Quantum chemical-guided steglich rearrangement of azlactones and isoxazolones

Article abstract of DOI:10.1021/acs.joc.9b02099

The theoretical-guided evaluation of the Steglich rearrangement of azlactones and isoxazolones allowed the determination of the reactivity patterns in these heterocycles, including the factors that drive the regioselectivity toward both possible sites. These results allowed the first experimental report on the regioselective Steglich rearrangement of isoxazolones, affording the nitrogen- or carbon-acyloxy adducts.

Full text of DOI:10.1021/acs.joc.9b02099

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Article
The Quantum Chemical Guided Steglich
Rearrangement of Azlactones and Isoxazolones
Pedro P. de Castro, Juliana A. dos Santos, Marcelo M. de Siqueira,
Gabriel M. F. Batista, Hélio F. Dos Santos, and Giovanni W. Amarante
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02099 • Publication Date (Web): 16 Sep 2019
Downloaded from pubs.acs.org on September 16, 2019
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The Quantum Chemical Guided Steglich Rearrangement
of Azlactones and Isoxazolones
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Pedro P. De Castro,‡ Juliana A. Dos Santos,‡ Marcelo M. De Siqueira, Gabriel M. F. Batista, Hélio
F. Dos Santos,* and Giovanni W. Amarante*
Chemistry Department, Federal University of Juiz de Fora, Campus Martelos, Juiz de Fora,
Minas Gerais 36036-900, Brazil.
* helio.santos@ufjf.edu.br
* giovanni.amarante@ufjf.edu.br
‡ These authors contributed equally to this work.
Keywords: Steglich Rearrangement, Isoxazol-5(4H)-one, azlactone, density functional theory
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ABSTRACT GRAPHIC
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ABSTRACT
The theoretical guided evaluation of the Steglich rearrangement of azlactones and isoxazolones
allowed the determination of the reactivity patterns in these heterocycles, including the factors
that drive the regioselectivity towards both possible sites. These results allowed the first
experimental report on the regioselective Steglich rearrangement of isoxazolones, affording the
nitrogen- or carbon-acyloxy adducts.
INTRODUCTION
Organic transformations involving the formation of new carbon-carbon bonds appear
as key reactions in organic synthesis, especially those that allow the formation of new
stereogenic centers.1,2 In this context, Steglich and Höfle described in 1968 the pyridine
catalyzed conversion of 5-carboxyl oxazole into a 4-carboxyl azlactone derivative, a reaction that
was henceforth known as the Steglich rearrangement.3 Since its discovery, this transformation
presented great development, mainly to the use of more nucleophilic organic bases (such as
DMAP and 4-(pyrrolidino)pyridine), to the development of regioselective protocols for the
acyloxy migration4,5 and to the development of asymmetric protocols employing novel chiral
catalysts.6
Concerning the azlactone substrate (also known as oxazol-5(4H)-one), several
methodologies for the Steglich rearrangement have been previous described, noteworthy those
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employing chiral DMAP (Schemes 1A),7–9 co-catalytic methodologies (Scheme 1B)10 and N-
heterocyclic carbene organocatalysts11 Moreover, most reports involves the acyloxy migration
to the azlactone 4-position carbon, although in fewer cases the 2-position migration was also
observed.12,13
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On the other hand, to the best of our knowledge, the same transformation has not been
previously described for isoxazol-5(4H)-one (Scheme 1C). Isoxazolones consist of azlactone
isomers with potential application in medicinal chemistry and organic synthesis.14–16 It is also
worth mentioning that this versatile heterocycle is also present in a variety of natural products.17
Scheme 1. Previous reports of the Steglich rearrangement of azlactones and this study proposal
A)
O
Bn
O
N
Catalyst (10 mol %)
O
O
O
OBn
R1
R1
N
O
Toluene,
20 °C, 1-6 days
O
R2
N
N
R2= OMe, OEt,
OBn or ONm
Catalyst
Ar
Ar
Ar = 4-(MeO)Ph or Ph
R1 = Alkyl or Aryl
Yied: 17-99%
e.e.: 58-95%
O
B)
Co-catalyst (20 mol %)
DMAP (20 mol %)
Ph
CF3
O
O
O
O
R
OPh
S
O
Toluene,
O
N
R
-78 °C, 1-8 h
N
N
Bn
N
N
CF3
H
H
Ar
Ar
O
Co-catalyst
Yield: 49-65%
e.e.: 87-91%
Ar = 3,5-(MeO)Ph
R = Alkyl
This work:
O
C)
O
O
O
Ph
O
O
R
DMAP (10 mol %)
DMAP (20 mol %)
R
OPh
O
N
O
R
N
O
Toluene,
75 °C, 30 min
CH2Cl2,
-25 °C, 11 days
O
Ph
N
Ph
O
Ph
Ph
Right after its development computational methods were only employed as tools to
explain empirical results after they were performed.18 However, the rapid advent of theoretical
chemistry field has made computational modeling more reliable, running into prediction of
reactivities and guiding experimentalists.19
Recently, an interesting study involving the catalytic regiodivergent Steglich
rearrangement of pyrazolyl carbonates was described by Smith’s group.20 Since, our research
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group has been studying the reactivity of oxazolone rings over the last years,21,22 we also got
intrigued with azlactone reactivity in the Steglich rearrangement, that can drive the acyloxy
transfer selectively to one of the reactive sites. With this purpose, we herein present a
theoretical study aiming to provide new insights to explain the behavior of the azlactone ring in
this process. Besides, we also present the first experimental report of the Steglich
rearrangement in isoxazolones and provide a viable explanation for the divergent reactivity of
these heterocycles when compared to azlactones.
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COMPUTATIONAL METHODS
The calculations were performed employing the Gaussian 09 package.23 Unless
otherwise noted, all calculations were performed at a pressure equal to 1 atm and at a
temperature of 298.15 K. All structures, molecular complexes (MCs) and transition states (TSs)
were fully optimized in the gas phase employing the Density Functional Theory (DFT) at the M06-
2X-D3/6-31G(d,p) level of theory.24,25 Vibrational analysis was undertaken to confirm the
identity of all stationary points and to allow the determination of the Gibbs free energy
corrections to the reaction profile. TSs were optimized using the Berny algorithm26 and
confirmed to have only one imaginary frequency (Intrinsic Reaction Coordinates27 were also
calculated and are available in the Supporting Information).
For attainment of the electronic energy at the desired level of theory, single point
energies were then subsequently calculated using the previously optimized geometries at the
M06-2X-D3/6-31++G(d,p) level of theory and the Solvation Model based on Density (SMD) for
toluene. The Gibbs Free Energy of each structure was then calculated by the following equation:
퐺°푠표푙 = 퐸퐺푎푠 + 퐺°푇 + 퐺푆표푙푣
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In which the terms are the Electronic Energy, the thermal correction to enthalpy and
entropy, and solvation Gibbs Free Energy, respectively.
