Evasive neutral 2-aza-cope rearrangements. Kinetic and computational studies with cyclic nitrones

Article abstract of DOI:10.1002/ejoc.201300836

A full experimental study of the activation energy required for the hitherto unknown neutral 2-aza-Cope rearrangement is presented. A kinetic study of the process showed activation energies in the range of 22.91-24.06 kcal/mol, in agreement with a process operating at moderate temperature (70°C). Calculations at B3LYP/6-311+G(d,p) and M06-2X/6-311+G(d,p) levels of theory considering solvent (dimethyl sulfoxide (DMSO) and toluene) effects (PCM model) predict reaction energy barriers that are in agreement with the values obtained from ¹H NMR-based kinetic experiments. Results obtained by using enantiomerically pure substrates demonstrate that the rearrangement takes place with complete transfer of chirality, in contrast to previously described cationic processes. The effects of solvent and acid catalysis, which converts the process into the more common cationic rearrangement, have also been studied. DFT calculations also predict correctly the acceleration of the process under acid catalysis, estimating energy barriers in the range of 16.80-18.57 kcal/mol. The hitherto unknown neutral 2-aza-Cope rearrangement of nitrones takes place under thermal conditions with complete transfer of chirality. The process can be catalyzed by acid through a classical cationic 2-aza-Cope rearrangement. Kinetic ¹H NMR experiments and DFT theoretical studies have been used to estimate the activation parameters and determine the energy of activation of the process. Copyright

Full text of DOI:10.1002/ejoc.201300836

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FULL PAPER
Aza-Cope Rearrangement
I. Delso, A. Melicchio, A. Isasi, T. Tejero,
P. Merino* ...................................... 1–11
Evasive Neutral 2-Aza-Cope Rearrange-
ments. Kinetic and Computational Studies
with Cyclic Nitrones
The hitherto unknown neutral 2-aza-Cope
rearrangement of nitrones takes place un-
der thermal conditions with complete
transfer of chirality. The process can be cat-
alyzed by acid through a classical cationic
2-aza-Cope rearrangement. Kinetic 1H
NMR experiments and DFT theoretical
studies have been used to estimate the acti-
vation parameters and determine the en-
ergy of activation of the process.
Keywords: Aza-Cope rearrangement / Kin-
etics / Nitrones / Density functional calcu-
lations / Allylation
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I. Delso, A. Melicchio, A. Isasi, T. Tejero, P. Merino
FULL PAPER
DOI: 10.1002/ejoc.201300836
Evasive Neutral 2-Aza-Cope Rearrangements. Kinetic and Computational
Studies with Cyclic Nitrones
Ignacio Delso,[a,b] Alessandro Melicchio,[a][‡] Arantzazu Isasi,[a] Tomás Tejero,[a] and
Pedro Merino*[a]
Dedicated to Professor Giovanni Romeo on the occasion of his 70th birthday
Keywords: Aza-Cope rearrangement / Kinetics / Nitrones / Density functional calculations / Allylation
A full experimental study of the activation energy required
for the hitherto unknown neutral 2-aza-Cope rearrangement
is presented. A kinetic study of the process showed activation
energies in the range of 22.91–24.06 kcal/mol, in agreement
with a process operating at moderate temperature (70 °C).
Calculations at B3LYP/6-311+G(d,p) and M06-2X/6-
311+G(d,p) levels of theory considering solvent (dimethyl
sulfoxide (DMSO) and toluene) effects (PCM model) predict
reaction energy barriers that are in agreement with the val-
ues obtained from 1H NMR-based kinetic experiments. Re-
sults obtained by using enantiomerically pure substrates
demonstrate that the rearrangement takes place with com-
plete transfer of chirality, in contrast to previously described
cationic processes. The effects of solvent and acid catalysis,
which converts the process into the more common cationic
rearrangement, have also been studied. DFT calculations
also predict correctly the acceleration of the process under
acid catalysis, estimating energy barriers in the range of
16.80–18.57 kcal/mol.
