A convenient procedure for the synthesis of N-acetyl-5,6-dihydro-2H-1,2- oxazines

Article abstract of DOI:10.1055/s-2007-990857

Acetylation of 5,6-dihydro-4H-1,2-oxazines with an acetyl bromide/acetic anhydride mixture provides a general and quite simple procedure for the synthesis of N-acetyl-5,6-dihydro-2H-1,2-oxazines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990857

PAPER
3461
A Convenient Procedure for the Synthesis of N-Acetyl-5,6-dihydro-2H-
1,2-oxazines
Synthesis of
N
a
-
Acetyl-5,6
v
-dihydro-2
H
e
-1,2-oxazin
l
es E. Ivashkin, Alexey Yu. Sukhorukov, Oleg L. Eliseev, Alexey V. Lesiv,* Yulja 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 23 April 2007; revised 2 August 2007
ents X on nitrogen (see 3, Scheme 2).7 Inter- or intramo-
Abstract: Acetylation of 5,6-dihydro-4H-1,2-oxazines with an
lecular trapping of the corresponding conjugated enimine
intermediates A (Scheme 2) formed under the reaction
conditions can afford various heterocyclic structures. Se-
lective reduction of the C=C bond is another possible sig-
nificant application of 5,6-dihydro-2H-1,2-oxazines 3
(e.g., see the transformation 3→4, Scheme 2).
acetyl bromide/acetic anhydride mixture provides a general and
quite simple procedure for the synthesis of N-acetyl-5,6-dihydro-
2H-1,2-oxazines.
Key words: 1,2-oxazines, acylations, cycloadditions, g-amino ac-
ids, hydroxylamines
Double-bond migration in the oxazine cycle can be
achieved by two different routes (Scheme 2, routes 1 and
2). Initial treatment of DO 1 or 2 with a base leads to for-
mation of the anionic intermediate B, resulting in the tar-
get 2H-oxazine 3 by the reaction with an electrophile XA
(Scheme 2, route 1). Another pathway involves interac-
tion of DO 1 or 2 with a strong electrophile, affording N-
oxyiminium cation C, followed by its deprotonation under
basic conditions (Scheme 2, route 2). In both cases, exo-
cyclic methylene group deprotonation may occur as a side
reaction, along with deprotonation at C-4.
5,6-Dihydro-4H-1,2-oxazines (DOs) and their derivatives
are widely used as intermediates in the synthesis of vari-
ous alkaloids,1 amino sugars,2 pyrrolidines,3 and pipe-
ridines.4 Previously, only unstable conjugated
nitrosoalkenes had been used as the main precursors of
DOs.5 We recently reported a new approach for the prep-
aration of 3-substituted DO derivatives (Scheme 1),6 in
which readily available aliphatic nitro compounds are first
converted into conjugated nitroalkenes, which are then
transformed into six-membered cyclic nitronates. The key
step of this reaction sequence is the transformation of 3-
methyl-substituted six-membered cyclic nitronates into 3-
halomethyl DO derivatives under silylation reaction con-
ditions (Scheme 1). 3-(Bromomethyl)-5,6-dihydro-4H-
1,2-oxazines 1 obtained by this method are useful inter-
mediates for the synthesis of a wide range of 3-function-
alized oxazines 2 (Scheme 1).3b
Alkylation,4a,7a trimethylsilylation,8 and acylation4,9 have
been used before for the transformation of 4H-1,2-ox-
azines into the corresponding 2H-analogues. In this study,
acetylation of 3-(bromomethyl)oxazines 1a–i and their
derivatives 2a–f was investigated (Scheme 3).
Acetylation by route 1 (Scheme 2) has been reported for
only one 4-(methoxycarbonyl)-5,6-dihydro-4H-ox-
azine.4a However, we found that the transformation of 1 or
2 into 3 cannot be carried out under mild conditions by
treatment of 1 or 2 with a strong base (LDA, BuLi, BuLi/
The transformation of 5,6-dihydro-4H-1,2-oxazines
(DOs) 1 or 2 into the corresponding 5,6-dihydro-2H-1,2-
oxazines 3 is also an interesting synthetic goal
(Scheme 2), because double-bond migration in the ox-
azine cycle provides additional opportunities for synthetic
applications, such as the well-known fragmentation of
5,6-dihydro-2H-1,2-oxazines containing various substitu-
t-BuOK) and acetyl chloride as acetylation reagent.10
A
rise in temperature causes degradation of the reaction
mixture. The second variant (Scheme 2, route 2) involv-
ing acylation of oxime ethers 1 or 2 also has significant
R1
R2
R3
nucleophilic
R1
R1
R1
substitution of
bromine3b
R2
R3
R2
R3
R2
R3
R1CHO
TMSBr
Et3N
R4
Br
Y
EtNO2
N+
or
N
N
O–
O
O
O
NO2
R4
catalytic
carbonylation12
R4
R4
DO 1
DO 2
Y = OR, NR2, N3, PPh3+, CO2Me, CH(CO2Me)2, CH(Ac)CO2Me, CH(CN)CO2Me
R1 = Me, Ph, p-ClC6H4, p-MeOC6H4, OBz; R2 = H, alkyl; R3 and R4 = H, alkyl, Ph, OR
Scheme 1
SYNTHESIS 2007, No. 22, pp 3461–3468
x
x.
x
x
.
2
0
0
7
Advanced online publication: 29.10.2007
DOI: 10.1055/s-2007-990857; Art ID: P04907SS
© Georg Thieme Verlag Stuttgart · New York

