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

Abstract

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.

1. Introduction

Triazines in general and 1,2,4-triazines in particular are a significant class of six-membered 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].

C-glycosyl 1,2,4-triazines are represented in the literature, to the best of our knowledge, by five compounds altogether: an O-perbenzoylated 6-(β-d-arabinofuranosyl)-3-amino-1,2,4-triazine, obtained from the corresponding C-glycosyl formaldehyde in a multistep one-pot transformation [10]; O-perbenzylated 5-(α- and β-d-ribofuranosyl)-3,6-bis(trifluoromethyl)-1,2,4-triazines [11] and their 2-deoxy-ribofuranosyl counterparts [12], prepared by cycloadditions of the corresponding C-glycosyl formimidates and 3,6-bis(trifluoromethyl)-1,2,4,5-tetrazine.

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.

2. Results and Discussion

For the construction of 3-substituted 1,2,4-triazines, the cyclocondensation of carboxamidrazones with 1,2-dicarbonyl derivatives is one of the most common methods [1,13,14]. Thus, for the synthesis of 3-(β-d-glucopyranosyl)-1,2,4-triazines, such transformations were envisaged starting from O-perbenzoylated C-β-d-glucopyranosyl formamidrazone 1 [15], prepared earlier in our laboratory to get C-glucosyl 1,2,4-triazoles [15] and -triazolones [16]. The ring-closures of 1 with α-keto aldehydes in dry EtOH under heating (

Table 1. Synthesis of 3-(β-d-glucopyranosyl)-1,2,4-triazines.

(i) dry EtOH, reflux; (ii) SeO2, DMSO, 110 °C; (iii) NIS, cat. TsOH, DMSO, 110 °C; (iv) NaOMe/MeOH, r.t.
				Conditions and Yields (%)
Entry		R1	R2		2		3
1	a	H	H	i	90	iv	63
2	b	CH3	H	i	84	iv	58
3	c	(CH3)3	H	i	83	iv	88
4	d		H	i	83	iv	72
5				ii	50
6				iii	60
7	e		H	i	97	iv	73
8	f		H	i	90	iv	72
9	g			i	53	iv	84

, i) provided a set of 5-alkyl- and -aryl-substituted 1,2,4-triazines 2b-f (Entries 2–4,7,8) in high yields. The cyclisations of 1 with glyoxal and benzil were also carried out, resulting in unsubstituted and 5,6-diphenyl-1,2,4-triazines 2a and 2g, respectively, in good yields (Entries 1 and 9).

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 SeO₂ 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. Synthesis of 3-(2′-deoxy-2′-phthalimido-3′,4′,6′-tri-O-acetyl-β-d-glucopyranosyl)-1,2,4-triazines.

(i) NH2NH2.H2O, EtOH, r.t.; (ii) dry EtOH, reflux
	R1	R2	Yield of 6 (%)
a	H	H	58
b	CH3	H	62
c	(CH3)3	H	67
d		H	73
e			65

). 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 R¹ substituent in 2b–f and 6b–d was also corroborated by ¹H 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 C-glycosyl 1,2,4-triazin-5(4H)-ones (

Table 3. Synthesis of 3-glycopyranosyl-1,2,4-triazin-5(4H)-ones.

(i) dry EtOH, reflux; (ii) dry toluene, reflux
Product	R1	R2	Yield (%)
7a	H	CH2CH3	39
7b	CH3	CH3	59
8a	H	-	57
8b	CH3	-	75
9a	H	-	51
9b	CH3	-	50

). In the reaction of 1 with ethyl glyoxalate or methyl pyruvate in boiling EtOH, a simple condensation took place, providing the corresponding N¹-alkoxycarbonylalkylidene amidrazones 7a,b in moderate yields. Carrying out the reaction in boiling toluene triggered the desired intramolecular cyclisation of intermediates 7a,b, accompanied, however, by a 1,2-elimination of benzoic acid from the sugar moiety, yielding glycal derivatives 8a,b. Similar concomitant elimination was described earlier in the synthesis of a 3-glycosyl-1H-1,2,4-triazol-5(4H)-one constructed by the thermal ring-closure of N¹-ethoxycarbonyl-C-(2,3,4,6-tetra-O-benzoyl-β-d-glucopyranosyl)formamidrazone [16]. Other analogous eliminations were reported during the syntheses of C-glycopyranosyl heterocycles (e.g., 1,2,4-oxadiazoles and -thiadiazoles, benzimidazoles, perimidines) from the corresponding O-peracylated precursors [5].

The cyclisations of amidrazone 5 with the same α-keto esters in boiling toluene were also carried out, producing the expected C-glucosaminyl heterocycles 9a,b in acceptable yields (Table 3).

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. IEDDA reactions of some 3-glucopyranosyl-1,2,4-triazines with a bicyclononyne derivative.

Triazine	R	R1	Reaction Time	Product	Yield (%)	Diastereomeric Ratio
2a	Bz	H	2 d	11a	97	5:4
2b	Bz	CH3	6 d	11b	41	5:4
2d	Bz	Ph	6 d	11d	73	5:4
3d	H	Ph	5 d	12d	94	1:1

). The [4+2] cycloadditions carried out with triazines 2a,b,d and 3d were accomplished in CH₂Cl₂ or MeOH at room temperature, producing diastereomeric mixtures of the expected annulated pyridine derivatives 11a,b,d and 12d in high yields, respectively.

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.

3. Experimental

3.1. General Methods

Melting points were measured on a Kofler hot stage, and the values are uncorrected. Optical rotations were obtained at ambient temperature using a P-2000 polarimeter (Jasco, Easton, MD, USA). The ¹H and ¹³C NMR spectra of the prepared compounds were recorded with DRX360 (360/90 MHz for ¹H/¹³C) or DRX400 (400/100 MHz for ¹H/¹³C) spectrometers (Bruker, Karlsruhe, Germany). Chemical shifts are referenced to Me₄Si (¹H-NMR) or to the residual solvent signals (¹³C-NMR). For HRMS measurements, a Bruker maXis II (ESI-HRMS) spectrometer was used, and the data were determined in positive ionisation mode. DC Kieselgel 60 F₂₅₄ plates (Sigma-Aldrich, Saint Louis, MO, USA) were used for TLC analysis, and the spots on the plates were visualised under UV light and developed by gentle heating. Column chromatographic purification was performed by using Kieselgel 60 silica gel (Molar Chemicals, Halásztelek, Hungary, particle size 0.063–0.2 mm). Anhydrous EtOH was purchased from VWR Chemicals. Anhydrous CHCl₃, toluene and MeOH were obtained by atmospheric distillation from P₄O₁₀ (CHCl₃ and toluene) or over Mg turnings and iodine (MeOH). C-(2,3,4,6-Tetra-O-benzoyl-β-d-glucopyranosyl)formamidrazone 1 [15] and ethyl C-(2-deoxy-2-phthalimido-3,4,6-tri-O-acetyl-β-d-glucopyranosyl)formimidate 4 [18] were synthesised according to our earlier reported methods. ((1R,8S,9r)-Bicyclo [6.1.0]non-4-yn-9-yl)methanol 10 [19] was obtained following a literature procedure.

3.2. 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) showed completion of the reaction. The solvent was then evaporated under reduced pressure, and the residue was purified by column chromatography.

3.3. 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)-1,2,4-triazine (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 CHCl₃-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.

3.4. General Procedure 3 for the Synthesis of O-Peracylated 3-Glycopyranosyl-1,2,4-triazin-5(4H)-ones 8 and 9

A solution of the C-glycopyranosyl formamidrazone (1 or 5) and the corresponding α-ketoester (1 equiv.) in anhydrous toluene (3 mL/100 mg substrate) was refluxed, and the transformation was monitored by TLC (2:1 EtOAc-hexane). After completion of the reaction, the solvent was removed in vacuo, and the residue was purified by column chromatography.

3.5. General Procedure 4 for the Preparation of 1-(β-d-Glucopyranosyl)-6,6a,7,7a,8,9-Hexahydro-5H-Cyclopropa[5,6]Cycloocta[1,2-c]Pyridin-7-yl)Methanols 11 and 12

To a solution of the corresponding 3-glucopyranosyl-1,2,4-triazine (2 or 3) in CH₂Cl₂ or MeOH (3 mL/100 mg triazine), ((1R,8S,9r)-bicyclo[6.1.0]non-4-yn-9-yl)methanol (10, 2 equiv.) was added, and the mixture was stirred at room temperature. When the TLC (1:1 EtOAc-hexane for 11 or 4:1 CHCl₃-MeOH for 12) showed complete disappearance of the triazine, the solvent was removed in vacuo. The residue was purified by column chromatography.