Introduction
Stereoselective [3,3]-sigmatropic processes are well-
known and powerful tools in organic synthesis.[1] Among
them, Claisen[2] and Cope[3] rearrangements have developed
exceptionally well in the past 50 years. In particular, aza-
Cope rearrangements have attracted great interest because
of the ubiquitous presence of nitrogen-containing structures
in natural and biological products as well as synthetic inter-
mediates. Moreover, the merging of aza-Cope rearrange-
ments with other reactions such as [3+2] cycloaddition[4] or
Mannich type reaction[5] provide direct access to a variety
of complex structures. Depending on the position of the
nitrogen atom, several aza-Cope rearrangements can be
identified (Scheme 1).
Scheme 1. Aza-Cope rearrangements.
The 1-aza-Cope rearrangement, developed by Fowler
and co-workers from aza-diene precursors,[6] has been used
in the synthesis of nitrogen heterocycles.[7] In 1992, Stille
and co-workers reported the inverse process as a 3-aza-
Cope rearrangement starting from N-alkyl-N-allylen-
amines.[8] This reaction has also been studied for quaternary
N-allyl enammonium salts.[9]
Both 1- and 3-aza-Cope rearrangements are thermal pro-
cesses that are catalyzed by Lewis acids. The 2-aza-Cope
rearrangement had only been described as an equilibrium
system for cationic substrates,[10] and several protocols were
developed to drive the process to a single product.[11] These
protocols included trapping the iminium ion with a nucleo-
phile incorporated into the structure[12] and a Mannich type
reaction.[13] The synthetic utility of the reaction has been
extensively demonstrated[14] and, more recently, a catalytic
asymmetric version has been reported for protonated
imines.[15]
[a] Laboratorio de Síntesis Asimétrica, Departamento de Síntesis
y Estructura de Biomoléculas, Instituto de Síntesis Química y
Catálisis Homogénea (ISQCH), Universidad de Zaragoza,
CSIC,
50009 Zaragoza, Aragón, Spain
E-mail: pmerino@unizar.es
Homepage: http://www.bioorganica.es
[b] Servicio de Resonancia Magnética Nuclear, Centro de Química
y Materiales de Aragón (CEQMA), Universidad de Zaragoza,
CSIC,
50009 Zaragoza, Aragón, Spain
[‡] Present address: Dipartimento di Chimica e Tecnologie
Chimiche, Università della Calabria, via Bucci 12 C, 87036
Rende (CS), Italy
Wuts and Jung reported the 2-aza-Cope rearrangement
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300836.
of nitrones under catalysis with trimethylsilyl triflate,[16]
2
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Neutral 2-Aza-Cope Rearrangements
which actually involves hydroxyiminium cations. A similar was obtained. The major isomer 10a was separated by
process was described twenty years later by Loh and co- chromatography and allylated following our standard pro-
workers using 10-camphorsulfonic acid (CSA) as a cata- cedure[24] to give hyroxylamine 11. Finally, oxidation of 11
lyst.[17] In both cases, the rearrangement involved cationic furnished nitrone 2 in 48% overall yield (five steps).
species, as in other 2-aza-Cope rearrangements. On the
other hand, the possibility of inducing a thermal 2-aza-
Cope rearrangement with neutral substrates had only been
suggested,[18] and in 2007 we reported for the first time ex-
perimental and theoretical evidence of a neutral thermal 2-
aza-Cope rearrangement of nitrones.[19] As far as we are
aware there are no examples in the literature concerning
thermal 2-aza-Cope rearrangements with neutral substrates
other than those reported from our laboratory.[20]
In this paper, we report a full experimental study based
on NMR kinetic experiments of the activation energies re-
quired for both neutral and catalyzed 2-aza-Cope re-
arrangements of nitrones. DFT calculations are also used
to compare experimental and theoretical values for noncat-
alyzed vs. catalyzed processes. The study has been extended
to include cyclic nitrones 1 and 2 and, ultimately, applied
to the rearrangement of enantiomerically pure nitrone 3
(Figure 1).
