Fe(II)-Catalyzed Isomerization of 4-Vinylisoxazoles into Pyrroles

Article abstract of DOI:10.1021/acs.joc.7b01351

The first synthesis of pyrroles by Fe(II)-catalyzed isomerization of 4-vinylisoxazoles is reported. 5-Alkoxy, amino, and N,N-dialkylamino-3-aryl/alkyl-4-(2-R-vinyl)isoxazoles afford 2-aryl/alkyl-5-aryl/alkyl/methoxycarbonyl-1H-pyrrol-3-carboxylic acid derivatives typically under mild conditions with cheap and available FeCl₂·4H₂O as a catalyst. The isomerization of 5-alkoxy/amino-3-arylisoxazoles, bearing unsaturated carbo and heterocyclic substituents at the position 4, gives the corresponding fused pyrrolecarboxylic acid derivatives in high yields. DFT calculations were used to elucidate a probable mechanism of the isomerization and explain the influence of steric congestion of the vinyl moiety on the isomerization pathway.

Full text of DOI:10.1021/acs.joc.7b01351

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Article
Fe(II)-Catalyzed Isomerization of 4-Vinylisoxazoles into Pyrroles
Ekaterina E. Galenko, Vladimir A. Bodunov, Alexey V. Galenko,
Mikhail Sergeevich Novikov, and Alexander F. Khlebnikov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01351 • Publication Date (Web): 20 Jul 2017
Downloaded from http://pubs.acs.org on July 20, 2017
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Fe(II)-Catalyzed Isomerization of 4-Vinylisoxazoles into Pyrroles
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Ekaterina E. Galenko, Vladimir A. Bodunov, Alexey V. Galenko, Mikhail S. Novikov,
Alexander F. Khlebnikov*
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Saint Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab.,
St. Petersburg, 199034 Russia.
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ABSTRACT: The first synthesis of pyrroles by Fe(II)ꢀcatalyzed isomerization of 4ꢀvinylisoxazoles
is reported. 5ꢀAlkoxy, amino and N,Nꢀdialkylaminoꢀ3ꢀaryl/alkylꢀ4ꢀ(2ꢀRꢀvinyl)isoxazoles afford 2ꢀ
aryl/alkylꢀ5ꢀaryl/alkyl/methoxycarbonylꢀ1Hꢀpyrrolꢀ3ꢀcarboxylic acid derivatives typically under
mild conditions with cheap and available FeCl2·4H2O as a catalyst. The isomerization of 5ꢀ
alkoxy/aminoꢀ3ꢀarylisoxazoles, bearing unsaturated carbo and heterocyclic substituents at the
position 4, gives the corresponding fused pyrrolecarboxylic acid derivatives in high yields. DFT
calculations were used to elucidate a probable mechanism of the isomerization and explain the
influence of steric congestion of the vinyl moiety on the isomerization pathway.
INTRODUCTION
Pyrrole moieties are widely present in natural compounds, pharmaceuticals and new materials.1, 2
Accordingly, the development of the synthesis of pyrrole containing compounds is a very active area
of research. While a plethora of preparative methods for the synthesis of this fiveꢀmembered ring
structure have been developed2 there still remains a great need to find new, efficient, and practical
methodologies for the preparation of functionalized pyrroles from inexpensive and available starting
materials. Although ringꢀtoꢀring intramolecular isomerization is a 100% atom economical reaction,3
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the use of this type of processes for the preparation of pyrrole derivatives is quite rare. The
dehydrative rearrangement of aryl and alkyl substituted isoxazolines gives the corresponding
pyrroles in 32ꢀ75% yields.4 To the best of our knowledge, only a single example of an isoxazoleꢀ
pyrrole isomerization was published.5 It involved the BoultonꢀKatritzky rearrangement6 of diethyl 2ꢀ
(4ꢀ(ethoxycarbonyl)ꢀ5ꢀmethylisoxazolꢀ3ꢀyl)pentꢀ2ꢀenedioate to diethyl 5ꢀ(1ꢀethoxyꢀ1,3ꢀdioxobutanꢀ
2ꢀyl)ꢀ1Hꢀpyrroleꢀ2,4ꢀdicarboxylate induced by a base (Scheme 1).
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Scheme 1. Pyrrole synthesis via isomerization of 4ꢀvinylizoxazoles
5ꢀHeterosubstituted isoxazoles can be transformed into the corresponding 2Hꢀazirines by reactions
with metal salts or complexes.7 Iron(II) salts are the most effective catalysts for this isomerization.7,
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It was assumed that the transformation proceeds via the formation of the isoxazole Feꢀcomplex 2,
which facilitates the cleavage of the NꢀO bond, and the subsequent 1,3ꢀcyclization of the iron vinyl
nitrene complex 3, leading to 2Hꢀazirine 5 (Scheme 2).7, 8 We argued that, if the starting isoxazole 1
will contain the vinylꢀsubstituent at the position 4, the corresponding iron vinyl nitrene complex 3
can, along with the 1,3ꢀcyclization into complex 4, undergo the 1,5ꢀcyclization into complex 6 to
form pyrrole derivatives 7.
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Scheme 2. Possible pathways of Fe(II)ꢀcatalyzed transformations of 4ꢀvinylizoxazoles
RESULTS AND DISCUSSION
To start with, we heated an acetonitrile solution of isoxazole 8a in the presence of 10 mol % of
FeCl2·4H2O at 65 °C. The starting material was completely consumed in 6 h giving pyrrole 9a as the
only product (Table 1). It was isolated by column chromatography in 97% yield. To evaluate the
scope of the reaction we synthesized a series of 4ꢀvinylisoxazoles 8a-o,t with different substituents
at the C3 and C5 positions of the ring and at position C2 of the alkenyl moiety (Scheme 3).
Isoxazoles 8a-j,m-p,t were prepared by the Wittig reaction of isoxazoleꢀ4ꢀcarbaldehydes 10a-j with
the ylides 11a-g. Compounds 8k,l with R2 = CO2Me and X = pyrrolidinꢀ1ꢀyl were prepared by
condensation of the corresponding isoxazoleꢀ4ꢀcarbaldehydes 10f,g with methyl acetate. Isoxazoles
8a,c,e,g,h,j-l are obtained as pure Eꢀisomers, while isoxazoles 8b,d,f,i,m-p are E/Zꢀmixtures
containing less than 17% of the Zꢀisomer. Only compound 8t contained the Zꢀisomer as the major
isomer (1:0.26 ratio). Isoxazoles 8q-s, bearing unsaturated cyclic substituents with the appropriate
C=C bond, (Scheme 3) were additionally synthesized to check whether the reaction could be used
for the preparation of fused pyrrole derivatives.
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Scheme 3. Synthesis of vinylisoxazoles 8
The results of Fe(II)ꢀcatalytic isomerization of 4ꢀvinylisoxazoles 8a-t are depicted in Table 1. Aryl
groups with halogen, nitro or methoxy substituents, thienꢀ2ꢀyl, methoxycarbonyl, amino and Nꢀ
substituted amino groups tolerate the reaction conditions, providing good yields of pyrroles 9a-t. All
1
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the new compounds were characterized by H and C NMR and mass spectrometry. The structure
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of compound 9e was also established by single crystal Xꢀray diffraction (see the Supporting
Information). Pyrroles 9a-m, p-r were obtained by heating the corresponding 4ꢀvinylisoxazoles with
a catalytic amount of FeCl2·4H2O in MeCN at 65 °C for 4ꢀ6 h. For the isomerization of isoxazoles
8n, o to pyrroles 9n, o within a reasonable time, a higher temperature, 80 °C, was required. When
the reaction of isoxazole 8s was carried out under the standard reaction conditions (10 mol % of
FeCl2·4H2O, MeCN, 65 °C), the only product was azirine 12a (88%). The use of harsher
isomerization conditions (DMSO, 160 °C) resulted in the expected pyrrole 9s (80%) formation. It is
worth noting that heating azirine 12a at 160 °C in DMSO in the absence of FeCl2·4H2O did not give
even traces of pyrrole 9s. At the same time, heating azirine 12a with FeCl2·4H2O at 160 °C in
DMSO led to a quantitative transformation of the azirine into pyrrole 9s (Scheme 4).
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Scheme 4. The reaction of isoxazole 8r
Unexpectedly, when a mixture of the cisꢀ and transꢀisomers of propenylisoxazole cisꢀ and transꢀ8t,
in the ratio 1:0.26, was reacted with a catalytic amount of FeCl2·4H2O in MeCN at 65 °C, azirine
12b and pyrrole 9t were isolated in practically the same ratio (1:0.28) (Scheme 5).
Scheme 5. The reaction of isoxazoles cisꢀ and transꢀ8t
This, together with the results presented above, suggests that azirine 12b and pyrrole 9t are formed
from cisꢀ and transꢀ8t, respectively. Therefore, this reaction is a good candidate for checking the
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reaction mechanism by quantumꢀchemical calculations to determine factors that affect the
isomerization pathway.
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Table 1. Synthesis of substituted pyrroles 9
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Taking into account (a) the crystal structure of FeCl2·4H2O,9 (b) the same results on Fe(II)ꢀcatalyzed
reactions of isoxazoles 8, in which anhydrous FeCl2 was used instead of the tetrahydrate, (c) the use
of MeCN as the reaction media, as well as (d) the ability of MeCN to displace water in FeCl2·4H2O
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with the formation of Fe(MeCN)4Cl2,10 we chose complexes 13ꢀ16 as the starting model compounds
for calculations (Scheme 6). Feꢀpyrrole complex 22, the most probable precursor of the 1Hꢀpyrrole
of type 9, was computed as the final isomerization product of complexes 13ꢀ16.
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Scheme 6. Model complexes 13-16, 22 for calculations
For a formally d6 Fe(II) complex four spin states are possible: singlet, triplet, quintet, and sextet.
The quintet state is usually the thermodynamically most stable in solution.11 Calculations of iron
complexes 13, 14, 22 and TS21-22 were performed (Table 2, Figs. 1, 2, Schemes S1, S2 in the
Supporting Information) and it was found that the singlet, triplet and sextet states are much higher in
energy than the quintet states for complexes 13, 14, 22 and TS21-22
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Table 2 Relative Gibbs free energies (in kcal mol–1, 298 K, PCM model for MeCN) of different spin
states for iron complexes 13, 14, 22 and TS21-22 computed at the DFT B3LYP/6ꢀ
31G(d){CHNOCl}/SDD{Fe} level.
