Intermolecular aza-Wittig reaction: One-step synthesis of pyrazolo[1,5-a]pyrimidine and imidazo[1,2-b]pyrazole derivatives

Article abstract of DOI:10.1002/jhet.5570430301

Pyrazolo[1,5-a]pyrimidine and imidazo[1,2-b]pyrazole derivatives were synthesized via intermolecular aza-Wittig reaction of 5- (triphenylphosphoranylideneamino)-3-phenylpyrazole 3 derived from 5-amino-3-phenylpyrazole with some selected α-chloroketones.

Full text of DOI:10.1002/jhet.5570430301

May-Jun 2006
523
Intermolecular Aza-Wittig Reaction: One-Step Synthesis of
Pyrazolo[1,5-a]pyrimidine and Imidazo[1,2-b]pyrazole Derivatives
Magda A. Barsy* and Eman A. El-Rady
Chemistry Department, Faculty of Science, South Valley University
Aswan - 81528, Egypt.
Received March 30. 2005
N
CH3
R
Ph
N
N
N=PPh3
chloroketones
R'
NH
Ph
N
N
3
R
Ph
N
N
R'
Pyrazolo[1,5-a]pyrimidine and imidazo[1,2-b]pyrazole derivatives were synthesized via intermolecular
aza-Wittig reaction of 5-(triphenylphosphoranylideneamino)-3-phenylpyrazole 3 derived from 5-amino-3-
phenylpyrazole with some selected ꢀ-chloroketones.
J. Heterocyclic Chem., 43, 523 (2006).
In recent years, there has been significant interest in the
chemistry of iminophosphoranes [1-5] because of their utility
in the synthesis of a wide variety of nitrogen heterocycles [6-
8]. The chemistry of 5-amino-pyrazole derivatives and their
use as excellent precursors for the preparation of fused and
isolated pyrazoles have received much attention in the last
few decades [9-17]. However, their use to prepare fused
pyrazolo-pyrimidine ring structure via the 5-iminophos-
phorane derivatives attracted less attention. In the course of
our studies directed toward the synthesis of fused hetero-
cycles [18-22], especially those based on Wittig reaction [23,
24], we now report a mild and facile one-step approach for
the synthesis of new fused pyrazoles.
corresponding pyrazolo[1,5-a]pyrimidine 6 in good yield,
(Scheme 2). The mechanism of the conversion involves
an initial aza-Wittig reaction between the iminophos-
phorane 3 and ꢀ-chloroketone to give 5 as a highly
reactive intermediate, which readily undergoes hetero-
cyclization with loss of water rather than elimination of
hydrogen chloride, to give the fused pyrazolo[1,5-a]-
pyrimidine 6. The mass spectrum of 6 showed the
molecular ions at m/z 259 (M + 2, 23) and at 257 (M+, 70)
showing the characteristics isotope pattern for one
chlorine atom. The 1H NMR spectrum showed one singlet
signal at 2.1 ppm assigned to the six protons of two
methyl groups, and one singlet signal at 6.9 ppm for the
H-4 proton of the pyrazole ring. Similarly, imino-
phosphorane 3 reacted with ꢀ-chloro ethyl acetoacetate 7
Results and Discussion.
The iminophosphorane 3 was prepared very easily
through the classical Staudinger reaction [25] of 5-azido-
to give the pyrazolo[1,5-a]pyrimidinone
9 via the
3-phenylpyrazole
2 with triphenylphosphine in dry
corresponding intermediate 8 which cyclized with loss of
ethanol. The IR spectrum of 9 revealed an absorption
band at v 1690 cm-1 due to a C=O function indicating the
elimination of ethanol rather than elimination of water as
shown in Scheme 2. Furthermore, the 13C NMR spectrum
also showed a signal at 185.6 ppm assigned to the
carbonyl carbon and a signal at 45.4 ppm assigned to the
sp3 C-6 bearing the chlorine atom. Also, iminophos-
phorane 3 easily reacted with ꢀ-chloroacetoacetanilide (2-
chloro-3-oxo-N-phenylbutanamide) 10 to yield the same
methylene chloride at room temperature. The iminophos-
phorane 3 was also prepared by reacting 5-amino-3-
phenylpyrazole 1 with triphenylphosphine and hexa-
chloroethane in the presence of triethylamine according to
Appel's procedure [26], (Scheme 1).
