Stereochemical aspects of novel 5,6-dihydro-4H-1,3-oxazines

Article abstract of DOI:10.1039/b008196p

Novel polysubstituted 5,6-dihydro-4H-1,3-oxazines are synthesized by 1,4-cycloaddition of unactivated olefins with N-acyliminiums from benzotriazole precursors. The configuration and conformation of the products are deduced from NMR investigation. The reg

Full text of DOI:10.1039/b008196p

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Stereochemical aspects of novel 5,6-dihydro-4H-1,3-oxazines
Alan R. Katritzky,a Ion Ghiviriga,b Ke Chen,a Dmytro O. Tymoshenkoa and
Ashraf A. A. Abdel-Fattaha
2
a Center for Heterocyclic Compounds, University of Florida, Gainesville, Florida, 32611-7200,
USA
b Department of Chemistry, University of Florida, Gainesville, Florida, 32611-7200, USA
Received (in Cambridge, UK) 11th October 2000, Accepted 17th January 2001
First published as an Advance Article on the web 19th March 2001
Novel polysubstituted 5,6-dihydro-4H-1,3-oxazines are synthesized by 1,4-cycloaddition of unactivated olefins
with N-acyliminiums from benzotriazole precursors. The configuration and conformation of the products are
deduced from NMR investigation. The regio- and exo–endo stereochemistry of the cycloaddition are discussed.
Conformations of compounds of six types of substitution (6-mono; 6,6-, 5,6- and 4,6-di; 4,6,6- and 4,5,6-tri)
are rationalized on the basis of axial-1,3-repulsion and the anomeric effect.
Introduction
The conformations of tetrahydro-1,3-oxazines have been much
studied:1 these rings normally assume chair structures similar
to those shown by cyclohexanes. Although ∆2-dihydro-1,3-
oxazines are well-known compounds2a,b their stereochemistry
is less documented. For cis-2,4,6-trisubstituted ∆2-dihydro-1,3-
oxazines3 a quasi-equatorial position of the 4- and 6-substi-
tuents minimizes 1,3-interactions. For 2,4,5,6-tetrasubstituted
compounds with alkyl substituents in positions 5 and 6, five
of the ring atoms are almost planar, with the C5 atom out of
the plane.4 These investigations3,4 along with X-ray study,5
demonstrated the “half boat” conformations (Fig. 1).
Configurational analysis of 5,6-dihydro-4H-1,3-oxazines was
discussed in the course of the elucidation of stereo- and
regiospecificity of their preparation.4,6–9 Generally, 5,6-dihydro-
4H-1,3-oxazines 3 are available via amidomethylation of
various unactivated olefins.10 Such transformations occur via
1,4-polar cycloadditions of an olefin 2 to an N-acyliminium
cation 1, with the formation of the heterocyclic system as the
primary product (Scheme 1). Regio- and stereospecificity of
the process are vital for further synthetic applications of
5,6-dihydro-4H-1,3-oxazines 3 which are known as key inter-
Fig. 1 Half boat conformation of ∆2-dihydro-1,3-oxazines.
mediates for the stereoselective syntheses of exo,cis-3-carboxy-
2-norborneol,†11 3-amino-12a–c and 3-amidopropanols.13
We now report on the synthesis of a series of polysubstituted
5,6-dihydro-4H-1,3-oxazines and the configurations and con-
formations of the products. These systems are readily available
via 1,4-cycloaddition of unactivated olefins to N-acyliminiums
1. Such reactive species were generated from N-(1-amido-
alkyl)benzotriazoles which we already reported as versatile
intermediates for a variety of amidoalkylations.14–16 Extending
previously documented synthetic approaches4,17a–g and our
recent work,18 this novel pathway provides a generalized route
to 5,6-dihydro-4H-1,3-oxazine ring systems (Table 1).
Results and discussion
† The IUPAC name for norborneol is bicyclo[2.2.1]heptan-2-ol, and the
IUPAC name for the compound mentioned in ref. 11 is 3-hydroxy-
bicyclo[2.2.1]heptane-2-carboxylic acid.
Preparation of the benzotriazole derivatives 4a–d
Adduct 4a19 was prepared by the literature method quoted.
Scheme 1
530
J. Chem. Soc., Perkin Trans. 2, 2001, 530–537
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b008196p

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Table 1 5,6-Dihydro-4H-1,3-oxazines 3. Yields and steric outcome in the amidoalkylation of alkenes with N-(α-amidoalkyl)benzotriazoles
Number of stereo- Configuration
isomers (isolated :
total possible)
Compd. R2
R4
R5
R6
R6Ј
Type
R4–R6
R5–R6
Yielda
3a
3b
3c
3d
3e
3f
Ph
Ph
H
H
H
H
H
Ph
H
–(CH2)4–
CH3
–(CH2)4–
CH3
(CH2)17CH3
H
Ph
ii
i
iii
v
vi
iv
v
1 : 1
1 : 1
1 : 2
1 : 2
1 : 4
1 : 2
2 : 2 71%
29%
—
—
—
trans
trans
trans
trans
cis
—
—
cis
—
cis
—
79
89
84
71
77
75
77
p-CH3O-C6H4
Ph
Ph
Ph
p-CH3-C6H4
p-CH3-C6H4
p-CH3-C6H4
p-Br-C6H4
H
H
H
H
H
CH3
(CH2)17CH3
Ph
3g
p-CH3O-C6H4
—
—
3h
3i
3j
p-CH3O-C6H4
p-CH3O-C6H4
p-CH3-C6H4
p-Br-C6H4
p-Br-C6H4
p-NO2-C6H4
H
H
(CH2)5CH3
H
Ph
iv
vi
vi
1 : 2
1 : 4
2 : 4 86%
14%
2 : 2 54%
46%
trans
trans
trans
cis
trans
cis
—
65
52
60
–(CH2)4–
cis
cis
cis
—
—
—
CH3
H
3k
3l
Ph
CH2CH2Ph
CH2CH2Ph
H
CH3
H
Ph
v
64
15
p-CH3-C6H4
H
n-C4H9
iv
2 : 2 77%
23%
trans
cis
—
3m
3n
3o
Ph
Ph
Ph
CH(CH3)2
p-CN-C6H4
p-CN-C6H4
H
H
CH3
CH3
H
H
Ph
Ph
Ph
v
iv
vi
N/A
N/A
3 : 4 55%
31%
N/A
N/A
trans
cis
N/A
N/A
cis
cis
trans
13
1(48)
1(7)
14%
trans
a Isolated yields. GCMS yields given in parentheses.
Compounds 4b–d were synthesized by the procedure19 similar
to that used for 4a, which was to combine benzotriazole, an
aldehyde and a corresponding amide in toluene with azeotropic
removal of water.
affect the regioselectivity of the process, which is consistent
with the results reported earlier.4
The generalized synthetic approach now utilized allowed
the synthesis of six classes of variously substituted oxazines
classified according to their substitution as (i) 6-monosub-
stituted (3b), (ii) 6,6-disubstituted (3a), (iii) 5,6-disubstituted
(3c), (iv) 4,6-disubstituted (3f,h,l,n), (v) 4,6,6-trisubstituted
(3d,g,k,m) and (vi) 4,5,6-trisubstituted (3e,i,j,o). This classi-
fication assisted the elucidation and systematization of the
configurations and conformations of polysubstituted 5,6-
dihydro-4H-1,3-oxazines 3a–o.
