Conformational preferences of the aldol adducts of oxadiazinones. 1H NMR spectroscopy and computational studies of N4-methyl and N4-isopropyloxadiazinones

Article abstract of DOI:10.1016/j.tet.2005.08.097

The conformational properties of the aldol adducts of some N ₄-isopropyl-oxadiazinones have been investigated by ¹H NMR spectroscopy and computational studies. An earlier study of the syn-aldol adducts of N₄-methyl-oxadiaz

Full text of DOI:10.1016/j.tet.2005.08.097

Tetrahedron 61 (2005) 10965–10974
Conformational preferences of the aldol adducts of oxadiazinones.
1H NMR spectroscopy and computational studies of N4-methyl
and N4-isopropyloxadiazinones
*
James R. Burgeson, Delvis D. Dore, Jean M. Standard and Shawn R. Hitchcock
*
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
Received 8 July 2005; revised 24 August 2005; accepted 25 August 2005
Available online 22 September 2005
1
Abstract—The conformational properties of the aldol adducts of some N4-isopropyl-oxadiazinones have been investigated by H NMR
spectroscopy and computational studies. An earlier study of the syn-aldol adducts of N4-methyl-oxadiazinone 2 led to the conclusion that the
solution and solid state conformation of these compounds involve syn-parallel arrangement of the C2- and N3-carbonyls of the oxadiazinones.
However, the synthesis and asymmetric aldol reactions of an N3-hydrocinnamoyl-N4-isopropyl-oxadiazinone 4 has yielded aldol adducts 5a–e in
which the orientation of the C2- and N3-carbonyls are most likely in the anti-parallel arrangement. These aldol adducts have been studied by
1H NMR spectroscopy and the shielding aspect observed clearly suggests the presence of the anti-parallel arrangement. The installment of a
N4-d6-isopropyl group further confirmed this assertion. Computational studies support the conclusion that solution state conformation of the
N4-methyl and N4-isopropyl-oxadiazinones involves anti-parallel carbonyls in contrast to the solid state evidence of the X-ray
crystallographic data of oxadiazinone 2.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
It was concluded that the conformation of 2 that gave rise to
the shielding of the C5-methyl group resembled the solid
state X-ray crystal structure involving a nearly syn-parallel
arrangement of the carbonyls, but had a different orientation
of the proximal aromatic ring of the N3-substituent. This
conformation was believed to be dominant in solution and in
the solid state based on an earlier study of oxadiazinones
that included 13C NMR spectroscopic data, X-ray crystallo-
graphic data, and computational data.2,3 Herein, we report
We recently reported on the conformational analysis of the
aldol addition adducts of a (1R,2S)-ephedrine based N3-
hydrocinnamoyloxadiazinone.1 It was determined that the
C5-methyl group of oxadiazinone 2 became strongly
shielded and shifted from the average value of 0.85 ppm
to a value of 0.02 ppm (Scheme 1). It was concluded from a
solution state NOESY study that the C5-methyl group was
being shielded by the proximal aromatic ring of the N3-side
chain. In contrast, solid state X-ray crystallographic studies
suggested that the terminal aromatic ring was responsible
for the shielding.
1
on the synthesis of the new oxadiazinones derivatives, H
NMR studies, and computational studies that strongly
suggest that the dominant conformation in solution is the
anti-parallel carbonyl arrangement, not the syn-parallel
Scheme 1.
Keywords: Oxadiazinone; Aldol addition reaction; Conformational analysis; Computational study.
*
Corresponding authors. Tel.: C1 309 438 7700; fax: C1 309 438 5538 (J.M.S.); tel.: +1 309 438 7854; fax: +1 309 438 5538 (S.R.H.); e-mail addresses:
standard@ilstu.edu; hitchcock@ilstu.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.097

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J. R. Burgeson et al. / Tetrahedron 61 (2005) 10965–10974
arrangement. Furthermore, a computational reinvestigation
of the previously studied oxadiazinone 2 suggests that the
lowest energy gas phase conformer has an anti-parallel
carbonyl arrangement and that the dominant conformation
in solution state is also likely to be the anti-parallel carbonyl
arrangement.
conformation involved an anti-parallel arrangement of the
carbonyls.4 This putative difference prompted a more
detailed investigation of the conformational aspects of the
N4-methyl-oxadiazinones as compared to the aldol adducts
of the N4-isopropyl-oxadiazinones. From the previous study
it was already established that the signal that was being
shielded in the ephedrine based N4-methyloxadiazinones
aldol adducts was the C5-methyl group.1 Likewise, the
identity of the signal that was shielded in the N4-isopropyl-
oxadiazinone aldol adducts 5a–e was also determined to be
the C5-methyl group based on an analysis of the observed
coupling constants (Fig. 1).
2. Results and discussion
The new oxadiazinone derivatives were synthesized using
an N4-isopropyloxadiazinone (3) derived from (1R,2S)-
norephedrine. This oxadiazinone was prepared as described
previously4 and was subsequently acylated with hydro-
cinnamoyl chloride to afford the desired N3-hydrocinna-
moyl-N4-isopropyloxadiazinone (4) in 64% yield after
chromatography (Scheme 2). The acylated oxadiazinone
was dissolved in tetrahydrofuran and treated with titantium
tetrachloride at 25 8C. The temperature of the reaction
mixture was cooled to K78 8C and triethylamine was
added. After 45 min, a selected aldehyde was then added to
the reaction mixture to yield aldol adducts 5a–e.
There was some concern that the shielded signal could be
attributed to one of the methyl groups of the isopropyl group
although this was unlikely based on the aforementioned
coupling constants. The identity of the signal was
unambiguously determined by the synthesis of an N4-d6-
isopropyloxadiazinone aldol adduct. Thus, (1R,2S)-nore-
phedrine (6) was reductively alkylated with acetone-d6 and
sodium borohydride in 72% yield (Scheme 3). The amine
was N-nitrosated in 88% yield by treatment with sodium
nitrite and hydrochloric acid.5 The N-nitrosamine 8 was
reduced to the 1,10-disubstituted hydrazine 9 by lithium
aluminum hydride and subsequently cyclized in 24% yield
from 8 by reaction with diethylcarbonate and lithium
hydride to afford oxadiazinone 10. This material was
acylated with hydrocinnamoyl chloride and lithium hydride
in 92% yield. The resultant N3-hydrocinnamoyl-oxadiazi-
none was reacted with titanium tetrachloride in THF
(0.3 M), deprotonated with triethylamine at K78 8C over
Interestingly, all of the adducts exhibited a signal in their
respective 400 MHz H NMR spectra that had an average
1
chemical shift of K0.15 ppm (Fig. 1). The same shielding
effect was observed in the ephedrine based N4-methyl-
oxadiazinone 2, which was believed to have the syn-parallel
arrangement of the C2- and N3-carbonyl groups.1 This
was intriguing as our previous results concerning the
N4-isopropyloxadiazinones suggested that the dominant
Scheme 2. Asymmetric aldol reactions with the N4-isopropyloxadiazinone.
