10-Aryl-7,7-dimethyl-5,6,7,8,9,10-hexahydro-11H-pyrido[3,2-b][1,4] benzodiazepin-9-ones

Article abstract of DOI:10.1023/B:COHC.0000044580.94570.18

In reactions of 3-(2-amino-3-pyridyl)amino-5,5-dimethylcyclohex-2-en-1-one with aromatic aldehydes (2- and 4-hydroxy-, 2-hydroxy-3-methoxy-, 4-dimethylamino-, 4-methoxy-, 2,4- and 3,4-dimethoxy-, 3,4-methylenedioxy-, 4-bromo-, 4-fluoro-, 4-chloro-, 2-nitr

Full text of DOI:10.1023/B:COHC.0000044580.94570.18

Chemistry of Heterocyclic Compounds, Vol. 40, No. 7, 2004
10-ARYL-7,7-DIMETHYL-5,6,7,8,9,10-HEXAHYDRO-
11H-PYRIDO[3,2-b][1,4]BENZODIAZEPIN-9-ONES
N. N. Tonkikh, A. Strakovs, and M. V. Petrova
In reactions of 3-(2-amino-3-pyridyl)amino-5,5-dimethylcyclohex-2-en-1-one with aromatic aldehydes
(2- and 4-hydroxy-, 2-hydroxy-3-methoxy-, 4-dimethylamino-, 4-methoxy-, 2,4- and 3,4-dimethoxy-,
3,4-methylenedioxy-, 4-bromo-, 4-fluoro-, 4-chloro-, 2-nitro- and 3-nitrobenzaldehydes, furfural, and
2-thiophenecarbaldehyde), we have obtained the corresponding 10-aryl-7,7-dimethyl-5,6,7,8,9,10-
hexahydro-11H-pyrido[3,2-b][1,4]benzodiazepin-9-ones.
Keywords: aromatic aldehydes, 2,3-diaminopyridine, dimedone, pyrido[3,2-b][1,4]benzodiazepine
derivatives.
Our attempts to synthesize derivatives of hydrogenated pyrido[3,2-b][1,4]- or pyrido[2,3-b]-
[1,4]benzodiazepines by reactions of 2,3-diaminopyridine (1) with 2-formyldimedone [1] and
2-carbamidodimedone [2] did not lead to the indicated type of compounds.
In this paper, we describe the reactions of 3-(2-amino-3-pyridyl)amino-5,5-dimethylcyclohex-2-en-1-
one with aromatic aldehydes, which lead to synthesis of 10-aryl-7,7-dimethyl-5,6,7,8,9,10-hexahydro-11H-
pyrido[3,2-b][1,4]benzodiazepin-9-ones. Such a general scheme (reaction of enamines, obtained from
1,3-cyclohexanediones, and aromatic o-diamines with aldehydes) has been widely used for synthesis of
derivatives of dibenzodiazepine [3-7] and also pyridobenzodiazepine [8], among which the pyrido[2,3-b]-
[1,4]benzodiazepine derivatives have the most valuable pharmacological properties [9-11].
O
NH2
HO
NH2
NH2
+
N
N
H
N
O
1
3
2
H
H
N
N
ArCHO
5a–o
N
N
H
N
NH2
O
6a–o
Ar
O
4
5, 6 a Ar = 2-HOC6H4; b Ar = 4-НОC6H4; c Ar = 2-НО-3-MeOC6H3; d Ar = 4-Me2NC6H4;
e Ar = 4-MeOC6H4; f Ar = 2,4-(MeO)2C6H3; g Ar = 3,4-(MeO)2C6H3; h Ar = 3,4-CH2O2C6H3;
i Ar = 4-BrC6H4; j Ar = 4-ClC6H4; k Ar = 4-FC6H4; l Ar = 2-O2NC6H4; m Ar = 3-O2NC6H4;
n Ar = 2-C4H3O; o Ar = 2-C4H3S
__________________________________________________________________________________________
Riga Technical University, Riga LV-1048, Latvia; e-mail: marina@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 1095-1100, July, 2004. Original article submitted March 13, 2001;
revision submitted September 29, 2003.
944
0009-3122/04/4007-0944©2004 Springer Science+Business Media, Inc.

