A convenient procedure for the synthesis of 3-substituted 5,6-dihydro-4H-1,2-oxazines from nitroethane

Article abstract of DOI:10.1055/s-2006-958930

A novel and efficient four-step procedure for the synthesis of C-3-functionalised 5,6-dihydro-4H-1,2-oxazines from nitroethane is described. It includes preparation of 3-methyl-substituted six-membered cyclic nitronates, 3-(bromomethyl)-substituted 5,6-dihydro-4H-1,2-oxazines as intermediates, and nucleophilic substitution of bromine. Total yields of the target C-3-functionalised oxazines are 15-30% from nitroethane. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-958930

PAPER
97
A Convenient Procedure for the Synthesis of 3-Substituted 5,6-Dihydro-4H-
1,2-oxazines from Nitroethane
S
ynthesis of 3-Sub
l
stituted
e
5, 6-Dihyd
x
ro-4
H
-1,2-o
e
y
N
itroethane Yu. Sukhorukov, Michael S. Klenov, Pavel E. Ivashkin, Alexey V. Lesiv,* Yulya A. Khomutova,
Sema L. Ioffe*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prosp. 47, 119991 Moscow, Russian Federation
Fax +7(095)1355328; E-mail: iof@ioc.ac.ru
Received 16 June 2006; revised 2 September 2006
ment of this strategy, a general and simple method for the
Abstract: A novel and efficient four-step procedure for the synthe-
synthesis of C-3-functionalised 5,6-dihydro-4H-1,2-ox-
sis of C-3-functionalised 5,6-dihydro-4H-1,2-oxazines from nitro-
azines 3 from nitroethane via six-membered cyclic nitr-
onates 1 and 3-(bromomethyl)-substituted oxazines 2 is
ethane is described. It includes preparation of 3-methyl-substituted
six-membered cyclic nitronates, 3-(bromomethyl)-substituted 5,6-
dihydro-4H-1,2-oxazines as intermediates, and nucleophilic substi- reported here (Scheme 1, Table 1).
tution of bromine. Total yields of the target C-3-functionalised ox-
azines are 15–30% from nitroethane.
This methodology includes four steps (Scheme 1). Over-
all yields of the target products 3 are 15–31% from nitro-
ethane. Readily available aromatic and aliphatic
aldehydes and olefins were used as additional reagents.
The first two steps were accomplished by previously de-
scribed procedures,9 giving cyclic nitronates 1.
Key words: nitro compounds, heterocycles, 1,2-oxazines, silyla-
tion, unnatural amino acids
5,6-Dihydro-4H-1,2-oxazines are convenient precursors
for the synthesis of various useful products such as substi-
tuted pyrrolidines,1 piperidines,2 unnatural a-amino ac-
ids,3 amino alcohols,4 and pyrroles.5 However, application
of 5,6-dihydro-4H-1,2-oxazines in organic synthesis is
significantly limited, because only one common method
for their preparation is known: [4+2] cycloaddition of
conjugated nitrosoalkenes with electron-rich alkenes.6
Furthermore, because of the high instability and wide
variability of reactivity of nitrosoalkenes, problematic op-
timisation is necessary in each case.7 Therefore, new ap-
proaches to the synthesis of 5,6-dihydro-4H-1,2-oxazines
are needed.
The third step (Scheme 1, step III) was carried out accord-
ing to our recent publication.8 However, a previously sug-
gested procedure8 has been modified and expanded to
develop a general and simple method for the synthesis of
the target (bromomethyl)oxazines 2 as key intermediates
on a molar scale (see experimental part for details). This
modification was accompanied by a decrease in the yields
of products 2a–l by 10–20% in comparison to the yields
obtained in the previous work.8 It is more appropriate to
use bromides 2 for the synthesis of oxazines 3, because
the chloride analogues of 2 were too inert towards nucleo-
philic substitution, while the iodides were unstable and
unselective in the fourth step of the general procedure.
Recently we reported a new convenient procedure for the
preparation of previously rare 3-(a-haloalkyl)-substituted
5,6-dihydro-4H-1,2-oxazines from six-membered cyclic
nitronates containing an alkyl group at the C-3-position.8
The synthesis of these products includes a simultaneous
reduction of the nitronate function and a halogenation at
the a-position of the alkyl substituent at C-3. The obtained
(a-haloalkyl)-substituted cyclic oxime ethers can be con-
sidered as convenient precursors of different C-3-func-
tionalised 5,6-dihydro-4H-1,2-oxazines. As a develop-
We focused on the optimisation of the fourth step of the
synthesis shown in Scheme 1.
Apart from our previous publication,8 nucleophilic substi-
tution of halogen in a-halo-substituted oxime ethers has
not been studied before (the interaction of a-halo oximes
with nucleophiles leads to nitrosoalkenes6). The reaction
which could compete with nucleophilic substitution in
(halomethyl)oxazines 2 is elimination of a proton from the
C-4 atom, followed by fragmentation with loss of the C-6
R1
R1
R2
R1
R1
O
O
NO2
R2
R3
R2
R3
CH
R2
R3
Methods
A–G
R1
R3 R4
, SnCl4
Br
Nu
TMSBr, Et3N
III
N
N
N
N
I
II
IV
O
O
O
R4
O
R4
R4
O
2
3
1
Scheme 1
SYNTHESIS 2007, No. 1, pp 0097–0107
x
x
.
x
x
.2
0
0
6
Advanced online publication: 12.12.2006
DOI: 10.1055/s-2006-958930; Art ID: P07406SS
© Georg Thieme Verlag Stuttgart · New York

98
A. Yu. Sukhorukov et al.
PAPER
Table 1 Synthesis of 5,6-Dihydro-4H-1,2-oxazines 3a–v
Entry
1 and 2
3
R1
R2
R3
R4
Nu
Yielda of 3 Overall yieldb Methodc
(%)
99
98
98
78
94
78
99
65
69
99
90
96
60
of 3 (%)
1
2
a
a
a
a
a
a
a
a
a
a
b
c
ad
bd
c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
CN
28
A
B
B
B
C
D
A
E
F
CH(CO2Me)2
CH(CO2Me)CN
CH(CO2Me)Ac
PPh3
29
3
29
4
d
ee
f
22
5
27
6
N3
22
7
g
NPhth
30
8
h
if
OEt
19
9
NH2
20
10
11
12
13
je
k
l
MeImg
30
G
B
B
B
-(CH)3-
-(CH)4-
CH(CO2Me)2
CH(CO2Me)2
CH(CO2Me)2
29
H
27
d
m
H
24
14
15
16
17
18
19
20
21
e
f
n
o
p
r
s
Ph
H
H
H
Ph
CH(CO2Me)2
CH(CO2Me)2
CH(CO2Me)2
CH(CO2Me)2
CH(CO2Me)2
CH(CO2Me)2
CH(CO2Me)2
CH(CO2Me)2
55
81
95
93
87
86
70
69
19
31
28
30
31
30
24
15
B
B
B
B
B
B
B
B
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
Me
Me
Me
H
g
h
i
-(CH)4-
H
H
H
H
H
H
OEt
OMe
Me
Me
Me
Me
Me
Me
Me
j
t
k
l
u
v
OBz
a Yield of 3 over one step (Scheme 1, step IV) from 2.
b Overall yield of 3 from nitroethane.
c Method A: NuK, DMF, 2 h, 50–60 °C; Method B: NuH, t-BuOK, DMF, 2 h, 60 °C; Method C: Nu, toluene, 2 h, 110 °C; Method D: NuNa,
DMF, 2 h, 50–60 °C; Method E: NuH, Na, EtOH, 2 h, 60 °C; Method F: NaN3, DMF, 1 h, 100 °C, then PPh3, H2O, HCl, 24 h, 20 °C; Method
G: Nu, toluene, 5 h, 110 °C.
d This compound 3 was previously obtained by a similar procedure.8
e This compound 3 was isolated as a bromide salt.
f This compound 3 was isolated as a chloride salt.
g MeIm = 3-methylimidazol-1-yl.
atom. This process was observed in the synthesis of ox- onic and acetylacetic esters), a cyanoacetic ester, as well
azine 3d from (bromomethyl)oxazine 2a (Table 1, entry as heteronucleophiles (azide, ethoxide, and phthalimide
4). Interaction of (bromomethyl)oxazine 2a (R1 = Ph; anions) react easily with 3-(bromomethyl)oxazine 2a un-
R2 = H; R3 = R4 = Me) with an acetylacetic ester by use of der moderate heating. More inert nucleophiles (nitro-
an excess of base leads to polymerisation of the active vi- ethane, phenylacetylene anions) in alcohols underwent no
nyl imine intermediate, but pyrrole 4, its cyclisation prod- reaction with 2a. The interaction of oxazine 2a with more
uct, can also be isolated in 18% yield (Scheme 2).10
active nucleophiles (e.g., metalloorganic compounds)
gives complex mixtures of unidentified products. Reac-
tion of oxazine 2a with diastereotopic nucleophiles (cy-
anoacetic or acetylacetic esters; Table 1, entries 3 and 4)
leads to the formation of both of the corresponding diaste-
reomers in nearly equimolar quantities.
Variation of the nucleophile (Scheme 1, step IV) was in-
vestigated on the model 3-(bromomethyl)oxazine 2a
(Table 1, entries 1–10). We found optimal reaction condi-
tions for each nucleophile to achieve the maximum yields
of target oxazines 3a–j. 1,3-Dicarbonyl compounds (mal-
Synthesis 2007, No. 1, 97–107 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Substituted 5,6-Dihydro-4H-1,2-oxazines from Nitroethane
99
R1
O
R1
–
R1
O
R1
R2
R3
R2
R3
R2
R3
R2
Nu
Nu
base
Nu
Nu
N–
N
N
N–
O
R4
R4
R4
Nu = Br
polymerisation
Nu = CH(CO2Me)Ac
18%
Ph
HN
CO2Me
4
Scheme 2
Interaction of oxazine 2a with triphenylphosphine or N- nient precursors of various useful products, especially un-
methylimidazole (Table 1, entries 5 and 10) gives salts 3e natural amino acids. This was demonstrated by the
and 3j, respectively. The Wittig reaction of 3e with ben- synthesis of amino acid 8 during selective catalytic hydro-
zaldehyde leads to previously unknown 3-styryloxazine 5 genation of the oxyimino fragment in oxazine 3r
(Z/E, 8:5) in high yield (Scheme 3). 3-Styryloxazine 5 (Scheme 4).
was prepared by an alternative route via aldehyde 6 (oxi-
dation of 2a with DMSO in the presence of base), which
underwent a Wittig reaction with a benzyl(triphe-
nyl)phosphonium salt (Scheme 3).
