Synthesis and properties of new functionalized 2-benzazepines

Article abstract of DOI:10.1007/s10593-006-0175-2

2-Aryl-4-hydroxy-2,3-dihydro-1H-2-benzazepine-5-carbonitriles were obtained by the cyclization of methyl esters of N-aryl-N-(2-cyanomethylbenzyl) aminoacetic acids by the action of sodium methylate. The keto-enol tautomerism of these compounds and their r

Full text of DOI:10.1007/s10593-006-0175-2

Chemistry of Heterocyclic Compounds, Vol. 42, No. 7, 2006
SYNTHESIS AND PROPERTIES OF NEW
FUNCTIONALIZED 2-BENZAZEPINES*
E. O. Kostyrko, V. A. Kovtunenko, and V. M. Kysil
2-Aryl-4-hydroxy-2,3-dihydro-1H-2-benzazepine-5-carbonitriles were obtained by the cyclization of
methyl esters of N-aryl-N-(2-cyanomethylbenzyl)aminoacetic acids by the action of sodium methylate.
The keto–enol tautomerism of these compounds and their reactions with hydrazines were studied.
Keywords: 1-aminopyrazolo[3,4-d]benzazepine, 2-benzazepines, keto–enol tautomerism.
Intramolecular acylation in o-functionalized phenylacetonitriles has been used in our previous work
[2-4] for the synthesis of dibenz[b,f]azocine derivatives. In a continuation of these studies and in light of the
promising search for biological activity in 2-benzazepine derivatives [5], we studied this approach for the
synthesis of previously unreported functionally substituted 2-benzazepines. The reaction of
2-bromomethylphenylacetonitrile 1 with methyl N-arylaminoacetate 2 in the presence of AcONa gave a series of
methyl N-aryl-N-(2-cyanomethylbenzyl)-2-aminoacetates 3. Heating of these products in methanolic sodium
methylate for 1.5 h would be expected to give intramolecular cyclization involving the cyano group (according
to Thorpe [6]), leading to iminobenzazepines 4 or the formation of cyanobenzazepines 5 due to ester
condensation.
The lack of bands in the IR spectra of the cyclization products corresponding to ester, imino, or amino
groups and the finding of a strong band in the vicinity of 2200 (conjugated C≡N), 3160 (broad, O–H), and
1610 cm-1 (C=C) indicate structure 5. Nitriles 5 are capable of existing in two tautomeric forms, namely,
ketonic K-5 and enolic E-5. In DMSO-d6 solution, 5 exists predominantly in enolic form E-5, as indicated by a
broad band at 11.39-11.46 ppm (OH), which disappears in the presence of D2O. On the other hand, both forms
are found in CDCl3.
Thus, the minor enolic form gives two methylene group singlets in the upfield portion of the spectrum at
4.43-4.49 (1-CH2) and 4.34-4.42 ppm (3-CH2). The ketonic form is seen as two AB-spin systems of
diastereotopic protons of the same methylene groups at 4.94-5.00 (d) and 4.71-4.74 ppm (d, J = 16 Hz, C(1)) and
also 4.06-4.14 (d) and 4.22-4.24 ppm (d, J = 18 Hz, C(3)). The methine proton at C(5) gives a singlet at
5.36-5.49 ppm. Integration of the intensities of the signals corresponding to each of these forms gives their ratio
→
in the equilibrium mixture K-5
E-5 equal to 1:0.7. The IR spectra of 5 show bands at 2200 (C≡N) and
←
3490 cm-1 for the enolic form and 2245 (C≡N) and 1735 cm-1 (C=O) for the ketonic form.
_______
* Previous communication, see ref. [1].
__________________________________________________________________________________________
Taras Shevchenko Kiev National University, 01033 Kiev, Ukraine; e-mail: kvm@sbet.com,
vkovtunenko@hotmail.com. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1026-1031,
July, 2006. Original article submitted April 23, 2003; revision submitted March 29, 2006.
886
0009-3122/06/4207-0886©2006 Springer Science+Business Media, Inc.