In the reaction of 2,3-diaminopyridine (1) with dimedone 2, two isomeric enamines 3 and 4 can be
formed. We know [8] that when diamine 1 reacts with 1,3-cyclohexanedione, the product of reaction at the
3-amino group is obtained. In the reaction under discussion of diamine 1 with dimedone, carried out under
conditions for azeotropic distillation of water, only one compound is isolated from the reaction mixture and
1
identified. Based on H NMR spectra, we have assigned this compound the structure of 3-(2-amino-3-pyridyl)-
amino-5,5-dimethylcyclohex-2-en-1-one (4). We identified enamine 4 by comparing its spectra with the
1H NMR spectra of 3-(2-amino-3-pyridyl)aminocyclohex-2-en-1-one [8]. The chemical shifts and spin–spin
coupling constants in the spectra of both these compounds virtually coincide: the differences between their
chemical shifts (∆δ) are 0.07 ppm for the NH2 group and 0.06 ppm for the =CH– group. The maximum chemical
shift difference is observed for the C(3)–H protons of the pyridine moiety of the molecule (∆δ = 0.12 ppm), where
the chemical shift values for the C(2)–H protons (∆δ = 0.05 ppm) and C(3)–H protons (∆δ = 0.03 ppm) are
3
virtually the same in both compounds, while the spin–spin coupling constants (3JHα,Hβ = 5 Hz, JHβ,Hγ = 7.5 Hz)
match within the experimental accuracy limits. In the spectra of both of the compared compounds, we observe a
strongly broadened signal from the NH proton relatively upfield at ~7.3 ppm. Chromatographic data for the
reaction mixture after isolation of enamine 4 suggest the presence of four more compounds in the mixture,
probably also including enamine 3, which unfortunately we could not isolate.
We carried out the reaction of enamine 4 with aldehydes 5a-d, containing the functional groups [OH,
N(CH3)2], by boiling equimolar amounts of the reagents in ethanol in the presence of piperidine acetate. We used
the same conditions in the reactions of enamine 4 with furfural 5n and 2-thiophenecarbaldehyde 5o. In the
TABLE 1. Characteristics of Synthesized Compounds
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
H
N
Hal (S)
4
C13H17N3O
C20H21N3O2
C20H21N3O2
C21H23N3O3
C22H26N4O
C21H23N3O2
C22H25N3O3
C22H25N3O3
C21H21N3O3
C20H20BrN3O
C20H20ClN3O
C20H20FN3O
C20H20N4O3
C20H20N4O3
C18H19N3O2
C18H19N3OS
67.30
67.50
71.44
71.62
71.50
71.62
69.19
69.02
66.81
66.98
72.01
72.18
69.42
69.63
69.50
69.63
69.21
69.40
60.11
60.31
67.71
67.89
71.01
71.20
65.70
65.92
65.77
65.92
69.65
69.88
66.26
66.43
7.49
7.41
6.16
6.31
6.33
6.31
6.16
6.34
6.49
6.64
6.69
6.63
6.60
6.64
6.73
6.64
5.70
5.83
5.01
5.06
5.56
5.70
6.04
5.98
5.50
5.53
5.39
5.53
6.03
6.19
5.80
5.88
18.10
18.17
12.60
12.53
12.42
12.53
11.42
11.50
14.14
14.20
11.91
12.03
11.11
11.07
10.93
11.07
11.60
11.56
