First Synthesis of 3-Glycopyranosyl-1,2,4-Triazines and Some Cycloadditions Thereof

C-glycopyranosyl derivatives of six-membered heterocycles are scarcely represented in the chemical literature and the title 3-glycopyranosyl-1,2,4-triazines are completely unknown. In this paper, the first synthesis of this compound class is accomplished by the cyclocondensation of C-glycosyl formamidrazones and 1,2-dicarbonyl derivatives. In addition, the synthesis of C-glycopyranosyl 1,2,4-triazin-5(4H)-ones was also carried out by the transformation of the above formamidrazones with α-keto-carboxylic esters. Inverse electron demand Diels–Alder reactions of 3-glycopyranosyl-1,2,4-triazines with a bicyclononyne derivative yielded the corresponding annulated 2-glycopyranosyl pyridines.


Introduction
Triazines in general and 1,2,4-triazines in particular are a significant class of sixmembered heterocyclic compounds that are constituents of many bioactive molecules, among them marketed drugs [1][2][3].
C-glycosyl compounds are one of the most intensively explored types of glycomimetics, compounds that resemble natural glycans in their chemical structure or/and biological activity [4]. While C-glycosyl derivatives of five-membered heterocycles are widely known and also studied for their biological effects, those of six-membered heterocycles are barely represented in the literature [5]. Recognising this deficiency, we have started a program to synthesise mostly unknown C-glycosylated six-membered heterocycles. Thus far, we have published the syntheses of 2-glycopyranosyl pyrimidines [6][7][8] and 3-glycopyranosyl 1,2,4,5-tetrazines [9].
In this work, the synthesis of 3-glycopyranosyl-1,2,4-triazines is reported, which compound class is completely unknown in the chemical literature. In addition, some transformations of these triazines in inverse electron demand Diels-Alder (IEDDA) reactions are also described.

