Mechanism of the migration of the substituent in 1,2,3,7a- tetrahydroimidazo[1,2-b]isoxazole derivatives

Article abstract of DOI:10.1007/s11172-010-0318-6

The thermolysis of 1,2,3,7a-tetrahydroimidazo[1,2-b]isoxazole derivatives results in intramolecular rearrangements by two main pathways. One rearrangement affords azomethine ylide derivatives. Another rearrangement leads to the migration of the substituen

Full text of DOI:10.1007/s11172-010-0318-6

Russian Chemical Bulletin, International Edition, Vol. 59, No. 9, pp. 1817—1826, September, 2010
1817
Mechanism of the migration of the substituent in
1,2,3,7aꢀtetrahydroimidazo[1,2ꢀb]isoxazole derivatives
N. V. Chukanov,a,b S. A. Popov,b T. N. Drebushchak,a,c and V. A. Reznikova,b
aNovosibirsk State University,
2 ul. Pirogova, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 2237. Eꢀmail: decan@fen.nsu.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: nikita@nioch.nsc.ru
cInstitute of Solid State Chemistry and Mechanochemistry, Siberian Branch of the Russian Academy of Sciences,
18 ul. Kutateladze, 630128 Novosibirsk, Russian Federation.
Fax: +7 (383) 332 1550. Eꢀmail: tanya@xray.nsu.ru
The thermolysis of 1,2,3,7aꢀtetrahydroimidazo[1,2ꢀb]isoxazole derivatives results in intraꢀ
molecular rearrangements by two main pathways. One rearrangement affords azomethine ylide
derivatives. Another rearrangement leads to the migration of the substituent from position 7а to
the nitrogen atom. The rate constants of these reactions were determined. Quantum chemical
calculations by the DFT method were carried out. Based on the data for the migration of the
substituent, the concerted mechanism was proposed.
Key words: 2,3ꢀdihydroisoxazole, 1,2,3,7aꢀtetrahydroimidazo[1,2ꢀb]isoxazole, sigmatropic
rearrangement, azomethine ylide, rate constants, quantum chemical calculations, DFT method,
Xꢀray diffraction study.
Previously, we have shown1 that the thermolysis of
1,2,3,7aꢀtetrahydroimidazo[1,2ꢀb]isoxazole derivatives 1,
which were synthesized by the 1,3ꢀdipolar cycloaddiꢀ
tion of nitrones of the 2ꢀimidazoline series with alkynes
(Scheme 1), results in their rearrangement into ylides 3
(path a) and/or the migration of the substituent from poꢀ
sition 7a of compound 1 to the nitrogen atom N(4) to
form imidazolidines 4 (path b). Previously, the formation
of azomethine ylides has been observed for a wide range of
2,3ꢀdihydroisoxazole derivatives,2—7 or these compounds
were assumed to be intermediates in the formation of oxꢀ
azole and pyrrole derivatives and in other rearrangements
of 2,3ꢀdihydroisoxazoles. The hydrogen migration is the
wellꢀknown transformation of bicyclic 2,3ꢀdihydroisoxꢀ
azole derivatives.8—11 However, the migration of the subꢀ
stituent containing the sp3ꢀhybridized12,13 or sp2ꢀhybridꢀ
ized14,15 carbon atom was observed only for a few substanꢀ
tially structurally different compounds. Hence, it was imꢀ
possible to draw a conclusion about the mechanism of this
reaction. We revealed for the first time the general characꢀ
ter of this process in the study of 2,2,3,3ꢀtetramethylꢀ7aꢀ
Rꢀ1,2,3,7aꢀtetrahydroimidazo[1,2ꢀb]isoxazole derivatives
1 and synthesized a series of migration products of the
substituent R (the structure of one of these products, 4k,
was confirmed by Xꢀray diffraction, Fig. 1).1 The aim of
the present study was to reveal the kinetic features of the
reaction and elucidate the mechanism of the rearrangeꢀ
ment (see Scheme 1) following the path b with the use of
DFT calculations.
The rectification of the kinetic curves in the lnk—t
coordinates (k is the reaction rate constant, and t is the
reaction time) showed that the reactions a and b (see
Scheme 1) are first order with respect to the reagent. The
concentrations of the components were determined by 1H
C(23)
C(5)
C(24)
C(6)
C(22)
C(14)
C(21)
N(1)
N(2)
C(1)
O(1)
C(2)
C(15)
C(13)
C(4)
C(7)
C(8)
C(16)
C(3)
C(12)
C(19)
C(18)
O(2)
C(17)
C(9)
C(11)
C(10)
N(3)
C(25)
C(20)
Fig. 1. Molecular structure of compound 4k (thermal ellipsoids
are drawn at the 30% probability level). The hydrogen atoms are
not shown.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1769—1777, September, 2010.
1066ꢀ5285/10/5909ꢀ1817 © 2010 Springer Science+Business Media, Inc.

1818
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 9, September, 2010
Chukanov et al.
Scheme 1
1
a
b
c
d
e
f
R1
H
H
H
H
H
H
Me
R2
Me
X
Y
1
h
i
j
k
l
R1
Me
Me
H
H
H
R2
Ph
X
Y
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
COMe
CN
CO2Me
CO2Me
CO2Me
Ph
Ph
Ph
But
4ꢀMeOꢀC6H4
—CH=CH—Ph
4ꢀMe2NꢀC6H4
4ꢀMe2NꢀC6H4
4ꢀMe2NꢀC6H4
4ꢀNO2ꢀC6H4
Ph
4ꢀMeOꢀC6H4
4ꢀMe2NꢀC6H4
4ꢀNO2ꢀC6H4
m
H
g
1
NMR spectroscopy of the reaction mixtures based on the
integrated intensities of the signals of the reaction prodꢀ
ucts and the reagent. The rate constants ka and kb for the
parallel reactions were calculated by the equations (1) and
(2), respectively.
aziridine 2 in the H NMR spectra of the reaction mixꢀ
tures indicates that the formation of this compound is the
rateꢀlimiting step (assuming that the reaction actually ocꢀ
curs through this compound). It was shown that the poꢀ
larity of the solvent (Table 1) and the nature of the substitꢀ
uent R2 (Table 2, see Scheme 1) have an insignificant
effect on the rate of the reaction a.
