One-pot regioselective annulation toward 3,4-dihydro-3-oxo-2H-1,4-benzoxazine scaffolds under controlled microwave heating

Article abstract of DOI:10.1016/j.tet.2005.12.059

An efficient and general synthesis of 2-alkyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines under controlled microwave heating has been established. It consists of a microwave-assisted reductive N-arylmethylation of substituted 2-aminophenols with aromatic aldehy

Full text of DOI:10.1016/j.tet.2005.12.059

Tetrahedron 62 (2006) 4635–4642
One-pot regioselective annulation toward 3,4-dihydro-3-oxo-2H-
1,4-benzoxazine scaffolds under controlled microwave heating*
Gaofeng Feng,a Jinlong Wua and Wei-Min Daia,b,
*
aLaboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
bDepartment of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
Received 21 September 2005; revised 30 November 2005; accepted 1 December 2005
Available online 20 March 2006
Abstract—An efficient and general synthesis of 2-alkyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines under controlled microwave heating has
been established. It consists of a microwave-assisted reductive N-arylmethylation of substituted 2-aminophenols with aromatic aldehydes
followed by a one-pot base-mediated regioselective O-alkylation of the N-arylmethyl-2-aminophenols with 2-bromoalkanoates to give the
acyclic intermediates, which cyclize spontaneously to furnish the benzoxazine scaffolds in good to excellent yields. It was found that micro-
ꢀ
wave heating over 180 C was necessary for ring closure of the acyclic intermediates possessing an electron-withdrawing group.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
followed by nitro reduction and subsequent intramolecular
N-substitution.6,9,13 In the case of 2-aminophenols, protec-
tion and deprotection manipulations were used to achieve
the desired regioselectivity.14 When treating 2-aminophe-
nols with 2-haloalkanoyl chlorides or bromides N-acylation
took place to give 2-(N-20-haloacylamino)phenols, which
underwent an intramolecular O-alkylation on heating at ca.
A variety of naturally occurring and synthetic bioactive
compounds are known to possess the 2H-1,4-benzoxazine
scalffold.1 For instance, the enediyne antitumor antibiotic,
C-1027,2 consists of a 2-methylene-3,4-dihydro-3-oxo-2H-
1,4-benzoxazine moiety in the chromophore subunit. Many
derivatives of 2H-1,4-benzoxazine have been reported as
plant resistance factors against microbial disease and in-
sects,3 serotonin-3 (5-HT3) receptor antagonists,4 potassium
channel modulators,5 antirheumatic agents,6 antihyperten-
sive agents,7 inotropic vasodilator agents,8 cannabinoid
receptor agonists,9 intracellular calcium antagonists,10 neu-
roprotective antioxidants,11 and others.12a,b 3,4-Dihydro-3-
oxo-2H-1,4-benzoxazine skeleton is also considered as the
bioisoster of 2(3H )-benzoxazolone12c and can be used as
the privileged scaffold in drug design. From the synthetic
point of view, 3,4-dihydro-3-oxo-2H-1,4-benzoxazine 1
presents a heterocycle system with three points of structural
diversity (X, Y, and Z) on the aromatic ring, the nitrogen, and
the C2 carbon (Fig. 1). 2-Aminophenols 2 and 2-nitrophe-
nols 3 are the common building blocks for the synthesis of
1.1b Normally, stepwise synthetic sequences were adopted,
for example, 2-nitrophenols underwent an O-alkylation
ꢀ
70 C in the presence of a base to afford 3,4-dihydro-3-
oxo-2H-1,4-benzoxazines.4c,5a–c,8,13a Microwave heating up
to 80 C was used in a recent synthesis.5c However, for the
ꢀ
electron-deficient 2-(N-20-haloacylamino)phenols, higher
temperatures were required for complete cyclization.15
Moreover, various annulation methods including Pd-cata-
lyzed reactions have been reported for the synthesis of 3,4-
dihydro-2H-1,4-benzoxazines.7,10,14a,16 In connection with
our previous studies on synthesis of indoles,17,18 benzo-
furans,19a and benzoxazines19b from substituted 2-amino-
phenols, we report here a regioselective annulation approach
O
Z
X
N
Y
O
1
OH
OH
* Part 6 of Chemistry of Aminophenols. For Part 5, see Ref. 19b.
Keywords: 1,4-Benzoxazines; 2-Aminophenols; Microwave; Regioselectiv-
ity; Annulation.
X
X
NH2
NO2
* Corresponding author at present address: Department of Chemistry, The
Hong Kong University of Science and Technology, Clear Water Bay,
Kowloon, Hong Kong SAR, China. Tel.: +852 23587365; fax: +852
23581594; e-mail addresses: chdai@ust.hk; chdai@zju.edu.cn
3
2
Figure 1. Common building blocks for 3,4-dihydro-3-oxo-2H-1,4-benzox-
azine scaffolds 1.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.059

4636
G. Feng et al. / Tetrahedron 62 (2006) 4635–4642
Table 1. Reductive N-alkylation of 2 at room temperature and under
for rapidly accessing 4-arylmethyl-3,4-dihydro-2-alkyl-3-
oxo-2H-1,4-benzoxazines in aqueous DMF under controlled
microwave heating.20
controlled microwave heatinga
ArCHO
OH
NH
OH
NaBH(OAc)3
X
X
THF, rt, 1-2 h or
80 °C, 3 min, MW
NH2
2. Results and discussion
Ar
4
2
In order to avoid the nitro reduction step in the synthesis
starting from 2-nitrophenols 3, we selected 2-aminophenols
2 as the building blocks in the current work. Although
2-haloalkanoyl halides were found to give an excellent re-
gioselectivity in reactions with 2,4c,5a–c,8,13a,15 a recent study
reported that reactions of 2-aminophenols with acyl chlo-
Entry 2: X
4
Yield (%)b
1
2
3
4
5
6
7
8
9
H
5-Me
5-Me
4,5-(CH2)4ꢁ
4-NO2
4-Cl
4-Cl
4-Cl
4a: X¼H, Ar¼2-furyl
4b: X¼5-Me, Ar¼Ph
73 (95)
79 (97)
75 (90)
58 (48)c
81 (98)
86 (99)
91 (99)
80
4c: X¼5-Me, Ar¼2-furyl
4d: X¼4,5-(CH2)4–, Ar¼2-furyl
4e: X¼4-NO2, Ar¼2-furyl
4f: X¼4-Cl, Ar¼2-furyl
ꢀ
rides at 210 C under microwave irradiation for 15 min
4g: X¼4-Cl, Ar¼Ph
afforded benzoxazoles.21 We preferred to use mild and
easily handling 2-bromoalkanoates4d as the annulation
agents, which are also suitable for running reactions in aque-
ous media. In our previous study,19b we found that heating
a mixture of 2-aminophenol 2 (X¼H) with ethyl 2-bromo-
4h: X¼4-Cl, Ar¼4-MeOC6H4
4-Cl
4i: X¼4-Cl, Ar¼3-pyridinyl
87
a
Compound 2 (1 equiv), 1.1 equiv of ArCHO, and 3 equiv of NaBH(OAc)3
were used. All reactions with microwave heating were carried out on
a commercial technical microwave reactor with temperature and pressure
controlling capacity.
Isolated yields of 4. The numbers given in the parentheses are the yields
for the room temperature reactions.
The bisalkylation byproduct was isolated in 20% yield.
