Synthesis of N-alkylated derivatives of pyrazolo[1,5-a]-pyrimidine and their reaction with methylamine

Article abstract of DOI:10.1023/A:1019517414682

With the object of studying the factors influencing the course of enamine rearrangements, we have carried out the N-alkylation of alkyl- and aryl-substituted pyrazolo[1,5-a]pyrimidines. Using the NOEDIF NMR spectroscopic method for the cases of 5,7-dimeth

Full text of DOI:10.1023/A:1019517414682

Chemistry of Heterocyclic Compounds, Vol. 38, No. 5, 2002
SYNTHESIS OF N-ALKYLATED
a
DERIVATIVES OF PYRAZOLO[1,5- ]-
PYRIMIDINE AND THEIR REACTION
WITH METHYLAMINE
G. G. Danagulyan1, G. A. Panosyan2, and A. P. Boyakhchyan1
With the object of studying the factors influencing the course of enamine rearrangements, we have
carried out the N-alkylation of alkyl- and aryl-substituted pyrazolo[1,5-a]pyrimidines. Using the
NOEDIF NMR spectroscopic method for the cases of 5,7-dimethyl-2-phenyl- and
2,5,7-triphenylpyrazolo[1,5-a]pyrimidines it was found that addition of the alkyl group occurs at the
N(4) atom of the pyrimidine fragment in the pyrazolo[1,5-a]pyrimidine. It was shown that, when
reacting with an alcoholic solution of methylamine, the 5,7-dimethyl-2-phenyl- and
2,5,7-triphenylpyrazolo[1,5-a]pyrimidine
iodomethylates
undergo
decomposition
to
give
5-methylamino-3-phenylpyrazole and 5-(1,3-diphenyl-3-methylamino-2-propenylid-1-ene)amino-3-
phenylpyrazole.
Keywords: iodoalkylates, methylamine, pyrazolo[1,5-a]pyrimidine, destruction, NOEDIF method,
rearrangement, NMR.
It is known that carrying out enamine rearrangements in the pyrimidine series generally requires
activation of the heterocycle towards nucleophilic attack. In the case of substituted 2-alkylpyrimidines this is
achieved by alkylation, i.e. conversion of the recycled models to the pyrimidinium salts [1-5]. Attempts to
rearrange several condensed pyrimidine systems containing a bridged nitrogen atom (e.g. pyrazolo[1,5-a]-
pyrimidines) have needed activation of the molecule via introduction into the pyrimidine fragment of a powerful
electron acceptor like the nitro group [6].
Our experiments have shown that pyrazolo[1,5-a]pyrimidines, containing alkyl or aryl groups in the
pyrimidine nucleus do not rearrange under the action of various nucleophiles. Hence heating 5,7-dimethyl-,
5,7-dimethyl-2-phenyl, 2,5,7-triphenyl-, and 5-methyl-7-phenylpyrazolo[1,5-a]pyrimidines in alcoholic sodium
ethylate solution or in alcoholic or aqueous-alcoholic solutions of potassium hydroxide, triethylamine, and
methylamine do not yield the rearranged recyclization product and the starting materials are returned
unchanged.
Continuing our study of the factors which influence the course of enamine rearrangements, we resolved
to study the potential activation towards nucleophilic attack of alkyl- and aryl-substituted pyrazolo[1,5-a]-
pyrimidines via N-alkylation of the biheterocycle. Hence we attempted to use the same system activation step as
__________________________________________________________________________________________
1
Institute of Organic Chemistry, National Academy of Sciences, Yerevan 375094, Armenian Republic;
e-mail: gdanag@email.com. 2 Center of Molecular Structure Investigation, National Academy of Sciences, Yerevan
375014, Armenian Republic. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 665-669, May,
2002. Original article submitted December 13, 1999.
0009-3122/02/3805-0581$27.00©2002 Plenum Publishing Corporation
581