The structure and purity of compounds 2–8 were con-
1
firmed by H NMR and 13C NMR spectroscopic data as
well as elemental analysis. The relative configurations of
the stereocentres in initial nitronates 1 remained un-
changed during their further transformations.
Ph
In conclusion, a novel strategy for the synthesis of C-3-
P+Ph3
Br–
functionalised 5,6-dihydro-4H-1,2-oxazines from nitro-
ethane via diastereomerically pure six-membered cyclic
nitronates 1 and 3-(bromomethyl)-5,6-dihydro-4H-1,2-
ozaxines 2 has been elaborated. By this means, (bromo-
methyl)oxazines 2 can be considered as a kind of ‘bridge’
connecting easily accessible six-membered cyclic nitro-
nates 1 and practically unavailable six-membered cyclic
ethers of oximes 3. Undoubtedly, this new approach will
allow the application of cyclic oxime ethers to be expand-
ed in organic synthesis.
BuLi, PhCHO
N
O
3e
PPh3
94%
Ph
O
Ph
60%
Ph
Br
N
N
DMSO
O
NaHCO3
Ph
PhCH2PPh3+Br–
KOtBu
5
2a
76%
O
65%
N
O
6
All silylation reactions were performed in oven-dried (150 °C)
glassware under an atmosphere of dry argon. NMR spectra were re-
corded on a Bruker AM-300 instrument (1H: 300.13 MHz, 13C:
75.47 MHz) and referenced to the residual solvent peaks. Atom
numbering for peak assignment is shown in Figures 1 and 2. Melt-
ing points were determined on a Koffler melting point apparatus
and are uncorrected. Analytical TLC was performed on Merck sili-
ca gel plates with QF-254 as indicator. All solvents for chromatog-
raphy and extractions were technical grade. Hexane and EtOAc
were distilled from P2O5. Column chromatography was performed
on silica gel (Merck, 230–400-mesh).
Scheme 3
We have also investigated the reaction of dimethyl mal-
onate with a representative series of (bromomethyl)ox-
azines 2a–l (Table 1, entries 2, 11–21). Nucleophilic
substitution of bromine by the dimethyl malonate anion
goes smoothly, and gives target oxazines 3b,k–v in 55–
96% yield.
Oxazines 3b,k–v (Table 1, entries 11–21) incorporating
the fragment –CH(CO2Me)2 can be considered as conve-
Ar
Ar
Ar
CO2Me
CO2Me
H2/Ni
53%
HCl, MeOH
CO2Me
CO2H
80%
N
CO2Me
N
EtO
O
Boc
NH2+
Cl–
3r
7
8
Ar = 4-MeOC6H4
Scheme 4
Synthesis 2007, No. 1, 97–107 © Thieme Stuttgart · New York

100
A. Yu. Sukhorukov et al.
PAPER
12
Cl
O
11
11
13
14
12
10
9
10
12
11
11
10
13
12
9
Ph
10
8
8
9
2
11
5
5
5
5
5
5
1
1
3
1
3
1
3
1
2
2
9
6
2
2
8
3
4
2
3
4
8
7
8
7
3
9
7
6
10
N
N
N
N
N
N
4
4
O
O
O
Ph
O
O
O
6
7
6
7
O
4
O
4
O
O
O
O
6
1b
1c
1d
1e
1f
1j
12
O
12
11
14
13
10
9
13
12
11
10
12
11
6
2
5
Ph
1
9
8
11
10
5
3
4
5
5
5
1
1
1
3
5
3
2
3
1
2
2
1
2
2
Br
9
6
9
8
6
3
Br
Br
3
4
N
8
7
Br
8
7
Br
7
O
8
10
7
O
N
N
N
N
N
4
4
4
Ph
O
4
O
O
O
6
7
O
6
1k
2b
2c
2d
2e
2f
12
Cl
11
10
11
10
9
9
8
6
8
5
O
O
5
1
5
1
2
2
1
3
4
Br
3
4
Br
2
Br
3
4
N
N
O
7
N
7
8
O
6
7
O
6
2j
2k
2l
Figure 1
5,6-Dihydro-4H-1,2-oxazine 2-Oxides 1a–l
HC(2)], 4.56 [s, 1 H, HC(4)], 7.15–7.36 [m, 5 H, HC(11), HC(12),
HC(13)].
13C NMR (75 MHz, CDCl3): d = 18.6 (C-5), 19.9, 24.6, 27.4, 28.7
(C-6, C-7, C-8, C-9), 42.3 (C-2), 55.4 (C-3), 78.9 (C-4), 121.0 (C-
1), 126.5, 128.6, 128.8 (C-11, C-12, C-13), 136.9 (C-10).
1,2-Oxazine 2-oxides 1a,g,h,i9 and 1l8 were prepared by known
procedures. The 2-oxides 1b–d were obtained by a procedure used
for the synthesis of rel-(4R,5S,6S)-4-(4-methoxyphenyl)-3-methyl-
4a,5,6,7,8,8a-hexahydro-4H-1,2-benzoxazine 2-oxide,9 with small
modifications: for compounds 1c,d, the reaction mixture was kept
at –30 °C for 30 min. The 2-oxides 1e,f,j,k were obtained by a pro-
cedure used for the synthesis of 5,6-dihydro-3,6,6-trimethyl-4-phe-
nyl-1,2-oxazine 2-oxide.9
Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C,
73.40; H, 7.80; N, 5.81.
rel-(4R,4aS,5S,8aS)-3-Methyl-4-phenyl-4a,5,6,7,8,8a-hexahy-
dro-4H-5,8-methano-1,2-benzoxazine 2-Oxide (1d)
Yield: 72%; mp 110–111 °C.
rel-(4S,4aS,7aS)-3-Methyl-4-phenyl-4,4a,5,6,7,7a-hexahydrocy-
clopenta[e][1,2]oxazine 2-Oxide (1b)
1H NMR (300 MHz, CDCl3): d = 1.19–1.72 [m, 6 H, H2C(7),
H2C(8), H2C(10)], 2.06 [s, 3 H, H3C(5)], 2.27, 2.31–2.45 [2 m, 3 H,
HC(3), HC(6), HC(9)], 3.57 [br s, 1 H, HC(2)], 4.06 [br s, 1 H,
HC(4)], 7.18–7.36 [m, 5 H, HC(12), HC(13), HC(14)].
13C NMR (75 MHz, CDCl3): d = 19.7 (C-5), 21.0, 26.1, 34.3 (C-7,
C-8, C-10), 37.4, 42.6 (C-6, C-9), 44.0, 44.2 (C-2, C-3), 75.5 (C-4),
122.0 (C-1), 126.7, 128.9, 128.7 (C-12, C-13, C-14), 136.9 (C-11).
Yield: 75%; mp 91–95 °C.
1H NMR (300 MHz, CDCl3): d = 1.42–1.93 [m, 6 H, H2C(6),
H2C(7), H2C(8)], 1.76 [s, 3 H, H3C(5)], 2.32 [dd, J = 4.6, 5.3 Hz, 1
H, HC(3)], 3.47 [d, J = 4.6 Hz, 1 H, HC(2)], 4.81 [dt, J = 3.3, 5.3
Hz, 1 H, HC(4)], 7.08–7.31 [m, 5 H, HC(10), HC(11), HC(12)].
13C NMR (75 MHz, CDCl3): d = 19.1 (C-5), 22.4, 30.4, 31.9 (C-6,
C-7, C-8), 46.8 (C-3), 48.0 (C-2), 84.7 (C-4), 124.2 (C-1), 127.6,
128.2, 129.1 (C-10, C-11, C-12), 140.1 (C-9).
Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found: C,
74.65; H, 7.40; N, 5.13.
Anal. Calcd for C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found: C,
72.63; H, 7.41; N, 6.00.
rel-(4S,6R)-3-Methyl-4,6-diphenyl-5,6-dihydro-4H-1,2-oxazine
2-Oxide (1e)
Yield: 75%; mp 60–68 °C.
1H NMR (300 MHz, CDCl3): d = 1.83 [s, 3 H, H3C(5)], 2.21 [ddd,
J = 11.0, 13.2, 8.8 Hz, 1 H, H2C(3)], 2.45 [dd, J = 8.5, 13.2 Hz, 1 H,
rel-(4S,4aS,8aS)-3-Methyl-4-phenyl-4a,5,6,7,8,8a-hexahydro-
4H-1,2-benzoxazine 2-Oxide (1c)
Yield: 80%; mp 87–88 °C.
1H NMR (300 MHz, CDCl3): d = 1.45–2.15 [m, 9 H, HC(3), H2C(6),
H2C(7), H2C(8), H2C(9)], 1.87 [s, 3 H, H3C(5)], 3.33 [s, 1 H,
Synthesis 2007, No. 1, 97–107 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Substituted 5,6-Dihydro-4H-1,2-oxazines from Nitroethane
101
16
16
16
15
14
15
14
15
14
13
13
13
9
7
7
9
Ph
7
9
H
5
H
5
H
5
18
18
11
2
7
9
2
2
17
5
1
1
1
3
6
2
3
6
3
6
CO2Me
CO2Me
CO2Me
1
6
17
12
17
12
CO2Me
3
19
11
12
11
4
4
4
4
N
CO2Me
N
CO2Me
N
CO2Me
10
8
N
CO2Me
8
O
8
O
O
10
10
8
Ph
O
10
H
H
H
3k
3l
3m
3n
17
Me
17
17
Me
O
OMe
OMe
O
16
16
16
16
15
14
15
14
15
14
15
14
13
2
13
13
7
6
9
7
9
H
5
7
9
18
11
13
5
2
5
7
9
2
1
3
5
1
6
CO2Me
2
1
3
CO2Me
6
3
CO2Me
1
19
12
6
3
CO2Me
4
4
4
N
CO2Me
11
4
N
CO2Me
N
CO2Me
11
8
N
CO2Me
O
10
8
10
O
11
O
8
MeO
O
10
8
12Me
Me
O
10
H
H
12Me
12
3o
3p
3r
3s
17
16
15
Cl
16
15
14
15
14
14
13
13
13
Me
2
12
5
13
O
O
2
7
9
7
9
7
9
5
7
9
5
2
5
2
1
6
1
6
1
6
3
CO2Me
3
CO2Me
1
6
3
CO2Me
3
CO2Me
4
4
4
4
11
10
11
N
CO2Me
11
N
CN
N
CO2Me
N
CO2Me
8
Me
O
8
10
Me
O
Me
12Me
O
8
10
Me
O
8
11Me
10
12Me
12Me
3t
3u
3v
3c
11
16
15
14
10
15
14
14
13
13
12
9
8
13
8
5
7
12
2
2
O
11
5
2
1
3
4
5
1
6
5
7
3
CO2Me
1
2
N3
6
O
1
8
3
3
4
N
9
4
6
11
N
4
10
N
C
9
10Me 11
O
Me
O
N
N
Me
O
6
O
7 Me
Me
7
12Me
O
Me
O
10Me
3h
Me
8
9
3d
3f
3g
12
11
15
15
9
6
10
9
11
10
14
13
5
14
13
8
9
8
7
12
12
5
5
2
2
2
6
1
5
1
2
1
6
1
3
4
NH3+Cl–
3
P +
3
4
Br–
3
4
N+
7
O
9
4
7
N
6
N
N
10
10
N
N
Me
O
Me
O
Me 11
O
8 Me
Me
O
8
7 Me
11Me
Me
Br–
3i
3e
3j
6
18
O
16
17
15
14
16
14
11
O
10
15
14
12
13
3
CO2Me
2
11
10
9
10
9
4
13
CO2Me
1
5
8
2
N
6
3
1
13
12
3
2
7
8
7
5
4
O
O
11
4
+
CO2H
N
1
6
Cl–
6
N
8
9
Me
12Me
O
7
H
5
H
5
7
8
Figure 2
Synthesis 2007, No. 1, 97–107 © Thieme Stuttgart · New York

