One-Pot Synthesis of Functionalized Pyrimido[2,1-B][1,3]Thiazin-6-Ones Via a Multicomponent Reaction

Article abstract of DOI:10.1080/10426507.2015.1050015

A facile and direct synthesis of pyrimido[2,1-b][1,3]thiazin-6-ones via a one-pot, three-component reaction of dialkyl acetylenedicarboxylates with alkyl or aryl isocyanides and 2-thioxopyrimidin-4-ones in good overall yields.

Full text of DOI:10.1080/10426507.2015.1050015

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
One-Pot Synthesis of Functionalized Pyrimido[2,1-
B][1,3]Thiazin-6-Ones Via a Multicomponent
Reaction
Khadijeh Yadollahzadeh, Javad Azizian & Haleh Sanaeishoar
To cite this article: Khadijeh Yadollahzadeh, Javad Azizian & Haleh Sanaeishoar (2015) One-
Pot Synthesis of Functionalized Pyrimido[2,1-B][1,3]Thiazin-6-Ones Via a Multicomponent
Reaction, Phosphorus, Sulfur, and Silicon and the Related Elements, 190:11, 2023-2030, DOI:
10.1080/10426507.2015.1050015
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Date: 02 December 2015, At: 23:16

Phosphorus, Sulfur, and Silicon, 190:2023–2030, 2015
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2015.1050015
ONE-POT SYNTHESIS OF FUNCTIONALIZED
PYRIMIDO[2,1-B][1,3]THIAZIN-6-ONES VIA A
MULTICOMPONENT REACTION
Khadijeh Yadollahzadeh,1 Javad Azizian,2
and Haleh Sanaeishoar3
1Chemistry Department, Aliabad Katoul Branch, Islamic Azad University, Aliabad
Katoul, Iran
2Chemistry Department, Science and Research Branch, Islamic Azad University,
Ponak, Tehran, Iran
3Department of Chemistry, College of Science, Ahvaz Branch, Islamic Azad
University, Ahvaz, Iran
GRAPHICAL ABSTRACT
Abstract A facile and direct synthesis of pyrimido[2,1-b][1,3]thiazin-6-ones via a one-pot,
three-component reaction of dialkyl acetylenedicarboxylates with alkyl or aryl isocyanides and
2-thioxopyrimidin-4-ones in good overall yields.
Keywords 2-Thioxopyrimidin-4-one; pyrimido[2; 1-b][1; 3]thiazin-6-one; isocyanide;
acetylenedicarboxylates
INTRODUCTION
Pyrimidines and related fused heterocyclic derivatives are of great biological interest
due to their anti-inflammatory, analgesic, antimicrobial, antileishmanial, and therapeutic
properties and especially their antiviral, antithyroid, and antitumor activities.1–7 Several
methods have been reported for the synthesis of some fused pyrimidine derivatives.8 Draw-
backs of some of these methods include multistep reactions,8f long reaction times,8g pro-
duction of mixture products,8h the use of catalysts8j and modest yields.8l Therefore, the
further development of synthetic methods to produce a variety of these templates remains
an important task.
Received 20 December 2014; accepted 5 May 2015.
Address correspondence to Dr. Khadijeh Yadollahzadeh, Chemistry Department, Aliabad Katoul Branch,
Islamic Azad University, Aliabad Katoul, Iran. E-mail: yadollahzadeh@gmail.com; yadollahzadeh@aliabad.ac.ir
2023

2024
K. YADOLLAHZADEH ET AL.
The reaction of isocyanide nucleophiles with activated acetylenic compounds such as
dialkyl acetylenedicarboxylates leads to activated zwitterions. These types of zwitterions
can be trapped by a variety of electrophiles such as activated carbonyl compounds or
reagents containing NH, OH, CH, and SH acidic groups to afford highly functionalized
novel aminofurans and iminolactones in good yields.9
As part of our current studies on the development of new routes in heterocyclic syn-
thesis,10 this work reports the results of our studies involving the reaction of the zwitterionic
intermediates derived from alkyl isocyanides 3 and acetylenic esters 2 with 2-thiouracils 1,
which constitutes a synthesis of pyrimido[2,1-b][1,3]thiazine derivatives 4 and 5 in 85–96%
yields (Scheme 1). The optimized results are summarized in Table 1.