Figure 1.

J. R. Burgeson et al. / Tetrahedron 61 (2005) 10965–10974
10967
Scheme 3.
a period of 45 min, and subsequently treated with
4-chlorobenzaldehyde. This process afforded the target
aldol adduct 12 in 97% yield and greater than 95:5
diastereoselectivity based on the analysis of the related
N3-hydrocinnamoyl side chain was responsible for the
shielding. This observation was in agreement with the
earlier study1 that the proximal aromatic ring was
responsible for the shielding of the C5-methyl group.
1
400 MHz H NMR spectrum.
A NOESY experiment was conducted with deuterated
adduct 12 to support this argument (Fig. 3). This spectro-
scopic data conclusively demonstrated that the shielding
involved the aforementioned C5-methyl group and the
N3-side chain. Specifically, when the signal at K0.15 ppm
was irradiated there was an enhancement of the aromatic
signals centered at 7.03 and 7.11 ppm. There was no
observed enhancement of the aromatic proton signals
attributed to the p-chlorophenyl group.
The 1H NMR spectrum of deuterated aldol adduct 12
exhibited a single doublet at K0.15 ppm. This provided
clear evidence that the C5-methyl group was being strongly
shielded by an aromatic ring of the N3-substituent. The
aromatic ring of the N3-side chain responsible for the
shielding effect was determined by comparing the 400 MHz
1H NMR spectra of aldol adducts 5a–c against aldol adducts
5d–e (Fig. 2). All of the adducts, 5a–e, exhibited a strongly
shielded signal near K0.15 ppm. The oxadiazinone adducts
5a–c possess two aromatic rings on the N3-side chain
whereas adducts 5d–e possess only a single aromatic ring. It
was concluded that the aromatic ring from the original
A second irradiation experiment was conducted wherein
irradiation of the protons of the p-chlorophenyl substituent
did not cause an enhancement of the C5-methyl group. The
combined results of the 400 MHz 1H NMR spectra of 5a–e,
the synthesis and analysis of the N4-d6-isopropyloxadiazi-
none adduct, and the NOESY evidence established the
relationship between the C5-methyl group and the aromatic
ring. The ephedrine based oxadiazinone adduct 2 from the
earlier study was observed to have the same characteristics
of shielding of the C5-methyl group but the conformation
was believed to be have the syn-parallel arrangement of the
carbonyls. In contrast the oxadiazinone adducts 5a–e are
believed to the have the anti-parallel arrangement of the
carbonyls (Fig. 4). Computational studies were employed to
resolve the conformational differences between the two sets
of oxadiazinone substrates.
A conformation search employing the AM1 semiempirical
molecular orbital method was carried out in the gas phase
out to locate low energy conformations of the N4-isopropyl-
oxadiazinone 5. The conformation search was performed
using the Spartan02 software package for Linux.6 In order to
Figure 2. Origin of shielding effect.

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J. R. Burgeson et al. / Tetrahedron 61 (2005) 10965–10974
Figure 3. 400 MHz 1H NMR NOESY spectrum of 12 with irradiation at K0.15 ppm. The signals located at 1.05 and 1.25 ppm are attributed to the residual
coupling from the (CD3)2CH– substituent.
include both syn- and anti-parallel arrangements of the
carbonyl groups, one conformation search was carried out in
which the starting structure had an approximately syn-
parallel carbonyl arrangement and a second conformation
search was carried out in which the starting structure had an
approximately anti-parallel carbonyl arrangement. Sys-
tematic conformation searches were performed in which
the key rotatable dihedral angles responsible for positioning
of the aromatic ring of the N3-hydrocinnamoyl unit and the
aromatic ring at the terminus of the N3-substituent chain
(Fig. 5) were varied to obtain initial structures, which were
then subjected to geometry optimization. A vibrational
frequency calculation was performed for each unique
structure found in the conformation searches in order to
verify that it corresponded to a minimum on the potential
energy surface. The 1H NMR chemical shifts of the protons
of the methyl group attached to the C5 position of
oxadiazinone 5 were determined for each conformation
from single-point energy density functional calculations at
the B3LYP/DZP level of theory using the gauge invariant
atomic orbital (GIAO) method. The PQS 3.1 software
package7 was employed for all the density functional
calculations.
Figure 4. Comparison of oxadiazinone adducts.
Figure 5. Rotatable dihedral angles included in conformation searches.

J. R. Burgeson et al. / Tetrahedron 61 (2005) 10965–10974
Table 1. Computational results for low-energy conformers of oxadiazinone 5
10969
Conformation
Relative DH, kJ/mol
(kcal/mol)
Dihedral angle (8)a
Average C5 methyl 1H
chemical shift (ppm)
Distance to benzene
b
˚
centroid (A)
1
2
3
4
5
15
0.00 (0.00)
4.70 (1.12)
7.42 (1.77)
8.72 (2.09)
12.74 (3.04)
19.05 (4.55)
K125.4
34.5
K115.7
K145.7
K163.1
28.9
0.141
0.978
0.856
0.024
0.514
0.040
3.90
3.94
4.65
3.79
a The dihedral angle listed is the O–C–C–O dihedral angle between the two carbonyl groups.
b The distance reported is the average distance from the protons of the methyl attached to C5 to the centroid of the benzene ring in close contact.
From the conformer searches, five conformers were located
within 13 kJ/mol (3.1 kcal/mol) of the lowest energy
conformer and a total of 16 conformers were located within
20 kJ/mol (4.8 kcal/mol) of the lowest energy conformer.