Scheme 1
NH2
N=PPh3
NH
N3
PPh3 / CH2Cl2
Et3N / rt
NaN3 / HCl
0 °C
NH
NH
Ph
Ph
Ph
N
N
N
1
2
3
pyrazolopyrimidinone
9
via loss of aniline from
intermediate 11. However, ethyl acetoacetate 12 itself
afforded the corresponding 6-dihydro-pyrazolo-pyrim-
idinone 14 via intermediate 13 which eliminated ethanol
rather than water, (Scheme 2). The structure of 14 is
supported by its molecular ion at m/z 225 (100 %), an
PPh3 / hexachloroethane / Et3N
dry benzene / reflux 2 h
The reaction of compound 3 with ꢀ-chloroacetyl-
acetone 4 in dry toluene at reflux temperature gave the

524
M. A. Barsy and E. A. El-Rady
Vol 43
intense carbonyl absorption at v 1695 cm-1, the 13C
resonance for the methylene carbon at 32.2 ppm and for
the carbonyl group at 187.1 ppm as well as the 1H signals
at 1.3 and 2.4 ppm for the methyl and the methylene
groups.
However, reaction of 3 with ethyl-2-chloro-3-oxo-2-
phenylazobutanoate 15, (Scheme 3) yielded the new
oligo-substituted 6-chloro-7-ethoxy-5-methyl-2-phenyl-
pyrazolo[1,5-a]pyrimidine 18. It appears that a conden–
sation step yielded the intermediate 16 via elimination of
triphenylphosphine oxide, followed by a nucleophilic
attack of pyrazole N-1 on the carbonyl carbon affording
the cyclic intermediate 17.
On the other hand, reaction of iminophosphorane 3 with
2-chloro-2-phenylacetophenone 19a, chloroacetylchloride
19b and ꢁ-chloro-ꢁ-phenylazoacetone 19c afforded the
imidazo[1,2-b]pyrazole derivatives 21a-c via elimination
of hydrogen cholride from the initially formed
intermediate 20, (Scheme 4). The mass spectra of 21a (R
= Ph) showed m/z at 335 (M+, 9), of 21b (R = Cl) at 219
(M + 2, 6) and of 21c at 301 (M+, 20).
Also the pyrazolo[1,5-a]pyrimidine ring structure 24
was obtained when compound
3 reacted with ꢁ-
cyanoacetophenone 22 via a nucleophilic addition of the
pyrazole N-1 to the cyano function of intermediate 23.
The IR spectrum of 24 showed the lack of a cyano group
Scheme 2
CH3
N
CH3
Cl
N
-H2O
4 CH3COCHClCOCH3
Ph
Cl
CH3
N
NH
HO
toluene / Et3N
Ph
N
N
reflux / 2h
CH3
N
6
5
CH3
CH3
N
7 CH3COCHClCO2Et
-EtOH
Cl
O
Ph
N
NH
toluene / Et3N
reflux / 3h
N
Cl
Ph
N
OEt
O
8
9
3
CH3
N
-PhNH2
10 CH3COCHClCONHPh
Cl
O
NH
toluene / Et3N
reflux / 2.5h
Ph
Ph
N
N
NHPh
11
N
O
CH3
CH3
N
Ph
12 CH3COCH2CO2Et
-EtOH
N
N
NH
OEt
toluene / Et3N
reflux / 3h
O
14
13
but exhibited an absorption band at v 3320 cm-1 due to the
NH2 function. The mass spectrum of 24 showed the
molecular ion as the base peak at m/z 286 (100 %).