Conditions and Yields (%)
To test the potential applicability of other starting reagents, the use of methyl ketones or alkynes for the in situ generation of 1,2-dioxo compounds under oxidative conditions [17] was also tried. Thus, one-pot reactions involving the oxidation of acetophenone or phenylacetylene to phenylglyoxal by SeO 2 or NIS, followed by ring-closure with amidrazone 1, were carried out (Table 1, ii and iii) to result in the expected 5-phenyl-1,2,4-triazine 2d in good yields (Table 1, Entries 5 and 6). A comparison of the yields obtained in the direct (i) and one-pot reactions (ii and iii) showed, however, the superior effectiveness of the former procedure (Entry 4 vs. Entries 5 and 6). In addition, O-debenzoylation of the newly synthesised 3-glycosyl 1,2,4-triazines was also performed under Zemplén conditions to give the unprotected derivatives 3a-g in good yields (Table 1).
In order to extend the scope of the 3-glycopyranosyl-1,2,4-triazines, the synthesis of peracylated glucosamine derivatives was also investigated. C-(2-deoxy-2-phthalimido-3,4,6-tri-O-acetyl-β-D-glucopyranosyl)formamidrazone (5) was prepared first as a precursor by the reaction of the corresponding iminoester 4 [18] with hydrazine hydrate ( Table 2). Heating of 5 with 1,2-dicarbonyl derivatives in EtOH furnished the expected heterocycles 6a-e in moderate to good yields ( Table 2).  The regioselectivity in the formation of 2b-f and 6b-d is based on the reactivity pattern of the functional groups involved in the two-step cyclocondensation process. Thus, the condensation between the aldehyde group of higher electrophilicity in the corresponding 1,2-dioxo compound and the hydrazine part of higher nucleophilicity in the amidrazone, as the first step, can be followed by an intramolecular cyclisation of the resulting hydrazone, involving the remaining keto group and the amide-type NH2, which leads to 3,5-disubstituted 1,2,4-triazines [13,14].
The position of the R 1 substituent in 2b-f and 6b-d was also corroborated by 1 H NMR. According to the literature data, the H-6 resonance of 5-substituted 1,2,4-triazines appears in the range of 9.0-10.0 ppm (Figure 1, A), while the corresponding H-5 signal for the isomeric 6-substituted derivatives is found below 9.0 ppm (B) [14]. This characteristic singlet for 2b-f and 6b-d appeared above 9.0 ppm in each case, providing evidence for the formation of the 5-substituted regioisomers. C-glycopyranosyl formamidrazones 1 and 5 were also used for the preparation of Cglycosyl 1,2,4-triazin-5(4H)-ones ( The regioselectivity in the formation of 2b-f and 6b-d is based on the reactivity pattern of the functional groups involved in the two-step cyclocondensation process. Thus, the condensation between the aldehyde group of higher electrophilicity in the corresponding 1,2-dioxo compound and the hydrazine part of higher nucleophilicity in the amidrazone, as the first step, can be followed by an intramolecular cyclisation of the resulting hydrazone, involving the remaining keto group and the amide-type NH2, which leads to 3,5-disubstituted 1,2,4-triazines [13,14].
The position of the R 1 substituent in 2b-f and 6b-d was also corroborated by 1 H NMR. According to the literature data, the H-6 resonance of 5-substituted 1,2,4-triazines appears in the range of 9.0-10.0 ppm (Figure 1, A), while the corresponding H-5 signal for the isomeric 6-substituted derivatives is found below 9.0 ppm (B) [14]. This characteristic singlet for 2b-f and 6b-d appeared above 9.0 ppm in each case, providing evidence for the formation of the 5-substituted regioisomers. C-glycopyranosyl formamidrazones 1 and 5 were also used for the preparation of Cglycosyl 1,2,4-triazin-5(4H)-ones ( The regioselectivity in the formation of 2b-f and 6b-d is based on the reactivity pattern of the functional groups involved in the two-step cyclocondensation process. Thus, the condensation between the aldehyde group of higher electrophilicity in the corresponding 1,2-dioxo compound and the hydrazine part of higher nucleophilicity in the amidrazone, as the first step, can be followed by an intramolecular cyclisation of the resulting hydrazone, involving the remaining keto group and the amide-type NH2, which leads to 3,5-disubstituted 1,2,4-triazines [13,14]. The position of the R 1 substituent in 2b-f and 6b-d was also corroborated by 1 H NMR. According to the literature data, the H-6 resonance of 5-substituted 1,2,4-triazines appears in the range of 9.0-10.0 ppm ( Figure 1, A), while the corresponding H-5 signal for the isomeric 6-substituted derivatives is found below 9.0 ppm (B) [14]. This characteristic singlet for 2b-f and 6b-d appeared above 9.0 ppm in each case, providing evidence for the formation of the 5-substituted regioisomers. C-glycopyranosyl formamidrazones 1 and 5 were also used for the preparation of Cglycosyl 1,2,4-triazin-5(4H)-ones (Table 3). In the reaction of 1 with ethyl glyoxalate or methyl pyruvate in boiling EtOH, a simple condensation took place, providing the 1 Table 2 The regioselectivity in the formation of 2b-f and 6b-d is based on the reactivity p tern of the functional groups involved in the two-step cyclocondensation process. Thu the condensation between the aldehyde group of higher electrophilicity in the cor sponding 1,2-dioxo compound and the hydrazine part of higher nucleophilicity in t amidrazone, as the first step, can be followed by an intramolecular cyclisation of the sulting hydrazone, involving the remaining keto group and the amide-type NH2, whi leads to 3,5-disubstituted 1,2,4-triazines [13,14].
The position of the R 1 substituent in 2b-f and 6b-d was also corroborated by 1 H NM According to the literature data, the H-6 resonance of 5-substituted 1,2,4-triazines appea in the range of 9.0-10.0 ppm ( Figure 1, A), while the corresponding H-5 signal for t isomeric 6-substituted derivatives is found below 9.0 ppm (B) [14]. This characteristic s glet for 2b-f and 6b-d appeared above 9.0 ppm in each case, providing evidence for t formation of the 5-substituted regioisomers. C-glycopyranosyl formamidrazones 1 and 5 were also used for the preparation of glycosyl 1,2,4-triazin-5(4H)-ones (Table 3). In the reaction of 1 with ethyl glyoxalate methyl pyruvate in boiling EtOH, a simple condensation took place, providing t 1 The regioselectivity in the formation of 2b-f and 6b-d is based on the reactivity pattern of the functional groups involved in the two-step cyclocondensation process. Thus, the condensation between the aldehyde group of higher electrophilicity in the corresponding 1,2-dioxo compound and the hydrazine part of higher nucleophilicity in the amidrazone, as the first step, can be followed by an intramolecular cyclisation of the resulting hydrazone, involving the remaining keto group and the amide-type NH 2 , which leads to 3,5-disubstituted 1,2,4-triazines [13,14].
The position of the R 1 substituent in 2b-f and 6b-d was also corroborated by 1 H NMR. According to the literature data, the H-6 resonance of 5-substituted 1,2,4-triazines appears in the range of 9.0-10.0 ppm ( Figure 1, A), while the corresponding H-5 signal for the isomeric 6-substituted derivatives is found below 9.0 ppm (B) [14]. This characteristic singlet for 2b-f and 6b-d appeared above 9.0 ppm in each case, providing evidence for the formation of the 5-substituted regioisomers.
The regioselectivity in the formation of 2b-f and 6b-d is based on the reactivity pattern of the functional groups involved in the two-step cyclocondensation process. Thus, the condensation between the aldehyde group of higher electrophilicity in the corresponding 1,2-dioxo compound and the hydrazine part of higher nucleophilicity in the amidrazone, as the first step, can be followed by an intramolecular cyclisation of the resulting hydrazone, involving the remaining keto group and the amide-type NH2, which leads to 3,5-disubstituted 1,2,4-triazines [13,14].
To demonstrate the synthetic utility of the prepared C-glycosyl 1,2,4-triazines, some IEDDA reactions with ((1R,8S,9r)-bicyclo[6.1.0]non-4-yn-9-yl)methanol (10, BCN) [19] were performed ( Table 4). The [4+2] cycloadditions carried out with triazines 2a,b,d and 3d were accomplished in CH 2 Cl 2 or MeOH at room temperature, producing diastereomeric mixtures of the expected annulated pyridine derivatives 11a,b,d and 12d in high yields, respectively. heterocycles could not be obtained even at elevated temperatures (e.g., in boiling m-xylene) as no significant conversion of the starting material could be observed, while a slow decomposition of the starting material began after a prolonged reaction time (1 day). This may be due to the lack of an electron-withdrawing substituent on the triazine ring, which could activate this heterocycle towards IEDDA reactions.

