Chemical reactions of 2-methyl-5,7-diphenyl-6,7-dihydropyrazolo[1,5-a] pyrimidine

Article abstract of DOI:10.1007/s10593-005-0177-5

The hydrolysis, oxidation, reduction, alkylation, formylation, and nitrosation reactions of 2-methyl-5,7-diphenyl-6,7-dihydropyrazolo[1,5-a] pyrimidine have been studied. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0177-5

Chemistry of Heterocyclic Compounds, Vol. 41, No. 4, 2005
CHEMICAL REACTIONS OF
2-METHYL-5,7-DIPHENYL-6,7-DIHYDRO-
PYRAZOLO[1,5-a]PYRIMIDINE
1
2
1
1
2
V. V. Lipson , S. M. Desenko , M. G. Shirobokova , V. V. Borodina , and V. I. Musatov
The hydrolysis, oxidation, reduction, alkylation, formylation, and nitrosation reactions of 2-methyl-5,7-
diphenyl-6,7-dihydropyrazolo[1,5-a]pyrimidine have been studied.
Keywords: dihydropyrimidine system, acylation, alkylation, hydrolysis, reduction, nitrosation,
oxidation.
The dihydropyrimidine system in 2-methyl-5,7-diphenyl-6,7-dihydropyrazolo[1,5-a]pyrimidine 1 is a
convenient model for investigation of the reactivity, chemical stability, and tautomerism of partially
hydrogenated azoloazines. The synthesis of compound 1, its tendency to oxidation in solutions to form a
6
-hydroxy derivative, and the stability of the latter to the action of dehydrating agents have been reported before
[1]. In this work we have studied the hydrolysis, oxidation, reduction, nitrosation, formylation, and alkylation of
the dihydropyrazolo[1,5-a]pyrimidine 1.
Ph
N
Ph
H
N
N
N
N
Ph
O
C
+
Me
Ph
Me
NH2
4
N
N
H
O
Ph
Br2,
NBS
POCl3
2
3
–H O
2
Me
N
H
Ph
+
7
+
H O, H
2
Ph
N
Ph
DMF
Ph
NOH
Ph
N
N
N
N
NaNO2
HOAc
Ph
Me
NaBH4
Me
N
Ph
Ph
O
1
O
Ph
5
HA
Ph
N
N
Ph
H
HB
Ph
HD
HC
N
N
Me
N
H
8
Me
N
Ph
H
6
_
_________________________________________________________________________________________
1
V. Ya. Danilevsky Institute of Endocrine Pathology Problems, Academy of Medicinal Sciences of
2
Ukraine, Kharkov 61002; e-mail: lipson@ukr.net. Institute for Single Crystals, National Academy of Sciences
of Ukraine, Kharkov 61001, Ukraine. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4,
pp. 577-581, April, 2005. Original article submitted September 23, 2002.
4
92
0009-3122/05/4104-0492©2005 Springer Science+Business Media, Inc.