R
R
N
Br
COOMe
+
HN
NH
CN
4
COOMe
1
R
2a–c
R
R
N
N
O
NC
COOMe
N
K-5
5a–c
CN
3a–c
5b
OH
NC
3b
5b
E-5
R
Br
Br
N
NHNH2
N
N
CN
O
H
8
NO2
N
H
N
NC
N
H2N
N
6a,b
Ph
NO2
7
2, 3, 5 a R = H, b R = Br, c R = Me; 6 a R = Br, b R = Me
The existence of a ketonic form for 5 provides for their reactivity in condensations with hydrazines.
Thus, under standard conditions [7], 5 readily react with 2,4-dinitrophenylhydrazine but the condensation
products 6 exist predominantly in the enehydrazine form, as indicated by the low-frequency position of the C≡N
band (2190 cm-1) in the IR spectrum and presence of two single proton singlets, which exchange in the presence
1
of D2O in the H NMR spectra in DMSO-d6. It is interesting that the condensation of phenylhydrazine with
azepine 5b does not stop upon formation of the corresponding enehydrazine (or hydrazone) and, as the result of
subsequent reactions of the nitrile and β-NH groups, gives 1-amino-5-(4-bromophenyl)-2-phenyl-
2,4,5,6-tetrahydropyrazolo[3,4-d]-2-benzazepine (7). The IR spectrum of 7 shows bands for the N–H group and
lacks nitrile bands. We should note that pyrazoles fused at the [d] side of the 2-benzazepine system have an
anxiolytic effect and have been described in several patents [8-11] but the nature of their fusion with the
benzazepine system is different.
The reaction of azepine 5b with 85% hydrazine hydrate proceeds unexpectedly with opening of the
azepine ring and 2-[N-(4-bromophenyl)-N-(2-cyanomethylbenzyl)amino]acethydrazide 8 was obtained in high
1
yield. The H NMR spectrum of 8 shows three two-proton singlets for methylene group protons and signals for
887

TABLE 1. Physicochemical Characteristics of Compounds 3-8
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °С
Yield, %
70
C
H
N
Br
3a
C18H18N2O2
73.61
73.45
6.22
6.16
9.72
9.52
107
3b
3c
5a
5b
5c
6a
6b
7
C18H17BrN2O2
C19H20N2O2
C17H14N2O
58.11
57.92
74.15
74.00
77.90
77.84
60.00
59.84
78.30
78.24
53.05
52.99
63.21
63.15
64.10
64.05
4.63
4.59
6.70
6.54
5.48
5.38
3.98
3.84
5.90
5.84
3.33
3.29
4.48
4.42
4.49
4.44
7.62
7.51
9.31
9.08
10.86
10.68
8.35
8.21
10.24
10.14
16.24
16.12
18.54
18.41
13.09
12.99
21.67
21.41
96
84
71
88
68
82
69
67
83
82
112
163
163
145
216
264
195
158
C17H13BrN2O
C18H16N2O
23.54
23.42
C23H17BrN6O4
C24H20N6O4
C23H19BrN4
C17H17BrN4O
15.52
15.33
18.60
18.52
21.58
21.41
8
54.74
54.70
4.63
4.59
15.20
15.01
the protons of NH protons, which exchange with D2O, while its IR spectra show bands for NH and amide C=O
groups. The structure of this compound was demonstrated by showing that it is identical to the sample obtained
by an independent synthesis involving hydrazinolysis of aminoester 3b.
EXPERIMENTAL
1
The IR spectra were taken on a Pye–Unicam SP3-300 spectrometer using KBr pellets. The H NMR
spectra were taken on Bruker WP-100SY (100 MHz) and Varian VXR-300 spectrometers (300 MHz) with TMS
as the internal standard. Benzazepine 6b was recrystallized from ethanol and the other products were
recrystallized from 2-propanol. The melting points of the products were taken on a Boetius block and not
corrected. The reaction course and purity of the products were monitored by thin-layer chromatography on
Silufol UV-254 plates.
The physicochemical and spectral characteristics of the products are given in Tables 1 and 2.
Methyl N-Aryl-N-(2-cyanomethylbenzyl)-2-aminoacetates 3a-c (General Method). A mixture of
(2-bromomethylphenyl)acetonitrile 1 (60 mmol), methyl N-arylglycidine 2 (14.6 g, 60 mmol), and sodium
acetate (24.6 g, 300 mmol) in 2-propanol (160 ml) was heated at reflux with stirring for 6 h. The reaction
mixture was cooled and filtered. The solvent was removed from the filtrate at reduced pressure. The residue was
triturated with cold water. The solid was filtered off, washed with water, and crystallized from 2-propanol.
2-Aryl-4-hydroxy-1,3-dihydro-1H-(2)-benzazepine-5-carbonitriles 5a-c (General Method). The
corresponding acetate 3 (10.54 g, 33 mmol) was added to a solution of sodium methylate obtained by dissolving
metallic sodium (1.15 g, 50 mmol) in methanol (80 ml). The reaction mixture was heated at reflux for 1.5 h and
cooled. Then, 150 ml water was added with stirring and the mixture was neutralized by adding acetic acid. The
precipitate formed was filtered off, washed with water, and crystallized from 2-propanol.
888

