Asymmetric conjugate addition reactions with chiral oxadiazinones: Unusual conformational properties of the oxadiazinones

Article abstract of DOI:10.1016/j.tet.2021.132002

A series of Ephedra based oxadiazinones have been prepared, acylated, and examined in the asymmetric conjugate addition reaction with Grignard reagents in the presence of copper(I) bromide-dimethyl sulfide complex. The highest diastereoselectivity that was obtained in the conjugate addition reaction was observed with the (1R,2S)-ephedrine based N₄-methyloxadiazinone (5:1 d.r.) favoring the formation of the (S)-configuration of the conjugate addition product. Efforts to enhance the level of diastereoselection via increasing the steric volume of the stereo-directing N₄-substituent of the oxadiazinone (N₄- = p-methoxyphenyl or -isopropyl) led to an observed decrease in the level of diastereoselection. A computational study was conducted to examine the conformations adopted by the N₄-methyloxadiazinone vs. the N₄-isopropyl-oxadiazinone that yielded the lower diastereoselectivity. An argument is made for the stereoelectronic properties of the N₄-substituent being the cause of both the moderate diastereoselectivity and the unexpected facial preference for the conjugate addition.

Full text of DOI:10.1016/j.tet.2021.132002

Tetrahedron 83 (2021) 132002
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Tetrahedron
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Asymmetric conjugate addition reactions with chiral oxadiazinones:
Unusual conformational properties of the oxadiazinones
Fatima Olayemi Obe, Ryan A. Davis, Jennifer Spurlock, Morgan M. Grunloh Barnes,
Tyler Lindvall, Micah S. Wendorf, Christina Delach, Gregory M. Ferrence,
Jean M. Standard**, Shawn R. Hitchcock*
Department of Chemistry, Illinois State University, Normal, IL, 61790-4160, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of Ephedra based oxadiazinones have been prepared, acylated, and examined in the asymmetric
conjugate addition reaction with Grignard reagents in the presence of copper(I) bromide-dimethyl
sulfide complex. The highest diastereoselectivity that was obtained in the conjugate addition reaction
was observed with the (1R,2S)-ephedrine based N4-methyloxadiazinone (5:1 d.r.) favoring the formation
of the (S)-configuration of the conjugate addition product. Efforts to enhance the level of diaster-
eoselection via increasing the steric volume of the stereo-directing N4-substituent of the oxadiazinone
(N4- ¼ p-methoxyphenyl or -isopropyl) led to an observed decrease in the level of diastereoselection. A
computational study was conducted to examine the conformations adopted by the N4-methylox-
adiazinone vs. the N4-isopropyl-oxadiazinone that yielded the lower diastereoselectivity. An argument is
made for the stereoelectronic properties of the N4-substituent being the cause of both the moderate
diastereoselectivity and the unexpected facial preference for the conjugate addition.
Received 26 November 2020
Received in revised form
25 January 2021
Accepted 2 February 2021
Available online 12 February 2021
Keywords:
Oxadiazinone
Chiral auxiliary
Asymmetric conjugate addition
Conformational analysis
Computational
© 2021 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of the Lycopodium alkaloid Lycopoclavamine-A (8) via an
asymmetric conjugate addition (Scheme 1) [18]. The ratio of di-
The stereoselective formation of new carbon-carbon bonds by
the process of asymmetric conjugate addition represents an
important class of reactions in synthetic organic chemistry [1].
While catalytic methods in asymmetric conjugate addition re-
actions have become dominant [2e4] chiral auxiliary mediated
reactions are still employed to achieve the goal of diaster-
eoselective bond formation [5e7]. Evans’oxazolidinones have
proven to be the most versatile chiral auxiliaries for this process
[8e15]. In this context, Mullins and coworkers were able to employ
the Evans’ auxiliary in an efficient synthesis of the individual en-
antiomers of Pilosinine (3) using an enantiodivergent process
originating from a single chiral oxazolidinone [16]. In 2019, Ortiz
astereomers that was obtained in the oxazolidinone directed con-
jugate addition was 94:6 favoring the desired isomer. The synthesis
of this key fragment allowed Takayama and coworkers to complete
the synthesis of their target with a key remote stereocenter set by
the conjugate addition. Based on the success of the Evans’ oxazo-
lidinones as chiral auxiliaries in conjugate addition reactions, we
became interested in exploring the application of 3,4,5,6-
tetrahydro-2H-1,3,4-oxadiazin-2-ones (oxadiazinones, 9) in these
same reactions. Oxadiazinones are aza-homologs of the Evans’
auxiliary and the additional nitrogen can be exploited as a stereo-
chemical control element in asymmetric aldol addition reactions
(Scheme 2) [19e24].
and coworkers [17] were able to synthesize a series of
g
-amino
The asymmetric induction in these reactions is proposed to
originate from the presence of the stereogenic N4-nitrogen sub-
stituent. Based on this assessment, it was proposed that the oxa-
diazinones might be viable chiral auxiliaries for the process of
asymmetric conjugate addition (Fig.1). It was further proposed that
a series of oxadiazinones could be prepared wherein the N4-ni-
trogen position could be modified to have an increasing steric de-
mand as a means of improving the level of diastereoselection. Thus,
a series of oxadiazinones were prepared for this process and then
acids (3) by the application of the Evans’ auxiliary in the asym-
metric conjugate addition reactions in diastereoselectivities
ranging from 96:4 to 98:2 (Scheme 1). In another recent example,
Takayama and coworkers employed the Evans’ oxazolidinone in the
* Corresponding author.
** Corresponding author.
E-mail address: srhitch@ilstu.edu (S.R. Hitchcock).
https://doi.org/10.1016/j.tet.2021.132002
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Scheme 1. Oxazolidinones as chiral auxiliaries in asymmetric conjugate addition.
tested in the process of conjugate addition.
coupled with trans-cinnamic acid via the use of 1-ethyl-3-(3-
dimethylamino propyl)carbodiimide (EDC) and DMAP in
dichloromethane (Scheme 3). The N4-trans-cinnamoylox-
adiazinone was obtained in 71% isolated yield after chromatog-
raphy. This product was then subjected to asymmetric conjugate
addition reaction with methylmagnesium bromide and copper(I)
bromide-dimethylsulfide complex at ꢀ78 ꢁC. The addition product
2. Results and discussion
The (1R,2S)-ephedrine based oxadiazinone 9a which had been
initially employed in the asymmetric aldol addition reaction was
prepared as previously described [24a]. This material was then
2

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Scheme 2. Oxadiazinones as chiral auxiliaries in the asymmetric aldol addition reaction.
coworkers conducted solution studies using ultrafast two-
dimensional infrared spectroscopy to suggest that the oxazolidi-
nones adopt the coordinated syn-s-cis-17 conformation during the
course of coordination with magnesium salts [25]. The anti-s-cis-17
conformation is also viable, but this conformation is more prevalent
with use of alternate reagents [25]. The syn-s-trans-17 and anti-s-
trans-17 conformations are not as populated due primarily to steric
interactions.
Using the Evans’ model of the asymmetric conjugate addition,
the expected product would have been the anti-addition pathway
leading to the formation of (R)-15. However, as described above, the
product was unambiguously assigned as the syn-addition product
(S)-15. This would suggest that either the anti-s-cis-14a conformer
or the syn-s-trans-14a conformer or some combination thereof
leads to the formation of the observed diastereomeric mixture of
products that favor the predominant formation of the (S)-stereo-
center (Scheme 5).
A NOESY spectrum of 14a suggested that the anti-s-cis-confor-
mation was the dominant form of the oxadiazinone as there was no
Fig. 1. Oxadiazinones as potential chiral auxiliaries for conjugate addition reactions.
observable NOE between the N4-methyl group and the b-proton of
was isolated as a 5:1 diastereomeric mixture of diastereomers as
determined by integration of the well-resolved NMR spectral sig-
the N3-cinnamoyl side chain (Fig. 2). In addition to the solution
state conformational analysis, an X-ray crystal structure was ob-
tained for 14a (Fig. 2). The crystal structure revealed in the solid
state, that the carbonyl groups adopt an anti-conformation with a
dihedral bond angle of ꢀ142.6ꢁ and the N3-cinnamoyl side-chain
retained its s-cis conformation. It is noted that while the X-ray
crystal structure is in agreement with the conformation suggested
by the NOE experiment, it is a reflection of the dominant confor-
mation in the solid state and may be the result of crystal packing
forces.
A conformational study was conducted involving the proposed
conformations of oxadiazinone 14a. Initial structures were gener-
ated using the MMFF94 molecular mechanics force field [26] within
the GMMX conformational searching facility of the GaussView 6.1
software package [27]. Over 50 potential conformers were then
nals of the methyl group (diastereomer 1,
d
¼ 0.59 ppm; diaste-
reomer 2,
d
¼ 0.82 ppm) of the appendant N3-acyl side chain. The
diastereomeric products could not be readily separated by flash
chromatography and the products were not crystalline so that
single crystal X-ray crystallography was not a viable option. Thus,
the absolute stereochemistry of the dominant stereoisomer was
unambiguously determined by the coupling of the (1R,2S)-ephed-
rine based oxadiazinone with enantiomerically enriched (S)-3-
phenylbutanoic acid using EDC and DMAP. Comparative analysis
of the 500 MHz 1H NMR spectrum of the crude conjugate addition
product and the coupling reaction with the enantiomerically
enriched 3-phenylbutanoic acid revealed that the diastereomer
possessing the (S)-stereocenter for the conjugate addition was
indeed the dominant diastereomer (Scheme 3).
optimized at the
u
b97x-D/6e311þþG(d,p) level of theory in the
There was a question of whether the application of different
Grignard reagents to the oxadiazinone ring system via conjugate
addition would yield improved results. Thus N3-crotonyl- oxadia-
zinone 14b was prepared (LiH, trans-crotonoyl chloride) from 9a
and reacted with a series of Grignard reagents (EtMgBr, C6H5MgBr,
and p-CH3OC6H4MgBr) in the presence of copper(I) bromide
dimethylsulfide complex. The diastereoselectivities ranged from
67:33 to 72:28 favoring the mode of stereochemical addition that
was observed in the application of oxadiazinone 14b.
This result of obtaining the (S)-conformation via the asymmetric
conjugate addition was somewhat unexpected as the related Evans’
oxazolidinones are known to predominantly form the product in
which the addition pathway is the anti-addition (leading to anti-18)
via the syn-s-cis-conformation of the acylated oxazolidinone sys-
tem when Grignard reagents are used in conjunction with copper(I)
reagents (Scheme 4). In this context, Schreiner, Bredenbeck and
gas phase and in solution using the Polarizable Continuum Model
(PCM) for solvation with a dielectric constant corresponding to
chloroform. The Gaussian 09 software package [28] was utilized for
all the gas and solution phase density functional theory
calculations.
The computational study revealed that the lowest energy
conformer in the gas phase and the solution phase corresponded to
an anti-s-cis conformation of oxadiazinone 14a, in accord with the
NOESY and X-ray crystal structure results; this finding holds for
both the gas and solution phase results. The lowest energy con-
formers of each type (anti-s-cis, anti-s-trans, syn-s-cis, and syn-s-
trans) of oxadiazinone 14a are shown in Figs. 3 and 4 for the gas and
solution phases, respectively, along with key dihedral angles
defining the conformations. Table 1 presents the first 20 con-
formers found in the gas phase ordered in terms of total energy,
while Table 2 provides a similar summary of the solution phase
3

