Chinese Chemical Letters  2016, Vol.27 Issue (01): 99-103   PDF    
A catalyst-and solvent-free multicomponent synthesis of 7-azagramine analogues via a Mannich type reaction
Sakharam B. Dongarea, Hemant V. Chavanb, Pravin S. Bhalea, Yoginath B. Mulea, Amol S. Kotmalea, Babasaheb P. Bandgara     
a School of Chemical Sciences, Solapur University, Solapur 413 255, Maharashtra, India;
b Department of Chemistry, A. S. P. College, Devrukh, Dist-Ratnagiri 415 804, Maharashtra, India
Abstract: A catalyst-and solvent-free protocol for the synthesis of 7-azagramine analogues is described via a three-component Mannich type reaction between 7-azaindole, aromatic aldehydes and heterocyclic amines in acceptable to excellent yields. Structures of the compounds were confirmed satisfactorily by 1H NMR, IR, mass, TOCSY, HSQC and HMBC spectral analyses.
Key words: Bioisosters     7-Azaindole     Mannich reaction     Multicomponent reaction    
1. Introduction

Gramine is a natural indole alkaloid that has been found in different plants like Arundo donax,Acer saccharinum (Silver Maple), Hordeum,Phalaris and coal tar [1]. Gramine shows various biological activities such as relaxation of bronchial smooth muscle,vaso relaxation,blood pressure elevation,reliefdrug for bronchitis aswell as nephritis and bronchial asthma like ephedrine [2]. It also plays an important role for the amino acid metabolism in living organism. Gramine has beenwidely used as a pharmaceutical lead scaffold for constructing various biologically active indole-containing compounds [3].

The introduction of a basic nitrogen atomin the aromatic ring of the indole leads to the azaindole derivatives,which are bioisosters of the indole-based compounds. Although the occurrence of azaindoles is less common in natural products,the synthesis of 7-azaindoles has attracted considerable interest due to their interesting biological activity in diverse therapeutic areas [4]. The 7-azaindole framework is present as a core nucleus in several natural products like Variolin (I) and Meriolins family (II) [5]. It is also considered as a versatile pharmacophore and has a wide range of biological applications,e.g. 2-substituted 4-aryl-7-azaindoles (III) as kinase inhibitors [6],3-substituted azaindoles (IV,V) as PDE-4 and ROCK inhibitors [7],Tropanamide (DF1012) (VI) and Vemurafenib (VII) as antileishmanial,cannabinoid agonist,dopamine D4 receptors (Fig. 1) [8, 9, 10].

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Fig. 1.Some biologically active 7-azaindole containing molecules.

Replacement of a carbon atom by a nitrogen atom in the benzene ring of indole unit could increase the affinity for the binding site on the target enzyme(s) and also modify the electronic distribution of the aromatic framework,which will affect the lipophilicity of the molecule as well as reactivity towards the electrophiles in substitution reactions [11].

To the best of our knowledge,only a few methods have been reported concerning to the synthesis of 3-amino-alkylated indoles i.e. heteroaryl gramine analogues usingMannich type reactions with different catalysts [12]. Although several useful synthetic procedures have been developed for indole derivatives,synthesis of 7- azagramine analogues via the condensation of 7-azaindole,heteroaryl amines and aromatic aldehydes has not previously been reported. Thus,a simple and efficient method to synthesize 7- azagramine analogues is desirable.

MCRs have been designed to produce elaborate biologically active compounds and have becomean important area of research in organic,combinatorial and medicinal chemistry [13]. The MCR approach offers considerable advantages over conventional lineartype synthesis because of its flexible,convergent and atomefficient nature [14, 15, 16]. The success of combinatorial chemistry in the drug discovery process depends on the advances in the heterocyclic MCR methodology and also on the environmentally benign multicomponent procedures. In fact,as clearly stated by R. A. Sheldon,it is generally recognized that "the best solvent is no solvent and if a solvent (diluent) is needed it should preferably be water" [17]. Considering the biological significance of 7-azaindole derivatives, it is valuable to synthesize azaindole libraries based on the multicomponent reaction techniques.

In continuation of our ongoing programme on the development of multicomponent reactions for the synthesis of heterocyclic compound libraries with high diversity [18],we wish to report the first uncatalysed solvent-free procedure for the preparation of 7- azagramine analogues via a one-pot three-component Mannichtype reaction (Scheme 1). This method uses readily available raw materials such as aromatic aldehydes,heterocyclic amines and 2- methyl-7-azaindole.

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Scheme 1.Uncatalysed solvent free synthesis of 7-azagramine analogues.
2. Experimental

All melting points (mp)were determinedwith the open capillary method and are uncorrected. 1H NMR and 13C NMR spectra were recorded on a Brucker spectrometer at 400 MHz and 100 MHz respectively with CDCl3/DMSO-d6 or mixture of both as a solvent andTMS as aninternal standard.Chemical shifts are reported inppm values. Coupling constants J are reported in Hz. Mass spectra were performed on a Mass Spectrometer (Thermo) API instrument. FT-IR spectrawere recorded on Brucker instruments with the direct or KBr pellets method in the range of 600-4000 cm-1. The reaction monitoring was accomplished by TLC analysis and UV light and/ or iodine vapour were used for the detection of compounds. All chemicals or reagents used for syntheses were commercially available,were of AR grade,and were used as received from freshly opened containers 2-Methyl-7-azaindole was synthesized as per literature precedent [19]

General procedure for the synthesis of 7-azagramine analogues: In a round-bottom flask containing a magnetic stirrer,a mixture of aldehyde (1mmol) and heteroaryl amine (1mmol) was placed and stirred at about 80-85 ℃ for 20 min. Then 2-methyl-7-azaindole (1mmol)was added in portions,and the mixture was heated to 80- 85 ℃. Completion of the reaction was monitored by thin-layer chromatography (TLC) analysis. After completion,the reaction mixture was cooled to room temperature and a small quantity of ethanol was added. The solutionwas poured into ice-water,and the precipitate formed was filtered,washed with an ice cold ethanol- water (1:1) mixture. The crude products were stirred in boiling nhexane and filtered to afford the pure products.

