Synthesis of new racemic α-heterocyclic α,α-diaminoesters and α-aminoester carboxylic

1 Introduction

The investigation of amino acids is of fundamental interest to scientists from many diverse fields. This interest derives from their role as the basic constituents of proteins in addition to their ability to serve as building blocks for the production of many classes of secondary metabolites.

α-Amino acids play an important role in different areas because of the wide spectrum of activity they have (enzymology, medicine and pharmacology, industry, asymmetric synthesis, …) (Beers et al., 1996; Mikolajczyk, 2005; Joly and Jacobsen, 2004; Leite et al., 2006; Moreira et al., 2007).

This has led to the development of numerous synthetic methods for a variety of compounds (Haemers et al., 1989).

The recent literature is enriched with progressive findings about the synthesis and pharmacological action of fused heterocycles. Heterocycles bearing a symmetrical triazole and furan are reported to show a broad spectrum of pharmacological properties such as anti-inflammatory, antiviral and antibacterial activities (Boschelli et al., 1993; Unangst et al., 1992; Hung and Chen, 2001; Srivastava et al., 1984; Saad, 1996; Hui et al., 2002).

Because of their multiple functionalities, amino acids heterocyclics play a considerable role in the biologic processes (Costantino et al., 2004; Jorgensen et al., 2007). So a large number of between them isolated of plants have a very varied biologic activity (Schenk and Werner, 1991).

Over the past decades, nitrogen-containing heterocyclic molecules have been considered as the privileged synthetic targets in the pharmaceutical and veterinary industries (Katritzky et al., 1996; Undheim and Benneche, 1999; Joule and Mills, 2000; Katritzky et al., 2003) because of their diverse biological properties and a wide variety of applications, e.g., anticancer, diuretic, anticonvulsant, anti-inflammatory and anti-hypertensive activities (Chan et al., 1997; Gackenheimer et al., 1996; Dempcy and Skibo, 1991).

The 1,2,4-triazole and its derivatives were reported to exhibit various pharmacological activities, such as antimicrobial, analgesic, anti-inflammatory, anticancer and antioxidant properties (Padmavathi et al., 2008; Amir et al., 2008; Sztanke et al., 2008; Kus et al., 2008). Some of the present day drugs, such as Ribavirin (antiviral agent), Rizatriptan (antimigraine agent), Alprazolam (anxiolytic agent), Fluconazole and Itraconazole (antifungal agents) are the best examples for potent molecules possessing triazole nucleus.

Quinaldine derivatives are very important photographic sensitizers; they are used as dyes (textile, printing inks, and food), drugs, cosmetics and indicators (Finar, 1995; Sanyal et al., 1979; Shashidhar, 1974).

For this reason, we considered it interesting to synthesize new compounds containing[1,2,4]-triazole nucleus, 2-tetrahydrofuran-2-ylmethanamine and 2-methylquinolin-4-amine fused with a amino acid, in order to study their biological activities. The present study describes the synthesis and characterization of novel α-aminoesters derivatives.

2 Results

We continued our investigations on the use of organic azides (Boukallaba et al., 2006, 2007) in heterocyclic synthesis; we reported in this paper another part of our investigations concerning the preparation of new carboxylic α,α-diaminoesters carrying a variety of heterocyclic in position α.

Our strategy is based on the nucleophilic substitution of methyl α-azido glycinate N-benzoylated 1 with amines (Scheme 1). Azide derivative 1 was prepared using Steglich method (Steglich and Kober, 1983) and Achamlale’s procedure (Achamlale et al., 1997, 1999).

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Scheme 1

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Methyl α-azido glycinate N-benzoylated 1 was obtained by the reaction (Achamlale et al., 1997, 1999) of sodium azide with the methyl α-bromo glycinate. The title compound is stable and can be stored for an unlimited time without any signs of decomposition. The methyl α-bromo glycinate also can be used and gives satisfactory results; the azide 1 is used especially for its stability.

The reaction of different amines Nu on azide derivative 1 results in Compounds 2–4 carrying heterocyclic amines.

As a first step and to optimize the different reaction conditions (choice of base, solvent, …), we conducted several test reactions. For all these tests, the reactions were followed by TLC and ¹H NMR. Yields are given as pure product after column chromatography on silica gel.

After several attempts of reactions without base or in the presence of bases such as triethylamine, reaction with diisopropylethylamine (DIEPA) gave the best results. The reaction was carried out in dry acetone at room temperature. Results are summarized in Table 1.

The products 2–4 were obtained in 60–77.5% overall yield from 1 and were analyzed by MS, ¹³C NMR and ¹H NMR.