10.66
10.55
11.72
11.88
12.33
12.45
15.27
15.38
15.19
15.38
13.42
13.58
12.73
12.91
223-224
252-253
291-292
243-244
252-253
197-198
213-215
126-127
233-234
237-239
249-251
237-238
196-197
179-181
244-245
271-272
26
82
70
47
70
38
43
60
66
62
38
73
73
77
74
83
6a
6b
6с
6d
6e
6f
6g
6h
6i
19.90
20.06
9.80
10.02
6j
6k
6l
6m
6n
6o
(9.60)
(9.85)
945

TABLE 2. IR and 1H NMR Spectra of Synthesized Compounds
IR spectrum,
Com-
pound
1Н NMR spectrum, δ, ppm. (SSCC, J, Hz)*
ν, cm-1
1
2
3
4
1666, 1595,
1.03 (6H, s, 2CH3); 2.18 (2H, s, CH2); 2.36 (2H, s, CH2);
1570, 550-1530; 4.71 (2H, br. s, NH2); 5.09 (1H, s, =CH-); 6.64 (1H, dd, 3J = 7.5,
3400, 3350,
3250-3100
4J = 5, С5Н3N); 7.30 (1H, br. s, NH); 7.38 (1H, dd, 3J = 7.5, 4J = 2,
С5Н3N); 7.87 (1H, dd, 3J = 5, 4J = 2, С5Н3N)
6a
1645;
3350-3250;
3200-3080
1.03 (3H, s, CH3); 1.14 (3H, s, CH3); 2.11 and 2.17 (2H, two d,
2J = 14, CH2); 2.69 (2H, s, CH2); 5.81 (1H, d, 3J = 6, CH);
6.00 (1H, d, 3J = 6, NH); 6.41-6.96 (6H, m, С6Н4, С5Н3N);
7.25 (1H, dd, 3J =7, 4J = 2, С5Н3N); 7.56 (1Н, dd, 3J = 5, 4J = 2,
C5H3N); 8.94 (1H, br. s, ОН); 9.76 (1Н, br. s, NH)
6b
6c
1642;
3450-3200;
3150-3050
0.95 (3H, s, CH3); 1.14 (3H, s, CH3); 2.12 and 2.20 (2H, two d,
2J = 14, CH2); 2.55 (2H, s, CH2); 5.74 (1H, d, 3J = 6, CH);
6.49-7.72 (8H, m, С6Н4, С5Н3N, NH); 7.77 (1H, br. s, NН);
9.14 (1H, br. s, ОН)
1645;
3300-3200;
3150-3050
1.05 (3H, s, CH3); 1.12 (3H, s, CH3); 2.12 and 2.20 (2H, two d,
2J = 14, CH2); 2.67 (2H, s, CH2); 3.76 (3H, s, OCH3); 5.77 (1H, d,
3J = 6, NH); 6.05 (1Н, d, 3J = 6, СН); 6.25-6.81 (4H, m, С6Н3,
С5Н3N); 7.34 (1H, dd, 3J = 7, 4J = 1.5, С5Н3N); 7.58 (1H, dd, 3J = 7,
4J = 1.5, С5Н3N); 8.96 (1Н, br. s, NH); 9.03 (1H, br. s, OH)
6d
6e
6f
1638; 3300,
1.01 (3H, s, CH3); 1.12 (3H, s, CH3); 2.15 and 2.21 (2H, two d,
3200; 3150-3050 2J = 16, CH2); 2.54 (2H, s, CH2); 2.81 (6H, s, NCH3); 5.77 (1H, d,
3J = 6, СH); 6.46-6.78 (4H, m, С6Н4, С5Н3N, NH); 7.03 (2H, m,
3J = 8, С6Н4); 7.27 (1Н, dd, 3J = 7, 4J = 1.5, С5Н3N); 7.65 (1H, dd,
3J = 5, 4J = 1.5, С5Н3N); 7.78 (1Н, br. s, NH)
1640; 3300,
3200-3100
1.01 (3H, s, CH3); 1.12 (3H, s, CH3); 2.13 and 2.21 (2H, two d,
2J = 14, CH2); 2.58 (2H, s, CH2); 3.67 (3H, s, OCH3); 5.76 (1H, d,
3J = 6, СH); 6.58-7.27 (6H, m, С6Н4, С5Н3N, NH); 7.27 (1Н, dd,
3J = 7, 4J = 1.5, С5Н3N); 7.63 (1H, dd, 3J = 5, 4J = 1.5, С5Н3N);
7.87 (1Н, br. s, NH)
1645;3350,
3250-3100
1.01 (3H, s, CH3); 1.09 (3H, s, CH3); 2.14 and 2.22 (2H, two d,
2J = 15, CH2); 2.56 (2H, s, CH2); 3.58 (3H, s, OCH3); 3.65 (3Н, s,
ОСН3); 5.76 (1H, d, 3J = 6, =СH-); 6.54 (5H, m, С6Н3, С5Н3N, NH);
7.25 (1Н, dd, 3J = 7, 4J = 1.5, С5Н3N); 7.63 (1H, dd, 3J = 5, 4J = 1.5,
С5Н3N); 8.81 (1Н, br. s, NH)
6g
6h
6i
1644; 3350,
1.03 (3H, s, CH3); 1.12 (3H, s, CH3); 2.12 and 2.20 (2H, two d,
