Synthesis and study of lactim ethers of 3,4-dihydrocarbostyryl and 2,3,4,5-tetrahydrobenz[b]azepin-2-one

Article abstract of DOI:10.1023/A:1023918911369

Alkylation of 3,4-dihydrocarbostyryl and 2,3,4,5-tetrahydrobenz[b]azepin-2-one using dimethyl sulfate and triethyloxonium fluoborate gives the corresponding lactim ethers. The reactions of lactim ethers with different compounds having primary amino groups

Full text of DOI:10.1023/A:1023918911369

Chemistry of Heterocyclic Compounds, Vol. 39, No. 3, 2003
SYNTHESIS AND STUDY OF LACTIM ETHERS
OF 3,4-DIHYDROCARBOSTYRYL AND
b
2,3,4,5-TETRAHYDROBENZ[ ]AZEPIN-2-ONE
T. V. Golovko1, N. P. Solov'eva2, O. S. Anisimova2, and V. G. Granik1
Alkylation of 3,4-dihydrocarbostyryl and 2,3,4,5-tetrahydrobenz[b]azepin-2-one using dimethyl sulfate
and triethyloxonium fluoborate gives the corresponding lactim ethers. The reactions of lactim ethers
with different compounds having primary amino groups (including ammonia, alkyl-, aralkyl-, and
arylamines, amino acids, and related compounds) have been studied. Novel heterocyclic compounds
based on the lactim ethers have been synthesized.
Keywords: dihydrocarbostyryl, lactim ether, tetrahydrobenz[b]azepinone, triethyloxonium fluoborate,
alkylation.
One of the productive routes for development of the chemistry of heterocyclic compounds is the
transformation of lactams to the corresponding lactim ethers, the high reactivity of which combined with their
preparative availability has led to novel routes to the synthesis of various amidine and enamine derivatives and,
based on them, to the preparation of a variety of azaheterocycles [1]. At the same time, data concerning the use
of benzannelated lactim ethers which do not have functional substituents in the lactam ring are very limited. Of
the published reports the following should be mentioned: the synthesis of O-ethyl-3,4-dihydrocarbostyryl (1)
from 2-chloroquinoline [2] and by alkylation of 3,4-dihydrocarbostyryl (2) using triethyloxonium fluoborate [3];
the preparation of 1-ethoxyindolenine (3) [4] and O-ethylbenzo[1,4]thiazan-3-one (4) by the same method; and
the synthesis of 2-methoxy-3,4-dihydroquinoline (5) [5] from the corresponding chloroimide. The preparation of
2-ethoxy-4,5-dihydro-3H-benzazepine (6) by the alkylation of the corresponding lactam
–
2,3,4,5-tetrahydrobenzazepin-2-one (7) using triethyloxonium fluoborate has been described only in the report
[6]. The properties of the previously obtained lactim ethers 1, 3-6 have been reported very fragmentarily [4-6].
The aim of our work was to study the reactions of the lactim ethers 1,6 with different compounds having
a primary amino group including ammonia, alkyl-, aralkyl-, and arylamines, amino acids, and related materials.
In the first step of the work we examined the alkylation of the lactams 2 and 7. It was found that the six-
membered lactam 2 did not react with dimethyl sulfate upon heating in dichloroethane whereas the seven-
1
membered analog 7, under these conditions, underwent partial O-alkylation. H NMR spectroscopic data
indicates that after 8 h a mixture of the corresponding methyl sulfate complex 8a and the starting lactam is
formed in the ratio 1:2. Triethyloxonium fluoborate has a much stronger alkylating potential [7] when compared
with dimethyl sulfate and readily alkylates both lactams to form the corresponding fluoborate salts 8b,c which
readily undergo conversion to lactim ethers 1,6 upon the treatment with alkali.
__________________________________________________________________________________________
1
NIOPIK State Scientific Center of the Russian Federation, Moscow 103787; e-mail:
2
makar-d@ropnet.ru.
Scientific Research Chemical-Pharmaceutical Institute, Moscow 119815, Russia.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 389-399, March, 2003. Original article
submitted November 17, 1999; revision submitted 17 October, 2002.
