Efficient synthesis of 2,3-disubstituted-1,3-benzoxazines by chlorotrimethylsilane-mediated aza-acetalizations of aromatic aldehydes

Article abstract of DOI:10.1002/jhet.1590

A series of novel substituted 3,4-dihydro-2H-1,3-benzoxazines were prepared in moderate to good yields by aza-acetalizations of aromatic aldehydes with 2-(N-substituted aminomethyl)phenols in the presence of chlorotrimethylsilane or SnCl₄. It w

Full text of DOI:10.1002/jhet.1590

Month 2013
Efficient Synthesis of 2,3-Disubstituted-1,3-benzoxazines by
Chlorotrimethylsilane-Mediated Aza-Acetalizations of Aromatic Aldehydes
a,b,c
Zilong Tang,a,b Zhonghua Zhu,
Lin Yan,a,b Shuhong Chang,a,b,c and Hanwen Liua,b
*
aSchool of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201, China
bKey Laboratory of Theoretical Chemistry and Molecular Simulation of Ministry of Education, Hunan University of
Science and Technology, Xiangtan 411201, China
cJiangxi Dongbang Pharmaceutical Co. Ltd, Fengxin 330700, China
*
E-mail: zltang67@yahoo.com.cn zltang67@yahoo.com.cn
Received October ,15 2011
DOI 10.1002/jhet.1590
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
R1
R1
H
C
CHO
H2
C
R1
N
NaBH4
CH3OH
N
N
H
R2
TMSCl
O
OH
OH
R2
R
R
R
A series of novel substituted 3,4-dihydro-2H-1,3-benzoxazines were prepared in moderate to good yields
by aza-acetalizations of aromatic aldehydes with 2-(N-substituted aminomethyl)phenols in the presence of
chlorotrimethylsilane or SnCl4. It was found that chlorotrimethylsilane was more effective for the reaction,
especially for the reaction of fluorobenzaldehyde, and thereby, an efficient method for the preparation of 3,4-
dihydro-2H-1,3-benzoxazines was developed. The structures of the compounds were determined by FT-IR,
1H NMR, 13C NMR, MS, and elemental analysis.
J. Heterocyclic Chem., 00 00 (2013).
INTRODUCTION
addition, the toxicity of SnCl4 will limit its application in this
kind of reactions. In these regards, we planned to develop
green and more efficient catalysts and, hence, will present
herein our results of the synthesis of substituted 3,4-dihydro-
2H-1,3-benzoxazines by using chlorotrimethylsilane (TMSCl)
[6] as catalyst (Scheme 1).
3,4-Dihydro-2H-1,3-benzoxazine and its derivatives have
been recognized to exhibit different antimicrobial properties
[1] such as bactericidal, fungicidal and many pharmaco-
logical features such as antitumour, antituberculosis, and
anthelmintic activity [2]. Along this line, N-substituted
3,4-dihydro-2H-1,3-benzoxazines are potential intermediates
for the preparation of high performance polymers [3].
Therefore, the synthesis of these compounds containing
special functional group has attracted great interest. Several
elegant methods for the preparation of these compounds
have been documented in the literature [4]. For example,
Burke and co-workers disclosed a Mannich-type condensa-
tion of phenols with primary amines and two equivalents
of formaldehyde to provide 2-unsubstituted 3,4-dihydro-
2H-1,3-benzoxazines [4a–d]. In addition, condensations of
2-aminomethylphenol with aliphatic aldehydes or ketones
provided another route to 3,4-dihydro-2H-1,3-benzoxazines
[4a–g]. It was noted that the condensations could be operated
without catalyst, but sometimes, catalysts such as TsOH or
triethylamines were necessary. Despite these advances, the
synthesis of novel 3,4-dihydro-2H-1,3-benzoxazines and
the search for more efficient routes to this type of compounds
are still highly desirable for drug discovery and medicinal
chemistry. In our previous report [5], we described a
new route to prepare aryl-substituted 3,4-dihydro-2H-1,
3-benzoxazines by using SnCl4-mediated aza-acetalization
reactions of aromatic aldehydes with 2-arylaminomethylphenols.
