One pot three-component regioselective and diastereoselective synthesis of halogenated pyrido[2,1-b][1,3]oxazines

Article abstract of DOI:10.1016/j.tet.2012.08.038

Three-component reactions of 3-substituted pyridines, dimethyl acetylenedicarboxylate (DMAD), and α-halo ketones led to regioselective and stereoselective synthesis of pyrido[2,1-b][1,3]oxazines in high to excellent yields under mild conditions. All the r

Full text of DOI:10.1016/j.tet.2012.08.038

Tetrahedron 68 (2012) 8890e8898
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One pot three-component regioselective and diastereoselective synthesis
of halogenated pyrido[2,1-b][1,3]oxazines
,
b
,
a
Sakineh Asghari a , Ahmad Khabbazi Habibi
*
a Department of Organic Chemistry, Faculty of Chemistry, University of Mazandaran, Babolsar 47416, Iran
b Nano and Biotechnology Research Group, University of Mazandaran, Babolsar, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 May 2012
Received in revised form 31 July 2012
Accepted 13 August 2012
Available online 21 August 2012
Three-component reactions of 3-substituted pyridines, dimethyl acetylenedicarboxylate (DMAD), and a-
halo ketones led to regioselective and stereoselective synthesis of pyrido[2,1-b][1,3]oxazines in high to
excellent yields under mild conditions. All the reactions gave the pyrido[2,1-b][1,3]oxazine derivatives
without formation of any indolizine products.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
3-Substituted pyridine
a
a
-Chloro ketone
-Bromo ketone
Dimethyl acetylenedicarboxylate
Pyrido[2,1-b][1,3]oxazine
1. Introduction
phenanthridine with activated acetylenes, were trapped by
electron-deficient carbonyl groups such as activated aldehydes and
Fused [1,3]oxazines with a bridgehead nitrogen-atom exhibit
remarkable biological and pharmacological properties, and have
both natural and synthetic origins.1e13 These properties include
moxalactam as an antibioticdrug,14e16 PA-824as an antituberculosis
drug,17e20 the alkaloid of myrioneurinol with antitumor activity,21
and hyperaspine, an alkaloid released from a kind of ladybird bee-
tle to repel predators and competitors.22 Due to importance of these
compounds as useful and key intermediates, synthesis of the fused
[1,3]oxazines has received much attention in organic synthesis.23e30
The reported procedures for the synthesis of fused [1,3]oxazines
include: multi-step reactions,31e38 the use of microwave irradia-
tion,39,40 specific catalysts,41e45 and using oxidation reagents in the
reaction media.46,47 In 1932, Diels and Alder reported the formation
of 1,4-dipolar intermediates by reacting pyridine with dimethyl
acetylenedicarboxylate (DMAD).48 In 1967, Huisgen et al. prepared
these 1,4-dipolar intermediates from reaction of nitrogen-
heterocycles such as pyridine and isoquinoline with DMAD and
treated them with different dipolarophiles such as carbon dioxide,
phenyl isocyanate, diethyl mesoxalate, and dimethyl azodicarbox-
ylate.49 Recently, the 1,4-dipolar intermediates derived by reacting
various aromatic N-heterocycles such as pyridine, quinoline, iso-
quinoline, 1-alkyl imidazoles, thiazole, benzothiazole, and
1,2-diketone derivatives,50e54 quinones,55,56ethyl pyruvate,57,58 N-
alkyl isatin,59 benzoyl cyanide,601,3-dimethylalloxan,61 and ben-
zofuran-2,3-diones62 to produce the corresponding fused [1,3]
oxazine derivatives. However, in 2006 Yavari et al. reported these
reactions with ethyl bromopyruvate63 and hexachloroacetone64 as
electron-deficient ketones to afford the indolizine products instead
of the corresponding oxazine derivatives. The indolizine products
have also been reported for the reaction of pyridine and acetylene
esters with phenacyl bromide under microwave conditions using
basic alumina.65 These results encouraged us to study the reactions
of pyridine derivatives with various
and DMAD in more details. Herein, we report three-component
reactions of pyridines 1aed and DMAD with different -halo ke-
a-chloro or a-bromo ketones
a
tones 2aef leading to stereoselective and regioselective haloge-
nated pyrido[2,1-b][1,3]oxazines 3aaedf in high yields without
formation of any corresponding indolizines 4 (Scheme 1).
Similarly, the reactions of pyridine and DMAD with
a-bromo
ketones 5aec afforded the corresponding pyrido[2,1-b][1,3]oxazine
derivatives 6aec in good yields (Scheme 2).
2. Results and discussion
Initially the reaction of pyridine and DMAD with chloroacetone
was carried out at room temperature for 8 h. The reaction
* Corresponding author. E-mail address: s.asghari@umz.ac.ir (S. Asghari).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.038

S. Asghari, A.K. Habibi / Tetrahedron 68 (2012) 8890e8898
8891
COOMe
COOMe
O
COOMe
X
N
N
H
Et2O CH2Cl2
C
COOMe
Cl
X
+
+
Y
Y
and no
r. t.
C
O
N
Y
Z
8-24 h
COOMe
COOMe
Cl
X
2
1
Z
O
4
3aa-df
Y
Z
2
a
b
c
d
e
f
X
H
CH3
Br
1
a
b
c
CH3
CH3
CH3
CH2Cl
Ph
H
CH3
Cl
H
H
Cl
d
Ph
Cl
Scheme 1.
COOMe
COOMe
COOMe
N
O
Et2O/CH2Cl2
C
Br
Y
+
+
O
r. t.
24 h
C
H
Br
N
COOMe
6a-c
5a-c
(a: X=H, b: X=NO2, c: X=Br)
Y
Scheme 2.
proceeded smoothly and afforded compound 3aa in good yield
with low stereoselectively (Table 1, entry 1). In order to examine the
scope and limitations of these reactions, we extended our study to
the reaction was performed with 3-chlorobutan-2-one 2b, which
contains an electron-donating substituent (methyl group), the yield
of the corresponding product 3ab was decreased (Table 1, entry 2),
while using 1,1-dichloroacetone 2c or 1,3-dichloroacetone 2d,
having an electronewithdrawing substituent, the yields of the re-
action products 3ac and 3ad were increased (Table 1, entries 3 and
4). The same trend was observed with 2-chloroacetophenone 2e
and 2,2-dichloroacetophenone 2f (Table 1, entries 5 and 6). These
results imply that the electrophilicity of the carbonyl group plays an
important role in these reactions. However, using 3-substituted
pyridines 1bed instead of pyridine 1a, higher yields of the prod-
ucts with excellent stereoselectivity were observed (Table 1, entries
3baedf). On the other hand, these reactions with 3-substituted
pyridines afforded the regioisomers 3 as sole product without
formation of any other regioisomers 7 (Scheme 3). 1H NMR spectra
of all of the products 3baedf exhibited a singlet at 5.20e5.98 ppm
for the methine proton of the NCHO group, confirming the
observed regioselectivity in the formation of products 3.
the other a-chloro and a-bromo ketones. Compared with 2a, when
Table 1
Reactions of pyridine derivatives, DMAD, and a-chloro ketone derivatives
Entry 1aed
2aef Product Yield of 3 (%)a Major diastereomer
(%)/minor
diastereomer (%)b
1
2
3
4
5
6
1a: (X¼H)
2a
2b
2c
2d
2e
2f
3aa
3ab
3ac
3ad
3ae
3af
71
50
83
82
70
80
(61:39)
(100:0)
(67:33)
(100:0)
(90:10)
(64:36)
7
8
9
10
11
12
1b: (X¼CH3) 2a
3ba
3bb
3bc
3bd
3be
3bf
74
64
87
85
72
83
(100:0)
(100:0)
(91: 9)
(100:0)
(100:0)
(100:0)
2b
2c
2d
2e
2f
Under similar reaction conditions, we carried out the reactions
of pyridine and DMAD with
a-bromo ketone derivatives 5aec
(Table 2). The results in the Table 2 show that the yields of the
products decreased, which could be probably due to the lower
electronegativity of the bromine atom, which makes the carbonyl
13
14
15
16
17
18
1c: (X¼Br)
1d: (X¼Cl)
2a
2b
2c
2d
2e
2f
3ca
3cb
3cc
3cd
3ce
3cf
87
d
(85:15)
d
group less electrophilic than that of the a-chloro ketones (cf. Table 1
93
95
80
93
(100:0)
(100:0)
(100:0)
(100:0)
vs Table 2). However, when 3-substituted pyridines 1bed were
used in these reactions, in all cases a complex mixture was
obtained, which could not be identified.
A proposed mechanism for the reactions is shown in Scheme 4.
On the basis of the well-established chemistry of aromatic N-het-
erocycle nucleophiles,48e65 it is reasonable to assume that the
zwitterionic intermediate 8 results from an initial addition of the
pyridines 1aed to DMAD. Then, intermediate 8 attacks the C]O
19
20
21
22
23
24
2a
2b
2c
2d
2e
2f
3da
3db
3dc
3dd
3de
3df
85
d
94
95
d
91
(71:29)
d
(100:0)
(100:0)
d
(100:0)
group of the a-halo ketone, which leads to the dipolar species 9.
The negative oxygen atom of intermediate 9 can either attack at
position 2 of the pyridinium ring (route a) to produce 3, or at
a
Isolated yield.
b
Determined by 1H NMR spectroscopy.

8892
S. Asghari, A.K. Habibi / Tetrahedron 68 (2012) 8890e8898
COOMe
COOMe
COOMe
C
O
COOMe
N
X
COOMe
Y
X
Et2O-CH2Cl2
Cl
N
H
and no
+
+
Y
Y
C
r.t.
O
O
Z
N
1
COOMe
H
Z
Cl
Cl
X
Z
2
7
3
X= CH3 , Br, Cl
Scheme 3.
position 6 of the pyridinium ring (route b) to form 7. Since the 1H
NMR spectra of the products 3baedf exhibited a singlet for the
methine proton of NCHO group, route a was confirmed for these
reactions.
