Synthesis and reactions of some pyrimidine derivatives

Article abstract of DOI:10.1080/10426500701752903

Three different series of compounds including N-formylated thioxopyrimidines 3a-d, thiazine derivatives 4a-c and N-formylated oxopyrimidines 5a-d were synthesized by reaction of an appropriate ethyl 6-methyl-4-aryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-

Full text of DOI:10.1080/10426500701752903

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Phosphorus, Sulfur, and Silicon
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Synthesis and Reactions of
Some Pyrimidine Derivatives
A. Mobinikhaledi a , N. Foroughifar a & T. Mosleh a
a Chemistry Department , Arak University , Arak,
Iran
Published online: 24 Jun 2008.
To cite this article: A. Mobinikhaledi , N. Foroughifar & T. Mosleh (2008) Synthesis
and Reactions of Some Pyrimidine Derivatives, Phosphorus, Sulfur, and Silicon and the
Related Elements, 183:7, 1790-1797, DOI: 10.1080/10426500701752903
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Phosphorus, Sulfur, and Silicon, 183:1790–1797, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701752903
Synthesis and Reactions of Some Pyrimidine Derivatives
A. Mobinikhaledi, N. Foroughifar, and T. Mosleh
Chemistry Department, Arak University, Arak, Iran
Three different series of compounds including N-formylated thioxopyrimidines
3a-d, thiazine derivatives 4a–c and N-formylated oxopyrimidines 5a–d were
synthesized by reaction of an appropriate ethyl 6-methyl-4-aryl-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate with DMF in the presence of POCl under dif-
3
ferent conditions. Furtherer reaction of the thiazine derivatives 4a–c with aqueous
HCl under heating followed by neutralization with NaOH gave 7a–c. IR and NMR
spectroscopy, as well as elemental analysis were used for the identification of the
new compounds.
Keywords Carboxylate; formyl; pyrimidine; thiazine
INTRODUCTION
The first Biginelli compound was synthesized in 1893.1 Recently
this reaction has been extended for preparation of a large num-
ber of 3,4-dihydropyrimidines.2 It is well known that a large num-
ber of 3,4-dihydropyrimidines show interesting pharmacological effi-
ciencies such as antitumor, antiviral, and antibacterial activities.2−9
In the past decade, 3,4-dihydropyrimidines with appropriate func-
tional groups have emerged as antihypertensive agents6−9 and potent
calcium channel blockers.4,5 Furthermore, several marine alkaloids
with interesting biological activities contain the dihydropyrimidine-
5-carboxylate moiety.7 The most convenient preparation methods of
these compounds include a one-pot reaction of β-ketoester or β-
diketone, arylaldehyde and (thio)urea using photochemical10 or mi-
crowave irradiation.11−13 However, because of the incessant interest
in this field, a new efficient synthesis of novel pyrimidine derivatives is
desirable.
Received 3 October 2007; accepted 17 October 2007.
Address correspondence to A. Mobinikhaledi, Chemistry Department, Arak Univer-
sity, Dr. Beheshti Ave, Arak, Iran. E-mail: akbar mobini@yahoo.com
1790