3462
P. E. Ivashkin et al.
PAPER
FG
FG
trapping
N
X
FG
XA
FG
A
N
[H]
– HA
N
O
X
O
3
1 or 2
N
O
X
4
–
FG
base
X-A
– A–
N
– [baseH+]
(route 1)
O
FG
FG
B
N
O
1 or 2
N
X-A
FG
A–
O
X
base
N
(route 2)
– [baseH+]A–
3
+
O
X
C
–
FG = Br or Y; X = alkyl, acyl, trialkylsilyl; A– = Cl–, BF4
Scheme 2
complications. Our attempts to acylate oxazines 1 and 2
with common acylation reagents such as acetic anhydride,
acetyl chloride, or benzoyl chloride at 20 °C failed regard-
less of the base used (K2CO3, Et3N, DBU, t-BuOK).9
However, oxazines 1 and 2 were efficiently N-acetylated
by an acetic anhydride/acetyl bromide mixture, giving the
corresponding N-acetyl-5,6-dihydro-2H-oxazines 3a–o in
good yields (Scheme 3, Table 1). Oxazines 3a–o can be
isolated as analytically pure substances by filtration of the
R1
R1
R2
R2
R3
AcBr, Ac2O
FG
FG
N
CH2Cl2, 20 °C, 2 h
N
R3
O
O
Ac
R4
R4
1a–i, 2a–f
3a–o
Scheme 3
Table 1 Acetylation of 5,6-Dihydro-4H-1,2-oxazines 1a–i and 2a–f with an Equimolar Mixture of Acetyl Bromide and Acetic Anhydride
Entry
Starting
material
Product
R1
R2
R3
R4
FG
Yield (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
4-MeOC6H4
H
Me
Me
H
Br
Br
Br
Br
Br
Br
Br
96
97
94
94
96
94
95
4-MeOC6H4
-(CH2)4-
4-ClC6H4
H
H
H
Me
Me
Me
Me
Me
Me
H
Me
Ph
Ph
Ph
-(CH2)4-
-(CH2)3-
1g
3g
H
8
1h
3h
Ph
H
Br
97
9
10
11
12
13
1i
3i
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
Ph
Br
89
95
91
54
74
2a
2b
2c
2d
3j
Me
Me
Me
Me
Me
Me
Me
Me
CO2Me
3k
3l
CH(CO2Me)2
CH(CO2Me)CN
3m
N3
O
14
15
2e
2f
3n
3o
Ph
Ph
H
H
Me
Me
Me
Me
84
59
N
O
OEt
Synthesis 2007, No. 22, 3461–3468 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Acetyl-5,6-dihydro-2H-1,2-oxazines
3463
Ac2O + D + Br–
(1)
(2)
3 + AcOH + AcBr
AcBr + AcOH
Ac2O + HBr
R1
R1
R1
R2
R3
R2
R3
R2
R3
EBr, Ac2O
FG
(E = Ac)
– HBr
FG
FG
N
N
N
+
O
Ac
Br–
E
O
O
R4
R4
R4
3
D or D'
1, 2
R1
EBr = AcBr or HBr
AcBr
E = H
R2
R3
(D')
FG
N
O
– HBr
H
R4
3'
Scheme 4
Ph
Ph
reaction mixture through silica gel, followed by solvent
evaporation.
CO2Me
AcBr
Ac2O
CO2Me
In this process (Scheme 3), acetic anhydride obviously
acts as a deprotonating agent. The use of other agents to
deprotonate cationic intermediates (triethylamine or pyri-
dine) does not significantly affect the reaction rate or the
products that result, but makes isolation of target com-
pounds 3 more complicated and slightly lowers their total
yields.
N
N
O
O
O
2g
5
87%
Scheme 5
ed in Scheme 3. In such a case, NMR spectra of the crude
reaction mixtures reveal the presence of unsaturated ke-
tones such as 6 (Scheme 6). We propose that this reaction
proceeds by the generation of 4H-oxazine 7 as intermedi-
ate followed by its retro-[4+2] cycloaddition.7
The mechanism for the transformation of 1 or 2 into 3 has
not been investigated thoroughly, but we propose that the
process occurs by route 2 (Scheme 2). We believe that ini-
tial treatment of an oxazine 1 or 2 with acetyl bromide or
traces of hydrogen bromide (Scheme 4) leads to the for-
mation of cation D or D¢, respectively, which can be sta-
bilized by regioselective elimination of the hydrogen
atom at C-4. Probably, in the case of E = H, cation D¢
transforms initially into the corresponding 2H-oxazine 3¢
(Scheme 4). The latter undergoes rapid acetylation under
these conditions to give target product 3.
2H-oxazines of type 3 with various substituents at the ni-
trogen atom have earlier been suggested to be convenient
precursors of highly reactive conjugated enimines.11
These intermediates have been transformed in situ into the
corresponding piperidine derivatives4a or unsaturated car-
bonyl compounds.7 However, the presence of a function-
alized methylene fragment at C-3 in products 3
significantly influences their chemical properties. For ex-
ample, heating of derivatives 3a, 3c, and 3e in toluene
(Scheme 7) affords bromodienes 8a, 8c, and 8e, respec-
tively, as mixtures of cis- and trans-isomers (with pre-
dominance of the cis-isomers). Products 8 are generated
both in the presence or the absence of standard trapping
agents for intermediate enimines E (Scheme 7). Similarly,
treatment of oxazine 3a with zinc powder at room temper-
ature resulted in the transformation of 3a into 9a
Transformation 1 or 2 into 3 is quite general, and can be
performed in the presence of various functional groups
(FG). The nature of the substituents at positions 3–5 of the
oxazine ring does not significantly affect the result of the
reaction. Oxazine 2g can be considered an exception. In
this case, bicyclic derivative 5 forms under the reaction
conditions (Scheme 5).
It is important to note that 6-alkoxy-substituted oxazines
1 and 2 cannot be used in the acetylation process present-
FG
Ph
Ph
O
Ph
Ph
E+
FG
base
FG
N
FG
N
N
– MeOE
– [baseH+]
i or ii
N
MeO
O
MeO
E
Me
O
Me
O
Me
Me
2h
7
6
86% (for ii)
FG = CH(CO2Me)2
i. AcBr, Ac2O, r.t. (E = Ac)
ii. AcOH, 100–120 °C (E = H)
Scheme 6
Synthesis 2007, No. 22, 3461–3468 © Thieme Stuttgart · New York

3464
P. E. Ivashkin et al.
PAPER
R1
R1
toluene,
reflux
Br
Ac
Br
for 3a,c,e
R1
HN
Ac
N
Ph
O
O
CO2Me
FG
H2, Pd/C
8a,c,e 72–78%
E
N
FG = Br
N
MeOH
CO2Me
O
Ac
An
O
Ac
84%
FG = CH(CO2Me)2
An
for 3k
3a,c,e,k
4
Zn, THF
H2O
ZnBr
for 3a
N
O
HN
Ac
9a 60%
F
R1 = p-MeOC6H4 (a), p-ClC6H4 (c), Ph (e, k)
An = p-MeOC6H4
Scheme 7
H, H2C(7)], 6.93 [d, J = 8.8 Hz, 2 H, HC(10)], 7.22 [d, J = 8.8 Hz,
2 H, HC(9)].
(Scheme 7). This process probably occurs through frag-
mentation of hypothetic intermediate F (Scheme 7).
13C NMR (75 MHz, CDCl3): d = 22.3 (C-6), 25.7 (C-13), 28.6 (C-
7), 43.3 (C-3), 55.3 (C-12), 79.7 (C-4), 114.1 (C-10), 126.1 (C-2),
130.4, 131.8 (C-1, C-8), 129.2 (C-9), 159.2 (C-11), 170.0 (C-5).
