Synthesis of alkyl 4-(diethoxymethyl)-3-pyridin-3-ylisoxazole-5- carboxylates: Useful scaffold for highly functionalised 3-(pyridin-3-yl) isoxazoles

Article abstract of DOI:10.1016/j.tet.2005.03.004

The methyl 4-(diethoxymethyl)-3-(pyridin-3-yl)isoxazole-5-carboxylate obtained by domino 1,3-dipolar cycloaddition and elimination starting of pyridine-3-nitrile oxide and methyl 4,4-diethoxy-3-p-tolylsulfinylbut-2-enoate is a convenient scaffold for the

Full text of DOI:10.1016/j.tet.2005.03.004

Tetrahedron 61 (2005) 4363–4371
Synthesis of alkyl
4-(diethoxymethyl)-3-pyridin-3-ylisoxazole-5-carboxylates:
useful scaffold for highly functionalised 3-(pyridin-3-yl)isoxazoles
*
´
Jose Luis Garcıa Ruano, Cristina Fajardo and M. Rosario Martın
*
´
´
´ ´ ´
Departamento de Quımica Organica, Universidad Autonoma de Madrid, Ciudad Universitaria de Cantoblanco, Madrid 28049, Spain
Received 6 January 2005; revised 24 February 2005; accepted 2 March 2005
Available online 23 March 2005
Abstract—The methyl 4-(diethoxymethyl)-3-(pyridin-3-yl)isoxazole-5-carboxylate obtained by domino 1,3-dipolar cycloaddition and
elimination starting of pyridine-3-nitrile oxide and methyl 4,4-diethoxy-3-p-tolylsulfinylbut-2-enoate is a convenient scaffold for the
synthesis of other new highly functionalised 3-pyridin-3-ylisoxazoles-5-carboxylic acid derivatives and isoxazole-annulated heterocycles.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
years ago our group reported that cycloadditions of
bromonitrile, benzonitrile or acetonitrile oxides to methyl
but-2-ynoates 1 evolved with moderate regioselectivity,
whereas with methyl 4,4-dimethoxy-3-(pyrrolidin-1-yl)but-
2-enoate 2 were completely regioselective,13 yielding the
adduct with the oxygen at the dipole joined to the C-3 at the
dipolarophile (Scheme 1). Afterwards we demonstrated that
the sulfinyl group was able to control the regioselectivity
and therefore the opposite regioisomer could be isolated,
as major or exclusive, in reactions of benzonitrile oxides
with tert-butyl 4,4-diethoxy-3-p-tolylsulfinylbut-2-enoate 3
and 5-alkoxy-3-p-tolylsulfinylfuranones14 (Scheme 1). This
strong influence of the sulfinyl group on the regioselectivity
of these reactions was rationalised on the basis of their
electrostatic interactions with the charged atoms at the
dipole.
Aromatic heterocycles are valuable synthetic templates for
the preparation of new compounds with specific biological
or material properties. The pursuit of these properties
requires efficient synthetic routes that allow rapid assembly
and variation of multiple pendant substituents on the hetero-
aromatic core, or the construction of diverse aromatic
heterocycles with defined substitution patterns. Isoxazole
derivatives have been used as key intermediates in
synthesis1 and have been investigated intensively for the
last several years because of their biological activities.2–7 In
spite of this wide spectrum of properties, the number of
isoxazoles trisubstituted by different functional groups,
useful as scaffolds in the synthesis of many differently
trisubstituted isoxazoles, is scarce. This is the case of the
3-pyridin-3-ylisoxazoles exhibiting interesting properties as
anti-inflammatory,8 herbicidal,9 antiaggregating agents,10
muscarinic acetylcholine receptor agonist11 (useful as
nootropics and therapeutic agents for cerebral neuronal
diseases), or plant growth-regulatory and with antistress
activity.12
The interest of 3-pyridin-3-ylisoxazoles derivatives and
the above mentioned results, prompted us to investigate
the reactions of pyridine-3-nitrile oxide (5) with alkyl
4,4-diethoxy-3-p-tolylsulfinylbut-2-enoates, and the corre-
sponding sulfones, in order to provide a regioselective way
for preparing highly functionalised 3-pyridin-3-ylisoxa-
zoles. The other method for obtaining isoxaxoles, i.e.
condensation of 1,3-dicarbonylic compounds with hydroxyl-
amine, afforded a regioisomeric mixture of 3-pyridin-3-
ylisoxazoles.15 In this paper we describe the results of this
study which has allowed to find a highly regioselective
synthesis of 4-(diethoxymethyl)-3-pyridin-3-ylisoxazole-5-
carboxylates. We will also describe their usefulness as a
scaffold in the synthesis of other 3-pyridin-3-ylisoxazole
derivatives containing multiple pendant substituents on the
heteroaromatic core.
One of the most general methods to prepare isoxazole
derivatives involves the 1,3-dipolar cycloaddition of nitrile
oxides to alkynes or alkenes bearing an easily removable
substituent at the double bond, which makes them act as
synthetic equivalents of alkynes. In this context, several
Keywords: 3-Pyridin-3-ylisoxazoles; Cycloaddition; Sulfoxides; Sulfones;
Nitrile oxides.
Corresponding authors. Tel.: C34 91 4974703; fax: C34 91 4973966;
e-mail: rosario.martin@uam.es
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.004

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4364
Scheme 1.
2. Results and discussion
purified and isolated in good yields (64 and 68%
respectively) by column chromatography from their crude
reaction. Also interesting is the fact that regioselectivity
observed in reactions of 3 with pyridine-3-nitrile oxide was
slightly higher than that obtained with benzonitrile oxide
(Scheme 1), which reinforces the hypothesis that electro-
static interactions of sulfinyl group with nitrile oxides could
be one of the main factors governing the regioselectivity of
these reactions (see above).
Initially we investigated the reactions of the pyridine-3-
nitrile oxide with the sulfinylbutenolide 4, because it had
shown to be the most efficient sulfinyl dipolarophile in the
reactions with benzonitrile oxide (higher reactivity and
selectivity than for acyclic acrylate 3). However, the cyclic
dipolarophiles afforded complex reaction mixtures where
the expected products were the minor ones and could not be
isolated.
The structure of adducts was assigned on the basis of the
chemical shifts of the acetalic protons of both regioisomeric
isoxazoles, and mainly, from the d value for the more
deshielded carbon at the isoxazole ring. In accordance with
the rule reported by us,13,14 the lowest d values of the
acetalic proton correspond to regioisomers exhibiting the
oxygen at dipole joined to C-2 at the dipolarophile.
The chemical shift of C-5 for the major regioisomers 6B
(157.8) and 8B (157.6 ppm) is in agreement with those
expected for 5-alkoxycarbonyl derivatives.18
Then we studied the reactions of nicotinonitrile oxide 5 with
tert-butyl 4,4-diethoxy-3-p-tolylsulfinylbut-2-enoate 3.14
The reaction was performed at 80 8C for 2 h, the dipole
being generated ‘in situ’ by slow addition of triethylamine
(via a syringe pump) on to 3-[chloro(hydroxyimino)-
methyl]pyridinium chloride.16 It afforded a mixture of two
regioisomeric isoxazoles 6A and 6B (Scheme 2).