Scheme 3. Synthesis of nitrone 2. Reagents and conditions:
(i) MeReO3 (2 mol-%), UHP, MeOH, room temp., 24 h; (ii) phenyl-
magnesium bromide, THF 0 °C, 2 h; (iii) MnO2, CH2Cl2, 0 °C, 7 h;
(iv) allylmagnesium bromide, THF 0 °C, 8 h.
Nitrone 3 was prepared with complete selectivity and
quantitative yield from nitrone 12,[20a] which was obtained
from d-arabinose in six steps and 21.8% overall yield
(Scheme 4).[27]
Figure 1. Cyclic nitrones.
Results and Discussion
Scheme 4. Synthesis of nitrone 3.
Preparation of Nitrones
Nitrone 1 was prepared starting from methyl prolinate 4
(Scheme 2). Oxidation of 4 catalyzed by methyltrioxorhen-
ium[21] afforded nitrone 5 in 80% yield.[22] Compound 5 was
also reported to be obtained from 4 by oxidation with hy-
drogen peroxide in the presence of a catalytic amount of
Kinetic Studies
Heating nitrones 1 or 2 in dimethyl sulfoxide (DMSO) in
sodium tungstate, but only in 42% yield.[23] Further allyl- a sealed tube at 70 °C for 6 h afforded mixtures of re-
ation[24] of 5 to give 6 and subsequent oxidation with man- arranged nitrones and the corresponding cycloadducts
ganese(IV) oxide[25] provided nitrone 1 in 58% overall yield formed through an intramolecular 1,3-dipolar cycload-
(three steps) from 4.
dition (Scheme 5). Prolonged heating for 36 h only provided
Nitrone 2 was prepared from nitrone 8, which was ob- cycloadducts 15 and 16, in quantitative yield, from nitrones
tained by oxidation of pyrrolidine 7 with methyltrioxorhen- 1 and 2, respectively, indicating that nitrones 13 and 14 are
ium as described (Scheme 3).[26] After nucleophilic addition intermediates of the reaction. On the other hand, nitrone
of phenylmagnesium bromide and oxidation with manga- 17 was obtained from nitrone 3 in quantitative yield and
nese(IV) oxide,[25] a 9:1 mixture of nitrones 10a and 10b complete selectivity under the same reaction conditions.
Scheme 2. Synthesis of nitrone 1. Reagents and conditions: (i) MeReO3 (2 mol-%), urea–hydrogen peroxide (UHP) complex, MeOH, room
temp., 24 h; (ii) allylmagnesium bromide, THF 0 °C, 8 h; (iii) MnO2, CH2Cl2, 0 °C, 7 h.
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I. Delso, A. Melicchio, A. Isasi, T. Tejero, P. Merino
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Prolonged heating of isolated 17 (or directly from 3) ulti- that the thermal 2-aza-Cope rearrangement takes place
mately led to the corresponding cycloadduct 18, as de- prior to the cycloaddition reaction. Indeed, a plot of the
scribed.[20a]
natural logarithm of concentration, i.e., ln(χ), against time,
was a straight line, confirming that the process is first-order
in all cases. From the reaction conducted at various tem-
peratures (40–90 °C), the corresponding kinetic constants
were calculated for each temperature. The Arrhenius plot
(see the Supporting Information) permitted evaluation of
the respective activation energies and Eyring plots (Fig-
ure 3), a direct evaluation of the activation parameters ΔH϶
and ΔS϶ and, in consequence ΔG϶ at 298.15 K (Table 1).
In all cases, all the values were similar and activation ener-
gies were found to be within a range of 1.2 kcal/mol (from
22.91 to 23.16 kcal/mol).
Scheme 5. Rearrangement of nitrones 1–3. Reagents and conditions:
(i) DMSO, 70 °C, 6 h, sealed tube; (ii) toluene 120 °C, 36 h, sealed
tube.
