One-pot synthesis of 2-substituted 4-aryl-4,5-dihydro-3,1-benzoxazepines from 2-(2-Aminophenyl)-1-arylethanols via dehydration of the corresponding amides

Article abstract of DOI:10.1002/hlca.201000421

An efficient method for the preparation of 2-substituted 4-aryl-4,5-dihydro-3,1-benzoxazepine derivatives under mild conditions has been developed. The reaction of 2-(2-aminophenyl)ethanols 1 with acid chlorides in the presence of excess Et₃N in THF at room temperature gave the corresponding N-acylated intermediates 2, which were dehydrated by treatment with POCl₃ to give 2-substituted 4-aryl-4,5-dihydro-3,1- benzoxazepines 3 in a one-pot reaction.

Full text of DOI:10.1002/hlca.201000421

Helvetica Chimica Acta – Vol. 94 (2011)
987
One-Pot Synthesis of 2-Substituted 4-Aryl-4,5-dihydro-3,1-benzoxazepines
from 2-(2-Aminophenyl)-1-arylethanols via Dehydration of the
Corresponding Amides
by Shuhei Fukamachi, Hisatoshi Konishi, and Kazuhiro Kobayashi*
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of
Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
(phone/fax: þ 81-857-315263; e-mail: kkoba@chem.tottori-u.ac.jp)
An efficient method for the preparation of 2-substituted 4-aryl-4,5-dihydro-3,1-benzoxazepine
derivatives under mild conditions has been developed. The reaction of 2-(2-aminophenyl)ethanols 1 with
acid chlorides in the presence of excess Et3N in THF at room temperature gave the corresponding N-
acylated intermediates 2, which were dehydrated by treatment with POCl3 to give 2-substituted 4-aryl-
4,5-dihydro-3,1-benzoxazepines 3 in a one-pot reaction.
Introduction. – The 4H-3,1-benzoxazine skeleton is found in many biologically
active compounds [1]. Therefore, compounds with the 4,5-dihydro-3,1-benzoxazepine
structure, a homolog of 4H-3,1-benzoxazine, are also of potential biological impor-
tance. However, few general methods for the preparation of 4,5-dihydro-3,1-
benzoxazepine derivatives have been elaborated, though Ito et al. have reported a
synthesis of 2-unsubstituted 4,5-dihydro-3,1-benzoxazepine derivatives by the treat-
ment of 2-(2-isocyanophenyl)ethanols, available from 2-methylphenyl isocyanides,
with Cu2O [2a]. In this article, we describe a facile one-pot procedure for the synthesis
of 2-substituted 4-aryl-4,5-dihydro-3,1-benzoxazepines from 2-(2-aminophenyl)-1-
arylethanols, easily prepared from 2-nitrotoluene and its derivatives by a conventional
two-step sequence, via dehydration of the corresponding amides. This is the first report
on the general preparation of 2-substituted 4-aryl-4,5-dihydro-3,1-benzoxazepines.
Although the formation of 4,5-dihydro-4-[(methylsulfanyl)methyl]-2-phenyl-3,1-ben-
zoxazepine [2b] and 4,5-dihydro-2-phenyl-3,1-benzoxazepine [2c] have been reported
by Capozzi et al., and Ganton and Kerr, respectively, their methods suffer from limited
generality.
Results and Discussion. – The one-pot synthesis of 2-substituted 4-aryl-4,5-dihydro-
3,1-benzoxazepine derivatives 3 from 2-(2-aminophenyl)ethanols 1 was conducted by
the process depicted in Scheme 1. The amino alcohols 1 were prepared by the treatment
of ortho-nitrotoluene and its derivatives with aryl aldehydes in the presence of MeONa,
followed by hydrogenation of the resulting 1-aryl-2-(2-nitrophenyl)ethanols with Pd on
activated C under reported condition [3]. Compounds 1 were treated with acid
chlorides in the presence of excess Et3N in THF at room temperature to give the
corresponding N-acylated intermediates 2, which were then dehydrated with 2 mol-
equiv. of POCl3 at the same temperature. The usual aqueous workup and subsequent
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

988
Helvetica Chimica Acta – Vol. 94 (2011)
purification by column chromatography on neutral alumina afforded the desired
products 3. The results are compiled in the Table; the yields are generally moderate-to-
fair. While isolation of the products by column chromatography on silica gel caused
considerable decreases of their yields owing to hydrolysis of the imino-ether moiety,
little hydrolysis seemed to take place during purification with neutral alumina in
general. However, the yields of the products with Me or Et groups at C(2) of the 4,5-
dihydro-3,1-benzoxazepine 3d, 3e, and 3k were rather low compared to the other
products (cf. Entries 4, 5, and 11). 4-Aryl-4,5-dihydro-3,1-benzoxazepines with
cinnamyl (Entry 6), heteraryl (Entries 7 and 14), trichloromethyl (Entry 8), or t-Bu
(Entry 13) substituent at C(2) could also be obtained. We also examined the reaction
using chloroacetyl chloride in order to obtain the product with a ClCH2 substituent,
which might be elaborated to structurally more complex molecules. Unfortunately,
however, the corresponding 4,5-dihydro-3,1-benzoxazepine derivative could not be
obtained due to its instability during the purification by column chromatography.