Scheme 1 Synthesis of pyrimido[2,1-b][1,3]thiazin-6-ones
RESULTS AND DISCUSSION
The reaction of 2-thiouracils 1 with dialkyl acetylenedicarboxylates 2 in the presence
of isocyanides 3 proceeded in refluxing toluene, over 1 h to give dialkyl 4-(alkylamino)-
2,6-dihydro-6-oxo-8-alkylpyrimido[2,1-b][1,3]thiazine-2,3-dicarboxylate 4 and dialkyl
4-(arylamino)-4,6-dihydro-6-oxo-8-alkylpyrimido[2,1-b][1,3]thiazine-2,3-dicarboxylate
5. The structures of compounds 4a–4h and 5a-5d were deduced from their elemental
1
analyses and IR, H and 13C NMR spectra. The mass spectra of these stable compounds
displayed molecular ion peaks at the appropriate m/z values. Any initial fragmentation
involves loss from, or complete loss of the side chains and scission of the heterocyclic
Table 1 Synthesis of pyrimido[2,1-b][1,3]thiazin-6-ones
Entry
R
Rꢁ
Rꢁꢁ
Product
Yield%
1
2
3
4
5
6
7
8
H
H
n-Pr
n-Pr
H
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Cyclohexyl
Cyclohexyl
Cyclohexyl
4a
4b
4c
4d
4e
4f
4g
4h
5a
5b
5c
5d
91
87
94
87
93
86
93
85
94
96
92
93
Cyclohexyl
1,1,3,3-Tetramethylbutyl
1,1,3,3-Tetramethylbutyl
1,1,3,3-Tetramethylbutyl
1,1,3,3-Tetramethylbutyl
2,6-Dimethyl phenyl
2,6-Dimethyl phenyl
2,6-Dimethyl phenyl
2,6-Dimethyl phenyl
H
n-Pr
n-Pr
H
H
n-Pr
n-Pr
9
10
11
12

ONE-POT SYNTHESIS OF FUNCTIONALIZED PYRIMIDO[2,1-B][1,3]THIAZIN-6-ONES 2025
ring system. The 1H NMR spectrum of 4a displayed cyclohexyl (δ = 1.27–2.01 ppm), two
methoxy (δ = 3.57 and 3.75 ppm), and methine (δ = 7.11 ppm) protons. The adjacent
alkene protons were exhibited as two doublets at δ = 6.42 and 7.83 ppm, along with a
broad singlet at δ = 9.67 ppm for the NH group. The proton decoupled 13C NMR spectrum
of 4a showed 17 distinct resonances in agreement with the proposed structure.
The 1H NMR spectrum of 5a exhibited five singlets identified as methyl (δ = 1.91
and 2.43 ppm), methoxy (δ = 3.73 and 3.87 ppm), and methine (δ = 4.96 ppm) protons.
Two doublets were observed at δ = 5.45 and 7.45 ppm for the adjacent alkene protons,
aromatic protons (δ = 6.87–7.06 ppm) and a broad singlet at δ = 10.57 ppm for the NH
group. The proton decoupled 13C NMR spectrum of 5a showed 19 distinct resonances in
agreement with the proposed structure.
Although we have not yet established the mechanism of formation of 4 and 5 in
an experimental manner, a plausible rationalization for the formation of functionalized
pyrimido[2,1-b][1,3]thiazin-6-ones 4a–4h and 5a-5d is shown in Scheme 2. Presumably,
the zwitterionic intermediate,11 formed from 2 and 3, is protonated by the NH acidic
compound 1. Then, the positively charged ion 7 undergoes an intramolecular reaction with
compounds 8 to produce the ketenimines 9, which apparently isomerize under the reaction
conditions employed to produce the final products 4 in excellent yields. Finally, a hydrogen
shift produces the final products 5 in good yields (Scheme 2). The absence of the strong
ketenimine absorption bands at about 2050 cm−1 in the IR spectra of compounds 4 and 5,
excludes the conjugate addition of the anion 8 to the intermediate 7.
Scheme 2 Proposed mechanism.
