Synthesis of N-substituted pyrrolo[1,2-a][1,4]benzodiazepines

Full text of DOI:10.1007/s10593-009-0392-6

Chemistry of Heterocyclic Compounds, Vol. 45, No. 9, 2009
SYNTHESIS OF N-SUBSTITUTED
PYRROLO[1,2-a][1,4]BENZODIAZEPINES
T. A. Stroganova1* and I. V. Malikov1
Keywords: pyrrolo[1,2-a]benzodiazepine, N-furfurylanthranilamides, furan ring recyclization.
In the framework of our study on the use of furan-containing substrates in the synthesis of condensed
heterocyclic systems, we continued our investigation of the transformations of N-furfurylanthranilamides in acid
media. In an attempt to effect the recyclization of tertiary N-furfurylanthranilamides and 3-aminothieno-
[2,3-b]pyridienecarboxamides by the action of a mixture of glacial acetic acid and hydrochloric acid, we found
that the furfuryl fragment is lost rather than opening of the furan ring [1].
In the present communication, we show that the major reaction pathway upon treatment of amides 1
with ethanolic HCl is recyclization of the furan ring to form the pyrrolo[1,2-a]diazepine system.
Me
NH2
Me
R1
N
R
R
R
R
O
HCl/EtOH
N
N
O
O
R1
1a–d
2a–d
1, 2 a R= H, R1 = Br; b–d R = МеO, b R1 = Br; c R1 = Ме; d R1 = H
This reaction was carried out upon heating aminoamides 1 in an ethanolic solution of gaseous hydrogen
chloride. The yields of N-substituted benzodiazepines 2a-d were 52-62%.
1
The H NMR spectra were taken on a Bruker DRX-500 spectrometer at 500 MHz for compounds 2a-c
and a Bruker AM-300 spectrometer at 300 MHz for compound 2d in DMSO-d6 with TMS as the internal
standard. The electron impact mass spectra were taken on a MAT-112 mass spectrometer with direct inlet into
the ion source. The ionizing energy was 70 eV.
Synthesis of Compounds 1a-d (General Method). Solution of gaseous hydrogen chloride in ethanol
(20 ml) was added to a solution of aminoamide 1a-d (0.5 mmol) in ethanol (20 ml) and the mixture obtained
was maintained at 55-60°C until the starting reagent was entirely consumed as indicated by thin-layer
_______
* To whom correspondence should be addressed, e-mail: tatka_s@mail.ru.
1Kuban State University of Technology, Krasnodar 350072, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1431-1433, September, 2009.
Original article submitted June 17, 2009.
0009-3122/09/4509-1149©2009 Springer Science+Business Media, Inc.
1149

