Transformation of 1,2,3,7a-tetrahydroimidazo[1,2-b]isoxazole derivatives into isoxazoles

Article abstract of DOI:10.1007/s11172-007-0185-y

The reactions of 1,2,3,7a-tetrahydroimidazo[1,2-b]isoxazole derivatives with electrophilic reagents, such as protic acids, benzoyl chloride, BF ₃, and bromine, produce isoxazole, 2,2,3,3-tetramethylaziridine, and 2,3,3-trimethylpropen-2-ylamine

Full text of DOI:10.1007/s11172-007-0185-y

Russian Chemical Bulletin, International Edition, Vol. 56, No. 6, pp. 1227—1233, June, 2007
1227
Transformation of 1,2,3,7aꢀtetrahydroꢀ
imidazo[1,2ꢀb]isoxazole derivatives into isoxazoles*
b
c
a,b
N. V. Chukanov,a S. A. Popov, G. V. Romanenko, and V. A. Reznikov
ꢀ
aNovosibirsk State University,
2 ul. Pirogova, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 0754. Eꢀmail: nikita@nioch.nsc.ru
bN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752. Eꢀmail: serge@nioch.nsc.ru
cInternational Tomography Center, Siberian Branch of the Russian Academy of Sciences,
3a ul. Institutskaya, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 333 1399. Eꢀmail: romanenko@tomo.nsc.ru
The reactions of 1,2,3,7aꢀtetrahydroimidazo[1,2ꢀb]isoxazole derivatives with electrophilic
reagents, such as protic acids, benzoyl chloride, BF3, and bromine, produce isoxazole,
2,2,3,3ꢀtetramethylaziridine, and 2,3,3ꢀtrimethylpropenꢀ2ꢀylamine derivatives.
Key words: isoxazole, 4ꢀisoxazoline, 1,2,3,7aꢀtetrahydroimidazo[1,2ꢀb]isoxazole, electroꢀ
phile, 1,3ꢀdipolar cycloaddition.
Scheme 1
The synthetic scope of the 1,3ꢀdipolar cycloaddition
reaction of nitrones with dipolarophiles is determined by
its high regioꢀ and stereoselectivity and the possibility
of subsequent transformations of the resulting cycloꢀ
adducts. 1,2,3,7aꢀTetrahydroimidazo[1,2ꢀb]isoxazole deꢀ
rivatives 1,1 which are produced by the cycloaddition of
nitrones of the 2ꢀimidazoline series with alkynes, contain
a heteroatomic substituent at position 3 of the isoxazoline
ring. As a result, untypical and previously unknown transꢀ
formations of these cycloadducts can be performed, inꢀ
cluding those with retention of the isoxazoline ring. In
the present study, we investigated the transformations of
cycloadducts 1 in the presence of electrophilic reagents.
The reactions of pꢀtoluenesulfonic acid with cycloꢀ
adducts 1 were demonstrated to be accompanied by the
imidazolidine ring opening to form isoxazoles 2 and a
mixture of amine 3 and aziridine 4 (Scheme 1). Structurꢀ
ally similar isoxazoles were detected in the reaction in
trifluoroacetic acid. The yields of compounds 2a—f in the
smallꢀbatch reactions were 47—90%.
1
R1 R2
R3
R4
Ph
1
R1
R2
R3
R4
a
b
c
d
H
H
Ph OMe
Ph OMe CO2Me
e
f
H
H
4ꢀMe2NC6H4 OMe CO2Me
Me
Me
Ph
Ph
Ph
Me Ph OMe CO2Me
Me OMe CO2Me
g
h
H
Me
4ꢀMeOC6H4 Me
H
Ph
R2
OMe
R3
The formation of isoxazoles 2 has been observed earꢀ
lier2 in the 1,3ꢀdipolar cycloaddition reaction of nitrone 5
with alkynes 6 in the presence of dimethylammonium
chloride. In the study,2 it was hypothesized that isoxazoles
2 are generated in the independent process competitive
with the 1,3ꢀdipolar cycloaddition (Scheme 2) rather than
in the acidꢀinitiated transformation of cycloadduct 7.
2
R2
R3
R4
2
R4
a
b
c
Ph
Ph
Me
OMe
OMe
OMe
Ph
CO2Me
CO2Me
d
e
f
4ꢀMe2NC6H4 OMe CO2Me
Me
Me
Me
Ph
Ph
4ꢀMeOC6H4
3, 4: R1 = H (a), Me (b)
We did not observe the formation of cycloadducts of
sterically hindered nitrone 8 and alkynes 9 at room temꢀ
perature (under the conditions typical of this process1).
* Dedicated to the memory of Academician N. N. Vorozhtsov
on the 100th anniversary of his birth.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1182—1187, June, 2007.
1066ꢀ5285/07/5606ꢀ1227 © 2007 Springer Science+Business Media, Inc.

1228
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Chukanov et al.
Scheme 2
O
N
O
O
R = CO2Me, CN
Fig. 1. Xꢀray threeꢀdimensional structure of methyl 3,5ꢀdiꢀ
phenylisoxazoleꢀ4ꢀcarboxylate (2a).