3.6. Synthesis and Characterisation of the New Compounds

3-(2,3,4,6-Tetra-O-benzoyl-β-d-glucopyranosyl)-1,2,4-triazine (2a)

Prepared from amidrazone 1 (0.80 g, 1.25 mmol) and an aq. 40 wt.% solution of glyoxal (144 µL, 1.25 mmol) according to general procedure 1. Reaction time: 3 h. Purified by column chromatography (1:2 EtOAc-hexane) to yield 0.75 g (90%) of pale yellow amorphous solids. R_f = 0.48 (1:1 EtOAc-hexane); [α]_D = −40 (c 0.20, CHCl₃). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 9.17, 8.70 (2 × 1H, 2 d, J = 2.1 Hz in each, H-5, H-6), 8.00, 7.95, 7.85, 7.75 (4 × 2H, 4 d, J = 7.92 Hz in each, Ar), 7.53-7.26 (12H, m, Ar), 6.18 (1H, pt, J = 9.5, 9.5 Hz, H-2′ or H-3′ or H-4′), 6.08 (1H, pt, J = 9.7, 9.6 Hz, H-2′ or H-3′ or H-4′), 5.90 (1H, pt, J = 9.5, 9.1 Hz, H-2′ or H-3′ or H-4′), 5.39 (1H, d, J = 9.7 Hz, H-1′), 4.69 (1H, dd, J = 12.1, < 1 Hz, H-6′a), 4.58 (1H, dd, J = 12.1, 5.3 Hz, H-6′b), 4.48-4.44 (1H, m, H-5′); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 166.1, 165.8, 165.2, 164.8, 164.3 (4 × C=O, C-3), 149.5, 149.4 (C-5, C-6), 133.4, 133.3, 133.2, 133.0, 129.8-129.6, 129.4, 128.7, 128.6, 128.5, 128.4-128.2 (Ar), 80.1, 76.9, 74.1, 71.6, 69.5 (C-1′ − C-5′), 63.4 (C-6′). ESI-HRMS positive mode (m/z): calcd for C₃₇H₃₀N₃O₉⁺ [M+H]⁺ 660.1977; C₃₇H₂₉N₃NaO₉⁺ [M+Na]⁺ 682.1796. Found: [M+H]⁺ 660.1972; [M+Na]⁺ 682.1785.

3-(2,3,4,6-Tetra-O-benzoyl-β-d-glucopyranosyl)-5-methyl-1,2,4-triazine (2b)

Prepared from amidrazone 1 (0.10 g, 0.16 mmol) and methyl glyoxal (24 µL, 0.16 mmol) according to general procedure 1. Reaction time: 3 h. Purified by column chromatography (2:3 EtOAc-hexane) to yield 89 mg (84%) of pale yellow amorphous solids. R_f = 0.38 (1:1 EtOAc-hexane); [α]_D = −12 (c 0.20, CHCl₃). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 9.03 (1H, s, H-6), 8.01, 7.94, 7.85, 7.75 (4 × 2H, 4 dd, J = 7.2, 1.2 Hz in each, Ar), 7.54-7.28 (12H, m, Ar), 6.14 (1H, pt, J = 9.5, 9.1 Hz, H-2′ or H-3′ or H-4′), 6.11 (1H, pt, J = 9.7, 9.5 Hz, H-2′ or H-3′ or H-4′), 5.90 (1H, pt, J = 9.6, 9.6 Hz, H-2′ or H-3′ or H-4′), 5.31 (1H, d, J = 9.3 Hz, H-1′), 4.67 (1H, dd, J = 12.3, 3.0 Hz, H-6′a), 4.56 (1H, dd, J = 12.3, 5.2 Hz, H-6′b), 4.42 (1H, ddd, J = 9.7, 5.2, 3.0 Hz, H-5′), 2.56 (3H, s, CH₃); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 166.1, 165.8, 165.2, 164.7, 163.2 (4 × C=O, C-3), 160.6 (C-5), 149.9 (C-6), 133.4, 133.2, 133.1, 133.0, 129.8-129.7, 129.5, 128.8, 128.7, 128.6, 128.4-128.2 (Ar), 80.1, 76.9, 74.3, 71.4, 69.5 (C-1′ − C-5′), 63.4 (C-6′), 21.8 (CH₃). ESI-HRMS positive mode (m/z): calcd for C₃₈H₃₂N₃O₉⁺ [M+H]⁺ 674.2133; C₃₈H₃₁N₃NaO₉⁺ [M+Na]⁺ 696.1953. Found: [M+H]⁺ 674.2134; [M+Na]⁺ 696.1950.

3-(2,3,4,6-Tetra-O-benzoyl-β-d-glucopyranosyl)-5-tert-butyl-1,2,4-triazine (2c)

Prepared from amidrazone 1 (0.30 g, 0.47 mmol) and 3,3-dimethyl-2-oxobutanal (62 mg, 0.47 mmol) according to general procedure 1. Reaction time: 7 h. Purified by column chromatography (3:7 EtOAc-hexane) to yield 0.28 g (83%) of pale yellow amorphous solids. R_f = 0.26 (3:7 EtOAc-hexane); [α]_D = −11 (c 0.20, CHCl₃). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 9.23 (1H, s, H-6), 8.02, 7.95, 7.86, 7.73 (4 × 2H, 4 dd, J = 7.1, 1.2 Hz in each, Ar), 7.54-7.24 (12H, m, Ar), 6.25 (1H, pt, J = 9.7, 9.7 Hz, H-2′ or H-3′ or H-4′), 6.13 (1H, pt, J = 9.6, 9.5 Hz, H-2′ or H-3′ or H-4′), 5.90 (1H, pt, J = 9.7, 9.6 Hz, H-2′ or H-3′ or H-4′), 5.35 (1H, d, J = 9.7 Hz, H-1′), 4.69 (1H, dd, J = 12.2, 2.9 Hz, H-6′a), 4.53 (1H, dd, J = 12.2, 5.0 Hz, H-6′b), 4.44 (1H, ddd, J = 9.7, 5.0, 2.9 Hz, H-5′), 1.31 (9H, s, C(CH₃)₃); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 170.0, 166.1, 165.9, 165.2, 164.5 (4 × C=O, C-3), 162.5 (C-5), 146.8 (C-6), 133.4, 133.1, 133.1, 133.0, 130.0-129.5, 129.5, 128.9, 128.8, 128.4-128.2 (Ar), 80.1, 76.9, 74.4, 71.0, 69.5 (C-1′ − C-5′), 63.2 (C-6′), 36.8 (C(CH₃)₃), 28.6 (C(CH₃)₃). ESI-HRMS positive mode (m/z): calcd for C₄₁H₃₈N₃O₉⁺ [M+H]⁺ 716.2603; C₄₁H₃₇N₃NaO₉⁺ [M+Na]⁺ 738.2422. Found: [M+H]⁺ 716.2602; [M+Na]⁺ 738.2419.

3-(2,3,4,6-Tetra-O-benzoyl-β-d-glucopyranosyl)-5-phenyl-1,2,4-triazine (2d).

Method A: Prepared from amidrazone 1 (1.0 g, 1.57 mmol) and phenyl glyoxal monohydrate (0.29 g, 1.88 mmol) according to general procedure 1. Reaction time: 4 h. Purified by column chromatography (1:2 EtOAc-hexane) to yield 0.95 g (83%) of pale yellow amorphous solids.

Method B: To a solution of acetophenone (19 µL, 0.16 mmol, 1 equiv.) in DMSO (2 mL), SeO₂ (21 mg, 0.19 mmol, 1.2 equiv.) was added. The mixture was heated at 110 °C until the TLC (1:9 EtOAc-hexane) showed the complete transformation of acetophenone (4 h). Formamidrazine 1 (0.10 g, 0.16 mmol) was then added to the mixture, and the heating was continued. When the TLC (1:1 EtOAc-hexane) showed the completion of the reaction (2 h), the mixture was diluted with EtOAc (50 mL) and extracted with water (20 mL). The separated aqueous phase was washed two times with EtOAc (2 × 50 mL). The combined organic phase was dried over MgSO₄, filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography (1:2 EtOAc-hexane). Yield: 57 mg (50%).

Method C: A solution of phenylacetylene (35 µL, 0.32 mmol, 2 equiv.), NIS (43 mg, 0.19 mmol, 1.2 equiv.) and TsOH (3.4 mg, 0.02 mmol, 0.1 equiv.) in DMSO (2 mL) was heated at 110 °C until the TLC (1:9 EtOAc-hexane) indicated the complete conversion of phenylacetylene (4 h). Formamidrazine 1 (0.10 g, 0.16 mmol) was then added to the mixture, and the heating was continued. After completion of the reaction monitored by TLC (2 h), the same steps as described in method B were carried out. Yield: 66 mg (60%). R_f = 0.55 (1:1 EtOAc-hexane); [α]_D = −68 (c 0.20, CHCl₃). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 9.58 (1H, s, H-6), 8.17, 8.02, 7.96, 7.87, 7.75 (5 × 2H, 5 d, J = 7.2 Hz in each, Ar), 7.59-7.21 (15H, m, Ar), 6.33, 6.18, 5.94 (3 × 1H, 3 pt, J = 9.7, 9.7 Hz in each, H-2′, H-3′, H-4′), 5.43 (1H, d, J = 9.7 Hz, H-1′), 4.72 (1H, dd, J = 12.2, 2.8 Hz, H-6′a), 4.55 (1H, dd, J = 12.2, 5.1 Hz, H-6′b), 4.49 (1H, ddd, J = 9.7, 5.1, 2.8 Hz, H-5′); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 166.1, 165.8, 165.2, 164.7, 163.4 (4 × C=O, C-3), 156.0 (C-5), 145.9 (C-6), 133.4, 133.1, 133.0, 132.8, 132.7, 129.8–129.3, 128.8, 128.7, 128.6, 128.5, 128.4–127.9 (Ar), 80.1, 76.9, 74.4, 71.1, 69.5 (C-1′ − C-5′), 63.2 (C-6′). ESI-HRMS positive mode (m/z): calcd for C₄₃H₃₃N₃NaO₉⁺ [M+Na]⁺ 758.2109. Found: 758.2107.