344
0009-3122/03/3903-0344$25.00©2003 Plenum Publishing Corporation

Me2SO4
or Et3O+BF4
OH–
)
( )n
(
( )n
n
+
N
OR
X–
N
OEt
N
H
O
H
1, 6
8a–c
2, 7
1, 2 n = 1; 6, 7 n = 2; 8 a R = Me, X = MeSO4, b, c R = Et, X = BF4; a, c n = 2, b n = 1
In contrast to data in [5], according to which lactim ether 5 does not react with cyclohexylamine, ethers
1 and 6 react under usual conditions with various amines to give the corresponding amidines. Hence, reaction of
ethers 1,6 with ammonia and different amines gave amidines 9a-g and 10a-h:
)
(
)
(
( )n
n
n
RNH2
N
OEt
NR
N
H
N
NHR
A
B
1, 6
9, 10
9 n = 1, 10 n = 2; 9, 10
a R = H, b R = n-Bu, c R = PhCH2, d R = homoveratryl, e R = Ph,
f R = p-MeC H ,
g R = p-MeOC6H4, 10 h R = CH2CH2NEt2
6
4
1
The structures of the derivatives obtained have been characterized by their H NMR spectroscopic and
1
mass spectrometric data (Tables 1 and 2). It is interesting to note the presence in the H NMR spectrum of
compound 9a of a broad signal at 6.60 ppm with an intensity of 2H assigned to an amino group which may be
connected with a significant shift of the tautomeric equilibrium A ↔ B towards the formation of the amino form
B. In the spectra of the compounds 9e and 10e taken at room temperature in DMSO-d6 strongly broadened
signals for the ortho protons of the N-phenyl substituents (~7.80 ppm) are observed. The broadening is so
marked that they do not show their multiplicity whereas the meta protons appear in the spectrum as narrow
signals with clearly defined multiplicity. For the six-membered compound 9e this broadening is observed also
for the aromatic 6- and 8-H protons as well as the protons of the 4-CH2 unit in the saturated ring whereas the
protons of the 3-CH2 unit appear as a narrow multiplet. In the 1H NMR spectrum of the analyzed solution taken
at an elevated temperature (70°C) the previously broadened signals are markedly narrowed: under these
conditions the ortho protons of the N–Ph group are seen as a broadened doublet with a simultaneous shift to
higher field. Upon cooling the solution the spectrum fully conforms to the starting spectrum. Such changes are
very likely connected with a relatively slow amine-imine equilibrium (A ↔ B). To explain the dependence of
the form of the signals in the spectra on the temperature of accumulation (as noted above) as an effect of
hindered "rotation" around the PhN=C– or N–Ph bonds in the imino form A is unreasonable since, in the first
case, this would affect the form of the 3-CH2 group signals (in this case narrow multiplets not changing with an
increase in the temperature of recording of spectra) and, in the second case, this would be unlikely to change the
form of the 6- and 8-H signals.
Lactim ethers react not only with primary amines but also with hydroxylamine, phenylhydrazine, and
cyanamide and in these examples form the corresponding derivatives 11a-c and 12a-c:
)
(
NH2X
n
1, 6
N
H
NX
11a–c, 12a–c
n = 1, 2; a X = NHPh; b X = OH; c X = CN
345

A reaction with aliphatic amino acids also occurs quite readily to form amidino acids 13a-d and 14a-e.
)
(
H2N–Y–COOH
n
1, 6
N
H
NYCOOH
13a–e, 14a–e
e Y = –CH(Me)–
a Y = –CH2–, b Y = –CH2CH2–, c Y = –(CH2)3– , d Y = –(CH2)5–,
n = 1, 2;
1H NMR spectroscopic data for compounds 11-14 are given in Table 1.
TABLE 1. 1H NMR and 13C NMR Spectral Characteristics of the
Synthesized Compounds.
Com-
δ, ppm (J, Hz), in DMSO-d6
pound
1
2
2.25 (2Н, t, 3-Н); 2.64 (2Н, t, 4-Н); 6.60 (2H, br. s, NН2);
6.72-6.78, 6.96-7.04 (two m, each 2Н, 5-, 6-, 7-, 8-Н)
0.90 (3Н, t, СН3 side chain); 1.35 (2Н, m, СН2 side chain); 1,50 (2Н, m, СН2 side chain);
3.27 (2Н, t, СН2 side chain; NCH2CH2CH2CH3); 2.24 (2Н, t, 3-Н); 2.61 (2Н, t, 4-Н);
6.86 (1H, br. s, NH); 6.73 (1Н, t, 6-Н); 6.80 (1Н, d, 8-Н); 6.95 (1Н, d, 5-Н);
7.00 (1Н, t, 7-Н)
9а
9b
9d
9e
9f
2.84 (2Н, m, 3-Н); 2.90 (2Н, m, 4-Н); 2.91 (2Н, t, СН2 side chain);
3.87 (2Н, br. t, СН2 side chain; NCH2CH2); 3.68 (3Н, s, OСН3);
3.76 (3Н, s, OСН3); 6.80-6.97 (2Н, m); 7.06 (1H, split, s); 7.10 (1H, t);
7.20-7.24 (2H, m); 7.70 (1Н, d, Н arom.); 10.60 (1Н, br. s, NH); 11.68 (1Н, br. s, NH+)
