Synthesis of benzoxazine and 1,3-oxazine derivatives via ligand-free copper(I)-catalyzed one-pot cascade addition/cyclization reaction

Article abstract of DOI:10.1016/j.tet.2011.10.075

A novel and efficient synthesis of benzoxazine and 1,3-oxazine derivatives via ligand-free copper(I)-catalyzed one-pot cascade addition/cyclization reaction has been developed. A variety of carbodiimides coupled with o-halophenylmethanols and/or substitut

Full text of DOI:10.1016/j.tet.2011.10.075

Tetrahedron 68 (2012) 166e172
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Tetrahedron
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Synthesis of benzoxazine and 1,3-oxazine derivatives via ligand-free
copper(I)-catalyzed one-pot cascade addition/cyclization reaction
,
Guodong Shen a, Dingben Chen a b, Yiliang Zhang a, Manman Sun a, Kai Chen a, Cong Jin a,
,
Kaining Li a, Weiliang Bao a
*
a Department of Chemistry, Xi Xi Campus, Zhejiang University, Hangzhou, Zhejiang 310028, PR China
b College of Pharmaceutical and Chemical Engineering, Taizhou University, Linhai 317000, Zhejiang, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 August 2011
Received in revised form 13 October 2011
Accepted 21 October 2011
Available online 28 October 2011
A novel and efficient synthesis of benzoxazine and 1,3-oxazine derivatives via ligand-free copper(I)-
catalyzed one-pot cascade addition/cyclization reaction has been developed. A variety of carbodiimides
coupled with o-halophenylmethanols and/or substituted (Z)-3-iodoprop-2-en-1-ols to give the corre-
sponding products in moderate to excellent yields under the mild condition.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cascade addition/cyclization
Benzoxazine
1,3-Oxazine
Carbodiimides
1. Introduction
workers have reported many processes to obtain heterocyclic
compounds.10 Our group also has done some works in this aspect
Benzoxazine derivatives have been shown to possess pharma-
cological properties1 and 1,3-oxazine derivatives are broadly found
in their potential as antibiotics,2 antitumor,3 analgesics,4 and anti-
convulsants.5 For example, 2-substituted-4H-benzo[d][1,3]oxazin-
4-ones are potent alternative substrate inhibitors of human leu-
kocyte elastase6 and have been reported to have plasma lipid al-
tering characteristics.7 In addition, 2-substituted-4H-benzo[d][1,3]
oxazin-4-ones also have been employed as useful synthetic in-
termediates for the preparation of heterocycles, which have been
shown to possess a variety of biological properties.8 Because of the
significant importance of these derivatives, it has a great value in
the preparation of compounds possessing benzoxazine or 1,3-
oxazine structures and evaluation of their biological properties.
After ligands were introduced and the reaction temperature was
decreased, copper-catalyzed Ullmann condensation-type reaction
(formation of sp2 C-heteroatom bonds) has drawn considerable
attention for their efficiency and low cost.9 Recently, Ullmann
condensation has been extended to synthesis of various heterocy-
clic compounds via one-pot cascade strategies.10 Buchwald and co-
and provided several convenient and efficient approaches to useful
heterocyclic compounds.11 For example, we have reported a group
examples of various benzoxazole and benzoimidazole derivatives
via copper(I)-catalyzed one-pot addition/cyclization reactions.11c,g
However, to the best of our knowledge, the synthesis of (Z)-1-
aryl-2-phenylimino-substituted benzoxazines and 1,3-oxazine de-
rivatives via copper-catalyzed one-pot process was not reported. As
a part of our continuing effort, we wish to report a new method to
synthesize these two types of heterocycles via a one-pot addition/
cyclization reaction catalyzed by copper(I) salt.
The reaction of o-iodophenylmethanol with p-methyl-
phenylcarbodiimide was carried out to search for the best reaction
condition. Firstly, the reaction was carried out in MeCN with CuI
(20 mol %), N,N-dimethylglycine (30 mol %) and Cs2CO3 (1.0 equiv)
at 100 ꢀC under N2 atmosphere. The anticipated product 4c was
obtained in 55% separated yield after 24 h reaction (Table 1, entry
1). Different ligands, such as 1,10-phenanthroline, ethyl 2-
oxocyclohexanecarboxylate (
the yields changed a little (Table 1, entries 2 and 3). Since the
products or intermediates were -diaza compounds, which may act
b-keto ester) were also tested and
b
as the ligand, a ‘ligand-free’ reaction was tested. When the reaction
was conducted in MeCN at 100 ꢀC with only CuI and Cs2CO3 added,
the product was obtained in 70% yield (Table 1, entry 4). In the
solvent of DMSO, only 30% yield was got (Table 1, entry 5). There
* Corresponding author. Fax: þ86 571 88273814; e-mail address: wlbao@css.zju.edu.cn
(W. Bao).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.075

G. Shen et al. / Tetrahedron 68 (2012) 166e172
167
Table 1
Optimization of the reaction conditions
O
N
N
Catalyst, N2
OH
N
C N
I
Cs2CO3, Solvent, T oC
Entry
Catalyst
Solvent
T [ꢀC]
Time [h]
Yielda (%)
1
2
3
4
5
6
7
8
CuI/N,N-dimethylglycine
CuI/1,10-phenanthroline
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
100
100
100
100
100
100
100
120
100
100
80
24
24
24
24
24
24
24
24
36
36
24
24
36
36
55b
40b
50b
70c
30c
0c
CuI/
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
\
b-keto ester
NMP
0c
n-PrCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
50c
73c
84d
41c
0e
9
10
11
12
13
14
100
100
100
Cu2O
Cu(OAc)2
60d
55d
a
Isolated yield after flash chromatography based on o-iodophenylmethanol.