Unlike the reduction of DOs, the reduction of 5,6-dihy-
dro-2H-1,2-oxazines has been investigated much less. We
found that compound 3k can be reduced diastereoselec-
tively into the corresponding hydroxylamine 4 with cis-
configuration of the substituents at C-3 and C-4 when hy-
drogen is used with palladium-on-carbon as catalyst
(Scheme 7). The reduction of related 4H-oxazines under
similar conditions affords the corresponding trans-iso-
mers.3b (Product 4 can be considered as a nearest precur-
sor of an unknown g-amino acid.)
Anal. Calcd for C16H20BrNO3: C, 54.25; H, 5.69; N, 3.95. Found: C,
54.01; H, 5.89; N, 3.65.
2-Acetyl-3-(bromomethyl)-4-(4-methoxyphenyl)-4a,5,6,7,8,8a-
hexahydro-2H-1,2-benzoxazine (3b)
Oil; Rf = 0.66 (silica gel, hexane–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): d = 1.32–1.83, 2.42 [2 m, 9 H, HC(3),
H2C(13), H2C(14), H2C(15), H2C(16)], 2.31 [s, 3 H, H3C(6)], 3.87
[s, 3 H, H3C(12)], 4.01 [d, J = 10.3 Hz, 1 H, H2C(7)], 4.22 [m, 1 H,
HC(4)], 5.21 [d, J = 10.3 Hz, 1 H, H2C(7)], 6.91 [d, J = 7.0 Hz, 2 H,
HC(10)], 7.95 [d, J = 7.0 Hz, 2 H, HC(9)].
In summary, a simple and efficient procedure for the N-
acetylation of 5,6-dihydro-4H-1,2-oxazines 1 and 2 was
developed. Some possible synthetic applications of N-
acetyl-5,6-dihydro-2H-1,2-oxazines 3 have been demon-
strated.
13C NMR (75 MHz, CDCl3): d = 20.6, 24.6, 27.0, 29.9, 32.0 (C-7,
C-13, C-14, C-15, C-16), 22.7 (C-6), 40.4 (C-3), 55.3 (C-12), 80.0
(C-4), 114.0 (C-10), 129.4 (C-9), 129.8, 130.7, 131.6 (C-1, C-2, C-
8), 159.1 (C-11), 171.2 (C-5).
All reactions were performed in oven-dried (150 °C) glassware un-
der an atmosphere of anhyd argon. The following solvents and re-
agents were distilled from the indicated drying agents: CH2Cl2
(CaH2), toluene (Na), THF (LAH), AcBr (CaH2) and Ac2O (CaH2).
MeOH, EtOAc, and hexane were distilled without drying agents.
Brine refers to sat. aq NaCl. 1H (300 MHz) and 13C (75 MHz) NMR
spectra were recorded on Bruker AM-300 instruments and are ref-
erenced relative to residual solvent peaks. Melting points were de-
termined on a Kofler melting point apparatus and are uncorrected.
Analytical TLC was performed on Merck silica gel plates with QF-
254 indicator. Column chromatography was performed on Merck
silica gel (230–400 mesh). The 5,6-dihydro-4H-1,2-oxazines 1a–i,
2b–f,3b,6 and 2a12 were prepared by known procedures. The struc-
tures of the products discussed here are shown in Table 2.
Anal. Calcd for C18H22BrNO3: C, 56.85; H, 5.83; N, 3.68. Found: C,
56.89; H, 5.90; N, 3.31.
2-Acetyl-3-(bromomethyl)-4-(4-chlorophenyl)-6,6-dimethyl-
5,6-dihydro-2H-1,2-oxazine (3c)
Oil; Rf = 0.65 (silica gel, hexane–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): d = 1.39 [s, 6 H, H3C(12)], 2.30 [s, 3
H, H3C(6)], 2.36 [s, 2 H, H2C(3)], 4.62 [s, 2 H, H2C(7)], 7.25 [d,
J = 8.1 Hz, 2 H, HC(10)], 7.38 [d, J = 8.1 Hz, 2 H, HC(9)].
13C NMR (75 MHz, CDCl3): d = 22.3 (C-12), 25.6 (C-6), 28.0 (C-
7), 43.1 (C-3), 79.6 (C-4), 124.7 (C-2), 133.9, 135.1 (C-1, C-8),
129.0, 129.4 (C-9, C-10), 138.6 (C-11), 170.2 (C-5).
Anal. Calcd for C15H17BrClNO2: C, 50.23; H, 4.78; N, 3.91. Found:
C, 50.28; H, 4.70; N, 3.90.
5,6-Dihydro-2H-1,2-oxazines 3a–o; General Procedure
Ac2O (1 mmol) and AcBr (1 mmol) were added to a stirred soln of
1 or 2 (1 mmol) in CH2Cl2 (3 mL). The resulting mixture was stirred
for 2 h at 20 °C. The solvent was evaporated under vacuum and the
residue was filtered through silica gel. (For yields of products 3, see
Table 1).
2-Acetyl-3-(bromomethyl)-4,6,6-trimethyl-5,6-dihydro-2H-1,2-
oxazine (3d)
Oil; Rf = 0.69 (silica gel, hexane–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): d = 1.28 [s, 6 H, H3C(9)], 1.80 [s, 3 H,
H3C(8)], 2.11 [s, 2 H, H2C(3)], 2.22 [s, 3 H, H3C(6)], 4.72 [s, 2 H,
H2C(7)].
2-Acetyl-3-(bromomethyl)-4-(4-methoxyphenyl)-6,6-dimethyl-
5,6-dihydro-2H-1,2-oxazine (3a)
Oil; Rf = 0.67 (silica gel, hexane–EtOAc, 1:1, UV).
13C NMR (75 MHz, CDCl3): d = 17.5 (C-8), 21.9 (C-6), 25.7 (C-9),
26.3 (C-7), 42.7 (C-3), 79.7 (C-4), 122.9 (C-2), 130.2 (C-1), 170.1
(C-5).