Preparation of 5,6-dihydro-4H-1,3-oxazines. Treatment of
adducts 4a–d with Lewis acids in refluxing dichloromethane
or 1,2-dichloroethane afforded the corresponding 5,6-dihydro-
4H-1,3-oxazines 3a–o (Scheme 1, Table 1). This synthetic
route improved the previously reported14 yield of compound
3b from 50 to 89% and extended the methodology to novel
4-unsubstituted derivative 3c. Further application of this
methodology to 4b–d derived from aromatic aldehydes
allowed us to synthesize previously unreported 4-substituted
5,6-dihydro-4H-1,3-oxazines 3d–o. The yields were rather
independent of the substituents in the 4-aryl ring, and both
strong electron withdrawing (3j, R4 = p-NO2C6H4) and electron
donating groups (3d–f, R4 = p-MeC6H4) led to 52–77%
yields. Exceptional behavior was observed in the case of
4-(p-cyanophenyl)-5,6-dihydro-4H-1,3-oxazine (3n), which,
according to GC-MS, was obtained in 48% yield. Apparently,
because of the high sensitivity of the 5,6-dihydro-4H-1,3-
oxazine ring to acidic conditions and of the cyano group
to basic ones, isolation of 3n by chromatography on neutral
alumina was achieved only in 1% yield.
Although the present route is favorable for the synthesis
of 4-aryl-5,6-dihydro-4H-1,3-oxazines, it has limitations for
other types of 4-substituents. Thus, compounds 3l,m with non-
aromatic carbon atoms attached at position 4 were obtained
only in 15 and 13% yields respectively, which may be con-
nected with deprotonation of the N-acyliminium inter-
mediates 1. Moreover, N-(1-amidoalkyl)benzotriazoles with
heteroaromatic substituents (R4 = pyridin-4-yl, thiophen-2-yl
and thiophen-3-yl) did not afford the expected dihydro-
oxazines 3.
NMR study and stereochemistry
The carbons in positions 4 and 6 (C4 and C6) were easily
identified by their characteristic chemical shifts, 40–50 ppm
1
for C4 and 70–80 ppm for C6. Subsequent one bond H–13C
correlation experiments then identified H4 and H6. Couplings
to H4 and H6 located the proton(s) in position 5. In
cases where the J4,5 and J5,6 coupling constants could not be
measured or assigned with certainty in the proton spectrum,
the DQCOSY technique was used. In every case, a multiple
1
bond H–13C correlation experiment identified the signals of
the substituents and confirmed the structural integrity of the
compounds. For example, a common feature of these com-
pounds is the long-range coupling of C2 at 155–157 ppm to
H4 and the ortho protons of R2, which were typically the
most deshielded aromatic protons, at 8.00–8.20 ppm. Another
interesting feature of compounds 3a–c, which all possess a
methylene group at position 4, is the large geminal coupling of
the protons in position 4 (16.6 Hz), due to the hyperconjugation
of the C4–H4 pseudo-axial bond with the C2᎐N bond.20
᎐
(i) The single 6-monosubstituted compound 3b can be con-
sidered the archetype of an unconstrained oxazoline ring.
The pseudo-axial–axial proton coupling constants H4a–H5a
and H5a–H6a are 10.5–10.8 Hz (Table 2). As for cyclohexanes,
axial protons are more shielded than those that are equatorial
(by 0.10 ppm at position 4 and by 0.28 ppm in position 5).
The NOESY spectrum of 3b displayed cross-peaks between
H4a and H6a, but not between H4e and the α-protons on the
alkyl chain in position 6 (1.75 and 1.60 ppm), indicating that
3b exists largely in the conformation with the alkyl chain
pseudo-equatorial.
Regioselectivity and product classification
According to 1H NMR, products 3a–o were all isolated as
single regioisomers; thus these cycloadditions are regiospecific
and follow the rule of electrophilic addition with the more
substituted side of the double bond ending up next to the
oxygen.6,8,9 Substituents in position 4 of the phenyl ring do not
J. Chem. Soc., Perkin Trans. 2, 2001, 530–537
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Table 2 Selected 1H chemical shifts and coupling constants for compounds 3
Compd.
δH2a,b
δH4a
δH4e
δH5a
δH5e
δH6a
δH6e
Selected coupling constantsc
3
3
3b
3a
3c
3e
3i
7.91
8.07
7.88
8.08
8.03
3.56
3.66
3.58
3.36
4.62
4.83
1.67
2.05
1.95
2.24
1.87
1.85
1.89
4.21
7.34
4.37
4.24
4.12
—
3J4a,5a = 10.8, J4a,5e = 5.2, J4e,5a = 5.3,
3J4e,5e = 2.8, 3J5a,6a = 10.5, 3J5e,6a = 3.2
3
3
3.22
1.70e
3J4a,5a = 9.5, J4a,5e = 5.0, J4e,5a = 4.8,
3J4e,5e = 4.8
3
3
3.63
1.50e
1.84 f
1.56d
1.72e
1.51d
1.84e
1.78
1.57d
2.05e
1.45d
2.10e
1.39d
2.10e
7.33a
5.12
3J4a,5 = 5.4, J4e,5 = 2.5, J5,5ꢀa = 14.0,
3J5,6 = 2.4, 3J6,6ꢀa = 2.4, 3J6,6ꢀe = 4.1
7.09a
7.08a
3J4e,5 = 2.1, J5,6 = 2.4, J5,5ꢀa = 11.8,
3
3
3J5,5ꢀe = 4.8, 3J6,6ꢀa = 2.9, 3J6,6ꢀe = 4.0
3J4e,5 < 2.0, J5,6 = 2.9, J5,5ꢀa = 12.5,
3J5,5ꢀe = 4.2, 3J6,6ꢀa = 2.9, 3J6,6ꢀe = 2.9
3J4,5 = 10.1, 3J5,6 = 10.4
3
3
3oЈ
3oЉ
3oٞ
3jЈ
3jЉ
3f
7.92
8.07
8.12
7.89
8.05
8.05
4.39
4.60
5.12
4.51
4.70
7.13a
7.38a
7.37a
7.56a
7.51a
7.49a
4.88
0.64c
2.37
2.48
0.71c
2.46
1.94
4.93
7.23a
5.68
4.99
7.31a
4.08
0.67c
0.23c
1.86
3J4,5 = 4.7, 3J5,6 = 5.0
7.37a
7.40a
5.21
3J4,5 = 4.6, 3J5,6 = 2.5
3J4,5 = 10.2, 3J5,6 = 10.3
0.75c
2.03
3J4,5 = 4.8, 3J5,6 = 4.7
3
3
1.74g
1.55 f
1.76 f
1.58 f
1.54 f,g
3J4e,5a = 5.5, J4e,5e = 3.5, J5a,6a = 9.4,
3J5e,6a = 3.5
3
3
3h
3lЈ
3lЉ
8.00
7.84
7.84
7.23a
5.15
3.57g
3.50
2.13
1.76
1.33
1.92
1.76
1.98
4.09
4.24g
4.15
3J4e,5a = 5.4, J4e,5e = 4.6, J5a,6a = 8.3,
3J5e,6a = 3.5
3
3
1.99 f,h
1.76 f,g
1.99 f
1.76 f
4.84
5.29
4.50
3.70
3J4e,5a = 5.4, J4e,5e = 4.6, J5a,6a = 8.3,
3J5e,6a = 3.5
1.54 f
3J4a,5a = 11.3, 3J4a,5e = 5.0, 3J5a,6a = 12.0,
3J5a,6e = 2.4
3d
8.17
8.20
8.24
8.09
7.29a
7.51a
7.50a
1.95 f
1.87 f
1.85 f
1.81 f
1.81
1.61
1.64
1.66
2.46
2.78
3.04
2.22
1.81c
1.92c
7.50a
1.67c
7.51a
7.56a
1.74c
7.51a
3J4a,5a = 11.6, 3J4a,5e = 4.6
3J4a,5a = 11.3, 3J4a,5e = 4.5
3J4a,5a = 11.7, 3J4a,5e = 4.2
3J4a,5a = 11.3, 3J4a,5e = 5.0
3gЈ
3gЉ
3kЈ
3kЉ
8.13
2.99
1.69
2.45
1.69c
7.41a
3J4a,5a = 11.7, 3J4a,5e = 4.7
a In ppm relative to TMS. b ortho protons of the aryl group. c In Hz. The proton spectra were acquired with a digital resolution of 0.1 Hz per point.
