Transformations of tetrahydro-1,4-benzoxazepines and tetrahydro-1,4- benzothiazepines under the action of alkynes. First example of the synthesis of tetrahydro-1,4-benzothiazonine-6-carboxylate

Article abstract of DOI:10.1007/s10593-013-1251-z

It was shown that 2,3,4,5-tetrahydro-1,4-benzoxazepines were cleaved at the N-C(5) bond under the action of activated alkynes in methanol, forming o-(methoxyethyl)- and o-(methoxybenzyl)-phenyl(aminoethyl) ethers. The cleavage rate depended on the electro

Full text of DOI:10.1007/s10593-013-1251-z

Chemistry of Heterocyclic Compounds, Vol. 49, No. 2, May, 2013 (Russian Original Vol. 49, No. 2, February, 2013)
TRANSFORMATIONS OF TETRAHYDRO-1,4-BENZOXAZEPINES
AND TETRAHYDRO-1,4-BENZOTHIAZEPINES UNDER THE ACTION
OF ALKYNES. FIRST EXAMPLE OF THE SYNTHESIS OF TETRAHYDRO-
1,4-BENZOTHIAZONINE-6-CARBOXYLATE
L. G. Voskressensky1*, S. V. Akbulatov1, T. N. Borisova1, L. N. Kulikova1,
A. V. Listratova1, E. A. Sorokina1, and A. V. Varlamov1
It was shown that 2,3,4,5-tetrahydro-1,4-benzoxazepines were cleaved at the N–C(5) bond under the
action of activated alkynes in methanol, forming o-(methoxyethyl)- and o-(methoxybenzyl)-
phenyl(aminoethyl) ethers. The cleavage rate depended on the electronic effects of the substituents at
the C-5 atom. Thiazepine ring expansion in tetrahydro-1,4-benzothiazepine was achieved for the first
time via reaction with methyl propiolate to give a benzothiazonine.
Keywords: alkynes, benzoxazepine, benzothiazepine, benzothiazonine, domino reaction, ring expansion,
ring cleavage.
Nine-membered monocyclic and condensed azaheterocycles (azonines) are present in many natural and
synthetic molecules, which show high and diverse biological activity [1]. The basic methods for constructing
azonines are the expansion of smaller rings [2-4], but there are also methods for synthesis from acyclic
precursors [5-7]. Azonines containing a second heteroatom (sulfur, nitrogen, or oxygen) in the nine-membered
ring have been much less studied. This type of heterocycle is obtained by sodium periodate oxidation of
tetrahydrocarbolines, pyranoindoles [8, 9], benzoxazepines and benzothiazepines condensed with a -lactam
ring [10]. Annelated oxazonines can be prepared in modest yield by expansion of the hydrogenated aza rings of
annelated N-hydroxypropyl- or N-hydroxyethylpyrrolines and pyridines using cyanogen bromide [11, 12]. We
have recently shown the possibility of expanding the tetrahydroazepine ring in isomeric indoloazepines by the
use of activated alkynes, that allowed the preparation of tetrahydroazonino[5,6-b]indoles in high yields [13, 14].
We have previously described reactions of tetrahydrobenzodiazepines with alkynes [15]. In the present work,
we report the synthesis and reactions of 2,3,4,5-tetrahydro-1,4-benzoxazepines and -1,4-benzothiazepines with
alkynes containing electron-withdrawing substituents.
The starting 3,5-dimethylphenol (1) or 3-methoxythiophenol (2) were alkylated with bromoacetonitrile
to the cyanomethyl ethers 3 and 4. Reduction of the nitrile group in ethers 3 and 4 by lithium aluminum hydride
gave the amines 5, 6, which were converted to the N-acyl derivatives 7-10 using acyl chlorides. Cyclization of
_______
*To whom correspondence should be addressed, e-mail: lvoskressensky@sci.pfu.edu.ru.
1Peoples' Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow 117198, Russia.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 357-366, February, 2013. Original
article submitted May 23, 2012.
0009-3122/13/4902-0331©2013 Springer Science+Business Media New York
331

latter under Bischler-Napieralski conditions [16] gave the corresponding dihydrobenzoxazepines 11-13 and
dihydrobenzothiazepine 14. The dihydro derivatives 11-14 were quaternized with methyl iodide under
microwave irradiation to give the quaternary salts 15-18, reduction of which by sodium borohydride in
methanol gave the 2,3,4,5-tetrahydro-1,4-benzoxazepines 19-21 and the 2,3,4,5-tetrahydro-1,4-benzothiazepine
22.
XH
R
X
CN
R
X
R
BrCH2CN
LiAlH4
Et2O
K2CO3, 
acetone
NH2
R1
R1
R1
5, 6
1, 2
3, 4
K2CO3,
MeCN
R2COCl
R
R2
Me
N+
R2
R
R
X
N
MeI
POCl3
MeCN, 
acetone,
MW
R1
NH
R1
X
X
R1
7–10
I
O
15–18
11–14
R2
NaBH4
MeOH/EtOH/H2O
R2
R
Me
N
1, 3, 5, 7–9, 11–13, 15–17, 19–21 X = O, R = R1 = Me;
7, 11, 15, 19 R2 = Ph; 8, 12, 16, 20 R2 = 4-O2NC6H4;
R1
X
9, 13, 17, 21 R2 = Me; 2, 4, 6, 10, 14, 18, 22 X = S, R = H, R1 = OMe;
10, 14, 18, 22 R2 = Ph
19–22
Initial studies indicated that compounds 19-21 did not react with dimethyl acetylene dicarboxylate
(DMAD) or methyl propiolate in acetonitrile even with the use of a fivefold excess of the alkyne; hence the
reaction of the benzoxa- and benzothiazepines 19-22 with acetylenes was carried out in methanol. In this way,
the oxazepines 19-21 were cleaved by methyl propiolate and DMAD at 20°C to give the o-(methoxyethyl)- and
o-(methoxybenzyl)phenyl(aminoethyl) ethers 23a-c and 24a-c. DMAD proved to be less active than methyl
propiolate in these reactions.