At this point we decided to study the behaviour of the
2-sulfonylacrylate 9 in their reactions with pyridine-3-nitrile
oxide. Our aim was to compare the regioselectivity of this
reaction with that observed for the sulfinyl derivatives 3 and
7 in order to collect proofs evidencing the role of the
electrostatic interactions in the course of these reactions.
Sulfone 9 required 3 h at 80 8C, to give a 62:38 mixture of
isoxazolines 10A and 10B (Scheme 3), which were isolated
by column chromatography with 41 and 26% yields,
respectively.
Scheme 2.
The low reactivity of the tert-butoxycarbonyl group in some
of the reactions that we will describe next, made necessary
the synthesis of the more reactive methoxycarbonyl
derivatives. For that reason we also performed the reaction
of 5 with the ester 7,17 under similar reaction conditions,
which afforded a mixture of compounds 8A and 8B
(Scheme 2).
The regioselectivity of theses reactions was very high (only
1
2% of 6A could be detected from H NMR of the crude
reaction). The major regioisomers 6B and 8B were easily
Scheme 3.

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4365
The structures of the primary adducts 10A and 10B (Scheme
3) were assigned on the basis of the chemical shift of 13C
NMR of CH at the isoxazoline ring. The largest difference
between the d values of the saturated carbons must be
assigned to regioisomer 10B and the lowest one to 10A (see
Scheme 3).
The election of the groups was made bearing in mind their
potential pharmacological usefulness. Thus, the introduc-
tion of amine and amide functions in our 3-pyridin-3-
ylisoxazoles was considered because there have been
reported interesting properties for some other isoxazoles
containing amide4,5a,22 or amine5b,23 groups. The sulfona-
mide moiety was also introduced because it is a
pharmacophore.24
The comparison of the results obtained from dipolarophiles
3 or 7 (Scheme 2) with those resulting from 9 (Scheme 3)
indicates a lower regioselectivity for the sulfone but, which
is more important, an inversion in the sense of the addition
(10A is the major one, whereas 6B and 8B were
predominant for sulfoxides) was observed.
The preparation of amides can be performed by reaction of
appropriate alkyl esters with ammonium hydroxide, primary
amines, or secondary amines. However, the reaction of the
highly hindered tert-butyl ester 6B was unsuccessful due to
the low reactivity of the tert-butoxycarbonyl group towards
nucleophiles. On the other hand, the best way to introduce
the amine functions at 4-position of 3-pyridin-3-ylisoxa-
zole-5-carboxylate from 6B involves the hydrolysis of the
acetal group and subsequently reductive amination. How-
ever the tert-butoxycarbonyl group is unstable under the
acidic conditions required for the hydrolysis of the acetal
and therefore, reaction of 6B with formic acid afforded a
mixture of the expected ester-aldehyde 11 along with the
acid–aldehyde 12 (Scheme 4). The 11/12 ratio depends on
the temperature and the reaction time. On the basis on these
poor results we decided to prepare the methyl ester 8B. The
reaction of 8B with different amines evolved smoothly and
afforded the corresponding amides 13a–c in high yields
(Scheme 4). Analogously, reaction of 8B with formic acid
exclusively yielded the ester–aldehyde 14 (Scheme 4).
Although only scattered studies19 dealting with the directing
effect of sulfoxides and sulfones, are reported in the
literature, the higher tendency of vinyl sulfones19,20 to
give adducts bearing the sulfonyl group at C-4 of isoxazo-
line, is in agreement with the results reported by us in this
paper. It is emphasised that the regioselectivity observed in
the addition of nitrile oxides to dipolarophiles 3 and 7 is the
same that reported for b-sulfinyl-a,b-unsaturated ketone19b
but opposite to that for vinyl sulfoxides.19a,21
2.1. Preparation of highly functionalised 3-pyridin-3-
ylisoxazoles
We then studied the use of our 3-pyridin-3-ylisoxazoles 6B
and 8B as scaffolds to the introduction of different
functional groups at C-4 and C-5 of the isoxazole ring.
The transformations carried out on the versatile formyl
group of 3-pyridin-3-yl-4-formylisoxazole-5-carboxylic
acid derivatives are show in Scheme 5.25
Reductive amination of the ester–aldehydes 11 and 14 gave
the corresponding ester–amines 15 and 16 in moderate
yields due to the formation of variable amounts of the
corresponding ester–alcohols 17 and 18. The alcohol 18 can
be obtained in quantitative yield as a sole compound by
reduction of 14 with sodium triacetoxyborohydride
(Scheme 5). The reaction of the ester aldehyde 14 with
diazomethane yielded the oxiranyl compound 20, in
moderate yield due to the formation of the ketone 21 as a
by product. The oxirane 20 could also be obtained in 74%
Scheme 4.
Scheme 5.

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4366
yield when diazomethane was added to an ether/MeOH
solution of acid 12.
4. Experimental
4.1. General
The hydroxymethylisoxazoles 17 or 18 open the access to
new isoxazole derivatives through Mitsunobu reaction.
Thus we have obtained the bioisoster of the homologous
carboxylic acid by reaction of 18 with the 5-phenyltetrazole
in the presence of triphenylphosphine and diethyl diazene-
1,2-dicarboxylate (Scheme 5). It is noteworthy the forma-
tion of the 2-substituted tetrazole 19 as the sole compound.
The structure of 19 has been assigned on the basis of the
preferential formation of the 2,5-disubstituted regioisomers
when the primary alcohols react with phenyltetrazol.26 The
comparison of the chemical shifts of the phenyl protons of
19 with those reported for the same group in other 1,5- and
2,5-tetrazoles confirms this assignment.
All moisture sensitive reactions were performed in flame-
dried glasswares equipped with rubber septa under positive
pressure of argon. THF was distilled from sodium-
benzophenone under argon and CH2Cl2 over P2O5. Silica
gel 60 (230–400 mesh ASTM) and DC-Alufolien 60 F254
were used for flash column chromatography and analytical
TLC, respectively. Melting points were determined in a
Gallenkamp apparatus in open capillary tubes and are
uncorrected. Microanalyses were performed with a Perkin–
Elmer 2400 CHN and Perkin Elmer 2400 C-10II CHNS/O
analysers. NMR spectra were determined in a CDCl3
solutions, unless otherwise is indicated, at 300 and
75 MHz for 1H and 13C NMR respectively; chemical shifts
(d) are reported in ppm and J values are given in hertz. The
IR spectra frequencies are given in cmK1. The dipolarofile
3 was obtained following the procedure previously reported
by us.14
Isoxazoles bearing a phenylsulfonamide substituent are
useful in the treatment of inflammatory processes.27 Our
scaffold is also suitable for introducing such a function.
Starting from 18, we have also incorporated this function by
reaction with tert-butyl (phenylsulfonyl)carbamate, under
Mitsunobu conditions [diethyl diazene-1,2-dicarboxylate
(DEAD) and triphenylphosphine]. The yield of compound
22 was high (94%) and its reaction with an excess of
piperidine at 40 8C gave the corresponding amide–sulfona-
mide 23 in one-pot process (Scheme 5).