After heating or prolonged storage, isoxazoles 2g,h
(Scheme 3) were isolated from the reaction mixtures. This
reaction in the presence of excess triethylamine afforded
when synthesizing cycloadduct 1a. This can be accounted
for by the presence of acidic impurities in the reaction
mixture.
The structures of the reaction products were confirmed
by IR, 1H NMR, and 13C NMR spectroscopy. The strucꢀ
ture of isoxazole 2a was established by Xꢀray diffraction
(Fig. 1). The bond lengths in molecule 2a are typical of
the isoxazole ring.
1
the corresponding cycloadducts 1i,j (the H NMR specꢀ
troscopic data), which were transformed into isoxazoles
2g,h after alumina or silica gel chromatography. Apparꢀ
ently, this is attributed to the successive formation of the
cycloadduct and its acidꢀcatalyzed cleavage. In this case,
the starting imidazoline 8 can serve as the proton source
because it exists partially (45%) in the Nꢀhydroxyaminoꢀ
imine tautomeric form in a solution in CHCl3.3 It should
be noted that we isolated isoxazole 2a as a byꢀproduct
A mixture of Nꢀmethylꢀsubstituted derivatives 3b and
4b was isolated from the reaction mixture, and the strucꢀ
tures of the products were confirmed by 1H and 13C NMR
spectroscopy. Volatile amines 3a and 4a were identified as
trifluoroacetamides 10 and 11, respectively (Scheme 4).
The structures and compositions of the latter were estabꢀ
Scheme 3
1
lished by H and 19F NMR spectroscopy and mass specꢀ
trometry.
Scheme 4
1
According to the H NMR spectroscopic data for the
reaction mixtures, the ratio between aziridine 4 and
amine 3 remained unchanged with time. It should be
noted that this ratio does not correspond to the position
R3 = OMe, R4 = CO2Me (1i, 2g, 9a);
R
3 = Ph, R4 = COMe (1j, 2h, 9b)

Synthesis of isoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1229
of the thermodynamic equilibrium because it depends on
the structures of the starting cycloadducts 1, all other
factors being the same. The reaction of cycloadducts 1b,c
in trifluoroacetic acid affords isoxazole along with
amines 3 and, apparently, 12 (Scheme 5), whereas
aziridine 4 is not generated. These data provide evidence
that amines 3 and 4 are not transformed into each other
under the reaction conditions.
pound 1 at the N(1) atom, resulting in the C(7a)—N(1)
bond cleavage to form aromatic cation 13, which is rather
stable under the reaction conditions (Scheme 6). For exꢀ
ample, the 1H NMR spectrum of a solution of compound
1d and pꢀtoluenesulfonic acid in deuteromethanol shows
a signal for the protons of the methyl group at the C(7a)
atom (δ 1.76) along with a signal for the protons of the
methyl group at δ 2.62, which does not disappear within
several tens of hours and belongs, apparently, to intermeꢀ
diate 13. This lowꢀfield signal cannot be attributed to the
formation of the protonated form 1H+ (see Scheme 6);
otherwise, only one exchangeꢀnarrowed signal of two
forms would be observed.
Scheme 5
Then elimination of isoxazole 2 occurs (the chemical
shift of the methyl group at the C(3) atom at δ 2.46) to
give amines 3 and 4. This step can follow three pathways.
The first pathway produces tertiary carbocation 14, which
can undergo cyclization to form aziridine 4 (SN1) or proꢀ
duce amine 3 (E1). The second pathway involves the
concerted elimination E2 giving rise to amine 3. The third
pathway involves the intramolecular nucleophilic substiꢀ
tution SN2 with the amino group yielding exclusively
aziridine 4 (see Scheme 6).
The relatively high percentage of amine 3 in going
from a methanolic solution of pꢀtoluenesulfonic acid to
trifluoroacetic acid, which is a substantially less alkaline
medium, is evidence against the E2 mechanism (see the
determination of the percentage of amines 3 and 12 and
aziridines 4 in the aboveꢀmentioned mixtures from the
1H NMR spectroscopic data).
3, 12: R1 = H (a), Me (b)
Presumably, the first step of the reaction under conꢀ
sideration involves the protonation of the starting comꢀ
Scheme 6

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Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Chukanov et al.
Reaꢀ R1
gent
Percentage
CD3OD—TsOH
mixture of the latter with hexane as the eluent. The compounds
were isolated by silica gel (Silica gel 60, Merk) or alumina (anaꢀ
lytical grade, neutral, for chromatography) column chromatoꢀ
graphy. Chloroform (technical) was dried with CaCl2 and disꢀ
tilled; DMSO was dried with NaOH and distilled in vacuo
over BaO. Hexane, ethyl acetate, and diethyl ether (highꢀpurity
grade) were used without additional purification. In all cases,
solutions were concentrated using a vacuum aspirator pump.
