Interaction of derivatives of 7-amino-1,5-benzo-diazepin-2-ones with α,β-unsaturated ketones

Article abstract of DOI:10.1007/s10593-010-0614-y

Derivatives of new condensed heterosystems, the tetracyclic [1,4]diazepino[3,2,1-hi]pyrido-[4,3,2-cd]indoles and tricyclic [1,4]diazepino[2,3-g]- and -[2,3-f]quinolines have been synthesized by the interaction of 7-amino-4-phenyl(or methyl)-1,3,4,5-tetrah

Full text of DOI:10.1007/s10593-010-0614-y

Chemistry of Heterocyclic Compounds, Vol. 46, No. 8, 2010
INTERACTION OF DERIVATIVES OF 7-AMINO-1,5-BENZO-
DIAZEPIN-2-ONES WITH α,β-UNSATURATED KETONES
R. Janciene1*, Z. Stumbreviciute1, A. Vektariene2, R. Sirutkaitis,
D. Podeniene1, A. Palaima1, and B. Puodziunaite1
Derivatives of new condensed heterosystems, the tetracyclic [1,4]diazepino[3,2,1-hi]pyrido-
[4,3,2-cd]indoles and tricyclic [1,4]diazepino[2,3-g]- and -[2,3-f]quinolines have been synthesized by the
interaction of 7-amino-4-phenyl(or methyl)-1,3,4,5-tetrahydro(or 1,3-dihydro)-2H-1,5-benzodiazepin-
2-ones with dimethyl 2-oxoglutaconate and methyl 4-oxo-2-pentenoate. The corresponding carboxylic
acids of the new derivatives were synthesized by alkaline hydrolysis of the methyl esters. The direction
of the cyclocondensation reaction was determined by both the structure of the diazepine ring of the
initial amines and also by the structure of the α,β-unsaturated ketones. Quantum-chemical calculations
have been carried out of the minimal values of the local energy of ionization and of the resonance
stabilization energy on specific atoms of the initial amines.
Keywords: 7-amino-1,5-diazepin-2-one, dimethyl 2-oxoglutaconate, methyl 4-oxopentenoate, local energy
of ionization, cyclocondensation, resonance stabilization energy.
Previously we investigated the interaction of 7-(or 8-, or 9-)amino-4-methyl-1-(or 5-)alkyl-substituted
tetrahydro-1,5-benzodiazepin-2-ones with dimethyl 2-oxoglutaconate with the aim of obtaining condensed
heterosystems containing a dicarboxy-substituted diazepinoquinoline fragment [1, 2]. It was established that the
direction of the cycloaddition reaction depends both on the position of the primary amino group in the benzene
ring of the benzodiazepinone, and on the presence of a substituent in positions 1 and 5 of the diazepine ring. It
was also shown that quantum-chemical calculations of the minimal values of the local ionization energy (Imin) on the
electron density surface of the molecules and the resonance stabilization energy of the initial amines fortunately
demonstrate the tendency of activation and deactivation of the benzene ring [2, 3]. The possibility of using quantum-
chemical calculations to determine the direction of ring formation of quinolines was followed in [4]. Continuing the
investigations of the synthesis of condensed systems of 1,5-benzodiazepinone, we considered in the present work the
direction of closure of the pyridine ring on interacting derivatives of 7-amino-4-phenyl(or methyl)-1,3,4,5-tetra-
hydro(or 1,3-dihydro)-2H-1,5-benzodiazepin-2-ones with α,β-unsaturated ketones under the conditions of the
modified Debner–Müller reaction.
_______
* To whom correspondence should be addressed, e-mail: r.janciene@bchi.lt.
1Institute of Biochemistry, Vilnius LT-08662, Lithuania.
2Institute of Theoretical Physics and Astronomy, Vilnius University, Vilnius LT-01108, Lithuania.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1235-1244, August, 2010.
Original article submitted December 14, 2009.
998
0009-3122/10/4608-0998©2010 Springer Science+Business Media, Inc.

