Synthesis and reaction of novel spiro pyrimidine derivatives

Article abstract of DOI:10.1002/jhet.2002

2-Mercapto-6-[(pyridin-4-ylmethylene)-amino]-3H-pyrimidin-4-one 1 was synthesized from Schiff base reaction of 6-amino-2-thiouracil with isonicotinaldehyde. The reaction of 1 with hydrazonyl chloride 2a-d afforded the novel pyrimidin-4-one 3a-d. Compounds 3a-d reacted with methyl iodide to give 4a-d. Subsequently, reaction of 4a-d with triethylamine as a catalyst in dry chloroform yielded tetraaza-spiro[4.5]deca-2, 8-dien-7-one 5a-d. In addition, reaction of 1 with acrylonitrile gave pyrimidin-propionitrile 6. The cyclization of 6 by reacting with sodium ethoxide to give pyrimido [2, 1-b] [1,3] thiazin-6-one 7. The refluxing of 1 with bromine in acetic acid yielded 2-bromo-pyrimidin-4-one 8. The latter compound 8 reacted with sodium azide gave tetrazolo-pyrimidine 10. The chemical structures of the newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, and mass spectral analysis. A novel series of 6-methyl-1, 3-(sub.)-9-[(pyridin-4- ylmethylene)-amino]-4-thia-1, 2, 6, 10-tetraaza-spiro[4.5]deca-2, 8-dien-7-one with some of new compounds for examples thiazin, tetrazolo-pyrimidine derivatives.

Full text of DOI:10.1002/jhet.2002

1020
Synthesis and Reaction of Novel Spiro Pyrimidine Derivatives
Vol 51
Ameen Ali Abu-Hashema,b
*
aPhotochemistry Department (Heterocyclic Unit), National Research Center, 12622, Dokki, Giza, Egypt
bChemistry Department, Faculty of Science, Jazan University, 2097 Jazan, Saudi Arabia
*
E-mail: aminaliabuhashem@yahoo.com
Additional Supporting Information may be found in the online version of this article.
Received June 17, 2012
DOI 10.1002/jhet.2002
Published online 16 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
2-Mercapto-6-[(pyridin-4-ylmethylene)-amino]-3H-pyrimidin-4-one 1 was synthesized from Schiff base
reaction of 6-amino-2-thiouracil with isonicotinaldehyde. The reaction of 1 with hydrazonyl chloride 2a–d
afforded the novel pyrimidin-4-one 3a–d. Compounds 3a–d reacted with methyl iodide to give 4a–d.
Subsequently, reaction of 4a–d with triethylamine as a catalyst in dry chloroform yielded tetraaza-spiro
[4.5]deca-2, 8-dien-7-one 5a–d. In addition, reaction of 1 with acrylonitrile gave pyrimidin-propionitrile 6.
The cyclization of 6 by reacting with sodium ethoxide to give pyrimido [2, 1-b] [1,3] thiazin-6-one 7.
The refluxing of 1 with bromine in acetic acid yielded 2-bromo-pyrimidin-4-one 8. The latter compound
8 reacted with sodium azide gave tetrazolo-pyrimidine 10. The chemical structures of the newly synthesized
compounds were characterized by IR, 1H NMR, 13C NMR, and mass spectral analysis.
J. Heterocyclic Chem., 51, 1020 (2014).
INTRODUCTION
As a result to that, most of synthetic methodologies have
been developed for constructing these spiro cycles, most of
which were based on cycloaddition or condensation reac-
tions [11–19]. In this report, we have been and continue
to discuss the development of new and simple synthetic
methods for the efficient preparation of spiro heterocycles
containing pyrimidine ring. Given the importance of the
biological activity of fused pyrimidines, we have prepared
heterocyclic compounds [20–26].
In this manuscript, we use new methods in the synthesis
of compounds derived thia-tetraaza-spir [4.5 deca-2, 8-
dien-7-one derivative. To our knowledge, this is the second
report [29–32] on the synthesis of 4-amino-8-[(pyridin-4-
ylmethylene)-amino]-2H-pyrimido [2, 1-b] [1,3] thiazin-
6-one and 7-[(pyridin-4-ylmethylene)-amino]-4H-tetrazolo
[1, 5-a]pyrimidin-5-one.
Several new organic compounds play an important
role in the drug discovery. Therefore, the syntheses of
polyfunctionalized heterocyclic compounds have received
the attention of many researchers all over the world. Espe-
cially, pyrimidine derivatives and new hetero ring are
known to exhibit promising antiviral [1], antibacterial [2],
anti-aids [3], and antinociceptive activities [4], inhibitors
for multidrug resistance (MDR) [5], antiplatelet and
antithrombotic drugs [6] have been firmly established by
clinical trials. These classes of pyrimidine based spirocyclic
systems containing one carbon atom common to two rings
are structurally interesting [7]. The asymmetric characteris-
tic of the molecule due to the chiral spiro carbon is one of
the important criteria of the biological activities. There are
many products in the natural organic compounds called
spiro compounds [8] have been discovered and proved.
Therefore, spiro compounds represent an important class
of naturally occurring substances characteristic by their
highly pronounced biological properties [9,10].
RESULTS AND DISCUSSION
This article describes our approach to the synthesis of
polyfunctional heterocyclic compounds. We reported here
© 2014 HeteroCorporation

July 2014
Synthesis and Reaction of Novel Spiro Pyrimidine Derivatives
1021
a convenient method for synthesis of tetraaza-spiro[4.5]
deca-2, 8-dien-7-one and tetrazolopyrimidines derivatives.
Thus, the Schiff base 1 was obtained by condensation of 6-
amino thiouracil with isonicotinaldehyde in dioxane/pi-
peridine. The structure assignments to new compounds
were based on their elemental analysis and spectral (IR, 1H,
13C NMR, and mass) data, (Scheme 1).
methyl iodide and ethanolic KOH. These data are included
within the assigned structures (Scheme 2).