Table 2
Reactions of pyridine, dimethyl acetylenedicarboxylate, and
derivatives
a
-bromo ketone
Entry
1
1
5aed
Product Yield of 6 (%)a Major diastereomer
(%)/minor diastereomer(%)b
The structure of 3cd was deuced from IR, 1H, 13C NMR, and mass
spectroscopy, elemental analyses as well as X-ray diffraction anal-
ysis. The IR spectrum of 3cd showed two strong signals at 1742 and
1702 cmꢀ1 for the two carbonyl groups of the ester moieties. The 1H
NMR spectrum of 3cd exhibited two singlets at 3.79 and 3.94 ppm
for the two methoxy groups, two doublets at 3.94 and 4.16 ppm
1
2
3
5a, Y¼H
6a
60
71
65
(100:0)
(74:26)
(87:13)
5b, Y¼NO2 6b
5c, Y¼Br
Isolated yield.
6c
a
b
Determined by 1H NMR spectroscopy.
X
:
N
MeO2C
CO2Me
1
MeOOC
COOMe
-
+
N
O
X
8
Cl
Y
Z
route b
route a
COOMe
COOMe
+
N
COOMe
Y
+
N
X
COOMe
Y
-
-
O
O
Cl
Cl
X
Z
Z
9
9
COOMe
COOMe
COOMe
X
COOMe
Y
N
H
N
H
Y
O
O
Cl
Z
Cl
X
Z
7
3
Scheme 4.

S. Asghari, A.K. Habibi / Tetrahedron 68 (2012) 8890e8898
8893
(2JHH¼12.0 Hz) for CH2Cl (AX system), an AB quartet system at 4.07
and 4.09 ppm (2JHH¼11.2 Hz) for another CH2Cl group, a singlet at
5.93 ppm for the methine proton of the NCHO group, a triplet at
5.26 (3JHH¼7.2 Hz) and two doublets at 6.35 and 6.65 ppm
(3JHH¼7.2 Hz) for the 3CH groups of the pyridine moiety. The 13C
NMR spectrum of 3cd exhibited 14 signals in agreement with the
proposed structure. The mass spectrum of this compound dis-
the CH3 should be in the same side of the molecule as 3cc-I or its
enantiomer.
The 1H and 13C NMR spectra of 3aaebf, 3cdedf, and 5aed were
similar to those of 3cc except to their substituents in pyridine and
oxazine moieties, which showed characteristic resonances in the
appropriate regions of the spectra.
ꢁ
ꢁ
played molecular ion peaks at 425 (Mþ , 9), 427 (Mþ þ2, 15), 429
3. Conclusions
ꢁ
ꢁ
(Mþ þ4, 7), and 431 (Mþ þ6, 1), due to the existence of the isotopes
of the chlorine atom (35Cl and 37Cl) and the bromine atom (79Br and
81Br).
In summary, we have developed a highly efficient procedure for
the regioselective and diastereoselective synthesis of pyrido[2,1-b]
Finally, the structure of 3cd was confirmed by a single-crystal X-
ray analysis (Fig. 1).
[1,3]oxazines involving various a-halo ketones and dimethyl ace-
tylenedicarboxylate in the presence of pyridine and 3-substituted
pyridines. Scope and limitations of the reaction are described.
The simplicity of the present procedure also makes it an interesting
alternative to other approaches.
4. Experimental
4.1. General
Dimethyl acetylenedicarboxylates (DMAD), pyridine,
b-chloro
pyridine, -bromo pyridine,
b
b-methyl pyridine, chloroacetone (¼1-
chloropropan-2-one), 1,1-dichloroacetone (¼1,1-dichloropropan-2-
one), 1,3-dichloroacetone (¼1,3-dichloropropan-2-one), 3-chloro-
butan-2-one, 2-chloroacetophenone (¼2-chloro-1-phenylethan-
one), 2,2-dichloroacetophenone (¼2,2-dichloro-1-phenylethan-
one), 2-bromoacetophenone (¼2-bromo-1-phenylethanone), 2-
bromo-4-nitroacetophenone (¼2-bromo-1-(4-nitrophenyl) etha-
none), 2-bromo-4-chloroacetophenone (¼2-bromo-1-(4-chloroph-
enyl) ethanone), and 2,4-dibromoacetophenone (¼2-bromo-1-(4-
bromophenyl) ethanone) were purchased from Fluka and Merck
andused withoutfurtherpurification. Melting points were measured
on an Electrothermal 9100 apparatus. NMR spectra were recorded
with a Bruker DRX-400 AVANCE instrument (400.1 MHz for 1H,
100.6 MHz for 13C) with CDCl3 as solvent. Chemical shifts are given in
parts per million (d) relative to TMS, and coupling constants (J) are
Fig. 1. ORTEP diagram of compound 3cd.
reported in hertz (Hz). IR spectra were recorded on an FT-IR Bruker
vector 22 spectrometer. Mass spectra were recorded on a Finnigan-
Matt 8430 mass spectrometer operating at an ionization potential
of 70 eV. Elemental analyses were performed using a Heraeus CHN-O
Rapid analyzer.
However, compound 3cd contains only one chiral center, but
other products that were formed from asymmetric ketones (2aec
and 2eef), have two and three chiral centers, which could lead to
a mixture of diastereomers. As shown in Fig. 2, compound 3cc
4.2. General procedure
To a stirred solution of the dimethyl acetylenedicarboxylate
(0.25 g, 2 mmol) and the
a-halo ketone derivative (2 mmol) in
CO2Me
CO2Me
N
*
CO2Me
CO2Me
N
*
*
*
CH2Cl2/Et2O (1:4) (10 ml) was added the pyridine derivative
(2 mmol) at room temperature. After completion of the reaction
(8e24 h) as indicated by TLC (n-hexane/EtOAc, 9:1), the solvent
was removed under reduced pressure. For mono chloro ketones
and bromo phenacyl derivatives, the residue was purified by col-
umn chromatography on silica gel (Merck, 230e240 mesh) using
a mixture of n-hexane/EtOAc as eluent to afford pure product. For
dichloro ketones, when 5 mL methanol was added to the residue,
the products precipitated as yellow powders.
Br
Br
H
H
O
O
H3C
H3C
Cl
Cl
Cl
Cl
3cc-I
3cc-II
Fig. 2. Two diastereoisomers of 3cc.
possesses two chiral centers and it can exist as two di-
astereoisomers, namely 3cc-I (RR) or its enantiomer (SS), and 3cc-II
(RS) or its enantiomer (SR). The 1H and 13C NMR spectrum of 3cc
showed only one diastereoisomer. Thus, the reaction is diaster-
eoselective. In order to determine the stereochemistry of the major
products, the nuclear Overhauser effect (NOE) was measured for
compound 3cc as an example. The NOE measurement for 3cc
showed that, when the methine signal of NCHO was irradiated, the
CH3 protons were enhanced by 6%. Thus the methine proton and
4.2.1. Dimethyl
2-(chloromethyl)-2-methyl-2H,9aH-pyrido[2,1-b]
[1,3]oxazine-3,4-dicarboxylate (3aa). Yellow powder, yield (0.45 g,
71%). Mp 103e105 ꢂC. IR (KBr) (nmax/cmꢀ1): 1738 and 1702 (2C]O),
1654 (C]C), 1243 ðCsp2 eOÞ, 773 (CeCl). NMR data for the major
isomer (61%): 1H NMR (400.13 MHz, CDCl3):
d 1.59 (s, 3H, CH3), 3.75
(s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.98 and 4.06 (AB quartet,
2JHH¼10.8Hz, 2H, CH2Cl), 5.25e5.29 (m, 1H, CH), 5.56 (dd,
4
3JHH¼3.2 Hz, JHH¼0.8 Hz, 1H, NCHO), 5.61e5.64 (m, 1H, CH),
6.25e6.30 (m, 2H, CH). 13C NMR (100.6 MHz, CDCl3):
d 24.3 (CH3),

8894
S. Asghari, A.K. Habibi / Tetrahedron 68 (2012) 8890e8898
50.8 (CH2Cl), 52.0 and 53.3 (2OCH3), 77.0 (NCHO), 77.6 (Cq), 100.9
(CH), 113.0 (NC]CCOOMe), 116.8 (CH), 125.3 (CH), 125.5 (CH), 144.7
(NC]CCOOMe), 163.8 and 165.0 (2C]O). NMR data for the minor
(CH2Cl), 48.8 (CH2Cl), 52.3 and 53.3 (2OCH3), 77.7 (Cq), 78.8 (NCHO),
101.8 (CH), 108.9 (NC]CCOOMe), 116.3 (CH), 125.1 (CH), 125.2 (CH),
146.7 (NC]CCOOMe), 163.4 and 164.5 (C]O). MS: m/z (%) 351
ꢁ
ꢁ
ꢁ
isomer (39%): 1H NMR (400.13 MHz, CDCl3):
d
1.66 (s, 3H, CH3), 3.76
(Mþ þ4, 2), 349 (Mþ þ2, 11), 347 (Mþ , 17), 300 (34), 298 (100), 254
(1), 252 (3), 234 (6), 202 (5), 190 (17), 176 (7), 143 (7), 111 (23), 79
(30), 59 (12). Anal. Calcd for C14H15Cl2NO5 (348.18): C, 48.29; H,
4.34; N, 4.02%. Found: C, 47.92; H, 4.18; N, 3.90%.
(s, 3H, OCH3), 3.93 (s, 3H, OCH3), 3.87 and 4.19 (AB quartet,
2JHH¼11.6 Hz, 2H, CH2Cl), 5.25e5.29 (m, 1H, CH), 5.66e5.69 (m, 1H,
3
4
CH), 5.91 (dd, JHH¼3.2 Hz, JHH¼1.2 Hz, 1H, NCHO), 6.25e6.30
(m, 2H, CH). 13C NMR (100.6 MHz, CDCl3):
d 24.90 (CH3), 50.6
(CH2Cl), 50.8 and 53.3 (2OCH3), 75.6 (Cq), 78.3 (NCHO), 101.0
(CH), 112.6 (NC]CCOOMe), 116.1 (CH), 124.9 (CH), 125.1 (CH), 143.9
4.2.5. Dimethyl 2-(chloromethyl)-2-phenyl-2H,9aH-pyrido[2,1-b][1,3]
oxazine-3,4-dicarboxylate (3ae). Yellow powder, yield (0.52 g, 70%).
