SYNTHESIS OF SOME SECONDARY AMINE DERIVATIVES BEARING A HETEROARYL FRAGMENT

VLADIMIR V. KOUZNETSOV*_, LUIS ASTUDILLOSAAVEDRA, LEONOR Y. VARGAS MÉNDEZ, MARÍA E. CAZAR RAMÍREZ

Instituto de Química de Recursos Naturales, Universidad de Talca, Casilla: 747, Talca, Chile E-mail: lastudi@utalca.cl

ABSTRACT

Diverse N-(heteroarylmethyl)anilines were easily prepared from corresponding aldimines derived from commercially available aromatic aldehydes and anilines. New series of substituted NH-tetrahydroquinolines were also prepared using imino-Diels-Alder reaction between aldimines and N-vinylpyrrolidin-2-one in the presence of BF₃^.OEt₂ and the multi-component condensation reactions using a friendly ecological catalyst (BiCl₃). The secondary amines obtained bearing a heteroaryl moiety were tested as possible antibacterial and antifungal agents.

INTRODUCTION

Secondary amines bearing a heteroaryl ring are a large class of organic compounds whose chemistry and biology have received considerable attention from both the theoretical and practical points of view. Although a great many of these amines have been prepared using well-documented methods of preparation, organic and medicinal chemists still continue to obtain them. Since they are biogenic amines, some of them represent very attractive biological targets. The condensation of aldehydes and heteroaromatic amines provides a widely popular class, the aryl-hetarylaldimines ^1,2). The ease of transformation of the C=N imine double bond (cycloaddition and addition reactions) is used successfully in the production of a large number of industrial compounds and also in drug preparation. The aldimines are valuable starting materials not only for different O- and/or N-containing heterocycles ²⁾, but also for diverse secondary heteroaromatic amines ³⁾. The reduction of imines using various reducing reagents represents an old but powerful means for the preparation of numerous important secondary amine products ⁴⁾. Oxygen and nitrogen heterocycles are frequently found in privileged structures (pharmacophores); among them, furan, pyridine and quinolines or their hydrogenated derivatives represent good candidates for bioscreening of diverse types of activities.

The synthesis of tetrahydroquinoline derivatives has long been an area of interest for organic chemists due to the presence of these scaffolds within the framework of numerous biologically interesting natural products ⁵⁾. In this context, tetrahydroquinolines with furan or pyridine moieties show interesting features that make them attractive for synthetic and pharmacological use. Many drugs based on pyridine and furan rings are used successfully in medical practice ⁶⁾.

As part of our ongoing research program aimed at the search for bioactive homoallylamines (A) and 4-methyl-1,2,3,4-tetrahydroquinolines (B) (Fig.1) from accessible aldimines, we found that molecules containing aryl or heteroaryl rings displayed significant activity (MIC < 50 mg/mL) against some pathogenic dermatophytes ^7,8). This fact encouraged us to develop other analogs of simple secondary amine derivatives with possible biological activity. Here we report the preparation of new series of N-benzyl-, N-(2-furylmethyl)-, and N-pyridylmethyl-anilines (C) using reduction reactions of different aldimines derived from some commercially available aromatic aldehydes (benzaldehydes, 2-furaldehyde, 3-pyridinecarboxyaldehyde) and anilines, and the synthesis of 2-heteroaryl-4-(2-oxopyrrolinidyl-1)-1,2,3,4-tetrahydroquinolines (D) (Fig.1).

Fig.1

EXPERIMENTAL

The melting points (uncorrected) were determined on a Fisher-Johns melting point apparatus. The ir spectra were recorded on a Nicolet Avatar 360-ft spectrophotometer in kbr. ¹h nmr spectra were recorded on a Bruker am-400 spectrometer. Chemical shifts are reported in ppm (d) relative to the solvent peak (chcl₃ in cdcl₃ at 7.24 ppm for protons) (Tables 1 and 2). Signals are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublets of doublets; t, triplet; dt, doublet of triplets; td, triplet of doublets; q, quartet; quint., quintet; sext., sextet; m, multiplet; br, broad. A Hewlett Packard 5890a series ii Gas Chromatograph interfaced to an hp 5972 Mass Selective Detector (msd) with an hp ms Chemstation Data system was used for ms identification at 70 ev using a 60 m capillary column coated with hp-5 [5%-phenyl-poly(dimethyl-siloxane)]. Elemental analyses were performed on a Perkin Elmer 2400 Series ii analyzers.

Table 1: 1H-NMR chemical shifts (ppm) and coupling constants (Hz) of compound 12 ­ 22.