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RESULTS AND DISCUSSION

AZLACTONES
We decided to start our investigation focusing on the azlactone scaffold, aiming to
explain the regioselectivity towards the acyloxy migration. The mechanism for the Steglich
rearrangement of this heterocycle is depicted in Scheme 2. Initially, an O-acylated azlactone (1)
reacts with 4-(dimethylamino)pyridine, transferring the acyloxy group and thus affording an ion-
pairing intermediate. The azlactone enolate formed during this step has three main resonance
forms (2a-c), that after another acyloxy transfer can lead both to C4 (3) or C2 (4) adducts. Almost
the totality of the reports in the literature describes only the formation of 3 and speculatively
evokes steric and/or electronic effects to suggest this regioselectivity. Furthermore, literature
data only describes azlactone acyloxy migration; thus, we also decide to evaluate if other groups,
such as acyl, can also be transferred. To this purpose both acyl (R = Ph and Bn) and acyloxy (R =
OPh and OBn) groups were simulated in the computational data below.
Scheme 2. Mechanism of the Steglich rearrangement of azlactones
O
DMAP
O
O
R
O
O
N
N
Ph
(2b)
Ph
(3)
O
R
O
N
N
O
O
R
N
N
+
+
O
O
N
N
Ph
(2a)
Ph
(1)
R = Ph, Bn,
OPh or OBn
O
O
O
O
O
N
N
Ph
Ph
(4)
DMAP
R
(2c)
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We found that the acyl/acyloxy migration of 1 to the DMAP proceeds through an
elementary transition state (TS1) instead of a stepwise reaction (Figure 1) and that these TSs are
very similar, independent of the substituent. For example, for R = OPh, this asynchronous TS is
structurally closer to the products than to the initial reagents, presenting a C---O bond length of
1.97 Å, much longer than the C---N (1.53 Å). Furthermore, the comparison of this TS structure
with the molecular complexes right before (MC1) and after (MC2) the acyloxy transfer indicates
the concomitant C---N formation (bond lengths 2.71, 1.53 and 1.43 Å, respectively) and C---O
bond cleavage (bond lengths 1.36, 1.97 and 2.52 Å, respectively) (the structure of all molecular
complexes are available in the SI). Another important intermolecular interaction present in all
these structures is the occurrence of π-stacking28 between the azlactone heterocycle moiety and
the DMAP heteroaryl group.
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Figure 1. Transition states involved in the Steglich rearrangement of azlactones. The values in
parenthesis corresponds to the atom distances in the molecular complexes right before and after the
transition states
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Considering the conversion of the initial species (1 + DMAP) into the ion-pairing
intermediate, it is possible to observe that during this step the barriers for the acyloxy migration
is favored over acyl transfer by 2-3 kcal/mol (Table 1 – TS1), what may explain the reason for
their experimental use. On the other hand, although acyl migration presents higher barriers, the
barriers probably are lower enough to be accessed at room temperature/mild heating.
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Table 1. Gibbs Free Energy Variation for the formation of products 3 and 4 based on the acyl/acyloxy
migrating group (kcal/mol)
TS1
TS2
TS3
Substituent (R)
횫퐆ퟏ‡→ퟐ퐚
횫퐆ퟐ‡퐛→ퟑ
횫퐆ퟐ‡퐜→ퟒ
횫퐆ퟏ→ퟐ퐚
횫퐆ퟐ퐛→ퟑ
횫퐆ퟐ퐜→ퟒ
Ph
Bn
OPh
OBn
15.26
15.19
11.97
13.07
10.94
10.33
7.49
10.68
11.28
10.33
11.23
-16.58
-16.52
-19.49
-19.61
14.93
15.93
14.30
15.94
-11.10
-11.14
-12.70
-13.84
7.48
* The barriers were calculated employing the most stable species or conformers: 1, 3 and 4 as the
isolated molecules and 2a-c as molecular complex 2 (MC2).
From this ion-pairing molecular complex (MC2), the reaction can proceed through two
possible pathways, leading to 3 or 4. Before accessing the transition states that would result in
these products, two other conformers of MC2 must be accessed (hereby named MC3 and MC5).
Since these molecular complexes presented higher overall energies than MC2, the barriers for
these TSs were calculated employing the latter.
For the formation of 3, the transition state (TS2) presents a C---C bond length of 2.18 Å
(against 2.79 Å in MC3 and 1.53 Å in the molecular complex between product 3 and DMAP (MC4),
evidencing carbon-carbon bond formation) and a N---C bond length of 1.49 Å (against 1.44 Å in
MC3 and 2.83 Å in MC4, indicating bond cleavage) (Figure 1). These TSs presented barriers
between 10-11 kcal/mol, independent of which substituent was employed (Table 1 – TS2). In all
cases the formation of the final adducts (3) was greatly thermodynamically favored, with ΔG
around -16 kcal/mol for the acyl derivatives and -19 kcal/mol for acyloxy adducts.
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Finally, the formation of product 4 proceeds through a transition state (TS3), in which
the C---C bond is being formed (bond lengths: 3.03 Å (MC5); 2.13 Å (TS3) and 1.55 Å (MC6))
simultaneously to the cleavage of the N---C bond (bond lengths: 1.42 Å (MC5); 1.49 Å (TS3) and
4.46 Å (MC6), leading to a molecular complex between 4 + DMAP (MC6). This TS presents two
important intermolecular interactions: π-stacking between the azlactone enolate moiety and
the DMAP pyridine group and also a noncovalent CH-Aryl interaction (Figure 1). For all
substituents, the barrier for the formation of 4 is considerably higher than for accessing 3
(between 4-5 kcal/mol) and its overall reaction is less favored by 5-7 kcal/mol (Table 1 – TS3).
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An overall reaction profile for the formation of both 3 and 4 is shown in Figure 2. The
association of kinetics and thermodynamic drives the reaction towards product 3 and explains
why almost the totality of the reports of the Steglich rearrangement of azlactones affords only
the C4-product (3). Besides, it is also possible to observe that although the use of acyl instead of
acyloxy-migrating groups might be experimentally possible, the considerably higher barrier
during TS1 would probably require harsh reaction conditions.
Figure 2. Reaction pathway for the formation of products 3 and 4 (R = OPh)
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All simulations realized so far employed alanine derived azlactones, in which the
heterocycle presents a 4-methyl group. Aiming to evaluate if the reaction profile can be altered
by enhancing the steric hindrance at this position (and thus starting to favor product 4 over 3),
this group was substituted for ethyl, isopropyl and tert-butyl analogues and the overall energies
are summarized in Table 2.
