Synthesis and halogenation of propargyl pyrazolo-[3,4-d]pyrimidine thioether

Article abstract of DOI:10.1007/s10593-008-0123-4

The reaction of 4-imino-1-methyl-5-phenyl-6-propargylthio-1,5-dihydro-4H- pyrazolo[3,4-d]pyrimidine with halogens leads to the formation of (Z)-8-halomethylene-4-imino-1-methyl-5-phenyl-4,5,7,8-tetrahydro-1H-pyrazolo[4, 3-e][1,3]thiazolo[3,2-a]pyrimidinium trihalide.

Full text of DOI:10.1007/s10593-008-0123-4

Chemistry of Heterocyclic Compounds, Vol. 44, No. 7, 2008
SYNTHESIS AND HALOGENATION
OF PROPARGYL PYRAZOLO-
[3,4-d]PYRIMIDINE THIOETHER
M. Yu. Onysko, O. V. Svalyavin, A. V. Turov, and V. G. Lendel
The reaction of 4-imino-1-methyl-5-phenyl-6-propargylthio-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine
with halogens leads to the formation of (Z)-8-halomethylene-4-imino-1-methyl-5-phenyl-4,5,7,8-
tetrahydro-1H-pyrazolo[4,3-e][1,3]thiazolo[3,2-a]pyrimidinium trihalide.
Keywords: 4-imino-6-propargylthiopyrazolo[3,4-d]pyrimidine, pyrazolo[3,4-d]pyrimidine, trihalide,
haloheterocyclization.
Earlier [1] it was reported that o-aminocyanopyrazoles condense effectively with isothiocyanates to
pyrazolo[3,4-d]pyrimidine-6-thiones. In the present work 5-amino-4-cyano-1-methyl-1H-pyrazole (1) was used
as initial aminopyrazole.
In [1] boiling ethanol was used as solvent for the condensation, and this was followed by cyclization
with alkali. We used a mixture of DMF with potassium hydroxide for the condensation and cyclization of the
pyrazole 1. The potassium salt of pyrazolo[3,4-d]pyrimidine-6-thione 2 was obtained as a result of the reaction
without isolation of the thiourea. The thione 3 was obtained when the salt 2 was neutralized with acetic acid.
HN
HN
PhNCS,
DMF,
KOH
Ph
S
Ph
N
N
CN
NH2
AcOH
SK
N
N
N
N
H
N
–AcOK
N
N
N
Me
Me
Me
2
1
3
HC CCH2Br
KOH
– KBr
CH
HN
HN
Ph
S
Ph
N
N
+
S
N
N
N
2Hal2, AcOH
N
N
N
CH2C
Me
Hal
Me
–
4
Hal3
H
5, 6
5 Hal = Br, 6 Hal = I
__________________________________________________________________________________________
Uzhgorod National University, Uzhgorod 88000, Ukraine; e-mail: muonysko@list.ru, e-mail:
depchem@univ.uzhgorod.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1085-1088,
July, 2008. Original article submitted August 8, 2007.
872
0009-3122/08/4407-0872©2008 Springer Science+Business Media, Inc.

