Construction of an isoquinoline fragment for the synthesis of condensed derivatives of 3-amino-isoquinoline as a method of forming the tricyclic azolo[b]isoquinoline system is rarely used [2,3]. Among the known methods of constructing these heterosystems in only two variants the key stage of cyclization is the formation of the C(3)–C(4) bond of the isoquinoline ring. One of them consists of the condensation of phthaloyl dichloride with benzimidazole in the presence of base [4], and the second, a more general method developed by us, is based on the cyclization of quaternary azolium salts formed on interacting o-bromomethyl-benzophenones with 1,3-diazoles [5]. The present work, in the indicated scheme of synthesis of azolo-[b]isoquinolines, uses derivatives of o-toluic acid, viz. 2-(chloromethyl)benzonitrile (1b), 2-(bromomethyl)-benzonitrile (1a), and methyl 2-(bromomethyl)benzoate (8). The latter is frequently used in various hetero-cyclizations, including those for obtaining isoquinoline derivatives [69], while nitriles 1a,b are rarely used for this purpose and the schemes for converting them are more complex [1013]. The relatively simple method of synthesis of azolo[b]isoquinolines proposed by us enables the preparation of their previously unavailable amino and hydroxy derivatives.

On interacting halo nitriles 1a,b with 1-alkyl-1H-imidazoles, 1-alkyl-1H-benzimidazoles, or 1-methyl-1H-1,2,4-triazole, quaternary azolium salts 2a-e, 3a,b, and 4 were formed respectively. Salts 2a-c were obtained in high yield (Table 1) on moderate heating (to 50 °C) of the reactants in acetonitrile.

figure a
Table 1 Physicochemical Characteristics of Compounds 26, 9, and 10

With benzimidazole derivatives and 1,2,4-triazole under these conditions, the reaction proceeded more slowly and led to products 3a,b and 4 in lower yield, increasing which may be achieved by fusing the reactants (110 °C, 5–10 min). The nature of the halogen in the starting halo nitrile did not prove to have a significant effect on the rate and yield of alkylation product, but in difference to bromides 2a-c, chlorides 2 d,e proved to be hygroscopic compounds, which complicated both the preparation of analytical samples of them and further conversion into cyclic products. The nature of the anion affected the spectral properties of imidazolium salts 2a,d and 2b,e insignificantly. The greatest marked changes in the spectral picture of chlorides 2 d,e, in comparison with bromides 2a,b were the shift of 0.25-0.27 ppm of the H-2 proton signal in the 1H NMR spectra towards low field (Table 2), and the high-frequency shift of the band of the stretching vibrations νCN by 5 cm-1 in the IR spectra (Table 3). This is caused by the changes in the spatial localization of the anion and the degree of bonding of it with the cation.

Table 2 Data of 1H NMR Spectra of Compounds 27, 9, 10
Table 3 Data of IR Spectra of Compounds 26, 9, 10

Examples are known of intramolecular cyclization of quaternary salts of 1,3-diazoles at position 2 with the participation of nitrile [14,15] or ester [16] groups, such as the intramolecular acylation of derivatives of α-methylsulfonylacetonitrile or malononitrile on heating in DMF in the absence of a basic catalyst. Conversion of diazolium salts 24 under such conditions does not occur, although cyclization does take place, but only on heating in the presence of base (K2CO3 or Et3N). We note that a significant role is played by the quality of the solvent, cyclization products are formed in good yield and with a high degree of purity only on using anhydrous DMF. 1-Alkyl-10-amino-1H-imidazo[1,2-b]isoquinolin-4-ium bromides 5a,b are obtained on using potassium carbonate. On heating 1-benzylimidazolium bromide 2c with base a complex mixture of reaction products is formed which we link with the effect of the substituent at the N(1) atom. The cyclization product of chlorides 2 d,e was isolated under the same conditions in only one case. 1-Ethyl-1H-imidazo[1,2-b]isoquinolinium chloride (5e) was obtained on using salt 2e, which is less hygroscopic than 2 d. The use of Et3N on cyclizing imidazolium salts 2 leads to a significant increase in reaction time, a reduction in the yield of the desired products, and accumulation of side products in the reaction mixture. At the same time in the case of benzimidazolium salts 3a,b the use of the indicated base was preferred, the yields of 5-alkyl-6-amino-5H-benz-imidazo[1,2-b]isoquinolin-12-ium bromides 6a,b were greater when using Et3N than with potassium carbonate. Cyclization of 1,2,4-triazolium salt 4 was accompanied by the formation of a large quantity of side products. The presence of 10-amino-1-methyl-1H-[1,2,4]triazolo[4,3-b]isoquinolin-4-ium bromide (7) in the reaction mixture was successfully recorded by 1H NMR on brief heating of salt 4 in the presence of Et3N. The structures of the amino derivatives of azolo[b]isoquinolines 57 were established on the basis of their spectral data. The signal of the primary amino group in the 1H NMR spectra of salts 57 was observed at 6.7-7.3 ppm as a two-proton singlet exchanging with D2O, and in the IR spectra two stretching vibrational absorption bands at 3354–3307 (asν) and 3307–3209 (sν) cm-1 correspond to this group. The formation of the aromatic system of azolo[b]isoquinoline is shown by the presence in their 1H NMR spectra of a one-proton singlet at 10.5-9.1 ppm at low field, assigned to the H-5 proton signal (for salts 5 and 7) or H-11 (for salts 6) on the basis of the data of the NOESY experiment carried out for compound 5a (Fig. 1).