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Scheme 3. Acylation and conjugate addition using oxadiazinone 9a.
Scheme 4. Potential conformations for oxazolidinones in conjugate additions.
results. In addition, Table 1 provides the gas phase dipole moments
of each of the conformers. Based on the collected results described
in Tables 1 and 2, the ordering of the relative energies of the con-
formations is: anti-s-cis < syn-s-cis < anti-s-trans < syn-s-trans. In
the gas phase, the separation in energy between the lowest anti-s-
cis and syn-s-cis conformers (Table 1, entries 1 and 2, respectively)
is 2.4 kcal/mol, but drops to 0.6 kcal/mol in solution phase (Table 2,
entries 1 and 2, respectively). This is a result of stabilization in polar
solvent of the highly polar syn-s-cis conformation, which possesses
a gas phase dipole moment of more than 7 Debye, much larger than
4

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Scheme 5. Proposed mechanistic pathway of conjugate addition with oxadiazinone 14a.
the dipole moments of the anti-conformations, which range from
about 1 to 4 Debye. Similarly, the higher-energy syn-s-trans
conformation (conformer 14 in the gas phase), with a gas phase
dipole moment of 8.0 Debye, is significantly stabilized in solution
relative to the anti-conformations and drops in energy from
8.0 kcal/mol in the gas phase to 5.1 kcal/mol in solution.
using the PCM solvation model for chloroform as described
previously.
It was observed that although the anti-s-cis-14a conformation is
lowest in energy in the gas and solution phases by a small amount
(0.6e2.4 kcal/mol) when un-complexed, the syn-s-cis-14a confor-
mation corresponds to the lowest energy structure when inter-
acting with MgBr2. The extra lowering in the energy for the syn
conformation comes as a result of the coordination of the magne-
sium to both carbonyl groups (Fig. 5).
Additional stabilization was also observed for anti-s-cis-14a-
MgBr2 due to interaction of the magnesium with the nearby N4-
nitrogen atom, although there is a longer magnesium-nitrogen
bond of 2.40 Å. Natural Bond Orbital (NBO) analysis [29] was
employed to confirm the interaction between the N4-nitrogen and
magnesium. Using NBO deletion analysis, the energy stabilization
of anti-s-cis-14a due to the N4eMg interaction was found to be
8.6 kcal/mol. In comparing these two structures, the syn-s-cis-14a-
MgBr2 conformation is more stable than the anti-s-cis-14a-MgBr2
conformation by 6.9 kcal/mol.
Despite the higher stability of the syn-s-cis-14a-MgBr2 confor-
mation, it is proposed that the anti-s-cis-14a-MgBr2 conformer is
more readily formed from the calculated initial conformation of the
un-complexed anti-s-cis-14a because there is no need for a
conformation change for complexation (the energetic cost for
conversion from anti-s-cis to syn-s-cis via transition state in solu-
tion was calculated to be 6.7 kcal/mol at the B3LYP/6-31G(d) level,
which is nearly the difference in energy between the two con-
formers). Thus, if the anti-s-cis conformation for 14a is the domi-
nant conformational form in solution, and if it is retained in the
course of the conjugate addition, then a Re-face attack would be the
preferred reaction pathway, and this would lead to the formation of
the observed (S)-stereocenter (Scheme 6).
Two of the key geometrical parameters describing the orienta-
tion of oxadiazinone 14a include the O25eC2eC15eO24 dihedral
angle (which will be referred to as O]CeNeC]O) using the X-ray
crystal structure numbering. For the lowest energy conformer of
each type, these dihedral angles change only a small amount in
solution phase relative to the gas phase values, as illustrated in
Figs. 3 and 4. For the lowest energy anti-s-cis conformer in gas and
solution phases (conformer 1 in both cases), the carbonyl groups
deviate from the ideal anti-parallel orientation of 180ꢁ, with O]
CeNeC]O dihedrals in the range of ꢀ142 to ꢀ146ꢁ. Similarly, the
lowest energy syn-s-cis conformer in gas and solution phases
(conformer 2 in both cases) exhibit O]CeNeC]O dihedral angles
that deviate from the ideal parallel carbonyl orientation of 0ꢁ, with
dihedrals in the range 26e31ꢁ. The conformations that tend to be
higher in energy, anti-s-trans and syn-s-trans, exhibit O]CeNeC]
O dihedral angles that show even greater deviations from the ex-
pected ideal O]CeNeC]O orientations ( 180ꢁ). Deviations from
the ideal dihedral angles for the lowest energy structures of the
anti-s-trans and syn-s-trans conformations are as large as 61ꢁ for
the O]CeNeC]O dihedral angle. These larger deviations are
reflective of more strain in the anti-s-trans and syn-s-trans confor-
mations, resulting in higher relative energies overall.
While these conformational studies provided a foundation of a
potential rationale for the observed stereochemical outcome
(Scheme 3), there was an interest in further evaluating the conju-
gate addition with oxadiazinone 14a in greater detail with the
putative coordinating MgBr2 derived from the Grignard reagent
combined with copper(I) bromide-dimethyl sulfide complex. Thus,
the lowest-energy solution phase anti-s-cis-14a and syn-s-cis-14a
conformers were allowed to coordinate with MgBr2 (Fig. 5) and the
resulting structures were optimized at the B3LYP/6-31G(d) level
In order to further study the chemical behavior of the oxadia-
zinones in the asymmetric conjugate addition reaction, (1S,2S)-
pseudoephedrine was employed. The (1S,2S)-pseudo ephedrine
oxadiazinone was prepared as previously described [24b]. The
oxadiazinone was coupled with trans-cinnamic acid to afford the
5