Scheme 1
Table. Preparation of 2-Substituted 4-Aryl-4,5-dihydro-3,1-benzoxazepine Derivatives 3
Entry
1
R3
3
Yielda) [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a (R1 ¼ R2 ¼ H, Ar¼ Ph)
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
52
55
57
34
43
56
62
62
35
68
56
74
54
72
1a
4-ClꢀC6H4
1a
1a
1a
1a
1a
1a
4-MeOꢀC6H4
Me
Et
(E)-PhCH¼CH
3-Py
CCl3
Ph
Ph
Et
i-Pr
t-Bu
Thiophen-2-yl
1b (R1 ¼ R2 ¼ H, Ar¼ 3-MeOꢀC6H4)
1c (R1 ¼ H, R2 ¼ Cl, Ar¼ 4-ClꢀC6H4)
1c
1d (R1 ¼ MeO, R2 ¼ H, Ar3 ¼ Ph)
1d
1d
a) Yields of isolated products.
Ethyl chloroformate (ClCOOEt) or phenyl isocyanate (PhNCO) proved to be
usable in the present reaction in place of acid chlorides, and 4-aryl-4,5-dihydro-3,1-
benzoxazepines with EtO or PhNH substituent at C(2) 5a or 5b, respectively, were
obtained, via the respective intermediates 4, as illustrated in Scheme 2.

Helvetica Chimica Acta – Vol. 94 (2011)
989
Scheme 2
In conclusion, we have developed a facile method for the synthesis of 2-substituted
4-aryl-4,5-dihydro-3,1-benzoxazepines 3 from 2-(2-aminophenyl)ethanols 1, via the
corresponding amides 2. Notable advantages of the present synthesis are: i) simplicity
of the procedure, ii) mild reaction conditions, and iii) easy availability of the starting
materials.
Experimental Part
General. All solvents used were dried over the appropriate drying agents and distilled under Ar prior
to use. 2-(2-Nitrophenyl)-1-phenylethanol and 2-(2-aminophenyl)-1-phenylethanol (1a) were prepared
according to the procedure in [3]. All other chemicals used were commercially available. TLC: Merck
Alumina 60 Neutral F254, or Merck Kieselgel 60 PF254. Column chromatography (CC): Merck Alumina,
activated neutral, activity I. M.p.: Laboratory Devices MEL-TEMP II melting-point apparatus;
1
uncorrected. IR Spectra: Shimadzu FTIR-8300 spectrometer. H-NMR Spectra: Me4Si as an internal
reference; in CDCl3; JEOL ECP 500 FT NMR spectrometer; at 500 MHz. 13C-NMR Spectra: Me4Si as
an internal reference; in CDCl3; JEOL ECP 500 FT NMR spectrometer; at 125 MHz. Low-resolution
(LR) MS spectra (EI, 70 eV): JEOL JMS AX 505 HA spectrometer.
1-Aryl-2-(2-nitrophenyl)ethanols were prepared by the treatment of ortho-nitrotoluene and its
derivatives with aryl aldehydes in the presence of a cat. amount of MeONa under conditions reported for
the preparation of 2-(2-nitrophenyl)-1-phenylethanol [3].
