Conversion of 2-ethyl- 3, 3, 5, 5-tetramethyl- and 2-ethyl- 1, 3, 3, 5, 5-pentamethyl-1, 2, 4, 5-tetra- hydro-3H-benz-2-azepines by the action of ethyl propiolate

Article abstract of DOI:10.1007/s10593-010-0414-4

It has been shown that, on interacting 2-ethyl-3, 3, 5, 5-tetramethyl- and 2-ethyl-1, 3, 3, 5, 5-pentamethyl-1, 2, 4, 5-tetrahydro-3H-benz-2-azepines with ethyl propiolate in methanol, fission of the azepine ring occurs at the C(1)-N(2) bond involving a m

Full text of DOI:10.1007/s10593-010-0414-4

Chemistry of Heterocyclic Compounds, Vol. 45, No. 10, 2009
CONVERSION OF 2-ETHYL-
3,3,5,5-TETRAMETHYL- AND 2-ETHYL-
1,3,3,5,5-PENTAMETHYL-1,2,4,5-TETRA-
HYDRO-3H-BENZ-2-AZEPINES BY THE
ACTION OF ETHYL PROPIOLATE
L. G. Voskressensky1*, T. N. Borisova1, E. A. Sorokina1, L. N. Kulikova1,
A. V. Kleimenov1, S. V. Tolkunov2, and A. V. Varlamov1
It has been shown that, on interacting 2-ethyl-3,3,5,5-tetramethyl- and 2-ethyl-1,3,3,5,5-pentamethyl-
1,2,4,5-tetrahydro-3H-benz-2-azepines with ethyl propiolate in methanol, fission of the azepine ring
occurs at the C(1)–N(2) bond involving a molecule of solvent. The indicated azepines do not react with
acetylenedicarboxylic acid ester under these conditions.
Keywords: activated alkynes, tetrahydrobenz-2-azepines, fission.
Tandem expansion reactions of the tetrahydropyridine ring condensed with heterocyclic fragments under
the action of activated alkynes, described by us for the firtst time, have been used to develop a new preparative
method for the synthesis of tetrahydroazocines condensed with pyrrole, indole, thiophene, and pyrimidine rings
[1-4]. It was shown recently that the hydrogenated azepine ring in hexahydro-azepino[4,3-b]indoles and
-[3,4-b]indoles is also subject to tandem fission under these conditions, as a result of which
hexahydroazonino[5,6-b]indoles are formed [5]. The reaction proceeds easily in both acetonitrile and methanol.
Me
Me
Me
Me
Me
Me
Me
Me
EtI
DMF, K2CO3
N
N
R
R
H
Et
1, 2
3, 4
1, 3 R = H; 2, 4 R = Me
_______
* To whom correspondence should be addressed, e-mail: lvoskressensky@sci.pfu.edu.ru.
1Peoples' Friendship University of Russia, Moscow 117198, Russia.
2L. M. Litvinenko Institute of Physical Organic Chemistry and Coal Chemistry, National Academy of Sciences
of Ukraine, Donetsk 83114, Ukraine; e-mail: tolkunov@uvika.dn.ua.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1554-1557, October, 2009.
Original article submitted November 18, 2008.
1248
0009-3122/09/4510-1248©2009 Springer Science+Business Media, Inc.