Stirring under reflux, compounds 4a–d with few drops
of triethylamine as a catalyst in dry chloroform for a long
time under TLC control afforded the cyclized product 6-
methyl-1,3-(sub)-9-[(pyridin-4-ylmethylene)-amino]-4-
thia-1,2,6,10-tetraaza-spiro[4.5]deca-2,8-dien-7-one 5a–d.
IR, 1H NMR, and 13C NMR spectra of 5a–d gave data that
are in agreement with the assigned structures and experi-
Moreover, stirring under reflux 2-mercapto-6-[(pyridin-4-
ylmethylene)-amino]-3H-pyrimidin-4-one
1
with
1
hydrazonoyl chloride derivatives 2a–d [27,28] in dry
chloroform for 4 h under TLC control afforded 2-(S-p-
(S)-phenylazo-methylsulfanyl)-6-[(pyridine-4-
mental. The H NMR spectrum of 5b showed two singlet
signal at d 2.24 and 2.93 ppm for two methyl groups,
singlet signal 5.75 ppm for one proton in pyrimidin ring,
multiplet signals 7.32–7.41, 7.74–7.85 ppm for eight pro-
tons on phenyl groups, singlet signal 7.98 ppm for one
methine proton, and an exchangeable broad signal at
8.30 ppm for one proton of the NH group. The 13C NMR
spectrum showed signals at d 22.8 and 25.6 ppm for two
methyl groups, signal 91.8 ppm for one spiro[4.5] carbon
atom, 93.7 ppm for one carbon atom in pyrimidin ring,
121.1–150.1 ppm for aromatic carbon atoms, 152.4 ppm
for carbon atom in pyrimidin ring, 162.3 ppm carbon atoms
in thiadiazol ring, 163.9 ppm for one carbon atom for
methine proton, 2 CO signals at 165.4, 182.2 ppm for the
amid carbonyl and acetyl carbonyl groups. MS, m/z 440
(M+, 81%); Scheme 3.
ylmethylene)-amino]-3H-pyrimidin-4-one 3a–d, respec-
tively. IR, 1H NMR, and 13C NMR spectra of 3a–d
were given in the experimental section. Their corre-
sponding 1H NMR spectra of 3a showed two singlet
signal at d 4.10, 5.85 ppm for phenyl protons and mul-
tiplet signal at 7.06–7.30 ppm for 10 protons phenyl
group and multiplet signal at 7.82–7.92 ppm for four pro-
tons phenyl group and singlet signal at 8.07 ppm for methine
proton and singlet broad signal 8.65 ppm for one proton NH
group with D2O exchangeable. The 13C NMR showed at d
65.5 ppm for one carbon atom in CH-phenyl, 112.5 ppm
for one carbon atom in pyrimidin ring, 122.4–150.5 ppm
for aromatic carbon atoms, 159.1, 162.5 ppm for two carbon
atoms in pyrimidin ring, 163.8 ppm for one carbon atom for
methine proton, and 169.6 ppm for one amid carbonyl group.
Structure 4a–d was prepared by alkylation 3a–d.with
Treatment of 1 undergo Michael type addition to
acrylonitrile [29] to give the corresponding 3-(6-oxo-4-
[(pyridine-4-ylmethylene)-amino]-1,6-dihydropyrimidin-
Scheme 1. Synthesis of 2-mercapto-6-[(pyridin-4-ylmethylene)-amino]-3H-pyrimidin-4-one (1) from isonicotinaldehyde with 6-amino-2-thiouracil
(Schiff base reaction) in high yield.
Scheme 2. Synthesis of 3-methyl-2-(azo-methyl sulfanyl)-6-[(pyridin)-amino]-pyrimidin (4a–d) from 3a–d and compound 1 with hydrazonyl chloride
derivatives in high yields.
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A. A. Abu-Hashem
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Scheme 3. Synthesis of 6-methyl-1, 3-(sub.)-9-[(pyridin-4-ylmethylene)-amino]-4-thia-1, 2, 6, 10-tetraaza-spiro[4.5]deca-2, 8-dien-7-one (5a–d) from
4a–d and triethylamine as a catalyst in dry chloroform in high yields.
2-ylsulfanyl) propionitrile (6). The latter compound
4-cyanoethylmercaptopyrimidine (6) underwent reduc-
tive cyclization upon heating under reflux in sodium
ethoxide resulting in 4-amino-8-[(pyridin-4-ylmethylene)-
amino]-2H-pyrimido [2, 1-b] [1,3] thiazin-6-one (7). Its IR
spectrum compound 6 displayed one group carbonitrile
absorption bands at 2200 cmÀ1 (CN), beside the absence of
the CN group of compound 7. Hence, the 1H NMR spectrum
of 7 showed doublet signal at d 3.68 ppm for two protons CH2
group, triplet signal 3.99 ppm for one proton on thiazin ring,
singlet signal 5.90 ppm for one proton on pyrimidin ring, an
exchangeable broad signal at 6.72 ppm for the two protons
of the amino group, doublet signal 7.94 ppm for two protons
J= 7.56 Hz pyridine ring, doublet signal 7.98 ppm for two
protons J= 7.59 Hz pyridine ring, and singlet signal
8.10 ppm for methine proton. The 13C NMR spectrum showed
at d 20.8 ppm for one carbon atom in CH2 group, 79.2 ppm for
one carbon atom within thiazin ring, 112.3 ppm for one carbon
atom in pyrimidin ring, 124.1, 138.2 ppm for three carbon
atoms in pyridine ring, 145.1 ppm for one carbon atom in
C–NH2 group, 149.9 ppm for two carbon atoms in pyridine
ring, 158.4, 160.8 ppm for two carbon atoms in pyrimidin
ring, 163.5 ppm for one carbon atom methine proton, and
165.2 ppm for carbonyl group (Scheme 4).