Mp 108e110 ꢂC. IR (KBr) (nmax/cmꢀ1): 1738 and 1709 (2C]O), 1649
(C]C), 1265 ðCsp2 eOÞ, 1109 ðCsp3 eOÞ, 770 (CeCl). NMR data for the
ꢁ
(NC]CCOOMe), 163.8 and 164.8 (2C]O). MS: m/z (%) 315 (Mþ þ2,
ꢁ
8), 313 (Mþ , 23), 300 (10), 298 (30), 278 (8), 264 (100), 222 (11), 202
(3), 190 (18), 162 (8), 111 (23), 80 (48). Anal. Calcd for C14H16ClNO5
(313.73): C, 53.60; H, 5.14; N, 4.46%. Found: C, 53.40; H, 5.12; N,
4.28%.
major isomer (90%): 1H NMR (400.13 MHz, CDCl3):
d 3.74 (s, 3H,
2
OCH3), 3.99 (s, 3H, OCH3), 4.35 and 4.50 (AB quartet, JHH¼11.2 Hz,
3
4
2H, CH2Cl), 5.21 (td, JHH¼6.6 Hz, JHH¼1.2 Hz, 1H, CH), 5.38e5.44
3
4
(m, 1H, CH), 5.45 (dd, JHH¼3.2 Hz, JHH¼1.2 Hz, 1H, NCHO),
3
4
4.2.2. Dimethyl 2-(1-chloroethyl)-2-methyl-2H,9aH-pyrido[2,1-b][1,3]
oxazine-3,4-dicarboxylate (3ab). Yellow powder, yield (0.33 g, 50%).
Mp 116e117 ꢂC. IR (KBr) (nmax/cmꢀ1): 1743 and 1697 (2C]O), 1655
6.15e6.19 (m, 1H, CH), 6.26 (dt, JHH¼7.6 Hz, JHH¼0.8 Hz, 1H, CH),
7.31e7.39 (m, 5H, 5CH). 13C NMR (100.6 MHz, CDCl3):
d
49.5 (CH2Cl),
52.1 and 53.3 (2OCH3), 78.0 (NCHO), 80.7 (Cq), 101.1 (CH), 108.3
(NC]CCOOMe), 116.1 (CH),125.1 (CH),125.3 (CH), 127.7 (2CH), 128.5
(CH), 128.6 (2CH), 142.0 (Cq), 146.2 (NC]CCOOMe), 164.0 and 165.4
(2C]O). NMR data for the minor isomer (10%): 1H NMR
(C]C), 1240 ðCsp2 eOÞ, 1080 ðCsp3 eOÞ, 771 (CeCl). 1H NMR
3
(400.13 MHz, CDCl3):
d
1.41 (d, JHH¼6.8 Hz, 3H, CH3), 1.69 (s, 3H,
CH3), 3.70 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 4.90 (q, 3JHH¼6.8 Hz, 1H,
3
4
CHCl), 5.28 (dd, JHH¼6.8 Hz, JHH¼0.8 Hz, 1H, CH), 5.54 (dd,
(400.13 MHz, CDCl3): d 3.63 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 4.52
3JHH¼3.6 Hz, JHH¼0.8 Hz, 1H, NCHO), 5.67e5.70 (m, 1H, CH),
and 4.63 (AB quartet, JHH¼12.0 Hz, 2H, CH2Cl), 5.21 (td,
4
2
6.25e6.30 (m, 2H, 2CH). 13C NMR (100.6 MHz, CDCl3):
d 18.9 (CH3),
3JHH¼6.6 Hz, 4JHH¼1.2 Hz, 1H, CH), 5.33e5.35 (m, 1H, CH), 5.45 (dd,
4
24.9 (CH3), 52.1 and 53.2 (2OCH3), 63.2 (CHCl), 77.6 (NCHO), 78.7
(Cq), 101.1 (CH), 115.1 (NC]CCOOMe), 116.5 (CH), 125.1 (CH), 125.3
(CH), 143.9 (NC]CCOOMe), 163.6 and 165.2 (C]O). MS: m/z (%) 329
3JHH¼3.2 Hz, JHH¼1.2 Hz, 1H, NCHO), 6.29e6.30 (m, 1H, CH),
6.35e6.38 (m,1H, CH), 7.31e7.39 (m, 5H, 5CH). 13C NMR (100.6 MHz,
CDCl3):
d 49.3 (CH2Cl), 51.9 and 53.2 (2OCH3), 79.4 (NCHO), 80.7
ꢁ
ꢁ
(Mþ þ2, 7), 327 (Mþ , 21), 264 (100), 222 (33), 190 (18), 163 (12), 111
(25), 80 (59), 59 (13). Anal. Calcd for C15H18ClNO5 (327.76): C, 54.97;
H, 5.54; N, 4.27%. Found: C, 54.82; H, 5.35; N, 4.13%.
(Cq), 101.6 (CH), 108.3 (NC]CCOOMe), 116.7 (CH), 124.9 (CH),
125.0 (CH), 127.0 (2CH), 127.9 (CH), 128.1 (2CH), 140.9 (Cq), 144.9
ꢁ
(NC]CCOOMe), 163.7 and 165.4 (2C]O). MS: m/z (%) 377 (Mþ þ2,
ꢁ
4), 375 (Mþ , 11), 340 (19), 326 (100), 309 (3), 300 (3), 298 (22), 280
4.2.3. Dimethyl 2-(dichloromethyl)-2-methyl-2H,9aH-pyrido[2,1-b]
[1,3]oxazine-3,4-dicarboxylate (3ac). Yellow powder, yield (0.58 g,
83%). Mp 138e140 ꢂC. IR (KBr) (nmax/cmꢀ1): 1741 and 1693 (2C]
O), 1657 (C]C), 1243 ðCsp2 eOÞ, 1074 ðCsp3 eOÞ, 770 (CeCl). NMR
data for the major isomer (67%): 1H NMR (400.13 MHz, CDCl3):
(8), 262 (15), 247 (23), 190 (12), 162 (5), 111 (15), 105 (100), 77 (31),
59 (8). Anal. Calcd for C19H18ClNO5 (375.80): C, 60.72; H, 4.83; N,
3.73%. Found: C, 60.52; H, 4.68; N, 3.62%.
4.2.6. Dimethyl 2-(dichloromethyl)-2-phenyl-2H,9aH-pyrido[2,1-b]
[1,3]oxazine-3,4-dicarboxylate (3af). Yellow powder, yield (0.65 g,
80%). Mp 103e105 ꢂC. IR (KBr) (nmax/cmꢀ1): 1740 and 1701 (2C]O),
1653 (C]C), 1271 ðCsp3 eOÞ, 769 (CeCl). NMR data for the major
d
1.74 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 5.30e5.34
3
4
(m, 1H, CH), 5.60 (dd, JHH¼3.4 Hz, JHH¼1.2 Hz, 1H, NCHO), 5.70
3
3
4
(ddt, JHH¼10.0 Hz, JHH¼3.4 Hz, JHH¼1.2 Hz, 1H, CH), 6.26e6.34
(m, 2H, 2CH), 6.58 (s, 1H, CHCl2). 13C NMR (100.6 MHz, CDCl3):
isomer (64%): 1H NMR (400.13 MHz, CDCl3):
d 3.81 (s, 3H, OCH3),
d
26.3 (CH3), 52.3 and 53.3 (2OCH3), 77.2 (CHCl2), 79.4 (Cq), 80.0
3.93 (s, 3H, OCH3), 5.32 (td, 3JHH¼6.6 Hz, 4JHH¼1.2 Hz, 1H, CH), 5.66
3
4
3
(NCHO), 101.5 (CH), 112.6 (NC]CCOOMe), 116.1 (CH), 125.2 (CH),
125.5 (CH), 145.5 (NC]CCOOMe), 163.4 and 164.9 (C]O). NMR
data for the minor isomer (33%): 1H NMR (400.13 MHz, CDCl3):
(dd, JHH¼3.4 Hz, JHH¼0.8 Hz, 1H, NCHO), 5.82 (ddt, JHH¼9.0 Hz,
3JHH¼3.6 Hz, 4JHH¼1.2 Hz, 1H, CH), 6.30 (dt, 3JHH¼6.8 Hz,
4JHH¼0.8 Hz, 1H, CH), 6.37e6.39 (m, 1H, CH), 6.99 (s, 1H, CHCl2),
7.30e7.41 (m, 3H, 3CH), 7.52e7.55 (m, 2H, 2CH). 13C NMR
d
1.71 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 5.30e5.34
(m, 2H, CH and NCHO), 5.78e5.82 (m, 1H, CH), 6.31e6.35 (m, 2H,
2CH), 6.50 (s, 1H, CHCl2). 13C NMR (100.6 MHz, CDCl3):
24.1
(100.6 MHz, CDCl3):
d 52.5 and 53.3 (2OCH3), 76.8 (CHCl2), 79.3
d
(NCHO), 80.7 (Cq), 101.4 (CH), 114.5 (NC]CCOOMe), 115.1 (CH),
125.8 (CH), 125.9 (CH), 126.6 (2CH), 128.2 (CH), 128.7 (2CH), 140.1
(C), 143.8 (NC]CCOOMe), 163.2 and 166.5 (2C]O). NMR data for
(CH3), 52.2 and 53.3 (OCH3), 77.8 (CHCl2), 77.9 (NCHO), 79.8 (Cq),
101.4 (CH), 112.6 (NC]CCOOMe), 116.5 (CH), 124.8 (CH), 124.9
(CH), 143.8 (NC]CCOOMe), 163.6 and 164.4 (C]O). MS: m/z (%)
the minor isomer (36%): 1H NMR (400.13 MHz, CDCl3):
d 3.70 (s, 3H,
ꢁ
ꢁ
ꢁ
351 (Mþ þ4, 2), 349 (Mþ þ2, 11), 347 (Mþ , 17), 336 (1), 334 (5),
332 (9), 320 (1), 318 (6), 316 (9), 264 (100), 222 (12), 190 (18), 162
(8), 111 (26), 80 (57), 59 (10). Anal. Calcd for C14H15Cl2NO5
(348.18): C, 48.29; H, 4.34; N, 4.02%. Found: C, 48.42; H, 4.51; N,
3.95%.