2.48 (2Н, t, 3-Н); 2.74 (2Н, br. t, 4-Н); 6.95 (1Н, t, р-Н arom.);
7.27 (2Н, t, m,m'-Н arom.); 7.94 (2Н, strongly br. s, о,о'-Н arom.; NPh);
6.85 (1Н, strongly br. t, 6-Н); 6.97 (1Н, strongly br. d, 8-Н); 7.05 (1Н, d, 5-Н);
7.09 (1Н, t, 7-Н); 9.05 (1Н, strongly br. s, NH)
2.46 (2Н, t, 3-Н); 2.73 (2Н, br. t, 4-Н); 2.24 (3Н, s, СН3);
7.80 (2Н, strongly br. s, о,о'-H arom.); 7.07 (2Н, d, m,m'-Н arom.; N-C6H4-CH3-p);
6.84 (1Н, br. t, 6-Н); 6.94 (1Н, br. d, 8-Н); 7.03 (1Н, d, 5-Н); 7.08 (1Н, t, 7-Н);
9.00 (1Н, strongly br. s, NH)
2.46 (2Н, t, 3-Н); 2.74 (2Н, t, 4-Н); 3.72 (3Н, s, OСН3); 6.86 (2Н, d, m,m'-H arom.);
7.80 (2Н, strongly br. s, о,о'-H arom.; N-C6H4-OCH3-p); 6.82 (1Н, br. t, 6-Н);
6.92 (1Н, br. d, 8-Н); 7.04 (1Н, d, 5-Н); 7.08 (1Н, t, 7-Н); 8.92 (1Н, strongly br. s, NH)
9g
2.00 (4H, m, 3-, 4-H); 2.40 (2H, br. t, 5-H); 2.80 (2H, t, CH2 side chain);
3.44 (2Н, br. t, CH2 side chain; NCH2CH2); 3.71, 3.73 ( 3H, two OCH3);
6.72-6.79 (3H, m); 6.85 (1H, split s); 6.86 (1H, d);
10d
7.00-7.09 (2H, m, o,o'-H arom., m-H arom., 6-, 7-, 8-, 9-H); 6.95 (1H, br. signal, NH)
2.18 (2Н, br. m, 2-, 4-Н); 2.25 (2Н, br. t, 5-Н); 2.51 (2Н, br. t, 3-Н);
6.81-6.88, 7.08-7.16 (two m, each 2Н, 6-, 7-, 8-, 9-Н); 6.94 (1Н, t, р-Н arom.);
7.26 (2Н, t, m,m'-Н arom.); 7.80 (2Н, strongly br. s, о,о'-H arom.; NC6H5);
9.10 (1Н, strongly br. s, NH)
2.16 (2Н, m, 4-Н); 2.24 (2Н, t, 3-Н); 2.50 (2Н, t, 5-Н); 2.24 (3Н, s, СН3);
7.68 (2Н, strongly br. s, о,о'-H arom.); 7.07 (2Н, d, m,m'-Н arom.; N-C6H4-СН3-р);
6.80-6.88, 7.08-7.16 (two m, each 2Н, 6-, 7-, 8-, 9-Н); 9.00 (1Н, strongly br. s, NH)
10e
10f
2.20 (2Н, m, 2-, 4-Н); 2.46 (2Н, t, 3-Н); 2.74 (2Н, t, 5-Н); 1.27 (6Н, t, СН3, СН3);
3.22 (4Н, br. q, СН2, СН2; N(CH2CH3)2); 3.47 (2Н, br. t, β-СН2);
4.10 (2Н, br. q, α-СН2; NНCH2CH2N); 7.22-7.40 (4Н, m, 6-, 7-, 8-, 9-Н);
10.98 (2Н, br. s); 11.72 (1Н, br. s; NH, 2NH+)
3.00 (2Н, t, 3-Н); 3.15 (2Н, t, 4-Н); 6.92 (1Н, t, р-H arom.); 7.00 (2Н, d, o,o'-Н arom.);
7.27 (2Н, t, m,m'-Н arom.); 9.00 (1Н, s, NH; NHC6H5); 7.13 (1Н, t); 7.24 (1Н, t);
7.28 (1Н, d); 7.42 (1Н, d, 5-, 6-, 7-, 8-Н); 11.81 (1Н, s, 1-NH); 12.60 (1Н, br. s, NH+)
10h
11a
2.37 (2Н, t, 3-Н); 2.71 (2Н, t, 4-Н); 6.72 (1Н, m); 6.98-7.06 (3Н, m, 5-, 6-, 7-, 8-Н);
11b
11c
8.78 (1Н, s); 9.44 (1Н, s, NH, OH)
2.80-3.00 (4Н, m, 3-, 4-Н); 6.95-7.05, 7.15-7.22 (two m, each 2Н, 5-, 6-, 7-, 8-H);
11.36 (1Н, s, NH)
346

TABLE 1 (continued)
1
2
13a*
13b*
13c*
2.65 (2Н, t, 3-Н); 2.77 (2Н, t, 4-Н); 3.89 (2Н, s, СН2 side chain); 6.90 (1Н, t, 6-Н);
7.00 (1Н, d, 8-Н); 7.07-7.17 (2Н, m, 5-, 7-Н)
2.40 (2Н, t, 3-Н); 2.69 (2Н, t, 4-Н); 2.50 (2Н, t, β-СН2); 3.48 (2Н, t, α-СН2;
NCH2CH2COOH); 6.80-6.95, 7.03-7.10 (two m, each 2Н, 5-, 6-, 7-, 8-H)
2.35 (2Н, t, 3-Н); 2.68 (2Н, t, 4-Н); 1.72 (2Н, m, β-СН2); 2.27 (2H, t, γ-CH2),
~3.30*2 (2H, α-CH2; NCH2CH2CH2-COOH); 6.80 (1Н, t, 6-Н); 6.90 (1Н, d, 8-Н);
7.01 (1Н, d, 5-Н); 7.05 (1Н, t, 7-Н)
13d*
2.27 (2Н, t, 3-Н); 2.63 (2Н, t, 4-Н); 1.33 (2Н, m); 1.52 (4Н, m, β-, γ-, σ-СН2 side chain);
2.19 (2Н, t, ω-СН2 side chain); 3.27 (2Н, t, α-СН2 side chain;
NCH2,CH2CH2CH2CH2COOH); 6.72-6.86, 6.95-7.04 (two m, each 2Н, 5-, 6-, 7-, 8-H)
14a*
14b*
2.17 (2Н, m, 4-Н); 2.33 (2Н, t, 3-Н); 2.58 (2Н, t, 5-Н); 3.90*3 (s, СН2 side chain);
6.98 (1Н, d, 9-Н); 7.03 (1Н, t, 7-Н); 7.20-7.26 (2Н, m, 6-, 8-Н)
2.08 (2Н, m, 4-Н); 2.16 (2Н, t, 3-Н); 2.50 (2Н, t, 5-Н); 2.46 (2Н, t, β-СН2);
3.48 (2Н, t, α-СН2; NCH2CH2COOH);
6.86-6.98, 7.10-7.20 (two m, each 2Н, 6-, 7-, 8-, 9-Н)
14c*
16*
2.10 (2Н, m, 4-Н); 2.12 (2Н, t, 3-Н); 2.47 (2Н, t, 5-Н); 1.78 (2Н, m, β-СН2);
2.27 (2Н, t, γ-СН2); 3.30 (2Н, t, α-СН2; NCH2CH2CH2COOH);
6.81-6.90, 7.06-7.16 (two m, each 2Н, 6-, 7-, 8-, 9-Н)
2.71 (2Н, br. t, 3-Н); 2.80 (2Н, br. t, 4-Н); 7.80 (1Н, strongly br. s, о-Н arom.);
7.99 (1Н, d); 7.54 (1Н, t, m,m'-Н arom.); 7.14 (1Н, t, р-H arom.; NC6H4-COOH-о);
6.94 (1Н, t, 6-Н); 7.03 (1Н, d, 7-Н); 7.15 (1Н, d, 5-Н); 7.16 (1Н, t, 8-Н)
17*4
1.96 (1H, m, 6-H); 2.20 (1H, m, 6-H); 2.30 (1H, m, 7-H); 2.58 (1H, m, 7-H);
2.71 (2H, m, 5-H); 7.40 (3H, m); 7.47 (1H, m); 7.53 (1H, m); 7.67 (1H, d, split);
7.84 (1H, t, split); 8.16 (1H, d, split arom. protons).
