A catalyst- and solvent-free multicomponent synthesis of 7-azagramine analogues via a Mannich type reaction

Chinese Chemical Letters 27 (2016) 99–103

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Original article

A catalyst- and solvent-free multicomponent synthesis of 7-azagramine analogues via a Mannich type reaction Sakharam B. Dongare a, Hemant V. Chavan b, Pravin S. Bhale a, Yoginath B. Mule a, Amol S. Kotmale a, Babasaheb P. Bandgar a,* a b

School of Chemical Sciences, Solapur University, Solapur 413 255, Maharashtra, India Department of Chemistry, A.S.P. College, Devrukh, Dist-Ratnagiri 415 804, Maharashtra, India

A R T I C L E I N F O

A B S T R A C T

Article history: Received 26 April 2015 Received in revised form 9 July 2015 Accepted 22 July 2015 Available online 31 August 2015

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 1 H NMR, IR, mass, TOCSY, HSQC and HMBC spectral analyses. ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.

Keywords: 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, relief drug for bronchitis as well as nephritis and bronchial asthma like ephedrine [2]. It also plays an important role for the amino acid metabolism in living organism. Gramine has been widely used as a pharmaceutical lead scaffold for constructing various biologically active indole-containing compounds [3]. The introduction of a basic nitrogen atom in 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 7azaindoles 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

* Corresponding author. E-mail address: [email protected] (B.P. Bandgar).

and ROCK inhibitors [7], Tropanamide (DF1012) (VI) and Vemurafenib (VII) as antileishmanial, cannabinoid agonist, dopamine D4 receptors (Fig. 1) [8–10]. 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 using Mannich type reactions with different catalysts [12]. Although several useful synthetic procedures have been developed for indole derivatives, synthesis of 7azagramine 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 7azagramine analogues is desirable. MCRs have been designed to produce elaborate biologically active compounds and have become an 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 atom efficient nature [14–16]. 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

http://dx.doi.org/10.1016/j.cclet.2015.07.029 1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.

S.B. Dongare et al. / Chinese Chemical Letters 27 (2016) 99–103

100

R OH

N

R4

N

N R1

O O S NH

NH 2 N

N N

R2

N H 2N Variolin Family (I)

N R3

N H Kinase Inhibitor (III)

R=I; L-75 0-667 R=Cl; L-745-870

N

Meriolins Family (II)

PDE-4 Inhibitors (IV )

O

O O HN S

N O

N HN

N

R

N H

N N

N

N

F NH

O

Cl

NH

O F

N H

N

R OCK Inhibi tors (V)

N H

N

Tropanamide (DF 1012) (VI)

N H

Vemuraf inib (VII)

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

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 7azagramine 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 2methyl-7-azaindole.

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 (1 mmol) and heteroaryl amine (1 mmol) was placed and stirred at about 80–85 8C for 20 min. Then 2-methyl-7-azaindole (1 mmol) was added in portions, and the mixture was heated to 80– 85 8C. 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 solution 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 nhexane and filtered to afford the pure products.

2. Experimental 3. Results and discussion All melting points (mp) were determined with 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 and TMS as an internal standard. Chemical shifts are reported in ppm values. Coupling constants J are reported in Hz. Mass spectra were performed on a Mass Spectrometer (Thermo) API instrument. FT-IR spectra were 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

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

Our initial efforts focused on the one-pot, three-component Mannich type reaction of 7-azaindole with aromatic aldehydes and heteroaromatic amines in polar solvents such as ethanol, acetone, etc. using different Lewis and Bronsted acid catalysts such as p-TSA, FeCl3, ZnCl2, L-proline,HCl,etc.Inordertoscreenthecatalysts,thereactionof the 2-methyl-7-azaindole 1, benzaldehyde 2a, and 2-aminopyridine 3a was taken as a model 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 Table 1 Screening of catalysts for one-pot synthesis of 7-azagramine analogues. Entry

Catalyst

Solvent

Yield (%)a

1 2 3 4 5 6 7 8 9 10 11 12b

p-TSA p-TSA FeCl3 FeCl3 ZnCl2 ZnCl2 L-Proline L-Proline HCl HCl None None

Ethanol Acetone Ethanol Acetone Ethanol Acetone Ethanol Acetone Ethanol Acetone Ethanol None

47 45 57 65 53 35 48 45 60 50 Trace 85

Reaction conditions: Conventional heating, 10 mol% catalyst, reflux, 3 h. a Isolated yields. b Solvent and catalyst free reaction under conventional heating at 80–85 8C.

S.B. Dongare et al. / Chinese Chemical Letters 27 (2016) 99–103

solventand intheabsenceofcatalyst,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 8C (Table 1, entry 12). With these optimized conditions in hand, an appropriately substituted aromatic aldehyde (1 mmol) and heteroaryl amine (1 mmol) were placed in a dried round-bottom flask containing a magnetic stirrer and the mixture was stirred at about 80–85 8C for 20 min. Then 2-methyl-7-azaindole (1 mmol) was added in portions, and the mixture was heated to 80–85 8C. 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 solution was poured into ice-water, and the precipitate formed was filtered,

101

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 from 71% to 87% were obtained. To expand the 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. 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

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

Aldehyde

Product

1

Time (h)

Yield (%)a

2.5

86

8

3

82

9

Entry

3.5

71

10

3

75

11

3

76

12

4

83

13

4

72

4c 4

4g

74

4

81

3.5

80

3.5

78

4

70

3.5

87

4l

4f 7

3

4k

4e 6

Yield (%)a

4j

4d 5

Time (h)

4i

4b 3

Product

4h

4a 2

Aldehyde

4m

S.B. Dongare et al. / Chinese Chemical Letters 27 (2016) 99–103

102

3.76 (s)

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

6.36 (d)

3.85 (s)

6.22-6.25 (m)

Entry

Aldehyde

Product

14

3.76 (s)

O

6.70 (s)

O

Time (h)

Yield (%)a

3.5

85

4

82

4.5

85

3

80

4

85

7.39-7.44 (m)

O

8.14 (d) N NH

7.61 (dd) 6.93-6.96 (m)

N

5.21 (d)

7a N H

6.08 (d)

15

2.54 (s)

8.16 (d) 10.48 (s)

Fig. 2. 1H NMR correlations of compound 4m.

7b 16

7c 17

7d 18 Fig. 3. TOCSY spectrum of compound 4m not in bold.

7e a

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

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). 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

Isolated yields.

(Scheme 2) in the absence of any catalyst and solvent, which gives the desired products 7a–e in excellent yields (Table 3). All these reactions showed rapid formation of 7-azagramine analogues at 80–85 8C 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).

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

S.B. Dongare et al. / Chinese Chemical Letters 27 (2016) 99–103

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.

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