1H NMR (300 MHz, CDCl3): d = 1.38 [s, 6 H, H3C(13)], 2.30 [s, 3
H, H3C(6)], 2.37 [s, 2 H, H2C(3)], 3.84 [s, 3 H, H3C(12)], 4.69 [s, 2
Synthesis 2007, No. 22, 3461–3468 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Acetyl-5,6-dihydro-2H-1,2-oxazines
3465
Table 2 Structures of Compounds 3a–o, 4, 5, 8a,c,e, 8a¢,c¢,e¢, and 9a
12
12
OMe
OMe
Cl
11
10
11
11
10
9
10
9
9
8
Me
2
8
8
8
7
7
7
7
13
16
2
2
2
1
1
1
1
3
3
4
3
4
3
4
Br
Br
O
Br
O
Br
O
14
15
4
9
12
N
5
O
N
5
N
5
5
13
N
O
Me
O
Me
O
Me
O
6
6
Me
Me
Me
6
Me6
Me
Me
Me
3a
3b
3c
3d
11
11
11
11
10
10
10
10
9
9
9
9
8
8
8
2
8
7
7
7
7
12
15
12
2
2
2
12
1
1
1
1
3
3
3
3
4
13
14
13
14
Br
O
Br
Br
Br
13
16
15
4
4
4
12
N
N
5
O
5
O
5
N
5
O
N
O
O
14
O
Me
O
6
6
6
6
Me
Me
Me
Me
Me
3e
3f
3g
3h
11
13
15
14
10
9
14
13
12
11
13
12
8
10
12
11
7
5
9
10
2
9
10
7
7
7
2
2
1
2
8
9
CO2Me
1
1
8
CO2Me
3
1
8
CO2Me
CO2Me
Br
O
3
3
4
3
4
13
4
CN
N
12
4
11
14
Me
15
N
O
16
Me17
Me
5
N
14
15
5
O
N
5
O
O
O
6
O
Me
O
6
Me
6
6
Me
Me
Me
Me
Me
3i
3j
3k
3l
18
11
13
15
10
14
17
16
12
11
O
13
9
10
8
8
12
10
15
9
7
9
7
7
5
7
8
9
2
2
2
2
11
1
1
N
1
1
6
CO2Me
10
3
3
4
3
4
3
4
N3
O
6
O
Me
8
4
12
Me
14
CO2Me
13Me14
N
5
16
Me
N
5
O
5
N
O
11
Me12
Me
N
O
O
O
Me
O
O
6
Me
Me
6
Me
Me
Me
O
Me
3m
3n
3o
4
14
13
12
H"
H'
H"
H'
H"
H'
4
4
4
3
Br
11
2
6
1
1
6
6
3
2
3
10
2
5
5
5
2
7
8
1
1
7
8
7
8
Br
Br
3
4
8
9
7
CO2Me
11
MeO
11
MeO
HN
HN
15
O
O
HN
O
N
5
Cl
Me
Me16
9
9
9
O
6
Me
10
Me10
Me10
Me
5
8a
8a¢
8c
H'
H'
H'
H"
H"
H"
4
3
Br
1
Br
4
4
4
6
6
1
6
1
6
1
3
3
3
2
5
2
5
2
5
5
2
7
8
7
7
7
8
Br
O
8
HN
HN
HN
HN
O
O
O
6'
8
6'
Cl
O
9
9
9
9
10
10
10
11
Me
Me
Me10
Me
Me
8c¢
8e
8e¢
9a
Synthesis 2007, No. 22, 3461–3468 © Thieme Stuttgart · New York

3466
P. E. Ivashkin et al.
PAPER
Anal. Calcd for C10H16BrNO2: C, 45.82; H, 6.15; N, 5.34. Found: C,
46.11; H, 6.10; N, 5.45.
1H NMR (300 MHz, CDCl3): d = 2.22 [s, 3 H, H3C(6)], 2.83 [m, 2
H, H2C(3)], 4.07 [s, 2 H, H2C(7)], 5.14 [dd, J = 5.9, 8.8 Hz, 1 H,
HC(4)], 7.38–7.44 [m, 10 H, HC(9), HC(10), HC(11), HC(13),
HC(14), HC(15)].
2-Acetyl-3-(bromomethyl)-6,6-dimethyl-4-phenyl-5,6-dihydro-
2H-1,2-oxazine (3e)
Oil; Rf = 0.67 (silica gel, hexane–EtOAc, 1:1, UV).
13C NMR (75 MHz, CDCl3): d = 22.2 (C-6), 28.7 (C-7), 37.7 (C-3),
82.9 (C-4), 121.8, 129.7 (C-1, C-2), 127.9, 127.9, 128.7, 128.8,
128.9, 129.1, 134.4, 137.9 (C-8, C-9, C-10, C-11, C-12, C-13, C-14,
C-15), 170.8 (C-5).
1H NMR (300 MHz, CDCl3): d = 1.41 [s, 6 H, H3C(12)], 2.29 [s, 3
H, H3C(6)], 2.39 [s, 2 H, H2C(3)], 4.66 [s, 2 H, H2C(7)], 7.29–7.34
[m, 5 H, HC(9), HC(10), HC(11)].
Anal. Calcd for C19H18BrNO2: C, 61.30; H, 4.87; N, 3.76. Found: C,
60.90; H, 4.32; N, 3.41.
13C NMR (75 MHz, CDCl3): d = 22.2 (C-6), 25.7 (C-12), 28.3 (C-
7), 43.3 (C-3), 79.6 (C-4), 126.1 (C-2), 127.9 (C-11), 128.0, 128.6
(C-9, C-10), 132.0 (C-1), 138.3 (C-8), 170.0 (C-5).
Methyl (2-Acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-
oxazin-3-yl)acetate (3j)
Oil; Rf = 0.66 (silica gel, hexane–EtOAc, 1:1, UV).
Anal. Calcd for C15H18BrNO2: C, 55.57; H, 5.60; N, 4.32. Found: C,
55.50; H, 5.80; N, 4.39.
1H NMR (300 MHz, CDCl3): d = 1.37 [s, 6 H, H3C(14)], 2.22 [s, 3
H, H3C(6)], 2.41 [s, 2 H, H2C(3)], 3.52 [s, 2 H, H2C(7)], 3.63 [s, 3
H, H3C(9)], 7.13–7.33 [m, 5 H, HC(11), HC(12), HC(13)].
2-Acetyl-3-(bromomethyl)-4-phenyl-4a,5,6,7,8,8a-hexahydro-
2H-1,2-benzoxazine (3f)
Oil; Rf = 0.66 (silica gel, hexane–EtOAc, 1:1, UV).
13C NMR (75 MHz, CDCl3): d = 22.4 (C-6), 25.3 (C-14), 36.1 (C-
7), 42.8 (C-3), 51.8 (C-9), 78.4 (C-4), 122.4 (C-2), 127.4 (C-1),
128.5 (C-11, C-12, C-13), 139.3 (C-10), 169.5, 171.0 (C-5, C-8).
1H NMR (300 MHz, CDCl3): d = 1.10–1.81, 2.20 [2 m, 8 H,
H2C(12), H2C(13), H2C(14), H2C(15)], 2.31 [s, 3 H, H3C(6)], 2.37
[ddd, J = 2.6, 8.1, 9.0 Hz, 1 H, HC(3)], 4.05 [d, J = 11.0 Hz, 1 H,
H2C(7)], 4.22 [dd, J = 2.6, 5.8 Hz, 1 H, HC(4)], 5.16 [d, J = 11.0
Hz, 1 H, H2C(7)], 7.30–7.40 [m, 5 H, HC(9), HC(10), HC(11)].