d Methyl protons. e Axial proton in α position. f Equatorial proton in α position. g Proton in α position. h The assignment of the coupling constants
and of the axial or equatorial position is uncertain—see text.
(ii) The single 6,6-disubstituted compound 3a displays
NOE’s between both protons in position 4 and each of the
corresponding cis groups in position 6, indicating that 3a exists
as a rapidly equilibrating mixture of the two possible confor-
mations (cf. Table 3). The vicinal coupling constant between
the proton at 3.22 ppm in position 4 and that at 2.05 ppm
in position 5 is 9.5 Hz. This value is smaller than that for the
Fig. 2 Conformational equilibrium for 3c.
J4,5 axial–axial coupling in 3b (10.8 Hz), which agrees with the
presence of conformational averaging, but is large enough to
indicate that one conformation is dominant, and that the
protons at 3.22 and 2.05 ppm spend most of the time in
a pseudo-axial position. The proton at 3.22 ppm displays an
NOE with the ortho protons of the phenyl in position 6 (7.34
ppm) suggesting an axial preference for the phenyl group. The
protons in position 4 in 3a, as compared to 3b, display strong
upfield shifts, 0.34 ppm for H4a and 0.08 ppm for H4e. These
shifts are not the result of conformational averaging, but of the
orientation of the phenyl ring in position 6 such as to minimize
the repulsive interaction with H4a. In this orientation the pro-
tons in position 5 fall in a deshielding zone, and their chemical
shift is higher than in 3b by 0.38 ppm for H5a and by 0.29 ppm
for H5e. Repulsion between the axial phenyl in position 6 and
the phenyl in position 2 rotates the latter more into the plane of
the NCO atoms, as indicated by a downfield shift of 0.16 ppm
of its ortho protons.
(iii) The single 5,6-disubstituted compound 3c has a cyclo-
hexane ring condensed in positions 5 and 6 of the oxazine
ring. The protons in position 4 (3.63 and 3.36 ppm) display
vicinal couplings smaller than 5.5 Hz, indicating that 3c exists
primarily in a conformation in which H5 is equatorial, and,
consequently, the junction of the two rings must be cis. Other
coupling constants (Table 2) support the conformation (Fig. 2),
in which H5 is equatorial to the oxazine ring and axial to the
cyclohexane ring, while H6 is axial to the oxazine ring and
equatorial to the cyclohexane ring. Further support for this
comes from the NOE’s (Fig. 2) between the axial protons: H4
axial (3.63 ppm) and H6 (4.37 ppm) on the oxazine ring;
H5 (1.87 ppm), H7 (1.57 ppm) and H9 (1.33 ppm) on the cyclo-
hexane ring. Axial proton H7 is in position α to C6, as indicated
by both coupling and NOE to H6. Equatorial proton H7
(2.05 ppm) displays a cross-peak in the NOESY spectrum with
the equatorial proton in position 4 (3.36 ppm), a proof that 3c
exists as a rapid equilibrium of the two possible conformations
shown in Fig. 2 and Table 3.
(iv) The 4,6-disubstituted oxazines 3f and 3h were isolated as
single isomers. The NOE’s between H4 and the α and β protons
of R6 and between H6 and the ortho protons of R4 demon-
strated the trans relationship of R4 and R6, and also the
presence of fast conformational equilibria for both 3f and 3h
(see Table 3). The large coupling constants (9.4 and 8.3 Hz)
between H6 and one of the protons in position 5 indicated
that in the preferred conformations H6 is axial, as in 3b.
The presence of fast equilibria in 3f and 3h (as opposed to
3b) indicates that an aryl in position 4 prefers an equatorial
position.
The 4,6-disubstituted oxazine 3l, in which R4 and R6 are both
alkyl groups, was isolated as a mixture of isomers, 3lЈ and 3lЉ,
in 1 : 0.30 ratio. Compound 3lЈ is the trans isomer, as indicated
by the NOE’s between H4 and the α protons of R6 and between
H6 and the α protons of R4. Unfortunately, it was impossible to
determine with certainty which is the dominant conformer in
532
J. Chem. Soc., Perkin Trans. 2, 2001, 530–537

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Table 3 Conformational preferences of oxazines 3
one coupling constant of 11.3–11.7 Hz, indicating that they all
adopt only the conformation in which H4 is axial.
Driving force
in the con-
formational
equilibrium
(vi) Two of the 4,5,6-trisubstituted oxazines 3e and 3i each
possess a cyclohexane-fused oxazine skeleton (as does 3c);
both 3e and 3i were isolated as single isomers. The protons in
position 5 of 3e and 3i each display just one large coupling (with
the cyclohexane axial proton in the position α to C5), proof
that in the dominant conformation H5 is axial with respect to
the cyclohexane ring. If the junctions of the oxazine and cyclo-
hexane rings were trans, H5 and H6 should display a coupling
constant of 10.0–14.0 Hz. A value of 2.8 Hz for this coupling
demonstrates that the ring junction is cis, as in 3c. H6 displays
in the NOESY spectrum a cross-peak with the ortho protons of
the aryl group in position 4, indicating that they are cis (and
both axial). As expected for the dominant conformation shown
in Table 3, H4 displays no NOE to H6, which is axial to the
oxazine ring, and a large NOE to H5αe, the equatorial proton
on the cyclohexane in position α to C5. However, an NOE
between H4 and H6αe of the cyclohexane ring demonstrates
the fast equilibrium with the other possible conformation
(Fig. 2), in which these two protons are both axial. We have
noticed similar NOE’s in molecules which have the geometry of
cis-decalin.21
Compd.
Conformation
3b
Axial–axial
repulsion
3a
Complex
steric inter-
actions—
see text
3c, 3e, 3i
Axial–axial
repulsion
3oЈ, 3jЈ, 3lЉ
3oЉ, 3jЉ
Axial–axial
repulsion
The proton spectra of the two 4,5,6-trisubstituted oxazines,
3j and 3o, each displayed signals for mixtures of isomers. In
the case of 3o the mixture contained three isomers in a ratio
3oЈ–3oЉ–3oٞ of 1 : 0.58 : 0.25. Coupling constants of 10.1 Hz
between H5 and H4 and 10.4 Hz between H5 and H6 demon-
strated that in 3oЈ these three protons are all pseudo-axial. This
was confirmed by the NOE between the protons in positions
4 and 6. The ortho protons of the aryl rings in positions 4
and 6 (7.38 and 7.33 respectively) were identified by (a) the
NOE’s to H4 and H6 and (b) NOE’s with both H5 and the
methyl in position 5; this confirmed that the 4- and 6-aryl
groups are equatorial.