4.1.1. Methyl (2E)-4,4-diethoxy-2-[(4-methylphenyl)sul-
finyl]but-2-enoate (7). This compound was obtained from
methyl bromoacetate following the procedure reported by
us for the preparation of racemic compound 3.14 Yield 81%,
white solid, mp 44–45 8C (hexane), IR (KBr): 1731, 1652,
1
1595, 1219, 1057. H NMR: 1.21 and 1.23 (2t, JZ7.1 Hz,
6H), 2.37 (s, 3H), 3.64 (m, 4H), 3.66 (s, 3H), 5.81 (d, JZ
6.9 Hz, 1H), 7.03 (d, JZ6.9 Hz, 1H), 7.26 and 7.53
(AA0BB0 system, 4H). 13C NMR: 15.2, 15.3, 21.5, and
52.1 (CH3), 61.7 (CH2), 96.6, 126.0 and 130.0 (CH), 139.7
(C), 139.9 (CH), 140.8, 142.5 and 162.3 (C). Anal. calcd for
C16H22O5S: C 58.87, H 6.79, S 9.82. Found: C 58.71, H
6.70, S 9.75.
Additionally, the relative position of the ester and acid
functions at our scaffold, is also proper to obtain annulated-
isoxazoles. The structural similarity of isoxazolopyridazi-
none and isoxazolopyridone, which has been reported as
metabotropic glutamate receptor antagonist (useful in the
treatment of anxiety, depression, schizophrenia, Alzheimer
disease, etc),28 prompted us to carry out the reactions shown
in Scheme 6, which gave 3-pyridin-3-ylisoxazolopyridazi-
none 24 in good yields.
4.1.2. Methyl (2E)-4,4-diethoxy-2-[(4-methylphenyl)sul-
fonyl]but-2-enoate (9). To a stirred solution of methyl-(E)-
4,4-diethoxy-2-[(4-methylphenyl)sulfinyl]-but-2-enoate (7)
(72 mg, 0.22 mmol) in dry dichloromethane (1.7 mL), under
argon at room temperature, was added a solution of
m-CPBA (100 mg, 0.48 mmol) in dry dichloromethane
(5.5 mL). The mixture was allowed to stand at room
temperature for 2 h, afterwards it was washed with NaHSO3
solution (40%) and saturated aqueous NaHCO3. The organic
layer was dried (Na2SO4) filtered and concentrated in vacuo.
The residue obtained was as colourless oil corresponding to
the sulfone 9 (73 mg, 97%). Colourless oil, IR (film): 1735,
1641, 1597, 1325, 1157, 1090. 1H NMR: 1.18 (t, JZ7.0 Hz,
6H), 2.44 (s, 3H), 3.74 (s, 3H), 3.59 (m, 4H), 5.47 (d, JZ
5.3 Hz, 1H), 7.19 (d, JZ5.3 Hz, 1H), 7.33 and 7.77
(AA0BB0 system, 4H). 13C NMR: 15.1, 21.7 and 52.7
(CH3), 62.1 (CH2), 97.1, 128.7 and 129.7 (CH), 136.3, 138.9
and 145.0 (C), 145.7 (CH), 161.9 (C). Anal. calcd for
C16H22O6S: C 56.12, H 6.48, S 9.36. Found: C 56.14, H
6.81, S 9.40.
Scheme 6.
3. Conclusion
The results reported in this paper reveal that the sulfinyl-
ester 7, is an adequate starting material for preparing
3-pyridin-3-ylisoxazoles in a one-pot sequence by cyclo-
addition with pyridine-3-nitrile oxide. The obtained isoxa-
zole is a good scaffold to the synthesis of a broad variety
of 3-pyridin-3-ylisoxazole-5-carboxylic acid derivatives
functionalised at C-4 and annulated-isoxazoles.
4.2. General procedure for the cycloaddition reaction
To a mixture of 1.4 mmol of sulfinyl or sulfonyl
dipolarophile 3, 7 or 9 and 19 mmol (for 3 and 7) or
8.4 mmol (for 9) of 3-[chloro(hydroximino)methyl]pyri-
dinium chloride in toluene (11 mL), heated at 80 8C, was

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4367
slowly added with a syringe pump (0.5 ml/seg) triethylamine
(40 or 18 mmol for the sulfinyl or sulfonyl dipolarophiles
respectively). After stirring at 80 8C, for additional 2 h in the
case of 3 and 7 or 3 h for 9, the reaction mixture was cooled
at room temperature and dichloromethane and water were
added. The organic layer was separated and the aqueous was
extracted with dichloromethane. The combined organic
layers were washed with brine, dried (Na2SO4) and the
solvent was removed in vacuum. The residue was analysed
solid, mp 115–116 8C, IR (KBr): 1762, 1595, 1326, 1146
and 1078. H NMR: 1.09 (t, JZ7.0 Hz, 3H), 1.20 (t, JZ
1
7.0 Hz, 3H), 2.41 (s, 3H), 3.41 (dq, JZ7.0, 9.1 Hz, 1H),
3.66 (m, 3H), 3.81 (s, 3H), 4.48 (d, JZ7.0 Hz, 1H), 5.38 (d,
JZ7.0 Hz, 1H), 7.34 (ddd, JZ0.8, 4.8, 8.1 Hz, 1H), 7.24
and 7.67 (AA0BB0 system, 4H), 8.14 (m, 1H), 8.65 (dd, JZ
1.6, 4.8 Hz, 1H), 9.00 (d, JZ1.9 Hz, 1H). 13C NMR: 14.7,
15.0, 21.6 and 53.5 (CH3), 61.4 and 64.5 (CH2), 87.0 (C),
88.2, 98.8, 123.0 (CH), 124.0 (C), 129.4 and 130.7 (CH),
132.3 (C), 135.1 (CH), 146.5 (C), 148.9 (CH), 150.4 (C),
150.8 (CH), 163.1 (C). Anal. calcd for C22H26N2O7S: C
57.13, H 5.67, N 6.06, S 6.93. Found: C 56.87, H 5.51, N
5.98, S 6.91.
1
by H NMR and the obtained ratio of the regioisomeric
adduct was indicated in Schemes 2 and 3. Purification and
yields are indicated in each case.
4.2.1. tert-Butyl 4-(diethoxymethyl)-3-pyridin-3-ylisoxa-
zole-5-carboxylate (6B). It was obtained as the major
adduct from 3, and purified by column chromatography
(hexane/ethyl acetate, 4:1). Colourless oil, yield 64%, IR
(film): 1737, 1723, 1597, 1572, 1298, 1155, 1061. 1H NMR:
1.04 (t, JZ7.1 Hz, 6H), 1.56 (s, 9H), 3.40 (dq, JZ7.1,
9.4 Hz, 2H), 3.66 (dq, JZ7.1, 9.4 Hz, 2H), 6.02 (s, 1H),
7.28 (ddd, JZ0.8, 4.8, 8.1 Hz, 1H), 8.26 (dt, JZ1.6, 8.1 Hz,
1H), 8.58 (dd, JZ1.6, 4.8 Hz, 1H), 9.10 (d, JZ1.6 Hz, 1H).
