Regioselective synthesis of 6-halomethyl-5,6-dihydro-4H-1,2-oxazines based on cyclizations of arylalkenyl-oximes

Article abstract of DOI:10.1016/j.tet.2008.05.116

6-Iodo- and 6-bromomethyl-5,6-dihydro-4H-1,2-oxazines were prepared by condensation of dilithiated acetophenone-oximes with allylbromide and subsequent regioselective iodine- or NBS-mediated cyclization.

Full text of DOI:10.1016/j.tet.2008.05.116

Tetrahedron 64 (2008) 8010–8015
Contents lists available at ScienceDirect
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Regioselective synthesis of 6-halomethyl-5,6-dihydro-4H-1,2-oxazines
based on cyclizations of arylalkenyl-oximes
,
,
Vahuni Karapetyan a b, Satenik Mkrtchyan a b, Tung T. Dang a, Alexander Villinger a,
Helmut Reinke a, Peter Langer a
,c,
*
a
¨
Institut fu¨r Chemie, Universitat Rostock, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany
b Faculty of Chemistry, Yerevan State University, Alex Manoogian 1, 0025 Yerevan, Armenia
c Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
6-Iodo- and 6-bromomethyl-5,6-dihydro-4H-1,2-oxazines were prepared by condensation of dilithiated
acetophenone-oximes with allylbromide and subsequent regioselective iodine- or NBS-mediated
cyclization.
Received 6 March 2008
Received in revised form 26 May 2008
Accepted 29 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 3 June 2008
1. Introduction
afforded the 6-iodomethyl-5,6-dihydro-4H-1,2-oxazines 4a–k in
moderate to excellent yields. The best yields were obtained when
1,2-Oxazines are of pharmacological relevance and represent
useful synthetic building blocks. They have been used, for instance,
as intermediates during the synthesis of glycosidase inhibitor an-
alogues1 and functionalized pyrroles.2 1,2-Oxazines have been
prepared, for example, by hetero-Diels–Alder reactions of alkenes
the reaction was carried out in dichloromethane using a saturated
aqueous solution of sodium bicarbonate as the base. The reaction of
3e,f,j,k with N-bromosuccinimide (NBS) afforded the 6-bromo-
methyl-5,6-dihydro-4H-1,2-oxazines 4l–o. The tricyclic oxazine 4p
was prepared in high yield from tetralone (1l) (Scheme 2). The
structure of all products was established by spectroscopic methods.
The structures of 4d,f,j were independently confirmed by X-ray
crystal structure analyses (Figs.1–3).16 Products 4j,k and 4n–p were
isolated as1:1 mixtures ofdiastereomers. Incase of 4j, one of thetwo
diastereomers could be separated by crystallization (Fig. 3).
with ene-nitroso compounds derived from
a
-haloximes3 and by
hetero-Diels–Alder reactions of dienes with nitroso compounds.4
1,2-Oxazines are also available by NBS-,5 diphenyldiselenide-,6
acid-7 and UV-mediated8 cyclization of alkenyl-substituted oximes.
1,2-Oxazines have also been prepared by base-mediated cycliza-
tions of
g g
-chloroximes9 and -sulfonyloximes.10 Other synthetic
approaches to 1,2-oxazines rely on Lewis acid-catalyzed reactions
OH
N
of allenoximes,11 acid-catalyzed cyclization of cyclopropyloximes12
OH
and on cyclizations of
g
-nitroketones.13 Recently, we have repor-
R
N
Ar
ted14 the synthesis of 1,2-oxazines by cyclization15 of oxime dia-
nions with epibromohydrin. Herein, we report what are, to the best
of our knowledge, the first syntheses of 6-iodomethyl-5,6-dihydro-
4H-1,2-oxazines by condensation of oxime dianions with
allylbromide and subsequent O-regioselective iodine-mediated
cyclization.
i
1a-k
Ar
Br
R
+
3a-k
2
O
R
N
X
ii
Ar
2. Results and discussion
4a-o
Scheme 1. Synthesis of 1,2-oxazines 4a–o. Reagents and conditions: (i) (1)
1
The reaction of the dianions of oximes 1a–k, generated by means
of n-BuLi (2.5 equiv), afforded the arylalkenyl-oximes 3a–k in good
yields (Scheme 1, Table 1). The reaction of the latter with iodine
(1.0 equiv), n-BuLi (2.5 equiv), THF, 1 h, ꢀ78 ꢁC, then 10 min, 20 ꢁC, (2) 2 (2.0 equiv),
ꢀ78/20 ꢁC, 16 h; (ii) 4a–k: I2 (2.0 equiv), CH2Cl2, NaHCO3 (saturated aqueous solu-
tion), 20 ꢁC, 12 h, 4l–o: NBS (1.0 equiv), CH2Cl2, 20 ꢁC, 2 h.
The regioselectivity of cyclization requires some discussion.
Oximes are ambident nucleophiles, which can react with electro-
philes either at the oxygen or at the nitrogen atom. Grigg and
* Corresponding author. Fax: þ49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.116

V. Karapetyan et al. / Tetrahedron 64 (2008) 8010–8015
8011
Table 1
Products and yields
1,3
4
X
R
Ar
Yield %
3a
4a
95
83
66
67
96
a
b
c
d
e
f
g
h
i
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
I
I
I
I
I
I
I
I
I
I
I
Br
Br
Br
Br
H
H
H
H
H
H
H
H
Ph
85
69
68
71
64
69
67
60
65
63
60
64
69
63
60
4-MeC6H5
3-(MeO)C6H5
4-(MeO)C6H5
2-(EtO)C6H5
4-(EtO)C6H5
4-FC6H5
4-ClC6H5
1-Naphthyl
Ph
4-(MeO)C6H5
2-(EtO)C6H5
4-(EtO)C6H5
Ph
61
81
52
66
H
j
Me
Me
H
H
Me
Me
50b
43b
57
Figure 3. ORTEP plot of 4j (50% probability level).