In 3oЉ, both H4 and H6 displayed the NOE’s with two
different aromatic protons (7.23 and 7.37 ppm) demonstrating
that the substituents in positions 4 and 6 are trans, and that
there is conformational exchange. The relative size of the
NOE’s indicated that the signal at 7.37 ppm belonged to the
4-aryl and the one at 7.23 ppm to the 6-aryl. The relative size
of the NOE’s of these protons with H5 and the protons of the
5-methyl indicated that R4 and R5 are cis. The lack of NOE
between H4 and H6 agrees with their trans relationship. Of
the two possible half-chair conformations, the one with R4
axial and R5 and R6 equatorial should display a coupling of
ca. 10.0 Hz between H5 and H6. An actual value of 5.0 Hz
indicates that the other conformation, with two substituents
in axial positions, prevails, or at least has a significant contri-
bution to the equilibrium (cf. Table 3).
The NOE between H4 and H6 in 3oٞ clearly demonstrates
that these protons are cis and both axial. Small values for the
coupling constants between H5 and H4 and between H5
and H6 indicate that H5 is equatorial. NOE’s with H4 and H6
identified the ortho protons in the 4- and 6-aryl groups as 7.56
and 7.37 ppm, respectively. Both of these protons display
NOE’s with H5.
Interestingly, the difference in the chemical shifts of H4
and H6 in 3oЈ and 3oٞ illuminates the conformations of these
molecules. Allinger and Tribble22 have shown that an equatorial
phenyl is most stable in the bisector plane of the cyclohexane
chair. Two facts clearly indicate that an axial methyl in position
5 confines the equatorial aryl groups in positions 4 and 6 of
3oٞ to a plane perpendicular to the plane of the oxazine ring
more than in 3oЈ: (a) a deshielding of ca. 0.75–0.80 ppm
for H4 and H6 in 3oٞ, as they are more into the plane of
the geminal aryl group, and (b) a significant shielding of
both the protons (0.23 vs. 0.64 ppm) and the carbon (11.7 vs.
13.0 ppm) of R5.
Anomeric
effect
3oٞ
Axial–axial
repulsion
3f, 3h, 3lЈ
3d, 3gЈ, 3kЈ
Axial–axial
repulsion
Axial–axial
repulsion
3gЉ, 3kЉ
Axial–axial
repulsion
the fast conformational equilibrium of 3lЈ. The two protons
in position 5 overlapped their signals with one of the α protons
in position 4 and prevented the assignment of the coupling
constants. However, H4 and H6 display in 3lЈ some couplings
similar to those in 3f and 3h, suggesting that the dominant
conformation has R4 in the axial position. In the minor isomer
3lЉ, both H4 and H6 display a large coupling with one of the
protons in position 5, indicative of both being pseudo-axial. A
NOE between H4 and H6 confirmed their cis relationship. The
NOESY spectrum did not display any cross-peaks indicative
of conformational exchange.
(v) The 4,6,6-trisubstituted oxazine 3d was isolated as a single
isomer, namely that in which the aryl substituents in positions
4 and 6 are cis and equatorial, as demonstrated by a NOE
between H4 and the methyl protons in position 6. A coup-
ling constant of 11.6 Hz between H4 and the axial proton
in position 5 also indicated that H4 is axial and that this is
by far the dominant conformation. No NOE’s indicative of
conformational exchange were observed.
The other two 4,6,6-trisubstituted oxazines 3g and 3k were
each isolated as mixtures of the two possible isomers, in ratios
3gЈ–3gЉ of 1 : 0.40 and 3kЈ–3kЉ of 1 : 0.85. In both cases, an NOE
between H4 and the methyl group indicated that the major
isomer is the one in which these groups are cis and axial, as in
3d. For all four compounds 3gЈ, 3gЉ, 3kЈ, 3kЉ, H4 displayed
Two isomers were identified in the 3j mixture, namely 3jЈ and
J. Chem. Soc., Perkin Trans. 2, 2001, 530–537
533

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3jЉ, in a ratio of 1 : 0.16. Their stereochemistry was the same
as that of 3oЈ and 3oЉ, respectively, as indicated by coupling
constants and NOE’s. It is possible that for 3j the mixture
contained other isomers also, but they were in quantities of
less than 5% of the major isomer.
In the case of monosubstituted (without counting R2)
oxazine 3b, repulsion between R6 axial and H4 axial protons
drives R6 into the equatorial position, as the only con-
formation. In all of the cases in which in position 6 there is a
substituent cis to R4 (3oЈ, 3jЈ, 3lЉ, 3oٞ, 3d, 3gЈ, 3kЈ, 3gЉ, 3kЉ),
repulsion between the R4 and R5 substituents shifts the con-
formational equilibrium completely towards the conformation
in which R4 and R6 are both equatorial. The conformational
equilibrium of the 4,6-disubstituted oxazines with R4 and R6
trans (3f, 3h, 3lЈ) is driven by steric repulsion; it appears that an
R6 in the axial position is more hindered than an axial R4.
Axial–axial interactions of R5 are not a factor in the con-
formational equilibrium of 4,5,6-trisubstituted oxazines, as
demonstrated by the similarity of 3J4e,5e in 3c, 3e, 3i on one hand
and 3f, 3h, 3lЈ on the other. As in the case of 3f, 3h, 3lЈ, the
conformational equilibria of 3c, 3e, 3i are determined by the
preference of the alkyl R6 for the equatorial position.
Steric outcome of the preparative cyclizations and mechanistic
consideration
In all of the products 3a–o the most substituted sp2 carbon of
the alkene ended up next to the oxygen. The regioselectivity
of the reaction between an N-acyliminium ion and an alkene is
well documented4,6,8,9 and demonstrates that in the transition
state the positive charge is delocalized from the diene into the
dienophile.
The reaction has also been found to be cis-stereospecific4,6,8,9
—the cis relationship of the R5 and R6 substituents in the
alkene is preserved in the oxazine—proof that the formation
of the two new bonds is synchronous. We found this to be true
for all of the compounds of types (ii) and (vi), for which the
cis stereospecificity is an issue (Table 1), except for 3o, which
contained 14% of the trans product 3oЉ. It is possible that 3oЉ
was formed by epimerization at C6 after cyclization.9
However, for 4,6-trans-disubstituted derivatives 3oЈ and 3jЉ in
which R6 is aryl, the major conformation in the equilibrium is
the one with R6 axial. The explanation we offer is an anomeric
effect, the electronegative atom geminal to the oxygen being an
sp2 carbon atom.
The explanation for the axial preference of the phenyl
group in 3a is the one offered by Hodgson et al.23 for the
case of 1-methyl-1-phenylcyclohexane: an equatorial phenyl
has a strong interaction of the ortho protons with either the
methyl group or the vicinal equatorial protons in positions 2
and 6, while an axial phenyl can minimize these interactions by
orienting itself parallel to the plane of the bonds C3–H3a and
C5–H5a.
Compounds of types (iv), (v) and (vi) can reveal the exo–
endo specificity of the reaction. To our knowledge, this type of
specificity has been previously encountered only with some
intramolecular cyclizations.8 We postulate that in the transition
state the acyliminium ion 1 approaches the geometry depicted
in Scheme 1, with R4 and the acyl anti, and the diene system
s-cis.