To obtain detailed information on the factors and acti-
vation energy of the process, we investigated the rearrange-
1
ment of nitrones 1–3 by H NMR spectroscopic analysis at
a range of temperatures between 40–90 °C, and determined
the activation parameters. The disappearance of the NMR
signal of nitrone 3 at δ = 7.00 ppm with the appearance of
the NMR signal of nitrone 17 at δ = 7.14 ppm, as shown
in Figure 2, is evidence that the process monitored is that
illustrated in Scheme 5. Similar kinetic NMR runs were
performed for nitrones 1 and 2. The changes in concentra-
tion of nitrones 1–3 were determined from the correspond-
ing 1H NMR spectra by measuring integral data. In the
Figure 3. Eyring plots [ln(K/T) vs. 1/T] for rearrangements of nitro-
nes 1–3.
We also investigated the rearrangement of nitrone 2 in
case of nitrones 1 and 2, we ascertained that the relation- toluene and under acid catalysis. Thus, the same reactivity
ship between the concentration of the rearranged nitrones illustrated in Scheme 5 was observed in toluene, although
13 and 14 and the corresponding starting nitrones is best the reaction was completed in 4 h, in agreement with a neu-
described by a straight line, which is a mathematical proof tral pericyclic transition state,[19] which should be stabilized
Figure 2. Stack plot illustrating 1H NMR signals (aromatic protons) for starting nitrone 3 and rearranged nitrone 17 at 343 K, at 30 min
intervals.
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Neutral 2-Aza-Cope Rearrangements
Figure 4. Eyring plots [ln(K/T) vs. 1/T] for rearrangement of nitrone 2 in DMSO, toluene, and in the presence of 20 mol-% PTSA.
Table 1. Kinetic parameters for the rearrangements of nitrones 1– a rate constant k (70 °C) = 2.61ϫ10–4 s–1 was found. In
3.
this case, the activation energy was Ea = 16.79 kcal/mol.
The Eyring plots for the acid-catalyzed rearrangement of
nitrone 2 are illustrated in Figure 4 and the corresponding
thermodynamic parameters are given in Table 2.
Thermodynamic
parameters
1
3
2
k (343 K, s–1)
Ea (kcal/mol)
1.25ϫ10–5
22.91
22.23
1.05ϫ10–4
24.06
23.40
–9.25
26.15
3.87ϫ10–5
23.16
21.68
–15.17
26.20
ΔH϶ (kcal/mol)
ΔS϶ (cal/Kmol)
Table 2. Kinetic parameters for the rearrangements of nitrone 2.
–16.68
Thermodynamic
parameters
DMSO
Toluene
ΔG϶ (298.15 K, kcal/ 27.20
mol)
uncata-
lyzed
catalyzed uncata-
lyzed
catalyzed
k (343 K, s–1)
Ea (kcal/mol)
ΔH϶ (kcal/mol)
ΔS϶ (cal/Kmol)
ΔG϶ (298.15 K,
kcal/mol)
1.05ϫ10–5 3.83ϫ10–4 8.72ϫ10–5 2.61ϫ10–4
in aromatic solvents. Three acid catalysts (CSA, PTSA and
phosphoric acid) were tested for the rearrangement of
nitrone 2, with the best results being obtained for CSA and
PTSA. In particular, the optimization study carried out for
the PTSA-catalyzed process showed that 20 mol-% catalyst
was necessary to achieve good conversion (Scheme 6). In
the case of acid-catalyzed reactions, nitrone 14 was ob-
tained as the only product of the reaction and no cycload-
dition was observed.
24.06
23.40
–9.25
26.15
18.57
17.90
–21.79
24.40
20.61
19.94
–18.76
25.54
16.79
16.12
–28.52
24.62
These studies reveal that the rearrangement performed in
the presence of 20 mol-% PTSA have lower transition state
energies than those of the uncatalyzed reaction. The cata-
lyzed process in toluene is faster than the corresponding
process in DMSO but with a minor difference (1.78 kcal/
mol) in the values of Ea with respect to the uncatalyzed
rearrangements (3.45 kcal/mol). This observation is in
agreement with a typical cationic 2-aza-Cope rearrange-
ment for the catalyzed processes in which the stability of
the transition structures could be increased, to some extent,
in polar solvents such as DMSO.