13C NMR: 14.9 (CH3), 28.0 (CH3), 63.5 (CH2), 84.7 (C),
95.7 (CH), 121.6 (C), 122.7 (CH), 125.1(C), 137.0, 150.0
and 150.4 (CH), 156.1, 157.8 and 160.3 (C). Anal. calcd for
C18H24N2O5: C 62.05, H 6.94, N 8.04. Found: C 61.63, H
7.05, N 8.01.
4.2.6. Methyl 4-(methoxymethyl)-5-[(4-methylphenyl)-
sulfonyl]-3-pyridin-3-yl-4,5-dihydroisoxazole-5-carb-
oxylate (10B). It was obtained as the minor adduct from 9
and purified by column chromatography (hexane/ethyl
acetate, 2:1), yield 26%, white solid, mp 144–145 8C
(ether/hexane), IR (KBr): 1754, 1595, 1328, 1235, 1075.
1H NMR: 0.96 (t, JZ7.0 Hz, 3H), 1.0 (t, JZ7.0 Hz, 3H),
2.40 (s, 3H), 3.19 (dq, JZ7.0, 9.1 Hz, 1H), 3.65 (m, 3H),
3.72 (s, 3H), 4.80 (d, JZ4.0 Hz, 1H), 4.95 (d, JZ4.0 Hz,
1H), 7.29 (m, 3H), 7.83 (m, 2H), 7.94 (m, 1H), 8.62 (dd, JZ
1.6, 4.8 Hz, 1H), 8.81 (bd, JZ1.6 Hz, 1H). 13C NMR: 14.5,
14.9, 21.7 and 53.3 (CH3), 56.1 (CH), 64.0 and 64.8 (CH2),
100.4 (CH), 104.0 (C), 122.9 (CH), 125.1 (C), 129.7 and
130.5 (CH), 130.9 (C), 135.4 (CH), 146.4 (C), 149.0 and
150.8 (CH), 156.8 (C), 163.1 (C). Anal. calcd for
C22H26N2O7S: C 57.13, H 5.67, N 6.06, S 6.93. Found: C
56.77, H 5.53, N 6.00, S 6.84.
4.2.2. tert-Butyl 5-(diethoxymethyl)-3-pyridin-3-ylisoxa-
zole-4-carboxylate (6A). This compound was obtained as
the minor adduct from 3 and could not be isolated as a pure
isomer. The signals are measured from the spectrum of a 6A
and 6B mixture. 1H NMR: 1.26 (t, JZ7.0 Hz, 6H), 1.40 (s,
9H) 3.78 (m, 4H), 6.14 (s, 1H), 7.39 (ddd, JZ0.9, 4.8,
7.9 Hz, 1H), 7.93 (m, 1H), 8.70 (dd, JZ1.7, 4.8 Hz, 1H),
8.82 (dd, JZ0.9, 2.3 Hz, 1H).
4.3. Formolysis of t-butyl or methyl 4-(diethoxymethyl)-
3-pyridin-3-ylisoxazole-5-carboxylates
Formic acid (75 mmol) was added to 6B or 8B (1.5 mmol)
and the mixture was allowed to stand under argon at room
temperature for 2.5 and 3 h, respectively. After removed of
formic acid and formates under reduced pressure, the crude
reaction mixture was analysed by 1H NMR (11 and 12 in a
ratio 84:16 from 6B, whereas starting from 8B only the
ester–aldehyde 14 was observed). The compounds obtained
are separated and purified as is indicated in each case.
4.2.3. Methyl 4-(diethoxymethyl)-3-pyridin-3-ylisoxa-
zole-5-carboxylate (8B). It was obtained as the major
adduct from 7, and purified by flash column chromato-
graphy (hexane/ethyl acetate, 4:1). Colourless oil, yield
1
69%, IR (film): 1734, 1597, 1572, 1295, 1061. H NMR:
1.09 (t, JZ7.0 Hz, 6H), 3.46 (dq, JZ7.0, 9.3 Hz, 2H), 3.72
(dq, JZ7.0, 9.3 Hz, 2H), 4.01 (s, 3H), 6.11 (s, 1H), 7.35
(ddd, JZ0.8, 4.8, 8.1 Hz, 1H), 8.33 (m, 1H), 8.66 (dd, JZ
1.6, 4.8 Hz, 1H), 9.18 (d, JZ1.6 Hz, 1H). 13C NMR: 14.9
and 53.0 (CH3), 63.7 (CH2), 95.5 and 122.7 (CH), 122.9 and
124.8 (C), 137.1, 150.0 and 150.6 (CH), 156.5, 157.6 and
160.5 (C). Anal. calcd for C15H18N2O5: C 58.82, H 5.92, N
9.15. Found: C 58.77, H 5.83, N 9.04.
4.3.1. tert-Butyl 4-formyl-3-pyridin-3-ylisoxazole-5-
carboxylate (11). It was obtained from 6B and isolated by
column chromatography (hexane/ethyl acetate, 2:1) after
removed of acid 12. Yield 82%, white solid, mp 74–
76 8C.(from ether/hexane), IR (film): 1743, 1724, 1697,
1
1592, 1152. H NMR: 1.68 (s, 9H), 7.43 (ddd, JZ1.2, 4.7,
8.2 Hz, 1H), 8.12 (m, 1H), 8.75 (dd, JZ1.8, 4.7 Hz, 1H),
8.98 (d, JZ2.3 Hz, 1H), 10.55 (s, 1H). 13C NMR: 28.0
(CH3), 86.6 and 120.3 (C), 123.1 (CH.), 123.3 (C), 137.0,
149.7 and 151.5 (CH), 154.9, 159.6 and 165.2 (C), 184.8
(CH).
4.2.4. Methyl 5-(diethoxymethyl)-3-pyridin-3-ylisoxa-
zole-4-carboxylate (8A). It was obtained as the minor
adduct from 7 and could not be isolated. The signal of the
acetalic proton at 6.15 ppm is observed in the H NMR of
the crude mixture.
1
4.3.2. 4-Formyl-3-pyridin-3-ylisoxazole-5-carboxylic
acid (12). It was obtained from 6B along with ester–
aldehyde 11. Compound 12 was isolated in 13% yield by
filtration of the solid formed by addition of dichloromethane
to the crude reaction mixture. White solid, decomposed at
higher temperature than 169 8C, IR (KBr): 3419, 3094,
4.2.5. Methyl 5-(diethoxymethyl)-4-[(4-methylphenyl)-
sulfonyl]-3-pyridin-3-yl-4,5-dihydroisoxazole-4-carb-
oxylate (10A). It was obtained as the major adduct from the
sulfonyl dipolarophile 9. This compound was isolated by
column chromatography (hexane/ethyl acetate, 2:1) and
subsequent precipitation with hexane, yield 41%, white
1
2523, 1689, 1626, 1568, 1211. H NMR (DMSO-d6): 7.59

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4368
(dd, JZ4.9, 7.9 Hz, 1H), 8.15 (m, 1H), 8.74 (d, JZ4.9 Hz,
1H), 8.87 (bs, 1H), 10.38 (s, 1H). 13C NMR (DMSO-d6):
119.9 and 123.6 (C), 123.8, 137.3, 149.2 and 151.3 (CH),
157.3 and 159.2 (C), 185.7 (CH), 185.9 (C).
(C), 123.2 (CH), 124.8 (C), 136.4, 149.6 and 150.8 (CH),
157.9, 158.8 and 163.1 (C).