Scheme 1
O
O
H
N
COOMe
O
H
N
O
OMe
+
OMe
O
N
N
MeOOC
N
Ph
N
H
Ph
(1a)
MeOOC
3
O
2
O
H
R1
N
N
O
COOH
N
O
H
N
N
N
Ph
H2N
N
HOOC
R2
N
H
HOOC
Ph
O
R3
O
4
R
OMe
5
Me
N
1a–c
Me
O
1
N
O
MeOOC
N
R2
3
R
6a–c
1, 6 a R1 = R3 = H, R2 = Ph; b R1 = H, R2 = R3 = Me; c R1 = R2 = Me, R3 = H
The cyclocondensation reaction of the appropriate amino components 1a-c (Scheme 1) and 7 (Scheme 2)
with an excess of dimethyl 2-oxoglutaconate or methyl 4-oxo-2-pentenoate was carried out in dichloromethane
solution at room temperature for 24 h with subsequent addition of 3 N HCl solution in glacial acetic acid to
dehydrate and aromatize the intermediate piperidinol derivative [5]. Thus on interacting 7-amino-4-phenyl-
benzodiazepinone 1a with dimethyl 2-oxoglutaconate two products were obtained, tetracyclic [1,4]di-
azepino[3,2,1-hi]pyrido[4,3,2-cd]indole 2 and tricyclic [1,4]diazepino[2,3-g]quinoline 3 (Scheme 1, Table 1).
TABLE 1. Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C (solvent)
Yield, %
21
С
Н
N
2
C21H15N3O4
C22H19N3O5
C20H13N3O4
C20H15N3O5
C21H19N3O3
C17H19N3O3
C17H19N3O3
C22H17N3O5
C21H21N3O4
67.47
67.56
65.25
65.18
66.53
66.85
63.37
63.66
69.87
69.79
65.30
65.16
65.02
65.16
65.64
65.50
4.17
4.05
4.87
4.72
3.47
3.65
4.19
4.01
5.23
5.30
6.17
6.11
6.08
6.11
4.21
4.25
11.10
11.25
10.19
10.37
11.83
11.69
11.01
11.14
11.51
11.63
13.33
13.41
13.49
13.41
10.29
10.42
339-341 (CHCl3)
3
149-151 (EtOAc–Et2O)
283 (decomp.) (H2O)
301-303 (H2O)
25
61
79
47
35
33
19
52
4
5
6a
6b
6c
8
268-270 (MeOH)
228-230 (EtOAc)
223-225 (Et2O)
310-312 (i-PrOH–t-BuMeO)
96-100* (i-PrOH–H2O)
10
66.59
66.48
5.51
5.58
11.26
11.08
_______
*Amorphous substance, no sharply expressed melting point.
999

TABLE 2. IR and 1H NMR Spectra of Compounds 1a, 2-5, 6a-c, 7-10
Com-
pound
IR spectrum,
1Н NMR spectrum, δ, ppm (J, Hz)
ν, cm-1
2
3239, 3175,
1727, 1675,
1651, 1632
3.36 (1H, dd, J = 2.8, J = 14.8, CH2); 3.50 (1H, dd, J = 5.5, J = 14.9, CH2);
4.01 (3H, s, OCH3); 5.94 (1H, dd, J =2.7, J = 5.6, CH);
7.22-7.38 (5H, m, H Ar); 7.59 (1H, d, J = 9.2, H-10);
7.97 (1H, d, J = 9.2, H-11); 8.52 (1H, s, H-3); 10.68 (1H, br. s, NH)
3
3319, 3196,
724, 1676
2.85 (1H, br. dd, CH2); 2.98 (1H, dd, J = 10.3, J = 13.7, CH2);
4.05 (3H, s, OCH3); 4.09 (3H, s, OCH3); 4.57 (1H, br. s, NH);
5.11 (1H, dd, J = 3.6, J = 10.3, CH); 7.30-7.42 (5H, m, H Ar);
7.74 (1H, s, H-6); 8.53 (1H, s, H-11); 8.55 (1H, s, H-9);
8.56 (1H, br. s, NH)
4
5
3263-2557,
1723, 1672,
1647, 1627
