7 Hz, 6H, CH(CH3)2), 1.9 (m, 1H,
1H-NMR (90 MHz, DMSO-d6): d ¼
J
¼
7-Cyano-3-(3-tolyl)-8-phenyl-3,4-dihydro-2H-pyrimido[2,1-b]-
1,3,5-thiadiazin-6-one (6j). This compound was obtained as
yellow crystals from ethanol, yield (0.32 g, 89 %). Mp 220–
NCH2CH(CH3)2), 2.55 (d, J ¼ 2.4 Hz, 2H, NCH2CH), 5.0 (s,
2H, SCH2N), 5.2 (s, NCH2N), 7.7–8.05 ppm (m, 4H, arom-H).
Anal. Calcd for C17H17ClN4OS: C, 56.58; H, 4.75; N,
15.53; S, 8.89. Found: C, 56.49; H, 4.70; N, 15.50; S, 8.80.
222ꢁC. IR (KBr): 3000, 2990, 2200, 1650, 1520, 1470 cmꢀ1
.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1300
H. A. H. El-Sherief, Z. A. Hozien, A. F. M. El-Mahdy, and A. A. O. Sarhan
Vol 47
was obtained as colorless crystals from benzene, yield (0.123
g, 30%). Mp 214–216ꢁC. IR (KBr): 3020, 2990, 2200, 1640,
3-Benzyl-8-(4-chlorophenyl)-7-cyano-3,4-dihydro-2H-pyri-
mido[2,1-b]-1,3,5-thiadiazin-6-one (7d). This compound was
obtained as colorless crystals from ethanol, yield (0.3 g, 77%).
Mp 162–164ꢁC. IR (KBr): 3150, 2985, 2200, 1685, 1590,
1
1590, 1520 cmꢀ1. H-NMR (90 MHz, DMSO-d6) d ¼ 3.9 (s,
3H, OCH3), 5.6 (s, 2H, SCH2N), 5.8 (s, 2H, NCH2N), 7.2–8.0
ppm (m, 8H, arom-H).
1520 cmꢀ1
.
1H-NMR (90 MHz, DMSO-d6): d ¼ 4.0 (s, 2H,
Anal. Calcd for C20H15ClN4O2S: C, 58.46; H, 3.68; N,
13.64; S, 7.80. Found: C, 58.36; H, 3.60; N, 13.61; S, 7.78.
8-(4-Chlorophenyl)-7-cyano-3-(3-tolyl)-3,4-dihydro-2H-pyri-
mido[2,1-b]-1,3,5-thiadiazin-6-one (7j). This compound was
obtained as colorless crystals from ethanol, yield (0.386 g,
98%). Mp 180–182ꢁC. IR (KBr): 3020, 2990, 2200, 1680,
NCH2Ph), 4.8 (s, 2H, SCH2N), 5.2 (s, NCH2N) 7.6–8.15 ppm
(m, 9H, arom-H).
Anal. Calcd for C20H15ClN4OS: C, 60.83; H, 3.83; N,
14.19; S, 8.12. Found: C, 60.70; H, 3.74; N, 14.17; S, 8.10.
8-(4-Chlorophenyl)-7-cyano-3-phenyl-3,4-dihydro-2H-pyri-
mido[2,1-b]-1,3,5- thiadiazin-6-one (7e). This compound was
obtained as yellow crystals from ethanol, yield (0.22 g, 60%).
Mp 168–170ꢁC. IR (KBr): 3020, 2950, 2200, 1680, 1590,
1
1590, 1520 cmꢀ1. H-NMR (90 MHz, DMSO-d6): d ¼ 2.2 (s,
3H, CH3), 5.4 (s, 2H, SCH2N), 5.8 (s, NCH2N), 7.1–8.1 ppm
(m, 8H, arom-H).
1520 cmꢀ1
.
1H-NMR (90 MHz, DMSO-d6): d ¼ 5.5 (s, 2H,
Anal. Calcd for C20H15ClN4OS: C, 60.83; H, 3.83; N,
14.19; S, 8.12. Found: C, 60.75; H, 3.81; N, 14.09; S, 8.09.