The bromonation of 1 by bromine in acetic acid yielded the
2-bromo-6-[(pyridin-4-ylmethylene)-amino]-3H-
pyrimidin-4-one (8).The conversion of 1 into 8 may be
proceeded through the formation of pyrimidine-2-
sulphonyl bromide that liberate SO2 to give 8 [29,30]. Elec-
tron deficient nature of pyrimidine ring facilitates the syn-
thesis of large number of pyrimidine derivatives through
nucleophilic aromatic substitution of suitable leaving
groups. The halogens have been especially useful in this
regard [31,32]. Thus, compound 8 that reacts with sodium
azide gave the corresponding tetrazolopyrimidine 10 pre-
sumably via the formation of azido form 9. The structure
of 10 was proved by the disappearance of azido group in
IR spectrum. IR, 1H, 13C NMR, and mass spectra of
8 and 10 supported the structures (Scheme 5).
CONCLUSION
New ring compounds were prepared. In continuation,
this paper describes our interest in the development of
synthetic strategy to polyfunctionalized spiro organic
heterocyclic compounds such as the synthesis of tetraaza-
spiro[4.5]deca-2,8-dien-7-one, pyrimido[2,1-b][1,3]thiazin-
6-one derivatives, and tetrazolo[1, 5-a]pyrimidin-5-one.
Scheme 4. Synthesis of 4-amino-8-[(pyridin-4-ylmethylene)-amino]-2H-pyrimido [2,1-b][1,3] thiazin-6-one (7) from compound (1) with acrylonitril
afforded (6).This compound 6 refluxing in C2H5ONa to gave (7) in high yields.
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Synthesis and Reaction of Novel Spiro Pyrimidine Derivatives
1023
Scheme 5. Synthesis of 7-[(pyridin-4-ylmethylene)-amino]-4H-tetrazolo[1, 5-a]pyrimidin-5-one (10) from compound (1) with bromine afforded 2-
bromo-6-[(pyridin-4-ylmethylene)-amino]-3H-pyrimidin-4-one (8). The latter compound 8 refluxing in NaN3 to gave (10) in high yields.
aliph.) 1688 (CO), 1615 (CN). 1H NMR (DMSO-d6) d 4.10
EXPERIMENTAL
(s, 1H, CH-phenyl), 5.85 (s, 1H, C5-H), 7.06–7.30 (m, 10H,
All melting points are in ꢀC and were determined on
Gallenkamp electric melting point apparatus. The IR spectra were
Ar–H) 7.82–7.92 (m, 4H, Ar–H), 8.07 (s, 1H, CH, methine),
8.65 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d6) d
recorded potassium bromide (KBr) on a Perkin–Elmer 1430
spectrometer. The 1H NMR and 13C NMR spectra (d, ppm) were
recorded on JEOL-ECA 500 and JEOL JNM-LA-400 FT NMR
spectrometers (Japan), and chemical shifts were expressed as d
values against TMS as an internal standard. Mass spectra were
recorded on GCMS-QP 1000 EX (Shimadzu) (gas chromatogra-
phy–mass spectrometer). Microanalytical data were obtained at
the Microanalytical Center at Cairo University and National
Research Center, Egypt.
2-Mercapto-6-[(pyridin-4-ylmethylene)-amino]-3H-pyrimidin-
4-one (1). General procedure. A suspension of compound 6-
aminothiouracil and isonicotinaldehyde (1.07 g, 10 mmol) in
dioxane (40 mL) containing piperidine (0.5 mL) as a catalyst was
stirred and heated under reflux for 6 h. The reaction mixture was
cooled, the formed precipitate filtered off, dried, and recrystallized
from DMF to afford 1. Yellow crystal, yield, 85%, mp 305–
307ꢀC (dec.). IR (KBr) nmax, cmÀ1: 3230 (br, NH), 3025 (br, CH,
aryl), 2995 (br, CH, aliph.) 1690 (CO), 1610 (CN), 1350 (CS). 1H
NMR (DMSO-d6) d 5.80 (s, 1H, C5-H), 7.85–7.95 (m, 4H, Ar–
H), 8.05 (s, 1H, CH methine), 8.35 (s, 1H, SH), 8.55 (s, 1H, NH,
D2O exchangeable); 13C NMR (DMSO-d6) d 113.1 (1C5, CH),
123.9, 138.6, 150.2 (5C pyridin), 159.4, 160.2 (2C2, 6 pyrimidin),
164.1 (1C, CH methine),169.3 (CO amid). MS (70ev, %) m/z 234
(M+ + 2, 8.2%), 233(M+ + 1, 40.3%), 232 (M+, 100%). Anal.
Calcd for C10H8N4OS (232.26): C, 51.71; H, 3.47; N, 24.12; S,
13.81. Found: C, 51.78; H, 3.40; N, 24.19; S, 13.88.
65.5(1C,CH-phenyl), 112.5 (1C5, CH pyrimidin), 122.4, 123.5,
125.4, 126.5, 127.4, 128.8, 129.2, 138.7, 141.3, 149.9, 150.5
(Ar–C), 159.1, 162.5 (2C, C2,6 pyrimidin)163.8 (1C, CH
methine),169.6 (CO amid). MS (70 ev, %) m/z 428 (M+ + 2,
6.8%), 427(M+ + 1, 20.6%), 426 (M+, 80%). Anal. Calcd for
C23H18N6OS (426.49): C, 64.77; H, 4.25; N, 19.70; S, 7.52.
Found: C, 64.70; H, 4.29; N, 19.78; S, 7.48.