3.25-3.55 (2H, br. m, CH2); 5.94 (1H, br. dd, CH);
7.23-7.37 (5H, m, H Ar); 7.58 (1H, d, J = 9.1, H-10);
7.95 (1H, d, J = 9.1, H-11); 8.50 (1H, s, H-3); 10.68 (1H, br. s, NH)
3269-2544,
1690-1620
2.82 (2H, br. m, CH2); 5.07 (1H, br. m, CH); 6.93 (1H, br. s, NH);
7.31 (1H, br. m, H-4'); 7.39 (2H, br. m, H-3',5'); 7.48 (2H, br. m, H-2',6');
7.70 (1H, s, H-6); 8.24 (1H, s, H-11); 8.41 (1H, s, H-9);
10.29 (1H, br. s, NH)
6a
6b
6c
3359, 3180,
1702, 1678
2.71 (3H, d, J = 0.8, 10-CH3); 2.81 (1H, dd, J = 4.5, J = 13.7, CH2);
2.95 (1H, dd, J = 10.5, J = 13.4, CH2); 4.07 (3H, s, OCH3);
4.42 (1H, s, NH); 5.11 (1H, dd, J = 4.0, J = 10.3, CH);
7.31-7.43 (5H, m, H Ar); 7.59 (1H, s, H-11); 7.72 (1H, s, H-6);
7.92 (1H, q, J = 0.8, H-9); 8.84 (1H, br. s, NH)
3319, 3217,
1718, 1674
1.25 (3H, d, J = 6.1, 4-CH3); 2.39 (1H, dd, J = 9.4, J = 13.2, CH2);
2.65 (1H, ddd, J = 1.1, J = 5.2, J = 13.2, CH2); 2.72 (3H, d, J = 0.8, 10-CH3);
3.00 (3H, s, 5-CH3); 3.93 (1H, m, CH); 4.08 (3H, s, ОCH3);
7.54 (1H, s, H-11); 7.83 (1H, s, H-6); 7.96 (1H, q, J = 0.8, H-9);
8.48 (1H, br. s, NH)
3350, 1734,
1660
1.32 (3H, d, J = 6.2, 4-CH3); 2.35 (1H, dd, J = 8.0, J = 13.1, CH2);
2.63 (1H, dd, J = 5.2, J = 13.1, CH2); 2.73 (3H, d, J = 0.8, 10-CH3);
3.52 (3H, s, 5-CH3); 3.75 (1H, br. s, NH); 4.10 (1H, m, CH);
4.06 (3H, s, OCH3); 7.69 (1H, s, H-6); 7.70 (1H, s, H-11);
7.96 (1H, q, J = 0.8, H-9)
8
9
3312, 3260,
3193, 1738,
1698
3.58 (3H, s, OCH3); 3.75 (2H, br. s, CH2); 4.00 (3H, s, OCH3);
7.56-7.68 (3H, m, H Ar); 7.77 (1H, d, J = 9.2, H-6);
8.11-8.17 (2H, m, H Ar); 8.14 (1H, d, J = 9.1, H-7);
8.17 (1H, s, H-10); 11.22 (1H, br. s, NH)
3600-3000,
1732, 1673
2.52 (1H, dd, J = 4.7, J = 13.6, C(10)H2);
2.64 (1H, dd, J = 6.2, J = 13.7, C(10)H2);
3.54 (3H, s, OCH3); 3.70 (2H, br. s, C(3)H2); 3.76 (3H, s, OCH3);
4.21 (1H, dd, J = 4.8, J = 5.8, CH); 4.82 (1H, br. s, NH);
5.47 (1H, br. s, OH); 6.58 (1H, d, J = 8.8, H-7);
6.83 (1H, d, J = 8.8, H-6); 7.40-7.55 (3H, m, H Ar);
8.00-8.10 (2H, m, H Ar); 9.01 (1H, br. s, NHCO)
10
1a
3315, 3199,
1739, 1715,
1673
2.20 (3H, s, CH3); 3.00-3.14 (2H, m, CH2); 3.55 (2H, br. s, C(3')H2);
3.75 (3H, s, OCH3); 4.45 (1H, m, H-2); 4.59 (1H, br. s, 2-NH);
6.59 (1H, dd, J = 2.7, J = 8.7, H-8'); 6.70 (1H, d, J = 2.7, H-6');
6.93 (1H, d, J = 8.7, H-9'); 7.43-7.52 (3H, m, H Ar);
8.06-8.13 (2H, m, H Ar); 8.80 (1H, br. s, H-1')
3467, 3376,
3335, 3185,
1660
2.65 (1H, ddd, J = 1.2, J = 4.0, J = 13.2, CH2);