Although the reactions gave the desired products in good
yields under mild conditions, the yields decreased with
benzaldehyde or fluorobenzaldehydes as reactants. In
RESULTS AND DISCUSSION
For the purpose of finding new type of fungicides, we
planned to prepare fluorine-containing 3,4-dihydro-2H-1,
3-benzoxazines because of the fluorine atom’s special struc-
ture and biological character. The synthetic route to the
target compound 1 is shown in Scheme 1. 2-(N-substituted
aminomethyl)phenols 4a–f were easily prepared in high
yields according to the literature [5,7]. Then, the reaction of
4a with 4-fluorobenzaldehyde 5d was initially performed in
the presence of TsOH (20 mol%) [2e] in mixed solvent of
chloroform and cyclohexane (v/v1:2) under reflux by
removing the water of condensation azeotropically; however,
the desired product 1a was obtained in only 9% yield (Table 1,
entry 1). Also, compound 1e was obatined in merely 12%
yield under the same conditions (entry 4). However, to our
surprise, the yield of compound 1e dramatically decreased
to 0% with AlCl3 (20 mol%) as catalyst (entry 5). We next
used SnCl4 (20 mol%) to promote the reaction, the yield of
1e was enhanced to 48% (entry 6) but still low. Similarly, a
relatively low yield of 43% was obtained for compound 1a
by reaction of 4a with 5d (entry 2). To further improve the
yield, TMSCl (20 mol%) was finally chosen as catalyst for
the reaction of 4a with 5d, and as expected, the reaction
gave the corresponding product 1a in higher yield of 57%
© 2013 HeteroCorporation

Z. Tang, Z. Zhu, L. Yan, S. Chang, and H. Liu
Vol 000
Scheme 1. Synthesis of disubstituted 3,4-dihydro-2H-1,3-benzoxazines 1.
R1
H
C
CHO
OH
C2H5OH
reflux
NaBH4
CH3OH
H2N R1
+
N
OH
R
2
R
3
R1
H2
C
R1
Cat.
N
N
H
O
CHO
OH
R2
4
R
R
R2
5
1
4a: R = H, R1 = 4-CH3C6H4; 4b: R = H, R1 = C6H5; 4c: R = H, R1 = 4-CH3OC6H4
4d: R = H, R1 = 4-ClC6H4; 4e: R = H, R1 = CH2COOCH3; 4f: R = CH3, R1 = 4-CH3C6H4
5a: R2 = 2-NO2; 5b: R2 = 4-NO2; 5c: R2 = 3-NO2; 5d: R2 = 4-F; 5e: R2 = H
Table 1
Searching catalyst for the preparation of compound 1.
Entry
R
R1
R2
Conditionsa
Product
Yield (%)b
1
2
3
4
5
6
7
H
H
H
H
H
H
H
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
CH2COOCH3
CH2COOCH3
CH2COOCH3
CH2COOCH3
4-F
4-F
4-F
4-F
4-F
4-F
4-F
TsOH
SnCl4
TMSCl
TsOH
AlCl3
1a
1a
1a
1e
1e
1e
1e
9
43
57
12
0
48
62
SnCl4
TMSCl
aThe mole ratio of n (aldehyde 5) : n (aminomethyl phenol 4) = 1.3:1 for all reactions. The amount of catalyst is 20 mol% based on aminomethyl phenol.
CHCl3/C6H12 = 1:2 (v: v). Reaction time: 5 h. Temperature: 85ꢀC.
bIsolated yield.
(entries 3). Also, a higher yield of 62% was obtained for
compound 1e (entry 7). Consequently, we synthesized
compounds 1b–l by reactions of aromatic aldehydes 5 with
2-(N-substituted aminomethyl)phenols 4a–f in the presence
of TMSCl. Moreover, to compare the catalytic activity of
the two catalysts, SnCl4-mediated reactions of 4 with 5 were
also performed. All the experimental results are depicted in
Table 2. It can be seen clearly from the table that all reactions
produced the desired products 1b–l in moderate to good
yields for both catalysts but in higher yields with TMSCl as
catalysts. Particularly, the reactions of p-fluorobenzaldehyde
5d or benzaldehyde 5e gave much higher yields in the
presence of TMSCl (Table 2, entries 1–3 and 5). In the
meantime, we observed for both catalysts that reactions of
2-aminomethylphenols with nitrobenzaldehydes afforded
the products in higher yields than those with fluorobenzalde-
hyde or benzaldehyde. In all cases, the reactions of
2-(N-alkylaminomethyl)phenols gave higher yields than
those of N-aryl-substituted aminomethylphenols. The lower
nucleophilicity of the latter can be attributed to the conjuga-
tion effect between the electron pair on the nitrogen atom and
the aryl group. All these results clearly indicated TMSCl was
the most efficient catalyst compared with SnCl4, AlCl3, and
TsOH, and to the best of our knowledge, this is the first time
to adopt TMSCl as catalyst for aza-acetalizations of aromatic
aldehydes with 2-(N-substituted aminomethyl)phenols to
prepare substituted 3,4-dihydro-2H-1,3-benzoxazines.