OCH3), 3.86 (s, 3H, OCH3), 5.45 (td, JHH¼6.6 Hz, JHH¼1.2 Hz, 1H,
3
4
3 4
CH), 6.45 (dd, JHH¼3.8 Hz, JHH¼1.2 Hz, 1H, NCHO), 5.94e5.98 (m,
1H, CH), 6.33e6.37 (m, 1H, CH), 6.37e6.39 (m, 1H, CH), 6.41 (s, 1H,
CHCl2), 7.30e7.41 (m, 3H, 3CH), 7.52e7.55 (m, 2H, 2CH). 13C NMR
(100.6 MHz, CDCl3):
d 52.2 and 53.2 (2OCH3), 77.3 (CHCl2), 76.6
(NCHO), 82.6 (Cq), 102.2 (CH), 114.6 (NC]CCOOMe), 116.7 (CH),
125.0 (CH), 125.9 (CH), 126.7 (2CH), 128.0 (CH), 128.6 (2CH), 141.2
(C), 143.9 (NC]CCOOMe), 163.3 and 164.1 (C]O). MS: m/z (%) 413
4.2.4. Dimethyl 2,2-bis(chloromethyl)-2H,9aH-pyrido[2,1-b][1,3]ox-
azine-3,4-dicarboxylate (3ad). Yellow powder, yield (0.57 g, 82%).
Mp 99e101 ꢂC. IR (KBr) (nmax/cmꢀ1): 1743 and 1704 (2C]O), 1654
(C]C), 1222 ðCsp2 eOÞ, 769 (CeCl). 1H NMR (400.13 MHz, CDCl3):
ꢁ
ꢁ
ꢁ
(Mþ þ4, 1), 411 (Mþ þ2, 6), 409 (Mþ , 9), 376 (3), 374 (8), 326 (100),
298 (6), 264 (4), 221 (4),190 (11),162 (6),129 (8),111 (21),105 (100),
77 (49), 63 (8), 51 (12). Anal. Calcd for C19H17Cl2NO5 (410.25): C,
55.63; H, 4.18; N, 3.41%. Found: C, 55.42; H, 4.06; N, 3.30%.
d
3.77 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 3.95 and 4.16 (AB quartet,
2
2JHH¼12.0 Hz, 2H, CH2Cl), 4.00 and 4.11 (AB quartet, JHH¼10.8 Hz,
3
4
2H, CH2Cl), 5.33 (td, JHH¼6.8 Hz, JHH¼1.2 Hz, 1H, CH), 5.72e5.75
3
4
(m, 1H, CH), 5.92 (dd, JHH¼3.6 Hz, JHH¼0.8 Hz, 1H, NCHO),
6.27e6.32 (m, 2H, 2CH). 13C NMR (100.6 MHz, CDCl3):
48.7
4.2.7. Dimethyl 2-(chloromethyl)-2,9-dimethyl-2H,9aH-pyrido[2,1-b]
[1,3]oxazine-3,4-dicarboxylate (3ba). Yellow powder, yield (0.49 g,
d

S. Asghari, A.K. Habibi / Tetrahedron 68 (2012) 8890e8898
8895
74%). Mp 76e78 ꢂC. IR (KBr) (nmax/cmꢀ1): 1738 and 1707 (2C]O),
1664 (C]C), 1230 ðCsp2 eOÞ, 1040 ðCsp3 eOÞ, 755 (CeCl). NMR data
(362.21): C, 49.74; H, 4.73; N, 3.87%. Found: C, 49.63; H, 4.58; N,
3.72%.
for the major isomer (75%): 1H NMR (400.13 MHz, CDCl3):
d 1.59 (s,
3H, CH3), 1.90 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 3.91 (s, 3H, OCH3),
4.2.10. Dimethyl 2,2-bis(chloromethyl)-9-methyl-2H,9aH-pyrido[2,1-
b][1,3]oxazine-3,4-dicarboxylate (3bd). Yellow powder, yield
(0.62 g, 85%). Mp 128e130 ꢂC. IR (KBr) (nmax/cmꢀ1): 1744 and 1705
(2C]O), 1665 (C]C), 1267 ðCsp2 eOÞ, 1053 ðCsp3 eOÞ, 758 (CeCl). 1H
2
3.95 and 4.05 (AB quartet, JHH¼11.2 Hz, 2H, CH2Cl), 5.22 (dd,
4
3JHH¼7.4 Hz, JHH¼6.0 Hz, 1H, CH), 5.98e6.00 (m, 1H, CH), 5.34 (s,
3
1H, NCHO), 5.98e6.00 (m, 1H, CH), 6.16 (d, JHH¼7.6 Hz, 1H, CH).
13C NMR (100.6 MHz, CDCl3):
d
18.9 (CH3), 24.2 (CH3), 50.8 (CH2Cl),
NMR (400.13 MHz, CDCl3): d1.99 (s, 3H, CH3), 3.77 (s, 3H, OCH3),
2
51.0 (OCH3), 53.2 (OCH3), 80.7 (NCHO), 81.0 (Cq), 101.5 (CH), 112.1
(NC]CCOOMe), 121.1 (CH), 123.0 (CH), 125.1 (C), 145.1 (NC]
CCOOMe), 164.1 and 165.1 (2C]O). NMR data for the minor isomer
3.94 (s, 3H, OCH3), 4.01 (d, JHH¼12.0 Hz, 1H, CHCl), 4.06 and 4.12
2 2
(AB quartet, JHH¼11.2 Hz, 2H, CH2Cl), 4.17 (d, JHH¼12.4 Hz, 1H,
3
3
CHCl), 5.29 (dd, JHH¼7.6 Hz, JHH¼6.4 Hz, 1H, CH), 5.98 (s, 1H,
(25%): 1H NMR (400.13 MHz, CDCl3):
d
1.78 (s, 3H, CH3), 1.96 (s, 3H,
NCHO), 6.01e6.03 (m, 1H, CH), 6.18 (d, JHH¼7.6 Hz, 1H, CH). 13C
3
CH3), 3.75 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.95 and 4.05 (AB
NMR (100.6 MHz, CDCl3): d 19.0 (CH3), 48.3 and 48.5 (2CH2Cl), 52.2
2
3
quartet, JHH¼11.2 Hz, 2H, CH2Cl), 5.23 (t, JHH¼6.4 Hz, 1H, CH),
5.34 (s, 1H, NCHO), 5.98e6.00 (m, 1H, CH), 6.14 (d, 3JHH¼7.2 Hz, 1H,
and 53.3 (2OCH3),77.8 (Cq), 81.5 (NCHO), 102.4 (CH), 107.9 (NC]
CCOOMe), 120.9 (CH), 122.5 (CH), 125.8 (C), 147.0 (NC]CCOOMe),
ꢁ
ꢁ
CH). 13C NMR (100.6 MHz, CDCl3):
d
19.0 (CH3), 24.5 (CH3), 50.2
163.6 and 164.7 (C]O). MS: m/z (%) 365 (Mþ þ4, 1), 363 (Mþ þ2, 6),
ꢁ
(CH2Cl), 50.6 (OCH3), 50.8 (OCH3), 75.7 (NCHO), 77.6 (Cq), 101.6
(CH), 111.8 (NC]CCOOMe), 120.6 (CH), 122.6 (CH), 125.9 (C), 143.5
361 (Mþ , 9), 314 (62), 312 (100), 274 (5), 254 (8), 204 (15), 176 (8),
119 (17), 111 (20), 93 (50), 78 (24), 65 (18). Anal. Calcd for
C15H17Cl2NO5 (362.21): C, 49.74; H, 4.73; N, 3.87%. Found: C, 49.62;
H, 4.58; N, 3.75%.
ꢁ
(NC]CCOOMe), 164.0 and 165.0 (2C]O). MS: m/z (%) 329 (Mþ þ2,
ꢁ
6), 327 (Mþ , 18), 314 (9), 312 (26), 292 (7), 278 (100), 236 (10), 204
(15), 176 (7), 147 (7), 111 (14), 94 (40), 77 (4). Anal. Calcd for
C15H18ClNO5 (327.76): C, 54.97; H, 5.54; N, 4.27%. Found: C, 54.68;
H, 5.30; N, 4.10%.
4.2.11. Dimethyl 2-(chloromethyl)-9-methyl-2-phenyl-2H,9aH-pyr-
ido[2,1-b][1,3]oxazine-3,4-dicarboxylate (3be). Yellow powder, yield
(0.56 g, 72%). Mp 110e112 ꢂC IR (KBr) (nmax/cmꢀ1): 1737 and 1709
(2C]O), 1667 (C]C), 1243 ðCsp2 eOÞ, 1051 ðCsp3 eOÞ, 774 (CeCl). 1H
4.2.8. Dimethyl 2-(1-chloroethyl)-2,9-dimethyl-2H,9aH-pyrido[2,1-
b][1,3]oxazine-3,4-dicarboxylate (3bb). Yellow powder, yield
(0.44 g, 64%). Mp 117e119 ꢂC. IR (KBr) (nmax/cmꢀ1): 1739 and 1702
NMR (400.13 MHz, CDCl3):
d 1.62 (s, 3H, CH3), 3.75 (s, 3H, OCH3),
2
3.99 (s, 3H, OCH3), 4.35 and 4.51 (AB quartet, JHH¼11.2 Hz, 2H,
3
4
(2C]O), 1667 (C]C), 1239 ðCsp2 eOÞ, 1076 ðCsp3 eOÞ, 798 (CeCl).