2.86 (1H, dd, J = 10.2, J = 13.2, CH2); 3.48 (1H, br. s, NH);
3.67 (2H, br. s, NH2); 4.98 (1H, dd, J = 4.0, J = 10.4, CH);
6.16 (1H, d, J = 2.4, H-6); 6.28 (1H, dd, J = 2.4, J = 8.3, H-8);
6.75 (1H, d, J = 8.3, H-9); 7.26-7.37 (5H, m, H Ar);
7.76 (1H, br. s, NHCO)
7
3.58 (2H, br. s, CH2); 3.75 (2H, br. s, NH2);
6.62 (1H, dd, J = 2.6, J = 8.5, H-8); 6.80 (1H, d, J = 2.6, H-6);
6.89 (1H, d, J = 8.5, H-9); 7.45-7.52 (3H, m, H Ar);
7.70 (1H, br. s, NHCO); 8.08-8.13 (2H, m, H Ar)
1000

The structures of compounds 2 and 3 were confirmed by 1H and 13C NMR spectra (Tables 2 and 3). In the
1H NMR spectrum of compound 3 three singlet signals were observed for the aromatic protons of the benzene and
pyridine rings, two singlets for the methoxycarbonyl groups at 4.05 and 4.09 ppm. The chemical shifts of the
protons of the diazepine hetero ring were changed insignificantly compared to the initial amine 1a. This shows the
linear structure of the condensed system. In the spectrum of compound 2 the two doublets observed at 7.59 and
7.97 and the singlet at 8.52 ppm in the aromatic region show the angular addition of the pyridine ring. In addition,
in the spectrum only one signal of metoxycarbonyl groups was obserwed, the signal for the amino group proton at
N(5) was absent, and the signal of the methine proton of the diazepine nucleus was displaced by 1 ppm towards
lower field in comparison with compound 3, which indicates the formation of the fourth ring. The 13C NMR spectra
confirm the structures of compounds 2 and 3.
The formation of compounds 2 and 3 indicates that the cyclocondensation occurs at positions 6 and 8 of
amine 1a similar. It should be mentioned that in the analogous interaction of 5-unsubstituted 7-amino-4-methyl-
benzodiazepines with glutaconate only one product is formed, the tetracyclic indole derivative [1, 2]. The
different direction of the reaction is seemingly caused by the influence of the 4-phenyl group of the initial amine
1a on the activity of positions 6 and 8 of the benzene ring. The activity in these positions of compound 1a is
demonstrated by calculations of the ionization energy Imin (Table 4). The close values of Imin (C(6) 366.42 and
C(8) 366.41 kcal/mol) indicates that the process of extracting an electron (ionization) occurs with the same
probability at atoms C(6) and C(8). For comparison values are given for Imin of amine 1c, which are cyclized
with glutaconate in position 6 of the benzene ring.