3-(2,3,4,6-Tetra-O-benzoyl-β-d-glucopyranosyl)-5-(p-methoxyphenyl)-1,2,4-triazine (2e)

Prepared from amidrazone 1 (0.10 g, 0.16 mmol) and p-methoxyphenyl glyoxal monohydrate (0.034 g, 0.19 mmol) according to general procedure 1. Reaction time: 4 h. Purification by column chromatography (1:2 EtOAc-hexane), followed by the crystallisation of the resulting syrup from a mixture of Et₂O (3 mL) and hexane (2 mL), which gave 116 mg (97%) pale yellow crystals. R_f = 0.45 (1:1 EtOAc-hexane); mp = 150–151 °C; [α]_D = −98 (c 0.53, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.50 (1H, s, H-6), 8.17 (2H, d, J = 8.9 Hz, Ar), 8.02, 7.96, 7.87, 7.74 (4 × 2H, 4 dd, J = 7.3, 1.2 Hz in each, Ar), 7.54–7.23 (12H, m, Ar), 7.01 (2H, d, J = 8.9 Hz, Ar), 6.33, 6.15, 5.92 (3 × 1H, 3 pt, J = 9.7, 9.7 Hz in each, H-2′, H-3′, H-4′), 5.37 (1H, d, J = 9.7 Hz, H-1′), 4.70 (1H, dd, J = 12.3, 2.7 Hz, H-6′a), 4.54 (1H, dd, J = 12.3, 5.1 Hz, H-6′b), 4.46 (1H, ddd, J = 9.7, 5.1, 2.7 Hz, H-5′), 3.89 (3H, s, OCH₃); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 166.1, 165.9, 165.2, 164.8, 163.6, 163.1 (4 × C=O, C-3, Ar-C_q), 155.5 (C-5), 145.3 (C-6), 133.4, 133.1, 133.0, 129.8–129.6, 128.9, 128.8, 128.8, 128.4–128.2 (Ar), 125.0 (Ar-C_q), 114.8 (Ar-CH), 80.1, 76.9, 74.5, 70.9, 69.5 (C-1′ − C-5′), 63.3 (C-6′), 55.5 (OCH₃). ESI-HRMS positive mode (m/z): calcd for C₄₄H₃₆N₃O₁₀⁺ [M+H]⁺ 766.2395; C₄₄H₃₅N₃NaO₁₀⁺ [M+Na]⁺ 788.2215. Found: [M+H]⁺ 766.2390; [M+Na]⁺ 788.2208.

3-(2,3,4,6-Tetra-O-benzoyl-β-d-glucopyranosyl)-5-(p-chlorophenyl)-1,2,4-triazine (2f)

Prepared from amidrazone 1 (0.10 g, 0.16 mmol) and p-chlorophenyl glyoxal monohydrate (0.035 g, 0.19 mmol) according to general procedure 1. Reaction time: 4 h. Purification by column chromatography (1:2 EtOAc-hexane) gave 109 mg (90%) of pale yellow amorphous solids. R_f = 0.60 (1:1 EtOAc-hexane); [α]_D = −82 (c 0.50, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 9.57 (1H, s, H-6), 8.13 (2H, d, J = 8.4 Hz, Ar), 8.02, 7.96, 7.86, 7.74 (4 × 2H, 4 d, J = 7.5 Hz in each, Ar), 7.56-7.24 (14H, m, Ar), 6.28, 6.16, 5.92 (3 × 1H, 3 pt, J = 9.6, 9.6 Hz in each, H-2′, H-3′, H-4′), 5.39 (1H, d, J = 9.6 Hz, H-1′), 4.72 (1H, dd, J = 12.2, 2.1 Hz, H-6′a), 4.54 (1H, dd, J = 12.2, 4.9 Hz, H-6′b), 4.47 (1H, ddd, J = 9.6, 4.9, 2.1 Hz, H-5′); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 166.1, 165.9, 165.2, 164.8, 163.5 (4 × C=O, C-3), 154.9 (C-5), 145.6 (C-6), 139.4 (Ar-C_q), 133.5, 133.3, 133.2, 133.1 (Ar), 131.3 (Ar-C_q), 129.9-128.3 (Ar), 80.1, 77.0, 74.4, 71.1, 69.5 (C-1′ − C-5′), 63.2 (C-6′). ESI-HRMS positive mode (m/z): calcd for C₄₃H₃₃ClN₃O₉⁺ [M+H]⁺ 770.1900; C₄₃H₃₂ClN₃NaO₉⁺ [M+Na]⁺ 792.1719. Found: [M+H]⁺ 770.1900; [M+Na]⁺ 792.1718.

3-(2,3,4,6-Tetra-O-benzoyl-β-d-glucopyranosyl)-5,6-diphenyl-1,2,4-triazine (2g)

Prepared from amidrazone 1 (1.0 g, 1.57 mmol) and benzil (0.33 g, 1.57 mmol) according to general procedure 1. Reaction time: 7 h. Purified by column chromatography (1:1 EtOAc-hexane) to yield 0.67 g (53%) of pale yellow solids. R_f = 0.71 (3:7 EtOAc-hexane); mp = 175–179 °C; [α]_D = −26 (c 0.20, CHCl₃); ¹H NMR (360 MHz, CDCl₃) δ (ppm): 8.02, 7.95, 7.87, 7.76 (4 × 2H, 4 d, J = 7.4 Hz in each, Ar), 7.55–7.24 (22H, m, Ar), 6.36 (1H, pt, J = 9.7, 9.7 Hz, H-2′ or H-3′ or H-4′), 6.15 (1H, pt, J = 9.6, 9.5 Hz, H-2′ or H-3′ or H-4′), 5.91 (1H, pt, J = 9.7, 9.7 Hz, H-2′ or H-3′ or H-4′), 5.45 (1H, d, J = 9.7 Hz, H-1′), 4.69 (1H, dd, J = 12.3, 2.6 Hz, H-6′a), 4.54 (1H, dd, J = 12.3, 5.1 Hz, H-6′b), 4.48 (1H, ddd, J = 9.5, 5.1, 2.6 Hz, H-5′); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 166.1, 165.9, 165.2, 164.7 (4 × C=O), 161.2, 157.3, 156.5 (C-3, C-5, C-6), 135.0–128.2 (Ar), 79.9, 77.0, 74.6, 71.1, 69.5 (C-1′ − C-5′), 63.3 (C-6′). ESI-HRMS positive mode (m/z): calcd for C₄₉H₃₈N₃O₉⁺ [M+H]⁺ 812.2603. Found: 812.2602.

3-(β-d-Glucopyranosyl)-1,2,4-triazine (3a)

Prepared from triazine 2a (0.25 g, 0.38 mmol) according to general procedure 2. Reaction time: 3 h. Purified by column chromatography (4:1 CHCl₃-MeOH) to yield 58 mg (63%) of pale yellow amorphous solids. R_f = 0.32 (7:3 CHCl₃-MeOH); [α]_D = −138 (c 0.22, DMSO). ¹H NMR (360 MHz, CD₃OD) δ (ppm): 9.30, 8.84 (2 × 1H, 2 d, J = 2.5 Hz in each, H-5, H-6), 4.61 (1H, d, J = 9.7 Hz, H-1′), 3.84 (1H, pt, J = 9.5, 9.1 Hz, H-2′ or H-3′ or H-4′), 3.83 (1H, dd, J = 12.1, 2.0 Hz, H-6′a), 3.68 (1H, dd, J = 12.1, 5.0 Hz, H-6′b), 3.56 (1H, pt, J = 9.1, 8.9 Hz, H-2′ or H-3′ or H-4′), 3.48-3.46 (2H, m, H-2′ or H-3′ or H-4′, H-5′); ¹³C NMR (90 MHz, CD₃OD) δ (ppm): 167.6 (C-3), 151.7, 150.9 (C-5, C-6), 83.1, 82.8, 79.4, 74.3, 71.4 (C-1′ − C-5′), 62.8 (C-6′). ESI-HRMS positive mode (m/z): calcd for C₉H₁₄N₃O₅⁺ [M+H]⁺ 244.0928; C₉H₁₃N₃NaO₅⁺ [M+Na]⁺ 266.0747. Found: [M+H]⁺ 244.0930; [M+Na]⁺ 266.0746.

3-(β-d-Glucopyranosyl)-5-methyl-1,2,4-triazine (3b)

Prepared from triazine 2b (0.20 g, 0.3 mmol) according to general procedure 2. Reaction time: 5 h. Purified by column chromatography (4:1 CHCl₃-MeOH) to yield 44 mg (58%) pale yellow syrup. R_f = 0.30 (4:1 CHCl₃-MeOH); [α]_D = +57 (c 0.20, MeOH). ¹H NMR (360 MHz, CD₃OD) δ (ppm): 9.26 (1H, s, H-6), 4.58 (1H, d, J = 9.7 Hz, H-1′), 3.88 (1H, dd, J = 11.9, 2.2 Hz, H-6′a), 3.87 (1H, pt, J = 9.4, 9.2 Hz, H-2′ or H-3′ or H-4′), 3.72 (1H, dd, J = 11.9, 3.3 Hz, H-6′b), 3.61-3.50 (3H, m, H-2′ and/or H-3′ and/or H-4′, H-5′), 2.63 (3H, s, CH₃); ¹³C NMR (90 MHz, CD₃OD) δ (ppm): 166.5, 163.0 (C-3, C-5), 151.2 (C-6), 83.0, 82.8, 79.4, 74.3, 71.4 (C-1′ − C-5′), 62.9 (C-6′), 21.9 (CH₃). ESI-HRMS positive mode (m/z): calcd for C₁₀H₁₅N₃NaO₅⁺ [M+Na]⁺ 280.0904. Found: 280.0903.