Scheme 6. Optimization study for the PTSA-catalyzed rearrange-
ment of nitrone 2e.
The rearrangement of 2 in toluene exhibited a first-order
rate constant k (70 °C) = 8.72 10–5 s–1 from which the acti-
vation energy (Ea) was calculated to be 20.61 kcal/mol
(Table 2). This value is clearly lower than that found for the
DFT Calculations
To explore the energetics of the 2-aza-Cope rearrange-
rearrangement in DMSO (Ea = 24.06 kcal/mol), in agree- ments studied above, we also performed DFT calculations
ment with a neutral rearrangement proceeding through a with both B3LYP[28] and M06-2X[29] functionals using the
pericyclic transition state. The rate constant for the re- 6-311+G(d,p)[30] basis set. B3LYP calculations have been
arrangement of 2 in DMSO and in the presence of 20 mol- reported to provide accurate results in the study of Cope
% PTSA was higher [k (70 °C) = 3.83ϫ10–4 s–1] than in the rearrangements,[31] although in the case of protonated spe-
absence of acid [k (70 °C) = 1.05ϫ10–5 s–1]. Accordingly, cies they lead to an underestimation of the activation ener-
the activation energy was lower (Ea = 18.57 kcal/mol). gies, indicating insufficient consideration of the electronic
When the acid-catalyzed process was carried out in toluene correlation effects.[32] On the other hand, Thrular’s func-
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FULL PAPER
tionals[33] have emerged as powerful tools that provide more
For C-phenyl nitrones 2 and 3 the presence of benzyloxy-
accurate energy values in several types of reactions.[34] All methyl substituents does not strongly influence the geomet-
the geometry optimizations were carried out with the ric or energetic features of the transition state. In both
Gaussian 09 suite of programs.[35] The solvent effect was cases, the forming C1–C4 bond is longer (1.85–1.86 Å) than
computed by using the polarizable continuum model the breaking C2–C5 bond (1.75–1.79 Å) and similar N3–
(PCM),[36] considering both DMSO and toluene as sol- C2–C5 and N3–C1–C4 angles are observed (100–101°). On
vents. Calculations for nitrones 1 and 2 were performed the other hand, TS1 corresponding to rearrangement of C-
with the complete model. In the case of nitrone 3, the sub- (methoxycarbonyl) nitrone 1 presents a forming C1–C4
strate was slightly simplified by replacing the benzyl groups bond (1.70–1.74 Å) shorter than the breaking C2–C5 bond
by methyl groups.
(1.81 Å). Consequently, it appears that TS2 and TS3 (corre-
The theoretical treatment involved optimization of nitro- sponding to C-phenyl nitrones 2 and 3, respectively) are
nes 1–3 and 13, 14 and 17 as well as transition state struc- earlier transition states than TS1. The N3–C2–C5 and N3–
tures for the interconversion between them. The computed C1–C4 angles are similar (101.4° and 102.7°, respectively)
reaction barriers are given in Table 3 and the geometrical to those observed for TS2 and TS3. Indeed, in all cases, the
structures of the transition states are illustrated in Figure 5. located transition states have a chair-like conformation that
is in agreement with a typical Cope rearrangement. The ax-
ial disposition of the nitrone oxygen is determined by the
Table 3. Experimental and calculated activation energies (ΔG϶,
required orientation of the orbitals involved in the re-
kcal/mol) at 298.15 K for the rearrangement of nitrones 1–3 in
arrangement.
DMSO as solvent.
Table 3 gives a comparison between experimental and
calculated free energies for the rearrangement of nitrones
1–3. The predictions are not very sensitive to variation in
functional and with both B3LYP and M06-2X the predicted
energy barrier was higher than that observed experimen-
Nitrone
Exp.
Calcd.