The behavior of compound 1 has been investigated. It is almost completely hydrolyzed to give the
aminopyrazole 2 and unsaturated ketone 3 when heated in hydrochloric acid (1:1) for 30 min.
In the presence of N-bromosuccinimide in alcohol or Br in acetic acid dehydrogenation of the
2
dihydropyrazolopyrimidine 1 to compound 4 occurs, the parameters of which have been previously reported in
[1].
It is known that 4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine in the presence of sodium nitrite in glacial
acetic acid forms a hydroximino derivative [2], in contrast to the dihydropyridines which undergo
heteroaromatization [3] under similar conditions. The dihydropyrazolopyrimidine 1 can also be nitrosated to
form the oxime 5. An absorption band for the –C=C– bond is absent in the IR spectrum of compound 5
1
(
(
Table 1) and this rejects a corresponding N-nitroso derivative structure. The H NMR spectrum of compound 5
Table 2) shows, beside a multiplet for the aromatic protons and singlets for the methyl group and pyrazole ring
methine protons, a singlet for the C(7) proton and a broadened singlet signal for the OH group. As a whole, the
spectrum resembles that of the 2-aza analog of 5, the structure of which was demonstrated by X-ray
investigation [2, 4, 5].
Reduction of the dihydropyrazolopyrimidine 1 with sodium borohydride gives the tetrahydro derivative
6
. Bearing in mind that the molecule of compound 6 has two chiral centers there arises the question of the
1
stereoselectivity of the process of its formation. The answer comes from analysis of the H NMR spectra. The
spectra, including that of the uncrystallized reduction product of 6, show a single isomer and point to the
stereoselectivity of the indicated reaction. Signals for the methine and methylene protons of the
tetrahydropyrimidine ring are identified in it. The assignment of the C(5) and C(7) proton signals was based on a
comparison of these spectra with data [2, 6] for the spectra of the 3-aza analogs of compound 6, according to
which the C(5) proton resonates at higher field. The values of JHB-5H and JHB-7H are 11.1 and 10.9 Hz and are
characteristic of a J type constant and so point to a diequatorial orientation of both phenyl substituents in the
aa
tetrahydropyrimidine ring. Hence compound 6 can be assigned to a trans isomer series.
An attempt to formylate the dihydropyrazolopyrimidine 1 under Vilsmeier conditions (DMF–POCl ) led
3
to formation of the aldehyde 7. The structure of the product 7 was proved by the following spectroscopic data.
-
1
The IR spectrum showed absorption bands for the carbonyl group ν at 1652 cm and a pyrimidine ring
CO
-
1
1
–
C=C– bond at 1620 cm . The presence in the H NMR spectrum (see Table 2) of singlets for the NH and C
(7)
protons and signals for the protons of the pyrazole ring methine, phenyl, methyl, and formyl substituents
unambiguously pointed to formylation at position 6 of the bicycle. It should be noted that dihydropyrazolo-
[1,5-a]pyrimidines, including compound 1, both in solutions and in the solid phase, usually exist in the imine
6
,7-dihydro form [1, 7]. However, in the case of the aldehyde 7 the introduction of an electron-acceptor
substituent at position 6 of the bicycle leads to a complete transfer to the enamine 4,7-dihydro form.
TABLE 1. Parameters for the Compounds Synthesized
Com-
pound
Empirical
formula
Found N, %
Calculated N, %
IR spectrum
(KBr), ν, cm
—
—————
mp, °С
-1
Yield, %
5
6
С
С
19
19
Н
16
18
N
4
3
O
17.75
289*
108*
3300-2500, 1556
3624, 3284,
91
70
1
7.71
Н
N
14.57
4.53
1
3
1
152-2800, 1648,
576
7
8
С
С
20
34
Н
17
29
N
3
3
O
O
13.36
3.32
178-180
179-181
3448, 1652, 1620,
536
3064, 3036, 2908,
684, 1620, 1564
71
52
1
1
Н
N
8.51
.48
8
1
_
*
______
Melted with decomposition.
4
93

1
TABLE 2. H NMR Spectra of Compounds 5-8
6
Chemical shifts, δ, ppm, spin-spin coupling (J, Hz) (DMSO-d )
Com-
pound
NH (OH)
СН
3
(3Н, s)
НAr, m
СН
СН
2
(1H, br. s)
5
6
13.1
7.1-7.7 (10Н)
7.2-7.5 (10Н)
С(3)Н: 6.71 (1Н, s);
С(7)Н: 6.36 (1Н, s)
—
2.14
5.2
С(3)Н: 6.27 (1Н, s);
С(7)Н: 5.25 (1Н, dd,
Н
Н
А
: 2.35 oct,
: 2.03 oct,
1.94
В
J
7А = 5.2, J7В = 10.9);
С(5)Н: 4.56 (1Н, d,
5А = 2.5, J5В = 11.1)
J
АВ = -13.4
J
7
8
10.2
—
7.0-7.5 (10Н)
6.7-8.1 (20Н)
С(Н)О: 9.02 (1Н, s);
С(3)Н: 6.19 (1Н, s);
С(7)Н: 5.91 (1Н, s)
2.63
2.08
—
С(3)Н: 5.94 (1Н, s);
С(7)Н: 5.62 (1Н, s);
Н
С
: 3.94
(1Н, dd,
С(6)Н
: 3.52 (1Н, dd,
АВ = 6.1)
А
:4.10 (1Н, d.d);
J
J
CD = -17.8,
CВ = 7.8);
Н
J
В
H
D
: 3.57
1Н, m*,
DВ = 5.0)
(
J
_
*
______
Partially obscured by the H signals.
B
In the case of dihydropyridines it has been shown that, depending on the conditions for carrying out the
reaction, their alkylation can occur both at a nitrogen and at a carbon atom [8]. We have previously found that
dihydro-1,2,4-triazolo[1,5-a]pyrimidines are alkylated in basic media both by methyl iodide and by
dimethylsulfate exclusively at a pyrimidine ring nitrogen atom [2]. When using analogous reaction conditions
the alkylation of the dihydropyrazolopyrimidine 1 gave a mixture of oily materials which were hard to identify.
However, refluxing of the discussed compound with benzalacetophenone 3 in methanol in the presence of
sodium methylate gave the product 8 which was shown to be 3-(2-methyl-5,7-diphenyl-6,7-dihydropyrazolo-
[
1,5-a]pyrimidin-6-yl)-1,3-diphenylpropanone on the basis of the following spectroscopic data. The IR spectrum
-
1
1
showed an absorption band for νCO at 1684 cm . The H NMR spectrum showed a phenyl substituent multiplet
with an integrated intensity corresponding to 20 protons. In addition, it showed singlets for the pyrazole C and
(
3)
pyrimidine C(7) ring methine protons as well as signals for a four spin system formed by the C H and
(6)
A
CH –CH (CD) protons of the propanone fragment. The absence of a signal for an NH group proton and the
B
2
presence of signals for C H forming an AB system with the propanone fragment methine proton points to the
6
A
existence of compound 8 in the imine 6,7-dihydro form.
EXPERIMENTAL
1
IR spectra were recorded on a Specord M-82 spectrometer for KBr tablets and H NMR spectra on a
Varian-200 (200 MHz) spectrometer using DMSO-d and TMS internal standard. Monitoring of the composition
6
of the reaction mixtures and the purity of the compounds obtained was carried out using TLC on Silufol UV-254
plates with benzene–methanol (10:1) or ethanol–chloroform–hexane (1:1:1) eluent.
Hydrolysis of 2-Methyl-5,7-diphenyl-6,7-dihydropyrazolo[1,5-a]pyrimidine (1). Compound 1
(
0.57 g, 2 mmol) in HCl (1:1, 20 ml) was refluxed for 30 min, neutralized using saturated Na CO solution, and
2 3
extracted with chloroform. The extract was dried over anhydrous Na SO . Removal of solvent gave the
2
4
4
94

