Construction of functionalized 2,3-dihydro-1,4-benzoxazines via [5 + 1] annulations of 2-halo-1,3-dicarbonyl compounds with imines

Article abstract of DOI:10.1039/c2ob25927c

A series of functionalized 2,3-dihydro-1,4-benzoxazines were obtained in moderate to excellent yields via domino [5 + 1] annulations of 2-halo-1,3-dicarbonyl compounds 2 with imines 1 under mild conditions and the application of this method in the synthesis of bioactive analogues, such as functionalized tetracyclic-1,4-benzoxazines which contain two new heterocyclic rings and one quaternary carbon center has also been developed.

Full text of DOI:10.1039/c2ob25927c

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PAPER
Construction of functionalized 2,3-dihydro-1,4-benzoxazines via
[5 + 1] annulations of 2-halo-1,3-dicarbonyl compounds with imines†
Ya-Ru Zhang, Jian-Wu Xie,* Xu-Jiao Huang and Wei-Dong Zhu*
Received 14th May 2012, Accepted 14th June 2012
DOI: 10.1039/c2ob25927c
A series of functionalized 2,3-dihydro-1,4-benzoxazines were obtained in moderate to excellent yields via
domino [5 + 1] annulations of 2-halo-1,3-dicarbonyl compounds 2 with imines 1 under mild conditions
and the application of this method in the synthesis of bioactive analogues, such as functionalized
tetracyclic-1,4-benzoxazines which contain two new heterocyclic rings and one quaternary carbon center
has also been developed.
imines 1 with moderate to good enantioselectivities catalyzed by
readily available chiral phase-transfer catalysts (PTC).
Introduction
2,3-Dihydro-1,4-benzoxazines are an important class of hetero-
cyclic molecules, principally because this heterocyclic ring is an
important recognition element in many natural products,1 bio-
logically active and medicinally significant compounds.2 Natural
products and pharmaceuticals possessing the 1,4-benzoxazine
skeleton exhibit a wide range of biological activities.3–11 For
example, 1,4-benzoxazine derivatives are potential drugs for
treating infections,3 heart disease,4 diabetes,5 neurodegenera-
tive,7,8 inflammatory,7,8 autoimmune7,8 and cardiovascular dis-
orders.7,8 Some additional biologically active 1,4-benzoxazines
have also been described in a broader-context review.11 Due to
the importance of 1,4-benzoxazines, different approaches
towards the synthesis of 2-amino-2-chromene derivatives have
been reported over the past few decades, and 1,4-benzoxazin
derivatives are often achieved from substituted 2-aminophenols
or substituted 2-nitrophenols.12,13 However, most of the reported
methods have one or more of the following drawbacks: such as
low yields owing to the somewhat lengthy, toxic catalysts used,
complicated reaction assembly, and tedious workup etc. As part
of our medicinal chemistry research program, we required a
robust facile synthesis of 1,4-benzoxazine derivatives wherein
we could vary the different substitutions. Herein we report an
efficient, mild, and convenient method for the preparation of
these derivatives via [5 + 1] annulation (Mannich–alkylation).
Notably, we also present the first asymmetric [5 + 1] annulation
(Mannich–alkylation) of diethyl α-bromomalonate (DBM) with
In the course of our investigation on the use of 2-halo-
1,3-dicarbonyl compounds (e.g. diethyl α-bromomalonate and
diethyl α-chloromalonate) in organic synthesis, the 2-halo-
1,3-dicarbonyl compounds turned out to be highly reactive and
versatile. Especially, the bromo or chloro group could behave as
a better leaving group in the reaction. Recently, a series of func-
tionalized 2,3-dihydrobenzofurans were easily obtained in
moderate to excellent yields under mild conditions from 2-halo-
1,3-dicarbonyl compounds in our group (eqn (1)).14 Encouraged
by the successful results mentioned above, we conceived that
1,4-benzoxazine derivatives 3 could be synthesized via the
[5 + 1] annulations of diethyl α-bromomalonate (DBM) with
imines 1 (eqn (2)).
ð1Þ
ð2Þ
Key Laboratory of the Ministry of Education for Advanced Catalysis
Materials, Department of Chemistry and Life Science, Zhejiang Normal
University, Jinhua 321004, P.R. of China. E-mail: xiejw@zjnu.cn,
weidongzhu@zjnu.cn; Fax: (+86) 579 82282610
Results and discussion
†Electronic supplementary information (ESI) available. CCDC
881882–881884. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c2ob25927c
The initial investigation started with the reaction of (E)-2-(benzyl-
ideneamino)phenol 1a with diethyl α-bromomalonate (DBM)
6554 | Org. Biomol. Chem., 2012, 10, 6554–6561
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Table 1 Reaction of (E)-2-(benzylideneamino)phenol 1a and diethyl
α-bromomalonate 2a under different conditionsa
Table 2 Synthesis
of
different
substituted
2,3-dihydro-1,4-
benzoxazinesa
Entry
Base
Solvent
Yieldb (%)
1
2
DBU
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
DCM
DMSO
Ethanol
H2O
83
0
Entry
R1
R2 (1)
2
Yieldb (%) (3)
87 (3aa)
72 (3ba)
71 (3ca)
69 (3da)
67 (3ea)
83 (3fa)
81 (3ga)
81 (3ha)
86 (3ia)
79 (3ja)
81 (3ka)
75 (3la)
DABCO
KOAc
K2CO3
KOH
KOH
KOH
KOH
3c
4c
5c
6c
7c
8c
9c
10c
63
78
87
65
74
21
3
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
4-Me
5-Me
4-Cl
5-Cl
H
H
H
Ph (1a)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
p-CH3C6H4 (1b)
p-CH3OC6H4 (1c)
o-CH3OC6H4 (1d)
m-CH3OC6H4(1e)
p-ClC6H4(1f)
m-ClC6H4 (1g)
o-ClC6H4 (1h)
p-BrC6H4 (1i)
o-BrC6H4 (1j)
p-NO2C6H4 (1k)
o-NO2C6H4 (1l)
Ph (1m)
Ph (1n)
Ph (1o)
Ph (1p)
C2H5 (1q)
Ph (1a)
Ph (1a)
Ph (1a)
KOH
KOH
0
9
a Otherwise noted, the reactions performed with 0.10 mmol of 1a,
0.20 mmol of 2a, 100 mol% of base in 1 mL solvent at room
temperature. b Isolated yield. c 20 mol% of TBAB was used.
10
11
12
13
14
15
16
17c
18
19
20
76 (3ma)
73 (3na)
82 (3oa)
85 (3pa)
51 (3qa)
83 (3ab)
56 (3ac)
2a. As could have been expected, the domino reaction proceeded
to provide desired product 3aa in good yield when the reaction
was carried out in the presence of DBU (1,8-diazabicyclo[5,4,0]-
undec-7-ene) in CH3CN at room temperature for 20 h (83%
yield, Table 1, entry 1). Other bases such as KOAc and K2CO3,
were also screened and moderate yields were obtained (entries
3–4). Weaker base DABCO (1,4-diazabicyclo[2.2.2]octane) was
inert in this reaction (entry 2). On the contrary, the best result
was obtained when the reaction was catalyzed with stronger base
KOH (87% yield, entry 5). Subsequently, we investigated the
effects of solvent on the reactivity. Low yields were obtained,
when other solvents, such as toluene and DCM, were used
(entries 6–7). When the reaction was carried out in strong polar
solvents, poor results were achieved due to decomposition of
imine 1a (entries 8–10). Based on the above screening, the
optimal reaction conditions (1.0 equiv 1a and 2.0 equiv 2a in
CH3CN with 1 equiv KOH and 0.2 equiv TBAB, room temp-
erature) were established.
