8-(Methyl(phenyl)sulfonyl)-2,6-dihydroimidazo[1,2-c]- pyrimidin-5(3Н)-ones and 9-(methyl(phenyl)sulfonyl)- 2,3,4,7-dihydro-6H-pyrimido[1,6-a]pyrimidin-6-ones: synthesis and antiviral activity

Article abstract of DOI:10.1007/s10593-019-02472-y

A convenient method for the synthesis of novel sulfonic cytosine derivatives, 8-(methyl(phenyl)sulfonyl)-2,6-dihydroimidazo[1,2-c]-pyrimidin-5(3Н)-ones and 9-(methyl(phenyl)sulfonyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,6-a]pyrimidin-6-ones, has been develope

Full text of DOI:10.1007/s10593-019-02472-y

DOI 10.1007/s10593-019-02472-y
Chemistry of Heterocyclic Compounds 2019, 55(4/5), 401–407
8-(Methyl(phenyl)sulfonyl)-2,6-dihydroimidazo[1,2-c]-
pyrimidin-5(3Н)-ones and 9-(methyl(phenyl)sulfonyl)-
2,3,4,7-dihydro-6H-pyrimido[1,6-a]pyrimidin-6-ones:
synthesis and antiviral activity
Roman N. Solomyannyi1, Olga V. Shablykina1,2, Viktoriia S. Moskvina1,2*,
Volodymir P. Khilya2, Eduard B. Rusanov3, Vladimir S. Brovarets1
1 V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
1 Murmanska St., Kyiv 02094, Ukraine
2 Kyiv Taras Shevchenko National University,
64/13 Volodymyrska St., Kyiv 01601, Ukraine; e-mail: v.moskvina@gmail.com
3 Institute of Organic Chemistry of the National Academy of Sciences of Ukraine,
5 Murmanska St., Kyiv 02660, Ukraine; e-mail: xray@ioch.kiev.ua
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(4/5), 401–407
Submitted February 28, 2019
Accpeted March 27, 2019
A convenient method for the synthesis of novel sulfonic cytosine derivatives, 8-(methyl(phenyl)sulfonyl)-2,6-dihydroimidazo[1,2-c]-
pyrimidin-5(3Н)-ones and 9-(methyl(phenyl)sulfonyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,6-a]pyrimidin-6-ones, has been developed
based on the reaction of 3-amino-2-(methyl(phenyl)sulfonyl)acrylonitriles with 2-chloroethyl isocyanate and 3-chloropropyl isocyanate.
The resulting heteryl sulfones possess antiviral activity.
Keywords: 3-amino-2-(methyl(phenyl)sulfonyl)acrylonitriles, 8-(methyl(phenyl)sulfonyl)-2,6-dihydroimidazo[1,2-c]pyrimidin-5(3Н)-
ones, 9-(methyl(phenyl)sulfonyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,6-a]pyrimidin-6-ones, heterocyclization, antiviral activity.
Derivatives of pyrimidines and purines are widely
represented in the plant world and are important
constituents of living organisms, whereas synthetic
structural analogs of pyrimidines and purines possess
different biological activity and are in the focus of research
in medicinal chemistry in search of new drugs. Among the
huge number of drugs used in medical practice, more than
90% contain a heterocyclic moiety in their structure.1 The
development of combinatorial chemistry and methods of
high-throughput screening, also of various nitrogen
heterocyclic systems, made it possible to identify key
structures on the basis of which new drugs of different
activity were created. Figure 1 represents the derivatives of
purines and pyrimidines used as drugs with antiviral
activity.2
Note that various structural modifications of pyrimidine
derivatives can be achieved by introducing new
substituents into the basic heterocyclic fragment, which
will make it possible to obtain a set of compounds with
Figure 1. Antiviral drugs based on purines and pyrimidines.
0009-3122/19/55(4/5)-0401©2019 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2019, 55(4/5), 401–407
Scheme 2
functional groups desirable from the point of view of
medicinal chemistry.
The goal of the present work was to create novel
pyrimidine derivatives containing methylsulfonyl and
phenylsulfonyl pharmacophore groups. These functional
groups are important structural fragments of many
biologically active compounds,3 and methylsulfonyl group
forms part of some natural compounds.4
A novel synthetic method was developed in order to
create new potential antiviral compounds based on (methyl)-
arylsulfones. Thus, heterocyclization of N-substituted
3-amino-2-(methyl(phenyl)sulfonyl)acrylonitriles 1a–h with
2-chloroethyl isocyanate (2) upon boiling in 1,4-dioxane
allowed for the first time to obtain 2,6-dihydroimidazo[1,2-c]-
pyrimidin-5(3H)-ones 3a–h with a sulfonyl group in
position 8 (Scheme 1).
Scheme 1
mild conditions, which makes it possible to vary the
substituent R (Schemes 1, 2). The heterocyclization using
chloroalkyl isocyanates 2, 4 proceeds as a domino process,
which begins with the acylation of the isocyanate group of
the NH fragment of the precursor acrylonitriles, followed
by a nucleophilic attack at the nitrile group and
N-alkylation of the resulting imino group (Scheme 3,
2-chloroethyl isocyanate (2) shown as an example).
Hydrolysis of the ester group of compounds 3e,g and 5g
was carried out in dilute hydrochloric acid, which made it
possible to obtain the corresponding compounds 3i,j and 5j
in the form of hydrochlorides (Schemes 2, 3).
Scheme 3
Heterocyclization using enaminonitriles 1a,b,d,g,h and
2-chloropropyl isocyanate (4) allowed to expand the
number of pyrimidine derivatives and resulted in the
formation of 2,3,4,7-tetrahydro-6H-pyrimido[1,6-a]pyri-
midin-6-ones 5a,b,d,g,h (Scheme 2).
