Synthesis of pyrazolo[1,5-c]pyrimidines from difluoroboron chelates of aroylacetones

Article abstract of DOI:10.1007/s11172-007-0154-5

A convenient method was developed for the synthesis of derivatives of 6H-pyrazolo[1,5-c]pyrimidine-7-thione and 7-aminopyrazolo[1,5-c]pyrimidine from difluoroboron chelate complexes of aroylacetones, amide acetals, and thiosemicarbazide or aminoguanidine.

Full text of DOI:10.1007/s11172-007-0154-5

Russian Chemical Bulletin, International Edition, Vol. 56, No. 5, pp. 1028—1031, May, 2007
1028
Synthesis of pyrazolo[1,5ꢀc]pyrimidines
from difluoroboron chelates of aroylacetones
V. A. Dorokhov,ꢀ I. V. Kravtsov, P. A. Belyakov, and S. V. Baranin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 5328. Eꢀmail: vador@ioc.ac.ru
A convenient method was developed for the synthesis of derivatives of 6Hꢀpyrazoꢀ
lo[1,5ꢀc]pyrimidineꢀ7ꢀthione and 7ꢀaminopyrazolo[1,5ꢀc]pyrimidine from difluoroboron cheꢀ
late complexes of aroylacetones, amide acetals, and thiosemicarbazide or aminoguanidine.
Key words: aroylacetones, difluoroboron chelates, amide acetals, thiosemicarbazide,
aminoguanidine, 6Hꢀpyrazolo[1,5ꢀc]pyrimidineꢀ7ꢀthiones, 7ꢀaminopyrazolo[1,5ꢀc]pyrimiꢀ
dines.
Recently,1 we have developed a convenient method
for the synthesis of 5ꢀaroylmethylpyrazoles and their
hydrazones from difluoroboron chelate complexes of
aroylacetones, amide acetals, and hydrazines. This method
is based on the ability of amide acetals to react with boron
βꢀdiketonates at the exocyclic methyl group. The resultꢀ
ing condensation products are difluoroboron chelates
of 1ꢀarylꢀ5ꢀdimethylaminopent(hex)ꢀ4ꢀeneꢀ1,3ꢀdiꢀ
ones 1a—e. Proceeding further in this area, we investiꢀ
gated reactions of chelates 1a—e with reagents containing
more than two nucleophilic centers: thiosemicarbazide
and aminoguanidine.
give the corresponding 6Hꢀpyrazolo[1,5ꢀc]pyrimidineꢀ7ꢀ
thione derivatives 2a—d (Scheme 1).
Compounds 2 are white crystalline solids that are
soluble in chloroform and benzene and negligibly soluble
in ethanol, ethyl acetate, and hexane. Their mass spectra
contain molecular ion peaks [M+]. The 1H NMR spectra
of compounds 2 in CDCl3 show broadened singlets for the
protons of the endocyclic NH group at δ ~10.27—10.14,
signals for the H(4) protons of the pyrimidine ring at
δ ~7.38—6.64, and signals for the H(3) protons of the
pyrazole ring at δ ~6.64—6.36. It should be noted that
compound 2d is insoluble in hexane, benzene, ethyl acꢀ
etate, ethanol, and acetonitrile and poorly soluble in chloꢀ
roform.
It turned out that chelate complexes 1a—d react with
thiosemicarbazide on prolonged reflux in butanol to
Chelates 1a—c,e reacted with aminoguanidine hydroꢀ
chloride in boiling butanol for ~30 h in the presence of an
equimolar amount of sodium acetate (for in situ transforꢀ
mation of the aminoguanidine salt into a free base). The
reaction products were 7ꢀaminopyrazolo[1,5ꢀc]pyrimiꢀ
dines 3a—c,e (Scheme 2).