in the example of the non condensed pyrimidines. It was expected that quaternization of the nitrogen would lead
to the formation of a strongly electron acceptor center and this might make easier the opening of the pyrimidine
ring with the possibility of rearrangement.
Treatment of 3-amino-5-phenylpyrazole with acetylacetone and with dibenzoylmethane gave the
5,7-dimethyl-2-phenyl- and 2,5,7-triphenylpyrazolo[1,5-a]pyrimidines 2a,b which were converted to the
corresponding N-alkyliodides by reaction with methyl- and ethyl iodides. Such an alkylation could occur
ambiguously since there are several possible centers for attack. Information about the alkylation of
pyrazolo[1,5-a]pyrimidines is absent in the literature. However, since the bridging nitrogen atom is evidently
not favored towards reaction with nucleophiles (its free electron pair is involved in the conjugative formation of
the aromaticity of the system), the targets for electrophilic attack by the alkyl group can be either of the other
N(1) and N(4) atoms of the pyrazole or the pyrimidine rings and this could lead to the formation of compounds 3
or 4. The structure of the synthesized materials, and hence the direction of attack of the alkyl group, was proved
1
by H and 13C NMR spectroscopy and included the use of the double resonance methods NOEDIF and
2D-HETCOR (HMQC). It was found that the NOEDIF method unambiguously shows the position of the
+
N-methyl group. Hence irradiation at the N–Me frequency (δ 4.30 ppm) caused an NOE (nuclear Overhauser
effect) on the 3-H and 5-methyl group protons and this uniquely shows that addition of the methyl group was at
pyrimidine N(4) to give the salt 3a.
A similar picture was also noted in a study of the methylation product of the 2,5,7-diphenyl derivative.
NOEDIF experiments showed that irradiation of the N-methyl group gave a positive NOE at the singlet signal
for proton 3-H and the doublet signal for the ortho protons of one of the phenyl groups. This is only possible
when the reaction occurs at the pyrimidine ring nitrogen atom to give the salt 3b.
Ph
R1
+
N
R
N
N
_
I
Ph
R
Ph
N
R
3a–c
R1I
CH2(COR)2
N
N
N
N
H
NH2
R
+
2a,b
1
Ph
N
R1
+ N
N
_
I
R
R
4a–c
2–4 a R = R1 = Me; b R = Ph, R1 = Me; c R = Me, R1 = Et
We have also studied the behavior of the synthesized salts with an alcoholic solution of methylamine,
i.e. under the conditions for the rearrangement of pyrimidinium salts [1, 2, 5]. It was found that the reaction of
compound 3a with methylamine gives 5-methylamino-3-phenylpyrazole 5 together with some of the product of
demethylation of the salt 2a and the aminopyrazole 1. Reaction of the triphenyl derivative 3b with the same
solution gave the aminopyrazoles 1 and 5 together with the demethylation product and also the acyclic adduct 6
which is obtained upon opening of the pyrimidine ring. In both cases the recyclization products were not
observed.
582