Reaction conditions: CuI (0.1 mmol), ligand (0.15 mmol), o-iodophenylmethanol (0.5 mmol), p-methylphenylcarbodiimide (0.75 mmol) and Cs2CO3 (0.5 mmol) in solvent
b
(2.0 mL) under N2 atmosphere.
c
Reaction conditions: Cu source (0.1 mmol), o-iodophenylmethanol (0.5 mmol), p-methylphenylcarbodiimide (0.75 mmol) and Cs2CO3 (0.5 mmol) in solvent (2.0 mL)
under N2 atmosphere.
d
Reaction conditions: CuI (0.1 mmol), o-iodophenylmethanol (0.5 mmol), p-methylphenylcarbodiimide (0.75 mmol) and Cs2CO3 (0.5 mmol) in MeCN (2.0 mL) under N2
atmosphere. 24 h later, p-methylphenylcarbodiimide (0.25 mmol) was added again for another 12 h.
e
No product was detected.
was no reaction in the solvents of DMF and NMP (Table 1, entries 6
and 7). To raise the reaction temperature, n-PrCN was used as the
solvent, which has a higher boiling point, but the result was dis-
appointing (Table 1, entry 8). When the reaction time was pro-
longed to 36 h, the yield increased slightly (Table 1, entry 9). From
the flash chromatography of the experiments above, it was found
that some of the o-iodophenylmethanol remained while p-meth-
ylphenylcarbodiimide was disappeared. Knowing carbodiimide
spoiled easily, another 0.25 mmol p-methylphenylcarbodiimide
was added after the reaction was conducted 24 h, and kept for
further 12 h. The yield was raised to 84% (Table 1, entry 10). Low-
ering the reaction temperature to 80 ꢀC, the yield was decreased
obviously (Table 1, entry 11). If CuI was not added in the reaction, no
product was detected (Table 1, entry 12). Some other copper salts,
such as Cu2O and Cu(OAc)2 were also tested, but CuI provided the
best yield (Table 1, entries 13 and 14).
With the optimal condition established, we tried to expand the
scope of substrates. The substituted phenylcarbodiimides bearing
both electron-donating groups (o-Me, m-Me, and p-Me) and
electron-withdrawing groups (p-Cl, p-OCF3, and m-CF3) were able
to couple with o-iodophenylmethanol in moderate to excellent
yields (Table 2, entries 2e7). Furthermore, o-iodophenylmethanols
with different functional groups (p-CH3 and p-Cl) were also in-
vestigated and moderate to good results were detected (Table 2,
entries 8e13). From the results it was obvious that the yields were
affected by the steric hindrance of carbodiimides (Table 2, entries
2e4). o-Methylphenyl-carbodiimide gave a lower yield than m-
methylphenylcarbodiimide and p-methylphenylcarbodiimide. In-
terestingly, the 3-substituted phenylcarbodiimides bearing both
electron-donating groups and electron-withdrawing groups were
able to couple with o-iodophenylmethanol in excellent yields
(Table 2, entries 3, 7). Both o-iodophenylmethanols and 4-
substituted carbodiimides bearing electron-withdrawing groups
were poor substrate candidates, and the reactions only afforded
moderate yield (Table 2, entries 5, 6, 9, 11e13). 2-
bromophenylmethanol was also used, giving 30% yield under the
optimal conditions (Table 2, entry 14). In order to synthesize seven-
membered ring heterocycle compounds, 2-(2-bromophenyl)etha-
nol was also tested as the substrate (Table 2, entry 15). To our de-
light, 15c could be synthesized successfully (Table 2, entry 15).
Theoretically, the imine should have Z/E isomers, but the TLC and
NMR spectra showed that only one isomer was formed. It should be
Z because it is more stable than E isomer. And the configuration was
confirmed by X-ray diffraction (Scheme 1).
Encouraged by the above results, we further investigated the
generality of the method (Table 3). (Z)-3-iodo-3-phenylprop-2-en-1-
ol can react with 4-methylphenyl-carbodiimide to give the isomers
1h and 1i in 72% total yield under the optimal condition (Table 3,
entry1). From the1H NMR, a h/i ratio of about 1:1 was determined. At
first, they can be separated on a big TLC plate (CH2Cl2/petroleum
ether v/v¼3/2). However, the higher dot onTLC gradually changed to
the lower dot in solution (for example, in CDCl3 or in CH3CN). Based
on the X-ray diffractionof 12c, we deduced thehigherdot should be i,
for product i may be unstable because of its big stereo hindrance.
When we used 4-chlorophenylcarbodiimide as the substrate, the
result was the same as the above. The ratio of h/i is about 3:2 and the
2i was also changed to 2h in solution (Table 3, entry 2). Substituted
(Z)-3-iodo-3-phenylprop-2-en-1-ols were also used, the reaction
yields were moderate and the ratio were all about 1:1 (Table 3, en-
tries 3 and 4). When (Z)-4-iodo-4-phenylbut-3-en-2-ol was used the
yield was reduced (Table 3, entry 6), maybe it is due to the sterical
hindrance of the methyl group. The products 6h and 6i could not be
separated by the flash chromatography, but from the 1H NMR spec-
trum we could see the ratio of 6h and 6i. Several days later, the un-
stable product 6i changed to 6h. Actually all i isomers will gradually
change to h products. The scope of this methodology was also ex-
panded by using the substrate of (Z)-3-cyclohexyl-3-iodoprop-2-en-
1-ol (Table 3, entry 7). The yield was moderate and the experimental

168
G. Shen et al. / Tetrahedron 68 (2012) 166e172
Table 2
Ligand-free CuI-catalyzed one-pot synthesis of benzoxazine derivatives from o-halophenylmethanols a and carbodiimides ba
Entry
n
X
R1
R
Product
Yieldb (%)
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
I
I
I
I
I
I
I
I
I
I
I
I
I
Br
I
H
H
H
H
H
H
H
4-CH3
4-CH3
4-CH3
4-Cl
4-Cl
4-Cl
H
C6H5
1c
2c
3c
4c
5c
6c
7c
8c
73
41
91
84
60
78
92
77
62
86
68
54
70
30
35
2-CH3eC6H4
3-CH3eC6H4
4-CH3eC6H4
4-CleC6H4
4-CF3OeC6H4
3-CF3eC6H4
4-CH3eC6H4
4-CleC6H4
3-CH3eC6H4
4-CH3eC6H4
4-CleC6H4
3-CH3eC6H4
4-CH3eC6H4
4-CH3eC6H4
9
9c
10
11
12
13
14
15
10c
11c
12c
13c
4c
H
15c
a
Reaction conditions: CuI (0.1 mmol), o-iodophenylmethanols (0.5 mmol), carbodiimides (0.75 mmol), and Cs2CO3 (0.5 mmol) in MeCN (2.0 mL) at 100 ꢀC under N2 at-
mosphere. 24 h later, carbodiimides (0.25 mmol) was added again for another 12 h.