Complex Singlet Triplet Quintet Septet
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31.0
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TS21-22
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This suggested a singleꢀstate reactivity of the complexes under consideration and, therefore, the
transformation pathways of complexes 13ꢀ16, leading to the pyrrole and azirine products were
computed in the quintet state.
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According to the calculations (Fig. 1, Scheme S1 in the Supporting Information), there are two
possible reaction pathways for the formation of pyrrole 22 from isoxazole complex 13.
Figure 1. Energy profiles for the transformations of complexes 13, 14. Relative Gibbs free energies
(in kcal mol–1, 298 K, PCM model for MeCN) computed at the DFT B3LYP/6ꢀ
31G(d){CHNOCl}/SDD{Fe} level.
The first pathway (blue) involves the isoxazole ring opening in 13 with the formation of Feꢀnitrene
complex 17, the cyclization of 17 into Feꢀazirine complex 18, and the lowꢀbarrier conformational
transformations of the latter to conformer 20, which can undergo the azirine ring opening to give Feꢀ
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nitrene complex 21 in a conformation appropriate for cyclization. This then cyclizes irreversibly into
pyrrole 22. The second pathway (red) involves the low barrier rotation of the propenyl group of
isoxazole complex 13 around the CꢀC bond to form conformer 14, followed by the isoxazole ring
opening, leading directly to Feꢀnitrene complex 21 (precursor of pyrrole 22). Complex 21, however,
has a very low barrier for the cyclization into azirine 20. The free energy barrier for the
transformation of the lowest energy azirine complex 19 into pyrrole 22 is about 25 kcal mol–1.
The change of the conformation of the C=C double bond from trans to cis alters the isomerization
pathway of complex 15 compared with complex 13 due to additional steric hindrance (Fig. 2,
Scheme S2 in the Supporting Information).
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Figure 2. Energy profiles for the transformations of complexes 15, 16. Relative Gibbs free energies
(in kcal mol–1, 298 K, PCM model for MeCN) computed at the DFT B3LYP/6ꢀ
31G(d){CHNOCl}/SDD{Fe} level.
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According to the calculations the isoxazole ring opening in 15 leads to Feꢀnitrene complex 23,
which transforms into conformer 24. The latter undergoes an almost barrierless cyclization into Feꢀ
azirine complex 25, which, via a low barrier, gives a more stable conformer 26. The latter can
undergo the azirine ring opening to give Feꢀnitrene complex 27, which can cyclize into pyrrole 22.
The second pathway (red) involves the low barrier rotation of the propenyl group of isoxazole
complex 15 around the CꢀC bond to form conformer 16, followed by the isoxazole ring opening in
16, leading directly to Feꢀnitrene complex 27, which has a very low barrier for the cyclization into
azirine 26. The free energy barrier for the transformation of the lowest energy azirine complex 26
into pyrrole 22 is about 29 kcal mol–1, i.e. by 4 kcal mol–1 higher than for the transformation
19→22.
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The change from the Meꢀgroup in the model compounds to Et, like in 8s, will further increase the
difference in the barriers for cyclization of the Etꢀanalogs of nitrene complexes 21 and 27. Therefore
we can conclude that the formation of azirine 12b and pyrrole 9t from cisꢀ and transꢀ8t,
respectively, under Fe(II)ꢀcatalysis in MeCN at 65 °C is due to a much higher barrier for the
transformation of the corresponding Feꢀ(cisꢀRꢀvinyl)azirine complex into the pyrrole complex
compared with the transꢀisomer due to a higher steric crowding of the vinyl moiety. The exclusive
formation of only pyrrole 9t (69%) from the mixture of cisꢀ and transꢀisomers of propenylisoxazole
cisꢀ and transꢀ8t at a higher temperature (110 °C) is in full agreement with the calculations .
Thus, according to the calculations and experimental results the increase of steric congestion in
isoxazole hinders the transformation of the transient Feꢀazirine complex into the corresponding
pyrrole derivative, thereby requiring a higher temperature for isomerization.
CONCLUSION
The first syntheses of pyrrole derivatives by Fe(II)ꢀcatalyzed intramolecular isomerization of
isoxazoles are developed. 5ꢀAlkoxy, amino or N,Nꢀdialkylaminoꢀ3ꢀaryl/alkylꢀ4ꢀ(2ꢀRꢀ
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vinyl)isoxazoles afford 2ꢀaryl/alkylꢀ5ꢀaryl/alkyl/methoxycarbonylꢀ1Hꢀpyrrolꢀ3ꢀcarboxylic acid
derivatives typically under mild reaction condition with a cheap and available FeCl2·4H2O as a
catalyst. The isomerization of 5ꢀalkoxy/aminoꢀ3ꢀarylisoxazoles, bearing cyclic substituents with the
appropriate C=C bond at the position 4, affords the corresponding fused pyrroles. The DFT
calculations suggest a singleꢀstate quintet reactivity of the Fe(II)ꢀcomplexes of the heterocycles
under consideration and Fe(II)ꢀnitrene complexes. According to the calculations, the isomerization
involves isoxazole ring opening of the Fe(II)ꢀisoxazole complex to form a Fe(II)ꢀnitrene complex.
The latter undergoes a lowꢀbarrier cyclization into the Fe(II)ꢀcomplex of 2ꢀ(2ꢀRꢀvinyl)ꢀ2Hꢀazirine.
The transꢀisomer of the azirine complex can give a Fe(II)ꢀ(transꢀ2ꢀRꢀvinyl)ꢀsubstituted nitrene
complex, which has the appropriate conformation to undergo a 1,5ꢀcyclization into the 2Hꢀpyrrole
derivative. The free energy barrier for the transformation of the Fe(II)ꢀcomplex of 2ꢀ(cisꢀ2ꢀRꢀvinyl)ꢀ
2Hꢀazirine into the pyrrole is much higher and this prevents the formation of the pyrrole derivative
under mild conditions due to higher steric crowding of the alkenyl moiety, so that in this case the
final isomerization product is 2ꢀ(cisꢀ2ꢀRꢀvinyl)ꢀ2Hꢀazirine. Since increase of steric congestion at the
vinyl moiety hinders the transformation of an intermediate Feꢀazirine complex into the
corresponding pyrrole, such isoxazoles require the use of harsher reaction conditions for
isomerization to pyrroles.
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EXPERIMENTAL SECTION
General Information and Methods
1
Melting points were determined on a capillary melting point apparatus using unsealed capillary. H
13
(400 MHz) and C (100 MHz) NMR spectra were recorded in CDCl3 and DMSOꢀd6 with NMRꢀ
spectrometer. Chemical shifts (δ) are reported in parts per million downfield from tetramethylsilane
(TMS δ 0.00). 1H NMR spectra were calibrated according to the residual peak of CDCl3 (7.26 ppm)
or DMSOꢀd6 (2.50 ppm). For new compounds 13C{1H} and 13C DEPT135 were recorded and
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calibrated according to the peak of CDCl3 (77.00 ppm) or DMSOꢀd6 (39.51 ppm). For all new final
pyrroles, initial isoxazoles and for the most of undescribed intermediate substances 13C{1H} and 13C
DEPT135 were recorded and calibrated according to the peak of CDCl3 (77.00 ppm). Mass spectra
were recorded on a HRMSꢀESIꢀQTOF massꢀanalyzer, electrospray ionization, positive mode. Thinꢀ
layer chromatography (TLC) was conducted on aluminium sheets with 0.2 mm silica gel with
fluorescent indicator, silica 60 M was used for column chromatography. The known compounds
were prepared by published procedures: 5ꢀchloroꢀ3ꢀphenylisoxazoleꢀ4ꢀcabaldehyde 29a,12 5ꢀchloroꢀ
3ꢀ(4ꢀnitrophenyl)isoxazoleꢀ4ꢀcabaldehyde 29c,13 3ꢀ(tertꢀbutyl)ꢀ5ꢀchloroisoxazoleꢀ4ꢀcarbaldehyde
29d,13 5ꢀmethoxyꢀ3ꢀphenylisoxazoleꢀ4ꢀcarbaldehyde 10a12 and phosphonium salts 11.14ꢀ16
Compounds 28a,b were synthesized by a slightly modified literature procedure.17 Compounds 10c,d
and 10e-j were synthesized by slightly modified literature procedures.8c
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Synthesis of Starting Materials
3-(4-Bromophenyl)-5-methoxyisoxazole-4-carbaldehyde (10b). N,N-Dimethylformamide (DMF)
(6.0 mL, 78 mmol) was added dropwise to phosphorus oxychloride (15.4 mL, 165 mmol) under
stirring and iceꢀcooling. The solution was stirred for 15 min, put in freezer (ꢀ18 °C) and held there
until a colorless precipitate was formed. 3ꢀ(4ꢀBromophenyl)isoxazolꢀ5(4H)ꢀone (2.33 g, 9.7 mmol)
was added to the preheated to 75 °C the reaction mixture and stirred for 3 h. The reaction mixture
was cooled and poured onto crushed ice. The precipitate formed was filtered off, washed with water
and dried in vacuum to give 1.93 g (70%) of 3ꢀ(4ꢀbromophenyl)ꢀ5ꢀchloroisoxazoleꢀ4ꢀcarbaldehyde
(29b) as a yellowish solid, mp 55ꢀ56 °C (water). 1H NMR (CDCl3): δ = 7.64ꢀ7.66 (m, 2H), 7.69ꢀ
13
7.72 (m, 2H), 9.96 (s, 1H). C NMR (CDCl3): δ = 113.2 (C), 125.2 (C), 126.0 (C), 130.6 (CH),
132.1 (CH), 162.1 (C), 163.4 (C), 181.5 (CH). Aldehyde 29b was used without further purification.
To a suspension of aldehyde 29b (715 mg, 2.5 mmol) in absolute methanol (10 mL) a solution of
sodium methoxide, prepared from sodium (230 mg, 10.0 mmol) and absolute methanol (5 mL), was
added dropwise. The reaction mixture was stirred for 30 min, poured into cold water and acidified
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with acetic acid. The precipitate was filtered off, washed with water and dried on air to give 557 mg
(79%) of pure product as a yellowish solid, mp 105ꢀ106 °C (water/MeOH). 1H NMR (CDCl3): δ =
4.35 (s, 3H), 7.61ꢀ7.63 (m, 2H), 7.71ꢀ7.73 (m, 2H), 9.74 (s, 1H). 13C NMR (CDCl3): δ = 59.0 (CH3),
96.0 (C), 125.5 (C), 126.4 (C), 130.4 (CH), 131.9 (CH), 162.9 (C), 175.8 (C), 181.0 (CH). HRMS
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+
(ESIꢀTOF) (m/z): [M+H]+ Calcd. for C11H9BrNO3 281.9760; Found 281.9790.