3260, 3200-3100 2J = 15, CH2); 2.63 (2H, s, CH2); 3.67 (3H, s, OCH3); 3.91 (3Н, s,
OСН3); 5.72 (1H, d, 3J = 6, NH); 5.83 (1H, d, 3J = 6, СН);
6.21-6.75 (4H, m, С6Н3, С5Н3N); 7.27 (1H, m, 3J = 8, С6Н3);
7.58 (1Н, dd, 3J = 5, 4J = 1, С5Н3N); 8.92 (1Н, br. s, NH)
1638; 3300,
3200-3050
1.01 (3H, s, CH3); 1.12 (3H, s, CH3); 2.15 and 2.21 (2H, two d,
2J = 16, CH2); 2.58 (2H, s, CH2); 5.74 (1H, d, 3J = 6, СH);
5.94 (2Н, s, СН2); 6.58-6.82 (5H, m, С6Н3, С5Н3N, NH);
7.27 (1H, dd, 3J = 7, 4J = 1.5, С5Н3N); 7.67 (1Н, dd, 3J = 5, 4J = 1.5,
С5Н3N); 8.85 (1Н, br. s, NH)
1638; 3300,
3200-3050
0.98 (3H, s, CH3); 1.09 (3H, s, CH3); 2.12 and 2.20 (2H, two d,
2J = 14, CH2); 2.56 (2H, s, CH2); 5.78 (1H, d, 3J = 6, СH);
6.67 (1Н, dd, 3J = 7, 3J = 5, С5Н3N); 6.87 (1H, d, 3J = 6, NH);
7.04-7.45 (5H, m, С6Н4, С5Н3N, NH); 7.67 (1H, dd, 3J = 5, 4J = 2,
С5Н3N); 8.89 (1Н, br. s, NH)
6j
1638; 3300,
3240-3080
1.03 (3H, s, CH3); 1.09 (3H, s, CH3); 2.14 and 2.22 (2H, two d,
2J = 15, CH2); 2.65 (2H, s, CH2); 5.83 (1H, d, 3J = 6, СH); 6.62 (1Н,
dd, 3J = 7, 3J = 5, С5Н3N); 6.85 (1H, d, 3J = 6, NH); 7.18-7.34 (5H, m,
С6Н4, С5Н3N); 7.69 (1H, dd, 3J = 5, 4J = 1.5, С5Н3N); 8.92 (1Н, br. s,
NH)
6k
1645; 3300,
3250-3100
1.01 (3H, s, CH3); 1.11 (3H, s, CH3); 2.14 and 2.22 (2H, two d,
2J = 14, CH2); 2.55 (2H, s, CH2); 5.83 (1H, d, 3J = 6, СH);
6.58-7.33 (7Н, m, С6Н4, С5Н3N, NH); 7.67 (1Н, dd, 3J = 5, 4J = 1.5,
С5Н3N); 8.89 (1Н, br. s, NH)
946

TABLE 2 (continued)
1
2
3
6l
1640; 3350,
3250-3100
0.98 (3H, s, CH3); 1.09 (3H, s, CH3); 2.06 and 2.14 (2H, two d,
2J = 14, CH2); 2.67 (2H, s, CH2); 5.78 (1H, d, 3J = 6, NH); 6.07 (1H, d,
3J = 6, СН); 6.78-8.06 (7Н, m, С6Н4, С5Н3N); 8.89 (1Н, br. s, NH)
6m
6n
1643; 3300,
3240-3080
1.01 (3H, s, CH3); 1.14 (3H, s, CH3); 2.21 and 2.29 (2H, two d,
2J = 15, CH2); 2.63 (2H, s, CH2); 6.09 (1H, br. s, СН); 6.89 (1Н, dd,
3J = 7, 3J = 5, С5Н3N); 7.49-8.12 (7Н, m, С6Н4, С5Н3N, NH);
9.25 (1Н, br. s, NH)
1635; 3320,
3200-3050
0.96 (3H, s, CH3); 1.07 (3H, s, CH3); 2.11 and 2.17 (2H, two d,
2J = 16, CH2); 2.51 (2H, s, CH2); 5.81 (1H, d, J = 6, CH);
5.82 (1Н, m, С4Н3O); 6.14 (1H, m, С4Н3O); 6.67 (2H, m, C5H3N, NH);
7.29-7.42 (2H, m, С4H3O, C5H3N); 7.72 (1Н, dd, 3J = 5,
4J = 1, C5H3N); 8.88 (1Н, br. s, NH)
6o
1637; 3350,
3220-3080
0.99 (3H, s, CH3); 1.05 (3H, s, CH3); 2.12 and 2.20 (2H, two d,
2J = 14, CH2); 2.55 (2H, s, CH2); 6.03 (1H, d, 3J = 6, CH);
6.58-6.92 (4Н, m, С5Н3N, C4H3S); 7.14-7.34 (2H, m, С5H3N, C4H3S);
7.69 (1H, dd, 3J = 5, 4J = 1.5, C5H3N); 8.89 (1Н, br. s, NH)
_______
* The 1H NMR spectrum of compound 4 was recorded in CDCl3; the spectra
for the rest of the compounds were recorded in DMSO-d6.
reactions with the aldehydes 5e-m, the best results were achieved by boiling in ethanol in the presence of
sulfuric acid.