CONCLUSION
In conclusion, we have developed a simple and efficient method for the synthesis
of functionalized pyrimido[2,1-b][1,3]thiazin-6-ones derivatives of potential synthetic and
pharmacological interest. The one-pot nature of the present procedure makes it an acceptable
method for the preparation of target molecules with variable functionalities. The advantages
of the present method include good functional group tolerance, high yields of products,
simple experimental procedure and purification, no need for dry solvent, no catalyst and

2026
K. YADOLLAHZADEH ET AL.
no prior activation, no mixture product, short reaction times and the starting materials and
reagents can be mixed without any activation or modification. We hope that this approach
may be of value to others seeking novel synthetic fragments with unique properties for
medicinal chemistry.
EXPERIMENTAL
2-Thioxopyrimidin-4-ones, acetylenic esters and isocyanides were obtained from
Fluka and were used without further purification. Melting points (uncorrected) were mea-
sured on an Electrothermal 9100 apparatus. Elemental analyses for C, H, and N were
performed using a Heraeus CHN-O-Rapid analyzer. The experimental data were in good
1
agreement with the calculated values. H and 13C NMR spectra (CDCl3) were measured
with a Bruker DRX-300 Avance spectrometer. IR spectra were recorded on a Shimadzu
IR-460 spectrometer. Mass spectra were obtained with a Finnigan-MAT-8430 mass spec-
trometer, in m/z. The Supplemental Materials contain sample 1H and 13C NMR spectra of
4e and 5a (Figures S–S4).
General Procedure for the Preparation of Compounds 4, 5
To a stirred solution of 1 (1 mmol) and 2 (1 mmol) in 5 mL toluene was added a
mixture of (3, 1 mmol) in 2 mL toluene. The reaction mixture was heated for 1 h. The
solvent was removed under reduced pressure, and the residue was purified by column
chromatography (SiO2; n-hexane/AcOEt = 3/1)
Typical procedure for the preparation of dimethyl 2-(cyclohexylamino)-4,8-dihydro-
6-methyl-8-oxopyrimido[2,1-b][1,3]thiazine-3,4-dicarboxylate (4a): To a stirred solution
of 2-Thioxopyrimidin-4-one (1, 1 mmol) and DMADs (2, 1 mmol) in toluene (5 mL) was
added a drop wise solution of cyclohexylisocyanide (3, 1 mmol) in toluene (2 mL). The
reaction mixture was heated for 1 h. The solvent was removed under reduced pressure,
and the residue was purified by column chromatography (SiO2; n-hexane/AcOEt = 3/1) to
afford the pure adducts. 4a as a White powder; m.p: 145–147 ◦C; yield: 0.35 g (91%). IR
(KBr) (νmax/cm−1): 3211, 1741, 1690, 1241 cm−1. 1H NMR: 1.27–2.01 (10 H, m, 5 CH2),
3.58 (1 H, m, CH), 3.75 (3 H, s, CH3O), 3.81 (3 H, s, CH3O), 6.42 (1 H, d, 3JHH = 6.7,
CH), 7.11 (1 H, s, CH), 7.83 (1 H, d,3JHH = 6.7, CH), 9.32 (1 H, br s, NH). 13C NMR: 24.7
(CH2), 25.5 (2CH2), 33.8 (CH2), 34.3 (CH2), 51.9 (CH–N), 53.0 (CH3O), 54.1 (CH3O),
54.7 (CH), 85.6 (C), 113.4 (CH),152.9 (CH), 156.0 (C), 156.4 (C N), 160.4 (C O), 167.2
(C O), 168.9 (C O). EI-MS, m/z (%): 379 (M+, 13), 320 (17), 253 (100), 83 (13), 59
(15); Anal. Calcd for C17H21N3O5S (379.12); C, 53.81; H, 5.58; N, 11.07; Found: C, 54.01;
H, 5.48; N, 10.97.