8-(4-Chlorophenyl)-7-cyano-3-(2-naphthyl)-3,4-dihydro-2H-
pyrimido[2,1-b]-1,3,5-thiadiazin-6-one (7k). This compound
was obtained as green crystals from ethanol, yield (0.344 g,
80%). Mp 216–218ꢁC. IR (KBr): 3050, 2950, 2200, 1620,
SCH2N), 5.8 (s, 2H, NCH2N), 7.3–7.9 ppm (m, 9H, arom-H).
Anal. Calcd for C19H13ClN4OS: C, 59.92; H, 3.44; N,
14.71; S, 8.42. Found: C, 59.82; H, 3.41; N, 14.69; S, 8.36.
3,8-Di(4-chlorophenyl)-7-cyano-3,4-dihydro-2H-pyrimido
[2,1-b]-1,3,5-thiadiazin-6-one (7f). This compound was
obtained as yellow crystals from ethanol, yield (0.3 g, 73%).
Mp 222–224ꢁC. IR (KBr): 3020, 2970,2200, 1660, 1590, 1520
1
1590, 1520 cmꢀ1. H-NMR (90 MHz, DMSO-d6): d ¼ 5.7 (s,
cmꢀ1
.
1H-NMR (500 MHz, DMSO-d6): d ¼ 5.7 (s, 2H,
2H, SCH2N), 6.0 (s, 2H, NCH2N), 7.5–8.0 ppm (m, 11H,
arom-H).
SCH2N), 5.9 (s, 2H, NCH2N), 7.1–8.0 ppm (m, 8H, arom-H).
13C-NMR (125 MHz, DMSO-d6): d ¼ 165, 164.0, 159.0, 142.0,
137.0, 133.0, 131.0, 130.0, 128.5, 126.0, 118, 115.0, 92.0, 60.0,
53.5. MS (EI, 70Ev): m/z (%) ¼ 418 [Mþ þ4] (17.5), 416 [Mþ
þ2] (36.3), 414 [Mþ] (54.8), 383.21 (16.8), 381.21 (21.3),
379.33(2.2), 379.17 (9.8), 280.17 (9.1), 278.14 (13.4), 277.28
(2.9), 277.14 (16.6), 276.15 (8.6), 263.15 (4.0), 262.12 (5.6),
249.11 (5.8), 248.17 (2.5), 247.15 (10.4), 245.115 (10.3),
240.17 (5.4), 217.19 (6.1), 197.16 (2.1), 195.17 (8.5), 193.09
(6.0), 187.12 (3.7), 175.08 (9.1), 169.10 (4.7), 167.06 (5.4),
163.05 (7.0), 162.10 (5.8), 161.08 (29.3), 155.14 (4.3), 153.12
(3.9), 151.09 (6.4), 142.08 (11.6), 141.08 (35.4), 140.08 (44.3),
139.08 (100), 138.22 (2.2), 138.06 (30.4), 137.03 (3.4), 129.07
(5.6), 127.08 (8.1), 126.12 (3.1), 125.08 (12.5), 114.11 (6.2),
113.08 (8.6), 112.09 (2.8), 111.10 (20.3), 105.14 (2.8), 99.07
(4.6), 88.10 (5.1), 86.02 (12.8), 85.06 (2.1), 84.99 (1.2), 80.98
(2.9), 77.07 (6.9), 76.6 (5.9), 75.05 (10.1), 74.05 (1.0).
Anal. Calcd for C23H15ClN4OS: C, 64.11; H, 3.51; N,
13.00; S, 7.44. Found: C, 64.05; H, 3.48; N, 12.97; S, 7.38.
8-(4-Nitrophenyl)-pyrimido[2, 1-b]-1,3,5-thiadiazine deriva-
tives (8a-e). These compounds were obtained according to the
general method using ethanol/acetic acid in a ratio of 2:1 as
solvent.
7-Cyano-3-ethyl-8-(4-nitrophenyl)-3,4-dihydro-2H-pyrimido
[2,1-b]-1,3,5-thiadiazin-6-one(8a). This compound was obtained
as colorless crystals from (benzene/cyclohexane), yield (0.137
g, 40 %). Mp 162–164ꢁC. IR (KBr): 3100, 2995, 2200, 1685,
1
1600, 1520 cmꢀ1. H-NMR (90 MHz, CDCl3): d ¼ 1.3 (t, J ¼
2.8 Hz, 3H, NCH2CH3), 2.9 (q, J ¼ 2.8 Hz, 2H, NCH2CH3),
4.9 (s, 2H, SCH2N), 5.25 (s, 2H, NCH2N), 8.1–8.3 ppm (m,
4H, arom-H).