Scheme 1
Scheme 2
i. THF, 20 °C; ii. BuOH, ∆, 40 h
i. BuOH, AcONa, ∆, 30 h
R = H; Ar = Ph (a), 2ꢀC10H7 (b);
R = H, Ar = Ph (a); R = H, Ar = 2ꢀC10H7 (b);
R = Me; Ar = 2,4ꢀMe2C6H3 (c), 2ꢀC10H7 (d)
R = Me, Ar = 2,4ꢀMe2C6H3 (c); R = H, Ar = 2,4ꢀMe2C6H3 (e)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 992—994, May, 2007.
1066ꢀ5285/07/5605ꢀ1028 © 2007 Springer Science+Business Media, Inc.

Synthesis of pyrazolo[1,5ꢀc]pyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
1029
Scheme 3
X = S, NH
Compounds 3 are white crystalline solids that are
soluble in chloroform and benzene but are poorly soluble
in ethanol, ethyl acetate, and hexane. Their mass spectra
contain molecular ion peaks [M+]. The 1H NMR spectra
of compounds 3 show broadened singlets for the protons
of the amino group at δ ~6.17—6.40, singlets for the H(4)
protons of the pyrimidine ring at δ ~6.75—7.31, and
singlets for the H(3) proton of the pyrazole ring at
δ ~6.19—6.51. The mechanism of the reactions of boron
complexes 1 with thiosemicarbazide and aminoguanidine,
as well as with hydrazines,1 involves initial replacement of
the NMe2 group by thiosemicarbazide or aminoguanidine
resulting in intermediate A, which undergoes cyclization
(with breaking of the chelate ring) into bicyclic comꢀ
pounds 2 or 3 (Scheme 3).
2D NMR studies revealed that the reaction is regioꢀ
selective and yields pyrazolo[1,5ꢀc]pyrimidines 2 or 3 as
the sole products. For instance, the COSY spectrum of
compound 3c in CDCl3 shows a cross peak due to a spinꢀ
spin coupling of the methyl protons (δ 2.49) at the
C(2) atom of the bicyclic compound with the H(3) proꢀ
ton of the pyrazole ring (δ 6.19).
It should be noted that pyrazolo[1,5ꢀc]pyrimidines are
least studied among various types of these bicyclic derivaꢀ
tives.2 In the known syntheses of thiones of the type 2 and
amines of the type 3, thiosemicarbazide and aminoꢀ
guanidine have been mainly used as well. A reaction of
thiosemicarbazide with heptaneꢀ2,4,6ꢀtrione gives 2,5ꢀdiꢀ
methylꢀ6Hꢀpyrazolo[1,5ꢀc]pyrimidineꢀ7ꢀthione and that
with aminoguanidine hydrochloride yields 7ꢀaminoꢀ2,5ꢀ
dimethylpyrazolo[1,5ꢀc]pyrimidine.3 In the patent,4 it is
stated that the range of the starting triones in these transꢀ
formations can be extended. The corresponding bicyclic
2,5ꢀdiphenyl thione has been synthesized from 2,6ꢀdiꢀ
phenylpyrylium perchlorate in two steps.5 Reactions of
thiosemicarbazide with 1ꢀarylꢀ5ꢀphenylpentꢀ1ꢀyneꢀ3,5ꢀ
diones produce 2ꢀarylꢀ5ꢀphenylꢀ6Hꢀpyrazolo[1,5ꢀc]pyriꢀ
midineꢀ7ꢀthiones.6 Some pyrazolo[1,5ꢀc]pyrimidines have
been reported to exhibit biological (e.g., hypnotic, sedaꢀ
tive, and antimicrobial) activities.4,7
proach, our method affords 2ꢀunsubstituted thiones 2 and
amines 3.
Experimental
1
H and 13C NMR spectra were recorded on a Bruker
WMꢀ250 instrument (250 and 63 MHz, respectively) at 25 °C.
11B NMR spectra were recorded on a Bruker ACꢀ200 instruꢀ
ment (64 MHz) with BF3•Et2O as the internal standard.
IR spectra were recorded on a Specord Mꢀ82 instrument
(KBr pellets).