1,2,3,7aꢀTetrahydroimidazo[1,2ꢀb]isoxazole derivatives
1a—d,f—h were synthesized according to a known procedure.1
Dimethyl 7aꢀ(4ꢀdimethylaminophenyl)ꢀ2,2,3,3ꢀtetramethylꢀ
1,2,3,7aꢀtetrahydroimidazo[1,2ꢀb]isoxazoleꢀ6,7ꢀdicarboxylate
(1e). 1) 2,3ꢀBis(hydroxyamino)ꢀ2,3ꢀdimethylbutane sulfate
(3.6 g, 13.6 mmol) and 4ꢀ(dimethylamino)benzaldehyde (2.0 g,
13.6 mmol) were dissolved in MeOH and refluxed under argon
until the starting aldehyde was completely consumed (TLC
monitoring). The reaction mixture was neutralized with a satuꢀ
rated NaHCO3 solution, MeOH was removed by evaporation,
and the precipitate was filtered off, washed with water, and
dried. The resulting 2ꢀ(4ꢀdimethylaminophenyl)ꢀ4,4,5,5ꢀtetraꢀ
methylimidazolidineꢀ1,3ꢀdiol was used without additional purifiꢀ
cation.
CF3COOH
1b
1c
H
Me
70 (3a)
17 (3b)
30 (4a)
83 (4b)
45 (3a)
32 (3b)
55 (12a)
68 (12b)
At the same time, the absence of aziridine 4 resistant
against acids in the reaction performed in trifluoroacetic
acid can be evidence against the intramolecular nucleoꢀ
philic substitution in cation 13 (SN2). The introduction of
the substituent R1 at the nitrogen atom should decrease
its nucleophilicity in the SN2 process, thus decreasing the
percentage of product 4. In the real situation, the introꢀ
duction of the methyl group, on the contrary, leads to an
increase in the percentage of aziridine 4 in the reaction
mixture by a factor of ~11, which is also evidence against
the SN2 mechanism. Therefore, the pathway involving
the formation of cation 14 seems to be most probable.
The reactions of cycloadducts
philes also lead to the imidazolidine ring cleavage giving
rise to isoxazoles . For example, the reaction of comꢀ
1 with other electroꢀ
2
2) A solution of 2ꢀ(4ꢀdimethylaminophenyl)ꢀ4,4,5,5ꢀtetraꢀ
methylimidazolidineꢀ1,3ꢀdiol (1.87 g, 6.7 mmol) in CHCl3
(30 mL) was stirred with a solution of NaIO4 (2 g) in water
(20 mL) for 20 min. The organic phase was separated, and the
aqueous phase was extracted with CHCl3 (2×20 mL). The comꢀ
bined solutions in CHCl3 were dried with MgSO4 and then
concentrated to ~20 mL. A solution of NaNO2 (0.5 g) in water
(15 mL) was added to the resulting solution. Then 5% HCl
(0.6 mL) was added dropwise with vigorous stirring. The organic
phase was separated, and the aqueous phase was extracted with
CHCl3 (20 mL). The combined solutions in CHCl3 were dried
with MgSO4 and concentrated. The reaction product, 2ꢀ(4ꢀdiꢀ
methylaminophenyl)ꢀ4,4,5,5ꢀtetramethylꢀ4,5ꢀdihydroꢀ1Hꢀimidꢀ
azole 1ꢀoxyl, was isolated by alumina chromatography using
CHCl3 as the eluent.
3) The product was reduced with hydrogen in MeOH in the
presence of Pd/C as the catalyst. The catalyst was filtered off
and the solution was concentrated. The residue, viz., 2ꢀ(4ꢀdiꢀ
methylaminophenyl)ꢀ4,4,5,5ꢀtetramethylꢀ4,5ꢀdihydroꢀ1Hꢀimidꢀ
azole 3ꢀoxide, crystallized out upon the addition of hexane. The
product was filtered off and washed on a filter with a 1 : 1
hexane—AcOEt mixture. The yield was 0.59 g (34%), m.p.
157.5—159 °C (hexane—AcOEt). 1H NMR (CDCl3), δ: 1.21
and 1.27 (both s, 6 H each, C(4)Me, C(5)Me); 2.92 (s, 6 H,
NMe2); 6.57 and 8.17 (both d, 2 H each, H arom., 3J = 8.1 Hz).
13C NMR (CDCl3), δ: 19.3, 24.2 (C(4)CH3, C(5)CH3); 39.8
(NMe2); 60.7 (C(4)); 73.2 (C(5)); 110.9 (C(3´)); 113.1 (C(1´));
128.5 (C(2´)); 144.2 (C(2)); 151.4 (C(4´)). Highꢀresolution mass
spectrum, found: m/z 261.1838 [M]+. C15H23N3O. Calculated:
M = 261.1841. IR (KBr), ν/cm–1: 2977, 1612, 1525, 1366, 1203.