The structures of the products were established on the
1
basis of their spectroscopic data (IR, H NMR, 13C NMR,
MS) and elemental analysis [5a]. All compounds exhibited
characteristic signals appropriately (see the Experimental
section). Typically, in IR spectrum of compound 1k, the
strong absorption at 1731 cmÀ1 is for the C═O group,
1524 and 1365 cmÀ1 are for the NO2 group, and 1585 and
1607 cmÀ1 for the C═C group. A singlet at 6.57 observed
in 1H NMR corresponded to OCHN proton of benzoxazine
ring. The downfield shift of OCHN proton was due to the
strong electron negative of nitrogen and oxygen atoms.
Particularly, the NCH2 group absorbed as two doublets
at 3.77 and 4.14 instead of a singlet. The 13C NMR spec-
trum showed 17 signals, which are in agreement with the
proposed structure.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1590

Month 2013
TMSCl-Catalyzed Synthesis of 2,3-Disubstituted-1,3-benzoxazines
Table 2
The results of the preparation of compound 1.a
Yieldb (%)
Entry
R
R1
R2
4-F
4-F
4-F
Product
SnCl4
TMSCl
1
2
3
4
5
6
7
8
9
H
H
H
H
C6H5
1b
1c
1d
1f
1g
1h
1i
1j
1k
1l
39
39
45
61
42
72
73
72
84
85
55
53
59
67
57
75
78
73
88
91
4-CH3OC6H4
4-ClC6H4
4-ClC6H4
3-NO2
H
H
4-ClC6H4
CH3
CH3
H
H
H
4-CH3C6H4
4-CH3C6H4
C6H5
CH2COOCH3
CH2COOCH3
2-NO2
3-NO2
4-NO2
2-NO2
4-NO2
10
aThe mole ratio of n (aldehyde 5) : n (aminomethyl phenol 4) = 1.3: 1 for all reactions. The amount of TMSCl: 20 mol% or SnCl4: 20 mol% based on
aminomethyl phenol. CHCl3/C6H12 = 1:2. (v/v) Reaction time: 5 h. Temperature: 85ꢀC.
bIsolated yield.
1499, 1459, 1436, 1389, 1358, 1316, 1301, 1266, 1251, 1237,
CONCLUSIONS
1184, 1166, 1114, 1088, 1056, 1040, 1025, 971, 903, 841, 796,
1
754, 727, 689 cmÀ1; H NMR (CDCl3, 500 MHz): d 4.45 (s, 2H,
CH2), 6.87–6.97 (m, 5H), 7.18 (d, J = 7.5 Hz, 1H), 7.24–7.30 (m,
3H); 13C NMR (CDCl3, 125 MHz): d 48.71, 115.93 (2C), 116.66,
120.13, 120.85, 122.99, 128.78, 129.26, 129.43 (2C), 147.22,
156.76.
In summary, we have prepared a series of novel 2,3-
disubstituted 3,4-dihydro-2H-1,3-benzoxazines 1a–l in mod-
erate to good yields in the presence of TMSCl or SnCl4.
TMSCl was shown to be a more effective Lewis acid catalyst
for the aza-acetalizations of aromatic aldehydes with 2-(N-
substituted aminomethyl)phenols, especially for the reaction
of fluorobenzaldehyde, and thereby, a green and efficient
method for the preparation of substituted 3,4-dihydro-2H-
1,3-benzoxazines was developed.
2-((4-Methoxyphenylamino)methyl)phenol (4c). Yield 85%,
purple solid, mp 132.1–133.8ꢀC; IR (KBr): 3444, 3253, 3000,
2956, 2862, 1714, 1637, 1593, 1510, 1468, 1457, 1409, 1358,
1289, 1249, 1225, 1177, 1112, 1058, 1033, 979, 909, 864, 830,
1
788, 759, 742, 717 cmÀ1; H NMR (CDCl3, 500 MHz): d 3.78
(s, 3H, OCH3), 4.40 (s, 2H, CH2), 6.83–6.87 (m, 4H), 6.88–
6.93 (m, 2H), 7.14 (d, J = 7 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H);
13C NMR (CDCl3, 125 MHz): d 50.24, 55.66, 114.77 (2C),
116.67, 117.85 (2C), 119.87, 122.78, 128.58, 129.18, 140.39,
154.61, 157.17.
2-((4-Chlorophenylamino)methyl)phenol (4d). Yield 89%,
white solid, mp 121.7–122.4ꢀC; IR (KBr): 3435, 3257, 3013,
2969, 2938, 2729, 2626, 1594, 1492, 1462, 1454, 1403, 1392,
1357, 1314, 1285, 1250, 1232, 1181, 1120, 1109, 1097, 1060,
1008, 974, 907, 866, 844, 829, 815, 796, 770, 758, 667 cmÀ1; 1H
NMR (CDCl3, 500 MHz): d 4.40 (s, 2H, CH2), 6.77 (d, J = 9 Hz,
2H), 6.90 (t, J = 6.5Hz, 2H), 7.17–7.28 (m, 4H); 13C NMR
(CDCl3, 125MHz): d 48.42, 116.62, 116.89 (2C), 120.31, 122.66,
125.52, 128.86, 129.28 (2C), 129.38, 145.77, 156.39.
