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Synthesis and Characterization of New Racemic α-Heterocyclic α,α-Diaminoester and α,α-Diamino Acid Carboxylic: 2-Benzamido-2-[(Tetrahydro-Furan-2-Ylmethyl)Amino]Acetate and 2-Benzamido-2-[(Tetrahydro-Furan-2-Ylmethyl)Amino] Acetic Acid

Written By

El Houssine Mabrouk

Submitted: 24 April 2021 Reviewed: 15 May 2021 Published: 11 May 2022

DOI: 10.5772/intechopen.98408

From the Edited Volume

Furan Derivatives - Recent Advances and Applications

Edited by Anish Khan, Mohammed Muzibur Rahman, M. Ramesh, Salman Ahmad Khan and Abdullah Mohammed Ahmed Asiri

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We reported here the synthesis of new α,α-diaminoester and α,α-diamino acid derivatives, as 2-benzamido-2-[(tetrahydro-furan-2-ylmethyl)amino] acetic acid through alkaline hydrolysis reaction of corresponding N-benzoylated methyl α,α-diamino ester. The α,α-diaminoester derivative was synthesized by nucleophilic substitution of methyl α-azido glycinate N-benzoylated with 2-tetrahydrofuran-2-ylmethan-amine. The structure of these products were established on the basis of NMR spectroscopy (1H, 13C), and MS data.


  • Amino acid
  • Amine
  • Heterocyclic molecules
  • Nucleophilic substitution
  • Methyl α-azido glycinate
  • α
  • α-Diamino ester
  • α
  • α-diamino acid
  • alkaline hydrolysis reaction

1. Introduction

α-amino acids are a considerable interest due to their diversity in several fields of research (asymmetric organic synthesis and medicine) and applications (food industry and drugs). Given the very broad activity they present, research teams are interested in evaluating and developing their role for very effective use [1, 2, 3, 4, 5]. This has led to the development of numerous synthetic methods for a variety of compounds [6]. Heterocyclic chemistry is the basis for the discovery of the importance of the multiple medical properties of these compounds [7, 8, 9, 10, 11, 12].

Because of their multiple functionalities, heterocyclic amino acids play a considerable role in the biologic processes [13, 14]. Therefore, a large number of between them isolated of plants have a very varied biologic activity [15].

Heterocyclic compounds have a wide spectrum activities, including antimicrobial [16, 17] and antibacterial properties [18, 19], anticancer agents [20], antiviral [21], antitumor activity [22], and in agricultural science as potent fungicides, herbicides and insecticides [23]. Heterocyclic amino acids and their derivatives represent a well-known group of organic compounds also presenting biological activity [24, 25, 26]. Considering the interest in these heterocyclic amino acids, several structurally related nonproteinogenic amino acids and their derivatives have been the subject of various investigations [27, 28, 29]. We present herein a convenient and easy procedure for the preparation of new racemic carboxylic α,α-diamino acid derivative with the aim to have access to new active biomolecule with a good yield.

For this reason, we considered it interesting to synthesize new compounds containing 2-tetrahydrofuran-2-ylmethanamine [30, 31] fused with an amino acid, in order to study their biological activities. The present study describes the synthesis and characterization of new α,α-diamino ester and α,α-diamino acid derivatives.


2. Results and discussions

2.1 Synthesis of new racemic α-carboxylic α,α-diamino ester

2.1.1 Preparation of azide dipole

The first step of the synthesis strategy that we have developed consists in preparing the methyl ester of glycine N-protected by benzoyl chloride. Thus, the esterification of the starting amino acid is carried out by the action of thionyl chloride in anhydrous methanol on glycine and leads to the corresponding hydrochloride 1 with good yield (Yield = 92%). The hydrochloride is neutralized by adding triethylamine or bubbling gaseous ammonia (Figure 1).

Figure 1.

Preparation of N-protected methyl α-azidoglycinate 5.

