Br?nsted acid-promoted domino reactions: a novel one-pot three-component synthesis of 3,4,5-trisubstituted-3,6-dihydro-2H-1,3-oxazines

Article abstract of DOI:10.1016/j.tetlet.2009.01.002

An efficient and novel one-pot synthesis of 3,4,5-trisubstituted-3,6-dihydro-2H-1,3-oxazine from alkynoates, anilines, and formaldehyde is described. The six-membered N,O-heterocyclic skeleton was constructed via Br?nsted acid-promoted domino hydroaminati

Full text of DOI:10.1016/j.tetlet.2009.01.002

Tetrahedron Letters 50 (2009) 1209–1214
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Tetrahedron Letters
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Brønsted acid-promoted domino reactions: a novel one-pot three-component
synthesis of 3,4,5-trisubstituted-3,6-dihydro-2H-1,3-oxazines
*
Hua Cao, Huan-Feng Jiang , Chao-Rong Qi, Wen-Juan Yao, Huo-Ji Chen
State Key Laboratory for Pulp and Paper Engineering, School of Chemistry and Chemical Engineering, South China University of Technology, 381 Wushan Road,
Guangzhou 510640, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and novel one-pot synthesis of 3,4,5-trisubstituted-3,6-dihydro-2H-1,3-oxazine from alkyno-
ates, anilines, and formaldehyde is described. The six-membered N,O-heterocyclic skeleton was con-
structed via Brønsted acid-promoted domino hydroamination/Prins reaction/cyclization/dehydration
reactions.
Received 19 November 2008
Revised 21 December 2008
Accepted 6 January 2009
Available online 9 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The development of simple synthetic routes to widely used or-
ganic compounds from readily available reagents is one of the ma-
jor tasks in organic synthesis.1 Consequently, domino reactions
including multicomponent reactions (MCRs) have been used as a
powerful tool to achieve this goal.2 At the forefront of these chem-
ical methodologies, these domino processes have created molecu-
lar complexity and diversity from readily accessible starting
materials in one single operation.3 The reactants of the one-pot
MCRs have been involved in the classical Mannich reaction, which
was discovered in 19124 and is one of the most important C–C
bond-forming reactions for production of nitrogenous molecules.5
Bridgehead nitrogen heterocycles are of interest because they con-
stitute an important class of natural and nonnatural products,
many of which exhibit useful biological activity.6
sequential Prins reaction.14,15 Therefore, the key step in this
hypothesis is to screen the suitable reaction conditions for the
two-component cyclization and intramolecular dehydration, and
we chose Brønsted acids to promote this process.
With this concept in mind, our initial experiment was successful,
displaying a modest induction of dimethyl 3-phenyl-3,6-dihydro-
2H-1,3-oxazine-4,5-dicarboxylate (4aa), when we used dichloro-
methane as a solvent and HCl as the Brønsted acid (Table 1, entry
1). Subsequently, other solvents such as MeOH, MeCN, 1,4-dioxane,
toluene, THF, and C2H5OH were employed, and the best result was
obtained when MeOH was used as solvent with a yield of 74 % (Table
1, entries 2–7). Due to ester exchange reaction, only 38 % of 4aa was
Previously, we have reported the preparation of polysubstituted
1,3-oxazine-6-ones7 and pyrimidines8 through domino reactions of
alkynoates, amine, and aldehydes (Scheme 1). These processes not
only represented an elegant procedure for the clean synthesis of
polysubstituted N or N,O-heterocycles, but also opened up a new
methodology in organic synthesis. The inspiring results prompted
us to search for a facile route for the synthesis of other heterocyclic
compounds. Various oxazine compounds have been found to show
versatile bioactivities,9 such as antibiotic,10 antitumor,11 analge-
sic,12 and anticonvulsant activities.13 Although several methods for
the preparation of 1,3-oxazine derivatives have previously been re-
ported,14,15 few have been focused on the MCRs method.