chromatographic monitoring. The reaction mixture was poured into 100 ml ice water, neutralized by adding dry
sodium carbonate to pH ~7, and extracted with ethyl acetate. The extract was dried over anhydrous sodium
sulfate and evaporated to dryness in vacuum. The residue was separated by column chromatography using
methylene chloride as the eluent for 2a and 5.0:7.5 CCl4-acetone as the eluent for 2c. Product 2b was
recrystallized with silica gel from a mixture of ethyl acetate and petroleum ether. Product 2d was recrystallized
with silica gel from a mixture of acetone and petroleum ether.
5-(4-Bromophenyl)-1-methyl-4,5-dihydro-6H-pyrrolo[1,2-a][1,4]benzodiazepin-6-one (2a) was
obtained in 54% yield as a white powder; mp 159-161°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.22 (3H, s, CH3);
4.58 (2H, s, CH2N); 6.06 (1H, d, J = 3.2, H pyrrole); 6.15 (1H, d, J = 3.2, H pyrrole); 7.28 (2H, d, J = 8.7,
H arom.); 7.47-7.53 (1H, m, H arom.); 7.61 (2H, d, J = 8.7, H arom.); 7.66-7.72 (3H, m, H arom.); 7.87 (1H, d,
J = 7.8, H arom.). Mass spectrum, m/z (Irel, %): 367 [M]+ (9), 366 (38), 354 (16), 353 (53), 352 (19), 351 (55),
196 (25), 184 (18), 183 (100), 182 (24), 169 (20), 168 (44), 167 (23), 155 (14), 154 (58), 127 (12), 107 (11), 101
(11), 76 (14), 65 (20), 59 (41), 58 (16), 57 (10), 52 (16), 51 (17), 43 (58), 42 (29). Found, %: C 62.18; H 4.03;
N 7.70. C19H15BrN2O. Calculated, %: C 62.14; H 4.12; N 7.63.
5-(4-Bromophenyl)-8,9-dimethoxy-1-methyl-4,5-dihydro-6H-pyrrolo[1,2-a][1,4]benzodiazepin-
6-one (2b) was obtained in 60% yield as beige crystals; mp 177-179°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.24
(3H, s, CH3); 3.85 (3H, s, OCH3); 3.89 (3H, s, OCH3); 4.54 (1H, d, J = 15.9, CH2N); 4.61 (1H, d, J = 15.9,
CH2N); 6.04 (1H, d, J = 3.3, H pyrrole); 6.11 (1H, d, J = 3.3, H pyrrole); 7.00 (1H, s, H arom.); 7.26 (2H, d,
J = 8.7, H arom.); 7.33 (1H, s, H arom.); 7.60 (2H, d, J = 8.7, H arom.). Mass spectrum, m/z (Irel, %): 427
[M]+ (7), 426 (34), 414 (18), 413 (96), 412 (17), 411 (100), 256 (27), 244 (10), 243 (68), 240 (11), 228 (26), 214
(11), 200 (16), 174 (12), 154 (13), 101 (10), 82 (11), 76 (17), 59 (32), 58 (19), 57 (19), 55 (11), 43 (34). Found,
%: C 59.12; H 4.39; N 6.54. C21H19BrN2O3. Calculated, %: C 59.03; H 4.48; N 6.56.
8,9-Dimethoxy-1-methyl-5-(4-methylphenyl)-4,5-dihydro-6H-pyrrolo[1,2-a][1,4]benzodiazepin-6-one
1
(2c) was obtained in 62% yield as white crystals; mp 167-169°C. H NMR spectrum, δ, ppm (J, Hz): 2.31 (3H,
s, CH3); 2.37 (3H, s, CH3); 3.85 (3H, s, OCH3); 3.89 (3H, s, OCH3); 4.45 (1H, d, J = 15.7, CH2N); 4.59 (1H, d,
J = 15.7, CH2N); 6.03 (1H, d, J = 3.2, H pyrrole); 6.11 (1H, d, J = 3.2, H pyrrole); 7.00 (1H, s, H arom.); 7.17
(2H, d, J = 8.2, H arom).; 7.20 (2H, d, J = 8.2, H arom.); 7.33 (1H, s, H arom.). Mass spectrum, m/z (Irel, %): 362
[M]+ (44), 348 (24), 347 (100), 256 (25), 243 (24), 228 (31), 101 (13), 59 (25), 57 (13), 43 (33), 42 (23). Found,
%: C 73.00; H 6.19; N 7.76. C22H22N2O3. Calculated, %: C 72.91; H 6.12; N 7.73.
8,9-Dimethoxy-1-methyl-5-phenyl-4,5-dihydro-6H-pyrrolo[1,2-a][1,4]benzodiazepin-6-one (2d) was
1
obtained in 53% yield as a beige powder; mp >130°C (dec.). H NMR spectrum, δ, ppm (J, Hz): 2.32 (3H, s,
CH3); 3.86 (3H, s, OCH3); 3.90 (3H, s, OCH3); 4.50 (1H, d, J = 15.7, CH2N); 4.63 (1H, d, J = 15.7, CH2N); 6.03
(1H, d, J = 3.2, H pyrrole); 6.11 (1H, d, J = 3.2, H pyrrole); 6.99 (1H, s, H arom.); 7.19-7.46 (6H, m, H arom.).
Mass spectrum, m/z (Irel, %): 348 [M]+ (51), 334 (20), 333 (100), 280 (13), 308 (12), 266 (14), 256 (15), 244
(11), 243 (14), 241 (14), 240 (12), 228 (11), 200 (13), 198 (12), 186 (10), 183 (11), 170 (16), 154 (13), 101 (17),
93 (12), 76 (41), 69 (17), 60 (20), 59 (40), 57 (34), 55 (22), 53 (18), 44 (22), 41 (61). Found, %: C 72.49;
H 5.70; N 8.10. C21H20N2O3. Calculated, %: C 72.40; H 5.79; N 8.04.
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T. A. Stroganova, V. K. Vasilin, E. A. Zelenskaya, V. M. Red'kin, and G. D. Krapivin, Synthesis, 19,
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