k
e
f
j
k
87
anhydrous potassium carbonate quantitatively afforded nitrone 6,
which was trapped by a subsequent [3þ2] cycloaddition (Scheme
3).19 Similar results were obtained for the oxime of ethyl 2-homo-
allyl-cyclohexanone-2-carboxylate. The N-regioselectivity was
explained by a rapid Z/E isomerization and subsequent attack of
the nitrogen atom onto the iodonium ion. The reaction of 5 with
N-bromosuccinimide (NBS) was reported to give a 2:1 mixture of
nitrone and 1,2-oxazine, which reflects the E/Z ratio of 5.5 In this
reaction, the E/Z isomerization was slow compared to the N- and
O-cyclization. Similar results have been reported for diphenyl dis-
elenide-mediated cyclizations.6
73b
25b
4-(MeO)C6H5
a
Yields of isolated product.
dr¼1:1.
b
OH
N
OH
N
i
1l
Br
+
3l (76%)
2
_
O
HO
Me
O
+
ii
N
I
I
N
N
i
Me
ref. 19
5 (E/Z = 2:1)
6 (quantitative)
4p (96%)
(6 was trapped by [3+2] cycloaddition
with N-methylmaleimide)
Scheme 2. Synthesis of 1,2-oxazine 4p. Reagents and conditions: (i) (1) 1 (1.0 equiv),
n-BuLi (2.5 equiv), THF, 1 h, ꢀ78 ꢁC, then 10 min, 20 ꢁC, (2) 2 (2.0 equiv), ꢀ78/20 ꢁC,
16 h; (ii) I2 (2.0 equiv), CH2Cl2, NaHCO3 (saturated aqueous solution), 20 ꢁC, 12 h,
dr¼1:1.
Scheme 3. Synthesis of nitrone 6 by Grigg and co-workers (Ref. 19). Reagents and
conditions: (i) I2 (2.0 equiv), CH2Cl2, K2CO3 (anhydrous), 25 ꢁC, 12 h.
co-workers showed that the regioselectivity is controlled by the
E/Z-configuration of the oxime and by the rate of E/Z-isomerization
with respect to the N- or O-nucleophilic attack.17–19 The intra-
molecular reaction of oximes with halonium ions has been repor-
ted to result in N-alkylation and formation of nitrones. For example,
treatment of a CH2Cl2 solution of alkenyl-oxime 5 with iodine and
In contrast to 5, the aryl-substituted oximes 3a–l contain an
E-configured C]N group, due to the steric effect of the aryl group.20
The excellent O-regioselectivity of the formation of 1,2-oxazines
4a–p can be explained by the assumption that the E/Z isomeri-
zation is slow compared to the O-regioselective 1,2-oxazine
formation.
3. Conclusions
In conclusion, 6-iodo- and 6-bromomethyl-5,6-dihydro-4H-1,2-
oxazines were prepared by condensation of dilithiated acetophe-
none-oximes with allylbromide and subsequent regioselective
iodine- or NBS-mediated cyclization. The results reported herein
show that oxazines are available from alkenyl-oximes containing
sterically demanding substituents.
Figure 1. ORTEP plot of 4d (50% probability level).
4. Experimental section
4.1. General comments
All solvents were dried by standard methods and all reactions
were carried out under an inert atmosphere. For 1H and 13C NMR
spectra the deuterated solvents indicated were used. Mass spec-
trometric data (MS) were obtained by electron ionization (EI,
70 eV), chemical ionization (CI, H2O) or electrospray ionization
(ESI). For preparative scale chromatography, silica gel (60–200
mesh) was used. Melting points are uncorrected.
Figure 2. ORTEP plot of 4f (50% probability level).

8012
V. Karapetyan et al. / Tetrahedron 64 (2008) 8010–8015
~
4.2. General procedure for the preparation of oximes 3
(C), 154.8 (C). IR (KBr, cmꢀ1):
n
¼3431 (br, w), 3034 (m), 2935 (br, w),
2910 (w), 1611 (w), 1592 (w), 1510 (w), 1418 (w), 1407 (m), 1380 (m),
1335 (s), 1297 (m), 1233 (m), 1198 (s), 1163 (w), 1111 (w), 1088 (w),
1062 (w), 1013 (s), 936 (w), 915 (s), 812 (s), 760 (w), 710 (w). MS
(GC/MS, 70 eV): m/z (%)¼315 (Mþ, 100), 188 (9), 174 (20), 143 (14),
132 (32), 117 (33), 105 (9), 91 (40), 77 (7), 65 (17). HRMS (EI): calcd
for C12H14NOI (Mþ): 315.01146, found: 315.011582.
To a THF solution (20 mL) of oxime 1 (2.0 mmol) was added n-
butyllithium (5.0 mmol, 2.5 M) at ꢀ78 ꢁC. After stirring for 1 h at
ꢀ78 ꢁC, the mixture was warmed to 20 ꢁC and stirred for 10 min.
Subsequently, allylbromide (0.484 g, 4.0 mmol) was added at
ꢀ78 ꢁC. After warming of the mixture to 20 ꢁC for 16 h, a saturated
aqueous solution of NH4Cl (30 mL) was added. The organic and the
aqueous layer were separated and the latter was extracted with
ethyl acetate (3ꢂ50 mL). The combined organic layers were dried
(Na2SO4), filtered and the solvent of the filtrate was removed in
vacuo. The residue was purified by column chromatography (silica
gel, n-heptane/EtOAc¼5:1).
4.4.3. 6-Iodomethyl-3-(3-methoxyphenyl)-5,6-dihydro-4H-
[1,2]oxazine (4c)
Starting with 1-(4-methoxyphenyl)pent-4-en-1-one oxime 3c
(0.205 g, 1 mmol), I2 (0.508 g, 2 mmol) and a saturated aqueous
solution of NaHCO3 (5 mL) in CH2Cl2 (10 mL), 4c was isolated as
a brownish oil (0.219 g, 66%). 1H NMR (300 MHz, CDCl3):
d¼1.76 (m,
4.3. General procedure for the synthesis of 1,2-oxazines
4a–k and 4p
1H, CH2), 2.22 (m,1H, CH2), 2.55 (m, 2H, CH2), 3.19, 3.35 (t, 2H, CH2),
3.75 (m, 1H, CH), 3.80 (s, 3H, OCH3), 7.12–7.25 (m, 3H, Ar), 7.85 (s,
1H, Ar). 13C NMR (75 MHz, CDCl3):
d
¼6.7, 22.0, 24.5 (3C, CH2), 55.4
To a CH2Cl2 solution (15 mL) of 3a–l (0.81 mmol) and I2 (0.406 g,
1.6 mmol) was added a saturated aqueous solution of NaHCO3
(16 mL) and the solution was stirred for 12 h at 20 ꢁC. The excess of
iodine was removed by addition of a saturated aqueous solution of
Na2SO3 (40 mL). The organic and the aqueous layer were separated
and the latter was extracted with ethyl acetate (3ꢂ50 mL). The
combined organic layers were dried (Na2SO4), filtered and the
solvent of the filtrate was removed in vacuo. The residue was pu-
rified by column chromatography (silica gel, n-heptane/n-hep-
tane/EtOAc¼4:1).