Pyrimidine Derivatives
1791
RESULTS AND DISCUSSION
The starting pyrimidines 1 were synthesized according to litera-
ture procedures.10−13 Compound 2, which acts as an intermedi-
ate, was prepared by reacting ethyl 6-methyl-4-aryl-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate 1 with DMF and POCl3 via a
Vilsmeier formylation. The compounds 3a–d was obtained by hydroly-
sis of the intermediate 2 at room temperature. However, hydrolysis of
2 under heating led to the formation of the thiazine carboxylates 4 and
the 3-formyl-2-oxopyrimidines 5 as the major and the minor product,
respectively. Compounds 5 are insoluble in an ice-cooled solution and
can be easily isolated by filtration. Hydrolysis of 4 under dilute acidic
conditions and heating afforded intermediately the hydrochloride 6.
Neutralization of the solution of 6 with 2 N NaOH gave 7, which was
isolated from an ice-cooled solution of EtOH/H2O (Scheme 1).
1
The H NMR spectra of the N-formylated thioxopyrimidines 3a–d
and the N-formylated oxopyrimidines 5a–d are very similar. The res-
onance of the formyl proton at low field and the absence of one of the
NH proton resonances compared to the starting material support the
structures of 3 and 5. The H-6 proton of these compounds showed a
downfield shift due to the adjacent electron withdrawing formyl group
at the N-1 nitrogen atom. Thus, the rearranged products 4a–c and 7a–c
were identified as 6H-1,3-thiazines.14
EXPERIMENTAL
Melting points were determined on an electrothermal digital melting
1
point apparatus Mettler Toledo Type FP62. H and 13C NMR spectra
were recorded with a Bruker Avance (300 MHz) spectrometer. The IR
spectra were recorded on Unicom Galaxy series FT-IR 5000 Spectrom-
eter. Microanalyses were performed by the Microanalytical Lab at the
Arak petrochemical company. Reactions were monitored by thin layer
chromatography using silica gel F254 aluminum sheets (Merck). All ma-
terials were used as obtained without further purification.
GENERAL PROCEDURES
Synthesis of 3a–d
To a solution of the appropriate ethyl 6-methyl-4-aryl-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (0.001 mol) in DMF (10 mL)
POCl3(0.001 mol) was added dropwise at 0◦C under stirring. Stirring
was continued at room temperature for 30 min 10 mL of ice water
was added to this solution and the precipitate was filtered to give the

1792
A. Mobinikhaledi et al.
SCHEME 1
N-formylated thioxopyrimidines 3a–d, which were recrystallized from
ethanol.
Synthesis of 4a–c and 5a–d
To a solution of the appropriate ethyl 6-methyl-4-aryl-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (0.001 mol) in DMF (10 mL) was
added POCl3(0.001 mol) under stirring at 0◦C. The reaction mixture
was heated at 85–90 ◦C for 1–2 h, allowed to cool to room temperature,
and poured in 10 mL of ice-cooled water. The precipitate was separated
by filtration and recrystallized from ethanol to give pure 5a–d. The
filtrate was made alkaline with NaOH (2N) to give 4a–c as the major
products.

Pyrimidine Derivatives
1793
Synthesis of 7a–c
A solution of 4 (0.001 mol) in 20 mL of HCl (37%) and 10 mL of water
was heated at 80◦C for 10 min. The precipitate was filtered to give the
hydrochloride 6. The ice-cooled solution of the precipitate in ethanol
(10 mL) was neutralized with 2N NaOH to give the free amine 7, which
was precipitated by adding ice water.
Ethyl 1-Formyl-4-methyl-6-phenyl-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (3a)
Yield 76%, m.p. 165–166◦C. IR (KBr): ν = 3213, 3153, 3009, 1712, 1645,
1
1630, 1520, 1498 cm−1. H NMR (CDCl3): δ = 1.23 (t, J = 7.1 Hz, 3H,
CH3), 2.46 (s, 3H, CH3), 4.17 (q, J = 7.1 Hz, 2H, OCH2), 6.46 (s, 1H,
4-H), 7.30 (m, 5H, arom-H), 9.71 (br s, 1H, NH), 11.10 (s, 1H, CHO). 13
C
NMR (CDCl3): δ = 14, 18, 52, 61, 107, 127, 128, 129, 139, 142, 163, 165,
178. Anal. calcd. for C15H16N2O3S: C, 59.19; H, 5.30; N, 9.20%. Found:
C, 59.48; H, 5.51; N, 9.61%.
Ethyl 6-[4-(Dimethylamino)phenyl]-1-formyl-4-methyl-2-
thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3b)
Yield 73%, m.p. 164–165◦C. IR (KBr): ν = 3248, 3011, 2833, 1678, 1710,
1
1662, 1527 cm−1. H NMR (CDCl3): δ = 1.17 (t, J = 7.2 Hz, 3H, CH3),
2.26 (s, 3H, CH3), 3.66 (s, 3H, NCH3), 3.68 (s, 3H, NCH3), 4.05 (q, J= 7.2
Hz, 2H, OCH2), 6.12 (s, 1H, 4-H), 6.84 (m, 4H, arom-H), 9.70 (br s, 1H,
NH), 11.70 (s, 1H, CHO). 13C NMR (CDCl3): δ = 14, 18, 52, 56, 61, 105,
112, 118, 128, 152, 153, 163, 165, 178. Anal. calcd. for C17H21N3O3S: C,
58.77; H, 6.09; N, 12.09%. Found: C, 59.10; H, 5.81; N, 12.28%.
Ethyl 1-Formyl-6-(4-methoxyphenyl)-4-methyl-2-thioxo-1,2,3,
4-tetrahydro-pyrimidine-5-carboxylate (3c)
Yield 33%, m.p. 112–113◦C. IR (KBr): ν = 3267, 3155, 2974, 1707, 1658,
1610, 1512, 1236, 1095 cm−1. 1H NMR (CDCl3): δ = 1.24 (t, J = 7.1 Hz,
3H, CH3), 2.38 (s, 3H, CH3), 2.52 (s, 3H, OCH3), 4.17 (q, J = 7.1 Hz,
2H, OCH2), 6.39 (s, 1H, 4-H), 7.10 (m, 4H, arom-H), 8.20 (br s, 1H, NH),
9.87 (s, 1H, CHO). Anal. calcd. for C16H18N2O4S: C, 57.47; H, 5.43; N,
8.38%. Found: C, 57.61; H, 5.46; N, 8.20%.
Ethyl 6-(2,5-Dimethoxyphenyl)-1-formyl-4-methyl-2-thioxo-1,
2,3,4-tetrahydropyrimidine-5-carboxylate (3d)
Yield 86%, m.p. 163–164◦C. IR (KBr): ν = 3383, 3100, 2941, 1678, 1610,
1
1512, 1207, 1066 cm−1. H NMR (CDCl3): δ = 1.21 (t, J = 7.2 Hz, 3H,
CH3), 2.20 (s, 3H, CH3), 3.71 (s, 6H, OCH3), 4.11 (q, J = 7.2 Hz, 2H,