Anal. Calcd for C17H21NO4: C, 67.31; H, 6.98; N, 4.62. Found: C,
67.45; H, 6.79; N, 4.66.
13C NMR (75 MHz, CDCl3): d = 20.5, 24.6, 27.0, 29.4, 29.7 (C-7,
C-12, C-13, C-14, C-15), 22.7 (C-6), 40.3 (C-3), 79.9 (C-4), 127.7
(C-11), 128.2, 128.5 (C-9, C-10), 130.8, 131.6 (C-1, C-2), 137.4 (C-
8), 171.3 (C-5).
Dimethyl 2-[(2-Acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-
1,2-oxazin-3-yl)methyl]malonate (3k)
Oil; Rf = 0.69 (silica gel, hexane–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): d = 1.36 [s, 6 H, H3C(15)], 2.25 [s, 3
H, H3C(6)], 2.34 [s, 2 H, H2C(3)], 3.29 [d, J = 8.1 Hz, 2 H, H2C(7)],
3.56 [t, J = 8.1 Hz, 1 H, HC(8)], 3.63 [s, 6 H, H3C(10)], 7.16–7.35
[m, 5 H, HC(12), HC(13), HC(14)].
Anal. Calcd for C17H20BrNO2: C, 58.30; H, 5.76; N, 4.00. Found: C,
58.58; H, 5.90; N, 3.73.
2-Acetyl-3-(bromomethyl)-4-phenyl-2,4a,5,6,7,7a-hexahydro-
cyclopenta[e][1,2]oxazine (3g)
Oil; Rf = 0.67 (silica gel, hexane–EtOAc, 1:1, UV).
13C NMR (75 MHz, CDCl3): d = 22.3 (C-6), 25.7 (C-15), 28.9 (C-
7), 43.0 (C-3), 49.9 (C-8), 52.4 (C-10), 79.3 (C-4), 124.7 (C-2),
130.9 (C-1), 127.4 (C-14), 128.5, 128.6 (C-12, C-13), 137.4 (C-11),
169.1 (C-9), 170.4 (C-5).
1H NMR (300 MHz, CDCl3): d = 1.37–1.50, 1.54–1.65, 1.72–1.91,
2.16–2.24 [4 m, 6 H, H2C(12), H2C(13), H2C(14)], 2.28 [s, 3 H,
H3C(6)], 2.67 [ddd, J = 2.2, 5.2, 8.6 Hz, 1 H, HC(3)], 4.04 [d,
J = 11.0 Hz, 1 H, H2C(7)], 4.49 [ddd, J = 2.8, 5.2, 7.3 Hz, 1 H,
HC(4)], 5.10 [d, J = 11.0 Hz, 1 H, H2C(7)], 7.31–7.40 [m, 5 H,
HC(9), HC(10), HC(11)].
Anal. Calcd for C20H25NO6: C, 63.99; H, 6.71; N, 3.73. Found: C,
64.30; H, 6.95; N, 3.50.
Methyl 3-(2-Acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-
oxazin-3-yl)-2-cyanopropanoate (3l)
Oil; Rf = 0.67 (silica gel, hexane–EtOAc, 1:1, UV).
13C NMR (75 MHz, CDCl3): d = 22.2 (C-6), 23.2 (C-13), 28.9, 30.8,
31.3 (C-7, C-12, C-14), 44.7 (C-3), 85.1 (C-4), 127.8, 128.6 (C-9,
C-10, C-11), 131.5, 132.2 (C-1, C-2), 137.6 (C-8), 170.3 (C-5).
1H NMR (300 MHz, CDCl3): d = 1.37, 1.40 [2 s, 6 H, H3C(16),
H3C(17)], 2.27 [s, 3 H, H3C(6)], 2.30 [d, J = 17.7 Hz, 1 H, H2C(3)],
2.50 [d, J = 17.7 Hz, 1 H, H2C(3)], 3.08 [dd, J = 9.6, 14.7 Hz, 1 H,
H2C(7)], 3.44 [dd, J = 6.0, 14.7 Hz, 1 H, H2C(7)], 3.71 [s, 3 H,
H3C(10)], 3.83 [dd, J = 6.0, 9.6 Hz, 1 H, HC(8)], 7.22–7.37 [m, 5 H,
HC(13), HC(14), HC(15)].
Anal. Calcd for C16H18NO2: C, 57.16; H, 5.40; N, 4.17. Found: C,
57.01; H, 5.78; H, 3.88.
2-Acetyl-3-(bromomethyl)-4-phenyl-4a,5,6,7,8,8a-hexahydro-
2H-5,8-methano-1,2-benzoxazine (3h)
Oil; Rf = 0.65 (silica gel, hexane–EtOAc, 1:1, UV).
13C NMR (75 MHz, CDCl3): d = 22.5 (C-6), 24.8, 26.1 (C-16, C-
17), 29.7 (C-7), 36.0 (C-8), 43.3 (C-3), 53.4 (C-10), 79.0 (C-4),
116.1 (C-11), 125.5 (C-2), 127.6, 128.7, 128.8 (C-13, C-14, C-15),
128.9 (C-1), 138.7 (C-12), 165.9 (C-9), 170.6 (C-5).
1H NMR (300 MHz, CDCl3): d = 1.01–1.35, 1.62–1.71, 1.84, 2.39
[4 m, 9 H, HC(3), HC(12), H2C(13), H2C(14), HC(15), H2C(16)],
2.28 [s, 3 H, H3C(6)], 3.94 [d, J = 11.2 Hz, 1 H, H2C(7)], 4.37 [d,
J = 5.9 Hz, 1 H, HC(4)], 4.94 [d, J = 11.2 Hz, 1 H, H2C(7)], 7.28–
7.43 [m, 5 H, HC(9), HC(10), HC(11)].
Anal. Calcd for C19H22N2O4: C, 66.65; H, 6.48; N, 8.18. Found: C,
66.71; H, 6.53; N, 8.04.
13C NMR (75 MHz, CDCl3): d = 21.7 (C-6), 23.7, 28.1, 29.1 (C-7,
C-13, C-14), 33.1 (C-16), 39.3, 40.8, 47.4 (C-3, C-12, C-15), 88.4
(C-4), 127.9, 128.7 (C-9, C-10, C-11), 132.7, 135.4 (C-1, C-2),
137.1 (C-8), 169.4 (C-5).