3-(β-d-Glucopyranosyl)-5-tert-butyl-1,2,4-triazine (3c)

Prepared from triazine 2c (0.20 g, 0.28 mmol) according to general procedure 2. Reaction time: 5 h. Purified by column chromatography (9:1 CHCl₃-MeOH) to yield 73 mg (88%) of pale yellow solids. R_f = 0.46 (4:1 CHCl₃-MeOH); mp = 196–200 °C; [α]_D = +17 (c 0.20, MeOH). ¹H NMR (360 MHz, CD₃OD) δ (ppm): 9.46 (1H, s, H-6), 4.59 (1H, d, J = 9.7 Hz, H-1′), 3.98 (1H, pt, J = 9.4, 9.2 Hz, H-2′ or H-3′ or H-4′), 3.90 (1H, dd, J = 12.0, 1.5 Hz, H-6′a), 3.70 (1H, dd, J = 12.0, 5.0 Hz, H-6′b), 3.59 (1H, pt, J = 9.0, 8.9 Hz, H-2′ or H-3′ or H-4′), 3.54–3.46 (2H, m, H-2′ or H-3′ or H-4′, H-5′), 1.43 (9H, s, C(CH₃)₃); ¹³C NMR (90 MHz, CD₃OD) δ (ppm): 172.0, 166.2 (C-3, C-5), 148.1 (C-6), 83.4, 82.9, 79.5, 74.2, 71.7 (C-1′ − C-5′), 63.0 (C-6′), 38.0 (C(CH₃)₃), 29.1 (C(CH₃)₃). ESI-HRMS positive mode (m/z): calcd for C₁₃H₂₂N₃O₅⁺ [M+H]⁺ 300.1554; C₁₃H₂₁N₃NaO₅⁺ [M+Na]⁺ 322.1373. Found: [M+H]⁺ 300.1550; [M+Na]⁺ 322.1369.

3-(β-d-Glucopyranosyl)-5-phenyl-1,2,4-triazine (3d)

Prepared from triazine 2d (0.20 g, 0.27 mmol) according to general procedure 2. Reaction time: 4 h. Purified by column chromatography (9:1 CHCl₃-MeOH) to yield 62 mg (72%) of pale yellow solids. R_f = 0.43 (4:1 CHCl₃-MeOH); mp = 236–240 °C; [α]_D = +44 (c 0.20, DMSO). ¹H NMR (360 MHz, DMSO-d₆) δ (ppm): 10.06 (1H, s, H-6), 8.36 (2H, d, J = 8.3 Hz, Ar), 7.71–7.62 (3H, m, Ar), 5.11–5.02, 5.57–4.55 (4H, OH), 4.52 (1H, d, J = 9.9 Hz, H-1′), 3.98–3.92, 3.75–3.71, 3.48–3.37, 3.27–3.20 (6H, m, H-2′, H-3′, H-4′, H-5′, H-6′a,b); ¹³C NMR (90 MHz, DMSO-d₆) δ (ppm): 165.2 (C-3), 154.8 (C-5), 146.1 (C-6), 133.0, 132.6, 129.3 (2), 127.8 (2) (Ar), 82.1, 82.0, 77.9, 72.0, 70.4 (C-1′ − C-5′), 61.2 (C-6′). ESI-HRMS positive mode (m/z): calcd for C₁₅H₁₈N₃O₅⁺ [M+H]⁺ 320.1241; C₁₅H₁₇N₃NaO₅⁺ [M+Na]⁺ 342.1060. Found: [M+H]⁺ 320.1239; [M+Na]⁺ 342.1054.

3-(β-d-Glucopyranosyl)-5-(p-methoxyphenyl)-1,2,4-triazine (3e)

Prepared from triazine 2e (96 mg, 0.13 mmol) according to general procedure 2. Reaction time: 2 h. Purified by column chromatography (8:1 CHCl₃-MeOH) to yield 32 mg (73%) of pale yellow amorphous solids. R_f = 0.50 (7:3 CHCl₃-MeOH); [α]_D = +24 (c 0.49, DMSO). ¹H NMR (400 MHz, CD₃OD) δ (ppm): 9.75 (1H, s, H-6), 8.33, 7.12 (2 × 2H, 2 d, J = 8.8 Hz in each, Ar), 4.62 (1H, d, J = 9.7 Hz, H-1′), 4.02 (1H, pt, J = 9.3, 9.2 Hz, H-2′ or H-3′ or H-4′), 3.92-3.90 (4H, m, H-6′a, OCH₃), 3.74 (1H, dd, J = 11.5, 2.9 Hz, H-6′b), 3.62 (1H, pt, J = 9.0, 9.0 Hz, H-2′ or H-3′ or H-4′), 3.55-3.53 (2H, m, H-2′ or H-3′ or H-4′, H-5′); ¹³C NMR (90 MHz, CD₃OD) δ (ppm): 166.8, 165.4 (C-3, Ar-C_q), 157.4 (C-5), 146.5 (C-6), 131.1 (2), 126.6, 116.0 (2) (Ar), 83.4, 82.9, 79.5, 74.3, 71.6 (C-1′ − C-5′), 62.9 (C-6′), 56.2 (OCH₃). ESI-HRMS positive mode (m/z): calcd for C₁₆H₂₀N₃O₆⁺ [M+H]⁺ 350.1347; C₁₆H₁₉N₃NaO₆⁺ [M+Na]⁺ 372.1166. Found: [M+H]⁺ 350.1340; [M+Na]⁺ 372.1159.

3-(β-d-Glucopyranosyl)-5-(p-chlorophenyl)-1,2,4-triazine (3f)

Prepared from triazine 2f (79 mg, 0.10 mmol) according to general procedure 2. Reaction time: 2 h. Purified by column chromatography (8:1 CHCl₃-MeOH) to yield 26 mg (72%) of pale yellow amorphous solids. R_f = 0.47 (7:3 CHCl₃-MeOH); [α]_D = +30 (c 0.53, DMSO). ¹H NMR (400 MHz, CD₃OD) δ (ppm): 9.87 (1H, s, H-6), 8.36, 7.62 (2 × 2H, 2 d, J = 8.6 Hz in each, Ar), 4.67 (1H, d, J = 9.7 Hz, H-1′), 4.02 (1H, pt, J = 9.3, 9.3 Hz, H-2′ or H-3′ or H-4′), 3.90 (1H, dd, J = 12.3, < 1 Hz, H-6′a), 3.73 (1H, dd, J = 12.3, 4.9 Hz, H-6′b), 3.62 (1H, pt, J = 9.0, 9.0 Hz, H-2′ or H-3′ or H-4′), 3.54-3.53 (2H, m, H-2′ or H-3′ or H-4′, H-5′); ¹³C NMR (90 MHz, CD₃OD) δ (ppm): ¹³C NMR (90 MHz, CD₃OD) δ (ppm): 167.0 (C-3), 156.8 (C-5), 147.0 (C-6), 140.4, 133.3, 130.8 (4) (Ar), 83.4, 82.9, 79.5, 74.3, 71.6 (C-1′ − C-5′), 62.9 (C-6′). ESI-HRMS positive mode (m/z): calcd for C₁₅H₁₇ClN₃O₅⁺ [M+H]⁺ 354.0851; C₁₅H₁₆ClN₃NaO₅⁺ [M+Na]⁺ 376.0671. Found: [M+H]⁺ 354.0851; [M+Na]⁺ 376.0668.

3-(β-d-Glucopyranosyl)-5,6-diphenyl-1,2,4-triazine (3g)

Prepared from triazine 2g (0.15 g, 0.18 mmol) according to general procedure 2. Reaction time: 4 h. Purified by column chromatography (9:1 CHCl₃-MeOH) to yield 61 mg (84%) pale yellow oil. R_f = 0.32 (9:1 CHCl₃-MeOH); [α]_D = +42 (c 0.44, MeOH). ¹H NMR (360 MHz, CD₃OD) δ (ppm): 7.60-7.34 (10H, m, Ar), 4.75 (1H, d, J = 9.7 Hz, H-1′), 4.05 (1H, pt, J = 9.5, 9.1 Hz, H-2′ or H-3′ or H-4′), 3.92 (1H, dd, J = 12.3, < 1 Hz, H-6′a), 3.75 (1H, dd, J = 12.3, 4.5 Hz, H-6′b), 3.65 (1H, pt, J = 9.1, 9.0 Hz, H-2′ or H-3′ or H-4′), 3.57-3.55 (2H, m, H-2′ or H-3′ or H-4′, H-5′); ¹³C NMR (90 MHz, CD₃OD) δ (ppm): ¹³C NMR (90 MHz, CD₃OD) δ (ppm): 165.0 (C-3), 158.8, 158.7 (C-5, C-6), 136.8, 136.7, 132.0, 131.2 (2), 131.0, 130.7 (2), 129.8 (2), 129.6 (2) (Ar), 83.0, 82.9, 79.5, 74.3, 71.5 (C-1′ − C-5′), 62.9 (C-6′). ESI-HRMS positive mode (m/z): calcd for C₂₁H₂₂N₃O₅⁺ [M+H]⁺ 396.1554; C₂₁H₂₁N₃NaO₅⁺ [M+Na]⁺ 418.1373. Found: [M+H]⁺ 396.1555; [M+Na]⁺ 418.1371.

