Metal free synthesis of morpholine fused [5,1-c] triazolyl glycoconjugates via glycosyl azido alcohols

Abstract

A series of diverse glycosyl 1,2-azido alcohols, obtained from readily available carbohydrates, were converted to structurally varied rare and novel sugar derived morpholine fused [5,1-c]-triazoles via a one-pot strategy. After incorporating a propargyl functionality at the hydroxyl group of the sugar derived 1,2-azido alcohols, the resulting in situ generated azido–alkyne affords numerous C- and O-glycosyl bicyclic ring systems with medicinal value via a metal free cycloaddition reaction. The structures of all the developed molecules have been elucidated using ¹H NMR, ¹³C NMR, IR and MS spectroscopy.

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1. Introduction

The design and development of medium-sized organic scaffolds and fused heterocyclic systems ‘found in numerous pharmaceutical molecules’ are attractive to chemists for the synthesis of novel mechanism based drugs and to improve the therapeutic efficacy of clinical medicines by adjoining these scaffolds.¹ 1,2-Azido alcohols have been considered as important precursors for the synthesis of such medium sized heterocyclic systems which can show excellent biological activities.² 1,2-Azido alcohols conjugated with carbohydrates pave the way for the creation of a large number of fused bicyclic molecules linked with biocompatible sugar, which is responsible for the enhancement of the biological action of such systems. Hence the synthesis of glycoconjugate azido alcohols and their application in organic chemistry is an increasing demand for the advancement of modern drug discovery. Morpholine, has been found to be an excellent pharmacophore in medicinal chemistry. A number of drugs including morpholine as a constituent are available in the market.³ Therefore, many new approaches toward the synthesis of morpholine derivatives have been reported in the literature.⁴

The 1,2,3-triazole core, which is part of a significant class of biologically active nitrogen compounds, exhibits a number of important biological properties such as antibacterial, anticancer, antivirus, antituberculosis, anti-HIV, antitumor, and glycosidase inhibition.^5–8 Moreover, 1,2,3-triazoles have found wide industrial applications as dyes, agrochemicals, corrosion inhibitors, and photostabilizers.⁹ Hence, the synthesis of the 1,2,3-triazole nucleus or its conjugation with a key part of a medicine has been the subject of ever growing synthetic efforts.

The Huisgen dipolar cycloaddition of alkynes with organic azides is a conventional path for the synthesis of 1,2,3-triazoles but is limited due to the formation of a regioisomeric mixture in the form of 1,4- and 1,5-isomers as products.¹⁰ The CuAAC reaction represents an extremely powerful tool for the rapid coupling of organic azides and terminal alkynes and produces 1,4-disubstituted 1,2,3-triazoles solely.¹¹ Likewise, the ruthenium catalyzed azide–alkyne cycloaddition (RuAAC) frequently gives the opposite 1,5-regioisomer of 1,2,3-triazole; although expensive ruthenium complexes are required as catalysts.¹² Furthermore, it is realized that the metal free intramolecular azide–alkyne cycloaddition is an economically favourable and easy to perform which affords the regioselective 1,5-disubstituted 1,2,3-triazoles fused with hetero and carbocyclic systems of medicinal value. Molecules having such scaffolds exhibit efficient and precious biological responses including α-glucosidase enzyme (I), α-galactosidase (II), and active against Alzheimer disease (IV) (Fig. 1).² It would thus be interesting to synthesize molecules possessing these moieties in conjugation with carbohydrates in fused form and evaluate their biological properties. Presently the world drug index contains numerous drugs having this structural feature in different forms including scaffold, side-chain, fused-ring, etc.¹³

Fig. 1 Biologically active morpholine-fused triazoles.

Herein, we report the synthesis of novel C- and O-glycosylated morpholine fused 1,5-triazoles from diverse glycosyl azido alcohols using a metal-free intramolecular thermal azide–alkyne cycloaddition reaction.

2. Results and discussion

Our synthetic investigation begins with readily available monosaccharides (D-glucose, D-mannose, D-galactose, D-ribose, D-xylose, etc.), which after processing with a number of high yielding steps of protections and modifications afford diverse orthogonally protected sugars 1a–e. The 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose 1a and 2,3:5,6-di-O-isopropylidene-D-mannofuranose 1b were taken as starting materials for the synthesis of diverse glucosidal and mannosidal furanosyl 1,2-azido alcohols. First of all, compound 1a was subjected to a substitution reaction with diverse organic halides (benzyl bromide, iodomethane, iodoethane, isopentyl bromide, and chloropropane) using basic conditions in dry DMF under argon atmosphere to afford their respective O-substituted derivatives 2a–e. Compounds 2a–e were further converted to their corresponding diols 3a–e via selective 5,6-isopropylidene deprotection using mild acidic conditions. Compounds 3a–e were next reacted with tosyl chloride in dry pyridine at 5–10 °C for 12 hours to afford their selective tosyl derivatives 4a–e. The subsequent azidation of all tosylated sugars with sodium azide in dry DMF at 115 °C employing anhydrous condition resulted in their respective deoxy-azido sugars 5a–e in excellent yields (Scheme 1, Table 1).¹⁴

Scheme 1 Synthesis of morpholine-fused [5,1-c]-triazoles (5a–e) from D-glucose via the azido alcohol route.

Once the synthesis of azido-alcohols 5a–e was achieved, we next attempted the metal free azide–alkyne intramolecular cycloaddition reaction. We utilized all the developed azido alcohols for the synthesis of the desired morpholine fused [5,1-c]-triazoles via O-propargylation at the secondary hydroxyl group of the 1,2-azido alcohols using strong base (NaH) in dry DMF at 0 °C–rt which gave an azido–alkyne as the intermediate. After quenching of the remaining NaH by adding a few drops of water to the reaction mixture and without isolating the azido–alkyne intermediate, the reaction system was subjected to the thermal intramolecular azide–alkyne cyclization.