[28.4 (t, 1JCH = 132) and 28.5 (t, 1JCH = 132, C(6) and C(7)); 33.2 (t, 1JCH = 132, C(5));
126.9 (C(11)), 127.0, 127.1, 128.1, 129.1, 129.2 (C arom.), 121.2 (q, C(12a)),
134.9 (d, 1JCH = 162, C(12)), 135.6 and 135.8 (m, C(4a) and C(14a)), 147.2 (q, C(8a)),
156.4 (m, C(7a)), 160.6 (split, C=O)]
18*4
19*4
2.40-2.56 (2Н, m, 3-Н); 2.68-2.80 (2Н, m, 4-Н); 3.65, 3.98 (2Н, two s, СН2CN)*5;
6.70-7.20 (4Н, m, Н arom.); 9.00, 9.08 (NH), 10.00, 10.20 (NH)
[24.3 (1JCH = 135.8); 25.1 (1JCH = 136.6, CH2CN); 25.0, 25.2 (1JCH = 125.9, С(3));
27.0, 27.5 (1JCH = 127.4, С(4)); 114.9, 115.4 (arom. C); 116.6, 116.7 (CN);
121.4, 121.6 (arom. C); 127.5, 127.6 (arom. C); 128.4, 128.8 (arom. C), (С(5), С(6), С(7)
,
С
(8)); 123.8, 124.2 (С(4a)); 138.1, 137.9 (С(8a)); 143.9, 151.5 (С(2)); 158.4, 164.2 (СО)]
2.12 (2H, 5-H); 2.32 (2H, 4-H), 2.68, 2.98 (two br. signals, each 1Н, 6-Н);
4.30, 4.50 (two br. signals, each 1Н, CH2CN), 7.42-7.58 (4H, m, Н arom.)
[10.8 (t, 1JCH = 138, СH2CN); 16.8 (t, 1JCH = 132.7, C(5)); 24.4, 24.8 (two t, 1JCH = 129.0,
C(4) and C(6)); 110.7 (t, 2JCN,CH = 11, CN); 119.0, 123.6, 125.0, 126.3 (four d, C(7), C(8)
,
2
C(9), C(10)); 128.6 (m, C(6a)); 131.8 (m, C(10a)); 140.2 (t, 2J2-S,CH = 8.4, C(1)); 151.4 (m, C(4a))]
2
_______
*
The mobile NH and COOH group protons take part in rapid exchange
between themselves and water in the solvent and form a general, intense,
strongly broadened signal in the spectrum (3.30-5.50 ppm).
2
*
The signal for the α-CH2 protons is partially overlapped by the strong
signal from the solvent water (3.30 ppm).
*3 The intensity of the signal is not given since it is partially overlapped by
the signal from water in the solvent.
*4 The 13C NMR spectroscopic data are given in square brackets.
*5 The CH2CN group signals at 3.67 and 3.87 ppm correspond to the minor
forms; the overall integrated intensity of the four signals of the CH2CN
group protons corresponds to 2H.
347

In the next stage of the work we undertook attempts to synthesize heterocycles based on lactim ethers 1
and 6. The reaction of ether 1 with hydrazine was expected to yield the corresponding hydrazone which might
further be converted to triazole and tetrazole derivatives [1]. However, in this case we isolated only azine 15
which was characterized using mass spectrometry, 1H NMR spectroscopy, and elemental analysis data.
The 1H NMR spectrum of compound 15 shows the presence of the following signals: 2.63 (2H, q, 3-H);
2.80 (2H, q, 4-H); 6.75-7.10 (4H, m, 5-, 6-, 7-, 8-H); 9.02 ppm (1H, s, NH). According to the mass spectrum this
compound has a dimeric structure. Since the 1H NMR spectrum shows one set of signals it is natural to propose
that, firstly, the dimer has a symmetrical structure and, secondly, there must be minimal steric interaction, i.e.
the bicyclic fragments apparently are trans-located at the central =N–N= bond. In solution the compound
discussed is quite unstable and the hydrolysis products are formed in solution upon standing.