5-Methoxy-3-(4-methoxyphenyl)isoxazole-4-carbaldehyde
(10c).
A
mixture
of
3ꢀ(4ꢀ
methoxyphenyl)isoxazolꢀ5(4H)ꢀone (1.68 g, 8.79 mmol) and triethyl orthoformate (6 g) was heated
at 100ꢀ110 °C for 1 h. The volatiles were evaporated in vacuum and the residue was suspended in
2% aq. H2SO4 and stirred for 1 h. Water was evaporated and the residue was stirred with a mixture
of diethyl ether/hexane (1:1, 10 mL). The precipitate formed was filtered off, washed with cold
ethanol and dried on air to give 3ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀoxoꢀ4,5ꢀdihydroisoxazoleꢀ4ꢀcarbaldehyde
1
(28a) (1.26 g, 65%), as an orange solid, mp 149ꢀ150 °C (dec.). H NMR spectrum of 28a consisted
of very wide signals due to the tautomeric equilibrium. HRMS (ESIꢀTOF) (m/z): 220.0604 Calcd.
for C11H10NO4 [M+H]+; Found 220.0596. Aldehyde 28a was used without further purification. To a
+
suspension of aldehyde 28a (1.00 g, 4.56 mmol) in THF (10 mL) a solution of diazomethane,
prepared from N-nitroso-N-methylurea (1.41 g, 13.6 mmol), 40% aq KOH (3.45 g, 61.2 mmol) and
ether(10 mL), was slowly added under stirring and iceꢀcooling. The reaction mixture was stirred for
1 h at room temperature, the excess of diazomethane was quenched with acetic acid and the solvents
were removed in vacuum. The residue was filtered through a pad of silica, eluting with light
petroleum/ethyl acetate (3:1) to give, after evaporation of the solvents, washing of the precipitate
with pentane and drying on air, aldehyde to give 153 mg (14%) of aldehyde 10c as a colorless solid,
1
mp 112ꢀ113 °C (ethyl acetate/light petroleum). H NMR (CDCl3): δ = 3.86 (s, 3H), 4.33 (s, 3H),
7.00 (d, J = 8.9 Hz, 2H), 7.78 (d, J = 8.9 Hz, 2H), 9.74 (s, 1H). 13C NMR (CDCl3): δ = 55.4 (CH3),
58.8 (CH3), 96.1 (C), 114.1 (CH), 119.7 (C), 130.4 (CH), 161.6 (C), 163.6 (C), 175.4 (C), 181.5
(CH). HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd. for C12H12NO4 234.0761; Found 234.0742.
+
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5-Methoxy-3-(thiophen-2-yl)isoxazole-4-carbaldehyde (10d).
A
mixture of 3ꢀ(thiophenꢀ2ꢀ
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yl)isoxazolꢀ5(4H)ꢀone (1.52 g, 9.10 mmol) and triethyl orthoformate (6 g) was heated at 100ꢀ110 °C
for 1 h. The volatiles were evaporated in vacuum and the residue was suspended in 2% aq. H2SO4
and stirred for 1 h. Water was evaporated and a mixture of diethyl ether/hexane (1:1, 10 mL) was
added to the residue. The precipitate formed was filtered off, washed with cool ethanol and dried on
air to give 5ꢀoxoꢀ3ꢀ(thiophenꢀ2ꢀyl)ꢀ4,5ꢀdihydroisoxazoleꢀ4ꢀcarbaldehyde (28b) (1.23 g, 69%), as an
orange solid, mp 145ꢀ146 °C (dec.), 1H NMR spectrum of 28b consisted of very wide signals due to
the tautomeric equilibrium. Aldehyde 28b was used without further purification. To a suspension of
aldehyde 28b (1.09 g, 5.56 mmol) in THF (10 mL) a solution of diazomethane, obtained from N-
nitroso-N-methylurea (1.55 g, 15.0 mmol), 40% aq KOH (3.45 g, 61.2 mmol) and ether (10 mL),
was slowly added under stirring and iceꢀcooling. The reaction mixture was stirred for 1 h at rt, the
excess of diazomethane quenched with acetic acid and the solvents were removed in vacuum. The
residue was filtered through a pad of silica, eluting with light petroleum/ethyl acetate (3:1) to give,
after evaporation of the solvents, washing of the precipitate with pentane and drying on air, aldehyde
10d as a colorless solid, mp 95ꢀ96 °C (ethyl acetate/light petroleum), yield 351 mg (30 %). 1H NMR
(CDCl3): δ = 4.33 (s, 3H), 7.16 (dd, J = 3.8, 1.1 Hz, 1H), 7.49 (dd, J = 5.0, 1.1 Hz, 1Hz), 8.19 (dd, J
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= 5.0, 3.8 Hz, 1H), 9.82 (s, 3H). C NMR (CDCl3): δ = 58.9 (CH3), 95.8 (C), 127.8 (CH), 128.2
(C), 129.1 (CH), 132.3 (CH), 157.9 (C), 176.1 (C), 180.7 (CH). HRMS (ESIꢀTOF) (m/z): [M+Na]+
Calcd. for C9H7NNaO3S+ 232.0039; Found 232.0038.
General procedure (A) for the synthesis of 5-amino-3-substituted isoxazole-4-carbaldehydes
10e-j. An excess of an appropriate amine (2 mmol) and potassium carbonate (1.5 mmole) was added
to a solution of 5ꢀchloroisoxazoleꢀ4ꢀcarbaldehyde 29 (1 mmol) in a minimum volume of dry DMF.
The mixture was stirred at room temperature until the reaction completion (monitored by TLC).
Water was added to the reaction mixture and the precipitate formed was filtered off, washed with
water and dried on air, then washed with ether and dried again to give pure product. If the product
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wasn’t crystallized, it was extracted with ether and the ether solution was washed with brine and
dried over sodium sulfate. Ether was evaporated and the residue was purified by filtration through a
pad of silica. After evaporation of solvents, the residue was washed with hexane, dried on air to give
pure compound.
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5-(N,N-Diethylamino)-3-phenylisoxazole-4-carbaldehyde (10e). Compound 10e was prepared from
5ꢀchloroꢀ3ꢀphenylisoxazoleꢀ4ꢀcarbaldehyde 29a (518 mg, 2.5 mmol), diethylamine (366 mg, 5.0
mmol) and potassium carbonate (525 mg, 3.8 mmol) for 1 week according to the general procedure
A. The product was purified by filtration through a pad of silica (light petroleum/ethyl acetate, 8:1)
to give a yellow solid (380 mg, 62%), mp 87ꢀ88 °C (light petroleum/EtOAc). 1H NMR (CDCl3): δ =
1.30 (t, J = 7.1 Hz, 6H), 3.82 (q, J = 7.1 Hz, 4H), 7.46ꢀ7.50 (m, 3H), 7.55ꢀ7.57 (m, 2H), 9.32 (s,
13
1H). C NMR (CDCl3): δ = 13.7 (CH3), 45.6 (CH2), 96.5 (C), 128.1 (C), 128.7 (CH), 129.3 (CH),
130.0 (CH), 166.6 (C), 167.8 (C), 181.5 (CH). HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd. for
+
C14H17N2O2 245.1285; Found 245.1286.
3-Phenyl-5-(pyrrolidin-1-yl)isoxazole-4-carbaldehyde (10f). Compound 10f was prepared from 5ꢀ
chloroꢀ3ꢀphenylisoxazoleꢀ4ꢀcarbaldehyde 29a (882 mg, 4.25 mmol), pyrrolidine (604 mg, 8.50
mmol) and potassium carbonate (880mg, 6.38 mmol) for 0.5 h according to the general procedure A.
1
A colorless solid, mp 120ꢀ121 °C (DMF/water), yield 735 mg (71%). H NMR (CDCl3): δ = 2.03ꢀ
13
2.06 (m, 4H), 3.84ꢀ3.88 (m, 4H), 7.46ꢀ7.50 (m, 3H), 7.59ꢀ7.62 (m, 2H), 9.45 (s, 1H). C NMR
(CDCl3): δ = 25.4 (CH2), 50.1 (CH2), 97.1 (C), 128.2 (C), 128.6 (CH), 129.2 (CH), 130.1 (CH),
+
165.3 (C), 167.3 (C), 181.6 (CH). HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd. for C14H15N2O2
243.1128; Found 243.1126.
3-(4-Bromophenyl)-5-(pyrrolidin-1-yl)isoxazole-4-carbaldehyde (10g). Compound 10g was
prepared from 3ꢀ(4ꢀbromophenyl)ꢀ5ꢀchloroisoxazoleꢀ4ꢀcarbaldehyde 29b (551 mg, 1.92 mmol),
pyrrolidine (273 mg, 3.85 mmol) and potassium carbonate (398 mg, 2.88 mmol) for 0.5 h according
to the general procedure A. A colorless solid, mp 137ꢀ138 °C (DMF/water), yield 467 mg (76%). 1H
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NMR (CDCl3): δ = 2.04ꢀ2.07 (m, 4H), 3.82ꢀ3.86 (m, 4H), 7.49ꢀ7.51 (m, 2H), 7.60ꢀ7.61 (m, 2H),
4
5
13
9.48 (s, 1H). C NMR (CDCl3): δ = 25.4 (CH2), 50.1 (CH2), 97.1 (C), 124.6 (C), 127.2 (C), 130.7
6
7
(CH), 131.8 (CH), 164.1 (C), 167.2 (C), 180.9 (CH). HRMS (ESIꢀTOF) (m/z): [M+H]+ 321.0233
8
9
+
Calcd. for C14H14BrN2O2 ; Found 321.0224.