Diethyl2-(cyclohexylamino)-4,8-dihydro-8-oxopyrimido[2,1-b][1,3]thiazine3,4-
◦
dicarboxylate (4b): White powder; m.p: 161–163 C; yield: 0.36 g (87%). IR (KBr)
(νmax/cm−1): 3223, 1735, 1691, 1241 cm−1. 1H NMR: 1.27–2.01 (10 H, m, 5 CH2), 1.26
(3 H, t, 3JHH = 7.1, CH3), 1.42 (3 H, t, 3JHH = 7.1, CH3), 3.58 (1 H, m, CH), 4.15 (2 H,
2
3
3
dq, JHH = 11.6, JHH = 7.1, CH2O), 4.53 (2 H, dq, 2JHH = 11.6, JHH = 7.1, CH2O),
6.45 (1H, d,3JHH = 6.7, CH), 7.03 (1 H, s, CH), 7.88 (1 H, d,3JHH = 6.7, CH), 9.32 (1
H, br s, NH). 13C NMR: 14.3 (CH3), 14.8 (CH3), 24.4 (CH2), 25.5 (2 CH2), 33.7 (CH2),
34.4 (CH2), 51.7 (CH–N), 54.7 (CH), 61.0 (CH2O), 61.7 (CH2O), 86.6 (C), 113.5 (CH),
152.6 (CH), 156.2 (C), 157.4 (C = N), 160.4 (C = O), 167.2 (C = O), 168.9 (C = O).

ONE-POT SYNTHESIS OF FUNCTIONALIZED PYRIMIDO[2,1-B][1,3]THIAZIN-6-ONES 2027
EI-MS, m/z (%):407 (M+, 13), 334 (17), 267 (100), 83 (13), 59 (47); Anal. Calcd for
C19H25N3O5S (407.15) C, 56.00; H, 6.18; N, 10.31; Found: C, 56.52; H, 6.76; N, 10.01.
Dimethyl2-(cyclohexylamino)-4,8-dihydro-8-oxo-6-propylpyrimido[2,1-b][1,3]
thiazine-3,4-dicarboxylate(4c): White powder; m.p: 155–157 ◦C; yield: 0.39 g (94%). IR
1
3
(KBr) (νmax/cm−1): 3120, 1739, 1691, 1241 cm−1. H NMR: 0.89 (3 H, t, JHH = 7.4,
CH3), 1.25–2.06 (10 H, m, 5 CH2), 1.54 (quin, 3JHH = 7.4, CH2), 2.27 (2 H, t, 3JHH = 7.4,
CH2), 3.58 (1H, m, CH), 3.71 (3H, s, CH3O), 3.83 (3H, s, CH3O), 5.98 (1H, s, CH), 7.14
(1H, s, CH), 9.37 (1H, br s, NH). 13C NMR: 13.8 (CH3), 21.3 (CH2), 24.7 (CH2), 25.3
(2 CH2), 33.8 (CH2), 34.1 (CH2), 39.2 (CH2), 51.4 (CH–N), 53.0 (CH3O), 53.9 (CH3O),
54.6 (CH), 85.6 (C), 113.4 (CH), 152.9 (C), 156.0 (C), 156.3 (C N), 160.4 (C O), 167.6
(C O), 168.9 (C O). EI-MS, m/z (%): 421 (M+, 13), 362 (17), 320 (15), 253 (100), 83
(15), 59 (47); Anal. Calcd for C20H27N3O5S (421.16) C, 56.99; H, 6.46; N, 9.97; Found:
C, 57.39; H, 6.96; N, 8.87.
Diethyl2-(cyclohexylamino)-4,8-dihydro-8-oxo-6-propylpyrimido[2,1-b][1,3]
thiazine-3,4-dicarboxylate(4d): White powder; m.p: 142–145 ◦C; yield: 0.39 g (87%). IR
1
3
(KBr) (νmax/cm−1): 3330, 1745, 1681, 1222 cm−1. H NMR: 0.88 (3 H, t, JHH = 7.4,
3
3
CH3), 1.27–2.01 (10 H, m, 5 CH2), 1.25 (3 H, t, JHH = 7.1, CH3), 1.41 (3 H, t, JHH
=
7.1, CH3), 1.52 (2H, quin, 3JHH = 7.4, CH2), 2.28 (2H, t, 3JHH = 7.4, CH2), 3.58 (1H, m,
CH),), 4.14 (2 H, dq, 2JHH = 11.6, 3JHH = 7.1, CH2O), 4.51 (2H, dq, 2JHH = 11.6, 3JHH
= 7.1, CH2O), 6.46 (1H, s, CH), 7.01 (1H, s, CH), 9.32 (1 H, br s, NH). 13C NMR:13.3
(CH3), 14.3 (CH3), 14.3 (CH3), 20.2 (CH2), 24.7 (CH2), 25.5 (CH2), 33.9 (2 CH2), 34.3
(CH2), 37.5 (CH2), 51.9 (CH-N), 54.7 (CH), 61.0 (CH2O), 61.7 (CH2O), 86.6 (C), 113.1
(CH), 152.5 (C), 156.2 (C), 157.4 (C N),160.4 (C O), 167.2 (C O), 168.9 (C O).