H
53 (dr 66 : 34)d (3ad)
a Otherwise noted, the reactions performed with 0.10 mmol of 1,
0.20 mmol of 2, 20 mol% of TBAB, 100 mol% of KOH in 1 mL of
CH3CN at room temperature. b Isolated yield. c 0.10 mmol of propanal,
0.10 mmol of 2-aminophenol and 4 Å MS (10.0 mg) were stirred in
1 mL of CH2Cl2 under N2 for 1 h, then 0.10 mmol of 2a, 20 mol% of
TBAB, 100 mol% of KOH were added. d Determined by 1H NMR.
With the optimal reaction conditions in hand, the scope of the
domino [5 + 1] annulation of 2-halo-1,3-dicarbonyl compounds
2 with imines 1 was explored (Table 2). To assess the impact of
the structural and functional motifs on the reaction, we tested a
range of imines 1. For all cases, 2-halo-1,3-dicarbonyl com-
pounds 2 reacted with imines 1 led to the corresponding substi-
tuted 2,3-dihydro-1,4-benzoxazines 3 in moderate to good
yields. High yields were obtained in [5 + 1] annulation of
diethyl α-bromomalonate (DBM) 2a with electron-withdrawing
substituents on the aryl ring of imines 1 (Table 2, entries 6–12
and 15–16). On the contrary, electron-donating substituents on
the aryl ring of imines 1 tended to decrease the reactivity and
yields (entries 2–5 and 13–14). Imines 1 with electron-withdraw-
ing substituents or electron-donating substituents on the ortho,
meta or para positions (R2) afforded 2,3-dihydro-1,4-benzoxa-
zines 3 with slightly inferior yields (entries 3–5 and 6–8). The
reaction with aliphatic imine 1q gave desired product 3qa in
moderate yield (entry 17). To extend the scope of the domino
Fig. 1 X-ray crystal structures of 3ad, 4ra and enantiopure 3ha.
reaction further, other 2-halo-1,3-dicarbonyl compounds 2b–2d
which also contain a good leaving group (Cl), were utilized as
nucleophiles in the [5 + 1] annulation under the same conditions
(entries 18–20). A good yield was obtained when the domino
reaction of imine 1a with diethyl α-chloromalonate 2b
(entry 18), while 2-halo-1,3-dicarbonyl compounds 2c–2d
afforded 2,3-dihydro-1,4-benzoxazines 3ac–3ad in moderate
yields (entries 19–20). The relative stereochemistry of products
3aa–3ad was established by a single crystal X-ray diffraction
study of compound 3ad (Fig. 1).
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Table 3 Synthesis
of
different
tetracyclic
2,3-dihydro-1,4-
Table 4 Asymmetric synthesis of differently substituted 2,3-dihydro-
benzoxazinesa
1,4-benzoxazinesa
Yieldb
Product 3 (%)
eec
(%)
Entry R1
R2
H
(1)
Product 4 Yieldb (%) drc
Entry R1
R2
(1)
1
2
3
4
5
6
7
8
9
H
H
H
H
(1r)
(4ra)
(4sa)
(4ta)
(4ua)
(4va)
61
63
46
56
45
66
74
48
47
>99 : 1
>99 : 1
>99 : 1
>99 : 1
60 : 40
>99 : 1
>99 : 1
>99 : 1
>99 : 1
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
Ph
(1a) 3aa
(1b) 3ba
p-CH3OC6H4 (1c) 3ca
66
51
48
62
70
65
63
57
61
81
60
61
30
63
44
62
60
54
4′-Me (1s)
5′-Me (1t)
4′-Cl
5′-Cl
H
H
H
p-CH3C6H4
(1u)
(1v)
(1w) (4wa)
(1x)
(1y)
(1z)
p-ClC6H4
o-ClC6H4
o-BrC6H4
(1f) 3fa
(1h) 3ha
H
5-OMe
4-Me
4-Cl
4-Br
(1j)
3ja
(4xa)
(4ya)
(4za)
4-Me Ph
5-Me Ph
5-Cl Ph
(1m) 3ma
(1n) 3na
(1p) 3pa
H
a Otherwise noted, the reactions performed with 0.10 mmol of 1,
0.20 mmol of 2a, 20 mol% of TBAB, 100 mol% of KOH in 1 mL of
CH3CN at room temperature to afford 3. Then 0.10 mmol of 3 and
10 mol% of p-toluenesulfonic acid were refluxed in toluene for 2 h to
generate 4. b Isolated yield for two steps. c Determined by 1H NMR.
a Otherwise noted, the reactions performed with 0.10 mmol of 1,
0.20 mmol of 2a, 10 mol% of 4c, 100 mol% of K2CO3 in 1 mL of
CH3Cl at 20 °C. b Isolated yield. c Determined by chiral HPLC analysis.
Development of novel synthetic methods for the construction
of new analogues of bioactive heterocyclic compounds rep-
resents a major challenge in synthetic organic and medicinal
chemistry. Having succeeded in synthesizing 2,3-dihydro-
1,4-benzoxazines, we considered that 1,4-benzoxazines fused to
coumarins provide new analogues of bioactive heterocyclic com-
pounds that might have important biological and pharmaceutical
activities. Thus, we turned our attention to the possible synthesis
of tetracyclic 2,3-dihydro-1,4-benzoxazines 4ra–4za from func-
tionalized imines 1r–1z. However, no tetracyclic 2,3-dihydro-
1,4-benzoxazine 4ra but 2,3-dihydro-1,4-benzoxazine 3ra was
isolated under the above optimal reaction conditions. Fortunately,
tetracyclic 2,3-dihydro-1,4-benzoxazine 4ra was obtained in
good yield when 2,3-dihydro-1,4-benzoxazine 3ra was treated
with p-toluenesulfonic acid in toluene. Then the scope of the
[5 + 1] annulation was extended to various imines 1 and diethyl
α-bromomalonate 2a. The reaction scopes proved to be broad
with respect to imines and the novel transformations were highly
diastereoselective. It appeared that substituents’ electronics
have a minimal impact on efficiencies of the [5 + 1] annulation.