In the reaction optimization study, we reacted 5a (1.0 equiv.) with propargyl bromide (1.3 equiv.) and NaH (3.0 equiv.) in dry DMF (8 ml) for 12 h, then after the quenching process, the reaction mixture was heated at 110 °C for the next 4 hours. Subsequent purification using column chromatography gave compound 6a in excellent yields (92%).

The structure of compound 6a was deduced from extensive spectral studies (IR, NMR, and MS). The ¹H NMR spectrum of compound 6a exhibited a singlet of one proton observed at δ 7.39 assigned to the triazole-H proton. In addition to other signals, the appearance of a double doublet at δ 4.92 is attributed to the characteristic OCH_A proton of the triazolo morpholine ring while the expected other characteristic double doublet for the corresponding OCH_B proton of the morpholine ring was found merged with benzylic protons which finally confirmed the occurrence of the thermal cyclization. A doublet at δ 5.87 (3.6 Hz) confirmed the presence of the anomeric proton while multiplets from δ 4.68 to δ 4.46 and δ 4.19 to 4.08 displayed the remaining carbohydrate protons. Two signals for six isopropylidene protons are observed at δ 1.43 and δ 1.26. ¹³C NMR of compound 6a showed two resonances at δ 129.6 and δ 127.8 corresponding to triazole-carbons. The molecular ion peak at 374 (M + H⁺) is evidence for the synthesis of compound 6a.

Similar chemistry has been implemented with 2,3:5,6-di-O-isopropylidene-D-mannofuranose. In this case, 1-O-substituted derivatives were obtained as a mixture of anomers where β-isomers 7a–d were isolated as the major constituent which were used for the subsequent formation of diols (8a–d), tosyl derivatives 9a–d, azido alcohols 10a–d and finally morpholine-fused [5,1-c]-triazoles 11a–d (Scheme 2). We further extended our investigation to the synthesis of another series of azido alcohols and their utilization in the synthesis of morpholine fused triazoles.

Scheme 2 Synthesis of morpholine-fused [5,1-c]-triazoles (11a–d) from D-mannose.

Therefore, the analogues 1a–f were treated with epichlorohydrin under basic medium in dry DMF affording an excellent yield of glycosyl epoxides 12a–e along with non sugar derivative 12f. These glycosyl epoxides underwent regioselective azidation using a NaN₃ in EtOH–H₂O system at 65 °C in the presence of ammonium chloride affording O-glycosylated azido alcohols 13a–e and N-azido alcohol 13f (Scheme 3). The azido alcohols 13a–f thus obtained, on base-mediated propargylation using propargyl bromide in DMF followed by subsequent metal free azide–alkyne cycloaddition under thermal condition successfully afforded the desired morpholine fused [5,1-c]-triazoles (14a–f) in good to excellent yields (Scheme 4, Table 1). The structure of all compounds was deduced from extensive spectral studies (IR, NMR, and MS).

Scheme 3 Synthesis of glycosyl azido alcohols using epichlorohydrin.

Scheme 4 Metal free synthesis of morpholine-fused [5,1-c]-triazoles.

Table 1 Synthesis of morpholine fused triazoles (14a–f)

Entry^a	Substrate	Product^b	Time^c (h)
a Molar ratios: carbohydrate and other azidohydroxy triazoles (1.0 equiv.), propargyl bromide (1.3 equiv.), NaH (3 equiv.).b Morpholine-fused triazoles.c Reaction time in h.
1	13a		16
2	13b		13
3	13c		16
4	13d		14
5	13e		14
6	13f		13

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Although a detailed investigation is required to confirm the mechanism, we envisaged that the reaction may first involve base-prompted propargylation of azido alcohols (5, 10, and 13) followed by the metal-free thermal cycloaddition of the intermediate azido–alkyne. The intramolecular cycloaddition to afford the morpholine-fused 1,2,3-triazole is possible via two different routes. Because of the strain free environment, cyclization via path-I is more feasible which results in the regioselective formation of the desired morpholine-fused 1,5-triazoles (6, 11, and 14). Alternatively, in the case of cyclization via path II, attack of C₂ of the terminal alkyne on the N₁-atom of azide, simultaneous with attack of the N₃ of azide on C₁ of alkyne is not feasible, possibly due to the highly steric and strained environment in the small cavity of 1,4-disubstituted triazolyl macrocycle (Scheme 5).¹⁵

Scheme 5 Proposed reaction mechanism.

In summary, we have developed diverse novel morpholine-fused [5,1,-c] triazolyl glycoconjugates using an efficient and high yielding practical methodology. Three different series of novel glycosyl azido alcohols have been developed which have been utilized as starting materials for the synthesis of triazolo morpholines. The protocol exhibits a wide substrate scope, uses cheap and readily available reagents, is easy to perform, and is a high yielding metal free reaction that creates rare and biologically relevant heterocyclic molecules.

3. Experimental

3.1. General methods

All of the reactions were executed in anhydrous solvents (where required) under an argon atmosphere in glassware oven dried for one hour at 100 °C. All reagents and solvents were of pure analytical grade. Thin layer chromatography (TLC) was performed on 60 F₂₅₄ silica gel, pre-coated on aluminum plates and revealed with either a UV lamp (λ_max = 254 nm) or a specific colour reagent (Dragendorff reagent or iodine vapours) or by spraying with methanolic-H₂SO₄ solution and subsequent charring by heating at 100 °C. ¹H and ¹³C NMR were recorded at 300 and 75 MHz, respectively. Chemical shifts are given in ppm downfield from internal TMS; J values in Hz. Mass spectra were recorded using electrospray ionization mass spectrometry (ESI-MS). Infrared spectra were recorded as Nujol mulls in KBr plates.