CO2Me
CO2Me
R2
Me
R2
C+
CO2Me
C
Me
Me
N+
C
X
X
H
19–21
X
MeOH
N
Me
Me
O
Me
O
A
B
Me
Me
R2
CO2Me
C
Me
X
MeOH
N
CO2Me
Me
O
N
+
Me
Me
X
O
R2
OMe
23a–c, 24a–c
23a–c X = H; 24a–c X = CO2Me; 23, 24 a R2 = Me; 23, 24 b R2 = Ph; 23, 24 c R2 = 4-O2NC6H4
332

CO2Me
Me
CO2Me
Ph
CO2Me
C
Ph
HC
N+
22
N Me
MeOH
MeO
S
MeO
S
25
C
We presume that the reaction of oxazepines with alkynes started with the formation of the ammonium
zwitterion A via a Michael reaction. This was followed by opening of the oxazine ring at the N+–C(5) bond to
form the intermediate B, which was facilitated by the substituents at the C-5 atom and, to a greater extent, the
electron donor mesomeric effect of the oxygen atom. The reaction of the zwitterion B with methanol led to the
ethers 23 and 24. Cleavage of the N+–C(5) bond was supported by the reaction rate dependence on the donor
effect of the R2 substituent, apparently related to its ability to stabilize the carbocation intermediate. The
reaction rate decreased in the series Me > Ph > 4-O2NC6H4, further confirming this interpretation. The products
23a-c and 24a-c were formed in 26-84% and 51-82% yields, respectively; the greatest yield was achieved in the
case of the 5-methyl-substituted derivative 23a.
The benzothiazepine 22 reacted with methyl propiolate somewhat differently. A multicomponent
mixture was formed in methanol at room temperature, from which a chromatographic separation gave the
benzothiazonine 25 as colorless crystals in 22% yield. It should be noted that such benzothiazonine structure has
not been reported before.
We propose that the formation of zwitterion C was followed by a nucleophilic attack of the anion center
at the C-5 atom, leading to azepine ring expansion by two carbon atoms. Evidently due to the decreased donor
effect of the sulfur atom, caused by a symmetry difference of its p-orbitals and the p-orbitals of the benzene
fragment, there was no such cleavage of the N+–C(5) bond and formation of a carbocation as observed in the
case of the oxazepines.
The structure of compounds 23 and 24 was confirmed by 1H NMR spectroscopy and mass spectrometry
data. The mass spectra of all the compounds showed molecular ion peaks corresponding to their empirical
formulae. The 1H NMR spectra showed signals for all of the protons with chemical shifts and coupling constants
Fig. 1. Molecular structure of compound 25 with atoms representated by
thermal vibration ellipsoids of 50% probability.
333

agreeing with their position in the molecules. Thus, the spectra of ethers 23a-c exhibited two doublets at 4.51-
3
4.60 and 7.49-7.55 ppm with a J coupling constant of 13.0 Hz, which was characteristic for a trans-enamine
fragment, and the ethers 24a-c exhibited a singlet for the terminal enamine proton at 4.60-4.68 ppm. The
1H NMR spectrum of product 25 had a singlet signal for the H-5 proton of the tetrahydrothiazonine ring at 7.44
ppm. The structure of compound 25 was also confirmed from X-ray structural data (Fig. 1).
According to the X-ray data, the thiazonine ring had a "twist boat" conformation. The N–C(5) bond was
shorter than N–C(3) (1.351 and 1.447 Å, respectively) due to conjugation in the enamine fragment.
Thus, the feasibility of 2,3,4,5-tetrahydro-1,4-benzothiazepine ring expansion by two carbon atoms to
2,3,4,7-tetrahydro-1,4-benzothiazonine under the action of activated alkynes has been demonstrated. The route
of the tandem transformation of the heteroazepine ring in the benzoxa- and benzothiazepines was apparently
determined by the different degrees of heteroatom conjugation with the aromatic ring.
EXPERIMENTAL
1
13
IR spectra were recorded on an Infralum FT-801 Fourier spectrometer for KBr pellets. The H and C
NMR spectra were recorded on a Varian Unity 400 instrument (400 and 100 MHz, respectively) with the
residual solvent signal as internal standard (7.26 and 77.36 ppm for CDCl3; 2.54 and 40.45 ppm for DMSO-d6,
respectively). Mass spectra were recorded on a Finnigan MAT 95XL and a Hewlett-Packard MS-5988 mass
spectrometers with direct introduction of the samples into the ion source and EI at 70 eV. Elemental analysis
was performed on a Carlo Erba 1106 instrument. Melting points were determined on an SMP 10 apparatus.
Sorbfil UV-254 plates were used for the TLC analysis (visualization with iodine vapor), and column
chromatography was performed on Merck 230-400 mesh silica gel. The synthesis of compounds 15-17 was
carried out using a Biotage Initiator microwave reactor.
Synthesis of Ethers 3 and 4 (General Method). Bromoacetonitrile (10.80 g, 90.03 mmol) was added
to a mixture of the phenol 1 or thiophenol 2 (81.85 mmol) and calcined potassium carbonate (14.71 g,
106.44 mmol) in dry acetone (150 ml), and refluxed for 18 h. After the completion of the reaction, the solvent
was evaporated and water (200 ml) was added to the residue. The precipitated derivative 3 was filtered off and
chromatographed on silica gel by eluting with chloroform. The product 4 was extracted with ether, the solvent
was removed by distillation, and the residue was fractionated in vacuo.
(3,5-Dimethylphenoxy)acetonitrile (3). Yield 9.89 g (75%). Pale-yellow powder; mp 58-60°C
(EtOAc–hexane) (mp 57-58°C (EtOH) [17]). IR spectrum, , cm-1: 2355 (CN). 1H NMR spectrum (DMSO-d6),
, ppm: 2.27 (6H, s, 2CH3); 5.10 (2H, s, CH2); 6.69-6.71 (3H, m, H Ar). Mass spectrum, m/z (Irel, %): 161 [M]+
(5), 121 (12), 91 (53), 77 (90), 65 (53), 39 (100).