In our previous studies, only one compound with the
methylsulfonyl group (SO2Me) in position 9 was obtained,
a synthetic analog of cytosine and the first example of
2,3,4,7-dihydro-6H-pyrimido[1,6-a]pyrimidin-6-one.5
It is worth noting that there are compounds with
antiviral activity among the few 2,6-dihydroimidazo[1,2-c]-
pyrimidin-5(3H)-ones known to date.6 These compounds
were also used as optical probes in studies of D-glycer-
aldehyde-3-phosphate dehydrogenase,7 and nucleosides
based on cytosine analogs were included in DNA
oligomers.8
The structure of the obtained heterylsulfones 3a–j and
5a,b,d,g,h,j was confirmed by 1H and 13C NMR
spectroscopy, LC-MS, and also by X-ray structural analysis
of compound 3b (Fig. 2).
The distribution of bond lengths and valence angles in
the bicyclic system N(1)–N(3)/C(1)–C(6) is illustrative
of such systems. The length of the C(2)–N(3) bond of
1.273 (2) Å is typical for the C–N double bond, and the
lengths of the remaining bonds in the six-membered ring
have mean values between the lengths of single and double
C–C and C–N bonds, which indicates a conjugated system.
It is interesting to note that not only is the six-membered
ring planar, but the entire bicyclic system is planar (the root-
mean-square deviation of atoms from the plane of the
bicyclic system is 0.0148 Å), despite the absence of conju-
gation through the sp3-hybridized carbon atoms C-5,6. The
N(1)–C(7) bond length of 1.472 (2) Å is close to the standard
value of the single C–N bond, which is 1.45 Å. The S(1)–C(3)
(1.7527 (18) Å) and S(1)–C(10) (1.7501 (19) Å) bonds are
equivalent within the experimental error.
Interestingly, the synthesis of the starting amino-
acrylonitriles 1a–h required for heterocyclization was
achieved via nucleophilic substitution of the ethoxy group
of the corresponding sulfonylacrylonitrile by the amino
group.5,9 The reaction was fairly fast and proceeded under
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Chemistry of Heterocyclic Compounds 2019, 55(4/5), 401–407
compounds 3d and 5b were in the order of the indicators of
the reference drug cidofovir (Table 1), and compounds 3d,
5b significantly exceeded the drug in the SI90 parameter.
Also note that compound 3j showed a significantly
higher activity with respect to the papilloma virus
compared to the reference drug (Table 2).
Table 2. Antiviral activity of compound 3j
with respect to the papilloma virus
compared to cidofovir*
ЕС50,
mol/l
ЕС90,
mol/l
СС50,
mol/l
Compound
SI50
SI90
Figure 2. Molecular structure of compound 3b. Major geo-
metrical parameters (bond length in Å, angles in deg): N(1)–C(1)
1.401(2), N(2)–C(1) 1.357(2), N(2)–C(2) 1.401(2), C(3)–C(2)
1.448(2), C(3)–C(4) 1.346(3), N(1)–C(4) 1.366(2), N(2)–C(5)
1.468(2), N(3)–C(2) 1.273(2), N(3)–C(6) 1.479(2); C(1)–N(2)–C(2)
127.46(16), N(2)–C(2)–C(3) 114.35(16), C(4)–C(3)–C(2) 119.05(16),
C(3)–C(4)–N(1) 122.89(17), C(4)–N(1)–C(1) 121.67(16),
N(2)–C(1)–N(1) 114.41(16), C(2)–N(2)–C(5) 108.38(15),
N(3)–C(2)–N(2) 115.90(16), C(2)–N(3)–C(6) 106.78(16),
C(1)–N(2)–C(5) 124.16(16).
4.16
44.04
>100.00
>24
>2
Cidofovir
148.00
>200.00 >200.00
>1
1
* See note at Table 1.
Antiviral activity of compounds 3a,d,h,j and 5d was
studied in the Department of Pediatrics of the University of
Alabama in Birmingham on the HFF cell line affected by
one of the polyomaviruses, BK virus (Gardner strain) and
the HEK 293 cell line affected by the papilloma virus
(Human papillomavirus strain HPV-11).
The result of the study was the detection of high activity
of compounds 3d and 5b in relation to the BK virus. The
quantitative parameters of the antiviral activity of
To conclude, we have developed a convenient method
for the synthesis of new derivatives of dihydroimidazo-
pyrimidin-5-one and dihydropyrimidopyrimidin-6-one
sulfones. The proposed synthetic methodology is based on
the use of commercially available reagents and also allows
access to a variety of functionalized structural analogs
based on the key pyrimidine system. Some of the obtained
compounds showed high antiviral activity (with respect to
the BK virus and the papilloma virus), which confirms the
significance of this work and is a convincing argument for
continuing research in this direction.
Table 1. Antiviral activity of compounds 3d, 5b
in relation to BK virus compared to cidofovir*
Experimental
ЕС50,
mol/l
ЕС90,
mol/l
СС50,
mol/l
Compound
SI50
SI90
1H and 13C NMR spectra were registered on a Varian
Unityplus 400 spectrometer (400 and 100 MHz,
respectively), with TMS as internal standard.
Interpretation of signals in the 13C NMR spectra was
performed using the APT technique. LC-MS spectra were
recorded on an Agilent 1100 Series HPLC system,
equipped with a diode array with an Agilent LC/MSD SL
mass selective detector, atmospheric pressure chemical
ionization. Elemental analysis was performed at the
Analitical laboratory of the V. P. Kukhar Institute of
Bioorganic Chemistry and Petrochemistry of the National
Academy of Sciences of Ukraine. The carbon and
hydrogen content was determined by the Pregl gravimetric
method, the nitrogen content was determined using a
Dumas gas micromethod, and the sulfur content was
determined using the Schöniger titrimetric method. Melting
points were determined on a Fisher-Johns apparatus.