The aboveꢀconsidered data do not contradict both the
concerted and biradical pathways of the formation of acylꢀ
aziridine. However, these data are inconsistent with the
reaction proceeding via the zwitterion; otherwise, the poꢀ
larity of the solvent would substantially influence the reꢀ
action rate.
(1)
where k = ka + kb = (1/t)ln[A/(A + B + C)].
(2)
Table 1. Dependence of the rate constant ka of the
reaction a for compound 1d on the nature of the
solvent at 105 °C
A, B, and C are the integrated intensities of compounds 1, 3, and
4 (5), respectively, and t is the reaction time.
The formation of azomethine ylides 3 is associated
with the rearrangement presented in Scheme 1 (path a),
which apparently occurs through the initial formation of
aziridine 2 followed by its cleavage. According to the pubꢀ
lished data, the concerted16 or nonꢀconcerted biradical17
pathways of the formation of the aziridine ring are the
most probable mechanisms. The absence of signals of acylꢀ
Solvent
ε*
ka•106/s–1
CCl4
2.28
2.38
20.7
49
3.0 0.4
9.3 0.9
5.6 0.5
7.6 0.6
Toluene
Acetone
DMSO
* ε is the dielectric permeability.

1,2,3,7aꢀTetrahydroimidazo[1,2ꢀb]isoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 9, September, 2010
1819
Table 2. Dependence of the rate constant ka of the
reaction a on the nature of the substituent R2 for comꢀ
pounds 1a—e in toluene
gration of the substituent in compounds 1d, 1e, and 1f
(reaction b, see Scheme 1).
The rate of this rearrangement substantially increases
with an increase in the polarity of the solvent, which is
indicative of the high polarity of the transition state of the
reaction.
R2
ka•105/s–1
105 °C
131 °C
The data on the influence of the substituents R1 and R2
on the reaction rate at different temperatures are presentꢀ
ed in Table 4. The Gibbs energies (ΔG#298), the enthalpies
(ΔH#298), and the entropies (ΔS#298) of activation were
calculated by the Eyring equation (lnk = ln(κT/h) –
– (ΔG#298/RT)).
Me
—
—
0.55 0.02
1.5 0.05
—
0.93 0.09
—
But
pꢀNO2—C6H4
Ph
pꢀMeO—C6H4
7.4 0.1
11.8 0.2
14.0 0.2
It was found that an increase in the πꢀdonor ability of
the substituent R2 leads to an increase in the rate of its
migration. The influence of the substituent Z in the para
position of the phenyl ring (Scheme 3) correlates with the
Hammett constants σ+,18 which provides an estimate of
the sensitivity of the reaction (ρ) in two reaction series,
which are –3.2 (R1 = H, X = Y = CO2Me) and –2.3
(R1 = Me, X = Y = CO2Me), respectively (Fig. 2).
It is worthy of note that the activation barrier for the
migration of the styryl group (R2 = —CH=CH—Ph, 1j) in
position 7a is 3 kcal mol–1 lower than that for the phenyl
group (R2 = Ph, 1d) (see Table 4).
The ease of the migration of the substituent R2 subꢀ
stantially depends also on the nature of the substituent R1.
Thus, the introduction of the methyl group at the nitrogen
atom N(1) (1h, 1i) leads to a decrease in the activation
barrier by approximately 2 kcal mol–1 compared to the
Nꢀunsubstituted compounds (1d, 1e).
It should be noted that the thermolysis of compound 1l
affords the migration product of the substituent 4l along
with ylide 3l; however, the latter compound undergoes the
ketone cleavage to form ylide 3l´ in the course of the
isolation (Scheme 2). The structure of 3l´ was confirmed
1
by H and 13C NMR spectroscopy, in particular, by the
absence of the signals of the acetyl group and the presence
of the signal for H(2) at δH 4.91, as well as by the highꢀ
resolution mass spectrum.
Scheme 2
There are the following three most probable mechaꢀ
nisms of the rearrangement: the nonꢀconcerted pathway
either through biradical intermediate 6 (see Scheme 3,
path a) or through zwitterionic intermediate 7 (path b)
and the concerted pathway through transition state 8
(Scheme 4).
As a rule, the polarity of the solvent has no substantial
effect on radical reactions, whereas the rate of these reacꢀ
tions substantially increases when nonpolar CCl4 is reꢀ
placed by DMSO (see Table 3). In addition, the substituꢀ
ents Z of any nature in the para position of the phenyl
moiety R2 should facilitate the formation of biradical inꢀ
Table 3 presents the kinetic data on the influence of
the polarity of the solvent on the rate constant of the miꢀ
Table 3. Dependence of the rate constant kb of the reaction b for compounds 1d, 1e, and 1f on
the nature of the solvent
Solvent
ε
kb•104/s–1
1d
1e
1f
(131 °C)
(20 °C)
105 °C
131 °C
CCl4
2.28
2.38
20.7
49
(0.5 0.1)•10–2
(1.6 0.1)•10–2
(2.2 0.3)•10–2
(14.0 0.3)•10–2
—
—
2.3 0.2
—
(7.6 0.5)•10–3
(3.2 0.2)•10–2
(1.3 0.1)•10–1
1.0 0.1
Toluene
Acetone
DMSO
(2.0 0.1)•10–1
—
17
2
21 2

1820
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 9, September, 2010
Chukanov et al.