(3-Methoxyphenylsulfanyl)acetonitrile (4). Yield 12.67 g (86%). Colorless oil; bp 135-137°C (1 mm Hg)
(bp 164-168°C (2.3 mm Hg) [18]). IR spectrum, , cm-1: 2245 (CN). 1H NMR spectrum (CDCl3), , ppm: 3.59
(2H, s, CH2); 3.83 (3H, s, CH3O); 6.90-6.92 (1H, m, H Ar); 7.10-7.12 (2H, m, H Ar); 7.29-7.31 (1H, m, H Ar).
Mass spectrum, m/z (Irel, %): 179 [M]+ (100), 164 (22), 152 (13), 146 (18), 139 (87), 124 (37), 96 (42), 95 (53),
77 (13). Found, %: C 60.19; H 5.09; N 7.85. C9H9NOS. Calculated, %: C 60.31; H 5.06; N 7.81.
Synthesis of Amines 5 and 6 (General Method). Nitrile 3 or 4 (0.11 mol) was added portionwise to a
suspension of lithium aluminum hydride (12.70 g, 0.33 mol) in dry ether (300 ml) under an argon stream at
0-5°C. The reaction mixture was stirred for 18 h at room temperature. Water (12 ml) and 15% aqueous NaOH
(12 ml) were added to the reaction mixture, and stirring was continued for a further 1 h. The inorganic phase
was removed by filtration. The filtrate was concentrated and the residue was distilled in vacuo to give
compounds 5 or 6 as colorless oils.
334

2-(3,5-Dimethylphenoxy)ethylamine (5). Yield 19.22 g (64%). Bp 95-96°C (1 mm Hg). IR spectrum,
, cm-1: 3375 (N–H). 1H NMR spectrum (CDCl3), , ppm: 1.41 (2H, br. s, NH2); 2.31 (6H, s, 2CH3); 3.06-3.08
(2H, m, CH2); 3.91-3.93 (2H, m, CH2); 6.57 (2H, s, H Ar); 6.62 (1H, s, H Ar). Found, %: C 72.72; H 9.13;
N 8.45. C10H15NO. Calculated, %: C 72.69; H 9.15; N 8.48.
2-(3-Methoxyphenylsulfanyl)ethylamine (6). Yield 15.89 g (78%). Bp 134-136°C (1 mm Hg). IR
spectroscopic data agreed with the literature [19]. 1H NMR spectrum (DMSO-d6), , ppm: 2.20 (2H, br. s, NH2);
2.70-2.72 (2H, m, CH2); 2.92-2.94 (2H, m, CH2); 3.74 (3H, s, CH3O); 6.72-6.74 (1H, m, H Ar); 6.86-6.88 (2H,
m, H Ar); 7.20-7.22 (1H, m, H Ar). Mass spectrum, m/z (Irel, %): 183 [M]+ (32), 154 (100), 140 (13), 138 (8),
121 (24), 109 (5), 95 (53), 77 (12). Found, %: C 58.90; H 7.10; N 7.72. C9H13NOS. Calculated, %: C 58.98;
H 7.15; N 7.64.
Synthesis of Amides 7-9 (General Method). Benzoyl, p-nitrobenzoyl, or acetyl chloride (18.44 mmol)
was added at 20°C to a mixture of the amine 5 (2.76 g, 16.76 mmol) and calcined potassium carbonate (3.00 g,
21.79 mmol) in absolute acetonitrile (50 ml). After 2 h, the solvent was removed in vacuo, and the residue was
treated with water (50 ml). The mixture was basified to pH 9 and extracted with chloroform (350 ml). The
residue after distillation of solvent was chromatographed on silica gel to give the amides 7-9, which were
recrystallized from a mixture of ethyl acetate and hexane.
N-[2-(3,5-Dimethylphenoxy)ethyl]benzamide (7). Yield 3.88 g (86%). Colorless crystals; mp 66-
68°C. IR spectrum, , cm-1: 3333 (N–H), 1633 (C=O). 1H NMR spectrum (CDCl3), , ppm: 2.30 (6H, s, 2CH3);
3.87-3.89 (2H, m, CH2); 4.14-4.16 (2H, m, CH2); 6.62-6.64 (4H, m, H Ar, H Ph); 7.49-7.51 (3H, m, H Ar,
H Ph); 7.77-7.80 (2H, m, H Ph, NH). Mass spectrum, m/z (Irel, %): 269 [M]+ (1), 148 (78), 133 (5), 91 (13), 77
(100), 65 (5), 51 (33). Found, %: C 75.83; H 7.14; N 5.18. C17H19NO2. Calculated, %: C 75.81; H 7.11; N 5.20.
N-[2-(3,5-Dimethylphenoxy)ethyl]-4-nitrobenzamide (8). Yield 4.05 g (78%). Gray powder; mp 127-
129°C. IR spectrum, , cm-1: 3307 (N–H), 1635 (C=O), 1530 (NO2), 1340 (NO2). 1H NMR spectrum (DMSO-d6),
, ppm (J, Hz): 2.11 (6H, s, 2CH3); 3.63-3.66 (2H, m, CH2); 4.07-4.09 (2H, m, CH2); 6.56 (3H, s, H Ar); 8.08
(2H, d, J = 8.8, H-2',6' Ar); 8.31 (2H, d, J = 8.8, H-3',5' Ar), 9.01-9.03 (1H, m, NH). Found, %: C 64.98; H
5.79; N 8.90. C17H18N2O4. Calculated, %: C 64.95; H 5.77; N 8.91.
N-[2-(3,5-Dimethylphenoxy)ethyl]acetamide (9). Yield 3.22 g (93%). Colorless crystals; mp 65-67°C.