2-Acetyl-3-(azidomethyl)-6,6-dimethyl-4-phenyl-5,6-dihydro-
2H-1,2-oxazine (3m)
Oil; Rf = 0.68 (silica gel, hexane–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): d = 1.38 [s, 6 H, H3C(12)], 2.28 [s, 3
H, H3C(6)], 2.42 [s, 2 H, H2C(3)], 4.38 [s, 2 H, H2C(7)], 7.18–7.36
[m, 5 H, HC(9), HC(10), HC(11)].
Anal. Calcd for C18H20BrNO2: C, 59.68; H, 5.56; N, 3.87. Found: C,
59.49; H, 5.19; N, 3.90.
13C NMR (75 MHz, CDCl3): d = 22.3 (C-6), 25.5 (C-12), 42.8 (C-
3), 48.3 (C-7), 79.2 (C-4), 125.7 (C-2), 127.8 (C-11), 128.5, 128.6
(C-9, C-10), 129.9 (C-1), 138.2 (C-8), 170.3 (C-5).
2-Acetyl-3-(bromomethyl)-4,6-diphenyl-5,6-dihydro-2H-1,2-
oxazine (3i)
Oil; Rf = 0.70 (silica gel, hexane–EtOAc, 1:1, UV).
Synthesis 2007, No. 22, 3461–3468 © Thieme Stuttgart · New York

PAPER
Synthesis of N-Acetyl-5,6-dihydro-2H-1,2-oxazines
3467
Anal. Calcd for C15H18N4O2: C, 62.92; H, 6.34; N, 19.57. Found: C,
63.31; H, 6.33; N, 19.34.
Yield: 87%; oil; Rf = 0.65 (silica gel, hexane–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): d = 1.40, 1.44 [2 s, 6 H, H3C(15),
H3C(16)], 2.00 [dd, J = 12.2, 13.2 Hz, 1 H, H2C(3)], 2.14 [dd,
J = 7.4, 13.2 Hz, 1 H, H2C(3)], 2.49 [s, 3 H, H3C(6)], 3.74 [s, 3 H,
H3C(9)], 4.13 [dd, J = 7.4, 12.2 Hz, 1 H, HC(2)], 6.00 [s, 1 H,
HC(10)], 7.27–7.35 [m, 5 H, HC(12), HC(13), HC(14)].
2-[(2-Acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-
3-yl)methyl]-1H-isoindole-1,3(2H)-dione (3n)
Oil; Rf = 0.62 (silica gel, hexane–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): d = 1.38 [s, 6 H, H3C(16)], 2.19 [s, 3
H, H3C(6)], 2.40 [s, 2 H, H2C(3)], 4.79 [s, 2 H, H2C(7)], 7.17–7.25
[m, 5 H, HC(13), HC(14), HC(15)], 7.64–7.71 [m, 4 H, HC(10),
HC(11)].
13C NMR (75 MHz, CDCl3): d = 9.5 (C-6), 23.0, 27.6 (C-15, C-16),
36.7 (C-2), 42.5 (C-3), 50.6 (C-9), 81.3 (C-4), 103.1 (C-10), 123.7
(C-7), 127.0 (C-14), 128.0, 128.6 (C-12, C-13), 128.4 (C-5), 136.3
(C-11), 142.5 (C-1), 165.9 (C-8).
13C NMR (75 MHz, CDCl3): d = 21.9 (C-6), 25.7 (C-16), 38.2 (C-
7), 43.3 (C-3), 79.7 (C-4), 123.0, 127.3, 128.3, 128.5, 133.6 (C-10,
C-11, C-13, C-14, C-15), 125.5 (C-2), 131.9 (C-9), 138.9 (C-12),
167.5 (C-8), 170.7 (C-5).
Anal. Calcd for C18H21NO3: C, 72.22; H, 7.07; N, 4.68. Found: C,
71.94; H, 7.12; N, 4.32.
Acetamides 8a,c,e and 8a¢,c¢,e¢; General Procedure
Anal. Calcd for C23H22N2O4: C, 70.75; H, 5.68; N, 7.17. Found: C,
70.57; H, 5.90; N, 7.01.
A soln of the appropriate oxazine 3 (1 mmol) in toluene (10 mL)
was stirred at 80 °C for 1 h. The solvent was evaporated under vac-
uum and the residue was purified by column chromatography (silica
gel, EtOAc–hexane, 1:5); this gave amides 8 as mixtures of the cis-
and trans-isomers 8 and 8¢, respectively.
2-Acetyl-3-(ethoxymethyl)-6,6-dimethyl-4-phenyl-5,6-dihydro-
2H-1,2-oxazine (3o)
Oil; Rf = 0.63 (silica gel, hexane–EtOAc, 1:1, UV).
N-[1-(Bromomethylene)-2-(4-methoxyphenyl)prop-2-
enyl]acetamide (8a)
Yield (8a + 8a¢): 72%; ratio 8a/8a¢ = 2:1; oil; Rf = 0.53 (silica gel,
hexane–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): d = 1.10 [t, J = 6.6 Hz, 3 H, H3C(9)],
1.37 [s, 6 H, H3C(14)], 2.26 [s, 3 H, H3C(6)], 2.41 [s, 2 H, H2C(3)],
3.38 [q, J = 6.6 Hz, 2 H, H2C(8)], 4.42 [s, 2 H, H2C(7)], 7.23–7.35
[m, 5 H, HC(11), HC(12), HC(13)].
Anal. Calcd for C13H14BrNO2: C, 52.72; H, 4.76; N, 4.73. Found: C,
52.70; H, 5.03; N, 4.70.
13C NMR (75 MHz, CDCl3): d = 15.3 (C-9), 22.4 (C-6), 25.7 (C-
14), 42.5 (C-3), 65.4 (C-7, C-8), 79.2 (C-4), 124.6 (C-2), 127.4 (C-
13), 128.3, 128.6 (C-11, C-12), 132.5 (C-1), 139.0 (C-10), 169.7 (C-
5).
Z-Isomer (8a)
1H NMR (300 MHz, CDCl3): d = 1.95 [s, 3 H, H3C(10)], 3.56 [s, 3
H, H3C(11)], 5.33 [s, 1 H, H¢C(4)], 5.42 [br s, 1 H, H¢¢C(4)], 5.95
[br s, 1 H, HC(1)], 6.82 [d, J = 7.0 Hz, 2 H, HC(7)], 7.25 [d, J = 7.0
Hz, 2 H, HC(6)]. Characteristic NOESY correlations: HC(6)/
H¢¢C(4), HC(1)/H¢C(4).