102
A. Yu. Sukhorukov et al.
PAPER
rel-(4S,4aS,7aS)-3-(Bromomethyl)-4-phenyl-4,4a,5,6,7,7a-
H2C(3)], 3.57 [dd, J = 8.5, 8.8 Hz, 1 H, HC(2)], 5.65 [d, J = 11.0
Hz, 1 H, HC(4)], 7.30–7.36 [m, 10 H, Ph].
hexahydrocyclopenta[e][1,2]oxazine (2b)
Yield: 50%; mp 45–49 °C; (hexane–AcOEt, 1:1); Rf = 0.81 (silica
gel, hexane–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): d = 1.42–2.18 [m, 7 H, HC(3), H2C(6),
H2C(7), H2C(8)], 3.72 [s, 1 H, HC(2)], 3.77 [d, J = 9.9 Hz, 1 H,
H2C(5)], 4.09 [d, J = 9.9 Hz, 1 H, H2C(5)], 4.22 [t, J = 3.3 Hz, 1 H,
HC(4)], 7.14–7.41 [m, 5 H, HC(10), HC(11), HC(12)].
13C NMR (75 MHz, CDCl3): d = 17.5 (C-5), 37.1 (C-3), 40.2 (C-2),
82.3 (C-4), 122.7 (C-1), 126.8, 126.9, 128.4, 128.6, 128.8, 136.7,
137.3 (Ph).
Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C,
76.90; H, 6.04; N, 5.59.
4-(4-Methoxyphenyl)-3,6,6-trimethyl-5,6-dihydro-4H-1,2-ox-
azine 2-Oxide (1f)
Yield: 71%; mp 114–115 °C.
13C NMR (75 MHz, CDCl3): d = 21.6, 28.9, 31.5 (C-6, C-7, C-8),
31.9 (C-5), 38.7 (C-3), 43.6 (C-2), 75.7 (C-4), 127.4, 127.9, 129.2
(C-10, C-11, C-12), 141.0 (C-9), 153.5 (C-1).
1H NMR (300 MHz, CDCl3): d = 1.37, 1.43 [2 s, 6 H, H3C(6),
H3C(7)], 1.82 [s, 3 H, H3C(5)], 1.91 [dd, J = 10.4, 13.8 Hz, 1 H,
H2C(3)], 2.06 [dd, J = 8.2, 13.8 Hz, 1 H, H2C(3)], 3.42 [dd, J = 8.2,
10.4 Hz, 1 H, HC(2)], 3.77 [s, 3 H, H3C(12)], 6.85 [d, J = 7.9 Hz, 2
H, HC(10)], 7.08 [d, J = 7.9 Hz, 2 H, HC(9)].
Anal. Calcd for C14H16BrNO: C, 57.16; H, 5.48; N, 4.76. Found: C,
57.57; H, 5.43; N, 4.50.
rel-(4S,4aS,8aS)-3-(Bromomethyl)-4-phenyl-4a,5,6,7,8,8a-
hexahydro-4H-1,2-benzoxazine (2c)
Yield: 40%; mp 70–74 °C; (hexane–EtOAc, 1:1); Rf = 0.80 (silica
gel, hexane–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): d = 0.79–2.14 [m, 9 H, HC(3), H2C(6),
H2C(7), H2C(8), H2C(9)], 3.61 [s, 1 H, HC(2)], 3.81 [d, J = 10.3 Hz,
1 H, H2C(5)], 4.04 [s, 1 H, HC(4)], 4.16 [d, J = 10.3 Hz, 1 H,
H2C(5)], 7.13–7.39 [m, 5 H, HC(11), HC(12), HC(13)].
13C NMR (75 MHz, CDCl3): d = 22.2 (C-5, C-6), 27.8 (C-7), 41.8
(C-3), 42.5 (C-2), 55.3 (C-12), 81.2 (C-4), 114.6 (C-10), 122.1 (C-
1), 128.9 (C-9), 132.3 (C-8), 159.1 (C-11).
Anal. Calcd for C14H19NO3: C, 67.45; H, 7.68; N, 5.62. Found: C,
67.44; H, 7.63; N, 5.60.
4-(4-Chlorophenyl)-3,6,6-trimethyl-5,6-dihydro-4H-1,2-ox-
azine 2-Oxide (1j)
Yield: 83%; mp 67–69 °C.
13C NMR (75 MHz, CDCl3): d = 20.0, 24.9, 27.4, 29.1 (C-6, C-7, C-
8, C-9), 32.0 (C-5), 38.3 (C-3), 43.2 (C-2), 69.4 (C-4), 127.4, 128.2,
129.0 (C-11, C-12, C-13), 140.6 (C-10), 152.2 (C-1).
1H NMR (300 MHz, CDCl3): d = 1.34, 1.43 [2 s, 6 H, H3C(6),
H3C(7)], 1.92 [s, 3 H, H3C(5)], 1.90 [dd, J = 10.7, 13.5 Hz, 1 H,
H2C(3)], 2.12 [dd, J = 8.5, 13.5 Hz, 1 H, H2C(3)], 3.40 [dd, J = 8.5,
10.7 Hz, 1 H, HC(2)], 7.13 [d, J = 8.8 Hz, 2 H, HC(10)], 7.33 [d,
J = 8.8 Hz, 2 H, HC(9)].
13C NMR (75 MHz, CDCl3): d = 19.0 (C-5), 22.7 (C-6), 27.8 (C-7),
40.1 (C-3), 43.6 (C-2), 80.7 (C-4), 122.1 (C-1), 129.3, 129.7 (C-9,
C-10), 133.3 (C-8), 138.6 (C-11).
Anal. Calcd for C15H18BrNO: C, 58.45; H, 5.89; N, 4.54. Found: C,
58.30; H, 5.90; N, 4.60.
rel-(4R,4aS,5S,8aS)-3-(Bromomethyl)-4-phenyl-4a,5,6,7,8,8a-
hexahydro-4H-5,8-methano-1,2-benzoxazine (2d)
Yield: 64%; mp 51–57 °C; (hexane–EtOAc, 1:1); Rf = 0.73 (silica
gel, hexane–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): d = 1.05–1.70, 1.98–2.30 [2 m, 8 H,
HC(3), H2C(7), H2C(8), H2C(10), HC(9)], 2.47 [d, J = 4.6 Hz, 1 H,
HC(6)], 3.39 [d, J = 7.5 Hz, 1 H, HC(2)], 3.90 [d, J = 5.5 Hz, 1 H,
HC(4)], 4.04 [s, 2 H, H2C(5)], 7.20–7.44 [m, 5 H, HC(12), HC(13),
HC(14)].
Anal. Calcd for C13H16ClNO2: C, 61.54; H, 6.36; N, 5.52. Found: C,
61.88; H, 6.53; N, 5.21.
3,4,6,6-Tetramethyl-5,6-dihydro-4H-1,2-oxazine 2-Oxide (1k)
Yield: 61%; oil.
1H NMR (300 MHz, CDCl3): d = 1.13 [d, J = 5.0 Hz, 3 H, H3C(6)],
1.29, 1.31 [2 s, 6 H, H3C(7), H3C(8)], 1.52 [dd, J = 10.3, 13.5, 1 H,
HC(3)], 1.86 [dd, J = 7.4, 13.5 Hz, 1 H, HC(3)], 2.00 [s, 3 H,
H3C(5)], 2.54 [m, 1 H, HC(2)].
13C NMR (75 MHz, CDCl3): d = 24.4, 28.5, 29.0, 33.5 (C-7, C-8, C-
10, C-5), 39.9 (C-2), 42.0, 42.5 (C-3, C-9), 53.4 (C-6), 83.0 (C-4),
127.6, 129.0, 129.5 (C-12, C-13, C-14), 137.6 (C-11), 172.6 (C-1).
Anal. Calcd for C16H18BrNO: C, 60.01; H, 5.67; N, 4.37. Found: C,
60.42; H, 5.90; N, 4.56.
13C NMR (75 MHz, CDCl3): d = 15.9 (C-6), 18.3 (C-5), 22.6, 27.7
rel-(4S,6R)-3-(Bromomethyl)-4,6-diphenyl-5,6-dihydro-4H-1,2-
oxazine (2e)
Yield: 53%; mp 83–87 °C; Rf = 0.79 (silica gel, hexane–EtOAc, 1:1,
UV).
(C-7, C-8), 30.2 (C-2), 40.0 (C-3), 80.6 (C-4), 124.1 (C-1).
Anal. Calcd for C8H15NO2: C, 61.12; H, 9.62; N, 8.91. Found: C,
61.40; H, 9.90; N, 8.96.
1H NMR (300 MHz, CDCl3): d = 2.22 [ddd, J = 12.0, 11.8, 13.3 Hz,
1 H, H2C(3)], 2.49 [ddd, J = 2.0, 8.6, 13.3 Hz, 1 H, H2C(3)], 3.88 [d,
J = 12.0 Hz, 1 H, H2C(5)], 4.10 [dd, J = 8.6, 12.0 Hz, 1 H, HC(2)],
4.22 [d, J = 12.0 Hz, 1 H, H2C(5)], 4.88 [dd, J = 2.0, 11.8 Hz, 1 H,
HC(4)], 7.36–7.41 [m, 10 H, Ph].
13C NMR (75 MHz, CDCl3): d = 30.5 (C-5), 34.0 (C-3), 36.6 (C-2),
73.8 (C-4), 126.7, 126,8, 128.6, 128.7, 129.0, 129.3, 139.0, 140.6
(Ph), 153.9 (C-3).