Scheme 3
logkx/kH
6
Table 4. Dependence of the rate constant kb of the reaction b on
the nature of the substituents R1 and R2 at different temperatures
for compounds 1d—j in toluene
NMe2
5
4
3
2
1
0
ρ = –3.2
R2
T/K
kb/s–1
ΔG#
kb (298)a
/s–1
298
/kcal mol–1
1d
378
394
404
413
423
358
378
404
293
333
353
358
378
404
378
404
423
358
378
404
333
353
378
(1.6 0.1)•10–6
(7.4 0.2)•10–6
(2.0 0.1)•10–5
(4.6 0.2)•10–5
(9.7 0.7)•10–5
(3.6 0.1)•10–6
(2.0 0.2)•10–5
(2.3 0.2)•10–4
(3.2 0.2)•10–6
(1.9 0.1)•10–4
(1.1 0.1)•10–3
(9.5 0.5)•10–6
(6.7 0.7)•10–5
(7.4 0.2)•10–4
(1.4 0.1)•10–6
(2.0 0.2)•10–5
(1.1 0.1)•10–4
(2.3 0.1)•10–6
(3.9 0.2)•10–5
(4.9 0.5)•10–4
(4.3 0.2)•10–6
(3.7 0.2)•10–5
(4.8 0.2)•10–4
32.1b
2.5•10–11
OMe
H
1e
1fc
1j
29.4
24.6
29.0
32.1
29.9
27.6
2.1•10–9
5.6•10–6
4.2•10–9
2.5•10–11
9.4•10–10
4.2•10–8
–1.6
logkX/kH
2.0
–1.2
–0.8
–0.4
0
σ+
OMe
1.5
1.0
ρ = –2.3
1g
1h
1i
0.5
H
0
–0.5
–1.0
–1.5
NO2
0.8
–0.4
0
0.4
σ+
a The rate constants are reduced to the temperature of 298 K.
b
ΔH#298 = 30.8 kcal mol–1, ΔS#298 = –4.4 cal mol–1 K.
Fig. 2. Sensitivity of the reaction (ρ) to the substituent Z for
compounds 1d—f and 1g—i at 25 °C.
c In deuteriotoluene.

1,2,3,7aꢀTetrahydroimidazo[1,2ꢀb]isoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 9, September, 2010
1821
Scheme 4
termediate 6´, which is inconsistent with the experimenꢀ
tal data. The N—O bond cleavage is not the rateꢀlimiting
step of the reaction; otherwise, the nature of the substituꢀ
ent Z would have no effect on the reaction rate. Hence,
the path a (see Scheme 3) is unlikely to occur.
the formation of intermediate 7 can be accompanied by
the generation of acylaziridines 2 in the competitive reacꢀ
tion, and in this case the reaction rate of the formation of
the latter compounds would depend on the polarity of the
solvent, which is inconsistent with the aboveꢀconsidered
experimental data.
Since the signals of intermediate 7 are absent in the
1H NMR spectra of the reaction mixtures, it is necessary
to analyze the following two alternative situations for the
evaluation of the possibility of the zwitterion mechanism
(see Scheme 3, path b): (1) the N—O bond cleavage giving
intermediate 7 is the rateꢀlimiting step (k1) and (2) the
migration of the substituent is the rateꢀlimiting step (k2).
In the former case (k1 < k2), the πꢀdonor effect of the
substituent R2 on the reaction rate would be insignificant,
which is inconsistent with the experimental data (see
Table 4). The second step involves the aromatic electroꢀ
philic substitution (electrophilic amination). The relatively
low magnitudes of ρ (from ca. –2 to –3) compared to the
known sensitivities of the electrophilic substitution in the
aromatic series (ρ from ca. –6 to –12)18,19 indicate that
the transition state is earlier than that observed in usual
electrophilic substitution reactions, and the degree of the
positive charge transfer to the "σ complex" is lower. These
values are also smaller than the sensitivity of the electroꢀ
philic amination by the reagents R2NOX; in the case of
phenylhydroxylamine, ρ = –5.2.20 It should be noted that
Therefore, the oneꢀstep reaction occurring through
polar transition state 8 (see Scheme 4) seems to be the
most probable process. In this transition state, the partial
positive charge is delocalized on the N(4) and C(7a) atꢀ
oms and the aromatic ring, and the negative charge is
delocalized on the π system of the leaving group of actiꢀ
vated complex 8. This structure of the activated complex
may be responsible for an increase in the reaction rate in
polar solvents.
In terms of the polar transition state, the influence of
the substituent R2 can be explained as follows. Substituꢀ
ents with stronger donor properties in the aromatic ring
(Z = OMe or NMe2) stabilize the "σ complex" in the
transition state, thus decreasing the activation energy and
increasing the reaction rate. On the contrary, the strong
acceptor (Z = NO2) destabilizes this complex, thus deꢀ
creasing the reaction rate.
The migration of the styryl group in the transition state
should afford the analog of the benzyl cation 9 (Scheme 5),
which is obviously energetically more favorable than the
Scheme 5

1822
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 9, September, 2010
Chukanov et al.
partial disturbance of the aromaticity in the route to "σ
complex" 8 containing R2 = Ph and is, apparently, reꢀ
sponsible for an increase in the rate of migration in the
case of compound 1j compared to 1d.
The substituents in positions 6 and 7 in molecule 1
should also influence the energetics of the transition state
(and the reaction rate). Thus, the electronꢀwithdrawing
groups should stabilize the partial negative charge in the
transition state and lead to an increase in the reaction rate.
In the case of compound 1k containing the substituent
with weaker electronꢀwithdrawing properties (phenyl
group, Y = Ph) in position 6, the isomerization occurs
approximately three orders of magnitude more slowly comꢀ
pared to compound 1f (Y = CO2Me). Substituents with
stronger electronꢀwithdrawing properties in position 7 in
compounds 1l,m (X = COMe or CN) increase the reacꢀ
tion rate of the rearrangement by a factor of 2—3 comꢀ
pared to compound 1k (X = CO2Me).
To explain the observed features of the migration of
the substituent (see Scheme 1, reaction b) and to consider
the reaction mechanism in detail, we performed quantum
mechanical calculations for this process. The DFT calcuꢀ
lations at the PBE level of theory with the 3z basis set gave
the energy surface of the reaction (Fig. 3) in the coordiꢀ
nates of the breaking N—O bond (d) and the R2—C—N
bond angle (ϕ) (Fig. 4). The bond length d(N—O) and the
bond angle ϕ(R2—C—N) in the starting compound 1 were
taken as the zero point.