The thioether 4 was obtained by alkylation of the thione 3 with propargyl bromide in 95% ethanol in the
presence of alkali. The thioether is capable of heterocyclization during halogenation in acetic acid.
We studied the halogenation of the thioether 4. As halogens we used iodine and bromine. The reaction
was carried out in acetic acid with twice the amount of halogen. The reaction was monitored by TLC (in the 1:3
acetic acid–hexane system). According to elemental analysis for nitrogen and halogen the trihalides 5 and 6
were formed as a result of the reaction.
1
13
In order to investigate the structure of the synthesized compound 6 we measured its H and C NMR
1
spectra, and we also carried out heteronuclear H13C correlation experiments through one chemical bond
(HMQC) and through 2-3 chemical bonds (HMBC). The assignment of the signals in the proton spectrum was
not subject to doubt since the two singlets present in the spectrum in the region of the signals for the aromatic
protons are separated from each other by almost 1 ppm. In order to assign the signals of the protonated carbon
atoms we made use of correlations in the HMQC spectrum, indicating the presence of a chemical bond between
the proton and the corresponding carbon atom. The assignment of the quaternary carbon atoms follows from the
presence of correlations through 2-3 chemical bonds in the HMBC spectrum. All the found heteronuclear 1H13C
correlations are given in Table 1.
It is possible to assign all the signals in the carbon spectrum on the basis of the obtained correlations.
Thus, for example, the presence of a correlation between the signal of a proton at 8.65 ppm and the signals of
the carbon atoms at 106.1 and 151.1 ppm makes it possible to assign the signals to the nodal carbon atoms. The
location of the last signal is also confirmed by the presence of a correlation with the signal of the methyl
protons. The assignment of the most downfield signal of a carbon atom (165.8 ppm) to the nodal carbon atom
10.57
H
7.25
N
8.65
126.3
129.5
137.5
N
149.6
137.5
7.43
106.1
151.1
N
124.1
7.58
N
165.8
N
S
34.8
CH3
139.7
39.3
4.57
3.78
83.0
I
H
7.75
TABLE 1. The HMQC and HMBC Correlations Obtained for the Signals
of the Protons in Compound 6
δ, ppm
HMQC
HMBC
10.57
8.65
7.75
7.58
7.43
7.25
4.57
3.78
—
137.5
83.0
—
151.1, 106.1
39.3
124.1
129.5
126.3
39.3
137.5, 126.3, 124.1
137.5, 129.5, 126.3
129.5, 124.1
165.8, 83.0, 139.7
151.1
34.8
873