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A. Mobinikhaledi et al.
OCH2), 6.24 (s, 1H, 4-H), 6.73 (m, 3H, arom-H), 8.21 (br s, 1H, NH), 9.30
(s, 1H, CHO). 13C NMR (CDCl3): δ = 14, 17, 52, 55, 56, 61, 105, 112, 114,
118, 128, 141, 152, 153, 163, 165, 178. Anal. calcd. for C17H20N2O5S: C,
56.03; H, 5.53; N, 7.69%. Found: C, 56.29; H, 5.34; N, 7.48%.
Ethyl 2-{(Dimethylamino)methyleneamino}-4-methyl-6-
phenyl-6H-1,3-thiazine-5-carboxylate (4a)
Yield 52%, m.p. 140–142◦C. IR (KBr): ν = 2990, 2930, 1687, 1615, 1580,
1
1471 cm−1. H NMR (CDCl3): δ = 1.23 (t, J = 7.2 Hz, 3H, CH3), 2.60
(s, 3H, CH3), 3.00 (s, 3H, NCH3), 3.12 (s, 3H, NCH3), 4.18 (q, J = 7.2
Hz, 2H, OCH2), 5.37 (s, 1H, 4-H), 7.22 (m, 5H, arom- H), 8.11 (s, 1H,
N CH ). 13C NMR (CDCl3): δ = 14, 24, 35, 41, 43, 60, 105, 126, 127,
128, 143, 158, 162, 165, 167. Anal. calcd. for C17H21N3O2S: C, 61.61; H,
6.39; N, 12.68%. Found: C, 61.50; H, 6.49; N, 12.30%.
Ethyl2-{(Dimethylamino)methyleneamino}-6-[4-
(dimethylamino)phenyl]-4-methyl-6H-1,3-thiazine-5-
carboxylate (4b)
Yield 61%, m.p. 146–148◦C. IR (KBr): ν = 2984, 2918, 1685, 1610, 1479
cm−1. 1H NMR (CDCl3): δ = 1.24 (t, J = 7.1 Hz, 3H, CH3), 2.61 (s, 3H,
CH3), 3.06 (s, 3H, NCH3), 3.08 (s, 3H, NCH3), 4.11 (q, J = 7.1 Hz, 2H,
OCH2), 5.74 (s, 1H, 4-H), 6.70 (m, 4H, arom-H), 8.10 (s, 1H, N CH ).
Anal. calcd. for C19H26N4O2S: C, 60.94; H, 7.00; N, 14.96%. Found: C,
61.24; H, 7.15; N, 14.55%.
Ethyl 6-(2,5-Dimethoxyphenyl)-2-{(dimethylamino)
methyleneamino}-4-methyl-6H-1,3-thiazine-5-carboxylate (4c)
Yield 61%, m.p. 132–133◦C. IR (KBr): ν = 3074, 2951, 1678 m 1645,
1
1610, 1531, 1493, 1276, 1053 cm−1. H NMR (CDCl3): δ = 1.21 (t, J =
7.0 Hz, 3H, CH3), 2.61 (s, 3H, CH3), 3.06 (s, 3H, NCH3), 3.08 (s, 3H,
NCH3), 3.68 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.12 (q, J = 7.0 Hz, 2H,
OCH2), 5.69 (s, 1H, 4-H), 6.71 (m, 3H, arom-H), 8.1 (s, 1H, N CH ).
Anal. calcd. for C19H25N3O4S: C, 58.29; H, 6.44; N, 10.73%. Found: C,
58.60; H, 6.62; N, 10.50%.
Ethyl 1-Formyl-4-methyl-2-oxo-6-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (5a)
Yield 20%, m.p. 216–218◦C. IR (KBr): ν = 3252, 3147, 2980, 1704, 1652,
1492 cm−1. 1H NMR (CDCl3): δ = 1.15 (t, J = 7.2 Hz, 3H, CH3), 2.35 (s,