3.1.1. Procedure for the synthesis of protected sugars. Compounds 1, 2, 3, 7, 8, 12 and 13 were prepared from readily available carbohydrates (D-glucose, D-galactose, D-ribose) using standard protection and modification including substitution and ring opening reactions.^13a–c

3.1.2. General procedure for the synthesis of tosyl-sugars (4a–e, 9a–d). A stirring solutions of the diol (3a–e, 8a–d; 1 equiv.) in pyridine at 0 °C was added to p-toluene sulphonyl chloride (1 equiv.) under anhydrous conditions. The reaction was allowed to stir below 10 °C for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated in vacuo and the crude material obtained was purified by flash column chromatography to afford tosyl-sugars 4a–e, 9a–d in good yields. Compound 1,2-O-isopropylidene-3-O-propyl-6-O-tosyl-α-D-glucofuranose 4a was obtained in good yield implementing similar chemistry.^13b
1,2-O-Isopropylidene-3-O-propyl-6-O-tosyl-α-D-glucofuranose (4b). A stirring solution of 1,2-O-isopropylidene-3-O-propyl-α-D-glucofuranose (1.34 g, 5.1 mmol) in pyridine was treated with p-toluene sulphonyl chloride (1.0 g, 5.1 mmol) at 0 °C under anhydrous conditions followed by stirring for 12 h at 5–10 °C to afford a viscous liquid (1.3 g, 62%); ¹H NMR (300 MHz, CDCl₃): δ 7.80 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 5.86 (d, J = 3.6 Hz, 1H), 4.53 (d, J = 3.6 Hz, 1H), 4.28–3.96 (m, 5H), 3.61–3.40 (m, 2H), 2.45 (s, 3H), 1.60–1.53 (m, 2H), 1.46, 1.30 (each s, 6H), 0.90 (t, J = 7.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 145.0, 132.5, 129.9, 128.1, 111.8, 105.0, 82.7, 82.0, 79.0, 72.2, 67.5, 26.6, 26.1, 22.8, 21.5, 10.4 ppm.
3-O-Isopentyl-1,2-O-isopropylidene-6-O-tosyl-α-D-glucofuranose (4c). A stirring solution of 3-O-isopentyl-1,2-O-isopropylidene-α-D-glucofuranose (1.6 g, 5.7 mmol) in pyridine was treated with p-toluene sulphonyl chloride (1.08 g, 5.7 mmol) at 0 °C under anhydrous conditions followed by stirring for 12 h at 10 °C to afford a viscous liquid (1.5 g, 60%); ¹H NMR (300 MHz, CDCl₃): δ 7.80 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 5.85 (d, J = 3.6 Hz, 1H), 4.52 (d, J = 3.6 Hz, 1H), 4.25 (dd, J = 2.7 Hz, 9.9 Hz, 1H), 4.17–4.15 (m, 1H), 4.11–4.06 (m, 2H), 4.04 (d, J = 3.0 Hz, 1H), 3.68–3.45 (m, 2H), 2.88 (d, J = 5.7 Hz, 1H), 2.45 (s, 3H), 1.67–1.60 (m, 2H), 1.46–1.43 (m, 4H), 1.31 (s, 3H), 0.89 (d, J = 6.6 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 145.1, 132.6, 130.0, 128.1, 111.9, 105.0, 82.8, 81.9, 79.0, 72.2, 68.9, 67.5, 38.4, 26.7, 26.1, 24.8, 22.5, 22.3, 21.5 ppm.
1,2-O-Isopropylidene-3-O-methyl-6-O-tosyl-α-D-glucofuranose (4d). A stirring solution of 1,2-O-isopropylidene-3-O-methyl-α-D-glucofuranose (2.0 g, 8.5 mmol) in pyridine was treated with p-toluene sulphonyl chloride (1.62 g, 8.5 mmol) at 0 °C under anhydrous conditions followed by stirring for 12 h at 10 °C to afford a viscous liquid (1.97 g, 60%); ¹H NMR (300 MHz, CDCl₃): δ 7.77 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 5.90 (d, J = 3.3 Hz, 1H), 4.60 (d, J = 3.6 Hz, 1H), 4.38 (dd, J = 4.8 Hz, 13.5 Hz, 1H), 4.17–4.10 (m, 4H), 3.90 (d, J = 1.8 Hz, 1H), 3.46 (s, 3H), 2.44 (s, 3H), 1.48, 1.32 (each s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 144.9, 132.3, 129.8, 127.8, 111.6, 105.0, 84.0, 81.1, 79.1, 67.4, 67.4, 57.6, 26.5, 26.0, 21.3 ppm.