1
In the H NMR spectra of the derivatives of pyridodiazepine 6, the proton at the C(10) atom is
characterized by a doublet δ 5.74-6.09 ppm (J = 6 Hz), and the proton at the adjacent N(11) atom gives a doublet
δ 5.72-6.87 ppm (J = 6 Hz). The protons of the methylene group at C(8) are magnetically nonequivalent and
coupled (geminal spin–spin coupling constant 14-16 Hz), representing an AB spin system.
In the IR spectra, the carbonyl group of compounds 6 is characterized by absorption bands in the interval
1645-1635 cm-1, while the stretching vibrations of the NH bonds are intense bands in the 3350-3100 cm-1 region.
EXPERIMENTAL
The IR spectra were taken on a Specord IR-75 for suspensions of the compounds in vaseline oil
(1800-1500 cm-1, only the absorption bands for the carbonyl group are given) and in hexachlorobutadiene (3600-
2000 cm-1, the stretching vibration bands for the C–H bonds in the 3050-2800 cm-1 region are not given). The
1H NMR spectra were measured on Bruker WH-90/DS (90 MHz) and Varian-BB Mercury (200 MHz)
spectrometers, internal standard HMDS (δ 0.055 ppm)
We used Fluka 2,3-diaminopyridine for synthesis of enamine 4.
3-(2-Amino-3-pyridyl)amino-5,5-dimethylcyclohex-2-en-1-one (4). A solution of dimedone (2.80 g,
20 mmol) and 2,3-diaminopyridine (2.18 g, 20 mmol) in toluene (100 ml) in the presence of a catalytic amount
of p-toluenesulfonic acid was boiled for 3 h with a Dean–Stark attachment. Then the toluene was distilled off
under vacuum and dry THF (30 ml) was added to the residue. The solution obtained was held for 24 hours in a
refrigerator; the precipitate was filtered out and recrystallized one more time from THF. Enamine 4 (1.20 g,
26%) was obtained.
10-(2-Hydroxyphenyl)- (6a), 10-(4-Hydroxyphenyl)- (6b), 10-(2-Hydroxy-3-methoxyphenyl)- (6c),
10-(4-Dimethylaminophenyl)- (6d), 10-(2-Furyl)- (6n), and 10-(2-Thiophenyl)- (6o) 7,7-dimethyl-
5,6,7,8,9,10-hexahydro-11H-pyrido[3,2-b][1,4]benzodiazepin-9-ones. A solution of enamine 4 (1.5 mmol),
947

the corresponding aldehyde 5 (1.5 mmol), glacial CH3COOH (0.15 ml), and piperidine (0.20 ml) in ethanol
(15 ml) was boiled for 3 h. The reaction mixture was poured into crushed ice to cool down. When a tarry residue
was formed, it was triturated until it solidified; the precipitate formed was filtered out, and the compounds
6a,c,d,n,o were recrystallized from ethanol and the diazepinone 6b was recrystallized from 2-propanol.
10-(4-Methoxyphenyl)- (6e), 10-(2,4-Dimethoxyphenyl)- (6f), 10-(3,4-Dimethoxyphenyl)- (6g),
10-(3,4-Methylenedioxyphenyl)-
(6h),
10-(4-Bromophenyl)-
(6i),
10-(4-Chlorophenyl)-
(6j),
10-(4-Fluorophenyl)- (6k), 10-(2-Nitrophenyl)- (6l), and 10-(3-Nitrophenyl)- (6m) 7,7-dimethyl-
5,6,7,8,9,10-hexahydro-11H-pyrido[3,2-b][1,4]benzodiazepin-9-ones. A solution of enamine 4 (1.5 mmol),
the corresponding aldehyde 5 (1.5 mmol), and conc. H2SO4 (0.15 ml) in ethanol (15 ml) was boiled for 3 h. Then
the solvent (7-10 ml) was distilled off under vacuum. The residue was poured into crushed ice and an aqueous
KOH solution was added until pH 7 was achieved; after 24 hours, the precipitate was filtered out and compounds
6e-g,j-m were recrystallized from 2-propanol, the diazepinone 6h was recrystallized from ethanol, and the
diazepinone 6i was recrystallized from dioxane.
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948