3-(Bromomethyl)-5,6-dihydro-4H-1,2-oxazines 2a–l; General
Procedure
The appropriate 1,2-oxazine 2-oxide 1 (0.1 mol) was slowly added
to a stirred soln of TMSBr (39.6 mL, 0.3 mol) and Et3N (16.7 mL,
0.12 mol) in CH2Cl2 (0.5 L) at –80 °C. The resulting mixture was
stirred for 1 h at –80 °C, then MeCN (50 mL) was added and the
temperature was increased to –30 °C within 1 h. The mixture was
kept for 3 h at –30 °C and then diluted with EtOAc (0.5 L) and
poured into a mixture of EtOAc (1.0 L) and a sat. aq soln of
NaHCO3 (0.5 L). The aqueous phase was back-extracted with
EtOAc (2 × 100 mL), and the combined organic layers were washed
with H2O (2 × 100 mL) and brine (200 mL) and dried (Na2SO4).
The solvents were evaporated in vacuo and the residue was filtered
through a thin layer of silica gel. Bromide 2e was further recrystal-
lised from hexane–EtOAc (5:1). (The characteristics of oxazines
2a,g–i have been published elsewhere.8)
Anal. Calcd for C17H16BrNO: C, 61.83; H, 4.88; N, 4.24. Found: C,
61.95; H, 5.00; N, 4.50.
3-(Bromomethyl)-4-(4-methoxyphenyl)-6,6-dimethyl-5,6-dihy-
dro-4H-1,2-oxazine (2f)
Yield: 57%; oil; Rf = 0.88 (silica gel, hexane–EtOAc, 1:1, UV).
Synthesis 2007, No. 1, 97–107 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Substituted 5,6-Dihydro-4H-1,2-oxazines from Nitroethane
103
1H NMR (300 MHz, CDCl3): d = 1.32, 1.37 [2 s, 6 H, H3C(6),
H3C(7)], 1.94 [dd, J = 12.5, 13.3 Hz, 1 H, H2C(3)], 2.11 [dd, J = 7.8,
13.3 Hz, 1 H, H2C(3)], 3.63 [d, J = 9.8 Hz, 1 H, H2C(5)], 3.80 [dd,
J = 7.8, 12.5 Hz, 1 H, HC(2)], 3.81 [s, 3 H, H3C(12)], 3.98 [d,
J = 9.8 Hz, 1 H, H2C(5)], 6.89 [d, J = 6.8, 2 H, HC(10)], 7.14 [d,
J = 6.8, 2 H, HC(9)].
13C NMR (75 MHz, CDCl3): d = 28.4 (C-6, C-7), 31.9 (C-5), 36.1
(C-3), 40.2 (C-2), 55.3 (C-12), 75.8 (C-4), 114.7 (C-10), 129.4 (C-
9), 130.9 (C-8), 155.8 (C-1), 159.1 (C-11).
the combined organic layers were washed with brine (50 mL) and
dried (Na2SO4). The solvent was evaporated in vacuo and the resi-
due was subjected to column chromatography on silica gel to give
corresponding derivatives (see Table 1 for yields).
Dimethyl 2-{[rel-(4S,4aR,7aR)-4-Phenyl-4,4a,5,6,7,7a-hexahy-
drocyclopenta[e][1,2]oxazin-3-yl]methyl}malonate (3k)
Mp 120–131 °C; Rf = 0.65 (silica gel, hexane–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.36–2.03, 2.06–2.22 [2 m, 7 H,
HC(3), H2C(11), H2C(12), H2C(17)], 2.58 [dd, J = 8.1, 16.9 Hz, 1
H, HC(5)], 2.77 [dd, J = 7.4, 16.9 Hz, 1 H, HC(5)], 3.22 [d, J = 2.2
Hz, 1 H, HC(2)], 3.70, 3.71 [2 s, 6 H, H3C(9), H3C(10)], 3.98 [dd,
J = 7.4, 8.1 Hz, 1 H, HC(6)], 4.11 [m, 1 H, HC(4)], 7.16–7.41 [m, 5
H, HC(14), HC(15), HC(16)].
13C NMR (75 MHz, CDCl3): d = 21.9, 29.6, 31.6 (C-11, C-12, C-
17), 33.4 (C-5), 43.3, 44.8 (C-2, C-3), 48.0 (C-6), 52.5 (C-9, C-10),
75.7 (C-4), 127.2, 128.1, 129.0 (C-14, C-15, C-16), 141.0 (C-13),
156.3 (C-1), 169.3, 169.4 (C-7, C-8).
Anal. Calcd for C14H18BrNO2: C, 53.86; H, 5.81; N, 4.49. Found: C,
53.80; H, 6.00; N, 4.40.
3-(Bromomethyl)-4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihy-
dro-4H-1,2-oxazine (2j)
Yield: 47%; mp 87–88 °C; (hexane–EtOAc, 1:1); Rf = 0.76 (silica
gel, hexane–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): d = 1.32, 1.38 [2 s, 6 H, H3C(6),
H3C(7)], 1.91 [dd, J = 12.3, 13.5 Hz, 1 H, HC(3)], 2.11 [dd,
J = 13.5, 7.6 Hz, 1 H, HC(3)], 3.62 [d, J = 10.1 Hz, 1 H, H2C(5)],
3.85 [dd, J = 12.3, 7.6 Hz, 1 H, HC(2)], 4.01 [d, J = 10.1 Hz, 1 H,
H2C(5)], 7.19 [d, J = 7.6 Hz, 2 H, HC(10)], 7.35 [d, J = 7.6 Hz, 2 H,
HC(9)].
13C NMR (75 MHz, CDCl3): d = 23.1, 28.3 (C-6, C-7), 31.3 (C-5),
38.2 (C-2), 40.0 (C-3), 77.1 (C-4), 129.5, 129.7 (C-9, C-10), 132.1
(C-8), 137.6 (C-11), 154.9 (C-1).
Anal. Calcd for C19H23NO5: C, 66.07; H, 6.71; N, 4.06. Found: C,
66.15; H, 6.80; N, 4.10.
Dimethyl 2-{[rel-(4S,4aR,8aR)-4-Phenyl-4a,5,6,7,8,8a-hexahy-
dro-4H-1,2-benzoxazin-3-yl]methyl}malonate (3l)
Mp 70–77 °C; Rf = 0.59 (silica gel, hexane–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.15–1.47, 1.50–1.78 [2 m, 9 H,
HeqC(3), H2C(11), H2C(12), H2C(17), H2C(18)], 2.60 [dd, J = 7.4,
16.9 Hz, 1 H, HC(5)], 2.83 [dd, J = 7.4, 16.9 Hz, 1 H, HC(5)], 3.06
[s, 1 H, HC(2)], 3.71 [s, 6 H, H3C(9), H3C(10)], 3.95 [s, 1 H,
HC(4)], 4.02 [t, J = 7.4 Hz, 1 H, HC(6)], 7.12–7.39 [m, 5 H,
HC(14), HC(15), HC(16)].
13C NMR (75 MHz, CDCl3): d = 19.9, 25.0, 27.7, 29.2 (C-11, C-12,
C-17, C-18), 33.8 (C-5), 39.3 (C-2), 47.5 (C-3), 48.0 (C-6), 52.6 (C-
9, C-10), 68.4 (C-4), 127.1, 128.2, 128.9 (C-14, C-15, C-16), 141.2
(C-13), 151.9 (C-1), 169.3, 169.5 (C-7, C-8).
Anal. Calcd for C13H15ClBrNO: C, 49.31; H, 4.78; N, 4.42. Found:
C, 49.50; H, 4.70; N, 4.40.
3-(Bromomethyl)-4,6,6-trimethyl-5,6-dihydro-4H-1,2-oxazine
(2k)
Yield: 62%; oil; Rf = 0.55 (silica gel, hexane–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): d = 1.19 [d, J = 7.4 Hz, 3 H, H3C(6)],
1.20, 1.31 [2 s, 6 H, H3C(7), H3C(8)], 1.50 [dd, J = 12.5, 13.0 Hz, 1
H, H2C(3)], 1.87 [dd, J = 7.4, 13.0 Hz, 1 H, H2C(3)], 2.70 [ddq,
J = 7.4, 11.0, 12.5 Hz, 1 H, HC(2)], 4.07 [d, J = 10.3 Hz, 1 H,
H2C(5)], 4.16 [d, J = 10.3 Hz, 1 H, H2C(5)].
Anal. Calcd for C20H25NO5: C, 66.84; H, 7.01; N, 3.90. Found: C,
66.99; H, 7.13; N, 4.04.
13C NMR (75 MHz, CDCl3): d = 16.5 (C-6), 23.5, 24.0 (C-7, C-8),
Dimethyl 2-{[rel-(4R,4aS,5R,8S,8aS)-4-Phenyl-4a,5,6,7,8,8a-
hexahydro-4H-5,8-methano-1,2-benzoxazin-3-yl]methyl}mal-
onate (3m)
28.3 (C-5), 31.2 (C-2), 38.8 (C-3), 75.4 (C-4), 156.7 (C-1).
Anal. Calcd for C8H14BrNO: C, 43.65; H, 6.41; N, 6.36. Found: C,
44.01; H, 6.53; N, 6.20.
Oil; Rf = 0.61 (silica gel, hexane–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.05–1.70, 1.88–2.19 [2 m, 8 H,
HC(3), H2C(12), H2C(17), H2C(19), HC(18)], 2.37 [dd, J = 7.2,
17.7 Hz, 1 H, HC(5)], 2.47 [d, J = 4.6 Hz, 1 H, HC(11)], 2.72 [dd,
J = 7.2, 17.2 Hz, 1 H, HC(5)], 3.19 [d, J = 10.5 Hz, 1 H, HC(2)],
3.66, 3.69 [s, 6 H, H3C(9), H3C(10)], 3.90 [s, 1 H, HC(4)], 3.90 [dd,
J = 7.2, 7.2 Hz, 1 H, HC(6)], 7.20–7.44 [m, 5 H, HC(14), HC(15),
HC(16)].
13C NMR (75 MHz, CDCl3): d = 24.7, 29.0, 27.7, 32.2 (C-12, C-17,
C-19), 33.4 (C-5), 39.9 (C-2), 42.0, 43.5 (C-3, C-18), 47.4 (C-6),
52.7, 53.0 (C-9,C-10, C-11), 82.8 (C-4), 127.6, 129.0, 129.5 (C-14,
C-15, C-16), 137.6 (C-13), 169.0, 169.5 (C-7, C-8), 172.6 (C-1).