4) A solution of dimethyl acetylenedicarboxylate (0.09 mL,
0.74 mmol) in CHCl3 cooled to 0 °C was added with stirring to a
suspension of 2ꢀ(4ꢀdimethylaminophenyl)ꢀ4,4,5,5ꢀtetramethylꢀ
4,5ꢀdihydroꢀ1Hꢀimidazole 3ꢀoxide (0.16 g, 0.62 mmol) in CHCl3
(10 mL). Within 20 min after dissolution of the precipitate, the
solvent was evaporated without heating, and hexane (10 mL)
was added to the residue. The precipitate of compound 1e was
filtered off and washed on a filter with a cold 5 : 1 hexane—AcOEt
mixture. The yield was 105 mg (42%), m.p. 174.5—176.5 °C
pound 1c with a small excess of boron trifluoride etherate
or benzoyl chloride in anhydrous DMSO at room temꢀ
perature produces isoxazole 2b (1H NMR spectroscopic
data). Under the same conditions, the reaction with benꢀ
zyl chloride or iodomethane does not proceed. The corꢀ
responding isoxazole 2a is generated also in the reaction
of cycloadduct 1h with bromine in chloroform at 0 °C.
To summarize, cycloadducts 1 are transformed into
isoxazoles 2 in high yield in the reactions with such
electrophiles as protic acids, PhCOCl, Br2, or BF3.
Amines 3 and 4 can be isolated along with isoxazoles from
the reaction mixtures obtained in the acidꢀcatalyzed reꢀ
actions. The reaction proceeds through the formation of
isoxazolinium cation 13, which undergoes cleavage to
give isoxazole 2 and cation 14.
Experimental
The 1H NMR spectra were recorded on Bruker AMꢀ400,
Bruker AVꢀ300, Bruker ACꢀ200, and Bruker WPꢀ200 spectromꢀ
eters using the signal of the solvent as the standard. The fully
JC,Hꢀdecoupled 13C NMR spectra were measured. The IR specꢀ
tra were recorded on a Vectorꢀ22 spectrometer (Bruker) in KBr
pellets. The UV spectra were measured on a Specord Mꢀ40
spectrometer in EtOH. The melting points were determined on
a Boetius hotꢀstage microscope. The highꢀresolution mass specꢀ
tra were obtained on a Finnigan MAT 8200 instrument at an
ionizing voltage of 70 eV. The elemental analysis was carried out
in the Laboratory of Microanalysis of the N. N. Vorozhtsov
Novosibirsk Institute of Organic Chemistry of the Siberian
Branch of the Russian Academy of Sciences. The GCꢀmass
spectra were recorded on a Hewlett Packard G1800A instruꢀ
ment consisting of an HP5890 Series II gas chromatograph and
an HP5971 massꢀselective detector. The course of the reactions
was monitored by TLC on Silufol UVꢀ254 plates and aluminum
oxide TLC cards (Fluka) using chloroform, ethyl acetate, or the

Synthesis of isoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1231
(hexane). Found (%): C, 62.35; H, 7.27; N, 10.35. C21H29N3O5.
Calculated (%): C, 62.51; H, 7.24; N, 10.41. 1H NMR (CDCl3),
δ: 0.92, 1.08, 1.21, and 1.33 (all s, 3 H each, C(2)Me, C(3)Me);
2.92 (s, 6 H, NMe2); 3.59 and 3.85 (both s, 3 H each, CO2Me);
6.65 and 7.49 (both d, 2 H each, H arom., 3J = 8.7 Hz).
UV (EtOH), λmax/nm (logε): 247 (3.99), 268 (4.09), 349 (3.40).
IR (KBr), ν/cm–1: 3350, 2981, 2951, 1740, 1719, 1648, 1611,
1521, 1434, 1341, 1308, 1211, 1074.
was added to the residue, and the solution was washed with an
aqueous NaHCO3 solution, dried with MgSO4, and concenꢀ
trated. The residue, viz., compound 2c, was recrystallized from
hexane. The yield was 0.010 g (47%). 1H NMR (CDCl3), δ: 2.45
(s, 3 H, C(3)Me); 3.88 and 3.98 (both s, 3 H each, CO2Me).
Highꢀresolution mass spectrum, found: m/z 199.04802 [M]+.
C8H9NO5. Calculated: M = 199.04807. IR (KBr), ν/cm–1: 2958,
1734, 1611, 1438, 1308, 1213, 1109.
Methyl 3,5ꢀdiphenylisoxazoleꢀ4ꢀcarboxylate (2a).4 A soluꢀ
tion of compound 1a (0.015 g, 0.04 mmol) and TsOH (0.008 g,
0.05 mmol) in MeOH (1.5 mL) was kept at ~20 °C for 2 days.
The solution was concentrated, the residue was made alkaline to
pH 9 with an aqueous Na2CO3 solution, the product was exꢀ
tracted with CHCl3 (3×10 mL), and the extract was dried with
MgSO4 and concentrated. Compound 2a was purified by silica
gel chromatography using CHCl3 as the eluent. The yield was
0.010 g (90%), m.p. 99—100 °C (hexane). 1H NMR (CDCl3), δ:
3.70 (s, 3 H, OMe); 7.45—7.53 (m, 6 H, H arom.); 7.62—7.67
and 7.88—7.93 (both m, 2 H each, H arom.). Highꢀresolution
mass spectrum, found: m/z 279.09019 [M]+. C17H13NO3. Calꢀ
culated: M = 279.08954. UV (EtOH), λmax/nm (logε): 238 (4.19),
264 (4.26). IR (KBr), ν/cm–1: 3061, 2957, 1727, 1613, 1593,
1572, 1448, 1408, 1326, 1237, 1121.