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Fig. 2. NOESY study and X-ray crystal structure of oxadiazinone 14a.
N3-trans-cinnamoyl derivative 18 in 59% isolated yield (Scheme 7).
In contrast to the diastereomeric (1R,2S)-ephedrine based oxadia-
zinone 14a, this oxadiazinone exhibited pyramidal inversion at the
N4-nitrogen that was evident from line broadening observed in the
125 MHz 13C NMR spectrum of 18 at the N4- and C5-positions
(Fig. 6). Such conformational motion had been previously reported
by our research group; variable temperature studies in the earlier
study suggested that pyramidal inversion was the key mode of
dynamic motion [24b]. Attempts to conduct conjugate addition
reactions with 19 led to the formation of (R/S)-20 as a mixture of
diastereomers that could not be evaluated due to line broadening.
Attempts to conduct an acid catalyzed hydrolysis to recover the 3-
phenylbutyric acid hydrolysis product were also met with failure.
At this stage, it was apparent that the pseudoephedrine based
system would not be a viable candidate for the asymmetric con-
jugate addition.
prepared as previously described [19]. This oxadiazinone was
acylated with trans-cinnamic acid using a carbodiimide approach
employing EDC and DMAP to yield the N3-trans-cinnamoylox-
adiazinone 25 (R
chromatography.
¼
Ph-) in 80% isolated yield after flash
In a similar fashion, oxadiazinone 24 was treated with sodium
hydride and acylated with trans-crotonoyl chloride to yield the N3-
trans-crotonoyloxadiazinone 26 (R ¼ eCH3) in 51% isolated yield.
Oxadiazinone 25 was then subjected to the conjugate addition re-
action by treatment with methylmagnesium bromide and copper(I)
bromide dimethylsulfide complex to yield a 3:1 ratio of di-
astereomers in 60% yield as illustrated in Scheme 8. The diaste-
reomeric ratio was determined from the well-resolved doublets
associated with the methyl group of the N3-side chain appearing at
0.58 ppm and 0.72 ppm.
There was an interest in determining the ratio of diastereomers
in the opposing structural case in which the N3-substiuent was a
crotonoyl group (oxadiazinone 26) and the added Grignard reagent
was phenylmagnesium bromide (Scheme 8). The end result was
that the observed level of diastereoselection was the same as it had
been when the N3-substituent was a trans-cinnamoyl group and the
added Grignard reagent was methylmagnesium bromide, i.e. 3:1.
This finding suggested that the size of the Grignard reagent did not
have a direct impact on the level of diastereoselection. Moreover,
this observation reinforced the fact that the diastereoselectivity of
the conjugate addition had been better in the case of the (1R,2S)-
In an effort to improve the level of diastereoselection in the
oxadiazinone mediated asymmetric conjugate addition, an alter-
nate oxadiazinone structure was pursued. The use of a (1R,2S)-
norephedrine
based
N4-p-methoxybenzyl-N3-propanoylox-
adiazinone 23 had been successfully employed in the asymmetric
aldol addition reaction with a variety of aldehydes to yield dia-
stereoselectivities ranging from 85:15 to 95:5 (Scheme 8).
It was reasoned that the increased steric volume of the N4-p-
methoxybenzyl group would offer an improved diastereoselectivity
in the conjugate addition reaction. To this end, oxadiazinone 24 was
6

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Fig. 3. Lowest energy gas phase conformers of oxadiazinone 14a,
CeC]C dihedral angle corresponds to O24eC15eC16eC17, using the X-ray crystal structure numbering.
u
b97x-D/6e311þþG(d,p) level. The O]CeNeC]O dihedral angle corresponds to O25eC2eC15eO24 and the O]
ephedrine based oxadiazinone where the diastereoselectivity was
measured to be 5:1.
considerable in its steric demand, it was still considered to be a
primary substituent. Thus, a secondary substituent was proposed
as a means of probing the cause of the lower diastereoselectivity
with the N4-p-methoxybenzyl system and a potential means of
increasing the diastereoselection in the oxadiazinone mediated
conjugate addition reaction. To this end, (1R,2S)-norephedrine was
used to create the N4-isopropyloxadiazinone (30) as previously
described [23]. This oxadiazinone was acylated by treatment with
lithium hydride and trans-cinnamoyl chloride to yield the corre-
sponding N3-acylated derivatives 31 in 95% (Scheme 10). This
substrate was then employed in the asymmetric conjugate addition
using copper(I) bromide-dimethyl sulfide complex and methyl-
magnesium bromide to yield 32. The level of diastereoselectivity
that was observed was comparable to that of the instances in which
the N4-p-methoxy benzyloxadiazinone substrates 24 and 25 were
employed, namely a 3:1 ratio of diastereomers. Based on this
assessment, the mode of the stereochemical addition for 32 was
In the context of the stereochemical mode of addition, the
(1R,2S)-ephedrine based oxadiazinone 15a was determined to have
had the (S)-conformation at the newly formed stereocenter. This
was also determined to be the case for the (1R,2S)-norephedrine
based oxadiazinone 26 through a process of oxidative cleavage of
the N3-side chain (Scheme 9). Analysis of the recovered 3-
phenylbutyric acid revealed an optical activity of [
a
]
¼ þ22
D
(c ¼ 1, benzene); lit. ¼ [
a]
¼ þ57 (c ¼ 1, benzene) [30]. This data
D
suggested that the stereochemical mode of the conjugate addition
favored the formation of the (S)-configuration.
This result was surprising as it was expected that the increased
steric volume of the N4-p-methoxybenzyl group would have led to
improved diastereoselection. A further investigation was pursued
in which the N4-substituent was further increased in its steric
volume. It was reasoned that while the N4-p-methoxybenzyl was
7

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Fig. 4. Lowest energy solution phase conformers for each conformation of oxadiazinone 14a,
O25eC2eC15eO24 and the O]CeC]C dihedral angle corresponds to O24eC15eC16eC17, using the X-ray crystal structure numbering.
u
b97x-D/6e311þþG(d,p) level. The O]CeNeC]O dihedral angle corresponds to
taken be the same as with substrates 24 and 25 by analogy.
The collected results suggested that the introduction of N4-
substituents to the oxadiazinone larger than the N4-methyl sub-
stituent (oxadiazinone 14a) would not have yielded an improved
level of diastereoselection. In fact, the use of the more sterically
demanding N4-isopropyl substituent of oxadiazinone 31 versus that
of the N4-methyl group of oxadiazinone 14a caused the diaster-
eoselection to decrease from a 5:1 ratio to a 3:1 ratio. The
computational study concerning the conformation dynamics of the
un-complexed-14a and MgBr2-complexed-14a suggested that the
stereochemical course of the reaction was heavily influenced by the
anti-s-cis-14a-MgBr2 intermediate (Scheme 6, vide supra). By
analogy, it was proposed that the N4-isopropyloxadiazinone 31
might follow a similar route as depicted in Scheme 11. Based on this
proposal, the N4-isopropyloxadiazinone would have yielded an
improved diastereoselection via the anti-s-cis-31-MgBr2
intermediate but this was not observed.
A computational study of N4-isopropyl-substituted system was
conducted in a similar fashion to that of oxadiazinone 14a. Initial
structures were generated using the MMFF94 molecular mechanics
force field [26] within the GMMX facility of the GaussView 6.1
software package [27]. The 80 lowest energy conformers from the
MMFF94 conformation search were then optimized in gas and so-
lution phase using the B3LYP/6-31G(d) level of theory. Finally, the
lowest 25 conformers from the B3LYP/6-31G(d) level were then re-
optimized at the
u
b97x-D/6e311þþG(d,p) level in the gas phase
and in solution using the Polarizable Continuum Model (PCM) for
solvation with a dielectric constant corresponding to chloroform.
The Gaussian 09 software package [28] was utilized for all the gas
and solution phase density functional theory calculations.
For the N4-isopropyl-substituted oxadiazinone 31, the lowest
energy conformer is different in the gas phase and in solution
8