TABLE 3. 13C NMR Spectrum of Compounds 1a, 2-5, 6a-c, 8, and 10
Com-
pound
Chemical shifts, δ, ppm
2
43.14 (C-7); 51.77 (C-6); 52.86 (OCH3);
118.17, 121.00, 121.30, 123.75, 124.16, 125.52 (2C);
127.56, 127.99, 128.68 (2C); 133.13, 138.77, 141.47, 148.49, 163.08 (CO); 164.92 (CO);
170.35 (8-CO)
3
41.66 (C-3); 52.86 (OCH3); 53.28 (OCH3); 61.77 (C-4); 116.69 (C-11); 118.15 (C-6);
120.75 (C-9); 122.21, 125.81 (2C); 128.43, 129.17 (2C);
133.30, 134.10, 141.90, 143.69, 146.95, 147.69, 165.35 (CO); 166.02 (CO); 171.29 (2-CO)
4
43.15 (C-7); 51.75 (C-6); 118.10, 120.76, 121.08, 123.75, 124.09, 125.54 (2C);
127.55, 127.74, 128.69 (2C); 133.02, 138.82, 141.55, 150.80, 163.78 (CO); 166.05 (CO);
170.31 (8-CO)
5
42.02 (C-3); 59.91 (C-4);
115.74, 115.85, 118.77, 120.42, 126.33 (2C); 127.46, 128.48 (2C);
133.68, 135.24, 143.66, 144.29, 146.90, 146.93, 166.15 (CO); 167.37 (CO); 170.48 (2-CO)
6a
6b
6c
8
18.82 (10-CH3); 41.37 (C-3); 53.13 (OCH3); 62.49 (C-4); 115.26 (C-11); 119.08 (C-6);
120.31 (C-9); 125.25, 125.81 (2C); 128.35, 129.12 (2C);
131.76, 141.48, 143.99, 144.92, 146.31, 147.20, 166.15 (8-CO); 171.82 (2-CO)
16.75 (10-CH3); 18.78 (4-CH3); 39.36 (5-CH3); 40.04 (C-3); 53.17 (OCH3); 60.91 (C-4);
114.56 (C-11); 120.73 (C-9); 121.18 (C-6);
125.38, 134.96, 144.51, 144.78, 146.40, 146.98, 166.17 (8-CO); 172.81 (2-CO)
18.85 (10-CH3); 22.75 (4-CH3); 36.48 (1-CH3); 40.09 (C-3); 53.09 (OCH3); 55.66 (C-4);
115.88 (C-6); 120.60 (C-9); 120.69 (C-11);
125.83, 139.94, 142.06, 144.98, 145.98, 147.30, 166.07 (8-CO); 170.77 (2-CO)
C-3 is overlapped by the solvent signal; 52.46 (OCH3);
52.75 (OCH3); 120.03, 122.28, 126.80, 128.31 (2C); 128.46, 128.84 (2C);
129.04, 131.45, 131.73, 135.82, 139.83, 145.30, 146.32, 155.92, 164.47 (CO);
165.17 (CO); 168.06 (CO)
9
36.04, 40.16, 50.86, 52.32, 52.68, 71.58, 115.33, 116.45, 121.17, 123.06, 127.80 (2C);
128.73 (2C); 131.29, 136.88, 137.82, 140.94, 158.76, 166.50, 173.13, 176.19
10
36.04 (CH3); 39.88 (C-3'); 45.41 (C-3); 52.60 (CH3O); 52.66 (C-2); 110.14 (C-6');
113.91 (C-8'); 121.25, 122.92 (C-9'); 127.66 (C-2'',6''); 128.61 (C-3'',5''); 130.85 (C-4'');
137.74 (C-1''); 140.99, 143.79, 158.82, 167.16 (CO); 173.00 (CO); 205.85 (CO)
1a
41.41 (CH2); 63.37 (CH); 106.98, 108.62, 119.49, 123.69, 125.94 (2C);
128.01, 128.92 (2C); 139.43, 144.66, 144.90, 171.84
1001

TABLE 4. Values of Imin on the Carbon Atoms of the Benzene Ring and on
the Nitrogen Atom of the Primary Amino Group of Compounds 1a,c and 7
Imin, kcal/mol
Compound
C(6)
C(7)
C(8)
C(9)
N(7)
1a
1c
7
366.42
358.28
365.27
401.71
399.40
401.71
366.41
380.49
369.42
398.10
381.64
377.49
366.88
358.58
382.10
Compounds containing the 2,4-dicarboxypyridine fragment are substances imitating the structure of
glutamic acid. Similar compounds were studied as inhibitors of L-glutamate transport in [6]. We carried out
alkaline hydrolysis of methyl esters 2 and 3. After stirring for 3 h at room temperature in aqueous methanolic
solution in the presence of 1 N NaOH the corresponding acids 4 and 5 were isolated. The obtained compounds
were brightly colored crystalline substances.