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Table 2. Gibbs Free Energy Variation for the formation of products 3 and 4 based on the 4-azlactone
substituent (kcal/mol)
TS1
TS2
TS3
C4-position
Substituenta
횫퐆ퟏ‡→ퟐ퐚
횫퐆ퟐ‡퐛→ퟑ
횫퐆ퟐ‡퐜→ퟒ
횫퐆ퟏ→ퟐ퐚
횫퐆ퟐ퐛→ퟑ
횫퐆ퟐ퐜→ퟒ
Me
Et
iPr
tBu
11.97
12.19
10.41
13.87
7.49
7.24
6.84
10.33
9.42
12.14
16.23
-19.49
-20.22
-19.62
-19.24
14.30
16.37
14.68
14.31
-12.70
-13.75
-13.87
-14.63
10.13
a In all simulations the acyloxy migrating group was defined as OPh. * The barriers were calculated
employing the most stable species or conformers: 1, 3 and 4 as the isolated molecules and 2a-c as
molecular complex 2 (MC2).
It is possible to observe that while the reaction profile is very similar for methyl and
ethyl substituents, the use of a more hindered isopropyl group promotes a slight enhancement
of the TS2 barrier (2-3 kcal/mol), leading to a smaller gap between TS2/TS3 barrier and to a small
regioselectivity towards product 3. This explains why literature rarely describes the Steglich
rearrangement employing valine-based azlactones.7 On the other hand, the use of tert-butyl
substituent completely alters the acyloxy group migration selectivity by enhancing the TS2
barrier by 4-7 kcal/mol, and thus making the formation of product 4 kinetic favored over 3.
Although in all cases the thermodynamic product remains as 3, the use of tBu is an interesting
alternative for future works aiming to develop an enantioselective protocol to access 4.
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
ISOXAZOLONES
We next turned our attention towards the isoxazolone heterocycle. Although the
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Steglich rearrangement of this cycle has never been described, similarly to azlactones it can lead
to two products 7 and 8 (Scheme 3). The main difference in this case is that while in 7 a carbon-
carbon bond is formed, in the case of the adduct 8, a carbamate is formed through a new carbon-
nitrogen bond. Moreover, during the reaction the enolate (6a-c) can delocalize its charge into
the more electron affinity nitrogen atom.
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Scheme 3. Mechanism of the Steglich Rearrangement of isoxazolones
O
DMAP
O
O
R
O
O
N
N
Ph
(6b)
Ph
(7)
O
R
O
N
N
O
O
R
N
N
+
+
O
O
N
N
Ph
(6a)
Ph
(5)
R = Ph, Bn,
OPh or OBn
O
O
O
O
N
N
Ph
O
Ph
DMAP
(6c)
R
(8)
We then simulated these two pathways for the same for acyl/acyloxy migrating groups
previously used for azlactones and the results are summarized in Table 3. It is possible to observe
that in all cases the formation of the ion-pairing intermediate is the rate-limiting step, with
barriers between 14 and 16 kcal/mol. Besides, once again the acyl migration presented slightly
higher barriers for the ion pair formation (1-2 kcal/mol) than the acyloxy groups. This first
transition state (hereby named TS1') is structurally related to the TS1 of azlactones, presenting
π-stacking interactions between the heterocycle moiety and the DMAP pyridine ring (Figure 3).
Furthermore, the comparison of bond distances in MC1', TS1' and MC2' evidences the C---O
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bond cleavage (1.36 Å, 1.80 Å and 2.61 Å, respectively) and C---N bond formation (2.87 Å, 1.58
Å and 1.44 Å, respectively) (the structure of these molecular complexes are available in the SI).
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Table 3. Gibbs Free Energy Variation for the formation of products 7 and 8 based on the acyl/acyloxy
migrating group (kcal/mol)
TS1'
TS2'
TS3'
Substituent (R)
횫퐆ퟓ‡→ퟔ퐚
횫퐆ퟔ‡퐛→ퟕ
횫퐆ퟔ‡퐜→ퟖ
횫퐆ퟓ→ퟔ퐚
횫퐆ퟔ퐛→ퟕ
횫퐆ퟔ퐜→ퟖ
Ph
Bn
OPh
OBn
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15.52
13.78
14.73
8.22
6.02
4.96
4.24
14.11
12.87
11.56
12.95
-10.89
-6.52
-12.76
-12.16
9.43
10.62
9.29
-13.59
-14.15
-11.66
-12.09
8.09
Figure 3. Transition states involved in the Steglich rearrangement of isoxazolones. The values in
parenthesis corresponds to the atom distances in the molecular complexes right before and after the
transition states
From this molecular complex (MC2'), the reaction can proceed to products 7 or 8. In
both cases π-stacking interactions between the isoxazolone moiety and the DMAP pyridine ring
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were found, as well as a CH-aryl interaction in TS3' (Figure 3). The considerable differences in
the barriers (12-14 kcal/mol for TS2' and 9-11 kcal/mol for TS3' suggest that adduct 8 be kinetic
favored during the reaction course and, therefore, could be selectively isolated at lower
temperatures (Figure 4). On the other hand, thermodynamic seems to play a minor role
(especially for acyloxy groups), in some cases driving the reaction towards 7 and in others
towards 8, without great selectivity.
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Figure 4. Reaction pathway for the formation of products 7 and 8 (R = OPh)
A key consideration must be evoked to allow the selective access to 7: while in product
7 the C---C bond is irreversible formed, the carbamate group formed in adduct 8 is susceptible
to DMAP nucleophilic attack (ΔG‡ = 20.95 kcal/mol), restoring the ion-pairing intermediate. Over
time, this would allow the selective access to 7. It is worth mentioning that this would only be
viable if enough energy is provided, thus requiring heating of the reaction mixture.
To sum up, at lower temperatures the kinetic product 8 would be accessed and at higher
temperatures reaction reversibility starts to play a key role and therefore allows the formation
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of 7. To test these hypotheses, we decided to carry out the experimental Steglich rearrangement
of isoxazolones based on computational findings. The desired precursors (13a-e) were prepared
employing a four steps protocol (Scheme 4), which included: 1) oxime formation/intramolecular
cyclization; 2) Knoevenagel condensation with different aldehydes; 3) double-bond reduction;
4) O-acyloxylation.
