Aqueous one-pot synthesis of pyrazoles, pyrimidines and isoxazoles promoted by microwave irradiation

Article abstract of DOI:10.1055/s-2002-33650

Microwave irradiation promotes the conversion of enaminoketones formed in situ into a variety of heterocycles by reaction with the appropriate bidentate nucleophile. The advantages of the method over previous approaches are short reaction times and facile purification by precipitation of the products in aqueous media. Moreover the convenient one-pot procedure makes these syntheses particularly suitable for library production. Organic reactions in aqueous media have become of great interest as water is not only more environmentally friendly, but also because organic reactions in water often display unique reactivity and selectivity.

Full text of DOI:10.1055/s-2002-33650

PAPER
1669
Aqueous One-Pot Synthesis of Pyrazoles, Pyrimidines and Isoxazoles
Promoted by Microwave Irradiation
S
ynthesis of Pyraz
a
oles, Pyrim
l
idines
e
and Isoxazo
n
les tina Molteni,* Matthew M. Hamilton, Long Mao, Christine M. Crane, Andreas P. Termin, Dean M. Wilson
Deltagen Research Laboratories, 4570 Executive Drive, Suite 400, San Diego, CA 92121, USA
Fax +1(858)4572897; E-mail: vmolteni@gnf.org
Received 26 March 2002; revised 24 May 2002
R
Abstract: Microwave irradiation promotes the conversion of
NH
O
O
HN
O
O
N
enaminoketones formed in situ into a variety of heterocycles by re-
action with the appropriate bidentate nucleophile. The advantages
of the method over previous approaches are short reaction times and
facile purification by precipitation of the products in aqueous me-
dia. Moreover the convenient one-pot procedure makes these syn-
theses particularly suitable for library production. Organic reactions
in aqueous media have become of great interest as water is not only
more environmentally friendly, but also because organic reactions
in water often display unique reactivity and selectivity.
H
N
N
n
+
R N NH2
n
n
O
R
1a n = 0
1b n = 1
1c n = 2
3a
3b
3c
4a
4b
4c
2
Scheme 1
Key words: bidentate nucleophiles, tandem addition-elimination/
cyclodehydration, enaminoketones, microwave irradiation
microwave irradiation could be used to enhance the utility
of this sequence.9 In the presence of AcOH, equimolar
mixtures of the enaminoketone 1b and 2,4-dimethylphe-
nylhydrazine hydrochloride were subjected to microwave
heating in a varitey of solvents (Table 1). Using n-butanol
(0.2 M) and 2.6 equivalents of AcOH, the reaction was
complete in 120 seconds at 170 °C, giving 4b-1 in an iso-
lated yield of 67% (entry 1). Increasing the reaction con-
centration to 0.5 M was beneficial, resulting in conversion
in 60 seconds at 190 °C with an isolated yield of 76% (en-
try 2). Further increase in the concentration with a reduc-
tion in AcOH resulted in a poorer yield (entry 3). Using
the stoichiometry from entry 2, different reaction solvents
were explored. Very short reaction times (entries 4, 5, 6
and 8) and very good isolated yields (usually >80%) were
obtained with DMF, THF, MeOH and water. Longer
times were required for MeOH (360 seconds), as pressure
limitations (20 bar) precluded temperatures beyond
160 °C. Alternatively, the reaction in MeOH was faster
(180 seconds) when the amount of AcOH was doubled
however a slight decrease in yield was observed (entry 7).
Interestingly, the reaction in water (entry 8) gave an iso-
lated yield of 84% when the reaction was irradiated to
200 °C for 120 seconds. An appealing aspect of the reac-
tion in water was that the product could be isolated by
simple filtration from the reaction mixture (entry 9). The
product appeared as an oil after microwave irradiation,
but subsequent agitation caused precipitation of the de-
sired compound. The yield and purity of 4b-1 obtained by
filtration was analogous to reactions involving chromato-
graphic purification (entry 8 vs entry 9). It was possible to
reduce the reaction time to 60 seconds (entry 10), and in-
creasing the temperature to 220 °C afforded a slighter
higher yield (88%, entry 11).
It is well established that formamide acetals react with ac-
tive methylene ketones to produce enaminoketones,1
which can subsequently yield a vast array of heterocyclic
compounds. Reaction of enaminoketones with the appro-
priate bidentate nucleophiles give pyrazoles,2 pyrim-
idines,3 pyrimidones,4 isoxazoles,5 pyrroles,6 and
pyridones.7 During an ongoing project we became inter-
ested in the synthesis of compounds 4, generally prepared
from the corresponding enaminoketones 1 by reaction
with substituted hydrazines 2 (Scheme 1).8,1a The reaction
is a tandem addition-elimination/cyclodehydration, which
takes place via a Michael addition of the terminal amino
group of hydrazines 2 to form the acyclic intermediate 3,
followed by intramolecular cyclodehydration to pyrazole
derivative 4. Conditions have been reported that afford
high yields of the products,1a but very limited variations in
the substituent R are precedented (R = Ph, Me).1 Further-
more, the known procedures require complex purification
of the final product by distillation or crystallization and
also proved to be unsatisfactory for the synthesis of ana-
logs different from the one already known. Being interest-
ed in the parallel synthesis of many derivatives of 4, we
sought to develop an experimentally more straightforward
and broadly applicable approach.