Mass spectra were recorded on a Kratos MSꢀ30 instrument
(EI, 70 eV).
A difluoroboron complex of benzoylacetone was prepared
according to a modified procedure:8 BF3 etherate was used inꢀ
stead of gaseous BF3.
Difluoroboron complexes of 2,4ꢀdimethylbenzoylacetone
and 2ꢀnaphthoylacetone were synthesized analogously, isolated,
and used without additional purification in reactions with amide
acetals.
A difluoroboron chelate complex of 5ꢀdimethylaminoꢀ1ꢀ
phenylpentꢀ4ꢀeneꢀ1,3ꢀdione (1a) was prepared as described
earlier.1 Difluoroboron chelates of 1ꢀarylꢀ5ꢀdimethylaminoꢀ
pent(hex)ꢀ4ꢀeneꢀ1,3ꢀdiones 1b—e were synthesized analogously
from difluoroboron complexes of appropriate aroylacetones.
Difluoroboron chelate complex of 5ꢀdimethylaminoꢀ1ꢀ(2ꢀ
naphthyl)pentꢀ4ꢀeneꢀ1,3ꢀdione (1b) was obtained from a diꢀ
fluoroboron chelate of 2ꢀnaphthoylacetone and dimethylformꢀ
amide dimethyl acetal. The yield was 95%, m.p. 274—275 °C.
Found (%): C, 64.80; H, 5.12; N, 4.44. C15H18BF2NO2. Calcuꢀ
lated (%): C, 64.97; H, 5.02; N, 4.59. MS, m/z (Irel (%)):
315 [M]+ (100), 271 [M – NMe2]+ (79). 1H NMR (DMSOꢀd6),
δ: 3.07, 3.35 (both s, 6 H, NMe2); 5.41 (d, 1 H, CH=, J =
12.3 Hz); 6.63 (s, 1 H, CH=); 7.59, 8.00 (both m, 6 H, Ar); 8.22
(d, 1 H, CH=, J = 12.3 Hz); 8.51 (s, 1 H, Ar). 11B NMR
(CH3CN), δ: 1.37. IR, ν/cm–1: 2908, 1640, 1600, 1544.
Difluoroboron chelate complex of 5ꢀdimethylaminoꢀ1ꢀ(2,4ꢀ
dimethylphenyl)hexꢀ4ꢀeneꢀ1,3ꢀdione (1c) was obtained from a
difluoroboron chelate of 2,4ꢀdimethylbenzoylacetone and diꢀ
methylacetamide dimethyl acetal. The yield was 84%, m.p.
216—217 °C. Found (%): C, 62.43; H, 6.72; N, 4.85.
C
16H20BF2NO2. Calculated (%): C, 62.57; H, 6.56; N, 4.56.
MS, m/z (Irel (%)): 307 [M]+ (87), 263 [M – NMe2]+ (94).
1H NMR (DMSOꢀd6), δ: 2.28 (s, 3 H, Me); 2.36, 2.57 (both s,
6 H, 2,4ꢀMe2C6H3); 3.17, 3.24 (both s, 6 H, NMe2); 5.26 (s,
1 H, CH=); 5.88 (s, 1 H, CH=); 7.07 (m, 2 H, Ar); 7.34 (d, 1 H,
We proposed a new strategy of construction of the
pyrazolo[1,5ꢀc]pyrimidine system from easily accessible
carbonyl compounds. In contrast to the previous apꢀ

1030
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
Dorokhov et al.
Ar, J = 7.9 Hz). 11B NMR (CH3CN), δ: 1.19. IR, ν/cm–1: 3012,
2932, 1572, 1560 (br).