Good yields were obtained in the [5 + 1] annulation of diethyl
α-bromomalonate 2a with electron-donating substituent on the
aryl ring of imines 1 (Table 3, entries 2, 6, 7). This method
features the creation of two new heterocyclic rings and one qua-
ternary carbon center in a simple procedure. The relative stereo-
chemistry of products was also established by a single crystal
X-ray diffraction study of compound 4ra (Fig. 1).
organic solvents, bases and chiral PTC were screened for the
[5 + 1] annulation of diethyl α-bromomalonate with imine 1a
(see Table S1 in the ESI†), the optimal reaction conditions
(1.0 equiv 1, 2.0 equiv 2a and 1.0 equiv K2CO3 in CHCl3 with
10 mol% 4c at 20 °C) were established. Subsequently, the scope
of the present organocatalytic asymmetric [5 + 1] annulation
using catalyst 4c was extended to various imines 1 and diethyl
α-bromomalonate 2a. As illustrated in Table 4, for the reactions
of DBM, moderate to good results were achieved with various
imines 1 bearing various substitutions (Table 4, entries 1–9). The
good enantioselectivity was obtained with moderate yield for the
model reaction (entry 1). It appeared that substituents’ elec-
tronics have a minimal impact on enantioselectivities of the
[5 + 1] annulation. Moderate enantioselectivities were obtained
in the [5 + 1] annulation of DBM with electron-donating substi-
tuent (R2) on aryl ring of imines 1 (entries 2 and 3). On the con-
trary, an electron-withdrawing substituent (R2) on aryl ring of
imines 1 tended to decrease the enantioselectivity (entry 4).
Imine 1h with electron-withdrawing substituent on the ortho
position (R2) afford 1,4-benzoxazines with moderate enantio-
selectivity (entry 5). In addition, imines 1 with electron-with-
drawing substituents or electron-donating substituents on the
aromatic ring (R1) afford 1,4-benzoxazines with slightly inferior
enantioselectivities (entries 7–9). The absolute configuration of
the substituted 1,4-benzoxazines was confirmed by a single-
crystal X-ray analysis of representative enantiopure 3ha that
bears a chlorine atom. As shown in Fig. 1, it composes of (C1R)
configuration.
Catalytic asymmetric construction of 1,4-benzoxazines is
somewhat difficult, and optically active 1,4-benzoxazines are
mostly constructed by the asymmetric reduction of imines in
the literature.15 Therefore, there is an eager desire for a new
synthetic method that allows the easy preparation of chiral
1,4-benzoxazines with good feasibility to assemble various sub-
stitution patterns. Herein we present a new organocatalytic
enantioselective [5 + 1] annulation of diethyl α-bromomalonate
with imines 1 to afford chiral 1,4-benzoxazines. After a series of
Conclusions
In summary, an efficient, mild, and convenient domino reaction
for preparing differently substituted 1,4-benzoxazines from
readily available starting materials was developed. In this trans-
formation, a broad substrate scope has been demonstrated. This
6556 | Org. Biomol. Chem., 2012, 10, 6554–6561
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1
methodology provides facile access to various new analogues of
bioactive heterocyclic compounds – tetracyclic-1,4-benzoxazines
which contain two new heterocyclic rings and one quaternary
carbon center. In addition, we also have successfully demon-
strated the first asymmetric [5 + 1] annulation of α-bromomalo-
nate (DBM) 2a to imines 1 with fair to good enantioselectivities,
employing readily available chiral quaternary ammonium salts as
organocatalysts. Application of this method in the synthesis of
other pharmaceutically intriguing compounds is being actively
pursued, and the results will be disclosed in due course.
yield 87%; H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 3.5 Hz,
5H), 7.12 (dd, J = 8.0, 1.3 Hz, 1H), 6.87 (td, J = 7.7, 1.4 Hz,
1H), 6.74 (td, J = 8.0, 1.5 Hz, 1H), 6.62 (dd, J = 7.9, 1.4 Hz,
1H), 5.30 (d, J = 3.9 Hz, 1H), 4.38 (s, 1H), 4.27–4.13 (m, 2H),
4.12–4.10 (m, 2H), 1.11 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 166.8, 164.9, 140.9, 139.2,
131.5, 128.4, 128.2, 127.8, 123.1, 118.8, 117.8, 115.2, 82.6,
62.6, 62.4, 56.9, 13.8, 13.7; IR (KBr) cm−1 3384, 2986, 1756,
1611, 1499, 1450, 1272, 1214, 1152, 748, 704; ESI-HRMS:
calcd for C20H21NO5 + H 356.1492, found 356.1495.
(R)-Diethyl 3-phenyl-3,4-dihydrobenzo[b][1,4]oxazine-2,2-di-
carboxylatediethyl (3aa). 23.4 mg, yield 66%; [α]2D0 = −18
(c 0.67, CHCl3), ee = 81.0%; The enantiomeric ratio was deter-
mined by HPLC on Chiralpak IC column (10% 2-propanol/
hexane, 1 mL min−1), tmajor = 10.42 min, tminor = 7.63 min.
Experimental section
General methods
NMR spectra were recorded with tetramethylsilane as the
internal standard. TLC was performed on glass-backed silica
plates. Column chromatography was performed using silica gel
(160–200 mesh) eluting with ethyl acetate and petroleum ether.
1H NMR spectra were recorded at 400 MHz, and 13C NMR
spectra were recorded at 100 MHz (Bruker Avance). Chemical
shifts (δ) are reported in ppm downfield from CDCl3
Diethyl 3-p-tolyl-3,4-dihydrobenzo[b][1,4]oxazine-2,2-di-
carboxylate (3ba). White solid, mp: 114–115 °C; 26.5 mg,
1
yield 72%; H NMR (400 MHz, CDCl3) δ 7.12 (t, J = 9.8 Hz,
3H), 7.04 (d, J = 7.9 Hz, 2H), 6.85 (t, J = 7.6 Hz, 1H), 6.72
(t, J = 7.7 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 5.25 (s, 1H), 4.36
(s, 1H), 4.27–4.12 (m, 2H), 4.11–4.00 (m, 2H), 2.27 (s, 3H),
1.10 (t, J = 6.1 Hz, 3H), 1.07 (t, J = 6.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.8, 164.9, 141.0, 137.9, 136.2, 131.6,
129.1, 127.7, 123.0, 118.7, 117.7, 115.1, 82.7, 62.5, 62.3, 56.6,
21.0, 13.8, 13.7; IR (KBr) cm−1 3401, 2981, 1749, 1612, 1501,
1455, 1249, 1212, 1181, 831, 743; ESI-HRMS: calcd for
C21H23NO5 + H 370.1649, found 370.1644.
1
(δ = 7.26 ppm) for H NMR and relative to the central CDCl3
resonance (δ = 77.0 ppm) for 13C NMR spectroscopy. Coupling
constants (J) are given in Hz. ESI-HRMS spectrometer was
measured with a Finnigan LCQDECA ion trap mass spectrometer.
Optical rotations were measured at 589 nm at 20 °C. Enantio-
meric excess was determined by HPLC analysis on Chiralpak
AS, IC and OD columns.
(R)-Diethyl 3-p-tolyl-3,4-dihydrobenzo[b][1,4]oxazine-2,2-di-
carboxylate (3ba). 18.8 mg, yield 51%; [α]2D0 = −38.9 (c 0.57,
CHCl3), ee = 60.0%; The enantiomeric ratio was determined
by HPLC on Chiralpak AS column (10% 2-propanol/hexane,
1 mL min−1), tmajor = 14.27 min, tminor = 7.08 min.