(C, CH3), 74.1 (C, CH), 110.4, 116.3, 119.5, 129.6 (4C, ArCH), 136.6,
154.6 (2C, ArC), 159.6 (C, CN). IR (KBr, cmꢀ1):
n
¼3067 (w), 2994 (w),
~
2954 (w), 2932 (w), 2832 (w), 1597 (m), 1568 (m), 1425 (m), 1287
(m), 1234 (m), 1175 (m), 1038 (s), 924 (m), 823 (m), 779 (m), 688
(m). MS (EI, 70 eV): m/z (%)¼332 (Mþ, 14), 331 (100), 204 (14), 190
(21), 187 (16), 186 (18), 178 (20), 133 (23). HRMS (EI, 70 eV): calcd
for C12H14NO2I (Mþ): 331.00637; found: 331.006082.
4.4.4. 6-Iodomethyl-3-(4-methoxyphenyl)-5,6-dihydro-4H-
[1,2]oxazine (4d)
Starting with 1-(4-methoxyphenyl)pent-4-en-1-one oxime 3d
(0.478 g, 2.33 mmol), I2 (1.184 g, 4.66 mmol) and a saturated
aqueous solution of NaHCO3 (23.3 mL) in CH2Cl2 (40.0 mL), 4d was
isolated as a red solid (0.517 g, 67%); mp 140 ꢁC. 1H NMR (300 MHz,
4.4. General procedure for the synthesis of 1,2-oxazines 4l–o
To a CH2Cl2 solution (10 mL) of 3e,f,j,k (2.0 mmol) was por-
tionwise added NBS (0.356 g, 2.0 mmol) over 15 min at 0 ꢁC. The
resultant solution was stirred for 2 h at room temperature. The
residue was purified by column chromatography (silica gel, n-
heptane/n-heptane/EtOAc¼4:1).
CDCl3):
d
¼1.84 (m, 1H, CH2), 2.31 (m, 1H, CHCH2), 2.66 (m, 2H,
CCH2), 3.26 (dd, 2J¼10.6 Hz, 3J¼7.2 Hz, 1H, CHCH2I), 3.41 (dd,
2J¼10.6 Hz, 3J¼5.0 Hz, 1H, CHCH2I), 3.81 (s, 3H, OCH3), 3.83 (m, 1H,
OCHCH2), 6.88 (d, 3J¼9.0 Hz, 2H, CHAr), 7.63 (d, 3J¼9.0 Hz, 2H, CHAr).
13C NMR (75.5 MHz, CDCl3):
d
¼5.4 (CH2I), 21.6 (CH2), 24.3 (CH2),
4.4.1. 6-Iodomethyl-3-phenyl-5,6-dihydro-4H-[1,2]oxazine (4a)
Starting with 1-phenyl-pent-4-en-1-one oxime 3a (0.141 g,
0.81 mmol), I2 (0.412 g, 1.62 mmol) and a saturated aqueous solu-
tion of NaHCO3 (8.1 mL) in CH2Cl2 (14 mL), 4a was isolated as
a brownish solid (0.232 g, 95%); mp 126–128 ꢁC. 1H NMR (300 MHz,
55.3 (OCH3), 74.0 (CHO), 113.8, 126.8 (CHAr), 127.5, 154.5, 160.9 (C).
IR (KBr, cmꢀ1):
¼2951 (w), 2905 (w), 2834 (w), 1611 (s), 1514 (s),
~
n
1462 (w), 1334 (w), 1295 (m), 1258 (s), 1199 (m), 1175 (s), 1030 (m),
1016 (m), 920 (m), 823 (s), 646 (w). MS (EI, 70 eV): m/z (%)¼331
(Mþ, 100), 187 (11), 172 (11), 133 (26), 90 (8), 77 (11). HRMS (EI):
calcd for C12H14NO2I (Mþ): 331.00637, found: 331.006054. Anal.
Calcd for C12H14NO2I (331.15): C, 43.52; H, 4.26; N, 4.23. Found: C,
43.68; H, 4.30; N, 3.91.
CDCl3):
d
¼1.86 (m, 1H, CHCH2), 2.34 (m, 1H, CHCH2), 2.68 (m, 2H,
CCH2), 3.27 (dd, 2J¼10.3 Hz, 3J¼7.3 Hz, 1H, CHCH2I), 3.42 (dd,
2J¼10.3 Hz, 3J¼5.0 Hz, 1H, CHCH2I), 3.85 (m, 1H, OCHCH2), 7.38 (m,
3H, CHAr), 7.68 (m, 2H, CHAr). 13C NMR (75.5 MHz, CDCl3):
d
¼5.3
(CH2I), 21.6, 24.2 (CHCH2CH2C), 74.1 (CHO), 125.4 (CHAr), 128.5
4.4.5. 3-(2-Ethoxyphenyl)-6-iodomethyl-5,6-dihydro-4H-
[1,2]oxazine (4e)
(CHAr), 129.7 (CHAr), 135.1 (C), 154.8 (C). IR (ATR, cmꢀ1):
~
n
¼3039 (br,
w), 2959 (w), 2905 (br, w), 2853 (w), 1589 (w), 1563 (w), 1490 (w),
1443 (w), 1404 (w), 1378 (w), 1330 (w), 1296 (w), 1260 (w), 1231
(w), 1195 (m), 1161 (w), 1086 (m), 1012 (m), 997 (m), 982 (m), 913
(m), 799 (m), 750 (s), 685 (s), 603 (m). MS (GC/MS, 70 eV): m/z
(%)¼301 (Mþ, 100), 207 (6), 174 (17), 156 (48), 144 (30), 128 (38), 118
(59), 104 (51), 77 (70). HRMS (EI): calcd for C11H12NOI (Mþ):
300.99581, found: 300.995322.