ꢀ
propionate in NMP at 180 C in the absence of a base
b
c
resulted in almost exclusive formation of 3-methyl-3,4-
dihydro-2-oxo-2H-1,4-benzoxazine along with some N,O-
bisalkylation byproduct. It was found that a base such as
DBU could preferentially remove the phenolic proton and
promote O-alkylation of 2-aminophenols with 2-bromoalka-
noates, leading to the formation of acyclic intermediates,
which then underwent in situ intramolecular amidation at
high temperatures under controlled microwave heating to
furnish the scaffolds 1 (Y¼H). By heating a mixture of
2-aminophenols 2, ethyl 2-bromopropionate, and DBU in
the following points: (a) use of 2 equiv of 2-bromoalka-
noates gave slightly higher yields (Table 2, entry 2 vs
entry 1); (b) N,O-bisalkylation byproducts were not ob-
served even using excess 2-bromoalkanoates with RsH;
(c) annulations using 2-bromoacetate (R¼H) always formed
N,O-bisalkylation byproducts and lower temperatures af-
forded higher yields of the desired products (Table 2, entry
6 vs entry 5 and entry 7 vs entry 10); and (d) for the reactions
of bulky 2-bromoalkanoates, excellent yields were obtained
at high reaction temperatures (Table 2, entries 11–13 vs
entries 8 and 9). Moreover, we found that the microwave-as-
ꢀ
NMP at 180 C for 3 min, we prepared a number of 3,4-
dihydro-2-methyl-3-oxo-2H-1,4-benzoxazines in 44–82%
yields. However, with bulky 2-bromoalkanoates, signifi-
cantly reduced yields were obtained for the desired benzox-
azine products.19b Moreover, the reactions of N-substituted
2-aminophenols have not been generally investigated for
the one-pot synthesis except for one report where ethyl bro-
moacetate was reacted with N-methyl 2-aminophenols in re-
fluxing MeOH in the presence of 10% aqueous NaOH.4d It is
the purpose of our current study to establish a reliable, gen-
eral, and efficient procedure for synthesis of the 3,4-dihydro-
3-oxo-2H-1,4-benzoxazine scaffolds 1 with three points of
diversity at X, Y, and Z.
ꢀ
sisted annulation reactions of bulky bromo esters at 180 C
gave comparable chemical yields as to those obtained from
Table 2. One-pot annulation of 4a–c under microwave heatinga
RCH(Br)CO2Et
X
OH
X
O
R
O
K2CO3 (1.5 eq)
DMF-H2O (2:1)
NH
N
MW
Ar
Ar
We prepared a variety of N-arylmethylated 2-aminophenols
4a–i22 from 2 and four representative electron-rich and
electron-deficient aromatic aldehydes (Table 1) under micro-
4a-c
5a-h
Entry T (ꢀC), t (min)
5
Yield (%)c
23
ꢀ
wave heating (80 C, 3 min). The yields of 4a–i were
comparable to those obtained from the reactions at room
temperature (1–2 h), despite that direct reduction of
aldehydes by NaBH(OAc)3 is a known competitive side-
reaction, especially for strongly electron-deficient alde-
hydes.24 An improved yield for the microwave-assisted
reaction was achieved for compound 4d (58%), which was
accompanied by bis-arylmethylation byproduct (20%) at
room temperature. The high-throughput rate is a unique
strength of the microwave-assisted reactions.
1
2
3
4
5
6
7
8
100, 20b
100, 20
100, 20
100, 25
120, 15b
100, 20b
80, 15b
100, 20b
100, 20b
180, 20
180, 20
180, 20
180, 20
5a: X¼R¼H, Ar¼2-furyl
5a: X¼R¼H, Ar¼2-furyl
5b: X¼H, R¼Et, Ar¼2-furyl
64d
68d
75
5c: X¼H, R¼n-Pr, Ar¼2-furyl
5d: X¼Me, R¼H, Ar¼Ph
74
51d
5d: X¼Me, R¼H, Ar¼Ph
60d
5e: X¼Me, R¼H, Ar¼2-furyl
5g: X¼Me, R¼Et, Ar¼2-furyl
5h: X¼Me, R¼n-Pr, Ar¼2-furyl
5e: X¼Me, R¼H, Ar¼2-furyl
5f: X¼Me, R¼Me, Ar¼2-furyl
5g: X¼Me, R¼Et, Ar¼2-furyl
5h: X¼Me, R¼n-Pr, Ar¼2-furyl
74d (80)
68
67
9
10
11
12
13
62d
85
81 (92)
80 (74)
The annulation of 4a–c with ethyl 2-bromoalkanoates was
examined using microwave heating in a mixture of DMF–
H2O (2:1) with dissolved K2CO3 as the base for avoiding
generation of ‘hot spots’, which may damage the reaction
vial (Table 2). On the basis of the results we can conclude
a
RCH(Br)CO2Et (2 equiv) was used.
RCH(Br)CO2Et (1.5 equiv) was used.
Isolated yields of 5. The numbers given in the parentheses are the yields
for the room temperature reactions (DMF, 3–4.5 h).
Various amounts of N,O-bisalkylation byproducts were detected.
b
c
d

G. Feng et al. / Tetrahedron 62 (2006) 4635–4642
Table 3. One-pot annulation of 4d under microwave heatinga Table 5. One-pot annulation of 4g–i under microwave heatinga
4637
RCH(Br)CO2Et
K2CO3 (1.5 eq)
n-PrCH(Br)CO2Et
OH
O
n-Pr
OH
O
N
R
K2CO3 (1.5 eq)
DMF-H2O (2:1)
100 °C, MW
DMF-H2O (2:1)
MW
180 °C, 30 min
Cl
NH
Cl
N
O
NH
O
O
O
Ar
Ar
4g-i
5t-v
4d
5i-k
Entry
5
Yield (%)b
Entry
t (min)
5
Yield (%)b
1
2
3
5t: Ar¼Ph
91
98
70
1
2
3
25
35
35
5i: R¼H
5j: R¼Et
5k: R¼n-Pr
67c
75
5u: Ar¼4-MeOC6H4
5v: Ar¼3-pyridinyl
RCH(Br)CO2Et (2 equiv) was used.
75
a
a
b
RCH(Br)CO2Et (2 equiv) was used.
Isolated yields of 5.
The N,O-bisalkylation byproduct was detected.
Isolated yields of 5.
b
c
2-alkyl-3,4-dihydro-6-nitro-3-oxo-2H-1,4-benzoxazines 5m–o
in 71–85% yields (Table 4, entries 2–4).
reactions of 4a–c at room temperature but with greatly short-
ened reaction times (Table 2, entries 12 and 13 vs entries
8 and 9).
Finally, we evaluated the one-pot annulation of 4g–i bearing
different arylmethyl groups on the nitrogen atom (Table 5).
ꢀ
By heating at 180 C for 30 min, the products 5t and 5u pos-
Table 3 shows the reactions of the bicyclic 2-aminophenol 4d
at 100 C under microwave irradiation. Good yields were ob-
sessing N-benzyl and N-4-methoxybenzyl (PMB) groups
were formed in 91% and 98% yields, respectively. The
3,4-dihydro-3-oxo-2H-1,4-benzoxazine 5v was isolated in
70% yield presumably due to the influence of the 3-pyri-
dinylmethyl group.
ꢀ
tained for 5i–k and the N,O-bisalkylation byproduct was also
detected in the reaction of 2-bromoacetate (Table 3, entry 1).
The reactions of 2-aminophenols 4e,f possessing an elec-
tron-withdrawing group are very different from those de-
scribed in Tables 2 and 3. When 4e was treated with ethyl
2-bromoacetate and K2CO3 in DMF at room temperature,
the O-alkylation intermediate25 was isolated in 99% yield
without formation of the expected 5l, which was formed in
3. Conclusion
In summary, we have established a high-throughput syn-
thesis for access to a variety of 2-alkyl-4-arylmethyl-3,4-
dihydro-3-oxo-2H-1,4-benzoxazine scaffolds starting from
readily available substituted 2-aminophenols. The synthesis
takes advantage of microwave-assisted fast reductive N-aryl-
ꢀ
56% yield by heating at 200 C for 40 min (Table 4, entry 1).