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3-(4-Nitrophenyl)-5-(pyrrolidin-1-yl)isoxazole-4-carbaldehyde (10h). Compound 10h was prepared
from 5ꢀchloroꢀ3ꢀ(4ꢀnitrophenylisoxazole)ꢀ4ꢀcarbaldehyde 29c (907 mg, 3.59 mmol), pyrrolidine
(512 mg, 7.20 mmol) and potassium carbonate (745 mg, 5.40 mmol) for 0.5 h according to the
general procedure A. A colorless solid, mp 166ꢀ167 °C (DMF/water), yield 942 mg (91%). 1H NMR
(DMSOꢀd6): δ = 1.99ꢀ2.02 (m, 4H), 3.72ꢀ3.75 (m, 4H), 7.87ꢀ7.90 (m, 2H), 8.31ꢀ8.33 (m, 2H), 9.60
(s, 1H). 13C NMR (DMSOꢀd6): δ = 24.9 (CH2), 49.6 (CH2), 96.8 (C), 123.3 (CH), 130.4 (CH), 135.0
(C), 148.9 (C), 161.7 (C), 168.1 (C), 180.3 (CH). HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd. for
+
C14H14N3O4 288.0979; Found 288.0972.
5-(Dibenzylamino)-3-(4-nitrophenyl)isoxazole-4-carbaldehyde (10i). Compound 10i was prepared
from 5ꢀchloroꢀ3ꢀ(4ꢀnitrophenylisoxazole)ꢀ4ꢀcarbaldehyde 29c (233 mg, 0.92 mmol), dibenzylamine
(364 mg, 1.85 mg) and potassium carbonate (192 mg, 1.38 mmol) for 2 h at 40 °C according to the
general procedure A. A colorless solid, mp 160ꢀ161 °C (DMF/water), yield 371 mg (90%). 1H NMR
(CDCl3): δ = 4.97 (s, 4H), 7.26ꢀ7.28 (m, 4H), 7.33ꢀ7.41 (m, 6H), 7.83 (d, J = 8.7 Hz, 2H), 8.36 (d, J
13
= 8.7 Hz, 2H), 9.41 (s, 1H). C NMR (CDCl3): δ = 53.3 (CH2), 96.9 (C), 123.8 (CH), 128.0 (CH),
128.3 (CH), 129.0 (CH), 130.4 (CH), 134.4 (C), 135.1 (C), 149.0 (C), 164.6 (C), 169.3 (C), 180.6
+
(C). HRMS (ESIꢀTOF) (m/z): [M+Na]+ Calcd. for C24H19N3NaO4 436.1268; Found 436.1286.
3-(tert-Butyl)-5-(pyrrolidin-1-yl)isoxazole-4-carbaldehyde (10j). Compound 10j was prepared from
3ꢀ(tertꢀbutyl)ꢀ5ꢀchloroisoxazoleꢀ4ꢀcarbaldehyde 29d (350 mg, 1.87 mmol), pyrrolidine (266 mg,
3.74 mmol) and potassium carbonate (387 mg, 2.80 mmol) for 0.5 h according to the general
1
procedure A. A colorless solid, mp 128ꢀ129 °C (DMF/water), yield 375 mg (91%). H NMR
(DMSOꢀd6): δ = 1.32 (s, 9H), 1.94ꢀ1.97 (m, 4H), 3.61ꢀ3.65 (m, 4H), 9.69 (s, 1H). 13C NMR
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(DMSOꢀd6): δ = 24.8 (CH2), 27.5 (CH3), 33.3 (C), 49.6 (CH2), 97.6 (C), 169.4 (C), 169.8 (C), 180.0
4
5
+
(CH). HRMS (ESIꢀTOF) (m/z): 245.1260 Calcd. for C12H18N2NaO2 [M+Na]+; Found 245.1263.
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8
9
General procedure B for the synthesis of 4-alkenylisoxazoles 8 by Wittig reaction. Compounds
8a-j,m-o,s were synthesized by a slightly modified literature procedure.18 Potassium tert-butoxide
was added to a suspension of alkyltriphenylphosphonium salt 11 (1.5ꢀ1.6 mmol) in dry THF. The
mixture was stirred for 0.5 h at rt, and then aldehyde 10 (1.0 mmol) was added. The reaction mixture
was refluxed until full conversion of starting aldehyde. If decomposition of phosphonium ylide was
proceeded faster, than the reaction ended (bleaching of reaction mixture), freshly prepared ylide in
dry THF was added. After full conversion of aldehyde, the reaction mixture was filtered, the solvent
was evaporated, and the residue purified by column chromatography, using a mixture of light
petroleum ether and ethyl acetate as eluent. The solid obtained after evaporation of the solvents was
washed with pentane.
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(E)-5-Methoxy-4-(4-nitrostyryl)-3-phenylisoxazole (8a). Compound 8a was prepared from (4ꢀ
nitrobenzyl)triphenylphosphonium bromide 11a (406 mg, 0.85 mmol), potassium tert-butoxide (95
mg, 0.85 mmol) and 5ꢀmethoxyꢀ3ꢀphenylisoxazoleꢀ4ꢀcarbaldehyde 10a (109 mg, 0.54 mmol) in
THF (12 mL) for 2 h according to the general procedure B. The product was purified by column
chromatography (light petroleum/ethyl acetate, 4:1ꢀ2:1). An orange solid, mp 145ꢀ146 °C (light
petroleum/ethyl acetate), yield 124 mg (72%). 1H NMR (CDCl3): 4.32 (s. 3H), 6.84 (d, J = 16.5 Hz,
1H), 7.00 (d, J = 16.5 Hz, 1H), 7.45ꢀ7.47 (m, 2H), 7.52ꢀ7.54 (m, 3H), 7.60ꢀ7.63 (m, 2H), 8.15ꢀ8.16
(m, 2H). 13C NMR (CDCl3): 58.3 (CH3), 91.2 (C), 119.9 (CH), 124.1 (CH), 126.2 (CH), 126.2 (CH),
128.6 (CH), 128.99 (CH), 129.01 (C), 130.1 (CH), 144.3 (C), 146.4 (C), 164.3 (C), 169.7 (C).
+
HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd. for C18H15N2O4 323.1032; Found 323.1026.
(E/Z)-4-(3-Chlorostyryl)-5-methoxy-3-phenylisoxazole (8b). Compound 8b was prepared from (3ꢀ
chlorobenzyl)triphenylphosphonium chloride 11b (511 mg, 1.20 mmol), potassium tert-butoxide
(135 mg, 1.20 mmol) and 5ꢀmethoxyꢀ3ꢀphenylisoxazoleꢀ4ꢀcarbaldehyde 10a (163 mg, 0.80 mmol)
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in THF (8 mL) for 3 h according to the general procedure B. The product was purified by column
chromatography (light petroleum/ethyl acetate, 8:1). A light yellow solid, mp 88ꢀ89 °C (light
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petroleum/ethyl acetate), yield 199 mg (80%), (E/Z)ꢀmixture (~1:0.15). H NMR (CDCl3): for (E)ꢀ
8
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isomer δ = 4.29 (m, 3H), 6.67 (d, J = 16.5 Hz, 1H), 6.89 (d, J = 16.5 Hz, 1H), 7.15ꢀ7.27 (m, 3H),
7.34 (s, 1H), 7.61ꢀ7.63 (m, 2H), 7.51ꢀ7.52 (m, 3H); for (Z)ꢀisomer 3.92 (s, 3H), 6.17 (d, J = 11.8 Hz,
1H), 6.54 (d, J = 11.8 Hz, 1H), 7.12ꢀ7.23 (m, 4H), 7.40ꢀ7.42 (m, 2H), 7.65ꢀ7.67 (m, 2H). 13C NMR
(CDCl3): for (E)ꢀisomer δ = 58.1 (CH3), 91.3 (C), 116.6 (CH), 124.1 (CH), 125.8 (CH), 127.1 (CH),
127.5 (CH), 128.5 (CH), 128.9 (CH), 129.8 (CH), 129.8 (C), 129.9 (CH), 134.6 (C), 139.6 (C),
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+
164.2 (C), 169.3 (C). HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd. for C18H15ClNO2 312.0786; Found
312.0790.
(E)-Methyl 3-(5-methoxy-3-phenylisoxazole-4-yl)acrylate (8c). Compound 8c was prepared from (2ꢀ
methoxyꢀ2ꢀoxoethyl)triphenylphosphonium bromide 11c (477 mg, 1.15 mmol), potassium tert-
butoxide (129 mg, 1.15 mmol) and 5ꢀmethoxyꢀ3ꢀphenylisoxazoleꢀ4ꢀcarbaldehyde 10a (145 mg, 0.71
mmol) in THF (8 mL)for 4 h according to the general procedure B. The product was purified by
column chromatography (light petroleum/ethyl acetate, 5:1). A colorless solid, mp 115ꢀ116 °C (light
1
petroleum/ethyl acetate), yield 81 mg (44%). H NMR (CDCl3): δ = 3.74 (s, 3H), 4.29 (s, 3H), 6.31
13
(d, J = 16.0 Hz, 1H), 7.37 (d, J = 16.0 Hz, 1H), 7.48ꢀ7.51 (m, 3H), 7.55ꢀ7.57 (m, 2H). C NMR
(CDCl3): δ = 51.5 (CH3), 58.4 (CH3), 90.2 (C), 116.8 (CH), 128.4 (C), 128.5 (CH), 129.0 (CH),
130.2 (CH), 131.8 (CH), 164.6 (C), 167.7 (C), 170.9 (C). HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd.
+
for C14H14NO4 260.0917; Found 260.0918.
(E/Z)-3-(4-Bromophenyl)-5-methoxy-4-styrylisoxazole (8d). Compound 8d was prepared from
benzyltriphenylphosphonium bromide 11d (433 mg, 1.00 mmol), potassium tert-butoxide (113 mg,
1.00 mmol) and 3ꢀ(4ꢀbromophenyl)ꢀ5ꢀmethoxyisoxazoleꢀ4ꢀcarbaldehyde 10b (169 mg, 0.60 mmol)
in THF (10 mL)for 0.17 h according to the general procedure B. The product was purified by
column chromatography (light petroleum/ethyl acetate, 5:1). A colorless solid, mp 65ꢀ69 °C (light
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petroleum/ethyl acetate), yield 50 mg (23%), (E/Z)ꢀmixture (~1:0.16). H NMR (CDCl3): for (E)ꢀ
isomer δ = 4.28 (s, 3H), 6.61 (d, J = 16.5 Hz, 1H), 6.95 (d, J = 16.5 Hz, 1H), 7.20ꢀ7.24 (m, 1H),
7.29ꢀ7.33 (m. 2H), 7.36ꢀ7.38 (m, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H); for (Z)ꢀ
isomer δ = 3.88 (s, 3H), 6.10 (d, J = 11.7 Hz, 1H), 6.66 (d, J = 11.7 Hz, 1H), 7.20ꢀ7.24 (m, 3H),
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7.29ꢀ7.38 (m, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H). C NMR (CDCl3): for (E)ꢀ
isomer δ = 58.1 (CH3), 91.5 (C), 114.6 (CH), 124.3 (C), 125.9 (CH), 127.4 (CH), 128.4 (C), 128.6
(CH), 129.5 (CH), 130.1 (CH), 132.1 (CH), 137.5 (C), 163.2 (C), 169.3 (C); for (Z)ꢀisomer δ = 57.8
(CH3), 128.0 (CH), 128.1 (CH), 129.2 (CH), 131.8 (CH), 133.4 (CH). HRMS (ESIꢀTOF) (m/z):
+
[M+H]+ Calcd. for C18H15BrNO2 356.0281; Found 356.0273.
