A convenient synthesis of pyrazolidine and 3-amino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one

Article abstract of DOI:10.1002/jhet.5570380310

A convenient four-step synthesis of the aminobicyclopyrazolone hydrochloride 1·HCl was achieved starting from di-tert-butyl hydrazodiformate (8). The route entails cyclization of 8 with 1,3-dibromopropane under phase transfer conditions followed by deprotection of 1,2-di-tert-butoxycarbonylpyrazolidine (9) to give pyrazolidine hydrochloride (2·HCl). Cyanoacetylation of the latter and ring closure of the resulting cyanoacetyl pyrazolidine (7) gave 1·HCl. This novel synthesis circumvents distillation of pyrazolidine (2) and flash chromatography to provide the hydrochloride of 1 in 35-46% overall yields compared to 6% yield for the patent procedure.

Full text of DOI:10.1002/jhet.5570380310

May-Jun 2001
A Convenient Synthesis of Pyrazolidine and
613
3
-Amino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one
Eric E. Boros,* Frédéric Bouvier, Sab Randhawa and Michael H. Rabinowitz
GlaxoSmithKline Research & Development, Five Moore Drive, Research Triangle Park, North Carolina 27709
Received November 6, 2000
A convenient four-step synthesis of the aminobicyclopyrazolone hydrochloride 1•HCl was achieved start-
ing from di-tert-butyl hydrazodiformate (8). The route entails cyclization of 8 with 1,3-dibromopropane
under phase transfer conditions followed by deprotection of 1,2-di-tert-butoxycarbonylpyrazolidine (9) to
give pyrazolidine hydrochloride (2•HCl). Cyanoacetylation of the latter and ring closure of the resulting
cyanoacetyl pyrazolidine (7) gave 1•HCl. This novel synthesis circumvents distillation of pyrazolidine (2)
and flash chromatography to provide the hydrochloride of 1 in 35-46% overall yields compared to 6% yield
for the patent procedure.
J. Heterocyclic Chem., 38, 613 (2001).
Introduction.
and 69% yield from tert-butylcarbazate employing pub-
lished procedures [11]. Hydrogenolysis of 4 and coupling
of the mono-protected pyrazolidine product 5 [11a] with
cyanoacetic acid gave the novel cyanoacetyl pyrazolidine
Aminobicyclopyrazolone 1 is described in the patent liter-
ature as a synthetic intermediate en route to photographic
developing agents [1]. This densely functionalized enam-
inone is a versatile synthon, reacting with a variety of elec-
trophiles in its enamine form [2] or through the correspond-
ing 1,3-dicarbonyl compound which is accessible by acid
hydrolysis [1]. Selective syntheses of pyrazolo[1,2-a]pyra-
zoles have recently been described [3] and a number of
aminopyrazolone congeners possess biological activity
including cardiovascular [4], antifungal [5], antiinflamma-
tory [6], angiotensin II antagonism [7], platelet aggregation
inhibition [8] and corticotropin releasing factor antagonism
6
in 72% overall yield from 4. Removal of the tert-
butoxycarbonyl group in 6 with hydrogen chloride in 1,4-
dioxane gave the hydrochloride of 7 and effected partial
ring closure to 1 based on proton nmr spectroscopy (ca.
25% cyclized). Heating a solution of 7•HCl in ethanol at
reflux completed cyclization to 1 within 30 minutes.
Cooling the reaction mixture and dropwise addition of
ethyl acetate precipitated the hydrochloride of 1 as a white
solid (73% yield from 6).
The synthesis of 1 from 4 supplied multigram quanti-
ties of product in 36% overall yield; however, the route is
lengthy (six steps from tert-butylcarbazate) and necessi-
tates one protection and two deprotection steps. For this
reason, a revised synthesis of 1 from di-tert-butyl hydra-
zodiformate (8) was explored (Scheme 1). Accordingly,
[9]. For these reasons, alternative aminodihydropyrazolone
syntheses are of interest to researchers in the fields of
organic and medicinal chemistry.
8
was reacted with sodium hydride in dimethylfor-
mamide followed by addition of 1,3-dibromopropane.