EI-MS, m/z (%):449 (M+, 13), 376 (18), 334 (15), 267 (100), 83 (15), 59 (45); Anal. Calcd
for C22H31N3O5S (449.19) C, 58.78; H, 6.95; N, 9.35; Found C, 58.62; H, 6.95; N, 9.34.
Dimethyl
2-(2,4,4-trimethylpentan-2-ylamino)-4,8-dihydro-8-oxopyrimido[2,1-
b][1,3]thiazine-3,4-dicarboxylate(4e):145–147 ◦C; yield: 0.38 g (93%). IR (KBr)
(νmax/cm−1): 3220, 1745, 1691, 1241 cm−1. H NMR: 1.02 (9 H, s, 3 CH3), 1.51 (3 H,
1
2
2
s, CH3), 1.52 (3 H, s, CH3), 1.62 (1 H, d, JHH = 15.3, CH), 1.92 (1 H, d, JHH = 15.3,
CH), 3.72 (3 H, s, CH3O), 3.80 (3 H, s, CH3O), 6.42 (1 H, d, 3JHH = 6.6, CH), 7.15 (1 H,
s, CH), 7.83 (1 H, d, 3JHH = 6.6, CH), 9.67 (1 H, br s, NH). 13C NMR: 31.3 (CH3), 31.7
(3 CH3), 32.1 (C), 39.5 (CH3), 51.9 (CH2), 52.7 (CH3O), 53.1 (C), 53.6 (CH3O), 58.4
(CH), 86.8 (C), 110.3 (CH), 154.4 (CH), 157.0 (C), 160.8 (C N), 167.4 (C O), 167.6
(C O), 169.2 (C O). EI-MS, m/z (%):409 (M+, 13), 350 (18), 283 (100), 113 (16), 59
(34); Anal. Calcd for C19H27N3O5S (409.16); C, 55.73; H, 6.65; N, 10.26. Found: C, 55.
37; H, 6.05; N, 10.36.
Diethyl2-(2,4,4-trimethylpentan-2-ylamino)-4,8-dihydro-8-oxopyrimido[2,1-b]
[1,3]thiazine-3,4-dicarboxylate(4f):White powder; m.p: 149–151 ◦C; yield: 0.40 g (86%).
IR (KBr) (νmax/cm−1): 3232, 1735, 1696, 1221 cm−1. 1H NMR: 1.02 (9 H, s, 3 CH3), 1.23
3
(3 H, t, JHH = 7.1 CH3), 1.43 (3 H, t,3JHH = 7.1, CH3), 1.54 (3 H, s, CH3), 1.58 (3 H,
2
2
s, CH3), 1.71 (1 H, d, JHH = 15.3, CH), 1.90 (1 H, d, JHH = 15.3, CH), 4.05 (2 H, dq,
2JHH = 11.6, 3JHH = 7.1, CH2O), 4.41 (2 H, dq, 2JHH = 11.6, 3JHH = 7.1, CH2O), 6.44 (1
H, d, 3JHH = 6.7, CH), 7.13 (1 H, s, CH), 7.83 (1 H, d, 3JHH = 6.7, CH), 9.52 (1 H, br s,
NH). 13C NMR: 14.3 (CH3), 14.8 (CH3), 30.2 (CH3), 32.1 (3 CH3), 32.8 (C), 33.1 (CH3),
52.9 (CH2), 53.6 (C), 60.1 (CH2O), 62.1 (CH2O), 64.4 (CH), 87.2 (C), 111.4 (CH), 153.9
(CH), 156.1(C), 160.8 (C N), 165.8 (C O), 167.4 (C O), 169.1 (C O). EI-MS, m/z
(%):437 (M+, 13), 364 (18), 297 (100), 113 (15), 59 (45); Anal. Calcd for C21H31N3O5S
(437.19) C, 57.64; H, 7.14; N, 9.60; Found: C, 58.04; H, 6.89; N, 9.34.