C-(2-Deoxy-2-phthalimido-3,4,6-tri-O-acetyl-β-d-glucopyranosyl)formamidrazone (5)

Ethyl C-(2-deoxy-2-phthalimido-3,4,6-tri-O-acetyl-β-d-glucopyranosyl)formimidate (4, 1.56 g, 3.17 mmol) was dissolved in anhydrous EtOH (30 mL), and hydrazine monohydrate (154 µL, 3.17 mmol) was added. The reaction mixture was stirred at room temperature, and the transformation of 4 was monitored by TLC (3:2 EtOAc-hexane). After the completion of the reaction (4.5 h), the precipitated product was filtered off and washed with EtOH to give 0.77 g of white solids. The mother liquor was evaporated under reduced pressure to give an oil, which was triturated with diethyl ether to give an additional 0.55 g of white solids. The combined yield of the product: 1.31 g (87%). R_f = 0.32 (3:2 EtOAc-hexane); [α]_D = −13 (c 0.49, MeOH). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 7.86-7.74 (4H, m, Ar), 5.98 (1H, pt, J = 9.8, 9.7 Hz, H-2 or H-3 or H-4), 5.19 (1H, pt, J = 9.7, 9.6 Hz, H-2 or H-3 or H-4), 4.81 (1H, d, J = 9.9 Hz, H-1), 4.58 (2H, br s, NH₂), 4.50 (1H, pt, J = 9.9, 9.6 Hz, H-2 or H-3 or H-4), 4.35 (1H, dd, J = 12.3, 4.6 Hz, H-6a), 4.17 (1H, dd, J = 12.5, 2.4 Hz, H-6b), 3.98 (1H, ddd, J = 9.9, 4.6, 2.4 Hz H-5′), 3.61-3.27 (2H, br signal, NH₂), 2.11, 2.05, 1.88 (3 × 3H, 3 s, CH₃); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 170.6, 169.9, 169.5 (CH₃-C=O), 167.8, 167.4 (Phth-C=O), 148.2 (C=N), 134.2, 134.0, 131.6, 131.0, 123.7, 123.3 (Ar), 75.6, 74.2, 70.9, 68.8 (C-1, C-3 − C-5), 62.1 (C-6), 52.7 (C-2), 20.7, 20.5, 20.4 (3 × CH₃). ESI-HRMS positive mode (m/z): calcd for C₂₁H₂₅N₄O₉⁺ [M+H]⁺ 477.1616. Found: 477.1613.

3-(2′-Deoxy-2′-phthalimido-3′,4′,6′-tri-O-acetyl-β-d-glucopyranosyl)-1,2,4-triazine (6a)

Prepared from amidrazone 5 (0.10 g, 0.21 mmol) and an aq. 40 wt.% solution of glyoxal (23.8 µL, 0.21 mmol) according to general procedure 1. Purified by column chromatography (1:1 EtOAc-hexane) to yield 58 mg (58%) of pale yellow syrup. R_f = 0.36 (3:2 EtOAc-hexane); [α]_D = −52 (c 0.23, CHCl₃). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 9.16, 8.67 (2 × 1H, 2 d, J = 2.4 Hz in each, H-5, H-6), 7.80-7.69 (4H, m, Ar), 6.09 (1H, dd, J = 10.3, 9.2 Hz, H-2′ or H-3′ or H-4′), 5.96 (1H, d, J = 10.5 Hz, H-1′), 5.36 (1H, dd, J = 9.9, 9.3 Hz, H-2′ or H-3′ or H-4′), 5.00 (1H, pt, J = 10.5, 10.5 Hz, H-2′ or H-3′ or H-4′), 4.38 (1H, dd, J = 12.4, 5.1 Hz, H-6′a), 4.23 (1H, dd, J = 12.5, 2.0 Hz, H-6′b), 4.17 (1H, ddd, J = 10.3, 5.1, 2.0 Hz, H-5′), 2.10, 2.08, 1.88 (3 × 3H, 3 s, CH₃); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 170.6, 170.1, 169.4 (CH₃-C=O), 167.6, 166.9 (Phth-C=O), 164.4 (C-3), 149.4 (2) (C-5, C-6), 134.3, 131.3, 130.8, 123.6 (Ar), 76.8, 76.5, 71.3, 68.8 (C-1′, C-3′ − C-5′), 62.2 (C-6′), 53.2 (C-2′), 20.7, 20.6, 20.4 (3 × CH₃).). ESI-HRMS positive mode (m/z): calcd for C₂₃H₂₃N₄O₉⁺ [M+H]⁺ 499.1460; C₂₃H₂₂N₄NaO₉⁺ [M+Na]⁺ 521.1279. Found: [M+H]⁺ 499.1455; [M+Na]⁺ 521.1279.

3-(2′-Deoxy-2′-phthalimido-3′,4′,6′-tri-O-acetyl-β-d-glucopyranosyl)-5-methyl-1,2,4-triazine (6b)

Prepared from amidrazone 5 (0.10 g, 0.21 mmol) and an aq. 40 wt.% solution of methylglyoxal (32 µL, 0.21 mmol) according to general procedure 1. Purified by column chromatography (2:1 EtOAc-hexane) to yield 67 mg (62%) of pale yellow syrup. R_f = 0.41 (2:1 EtOAc-hexane); [α]_D = −16 (c 0.25, CHCl₃). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 9.00 (1H, s, H-6), 7.86-7.69 (4H, m, Ar), 6.07 (1H, dd, J = 10.3, 9.3 Hz, H-2′ or H-3′ or H-4′), 5.88 (1H, d, J = 10.5 Hz, H-1′), 5.37 (1H, pt, J = 9.9, 9.4 Hz, H-2′ or H-3′ or H-4′), 5.05 (1H, pt, J = 10.5, 10.5 Hz, H-2′ or H-3′ or H-4′), 4.38 (1H, dd, J = 12.5, 5.0 Hz, H-6′a), 4.23 (1H, dd, J = 12.5, 2.1 Hz, H-6′b), 4.15 (1H, ddd, J = 10.2, 5.0, 2.1 Hz, H-5′), 2.52 (3H, s, CH₃), 2.10, 2.08, 1.88 (3 × 3H, 3 s, CH₃); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 170.7, 170.2, 169.5 (CH₃-C=O), 167.8, 166.4 (Phth-C=O), 163.2. 160.5 (C-3, C-5), 149.9 (C-6), 134.2, 131.4, 131.0, 123.6 (Ar), 76.8, 76.5, 71.4, 68.8 (C-1′, C-3′ − C-5′), 62.2 (C-6′), 53.0 (C-2′), 21.7, 20.7, 20.6, 20.4 (4 × CH₃). ESI-HRMS positive mode (m/z): calcd for C₂₄H₂₅N₄O₉⁺ [M+H]⁺ 513.1616; C₂₄H₂₄N₄NaO₉⁺ [M+Na]⁺ 535.1435. Found: [M+H]⁺ 513.1612; [M+Na]⁺ 535.1429.

3-(2′-Deoxy-2′-phthalimido-3′,4′,6′-tri-O-acetyl-β-d-glucopyranosyl)-5-tert-butyl-1,2,4-triazine (6c)

Prepared from amidrazone 5 (0.10 g, 0.21 mmol) and 3,3-dimethyl-2-oxobutanal (0.028 g, 0.21 mmol) according to general procedure 1. Purified by column chromatography (4:5 EtOAc-hexane) to yield 78 mg (67%) of white syrup. R_f = 0.51 (4:5 EtOAc-hexane); [α]_D = +14 (c 0.28, CHCl₃). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 9.21 (1H, s, H-6), 7.81-7.68 (4H, m, Ar), 6.05 (1H, pt, J = 10.3, 9.3 Hz, H-2′ or H-3′ or H-4′), 5.93 (1H, d, J = 10.5 Hz, H-1′), 5.37 (1H, pt, J = 10.0, 9.3 Hz, H-2′ or H-3′ or H-4′), 5.11 (1H, pt, J = 10.5, 10.5 Hz, H-2′ or H-3′ or H-4′), 4.35 (1H, dd, J = 12.4, 4.9 Hz, H-6′a), 4.25 (1H, dd, J = 12.4, 1.8 Hz, H-6′b), 4.15 (1H, ddd, J = 10.0, 4.9, 1.8 Hz, H-5′), 2.10, 2.08, 1.88 (3 × 3H, 3 s, CH₃), 1.28 (9H, s, C(CH₃)₃); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 170.6, 170.1, 169.7, 169.5 (3 × CH₃-C=O, C-5), 167.5, 166.5 (2 × Phth-C=O), 162.6 (C-3), 146.8 (C-6), 134.2, 131.4, 130.9, 123.4 (Ar), 76.9, 76.5, 71.5, 68.9 (C-1′, C-3′ − C-5′), 62.2 (C-6′), 52.9 (C-2′), 36.7 (C(CH₃)₃), 28.5 (C(CH₃)₃), 20.7, 20.6, 20.4 (3 × CH₃). ESI-HRMS positive mode (m/z): calcd for C₂₇H₃₁N₄O₉⁺ [M+H]⁺ 555.2086; C₂₇H₃₀N₄NaO₉⁺ [M+Na]⁺ 577.1905. Found: [M+H]⁺ 555.2088; [M+Na]⁺ 577.1904.

3-(2′-Deoxy-2′-phthalimido-3′,4′,6′-tri-O-acetyl-β-d-glucopyranosyl)-5-phenyl-1,2,4-triazine (6d)

Prepared from amidrazone 5 (0.10 g, 0.21 mmol) and phenylglyoxal monohydrate (0.032 g, 0.21 mmol) according to general procedure 1. Purified by column chromatography (1:1 EtOAc-hexane) to yield 88 mg (73%) of yellow syrup. R_f = 0.41 (3:2 EtOAc-hexane); [α]_D = −86 (c 0.22, CHCl₃). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 9.57 (1H, s, H-6), 8.17–7.52 (9H, m, Ar), 6.10 (1H, pt, J = 9.8, 9.7 Hz, H-2′ or H-3′ or H-4′), 6.01 (1H, d, J = 10.5 Hz, H-1′), 5.40 (1H, pt, J = 9.7, 9.5 Hz, H-2′ or H-3′ or H-4′), 5.24 (1H, pt, J = 10.5, 10.5 Hz, H-2′ or H-3′ or H-4′), 4.38 (1H, dd, J = 12.3, 4.8 Hz, H-6′a), 4.26-4.17 (2H, m, H-5′, H-6′b), 2.09, 1.90 (9H, 2 s, CH₃). ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 170.7, 170.2, 169.5 (CH₃-C=O), 167.8, 167.7 (Phth-C=O), 163.4, 155.8 (C-3, C-5), 145.9 (C-6), 134.2, 132.8, 132.6, 129.3, 127.8, 123.5 (Ar), 76.9, 76.6, 71.6, 68.8 (C-1′, C-3′ − C-5′), 62.2 (C-6′), 52.8 (C-2′), 20.7, 20.6, 20.4 (3 × CH₃). ESI-HRMS positive mode (m/z): calcd for C₂₉H₂₇N₄O₉⁺ [M+H]⁺ 575.1773; C₂₉H₂₆N₄NaO₉⁺ [M+Na]⁺ 597.1592. Found: [M+H]⁺ 575.1777; [M+Na]⁺ 597.1593.