Subsequent elimination of phenyldiazonium hydroxide
finally yielding the pyrazolo[1,5-a]pyrimidine 18.
In contrast, it was expected that the reaction of 3 with
phenacylbromide 25 would afford the imidazolopyrazole
27. However, based on the spectral data this assumption
had to be ruled out. The mass spectrum of the product
showed m/z at 537 (30 %). The IR spectrum revealed an
intense absorption band at v 1701 cm-1 assigned to an
Scheme 3
CH3
N=PPh3
O
O
N
CH3
N=NPh
Cl
OEt
Ph
+
Ph
N=NPh
Cl
NH
NH
N
N
O
OEt
3
15
16
1
acyclic carbonyl group. The H NMR spectrum showed
several multiplets at ꢀ 7.1-7.8 and a singlet signal at ꢀ
4.3 ppm for two protons. Thus, structure 26 was
suggested as the reaction product, which seemed
thermodynamically stable, insoluble in most organic
solvents and remain unreacted. This may be due to the
steric hindrance as was previously observed for the aza-
Wittig cyclization of lactam carbonyl groups [27].
It should be noted that the C-Cl bond in intermediates 5,
8 and 11 is strong enough and elimination of water,
ethanol or aniline is highly favoured over the elimination
N
CH3
N
CH3
Cl
Ph
Ph
N=NPh
Cl
-PhN=NOH
N
N
N
N
OH
EtO
OEt
18
17
The mass spectrum of 18 showed m/z at 289 (M + 2, 2),
and the H NMR revealed the characteristic absorption
pattern of ethoxy protons at ꢀ 1.3 and 3.5 ppm in support
1
for the proposed pathway in Scheme 3.

May-Jun 2006
Intermolecular Aza-Wittig Reaction
525
9.5 (s, 1H, NH); m/z (%): 419 (M+, 91), 265 (5), 183(100), 157
(6), 108 (50).
Anal. Calcd. for C27H22N3P: C, 77.31; H, 5.29; N, 10.02.
Found: C, 77.61; H, 5.48; N, 10.13.
of hydrogen chloride even in the presence of
triethylamine unless there is no other option such as in the
case of formation of 21.
Reaction of Iminophosphorane 3 with Ketones.
General Procedure.
Scheme 4
R
O
N
N
R
Cl R'
-HCl
R
To a solution of iminophosphorane 3 ( 419 mg, 1.0 mmol) in
20 mL dry toluene the appropriate ketone (1.0 mmol) and
triethylamine (0.2 mL, 2 mmol) were added, and the reaction
mixture was refluxed for 5 h. After cooling the solid that
precipitated was separated by filtration, dried and recrystallized
from proper solvent.
Ph
Ph
N
NH
N
19a-c
N
Cl R'
R'
21 a, R = R' = Ph
b, R = Cl, R' = H
c, R = CH, R' = (-N=NPh)
20
Ph
O
N
Ph
N
NH
Ph
Ph
CN
22
Ph
Ph
N
6-Chloro-2-phenyl-5,7-dimethylpyrazolo[1,5-a]pyrimidine (6).
3
N
N
NC
NH2
Colourless crystals from methanol (0.18 g, 70 %), mp >300
1
°C; H NMR (DMSO) ꢀ: 2.1 (s, 6H, 2 CH3), 6.9 (s, 1H, CH-
pyrazole), 7.4-7.9 (m, 5H, Ar-H); m/z (%) 259 (M + 2, 23), 257
(M+, 70), 242 (15), 227(19), 191 (6), 114 (50).
Anal. Calcd. for C14H12ClN3: C, 65.25; H, 4.69; N, 16.30; Cl,
13.76. Found: C, 65.47; H, 4.89; N, 16.76; Cl, 13.69.
24
23
Ph
O
N=PPh3
O
N
Ph
Ph
25 Br
N
N
N
N
Ph
26
27
6-Chloro-5-methyl-2-phenyl-6H-pyrazolo[1,5-a]pyrimidin-7-
one (9).
