Synthesis of alkyl thioethers of pyrazolo[3,4-d]pyrimidine

Article abstract of DOI:10.1007/s10593-009-0352-1

Reaction of 4-imino-1-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d] pyrimidine-6-thione with unsaturated alkyl halides gives 4-imino-6- methallylthio(cinnamylthio, allylthio)-1-methyl-5-phenyl-4,5-dihydro-1H- pyrazolo[3,4-d]pyrimidines.

Full text of DOI:10.1007/s10593-009-0352-1

Chemistry of Heterocyclic Compounds, Vol. 45, No. 7, 2009
SYNTHESIS OF ALKYL THIOETHERS
OF PYRAZOLO[3,4-d]PYRIMIDINE
O. V. Svalyavin1, M. Yu. Onysko1*, and V. G. Lendel1
Reaction of 4-imino-1-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d]pyrimidine-6-thione with
unsaturated alkyl halides gives 4-imino-6-methallylthio(cinnamylthio, allylthio)-1-methyl-5-phenyl-
4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidines.
Keywords: 6-allylthio-4-iminopyrazolo[3,4-d]pyrimidine, 4-imino-6-methallylthio-pyrazolo[3,4-d]pyrimi-
dine, pyrazolo[3,4-d]pyrimidine, 6-cinnamylthio-4-iminopyrazolo[3,4-d]pyrimidine, alkylation, regio-
selectivity.
We have previously reported [1, 2] that alkylation of pyrazolo[3,4-d]pyrimidine-6-thiones using allyl
and propargyl bromides gives the corresponding unsaturated thioethers which are used as substrates for studying
electrophilic heterocyclization reactions. With the aim of increasing the number of unsaturated thioethers for
studying the heterocyclization reaction we have carried out the alkylation of the starting 4-imino-1-methyl-
5-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d]pyrimdine-6-thione (1) using methallyl chloride and cinnamyl
bromide.
In the alkylation of the pyrazolo[3,4-d]pyrimidine-6-thione 1 both KOH and sodium ethylate in ethanol
were used as base to give the thioethers 2-4. It should be noted that the use of sodium ethylate gives increased
yields of the reaction products.
HN
HN
Ph
S
Ph
N
N
B, HalAlk
S
Alk
N
N
N
N
N
N
H
Me
Me
2–4
1
Hal = Cl (synthesis of compound 2), Br (preparation of compound 3, 4); B = KOH, EtONa;
2 Alk = CH2C(Me)=CH2, 3 Alk = CH2CH=CHPh, 4 Alk = CH2CH=CH2
_______
* To whom correspondence should be addressed, e-mail: muonysko@list.ru, depchem@univ.uzhgorod.ua.
1 Uzhgorod National University, Uzhgorod 88000, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1044-1045, July, 2009. Original
article submitted July 23, 2008.
0009-3122/09/4507-0827©2009 Springer Science+Business Media, Inc.
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To prove the regioselectivity of the alkylation process we have recorded the 13C NMR spectrum for
4-imino-6-methallylthiopyrazolo[3,4-d]pyrimidine (2). A characteristic for determining the regioselectivity of
the alkylation is the signal for the sp3 hybridized methylene carbon atom in the alkyl chain which appears at
33.82 ppm and which points to the formation of thioether 2. In the alternative variant of alkylation at the
endocyclic nitrogen atom the signal for this carbon atom would appear at lower fields (~ 50-60 ppm [3]).
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on a Varian VXR-300 spectrometer (300 and 75 MHz
respectively) using TMS as internal standard.
Preparation of Thioethers 2 and 3 (General Method). A. A solution of KOH (9.4 mmol) in water
(2 ml) was added to a solution of 4-imino-1-methyl-5-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-d]pyrimidine-
6-thione (1) in ethanol (20 ml). The reaction mixture was heated to full dissolving and a 90% solution of
methallyl chloride (1.06 ml, 9.4 mmol) or cinnamyl bromide (1.4 ml, 9.4 mmol) was added and heated for 1 h at
50-60ºC. The precipitate was filtered off and recrystallized from ethanol or acetic acid.
B. Compound 1 (7.8 mmol) was added to a solution of metallic sodium (7.8 mmol) in ethanol (15 ml).
The reaction mixture was heated to full dissolving and a 90% solution of methallyl chloride (1.06 ml, 9.4 mmol)
or cinnamyl bromide (1.4 ml, 9.4 mmol) was added and heated for 1 h at 50-60ºC. The precipitate was filtered
off and recrystallized from ethanol or acetic acid.
4-Imino-6-methallylthio-1-methyl-5-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine (2). Yield
1
67 (method A) and 78% (method B); mp 130-132ºC. H NMR spectrum (CDCl3), δ, ppm: 1.88 (3H, s, CH3);
3.98 (3H, s, NCH3); 4.01 (2H, s, SCH2); 4.94 (1H, s, =CH2); 5.08 (1H, s, =CH2); 7.09, 7.25, 7.40 (5H, m, C6H5);
13
7.76 (1H, s, CH pyrazole); 7.87 (1H, s, =NH). C NMR spectrum (DMSO-d6), δ, ppm: 21.65, 33.82, 34.80,
105.85, 114.85, 119.87, 122.29, 128.95, 131.77, 140.70, 141.13, 153.38, 157.35, 164.20. Found, %: N 22.19.
C16H17N5S. Calculated, %: N 22.49.
6-Cinnamylthio-4-imino-1-methyl-5-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine (3). Yield
1
64 (method A) and 81% (method B); mp 162-164ºC. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 3.99 (3H, s,
NCH3); 4.18 (2H, d, J = 5.0, SCH2); 6.38 (1H, m, =CH); 6.64 (1H, d, J = 16.0, =CH); 7.08, 7.38 (10H, m,
C6H5); 7.77 (1H, s, CH pyrazole); 7.87 (1H, s, =NH). Found, %: N 18.23. C21H19N5S. Calculated, %: N 18.75.
6-Allylthio-4-imino-1-methyl-5-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine (4). Yield 72
1
(method A) and 93% (method B); mp 134-136ºC. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 4.03 (3H, s,
NCH3); 4.07 (2H, d, J = 5.0, SCH2); 5.21 (1H, d, J = 10.0, =CH2); 5.37 (1H, d, J = 17.0, =CH2); 6.05 (1H, m,
=CH); 7.11, 7.29, 7.41 (5H, m, C6H5); 7.76 (1H, s, CH pyrazole); 7.89 (1H, s, =NH). Found, %: N 23.15.
C15H15N5S. Calculated, %: N 23.55.
REFERENCES
1.
2.
3.
M. Yu. Onysko, O. V. Svalyavin, and V. G. Lendel, Khim. Geterotsikl. Soedin., 602 (2007). [Chem.
Heterocycl. Comp., 43, 496 (2007).
M. Yu. Onysko, O. V. Svalyavin, A. V. Turov, and V. G. Lendel, Khim. Geterotsikl. Soedin., 1805
(2008). [Chem. Heterocycl. Comp., 44, 872 (2008)].
G. C. Levy and G. L. Nelson, Guidebook to 13C Nuclear Magnetic Resonance [Russian translation], Mir,
Moscow (1975), p. 77.
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