3-O-Ethyl-1,2-O-isopropylidene-6-O-tosyl-α-D-glucofuranose (4e). A stirring solution of 1,2-O-isopropylidene-3-O-ethyl-α-D-glucofuranose (0.80 g, 3.2 mmol) in pyridine was treated with p-toluene sulphonyl chloride (0.61 g, 3.2 mmol) at 0 °C under anhydrous conditions followed by stirring for 12 h at 5–10 °C to afford a viscous liquid (1.00 g, 78%); ¹H NMR (300 MHz, CDCl₃): δ 7.80 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 5.87 (d, J = 3.6 Hz, 1H), 4.53 (d, J = 3.6 Hz, 1H), 4.26 (dd, J = 2.7 Hz, 9.6 Hz, 1H), 4.18 (m, 1H), 4.12–4.06 (m, 2H), 4.00–3.97 (m, 1H), 3.74–3.51 (m, 2H), 2.94 (s, 1H), 2.45 (s, 3H), 1.46, 1.30 (each s, 6H), 1.19 (t, J = 6.6 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 145.1, 132.9, 130.0, 128.1, 111.8, 105.8, 82.6, 78.9, 78.4, 72.2, 67.5, 65.9, 26.7, 26.6, 21.5, 15.1 ppm.
Benzyl-2,3-O-isopropylidene-6-O-tosyl-β-D-mannofuranose (9a). A stirring solution of benzyl-2,3-O-isopropylidene-β-D-mannofuranose (2.70 g, 8.4 mmol) in pyridine was treated with p-toluene sulphonyl chloride (1.90 g, 8.4 mmol) at 0 °C under anhydrous conditions followed by stirring for 12 h at 10 °C to afford a white solid (1.96 g, 50%); ¹H NMR (300 MHz, CDCl₃): δ 7.82 (d, J = 8.1 Hz, 1H), 7.35–7.26 (m, 7H), 5.05 (s, 1H), 4.82 (dd, J = 4.2 Hz, 5.7 Hz, 1H), 4.64–4.56 (m, 2H), 4.41 (d, J = 11.7 Hz, 1H), 4.28–4.24 (m, 1H), 4.16–4.13 (m, 2H), 3.94 (dd, J = 3.6 Hz, 7.2 Hz, 1H), 2.68 (s, 1H), 2.43 (s, 3H), 1.42, 1.30 (each s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 145.0, 132.8, 129.9, 128.5, 128.0, 112.8, 105.2, 84.7, 79.6, 78.2, 71.5, 69.0, 68.0, 25.7, 24.4, 21.5 ppm.
Propyl-2,3-O-isopropylidene-6-O-tosyl-β-D-mannofuranose (9b). A stirring solution of propyl-2,3-O-isopropylidene-β-D-mannofuranose (2.68 g, 10.2 mmol) in pyridine was treated with p-toluene sulphonyl chloride (1.9 g, 10.2 mmol) at 0 °C under anhydrous conditions followed by stirring for 12 h at 10 °C to afford a viscous liquid (2.6 g, 62%); ¹H NMR (300 MHz, CDCl₃): δ 7.82 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 4.96 (s, 1H), 4.81 (dd, J = 3.9 Hz, 5.7 Hz, 1H), 4.57 (d, J = 6.0 Hz, 1H), 4.32–4.16 (m, 3H), 3.91 (dd, J = 3.6 Hz, 7.5 Hz, 1H), 3.51 (d, J = 6.6 Hz, 15.6 Hz, 3H), 3.33–3.26 (m, 1H), 2.70 (s, 1H), 2.45 (s, 3H), 1.57–1.48 (m, 2H), 1.43, 1.30 (each s, 6H), 0.89 (t, J = 7.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 145.0, 132.8, 129.9, 128.0, 112.7, 105.9, 84.7, 79.7, 78.0, 71.5, 69.0, 68.1, 25.7, 24.4, 22.5, 21.5, 10.4 ppm.
Isopentyl-2,3-O-isopropylidene-6-O-tosyl-β-D-mannofuranose (9c). A stirring solution of isopentyl-2,3-O-isopropylidene-β-D-mannofuranose (3.28 g, 11.3 mmol) in pyridine was treated with p-toluene sulphonyl chloride (2.14 g, 11.3 mmol) at 0 °C under anhydrous conditions followed by stirring for 12 h at 5–10 °C to afford a white solid (2.75 g, 55%); ¹H NMR (300 MHz, CDCl₃): δ 7.81 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 4.96 (s, 1H), 4.82–4.78 (m, 1H), 4.55 (d, J = 6.0 Hz, 1H), 4.31 (d, J = 7.5 Hz, 1H), 4.17–4.15 (m, 2H), 3.89 (dd, J = 3.6 Hz, 7.2 Hz, 1H), 3.60 (dd, J = 6.9 Hz, 16.5 Hz, 1H), 3.36 (dd, J = 6.3 Hz, 16.2 Hz, 1H), 2.67 (d, J = 5.4 Hz, 1H), 2.45 (s, 3H), 1.69–1.58 (m, 2H), 1.48 (m, 1H), 1.43, 1.30 (each s, 6H), 0.88 (d, J = 4.8 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 145.0, 132.6, 129.9, 128.0, 112.7, 106.0, 84.7, 79.7, 78.1, 71.6, 68.2, 65.8, 38.0, 25.7, 24.8, 24.4, 22.4, 22.3, 21.5 ppm.
Methyl-2,3-O-isopropylidene-6-O-tosyl-β-D-mannofuranose (9d). A stirring solution of methyl-2,3-O-isopropylidene-β-D-mannofuranose (1.96 g, 8.3 mmol) in pyridine was treated with p-toluene sulphonyl chloride (1.5 g, 8.3 mmol) at 0 °C under anhydrous conditions followed by stirring for 12 h at 10 °C to afford a viscous liquid (2.0 g, 65%); ¹H NMR (300 MHz, CDCl₃): δ 7.82 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 4.86–4.80 (m, 2H), 4.54 (d, J = 5.7 Hz, 1H), 4.31 (d, J = 7.5 Hz, 1H), 4.19–4.17 (m, 2H), 3.91 (s, 1H), 3.26 (s, 3H), 2.68 (s, 1H), 2.44 (s, 3H), 1.49, 1.30 (each s, 6H).

