The Synthesis of Novel 7-(Substituted benzyl)-4,5-dihydro[1,2,3]-triazolo[1,5- a ]pyrazin-6(7 H )-ones via Tandem Ugi–Huisgen Reactions

A convenient method for the synthesis of 2-azido-3-aryl- propanoic acids via the Meerwein halogenoarylation reaction of acrylic acid esters with diazonium salts, subsequent nucleophilic substitution of the halogen by an azide, and saponification is developed. The newly formed 2-azido-3-arylpropanoic acids react under the conditions of non-catalytic four-component Ugi reactions, leading to the formation of  -azidoamides in good yields. The use of propargylamine as the amine component allows the formation of Ugi adducts with azide and acetylene motifs ready for intramolecular 1,3-dipolar Huisgen cycload- dition to give the [1,2,3]triazolo[1,5- a ]pyrazine annulated system. The Ugi reaction is found to give 2-azido-3-aryl- N -(2-oxo-1,2-disubstituted ethyl)- N -(prop-2-yn-1-yl)propanamides at room temperature without azide–alkyne cycloaddition. These dipeptides are converted into 4,5-di- hydro[1,2,3]triazolo[1,5- a ]pyrazin-6(7 H )-ones in near quantitative yields by heating in toluene. However, when the Ugi reaction is carried out by heating, it results in a one-pot Ugi–Huisgen tandem reaction leading to 4,5-dihydro[1,2,3]triazolo[1,5- a ]pyrazin-6(7 H )-ones in excel- lent yields. Moreover, the possibility of the incorporation of a bromovi-nyl fragment (the synthetic equivalent of an acetylene fragment) via the aldehyde component of the Ugi reaction is demonstrated in an al-ternative preparation of the [1,2,3]triazolo[1,5- a ]pyrazine system.

Reactions of acrylic acid esters with diazonium salts under Meerwein arylation conditions is a convenient route to a variety of alkyl 3-aryl-2-bromopropanoates. Such esters have already been used for the incorporation of substituted benzyl motifs into thiazoles, quinoxalines, 1,4-thiazines, and thiomorpholines, 18 and for the preparation of alkyl 2-(1,2,3-triazol-1-yl)-3-arylpropanoates. 19 We have investigated this approach for the formation of a combinatorial library of 2-azido-3-arylpropanoic acids. CuBr-catalyzed arylation of acrylic acid esters 2a,b with diazonium salts obtained from readily available anilines 1a-k gave methyl 3-aryl-2-bromopropanoates. Subsequent nucleophilic substitution of bromine with sodium azide and saponification of the ester group under mild conditions produced novel 2-azido-3-arylpropionic acids 3a-k in good overall yields (Scheme 2). The 2-azido-3-arylpropionic acids 3a-k were produced pure without the need for chromatographic purification. Remarkably, substitution of the bromine by the azide and hydrolysis of the ester group proceeded quantitatively without side reactions such as nucleophilic elimination leading to cinnamic acids. Using this method, a diverse combinatorial library of 2-azido-3-arylpropionic acids could be obtained in gram quantities, with both donor and acceptor substituents on the aromatic core, thereby expanding the possibilities for studying their chemical properties.
Scheme 2 Synthesis of 2-azido-3-arylpropanoic acids 3a-k The synthesized 2-azido-3-arylpropionic acids 3 were studied in a non-catalytic four-component Ugi reaction. It is well-known that the four-component Ugi reaction represents one of the most powerful tools for the rapid and direct synthesis of linear dipeptides. 20 The growing interest in peptidomimetics as pharmacological agents has promoted active research and applications of the Ugi reaction. Due to the high flexibility of the Ugi reaction, a wide range of linear bis-amides and pseudo-peptides (linear or cyclic) with different functional groups can be obtained. A variety of heterocyclic compounds with different biological activities can also be synthesized by various post-modifications. 21 For example, in 2019, the anticancer drug ivosidenib was approved in the United States, which was the first drug produced using the Ugi reaction. 22 Moreover, Ugi adducts are convenient precursors for further heterocyclization to obtain a wide range of heterocyclic derivatives with different ring sizes, as discussed in recent reviews. 23 It should be noted that for a long time the main limitation in the application of the Ugi reaction was the problematic odors associated with the preparation and purification of the starting isonitriles. Recently, however, a practical flash chromatography protocol has been proposed that enables the preparation of highly pure isonitriles in short times. 24 N. T. Pokhodylo et al.