(E)-3-(4-Bromophenyl)-5-methoxy-4-(4-nitrostyryl)isoxazole (8e). Compound 8e was prepared from
(4ꢀnitrobenzyl)triphenylphosphonium bromide 11a (478 mg, 1.00 mmol), potassium tert-butoxide
(113 mg, 1.00 mmol) and 3ꢀ(4ꢀbromophenyl)ꢀ5ꢀmethoxyisoxazoleꢀ4ꢀcarbaldehyde 10b (169 mg,
0.60 mmol) in THF (12 mL) for 1 h according to the general procedure B. The product was purified
by column chromatography (light petroleum/ethyl acetate, 5:1ꢀ2:1). An orange solid, mp 160ꢀ161 °C
(light petroleum/ethyl acetate), yield 111 mg (46%). 1H NMR (DMSOꢀd6): δ = 4.31 (s, 3H), 6.95 (d,
J = 16.4 Hz, 1H), 7.03 (d, J = 16.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.79
(d, J = 8.4 Hz, 2H), 8.15 (d, J = 8.8 Hz, 2H). 13C NMR (DMSOꢀd6): δ = 59.0 (CH3), 90.6 (C), 119.7
(CH), 123.9 (CH), 126.4 (CH), 126.8 (CH), 127.7 (C), 128.0 (C), 130.4 (CH), 132.2 (CH), 143.9
(C), 145.9 (C), 162.5 (C), 169.7 (C). HRMS (ESIꢀTOF) (m/z): [M+Na]+ Calcd. for
+
C18H13BrN2NaO4 422.9951; Found 422.9968.
(E/Z)-5-Methoxy-3-(4-methoxyphenyl)-4-styrylisoxazole (8f). Compound 8f was prepared from
benzyltriphenylphosphonium bromide 11d (315 mg, 0.73 mmol), potassium tert-butoxide (82 mg,
0.73 mmol) and 5ꢀmethoxyꢀ3ꢀ(4ꢀmethoxyphenyl)isoxazoleꢀ4ꢀcarbaldehyde 10c (106 mg, 0.45
mmol) in THF (9 mL) for 1.5 h according to the general procedure B. The product was purified by
column chromatography (light petroleum/ethyl acetate, 8:1ꢀ5:1). A colorless solid, mp 81ꢀ83 °C
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(hexane), yield 95 mg (68%), (E/Z)ꢀmixture (~1:0.13). 1H NMR (CDCl3): for (E)ꢀisomer δ = 3.88 (s,
3H), 4.27 (s, 3H), 6.68 (d, J = 16.5 Hz, 1H), 6.98 (d, J = 16.5 Hz, 1H), 7.02 (d, J = 8.7 Hz, 2H),
7.18ꢀ7.24 (m, 1H), 7.29ꢀ7.33 (m, 2H), 7.37ꢀ7.39 (m, 2H), 7.58 (d, J = 8.7 Hz, 2H); for (Z)ꢀisomer δ
= 3.83 (s, 3H), 3.84 (s, 3H), 6.13 (d, J = 11.6 Hz, 1H), 6.65 (d, J = 11.6 Hz, 1H), 6.94 (d, J = 8.5 Hz,
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2H), 7.18ꢀ7.24 (m, 3H), 7.29ꢀ7.33 (m, 2H), 7.69 (d, J = 8.5 Hz, 2H). C NMR (CDCl3): for (E)ꢀ
isomer δ = 55.4 (CH3), 58.0 (CH3), 91.4 (C), 114.3 (CH), 115.3 (CH), 121.8 (C), 125.9 (CH), 127.2
(CH), 128.6 (CH), 129.0 (CH), 129.9 (CH), 137.8 (C), 160.9 (C), 163.9 (C), 169.0 (C); for (Z)ꢀ
isomer 57.6 (CH3), 114.0 (CH), 116.2 (CH), 127.2 (CH), 128.0 (CH), 128.1 (CH), 129.1 (CH),
132.8 (CH). HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd. for C19H18NO3 308.1281; Found 308.1274.
+
(E)-5-Methoxy-4-styryl-3-(thiophen-2-yl)isoxazole (8g). Compound 8g was prepared from
benzyltriphenylphosphonium bromide 11d (303 mg, 0.70 mmol), potassium tert-butoxide (79 mg,
0.70 mmol) and 5ꢀmethoxyꢀ3ꢀ(thiophenꢀ2ꢀyl)isoxazoleꢀ4ꢀcarbaldehyde 10d (88 mg, 0.42 mmol) in
THF (11 mL) for 1 h according to the general procedure B. The product was purified by column
chromatography (light petroleum/ethyl acetate, 8:1). A colorless solid, mp 95ꢀ96 °C (light
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petroleum/ethyl acetate), yield 76 mg (64%). H NMR (CDCl3): δ = 4.27 (s, 3H), 6.85 (d, J = 16.4
Hz, 1H), 7.03 (d, J = 16.4 Hz, 1H), 7.18ꢀ7.20 (m, 1H), 7.22ꢀ7.26 (m, 1H), 7.32ꢀ7.36 (m, 2H), 7.42ꢀ
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7.44 (m, 2H), 7.49ꢀ7.50 (m, 2H). C NMR (CDCl3): δ = 58.1 (CH3), 91.5 (C), 114.7 (CH), 126.0
(CH), 127.4 (CH), 127.7 (CH), 127.8 (CH), 128.2 (CH), 128.6 (CH), 129.9 (CH), 130.1 (C), 137.6
(C), 158.5 (C), 169.3 (C). HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd. for C16H14NO2S+ 284.0740;
Found 284.0734.
(E)-5-Methoxy-4-(4-nitrostyryl)-3-(thiophen-2-yl)isoxazole (8h). Compound 8h was prepared from
(4ꢀnitrobenzyl)triphenylphosphonium bromide 11a (383 mg, 0.80 mmol), potassium tertꢀbutoxide
(90 mg, 0.80 mmol) and 5ꢀmethoxyꢀ3ꢀ(thiophenꢀ2ꢀyl)isoxazoleꢀ4ꢀcarbaldehyde 10d (97 mg, 0.46
mmol) in THF (13 mL) for 3 h according to the general procedure B. The product was purified by
column chromatography (light petroleum/ethyl acetate, 5:1 + 1% of CH2Cl2). An orange solid, mp
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170ꢀ172 °C (light petroleum/ethyl acetate), yield 85 mg (56%). H NMR (DMSOꢀd6): δ = 4.31 (s,
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3H), 7.10 (d, J = 16.4 Hz, 1H), 7.18 (d, J = 16.4 Hz, 1H), 7.30 (dd, J = 4.8, 3.9 Hz, 1H), 7.70ꢀ7.71
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(m, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.83ꢀ7.85 (m, 1H), 8.19 (d, J = 8.8 Hz, 2H). C NMR (DMSOꢀ
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d6): δ = 59.0 (CH3), 90.4 (C), 119.6 (CH), 124.0 (CH), 126.8 (CH), 126.8 (CH), 128.5 (CH), 128.6
(C), 129.0 (CH), 129.3 (CH), 143.9 (C), 146.0 (C), 157.7 (C), 169.8 (C). HRMS (ESIꢀTOF) (m/z):
[M+Na]+ Calcd. for C16H12N2NaO4S+ 351.0410; Found 351.0415.
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(E/Z)-N,N-Diethyl-3-phenyl-4-styrylisoxazole-5-amine (8i). Compound 8i was prepared from
benzyltriphenylphosphonium bromide 11d (766 mg, 1.77 mmol), potassium tert-butoxide (199 mg,
1.77 mmol), 5ꢀ(diethylamino)ꢀ3ꢀphenylisoxazoleꢀ4ꢀcarbaldehyde 10e (288 mg, 1.18 mmol) in THF
(11 mL) and additional ylide from benzyltriphenylphosphonium bromide 11d (156 mg, 0.36 mmol)
and potassium tert-butoxide (41 mg, 0.36 mmol) in 5mL of THF for 2.5 h according to the general
procedure B. The product was purified by column chromatography (light petroleum/ethyl acetate,
8:1). A yellow solid, mp 80ꢀ82 °C (pentane), yield 302 mg (82%), (E/Z)ꢀmixture (~1:0.16). 1H NMR
(CDCl3): for (E)ꢀisomer δ = 1.29 (td, J = 7.0, 0.7 Hz, 6H), 3.52 (qd, J = 7.0, 0.7 Hz, 4H), 6.36 (dd, J
= 16.3, 1.5 Hz, 1H), 6.84 (dd, J = 16.3, 1.5 Hz, 1H), 7.21ꢀ7.24 (m, 1H), 7.29ꢀ7.34 (m, 4H), 7.44ꢀ
7.47 (m, 3H), 7.63ꢀ7.66 (m, 2H); for (Z)ꢀisomer δ = 1.10 (td, J = 7.1, 0.9 Hz, 6H), 3.37 (qd, J = 7.1,
0.9 Hz, 4H), 6.38 (dd, J = 11.6, 1.3 Hz, 1H), 6.59 (dd, J = 11.6, 1.3 Hz, 1H), 7.15ꢀ7.24 (m, 3H),
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7.29ꢀ7.34 (m, 2H), 7.44ꢀ7.47 (m, 3H), 7.59ꢀ7.62 (m, 2H). C NMR (CDCl3): for (E)ꢀisomer δ =
13.7 (CH3), 43.9 (CH2), 92.0 (C), 117.1 (CH), 125.7 (CH), 127.1 (CH), 128.1 (CH), 128.4 (CH),
128.8 (CH), 129.1 (C), 130.4 (C), 130.7 (CH), 137.1 (C), 163.4 (C), 166.8 (C); for (Z)ꢀisomer δ =
13.8 (CH3), 43.0 (CH2), 88.0 (C), 119.0 (CH), 125.7 (CH), 127.2 (CH), 128.0 (CH), 128.5 (CH),
128.9 (CH), 129.2 (CH), 130.4 (CH), 131.2 (C), 133.4 (CH), 163.3 (C), 165.1 (C). HRMS (ESIꢀ
TOF) (m/z): [M+H]+ Calcd. for C21H23N2O+ 319.1805; Found 319.1807.
