Novel strategy for the synthesis of the pyrrolo[3,4-d][1,2]diazepine heterocyclic system

Full text of DOI:10.1007/s10593-013-1204-6

Chemistry of Heterocyclic Compounds, Vol. 48, No. 11, February, 2013 (Russian Original Vol. 48, No. 11, November, 2012)
NOVEL STRATEGY FOR THE SYNTHESIS OF THE
PYRROLO[3,4-d][1,2]DIAZEPINE HETEROCYCLIC SYSTEM
O. I. Kharaneko1* and S. L. Bogza1
Keywords: hydrazine, pyrano[3,4-c]pyrrol-4(2H)-one, pyrrole, pyrrolo[3,4-d][1,2]diazepine, cyclization,
recyclization.
Pyrrolo[3,4-d][1,2]diazepines are heterocyclic analogs of the 2,3-benzodiazepine structure, but remain
rare and little studied to this time. Their synthesis consists of the stepwise addition of a tosylmethylisocyanide
dianion to 1,2-diazepines and has been reported only once [1]. At the same time, the interest in these compounds
is linked to the search for convenient methods of synthesis for heterocyclic analogs of tofisopam [2] and
talampanel [3], and to broadening of the range of lead compounds for design of medicinal compounds.
The aim of our work was the development of a simple method for preparing pyrrolo[3,4-d]-
[1,2]diazepines by the cyclization of pyrrole polycarbonyl compounds using hydrazine.
We developed a novel general method for the preparation of the 5,7-dihydropyrrolo[3,4-d]-
[1,2]diazepin-1(2H)-ones 3a,b by recylization of the pyrano[3,4-c]pyrrol-4(2H)-ones 2a,b using hydrazine. The
pyrano[3,4-c]pyrrol-4(2H)-ones 2a,b were formed in quantitative yields by fusing the pyrroles 1a,b in the
presence of catalytic amounts of toluenesulfonic acid. Pyrroles 1a,b were obtained by an addition reaction with
simultaneous cyclization using acetoacetate enamines and dibenzoylethylene [4].
3
N
Ph
6
Ph
5
O
2
HN
4
O
Ph
4
3
EtO
1
O
7
5
N2H4
p-TsOH
O
O
180°C
6
8
Ph
Me
N
R
Me
Ph
Me
Ph
1
7N
R
2N
R
1a,b
3a,b
2a,b
a R = H, b R = Me
The 1H NMR spectra of the obtained diazepinones 3a,b had characteristic signals for the NH protons at
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9.81-9.86 ppm and the CH2 protons at 3.69-3.96 ppm. The C NMR spectra showed the presence of carbonyl
carbon signals at 164.5-164.7 ppm and methylene group carbon signals at 26.2-26.5 ppm.
_______
*To whom correspondence should be addressed, e-mail: e-mail: kharaneko@ukr.net.
1L. M. Litvinenko Institute of Physical-Organic Chemistry and Coal Chemistry, National Academy of Sciences
of Ukraine, 70 R. Luxemburg St., Donetsk 83114, Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1849-1850, November, 2012.
Original article submitted May 27, 2012.
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0009-3122/13/4811-1734©2013 Springer Science+Business Media New York