Anal. Calcd for C15H13N5O3S: C, 52.47; H, 3.82; N, 20.40;
S, 9.34. Found: C, 52.30; H, 3.79; N, 20.36; S, 9.28.
3-Butyl-7-cyano-8-(4-nitrophenyl)-3,4-dihydro-2H-pyrimido
[2,1-b]-1,3,5-thiadiazin-6-one (8b). This compound was ob-
tained as colorless crystals from (benzene/cyclohexane), yield
(0.163 g, 44%). Mp 180–182ꢁC. IR (KBr): 3080, 2995-2800,
Anal. Calcd for C19H12Cl2N4OS: C, 54.95; H, 2.91; N,
13.49; S, 7.72. Found: C, 54.89; H, 2.86; N, 13.40; S, 7.68.
3-(4-Bromophenyl)-8-(4-chlorophenyl)-7-cyano-3,4-dihydro-
2H-pyrimido[2,1-b]-1,3,5-thiadiazin-6-one (7g). This com-
pound was obtained as green crystals from benzene, yield
(0.21 g, 47%). Mp 224–226ꢁC. IR (KBr): 3020, 2975, 2200,
1
2200, 1685, 1600, 1520 cmꢀ1. H-NMR (90 MHz, CDCl3): d
¼ 1.0 (t, J ¼ 3.4 Hz, 3H, CH2CH3), 1.4 (m, 2H, CH2CH3),
2.1 (m, 2H, NCH2CH2), 2.8 (t, J ¼ 3.3 Hz, 2H, NCH2CH2),
4.85 (s, 2H, SCH2N), 5.2 (s, 2H, NCH2N) 8.0–8.2 ppm (m,
4H, arom-H).
1660, 1590, 1520 cmꢀ1
.
1H-NMR (90 MHz, DMSO-d6): d ¼
5.56 (s, 2H, SCH2N), 5.8 (s, 2H, NCH2N), 7.2–8.0 ppm (m,
8H, arom-H).
Anal. Calcd for C19H12BrClN4OS: C, 49.64; H, 2.63; N,
12.19; S, 6.97. Found: C, 49.56; H, 2.59; N, 12.17; S, 6.92.
8-(4-Chlorophenyl)-7-cyano-3-(4-tolyl)-3,4-dihydro-2H-pyri-
mido[2,1-b]-1,3,5-thiadiazin-6-one (7h). This compound was
obtained as colorless crystals from benzene, yield (0.12 g,
30%). Mp 210–212ꢁC. IR (KBr): 3020, 2990, 2200, 1680,
Anal. Calcd for C17H17N5O3S: C, 54.97; H, 4.61; N, 18.86;
S, 8.63. Found: C, 54.90; H, 4.51; N, 18.77; S, 8.56.
7-Cyano-3-isobutyl-8-(4-nitrophenyl)-3,4-dihydro-2H-pyrimido
[2,1-b]-1,3,5-thiadiazin-6-one (8c). This compound was ob-
tained as colorless crystals from ethanol, yield (0.237 g, 64%).
Mp 314–316ꢁC. IR (KBr): 3060, 2985-2800, 2200, 1670, 1550,
1
1590, 1520 cmꢀ1. H-NMR (90 MHz, DMSO-d6): d ¼ 2.2 (s,
1510 cmꢀ1
.
1H-NMR (90 MHz, DMSO-d6): d ¼ 1.0 (d, J ¼
3H, CH3), 5.7 (s, 2H, SCH2N), 5.8 (s, 2H, NCH2N), 7.2–8.0
ppm (m, 8H, arom-H).
Anal. Calcd for C20H15ClN4OS: C, 60.83; H, 3.83; N,
14.19; S, 8.12. Found: C, 60.56; H, 3.76; N, 14.16; S, 8.09.
8-(4-Chlorophenyl)-7-cyano-3-(4-methoxyphenyl)-3,4-dihydro-
2H-pyrimido-[2,1-b]-1,3,5-thiadiazin-6-one (7i). This compound
2.4 Hz, 6H, CH(CH3)2), 1.6 (m, 1H, NCH2CH(CH3)2), 2.4 (d,
J ¼ 2.3 Hz, 2H, NCH2CH), 4.9 (s, 2H, SCH2N), 5.2 (s, 2H,
NCH2N) 7.9–8.1 ppm (m, 4H, arom-H).