In order to establish the effect of the aromatic fragment and the substituents in the azepine ring we have studied the
interaction of 2-ethyl-3,3,5,5-tetramethyl- and 2-ethyl-1,3,3,5,5-pentamethyl-1,2,4,4-tetrahydro-3H-benz-2-aze-
pines 3 and 4 with acetylenedicarboxylic acid ester (ADCE) in methanol and with ethyl propiolate in ethanol.
Azepines 3 and 4 were obtained by the ethylation with ethyl iodide of benzazepines 1 and 2, synthesized
by the procedure described in [6].
Unlike azepinoindoles [5], benzazepines 3 and 4 do not react with ADCE, and for the reaction with ethyl
propiolate in ethanol it was necessary to boil for 48 h.
Me
Me
Me
Me
+
CO2Et
Me
Me
Me
+
3, 4
Me
Et
–
N
EtOH
N
Et
R
R
–
O
CO2Me
.
MeO2C
Me
H
A
B
Me
+
Me
N
Me
Me
Me
Me
Me
EtOH
Me
Et
+
–
+
–EtO
N
Et
R
R
CO2Me
CO2Me
.
C
D
–
Me
R
EtO
Me
Me
Me
N
Et
EtO
CO2Me
5, 6
5 R = H, 6 R = Me
This is seemingly caused by steric obstacles to the approach of the alkyne to the nitrogen atom of the
azepine ring. On reaction with ethyl propiolate multicomponent mixtures were formed from which products
were isolated, by chromatography in 19-22% yield, from the decomposition of the azepine ring involving a
molecule of ethanol, viz. the aminoacrylates 5, 6.
The reaction begins with the formation of the ammonium zwitter-ion A, which is converted through the
transition state B into aminoacrylates 5 and 6. The presence of secondary and tertiary carbon atoms in the
α-position to the ammonium nitrogen atom seemingly causes fission of the C(1)–N+ and C(3)–N+ bonds with the
formation of stable cations of type C and D. These cations, apart from reacting with ethanol, undergo processes
of isomerization and rearrangement characteristic of carbocations, which also explains the formation of
multicomponent mixtures.
In the mass spectra compounds 5 and 6 have peaks for molecular ions corresponding to their empirical
formulas. In the 1H NMR spectra the presence of two doublets at 5.62-5.65 and 7.55-7.60 ppm for the protons of
the acryloyl group with J = 13.1 Hz are characteristic. This shows the trans configuration of this fragment.
1249