Pyrimidine Derivatives
1795
3H, CH3), 3.39 (q, J = 7.2 Hz, 2H, OCH2), 6.18 (s, 1H, 4-H), 7.43 (m, 5H,
arom-H), 9.25 (br s, 1H, NH), 10.35 (s, 1H, CHO). 13C NMR (CDCl3): δ
= 14, 18, 53, 61, 105, 127, 128, 129, 140, 145, 152, 161, 165. Anal. calcd.
for C15H16N2O4: C, 62.49; H, 5.59; N, 9.72%. Found: C, 62.31; H, 5.66;
N, 9.79%.
Ethyl 6-[4-(Dimethylamino)phenyl]-1-formyl-4-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (5b)
Yield 20%, m.p. 171–172◦C. IR (KBr): ν = 3369, 3054, 2951, 1678, 1610,
1512 cm−1. 1H NMR (CDCl3): δ = 1.21 (t, J = 7.2 Hz, 3H, CH3), 2.30 (s,
3H, CH3), 3.67 (s, 3H, NCH3), 3.69 (s, 3H, NCH3), 4.11 (q, J = 7.1 Hz,
2H, OCH2), 6.60 (s, 1H, 4-H), 6.79 (m, 4H, arom-H), 9.19 (br s, 1H, NH),
10.11 (s, 1H, CHO). Anal. calcd. for C17H21N3O4: C, 61.62; H, 6.39; N,
12.68%. Found: C, 61.94; H, 6.48; N, 12.80%.
Ethyl 1-Formyl-6-(4-methoxyphenyl)-4-methyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (5c)
Yield 42%, m.p. 118–119◦C. IR (KBr): ν = 3252, 3136, 2955, 1705, 1649,
1
1512, 1248, 1082 cm−1. H NMR (CDCl3): δ = 1.13 (t, J = 7.2 Hz, 3H,
CH3), 2.35 (s, 3H, CH3), 3.69 (s, 3H, OCH3), 4.01 (q, J = 7.2 Hz, 2H,
OCH2), 6.21 (s, 1H, 4-H), 6.99 (m, 4H, arom-H), 8.64 (br s, 1H, NH),
9.21 (s, 1H, CHO). Anal. calcd. for C16H18N2O5: C, 60.37; H, 5.70; N,
8.80%. Found: C, 60.55; H, 5.91; N, 8.63%.
Ethyl 6-(2,5-Dimethoxyphenyl)-1-formyl-4-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (5d)
Yield 20%, m.p. 165–167◦C. IR (KBr): ν = 3379, 3074, 2951, 1678, 1610,
1512, 1238, 1053 cm−1. 1H NMR (CDCl3): δ = 1.25 (t, J = 7.1 Hz, CH3),
2.38 (s, 3H, CH3), 3.75 (s, 6H, OCH3), 4.11 (q, J = 7.1 Hz, 2H, OCH2),
6.22 (s, 1H, 4-H), 6.91 (m, 3H, arom-H), 8.16 (br s, 1H, NH), 9.29 (s, 1H,
CHO). 13C NMR (CDCl3): δ = 14, 18, 53, 55, 56, 60, 102, 112, 114, 118,
128, 144, 151, 152, 153, 163, 165. Anal. calcd. for C17H20N2O6: C, 58.61;
H, 5.79; N, 8.04%. Found: C, 58.51; H, 5.90; N, 7.82%.
Ethyl 2-Imino-4-methyl-6-phenyl-3,6-dihydro-2H-1,3-thiazine-
5-carboxylate (7a)
Yield 85%, m.p. 122–124◦C. IR (KBr): ν = 3200, 3184, 2972, 1732, 1690,
1
1610, 1581 cm−1. H NMR (CDCl3): δ = 1.04 (t, J = 7.1 Hz, 3H, CH3),
2.25 (s, 3H, CH3), 4.11 (q, J = 7.1 Hz, 2H, OCH2), 5.68 (s, 1H, 4-H), 7.32