M06-2X
B3LYP
1
2
3
27.20
26.15
26.20
31.85
29.46
27.08
30.68
28.14
27.15
Figure 5. Calculated [PCM(DMSO)/B3LYP/6-311+G(d,p) and PCM(DMSO)/M06-2X/6-311+G(d,p)] transition structures for the re-
arrangement of nitrones 1–3. Bond lengths (Å) and activation energies (kcal/mol) at 298.15 K. TS1 corresponds to the rearrangement of
nitrone 1 into 13; TS2 corresponds to the rearrangement of nitrone 2 into 14; TS3 corresponds to the rearrangement of nitrone 3 into
15.
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Neutral 2-Aza-Cope Rearrangements
tally. Closer values to experimental were observed with since differences of 3.48 (B3LYP) and 4.65 (M06-2X) kcal/
B3LYP calculations and, in the case of nitrones 2 (TS2) and mol were observed. Nevertheless, the calculations reflect the
3 (TS3), a difference of less than 2 kcal/mol was obtained. experimentally observed trend that nitrone 1 has a higher
The calculations were not so accurate for nitrone 1 (TS1) activation barrier than those corresponding to nitrones 2
Figure 6. Calculated [PCM(DMSO)/B3LYP/6-311+G(d,p) (plain text) and PCM(DMSO)/M06-2X/6-311+G(d,p) (in parentheses)] energy
profiles for the rearrangements of nitrones 1 and 2 into 13 and 14, respectively, and intramolecular cycloadditions to give cycloadducts
15 and 16. Relative energies are given in kcal/mol.
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and 3, which have similar values (compare Table 3, entry 1 (B3LYP). The predicted energy differences between TS2
and entries 2–3). and TS7 (and TS6) agree with the experimentally observed
We also located the corresponding transition structures higher ratio between nitrone 14 and cycloadduct 16 (6:1)
for the intramolecular dipolar cycloaddition leading to cy- with respect to that observed between nitrone 13 and cy-
cloadducts 15, 16 and 18. In principle, these cycloadducts cloadduct 15 (3:2) (Scheme 5).
could be formed from both starting and rearranged nitrones
In the case of nitrone 3, similar results were observed
through different transition structures. For nitrone 1 (N1), with both B3LYP and M06-2X functionals. The calculated
both B3LYP and M06-2X calculations predict the direct in- energy differences are similar to those observed for nitrone
tramolecular cycloaddition from nitrone N1 (through TS4) 2 (N2) (see the Supporting Information).
as the most favored process and the 2-aza-Cope rearrange-
DFT calculations on 2-aza-Cope rearrangements of
ment as less favored (Figure 6). However, the small energy nitrone 2 considering toluene as a solvent and under cata-
differences between TS1 and TS4 (less than 1 kcal/mol in lytic conditions were also performed. The geometrical
B3LYP calculations) are in agreement with the experimental structures of the transition states are depicted in Figure 6
observations that both processes are observed simulta- and the corresponding free energy barriers are given in
neously. Indeed, although TS5 is lower in energy than TS4 Table 4.
[0.91 kcal/mol (B3LYP) or only 0.21 kcal/mol (M06-2X)],
the possibility that the cycloadduct could also be obtained
directly from nitrone 1 (N1) through TS4 cannot be dis-
carded.
Table 4. Experimental and calculated activation energies (ΔG϶,
kcal/mol) at 298.15 K for the rearrangement of nitrone 2.
For nitrone 2 (N2), both B3LYP and M06-2X also pre-
dict the intramolecular cycloaddition from the rearranged
nitrone (through TS7) as the most favored process (Fig-
ure 6). In this case, however, the 2-aza-Cope rearrangement
(through TS2) is predicted to be more favored than the di-
rect cycloaddition from N2 (through TS6) by 1.0 kcal/mol
Solvent
Catalyzed
Exp.
Calcd.
M06-2X
B3LYP
DMSO
Toluene
DMSO
Toluene
no
no
yes
yes
26.15
25.54
24.40
24.62
29.46
27.39
19.43
19.00
28.14
28.08
20.98
20.26
Figure 7. Calculated [PCM(DMSO)/B3LYP/6-311+G(d,p) and PCM(DMSO)/M06-2X/6-311+G(d,p)] transition structures for the re-
arrangement of nitrone 2 into 14. Bond lengths (Å) and activation energies (kcal/mol) at 298.15 K. TS2 and TS8 correspond to the
rearrangement in DMSO and toluene, respectively; TS9 and TS10 correspond to the PTSA-catalyzed rearrangement in DMSO and
toluene, respectively.