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Table 1
energy ordering in solution phase of the lowest energy conforma-
tion for each conformation of isopropyl-substituted oxadiazinone
31, shown in Table 4, is: syn-s-cis < anti-s-cis < anti-s-trans < syn-s-
trans. The energy separation between the lowest anti-s-cis and syn-
s-cis conformers is 0.8 kcal/mol in the gas phase, with the anti-s-cis
conformation lower. This reverses in solution phase, with the syn-s-
cis conformation lower by 1.0 kcal/mol. These results are consistent
with the greater stabilization in polar solvent of the syn-s-cis
conformation with its large gas phase dipole moment (7.6 Debye)
relative to the anti-s-cis conformation with a dipole moment of 2.6
Debye. Similarly, the lowest syn-s-trans conformer, also with a
dipole moment of more than 7 Debye, drops in energy from
7.8 kcal/mol in the gas phase to 6.3 kcal/mol in solution.
The changes in the key O]CeNeC]O and O]CeC]C dihedral
angles in going from gas to solution phase are generally small, as
indicated in Figs. 7 and 8. Variations overall are less than 20ꢁ and in
most cases are less than 12ꢁ. For the N4-isopropyl-substituted
oxadiazinone 31, the lowest-energy conformations of the anti-s-cis
and syn-s-cis conformations exhibit O]CeNeC]O dihedral angles
that deviate by up to 36ꢁ from the ideal expected values of 180ꢁ
and 0ꢁ for the anti and syn conformations, respectively, in both gas
and solution phases. The O]CeC]C dihedral angles for these
conformations are within 15ꢁ of the expected 0ꢁ result for the cis
orientation. The higher-energy conformations, anti-s-trans and syn-
s-trans, show even greater deviations from ideal for the O]
CeNeC]O and O]CeC]C dihedrals. Differences of up to 57ꢁ are
observed for the O]CeNeC]O dihedral angles and deviations of
up to 32ꢁ are observed for the O]CeC]C dihedral angles.
In comparing the lowest energy conformer of each type for N4-
isopropyl oxadiazinone 31 with those of N4-methyloxadiazinone
14a, it can be observed that the isopropyl substitution has little
effect on the geometries of the lowest energy conformers of the
anti-s-cis-31 and syn-s-cis-31 conformations. For these cases, the
O]CeNeC]O and O]CeC]C dihedral angles of 31 are within 15ꢁ
(and in most cases within 7ꢁ) of those for oxadiazinone 14a. In
contrast, the effect of isopropyl substitution is much more signifi-
cant for the lowest energy conformers of anti-s-trans-31 and syn-s-
trans-31. For these cases, the O]CeNeC]O and O]CeC]C
dihedral angles of the isopropyl-substituted compound can vary
widely, with swings of up to nearly 180ꢁ in some cases.
With the conformational aspects of oxadiazinone 31 estab-
lished, a series of computations were carried out in which 31 was
complexed with MgBr2 (Fig. 9). For the isopropyl-substituted oxa-
diazinone 31, the interaction with MgBr2 is similar to what was
observed for oxadiazinone 14a. As shown in Fig. 9, the syn-s-cis and
syn-s-trans conformations of 31-MgBr2 are the lowest conforma-
tions as a result of the interaction of magnesium with both O25 and
O24; however, the syn-s-trans-conformation lies more than 8 kcal/
mol above the syn-s-cis conformation (compared with 6.4 kcal/mol
for oxadiazinone 14a).
Due to the presence of the bulkier isopropyl group attached to
N4-nitrogen in oxadiazinone 31, the anti-s-trans conformation with
MgBr2 does not exhibit any additional stabilization as a result of
interaction of the magnesium with nitrogen N4; the isopropyl
group effectively blocks access to this interaction. Interestingly, this
same anti-s-trans-31 conformation in the un-complexed system is
only 1 kcal/mol less stable than the syn-s-cis counterpart-31.
Based on the computational study on oxadiazinone 31 in its un-
complexed form and complexed form with MgBr2, it became clear
that there were discrete conformational differences from oxadia-
zinone 14a. These differences led to significant shifts in the
conformational positioning of the N3-cinnamoyl side chain upon
complexation, thereby leading to the different stereochemical
outcomes for oxadiazinones 14a (N4-methyl) and 31 (N4-isopropyl)
(Fig. 10).
Results for the first 20 conformers of oxadiazinone 14a, found in the gas phase at the
u
b97x-D/6e311þþG(d,p) level of theory. The lowest energy conformer of each type
is highlighted in gray.
Conformer entry
Classification
Relative E
(kcal/mol)
Dipole Moment
(Debye)
1
2
3
4
5
6
7
8
anti-s-cis
syn-s-cis
anti-s-cis
anti-s-cis
anti-s-trans
anti-s-trans
anti-s-trans
anti-s-cis
anti-s-cis
syn-s-cis
anti-s-cis
syn-s-cis
anti-s-cis
syn-s-trans
syn-s-trans
anti-s-trans
anti-s-trans
anti-s-trans
anti-s-trans
anti-s-trans
0.000
2.388
2.905
3.754
4.022
4.086
4.468
5.104
5.307
5.622
5.824
5.965
5.984
7.103
7.401
7.484
8.378
8.422
8.537
8.798
2.939
7.503
3.003
3.064
4.075
4.247
3.501
2.373
2.542
7.733
2.409
7.280
2.612
8.009
7.962
4.272
2.543
2.598
3.008
1.170
9
10
11
12
13
14
15
16
17
18
19
20
Table 2
Results for the first 20 conformers of oxadiazinone 14a found in solution phase
(chloroform) at the
b97x-D/6e311þþG(d,p) level of theory. The lowest energy
conformer of each type is highlighted in gray.
u
Conformer entry
Classification
Relative E
(kcal/mol)
1
2
3
4
5
6
7
8
anti-s-cis
syn-s-cis
syn-s-cis
anti-s-cis
anti-s-trans
anti-s-cis
syn-s-cis
anti-s-trans
syn-s-cis
syn-s-trans
anti-s-cis
anti-s-cis
anti-s-cis
anti-s-trans
anti-s-cis
anti-s-trans
syn-s-trans
anti-s-trans
anti-s-trans
anti-s-trans
0.000
0.598
1.066
3.141
3.508
3.743
3.840
4.019
4.260
5.137
6.113
6.285
6.585
6.613
7.149
7.657
8.222
8.569
8.916
9.888
9
10
11
12
13
14
15
16
17
18
19
20
phase; this is in contrast to the N4-methyloxadiazinone 14a, for
which the lowest energy conformer corresponds to the anti-s-cis
conformation in both the gas and solution phases. In the gas phase,
the lowest energy conformer of N4-isopropyl-substituted oxadia-
zinone 31 is the anti-s-cis conformation (Fig. 7); however, in solu-
tion phase, the lowest energy conformer of 31 corresponds to the
syn-s-cis conformation (Fig. 8). Table 3 lists the first 25 conformers
found in the gas phase, and Table 4 presents the solution phase
results. The lowest energy conformers for each conformation of the
isopropyl-substituted oxadiazinone 31 are shown in Figs. 7 and 8
for the gas and solution phases, respectively, along with key dihe-
dral angles.
In the gas phase, the energy ordering of the lowest energy
conformation for each conformation of 31, shown in Table 3, is:
anti-s-cis < syn-s-cis < anti-s-trans < syn-s-trans. In contrast, the
9

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Fig. 5. Properties of structures obtained for the interaction of MgBr2 with oxadiazinone 14a in chloroform, determined at the B3LYP/6-31G(d) level. The O]CeNeC]O dihedral
angle shown corresponds to O25eC2eC15eO24 and the O]CeC]C dihedral angle corresponds to O24eC15eC16eC17, using the X-ray crystal structure numbering.
It is proposed that the anti-s-cis-31 and syn-s-cis-31 conforma-
tions are present in solution along with other conformations that
are non-ideal in terms of their geometries that lead to the stereo-
chemical induction that was compromised as compared to the
complexed N4-methyloxadiazinone 14a. Perhaps the most impor-
tant difference established by the computational studies was that
oxadiazinone 14a possesses an anti-s-cis-conformation stabilized
through coordination with the N4-nitrogen of the ring system.In
contrast, the complexed N4-isopropyloxadiazinone 31 proved to be
significantly higher in energy due to the steric volume of the N4-
isopropyl group. With this conformation destabilized, other con-
formations become viable options for the asymmetric conjugate
addition leading to the compromised stereoselection.
formation of the (S)-conformation. The use of larger stereo-
directing substituents (N4 ¼ -benzyl, 25; N4 ¼ -isopropyl, 31) to
enhance the level of diastereoselection yielded compromised dia-
stereoselectivities of 3:1. The lower diastereomeric ratio is attrib-
uted to the conformations present for the oxadiazinones. In this
context, the computational conformational studies suggested that
the N4-methyloxadiazinone 14a adopted an anti-s-cis-conforma-
tion which was in alignment with the observed solution phase
conformation (NOE). In contrast, by way of the computational
study, the N4-isopropyloxadiazinone was found to have the anti-s-
cis-conformation favored in the gas phase and the syn-s-cis
conformation favored in the solution phase. In addition to this, the
N4-isopropyloxadiazinone was also found to have deviations in key
bond angles in the lowest energy conformers that were not as
prevalent in the N4-methyloxadiazinone. With the experimental
observations and the computational study, it is suggested that the
conformational stability of the oxadiazinone in the asymmetric
conjugate addition reaction is determined, in part, by the steric
volume of the N4-substituent. The smaller substituent in 14a (N4-
methyl) yields a dominant conformation that readily undergoes the
3. Conclusion
A (1R,2S)-ephedrine based oxadiazinone and two (1R,2S)-nor-
ephedrine based oxadiazinones were employed as chiral auxiliaries
in the asymmetric conjugate addition reaction. The N4-methylox-
adiazinone 14a yielded a diastereomeric ratio of 5:1 favoring the
10

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Scheme 6. Proposed stereochemical course of the conjugate addition with 14a.
Scheme 7. Acylation of the (1S,2S)-pseudoephedrine based oxadiazinone 9b.
conjugate addition, while a larger substituent, as in 25 (N4-benzyl)
or 31 (N4-isopropyl) causes there to be multiple conformational
intermediates that ultimately erode the level of diastereoselection.
using an automated flash chromatograph. The stationary phase was
40 g normal phase silica gel cartridges. The collected fractions were
analyzed by thin layer chromatography with tlc plates coated with
fluorescent indicator F254 and visualized with UV light. All 1H and
13C NMR spectra were recorded in deuterated chloroform (CDCl3)
using a Bruker Ultrashield Avance III NMR spectrometer operating
at 500 MHz (or 400 MHz) for 1H NMR spectra and operating at
125 MHz (or 100 MHz), respectively. Chemical shifts were reported
4. Experimental
4.1. General information
in parts per million (
listed in Hertz (Hz). Tetramethylsilane (TMS) was used as internal
standard (
d scale) and coupling constant (J values) are
Chemical reagents were used as purchased. Methyl sulfide was
purchased as an anhydrous solution. All Grignard reagents were
used as purchased and stoichiometric calculations were based on
the stated concentration from the vendor. All reactions were con-
ducted in flame-dried glassware under a dry nitrogen atmosphere.
Crude reaction mixtures were purified by flash chromatography
d
¼ 0 ppm). Infrared spectra were recorded using NaCl
plates. Infrared spectral values were reported in reciprocal centi-
meters (cm:1) and were measured as a neat liquid, nujol mull, or as
a
neat liquid film from an evaporated CDCl3 solution. For
11