Monitoring of the reaction progress and assessment of the
purity of synthesized compounds were done by TLC on 60
0.66
0.96
1.03
1.14
>150.00 >229 >146
>150.00 >157 >132
NH2
N
O
N
0.24
9.53
>150.00 >600
>16
OH
H2O3P
O
Cidofovir
F
254 Merck TLC plates.
Methods of synthesis and physicochemical character-
* EC50 – concentration that causes a 50% decrease in virus replication; EC90
concentration that causes a 90% decrease in virus replication; CC50
–
–
ristics of 3-ethoxy-2-(methylsulfonyl)acrylonitrile (2) are
published in the literature.10
concentration at which 50% of cells survive; SI50 = CC50/EC50; SI90 = CC50 /EC90.
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Chemistry of Heterocyclic Compounds 2019, 55(4/5), 401–407
NCH2CH2OAc); 4.11 (2Н, t, J = 5.1, NCH2CH2OAc); 7.58–
2-[Methyl(phenyl)sulfonyl]-3-aminoacrylonitriles
1b–d,f–h were obtained by a published method3 from the
corresponding 3-ethoxy-2-sulfonylacrylonitrile (4 mmol).
Physicochemical characteristics of 3-amino-2-(methyl-
sulfonyl)acrylonitrile (1а)11 and 2-{[2-cyano-2-(methyl-
sulfonyl)-vinyl]amino}ethyl acetate (1e)5 match previously
published data. Samples of aminoacrylonitriles 1b–d,f–h
represented a mixture of E- and Z-isomers. NMR spectral
data of the major isomer (70–95%) are given below.
7.69 (3Н, m, H-3–5 Ph); 7.83 (2Н, d, J = 7.2, H-2,6 Ph);
7.98 (1H, d, J = 14.7, =СН); 8.94–9.05 (1Н, m, NH).
13C NMR spectrum (DMSO-d6), δ, ppm: 21.1 (CH3); 48.2
(CH2); 63.0 (CH2); 80.9 (С); 114.7 (С); 126.6 (2СН); 130.0
(2СН); 133.3 (СН); 143.3 (С); 159.0 (СН); 170.6 (С).
Mass spectrum, m/z (Irel, %): 295 [M+H]+ (100). Found, %:
С 53.21; H 4.53; N 9.28; S 10.98. C13H14N2O4S.
Calculated, %: С 53.05; H 4.79; N 9.52; S 10.89.
2-(Methylsulfonyl)-3-(propylamino)prop-2-enenitrile
(1b). Yield 6.63 g (83%), fine colorless crystals, mp 113–
115°C. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 0.84
(3Н, t, J = 7.4, NCH2CH2СН3); 1.52 (2Н, sext, J = 7.4,
NCH2CH2СН3); 3.05 (3Н, s, CH3SO2); 3.19–3.27 (2Н, m,
NСН2); 7.71 (1H, d, J = 14.3, =СН); 8.80 (1Н, br. s, NH).
13C NMR spectrum (DMSO-d6), δ, ppm: 11.1 (CH3); 23.6
(CH2); 45.1 (CH3); 51.2 (CH2); 79.4 (С); 115.2 (С); 158.3
(СН). Mass spectrum, m/z (Irel, %): 189 [M+H]+ (100).
Found, %: С 44.96; Н 6.22; N 14.71; S 17.12. C7H12N2O2S.
Calculated, %: С 44.66; H 6.43; N 14.88; S 17.03.
3-[(4-Methylphenyl)amino]-2-(phenylsulfonyl)prop-
2-enenitrile (1h). Yield 1.06 g (89%), fine colorless
1
crystals, mp 215–216°C. H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 2.29 (3Н, s, 4-CH3 Tol); 7.21 (2Н, d,
J = 8.1, H-3,5 Tol); 7.29 (2Н, d, J = 8.1, H-2,6 Tol); 7.64
(2Н, t, J = 7.4, H-3,5 Ph); 7.71 (1Н, t, J = 7.4, H-4 Ph);
7.96 (2Н, d, J = 7.4, H-2,6 Ph); 8.24 (1H, d, J = 14.0,
=СН); 10.95 (1Н, br. d, J = 14.0, NH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 20.9 (CH3); 85.2 (С); 114.2 (С); 118.8
(2СН); 127.3 (2СН); 130.0 (2СН); 130.4 (2СН); 133.8
(СН); 135.2 (С); 137.5 (С); 142.2 (С); 151.2 (СН). Mass
spectrum, m/z (Irel, %): 299 [M+H]+ (100). Found, %:
С 64.54; H 4.59; N 9.21; S 10.93. C16H14N2O2S.
Calculated, %: С 64.41; H 4.73; N 9.39; S 10.75.
2-(Methylsulfonyl)-3-(phenylamino)prop-2-enenitrile
(1с). Yield 0.69 g (78%), fine colorless crystals, mp 190–
1
191°C. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
3.19 (3Н, s, CH3SO2); 7.20 (1H, br. t, J = 6.5, H-4 Ph);
7.30–7.45 (4Н, m, H-2,3,5,6 Ph); 8.09 (1H, d, J = 13.2,
=СН); 10.86 (1Н, m, NH). 13C NMR spectrum (DMSO-d6),
δ, ppm: 44.7 (CH3); 85.5 (С); 114.3 (С); 118.6 (2СН);
125.6 (СН); 129.9 (2СН); 140.0 (С); 152.0 (СН). Mass
spectrum, m/z (Irel, %): 223 [M+H]+ (100). Found, %:
С 54.19; H 4.36; N 12.46; S 14.51. C10H10N2O2S.
Calculated, %: С 54.04; H 4.54; N 12.60; S 14.42.