Of the compounds of type (iv), we found 3f and 3h to
be obtained with complete stereospecificity, as the products
derived from the transition state in which the repulsion between
R2 and R6 (alkyl) is minimal. The acyliminium ion is more
reactive when R4 is an alkyl, and indeed for 3l 23% of the other
product is also obtained.
All of the examples of type (v) have been obtained from
reactions of α-methylstyrene. In the case of 3d the reaction
affords entirely the product from the transition state in which
the phenyl and not the methyl overlaps the aromatic R2. A
possible explanation might be the π-stacking of R2 and R6, in
the transition state, which reduces the electron deficiency of
the acyliminium ion. For 3g, in which R2 is p-anisyl instead
of phenyl, this electron deficiency is reduced and 29% of the
other product is formed. In the case of 3k, there is basically no
stereoselectivity of the cycloaddition because of the higher
reactivity of the acyliminium ion with R4 alkyl.
Compounds of type (vi) were obtained in the reactions of
cyclohexene (3e, 3i) and of trans-β-methylstyrene (3j, 3o). The
reactions of cyclohexene with acyliminium ions, in which R4 is
an aryl, resemble those of monosubstituted alkenes—the same
as for 3f and 3h. Compounds 3e and 3i were derived only from
the transition state in which the repulsion between R2 and R6 is
minimized. In reactions of trans-β-methylstyrene to give 3j and
3o, minimal repulsion between R2 and R6Ј in one transition
state is counteracted with the other by π-stacking or by steric
interactions of R5 and mixtures of products 3jЈ and 3jЉ, and
3oЈ, 3oЉ and 3oٞ are formed.
Similar preference of an sp2 substituent for the axial position
has been found in the case of 6-methoxycarbonyl-6-methyl-4-
phenyl-5,6-dihydro-4H-1,3-oxazine:4 the isomer in which the
methyl in position 6 and the phenyl in position 4 are cis, exists
solely as the conformation in which these groups are both
equatorial, while the isomer in which these groups are trans
exists as a mixture of comparably populated conformers.
Conclusion
In conclusion, a novel amidoalkylation of unactivated olefins
with N-(1-amidoalkyl)benzotriazoles to produce 5,6-dihydro-
4H-1,3-oxazines involves regio- and cis-stereoselective polar
[2 ϩ 4] cycloaddition. The reaction displays exo–endo stereo-
selectivity in several cases. The factors, which determine this
type of selectivity, have been discussed. The conformational
preferences of oxazines with various substitutions have been
reported. Anomeric interaction between the oxygen in position
1 and an sp2 carbon attached to position 6 was found to play a
role in these conformational equilibria.
Experimental
General
Melting points were determined on a hot-stage apparatus and
are uncorrected. NMR spectra were recorded in CDCl3 with
1
tetramethylsilane as the internal standard for H (300 MHz)
In conclusion, we have demonstrated that exo–endo selec-
tivity can be obtained in reactions of an acyliminium ion
stabilized by an aryl R4 with each of the following types of
alkene (a) monosubstituted, (b) cis-disubstituted or (c) 1,1-
disubstituted with one aromatic and one aliphatic substituent.
or the solvent as the internal standard for 13C (75 MHz).
Microanalyses were performed on a Carlo Erba-1106 elemental
analyzer. Benzene and toluene were dried over molecular
sieves. Column chromatography was conducted with silica gel
200–425 mesh.
Conformational characteristics of 5,6-dihydro-4H-1,3-oxazines
General procedure for the preparation of 5,6-dihydro-4H-1,3-
oxazines
The conformational preferences encountered in this series of
19 variously substituted oxazines are summarized in Table 3.
One can identify two factors which drive the conformational
equilibrium, the van der Waals repulsion and the anomeric
effect.
A mixture of N-(benzotriazol-1-ylmethyl)benzamide (1 mmol),
unactivated olefin (1 mmol) and zinc bromide (0.45 g, 2 mmol)
in dry 1,2-dichloroethane (30 cm3) was refluxed for 24 h and
poured into ice–water (50 cm3). The organic layer was washed
534
J. Chem. Soc., Perkin Trans. 2, 2001, 530–537

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with 10% NaOH (30 cm3) and water (30 cm3) and dried over
MgSO4 (5 g). The solvent was evaporated and the residue was
purified by column chromatography on neutral alumina using
CH2Cl2–hexanes as an eluent.
(75%); mp 64.0–66.0 ЊC. Found: N, 2.81. Calc. for C35H53NO:
N, 2.78%. δH(300 MHz; CDCl3; Me4Si) 8.05 (2 H, d, J 7.4, Ph),
7.41 (3 H, dd, J 7.3 and 1.1, Ph), 7.14 (4 H, s, Ph), 4.88 (1 H, dd,
J 4.0 and 5.2, NCH), 4.08 (1 H, m, OCH), 2.33 (3 H, s, ArCH3),
2.02–1.92 (2 H, m, NCHCH2), 1.83–1.70 (2 H, m, (CH2)17),
1.56–1.49 (2 H, m, (CH2)17), 1.43–1.11 (30 H, m, (CH2)17), 0.88
(3 H, t, J 6.3, (CH2)17CH3); δC(75 MHz; CDCl3; Me4Si)
6-Methyl-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (3a). This
compound was obtained as a colorless oil (79%). Found: C,
80.96; H, 6.98. Calc. for C17H17NO: C, 81.24; H, 6.82%. δH(300
MHz; CDCl3; Me4Si) 8.06 (2 H, d, J 7.6, Ph), 7.44–7.25 (8 H,
m, Ph), 3.63–3.55 (1 H, m, NCH2), 3.28–3.18 (1 H, m, NCH2),
2.28–2.20 (1 H, m, CCH2), 2.14–1.92 (1 H, m, CCH2), 1.70
156.1 (N᎐C), 141.4 (ArC), 136.1 (ArC), 134.2 (ArC), 130.4
᎐
(ArC), 129.0 (ArC), 128.0 (ArC), 127.2 (ArC), 126.8 (ArC),
71.2 (O-CH), 54.1 (N-CH), 35.3 (NCHCH2), 34.7 ((CH2)17),
31.9 ((CH2)17), 29.7 ((CH2)17), 29.6 ((CH2)17), 29.4 ((CH2)17),
25.1 ((CH2)17), 22.7 ((CH2)17), 21.0 (ArCH3), 14.1 (CH3).
(3 H, s, CCH ); δ (75 MHz; CDCl ; Me Si) 155.0 (N᎐C), 145.1
᎐
3
C
3
4
(ArC), 134.1 (ArC), 130.3 (ArC), 128.6 (ArC), 128.1 (ArC),
127.2 (ArC), 127.0 (ArC), 124.1 (ArC), 78.4 (C-O), 41.0 (C-N),
33.5 (CH2), 29.7 (CH3).