O
R
N
EtO2C
N
R
R1
R1CHO
RNH2
O
COOEt
EtO2C
EtO2C
CH2O
ArNH2
R1CHO
RNH2
O
O
N
EtO2C
N
R
R1
COOEt
Ar
In this Letter, we would like to report the synthesis of a series of
oxazines. According to our retro-synthesis hypothesis (Scheme 2),
the 3,6-dihydro-2H-1,3-oxazine should be cyclized from interme-
diate 5 and formaldehyde under certain reaction conditions. In
connection with our previous work, intermediate 5 has been suc-
cessfully formed via the two-component hydroamination and
CH2O RNH2
EtO2C
EtO2C
R
N
N
R
R1, R= alkyl, aryl
* Corresponding author. Tel.: +86 20 22236518; fax: +86 20 87112906.
E-mail address: jianghf@scut.edu.cn (H.-F. Jiang).
Scheme 1. Divergent pathways for domino reaction.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.002

1210
H. Cao et al. / Tetrahedron Letters 50 (2009) 1209–1214
Table 1
MeOOC
Optimization of reaction conditions for the three-component reactiona
O
NH2
COOMe
MeOOC
N
HCHO
MeO2C
MeO2C
O
CO2Me
COOMe
acid, rt
solvent
N
2a
1a
3
+
+
CH2O
NH2
h
y
3,6-dihydro-2H-1,3-oxazine
d
CO2Me
r
o
a
m
d
c
i
n
y
e
a
c
h
t
l
b
y
i
i
z
o
Entry
Solvent
Acid (mmol)
t (h)
Yield (%)
d
a
n
r
t
a
i
o
t
i
n
o
1
2
3
4
5
6
7
8
9
CH2Cl2
CH3OH
MeCN
1,4-Dioxane
Toluene
THF
C2H5OH
CH3OH
CH3OH
CH3OH
CH3OH
CH3OH
HCl
HCl
HCl
HCl
HCl
HCl
HCl
NaHSO4
NaH2PO4
50
15
15
15
15
15
15
15
15
15
15
15
10
74
24
27
35
32
38
53
41
58
36
37
n
MeOOC
MeOOC
H
MeOOC
MeOOC
OH
/H+
H2C=O
NH
NH
Prins reaction
10
11
12
L-Proline
F3CCOOH
HCOOH
5
4
Scheme 2. Proposed mechanism for the domino reaction.
a
Reaction conditions: dimethyl acetylenedicarboxylate (0.26 mmol), aniline
(0.25 mmol), formaldehyde (1.0 mmol), acid (3 mol %).
b
Determined by GC.
obtained when using C2H5OH as solvent (Table 1, entry 7). We also
explored the reaction using other acids such as NaHSO4, NaH2PO4,
and L-proline, and the desired product 4aa can only be formed in
Table 2
Synthesis of 3,4,5-trisubstituted-3,6-dihydro-2H-1,3-oxazinea
RO2C
O
CO2R
HCl, rt
ROH
RO2C
N
CH2O
+
NH2
+
R'
CO2R
R'
4aa-4ai, 4ba-4bf
2a-2f
3
1a-1b
Entry
Alkynoates
Amines
Product
Yieldb (%)
H3CO2C
H3CO2C
O
O
N
NH2
1
H3CO2C„CO2CH3 1a
70
2a
4aa
H3CO2C
H3CO2C
N
F
F
NH2
2
1a
80
2b
4ab
H3CO2C
H3CO2C
O
N
Br
NH2
3
1a
79
2c
Br
4ac

H. Cao et al. / Tetrahedron Letters 50 (2009) 1209–1214
1211
Table 2 (continued)
Entry
Alkynoates
Amines
Product
Yieldb (%)
H3CO2C
O
H3CO2C
N
H3C
NH2
4
5
6
7
1a
74
75
82
80
2d
CH3
4ad
H3CO2C
H3CO2C
O
N
H3CO
NH2
1a
1a
1a
2e
OCH3
4ae
H3CO2C
H3CO2C
O
N
Cl
NH2
2f
Cl
4af
H3CO2C
H3CO2C
O
N
NH2
Cl
2g
Cl
4ag
H3CO2C
H3CO2C
O
N
Cl
Cl
NH2
8
1a
84
Cl
2h
Cl
N
4ah
H3CO2C
H3CO2C
O
H3C
NH2
9
1a
76
H3C
CH3
2i
CH3
4ai
C2H5O2C
C2H5O2C
O
N
10
EtO2C„CO2Et 1b
2a
71
4ba
(continued on next page)

1212
H. Cao et al. / Tetrahedron Letters 50 (2009) 1209–1214
Table 2 (continued)
Entry