Calculated results for the five lowest energy conformers
plus one other are listed in Table 1.
a syn-parallel carbonyl arrangement that also exhibits an
unusual C5-methyl 1H chemical shift. This syn-parallel
conformer is 19 kJ/mol above the lowest energy anti-
parallel conformer. In addition, it is the terminal aromatic
ring of the N3-substituent rather than the aromatic ring of the
˚
N3-hydrocinnamoyl unit that is in close contact (3.8 A) with
the C5-methyl protons in conformer 15 and thus, is the
interaction responsible for the unusual chemical shift. The
NOE study established this relationship as described earlier.
The lowest energy conformer (Fig. 6) and four of the first
five lowest energy conformers of oxadiazinone 5 have
approximately anti-parallel arrangements of the carbonyl
groups. Of these, two (conformers 1 and 4) exhibit
unusually low 1H chemical shifts (0.0–0.1 ppm) for the
protons of the methyl group at the C5 position and a third
(conformer 5) exhibits a partial decrease in the chemical
shift (0.5 ppm) compared to a typical chemical shift of
around 1 ppm for methyl protons. In previous work,1 the
unusual chemical shift of the methyl protons was attributed
to close contact with one of the substituent benzene rings of
the N3-substituent. In conformers 1 and 4, the aromatic ring
of the N3-hydrocinnamoyl unit is in close proximity (at a
The general trend observed in the conformer search is that
the lower energy conformers tend to have the anti-parallel
arrangement of carbonyl groups while conformers with the
syn-parallel carbonyl arrangement tend to occur at higher
energy. The interaction responsible for the unusual chemical
shift of the C5-methyl protons in conformers with an
approximately anti-parallel carbonyl arrangement is in
close contact with the aromatic ring of the N3-hydro-
cinnamoyl unit (Fig. 7). On the other hand, the interaction
responsible for the unusual chemical shift of the C5-methyl
protons in conformers with an approximately syn-parallel
carbonyl arrangement is in close contact with the terminal
aromatic ring of the N3-substituent (Fig. 7).
˚
average distance of 3.9 A) to the protons of the C5-methyl
group and this interaction is responsible for the unusually
low chemical shift that was observed. In conformer 5, the
aromatic ring of the N3-hydrocinnamoyl unit is interacting
with the protons of the C5-methyl group but at a larger
Previous work on the ephedrine based N4-methyl-oxadia-
zinone 2 involved X-ray crystallography, solution phase
NMR (including NOE studies), and gas phase compu-
tational studies.1 The X-ray crystallography results indi-
cated that the carbonyls adopt a syn-parallel orientation in
the solid state. Solution phase NOE results and compu-
tational studies were carried out and interpreted based on the
assumption that the system also would adopt a syn-parallel
orientation in solution and gas phases. These observations
lead to a discrepancy as to which conformation was
responsible for the unusual chemical shift of the C5-methyl
protons. Based on the results obtained in this work for
˚
distance of 4.7 A so the chemical shift of the methyl protons
is only reduced to about 0.5 ppm.
To further explore the question of whether oxadiazinone 5
prefers the syn-parallel or anti-parallel arrangement of
carbonyl groups, results are included in Table 1 for
conformer 15, which is the lowest energy conformer with
Figure 7. Origin of unusual chemical shift of C5-methyl protons in
oxadiazinone 5 with syn- and anti-parallel carbonyl arrangements.
Figure 6. Lowest energy conformer of oxadiazinone 5.

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J. R. Burgeson et al. / Tetrahedron 61 (2005) 10965–10974
oxadiazinone 5, further computational studies have been
performed on oxadiazinone 2.
two other conformers (3 and 5) exhibit a partial decrease in
the chemical shift (0.3–0.4 ppm). In agreement with results
found for oxadiazinone 5, the unusual chemical shift of
the C5-methyl protons of conformer 1 arises because the
aromatic ring of the N3-hydrocinnamoyl unit is in close
Conformation searches starting from both the syn- and anti-
parallel arrangements of the carbonyl groups were
performed using the AM1 semiempirical method as
implemented in the Spartan02 software package for
Linux.6 The same dihedral angles shown in Figure 5 were
allowed to vary in the conformation searches of oxadiazi-
none 2. NMR chemical shifts again were determined from
single-point energy calculations at the B3LYP/DZP level of
theory using GIAO method implemented in the PQS 3.1
software package.7
˚
contact (at a average distance of 4.3 A) with the protons of
the C5-methyl group. In conformers 3 and 5, the aromatic
ring of the N3-hydrocinnamoyl unit interacts with the
protons of the C5-methyl group at a larger distance (4.7–
˚
4.8 A), leading to a partial reduction in the chemical shift of
the C5-methyl protons. The lowest energy conformer with a
syn-parallel carbonyl arrangement to exhibit an unusual
1
C5-methyl H chemical shift is conformer 7, 13.2 kJ/mol
above the lowest energy conformer.
For oxadiazinone 2, five conformers were located within
13 kJ/mol (3.1 kcal/mol) of the lowest energy conformer
and a total of 28 conformers were located within 20 kJ/mol
(4.8 kcal/mol) of the lowest energy conformer. Calculated
results for the seven lowest energy conformers are listed in
Table 2.
In accord with the findings for oxadiazinone 5, the terminal
aromatic ring of the N3-substituent is in close contact with
the C5-methyl protons in conformers with syn-parallel
carbonyl arrangements (such as conformer 7) and is the
interaction responsible for the unusual chemical shift of the
C5-methyl protons (Fig. 8).
The two lowest energy conformers of oxadiazinone 2 are
very similar to those found for N4-isopropyl-oxadiazinone
5. The lowest energy conformer (Fig. 8) and five of the first
six conformers of oxadiazinone 2 have approximately anti-
parallel carbonyl arrangements. The lowest energy con-
former exhibits an unusually low 1H chemical shift
(0.065 ppm) for the protons of the C5-methyl group and
In the conformer search for oxadiazinone 2, conformer 4 has
an orientation in which close contact between the aromatic
ring of the N3-hydrocinnamoyl unit is observed and the
C5-methyl group is in the anti-parallel carbonyl arrange-
ment. In comparing conformers 1 and 4, the dihedral angle
between the carbonyls is very similar (K124 vs K1438) as
Table 2. Computational results for low-energy conformers of oxadiazinone 2
Conformation
Relative DH, kJ/mol
(kcal/mol)
Dihedral angle (8)a
Average C5 methyl 1H
chemical shift (ppm)
Distance to benzene
b
˚
centroid (A)
1
2
3
4
5
6
7
0.00 (0.00)
6.57 (1.57)
8.73 (2.09)
10.12 (2.42)
12.82 (3.07)
12.95 (3.10)
13.24 (3.17)
K123.6
32.0
0.065
0.950
0.288
0.959
0.420
4.29
K145.6
K142.9
K173.2
K136.0
31.8
4.65
4.34
4.79
0.976
K0.370
3.66
a The dihedral angle listed is the O–C–C–O dihedral angle between the two carbonyl groups.
b The distance reported is the average distance from the protons of the C5-methyl group to the centroid of the benzene ring in close contact.