Synthesis of 8-(methyl(phenyl)sulfonyl)-2,3-dihydro-
imidazo[1,2-c]pyrimidin-5(3Н)-ones 3a–h and 9-(methyl-
(phenyl)sulfonyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,6-a]-
pyrimidin-6-ones 5a,b,d,g, (General method). 2-Chloroethyl
isocyanate (2) (0.19 ml, 2.26 mmol) or 3-chloropropyl
isocyanate (4) (0.32 ml, 2.30 mmol) followed by Et3N
(0.4 ml, 2.29 mmol) were added to a solution of the
corresponding aminoacrylonitrile 1a–h (2.15 mmol) in dry
1,4-dioxane (5 ml). The reaction mixture was heated under
reflux with stirring for 2 h. It was then cooled to room
temperature, and the precipitate of Et3N·HCl was filtered
off. The filtrate was evaporated under reduced pressure,
and the residue was recrystallized from EtOH.
3-(Benzylamino)-2-(methylsulfonyl)prop-2-enenitrile
(1d). Yield 0.68 g (72%), fine colorless crystals, mp 121–
1
123°C. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
3.05 (3Н, s, CH3SO2); 4.53 (2H, s, CH2Ph); 7.30–7.42 (5H,
m, H Ph); 7.95 (1H, d, J = 10.8, =СН); 9.32 (1Н, m, NH).
13C NMR spectrum (DMSO-d6), δ, ppm: 44.9 (CH3); 51.9
(CH2); 81.2 (С); 115.1 (С); 128.0 (2CH); 128.3 (CH);
129.5 (2CH); 137.1 (C); 156.4 (СН). Mass spectrum, m/z
(Irel, %): 237 [M+H]+ (100). Found, %: С 56.04; H 5.28;
N 11.71; S 13.33. C11H12N2O2S. Calculated, %: С 55.92;
H 5.12; N 11.86; S 13.57.
8-(Methylsulfonyl)-2,6-dihydroimidazo[1,2-c]pyrimi-
din-5(3Н)-one (3a). Yield 0.41 g (89%), large light-beige
1
crystals, mp 283–285°C. H NMR spectrum (CF3COOD),
δ, ppm (J, Hz): 3.77 (3Н, s, CH3SO2); 4.78 (2Н, t, J = 9.4,
СН2); 4.97 (2Н, t, J = 9.4, СН2); 9.10 (1H, s, H-7). 13C NMR
spectrum (CF3COOD), δ, ppm: 44.2 (CH3); 45.2 (CH2);
45.3 (CH2); 105.5 (C); 146.5 (C); 154.1 (CН); 157.3 (C).
Mass spectrum, m/z (Irel, %): 216 [M+H]+ (100). Found, %:
С 38.89; H 4.38; N 19.63; S 14.78. C7H9N3O3S.
Calculated, %: С 39.06; H 4.22; N 19.52; S 14.90.
3-(Benzylamino)-2-(phenylsulfonyl)prop-2-enenitrile
(1f). Yield 1.06 g (89%), large colorless prisms, mp 162–
1
163°C. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
4.56 (2H, s, CH2Ph); 7.26–7.34 (3H, m, H Ph); 7.34–7.42
(2H, m, H Ph); 7.59–7.68 (3H, m, H-3,4,5 PhSO2); 7.84
(2Н, d, J = 7.1, H-2,6 PhSO2); 8.13 (1H, d, J = 11.9, =СН);
9.39 (1Н, br. s, NH). 13C NMR spectrum (DMSO-d6), δ, ppm:
52.7 (CH2); 80.8 (С); 114.7 (С); 126.6 (2СН); 128.2
(3СН); 129.1 (2СН); 130.0 (2СН); 133.4 (СН); 138.1 (С);
143.3 (С); 158.4 (СН). Mass spectrum, m/z (Irel, %): 299
[M+H]+ (100). Found, %: С 64.54; H 4.53; N 9.18;
S 10.91. C16H14N2O2S. Calculated, %: С 64.41; H 4.73;
N 9.39; S 10.75.
8-(Methylsulfonyl)-6-propyl-2,6-dihydroimidazo[1,2-c]-
pyrimidin-5(3Н)-one (3b). Yield 0.51 g (92%), large
colorless crystals, mp 152–154°C. 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 0.86 (3Н, t, J = 5.6,
NCH2CH2СН3); 1.59 (2Н, sex, J = 5.6, NCH2CH2СН3);
3.22 (3Н, s, CH3SO2); 3.70 (2Н, t, J = 5.6, NCH2CH2СН3);
3.78 (2Н, t, J = 8.0, СН2); 3.93 (2Н, t, J = 8.0, СН2); 8.01
(1H, s, H-7). 13C NMR spectrum (DMSO-d6), δ, ppm: 11.1
(CH3); 22.5 (CH2); 42.2 (CH3); 44.2 (CH2); 50.1 (CH2);
54.1 (CH2); 108.8 (C); 147.2 (CH); 148.2 (C); 149.2 (C).
Mass spectrum, m/z (Irel, %): 258 [M+H]+ (100). Found, %:
С 46.49; H 5.95; N 16.21; S 12.53. C10H15N3O3S.
Calculated, %: С 46.68; H 5.88; N 16.33; S 12.46.