Alkynoates
Amines
Product
Yieldb (%)
EtO2C
EtO2C
O
O
O
N
F
11
12
13
14
1b
2b
78
4bb
4bc
4bd
EtO2C
EtO2C
N
1b
1b
1b
1b
2c
2d
2e
2f
77
72
73
81
Br
EtO2C
EtO2C
N
CH3
O
EtO2C
EtO2C
N
4be
OCH3
EtO2C
EtO2C
O
N
15
4bf
Cl
a
Reaction conditions: dimethyl acetylenedicarboxylate (1.2 mmol), amines (1.0 mmol), formaldehyde (4.0 mmol), HCl (10 mol %).
Determined by GC.
b
41–58% yields (Table 1, entries 8–12). So the optimized reaction con-
ditions are chosen and shown in entry 2.
In conclusion, we have developed a novel and highly efficient
method for the synthesis of 3,4,5-trisubstituted-1,3-oxazine from
alkynoates, amines, and formaldehyde with a simple experimental
workup procedure, and the target molecules are obtained in good
to excellent yields under mild reaction conditions. This domino
hydroamination/Prins reaction/cyclization/dehydration sequence
proceeded smoothly and rapidly owing to the promotion of
Brønsted acids. Further studies and applications on the domino
reactions are ongoing in our laboratory, and will be published in
due course.
On the basis of the above optimization, we proceeded to probe
into the scope of the substrates for the formation of 1,3-oxazine
(Table 2).16 It was pleasing to find that all the reactions proceeded
rapidly and afforded the desired products in good to excellent
yields. For reaction of dimethyl acetylenedicarboxylate 1a, aniline
2, and formaldehyde 3, which are suitable partners in this process
similar yields were obtained (Table 2, entries 1–9). This indicates
that substituents present on the p- and m- of aromatic group of
aniline have no obvious effects on the reaction. But if we used more
sterically hindered o-disubstituted amines such as 2,3-difluoro-
and 2-methylaniline as substrates, the desired products cannot
be formed. When diethyl acetylenedicarboxylate was applied, the
solvent methanol should be exchanged to ethanol in order to avoid
ester exchange reaction (Table 2, entries 10–15).
Acknowledgments
The authors thank the National Natural Science Foundation of
China (Nos. 20772034, 20625205, 20572027, and 20332030) and

H. Cao et al. / Tetrahedron Letters 50 (2009) 1209–1214
1213
Dimethyl 3,6-dihydro-3-p-tolyl-2H-1,3-oxazine-4,5-dicarboxylate (4ad): IR (KBr):
3427, 3013, 2918, 1770, 1696, 1510, 1283, 811. 1H NMR (400 MHz, CDCl3):
d = 7.74 (d, 2H, J = 8.4 Hz), 7.26 (d, 1H, J = 8.4 Hz), 4.49 (d, 1H, J = 10.8 Hz), 4.24
(d, 1H, J = 10.8 Hz), 3.98 (d, 1H, J = 8.8 Hz), 3.89 (d, 1H, J = 9.2 Hz), 3.77 (s, 3H),
3.31 (s, 3H), 2.37 (s, 3H). 13C NMR (100 MHz, CDCl3): d = 193.3, 166.4, 156.1,
137.1, 135.9, 129.8, 119.4, 59.6, 55.1, 53.7, 48.9, 21.1. MS (EI) m/z: 291, 133,
119, 91, 65, 45. Anal. Calcd for C15H17NO5: C, 61.85; H, 5.88; N, 4.81. Found: C,
61.79; H, 5.90; N, 4.76.