2028
K. YADOLLAHZADEH ET AL.
Dimethyl2-(2,4,4-trimethylpentan-2-ylamino)-4,8-dihydro-8-oxo-6-propyl
pyrimido[2,1-b][1,3]thiazine-3,4-dicarboxylate(4g):White powder; m.p: 153–157 ◦C;
yield: 0.38 g (93%). IR (KBr) (νmax/cm−1): 3220, 1745, 1691, 1241 cm−1. 1H NMR: 0.88
3
(3 H, t, JHH = 7.4, CH3), 1.02 (9 H, s, 3 CH3), 1.51 (3 H, s, CH3), 1.56 (3 H, s, CH3),
1.57 (quin, 3JHH = 7.4, CH2), 1.70 (1 H, d, 2JHH = 15.3, CH), 1.92 (1 H, d, 2JHH = 15.3,
CH), 2.27 (2H, t, 3JHH = 7.4, CH2), 3.72 (3 H, s, CH3O), 3.81 (3 H, s, CH3O), 5.46 (1 H,
s, CH), 7.05 (1 H, s, CH), 9.67 (1 H, br s, NH). 13C NMR: 13.9 (CH3), 21.5 (CH2), 31.3
(CH3), 31.7 (3 CH3), 31.9 (C), 32.0 (CH3), 39.5 (CH2), 51.9 (CH2), 52.7 (CH3O), 53.1
(C), 53.6 (CH3O), 58.4 (CH), 86.8 (C), 110.3 (CH), 154.4 (C), 157.0 (C), 161.8 (C = N),
167.4 (C O), 167.6 (C O), 169.2 (C O). EI-MS, m/z (%):451 (M+, 13), 392 (18), 350
(17), 283 (100), 113 (17), 59 (34); Anal. Calcd for C22H33N3O5S (451.21); C, 58.51; H,
7.37; N, 9.31; Found: C, 58.42; H, 7.07; N, 8.91.
Diethyl2-(2,4,4-trimethylpentan-2-ylamino)-4,8-dihydro-8-oxo-6-propyl pyrimido
[2,1-b][1,3]thiazine-3,4-dicarboxylate(4h): White powder; m.p: 144–146 ◦C; yield: 0.41 g
(85%). IR (KBr) (νmax/cm−1): 3232, 1741, 1687, 1237 cm−1. 1H NMR: 0.87 (3 H, t, 3JHH
= 7.4, CH3), 1.09 (9 H, s, 3 CH3), 1.23 (3 H, t, 3JHH = 7.1, CH3), 1.44 (3 H, t, 3JHH = 7.1,
3
CH3), 1.53(3 H, s, CH3), 1.57 (2 H, quin, JHH = 7.4, CH2), 1.58 (3 H, s, CH3), 1.72 (1
H, d, 2JHH = 15.3, CH), 1.95 (1 H, d, 2JHH = 15.3, CH), 2.26 (2 H, t, 3JHH = 7.4, CH2),
4.04 (2 H, dq, 2JHH = 11.6, 3JHH = 7.1, CH2O), 4.41 (2 H, dq, 2JHH = 11.6, 3JHH = 7.1,
CH2O), 5.48 (1 H, s, CH), 7.11 (1 H, s, CH), 9.52 (1H, br s, NH). 13C NMR: 13.9 (CH3),
14.3 (CH3), 14.8 (CH3), 21.5 (CH2), 30.2 (CH3), 32.1 (3 CH3), 32.9 (C), 33.1(CH3), 39.6
(CH2), 52.9 (CH2), 53.6 (C), 60.1 (CH2O), 62.1 (CH2O), 64.4 (CH), 87.2 (C), 111.4 (CH),
153.9 (C), 156.1 (C), 160.8 (C N), 165.8 (C O), 167.4 (C O), 169.1 (C O). EI-MS,
m/z (%):479 (M+, 12), 406 (15), 364 (17), 297 (100), 113 (15), 59 (41); Anal. Calcd for
C24H37N3O5S (479.24); C, 60.10; H, 7.78; N, 8.76; Found: C, 61.32; H, 7.12; N, 7.96.