Anal. Calcd for C17H17N5O3S: C, 54.97; H, 4.61; N, 18.86;
S, 8.63. Found: C, 54.90; H, 4.58; N, 18.82; S, 8.60.
3-Benzyl-7-cyano-8-(4-nitrophenyl)-3,4-dihydro-2H-pyrimido
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
Intramolecular Cyclization of Mannich Reaction for Synthesis of
Pyrimido[2,1-b]-1,3,5-thiadiazines
1301
obtained as colorless crystals from (benzene/cyclohexane),
yield (0.129 g, 41 %). Mp 160–162ꢁC. IR (KBr): 3200, 2995,
[2,1-b]-1,3,5-thiadiazin-6-one (8d). This compound was
obtained as colorless crystals from (benzene/cyclohexane),
yield (0.31 g, 77%). Mp 172–174ꢁC. IR (KBr): 3110, 2975,
1
2200, 1660, 1580, 1520 cmꢀ1. H-NMR (90 MHz, CDCl3): d
2200, 1680, 1590, 1550 cmꢀ1 1H-NMR (500 MHz, DMSO-
.
1.0 (t, J ¼ 1.8 Hz, 3H, CH2CH3), 1.4 (m, 2H, CH2CH3), 2.1
(m, 2H, NCH2CH2), 2.8 (t, J ¼ 1.8 Hz, 2H, NCH2CH2), 4.8
(s, 2H, SCH2N), 5.05 (s, 2H, NCH2N), 6.5 (s, 1H, furan-H),
7.4 (s, 1H, furan-H), 7.6 ppm (s, 1H, furan-H).
d6): d ¼ 4.0 (s, 2H, NCH2Ph), 5.0 (s, 2H, SCH2N), 5.2 (s, 2H,
NCH2N), 7.4 (m, 6H, arom-H), 8.1 (d, 2H, arom-H), 8.4 ppm
(d, 2H, arom-H). 13C-NMR (125 MHz, DMSO-d6): d ¼ 166,
164.0, 159.0, 149.0, 140.5, 136.0, 130.0, 128.0, 127.8, 124.0,
115.0, 92, 63.5, 56.5, 53.5. MS (EI, 70Ev): m/z (%) ¼ 405.85
[Mþ] (2.2), 375.99 (1.2), 369.11 (1.1), 364.09 (1.1), 348.22
(1.0), 377.15 (1.2), 334.3 (1.3), 298.13 (1.4), 293.12 (1.7),
289.99 (1.2), 280.06 (1.4), 277.02 (1.2), 275.11 (1.7), 271.09
(1.6), 256.11 (6.1), 251.97 (1.5), 244.07 (1.1), 242.13 (1.4),
237.05 (1.1), 228.99 (1.0), 227.10 (1.4), 224.11 (7.8), 221.12
(1.5), 215.18 (1.8), 207.05 (1.8), 207.05 (1.8), 200.11 (19.4),
192.03 (2.0), 191.07 (1.3), 185.09 (45.2), 178.12 (3.0), 173.08
(1.0), 168.08 (1.5), 167.08 (1.5), 166.06 (3.4), 159.10 (1.5),
149.07 (20.9), 145.042 (2.0), 136.10 (2.2), 133.07 (2.9),
127.04 (1.2), 123.06 (2.9), 117.01 (11.0), 113.99 (1.4), 109.02
(11.4), 108.01 (96.3), 106.99 (5.7), 102.99 (3.6), 100.97 (1.2),
98.99 (2.6), 93.01 (100.0), 91.01 (58.0).
Anal. Calcd for C15H16N4O2S: C, 56.94; H, 5.10; N, 17.71;
S, 10.14. Found: C, 56.89; H, 5.08; N, 17.69; S, 10.12.
7-Cyano-8-(2-furyl)-3-isobutyl-3,4-dihydro-2H-pyrimido
[2,1-b]-1,3,5-thiadiazin-6-one (9c). This compound was
obtained as colorless crystals from (benzene/cyclohexane),
yield (0.158 g, 50 %). Mp 176–178ꢁC. IR(KBr): 3200, 2995,
1
2200, 1660, 1600, 1520 cmꢀ1. H-NMR (90 MHz, CDCl3): d
¼ 1.0 (d, J ¼ 3.16 Hz, 6H, CH(CH3)2), 1.8 (m, 1H,
NCH2CH(CH3)2), 2.5 (d, J ¼ 3.2 Hz, 2H, NCH2CH), 4.7 (s,
2H, SCH2N), 5.1 (s, 2H, NCH2N), 6.5 (s, 1H, furan-H), 7.5 (s,
1H, furan-H), 7.7 ppm (s, 1H, furan-H).