Figure 8. Conformers of oxadiazinone 2. Conformer 1 shows the anti-parallel carbonyl arrangement and close contact between the aromatic ring of the N3-
hydrocinnamoyl unit and the C5-methyl group. Conformer 7 shows the syn-parallel carbonyl arrangement and close contact between the terminal aromatic ring
of the N3-substituent and the C5-methyl group.

J. R. Burgeson et al. / Tetrahedron 61 (2005) 10965–10974
10971
is the average distance between the C5-methyl protons and
the centroid of the benzene ring of the N3-hydrocinnamoyl
N4-methyl-oxadiazinone 2 suggested that these compounds
have syn-parallel arrangement of the C2- and N3-carbonyls
of the oxadiazinones in the solution state and solid state. The
results of the current body of work have revealed that the
earlier analysis was not complete. The syntheses and
asymmetric aldol reactions of an N3-hydrocinnamoyl-N4-
isopropyl-oxadiazinone 4 has yielded aldol adducts 5a–e in
which the orientation of the C2- and N3-carbonyls are most
likely in the anti-parallel arrangement. These aldol adducts
˚
unit (4.3 A). It would be expected, therefore, that the
C5-methyl protons of conformer 4 would exhibit a chemical
shift of close to 0 ppm, however, the chemical shift is
calculated to be normal (0.96 ppm). Further investigation of
the lack of unusual chemical shift suggests that not only
must the aromatic ring be in close proximity to the
C5-methyl group but that the C5-methyl must be positioned
between the aromatic ring of the N3-hydrocinnamoyl unit
and the aromatic ring at the C6 position. This is illustrated in
Figure 9 where a comparison between conformer 1 (unusual
C5-methyl shift) and conformer 4 (normal C5-methyl shift)
is shown. A normal chemical shift for the C5-methyl group
protons also is observed in one other conformer of
oxadiazinone 2 (conformer 8, relative DHZ13.6 kJ/mol).
This conformer also has the aromatic ring of the N3-
hydrocinnamoyl unit in close contact with the C5-methyl
group but exhibits a normal C5-methyl chemical shift for the
same reasons illustrated in Figure 9.
1
were studied by H NMR spectroscopy and the shielding
aspect observed in the N4-isopropyl-oxadiazinone clearly
suggests the presence of the anti-parallel arrangement. The
installment of a N4-d6-isopropyl group further confirmed
this assertion.
The computational studies of the N4-isopropyl-oxadiazi-
nones 5 and N4-methyl-oxadiazinone 2 in the gas phase
yield a set of consistent results. First, most of the lowest
energy conformers of oxadiazinones 5 and 2 have the anti-
parallel carbonyl arrangement, which supports the con-
clusion that it is the most stable orientation of both
oxadiazinones 5 and 2. Conformers of oxadiazinones 5
and 2 that exhibit the syn-parallel carbonyl arrangement
tend to have higher energies than those with anti-parallel
carbonyl groups.
3. Summary
The conformational properties of the aldol adducts of
N4-isopropyl-oxadiazinones 5a–e have been investigated by
1H NMR spectroscopy, NOE studies, and computational
studies. An earlier study of the syn-aldol adducts of
Some of the low energy conformers of the oxadiazinones
1
exhibit unusually low H chemical shifts of the C5-methyl
Figure 9. Two views of conformers 1 and 4 of oxadiazinone 2. The C5-methyl group is highlighted in yellow. View 1 shows the anti-parallel carbonyl
arrangement and close contact between the aromatic ring of the N3-hydrocinnamoyl unit and the C5-methyl group. View 2 shows the aromatic ring at the C6
position overlaying the aromatic ring of the N3-hydrocinnamoyl unit. The C5-methyl group is positioned between the rings in conformer 1 but is outside the
rings in conformer 4.

10972
J. R. Burgeson et al. / Tetrahedron 61 (2005) 10965–10974
protons. The low chemical shifts of about 0 ppm arise due to
close contact between the aromatic ring of the N3-
hydrocinnamoyl unit and the C5-methyl protons. Further-
more, from the studies of oxadiazinone 2, in order for the
interaction to lead to a low chemical shift, the C5-methyl
group must be positioned between the aromatic ring
attached to the C6 position and the aromatic ring of the
N3-hydrocinnamoyl unit.
128.2, 128.5, 128.5, 135.8, 140.6, 148.7, 173.9. IR (neat):
2980, 1728, 1242, 754 cmK1
HRMS calcd for
C22H26N2O3: 366.1943. Found: 366.1936.
.
4.2. General procedures for aldol adducts 5a–e
In a 100 mL round-bottom flask was placed oxadiazinone 4
(1.0 g, 2.73 mmol) and dissolved in THF (8.9 mL). To this
mixture was added TiCl4 (0.65 mL, 5.92 mmol). This
mixture was allowed to stir for 25 min at room temperature
and then cooled to K78 8C for a period of 5 min.
Triethylamine (0.43 mL, 3.11 mmol) was added and the
solution was allowed to warm to room temperature over a
period of 45 min. After this time, the solution was again
cooled to K78 8C. After stirring for an additional 5 min, the
appropriate aldehyde (3.85 mmol) was added and the
solution was allowed to come to room temperature and
react for 18 h. The reaction was quenched with a saturated
NH4Cl solution (50 mL) and extracted with EtOAc (2!
50 mL). The combined extracts were washed with a
saturated brine solution (50 mL) and dried (MgSO4). The
solvents were removed by evaporation and the crude
products were purified via column chromatography
(EtOAc/hexanes 1:1).