IR spectrum, , cm-1: 3249 (N–H), 1633 (C=O). 1H NMR spectrum (CDCl3), , ppm: 2.02 (3H, s, CH3CO); 2.30
(6H, s, 2CH3); 3.64-3.66 (2H, m, CH2); 4.01-4.03 (2H, m, CH2); 6.08 (1H, br. s, NH); 6.54 (2H, s, H Ar); 6.64 (1H,
s, H Ar). Mass spectrum, m/z (Irel, %): 207 [M]+ (3), 148 (5), 133 (8), 122 (6), 105 (5), 91 (6), 86 (100), 77 (16), 43
(22). Found, %: C 69.56; H 8.29; N 6.75. C12H17NO2. Calculated, %: C 69.54; H 8.27; N 6.76.
N-[2-(3-Methoxyphenylsulfanyl)ethyl]benzamide (10) was prepared from the amine 6 (3.00 g,
16.37 mmol) and benzoyl chloride (2.53 g, 18.10 mmol) in absolute acetonitrile (50 ml) in the presence of
calcined potassium carbonate (2.94 g, 21.28 mmol) similarly to the method above. Yield 3.54 g (75%).
1
Colorless oil. IR spectrum, , cm-1: 3324 (N–H), 1655 (C=O). H NMR spectrum (CDCl3), , ppm: 3.19-3.21
(2H, m, CH2); 3.70-3.72 (2H, m, CH2); 3.79 (3H, s, CH3O); 6.58 (1H, br. s, NH); 6.74-6.76 (1H, m, H Ar);
6.98-7.00 (2H, m, H Ar); 7.21-7.23 (1H, m, H Ar); 7.41-7.43 (2H, m, H Ar); 7.49-7.51 (1H, m, H Ar);
7.69-7.71 (2H, m, H Ar). Mass spectrum, m/z (Irel, %): 287 [M]+ (14), 166 (100), 148 (11), 135 (18), 121 (12),
105 (43), 77 (54). Found, %: C 66.95; H 5.99; N 4.83. C16H17NO2S. Calculated, %: C 66.87; H 5.96; N 4.87.
Synthesis of 2,3-Dihydro-1,4-benzoxazepines 11-13 (General Method). POCl3 (0.7 ml, 7.44 mmol)
was added dropwise to a solution of amide 7, 8, or 9 (1.86 mmol) in absolute acetonitrile (15 ml) at 20°C under
an argon stream. The reaction mixture was refluxed until the reaction was complete (TLC), cooled, poured into
25% NH4OH solution (50 ml), extracted with ethyl acetate (5×50 ml), and dried over sodium sulfate. The
solvent was removed by distillation, and the residue was chromatographed on silica gel (eluent EtOAc–hexane,
gradient from 1:20 to 1:5). The azepine 13 was isolated as hydrochloride.
6,8-Dimethyl-5-phenyl-2,3-dihydro-1,4-benzoxazepine (11). Yield 229 mg (49%). Yellowish
crystals; mp 67-69°C (EtOAc–hexane). IR spectrum, , cm-1: 1605 (C=N). 1H NMR spectrum (CDCl3), , ppm:
1.84 (3H, s, CH3); 2.37 (3H, s, CH3); 3.69-3.71 (2H, m, CH2); 4.65-4.67 (2H, m, CH2); 6.82 (1H, s) and 6.86
335

(1H, s, H-7,9); 7.37-7.40 (3H, m, H Ph), 7.56-7.58 (2H, m, H Ph). Mass spectrum, m/z (Irel, %): 251 [M]+ (45),
236 (5), 223 (100), 208 (8), 195 (79), 180 (39), 165 (45), 130 (35), 115 (20), 104 (37), 91 (38), 77 (63). Found,
%: C 81.28; H 6.83; N 5.55. C17H17NO. Calculated, %: C 81.24; H 6.82; N 5.57.
6,8-Dimethyl-5-(4-nitrophenyl)-2,3-dihydro-1,4-benzoxazepine (12). Yield 275 mg (50%).
Yellowish crystals; mp 110-112°C (EtOAc–hexane). IR spectrum, , cm-1: 1594 (C=N), 1523 (NO2), 1352
(NO2). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.76 (3H, s, CH3); 2.32 (3H, s, CH3); 3.69-3.71 (2H, m,
CH2); 4.42-4.44 (2H, m, CH2); 6.85 (1H, s) and 6.95 (1H, s, H-7,9); 7.70 (2H, d, J = 8.8, H-2',6' Ar); 8.27 (2H,
d, J = 8.8, H-3',5' Ar). Mass spectrum, m/z (Irel, %): 296 [M]+ (8), 268 (33), 240 (7), 179 (44), 165 (27), 152
(22), 115 (25), 103 (46), 91 (38), 77 (62), 63 (59), 51 (82), 39 (100). Found, %: C 68.95; H 5.46; N 9.42.
C17H16N2O3. Calculated, %: C 68.91; H 5.44; N 9.45.
5,6,8-Trimethyl-2,3-dihydro-1,4-benzoxazepinium Hydrochloride (13). Yield 55 mg (13%).
Colorless crystals; mp 187-189°C (EtOH). IR spectrum, , cm-1: 2661 (N–H+), 1608 (C=N). 1H NMR spectrum
(DMSO-d6), , ppm: 2.33 (3Н, s, CH3); 2.43 (3H, s, CH3); 2.85 (3H, s, CH3); 3.70-3.72 (2H, m, CH2); 4.54-4.56
(2H, m, CH2); 6.95 (1H, s) and 7.11 (1H, s, H-7,9); 15.06 (1H, br. s, NH+). Mass spectrum, m/z (Irel, %): 189
[M-HCl]+ (62), 174 (13), 161 (100), 146 (39), 133 (80), 115 (28), 91 (43), 77 (47), 68 (19), 42 (7). Found, %:
C 63.96; H 7.18; N 6.17. C12H15NO·HCl. Calculated, %: C 63.86; H 7.14; N 6.21.