4.4.2. N-Benzyl-4-(diethoxymethyl)-3-pyridin-3-ylisoxa-
zole-5-carboxamide (13c). It was obtained after 2 h of
reaction of 8B with benzylamine. It was isolated as an oil by
column chromatography (hexane–ethyl acetate, 2:1), yield
99%, IR (film): 3284, 1678, 1598, 1537, 1524, 1291, 1060.
1H NMR: 1.09 (t, JZ7.0 Hz, 6H), 3.50 (dq, JZ7.0, 9.5 Hz,
2H), 3.70 (dq, JZ7.0, 9.5 Hz, 2H), 4.64 (d, JZ5.8 Hz, 2H),
6.14 (s, 1H), 7.30–7.39 (m, 6H), 7.58 (m, 1H), 8.29 (dt, JZ
2.0, 8.1 Hz, 1H), 8.68 (dd, JZ1.5, 4.8 Hz, 1H), 9.11 (d, JZ
1.9 Hz, 1H). 13C NMR: 14.9 (CH3), 43.5 and 63.5 (CH2),
95.5 (CH2), 119.6 (C), 123.0 (CH), 124.8 (C), 127.9 and
128.8 (CH), 136.9 (C), 137.0, 149.8 and 150.7 (CH), 156.2,
159.2 and 160.7 (C).
4.3.3. Methyl 4-formyl-3-pyridin-3-ylisoxazole-5-carb-
oxylate (14). It was isolated in quantitative yield by
filtration of the solid formed by addition of ether to the
crude reaction mixture obtained from 8B. White solid, mp
95–96 8C (diethyl ether), IR (KBr): 1732, 1683, 1592, 1438,
1
1305, 1258. H NMR: 4.11 (s, 3H), 7.44 (ddd, JZ0.8, 5.1,
7.8 Hz, 1H), 8.13 (dt, JZ2.0, 8.2 Hz, 1H), 8.75 (dd, JZ1.6,
4.7 Hz, 1H), 8.99 (d, JZ2.0 Hz, 1H), 10.57 (s, 1H). 13C
NMR: 53.8 (CH3), 121.0 (C), 123.1, 136.9, 149.7 and 151.6
(CH), 156.3, 159.6 and 163.8 (C), 184.3 (CH). Anal. calcd
for C11H8N2O4: C 56.90, H 3.47, N 12.04. Found: C 56.76,
H 3.59, N 11.79.
4.5. Synthesis of 4-(dialkylamino)methyl-3-pyridin-3-
ylisoxazole-5-carboxylates. General procedure
4.3.4. 4-(Diethoxymethyl)-3-pyridin-3-ylisoxazole-5-
carboxamide (13a). A mixture of concentrated ammonium
hydroxyde (1.73 mL of 25% solution) and methyl
4-(diethoxymethyl)-3-pyridin-3-ylisoxazole-5-carboxylate
(8B) (115 mg, 0.37 mmol) was stirred at room temperature
for 2 h and then extracted with dichloromethane. The
combined organic layers were dried (Na2SO4) and the
solvent was removed under reduced pressure to gave a
residue. It was purified by flash column chromatography on
silica gel (hexane/ethyl acetate, 2:1) to give 95 mg (87%) of
pure amide 13a. White solid, mp 87–88 8C (diethyl ether/
hexane), IR (KBr): 3416, 3141, 1700, 1629, 1101, 1046. 1H
NMR: 1.14 (t, JZ7.1 Hz, 6H), 3.52 (dq, JZ7.1, 9.5 Hz,
2H), 3.75 (dq, JZ7.1, 9.5 Hz, 2H), 5.99 (bs, 1H), 6.14
(s, 1H), 7.03 (bs, 1H), 7.39 (ddd, JZ0.9, 4.9, 8.0 Hz, 1H),
8.31 (ddd, JZ1.6, 2.2, 8.0 Hz, 1H), 8.70 (dd, JZ1.6,
4.9 Hz, 1H), 9.14 (d, JZ2.2 Hz, 1H). 13C NMR: 14.8 (CH3),
63.4 (CH2), 95.4 (CH), 120.2 (C), 122.9 (CH), 124.8 (C),
137.1, 149.5 and 150.5 (CH), 158.2, 158.8 and 160.7 (C).
Anal. calcd for C14H17N3O4: C 57.72, H 5.88, N 14.42.
Found: C 57.60, H 5.92, N 14.30.
A solution of aldehydes 11 or 14 (0.5 mmol), amine
(0.5 mmol, except with piperidine, that 0.6 mmol of amine
was used) and acetic acid (0.5 mmol) in dichloroethane
(4 mL), under argon at room temperature, was allowed to
stand during the time t1 indicated in each case. After
0.70 mmol of sodium triacetoxyborohydride was added to
the reaction mixture and then it was allowed to stand at
room temperature for the time t2 indicated in each case.
Saturated sodium bicarbonate solution was added to the
reaction mixture and the aqueous layer was extracted with
dichloromethane. The combined organic layers were dried
(Na2SO4) and, after removing the solvent under reduced
pressure, the residue was analysed by 1H NMR. The
products were isolated as indicated in each case.
4.5.1. tert-Butyl 4-[(4-phenylpiperazin-1-yl)methyl]-3-
pyridin-3-ylisoxazole-5-carboxylate (15a). It was
obtained along with compound 17 (75:25 mixture of 15a/
17) from aldehyde 11 and 4-phenylpiperazine, after 1 (t1)
and 3 (t2) hours, respectively. Flash column chromato-
graphy (hexane/ ethyl acetate, 3:2), yield 69%, solid, mp
98–99 8C (hexane), IR (KBr): 1722, 1602, 1576, 1448,
4.4. General procedure for the preparation of amides
from amines and the ester–isoxazole 8B
1
1296, 1156. H NMR: 1.65 (s, 9H), 2.68 (m, 4H), 3.16 (m,
A mixture of 0.14 mmol methyl 4-(diethoxymethyl)-3-
pyridin-3-ylisoxazole-5-carboxylate (8B) and 0.30 mmol
of the corresponding amine was stirred at room temperature
for the time indicated in each case. The crude mixture was
dissolved in dichloromethane and washed with water. The
organic layer was dried (Na2SO4) and the solvent was
removed under reduced pressure. The amide was isolated
following the procedure indicated in each case.
4H), 3.73 (s, 2H), 6.87 (m, 3H), 7.25 (m, 2H), 7.41 (dd, JZ
4.8, 7.8 Hz, 1H), 8.37 (m, 1H), 8.71 (dd, JZ1.6, 4.8 Hz,
1H), 9.24 (d, JZ1.6 Hz, 1H). 13C NMR: 28.2 (CH3), 49.0,
49.2 and 52.4 (CH2), 84.6 (C), 116.1 (CH), 119.1 (C), 119.8
and 123.4 (CH), 125.0 (C), 129.1, 136.4, 149.9 and 150.9
(CH), 151.1, 156.4, 158.9 and 162.1 (C). Anal. calcd for
C24H28N4O3: C 68.55, H 6.71, N 13.32. Found: C 68.59, H
6.80, N 13.33.