3-(Bromomethyl)-6,6-dimethyl-5,6-dihydro-4H-1,2-oxazin-4-yl
Benzoate (2l)
Yield: 68%; oil; Rf = 0.76 (silica gel, hexane–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): d = 1.40, 1.45 [2 s, 6 H, H3C(6),
H3C(7)], 2.01 [dd, J = 6.0, 13.8 Hz, 1 H, H2C(3)], 2.40 [dd, J = 6.6,
13.8 Hz, 1 H, H2C(3)], 4.15 [d, J = 11.8 Hz, 1 H, H2C(5)], 4.47 [d,
J = 11.8 Hz, 1 H, H2C(5)], 5.80 [dd, J = 6.6, 6.0 Hz, 1 H, HC(2)],
7.48 [t, J = 7.2 Hz, 2 H, HC(11)], 7.63 [t, J = 7.2 Hz, 1 H, HC(12)],
8.10 [d, J = 7.2 Hz, 2 H, HC(10)].
13C NMR (75 MHz, CDCl3): d = 25.7 (C-6, C-7), 30.3 (C-5), 36.1
(C-3), 59.5 (C-2), 75.7 (C-4), 128.6 (C-11), 129.2 (C-9), 129.7 (C-
10), 133.6 (C-12), 151.3 (C-1), 165.2 (C-8).
Anal. Calcd for C21H25NO5: C, 67.91; H, 6.78; N, 3.77. Found: C,
67.82; H, 6.79; N, 3.90.
Anal. Calcd for C14H16BrNO3: C, 51.55; H, 4.94; N, 4.29. Found: C,
51.50; H, 4.90; N, 4.24.
Dimethyl 2-{[rel-(4S,6R)-4,6-Diphenyl-5,6-dihydro-4H-1,2-ox-
azin-3-yl]methyl}malonate (3n)
Mp 83–89 °C; Rf = 0.61 (silica gel, hexane–EtOAc, 1:1).
Malonates 3b,k–v; General Procedure
t-BuOK (0.13 g, 1.2 mmol) was added to a stirred soln of dimethyl
malonate (0.16 g, 1.2 mmol) in DMF (1 mL) at 0 °C. After 5 min, a
soln of the appropriate oxazine 2 (1 mmol) in DMF (1.5 mL) was
carefully added. The resulting mixture was stirred for 2 h at 60 °C
and poured into a mixture of EtOAc (100 mL) and H2O (100 mL).
The aqueous phase was back-extracted with EtOAc (2 × 50 mL) and
1H NMR (300 MHz, CDCl3): d = 2.01 [ddd, J = 6.8, 13.0, 2.0 Hz, 1
H, HC(3)], 2.43 [ddd, J = 7.3, 13.0, 10.1 Hz, 1 H, HC(3)], 2.70 [dd,
J = 8.0, 17.0 Hz, 1 H, HC(5)], 2.92 [dd, J = 8.0, 17.0 Hz, 1 H,
HC(5)], 3.60 [m, 7 H, HC(2), H3C(9), H3C(10)], 4.10 [t, J = 8.0 Hz,
Synthesis 2007, No. 1, 97–107 © Thieme Stuttgart · New York

104
A. Yu. Sukhorukov et al.
PAPER
Dimethyl 2-{[rel-(4S,6S)-6-Methoxy-4-(4-Methoxyphenyl)-6-
1 H, HC(6)], 4.99 [dd, 1 H, J = 2.0, 10.1 Hz, HC(4)], 7.20–7.44 [m,
10 H, Ph].
methyl-5,6-dihydro-4H-1,2-oxazin-3-yl]methyl}malonate (3s)
Oil; Rf = 0.61 (silica gel, hexane–EtOAc, 1:1).
13C NMR (75 MHz, CDCl3): d = 33.9 (C-5), 34.5 (C-3), 40.0 (C-2),
47.5 (C-6), 52.7, 53.0 (C-9, C-10), 73.0 (C-4), 127.6, 127.9, 128.5,
129.0, 129.5, 138.0, 139.9 (Ph), 153.7 (C-1), 169.0, 169.5 (C-7,
C-8).
1H NMR (300 MHz, CDCl3): d = 1.38 [s, 3 H, H3C(12)], 1.85 [dd,
J = 11.8, 13.2 Hz, 1 H, H2C(3)], 2.19 [dd, J = 8.1, 13.2 Hz, 1 H,
H2C(3)], 2.51 [m, 2 H, H2C(5)], 3.20 [s, 3 H, H3C(11)], 3.50 [dd,
J = 8.1, 11.8 Hz, 1 H, HC(2)], 3.66 [s, 6 H, H3C(9), H3C(10)], 3.76
[s, 3 H, H3C(17)], 3.96 [t, J = 8.1 Hz, 1 H, HC(6)], 6.84 [d, J = 8.5
Hz, 2 H, HC(15)], 7.07 [d, J = 8.5 Hz, 2 H, HC(14)].
Anal. Calcd for C22H23NO5: C, 69.28; H, 6.08; N, 3.67. Found: C,
69.29; H, 6.12; N, 3.45.
Dimethyl 2-{[4-(4-Methoxyphenyl)-6,6-dimethyl-5,6-dihydro-
4H-1,2-oxazin-3-yl]methyl}malonate (3o)
Oil; Rf = 0.59 (silica gel, hexane–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.22, 1.32 [2 s, 6 H, H3C(11),
H3C(12)], 1.88 [dd, J = 11.8, 13.2 Hz, 1 H, H2C(3)], 2.03 [dd,
J = 8.1, 13.2 Hz, 1 H, H2C(3)], 2.55 [m, 2 H, H2C(5)], 3.40 [dd,
J = 8.1, 11.8 Hz, 1 H, HC(2)], 3.68, 3.69 [2 s, 6 H, H3C(9),
H3C(10)], 3.81 [s, 3 H, H3C(17)], 3.96 [t, J = 7.9 Hz, 1 H, HC(6)],
6.89 [d, J = 8.5 Hz, 2 H, HC(15)], 7.12 [d, J = 8.5 Hz, 2 H, HC(14)].
13C NMR (75 MHz, CDCl3): d = 21.3 (C-12), 32.4 (C-5), 38.5, 39.6
(C-2, C-3), 48.0 (C-6), 49.3 (C-11), 52.6 (C-9, C-10), 55.2 (C-17),
97.4 (C-4), 114.5 (C-15), 129.4 (C-14), 131.5 (C-13), 157.7 (C-1),
158.8 (C-16), 169.3, 169.4 (C-7, C-8).
Anal. Calcd for C19H25NO7: C, 60.15; H, 6.64; N, 3.69. Found: C,
59.88; H, 6.35; N, 3.90.
Dimethyl 2-{[4-(4-Chlorophenyl)-6,6-dimethyl-5,6-dihydro-
4H-1,2-oxazin-3-yl]methyl}malonate (3t)
Oil; Rf = 0.69 (silica gel, hexane–EtOAc, 1:1).
13C NMR (75 MHz, CDCl3): d = 22.6, 28.5 (C-11, C-12), 32.5 (C-
5), 39.7 (C-2), 41.3 (C-3), 48.2 (C-6), 52.7 (C-9, C-10), 55.3 (C-17),
74.4 (C-4), 114.6 (C-15), 129.4 (C-14), 131.9 (C-13), 155.6 (C-1),
158.9 (C-16), 169.7 (C-7, C-8).
1H NMR (300 MHz, CDCl3): d = 1.22, 1.32 [2 s, 6 H, H3C(11),
H3C(12)], 1.83 [dd, J = 11.8, 13.2 Hz, 1 H, H2C(3)], 2.03 [dd,
J = 8.1, 13.2 Hz, 1 H, H2C(3)], 2.52 [m, 2 H, H2C(5)], 3.38 [dd,
J = 8.1, 11.8 Hz, 1 H, HC(2)], 3.70 [ s, 6 H, H3C(9), H3C(10)], 3.97
[t, J = 7.7 Hz, 1 H, HC(6)], 7.13 [d, J = 8.8 Hz, 2 H, HC(15)], 7.33
[d, J = 8.8 Hz, 2 H, HC(14)].
Anal. Calcd for C19H25NO6: C, 62.80; H, 6.93; N, 3.85. Found: C,
62.51; H, 6.80; N, 3.80.
Dimethyl 2-{[rel-(4S,4aR,8aR)-4-(4-Methoxyphenyl)-
4a,5,6,7,8,8a-hexahydro-4H-1,2-benzoxazin-3-yl]methyl}mal-
onate (3p)
Mp 101–107 °C; (hexane–EtOAc, 1:1); Rf = 0.63 (silica gel, hex-
ane–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.20–1.49, 1.51–1.81 [2 m, 9 H,
HC(3), H2C(11), H2C(12), H2C(18), H2C(19)], 2.59 [dd, J = 7.4,
16.9 Hz, 1 H, HC(5)], 2.83 [dd, J = 8.1, 16.9 Hz, 1 H, HC(5)], 3.00
[s, 1 H, HC(2)], 3.72, 3.74 [2 s, 6 H, H3C(9), H3C(10)], 3.78 [s, 3 H,
H3C(17)], 3.94 [s, 1 H, HC(4)], 4.01 [dd, J = 7.4, 8.1 Hz, 1 H,
HC(6)], 6.87 [d, J = 8.5 Hz, 2 H, HC(15)], 7.07 [d, J = 8.5 Hz, 2 H,
HC(14)].
13C NMR (75 MHz, CDCl3): d = 19.7, 25.0, 27.6, 29.2 (C-11, C-12,
C-18, C-19), 33.7 (C-5), 39.4 (C-2), 46.6 (C-3), 48.0 (C-6), 52.6 (C-
9, C-10), 55.2 (C-17), 68.4 (C-4), 114.6 (C-15), 129.4 (C-14), 131.9
(C-13), 152.2 (C-1), 158.7 (C-16), 169.4, 169.5 (C-7, C-8).
13C NMR (75 MHz, CDCl3): d = 22.5, 28.3 (C-11, C-12), 32.4 (C-
5), 40.0 (C-2), 41.3 (C-3), 48.2 (C-6), 52.6 (C-9, C-10), 74.2 (C-4),
129.3, 129.7 (C-14, C-15), 133.3 (C-13), 138.6 (C-16), 154.6 (C-1),
169.4, 169.5 (C-7, C-8).
Anal. Calcd for C18H22ClNO5: C, 58.78; H, 6.03; N, 3.81. Found: C,
58.27; H, 5.87; N, 3.49.