Synthesis of different substituted 2,3-dihydro-1,4-benzo-
xazines. General procedure: 1a (19.7 mg, 0.10 mmol), 2a
(47.4 mg, 0.20 mmol), TBAB (6.44 mg, 0.02 mmol) and KOH
(5.6 mg, 0.10 mmol) were stirred in CH3CN (1 mL) at room
temperature for 20 h. Then flash chromatography on silica gel
(10% ethylacetate/petroleum ether) gave product 3aa as a white
solid (30.8 mg, 87% yield).
Diethyl 3-(4-methoxyphenyl)-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3ca). White solid, mp: 94–95 °C; 27.3 mg,
1
yield 71%; H NMR (400 MHz, CDCl3) δ 7.22–7.16 (m, 2H),
Synthesis of different tetracyclic 2,3-dihydro-1,4-benzoxazines.
General procedure: 1r (21.3 mg, 0.10 mmol), 2a (47.4 mg,
0.20 mmol), TBAB (6.44 mg, 0.02 mmol) and KOH (5.6 mg,
0.10 mmol) were stirred in CH3CN (1 mL) at room temperature
for 20 h. Then flash chromatography on silica gel (10% ethylace-
tate/petroleum ether) gave product 3ra as a white solid (24.1 mg,
65% yield); 3ra (37.1 mg, 0.10 mmol) and p-toluenesulfonic
acid (1.72 mg, 0.01 mmol) were refluxed in toluene for 2 h.
Then flash chromatography on silica gel (20% ethylacetate/
petroleum ether) gave product 4ra as a white solid (30.5 mg,
94% yield).
7.12 (dd, J = 8.0, 1.4 Hz, 1H), 6.86 (td, J = 7.6, 1.4 Hz, 1H),
6.80–6.70 (m, 3H), 6.61 (dd, J = 7.9, 1.5 Hz, 1H), 5.25 (s, 1H),
4.37 (s, 1H), 4.28–4.14 (m, 2H), 4.14–4.01 (m, 2H), 3.74
(s, 3H), 1.12 (t, J = 4.5 Hz, 3H), 1.09 (t, J = 4.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 166.8, 165.0, 159.4, 140.9, 131.5,
131.4, 129.0, 123.0, 118.7, 117.7, 115.2, 113.7, 82.8, 62.6, 62.3,
56.2, 55.2, 13.8; IR (KBr) cm−1 3407, 2977, 1747, 1612, 1508,
1458, 1251, 1212, 1179, 834, 747; ESI-HRMS: calcd for
C21H23NO6 + H 386.1598, found 386.1597.
(R)-Diethyl 3-(4-methoxyphenyl)-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3ca). 18.4 mg, yield 48%; [α]2D0 = −64.5 (c =
1.10, CHCl3), ee = 61.0%; The enantiomeric ratio was deter-
mined by HPLC on Chiralpak AS column (10% 2-propanol/
hexane, 1 mL min−1), tmajor = 23.09 min, tminor = 10.51 min.
Asymmetric synthesis of differently substituted 2,3-dihydro-
1,4-benzoxazines. General procedure: 1a (19.7 mg, 0.10 mmol),
2a (47.4 mg, 0.20 mmol), K2CO3 (13.8 mg, 0.10 mmol) and 4c
(5.32 mg, 0.01 mol) were stirred in CHCl3 (1 mL) at 20 °C for
20 h. Then flash chromatography on silica gel (10% ethyl
acetate/petroleum ether) gave product 3aa as a white solid
(23.4 mg, 66% yield).
Diethyl 3-(2-methoxyphenyl)-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3da). White solid, mp: 81–83 °C; 26.5 mg,
1
yield 69%; H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 7.7 Hz,
1H), 7.18 (dd, J = 11.2, 4.5 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H),
6.87–6.75 (m, 3H), 6.74–6.66 (m, 1H), 6.53 (dd, J = 7.7,
1.3 Hz, 1H), 5.80 (d, J = 3.5 Hz, 1H), 4.41 (d, J = 3.0 Hz, 1H),
Diethyl
3-phenyl-3,4-dihydrobenzo[b][1,4]oxazine-2,2-di-
carboxylate (3aa). White solid, mp: 127–128 °C; 30.8 mg,
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4.31–4.16 (m, 2H), 4.16–4.06 (m, 2H), 3.87 (s, 3H), 1.15 (t, J =
7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.0, 165.1, 156.6, 141.2, 131.2, 128.8, 127.7, 122.6,
120.8, 118.9, 117.3, 115.6, 110.0, 82.8, 62.6, 62.3, 55.4, 48.8,
13.8, 13.6; IR (KBr) cm−1 3399, 2972, 1745, 1612, 1504, 1453,
1250, 1212, 1170, 841, 739; ESI-HRMS: calcd for C21H23NO6
+ H 386.1598, found 386.1617.
164.2, 140.8, 136.6, 133.4, 130.4, 129.4, 129.1, 128.7, 127.5,
123.0, 119.1, 117.7, 115.5, 82.2, 62.8, 62.5, 51.6, 13.8, 13.5; IR
(KBr) cm−1 3400, 2978, 1752, 1728, 1613, 1500, 1295, 1211,
1146, 868, 743; ESI-HRMS: calcd for C20H20ClNO5 + H
390.1103, found 390.1091.
(R)-Diethyl 3-(2-chlorophenyl)-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3ha). 27.2 mg, yield 70%; [α]2D0 = −15.4 (c =
1.17, CHCl3), ee = 63.0%; The enantiomeric ratio was deter-
mined by HPLC on Chiralpak OD column (10% 2-propanol/
hexane, 1 mL min−1), tmajor = 6.72 min, tminor = 5.85 min.
Diethyl 3-(3-methoxyphenyl)-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3ea). White solid, mp: 91–92 °C; 25.8 mg,
1
yield 67%; H NMR (400 MHz, CDCl3) δ 7.20–7.07 (m, 2H),
6.90–6.69 (m, 5H), 6.62 (dd, J = 7.8, 1.4 Hz, 1H), 5.27 (s, 1H),
4.37 (s, 1H), 4.28–4.14 (m, 2H), 4.14–4.02 (m, 2H), 3.69
(s, 3H), 1.11 (t, J = 5.1 Hz, 3H), 1.08 (t, J = 5.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 166.8, 164.9, 159.4, 140.9, 140.6,
131.4, 129.5, 123.1, 120.1, 118.8, 117.8, 115.2, 113.7, 113.4,
82.6, 62.7, 62.4, 56.7, 55.1, 13.9, 13.8; IR (KBr) cm−1 3407,
2974, 1749, 1611, 1500, 1456, 1253, 1215, 1180, 827, 738;
ESI-HRMS: calcd for C21H23NO6 + H 386.1598, found
386.1617.