Typical procedure for the preparation of dimethyl 2-(2,6-dimethyl phenyl amino)-2,8-
dihydro-8-oxopyrimido[2,1-b][1,3]thiazine-3,4-dicarboxylate (5a): To a stirred solution of
2-Thioxopyrimidin-4-one (1, 1 mmol) and DMADs (2, 1 mmol) in toluene (5 mL) was
added, drop wise, a solution of 2,6-dimethylphenylisocyanide (3, 1 mmol) in toluene (2 mL).
The reaction mixture was heated for 1 h. The solvent was removed under reduced pressure,
and the residue was purified by column chromatography (SiO2; n-hexane/AcOEt = 3/1) to
afford the pure adducts.
5a as Yellow powder; m.p: 162–165 ◦C; yield: 0.38 g (94%). IR (KBr) (νmax/cm−1):
3220, 1745, 1691, 1241 cm−1. 1H NMR: 1.91 (3 H, s, CH3), 2.43 (3 H, s, CH3), 3.71 (3H,
s, CH3O), 3.88 (3H, s, CH3O), 4.94 (1H, s, CH), 5.65 (1H, d, 3JHH = 6.7, CH), 6.87 (1H,
3
3
3
d, JHH = 7.3, CH), 7.01 (1H, d, JHH = 7.3, CH), 7.06 (1 H, t, JHH = 7.3), 7.45 (1 H,
d, 3JHH = 6.7, CH), 10.57 (1H, brs, NH). 13C NMR: 19.1 (CH3), 20.9 (CH3), 40.2 (CH),
52.4 (CH3O), 53.7 (CH3O), 88.2 (C), 109.5 (CH), 127.2 (CH), 128.5 (CH), 128.9 (CH),
132.8 (C), 135.4 (C), 136.2 (C), 152.7 (CH), 158.3 (C), 159.5 (C N), 164.9(C O), 167.8
(C O), 169.9 (C O). EI-MS, m/z (%): 401 (M+, 13), 342 (17), 274 (100), 149 (13), 105
(15), 57 (47); Anal. Calcd for C19H19N3O5S (401.10) C, 56.85; H, 4.77; N, 10.47; Found:
C, 57.12; H, 4.07; N, 9.86.
Diethyl2-(2,6-dimethylphenylamino)-2,8-dihydro-8-oxopyrimido[2,1-b][1,3]
thiazine-3,4-dicarboxylate(5b): Yellow powder; m.p: 145–147 ◦C; yield: 0.41 g (96%). IR
1
3
(KBr) (νmax/cm−1): 3220, 1745, 1691, 1241 cm−1. H NMR: 1.23 (3 H, t, JHH = 7.1,
3
CH3), 1.41 (3 H, t, JHH = 7.1, CH3), 1.96 (3 H, s, CH3), 2.43 (3 H, s, CH3), 4.15 (2 H,
dq, 2JHH = 11.6, JHH = 7.1, CH2O), 4.51 (2 H, dq, 2JHH = 11.6, JHH = 7.1, CH2O),
3
3
4.94 (1H, s, CH), 5.65 (1H, d, 3JHH = 6.7, CH), 6.87 (1 H, d, JHH = 7.3, CH), 7.02
3

ONE-POT SYNTHESIS OF FUNCTIONALIZED PYRIMIDO[2,1-B][1,3]THIAZIN-6-ONES 2029
3
3
(1 H, d, JHH = 7.3, CH), 7.06 (1 H, t, JHH = 7.3, CH), 7.33 (1 H, d, 3JHH = 6.7, CH),
10.57 (1H, br s, NH). 13C NMR: 14.4 (CH3), 14.4 (CH3), 19.6 (CH3), 21.0 (CH3), 40.5
(CH), 61.5 (CH2O), 62.6 (CH2O), 86.8 (C), 109.1 (CH), 127.8 (CH), 128.5 (CH), 128.8
(CH), 132.5 (C), 135.5 (C), 136.0 (C), 152.3(CH), 157.0 (C), 159.8 (C N), 164.4 (C O),
167.6 (C O), 169.3 (C O). EI-MS, m/z (%):429 (M+, 13), 401 (14), 342(100), 274 (15),
105 (12), 57 (44); Anal. Calcd for C21H23N3O5S (429.13); C, 58.73; H, 5.40; N, 9.78;
Found: C, 58.45; H, 5.37; N, 9.72.