In other investigated processes there is a distinct difference in the reaction course depending on the size
of the saturated ring [9] in the lactim ethers 1 and 6. Hence the reaction of compound 1 with anthranilic acid
gives amidine 16 which does not cyclize under the reaction conditions. According to mass spectroscopic data,
besides the signal M+ 266, a peak for M+ 248 is observed, however the amount of this substance is negligible
1
and it could be formed in the conditions of the recording of the mass spectrum. The H NMR spectrum of
compound 16 (Table 1) shows the presence of a strongly broadened signal (no multiplicity seen) for the ortho
proton of the N-(o-carboxy)phenyl substituent at 7.80 ppm. Upon recording the spectrum at 70°C the signal is
markedly narrowed but its position does not change. The mobile protons at the heteroatoms are observed as an
overall signal at 3.60 ppm (due to rapid exchange between themselves and water in the solvent). The multiplet
for the 3-CH2 group at 2.71 ppm is markedly broadened and the multiplet for the 4-CH2 at 2.80 ppm is
broadened to a lesser degree. Such a signal broadening is characteristic of amidines due to the possibility of syn-
anti isomerization around the C=N– double bond. The isomerization process is accelerated upon heating and the
signals become narrowed when the spectrum is recorded at an increased temperature. It should be noted that
protons of the 3-CH2 group are sterically close to the N-aryl substituents in the predominant conformation as
indicated by the results of a nuclear Overhauser effect (NOE) experiment. Irradiation of the signals from protons
of the 3-CH2 group at 2.71 ppm brings about a marked increase in the intensity of the multiplets for the meta
protons of the N–C6H4–COOH-p unit at 7.59 (by 30%) and 7.99 ppm (by 4%). The effect is not observed for the
ortho proton because of the significant broadening of the signal of the latter (see above). Irradiation of the signal
for the 4-CH2 group at 2.80 ppm leads to a 10% increase in the intensity of the 5-H signal at 7.15 ppm (d).
N2H4 · H2O
1, 6
H
N
N
for 6
N
H
N
for 1
15
N
H
N
H
N
H
N
+
–
COO
COOH
16
for 1
for 6
5
8
4
4a
6
3
N
N
2
7
N
N
N
8a N 1
H
NNHCOCH2CN
O
NCH2C
18
19
17
348

Another picture is seen when carrying out the reaction of lactim ether 6 with anthranilic acid. In this
case 6,7,13,14-5H-tetrahydrobenz[f]azepino[1,2-b]quinazolin-13-one (17) is formed readily and in high yield.
The structure follows from 1H NMR and 13C NMR spectroscopic data (Table 1) and from mass spectroscopy.
Since the condensation of the seven-membered lactim ether 6 with anthranilic acid to give tetracycle 17
occurs under more drastic conditions than the condensation of six-membered lactim ether 1 (see Table 3) we
have carried out the condensation reaction of compound 1 with anthranilic acid under the conditions for
preparing the tetracycle 17 and compound 6 in the conditions for preparing amidine 16 and we have studied the
reaction products using 1H NMR spectroscopy.
1
According to the H NMR spectrum of the reaction product of the seven-membered derivative (in
DMSO-d6), in the solution discussed only signals for the starting compounds (lactim ether 6 and anthranilic
acid) and ethanol are present in addition to those of the tetracycle 17 itself.
A different situation is observed when analyzing the reaction product formed in the course of
preparation of the six-membered derivative. The 1H NMR spectrum shows intense signals corresponding to the
noncyclic derivative 16 along with clearly identified, low intensity signals for the cyclic derivative (analog of
compound 17) in the ratio 10:1. The solution also contains a small amount of both starting compound 1 and
anthranilic acid as well as ethanol.
Hence, also in the case of the six-membered lactim ether 1 in the course of the studied reaction the
formation of a tetracyclic product is observed, although its content is much less than that of the noncyclic
compound 16.
The difference in behavior of lactim ethers 1 and 6 is retained when studying their reactions with
cyanoacetic acid hydrazide. According to mass spectroscopic data (Table 2) ether 1 forms compound 18.