b
Isolated yield after flash chromatography based on o-iodophenylmethanols.
process, intermediate f converted into product c through intra-
molecular CeN coupling.
In summary, we have developed a new method to synthesize
benzoxazine and 1,3-oxazine derivatives under ligand-free cop-
per(I)-catalyzed condition. A simple ‘one-pot’ operation was con-
ducted and relatively mild condition was applied. Various
benzoxazine and 1,3-oxazine derivatives, which might be poten-
tially applicable in the pharmaceutical and biochemical areas, were
conveniently synthesized in moderate to excellent yields.
2. Experimental section
2.1. General procedure for the synthesis of benzoxazine and
1,3-oxazine derivatives
An oven-dried Schlenk tube equipped with a Teflon valve was
charged with a magnetic stir bar, CuI (0.1 mmol, 20 mol %), Cs2CO3
(0.5 mmol, 100 mol %), and o-halophenylmethanol and/or (Z)-3-
iodo-3-phenylprop-2-en-1-ol (0.5 mmol). The tube was evacuated
and backfilled with N2 (this procedure was repeated three times).
Scheme 1. The X-ray diffraction of 12c.
Carbodiimide (0.75 mmol) was added via syringe under a counter
phenomenon was the same with others. To the best of our knowl-
edge, there are few reports about synthesizing these 1,3-oxazine
derivatives. In 1993, Saito and co-workers employed N-((1-
phenylvinylimino)methylene)aniline and benzaldehyde via [4þ2]
cycloaddition to synthesize the 2-benzylidene-5,6-diphenyl-3,6-
dihydro-2H-1,3-oxazine.12 Although this reaction proceeds effi-
ciently, the N-((1-phenylvinylimino) methylene)aniline was hard to
prepare. Here we provide a new synthetic methodology via readily
available starting materials and relatively mild reaction conditions.
This may help accumulating molecular libraries, from which phar-
macological potentials may be found.
flow of N2. Then under a counter flow of N2, MeCN (2.0 mL) was
added by syringe. The reaction mixture was sealed and stirred for
24 h at 100 ꢀC. Then another part of carbodiimide (0.25 mmol) was
added and stirred for 12 h at 100 ꢀC. The reaction was monitored by
TLC. After the starting material was consumed completely, the
resulting suspension was cooled to room temperature and filtered
through a pad of filter paper with the help of 30 mL of ethyl acetate.
After evaporating the solvent under reduced pressure, the residue
was purified by column chromatography on silica gel to give the
pure product (AcOEt/petroleum ether v/v¼1/10).
A plausible mechanism for the formation of the (Z)-N-(1-
phenyl-1H-benzo[d][1,3]oxazin-2(4H)-ylidene)anilines is shown
in Scheme 2. The nucleophilic O atom of o-iodophenylmethanols
a would attack the carbon atom on carbodiimides b and in-
termediate d could be formed in the presence of a proper base.
With a proper copper(I)-catalyst, a chelating intermediate e was
formed. After an oxidative addition and a reductive elimination
2.1.1. (Z)-N-(1-Phenyl-1H-benzo[d][1,3]oxazin-2(4H)-ylidene)aniline
(1c). Light yellow solid; yield 110 mg, 73%; mp 149e150 ꢀC; 1H
NMR (400 MHz, CDCl3/TMS):
d
5.15 (s, 2H), 6.32 (d, J¼8.4 Hz, 1H),
6.91e7.00 (m, 4H), 7.13 (t, J¼7.6 Hz, 2H), 7.22 (t, J¼8.0 Hz, 2H),
7.41e7.56 (m, 5H). 13C NMR (100 MHz, CDCl3/TMS): 147.4, 147.2,
140.7, 139.2, 130.0, 129.9, 128.9, 128.4, 128.2, 124.2, 123.3, 122.4,
121.8, 121.2, 115.1, 67.4. IR:
n
¼3042, 2921, 2868, 1659, 1587, 1492,

G. Shen et al. / Tetrahedron 68 (2012) 166e172
169
Table 3
Synthesis of 1,3-oxazine derivatives from (Z)-3-iodo-3-phenylprop-2-en-1-ol g and carbodiimides ba
Entry
1
R
R2
R3
H
Product
Yieldc (%)
h/ib
4-CH3eC6H4
C6H5
72
1:1
2
4-CleC6H4
C6H5
H
63
3:2
3
4
C6H5
4-CH3eC6H4
H
H
60
61
1:1
1:1
C6H5
4-CleC6H4
5
6
C6H5
C6H5
H
66
33
2:1
4-CleC6H4
C6H5
CH3
>1:14
7
C6H5
C6H11
H
66
1:5
a
Reaction conditions: CuI (0.1 mmol), substituted (Z)-3-iodoprop-2-en-1-ols (0.5 mmol), carbodiimides (0.75 mmol), and Cs2CO3 (0.5 mmol) in MeCN (2.0 mL) at 100 ꢀC
under N2 atmosphere. 24 h later, carbodiimides (0.25 mmol) was added again for another 12 h.
b
The ratio was based on 1H NMR spectrum and calculation.
