(150 mL). The suspension was cooled to room temperature, filtered,
and dried to yield 7-oxo-4,7-dihydropyrazolo[1,5-R]pyrimidine-6-
carboxylic acid (1.80 g, 10 mmol, 100%) as a white solid.
In summary, we have shown two distinct routes to prepare
pyrazolo[1,5-R]pyrimidin-7-ones, such as 14 (Schemes 3 and
4). Both of these routes are applicable to a variety of pyrazole
substrates, offering products with optimal substitution patterns.
Alternatively, we have shown two distinct routes for the
preparation of pyrazolo[1,5-R]pyrimidin-5-ones, such as 19
(Schemes 6 and 8). Table 1 summarizes these findings.
Method A: Pyrazolo[1,5-R]pyrimidin-7(4H)-one (8). To 7-oxo-
4,7-dihydropyrazolo[1,5-R]pyrimidine-6-carboxylic acid, 7, (12.10
g, 68 mmol) was added Dowtherm A (100 mL). The suspension
was heated to 250 °C for 2 h. The reaction mixture was cooled to
room temperature, then diluted with hexanes (300 mL), stirred
vigorously, filtered, and dried to afford pyrazolo[1,5-R]pyrimidin-
7(4H)-one (8.90 g, 66 mmol, 98%) as a pink solid.
TABLE 1. Summary of Results
Method B: 2-(3-Bromophenyl)pyrazolo[1,5-R]pyrimidin-
7(4H)-one (14). Sodium, prewashed with hexanes (0.13 g, 5.6
mmol, 2.8 equiv), was added to a scintillation vial (20 mL) to which
toluene (2 mL) was added. The vial was heated in a 120 °C oil
bath until the sodium became molten. The vial was shook vigorously
to produce a fine suspension of sodium as the mixture cooled. To
the suspension at room temperature under N2 was added ethyl
acetate (430 µL, 4.4 mmol, 2.2 equiv) followed by EtOH (3 drops).
Ethyl formate (355 µL, 4.4 mmol, 2.2 equiv) was added in portions
over 20 min. The suspension was allowed to stir for 16 h at room
temperature under N2. A solution of 3-(3-bromophenyl)-1H-pyrazol-
5-amine, 11 (0.43 g, 2 mmol, 1 equiv), in EtOH (2 mL) was added
to the suspension and then heated to 80 °C for 4 h. The solvent
was removed, H2O (50 mL) was added, and the crude product was
heated to boiling, filtered through Celite, cooled, and brought to
pH 1 by addition of 6 N HCl. The precipitate was filtered and
washed with H2O. The wet solid was triturated with EtOH, filtered,
and dried to yield 2-(3-bromophenyl)pyrazolo[1,5-R]pyrimidin-
7(4H)-one (0.27 g, 0.93 mmol, 47%) as a pale yellow solid.
Further experimentation and mechanistic studies are required
to fully understand the differences in regioisomer selectivity. It
seems that both the conditions (acidic vs basic) and the
electrophile play important roles in determining the course of
the cyclization reaction.
Method C: 2-(3-Bromophenyl)pyrazolo[1,5-R]pyrimidin-
5(4H)-one (19). To 3-(3-bromophenyl)-1H-pyrazol-5-amine, 11
(1.19 g, 5 mmol, 1 equiv), under a N2 atmosphere was added a
solution of sodium ethoxide in EtOH (1 N, 17.5 mL). Solid 1,3-
dimethyluracil (0.77 g, 5.5 mmol, 1.1 equiv) was added, and the
mixture was heated to 90 °C for 3 h. The reaction mixture was
then cooled in an ice-water bath. The resulting amber precipitate
was filtered off and dissolved in water (20 mL) and neutralized
with acetic acid. The solid was then washed with H2O and
azeotroped to dryness by refluxing in toluene (100 mL) to give
2-(3-bromophenyl)pyrazolo[1,5-R]pyrimidin-5(4H)-one (1.09 g, 3.8
mmol, 75%) as a cream-colored solid.