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Fig. 6. Observable 125 MHz C-13 spectrum showing line broadening for oxadiazinone 19.
Scheme 8. Application of (1R,2S)-norephedrine based oxadiazinone 25 in the conjugate addition.
Electrospray Ionization High Resolution Mass Spectrometry (ESI-
HRMS), samples were prepared in concentrations of 5e25 ppm in
HPLC grade methanol/water/formic acid (1:1:0.01). Analytical data
4.2. (5S,6R)-3-trans-cinnamoyl-4,5-dimethyl-6-phenyl-1,3,4-
oxadiazinone (14a)
was collected using
spectrometer.
a
ThermoScientific Q-Exactive ESI mass
To a flame dried, nitrogen purged 250 mL round bottom flask
was added trans-cinnamic acid (1.29 g, 8.72 mmol) and dissolved in
anhydrous dichloromethane (16 mL). This was followed with the
addition of the coupling agent 1-ethyl-3-(3-dimethylaminopropyl)
carbodiimide (EDC) (1.671 g, 8.72 mmol), DMAP (0.134 g,
12

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Scheme 9. Oxidative cleavage and stereochemical determination.
1.09 mmol) and the oxadiazinone substrate (0.900 g, 4.36 mmol),
sequentially and left stirring at room temperature for 16 h. The
reaction was then diluted with dichloromethane (80 mL) and
washed with 1 M HCl (20 mL), 1 M NaOH (2 ꢂ 20 mL) followed by
brine (20 mL) wash. The organic layer thus recovered was dried
(MgSO4), gravity filtered, and the solvent removed under reduced
pressure. The crude product was purified by flash column chro-
matography (hexanes:ethyl acetate, 70:30) to yield the title com-
pound (1.034 g, 71%) as a white solid: mp: 125e128 ꢁC. 1H NMR
(500 MHz, CDCl3):
d
0.93 (d, J ¼ 7.0 Hz, 3H), 3.08 (s, 3H), 3.48 (dq,
J ¼ 6.9, 4.6 Hz, 1H), 6.12 (d, J ¼ 4.6 Hz, 1H), 7.34e7.38 (m, 3H),
7.41e7.45 (m, 5H), 7.61e7.64 (m, 3H), 7.88 (d, J ¼ 15.6 Hz, 1H); 13C
NMR (125 MHz, CDCl3):
d 12.7, 43.8, 56.9, 77.9, 119.0, 125.0, 128.2,
128.4,128.7, 128.9,130.5,134.8,135.8, 145.8,148.1, 166.6; IR (CHCl3):
1730, 1704, 1623, 1267, 1197, 724, 703 cmꢀ1. ESI HRMS for
Scheme 10. Conjugate addition with the N4-isopropyloxadiazinone 31.
C
20H20N2NaOþ3 : calcd (M þ Naþ) 359.1366, found 359.1366.
Scheme 11. Proposed mechanistic pathway of conjugate addition with oxadiazinone 31.
13

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Fig. 7. Lowest energy gas phase conformers of isopropyl-substituted oxadiazinone 31,
O25eC2eC15eO24 and the O]CeC]C dihedral angle corresponds to O24eC15eC16eC17.
u
b97x-D/6e311þþG(d,p) level. The O]CeNeC]O dihedral angle corresponds to
4.3. (5S,6R)-4,5-dimethyl-6-phenyl-3-(30-phenylbutanoyl)-1,3,4-
oxadiazinone (15a)
The reaction was then diluted with ethyl acetate (80 mL) and
washed with 1 M NaOH (20 mL),1 M HCl (20 mL) and brine solution
(20 mL). The recovered organic layer was dried (MgSO4), filtered
under gravity and the solvent removed under high vacuum. The
crude product was purified by flash column chromatography
(hexanes:ethyl acetate, 70:30) to yield 0.348 g (65%) of the titled
compound as a colorless viscous oil. Only the major isomer is re-
To a 100 mL flame-dried, nitrogen-purged three-neck round
bottomed flask fitted centrally with a 60 mL addition funnel was
added copper bromide-dimethyl sulfide complex (0.933
g
4.54 mmol), THF (5 mL), and dimethyl sulfide (5 mL). This reaction
mixture was then cooled to ꢀ78 ꢁC in a dry ice/ethanol bath. Methyl
magnesium bromide (3 M, 1.51 mL, 4.54 mmol) was then carefully
added to the solution by syringe and the reaction was stirred for
45 min at ꢀ78 ꢁC. The N3-cinnamoyloxadiazinone (14) (0.509 g,
1.51 mmol) was placed into a 25 mL flame-dried glass vial fitted
with a rubber septum for nitrogen purging and dissolved in THF
(6 mL). This solution was transferred to the addition funnel and
added by dropwise addition to the reaction vessel. The reaction
stirred for 17 h while it gradually warmed up to room temperature.
ported: 1H NMR (500 MHz, CDCl3):
d
0.79 (d, J ¼ 7.0 Hz, 3H), 1.32 (d,
J ¼ 6.8 Hz, 3H), 2.82 (s, 3H), 3.11 (dd, J ¼ 7.6, 16.4 Hz, 1H), 3.27e3.49
(m, 3H), 5.99 (d, J ¼ 4.4 Hz, 1H), 7.15e7.20 (m, 1H), 7.25e7.29 (m,
6H), 7.31e7.34 (m, 1H), 7.37e7.41 (m, 2H); 13C NMR (125 MHz,
CDCl3):
d 12.4, 21.8, 36.2, 43.3, 45.9, 56.8, 124.9, 126.3, 127.1, 128.2,
128.4, 128.7, 135.7, 146.0, 148.4, 172.6; IR (CHCl3): 1778, 1724, 1257,
1137, 744, 700 cmꢀ1; ESI HRMS for C21H24N2NaO3þ: calcd (M þ Naþ)
375.1679, found 375.1678.
14

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Fig. 8. Lowest energy solution phase conformers of isopropyl-substituted oxadiazinone 31,
O25eC2eC15eO24 and the O]CeC]C dihedral angle corresponds to O24eC15eC16eC17.
u
b97x-D/6e311þþG(d,p) level. The O]CeNeC]O dihedral angle corresponds to
4.4. Example general procedure for the asymmetric conjugate
addition with oxadiazinone 14b
bicarbonate (3 ꢂ 75 mL), brine (75 mL), dried (MgSO4, and the
solvents were removed by rotary evaporation. The crude product
was then purified by flash chromatography on silica gel.
In a flame dried nitrogen-purged 100 mL, 3-neck round bottom
flask fitted with a pressure-equalizing addition funnel chilled
to ꢀ78 ꢁC was placed CuBreS(CH3)2 (1.65 g, 8.02 mmol), anhydrous
THF (16 mL) and dimethyl sulfide (16 mL) and phenylmagnesium
bromide (10.6 mmol, 10.6 mL, 1.0 M solution in THF) was added by
syringe. The reaction solution was allowed to stir for 5 min before
the addition of oxadiazinone 14b (1.00 g, 3.65 mmol) dissolved in
freshly distilled THF (9 ml), delivered via the addition funnel. The
reaction stirred for 30 min and determined complete by TLC anal-
ysis. The reaction was quenched by the addition of aqueous sodium
bicarbonate (75 mL). The resulting mixture was extracted with
ethyl acetate (2 ꢂ 75 mL) and washed with aqueous sodium
4.4.1. (5S,6R)-4,5-dimethyl-3-[3-methylpentanoyl]-6-phenyl-1,3,4-
oxadiazinone (15b)
The crude product was purified using a mobile phase of 80:20
(hexanes:ethyl acetate) yielding the title compound (0.868, 78%) as
a clear yellow oil. The product was obtained as a mixture of di-
astereomers. The major diastereomer is reported. 1H NMR
(400 MHz, CDCl3):
d
0.85 (d, J ¼ 7.0 Hz, 3H), 0.90 (d, J ¼ 7.7 Hz, 3H),
0.96 (d, J ¼ 7.7 Hz, 3H), 1.19e1.32 (m, 1H), 1.36e1.46 (m, 1H),
1.97e2.05 (m, 1H), 2.72e3.03 (m, 2H), 2.99 (s, 3H), 3.42 (dq, J ¼ 7.0,
4.4 Hz, 1H), 6.04 (d, J ¼ 4.4 Hz, 1H), 7.26e7.43 (m, 5H). 13C NMR
(100 MHz, CDCl3):
d 11.1, 12.3, 19.0, 29.2, 31.2, 43.2, 44.3, 56.5, 77.6,
15