1-(3-Methoxyphenyl)-2-(2-nitrophenyl)ethanol. Yield: 58%. Yellow oil. Rf (SiO2; THF/hexane 1:4)
0.22. IR (neat): 3453, 1603, 1524, 1348. 1H-NMR: 1.92 – 2.33 (br., 1 H); 3.22 (dd, J ¼ 13.7, 9.2, 1 H); 3.38
(dd, J ¼ 13.7, 4.1, 1 H); 3.82 (s, 3 H); 5.02 (dd, J ¼ 9.2, 4.1, 1 H); 6.84 (ddd, J ¼ 8.2, 2.7, 1.4, 1 H); 6.96 (d,
J ¼ 2.7, 1 H); 6.98 (dd, J ¼ 7.8, 1.4, 1 H); 7.27 (t, J ¼ 8.2, 1 H); 7.34 (dd, J ¼ 8.2, 1.4, 1 H); 7.40 (td, J ¼ 7.8,
1.4, 1 H); 7.52 (td, J ¼ 7.8, 1.4, 1 H); 7.95 (dd, J ¼ 7.8, 1.4, 1 H). Anal. calc. for C15H15NO4 (273.28): C 65.92,
H 5.53, N 5.13; found: C 65.73, H 5.64, N, 5.03.
2-(4-Chloro-2-nitrophenyl)-1-(4-chlorophenyl)ethanol. Yield: 52%. Yellow oil. Rf (SiO2; THF/
hexane 1:5) 0.27. IR (neat): 3383, 1537, 1348. 1H-NMR: 2.08 (d, J ¼ 3.7, 1 H); 3.15 (dd, J ¼ 13.7, 8.7, 1 H);
3.21 (dd, J ¼ 13.7, 3.7, 1 H); 4.99 – 5.02 (m, 1 H); 7.25 (d, J ¼ 8.2, 1 H); 7.30 – 7.35 (m, 4 H); 7.49 (dd, J ¼ 8.2,
1.8, 1 H); 7.96 (d, J ¼ 1.8, 1 H). Anal. calc. for C14H11Cl2NO3 (312.15): C 53.87, H 3.55, N 4.49; found: C
53.89, H 3.64, N 4.42.
2-(5-Methoxy-2-nitrophenyl)-1-phenylethanol. Yield: 54%. Pale-yellow solid. M.p. 62 – 648 (hexane/
Et2O). IR (KBr): 3440, 1512, 1337. 1H-NMR: 2.08 – 2.42 (br., 1 H); 3.21 (dd, J ¼ 13.2, 8.7, 1 H); 3.46 (dd,
J ¼ 13.2, 4.1, 1 H); 3.81 (s, 3 H); 5.06 (dd, J ¼ 8.7, 4.1, 1 H); 6.71 (d, J ¼ 2.7, 1 H); 6.84 (dd, J ¼ 9.2, 2.7,
1 H); 7.30 (t, J ¼ 7.3, 1 H); 7.36 (t, J ¼ 7.3, 2 H); 7.42 (d, J ¼ 7.3, 2 H); 8.07 (d, J ¼ 9.2, 1 H). Anal. calc. for
C15H15NO4 (273.28): C 65.92, H 5.53, N 5.13; found: C 65.72, H 5.59, N 5.03.
2-(2-Aminophenyl)-1-arylethanol derivatives 1 were prepared by the hydrogenation of the respective
1-aryl-2-(2-nitrophenyl)ethanol derivatives on Pd/C under the conditions reported for the preparation of
1a [3].
2-(2-Aminophenyl)-1-(3-methoxyphenyl)ethanol (1b). Yield: 82%. Pale-yellow oil. Rf (SiO2; THF/
hexane 2 :5) 0.47. IR (neat): 3426, 3374, 1603. 1H-NMR: 1.38 – 1.82 (br., 1 H); 2.89 (dd, J ¼ 14.1, 3.7, 1 H);

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Helvetica Chimica Acta – Vol. 94 (2011)
3.01 (dd, J ¼ 14.1, 8.7, 1 H); 3.20 – 3.70 (br., 2 H); 3.80 (s, 3 H); 4.96 (dd, J ¼ 8.7, 3.7, 1 H); 6.72 (dd, J ¼ 7.8,
1.4, 1 H); 6.75 (td, J ¼ 7.8, 1.4, 1 H); 6.83 (dd, J ¼ 8.2, 2.7, 1 H); 6.93 (d, J ¼ 2.7, 1 H); 6.97 (d, J ¼ 8.2, 1 H);
7.01 (dd, J ¼ 7.8, 1.4, 1 H); 7.07 (td, J ¼ 7.8, 1.4, 1 H); 7.28 (t, J ¼ 8.2, 1 H). Anal. calc. for C15H17NO2
(243.30): C 74.05, H 7.04, N 5.76; found: C 73.91, H 7.13, N 5.51.
2-(2-Amino-4-chlorophenyl)-1-(4-chlorophenyl)ethanol (1c). Yield: 83%. Pale-yellow solid. M.p.