2ꢀMethylꢀ5ꢀ(2ꢀnaphthyl)ꢀ6Hꢀpyrazolo[1,5ꢀc]pyrimidineꢀ7ꢀ
thione (2d). The yield was 41%, m.p. 279—280 °C. Found (%):
C, 69.95; H, 4.61; N, 14.28. C17H13N3S. Calculated (%):
C, 70.08; H, 4.50; N, 14.42. MS, m/z (Irel (%)): 291 [M]+ (100),
Difluoroboron chelate complex of 5ꢀdimethylaminoꢀ1ꢀ(2ꢀ
naphthyl)hexꢀ4ꢀeneꢀ1,3ꢀdione (1d) was obtained from a diꢀ
fluoroboron chelate of 2ꢀnaphthoylacetone and dimethylacetꢀ
amide dimethyl acetal. The yield was 88%, m.p. 248—249 °C.
Found (%): C, 65.50; H, 5.72; N, 4.55. C18H18BF2NO2. Calcuꢀ
lated (%): C, 65.68; H, 5.51; N, 4.26. MS, m/z (Irel (%)):
329 [M]+ (50), 285 [M – NMe2]+ (75). 1H NMR (DMSOꢀd6),
δ: 2.61 (s, 3 H, Me); 3.22, 3.27 (both s, 6 H, NMe2); 5.37 (s,
1 H, CH=); 6.62 (s, 1 H, CH=); 7.58, 8.00 (both m, 6 H, Ar);
1
276 (18). H NMR (DMSOꢀd6), δ: 2.40 (s, 3 H, Me); 6.56 (s,
1 H, H(3)); 7.38 (s, 1 H, H(4) pyrim.); 7.60—8.00 (m, 6 H, Ar);
8.39 (s, 1 H, oꢀHnapht); 13.19 (s, 1 H, NH). IR, ν/cm–1: 3168,
3128, 3060, 3008, 1636, 1600, 1520.
7ꢀAminoꢀ5ꢀarylꢀ2ꢀRꢀpyrazolo[1,5ꢀc]pyrimidines 3a—c,e
(general procedure). A mixture of difluoroboron complex 1a—c,e
(1 mol), aminoguanidine (1.2 mol), and anhydrous sodium acꢀ
etate (1.2 mol) was refluxed in nꢀbutanol (15 mL) for 15 h. After
the reaction was completed (TLC data), the solvent was reꢀ
moved and the dry residue was dissolved in chloroform and
filtered through a short column with SiO2. The filtrate was conꢀ
centrated and the residue was recrystallized from a suitable solꢀ
vent and dried in vacuo. The resulting white crystals were poorly
soluble in hexane, ethyl acetate, and ethanol, yet being soluble
in diethyl ether and chloroform.
8.46 (s, 1 H, Ar). 11B NMR (CH3CN), δ: 1.37. IR, ν/cm–1
:
3060, 1600, 1552 (br).
Difluoroboron chelate complex of 5ꢀdimethylaminoꢀ1ꢀ(2,4ꢀ
dimethylphenyl)pentꢀ4ꢀeneꢀ1,3ꢀdione (1e) was obtained from a
difluoroboron chelate of 2,4ꢀdimethylbenzoylacetone and diꢀ
methylformamide dimethyl acetal. The yield was 93%, m.p.
195—196 °C. Found (%): C, 61.42; H, 6.22; N, 4.82.
C
15H18BF2NO2. Calculated (%): C, 61.46; H, 6.19; N, 4.78.
MS, m/z (Irel (%)): 293 [M]+ (100), 249 [M – NMe2]+ (38),
228 (46). 1H NMR (CDCl3), δ: 2.34, 2.51 (both s, 6 H,
2,4ꢀMe2C6H3); 3.01, 3.26 (both s, 6 H, NMe2); 4.98 (d, 1 H,
CH=, J = 12.3 Hz); 5.78 (s, 1 H, CH=); 7.02 (d, 1 H, Ar, J =
7.9 Hz); 7.04 (s, 1 H, Ar); 7.43 (d, 1 H, Ar, J = 7.9 Hz); 8.08 (d,
1 H, CH=, J = 12.3 Hz). 11B NMR (CH3CN), δ: 1.20. IR,
ν/cm–1: 2912, 1640, 1580, 1560.