Fig. 4. Reaction coordinates: the d(N—O) bond length and the
ϕ(R2—C—N) bond angle.
getically most favorable in the gas phase (see Fig. 3),
which, in particular, casts doubt on the possibility of the
formation of zwitterionic intermediate 8 in polar solvents
in the route to products 4 as a result of the migration of the
substituent.
The structures of the transition states of the rearrangeꢀ
ments of 1c—j into 4c—j, respectively, were determined
with the use of standard calculation methods (Fig. 5).
The geometric characteristics of the transition states,
the calculated activation barriers (ΔG#298),* and the calꢀ
culated free energies of the reactions (ΔGr°298) are given in
Table 5.
The ΔGr°298 values indicate that this reaction is therꢀ
modynamically favorable and, consequently, irreversible.
According to the Hammond postulate, exothermic reacꢀ
tions proceed through early transition states, which is in
complete agreement with the aboveꢀdescribed model.
A comparison of the calculated and experimental ΔG#
298
The absence of local minima on the potential energy
surface indicates that the concerted pathway is the enerꢀ
values shows that these values are in good quantitative
agreement in the series of Nꢀunsubstituted (1d—f) and
Nꢀmethylꢀsubstituted (1g—i) derivatives (Fig. 6). Howꢀ
ever, the difference in the calculated and experimental
ΔG#298 values is 10 kcal mol–1, which can be attributed to
the fact that the experimentally observed solvent effect
* EA = ΔG#
on the assumption of the isobaricꢀisothermal
298
process.
E/kcal mol–1
80
d(N—O)
60
0.4
0.8
1.2
1.6
2.0
40
20
0
–20
ϕ(R2—C—N)
60
50
40
30
20
10
Fig. 3. Energy surface of the rearrangement of 1d into 4d in the
bond length d (N—O)—bond angle ϕ(R2—C—N) coordinates.
Fig. 5. Structure of the transition state of the rearrangement of
compound 1d into compound 4d.

1,2,3,7aꢀTetrahydroimidazo[1,2ꢀb]isoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 9, September, 2010
1823
Table 5. Calculated activation barriers (ΔG#298), free enerꢀ
gies of the reactions (ΔGr°298), and geometric characteristics
(Δd, Δϕ) of the transitions states of the rearrangements for
compounds 1c—j
Comꢀ
pound
ΔG#
ΔGr°298 Δd(N—O) Δϕ(Ar—C—N)
(Å)
298
/kcal mol–1
1c
1d
1e
1f
24.60
–47.76
–48.20
–48.09
–48.57
–50.38
–48.55
–47.87
–51.06
0.953
0.960
0.964
0.966
—
0.932
0.930
0.926
32.443
32.052
31.514
30.14
—
30.051
29.617
28.898
22.58
20.26
16.90
17.74
21.58
19.61
17.34
1j
1g
1h
1i
Fig. 7. Highest occupied molecular orbital of the transition state
of the rearrangement of 1d into 4d.
Note. ΔG#298 = Ef# – Efr, where Ef is the energy of the formaꢀ
= ΔGf°298 – ΔGf°298r; Δd = d# – dr; Δϕ =
p
tion, ΔGr°
298
r
#
= ϕ – ϕ ; the superscripts r, p, and # refer to the reagents,
the products, and the transition state, respectively.
ing C(7a)—C(i) bond (1.669 Å) and the newly formed
C(i)—N(4) bond (1.940 Å) (see Fig. 5). The typical bond
lengths for the sp3ꢀhybridized centers19 are 1.537 Å and
1.472 Å, respectively. Therefore, the transition states of
the reactions b can be considered as σ complex 8 in the
early step of its formation.
was not taken into account in the calculations. The calcuꢀ
lated sensitivities of the reaction ρ (calculated by the forꢀ
mula ρ = [(ΔG#
)
– (ΔG#298)H]/[2.303σ+]) are –1.4
298 Z
(R1 = H) and –1.3 (R1 = Me) in the two reaction series
under consideration, whereas the experimental ρ values
are –3.2 and –2.3, respectively, i.e., the calculations preꢀ
dicted the earlier transition state with the smaller charge
separation and, consequently, with the lower sensitivity
compared to the experimental value.
The calculated activation barriers for Nꢀmethylꢀsubꢀ
stituted derivatives 1g—i are, on the average, 3 kcal mol–1
lower than those of the corresponding Nꢀunsubstituted
compounds 1c—e (see Table 5). This result is in agreeꢀ
ment with the observed effect of this substituent (see Table 4).
The observed increase in the rate of migration upon the
introduction of the methyl group can be explained by conꢀ
sidering the frontier orbitals of the transition state. The
DFT calculations showed that the lone pair of the nitroꢀ
gen atom N(1) makes a considerable contribution to
HOMO of the transition state (Fig. 7), thus stabilizing
the structure. The introduction of the methyl group R1
increases the electronꢀreleasing ability of the nitrogen
atom N(1), resulting in the observed increase in the reacꢀ
tion rate.
The overall situation is indicative of the correctness of
the quantum mechanical model, which can be used for
the quantitative estimation of experimental data in partiꢀ
cular reaction series.
According to the results of calculations, the structure
of the transition state is characterized by the longer breakꢀ
ΔGacalc /kcal mol–1
R1 = H
In summary, we evaluated the influence of the polarity
of the solvent and the structural factors on the rate of the
rearrangement into 1,2,3,7aꢀtetrahydroimidazo[1,2ꢀb]ꢀ
isoxazole derivatives 1. Based on the experimental data
and the results of DFT calculations for the rearrangement
associated with the migration of the substituent and the
formation of dimethyl 2ꢀoxoꢀ3ꢀ(4,4,5,5ꢀtetramethylꢀ1ꢀ
arylimidazolidinꢀ2ꢀylidene)succinate derivatives, the meꢀ
chanism of the concerted process through the polar tranꢀ
sition state was proposed.
23
Ph
R1 = H
R1 = Me
22
21
20
19
18
17
16
C6H4—NO2
C6H4—OMe
Ph
CH=CH—Ph
C6H4—NMe2
C6H4—OMe
23 24 25 26 27 28 29 30 ΔGaexp /kcal mol–1
Experimental
Fig. 6. Comparison of the experimental and calculated activaꢀ
tion free energies ΔGa for the reaction b (see Scheme 1) of comꢀ
pounds 1c—j.