Finally, the synthetic studies, 1H NMR spectroscopic
studies (including the NOE studies) and computational
studies all suggest together that the dominant conformation
is that of the anti-parallel carbonyls. Interestingly, the X-ray
crystallographic data of 2 and related compounds point to
a solid state structure wherein the carbonyls are in a syn-
parallel arrangement. It would seem that there is a
conformational change in the structure of oxadiazinones
as there is a change in state. This change may be due to
steric interactions, lone pair-lone pair repulsions, or
hydrogen bonding phenomena.
4. Experimental
4.1. General remarks
4.2.1. (5S,6R)-[(2S,3S)-3-(2-Benzyl-3-(4-chlorophenyl)-3-
hydroxypropanoyl)]-4-isopropyl-5-methyl-6-phenyl-2H-
1,3,4-oxadiazinan-2-one (5a). The crude product was
purified by silica gel column chromatography with
EtOAc:hexanes 2:3 to yield 0.519 g of 5a (73%) as a
yellow oil: [a]2D5K18.3 (c 0.329, CHCl3); RfZ0.28 (EtOAc/
hexanes, 2:3). 1H NMR (CDCl3): K0.16 (C5-methyl, d, JZ
7.0 Hz, 3H), 1.10 (d, JZ6.2 Hz, 3H), 1.30 (d, JZ6.2 Hz,
3H), 2.61 (dd, JZ10.3, 3.3 Hz, 1H), 3.00 (dd, JZ13.6,
12.1 Hz, 1H), 3.20 (s, 1H), 3.31 (septet, JZ6.2 Hz, 1H),
3.53 (C5-methine, septet, JZ7.0 Hz, 1H), 4.61 (dt, JZ5.9,
3.3 Hz, 1H), 5.34 (br s, 1H), 5.82 (d, JZ5.5 Hz, 1H), 6.98–
7.40 (m, 12H), 7.57 (d, JZ8.4 Hz, 2H). 13C NMR (CDCl3):
12.0, 20.3, 20.6, 31.8, 50.8, 53.8, 54.1, 72.8, 79.6, 124.8,
126.3, 127.7, 128.2, 128.3, 128.4, 128.5, 129.3, 133.2,
135.4, 138.8, 139.4, 149.7, 175.3. IR (CCl4): 3442, 2980,
1733, 1239, 734 cmK1. HRMS calcd for C29H31ClN2O4:
506.1972. Found: 506.1962. HPLC: 10 m silica, 4.6 mm!
25 cm, EtOAc/hexanes 35:65, RTZ9.67 min, crude ratioZ
15:1.
Tetrahydrofuran (THF) and diethyl ether (Et2O) were
distilled from a potassium/sodium alloy with benzophenone
ketyl. Methylene chloride (CH2Cl2) was distilled from
calcium hydride. All reactions were run under a nitrogen
1
atmosphere. Unless otherwise noted, all H and 13C NMR
spectra were recorded at 25 8C on a Varian spectrometer in
CDCl3 operating at 400 and 100 MHz, respectively.
Chemical shifts are reported in parts per million (d scale),
and coupling constants (J values) are listed in hertz (Hz).
The NOESY spectra was collected by Spectral Data
Services, Inc. Infrared spectra are reported in reciprocal
centimeters (cmK1) and are measured either as a neat liquid
or as a KBr window. Melting points were recorded on a
Mel-Temp apparatus and were uncorrected.
4.1.1. (5S,6R)-4-Isopropyl-5-methyl-6-phenyl-3-(3-phen-
ylpropanoyl)-2H-1,3,4-oxadiazinan-2-one (4). In a flame-
dried, nitrogen purged 500 mL round-bottom flask fitted
with a condenser was placed N4-isopropyloxadiazinone 3
(6.0 g, 25.61 mmol) and dissolved in dichloroethane
(26 mL). To this stirred mixture was added hydrocinnamoyl
chloride (5.71 mL, 38.42 mmol). This mixture was heated
to reflux and LiH (0.22 g, 28.17 mmol) was added in
portions. After 18 h, the reaction was quenched with
saturated NH4Cl solution (150 mL) and extracted with
EtOAc (3!100 mL). The combined extracts were washed
with a saturated brine solution (150 mL) and dried
(MgSO4). The solvents were removed by evaporation and
the crude products were purified via column chromato-
graphy (EtOAc/hexanes 1:3). The purified product was
isolated as a brown oil and gave a yield of 64%; RfZ0.37
4.2.2. (5S,6R)-[(2S,3S)-3-(2-Benzyl-3-hydroxy-3-(4-nitro-
phenyl)propanoyl)]-4-isopropyl-5-methyl-6-phenyl-1,3,
4-2H-oxadiazinan-2-one (5b). The crude product was
purified by silica gel column chromatography with
EtOAc/hexanes 1:1 to yield 1.100 g of 5b (84%) as a
brown oil: [a]2D5K10.2 (c 0.311, CHCl3); RfZ0.38 (EtOAc/
1
hexanes 50:50). H NMR (CDCl3): K0.14 (C5-methyl, d,
JZ7.0 Hz, 3H), 1.15 (d, JZ6.2 Hz, 3H), 1.33 (d, JZ
6.2 Hz, 3H), 2.52 (dd, JZ13.4, 3.3 Hz, 1H), 3.03 (dd, JZ
13.4, 12.0 Hz, 1H), 3.35 (septet, JZ6.2 Hz, 1H), 3.43 (s,
1H), 3.56 (C5-methine, septet, JZ7.0 Hz, 1H), 4.64 (dt, JZ
12.0, 3.3 Hz, 1H), 5.47 (br s, 1H), 5.85 (d, JZ5.1 Hz, 1H),
7.00–7.38 (m, 10H), 7.82 (d, JZ8.8 Hz, 2H), 8.27 (d, JZ
8.8 Hz, 2H). 13C NMR (CDCl3): 12.1, 20.3, 20.6, 31.7, 50.9,
53.8, 53.9, 72.6, 79.7, 123.5, 124.8, 126.5, 127.2, 128.3,
128.4, 128.6, 129.2, 135.2, 138.3, 147.4, 148.3, 149.9,
175.1. IR (neat): 3437, 2981, 1728, 1604, 1521, 1346, 1240,
1
(EtOAc/hexanes 30:70). H NMR (CDCl3): 0.67 (d, JZ
6.6 Hz, 3H), 1.09 (d, JZ6.2 Hz, 3H) 1.34 (d, JZ6.2 Hz,
3H), 2.69 (apparent triplet, JZ7.3, 8.4 Hz, 2H), 2.92–3.08
(m, 1H), 3.17–3.25 (m, 1H), 3.80–3.41 (m, 2H), 5.93 (d, JZ
5.1 Hz, 1H), 7.12–7.41 (m, 10H). 13C NMR (CDCl3): 12.8,
20.2, 20.6, 30.8, 38.8, 51.2, 53.7, 78.7, 124.7, 126.0, 128.0,

J. R. Burgeson et al. / Tetrahedron 61 (2005) 10965–10974
10973
699 cmK1. HRMS calcd for C29H31N3O6: 517.2213. Found:
517.2207. HPLC: 10 m silica, 4.6 mm!25 cm, EtOAc/
hexanes 35:65, RTZ13.08 min, crude ratioZ55:1.