Guangdong Natural Science Foundation (No. 07118070) for finan-
cial support of this work.
References and notes
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2004, 4957; (d) Dömling, A. Chem. Rev. 2006, 106, 17; (e) Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134; . Angew.
Chem. 2006, 118, 7292; (f) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem.,
Int.Ed. 2007, 46, 1545; . Angew. Chem. 2007, 119, 1567; (g) Trost, B. M. Angew.
Chem., Int. Ed. 1995, 34, 259; (h) Tietze, L. F. Chem. Rev. 1996, 96, 115; (i)
Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. 1997, 765.
Dimethyl
3,6-dihydro-3-(4-methoxyphenyl)-2H-1,3-oxazine-4,5-dicarboxylate
(4ae): IR (KBr):3411, 3014, 2962, 1767, 1695, 1511, 1094, 786. 1H NMR
(400 MHz, CDCl3) d = 7.76–7.80 (m, 2H), 6.95–7.00 (m, 2H), 4.48 (d, 1H,
J = 10.8 Hz), 4.22 (d, 1H, J = 10.8 Hz), 3.98 (d, 1H, J = 9.2 Hz), 3.89 (d, 1H,
J = 8.8 Hz), 3.83 (s, 3H), 3.77 (s, 3H), 3.32 (s, 3H).13C NMR (100 MHz, CDCl3):
d = 193.2, 166.5, 158.3, 156.0, 131.6, 121.1, 114.4, 72.8, 59.6, 55.6, 55.1, 53.6,
49.1. MS (EI) m/z: 307, 149, 135, 120, 105, 92, 77, 45. Anal. Calcd for
C15H17NO6: C, 58.63; H, 5.58; N, 4.56. Found: C, 57.52; H, 5.61; N, 4.50.
Dimethyl
3-(4-chlorophenyl)-3,6-dihydro-2H-1,3-oxazine-4,5-dicarboxylate
(4af): IR (KBr): 3400, 3010, 2925, 1769, 1701, 1491, 1100, 994. 1H NMR
(400 MHz, CDCl3): d = 7.83 (d, 2H, J = 8.8 Hz), 7.42 (d, 1H, J = 9.2 Hz), 4.48 (d,
1H, J = 10.4 Hz), 4.23 (d, 1H, J = 10.4 Hz), 3.99 (d, 1H, J = 9.2 Hz), 3.88 (d, 1H,
J = 8.8 Hz), 3.77 (s, 3H), 3.31 (s, 3H). 13C NMR (100 MHz, CDCl3): d = 192.7,
166.2, 156.1, 136.9, 132.5, 129.4, 120.6, 72.8, 59.6, 55.1, 53.8, 48.8. MS (EI) m/z:
311, 283, 281, 277, 222, 207, 113, 112, 96, 55.
Dimethyl
3-(3-chlorophenyl)-3,6-dihydro-2H-1,3-oxazine-4,5-dicarboxylate
(4ag): IR (KBr): 3408, 3008, 2905, 1773, 1711, 1485, 1103, 982. 1H NMR
(400 MHz, CDCl3): d = 7.86 (s, 1H), 7.80–7.82 (d, 1H, J = 8.0 Hz), 7.39 (t, 1H,
J = 8.0 Hz), 7.28 (d, 1H, J = 8.0 Hz), 4.48 (d, 1H, J = 10.0 Hz), 4.23 (d, 1H,
J = 10.4 Hz), 3.99 (d, 1H, J = 8.8 Hz), 3.87 (d, 1H, J = 8.8 Hz), 3.77 (s, 3H), 3.31 (s,
3H). 13C NMR (100 MHz, CDCl3): d = 192.7, 166.1, 156.1, 139.4, 135.1, 130.3,
127.0, 119.4, 117.4, 72.8, 59.6, 55.0, 53.7, 48.8. MS (EI) m/z: 311, 283, 281, 224,
222, 168, 113, 111, 75. Anal. Calcd for C14H14ClNO5: C, 53.94; H, 4.53; N, 4.49.