Isolated yield after flash chromatography based on (Z)-3-iodo-3-phenylprop-2-en-1-ols.
c
1461, 1387, 1325, 1232, 1200, 1047, 933, 904, 791, 694. MS (EI) m/z
(Mþ) 300. Anal. Calcd for C20H16N2O: C, 79.98; H, 5.37; N, 9.33;
Found: C, 79.95; H, 5.39; N, 9.34.
J¼8.4 Hz, 1H), 6.83e6.89 (m, 2H), 6.96 (t, J¼7.6 Hz, 1H), 7.04e7.12
(m, 4H), 7.35e7.37 (m, 4H). 13C NMR (100 MHz, CDCl3/TMS): 146.3,
145.6, 139.5, 137.8, 137.2, 131.6, 130.4, 130.1, 129.9, 129.1, 128.8, 127.7,
125.9, 124.3, 122.53, 122.48, 121.7, 120.5, 114.2, 67.2, 18.3, 17.8. IR:
2.1.2. (Z)-2-Methyl-N-(1-o-tolyl-1H-benzo[d][1,3]oxazin-2(4H)-yli-
n
¼3058, 2962, 2922, 2863, 1654, 1592, 1493, 1459, 1388, 1322, 1293,
dene)aniline (2c). Light yellow solid; yield 67 mg, 41%; mp
1207, 1108, 1043, 936, 793, 751, 724. MS (EI) m/z (Mþ) 328. Anal.
Calcd for C22H20N2O: C, 80.46; H, 6.14; N, 8.53; Found: C, 80.45; H,
6.15; N, 8.55.
96e98 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
d
2.07 (s, 3H), 2.27 (s,
3H), 5.12 (Ha, d, J¼13.6 Hz, 1H), 5.16 (Hb, d, J¼13.6 Hz, 1H), 6.24 (d,

170
G. Shen et al. / Tetrahedron 68 (2012) 166e172
1
R
OH
I
base
O
1
R
RN
C
NR
RN
I
a
b
NR
d
2
R
I
Cu
O
1
R
O
I
N
R
NR
RN
NR
reductive
elimination
c
I
Cu
oxdative
addition
1
R
e
O
Cu
NR
N
R
I
f
Scheme 2. Plausible mechanism.
2.1.3. (Z)-3-Methyl-N-(1-m-tolyl-1H-benzo[d][1,3]oxazin-2(4H)-yli-
CDCl3/TMS):
d
5.16 (s, 2H), 6.33 (d, J¼8.0 Hz, 1H), 6.92 (d, J¼8.4 Hz,
dene)aniline (3c). Light yellow solid; yield 149 mg, 91%; mp
2H), 7.00e7.07 (m, 3H), 7.15e7.18 (m, 2H), 7.36 (d, J¼8.4 Hz, 2H), 7.48
(d, J¼8.8 Hz, 2H).13C NMR (100 MHz, CDCl3/TMS): 148.7,147.4,145.8,
144.6,140.3,137.5,131.6,129.2,124.5,124.4,122.4,122.2,122.0e121.9
122e124 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
d 2.78 (s, 3H), 2.41 (s,
3H), 5.14 (s, 2H), 6.33 (d, J¼8.4 Hz, 1H), 6.72e6.74 (m, 2H), 6.78 (d,
J¼7.2 Hz, 1H), 6.97 (t, J¼7.2 Hz, 1H), 7.09e7.13 (m, 3H), 7.22e7.26
(m, 3H), 7.41 (t, J¼8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3/TMS):
147.4, 147.1, 140.8, 139.8, 139.0, 138.1, 130.4, 129.6, 129.1, 128.8, 128.2,
127.0, 124.2, 124.0, 123.2, 121.6, 121.1, 120.2, 115.1, 67.4, 21.6, 21.5. IR:
(q), 121.3, 121.2, 119.5e119.3 (q), 115.1, 67.5. IR:
n
¼3056, 2923, 2863,
1646,1597,1500,1461,1389,1262,1149,1039, 919, 854, 821, 759, 710,
662. MS (EI) m/z (Mþ) 468. Anal. Calcd for C22H14F6N2O3: C, 56.42; H,
3.01; N, 5.98; Found: C, 56.40; H, 3.05; N, 5.99.
n
¼3050, 2912, 2872, 1660, 1592, 1492, 1460, 1385, 1324, 1249, 1162,
1044, 893, 794, 747, 694. MS (EI) m/z (Mþ) 328. HRMS Calcd for
2.1.7. (Z)-3-(Trifluoromethyl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-
benzo[d][1,3]oxazin-2(4H)-ylidene)aniline (7c). Light yellow solid;
yield 201 mg, 92%; mp 106e108 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
C22H20N2O: 328.1576; Found: 328.1573.
2.1.4. (Z)-4-Methyl-N-(1-p-tolyl-1H-benzo[d][1,3]oxazin-2(4H)-yli-
d
5.21 (s, 2H), 6.30 (d, J¼8.0 Hz,1H), 7.03e7.10 (m, 2H), 7.16e7.23 (m,
dene)aniline (4c). Light yellow solid; yield 138 mg, 84%; mp
4H), 7.32 (t, J¼8.0 Hz, 1H), 7.70e7.72 (m, 4H). 13C NMR (100 MHz,
CDCl3/TMS): 147.6,147.4,140.0,139.5,133.9,132.6,132.3,131.0,130.7,
130.4,129.3,129.0,127.0,126.9,125.4,125.3,124.6,122.7,121.2,120.3,
137e139 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
d 2.27 (s, 3H), 2.42 (s,
3H), 5.12 (s, 2H), 6.34 (d, J¼7.6 Hz, 1H), 6.81 (d, J¼8.0 Hz, 2H), 6.95
(t, J¼7.6 Hz, 1H), 7.01 (d, J¼7.6 Hz, 2H), 7.11e7.12 (m, 2H), 7.32 (b,
4H). 13C NMR (100 MHz, CDCl3/TMS): 147.3, 144.9, 141.0, 138.0,
136.6, 131.5,130.5, 129.7,129.0.128.8,124.2,123.1,121.6,121.2,115.0,
119.3, 119.3, 115.1, 67.6. IR:
n
¼3060, 2923, 2863, 1657, 1601, 1497,
1444,1393,1314,1272,1166,1127,1058, 985, 899, 821, 753, 698, 655.