The synthesis of aldimines 1-11 and the corresponding amines 12-22 was done as described in the literature ^1,14). The preparation of tetrahydroquinoline 23 was described recently ¹⁵⁾. Diels-Alder reactions were carried out in an inert atmosphere (N₂).

N-(Heteroarylmethyl)anilines (12-15, 17-22). General procedure.

Reactions were carried out in 50-mL round-bottom flasks with 1.0 mmol of aldimines 1-5, 7-11 in 30 mL of methanol. Portions of solid NaBH₄ (3.5 mmol) were added to the magnetically stirred solutions at room temp. Stirring was maintained over the course of the reactions, which were followed by TLC. Then, 15-20 mL of water was added to the reaction mixture. Methanol was distilled off and the products were extracted with CH₂Cl₂ (3 x 15 mL). The combined extracts were washed with water, dried over Na₂SO₄, filtered, and distilled to give the crude products, which were purified by silica gel column chromatography. The respective amines 12-15 and 17-22 were obtained as stable solids. ¹H-NMR analysis is shown in Table 1.

N-(4-Dimethylaminobenzyl)aniline (12). White crystals. Yield 79%; mp. 130-132 °C; IR: n_NH 3402, 1611 cm^-1; MS: m/z = 226 (M⁺). Anal. Calcd. for C₁₅H₁₈N₂: C, 79.65; H, 7.96; N, 12.39%; found: C, 79.38; H, 7.80; N, 12.70%.

N-(4-Metoxybenzyl)aniline (13). Colorless crystals. Yield 85%; mp. 61-62 °C (46.5-47 ^oC reported in ¹⁴) ; IR: n_NH 3418, 1604 cm^-1; MS: m/z = 213 (M⁺). Anal. Calcd. for C₁₄H₁₅NO: C, 78.87; H, 7.04; N, 6.57%; found: C, 78.55; H, 7.20; N, 6.20%.

N-(4-Metoxybenzyl)-3-nitroaniline (14) . Yellow crystals. Yield 95%; mp. 94-95 °C; IR: n_NH 3407, 1622, n_NO2 1543, 1345 cm^-1; MS: m/z = 258 (M⁺). Anal. Calcd. for C₁₄H₁₄N₂O₃ : C, 65.12; H, 5.43; N, 10.85%; found: C, 65.25; H, 5.20; N, 10.50 %.

N-(4-Hydroxybenzyl)aniline (15). Yellow crystals. Yield 28%; mp. 114-116°C; IR: n_NH 3313, 1613 cm^-1; MS: m/z = 199 (M⁺). Anal. Calcd. for C₁₃H₁₃NO: C, 78.39; H, 6.53; N, 7.04 %; found: C, 78.25; H, 6.71; N, 7.10 %.

N-(2-Furylmethyl)aniline (17). Yellow oil. Yield 96%; n_D²⁵ = 1.607; IR: n_NH 3411 cm^-1; MS: m/z = 173 (M⁺). Anal. Calcd. for C₁₁H₁₁NO: C, 76.30; H, 6.36; N, 8.09 %; found: C, 76.25; H, 6.55; N, 7.85 %.

N-(2-Furylmethyl)-4-fluoroaniline (18). Yellow oil. Yield quantitative; n_D²⁵ = 1.587; IR: n_NH 3413 cm^-1; MS: m/z = 191 (M⁺). Anal. Calcd. for C₁₁H₁₀FNO: C, 69.11; H, 5.23; N, 7.33%; found: C, 68.94; H, 5.67; N, 7.14%.

N-(3-Pyridylmethyl)toluidine (19). Brown crystals. Yield 91%; mp. 81-82 °C; IR: n_NH 3266, 1613 cm^-1; MS: m/z = 198 (M⁺). Anal. Calcd. for C₁₃H₁₄N₂: C, 78.79; H, 7.07; N, 14.14%; found: C, 78.25; H, 7.20; N, 14.50%.

N-(3-Pyridylmethyl)-4-iodoaniline (20). White crystals. Yield 81%; mp. 105-106 °C; IR: n_NH 3308, 1588 cm^-1; MS: m/z = 310 (M⁺). Anal. Calcd. for C₁₂H₁₁IN₂: C, 46.45; H, 3.55; N, 9.03%; found: C, 46.15; H, 3.87; N, 8.90%.

N-(3-Pyridylmethyl)-3-nitroaniline (21). Yellow crystals. Yield 58%; mp. 117 °C; IR: n_NH 3251, 1628, n_NO2 1520, 1345 cm^-1; MS: m/z = 229 (M⁺). Anal. Calcd. for C₁₂H₁₁N₃O₂ : C, 62.88; H, 4.80; N, 18.34%; found: C, 62.45; H, 5.03; N, 18.01%.