Fig. 1
figure 1

Structurally important NOESY correlations for compound 5a cation.

The structure of the azolo[b]isoquinolinium salts 5b and 6a,b was confirmed by data of UV spectra. The shape of the absorption curve in the long-wave region corresponded to their 10-aryl- and 6-aryl-substituted analogs obtained previously [5] (Fig. 2), and the observed bathochromic shift of the absorption maxima (by ~10-20 nm) into the long-wave region agreed with the presence of a more donating NH2 group in the chromophor.

Fig. 2
figure 2

Absorption spectra (in MeOH) of 10-(4-chlorophenyl)-1-methyl-1H-imidazo[1,2-b]isoquinolin-4-ium bromide [5] (1), 6-(4-chlorophenyl)-5-methyl-5H-[3,1]benzimidazo[1,2-b]isoquinolin-12-ium bromide [5] (2), 10-amino-1-ethyl-1H-imidazo[1,2-b]isoquinolin-4-ium bromide (5b) (3), and 6-amino-5-methyl-5H-[3,1]benz-imidazo[1,2-b]isoquinolin-12-ium bromide (6a) (4).

The sequence of conversions which leads to azolo[b]isoquinoline derivatives may also be carried out using o-bromomethylbenzoic acid ester 8. On interacting ester 8 with 1-alkylimidazoles in MeCN at room temperature the corresponding 1-alkyl-3-[2-(methoxycarbonyl)benzyl]-1H-imidazol-3-ium bromides 9a,b were formed. Compound 9 was isolated in a pure state but salt 9b contained a mixture of products of further conversions.

figure b

On heating imidazolium bromides 9a,b with bases an intramolecular cyclization occurred with the formation of derivatives of imidazo[1,2-b]isoquinoline, the structure of which depended on the reaction conditions. Boiling the reaction mixture for 3 h in ethanol in the presence of potassium carbonate led to 1-alkyl-1H-imidazo[1,2-b]isoquinolin-4-ium-10-olates 10a,b, difficultly soluble compounds having a deeper color (orange) than the corresponding amino derivatives 57 (yellow). The betaine structure of the cyclization products 10a,b was established on the basis of data of elemental analysis and spectral characteristics. In particular, in the 1H NMR spectra all the signals of the aromatic protons of the imidazo[1,2-b]isoquinoline tricycle were shifted towards high field, and in the IR spectra there were no bands at ν > 3100 cm-1. However a strong band was observed at 1477 cm-1, characteristic of the vibrations of a carboxyl group anion (Table 3). The structure of compound 10b was also confirmed by UV spectral data, taken in methanol in the presence of NaOH and HCl. An increase of base did not affect the position of maxima and the shape of the absorption curve, while in the presence of acid (HCl) a hypsochromic shift of 35 nm was observed for the long-wave maximum (λ = 445 nm), which is the result of forming a protonated form of type 11. It is known that isoquinolinium salts readily add nucleophiles at position 1 [17]. Since in the case of azolo[b]isoquinolinium salts the C(5) atom is in such a position [18], the formation of a protonated form of type 11 assists the progress of such a reaction.

figure c

This was confirmed by the mass spectral data of compound 10b, recorded by the GLC method (the low solubility of methyl derivative 10a did not enable its qualitative mass spectrum to be obtained) on introducing the sample in CF3CO2H solution. In its spectrum signals were observed for cations with an m/z value corresponding to the dimerization product, but the signal for the protonated form of the starting compound 11 was absent. Dimerization may be effected in two ways, with the participation of the protonated form of 11 and the formation of compound 12, to which the low intensity signal (10%) in the spectrum corresponds, or without its participation with the formation of dimer 13. Oxidation of compound 12 leads to salt 14, to which the signal with I rel = 40% corresponds, and oxidation of compound 13 leads to salt 15 with a signal of intensity 100%. Further conversions of salts 12 and 14 may also lead to the most stable product 15. In the spectrum of compound 10b low intensity signals are observed for the products of cleavage of substituents at atoms N(1) and N(1') in a type 15 dimer.

Experimental

The IR spectra were recorded on a Perkin–Elmer Spectrum BX instrument in KBr disks. The 1H NMR spectra were recorded on a Bruker Avance DRX 500 instrument (at 500 MHz) with TMS as internal standard. The NOESY experiment was carried out on a Varian Mercury 400 instrument (at 400 MHz), internal standard was TMS. The UV spectra were obtained on a Perkin–Elmer Lambda 20 UV–vis spectrometer in methanol.

Melting points were determined on a Tile heating instrument. A check on the purity of the obtained compounds was effected by the GLC mass spectrometric method on an Agilent 1100 Series instrument, with an Agilent LC/MSD SL selective detector (samples were introduced in a matrix of CF3CO2H, ionization by EI).