For the reaction of 3-amino-1,2,4-triazole with azide 1, our estimate was to have two products with the predominance of one over another, but the spectroscopic data obtained showed the existence of only a single product: methyl 2-benzamido-2-(3-amino-1,2,4-triazol-1-yl) acetate 2 (Scheme 2).

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Scheme 2

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Comparing these results with the work done by our team (Boukallaba et al., 2006, 2007): synthesis of new α-heterocyclic α-aminophosphonates and synthesis of α-heterocyclic α-aminophosphonates, Part II: morpholine, piperidine, pyrrolidine, tetrahydrofurylmethylamine, N-benzyl-N-methylamine, and aniline derivatives, we see that we have obtained almost the same results.

The methyl glycinate prepared may be protected by different protecting groups: trifluoroacetic anhydride, trichloroethoxycarbonyl chlorides, acetyl chloride and benzoyl chloride. The protection reaction is carried out in dichloromethane in the presence of triethylamine or pyridine. After column chromatography on silica gel the aminoesters N-protected are obtained in good yields.

3 Conclusion

In conclusion, this method provides general and convenient access to a wide range of α,α-diaminoesters and α-aminoesters derivatives starting from the appropriate azide derivative 1. The nucleophilic substitution of methyl α-azido glycinate N-benzoylated 1 with different amines (3-amino-1,2,4-triazole, 2-tetrahydrofuran-2-ylmethan-amine and 2-methylquinolin-4-amine) occurred under very mild conditions and led to the desired products in good yields.

4 Experimental

4.3

4.3 Methyl 2-benzamido-2-(3-amino-1,2,4-triazol-1-yl) acetate 2: yield: 77.5%; mp

214–216 °C (ether/hexane); R_f: 0.3 (ether) ¹H NMR (CDCl₃): δppm: 3.9 (s, 3H, OCH₃); 5.6 (br s, 2H, NH₂); 6.45 (d, 1H, J = 7.2 Hz, H_α); 7.47–8.05 (3 m, 7H, Ar + H_triazol + NH_amid). ¹³C NMR (CDCl₃): δppm: 54.04 (OCH₃); 60.67 (–CH–); 106.42, 127.42, 128.92, 133.01, 149.92, 155.70, (C₆H₅ aromatic carbons); 165.62, 168.16 (2CO). M.S-E.I: m/z = 275.8[M]; C₁₂H₁₃N₅O₃.

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4.4

4.4 Methyl 2-benzamido-2-[(tetrahydro-furan-2-ylmethyl)amino]acetate 3: yield

72%; m.p.: 130–132 °C (ether/hexane); R_f: 0.6 (ether); ¹H NMR (CDCl₃): δppm: 1.2–1.75 (2 m, 5H, H_T.H.F); 2.9 (m, 2H, NCH₂); 3.75 (s, 3H, OCH₃); 4.1–4.45 (2 m, 3H, H_T.H.F + NH); 5.6 (br s, 1H, H_α); 7.4–8.02 (3 m, 5H, Ar + NH_amid). ¹³C NMR (CDCl₃): δppm: 4× (CH₂) 24.13, 27.07, 50.25, 66.12; 54.49 (OCH₃); 71.32 (–CH–); 77.23 (OCH); 128.34, 129.54, 131.33, 135.77 (C₆H₅ aromatic carbons); 169.07, 171.98 (2CO). MS (electrospray) m/z = 293.3[M+1]; 292.3[M]; C₁₅H₂₀N₂O₄.

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4.5

4.5 Methyl 2-benzamido-2-(2-methylquinolin-4-ylamino) acetate 4

yield: 60%; m.p.: 158–160 °C (ether/hexane); R_f: 0.6 (ether); ¹H NMR (CDCl₃): δppm: 3.57 (3H, s, CH₃); 3.88 (s, 3H, OCH₃); 4.9 (br s, 1H, NH); 5.8 (d, 1H, J = 9.0 Hz, H_α); 6.2 (br s, 1H, Ar); 6.7–7.9 (3 m, 10H, Ar + NH_amid). ¹³C NMR (CDCl₃): δppm: 24.13 (CH₃); 53.08 (OCH₃); 56.98 (–CH–); 78.69, 109.23, 116.34, 120, 125.33,127.25, 128.77,132.38, 133, 149.12, 149.23, 159.77, (C₆H₅ aromatic carbons); 168.58, 171 (2CO) M.S-E.I: m/z = 349.1[M]; C₂₀H₁₉N₃O₃.

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