Alsoꢀ, the annulation of 4f with ethyl 2-bromovalerate at
100 C for 30 min produced a mixture of the acyclic
O-alkylation intermediate and 5s in 20% and 68% yields, re-
spectively (Table 4, entry 8). The one-pot reactions of 4f
ꢀ
methylation (80 C, 3 min) of 2-aminophenols, followed by
microwave-assisted one-pot regioselective annulation with
2-bromoalkanoates in aqueous DMF in the presence of
ꢀ
with 2-bromoalkanoates at 180 C furnished the products
ꢀ
heating at 180 C or above is necessary for high yielding
5q–s in 81–96% yields (Table 4, entries 5–7 and 9). On
the other hand, annulation reactioꢀns of 4e with 2-bromoalka-
noates required heating at 190 C for 40–45 min to give
K2CO3 (100–200 C, 20–45 min). In particular, microwave
ꢀ
of the 3,4-dihydro-3-oxo-2H-1,4-benzoxazines possessing
an electron-withdrawing NO2 or Cl group at the C6 position.
Table 4. One-pot annulation of 4e,f under microwave heatinga
4. Experimental
OH
O
R
RCH(Br)CO2Et
K2CO3 (1.5 eq)
4.1. General information and the microwave reactor
X
NH
X
N
O
O
DMF-H2O (2:1)
O
MW
1H and 13C NMR spectra were recorded in CDCl3, acetone-
d6, or DMSO-d6 (500 or 400 MHz for 1H and 125 or
100 MHz for 13C, respectively) with CHCl3, acetone, or
DMSO as the internal reference. IR spectra were taken on
an FTIR spectrophotometer. Mass spectra (MS) were mea-
sured by the ESI method. Elemental analyses were per-
formed at Zhejiang University. All reactions were carried
out on an Emrys creator from Personal Chemistry AB
(now under Biotage AB, Uppsala Sweden) with temperature
measured by an IR sensor. The microwave-assisted reaction
time is the hold time at the final temperature. The reaction
mixture was checked by thin-layer chromatography on silica
gel plates (60 F-254) using UV light, or 7% ethanolic phos-
phomolybdic acid and heating as the visualizing methods.
Flash column chromatography over silica gel was used for
4e,f
5l-s
Entry
T (ꢀC), t (min)
5
Yield (%)b
1
2
3
4
5
6
7
8
9
200, 40
190, 40
190, 45
190, 40
180, 30
180, 30
180, 30
100, 30
180, 30
5l: X¼NO2, R¼H
5m: X¼NO2, R¼Me
5n: X¼NO2, R¼Et
5o: X¼NO2, R¼n-Pr
5p: X¼Cl, R¼H
56
74
71
85
81
88
90
68c
96
5q: X¼Cl, R¼Me
5r: X¼Cl, R¼Et
5s: X¼Cl, R¼n-Pr
5s: X¼Cl, R¼n-Pr
a
RCH(Br)CO2Et (2 equiv) was used.
Isolated yields of 5.
The O-alkylation intermediate was obtained in 20% yield.
b
c

4638
G. Feng et al. / Tetrahedron 62 (2006) 4635–4642
purification. Yields refer to chromatographically and spec-
troscopically (1H NMR) homogeneous materials. Reagents
were obtained commercially and used as received.
3339, 2921, 1527, 1448, 1258, 1188, 1146 cmꢁ1; 1H NMR
(400 MHz, CDCl3) d 7.38 (s, 1H), 6.48 (s, 1H), 6.40 (s,
1H), 6.33 (dd, J¼1.2, 3.2 Hz, 1H), 6.24 (d, J¼3.2 Hz, 1H),
4.63 (br s, 2H), 4.27 (s, 2H), 2.66–2.60 (m, 4H), 1.75 (br s,
4H); C NMR (100 MHz, DMSO-d6, recorded at 80 C)
d 154.0, 142.6, 141.7, 135.0, 127.1, 124.4, 114.4, 111.2,
110.3, 106.5, 40.9, 28.6, 28.2, 23.3, 23.3; MS (ꢁESI) m/z
242 (MꢁH+, 100). Anal. Calcd for C15H17NO2: C, 74.05;
H, 7.04; N, 5.76. Found: C, 73.73; H, 6.94; N, 4.88%.
13
ꢀ
4.2. General procedure for reductive N-alkylation of
2-aminophenols under microwave irradiation
A 10 mL pressurized process vial was charged with a mixture
of an aldehyde (0.74 mmol), 2-aminophenol 2 (0.66 mmol),
and NaBH(OAc)3 (424.0 mg, 2 mmol) in THF (5 mL) and
was tightly sealed with a cap containing a silicon septum.
The loaded vial was then placed into the microꢀwave reactor
cavity and heated at the final temperature of 80 C for 3 min.
After cooling to room temperature the reaction mixture was
diluted with water and the resultant mixture was extracted
with EtOAc (10 mLꢂ3). The combined organic layer was
washed with brine, dried over anhydrous Na2SO4, and evap-
orated under reduced pressure. The residue was purified by
column chromatography over silica gel to provide the prod-
uct 4. The yields are listed in Table 1.
4.2.5. 2-(20-Furylmethyl)amino-4-nitrophenol (4e). Pre-
pared in 81%ꢀyield. Compound 4e. A red crystalline solid;
mp 118–120 C (EtOAc–hexane); Rf¼0.17 (20% EtOAc
in hexane); IR (KBr) 3407, 1527, 1468, 1335, 1275, 1245,
1
1101 cmꢁ1; H NMR (400 MHz, DMSO-d6) d 11.04 (br s,
1H), 7.58 (d, J¼1.6 Hz, 1H), 7.46 (dd, J¼2.8, 8.4 Hz, 1H),
7.34 (d, J¼2.8 Hz, 1H), 6.80 (d, J¼8.4 Hz, 1H), 6.39 (dd,
J¼1.6, 3.2 Hz, 1H), 6.29 (d, J¼3.2 Hz, 1H), 5.81 (br s,
1H), 4.39 (s, 2H); 13C NMR (100 MHz, DMSO-d6)
d 153.0, 151.4, 142.5, 140.7, 137.6, 113.8, 112.6, 110.8,
107.4, 104.0, 31.1; MS (ꢁESI) m/z 233 (MꢁH+, 100).
Anal. Calcd for C11H10N2O4: C, 56.41; H, 4.30; N, 11.96.
Found: C, 56.29; H, 4.37; N, 12.31%.
4.2.1. 2-(20-Furylmethyl)aminophenol (4a). Prepared in
73% yield. Compound 4a. A pale yellow gum; Rf¼0.40
(20% EtOAc in hexane); IR (film) 3406, 3327, 3120, 1609,
1509, 1449, 1265, 1195 cmꢁ1
;
1H NMR (400 MHz,
4.2.6. 4-Chloro-2-(20-furylmethyl)aminophenol (4f). Pre-
pared in 86% yield. Compound 4f. A white crystalline solid;
CDCl3) d 7.38 (s, 1H), 6.89–6.67 (m, 4H), 6.33 (br s, 1H),
6.25 (br s, 1H), 5.50–4.50 (br s, 2H), 4.32 (s, 2H); 13C
NMR (100 MHz, CDCl3) d 152.6, 144.2, 141.9, 136.2,
121.4, 118.9, 114.7, 113.4, 110.3, 107.1, 41.9; MS (ꢁESI)
m/z 188 (MꢁH+, 100). HRMS (+ESI) calcd for
C11H11NO2Na 212.0683 (M+Na+), found 212.0680.
ꢀ
in hexane); IR (KBr) 3407, 1611, 1512, 1445, 1419,
mp 84–87 C (CH2Cl2–hexane); Rf¼0.31 (20% EtOAc
1
1190 cmꢁ1; H NMR (400 MHz, CDCl3) d 7.38 (s, 1H),
6.69 (s, 1H), 6.60–6.55 (m, 2H), 6.34 (dd, J¼1.6, 3.2 Hz,
1H), 6.25 (d, J¼3.2 Hz, 1H), 4.76 (br s, 2H), 4.29 (s, 2H);
13C NMR (100 MHz, CDCl3) d 151.8, 142.1, 142.0, 137.4,
126.5, 117.4, 115.1, 112.3, 110.4, 107.4, 41.3; MS (ꢁESI)
m/z 222 (MꢁH+, 61.5), 224 (M+2ꢁH+, 19.7), 445
(2MꢁH+, 100). Anal. Calcd for C11H10ClNO2: C, 59.07;
H, 4.51; N, 6.26. Found: C, 58.82; H, 4.64; N, 5.95%.