MS (EI) m/z (Mþ) 436. Anal. Calcd for C22H14F6N2O: C, 60.56; H, 3.23;
N, 6.42; Found: C, 60.57; H, 3.25; N, 6.40.
67.3, 21.4, 21.0. IR:
n
¼3040, 2922, 2865,1641,1603, 1584,1489,1462,
1385, 1238, 1197, 1087, 1034, 934, 746, 716, 621. MS (EI) m/z (Mþ)
328. Anal. Calcd for C22H20N2O: C, 80.46; H, 6.14; N, 8.53; Found: C,
80.46; H, 6.13; N, 8.57.
2.1.8. (Z)-4-Methyl-N-(6-methyl-1-p-tolyl-1H-benzo[d][1,3]oxazin-
2(4H)-ylidene)aniline (8c). Light yellow solid; yield 132 mg, 77%;
mp 151e153 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
d 2.20 (s, 3H), 2.27
2.1.5. (Z)-4-Chloro-N-(1-(4-chlorophenyl)-1H-benzo[d][1,3]oxazin-
(s, 3H), 2.44 (s, 3H), 5.09 (s, 2H), 6.15 (s, 1H), 6.77e6.81 (m, 3H),
7.00e7.01 (m, 3H), 7.32 (b, 4H). 13C NMR (100 MHz, CDCl3/TMS):
147.6, 145.0, 140.8, 138.9, 137.9, 136.5, 131.5, 130.6, 129.7, 129.0,
2(4H)-ylidene)aniline (5c). White solid; yield 110 mg, 60%; mp
159e160 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
d 5.15 (s, 2H), 6.34 (d,
J¼8.0 Hz, 1H), 6.84 (d, J¼8.8 Hz, 2H), 7.01 (t, J¼7.6 Hz, 1H), 7.14e7.18
(m, 4H), 7.38 (d, J¼8.4 Hz, 2H), 7.50 (d, J¼8.4 Hz, 2H). 13C NMR
(100 MHz, CDCl3/TMS): 147.4, 145.7, 140.3, 137.6, 134.1, 131.4, 130.2,
124.0, 123.1, 122.3, 118.3, 115.6, 67.3, 21.7, 21.5, 21.0. IR:
n
¼3058,
2923, 2862, 1647, 1614, 1586, 1486, 1450, 1309, 1272, 1202, 1162,
1089, 1050, 1013, 935, 834, 808, 709, 675. MS (EI) m/z (Mþ) 342.
Anal. Calcd for C23H22N2O: C, 80.67; H, 6.48; N, 8.18; Found: C,
80.69; H, 6.45; N, 8.18.
129.1, 128.5, 127.7, 124.7, 124.4, 122.3, 121.1, 115.1, 67.5. IR:
n
¼3059,
2921, 2867, 1646, 1600, 1503, 1460, 1383, 1321, 1237, 1199, 1111, 935,
832, 755, 708, 639. MS (EI) m/z (Mþ) 368. Anal. Calcd for
C20H14Cl2N2O: C, 65.06; H, 3.82; N, 7.59; Found: C, 65.04; H, 3.83;
N, 7.58.
2.1.9. (Z)-4-Chloro-N-(1-(4-chlorophenyl)-6-methyl-1H-benzo[d]
[1,3]oxazin-2(4H)-ylidene)aniline (9c). Light yellow solid; yield
118 mg, 62%; mp 177e178 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
2.1.6. (Z)-4-(Trifluoromethoxy)-N-(1-(4-(trifluoromethoxy)phenyl)-
1H-benzo[d][1,3]oxazin-2(4H)-ylidene)aniline (6c). Light yellow
solid; yield 183 mg, 78%; mp 110e112 ꢀC; 1H NMR (400 MHz,
d 2.21 (s, 3H), 5.11 (s, 2H), 6.12 (s, 1H), 6.82e6.85 (m, 3H), 7.03 (d,
J¼7.6 Hz, 1H), 7.16 (d, J¼8.8 Hz, 2H), 7.37 (d, J¼8.4 Hz, 2H), 7.50 (d,
J¼8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3/TMS): 147.6, 145.8, 140.1,

G. Shen et al. / Tetrahedron 68 (2012) 166e172
171
139.3, 137.5, 134.0, 131.4, 130.2, 128.5, 127.6, 124.7, 124.3, 123.0,
118.2, 115.6, 67.4, 21.7. IR:
1486, 1424, 1382, 1303, 1243, 1200, 1088, 1048, 1012, 935, 838, 801,
710, 677. MS (EI) m/z (Mþ) 382. Anal. Calcd for C21H16Cl2N2O: C,
65.81; H, 4.21; N, 7.31; Found: C, 65.86; H, 4.20; N, 7.33.
821, 752, 633. MS (EI) m/z (Mþ) 342. HRMS Calcd for C23H22N2O:
342.1732; Found: 342.1731.