Found: C, 53.85; H, 4.56; N, 4.45.
4. Mannich, C.; Kroesche, W. Arch. Pharm. 1912, 250, 647.
5. (a) Tramontini, M.; Angiolini, L. Tetrahedron 1990, 46, 1791; (b) Kobayashi, S.;
Ishitani, H. Chem. Rev. 1999, 99, 1069; (c) Cordova, A. Acc. Chem. Res. 2004, 37, 102.
6. Swinbourne, J. F.; Hunt, H. J.; Klinkert, G. Adv. Heterocycl. Chem. 1987, 23, 103.
7. (a) Zhang, M.; Jiang, H. F.; Wang, A. Z. Synlett 2007, 3214; (b) Cao, H.;
Wang, X. J.; Jiang, H. F.; Zhu, Q. H.; Zhang, M.; Liu, H. Y. Chem. Eur. J.
2008, 14, 11623.
Dimethyl 3-(3,4-dichlorophenyl)-3,6-dihydro-2H-1,3-oxazine-4,5-dicarboxylate
(4ah): IR (KBr): 3409, 3020, 2983, 1766, 1699, 1501, 893. 1H NMR (400 MHz,
CDCl3): d = 7.98 (d, 1H, J = 1.6 Hz), 7.79 (d, 1H, J = 8.8 Hz), 7.51 (d, 1H,
J = 8.8 Hz), 4.47 (d, 1H, J = 10.0 Hz), 4.21 (d, 1H, J = 10.4 Hz), 3.99 (d, 1H,
J = 9.2 Hz), 3.89 (d, 1H, J = 8.8 Hz), 3.77 (s, 3H), 3.31 (s, 3H). 13C NMR (100 MHz,
CDCl3): d = 192.3, 166.0, 156.1, 137.7, 133.5, 130.9, 130.7, 120.9, 118.5, 72.8,
59.6, 55.1, 53.8, 48.8. MS (EI) m/z: 345, 315, 283, 189, 173, 59. Anal. Calcd for
C14H13Cl2NO5: C, 48.58; H, 3.79; N, 4.05. Found: C, 48.66; H, 3.82; N, 3.98.
Dimethyl 3,6-dihydro-3-(3,4-dimethylphenyl)-2H-1,3-oxazine-4,5-dicarboxylate
(4ai): IR (KBr): 3420, 3031, 2974, 1771, 1703, 1482, 874. 1H NMR (400 MHz,
CDCl3): d = 7.60 (s, 1H), 7.55 (d, 1H, J = 10.0 Hz), 7.19 (d, 1H, J = 8.4 Hz), 4.46 (d,
1H, J = 10.4 Hz), 4.22 (d, 1H, J = 10.8 Hz), 3.96 (d, 1H, J = 9.2 Hz), 3.88 (d, 1H,
J = 9.2 Hz), 3.75 (s, 3H), 3.31 (s, 3H), 2.30 (s, 3H), 3.26 (s, 3H). 13C NMR
(100 MHz, CDCl3): d = 193.2, 166.5, 156.1, 137.7, 136.2, 135.9, 135.8, 130.3,
120.7, 117.1, 72.9, 59.6, 55.2, 53.6, 49.0, 20.1, 19.4. MS (EI) m/z: 305, 288, 148,
147, 132, 105, 77. Anal. Calcd for C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found:
C, 63.05; H, 6.23; N, 4.73.