97 – 998 (hexane/Et2O). IR (KBr): 3395, 3296. 1H-NMR: 2.36 (s, 1 H); 2.83 (dd, J ¼ 14.6, 4.1, 1 H); 2.91
(dd, J ¼ 14.6, 8.2, 1 H); 3.98 (s, 2 H); 4.93 – 4.96 (m, 1 H); 6.67 (d, J ¼ 7.8, 1 H); 6.69 (s, 1 H); 6.81 (d, J ¼
7.8, 1 H); 7.26 (d, J ¼ 8.2, 2 H); 7.32 (d, J ¼ 8.2, 2 H). Anal. calc. for C14H13Cl2NO (282.17): C 59.59, H
4.64, N 4.96; found: C 59.41, H 4.82, N, 4.64.
2-(2-Amino-5-methoxyphenyl)-1-phenylethanol (1d). Yield: 94%. Pale-yellow crystal. M.p. 64 – 668
(hexane/Et2O). IR (KBr): 3356, 3277. 1H-NMR: 2.70 – 3.75 (br., 3 H); 2.88 (dd, J ¼ 14.2, 4.1, 1 H); 3.01
(dd, J ¼ 14.2, 8.7, 1 H); 3.70 (s, 3 H); 4.98 (dd, J ¼ 8.7, 4.1, 1 H); 6.57 (d, J ¼ 2.3, 1 H); 6.64 – 6.68 (m, 2 H);
7.29 (tt, J ¼ 7.3, 1.8, 1 H); 7.34 – 7.39 (m, 4 H). Anal. calc. for C15H17NO2 (243.30): C 74.05, H 7.04, N 5.76;
found: C 73.96, H 7.01, N 5.66.
4,5-Dihydro-2,4-diphenyl-3,1-benzoxazepine (3a; Representative Procedure). To a stirred soln. of 1a
(0.21 g, 1.0 mmol) and Et3N (1.32 g, 13 mmol) in THF (5 ml) at r.t. was added BzCl (0.14 g, 1.0 mmol)
dropwise. After 5 min, the resulting mixture was treated with POCl3 (0.31 g, 2.0 mmol), and stirring was
continued overnight at the same temp. before sat. aq. NaHCO3 (10 ml) was added. The org. materials
were extracted with AcOEt (3 ꢁ 10 ml), and the combined extracts were washed with brine (10 ml),
dried (Na2SO4), and concentrated by evaporation. The residue was purified by CC (Al2O3; Et2O/hexane
1:5) to afford 3a (0.16 g, 52%). White solid. M.p. 86 – 888 (hexane/Et2O). IR (KBr): 1647. 1H-NMR: 3.22
(d, J ¼ 15.6, 1 H); 3.54 (dd, J ¼ 15.6, 8.2, 1 H); 5.60 (d, J ¼ 8.2, 1 H); 6.75 – 7.09 (m, 2 H); 7.29 (td, J ¼ 7.8,
2.7, 1 H); 7.35 – 7.47 (m, 9 H); 8.15 (dd, J ¼ 8.2, 1.8, 2 H). 13C-NMR: 44.52; 84.17; 124.94; 125.85; 127.61;
128.03; 128.18; 128.56; 128.74; 128.86; 129.32; 130.51; 133.40; 135.38; 141.07; 143.26; 151.51. MS: 299 (24,
Mþ), 106 (100). Anal. calc. for C21H17NO (299.37): C 84.25, H 5.72, N 4.68; found: C 84.22, H 5.79, N 4.69.
2-(4-Chlorophenyl)-4,5-dihydro-4-phenyl-3,1-benzoxazepine (3b). Pale-yellow viscous oil. Rf
(Al2O3; Et2O/hexane 1:5) 0.85. IR (neat): 1651. 1H-NMR: 3.21 (d, J ¼ 16.0, 1 H), 3.53 (dd, J ¼ 16.0,
8.2, 1 H); 5.57 (d, J ¼ 8.2, 1 H); 7.07 (td, J ¼ 7.8, 2.3, 1 H); 7.09 (td, J ¼ 7.8, 2.3, 1 H); 7.29 (td, J ¼ 7.8, 2.3,
1 H); 7.35 (d, J ¼ 8.7, 2 H); 7.36 – 7.45 (m, 6 H); 8.07 (d, J ¼ 8.7, 2 H). 13C-NMR: 44.45; 84.20; 125.17;
125.83; 127.68; 128.21; 128.29; 128.79; 128.93; 129.37; 129.94; 133.39; 133.89; 136.66; 140.88; 142.97;
150.50. MS: 333 (25, Mþ), 106 (100). Anal. calc. for C21H16ClNO (333.81): C 75.56, H 6.82, N 5.57; found:
C 75.50, H 6.80, N, 5.30.