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Neutral 2-Aza-Cope Rearrangements
For the uncatalyzed reaction, both B3LYP and M06-2X the energy barriers for the cationic rearrangement are
calculations reflect the observed slight acceleration of the underestimated in both B3LYP and M06-2X calculations,
reaction when solvent was changed from DMSO to toluene. and lower barriers than those observed experimentally are
Again, B3LYP calculations proved to be more accurate, pre- predicted (Table 4).
dicting a negligible difference (0.06 kcal/mol), in agreement
As expected for a cationic rearrangement, transition
with that observed experimentally (0.61 kcal/mol). The ob- states TS9 and TS10 are more asynchronous than their re-
served overestimation of calculated energy barriers of 2– spective counterparts TS2 and TS8. Consequently, whereas
3 kcal/mol for DMSO was reproduced for toluene. The ge- the breaking C2–C5 bond is shortened (from 1.75 to 1.68 Å
ometry of the transition states in DMSO (TS2) and toluene in DMSO and toluene), the forming C1–C4 bond is slightly
(TS8) are quite similar, with very close values of lengthened (from 1.85 to 1.87 Å in DMSO and from 1.86
forming C1–C4 bonds (1.85 Å in DMSO and 1.86 Å in tol- to 1.88 Å in toluene).
uene) and breaking C2–C5 bonds (1.75 Å in both DMSO
When the cycloaddition process was considered, the cal-
and toluene). Similarly, no remarkable variations culations were found to reflect the observed experimental
were observed in N3–C2–C5 and N3–C1–C4 angles (see results. For protonated species, the intramolecular cycload-
Figure 7).
dition is disfavored both kinetically (high energy barriers
In the case of catalyzed rearrangement of nitrone 2, we for TS11 and TS12) and thermodynamically (the proton-
considered protonated species at the nitrone oxygen (Fig- ated cycloadduct is less stable than the corresponding pro-
ure 7). Calculations reflect the observed acceleration of the tonated nitrones). In consequence, the calculations correctly
process, predicting lower energy barriers in all cases. In con- predict that only the rearranged nitrone would be obtained
trast to calculations corresponding to the neutral process, (Figure 8).
Figure 8. Calculated [PCM(DMSO)/B3LYP/6-311+G(d,p) (plain text) and PCM(DMSO)/M06-2X/6-311+G(d,p) (in parentheses)] energy
profiles for the PTSA-catalyzed rearrangement of nitrone 2 into 14 and intramolecular cycloaddition to give protonated cycloadduct 16.
Relative energies are given in kcal/mol. TS9 and TS10 correspond to the rearrangement in DMSO and toluene, respectively.
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Job/Unit: O30836
/KAP1
Date: 22-07-13 10:33:28
Pages: 11
I. Delso, A. Melicchio, A. Isasi, T. Tejero, P. Merino
FULL PAPER
J = 11.5 Hz, 1 H), 4.50 (d, J = 11.7 Hz, 1 H), 4.51 (d, J = 11.5 Hz,
1 H), 4.67 (d, J = 11.2 Hz, 1 H), 4.69 (d, J = 11.5 Hz, 1 H), 4.74
(d, J = 11.8 Hz, 1 H), 4.80 (d, J = 4.3 Hz, 1 H), 5.01 (dd, J = 10.2,
2.0 Hz, 1 H), 5.15 (ddt, J = 17.1, 2.1, 1.2 Hz, 1 H), 5.33 (d, J =
4.3 Hz, 1 H), 5.82 (ddt, J = 17.4, 10.1, 7.3 Hz, 1 H), 7.10–7.13 (m,
2 H), 7.26–7.32 (m, 8 H), 7.34–7.41 (m, 5 H), 7.43–7.47 (m, 3 H),
8.41–8.45 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 34.9,
68.5, 71.2, 72.8, 73.6, 78.5, 82.1, 83.7, 120.1, 127.7, 127.7, 127.8,
127.8, 128.0, 128.0, 128.2, 128.3, 128.4, 128.5, 130.2, 131.7, 137.6,
137.7, 137.8, 139.1 ppm. C35H35NO4 (533.67): calcd. C 78.77, H
6.61, N 2.62; found C 78.54, H 6.40, N 2.45.