Dimethyl 3ꢀ(4ꢀdimethylaminophenyl)isoxazoleꢀ4,5ꢀdicarbꢀ
oxylate (2d). A solution of dimethyl acetylenedicarboxylate
(0.01 mL, 0.07 mmol) in CHCl3 (1 mL) was added to a solution
of 2ꢀ(4ꢀdimethylaminophenyl)ꢀ4,4,5,5ꢀtetramethylꢀ2ꢀimidꢀ
azoline 1ꢀoxide (16 mg, 0.06 mmol) in CHCl3 (2 mL). After
1 min, the reaction solution was concentrated, and the residue
was dissolved in CF3COOH (1 mL). After 5 h, the reaction
mixture was made alkaline to pH 8.5 with an aqueous NaHCO3
solution and extracted with CHCl3 (3×10 mL). The extract was
dried with MgSO4 and concentrated. Compound 2d was isolated
by silica gel chromatography using a 4 : 1 hexane—AcOEt mixꢀ
ture as the eluent. The yield was 10 mg (55%), oil. 1H NMR
(CDCl3), δ: 3.00 (s, 6 H, NMe2); 3.90 and 3.97 (both s, 3 H each,
CO2Me); 6.70 and 7.54 (both dt, 2 H each, H arom., 3J =
9.0 Hz, 4J = 1.5 Hz). 13C NMR (CDCl3), δ: 40.0 (NCH3); 53.0,
53.1 (CO2CH3); 111.7 (C(3´)); 113.7 (C(1´)); 115.8 (C(4));
128.8 (C(2´)); 151.7 (C(4´)); 156.5, 158.4 (C(3), C(5)); 160.9,
162.4 (CO2CH3). Highꢀresolution mass spectrum, found:
m/z 304.10720 [M]+. C15H16N2O5. Calculated: M = 304.10591.
IR (CCl4), ν/cm–1: 2956, 2927, 2854, 1744, 1615, 1457, 1444,
1431, 1313, 1279, 1223, 1203, 1137, 1072.
Reaction of compound 1h with bromine. A solution of broꢀ
mine (0.31 mL) in CHCl3 (0.064 mL of Br2 in 3 mL of CHCl3)
was added dropwise with stirring to a solution of compound 1h
(50 mg, 0.12 mmol) cooled to 0 °C. The reaction mixture was
kept at 0 °C for 30 min. Then the solution was concentrated and
the reaction mixture was analyzed by 1H NMR spectroscopy.
The transformation 1h → 2a was brought to completion.
Dimethyl 3ꢀphenylisoxazoleꢀ4,5ꢀdicarboxylate (2b).5 A. Caꢀ
talysis with pꢀtoluenesulfonic acid. A solution of compound 1c
(0.103 g, 0.29 mmol) and TsOH (0.060 g, 0.34 mmol) in MeOH
(2 mL) was kept at ~20 °C for 2 day. Then the reaction solution
was concentrated, and the residue was analyzed by 1H NMR
spectroscopy. The residue was made alkaline to pH 8 with an
aqueous NaHCO3 solution, the product was extracted with
CHCl3 (3×10 mL), and the extract was dried with MgSO4 and
concentrated. Compound 2b was purified by silica gel chromaꢀ
tography using a 4 : 1 hexane—AcOEt mixture as the eluent and
recrystallized from hexane at –10 °C. The yield was 0.056 g
(75%), m.p. 62—63 °C (hexane). 1H NMR (CDCl3), δ: 3.87 and
3.98 (both s, 3 H each, OMe); 7.43—7.47 (m, 3 H, H arom.);
7.64—7.69 (m, 2 H, H arom.). 13C NMR (CDCl3), δ: 52.9, 53.2
(CO2CH3); 115.8 (C(4)); 126.7 (C(1´)); 127.9, 128.7 (C(2´),
C(3´)); 130.5 (C(4´)); 156.3 (C(3)); 159.2 (C(5)); 161.1,
161.6 (CO2CH3). Highꢀresolution mass spectrum, found:
m/z 261.06474 [M]+. C13H11NO5. Calculated: M = 261.06371.
1ꢀ(3ꢀMethylꢀ5ꢀphenylisoxazolꢀ4ꢀyl)ethanone (2e).6 A soluꢀ
tion of compound 1f (120 mg, 0.4 mmol) and TsOH (200 mg,
1.2 mmol) in MeOH (10 mL) was kept at 50 °C for 15 h. Then
the reaction solution was concentrated, the residue was made
alkaline to pH 8 with an aqueous NaHCO3 solution, and the
solution was extracted with CHCl3 (3×10 mL). The combined
extracts were dried with MgSO4 and concentrated. Compound
2e was isolated by silica gel chromatography using a 4 : 1 hexꢀ
ane—AcOEt mixture as the eluent. The yield was 64 mg (80%),
1
colorless oil. H NMR (CDCl3), δ: 2.17 (s, 3 H, COMe); 2.43
(s, 3 H, C(3)Me); 7.48—7.55 (m, 5 H, H arom.). 13C NMR
(CDCl3), δ: 11.8 (C(3)CH3); 30.0 (COCH3); 117.0 (C(4)); 127.3
(C(1´)); 128.6, 128.9 (C(2´), C(3´)); 131.1 (C(4´)); 159.8
(C(3)); 172.2 (C(5)). Highꢀresolution mass spectrum, found:
m/z 201.07923 [M]+. C12H11NO2. Calculated: M = 201.07897.