3-(2′-Deoxy-2′-phthalimido-3′,4′,6′-tri-O-acetyl-β-d-glucopyranosyl)-5,6-diphenyl-1,2,4-triazine (6e)

Prepared from amidrazone 5 (0.10 g, 0.21 mmol) and benzil (0.042 g, 0.21 mmol) according to general procedure 1. Purified by column chromatography (4:5 EtOAc-hexane) to yield 84 mg (65%) of pale yellow syrup. R_f = 0.51 (4:5 EtOAc-hexane); [α]_D = −60 (c 0.20, CHCl₃). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 7.81-7.27 (14H, m, Ar), 6.10 (1H, dd, J = 10.3, 9.3 Hz, H-2′ or H-3′ or H-4′), 6.05 (1H, d, J = 10.6 Hz, H-1′), 5.40 (1H, pt, J = 10.0, 9.3 Hz, H-2′ or H-3′ or H-4′), 5.30 (1H, pt, J = 10.5, 10.5 Hz, H-2′ or H-3′ or H-4′), 4.39 (1H, dd, J = 12.6, 5.1 Hz, H-6′a), 4.25 (1H, dd, J = 12.6, < 1 Hz, H-6′a), 4.21-4.19 (1H, m, H-5′), 2.08, 1.90 (9H, 2 s, CH₃). ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 170.6, 170.1, 169.4 (CH₃-C=O), 167.8, 166.8 (Phth-C=O), 161.1, 157.1, 156.2 (C-3, C-5, C-6), 134.8-123.4 (Ar), 76.6, 76.5, 71.6, 68.8 (C-1′, C-3′ − C-5′), 62.2 (C-6′), 52.7 (C-2′), 20.7, 20.6, 20.4 (3 × CH₃). ESI-HRMS positive mode (m/z): calcd for C₃₅H₃₁N₄O₉⁺ [M+H]⁺ 651.2086; C₃₅H₃₀N₄NaO₉⁺ [M+Na]⁺ 673.1905. Found: [M+H]⁺ 651.2085; [M+Na]⁺ 673.1902.

N¹-Ethoxycarbonylmethylidene-C-(2′,3′,4′,6′-tetra-O-benzoyl-β-d-glucopyranosyl)formamidrazone (7a)

A solution of amidrazone 1 (0.10 g, 0.16 mmol) and ethyl glyoxalate (31 µL, 0.16 mmol, an 50% solution in toluene) was boiled in dry EtOH (3 mL) until the TLC (1:1 and 7:3 EtOAc-hexane) showed the complete conversion of 1. After the completion of the reaction (1 h), the solvent was removed under reduced pressure. After column chromatographic purification (2:3 EtOAc-hexane), 44 mg (39%) of the title compound was obtained as a pale yellow syrup. R_f = 0.53 (1:1 EtOAc-hexane); [α]_D = +23 (c 0.27, CHCl₃). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 8.06-7.83, 7.59-7.26, 7.07 (21H, m, Ar, CH=N), 6.02 (1H, pt, J = 9.6, 9.6 Hz, H-2′ or H-3′ or H-4′), 5.76 (1H, pt, J = 9.8, 9.7 Hz, H-2′ or H-3′ or H-4′), 5.67 (1H, pt, J = 9.7, 9.7 Hz, H-2′ or H-3′ or H-4′), 4.69 (1H, dd, J = 12.4, 2.7 Hz, H-6′a), 4.54 (1H, dd, J = 12.4, 5.2 Hz, H-6′b), 4.51 (1H, d, J = 9.7 Hz, H-1′), 4.35-4.25 (1H, m, H-5′), 4.23 (2H, q, J = 7.1 Hz, CH₂), 1.28 (3H, t, J = 7.1 Hz, CH₃); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 166.2, 165.6, 165.3, 165.2, 163.7, 160.9 (5 × C=O, C=N), 146.1 (CH=N), 133.6, 133.3, 133.2, 129.9-128.3 (Ar), 76.4, 76.3, 73.4, 70.5, 69.1 (C-1′ − C-5′), 62.8, 61.2 (C-6′, CH₂), 14.1 (CH₃).

N¹-Methoxycarbonylethylidene-C-(2′,3′,4′,6′-tetra-O-benzoyl-β-d-glucopyranosyl)formamidrazone (7b)

A solution of amidrazone 1 (0.10 g, 0.16 mmol) and methyl pyruvate (14 µL, 0.16 mmol) was boiled in dry EtOH (3 mL) until the TLC (1:1 and 7:3 EtOAc-hexane) showed the complete conversion of 1. After the completion of the reaction (1.5 h), the solvent was removed under reduced pressure. After column chromatographic purification (2:3 EtOAc-hexane), 67 mg (59%) of the title compound was obtained as a pale yellow syrup. R_f = 0.53 (1:1 EtOAc-hexane). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 8.05-7.83, 7.58-7.25, 7.07 (20H, m, Ar), 6.03 (1H, pt, J = 9.6, 9.6 Hz, H-2′ or H-3′ or H-4′), 5.94-5.83 (2H, broad signal, NH), 5.75 (1H, pt, J = 9.8, 9.7 Hz, H-2′ or H-3′ or H-4′), 5.73 (1H, pt, J = 9.6, 9.6 Hz, H-2′ or H-3′ or H-4′), 4.68 (1H, dd, J = 12.3, < 1 Hz, H-6′a), 4.55 (1H, dd, J = 12.4, 5.4 Hz, H-6′b), 4.55 (1H, d, J = 9.7 Hz, H-1′), 4.27 (1H, ddd, J = 9.7, 5.4, 2.3 Hz, H-5′), 3.75 (3H, s, OCH₃), 1.60 (3H, s, CH₃); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 166.1, 165.7, 165.6, 165.2, 165.0 (5 × C=O), 158.3, 153.7 (2 × C=N), 133.6, 133.5, 133.4, 133.2, 129.8-128.3 (Ar), 76.8, 76.4, 73.6, 70.5, 69.2 (C-1′ − C-5′), 62.9 (C-6′), 52.3 (OCH₃), 13.0 (CH₃).

3-(3′,4′,6′-Tri-O-benzoyl-2′-deoxy-d-arabino-hex-1′-enopyranosyl)-1,2,4-triazin-5(4H)-one (8a)

Prepared from amidrazone 1 (0.10 g, 0.16 mmol) and ethyl glyoxalate (31 µL, 0.16 mmol, an 50% solution in toluene) according to general procedure 3. Reaction time: 3 d. Purified by column chromatography (7:3 EtOAc-hexane) to yield 50 mg (57%) of pale yellow amorphous solids. R_f = 0.24 (7:3 EtOAc-hexane); [α]_D = −44 (c 0.26, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 14.05 (1H, br s, NH), 7.97-7.93, 7.67-7.64, 7.53-7.49 (16H, m, Ar, H-6), 6.60 (1H, d, J = 3.5 Hz, H-2′), 6.00 (1H, dd, J = 5.6, 3.5 Hz, H-3′), 5.87 (1H, pt, J = 7.6, 5.6 Hz, H-4′), 5.15 (1H, ddd, J = 7.6, 4.6, 3.3 Hz, H-5′), 4.82 (1H, dd, J = 12.4, 4.6 Hz, H-6′a), 4.74 (1H, dd, J = 12.4, 3.3 Hz, H-6′b); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 165.3, 164.9, 164.2 (3 × C=O), 161.8, 152.6, 144.6 (C-3, C-5, C-6), 145.4 (C-1′), 133.8, 133.6, 133.4, 129.3-128.6 (Ar), 104.0 (C-2′), 74.8, 67.8, 66.8 (C-3′ − C-5′), 61.2 (C-6′). ESI-HRMS positive mode (m/z): calcd for C₃₀H₂₃N₃NaO₈⁺ [M+Na]⁺ 576.1377. Found: 576.1377.

3-(3′,4′,6′-Tri-O-benzoyl-2′-deoxy-d-arabino-hex-1′-enopyranosyl)-6-methyl-1,2,4-triazin-5(4H)-one (8b)

Prepared from amidrazone 1 (0.10 g, 0.16 mmol) and methyl pyruvate (14 µL, 0.16 mmol) according to general procedure 3. Reaction time: 6 h. Purified by column chromatography (7:3 EtOAc-hexane) to yield 67 mg (75%) of pale yellow amorphous solids. R_f = 0.42 (7:3 EtOAc-hexane); [α]_D = −29 (c 0.23, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 13.82 (1H, br s, NH), 7.96-7.95, 7.68-7.64, 7.53-7.49 (15H, m, Ar), 6.37 (1H, broad signal, H-2′), 5.98 (1H, broad signal, H-3′), 5.87 (1H, pt, J = 7.0, 6.0 Hz, H-4′), 5.14 (1H, broad signal, H-5′), 4.82 (1H, dd, J = 12.3, 4.6 Hz, H-6′a), 4.73 (1H, dd, J = 12.3, 2.5 Hz, H-6′b), 2.18 (3H, s, CH₃); ¹³C NMR (90 MHz, DMSO-d₆) δ (ppm): 165.2, 164.9, 164.4 (3 × C=O), 162.3, 153.2, 152.4 (C-3, C-5, C-6), 145.4 (C-1′), 133.7, 133.6, 133.3, 129.3-128.6 (Ar), 103.5 (C-2′), 74.7, 67.7, 66.8 (C-3′ − C-5′), 61.2 (C-6′), 17.1 (CH₃). ESI-HRMS positive mode (m/z): calcd for C₃₁H₂₆N₃O₈⁺ [M+H]⁺ 568.1714; C₃₁H₂₅N₃NaO₈⁺ [M+Na]⁺ 590.1534. Found: [M+H]⁺ 568.1711; [M+Na]⁺ 590.1531.