2-[1-(4-Chloro-phenylazo)-2-oxo-propylsulfanyl]-6-[(pyridin-
4-ylmethylene)-amino]-3H-pyrimidin-4-one (3b). The compound
was obtained from 1 (2.32 g,10 mmol) and 1-p-chlorophenyl-
azo-1-chloroacetone 2b (1.96 g, 10 mmol) as pale brown
crystals, crystallized from DMF in 60% yield, mp 195–197ꢀC
(melted); IR (KBr) nmax, cmÀ1: 3223 (br, NH), 3027 (br, CH,
aryl), 2996 (br, CH, aliph.) 1682, 1725 (2CO), 1619 (CN).1H
NMR (DMSO-d6) d 2.1(s, 3H, CH3), 4.01 (s, 1H, CH acetyl),
5.92 (s, 1H, C5-H), 7.21–7.30 (m, 4H, Ar–H) 7.82–7.92
(m, 4H, Ar–H), 8.02 (s, 1H, CH methine), 8.74 (s, 1H, NH,
D2O exchangeable); 13C NMR (DMSO-d6) d 22.2 (1C, CH3),
75.8 (1C, CH-acetyl), 111.9 (1C5, CH pyrimidin),123.5, 124.3,
129.6, 138.6, 148.8, 150.1 (Ar–C), 159.8, 162.7 (2C, C2,6
pyrimidin) 163.9 (1C, CH methine), 169.8, 190.2 (2C, CO amid,
CO acetyl). MS (70 ev, %) m/z 428 (M+ + 2, 11.2%), 427 (M+ + 1,
27.8%), 426 (M+, 70%). Anal. Calcd for C19H15ClN6O2S
(426.88): C, 53.46; H, 3.54; Cl, 8.31; N, 19.69; S, 7.51. Found:
C, 53.40; H, 3.59; Cl, 8.28; N, 19.60; S, 7.59.
2-[1-(4-Nitro-phenylazo)-2-oxo-propylsulfanyl]-6-[(pyridin-
4-ylmethylene)-amino]-3H-pyrimidin-4-one (3c). The compound
was obtained from 1 (2.32 g,10 mmol) and 1-p-nitrophenyl-azo-
1-chloroacetone 2c (2.41 g, 10 mmol) as pale yellow crystals,
crystallized from dioxane in 61% yield, mp 210–212ꢀC
(melted); IR (KBr) nmax, cmÀ1:3229 (br, NH), 3028 (br, CH,
2-(S-p-(S)-phenylazo-methylsulfanyl)-6-[(pyridin-4-ylmethylene)-
amino]-3H-pyrimidin-4-one (3a–d). A suspension of compound 1
(2.32 g, 10 mmol) and the appropriate hydrazonoyl chlorides 2a–d
(10 mmol) in (35mL) dry chloroform were stirred under reflux for
4 h under TLC control. The deposited so-precipitate was filtered
off, washed with 40mL chloroform, dried, and crystallized from
appropriate solvent to produce (3a–d) in high yields.
1
aryl), 2988 (br, CH, aliph.) 1685, 1730 (2CO), 1615 (CN). H
NMR (DMSO-d6) d 2.08 (s, 3H, CH3),4.03 (s, 1H, CH acetyl),
5.97 (s, 1H, C5-H), 7.35–7.43 (m, 4H, Ar–H) 7.80–7.90 (m,
4H, Ar–H), 8.01 (s, 1H, CH, methine), 8.70 (s, 1H, NH, D2O
exchangeable); 13C NMR (DMSO-d6) d 22.4 (1C, CH3), 73.2
(1C, CH-acetyl), 112.5 (1C5, CH pyrimidin),123.3, 124.2,
124.6, 138.5, 145.2, 150.2, 155.9 (Ar–C), 158.8, 162.9 (2C,
C2,6 pyrimidin) 163.6 (1C, CH methine),169.5, 178.6 (2C, CO
2-(Phenyl-phenylazo-methylsulfanyl)-6-[(pyridin-4-ylmethylene)-
amino]-3H-pyrimidin-4-one (3a). The compound was obtained
from 1 (2.32g,10 mmol) and N-phenylbenzene-carbo-hydrazonoyl
chloride 2a (2.310 g, 10mmol) as pale brown crystals, crystallized
from dioxane in 70% yield, mp 252–254ꢀC (melted); IR (KBr)
n
max, cmÀ1: 3220 (br, NH), 3023 (br, CH, aryl), 2992 (br, CH,
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amid, CO acetyl). MS (70 ev, %) m/z 439 (M+ + 2, 11.2%), 438
(M+ + 1, 27.8%), 437 (M+, 70%). Anal. Calcd for
C19H15N7O4S (437.43): C, 52.17; H, 3.46; N, 22.41; S, 7.33.
Found: C, 52.10; H, 3.40; N, 22.49; S, 7.38.
CO acetyl). MS (70 ev, %) m/z 442 (M+ + 2, 17.4%), 441
(M+ + 1, 21.6%), 440 (M+, 79%). Anal. Calcd for C20H17ClN6O2S
(440.91): C, 54.48; H, 3.89; Cl, 8.04; N, 19.06; S, 7.27. Found:
C, 54.40; H, 3.80; Cl, 8.10; N, 19.12; S, 7.32.
(6-Oxo-4-[(pyridin-4-ylmethylene)-amino]-1,6-dihydro-
pyrimidin-2-ylsulfanyl)-phenyl-azo-acetic acid ethyl ester
3-Methyl-2-[1-(4-nitro-phenylazo)-2-oxo-propylsulfanyl]-6-
[(pyridin-4-ylmethylene)-amino]-3H-pyrimidin-4one (4c). The
compound was obtained from 3c (4.37g,10mmol) and methyl
iodide (20mmol) as yellow crystals, crystallized from dimethyl
(3d).