2-{[2-Cyano-2-(phenylsulfonyl)ethenyl]amino}ethyl
acetate (1g). Yield 1.10 g (93%), fine colorless crystals,
mp 92–93°C. 1H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 2.00 (3H, s, CH3CO2); 3.53–3.61 (2Н, m,
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Chemistry of Heterocyclic Compounds 2019, 55(4/5), 401–407
8-(Methylsulfonyl)-6-phenyl-2,6-dihydroimidazo[1,2-c]-
J = 7.6, H-4 Ph); 8.00 (2Н, d, J = 7.6, H-2,6 Ph); 8.22 (1H, s,
H-7). 13C NMR spectrum (DMSO-d6), δ, ppm: 21.1 (CH3);
43.8 (CH2); 47.6 (CH2); 54.1 (CH2); 62.0 (CH2); 108.5 (C);
128.3 (2CH); 129.5 (2CH); 134.1 (CH); 140.8 (C); 147.9
(C); 148.0 (C); 149.0 (CH); 170.6 (C). Mass spectrum, m/z
(Irel, %): 364 [M+H]+ (100). Found, %: С 52.80; H 4.75;
N 11.38; S 8.91. C16H17N3O5S. Calculated, %: С 52.88;
H 4.72; N 11.56; S 8.82.
pyrimidin-5(3Н)-one (3c). Yield 0.52 g (84%), fine beige
1
crystals, mp 189–191°C. H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 3.26 (3Н, s, CH3SO2); 3.84 (2Н, t, J = 8.0,
СН2); 4.00 (2Н, t, J = 8.0, СН2); 7.40–7.55 (5Н, m, H Ph);
7.72 (1H, s, H-7). 13C NMR spectrum (DMSO-d6), δ, ppm:
42.3 (CH3); 44.3 (CH2); 54.3 (CH2); 110.0 (C); 127.4
(2CH); 129.2 (CH); 129.8 (2CH); 140.0 (C); 146.7 (CH);
147.5 (C); 149.0 (C). Mass spectrum, m/z (Irel, %): 292
[M+H]+ (100). Found, %: С 53.45; H 4.56; N 14.51;
S 11.09. C13H13N3O3S. Calculated, %: С 53.60; H 4.50;
N 14.42; S 11.00.
6-(4-Methylphenyl)-8-(phenylsulfonyl)-2,6-dihydroimid-
azo[1,2-c]pyrimidin-5(3Н)-one (3h). Yield 0.70 g (88%),
1
fine colorless needles, mp 215–216°C. H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 2.37 (3Н, s, 4-CH3 Tol); 3.72
(2Н, t, J = 8.9, СН2); 3.87 (2Н, t, J = 8.9, СН2); 7.30 (2Н,
d, J = 8.1, H-3,5 Ar); 7.36 (2Н, d, J = 8.1, H-2,6 Ar); 7.60
(2Н, t, J = 7.6, H-3,5 Ph); 7.69 (1Н, t, J = 7.6, H-4 Ph); 7.97
(1H, s, H-7); 8.07 (2Н, d, J = 7.6, H-2,6 Ph). 13C NMR
spectrum (DMSO-d6), δ, ppm: 21.2 (CH3); 44.0 (CH2); 54.3
(CH2); 109.5 (C); 127.2 (2CH); 128.7 (2CH); 129.4 (2CH);
130.1 (2CH); 134.1 (CH); 136.5 (C); 138.8 (C); 140.5 (C);
147.4 (C); 148.0 (CH, C). Mass spectrum, m/z (Irel, %): 368
[M+H]+ (100). Found, %: С 62.02; H 4.75; N 11.50;
S 8.81. C19H17N3O3S. Calculated, %: С 62.11; H 4.66;
N 11.44; S 8.73.
6-Benzyl-8-(methylsulfonyl)-2,6-dihydroimidazo[1,2-c]-
pyrimidin-5(3Н)-one (3d). Yield 0.56 g (86%), fine
colorless crystals, mp 203–205°C. 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 3.21 (3Н, s, CH3SO2); 3.79
(2Н, t, J = 8.0, СН2); 3.93 (2Н, t, J = 8.0, СН2); 4.96 (2H,
s, CH2Ph); 7.26–7.42 (5Н, m, H Ph); 8.09 (1H, s, H-7).
13C NMR spectrum (DMSO-d6), δ, ppm: 42.2 (CH3); 44.2
(CH2); 51.2 (CH2); 54.2 (CH2); 109.6 (C); 128.1 (2CH);
128.3 (CH); 129.6 (2CH); 137.1 (C); 146.9 (CH); 148.2
(C); 149.1 (C). Mass spectrum, m/z (Irel, %): 306 [M+H]+
(100). Found, %: С 54.96; H 5.03; N 13.82; S 10.62.
C14H15N3O3S. Calculated, %: С 55.07; H 4.95; N 13.76;
S 10.50.
9-(Methylsulfonyl)-2,3,4,7-tetrahydro-6H-pyrimido-
[1,6-a]pyrimidin-6-one (5a).Yield 0.34 g (69%), fine light-
beige crystals, mp 205–205.5°C. 1H NMR spectrum
(CF3COOD), δ, ppm (J, Hz): 2.69–2.77 (2Н, m, 3-СН2);
3.73 (3Н, s, CH3SO2); 4.22 (2Н, br. t, J = 5.2, СН2); 4.63
(2Н, br. t, J = 5.2, СН2); 8.97 (1H, s, H-8). 13C NMR
spectrum (CF3COOD); δ, ppm: 17.0 (CH2); 40.6 (CH2);
43.1 (CH2); 44.3 (CH3); 107.3 (C); 147.8 (C); 150.2 (CН);
154.5 (C). Mass spectrum, m/z (Irel, %): 230 [M+H]+ (100).
Found, %: С 41.81; H 4.90; N 18.42; S 14.05. C8H11N3O3S.
Calculated, %: С 41.91; H 4.84; N 18.33; S 13.98.