8-Methoxy-5-phenyl-2,3-dihydro-1,4-benzothiazepine (14). POCl3 (39.23 g, 255.85 mmol) was
added dropwise to a solution of the benzamide 10 (18.38 g, 63.97 mmol) in absolute acetonitrile (500 ml) at
20°C under an argon stream. The reaction mixture was refluxed until the reaction completion (~ 3 h, TLC), the
solvent was evaporated, water (500 ml) was added to the residue, and the product was extracted with ether
(3200 ml). The ether layer was discarded. The aqueous layer was basified to pH 9, extracted with EtOAc
(3200 ml), and dried over sodium sulfate. After removing the solvent by distillation, the residue was
chromatographed on silica gel (eluent EtOAc–hexane, gradient from 1:20 to 1:5). Yield 1.96 g (11%). Colorless
1
oil. IR spectrum, , cm-1: 1589 (C=N). H NMR spectrum (CDCl3), , ppm: 3.56-3.58 (2H, m, CH2); 3.76-3.79
(2H, m, CH2); 3.87 (3H, s, СH3O); 6.89-6.90 (1H, m, H Ar); 7.05-7.07 (1H, m, H Ar); 7.19-7.20 (1H, m, H Ar);
7.37-7.40 (3H, m, H Ph); 7.58-7.60 (2H, m, H Ph). Mass spectrum, m/z (Irel, %): 269 [M]+ (32), 268 (39), 241
(100), 240 (41), 226 (16), 210 (12), 198 (7), 165 (9), 152 (12), 77 (11). Found, %: C 71.48; H 5.55; N 4.83.
C16H15NOS. Calculated, %: C 71.34; H 5.61; N 5.20.
Synthesis of 8-Methyl-2,3-dihydro-1,4-benzoxazepinium Iodides 15-17 (General Method). A
solution of the benzoxazepine 11, 12 or 13 (5.49 mmol) and methyl iodide (3.90 g, 27.45 mmol) in absolute
acetone (15 ml) was stirred for 1 h at 130°C in a microwave oven. The precipitate formed was filtered off and
recrystallized from acetone to give the iodides 15-17 as light-yellow crystals.
4,6,8-Trimethyl-5-phenyl-2,3-dihydro-1,4-benzoxazepinium Iodide (15). Yield 0.96 g (66%). Mp
244-246°C. IR spectrum, , cm-1: 1604 (C=N). 1H NMR spectrum (DMSO-d6), , ppm: 1.63 (3H, s, CH3); 2.40
(3H, s, CH3); 3.91 (3H, s, CH3); 4.21-4.23 (2H, m, CH2); 4.86-4.88 (2H, m, CH2); 7.03 (2H, s, H-7,9); 7.59-7.61
(2H, m, H Ph); 7.65-7.67 (2H, m, H Ph); 7.77-7.78 (1H, m, H Ph). Mass spectrum, m/z (Irel, %): 266 [M-I]+ (1),
251 (4), 223 (10), 195 (7), 165 (9), 142 (12), 127 (12), 104 (22), 91 (34), 77 (78), 63 (42), 42 (37), 39 (100).
Found, %: C 55.04; H 5.15; N 3.55. C18H20INO. Calculated, %: C 54.98; H 5.13; N 3.56.
4,6,8-Trimethyl-5-(4-nitrophenyl)-2,3-dihydro-1,4-benzoxazepinium Iodide (16). Yield 1.16 g
1
(68%). Mp 205-207°C. IR spectrum, , cm-1: 1604 (C=N), 1524 (NO2), 1348 (NO2). H NMR spectrum
(DMSO-d6), , ppm (J, Hz): 1.63 (3H, s, CH3); 2.38 (3H, s, CH3); 3.85 (3H, s, CH3); 4.23-4.25 (2H, m, CH2);
4.91-4.93 (2H, m, CH2); 7.08 (1H, s) and 7.11 (1H, s, H-7,9); 7.85-7.87 (2H, m, H-2',6' Ar); 8.43 (2H, d,
J = 8.8, H-3',5' Ar). Mass spectrum, m/z (Irel, %): 311 [M-I]+ (1), 296 (33), 268 (85), 179 (32), 142 (100), 127
(70), 103 (25). Found, %: C 49.35; H 4.38; N 6.36. C18H19IN2O3. Calculated, %: C 49.33; H 4.37; N 6.39.
4,5,6,8-Tetramethyl-2,3-dihydro-1,4-benzoxazepinium Iodide (17). Yield 1.39 g (73%). Mp
217-220°C. IR spectrum, , cm-1: 1607 (C=N). 1H NMR spectrum (DMSO-d6), , ppm: 2.34 (3H, s, CH3); 2.40
(3H, s, CH3); 2.81 (3H, s, CH3); 3.86 (3H, s, CH3); 4.07-4.09 (2H, m, CH2), 4.43-4.44 (1H, m) and 4.90-4.91
(1H, m, CH2); 6.92 (1H, s) and 7.13 (1H, s, H-7,9). Mass spectrum, m/z (Irel, %): 204 [M-I]+ (13), 203 (100),
336

188 (79), 159 (29), 145 (26), 115 (13), 91 (12), 77 (7), 42 (10). Found, %: C 47.14; H 5.49; N 4.24. C13H18INO.
Calculated, %: C 47.15; H 5.48; N 4.23.
8-Methoxy-4-methyl-5-phenyl-2,3-dihydro-1,4-benzothiazepinium Iodide (18). A solution of the
benzothiazepine 14 (1.70 g, 6.31 mmol) and methyl iodide (4.48 g, 31.55 mmol) in absolute acetone (15 ml)
was stirred for 1 h at 130°C in a microwave oven. The precipitate that formed was filtered off and recrystallized
from acetone. Yield 2.16 g (83%). Light-yellow crystals; mp 220-222°C. IR spectrum, , cm-1: 1591 (C=N).
1H NMR spectrum (DMSO-d6), , ppm: 3.78 (3H, s, OCH3); 3.91 (3H, s, NCH3); 3.96-3.98 (2H, m, CH2);
4.14-4.16 (2H, m, CH2); 7.01-7.02 (1H, m, H Ar); 7.13-7.14 (1H, m, H Ar); 7.41-7.43 (1H, m, H Ar); 7.54-7.57
(2H, m, H Ph); 7.67-7.69 (2H, m, H Ph); 7.79-7.80 (1H, m, H Ph). Mass spectrum, m/z (Irel, %): 284 [M-I]+(17),
257(100). Found, %: C 49.69; H 4.44; N 3.37. C17H18INOS. Calculated, %: C 49.64; H 4.41; N 3.41.