Ph
Ph
2a
+
1
+
+
R = Me
N
N
N
H
5
NHMe
MeNH2
3a,b
1
5
2
+
+
N
H
N
R = Ph
MeHN
Ph
Ph
6
Hence quaternization of the nitrogen atom in the pyrimidine ring leads to opening of the ring but,
evidently, the low nucleophilicity of the pyrazole ring hinders the recyclization. As a result, destruction of the
pyrimidine fragment occurs to give the aminopyrazole derivative. A similar picture was noted previously with
attempts to rearrange the unsubstituted pyrazolo[1,5-a]pyrimidine and also in the reaction of substituted
1,2,4-triazolo[4,3-a]pyrimidine with base where we isolated the destruction rather than the rearranged products
[6, 7].
EXPERIMENTAL
NMR spectra were taken on a Varian Mercury 300 (300 MHz) spectrometer within the terms of the US
CRDF RESC 17-5 program. TLC was performed on Silufol UV-254 plates in the system benzene–acetone (3:1)
and visualized using iodine vapor. Preparative separation was carried out on L 5/40 silica gel.
a
Acetylacetone (0.5 g, 0.005 mol) and glacial
5,7-Dimethyl-2-phenylpyrazolo[1,5- ]pyrimidine (2a).
acetic acid (3-4 drops) were added to a solution of 5-amino-3-phenylpyrazole [8] (0.8 g, 0.005 mol) in absolute
ethanol (20 ml). After 10 min a white crystalline precipitate was formed. The mixture was allowed to stand for a
further 1 h. Yield 1 g (90%) of compound 2a; mp 169-170°C (alcohol), Rf 0.57 (benzene–acetone, 4:1).
1H NMR spectrum (DMSO-d6), δ, ppm, J (Hz): 2.5 (3H, s, CH3); 2.76 (3H, s, CH3); 6.68 (1H, s, 6-H); 6.81 (1H,
s, 3-H); 7.35 (1H, m, 4'-H); 7.42 (2H, m, 3'- and 5'-H); 7.98 (2H, d, J = 7.2, 2'- and 6'-H). Found, %: C 75.50;
H 5.99; N 18.53. C14H13N3. Calculated, %: C 75.34; H 5.83; N 18.83.
a
A mixture of 5-amino-3-phenylpyrazole
2,5,7-Triphenylpyrazolo[1,5- ]pyrimidine (2b).
1
(0.8 g,
0.005 mol), dibenzoylmethane (1.12 g, 0.005 mol), absolute ethanol (30 ml), and glacial acetic acid (1 ml) was
refluxed for 12 h to give 1.2 g (70%) of the bright-yellow, powdery substance with mp 161-162°C (ethanol),
Rf 0.85 (benzene–acetone, 3:1). 1H NMR spectrum (CDCl3), δ, ppm: 7.1 (1H, s, 6-H); 7.38 (1H, s, 3-H); 7.4-7.65
and 8.1-8.25 (15H, m, C6H5). Found, %: C 82.73; H 4.70; N 11.79. C24H17N3. Calculated, %: C 82.99; H 4.98;
N 12.10.
a
A
mixture of the
5,7-Dimethyl-2-phenylpyrazolo[1,5- ]pyrimidine Iodomethylate (3a).
pyrazolopyrimidine 2a (0.56 g, 0.0025 mol) and methyl iodide (2 ml) was heated in a sealed ampule on a water
bath for 12 h. The precipitated iodomethylate was filtered off and washed on the filter with ether to give 0.9 g
1
(99%) of the light-yellow powdery substance with mp above 300°C. H NMR spectrum (DMSO-d6), δ, ppm,
J (Hz): 2.94 (3H, s, 5-CH3); 3.05 (3H, s, 7-CH3); 4.30 (3H, s, N–CH3); 7.52 (3H, m, 3'-, 4'-, and 5'- H); 7.60 (1H,
13
br. s, 6-H); 7.85 (1H, s, 3-H); 8.13 (2H, dd, J1 = 7.8, J2 = 1.9, 2'- and 6'-H). C NMR spectrum (DMSO-d6,
583