Both routes for formation of the pyrimidin-5-ones are
noteworthy. First, use of 1,3-dimethyluracil as the electrophile
in the preparation of regioisomers 21 and 22 represents a
correction from previously reported results.13 This one-step
procedure can be used to prepare a variety of novel compounds.
Also, we report here for the first time that reaction of an
aminopyrazole with ethyl 3-ethoxyacrylate in the presence of
cesium carbonate affords the pyrimidin-5-one regioisomer.
Furthermore, the mechanism of formation of 19 was revealed
by isolation of intermediates within the reaction pathway. This
work provides the experimentalist with a variety of synthetic
pathways that will afford either the pyrimidin-7-one or the
pyrimidin-5-one regioisomer.
Method D: 2-(3-Bromophenyl)pyrazolo[1,5-R]pyrimidin-
5(4H)-one (19). To a solution of 3-(3-bromophenyl)-1H-pyrazol-
5-amine, 11 (0.238 g, 1.0 mmol), and ethyl 3-ethoxyacrylate (220
µL, 1.5 mmol) in DMF (15 mL) was added cesium carbonate (480
mg, 1.5 mmol). The reaction mixture was heated to 110 °C for 4
h. The mixture was then allowed to cool, and acetic acid (3 mL)
was added. The solvent was evaporated, and the product was
partitioned between H2O and ethyl acetate. The organic layer was
washed with brine, dried over MgSO4, filtered, and evaporated to
give crude product. The resultant material was purified by trituration
with ethyl acetate:EtOH to give 2-(3-bromophenyl)pyrazolo[1,5-
R]pyrimidin-5(4H)-one (0.273 g, 0.94 mmol, 94%) as a white solid.
Experimental Section
Method A: Ethyl 7-Oxo-4,7-dihydropyrazolo[1,5-R]pyrimi-
dine-6-carboxylate (6). To a solution of 2H-pyrazol-3-ylamine
(4.15 g, 50 mmol, 1 equiv) in glacial acetic acid (60 mL) at room
temperature was added diethyl ethoxymethylenemalonate (11.89
g, 55 mmol, 1.1 equiv). The mixture was heated at 120 °C for 4.5
h. The suspension was filtered warm, then washed several times
with EtOH, and dried to yield ethyl 7-oxo-4,7-dihydropyrazolo-
[1,5-R]pyrimidine-6-carboxylate (5.76 g, 28 mmol, 56%) as a white
powder.
Method A: 7-Oxo-4,7-dihydropyrazolo[1,5-R]pyrimidine-6-
carboxylic Acid (7). To a suspension of ethyl 7-oxo-4,7-dihydro-
pyrazolo[1,5-R]pyrimidine-6-carboxylate, 6, (2.07 g, 10 mmol) in
EtOH (10 mL) at room temperature was added 2.5 N NaOH (10
mL). The resulting suspension was heated to 100 °C for 3.5 h. The
suspension was cooled to room temperature and diluted with H2O
(300 mL) and citric acid (5.78 g, 30 mmol). The white suspension
was stirred an additional 30 min, filtered, and washed with water.
The wet solid was azeotroped to dryness by refluxing in toluene
Acknowledgment. The authors thank Dr. John Ellingboe
for his support of this project and both Dr. Nelson Huang and
Ms. Ning Pan for LC-MS and HRMS measurements. We also
thank Professor Michael Jung for insightful discussions.
Supporting Information Available: Full characterization and
purity data for compounds 6, 7, 8, 14, and 19. Experimentals,
characterization and purity data for compounds 10, 11, 11A, 11B,
12, 13, 15, 17, 18, 20, 21, 22, 23, and 24. NOE experimental details
and data for compounds 23 and 24. This material is available free
JO062120G
1046 J. Org. Chem., Vol. 72, No. 3, 2007