Synthesis of 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides and their tautomerism

Two complementary pathways for the preparation of N-substituted 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides (5) were proposed and successfully realized in the synthesis of 20 representative examples. These methods use the same types of starting materials viz. succinic anhydride, aminoguanidine hydrochloride, and a variety of amines. The choice of the pathway and sequence of the introduction of reagents to the reaction depended on the amine nucleophilicity. The first pathway started with the preparation of N-guanidinosuccinimide, which then reacted with amines under microwave irradiation to afford 5. The desired products were successfully obtained in the reaction with aliphatic amines (primary and secondary) via a nucleophilic opening of the succinimide ring and the subsequent recyclization of the 1,2,4-triazole ring. This approach however failed when less nucleophilic aromatic amines were used. Therefore, an alternative pathway, with the initial preparation of N-arylsuccinimides and their subsequent reaction with aminoguanidine hydrochloride under microwave irradiation, was applied. The annular prototropic tautomerism in the prepared 1,2,4-triazoles 5 was studied using NMR spectroscopy and X-ray crystallography.

Over the past decade, there has been a substantial increase in the application of microwave irradiation in organic synthesis. It is a valuable tool used for improving the outcome of reactions, oen resulting in higher yield and product purity. 14 Utilization of microwave irradiation for the synthesis of 1,2,4triazoles has shown to provide practical and economical advantages. 11e,15 Herein, we report the development of efficient microwave-assisted methods for the preparation of 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides (5).
Annular prototropic tautomerism is an interesting phenomenon oen observed in compounds possessing a 1,2,4-triazole ring in their structure. The tautomeric preferences and factors affecting equilibrium between tautomers have been studied theoretically and experimentally, thermodynamically and kinetically due to their importance in determining chemical and biological properties of compounds. 16 We applied NMR spectroscopy to explore tautomerism in the prepared compounds and report here our ndings. X-ray crystallography was used to determine a position of the triazole ring hydrogen in the solid state.
In the model reaction, N-guanidinosuccinimide (2), prepared from succinic anhydride (1) according to the reported method, 11c was treated with morpholine under microwave irradiation to give 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamide 5a (Table 1). The optimization of conditions for the synthesis of 5a started with an attempt to perform the reaction of 2 with morpholine in ethanol under microwave irradiation at 180 C for 25 min (Table 1, Entry 1). To our satisfaction, we successfully obtained the desired product 5a in high purity aer simple ltration; however the yield was rather low (27%). The screening of solvents revealed that conducting the reaction in acetonitrile led to a better yield (Entry 4). Further optimising of the reaction conditions, we found that decreasing the reaction temperature to 170 C led to yield improvements (Entry 5). Therefore, the satisfactory results were achieved when the synthesis of Nmorpholino-substituted 3-(5-amino-1H-1,2,4-triazol-3-yl) propanamide (5a) was performed using reaction of 2 with morpholine in acetonitrile at 170 C for 25 minutes.
The optimized conditions for the preparation of 5a were successfully applied for the synthesis of 5b-i allowing the preparation of a diverse library of substituted amides of 3-(5amino-1H-1,2,4-triazol-3-yl)propanoic acid (5a-i) in the 1 mmol scale ( Table 2). Using these optimized conditions, we attempted to scale up the reaction from 1 mmol to 10 mmol. The synthesis of some products (5a, 5b, 5d, and 5i) was performed in the 10 mmol scale with similar results.
However, when we attempted to further extend the reaction scope and involve aniline in the reaction with N-guanidinosuccinimide (2) under the optimized conditions, only starting material 2 was isolated. The analysis of the reaction mixture in the attempt to prepare 5j from 2 revealed the presence of aniline and unreacted 2 only. We propose that the nucleophilicity of aniline was not sufficient to initiate the ring opening of the cyclic imide and undergo the cascade of transformations.
We attempted to carry out both steps in a one-pot fashion under microwave irradiation. First, N-phenylsuccinimide (4a) was heated with aminoguanidine hydrochloride in ethanol at 170 C Scheme 1 Two pathways to the synthesis of N-substituted 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides (5). Table 1 Optimization of conditions for the synthesis of N-morpholino-substituted 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamide (5a) a Entry Solvent Temperature ( C)  a The reaction was performed using Discover SP CEM microwave synthesizer with 1 mmol of 2 and 2 mmol of morpholine in 1 mL of the specied solvent. b 1 mmol of 2 and 3 mmol of morpholine were used for the reaction. c 1 mmol of 2 and 1.5 mmol of morpholine were used for the reaction.
for 50 min. Aer cooling, an aqueous solution of potassium hydroxide was added to the reaction mixture and heating was continued at 180 C for 15 min. We found that using non-aqueous solution of the same base dramatically increased the yield, while altering the solvent of the reaction had minimal effect on the outcome of the reaction (Table 3, Entries 2-5). Continuing optimization of the process using ethanol as the solvent, we observed that altering the reaction time before and aer the addition of the base did not improve the outcome of the reaction (Entries 6-8).
Unfortunately, further manipulations with the reaction temperature, time, type of base, or ratio of the reagents did not lead to any improvement in yields (e.g. Entries 9-11). These conditions were the most efficient for the preparation of 3-(5-amino-1H-1,2,4triazol-3-yl)propananilide (5j), which was obtained using this onepot process in 58% yield (Entry 3).
In the 13 C NMR spectra of the prepared compounds, the triazole ring signals appeared as two broad signals conrming its involvement in tautomerism. However, the tautomeric transformations were probably too fast to be detected by the 13 C NMR spectroscopy under the experimental conditions and therefore tautomers were indistinguishable.