The synthesis of compound 4b-1 (R = 2, 4-dimethylphe-
nyl) was chosen as a model reaction to investigate the re-
action conditions. Typically, the tandem Michael
addition-elimination/cyclodehydration requires refluxing
in high boiling solvent (such as n-butanol) under acid ca-
talysis (AcOH), therefore we decided to explore whether
To expand the scope of the reaction, various hydrazines
were investigated under the same conditions (Scheme 1,
Table 2). A slight modification in the purification step
Synthesis 2002, No. 12, Print: 06 09 2002.
Art Id.1437-210X,E;2002,0,12,1669,1674,ftx,en;M01302SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1670
V. Molteni et al.
PAPER
Table 2 Reaction of 1b with Substituted Hydrazines
Table 1 Study of the Reaction Conditions for the Model Reaction
(1b + 2,4-Dimethylphenylhydrazine)a
Product
4b-1
4b-2
4b-3
4b-4
4b-5
4b-6
4b-7
4b-8
4b-9
Ra
Yield %
Entry Solvent (M)
AcOH
Microwave
Yield of
2,4-Me2C6H3
Ph
92b
86b
83b
78b
65b
85b
79c
99d
80c,e
(equiv) Conditions
4b-1 (%)
1
2
n-BuOH (0.2)
n-BuOH (0.5)
n-BuOH (1.1)
DMF (0.5)
THF (0.5)
2.6
2.6
0.5
2.6
2.6
2.6
5.2
2.6
2.6
2.6
2.6
170 °C, 120 s
180 °C, 60 s
190 °C, 120 s
200 °C, 60 s
170 °C, 180 s
150 °C, 360 s
150 °C, 180 s
200 °C, 120 s
200 °C, 120 s
200 °C, 60 s
220 °C, 60 s
67b
76b
39b
83b
79b
83b
79b
84b
83c
84c
88c
2,4-F2-C6H3
3,5-Me2C6H3
4-CF3,6-Me-2-pyridyl
2-pyridyl
cyclohexyl
t-Bu
3
4
5
6
MeOH (0.5)
MeOH (0.5)
H2O (0.5)
7
H
8
a Hydrazine substituent, Scheme 2.
9
H2O (0.5)
b Yield of product isolated by filtration followed by washing only
with water.
10
11
H2O (0.5)
c Yield of product isolated by column chromatography.
d Yield of product isolated by extraction with CH2Cl2.
e Product isolated is the N-unsubstituted pyrazole (R = H).
H2O (0.5)
a Observed pressures were between 15–18 bar.
b Yield after column chromatography.
c Yield obtained on the filtrated product after washings with water and
hexane.
diketone/DMFDMA mixture was unimportant; 4) prior to
microwave irradiation the intermediate 3b-1 was detected
by LC/MS, with only trace enaminoketone 1b remaining;
and 5) after microwave irradiation the intermediate 3b-1
was completely converted to the pyrazole 4b-1. The reac-
tion also proceeded without addition of AcOH, but in gen-
eral led to formation of more side products. For
comparison, the reaction under conventional heating re-
quired 4 hours at reflux for completion, and the product
obtained was less pure (67% vs 94% by HPLC). The mi-
crowave reaction was also run in other solvents, but water
proved optimal (H2O 87%, THF 75%, DMF 78%, MeCN
67%, CH2Cl2 79%). The process was scalable to higher
concentrations (up to 4 fold with the same type of reactor)
without affecting yield or purity. This was especially
valuable given that neither the reaction nor purification re-
quired any organic solvents.
(the filtered product was washed only with water, not with
hexanes) afforded a better yield and more convenient pro-
cedure for 4b-1 (92%), without affecting the purity of the
product. Excellent yields were obtained for all aryl substi-
tuted (4b-2 to 4b-6) and alkyl substututed hydrazines (4b-
7, 4b-8) attempted. An unusual reaction was observed us-
ing 4,5-dihydroimidazol-2-ylhydrazine, which afforded
the N-unsubstituted pyrazole 4b-9 in 80% yield. Loss of
the imidazoline fragment occurred in the cyclization step,
as evidenced by gas chromatography (GC/MS). Con-
versely, the direct reaction with hydrazine hydrochloride
did not afford compound 4b-9, rather generating a sym-
metrical dimer via hydrazine addition to two molecules of
enaminoketone, as demonstrated by MS and NMR data.
The overall process was simplified via a one-pot reaction
in which the enaminoketone was generated in situ from
the corresponding diketone (Scheme 2). Equimolar
amounts of dimethylformamide dimethyl acetal (DMFD-
MA) and 1,3-cyclohexanedione were mixed, followed by
the addition of N-phenylhydrazine, water (to 0.5 M), and
2.6 equivalents of AcOH. The heterogeneous mixture was
then heated in the microwave for 120 seconds at 200 °C.