4-(4-Bromophenyl)-2-(4-methoxyphenyl)-6-methyl-6-phenyl-
5,6-dihydro-4H-1,3-oxazine (3g). This compound was obtained
as white prisms (77%); mp 65.0–67.0 ЊC. Found: C, 66.28;
H, 5.14; N, 3.21. Calc. for C24H22BrNO2: C, 66.06; H, 5.08;
N, 3.21%. δH(300 MHz; CDCl3; Me4Si) 8.17 (1 H, d, J 9.1, Ph),
8.13 (1 H, d, J 8.8, Ph), 7.53–7.23 (8 H, m, Ph), 7.09 (1 H, t,
J 7.6, Ph), 6.97 (2 H, t, J 8.5, Ph), 5.22 (0.7 H, dd, J 4.6 and
11.4, NCH), 4.43 (0.3 H, dd, J 4.2 and 11.5, NCH), 3.87 (3 H, s,
ArOCH3), 3.00 (0.3 H, dd, J 4.1 and 13.5), 2.73 (0.7 H, dd,
J 4.6 and 13.5, NCHCH2), 1.87 (s, 2H), 1.69 (s, 1H), 1.65–1.51
6-Octadecyl-2-phenyl-5,6-dihydro-4H-1,3-oxazine (3b). This
compound was obtained as white prisms (89%); mp 64 ЊC.
Found: N, 3.40. Calc. for C28H47NO: N, 3.39%. δH(300 MHz;
CDCl3; Me4Si) 7.91 (2 H, d, J 6.5, Ph), 7.46–7.30 (3 H, m, Ph),
4.27–4.16 (1 H, m, OCH), 3.70–3.50 (2 H, m, NCH2), 2.00–1.92
(1 H, m, NCH2CH2), 1.77–1.11 (35 H, m, NCH2CH2 and
(CH2)17), 0.88 (3 H, t, J 6.6, CH3); δC(75 MHz; CDCl3; Me4Si)
(1 H, m, NCHCH ); δ (75 MHz; CDCl ; Me Si) 161.7 (N᎐C),
᎐
2
C
3
4
155.9 (N᎐C), 134.2 (ArC), 130.2 (ArC), 127.9 (ArC), 126.9
᎐
161.6 (ArC), 155.6 (ArC), 146.0 (ArC), 144.2 (ArC), 143.7
(ArC), 143.3 (ArC), 132.3 (ArC), 128.9 (ArC), 128.9 (ArC),
128.8 (ArC), 128.6 (ArC), 128.4 (ArC), 128.2 (ArC), 128.1
(ArC), 127.9 (ArC), 127.8 (ArC), 127.4 (ArC), 127.3 (ArC),
126.7 (ArC), 126.4 (ArC), 124.1 (ArC), 122.5 (ArC), 122.4
(ArC), 113.5 (ArC), 113.4 (ArC), 79.4 (O-CH), 78.2 (O-CH),
55.4 (ArOCH3), 53.9 (NCH), 53.8 (NCH), 40.7 (NCHCH2),
40.1 (NCHCH2), 31.1 (OCCH3), 26.5 (OCCH3).
(ArC), 74.9 (C-O), 43.0 (C-N), 35.6 (N-C-C), 31.9 ((CH2)17),
29.7 ((CH2)17), 29.6 ((CH2)17), 29.4 ((CH2)17), 27.3 ((CH2)17),
25.0 ((CH2)17), 22.7 ((CH2)17), 14.1 (CH3).
4-(4a,5,6,7,8,8a-Hexahydro-4H-1,3-benzoxazin-2-yl)phenyl
methyl ether (3c). This compound was obtained as white prisms
(84%); mp 45.0–47.0 ЊC. Found: N, 5.78. Calc. for C15H19NO:
N, 5.71%. δH(300 MHz; CDCl3; Me4Si) 7.89 (2 H, d, J 7.1, Ph),
6.87 (2 H, d, J 7.4, Ph), 4.39 (1 H, dd, J 4.0 and 5.5, OCH), 3.82
(3 H, s, OCH3), 3.64 (1 H, dd, J 4.2 and 15.9, NCH2), 3.37 (1 H,
dd, J 2.5 and 16.5, NCH2), 2.05–2.04 (1 H, m, NCH2CH), 1.88–
1.87 (1 H, m, (CH2)4), 1.71–1.34 (7 H, m, (CH2)4); δC(75 MHz;
4-[4-(4-Bromophenyl)-6-hexyl-5,6-dihydro-4H-1,3-oxazin-2-
yl]phenyl methyl ether (3h). This compound was obtained as a
colorless oil (65%). Found: C, 64.16; H, 6.77; N, 3.55. Calc. for
C23H28BrNO2: C, 64.19; H, 6.56; N, 3.25%. δH(300 MHz;
CDCl3; Me4Si) 8.01 (2 H, d, J 8.7, Ph), 7.58–7.46 (1 H, m, Ph),
7.36–7.23 (2 H, m, Ph), 7.19–7.09 (1 H, m, Ph), 6.92 (2 H, d,
J 8.9, Ph), 5.16 (1 H, t, J 4.4, NCH), 4.12–4.07 (1 H, m, OCH),
3.85 (3 H, s, ArOCH3), 2.19–2.09 (1 H, m, NCHCH2), 1.96–
0.96 (11 H, m, NCHCH2 and (CH2)5), 0.90 (3 H, t, J 6.9, CH2-
CDCl ; Me Si) 161.2 (N᎐C), 154.7 (ArCO), 128.4 (ArC), 126.6
᎐
3
4
(ArC), 113.1 (ArC), 72.5 (OCH3), 55.2 (OCH), 48.7 (NCH2),
32.0 (NCH2CH), 30.4 ((CH2)4), 25.3 ((CH2)4), 24.4 ((CH2)4),
20.2 ((CH2)4).
6-Methyl-4-(4-methylphenyl)-2,6-diphenyl-5,6-dihydro-4H-
1,3-oxazine (3d). This compound was obtained as a colorless
oil (71%). Found: N, 4.26. Calc. for C24H23NO: N, 4.10%.
δH(300 MHz; CDCl3; Me4Si) 8.18 (2 H, d, J 6.0, Ph), 7.50 (2 H,
d, J 7.2, Ph), 7.43–7.20 (8 H, m, Ph), 7.14 (2 H, d, J 7.2, Ph),
4.84 (1 H, dd, J 5.0 and 11.8, NCH), 2.45 (1 H, dd, J 4.5 and
13.5, NCHCH2), 2.32 (3 H, s, ArCH3), 1.85–1.77 (1 H, m,
NCHCH2), 1.80 (3 H, s, CCH3); δC(75 MHz; CDCl3; Me4Si)
CH ); δ (75 MHz; CDCl ; Me Si) 161.6 (N᎐C), 156.7 (ArC),
᎐
3
C
3
4
143.1 (ArC), 132.7 (ArC), 129.3 (ArC), 128.8 (ArC), 128.2
(ArC), 127.3 (ArC), 113.3 (ArC), 71.5 (OCH), 55.3 (ArOCH3),
53.9 (NCH), 35.0 (NCHCH2), 32.3 ((CH2)5), 31.7 ((CH2)5), 29.2
((CH2)5), 25.1 ((CH2)5), 22.6 ((CH2)5), 14.1 (CH2CH3).
4-(4-Bromophenyl)-2-(4-methoxyphenyl)-4a,5,6,7,8,8a-hexa-
hydro-4H-1,3-benzoxazine (3i). This compound was obtained as
a colorless oil (52%). Found: N, 3.27. Calc. for C21H22BrNO2:
N, 3.50%. δH(300 MHz; CDCl3; Me4Si) 8.04 (2 H, d, J 8.7, Ph),
7.56 (1 H, d, J 8.0, Ph), 7.23 (1 H, d, J 7.7, Ph), 7.09 (2 H,
t, J 7.4, Ph), 6.92 (2 H, d, J 8.8, Ph), 4.83 (1 H, s, OCH), 4.12
(1 H, br s, NCH), 3.83 (3 H, s, ArOCH3), 2.15–2.07 (1 H,
m, NCHCH), 1.91–1.75 (3 H, m, (CH2)4), 1.62–1.32 (5 H, m,
154.8 (N᎐C), 146.1 (ArC), 141.3 (ArC), 136.2 (ArC), 134.3
᎐
(ArC), 130.4 (ArC), 129.0 (ArC), 128.4 (ArC), 128.0 (ArC),
127.3 (ArC), 127.2 (ArC), 126.5 (ArC), 124.0 (ArC), 77.9
(O-C), 53.8 (N-C), 43.0 (OCCH2), 26.5 (ArCH3), 21.0 (CCH3).