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Table 3
a clear yellow oil. The product was obtained as a mixture of di-
astereomers. The major diastereomer is reported. 1H NMR
Results for the first 25 conformers of isopropyl-substituted oxadiazinone 31, found
in the gas phase with the
energy conformer of each type is highlighted in gray.
u
b97x-D/6e311þþG(d,p) level of theory. The lowest
(400 MHz, CDCl3):
d
0.56 (d, J ¼ 7.0 Hz, 3H), 1.34 (d, J ¼ 7.0 Hz, 3H),
3.00 (s, 3H), 3.06e3.18 (m, 1H), 3.27e3.47 (m, 3H), 5.99 (d,
J ¼ 4.4 Hz, 1H), 7.12e7.42 (m, 10H). 13C NMR (100 MHz, CDCl3):
Conformer entry
Classification
Relative E
(kcal/mol)
Dipole Moment
(Debye)
d
11.9, 21.8, 36.1, 43.0, 45.5, 56.3, 77.6, 124.6, 126.0,126.8, 127.9,
1
2
3
4
5
6
7
8
anti-s-cis
anti-s-cis
anti-s-cis
syn-s-cis
anti-s-cis
syn-s-cis
anti-s-cis
syn-s-cis
anti-s-cis
anti-s-cis
anti-s-trans
syn-s-cis
syn-s-cis
anti-s-trans
anti-s-cis
syn-s-cis
anti-s-cis
anti-s-trans
syn-s-cis
anti-s-cis
anti-s-cis
syn-s-cis
anti-s-cis
anti-s-cis
syn-s-trans
0.000
0.776
1.315
1.481
2.464
2.662
2.955
2.993
3.409
3.417
3.817
3.842
4.034
4.433
4.978
5.016
5.096
5.248
5.587
6.760
6.779
7.270
7.278
7.391
7.743
2.647
2.806
2.278
7.575
2.733
7.054
2.475
7.700
2.952
2.779
3.413
7.655
7.140
3.345
2.410
7.026
2.425
3.958
7.152
2.814
2.272
7.161
2.288
2.320
7.802
128.2, 128.4, 135.4, 145.5, 148.1, 172.3. IR (CDCl3): 1777, 1731, 746,
700 cmꢀ1. EI-HRMS: calcd for C21H24N2O3: 352.1786. Found:
352.1787.
4.4.3. (5S,6R)-4,5-dimethyl-6-phenyl-3-[3-(p-methoxybutanoyl]-
1,3,4-oxadiazinone (15d)
The crude product was purified using a mobile phase of 60:40
(hexanes:ethyl acetate) yielding the title compound (0.997 g, 67%)
as a clear yellow oil. The product was obtained as a mixture of di-
astereomers. The major diastereomer is reported. 1H NMR
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
(400 MHz, CDCl3):
d
0.58 (d, J ¼ 7.0 Hz, 3H), 1.31 (d, J ¼ 7.0 Hz, 3H),
2.88 (s, 3H), 3.05e3.13 (m, 1H), 3.29e3.42 (m, 2H), 3.72 (s, 3H), 5.99
(d, J ¼ 4,4 Hz, 1H), 6.82 (m, 2H), 7.17e7.39 (m, 9H). 13C NMR
(100 MHz, CDCl3): d 11.6, 21.6, 34.9, 42.6, 45.2, 54.5, 55.9, 83.1, 113.2,
124.3, 127.3, 127.5, 128.0, 135.2, 137.4, 147.6, 157.4, 172.0. IR (neat):
1776, 1723, 765, 700 cmꢀ1. EI-HRMS (calcd for C22H26N2O4:
382.1886. Found: 382.1892.
4.5. (4S,5S)-3-trans-cinnamoyl-4,5-dimethyl-6-phenyl-1,3,4-
oxadiazinone (19)
trans-Cinnamic acid (2.58 g, 17.4 mmol) was added to a flame
dried, nitrogen purged 250 mL round bottom flask and dissolved in
anhydrous dichloromethane (16 mL). This was followed with a
sequential addition of 1-ethyl-3-(3-dimethylaminopropyl)carbo-
diimide (EDC, 3.34 g, 17.4 mmol), DMAP (0.268 g, 2.18 mmol) and
oxadiazinone 9b (1.80 g, 8.72 mmol). The reaction was stirred for
16 h at room temperature after which the reaction was diluted with
dichloromethane (80 mL) and sequentially treated with 1 M HCl
(20 mL), 1 M NaOH (2 ꢂ 20 mL), and brine (20 mL). The organic
layer was dried (MgSO4), gravity filtered, and the solvent was
removed under reduced pressure. The crude product obtained was
purified by flash column chromatography (hexanes: ethyl acetate,
75:25) to yield the title compound (1.74 g, 59%) as a white fluffy
Table 4
Results for the first 25 conformers of isopropyl-substituted oxadiazinone 31 found in
solution phase (chloroform) at the
b97x-D/6e311þþG(d,p) level of theory. The
lowest energy conformer of each type is highlighted in gray.
u
Conformer entry
Classification
Relative E
(kcal/mol)
1
2
3
4
5
6
7
8
syn-s-cis
0.000
1.013
1.722
1.768
2.017
2.097
3.472
3.527
3.764
3.887
4.003
4.010
4.181
4.371
4.399
4.937
6.128
6.313
6.319
6.321
6.605
6.930
7.071
8.574
8.678
anti-s-cis
anti-s-cis
syn-s-cis
anti-s-cis
syn-s-cis
anti-s-cis
syn-s-cis
anti-s-cis
anti-s-trans
syn-s-cis
solid. mp: 47e50 ꢁC. 1H NMR (500 MHz, CDCl3):
d
1.21 (d, J ¼ 6.8 Hz,
3H), 2.91 (s, 3H), 3.42 (dq, J ¼ 6.8, 10.4 Hz, 1H). 5.30 (d, J ¼ 9.8 Hz,
1H), 7.36e7.38 (m, 2H), 7.42e7.45 (m, 6H), 7.53 (d, J ¼ 15.7, 1H),
7.62e7.64 (m, 1H), 7.89 (d, J ¼ 15.7 Hz, 1H); 13C NMR (125 MHz,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
anti-s-cis
syn-s-cis
CDCl3): d 15.4, 38.7, 61.0, 84.1, 118.7, 126.9, 128.4, 128.9, 129.0, 129.3,
130.5, 134.8, 136.0, 145.8, 149.5, 165.8; IR (CHCl3): 1704, 1626, 1577,
1204, 1128, 1045, 700 cmꢀ1. ESI HRMS for C20H20N2NaOþ3 : calcd
(M þ Naþ) 359.1366, found 359.1358.
anti-s-cis
anti-s-trans
anti-s-trans
anti-s-cis
syn-s-trans
anti-s-cis
syn-s-trans
syn-s-trans
syn-s-cis
4.6. (5S,6S)-4,5-dimethyl-6-phenyl-3-(30-phenylbutanoyl)-1,3,4-
oxadiazinone (20)
To a 100 mL flame-dried, nitrogen-purged three-neck round
bottomed flask fitted centrally with a 60 mL addition funnel was
added copper bromide dimethyl sulfide complex (1.00 g,
4.87 mmol), tetrahydrofuran (5 mL), and dimethyl sulfide (5 mL).
This reaction mixture was then cooled to ꢀ78 ꢁC in a dry ice/
ethanol bath. Methyl magnesium bromide (3 M, 1.62 mL,
4.86 mmol) was then carefully added to the solution by syringe and
the reaction was stirred for 45 min at ꢀ78 ꢁC. The N3-cinnamoy-
loxadiazinone (19) (0.546 g, 1.62 mmol) was placed into a 25 mL
flame-dried glass vial fitted with a rubber septum for nitrogen
purging and dissolved in THF (6 mL). This solution was transferred
to the addition funnel and added by dropwise addition to the re-
action vessel. The reaction stirred for 17 h while it gradually
anti-s-cis
anti-s-cis
anti-s-cis
124.7, 128.0, 128.5, 135.5, 148.2,173.2. IR (neat): 1720,746, 700 cm-1.
EI-HRMS: calcd for C17H24N2O3: 304.1785. Found: 304.1787.
4.4.2. (5S,6R)-4,5-dimethyl-6-phenyl-3-[3-phenylbutanoyl]1,3,4-
oxadiazinone (15c)
The crude product was purified using a mobile phase of 65:35
(hexanes:ethyl acetate) yielding the title compound (0.897, 70%) as
16