4.2.2. 2-Benzylamino-5-methylphenol (4b). Prepared in
79% yield. Compound 4b. A white crystalline solid; mp
ꢀ
hexane); IR (KBr) 3422 (br), 3314, 3033, 2918, 1527,
98–102 C (EtOAc–hexane); Rf¼0.46 (20% EtOAc in
1474, 1451, 1420, 1126 cmꢁ1
;
1H NMR (400 MHz,
CDCl3) d 7.34–7.19 (m, 5H), 6.59 (s, 2H), 6.44 (s, 1H),
4.71 (br s, 2H), 4.25 (s, 2H), 2.15 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 144.2, 139.4, 134.1, 128.6 (ꢂ2),
128.5, 127.7 (ꢂ2), 127.2, 121.6, 115.6, 113.6, 49.3, 20.6;
MS (+ESI) m/z 235 (M+Na+, 81), 213 (M+, 100). Anal.
Calcd for C14H15NO: C, 78.84; H, 7.09; N, 6.57. Found:
C, 78.92; H, 7.16; N, 6.65%.
4.2.7. 2-Benzylamino-4-chlorophenol (4g). Prepared in
91% yield. Compound 4g. A pale yellow crystalline solid;
mp 118–120 C (EtOAc–hexane); Rf¼0.36 (20% EtOAc
ꢀ
in hexane); IR (KBr) 3505, 3403, 1609, 1514, 1154,
1
1114 cmꢁ1; H NMR (400 MHz, CDCl3) d 7.38–7.28 (m,
5H), 6.63 (d, J¼8.0 Hz, 1H), 6.62 (d, J¼2.0 Hz, 1H), 6.56
(dd, J¼2.0, 8.0 Hz, 1H), 4.32 (s, 2H) (signals for OH and
NH were not found); 13C NMR (100 MHz, CDCl3)
d 141.6, 138.4, 137.9, 128.7 (ꢂ2), 127.6 (ꢂ2), 127.5,
126.6, 116.8, 114.9, 111.8, 48.2; MS (ꢁESI) m/z 232
(MꢁH+, 100), 234 (M+2ꢁH+, 31). Anal. Calcd for
C13H12ClNO: C, 66.81; H, 5.18; N, 5.99. Found: C, 66.87;
H, 5.19; N, 6.00%.
4.2.3. 2-(20-Furylmethyl)amino-5-methylphenol (4c). Pre-
pared in 75% yield. Compound 4c. Awhite crystalline solid;
ꢀ
hexane); IR (KBr) 3429 (br), 3350, 3339, 2919, 1529,
mp 80–82 C (EtOAc–hexane); Rf¼0.42 (20% EtOAc in
1451, 1419, 1125 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d 7.38 (d, J¼1.6 Hz, 1H), 6.71 (d, J¼8.0 Hz, 1H), 6.67 (d,
J¼8.4 Hz, 1H), 6.46 (s, 1H), 6.33 (dd, J¼1.6, 3.2 Hz, 1H),
6.23 (d, J¼3.2 Hz, 1H), 5.16 (br s, 2H), 4.29 (s, 2H), 2.11
(s, 3H); 13C NMR (100 MHz, CDCl3) d 152.7, 145.0,
141.9, 133.3, 129.5, 121.4, 115.8, 114.5, 110.3, 107.2,
42.5, 20.6; MS (ꢁESI) m/z 202 (MꢁH+, 100). Anal. Calcd
for C12H13NO2$1/8 H2O: C, 70.14; H, 6.50; N, 6.82. Found:
C, 70.31; H, 6.67; N, 5.62%.
4.2.8. 4-Chloro-2-((40-methoxyphenyl)methyl)amino-
phenol (4h). Prepared in 80%ꢀyield. Compound 4h. A white
crystalline solid; mp 148–151 C (EtOAc–hexane); Rf¼0.34
(20% EtOAc in hexane); IR (KBr) 3497, 3409, 1608, 1513,
1
1415, 1253, 1116 cmꢁ1; H NMR (400 MHz, acetone-d6)
d 8.59 (s, 1H), 7.33 (d, J¼8.4 Hz, 2H), 6.90 (d, J¼8.4 Hz,
2H), 6.70 (d, J¼8.4 Hz, 1H), 6.48 (d, J¼2.4 Hz, 1H), 6.42
(dd, J¼2.4, 8.4 Hz, 1H), 5.11 (br s, 1H), 4.34 (s, 2H), 3.78
(s, 3H); 13C NMR (100 MHz, acetone-d6) d 158.8, 142.7,
138.8, 131.5, 128.3 (ꢂ2), 124.6, 114.9, 113.9, 113.7 (ꢂ2),
109.8, 54.5, 46.3; MS (ꢁESI) m/z 262 (MꢁH+, 72), 264
(M+2ꢁH+, 23), 525.3 (2MꢁH+, 100). Anal. Calcd for
4.2.4. 3-(20-Furylmethyl)amino-5,6,7,8-tetrahydro-2-
naphthol (4d). Prepared in 58% yield. Compound 4d. A
ꢀ
white crystalline solid; mp 76–78 C (CH2Cl2–hexane);
Rf¼0.44 (20% EtOAc in hexane); IR (KBr) 3456 (br),

G. Feng et al. / Tetrahedron 62 (2006) 4635–4642
4639
C14H14ClNO2: C, 63.76; H, 5.35; N, 5.31. Found: C, 63.52;
H, 5.52; N, 3.51%.
4.3.3. 3,4-Dihydro-4-(20-furylmethyl)-3-oxo-2-propyl-
2H-1,4-benzoxazine (5c). Prepared in 74% yield. Com-
pound 5c. A white amorphous solid; Rf¼0.65 (11% EtOAc
in hexane); IR (KBr) 2962, 1688, 1502, 1401, 1279,
4.2.9. 4-Chloro-2-(30-pyridinylmethyl)aminophenol (4i).
Prepared in 87% yield. Compound 4i. A pale green crystal-
1147 cmꢁ1 1H NMR (400 MHz, CDCl3) d 7.34 (dd,
;
ꢀ
in hexane); IR (KBr) 3435, 2931, 1609, 1582, 1519, 1428,
line solid; mp 168–174 C (MeOH); Rf¼0.19 (67% EtOAc
J¼1.6, 0.8 Hz, 1H), 7.18–7.16 (m, 1H), 7.01–6.97 (m, 3H),
6.31 (dd, J¼2.8, 1.6 Hz, 1H), 6.28 (dd, J¼2.8, 0.8 Hz, 1H),
5.11 and 5.03 (ABq, J¼16.2 Hz, 2H), 4.59 (dd, J¼8.4,
5.2 Hz, 1H), 1.88–1.81 (m, 2H), 1.64–1.49 (m, 2H), 0.96
(t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 166.4,
149.9, 144.1, 142.1, 128.9, 124.0, 122.5, 117.4, 115.1,
110.6, 108.4, 76.9, 38.6, 32.2, 18.3, 13.7; MS (+ESI) m/z
565 (2M+Na+, 100), 294 (M+Na+, 29). HRMS (+ESI) calcd
for C16H17NO3Na 294.1101 (M+Na+), found 294.1108.