CH2Cl), 5.16 (dd, JHH¼7.4 Hz, JHH¼6.0 Hz, 1H, CH), 5.20 (br s, 1H,
3
3
1H NMR (400.13 MHz, CDCl3):
d
1.40 (d, JHH¼6.8 Hz, 3H, CH3),
NCHO), 5.87e5.89 (m, 1H, CH), 6.16 (d, JHH¼7.6 Hz, 1H, CH),
1.71 (s, 3H, CH3), 1.92 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 3.90 (s, 3H,
7.31e7.41 (m, 5H, aromatic). 13C NMR (100.6 MHz, CDCl3):
d 18.7
3
3
OCH3), 4.52 (q, JHH¼6.8 Hz, 1H, CHCl), 5.22 (dd, JHH¼7.4 Hz,
(CH3), 49.6 (CH2Cl), 52.0 and 53.3 (2OCH3), 80.8 (NCHO), 81.1 (Cq),
101.7 (CH), 107.1 (NC]CCOOMe), 120.9 (CH), 122.9 (CH), 125.0 (C),
128.0 (2CH), 128.4 (2CH), 128.5 (CH), 142.1 (C), 146.7 (NC]
4JHH¼6.4 Hz, 1H, CH), 5.36 (s, 1H, NCHO), 5.99 (dd, JHH¼6.0 Hz,
3
4JHH¼0.8 Hz, 1H, CH), 6.14 (d, JHH¼7.6 Hz, 1H, CH). 13C NMR
3
ꢁ
(100.6 MHz, CDCl3):
d
18.8 (CH3), 18.9 (CH3), 24.7 (CH3), 52.0 and
CCOOMe), 164.3 and 165.6 (C]O). MS: m/z (%) 391 (Mþ þ2, 5), 389
ꢁ
53.2 (2OCH3), 63.3 (CHCl), 78.7 (NCHO), 80.6 (Cq), 101.7 (CH),
113.8 (NC]CCOOMe), 120.7 (CH), 122.7 (CH), 125.8 (C), 144.3
(Mþ , 15), 355 (25), 340 (100), 294 (9), 278 (11), 262 (13), 247 (20),
204 (15), 176 (8), 129 (7), 111 (25), 105 (100), 77 (34), 59 (8). Anal.
Calcd for C20H20ClNO5 (389.82): C, 61.62; H, 5.17; N, 3.59%. Found:
C, 61.30; H, 4.85; N, 3.28%.
ꢁ
(NC]CCOOMe), 163.9 and 165.3 (C]O). MS: m/z (%) 343 (Mþ þ2,
ꢁ
9), 341 (Mþ , 27), 328 (4), 326 (11), 278 (100), 262 (3), 236 (16),
204 (18), 176 (10), 111 (20), 94 (54), 77 (4). Anal. Calcd for
C16H20ClNO5 (341.79): C, 56.23; H, 5.90; N, 4.10%. Found: C, 55.96;
H, 5.65; N, 3.95%.
4.2.12. Dimethyl 2-(dichloromethyl)-9-methyl-2-phenyl-2H,9aH-pyr-
ido[2,1-b][1,3]oxazine-3,4-dicarboxylate (3bf). Yellow powder, yield
(0.70 g, 83%). Mp 112e113 ꢂC. IR (KBr) (nmax/cmꢀ1): 1731 and 1717
(2C]O), 1663 (C]C), 1265 ðCsp2 eOÞ, 1054 ðCsp3 eOÞ 760 (CeCl). 1H
4.2.9. Dimethyl 2-(dichloromethyl)-2,9-dimethyl-2H,9aH-pyrido[2,1-
b][1,3]oxazine-3,4-dicarboxylate (3bc). Yellow powder, yield
(0.63 g, 87%). Mp 136e138 ꢂC. IR (KBr) (nmax/cmꢀ1): 1735 and 1698
(2C]O), 1667 (C]C), 1244 ðCsp2 eOÞ, 1072 ðCsp3 eOÞ, 781 (CeCl).
NMR data for the major isomer (91%): 1H NMR (400.13 MHz,
NMR (400.13 MHz, CDCl3):
d 2.05 (s, 3H, CH3), 3.81 (s, 3H, OCH3),
3.94 (s, 3H, OCH3), 5.24 (dd, 3JHH¼7.4 Hz, 3JHH¼6.4 Hz, 1H, CH), 5.51
(s, 1H, NCHO), 6.0 (m, 1H, CH), 6.16 (d, 3JHH¼7.2 Hz, 1H, CH), 6.93 (s,
1H, CHCl2), 7.34e7.44 (m, 3H, 3CH), 7.61e7.64 (m, 2H, 2CH). 13C NMR
CDCl3):
d
1.75 (s, 3H, CH3), 1.95 (s, 3H, CH3), 3.75 (s, 3H, OCH3),
(100.6 MHz, CDCl3): d 19.9 (CH3), 52.4 and 53.3 (2OCH3), 81.9
3
3
3.91 (s, 3H, OCH3), 5.27 (dd, JHH¼7.2 Hz, JHH¼6.4 Hz, 1H, CH),
(CHCl2), 82.6 (Cq), 83.5 (CHNO), 102.0 (CH), 111.8 (NC]CCOOMe),
121.8 (CH), 123.4 (CH), 124.7 (C), 127.9 (2CH), 128.1 (C), 128.3 (2CH),
128.7 (CH), 144.6 (NC]CCOOMe), 163.6 and 166.4 (2C]O). MS: m/z
3
4
5.42 (s, 1H, NCHO), 6.03 (dd, JHH¼6.2 Hz, JHH¼1.6 Hz, 1H, CH),
6.17 (d, JHH¼7.6 Hz, 1H, CH), 6.59 (s, 1H, CHCl2). 13C NMR
3
ꢁ
ꢁ
ꢁ
(100.6 MHz, CDCl3):
d
18.9 and 24.0 (2CH3), 52.1 and 53.3 (2OCH3),
(%) 427 (Mþ þ4,1), 425 (Mþ þ2, 6), 423 (Mþ , 9), 390 (2), 388 (6), 340
(71), 318 (50), 278 (11), 260 (12), 233 (8), 204 (12), 176 (6), 143 (10),
111 (13), 105 (100), 77 (50), 59 (17). Anal. Calcd for C20H19Cl2NO5
(424.27): C, 56.62; H, 4.51; N, 3.30%. Found: C, 56.55; H, 4.34; N,
3.18%.
77.3 (CHCl2), 79.9 (Cq), 80.9 (CHNO), 102.2 (CH), 111.5 (NC]
CCOOMe), 121.2 (CH), 122.7 (CH), 125.2 (C), 145.8 (NC]CCOOMe),
163.7 and 165.0 (2C]O). NMR data for the minor isomer (9%): 1H
NMR (400.13 MHz, CDCl3):
d 1.70 (s, 3H, CH3), 1.82 (s, 3H, CH3),
3
3.77 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 5.27 (dd, JHH¼7.2 Hz,
3JHH¼6.4 Hz, 1H, CH), 5.42 (s, 1H, NCHO), 6.03 (dd, JHH¼6.2 Hz,
4.2.13. Dimethyl 9-bromo-2-(chloromethyl)-2-methyl-2H,9aH-pyr-
ido[2,1-b][1,3]oxazine-3,4-dicarboxylate (3ca). Yellow powder, yield
(0.68 g, 87%). Mp 107e109 ꢂC. IR (KBr) (nmax/cmꢀ1): 1738 and 1706
(2C]O), 1651 (C]C), 1241 ðCsp2 eOÞ, 1078 ðCsp3 eOÞ, 755 (CeCl), 531
(CeBr). NMR data for the major isomer (85%): 1H NMR
3
4JHH¼1.6 Hz, 1H, CH), 6.17 (d, 3JHH¼7.6 Hz, 1H, CH), 6.52 (s, 1H, CH).