UV (EtOH), λmax/nm (logε): 262 (3.66). IR (CCl4), ν/cm–1
:
2929, 1679, 1584, 1448, 1414, 1378, 1134, 696.
1ꢀ[3ꢀ(4ꢀMethoxyphenyl)ꢀ5ꢀphenylisoxazolꢀ4ꢀyl]ethanone
(2f). A solution of compound 1g (165 mg, 0.42 mmol) and
TsOH (220 mg, 1.3 mmol) in MeOH (10 mL) was kept at 50 °C
for 5 h. Then the reaction solution was concentrated, and the
residue was made alkaline to pH 8 with an aqueous NaHCO3
solution and extracted with CHCl3 (3×10 mL). The combined
extracts were dried with MgSO4 and concentrated. The residue
was recrystallized from hexane (20 mL). The yield was 95 mg
(77%), m.p. 105—106 °C (hexane). Found (%): C, 73.24;
H, 5.12; N, 4.77. C18H15NO3. Calculated (%): C, 73.71; H, 5.15;
N, 4.78. 1H NMR (CDCl3), δ: 2.19 (s, 3 H, COMe); 3.84 (s,
UV (EtOH), λmax/nm (logε): 227 (4.25). IR (KBr), ν/cm–1
:
3077, 2958, 1733, 1627, 1463, 1443, 1426, 1320, 1302, 1283,
1229, 1186, 1138, 1067.
B. Catalysis by PhCOCl or BF3. A 1.5ꢀfold molar excess of
boron trifluoride etherate or benzoyl chloride was added to a
solution of compound 1c in anhydrous DMSOꢀd6 (0.5 mL), and
the reaction mixture was kept for 1 day. According to the
1H NMR spectroscopic data, the reaction mixture contained
isoxazole 2b, whereas the starting compound 1c was absent.
Dimethyl 3ꢀmethylisoxazoleꢀ4,5ꢀdicarboxylate (2c).5 A soluꢀ
tion of compound 1d (0.032 g, 0.09 mmol) and a twofold molar
excess of TsOH in MeOH (1 mL) was kept at ~20 °C for 20 h.
Then the reaction solution was concentrated, CHCl3 (10 mL)
3
4
3 H, OMe); 7.00 (dt, 2 H, H arom., J = 8.8 Hz, J = 1.5 Hz);
7.49—7.51 (m, 3 H, H arom.); 7.56 (dt, 2 H, H arom., 3J =
8.8 Hz, J = 8.8 Hz); 7.81—7.83 (m, 2 H, H arom.). 13C NMR
4
(CDCl3), δ: 31.4 (COCH3); 55.2 (OCH3); 117.0 (C(4)); 114.2,

1232
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
Chukanov et al.
120.5, 126.9, 128.3, 128.7, 130.0, 131.2, 161.0 (C arom.); 161.6
(C(3)); 170.0 (C(5)); 195.5 (CO). UV (EtOH), λmax/nm (logε):
263 (4.08). IR (KBr), ν/cm–1: 2946, 1693, 1608, 1527, 1495,
1427, 1395, 1365, 1305, 1249, 1179, 1028, 838, 780.
using a reflux condenser to ~2 mL. For further evaporation, the
residue was sublimed at 70 °C (450 Torr). The ratio 3b : 4b =
1
33 : 67. H NMR (CDCl3), δ: 1.16 (s, 6 H, C(1)Me); 1.68 (dd,
3 H, C(2)Me, 4J = 1.5 Hz, 4J = 0.7 Hz); 2.15 (s, 3 H, NMe);
2
4
Dimethyl 3ꢀ(2,4ꢀdimethylphenyl)isoxazoleꢀ4,5ꢀdicarboxylate
(2g). A solution of 2ꢀ(2,4ꢀdimethylphenyl)ꢀ4,4,5,5ꢀtetramethylꢀ
2ꢀimidazoline 1ꢀoxide (8) (0.055 g, 0.19 mmol) and dimethyl
acetylenedicarboxylate (0.038 mL, 0.31 mmol) in CHCl3 (5 mL)
was kept at ~20 °C for 20 days. Then the reaction solution was
concentrated, and the product was isolated by alumina chromaꢀ
tography using CHCl3 as the eluent. The yield was 0.015 g
(24%), m.p. 67—68 °C (hexane). Found (%): C, 62.72; H, 5.49;
N, 4.90. C15H15NO5. Calculated (%): C, 62.28; H, 5.23; N, 4.84.