2ꢀSubstituted 5ꢀarylꢀ6Hꢀpyrazolo[1,5ꢀc]pyrimidineꢀ7ꢀ
thiones 2a—d (general procedure). A mixture of difluoroboron
complex 1a—d (1 mol) and thiosemicarbazide (1.5 mol) was
refluxed in nꢀbutanol (15 mL) for 30 h. After the reaction was
completed (TLC data), the solvent was removed and the dry
residue was dissolved in chloroform and filtered through a short
column with SiO2. The solvent was removed and the residue was
recrystallized from a suitable solvent and dried in vacuo.
5ꢀPhenylꢀ6Hꢀpyrazolo[1,5ꢀc]pyrimidineꢀ7ꢀthione (2a). The
yield was 54%, m.p. 205—206 °C (from benzene). Found (%):
C, 63.18; H, 4.08; N, 18.22. C12H9N3S. Calculated (%):
C, 63.41; H, 3.99; N, 18.49. MS, m/z (Irel (%)): 226 [M]+ (100),
195 (10), 169 (27), 139 (20), 115 (21). 1H NMR (CDCl3), δ:
6.60 (d, 1 H, H(3), J = 2.0 Hz); 7.02 (s, 1 H, H(4)); 7.50—7.70
(m, 5 H, Ph); 8.17 (d, 1 H, H(2), J = 2.0 Hz); 10.27 (s, 1 H,
NH). 13C NMR (CDCl3), δ: 99.7, 101.7, 126.3, 129.4, 130.5,
131.4, 138.2, 138.7, 147.0, 168.8. IR, ν/cm–1: 3164, 3108, 2988,
2844, 1640, 1524, 1328, 1256.
5ꢀ(2ꢀNaphthyl)ꢀ6Hꢀpyrazolo[1,5ꢀc]pyrimidineꢀ7ꢀthione (2b).
The yield was 43%, m.p. 240—241 °C (from benzene).
Found (%): C, 69.14; H, 4.13; N, 15.04. C16H11N3S. Calcuꢀ
lated (%): C, 69.29; H, 4.00; N, 15.15. MS, m/z (Irel (%)):
277 [M]+ (69), 245 (13), 219 (23). 1H NMR (CDCl3), δ: 6.64
(d, 1 H, H(3), J = 2.0 Hz); 7.15 (s, 1 H, H(4)); 7.60—8.10 (m,
7 H, Ar); 8.20 (d, 1 H, H(2), J = 2.0 Hz); 10.16 (s, 1 H, NH).
IR, ν/cm–1: 3160, 3044, 2984, 2848, 1632, 1524, 1332, 1256.
5ꢀ(2,4ꢀDimethylphenyl)ꢀ2ꢀmethylꢀ6Hꢀpyrazolo[1,5ꢀc]pyriꢀ
midineꢀ7ꢀthione (2c). The yield was 47%, m.p. 217—218 °C
(from benzene—hexane). Found (%): C, 66.73; H, 5.76;
N, 15.53. C15H15N3S. Calculated (%): C, 66.88; H, 5.61;
N, 15.60. MS, m/z (Irel (%)): 269 [M]+ (100), 254 (79), 236
(13), 211 (13). 1H NMR (CDCl3), δ: 2.35, 2.39, 2.54 (all s, 9 H,
3 Me); 6.36 (s, 1 H, H(3)); 6.64 (s, 1 H, H(4)); 7.10—7.30 (m,
3 H, Ar); 10.14 (s, 1 H, NH). IR, ν/cm–1: 3380, 3164, 3108,
3076, 2956, 2844, 1640, 1596, 1528.