13C NMR (100.6 MHz, CDCl3):
d 17.7 and 26.4 (2CH3), 52.1 and 53.3
(2OCH3), 77.6 (CHCl2), 79.9 (Cq), 78.6 (CHNO), 102.2 (CH), 116.8
(NC]CCOOMe), 120.7 (CH), 122.7 (CH), 128.8 (Cq), 145.8 (NC]
ꢁ
CCOOMe), 163.7 and 165.0 (2C]O). MS: m/z (%) 365 (Mþ þ4, 2),
(400.13 MHz, CDCl3): d 1.61 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 3.92 (s,
ꢁ
ꢁ
363 (Mþ þ2, 13), 361 (Mþ , 18), 350 (2), 348 (12), 346 (18), 334 (1),
332 (6), 330 (9), 278 (100), 248 (7), 236 (16), 204 (24), 176 (13), 147
(7), 111 (21), 94 (51), 83 (7), 65 (11). Anal. Calcd for C15H17Cl2NO5
3H, OCH3), 3.95 and 4.14 (AB quartet, 2JHH¼11.2 Hz, 2H, CH2Cl), 5.20
(t, 3JHH¼7.0 Hz, 1H, CH), 5.50 (s, 1H, NCHO), 6.35 (d, 3JHH¼7.6 Hz, 1H,
3
CH), 6.63 (d, JHH¼6.8 Hz, 1H, CH). 13C NMR (100.6 MHz, CDCl3):

8896
S. Asghari, A.K. Habibi / Tetrahedron 68 (2012) 8890e8898
d
23.7 (CH3), 50.3 (CH2Cl), 52.2 and 53.3 (2OCH3), 77.9 (NCHO), 81.2
(0.73 g, 80%). Mp 113e115 ꢂC. IR (KBr) (nmax/cmꢀ1): 1740 and 1705
(2C]O), 1651 (C]C), 1261 ðCsp2 eOÞ, 1062 ðCsp3 eOÞ, 780 (CeCl), 556
(Cq),100.3 (CH), 109.7 (C), 116.2 (NC]CCOOMe), 125.1 (CH), 128.0
(CH), 143.5 (NC]CCOOMe), 163.3 and 164.8 (2C]O). NMR data for
(CeBr). 1H NMR (400.13 MHz, CDCl3):
d 3.77 (s, 3H, OCH3), 3.99 (s,
the minor isomer (15%): 1H NMR (400.13 MHz, CDCl3):
d
1.59 (s, 3H,
3H, OCH3), 4.35 and 4.51 (AB quartet, 2JHH¼11.2 Hz, 2H, CH2Cl), 5.13
3
4
4
CH3), 3.78 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.95 and 4.14 (AB
(dd, JHH¼7.8 Hz, JHH¼6.8 Hz, 1H, CH), 5.38 (d, JHH¼0.8 Hz, 1H,
3 4
quartet, 2JHH¼11.2 Hz, 2H, CH2Cl), 5.25 (t, 3JHH¼7.0 Hz, 1H, CH), 5.55
NCHO), 6.32 (dd, JHH¼7.4 Hz, JHH¼0.8 Hz, 1H, CH), 6.53 (d,
3
3
(s, 1H, NCHO), 6.35 (d, JHH¼7.6 Hz, 1H, CH), 6.62 (d, JHH¼7.2 Hz,
3JHH¼6.4 Hz, 1H, CH), 7.35e7.43 (m, 5H, 5CH). 13C NMR (100.6 MHz,
1H, CH). 13C NMR (100.6 MHz, CDCl3):
d
23.7 (CH3), 50.3 (CH2Cl),
CDCl3): d 49.4 (CH2Cl), 52.3 and 53.4 (2OCH3), 81.0 (NCHO), 81.7
52.2 (OCH3), 53.3 (OCH3), 77.9 (NCHO), 81.5 (Cq), 101.0 (CH), 108.0
(C), 116.5 (NC]CCOOMe), 124.8 (CH), 128.2 (CH), 143.5 (NC]
(Cq), 100.4 (CH), 110.0 (NC]CCOOMe), 110.8 (C), 125.0 (CH), 128.0
(CH), 128.1 (2CH), 128.4 (2CH), 128.8 (CH), 140.8 (C), 145.4 (NC]
ꢁ
ꢁ
CCOOMe),163.3 and 164.8 (2C]O). MS: m/z (%) 395 (Mþ þ4, 4), 393
CCOOMe), 163.7 and 165.3 (C]O). MS: m/z (%) 457 (Mþ þ4, 1), 455
ꢁ
ꢁ
ꢁ
ꢁ
(Mþ þ2, 15), 391 (Mþ , 11), 344 (100), 342 (100), 300 (9), 298 (9),
270 (6), 268 (6), 211 (3), 209 (3), 158 (20), 111 (23), 78 (16), 59 (10).
Anal. Calcd for C14H14ClBrNO5 (392.62): C, 42.83; H, 3.85; N, 3.57%.
Found: C, 42.65; H, 3.77; N, 3.48%.
(Mþ þ2, 6), 453 (Mþ , 4), 406 (33), 404 (33), 362 (6), 360 (26), 358
(19), 247 (24), 213 (13), 185 (9), 159 (16), 129 (9), 111 (16), 105 (100),
77 (24), 59 (11). Anal. Calcd for C19H17ClBrNO5 (454.69): C, 50.19; H,
3.77; N, 3.08%. Found: C, 49.85; H, 3.60; N, 2.92%.
4.2.14. Dimethyl 9-bromo-2-(dichloromethyl)-2-methyl-2H,9aH-pyr-
ido[2,1-b][1,3]oxazine-3,4-dicarboxylate (3cc). Yellow powder, yield
(0.80 g, 93%). Mp 167e169 ꢂC. IR (KBr) (nmax/cmꢀ1): 1732 and 1704
(2C]O), 1652 (C]C), 1266 ðCsp2 eOÞ, 1054 ðCsp3 eOÞ, 770 (CeCl); 1H
4.2.17. Dimethyl 9-bromo-2-(dichloromethyl)-2-phenyl-2H,9aH-pyr-
ido[2,1-b][1,3]oxazine-3,4-dicarboxylate (3cf). Yellow powder, yield
(0.91 g, 93%). Mp 154e156 ꢂC. IR (KBr) (nmax/cmꢀ1): 1734 and 1712
(2C]O), 1643 (C]C), 1262 ðCsp2 eOÞ, 1059 ðCsp3 eOÞ, 740 (CeCl). 1H
NMR (400.13 MHz, CDCl3):
d
1.76 (s, 3H, CH3), 3.77 (s, 3H, OCH3),
NMR (400.13 MHz, CDCl3): d 3.81 (s, 3H, OCH3), 3.93 (s, 3H, OCH3),
3.92 (s, 3H, OCH3), 5.25 (dd, 3JHH¼7.2 Hz, 3JHH¼6.8 Hz, 1H, CH), 5.55
5.26 (dd, 3JHH¼7.2 Hz, 3JHH¼6.8 Hz, 1H, CH), 5.70 (s, 1H, NCHO), 6.36
(s, 1H, NCHO), 6.34 (d, 3JHH¼7.2 Hz, 1H, CH), 6.57 (s, 1H, CHCl2), 6.65
(d, JHH¼7.2 Hz, 1H, CH), 6.70 (d, JHH¼6.8 Hz, 1H, CH), 6.92 (s, 1H,
3
3
(d, 3JHH¼6.8 Hz, 1H, CH). 13C NMR (100.6 MHz, CDCl3):
d 23.4 (CH3),
CHCl2), 7.36e7.42 (m, 3H, 3CH), 7.74e7.76 (m, 2H, 2CH). 13C NMR
52.4 and 53.4 (2OCH3), 76.8 (CHCl2), 80.6 (Cq), 81.5 (NCHO), 101.0
(100.6 MHz, CDCl3): d 52.8 and 53.5 (2OCH3), 76.7 (CHCl2), 82.3
(CH), 109.8 (NC]CCOOMe), 115.5 (Cq), 124.8 (CH), 128.2 (CH), 144.2
(NCHO), 83.1 (Cq), 100.8 (CH), 108.7 (Cq), 117.9 (NC]CCOOMe),
125.9 (CH), 127.3 (2CH), 128.5 (2CH), 128.9 (CH), 129.1 (CH), 138.9
(Cq), 142.1 (NC]CCOOMe), 162.7 and 166.3 (C]O). MS: m/z (%) 503
ꢁ
(NC]CCOOMe), 163.0 and 164.7 (C]O). MS: m/z (%) 431 (Mþ þ6, 1),
ꢁ
ꢁ
ꢁ
429 (Mþ þ4, 7), 427 (Mþ þ2, 14), 425 (Mþ , 8), 400 (2), 398 (14), 396
(30), 394 (18), 344 (100), 342 (100), 302 (6), 300 (6), 270 (9), 268 (9),
242 (4), 240 (4), 158 (28), 131 (7), 111 (45), 78 (19), 51 (17). Anal.
Calcd for C14H14Cl2BrNO5 (427.07): C, 39.37; H, 3.30; N, 3.28%.
Found: C, 39.10; H, 3.21; N, 3.18%.
ꢁ
ꢁ
ꢁ
ꢁ
(Mþ þ6, 1), 501 (Mþ þ4, 7), 489 (Mþ þ2, 15), 487 (Mþ , 9), 456 (1),
454 (5), 452 (9), 406 (65), 404 (65), 340 (25), 312 (27), 183 (8), 181
(8), 159 (24), 157 (24), 129 (13), 111 (25), 105 (100), 77 (54), 51 (37).
Anal. Calcd for C19H16Cl2BrNO5 (489.14): C, 46.65; H, 3.30; N, 2.86%.
Found: C, 46.48; H, 3.15; N, 2.78%.
4.2.15. Dimethyl 9-bromo-2,2-bis(chloromethyl)-2H,9aH-pyrido[2,1-
b][1,3]oxazine-3,4-dicarboxylate (3cd). Yellow powder, yield
(0.81 g, 95%). Mp 172e174 ꢂC. IR (KBr) (nmax/cmꢀ1): 1742 and 1702
(2C]O), 1650 (C]C), 1264 ðCsp2 eOÞ, 1059 ðCsp3 eOÞ, 767 (CeCl). 1H
4.2.18. Dimethyl 9-chloro-2-(chloromethyl)-2-methyl-2H,9aH-pyrido
[2,1-b][1,3]oxazine-3,4-dicarboxylate (3da). Yellow powder, yield
(0.60 g, 85%). Mp 111e113 ꢂC. IR (KBr) (nmax/cmꢀ1): 1742 and 1711
(2C]O), 1655 (C]C), 1242 ðCsp2 eOÞ, 1061 ðCsp3 eOÞ, 772 (CeCl).