The compound was obtained from 1 (2.32 g,10mmol)
and 1-phenyl azo-1-chloroethylacetate 2d (2.26g, 10mmol) as
pale brown crystals crystallized from n-hexane in 58% yield, mp
235–237ꢀC (melted); IR (KBr) nmax, cmÀ1: 3230 (br, NH), 3035
(br, CH, aryl), 2975 (br, CH, aliph.) 1687, 1745 (2CO), 1610
(CN). 1H NMR (DMSO-d6) d 1.35 (t, 3H, CH3), 4.08 (s, 1H, CH
ester), 4.21 (q, 2H, CH2), 5.98 (s, 1H, C5-H), 7.37–7.48 (m, 5H,
Ar–H) 7.75–7.85 (m, 4H, Ar–H), 8.05 (s, 1H, CH, methine), 8 .76
(s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d6) d 21.8
(1C,CH3), 58.5 (1C, CH2), 70.1 (1C, CH ester), 112.4 (1C5,
CH pyrimidin), 122.6, 124.5, 125.7, 129.3, 138.7, 150.1, 151.2
(Ar–C), 158.6, 162.8 (2C, C2,6 pyrimidin) 163.8 (1C, CH
methine), 169.1, 172.2 (2C, CO amid, CO ester). MS (70ev, %)
m/z 424 (M+ + 2, 15.1%), 423 (M+ + 1, 21.2%), 422 (M+, 76%).
Anal. Calcd for C20H18N6O3S (422.46): C, 56.86; H, 4.29; N,
19.89; S, 7.59. Found: C, 56.79; H, 4.32; N, 19.95; S, 7.62.
formamide in 63% yield, mp 240–242ꢀC (melted); IR (KBr) nmax
,
cmÀ1: 3032 (br, CH, aryl), 2979 (br, CH, aliph.) 1682, 1736
(2CO), 1612 (CN). 1H NMR (DMSO-d6) d 2.07 (s, 3H, CH3)
2.76 (s, 3H, CH3), 4.08 (s, 1H, CH acetyl), 5.98 (s, 1H, C5-H),
7.37–7.45 (m, 4H, Ar–H) 7.82–7.92 (m, 4H, Ar–H), 8.02 (s, 1H,
CH methine); 13C NMR (DMSO-d6) d 22.2 (1C, CH3), 25.8 (1C,
CH3), 73.1 (1C, CH acetyl), 112.2 (1C5, CH pyrimidin), 123.2,
124.3, 124.7, 138.3, 145.3, 150.1, 155.1 (Ar–C), 158.6, 162.5
(2C, C2,6 pyrimidin) 163.2 (1C, CH methine), 169.2, 178.4 (2C,
CO amid, CO acetyl). MS (70 ev, %) m/z 453 (M+ + 2, 15.9%),
452 (M+ + 1, 20.1%), 451 (M+, 65%). Anal., Calcd for
C20H17N7O4S (451.46): C, 53.21; H, 3.80; N, 21.72; S, 7.10.
Found: C, 53.28; H, 3.87; N, 21.76; S, 7.19.
(1-Methyl-6-oxo-4-[(pyridin-4-ylmethylene)-amino]-1,6-
dihydro-pyrimidin-2-ylsulfanyl) phenylazo-acetic acid ethyl
ester (4d). The compound was obtained from 3d
(4.22g,10 mmol) and methyl iodide (20mmol) as yellow crystals,
crystallized from dioxane in 68% yield, mp 265–267ꢀC (melted);
IR (KBr) nmax, 3032 (br, CH, aryl), 2973 (br, CH, aliph.) 1682,
1743 (2CO), 1609 (CN). 1H NMR (DMSO-d6) d 1.34 (t, 3H,
CH3), 2.78 (s, 3H, CH3), 4.09 (s, 1H, CH ester), 4.23 (q, 2H,
CH2), 5.99 (s, 1H, C5-H), 7.38–7.49(m, 5H, Ar–H) 7.76–7.86 (m,
4H, Ar–H), 8.07 (s, 1H, CH, methine); 13C NMR (DMSO-d6) d
21.8, 25.9 (2C, 2CH3), 58.6 (1C, CH2), 70.2(1C, CH-ester), 112.7
(1C5, CH pyrimidin), 122.8, 124.7, 125.9, 129.5, 138.8, 150.4,
151.4 (Ar–C), 158.7, 162.9 (2C, C2,6 pyrimidin) 163.4 (1C, CH
methine), 169.3, 172.5 (2C, CO amid, CO ester). MS (70ev, %)
m/z 438 (M+ + 2, 19.3%), 437 (M+ + 1, 27.5%), 436 (M+, 79%).
Anal. Calcd for C21H20N6O3S (436.49): C, 57.79; H, 4.62; N,
19.25; S, 7.35. Found: C, 57.70; H, 4.58; N, 19.17; S, 7.30.
6-Methyl-1, 3-(sub.)-9-[(pyridin-4-ylmethylene)-amino]-4-
thia-1, 2, 6, 10-tetraaza-spiro[4.5]deca-2, 8-dien-7-one (5a–d). A
mixture from compound 4a-d (10 mmol) was stirred under
reflux in dry chloroform (40 mL) and 4 drops of triethylamine
as a catalyst for a long time under TLC control for 7 h. The
solvent was evaporated under reduced pressure. The solid
produced was washed four times with 50 mL methanol and
crystallized form an appropriate solvent to produce 5a-d in
high yields.
3-Methyl-2-(Sub-p-(sub)-phenylazo-methylsulfanyl)-6-
[(pyridin-4-ylmethylene)-amino]-3H-pyrimidin-4-one (4a–d). To
a warmed ethanolic potassium hydroxide solution (prepared by
dissolving 0.56 g, 10 mmol of potassium hydroxide in 50 mL
ethanol) was added compound 3a–d (10 mmol), and heating was
continued for 30 min. The mixture was allowed to cool to room
temperature, and methyl iodide (10 mmol) was added. The mixture
was stirred under reflux for 6 h and then allowed to cool to room
temperature and finally poured into cold water (100 mL). The solid
product precipitated was filtered off and washed with 100 mL
water. The compound was obtained as crystals (4a–d) in high yields.