1H NMR (CDCl3), δ: 2.23 and 2.34 (both s, 3 H each, C(2´)Me,
C(4´)Me); 3.75 and 4.01 (both s, 3 H each, CO2Me); 7.03—7.10
(m, 2 H, H arom.); 7.15—7.19 (m, 1 H, H arom.). 13C NMR
(CDCl3), δ: 19.8, 21.2 (C(2´)CH3, C(4´)CH3); 52.6, 53.3
(CO2CH3); 116.4 (C(4)); 123.4, 126.4, 129.5, 131.2 (C(1´),
C(3´), C(5´), C(6´)); 137.0 (C(2´)); 140.1 (C(4´)); 156.7,
159.5, 160.9, 162.1 (C(3), C(5), CO2CH3). UV (EtOH),
4.79 (dq, 1 H, H(3), J = 1.5 Hz, J = 0.7 Hz); 4.86 (dq, 1 H,
H(3), 2J = 1.5 Hz, 4J = 1.5 Hz). 13C NMR (CDCl3), δ: 18.9
(C(1)CH3); 26.5 (C(2)CH3); 29.3 (NCH3); 58.2 (C(1)); 112.9
(C(3)); 148.3 (C(2)).
2,2,3,3ꢀTetramethylaziridine (4a).7 A solution of comꢀ
pound 1b (0.10 g, 0.29 mmol) and TsOH (0.06 g, 0.34 mmol) in
CD3OD (0.5 mL) was kept at ~20 °C for 24 h. Then the reaction
mixture was analyzed by 1H NMR spectroscopy. The ratio
3a : 4a = 70 : 30. 1H NMR (CD3OD), δ: 1.52 (s, 12 H, C(2)Me,
C(3)Me). 13C NMR (CD3OD), δ: 19.76 (C(2)CH3, C(3)CH3);
51.94 (C(2), C(3)).
1,2,2,3,3ꢀPentamethylaziridine (4b)8 was synthesized accordꢀ
ing to the general procedure from compound 1c (0.237 g,
0.73 mmol). The ether was distilled off from the extract to the
volume of ~2 mL using a reflux condenser. For further evaporaꢀ
tion, the residue was sublimed at 70 °C (450 Torr). The ratio
1
λ
max/nm (logε): 227 (4.15). IR (KBr), ν/cm–1: 3001, 2951, 1753,
3b : 4b = 33 : 67. H NMR (CDCl3), δ: 1.12 and 1.04 (both s,
1732, 1635, 1615, 1462, 1439, 1391, 1314, 1277, 1221, 1192,
1156, 1120, 1067, 988, 949, 905.
6 H each, C(2)Me, C(3)Me); 2.19 (s, 3 H, NMe). 13C NMR
(CDCl3), δ: 14.2 (C(2)CH3); 23.4 (C(3)CH3); 31.4 (NCH3);
40.9 (C(2), C(3)).
1ꢀ[3ꢀ(2,4ꢀDimethylphenyl)ꢀ5ꢀphenylisoxazolꢀ4ꢀyl]ethanone
(2h). A solution of 2ꢀ(2,4ꢀdimethylphenyl)ꢀ4,4,5,5ꢀtetramethylꢀ
2ꢀimidazoline 1ꢀoxide (8) (0.139 g, 0.56 mmol) and 4ꢀphenylbutꢀ
3ꢀynꢀ2ꢀone (0.196 mL, 1.35 mmol) in CHCl3 (3 mL) was reꢀ
fluxed for 6 h. Then the reaction solution was concentrated, and
the product was isolated by alumina chromatography using
CHCl3 as the eluent. The yield was 0.044 g (27%), m.p.
82.5—83.5 °C (hexane). Found (%): C, 78.48; H, 6.02; N, 4.92.
Nꢀ(1,1,2ꢀTrimethylpropꢀ2ꢀenyl)ꢀ2,2,2ꢀtrifluoroacetamide
(10) and 2,2,3,3ꢀtetramethylꢀ1ꢀ(trifluoroacetyl)aziridine (11)
were synthesized from a mixture of amines 3a and 4a, which was
prepared according to the general procedure from compound 1b
(0.26 g, 0.72 mmol). Trifluoroacetic anhydride (0.20 mL,
1.44 mmol) was added to the resulting ethereal solution, and the
reaction mixture was kept at ~20 °C for 40 min. Then the ether
was distilled off to the volume of ~0.5 mL using reflux conꢀ
denser. The residue was dissolved in CH2Cl2 (4 mL) and washed
with an aqueous sodium carbonate solution to steady weakly
alkaline pH of the washing liquor. The solution was dried with
MgSO4, the solvent was evaporated by distillation to the volume
of ~0.5 mL using a reflux condenser. According to the 1H NMR
spectroscopic data, the resulting mixture contained 88.5% of
compound 10 and 11.5% of compound 11. Compound 10.
1H NMR (CDCl3), δ: 1.48 (s, 6 H, C(1)Me); 1.72 (dd, 3 H,
C(2)Me, 4J = 1.4 Hz, 4J = 0.7 Hz); 4.88 and 4.90 (both m,
1 H each, H(3)); 6.37 (br.s, 1 H, NH). 19F NMR (CDCl3), δ:
85.8 (CF3). Compound 11a. 1H NMR (CDCl3), δ: 1.11 and
1.38 (both s, 6 H each, C(2)Me, C(3)Me). 19F NMR (CDCl3),
δ: 85.5 (CF3). Highꢀresolution mass spectrum, found:
m/z 195.08737 [M]+. C8H12F3NO. Calculated: M = 195.08709.