Diethyl 3,6-dihydro-3-phenyl-2H-1,3-oxazine-4,5-dicarboxylate (4ba): IR (KBr):
3394, 3014, 2980, 1756, 1692, 1481, 720. 1H NMR (400 MHz, CDCl3): d = 7.83
(d, 2H, J = 8.4 Hz), 7.43–7.47 (m, 2H), 7.25–7.31 (m, 1H), 4.50 (d, 1H,
J = 10.4 Hz), 4.18–4.27 (m, 3H), 4.02 (d, 1H, J = 8.8 Hz), 3.89 (d, 1H, J = 9.2 Hz),
3.43–3.49 (q, 2H, J = 7.2 Hz), 1.20–1.23 (t, 3H, J = 7.2 Hz), 1.08 (t, 3H, J = 7.2 Hz).
13C NMR (100 MHz, CDCl3): d = 193.6.165.9, 156.4, 138.4, 129.3, 129.0, 127.1,
125.5, 119.6, 70.8, 67.4, 63.7, 62.3, 55.3, 49.1, 14.7, 13.9. MS (EI) m/z: 305, 275,
229, 199, 119, 105, 77. Anal. Calcd for C16H19NO5: C, 62.94; H, 6.27; N, 4.59.
Found: C, 62.80; H, 6.31; N, 4.65.
Diethyl 3-(4-fluorophenyl)-3,6-dihydro-2H-1,3-oxazine-4,5-dicarboxylate (4bb):
IR (KBr): 3453, 3081, 2985, 1703, 1687, 1089, 915. 1H NMR (400 MHz, CDCl3):
d = 7.74–7.78 (m, 2H), 7.05–7.09 (m, 2H), 4.44 (d, 1H, J = 10.4 Hz), 4.12–4.19
(m, 3H), 3.97 (d, 1H, J = 9.2 Hz), 3.84 (d, 1H, J = 9.2 Hz), 3.39 (q, 2H, J = 7.2 Hz),
1.17 (t, 3H, J = 7.2 Hz), 1.02 (t, 3H, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3):
d = 193.4, 165.8, 162.1, 159.6, 156.3, 154.1, 70.7, 67.3, 62.9, 55.3, 49.3, 14.6,
13.9. MS (EI) m/z: 323, 293, 247, 137, 123, 109, 59. Anal. Calcd for C16H18FNO5:
C, 59.44; H, 5.61; N, 4.33. Found: C, 59.32 H, 5.57; N, 4.39.
Diethyl 3-(4-bromophenyl)-3,6-dihydro-2H-1,3-oxazine-4,5-dicarboxylate (4bc):
IR (KBr): 3409, 2979, 2854, 1769, 1704, 1489, 1224, 1083, 829. 1H NMR
(400 MHz, CDCl3): d = 7.77 (d, 2H, J = 9.2 Hz), 7.59 (d, 2H, J = 10.4 Hz), 4.49 (d,
1H, J = 10.4 Hz), 4.21–4.25 (m, 3H), 4.03 (d, 1H, J = 8.8 Hz), 3.91 (d, 1H,
J = 9.2 Hz), 3.47 (q, 2H, J = 7.2 Hz), 1.25 (t, 3H, J = 7.2 Hz), 1.10 (t, 3H, J = 7.2 Hz).
13C NMR (100 MHz, CDCl3): d = 193.3, 165.8, 156.3, 137.5, 132.4, 121.0, 120.3,
70.7, 67.4, 63.1, 55.3, 48.9, 30.9, 14.7, 14.0. MS (EI) m/z: 385, 383, 309, 307, 199,
197, 185, 183, 59. Anal. Calcd for C16H18BrNO5: C, 50.02; H, 4.72; N, 3.65.
Found: C, 50.14; H, 4.67; N, 3.70.
8. Zhang, M.; Jiang, H. F. J.; Liu, H. L.; Zhu, Q. H. Org. Lett. 2007, 9, 4111.
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16. General procedure: To
a mixture of dimethyl acetylenedicarboxylate 1a
(1 mmol) and aniline 2 (1 mmol), 3 mL methanol was added successively.