Anal. Calcd for C15H16N4O2S: C, 56.94; H, 5.10; N, 17.71;
S, 10.14. Found: C, 56.88; H, 5.05; N, 17.66; S, 10.10.
3-Benzyl-7-cyano-8-(2-furyl)-3,4-dihydro-2H-pyrimido
[2,1-b]-1,3,5-thiadiazin-6-one (9d). This compound was
obtained as colorless crystals from ethanol, yield (0.28 g, 80
%). Mp 194–196ꢁC. IR (KBr) 3200, 3030, 2900, 2200, 1650,
Anal. Calcd for C20H15N5O3S: C, 59.25; H, 3.73; N, 17.27;
S, 7.91. Found: C, 59.15; H, 3.68; N, 17.19; S, 7.88.
7-Cyano-8-(4-nitrophenyl)-3-phenyl-3,4-dihydro-2H-pyrimido
[2,1-b]-1,3,5-thiadiazin-6-one (8e). This compound was
obtained as yellow crystals from (benzene/cyclohexane), yield
(0.226 g, 58%). Mp 154–156ꢁC. IR (KBr): 3070, 2920, 2200,
1
1560, 1520 cmꢀ1. H-NMR (90 MHz, DMSO-d6): d ¼ 3.9 (s,
2H, NCH2Ph), 4.95 (s, 2H, SCH2N), 5.1 (s, 2H, NCH2N), 6.9
(s, 1H, furan-H), 7.3 (m, 1H, furan-H), 7.4 (m, 5H, arom-H),
8.15 ppm (s, 1H, furan-H).
1660, 1530, 1500 cmꢀ1
5.6 (s, 2H, SCH2N), 5.8 (s, 2H, NCH2N), 7.3–8.3 ppm (m, 9H,
arom-H).
.
1H-NMR (90MHz, DMSO-d6): d ¼
Anal. Calcd for C18H14N4O2S: C, 61.70; H, 4.03; N, 15.99;
S, 9.15. Found: C, 61.69; H, 4.01; N, 15.90; S, 9.12.
7-Cyano-8-(2-furyl)-3-phenyl-3,4-dihydro-2H-pyrimido
[2,1-b]-1,3,5-thiadiazin-6-one (9e). This compound was
obtained as yellow crystals from ethanol, yield (0.289 g, 86
%). Mp 210–212ꢁC. IR (KBr): 3200, 3030, 2940, 2200, 1640,
Anal. Calcd for C19H13N5O3S: C, 58.30; H, 3.35; N, 17.89;
S, 8.19.Found: C, 58.42; H, 3.23; N, 17.72; S, 8.06.
8-(2-Furyl)-pyrimido[2,1-b]-1,3,5-thiadiazine
derivatives
(9a-h). These compounds were obtained according to general
method using ethanol as solvent.
1
1580, 1520 cmꢀ1. H-NMR (90 MHz, DMSO-d6): d ¼ 5.3 (s,
2H, SCH2N), 5.4 (s, 2H, NCH2N), 6.6 (s, 1H, furan-H), 7.1 (s,
1H, furan-H), 7.2 (m, 5H, arom-H), 7.9 ppm (s, 1H, furan-H).
Anal. Calcd for C17H12N4O2S: C, 60.70; H, 3.60; N, 16.66;
S, 9.53. Found: C, 60.60; H, 3.55; N, 16.65; S, 9.51.