4,5-Dihydro-2-(4-methoxyphenyl)-4-phenyl-3,1-benzoxazepine (3c). Colorless crystals. M.p. 104 –
1068 (hexane/Et2O). IR (KBr): 1643. 1H-NMR: 3.20 (d, J ¼ 16.0, 1 H); 3.52 (dd, J ¼ 16.0, 8.7, 1 H);
3.84 (s, 3 H); 5.58 (d, J ¼ 8.7, 1 H); 6.89 (d, J ¼ 9.1, 2 H); 7.04 – 7.06 (m, 2 H); 7.26 – 7.44 (m, 7 H); 8.80 (d,
J ¼ 9.1, 2 H). 13C-NMR: 44.43; 55.33; 84.20; 113.31; 124.58; 125.85; 127.57; 127.87; 128.13; 128.71; 128.82;
129.07; 130.28; 133.18; 141.20; 143.51; 151.59; 161.63. MS: 329 (21, Mþ), 106 (100). Anal. calc. for
C22H19NO2 (329.39): C 80.22, H 5.81, N 4.25; found: C 80.05, H 5.93, N 4.14.
4,5-Dihydro-2-methyl-4-phenyl-3,1-benzoxazepine (3d). Colorless oil. Rf (Al2O3; Et2O/hexane 1:5)
0.83. IR (neat): 1668, 1599. 1H-NMR: 2.26 (s, 3 H); 3.12 (d, J ¼ 16.0, 1 H); 3.44 (dd, J ¼ 16.0, 8.2, 1 H);
5.40 (d, J ¼ 8.2, 1 H); 7.00 (d, J ¼ 7.3, 1 H); 7.03 (td, J ¼ 7.3, 1.4, 1 H); 7.21 – 7.26 (m, 2 H); 7.31 – 7.41 (m,
5 H). 13C-NMR: 24.61; 44.25; 84.20; 99.90; 124.59; 125.71; 127.56; 128.16; 128.25; 128.71; 133.25; 140.98;
143.17; 154.91. MS: 237 (19, Mþ), 106 (100). Anal. calc. for C16H15NO (237.30): C 80.98, H 6.37, N 5.90;
found: C 80.95, H 6.43, N 5.75.
2-Ethyl-4,5-dihydro-4-phenyl-3,1-benzoxazepine (3e). Pale-yellow oil. Rf (Al2O3; Et2O/hexane 1:5)
0.89. IR (neat): 1667. 1H-NMR: 1.28 (t, J ¼ 7.3, 3 H); 2.47 – 2.52 (m, 2 H); 3.12 (d, J ¼ 15.6, 1 H); 3.41 (dd,
J ¼ 15.6, 8.2, 1 H); 5.40 (d, J ¼ 8.2, 1 H); 7.00 (d, J ¼ 7.3, 1 H); 7.03 (td, J ¼ 7.3, 1.4, 1 H); 7.23 (td, J ¼ 7.3,
1.4, 1 H); 7.26 – 7.41 (m, 6 H). 13C-NMR: 11.77; 31.17; 44.33; 84.15; 124.47; 125.66; 127.52; 128.08; 128.30;
128.63; 128.64; 133.23; 141.15; 143.29; 158.63. MS: 251 (17, Mþ), 106 (100). Anal. calc. for C17H17NO
(251.32): C 81.24, H 6.82, N 5.57; found: C 81.23, H 6.77, N 5.54.
4,5-Dihydro-4-phenyl-2-[(E)-2-phenylethenyl]-3,1-benzoxazepine (3f). Pale-yellow solid. M.p.
1
116 – 1188 (hexane/Et2O). IR (KBr): 1632, 1620. H-NMR: 3.18 (d, J ¼ 15.6, 1 H); 3.47 (dd, J ¼ 15.6,
8.2, 1 H); 5.55 (d, J ¼ 8.2, 1 H); 6.75 (d, J ¼ 16.0, 1 H); 7.05 (td, J ¼ 7.8, 1.8, 1 H); 7.07 (td, J ¼ 7.8, 1.4, 1 H);

Helvetica Chimica Acta – Vol. 94 (2011)
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7.26 – 7.45 (m, 11 H); 7.49 (dd, J ¼ 7.3, 1.4, 2 H). 13C-NMR: 44.09; 84.83; 125.06; 125.42; 125.85; 127.50;
127.70 (two overlapped Cs); 128.21; 128.71 (two overlapped Cs); 128.92; 128.96; 132.96; 135.75; 138.12;
141.07; 143.67; 153.02. MS: 325 (14, Mþ), 106 (100). Anal. calc. for C23H19NO (325.40): C 84.89, H 5.89, N
4.30; found: C 84.70, H 5.93, N, 4.29.