Anal. Calcd for C17H23NO2: C, 70.56; H, 8.01; N, 4.84. Found: C,
70.01; H, 8.41; N, 4.90.
Dimethyl 2-[(2-Acetyl-6,6-dimethyl-4-phenyl-1,2-oxazinan-3-
yl)methyl]propanedioate (4)
13C NMR (75 MHz, CDCl3): d = 29.1 (C-10), 55.1 (C-11), 97.4 (C-
1), 113.6 (C-7), 114.8 (C-4), 126.5 (C-5), 128.4 (C-6), 140.7, 144.7
(C-2, C-3), 160.0 (C-8).
To a soln of oxazine 3k (0.4 mmol, 0.15 g) in MeOH (5.0 mL) was
added 10% Pd/C (0.12 g). The suspension was hydrogenated with
H2 (50 bar) at 45 °C with intensive stirring for 2 h, then filtered and
concentrated under vacuum. The residue was purified by column
chromatography (silica gel, EtOAc–hexane, 1:5→1:1); this gave 4
as a white solid.
E-Isomer (8a¢)
1H NMR (300 MHz, CDCl3): d = 1.96 [s, 3 H, H3C(10)], 3.57 [s, 3
H, HC(11)], 5.40 [s, 1 H, H¢¢C(4)], 5.80 [s, 1 H, H¢C(4)], 6.50 [br
s, 1 H, HN], 6.85 [d, J = 7.0 Hz, 2 H, HC(7)], 7.25 [d, J = 7.0 Hz, 1
H, HC(6¢)], 7.38 [d, J = 7.0 Hz, 1 H, HC(6)], 7.45 [br, 1 H, HC(1)].
Characteristic NOESY correlations: HC(6)/H¢¢C(4).
Yield: 0.13 g (84%); mp 119–122 °C; Rf = 0.18 (silica gel, hexane–
EtOAc, 1:1, UV).
1H NMR (500 MHz, CDCl3): d = 1.37, 1.44 [2 s, 6 H, H3C(11),
H3C(12)], 1.63 [ddd, 1 H, J = 12.0, 9.6, 3.5 Hz, HC(5)], 1.70 [dd,
J = 13.2, 3.7 Hz, 1 H, HC(3)], 2.11 [s, 3 H, H3C(14)], 2.21 [ddd,
J = 12.0, 11.0, 5.1 Hz, 1 H, HC(5)], 2.25 [dd, J = 13.2, 13.2 Hz, 1
H, HC(3)], 3.22 [dd, J = 9.6, 5.1 Hz, 1 H, HC(6)], 3.42 [ddd,
J = 13.2, 4.4, 3.7 Hz, 1 H, HaxC(2)], 3.65, 3.66 [2 s, 6 H, H3C(9),
H3C(10)], 5.01 [ddd, J = 11.0, 4.4, 3.5 Hz, 1 H, HeqC(1)], 7.21–7.40
[m, 5 H, HC(16), HC(17), HC(18)].
13C NMR (75 MHz, CDCl3): d = 26.7 (C-10), 55.1 (C-11), 97.4 (C-
1), 114.1 (C-7), 116.2 (C-4), 127.4 (C-6), 127.7 (C-5), 140.7, 144.7
(C-2, C-3), 160.0 (C-8).
N-[1-(Bromomethylene)-2-(4-chlorophenyl)prop-2-enyl]acet-
amide (8c)
Yield (8c + 8c¢): 78%; ratio 8c/8c¢ = 3:1; oil; Rf = 0.54 (silica gel,
hexane–EtOAc, 1:1, UV).
13C NMR (125 MHz, CDCl3): d = 20.1 (C-14), 21.9, 28.7 (C-11, C-
12), 24.1 (C-5), 34.8 (C-3), 38.0 (C-2), 48.5 (C-6), 51.1 (C-1), 52.6
(C-9, C-10), 80.0 (C-4), 127.1, 127.4, 128.7 (C-16, C-17, C-18),
139.4 (C-15), 168.9, 169.7 (C-7, C-8, C-13).
Anal. Calcd for C12H11ClBrNO: C, 47.95; H, 3.69; N, 4.66. Found:
C, 48.05; H, 3.70; N, 4.71.
Z-Isomer (8c)
Anal. Calcd for C20H27NO6: C, 63.64; H, 7.21; N, 3.71. Found: C,
63.90; H, 7.29; N, 3.53.
1H NMR (300 MHz, CDCl3): d = 1.96 [s, 3 H, H3C(10)], 5.37 [s, 1
H, H¢C(4)], 5.45 [br s, 1 H, H¢¢C(4)], 5.94 [br s, 1 H, HC(1)], 7.04
[br s, 1 H, HC(1)], 7.28 [s, 4 H, HC(6), HC(7)]. Characteristic NOE-
SY correlations: HC(6)/H¢¢C(4), HC(1)/H¢C(4).
Methyl 2,2,7-Trimethyl-4-phenyl-3,4-dihydro-2H-pyrrolo[1,2-
b][1,2]oxazine-6-carboxylate (5)
13C NMR (75 MHz, CDCl3): d = 29.8 (C-10), 96.4 (C-1), 116.5 (C-
4), 128.5 (C-6, C-7), 134.2 (C-5), 137.9 (C-8), 140.2, 144.3 (C-2, C-
3).
Ac2O (1 mmol) and AcBr (1 mmol) were added to a stirred soln of
2g (1 mmol) in CH2Cl2 (3 mL). The resulting mixture was stirred for
2 h at 20 °C. Then the solvent was evaporated under vacuum and the
dark residue was purified by column chromatography (silica gel,
EtOAc–hexane, 1:3).
Synthesis 2007, No. 22, 3461–3468 © Thieme Stuttgart · New York

3468
P. E. Ivashkin et al.
PAPER
E-Isomer (8c¢)
Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C,
71.93; H, 7.36; N, 6.17.
1H NMR (300 MHz, CDCl3): d = 1.96 [s, 3 H, H3C(10)], 5.48 [s, 1
H, H¢¢C(4)], 5.86 [s, 1 H, H¢C(4)], 7.32 [m, 4 H, HC(6), HC(7)],
7.46 [br, 1 H, HC(1)]. Characteristic NOESY correlations: HC(6)/
H¢¢C(4).
Acknowledgment
13C NMR (75 MHz, CDCl3): d = 29.4 (C-10), 98.2 (C-1), 119.0 (C-
4), 127.6, 128.0 (C-6, C-7), 134.2 (C-5), 137.9 (C-8).
This study was supported by the Russian Foundation for Basic
Research (project no. 06-03-32607).