N-(3-Pyridylmethyl)-3,5-dimethylaniline (22). White crystals. Yield 83%; mp. 86-87 °C; IR: n_NH 3277, 1601 cm^-1; MS: m/z = 212 (M⁺). Anal. Calcd. For C₁₄H₁₆N₂: C, 79.24; H, 7.55; N, 13.21%; found: C, 79.25; H, 7.87; N, 13.05%.

N-(4-Aminobenzyl)toluidine (16).

Reaction was carried out in 150-mL round-bottom flasks with 4.0 mmol of aldimines 6 in 80 mL of methanol. Portions of solid NaBH₄ (23.0 mmol) were added to the magnetically stirred solution at rt. Then 0.005 g of 10% Pd/C was added to the reaction mixture. Stirring was maintained over the course of the reaction, which was followed by TLC. Then 35 mL of water was added to the reaction mixture, the methanol was distilled off, and the product was extracted with CH₂Cl₂ (3 x 25 mL). The combined extracts were washed with water, dried over Na₂SO₄, filtered through a short column (SiO₂) and distilled to give the crude product, which was purified by silica gel column chromatography. The amine 16 was obtained as yellow crystals. Yield 68%; mp. 57 °C; IR: n_NH 3377, n_NH2 3419, 3335 cm^-1; MS: m/z = 212 (M⁺). Anal. Calcd. for C₁₄H₁₆N₂: C, 79.24; H, 7.55; N, 13.21%; found: C, 79.48; H, 7.30; N, 13.25%.

2-(2-Furyl)-6-fluoro-4-(2'-oxopyrrolinidyl-1')-1,2,3,4 -tetrahydroquinoline (24).

A solution of 1.58 g (8.3 mmol) of 6 in anhydrous CH₂Cl₂ (15 mL) was cooled to 0 ^oC. BF₃^.OEt₂ 0.39 g ( 0.36 mL, 2.8 mmol) of was added dropwise over a period of 20 min. The resulting mixture was allowed to warm to room temp. and the NVP (1.02 g, 0.98 mL, 9.1 mmol) in CH₂Cl₂ (10 mL) was then added with vigorous stirring. The reaction mixture was stirred at room temp. for 12 h and then poured into H₂O. The organic layer was separated, and dried with Na₂SO₄. The organic solvent was removed in vacuo. The residue was purified by recrystallization from the CH₂Cl₂ and EtOAc (2:1) mixture to give tetrahydroquinoline 24 as white crystals. Yield 92%; mp. 161-162 °C; IR: n_NH 3367 cm^-1; MS: m/z = 300 (M⁺). Anal. Calcd. for C₁₇H₁₇FN₂O₂ : C, 68.00; H, 5.67; N, 9.33%; found: C, 67.85; H, 5.98; N, 9.10%.

2-Aryl-4-(2'-oxopyrrolinidyl-1')-1,2,3,4-tetrahydroquinolines (23-30). General procedure.

A mixture of aryl amine (2.8 mmol) and heteroaldehyde (3.4 mmol) in anhydrous CH₃CN (15 mL) was stirred at room temp. for 30 min. BiCl₃ (20 mol%) was added. A solution of NVP (5.5 mmol) in CH₃CN (10 mL) was added dropwise over a period of 20 min. The resulting mixture was stirred for 10-14 h. After completion of the reaction as shown by TLC, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 15 mL). The organic layer was separated and dried (Na₂SO₄), concentrated in vacuo, and the resulting product was purified by column chromatography (silica gel, petroleum ether:EtOAc) to yield the pure tetrahydroquinolines. ¹H-NMR analysis was given in table 2.

Table 2: 1H-NMR chemical shifts (ppm) and coupling constants (Hz) of compound 24 ­ 30

2-(3-Nitrophenyl)-6-methyl-4-(2'-oxopyrrolinidyl-1')-1,2,3,4 -tetrahydroquinoline (25). Yellow crystals. Yield 65%; mp. 242-243 °C; IR: n_NH 3326 cm^-1; ppm. MS: m/z = 351 (M⁺). Anal. Calcd. for C₂₀H₂₁N₃O₃ : C, 68.38; H, 5.98; N, 11.97%; found: C, 68.06; H, 5.64; N, 12.04%.

2-(3-Nitrophenyl)-4-(2'-oxopyrrolinidyl-1')-1,2,3,4 -tetrahydroquinoline (26). Yellow crystals. Yield 93%; mp. 190-191 °C; IR: n_NH 3331 cm^-1. MS: m/z = 337 (M⁺). Anal. Calcd. for C₁₉H₁₉N₃O₃ : C, 67.66; H, 5.64; N, 12.46%; found: C, 67.35; H, 5.97; N, 12.15%.