Paper Synthesis
Firstly, 2-azido-3-arylpropionic acids 3a-k were tested in the Ugi reaction with cyclopropylamine (4a) and 2,2,2trifluoroethylamine (4b). The target Ugi adducts 7a-c were obtained by mixing the components in methanol at room temperature for 20-30 minutes (Scheme 3). The reaction was monitored by TLC for the disappearance of the starting azido acid. Compounds 7a-c did not require further purification and were separated from the reaction mixture by filtration as individual white crystalline substances.
LC-MS analysis data confirmed that compounds 7a-c were indeed pure, individual reaction products, indicating excellent selectivity. The presence of a highly reactive azide group in the obtained adducts 7a-c makes them suitable building blocks for the modification of peptide molecules.
To allow intramolecular cyclization to form a cyclic [1,2,3]triazolo[1,5-a]pyrazine system, propargylamine (4c) was introduced into the Ugi reaction, and a series of compounds (8a-i) was obtained (Scheme 4). In this case, the reaction took place at room temperature, and the target products precipitated from the reaction medium in the form of a white precipitate. With the participation of alkyl isonitriles, the reaction proceeded within 10-30 minutes, whilst the introduction of aryl isonitriles into the reaction prolonged the reaction time to 40-60 minutes.
Considering that there are rotamers present in compounds 8 (see the Supporting Information), which complicate the signal assignments in the 1 H NMR spectra, 13 C NMR spectra were used to monitor the progress of the cycloaddition based on the acetylene signals appearing in the region

Paper Synthesis
of the spectrum highlighted within the red frame in Figure  2. The 13 C NMR spectrum of the non-cyclic Ugi adduct 8c is shown in Figure 2A, whilst that of the corresponding Huisgen cyclization product 9b is displayed in Figure 2B. The 13 C NMR spectrum of compound 8c exhibits characteristic signals at 79.24 (C sp ) and 74.70 (CH sp ) ppm, indicating the presence of a propargyl fragment, while no such peaks were observed in the 13 C NMR spectrum of the dry residue after refluxing in toluene (compound 9b). The target products 9a-f were obtained from the reaction medium by evaporation of toluene under reduced pressure, and they did not require any further purification. Thus, the Huisgen cyclization of compounds 8a-i occurs quantitatively without the formation of side products. It is known that similar cyclizations of NH-unsubstituted 2-azido-N-(prop-2ynyl)propanamides are accompanied by the formation of intermolecular interaction products, and the formation of the targeted 4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones is achieved under high pressure in the presence of microwave irradiation. 25 Apparently, intermolecular conjugation leading to the formation of oligomeric products is unfavorable due to steric factors.
Next, the one-pot tandem Ugi-Huisgen reaction was studied. After increasing the temperature of the Ugi reaction to 50 °C and extending the reaction time to 72 hours, cyclic [1,2,3]triazolo[1,5-a]pyrazin-6(7H)-one adducts 9 were obtained as individual products (Scheme 6). This synthetic approach minimizes losses during isolation of the intermediate and is effective when the linear Ugi adducts are markedly soluble in methanol, making their isolation difficult.

Scheme 6
The one-pot tandem Ugi-Huisgen reaction

Paper Synthesis
The [1,2,3]triazolo[1,5-a]pyrazin-6(7H)-ones 9g,h obtained by the one-pot method were further purified by recrystallization from dichloromethane/hexane (3:1). It should be noted that different types of crystals were formed depending on the crystallization rate, which affects the physicochemical properties of the substance. Thus, rapid crystallization (1 day) of product 9g resulted in the formation of crystals with mp = 238-240 °C, whilst slow crystallization over 10 days led to the formation of crystals with mp = 181-183 °C. X-ray diffraction analyses were performed on both crystal types. 26 The two diastereomers of 9g [9g (A) and 9g (B)] crystallize in the centrosymmetric space groups C2/c and Pbcn, respectively, each with one molecule in the asymmetric unit ( Figure 3). The molecules exhibit some differences in their geometries; for example, the corresponding N4-C13-C17-N5 torsion angles are 127.1(2)° in 9g (A) and -90. 9(2)° in 9g (B).
X-ray structural analysis data showed that the 4 optical isomers of compound 9g separated into two pairs of enantiomers during crystallization. A pair of (R,S)-and (S,R)-isomers [9g (A)] crystallized first, and after a lengthy period of time (approximately 2 weeks), a pair of (R,R)-and (S,S)-isomers [9g (B)] crystallized. The significant difference in crystallization times of the different optical isomers is a convenient and effective technique in separating the diastereomeric mixture of products 9 into separate optical isomers.
The dipolarophilic group for the Huisgen-1,3-dipolar cycloaddition to construct the [1,2,3]triazolo[1,5-a]pyrazin-6(7H)-one system could also be involved in the Ugi reaction via the aldehyde moiety. First, 3-phenylpropiolaldehyde was tested in the Ugi reaction with 2-azido-3-arylpropionic acids. However, we were unable to obtain any linear Ugi adducts, probably due to the instability of the intermediate Schiff bases formed during the Ugi reaction with 2-azido-3-arylpropionic acids. However, this synthetic route could be successfully carried out with the synthetic precursor (Z)-2-bromo-3-phenylacrylaldehyde. Thus, the Ugi product 7a, on refluxing in toluene with one equivalent of triethylamine, undergoes a Huisgen cyclization to give polysubstituted [1,2,3]triazolo[1,5-a]pyrazin-6(7H)-one 10 in a high yield (Scheme 7). Finally, we decided to test the chemoselectivity of the 1,3-dipolar Huisgen cycloaddition in the presence of the two dipolarophiles we had studied in the Ugi reaction. For this purpose, adduct 8j was prepared. A thermally initiated cycloaddition was performed and it was found that in our case only the propargyl fragment was involved in the 1,3dipolar cycloaddition. Compound 11 was the only product produced from the reaction mixture. The possible alternative product 12 or its intermediate were not observed (Scheme 8).