Synthesis of 2,3,4,5-Tetrahydro-1,4-benzoxazepines (19-22) (General Method). Sodium borohydride
(0.71 mmol) was added portionwise at 0-5°C to a solution of the corresponding iodide 15, 16, 17, or 18
(1.02 mmol) in a mixture of methanol (8 ml) and 60% ethanol (10 ml), and the reaction mixture was stirred for 2
h at 0-10°C. At the end of the reaction (TLC), the solvent was evaporated in vacuo, water (10 ml) was added,
and the product was extracted with ethyl acetate (315 ml). After removing the solvent by distillation, the
residue was chromatographed on a silica gel column (eluent chloroform) to give the azepines 19-22 as colorless
oils.
4,6,8-Trimethyl-5-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (19). Yield 215 mg (79%). 1H NMR
spectrum (CDCl3), , ppm: 2.24 (3H, s, CH3); 2.32 (3H, s, CH3); 2.59 (3H, s, CH3); 2.66-2.67 (1H, m) and
3.29-3.31 (1H, m, CH2); 3.90-3.91 (1H, m) and 4.06-4.08 (1H, m, CH2); 5.33 (1H, s, 5-СН); 6.79 (2H, s,
H-7,9); 7.47-7.49 (1H, m, H Ph); 7.27-7.30 (4H, m, H Ph). Found, %: C 80.90; H 7.97; N 5.20. C18H21NO.
Calculated, %: C 80.86; H 7.92; N 5.24.
4,6,8-Trimethyl-5-(4-nitrophenyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (20). Yield 210 mg (66%).
1
IR spectrum, , cm-1: 1518 (NO2), 1347 (NO2). H NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.22 (3H, s,
CH3); 2.28 (3H, s, CH3); 2.51 (3H, s, CH3); 2.64-2.66 (1H, m) and 3.04-3.05 (1H, m, CH2); 3.80-3.82 (1H, m)
and 3.93-3.95 (1H, m, CH2); 5.31 (1H, s, 5-СН); 6.70 (1H, s) and 6.80 (1H, s, H-7,9); 7.40 (2H, d, J = 8.8,
H-2',6' Ar); 8.12 (2H, d, J = 8.8, H-3',5' Ar). Mass spectrum, m/z (Irel, %): 312 [M]+ (13), 297 (1), 254 (2), 208
(4), 190 (100), 178 (4), 165 (6), 147 (8), 119 (4). Found, %: C 69.25; H 6.49; N 8.94. C18H20N2O3. Calculated,
%: C 69.21; H 6.45; N 8.97.
1
4,5,6,8-Tetramethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (21). Yield 159 mg (76%). H NMR
spectrum (CDCl3), , ppm (J, Hz): 1.50 (3H, d, J = 7.1, 5-CH3); 2.25 (3H, s, CH3); 2.31 (3H, s, CH3); 2.43 (3H,
s, CH3); 2.70-2.72 (1H, m) and 3.68-3.67 (1H, m, CH2); 4.05-4.08 (2H, m, CH2); 4.22 (1H, q, J = 7.1, 5-СН);
6.69 (1H, s) and 6.72 (1H, s, H-7,9). Mass spectrum, m/z (Irel, %): 205 [M]+ (13), 190 (100); 174 (4), 160 (5),
147 (35), 119 (28), 91 (24), 77 (27), 42 (18). Found, %: C 76.09; H 9.35; N 6.81. C13H19NO. Calculated, %:
C 76.06; H 9.33; N 6.82.
1
8-Methoxy-4-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (22). Yield 267 mg (92%). H NMR
spectrum (DMSO-d6), , ppm: 2.21 (3H, s, NCH3); 2.68-2.70 (1H, m) and 2.87-2.89 (1H, m, CH2); 3.18-3.19
(2H, m, CH2); 3.74 (3H, s, OCH3); 5.49 (1H, s, 5-СН); 6.74-6.76 (2H, m, H Ar); 7.12-7.13 (1H, m, H Ar);
7.21-7.24 (3H, m, H Ph); 7.30-7.33 (2H, m, H Ph). Mass spectrum, m/z (Irel, %): 285 [M]+ (11), 257 (100), 241
(52), 227 (28), 208 (26), 184 (13), 165 (67), 152 (27), 150 (21), 121 (9), 77 (9). Found, %: C 71.60; H 6.78;
N 4.83. C17H19NOS. Calculated, %: C 71.54; H 6.71; N 4.91.
Reaction of 1,4-Benzoxazepines with Methyl Propiolate and Dimethyl Acetylene Dicarboxylate
(DMAD). A solution of benzoxazepine 19-21 (0.64 mmol) and methyl propiolate or DMAD (0.74 mmol) in
methanol (10 ml) was maintained at 20°C under an argon atmosphere. At the end of the reaction (TLC), the
methanol was evaporated in vacuo, and the residue was chromatographed on silica gel (eluent EtOAc–hexane,
gradient from 1:10 to 1:2) to give the derivatives 23 and 24.
Methyl (2E)-3-[{2-[2-(1-Methoxyethyl)-3,5-dimethylphenoxy]ethyl}methylamino]acrylate (23a).