1
1251, 1206 cmꢁ1; H NMR (400 MHz, DMSO-d6) d 9.64
(s, 1H), 8.56 (s, 1H), 8.43 (d, J¼4.8 Hz, 1H), 7.72
(d, J¼7.6 Hz, 1H), 7.33 (dd, J¼4.8, 7.6 Hz, 1H), 6.63
(d, J¼8.4 Hz, 1H), 6.39 (dd, J¼2.0, 8.4 Hz, 1H), 6.35 (d,
J¼2.0 Hz, 1H), 5.77 (br s, 1H), 4.35 (s, 2H); 13C NMR
(100 MHz, DMSO-d6) d 149.1, 148.3, 143.5, 138.6, 135.8,
135.3, 123.9, 123.6, 115.3, 114.5, 109.7, 43.9; MS (ꢁESI)
m/z 233 (MꢁH+, 100), 235 (M+2ꢁH+, 32). Anal. Calcd
for C12H11ClN2O$1/8 H2O: C, 60.83; H, 4.79; N, 11.82.
Found: C, 60.74; H, 4.96; N, 11.08%.
4.3.4. 4-Benzyl-3,4-dihydro-7-methyl-3-oxo-2H-1,4-
benzoxazine (5d). Prepared in 60% yield. Compound 5d.
ꢀ
A white crystalline solid; mp 87–89 C (EtOAc–hexane);
4.3. General procedure for microwave-assisted
one-pot synthesis of 5
Rf¼0.53 (20% EtOAc in hexane); IR (KBr) 1683, 1513,
1405, 1296, 1150 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d 7.34–7.24 (m, 5H), 6.82 (s, 1H), 6.76 (d, J¼8.0 Hz, 1H),
6.70 (d, J¼8.0 Hz, 1H), 5.15 (s, 2H), 4.71 (s, 2H), 2.26
(s, 3H); 13C NMR (100 MHz, CDCl3) d 164.6, 145.2,
136.1, 134.1, 128.9 (ꢂ2), 127.5, 126.7 (ꢂ2), 126.3, 123.3,
117.6, 115.5, 67.8, 45.0, 20.7; MS (+ESI) m/z 529
(2M+Na+, 100), 276 (M+Na+, 85). Anal. Calcd for
C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C, 75.75;
H, 5.94; N, 5.52%.
A 10 mL pressurized process vial was charged with a mixture
of the aminophenol 4 (0.30 mmol), ethyl 2-bromo ester
(0.60 mmol), and K2CO3 (62.8 mg, 0.45 mmol) in water
(1 mL) and DMF (2 mL) and was tightly sealed with a cap
containing a silicon septum. The loaded vial was then placed
into the microwave reactor cavity and was heated at the
final temperature for the specified time (see Tables 2–5 for
details). After cooling to room temperature the reaction
mixture was diluted with water (5 mL) and the resultant mix-
ture was extracted with EtOAc (10 mLꢂ3). The combined
organic layer was washed with brine, dried over anhydrous
Na2SO4 and evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel to fur-
nish the product 5. The yields are listed in Tables 2–5.
4.3.5. 3,4-Dihydro-4-(20-furylmethyl)-7-methyl-3-oxo-
2H-1,4-benzoxazine (5e). Prepared in 74% yield. Coꢀm-
pound 5e. A yellowish crystalline solid; mp 75–76 C
(EtOAc–hexane); Rf¼0.38 (11% EtOAc in hexane); IR
(KBr) 1679, 1514, 1407, 1152, 1011 cmꢁ1 1H NMR
;
(400 MHz, CDCl3) d 7.34 (s, 1H), 7.08 (d, J¼8.0 Hz, 1H),
6.81 (d, J¼8.0 Hz, 1H), 6.81 (s, 1H), 6.31 (s, 1H), 6.30 (s,
1H), 5.06 (s, 2H), 4.61 (s, 2H), 2.28 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 164.2, 149.6, 145.0, 142.1, 134.1,
126.2, 123.2, 117.5, 115.1, 110.5, 108.6, 67.7, 38.2, 20.7;
MS (+ESI) m/z 509 (2M+Na+, 100), 266 (M+Na+, 46).
Anal. Calcd for C14H13NO3: C, 69.12; H, 5.39; N, 5.76.
Found: C, 69.26; H, 5.46; N, 5.68%.
4.3.1. 3,4-Dihydro-4-(20-furylmethyl)-3-oxo-2H-1,4-
benzoxazine (5a). Prepared in 68% yield. Compound 5a.
A yellow oil; Rf¼0.41 (11% EtOAc in hexane); IR (film)
3120, 2890, 1690, 1502, 1400, 1281, 1054 cmꢁ1; 1H NMR
(400 MHz, CDCl3) d 7.34 (dd, J¼1.6, 1.2 Hz, 1H), 7.24–
7.21 (m, 1H), 7.03–6.97 (m, 3H), 6.33–6.31 (m, 2H), 5.08
(s, 2H), 4.63 (s, 2H); 13C NMR (100 MHz, CDCl3)
d 164.4, 149.6, 145.3, 142.2, 128.7, 124.1, 122.8, 117.0,
115.5, 110.6, 108.8, 67.7, 38.3; MS (+ESI) m/z 481
(2M+Na+, 100), 252 (M+Na+, 98). HRMS (+ESI) calcd
for C13H11NO3Na 252.0631 (M+Na+), found 252.0629.
4.3.6. 3,4-Dihydro-4-(20-furylmethyl)-2,7-dimethyl-3-
oxo-2H-1,4-benzoxazine (5f). Prepared in 85% yield. Coꢀm-
pound 5f. A yellowish crystalline solid; mp 67–68 C
(EtOAc–hexane); Rf¼0.48 (11% EtOAc in hexane); IR
(KBr) 2981, 1513, 1399, 1158, 1019 cmꢁ1 1H NMR
;
4.3.2. 2-Ethyl-3,4-dihydro-4-(20-furylmethyl)-3-oxo-2H-
1,4-benzoxazine (5b). Prepared in 75% yieldꢀ. Compound
5b. A yellowish crystalline solid; mp 54–55 C (EtOAc–
hexane); Rf¼0.53 (11% EtOAc in hexane); IR (KBr) 2972,
(400 MHz, CDCl3) d 7.34 (s, 1H), 7.06 (d, J¼8.4 Hz, 1H),
6.81 (d, J¼8.4 Hz, 1H), 6.80 (s, 1H), 6.30 (dd, J¼3.2,
2.0 Hz, 1H), 6.28 (d, J¼3.2 Hz, 1H), 5.12 and 4.97 (ABq,
J¼15.8 Hz, 2H), 4.62 (q, J¼6.8 Hz, 1H), 2.28 (s, 3H),
1.56 (d, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.5, 149.9, 144.3, 142.1, 134.0, 126.5, 123.1, 117.8,
114.9, 110.5, 108.4, 73.5, 38.7, 20.7, 16.2; MS (+ESI) m/z
537 (2M+Na+, 100), 280 (M+Na+, 44). Anal. Calcd for
C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.16;
H, 6.10; N, 5.46%.
1687, 1502, 1401, 1278, 1141, 1016 cmꢁ1 1H NMR
;
(400 MHz, CDCl3) d 7.34 (dd, J¼2.0, 0.8 Hz, 1H), 7.19–
7.15 (m, 1H), 7.01–6.98 (m, 3H), 6.31 (dd, J¼3.2, 2.0 Hz,
1H), 6.29 (dd, J¼3.2, 0.8 Hz, 1H), 5.10 and 5.04 (ABq,
J¼16.2 Hz, 2H), 4.50 (dd, J¼8.8, 4.8 Hz, 1H), 1.99–1.83
(m, 2H), 1.08 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 166.3, 149.9, 144.2, 142.1, 128.9, 124.0, 122.5,
117.3, 115.1, 110.6, 108.4, 78.2, 38.6, 23.7, 9.4; MS
(+ESI) m/z 537 (2M+Na+, 100), 280 (M+Na+, 41). Anal.
Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found:
C, 70.05; H, 6.07; N, 5.48%.
4.3.7. 2-Ethyl-3,4-dihydro-4-(20-furylmethyl)-7-methyl-
3-oxo-2H-1,4-benzoxazine (5g). Prepared in 81% yield.