3.1.3. General procedure for the synthesis of C-glycosylated azido alcohols (5a–e, 10a–d). A stirred solution of compound 4a–e or 9a–d in dry DMF was treated with NaN₃. The reaction mixture was further heated at 115–120 °C under anhydrous conditions followed by constant stirring for 12–16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated in vacuo followed by silica gel column chromatography to afford compounds 5a–e and 10a–d in good yields. Compound 5a was also achieved in good yield by implementing similar chemistry.^13b
6-Azido-6-deoxy-1,2-O-isopropylidene-3-O-propyl-α-D-glucofuranose (5b). Reaction of compound 4b (1.34 g, 3.2 mmol) with NaN₃ (0.624 g, 9.6 mmol) in DMF at 115 °C afforded compound 5b. Oily liquid (0.81 g, 88% yield); IR (KBr) cm⁻¹: 3453, 2964, 2935, 2878, 2103, 1633, 1455, 1080; ¹H NMR (300 MHz, CDCl₃): δ 5.91 (d, J = 3.6 Hz, 1H), 4.57 (d, J = 3.6 Hz, 1H), 4.10–4.00 (m, 3H), 3.66–3.42 (m, 4H), 2.74 (s, 1H), 1.65–1.58 (m, 2H), 1.49, 1.32 (each s, 6H), 0.94 (t, J = 7.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 111.8, 105.1, 82.8, 81.9, 79.7, 71.9, 68.9, 54.5, 26.7, 26.1, 22.8, 10.4 ppm.
6-Azido-6-deoxy-3-O-isopentyl-1,2-O-isopropylidene-α-D-glucofuranose (5c). Reaction of compound 4c (1.5 g, 3.3 mmol) with NaN₃ (0.658 g, 10.0 mmol) in DMF at 115 °C afforded compound 5c. Oily liquid (0.98 g, 92% yield); IR (KBr) cm⁻¹: 3472, 2958, 2872, 2104, 1711, 1633, 1466, 1081; ¹H NMR (300 MHz, CDCl₃): δ 5.90 (d, J = 3.6 Hz, 1H), 4.57 (d, J = 3.6 Hz, 1H), 4.10–3.98 (m, 3H), 3.73–3.42 (m, 4H), 2.64 (s, 1H), 1.72–1.63 (m, 2H), 1.49 (m, 4H), 1.32 (s, 3H), 0.91 (d, J = 6.6 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 111.9, 105.1, 82.9, 81.9, 79.8, 68.9, 68.7, 54.5, 38.4, 26.7, 26.2, 24.9, 22.5, 22.3 ppm.
6-Azido-6-deoxy-1,2-O-isopropylidene-3-O-methyl-α-D-glucofuranose (5d). Reaction of compound 4d (2.0 g, 5.1 mmol) with NaN₃ (1.0 g, 15.4 mmol) in DMF at 115 °C afforded compound 5d. Oily liquid (1.13 g, 85% yield); IR (KBr) cm⁻¹: 3460, 2955, 2867, 2103, 1718, 1633, 1460, 1070; ¹H NMR (300 MHz, CDCl₃): δ 5.89 (d, J = 3.6 Hz, 1H), 4.60 (d, J = 3.6 Hz, 1H), 4.09 (s, 2H), 3.90 (s, 1H), 3.61–3.46 (m, 5H), 2.61 (s, 1H), 1.49, 1.33 (each s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 111.9, 105.1, 84.3, 81.3, 79.7, 68.7, 57.7, 54.4, 26.7, 26.1 ppm.
6-Azido-6-deoxy-1,2-O-isopropylidene-3-O-ethyl-α-D-glucofuranose (5e). Reaction of compound 4e (1.0 g, 2.4 mmol) with NaN₃ (0.48 g, 7.2 mmol) in DMF at 115 °C afforded compound 5e. Viscous liquid (0.6 g, 90% yield); IR (KBr) cm⁻¹: 3466, 2944, 2857, 2103, 1710, 1633, 1470, 1080; ¹H NMR (300 MHz, CDCl₃): δ 5.91 (d, J = 3.6 Hz, 1H), 4.57 (d, J = 3.6 Hz, 1H), 4.10–4.01 (m, 3H), 3.76–3.42 (m, 4H), 2.73 (s, 1H), 1.49, 1.32 (each s, 6H), 1.24 (t, J = 7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 111.8, 105.0, 82.7, 81.9, 79.6, 68.8, 65.7, 54.5, 26.7, 26.1, 15.0 ppm.
Benzyl-6-azido-6-deoxy-2,3-O-isopropylidene-β-D-mannofuranose (10a). Reaction of compound 9a (1.96 g, 4.2 mmol) with NaN₃ (0.82 g, 12.6 mmol) in DMF at 115 °C afforded compound 10a. Oily liquid (1.18 g, 84% yield); IR (KBr) cm⁻¹: 3457, 3032, 2988, 2937, 2103, 1638, 1497, 1086; ¹H NMR (300 MHz, CDCl₃): δ 7.24 (m, 5H), 5.06–5.02 (m, 1H), 4.78 (m, 1H), 4.59–4.38 (m, 3H), 4.03–3.88 (m, 2H), 3.46–3.36 (m, 2H), 2.60 (s, 1H), 1.38, 1.24 (each s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 137.2, 130.2, 128.5, 128.1, 112.8, 105.4, 84.8, 79.8, 79.4, 69.5, 69.1, 54.3, 25.8, 24.5 ppm.
Propyl-6-azido-6-deoxy-2,3-O-isopropylidene-β-D-mannofuranose (10b). Reaction of compound 9b (2.6 g, 6.2 mmol) with NaN₃ (1.21 g, 18.7 mmol) in DMF at 115 °C afforded compound 10b. White solid (1.6 g, 90% yield); IR (KBr) cm⁻¹: 3478, 2989, 2964, 2939, 2883, 2106, 1754, 1633, 1469, 1084; ¹H NMR (300 MHz, CDCl₃): δ 4.93 (s, 1H), 4.77 (dd, J = 3.9 Hz, 5.7 Hz, 1H), 4.53 (d, J = 5.7 Hz, 1H), 4.04–3.99 (m, 1H), 3.86–3.83 (m, 1H), 3.52–3.48 (m, 2H), 3.45–3.36 (m, 1H), 3.31–3.24 (m, 1H), 2.57 (s, 1H), 1.53–1.46 (m, 2H), 1.40, 1.26 (each s, 6H), 0.83 (t, J = 7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 112.7, 106.0, 84.8, 79.8, 79.2, 69.5, 69.1, 54.3, 25.8, 24.4, 25.5, 10.4 ppm.
Isopentyl-6-azido-6-deoxy-2,3-O-isopropylidene-β-D-mannofuranose (10c). Reaction of compound 9c (2.75 g, 6.1 mmol) with NaN₃ (1.2 g, 18.5 mmol) in DMF at 115 °C afforded compound 10c. White semi solid (1.53 g, 80% yield); IR (KBr) cm⁻¹: 3453, 2922, 2871, 2101, 1744, 1633, 1465, 1088; ¹H NMR (300 MHz, CDCl₃): δ 4.99 (s, 1H), 4.86–4.82 (m, 1H), 4.58 (d, J = 5.7 Hz, 1H), 4.12–4.07 (m, 1H), 3.91 (dd, J = 4.2 Hz, 7.5 Hz, 1H), 3.68–3.36 (m, 4H), 1.68–1.62 (m, 1H), 1.47–1.39 (m, 5H), 1.33 (s, 3H), 0.89 (d, J = 6.6 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 112.7, 106.0, 84.8, 79.8, 79.2, 69.6, 65.8, 54.3, 38.0, 25.8, 24.8, 24.5, 22.5, 22.2 ppm.
Methyl-6-azido-6-deoxy-2,3-O-isopropylidene-β-D-mannofuranose (10d). Reaction of compound 9d (2.0 g, 5.1 mmol) with NaN₃ (1.00 g, 15.4 mmol) in DMF at 115 °C afforded compound 10d. Oily liquid (1.13 g, 86% yield); IR (KBr) cm⁻¹: 3452, 2991, 2937, 2836, 2099, 1628, 1443, 1089; ¹H NMR (300 MHz, CDCl₃): δ 4.90–4.82 (m, 2H), 4.58 (d, J = 5.7 Hz, 1H), 4.12–4.07 (m, 1H), 3.90 (dd, J = 3.6 Hz, 8.1 Hz, 1H), 3.60–3.44 (m, 2H), 3.31 (s, 3H), 2.62 (s, 1H), 1.47, 1.33 (each s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 112.8, 107.0, 84.7, 79.7, 79.2, 69.6, 54.5, 54.2, 25.8, 24.5 ppm.