Dimethyl 2-[(4,6,6-Trimethyl-5,6-dihydro-4H-1,2-oxazin-3-
yl)methyl]malonate (3u)
Mp 71–79 °C; (hexane–EtOAc, 1:1); Rf = 0.57 (silica gel, hexane–
EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.07, 1.22 [2 s, 6 H, H3C(11),
H3C(12)], 1.13 [d, J = 6.6 Hz, 3 H, H3C(13)], 1.43 [dd, J = 11.8,
13.2 Hz, 1 H, H2C(3)], 1.77 [dd, J = 7.4, 13.2 Hz, 1 H, H2C(3)], 2.24
[m, 1 H, HC(2)], 2.72 [dd, J = 8.1, 16.7 Hz, 1 H, HC(5)], 2.87 [dd,
J = 7.4, 16.7 Hz, 1 H, HC(5)], 3.69, 3.70 [2 s, 6 H, H3C(9),
H3C(10)], 3.95 [dd, J = 7.4, 8.1 Hz, 1 H, HC(6)].
13C NMR (75 MHz, CDCl3): d = 17.1 (C-13), 23.0, 27.1 (C-11, C-
12), 28.2 (C-2), 31.5 (C-5), 39.6 (C-3), 48.0 (C-6), 52.5 (C-9, C-10),
73.9 (C-4), 156.9 (C-1), 169.5, 169.6 (C-7, C-8).
Anal. Calcd for C21H27NO6: C, 64.77; H, 6.99; N, 3.60. Found: C,
64.90; H, 7.05; N, 3.66.
Dimethyl 2-{[rel-(4S,6R)-6-Ethoxy-4-(4-methoxyphenyl)-5,6-di-
hydro-4H-1,2-oxazin-3-yl]methyl}malonate (3r)
Mp 56–59 °C; (hexane–EtOAc, 1:1); Rf = 0.63 (silica gel, hexane–
EtOAc, 1:1).
Anal. Calcd for C13H21NO5: C, 57.55; H, 7.80; N, 5.16. Found: C,
57.29; H, 7.89; N, 5.00.
1H NMR (300 MHz, CDCl3): d = 1.28 [m, 3 H, H3C(12)], 1.80 [dd,
J = 11.8, 13.7 Hz, 1 H, H2C(3)], 2.20 [m, 1 H, H2C(3)], 2.45 [m, 2
H, H2C(5)], 3.50 [m, 2 H, HC(2), H2C(11)], 3.66 [s, 6 H, H3C(9),
H3C(10)], 3.76 [m, 4 H, H3C(17), HC(11)], 3.96 [t, J = 8.1 Hz, 1 H,
HC(6)], 5.64 [br s, 1 H, HC(4)], 6.84 [d, J = 8.5 Hz, 2 H, HC(15)],
7.07 [d, J = 8.5 Hz, 2 H, HC(14)].
13C NMR (75 MHz, CDCl3): d = 12.3 (C-12), 32.8 (C-5), 37.4 (C-
2), 40.0 (C-3), 48.0 (C-6), 52.7 (C-9, C-10), 55.2 (C-17), 62.3 (C-
11), 101.0 (C-4), 114.5 (C-15), 129.4 (C-14), 131.5 (C-13), 158.1
(C-1), 158.8 (C-16), 169.3, 169.4 (C-7, C-8).
Dimethyl 2-{[4-(Benzoyloxy)-6,6-dimethyl-5,6-dihydro-4H-1,2-
oxazin-3-yl]methyl}malonate (3v)
Oil; Rf = 0.61 (silica gel, hexane–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.30, 1.40 [2 s, 6 H, H3C(11),
H3C(12)], 1.93 [dd, J = 6.2, 12.5 Hz, 1 H, H2C(3)], 2.17 [dd, J = 7.0,
12.5 Hz, 1 H, H2C(3)], 2.69 [m, 2 H, H2C(5)], 3.68 [s, 6 H, H3C(9),
H3C(8)], 3.72 [t, J = 7.8 Hz, 1 H, HC(6)], 5.60 [dd, J = 6.2, 7.0 Hz,
1 H, HC(2)], 7.45 [t, J = 7.2 Hz, 2 H, HC(16)], 7.65 [t, J = 7.2 Hz,
1 H, HC(17)], 8.10 [d, J = 7.2 Hz, 2 H, HC(15)].
13C NMR (75 MHz, CDCl3): d = 23.1, 27.0 (C-11, C-12), 31.5 (C-
5), 40.2 (C-3), 48.0 (C-6), 52.5 (C-9, C-10), 60.0 (C-2), 73.9 (C-4),
128.7 (C-16), 129.0 (C-14), 129.9 (C-15), 133.4 (C-17), 151.9 (C-
1), 165.2 (C-13), 169.5, 169.6 (C-7, C-8).
Anal. Calcd for C19H25NO7: C, 60.15; H, 6.64; N, 3.69. Found: C,
60.35; H, 6.69; N, 3.81.
Anal. Calcd for C19H23NO7: C, 60.47; H, 6.14; N, 3.71. Found: C,
60.78; H, 6.01; N, 4.02.
Synthesis 2007, No. 1, 97–107 © Thieme Stuttgart · New York

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Synthesis of 3-Substituted 5,6-Dihydro-4H-1,2-oxazines from Nitroethane
105
Methyl 2-Cyano-3-(6,6-dimethyl-4-phenyl-5,6-dihydro-4H-1,2-
oxazin-3-yl)propanoate (3c)
(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-yl)meth-
yl Azide (3f)
Oil; Rf = 0.66 (silica gel, hexane–EtOAc, 1:1).
Methyl cyanoacetate (0.1 mL, 1.2 mmol) was added dropwise to a
stirred soln of t-BuOK (0.13 g, 1.2 mmol) in DMF (1 mL) at 0 °C.
After 20 min, a soln of oxazine 2a (0.28 g, 1 mmol) in DMF (1.5
mL) was added, and the resulting mixture was stirred for 2 h at 60
°C. Then the mixture was poured into a mixture of EtOAc (100 mL)
and H2O (100 mL). The aqueous phase was back-extracted with
EtOAc (2 × 50 mL); and the combined organic layers were washed
with brine (50 mL) and dried (Na2SO4). The solvent was evaporated
in vacuo and the residue was subjected to column chromatography
on silica gel; this gave 3c as a mixture of isomers (1.1:1).
1H NMR (300 MHz, CDCl3): d = 1.33, 1.38 [2 s, 6 H, H3C(6),
H3C(7)], 1.94 [dd, J = 11.8, 13.1 Hz, 1 H, H2C(3)], 2.12 [dd, J = 7.9,
13.1 Hz, 1 H, H2C(3)], 3.59 [dd, J = 7.9, 11.8 Hz, 1 H, HC(2)], 3.49,
3.87 [2 d, J = 13.1 Hz, 2 H, H2C(5)], 7.16–7.42 [m, 5 H, HC(9),
HC(10), HC(11)].
13C NMR (75 MHz, CDCl3): d = 22.5, 28.4 (C-6, C-7), 37.8 (C-2),
40.1 (C-3), 52.7 (C-5), 75.1 (C-4), 127.7, 128.3, 129.3 (C-9, C-10,
C-11), 139.3 (C-8), 154.4 (C-1).
Anal. Calcd for C13H16N4O: C, 63.92; H, 6.60; N, 22.93. Found: C,
63.82; H, 6.30; N, 22.92.
Yield: 0.29 g (98%); oil; Rf = 0.62 (silica gel, hexane–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.25, 1.28, 1.34 [3 s, 3 H, 3 H, 6
H, H3C(10), H3C(11)], 1.90 [dd, J = 11.8, 13.8 Hz, 1 H, H2C(3)],
2.08 [dd, J = 7.9, 13.8 Hz, 1 H, H2C(3)], 2.47, 2.57, 2.71 [dd,
J = 7.2, 16.7 Hz, d, J = 7.2 Hz, dd, J = 6.6, 16.7 Hz, 2 H, H2C(5)],
3.40 [dd, J = 7.9, 11.8 Hz, 1 H, HC(2)], 3.76, 3.78 [s, 3 H, H3C(9)],
3.96, 4.02 [dd, J = 7.2, 6.6 Hz, dd, J = 7.2, 7.2 Hz, 1 H, HC(6)],
7.12–7.42 [m, 5 H, HC(13), HC(14), HC(15)].
13C NMR (75 MHz, CDCl3): d = 22.6, 22.7, 28.4 (C-10, C-11), 32.8,
33.1, 33.2, 33.8 (C-5, C-6), 40.4 (C-2), 40.9 (C-3), 53.6 (C-9), 74.9
(C-4), 116.5 (C-8), 127.7, 128.3, 129.4 (C-13, C-14, C-15), 139.4
(C-12), 152.9, 153.1 (C-1), 166.1 (C-7).
2-[(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-
yl)methyl]-1H-isoindole-1,3(2H)-dione (3g)
Mp 148–150 °C; Rf = 0.59 (silica gel, hexane–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.29, 1.32 [2 s, 6 H, H3C(10),
H3C(11)], 1.91 [dd, J = 11.8, 13.5 Hz, 1 H, H2C(3)], 2.09 [dd,
J = 7.9, 13.5 Hz, 1 H, H2C(3)], 3.51 [dd, J = 7.9, 11.8 Hz, 1 H,
HC(2)], 4.12, 4.27 [2 d, J = 16.7 Hz, 2 H, H2C(5)], 7.16–7.42 [m, 5
H, HC(13), HC(14), HC(15)], 7.63–7.73, 7.75–7.84 [2 m, 4 H,
HC(8), HC(9)].
13C NMR (75 MHz, CDCl3): d = 22.8, 28.3 (C-10, C-11), 39.2 (C-
2), 40.0 (C-3), 41.1 (C-5), 74.9 (C-4), 123.4 (C-8), 127.7, 128.3,
129.3 (C-13, C-14, C-15), 132.3 (C-7), 133.9 (C-9), 139.1 (C-12),
152.0 (C-1), 166.0 (C-6).
Anal. Calcd for C17H20N2O3: C, 67.98; H, 6.71; N, 9.33. Found: C,
68.15; H, 6.63; N, 9.04.
Methyl 2-[(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-
3-yl)methyl]-3-oxobutanoate (3d)
Anal. Calcd for C21H20N2O3: C, 72.40; H, 5.79; N, 8.04. Found: C,
72.29; H, 5.70; N, 8.13.
Methyl acetoacetate (0.15 mL, 1.2 mmol) was added dropwise to a
stirred soln of t-BuOK (0.13 g, 1.2 mmol) in DMF (1 mL), and then
a soln of oxazine 2a (0.28 g, 1 mmol) in DMF (1.5 mL) was added
dropwise. The resulting mixture was stirred for 3 h at 60 °C and
poured into a mixture of EtOAc (100 mL) and H2O (100 mL). The
aqueous phase was back-extracted with EtOAc (2 × 50 mL) and the
combined organic layers were washed with brine (50 mL) and dried
(Na2SO4). The solvent was evaporated in vacuo and the residue was
subjected to column chromatography on silica gel; this gave 3d as a
mixture of isomers (1.1:1).