Diethyl 3-(4-bromophenyl)-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3ia). White solid, mp: 118–119 °C; 38.0 mg,
yield 86%; H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.3 Hz,
1
2H), 7.24–6.96 (m, 3H), 6.88 (t, J = 7.3 Hz, 1H), 6.75 (t, J = 7.4
Hz, 1H), 6.63 (d, J = 7.4 Hz, 1H), 5.27 (s, 1H), 4.37 (s, 1H),
4.25–4.14 (m, 2H), 4.13–4.04 (m, 2H), 1.11 (d, J = 6.3 Hz, 3H),
1.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6, 164.8,
140.8, 138.2, 131.5, 131.1, 129.5, 123.2, 122.3, 119.1, 117.9,
115.3, 82.3, 62.7, 62.5, 56.4, 13.8; IR (KBr) cm−1 3402, 2980,
1750, 1724, 1611, 1500, 1297, 1214, 1138, 860, 748;
ESI-HRMS: calcd for C20H20BrNO5 + H 434.0598, found
434.0602.
Diethyl 3-(4-chlorophenyl)-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3fa). White solid, mp: 109–110 °C; 32.3 mg,
1
yield 83%; H NMR (400 MHz, CDCl3) δ 7.25–7.14 (m, 4H),
7.11 (d, J = 8.0 Hz, 1H), 6.87 (t, J = 7.2 Hz, 1H), 6.75 (t, J =
7.7 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 5.29 (s, 1H), 4.39 (s, 1H),
4.27–4.13 (m, 2H), 4.13–4.00 (m, 2H), 1.15–1.10 (m, 3H),
1.10–1.03 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6,
164.8, 140.8, 137.7, 134.1, 131.1, 129.2, 128.6, 123.2, 119.0,
117.9, 115.3, 82.4, 62.7, 62.5, 56.3, 13.8; IR (KBr) cm−1 3400,
2983, 1758, 1727, 1612, 1500, 1298, 1213, 1141, 866, 743;
ESI-HRMS: calcd for C20H20ClNO5 + H 390.1103, found
390.1140.
Diethyl 3-(2-bromophenyl)-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3ja). White solid, mp: 129–130 °C; 34.9 mg,
yield 79%; H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.9 Hz,
1
1H), 7.49 (d, J = 7.7 Hz, 1H), 7.17 (dd, J = 13.4, 7.3 Hz, 2H),
7.09 (t, J = 7.2 Hz, 1H), 6.83 (t, J = 7.4 Hz, 1H), 6.75 (t, J = 7.4
Hz, 1H), 6.56 (d, J = 7.7 Hz, 1H), 5.91 (d, J = 4.4 Hz, 1H), 4.50
(d, J = 3.7 Hz, 1H), 4.28–4.18 (m, 2H), 4.17–4.05 (m, 2H), 1.16
(t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.5, 164.6, 140.7, 138.1, 132.8, 130.3,
129.4, 128.8, 128.2, 124.1, 123.0, 119.1, 117.6, 115.5, 82.3,
62.8, 62.5, 54.2, 13.8, 13.6; IR (KBr) cm−1 3398, 2976, 1753,
1728, 1611, 1502, 1290, 1214, 1146, 857, 744; ESI-HRMS:
calcd for C20H20BrNO5 + H 434.0598, found 434.0586.
(R)-Diethyl 3-(4-chlorophenyl)-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3fa). 24.1 mg, yield 62%; [α]2D0 = −40.0
(c 0.50, CHCl3), ee = 30.0%; The enantiomeric ratio was deter-
mined by HPLC on Chiralpak AS column (10% 2-propanol/
hexane, 1 mL min−1), tmajor = 16.47 min, tminor = 8.13 min.
(R)-Diethyl 3-(2-bromophenyl)-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3ja). 28.1 mg, yield 65%; [α]2D0 = −24.2 (c =
0.87, CHCl3), ee = 44.0%; The enantiomeric ratio was deter-
mined by HPLC on Chiralpak OD column (10% 2-propanol/
hexane, 1 mL min−1), tmajor = 6.75 min, tminor = 5.90 min.
Diethyl 3-(3-chlorophenyl)-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3ga). White solid, mp: 130–131 °C; 31.5 mg,
yield 81%; H NMR (400 MHz, CDCl3) δ 7.25–7.19 (m, 2H),
1
7.14 (dd, J = 19.5, 8.3 Hz, 3H), 6.88 (t, J = 7.3 Hz, 1H), 6.75
(t, J = 7.4 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 5.28 (d, J = 3.7 Hz,
1H), 4.42 (s, 1H), 4.27–4.14 (m, 2H), 4.13–4.05 (m, 2H),
1.16–1.10 (m, 3H), 1.10–1.04 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.5, 164.8, 141.2, 140.8, 134.1, 131.1, 129.8, 128.3,
128.1, 125.9, 123.3, 119.0, 118.0, 115.2, 82.3, 62.7, 62.6, 56.6,
13.8, 13.7; IR (KBr) cm−1 3398, 2979, 1752, 1721, 1612, 1500,
1291, 1213, 1143, 857, 751; ESI-HRMS: calcd for
C20H20ClNO5 + H 390.1103, found 390.1140.
Diethyl
3-(4-nitrophenyl)-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3ka). Yellow solid, mp: 136–137 °C;
32.4 mg, yield 81%; 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J =
8.7 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 8.0 Hz, 1H),
6.91 (t, J = 7.6 Hz, 1H), 6.80 (t, J = 7.7 Hz, 1H), 6.70–6.64
(m, 1H), 5.44 (d, J = 5.1 Hz, 1H), 4.46 (d, J = 5.0 Hz, 1H),
4.29–4.15 (m, 2H), 4.14–4.03 (m, 2H), 1.16–1.11 (m, 3H),
1.11–1.05 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3,
164.6, 147.6, 146.3, 140.7, 130.6, 128.9, 123.6, 123.5, 119.5,
118.1, 115.5, 81.8, 62.9, 62.7, 56.5, 13.8, 13.7; IR (KBr) cm−1
3408, 2969, 1750, 1733, 1611, 1505, 1288, 1211, 1175, 869,
735; ESI-HRMS: calcd for C20H20N2O7 + H 401.1343, found
401.1343.
Diethyl 3-(2-chlorophenyl)-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3ha). White solid, mp: 120–122 °C; 31.5 mg,
1
yield 81%; H NMR (400 MHz, CDCl3) δ 7.47 (dd, J = 7.4, 2.0
Hz, 1H), 7.35 (dd, J = 7.7, 1.5 Hz, 1H), 7.20–7.10 (m, 3H), 6.83
(dd, J = 10.8, 4.4 Hz, 1H), 6.79–6.70 (m, 1H), 6.57 (dd, J = 7.8,
1.3 Hz, 1H), 5.94 (d, J = 4.7 Hz, 1H), 4.46 (d, J = 4.6 Hz, 1H),
4.35–4.18 (m, 2H), 4.17–4.05 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H),
1.05 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.5,
Diethyl 3-(2-nitrophenyl)-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3la). Yellow solid, mp: 153–155 °C;
6558 | Org. Biomol. Chem., 2012, 10, 6554–6561
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30.0 mg, yield 75%; 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J =
8.0 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H),
7.39 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.86 (t, J =
7.4 Hz, 1H), 6.77 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 7.8 Hz, 1H),
5.81 (d, J = 4.3 Hz, 1H), 4.75 (d, J = 3.8 Hz, 1H), 4.30–4.13
(m, 2H), 4.08–4.03 (m, 2H), 1.15 (t, J = 7.1 Hz, 3H), 0.98 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.8, 164.4,
149.8, 140.4, 133.6, 133.5, 130.1, 128.9, 128.6, 124.4, 123.2,
119.2, 117.6, 115.4, 82.4, 63.0, 62.7, 49.9, 13.8, 13.5; IR (KBr)
cm−1 3393, 2979, 1759, 1726, 1615, 1507, 1293, 1210, 1177,
855, 748; ESI-HRMS: calcd for C20H20N2O7 + H 401.1343,
found 401.1350.