Compound 5g. A yellowish oil; Rf¼0.56 (11% EtOAc in
hexane); IR (film) 2971, 1686, 1514, 1403, 1149 cmꢁ1
;

4640
G. Feng et al. / Tetrahedron 62 (2006) 4635–4642
1H NMR (400 MHz, CDCl3) d 7.33 (d, J¼2.0 Hz, 1H), 7.03
(d, J¼7.6 Hz, 1H), 6.81 (s, 1H), 6.79 (d, J¼8.0 Hz, 1H),
6.30 (dd, J¼3.2, 2.0 Hz, 1H), 6.27 (d, J¼3.2 Hz, 1H),
5.09 and 5.02 (ABq, J¼16.0 Hz, 2H), 4.48 (dd, J¼8.4,
4.4 Hz, 1H), 2.28 (s, 3H), 1.95–1.82 (m, 2H), 1.07
(t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 166.1,
149.9, 143.9, 142.0, 134.0, 126.3, 122.9, 117.8, 114.8,
110.5, 108.2, 78.2, 38.5, 23.6, 20.7, 9.4; MS (+ESI) m/z
565 (2M+Na+, 100), 294 (M+Na+, 41). HRMS (+ESI)
calcd for C16H17NO3Na 294.1101 (M+Na+), found
294.1102.
96–97 C (EtOAc–hexane); Rf¼0.58 (11% EtOAc in
hexane); IR (KBr) 2958, 1682, 1509, 1395, 1146 cmꢁ1; 1H
NMR (400 MHz, CDCl3) d 7.34 (d, J¼2.0 Hz, 1H), 6.82
(s, 1H), 6.68 (s, 1H), 6.31 (dd, J¼3.2, 2.0 Hz, 1H), 6.27
(d, J¼3.2 Hz, 1H), 5.09 and 4.99 (ABq, J¼16.0 Hz, 2H),
4.54 (dd, J¼7.2, 6.0 Hz, 1H), 2.71–2.68 (m, 4H), 1.85–
1.78 (m, 2H), 1.77–1.75 (m, 4H), 1.61–1.47 (m, 2H), 0.96
(t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 166.5,
150.0, 142.0, 141.7, 132.9, 131.0, 126.4, 117.2, 115.2,
110.5, 108.2, 76.9, 38.5, 32.1, 29.1, 28.8, 23.2, 23.0, 18.3,
13.6; MS (+ESI) m/z 673 (2M+Na+, 100), 348 (M+Na+,
45). Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12; N,
4.30. Found: C, 73.79; H, 7.67; N, 4.41%.
ꢀ
4.3.8. 3,4-Dihydro-4-(20-furylmethyl)-7-methyl-3-oxo-2-
propyl-2H-1,4-benzoxazine (5h). Prepared in 80% yield.
Compound 5h. A yellow amorphous solid; Rf¼0.62 (11%
EtOAc in hexane); IR (KBr) 2961, 1686, 1514, 1401,
4.3.12. 3,4-Dihydro-4-(20-furylmethyl)-6-nitro-3-oxo-2H-
1,4-benzoxazine (5l). Prepared in 56% yield. ꢀCompound 5l.
A yellow crystalline solid; mp 125–126 C (CH2Cl2–
hexane); Rf¼0.14 (11% EtOAc in hexane); IR (KBr) 1705,
1
1292, 1149 cmꢁ1; H NMR (400 MHz, CDCl3) d 7.33 (d,
J¼1.2 Hz, 1H), 7.03 (d, J¼8.4 Hz, 1H), 6.80 (s, 1H), 6.79
(d, J¼8.4 Hz, 1H), 6.30 (dd, J¼2.8, 1.2 Hz, 1H), 6.26 (d,
J¼2.8 Hz, 1H), 5.09 and 5.00 (ABq, J¼15.8 Hz, 2H), 4.56
(dd, J¼8.0, 4.8 Hz, 1H), 2.28 (s, 3H), 1.86–1.80 (m, 2H),
1.61–1.48 (m, 2H), 0.96 (t, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 166.2, 149.9, 143.8, 142.0, 134.0,
126.3, 122.9, 117.9, 114.8, 110.5, 108.2, 76.9, 38.5, 32.1,
20.7, 18.3, 13.6; MS (+ESI) m/z 593 (2M+Na+, 100), 308
(M+Na+, 32). HRMS (+ESI) calcd for C17H19NO3Na
308.1257 (M+Na+), found 308.1256.
1519, 1341, 1276 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d 8.21 (d, J¼2.4 Hz, 1H), 7.93 (dd, J¼8.8, 2.4 Hz, 1H),
7.38 (dd, J¼2.0, 0.8 Hz, 1H), 7.06 (d, J¼8.8 Hz, 1H), 6.43
(dd, J¼3.6, 0.8 Hz, 1H), 6.34 (dd, J¼3.6, 2.0 Hz, 1H),
5.16 (s, 2H), 4.77 (s, 2H); 13C NMR (100 MHz, CDCl3)
d 162.8, 150.0, 148.3, 143.0, 142.8, 128.7, 120.0, 117.1,
111.3, 110.7, 109.8, 67.3, 38.2; MS (+ESI) m/z 571
(2M+Na+, 43), 297 (M+Na+, 100). Anal. Calcd for
C13H10N2O5: C, 56.94; H, 3.68; N, 10.22. Found: C,
56.84; H, 3.66; N, 10.25%.
4.3.9. 6,7,8,9-Tetrahydro-4-(20-furylmethyl)-3-oxo-2H-
naphtho[2,3,b][1,4]oxazine (5i). Prepared in 67% yieꢀld.
Compound 5i. A white crystalline solid; mp 104–106 C
(EtOAc–hexane); Rf¼0.39 (11% EtOAc in hexane); IR
(KBr) 2926, 1701, 1679, 1515, 1389, 1017 cmꢁ1; 1H NMR
(400 MHz, CDCl3) d 7.35 (dd, J¼1.6, 0.8 Hz, 1H), 6.88
(s, 1H), 6.69 (s, 1H), 6.32 (dd, J¼3.2, 1.6 Hz, 1H), 6.30
(dd, J¼3.2, 0.8 Hz, 1H), 5.06 (s, 2H), 4.58 (s, 2H), 2.71–
2.68 (m, 4H), 1.79–1.74 (m, 4H); 13C NMR (100 MHz,
CDCl3) d 164.5, 149.8, 143.2, 142.1, 133.0, 131.4, 126.4,
116.9, 115.6, 110.6, 108.6, 67.8, 38.3, 29.1, 28.8, 23.1,
23.0; MS (+ESI) m/z 589 (2M+Na+, 100), 306 (M+Na+,
34). Anal. Calcd for C17H17NO3: C, 72.07; H, 6.05; N,
4.94. Found: C, 72.08; H, 6.30; N, 5.15%.
4.3.13. 3,4-Dihydro-4-(20-furylmethyl)-2-methyl-6-nitro-
3-oxo-2H-1,4-benzoxazine (5m). Prepared in 74% yieꢀld.
Compound 5m. A yellow crystalline solid; mp 146–147 C
(CH2Cl2–hexane); Rf¼0.24 (11% EtOAc in hexane);
IR (KBr) 1685, 1522, 1341, 1005 cmꢁ1
;
1H NMR
(400 MHz, CDCl3) d 8.18 (d, J¼2.4 Hz, 1H), 7.93 (dd,
J¼8.8, 2.4 Hz, 1H), 7.37 (d, J¼1.6 Hz, 1H), 7.06 (d,
J¼8.8 Hz, 1H), 6.40 (d, J¼3.2 Hz, 1H), 6.33 (dd, J¼3.2,
1.6 Hz, 1H), 5.20 and 5.07 (ABq, J¼16.2 Hz, 2H), 4.78
(q, J¼6.8 Hz, 1H), 1.61 (d, J¼6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 165.4, 149.6, 148.5, 143.0, 142.8,
129.0, 120.0, 117.4, 111.1, 110.6, 109.5, 73.9, 38.6, 16.9;
MS (+ESI) m/z 311 (M+Na+, 100). Anal. Calcd for
C14H12N2O5: C, 58.33; H, 4.20; N, 9.72. Found: C,
58.32; H, 4.36; N, 9.88%.