Paper Synthesis
propionic acids could be used in a multicomponent Ugi reaction to obtain new polysubstituted dipeptides. In the Huisgen reaction, these compounds form a triazole ring from which 2-(7-aryl-6-oxo-6,7-dihydro[1,2,3]triazolo[1,5-a]pyrazin-5(4H)-yl)acetamides are formed. A convenient onepot method was also proposed and developed for the tandem Ugi-Huisgen reaction. Thus, the sequential combination of the Ugi reaction and Huisgen cyclization is a convenient synthetic approach for the preparation of a broad range of 7-(substituted benzyl)-4,5-dihydro[1,2,3]triazolo-[1,5-a]pyrazin-6(7H)-ones, starting from 2-azido-3-arylpropionic acids, without the use of metal catalysts, specific equipment and chromatographic purification of the target products, which is in good agreement with modern concepts of organic synthesis. The method is generally applicable to a wide range of starting substrates and allows the introduction of pharmacophoric fragments of natural amino acid residues into the target molecule, for example, the compounds we obtained containing glycine (9c), valine (9g) and tryptophan (9h) residues. The obtained compounds are of significant interest as potential biologically active compounds. In addition, the products obtained with 2-bromobenzaldehyde may serve as suitable precursors for further intramolecular cross-couplings, giving rise to new polycyclic systems. 1 H and 13 C NMR spectra were recorded on Varian Unity Plus 400 (400 and 101 MHz, respectively), Bruker 170 Avance 500 (500 and 126 MHz, respectively), and Agilent 600 MHz Premium COMPACT (600 and 151 MHz, respectively) spectrometers in DMSO-d 6 , using TMS or the residual solvent peaks (2.50 ppm for 1 H nuclei and 39.5 ppm for 13 C nuclei) as internal references. Mass spectral analyses were performed using an Agilent 1100 series LC/MSD in API-ES/APCI mode (200 eV). Elemental analysis was accomplished using a Carlo Erba 1106 instrument. Melting points were determined on a Boetius melting point apparatus. The starting anilines 1, amines 4, aldehydes 5 and toluenesulfonylmethyl isocyanide (6h) were commercially available and ware used without further purification.

2-Azido-3-arylpropanoic Acids 3a-k; General Procedure
Aniline 1 (0.25 mol) was dissolved in an excess of 48% bromic acid (62.3 mL, 0.55 mol). The obtained mixture was cooled to 0 °C and a solution of sodium nitrite (17.25 g, 0.25 mol) in water (10 mL) was added. The resulting diazonium bromide solution was added dropwise to a mixture of methyl acrylate 2 (0.25 mol), acetone (250 mL), water (15 mL), and copper(I) bromide (2.5 g) with stirring. After 40 min, the reaction mixture was poured into water. The liquid products were extracted with DCM and the solvent evaporated in vacuo. The crude methyl 2-bromo-3-aryl propanoates were purified by vacuum distillation at 1 mm Hg. The obtained methyl 2-bromo-3-arylpropanoate (0.1 mol) was dissolved in MeOH (50 mL) and a solution of NaN 3 (6.5 g) in H 2 O (15 mL) was added. The resulting mixture was then heated under reflux for 3-4 h with vigorous stirring. The methanol was evaporated in vacuo and the residue was poured into water (20 mL). Extraction with DCM (3 × 20 mL) and evaporation of the combined organic layers in vacuo gave the corresponding methyl 2-azido-3-arylpropanoate residue. This was dissolved in MeOH (225 mL) at 0°C and a solution of NaOH (4 g) in water (50 mL) was added with vigorous stirring. The mixture was then allowed to stand overnight. The methanol was evaporated in vacuo without heating and the acidic sodium salt solution was washed with DCM and TBME. HCl was added to adjust the pH to 2, and the obtained 2-azido-3-arylpropanoic acid was extracted with DCM. The DCM was removed in vacuo to afford pure acid 3. The products were used in further reactions without any additional purification.

Paper Synthesis
Funding Information