3-(Ethoxymethyl)-6,6-dimethyl-4-phenyl-5,6-dihydro-4H-1,2-
oxazine (3h)
A soln of oxazine 2a (0.28 g, 1 mmol) in EtOH (3 mL) was added
to a soln of NaOEt [freshly obtained from Na (0.025 g, 1.1 mmol)
and EtOH (2 mL)]. The resulting mixture was stirred for 4 h at 50–
60 °C and poured into a mixture of EtOAc (100 mL) and H2O (100
mL). The aqueous phase was back-extracted with EtOAc (2 × 50
mL); the combined organic layers were washed with brine (50 mL)
and dried (Na2SO4). The solvent was evaporated in vacuo and the
residue was subjected to column chromatography on silica gel.
Yield: 0.26 g (78%); oil; Rf = 0.58 (silica gel, hexane–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.17, 1.22, 1.30 [3 s, 3 H, 3 H, 6
H, H3C(11), H3C(12)], 1.83 [dd, J = 7.2, 13.1 Hz, 1 H, H2C(3)],
2.02 [dd, J = 8.2, 13.1 Hz, 1 H, H2C(3)], 2.29 [s, 3 H, H3C(10)], 2.37
[dd, J = 11.6, 17.1 Hz, 1 H, H2C(5)], 2.59 [dd, J = 9.2, 17.1 Hz, 1
H, H2C(5)], 3.35 [dd, J = 8.2, 11.2 Hz, 1 H, HC(2)], 3.66 [s, 3 H,
H3C(8)], 4.13 [m, 1 H, HC(6)], 7.08–7.39 [m, 5 H, HC(14), HC(15),
HC(16)].
13C NMR (75 MHz, CDCl3): d = 22.7, 28.5 (C-11, C-12), 31.8 (C-
5), 40.5, 40.8 (C-2, C-10), 41.4 (C-3), 52.6 (C-8), 54.8 (C-6), 74.3
(C-4), 127.5, 128.4, 129.2 (C-14, C-15, C-16), 140.2 (C-13), 155.6,
155.9 (C-1), 169.8 (C-7), 202.9 (C-9).
Yield: 0.16 g (65%); colourless oil; Rf = 0.66 (silica gel, hexane–
EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.10 [dd, J = 6.6, 7.2 Hz, 3 H,
H3C(8)], 1.31, 1.36 [2 s, 6 H, H3C(9), H3C(10)], 1.91 [dd, J = 11.8,
13.8 Hz, 1 H, H2C(3)], 2.08 [dd, J = 7.9, 13.8 Hz, 1 H, H2C(3)],
3.19, 3.40 [2 m, 2 H, H2C(7)], 3.59 [dd, J = 7.9, 11.8 Hz, 1 H,
HC(2)], 3.80 [s, 2 H, H2C(5)], 7.16–7.38 [m, 5 H, HC(12), HC(13),
HC(14)].
13C NMR (75 MHz, CDCl3): d = 15.1 (C-8), 22.8, 28.6 (C-9, C-10),
37.3 (C-2), 40.1 (C-3), 65.8, 70.2 (C-5, C-7), 74.6 (C-4), 127.2,
128.5, 128.9 (C-9, C-10, C-11), 140.3 (C-11), 156.5 (C-1).
Anal. Calcd for C18H23NO4: C, 68.12; H, 7.30; N, 4.41. Found: C,
68.25; H, 7.33; N, 4.01.
Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C,
72.59; H, 8.43; N, 5.19.
1,2-Oxazines 3a,f,g; General Procedure
(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-yl)meth-
anaminium Chloride (3i)
To a soln of oxazine 2a (0.28 g, 1 mmol) in DMF (2.5 mL) was add-
ed the corresponding nucleophile (2 mmol). The resulting mixture
was stirred for 2 h at 50–60 °C and poured into a mixture of EtOAc
(100 mL) and H2O (100 mL). The aqueous phase was back-extract-
ed with EtOAc (2 × 50 mL) and the combined organic layers were
washed with brine (50 mL) and dried (Na2SO4). The solvent was
evaporated in vacuo and the residue was subjected to column chro-
matography on silica gel (see Table 1 for yields).
To a soln of oxazine 2a (0.28 g, 1 mmol) in DMF (2.5 mL) was add-
ed NaN3 (0.13 g, 2 mmol). The resulting mixture was stirred for 1 h
at 100 °C and poured into a mixture of EtOAc (100 mL) and H2O
(100 mL). The aqueous phase was back-extracted with EtOAc (2 ×
50 mL); the combined organic layer was collected, concentrated in
vacuo, and dissolved in Et2O (1.2 mL). PPh3 (0.33 g, 1.26 mmol)
was added to the mixture at r.t., and after 3 h, H2O (0.066 mL, 3.6
Synthesis 2007, No. 1, 97–107 © Thieme Stuttgart · New York

106
A. Yu. Sukhorukov et al.
PAPER
mmol) was added. The mixture was stirred for 24 h at r.t., the sol-
vent was evaporated in vacuo, and the residue was subjected to col-
umn chromatography on silica gel. This gave the free amine as a
colourless oil; to this 4 M HCl in dioxane (0.6 mL) was added, and
the resulting solid was dried in vacuo.
mL) and dried (Na2SO4). The solvent was evaporated in vacuo and
the residue was subjected to column chromatography on silica gel.
Yield: 0.16 g (76%); colourless oil; Rf = 0.76 (silica gel, hexane–
EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.30, 1.45 [2 s, 6 H, H3C(6),
H3C(7)], 1.89 [dd, J = 11.4, 14.0 Hz, 1 H, H2C(3)], 2.19 [dd, J = 8.1,
14.0 Hz, 1 H, H2C(3)], 3.71 [dd, J = 8.1, 11.4 Hz, 1 H, HC(2)],
7.10–7.37 [m, 5 H, HC(9), HC(10), HC(11)], 9.48 [s, 1 H, HC(5)].
13C NMR (75 MHz, CDCl3): d = 23.0, 28.0 (C-6, C-7), 34.8 (C-2),
40.5 (C-3), 78.4 (C-4), 127.1, 127.4, 129.0 (C-9, C-10, C-11), 134.7
(C-8), 157.9 (C-1), 189.9 (C-5).
Yield: 0.20 g (69%); mp 32–39 °C.
1H NMR (300 MHz, CDCl3): d = 1.30, 1.32 [2 s, 6 H, H3C(7),
H3C(8)], 1.84 [dd, J = 12.5, 12.9 Hz, 1 H, H2C(3)], 2.06 [dd, J = 7.4,
12.9 Hz, 1 H, H2C(3)], 3.48, 3.60 [2 m, 3 H, HC(2), HC(5)], 7.17–
7.38 [m, 5 H, HC(10), HC(11), HC(12)], 8.6 [br, 3 H, HN(6)].
13C NMR (75 MHz, CDCl3): d = 23.1, 28.3 (C-7, C-8), 38.8 (C-2),
40.3, 40.6 (C-5, C-3), 75.8 (C-4), 127.8, 128.4, 129.4 (C-10, C-11,
C-12), 138.4 (C-9), 151.3 (C-1).
Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C,
71.89; H, 7.26; N, 6.80.
Anal. Calcd for C13H19ClN2O: C, 61.29; H, 7.52; N, 11.00. Found:
C, 61.34; H, 7.60; N, 11.04.
6,6-Dimethyl-4-phenyl-3-styryl-5,6-dihydro-4H-1,2-oxazine (5)
To a stirred soln of phosphonium bromide 3e (0.15 g, 0.28 mmol)
in toluene–CH2Cl2 (2:1, 1.5 mL) at –78 °C was added a 2.5 M soln
of n-BuLi in hexane (0.11 mL). The mixture was stirred for 0.5 h,
and a soln of PhCHO (0.031 mL, 0.3 mmol) in toluene (1.5 mL) was
added. The temperature was raised to 0 °C, and the mixture was
stirred for 1 h at the same temperature and then poured into a mix-
ture of EtOAc (100 mL) and H2O (100 mL). The aqueous phase was
back-extracted with EtOAc (2 × 50 mL); the combined organic lay-
ers were washed with brine (50 mL) and dried (Na2SO4). The sol-
vent was evaporated in vacuo and the residue was subjected to
column chromatography on silica gel.
[(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-yl)meth-
yl]triphenylphosphonium Bromide (3e)
A soln of oxazine 2a (0.28 g, 1 mmol) and PPh3 (0.26 g, 1 mmol) in
toluene (3 mL) was boiled for 2 h. After the mixture had cooled to
r.t., the resulting white precipitate was collected by filtration.
Yield: 0.51 g (94%); white crystals; mp 112–114 °C.
1H NMR (300 MHz, CDCl3): d = 1.22, 1.36 [2 s, 6 H, H3C(10),
H3C(11)], 1.83 [dd, J = 12.5, 13.1 Hz, 1 H, H2C(3)], 2.11 [dd,
J = 7.9, 13.1 Hz, 1 H, H2C(3)], 4.57 [m, 1 H, HC(2)], 3.33, 6.63 [2
dd, J = 11.2, 18.4, 13.8, 18.4 Hz, 2 H, H2C(5)], 7.17–7.41 [m, 5 H,
HC(12), HC(13), HC(14)], 7.49–7.94 [m, 15 H, HC(7), HC(8),
HC(9)].
Yield: 0.048 g (60%); colourless oil; Rf = 0.72 (silica gel, hexane–
EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d (cis-5) = 1.32 [s, 6 H, H3C(11),
H3C(12)], 1.79 [dd, J = 12.1, 13.1 Hz, 1 H, H2C(3)], 1.95 [dd,
J = 7.9, 13.1 Hz, 1 H, H2C(3)], 3.33 [dd, J = 7.9, 12.1 Hz, 1 H,
HC(2)], 5.97, 6.47 [2 d, J = 12.5 Hz, 2 H, HC(5), HC(6)], 6.77,
7.16–7.42 [2 m, 2 H, 8 H, HC(8), HC(9), HC(10), HC(14), HC(15),
HC(16)].
1H NMR (300 MHz, CDCl3): d (trans-5) = 1.36 [s, 6 H, H3C(11),
H3C(12)], 1.92 [dd, J = 11.5, 13.1 Hz, 1 H, H2C(3)], 2.29 [dd,
J = 8.2, 13.1 Hz, 1 H, H2C(3)], 3.77 [dd, J = 8.2, 11.5 Hz, 1 H,
HC(2)], 6.55, 6.68 [2 d, J = 16.9 Hz, 2 H, HC(5), HC(6)], 6.77,
7.16–7.42 [2 m, 2 H, 8 H, HC(8), HC(9), HC(10), HC(14), HC(15),
HC(16)].