The 1H NMR spectra were recorded on Bruker AMꢀ400 and
Bruker AVꢀ300 spectrometers with the use of the signal of the

1824
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 9, September, 2010
Chukanov et al.
solvent as the internal standard. The 13C NMR spectra were
measured with complete decoupling from the constants JCH
127—128 °C (heptane). Found (%): C, 74.09; H, 8.03; N, 10.44.
C25H31N3O2. Calculated (%): C, 74.04; H, 7.70; N, 10.36.
1H NMR (CDCl3), δ: 0.99, 1.13, 1.24, and 1.32 (all s, 3 H,
C(2)Me, C(3)Me); 1.78 (s, 3 H, COMe); 2.91 (s, 6 H, NMe2);
6.66 (d, 2 H, CH arom., 3J = 8.9 Hz); 7.40—7.47 (m, 3 H,
CH arom.); 7.51—7.54 (m, 2 H, CH arom.); 7.56 (d, 2 H,
CH arom., 3J = 8.9 Hz). 13C NMR (CDCl3), δ: 18.6, 24.4, 25.2,
25.8, 29.4, 40.1, 63.1, 71.6, 93.2, 111.2, 119.7, 126.8, 128.2,
128.6, 130.3, 133.1, 149.1, 161.2, 193.8. IR (KBr), ν/cm–1: 3357,
2975, 2804, 1676, 1610, 1522, 1491, 1445, 1366, 1333, 1229,
1160, 1101, 1064, 1032.
7aꢀ(4ꢀDimethylaminophenyl)ꢀ2,2,3,3ꢀtetramethylꢀ6ꢀphenylꢀ
1,2,3,7aꢀtetrahydroimidazo[1,2ꢀb]isoxazoleꢀ7ꢀcarbonitrile (1m).
A solution of 2ꢀ[(4ꢀdimethylaminophenyl)]ꢀ4,4,5,5ꢀtetramethꢀ
ylꢀ4,5ꢀdihydroꢀ1Hꢀimidazole 1ꢀoxide (0.085 g, 0.33 mmol) and
3ꢀphenylpropꢀ2ꢀynenitrile (0.034 g, 0.27 mmol) in a mixture of
toluene (2.5 mL) and CHCl3 (2.5 mL) was heated at 65 °C for
3 h. The solvent was evaporated, and the product was purified by
chromatography on alumina with the use of a hexane—ethyl
acetate mixture (4 : 1) as the eluent. The reaction product crysꢀ
tallized after the addition of hexane, and the precipitate was
filtered off. The yield was 0.028 g (28%), m.p. 148—150 °C (hepꢀ
tane). Found (%): C, 74.73; H, 7.47; N, 14.40. C24H28N4O.
Calculated (%): C, 74.20; H, 7.26; N, 14.42. 1H NMR (CDCl3),
δ: 1.01, 1.11, 1.18, and 1.46 (all s, 3 H, C(2)Me, C(3)Me); 2.94
(s, 6 H, NMe2); 6.72 (d, 2 H, CH arom., 3J = 9.09 Hz);
7.38—7.45 (m, 3 H, CH arom.); 7.56 (d, 2 H, CH arom.,
3J = 9.0 Hz); 7.83—7.86 (m, 2 H, CH arom.). 13C NMR
(CDCl3), δ: 18.9, 24.6, 24.9, 25.4, 40.1, 63.9, 72.5, 94.0, 111.9,
115.9, 125.5, 125.9, 126.5, 128.4, 130.9, 131.2, 149.8, 160.5. IR
(KBr), ν/cm–1: 3324, 3005, 2975, 2931, 2809, 2207, 1646, 1611,
1525, 1494, 1447, 1369, 1332, 1232, 1196, 1161.
.
The IR spectra were recorded on a Bruker Vectorꢀ22 spectromeꢀ
ter in KBr pellets. The melting points were measured on a Boetꢀ
ius hotꢀstage apparatus. The elemental analysis of the compounds
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 course
of the reactions was monitored by TLC on Silufol UVꢀ254 plates
and aluminum oxide/TLC cards (Fluka) with the use of chloroꢀ
form, a chloroform—methanol mixture, and a hexane—ethyl
acetate mixture as the eluents. The compounds were isolated by
column chromatography on silica gel (Merck, Silica gel 60) or
aluminum oxide (analytical grade, neutral, for chromatography).
Chloroform of technical purity was dried over CaCl2 and disꢀ
tilled. Hexane, ethyl acetate, and diethyl ether (highꢀpurity
grade) were used without additional purification. In all cases,
the solutions were concentrated in a waterꢀjet pump vacuum.
Quantum chemical calculations of the energies of the forꢀ
mation, the geometry, and the dipole moments for reagents 1c—j
and the transition states of their rearrangements into 4c—j were
carried out by the DFT method at the PBE level of theory21 with
the 3z basis set using the Priroda program.22
Compounds 1a—j have been synthesized previously.23,24
Compounds 1k—m were synthesized in a similar way by the 1,3ꢀdiꢀ
polar cycloaddition of the nitrone 2ꢀ[(4ꢀdimethylaminophenyl)]ꢀ
4,4,5,5ꢀtetramethylꢀ4,5ꢀdihydroꢀ1Hꢀimidazole 1ꢀoxide with
alkynes. The syntheses of 2ꢀ[(4ꢀdimethylaminophenyl)]ꢀ4,4,5,5ꢀ
tetramethylꢀ4,5ꢀdihydroꢀ1Hꢀimidazole 1ꢀoxide24 and comꢀ
pounds 3a—e,g, 4g—i, and 5d—f,j have been described previousꢀ
ly.1 Alkynes, viz., methyl 3ꢀphenylpropꢀ2ꢀynoate 11k,25 4ꢀpheꢀ
nylbutꢀ3ꢀynꢀ2ꢀone 11l,26 and 3ꢀphenylpropꢀ2ꢀynenitrile 11m,27
were synthesized according to procedures described in the
literature.
