A facile synthesis of 7,12-dihydro-1,3,6,7,12-pentaazapleiadenes by domino reaction

Introduction

Nitrogen containing heteroaryl moieties are present in a large number of pharmaceutically relevant and biologically active compounds [1]. Cyclic nitrogen-linked biaryls represent a therapeutically important motif in medicinal chemistry. In particular, seven-membered N-linked biaryl scaffolds have been known to show a wide range of biological properties [2, 3]. Oxcarbazepine (1) shows antiepileptic activity [4], and olanzapine (2) and clozaopine (3) exhibit strong antipsychotic activity [5, 6]. These three compounds have a common seven-membered ring-linked biaryl (Figure 1). 7-Azasampangine (4), with a six-membered N-linked biaryl backbone is an antimicrobial agent [7]. We envisaged that tetracyclic pentaazapleiadene (10) having a seven-membered N-linked biaryl scaffold could be exploited to elicit enhanced biological activity similar to that of 7-azasampangine (4) or clozaopine (3).

Figure 1

Biologically active compounds 1–4 and 10.

Results and discussion

We have recently reported a novel methodology involving an acid-mediated domino reaction to build tetracyclic 7-azasampangine (4) [8]. We have utilized this domino methodology to build the complex tetracyclic pentaazapleiadene (10). In this methodology, stannous chloride not only reduces the nitro group but also provides the acidic environment required to facilitate the domino reaction.

(Z)-3-Amino-2-cyanobut-2-enamide (5) was obtained by condensation of cyanoacetamide and acetamidine hydrochloride under basic conditions [9]. Treatment of the enamide (5) with triethyl orthoformate and acetic anhydride yielded 4-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (6) [9]. Compound 6 was treated with POCl₃ to give 4-chloro-6-methylpyrimidine-5-carbonitrile (7) [10, 11]. Compound 7 is a key intermediate for the current methodology. Compound 7 was reacted with various 4-substituted 2-nitroanilines to produce the trisubstituted pyrimidine intermediates 8a–j. By contrast, intermediate products 11a–f were obtained by reacting compound 7 with various 4-substituted 2-nitrophenols. The enamines 9a–j and 12a–f were obtained by reaction of 8a–j and 11a–f with dimethylformamide-dimethylacetal (DMF-DMA) [12, 13]. In this reaction, a proton from the benzylic methyl group is removed by DMF-DMA and a molecule of methanol is eliminated resulting in the formation of an activated benzylic methylene function and methoxymethylene imidinium ion. The activated benzylic methylene group traps the imidinium ion, and the subsequent elimination of another molecule of methanol results in the formation of enamine [13].

Compounds 9a–j, with 2-nitroaniline, a nitrile, and enamine functional groups on the consecutive carbon atoms of the pyrimidine ring, are the key functionalities that undergo the domino reaction upon treatment with anhydrous SnCl₂ in dry tetrahydrofuran (THF). In this transformation, after nitro reduction, two C-N bonds are formed in one pot to yield the tetracyclic pentaazapleiadenes 10a–j (Scheme 1). The tetracyclic pentaazapleiadene derivatives were obtained in good yields in the case of various 4-substituted 2-nitroanilines. However, when 4-substituted 2-nitrophenols were used in place of the 2-nitroanilines in the presence of anhydrous SnCl₂ in dry THF, the corresponding 2-aminoenamine derivatives 13a–f were obtained (Scheme 2). When compounds 12a–f were treated with SnCl₂×2H₂ O in dry THF, the corresponding aminopyridopyrimidinone derivatives 14a–f were formed (Scheme 2).

Scheme 1

Synthesis of 9-substituted 7,12-dihydro-1,3,6,7,12-pentaazapleiadenes. Reagents and conditions: (i) acetamidine hydrochloride (1 equiv.), Na (1 equiv.), EtOH, at 0°C to rt (24 h), reflux, 2 h; (ii) HC(OEt)₃ (10 mL/g), (CH₃ CO)₂ O (10 mL/g), 140°C, 3.5 h; (iii) Et₃ N (0.2 equiv.), POCl₃ (1 equiv.), toluene, 100°C, 12 h; (iv) neat 130°C, 0.5 h; (v) DMF-DMA, 130°C, 3.5 h; (vi) anhydrous SnCl₂ (5 equiv.) or SnCl₂×2H₂ O (5 equiv.), dry THF, reflux, 18 h.

Scheme 2

Synthesis of 13 and 14. Reagents and conditions: (i) K₂ CO₃ (2 equiv.), DMF, rt, 0.5 h; (ii) DMF-DMA, 130°C, 3.5 h; (iii) anhydrous SnCl₂ (5 equiv.), dry THF, reflux, 6 h; (iv) SnCl₂×2H₂ O (5 equiv.), dry THF, reflux, 18 h.

The acid catalyzed domino reaction to give the tetracyclic pentaazapleiadenes 10a–j may be explained by the mechanism proposed in Scheme 3. Under acidic conditions, protonation of the β-carbon of the dimethylaminoenamine group generates an iminium ion [14]. The iminium cation is involved in a cascade of electron transfers, from the newly formed amino group to the cyano group that finally leads to quenching of the positive charge in the iminium ion, thereby resulting in the formation of two C-N bonds. The elimination of dimethylamine gives the tetracyclic pentaazapleiadenes. Similar transformations were earlier exploited for the synthesis of diazapines and azaphenalenes [15]. However, analogous domino transformations were not observed for compounds 12a–f, possibly due to the electronegative nature of the oxygen atom ortho to the anilinic amino group.

Scheme 3

Proposed mechanism for the formation of 7,12-dihydro-1,3,6,7,12-pentaazapleiadene.

Conclusion

A variety of tetracyclic pentaazapleiadenes utilizing our domino methodology [8] were synthesized. In this methodology, stannous chloride plays the dual role of reducing the nitro group and providing the necessary acidic conditions to trigger the domino reaction.

Experimental

THF was dried with sodium and distilled. All other solvents and reagents were used as received. Melting points were determined on a Buchi melting point B-540 apparatus. The ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were obtained on a Varian 400 spectrometer in DMSO-d₆. Mass spectra were obtained on an API 2000 Perkin Elmer (PE-SCIEX) mass spectrometer. IR spectra were recorded on an IR Prestage-21 FTIR spectrometer using KBr pellets. High resolution mass spectra were recorded in a positive ESI mode on a quadrupole time-of-flight (Q-TOF) mass spectrometer (Q-TOF, LC/MS 6510 series classic G6510A, Agilent Technologies, USA). The data acquisition was controlled by Mass Hunter workstation software.