situated between the two nitrogen atoms and the sulfur atom follows from the presence of a correlation with the
signal of the protons of the methylene group, the protons of which are separated from the given carbon atom by
three chemical bonds. The main assignments of the signals in the proton and carbon spectra of compound 6 are
shown in the scheme, and the HMBC correlations, which served as the basis for the assignments, are presented.
The only signal for which HMBC correlations were not found is the signal of the quaternary carbon
atom with a chemical shift of 149.6 ppm. We assigned it by the exclusion method. Our proposed structure for
compound 6 agrees well with the obtained chemical shifts.
It is not possible to determine the orientation of the iodine atom and the olefinic proton in the molecule
in relation to the exocyclic double bond directly from the NMR spectra. To solve this problem we measured the
13C NMR spectrum without spin–spin decoupling with the protons. For the signal of the carbon atom with a
chemical shift of 39.3 ppm under these conditions a spin–spin coupling constant with the olefinic protons of 3JCH
= 6 Hz was observed. This indicates a cisoid orientation for the olefinic proton and the carbon atom of the
methylene group contained in the thiazoline ring. A further argument in favor of the given geometry of the
molecule is the absence of an appreciable NOE between the signal of the protons of the methyl group and the
signal of the olefinic proton in a NOESY-1D experiment.
EXPERIMENTAL
1
13
The H and C NMR spectra and HMQC and HMBC heteronuclear correlation spectra were obtained
on a Varian Mercury-400 spectrometer (400 and 100 MHz respectively). All the two-dimensional experiments
were performed with gradient selection of the useful signals. The mixing time in the pulse sequences
1
2-3
corresponded to JCH = 140 in the HMQC method and
J
CH
= 8 Hz in the HMBC method. The number of
increments amounted to 128 in the HMQC spectra and 400 in the HMBC spectra. In all cases the solvent was
DMSO-d6 and the internal standard TMS.
4-Imino-1-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d]pyrimidine-6-thione (3). To a
solution of 5-amino-1-methyl-1H-4-pyrazolecarbonitrile (1) (5 mmol) we added DMF (10 ml), phenyl
isothiocyanate (0.52 ml), and potassium hydroxide (0.28 g). The mixture was heated for 2.5 h, cooled, and
acidified with 85% acetic acid solution. The yellow precipitate was filtered off, washed with water, and
1
recrystallized from acetic acid. The yield was 55%; mp 290-292°C. H NMR spectrum, δ, ppm (J, Hz): 3.83
(3H, s, N–CH3); 7.05, 7.36, 7.68 (5H, m, C6H5); 7.91 (1H, s, H-3); 9.05 (1H, s, ═NH); 11.83 (1H, m, NH).
Found, %: N 27.29. C12H11N5S. Calculated, %: N 27.12.
1-Methyl-5-phenyl-6-(2-propynylthio)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-4-imine (4). To a
solution of the thione 3 (6.8 mmol) in ethanol (15 ml) we added potassium hydroxide (8 mmol) and propargyl
bromide (8 mmol). The reaction mixture was heated at 60°C for 1 h and cooled. The light-yellow precipitate was
1
filtered off and recrystallized from ethanol. The yield was 88%; mp 155-157°C. H NMR spectrum, δ, ppm (J,
Hz): 3.04 (1H, s, ≡CH); 3.87 (3H, s, N–СH3); 4.21 (2H, s, CH2); 6.96, 7.28, 7.86 (5H, m, C6H5); 7.90 (1H, s, H-
3); 9.71 (1H, s, =NH). Found, %: N 23.27. C15H13N5S. Calculated, %: N 23.71.
(Z)-8-Bromomethylene-4-imino-1-methyl-5-phenyl-4,5,7,8-tetrahydro-1H-pyrazolo[4,3-e][1,3]thiazolo-
[3,2-a]pyrimidinium Tribromide (5). To a solution of the thioether 4 (10 mmol) in acetic acid (20 ml) with
constant stirring we slowly added bromine (20 mmol) dissolved in acetic acid (5 ml). The reaction mixture was
stirred for a further 3 h. The yellow precipitate was filtered off and recrystallized from DMF. The yield was
1
79%; mp 189-191°C. H NMR spectrum, δ, ppm (J, Hz): 3.84 (3H, s, N–CH3); 4.63 (2H, s, S–CH2); 7.60 (5H,
m, C6H5); 7.70 (1H, s, =CHBr); 8.60 (1H, s, H-3); 10.45 (1H, s, =NH). Found, %: Br 52.03; N 11.38.
C15H13Br4N5S. Calculated, %: Br 51.32; N 11.20.
(Z)-8-Iodomethylene-4-imino-1-methyl-5-phenyl-4,5,7,8-tetrahydro-1H-pyrazolo[4,3-e][1,3]thiazolo-
[3,2-a]pyrimidinium Triiodide (6). To a solution of the thioether 4 (10 mmol) in acetic acid (20 ml) with
874

constant stirring we slowly added iodine (20 ml) dissolved in acetic acid (40 ml). The reaction mixture was
stirred for a further 3 h. The brown precipitate was filtered off and recrystallized from DMF. The yield 74%; mp
198-200°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.78 (3Н, s, N–CH3); 4.57 (2Н, s, S–CH2); 7.25, 7.43, 7.58 (5Н,
13
m, С6Н5); 7.75 (1H, s, =СНI); 8.65 (1Н, s, Н-3); 10.57 (1Н, s, ═NH). C NMR spectrum, δ, ppm: 34.8, 39.3,
83.0, 106.1, 124.1, 126.3, 129.5, 137.5, 139.7, 149.6, 151.1, 165.8. Found, %: I 63.26; N 8.72. C15H13I4N5S.
Calculated, %: I 61.79; N 8.36.
REFERENCES
1.
M. Yu. Onysko, O. V. Svalyavin, and V. G. Lendel, Khim. Geterotsikl. Soedin., 602 (2007). [Chem.
Heterocycl. Comp., 43, 496 (2007).]
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