3.1.4. General procedure for the synthesis of glycosyl epoxides (12a–f)^13c. A solution of orthogonally protected sugar including a morpholine heterocycle having an OH- and NH-reaction site (1 equiv.) in anhydrous DMF was cooled to 0 °C and sodium hydride (2.0 equiv.) was added portion wise. The reaction mixture was stirred at 0 °C under argon atmosphere for 20 minutes. Epichlorohydrin (1.2 mmol) was added at 0 °C and the reaction was allowed to stir for 12 hour at room temperature. Upon completion of the reaction, the remaining sodium hydride was quenched by water; the solvent was removed under reduced pressure followed by extraction with ethyl acetate. The combined organic layer was washed with brine solution, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to get the crude product. Purification using flash chromatography (ethyl acetate : hexane) afforded the desired epoxides 12a–f.^13c

3.1.5. General procedure for the synthesis of glycosyl azido alcohols 13a–f (ref. 13c). A solution of compounds 12a–f in EtOH–H₂O (1 : 1) was treated with NaN₃ and NH₄Cl at 65 °C for 8 h. Upon completion of the reaction, the solvent was removed under reduced pressure, extracted with ethyl acetate and water. The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated under vacuum, followed by flash chromatography (ethyl acetate–hexane) to afford the desired glycosyl azido alcohols 13a–f in good yields.^13c