By reacting 7-amino-4-phenyl(or methyl)benzodiazepinones 1a-c with methyl 4-oxo-2-pentenoate only
10-methyl-substituted [1,4]diazepino[2,3-g]quinolines 6a-c were synthesized, i.e. cyclization occurs at position
8 of the benzene ring of the initial amines. In the interaction of amine 1c with glutaconate, cyclization occurred
at position 6 of the benzene ring [2]. The change of direction of the reaction is probably linked with the spatial
effect of the methyl group. The Taft's constants of the methyl and carboxyl groups [7] indicate that the methyl
group has a more expressed steric action on the course of the reaction than the carboxyl group. Consequently in
the interaction of amines 1a and 1c with methyl 4-oxo-2-pentenoate the methyl group next to the cyclizaton
reaction center shows a more expressed steric hindrance to the course of the reaction at position 6 of the benzene
ring in comparison with the effect of the carboxyl grouping in the interaction of amines 1a and 1c with
glutaconate. It is evident that in the present case the decisive effect on the course of cyclization proved to be the
resonance stabilization energy and not the ability of the initial amines to ionize (delivery of an electron). The
stabilization energy of amine 1c at C(8) is greater by 5 kcal/mol than the stabilization energy at C(6) (238.63
and 233.21 kcal/mol respectively), consequently cyclization occurs preferentially at position 8 of amine 1c with
the formation of the energetically more favored structure 6c. The difference in the stabilization energy of amine
1a at atoms C(6) and C(8) is less (C(6) 235.33 and C(8) 237.21 kcal/mol), but the tendency of the energy
advantage towards cyclization at position 8 with the formation of 6a is retained.
Scheme 2
O
O
OMe
O
H
N
O
H
N
OMe
O
+
N
N
HN
N
Ph
Ph
O
H
N
COOMe
COOMe
MeOOC
MeOOC
OH
8
9
TosOH, 
H2N
N
Ph
7
O
9'
H
N
O
8'
OMe
Me
3'
O
2''
HN
N
6'
COOMe
2
3
4''
O
Me
10
1002

1
The H NMR spectra indicate a linear coupling of rings in compounds 6a-c, in which two separate
signals are displayed for the protons of the benzene ring and a quartet is displayed for the proton at atom C(9) of
the pyridine ring (J = 0.8 Hz). The position of the methyl group in the pyridine ring of compounds 6a-c is
unequivocally established by the NOE method, and further confirms that the first step of the cyclocondensation
reaction is the nucleophilic addition of the primary amino group to the β-carbon of the unsaturated ketone.
The condensation of 7-amino-4-phenyl-1,3-dihydro-2H-1,5-benzodiazepin-2-one (7) with α,β-unsaturated
ketones (Scheme 2) proceeds in an unusual way. Two compounds were obtained by the interaction of
1,5-benzodiazepin-2-one 7 with glutaconate, viz. [1,4]diazepino[2,3-f]quinoline 8 and piperidinol derivative 9
(yields of 19 and 31% respectively).
The cycloaddition therefore occurs at position 6 of the benzene ring of amine 7, which agrees with the
value of Imin at the C(6) and C(8) atoms of compound 7. Under the reaction conditions dehydration of product 9
does not occur completely. The formation of the piperidinol derivative is described in [5]. The presence in the
1H NMR spectrum of compound 9 of two doublet signals at 6.58 and 6.83 ppm confirmed the angular
cycloaddition. Signals were also observed for the protons of the ABX system of the CH2CH fragment, for the
amino group proton N(8)–H at 4.82 ppm, two methyl singlets (3.54 and 3.76 ppm), and a broadened singlet for
the OH proton at 5.47 ppm, indicating the formation of the piperidine ring. In addition derivative 8 was
synthesized by boiling compound 9 in dichloromethane solution in the presence of p-toluenesulfonic acid. In the
reaction of amine 7 with pentenoate no cyclic derivative was formed but the product 10 was practically
exclusively that of addition of unsaturated ketone to the primary amino group. On chromatography of the
reaction mixture no cyclization products were detected. In favor of the formation of methyl pentenoate 10 are
1
the position of the signals in the H NMR spectrum and the multiplicity of the diazepine and benzene protons
were changed insignificantly in comparison with the initial amine 7*. Also observed were the signals of the
ABX protons of the CH2CH fragment, two singlet signals at 2.20 and 3.75 ppm belonging to the COMe and
COOMe groups respectively, and in place of the signal of the NH2 protons a broadened signal appeared for the
NH group at 4.59 ppm. The data of the IR and 13C NMR spectra were not at variance with the proposed formula.