4,5-Dihydro-4-phenyl-2-(pyridin-3-yl)-3,1-benzoxazepine (3g). Yellow oil. Rf (Al2O3; Et2O/hexane
1:5) 0.34. IR (neat): 1651. 1H-NMR: 3.24 (d, J ¼ 16.0, 1 H); 3.55 (dd, J ¼ 16.0, 8.2, 1 H); 6.75 (d, J ¼ 8.2,
1 H); 7.08 (t, J ¼ 7.3, 1 H); 7.11 (t, J ¼ 7.3, 1 H); 7.29 – 7.33 (m, 2 H); 7.36 – 7.44 (m, 5 H); 7.47 (d, J ¼ 7.3,
1 H); 8.39 (d, J ¼ 7.3, 1 H); 8.66 (d, J ¼ 4.6, 1 H); 9.33 (s, 1 H). 13C-NMR: 44.49; 84.13; 122.81; 125.45;
125.74; 127.71; 128.32; 128.79; 128.95; 129.50; 131.03; 133.44; 135.86; 140.59; 142.65; 149.34; 150.01;
151.03. MS: 300 (17, Mþ), 106 (100). Anal. calc. for C20H16N2O (300.35): C 79.98, H 5.37, N 9.33; found: C
79.98, H 5.56, N 9.28.
4,5-Dihydro-4-phenyl-2-(trichloromethyl)-3,1-benzoxazepine (3h). Pale-yellow oil. Rf (Al2O3; Et2O/
hexane 1:5) 0.55. IR (neat): 1684. 1H-NMR: 2.99 (d, J ¼ 15.1, 1 H); 3.80 (dd, J ¼ 15.1, 8.2, 1 H); 6.22 (d,
J ¼ 8.2, 1 H); 7.09 (d, J ¼ 7.3, 2 H); 7.12 – 7.19 (m, 3 H); 7.23 (t, J ¼ 7.3, 2 H); 7.34 (td, J ¼ 8.2, 2.7, 1 H); 8.23
(d, J ¼ 8.2; 1 H). 13C-NMR: 39.36; 65.33; 93.28; 118.83; 124.87; 125.33; 125.96; 127.24; 127.84; 128.58;
130.07; 142.36; 143.33; 158.61. MS: 339 (19, Mþ), 106 (100). Anal. calc. for C16H12ClNO (340.63): C 56.42,
H 3.55, N 4.11; found: C 56.36, H 3.64, N 3.87.
4,5-Dihydro-4-(3-methoxyphenyl)-2-phenyl-3,1-benzoxazepine (3i). Pale-yellow oil. Rf (Al2O3;
1
Et2O/hexane 1:5) 0.82. IR (neat): 1651. H-NMR: 3.22 (d, J ¼ 16.0, 1 H); 3.52 (dd, J ¼ 16.0, 8.2, 1 H);
3.83 (s, 3 H); 5.57 (d, J ¼ 8.2, 1 H); 6.91 (dd, J ¼ 8.2, 2.7, 1 H); 6.98 (d, J ¼ 2.7, 1 H); 7.02 (d, J ¼ 7.8, 1 H);
7.06 – 7.10 (m, 2 H); 7.29 (td, J ¼ 8.2, 2.7, 1 H); 7.34 (t, J ¼ 7.8, 1 H); 7.38 – 7.47 (m, 4 H); 8.15 (dd, J ¼ 7.8,
1.4, 2 H). 13C-NMR: 44.52; 55.28; 84.09; 111.57; 113.49; 118.14; 124.95; 127.61; 128.03; 128.57; 128.86;
129.30; 129.81; 130.51; 133.34; 135.35; 142.63; 143.24; 151.47; 159.88. MS: 329 (27, Mþ), 136 (100). Anal.
calc. for C22H19NO2 (329.39): C 80.22, H 5.81, N 4.25; found: C 80.25, H 5.85, N 4.06.
8-Chloro-4-(4-chlorophenyl)-4,5-dihydro-2-phenyl-3,1-benzoxazepine (3j). Colorless needles. M.p.