The mixture was stirred at room temperature for 10 min. Subsequently,
hydrochloric acid (10 mmol %) and formaldehyde 3 (3.5 mmol) were added,
and the stirring was continued for 5 min. The solution was evaporated to
dryness under reduced pressure, and 8 mL of water was added. The aqueous
solution was extracted with diethyl ether (3 Â 15 mL), and the combined
extract was dried with anhydrous MgSO4. Solvent was removed, and the
residue was separated by column chromatography to give a pure sample 4aa.
Dimethyl 3,6-dihydro-3-phenyl-2H-1,3-oxazine-4,5-dicarboxylate (4aa): IR (KBr):
3395, 3045, 2858, 1769, 1700, 1457, 1091, 753. 1H NMR (400 MHz,
CDCl3):d = 7.86 (d, 2H, J = 8.0 Hz), 7.47 (t, 2H, J = 8.0 Hz), 7.31 (t, 1H,
J = 7.2 Hz), 4.52 (d, 1H, J = 10.8 Hz), 4.27 (d, 1H, J = 10.0 Hz), 3 4.00 (d, 1H,
J = 9.2 Hz), 3.89 (d, 1H, J = 9.2 Hz), 3.77 (s, 3H), 3.32 (s, 3H). 13C NMR (100 MHz,
CDCl3): d = 193.2, 166.4, 156.2, 138.3, 129.3, 127.1, 119.5, 72.8, 59.6, 55.1, 53.7,
48.9. MS (EI) m/z: 277, 247, 200, 119, 91, 77, 59, 45. Anal. Calcd for C14H15NO5:
C, 60.64; H, 5.45; N, 5.05. Found: C, 60.12; H, 5.01; N, 5.10.
Dimethyl
3-(4-fluorophenyl)-3,6-dihydro-2H-1,3-oxazine-4,5-dicarboxylate
(4ab): IR (KBr): 3397, 3022, 2958, 1773, 1704, 1514, 1009, 835. 1H NMR
(400 MHz, CDCl3): d = 7.83–7.86 (m, 2H), 7.14–7.18 (m, 2H), 4.50 (d, 1H,
J = 10.4 Hz), 4.24 (d, 1H, J = 10.4 Hz), 4.00 (d, 1H, J = 9.2 Hz), 3.89 (d, 1H,
J = 10.4 Hz), 3.78 (s, 3H), 3.33 (s, 3H).13C NMR (100 MHz, CDCl3): d = 192.9,
166.2, 156.1, 134.5, 121.5, 121.4, 116.3, 116.1, 59.6, 55.1, 53.7, 49.1. MS (EI) m/
z: 295, 295, 137, 123, 109, 95, 75, 64, 59, 45. Anal. Calcd for C14H14FNO5: C,
56.95; H, 4.78; N, 4.74. Found: C, 56.37; H, 4.82; N, 4.69.
Diethyl 3,6-dihydro-3-p-tolyl-2H-1,3-oxazine-4,5-dicarboxylate (4bd): IR (KBr):
3421, 2981, 2885, 1752, 1698, 1515, 1089, 818. 1H NMR (400 MHz, CDCl3):
d = 7.71 (d, 2H, J = 8.4 Hz), 7.24 (d, 1H, J = 8.4 Hz), 4.48 (d, 1H, J = 10.4 Hz), 4.19–
4.24 (m, 3H), 4.01 (d, 1H, J = J = 8.8 Hz), 3.90 (d, 1H, J = 8.8 Hz), 3.45 (q, 2H,
J = 7.2 Hz), 1.22 (t, 3H, J = 7.2 Hz), 1.08 (t, 3H, J = 7.2 Hz). 13C NMR (100 MHz,
CDC3): d = 193.6, 166.0, 156.3, 137.0, 136.0, 129.8, 125.6, 119.5, 70.8, 67.4, 62.9,
55.3, 49.1, 21.0, 14.7, 13.9. MS (EI) m/z: 319, 289, 243, 214, 133, 119, 105, 91,
59. Anal. Calcd for C17H21NO5: C, 63.94; H, 6.63; N, 4.39. Found: C, 64.06; H,
6.59; N, 4.44.