3.1.6. General procedure for the synthesis of 1,2,3-triazolo[5,1-c]morpholine (6a–e, 11a–d and 14a–f). A solution of azido alcohol (5, 1.0 mmol) in anhydrous DMF (8 ml) was cooled to 0 °C and NaH (3 mmol) was added portion wise. The reaction mixture was stirred at 0 °C under argon atmosphere for 20 minutes. Then at the same temperature, propargyl bromide (1.3 mmol) was added and the reaction mixture was further stirred for 12 hour at room temperature. After disappearance of starting materials (monitored by TLC), the reaction was quenched by water and the whole reaction mixture was heated at 110 °C with constant stirring for 3–4 hour. Upon completion of the reaction, the solvent was removed under vacuum; the residue was mixed with water (10 ml) and then extracted with ethyl acetate (3 × 15 ml). The combined organic extracts were washed with brine solution (10 ml), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was subjected to flash chromatography (silica gel 234–400 mesh, CHCl₃–CH₃OH as eluent) to give title compounds 6, 11 and 14.
6-(3-O-Benzyl-1,2-O-isopropylidene-α-D-glucofuranose)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine, 6a. Compound 5a (100 mg, 0.3 mmol), sodium hydride (21 mg, 0.9 mmol) and propargyl bromide (0.034 ml, 4 mmol) were reacted in DMF (8 ml) using the procedure described above to give 6a (102 mg, 92%) as a white solid; R_f = 0.40 (60% ethyl acetate–n-hexane); MS: m/z 374 [M + H]⁺; IR (KBr) cm⁻¹ 2963, 2927, 2856, 1628, 1455, 1375, 1261, 1094, 1023, 801: ¹H NMR (300 MHz, CDCl₃): δ 7.39 (s, 1H), 7.26–7.24 (m, 5H), 5.87 (d, J = 3.6 Hz, 1H), 4.92 (d, J = 15.0 Hz, 1H), 4.68–4.46 (m, 5H), 4.19–4.08 (m, 4H), 1.43, 1.26 (each s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 137.1, 130.2, 128.5, 128.1, 127.7, 112.0, 105.1, 81.8, 81.0, 80.2, 72.2, 70.3, 61.7, 48.1, 26.5, 25.9 ppm.
6-(1,2-O-Isopropylidene-3-O-propyl-α-D-glucofuranose)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine, 6b. 5b (150 mg, 0.52 mmol), sodium hydride (37 mg, 1.5 mmol) and propargyl bromide (0.06 ml, 0.6 mmol) were reacted in DMF (8 ml) using the procedure described above to give 6b (162 mg, 96%) as a yellowish viscous liquid; R_f = 0.25 (40% ethyl acetate–n-hexane); MS: m/z 326 [M + H]⁺; IR (KBr) cm⁻¹ 3142, 2965, 2936, 1636, 1455, 1375, 1217, 1081, 1022: ¹H NMR (300 MHz, CDCl₃): δ 7.48 (s, 1H), 5.91 (d, J = 3.3 Hz, 1H), 5.09 (d, J = 14.7 Hz, 1H), 4.82–4.59 (m, 3H), 4.25–4.21 (m, 3H), 3.99 (d, J = 2.1 Hz, 1H), 3.64 (dd, J = 6.3 Hz, 15.3 Hz, 1H), 3.45 (dd, J = 6.6 Hz, 15.3 Hz, 1H), 1.64–1.57 (m, 2H), 1.50, 1.33 (each s, 6H), 0.93 (t, J = 7.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 130.1, 127.7, 111.8, 105.0, 81.8, 81.5, 80.2, 72.0, 70.3, 61.6, 48.0, 26.5, 25.9, 22.6, 10.3 ppm.
6-(3-O-Isopentyl-1,2-O-isopropylidene-α-D-glucofuranose)-6,7-dihydro-4H [1,2,3]triazolo[5,1-c][1,4]oxazine, 6c. 5c (150 mg, 0.47 mmol), sodium hydride (34 mg, 1.42 mmol) and propargyl bromide (0.054 ml, 0.61 mmol) were reacted in DMF (8 ml) using the procedure described above to give 6c (146 mg, 88%) as a white solid; R_f = 0.25 (40% ethyl acetate–n-hexane); MS: m/z 354 [M + H]⁺; IR (KBr) cm⁻¹ 3429, 2963, 2924, 2936, 1622, 1453, 1374, 1217, 1126, 1082, 1020: ¹H NMR (300 MHz, CDCl₃): δ 7.39 (s, 1H), 5.82 (d, J = 3.6 Hz, 1H), 5.2–4.97 (m, 1H), 4.71–4.49 (m, 3H), 4.15–4.10 (m, 3H), 3.89 (d, J = 2.7 Hz, 1H), 3.62–3.57 (m, 1H), 3.44–3.37 (m, 1H), 1.61–1.53 (m, 1H), 1.41–1.37 (m, 5H), 1.24 (s, 3H), 0.81 (d, J = 6.3 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 130.1, 127.8, 111.8, 105.1, 81.7, 81.6, 80.2, 70.3, 68.7, 61.6, 48.0, 38.2, 26.5, 25.9, 24.6, 22.3, 22.0 ppm.
6-(1,2-O-Isopropylidene-3-O-methyl-α-D-glucofuranose)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine, 6d. 5d (130 mg, 0.5 mmol), sodium hydride (0.36 mg, 1.5 mmol) and propargyl bromide (0.057 ml, 0.65 mmol) were reacted in DMF (8 ml) using the procedure described above to give 6d (133 mg, 90%) as a yellowish viscous liquid; R_f = 0.25 (40% ethyl acetate–n-hexane); MS: m/z 298 [M + H]⁺; IR (KBr) cm⁻¹ 3442, 2988, 2935, 1635, 1455, 1375, 1217, 1082: ¹H NMR (300 MHz, CDCl₃): δ 7.39 (s, 1H), 5.82 (d, J = 3.9 Hz, 1H), 5.01 (d, J = 15.0 Hz, 1H), 4.75 (d, J = 15.0 Hz, 1H), 4.62–4.53 (m, 2H), 4.19–4.04 (m, 3H), 3.82 (d, J = 2.7 Hz, 1H), 3.38 (s, 3H), 1.42, 1.26 (each s, 6H); ¹³C NMR (75 MHz, CDCl₃): 130.1, 127.7, 111.8, 105.0, 83.2, 81.2, 80.0, 70.3, 61.6, 57.9, 47.8, 26.5, 25.8 ppm.
6-(3-O-Ethyl-1,2-O-isopropylidene-α-D-glucofuranose)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine, 6e. Compound 5e (100 mg, 0.36 mmol), sodium hydride (26 mg, 1.09 mmol) and propargyl bromide (0.041 ml, 0.46 mmol) were reacted in DMF (8 ml) using the procedure described above to give 6e (97 mg, 87%) as a viscous liquid; R_f = 0.25 (40% ethyl acetate–n-hexane); MS: m/z 312 [M + H]⁺; IR (KBr) cm⁻¹ 2976, 2930, 2886, 1738, 1551, 1449, 1378, 1088, 888, 474: ¹H NMR (300 MHz, CDCl₃): δ 7.49 (s, 1H), 5.94–5.92 (m, 1H), 5.09 (dd, J = 2.1 Hz, 15.0 Hz, 1H), 4.83–4.59 (m, 3H), 4.30–4.17 (m, 3H), 4.01 (s, 1H), 3.74 (t, J = 7.2 Hz, 1H), 3.58–3.53 (m, 1H), 1.51, 1.34 (each s, 6H), 1.22 (t, J = 6.9 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 130.2, 127.9, 111.9, 105.1, 82.1, 81.4, 80.1, 70.6, 66.0, 61.8, 48.1, 26.6, 25.9, 15.0 ppm.