3-(2′-Deoxy-2′-phthalimido-3′,4′,6′-tri-O-acetyl-β-d-glucopyranosyl)-1,2,4-triazin-5(4H)-one (9a)

Prepared from amidrazone 5 (0.10 g, 0.21 mmol) and ethyl glyoxylate (43 µL, 0.21 mmol) according to general procedure 3. Reaction time: 2 d. Purified by column chromatography (3:2 EtOAc-hexane) to yield 55 mg (51%) of pale yellow syrup. R_f = 0.25 (5:2 EtOAc-hexane); [α]_D = +17 (c 0.21, CHCl₃). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 11.73 (1H, s, NH), 7.90–7.72 (5H, m, Ar, H-6), 6.07 (1H, pt, J = 9.8, 9.8 Hz, H-2′ or H-3′ or H-4′), 5.35 (1H, d, J = 9.4 Hz, H-1′), 5.23 (1H, pt, J = 9.8, 9.6 Hz, H-2′ or H-3′ or H-4′), 4.54 (1H, pt, J = 10.5, 10.5 Hz, H-2′ or H-3′ or H-4′), 4.40 (1H, dd, J = 12.6, 5.3 Hz, H-6′a), 4.26 (1H, dd, J = 12.6, 1.7 Hz, H-6′b), 4.12 (1H, ddd, J = 10.0, 5.3, 1.7 Hz, H-5′), 2.13, 2.09, 1.90 (3 × 3H, 3 s, CH₃); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 171.1, 169.8, 169.6 (CH₃-C=O), 167.8 (2 × Phth-C=O), 161.2, 159.2 (C-3, C-5), 144.3 (C-6), 134.5, 131.3, 123.9 (Ar), 76.2, 71.4, 70.5, 68.5 (C-1′, C-3′ − C-5′), 62.1 (C-6′), 52.5 (C-2′), 20.8, 20.6, 20.4 (3 × CH₃). ESI-HRMS positive mode (m/z): calcd for C₂₃H₂₃N₄O₁₀⁺ [M+H]⁺ 515.1409; C₂₃H₂₂N₄NaO₁₀⁺ [M+Na]⁺ 537.1228. Found: [M+H]⁺ 515.1409; [M+Na]⁺ 537.1226.

3-(2′-Deoxy-2′-phthalimido-3′,4′,6′-tri-O-acetyl-β-d-glucopyranosyl)-6-methyl-1,2,4-triazin-5(4H)-one (9b)

Prepared from amidrazone 5 (0.10 g, 0.21 mmol) and methyl pyruvate (23 µL, 0.21 mmol) according to general procedure 3. Reaction time: 2 d. Purified by column chromatography (3:2 EtOAc-hexane) to yield 56 mg (50%) of pale yellow syrup. R_f = 0.25 (5:2 EtOAc-hexane); [α]_D = +45 (c 0.21, CHCl₃). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 11.39 (1H, s, NH), 7.86–7.72 (4H, m, Ar), 6.06 (1H, pt, J = 9.8, 9.6 Hz, H-2′ or H-3′ or H-4′), 5.31 (1H, d, J = 10.5 Hz, H-1′), 5.23 (1H, pt, J = 9.8, 9.5 Hz, H-2′ or H-3′ or H-4′), 4.54 (1H, pt, J = 10.5, 9.8 Hz, H-2′ or H-3′ or H-4′), 4.39 (1H, dd, J = 12.1, 5.0 Hz, H-6′a), 4.27 (1H, dd, J = 12.3, < 1 Hz, H-6′b), 4.16-4-07 (1H, m, H-5′), 2.20 (3H, s, CH₃), 2.14, 2.09, 1.89 (3 × 3H, 3 s, CH₃); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 171.0, 169.9, 169.6 (CH₃-C=O), 167.9, 167.7 (2 × Phth-C=O), 161.9, 158.8, 153.8 (C-3, C-5, C-6), 134.4 (2), 131.4, 131.3, 123.8 (2) (Ar), 76.1, 71.3, 70.5, 68.5 (C-1′, C-3′ − C-5′), 62.1 (C-6′), 52.6 (C-2′), 20.8, 20.6, 20.4 (3 × CH₃), 17.4 (CH₃). ESI-HRMS positive mode (m/z): calcd for C₂₄H₂₅N₄O₁₀⁺ [M+H]⁺ 529.1565; C₂₄H₂₄N₄NaO₁₀⁺ [M+Na]⁺ 551.1385. Found: [M+H]⁺ 529.1569; [M+Na]⁺ 551.1386.

((6aS,7R,7aR)-1-(2′,3′,4′,6′-Tetra-O-benzoyl-β-d-glucopyranosyl)-6,6a,7,7a,8,9-hexahydro-5H-cyclopropa[5,6]cyclookta[1,2-c]pyridin-7-yl)methanol and ((6aR,7S,7aS)-1-(2′,3′,4′,6′-tetra-O-benzoyl-β-d-glucopyranosyl)-6,6a,7,7a,8,9-hexahydro-5H-cyclopropa[5,6]cyclookta[1,2-c]pyridin-7-yl)methanol (11a)

Prepared from triazine 2a (0.10 g, 0.15 mmol) and ((1R,8S,9r)-bicyclo[6.1.0]non-4-yn-9-yl)methanol (10, 46 mg, 0.30 mmol) in CH₂Cl₂ according to general procedure 4. Reaction time: 2 d. Purified by column chromatography (1:1 EtOAc-hexane) to give 115 mg (97%) of colourless syrup. Diastereomeric ratio: 5:4. R_f = 0.15 (1:1 EtOAc-hexane). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 8.29, 8.26 (2 × 1H, 2 d, J = 4.8 Hz in each, 2 × H-3), 8.02–7.21 (2 × 20H, m, Ar), 6.94, 6.92 (2 × 1H, 2 d, J = 4.8 Hz in each, 2 × H-4), 6.44 (2H, pt, J = 9.6, 9.5 Hz, 2 × (H-2′ or H-3′ or H-4′)), 6.11 (2H, pt, J = 9.5, 9.5 Hz, 2 × (H-2′ or H-3′ or H-4′)), 5.88, 5.87 (2 × 1H, 2 pt, J = 9.7, 9.6 Hz in each, 2 × (H-2′ or H-3′ or H-4′)), 5.27, 5.25 (2 × 1H, 2 d, J = 9.7 Hz in each, 2 × H-1′), 4.81, 4.71 (2 × 1H, 2 dd, J = 12.2, 2.1 Hz in each, 2 × H-6′a), 4.51, 4.46 (2 × 1H, 2 dd, J = 12.2, 5.1 Hz in each, 2 × H-6′b), 4.44–4.37 (2 × 1H, m, 2 × H-5′), 3.36–3.31, 3.18–2.87, 2.75–2.45, 2.38–2.33, 1.47–1.26, 0.66–0.52, 0.36–0.20 (2 × 14H, m, aliphatics, OH); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 166.2, 166.1, 166.0, 165.9, 165.2, 165.2, 164.5, 164.4 (2 × 4 × C=O), 152.4, 152.3, 151.2, 151.1 (2 × C-1, 2 × C-4a), 146.4 (2 × C-3), 137.6, 137.4 (2 × C-9a), 133.3-132.7, 130.0-128.0 (Ar), 125.9, 125.8 (2 × C-4), 79.0, 78.3, 76.8, 76.8, 75.1, 75.1, 71.3, 71.2, 69.9, 69.8 (2 × (C-1′ − C-5′)), 66.1, 66.1 (2 × C-6′), 63.5, 63.2 (2 × CH₂OH), 33.3, 33.2, 30.0, 29.7, 29.2, 28.5, 28.3, 28.0, 25.8, 25.4, 21.4, 20.8, 20.4, 19.9 (2 × (C-5, C-6, C-6a, C-7, C-7a, C-8, C-9)). ESI-HRMS positive mode (m/z): calcd for C₄₇H₄₄NO₁₀⁺ [M+H]⁺: 782.2960; C₄₇H₄₃NNaO₁₀⁺ [M+Na]⁺: 804.2779. Found: [M+H]⁺: 782.2959; [M+Na]⁺: 804.2779.