127.8, 128.1, 128.3, 128.4, 128.5, 129.4, 135.5, 137.9,
139.1, 149.7, 174.6. IR (neat): 3458, 2982, 1728, 1240,
733 cmK1. HRMS calcd for C31H36N2O5: 516.2624. Found:
516.2637. HPLC: 10 m silica, 4.6 mm!25 cm, EtOAc/
hexanes 35:65, RTZ11.50 min, crude ratioZ99:1.
4.2.3. (5S,6R)-[(2S,3S)-3-(2-Benzyl-3-hydroxy-3-naph-
thalen-2-yl-propanoyl)]-4-isopropyl-5-methyl-6-phenyl-
2H-1,3,4-oxadiazin-2-one (5c). The crude product was
purified by silica gel column chromatography with EtOAc/
hexanes 1:1 to yield 0.613 g of 5c (40%) as a brown solid:
mp Z136–138 8C; RfZ0.38 (EtOAc/hexanes 1:1). 1H
NMR (CDCl3): K0.13 (C5-methyl, d, JZ7.0 Hz, 3H),
1.09 (d, JZ6.2 Hz, 3H), 1.29 (d, JZ6.2 Hz, 3H), 2.68 (dd,
JZ13.4, 3.2 Hz, 1H), 2.97 (dd, JZ13.4, 12.0 Hz, 1H),
3.21–3.24 (m, 1H), 3.49–3.59 (C5-methine, dq, JZ7.0,
5.5 Hz, 1H), 4.77–4.80 (dt, JZ12.0, 3.2 Hz, 1H), 5.55 (m,
1H), 5.83 (d, JZ5.1 Hz, 1H), 6.96–7.40 (m, 10H), 7.47–
7.52 (m, 2H), 7.58–7.68 (m, 1H), 7.78 (dd, JZ8.8, 1.8 Hz,
1H), 7.86–8.09 (m, 2H), 8.36 (s, 1H). The alcoholic proton
was not observed. 13C NMR (CDCl3): 12.1, 20.3, 20.6, 31.9,
50.9, 53.8, 54.1, 73.4, 79.6, 124.3, 124.9, 125.1, 125.8,
126.0, 126.2, 127.6, 128.1, 128.2, 128.3, 128.5, 129.3,
132.9, 133.2, 135.5, 138.4, 139.0, 149.6, 175.7. IR (CCl4):
3496, 2983, 1741, 1697, 1220, 736 cmK1. HRMS calcd for
C33H34N2O4: 522.2519. Found: 522.2514. HPLC: 10 m
silica, 4.6 mm!25 cm, EtOAc/hexanes 35:65, RTZ
10.25 min, crude ratioO20:1.
4.2.6. 2-d6-Isopropylamino-1-phenylpropan-1-ol (7). In a
2 L round-bottom flask was placed (1R,2S)-norephedrine
(25.0 g, 165 mmol) and dissolved in Ethanol (400 mL).
Acetone-d6 (21.0 mL, 258 mmol) and MgSO4 (8.5 g) were
added to the solution and the reaction mixture was allowed
to stir overnight. After stirring overnight, the reaction flask
was placed into an ice bath and NaBH4 (15.65 g,
412.5 mmol) was added over the course of 15 min. The
reaction was diluted with 6 M NaOH (100 mL) and stirred
for 15 min. After this time, the EtOH was evaporated and
the product extracted with EtOAc, NaHCO3, and brine, then
dried with MgSO4. EtOAc was removed by rotary
evaporation and the purified product was isolated via
crystallization (hexanes/EtOAc 2:1), affording 20.49 g of a
white solid in 63% yield. 1H NMR (CDCl3): d 0.80 (d, JZ
6.6 Hz, 3H), 2.94 (br s,1H), 3.04 (dq, JZ6.6, 4.0 Hz, 1H),
4.69 (d, JZ4.0 Hz, 1H), 7.24–7.35 (m, 5H). 13C NMR
(CDCl3): ( 15.2, 22.7, 22.9, 23.0 (–CD3), 45.3, 45.4, 45.4,
55.1, 73.4, 126.1, 126.9, 128.0, 141.4. IR (CHCl3): 3500,
703 cmK1. HRMS (FAB): Anal. Calcd for C12H13D6NO:
200.1921. Found: 200.1920.
4.2.4.
(5S,6R)-[(2S,3S)-3-(2-Benzyl-3-hydroxy-4,4-
dimethylpentanoyl)]-4-isopropyl-5-methyl-6-phenyl-2H-
1,3,4-oxadiazinan-2-one (5d). The crude product was
purified by silica gel column chromatography with
EtOAc/hexanes 2:3 to yield 0.622 g of 5d (91%) as a
brown oil: [a]2D5K9.80 (c 0.320, CHCl3); RfZ0.37 (EtOAc/
hexanes 2:3). 1H NMR (CDCl3): K0.22 (C5-methyl, d, JZ
7.0 Hz, 3H), 1.10 (d, JZ6.2 Hz, 3H), 1.17 (s, 9H), 1.29 (d,
JZ6.2 Hz, 3H), 2.93 (s, 1H), 3.07 (dd, JZ13.9, 11.7 Hz,
1H), 3.14 (dd, JZ13.9, 4.8 Hz, 1H), 3.30 (septet, JZ6.2 Hz,
1H), 3.50 (C5 methine, dq, JZ7.0, 5.5 Hz, 1H), 3.67 (s, 1H),
4.93 (dd, JZ11.7, 4.8 Hz, 1H), 5.77 (d, JZ5.5 Hz, 1H),
7.00–7.06 (m, 5H), 7.16–7.36 (m, 5H). Diastereomeric
4.2.7. 2-d6-Isopropylamino-N-nitroso-1-phenylpropan-
1-ol (8). In a 1 L round-bottom flask was placed deuterated
amino alcohol 7 (20.5 g, 103 mmol). To this solution was
added 45 mL of HCl (2.74 M, 123 mmol) and THF (50 mL)
was then added, followed by NaNO2 (8.15 g, 118 mmol).