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Scheme 4. Preparation of intermediates 13a-e
O
O
O
Ar
H
Ar
NH2OH HCl
NaOAc
O
O
Piperidin (5 mol %)
O
O
N
N
EtOH
78 °C, 4 h
Ph
O
Isopropanol,
50 °C, 5-6 h
Ph
Ph
(9)
(11a-e)
17-69% Yield
(10)
96% Yield
NaBH4 (3 equiv)
CH2Cl2
r.t., 5.5-7.5 h
O
O
Ar = Ph
4-OMe(C6H4)
Ph
Ph
O
O
O
O
Cl
4-Cl(C6H4)
3-Cl(C6H4)
2-Cl(C6H4)
NEt3
O
N
O
N
Ar
Ar
THF
0 °C, 2-6 h
Ph
Ph
(13a-e)
42-88% Yield
(12a-e)
87-99% Yield
Next, the Steglich rearrangement was carried out at -25 °C, room temperature (≈25 °C)
and 90 °C to check if our hypothesis is plausible to experimentally occur (full details concerning
the reaction optimization are available in the SI). We observed that at room temperature both
products (14 and 15) are formed without selectivity and in near a 1:1 ratio. The reaction at -25 °C
selectively afforded the desired adducts 15a-d, although, in this case, longer reaction times were
required to complete consumption of the starting material (Scheme 5). Particularly, the kinetic
control perfect explains the reaction selectivity towards this site. Most interesting, the heating
of the reaction completely inverted the regioselectivity, affording only products 14a-e in
moderate to good yields after less than an hour. These results are also in good agreement with
our prediction, suggesting that indeed the reversibility of 15 seem to be involved.
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Scheme 5. Reaction scope towards both reactive sites
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7
8
O
Ph
O
Ph
O
O
O
O
DMAP (10 mol%)
DMAP (20 mol %)
O
O
Ar
O
O
Ar
Toluene
90 ºC, 1 h
CH2Cl2
-25 °C, 11 days
N
Ar
N
9
N
Ph
O
Ph
Ph
OPh
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(13a-e)
Ar = Ph
(14a)
(14b)
(14c)
(14d)
(14d)
Ar = Ph
58%
28%
53%
54%
33%
(15a)
(15b)
(15c)
(15d)
Ar = Ph
28%
4-OMe(C6H4)
4-Cl(C6H4)
3-Cl(C6H4)
2-Cl(C6H4)
4-OMe(C6H4)
4-Cl(C6H4)
3-Cl(C6H4)
2-Cl(C6H4)
4-OMe(C6H4)
4-Cl(C6H4)
3-Cl(C6H4)
33%
18%
15%
Finally, a control experiment was carried out to validate our hypothesis of reaction
reversibility (Scheme 6). To this purpose, product 15a was employed as substrate in the
presence of catalytic DMAP, toluene as solvent, at 90 °C. With this process, we aimed to detect
either 13a and/or 14a after a few minutes, indicating that the ion-pairing intermediate can be
formed through the adduct 15a. To our delight, we observed the formation of product 13a (full
details concerning this control experiment are available in the SI).
Scheme 6. Reaction reversibility investigation.
O
O
DMAP (10 mol%)
Toluene
Ph
O
O
Detected by crude
1H and 13C NMR
analysis
O
N
90 ºC, 1 h
Ph
O
Ph
Ph
O
N
OPh
(15a)
Ph
(13a)
CONCLUSIONS
In summary, the theoretical evaluation of the Steglich rearrangement of azlactones,
aiming to get new insights towards the reaction regioselectivity has been presented. The data
revealed that the C4 products are kinetic and thermodynamic favored over the C2 adduct. The
drastic enhancement in the steric hindrance inverted the reactivity and allowed the access to C2
product. The use of the same model in isoxazolones allowed the prediction of the reactivity of
these cycles, based on kinetic control or reaction reversibility as driving factors. These
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computational findings allowed the first experimental report on the highly regioselective
Steglich rearrangement of isoxazolones, rendering both N2 and C4 adducts in moderate to good
yields.
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EXPERIMENTAL SECTION
General Remarks. All purchased chemicals were employed without further purification.
Solvents were dried according to standard procedures. Thin layer chromatography (TLC) was
performed on TLC plates (silica gel 60 F254) and visualized by a UV lamp; column chromatography
was performed using 230− 400 mesh silica gel. Yields refer to chromatographically purified and
spectroscopically pure compounds. The 1H and 13C NMR spectra were recorded at 500 MHz and
125 MHz, respectively. Chemical shifts for 1H and 13C NMR were reported as δ (parts per million)
relative to the signals of CHCl3 at 7.26 ppm (singlet) and 77 ppm (triplet), respectively. Chemical
shifts are reported employing the following peak abbreviations pattern: br, broad; s, singlet; d,
doublet; dd, double doublet; t, triplet; dt, double triplet; q, quartet; pent, pentet; sext, sextet;
m, multiplet. High resolution mass spectra were acquired in the positive ion mode using a time-
of-flight (TOF) mass spectrometer equipped with an ESI source. Melting points were recorded
on a melting point apparatus.
General Method for the Synthesis of 3-phenylisoxazol-5(4H)-one (10)
3-phenylisoxazol-5(4H)-one was prepared according to the literature method15 and obtained as
a violet solid (3.506 g, 96%).
General procedure for the synthesis of condensed compounds (11a-e)
Condensed compounds were prepared according to the literature method.15
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(Z)-4-(benzylidene)-3-phenylisoxazol-5(4H)-one (11a).15 This compound was isolated by filtration
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as a yellow solid (3.54 g, 69%).
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(Z)-4-(4-methoxybenzylidene)-3-phenylisoxazol-5(4H)-one (11b).30 This compound was isolated
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by filtration as a yellow solid (1.76 g, 68%).
(Z)-4-(4-chlorobenzylidene)-3-phenylisoxazol-5(4H)-one (11c).31 This compound was isolated by
filtration as a yellow solid (1.63 g, 62%).
(Z)-4-(3-chlorobenzylidene)-3-phenylisoxazol-5(4H)-one (11d). This compound was isolated by
flash chromatography on silica gel (Hexanes: EtOAc = 9:1) as an orange solid (0.45 g, 17%). Mp:
135.1-136.0 °C. FT-IR (NaCl, cm-1)  3103, 3065, 2914, 1757, 1617, 1117, 1097. 1H NMR (500 MHz,
CDCl3) : 8.26-8.24 (m, 2H), 7.60-7.53 (m, 7H), 7.45 (t, 1H, J = 7.8 Hz). 13C {1H} NMR (125 MHz,
CDCl3) : 167.8, 163.9, 150.8, 148.9, 135.1, 133.9, 133.8, 132.1, 131.8, 131.7, 131.3, 131.0, 130.3,
130.0, 129.6, 128.8, 128.2, 127.1, 120.4. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H11ClNO2
284.0478, found 284.0467.
(Z)-4-(2-chlorobenzylidene)-3-phenylisoxazol-5(4H)-one (11e).15 This compound was isolated by
flash chromatography on silica gel (Hexanes: EtOAc = 9:1) as a yellow solid (0.97 g, 37%).