The initial amine 1a was synthesized by the hydrogenation of 7-nitro-4-phenyl-1,3-dihydro-2H-1,5-
benzodiazepin-2-one over 10% Pd/C. Syntheses of the dihydronitro derivative and amine 7 are described in [8].
Amines 1b,c were obtained according to [2].
EXPERIMENTAL
The IR spectra (KBr disks) were recorded on a Perkin-Elmer Spectrum GXFT-IR spectrometer. The 1H
and C NMR spectra were obtained on a Varian Unity Inova 300 spectrometer (300 and 75 MHz respectively)
13
in CDCl3 (compounds 1a, 3a, 6a-c, 7, 9, 10) and in DMSO-d6 (compounds 2, 4, 5, 8). Assignment of signals in
1
the H NMR spectra was based on their integral intensities, multiplicity, and size of chemical shifts using NOE
13
and COSY methods, and also APT and HETCOR for C NMR spectra. Chemical shifts were referred to TMS
(δ1(H) = 0 ppm) and to the solvent signal for CDCl3 (δ(13C) = 77.0 ppm) and DMSO-d6 (δ(13C) = 39.5 ppm). The
melting points of the synthesized compounds were determined in capillaries on a MEL-TEMP 1202D instrument
and are not corrected. A check on the progress of reactions and the purity of the obtained compounds was
effected by TLC on Silicagel 60F TLC plates (Merck), eluent was chloroform–ethyl acetate–methanol, 14:7:1,
developing with a UV detector. Silica gel L5/40 μm (Chemapol) was used for column chromatography in the
system dichloroethane–ethyl acetate with a gradient from 10:0 to 10:5 [9].
_______
*The 1H NMR spectrum of compound 7 is given in Table 2 since no spectral data were given in [8].
1003

Quantum-chemical calculations were carried out using the B3LYP functional and 6-31G* basis with
complete optimization of the geometric structures with SPARTAN 06 programs [11]. Values of the local
ionization energy Imin obtained on the molecular electron density surface, were equal to 0.025 electron/Bohr
radius3.
Dimethyl 2-oxoglutaconate was synthesized from 2-oxoglutaric acid according to [6], methyl 4-oxo-
2-pentenoate was synthesized analogously from 3-bromolevulinic acid methyl ester [10].
Methyl Ester of 4,8-Dioxo-6-phenyl-6,7,8,9-tetrahydro-4H-[1,4]diazepino[3,2,1-hi]pyrido[4,3,2-cd]-
indole-2-carboxylic Acid (2) and Dimethyl Ester of 2-Oxo-4-phenyl-2,3,4,5-tetrahydro-1H-[1,4]-
diazepino[2,3-g]quinoline-8,10-dicarboxylic Acid (3). A solution of aminobenzodiazepinone 1a (1.27 g,
5.0 mmol) and dimethyl 2-oxoglutaconate (1.28 g, 7.5 mmol) in absolute dichloromethane (300 ml) was stirred
at room temperature for 24 h. A 3 N solution of hydrochloric acid in glacial acetic acid (4 ml, 12.0 mmol) was
added and the mixture stirred a further 24 h at room temperature. Saturated aqueous NaHCO3 solution was
added to the reaction mixture to pH 7 in the aqueous layer. After separating, the organic layer was washed with
water, dried over MgSO4, and evaporated. The residue was chromatographed, collecting fractions with Rf 0.50
(2) and 0.68 (3), evaporated, and recrystallized. Compound 2 (0.4 g), sandy-colored crystals, and compound 3
(0.5 g), orange crystals were obtained.
Methyl Esters of 1-R1-4-R2-5-R3-10-methyl-2-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[2,3-g]-
quinoline-8-carboxylic Acids 6a-c were obtained analogously from the appropriate aminobenzodiazepinones
1a-c (5 mmol) and methyl 4-oxo-2-pentenoate (0.96 g, 7.5 mmol). After evaporating the organic phase the solid
residue was recrystallized. Compound 6a (0.95 g), compound 6b (0.62 g), and compound 6c (0.60 g) were
obtained as yellow crystals.