Reaction time 4 h. Yield 172 mg (84%). Colorless powder; mp 87-88°C (EtOAc–hexane). IR spectrum, , cm-1:
337

1
1691 (C=O). H NMR spectrum (CDCl3, , ppm (J, Hz): 1.43 (3H, d, J = 6.6, CHCH3); 2.29 (3H, s, 3-CH3);
2.41 (3H, s, 5-CH3); 2.95 (3H, br. s, NCH3); 3.17 (3H, s, CHOCH3); 3.58-3.61 (2H, m, CH2N); 3.68
(3H, s, CO2CH3); 4.04-4.06 (2H, m, CH2O); 4.60 (1H, d, J = 13.0, CH=); 5.00 (1H, q, J = 6.6, CHCH3); 6.50
(1H, s, H-4); 6.52 (1H, s, H-6); 7.55 (1H, d, J = 13.0, CH=). Mass spectrum, m/z (Irel, %): 321 [M]+ (13), 306
(9), 290 (30), 274 (81), 191 (46), 178 (42), 142 (71), 128 (100), 119 (15), 91 (15), 82 (58), 42 (34). Found, %:
C 67.27; H 8.49; N 4.36. C18H27NO4. Calculated, %: С 67.26; H 8.47; N 4.36.
Methyl (2E)-3-[(2-{2-[Methoxy(phenyl)methyl]-3,5-dimethylphenoxy}ethyl)(methyl)amino]acrylate
1
(23b). Reaction time 25 h. Yield 64 mg (26%). Colorless oil. IR spectrum, , cm-1: 1695 (C=O). H NMR
spectrum (CDCl3), , ppm (J, Hz): 2.13 (3H, s, 3-CH3); 2.32 (3H, s, 5-CH3); 2.84 (3H, br. s, NCH3); 3.36 (3H, s,
CHOCH3); 3.50-3.52 (2H, m, CH2N); 3.63 (3H, s, CO2CH3); 4.07-4.09 (2H, m, CH2O); 4.53 (1H, d, J = 13.0,
CH=); 6.07 (1H, s, CHOCH3); 6.58 (1H, s, H-4); 6.63 (1H, s, H-6); 7.19-7.21 (1H, m, H Ph); 7.24-7.28 (4H, m,
H Ph); 7.49 (1H, d, J = 13.0, CH=). 13C NMR spectrum (CDCl3), , ppm: 19.9; 21.3; 38.4; 50.3; 54.9; 56.7;
66.7; 77.2; 85.6; 110.7; 125.0; 125.9; 126.0 (2C); 126.3; 127.9 (2C); 138.4; 139.8; 142.5; 152.2; 157.4; 169.5.
Mass spectrum, m/z (Irel, %): 383 [M]+ (15), 352 (5), 336 (87), 237 (10), 209 (36), 178 (15), 165 (22), 149 (29);
128 (82), 102 (47), 82 (65), 42 (100). Found, %: C 72.05; H 7.64; N 3.64. C23H29NO4. Calculated, %: C 72.04;
H 7.62; N 3.65.
Methyl (2E)-3-[(2-{2-[Methoxy(4-nitrophenyl)methyl]-3,5-dimethylphenoxy}ethyl)(methyl)amino]-
acrylate (23c). Reaction time 96 h. Yield 107 mg (39%). Colorless oil. IR spectrum, , cm-1: 1689 (C=O).
1H NMR spectrum (CDCl3), , ppm (J, Hz): 2.05 (3H, s, 3-CH3); 2.32 (3H, s, 5-CH3); 2.86 (3H, br. s, NCH3);
3.35 (3H, s, CHOCH3); 3.54-3.56 (2H, m, CH2N); 3.58 (3H, s, CO2CH3); 4.10-4.12 (2H, m, CH2O); 4.51 (1H,
d, J = 13.0, CH=); 6.11 (1H, s, CHOCH3); 6.61 (1H, s, H-4); 6.62 (1H, s, H-6); 7.43 (2H, d, J = 8.8, H-2',6' Ar);
7.49 (1H, d, J = 13.0, CH=); 8.11 (2H, d, J = 8.8, H-3',5' Ar). Mass spectrum, m/z (Irel, %): 428 [M]+ (2), 396
(5), 381 (35), 282 (10), 238 (10), 142 (14), 128 (100), 110 (9), 82 (33), 59 (21), 42 (59). Found, %: C 64.52;
H 6.63; N 6.52. C23H28N2O6. Calculated, %: C 64.47; H 6.59; N 6.54.
Dimethyl 2-[{2-[2-(1-Methoxyethyl)-3,5-dimethylphenoxy]ethyl}(methyl)amino]but-2-enedioate (24a).
Reaction time 10 min. Yield 199 mg (82%). Colorless oil. IR spectrum, , cm-1: 1735 (C=O), 1685 (C=O).
1H NMR spectrum (CDCl3), , ppm (J, Hz): 1.43 (3H, d, J = 6.6, CHCH3); 2.29 (3H, s, 3-CH3); 2.41 (3H, s,
5-CH3); 3.02 (3H, br. s, NCH3); 3.17 (3H, s, CHOCH3); 3.56-3.58 (2H, m, CH2N); 3.66 (3H, s, CO2CH3); 3.95
(3H, s, CO2CH3); 4.09-4.11 (2H, m, CH2O); 4.68 (1H, s, CH=); 5.01 (1H, q, J = 6.6, CHCH3); 6.52 (1H, s,
H-4); 6.63 (1H, s, H-6). 13C NMR spectrum (CDCl3), , ppm: 19.6; 20.4; 21.0; 38.9; 50.5; 52.4; 52.6; 55.9;
66.6; 73.2; 85.7; 110.8; 125.7; 126.0; 137.5; 138.0; 154.6; 156.5; 165.7; 167.6. Mass spectrum, m/z (Irel, %):
379 [M]+ (2), 348 (13), 332 (7), 320 (7), 288 (10), 200 (30), 191 (42), 186 (100), 178 (35), 149 (17), 140 (37),
119 (11), 82 (60). Found, %: C 63.33; H 7.72; N 3.70. C20H29NO6. Calculated, %: C 63.31; H 7.70; N 3.69.
Dimethyl 2-[(2-{2-[Methoxy(phenyl)methyl]-3,5-dimethylphenoxy}ethyl)(methyl)amino]but-2-enedioate
(24b). Reaction time 12 h. Yield 161 mg (57%). Colorless oil. IR spectrum, , cm-1: 1734 (C=O), 1684 (C=O).