7-Cyano-3-ethyl-8-(2-furyl)-3,4-dihydro-2H-pyrimido
[2,1-b]-1,3,5-thiadiazin-6-one (9a). This compound was
obtained as pale yellow crystals from (benzene/cyclohexane),
yield (0.17 g, 60 %). Mp 176–178ꢁC. IR (KBr): 3200, 2995,
1
2200, 1660, 1600, 1520 cmꢀ1. H-NMR (500 MHz, CDCl3): d
3-(4-Chlorophenyl)-7-cyano-8-(2-furyl)-3,4-dihydro-2H-
pyrimido[2,1-b]-1,3,5-thiadiazin-6-one (9f). This compound
was obtained as yellow crystals from ethanol, yield (0.318 g,
86 %). Mp 298–300ꢁC. IR (KBr): 3200, 3030, 2970, 2200,
¼ 1.18 (t, J ¼ 1.62 Hz, 3H, NCH2CH3), 2.77 (q, J ¼ 1.62 Hz,
2H, NCH2CH3), 4.74 (s, 2H, SCH2N), 5.10 (s, 2H, NCH2N),
6.60 (q, J ¼ 3.01 Hz, 1H, furan-H), 7.56 (d, J ¼ 3.0 Hz, 1H,
furan-H), 7.71 ppm (d, J ¼ 1.0 Hz, 1H, furan-H). 13C-NMR
(125 MHz, CDCl3): d ¼ 159.8, 153.8, 147.2, 118.9, 114.5,
112.9, 77.3, 77.05, 76.7, 63.4, 56.3, 44.46, 12.7. MS (EI,
70Ev): m/z (%) ¼ 288.93 [Mþ] (100.0), 287.96 (10.5), 272.97
(2.2), 270.04 (2.1), 264.92 (2.1), 260.89 (1.9), 256.95 (1.7),
246.98 (2.2), 240.97 (5.5), 236.99 (2.7), 231.93 (52.4), 223.04
(2.1), 215.96 (3.1), 214.04 (1.5), 205.99 (1.7), 204.95 (4.3),
202.92 (21.6), 190.98 (2.2), 185.01 (51.4), 183.01 (2.3),
176.01 (5.2), 172.98 (23.1), 171.02 (5.8), 161.98 (8.1), 159.02
(4.6), 153.02 (2.4), 149.01 (13.2), 147.01 (6.7), 144.03 (6.0),
138.05 (9.0), 134.02 (4.1), 129.02 (15.5), 123.01 (4.1), 116.98
(14.4), 114.96 (7.0), 110.98 (4.1), 103.94 (10.2), 101.95 (12.8),
92.97 (76.6), 85.94 (12.2), 78.97 (13.9), 74.99 (30.4), 72.00
(35.2), 70.02 (7.9), 67.01 (1.9).
1640, 1580, 1520 cmꢀ1
5.5 (s, 2H, SCH2N), 5.7 (s, 2H, NCH2N), 6.9 (s, 1H, furan-H),
7.3 (s, 1H, furan-H), 7.35 (m, 4H, arom-H), 8.15 ppm (s, 1H,
furan-H).
.
1H-NMR (90 MHz, DMSO-d6): d ¼
Anal. Calcd for C17H11ClN4O2S: C, 55.06; H, 2.99; N,
15.11; S, 8.65. Found: C, 54.99; H, 2.90; N, 15.07; S, 8.55.
3-(4-Bromophenyl)-7-cyano-8-(2-furyl)-3,4-dihydro-2H-pyr-
imido[2,1-b]-1,3,5-thia-diazin-6-one (9g). This compound was
obtained as yellow crystals from benzene, yield (0.249 g, 60
%). Mp 270–272ꢁC. IR (KBr): 3200, 3030, 2950, 2200, 1650,
1580, 1520 cmꢀ1
.
1H-NMR (500 MHz, DMSO-d6): d ¼ 5.45
(s, 2H, SCH2N), 5.66 (s, 2H, NCH2N), 6.76 (q, J ¼ 1.0 Hz,
1H, furan-H), 7.09 (d, J ¼ 9.0 Hz, 2H, arom-H.), 7.42 (d, J ¼
4.0 Hz, 1H, furan-H ), 7.46 (d, J ¼ 9.0 Hz, 2H, arom-H), 8.08
ppm (d, J ¼ 1.0 Hz, 1H, furan-H). 13C-NMR (125 MHz,
DMSO-d6): d ¼ 159.6, 153.4, 448.7, 143.2, 142.5, 134.5,
132.7, 119.3, 119.0, 115.2, 114.6, 113.9, 62.1, 60.2, 53.8. MS
(EI, 70Ev): m/z (%) ¼ 416 [Mþþ2] (100.0), 414 [Mþ]
Anal. Calcd for C13H12N4O2S: C, 54.15; H, 4.20; N, 19.43;
S, 11.12. Found: C, 54.10; H, 4.14; N, 19.39; S, 11.10.