Thermolysis of tetrahydroimidazoisoxazoles 1k—m (general
procedure). A solution of compound 1 (0.1—0.2 mmol) in toluꢀ
ene (1—3 mL) was heated in a sealed tube. Then the solvent was
concentrated. Products 4 and 5 were purified by chromatography
and/or recrystallization.
Methyl 7aꢀ(4ꢀdimethylaminophenyl)ꢀ2,2,3,3ꢀtetramethylꢀ6ꢀ
phenylꢀ1,2,3,7aꢀtetrahydroimidazo[1,2ꢀb]isoxazoleꢀ7ꢀcarboxyꢀ
late (1k). A solution of 2ꢀ[(4ꢀdimethylaminophenyl)]ꢀ4,4,5,5ꢀ
tetramethylꢀ4,5ꢀdihydroꢀ1Hꢀimidazole 1ꢀoxide (0.071 g,
0.27 mmol) and methyl 3ꢀphenylpropꢀ2ꢀynoate (0.050 g,
0.33 mmol) in CHCl3 (1 mL) was refluxed for 6 h. The solvent was
evaporated, and the residue was purified by chromatography on
alumina with the use of chloroform as the eluent. The product
was recrystallized from a hexane—ethyl acetate mixture. The
yield was 0.082 g (74%), m.p. 124—125 °C (heptane). Found (%):
C, 71.23; H, 7.33; N, 9.94. C25H31N3O3. Calculated (%):
C, 71.23; H, 7.41; N, 9.97. 1H NMR (CDCl3), δ: 0.98, 1.12,
1.24, and 1.34 (all s, 3 H, C(2)Me, C(3)Me); 2.92 (s, 6 H, NMe2);
3.48 (s, 3 H, CO2Me); 6.66 (d, 2 H, CH arom., 3J = 9.0 Hz);
7.35—7.43 (m, 3 H, CH arom.); 7.56 (d, 2 H, CH arom.,
Methyl 2ꢀ[1ꢀ(4ꢀdimethylaminophenyl)ꢀ4,4,5,5ꢀtetramethꢀ
ylimidazolidinꢀ2ꢀylidene]ꢀ3ꢀoxoꢀ3ꢀphenylpropanoate (4k) was
synthesized from 1k (0.020 g) at 150 °C during 6 h and purified
by recrystallization from hexane; the yield was 0.010 g (50%),
m.p. 156—158 °C (hexane). Found (%): C, 71.23; H, 7.33;
N, 9.94. C25H31N3O3. Calculated (%): C, 70.91; H, 7.37; N,
10.23. 1H NMR (CDCl3), δ: 1.10 and 1.31 (both s, 6 H, C(4)Me,
C(5)Me); 2.86 (s, 6 H, NMe2); 2.98 (s, 3 H, CO2Me); 6.47
(d, 2 H, CH arom., 3J = 8.9 Hz); 6.78 (d, 2 H, CH arom.,
3J = 8.9 Hz); 7.18—7.21 (m, 3 H, CH arom.); 7.32—7.34 (m, 2 H,
CH arom.); 9.80 (br.s, 1 H, NH). IR (KBr), ν/cm–1: 3196, 3046,
2973, 2942, 2806, 1711, 1611, 1569, 1510, 1477, 1445, 1391,
1361, 1266, 1230, 1191, 1158, 1087.
3J = 9.0 Hz); 7.62—7.65 (m, 2 H, CH arom.). IR (KBr), ν/cm–1
:
3345, 3063, 2980, 2945, 2805, 1702, 1643, 1611, 1522, 1437,
1340, 1165, 1117, 1070.
Xꢀray diffraction study. Single crystals of compound 4k suitꢀ
able for the Xꢀray diffraction study were obtained by recrystalliꢀ
zation from hexane. The measurements were carried out on an
Oxford Diffraction KM4 singleꢀcrystal diffractometer equipped
with a CCD detector (MoꢀKα radiation, λ = 0.71073 Å, graphite
monochromator, ωꢀscanning technique) at room temperature.
The empirical multiscan absorption correction was applied based
on equivalent reflections (Tmin = 0.902, Tmax = 0.996). The
Xꢀray diffraction data were collected and processed with the use
of the CrysAlisPro program package.28 Crystallographic data and
the structure refinement statistics for compound 4k are given in
1ꢀ[7aꢀ(4ꢀDimethylaminophenyl)ꢀ2,2,3,3ꢀtetramethylꢀ6ꢀ
phenylꢀ1,2,3,7aꢀtetrahydroimidazo[1,2ꢀb]isoxazolꢀ7ꢀyl]ethanone
(1l). A solution of 2ꢀ[(4ꢀdimethylaminophenyl)]ꢀ4,4,5,5ꢀtetraꢀ
methylꢀ4,5ꢀdihydroꢀ1Hꢀimidazole 1ꢀoxide (0.110 g, 0.42 mmol)
and 4ꢀphenylbutꢀ3ꢀynꢀ2ꢀone (0.073 g, 0.51 mmol) in toluene
(1 mL) was stirred at room temperature for 12 h. The solvent was
evaporated, and the residue was chromatographed on alumina
with the use of chloroform as the eluent. The product was
recrystallized from hexane. The yield was 0.11 g (65%), m.p.

1,2,3,7aꢀTetrahydroimidazo[1,2ꢀb]isoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 9, September, 2010
1825
Table 6. The structure was solved by direct methods and refined
by the fullꢀmatrix leastꢀsquares method with the use of the
SHELXꢀ97 program package29 and the WinGX software packꢀ
age.30 All nonhydrogen atoms were refined with anisotropic disꢀ
placement parameters. The hydrogen atoms were positioned geoꢀ
metrically and refined using a riding model. The C—C distances
were not sufficiently accurately refined because of the relatively
high temperature factors of the carbon atoms of one of the pheꢀ
nyl rings (C(7)—C(8)—C(9)—C(10)—C(11)—C(12)), the geoꢀ
metry of this ring was fixed (the distances were 1.39 Å; the angles
were 120°), and only the thermal parameters of the carbon atoms
were refined. The structure was deposited with the Cambridge
Crystallographic Data Centre (CCDC 748018) and can be obꢀ
tained, free of charge, on application to www.ccdc.cam.ac.uk/
data_request/cif.