4-(4-Methylphenyl)-2-phenyl-4a,5,6,7,8,8a-hexahydro-4H-
1,3-benzoxazine (3e). This compound was obtained as a color-
less oil (77%). Found: N, 4.70. Calc. for C21H23NO: N, 4.59%.
δH(300 MHz; CDCl3; Me4Si) 8.09 (2 H, d, J 6.7, Ph), 7.47–7.38
(3 H, m, Ph), 7.18–7.09 (4 H, m, Ph), 4.59 (1 H, d, J 2.0, OCH),
4.21 (1 H, dd, J 2.7 and 6.4, NCH), 2.33 (3 H, s, ArCH3),
2.07 (1 H, dd, J 3.4 and 13.5, NCHCH), 1.84–1.26 (8 H, m,
(CH ) ); δ (75 MHz; CDCl ; Me Si) 161.6 (N᎐C), 156.3 (ArC),
᎐
2
4
C
3
4
142.7 (ArC), 132.8 (ArC), 129.3 (ArC), 128.8 (ArC), 128.1
(ArC), 127.0 (ArC), 126.1 (ArC), 123.0 (ArC), 113.3 (ArC),
67.9 (OCH), 61.3 (NCH), 55.3 (ArCH3), 37.4 (NCHCH), 30.3
((CH2)4), 26.4 ((CH2)4), 25.1 ((CH2)4), 20.0 ((CH2)4).
(CH ) ); δ (75 MHz; CDCl ; Me Si) 155.5 (N᎐C), 141.2 (ArC),
᎐
5-Methyl-2-(4-methylphenyl)-4-(4-nitrophenyl)-6-phenyl-5,6-
dihydro-4H-1,3-oxazine (3j). This compound was obtained as a
yellow oil (60%). Found: N, 6.95. Calc. for C24H22N2O3: N,
7.25%. δH(300 MHz; CDCl3; Me4Si) 8.20 (2 H, d, J 8.0, Ph),
8.05 (2 H, d, J 8.0, Ph), 7.49 (2 H, d, J 8.5, Ph), 7.39 (2 H, d,
J 8.0, Ph), 7.37–7.25 (5 H, m, Ph), 5.22 (1 H, d, J 4.4, OCH),
4.69 (1 H, d, J 4.0, NCH), 2.44–2.42 (1 H, m, NCHCH), 2.42
(3 H, s, ArCH3), 0.75 (3 H, d, J 6.9, CHCH3); δC(75 MHz;
2
4
C
3
4
136.2 (ArC), 134.0 (ArC), 130.4 (ArC), 128.9 (ArC), 128.0
(ArC), 127.2 (ArC), 126.9 (ArC), 68.7 (O-CH), 61.0 (N-CH),
39.7 (NCHCH), 30.2 ((CH2)4), 26.8 ((CH2)4), 24.6 ((CH2)4),
21.0 (ArCH3), 20.5 ((CH2)4).
6-Octadecyl-4-(4-methylphenyl)-2-phenyl-5,6-dihydro-4H-
1,3-oxazine (3f). This compound was obtained as white prisms
J. Chem. Soc., Perkin Trans. 2, 2001, 530–537
535

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CDCl ; Me Si) 155.4 (N᎐C), 149.4 (ArC), 146.8 (ArC), 141.4
(13%). Found: N, 4.44. Calc. for C20H23NO: N, 4.77%. δH(300
᎐
3
4
(ArC), 140.3 (ArC), 130.3 (ArC), 128.9 (ArC), 128.8 (ArC),
128.6 (ArC), 128.4 (ArC), 128.2 (ArC), 127.3 (ArC), 125.4
(ArC), 123.5 (ArC), 123.3 (ArC), 80.2 (OCH), 55.5 (NCH),
36.6 (NCHCH), 21.4 (ArCH3), 13.1 (CHCH3).
MHz; CDCl3; Me4Si) 8.13 (2 H, dd, J 2.0 and 7.2, Ph), 7.44–
7.40 (3 H, m, Ph), 7.30–7.21 (5 H, m, Ph), 2.77–2.69 (1 H, m,
N-CH), 2.36 (1 H, dd, J 4.4 and 13.4, NCHCH2), 1.78–1.71
(1 H, m, NCHCH2), 1.70–1.65 (4H, m, CCH3 and CH(CH3)2),
0.98 (3 H, d, J 6.7, CH(CH3)2), 0.94 (3 H, d, J 6.7, CH(CH3)2);
δ (75 MHz; CDCl ; Me Si) 153.5 (N᎐C), 145.2 (ArC), 134.2
(4R*,5S*,6R*)-5-Methyl-2-(4-methylphenyl)-4-(4-nitro-
phenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazine (3jЈ). This com-
pound was obtained by column separation (first fraction,
alumina, hexanes–ethyl acetate 6 : 1) as a yellow oil (30%).
δH(300 MHz; CDCl3; Me4Si) 8.20 (2 H, d, J 8.4, Ph), 8.05 (2 H,
d, J 8.1, Ph), 7.49 (2 H, d, J 8.7, Ph), 7.42–7.34 (3 H, m, Ph),
7.31–7.25 (4 H, m, Ph), 5.22 (1 H, d, J 4.7, OCH), 4.69 (1 H, d,
J 4.6, NCH), 2.49–2.38 (4 H, m, ArCH3 and NCHCH), 0.75
(3 H, d, J 7.2, CHCH3); δC(75 MHz; CDCl3; Me4Si) 155.4
᎐
C
3
4
(ArC), 130.2 (ArC), 128.6 (ArC), 128.0 (ArC), 127.2 (ArC),
126.9 (ArC), 124.1 (ArC), 78.8 (OCCH3), 55.3 (NCH), 36.2
(NCHCH2), 33.3 (CCH3), 31.5 (CH(CH3)2), 18.7 (CH(CH3)2),
18.6 (CH(CH3)2).
4-(2,6-Diphenyl-5,6-dihydro-4H-1,3-oxazin-4-yl)benzonitrile
(3n). This compound was obtained as a colorless oil (13%).
Found: C, 81.89; H, 5.34. Calc. for C23H18N2O: C, 81.63; H,
5.36%. δH(300 MHz; CDCl3; Me4Si) 8.13 (2 H, d, J 7.8, Ph),
7.66 (2 H, d, J 8.1, Ph), 7.54–7.26 (10 H, m, Ph), 5.29–5.25 (1 H,
m, OCH), 4.78 (1 H, t, J 6.0, NCH), 2.45–2.38 (1 H, m,
NCHCH2), 2.24–2.17 (1 H, m, NCHCH2); δC(75 MHz; CDCl3;
(N᎐C), 149.4 (ArC), 146.8 (ArC), 141.3 (ArC), 140.3 (ArC),
᎐
130.3 (ArC), 129.0 (ArC), 128.8 (ArC), 128.5 (ArC), 128.2
(ArC), 127.3 (ArC), 125.4 (ArC), 123.3 (ArC), 80.2 (OCH),
55.5 (NCH), 36.6 (NCHCH), 21.4 (ArCH3), 13.1 (CHCH3).
