SYNTHESIS AND REACTIONS OF SOME NEW MORPHOLINYLPYRROLYL TETRAHYDROTHIENO[2,3-c] ISOQUINOLINE

Hydrazinolysis of ethyl-5-morpholin-4-yl-1-(1H-pyrrol-1-yl)-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-2-carboxylate afforded the corresponding carbohydrazide which upon condensation with aromatic aldehydes, acetyl acetone and/ or carbon disulfide gave Narylidinecarbohydrazide, dimethylpyrazolyl methanone, [1,3,4]oxadiazole-2-thiol and its ethyl ester derivatives respectively. Diazotization of the carbohydrazide with nitrous acid afforded the corresponding carboazide which was used for synthesis of carbamates and substituted carboxamides. Boiling of the carboazide in dry xylene afforded the pyrazinone compound which was used for synthesis of other heterocycles containing pyrrolopyrazinothinoisoquinoline moeity.


INTRODUCTION
Isoquinoline alkaloids are a large family of natural products and display a broad variety of biological activities. 1 among the members of this class of compounds, tetrahydroisoquinoline derivatives constitute a major group. Many of them exhibit important biological activities, for example, anti-inflammatory, anti-microbial, anti-leukemic, and anti-tumor properties.

RESULTS AND DISCUSSION
In continuation of our work about synthesis of heterocyclic compounds containing morpholinyl-tetrahydrothieno [2,3c]isoquinoline moiety as described in references 17-21 hoping these new compounds show biological activity. The authors incorporated pyrrolyl ring to the thienotetrahydroisoquinoline system through the reaction of ethyl-1-amino-5-morpholin-4yl- 6,7,8,9-tetrahydrothino [2,3-c]isoquinole-2-carboxylate 1 with 2,5-dimethoxytetrahydrofuran in glacial acetic acid to afford the corresponding pyrrolyl ester 2. The structure of compound 2 was established by IR, 1 H-NMR and mass spectra. IR spectrum showed disappearance of absorption bands characteristic for NH2 group and absorption band at 1720 cm -1 for ester group is still remaining. 1 H-NMR in CDCl3 of compound 2 showed singlet signal characteristic for pyrrolyl group at 6.30 and 6.70 ppm. Mass spectrum showed a peak at 411 as molecular ion peak and a base peak. Reaction of pyrrolyl ester 2 with hydrazine hydrate afforded the pyrrolyl carbohydrazide 3. The structure of 3 was elucidated by elemental and spectral analysis. IR spectrum showed absorption bands at 3400, 3500 and 3100 cm -1 characteristic for NH, NH2 groups and lowering the wave number of CO group in hydrazide from 1720 cm -1 in ester compound 2 to 1645 cm -1 in carbohydrazide 3. 1 H-NMR spectrum in DMSO-d6 showed signals at, 5.80 and 4.70 for NH2, NH groups respectively. Mass spectrum showed at peak at 397 as molecular ion peak.
The pyrrolyl carbohydrazide 3 was used as versatile precursor for synthesis of other hetero cyclic system. Thus, condensation of the carbohydrazide 3 with aromatic aldehydes namely benzaldhyde, p-anisaldehyde and/ or cinnamaldehyde afforded the corresponding Schiff's bases (imines) (4a-c). IR spectrum of 4a revealed disappearance of absorption bands characteristic for NH2 group in hydrazide 3.
1 H-NMR spectrum in DMSO-d6 showed multiplet signals at δ 7.30-7.70 characteristic for aromatic protons and at 7.85 for CH benzylidene (scheme 1). Condensation of carbohydrazide 3 with acetyl acetone afforded the dimethylpyrazolyl derivative 5. The structure of the latter compound was established by elemental and spectral analysis. IR spectrum showed disappearance of absorption bands characteristic for NH, NH2 group of carbohydrazide 3.
1 H-NMR in CDCl3 showed two singlet signals at δ 2.30 and 2.50 for two methyl groups of pyrazole and singlet signals at 5.95 ppm for CH pyrazole. Also reaction of compound 3 with carbon disulfide in dry pyridine gave the oxadiazole thione 6 which was alkylated using ethyl chloroacetate in presence of ethanol and fused sodium acetate to afford the ethyl sulfanyl acetate 7 (scheme 2). J u l y 3 1 , 2 0 1 4 The carboazide 8 undewent Curtius rearrangement upon boiling dry xylene to afford the corresponding pyrrolopyrazinothienoisoquinoline 11. The structure of the latter compound 11 was established by elemental and spectral analysis. IR spectrum revealed the disappearance of absorption band at 2150 cm -1 characteristic for azido group and appearance of absorption band at 3280 cm -1 for NH group. 1 H-NMR in CF3CO2D showed three singlet signals at δ 6.20, 6.50 and 7.00 ppm characteristic for the three CH pyrrolo groups.
Chlorination of the pyrazino compound 11 with phosphorus oxychloride under reflux gave the corresponding chloro derivative 12, which underwent nucleophilic substitution reactions with primary amines such as aniline and/or hydrazine hydrate to afford the corresponding phenyl amino 13 and hydrazino 14 respectively. The structure of compounds 13, 14 was proved by IR, 1 H-NMR spectra. IR spectrum of compound 13 showed absorption band at 3400 cm -1 for NH group. 1H-NMR spectrum in DMSO-d6 showed multiplet signals at δ 7.20-7.80 ppm characteristic for aromatic protons. While IR spectrum of hydrazine 14 showed absorption band at 3350, 3300 and 3250 for NH, NH2 groups. 1 H-NMR of compound 14 in CDCl3 showed singlet signals at δ 6.50 and δ 7.90 for NH2 and NH groups respectively. Numbering of carbon atoms for compounds 2, 10a needed for 13 C-NMR analysis are described in the following figure:
Obtained from carbohydrazide 3 and benzaldehyde. The solid precipitate which is formed during reflux was filtered off, dried and recrystallized from acetic acid as white crystals. IR ν (cm

General procedure:
A mixture of pyrrol-1-ylcarboazide 8 (0.5 g, 1.2 mmol) and primary (secondry) amine (1.25 mmol) was refluxed in dry toluene for 2 hrs. The solid product which formed on cooling was filtered off, dried and recrystallized from the proper solvent.