2ꢀ[1ꢀ(4ꢀDimethylaminophenyl)ꢀ4,4,5,5ꢀtetramethylimidazolꢀ
idinꢀ2ꢀylidene]ꢀ1ꢀphenylbutaneꢀ1,3ꢀdione (4l) and 2ꢀ[4,4,5,5ꢀ
tetramethylꢀ2ꢀ(4ꢀdimethylaminophenyl)ꢀ1ꢀphenylꢀ4,5ꢀdihydroꢀ
1Hꢀ3ꢀλꢀ5ꢀimidazolꢀ3ꢀylidene]ethanone (3l´) were synthesized
from 1l (0.031 g) at 131 °C during 6.5 h and purified by chromaꢀ
tography on silica gel with the use of a CHCl3—MeOH mixture
(100 : 1) as the eluent followed by recrystallization from hexane.
The yields of 4l (m.p. 161—163 °C) and 3l´ (m.p. 213—215 °C)
were 0.015 g (50%) and 0.007 g (25%), respectively.
Compound 3l´. Found m/z 363.2301 [M]+. C23H29N3O. Calꢀ
culated M = 363.2305. 1H NMR (CDCl3), δ: 1.11 and 1.32
(both s, 6 H, C(4)Me, C(5)Me); 3.00 (s, 6 H, NMe2); 4.91
(s, 1 H, H(2)); 6.7 (d, 2 H, CH arom., 3J = 8.9 Hz)); 7.04
(d, 2 H, CH arom., 3J = 8.9 Hz); 7.25—7.28 (m, 3 H, CH arom.);
7.66—7.69 (m, 2 H, CH arom.); 9.63 (br.s, 1 H, NH). 13C NMR
(CDCl3, 50.32 MHz), δ: 21.1, 23.7 40.5, 62.2, 67.5, 74.9, 112.3,
124.3, 126.7, 127.8, 129.5, 131.1, 141.6, 150.0, 162.9, 185.1. IR
(KBr), ν/cm–1: 2977, 2887, 2805, 1607, 1593, 1572, 1524, 1446,
1404, 1367, 1291, 1211, 1186, 1155, 1134.
2ꢀ[1ꢀ(4ꢀDimethylaminophenyl)ꢀ4,4,5,5ꢀtetramethylimidazolꢀ
idinꢀ2ꢀylidene]ꢀ3ꢀoxoꢀ3ꢀphenylpropanenitrile (4m) and 2ꢀ[2ꢀ(4ꢀ
dimethylaminophenyl)ꢀ4,4,5,5ꢀtetramethylꢀ4,5ꢀdihydroꢀ1Hꢀ3ꢀλꢀ
5ꢀimidazolꢀ3ꢀylidene]ꢀ3ꢀoxoꢀ3ꢀphenylpropanenitrile (3m) were
synthesized according to the general procedure from 1m (0.031 g)
at 131 °C during 7.5 h. The product was purified by column
chromatography on silica gel. Compound 4m, CHCl3—MeOH
(80 : 1) as the eluent, the yield was 0.017 g (55%), m.p. 280—282 °C.
Compound 3m, CHCl3—MeOH (10 : 1) as the eluent, the yield
was 0.007 g (23%), m.p. 298—300 °C.
Compound 4m. Found m/z 388.2251 [M]+. C24H28N4O.
1
Calculated M = 388.2258. H NMR (CDCl3), δ: 1.15 and 1.35
(both s, 6 H, C(4)Me, C(5)Me); 2.96 (s, 6 H, NMe2); 6.67
(d, 2 H, CH arom., 3J = 9.0 Hz); 7.04 (d, 2 H, CH arom.,
3J = 9.0 Hz); 7.25—7.31 (m, 3 H, CH arom.); 7.60—7.62 (m, 2 H,
CH arom.); 10.23 (br.s, 1 H, NH). 13C NMR (CDCl3, 50.32
MHz), δ: 20.8, 23.3, 39.9, 62.4, 68.5, 66.9, 111.4, 119.3, 122.4,
125.6, 127.2, 127.5, 130.8, 129.7, 139.9, 150.4, 162.4, 192.2. IR
(KBr), ν/cm–1: 3225, 2985, 2918, 2817, 2191, 1611, 1589, 1539,
1524, 1479, 1447, 1368, 1345, 1290, 1175, 1153, 1128, 702.
Compound 3m. Found m/z 388.2254 [M]+. C24H28N4O.
Compound 4l. Found m/z 405.2413 [M]+. C25H31N3O2. Calꢀ
culated M = 405.2411. 1H NMR (CDCl3), δ: 0.97 and 1.27 (both s,
6 H, C(4)Me, C(5)Me); 2.15 (s, 3 H, COMe); 2.86 (s, 6 H,
NMe2); 6.21 (d, 2 H, CH arom., 3J = 9.0 Hz); 6.27 (d, 2 H,
CH arom., 3J = 9.0 Hz); 7.14—7.17 (m, 2 H, CH arom.);
7.22—7.25 (m, 2 H, CH arom.); 7.30—7.34 (m, 1 H, CH arom.);
10.73 (br.s, 1 H, NH). 13C NMR (CDCl3, 50.32 MHz), δ: 21.1,
23.2, 28.2, 40.1, 62.5, 67.5, 95.9, 111.7, 125.6, 127.1, 128.3,
128.6, 130.9, 140.9, 148.6, 163.2, 193.3, 194.3.
1
Calculated M = 388.2258. H NMR (CDCl3), δ: 0.77 and 1.20
(both s, 3 H, C(4)Me, C(5)Me); 1.26 (s, 6 H, C(4)Me, C(5)Me);
2.94 (s, 6 H, NMe2); 6.44 (d, 2 H, CH arom., 3J = 9.1 Hz);
7.14—7.18 (m, 3 H, CH arom.); 7.35—7.37 (m, 2 H, CH arom.);
7.78 (d, 2 H, CH arom., 3J = 9.0 Hz); 10.93 (br.s, 1 H, NH). IR
(KBr), ν/cm–1: 2976, 2923, 2732, 2161, 1611, 1576, 1539, 1512
1437, 1385, 1299, 1205, 1174, 1141.