Product 4b-1 (Table 3) was obtained by simple filtration
with a yield and purity comparable to the two step reaction
(Table 2). Chromatographic analyses (GC/MS and LC/
MS) of the reaction indicated: 1) thorough agitation of the
diketone/DMFDMA mixture was required prior to the ad-
dition of water; 2) reaction between the diketone and DM-
FDMA was complete by the time an initial GC/MS
sample was obtained (less than one minute); 3) the order
of addition of the hydrazine, water, and acetic acid to the
O
O
H2O
MeO
MeO
Me
N
Me
H
N
n
+
R N NH2
+
n
N
O
Microwave Irradiation
R
n = 0 1,3-cyclopentanedione
n = 1 1,3-cyclohexanedione
n = 2 1,3-cycloheptanedione
n = 0 4a
n = 1 4b
n = 2 4c
Scheme 2
To demonstrate the generality of the one-pot reaction, the
substrate scope of the sequence was explored. Several
substituted hydrazines were used successfully, as shown
in Table 3 (Scheme 2). The yields of the compounds re-
synthesized with the one-pot procedure were comparable
to those obtained starting with the isolated enaminoketone
(Table 2), hence making the isolation of the enaminoke-
Synthesis 2002, No. 12, 1669–1674 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrazoles, Pyrimidines and Isoxazoles
1671
O
tone generally unnecessary. The reaction was also extend-
ed to other cyclic diketones. When 1,3-cycloheptanedione
and phenylhydrazine were used, the reaction was com-
plete in 120 seconds at 200 °C, giving 4c-2 in 79% yield.
In contrast, 1,3-cyclopentanedione was less successful.
While the formation of the intermediate 3a (R = Ph) pro-
ceeded smoothly at room temperature, the cyclodehydra-
tion step was problematic (as previously described),1a
even with microwave heating. After only 60 seconds at
200 °C, several compounds were detectable by LC/MS,
along with a still significant amount of intermediate 3a.
Lower temperatures did not improve the outcome of the
reaction. Optimal conversion to 4a-21a was obtained by
heating for 600 seconds at 120 °C using p-toluenesulfonic
acid instead of AcOH, giving a 27% yield after column
chromatography. The reaction was also successful, with
moderate yields, with acyclic symmetrical and asym-
metrical ketones and with acyclic -keto esters, -keto
sulfones, -keto nitriles and -keto amides.10
O
MeO
MeO
Me
N
Me
NH
N
+
+
n
n
R
NH2
O
R
N
n =1 5a
n =2 5b
O
O
MeO
MeO
Me
N
Me
NH2 OH
+
+
N
n
n
O
O
n = 0 1,3-cyclopentanedione
n = 1 1,3-cyclohexanedione
n = 2 1,3-cycloheptanedione
n = 1 6a
n = 2 6b
Scheme 3
The outcome of these reactions in water is counter intui-
tive considering that the reactions are cyclodehydrations
and as such proceed with elimination of water. However,
water has been recently demonstrated to be the solvent of
choice for several reactions which previously were run
only in organic solvents.13 One of the reasons why many
reactions were never attempted in water was because of
the insolubility of many organic compounds in this media.
The insolubility of reactants in water can definitely be an
obstacle for reactions performed at room temperature but
at higher temperature these reactions become more acces-
sible.14 If in addition to high temperature, higher pressures
are also applied, the solubility becomes less of a concern.
Therefore, the use of the microwave synthesizer, which
allows for both high temperatures and higher pressures,
may be very beneficial for running reactions when poor
solubility is a limiting factor.
Table 3 One-Pot Procedure for the Preparation of Pyrazoles 4b
Product
4b-1
4b-2
4b-6
4b-7
4b-8
4b-9
Ra
Yield %
83b
2,4-Me2C6H3
Ph
87
2-pyridyl
cyclohexyl
t-Bu
69b
66b
78c
H
76d
a Hydrazine substituent, Scheme 2.
In summary, we have developed an extremely simple one-
pot reaction for transforming diketones into the corre-
sponding pyrazoles, pyrimidines and isoxazoles. In addi-
tion the use of microwave heating dramatically shortens
reaction times, and the use of aqueous reaction conditions
results in simple, environmentally friendly workup proce-
dures. The outcome of these reactions demonstrates that
reactions that are historically performed in organic sol-
vents can have facile and more convenient aqueous coun-
terparts. Our continued efforts in this area shall be
reported in due course.
b Yield of product isolated by filtration followed by washing only with
water.
c Yield of product isolated by extraction with CH2Cl2.
d Product isolated by column chromatography is the N-unsubstituted
pyrazole (R = H).