The solution was stirred overnight. The THF was removed
by rotary evaporation and the reaction mixture was
extracted with EtOAc and brine then dried with MgSO4.
The EtOAc was removed by rotary evaporation and the
product was isolated via crystallization (hexanes/EtOAc
1
2:1) to afford 13.75 g of a yellow solid in 59% yield. H
1
excess (400 MHz H NMR): crude ratioZ19:1. 13C NMR
NMR (CDCl3): d 1.55 (d, JZ6.6 Hz, 3H), 3.19 (br s, 1H),
4.06 (dq, JZ6.6, 5.5 Hz, 1H), 4.38 (s, 1H), 5.15 (d, JZ
5.5 Hz, 1H), 7.26–7.37 (m, 5H). 13C NMR (CDCl3, mixture
of diastereomers): 10.3, 17.4, 21.9 (–CD3), 44.6, 54.4, 59.2,
60.2, 74.2, 76.8, 126.1, 126.7, 128.1, 128.2, 128.58, 128.63,
141.6, 142.0. IR: 3345, 1219, 757, 702 cmK1. HRMS
(FAB): Anal. Calcd for C12H12D6N2O2: 229.1823. Found:
229.1827.
(CDCl3): 11.9, 20.3, 20.7, 27.5, 32.7, 36.2, 48.5, 50.7, 53.8,
78.2, 79.5, 124.8, 126.4, 128.1, 128.4, 128.5, 129.5, 135.6,
139.3, 149.0, 177.8. IR (neat): 3525, 2977, 1733, 1232,
730 cmK1. HRMS calcd for C27H36N2O4 (MCC1):
453.2675. Found: 453.2751.
4.2.5. (5S,6R)-[(2S,3S)-3-(2-Benzyl-4-benzyloxy-3-hydro-
xybutanoyl)]-4-isopropyl-5-methyl-6-phenyl-2H-1,3,4-
oxadiazinan-2-one (5e). The crude product was purified by
silica gel column chromatography with EtOAc/hexanes 1:1
to yield 0.689 g of 5e (51%) as a brown oil: [a]2D5K17.2
(c 0.312, CHCl3); RfZ0.35 (EtOAc/hexanes 1:1). 1H NMR
(CDCl3): K0.09 (C5-methyl, d, JZ7.0 Hz, 3H), 1.09 (d, JZ
6.2 Hz, 3H), 1.29 (d, JZ6.2 Hz, 3H), 2.96 (dd, JZ13.6,
4.4 Hz, 1H), 3.08 (dd, JZ13.6, 11.0 Hz, 1H), 3.27 (septet,
JZ6.2 Hz, 1H), 3.54 (C5 methine, dq, JZ7.0, 5.1 Hz, 1H),
3.66 (dd, JZ9.9, 7.7 Hz, 1H), 3.72 (dd, JZ9.9, 4.0 Hz, 1H),
4.33–4.37 (m, 1H), 4.50 (dt, JZ11.0, 4.4 Hz, 1H), 4.57 (d,
JZ12.2 Hz, 1H), 4.65 (d, JZ12.2 Hz, 1H), 5.80 (d, JZ
5.1 Hz, 1H), 7.04–7.39 (m, 15H). The alcoholic proton was
not observed. 13C NMR (CDCl3): 12.0, 20.3, 20.7, 33.6,
50.1, 50.8, 53.8, 71.4, 71.9, 73.3, 79.4, 124.8, 126.3, 127.7,
4.2.8. 3,4,5,6-Tetrahydro-4-d6-isopropyl-5-methyl-6-
phenyl-2H-1,3,4-oxadiazin-2-one (10). In a flame-dried,
nitrogen-purged, 3 L round-bottom flask fitted with a
Claisen adapter fitted with a condenser and an addition
funnel was placed lithium aluminum hydride (4.50 g,
121 mmol) and THF (1 L). This stirred mixture was brought
to reflux and N-nitrosamine 8, (13.8 g, 60.3 mmol)
dissolved in THF (250 mL), was added to the flask dropwise
via the addition funnel. After the last drop, the reaction
stirred and allowed to reflux for 2 h, and at the end of this
time cooled with an ice bath. NaOH (3 M, 200 mL) was
added dropwise to quench the reaction. The reaction
mixture was extracted with EtOAc, Rochelle’s salt, and
brine, then dried with MgSO4. The EtOAc was evaporated

10974
J. R. Burgeson et al. / Tetrahedron 61 (2005) 10965–10974
to afford hydrazine 9, which immediately underwent
cyclization without characterization.
4-chlorobenzaldehyde (0.57 g, 4.1 mmol) was added to the
flask. The bath was removed and the reaction stirred
overnight. The reaction mixture was extracted with CHCl3
and washed with NH4Cl and brine, then dried with MgSO4.
The solvent was removed by rotary evaporation and the
crude product was purified via column chromatography
(hexanes/EtOAc 70:30). A light-yellow oil (1.34 g) was
isolated as the purified product in 97% yield. Diastereo-
meric excess 1H NMR (CDCl3): crude ratioR19:1 (CDCl3):
dK0.15 (d, JZ7.0 Hz, 3H), 2.61 (dd, JZ13.4, 10.2 Hz,
1H), 3.00 (dd, JZ13.4, 12.1 Hz, 1H), 3.19 (s, 1H), 3.29 (s,
1H), 4.61 (dt, JZ12.1, 3.5 Hz, 1H), 5.34 (br s, 1H), 5.83 (d,
JZ5.1 Hz, 1H), 7.00–7.05 (m, 5H), 7.10–7.14 (m, 2H),
7.30–7.39 (m, 5H), 7.57 (d, JZ8.0 Hz, 2H). 13C NMR
(CDCl3): d 12.1 (CH3), 19.9 (2!CD3), 31.9, 50.9, 53.5,
54.1, 72.9, 79.7, 124.8, 126.4, 127.7, 128.2, 128.3, 128.4,
128.6, 129.3, 133.3, 135.5, 138.9, 139.5, 149.8, 175.4. IR
(CHCl3): 3438, 1729, 1239, 736, 700 cmK1. HRMS (FAB):
Anal. Calcd for C29H25D6N2O4Cl: 512.2349. Found:
512.2351.