4.3.10. 2-Ethyl-6,7,8,9-tetrahydro-4-(20-furylmethyl)-3-
oxo-2H-naphtho[2,3,b][1,4]oxazine (5j). Prepared in 75%
yield. Compound 5j. A white crystalline solid; mp 79–
4.3.14. 2-Ethyl-3,4-dihydro-4-(20-furylmethyl)-6-nitro-3-
oxo-2H-1,4-benzoxazine (5n). Prepared in 71% yieꢀld.
Compound 5n. A yellow crystalline solid; mp 77–78 C
(CH2Cl2–hexane); Rf¼0.32 (11% EtOAc in hexane); IR
ꢀ
80 C (EtOAc–hexane); Rf¼0.53 (11% EtOAc in hexane);
IR (KBr) 2936, 1680, 1514, 1262 cmꢁ1
;
1H NMR
(400 MHz, CDCl3) d 7.34 (dd, J¼2.0, 0.4 Hz, 1H), 6.81 (s,
1H), 6.69 (s, 1H), 6.31 (dd, J¼2.8, 2.0 Hz, 1H), 6.30 (dd,
J¼2.8, 0.4 Hz, 1H), 5.08 and 5.00 (ABq, J¼15.8 Hz, 2H),
4.45 (dd, J¼8.4, 4.4 Hz, 1H), 2.71–2.67 (m, 4H), 1.94–
1.82 (m, 2H), 1.78–1.73 (m, 4H), 1.06 (t, J¼7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 166.3, 150.0, 142.0, 141.7,
132.9, 131.0, 126.4, 117.2, 115.2, 110.5, 108.2, 78.3, 38.5,
29.1, 28.8, 23.6, 23.2, 23.0, 9.5; MS (+ESI) m/z 645
(2M+Na+, 100), 334 (M+Na+, 86). Anal. Calcd for
C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C, 73.31;
H, 7.36; N, 4.74%.
(KBr) 2976, 1689, 1523, 1243, 1272 cmꢁ1 1H NMR
;
(400 MHz, CDCl3) d 8.14 (d, J¼2.4 Hz, 1H), 7.91 (dd,
J¼2.4, 2.8 Hz, 1H), 7.35 (d, J¼2.0 Hz, 1H), 7.05 (d,
J¼8.8 Hz, 1H), 6.39 (d, J¼3.2 Hz, 1H), 6.32 (dd, J¼3.2,
2.0 Hz, 1H), 5.17 and 5.09 (ABq, J¼15.8 Hz, 2H), 4.72
(dd, J¼8.8, 4.8 Hz, 1H), 1.91–1.82 (m, 2H), 0.95 (t,
J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 164.9,
149.4, 148.5, 142.8, 142.7, 128.8, 120.0, 117.3, 110.9,
110.6, 109.4, 78.5, 38.4, 24.3, 9.1; MS (+ESI) m/z 325
(M+Na+, 100). Anal. Calcd for C15H14N2O5: C, 59.60; H,
4.67; N, 9.27. Found: C, 59.65; H, 4.81; N, 9.47%.
4.3.11. 6,7,8,9-Tetrahydro-4-(20-furylmethyl)-3-oxo-2-
propyl-2H-naphtho[2,3,b][1,4]oxazine (5k). Prepared in
75% yield. Compound 5k. A white crystalline solid; mp
4.3.15. 3,4-Dihydro-4-(20-furylmethyl)-6-nitro-3-oxo-2-
propyl-2H-1,4-benzoxazine (5o). Prepared in 85% yield.

G. Feng et al. / Tetrahedron 62 (2006) 4635–4642
4641
ꢀ
ꢀ
Compound 5o. A yellow crystalline solid; mp 62–64 C
(EtOAc–hexane); Rf¼0.40 (11% EtOAc in hexane); IR
Compound 5s. A white crystalline solid; mp 46–47 C
(EtOAc–hexane); Rf¼0.63 (11% EtOAc in hexane); IR
(KBr) 2966, 1692, 1525, 1340, 1014 cmꢁ1
;
1H NMR
(KBr) 2964, 1679, 1500, 1437, 1366, 1273, 1150 cmꢁ1
;
(400 MHz, CDCl3) d 8.14 (d, J¼2.4 Hz, 1H), 7.91 (dd,
J¼8.8, 2.8 Hz, 1H), 7.35 (d, J¼1.6 Hz, 1H), 7.05 (d,
J¼8.8 Hz, 1H), 6.38 (d, J¼3.2 Hz, 1H), 6.32 (dd, J¼3.2,
1.6 Hz, 1H), 5.17 and 5.09 (ABq, J¼15.8 Hz, 2H), 4.72
(dd, J¼8.8, 4.8 Hz, 1H), 1.91–1.82 (m, 2H), 1.58–1.48 (m,
2H), 0.95 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 165.1, 149.3, 148.5, 142.8, 142.7, 128.8, 120.0, 117.4,
110.1, 110.6, 109.4, 77.3, 38.4, 32.8, 18.0, 13.5; MS
(+ESI) m/z 339 (M+Na+, 100). Anal. Calcd for
C16H16N2O5: C, 60.75; H, 5.10; N, 8.86. Found: C, 60.80;
H, 5.21; N, 8.87%.
1H NMR (400 MHz, CDCl3) d 7.36 (dd, J¼2.0, 0.8 Hz,
1H), 7.18 (d, J¼2.0 Hz, 1H), 6.95 (dd, J¼8.4, 2.0 Hz,
1H), 6.89 (d, J¼8.4 Hz, 1H), 6.32 (dd, J¼3.2, 2.0 Hz,
1H), 6.31 (dd, J¼3.2, 0.8 Hz, 1H), 5.07 and 4.98 (ABq,
J¼16.0 Hz, 2H), 4.56 (dd, J¼8.8, 4.8 Hz, 1H), 1.86–1.78
(m, 2H), 1.58–1.49 (m, 2H), 0.95 (t, J¼7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 166.0, 149.2, 142.7, 142.3,
129.9, 127.5, 123.6, 118.2, 115.3, 110.6, 108.8, 76.9,
38.6, 32.1, 18.2, 13.6; MS (+ESI) m/z 328 (M+Na+, 100),
331 (M+2+Na+, 32). Anal. Calcd for C16H16ClNO3: C,
62.85; H, 5.27; N, 4.58. Found: C, 63.01; H, 5.64; N,
4.82%.
4.3.16. 6-Chloro-3,4-dihydro-4-(20-furylmethyl)-3-oxo-
2H-1,4-benzoxazine (5p). Prepared in 81% yield. Coꢀm-
pound 5p. A white crystalline solid; mp 88–90 C
(CH2Cl2–hexane); Rf¼0.39 (11% EtOAc in hexane); IR
4.3.20. 4-Benzyl-6-chloro-3,4-dihydro-3-oxo-2-propyl-
2H-1,4-benzoxazine (5t). Prepared in 91% yieꢀld.
Compound 5t. A white crystalline solid; mp 70–73 C
(EtOAc–hexane); Rf¼0.71 (20% EtOAc in hexane); IR
(KBr) 2962, 1688, 1497, 1439, 1377, 1266 cmꢁ1; 1H NMR
(400 MHz, CDCl3) d 7.32–7.17 (m, 5H), 6.87 (s, 2H), 6.80
(s, 1H), 5.15 and 4.96 (ABq, J¼16.4 Hz, 2H), 4.63 (dd,
J¼8.4, 5.6 Hz, 1H), 1.89–1.82 (m, 2H), 1.62–1.47 (m,
2H), 0.95 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.4, 142.5, 135.5, 129.9, 128.9 (ꢂ2), 127.6, 127.4,
126.4 (ꢂ2), 123.6, 118.3, 115.4, 76.9, 45.1, 32.2, 18.2,
13.6; MS (+ESI) m/z 338 (M+Na+, 100), 340 (M+2+Na+,
31). HRMS (+ESI) calcd for C18H20ClNO2Na 338.0919
(M+Na+), found 338.0920.