Me Si) 156.7 (N᎐C), 149.8 (ArC), 140.5 (ArC), 133.6 (ArC),
᎐
4
(4S*,5S*,6R*)-5-Methyl-2-(4-methylphenyl)-4-(4-nitro-
phenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazine (3jЉ). This com-
pound was obtained by separation on a column (second frac-
tion, alumina, hexanes–ethyl acetate 6 : 1) as a yellow oil (30%).
δH(300 MHz; CDCl3; Me4Si) 8.22 (2 H, d, J 8.4, Ph), 7.88 (2 H,
d, J 8.1, Ph), 7.50 (2 H, d, J 8.4, Ph), 7.40 (5 H, s, Ph), 7.17 (2 H,
d, J 8.1, Ph), 5.00 (1 H, d, J 10.6, OCH), 4.51 (1 H, d, J 10.0,
NCH), 2.38 (3 H, s, ArCH3), 1.90–1.81 (1 H, m, NCHCH), 0.71
132.6 (ArC), 131.4 (ArC), 129.1 (ArC), 128.6 (ArC), 128.5
(ArC), 127.9 (ArC), 127.7 (ArC), 125.6 (ArC), 73.6 (OCH),
53.3 (NCH), 36.6 (NCHCH2).
4-[(4R*,5S*,6R*)-5-Methyl-2,6-diphenyl-5,6-dihydro-4H-1,3-
oxazin-4-yl]benzonitrile (3oЈ). This compound was obtained
by column separation (first fraction, alumina, hexanes–ethyl
acetate 6 : 1) as a yellow oil (0.3% isolated yield). Found:
N, 7.64. Calc. for C24H20N2O: N, 7.95. δH(300 MHz; CDCl3;
Me4Si) 8.15 (2 H, d, J 6.9, Ph), 7.64 (2 H, d, J 8.4, Ph),
7.51–7.25 (10 H, m, Ph), 5.20 (1 H, d, J 5.0, OCH), 4.67 (1 H, d,
J 4.7, NCH), 2.44 (1 H, m, NCHCH), 0.74 (3 H, d, J 7.1, CH3);
(3 H, J 6.9, CH ); δ (75 MHz; CDCl ; Me Si) 156.8 (N᎐C),
᎐
3
C
3
4
150.8 (ArC), 147.1 (ArC), 141.2 (ArC), 138.2 (ArC), 130.3
(ArC), 128.8 (ArC), 128.7 (ArC), 128.6 (ArC), 127.4 (ArC),
127.3 (ArC), 123.6 (ArC), 82.8 (O-CH), 64.1 (N-CH), 40.3
(NCHCH), 21.4 (ArCH3), 14.0 (CHCH3).
δ (75 MHz; CDCl ; Me Si) 155.3 (N᎐C), 147.0 (ArC), 140.1
᎐
C
3
4
(ArC), 133.0 (ArC), 131.9 (ArC), 130.9 (ArC), 128.7 (ArC),
128.4 (ArC), 128.2 (ArC), 128.1 (ArC), 127.3 (ArC), 125.4
(ArC), 118.9 (ArCN), 110.5 (ArC), 80.2 (OCH), 55.8 (NCH),
36.5 (NCHCH), 13.0 (CH2).
6-Methyl-4-phenethyl-2,6-diphenyl-5,6-dihydro-4H-1,3-
oxazine (3k). This compound was obtained as a yellow oil
(64%). Found: C, 84.70; H, 7.51; N, 3.64. Calc. for C25H25NO:
C, 84.47; H, 7.09; N, 3.94%. δH(300 MHz; CDCl3; Me4Si) 8.13
(2 H, dd, J 2.0 and 7.4, Ph), 7.47–7.40 (3 H, m, Ph), 7.32–7.13
(10 H, m, Ph), 2.95 (2 H, m, NCH and CH2CH2Ph), 2.74–2.64
(1 H, m, NCHCH2), 2.45 (1 H, dd, J 4.2 and 13.5, NCHCH2),
1.83–1.75 (2 H, m, CH2Ph), 1.69 (4 H, m, CCH3 and
4-[(4S*,5S*,6R*)-5-Methyl-2,6-diphenyl-5,6-dihydro-4H-1,3-
oxazin-4-yl]benzonitrile (3oЉ). This compound was obtained by
column separation (second fraction, alumina, hexanes–ethyl
acetate 6 : 1) as a yellow oil (0.3% isolated yield). Found: N,
7.67. Calc. for C24H20N2O: N, 7.95%. δH(300 MHz; CDCl3;
Me4Si) 7.99 (2 H, d, J 7.4, Ph), 7.65 (2 H, d, J 8.1, Ph), 7.46–
7.25 (10 H, m, Ph), 5.00 (1 H, d, J 10.3, OCH), 4.46 (1 H, d,
J 9.9, NCH), 1.88–1.63 (1 H, m, NCHCH), 0.70 (3 H, d, J 6.6,
CH CH Ph); δ (75 MHz; CDCl ; Me Si) 153.7 (N᎐C), 145.0
᎐
2
2
C
3
4
(ArC), 142.6 (ArC), 134.0 (ArC), 130.4 (ArC), 128.6 (ArC),
128.4 (ArC), 128.2 (ArC), 128.1 (ArC), 127.2 (ArC), 127.0
(ArC), 125.6 (ArC), 124.1 (ArC), 79.0 (O-CCH3), 49.9 (NCH),
39.7 (NCHCH2), 38.8 (CH2Ph), 32.2 (CH2CH2Ph), 31.3
(CCH3).
CH ); δ (75 MHz; CDCl ; Me Si) 156.7 (N᎐C), 148.6 (ArC),
᎐
3
C
3
4
138.2 (ArC), 133.1 (ArC), 132.2 (ArC), 130.9 (ArC), 128.8
(ArC), 128.7 (ArC), 128.6 (ArC), 128.1 (ArC), 127.4 (ArC),
127.3 (ArC), 118.9 (CN), 111.0 (ArC), 82.8 (OCH), 64.3
(NCH), 40.2 (NCHCH), 14.0 (CH3).
6-Butyl-2-(4-methylphenyl)-4-phenethyl-5,6-dihydro-4H-1,3-
oxazine (3l). This compound was obtained as a colorless oil
(15%). Found: C, 82.16; H, 9.05; N, 4.36. Calc. for C23H29NO:
C, 82.34; H, 8.71; N, 4.18%. δH(300 MHz; CDCl3; Me4Si) 7.85
(2 H, dd, J 3.3 and 8.1, Ph), 7.34–7.14 (5 H, m, Ph), 7.16 (2 H, d,
J 7.7, Ph), 4.26–4.20 (1 H, m, OCH), 3.60–3.54 (1 H, m, NCH),
2.90–2.77 (2 H, m, NCHCH2), 2.35 (3 H, s, ArCH3), 2.01–1.94
(2 H, m, CH2Ph), 1.83–1.68 (3 H, m, CH2CH2Ph and CH-
(CH2)3), 1.61–1.53 (2 H, m, CH(CH2)3), 1.45–1.35 (3 H, m,
CH(CH2)3), 0.94 (3 H, t, J 6.8, CH2CH3); δC(75 MHz; CDCl3;
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᎐
4
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536
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