New strategy for the synthesis of tetrahydrobenzothieno-[1,2]diazepines

Full text of DOI:10.1007/s10593-007-0231-6

Chemistry of Heterocyclic Compounds, Vol. 43, No. 11, 2007
NEW STRATEGY FOR THE SYNTHESIS
OF TETRAHYDROBENZOTHIENO-
[1,2]DIAZEPINES
A. S. Tolkunov and S. L. Bogza
Keywords:
3-amino-2-(3-benzo[b]thienylmethyl)quinazolines-4(3H)-one,
tetrahydrobenzothieno-
[2',3':4,5][1,2]diazepino[7,1-b]quinazolin-9-one, Pictet-Spengler reaction, cyclization.
Derivatives of 2,3-benzodiazepine display considerable biological activity and are under extensive
investigation [1]. Condensed benzodiazepines are less available and the methods for their synthesis are based on
adding on a heterocycle to one of the edges of the benzodiazepine system [2] or expansion of the pyran ring in
heterofused isocoumarins [3].
The heterocyclic [5H]benzothieno[2,3-e]diazepine system was first prepared in the recyclization of
1,3-disubstituted benzothieno[2,3-c]pyrilium salts by hydrazine hydrate [4]. The reaction of 3-amino-
2-(5-methyl-3-benzo[b]thienylmethyl)quinazolin-4(3H)-one (1) with aromatic aldehydes under conditions of the
Pictet-Spengler reaction was used to obtain derivatives of a new heterocyclic system, namely, tetrahydro-
benzothieno[2',3':4,5][1,2]diazepinoquinazolines 2a,b. The yields of products 2a,b were 57-65%. The reaction
O
RCHO
N
NH2
N
Me
CF3COOH
N
O
N
NH
S
S
R
2a,b
CF3COOH
Me
1
N
Me
N
O
N
S
R
3a,b
2, 3 a R = 4-MeOC6H4, b R = 4-ClC6H4
__________________________________________________________________________________________
L. M. Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of
Ukraine, 83114 Donetsk; e-mail: s_tolkunov@yahoo.com. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 11, pp. 1740-1741, November, 2007. Original article submitted July 12, 2007.
0009-3122/07/4311-1485©2007 Springer Science+Business Media, Inc.
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proceeds through intermediate formation of Schiff bases 3, which was confirmed by the cyclization of
azomethine 3b to give benzothienoquinazolinodiazepine 2b under conditions of the basic reaction. The structure
1
1
of benzothienodiazepines 2a,b was demonstrated using H NMR spectroscopy. The H NMR spectra of 2a,b
have characteristic doublets for the CH2 group of the diazepine ring at 4.40-4.85 ppm with coupling constant
14-15 Hz, which indicates nonplanar structure of the diazepine ring.
The 1H NMR spectra were taken on a Varian Gemini 200 spectrometer at 200 MHz in DMSO-d6 at 50°C
with TMS as the internal standard.
General Procedure. A mixture of amine 1 (0.64 g, 2 mmol), an equivalent amount of an aromatic
aldehyde (or 2 mmol Schiff base 3a or 3b), and trifluoroacetic acid (4 ml) was heated at reflux for 5 h.
Trifluoroacetic acid was removed at reduced pressure and 10 ml 5% aqueous ammonia was added to the residue.
The crystals were filtered off, washed with water, and recrystallized from DMF–acetonitrile.
6-(4-Methoxyphenyl)-2-methyl-6,7,8,9-tetrahydrobenzothieno[2'3':4,5][1,2]diazepino[7,1-b]quin-
1
azolin-9-one (2a) was obtained in 57% yield; mp 219-220°C (DMF–acetonitrile). H NMR spectrum, δ, ppm
(J, Hz): 2.51 (3H, s, CH3); 3.78 (3H, s, OCH3); 4.39 (1H, d, J = 14.8, CH2); 4.85 (1H, d , J = 14.8, CH); 5.60
(1H, s, CH); 6.86-7.74 (6H, m, Harom); 7.61 (2H, d, J = 8.1, Harom-2',6' ), 7.75 (2h,d, J = 8.1, Harom-3',5'); 8.09 (1H,
d, J = 7.7, Harom-10). Found, %: C 71.05; H 4.82; N 9.56; S, 7.29. C26H21N3O2S. Calculated %: C 71.19; H 4.91;
N 9.42; S 7.12.
6-(4-Chlorophenyl)-2-methyl-6,7,8,15-tetrahydrobenzothieno[2',3':4,5][1,2]diazepino[7,1-b]quin-
azolin-9-one (2b) was obtained in 65% yield; mp 232°C (DMF–acetonitrile). 1H NMR spectrum, δ, ppm (J, Hz):
2.51 (3H, s, CH3); 4.42 (1H,d, J = 14.1, CH2); 4.85 (1H, d, J = 14.1, CH2); 5.73 (1H, s, CH); 7.15-7.79 (10H, m,
Harom); 8.10 (1H,d, J = 6.7, Harom10). Found, %: C 67.78; H 4.17; Cl 7.81; N 9.38; S 7.12. C25H18ClN3OS.
Calculated, %: C 67.64; H 4.09; Cl 7.99; N 9.46; S 7.22.
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