A convenient synthesis of 2-substituted [1,2,4]triazolo-[1,5-a ]quinolines and [1,2,4]triazolo[5,1-a ]isoquinolines

Upon reaction with aqueous potassium hydroxide and aliphatic and aromatic aldehydes 2 the salts 1,2-diaminoquinolinium tosylate 4 and 1,2-diaminoisoquinolinium tosylate 9 were converted into the corresponding 2-substituted [1,2,4]triazolo[1,5-a ]quinolines 8 and [1,2,4]triazolo[5,1-a ]isoquinolines 13 , respectively. The formation of the final products requires aerial oxidation.


Scheme 1
In continuation of this study, and pursuing our continuous interest in the synthesis of polycyclic heteroaromatic compounds we decided to explore if this straightforward ring formation procedure can be extended.In this paper we describe a successful application of this synthetic strategy to prepare 2-substituted angularly fused benzo homologues of 3, i.e. the title ring systems 8 and 13 (Scheme 2).

Results and Discussion
Here we report the formation of the tricyclic structures 8 and 13 in the course of the condensation reaction of 1,2-diaminoquinoline 5 or -isoquinoline 10 with an aldehyde forming two bonds 1-N/2-C and 2-C-3-N of the triazole ring.The starting compounds of this reaction, 1,2-diaminoquinolinium tosylate 4 19 and 1,2-diaminoisoquinolinium tosylate 9 19 are readily available from 2-aminoquinoline and 1-aminoisoquinoline by direct N-amination procedure using O-tosylhydroxylamine 20 according to our previously published procedure. 21When a solution of the tosylates 4 or 9 in methanol is mixed with an aliphatic or aromatic aldehyde 2 and treated with aqueous potassium hydroxide at room temperature the respective 2-substituted fused [1,2,4]triazoles 8 and 13 are obtained within a few hours (Scheme 2).In some cases the crystalline products 8 and 13 precipitate from the reaction mixture and are collected by filtration (Method A).Alternatively, the products are isolated upon extraction from the reaction mixture with dichloromethane (Method B).The yields of the tricyclic products 8 (69-95%) and 13 (57-86%) are generally very good.It is interesting to note that these yields are significantly higher than those found for the bicyclic ring system 3. 1 The higher conversion rates may be due to the enhanced stability of the imino-amino bases 5 and 10 which -in contrast to the quite unstable conjugate base formed from 1 -have been isolated as stable crystalline compounds.
The reaction proceeds via the in situ generation of the free bases 1-amino-2-iminoquinoline 5 22 and 2-amino-1-iminoisoquinoline 10, 23 respectively.This has been proved by separate experiments with these compounds reacting with benzaldehyde 2c and affording the fused [1,2,4]triazoles 8c and 13c, respectively.Thus the free base 5 or 10 reacts with aldehydes 2 to give the condensation products 6 and 11, respectively.These hydrazones 6 and 11 are presumed to coexist in an equilibrium with ring chain tautomers, the corresponding dihydrotriazole derivatives 7 and 12 which, in turn, upon dehydrogenation induced by air oxidation yield the final heteroaromatic products 8 and 13, respectively.Oxygen from air is required for this oxidation step.This has been proved by carrying out the reaction of 2-amino-1iminoisoquinoline 10 with benzaldehyde 2c under exclusion of air.After 6 h no product 2phenyl [1,2,4]triazolo[5,1-a]isoquinoline 13c could be detected.When this reaction mixture was stirred and exposed to air the product 13c was isolated in virtually the same yield as following Procedure A.

Scheme 2
The structures of products 8 and 13 were confirmed by 1 H and 13 C NMR spectra.The assignment of the significant signals is according to a two-dimensional NMR study on [1,2,4]triazolo [1,5-f]phenanthridines, a tetracyclic system that has embedded both tricyclic structures 8 and 13. 24 The 1 H NMR spectra of the quinoline derivatives 8 exhibit the doublet signal of 9-H at lowest field (δ 8.40-8.62).The isoquinoline derivatives 13 show the AB system of 5-H and 6-H at of δ 7.11-7.33and δ 8.22-8.38,respectively; the signal of 10-H appears in the range of δ 8.53-8.74.On the basis of the NMR data established for [1,2,4]triazolo[1,5f]phenanthridines 24 most of the significant 13 C NMR data of compounds 8 and 13 have been assigned.
Further investigation on the application of this triazole ring closure strategy is in progress and is currently extended to 2,3-diaminoisoquinolines 14 (Scheme 2) aiming at the preparation of linearly fused [1,2,4]triazolo [1,5-b]isoquinolines.

Experimental Section
General Procedures.Melting points were determined with a Büchi apparatus.IR spectra were recorded with a Nicolet 205 FT spectrometer, NMR spectra were recorded on a Varian VXR-200 (200 MHz 1 H NMR) spectrometer, and mass spectra were measured with a MS-902 instrument (70 eV).

General procedures
For the Synthesis of Triazoles 8 and 13.Procedure A. An aqueous solution (14 mL) of potassium hydroxyde (2.8 g, 50 mmol) was added to a solution of 1,2-diaminoquinolinium tosylate (4) or 1,2-diaminoisoquinolinium tosylate (9) (1.66 g, 5 mmol) and aldehyde 2 (7 mmol) in methanol (50 mL).Upon stirring the reaction solution in an open flask at rt for 3-5 min a precipitate appeared.After 1 h the precipitate formed was filtered off and washed with methanol (5 mL).This procedure was repeated in 1 h intervals until no more precipitate was formed and the filtrate remained as a clear solution.The combined crop of solid material was washed with water and dried in a desiccator.Recrystallization from an appropriate solvent provided the pure crystalline products 8 and 13, respectively.Procedure B. The reaction mixture of the 1,2-diaminoquinolinium tosylate (4) or 1,2diaminoisoquinolinium tosylate 9 (1.66 g, 5 mmol), the aldehyde 2 (20 mmol) in methanol (50 mL) and an aqueous solution (14 mL) of potassium hydroxyde (2.8 g, 50 mmol) was stirred in an opened flask at rt for 6 h.The reaction solution was then poured into water (100 mL) and extracted with dichloromethane (3 x 50 mL).The combined organic layers were washed until neutral and dried over sodium sulfate.The residue after evaporation of the solvent was purified by column chromatography on silica gel with diethyl ether.Removal of the eluent solvent from the appropriate fractions furnished the solid product on cooling or on standing.Recrystallization from petroleum ether or n-hexane gave the pure product.5) 22 (0.80 g, 5 mmol) and water (11 mL, instead of an aqueous potassium hydroxide solution) afforded after 6 h 8c (0.90 g, 73%).