Starting with 1-(2-ethoxyphenyl)pent-4-en-1-one oxime 3e
(0.438 g, 2.00 mmol), I2 (1.016 g, 4.00 mmol) and a saturated
aqueous solution of NaHCO3 (20 mL) in CH2Cl2 (34 mL), 4e was
isolated as a brownish viscous (0.656 g, 95%). 1H NMR (250 MHz,
CDCl3):
d
¼1.40 (t, 3J¼7.0 Hz, 3H, OCH2CH3), 1.84 (m, 1H, CHCH2CH2),
2.27 (m, 1H, CHCH2CH2), 2.69 (dd, 2J¼8.3 Hz, 3J¼5.5 Hz, 2H, CCH2),
3.28 (dd, 2J¼10.2 Hz, 3J¼7.7 Hz, 1H, CHCH2I), 3.44 (dd, 2J¼10.2 Hz,
3J¼4.9 Hz, 1H, CHCH2I), 3.96 (m, 1H, OCHCH2), 4.05 (q, 3J¼7.0 Hz,
2H, OCH2CH3), 6.92 (m, 2H, CHAr), 7.32 (m, 2H, CHAr). 13C NMR
4.4.2. 6-Iodomethyl-3-p-tolyl-5,6-dihydro-4H-[1,2]oxazine (4b)
Starting with 1-(3-tolyl)pent-4-en-1-one oxime 3b (0.342 g,
1.80 mmol), I2 (0.914 g, 3.60 mmol) and a saturated aqueous solu-
tion of NaHCO3 (18 mL) in CH2Cl2 (30 mL), 4b was isolated as
(62.9 MHz, CDCl3):
d
¼5.8 (CH2I), 14.8 (OCH2CH3), 24.1, 24.2
(CHCH2CH2C), 63.8 (OCH2CH3), 74.2 (CHO), 111.9 (CHAr), 120.6
(CHAr), 125.7 (C), 129.6 (CHAr), 130.4 (CHAr), 156.6, 158.5 (C). IR (ATR,
~
n
a
colourless solid (0.471 g, 83%); mp 120–122 ꢁC. 1H NMR
cmꢀ1):
¼3061 (br, w), 2975 (w), 2927 (w), 2875 (w), 1600 (m),
(250 MHz, CDCl3):
d
¼1.85 (m, 1H, CH2), 2.32 (m,1H, CHCH2), 2.36 (s,
1490 (m), 1446 (s), 1391 (m), 1290 (m), 1237 (s), 1161 (m), 1122 (s),
1039 (s), 1010 (m), 892 (s), 802 (w), 750 (s), 681 (m), 640 (w), 604
(m). MS (EI, 70 eV): m/z (%)¼345 (Mþ, 9), 313 (54), 256 (2), 204 (27),
185 (28), 158 (22), 145 (100), 128 (36), 119 (24), 91 (22), 77 (13).
3H, CArCH3), 2.68 (m, 2H, CCH2), 3.25 (dd, 2J¼10.5 Hz, 3J¼7.3 Hz, 1H,
CHCH2I), 3.41 (dd, 2J¼10.5 Hz, 3J¼5.0 Hz, 1H, CHCH2I), 3.84 (m, 1H,
OCHCH2), 7.18 (d, 3J¼8.1 Hz, 2H, CHAr), 7.57 (d, 3J¼8.1 Hz, 2H, CHAr).
13C NMR (75.5 MHz, CDCl3):
(CHCH2CH2C), 74.0 (CHO),125.3 (CHAr),129.2 (CHAr),132.3 (C),139.8
d¼5.5 (CH2I), 21.3 (CArCH3), 21.6, 24.3
HRMS (EI): calcd for
345.022935.
C
13H16NO2I (Mþ): 345.02202, found:

V. Karapetyan et al. / Tetrahedron 64 (2008) 8010–8015
8013
4.4.6. 3-(4-Ethoxyphenyl)-6-iodomethyl-5,6-dihydro-4H-
[1,2]oxazine (4f)
Starting with 1-(4-ethoxyphenyl)pent-4-en-1-one oxime 3f
(0.438 g, 2.00 mmol), I2 (1.016 g, 4.00 mmol) and a saturated
aqueous solution of NaHCO3 (20 mL) in CH2Cl2 (34 mL), 4f was
isolated as a brownish solid (0.352 g, 51%); mp 131–135 ꢁC. 1H NMR
as a brownish oil (0.232 g, 66%). 1H NMR (300 MHz, CDCl3):
d
¼1.92 (m, 1H, CH2), 2.31 (m, 1H, CH2), 2.35 (t, 1H, CH2), 2.41 (t,
1H, CH2), 2.61 (t, 2H, CH2), 3.94 (m, 1H, CH), 74.2 (CH), 7.31 (t,
3J¼8.2 Hz, 2H, Ar), 7.38 (d, 3J¼8.2 Hz, 2H, Ar), 7.73 (d, 3J¼8.2 Hz,
1H, Ar), 7.79 (d, 3J¼8.2 Hz, 1H, Ar), 7.87 (t, 3J¼8.2 Hz, 1H, Ar). 13C
NMR (75 MHz, CDCl3):
d
¼5.6, 24.6, 26.3 (CH2), 74.4 (CH), 125.0,
(250 MHz, CDCl3):
d
¼1.41 (t, 3J¼7.0 Hz, 3H, OCH2CH3), 1.84 (m, 1H,
125.1, 125.7, 126.1, 126.8, 128.5, 129.6 (ArCH), 131.3, 133.8, 133.9
(ArC), 158.0 (C, CN). IR (KBr, cmꢀ1):
n
¼3044 (w), 2953 (w), 2932
~
CHCH2CH2), 2.32 (m, 1H, CHCH2CH2), 2.65 (m, 2H, CCH2), 3.25 (dd,
2J¼10.8 Hz, 3J¼7.3 Hz, 1H, CHCH2I), 3.41 (dd, 2J¼10.8 Hz, 3J¼5.1 Hz,
1H, CHCH2I), 3.82 (m, 1H, OCHCH2), 4.04 (q, 3J¼7.0 Hz, 2H,
OCH2CH3), 6.87 (d, 3J¼9.0 Hz, 2H, CHAr), 7.61 (d, 3J¼9.0 Hz, 2H,
(m), 2852 (m), 1673 (m), 1506 (m), 1368 (m), 1280 (m), 1127 (m),
999 (m), 895 (s), 772 (s). MS (EI, 70 eV): m/z (%)¼351 (Mþ, 100),
350 (11), 224 (15), 206 (15), 165 (15), 153 (46), 152 (33), 127 (38).