EXPERIMENTAL
1
The H NMR spectra were obtained on a Bruker WP 400 (400 MHz) instrument in CDCl3, internal
standard TMS. The IR spectra were recorded on a INFRALYUM FT 801 Fourier spectrometer in KBr pellets.
The ESI mass spectra were recorded on a Agilent 1100 Series LC/MSD Trap System VL mass spectrometer.
Silufol UV 254 plates were used for TLC (visualization with iodine vapor), neutral Al2O3 Fluka 507c (size
0.05-0.15 mm) was used for column chromatography.
2-Ethyl-3,3,5,5-tetramethyl-1,2,4,5-tetrahydro-3H-benz-2-azepine (3) and 2-Ethyl-1,3,3,5,5-penta-
methyl-1,2,4,5-tetrahydro-3H-benz-2-azepine (4) (General Method). Anhydrous potassium carbonate (10 g,
72 mmol) was added to a solution of azepines 1 or 2 (48 mmol) in DMF (25 ml). After 15 min ethyl iodide
(10.92 g, 5.6 ml, 70 mmol) was added dropwise. The mixture was heated at 60oC until disappearance of the
starting material (check by TLC). The mixture was poured into water (100 ml), extracted with ether, and the
extract dried over magnesium sulfate. After distilling off the solvent (DMF in vacuum) the residue was
chromatographed, eluent ethyl acetate–hexane, 1:20. Azepines 3 (6.8 g: 68%) and 4 (4.5 g: 38.3%) were
isolated.
Compound 3. Yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 1.08 (3H, t, J = 7.2, CH3CH2); 1.15 (3H,
s, CH3); 1.17 (3H, s, CH3); 1.31 (1H, d, J = 13.8, H-1); 1.35 (3H, s, CH3); 1.3 (3H, s, CH3); 1.42 (3H, s, CH3);
1.61 (1H, d, J = 13.8, H-4); 2.67 (2H, q, J = 7.2, CH3CH2); 3.67 (1H, d, J = 15.1, H-1); 4.18 (1H, d, J = 15.1,
H-1); 7.13-7.32 (4H, m, H Ar). Found, %: C 83.29; H 11.00; N 6.26. M+ 231. C16H25N. Calculated, %: C 82.91;
H 10.82; N 6.01. M 231.
Compound 4. Yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 1.03 (3H, t, J = 7.2, CH3CH2); 1.05 (3H,
s, CH3); 1.26 (3H, s, CH3); 1.42 (3H, s, CH3); 1,51 (3H, s, CH3); 1.53 (3H, d, J = 6.9, 1-CH3); 1.61 (1H, d,
J = 15.0, H-4); 2.14 (1H, d, J = 15.0, H-4); 2.70 (2H, q, J = 7.2, CH3CH2); 4.48 (1H, q, J = 6.9, H-1); 7.12-7.38
(4H, m, H Ar). Found, %: C 83.00; H 10.83; N 5.87. M+ 245. C17H27N. Calculated, %: C 83.37; H 11.02;
N 5.71. M 245.
Methyl (E)-3-{1,1,3-Trimethyl-3-[2-(ethoxymethyl)phenyl]butyl}(ethyl)aminoacrylate (5).
A
mixture of benzazepine 3 (1 g, 4.3 mmol) and ethyl propiolate (0.52 g, 5.3 mmol) was boiled for 48 h (check by
TLC). The solvent was distilled in vacuum. The residue was chromatographed (eluent ethyl acetate–hexane,
1:40 to 1:10). Compound 5 (0.32 g: 20%) was isolated as a yellow oil. IR spectrum, ν, cm-1: 1730 (CO), 1645
1
(C=C). H NMR spectrum, δ, ppm (J, Hz): 1.10 (3H, s, CH3); 1.17 (3H, t, J = 6.8, NCH2CH3); 1.25 (3H, t,
J = 7.1, CH3CH2O); 1.28 (3H, t, J = 7.1, CH3CH2O); 1.42 (3H, s, CH3); 1.44 (3H, s, CH3); 1.51 (3H, s, CH3);
1.69 (2H, s, CH2); 3.20 (2H, m, NCH2CH3); 4.12 (2H, q, J = 7.1, CH3CH2O); 4.40 (2H, s, CH2O); 4.42 (2H, m,
CH3CH2CO2); 5.62 (1H, d, J = 13.1, CH=); 7.55 (1H, d, J = 13.1, CH=). Found, %: C 73.21; H 10.01; N 3.91.
M+ 375. C23H37NO3. Calculated, %: C 73.60; H 9.87; N 3.73. M 375.
Methyl (E)-3-{1,1,3-Trimethyl-3-[2-(1-ethoxyethyl)phenyl]butyl}(ethyl)aminoacrylate (6) was
obtained by the procedure described above from benzazepine 4 (1 g, 4 mmol) in a yield of 0.35 g (22%) as a
light-yellow oil. IR spectrum, ν, cm-1: 1740 (CO), 1638 (C=C). 1H NMR spectrum, δ, ppm (J, Hz): 1.12 (3H, s,
CH3); 1.19 (3H, t, J = 6.9, NCH2CH3); 1.26 (3H, t, J = 7.1, CH3CH2CO2); 1.29 (3H, t, J = 7.1, CH3CH2CO2);
1.43 (3H, s, CH3); 1.45 (3H, s, CH3); 1.53 (3H, s, CH3); 1.62 (3H, d, J = 6.9, CH3CH); 1.70 (2H, s, CH2); 3.32
(2H, m, N-CH2CH3); 4.12 (2H, q, J = 6.9, CH3CH2O); 4.32 (1H, q, J = 6.9, CH3CH); 4.43 (2H, q, J = 7.1,
CH3CH2CO2); 5.70 (1H, d, J = 13.5, CH=); 7.60 (1H, d, J = 13.5, CH=). Found, %: C 74.25; H 10.41; N 3.91.
M+ 375. C24H39NO3. Calculated, %: C 73.60; H 10.02; N 3.60. M 375.
The investigations were carried out within the framework of a joint project of the Russian Foundation
for Basic Research (Grant No. 08-03-90451) and the National Academy of Sciences of Ukraine.
1250

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