EXPERIMENTAL
Colourless crystals from methanol (0.17 g, 66 %), mp 340 °C;
1
IR: v 1690 (CO) cm-1; H NMR (DMSO) ꢀ : 1.9 (s, 3H, CH3),
Preparation of 5-(triphenylphosphoranylideneamino)-3-phenyl-
pyrazole (3).
3.8 (s, 1H, 6-H), 7.1-7.8 (m, 6H Ar-H); 13C NMR: 185.6 (C=O),
144.7 (C-3a), 142.5 (C-2), 140.6 (C-5), 138.7 (C-3), 128-135 (C-
Phenyl), 45.4 (C-6), 18.3 (CH3). m/z (%) 261 (M + 2, 34), 259
(M+, 100), 225 (14), 169 (8), 183 (6).
Anal. Calcd. for C13H10ClN3O: C, 60.12; H, 3.88; N, 16.18;
Cl, 13.65. Found: C, 60.22; H, 3.79; N, 16.25; Cl, 13.47.
Method A.
5-Amino-3-phenylpyrazole 1, (90 mg, 0.57 mmol), hexa-
chloroethane (134 mg, 0.57 mmol, 1.0 equiv.) and triphenyl-
phosphine (150 mg, 0.57 mmol, 1.0 equiv.) were dissolved in
5.0 mL anhydrous benzene and stirred for 10 minutes.
Triethylamine 0.16 mL, (1.15 mmol, 2.0 equiv.) was added
dropwise over 5 minutes with stirring and the reaction mixture
was kept at reflux for 2 hours. After cooling, the solid formed
was filtered off and the mother liquor was concentrated under
vacuum and the residue was subjected to column chromato-
graphy using mixture of ethylacetate / hexane (1:2, v/v) as eluent
to afford 3 (0.18 g, 77 %).
5-Methyl-2-phenyl-6-dihydropyrazolo[1,5-a]pyrimidin-7-one
(14).
Colourless crystals from methanol (0.18 g, 80 %), mp 310 °C;
1
IR : v 1695 (C=O) cm-1; H NMR (DMSO) ꢀ: 1.3, (s, 3H, CH3),
2.4 (s, 2H, CH2), 7.1-7.9 (m, 6H Ar-H); 13C NMR: 187.1 (C=O),
147.1 (C-3a), 141.1 (C-2), 140.1 (C-5), 136.9 (C-3), 128-133 (C-
Phenyl), 32.2 (C-6), 17.2 (CH3). m/z (%) 225 (M+, 100), 169
(38), 168 (30), 145 (11), 102 (22).
Method B.
Anal. Calcd. for C13H11N3O: C, 69.32; H, 4.92; N, 18.66.
Found: C, 69.44; H, 4.45; N, 18.77.
A sample (630 mg, 3.96 mmol) of the amine 1 was dissolved
in a mixture of water (4.5 mL) and conc. H2SO4 (0.8 mL) and
cooled to 0 °C. A cooled solution of NaNO2 (350 mg, 5.2 mmol)
in 3.2 mL of water was added dropwise and the reaction mixture
was stirred at 0 °C for 30 min. Then a cooled solution of sodium
azide (470 mg, 7.3 mmol) in 3 mL of water was added with
stirring and the mixture was kept in a refrigator for 12 hours.
The solid formed was separated by filtration to give the azide 2
which was crystallized from methylene chloride to give (151
mg, 82 %) of colourless crystals, mp 127 °C. The azide 2 (170
mg, 0.93 mmol) was dissolved in 10 ml of dry methylene
chloride and then added dropwise to a solution of 10 mL of dry
methylene chloride containing 240 mg of triphenylphosphine
(0.93 mmol) at room temperature under nitrogen and the mixture
was stirred for one hour. The solid product was collected by
filtration and crystallized from ethyl acetate as colourless
crystals, mp 198-200 °C; IR: ꢀ 3134 cm-1 (NH); 1H NMR
(DMSO) ꢀ: 6.8 (s, 1H, CH-pyrazole), 7.1-7.9 (m, 20H, Ar-H),
6-Chloro-7-ethoxy-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine
(18).