Dimethyl Ester of 4-Oxo-2-phenyl-4,5-dihydro-3H-[1,4]diazepino[2,3-f]quinoline-9,11-dicarboxylic
Acid (8) and Dimethyl Ester of 11-Hydroxy-4-oxo-2-phenyl-4,5,8,9,10,11-hexahydro-3H-[1,4]diazepino-
[2,3-f]quinoline-9,11-dicarboxylic Acid (9) were obtained analogously from dihydrobenzodiaze-pinone 7
(1.26 g, 5.0 mmol) and dimethyl 2-oxoglutaconate (1.28 g, 7.5 mmol) in a mixture (400 ml) of absolute
dichloromethane–THF, 1:1. The solvent was evaporated, the residue suspended in chloroform, and compounds 8
and 9 isolated as described for compounds 2 and 3. Compound 8 (Rf 0.52) (0.4 g) was obtained as yellow
crystals. Hexane was added to the residue of fractions with Rf 0.38, the solid filtered off, and compound 9
(0.65 g, 31%) was isolated as sandy-colored crystals, mp 108oC (decomp.). The substance was unstable and was
not purified by crystallization.
Methyl Ester of 4-Oxo-2-[(2-oxo-4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-7-yl)amino]pentanoic
Acid (10) was obtained from dihydrobenzodiazepinone 7 (1.26 g, 5.0 mmol) and methyl 4-oxo-2-pentenoate
(0.96 g, 7.5 mmol) analogously to that described for compounds 8 and 9. Compound 10 (1.4 g) (Rf 0.37) was
obtained.
Preparation of Compound 8 by Dehydration of Compound 9. A solution of compound 9 (0.5 g,
1.2 mmol) and p-toluenesulfonic acid (0.21 g, 1.2 mmol) in abs. CH2Cl2 (100 ml) was boiled for 3 h. The
reaction mixture was cooled, and saturated aqueous NaHCO3 solution was added to pH 7 in the aqueous layer.
After separation the organic phase was washed with water, dried over MgSO4, and evaporated to dryness. The
obtained residue was wetted with t-BuOMe and filtered off. Compound 8 (0.2 g, 42%) was obtained, having mp
309-311oC. A test sample mixed with samples obtained by various methods gave no depression of melting point.
4,8-Dioxo-6-phenyl-6,7,8,9-tetrahydro-4H-[1,4]diazepino[3,2,1-hi]pyrido[4,3,2-cd]indole-2-carboxylic
Acid (4). A 1 N solution of NaOH (10 ml) was added with stirring to a suspension of compound 2 (0.19 g,
0.5 mmol) in aqueous MeOH (1:1) (40 ml). The bright raspberry-colored solution obtained was stirred for 1 h at
room temperature, and solvent (about 20 ml) was evaporated in vacuum. The aqueous solution was extracted
with chloroform, and acidified with 1 N HCl solution. After cooling, the precipitated light–orange solid was
filtered off, and acid 4 (0.11 g) was obtained.
1004

2-Oxo-4-phenyl-2,3,4,5-tetrahydro-4H-[1,4]diazepino[2,3-g]quinoline-8,10-dicarboxylic Acid (5).
Compound 5 was obtained analogously as dark-cherry crystals from compound 3 (0.2 g, 0.5 mmol).
7-Amino-4-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one (1a). A suspension of 7-nitro-
4-phenyl-1,3-dihydro-2H-1,5-benzodiazepin-2-one [8] (5.62 g, 20.0 mmol) in MeOH (500 ml) was hydro-
genated in the presence of 10% Pd/C catalyst. After absorption of hydrogen (1.79 l, 80 mmol), the catalyst was
filtered off, the solvent evaporated, and the solid residue recrystallized from EtOAc–ether. Compound 7 (3.9 g,
77%) was obtained as light-gray crystals; mp 159-161oC. Found, %: C 71.30; H 5.89; N 16.71. C15H15N3O.
Calculated, %: C 71.13; H 5.97; N 16.59.
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