2-(3-Nitrophenyl)-6-methoxy-4-(2'-oxopyrrolinidyl-1')-1,2,3,4 -tetrahydroquinoline (27). Orange crystals. Yield 81%; mp. 220-222 °C; IR: n_NH 3314 cm^-1; MS: m/z = 336 (M⁺-I). Anal. Calcd. for C₁₉H₁₈IN₃O₃ : C, 49.24; H, 3.89; N, 9.07%; found: C, 49.40; H, 3.57; N, 8.94%.

6-Iodo-2-(3-nitrophenyl)-4-(2'-oxopyrrolinidyl-1')-1,2,3,4 -tetrahydroquinoline (28). Yellow crystals. Yield 70%; mp. 179-181 °C; IR: n_NH 3335 cm^-1; ppm.. MS: m/z = 336 (M⁺-I). Anal. Calcd. for C₁₉H₁₈IN₃O₃ : C, 49.24; H, 3.89; N, 9.07%; found: C, 49.40; H, 3.57; N, 8.94%.

5,7-Dimethyl-2-(3-nitrophenyl)-4-(2'-oxopyrrolinidyl-1') -1,2,3,4-tetrahydroquinoline (29). Yellow crystals. Yield 75%; mp. 173-175 °C; IR: n_NH 3312 cm^-1; MS: m/z = 365 (M⁺). Anal. Calcd. for C₂₁H₂₃N₃O₃ : C, 69.04; H, 6.30; N, 11.51%; found: C, 69.28; H, 6.05; N, 11.84%.

6-Methyl-2-(4-methoxyphenyl)-4-(2'-oxopyrrolinidyl-1') -1,2,3,4-tetrahydroquinoline (30). White crystals. Yield 50%; mp. 184-186 °C; IR: n_NH 3334 cm^-1; MS: m/z = 336 (M⁺). Anal. Calcd. for C₂₁H₂₄N₂O₂ : C, 75.00; H, 7.14; N, 8.33%; found: C, 74.73; H, 7.40; N, 8.57%.

Results and Discussion

The synthetic routes used for the preparation of the amino compounds are shown in scheme 1. The selected aldimines 1-11 were obtained by the reaction of various heteroaryl aldehydes and aromatic primary amines in the usual way, refluxing a mixture in dry ethanol. Because the reduction of aldimines with an excess of NaBH₄ in methanol is still the reaction of choice to produce the secondary amines in reasonably good yield ⁴⁾, we used this method in our work. Thus, the series C of some N-(heteroarylmethyl)anilines 12-15, 17-22 (Scheme 1, Table 3) was easily prepared, producing these secondary amines as colored solids in 28-95% yields after purification using SiO₂ column chromatography. Transformation of aldimine 6 into compound 16 was done under different reduction conditions (NaBH₄ in the presence of catalytic amounts of Pd /C in methanol) because the C=N double bond of this aldimine was not reduced in the usual way.

Scheme 1

Table 3: Secondary amines 12-22 obtained from the corresponding imines 1-11.

Having in our hands aldimines 1-11 (Table 3), we wanted to synthesize various cyclic analogs of 12-22. We concentrated our synthetic efforts on substituted tetrahydroquinolines. They are rigid and compact molecules that are very interesting to medicinal chemists. Conformational rigidity may give increased potency, receptor selectivity, metabolic stability and bioavailability to biologically active secondary amines.

Taking into account that the acid-promoted aza-Diels-Alder reaction between N-arylimines and electron-rich alkenes is one of the most appropriate synthetic tools for constructing these heterocycles,^9,10) the multi-component condensations have emerged as a powerful tool for delivering the molecular diversity needed in the combinatorial approaches for the preparation of bioactive compounds.^11,12) Thus, we prepared some heteroaryl substituted tetrahydroquinolines, 23-31, of general formula D. Initially we carried out the cycloaddition of the N-vinylpyrrolidin-2-one (NVP) and N-(a-furyliden)anilines 6,7 in the presence of Lewis acid (BF₃^.OEt₂, 20 mol%) to give the corresponding 2-(2-furyl)-6-methyl-4-(2-oxopyrrolinidyl-1)-1,2,3,4 -tetrahydroquinoline (23) and 2-(2-furyl)-6-fluoro-4-(2-oxopyrrolinidyl-1)-1,2,3,4-tetrahydroquinoline (24) in excellent yields (Scheme 1). Then, we made three-component condensation reactions (anilines, aldehydes and NVP). Using ptoluidine, NVP and 3-nitrobenzaldehyde as substrates, the reaction has been carefully examined in the presence of various Lewis or Brönsted acids. This coupling reaction proceeds smoothly at room temperature and the desired products are obtained in good yield with almost no by-products. BiCl₃ and p-TsOH are the best acid catalysts for this reaction to give tetrahydroquinoline 25 in 60-65% yield in 14 h in MeCN at room temperature (Table 4).