Dimethyl2-(2,6-dimethylphenylamino)-2,8-dihydro-8-oxo-6-propylpyrimido [2,1-
◦
b][1,3]thiazine-3,4-dicarboxylate (5c):Yellow powder; m.p: 159–161 C; yield: 0.40 g
(92%). IR (KBr) (νmax/cm−1): 3320, 1745, 1694, 1231 cm−1. 1H NMR: 0.88 (3 H, t, 3JHH
= 7.4, CH3), 1.57 (2 H, quin, 3JHH = 7.4, CH2), 1.92 (3 H, s, CH3), 2.27 (2 H, t, 3JHH
=
7.4, CH2), 2.33 (3 H, s, CH3), 3.71 (3 H, s, CH3O), 3.87 (3 H, s, CH3O), 4.95 (1 H, s, CH),
5.46 (1 H, s,CH), 6.87 (1 H, d, 3JHH = 7.3, CH), 7.00 (1 H, d, 3JHH = 7.3, CH), 7.05 (1 H,
t, 3JHH = 7.3), 10.47 (1 H, br s, NH). 13C NMR: 13.6 (CH3), 17.9 (CH2), 19.2 (CH3), 21.0
(CH3), 38.6 (CH2), 40.5 (CH), 52.7 (CH3O), 53.6 (CH3O), 86.8 (C), 109.3 (CH), 127.1
(CH), 128.7 (CH), 128.8 (CH), 132.6 (C), 135.3 (C), 136.0 (C), 152.4 (C), 158.0 (C),159.8
(C N),164.4 (C O), 167.6 (C O), 169.2 (C O). EI-MS, m/z (%):443 (M+, 13), 384
(15), 274 (100), 149 (14), 105 (13), 57 (44); Anal. Calcd for C22H25N3O5S (443.15) C,
59.58; H, 5.68; N, 9.47; Found: C, 59.83; H, 5.23; N, 9.34.
Diethyl 2-(2,6-dimethylphenylamino)-2,8-dihydro-8-oxo-6-propylpyrimido [2,1-
b][1,3]thiazine-3,4-dicarboxylate(5d):Yellow powder; m.p: 148–150 ◦C; yield: 0.42 g
(93%). IR (KBr) (νmax/cm−1): 3210, 1732, 1686, 1241 cm−1. 1H NMR: 0.89 (3 H, t, 3JHH
= 7.4, CH3), 1.54 (2H, quin, 3JHH = 7.4, CH2), 1.26 (3 H, t, 3JHH = 7.1, CH3), 1.41 (3 H,
t, 3JHH = 7.1, CH3), 1.93 (3H, s, CH3), 2.27 (2H, t, 3JHH = 7.4, CH2), 2.42 (3 H, s, CH3),
4.13 (2 H, dq, 2JHH = 11.6, 3JHH = 7.1, CH2O), 4.58 (2 H, dq, 2JHH = 11.6, 3JHH = 7.1,
3
CH2O), 4.84 (1 H, s, CH), 5.43 (1 H, s, CH), 6.87 (1 H, d, JHH = 7.3, CH), 7.00 (1 H,
3
3
d, JHH = 7.3, CH), 7.06 (1H, t, JHH = 7.3, CH), 10.54 (1H, br s, NH). 13C NMR: 13.8
(CH3), 14.1 (CH3), 14.8 (CH3), 17.4 (CH2), 19.6 (CH3), 21.0 (CH3), 38.1 (CH2), 40.3
(CH), 61.6 (CH2O), 62.6 (CH2O), 86.8 (C), 109.1 (CH), 127.2 (CH), 128.5 (CH), 128.8
(CH), 132.8 (C), 135.5 (C), 136.0 (C), 152.4 (C), 158.0 (C), 159.6 (C N),164.3 (C O),
167.1 (C O), 169.6 (C O). EI-MS, m/z (%): 471 (M+, 13), 398 (14), 289 (100), 149
(15), 105 (12), 57 (44); Anal. Calcd for C24H29N3O5S (471.18) C, 61.13; H, 6.20; N, 8.91;
Found: C, 61.23; H, 6.34; N, 8.54.
ACKNOWLEDMENTS
This study is extracted from the research project supported by Islamic Azad University
of Aliabad Katoul branch.
SUPPLEMENTARY MATERIAL
Supplemental data for this article can be accessed on the publisher’s website at
http://dx.doi.org/10.1080/10426507.2015.1050015.
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