3-Methyl-2-(phenyl-phenylazo-methylsulfanyl)-6-[(pyridin-
4-ylmethylene)-amino]-3H-pyrimidin-4-one (4a). The compound
was obtained from 3a (4.26 g, 10mmol) and methyl iodide
(20 mmol) as brown crystals, crystallized from methanol in 80%
yield, mp 275–277ꢀC (melted); IR (KBr) nmax, cmÀ1: 3024 (br,
CH, aryl), 2990 (br, CH, aliph.) 1686 (CO), 1614 (CN). 1H NMR
(DMSO-d6) d 2.75 (s, 3H, CH3), 4.11 (s, 1H, CH-phenyl),
5.86 (s, 1H, C5-H), 7.07–7.31 (m, 10H, Ar–H) 7.83–7.93 (m, 4H,
Ar–H), 8.06 (s, 1H, CH methine); 13C NMR (DMSO-d6) d 24.6
(1C, CH3), 62.1 (1C, CH-phenyl), 112.4 (1C5, CH pyrimidin),
122.5, 123.6, 125.3, 126.7, 127.2, 128.5, 129.1, 138.5, 141.1,
149.8, 150.4 (Ar–C), 159.3, 162.2 (2C, C2,6 pyrimidin) 163.1
(1C, CH methine), 169.2 (CO, amid). MS (70 ev, %) m/z 442
(M+ + 2, 9.5%), 441(M+ + 1, 18.3%), 440 (M+, 84%). Anal.
Calcd for C24H20N6OS (440.52): C, 65.44; H, 4.58; N, 19.08; S,
7.28. Found: C, 65.49; H, 4.50; N, 19.12; S, 7.32.
6-Methyl-1, 3-diphenyl-9-[(pyridin-4-ylmethylene)-amino]-4-
thia-1, 2, 6, 10-tetraaza-spiro[4.5]deca-2, 8-dien-7-one (5a). The
compound was obtained from 4a (4.40 g, 10 mmol) and tri-ethyl
amine (1 mL as a catalyst); as white crystals, crystallized from
2-[1-(4-Chloro-phenylazo)-2-oxo-propylsulfanyl]-3-methyl-
6-[(pyridin-4-ylmethylene)-amino]-3H-pyrimidin-4-one (4b).
The compound was obtained from 3b (4.26 g,10 mmol) and
methyl iodide (20mmol) as pale yellow crystals, crystallized from
benzene in 71% yield, mp 340–342ꢀC (melted); IR (KBr) nmax
,
cmÀ1: 3240 (br, NH), 3045 (br, CH, aryl), 2970 (br, CH, aliph.)
1673 (CO), 1627 (CN), 1570 (CC).1H NMR (DMSO-d6) d 2.95
(s,3H,CH3),5.72 (s, 1H, CH, pyrimidin), 7.05 –7.30 (m, 10H,
Ar–H) 7.75–7.88 (m, 4H, Ar–H), 7.96 (s, 1H, CH methine),
8.35 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d6) d
22.1 (1C,CH3), 92.01(1C,spiro[4.5] carbon atom), 93.6 (1C,
CH pyrimidin), 122.4, 124.3, 128.5, 128.8, 129.4,130.1, 131.5,
138.3,143.5,149.7 (Ar-C), 154.1, 162.2 (2C; C, pyrimidin, C,
thiadiazol), 163.1 (1C, CH methine),165.5 (CO). MS (70 ev,
%) m/z 442 (M+ + 2, 15.3%), 441(M+ + 1, 14.2%), 440 (M+,
dioxane in 73% yield, mp 220–222ꢀC (melted); IR (KBr) nmax
,
cmÀ1: 3025 (br, CH, aryl), 2991 (br, CH, aliph.) 1680,
1723 (2CO), 1614 (CN). 1H NMR (DMSO-d6) d 2.1(s, 3H, CH3),
2.73(s, 3H, CH3), 4.02 (s, 1H, CH acetyl), 5.93 (s, 1H, C5-H),
7.22–7.31 (m, 4H, Ar–H) 7.83–7.93 (m, 4H, Ar–H), 8.04 (s, 1H,
CH methine); 13C NMR (DMSO-d6) d 22.2 (1C, CH3), 25.4 (1C,
CH3), 75.1 (1C, CH acetyl),111.7 (1C5, CH pyrimidin), 123.4,
124.2, 129.5, 138.4, 148.7, 150.2 (Ar–C), 159.4, 162.2 (2C, C2,6
pyrimidin) 163.8 (1C, CH methine), 169.5, 190.1 (2C, CO amid,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Synthesis and Reaction of Novel Spiro Pyrimidine Derivatives
1025
174 ꢀC (melted); IR (KBr) nmax, 3230 (br, NH), 3025 (br, CH,
aryl), 2960 (br, CH, aliph.), 2200 (CN), 1665 (CO), 1620 (CN),
1572 (CC). 1H NMR (DMSO-d6) d 3.09(t, 2H, CH2), 3.25(t,
2H, CH2), 5.88 (s, 1H, pyrimidine), 7.92 (d, 2H, J = 7.55 Hz,
pyridine), 7.96 (d, 2H, J = 7.58 Hz, pyridine), 8.08 (s, 1H, CH,
methine proton), 8.35 (s, 1H, NH, D2O exchangeable);
13C NMR (DMSO-d6) d 20.2, 22.4 (2C, CH2), 112.4 (1C5,
pyrimidine), 118.1(1C,CN), 124.2, 138.4, 150.1 (5C, pyridine),
158.6, 160.5 (2C, C2,6 pyrimidin), 163.8 (1C, methine proton),
169.1 (CO, amid). MS (70 ev, %) m/z 287 (M+ + 2, 11.3%),
286 (M+ + 1, 25.4%), 285 (M+, 100%). Anal. Calcd for
C13H11N5OS (285.32): C, 54.72; H, 3.89; N, 24.55; S, 11.24.