This cyclization technique produced the desired pyrazoli-
dine (9) in good yield; however, in view of the hazards
associated with sodium hydride/dimethylformamide mix-
tures [12,13], we explored alternative conditions for this
transformation. We soon discovered that this reaction
could be readily accomplished with 50% sodium hydrox-
ide and toluene at 100 °C in the presence of 10 mol%
tetraethyl ammonium bromide (TEAB) (Scheme 1).
These phase-transfer catalysis (PTC) conditions [14] are
a safer alternative to the sodium hydride method and
facilitate practical access to the medicinally interesting
The patent synthesis of 1 [1] involves preparation of
pyrazolidine (2) from hydrazine hydrate and 1,3-dibromo-
propane as described by Buhle et al. [10]. Fractional dis-
tillation of 2 and reaction with ethyl aminoethoxyacrylate
(3) gave 1 in ca. 6% overall yield. We required multigram
quantities of 1 for analog synthesis [2] and wished to
develop an improved synthetic route to this compound that
provided pure material in reasonable overall yields. In this
paper, we describe a convenient four-step synthesis of 1
that affords a tractable hydrochloride salt of the product in
[
11] pyrazolidine ring system.
Pyrazolidine hydrochloride (2•HCl) [15,16] was
obtained as a hygroscopic white solid by treatment of 9
with hydrogen chloride in 1,4-dioxane. Our efforts to con-
vert 2 to 1 with the hydrochloride of 3 in a refluxing solu-
tion of sodium ethoxide in ethanol were unsuccessful.
Alternatively, cyanoacetylation of the hydrochloride of 2
with cyanoacetic acid and dicyclohexylcarbodiimide in the
3
5-46% overall yields and avoids tedious distillation of 2
and chromatography.
Results and Discussion.
Our initial approach to 1 utilized an orthogonally pro-
tected pyrazolidine (4) which was prepared in two steps

614
E. E. Boros, F. Bouvier, S. Randhawa and M. H. Rabinowitz
Vol. 38
presence of triethyl amine (TEA) gave the cyanoacetyl
pyrazolidine 7. Cyclization of 7 in a refluxing solution of
hydrogen chloride in ethanol afforded 1•HCl in 35-46%
overall yield from 8. This revised synthesis of 1 reduced
the number of synthetic transformations by two and
increased the overall yield of product by up to ten percent.
It is important to note that melting point analysis of
(δ 7.24) or d -dimethylsulfoxide (δ 2.49). Coupling constants are
6
reported in hertz. Carbon-13 nmr spectra were recorded at 74
MHz and chemical shifts are reported in ppm relative to the mul-
tiplet for dimethylsulfoxide (δ 40.2). Mass spectra (ms) are
reported in the form m/z (positive ion, relative intensity).
1-tert-Butoxycarbonylpyrazolidine (5).
A solution of 4 [11a] (83 g, 271 mmol) in 85% methanol/water
(600 mL) was hydrogenolyzed at atmospheric pressure over 5%
palladium on carbon (Degussa type, 16 g) for 3 days. The cata-
lyst was removed by filtration, and the filtrate was resubjected to
the same hydrogenolysis conditions overnight. The catalyst was
removed by filtration, and the filtrate was concentrated at
reduced pressure to yield 5 [11a] (40.6 g, 235 mmol, 87% yield)
1
•HCl revealed vigorous decomposition with gas evolu-
tion above 174 °C. Furthermore, the energy of exothermic
decomposition of 1•HCl as measured by differential scan-
ning calorimetry (DSC) was 0.82 kJ/g over the 153-325 °C
range. For these reasons, synthetic operations involving
1
•HCl should be kept well below 150 °C.
1
as a colorless oil: H nmr (d -dimethylsulfoxide): δ 5.05 (1H, br),
6
In summary, convenient syntheses of the hydrochlo-
3
.23 (2H, t, J = 7.2), 2.74 (2H, t, J = 6.4), 1.85 (2H, m), 1.35
rides of pyrazolidine (2) and bicyclopyrazolone 1 were
accomplished starting from di-tert-butyl hydrazodifor-
mate (8). The route entails cyclization of 8 with 1,3-
dibromopropane under phase transfer conditions followed
by removal of the tert-butoxycarbonyl protecting groups
in 9 to give pyrazolidine hydrochloride (2•HCl).