146 – 1488 (hexane/Et2O). IR (KBr): 1643. 1H-NMR: 3.18 (d, J ¼ 15.6, 1 H); 3.44 (dd, J ¼ 15.6, 7.8, 1 H);
5.56 (d, J ¼ 7.8, 1 H); 6.95 (d, J ¼ 8.2, 1 H); 7.04 (dd, J ¼ 8.2, 2.3, 1 H); 7.33 (d, J ¼ 8.7, 2 H); 7.38 – 7.41 (m,
4 H); 7.44 (d, J ¼ 2.3, 1 H); 7.46 (tt, J ¼ 8.7, 1.4, 1 H); 8.10 (dd, J ¼ 8.7, 1.4, 2 H). 13C-NMR: 43.57; 83.55;
124.81; 127.21; 128.15; 128.59; 129.00; 129.05; 129.83; 130.95; 131.35; 133.10; 134.16; 134.78; 139.06;
144.47; 152.28. MS: 367 (28, Mþ), 140 (100). Anal. calc. for C21H15ClNO (368.26): C 68.49, H 4.11, N 3.80;
found: C 68.49, H 4.29, N 3.77.
8-Chloro-4-(4-chlorophenyl)-2-ethyl-4,5-dihydro-3,1-benzoxazepine (3k). Pale-yellow solid. M.p.
80 – 828 (hexane/Et2O). IR (KBr): 1667. 1H-NMR: 1.25 (t, J ¼ 7.3, 3 H); 2.47 (q, J ¼ 7.3, 2 H); 3.08 (d, J ¼
15.6, 1 H); 3.31 (dd, J ¼ 15.6, 7.8, 1 H); 5.36 (d, J ¼ 7.8, 1 H); 6.89 (d, J ¼ 7.8, 1 H); 6.98 (dd, J ¼ 7.8, 2.3,
1 H); 7.24 (d, J ¼ 8.2, 2 H); 7.26 (d, J ¼ 2.3, 1 H); 7.35 (d, J ¼ 8.2, 2 H); 13C-NMR: 11.57; 30.96; 43.48;
83.39; 124.39; 127.02; 128.25; 128.87; 129.62; 131.24; 133.02; 134.02; 139.16; 144.49; 159.40. MS: 319 (30,
Mþ), 140 (100). Anal. calc. for C17H15ClNO (320.21): C 63.76, H 4.72, N 4.37; found: C 63.68, H 4.79, N
4.38.
4,5-Dihydro-7-methoxy-2-(1-methylethyl)-4-phenyl-3,1-benzoxazepine (3l). Pale-yellow oil. Rf
1
(Al2O3; Et2O/hexane 1:5) 0.57. IR (neat): 1668. H-NMR: 1.15 (d, J ¼ 7.3, 3 H); 1.18 (d, J ¼ 7.3, 3 H);
2.58 – 2.62 (m, 1 H); 2.97 (d, J ¼ 15.6, 1 H); 3.25 (dd, J ¼ 15.6, 8.2, 1 H); 3.67 (s, 3 H); 5.26 (d, J ¼ 8.2,
1 H); 6.45 (d, J ¼ 2.7, 1 H); 6.67 (dd, J ¼ 8.7, 2.7, 1 H); 7.13 (d, J ¼ 8.7, 1 H); 7.21 – 7.31 (m, 5 H). 13C-NMR:
20.79; 20.85; 36.65; 44.71; 55.37; 83.00; 112.35; 114.03; 125.61; 127.97; 128.60; 129.77; 134.35; 136.75;
141.37; 156.50; 159.70. MS: 295 (30, Mþ), 106 (100). Anal. calc. for C19H21NO2 (295.38): C 77.26, H 7.17, N
4.74; found: C 76.98, H 7.23, N 4.44.
2-(tert-Butyl)-4,5-dihydro-7-methoxy-4-phenyl-3,1-benzoxazepine (3m). Colorless oil. Rf (Al2O3;
Et2O/hexane 1:5) 0.71. IR (neat): 1667. 1H-NMR: 1.21 (s, 9 H), 2.97 (d, J ¼ 16.0, 1 H); 3.22 (dd, J ¼ 16.0,
7.8, 1 H); 3.67 (s, 3 H); 5.25 (d, J ¼ 7.8, 1 H); 6.45 (d, J ¼ 2.7, 1 H); 6.67 (dd, J ¼ 8.2, 2.7, 1 H); 7.13 (d, J ¼
8.2, 1 H); 7.21 – 7.31 (m, 5 H). 13C-NMR: 28.82; 39.24; 44.79; 55.37; 82.68; 112.31; 113.92; 125.56; 127.82;
128.53; 130.06; 134.29; 136.82; 141.53; 156.41; 160.90. MS: 309 (32, Mþ), 106 (100). Anal. calc. for
C20H23NO2 (309.40): C 77.64, H 7.49, N 4.53; found: C 77.60, H 7.62, N 4.40.