Found: C, 54.78; H, 3.42; N, 24.50; S, 11.29.
87%). Anal. Calcd for C24H20N6OS (440.52): C, 65.44; H, 4.58;
N, 19.08; S, 7.28. Found: C, 65.50; H, 4.55; N, 19.15; S, 7.34.
3-Acetyl-1-(4-chloro-phenyl)-6-methyl-9-[(pyridin-4-
ylmethylene)-amino]-4-thia-1, 2, 6, 10-tetraaza-spiro[4.5]deca-
2, 8-dien-7-one (5b).
The compound was obtained from 4b
(4.40 g,10mmol) and triethylamine (1 ml as a catalyst) as yellow
crystals, crystallized from DMF in 69% yield, mp 260–262ꢀC
(melted); IR (KBr) nmax, cmÀ1: 3245 (br, NH), 3048 (br, CH,
aryl), 2975 (br, CH, aliph.)1675, 1730 (2CO),1625 (CN),1575
(CC).1H NMR (DMSO-d6) d 2.24 (s, 3H, CH3), 2.93 (s, 3H,
CH3), 5.75 (s, 1H, CH pyrimidin ),7.32–7.41 (m, 4H, Ar–H)
7.74–7.85 (m, 4H, Ar–H), 7.98 (s, 1H, CH methine), 8.30 (s, 1H,
NH, D2O exchangeable); 13C NMR (DMSO-d6) d 22.8, 25.6 (2C,
2CH3), 91.8 (1C,spiro[4.5] carbon atom), 93.7 (1C,CH pyrimidin),
121.1, 122.5, 124.3, 129.8, 138.2, 141.7, 150.1 (Ar-C), 152.4, 162.3
(2C,C pyrimidin, C thiadiazol),163.9 (1C, CH methine), 165.4,
182.2 (2C, CO amid, CO acetyl). MS (70 ev, %) m/z 442 (M+ +2,
13.7%), 441 (M+ + 1, 26.9%), 440 (M+, 81% ). Anal., Calcd for
C20H17Cl N6O2S (440.91): C, 54.48; H, 3.89; Cl, 8.04; N, 19.06; S,
7.27. Found: C, 54.38; H, 3.82; Cl, 8.12; N, 19.10; S, 7.35.
4-Amino-8-[(pyridin-4-ylmethylene)-amino]-2H-pyrimido
[2, 1-b] [1,3] thiazin-6-one (7).
A solution of 6 (2.85 g,
10mmol) in sodium ethoxide (0.23 g of sodium metal in
40 cm3 ethanol) was stirred under reflux for 7 h. After cooling
the reaction mixture was neutralized with cooled 10% HCl and
the solid formed was collected by filtration, washed with
water, dried, and recrystallized from ethanol in 74% yield, mp
246–248ꢀC (melted); IR (KBr) nmax, 3420 (br, NH2),3021(br,
CH, aryl), 2970 (br, CH, aliph.), 1666 (CO),1628 (CN), 1578
(CC). 1H NMR (DMSO-d6) d 3.68(d,2H,CH2), 3.99 (t,1H,
thiazin ring), 5.90 (s, 1H, pyrimidin), 6.72 (s, 1H, NH2, D2O
exchangeable), 7.94 (d, 2H, J = 7.56 Hz, pyridine ),7.98 (d, 2H,
J = 7.59 Hz, pyridine), 8.10 (s, 1H, methine proton); 13C NMR
(DMSO-d6) d 20.8 (1C, CH2),79.2 (1C, CH, thiazin ring),
112.3 (1C, pyrimidin), 124.1, 138.2, (3C, pyridine), 145.1 (1C,
C-NH2), 149.9 (2C, pyridine), 158.4, 160.8 (2C, pyrimidin),
163.5 (1C, methine proton),165.2 (CO). MS (70 ev, %) m/z
287 (M+ + 2, 14.5%), 286 (M+ + 1, 20.3%), 285 (M+, 90%).
Anal. Calc. for C13H11N5OS (285.32): C, 54.72; H, 3.89; N,
24.55; S, 11.24. Found: C, 54.69; H, 3.45; N, 24.60; S, 11.27.
2-Bromo-6-[(pyridin-4-ylmethylene)-amino]-3H-pyrimidin-
4-one (8). Bromine gas was bubbled through a suspension of 1
(2.32 g, 10mmol) in acetic acid (50 mL, 25%) for about 4 hours.
The result white precipitate was collected by filtration, washed
with water and dried to give 8 and recrystallized from methanol in
70% yield, mp >350ꢀC (melted); IR (KBr) nmax, 3218 (br, NH),
3030 (br, CH, aryl), 2960 (br, CH, aliph.), 1660 (CO), 1625 (CN),
3-Acetyl-6-methyl-1-(4-nitro-phenyl)-9-[(pyridin-4-ylmethylene)-
amino]-4-thia-1, 2, 6, 10-tetraaza-spiro[4.5]deca-2, 8-
dien-7-one (5c). The compound was obtained from 4c
(4.51 g,10mmol) and triethylamine (1mL as a catalyst) as
pale yellow crystals, crystallized from methanol in 66% yield, mp
271–273ꢀC (melted); IR (KBr) nmax, cmÀ1: 3241 (br, NH),3046
(br, CH, aryl), 2970 (br, CH, aliph.) 1677, 1738 (2CO),1622
(CN), 1572 (CC).1H NMR (DMSO-d6) d 2.25 (s, 3H, CH3)
2.91 (s, 3H, CH3), 5.72 (s, 1H, CH pyrimidin), 7.15–7.35 (m, 4H,
Ar–H) 7.65–7.76 (m, 4H, Ar–H),7.90 (s, 1H, CH methine), 8.25
(s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d6) d 22.1,
25.3 (2C, 2CH3), 91.9 (1C, spiro[4.5]carbon atom), 93.8 (1C,
CH pyrimidin), 120.2, 123.5, 124.6, 136.8, 138.5, 149.4, 150.3
(Ar– C), 153.6, 162.7 (2C; C , pyrimidin, C, thiadiazol),163.6 (1C,
CH methine), 165.4, 185.3 (2C, CO amid, CO acetyl). MS (70 ev,
%) m/z 453 (M+ + 2, 25.1%), 452 (M+ + 1, 22.2%), 451 (M+,
70%). Anal., Calcd for C20 H17 N7 O4 S (451.46): C, 53.21; H,
3.80; N, 21.72; S, 7.10. Found: C, 53.17; H, 3.85; N, 21.70; S, 7.09.