TABLE 2. Mass Spectral Characteristics of the Synthesized Compounds*
Com-
m/z (I, %)
pound
202 M+ (93), 201 [M–H]+ (44), 173 [М–C2H5]+ (60), 159 [M–C3Н7]+ (80), 146 [C4H8]+
(100), 130 [М–C4H10N]+ (56), 118 [CH2CHC6H4NH]+ (10), 106 [CH2C6H4NH2]+ (54),
103 [CH2CHC6H4]+ (20), 77 [Ph]+ (21)
9b
9d
310 M+ (15), 164 [СН2=СНС6Н3(ОСН3)2]+ (100), 159 [М–CН2С6Н3(ОСН3)2]+ (20),
151 [CН2С6Н3(ОСН3)2]+ (10), 146 [М–СН2=СНС6Н3(ОСН3)2]+ (23),
130 [М–NH(СН2)2С6Н3 (ОСН3)2]+ (15), 106 [CH2C6H4NH2]+ (8), 77 [Ph]+ (7)
236 M+ (70), 235 [M–H]+ (100), 130 [М–NH–C6H4СН3]+ (8),
117 [М–H2C–NC6H4CH3]+ (10), 91 [CH2Ph]+ (10)
9f
251 M+ (100), 159 [M–NHPh]+ (8), 144 [М–N2H2Ph]+ (68), 133 [M–C=N–NHPh]+ (10),
12a
12c
13b
106 [CH2C6H4NH2]+ (17), 93 [PhNH2]+ (19)
185 M+ (80), 157 [M–C2H4]+ (5), 144 [М–NHCN]+ (100), 116 [M–NHCN–C2H4]+ (15),
106 [CH2C6H4NH2]+ (13), 91 [C6H4NH]+ (8), 77 [Ph]+ (10)
218 M+ (90), 217 [M–H]+ (57), 173 [М–CООH]+ (100), 159 [M–CН2СОOН]+ (22),
146 [M–CН2СНСОOН]+ (60), 130 [M–NHCH2CH2COOH]+ (50), 106 [СH2C6H4NH2]+
(40), 77 [Ph]+ (20)
266 [M]+ (75), 265 [M–H]+ (30), 247 [M–H–H2O]+ (80), 221 [M–COOH]+ (100),
130 [M–NHC6H4COOH]+ (12), 116 [M–HC–NC6H4COOH]+ (15), 77 [Ph]+ (15)
16
17
18
262 M+ (80), 261 [M–H]+ (100), 247 [М–CH3]+ (7), 234 [M–CO]+ (10),
233 [M–H–CO]+ (7), 205 [M–H–CO–C2H4]+ (6), 89 [C7H5]+ (7)
228 [M]+ (70), 227 [M–H]+ (40), 210 [M–H2O]+ (10), 188 [М–CH2CN]+ (100),
160 [M–COCH2CN]+ (14), 146 [M–NCOCH2CN]+ (19), 143 [M–H–NH2COCH2CN]+
(23), 130 [M–H2NNCOCH2CN]+ (55), 118 [M–CHNNHCOCH2CN]+ (12),
106 [CH2C6H4NH2]+ (12), 77 [Ph]+ (15)
224 [M]+ (100), 223 [M–H]+ (43), 209 [N–CH3]+ (16), 196 [M–C2H4]+ (20),
184 [M–CH2CN]+, 168 [M–C2H4–N2]+ (10), 157 [M–CH2CN–HCN]+ (12), 143
[M–CH2CN–CHN2]+ (10), 130 [M–NCCH2C2H2N2]+ (45), 116
19
[M–NCCH2CHN2–HCN]+ (12), 103 [M–CH2CNC2H2N2–HCN]+ (20), 77 [Ph]+ (15)
_______
* DCI Mass spectra: 14b - [MH]+ 233, 14c - [MH]+ 247.
349

TABLE 3. Conditions for the Reaction of Lactim Ethers with Amines*
Reactions
conditions
Reactions
conditions
Com-
Molar ratio
Com-
pound
Molar ratio
pound 1 (6) : amine
1 (6) : amine
Time, min
T, °С
Time, min
T, °С
1:1.03
1:1
1:1
1.02:1
1:1
1:1.03
1:0.83
1:1
40
60
45
60
60
40
60
45
60
60
120-125
155-160
200
1:1
1:1
1:0.86
1:1
90
180
30
180
30
10
40
9с
10h
11a
11c
12а
12c
16
170
195-200
100
195-200
100
100
110
9d
9e
130
9f
160
1:0.86
1:0.83
9g
120-125
125-130
200
150
160
10c
10d
10e
10f
10g
17*2 1:0.78
1:1
1:1
30
20
95-100
95-100
18
19
1.02:1
1:1
_______
* For compounds 9a-g and 10e-g the reaction was carried out in the
presence of a catalytic amount of p-TsOH.
*2 The reaction product was then heated for 15 min at 130°C until complete
disappearance of anthranilic acid on TLC.
1
Judged by the number of signals for the CH2CN methylene proton signals in the H NMR spectrum of
compound 18 it exists as a mixture of four rotamers. The 1H NMR spectra of the two main rotamers are given in
Table 1. Heating the analyzed solution leads to a simplification of the spectrum. In the spectrum of the solution
heated to 60°C the signals for two rotamers are clearly seen (in the case of the CH2CN group at 3.62 and
3.93 ppm). The 1H NMR spectrum of the cooled solution of 18 fully agrees with the starting spectrum.
A similarly complex situation is also observed for compound 18 in its 13C NMR spectrum. As in the
1
case of the H NMR spectrum, a set of four is seen for a number of signals. In order to characterize the
1
compound under investigation we report the signals of the two predominant rotamers. As in the H NMR
spectra, the recording of the spectra of the solution heated to 60°C leads to a simplification of the 13C NMR
spectrum – only the signals from two forms are present. The 13C NMR spectrum of the cooled solution fully
corresponds to the initial spectrum.
Hence the spectroscopic characterization considered above unambiguously shows that compound 18 is
bicyclic. However, when the seven-membered lactim ether 6 is used in this reaction there occurs a cyclization
involving the imino ether and hydrazide fragments to give 1-cyanomethyl-4H,5,6-dihydro-1,2,4-triazolo[4,3-a]-
benz[f]azepine (19). The structure of the tricycle 19 follows from the mass spectroscopic data (Table 2) and the
1H NMR and 13C NMR spectra (Table 1).
1
The features of the H NMR spectrum include very broad signals for the methylene protons in the
seven-membered ring: 2.12 (2H, 5-H); 2.32 ppm (2H, 4-H) and two equal intensity, broad signals at 2.68 and
2.98 ppm (each 1H, 6-H). The methylene protons of the CH2CN fragment in the spectrum also appear as two
strongly broadened signals at 4.30 and 4.50 ppm (each 1H).