1
(KBr) 1687, 1498, 1373, 1014 cmꢁ1; H NMR (400 MHz,
CDCl3) d 7.37 (d, J¼0.8 Hz, 1H), 7.23 (d, J¼2.0 Hz, 1H),
6.96 (dd, J¼8.4, 2.0 Hz, 1H), 6.90 (d, J¼8.4 Hz, 1H),
6.35–6.32 (m, 2H), 5.05 (s, 2H), 4.62 (s, 2H); 13C NMR
(100 MHz, CDCl3) d 164.9, 149.0, 143.8, 142.4, 129.7,
127.8, 123.7, 117.9, 115.6, 110.6, 109.1, 67.5, 38.3; MS
(+ESI) m/z 286 (M+Na+, 100), 288 (M+2+Na+, 32). Anal.
Calcd for C13H10ClNO3: C, 59.22; H, 3.82; N, 5.31. Found:
C, 59.12; H, 3.80; N, 5.22%.
4.3.17. 6-Chloro-3,4-dihydro-4-(20-furylmethyl)-2-
methyl-3-oxo-2H-1,4-benzoxazine (5q). Prepared in 88%
yield. Compound 5q. A white crystalline solid; mp 96–
4.3.21. 6-Chloro-3,4-dihydro-4-(40-methoxybenzyl)-3-
oxo-2-propyl-2H-1,4-benzoxazine (5u). Prepared in 98%
yield. Compound 5u. A white crystalline solid; mp 74–
ꢀ
97 C (CH2Cl2–hexane); Rf¼0.50 (11% EtOAc in hexane);
1
IR (KBr) 2938, 1672, 1499, 1374, 1264, 1016 cmꢁ1; H
ꢀ
NMR (400 MHz, CDCl3) d 7.37 (s, 1H), 7.21 (d,
J¼2.0 Hz, 1H), 6.95 (dd, J¼8.4, 2.0 Hz, 1H), 6.90
(d, J¼8.4 Hz, 1H), 6.33 (s, 2H), 5.11 and 4.94 (ABq,
J¼15.8 Hz, 2H), 4.62 (q, J¼6.4 Hz, 1H), 1.56 (d,
J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 166.3,
149.2, 143.1, 142.4, 130.1, 127.6, 123.6, 118.2, 115.4,
110.6, 108.9, 73.5, 38.8, 16.1; MS (+ESI) m/z 300
(M+Na+, 100), 302 (M+2+Na+, 32). Anal. Calcd for
C14H12ClNO3: C, 60.55; H, 4.36; N, 5.04. Found: C,
60.53; H, 4.46; N, 5.19%.
75 C (EtOAc–hexane); Rf¼0.63 (20% EtOAc in hexane);
IR (KBr) 2963, 1685, 1513, 1498, 1439, 1382, 1249 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 7.17 (d, J¼8.8 Hz, 2H),
6.90–6.85 (m, 5H), 5.12 and 4.94 (ABq, J¼16.0 Hz, 2H),
4.65 (dd, J¼8.4, 5.2 Hz, 1H), 3.78 (s, 3H), 1.91–1.84 (m,
2H), 1.63–1.52 (m, 2H), 0.98 (t, J¼7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 166.4, 159.0, 142.6, 129.9, 127.9
(ꢂ2), 127.6, 127.3, 123.5, 118.2, 115.4, 114.3 (ꢂ2),
76.9, 55.2, 44.6, 32.2, 18.2, 13.6; MS (+ESI) m/z 368
(M+Na+, 100), 370 (M+2+Na+, 32). Anal. Calcd for
C19H20ClNO3: C, 65.99; H, 5.83; N, 4.05. Found: C,
65.72; H, 6.01; N, 3.35.
4.3.18. 6-Chloro-2-ethyl-3,4-dihydro-4-(20-furylmethyl)-
3-oxo-2H-1,4-benzoxazine (5r). Prepared in 90% yieꢀld.
Compound 5r. A white crystalline solid; mp 98–100 C
(EtOAc–hexane); Rf¼0.56 (11% EtOAc in hexane); IR
4.3.22. 6-Chloro-3,4-dihydro-3-oxo-2-propyl-4-(30-pyri-
dinylmethyl)-2H-1,4-benzoxazine (5v). Prepared in 70%
yield. Compound 5v. A white crystalline solid; mp 80–
(KBr) 2975, 1667, 1499, 1375, 1264 cmꢁ1 1H NMR
;
ꢀ
(400 MHz, CDCl3) d 7.36 (d, J¼0.8 Hz, 1H), 7.18
(d, J¼2.0 Hz, 1H), 6.95 (dd, J¼8.4, 2.0 Hz, 1H), 6.90 (d,
J¼8.4 Hz, 1H), 6.33–6.30 (m, 2H), 5.06 and 5.00 (ABq,
J¼16.0 Hz, 2H), 4.48 (dd, J¼8.4, 4.4 Hz, 1H), 1.96–1.81
(m, 2H), 1.06 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 165.9, 149.2, 142.7, 142.3, 129.8, 127.5, 123.6,
118.2, 115.3, 110.6, 108.8, 78.2, 38.6, 23.6, 9.3; MS
(+ESI) m/z 314 (M+Na+, 100), 316 (M+2+Na+, 31). Anal.
Calcd for C15H14ClNO3: C, 61.76; H, 4.84; N, 4.80. Found:
C, 61.86; H, 5.10; N, 5.05%.
81 C (EtOAc–hexane); Rf¼0.11 (20% EtOAc in hexane);
IR (KBr) 2963, 1685, 1498, 1437, 1382, 1267 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 8.54 (s, 1H), 8.51 (d,
J¼4.8 Hz, 1H), 7.51 (d, J¼8.0 Hz, 1H), 7.25 (dd, J¼8.0,
4.8 Hz, 1H), 6.93–6.88 (m, 2H), 6.78 (s, 1H), 5.17 and
5.01 (ABq, J¼16.4 Hz, 2H), 4.63 (dd, J¼8.0, 5.2 Hz, 1H),
1.88–1.82 (m, 2H), 1.58–1.49 (m, 2H), 0.95 (t, J¼7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 166.5, 149.1, 148.3,
142.6, 134.4, 131.3, 129.4, 127.5, 123.9, 123.8, 118.5,
114.9, 76.9, 42.8, 32.1, 18.2, 13.6; MS (+ESI) m/z 339
(M+Na+, 100), 341 (M+2+Na+, 31). Anal. Calcd for
C17H17ClN2O2: C, 64.46; H, 5.41; N, 8.84. Found: C,
64.51; H, 5.47; N, 8.83.
4.3.19. 6-Chloro-3,4-dihydro-4-(20-furylmethyl)-3-oxo-2-
propyl-2H-1,4-benzoxazine (5s). Prepared in 96% yield.

4642
G. Feng et al. / Tetrahedron 62 (2006) 4635–4642
1995, 51, 4953–4968; (d) Largeron, M.; Neudorffer, A.;
Acknowledgments
Vuilhorgne, M.; Blattes, E.; Fleury, M.-B. Angew. Chem., Int.
Ed. 2002, 41, 824–827; (e) Blattes, E.; Fleury, M.-B.; Largeron,
M. J. Org. Chem. 2004, 69, 882–890.
This work is supported by a research grant provided by Zhe-
jiang University. W.-M. Dai is the recipient of Cheung Kong
Scholars Award of The Ministry of Education of China.
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´
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