2-[8-(Methylsulfonyl)-5-oxo-2,3-dihydroimidazo[1,2-c]-
pyrimidin-6(5H)-yl]ethyl acetate (3e). Yield 0.60 g
1
(92%), fine light-beige crystals, mp 146–147 °C. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 2.00 (3Н, s,
CH3CO2); 3.20 (3Н, s, CH3SO2); 3.78 (2Н, t, J = 8.0, СН2);
3.93 (2Н, t, J = 8.0, СН2); 4.00 (2Н, br. s, NCH2CH2OAc);
4.20 (2Н, br. s, NCH2CH2OAc); 7.96 (1H, s, H-7). 13C NMR
spectrum (DMSO-d6), δ, ppm: 21.1 (CH3); 42.3 (CH3);
44.1 (CH2); 47.4 (CH2); 54.1 (CH2); 62.0 (CH2); 109.1 (C);
147.5 (CH); 148.1 (C); 149.0 (C); 170.6 (C). Mass
spectrum, m/z (Irel, %): 302 [M+H]+ (100). Found, %:
С 43.73; H 5.13; N 14.01; S 10.78. C11H15N3O5S.
Calculated, %: С 43.85; H 5.02; N 13.95; S 10.64.
9-(Methylsulfonyl)-7-propyl-2,3,4,7-tetrahydro-6H-pyri-
mido[1,6-a]pyrimidin-6-one (5b). Yield 0.44 g (76%),
1
fine colorless crystals, mp 137–139°C. H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 0.85 (3Н, t, J = 7.4,
NCH2CH2СН3); 1.58 (2Н, sex, J = 7.4, NCH2CH2СН3);
1.74–1.83 (2Н, m, 3-СН2); 3.22 (3Н, s, CH3SO2); 3.40 (2Н,
t, J = 5.3, СН2); 3.65–3.74 (4Н, m, СН2, NCH2CH2СН3);
7.92 (1H, s, H-8). 13C NMR spectrum (DMSO-d6), δ, ppm:
11.1 (CH3); 20.0 (CH2); 22.3 (CH2); 41.8 (CH2); 42.8
(CH3); 43.7 (CH2); 50.8 (CH2); 113.5 (С); 142.1 (С); 143.9
(СН); 150.0 (С). Mass spectrum, m/z (Irel, %): 272 [M+H]+
(100). Found, %: С 48.51; H 6.43; N 15.63; S 11.98.
C11H17N3O3S. Calculated, %: С 48.69; H 6.32; N 15.49;
S 11.82.
6-Benzyl-8-(phenylsulfonyl)-2,6-dihydroimidazo[1,2-c]-
pyrimidin-5(3Н)-one (3f). Yield 0.74 g (94%), fine light-
beige crystals, mp 190–191°C. 1H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 3.68 (2Н, t, J = 8.9, СН2); 3.80 (2Н, t, J = 8.9,
СН2); 4.99 (2H, s, CH2Ph); 7.28–7.42 (5Н, m, H Ph); 7.59
(2Н, t, J = 7.2, H-3,5 PhSO2); 7.69 (1Н, t, J = 7.2, H-4
PhSO2); 7.99 (2Н, d, J = 7.2, H-2,6 PhSO2); 8.34 (1H, s,
H-7). 13C NMR spectrum (DMSO-d6), δ, ppm: 43.9 (CH2);
51.3 (CH2); 54.2 (CH2); 109.1 (C); 128.1 (2CH); 128.3
(CH); 128.4 (2CH); 129.2 (2CH); 129.5 (2CH); 134.1 (CH);
137.1 (C); 140.6 (C); 148.0 (2C); 148.4 (CH). Mass spectrum,
m/z (Irel, %): 368 [M+H]+ (100). Found, %: С 61.99; H 4.76;
N 11.45; S 8.74. C19H17N3O3S. Calculated, %: С 62.11;
H 4.66; N 11.44; S 8.73.
2-[5-Oxo-8-(phenylsulfonyl)-2,3-dihydroimidazo[1,2-c]-
pyrimidin-6(5H)-yl]ethyl acetate (3g). Yield 0.72 g (92%),
fine beige crystals, mp 92–93°C. 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 2.00 (3Н, s, CH3CO2); 3.67
(2Н, t, J = 9.4, СН2); 3.81 (2Н, t, J = 9.4, СН2); 4.03 (2Н, t,
J = 4.8, NCH2CH2OAc); 4.22 (2Н, t, J = 4.8,
NCH2CH2OAc); 7.61 (2Н, t, J = 7.6, H-3,5 Ph); 7.69 (1Н, t,
7-Benzyl-9-(methylsulfonyl)-2,3,4,7-tetrahydro-6H-pyri-
mido[1,6-a]pyrimidin-6-one (5d). Yield 0.55 g (80%),
1
fine colorless crystals, mp 168–169°C. H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 1.75–1.83 (2Н, m, 3-СН2);
3.23 (3Н, s, CH3SO2); 3.42 (2Н, t, J = 5.1, СН2); 3.74 (2Н,
t, J = 5.1, СН2); 4.97 (2H, s, CH2Ph); 7.27–7.40 (5Н, m,
H Ph); 8.08 (1H, s, H-8). 13C NMR spectrum (DMSO-d6),
δ, ppm: 19.9 (CH2); 41.9 (CH2); 42.8 (CH3); 43.7 (CH2);
51.9 (CH2); 114.2 (С); 128.2 (2СН); 128.3 (СН); 129.2
(2СН); 137.1 (С); 142.0 (С); 143.6 (СН); 150.1 (С). Mass
spectrum, m/z (Irel, %): 320 [M+H]+ (100). Found, %:
405

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 401–407
С 56.26; H 5.48; N 13.03; S 10.16. C15H17N3O3S.
Yield 0.73 g (95%), fine light-beige crystals, mp 290°C
1
Calculated, %: С 56.41; H 5.37; N 13.16; S 10.04.