3. Results and discussion

Our initial efforts focused on the one-pot,three-component Mannich type reaction of 7-azaindole with aromatic aldehydes and heteroaromaticamines inpolar solventssuchasethanol,acetone,etc. usingdifferentLewisandBronstedacidcatalystssuchasp-TSA,FeCl3, ZnCl2,L-proline,HCl,etc.Inordertoscreenthecatalysts,thereactionof the 2-methyl-7-azaindole 1,benzaldehyde 2a,and 2-aminopyridine 3a was taken as amodel reaction and the results are summarized in Table 1. Screening of the reaction conditions revealed that the nature of the catalyst had no significant role on the yield of the desired product. When the identical reaction was carried out in ethanol as solventandintheabsenceofcatalyst,traceamountofdesiredproduct 4a was obtained. Interestingly,in the absence of catalyst and solvent, this three-component reaction proceeded smoothly to afford the desired 7-azagramine analogue 4a in excellent yield (85%) after heating for 3 h at 80-85 ℃ (Table 1,entry 12).

Table 1
Screening of catalysts for one-pot synthesis of 7-azagramine analogues.

With these optimized conditions in hand,an appropriately substituted aromatic aldehyde (1mmol) and heteroaryl amine (1mmol) were placed in a dried round-bottom flask containing a magnetic stirrer and the mixture was stirred at about 80-85 ℃ for 20 min. Then 2-methyl-7-azaindole (1mmol) was added in portions,and the mixture was heated to 80-85 ℃. Completion of the reaction was monitored by thin-layer chromatography (TLC) analysis. After completion,the reactionmixture was cooled to room temperature and asmall quantity of ethanolwas added. Thesolution was poured into ice-water,and the precipitate formed was filtered, washed with an ice cold ethanol-water (1:1) mixture. The crude products were stirred in boiling n-hexane and filtered to give pure products. The procedure was simple and easy to operate; generally the reactions completed within 3-4 h. In all these cases good yields in the range from71%to87%were obtained.To expandthe scope and generality of this established reaction conditions,diverse range of substituted aryl aldehydes were reacted with 2-aminopyridine and 2-methyl-7-azaindole to give a series of 7-azagramine analogues 4a-m without the formation of bis-azaindole 5a-m. All the synthesized compounds are listed in Table 2.

Table 2
One-pot synthesis of 7-azagramine analogues (4a–m).

The structures of all the synthesized compounds were identified using IR,1H NMR,13C NMR and mass spectrometry. The 1H NMR spectrum of compound 4m showed a singlet for the azaindole -NH at 10.48 ppm. The NH proton of amine adjacent to CH appears as a doublet within the range of 5.18-8.08 ppm and the methine proton appears as a doublet in the range of 6.03-6.67 ppm (Fig. 2). The structure of this representative compound 4m also confirmed by 2D NMR i.e. TOCSY,HSQC and HMBC analyses (Fig. 3).

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Fig. 2.1H NMR correlations of compound 4m.

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Fig. 3.TOCSY spectrum of compound 4m not in bold.

To further expand the scope and generality of this established reaction conditions,a reaction of 2-methyl-7-azaindole and aryl aldehydes with 2-aminobenzthiazole 6 was also performed (Scheme 2) in the absence of any catalyst and solvent,which gives the desired products 7a-e in excellent yields (Table 3).

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Scheme 2.Synthesis of azagramine analogues using 2-aminobenzthiazole.

Table 3
Products of the reaction of 2-methyl-7-azaindole, aryl aldehyde and 6.

All these reactions showed rapid formation of 7-azagramine analogues at 80-85 ℃ under catalyst- and solvent-free conditions with high efficiency. However,the variations in the yields were very small and aldehydes bearing both activating and deactivating groups gave the condensed products in excellent yields in a short reaction time. A plausible mechanism for the synthesis of azagramine analogues involves the condensation between aldehyde 2 and amine 3,which leads to the formation of imine intermediate followed by the attack of indole 1 to yield the final product 4 (Scheme 3).

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Scheme 3.Plausible mechanism for the synthesis of azagramine analogues.
4. Conclusions

In conclusion,we have identified a simple and efficient synthetic route to access 7-azagramine analogues via a one-pot, three-component Mannich-type reaction. The significant features of this method are catalyst- and solvent-free conditions,short reaction time,high yield of the products,operational simplicity, and easy workup procedure,which make it a useful method for the synthesis of bioactive 7-azagramine analogues.

Acknowledgments

Authors are thankful to the Director,School of Chemical Sciences,Solapur University Solapur,for providing all necessary laboratory facilities. The authors also acknowledge the instrument centre facility for providing spectral and analytical data.

Appendix A. Supplementary data

Supplementary data associated with this article can be found,in the online version,at http://dx.doi.org/10.1016/j.cclet.2015.07.029.

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