benzalacetophenone 3 (0.38 g, 92%); mp 59°C (ethanol) [9]). TLC showed that the aqueous layer after
extraction contained 3-amino-5-methylpyrazole 2 (R 0.44), eluent ethanol–chloroform–hexane, 1:1:1.
f
Oxidation of 2-Methyl-5,7-diphenyl-6,7-dihydropyrazolo[1,5-a]pyrimidine (1). A. A solution of
bromine (0.7 g, 4.4 mmol) in acetic acid (2 ml) was added to a solution of compound 1 (1.15 g, 4 mmol) in
acetic acid (15 ml). The product was stirred for 1 h and the reaction mixture was poured into water and filtered to
give compound 4 (0.98 g, 86%); mp 110-112°C (from 2-propanol) [1].
B. N-Bromosuccinimide (0.62 g, 3.5 mmol) was added to a solution of compound 1 (0.86 g, 3 mmol) in
2
-propanol and refluxed with a reflux condenser for 1 h. Pouring into water, neutralizing with saturated NaHCO3
solution, and filtration gave the product 4 (0.77 g, 90%).
-Hydroximino-2-methyl-5,7-diphenyl-6,7-dihydropyrazolo[1,5-a]pyrimidine (5). Sodium nitrite
6
(
(
0.37 g, 5.3 mmol) was added in about 0.1 g portions to a solution of compound 1 (1.15 g, 4 mmol) in acetic acid
15 ml). At the end of the evolution of gaseous products the reaction mixture was poured into water and filtered
to give compound 5 (1.15 g) which was crystallized from ethanol.
-Methyl-5,7-diphenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (6). NaBH (1.52 g, 40 mmol)
2
4
was added to a suspension of compound 1 (1.15 g, 4 mmol) in methanol (10 ml). At the end of the evolution of
gaseous products the reaction mixture was refluxed with a reflux condenser for 20 min, poured into water, and
filtered to give compound 6 (0.81 g) which was crystallized from methanol.
2
-Methyl-5,7-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carbaldehyde (7). POCl (0.32 ml,
3
3
.5 mmol) was added to a solution of compound 1 (0.86 g, 3 mmol) in DMF (3 ml) at 5-10°C. The reaction
mixture was gradually heated, held on a refluxing water bath for 3 h, poured onto ice, neutralized with 20%
NaOH solution, and filtered to give compound 7 (0.67 g) which was crystallized from methanol.
3
-(2-Methyl-5,7-diphenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)-1,3-diphenylpropanone (8). A
solution of sodium methylate (0.05 g, 2.2 mmol), compound 1 (0.32 g, 1.1 mmol), and benzalacetophenone 3
0.25 g, 1.2 mmol) in methanol (10 ml) was refluxed with a reflux condenser for 2 h. After cooling, the reaction
(
mixture was filtered off to give compound 8 (0.29 g) which was crystallized from ethanol.
This work was carried out with the support of the Ukraine Fund for Fundamental Research (project
No. 0307/00154).
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1
.
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