3-Butyl-7-cyano-8-(2-furyl)-3,4-dihydro-2H-pyrimido
[2,1-b]- 1,3,5-thiadiazin-6-one (9b). This compound was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1302
H. A. H. El-Sherief, Z. A. Hozien, A. F. M. El-Mahdy, and A. A. O. Sarhan
Vol 47
Palaska, E.; Yulug, N. Arzneim Forsch 1992, 42, 160; (c) Ertan, M.;
Ayyildiz, H. G.; Yulug, N. Arzneim Forsch 1991, 41, 1182; (d) Lal
Dhar, S. Y.; Anjum, V.; Sangeeta, S. J Agric Food Chem 1994, 42,
811.
(97.72), 383.2 (27.34), 381.3 (23.49), 371.3 (1.2), 369.2 (1.46),
330.3 (1.72), 328.3 (1.74), 2.33.4 (5.87), 227.3 (2.67), 219.3
(3.45), 203.2 (13.47), 201.3 (8.38), 197.2 (2.85), 185.2 (18.92),
171.2 (3.94), 119.2 (2.38).
[6] Shishoo, C. J.; Devain, M. B.; Bhadit, V. S.; Jain, K. S.;
Rahod, I. S.; Goyal, R. K.; Gandhi, T. P.; Patel, R. B.; Naik, S. R.
Arzneim Forsch 1990, 40, 567.
Anal. Calcd for C17H11BrN4O2S: C, 49.17; H, 2.67; N,
13.49; S, 7.72. Found: C, 49.10; H, 2.61; N, 13.48; S, 7.69.
7-Cyano-8-(2-furyl)-3-(4-tolyl)-3,4-dihydro-2H-pyrimido
[2,1-b]-1,3,5-thiadiazin-6-one (9h). This compound was
obtained as colorless crystals from ethanol, yield (0.269 g, 77
%). Mp 280–282ꢁC. IR (KBr): 3200, 3030, 2900, 2200, 1650,
[7] Sugiyama, M. T.; Sakamoto, K.; Tabata, K.; Endo, K.; Ito,
M. Kobayashi; Fukumi, H. Chem Pharm Bull 1989, 37, 2122.
[8] Kienzle, F.; Kaiser, A.; Minder, R. E. Helv Chim Acta
1983, 48, 66.
1
1560, 1520 cmꢀ1. H-NMR (90 MHz, DMSO-d6): d ¼ 2.1 (s,
[9] Jordis, U.; Sauter, F.; Siddiqi, S. M. Vest Slov Kem Drus
1986, 217, 33.
3H, CH3), 5.4 (s, 2H, SCH2N), 5.5 (s, 2H, NCH2N), 7.1 (s,
1H, furan-H), 7.3 (s, 1H, furan-H), 7.36 (m, 4H, arom-H), 8.1
ppm (s, 1H, furan-H).
Anal. Calcd for C18H14N4O2S: C, 61.70; H, 4.03; N, 15.99;
S, 9.15. Found: C, 61.60; H, 3.89; N, 15.91; S, 9.11.
[10] Ram, V. J. Arch Pharm 1979, 312, 19.
´
[11] Craciunescu, D.; Lopez, A. D.; Iriarte, E. G.; Tena, A.;
´
Gome, A.; Ghirvu, C. Anal Real Acad National Farmac 1985, 241, 51.
[12] Newberry, R. A.; Bushell, B. J. US Pat, 3,979,402; Chem
Abstr 1977, 86, 29795z.
Acknowledgments. The authors thank Assiut University
(Egypt) for supporting this work and to faculty of science, Ge-
neva University for X-ray single crystal measurements.
[13] Hozien, Z. A.; Sarhan, A. A. O.; El-Sherief, H. A. H.; Mah-
moud, A. M. Z. Naturforsch 1997, 52B, 1401.
[14] Sarhan, A. A. O.; Hafez, S. A.; El-Sherief, H. A. H.; Tarek,
A. Synth Commun 2006, 35, 987.
[15] Mahmoud, A. M. Z.; El-Sherief, H. A. H.; Habib, O. M. A.;
Sarhan, A. A. O. Phosphorus Sulfur Silicon and Relat Elem 2007, 182,
1757.
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DOI 10.1002/jhet