1H NMR spectrum (CDCl3), , ppm: 2.14 (3H, s, 3-CH3); 2.32 (3H, s, 5-CH3); 2.86 (3H, br. s, NCH3); 3.37 (3H,
s, CHOCH3); 3.44-3.46 (2H, m, CH2N); 3.64 (3H, s, CO2CH3); 3.88 (3H, s, CO2CH3); 4.10-4.13 (2H, m,
CH2O); 4.60 (1H, s, CH=); 6.08 (1H, s, CHОCH3); 6.59 (1H, s, H-4); 6.64 (1H, s, H-6); 7.20-7.21 (1H, m,
H Ph); 7.25-7.28 (4H, m, H Ph). 13C NMR spectrum (CDCl3), , ppm: 20.0; 21.3; 39.0; 50.8; 52.3; 52.9; 56.6;
66.6; 76.8; 85.3; 110.3; 124.2; 125.6; 125.8 (2C); 126.3; 127.8 (2C); 135.8; 139.5; 142.3; 152.5; 157.1; 167.8;
169.9. Mass spectrum, m/z (Irel, %): 441 [M]+ (10), 394 (31), 237 (20), 209 (29), 186 (100), 140 (32), 121 (13),
105 (19), 82 (87). Found, %: C 68.03; H 7.11; N 3.15. C25H31NO6. Calculated, %: C 68.01; H 7.08; N 3.17.
Dimethyl 2-[(2-{2-[Methoxy(4-nitrophenyl)methyl]-3,5-dimethylphenoxy}ethyl)(methyl)amino]-
but-2-enedioate (24c). Reaction time 80 h. Yield 159 mg (51%). Colorless oil. IR spectrum, , cm-1: 1732
(C=O), 1689 (C=O). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 2.06 (3H, s, 3-CH3); 2.33 (3H, s, 5-CH3); 2.90
(3H, br. s, NCH3); 3.36 (3H, s, CHOCH3); 3.50-3.52 (2H, m, CH2N); 3.62 (3H, s, CO2CH3); 3.89 (3H, s,
CO2CH3); 4.10-4.12 (2Н, m, CH2O); 4.60 (1H, s, CH=); 6.15 (1H, s, CHOCH3); 6.62 (1H, s, H-4); 6.64 (1H, s,
H-6); 7.44 (2H, d, J = 8.8, H-2',6' Ar); 8.12 (2H, d, J = 8.8, H-3',5' Ar). Mass spectrum, m/z (Irel, %): 486 [M]+
338

(1), 439 (9), 282 (15), 238 (12), 200 (7), 186 (100), 140 (17), 126 (6), 82 (39). Found, %: C 61.75; H 6.24;
N 5.74. C25H30N2O8. Calculated, %: C 61.72; H 6.22; N 5.76.
Methyl 10-Methoxy-4-methyl-7-phenyl-2,3,4,7-tetrahydro-1,4-benzothiazonine-6-carboxylate (25).
A mixture of the thiazepine 22 (50.0 mg, 0.18 mmol) and methyl propiolate (17.7 mg, 0.21 mmol) was
maintained at 20°C for 24 h, and a further aliquot of methyl propiolate (8.85 mg, 0.12 mmol) in methanol (10
ml) was added. The mixture was left for 2 days, and the precipitated benzothiazonine 25 was filtered off and
recrystallized from a mixture of hexane and ethyl acetate. Yield 15 mg (22%). Colorless crystals; mp 163-
165°C. IR spectrum, , cm-1: 1653 (C=O). 1H NMR spectrum (DMSO-d6), , ppm (J, Hz): 2.70 (1H, m, 2-CH2);
2.95 (3H, s, NCH3); 3.27-3.40 (2H, m, 3-CH2); 3.44 (3H, s, 10-OCH3); 3.72-3.73 (1H, m, 2-CH2); 3.76 (3H, s,
CO2CH3); 6.33 (1H, s, 7-CH); 6.89-6.91 (2H, m, H Ph); 7.00 (1H, dd, J = 8.8, J = 2.8, H-9); 7.07-7.09 (1H, m,
H Ph); 7.13-7.16 (3H, m, H-11, H Ph); 7.44 (1H, s, H-5); 7.91 (1H, d, J = 8.8, H-8). 13C NMR spectrum
(DMSO-d6), , ppm: 34.9; 42.9; 45.5; 50.3; 55.1; 103.5; 115.8; 119.3; 124.8; 126.5 (2C); 127.6 (2C); 131.6;
135.9; 138.8; 144.5; 151.5; 157.4; 167.9. Mass spectrum, m/z (Irel, %): 369 [M]+ (32), 310 (46), 282 (45), 227
(46), 165 (43), 152 (20), 102 (44), 91 (31), 58 (18), 42 (100). Found, %: C 68.33; H 6.30; N 3.76. C21H23NO3S.
Calculated, %: C 68.27; H 6.27; N 3.79.
X-ray Structural Investigation of Compound 25 (C21H23NO3S, M 369.46). Crystals were triclinic, at
296 K: a 8.6184(4), b 8.9276(5), c 13.4034(7) Å,  99.9760(10),  96.8990(10),  107.4030(10)°, V 952.84(9)
Å3, space group P1, Z 2, calc 1.288 g/cm3,  0.190 mm-1, F(000) 392. The unit cell parameters and intensities of
11187 reflections (5806 independent, Rint 0.0151) were measured on a Bruker Apex-II CCD automatic three-
circle diffractometer with dual detector (MoK radiation, graphite monochromator, with - and -scanning).
The structure was solved by a direct method and refined with F2 full-matrix least-squares analysis in anisotropic
approximation for non-hydrogen atoms. The final probability factors were R1 0.0431 for 4789 independent
reflections with I > 2(I) and wR2 0.1302 for all of the independent reflections. All of the calculations were
carried out using the SHELXTL software package [6]. The tables of atomic coordinates, bond lengths, valence
angles, and anisotropic temperature parameters for the compound 25 have been submitted to the Cambridge
Crystallographic Data Center as deposit CCDC 914506.
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