Cyanoacetylation of the latter and ring closure of the
resulting cyanoacetyl pyrazolidine (7) gave the desired
bicyclopyrazolone (1•HCl). The title synthesis avoids
fractional distillation of pyrazolidine (2) and preparative
chromatography to provide a tractable hydrochloride salt
of 1 in 35-46% overall yields. Pyrazolidine 2 and amino-
bicyclopyrazolone 1 are versatile intermediates in organic
synthesis and medicinal chemistry [1,2].
(9H, br s). This material was used without further purification.
1-tert-Butoxycarbonyl-2-cyanoacetylpyrazolidine (6).
To a stirring solution of 5 (35.5 g, 206 mmol), cyanoacetic
acid (17.5 g, 206 mmol) and 1-hydroxybenzotriazole (HOBT)
2.78 g, 20.6 mmol) in dichloromethane (500 mL) at 0 °C was
(
added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (EDCI) (49.4 g, 258 mmol). The reaction mixture
was stirred at room temperature overnight and then washed with
water, 10% citric acid solution and brine. The organic layer was
dried and concentrated at reduced pressure to afford 6 as an oil
(41.0 g, 0.171 mmol, 83% yield). This material was used without
further purification. An analytical sample of 6 was obtained by
flash chromatography on silica gel eluting with 1.5%
1
methanol/dichloromethane: H nmr (deuteriochloroform): δ 4.11
(1H, m), 4.04 (1H, m), 3.69 (1H, d, J = 18.3), 3.54 (1H, d, J =
1
1
8.3), 3.27 (1H, m), 3.13 (1H, m), 2.13 (1H, m), 2.07 (1H, m),
.50 (9H, s); ms m/z 140 (100), 262 (M+Na , 5).
+
EXPERIMENTAL
Anal. Calcd for C H N O : C, 55.22; H, 7.16; N, 17.56.
11 17 3 3
Found: C, 54.98; H, 7.16; N, 17.35.
General.
1-Cyanoacetylpyrazolidine Hydrochloride (7•HCl) from 6.
All reagent chemicals were used without purification.
Elemental analyses were performed by Atlantic Microlabs,
Norcross, Georgia. Proton nmr spectra were recorded at 300 or
A solution of 6 (41 g, 171 mmol) in 4 M hydrogen chloride/1,4-
dioxane (400 mL) was stirred at room temperature for 4 hours. The
reaction mixture was diluted with diethyl ether (1 L) and the super-
natant was decanted. The remaining hygroscopic solid was dried
under high vacuum to yield the crude hydrochloride of 7 as a white
400 MHz and chemical shifts are reported in ppm relative to the
residual protonated solvent resonance of deuteriochloroform

May-Jun 2001
Pyrazolidine and 3-Amino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one
615
hygroscopic solid (91-100% yield): mp 54-56 °C; 1H nmr
solid (30 g, 100% crude yield). This material was used in the next
step without further purification. An analytical sample of the free
base was obtained by washing a dichloromethane solution of 7•HCl
with aqueous sodium bicarbonate solution. The organic layer was
dried and concentrated in vacuo to afford 7 as an oil that crystallized
(d -dimethylsulfoxide): δ 8.25 (4H, br), 3.01 (4H, t, J = 7.2),
6
1
3
1.93 (2H, quint, J = 7.2); C nmr (d -dimethylsulfoxide): δ
46.58 (2CH ), 26.18 (CH ); ms m/z 73 (M+1, 100).
6
2
2
Anal. Calcd for C H N •(1.31 HCl): C, 30.06; H, 7.83; N,
3
8 2
1
on standing: H nmr (deuteriochloroform): δ 4.08 (1H, t, J = 8.7),
23.37. Found: C, 30.10; H, 8.05; N, 23.01.
3.63 (2H, s), 3.58 (2H, t, J = 7.3), 3.04 (2H, m), 2.14 (2H, m).
1-Cyanoacetylpyrazolidine (7) from 2•HCl.
Anal. Calcd for C H N O: C, 51.79; H, 6.52; N, 30.20.
6
9 3
Found: C, 51.73; H, 6.56; N, 30.06.
Neat triethyl amine (6.26 mL, 44.9 mmol) was added dropwise
to a stirred mixture of 2•HCl and cyanoacetic acid (1.91 g, 22.46
mmol) in ethyl acetate (65 mL) at room temperature.