790, 702; ESI-HRMS: calcd for C20H20ClNO5 + H 390.1103,
found 390.1138.
Diethyl
7-chloro-3-phenyl-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3pa). White solid, mp: 110–111 °C; 33.1 mg,
1
yield 85%; H NMR (400 MHz, CDCl3) δ 7.28–7.20 (m, 5H),
7.14 (d, J = 2.3 Hz, 1H), 6.84 (dd, J = 8.5, 2.3 Hz, 1H), 6.54
(d, J = 8.5 Hz, 1H), 5.28 (s, 1H), 4.43 (s, 1H), 4.28–4.14
(m, 2H), 4.12–3.99 (m, 2H), 1.14 (t, J = 7.1 Hz, 3H), 1.04 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 164.5,
141.2, 138.8, 130.2, 128.5, 128.4, 127.8, 123.1, 123.0, 117.9,
115.7, 82.6, 62.8, 62.5, 56.6, 13.8, 13.7; IR (KBr) cm−1 3364,
2991, 1762, 1743, 1600, 1500, 1284, 1213, 1157, 854, 788,
707; ESI-HRMS: calcd for C20H20ClNO5 + H 390.1103, found
390.1075.
Diethyl 6-methyl-3-phenyl-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3ma). White solid, mp: 125–127 °C;
28.1 mg, yield 76%; 1H NMR (400 MHz, CDCl3) δ 7.24
(s, 5H), 7.00 (d, J = 8.2 Hz, 1H), 6.54 (dd, J = 8.1, 1.3 Hz, 1H),
6.43 (d, J = 0.9 Hz, 1H), 5.28 (s, 1H), 4.36 (s, 1H), 4.26–4.13
(m, 2H), 4.12–3.99 (m, 2H), 2.22 (s, 3H), 1.13 (t, J = 7.1 Hz,
3H), 1.04 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 166.9, 165.1, 139.3, 138.7, 132.6, 131.1, 128.4, 128.2, 127.8,
119.4, 117.5, 115.6, 82.6, 62.6, 62.4, 56.8, 20.9, 13.9, 13.7; IR
(KBr) cm−1 3376, 2982, 1763, 1741, 1615, 1500, 1450, 1295,
1216, 1151, 854, 793, 701; ESI-HRMS: calcd for C21H23NO5
+ H 370.1649, found 370.1647.
(R)-Diethyl 7-chloro-3-phenyl-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3pa). 23.7 mg, yield 61%; [α]2D0 = −23.5 (c =
1.23, CHCl3), ee = 54.0%; The enantiomeric ratio was deter-
mined by HPLC on Chiralpak AS column (10% 2-propanol/
hexane, 1 mL min−1), tmajor = 15.55 min, tminor = 8.14 min.
1,1′-(3-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,2-diyl)bis-
(propan-1-one) (3qa). White solid, mp: 103–104 °C; 14.0 mg,
1
yield 51%; H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 7.11
(t, J = 7.7 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 7.9 Hz,
1H), 4.93 (s, 1H), 4.50–4.43 (m, 2H), 4.41–4.29 (m, 2H), 3.72
(d, J = 6.8 Hz, 1H), 1.58 (s, 3H), 1.36–1.35 (m, 3H), 1.35–1.32
(m, 3H), 1.24 (t, J = 6.7 Hz, 2H); 13C NMR (100 MHz, CDCl3)
δ 167.7, 155.5, 142.2, 130.2, 126.4, 125.7, 123.0, 116.1, 110.0,
88.9, 63.9, 63.0, 29.0, 22.6, 14.0, 13.9; IR (KBr) cm−1 3380,
2979, 1756, 1612, 1501, 1450, 1212, 1152, 734, 704;
ESI-HRMS: calcd for C16H21NO3 + Na 298.1414, found
298.1361.
(R)-Diethyl 6-methyl-3-phenyl-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3ma). 18.8 mg, yield 63%; [α]2D0 = −49.2 (c =
2.03, CHCl3), ee = 62.0%; The enantiomeric ratio was deter-
mined by HPLC on Chiralpak AS column (10% 2-propanol/
hexane, 1 mL min−1), tmajor = 13.79 min, tminor = 7.35 min.
Diethyl 7-methyl-3-phenyl-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3na). White solid, mp: 94–95 °C; 26.9 mg,
1
yield 73%; H NMR (400 MHz, CDCl3) δ 7.24 (s, 5H), 6.96
(s, 1H), 6.68 (dd, J = 8.0, 1.1 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H),
5.26 (s, 1H), 4.29 (s, 1H), 4.25–4.15 (m,2H), 4.12–4.01 (m,2H),
2.27 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 166.9, 165.1, 141.0, 139.3,
128.8, 128.6, 128.4, 128.1, 127.8, 123.6, 118.2, 115.4, 82.6,
62.6, 62.3, 56.9, 20.6, 13.8, 13.7; IR (KBr) cm−1 3371, 2974,
1761, 1749, 1613, 1500, 1450, 1290, 1213, 1163, 859, 787,
703; ESI-HRMS: calcd for C21H23NO5 + H 370.1649, found
370.1647.
Diethyl 3-phenyl-3,4-dihydrobenzo[b][1,4]oxazine-2,2-di-
carboxylate (3ab). White solid, mp: 127–128 °C; 29.4 mg,
1
yield 83%; H NMR (400 MHz, CDCl3) δ 7.25 (s, 5H), 7.12
(dd, J = 8.0, 1.3 Hz, 1H), 6.87 (td, J = 7.7, 1.4 Hz, 1H), 6.74
(td, J = 8.0, 1.5 Hz, 1H), 6.62 (dd, J = 7.9, 1.4 Hz, 1H), 5.30
(d, J = 3.9 Hz, 1H), 4.39 (s, 1H), 4.27–4.14 (m, 2H), 4.13–4.00
(m, 2H), 1.11 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 166.8, 164.9, 140.9, 139.2, 131.5,
128.4, 128.2, 127.8, 123.1, 118.8, 117.8, 115.2, 82.6, 62.6, 62.4,
56.9, 13.8, 13.7; IR (KBr) cm−1 3382, 2988, 1754, 1611, 1500,
1450, 1272, 1214, 1152, 748, 704; ESI-HRMS: calcd for
C20H21NO5 + H 356.1492, found 356.1502.