When 2 drops of DCl/D2O are added to the analyzed solution a marked decrease in the intensity of the
latter signals is observed (the intensity of the other signals being unchanged) and this is related to a deuterium
exchange of the acidic protons of the CH2CN group. In the spectrum taken at 70°C a clear narrowing of the
signals for the 4-CH2 and 6-CH2 groups is seen and for the 5-CH2 group protons (2.11 ppm) their characteristic
quintet multiplicity is revealed. The form of the signals for the CH2CN group protons also undergoes a
significant change and these protons appear as a singlet at 4.34 ppm with a two proton unit intensity. The
multiplicity of the aromatic protons in the range of 7.42-7.58 ppm (4H) is virtually unchanged upon heating the
solution under investigation.
350

TABLE 4. Characteristics of the Synthesized Compounds
Found, %
——————
Com-
Empirical
formula
Solvent for
Yield,
%
Calculated, %
mp, °С
pound*
recrystallization
C
3
H
4
N
5
1
9а
2
6
7
8
С9Н10N2
73.99 6.83 19.35
73.94 6.90 19.16
109-112
58-60
Heptane
Heptane
Heptane
Ethanol
70
77
75
79
100
85
87
72
73
100
15
С13Н18N2
77.22 9.00 13.97
9b
77.18 8.97 13.85
С16Н16N2
81.38 6.90 11.77
81.32 6.82 11.85
130-133
233-234.5
160-162
165-167
181-182
124-127
69-72
9c
С19Н22N2О2·HCl
С15Н14N2
65.96 6.87
8.25
9d
65.79 6.68
8.08
80.78 6.44 12.64
81.05 6.35 12.60
Propan-2-ol
Heptane
Propan-2-ol
Heptane
Heptane
Heptane
9e
С16Н16N2
81.15 6.93 11.86
9f
81.32 6.83 11.85
С16Н16N2О
С10Н12N2
76.01 6.46 11.11
76.16 6.39 11.10
9g
74.90 7.72 17.47
10a
10b
10c
10d
74.96 7.55 17.49
С14Н20N2
77.56 9.57 12.66
77.73 9.32 12.95
С17Н18N2
81.44 7.63 11.01
123-125
121-123
81.56 7.25 11.19
С20Н24N2О2
74.00 7.51
74.04 7.46
8.61
8.64
33% aqueous
propan-2-ol
С16Н16N2
81.57 7.01 11.52
143-147
146-147.5
141-143
236-239
231-236
126-129
183-185
Heptane
56
55
74
54
76
90
83
42
10e
10f
81.32 6.82 11.85
С17Н18N2
81.60 7.32 11.24
81.56 7.25 11.19
Heptane
С17Н18N2О
С16Н25N3·2HCl
С15Н15N3·HCl
С9Н10N2О
76.38 7.08 10.54
Heptane
10g
10h
11a
11b
11c
12a
76.66 6.81 10.52
57.90 8.20 12.83
57.83 8.19 12.64
Acetonitrile
Ethanol
65.98 5.70 15.65
65.81 5.89 15.35
66.55 6.18 17.28
66.65 6.22 17.27
Acetonitrile
Propan-2-ol
Ethanol
С10Н9N3
70.06 5.43 24.45
70.15 5.30 24.55
С16Н17N3·HCl
66.71 6.51 14.66
66.77 6.30 14.60
245-247
(dec. from 205)
С10Н12N2О
С10Н9N3
68.00 6.90 15.82
121-122
Acetonitrile
Propan-2-ol
Water
75
83
12b
12c
68.18 6.86 15.90
70.06 5.43 24.45
70.15 5.30 24.55
183-185
13a*2
13b
13c
59.62 6.26 12.62
239-239.5
236-237
78
С11Н12N2О2·H2О
С12Н14N2О2
С13Н16N2О2
59.45 6.35 12.61
66.13 6.41 12.80
66.04 6.47 12.84
Water
97
67.14 6.98 11.80
265.5-270.5
85-89
Methanol
Propan-2-ol
80
67.22 6.94 12.06
С15Н20N2О2·
·0.5 i-PrOH
С12Н14N2О2
68.09 8.55
68.24 8.33
9.20
9.65
100
13d
66.15 6.61 13.10
215-217
96% aqueous
ethanol
Water
78
14a
66.04 6.47 12.84
14b*3
14c
62.27 7.28 11.17
62.38 7.25 11.19
136-140
195-196
165-167
213-216
77
97
С13Н16N2О2·H2О
С14Н18N2О2·i-PrOH
С16Н22N2О2
66.54 8.43
9.49
Propan-2-ol
DMF
66.64 8.55
9.14
70.22 8.48 10.33
70.04 8.08 10.21
100
26
14d
14e
С13Н16N2О2
66.86 7.01 12.14
DMF
67.22 6.94 12.06
351

TABLE 4 (continued)
1
2
3
4
5
6
7
8
С18Н18N4
74.14 6.29 19.54
74.45 6.25 19.30
214-217.5
207.5-210.5
160-161
160-162
182-184
Acetonitrile
DMF
80
94
67
96
89
15
16
17
18
19
С16Н14N2О2
С17Н14N2О
С12Н12N4О
С13Н12N4
71.86 5.37 10.54
72.16 5.30 10.52
77.61 5.70 10.76
77.84 5.38 10.68
Propan-2-ol
Acetonitrile
Propan-2-ol
63.08 5.05 24.61
63.14 5.29 24.55
69.50 5.50 25.11
69.63 5.39 24.99
_______
* Compound 9d - Cl. Found, % 10.30. Calculated, %: 10.22. 10h - Cl.