Dicyclohexylcarbodiimide (DCC) (4.64 g, 22.50 mmol) was
added portionwise, and the reaction mixture was heated gently to
aid dissolution and then stirred at room temperature overnight.
The precipitated dicyclohexyl urea was removed by filtration and
the filtrate was diluted with diethyl ether and refiltered. The fil-
trate was concentrated at reduced pressure to provide 7 as a col-
orless oil that partially crystallized on standing (3 g, 21.6 mmol,
96% yield). Spectral data were identical to that described for 7
above. This material was used without further purification.
3
-Amino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one
Hydrochloride (1•HCl) from 7•HCl.
A solution of 7•HCl (30 g, 171 mmol) in ethanol (400 mL) was
heated at reflux for 20 minutes and cooled to room temperature.
Diethyl ether (1 L) was added dropwise and the resulting precip-
itate (1•HCl) was collected by filtration as a white solid (22 g,
1
25 mmol, 73% yield): mp 174-176 °C (decomposition);
Differential scanning calorimetry (DSC): energy of exothermic
decomposition = 0.82 kJ/g from 153-325 °C; ir: 3289, 3143,
-1 1
2
587, 1582 (C=O) cm ; H nmr (d -dimethylsulfoxide): δ 7.06
6
1
3
(2H, br), 4.96 (1H, s), 3.79 (4H, m), 2.55 (2H, m); C nmr (d -
6
3
-Amino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one
dimethylsulfoxide): δ 158.13 (C), 152.70 (C), 77.76 (C), 45.20
Hydrochloride (1•HCl) from 7.
(CH ), 44.23 (CH ), 28.09 (CH ); ms m/z 140 (M+1, 100).
2 2 2
Anal. Calcd for C H ClN O•(0.4 H O): C, 39.42; H, 5.95; N,
2.98. Found: C, 39.42; H, 6.16; N, 22.80.
A solution of 7 (3 g, 21.6 mmol) in 0.75 M hydrogen chlo-
ride/ethanol (33 mL) (prepared from ethanol and acetyl chloride
at 0 °C) was heated at reflux for 30 minutes. The solution was
diluted with ethyl acetate and allowed to cool to room tempera-
ture. The title compound (1•HCl) was collected by filtration as a
white solid (2.2 g, 12.2 mmol, 57% yield). Spectral data were
identical to that described for 1•HCl above.
6
10
3
2
2
1
,2-Bis-tert-butoxycarbonylpyrazolidine (9) (Sodium Hydride
Method).
A solution of 8 (10.2 g, 43.7 mmol) in dimethylformamide
100 mL) was added dropwise to a stirred suspension of sodium
hydride (2.20 g, 91.67 mmol) in dimethylformamide (50 mL)
caution!) [12,13] at room temperature. After stirring 30 minutes,
(
Acknowledgements.
(
neat 1,3-dibromopropane (4.43 ml, 43.69 mmol) was added drop-
wise and the reaction mixture was stirred overnight. The reaction
was quenched with water and the dimethylformamide was
removed by distillation at reduced pressure. The crude material
was dissolved in ethyl acetate, washed with water, dried, filtered
and concentrated to afford 9 [17] as a colorless oil (10.0 g, 36.7
The authors thank Paul L. Feldman, David J. Cowan, Anthony
L. Handlon and Philip S. Turnbull for helpful discussion. We
also thank Bill Hinkley for the differential scanning calorimetric
analysis of 1•HCl.
1
REFERENCES AND NOTES
mmol, 84% yield): H nmr (deuteriochloroform): δ 3.85 (2H, m),
3
.18 (2H, m), 1.98 (2H, quint, J = 7.2), 1.45 (18H, br s). This
material was used without further purification.
,2-Bis-tert-butoxycarbonylpyrazolidine (9) (Phase Transfer
Method).
A mixture of 8 (5.00 g, 21.5 mmol), 1,3-dibromopropane (6.5
[1] R. B. Greenwald, United States Patent 4,128,425 (1978);
Chem. Abstr., 90, 95418n (1979).
1
[
2] For a review of the organic chemistry of enaminones, see:
J. V. Greenhill, Chem. Soc. Rev., 277 (1977).
3] T. H. Chuang and K. B. Sharpless, Helv. Chim. Acta, 83,
734 (2000).