NMR data for the major isomer (71%): 1H NMR (400.13 MHz,
NMR (400.13 MHz, CDCl3):
d 3.79 (s, 3H, OCH3), 3.94 (s, 3H, OCH3),
2
3.94 (d, JHH¼12.0 Hz, 1H, CHCl), 4.07 and 4.09 (AB quartet,
2
2JHH¼11.2 Hz, 2H, CH2Cl), 4.16 (d, JHH¼12.0 Hz, 1H, CHCl), 5.26 (t,
CDCl3): d 1.61 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 3.92 (s, 3H, OCH3),
3
2
3JHH¼7.2 Hz, 1H, CH), 5.93 (s, 1H, NCHO), 6.35 (d, JHH¼7.2 Hz, 1H,
3.94 and 4.14 (AB quartet, JHH¼11.2 Hz, 2H, CH2Cl), 5.26 (t,
3
3
CH), 6.65 (d, JHH¼6.8 Hz, 1H, CH). 13C NMR (100.6 MHz, CDCl3):
3JHH¼6.8 Hz, 1H, CH), 5.43 (s, 1H, NCHO), 6.29 (d, JHH¼6.8 Hz, 1H,
3
d48.2 and 48.4 (CH2Cl), 52.4 and 53.5 (2OCH3), 78.7 (Cq), 82.1
CH), 6.42 (d, JHH¼6.8 Hz, 1H, CH). 13C NMR (100.6 MHz, CDCl3):
(NCHO), 101.2 (CH), 109.9 (NC]CCOOMe), 117.3 (C), 124.7 (CH),
127.9 (CH), 145.7 (NC]CCOOMe), 163.0 and 164.4 (C]O). MS: m/z
d 23.9 (CH3), 50.2 (CH2Cl), 52.2 and 53.4 (2OCH3), 77.5 (NCHO), 80.2
(Cq), 99.8 (CH), 116.0 (NC]CCOOMe), 120.4 (C), 124.1 (CH), 124.7
(CH), 143.5 (NC]CCOOMe), 163.4 and 164.9 (C]O). NMR data for
ꢁ
ꢁ
ꢁ
ꢁ
(%) 431 (Mþ þ6, 1), 429 (Mþ þ4, 7), 427 (Mþ þ2, 15), 425 (Mþ , 9),
380 (28), 378 (100), 376 (76), 334 (1), 332 (4), 330 (3), 312 (1), 310
(3), 270 (7), 268 (7), 241 (5), 239 (5), 211 (7), 209 (7), 159 (18), 131
(5), 111 (33), 78 (16), 59 (22). Anal. Calcd for C14H14Cl2BrNO5
(427.07): C, 39.37; H, 3.30; N, 3.28%. Found: C, 39.12; H, 3.15; N,
3.10%. Crystal data for 3cd C14H14Cl2BrNO5 (CCDC 878070):
Mw¼427.06, orthorhombic, space group P212121, unit cell di-
the minor isomer (29%): 1H NMR (400.13 MHz, CDCl3):
d 1.76 (s, 3H,
CH3), 3.77 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 3.94 and 4.14 (AB
quartet, 2JHH¼11.2HZ, 2H, CH2Cl), 5.31 (t, 3JHH¼6.8HZ, 1H, CH), 5.48
(s, 1H, NCHO), 6.27 (d, 3JHH¼6.8HZ, 1H, CH), 6.45 (d, 3JHH¼6.8HZ, 1H,
CH). 13C NMR (100.6 MHz, CDCl3):
d 23.5 (CH3), 51.2 (CH2Cl), 52.4
and 53.5 (2OCH3), 77.8 (NCHO), 80.5 (Cq), 100.5 (CH), 115.3 (NC]
CCOOMe), 121.3 (C), 124.2 (CH), 124.3 (CH), 143.5 (NC]CCOOMe),
ꢀ
ꢀ
ꢀ
mensions a¼7.3176(5) A, b¼13.9308(9) A, c¼16.3749(15) A,
ꢁ
ꢁ
3
ꢀ
a¼
b¼
g
¼90.00ꢂ; V¼1669.3(2) A , Z¼4, Dcalcd¼1.699 g cmꢀ3
;
163.4 and 164.9 (C]O). MS: m/z (%) 350 (Mþ þ4, 1), 349 (Mþ þ2, 7),
ꢁ
F(000)¼856, crystal dimension 0.35ꢃ0.25ꢃ0.15 mm, radiation, Mo
347 (Mþ , 9), 336 (2), 334 (12), 332 (18), 314 (2), 312 (6.6), 300 (35),
ꢀ
Ka
(l
¼0.71073 A), 2.92ꢄ2
q
ꢄ29.28, intensity data were collected at
298 (100), 258 (2), 256 (6), 226 (3), 224 (10), 214 (1), 212 (3), 111
(22), 78 (8), 59 (8). Anal. Calcd for C14H15Cl2NO5 (348.17): C, 48.29;
H, 4.34; N, 4.02%. Found: C, 48.65; H, 3.67; N, 3.42%.
298(2) K with a STOE IPDS-II diffractometer, and employing
u
/2
q
scanning technique, in the range of ꢀ10ꢄhꢄ8; ꢀ19ꢄkꢄ16;
ꢀ22ꢄlꢄ18; the structure was solved by a rotation method, all non-
hydrogen atoms were positioned and anisotropic thermal param-
eters refined from 2487 observed reflections with R(into)¼0.0609
by a full-matrix least-squares technique converted to R¼0.1256 and
4.2.19. Dimethyl 9-chloro-2-(dichloromethyl)-2-methyl-2H,9aH-pyr-
ido[2,1-b][1,3]oxazine-3,4-dicarboxylate (3dc). Yellow powder, yield
(0.72 g, 94%). Mp 163e165 ꢂC. IR (KBr) (nmax/cmꢀ1): 1733 and 1705
(2C]O), 1655 (C]C), 1267 ðCsp2 eOÞ, 1060 ðCsp3 eOÞ, 771 (CeCl). 1H
Raw¼0.1122 [I>2s(I)].
NMR (400.13 MHz, CDCl3):
d 1.76 (s, 3H, CH3), 3.77 (s, 3H, OCH3),
4.2.16. Dimethyl 9-bromo-2-(chloromethyl)-2-phenyl-2H,9aH-pyr-
ido[2,1-b][1,3]oxazine-3,4-dicarboxylate (3ce). Yellow powder, yield
3.92 (s, 3H, OCH3), 5.30 (dd, 3JHH¼7.6 Hz, 3JHH¼6.8 Hz, 1H, CH), 5.48
(s, 1H, NCHO), 6.29 (dd, 3JHH¼7.6 Hz, 4JHH¼0.4 Hz, 1H, CH), 6.45 (d,

S. Asghari, A.K. Habibi / Tetrahedron 68 (2012) 8890e8898
8897
3JHH¼6.4 Hz, 1H, CH), 6.58 (s, 1H, CHCl2). 13C NMR (100.6 MHz,
(0.66 g, 71%). Mp 127e129 ꢂC. IR (KBr) (nmax/cmꢀ1): 1739 and 1695
(2C]O), 1655 (C]C), 1240 ðCsp2 eOÞ, 1107 ðCsp3 eOÞ, 525 (CeBr).
NMR data for the major isomer (74%): 1H NMR (400.13 MHz,
CDCl3): d 23.5 (CH3), 52.8 and 53.4 (2OCH3), 76.8 (CHCl2), 80.4 (Cq),
80.5 (NCHO), 100.5 (CH), 115.5 (NC]CCOOMe), 120.5 (C), 124.2
(CH), 124.3 (CH), 144.3 (NC]CCOOMe), 163.0 and 164.7 (C]O). MS:
CDCl3):
d 3.77 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 4.26 and 4.39 (AB
ꢁ
ꢁ
ꢁ
m/z (%) 385 (Mþ þ4, 1.5), 383 (Mþ þ2, 5), 381 (Mþ , 5), 300 (33), 298
(100), 258 (2), 256 (5), 226 (7), 224 (6), 167 (4),111 (19), 78 (7), 59
(7). Anal. Calcd for C14H14Cl3NO5 (382.62): C, 43.95; H, 3.69; N,
3.66%. Found: C, 43.68; H, 3.52; N, 3.48%.
quartet, 2JHH¼10.4 Hz, 2H, CH2Br), 5.28 (td, 3JHH¼6.6 Hz,
4JHH¼0.8 Hz, 1H, CH), 5.36 (dd, JHH¼2.8 Hz, JHH¼1.2 Hz, 1H,
3
4
NCHO), 5.41e5.43 (m, 1H, CH), 6.22 (ddt, 3JHH¼9.6 Hz, 3JHH¼6.0 Hz,
4JHH¼1.2 Hz, 1H, CH), 6.28 (dt, JHH¼7.6 Hz, JHH¼1.2 Hz, 1H, CH),
3
4
7.61 (d, JHH¼9.2 Hz, 2H, 2CH), 8.25 (d, JHH¼9.2 Hz, 2H, 2CH). 13
C
3
3
4.2.20. Dimethyl 9-chloro-2,2-bis(chloromethyl)-2H,9aH-pyrido[2,1-
b][1,3]oxazine-3,4-dicarboxylate (3dd). Yellow powder, yield
(0.72 g, 95%). Mp 164e166 ꢂC. IR (KBr) (nmax/cmꢀ1): 1742 and 1704
(2C]O), 1653 (C]C), 1266 ðCsp2 eOÞ, 1064 ðCsp3 eOÞ, 783 (CeCl). 1H
NMR (100.6 MHz, CDCl3): d 38.3 (CH2Br), 52.3 and 53.5 (2OCH3),
78.4 (NCHO), 79.1 (Cq), 101.7 (CH), 107.7 (NC]CCOOMe), 115.8 (CH),
123.8 (CH), 125.1 (CH), 125.5 (2CH), 128.7 (CH), 128.8 (2CH), 146.7
(Cipso),148.5 (NC]CCOOMe),163.6 and 165.0 (2C]O). NMR data for
NMR (400.13 MHz, CDCl3):
d
3.79 (s, 3H, OCH3), 3.94 (s, 3H, OCH3),
the minor isomer (26%): 1H NMR (400.13 MHz, CDCl3):
d 3.63 (s, 3H,
3.94 (d, 2JHH¼12.0 Hz, 1H, CHCl), 4.07 and 4.09 (d, 2JHH¼11.2 Hz, 2H,
OCH3), 3.91 (s, 3H, OCH3), 4.37 and 4.55 (AB quartet, 2JHH¼11.6 Hz,
2
3
3
CH2Cl), 4.16 (d, JHH¼12.0 Hz, 1H, CHCl), 5.31 (dd, JHH¼7.2 Hz,
2H, CH2Br), 5.77e5.81 (m, 1H, CH), 6.02 (dd, JHH¼3.2 Hz,
3JHH¼6.8 Hz, 1H, CH), 5.87 (s, 1H, NCHO), 6.30 (d, JHH¼7.2 Hz, 1H,
4JHH¼1.2 Hz, 1H, NCHO), 5.38e5.40 (m, 1H, CH), 6.31e6.36 (m, 1H,
3
3
3
4
CH), 6.44 (d, JHH¼6.8 Hz, 1H, CH). 13C NMR (100.6 MHz, CDCl3):
CH), 6.38 (dt, JHH¼7.2 Hz, JHH¼0.8 Hz, 1H, CH), 7.73 (d,
3
d
48.3 (CH2Cl), 48.4 (CH2Cl), 52.4 and 53.5 (2OCH3), 78.6 (Cq), 81.2
3JHH¼9.2 Hz, 2H, 2CH), 8.18 (d, JHH¼9.2 Hz, 2H, 2CH). 13C NMR
(NCHO), 100.6 (CH), 111.8 (NC]CCOOMe), 120.8 (C), 126.0 (CH),
124.0 (CH), 145.8 (NC]CCOOMe), 163.0 and 164.4 (C]O). MS: m/z
(100.6 MHz, CDCl3): d 36.6 (CH2Br), 52.1 and 54.3 (2OCH3), 77.2
(NCHO), 79.2 (Cq), 102.4 (CH), 107.7 (NC]CCOOMe), 116.6 (CH),
123.6 (CH), 124.1 (CH), 124.8 (2CH), 125.2 (CH), 126.0 (2CH), 146.7
(Cq), 147.6 (NC]CCOOMe), 163.6 and 165.0 (2C]O). MS: m/z (%)
ꢁ
ꢁ
ꢁ
ꢁ
(%) 387 (Mþ þ6, 1), 385 (Mþ þ4, 9), 383 (Mþ þ2, 27), 381 (Mþ , 27),
336 (11), 334 (67), 332 (100), 352 (3), 350 (3), 288 (4), 286 (6), 226
(3), 224 (8), 151 (18), 129 (12), 111 (19), 77 (12), 79 (4), 51 (13). Anal.