N-[1-(Bromomethylene)-2-phenylprop-2-enyl]acetamide (8e)
Yield (8e + 8e¢): 78%; ratio 8e/8e¢ = 3:2; oil; Rf = 0.53 (silica gel,
hexane–EtOAc, 1:1, UV).
References
(1) (a) Gallos, J. K.; Sarli, V. C.; Koftis, T. V. Tetrahedron Lett.
2000, 41, 4819. (b) Angermann, J.; Homman, K.; Reissig,
H.-U.; Zimmer, R. Synlett 1995, 1014.
Anal. Calcd for C12H12BrNO: C, 54.16; H, 4.54; N, 5.26. Found: C,
54.01; H, 4.72; N, 5.26.
(2) (a) Humphrey, A. J.; Parsons, S. F.; Smith, M. E.; Turner, N.
J. Tetrahedron Lett. 2000, 41, 4481. (b) Joubert, M.;
Defoin, A.; Tarnus, C.; Streith, J. Synlett 2000, 1366.
(3) (a) Bucholz, M.; Reissig, H.-U. Eur. J. Org. Chem. 2003,
3524. (b) Sukhorukov, A. Yu.; Klenov, M. S.; Ivashkin, P.
E.; Lesiv, A. V.; Khomutova, Yu. A.; Ioffe, S. L. Synthesis
2007, 97.
(4) (a) Tishkov, A. A.; Reissig, H.-U.; Ioffe, S. L. Synlett 2002,
863. (b) Reissig, H.-U.; Hippeli, C. Chem. Ber. 1991, 124,
115.
Z-isomer (8e)
1H NMR (300 MHz, CDCl3): d = 2.05 [s, 3 H, H3C(10)], 5.38 [br s,
1 H, H¢¢C(4)], 5.42 [br s, 1 H, H¢C(4)], 5.92 [br s, 1 H, HC(1)], 7.00
[br s, 1 H, NH], 7.21–7.35 [m, 5 H, HC(6), HC(7), HC(8)]. Charac-
teristic NOESY correlations: HC(6)/H¢¢C(4), HC(1)/H¢C(4).
13C NMR (75 MHz, CDCl3): d = 24.2 (C-10), 97.1 (C-1), 118.5 (C-
4), 127.3 (C-6), 128.3 (C-8), 128.8 (C-7), 138.4 (C-5), 140.2, 143.1
(C-2, C-3).
(5) Hippeli, C.; Reissig, H.-U. Liebigs Ann. Chem. 1990, 5, 475.
(6) Klenov, M. S.; Lesiv, A. V.; Khomutova, Yu. A.; Nesterov,
I. D.; Ioffe, S. L. Synthesis 2004, 8, 1159.
(7) (a) Shatzmiller, S.; Shalom, E. Liebigs Ann. Chem. 1983,
897. (b) Goldberg, I.; Saad, D.; Shalom, E.; Shatzmiller, S.
J. Org. Chem. 1982, 47, 2192.
(8) Ioffe, S. L.; Lyapkalo, I. M.; Tishkov, A. A.; Danilenko, V.
M.; Strelenko, Yu. A.; Tartakovsky, V. A. Tetrahedron
1997, 53, 13085.
E-isomer (8e¢)
1H NMR (300 MHz, CDCl3): d = 2.00 [s, 3 H, H3C(10)], 5.49 [s, 1
H, H¢C(4)], 5.88 [s, 1 H, H¢¢C(4)], 6.70 [br, 1 H, HN], 7.21–7.35 [m,
3 H, HC(7), HC(8)], 7.42 [d, 2 H, J = 7.5 Hz, HC(6)], 7.47 [s, 1 H,
HC(1)]. Characteristic NOESY correlations: HC(6)/H¢¢C(4).
13C NMR (75 MHz, CDCl3): d = 24.2 (C-10), 97.8 (C-1), 118.5 (C-
4), 126.2 (C-6), 128.1, 128.6 (C-7, C-8), 138.0 (C-5), 140.0, 143.1
(C-2, C-3).
(9) Only one example of acylation of 4H-1,2-oxazines with
acetyl chloride without base is known; Lee, V. J.;
Woodward, R. E. J. Org. Chem. 1979, 44, 2487. The
mechanism of this transformation is unclear.
(10) The reaction of oxazine 1a with lithium diisopropylamide,
butyllithium, or butyllithium/potassium tert-butoxide at
0 °C, –30 °C, and –50 °C, respectively (for two hours),
followed by treatment with acetyl chloride led to the
recovery of the initial oxazine 1a in almost quantitative yield
after treatment of the resulting mixtures with water.
(11) (a) Ishar, M. P. S.; Jayakumar, S.; Mahayan, M. P.
Tetrahedron 2002, 58, 379. (b) Tietze, L. F.; Kettschau, G.
Top. Curr. Chem. 1997, 189, 1.
N-[3-(4-Methoxyphenyl)buta-1,3-dien-2-yl)acetamide (9a)
Zn dust (3 mmol) was added to a stirred soln of 3a (1 mmol) in an-
hyd THF (10 mL) at 0 °C. The resulting mixture was stirred for 30
min at 0 °C and poured into a mixture of EtOAc (50 mL) and H2O
(50 mL). The aqueous phase was back-extracted with EtOAc (2 ×
10 mL); the combined organic layers were washed with brine (50
mL) and dried (Na2SO4). The solvents were evaporated under vac-
uum and the residue was subjected to column chromatography (sil-
ica gel, EtOAc–hexane, 1:3).
Yield: 60%; oil; Rf = 0.50 (silica gel, hexane–EtOAc, 1:1, UV).
1H NMR (300 MHz, CDCl3): d = 2.00 [s, 3 H, H3C(10)], 3.81 [s, 3
H, H3C(11)], 4.93 [br, 1 H, H2C(1)], 5.27 [br, 1 H, H2C(4)], 5.33 [br,
1 H, H2C(4)], 5.91 [br, 1 H, H2C(1)], 6.69 [br, 1 H, HN], 6.86 [d,
J = 8.5 Hz, 2 H, HC(7)], 7.30 [d, J = 8.5 Hz, 2 H, HC(6)].
(12) Eliseev, O. L.; Ivashkin, P. E.; Ostapenko, A. G.; Lesiv, A.
V.; Khomutova, Yu. A.; Ioffe, S. L.; Lapidus, A. L. Synlett
2006, 2239.
13C NMR (75 MHz, CDCl3): d = 24.5 (C-10), 55.3 (C-11), 104.7
(C-1), 113.5 (C-4), 113.9 (C-7), 127.8 (C-5), 129.2 (C-6), 130.8 (C-
3), 146.9 (C-2), 159.8 (C-8).
Synthesis 2007, No. 22, 3461–3468 © Thieme Stuttgart · New York