HRMS (EI, 70 eV): calcd for C15H14NO2I (Mþ): 351.01146; found:
351.011650.
CHAr). 13C NMR (62.9 MHz, CDCl3):
d¼5.5 (CH2I), 14.7 (OCH2CH3),
21.2, 24.3 (CHCH2CH2C), 63.5 (OCH2CH3), 73.9 (CHO), 114.3 (CHAr),
126.7 (CHAr), 127.4 (C), 154.4 (C), 160.2 (C). IR (ATR, cmꢀ1):
n
¼3047
~
(w), 2976 (w), 2929 (w), 1608 (s), 1590 (m), 1510 (s), 1481 (m), 1444
(w), 1394 (m), 1334 (m), 1296 (w), 1253 (s), 1232 (m), 1196 (m), 1174
(m), 1116 (m), 1046 (m), 1015 (s), 984 (w), 916 (m), 817 (s), 759 (w),
662 (m), 553 (m). MS (EI, 70 eV): m/z (%)¼345 (Mþ, 100), 256 (6),
201 (20), 172 (31), 147 (11), 119 (21), 97 (16), 69 (24). Anal. Calcd for
4.4.10. 6-Iodomethyl-4-methyl-3-phenyl-5,6-dihydro-4H-
[1,2]oxazine (4j)
Starting with 2-methyl-1-phenyl-pent-4-en-1-one oxime 3j
(0.378 g, 2.00 mmol), I2 (1.016 g, 4.00 mmol) and a saturated
aqueous solution of NaHCO3 (20 mL) in CH2Cl2 (34 mL), 4j was
isolated as a colourless solid (0.315 g, 50%); mp 70–72 ꢁC. The
product was isolated as an inseparable mixture of diastereomers
(dr¼1:1). Therefore, most signals are splitted. 1H NMR (250 MHz,
C
13H16INO2 (345.176): C, 45.23; H, 4.67; N, 4.06. Found: C, 45.17; H,
4.58; N, 3.81. HRMS (EI): calcd for C13H16NO2I (Mþ): 345.02202,
found: 345.022376.
CDCl3):
d
¼1.08, 1.17 (d, 3J¼7.3 Hz, 3H, CHCH3), 1.57, 1.88 (m, 1H,
4.4.7. 3-(4-Fluorophenyl)-6-iodomethyl-5,6-dihydro-4H-
[1,2]oxazine (4g)
Starting with 1-(4-fluorophenyl)pent-4-en-1-one oxime 3g
(0.290 g, 1.50 mmol), I2 (0.762 g, 3.00 mmol) and a saturated
aqueous solution of NaHCO3 (15 mL) in CH2Cl2 (25 mL), 4g was
isolated as a brownish solid (0.388 g, 81%); mp 129–131 ꢁC. 1H NMR
CHCH2CH), 2.06, 2.47 (m, 1H, CHCH2CH), 3.05 (m, 1H, CHCH3), 3.28
(m, 1H, CH2I), 3.42 (m, 1H, CH2I), 3.84 (m, 1H, OCHCH2), 7.37 (m, 3H,
CHAr), 7.48, 7.61 (m, 2H, CHAr). 13C NMR (62.9 MHz, CDCl3):
d¼5.6,
5.9 (CH2I), 19.1, 20.2 (CHCH3), 25.7, 28.2 (CHCH3), 31.6, 34.7
(CHCH2CH), 70.9, 74.7 (OCH), 126.2, 126.8 (CHAr), 128.3, 128.5
(CHAr), 129.1, 129.4 (CHAr), 134.5, 134.6 (C), 159.1, 161.8 (C). IR (ATR,
~
(250 MHz, CDCl3):
d
¼1.86 (m,1H, CHCH2), 2.34 (m,1H, CHCH2), 2.65
cmꢀ1):
n
¼3047 (br, w), 2964 (w), 2929 (w), 2867 (w), 1589 (w),
(m, 2H, CCH2), 3.27 (dd, 2J¼10.4 Hz, 3J¼7.2 Hz, 1H, CHCH2I), 3.42
1493 (w),1440 (m),1410 (w),1376 (w),1258 (m),1219 (w),1187 (m),
1090 (w), 1034 (s), 1007 (s), 965 (s), 928 (w), 897 (s), 765 (s), 739
(m), 689 (s), 609 (m). MS (EI, 70 eV): m/z (%)¼315 (Mþ, 100), 256
(27), 239 (11), 188 (20), 170 (27), 132 (52), 117 (45), 104 (35), 77 (46),
55 (52). HRMS (EI): calcd for C12H14INO (Mþ): 315.01146, found:
315.011677. Anal. Calcd for C12H14NOI (315.01): C, 45.73; H, 4.48; N,
4.44. Found: C, 45.80; H, 4.42; N, 4.32.
(dd, 2J¼10.4 Hz, 3J¼5.0 Hz, 1H, CHCH2I), 3.84 (m, 1H, OCHCH2), 7.05
(m, 2H, CHAr), 7.67 (m, 2H, CHAr). 13C NMR (62.9 MHz, CDCl3):
d¼5.2
(CH2I), 21.6, 24.1 (CHCH2CH2C), 74.1 (CHO), 115.5 (d, 2J¼22.0 Hz,
CHCHCFAr), 127.2 (d, 3J¼8.5 Hz, CHCHCFAr), 131.3 (d, 4J¼3.3 Hz,
CCHCHCFAr), 153.8 (CN), 163.6 (d, 1J¼249.7 Hz, CHCFAr). IR (ATR,
~
cmꢀ1):
n
¼3053 (w), 2933 (br, w), 2904 (w), 2872 (w), 1606 (m),
1508 (s), 1444 (w), 1405 (w), 1379 (w), 1331 (m), 1294 (w), 1232 (s),
1197 (s), 1158 (m), 1099 (m), 1061 (w), 1012 (m), 1002 (m), 986 (m),
913 (s), 852 (m), 829 (s), 785 (w), 758 (w), 644 (m), 552 (s). MS (EI,
70 eV): m/z (%)¼319 (Mþ, 100), 192 (16), 174 (37), 162 (16), 148 (14),
136 (47), 121 (40), 95 (19), 83 (18). HRMS (EI): calcd for C11H11INOF
(Mþ): 318.98639, found: 318.985435.