General procedure for the synthesis of reduced compounds (12a-e)
The corresponding condensed product (3.52 mmol, 1.0 equiv.) was dissolved in 40.0 mL of CH2Cl2
and then NaBH4 (10.5 mmol, 3.0 equiv.) was added, in small portions. The resultant solution was
stirred at room temperature and monitored by TLC analysis (reaction time between 5.5 and 7.5
hours). After the reaction was complete, the mixture was treated with a 9% aqueous HCl
solution. Then, the organic phase was separated and the aqueous phase extracted once more
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with CH2Cl2. The combined organic phases were dried with anhydrous Na2SO4, filtered and
concentrated under reduced pressure. The resulting crude material was employed in the next
reaction step without further purification and were obtained as a mixture of imine/enamine
tautomers.
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4-benzyl-3-phenylisoxazol-5(4H)-one (12a).31 The product was obtained as a yellow solid (0.98
g, 87%). Reaction time: 5.5 h. Mp: 104.2-105.0 °C. FT-IR (NaCl, cm-1)  3062, 3029, 2912, 2849,
1798, 1693, 1612, 1029. 1H NMR (500 MHz, CDCl3) : 7.60-7.39 (m, 7.7H), 7.27-7.15 (m, 5.7H),
6.87 (dd, 1H, J = 1.65, 1.3 Hz), 4.15 (dd, 0.95H, J = 5.6, 4.8 Hz), 3.76 (s, 0.7H), 3.37 (dd, 1H, J =
14.1, 4.8 Hz), 3.29 (dd, 1H, J = 14.1, 5.6 Hz). 13C {1H} NMR (125 MHz, CDCl3) : 171.7, 173.9, 165.9,
162.9, 138.9, 134.4, 131.9, 131.5, 129.4, 129.3, 129.1, 128.7, 128.2, 127.8, 127.7, 127.6, 127.1,
126.5, 102.1, 46.6, 34.8, 28.2.
4-(4-methoxybenzyl)-3-phenylisoxazol-5(4H)-one (12b).31 The product was obtained as a yellow
solid (1.285 g, 98 %). Reaction time: 7 h. Mp: 110.9-111.8 °C. FT-IR (NaCl, cm-1)  3064, 2932,
1
2835, 1797, 1694, 1612, 1513, 1246, 1033. H NMR (500 MHz, CDCl3) : 7.62-7.60 (m, 1.99H),
7.57-7.54 (m, 1.04H), 7.51-7.44 (m, 3.14H), 7.17-7.14 (m, 0.46H), 6.81-6.76 (m, 2.47H), 6.70-6.67
(m, 1.97H), 4.12-4.10 (m, 0.95H), 3.76-3.73 (m, 4.26H), 3.33 (dd, 1.01H, J = 14.2, 4.6 Hz), 3.24
(dd, 1H, J = 14.2, 5.4 Hz). 13C {1H} NMR (125 MHz, CDCl3) : 177.8, 173.7, 165.9, 162.8, 159.1,
158.3, 132.0, 131.5, 130.3, 129.4, 129.2, 127.9, 127.7, 127.1, 126.3, 114.2, 114.1, 103.4, 55.4,
55.3, 46.9, 34.0, 27.4.
4-(4-chlorobenzyl)-3-phenylisoxazol-5(4H)-one (12c).31 The product was obtained as a yellow
solid (0.977 g, 97 %). Reaction time: 5.5 h. Mp: 115.5-116.6 °C. FT-IR (NaCl, cm-1)  3065, 2814,
1
1796, 1694, 1614, 1491, 1014. H NMR (500 MHz, CDCl3) : 7.60-7.55 (m, 3.2H), 7.52-7.49 (m,
2.5H), 7.47-7.46 (m, 1.7H), 7.23-7.21 (m, 0.95H), 6.80-6.78 (m, 1.9H), 4.15 (dd, 0.98H, J = 5.4, 4.8
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Hz), 3.71 (s, 0.84H), 3.51 (dd, 1.06H, J = 14.1, 4.6 Hz), 3.25 (dd, 1H, J = 14.2, 5.6 Hz). 13C {1H} NMR
(125 MHz, CDCl3) : 177.5, 173.7, 165.6, 163.0, 137.3, 135.3, 133.9, 132.8, 132.4, 132.2, 131.7,
130.6, 129.6, 129.5, 128.9, 128.8, 127.7, 127.6, 127.2, 127.0, 101.9, 46.5, 34.1, 27.6.
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4-(3-chlorobenzyl)-3-phenylisoxazol-5(4H)-one (12d). The product was obtained as a red oil
(0.453 g, 99 %). Reaction time: 7.5 h. FT-IR (NaCl, cm-1)  3063, 2820, 1798, 1692, 1611, 1474,
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1431, 1044. H NMR (500 MHz, CDCl3) : 7.59-7.55 (m,3H), 7.53-7.49 (m, 2.7H), 7.47-7.46 (m,
2.1H), 7.20-7.16 (m, 3.09H), 7.13-7.10 (1.59H), 6.81-6.79 (m, 1.83H), 4.18 (dd, 0.91H, J = 5.7, 4.7
Hz), 3.75 (s, 1.14H), 3.35 (dd, 1.08H, J = 14.1, 4.7 Hz), 3.26 (dd, 1H, J = 14.1, 5.7 Hz). 13C {1H} NMR
(125 MHz, CDCl3) : 177.4, 173.7, 165.7, 163.1, 140.9, 136.4, 134.5, 132.2, 131.7, 130.1, 130.0,
129.6, 129.5, 129.4, 128.3, 128.1, 127.7, 127.6, 127.3, 127.1, 126.9, 126.4, 46.4, 34.3, 27.9.
HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C16H12ClNNaO2 308.0454, found 308.0439.
4-(2-chlorobenzyl)-3-phenylisoxazol-5(4H)-one (12e).32 The product was obtained as a pink solid
(0.182 g, 95 %). Reaction time: 5.5 h. Mp: 113.2-114.9 °C. FT-IR (NaCl, cm-1)  3067, 2927, 2817,
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1801, 1695, 1613, 1445, 1050. H NMR (500 MHz, CDCl3) : 7.57-7.55 (m 2H), 7.49-7.46 (m,
1.75H), 7.43-7.42 (m, 2.15H), 7.40-7.37 (m, 2.14H), 7.35-7.33 (m, 1.5H), 7.24-7.19 (m, 1.6H),
7.17-7.14 (m, 1H), 7.13-7.06 (m, 1.9H), 4.25 (dd, 0.90H, J = 6.7, 8.5 Hz), 3.87 (s, 1H), 3.40 (dd,
0.95H, J = 14.2, 6.7 Hz), 3.21 (dd, 1H, J = 14.2, 8.5 Hz). 13C {1H} NMR (125 MHz, CDCl3) : 177.0,
173.5, 166.7, 163.6, 134.1, 132.7, 132.3, 131.9, 131.7, 129.8, 129.6, 129.5, 129.4, 129.3, 129.2,
128.0, 127.6, 127.5, 127.3, 127.2, 127.1, 101.0, 43.7, 33.8, 26.0.