4.4.1. 3-[4-(Diethoxymethyl)-5-(piperidin-1-ylcarbonyl)-
isoxazol-3-yl]pyridine (13b). It was obtained after 3 days
of reaction of 8B with piperidine and isolated by filtration of
the solid precipitate by addition of hexane to the crude
reaction mixture. Yield 87%, mp: 84–85 8C, IR (KBr):
1657, 1592, 1570, 1286, 1053. 1H NMR: 1.11 (t, JZ7.0 Hz,
6H), 1.61–1.68 (m, 6H), 3.31 (m, 2H), 3.51 (dq, JZ7.0,
9.4 Hz, 2H), 3.60–3.73 (m, 4H), 5.62 (s, 1H), 7.38 (ddd, JZ
0.9, 4.8, 8.1 Hz, 1H), 8.22 (m, 1H), 8.68 (dd, JZ1.8, 4.8 Hz,
1H), 9.08 (dd, JZ0.9, 2.1 Hz, 1H). 13C NMR: 14.9 (CH3),
24.3, 25.3, 26.2, 43.1, 48.0 and 62.3 (CH2), 95.3 (CH), 116.4
4.5.2. tert-Butyl 4-[(4-phenylpiperidin-1-yl)methyl]-3-
pyridin-3-ylisoxazole-5-carboxylate (15b). It was
obtained along with compound 17 (77:23 mixture of 15b/
17) from aldehyde 11 and 4-phenylpiperidine, after 2 (t1)
and 4 (t2) hours, respectively. Flash column chromato-
graphy (hexane/ acetone, 10:1), yield 48%, colourless oil,
1
IR (film): 1734, 1599, 1216, 1156. H NMR: 1.63 (s, 9H),
1.65 (m, 2H), 1.82 (m, 2H), 2.24 (m, 2H), 2.50 (m, 1H), 2.95
(m, 2H), 3.66 (s, 2H), 7.18–7.33 (m, 5H). 7.42 (ddd, JZ0.8,
4.8, 7.8 Hz, 1H), 8.57 (m, 1H), 8.72 (dd, JZ1.6, 4.8 Hz,
1H), 9.27 (d, JZ2.4 Hz, 1H). 13C NMR: 28.2 (CH3), 33.5

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4369
(CH2), 42.5 (CH), 49.4 and 53.6 (CH2), 84.4 and 119.9 (C),
123.4 (CH), 125.2 (C), 126.2, 126.8, 128.4 and 136.5 (CH),
146.1 (C), 150.0 and 150.9 (CH), 156.6, 158.8 and 162.2
(C).
pressure to give 78 mg (0.34 mmol) of compound 18 as a
white solid. Quantitative yield.
Procedure (b). It was obtained along with the reductive
amination products of aldehyde 14 with piperidine and
4-(2-methoxyphenyl)piperidine. It was isolated as a pure
compound by column chromatography (hexane/ ethyl
acetate, 3:2; or hexane/ethyl acetate 2:1, respectively) in
24 and 12% yields, respectively. White solid, mp 119–
120 8C (ethyl acetate/hexane), IR (film): 3129, 1737, 1623,
1599, 1577, 1459, 1308, 1212. 1H NMR: 2.80 (bs, 1H), 4.05
(s, 3H), 4.83 (s, 2H), 7.47 (ddd, JZ0.8, 4.8, 8.1 Hz, 1H),
8.12 (m, 1H), 8.74 (dd, JZ1.6, 4.8 Hz, 1H), 9.00 (d, JZ
2.2 Hz, 1H).13C NMR: 53.1 (CH2), 53.3 (CH3), 123.8 (CH),
124.0 and 124.1 (C), 136.2, 149.1 and 151.2 (CH), 157.5,
158.2 and 161.0 (C).
4.5.3. Methyl 4-(piperidin-1-ylmethyl)-3-pyridin-3-yl-
isoxazole-5-carboxylate (16a). It was obtained along with
compound 18 (77:23 mixture of 16a/18) from aldehyde 14
and piperidine, after 1 (t1) and 3 (t2) hours, respectively.
Flash column chromatography (hexane/ ethyl acetate, 3:2),
yield 63%, white solid, mp 100–101 8C (ethyl acetate/
hexane), IR (KBr): 1732, 1598, 1572, 1310, 1296, 1232. 1H
NMR: 1.48 (m, 6H), 2.44 (m, 4H), 3.61 (s, 2H), 4.01 (s, 3H),
7.41 (dd, JZ4, 8, 8, 1 Hz, 1H), 8.42 (m, 1H), 8.71 (dd, JZ
1.6, 4.8 Hz, 1H), 9.25 (d, JZ1.6 Hz, 1H). 13C NMR: 24.2,
26.0 and 49.6 (CH2), 52.7 (CH3), 53.8 (CH2), 121.3 (C),
123.3 (CH), 124.9 (C), 136.6, 150.0 and 150.9 (CH), 157.3,
157.8 and 162.3 (C). Anal. calcd for C16H19N3O3: C 63.77,
H 6.36, N 13.94. Found: C 64.07, H 6.66. N 13.93.
4.6. Reaction of diazomethane with 4-formyl-3-
isoxazole-5-carboxylic acid and their corresponding
methyl ester
4.5.4. Methyl 4-{[4-(2-methoxyphenyl)piperazin-1-
yl]methyl}-3-pyridin-3-ylisoxazole-5-carboxylate (16b).
It was obtained along with compound 18 (88:12 mixture
of 16b/18) from the aldehyde 14 and 4-(2-methoxyphenyl)-
phenylpiperazine, after 4 (t1 and t2) hours. Flash column
chromatography (hexane/ ethyl acetate, 2:1), yield 53%,
solid, mp 109–110 8C, IR (KBr): 1734, 1596, 1502, 1294,
Procedure (a). To a stirred solution of methyl 4-formyl-3-
pyridin-3-ylisoxazole-5-carboxylate (14) (128 mg,
0.55 mmol) in methanol (4 mL), cooled at 0 8C, was
added a ethereal solution of diazomethane (4 mL, c.a.
24 mmol) and the resulting mixture was stirred for 1 h. The
1
solid was filtered off (55 mg) and analysed by H NMR
1
(starting material and the corresponding hemiketal). The
residue obtained after removed the solvent of the filtrate was
purified by column chromatography (hexane/ethyl acetate,
3:2) to give pure oxirane 20 and ketone 21 in 36 and 6% of
yield respectively (63 and 10% based on the recovered
starting material).
1238. H NMR: 2.71 (m, 4H), 3.03 (m, 4H), 3.75 (s, 2H),
3.85 (s, 3H), 4.01 (s, 3H), 6.92 (m, 4H), 7.41 (ddd, JZ0.9,
4.8, 8.0 Hz, 1H), 8.39 (m, 1H), 8.71 (dd, JZ1.8, 4.8 Hz,
1H), 9.27 (d, JZ1.6 Hz, 1H). 13C NMR: 48.9, 50.6 and 52.6
(CH2), 52.7 and 55.3 (CH3), 111.2 and 118.2 (CH), 120.4
(C); 120.9, 123.0 and 123.4 (CH), 124.8 (C), 136.4 (CH),
141.0 (C), 149.9 and 150.9 (CH), 152.2, 157.6, 157.7 and
162.2 (C).