Colourless crystals from ethylacetate/methanol (0.22 g, 77
1
%), mp 220 °C; H NMR (DMSO) ꢀ : 1.3 (t, 3H, CH3), 2.2 (s,
3H, CH3), 3.5 (q, 2H, CH2), 7.1-7.8 (m, 6H, Ar-H); m/z (%) :
289 (M + 2, 2), 287 (M+, 5), 259 (50), 225 (100), 196 (37).
Anal.Calcd. for C15H14ClN3O: C, 62.61; H, 4.90; N, 14.60;
Cl, 12.32. Found: C, 62.75; H, 4.99; N, 14.97; Cl, 12.45.
2,3,6-Triphenyl-3H-imidazo[1,2-b]pyrazole (21a).
Buff crystals from ethyl acetate, (0.25 g, 75 %), mp 270 °C;
1H NMR (DMSO) ꢀ: 5.6 (s, 1H, 3-H), 6.8-7.9 (m, 16H, Ar-H);
m/z (%): 335 (M+, 9), 313 (13), 286 (12),
225 (8).
Anal. Calcd. for C23H17N3: C, 82.36; H, 5.11; N, 12.53.
Found: C, 82.47; H, 5.25; N, 12.64.

526
M. A. Barsy and E. A. El-Rady
Vol 43
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[4] P. Molina, J. Alcantara, C. Lopez-leonardo, Tetrahedron, 53,
2-Chloro-3-dihydro-6-phenylimidazo[1,2-b]pyrazole (21b).
Colourless crystals from ethyl acetate/methanol (2:1), (0.17 g,
1
78 %), mp 220 °C; H NMR (DMSO) ꢀ : 3.6 (s, 2H, CH2), 7.1-
3281 (1997).
7.8 (m, 6H, Ar-H); m/z (%) : 219 (M + 2, 6), 217 (M+, 20), 140
(15), 104 (12).
[5] P. Molina, A. Arques, A. Alias, M. C. Foces-Foces, A. Luis,
J. Chem. Res. (S), 424 (1994).
[6] T. Okawa, M. Toda, S. Eguchi, A. Kakehi, Synthesis, 1467
(1998).
[7] T. Sugimori, T. Okawa, S. Eguchi, A. Kakehi, E. Yashima,
Y. Okamoto, Tetrahedron, 54 (1998).
Anal. Calcd for C11H8N3Cl: C, 60.70; H, 3.70; N, 19.31; Cl,
16.29. Found: C, 60.95; H, 3.69; N, 19.45; Cl, 16.38.
2-Methyl-6-phenyl-3-phenylazo-3H-imidazo[1,2-b]pyrazole (21c).
[8] H. Poschenrieder, H. Stachel, J. Heterocyclic Chem., 32,
1457 (1995).
[9] E. A. A. Hafez, N. M. Abed, M. R. H. Elmoghayar, A. G. A.
El-Agamey, Heterocycles, 22, 1821 (1984) and the references therein.
[10] M. H. Elnagdi, D. H. Fleita, M. R. H. El-Moghayar,
Tetrahedron, 31, 63 (1975).
[11] M. H. Elnagdi, E. M. Zayed, M. A. E. Khalifa, S. A. S.
Ghozlan, Monatsch, Chem., 112, 245 (1981).
[12] E. A. A. Hafez, N. M. Abed, I. A. El Sakka, M. H. Elnagdi, J.
Heterocyclic Chem., 20, 285 (1983).
[13] K. U. Sadek, M. A. Selim, M. A. El-Maghraby, J. Chem.