n
¼3060, 2922, 2862, 1646, 1616, 1585,
2.1.15. (Z)-4-Methyl-N-(4-phenyl-3-p-tolyl-3,6-dihydro-2H-1,3-
oxazin-2-ylidene)aniline (1h). Light yellow solid; yield 64 mg, 37%;
mp 146e148 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
d 2.28 (s, 3H), 2.43
2.1.10. (Z)-3-Methyl-N-(6-methyl-1-m-tolyl-1H-benzo[d][1,3]oxazin-
(s, 3H), 5.37 (s, 2H), 5.50 (s, 1H), 6.94e6.96 (m, 4H), 7.05 (d,
J¼8.0 Hz, 2H), 7.12 (t, J¼7.6 Hz, 1H), 7.29 (t, J¼7.6 Hz, 2H), 7.34e7.39
(m, 4H). 13C NMR (100 MHz, CDCl3/TMS): 150.5, 144.0, 138.9, 138.5,
136.3, 132.4, 132.2, 130.6, 129.2, 128.9, 128.5, 126.9, 125.5, 123.3,
2(4H)-ylidene)aniline (10c). Light yellow solid; yield 147 mg, 86%;
mp 140e142 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
d 2.20 (s, 3H), 2.27
(s, 3H), 2.42 (s, 3H), 5.10 (s, 2H), 6.12 (s, 1H), 6.71e6.73 (m, 2H), 6.77
(t, J¼6.4 Hz, 2H), 7.01 (d, J¼7.6 Hz, 1H), 7.10 (t, J¼8.0 Hz, 1H),
7.23e7.25 (m, 3H), 7.41 (t, J¼8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3/
TMS): 147.5,147.3,140.8,139.7,139.1,138.9,138.1,130.5,129.6,129.0,
128.2, 127.1, 124.0, 123.2, 122.4, 120.2, 118.3, 115.7, 67.3, 21.8, 21.6,
98.9, 69.5, 69.5, 21.5, 21.0. IR:
n
¼3042, 2922, 2858, 1691, 1646, 1604,
1511, 1415, 1372, 1324, 1229, 1172, 1079, 1039, 822, 752, 690. MS (EI)
m/z (Mþ) 354. Anal. Calcd for C24H22N2O: C, 81.33; H, 6.26; N, 7.90;
Found: C, 81.35; H, 6.28; N, 7.90.
21.5. IR:
n
¼3062, 2918, 1863, 1663, 1600, 1511, 1484, 1376, 1320,
1249,1211,1157,1051,1004, 925, 893, 821, 786, 749, 694. MS (EI) m/z
(Mþ) 342. Anal. Calcd for C23H22N2O: C, 80.67; H, 6.48; N, 8.18;
Found: C, 80.64; H, 6.48; N, 8.18.
2.1.16. (Z)-4-Chloro-N-(3-(4-chlorophenyl)-4-phenyl-3,6-dihydro-
2H-1,3-oxazin-2-ylidene)aniline (2h). Light yellow solid; yield
92 mg, 47%; mp 184e186 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
d 5.40
(d, J¼2.0 Hz, 2H), 5.54 (b, 1H), 6.95e7.01 (m, 4H), 7.14e7.21 (m, 3H),
7.31 (t, J¼7.6 Hz, 2H), 7.44 (d, J¼8.0 Hz, 2H), 7.54 (d, J¼8.4 Hz, 2H).
13C NMR (100 MHz, CDCl3/TMS): 150.4, 144.8, 137.9, 135.7, 134.5,
133.4, 130.3, 130.0, 129.0, 128.7, 128.2, 126.9, 126.0, 124.9, 99.9, 69.7.
2.1.11. (Z)-N-(6-Chloro-1-p-tolyl-1H-benzo[d][1,3]oxazin-2(4H)-yli-
dene)-4-methylaniline (11c). White solid; yield 123 mg, 68%; mp
168e170 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
d 2.27 (s, 3H), 2.43 (s,
3H), 5.09 (s, 2H), 6.33 (s, 1H), 6.79 (d, J¼8.0 Hz, 2H), 6.93 (dd,
IR:
n
¼3056, 2920, 2856, 1683, 1640, 1588, 1490, 1453, 1372, 1327,
J1¼2.0 Hz, J2¼7.6 Hz, 1H), 7.01e7.04 (m, 3H), 7.28e7.35 (m, 4H). 13
C
1229, 1168, 1087, 1042, 1011, 955, 828, 753, 689. MS (EI) m/z (Mþ)
394. Anal. Calcd for C22H16Cl2N2O: C, 66.85; H, 4.08; N, 7.09; Found:
C, 66.88; H, 4.10; N, 7.08.
NMR (100 MHz, CDCl3/TMS): 146.7, 144.5, 142.0, 138.4, 135.9, 134.6,
131.9, 130.8, 129.5, 129.1, 125.3, 123.0, 121.5, 119.4, 115.2, 66.9, 21.5,
21.0. IR:
n
¼3056, 2922, 2867, 1650, 1596, 1511, 1492, 1425, 1379,
1316, 1202, 1087, 1049, 933, 906, 834, 727, 642. MS (EI) m/z (Mþ)
362. Anal. Calcd for C22H19ClN2O: C, 72.82; H, 5.28; N, 7.72; Found:
C, 72.83; H, 5.29; N, 7.71.
2.1.17. (Z)-N-(3-Phenyl-4-p-tolyl-3,6-dihydro-2H-1,3-oxazin-2-
ylidene)aniline (3h). Light yellow solid; yield 51 mg, 30%; mp
135e136 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
d 2.30 (s, 3H), 5.35 (s,
2H), 5.50 (s, 1H), 6.84 (d, J¼7.6 Hz 2H), 6.99 (t, J¼7.2 Hz 1H),
7.05e7.10 (m, 4H), 7.22e7.26 (m, 2H), 7.42 (t, J¼8.0 Hz 1H),
7.49e7.55 (m, 4H). 13C NMR (100 MHz, CDCl3/TMS): 150.4, 146.6,
137.8, 135.3, 135.2, 133.2, 129.9, 129.6, 128.7, 128.6, 128.4, 126.8,
2.1.12. (Z)-4-Chloro-N-(6-chloro-1-(4-chlorophenyl)-1H-benzo[d]
[1,3]oxazin-2(4H)-ylidene)aniline (12c). White solid; yield 109 mg,
54%; mp 195e197 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
d 5.14 (s, 2H),
6.32 (d, J¼1.6 Hz, 1H), 6.83 (d, J¼8.8 Hz, 2H), 6.99 (dd, J1¼1.6 Hz,
J2¼8.0 Hz, 1H), 7.08 (d, J¼8.0 Hz, 1H), 7.17 (d, J¼8.8 Hz, 2H), 7.37 (d,
J¼8.8 Hz, 2H), 7.53 (d, J¼8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3/
TMS): 146.8, 145.2, 141.3, 136.9, 134.9, 134.6, 131.2, 130.5, 128.5,
123.5, 122.9, 99.1, 69.5, 21.2. IR:
n
¼3857, 3745, 3049, 2922, 1769,
1692, 1646, 1588, 1493, 1458, 1413,1369, 1322,1222,1170, 1035, 898,
797, 762, 739, 689. MS (EI) m/z (Mþ) 340. Anal. Calcd for C23H20N2O:
C, 81.15; H, 5.92; N, 8.23; Found: C, 81.19; H, 5.88; N, 8.26.