Considering the availability of the starting reagents and the high yields of the final product, we propose
that this method can be used for the synthesis of 5,7-dihydropyrrolo[3,4-d][1,2]diazepin-1-ones.
1
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IR spectra were recorded on an IR-75 instrument for KBr pellets. The H and C NMR spectra were
recorded on a Bruker Avance II 400 instrument (400 and 100 MHz, respectively) using DMSO-d6 with HMDS
as internal standard. Elemental analysis was carried out on an Elementar Vario EL Cube. The melting points for
the synthesized compounds were determined on a Boetius hot stage apparatus, and were not corrected.
Pyrano[3,4-c]pyrrol-4(2H)-ones 2a,b (General Method). p-Toluenesulfonic acid (0.1 g, 0.6 mmol)
was added to a melt of the 3-ethoxycarbonyl-2-methyl-4-(2-oxo-2-phenylethyl)-5-phenyl-1H-pyrrole (1a) or the
3-ethoxycarbonyl-1,2-dimethyl-4-(2-oxo-2-phenylethyl)-5-phenyl-1H-pyrrole (1b) (5.0 g, 14.0 mmol) at
185°C. The mixture was maintained with stirring for 10 min, cooled to 80°C, and the solidified crystalline mass
was recrystallized from ethyl cellosolve.
3-Methyl-1,6-diphenylpyrano[3,4-c]pyrrol-4(2H)-one (2a). Yield 4.0 g (93%). Colorless, fine
crystals; mp 285-286°C. 1H NMR spectrum, , ppm (J, Hz): 12.10 (1H, s, NH); 7.83 (2H, d, J = 8.4, H Ph); 7.64
(2H, d, J = 8.4, H Ph); 7.43 (2H, t, J = 7.6, H Ph); 7.40 (2H, t, J = 7.6, H Ph); 7.31 (1H, t, J = 7.6, H Ph); 7.25
13
(1H, t, J = 7.6, H Ph); 7.16 (1H, s, H-7); 2.66 (3H, s, CH3). C NMR spectrum, , ppm: 165.6 (CO); 158.7;
149.8; 134.5; 133.2; 131.8; 128.5; 128.1; 127.9; 125.9; 125.5; 124.2; 122.9; 118.3; 96.7; 11.8. Found, %:
C 79.80; H 5.01; N 4.62. C20H15NO2. Calculated, %: C 79.72; H 5.02; N 4.65.
2,3-Dimethyl-1,6-diphenylpyrano[3,4-c]pyrrol-4(2H)-one (2b). Yield 3.4 g (78%). Colorless, fine
1
crystals; mp 218-219°C. H NMR spectrum, , ppm (J, Hz): 7.74 (2H, d, J = 7.6, H Ph); 7.52 (2H, t, J = 7.6,
H Ph); 7.48-7.33 (5H, m, H Ph); 7.33 (1H, t, J = 7.6, H Ph); 6.84 (1H, s, H-7); 3.64 (3H, s, NCH3); 2.69 (3H, s,
3-CH3). 13C NMR spectrum, , ppm: 165.9 (CO); 158.8; 149.7; 134.5; 133.0; 130.1; 129.4; 128.5; 128.1; 127.9;
127.3; 126.0; 124.0; 119.2; 95.8; 31.9; 11.0. Found, %: C 80.02; H 5.51; N 4.38. C21H17NO2. Calculated, %:
C 79.98; H 5.43; N 4.44.
5,7-Dihydropyrrolo[3,4-d][1,2]diazepin-1(2H)-ones (3a,b) (General Method). A mixture of
compound 2a,b (2 mmol), hydrazine hydrate (0.5 g, 10 mmol), and ethyl cellosolve (5 ml) was refluxed for 16 h.
The crystals precipitated were filtered off and washed with ethyl cellosolve.
8-Methyl-4,6-diphenyl-5,7-dihydropyrrolo[3,4-d][1,2]diazepin-1(2H)-one (3a). Yield 0.6 g (95%).
Colorless crystals; mp 233-234°C. IR spectrum, , cm-1: 3400 (NH), 1640 (C=O). 1H NMR spectrum, , ppm (J,
Hz): 11.40 (1H, s, 7-NH); 9.81 (1H, s, 2-NH); 7.60 (2H, dd, J = 7.2, J = 1.6, H Ph); 7.39 (4H, d, J = 4.4, H Ph);
7.33-7.22 (4H, m, H Ph); 3.96 (2H, s, 5-CH2); 2.48 (3H, s, CH3). 13C NMR spectrum, , ppm: 164.7 (CO);
158.1; 136.5; 134.3; 131.8; 129.0; 128.3; 128.0; 126.5; 126.2; 125.0; 123.8; 115.2; 113.6; 26.5 (CH2); 11.0.
Found, %: C 76.21; H 5.42; N 13.28. C20H17N3O. Calculated, %: C 76.17; H 5.43; N 13.32.
7,8-Dimethyl-4,6-diphenyl-5,7-dihydropyrrolo[3,4-d][1,2]diazepin-1(2H)-one (3b). Yield 0.5 g
1
(82%). Colorless crystals; mp 236-237°C. IR spectrum, , cm-1: 1640 (C=O). H NMR spectrum, , ppm (J,
Hz): 9.86 (1H, s, NH); 7.55-7.36 (5H, m, H Ph); 7.36-7.20 (5H, m, H Ph); 3.69 (2H, s, 5-CH2); 3.43 (3H, s,
NCH3); 2.53 (3H, s, 8-CH3). 13C NMR spectrum, , ppm: 164.5 (CO); 158.1; 138.4; 136.1; 134.0; 130.3; 130.0;
129.3; 128.2; 127.9; 127.4; 126.9; 126.1; 116.0; 112.5; 31.1; 26.2 (CH2); 10.6. Found, %: C 76.59; H 5.86;
N 12.64. C21H19N3O. Calculated, %: C 76.57; H 5.81; N 12.76.
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