Table 4: Effect of various Lewis acids or Brönsted acids in the reactions of p-toluidine (2.8 mmol), NVP (5.5 mmol) and 3-nitrobenzaldehyde (3.4 mmol) to give tetrahydroquinoline 25.

Then, we carried out this reaction of NVP with various anilines and aldehydes in the presence of BiCl₃ (20 mol %) under these optimized conditions. The use of bismuth(III) chloride as catalyst is justified because of its friendly ecological behavior. Bismuth is less toxic among heavy metals. The results are summarized in Table 3. The electron-donating (MeO) or electron withdrawing (NO₂) substituents on the phenyl rings did not significantly affect this coupling reaction. However, we were unable to obtain tetrahydroquinoline 31 from p-methoxyaniline, NVP and p-methoxybenzaldehyde (entry 7, Table 5).

Table 5: Three-component Aza-Diels-Alder reaction promoted by BiCl3 (MeCN, rt, 14 h).

It should be noted that the three-component (p-toluidine, NVP and 3-pyridinecarboxyaldehyde) condensation under the same procedure protocol to obtain the corresponding pyridyl-tetrahydroquinoline derivatives (Scheme 1) failed. The presence of the pyridine nitrogen in the aldehyde components complicates the course of the reaction yielding various unexpected products.¹³⁾

All the substituted tetrahydroquinolines, 23-30, obtained were purified by SiO₂ column chromatography and exist as the cis-diastereoisomers. Their structural elucidation was based on ¹H NMR. The relative trans orientation of H₂, H₃ and H₄ was established from the large vicinal coupling constants J_2,3 = 8.8-10.8 Hz and J_3,4 = 8.8-11.1 Hz (Fig. 2).

Fig. 2.

Preliminary assays have shown that some compounds of general formula C possess both antimicrobial and antifungal activities (Table 6). Analyzing these biological results, we can report that the N-(p-methoxy or hydroxybenzyl)anilines 13 and 15 are active against Bacillus subtilis sp., while the m-aminobenzyl derivative 16 acts as an antifungal agent on the Paecylomyces variotii and Penicillium notatum species. It is interesting to note that a nitro group on another ring of benzyl anilines (derivative 14) does not affect the growth of either bacteria or fungi. Among the series of N-(2-furylmethyl)anilines 17 and 18, fluoro derivative 18 possesses moderate antibacterial activity. In the series of N-pyridylmethylanilines 19-22, the 3-pyridyl derivative 20 is selective, acting as a moderate antifungal agent, while its analogs 21 and 22 show antibacterial activity. Tetrahydroquinoline derivatives 23-29 of general formula D possess neither antimicrobial nor antifungal activity.

Table 6: Antibacterial and antifungal activity of the compounds obtained in the agar diffusion assay after 24 hours with 50 and 100 mg/ paper disks (8 mm diameter)

* B.b. - Bacillus brevis; B.s. - Bacillus subtilis; M.l. - Micrococcus luteus; E.d. - Enterobacter dissolvens; M.m. - Mucor miehei; P.v. - Paecylomyces variotii; P.n. - Penicillium notatum. Reference antimicrobial compounds: Chloramphenicol as antibacterial (sensidisks), Nystatin and Amphotericin-B as antifungal (sensitabs).

CONCLUSION

Some new N-(heteroarylmethyl)anilines have been prepared from available aldimines. New series of substituted NH-tetrahydroquinolines were also prepared using the imino-Diels-Alder reaction between aldimines and N-vinylpyrrolidin-2-one in the presence of BF₃^.OEt₂, and multi-component condensation reactions using a friendly ecological catalyst (BiCl₃). The secondary amines obtained bearing a heteroaryl moiety were tested as possible antibacterial and antifungal agents. Some of them possess moderate activity against Penicillium notatum sp.

ACKNOWLEDGMENTS

The authors acknowledge with thanks the financial support of the Dirección de Investigación, Universidad de Talca (grant VAC 600-354, Fondecyt-Enlace), Programa de Productos Naturales Bioactivos and Programa de Doctorado del Instituto de Química de Recursos Naturales.

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(Received: May 24, 2004 - Accepted: September 20, 2004)