4a] K. Atwal, International Patent Application WO 89 06,535
1989); Chem. Abstr., 112, 77212j (1990); [b] F. Wiedemann, W.
Kampe, K. Dietmann and G. Sponer, United States Patent 4,608,383
1986); Chem. Abstr., 106, 5075v (1987).
5] M. Hashizume, N. Kimura and N. Yamamoto,
[
1
g, 32.3 mmol), tetraethyl ammonium bromide (680 mg, 3.23
mmol), 50% sodium hydroxide (25 mL) and toluene (50 mL) was
stirred vigorously at 100 °C for two hours. The reaction mixture
was diluted with ethyl acetate and washed with aqueous sodium
bicarbonate, water and brine. The organic phase was dried, fil-
tered and concentrated to give 9 [17] (6 g) as an oil. Spectral data
were identical to that described for 9 above and showed the pres-
ence of excess 1,3-dibromopropane (70% crude yield based on
proton nmr). This material was used without further purification.
[
(
(
[
International Patent Application WO 99 54,307, (1999); Chem.
Abstr., 131, 310634 (1999).
[6] K. C. Joshi, V. N. Pathak and U. Garg, J. Indian Chem.
Soc., 58, 1180 (1981).
[
7] Y. Kuroki, S. Takamura, H. Ueno, I. Nakakoshi, H.
Pyrazolidine Hydrochloride (2•HCl).
Fujiwara and T. Kimura, Japanese Patent 06,100,541 (1994); Chem.
Abstr., 121, 134110m (1994).
[8] K. Tanikawa, T. Matsumoto, M. Nakamura, Y. Asada and
N. Shudo, International Patent Application WO 97 13,757 (1997);
Chem. Abstr., 126, 343565 (1997).
In a typical procedure, a 0.4 M solution of 9 (prepared by the
sodium hydride or phase transfer method) in 4 M hydrogen chlo-
ride/1,4-dioxane was stirred 3 hours at room temperature. The
mixture was diluted with diethyl ether and the hydrochloride of 2
[
15,16] was collected by filtration under nitrogen as a white,
[9] M. E. Abreu, W. Rzeszotarski, D. J. Kyle, R. N. Hiner and

616
E. E. Boros, F. Bouvier, S. Randhawa and M. H. Rabinowitz
Vol. 38
R. L. Elliot, United States Patent 5,063,245 (1991); Chem. Abstr.,
16, 83668m (1992).
10] E. L. Buhle, A. M. Moore and F. Y. Wiselogle, J. Am.
Chem. Soc., 65, 29 (1943).
11a] A. S. Dutta and J. S. Morley, J. Chem. Soc., Perkin Trans.
, 1712 (1975); [b] F. Pinnen, G. Luisi, A. Calcagni, G. Lucente, E.
Gavuzzo and S. Cerrini, J. Chem. Soc., Perkin Trans. 1, 1611 (1994);
c] A. Lecoq, G. Boussard, M. Marraud and A. Aubry, Tetrahedron
Lett., 33, 5209 (1992).
12] Dangerous exotherms involving sodium hydride/dimethyl-
Heinemann Ltd: Oxford, 1995; pp 1500-1501.
1
[13] Substituting tetrahydrofuran or N-methylpyrrolidinone for
dimethylformamide in the sodium hydride-mediated conversion of 8
to 9 produced a product of lesser purity.
[14] M. Halpern, Y. Sasson and M. Rabinovitz, Tetrahedron,
38, 3183 (1982).
[
[
1
[15] S. Groszkowski and J. Wrona, Pol. J. Chem., 56, 1131
(1982).
[
[16] For syntheses of 2 from 1,2-diisobutyrylpyrazolidine see:
[a] H. Stetter and H. Spangenberger, Chem. Ber., 91, 1982 (1958); [b]
J. Hine and R. A. Evangelista, J. Am. Chem. Soc., 102, 1649 (1980).
[17] H. G. Brunner, H. Moser and G. Pissiotas, International
Patent Application WO 92 21,684 (1992); Chem. Abstr., 118,
191744h (1993).
[
formamide have been reported; holding this mixture for
extended time periods should be avoided, particularly with
large scale reactions; see Bretherick's Handbook of Reactive
Chemical Hazards, 5th ed.; Urben, P.G., Ed.; Butterworth-