(R)-Diethyl 7-methyl-3-phenyl-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3na). 21.0 mg, yield 57%; [α]2D0 = −21.9 (c =
0.87, CHCl3), ee = 60.0%; The enantiomeric ratio was deter-
mined by HPLC on Chiralpak AS column (10% 2-propanol/
hexane, 1 mL min−1), tmajor = 12.41 min, tminor = 7.02 min.
1,1′-(3-Phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2,2-diyl)-
diethanone (3ac). White solid, mp: 143–144 °C; 16.5 mg, yield
Diethyl 6-chloro-3-phenyl-3,4-dihydrobenzo[b][1,4]oxazine-
2,2-dicarboxylate (3oa). White solid, mp: 134–135 °C;
1
56%; H NMR (400 MHz, CDCl3) δ 7.25–7.19 (m, 3H), 7.15
1
31.9 mg, yield 82%; H NMR (400 MHz, CDCl3) δ 7.26–7.18
(dd, J = 6.5, 2.8 Hz, 2H), 7.09 (dd, J = 8.0, 1.0 Hz, 1H),
6.93–6.86 (m, 1H), 6.81–6.74 (m, 1H), 6.63 (dd, J = 7.9, 1.2
Hz, 1H), 5.30 (s, 1H), 4.37 (s, 1H), 2.15 (s, 3H), 1.87 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 203.5, 201.0, 140.6, 139.4,
132.3, 128.6, 128.0, 128.0, 123.4, 118.8, 117.4, 115.6, 93.0,
55.9, 26.8, 25.7; IR (KBr) cm−1 3386, 2979, 1749, 1613, 1502,
1450, 1277, 1212, 1139, 733, 702; ESI-HRMS: calcd for
C18H17NO3 + H 296.1281, found 296.1279.
(m, 5H), 7.03 (d, J = 8.6 Hz, 1H), 6.68 (dd, J = 8.6, 2.4 Hz,
1H), 6.60 (d, J = 2.3 Hz, 1H), 5.29 (d, J = 4.3 Hz, 1H), 4.53
(d, J = 4.2 Hz, 1H), 4.28–4.13 (m, 2H), 4.11–3.99 (m, 2H), 1.13
(s, 3H), 1.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.5,
164.6, 139.3, 138.7, 132.5, 128.5, 128.4, 127.9, 127.8, 118.8,
118.3, 114.4, 82.6, 62.8, 62.6, 56.5, 13.9, 13.7; IR (KBr) cm−1
3367, 2988, 1764, 1741, 1608, 1501, 1289, 1216, 1151, 847,
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Ethyl 2-acetyl-3-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-
2-carboxylate (3ad). White solid, mp: 127–130 °C; 17.2 mg,
yield 53%; H NMR (400 MHz, CDCl3) δ 7.23 (t, J = 3.0 Hz,
1132, 803, 762; ESI-HRMS: calcd for C18H14ClNO5 + H
360.0633, found 360.0687.
1
Ethyl 9-chloro-6-oxo-6,6a,12,12a-tetrahydrobenzo[b]chro-
meno[4,3-e][1,4]oxazine-6a-carboxylate (4va). White solid,
mp: 198–200 °C; 29.8 mg, yield 83%; 1H NMR (400 MHz,
CDCl3) δ 7.48–7.27 (m, 2H), 7.23–7.12 (m, 2H), 7.06 (s, 1H),
6.93 (s, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.56 (d, J = 8.5 Hz, 1H),
4.71 (s, 1H), 4.26–3.86 (m, 3H), 1.04 (t, J = 7.1 Hz, 2H), 0.85
(t, J = 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 164.2,
150.3, 140.9, 130.6, 129.6, 128.5, 124.8, 122.9, 122.1, 120.9,
116.4, 116.2, 62.7, 51.0, 13.3; IR (KBr) cm−1 3391, 2963, 1765,
1744, 1612, 1500, 1453, 1299, 1255, 1214, 1137, 806, 763;
ESI-HRMS: calcd for C18H14ClNO5 + H 360.0633, found
360.0645.
3H), 7.19–7.15 (m, 2H), 7.07 (d, J = 8.0 Hz, 1H), 6.88 (dt, J =
13.4, 6.8 Hz, 1H), 6.77–6.73 (m, 1H), 6.64 (d, J = 7.9 Hz, 1H),
5.28 (s, 1H), 4.45 (s, 1H), 4.22–4.01 (m, 2H), 1.89 (s, 3H),
1.11–1.03 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 203.6,
167.0, 139.3, 132.1, 128.5, 128.1, 127.8, 123.2, 118.6, 117.6,
115.2, 110.0, 87.4, 62.5, 56.8, 26.6, 13.8; IR (KBr) cm−1 3389,
2984, 1757, 1612, 1503, 1450, 1277, 1211, 1147, 734, 700;
ESI-HRMS: calcd for C19H19NO4 + H 326.1387, found
326.1389.
Ethyl 6-oxo-6,6a,12,12a-tetrahydrobenzo[b]chromeno[4,3-e]-
[1,4]oxazine-6a-carboxylate
(4ra). White
solid,
mp:
1
167–169 °C; 30.2 mg, yield 93%; H NMR (400 MHz, CDCl3)
δ 7.42 (t, J = 7.2 Hz, 1H), 7.36 (d, J = 7.4 Hz, 1H), 7.24–7.10
(m, 2H), 7.05 (d, J = 7.9 Hz, 1H), 6.87–6.78 (m, 2H), 6.63 (d,
J = 7.7 Hz, 1H), 4.71 (s, 1H), 4.23–4.07 (m, 2H), 4.03 (s, 1H),
1.03 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.2,
150.9, 141.4, 131.2, 129.7, 128.4, 125.1, 122.7, 121.0, 120.7,
117.1, 115.9, 63.1, 51.9, 13.6; ESI-HRMS: calcd for
C18H15NO5 + H 326.1023, found 326.1063.
Ethyl 3-methoxy-6-oxo-6,6a,12,12a-tetrahydrobenzo[b]chro-
meno[4,3-e][1,4]oxazine-6a-carboxylate (4wa). White solid, mp:
148–150 °C; 32.3 mg, yield 91%; H NMR (400 MHz, CDCl3)
1
δ 7.24 (d, J = 8.1 Hz, 1H), 7.06 (d, J = 7.9 Hz, 1H), 6.87–6.78
(m, 2H), 6.72–6.70 (m, 2H), 6.62 (dd, J = 7.6, 1.5 Hz, 1H), 4.64
(s, 1H), 4.24–4.09 (m, 2H), 3.94 (s, 1H), 3.82 (s, 3H), 1.07 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.9, 152.0,
129.8, 129.2, 123.7, 122.7, 120.6, 117.1, 115.8, 115.0, 112.8,
110.8, 105.5, 102.8, 63.1, 55.7, 51.4, 13.7; IR (KBr) cm−1 3351,
2969, 1791, 1726, 1615, 1499, 1433, 1271, 1207, 1169, 834,
744; ESI-HRMS: calcd for C19H17NO6 + H 356.1129, found
356.1125.