4.4.11. 6-Iodomethyl-3-(4-methoxyphenyl)-4-methyl-5,6-dihydro-
4H-[1,2]oxazine (4k)
Starting with 1-(4-methoxyphenyl)-2-methylpent-4-en-1-one
oxime 3k (0.657 g, 3.00 mmol), I2 (1.524 g, 6.00 mmol) and a
saturated aqueous solution of NaHCO3 (30 mL) in CH2Cl2 (51 mL),
4k was isolated as a colourless solid (0.445 g, 43%); mp 100–
102 ꢁC. The product was isolated as an inseparable mixture of
diastereomers (dr¼1:1). Therefore, most signals are splitted.
For most of the diastereomers, the difference of the chemical shifts
4.4.8. 3-(4-Chlorophenyl)-6-iodomethyl-5,6-dihydro-4H-
[1,2]oxazine (4h)
Starting with 1-(4-chlorophenyl)pent-4-en-1-one oxime 3h
(0.209 g, 1.0 mmol), I2 (0.508 g, 2.0 mmol) and a saturated aqueous
solution of NaHCO3 (5 mL) in CH2Cl2 (10 mL), 4h was isolated as
is very small. Therefore, only
a
single value is given. 1H
NMR (250 MHz, CDCl3):
d
¼1.18 (d, 3J¼7.3 Hz, 3H, CHCH3), 1.86 (m,
a brownish oil (0.172 g, 52%). 1H NMR (300 MHz, CDCl3):
d
¼1.82 (m,
1H, CHCH2CH), 2.06 (m, 1H, CHCH2CH), 3.03 (m, 1H, CHCH3), 3.27
(dd, 2J¼10.5 Hz, 3J¼6.9 Hz, 1H, CHCH2I), 3.44 (dd, 2J¼10.5 Hz,
3J¼5.1 Hz, 1H, CHCH2I), 3.82 (s, 3H, OCH3), 3.89 (m, 1H, OCHCH2),
6.90 (d, 3J¼9.0 Hz, 2H, CHAr), 7.55 (d, 3J¼9.0 Hz, 2H, CHAr). 13C NMR
1H, CH2), 2.22 (m, 1H, CH2), 2.65 (q, 2H, CH2), 3.19 (t, 1H, CH2), 3.31
(t, 1H, CH2), 3.75 (m, 1H, CH), 7.25 (d, 3J¼8.2 Hz, 1H, Ar), 7.46 (d,
3J¼8.2 Hz, 1H, Ar). 13C NMR (75 MHz, CDCl3):
¼5.4, 23.0, 26.0
d
(CH2), 74.4 (CH), 127.7, 129.3 (4C, ArCH), 134.0, 136.0 (2C, ArC), 153.7
(62.9 MHz, CDCl3):
d
¼6.02 (CH2I), 20.4 (CHCH3), 25.7 (CHCH3), 31.8
(C, CN). IR (KBr, cmꢀ1):
n
¼3049 (w), 3005 (w), 2928 (w), 1548 (m),
(CHCH2CH), 55.3 (OCH3), 70.9 (OCHCH2), 113.9 (CHAr), 127.0 (C),
~
127.6 (CHAr), 158.6 (C), 160.6 (C). IR (ATR, cmꢀ1):
n
¼2960 (w), 2930
~
1456 (m), 1349 (m), 1075 (m), 924 (s), 819 (s), 752 (m). MS (EI,
70 eV): m/z (%)¼336 (Mþ, 37Cl, 7), 334 (Mþ, 35Cl, 19), 192 (55), 180
(100), 177 (38), 143 (61), 137 (29), 112 (35), 101 (19). HRMS (EI,
(w), 2881 (w), 2837 (w), 1606 (m), 1585 (w), 1511 (m), 1456 (m),
1411 (w), 1374 (w), 1346 (w), 1295 (m), 1244 (s), 1178 (m), 1129
(w), 1110 (w), 1093 (w), 1074 (m), 1031 (m), 1007 (m), 961 (m), 927
(m), 899 (s), 860 (m), 831 (s), 814 (s), 749 (m), 725 (w), 639 (m),
628 (s), 608 (m), 551 (m). MS (EI, 70 eV): m/z (%)¼345 (Mþ, 91),
256 (50), 239 (19), 201 (17), 186 (16), 133 (19), 111 (25), 102
(45), 83 (64), 69 (69), 57 (100). HRMS (EI): calcd for C13H16INO2
(Mþ): 345.02202, found: 345.022506. Anal. Calcd for C13H16NO2I
(345.18): C, 45.23; H, 4.67; N, 4.06. Found: C, 45.38; H, 4.60;
N, 3.86.
70 eV): calcd for
334.95742.
C
11H11INOCl (Mþ, 35Cl): 334.95738; found:
4.4.9. 6-Iodomethyl-4-(naphthalen-1-yl)-5,6-dihydro-4H-
[1,2]oxazine (4i)
Starting with 1-(1-naphthyl)pent-4-en-1-one oxime 3i
(0.225 g, 1.0 mmol), I2 (0.508 g, 2.0 mmol) and a saturated aque-
ous solution of NaHCO3 (5 mL) in CH2Cl2 (10 mL), 4i was isolated

8014
V. Karapetyan et al. / Tetrahedron 64 (2008) 8010–8015
4.4.12. 6-Bromomethyl-3-(2-ethoxyphenyl)-5,6-dihydro-4H-
[1,2]oxazine (4l)
4.4.15. 6-Bromomethyl-3-(4-methoxyphenyl)-4-methyl-5,6-
dihydro-4H-[1,2]oxazine (4o)
Starting with 1-(2-ethoxyphenyl)pent-4-en-1-one oxime 3e
(0.329 g, 1.50 mmol) and NBS (0.267 g, 1.50 mmol) in CH2Cl2
(7.5 mL), 4l was isolated as a brownish viscous oil (0.256 g, 57%). 1H
Starting with 1-(4-methoxyphenyl)-2-methylpent-4-en-1-one
oxime 3k (0.519 g, 2.70 mmol) and NBS (0.480 g, 2.70 mmol) in
CH2Cl2 (13.5 mL), 4o was isolated as a colourless solid (0.201 g,
25%); mp 88–91 ꢁC. The product was isolated as an inseparable
mixture of diastereomers (dr¼1:1). Therefore, most signals are
splitted. For most of the diastereomers, the difference of the
chemical shifts is very small. Therefore, only a single value is given.