Xꢀray diffraction study. Single crystals of compound 2a suitꢀ
able for Xꢀray diffraction were grown by recrystallization from
hexane. Xꢀray diffraction data were collected on a Smart Apex
diffractometer (graphite monochromator, MoꢀKα radiation).
Crystals are triclinic: a = 8.205(4) Å, b = 9.153(4) Å, c =
9.786(4) Å, α = 82.882(8)°,–β = 78.285(8)°, γ = 70.745(7)°, V =
678.0(5) Å3, space group P1, C17H13NO3, Z = 2, Mr = 279.09,
dcalc = 1.368 g cm–3, µ = 0.095 mm–1. The intensities of 2799 reꢀ
flections (1912 independent reflections, Rint = 0.0290) were meaꢀ
sured in the range of 2.96° < θ < 23.31° (–9 ≤ h ≤ 9, –8 ≤ k ≤ 10,
–7 ≤ l ≤ 10), R1 = 0.0663, wR2 = 0.1746 (I > 2σ(I )), R1 = 0.0782,
wR2 = 0.1839 (based on all data), GOOF 1.036, the residual
electron density (ρmax/ρmin) 0.286/–0.268 e Å–3. The structure
of compound 2a was solved by direct methods. All nonhydrogen
atoms were refined by the fullꢀmatrix leastꢀsquares method with
C
19H17NO2. Calculated (%): C, 78.33; H, 5.88; N, 4.81.
1H NMR (CDCl3), δ: 2.00 (s, 3 H, COMe); 2.26 and 2.38
(both s, 3 H each, C(2´)Me, C(4´)Me); 7.09—7.14 (m, 2 H,
H arom.); 7.22 (m, 1 H, H arom.); 7.49—7.52 (m, 3 H, H arom.);
7.91—7.94 (m, 2 H, H arom.). 13C NMR (CDCl3), δ: 19.7, 21.2
(C(2´)CH3, C(4´)CH3); 30.6 (COCH3); 117.6 (C(4)); 125.3,
126.7, 126.8, 128.5, 128.7, 129.5, 131.3, 131.3, 136.7, 139.9
(C arom.); 162.3 (C(3)); 170.9 (C(5)); 193.8 (CO). UV (EtOH),
λ
max/nm (logε): 269 (4.22). IR (KBr), ν/cm–1: 2988, 2952, 1681,
1614, 1585, 1561, 1490, 1411, 1385, 1094, 939, 825.
Isolation of amines formed under acid catalysis (general proꢀ
cedure). A solution of compound 1b or 1h and a 1.5—2ꢀfold
molar excess of TsOH in MeOH (2—5 mL) was kept at ~20 °C
for 24 h and then concentrated. Acetic acid was added to the
residue to bring the solution to pH 1—2. The solution was washed
three times with diethyl ether, made alkaline to pH 8—9 with a
sodium carbonate solution, and extracted with diethyl ether.
The extract was dried with MgSO4.
1,1,2ꢀTrimethylpropꢀ2ꢀenylamine (3a). A solution of comꢀ
pound 1b (0.10 g, 0.29 mmol) and TsOH (0.06 g, 0.34 mmol) in
CD3OD (0.5 mL) was kept at ~20 °C for 24 h. The reaction
mixture was analyzed by 1H NMR spectroscopy. The ratio
3a : 4a = 70 : 30. 1H NMR (CD3OD), δ: 1.48 (s, 6 H, C(1)Me);
1.86 (dd, 3 H, C(2)Me, 4J = 1.5 Hz, 4J = 0.7 Hz); 5.01 and
5.03 (both m, 1 H each, H(3)). 13C NMR (CD3OD), δ:
19.9 (C(1)CH3); 26.7 (C(2)CH3); 56.4 (C(1)); 111.2 (C(3));
149.2 (C(2)).
(1,1,2ꢀTrimethylpropꢀ2ꢀenyl)methylamine (3b) was syntheꢀ
sized according to the general procedure from compound 1c
(0.237 g, 0.73 mmol). The ether was distilled off from the extract

Synthesis of isoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 6, June, 2007
1233
anisotropic displacement parameters (H atoms were located in
difference electron density maps and refined isotropically). All
calculations were carried out using the Bruker SHELXTL softꢀ
ware (Version 6.14). The atomic coordinates, equivalent disꢀ
placement parameters, and geometric characteristics for the
structure of compound 2a were deposited at the Cambridge
Crystallographic Data Centre (CCDC 633036).
3. S. A. Popov, R. V. Andreev, G. V. Romanenko, V. I.
Ovcharenko, and V. A. Reznikov, J. Mol. Struct., 2004,
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Stevenson, J. Org. Chem., 1990, 55, 4011.
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Received February 19, 2007;
in revised form April 5, 2007
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