4,5-Dihydro-7-methoxy-4-phenyl-2-(thiophen-2-yl)-3,1-benzoxazepine (3n). Yellow solid. M.p. 122 –
1248 (hexane/Et2O). IR (KBr): 1641. 1H-NMR: 3.16 (d, J ¼ 16.0, 1 H); 3.51 (dd, J ¼ 16.0, 8.2, 1 H); 3.79

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Helvetica Chimica Acta – Vol. 94 (2011)
(s, 3 H); 5.56 (d, J ¼ 8.2, 1 H); 6.61 (d, J ¼ 2.3, 1 H); 6.81 (dd, J ¼ 8.7, 2.3, 1 H); 7.01 (dd, J ¼ 5.0, 3.2, 1 H);
7.33 – 7.42 (m, 7 H); 7.55 (d, J ¼ 3.2, 1 H). 13C-NMR: 44.48; 55.41; 83.19; 112.54; 114.35; 125.72; 127.45;
128.13; 128.68 (two overlapped Cs); 128.92; 129.17; 130.64; 134.34; 136.32; 140.95; 147.00; 156.97. MS:
335 (32, Mþ), 106 (100). Anal. calc. for C20H17NO2S (335.42): C 71.62, H 5.11, N 4.18; found: C 71.56, H
5.13, N 3.93.
2-Ethoxy-4,5-dihydro-4-phenyl-3,1-benzoxazepine (5a). Colorless oil. Rf (Al2O3; Et2O/hexane 1:5)
0.45. IR (neat): 1667. 1H-NMR: 1.37 (t, J ¼ 7.3, 3 H); 3.12 (dd, J ¼ 16.0, 1.4, 1 H); 3.44 (dd, J ¼ 16.0, 8.2,
1 H); 4.24 – 4.38 (m, 2 H); 5.49 (dd, J ¼ 8.2, 1.4, 1 H); 6.95 – 6.99 (m, 2 H); 7.16 (d, J ¼ 7.8, 1 H); 7.19 – 7.23
(m, 1 H); 7.29 – 7.38 (m, 5 H). 13C-NMR: 14.28; 42.83; 64.42; 84.44; 123.43; 125.83; 127.00; 127.74; 128.26;
128.62; 128.97; 131.83; 140.26; 142.20; 149.97. MS: 267 (49, Mþ), 238 (100). Anal. calc. for C17H17NO2
(267.32): C 76.38, H 6.41, N 5.24; found: C 76.33, H 6.49, N 4.94.
4,5-Dihydro-7-methoxy-N,4-diphenyl-3,1-benzoxazepin-2-amine (5b). White solid. M.p. 125 – 1278
1
(hexane/CH2Cl2). IR (KBr): 3404, 1672. H-NMR: 2.99 (dd, J ¼ 16.5, 4.1, 1 H); 3.76 (s, 3 H); 3.77 (dd,
J ¼ 16.5, 6.4, 1 H); 5.34 (dd, J ¼ 6.4, 4.1, 1 H); 6.31 (s, 1 H); 6.71 (d, J ¼ 2.7, 1 H); 6.79 (dd, J ¼ 8.7, 2.7,
1 H); 6.97 (ddd, J ¼ 8.7, 7.3, 1.4, 1 H); 7.10 (dd, J ¼ 7.3, 1.4, 2 H); 7.19 (t, J ¼ 8.7, 2 H); 7.32 – 7.41 (m, 5 H);
7.96 (d, J ¼ 8.7, 1 H). 13C-NMR: 39.26; 55.62; 63.00; 111.07; 112.34; 115.99; 119.72; 123.20; 125.46; 128.63;
128.76; 129.67; 129.96; 137.34; 138.27; 142.27; 152.52; 155.79. MS: 344 (69, Mþ), 225 (100). Anal. calc. for
C22H20N2O2 (344.41): C 76.72, H 5.85, N 8.13; found: C 76.66, H 5.81, N 8.05.
We thank Mrs. Miyuki Tanmatsu for recording the mass spectra and performing combustion
analyses.
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Received November 16, 2010