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Fig. 9. Optimized structures for MgBr2 interacting with each conformation of oxadiazinone 31 in chloroform at the B3LYP/6-31G(d) level. The O]CeNeC]O dihedral angle shown
corresponds to O25eC2eC15eO24 and the O]CeC]C dihedral angle corresponds to O24eC15eC16eC17.
warmed up to room temperature. The reaction was then diluted
with ethyl acetate (80 mL) and washed with 1 M NaOH (20 mL),1 M
HCl (20 mL) and brine solution (20 mL). The recovered organic layer
was dried (MgSO4), filtered under gravity and solvent was removed
under high vacuum. The crude product was purified by flash col-
umn chromatography (hexanes:ethyl acetate, 70:30) to yield
0.451 g (79%) of the titled compound as a colorless oil that was
determined to be a mixture of diastereomers in which there was
dried, nitrogen-purged 250 mL round bottom flask and dissolved in
anhydrous dichloromethane (16 mL). This was followed with the
addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)
(1.05 g, 5.45 mmol), DMAP (0.110 g, 0.900 mmol) and the oxadia-
zinone 22 (1.42 g, 4.54 mmol). The reaction was then stirred for 16 h
at room temperature after which the reaction was diluted with
dichloromethane (80 mL) and washed with 1 M HCl (20 mL), 1 M
NaOH (2 ꢂ 20 mL) followed by brine (20 mL) wash. The organic
layer was dried (MgSO4), gravity filtered, and solvent was removed
under reduced pressure. The crude product obtained was purified
by flash column chromatography (hexanes:ethyl acetate, 80:20) to
yield 1.14 g (80%) of the title compound as a white fluffy solid: mp:
observable line broadening. 1H NMR (500 MHz, CDCl3):
d 0.96 (d,
J ¼ 6.8 Hz, 3H), 1.29 (d, J ¼ 6.9 Hz, 3H), 2.62 (s, 3H), 2.90e3.04 (m,
2H), 3.25e3.29 (dd, J ¼ 7.7, 15.7 Hz, 1H), 3.35 (sextet, J ¼ 7.1 Hz, 1H),
5.1 (bs, 1H), 7.13e7.18 (m, 4H), 7.21e7.24 (m, 3H), 7.31e7.33 (m, 3H);
13C NMR (125 MHz, CDCl3):
d
15.6, 22.0, 36.8, 36.9, 44.7, 45.1 83.9,
57e61 ꢁC. 1H NMR (500 MHz, CDCl3):
d
0.85 (d, J ¼ 7.0 Hz, 3H) 3.47
126.5, 126.9, 127.1, 128.5, 128.6, 128.9, 129.3, 135.9, 145.9, 171.9; IR
(dq, J ¼ 4.8, 7.0 Hz, 1H) 3.82 (s, 3H) 4.20 (d, J ¼ 12.5 Hz, 1H) 4.39 (d,
J ¼ 12.5 Hz,1H) 6.14 (d, J ¼ 4.6 Hz,1H) 6.94 (d, J ¼ 8.6 Hz, 2H) 7.26 (d,
J ¼ 7.8 Hz, 2H) 7.33 (t, J ¼ 7.3, 1H), 7.39 (d, J ¼ 7.8, 2H) 7.41e7.43 (m,
3H), 7.47 (d, J ¼ 8.6 Hz, 2H) 7.52 (d, J ¼ 15.7 Hz, 1H) 7.59 (m, 2H) 7.78
(neat): 1781, 1728, 1211, 1126, 760, 700 cmꢀ1. ESI HRMS for
C
21H24N2NaOþ3 : calcd (M þ Naþ) 375.1679, found 375.1673.
(d, J ¼ 15.7 Hz, 1H). 13C NMR (125 MHz, CDCl3):
d 12.5, 52.0, 55.3,
4.7. N3-trans-cinnamoyl-N4-p-methoxybenzyl-5-methyl-6-
phenyl-1,3,4-oxadiazinone (25)
59.3, 78.0, 114.4, 119.1, 124.9, 127.0, 128.2, 128.4, 128.7, 128.8, 130.4,
130.7, 134.9, 135.9, 145.4, 148.2, 159.8, 166.8. IR (CHCl3): 1760, 1727,
1615, 1247, 1216, 1136, 823, 736, 701 cmꢀ1. ESI-HRMS calc’d for
trans-Cinnamic acid (0.807 g, 5.45 mmol) was added to a flame-
17

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
Fig. 10. Comparison of key intermediates in the conjugate addition pathways with oxadiazinones 14a and 31.
C27H26N2NaO4 (M þ Naþ): 465.1785. Found: 465.1779.
was then cooled to ꢀ78 ꢁC and methyl magnesium bromide (3 M,
1.13 mL, 3.39 mmol) was then carefully added to the solution by
syringe and the solution stirred for 45 min at ꢀ78 ꢁC. The N3-cin-
namoyloxadiaxinone (25) substrate (0.500 g, 1.13 mmol) was
placed into a 25 mL flame-dried glass vial fitted with a rubber
septum for nitrogen purging and dissolved in THF (6 mL). This so-
lution was transferred to the addition funnel and added by drop-
wise addition to the reaction vessel. The reaction stirred for 17 h
while it gradually warmed up to room temperature. The reaction
was then diluted with ethyl acetate (80 mL) and washed with 1 M
NaOH (20 mL), 1 M HCl (20 mL) and brine solution (20 mL). The
recovered organic layer was dried (MgSO4), filtered under gravity
and solvent was removed under high vacuum. The crude product
was purified by flash column chromatography (hexanes: ethyl ac-
etate, 80:20) to yield 0.321 g (60%) of the titled compound as a
yellow viscous oil as a mixture of diastereomers. Only the major
4.8. N3-trans-crotonyl-N4-p-methoxybenzyl-5-methyl-6-phenyl-
1,3,4-oxadiazinone (26)
To a flame-dried, nitrogen-purged 100 mL round bottom flask
was added the oxadiazinone 22 (0.50 g, 1.6 mmol) which was dis-
solved in DMF (8.00 mL). To the solution was added sodium hydride
(0.077 g, 3.2 mmol). The reaction was stirred for 10 min and cro-
tonyl chloride (0.17 mL, 1.8 mmol) was then added. The reaction
stirred for an additional 18 h at room temperature, after which it
was diluted with dichloromethane (50 mL) and washed with 1 M
HCl (20 mL) and brine (20 mL). The organic layer was dried
(MgSO4), gravity filtered, and the solvent removed under reduced
pressure. The title compound was isolated as a yellow solid in a
yield of 0.595 g (98%) after purification by flash column chroma-
tography (hexanes: ethyl acetate, 80:20): mp ¼ 54e56 ꢁC. 1H NMR
diastereomer is reported. 1H NMR (500 MHz, CDCl3):
d 0.61 (d,
J ¼ 7.0 Hz, 3H), 1.20 (d, J ¼ 6.9 Hz, 3H), 2.95 (dd, J ¼ 7.9, 16.7 Hz, 1H),
3.22e3.27 (m, 3H), 3.30e3.37 (m, 1H), 3.75 (s, 3H), 3.92 (d, J ¼ 12.5,
1H), 4.01 (d, J ¼ 12.5, 1H), 5.93 (d, J ¼ 4.5, 1H), 6.82e6.85 (m, 2H),
7.07e7.11 (m, 3H), 7.17e7.20 (m, 5H), 7.25e7.28 (m, 2H), 7.32e7.34
(500 MHz, CDCl3).
d
0.77 (d, J ¼ 6.9 Hz, 3H), 1.93 (dd, J ¼ 1.4, 6.9, 3H),
3.38 (dq, J ¼ 4.5, 7.0 Hz, 1H) 3.83 (s, 3H) 4.13 (d, J ¼ 12.6 Hz, 1H) 4.31
(d, J ¼ 12.6 Hz, 1H) 6.07 (d, J ¼ 4.5 Hz, 1H) 6.92 (d, J ¼ 8.5 Hz, 2H)
7.07 (dq, J ¼ 7.5, 15.2 Hz, 1H) 7.20 (d, J ¼ 7.5, 2H) 7.26e7.37 (m, 4H),
(m, 2H). 13C NMR (125 MHz, CDCl3):
d 12.3, 21.9, 36.0, 45.6, 51.4,
7.42 (d, J ¼ 8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3):
d 12.4, 18.5, 51.5,
55.3, 58.7, 77.9, 114.3, 124.8, 126.2, 127.0, 127.1, 128.1, 128.5, 128.7,
55.3, 59.1, 77.9, 114.3, 123.6, 124.9, 127.0, 128.1, 128.7, 130.7, 135.9,
145.7, 148.2, 159.7, 166.6; IR (CHCl3): 1762, 1725, 1639, 1248, 790,
823, 733 cmꢀ1. ESI-HRMS calc’d for C22H24N2NaO4 (M þ Naþ):
403.1628. Found: 403.1622.
130.7, 135.9, 146.2, 148.4, 159.8, 172.6. ESI-HRMS calc’d for
C
28H30N2NaO4 (M þ Naþ): 481.2098. Found: 481.2099.
4.10. N4-p-methoxybenzyl-5-methyl-6-phenyl-3-(30-
phenylbutanoyl)-1,3,4-oxadiazinone (27) derived from
oxadiazinone 26
4.9. N4-p-methoxybenzyl-5-methyl-6-phenyl-3-(30-
phenylbutanoyl)-1,3,4-oxadiazinone (27) derived from
oxadiazinone 25
To a flame dried, nitrogen-purged, three-neck 100 mL round
bottomed flask centrally fitted with a 60 ml separatory funnel was
added copper bromide dimethyl sulfide complex (0.580 g,
2.82 mmol), THF (5 mL) and dimethyl sulfide (5 mL). The reaction
was then cooled to ꢀ78 ꢁC and methyl magnesium bromide (3 M,
To a flame dried, nitrogen-purged, three-neck 100 mL round
bottomed flask centrally fitted with a 60 mL addition funnel was
added copper bromide-dimethyl sulfide complex (0.696 g,
3.39 mmol), THF (5 mL), and dimethyl sulfide (5 mL). The reaction
18