Having established the utility and aqueous stability of the
enaminoketones prepared ‘in situ’, we wanted to identify
more aqueous, microwave-induced heterocycle syntheses
via enaminoketones. It was well known that enaminoke-
tones react with amidines or hydroxylamine to give pyri-
midines and isoxazoles, respectively, therefore we
attempted the synthesis of these molecules with our one-
pot method (Scheme 3). A preliminary investigation indi-
cated that the reaction of 1,3-diketones with benzamidine
hydrochloride afforded pyrimidines 5a-1 (54%)3b and 5b-
1 (60%)11 and reaction with 4-amidinopyridinium chlo-
ride afforded 5a-2 (68%).12 Reaction with tert-butylcarb-
amidine hydrochloride afforded pyrimidine 5a-3 in poor
yield (21%), while reaction with acetamidine hydrochlo-
ride was unsuccessful, giving rise to a complex mixture of
products with only traces of the desired compound. Reac-
tion of 1,-3-cycloheptanedione with hydroxylamine hy-
drochloride afforded the isoxazole 6b (34%) whereas
reaction with 1,3-cyclohexanedione afforded 6a5a with
low purity.
Solvents and reagents were obtained from commercial sources and
used without further purification. Microwave assisted syntheses
were carried out using the Smith Synthesizer from Personal Chem-
istry and Smith process vialsTM (2–5 mL), with septum caps and
magnetic stirring bars. Flash chromatography was performed using
the ISCO CombiFlash system with Biotage columns and EtOAc–
hexane gradients as indicated. EM Science precoated silca gel 60
F254 plates were used for TLC analyses using EtOAc–hexane mix-
tures as eluents. Analytical HPLC experiments were performed
with a PE Sciex LC/MS system with Shimadzu SCL-10A system
controller, Shimadzu SPD-10A UV-VIS detector, Shimadzu LC-
8A pumps, Gilson 215 autosampler, API 150 EX mass spectrome-
ter, and PE Sciex Sample Control 1.5 software running on a Macin-
tosh G3 (OS 8.6). Analytical HPLC columns were YMC
CombiScreen ODS-A (50 4.6 mm) and a gradient of MeCN 10%
to 90% (MeCN with 0.035% TFA/H2O with 0.05% TFA) was used
Synthesis 2002, No. 12, 1669–1674 ISSN 0039-7881 © Thieme Stuttgart · New York

1672
V. Molteni et al.
PAPER
as eluent with run time of 6 min unless otherwise specified. Analyt-
ical GC experiments utilized an Agilent 6890, Agilent 7673 injec-
tor, and Agilent 6890 MSD detector. Analytical GC columns were
J & W Scientific (5% diphenyl, 95% dimethyl polysiloxane; length:
29 m; diameter: 250.00 m, film thickness: 0.25 m). The column
used was 8.17 min long with a flow rate of 19.2 mL/min. Tempera-
ture profile was: initial temp 70 °C for 1 min, 115 °C @ 45 °C/min
for 1 min, 175 °C @ 40 °C/min for 1.5 min, 300 °C @ 30 °C/min
for 4.17 min, the oven remained at 300 °C for 0.5 min. Retention
times for both LC/MS and GC/MS are reported with the % area of
the peak. NMR spectra were obtained using either Varian 300 MHz
or 400 MHz instruments. Chemical shifts are reported in ppm rela-
tive to internal solvent signals. Coupling constants are reported in
Hertz (Hz). Carbon spectra are proton spin decoupled and observed
multiplicities are indicated for fluorine containing molecules.
MS (ESI): m/z = 249.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H10F2N2O, 249.0839;
found, 249.0842.
1-(3,5-Dimethylphenyl)-1,5,6,7-tetrahydro-4H-indazol-4-one
(4b-4)
Yield: 71% (213 mg); mp 120–121 °C; HPLC tR 3.27 min (100%);
GC/MS tR 6.62 min (100%).
1H NMR (300 MHz, CDCl3): = 7.97 (s, 1 H, CH), 7.03 (s, 2 H,
Ar), 6.98 (s, 1 H, Ar), 2.89 (t, 2 H, J = 5.7 Hz, CH2CO), 2.47 (t, 2
H, J = 5.7 Hz, CH2C=), 2.31 (s, 6 H, 2 CH3), 2.09 (m, 2 H,
CH2CH2CH2).
13C NMR (300 MHz, CDCl3): = 193.50, 149.19, 139.53, 138.53,
138.43, 130.15, 121.59, 120.33, 38.13, 23.84, 23.48, 21.51.
MS (ESI): m/z = 241.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H16N2O, 241.1341; found,
Bicyclic 4-Acylpyrazoles 4b from Enaminoketones; General
Procedure (Table 2)
In a Smith process vial, the enaminoketone1 1a–c (1.25 mmol) was
dissolved in H2O (2.5 mL) and the corresponding hydrazine
monochloride was added (1.25 mmol), followed by AcOH (3.25
mmol). The vial was sealed and submitted to microwave irradiation
for 120 s at 200 °C using the Smith Synthesizer. Upon cooling and
stirring with a spatula, the product precipitated from the reaction
mixture. It was filtered, washed with water and hexane, and dried.
241.1341.
1-(6-Methyl-4-trifluoromethylpyridin-2-yl)-1,5,6,7-tetrahydro-
4H-indazol-4-one (4b-5)
Yield: 65% (239 mg); mp 121–122 °C; HPLC tR 3.63 min (82%);
GC/MS tR 5.83 min (100%).
1H NMR (300 MHz, CDCl3): = 7.97 (s, 1 H, CH), 7.94 (s, 1 H,
Ar), 7.21 (s, 1 H, Ar), 3.40 (t, 2 H, J = 6.3 Hz, CH2CO), 2.56 (s, 3
H, CH3), 2.46 (t, 2 H, J = 6.0 Hz, CH2C=), 2.12 (m, 2 H,
CH2CH2CH2).
13C NMR (300 MHz, CDCl3): = 193.96, 159.20, 153.06, 151.49,
141.5 (q), 139.43, 124.52, 122.03, 120.89, 117.06 (d), 108.8 (q),
38.14, 25.46, 24.48, 23.60.
1-(2,4-Dimethylphenyl)-1,5,6,7-tetrahydro-4H-indazol-4-one
(4b-1)
Yield: 92% (276 mg); mp 127–128 °C; HPLC tR 3.05 min (95%);
GC/MS tR 6.3 min (100%).
1H NMR (300 MHz, CDCl3): = 7.94 (s, 1 H, CH), 7.06 (s, 1 H,
Ar), 7.01 (s, 2 H, Ar), 2.53 (t, 2 H, J = 6.3 Hz, CH2CO), 2.42 (t,
2 H, J = 6.3 Hz, CH2C=), 2.28 (s, 3 H, CH3), 2.03 (m, 2 H,
CH2CH2CH2), 1.95 (s, 3 H, CH3).
MS (ESI): m/z = 296.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C14H12F3N3O, 296.1011;
13C NMR (300 MHz, CDCl3): = 193.44, 150.79, 140.09, 138.08,
135.24, 134.73, 132.15, 127.59, 127.01, 119.29, 38.19, 23.66,
21.99, 21.40, 17.52.
MS (ESI): m/z = 241.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H16N2O, 241.1341; found,
found, 296.1008.
1-Pyridin-2-yl-1,5,6,7-tetrahydro-4H-indazol-4-one (4b-6)
Yield: 85% (226 mg); mp 125–126 °C; HPLC tR 2.60 min (92%);
GC/MS tR 6.0 min (100%).
1H NMR (300 MHz, CDCl3): = 8.38 (m, 1 H, CH), 7.97 (s, 1 H,
Ar), 7.89 (m, 1 H, Ar), 7.78 (m, 1 H, Ar), 7.18 (m, 1 H, Ar), 3.40 (t,
2 H, J = 6.3 Hz, CH2CO), 2.46 (t, 2 H, J = 5.7 Hz, CH2C=), 2.11 (m,
2 H, CH2CH2CH2).
13C NMR (300 MHz, CDCl3): = 194,15, 152.89, 151.14, 147.97,
139.02, 138.98, 122.32, 121.65, 115.85, 38.24, 25.25, 23.69.
MS (ESI): m/z = 214.2 [M + H]+.
241.1335.
1-Phenyl-1,5,6,7-tetrahydro-4H-indazol-4-one (4b-2)
Yield: 86% (228 mg); mp 139–140 °C (Lit.1a mp 140 °C); HPLC tR
2.66 min (94%); GC/MS tR 6.0 min (100%).
1H NMR (300 MHz, CDCl3): = 7.99 (s, 1 H, CH), 7.43 (m, 5 H,
Ar), 2.90 (t, 2 H, J = 6.3 Hz, CH2CO), 2.48 (t, 2 H, J = 6.3 Hz,
CH2C=), 2.09 (m, 2 H, CH2CH2CH2).
HRMS (ESI): m/z [M + H]+ calcd for C12H11N3O, 214.098; found,
13C NMR (300 MHz, CDCl3): = 193.45, 149.25, 138.69, 138.67,
129.63, 128.47, 123.80, 120.54, 38.10, 23.83, 23.46.
214.0984.
1-Cyclohexyl-1,5,6,7-tetrahydro-4H-indazol-4-one (4b-7)
Yield: 79% (215 mg); mp 87–88 °C; HPLC tR 2.77 min (100%);
GC/MS tR 5.98 min (100%).
MS (ESI): m/z = 213.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H12N2O, 213.1028; found,
213.1029.
1H NMR (300 MHz, CDCl3): = 7.81 (s, 1 H, CH=N), 3.87 (m, 1
H, CHN), 2.75 (t, 2 H, J = 6.0 Hz, CH2CO), 2.40 (t, 2 H, J = 6.0 Hz,
CH2C=), 2.10 (m, 2 H, CH2CH2CH2), 1.86 (m, 6 H, CH2 cyclohex-
yl), 1.64 (m, 2 H, CH2 cyclohexyl), 1.29 (m, 2 H, CH2 cyclohexyl).
13C NMR (300 MHz, CDCl3): = 193.42, 148.09, 137.04, 118.91,
58.75, 38.26, 32.74, 25.69, 25.26, 23.48, 21.49.
MS (ESI): m/z = 219.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H18N2O, 219.1497; found,
1-(2,4-Difluorophenyl)-1,5,6,7-tetrahydro-4H-indazol-4-one
(4b-3)
Yield: 83% (257 mg); mp 121–122 °C; HPLC tR 2.74 min (93%);
GC/MS tR 5.6 min (100%).
1H NMR (300 MHz, CDCl3): = 7.01 (s, 1 H, CH), 7.46 (m, 1 H,
Ar), 6.96 (m, 2 H, Ar), 2.70 (t, 2 H, J = 5.4 Hz, CH2CO), 2.47 (t, 2
H, J = 6 Hz, CH2C=), 2.10 (m, 2 H, CH2CH2CH2).
13C NMR (300 MHz, CDCl3): = 193.42, 164.79 (d), 161.43 (d),
158.28 (d), 154.91 (d), 151.86, 139.30, 129.76 (d), 122.93 (d),
120.34, 112.57 (d), 105.41 (t), 38.07, 23.54, 21.99.
219.1494.
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Synthesis of Pyrazoles, Pyrimidines and Isoxazoles
1673
1-(tert-Butyl)-1,5,6,7-tetrahydro-4H-indazol-4-one (4b-8)
Yield: 99% (238 mg); mp 80–81 °C; HPLC tR 2.57 min (100%);
GC/MS tR 4.77 min (100%).
4b-9
Yield: 76% (129 mg); mp 164–165 °C; HPLC tR 0.69 min (100%);
GC/MS tR 4.53 min (100%).
1H NMR (300 MHz, CDCl3): = 7.78 (s, 1 H, CH), 2.98 (t, 2 H,
J = 6.0 Hz, CH2CO), 2.40 (t, 2 H, J = 6.0 Hz, CH2C=), 2.10 (m, 2
H, CH2CH2CH2), 1.57 (s, 9 H, 3 CH3).
13C NMR (300 MHz, CDCl3): = 193.82, 148.21, 135.72, 120.81,
60.92, 37.76, 30.02, 24.93, 24.01.
MS (ESI): m/z = 193.4 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C11H16N2O, 193.1341; found,
MS (ESI): m/z = 137.2 [M + H]+.
1-Phenyl-5,6,7,8-tetrahydrocyclohepta[c]pyrazol-4(1H)-one
(4c-2)
Yield: 79% (223 mg); mp 106–108 °C; HPLC 4.62 tR min (93%);
GC/MS tR 6.37 min (100%).
1H NMR (300 MHz, CDCl3): = 8.01 (s, 1 H, CH), 7.41–7.30 (m,
5 H, Ar), 2.84 (br, 2 H, CH2CO), 2.67 (br, 2 H, CH2C=), 1.87 (br, 4
H, CH2CH2CH2CH2).
193.1344.
13C NMR (300 MHz, CDCl3): = 196.63, 146.09, 141.88, 139.07,
129.53, 129.04, 125.94, 123.61, 43.62, 27.54, 25.64, 22.80.
MS (ESI): m/z = 227.2 [M + H]+.
1,5,6,7-Tetrahydro-4H-indazol-4-one (4b-9)
Yield: 80% (136 mg); mp 164–165 °C; HPLC tR 0.56 min (100%);
GC/MS tR 4.53 min (100%).
1H NMR (300 MHz, CDCl3): = 7.94 (s, 1 H, CH), 2.83 (t, 2 H,
J = 5.7 Hz, CH2CO), 2.44 (t, 2 H, J = 5.4 Hz, CH2C=), 2.10 (m, 2
H, CH2CH2CH2).
HRMS (ESI): m/z [M + H]+ calcd for C14H14N2O, 226.1106; found,
227.1185.
One-Pot Preparation of Bicyclic 4-Acylpyrimidines 5 from 1,3-
Diketones via Enaminoketones; General Procedure
13C NMR (300 MHz, CDCl3): = 194.66, 153.17, 134.55, 118.95,
38.66, 23.77, 22.03.
In a Smith process vial, the 1,3-diketone 1a or 1b (1.25 mmol) and
DMFDMA (1.25 mmol) were mixed and the substituted amidine
monochloride was added (1.25 mmol) followed by addition of dis-
tilled H2O (3 mL). The vial was sealed with the appropriate cap with
septa and submitted to microwave irradiation for 120 s at 200 °C us-
ing the Smith Synthesizer. Upon cooling and stirring with a spatula
the product precipitated down from the reaction mixture. It was fil-
tered, washed with H2O and dried.
MS (ESI): m/z = 137.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C7H8N2O, 137.0715; found,
137.0709.
One-Pot Preparation of Bicyclic 4-Acylpyrazoles 4b and 4c
from 1,3-Diketones via Enaminoketones; General Procedure
In a Smith process vial, the 1,3-diketone 1b (140 mg, 1.25 mmol)
and DMFDMA (1.5 mmol) were mixed and the substituted hydra-
zine monochloride 2 was added (1.25 mmol) followed by addition
of distilled H2O (3 mL) and AcOH (3.25 mmol). The vial was sealed
with the appropriate cap with septa and submitted to microwave ir-
radiation for 120 s at 200 °C using the Smith Synthesizer. Upon
cooling and stirring with a spatula, the product precipitated down
from the reaction mixture. It was filtered, washed with H2O and
dried.
2-Phenyl-7,8-dihydroquinazolin-5(6H)-one (5a-1)
Yield: 54% (151 mg); mp 123–124 °C (Lit.3a mp 126–127 °C);
HPLC tR 4.96 min (100%); GC/MS tR 6.17 min (100%).
1H NMR (300 MHz, CDCl3): = 9.18 (s, 1 H, CH), 8.45 (m, 2 H,
Ar), 7.44 (m, 3 H, Ar), 3.08 (t, 2 H, J = 6.0 Hz, CH2CO), 2.66 (t, 2
H, J = 6.0 Hz, CH2C=), 2.17 (m, 2 H, CH2CH2CH2).
13C NMR (300 MHz, CDCl3): = 196.87, 172.13, 166.68, 157.14,
137.01, 132.05, 129.30, 128.95, 123.41 38.80, 32.34, 21.46.
MS (ESI): m/z = 225.2 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C14H12N2O, 225.1028; found,
4b-1
Yield: 83% (249 mg); mp 123–124 °C; HPLC tR 3.09 min (94%);
GC/MS tR 6.3 min (100%).
MS (ESI): m/z = 241.2 [M + H]+.
225.1027.
4b-2
2-Pyridin-4-yl-7,8-dihydroquinazolin-5(6H)-one (5a-2)
Yield: 68% (191 mg); mp 162–163 °C (Lit.10 mp 140–141 °C);
HPLC tR 3.19 min (100%); GC/MS tR 6.34 min (100%).
Yield: 87% (230 mg); mp 137–138 °C; HPLC tR 2.72 min (94%);
GC/MS tR 6.1 min (100%).
MS (ESI): m/z = 213.2 [M + H]+.
1H NMR (300 MHz, CDCl3): = 9.21 (s, 1 H, CH), 8.71 (m, 2 H,
Ar), 8.26 (m, 2 H, Ar), 3.10 (t, 2 H, J = 6.3 Hz, CH2CO), 2.67 (t, 2
H, J = 6.0 Hz, CH2C=), 2.18 (m, 2 H, CH2CH2CH2).
4b-6
Yield: 69% (183 mg); mp 126–127 °C; HPLC tR 2.63 min (92%);
GC/MS tR 6.0 min (100%).
MS (ESI): m/z = 214.2 [M+H]+.
13C NMR (300 MHz, CDCl3): = 196.55, 172.45, 164.85, 157.26,
150.77, 144.13, 124.57, 122.70, 38.74, 32.21, 21.32.
MS (ESI): m/z = 226.4 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H11N3O, 226.098; found,
226.0977.
4b-7
Yield: 66% (180 mg); mp 90–91 °C; HPLC tR 2.90 min (100%);
GC/MS tR 5.95 min (100%).
MS (ESI): m/z = 219.2 [M + H]+.
2-tert-Butyl-7,8-dihydroquinazolin-5(6H)-one (5a-3)
Yield: 21% (53 mg); mp 66–67 °C; HPLC tR 3.54 min; GC/MS tR
4.38 min (100%).
1H NMR (300 MHz, CDCl3): = 9.03 (s, 1 H, CH), 2.96 (t, 2 H,
J = 6. 0 Hz, CH2CO), 2.58 (t, 2 H, J = 6.0 Hz, CH2C=), 2.10 (m, 2
H, CH2CH2CH2), 1.30 (s, 9 H, t-C4H9).
4b-8
Yield: 78% (187 mg); HPLC tR 2.56 min (100%); GC/MS
tR 4.76min (100%).
MS (ESI): m/z = 193.2 [M + H]+.
13C NMR (300 MHz, CDCl3): = 197.08, 171.32, 156.30, 122.88,
38.78, 32.22, 29.90, 29.63, 21.51.
Synthesis 2002, No. 12, 1669–1674 ISSN 0039-7881 © Thieme Stuttgart · New York

1674
V. Molteni et al.
PAPER
MS (ESI): m/z = 205.2 (100%) [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C12H16N2O, 205.1341; found,
References
(1) (a) Schenone, P.; Mosti, L.; Menozzi, G. J. Heterocycl.
Chem. 1982, 19, 1355. (b) Dawood, K. M.; Farag, A. M.;
Kandeel, Z. E. J. Chem. Res., Synop. 1999, 88.
(2) (a) Lemke, T. L.; Sawhney, K. N. J. Heterocycl. Chem.
1982, 19, 1335. (b) Olivera, R.; SanMartin, R.; Dominguez,
E. J. Org. Chem. 2000, 65, 7010. (c) Olivera, R.;
SanMartin, R.; Dominguez, E. Tetrahedron Lett. 2000, 41,
4353.