(E)-4-(3-Chlorostyryl)-3-phenyl-5-(pyrrolidin-1-yl)isoxazole (8j). Compound 8j was prepared from
(3ꢀchlorobenzyl)triphenylphosphonium chloride 11b (511 mg, 1.20 mmol), potassium tert-butoxide
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(135 mg, 1.20 mmol), 3ꢀphenylꢀ5ꢀ(pyrrolidinꢀ1ꢀyl)isoxazoleꢀ4ꢀcarbaldehyde 10f (194 mg, 0.80
mmol) in THF (7 mL) and additional ylide from (3ꢀchlorobenzyl)triphenylphosphonium bromide
11b (191 mg, 0.45 mmol) and potassium tert-butoxide (51 mg, 0.45 mmol) in THF (8 mL) for 6 h
according to the general procedure B. The product was purified by column chromatography (light
petroleum/ethyl acetate, 4:1). A colorless solid, mp 133ꢀ134 °C (light petroleum/ethyl acetate), yield
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198 mg (71%). H NMR (CDCl3): δ = 2.00ꢀ2.03 (m, 4H), 3.63ꢀ3.66 (m, 4H), 6.10 (d, J = 16.2 Hz,
1H), 6.92 (d, J = 16.2 Hz, 1H), 7.06ꢀ7.08 (m, 1H), 7.12ꢀ7.14 (m, 1H), 7.17ꢀ7.18 (m, 1H), 7.21ꢀ7.22
(m, 1H), 7.43ꢀ7.46 (m, 3H), 7.57ꢀ7.61 (m, 2H). 13C NMR (CDCl3): δ = 25.5 (CH2), 48.8 (CH2), 90.5
(C), 118.5 (CH), 123.8 (CH), 125.3 (CH), 126.6 (CH), 127.3 (CH), 128.5 (CH), 128.7 (CH), 129.3
(CH), 129.7 (CH), 130.5 (C), 134.5(C), 139.9 (C), 163.2 (C), 165.7 (C). HRMS (ESIꢀTOF) (m/z):
[M+H]+ Calcd. for C21H20ClN2O+ 351.1259; Found 351.1255.
(E/Z)-3-(4-Nitrophenyl)-5-(pyrrolidin-1-yl)-4-styrylisoxazole (8m). Compound 8a was prepared
from benzyltriphenylphosphonium bromide 11d (520 mg, 1.20 mmol), potassium tert-butoxide (135
mg, 1.20 mmol) and 3ꢀ(4ꢀnitrophenyl)ꢀ5ꢀ(pyrrolidinꢀ1ꢀyl)isoxazoleꢀ4ꢀcarbaldehyde 10h (230 mg,
0.80 mmol) in THF (14 mL) for 2 h according to the general procedure B. The product was purified
by column chromatography (light petroleum/ethyl acetate, 5:1ꢀ4:1). A red solid, mp 144ꢀ145 °C
(light petroleum/ethyl acetate), yield 274 mg (70%), (E/Z)ꢀmixture (~1:0.05). 1H NMR (CDCl3): for
(E)ꢀisomer δ = 2.00ꢀ2.03 (m, 4H), 3.64ꢀ3.67 (m, 4H), 6.20 (d, J = 16.2 Hz, 1H), 6.90 (d, J = 16.2
Hz, 1H), 7.20ꢀ7.32 (m, 5H), 7.82ꢀ7.85 (m, 2H), 8.26ꢀ8.29 (m, 2H); for (Z)ꢀisomer 1.84ꢀ1.88 (m,
4H), 3.51ꢀ3.54 (m, 4H), 6.41 (d, J = 11.6 Hz, 1H), 6.55 (d, J = 11.6 Hz, 1H), 7.20ꢀ7.32 (m, 5H),
7.68 (d, J = 8.9 Hz, 2H), 8.10 (d, J = 8.9 Hz, 2H). 13C NMR (CDCl3): for (E)ꢀisomer δ = 25.5 (CH2),
48.7 (CH2), 90.3 (C), 116.2 (CH), 123.7 (CH), 125.7 (CH), 127.3 (CH), 128.7 (CH), 129.6 (CH),
131.1 (CH), 137.2 (C), 137.3 (C), 148.2 (C), 161.1 (C), 165.9 (C). HRMS (ESIꢀTOF) (m/z): [M+H]+
+
Calcd. for C21H20N3O3 362.1499; Found 362.1497.
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(E/Z)-N,N-Dibenzyl-3-(4-nitrophenyl)-4-styrylisoxazole-5-amine (8n). Compound 8n was prepared
from benzyltriphenylphosphonium bromide 11d (433 mg, 1.00 mmol), potassium tert-butoxide (113
mg, 1.00 mmol) and 5ꢀ(dibenzylamino)ꢀ3ꢀ(4ꢀnitrophenyl)isoxazoleꢀ4ꢀcarbaldehyde 10i (180 mg,
0.44 mmol) in THF (11 mL) for 4 h according to the general procedure B. The product was purified
by column chromatography (light petroleum/ethyl acetate, 8:1). A yellow oil, yield 186 mg (88%),
(E/Z)ꢀmixture (~1:0.1). 1H NMR (CDCl3): for (E)ꢀisomer δ = 4.65 (s, 4H), 6.28 (d, J = 16.3 Hz, 1H),
6.66 (d, J = 16.3 Hz, 1H), 7.03ꢀ7.05 (m, 2H), 7.17ꢀ7.25 (m, 3H), 7.29ꢀ7.42 (m, 10H), 7.83ꢀ7.86 (m,
2H), 8.27ꢀ8.30 (m, 2H); for (Z)ꢀisomer 4.60 (s, 4H), 6.26 (d, J = 11.5 Hz, 1H), 6.54 (d, J = 11.5 Hz,
1H), 7.05ꢀ7.07 (m, 2H), 7.17ꢀ7.25 (m, 3H), 7.29ꢀ7.42 (m, 10H), 7.66ꢀ7.68 (m, 2H), 8.08ꢀ8.10 (m,
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2H). C NMR (CDCl3): for (E)ꢀisomer δ = 52.5 (CH2), 92.3 (C), 115.8 (CH), 123.7 (CH), 125.8
(CH), 127.6 (CH), 127.6 (CH), 127.8 (CH), 128.6 (CH), 128.9 (CH), 129.7 (CH), 132.9 (CH), 136.6
(C), 136.7 (C), 136.8 (C), 148.3 (C), 161.7 (C), 167.4 (C). HRMS (ESIꢀTOF) (m/z): [M+Na]+ Calcd.
+
for C31H25N3NaO3 510.1788; Found 510.1785.
(E/Z)-3-(tert-Butyl)-5-(pyrrolidin-1-yl)-4-styrylisoxazole (8o). Compound 8o was prepared from
benzyltriphenylphosphonium bromide 11d (476 mg, 1.10 mmol), potassium tert-butoxide (124 mg,
1.10 mmol), 3ꢀ(tertꢀbutyl)ꢀ5ꢀ(pyrrolidinꢀ1ꢀyl)isoxazoleꢀ4ꢀcarbaldehyde 10j (150 mg, 0.67 mmol) in
THF (10 mL) and additional ylide from benzyltriphenylphosphonium bromide 11d (200 mg, 0.46
mmol) and potassium tert-butoxide (53 mg, 0.47 mmol) in 7 mL of THF for 20 h according to the
general procedure B. The product was purified by column chromatography (light petroleum/ethyl
acetate, 8:1). A colorless solid, mp 112ꢀ113 °C (light petroleum/ethyl acetate), yield 100 mg (52%),
(E/Z)ꢀmixture (~1:0.1). 1H NMR (CDCl3): for (E)ꢀisomer δ = 1.37 (s, 9H), 1.87ꢀ1.93 (m, 4H), 3.40ꢀ
3.44 (m, 4H), 6.35 (d, J = 15.9 Hz, 1H), 6.88 (d, J = 15.9 Hz, 1H), 7.21ꢀ7.27 (m, 1H), 7.33ꢀ7.37 (m,
2H), 7.41ꢀ7.43 (m, 2H); for (Z)ꢀisomer 1.34 (s, 9H), 1.95ꢀ1.99 (m, 4H), 3.35ꢀ3.39 (m, 4H), 6.42 (d, J
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= 11.7 Hz, 1H), 6.53 (d, J = 11.7 Hz, 1H). C NMR (CDCl3): for (E)ꢀisomer δ = 25.5 (CH2), 28.8
(CH3), 33.3 (C), 48.6 (CH2), 86.8 (C), 118.5 (CH), 125.9 (CH), 127.2 (CH), 128.7 (CH), 132.3
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(CH), 137.6 (C), 165.8 (C), 170.8 (C). HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd. for C19H25N2O+
297.1961; Found 297.1957.