The methyl glycinate 2 thus prepared is protected with benzoyl chloride. The protection reaction is carried out in dichloromethane in the presence of triethylamine or pyridine. After chromatography on a silica gel column, the N-protected aminoester 3 is obtained in good yields. Different protecting groups may protect the methyl glycinate 2: trifluoroacetic anhydride, trichloroethoxycarbonyl chlorides and acetyl chloride.

The bromination reaction of N-protected amino ester is carried out by bromine in the presence of α,α’-azo-bis-isobutyronitrile (AIBN) in a catalytic amount or by N-bromosuccinimide, in reflux of carbon tetrachloride and under the irradiating action of a 300 W lamp. In general, methyl N-benzoyl α-bromoglycinate 4 is obtained in excellent yields. This product is used in most cases without purification in the next step (Figure 1).

The substitution of bromine by the azide group is effected by the action of sodium azide, in acetone, at room temperature for a period ranging from 4 to 5 hours. Purification of the reaction crude by chromatography on a silica gel column (eluent: 50/50 ether/hexane) allows substitution product 5 to be obtained with excellent yield. The title compound is stable and can be stored for an unlimited time without any signs of decomposition. The methyl α-bromo glycinate 4 also can be used and gives satisfactory results; the azide 5 is used especially for its stability.

2.1.2 N-alkylation of the amine by N-protected methyl α-azidoglycinate 5

We continued our investigations on the use of organic azides [30, 32, 33, 34, 35, 36, 37] in heterocyclic synthesis; we reported in this paper another part of our investigations concerning the preparation of new carboxylic α,α-diaminoester carrying heterocyclic in position α. Our strategy is based on the nucleophilic substitution of methyl α-azido glycinate N-benzoylated 5 with 2-tetrahydrofuran-2-ylmethanamine (Figure 2).

Figure 2.

2-Benzamido-2-[(tetrahydro-furan-2-ylmethyl) amino] methyl acetate 6.

In order to make a comparative study and to find the best experimental mode for this synthesis strategy, we carried out the synthesis reaction of the α,α-diaminoester in the absence and in the presence of a base (triethylamine (Et3N) or diisopropylethylamine (DIEPA)) in a solvent (dichloromethane (DCM) or acetone). The results in Table 1 clearly show that the good yield is obtained using acetone in the presence of DIEPA.

Yield (%)
Yield (%)
Yield (%)
Yield (%)
Yield (%)

Table 1.

Different operating conditions for the synthesis reaction of 2-benzamido-2 - [(tetrahydro-furan-2-ylmethyl) amino] methyl acetate 6.

2.2 Synthesis of new racemic α-carboxylic α,α-diamino acid

In continuation of our research, we will present in this work, our results concerning the synthesis of new α,α-diamino acid derivative, as 2-benzamido-2-[(tetrahydro-furan-2-ylmethyl)amino] acetic acid through alkaline hydrolysis reaction of corresponding N-benzoylated methyl α,α-diamino ester [31]. After the obtaining of the N-protected methyl α,α-diamino ester 6, we proceeded to the cleavage of the protecting groups to obtain the corresponding α,α-diamino acid 7. The hydrolysis reaction of the α,α-diamino ester methyl 2-benzamido-2-[(tetrahydro-furan-2-ylmethyl)amino]acetate 6 in a basic medium is carried out for approximately 30 minutes and leads, after acidification of the reaction medium with sulfuric acid or hydrochloric acid, to the corresponding α,α-diamino acid 2-benzamido-2-[(tetrahydro-furan-2-ylmethyl) amino] acetic acid 7 in good yield (Figure 3).

Figure 3.

2-Benzamido-2-[(tetrahydro-furan-2-ylmethyl)amino] acetic acid 7.