EXPERIMENTAL
All solvents were dried by standard procedure. Aromatic alde-
hydes and substituted anilines were commercially available. IR
spectra were recorded on a PE-2000 FT-IR. 1H and 13C NMR spectra
were recorded on Bruker Avance-500 MHz spectrometer.
Chemical shifts (d) were given relative to Me4Si (0, 1H) or
CDCl3 (77.0, 13C). Mass spectra were obtained with Thermo
Finnigan LCQ Advantage spectrometer. Elemental analysis
was measured on a PE 2400 II CHNS instrument. Melting
points were determined on a WRS-1B digital melting point
instrument. Thin-layer chromatography was run on precoated silica
gel plates (Merck 60F254). Column chromatography was carried
out using flash silica gel.
2-((3-Methoxycarbonylmethylamino)methyl)phenol (4e).Yield
74%, white solid, mp 84.9–85.9ꢀC; IR (KBr): 3 451, 3 352, 2 894,
2 857, 2 118, 1 898, 1 735, 1 616, 1 587, 1 484, 1 429, 1 369, 1
302, 1 260, 1 224, 1 206, 1 185, 1 136, 1 104, 1 037, 988, 929,
Synthesis of 2-(N-substituted aminomethyl)phenols 4a–f
[5,7]
2-((4-Methylphenylamino)methyl)phenol (4a).Yield 91%, white
899, 866, 847, 756, 720 cmÀ1 1H NMR (CDCl3, 500 MHz): d
;
solid, mp 120.5–121.2ꢀC; IR (KBr): 3435, 3260, 3032, 3011, 2977,
2861, 2734, 1614, 1592, 1512, 1467, 1456, 1402, 1291, 1249,
1232, 1187, 1110, 1057, 976, 911, 863, 834, 820, 801, 788, 753,
3.46 (s, 2H), 3.76 (s, 3H), 4.00 (s, 2H), 6.77–6.80 (m, 1H), 6.85
(d, J = 8.0 Hz, 1H), 6.9 8(d, J = 7.0Hz, 1H), 7.17 (t, J = 7.5 Hz,
1H); 13C NMR (CDCl3, 125 MHz) d/ppm: 48.57, 51.99, 52.07,
116.44, 119.19, 121.72, 128.66, 129.00, 157.81, 171.83.
742, 719, 706cmÀ1; H NMR (CDCl3, 500 MHz): d 2.30 (s, 3H,
1
CH3), 4.42 (s, 2H, CH2), 6.79 (d, J = 8.5Hz, 2H), 6.88–6.93
(m, 2H), 7.08 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.5Hz, 1H), 7.23
(t, J = 7.45 Hz, 1H); 13C NMR (CDCl3, 125MHz): d 20.60, 49.34,
116.25 (2C), 116.67, 119.98, 122.98, 128.67, 129.19, 129.91
(2C), 130.46, 144.64, 157.00.
2-((4-Methylphenylamino)methyl)-6-methyl phenol (4f). Yield
85%, white solid, mp 81.0–81.7ꢀC; IR (KBr): 3421, 3335, 2919,
2853, 2731, 1714, 1615, 1592, 1517, 1471, 1446, 1432, 1314,
1259, 1237, 1217, 1123, 1085, 1051, 1012, 930, 883, 822, 812,
762 cmÀ1 1H NMR (CDCl3, 500 MHz): d 2.24 (s, 3H), 2.28
;
2-((Phenylamino)methyl)phenol (4b). Yield 85%, white solid,
mp 129.4–130.8ꢀC; IR (KBr): 3445, 3264, 30652, 2854, 1594,
(s, 3H), 4.37 (s, 2H), 6.77 (t, J= 7.5 Hz, 3H), 6.98 (d, J=7.5Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1590

Z. Tang, Z. Zhu, L. Yan, S. Chang, and H. Liu
Vol 000
1H), 7.05 (dd, J=8.0Hz, J= 7.5 Hz, 3H), 8.93 (s, 1H, OH); 13C
NMR (CDCl3, 125 MHz) d/ppm: 15.73, 20.51, 49.34, 116.14 (2C),
119.32, 122.08, 125.47, 126.13, 129.77 (2C), 130.29, 130.33,
144.54, 155.07.
General procedure for the synthesis of 3,4-dihydro-2H-1,
3-benzoxazines 1a–l.