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(E/Z)-4-(2-(Naphthalen-1-yl)vinyl)-3-phenyl-5-(pyrrolidin-1-yl)isoxazole (8p). Compound 8p was
prepared from (naphthaleneꢀ1ꢀylmethyl)triphenylphosphonium bromide 11e (482 mg, 1.00 mmol),
potassium tert-butoxide (112 mg, 1.00 mmol), 3ꢀphenylꢀ5ꢀ(pyrrolidinꢀ1ꢀyl)isoxazolꢀ4ꢀcarbaldehyde
10f (170 mg, 0.70 mmol) in THF (10 mL) and additional ylide from (naphthaleneꢀ1ꢀ
ylmethyl)triphenylphosphonium bromide 11e (375 mg, 0.78 mmol) and potassium tert-butoxide (87
mg, 0.78 mmol) in THF (7 mL) for 17 h according to the general procedure B. The product was
purified by column chromatography (light petroleum/ethyl acetate, 8:1). A yellowish solid, mp 128ꢀ
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131 °C, yield 227 mg (88%), (E/Z)ꢀmixture (~1:0.21). H NMR (CDCl3): for (E)ꢀisomer δ = 2.00ꢀ
2.03 (m, 4H), 3.68ꢀ3.71 (m, 4H), 6.93 (d, J = 15.9 Hz, 1H), 7.00 (d, J = 15.9 Hz, 1H), 7.33ꢀ7.48 (m,
6H), 7.54ꢀ7.56 (m, 1H), 7.67ꢀ7.74 (m, 4H), 7.81ꢀ7.83 (m, 1H); for (Z)ꢀisomer δ = 1.67ꢀ1.70 (m, 4H),
3.41ꢀ3.49 (m, 4H), 6.69 (d, J = 11.6 Hz, 1H), 7.01ꢀ7.08 (m, 3H), 7.21ꢀ7.25 (m, 1H), 7.33ꢀ7.50 (m,
6H), 7.59ꢀ7.61 (m, 1H), 7.69ꢀ7.73 (m, 1H), 7.81ꢀ7.85 (m, 1H). 13C NMR (CDCl3): for (E)ꢀisomer δ
= 25.5 (CH2), 48.7 (CH2), 91.2 (C), 119.7 (CH), 122.3 (CH), 123.7 (CH), 125.6 (CH), 125.68 (CH),
125.73 (CH), 126.1 (CH), 127.2 (CH), 128.4 (CH), 128.6 (CH), 128.9 (CH), 129.1 (CH), 130.8 (C),
131.0 (C), 133.6 (C), 135.6 (C), 163.4 (C), 165.5 (C); for (Z)ꢀisomer δ = 25.1 (CH2), 47.8 (CH2),
88.5 (C), 120.1 (CH), 123.9 (CH), 125.1 (CH), 125.3 (CH), 125.4 (CH), 126.1 (CH), 127.3 (CH),
127.5 (CH), 127.8 (CH), 128.2 (CH), 128.3 (CH), 128.9 (CH), 130.0 (C), 131.3 (C), 133.4 (C),
133.9 (C), 163.5 (C), 165.1 (C). HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd. for C25H23N2O+
367.1805; Found 367.1808.
(E/Z)-4-(But-1-en-1-yl)-5-methoxy-3-phenylisoxazole (8t). Compound 8t was prepared from was
prepared by using the general procedure from triphenyl(propyl)phosphonium bromide 11g (1079
mg, 2.80 mmol), potassium tert-butoxide (314 mg, 2.80 mmol), 5ꢀmethoxyꢀ3ꢀphenylisoxazoleꢀ4ꢀ
carbaldehyde 10a (379 mg, 1.87 mmol) in THF (26 mL) and additional ylide from
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triphenyl(propyl)phosphonium bromide 11g (269 mg, 0.70 mmol) and potassium tert-butoxide (78
mg, 0.70 mmol) in THF (5 mL) for 5 h according to the general procedure B. The product was
purified by column chromatography (light petroleum/ethyl acetate, 8:1). A yellow oil, yield 342 mg
(80%), (E/Z)ꢀmixture (~0.26:1). 1H NMR (CDCl3): for (E)ꢀisomer δ = 1.08 (t, J = 7.5 Hz, 3H), 2.10ꢀ
2.18 (m, 2H), 4.20 (s, 3H), 5.94 (dt, J = 16.1, 1.4 Hz, 1H), 6.08 (dt, J = 16.1, 6.4 Hz, 1H), 7.45ꢀ7.47
(m, 3H), 7.59ꢀ7.61 (m, 2H); for (Z)ꢀisomer δ = 0.96 (t, J = 7.5 Hz, 3H), 2.03 (pd, J = 7.5, 1.5 Hz,
2H), 4.15 (s, 3H), 5.70 (dt, J = 10.9, 7.2 Hz, 1H), 5.85 (dt, J = 10.9, 1.5 Hz, 1H), 7.45ꢀ7.44 (m, 3H),
7.67ꢀ7.72 (m, 2H). 13C NMR (CDCl3): for (E)ꢀisomer δ = 13.7 (CH3), 26.5 (CH2), 57.8 (CH3), 114.8
(CH), 128.4 (CH), 128.6 (CH), 129.6 (C), 133.8 (CH); for (Z)ꢀisomer δ = 13.6 (CH3), 22.7(CH2),
57.9 (CH3), 89.7 (C), 114.3 (CH), 127.9 (CH), 128.5 (CH), 129.6 (CH), 130.0 (C), 137.7 (CH),
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163.9 (C), 168.3 (C). HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd. for C15H18NO3 260.1276; Found
260.1274.
General procedure C for the synthesis of (5-aminoisoxazole-4-yl)acrylates 8k,l. Compounds 8k,l
were synthesized by a slightly modified literature procedure.8b A solution of N,Nꢀdiisopropylamine
(DIPA) (2 mmol) in dry THF was cooled down to ꢀ78°C and solution of butyl lithium in hexane (2
mmol) was added under stirring. Methyl acetate (2 mmol) was added in 10 min and then a solution
of isoxazolꢀ4ꢀcarbaldehyde 10 (1 mmol) in dry THF was added in 10 min. The mixture was stirred
for 20 min and then quenched with saturated aq NH4Cl. The product was extracted with ethyl
acetate, washed with brine and dried over sodium sulfate. The solvents were evaporated, the residue
was dissolved in benzene and pꢀtoluenesulphonic acid (5 mg) was added to the solution. The
mixture was refluxed for 2 h with DeanꢀStark trap. The solvent was evaporated and the residue was
purified by column chromatography. The corresponding 5ꢀaminoꢀ4ꢀunsubstitutedꢀisoxazole was
eluted first, followed by the target product as pure (E)ꢀisomer.
(E)-Methyl 3-(3-phenyl-5-(pyrrolidin-1-yl)isoxazole-4-yl)acrylate (8k). Compound 8k as a colorless
solid, mp 188ꢀ189 °C (light petroleum/ethyl acetate), yield 199 mg (71%), and 3-phenyl-5-
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(pyrrolidin-1-yl)isoxazole (30a), as a colorless solid, mp 105ꢀ107 °C (light petroleum/ethyl acetate),
yield 47 mg (23%), were obtained from DIPA (202 mg, 2.00 mmol), nꢀBuLi (2.5 M, 1 mL, 2.00
mmol), methyl acetate (149 mg, 2.00 mmol) and 3ꢀphenylꢀ5ꢀ(pyrrolidinꢀ1ꢀyl)isoxazoleꢀ4ꢀ
carbaldehyde 10f (230 mg, 0.95 mmol) in THF (14 mL) according to the general procedure C. The
products were purified by column chromatography (light petroleum/ethyl acetate 4:1). 30a: 1H NMR
(CDCl3): 2.00ꢀ2.04 (m, 4H), 3.44ꢀ3.47 (m, 4H), 5.14 (s, 1H), 7.39ꢀ7.43 (m, 3H), 7.74ꢀ7.77 (m, 2H).
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The spectral data are in agreement with previously reported values.8e 8k: H NMR (CDCl3): 2.03ꢀ
2.07 (m, 4H), 3.65 (s, 2H), 3.70ꢀ3.73 (m, 4H), 5.37 (d, J = 15.7 Hz, 1H), 7.45ꢀ7.51 (m, 5H), 7.71 (d,
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J = 15.7 Hz, 1H). C NMR (CDCl3): 25.4 (CH2), 49.0 (CH2), 51.2 (CH3), 89.9 (C), 112.0 (CH),
128.69 (CH), 128.73 (CH), 129.6 (CH), 129.8 (C), 134.0 (CH), 163.5 (C), 166.5 (C), 168.3 (C).
+
HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd. for C17H19N2O3 299.1390; Found 299.1388.
(E)-Methyl 3-(3-(4-bromophenyl)-5-(pyrrolidin-1-yl)isoxazole-4-yl)acrylate (8l). Compound 8l as a
light yellow solid, mp 184ꢀ185 °C (light petroleum/ethyl acetate), yield 100 mg (44%), and 3-(4-
bromophenyl)-5-(pyrrolidin-1-yl)isoxazole (30b), as a colorless solid, mp 115ꢀ116 °C (light
petroleum/ethyl acetate), yield 74 mg (45%), were obtained from DIPA (122 mg, 1.20 mmol), nꢀ
BuLi (2.5 M, 0.5 mL, 1.25 mmol), methyl acetate (89 mg, 1.20 mmol) and 3ꢀ(4ꢀbromophenyl)ꢀ5ꢀ
(pyrrolidinꢀ1ꢀyl)isoxazoleꢀ4ꢀcarbaldehyde 10g (180 mg, 0.56 mmol) in THF (11 mL) according to
the general procedure C. The products were purified by column chromatography (light
petroleum/ethyl acetate 6:1ꢀ4:1). 30b: 1H NMR (CDCl3): δ = 2.00ꢀ2.04 (m, 4H), 3.43ꢀ3.47 (m, 4H),
5.10 (s, 1H), 7.53ꢀ7.56 (m, 2H), 7.61ꢀ7.64 (m, 2H). 13C NMR (CDCl3): 25.6 (CH2), 47.8 (CH2), 74.0
(CH), 123.6 (C), 128.1 (CH), 129.3 (CH), 131.8 (C), 162.6 (C), 169.3 (C). HRMS (ESIꢀTOF) (m/z):
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293.0284 Calcd. for C13H14BrN2O [M+H]+; Found 293.0272. 8l: H NMR (CDCl3): δ = 2.03ꢀ2.06
(m, 4H), 3.67 (s, 3H), 3.69ꢀ3.71 (m, 4H), 5.39 (d, J = 15.7 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.59
(d, J = 8.4 Hz, 2H), 7.69 (d, J = 15.7, 1H). 13C NMR (CDCl3): 25.4 (CH2), 49.0 (CH2), 51.3 (CH3),
89.7 (C), 112.5 (CH), 124.1 (C), 128.8 (C), 130.4 (CH), 132.0 (CH), 133.8 (CH), 162.5 (C), 166.6
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(C), 168.2 (C). HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd. for C17H18BrN2O3 377.0495; Found
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5
377.0483.