Engineering Data, 30, 514 (1985).
[14] Z. E. Kandeel, A. M. Farag, A. M. Negm, A. K. Khalafalla,
M. A. M. Rasslan M. H. Elnagdi, J. Chem. Res. (S), 416 (1994).
[15] A. M. Farag, Z. E. Kandeel, M. H. Elnagdi, J. Chem. Res.
(S), 10 (1994).
Colourless crystals from ethyl acetate/methanol (0.26 g, 86
1
%), mp 210 °C; H NMR (DMSO) ꢀ: 2.1 (s, 3H, CH3), 5.9 (s,
1H, 3-H), 7.1-7.9 (m, 11H, Ar-H and 7-H); m/z (%): 301 (M+,
20), 286 (45), 209 (30), 181 (35).
Anal. Calcd. for C18H15N5: C, 71.74; H, 5.02; N, 23.24.
Found: C, 71.86; H, 5.15; N, 23.37.
7-Amino-2,5-diphenylpyrazolo[1,5-a]pyrimidine (24).
Colourless crystals from ethyl acetate (0.20 g, 70 %), mp 265
1
°C; IR: v 3320 cm-1 (NH2); H NMR (DMSO) ꢀ: 7.1-7.9 (m,
12H, Ar-H), 9.1 (s, 2H, NH2); m/z (%): 286 (M+, 100), 248 (10),
143 (5), 128 (3) 102 (11).
Anal. Calcd. for C18H14N4: C, 75.50; H, 4.93; N, 19.57.
Found: C, 75.65; H, 4.74; N, 19.66.
[16] Z. E. Kandeel, J. Chem. Res. (S), 290 (1995).
[17] B. Al-Saleh, M. M. Abdel-Khalik, A. Al-Enzy, M. H.
Elnagdi, J. Chem. Res. (S), 654 (1999).
5-(Triphenylphosphoranylideneamino)-1-(2-oxo-2-phenylethyl)-
3-phenylpyrazole (26).
Colorless crystals from ethyl acetate (0.42 g, 78 %), mp 240
1
[18] F. M. Abd El Latif, M. A. Barsy, E. A. El Rady, M. E.
Hassan, M. A. El Maghraby, Synthetic Commun., 31(17), 2569 (2001).
[19] M. A. Barsy, F. M. Abd El Latif, S. M. Ahmed, M. A. El-
Maghraby, Phosphorus, Sulfur and Silicon, 165, 1 (2000).
[20] M. H. Elnagdi, M. A. Barsy, F. M. Abd El Latif, K. U.
Sadek, J. Chem. Res (S), 26 (1998).
[21] M. A. Barsy, J. Chin. Chem. Soc., 47, 951 (2000).
[22] F. M. Abd El Latif, M. A. Barsy, E. A. El-Rady, M. E.
Hassan, J. Chem. Res. (S), 696 (1999).
°C; IR : v 1701 cm-1 (C=O) H NMR (DMSO) ꢀ: 4.3 (s, 2H,
CH2), 7.1-7.8 (m, 26H, Ar-H); m/z (%): 537 (M+, 30), 430 (15),
262 (50), 183 (75).
Anal. Calcd. for C35H28N3OP: C, 78.20; H, 5.25; N, 7.81.
Found: C, 78.32; H, 5.37; N, 7.29.
Acknowledgement.
The author is indebted to the Royal Society of Chemistry,
Awards and Lectureships International Affairs for funding this
research.
[23] M. A. Barsy, E. A. El Rady, M. E. Hassan, F. M. Abd El
Latif, Heterocyclic Commun., 6, 545 (2000).
[24] M. A. Barsy, J. Chin. Chem. Soc., 50, 1189 (2003).
[25] H. Staudinger, J. Meyer, Helv. Chim. Acta., 2, 635 (1919).
[26] R. Appel, R. Kleistuk, K. D. Ziehn, F. Knoll, Chem. Ber.,
103, 3631 (1970).
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