889

4-Hydroxy-2-phenyl-2,3-dihydro-1H-2-benzazepine-5-carbonitrile
(5a).
1H NMR
spectrum
(CDCl3)*, δ, ppm (J, Hz): 4.14 (1H, d, J = 18, C(3)HB) (K); 4.23 (1H, d, J = 18, C(3)HA) (K); 4.42 (1.4H, s,
C(3)H2) (E); 4.49 (1.4H, s, C(1)H2) (E); 4.74 (1H, d, J = 16, C(1)HB) (K); 5.04 (1H, d, J = 16, C(1)HA) (K); 5.46
(1H, s, C(5)H) (K); 6.75-6.82 (5.1H, m, ArH); 6.90 (1.7H, t, J = 7, ArH); 7.16-7.53 (6.8H, m, ArH); 7.64 (1.7H,
d, J = 7, ArH).
1
2-Bromophenyl)-4-hydroxy-2,3-dihydro-1H-2-benzazepine-5-carbonitrile (5b). H NMR spectrum
(CDCl3),* δ, ppm (J, Hz): 4.06 (1H, d, J = 18, C(3)HB) (K); 4.24 (1H, d, J = 18, C(3)HA) (K); 4.39 (1.4H, s,
C(3)H2) (E); 4.47 (1.4H, s, C(1)H2) (E); 4.74 (1H, d, J = 16, C(1)HB) (K); 4.95 (1H, d, J = 16, C(1)HA) (K); 5.36
(1H,s, C(5)H) (K); 6.64-6.70 (3.4H, m, ArH); 7.19-7.29 (3.4H, m, ArH); 7.33-7.43 (5.1H, m, ArH); 7.52-7.64
(1.7H, m, ArH).
4-Hydroxy-2-(4-methylphenyl)-2,3-dihydro-1H-2-benzazepine-5-carbonitrile (5c). IR spectrum,
ν, cm-1: 2200 (s) (E), 2245 (w) (K) (C≡N), 1735 (C=O) (K), 3490 (OH) (E). 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 2.18 (2.1H, s, CH3) (E); 2.28 (3H, s, CH3) (K); 4.07 (1H, d, J = 18, C(3)HB) (K); 4.22 (1H, d, J = 18,
C(3)HA) (K); 4.34 (2H, s, C(3)H2) (E); 4.43 (2H, s, C(1)H2) (E); 4.71 (1H, d, J = 15, C(1)HB) (K); 5.00 (1H, d,
J = 16, C(1)HA) (K); 5.49 (1H, s, C(5)H) (K); 6.68-6.73 (3.4H, m, ArH); 6.95-6.97 (3.4H, m, ArH); 7.10-7.42
(5.1H, m, ArH); 7.50-7.64 (1.7H, m, ArH).
2-(4-Bromophenyl)-4-(2,4-dinitrophenylhydrazino)-1,3-dihydro-1H-2-benzazepine-5-carbonitrile
(6a). Water (1.5 ml) and, then, ethanol (5 ml) were added with stirring consecutively to a mixture of
2,4-dinitrophenylhydrazine (0.26 g, 1.3 mmol) and concentrated sulfuric acid (1 ml). A solution of
2-benzazepine 5b (0.34 g, 1 mmol) in a minimal amount of ethanol was added to the prepared mixture. The
precipitate formed was filtered off, washed with water, and recrystallized from ethanol.
4-[2-(2,4-Dinitrophenyl)hydrazino]-2-(4-methylphenyl)-2,3-dihydro-1H-2-benzazepine-5-carbo-
nitrile (6b) was obtained analogously to 5c.
1-Amino-5-(4-bromophenyl)-2-phenyl-2,4,5,6-tetrahydropyrazolo[3,4-d]-2-benzazepine
(7).
Phenylhydrazine (0.11 ml, 1 mmol) was added to a solution of 2-benzazepine 5b (0.34 g, 1 mmol) in 2-propanol
(10 ml). The mixture was heated at reflux for 2 h and cooled. The precipitate formed was filtered off and
crystallized from 2-propanol.
N-4-Bromophenyl-N-(2-cyanomethylbenzylamino)acethydrazide (8). A sample of 85% hydrazine
hydrate (1 ml, 17 mmol) was added to a solution of benzazepine 5b (0.34 g, 1 mmol) in 2-propanol (10 ml). The
reaction mixture was heated at reflux for 4 h and cooled. Then, ice water was added. The precipitate formed was
filtered off and crystallized from 2-propanol.
The same compound was obtained under the same conditions from ester 3b.
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_______
* The integral intensities of the signals are given relative to proton absorption of the ketonic form K.
890

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891