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4-(Cyclohex-1-en-1-yl)-5-methoxy-3-phenylisoxazole (8q). A suspension of morpholinium 4ꢀ
(cyclohexꢀ1ꢀenyl)ꢀ3ꢀphenylisoxazolꢀ5ꢀolate19 (129 mg, 0.393 mmol) in THF (15 mL) was cooled to
0 °C and the ether solution of diazomethane, obtained from NꢀnitrozoꢀNꢀmethylurea (412 mg, 4
mmol), was slowly added. The mixture was stirred at rt for 2 hours, quenched by AcOH and the
solvents were removed in vacuo. The residue was purified by column chromatography, using a
mixture of light petroleum ether and ethyl acetate (8:1) as eluent to give pure product as colorless
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oil, yield 55 mg (55%). H NMR (CDCl3): δ = 1.62ꢀ1.93 (m, 4H), 2.02ꢀ2.03 (m, 2H), 2.10ꢀ2.11 (m,
2H), 4.12 (s, 3H), 5.69ꢀ5.70 (m, 1H), 7.40ꢀ7.43 (m, 3H), 7.62ꢀ7.64 (m, 2H). 13C NMR (CDCl3): δ =
21.9 (CH2), 22.8 (CH2), 25.5 (CH2), 28.7 (CH2), 57.9 (CH3), 95.7 (C), 126.0 (C), 127.9 (CH), 128.4
(CH), 129.3 (CH), 129.4 (CH), 130.4 (C), 163.4 (C), 168.5 (C). HRMS (ESIꢀTOF) (m/z): [M+H]+
+
Calcd. for C16H18NO2 256.1332; Found 256.1335.
4-(5-Methoxy-3-phenylisoxazol-4-yl)-2H-chromen-2-one (8s). A solution of HN(SiMe3)2 (1.06 mL,
5.1 mmol) in dry THF (5mL) was cooled down to ꢀ78 °C under Ar. A solution of nꢀBuLi (2.5 M in
hexane, 2.05 mL, 5.1 mmol) was added and the mixture was stirred for 10 min. A solution of methyl
2ꢀ(2ꢀoxoꢀ2Hꢀchromenꢀ4ꢀyl)acetate (923 mg, 4.2 mmol) in THF (16 mL) was added to the reaction
mixture for 3 minutes and the mixture was stirred for 15 min, the solution of benzoyl chloride (682
mg, 4.9 mmol) in THF (5 mL) was then added in one portion, and the mixture was stirred for 15 min
at ꢀ78 °C and 2 days at rt. The reaction mixture was quenched by aq saturated NH4Cl, extracted with
EtOAc, the organic layer was washed with brine and dried over Na2SO4. The solvents were
evaporated to give light yellow solid (1.67 g). The mixture of this solid and NH2OH·HCl (1.34 g,
19.3 mmol) was refluxed in MeOH (15 mL) for 24 h. Water was added, precipitate formed was
filtered of, washed with water, ether and dried on air to give 4ꢀ(2ꢀoxoꢀ2Hꢀchromenꢀ4ꢀyl)ꢀ3ꢀ
phenylisoxazolꢀ5(4H)ꢀone 32 as colorless solid, mp 183ꢀ184 °C (dec., MeOH/H2O), yield 1027 mg
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(79% on 2 steps). H NMR (DMSOꢀd6): δ = 7.26ꢀ7.42 (m, 2H), 7.45ꢀ7.53 (m, 5H), 7.59ꢀ7.64 (m,
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1H), 7.76ꢀ7.78 (m, 1H), 8.17 (s, 1H). C NMR (DMSOꢀd6): δ = 89.9 (C), 116.0 (CH), 117.9 (C),
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119.1 (C), 124.7 (CH), 127.1 (CH), 128.1 (C), 128.4 (CH), 129.0 (CH), 130.9 (CH), 131.8 (CH),
142.9 (CH), 152.9 (C), 158.7 (C), 161.6 (C), 170.3 (C). HRMS (ESIꢀTOF) (m/z): [M+Na]+ Calcd.
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for C18H11NNaO4 328.0580; Found 328.0573. A suspension of 4ꢀ(2ꢀoxoꢀ2Hꢀchromenꢀ4ꢀyl)ꢀ3ꢀ
phenylisoxazolꢀ5(4H)ꢀone 32 (455 mg, 1.42 mmol) in THF (13 mL) was cooled to 0 °C and an ether
solution of diazomethane, obtained from NꢀnitrozoꢀNꢀmethylurea (440 mg, 4.27 mmol), was slowly
added. The mixture was stirred at rt for 1 h, quenched by AcOH and the solvents were removed in
vacuo. The residue was purified by column chromatography, using DCM as eluent to give pure
product. A colorless solid, mp 162ꢀ163 °C (DCM), yield 336 mg (74%). 1H NMR (CDCl3): δ = 4.19
(s, 3H), 7.24ꢀ7.28 (m, 1H), 7.32ꢀ7.43 (m, 5H), 7.49ꢀ7.55 (m, 3H), 7.59 (s, 1H). 13C NMR (CDCl3): δ
= 58.2 (CH3), 87.8 (C), 116.6 (CH), 117.9 (C), 119.0 (C), 124.5 (CH), 127.6 (CH), 127.8 (CH),
128.7 (CH), 129.5 (C), 129.7 (CH), 131.6 (CH), 142.9 (CH), 153.6 (C), 159.5 (C), 163.9 (C), 170.0
(C). HRMS (ESIꢀTOF) (m/z): [M+Na]+ Calcd. for C19H13NNaO4 342.0737; Found 342.0733.
+
General procedure D for the synthesis of pyrroles 9 from 4-vinylisoxazoles 8. A mixture of
isoxazole 8 (1 mmol) and FeCl2·4H2O (0.1 mmol) was stirred at 65°C in acetonitrile for 6 h, unless
otherwise specified. The solvents were evaporated and the residue was dissolved in CH2Cl2 or
CHCl3 and filtered through a pad of silica. The solvents were evaporated and solid compounds were
washed with pentane, dried on air to give pure products.
Methyl 5-(4-nitrophenyl)-2-phenyl-1H-pyrrole-3-carboxylate (9a). Compound 9a was obtained from
(E)ꢀ5ꢀmethoxyꢀ4ꢀ(4ꢀnitrostyryl)ꢀ3ꢀphenylisoxazole 8a (64 mg, 0.20 mmol) and FeCl2·4H2O (4 mg,
0.02 mmol) in MeCN (3 mL) according to the general procedure D. The product was purified by
filtration through a pad of silica (CH2Cl2/MeOH 1:0ꢀ20:1). An orange solid, mp 245ꢀ247 °C
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(CH2Cl2/MeOH), yield 62 mg (97%). H NMR (DMSOꢀd6): δ = 3.67 (s, 3H), 7.31 (d, J = 2.4 Hz,
1H), 7.43ꢀ7.49 (m, 3H), 7.64ꢀ7.66 (m, 2H), 8.07 (d, J = 8.8 Hz, 2H), 8.22 (d, J = 8.8 Hz, 2H), 12.19
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(s, 1H). C NMR (DMSOꢀd6): δ = 50.8 (CH3), 112.3 (CH), 113.2 (C), 124.2 (CH), 124.5 (CH),
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(C). HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd. for C18H15N2O4 323.1026; Found 323.1026.
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Methyl 5-(3-chlorophenyl)-2-phenyl-1H-pyrrole-3-carboxylate (9b). Compound 9b was obtained
from (E/Z)ꢀ4ꢀ(3ꢀchlorostyryl)ꢀ5ꢀmethoxyꢀ3ꢀphenylisoxazole 8b (99 mg, 0.32 mmol) and
FeCl2·4H2O (7 mg, 0.035 mmol) in MeCN (3 mL) according to the general procedure D. The
product was purified by filtration through a pad of silica (light petroleum/ethyl acetate 4:1). A light
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yellow solid, mp 58ꢀ60 °C (light petroleum/ethyl acetate), yield 88 mg (87%). H NMR (CDCl3): δ
= 3.77 (s, 3H), 7.02 (d, J = 3.0 Hz, 1H), 7.22ꢀ7.24 (m, 1H), 7.30ꢀ7.34 (m, 1H), 7.36ꢀ7.45 (m, 4H),
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7.49ꢀ7.50 (m, 1H), 7.62ꢀ7.64 (m, 2H), 8.65 (br.s., 1H). C NMR (CDCl3): δ = 51.1 (CH3), 110.1
(CH), 113.6 (C), 122.0 (CH), 124.0(CH), 127.0 (CH), 128.3 (CH), 128.6 (CH), 128.9 (CH), 130.29
(CH), 130.33 (C), 131.5 (C), 133.2 (C), 135.1 (C), 138.4 (C), 165.0 (C). HRMS (ESIꢀTOF) (m/z):
[M+H]+ Calcd. for C18H15ClNO2 312.0786; Found 312.0786.
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Dimethyl 5-phenyl-1H-pyrrole-2,4-dicarboxylate (9c). Compound 9c was obtained from (E)ꢀmethyl
3ꢀ(5ꢀmethoxyꢀ3ꢀphenylisoxazole)acrylate 8c (49 mg, 0.19 mmol) and FeCl2·4H2O (4 mg, 0.02
mmol) in MeCN (4 mL) for 18 h according to the general procedure D. The product was purified by
filtration through a pad of silica (ethyl acetate). A colorless solid, mp 150ꢀ152 °C (ethyl acetate),
yield 44 mg (90%). 1H NMR (CDCl3): δ = 3.76 (s, 3H), 3.82 (s, 3H), 7.39 (d, J = 2.8 Hz, 1H), 7.41ꢀ
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7.46 (m, 3H), 7.61ꢀ7.64 (m, 2H), 9.57 (br.s., 1H). C NMR (CDCl3): δ = 51.2 (CH3), 51.8 (CH3),
113.8 (C), 118.5 (CH), 122.0 (C), 128.2 (CH), 129.1 (CH), 129.2 (CH), 130.7 (C), 140.8 (C), 161.3
+
(C), 164.4 (C). HRMS (ESIꢀTOF) (m/z): [M+H]+ Calcd. for C14H14NO4 260.0917; Found 260.0910.
Methyl 2-(4-bromophenyl)-5-phenyl-1H-pyrrole-3-carboxylate (9d). Compound 9d was obtained
from (E/Z)ꢀ3ꢀ(4ꢀbromophenyl)ꢀ5ꢀmethoxyꢀ4ꢀstyrylisoxazole 8d (37 mg, 0.10 mmol) and
FeCl2·4H2O (2 mg, 0.01 mmol) in MeCN (3 mL) according to the general procedure D. The product
was purified by filtration through a pad of silica (light petroleum/ethyl acetate 3:1). A colorless
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