10-Methyl-9-oxo-1-phenyl-7-[(pyridin-4-ylmethylene)-
amino]-4-thia-1, 2, 6, 10-tetraaza-spiro[4.5]deca-2, 7-diene-3-
carboxylic acid ethyl ester (5d). The compound was obtained
from 4d (4.36 g,10 mmol) and triethylamine (1mL as a catalyst)
as brown crystals, crystallized from ethanol in 62% yield, mp
331–333ꢀC (melted); IR (KBr) nmax, 3240 (br, NH), 3040 (br,
CH, aryl), 2968 (br, CH, aliph.) 1670, 1740 (2CO), 1625 (CN),
1
1570 (CC). H NMR (DMSO-d6) d 5.85 (s, 1H, pyrimidin),7.92
(d, 2H, J = 7.55 Hz, pyridine),7.95 (d, 2H, J = 7.57 Hz, pyridine),
8.07 (s,1H, methine proton), 8.30 (s, 1H, NH, D2O
exchangeable);13C NMR (DMSO-d6) d 112.4 (1C,pyrimidin),
124.2,138.4,149.8 (5C, pyridine), 158.6,162.1 (2C, pyrimidin),
163.9 (1C, methine proton), 167.3 (CO). MS (70 ev, %) m/z 281
(M+ + 2, 24.1%), 280 (M+ + 1, 11.2%), 279 (M+, 80%). Anal.
Calcd for C10H7Br N4O 279.09): C, 43.03; H, 2.53; Br, 28.63; N,
20.07. Found: C, 43.10; H, 2.58; Br, 28.72; N, 20.11.
1
1577 (CC). H NMR (DMSO-d6) d 1.35 (t,3H,CH3), 2.94 (s,3H,
CH3), 4.25 (q, 2H,CH2), 5.78 (s, 1H, CH pyrimidin),7.17 –7.28
(m, 5H, Ar-H) 7.79 –7.89(m, 4H, Ar-H), 8.02 (s, 1H, CH methine ),
8.21 (s, 1H, NH, D2O exchangeable); 13C NMR (DMSO-d6) d 22.7,
25.8 (2C, 2CH3), 59.1 (1C,CH2), 91.5 (1C,spiro[4.5] carbon atom),
93.7 (1C,CH pyrimidin), 120.08, 122.4,124.2,129.4, 137.9,143.4,
149.7 (Ar-C), 155.1, 162.5 (2C; C, thiadiazol, C, pyrimidin), 163.4
(1C,CH methine),165.3,179.2 (2C, CO amid, CO ester). MS (70 ev,
%) m/z 438 (M+ + 2, 12.1%), 437 (M+ + 1, 17.6%), 436 (M+, 71%).
Anal. Calcd for C21H20N6O3S (436.49): C, 57.79; H, 4.62; N,
19.25; S, 7.35. Found: C, 57.72; H, 4.55; N, 19.19; S, 7.28.
3-(6-Oxo-4-[(pyridin-4-ylmethylene)-amino]-1, 6-dihydro-
7-[(Pyridin-4-ylmethylene)-amino]-4H-tetrazolo[1,5-a]
pyrimidin-5-one (10).
A mixture of 8 (2.79 g, 10mmol) and
sodium azide (.65g, 10 mmol) in ethanol (40 mL) were refluxed
for 5 hours. The solid that separated after cooling and pouring
onto water was collected by filtration and crystallized
from dioxane to give pale yellow crystals of 10, in 62% yield, mp
280–282ꢀC (melted); IR (KBr) nmax, 3232 (br, NH), 3035
(br, CH, aryl), 2970 (br, CH, aliph.), 1655 (CO), 1620 (CN), 1580
(CC). 1H NMR (DMSO-d6) d 5.90 (s, 1H, pyrimidin),7.98 (d, 2H,
J = 7.60 Hz, pyridine) ,7.99 (d, 2H, J = 7.62 Hz, pyridine), 8.12
(s,1H, methine proton), 8.38 (s, 1H, NH, D2O exchangeable);
13C NMR (DMSO-d6) d 100.1 (1C, pyrimidin), 124.3, 138.2,
149.7 (5C, pyridine), 151.1, 159.5 (2C, pyrimidin), 163.6 (1C,
pyrimidin-2-ylsulfanyl)-propionitrile (6).
A mixture of 1
(2.32 g, 10 mmol) and acrylonitrile (.53 g, 10 mmol) and TEM
(3 drops) in ethanol (10 mL) was heated under reflux for 2 h.
After cooling, the precipitate was collected and crystallized
from methanol to give white crystals in 74% yield, mp 172–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1026
A. A. Abu-Hashem
Vol 51
methine proton),165.1 (CO). MS (70 ev, %) m/z 243 (M+ + 2,
20.2%), 242 (M+ + 1, 16.5%), 241 (M+, 68%). Anal. Calcd for
C10H7N7O (241.21): C, 49.79; H, 2.93; N, 40.65. Found: C,
49.70; H, 2.98; N, 40.57.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet