Modular synthesis of isoxazolopyridones and pyrazolopyridones

Article abstract of DOI:10.1016/j.tet.2006.12.044

Herein we described the preparation of two novel heterocyclic nuclei isoxazolopyridone and pyrazolopyridone. The syntheses are modular in nature and fast to execute. The title compounds were obtained pure without intervention of chromatography.

Full text of DOI:10.1016/j.tet.2006.12.044

Tetrahedron 63 (2007) 2047–2052
Modular synthesis of isoxazolopyridones and pyrazolopyridones
a
b
c
Mauro F. A. Adamo,a, Eleanor F. Duffy, Donato Donati and Piero Sarti-Fantoni
*
aCentre for Synthesis and Chemical Biology (CSCB), Department of Pharmaceutical and Medicinal Chemistry,
The Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland
bDipartimento di Chimica, Universitaꢀ di Siena, Via Aldo Moro, Siena 53100, Italy
cDipartimento di Chimica Organica ‘U. Schiff’, Universitaꢀ di Firenze, Via della Lastruccia, Sesto Fiorentino 50019, Italy
Received 12 October 2006; revised 29 November 2006; accepted 14 December 2006
Available online 17 December 2006
Abstract—Herein we described the preparation of two novel heterocyclic nuclei isoxazolopyridone and pyrazolopyridone. The syntheses are
modular in nature and fast to execute. The title compounds were obtained pure without intervention of chromatography.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
acids,7 or 3-indolepropionic acids8 were obtained in one-pot
from commercially available components 4 and 5 and a suit-
able Michael donor. In these syntheses, a number of compo-
nents reacted together in a Knoevenagel–Michael tandem
sequence.3,6–9 Considering the ease of reaction of 3 as a
Michael acceptor, we decided to explore the reaction of 3
with the anion of nitromethane 6, which has been repeatedly
reported as an excellent nucleophile (Scheme 1).10
Fused heterocycles have a wide variety of uses in medicinal
chemistry.1 Despite the wealth of fused heterocycles devel-
oped to date, there is a continuing demand for novel fused
heterocycles due to the plethora of medicinal applications
which these molecular types have.2 As a part of our ongoing
efforts in developing multicomponent one-pot procedures
using commercially available materials,3–9 we envisaged a
novel modular synthesis leading to fused isoxazolopyridones
1 and pyrazolopyridones 2 (Fig. 1). We are now pleased
to report a detailed study on the preparation of a small family
of compounds 1 and 2. We have shown that all except one of
the five synthetic steps can be carried out in one pot, thus
making this two-step procedure a simple and efficient way
of accessing these molecules.
We reasoned that if nitromethane 6 was reacted with 3
in a Michael reaction, then adducts 7 could easily be pre-
pared through a one-pot procedure involving a sequential
Knoevenagel–Michael reactionfrom commerciallyavailable
components 4, 5 and 6. Adducts 7 could then be elaborated
to obtain two novel heterocyclic types isoxazolopyridones 1
and pyrazolopyridones 2 (Scheme 1).
This involved transformation of 7 to carboxylic acid 8 using
the Victor-Meyer reaction,11 and a subsequent tandem re-
duction–lactamisation sequence to cyclise 8 to 1.12 Signifi-
cantly, compound 8 could serve as a precursor of pyrazole
acid 9. This transformation is viable only for 4-nitro-
isoxazoles where position 5 of the heterocycle is rendered
electrophilic by conjugation to a nitro group.13 Application
of the tandem reduction–lactamisation sequence to 9 would
then lead to scaffolds 2.
H
N
H
N
O
O
Ar
Ar
N
N
O
1
N
H
2
Figure 1. Target compounds 1 and 2.
2. Results and discussion
Our approach to the development of multicomponent
one-pot syntheses is based on the generation of building
blocks containing multiple functionalities, each of which can
be selectively reacted.3–9 We have recently shown some syn-
thetic applications of 3-methyl-4-nitro-5-styrylisoxazoles 3
(Fig. 2), in which spiroisoxazolines,3,6 3-heteroarylpropionic
NO2
NO2
N
O
O
N
Ar
O
+
Ar
E1
+
E2
3
4
5
electrophilic
centres
Keywords: Fused isoxazoles; Polyfunctional scaffold; Fused pyrazoles.
* Corresponding author. Tel.: +353 1 4022208; fax: +353 1 4022168;
e-mail: madamo@rcsi.ie
Figure 2. A polyfunctional scaffold: 3-methyl-4-nitro-5-styryl-isoxazoles 3.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.044

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M. F. A. Adamo et al. / Tetrahedron 63 (2007) 2047–2052
H
N
O
NO2
NO2
H
N
Tandem reduction
O
Tandem reduction
lactamisation sequence
lactamisation sequence
Ar
N
N
N
Ar
N
H
O
N
N
H
O
Ar
9
COOH
Ar
8
COOH
1
2
Victor-Meyer
reaction
NO2
O
NO2
Tandem Knoevenagel
Michael sequence
Ar
N
+
O
5
4
N
O
one-pot
NO2
H3C–NO2
6
Ar
7
Scheme 1. A disconnection of compounds 1 and 2.
Table 1. Yields (%) for the one-pot synthesis of 7a–c and 8a–c and for the
preparation of 9a–c, 1a–c and 2a–c
In our first experiment, styrylisoxazole 3a was prepared and
subsequently reacted with 3 equiv of nitromethane 6. We
were delighted to find that a limited amount of piperidine was
sufficient to obtain adduct 7a in 89% yield (Scheme 2). We
then optimised this reaction procedure and found that only
1.1 equiv of 6 was required to obtain 7a in similar high
yields. This was an important finding, as a limited catalyst
loading and a ratio of reagents close to one usually maxi-
mises the purity of the resultant products and is actually a re-
quirement of tandem reaction processes. We then confirmed
that components 4, 5a and 6 could be reacted in a one-pot
fashion to give adduct 7a in high yields (Scheme 1 and
Table 1). The optimised conditions involved: (a) reacting
1 equiv of 4 with 1 equiv of 5a in the presence of 0.1 equiv
piperidine in ethanol, at 65 ꢀC for 2 h; (b) addition of
1.1 equiv of nitromethane and continuation of the reaction
for 4 h. Compound 7a was obtained in 85% isolated yield
after chromatography. Alternatively, compound 7a could
be purified by crystallisation from hot ethanol in 60–75%
isolated yield. Adduct 7a was then subjected to the Victor-
Meyer reaction,11 and it was confirmed that acid 8a could
be obtained in high yields (Scheme 2). We then considered
extending the one-pot preparation of 7a to include the trans-
formation of 7a to 8a. Thus, we reacted 4, 5a–c and 6 in the
presence of 0.1 equiv of piperidine, then we added an excess
of 36% w/v HCl and heated at reflux the reaction mixture.
Compounds 8a–c were obtained through this one-pot proce-
dure in good yield (Scheme 3 and Table 1).
Compound
Structure
a R¼H b R¼p-Cl c R¼m-OCH3
(%)
(%)
(%)
NO2
N
O
7
94
82
80
NO2
R
NO2
N
O
8
1
9
2
80
84
99
81
96
81
95
89
75
77
95
86
COOH
R
H
N
O
N
O
R
NO2
N
N
H
COOH
R
H
N
O
N
With compounds 8a–c in hand we turned our attention to the
reduction of the aromatic nitro group. One very common
methodology for the reduction of nitroisoxazoles involves
the use of SnCl2 as the reductant under strongly acidic con-
ditions (Scheme 4). We selected this procedure as it presents
the additional advantage of promoting a subsequent lactami-
sation of the resulting d-aminoacid 10a to cyclic lactam 1a
N
H
R
due to the ability of Sn4+ formed during the reaction to act
as a Lewis acid.12 Cyclisation of d-aminoacids has been
repeatedly reported to occur either under strongly acidic
NO2
O
NO2
NO2
NO2
H3C NO2
6
HCl
N
N
N
N
O
10 mol%
Piperidine
O
10 mol%
Piperidine
89%
O
O
NO2
Ph
COOH
Ph
Ph
4
5a
3a
7a
8a
10 mol%
Piperidine
H3C NO2
6
Scheme 2. Stepwise preparation of 7a and 8a and one-pot preparation of 7a.

M. F. A. Adamo et al. / Tetrahedron 63 (2007) 2047–2052
2049
NO2
NO2
R1 NHNH2
N
N
O
N
NO2
O
NO2
R'
Ar
5a-c
N
1. Piperidine (0.1 eq.)
2. HCl conc (excess)
R' = H, CH3, Ph
N
11
12
O
O
4
COOH
8a-c
Ar
Scheme 5. Conversion of 4-nitroisoxazoles to 4-nitropyrazoles.
H3C NO2
6
5a, 8a Ar = Ph
5b, 8b Ar = p-Cl-Ph
5c, 8c Ar = m-OCH3-Ph
found that 9a was obtained in nearly quantitative yield
(Scheme 6). Compound 9a was obtained in sufficient purity
to be used directly in the following step without the need for
further purification, and was reacted to obtain the pyrazolo-
pyridinone 2a following the procedure developed for com-
pound 1a.
Scheme 3. One-pot synthesis of carboxylic acid 8a–c.
14
conditions
or in the presence of a suitable Lewis acid
catalyst.15 The reaction is believed to involve a dehydration
of the carboxylic acid to generate a reactive acylium ion,
which then undergoes nucleophilic attack by the amine
functionality.14,15 Therefore compound 8a was reacted in
the presence of 2.2 equiv of SnCl2 under acidic conditions
(HCl). We observed that the solvent used, the reaction tem-
perature and reaction time were all critical to obtain the
desired product 1a (Scheme 4).
The generality of these newly developed syntheses has been
demonstrated with respect to variation in the aldehyde
component by synthesising a small family of compounds
(Table 1). Compounds 1a–c and 2a–c were all obtained in
good isolated yields without the use of chromatography.
In conclusion we have developed two novel one-pot synthe-
ses in which 3,5-dimethyl-4-nitroisoxazole 4, aromatic alde-
hydes 5a–c and nitromethane 6 were reacted to furnish
adducts 7a–c or 8a–c. We elaborated on 7a–c and 8a–c to
obtain two novel heterocyclic cores 1a–c and 2a–c. These
reactions are modular in nature, fast to execute and can be
run without the intervention of chromatography. We believe
that this study will be of interest for those involved in drug
discovery and in the preparation of novel heterocyclic cores.
We found that reduction of the nitro group in 8a to the amino
group was a fast process, and full conversion of 8a was ob-
served after an hour. Full conversion of 8a was also observed
at room temperature. However, we found that appearance of
1a only occurred when the reaction was carried out at high
temperatures (>70 ꢀC) and after prolonged reaction times.
We did not attempt to isolate 10a, which is probably the
intermediate formed during the synthesis of 1a. In order to
optimise this sequence the transformation of 8a to 1a was
studied under a number of different conditions, including dif-
ferent solvent systems (methanol, ethanol, methanol/water,
ethanol/water, dichloromethane, toluene, tetrahydrofuran
and tetrahydrofuran/water) and different reaction times. This
study identified a 1:1 mixture of water/tetrahydrofuran as the
optimum solvent system. Typically, in an optimised proce-
dure, 1 mmol of 8a–c was heated at reflux with 2.2 equiv
of SnCl2 and 1 mL of concd HCl in 20 mL of 1:1 THF/water
for 16 h.
3. Experimental
3.1. General experimental
1H and 13C spectra were recorded on 200 or 400 MHz spec-
trometers at ambient temperatures. 1H NMR spectral assign-
1
ments are supported by H–1H COSY and 13C–1H COSY
where necessary. For 1H NMR recorded in CDCl3, chemical
shifts (dH) are quoted in parts per million (ppm) and are ref-
erenced to the residual solvent peak. The following abbrevi-
ations are used: s, singlet; d, doublet; t, triplet; dd, doublet of
doublets; dt, doublet of triplets; tt, triplet of triplets; m, mul-
tiplet; br, broad. Coupling constants (J) were recorded in
hertz (Hz) to the nearest 0.1 Hz. Carbon spectra are sup-
ported by DEPT analysis where necessary. Infrared (IR)
spectra were recorded as thin films between NaCl plates.
Absorption maximum (nmax) was reported in wave numbers
(cmꢁ1) and only selected peaks are reported. The following
abbreviations are used: w, weak; m, medium; s, strong; br,
broad. Flash chromatography was carried out using silica
gel 60 (0.040–0.063 mm, 230–400 mesh) as the stationary
phase. Thin layer chromatography was carried out on alu-
minium backed plates pre-coated with silica gel 60, which
One important characteristic of nitroisoxazoles is the activa-
tion of position 5 to nucleophilic attack due to the electron
withdrawing effects of the nitro functionality. In particular,
hydrazine and alkyl or aryl hydrazines have been shown
by Musante to convert the 4-nitroisoxazolyl core 11 into
a 4-nitropyrazolyl core 12 (Scheme 5).13 Musante also re-
ported that this reaction usually proceeded to completion
when nitroisoxazoles were reacted with equimolar quantities
of hydrazine. This is a notable feature and qualifies this
transformation as a click reaction.16
Significantly, this reaction expands the range of diverse
products achievable from a 4-nitroisoxazole core. Therefore,
we reacted 8a with an equimolar quantity of hydrazine and
NO2
NH2
H
N
O
SnCl2 2.2 eq.
8a, 10a, 1a Ar = Ph
8b, 10b, 1b Ar = p-Cl-Ph
8c, 10c, 1c Ar = m-OCH3-Ph
N
N
Ph
O
O
N
THF : H2O (1 : 1) 16h
COOH
O
Ph
Ph
COOH
10a-c
8a-c
1a-c
Scheme 4. Synthesis of isoxazolopyridones 1a–c.

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M. F. A. Adamo et al. / Tetrahedron 63 (2007) 2047–2052
NO2
H
N
O
NO2
N
SnCl2 2.2 eq.
NaOH 1 eq., EtOH
NH2NH2 1 eq., 12h.
N
Ar
O
N
N
H
THF : H2O (1 : 1) 16h
N
H
Ar
8a-c
COOH
Ar
COOH
9a-c
2a-c
8a, 9a, 2a Ar = Ph
8b, 9b, 2b Ar = p-Cl-Ph
8c, 9c, 2c Ar = m-OCH3-Ph
Scheme 6. Preparation of pyrazolopyridinone 2a–c.
were visualised by quenching of UV fluorescence (lmax
¼
7.23–6.75 (3H, m, m-CH3O–Ph), 4.73 (2H, dq, J¼13.2,
7.8, CH2NO2), 4.17–4.09 (1H, m, CHPh(m-CH3O)), 3.80
(3H, s, CH3O), 3.78 (1H, dd, J¼15.0, 9.1, Is-CHaHb), 3.58
(1H, dd, J¼15.0, 6.5, CHaHbCHPh(p-Cl)), 2.51 (3H, s,
CH3C]N); dC (100 MHz, DMSO-d6) 170.6 (O–C]
C–NO2), 165.6 (m-CH3O–Ph), 155.2 (CH3C]N), 137.7
(m-CH3O–Ph), 132.1 (O–C]C–NO2), 129.9 (m-CH3O–
Ph), 118.7 (m-CH3O–Ph), 113.3 (m-CH3O–Ph), 112.7
(m-CH3O–Ph), 78.7 (CH2NO2), 54.8 (CH3O), 41.1
(CHPh), 30.7 (Is-CH2), 11.1 (CH3C]N). HRMS (EI) found
[MꢁH]+: 320.0898, C14H14N3O6 requires: 320.0883; m/z
(EI) 320 (50, [MꢁH]+).
254 nm) or by staining with either 10% w/v ammonium
molybdate in 2 M sulfuric acid or basic potassium perman-
ganate solution (followed by heat) as appropriate. Retention
factors (Rf) are reported to be ꢂ0.5.
3.2. General procedure for the preparation of 7a–c
To a stirred solution of 3,5-dimethyl-4-nitroisoxazole 4
(426 mg, 3 mmol) in ethanol (10 mL), were added piperi-
dine (26 mg, 0.3 mmol, 0.1 equiv) and an aromatic alde-
hyde 5a–c (3 mmol, 1 equiv). The resulting solution was
reacted at 65 ꢀC for 2 h, before nitromethane 6 (200 mg,
3.3 mmol, 1.1 equiv) was added. The reaction was continued
at 65 ꢀC for a further 4 h. The solvent was then evaporated
in vacuo and the product was isolated by column chromato-
graphy.
3.3. General procedure for the one-pot preparation of
compounds 8a–c
To a stirred solution of 3,5-dimethyl-4-nitroisoxazole 4
(426 mg, 3 mmol) in ethanol (10 mL), were added piperi-
dine (26 mg, 0.3 mmol, 0.1 equiv) and an aromatic alde-
hyde 5a–c (3 mmol, 1 equiv). The resulting solution was
reacted at 65 ꢀC for 2 h, before nitromethane 6 (200 mg,
3.3 mmol, 1.1 equiv) was added. The reaction was continued
at 65 ꢀC for a further 4 h, then diluted with 36% w/v HCl
(20 mL) and heated at reflux for 24 h. The reaction mixture
was then cooled to room temperature and extracted with
chloroform (100 mLꢃ2). The sodium salt of the carboxylic
acid 8a–c was extracted from the organic layer using a satu-
rated aqueous solution of NaHCO3 (20 mL). The water layer
was slowly acidified to pH¼4 by dropwise addition of concd
HCl. The product was then precipitated with cooling to 4 ꢀC
or alternatively extracted into chloroform and concentrated
in vacuo.
3.2.1. 3-Methyl-4-nitro-5-(3-nitro-2-phenylpropyl)isox-
azole7a.Colourless solid(820 mg, 94%yield);Rf¼0.2(ethyl
acetate/petroleum ether 1:9); mp 116–118 ꢀC (ethanol); nmax
(Film)/cmꢁ1: 1581m, 1576m; dH (400 MHz, DMSO-d6)
7.31–7.20 (5H, m, Ph), 4.78–4.69 (2H, m, CH2NO2), 4.21–
4.10 (1H, m, CHPh), 3.76 (1H, dd, J¼15.0, 9.0, Is-CHaHb),
3.55 (1H, dd, J¼15.0, 6.5, CHaHbCHPh), 2.50 (3H, s,
CH3C]N); dC (100 MHz, DMSO-d6) 170.5 (O–C]C–
NO2), 155.3 (CH3C]N), 136.2 (Ph), 131.5 (O–C]C–
NO2), 128.9 (Ph), 128.5 (Ph), 126.7 (Ph), 78.7 (CH2NO2),
41.1 (CHPh), 30.8 (Is-CH2), 11.1 (CH3C]N). HRMS
(EI) found [MꢁH]+: 290.0763, C13H12N3O5 requires:
290.0777; m/z (EI) 290 (100%, [MꢁH]+).
3.2.2. 5-[2-(4-Chlorophenyl)-3-nitropropyl]-3-methyl-4-
nitroisoxazole 7b. Colourless solid (819 mg, 82% yield);
Rf¼0.3 (ethyl acetate/petroleum ether 15:85); mp 119–
121 ꢀC (ethanol); nmax (Film)/cmꢁ1: 1580m, 1575m; dH
(400 MHz, CDCl3) 7.32 (2H, d, J¼7.9, p-Cl–Ph), 7.19
(2H, d, J¼7.9, p-Cl–Ph), 4.71 (2H, d, J¼8.0, CH2NO2),
4.20–4.12 (1H, m, CHPh(p-Cl)), 3.76 (1H, dd, J¼15.0,
9.1, Is-CHaHb), 3.56 (1H, dd, J¼15.0, 6.5, CHaHbCHPh-
(p-Cl)), 2.52 (3H, s, CH3C]N); dC (100 MHz, DMSO-d6)
170.1 (O–C]C–NO2), 155.3 (CH3C]N), 134.6 (p-Cl–
Ph), 134.6 (p-Cl–Ph), 134.2 (O–C]C–NO2), 129.1 (p-Cl–
Ph), 128.1 (p-Cl–Ph), 78.5 (CH2NO2), 40.5 (CHPh), 30.6
(Is-CH2), 11.1 (CH3C]N). HRMS (EI) found [MꢁH]+:
324.0381, C13H11ClN3O5 requires: 324.0387; m/z (EI) 324
(100, [MꢁH]+).
3.3.1. 3-(3-Methyl-4-nitroisoxazol-5-yl)-2-phenylprop-
ionic acid 8a. Colourless solid (662 mg, 80% yield);
Rf¼0.1 (ethyl acetate/petroleum ether 40:60); mp 145–
146 ꢀC; nmax (Film)/cmꢁ1: 3420b, 1701s; dH (400 MHz,
CDCl3) 7.36–7.27 (5H, m, Ph), 4.32 (1H, t, J¼8.1, CHPh),
3.96 (1H, dd, J¼15.0, 8.1, Is-CHaHb), 3.71 (1H, dd,
J¼15.0, 8.1, Is-CHaHb), 2.54 (3H, s, CH3C]N); dC
(100 MHz, CDCl3) 174.7 (C]O), 171.3 (O–C]C–NO2),
155.2 (CH3C]N), 135.5 (Ph), 131.7 (O–C]C–NO2),
128.7 (Ph), 128.0 (Ph), 127.3 (Ph), 46.9 (CHPh), 29.5
(Is-CH2), 11.1 (CH3C]N). HRMS (EI) found [MꢁH]+:
275.0675, C13H11N2O5 requires: 275.0668; m/z (EI) 275
(50, [MꢁH]+).
3.3.2. 2-(4-Chlorophenyl)-3-(3-methyl-4-nitroisoxazol-
5-yl)propionic acid 8b. Colourless solid (894 mg, 96%
yield); Rf¼0.2 (ethyl acetate/petroleum ether 40:60); mp
151–152 ꢀC (ethanol); nmax (Film)/cmꢁ1: 3412b, 1698s; dH
(400 MHz, CDCl3) 7.34 (2H, d, J¼7.8, p-Cl–Ph), 7.27
(2H, d, J¼7.8, p-Cl–Ph), 4.28 (1H, t, J¼7.5, CHPh(p-Cl)),
3.2.3. 5-[2-(3-Methoxyphenyl)-3-nitropropyl]-3-methyl-
4-nitroisoxazole 7c. Colourless solid (781 mg, 80% yield);
Rf¼0.2 (ethyl acetate/petroleum ether 10:90); mp 112–
114 ꢀC (ethanol); nmax (Film)/cmꢁ1: 1581m, 1575m;
dH (400 MHz, CDCl3) 7.28–7.25 (1H, m, m-CH3O–Ph),

M. F. A. Adamo et al. / Tetrahedron 63 (2007) 2047–2052
2051
3.92 (1H, dd, J¼15.1, 7.5, Is-CHaHb), 3.69 (1H, dd, J¼15.1,
7.5, Is-CHaHb), 2.54 (3H, s, CH3C]N); dC (100 MHz,
CDCl3) 176.6 (C]O), 170.8 (O–C]C–NO2), 155.3
(CH3C]N), 134.1 (p-Cl–Ph), 133.7 (p-Cl–Ph), 130.3
(O–C]C–NO2), 128.9 (p-Cl–Ph), 128.3 (p-Cl–Ph), 46.6
(CHPh(p-Cl)), 30.3 (Is-CH2), 11.1 (CH3C]N). HRMS
(EI) found [MꢁH]+: 309.0269, C13H10ClN2O5 requires:
309.0278; m/z (EI) 309 (20, [MꢁH]+).
137.6, 132.1, 130.0, 129.3 (p-Cl–Ph), 128.1 (p-Cl–Ph),
47.7 (CH), 30.5 (CH2), 11.2 (CH3C]N). HRMS (EI) found
[MꢁH]+: 308.0433, C13H11N3O4Cl requires: 308.0438; m/z
(EI) 308 (95, [MꢁH]+).
3.4.3. 2-(3-Methoxyphenyl)-3-(5-methyl-4-nitro-2H-pyr-
azol-3-yl)propionic acid 9c. Colourless solid (869 mg,
95% yield); Rf¼0.6 (acetone/petroleum ether 40:60); mp
163–165 ꢀC (ethanol); nmax (Film)/cmꢁ1: 3214–3065b,
1707s; dH (400 MHz, DMSO-d6) 7.13–7.09 (1H, m,
m-CH3O–Ph), 6.82–6.69 (3H, m, m-CH3O–Ph), 3.78 (1H,
t, J¼7.2, CHPh(m-CH3O)), 3.70 (3H, s, CH3O), 3.47 (1H,
dd, J¼15.1, 7.2, Is-CHaHb), 3.22 (1H, dd, J¼15.1, 7.2,
Is-CHaHb), 2.38 (3H, s, CH3C]N); dC (100 MHz, CDCl3)
175.3 (C]O), 157.8 (m-CH3O–Ph), 145.6 (N–C]C–
NO2), 143.7 (CH3C]N), 143.4 (HN–C]C–NO2), 129.7
(m-CH3O–Ph), 128.8 (m-CH3O–Ph), 120.1 (m-CH3O–Ph),
113.5 (m-CH3O–Ph), 111.3 (m-CH3O–Ph), 54.8 (CH3O),
51.6 (CHPh), 30.8 (Pyr-CH2), 13.1 (CH3C]N). HRMS
(EI) found [MꢁH]+: 304.0920, C14H13N3O5 requires:
304.0933; m/z (EI) 304 (50, [MꢁH]+).
3.3.3. 2-(3-Methoxyphenyl)-3-(3-methyl-4-nitroisoxazol-
5-yl)propionic acid 8c. Colourless solid (689 mg, 75%
yield); Rf¼0.2 (ethyl acetate/petroleum ether 50:50); mp
138–139 ꢀC (ethanol); nmax (Film)/cmꢁ1: 3450b, 1699s; dH
(400 MHz, DMSO-d6) 7.28–7.24 (1H, m, m-CH3O–Ph),
6.89–6.84 (3H, m, m-CH3O–Ph), 4.17 (1H, t, J¼7.0,
CHPh(m-CH3O)), 3.86 (1H, dd, J¼15.1, 7.0, Is-CHaHb),
3.73 (3H, s, m-CH3O–Ph), 3.59 (1H, dd, J¼15.1, 7.0,
Is-CHaHb), 2.44 (3H, s, CH3C]N); dC (100 MHz, DMSO-
d6) 173.0 (C]O), 172.8 (O–C]C–NO2), 165.5 (m-CH3O–
Ph), 155.3 (CH3C]N), 139.3 (m-CH3O–Ph), 130.3
(O–C]C–NO2), 128.6 (m-CH3O–Ph), 119.8 (m-CH3O–Ph),
113.6 (m-CH3O–Ph), 113.0 (m-CH3O–Ph), 55.1 (CH3O),
47.2 (CHPh(m-CH3O)), 31.30 (Is-CH2), 11.1 (CH3C]N).
HRMS (EI) found [MꢁH]+: 305.0787, C14H13N2O6 requires:
305.0774; m/z (EI) 305 (20, [MꢁH]+).
3.5. Procedure for the preparation of compounds 1a–c
and 2a–c
Compounds 8a–c or 9a–c (1 mmol) were combined with
2.2 equiv of SnCl2$2H2O (490 mg, 6.6 mmol), THF
(20 mL), water (20 mL) and 36% w/v HCl (1 mL). The reac-
tants were heated at reflux for 16 h and then cooled to room
temperature. THF was evaporated in vacuo and the water
layer was extracted with diethyl ether (100 mLꢃ5). The
organic layer was dried over MgSO4 and concentrated
in vacuo to give a colourless solid.
3.4. General procedure for the preparation of
compounds 9a–c
In a round bottom flask were put compounds 8a–c (3 mmol),
NaOH (120 mg, 3 mmol, 1 equiv), ethanol (10 mL), and
hydrazine hydrate (0.15 mL, 3 mmol). The reaction mixture
was stirred at 75 ꢀC for 12 h. It was then transferred into
a large beaker, diluted with water (120 mL) and cooled
with an ice-bath. It was acidified with 3 M HCl until a white
precipitate was obtained. The precipitate was extracted into
ethyl acetate (50 mLꢃ2), washed with water (50 mL), dried
over Na2SO4 and evaporated in vacuo.
3.5.1. 3-Methyl-6-phenyl-6,7-dihydro-4H-isoxazolo[4,5-
b]pyridine-5-one 1a. Colourless solid (192 mg, 84% yield);
Rf¼0.2 (ethyl acetate/acetone/petroleum ether 25:15:60);
mp 179–180 ꢀC (ethanol); nmax (Film)/cmꢁ1: 3440–3158b,
1667s; dH (400 MHz, acetone-d6) 12.85 (1H, s, HNC]O),
7.37–7.29 (5H, m, Ph), 4.19 (1H, t, J¼8.0, CHPh), 3.87
(1H, dd, J¼15.6, 8.0, CHaHbCHPh), 3.59 (1H, dd, J¼15.6,
8.0, CHaHbCHPh), 2.44 (3H, s, CH3C]N); dC (100 MHz,
DMSO-d6) 173.1, 172.7, 155.5, 137.8, 129.9, 128.8, 127.7,
47.2, 31.1, 11.5. HRMS (EI) found [M+H]+: 229.9761,
C13H13N2O2 requires: 229.0977;m/z (EI) 229 (100, [M+H]+).
3.4.1. 3-(5-Methyl-4-nitro-2H-pyrazol-3-yl)-2-phenyl-
propionic acid 9a. Colourless solid (810 mg, 99% yield);
Rf¼0.6 (ethyl acetate/petroleum ether 90:10); mp 181–
183 ꢀC (ethanol); nmax (Film)/cmꢁ1: 3247–3083b, 1708s;
dH (400 MHz, acetone-d) 7.25–7.14 (5H, m, Ph), 3.84
(1H, dd, J¼9.0, 7.5, CHPh), 3.51 (1H, dd, J¼15.1, 9.0,
Is-CHaHb), 3.20 (1H, dd, J¼15.1, 7.5, Is-CHaHb), 2.39
(3H, s, CH3C]N); dC (100 MHz, CDCl3) 175.4 (C]O),
145.7 (N–C]C–NO2), 143.6 (CH3C]N), 141.7 (HN–
C]C–NO2), 129.7 (Ph), 127.9 (Ph), 127.8 (Ph), 126.0 (Ph),
51.4 (CHPh), 30.9 (Is-CH2), 13.0 (CH3C]N). HRMS (EI)
found [MꢁH]+: 274.0821, C13H12N2O5 requires: 274.0828;
m/z (EI) 274 (20, [MꢁH]+).
3.5.2. 6-(4-Chlorophenyl)-3-methyl-6,7-dihydro-4H-isox-
azolo[4,5-b]pyridin-5-one 1b. Colourless solid (213 mg,
81% yield); Rf¼0.2 (ethyl acetate/petroleum ether 20:80),
mp 181–182 ꢀC (ethanol); nmax (Film)/cmꢁ1: 3440–3158b,
1705s; dH (400 MHz, DMSO-d6) 13.0 (1H, s, HNC]O),
7.23 (2H, d, J¼7.3, p-ClPh), 7.16 (2H, d, J¼7.3, p-ClPh),
4.22 (1H, t, J¼8.0, CHPh(p-Cl)), 3.87 (1H, dd, J¼15.6,
8.0, CHaHbCH), 3.58 (1H, dd, J¼15.6, 8.0, CHaHbCH),
2.44 (3H, s, CH3C]N); dC (100 MHz, DMSO-d6) 173.1,
172.6, 155.5, 136.7, 132.2, 129.7, 128.7, 46.7 (CH), 30.8
(CH2), 9.2 (CH3C]N). HRMS (EI) found [M+H]+:
263.0588, C13H12ClN2O2 requires: 263.0587; m/z (EI) 263
(20, M+H+).
3.4.2. 2-(4-Chlorophenyl)-3-(5-methyl-4-nitro-2H-pyr-
azol-3-yl)propionic acid 9b. Colourless solid (880 mg,
95% yield); Rf¼0.1 (ethyl acetate/petroleum ether 1:1);
mp 188–190 ꢀC (ethanol); nmax (Film)/cmꢁ1: 3250–3083b,
1710s; dH (400 MHz, DMSO-d6) 7.41 (2H, d, J¼8.5,
p-Cl–Ph), 7.37 (2H, d, J¼8.5, p-Cl–Ph), 4.28 (1H, t,
J¼8.0, CHPh(p-Cl)), 3.72 (1H, dd, J¼15.0, 7.5, Py–CHaHb),
3.33 (1H, dd, J¼15.0, 7.5, Py–CHaHb), 2.54 (3H, s,
CH3C]N); dC (100 MHz, CDCl3) 172.8 (C]O), 157.7
(C]N), 145.0 (N–C]C–NO2), 142.4 (HN–C]C–NO2),
3.5.3. 6-(3-Methoxyphenyl)-3-methyl-6,7-dihydro-
4H-isoxazolo[4,5-b]pyridine-5-one 1c. Colourless solid
(199 mg, 77% yield); Rf¼0.2 (ethyl acetate/petroleum ether

2052
M. F. A. Adamo et al. / Tetrahedron 63 (2007) 2047–2052
20:80); mp 164–166 ꢀC (ethanol); nmax (Film)/cmꢁ1: 3480–
3120b, 1707s; dH (400 MHz, DMSO-d6) 13.2 (1H, s,
HNC]O), 7.13–7.07 (1H, m, m-CH3O–Ph), 6.85–6.71
(3H, m, m-CH3O–Ph), 4.25 (1H, t, J¼7.8, CHAr), 3.88
(1H, dd, J¼15.8, 8.0, CHaHbCH), 3.70 (3H, s, CH3O),
3.57 (1H, dd, J¼15.8, 8.0, CHaHbCH), 2.42 (3H, s,
CH3C]N); dC (100 MHz, DMSO-d6) 173.0, 172.6, 139.9,
155.5, 136.7, 130.5, 122.3, 115.7, 112.8, 57.9, 45.7 (CH),
30.3 (CH2), 9.2 (CH3C]N). HRMS (EI) found [M+H]+:
259.1079, C14H15N2O3 requires: 259.1082; m/z (EI) 259
(80, [M+H]+).
dd, J¼14.7, 7.9, CHaHbCHPh), 3.35 (1H, s, br, HNC]O),
2.50 (3H, s, CH3C]N), 2.46 (1H, s, br, NH); dC (100 MHz,
DMSO-d6) 172.3 (C]O), 165.3, 140.5, 136.8, 128.6, 122.5,
121.7, 119.8, 113.5, 112.5, 56.0 (CH3), 48.3 (CHPh), 30.7
(CH2CH), 8.0 (CH3C]N). HRMS (EI) found [MꢁH]+:
256.1100, C14H14N3O2 requires: 256.1086; m/z (EI) 256
(50, [MꢁH]+).
Acknowledgements
We like to acknowledge The Royal Society of Chemistry for
a grant to M.F.A.A., the RCSI Research Committee and
PTRLI cycle III for a grant to E.F.D.
3.5.4. 6-Phenyl-3-methyl-1,4,6,7-tetrahydropyrazolo-
[4,3-b]pyridin-5-one 2a. Colourless solid (183 mg, 81%
yield); Rf¼0.1 (acetone/petroleum ether 3:7); mp 272–
275 ꢀC (ethanol); nmax (Film)/cmꢁ1: 3460–3120b, 1665s;
dH (400 MHz, DMSO-d6) 12.00 (1H, s, HNC]O), 9.92
(1H, s, HN–N), 7.15–7.00 (5H, Ph), 3.87 (1H, t, J¼7.0,
CHPh), 3.46 (1H, dd, J¼15.2, 7.0, CHaHbCHPh), 3.11
(1H, dd, J¼15.2, 7.0, CHaHbCHPh), 2.41 (3H, s,
CH3C]N); dC (100 MHz, DMSO-d6) 169.6 (C]O),
140.3 (Ph), 136.7, 128.1, 128.0, 126.1, 122.4, 118.6, 46.9
(CHPh), 27.6 (CH2CH), 8.2 (CH3C]N). HRMS (EI) found
[MꢁH]+: 226.0986, C13H12N3O requires: 226.0980; m/z
(EI) 226 (100, [MꢁH]+).
References and notes
1. Sperry, J. B.; Wright, D. L. Curr. Opin. Drug Discov. Devel.
2005, 8, 723; Ziegert, R. E.; Toraeng, J.; Knepper, K.;
Braese, S. J. Comb. Chem. 2005, 7, 147.
2. Loughlin, W. A.; Tyndall, J. D. A.; Glenn, M. P.; Fairlie, D. P.
Chem. Rev. 2004, 104, 6085.
3. Adamo, M. F. A.; Chimichi, S.; De Sio, F.; Donati, D.; Sarti-
Fantoni, P. Tetrahedron Lett. 2002, 43, 4157.
4. Adamo, M. F. A.; Baldwin, J. E.; Adlington, R. M. J. Org.
Chem. 2005, 70, 3307.
5. Adamo, M. F. A.; Adlington, R. M.; Baldwin, J. E.; Pritchard,
G. J.; Rathmell, R. E. Tetrahedron 2003, 59, 2197.
6. Adamo, M. F. A.; Donati, D.; Duffy, E. F.; Sarti-Fantoni, P.
J. Org. Chem. 2005, 70, 8395.
7. Adamo, M. F. A.; Duffy, E. F. Org. Lett. 2006, 8, 5157.
8. Adamo, M. F. A.; Konda, V. R. Org. Lett., in press.
9. Donati, D.; Fusi, S.; Ponticelli, F.; Rossi Paccani, R.; Adamo,
M. F. A. Tetrahedron, in press. doi:10.1016/j.tet.2006.12.009
10. Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M.
Chem. Rev. 2005, 105, 933.
3.5.5. 6-(4-Chlorophenyl)-3-methyl-1,4,6,7-tetrahydro-
pyrazolo[4,3-b]pyridin-5-one 2b. Colourless solid (233 mg,
89% yield); Rf¼0.4 (ethyl acetate/acetone/petroleum ether
15:15:70); mp 290–291 ꢀC (ethanol); nmax (Film)/cmꢁ1
:
3480–3190b, 1658s; dH (400 MHz, DMSO-d6) 12.02 (1H, s,
HNC]O), 9.95 (1H, s, br, HN–N), 7.37 (2H, d, J¼7.5,
p-ClPh), 7.26 (2H, d, J¼7.5, p-ClPh), 3.88–3.84 (1H, m,
CHPh(p-Cl)), 3.10–3.01 (2H, m, CH2CHPh(p-Cl)), 2.14
(3H, s, CH3C]N); dC (100 MHz, DMSO-d6) 169.3 (C]O),
139.2 (p-ClPh), 136.8, 131.3 (p-ClPh), 130.2 (p-ClPh), 128.1
(p-ClPh), 122.4, 118.8, 46.3 (CH), 27.5 (CH2), 8.2 (CH3).
HRMS (EI) found [MꢁH]+: 260.0599, C13H11ClN3O
requires: 260.0591; m/z (EI) 260 (100, [MꢁH]+).
11. Nielsen, A. T. The Chemistry of the Nitro and Nitroso Groups;
Feuer, H., Ed.; Wiley Interscience: New York, NY, 1969; Part 1,
p 349.
3.5.6. 6-(3-Methoxyphenyl)-3-methyl-1,4,6,7-tetrahydro-
pyrazolo[4,3-b]pyridin-5-one 2c. Colourless solid (222 mg,
86% yield); Rf¼0.5 (acetone/petroleum ether 6:4); mp 255–
257 ꢀC (ethanol); nmax (Film)/cmꢁ1: 3420–3165b, 1655s; dH
(400 MHz, acetone-d6) 7.24 (1H, t, J¼7.1, Ar), 6.82–6.85
(3H, m, Ar), 4.07 (1H, app. t, J¼7.0, CHAr), 3.73 (3H, s,
OCH3), 3.55 (1H, dd, J¼14.7, 7.9, CHaHbCHPh), 3.42 (1H,
12. Baracchi, A.; Chimichi, S.; De Sio, F.; Donati, D.; Polo, C.;
Sarti-Fantoni, P. Heterocycles 1990, 31, 1823.
13. Musante, C. Gazz. Chim. Ital. 1942, 72, 537.
14. Blade-Font, A. Tetrahedron Lett. 1980, 21, 2443.
15. Mader, M.; Helquist, P. Tetrahedron Lett. 1988, 29, 3049.
16. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004.