3-(2-Cyanobenzyl)-1-R-1 H -imidazolium Bromides 2a-c (General Method). 1-R-1H-imidazole (2.55 mmol) was added to a solution of 2-(bromomethyl)benzonitrile (1a) (0.5 g, 2.55 mmol) in MeCN (10 ml). The mixture was heated on a water bath at 50 °C for 10 h. The solvent was evaporated in vacuum, and diethyl ether (10 ml) was added to the residue. The solid was filtered off and washed with ether.

3-(2-Cyanobenzyl)-1-R-1 H -imidazol-3-ium chlorides 2 d,e were obtained by the method of synthesis of products 2a-c using 2-(chloromethyl)benzonitrile 1b. Oily products were obtained (2 d,e·n H 2 O) rapidly deliquescing in the air, which were dried and stored without access to air.

3-(2-Cyanobenzyl)-1-R-1 H -benzimidazol-3-ium Bromides 3a,b and 4-(2-Cyanobenzyl)-1-methyl-1 H -1,2,4-triazol-4-ium Bromide (4) (General Method). A mixture of benzonitrile 1a (0.5 g, 2.55 mmol) and 1-R-1H-benzimidazole or 1-methyl-1H-1,2,4-triazole (2.55 mmol) was heated on an oil bath for 5–10 min at 110 °C. Acetone (10 ml) was added to the melt, which was triturated, and the crystalline solid was filtered off and washed with acetone.

1-Alkyl-10-amino-1 H -imidazo[1,2- b ]isoquinolin-4-ium Bromides 5a,b (General Method). Potassium carbonate (0.3 g, 2.17 mmol) was added to a solution of salt 2a,b (2.16 mmol) in anhydrous DMF (10 ml). The mixture was stirred for 1 h at room temperature, then heated for 30 min gradually raising the temperature to 100°FC. After cooling, the solid was filtered off, washed with acetone and with water, and then recrystallized from DMF.

Compound 5b. UV spectrum, λmax, nm (log ε): 242 (5.02), 270 (5.08), 341Footnote 1 (4.17), 354 (4.39), 378* (4.41), 396 (4.67), 415 (4.71).

10-Amino-1-ethyl-1 H -imidazo[1,2- b ]isoquinolin-4-ium chloride (5e) was obtained by the method of synthesis of products 5a,b, using the hydrate of chloride 2e.

5-Alkyl-6-amino-5 H -benzimidazo[1,2- b ]isoquinolin-12-ium bromides 6a,b were obtained by the method of synthesis of products 5a,b, using Et3N (0.5 ml, 3.6 mmol) in place of K2CO3.

Compound 6a. UV spectrum, λmax, nm (log ε): 282 (5.44), 344 (4.55), 361 (4.65), 423* (4.76), 442 (4.99), 467 (4.99).

Compound 6b. UV spectrum, λmax, nm (log ε): 280 (5.46), 342 (4.56), 359 (4.65), 422* (4.80), 440 (5.03), 465 (5.03).

3-[2-(Methoxycarbonyl)benzyl]-1-methyl-1 H -imidazol-3-ium Bromide (9a). 1-Methyl-1H-imidazole (1 ml, 12.2 mmol) was added to a solution of 2-(bromomethyl)benzoic acid ester 8 (2.79 g, 12.2 mmol) in acetonitrile (25 ml) and the mixture was maintained at room temperature for 2 day. The precipitated solid was filtered off, washed with a small volume of acetonitrile, and recrystallized from acetonitrile.

1-Methyl-1 H -imidazo[1,2- b ]isoquinolin-4-ium-10-olate (10a). Salt 9a (3 g, 9.64 mmol) was dissolved by heating in ethanol (50 ml) and K2CO3 (2.66 g, 19.30 mmol) was added. The mixture was boiled for 3.5 h, cooled, and the solid filtered off. The filtrate was evaporated, acetonitrile (10 ml) was added to the residue, and triturated. The solid was filtered off, thoroughly washed with hot water, and with hot DMF.

1-Benzyl-1 H -imidazo[1,2- b ]isoquinolin-4-ium-10-olate (10b). 1-Benzyl-1H-imidazole (1 g, 6.32 mmol) was added to a solution of 2-(bromomethyl)benzoic acid ester 8 (1.45 g, 6.32 mmol) in acetonitrile (25 ml). The solution was maintained at room temperature for 2 day and 50% solvent evaporated. Diethyl ether (20 ml) was added, the solution was separated from the oily residue containing imidazolium salt 9b (85%). The residue was dissolved in ethanol (30 ml) and K2CO3 (1.74 g, 12.64 mmol) was added. The mixture was boiled for 3 h, and after cooling, the solid was filtered off. The filtrate was evaporated, acetonitrile (10 ml) was added to the residue, and triturated. The solid was filtered off, thoroughly washed with hot water, and crystallized from DMF.

UV spectrum, λmax, nm (log ε): 262 (5.23), 340* (4.82), 353 (5.00), 407* (4.91), 445 (5.06). Mass spectrum, m/z (I rel, %): 549 (10), 548 (40), 547 [M]+ (100), 456 (10), 365 (15), 199 (11).