Procedure (b). To a stirred mixture of acid 12 (0.092 mmol),
ethyl ether (2 mL), and methanol (0.2 mL), cooled at 0 8C,
was added an excess of 0.6 M ethereal solution of
diazomethane for 6 h. The solvents were evaporated under
4.5.5. tert-Butyl 4-(hydroxymethyl)-3-pyridin-3-ylisoxa-
zole-5-carboxylate (17). It was obtained along with the
amines resulting from reductive amination of aldehyde 11
with 4-phenylpiperazine and 4-phenylpiperidine. It was
isolated as pure compound by column chromatography
(hexane/ ethyl acetate, 3:2; or hexane/acetone 10:1) in 22
and 17% yields, respectively. White solid, mp 123–124 8C
(ethyl acetate/hexane), IR (KBr): 3240, 1729, 1607, 1312,
1
vacuum and the residue analysed by H NMR showed the
signal corresponding to the oxirane 20 and the ketone 21
(83:17), which were isolated by column chromatography
(ethyl acetate–hexane, 1:2) in 74 and 14% yields,
respectively.
1
4.6.1. Methyl 4-oxiran-2-yl-3-pyridin-3-ylisoxazole-5-
carboxylate (20). White solid, mp 98–99 8C (ethyl
acetate/hexane), IR (KBr): 1736, 1613, 1591, 1444, 1304.
1H NMR: 2.75 (dd, JZ2.6, 5.0 Hz, 1H), 3.12 (dd, JZ4.2,
5.0 Hz, 1H), 4.04 (s, 3H), 4.29 (dd, JZ2.6, 4.2 Hz, 1H),
7.42 (dd, JZ4.8, 8.0 Hz, 1H), 8.10 (m, 1H), 8.74 (dd, JZ
1.6, 4.8 Hz, 1H), 8.97 (d, JZ2.1 Hz, 1H). 13C NMR: 44.0
(CH), 48.2 (CH2), 53.1 (CH3), 120.7 (C), 123.3 (CH), 124.0
(C), 136.3, 149.3 and 151.3 (CH), 157.2, 158.3 and 160.6
(C).
1156. H NMR: 1.66 (s, 9H), 3.23 (bs, 1H), 4.77 (s, 2H),
7.45 (ddd, JZ0.8, 4.8, 8.1 Hz, 1H), 8.05 (m, 1H), 8.75 (dd,
JZ1.1, 4.8 Hz, 1H), 8.94 (bs, 1H). 13C NMR: 28.1 (CH3),
53.1 (CH2), 85.2 (C), 123.1 (CH), 123.8 and 124.4 (C),
136.1, 149.1 and 151.0 (CH), 156.8, 158.8 and 160.8 (C).
Anal. calcd for C14H16N2O4: C 60.86, H 5.84, N 10.14.
Found: C 60.59, H 6.23, N 9.99.
4.5.6. Methyl 4-(hydroxymethyl)-3-pyridin-3-ylisoxa-
zole-5-carboxylate (18). Procedure (a). To a solution of
78 mg (0.34 mmol) of methyl 4-formyl-3-pyridin-3-
ylisoxazol-5-carboxylate (14) in 2 mL of dichloromethane
was added, at room temperature, 450 mg (2.02 mmol) of
sodium triacetoxyborohydride. After stirring for 4 h at room
temperature the mixture was neutralised with a saturated
solution of sodium bicarbonate to pH 7, and then extracted
several times with dichloromethane. The combined organic
layers were dried and the solvent was removed at reduced
4.6.2. Methyl 4-acetyl-3-pyridin-3-ylisoxazole-5-carb-
oxylate (21). IR (film): 1735, 1703, 1597, 1304, 1259. H
1
NMR: 2.61 (s, 3H), 4.05 (s, 3H), 7.41 (ddd, JZ0.9, 4.8,
8.0 Hz, 1H), 7.97 (m, 1H), 8.74 (dd, JZ1.6, 4.8 Hz, 1H),
8.85 (d, JZ2.4 Hz, 1H). 13C NMR (CDCl3): 32.2 and 53.5
(CH3), 123.5 (C), 123.6 (CH), 124.1 (C), 135.9, 149.0 and
151.6 (CH), 156.6, 157.7, 158.9, and 194.6 (C).

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4.6.3. Methyl 4-[(5-phenyl-2H-tetrazol-2-yl)methyl]-3-
pyridin-3-ylisoxazole-5-carboxylate (19). To a solution
of 63 mg (0.27 mmol) of methyl 4-(hydroxymethyl)-3-
Procedure (b). Following the procedure (a) outlined above,
methyl ester 14 (0.19 mmol) and hydrazine hydrate of 80%
(0.28 mmol), after refluxing for 2 h afforded the compound
24 in 81% yield.
pyridin-3-ylisoxazol-5-carboxylate
(18),
47 mg
(0.32 mmol) of 5-phenyl-1H-tetrazole and 106 mg
(0.40 mmol) of triphenylposphine in 3 mL of dry tetra-
hydrofurane, was added, at room temperature under argon,
64 mL (0.40 mmol) of diethyl diazene-1,2-dicarboxylate
(DEAD). The mixture was stirred at room temperature
for 3.5 h. The solvent was removed under reduced pressure
and the residue was purified by flash column chromato-
graphy on silica gel (hexane/ethyl acetate, 1:1). White solid,
mp 81–82 8C (ethyl acetate/hexane), yield 90%, IR (KBr):
1751, 1735, 1608, 1447, 1229. 1H NMR: 4.03 (s, 3H), 6.03
(s, 2H), 7.43 (m, 4H), 8.01 (m, 3H), 8.72 (bd, JZ3.6 Hz,
1H), 8.95 (bs, 1H). 13C NMR: 44.9 (CH2), 53.3 (CH3), 115.8
and 123.2 (C), 123.7 (CH), 126.7 (C), 126.8, 128.8, 130.5,
135.9, 149.0 and 151.6 (CH), 156.8, 158.9, 161.2 and 165.3
(C). Anal. calcd for C18H14N6O3: C 59.67, H 3.89, N 23.19.
Found: C 59.49, H 3.81, N 23.03.
Procedure (c). A mixture of 8B (0.10 mmol), hydrazine
hydrate 80% (0.15 mmol), acetic acid (0.7 mL) and water
(1 mL) was heated at 90 8C for 1 h. After cooling the
reaction mixture the isoxazolopyridazinone 24 was isolated
by filtration and washed with ethanol. Yield 79%.
Pale yellow solid (decomposed at higher temperature than
201 8C), IR (KBr): 3072 (broad), 1648, 1356. 1H NMR
(DMSO-d6): 7.66 (dd, JZ4.8, 8.0 Hz, 1H), 8.42 (m, 1H),
8.80 (s, 1H), 8.83 (dd, JZ1.6, 4.8 Hz, 1H), 9.19 (d, JZ
2.0 Hz, 1H), 13.60 (s, 1H). 13C NMR (DMSO-d6): 119.1 and
123.0 (C), 124.6, 132.5, 135.9 and 148.5 (CH), 152.2 (C),
152.3 (CH), 155.7 and 159.9 (C). Anal. calcd for
C10H6N4O2: C 56.08, H 2.82, N 26.16. Found: C 55.85, H
2.98, N 25.66.