3. Conclusion

The first step in our synthesis strategy is to prepare the azide dipole. In the second step, our objective is the preparation of carboxylic α,α-diaminoester and diamino acid carrying a heterocycle in position α. This method provides an easy procedure for the preparation of new carboxylic α,α-diamino acids derivatives in very satisfactory yields starting from the appropriate azide derivative 5. The nucleophilic substitution of methyl α-azido glycinate N-benzoylated 5 by 2-tetrahydrofuran-2-ylmethanamine occurred under very mild conditions and led to the 2-benzamido-2-[(tetrahydro-furan-2-ylmethyl)amino]acetate in good yield. 2-benzamido-2-[(tetrahydro-furan-2-ylmethyl)amino] acetic acid was synthesized through alkaline hydrolysis reaction of corresponding N-benzoylated methyl α,α-diaminoester.


4. Experimental

4.1 N-alkylation reaction procedure

To facilitate the nucleophilic attack of 2-tetrahydrofuran-2-ylmethanamine (5.72. 10−3 moles) on methyl α-azido glycinate (5.2. 10−3 moles), one adds at the start (6.24. 10−3 moles) of diisopropylethylamine on the amine in 20 ml of dry acetone. Deprotonation of the amine is carried out with stirring for one hour before adding the azide. At the end of the reaction which takes place for 48 hours, the evaporation of the solvent takes place under reduced pressure, decantation is ensured by dichloromethane or ethyl acetate using (Na2SO4) as desiccant, the product N-alkylated is purified by recrystallization or chromatography on a silica gel column (hexane/ether).

4.2 N-benzoylated methyl α,α-diaminoester: Methyl 2-benzamido-2-[(tetrahydro-furan-2-ylmethyl)amino]acetate 6

Yield = 72.0%; m. p. °C (hexane/ether (1/1)): 130–132; Rf (ether) = 0.63; M.S. (electrospray) m/z = 292.3 [M]; 293.3 [M + 1]; C15H20N2O4. 13C NMR (δppm, CDCl3): (2CO): 171.98, 169.07; C6H5 (aromatic): 135.77, 131.33, 129.54, 128.34; (OCH): 77.23; (-CH-): 71.32; (OCH3): 54.49; 4· (CH2): 66.12, 50.25, 27.07, 24.13. 1H NMR (δppm, CDCl3): 8.02–7.40 (5H, NHamid + Ar, 3 m); 5.60 (1H, Hα, br s); 4.45–4.10 (3H, NH + HTHF, 2 m); 3.75 (3H, OCH3, s); 2.90 (2H, NCH2, m); 1.75–1.20 (5H, HTHF, 2 m).

4.3 Deprotection of acid function: Synthesis of N-benzoylated α,α-diamino acid derivative 7

To a solution of the N-benzoylated α,α-diamino ester derivative (1 mmole) in 10 mL of dioxane/water mixture (8/2), one adds 1.5 mmole of NaOH (0.5 N) with stirring and at 0°C. The stirring is maintained at room temperature until disappearance of the starting material. The reaction is always followed by TLC. The solvent is then evaporated and the pH of the aqueous phase is adjusted to 6 using a solution of sulfuric acid or hydrochloric acid (0.5 N). One extracts with ethyl acetate and the organic layers recovered, are dried and concentrated under vacuum. The product is recrystallized from ether/hexane.

4.4 2-Benzamido-2-[(tetrahydro-furan-2-ylmethyl)amino]acetic acid 7

Yield: 88%; Rf: 0.7 (ether); 1HNMR (CDCl3): δppm: 1.25–1.80 (2 m, 5H, HT.H.F); 2.85 (m, 2H, NCH2); 4.20–4.50 (2 m, 3H, HT.H.F + NH); 5.5 (br s, 1H, Hα); 7.45–8.00 (3 m, 5H, Ar + N-Hamid). 13C NMR (CDCl3): δppm: 4 (CH2) 25.45, 27.18, 52.05, 66.42; 72.12 (-CH-); 77.26 (OCH); 127.84, 129.34, 131.72, 135.68 (C6H5 aromatic carbons); 169.12, 171.92 (2CO). MS (electrospray) m/z = 279.2 [M + 1]; 278.2 [M]; C14H18N2O4.


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Written By

El Houssine Mabrouk

Submitted: 24 April 2021 Reviewed: 15 May 2021 Published: 11 May 2022