2-(4-Fluorophenyl)-3-(4-chlorophenyl)-3,4-dihydro-2H-1,
3-benzoxazine (1d). Yield 59% (Method A), 45% (Method B);
white solid, m.p 80.7–81.3ꢀC; IR (KBr): 3436, 3059, 2955, 1894,
1710, 1605, 1584, 1507, 1488, 1457, 1381, 1342, 1224, 1158,
1
1022, 1006, 982, 959, 952, 838, 830, 763, 724 cmÀ1; H NMR
(CDCl3, 500 MHz): d 4.29 (s, 2H), 6.51 (s, 1H), 6.83–6.87
(m, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 8.5 Hz, 2H), 7.08 (d,
J = 8.5 Hz, 2H), 7.14 (t, J = 7.0 Hz, 1H), 7.19 (d, J =8.5 Hz, 2H),
7.46–7.49 (m, 2H); 13C NMR (CDCl3, 125 MHz): d 46.65, 87.58,
115.44, 115.61, 116.89, 119.89, 120.88, 121.68, 126.53, 127.33,
128.24, 128.38, 128.44, 129.15 (2C), 134.35 (d, JCF =3.1Hz),
148.09, 152.47, 161.52, 163.48. Anal. Calcd for C20H15ClFNO: C,
70.69; H, 4.45; N, 4.12. Found: C, 70.37; H, 4.47; N, 4.09.
Method A: Under nitrogen, into a 250-mL three-necked flask
equipped with a Dean-stark, 2-(phenylaminomethyl)phenol 4b
(0.99 g, 5 mmol), 4-nitrobenzaldehyde 5b (0.98 g, 6.5 mmol),
mixed solvent of chloroform and cyclohexane (150mL, v/v 1:2),
and TMSCl (0.11g, 20mol%) were added with stirring. The
solution was heated at 85ꢀC for 5 h (checked by thin-layer
chromatography), and the water of condensation was removed by
azeotropic distillation of most of solvent. Then, triethyl amine was
added to make solution at pH= 8 followed by ethyl acetate
(100 mL) and washed sequentially with water (2Â 100 mL) and
saturated brine (2 Â 100mL). The organic phase was dried over
Na2SO4 and evaporated under reduced pressure. The obtained
yellow oil was purified by recrystallization from ethyl acetate-
petroleum ether to give the product 1j (73% yield) as a yellow solid.
Method B: See Method A for the procedure, but SnCl4 (0.26 g,
20 mol%) was used as catalyst.
Methyl 2-(2-(4-fluorophenyl)-2H-1,3-benzoxazin-3(4H)-yl)
acetate (1e). Yield 62% (Method A), 48% (Method B); white
solid, mp 119.8–120.3ꢀC; IR (KBr): 3472, 3084, 3061, 2956,
2909, 1909, 1747, 1607, 1582, 1510, 1487, 1450, 1389, 1341,
1310, 1248, 1219, 1157, 1138, 1107, 1032, 1000, 992, 948,
1
903, 861, 827, 761 cmÀ1; H NMR (CDCl3, 500 MHz): d 3.42
(s, 2H), 3.68 (s, 3H, CH3), 3.94 (d, J = 17.0 Hz, 1H), 4.25 (d,
J = 1 Â 7.0 Hz, 1H), 5.95 (s, 1H), 6.89–6.98 (m, 3H), 7.05–7.08
(m, 2H), 7.16–7.20 (m, 1H), 7.59–7.62 (m, 2H); 13C NMR
(CDCl3, 125 MHz): d 49.47, 49.91, 51.84, 89.87, 115.23,
115.42, 116.63, 119.07, 121.06, 127.66, 128.02, 128.59,
128.66, 133.46 (d, JCF = 3.0 Hz), 133.48, 153.30, 171.36; MS
(ESI): 319 [M + NH4]+. Anal. Calcd for C17H16FNO3: C, 67.76;
H, 5.35; N, 4.65. Found: C, 67.42; H, 5.32; N, 4.63.
2-(4-Fluorophenyl)-3-p-tolyl-3,4-dihydro-2H-1,3-benzoxazine
(1a). Yield 57% (Method A), 43% (Method B); white solid, mp
66.5–66.9ꢀC; IR (KBr): 3427, 2922, 2869, 2339, 1612, 1585,
1514, 1505, 1456, 1382, 1339, 1232, 1217, 1194, 1154, 1128,
1034, 975, 949, 898, 819, 753, 714 cmÀ1 1H NMR (CDCl3,
.
500 MHz): d 2.27 (s, 3H, CH3), 4.29 (s, 2H), 6.54 (s, 1H), 6.82–
6.88 (m, 2H), 6.95 (d, J = 8.5 Hz, 1H), 7.00 (t, J = 8.5 Hz, 2H),
7.07 (s, 4H), 7.13 (t, J = 7.0 Hz, 1H), 7.50 (t, J =6.0 Hz, 2H); 13C
NMR (CDCl3, 125MHz): d 20.67, 46.59, 88.17, 115.39, 115.56,
116.90, 120.47, 120.60 (2C), 120.70, 126.61, 128.08, 128.55,
128.61, 129.82, 131.95, 135.02 (d, JCF = 3.0 Hz), 147.30, 152.83,
161.55, 163.51; MS (ESI): 320 [M+ H]+. Anal. Calcd for
C21H18FNO: C, 78.98; H, 5.68; N, 4.39. Found: C, 78.46;
H, 5.64; N, 4.42.