Calcd for C14H14Cl3NO5 (382.62): C, 43.95; H, 3.69; N, 3.66%. Found:
C, 43.65; H, 3.55; N, 3.48%.
ꢁ
ꢁ
466 (Mþ þ2, 2), 464 (Mþ , 2), 385 (27), 371 (31), 325 (7), 222 (7), 191
(15), 150 (100), 111 (100), 79 (100), 52 (93). Anal. Calcd for
C19H17BrN2O5 (465.25): C, 49.05; H, 3.68; N, 6.02%. Found: C, 48.65;
H, 3.48; N, 5.85%.
4.2.21. Dimethyl 9-chloro-2-(dichloromethyl)-2-phenyl-2H,9aH-pyr-
ido[2,1-b][1,3]oxazine-3,4-dicarboxylate (3df). Yellow powder, yield
(0.81 g, 91%). Mp 149e151 ꢂC. IR (KBr) (nmax/cmꢀ1): 1733 and 1705
(2C]O), 1645 (C]C), 1260 ðCsp2 eOÞ, 1063 ðCsp3 eOÞ, 769 (CeCl). 1H
4.2.24. Dimethyl 2-(bromomethyl)-2-(4-bromophenyl)-2H,9aH-pyr-
ido[2,1-b][1,3]oxazine-3,4-dicarboxylate (6c). Yellow powder, yield
(0.65 g, 65%). Mp 129e131 ꢂC. IR (KBr) (nmax/cmꢀ1): 1739 and 1695
(2C]O), 1655 (C]C), 1240 ðCsp2 eOÞ, 1107 ðCsp3 eOÞ, 525 (CeBr).
NMR data for the major isomer (87%): 1H NMR (400.13 MHz,
NMR (400.13 MHz, CDCl3):
d 3.82 (s, 3H, OCH3), 3.93 (s, 3H, OCH3),
5.32 (dd, 3JHH¼7.2 Hz, 3JHH¼6.8 Hz, 1H, CH), 5.64 (s, 1H, NCHO), 6.31
3
3
(d, JHH¼7.2 Hz, 1H, CH), 6.50 (d, JHH¼6.8 Hz, 1H, CH), 6.93 (s, 1H,
CDCl3): d 3.74 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 4.22 and 4.39 (AB
CH), 7.36e7.42 (m, 3H, 3CH), 7.70e7.72 (m, 2H, 2CH). 13C NMR
quartet, JHH¼10.40 Hz, 2H, CH2Br), 5.24 (td, JHH¼7.0 Hz,
2
3
(100.6 MHz, CDCl3):
d 52.8 and 53.5 (2OCH3), 76.7 (CHCl2), 81.6
4JHH¼1.2 Hz, 1H, CH), 5.35e5.39 (m, 2H, CH and NCHO), 6.16e6.21
3
4
(NCHO), 83.0 (Cq), 100.2 (CH), 117.9 (NC]CCOOMe), 119.7 (Cq),
125.0 (CH), 125.4 (CH), 127.0 (2CH), 128.6 (2CH), 128.8 (CH), 139.1
(Cq), 14.1 (NC]CCOOMe), 162.8 and 166.4 (C]O). MS: m/z (%) 447
(m, 1H, CH), 6.26 (dt, JHH¼7.6 Hz, JHH¼1.2 Hz, 1H, CH), 7.27 (d,
3JHH¼8.8 Hz, 2H, 2CH), 7.51 (d, JHH¼8.8 Hz, 2H, 2CH). 13C NMR
3
(100.6 MHz, CDCl3):
d 38.7 (CH2Br), 52.2 and 53.4 (2OCH3), 78.1
ꢁ
ꢁ
ꢁ
(Mþ þ4, 3), 445 (Mþ þ2, 9), 443 (Mþ , 9), 412 (1), 410 (6), 408 (9),
362 (27), 360 (82), 348 (23), 332 (1), 330 (3), 295 (5), 247 (12), 224
(7), 167 (6), 139 (12), 111 (24), 105 (100), 77 (73), 51 (31). Anal. Calcd
for C19H16Cl3NO5 (444.69): C, 51.32; H, 3.63; N, 3.15%. Found: C,
51.12; H, 3.51; 2.98%.
(NCHO), 79.1 (Cq), 101.4 (CH), 108.4 (NC]CCOOMe), 116.0 (CH),
122.8 (CH), 125.2 (CH), 125.3 (2CH), 129.5 (CH), 131.7 (2CH), 140.9
(Cq), 146.3 (NC]CCOOMe), 163.9 and 165.2 (2C]O). NMR data for
the minor isomer (13%): 1H NMR (400.13 MHz, CDCl3):
d 3.63 (s, 3H,
OCH3), 3.91 (s, 3H, OCH3), 4.37 and 4.46 (AB quartet, 2JHH¼11.6 Hz,
3
3
4
2H, CH2Br), 5.75 (td, JHH¼9.8 Hz, JHH¼3.6 Hz, JHH¼0.8 Hz, 1H,
3
4
4.2.22. Dimethyl 2-(bromomethyl)-2-phenyl-2H,9aH-pyrido[2,1-b]
[1,3]oxazine-3,4-dicarboxylate (6a). Yellow powder, yield (0.50 g,
60%). Mp 127e129 ꢂC. IR (KBr) (nmax/cmꢀ1): 1741 and 1707 (2C]O),
1649 (C]C), 1263 ðCsp2 eOÞ, 1107 ðCsp3 eOÞ, 524 (CeBr). 1H NMR
CH), 6.05 (dd, JHH¼3.2 Hz, JHH¼1.2 Hz, 1H, NCHO), 5.35e5.39 (m,
1H, CH), 6.30 (ddt, 3JHH¼10.0 Hz, 3JHH¼6.0 Hz, 4JHH¼1.2 Hz, 1H, CH),
6.34 (dt, 3JHH¼7.6 Hz, 4JHH¼1.2 Hz, 1H, CH), 7.27 (d, 3JHH¼8.8 Hz, 2H,
2CH), 7.51 (d, 3JHH¼8.8 Hz, 2H, 2CH). 13C NMR (100.6 MHz, CDCl3):
(400.13 MHz, CDCl3):
d
3.75 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 4.28
d 37.4 (CH2Br), 52.0 and 53.3 (2OCH3), 79.5 (NCHO), 77.2 (Cq), 101.9
2
and 4.44 (AB quartet, JHH¼10.4 Hz, 2H, CH2Br), 5.22 (td,
(CH), 108.4 (NC]CCOOMe), 116.6 (CH), 122.0 (CH), 124.9 (CH), 125.0
(CH), 129.2 (CH), 131.1 (2CH), 139.8 (Cq), 144.1 (NC]CCOOMe), 163.4
3JHH¼6.8 Hz, 4JHH¼0.8 Hz, 1H, CH), 5.36e5.40 (m, 1H, CH), 5.42 (dd,
ꢁ
ꢁ
4
3
3JHH¼3.6 Hz, JHH¼1.2 Hz, 1H, CH), 6.17 (ddt, JHH¼8.8 Hz,
3JHH¼6.0 Hz, 4JHH¼1.2 Hz, 1H, CH), 6.26 (dt, 3JHH¼7.6 Hz,
4JHH¼1.2 Hz, 1H, CH), 7.29e7.39 (m, 5H, 5CH). 13C NMR (100.6 MHz,
and 164.3 (2C]O). MS: m/z (%) 501 (Mþ þ4, 1), 449 (Mþ þ2, 2), 497
ꢁ
(Mþ , 1), 420 (20), 418 (20), 405 (19), 403 (19), 360 (3), 358 (3), 339
(4), 280 (2), 278 (4), 276 (2), 262 (14), 185 (100), 183 (100), 157 (21),
155 (21), 111 (38), 79 (48). Anal. Calcd for C19H17Br2NO5 (499.15): C,
45.72; H, 3.43; N, 2.81%. Found: C, 45.51; H, 3.35; N, 2.70%.
CDCl3): d39.1 (CH2Br), 52.1 and 53.3 (2OCH3), 78.0 (NCHO), 80.0
(Cq), 101.1 (CH), 109.2 (NC]CCOOMe), 116.1 (CH), 125.1 (CH), 125.3
(CH), 127.7 (2CH), 128.5 (CH), 128.6 (2CH), 141.9 (Cq), 146.0 (NC]
ꢁ
CCOOMe), 160.0 and 165.4 (2C]O). MS: m/z (%) 421 (Mþ þ2, 7), 419
ꢁ
(Mþ , 7), 419 (94), 329 (100), 308 (5), 280 (16), 262 (20), 248 (7), 234
References and notes
(4), 190 (10), 162 (5), 145 (6), 129 (8), 111 (16), 105 (100), 77 (30), 59
(9). Anal. Calcd for C19H18BrNO5 (420.25): C, 54.30; H, 4.32; N,
3.33%. Found: C, 53.95; H, 4.05; N, 3.21%.
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