7ꢀAminoꢀ5ꢀphenylpyrazolo[1,5ꢀc]pyrimidine (3a). The yield
was 60%, m.p. 156—157 °C (from hexane). Found (%): C, 68.44;
H, 4.82; N, 26.57. C12H10N4. Calculated (%): C, 68.56; H, 4.79;
N, 26.65. MS, m/z (Irel (%)): 210 [M]+ (100), 182 (28), 168
(36), 154 (27), 140 (35). 1H NMR (CDCl3), δ: 6.17 (s, 2 H,
NH2); 6.46 (d, 1 H, H(3), J = 2.0 Hz); 7.31 (s, 1 H, H(4));
7.35—7.55 (m, 3 H, Ph); 8.05 (m, 3 H, Ph, H(2)). IR,
ν/cm–1 (KBr): 3460, 3284, 3192, 3060, 1652, 1608, 1544. IR,
ν/cm–1 (CHCl3): 3520, 3460, 3404, 3300, 3060, 3012, 1648,
1632, 1604, 1540.
7ꢀAminoꢀ5ꢀ(2ꢀnaphthyl)pyrazolo[1,5ꢀc]pyrimidine (3b). The
yield was 42%, m.p. 199—200 °C (from benzene). Found (%):
C, 73.73; H, 4.74; N, 21.45. C16H12N4. Calculated (%): C, 73.83;
H, 4.65; N, 21.52. MS, m/z (Irel (%)): 260 [M]+ (100). 1H NMR
(CDCl3), δ: 6.00 (s, 2 H, NH2); 6.51 (d, 1 H, H(3), J = 2.0 Hz);
7.27 (s, 1 H, H(4)); 7.48 (s, 1 H, H(2)); 7.50, 8.00 (both m, 6 H,
Ar); 8.54 (s, 1 H, oꢀHnapht). IR, ν/cm–1: 3300, 3132, 3048, 1664,
1608, 1560.
7ꢀAminoꢀ5ꢀ(2,4ꢀdimethylphenyl)ꢀ2ꢀmethylpyrazoꢀ
lo[1,5ꢀc]pyrimidine (3c). The yield was 45%, m.p. 202—203 °C
(from benzene). Found (%): C, 71.18; H, 6.54; N, 22.07.
C
15H16N4. Calculated (%): C, 71.40; H, 6.39; N, 22.20. MS,
m/z (Irel (%)): 252 [M]+ (87), 251 [M – H]+ (100), 237 (10), 211
1
(10). H NMR (CDCl3), δ: 2.37, 2.38, 2.49 (all s, 9 H, 3 Me);
6.19 (s, 1 H, H(3)); 6.22 (s, 2 H, NH2); 6.78 (s, 1 H, H(4));
7.08—7.30 (m, 3 H, Ar). IR, ν/cm–1: 3312, 3220, 3096, 2912,
1664, 1608, 1560.
7ꢀAminoꢀ5ꢀ(2,4ꢀdimethylphenyl)pyrazolo[1,5ꢀc]pyrimidine
(3e). The yield was 48%, m.p. 166—167 °C (from benꢀ
zene—hexane). Found (%): C, 70.42; H, 6.04; N, 23.42.
C14H14N4. Calculated (%): C, 70.57; H, 5.92; N, 23.51. MS,
m/z (Irel (%)): 238 [M]+ (100), 237 [M]+ (88). 1H NMR
(CDCl3), δ: 2.38, 2.39 (both s, 6 H, 2 Me); 6.40 (s, 2 H, NH2);
6.42 (d, 1 H, H(3), J = 2.0 Hz); 6.90 (s, 1 H, H(4)); 7.10 (s, 1 H,
H(2)); 7.35 (m, 2 H, Ar); 7.98 (s, 1 H, oꢀHarom). 13C NMR
(CDCl3), δ: 20.3, 21.3, 97.4, 101.9, 126.6, 129.3, 131.6, 135.7,
136.5, 138.2, 142.1, 143.7, 146.8, 149.6. IR, ν/cm–1: 3448, 3284,
3188, 3052, 2956, 1652, 1608, 1548, 1508.
This work was financially supported by the Russian
Academy of Sciences (Basic Research Program of the
Presidium of the Russian Academy of Sciences "Developꢀ

Synthesis of pyrazolo[1,5ꢀc]pyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 5, May, 2007
1031
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Received January 30, 2007;
in revised form February 21, 2007