Ethyl 10-methyl-6-oxo-6,6a,12,12a-tetrahydrobenzo[b]chro-
meno[4,3-e][1,4]oxazine-6a-carboxylate (4sa). White solid, mp:
1
118–120 °C; 30.1 mg, yield 89%; H NMR (400 MHz, CDCl3)
δ 7.42 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.17 (dd,
J = 17.9, 7.9 Hz, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.44 (s, 1H),
4.70 (s, 1H), 4.23–4.07 (m, 2H), 3.95 (s, 1H), 2.21 (s, 3H), 1.03
(t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.3,
150.9, 139.3, 132.3, 131.1, 129.2, 128.3, 125.1, 121.4, 121.1,
117.1, 116.8, 116.3, 63.1, 51.9, 20.7, 13.6; IR (KBr) cm−1 3359,
2922, 1783, 1759, 1614, 1515, 1468, 1300, 1254, 1214, 1164,
803, 759; ESI-HRMS: calcd for C19H17NO5 + H 340.1179,
found 340.1191.
Ethyl 2-methyl-6-oxo-6,6a,12,12a-tetrahydrobenzo[b]chro-
meno[4,3-e][1,4]oxazine-6a-carboxylate (4xa). White solid,
mp: 158–160 °C; 31.8 mg, yield 94%; 1H NMR (400 MHz,
CDCl3) δ 7.21 (d, J = 8.5 Hz, 1H), 7.16 (s, 1H), 7.05 (t, J =
9.0 Hz, 2H), 6.83 (dt, J = 22.0, 6.9 Hz, 2H), 6.63 (d, J = 7.7 Hz,
1H), 4.67 (s, 1H), 4.25–4.09 (m, 2H), 3.98 (s, 1H), 2.35 (s, 3H),
1.06 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.3,
148.7, 141.4, 134.9, 131.6, 129.8, 128.8, 122.7, 120.6, 120.5,
117.1, 116.9, 115.8, 63.1, 51.9, 20.7, 13.6; IR (KBr) cm−1 3348,
2966, 1790, 1725, 1615, 1499, 1436, 1270, 1204, 1175, 823,
743; ESI-HRMS: calcd for C19H17NO5 + Na 362.0999, found
362.1013.
Ethyl
9-methyl-6-oxo-6,6a,12,12a-tetrahydrobenzo[b]chro-
meno[4,3-e][1,4]oxazine-6a-carboxylate (4ta). White solid, mp:
1
206–208 °C; 27.4 mg, yield 81%; H NMR (400 MHz, CDCl3)
δ 7.43–7.34 (m, 2H), 7.16 (dd, J = 16.0, 8.1 Hz, 2H), 6.88
(s, 1H), 6.66 (d, J = 7.9 Hz, 1H), 6.54 (d, J = 7.9 Hz, 1H), 4.69
(s, 1H), 4.23–4.07 (m, 2H), 3.89 (s, 1H), 2.24 (s, 3H), 1.03
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.2,
150.7, 141.0, 130.8, 129.7, 128.5, 127.7, 124.9, 123.1, 121.3,
117.0, 116.7, 115.8, 62.8, 51.7, 20.5, 13.5; IR (KBr) cm−1 3361,
2925, 1780, 1751, 1613, 1509, 1463, 1300, 1252, 1214, 1166,
805, 751; ESI-HRMS: calcd for C19H17NO5 + H 340.1179,
found 340.1162.
Ethyl 2-chloro-6-oxo-6,6a,12,12a-tetrahydrobenzo[b]chro-
meno[4,3-e][1,4]oxazine-6a-carboxylate (4ya). White solid,
mp: 152–154 °C; 30.8 mg, yield 86%; 1H NMR (400 MHz,
CDCl3) δ 7.39–7.36 (m, 2H), 7.11–7.09 (m, 1H), 7.03 (d, J =
8.0 Hz, 1H), 6.87 (td, J = 7.5, 1.4 Hz, 1H), 6.81 (td, J = 7.7, 1.5
Hz, 1H), 6.67 (dd, J = 7.7, 1.4 Hz, 1H), 4.77 (s, 1H), 4.27–4.14
(m, 2H), 4.10 (s, 1H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 161.6, 149.2, 141.3, 130.9, 130.2, 129.2,
128.1, 122.9, 121.0, 118.5, 117.2, 116.2, 63.3, 58.4, 51.5, 18.4,
13.7; IR (KBr) cm−1 3344, 2969, 1793, 1720, 1611, 1501, 1428,
1273, 1201, 1181, 832, 737; ESI-HRMS: calcd for
C18H14ClNO5 + H 360.0633, found 360.0605.
Ethyl
10-chloro-6-oxo-6,6a,12,12a-tetrahydrobenzo[b]chro-
meno[4,3-e][1,4]oxazine-6a-carboxylate (4ua). White solid, mp:
1
164–166 °C; 31.2 mg, yield 87%; H NMR (400 MHz, CDCl3)
δ 7.43 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.22–7.15
(m, 2H), 6.97 (d, J = 8.6 Hz, 1H), 6.75 (d, J = 8.7 Hz, 1H), 6.62
(s, 1H), 4.72 (s, 1H), 4.26–4.14 (m, 2H), 4.11 (d, J = 7.8 Hz,
1H), 1.04 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
164.0, 150.8, 139.8, 131.4, 130.5, 128.3, 127.5, 125.2, 120.5,
120.4, 118.2, 117.2, 115.4, 63.3, 51.6, 13.6; IR (KBr) cm−1
3390, 2966, 1764, 1743, 1610, 1499, 1455, 1299, 1257, 1214,
Ethyl 2-bromo-6-oxo-6,6a,12,12a-tetrahydrobenzo[b]chro-
meno[4,3-e][1,4]oxazine-6a-carboxylate (4za). White solid,
mp: 162–164 °C; 37.1 mg, yield 92%; 1H NMR (400 MHz,
CDCl3) δ 7.54–7.51 (m, 2H), 7.04 (dd, J = 7.6, 3.0 Hz, 2H),
6.85 (dt, J = 23.4, 7.5 Hz, 2H), 6.66 (d, J = 7.7 Hz, 1H), 4.77
(s, 1H), 4.28–4.12 (m, 2H), 4.05 (s, 1H), 1.12 (t, J = 7.1 Hz,
6560 | Org. Biomol. Chem., 2012, 10, 6554–6561
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3H); 13C NMR (100 MHz, CDCl3) δ 161.5, 149.8, 141.3, 133.9,
131.0, 129.2, 122.9, 121.0, 118.9, 117.6, 117.2, 116.2, 63.3,
51.4, 13.7; IR (KBr) cm−1 3365, 2971, 1787, 1730, 1611, 1499,
1437, 1274, 1201, 1165, 845, 736; ESI-HRMS: calcd for
C18H14BrNO5 + H 404.0128, found 404.0136.
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Acknowledgements
10 P. Štefanič, M. Anderluh, J. Ilaš, J. Mravljak, D. M. Sollner, M. Stegnar
We are grateful for the financial support from the National
Natural Science Foundation of China (20902083) and the
Program for Changjiang Scholars and Innovative Research Team
in Chinese Universities (IRT0980).
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