13C NMR (75 MHz, CDCl3): d (mixture of cis- and trans-5) = 22.9,
23.4, 28.3, 28.5 (C-11, C-12), 37.6, 39.1 (C-2), 41.1, 42.5 (C-3),
74.3, 74.9 (C-4), 124.4, 125.7 (C-5), 126.7, 126.7, 126.9, 127.8,
127.9, 128.0, 128.2, 128.2, 128.5, 128.6, 129.0, 129.1 (C-8, C-9, C-
10, C-14, C-15, C-16), 133.8, 134.2 (C-6), 140.8, 143.4 (C-7, C-13),
155.4, 156.7 (C-1).
13C NMR (75 MHz, CDCl3): d = 22.7, 28.0 (C-10, C-11), 29.6 (d,
J = 57.5 Hz, C-5), 39.7 (d, J = 7.2 Hz, C-2), 40.7 (C-3), 76.0 (C-4),
119.9 (d, J = 89.8 Hz, C-6), 127.5, 128.9, 129.4 (C-13, C-14, C-15),
129.9 (d, J = 14.4 Hz, C-8), 133.8 (d, J = 10.8 Hz, C-7), 134.3 (d,
J = 3.6 Hz, C-9), 139.6 (C-12), 153.3 (d, J = 7.2 Hz, C-1).
Anal. Calcd for C31H31BrNOP: C, 68.39; H, 5.74; N, 2.57. Found:
C, 68.18; H, 5.72; N, 2.50.
1-[(6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazin-3-
yl)methyl]-3-methyl-1H-imidazol-3-ium Bromide (3j)
A soln of oxazine 2a (0.28 g, 1 mmol) and N-methylimidazole (0.16
g, 1 mmol) in toluene (3 mL) was boiled for 5 h. After the mixture
had cooled to r.t., the solvent was evaporated in vacuo.
Yield: 0.44 g (99%); colourless oil.
1H NMR (300 MHz, CDCl3): d = 1.22, 1.35 [2 s, 6 H, H3C(10),
H3C(11)], 1.80 [dd, J = 12.5, 13.7 Hz, 1 H, H2C(3)], 2.20 [dd,
J = 7.0, 13.7 Hz, 1 H, H2C(3)], 3.77 [dd, J = 12.5, 7.0 Hz, 1 H,
HC(2)], 3.90 [s, 3 H, H3C(9)], 5.04 [s, 2 H, H2C(5)], 7.17–7.41 [m,
5 H, HC(12), HC(13), HC(14)], 7.77, 7.84 [2 s, 2 H, HC(7), HC(8)],
9.45 [s, 1 H, HC(6)].
Anal. Calcd for C20H21NO: C, 82.44; H, 7.26; N, 4.81. Found: C,
82.90; H, 7.41; N, 4.48.
13C NMR (75 MHz, CDCl3): d = 22.4, 28.1 (C-10, C-11), 35.8 (C-
9), 40.0 (C-2), 40.5 (C-3), 54.3 (C-5), 78.2 (C-4), 123.0, 123.6 (C-
7, C-8), 127.9, 129.1, 129.5 (C-13, C-14, C-15), 137.3, 140.0 (C-12,
C-6), 157.1 (C-1).
Dimethyl 2-{[1-(tert-Butoxycarbonyl)-3-(4-methoxyphenyl)pyr-
rolidin-2-yl]methyl}malonate (7)
A suspension of Raney Ni (ca. 10 g) in MeOH (8 mL) was blown
out with H2 from a Kipp apparatus for 1 h, then a soln of oxazine 3r
(0.3 g, 0.8 mmol), Boc2O (0.26 g, 1.2 mmol), and Et3N (0.07 mL,
0.5 mmol) in MeOH (16 mL) was added, and H2 was bubbled
through the resulting mixture for 3 h. The mixture was filtered, the
solvent was evaporated, and the residue was subjected to column
chromatography on silica gel.
Anal. Calcd for C17H22BrN3O: C, 56.05; H, 6.09; N, 11.54. Found:
C, 56.43; H, 6.46; N, 12.00.
6,6-Dimethyl-4-phenyl-5,6-dihydro-4H-1,2-oxazine-3-carb-
aldehyde (6)
To a soln of oxazine 2a (0.28 g, 1 mmol) in DMSO (5.0 mL) was
added NaHCO3; the resulting mixture was stirred for 1.5 h at 110–
120 °C and then poured into a mixture of EtOAc (100 mL) and H2O
(100 mL). The aqueous phase was back-extracted with EtOAc (2 ×
50 mL); the combined organic layers were washed with brine (50
Yield: 0.179 g (53%); colourless oil; Rf = 0.75 (silica gel, hexane–
EtOAc, 1:1), cis/trans = 15:85.
1H NMR (300 MHz, CDCl3): d = 1.48 [s, 9 H, H3C(7)], 1.87 [m,
J = 5.9 Hz, 1 H, HC(3)], 2.27 [ dd, m, J = 6.6, 6.6 Hz, 3 H, H2C(8),
HC(3)], 2.50 [dd, J = 7.4, 7.4 Hz, 2 H, H2C(8), minor isomer], 3.29
Synthesis 2007, No. 1, 97–107 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Substituted 5,6-Dihydro-4H-1,2-oxazines from Nitroethane
107
[ddd, J = 5.9, 6.6, 11.0 Hz, 1 H, HC(2)], 3.69, 3.74, 3.78 [3 s, 9 H,
H3C(11), H3C(13), H3C(18)], 3.04, 3.62, 4.0 [3 m, 4 H, HC(8),
HC(1), H2C(4)], 6.83 [d, J = 8.8 Hz, 2 H, HC(16)], 6.87 [d, J = 8.8
Hz, 2 H, HC(16), minor isomer], 7.06 [d, J = 8.8 Hz, 2 H, HC(15)],
7.16 [d, J = 8.8 Hz, 2 H, HC(15)].
Acknowledgment
This work was supported by the RFBR (grants 05-03-32733, 05-03-
08175).
13C NMR (75 MHz, CDCl3): d = 28.4 (C-7), 32.3, 33.7 (C-8, C-3),
45.6 (C-4), 48.6, 48.7, 48.9 (C-2, C-9), 52.3, 52.5 (C-11, C-13),
55.2 (C-18), 62.3 (C-1), 79.7 (C-6), 114.1, 114.2, 127.8, 129.0 (C-
15, C-16), 135.2 (C-14), 154.7 (C-17), 158.5 (C-5), 168.7, 169.5,
169.7 (C-10, C-12).
References
(1) Buchholz, M.; Reissig, H.-U. Eur. J. Org. Chem. 2003,
3524; and references cited therein.
(2) Tishkov, A. A.; Reissig, H.-U.; Ioffe, S. L. Synlett 2002, 863.
(3) Henning, R.; Lerch, V.; Urbach, H. Synthesis 1989, 265.
(4) Zimmer, R.; Reissig, H.-U. J. Org. Chem. 1992, 57, 343.
(5) Hippeli, C.; Zimmer, R.; Reissig, H.-U. Liebigs Ann. Chem.
1990, 469; and references cited therein.
(6) (a) Tsoungas, P. G. Heterocycles 2002, 57, 1149. (b) An
alternative route to 5,6-dihydro-4H-oxazines by cyclisation
of d-functionalised oximes is known; for example, see:
Grigg, R.; Hadjisoteriou, M.; Kennewell, P.; Markandu, J. J.
Chem. Soc., Chem. Commun. 1992, 1537; this is, however,
not of great significance, owing to low chemoselectivities
and unavailability of the initial reagents.
rel-(2R,3S)-2-(2-Carboxyethyl)-3-(4-methoxyphenyl)pyrroli-
dinium Chloride (8)
A soln of pyrrolidine (0.11 g, 0.26 mmol) in a mixture of MeOH
(1.5 mL) and 4 M aq HCl (5.8 mL) was refluxed for 24 h; then the
solvent was evaporated and the crude product was recrystallised
from CHCl3.
Yield: 0.06 g (80%); white solid; mp 71–74 °C (CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.96 [ddd, J = 7.5, 7.5, 7.5 Hz, 2
H, H2C(3)], 2.14 [dddd, J = 9.7, 9.7, 9.7, 12.3 Hz, 1 H, HC(6)], 2.37
[ddd, J = 2.2, 7.0, 7.0 Hz, 2 H, H2C(7)], 2.42 [m, 1 H, HC(6)], 3.09
[ddd, J = 7.5, 11.0 Hz, 1 H, HC(2)], 3.41 [ddd, J = 7.5, 7.5, 9.2 Hz,
1 H, HC(4)], 3.54 [ddd, J = 7.5, 9.7, 9.7 Hz, 1 H, HC(1)], 3.56 [ddd,
J = 7.5, 7.5, 9.2 Hz, 1 H, HC(4)], 3.78 [s, 3 H, H3C(14)], 4.77 [br, 3
H, H2N(5), HO(9)], 6.93 [d, J = 8.8 Hz, 2 H, HC(15)], 7.25 [d,
J = 8.8 Hz, 2 H, HC(14)].
(7) Francote, E.; Mereny, R.; Vandenbulke-Coyette, B.; Viehe,
H.-G. Helv. Chim. Acta. 1981, 64, 1208.
(8) Klenov, M. S.; Lesiv, A. V.; Khomutova, Yu. A.; Nesterov,
I. D.; Ioffe, S. L. Synthesis 2004, 1159.
(9) Tishkov, A. A.; Lesiv, A. V.; Khomutova, Yu. A.; Strelenko,
Yu. A.; Nesterov, I. D.; Antipin, M. Yu.; Ioffe, S. L.;
Denmark, S. E. J. Org. Chem. 2003, 68, 9477.
(10) Similar fragmentation is known for six-membered cyclic
nitronates, see: Yasuo, T.; Norihiko, Y.; Hiroko, M.;
Toshihide, K.; Masahiro, A.; Yataka, M. Bull. Chem. Soc.
Jpn. 1988, 61, 461.
13C NMR (75 MHz, CDCl3): d = 25.0 (C-3), 29.7 (C-7), 32.3 (C-6),
43.5 (C-4), 48.8 (C-2), 53.9 (C-14), 64.6 (C-1), 113.6 (C-12), 127.8
(C-11), 130.8 (C-10), 158.9 (C-13), 175.4 (C-8).
Anal. Calcd for C14H20ClNO3: C, 58.84; H, 7.05; N, 4.90. Found: C,
58.80; H, 7.11; N, 4.95.
Synthesis 2007, No. 1, 97–107 © Thieme Stuttgart · New York