2-(4-Fluorophenyl)-3-phenyl-3,4-dihydro-2H-1,3-benzoxazine
(1b). Yield 55% (Method A), 39% (Method B); white solid, mp
85.0–86.2ꢀC; IR (KBr): 3040, 2959, 2853, 2369, 1942, 1899,
1601, 1581, 1509, 1495, 1451, 1394, 1346, 1293, 1226, 1158,
1125, 1110, 1033, 1014, 976, 952, 937, 822, 764, 697 cmÀ1; 1H
NMR (CDCl3, 500 MHz): d 4.33 (d, J = 4.5 Hz, 2H), 6.61 (s,
1H), 6.83–6.89 (m, 2H), 6.97–7.04 (m, 4H), 7.14–7.19 (m, 3H),
7.26–7.29 (m, 2H), 7.50–7.53 (m, 2H); 13C NMR (CDCl3, 125
MHz): d 46.14, 87.59, 115.37, 115.54, 116.86, 120.09, 120.29,
120.68, 122.18, 126.51, 128.06, 128.43, 128.49, 129.24, 134.78
(d, JCF = 3.0 Hz), 149.58, 152.61, 156.67, 161.47, 163.43, Anal.
Calcd for C20H16FNO: C, 78.67; H, 5.28; N, 4.59. Found:
C, 78.24; H, 5.31; N, 4.56.
2-(3-Nitrophenyl)-3-(4-chlorophenyl)-3,4-dihydro-2H-1,
3-benzoxazine (1f). Yield 67% (Method A), 61% (Method B);
yellow solid, mp 145.1–145.8ꢀC; IR (KBr): 3444, 3074, 3040,
2973, 2873, 1884, 1732, 1594, 1583, 1521, 1495, 1455, 1386,
1348, 1231, 1198, 1131, 1095, 1034, 990, 954, 893, 824, 808,
757, 725, 706 cmÀ1 1H NMR (CDCl3, 500 MHz): d 4.26
;
(d, J = 17.0 Hz, 1H), 4.36 (d, J = 17.0 Hz, 1H), 6.55 (s, 1H),
6.87 (d, J = 4.5 Hz, 2H), 7.02 (d, J = 8.0 Hz, 1H), 7.13
(d, J = 8.5 Hz, 2H), 7.17 (q, J = 4.5 Hz, 1H), 7.21 (d, J = 8.5 Hz,
2H), 7.52 (t, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 8.16
(d, J = 8.5 Hz, 1H), 8.43 (s, 1H); 13C NMR (CDCl3, 125 MHz):
d 47.25, 87.02, 117.08, 119.54, 121.34, 122.11 (3C), 123.34,
126.59, 127.98, 128.53, 129.26 (2C), 129.76, 132.91, 140.99,
147.78, 148.59, 152.00. Anal. Calcd for C20H15ClN2O3:
C, 66.49; H, 4.12; N, 7.64. Found: C, 66.68; H, 4.14; N, 7.61.
3-(4-Chlorophenyl)-2-phenyl-3,4-dihydro-2H-1,3-benzoxazine
(1g). Yield 57% (Method A), 42% (Method B); white solid, mp
108.6–108.8ꢀC; IR (KBr): 3432, 3044, 2980, 1887, 1711, 1609,
1575, 1500, 1479, 1368, 1346, 1220, 1141, 1036, 1001, 968, 854,
836, 831, 768, 720 cmÀ1 1H NMR (CDCl3, 500 MHz): d 4.27
;
(d, J= 16.5 Hz, 1H), 4.32 (d, J= 16.5 Hz, 1H), 6.57 (s, 1H), 6.83–
6.88 (m, 2H), 6.98 (d, J= 8.0 Hz, 1H), 7.11 (d, J= 7.0 Hz, 2H),
7.14 (t, J= 8.5 Hz, 1H), 7.20 (d, J=9.0Hz, 2H), 7.28–7.36
(m, 3H), 7.51 (d, J= 8.0 Hz, 2H); 13C NMR (CDCl3, 125 MHz):
d 46.55, 88.02, 116.58, 116.87, 120.06, 120.19, 120.71, 121.48,
126.52, 127.10, 128.16, 128.59, 128.96, 129.12, 129.33, 129.72,
134.44, 138.69, 148.29, 152.75. Anal. Calcd for C20H16ClNO:
C, 74.65; H, 5.01; N, 4.35. Found: C, 75.98; H, 4.98; N, 4.33.