Conclusions
We have studied the first reported neutral 2-aza-Cope re-
arrangement of nitrones both experimentally (kinetically)
and theoretically to determine the main factors affecting
the process. Kinetic studies reveal that the rearrangement is
favored in aromatic solvents, in agreement with an aromatic
transition state. Acid catalysis accelerates the process and
diminishes the difference between aromatic and polar sol-
vents. These results clearly demonstrate that whereas the
uncatalyzed process occurs through a neutral transition
state, the catalyzed process takes place through cationic spe-
cies. In spite of these observations, the aromaticity of the
transition state favors in all cases the reaction conducted
in an aromatic solvent (toluene). DFT calculations support
these results and predict an activation energy barrier for
the rearrangement that is in reasonable agreement with the
kinetic experimental observations. The observed ratios be-
tween rearranged nitrones and cycloadducts are supported
in part by calculations. Small energy differences are ob-
tained with both B3LYP and M06-2X calculations (in most
cases within experimental error) and, in consequence, it is
not possible to describe accurately the process despite that
high level calculations [6-311+G(d,p) basis set] have been
carried out. The complete stereoselectivity observed for
nitrone 3 is well-supported by DFT calculations since a
pericyclic process with complete transfer of chirality is pre-
dicted for the rearrangement.
General Procedure for the Catalyzed Rearrangement of Nitrone 2: A
solution of nitrone 2 (0.201 g, 1 mmol) was dissolved in anhydrous
DMSO (25 mL), treated with p-toluensulfonic acid (34 mg,
0.2 mmol), placed in a sealed tube, and heated at 40 °C under an
argon atmosphere for 6 h, at which time the solvent was partially
evaporated and the resulting solution was filtered through a pad of
silica gel. After washing the silica with diethyl ether, the resulting
solution was evaporated under reduced pressure and the residue
was purified by column chromatography (hexane/EtOAc, 4:1).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for the preparation of nitrones 1–3.
Arrhenius plots of kinetically studied reactions. Experimental de-
tails of NMR kinetic experiments. Additional computational de-
tails including energy diagrams, tables with absolute and relative
electronic and free energies, and coordinates of stationery points
(nitrones, transition structures and cycloadducts). Copies of 1H and
13C NMR spectra.
Acknowledgments
The authors thank for support by the Spanish Ministry of Science
and Innovation (MICINN) (project number CTQ2010-19606), by
the European Union (EU) (FEDER Program) and by the Govern-
ment of Aragon (Research group E-10, Zaragoza, Spain). A. M.
thanks the European Commission and European Social Fund
(POR Calabria 2007/2013) for a grant.
Experimental Section
General Procedure for the Rearrangement of Nitrones 1–3: A solu-
tion of the corresponding nitrone (1 mmol) was dissolved in anhy-
drous DMSO (25 mL), placed in a sealed tube and heated at 70 °C
under an argon atmosphere for 6 h, at which time the solvent was
partially evaporated and the resulting solution was filtered through
a pad of silica gel. After washing the silica with diethyl ether, the
resulting solution was evaporated under reduced pressure and the
residue was purified by column chromatography (hexane/EtOAc,
4:1).
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2-Allyl-5-(methoxycarbonyl)-3,4-dihydro-2H-pyrrole 1-Oxide (13):
1H NMR (300 MHz, CDCl3): δ = 1.90–1.96 (m, 1 H), 2.42–2.52
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10
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Neutral 2-Aza-Cope Rearrangements
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Received: June 6, 2013
Published Online: ᭿
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