General procedure for the synthesis of isoxazolone carbonates (13a-e)
Isoxazolone carbonates 13a-e were prepared by adapting a methodology described for
azlactone enol carbonate synthesis.9 To a solution of a reduced intermediate (12a-e) (2.1 mmol,
1.0 equiv.) in THF (18.0 mL, 8.5 mL/mmol of intermediate) at 0 °C, Et3N (2.3 mmol, 1.1 equiv.)
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and phenyl chloroformate (2.3 mmol, 1.1 equiv.) were added, with the formation of a white
precipitate. The resulting mixture was stirred at 0 °C, until no starting material was detected by
TLC (reaction time between 2 and 6 hours). Then, the reaction was washed with H2O and
extracted with Et2O (2x). The combined organic phases were washed with 0.1 M aqueous HCl
solution, 0.1 M aqueous NaHCO3 solution and brine. Then, it was dried with anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The residue was purified through flash
chromatography on silica gel (Hexanes: EtOAc = 95:5 to 80:20) or recrystallization in Hexanes.
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4-benzyl-3-phenylisoxazol-5-yl phenyl carbonate (13a). This compound was isolated by
recrystallization as a white solid (0.58 g, 74%). Reaction time: 2 h. Mp: 100.6-101.9 °C. FT-IR
(NaCl, cm-1)  3062, 3030, 2914, 1776, 1751, 1333, 1212. 1H NMR (500 MHz, CDCl3) : 7.55-7.49
(m, 3H), 7.47-7.45 (m, 2H), 7.38-7.35 (m, 2H), 7.33-7.28 (m, 2H), 7.27-7.21 (m, 4H), 7.22-7.21 (m,
2H), 3.65 (s, 2H). 13C {1H} NMR (125 MHz, CDCl3) : 167.4, 156.6, 149.8, 146.2, 137.9, 129.7, 128.8,
128.7, 128.6, 128.4, 126.9, 120.9, 109.0, 28.3. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for
C23H17NNaO4 394.1055, found 394.1047.
4-(4-methoxybenzyl)-3-phenylisoxazol-5-yl phenyl carbonate (13b). This compound was isolated
by flash chromatography (Hexanes: EtOAc = 90:10) as a white solid (0.69 g, 42%). Reaction time:
6 h. Mp: 118.6-119.5 °C. FT-IR (NaCl, cm-1)  3064, 2911, 2837 1775, 1752, 1513, 1209. 1H NMR
(500 MHz, CDCl3) : 7.54-7.47 (m, 3H), 7.45-7.42 (m, 2H), 7.35-7.32 (m, 2H), 7.24-7.21 (m, 1H),
7.10-7.07 (m, 4H), 6.82-6.81 (m, 1H), 3.78 (s, 3H), 3.55 (s, 2H). 13C {1H} NMR (125 MHz, CDCl3) :
167.5, 158.5, 156.4, 149.8, 146.2, 131.0, 130.0, 129.7, 129.5, 128.8, 128.7, 127.5, 126.7, 120.9,
114.2, 109.4, 55.4, 27.4. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C24H19NNaO5 424.1161, found
424.1148.
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4-(4-chlorobenzyl)-3-phenylisoxazol-5-yl phenyl carbonate (13c). This compound was isolated by
recrystallization as a white solid (1.49 g, 88%). Reaction time: 4 h. Mp: 119.9-121.2 °C. FT-IR
(NaCl, cm-1)  3065, 2922, 2853, 1773, 1750, 1493, 1339, 1214. 1H NMR (500 MHz, CDCl3) : 7.54-
7.51 (m, 1H), 7.50-7.47 (m, 2H), 7.42-7.39 (m, 2H), 7.35-7.31 (m, 2H), 7.25-7.21 (m, 3H), 7.10-
7.07 (m, 4H), 3.57 (s, 2H). 13C {1H} NMR (125 MHz, CDCl3) : 167.3, 156.8, 149.8, 146.1, 136.4,
131.2, 129.8, 129.7, 128.9, 128.8, 128.7, 126.8, 120.9, 108.5, 27.7. HRMS (ESI-TOF) m/z: [M+Na]+
calcd for C23H16ClNNaO4 428.0666, found 428.0658.
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4-(3-chlorobenzyl)-3-phenylisoxazol-5-yl phenyl carbonate (13d). This compound was isolated by
flash chromatography (Hexanes: EtOAc = 95:5 to 80:20) as a pink solid (0.35 g, 62%). Reaction
time: 2 h. Mp: 101.4-102.3 °C. FT-IR (NaCl, cm-1)  3065, 2926, 1775, 1752, 1344, 1307, 1213. 1H
NMR (500 MHz, CDCl3) : 7.52-7.47 (m, 3H), 7.41-7.39 (m, 2H), 7.35-7.32 (m, 2H), 7.24-7.21 (m,
1H), 7.20-7.19 (m, 2H), 7.11-7.07 (m, 3H), 7.06-7.04 (m, 1H), 3.58 (s, 2H). 13C {1H} NMR (125 MHz,
CDCl3) : 167.2, 156.9, 149.8, 139.9, 131.2, 130.1, 129.7, 128.8, 128.6, 128.5, 127.2, 127.1, 126.8,
126.6, 120.9, 108.2, 27.9. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C23H16ClNNaO4 428.0666,
found 428.0665.
4-(2-chlorobenzyl)-3-phenylisoxazol-5-yl phenyl carbonate (13e). This compound was isolated by
recrystallization as a white solid (0.20 g, 77%). Reaction time: 4 h. Mp: 100.3-101.9 °C. FT-IR
(NaCl, cm-1)  3063, 3021, 2921, 1777, 1752, 1630, 1346, 1312, 1213. 1H NMR (500 MHz, CDCl3)
: 7.48-7.45 (m 1H), 7.43-7.40 (m, 2H), 7.38-7.32 (m, 4H), 7.30-7.29 (m, 1H), 7.30 (m, 1H), 7.24-
7.21 (m, 2H), 7.19-7.13 (m, 2H), 7.11-7.09 (m, 2H), 3.76 (s, 2H). 13C {1H} NMR (125 MHz, CDCl3)
: 167.2, 157.4, 149.9, 146.1, 131.0, 130.2, 129.7, 129.6, 128.7, 128.6, 128.3, 127.0, 126.8, 120.9,
107.2, 26.2. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C23H16ClNNaO4 428.0666, found 428.0658.