((6aS,7R,7aR)-3-Methyl-1-(2′,3′,4′,6′-tetra-O-benzoyl-β-d-glucopyranosyl)-6,6a,7,7a,8,9-hexahydro-5H-cyclopropa[5,6]cyclookta[1,2-c]pyridin-7-yl)methanol and ((6aR,7S,7aS)-3-methyl-1-(2′,3′,4′,6′-tetra-O-benzoyl-β-d-glucopyranosyl)-6,6a,7,7a,8,9-hexahydro-5H-cyclopropa[5,6]cyclookta[1,2-c]pyridin-7-yl)methanol (11b)

Prepared from triazine 2a (0.05 g, 0.074 mmol) and ((1R,8S,9r)-bicyclo[6.1.0]non-4-yn-9-yl)methanol (10, 22 mg, 0.148 mmol) in CH₂Cl₂ according to general procedure 4. Reaction time: 6 d. Purified by column chromatography (4:5 EtOAc-hexane) to give 24 mg (41%) of colourless amorphous solids. Diastereomeric ratio: 5:4. R_f = 0.28 (1:1 EtOAc-hexane). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 8.05-7.23 (2 × 20H, m, Ar), 6.77, 6.76 (2 × 1H, 2 s, 2 × H-4), 6.47, 6.43 (2 × 1H, 2 pt, J = 9.7, 9.6 Hz in each, 2 × (H-2′ or H-3′ or H-4′)), 6.07 (2H, pt, J = 9.6, 9.6 Hz, 2 × (H-2′ or H-3′ or H-4′)), 5.86, 5.84 (2 × 1H, 2 pt, J = 9.7, 9.6 Hz in each, 2 × (H-2′ or H-3′ or H-4′)), 5.17, 5.16 (2 × 1H, 2 d, J = 9.7 Hz in each, 2 × H-1′), 4.88, 4.70 (2 × 1H, 2 dd, J = 12.1, 2.8 Hz in each, 2 × H-6′a), 4.49 (1H, dd, J = 12.1, 5.3 Hz, H-6′b), 4.42-4.33 (3H, m, H-6′b, 2 × H-5′), 3.50-2.32 (m, aliphatics), 2.30, 2.26 (2 × 3H, 2 s, 2 × CH₃), 1.40-0.31 (m, aliphatics, OH); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 166.3, 166.2, 166.1, 166.0, 165.3, 165.3, 164.7, 164.6 (2 × 4 × C=O), 154.8, 154.6, 152.4, 152.3, 150.4, 150.3 (2 × C-1, 2 × C-4a, 2 × C-3), 134.4, 134.3 (2 × C-9a), 133.3-132.6, 130.1-128.0 (Ar), 125.4, 125.3 (2 × C-4), 79.6, 78.8, 76.9, 76.9, 75.3, 75.2, 71.1, 70.8, 70.0, 69.8 (2 × (C-1′ − C-5′)), 66.3, 65.7 (2 × C-6′), 63.6, 63.0 (2 × CH₂OH), 33.1, 33.0, 30.0, 29.9, 28.8, 28.2, 28.1, 26.8, 25.5, 25.3, 23.5, 23.4, 21.6, 20.8, 20.6, 20.4 (2 × (C-5, C-6, C-6a, C-7, C-7a, C-8, C-9), 2 × CH₃). ESI-HRMS positive mode (m/z): calcd for C₄₈H₄₅NNaO₁₀⁺ [M+Na]⁺: 818.2936. Found: 818.2935.

((6aS,7R,7aR)-3-Phenyl-1-(2′,3′,4′,6′-tetra-O-benzoyl-β-d-glucopyranosyl)-6,6a,7,7a,8,9-hexahydro-5H-cyclopropa[5,6]cyclookta[1,2-c]pyridin-7-yl)methanol and ((6aR,7S,7aS)-3-phenyl-1-(2′,3′,4′,6′-tetra-O-benzoyl-β-d-glucopyranosyl)-6,6a,7,7a,8,9-hexahydro-5H-cyclopropa[5,6]cyclookta[1,2-c]pyridin-7-yl)methanol (11d)

Prepared from triazine 2d (0.05 g, 0.068 mmol) and ((1R,8S,9r)-bicyclo[6.1.0]non-4-yn-9-yl)methanol (10, 20 mg, 0.136 mmol) in CH₂Cl₂ according to general procedure 4. Reaction time: 6 d. Purified by column chromatography (1:1 EtOAc-hexane) to give 43 mg (73%) of colourless amorphous solids. Diastereomeric ratio: 5:4. R_f = 0.28 (1:1 EtOAc-hexane). ¹H NMR (360 MHz, CDCl₃) δ (ppm): 8.04-7.15 (2 × 26H, m, Ar, 2 × H-4), 6.69, 6.65 (2 × 1H, 2 pt, J = 9.7, 9.7 Hz in each, 2 × (H-2′ or H-3′ or H-4′)), 6.12 (2H, pt, J = 9.6, 9.5 Hz, 2 × (H-2′ or H-3′ or H-4′)), 5.89, 5.86 (2 × 1H, 2 pt, J = 9.8, 9.6 Hz in each, 2 × (H-2′ or H-3′ or H-4′)), 5.31, 5.29 (2 × 1H, 2 d, J = 9.8 Hz in each, 2 × H-1′), 4.90, 4.67 (2 × 1H, 2 dd, J = 12.1, 2.9 Hz in each, 2 × H-6′a), 4.50 (1H, dd, J = 12.1, 5.3 Hz, H-6′b), 4.42–4.36 (3 × 1H, m, H-6′b, 2 × H-5′), 3.43–3.38, 3.20–2.52, 2.46–2.34, 1.52–1.36, 0.74–0.34 (2 × 13H, m, aliphatics); ¹³C NMR (90 MHz, CDCl₃) δ (ppm): 166.3, 166.3, 166.2, 166.1, 165.3, 165.2, 164.8, 164.6 (2 × 4 × C=O), 154.0, 153.6, 153.0, 153.0, 150.9, 150.8 (2 × C-1, 2 × C-3, 2 × C-4a), 138.9, 138.7, 136.4, 136.1 (2 × C-9a, 2 × Ar-C_q), 133.4-132.5, 129.9-126.8 (Ar), 122.6, 122.3 (2 × C-4), 79.0, 78.4, 76.9, 76.9, 75.6, 75.4, 70.8, 70.5, 69.9, 69.6 (2 × (C-1′ − C-5′)), 66.2, 66.2 (2 × C-6′), 63.7, 62.9 (2 × CH₂OH), 33.5, 30.0, 29.9, 29.1, 28.8, 28.2, 28.0, 25.6, 25.4, 20.5, 20.5, 20.4, 20.3 (2 × (C-5, C-6, C-6a, C-7, C-7a, C-8, C-9)). ESI-HRMS positive mode (m/z): calcd for C₅₃H₄₈NO₁₀⁺ [M+H]⁺: 858.3273; C₅₃H₄₇NNaO₁₀⁺ [M+Na]⁺: 880.3092. Found: [M+H]⁺: 858.3272; [M+Na]⁺: 880.3093.

((6aS,7R,7aR)-1-(β-d-glucopyranosyl)-3-phenyl-6,6a,7,7a,8,9-hexahydro-5H-cyclopropa[5,6]cyclookta[1,2-c]pyridin-7-yl)methanol and ((6aR,7S,7aS)-1-(β-d-glucopyranosyl)-3-phenyl-6,6a,7,7a,8,9-hexahydro-5H-cyclopropa[5,6]cyclookta[1,2-c]pyridin-7-yl)methanol (12d)

Prepared from triazine 3d (20 mg, 0.063 mmol) and ((1R,8S,9r)-bicyclo[6.1.0]non-4-yn-9-yl)methanol (10, 19 mg, 0.126 mmol) in MeOH according to general procedure 4. Reaction time: 5 d. Purified by column chromatography (8:1 CHCl₃-MeOH) to give 26 mg (94%) of pale yellow amorphous solids. Diastereomeric ratio: 1:1. R_f = 0.21 (8:1 CHCl₃-MeOH). ¹H NMR (360 MHz, CD₃OD) δ (ppm): 8.02–8.01 (2 × 2H, Ph), 7.58 (2H, s, 2 × H-4), 7.47–7.36 (2 × 3H, m, Ph), 4.65, 4.63 (2 × 1H, 2 d, J = 9.3 Hz in each, H-1′), 4.34, 4.33 (2 × 1H, 2 pt, J = 9.1, 9.1 Hz in each, 2 × (H-2′ or H-3′ or H-4′)), 3.87–3.51 (2 × 4H, m, 2 × (H-2′ and/or H-3′ and/or H-4′, H-6′a, H6′b), 4.46–3.30 (2H, m, 2 × H-5′), 3.30–3.22, 3.14–3.05, 2.99–2.89, 2.65–2.44, 1.51–1.39, 0.72–0.61 (2 × 13H, m, aliphatics); ¹³C NMR (90 MHz, CD₃OD) δ (ppm): 155.5, 155.3, 155.3, 155.2, 155.2, 155.1 (2 × C-1, 2 × C-3, 2 × C-4a), 140.8, 140.7, 138.5, 138.5 (2 × C-9a, 2 × Ph-C_q), 129.8, 129.7, 129.6, 129.6, 128.0 (Ph), 123.3, 123.2 (2 × C-4), 82.4, 82.4, 79.7, 79.7, 79.6, 73.8, 73.7, 71.6, 71.5 (2 × (C-1′ − C-5′)), 66.6, 66.5 (2 × C-6′), 62.9, 62.8 (2 × CH₂OH), 35.0, 34.8, 31.1, 31.0, 30.3, 30.1, 29.9, 29.8, 26.6, 26.5, 23.0, 22.9, 22.6, 22.5 (2 × (C-5, C-6, C-6a, C-7, C-7a, C-8, C-9)). ESI-HRMS positive mode (m/z): calcd for C₂₅H₃₁NNaO₆⁺ [M+Na]⁺: 464.2044. Found: 464.2042 (Supplementary Materials).

4. Conclusions

The reactions of C-glycopyranosyl formamidrazones with 1,2-dielectrophiles (α-keto-aldehydes and esters as well as 1,2-diketones) represent a simple method for the synthesis of hitherto unknown 3-glycopyranosyl-1,2,4-triazines and -1,2,4-triazin-5(4H)-ones. The C-glycosyl 1,2,4-triazines can be transformed into the corresponding 2-glycopyranosyl pyridines in strain-promoted inverse electron demand Diels–Alder reactions. These new compounds may be interesting for yet unknown applications to be explored in the future.