F.O. Obe, R.A. Davis, J. Spurlock et al.
Tetrahedron 83 (2021) 132002
0.940 mL, 2.82 mmol) was then carefully added to the solution and
the reaction stirred for 45 min at ꢀ78 ꢁC. The N3-crotonylox-
adiaxinone (26) was placed into a 25 mL flame-dried glass vial
fitted with a rubber septum for nitrogen purging and dissolved in
THF (6 mL). This solution was transferred to the addition funnel and
added by dropwise addition to the reaction vessel. The reaction
stirred for 17 h while it gradually warmed up to room temperature.
The reaction was then diluted with ethyl acetate (80 mL) and
washed with 1 M NaOH (20 mL),1 M HCl (20 mL) and brine solution
(20 mL). The recovered organic layer was dried with magnesium
sulfate, filtered under gravity and solvent removed under high
vacuum. The crude product obtained was purified by flash column
chromatography (hexanes: ethyl acetate, 70:30) to yield 0.224g
(52%) of the titled compound as a yellow viscous oil as a mixture of
diastereomers. Only the major diastereomer is reported: 1H NMR
purified by flash chromatography (hexanes:ethyl acectate, 85:15).
The isolated product was recovered as a yellow oil (7.52 g, 95%). 1H
NMR (400 MHz, CDCl3):
d
0.83 (d, J ¼ 6.6 Hz, 3H), 1.19 (d, J ¼ 6.6 Hz,
3H), 1.37 (d, J ¼ 6.3 Hz, 3H), 3.47 (septet, J ¼ 6.3 Hz, 1H), 3.81 (m,
1H), 5.97 (d, J ¼ 5.1 Hz, 1H), 7.24e7.37 (m, 10H). 13C NMR (100 MHz,
CDCl3):
d 13.4, 20.9, 21.2, 52.0, 54.6, 79.1, 118.7, 125.1, 128.4, 128.6,
129.1, 130.7, 135.0, 136.2, 146.1, 148.4, 168.0; IR (neat): 3031, 1759,
1725, 1619, 1218, 1024, 742, 700 cmꢀ1
EI-HRMS calc’d for
22H24N2NaO3 (Mþ): 364.1787. Found: 364.1787.
.
C
4.13. N4-isopropyl-5-methyl-6-phenyl-3-(30-phenylbutanoyl)-
1,3,4-oxadiazinone (32)
In a flame-dried, nitrogen-purged three-necked 100 ml round
bottom flask equipped with a pressure-equalizing addition funnel
was placed copper(I) bromide-dimethyl sulfide complex (1.02 g,
4.97 mmol), dimethyl sulfide (5 mL), and THF (10 mL). The reaction
vessel was then cooled to ꢀ78 ꢁC and methylmagnesium bromide
(1 M, 8.3 mL, 8.3 mmol) was added to the reaction vessel via sy-
ringe. The reaction mixture in the round bottom flask stirred for an
additional 20 min. To the addition funnel was added the oxadia-
zinone 31 (0.25 g, 0.83 mmol) dissolved in THF (5 mL). The oxa-
diazinone was added by dropwise addition to the reaction mixture,
and after the additionthe reaction mixture stirred for an additional
2 h. The reaction was quenched by the addition of a saturated
aqueous sodium bicarbonate. The desired product was then
extracted with ethyl acetate (2 ꢂ 20 mL) and the organic solution
was washed with a saturated solution of brine (20 mL). The organic
layer was then dried (MgSO4), and the solvents were removed
under reduced pressure. This process afforded a yellow oil that was
purified by flash chromatograph (hexanes:ethyl acetate, 80:20) to
yield the target compound as a viscous oil (0.142 g, 0.455 mol) in
(500 MHz, CHCl3):
d
0.58 (d, J ¼ 7.0 Hz, 3H), 1.33 (d, J ¼ 7.0 Hz, 3H),
3.17 (dd, J ¼ 7.3, 16.7 Hz, 1H) 3.29e3.33 (m, 2H), 3.35e3.38 (sxt,
J ¼ 6.9 Hz, 1H), 3.85 (s, 3H), 4.07 (d, J ¼ 12.4, 1H), 4.19 (d, J ¼ 12.4,
1H), 6.05 (d, J ¼ 4.6, 1H) 6.93e6.96 (m, 2H), 7.17e7.21 (m, 3H),
7.26e7.32 (m, 4H) 7.35e7.38 (m, 2H), 7.42e7.47 (m, 3H); 13C NMR
(125 MHz, CHCl3) d 12.2, 22.1, 36.2, 45.6, 51.2, 55.3, 58.6, 78.0, 114.3,
124.8, 126.3, 127.0, 128.1, 128.5, 128.7, 128.8, 130.6, 135.9, 146.1,
148.7, 159.7, 172.5; IR (CHCl3): 1775, 1726, 1213, 1136, 850, 740,
700 cmꢀ1. ESI-HRMS calc’d for C28H30N2NaO4 (M þ Naþ): 481.2098.
Found: 481.2100.
4.11. (S)-(þ)-3-phenylbutanoic acid (16) derived from the oxidative
cleavage of the diastereomeric mixture of oxadiazinone 27
Into a 250 mL round bottomed flask was added oxadiazinone 27
(1.26 g, 2.74 mmol) and acetonitrile (50 mL). To the homogenized
mixture was added ceric ammonium nitrate (7.53 g, 13.7 mmol)
pre-dissolved in deionized water (50 mL). The reaction was stirred
for 3 h. The reaction solvent was thereafter removed under reduced
pressure. The concentrated solution was then reconstituted with
diethyl ether (50 mL) and treated with brine solution (30 mL) to
effect the removal of residual cerium ammonium nitrate. The
organic layer was then treated with 1 M NaOH (30 mL). The
aqueous layer was collected and treated with 3 M HCl (30 mL) and
extracted with diethyl ether (50 mL). The collected organic layer
was treated with brine, dried (MgSO4), and the solvent was
removed under reduced pressure. This material and was purified by
flash column chromatography (hexanes:ethyl acetate, 80:20). This
process yielded the title compound (0.10 g, 22%) as a colorless oil:
55%yield. 1H NMR (400 MHz, CDCl3):
d
0.41 (d, J ¼ 6.6 Hz, 3H), 0.72
(d, J ¼ 6.6 Hz, 3H), 0.94 (d, J ¼ 6.3 Hz, 3H), 1.11 (d, J ¼ 6.3 Hz, 3H),
1.29e1.34 (m, 2H), 3.07e3.14 (m, 1H), 3.33 (septet, J ¼ 6.3 Hz, 1H),
3.75 (dq, J ¼ 13.7, 6.6 Hz, 1H), 5.92 (d, 5.1 Hz, 1H), 7.16e7.40 (m,
10H). 13C NMR (100 MHz, CDCl3):
d 13.2, 20.6, 20.8, 21.9, 36.0, 46.0,
51.6, 79.1, 115.6, 125.0, 126.5, 127.4, 128.4, 128.6, 128.9, 136.2, 146.3,
173.6; IR (neat): 1726, 1605, 1243, 1168, 1022, 754, 700 cmꢀ1. ESI-
HRMS calc’d for C23H29N2NaO3 (M þ Naþ): 381.2181. Found:
381.2178.
Declaration of competing interest
[
a
] [23]D ¼ þ22. 1H NMR (500 MHz, CHCl3):
1.33 (d, J ¼ 7.0 Hz, 3H),
d
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
2.58 (dd, J ¼ 15.5, 8.2, Hz, 1H), 2.68 (dd, J ¼ 6.8 Hz, 1H), 3.28 (sxt,
J ¼ 7.0 Hz, 1H), 7.19-0.23 (m, 3H), 7.29e7.32 (m, 2H). 13C NMR
(CHCl3): d 21.9, 36.2, 42.6, 126.5, 126.7, 128.6, 145.5, 178.5; IR (neat):
2970, 1706, 1296, 763, 700 cmꢀ1. ESI-HRMS for C11H14N2NaOþ2 :
Acknowledgements
calcd (M þ Naþ) 187.0730, found 187.0730.
We thank the Department of Chemistry of Illinois State Uni-
versity for an internal summer research grant for Fatima Olayemi
Obe. Acknowledgment is made to the National Science Foundation
(NSF) for SC-XRD (CHE-1039689) analyses from Departmental
instrumentation obtained from the Major Research Instrumenta-
tion (MRI) program.
4.12. N3-trans-cinnamoyl-N4-isopropyl-5-methyl-6-phenyl-1,3,4-
oxadiazinone (31)
In a flame-dried, nitrogen purged 1 L round bottomed flask
fitted with a condenser was placed oxadiazinone 30 (5.00 g,
21.3 mmol), dissolved in methylal chloride (25 mL). To this stirred
mixture was added trans-cinnamoyl chloride (4.25 g, 25.5 mol).
This mixture was heated to reflux and then lithium hydride (0.18 g,
22.4 mmol) was added. The reaction stirred for 18 h and was then
cooled to room temperature and quenched with a saturated solu-
tion of sodium bicarbonate (50 mL). The target product was
extracted with methylene chloride (3 ꢂ 20 mL), and the extract was
washed with brine (30 mL), died (MgSO4). The solvents were
removed under reduced pressure and the crude product was
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132002.
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