NMR (250 MHz, CDCl3):
d
¼1.40 (t, 3J¼7.0 Hz, 3H, OCH2CH3),1.89 (m,
1H, CHCH2CH2), 2.23 (m, 1H, CHCH2CH2), 2.69 (dd, 2J¼8.2 Hz,
3J¼5.7 Hz, 2H, CCH2), 3.47 (dd, 2J¼10.4 Hz, 3J¼7.3 Hz, 1H, CHCH2Br),
3.62 (dd, 2J¼10.4 Hz, 3J¼4.9 Hz, 1H, CHCH2Br), 4.05 (q, 3J¼7.0 Hz,
2H, OCH2CH3), 4.11 (m, 1H, OCHCH2), 6.92 (m, 2H, CHAr), 7.32 (m,
1H NMR (250 MHz, CDCl3):
d
¼1.19 (d, 3J¼7.3 Hz, 3H, CHCH3), 1.96
2H, CHAr). 13C NMR (62.9 MHz, CDCl3):
(CH2), 23.9 (CH2), 32.5 (CH2Br), 63.8 (OCH2CH3), 73.9 (CHO), 111.9
d
¼14.8 (OCH2CH3), 22.7
(m, 2H, CHCH2CH), 3.03 (m, 1H, CHCH3), 3.40 (dd, 2J¼10.6 Hz,
3J¼6.4 Hz, 1H, CHCH2Br), 3.56 (dd, 2J¼10.6 Hz, 3J¼5.1 Hz, 1H,
CHCH2Br), 3.82 (s, 3H, OCH3), 4.04 (m, 1H, OCHCH2), 6.90 (d,
3J¼9.0 Hz, 2H, CHAr), 7.55 (d, 3J¼9.0 Hz, 2H, CHAr). 13C NMR
(CHAr), 120.6 (CHAr), 125.8 (C), 129.6 (CHAr), 130.4 (CHAr), 156.6,
158.5 (C). IR (ATR, cmꢀ1):
n
¼3061 (br, w), 2976 (w), 2929 (w), 1600
~
(m), 1491 (m), 1475 (w), 1446 (s), 1391 (w), 1291 (m), 1236 (s), 1161
(w), 1122 (m), 1039 (s), 1023 (s), 924 (w), 897 (s), 800 (w), 750 (s),
682 (w), 656 (w). MS (GC/MS, 70 eV): m/z (%)¼299 (Mþ, 81Br, 7),
297 (Mþ, 79Br, 7), 267 (4), 265 (4), 204 (34), 174 (24), 158 (60), 145
(100), 132 (21), 103 (9), 91 (35), 77 (18). HRMS (EI): calcd for C13H16
O2NBr (Mþ): 297.03589, found: 297.035775.
(75.5 MHz, CDCl3):
d
¼20.3 (CHCH3), 25.3 (CHCH3), 30.4 (CHCH2),
32.9 (CH2Br), 55.3 (OCH3), 70.7 (OCHCH2), 114.0 (CHAr), 127.1 (C),
127.6 (CHAr), 158.7 (C), 160.7 (C). IR (ATR, cmꢀ1):
n
¼2965 (w), 2931
~
(w), 2877 (w), 1606 (s), 1510 (s), 1461 (m), 1374 (w), 1294 (m), 1245
(s), 1176 (m), 1109 (w), 1095 (w), 1079 (w), 1044 (m), 1029 (m), 1013
(s), 969 (m), 911 (s), 831 (s), 813 (s), 755 (m), 655 (m), 624 (m). MS
(GC/MS, 70 eV): m/z (%)¼299 (Mþ, 81Br, 100), 297 (Mþ, 79Br, 99.7),
218 (2), 204 (23), 186 (11), 162 (15), 160 (15), 147 (32), 134 (55), 133
(50), 115 (16), 103 (20), 91 (16), 77 (21). HRMS (EI): calcd for
4.4.13. 6-Bromomethyl-3-(4-ethoxyphenyl)-5,6-dihydro-4H-
[1,2]oxazine (4m)
Starting with 1-(4-ethoxyphenyl)pent-4-en-1-one oxime 3f
(0.438 g, 2.00 mmol) and NBS (0.356 g, 2.00 mmol) in CH2Cl2
(10.0 mL), 4m was isolated as a colourless solid (0.519 g, 87%); mp
C
13H16NO2Br (Mþ): 297.03589, found: 297.035394.
4.4.16. 3-Iodomethyl-4,4a,5,6-tetrahydro-3H-naphtho[1,2-c]
[1,2]oxazine (4p)
130–135 ꢁC. 1H NMR (250 MHz, CDCl3):
d
¼1.41 (t, 3J¼7.0 Hz, 3H,
OCH2CH3),1.91 (m,1H, CHCH2CH2), 2.28 (m,1H, CHCH2CH2), 2.65 (m,
2H, CCH2), 3.44 (dd, 2J¼10.8 Hz, 3J¼7.0 Hz, 1H, CHCH2Br), 3.60 (dd,
2J¼10.8 Hz, 3J¼5.0 Hz, 1H, CHCH2Br), 3.98 (m, 1H, OCHCH2), 4.04
(q, 3J¼7.0 Hz, 2H, OCH2CH3), 6.88 (d, 3J¼9.0 Hz, 2H, CHAr), 7.61
Starting with 2-allyl-3,4-dihydro-2H-naphthalen-1-one oxime
3l (0.221 g, 1.1 mmol), I2 (0.559 g, 2.2 mmol) and a saturated
aqueous solution of NaHCO3 (11.0 mL) in CH2Cl2 (18.0 mL), 4p was
isolated as a colourless solid (0.345 g, 96%); mp 105–107 ꢁC. The
product was isolated as an inseparable mixture of diastereomers
(dr¼1:1). Therefore, most signals are splitted. For most of the di-
astereomers, the difference of the chemical shifts is very small.