(3) (a) Chen, W.-Y.; Gilman, N. W. J. Heterocycl. Chem. 1983,
20, 663. (b) Mosti, L.; Menozzi, G.; Schenone, P. J.
Heterocycl. Chem. 1983, 20, 649. (c) Menozzi, G.; Mosti,
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(d) Bruno, O.; Schenone, S.; Ranise, A.; Bondavalli, F.;
Filippelli, W.; Falcone, G.; Motola, G.; Mazzeo, F. Farmaco
1999, 54, 95.
205.1322.
2-Phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-5-one
(5b-1)
Yield 60% (143 mg); mp 65–66 °C (Lit.11 mp 64–65 °C); HPLC tR
3.58 min (100%); GC/MS tR 6.49 min (100%).
1H NMR (300 MHz, CDCl3): = 8.97 (s, 1 H, CH), 8.43 (m, 2 H,
Ar), 7.32 (m, 3 H, Ar), 3.15 (t, 2 H, J = 5.7 Hz, CH2CO), 2.77 (t, 2
H, 6.6 Hz, CH2C=), 1.92 (m, 4 H, CH2CH2CH2CH2).
13C NMR (300 MHz, CDCl3): = 202.41, 170.04, 165.78, 158.10,
137.04, 131.76, 129.10, 128.90, 41.59, 36.27, 23.95, 21.86.
MS (ESI): m/z = 239.0 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H14N2O, 239.1184; found,
(4) Jones, W. D. Jr.; Huber, E. W.; Grisar, J. M.; Schnettler, R.
A. J. Heterocycl. Chem. 1987, 24, 1221.
239.1186.
(5) (a) Menozzi, G.; Schenone, P.; Mosti, L. J. Heterocycl.
Chem. 1983, 20, 645. (b) Schenone, P.; Fossa, P.; Menozzi,
G. J. Heterocycl. Chem. 1991, 28, 453. (c) Olivera, R.;
SanMartin, R.; Dominguez, E. Synlett 2000, 1028.
(6) Cohnen, E.; Dewald, R. Synthesis 1987, 566.
(7) (a) Mosti, L.; Schenone, P.; Menozzi, G. J. Heterocycl.
Chem. 1985, 22, 1503. (b) Fossa, P.; Boggia, R.; Lo Presti,
E.; Mosti, L.; Dorigo, P.; Floreani, M. Farmaco 1997, 52,
523.
(8) Peet, N. P.; LeTourneau, M. E. Heterocycles 1991, 32, 41.
(9) Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9225.
(10) Reaction of phenylhydrazine with pentane-2,4-dione (29%),
3-oxo-3-phenylpropionic acid ethyl ester (20%), 1-
methanesulfonylpropan-2-one (32%), 2-methanesulfonyl-1-
phenylethanone (72%), N,N-diethyl-3-oxo-3-
phenylpropionamide (37%), and 3-oxo-3-
One-Pot Preparation of 5,6,7,8-Tetrahydro-4H-cyclohep-
ta[d]isoxazol-4-one (6b) from 1,3-Diketone 1b via Enaminoke-
tones; Typical Procedure
The diketone 1b (1.25 mmol) and DMFDMA (1.25 mmol) were
mixed and hydroxylamine hydrochloride was added (87 mg, 1.25
mmol) followed by addition of distilled H2O (0.5 mL). The com-
pound was purified by column chromatography upon evaporation
of H2O; yield: 34% (64 mg); mp 61–62 °C; GC/MS tR 3.75 min
(100%).
1H NMR (300 MHz, CDCl3): = 8.42 (s, 1 H, CH), 3.04 (t, 2 H,
J = 6.3 Hz, CH2CO), 2.66 (t, 2 H, J = 5.7 Hz, CH2C=), 2.04–1.84
(m, 4 H, CH2CH2CH2CH2).
13C NMR (300 MHz, CDCl3): = 194.72, 175.32, 150.61, 119.48,
44.71, 28.42, 24.65, 22.77.
HRMS (ESI): m/z [M + H]+ calcd for C8H9NO2, 151.0711; found,
152.0707.
phenylpropionitrile (10%) gave the yields shown in the
parenthesis.
(11) Stolle, W. A. W.; Veurink, J. M.; Marcelis, A. T. M.; van der
Plas, H. C. Tetrahedron 1992, 48, 1643.
(12) Tonkikh, N. N.; Strakov, A. Y.; Petrova, M. V. Chem.
Heterocycl. Compd. (Engl. Transl.) 2000, 36, 212.
(13) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66,
7945.
Acknowledgement
We thank Mark Suto, Peter Myers, and Robyn Rourick for their
support, technical assistance, and helpful discussions.
(14) An, J.; Bagnell, L.; Cablewski, T.; Strauss, C. R.; Trainor, R.
W. J. Org. Chem. 1997, 62, 2505.
Synthesis 2002, No. 12, 1669–1674 ISSN 0039-7881 © Thieme Stuttgart · New York