X-ray crystallography
The tautomerizable 1,2,4-triazoles with a primary amino on a carbon atom typically crystallize as 5-amino-forms with an annular hydrogen atom located at the side of the amino group. 19 An example of two tautomers (5-amino-and 3-amino-forms) of 1H-1,2,4-triazoles appearing together in one crystal was also reported. 20 To explore tautomeric preferences in the prepared compounds in solid state, the crystal and molecular structures of a representative compound 5j were determined by X-ray crystallography; the molecular structure is shown in Fig. 1.
The key point of interest in the structure determination is the assignment of the tautomeric form for the triazole ring. The crystallographic analysis indicates the ring-H atom to be located on the N1 atom of the 5-amino-form (see Experimental). This assignment, i.e. 5-amino-1H-1,2,4-triazole, is conrmed in the distribution of bond lengths within the ring and in the nature of the supramolecular association in the crystal of 5j (see below). Thus, the C5-N1 bond length of 1.3359(15)Å is considerably longer than the C3-N2 bond of 1.3164(15)Å; the N1-N2 bond length is 1.3837(14)Å. Further, the C3-N4 and C5-N4 bond lengths vary systematically, i.e. 1.3681(15)Å is longer than 1.3351(15)Å. These observations are consistent with localisation of p-electron density in the C3-N2 and C5-N4 bonds. Overall, the molecule has the shape of the letter L as seen in the values of the dihedral angles formed between the central amide residue (r.m.s. deviation of the O8, N8, C7 and C8 atoms from the least-squares plane ¼ 0.0084Å) and the veand sixmembered rings of 79.54(4) and 24.78(6) , respectively, indicating, to a rst approximation, a co-planar relationship between the amide and phenyl groups with the triazole ring lying perpendicular to this; the dihedral angle between the veand six-membered rings is 86.65(4) .
As mentioned above, the molecular packing in the crystal of 5j conrms the assignment of the tautomeric form of the vemembered ring. The crucial hydrogen bonding involving the a The reactions were performed using a Discover SP CEM microwave synthesizer with 1 mmol of 4a and 1 mmol of aminoguanidine hydrochloride in 1 mL of the specied solvent in the rst step and addition of 1.2 mmol of the base in the second step. b 1.2 mmol of aminoguanidine hydrochloride and 1.4 mmol of KOH were used in the reaction.

Scheme 2 Synthesis of N-arylsuccinimides (4).
triazole ring sees the formation of donor triazole-N1-H/O8 (carbonyl) and acceptor amine-N5-H/N2 (triazole) hydrogen bonds conrming protonation at the triazole-N1 atom at the amino group side. The second amine-N5-H atom forms a comparatively weaker hydrogen bond to the carbonyl-O8 atom to close a seven-membered {NH/O/HNH/N} supramolecular synthon; geometric details of the hydrogen bonding are given in the caption to ESI Fig. S1. † As shown in Fig. 2, three molecules are involved in the aforementioned hydrogen bonding scheme so that the seven-membered synthon is anked on either side by 11-membered {NH/OC 4 N/HNC} synthons. Connections between the aforementioned aggregates Table 4 Microwave-assisted synthesis of N-arylamides of 3-(5-amino-1H-1,2,4-triazol-3-yl)propanoic acid (5j-t) a are of the type amide-N8-H/N4 (triazole) which generate centrosymmetric, 14-membered {/NC 4 NH} 2 synthons. The hydrogen scheme just described extends laterally to form a supramolecular layer parallel to (1 0 1), see ESI Fig. S1a. † The most obvious directional points of contact between layers to consolidate the three-dimensional molecular packing are of the type methylene-C7-H/p(C9-C14); a view of the unit cell contents is shown in ESI Fig. S1b. †

General information
Melting points (uncorrected) were determined on a Stuart™ SMP40 automatic melting point apparatus. 1 H and 13 C NMR spectra were recorded on a Bruker Fourier 300 spectrometer (300 MHz), using DMSO-d 6 as a solvent and TMS as an internal reference. IR spectra were recorded on a Varian 640-IR FT-IR spectrometer using KBr mode. Microwave-assisted reactions were performed in closed vessel focused single mode using a CEM Discover SP microwave synthesizer (CEM, USA). The reaction temperatures were measured by an equipped IR sensor.