8-Methyl-2-(2-nitrophenyl)-3-p-tolyl-3,4-dihydro-2H-1,
3-benzoxazine (1h). Yield 75% (Method A), 72% (Method B);
yellow solid, mp 138.3–139.3ꢀC; IR (KBr): 3433, 3082, 2981,
2918, 1611, 1594, 1531, 1514, 1468, 1439, 1389, 1365, 1224,
2-(4-Fluorophenyl)-3-(4-methoxyphenyl)-3,4-dihydro-2H-1,
3-benzoxazine (1c). Yield 53% (Method A), 39% (Method B);
white solid, mp 76.9–77.4ꢀC; IR (KBr): 3256, 2954, 2911, 1839,
2052, 1908, 1870, 1605, 1581, 1509, 1490, 1456, 1437, 1379,
1346, 1240, 1230, 1153, 1105, 1038, 1019, 980, 956, 894, 836,
1
759 cmÀ1; H NMR (CDCl3, 500MHz): d 3.74 (s, 3H, OCH3),
4.27 (d, J = 4.0Hz, 2H), 6.42 (s, 1H), 6.78 (d, J = 9.0 Hz, 2H),
6.85–6.88 (m, 2H), 6.96–7.03 (m, 3H), 7.10–7.16 (m, 3H), 7.51–
7.54 (m, 2H); 13C NMR (CDCl3, 125MHz): d 47.37, 55.40, 88.83,
114.25, 114.63, 115.25, 115.42, 116.78, 117.93, 120.66, 122.92,
126.54, 127.98, 128.52, 128.58, 129.16, 134.86 (d, JCF =3.1Hz),
143.08, 152.89, 161.43, 163.39. Anal. Calcd for C21H18FNO2: C,
75.21; H, 5.41; N, 4.18. Found: C, 75.53; H, 5.39; N, 4.20.
;
1200, 1144, 968, 820,766, 735 cmÀ1 1H NMR (CDCl3,
500 MHz): d 2.24 (s, 3H, CH3), 2.32 (s, 3H,CH3), 3.98
(d, J = 17.0 Hz, 1H), 4.19 (d, J = 17.0Hz, 1H), 6.68 (d, J = 7.5Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1590

Month 2013
TMSCl-Catalyzed Synthesis of 2,3-Disubstituted-1,3-benzoxazines
1H), 6.75 (t, J = 7.0 Hz, 1H), 7.03 (t, J = 9.0 Hz, 6H), 7.43–7.46 (m,
2H), 7.49–7.51 (m, 1H), 7.72–7.73 (m, 1H); 13C NMR (CDCl3,
125 MHz): d 15.81, 20.65, 47.04, 85.43, 119.65, 120.29, 120.70
(2C), 124.05, 124.35, 125.60, 128.28, 129.08, 129.34, 129.64
(2C), 131.79, 132.49, 132.99, 146.69, 148.92, 150.36. Anal.
Calcd for C22H20N2O3: C, 73.32; H, 5.59; N, 7.77. Found: C,
73.59; H, 5.56; N, 7.73.
(s, 2H), 3.71 (s, 3H, CH3), 3.94 (d, J= 17.0 Hz, 1H), 4.21
(d, J= 17.0 Hz, 1H), 6.03 (s, 1H), 6.92–7.00 (m, 3H), 7.20
(t, J=7.0Hz, 1H), 7.84 (d, J=8.5Hz, 2H), 8.24 (d, J= 8.5 Hz, 2H);
13C NMR (CDCl3, 125 MHz): d 49.11, 50.41, 51.97, 89.34, 116.68,
118.80, 121.45, 123.68 (2C), 127.72, 127.92 (2C), 128.26, 144.90,
147.82, 152.70, 171.04. Anal. Calcd for C17H16N2O5: C, 62.19;
H, 4.91; N, 8.53. Found: C, 62.50; H, 4.89; N, 8.57.