4.6.4. Methyl 4{[(tert-butoxycarbonyl)(phenylsulfonyl)-
amino]methyl}-3-pyridin-3-ylisoxazole-5-carboxylate
(22). A mixture of methyl 4-(hydroxymethyl)-3-pyridin-3-
ylisoxazole-5-carboxylate (18) (59 mg, 0.25 mmol), tert-
butyl (phenylsulfony)carbamate (219.49 mg, 0.83 mmol),
diethyl diazene-1,2-dicarboxylate (DEAD) (65.31 mg,
0.375 mmol) and triphenylphosphine (98.36 mg,
0.375 mmol) in tetrahydrofurane (8.8 mL), was allowed
stirred at room temperature under argon for 2.5 h. After
removed the solvent the residue was purified by column
chromatography [first ethyl acetate/hexane, 1:3, and then
ethyl acetate/hexane, 1:2] to give 112 mg (94%) of
Acknowledgements
We thank CAICYT (Grant BQU2003-04012) and Janssen-
Cilag S.A. for financial support. We thank Comunidad
Autonoma de Madrid for a Predoctoral Fellowship to C.F.
and Miss Pleite S. for the preparation of sulfonamides 22
and 23.
´
1
References and notes
sulfonamide 22. H NMR: 1.22 (s, 9H), 4.00 (s, 3H), 5.37
(s, 2H), 7.37 (dd, JZ4.9, 7.9 Hz, 1H), 7.46 (m, 2H), 7.58
(m, 3H), 7.84 (dt, JZ1.9, 7.9 Hz, 1H), 8.64 (d, JZ1.9 Hz,
1H), 8.69 (dd, JZ1.5, 4.9 Hz, 1H). 13C NMR: 27.7 (CH3),
38.6 (CH2), 53.0 (CH3), 85.4 (C), 120.1 (C), 123.4 (CH),
124.0 (C), 127.6, 128.7, 133.6 and 136.5 (CH), 139.6 (C),
149.3 (CH), 150.0 (C), 151.0 (CH), 157.4, 158.0 and
161.2 (C).
1. (a) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Simoni,
D. Synthesis 1987, 857–869. (b) Martin, L.; Polo, C.; Ramos,
V.; Torroba, T.; Marcaccini, S. Heterocycles 1993, 36,
2259–2265.
2. AMPA receptor antagonist: Madsen, U.; Sløk, F. A.; Stensbøl,
¨
¨
T. B.; Brauner-Osborne, H.; Lutzhøft, H. H.; Poulsen, M. V.;
Eriksen, L.; Krogsgaard-Larsen, P. Eur. J. Med. Chem. 2000,
35, 69–76.
4.6.5. N-{[5-(Piperidin-1-ylcarbonyl)-3-pyridin-3-yl-
isoxazol-4-yl]methyl}benzenesulfonamide (23). To a
mixtureofmethyl4{[(tert-butoxycarbonyl)(phenylsulfonyl)-
amino]methyl}-3-pyridin-3-ylisoxazole-5-carboxylate (22)
(60 mg, 0.13 mmol) and piperidine (1.01 mmol) was stirred
for 4 dais at 40 8C. The compound 23 was isolated by
column chromatography (ethyl acetate/hexane, 3:2) in 56%
3. Antibacterial activity: Kang, Y. K.; Shin, K. J.; Yoo, K. H.;
Seo, K. J.; Hong, C. Y.; Lee, C.; Park, S. Y.; Kim, D. J.; Park,
S. W. Biorg. Med. Chem. Lett. 2000, 10, 95–99.
4. Antiplatelet effect: Xue, C.; Roderick, J.; Mousa, S.; Olson,
R. E.; DeGrado, W. F. Biorg. Med. Chem. Lett. 1998, 8,
3499–3504.
1
yield. H NMR: 1.72 (m, 6H), 3.68 (m, 4H), 4.05 (d, JZ
5. Anticonvulsant agents: (a) Lepage, F.; Tombret, F.; Cuvier,
G.; Marivain, A.; Gillardin, J. M. Eur. J. Med. Chem. 1992, 27,
581–593. (b) Eddintong, N. D.; Cox, D. S.; Roberts, R. R.;
Butcher, R. J.; Edafiogho, I. O.; Stables, J. P.; Cooke, N.;
Goodwin, A. M.; Smith, C. A.; Scott, K. R. Eur. J. Med. Chem.
2002, 37, 635–648.
6.4 Hz, 2H), 6.36 (t, JZ6.4 Hz, 1H), 7.51 (m, 4H), 7.79 (m,
2H), 8.02 (m, 1H), 8.75 (dd, JZ1.7, 4.9 Hz, 1H), 8.85 (dd,
JZ0.7, 3.1 Hz, 1H). 13C NMR: 24.3, 25.6, 26.6, 36.1, 44.2
and 47.9 (CH2), 118.2 and 123.7 (C), 123.8, 127.0, 129.1,
132.7, 136.1 (CH), 139.5 (C), 149.16 and 151.3 (CH), 156.8,
160.0 and 162.9 (C).
6. Antiviral properties: (a) Lee, Y.; Kim, B. H. Biorg. Med.
Chem. Lett. 2002, 12, 1395–1397. (b) Diana, G. D.; McKinlay,
M. A.; Brisson, C. J.; Zalay, E. S.; Miralles, J. V.; Salvador,
U. J. J. Med. Chem. 1985, 28, 748–752.
4.6.6. 3-Pyridin-3-ylisoxazolo[4,5-d]pyridazin-7(6H)-one
(24). Procedure (a). A mixture of acid 12 (0.29 mmol),
hydrazine hydrate 80% (0.44 mmol), acetic acid (0.3 mL)
and ethanol (3 mL) was refluxed for 3.5 h. After cooling the
reaction mixture the isoxazolopyridazinone 24 was isolated
by filtration and washed with ethanol. Yield 83%.
´
7. Immunostimulatory activity: Ryng, S.; Machon, Z.;
Wieczorek, Z.; Zimecki, M.; Mokrosz, M. Eur. J. Med.
Chem. 1998, 33, 831–836.
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(b) Barzaghi, M.; Beltrame, P. L.; Dalla, P.; Del Buttero, P.;
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3807–3810.
10. Demina, O. V.; Varfolomeev, S. D.; Vzheshch, P. V.;
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20. de Blas, J.; Carretero, J. C.; Domınguez, E. Tetrahedron:
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21. (a) Bravo, P.; Bruche, L.; Crucianelli, M.; Farina, A.; Meille,
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1901–1923. (b) Bravo, P.; Bruche, L.; Merli, A.; Fronza, G.
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13. Farin˜a, F.; Fraile, M. T.; Martın, M. R.; Martın, M. V.;
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14. Garcıa, J. L.; Fraile, A.; Martın, M. R. Tetrahedron 1999, 55,
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pyridin-3-ylisoxazol-5-carboxamides followed by reductive
amination also afforded the corresponding amide-amines in
good yields, personal communication.
17. The dipolarophile 7 was obtained from methyl bromoacetate
following the procedure reported by us in reference 14 for the
preparation of racemic compound 3.
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are close to 170 ppm, see reference 13. Unfortunately, the 13
C
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due to their low proportion in the reaction mixture.
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