General Procedure 1 for the Synthesis of O-Peracylated 3-Glycopyranosyl-1,2,4-triazines 2 and 6
C-glycopyranosyl formamidrazone (1 or 5) and the appropriate 1,2-dicarbonyl derivative (1.0-1.2 equiv.) were suspended in anhydrous EtOH (3 mL/100 mg substrate), and the mixture was stirred at reflux temperature until the TLC (1:1 EtOAc-hexane) To get further 2-glucopyranosyl pyridines, the transformations of 1,2,4-triazine 2a with norbornadiene and 1-pyrrolidino-1-cyclopentene were also attempted. The desired heterocycles could not be obtained even at elevated temperatures (e.g., in boiling m-xylene) as no significant conversion of the starting material could be observed, while a slow decomposition of the starting material began after a prolonged reaction time (1 day). This may be due to the lack of an electron-withdrawing substituent on the triazine ring, which could activate this heterocycle towards IEDDA reactions.

General Procedure 2 for the O-Debenzoylation of Compounds 2 by the Zemplén Method to obtain 1,2,4-Triazines 3
To a solution of the corresponding O-perbenzoylated 3-(β-D-glucopyranosyl)-1,2,4triazine (2) in dry MeOH (5 mL/100 mg substrate), a catalytic amount of NaOMe in dry MeOH (~1M solution) was added. The reaction mixture was allowed to stand at room temperature, and the transformation was judged by TLC (1:1 EtOAc-hexane and 7:3 CHCl 3 -MeOH). After complete conversion, the reaction mixture was neutralised with a cation exchange resin Amberlyst 15 (H + form). The resin was then filtered off, and MeOH was removed under reduced pressure. The resulting crude product was purified by column chromatography.