1796
A. Mobinikhaledi et al.
(m, 5H, arom-H), 9.33 (br s, 1H, NH), 10.35 (br s, 1H, NH). 13C NMR
(CDCl3): δ = 14, 20, 42, 62, 106, 127, 128, 129, 139, 145, 164, 167. Anal.
calcd. for C14H16N2O2S: C, 60.84; H, 5.84; N, 10.14%. Found: C, 60.57;
H, 6.16; N, 10.36%.
Ethyl 2-Amino-6-[4-(dimethylamino)phenyl]-4-methyl-6H-1,3-
thiazine-5-carboxylate (7b)
Yield 90%, m.p. 161–163◦C. IR (KBr): ν = 3377, 3360, 3090, 2955, 1678,
1
1650, 1520, 1496 cm−1. H NMR (CDCl3): δ = 1.22 (t, J = 7.1 Hz, 3H,
CH3), 2.54 (s, 3H, CH3), 3.71 (s, 3H, NCH3), 3.87 (s, 3H, NCH3) 4.13 (q,
J = 7.2 Hz, 2H, OCH2), 5.69 (s, 1H, 4-H), 6.69 (m, 4H, arom-H), 7.28
(br s, 2H, NH2). 13C NMR (CDCl3): δ = 14, 23, 36, 56, 60, 102, 111, 112,
114, 130, 150, 153, 167. Anal. calcd. for C16H21N3O2S: C, 60.16; H, 6.63;
N, 13.16%. Found: C, 60.55; H, 6.19; N, 13.32%.
Ethyl 2-Amino-6-(2,5-dimethoxyphenyl)-4-methyl-6H-1,3-
thiazine-5-carboxylate (7c)
Yield 90%, m.p. 207–209◦C. IR(KBr): ν = 3232, 3134, 2980, 1710, 1643,
1
1504, 1230, 1087 cm−1. H NMR (CDCl3): δ = 1.22 (t, J = 7.2 Hz, 3H,
CH3), 2.54 (s, 3H, CH3), 3.71 (s, 6H, OCH3) 4.13 (q, J = 7.2 Hz, 2H,
OCH2), 5.69 (s, 1H, 4-H), 6.67 (m, 3H, arom-H), 7.21 (br s, 2H, NH2).
13C NMR (CDCl3): δ = 14, 23, 36, 55, 56, 60, 101, 111, 112, 113, 114,
115, 130, 150, 153, 166. Anal. calcd. for C16H20N2O4S: C, 57.12; H, 5.99;
N, 8.33%. Found: C, 57.35; H, 5.61; N, 8.37%.
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