General procedures for the synthesis of compounds 14a-e
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To a solution of the corresponding isoxazolone carbonates (13a-e) (0.13 mmol, 1.0 equiv.) in 1.0
mL of toluene at 90 °C, 10 mol% of DMAP (0.013 mmol, 0.1 equiv.) was added. The reaction
mixture was stirred at 90 °C in an oil bath for 1 h (monitored by TLC analysis). After that, the
mixture was cooled to room temperature and treated with 10.0 mL of 0.1 M aqueous HCl
solution. The organic phase was separated and concentrated under reduced pressure. The crude
Steglich rearrangement products were purified through flash chromatography on silica gel
(Hexanes: EtOAc = 9:1).
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Phenyl-4-benzyl-5-oxo-3-phenyl-4,5-dihydroisoxazole-4-carboxylate (14a). This compound was
isolated as a colorless oil (29 mg, 58%). FT-IR (NaCl, cm-1)  3067, 3032, 2929, 1803, 1765, 1589,
1493 1180. 1H NMR (500 MHz, CDCl3) : 7.78-7.76 (m, 2H), 7.72-7.70 (m, 1H), 7.57-7.54 (m, 2H),
7.39-7.35 (m, 2H), 7.28-7.27 (m, 1H), 7.25-7.22 (m, 1H), 7.19-7.16 (m, 2H), 7.01-6.99 (m, 2H),
6.88-6.86 (m, 2H), 3.77 (d, 1H, J = 14.1 Hz), 3.70 (d, 1H, J = 14.1 Hz).13C {1H} NMR (125 MHz,
CDCl3) : 174.4, 163.9, 163.1, 150.0, 132.6, 131.9, 129.8, 129.8, 129.7, 128.8, 128.3, 127.4, 127.1,
126.7, 120.9, 62.7, 38.5. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C23H17NNaO4 394.1055, found
394.1047.
Phenyl-4-(4-methoxybenzyl)-5-oxo-3-phenyl-4,5-dihydroisoxazole-4-carboxylate (14b). This
compound was isolated as a colorless oil (15 mg, 28%). FT-IR (NaCl, cm-1)  3044, 2935, 2838,
1800, 1763, 1612, 1513, 1446, 1254, 1179. 1H NMR (500 MHz, CDCl3) : 7.78-7.77 (m, 2H), 7.63-
7.60 (m, 1H), 7.56-7.53 (m, 2H), 7.38-7.34 (m, 2H), 7.27-7.24 (m, 1H), 7.00-6.98 (m, 2H), 6.80-
6.78 (m, 2H), 6.70-6.69 (m, 2H), 3.74 (s, 3H), 3.73 (d, 1H, J = 14.2 Hz), 3.65 (d, 1H, J = 14.2 Hz).
13C {1H} NMR (125 MHz, CDCl3) : 174.4, 163.9, 163.2, 159.5, 150.0, 132.5, 130.8, 129.8, 129.7,
127.4, 127.0, 126.7, 123.8, 120.9, 114.2, 62.8, 55.3, 37.8. HRMS (ESI-TOF) m/z: [M+Na]+ calcd for
C24H19NNaO5 424.1161, found 424.1155.
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Phenyl-4-(4-chlorobenzyl)-5-oxo-3-phenyl-4,5-dihydroisoxazole-4-carboxylate
(14c).
This
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compound was isolated as a colorless oil (28 mg, 53%). FT-IR (NaCl, cm-1)  3065, 2922, 2853,
1803, 1765, 1589, 1493, 1228, 1181. 1H NMR (500 MHz, CDCl3) : 7.74-7.72 (m, 2H), 7.61-7.58
(m, 1H), 7.54-7.51 (m, 2H), 7.40-7.32 (m, 2H), 7.25-7.22 (m, 1H), 7.13-7.11 (m, 2H), 6.97-6.95 (m,
2H), 6.78-6.76 (m, 2H), 3.69 (d, 1H, J = 14.2 Hz), 3.63 (d, 1H, J = 14.2 Hz). 13C {1H} NMR (125 MHz,
CDCl3) : 174.2, 163.7, 162.9, 152.2, 151.1, 150.0, 134.4, 132.7, 131.0, 130.5, 129.9, 129.8, 129.7,
129.1, 127.2, 127.1, 126.6, 126.4, 121.0, 120.9, 62.5, 37.8. HRMS (ESI-TOF) m/z: [M+Na]+ calcd
for C23H16ClNNaO4 428.0666, found 428.0657.
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Phenyl-4-(3-chlorobenzyl)-5-oxo-3-phenyl-4,5-dihydroisoxazole-4-carboxylate
(14d).
This
compound was isolated as a colorless oil (29 mg, 54%). FT-IR (NaCl, cm-1)  3065, 2930, 1800,
1764, 1598, 1492, 1204, 1183. 1H NMR (500 MHz, CDCl3) : 7.76-7.73 (m, 2H), 7.65-7.62 (m, 1H),
7.58-7.55 (m, 2H), 7.39-7.36 (m, 2H), 7.29-7.27 (m, 1H), 7.23-7.21 (m, 1H), 7.14-7.11 (m, 1H),
7.02-7.00 (m, 2H), 6.80 (d, 1H, J = 7.7 Hz), 6.77 (t, 1H, J = 1.7 Hz), 3.71 (d, 1H, J = 14.1 Hz), 3.64
(d, 1H, J = 14.1 Hz). 13C {1H} NMR (125 MHz, CDCl3) : 174.1, 163.6, 162.9, 150.0, 134.6, 133.9,
132.8, 130.2, 129.9, 129.8, 128.6, 127.8, 127.2, 127.1, 126.7, 120.9, 62.4, 37.9. HRMS (ESI-TOF)
m/z: [M+Na]+ calcd for C23H16ClNNaO4 428.0666, found 428.0666.
Phenyl-4-(2-chlorobenzyl)-5-oxo-3-phenyl-4,5-dihydroisoxazole-4-carboxylate
(14e).
This
compound was isolated as a yellow oil (18 mg, 33%). FT-IR (NaCl, cm-1)  3066, 2925, 2850, 1803,
1765, 1592, 1493, 1231, 1179. 1H NMR (500 MHz, CDCl3) : 7.69-7.68 (m, 2H), 7.54-7.51 (m, 1H),
7.46-7.42 (m, 2H), 7.40-7.37 (m, 2H), 7.35-7.32 (m, 2H), 7.25-7.22 (m, 2H), 7.20-7.18 (m, 1H),
7.15-7.10 (m, 1H), 6.96-6.95 (m, 1H), 3.96 (d, 1H, J = 14.6 Hz), 3.90 (d, 1H, J = 14.6 Hz). 13C {1H}
NMR (125 MHz, CDCl3) : 174.1, 164.0, 163.5, 151.1, 150.0, 135.1, 132.4, 131.6, 130.5, 130.0,
129.8, 129.7, 129.6, 129.5, 127.3, 127.2, 127.1, 126.9, 126.4, 121.1, 120.9, 61.5, 34.8. HRMS (ESI-
TOF) m/z: [M+Na]+ calcd for C23H16ClNNaO4 428.0666, found 428.0659.