To a nitrogen-purged 1 L round-bottom flask fitted with a
condenser was placed the hydrazine and dissolved in
hexanes (120 mL) and stirred. To this solution was added
diethyl carbonate (5.4 mL, 45 mmol) and heated to a gentle
reflux. At this time, LiH (0.210 g, 25.2 mmol) was added
and the solution stirred overnight. The reaction was cooled
to room temperature and quenched with saturated NH4Cl
and the THF evaporated. The contents of the flask were
extracted with EtOAc and brine then dried with MgSO4.
The solvent was evaporated, yielding a white solid. The
purified product (3.44 g) was isolated via crystallization
1
(hexanes/EtOAc 2:1) in 24% yield. H NMR (CDCl3): d
0.92 (d, JZ7.0 Hz, 3H), 3.21 (br s, 1H), 3.50 (dq, JZ7.0,
3.3 Hz, 1H), 5.69 (br s,1H), 6.73 (br s, 1H), 7.26–7.41 (m,
5H). 13C NMR (CDCl3): d 12.2 (CH3), 19.9 (2!CD3), 52.2,
55.4, 55.5, 55.5, 75.8, 125.3, 127.9, 128.6, 137.0, 152.1. IR
(nujol): 3230, 1693, 1049, 745, 702 cmK1. HRMS (ESI):
Anal. Calcd for C13H12D6N2O2: 241.1823. Found:
241.1819.
Acknowledgements
4.2.9. 3-Hydrocinnamoyl-4-d6-isopropyl-5-methyl-6-
phenyl-2H-1,3,4-oxadiazin-2-one (11). In a flame-dried,
nitrogen-purged 1 L round-bottom flask fitted with a
condenser was placed 10 (3.44 g, 14.3 mmol) and CH2Cl2
(15 mL). To this stirred solution was added hydrocinnamoyl
chloride (3.0 mL, 18 mmol) and the solution was refluxed.
While refluxing, LiH (0.16 g, 22 mmol) was added and the
solution stirred overnight. The contents of the flask were
extracted with CH2Cl2 and washed with NH4Cl and brine,
then dried with MgSO4. The solvent was evaporated
yielding an oil, which upon standing turned into a solid.
The solid was purified via column chromatography
(hexanes/EtOAc 65:35) affording 4.91 g an off-white solid
in 92% yield. 1H NMR (CDCl3): d 0.67 (d, JZ7.0 Hz, 3H),
2.95–3.07 (m, 1H), 3.16–3.35 (m, 2H), 3.71–3.77 (m, 1H),
5.93 (d, JZ5.1 Hz, 1H), 7.14–7.40 (m, 10H). 13C NMR
(CDCl3): ( 12.9 (CH3), 20.3 (2!CD3), 31.0, 39.0, 51.5,
53.6, 78.9, 124.8, 126.1, 128.1 128.4, 128.6, 128.7, 136.1,
140.8, 148.9, 173.9. IR (CHCl3): 1715, 1049, 703, 754 cm1.
HRMS (ESI): Anal. Calcd for C22H20D6N2O3: 373.2398.
Found: 373.2402.
Acknowledgement is made to the donors of the American
Chemical Society Petroleum Research Fund for support of
this research. We thank Merck&Co., Inc. for their continued
generous support of our research efforts. We also thank
Pfizer, Inc. for material support for this research.
References and notes
1. Burgeson, J. R.; Renner, M.; Hardt, I.; Ferrence, G. M.;
Standard, J. M.; Hitchcock, S. R. J. Org. Chem. 2004, 69,
727–734.
2. Casper, D. M.; Blackburn, J. R.; Maroules, C. D.; Brady, T.;
Esken, J. M.; Ferrence, G. M.; Standard, J. M.; Hitchcock, S. R.
J. Org. Chem. 2002, 67, 8871–8876.
3. Hitchcock, S. R.; Nora, G. P.; Casper, D. M.; Squire, M. D.;
Maroules, C. D.; Ferrence, G. M.; Szczepura, L. F.; Standard,
J. M. Tetrahedron 2001, 57, 9789–9798.
4.2.10. 3-[2-Benzyl-3-(4-chlorophenyl)-3-hydroxypro-
pionyl]-4-d6-isopropyl-5-methyl-6-phenyl-2H-1,3,4-oxa-
diazin-2-one (12). To a flame-dried, nitrogen-purged,
100 mL round-bottom flask was added 11 (1.0 g,
2.7 mmol) and THF (10 mL). TiCl4 (0.56 mL, 5.7 mmol)
was added to this stirred solution and allowed to sit at room
temperature for 25 min. After this time, the solution was
cooled to K78 8C and after 5 min triethylamine (0.43 mL,
3.1 mmol) was introduced to the flask via syringe. Over the
course of 45 min the solution was allowed to warm up while
the enolate formed. After the 45 min had elapsed, the
solution was chilled to K78 8C again and after 5 min,
4. Hitchcock, S. R.; Casper, D. M.; Vaughn, J. F.; Finefield, J. M.;
Ferrence, G. M.; Esken, J. M. J. Org. Chem. 2004, 69, 714–718.
5. Caution. It should be noted that many N-nitrosamines are
potentially carcinogenic and should be handled with great care.
For more information on N-nitrosamines, please see: Lawley,
P. D. In Chemical Carcinogens; Searle, C. D., Ed.; ACS
monograph 182; American Chemical Society: Washington, DC,
1984.
6. Spartan 02; Wavefunction, Inc.: 18401 Von Karman Avenue,
Suite 370, Irvine, CA, USA, 2002.
7. PQS version 3.1; Parallel Quantum Solutions: 2013 Green
Acres, Suite A, Fayetteville, AR, USA, 2003.