Found, %: 21.36. Calculated, %: 21.34. 11a - Cl. Found, %: 13.01.
Calculated, %: 12.95. 12a - Cl. Found, %: 12.03. Calculated %: 12.32.
*2 H2O. Found, %: 7.96. Calculated, %: 8.10.
*3 H2O. Found, %: 7.70. Calculated, %: 7.20.
The 13C NMR spectrum of compound 19 agrees well with the proposed structure. In contrast to the
1H NMR spectrum, all of the signals in the 13C NMR spectrum are narrow and this allows us to propose that the
broadening of the signals in the proton spectrum is related to a slowed inversion of the seven-membered ring.
The high conformational freedom of the seven-membered ring is also possibly the reason for the difference in
the reactivity of lactim ethers 1 and 6, as manifested in the examples of their reactions with anthranilic acid and
cyanoacetic acid hydrazide.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian Unity+400 spectrometer (working frequencies 400 (1H) and
100 MHz (13C)) using DMSO-d6 with TMS internal standard. EI and DCI mass spectra were taken on a
Finnigan-MAT SSQ-710 instrument with direct introduction of the sample into the ion source (ionizing voltage
70 eV, ionization chamber temperature 150°C). Melting points were determined on a Boetius heating block.
Physicochemical and spectroscopic parameters for the synthesized compounds are given in Tables 1, 2,
and 4.
c
Mixture of
Alkylation of 1H,2,3,4,5-Tetrahydrobenz[ ]azepin-2-one by Dimethyl Sulfate.
compound 7 (1.61 g, 0.01 mol) and dimethyl sulfate (1.72 ml, 2.32 g, 0.018 mol) in dichloroethane (15 ml) was
refluxed for 3 h, dimethyl sulfate (1.2 ml) was added, and refluxing continued for a further 5 h. The reaction
product was evaporated and the residue was washed with heptane and then ether and dried in vacuo to give a
mixture of compounds 8a and 7 in the ratio 1:2 (according to 1H NMR spectroscopic data).
General Method for the Preparation of Compounds 9c-g, 10c-h, 11a,c 12a,c, and 16-19 (Table 3).
Mixture of lactim ether 1 or 6 and the corresponding amine was heated to the temperature of the start of the
condensation and held at this temperature with distillation of alcohol formed to the conclusion of the reaction
(cessation of the distillation). The reaction product was triturated with heptane (for compounds 9c,e-g, 10c,e-g,
11c, 12c, and 16), with heptane and then absolute ether (for compounds 10d, 18, and 19) or with propan-2-ol
(for compound 17). Compounds 9d, 10h, and 11a were isolated as hydrochlorides by solution of the reaction
product in ethyl acetate (for compounds 9d and 10h) or absolute ether (for compound 11a) with subsequent
acidification with a saturated solution of HCl in ethyl acetate (for compounds 9d and 10h) or in alcohol (for
compound 11a).
352

General Method for the Preparation of Compounds 11b and 12b. Mixture of the corresponding
lactim ether 1 or 6, hydroxylamine hydrochloride, and NaHCO3 (molar ratio 1:1.39:1.39) in DMF was stirred at
60°C (for compound 11b) or refluxed (for compound 12b) for 3 h. The precipitate was filtered off, the mother
liquor was evaporated, and the residue was triturated with water to give compound 11b or 12b.
General Method for the Preparation of Compounds 13a-d and 14a-e. Mixture of lactim ether 1 or 6
and the corresponding amino acid (molar ratio 1:0.89) in alcohol was refluxed for 4 h (for compounds 14b,d),
3.5 h (for compound 14a), 6 h (for compound 14c), 7 h (for compound 14e), 1 h (for compounds 13b-d), or
1.5 h (for compound 13a). The reaction product was cooled, the corresponding amidines 14a,b,e and 13a-d
were filtered off or evaporated in vacuo and the residue triturated with ether (for compound 14c) or with
heptane and then propan-2-ol (for compound 14d).
General Method for the Preparation of Compounds 9b, 10b. Mixture of lactim ether 1 or 6
(11.5 mmol) and butylamine (10 ml) was heated in a bomb for 4 h at 115-120°C. The reaction product was
evaporated and the residue was triturated with heptane to give the compound 9b or 10b.
General Method for the Preparation of Compounds 9a, 10a. Mixture of lactim ether 1 or 6 (5 ml)
and saturated solution of ammonia in methanol (20 ml) was heated in a bomb for 6 h at 120-125°C. The reaction
product was evaporated and the residue was triturated with heptane to give the compound 9a or 10a. Compound
9a was additionally purified by reprecipitation with 2 N NaOH from an aqueous HCl solution.
N,N,N',N'-Bis(1,2,3,4-tetrahydroquinol-2-en)azine (15). Solution of compound 1 (0.95 g, 5.4 mmol)
in toluene (10 ml) was added dropwise to solution of hydrazine hydrate (6 ml) in toluene (10 ml) at 105°C. The
reaction product was refluxed for 1.25 h, cooled, and compound 15 was filtered off.
The work was carried out with the financial support of the Russian Fund for Basic Research (grant
No. 93-03-33066a).
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3.
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5.
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353