Table 6. Crystallographic parameters and the Xꢀray difꢀ
fraction data collection and structure refinement statistics
Determination of the reaction rate constant (general proceꢀ
dure). A solution of compound 1 (5—50 mg) in a solvent (0.5 mL)
was placed in a sealed glass tube (in the case of a deuterated
solvent, in a carefully sealed NMR tube) and kept at 20—150 °C.
The reaction time was varied from 1 to 80 h. Then the tube was
broken, the solvent was evaporated (except the cases of the deuꢀ
terated solvents), and the 1H NMR spectra of the mixtures were
recorded. The rate constants ka and kb were evaluated by the
equations (1) and (2). These operations were repeated 2—4 times
at one temperature and at different reaction times.
Molecular formula
C25H31N3O3
Molecular weight
Crystal system
Space group
a/Å
b/Å
c/Å
α/deg
β/deg
421.53
Triclinic
P1
10.7797(11)
11.0239(11)
12.3057(12)
114.583(10)
101.122(9)
107.597(9)
1178.8(2)
2
1.188
0.079
3.16—25.35
8141
γ/deg
V/Å3
References
Z
dcalc/g cm–3
μ/cm–1
1. N. V. Chukanov, S. A. Popov, G. V. Romanenko, V. A.
Reznikov, Tetrahedron, 2008, 64, 7432.
2. J. P. Freeman, Chem. Rev., 1983, 83, 241.
3. H. Seidl, R. Huisgen, Chem. Ber., 1969, 102, 904.
4. R. M. Acheron, A. S. Bailey, I. A. Selby, J. Chem. Soc. (C),
1967, 20, 2066.
5. S.Takahashi, H. Kano, J. Org. Chem., 1965, 30, 1118.
6. F. Heaney, T. McCarthy, M. Mahon, V. McKee, Org. Bioꢀ
mol. Chem., 2005, 3, 4351.
θꢀScan range/deg
Number of measured reflections
Number of independent reflections
4194
(Rint = 0.0611)
1229
Number of reflections with I > 2σ(I)
Number of refined parameters
R1(F 2 > 2σ(F2 ))
275
0.0564
0.1622
wR2(F 2) based on all reflections

1826
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 9, September, 2010
Chukanov et al.
7. N. Coskun, S. Tuncman, Tetrahedron, 2006, 62, 1345.
8. T. A. Berezina, V. A. Reznikov, L. B. Volodarskii, I. Ya.
Bagryanskaya, Yu. V. Gatilov, Izv. Akad. Nauk, Ser. Khim.,
2000, 112 [Russ. Chem. Bull., Int. Ed., 2000, 49, 116].
9. A. Padwa, M. Meske, Z. Ni, Tetrahedron, 1995, 51, 89.
10. B. Alcaide, E. Saez, Tetrahedron Lett., 2000, 41, 1647.
11. R. C. F. Jones, J. N. Martin, P. Smith, T. Gelbrich, M. E.
Light, M. B. Hursthouse, Chem. Commun., 2000, 19, 1949.
12. M. L. M. Pennings, G. Okay, D. N. Reinhoudt, S. Harkeꢀ
ma, G. J. Van Hummel, J. Org. Chem., 1982, 47, 4413.
13. R. Huisgen, H. Giera, K. Polborn, Liebigs Ann./Recueil,
1997, 8, 1691.
20. H.Takeuchi, T. Taniguchi, T. Ueda, J. Chem. Soc., Perkin.
Trans. 2, 2000, 2, 295.
21. J. P. Perdew, K. Burke, M. Ernzerhof, Phys. Rev. Lett., 1996,
77, 3865.
22. D. N. Laikov, Chem. Phys. Lett., 1997, 281, 151.
23. S. A. Popov, N. V. Chukanov, G. V. Romanenko, T. V.
Rybalova, Y. V. Gatilov, V. A. Reznikov, J. Heterocycl.
Chem., 2006, 43, 277.
24. N. V. Chukanov, S. A. Popov, G. V. Romanenko, V. A.
Reznikov, Izv. Akad. Nauk, Ser. Khim., 2007, 1182 [Russ.
Chem. Bull., Int. Ed., 2007, 56, 1227].
25. V. L. Heasley, D. F. Shellhamer, A. E. Chappell, J. M. Cox,
D. J. Hill, S. L. McGovern, C. C. Eden, J. Org. Chem., 1998,
63, 4433.
14. Y. Kobayashi, I. Kumadaki, T. Yoshida, Heterocycles, 1977,
8, 387.
15. J. P. Freeman, D. J. Duchamp, C. G. Chidester, G. Slomp,
J. Szmuszkovicz, M. Raban, J. Am. Chem. Soc., 1982,
104, 1380.
16. R. Gree, R. Carrie, J. Am. Chem. Soc., 1977, 99, 6667.
17. R. Huisgen, K. Niklas, Heterocycles, 1984, 22, 21.
18. The Chemist´s Companion: A Handbook of Practical Data,
Techniques and References, Ed. A. J. Gordon, R. A. Ford,
Wiley, New York, 1972, 311 pp.
26. P. Simunek, V. Bertolasi, M. Peskova, V. Machacek, A. Lyꢀ
cka, Org. Biomol. Chem., 2005, 3, 1217.
27. H. Adkins, G. M. Whitman, J. Am. Chem. Soc., 1942, 64, 150.
28. Oxford Diffraction, CrysAlisPro, Oxford Diffraction Ltd.,
Abingdon, England, 2008.
29. G. M. Sheldrick, Acta Crystallogr. Sec. A, 2008, 64, 112.
30. L. J. Farrugia, J. Appl. Crystallogr., 1999, 32, 837.
19. A. S. Dneprovskii, T. I. Temnikova, Teoreticheskie osnovy
organicheskoi khimii [Theoretical Fundamentals of Organic
Chemistry], Khimiya, Leningrad, 1979, 520 pp. (in Russian).
Received October 15, 2009;
in revised form July 8, 2010