(decomp.). H NMR spectrum (D2O), δ, ppm (J, Hz): 3.70
3,4-Dihydro-2-[6-oxo-9-(phenylsulfonyl)-2H-pyrimido-
[1,6-a]pyrimidin-7(6H)-yl]ethyl acetate (5g). Yield 0.64 g
(2Н, t, J = 5.0, СН2); 3.98–4.05 (4Н, m, СН2,
NCH2CH2OH); 4.17 (2Н, t, J = 8.4, NCH2CH2OH); 7.55
(2Н, t, J = 7.6, H-3,5 Ph); 7.66 (1Н, t, J = 7.6, H-4 Ph); 7.86
(2Н, d, J = 7.6, H-2,6 Ph); 8.76 (1H, s, H-7). 13C NMR
spectrum (D2O), δ, ppm: 45.0 (CH2); 52.9 (CH2); 58.2
(CH2); 104.4 (C); 127.1 (2CH); 130.1 (2CH); 135.4 (CH);
138.2 (C); 146.4 (C); 151.5 (C); 154.8 (C); 156.1 (CH).
Mass spectrum, m/z (Irel, %): 322 [M+H–HCl]+ (100).
Found, %: С 46.87; H 4.69; N 11.78; S 9.03.
C14H16ClN3O4S. Calculated, %: С 47.00; H 4.51; N 11.74;
S 8.96.
1
(79%), fine light-beige crystals, mp 125–126°C. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 1.60–1.70 (2Н, m,
3-СН2); 2.02 (3Н, s, CH3CO2); 3.20–3.28 (2Н, m, СН2);
3.57–3.65 (2Н, m, СН2); 4.04 (2Н, t, J = 4.6,
NCH2CH2OAc); 4.22 (2Н, t, J = 4.6, NCH2CH2OAc); 7.56
(2Н, t, J = 7.4, H-3,5 Ph); 7.65 (1Н, t, J = 7.4, H-4 Ph);
7.92 (2Н, d, J = 7.4, H-2,6 Ph); 8.19 (1H, s, H-8).
13C NMR spectrum (DMSO-d6), δ, ppm: 19.9 (CH2); 21.1
(CH3); 41.8 (CH2); 43.5 (CH2); 48.3 (CH2); 62.0 (CH2);
112.9 (С); 128.6 (2СН); 129.0 (2СН); 133.6 (СН); 140.6
(С); 141.4 (С); 145.7 (СН); 150.0 (С); 170.6 (С). Mass
spectrum, m/z (Irel, %): 378 [M+H]+ (100). Found, %:
С 53.98; H 5.19; N 11.20; S 8.39. C17H19N3O5S. Calculated,
%: С 54.10; H 5.07; N 11.13; S 8.49.
7-(2-Hydroxyethyl)-9-(phenylsulfonyl)-2,3,4,7-tetra-
hydro-6H-pyrimido[1,6-a]pyrimidin-6-one hydrochloride
(5j). Yield 0.78 g (97%), fine colorless crystals, mp 170–
1
172°C. H NMR spectrum (D2O), δ, ppm (J, Hz): 2.03–
1.94 (2Н, m, 3-СН2); 3.49 (2Н, br. t, J = 5.6, СН2); 3.72
(2Н, t, J = 5.0, NCH2CH2OН); 3.89 (2Н, br. t, J = 5.6,
СН2); 4.04 (2Н, t, J = 5.0, NCH2CH2OН); 7.56 (2Н, t,
J = 7.6, H-3,5 Ph); 7.68 (1Н, t, J = 7.6, H-4 Ph); 7.88 (2Н,
d, J = 7.6, H-2,6 Ph); 8.72 (1H, s, H-8). 13C NMR spectrum
(D2O), δ, ppm: 16.9 (CH2); 39.9 (CH2); 43.1 (CH2); 53.6
(CH2); 58.0 (CH2); 105.9 (С); 127.0 (2СН); 130.1 (2СН);
135.3 (СН); 138.1 (С); 147.5 (С); 152.4 (С); 152.9 (СН).
Mass spectrum, m/z (Irel, %): 336 [M+H–HCl]+ (100).
Found, %: С 48.35; H 4.99; N 11.43; S 8.78.
C15H18ClN3O4S. Calculated, %: С 48.45; H 4.88; N 11.30;
S 8.62.
7-(4-Methylphenyl)-9-(phenylsulfonyl)-2,3,4,7-tetrahydro-
6H-pyrimido[1,6-a]pyrimidin-6-one (5h). Yield 0.77 g
1
(94%), fine light-beige needles, mp 206–207°C. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 1.65–1.74 (2Н, m,
3-СН2); 2.36 (3Н, s, 4-CH3 Tol); 3.24–3.31 (2Н, m, СН2);
3.59–3.69 (2Н, m, СН2); 7.31 (2Н, d, J = 8.2, H-3,5 Ar);
7.37 (2Н, d, J = 8.2, H-2,6 Ar); 7.57 (2Н, t, J = 7.5, H-3,5
Ph); 7.66 (1Н, t, J = 7.5, H-4 Ph); 7.94 (1H, s, H-8); 8.00
(2Н, d, J = 7.5, H-2,6 Ph). 13C NMR spectrum (DMSO-d6),
δ, ppm: 19.9 (CH2); 21.2 (CH3); 41.9 (CH2); 43.7 (CH2);
113.8 (С); 127.2 (2СН); 128.9 (2СН); 129.0 (2СН); 130.1
(2СН); 133.6 (СН); 137.2 (С); 138.7 (С); 140.8 (С); 141.2
(С); 144.6 (СН); 149.6 (С). Mass spectrum, m/z (Irel, %):
382 [M+H]+ (100). Found, %: С 62.76; H 5.11; N 11.14;
S 8.28. C20H19N3O3S. Calculated, %: С 62.98; H 5.02;
N 11.02; S 8.40.