75.46 MHz), δ, ppm: 16.71 (7-CH3); 19.60 (5-CH3); 39.5 (N–CH3); 90.46 (C-3); 109.24 (C-6); 126.12
(C1-ortho); 128.33 (C1-meta); 129.72 (C1-para); 129.79 (C1-ipso); 141.71, 153.89, 156.69, 159.43 (C-2, C-3a,
C-7, C-5). Found, %: C 49.05; H 4.31; N 11.28. C14H13N3·CH3I. Calculated, %: C 49.33; H 4.42; N 11.51.
a
A mixture of the pyrazolopyrimidine
2,5,7-Triphenylpyrazolo[1,5- ]pyrimidine Iodomethylate (3b).
2b (0.7 g, 0.002 mol) and methyl iodide (3 ml) was heated in a sealed ampule for 20 h. The precipitated
iodomethylate was filtered off and washed on the filter with ether to give 0.7 g (71%) of the dark-red colored
crystals with mp 212°C. 1H NMR spectrum (CDCl3), δ, ppm: 4.35 (3H, s, CH3N); 7.29 (1H, s, 6-H); 7.53 (1H, s,
3-H); 7.5-8.37 (15H, m, Ph). Found, %: C 61.59; H 4.21; N 8.48. C24H17N3·CH3I. Calculated, %: C 61.36;
H 4.12; N 8.59.
a
A
mixture of the
5,7-Dimethyl-2-phenylpyrazolo[1,5- ]pyrimidine Iodoethylate (3c).
pyrazolopyrimidine 2a (0.22 g, 0.001 mol) and ethyl iodide (4 ml) was heated at 90-100°C in a sealed ampule
for 40 h. The precipitated iodoethylate was filtered off and washed on the filter with ether to give 0.35 g (92%)
of the light-brown crystals not melting below 300°C. 1H NMR spectrum (DMSO-d6), δ, ppm, J (Hz): 1.58 (3H,
t, J = 7.2, CH3CH2N); 2.98 (3H, s, 7-CH3); 3.03 (3H, s, 5-CH3); 4.78 (2H, q, J = 7.2, CH3CH2N); 7.46-7.59 (3H,
m, 3'-, 4'-, and 5'-H); 7.62 (1H, s, 6-H); 7.93 (1H, s, 3-H); 8.15 (2H, dd, J1 = 7.9, J2 = 1.6, 2'- and 6'-H).
Found, %: C 50.43; H 4.51; N 10.98. C14H13N3·C2H5I. Calculated, %: C 50.67; H 4.78; N 11.08.
a
Reaction of 5,7-Dimethyl-2-phenylpyrazolo[1,5- ]pyrimidine Iodomethylate (3a) with
Methylamine. A mixture of the iodomethylate 3a (0.37 g, 0.001 mol) and an ethanol solution of methylamine
(15%, 12 ml) was heated in a sealed ampule on a water bath for 15 h. Solvent was removed at reduced pressure
and the residue was washed with hot hexane (3×20 ml). Crystalline 5-methylamino-3-phenylpyrazole 5
1
precipitated from the hexane solution (0.08 g, 46%); mp 121-122°C. H NMR spectrum (CDCl3), δ, ppm: 2.93
(3H, d, CH3NH); 4.75-5.4 (2H, br. s, NH); 5.90 (1H, s, 4-H); 7.31-7.55 (5H, m, C6H5). Found, %: C 69.09;
H 6.28; N 24.11. C10H11N3. Calculated, %: C 69.34; H 6.40; N 24.26.
The hexane solution remaining after the separation of the pyrazole was placed on a column (hexane–
ethyl acetate, 4:1) to give the pyrazolopyrimidine 2a (0.05 g, 23%) with Rf 0.68 (benzene–acetone, 3:1) and
3-amino-5-phenylpyrazole 1 (0.02 g, 13%) with Rf 0.4 (benzene–acetone, 1:1). These two materials were
identical to known samples in their melting point and chromatographic mobility.
a
A
Reaction of 2,5,7-Triphenylpyrazolo[1,5- ]pyrimidine Iodomethylate (3b) with Methylamine.
mixture of the iodomethylate 3b (0.2 g, 0.0004 mol) and an alcohol solution of methylamine (15%, 6 ml) was
heated in a sealed ampule on a water bath for 20 h. Solvent was removed at reduced pressure and the residue
was washed with hot hexane and chromatographed on a column (benzene–acetone, 8:1) to give compound 2b
(0.07 g, 50%); mp 161°C and Rf 0.83 (benzene–acetone, 3:1), compound 6 (0.02 g, 13%) with Rf 0.74, the
methylaminopyrazole 5 (0.1 g, 14%); mp 121°C and Rf 0.12, and the aminopyrazole 1 (0.01 g, 17%); Rf 0.4
(benzene–acetone, 1:1).
1H NMR spectrum of compound 6 (CDCl3), δ, ppm: 2.95 (3H, d, CH3NH); 4.18 (1H, q, NHCH3); 5.79
(1H, s, CH=); 7.39-7.91 (16H, m, 3- and 4-H, C6H5); 11.33 (1H, br. s, NH). Found, %: C 79.09; H 5.63;
N 14.67. C25H22N4. Calculated, %: C 79.34; H 5.86; N 14.80.
Compounds 1, 2b, and 5 were identical in chromatographic mobility and in melting point with known
samples.
This work was carried out as a joint project with the financial support of the Armenian National Fund
for Science and Advanced Technology and the US Fund for Civic Research and Development (NFSAT RA-US
CRDF, grant ACH 006-98/ACI-955) together with the Armenian Republic State Centralizing Financing Grant
96-559.
The authors thank Professor Alan. R. Katritzky (Florida University, USA) for his support and
collaboration.
584

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