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To a solution of the corresponding isoxazolone carbonates (13a-d) (0.13 mmol, 1.0 equiv.) in 1.0
mL of toluene, 20 mol% of DMAP (0.026 mmol, 0.2 equiv.) was added. The reaction mixture was
maintained at -25 °C for 11 days (monitored by TLC analysis). The mixture was then treated with
10.0 mL of 0.1 M aqueous HCl solution. The organic phase was separated and concentrated
under reduced pressure. The crude reaction mixtures were purified through flash
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Phenyl-4-benzyl-5-oxo-3-phenylisoxazole-2(5H)-carboxylate (15a). This compound was isolated
as a colorless oil (14 mg, 28%). FT-IR (NaCl, cm-1)  3066, 3034, 2921, 2850, 1810, 1767, 1494,
1262, 1086. 1H NMR (500 MHz, CDCl3) : 7.89-7.88 (m, 2H), 7.61-7.52 (m, 1H), 7.55-7.52 (m, 2H),
7.36-7.33 (m, 2H), 7.28-7.27 (m, 1H), 7.24-7.20 (m, 3H), 7.12-7.10 (m, 2H), 6.96-6.94 (m, 2H),
3.60 (d, 1H, J = 13.2 Hz), 3.56 (d, 1H, J = 13.2 Hz). 13C {1H} NMR (125 MHz, CDCl3) : 173.4, 161.2,
151.2, 150.7, 132.6, 130.4, 129.8, 129.7, 129.4, 129.2, 128.9, 128.7, 126.9, 126.6, 126.5, 120.6,
82.4, 41.5. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C23H17NNaO4 394.1055, found 394.1049.
Phenyl-4-(4-methoxybenzyl)-5-oxo-3-phenylisoxazole-2(5H)-carboxylate (15b). This compound
was isolated as a colorless oil (18 mg, 33%). FT-IR (NaCl, cm-1)  3035, 2932, 2838, 1812, 1768,
1614, 1514, 1255, 1085. 1H NMR (500 MHz, CDCl3) : 7.91-7.89 (m, 2H), 7.61-7.58 (m, 1H), 7.55-
7.52 (m, 2H), 7.36-7.32 (m, 2H), 7.25-7.22 (m, 1H), 7.12-7.10 (m, 2H), 6.87-6.85 (m, 2H), 6.75-
6.72 (m, 2H), 3.75 (s, 3H), 3.55 (d, 1H, J = 13.4 Hz), 3.51 (d, 1H, J = 13.4 Hz). 13C {1H} NMR (125
MHz, CDCl3) : 173.5, 161.3, 159.8, 151.3, 150.7, 132.6, 131.5, 130.6, 129.8, 129.7, 129.0, 128.7,
128.1, 126.9, 126.6, 120.9, 120.6, 114.3, 114.2, 113.9, 82.4, 55.3, 40.7. HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C24H19NNaO5 424.1161, found 424.1155.
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Phenyl-4-(4-chlorobenzyl)-5-oxo-3-phenylisoxazole-2(5H)-carboxylate (15c). This compound was
isolated as a colorless oil (10 mg, 18%). FT-IR (NaCl, cm-1)  3063, 2925, 2852, 1811, 1765, 1492,
1263, 1087. 1H NMR (500 MHz, CDCl3) : 7.90-7.87 (m, 2H), 7.63-7.59 (m, 1H), 7.56-7.53 (m, 2H),
7.37-7.32 (m, 2H), 7.24-7.23 (m, 1H), 7.21-7.18 (m, 2H), 7.12-7.10 (m, 2H), 6.90-6.87 (m, 2H),
3.55 (d, 1H, J = 13.4 Hz), 3.52 (d, 1H, J = 13.4 Hz). 13C {1H} NMR (125 MHz, CDCl3) : 173.1, 161.1,
151.2, 150.7, 134.9, 132.7, 131.7, 129.8, 129.7, 129.1, 127.7, 127.0, 126.5, 126.4, 120.6, 82.0,
40.8. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C23H16ClNNaO4 428.0666, found 428.0661.
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Phenyl-4-(3-chlorobenzyl)-5-oxo-3-phenylisoxazole-2(5H)-carboxylate (15d). This compound
was isolated as a colorless oil (8 mg, 15%). FT-IR (NaCl, cm-1)  3067, 2925, 2853, 1811, 1768,
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1598, 1493, 1265, 1089. H NMR (500 MHz, CDCl3) : 13C {1H} NMR (125 MHz, CDCl3) : 7.88-
7.86 (m, 2H), 7.63-7.60 (m, 1H), 7.57-7.53 (m, 2H), 7.37-7.33 (m, 2H), 7.27-7.23 (m, 2H), 7.18-
7.15 (m, 1H), 7.13-7.11 (m, 2H), 6.90-6.87 (m, 2H), 3.52 (br, 2H). 13C {1H} NMR (125 MHz, CDCl3)
: 173.0, 161.1, 151.2, 150.7, 134.6, 132.8, 131.2, 130.5, 130.1, 129.8, 129.7, 129.0, 128.6, 127.0,
126.5, 126.4, 120.6, 81.9, 40.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C23H16ClNNaO4 428.0666,
found 428.0663.
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Supporting Information
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Reaction optimization data, reaction reversibility study, copies of H NMR, 13C NMR, and IR
spectra for all compounds, Molecular complexes structures, Cartesian coordinates and total
energy data for all stationary points on the potential energy surface.
AUTHOR INFORMATION

Corresponding Authors
* helio.santos@ufjf.edu.br
* giovanni.amarante@ufjf.edu.br

ORCID
Pedro Pôssa de Castro: 0000-0002-3018-3130
Giovanni Wilson Amarante: 0000-0003-1004-5395

Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
We are grateful for generous financial support from CAPES (Finance Code 001), CNPq, FAPEMIG,
and Rede Mineira de Química. Furthermore, we are grateful to Beatriz Rocha de Moraes
(Chemistry Department/UFJF) for helpful contributions concerning the IR analyses and Prof.
Giuliano Clososki and Thiago Santos (FCFRP-USP) for all their help with HRMS analyses. We thank
Dr. Danielle Pinheiro for initial studies.
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