X-ray structural analysis of a single crystal of com-
pound 3b with linear dimensions of 0.14 × 0.18 × 0.39 mm
was performed at ambient temperature on a Bruker Smart
Apex II diffractometer (λ MoKα radiation, graphite
monochromator, θmax 25.49°, Miller indices –13 ≤ h ≤ 13,
–15 ≤ k ≤ 15, –9 ≤ l ≤ 10). Crystals of compound 3b
(C3H2BrF2N3, M 197.99) are monoclinic; spatial symmetry
group Р21/с; а 11.2085(3), b 13.2041(3), c 8.6048(2) Å;
β 108.865(2)°; V 1205.09(5) Å3; Z 4, dcalc 1.418 g/cm3;
μ 0.270 mm–1; F(000) 544. 8932 reflections were collected,
2224 of which were independent (averaging R factor
0.0255). The structure was solved by the direct method and
refined by the least-squares technique in the full-matrix
anisotropic approximation using the Bruker SHELXTL
program set.12 Positions of all hydrogen atoms bonded to C
atoms were calculated geometrically and refined according
to the "rider" model. 2224 independent reflections were
used in the refinement, 1939 of which with I > 2σ(I)
(154 refinement parameters, weight scheme that was used
in the refinement ω = 1/(σ2(Fo2) + (0.0593P)2 + 07456P),
where Р = (Fo2 + 2Fc2)/3, the ratio of the maximum
(average) shift to the error in the last cycle was 0.015
(0.002)). The final values of the probability factors were
R1(F) 0.0328, wR2(F2) 0.0961 for reflections with I > 2σ(I),
R1(F) 0.0387, wR2(F2) 0.1018, GOF 1.016 for all
independent reflections. The residual electron density from
the Fourier difference series after the last refinement cycle
was – 0.33 and –0.34 е/Å3. The full set of X-ray structural
data was deposited at the Cambridge Crystallographic Data
Center (deposit CCDC 1899486).
Synthesis of alcohols 3i,j, и 5j (General method). 2 N
aqueous HCl (15 ml) was added to the crude compound
3e,g or 5g, obtained according to the above method. The
obtained mixture was heated under reflux for 3 h, then
evaporated under reduced pressure. The residue was treated
with i-PrOH (10–15 ml), whereupon crystalline precipitate
formed. It was filtered off and washed with cold i-PrOH to
afford spectrally pure compound (yield over two steps
calculated from the starting aminoacrylonitriles is given
below).
6-(2-Hydroxyethyl)-8-(methylsulfonyl)-2,6-dihydro-
imidazo[1,2-c]pyrimidin-5(3Н)-one hydrochloride (3i).
Yield 0.53 g (83%), fine colorless crystals, mp 270°C
(subl.). 1H NMR spectrum (D2O), δ, ppm (J, Hz): 3.22 (3Н,
s, CH3SO2); 3.75 (2Н, t, J = 5.2, СН2); 4.04 (2Н, t, J = 5.2,
СН2); 4.09 (2Н, t, J = 8.0, NCH2CH2OН); 4.26 (2Н, t,
J = 8.0, NCH2CH2OН); 8.63 (1H, s, H-7). 13C NMR
spectrum (D2O), δ, ppm: 42.0 (CH3); 45.0 (CH2); 45.1 (CH2);
52.9 (CH2); 58.4 (CH2); 103.5 (C); 146.6 (C); 155.3 (C); 156.3
(CH). Mass spectrum, m/z (Irel, %): 260 [M+H–HCl]+ (100).
Found, %: С 36.33; H 4.89; N 14.28; S 10.97.
C9H14ClN3O4S. Calculated, %: С 36.55; H 4.77; N 14.21;
S 10.84.
6-(2-Hydroxyethyl)-8-(phenylsulfonyl)-2,6-dihydro-
imidazo[1,2-c]pyrimidin-5(3Н)-one hydrochloride (3j).
406

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 401–407
7. Ermolin, S. V.; Kost, A. A.; Ivanov, M. V.; Nagradova, N. K.
References
Dokl. Akad. Nauk SSSR 1978, 238(1), 245.
8. Zhang, W.; Rieger, R.; Iden, C.; Johnson, F. Chem. Res.
Toxicol. 1995, 8, 148.
1. Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem.
2014, 57, 5845.
2. Razonable, R. R. Mayo Clin. Proc. 2011, 86, 1009.
3. Straub, A.; Stasch, J.-P.; Alonso-Alija, C.; Benet-Buchholz, J.;
Ducke, B.; Feurer, A.; Fürstner, C. Bioorg. Med. Chem. Lett.
2001, 11, 781.
9. Slivchuk, S. R.; Brovarets, V. S.; Drach, B. S. Dopov. Nats.
Akad. Nauk Ukr. (Reports of the National Academy of
Sciences of Ukraine) 2006, 3, 146.
10. Lunt, E.; Newton, C. G.; Smith, C.; Stevens, G. P.;
Stevens, M. F. G.; Straw, C. G.; Walsh, R. J. A.; Warren, P. J.;
Fizames, C.; Lavelle, F.; Langdon, S. P.; Vickers, L. M.
J. Med. Chem. 1987, 30, 357.
4. Semenov, А. А.; Kartsev, V. G. Fundamentals of Chemistry
of Natural Compounds [in Russian]; ICSPF: Moscow, 2009,
Vol. 2, p. 420.
5. Brovarets, V.; Solomyannyi, R.; Slivchuk, S.; Zhirnov, V.;
Rusanov, E.; Smee, D.; Choi, J. Curr. Bioact. Compd. 2018, 14,
(E-pub Ahead of Print), DOI: 10.2174/1573407214666180720120509.
6. Kifli, N.; De Clercq, E.; Balzarini, J.; Simons, C. Bioorg.
Med. Chem. 2004, 12, 4245.
11. Pigošová, J.; Gatial, A.; Milata, V.; Černuchová, P.;
Prónayová, N.; Liptaj, T.; Matějka, P. J. Mol. Struct. 2005,
744–747, 315.
12. Sheldrick, G. Acta Crystallogr., Sect. A: Found. Crystallogr.
2008, A64, 112.
407