Therefore, only a single value is given. 1H NMR (300 MHz, CDCl3):
(d, 3J¼9.0 Hz, 2H, CHAr).13CNMR(62.9 MHz,CDCl3):
¼14.7 (OCHCH3),
d
21.2 (CH2), 22.9 (CH2), 32.4 (CH2Br), 63.5 (OCH2CH3), 73.7 (OCHCH2),
114.3 (CHAr), 126.7 (CHAr), 127.6, 154.5, 160.2 (C). IR (ATR, cmꢀ1):
~
n
¼2977 (w), 2909 (br, w),1608 (w),1590 (m),1511 (m),1479 (m),1449
(br, w), 1414 (w), 1392 (m), 1384 (m), 1356 (m), 1337 (m), 1292 (m),
1247 (s), 1225 (m), 1170 (m), 1116 (m), 1093 (w), 1064 (w), 1043 (m),
1022 (m), 988 (m), 941 (w), 911 (m), 852 (m), 816 (s), 763(m), 664 (m),
621 (m), 547 (s). MS (GC/MS, 70 eV): m/z (%)¼299 (Mþ, 81Br, 98), 297
(Mþ, 79Br,100), 268 (3), 204 (28),176 (17),148 (22),147 (20),134 (21),
119 (56), 91 (22), 77 (11), 65 (20). HRMS (EI): calcd for C13H16 BrNO2
(Mþ): 297.03589, found: 297.035839. Anal. Calcd for C13H16NO2Br
(298.18): C, 52.36; H, 5.41; N, 4.70. Found: C, 52.01; H, 5.32; N, 4.52.
d
¼1.37–1.65 (m, 2H, CH2), 2.09 (m, 1H, CH2), 2.33 (m, 1H, CH2), 2.48
(m, 1H, CCHCH2), 2.85 (m, 2H, CH2), 3.20 (dd, 2J¼10.6 Hz, 3J¼7.0 Hz,
1H, CHCH2I), 3.36 (dd, 2J¼10.6 Hz, 3J¼5.0 Hz, 1H, CHCH2I), 3.88 (m,
1H, OCH), 7.14 (m, 3H, CHAr), 7.96 (d, 3J¼7.8 Hz, 1H, CHAr). 13C NMR
(75.5 MHz, CDCl3):
d
¼5.8 (CH2I), 28.9 (CH2), 29.0 (CH2), 32.0 (CH2),
33.0 (CCHCH2), 73.6, 75.3 (OCH), 124.7 (CHAr), 126.5 (CHAr), 129.0
(CHAr), 129.6 (CHAr), 129.5 (C), 138.1 (C), 154.4 (C). IR (ATR, cmꢀ1):
~
n
¼3016 (br, w), 2924 (w), 2855 (w), 2831 (w), 1728 (w), 1610 (w),
1479 (w),1445 (w),1431 (w),1372 (w),1323 (w),1307 (w),1291 (w),
1259 (w), 1198 (s), 1151 (w), 1125 (w), 1098 (w), 1079 (w), 1009 (s),
968 (m), 945 (m), 919 (s), 880 (s), 763 (s), 728 (s), 677 (m), 646 (m),
620 (w). MS (EI, 70 eV): m/z (%)¼327 (Mþ, 100), 297 (4), 182 (13),
170 (15), 144 (16), 128 (50), 116 (23), 89 (11), 77 (13). HRMS (EI):
calcd for C13H14INO (Mþ): 327.01146, found: 327.010903.
4.4.14. 6-Bromomethyl-4-methyl-3-phenyl-5,6-dihydro-4H-
[1,2]oxazine (4n)
Starting with 2-methyl-1-phenyl-pent-4-en-1-one oxime 3j
(0.567 g, 3.00 mmol) and NBS (0.534 g, 3.00 mmol) in CH2Cl2
(15 mL), 4n was isolated as a brownish viscous oil (0.584 g, 73%).
The product was isolated as an inseparable mixture of di-
astereomers (dr¼1:1). Therefore, most signals are splitted. 1H NMR
Acknowledgements
(250 MHz, CDCl3):
d
¼1.10, 1.18 (d, 3J¼7.2 Hz, 3H, CHCH3), 1.98 (m,
2H, CHCH2CH), 3.07 (m, 1H, CHCH3), 3.47 (m, 1H, CH2I), 3.62 (m, 1H,
CH2I), 4.04 (m, 1H, OCHCH2), 7.36–7.41 (m, 3H, CHAr), 7.41–7.62 (m,
We are grateful to Dr. Tuan T. Dang for his help. Financial support
by the State of Mecklenburg-Vorpommern (scholarship for V.K.)
and by the State of Vietnam (MOET scholarship for T.T.D.) is
gratefully acknowledged.
2H, CHAr). 13C NMR (62.9 MHz, CDCl3):
d¼19.2, 20.2 (CHCH3), 25.4,
27.9 (CHCH3), 30.3, 32.6 (CHCH2CH), 32.8, 33.2 (CH2Br), 70.8, 74.5
(OCH), 126.3, 126.8 (CHAr), 128.4, 128.6 (CHAr), 129.2, 129.5 (CHAr),
134.7 (C), 159.2, 161.9 (C). IR (ATR, cmꢀ1):
~
n
¼3055 (br, w), 2964 (w),
References and notes
2932 (w), 2893 (w), 1588 (w), 1563 (w), 1493 (w), 1452 (w), 1441
(m), 1417 (m), 1376 (m), 1340 (w), 1290 (w), 1262 (m), 1226 (m),
1177 (w), 1138 (w), 1096 (w), 1083 (m), 1043 (m), 1011 (m), 973 (m),
919 (s), 902 (s), 863 (m), 817 (w), 765 (s), 745 (s), 689 (s), 656 (s),
628 (m), 557 (m). MS (GC/MS, 70 eV): m/z (%)¼269 (Mþ, 81Br, 92),
267 (Mþ, 79Br, 93), 188 (7), 174 (90), 146 (17), 132 (45), 117 (90), 104
(78), 91 (42), 77 (98), 55 (100). HRMS (EI): calcd for C12H14NOBr
(Mþ): 267.01146, found: 267.011677.
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