128.0, 125.5, 124.6, 122.2, 119.3, 115.2, 67.0. IR:
n
¼3058, 3020, 2921,
2868, 1653, 1602, 1582, 1483, 1453, 1403, 1381, 1309, 1258, 1201,
1083, 1045, 1011, 933, 839, 801, 774, 719, 674. MS (EI) m/z (Mþ) 402.
Anal. Calcd for C20H13Cl3N2O: C, 59.50; H, 3.25; N, 6.94; Found: C,
59.53; H, 3.24; N, 6.93.
2.1.18. (Z)-N-(4-(4-Chlorophenyl)-3-phenyl-3,6-dihydro-2H-1,3-
oxazin-2-ylidene)aniline (4h). Light yellow solid; yield 55 mg, 31%;
mp 140 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
d
5.34 (d, J¼2.0 Hz 2H),
5.46 (b, 1H), 6.86 (d, J¼8.4 Hz 2H), 7.00 (t, J¼7.2 Hz 1H), 7.05 (d,
J¼7.6 Hz 2H), 7.23e7.26 (m, 4H), 7.44e7.50 (m, 3H), 7.54e7.58 (m,
2H). 13C NMR (100 MHz, CDCl3/TMS): 150.2, 146.4, 139.2, 135.0,
134.7, 131.1, 130.0, 129.0, 128.7, 128.0, 123.5, 123.1, 98.0, 69.4. IR:
2.1.13. (Z)-N-(6-Chloro-1-m-tolyl-1H-benzo[d][1,3]oxazin-2(4H)-yli-
dene)-3-methylaniline (13c). White solid; yield 127 mg, 70%; mp
182e184 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
d
2.27 (s, 3H), 2.42 (s,
n
¼3858, 3745, 3031, 2925, 1695, 1647, 1588, 1492, 1450, 1414, 1371,
3H), 5.09 (s, 2H), 6.31 (d, J¼2.0 Hz 1H), 6.71e6.72 (m, 2H), 6.78 (d,
J¼7.2 Hz, 1H), 6.93 (dd, J1¼2.0 Hz, J2¼8.0 Hz, 1H), 7.04 (d, J¼8.0 Hz,
1H), 7.11 (t, J¼8.0 Hz,1H), 7.21e7.24 (m, 3H), 7.42 (t, J¼8.0 Hz,1H).13C
NMR (100 MHz, CDCl3/TMS): 147.0, 146.6, 141.9, 140.1, 138.5, 138.2,
134.6,130.2,129.9,129.5,128.3,126.8,125.3,123.9,123.5,121.6,120.1,
1326, 1295, 1226, 1195, 1169, 1094, 899, 693. MS (EI) m/z (Mþ) 360.
Anal. Calcd for C22H17ClN2O: C, 73.23; H, 4.75; N, 7.76; Found: C,
73.20; H, 4.75; N, 7.71.
2.1.19. (Z)-N-(3,4-Diphenyl-3,6-dihydro-2H-1,3-oxazin-2-ylidene)
119.4,115.3, 66.9, 21.6, 21.5. IR:
n
¼3033, 2952, 2922, 2858,1652,1584,
aniline (5h). Light yellow solid; yield 55 mg, 72%; mp 130e132 ꢀC;
1488, 1424, 1374, 1309, 1250, 1204, 1162, 1082, 1039, 896, 853, 797,
780, 695. MS (EI) m/z (Mþ) 362. Anal. Calcd for C22H19ClN2O: C, 72.82;
H, 5.28; N, 7.72; Found: C, 72.82; H, 5.29; N, 7.71.
1H NMR (400 MHz, CDCl3/TMS):
d 5.39 (s, 2H), 5.53 (s, 1H),
6.94e7.02 (m, 3H), 7.06 (d, J¼8.0 Hz 2H), 7.13 (t, J¼7.6 Hz 1H),
7.23e7.31 (m, 4H), 7.42e7.58 (m, 5H). 13C NMR (100 MHz, CDCl3/
TMS):150.4, 146.5, 138.6, 136.1, 135.2, 129.9, 128.9, 128.7, 128.6,
2.1.14. (Z)-4-Methyl-N-(1-p-tolyl-4,5-dihydrobenzo[d][1,3]oxazepin-
128.5, 126.9, 125.6, 123.5, 123.0, 99.2, 69.6. IR:
n
¼3839, 3745, 3674,
2(1H)-ylidene)aniline (15c). Light yellow solid; yield 60 mg, 35%;
3054, 2923, 1679, 1638, 1585, 1494, 1456, 1410, 1371, 1321, 1281,
1218, 1165, 1080, 1047, 898, 831, 749, 686. MS (EI) m/z (Mþ) 326.