8-Methyl-2-(3-nitrophenyl)-3-p-tolyl-3,4-dihydro-2H-1,
3-benzoxazine (1i). Yield 78% (Method A), 73% (Method B);
yellow solid, mp 118.4–118.7ꢀC; IR (KBr): 3434, 3090, 3026,
2917, 2856, 1714, 1612, 1595, 1579, 1528, 1514, 1472, 1451,
1378, 1345, 1222, 1194, 1127, 1079, 998, 967, 940, 811, 767,
730, 691cmÀ1; 1H NMR (CDCl3, 500MHz): d 2.28 (s, 3H, CH3),
2.37 (s, 3H, CH3), 4.25 (d, J = 17.0Hz, 1H), 4.35 (d, J = 17.0Hz,
1H), 6.61 (s, 1H), 6.71 (d, J = 7.0Hz, 1H), 6.75 (t, J = 7.0 Hz, 1H),
7.03 (d, J = 7.0 Hz, 1H), 7.07–7.12 (m, 4H), 7.51 (t, J = 8.0Hz,
1H), 7.86 (d, J = 7.5Hz, 1H), 8.15–8.17 (m, 1H), 8.43 (s, 1H);
13C NMR (CDCl3, 125 MHz): d 15.86, 20.62, 46.98, 87.55,
119.39, 120.41, 120.77 (2C), 122.01, 123.16, 124.02, 125.99,
129.31, 129.65, 129.80 (2C), 132.29, 132.75, 141.66, 146.99,
148.59, 150.19. Anal. Calcd for C22H20N2O3: C, 73.32; H, 5.59;
N, 7.77. Found: C, 73.64; H, 5.56; N, 7.74.
Acknowledgments. The authors are grateful to the Science
Foundation from National Natural Science Foundation of China
(21042011), the Scientific Research Fund of Hunan Provincial
Education Department (10A034) and Hunan Provincial Postdoctoral
Science Foundation (2010RS4033) for the financial support of this
work.
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2-(4-Nitrophenyl)-3-phenyl-3,4-dihydro-2H-1,3-benzoxazine
(1j). Yield 73%, (Method A), 72% (Method B); yellow solid, mp
117.2–118.8ꢀC; IR (KBr): 3444, 3087, 3056, 3038, 3007, 2970,
2912, 1707, 1596, 1581, 1522, 1492, 1453, 1388, 1346, 1230,
1208, 1144, 1109, 1034, 978, 958, 888, 853, 828, 759, 741cmÀ1
;
1H NMR (CDCl3, 500MHz): d 4.25 (d, J = 17.0 Hz, 1H), 4.40
(d, J = 17.0Hz, 1H), 6.64 (s, 1H), 6.87 (d, J = 7.5 Hz, 2H), 7.00–
7.03 (m, 2H), 7.17–7.21 (m, 3H), 7.26–7.31 (m, 2H), 7.74
(d, J = 8.5 Hz, 2H), 8.19 (d, J = 7.0 Hz, 2H); 13C NMR (CDCl3,
125 MHz): d 46.72, 87.22, 116.51, 116.95, 119.96, 120.28,
121.15, 122.68, 123.84, 124.26, 126.60, 127.86, 128.31, 129.34
(2C), 130.46, 146.28, 147.68, 149.21, 152.21. Anal. Calcd for
C20H16N2O3: C, 72.28; H, 4.85; N, 8.43. Found: C, 72.59;
H, 4.83; N, 8.39.
Methyl 2-(2-(2-nitrophenyl)-2H-1,3-benzoxazin-3(4H)-yl)acetate
(1k). Yield 88% (Method A), 84% (Method B); white solid, mp
108.6–109.0ꢀC; IR (KBr): 3446, 3010, 2958, 2881, 1953, 1912,
1731, 1607, 1585, 1524, 1488, 1461, 1444, 1424, 1365, 1275,
1263, 1222, 1122, 1109, 1034, 1002, 963, 780, 761, 742 cmÀ1
;
1H NMR (CDCl3, 500 MHz): d 3.38 (s, 2H), 3.66 (s, 3H, CH3),
3.78 (d, J = 17.0 Hz, 1H), 4.14 (d, J = 17.0 Hz, 1H), 6.57 (s, 1H),
6.94–7.00 (m, 3H), 7.21–7.24 (m, 1H), 7.49–7.53 (m, 1H), 7.57–
7.60 (m, 1H), 7.81–7.84 (m, 2H); 13C NMR (CDCl3, 125MHz):
d 48.99, 51.33, 51.92, 87.19, 116.58, 119.18, 121.39, 124.71,
127.86, 128.20, 128.26, 129.41, 131.95, 132.16, 148.86, 152.95,
170.57; MS (ESI): 346 [M+ NH4]+. Anal. Calcd for C17H16N2O5:
C, 62.19; H, 4.91; N, 8.53. Found: C, 62.47; H, 4.88; N, 8.49.
Methyl 2-(2-(4-nitrophenyl)-2H-1,3-benzoxazin-3(4H)-yl)acetate
(1l). Yield 91% (Method A), 85% (Method B); white solid, mp
137.2–138.9ꢀC; IR (KBr): 3468, 3079, 3038, 2854, 1745, 1609,
1580, 1523, 1488, 1447, 1420, 1384, 1346, 1313, 1221, 1134, 1109,
992, 952, 904, 826, 764 cmÀ1; 1H NMR (CDCl3, 500 MHz): d 3.37
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet.1590