Dimethyl
3-(4-bromophenyl)-3,6-dihydro-2H-1,3-oxazine-4,5-dicarboxylate
(4ac): IR (KBr): 3400, 3010, 2925, 1769, 1701, 1491, 1100, 994. 1H NMR
(400 MHz, CDCl3): d = 7.81 (d, 2H, J = 8.8 Hz), 7.62 (d, 2H, J = 9.2 Hz), 4.53 (d,
1H, J = 10.4 Hz), 4.27 (d, 1H, J = 10.4 Hz), 4.04 (d, 1H, J = 8.8 Hz), 3.91–3.94 (d,
1H, J = 9.2 Hz), 3.81 (s, 3H), 3.36 (s, 3H). 13C NMR (100 MHz, CDCl3): d = 192.7,
166.2, 156.1, 137.4, 132.8, 120.9, 120.3, 72.8, 59.6, 55.0, 53.8, 48.8. MS (EI) m/z:
357, 355, 199, 197, 185, 183, 169, 90, 59, 45. Anal. Calcd for C14H14BrNO5: C,
47.21; H, 3.96; N, 3.93. Found: C, 47.32; H, 4.00; N, 3.84.
Diethyl
3,6-dihydro-3-(4-methoxyphenyl)-2H-1,3-oxazine-4,5-dicarboxylate
(4be): IR (KBr): 3406, 2980, 2879, 1769, 1695, 1611, 1513, 1089, 834. 1H

1214
H. Cao et al. / Tetrahedron Letters 50 (2009) 1209–1214
NMR (400 MHz, CDCl3): d = 7.72 (d, 2H, J = 9.6 Hz), 6.92 (d, 2H, J = 10.0 Hz), 4.42
IR (KBr): 3403, 2983, 2877, 1771, 1734, 1493, 1280, 1088, 855. 1H NMR
(400 MHz, CDCl3): d = 7.81(d, 1H, J = 8.8 Hz), 7.41 (d, 1H, J = 8.8 Hz), 4.49 (d, 1H,
J = 10.4 Hz), 4.19–4.24 (m, 3H), 4.03 (d, 1H, J = 8.8 Hz), 3.90 (d, 1H, J = 8.8 Hz),
3.46 (q, 2H, J = 7.2 Hz), 1.23 (t, 3H, J = 7.2 Hz), 1.08 (t, 3H, J = 7.2 Hz). 13C NMR
(100 MHz, CDCl3): d = 193.1, 165.8, 156.3, 136.9, 132.4, 129.4, 120.7, 70.8, 67.4,
63.0, 55.3, 49.0. MS (EI) m/z: 339, 309, 263, 236, 153, 139, 59. Anal. Calcd for
C16H18ClNO5: C, 56.56; H, 5.34; N, 4.12. Found: C, 56.63; H, 5.37; N, 4.16..
(d, 1H, J = 10.4 Hz), 4.16–4.20 (m, 3H), 3.97 (d, 1H, J = 9.2 Hz), 3.87 (d, 1H,
J = 9.2 Hz), 3.46 (q, 2H, J = 7.2 Hz), 1.19 (t, 3H, J = 7.2 Hz), 1.05 (t, 3H, J = 7.2 Hz).
13C NMR (100 MHz, CDCl3): d = 193.7, 166.0, 158.3, 156.2, 131.6, 121.2, 114.4,
70.7, 67.3, 62.8, 55.5, 55.3, 49.3, 14.7, 13.9. MS (EI) m/z: 335, 259, 149, 135, 120,
105, 92, 59. Anal. Calcd for C17H21NO6: C, 60.89; H, 6.31; N, 4.18; N, 4.39.
Found: C, 60.78; H, 6.27; N, 4.21.
Diethyl 3-(4-chlorophenyl)-3,6-dihydro-2H-1,3-oxazine-4,5-dicarboxylate (4bf):