Anal. Calcd for C22H18N2O: C, 80.96; H, 5.56; N, 8.58; Found: C,
81.01; H, 5.58; N, 8.55.
mp 125e127 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
d 2.21 (s, 3H), 2.26
(s, 3H), 3.07 (t, J¼6.4 Hz, 2H), 4.10 (t, J¼6.4 Hz, 2H), 6.74 (d, J¼8.4 Hz,
1H), 6.80 (d, J¼8.0 Hz, 2H), 6.86e7.01 (m, 3H), 7.05e7.13 (m, 4H),
7.17 (d, J¼9.2 Hz, 2H). 13C NMR (100 MHz, CDCl3/TMS): 150.5, 144.6,
144.2, 141.0, 136.0, 132.1, 131.7, 129.8, 128.8, 127.9, 127.8, 124.7, 124.3,
2.1.20. (Z)-4-Chloro-N-(3-(4-chlorophenyl)-6-methyl-4-phenyl-3,6-
dihydro-2H-1,3-oxazin-2-ylidene)aniline (6h). Light yellow solid;
yield 55 mg, 31%; mp 145e146 ꢀC; 1H NMR (400 MHz, CDCl3/TMS):
122.5, 75.2, 32.3, 21.2, 21.0. IR:
1506, 1456, 1378, 1308, 1268, 1225, 1189, 1110, 1049, 1022, 934, 865,
n
¼3030, 2920, 2858, 1646, 1599,

172
G. Shen et al. / Tetrahedron 68 (2012) 166e172
A.; Thomas, G. J.; Smith, R. M.; Karim, A.; Gilmore, C. J.; Haltivanger, R. C.; Bryan,
d
1.69 (d, J¼6.4 Hz 3H), 5.35 (q, J¼6.4 Hz 1H), 5.57 (s, 1H), 6.69 (d,
R. F. J. Am. Chem. Soc. 1972, 94, 1354.
J¼7.2 Hz 2H), 6.89e7.01 (m, 7H), 7.06 (d, J¼8.8 Hz 2H), 7.20 (d,
J¼8.4 Hz 2H). 13C NMR (100 MHz, CDCl3/TMS): 150.8, 144.9, 138.8,
134.6, 133.7, 132.3, 130.2, 128.6, 128.5, 128.3, 128.2, 127.4, 126.0,
3. (a) Wani, M. C.; Taylor, H. L.; Wall, M. E. J. Chem. Soc., Chem. Commun. 1973,
390; (b) Johnson, P. Y.; Silver, R. B. J. Heterocycl. Chem. 1975, 10, 1029; (c) Re-
nullard, S.; Rebhun, L. I.; Havic, G. A.; Kupchan, S. M. Science 1975, 189, 1002.
ꢀ
4. (a) Urbanski, T.; Ghrne, D.; Szczerek, I.; Modaski, M. Polish Patent, 1967, 54, 007;
125.0, 98.8, 78.3, 21.7. IR:
n
¼3745, 2954, 1709, 1672, 1589, 1494,
(b) Lesher, G. Y.; Surrey, A. R. J. Am. Chem. Soc. 1955, 77, 636; (c) Palazzo, S.;
Giannola, L. I. Atii Acad. Sci., Lett. Arti Palermo, Parte 1 1976, 34, 83; (d) Palazzo,
S.; Giannola, L. I. Chem. Abstr. 1978, 89, 43276z.
1463, 1408, 1346, 1203, 1172, 1109, 1046, 900, 759, 693. MS (EI) m/z
(Mþ) 408. Anal. Calcd for C23H18Cl2N2O: C, 67.49; H, 4.43; N, 6.84;
Found: C, 67.50; H, 4.46; N, 6.82.
5. Mosher, H. S.; Frankel, M. B.; Gregory, M. J. Am. Chem. Soc. 1953, 75, 5326.
6. Krantz, A.; Spencer, R. W.; Tam, T. F.; Liak, T. J.; Copp, L. J.; Thomas, E. M.;
Rafferty, S. P. J. Med. Chem. 1990, 33, 464.
2.1.21. (Z)-N-(4-Cyclohexyl-3-phenyl-3,6-dihydro-2H-1,3-oxazin-2-
7. Fenton, G.; Newton, G. C.; Wyman, B. M.; Bagge, P.; Dron, D. I.; Riddell, D.; Jones,
G. D. J. Med. Chem. 1989, 32, 256.
8. Simth, K.; El-Hiti, G. A.; Abdel-Megeed, M. F.; Abdo, M. A. J. Org. Chem. 1996, 61,
647.
ylidene)aniline (7h). Light yellow oil; yield 110 mg, 66%; 1H NMR
(400 MHz, CDCl3/TMS):
d 0.63e0.65 (m, 6H), 0.95e1.01 (m, 2H),
1.19e1.26 (m, 1H), 1.34e1.40 (m, 2H), 4.23 (t, J¼7.6 Hz 1H), 4.88 (s,
9. (a) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054; (b) Ma, D.;
Cai, Q. Acc. Chem. Res. 2008, 41, 1450; (c) Monnier, F.; Taillefer, M. Angew. Chem.,
Int. Ed. 2008, 47, 3096; (d) Correaa, A.; Bolm, C. Adv. Synth. Catal. 2007, 349,
2673; (e) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123,
2074; (f) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337;
(g) Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem. 2002, 114, 2651; Angew.
Chem., Int. Ed. 2002, 41, 2535; (h) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V.
V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210;
(i) Kondoh, A.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2007, 129, 4099; (j)
Isobe, H.; Cho, K.; Solin, N.; Werz, D. B.; Seeberger, P. H.; Nakamura, E. Org. Lett.
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Org. Lett. 2008, 10, 3081.
2H), 6.95 (t, J¼7.6 Hz 1H), 7.00 (d, J¼8.0 Hz 2H), 7.20 (t, J¼7.2 Hz
2H), 7.42e7.46 (m, 5H). IR:
n
¼3839, 3745, 3674, 2981, 1698, 1655,
1587, 1488, 1448, 1403, 1326, 1227, 1201, 1167, 1087, 1058, 1009, 961,
907, 832, 728, 697, 641.MS (EI) m/z (Mþ) 332. Anal. Calcd for
C22H24N2O: C, 79.48; H, 7.28; N, 8.43; Found: C, 79.45; H, 7.29; N,
8.44.
Acknowledgements
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This work was financially supported by the Natural Science
Foundation of China (No. 21072168).
Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.10.075.
References and notes
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