6-(Benzyl-1,2-O-isopropylidene-3-O-β-D-mannofuranose)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine, 11a. Compound 10a (130 mg, 0.38 mmol), sodium hydride (27 mg, 1.16 mmol) and propargyl bromide (0.043 ml, 0.5 mmol) were reacted in DMF (8 ml) using procedure described above to give 11a (119 mg, 84%) as R_f = 0.25 (35% ethyl acetate–n-hexane); MS: m/z 374 [M + H]⁺; white solid; IR (KBr) cm⁻¹ 3421, 3090, 2988, 2941, 2913, 1743, 1682, 1447, 1380, 1255, 1106, 1083: ¹H NMR (300 MHz, CDCl₃): δ 7.40 (s, 1H), 7.29–7.24 (m, 5H), 5.05–4.96 (m, 2H), 4.78–4.73 (m, 2H), 4.60–4.43 (m, 4H), 4.16–3.96 (m, 3H), 1.37, 1.24 (each s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 137.1, 130.3, 128.3, 127.8, 127.8, 112.6, 105.6, 84.5, 79.6, 79.1, 70.7, 69.3, 61.7, 47.6, 25.7, 24.4 ppm.
6-(Propyl-1,2-O-isopropylidene-3-O-β-D-mannofuranose)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine, 11b. Compound 10b (150 mg, 0.52 mmol), sodium hydride (37 mg, 1.5 mmol) and propargyl bromide (0.060 ml, 0.67 mmol) were reacted in DMF (8 ml) using the procedure described above to give 11b (158 mg, 94%) as a yellowish viscous liquid; R_f = 0.25 (35% ethyl acetate–n-hexane); MS: m/z 326 [M + H]⁺; IR (KBr) cm⁻¹ 3434, 3137, 2963, 2938, 2878, 1714, 1630, 1456, 1374, 1210, 1163, 1043, 862: ¹H NMR (300 MHz, CDCl₃): δ 7.41 (s, 1H), 5.05–4.95 (m, 2H), 4.82–4.77 (m, 2H), 4.70–4.60 (m, 1H), 4.54 (d, J = 5.7 Hz, 1H), 4.18–4.15 (m, 2H), 4.00 (d, J = 3.9 Hz, 1H), 3.51 (dd, J = 6.9 Hz, 13.8 Hz, 1H), 3.31 (d, J = 6.6 Hz, 15.9 Hz, 1H), 1.53–1.46 (m, 2H), 1.38, 1.25 (each s, 6H), 0.83 (t, J = 7.2 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃): δ 130.3, 127.7, 112.5, 106.0, 84.6, 79.4, 79.1, 70.8, 69.0, 61.6, 47.6, 25.7, 24.3, 22.3, 10.2 ppm.
6-(Isopentyl-1,2-O-isopropylidene-3-O-β-D-mannofuranose)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine, 11c. Compound 10c (130 mg, 0.41 mmol), sodium hydride (29 mg, 1.2 mmol) and propargyl bromide (0.047 ml, 5.3 mmol) were reacted in DMF (8 ml) using the procedure described above to give 11c (133 mg, 92%) as a yellowish viscous liquid; R_f = 0.25 (35% ethyl acetate–n-hexane); MS: m/z 354 [M + H]⁺; IR (KBr) cm⁻¹ 3444, 3130, 2983, 2948, 2870, 1710, 1604, 1456, 1374, 1211, 1150, 1045, 860: ¹H NMR (300 MHz, CDCl₃): δ 7.43 (s, 1H), 5.05–4.53 (m, 6H), 4.17–3.98 (m, 3H), 3.63–3.56 (m, 1H), 3.37 (dd, J = 6.6 Hz, 15.9 Hz, 1H), 1.64–1.53 (m, 1H), 1.39, 1.27 (each s, 6H), 0.83 (d, J = 6.6 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃): 130.4, 127.9, 112.7, 106.2, 74.7, 79.5, 79.1, 71.0, 65.9, 61.8, 47.8, 38.0, 25.8, 24.7, 24.4, 22.4, 22.1 ppm.
6-(Methyl-1,2-O-isopropylidene-3-O-β-D-mannofuranose)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine, 11d. Compound 10d (120 mg, 0.46 mmol), NaH (33 mg, 1.3 mmol) and propargyl bromide (0.053 ml, 5.8 mmol) were reacted in DMF (8 ml) using the procedure described above to give 11d (117 mg, 86%) as a white solid; R_f = 0.25 (35% ethyl acetate–n-hexane); MS: m/z 298 [M + H]⁺; IR (KBr) cm⁻¹ 3137, 2989, 2947, 2833, 1716, 1625, 1450, 1381, 1270, 1207, 1160, 1105, 1049, 860: ¹H NMR (300 MHz, CDCl₃): δ 7.50 (s, 1H), 5.10 (dd, J = 15.9 Hz, 1H), 4.93–4.85 (m, 3H), 4.75 (d, J = 8.1 Hz, 1H), 4.60 (d, J = 5.7 Hz, 1H), 4.27–4.25 (m, 2H), 4.06 (t, J = 3.0 Hz, 1H), 3.34 (s, 3H), 1.46, 1.34 (each s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 130.4, 127.9, 112.8, 107.1, 84.5, 79.5, 79.1, 70.9, 61.8, 54.6, 47.7, 25.8, 24.4.
6-(1,2:5,6-Di-O-isopropylidene-3-O-oxymethylene-α-D-glucofuranose)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine, 14a. Compound 13a (166 mg, 0.46 mmol), sodium hydride (33 mg, 1.3 mmol) and propargyl bromide (0.053 ml, 0.59 mmol) were reacted in DMF (8 ml) using the procedure described above to give 14a (158 mg, 87%) as a yellowish viscous liquid; R_f = 0.30 (60% ethyl acetate–n-hexane); MS: m/z 398 [M + H]⁺; IR (KBr) cm⁻¹ 3447, 2987, 2935, 1713, 1634, 1456, 1374, 1216, 1073, 1020: ¹H NMR (300 MHz, CDCl₃): δ 7.42 (s, 1H), 5.82 (s, 1H), 5.04 (d, J = 15.0 Hz, 1H), 4.79–4.74 (m, 1H), 4.51 (m, 2H), 4.20–3.75 (m, 9H), 1.43, 1.34, 1.32, 1.25 (each s, 12H); ¹³C NMR (75 MHz, CDCl₃): δ 130.3, 127.9, 111.9, 109.1, 105.2, 83.2, 82.5, 81.1, 72.7, 72.1, 70.4, 67.5, 61.8, 47.0, 26.6, 26.6, 26.0, 25.1 ppm.
6-(2,3:4,6-Di-O-isopropylidene-1-O-oxymethylene-β-D-mannofuranose)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine, 14b. Compound 13b (140 mg, 0.39 mmol), sodium hydride (28 mg, 1.1 mmol) and propargyl bromide (0.045 ml, 0.5 mmol) were reacted in DMF (8 ml) using the procedure described above to give 14b (123 g, 80%) as a brownish solid; R_f = 0.30 (60% ethyl acetate–n-hexane); MS: m/z 398 [M + H]⁺; IR (KBr) cm⁻¹ 3456, 3140, 2995, 2946, 1644, 1466, 1375, 1210, 1078: ¹H NMR (300 MHz, CDCl₃): δ 7.49 (s, 1H), 5.14–5.04 (m, 2H), 4.78 (m, 2H), 4.64 (s, 1H), 4.49–4.41 (m, 2H), 4.13–3.85 (m, 2H), 3.72 (m, 1H), 1.45, 1.43, 1.37, 1.32 (each s, 12H); ¹³C NMR (75 MHz, CDCl₃): δ 130.1, 127.8, 112.6, 108.9, 106.6, 84.7, 80.3, 79.2, 72.8, 72.4, 72.2, 66.9, 66.5, 61.7, 46.7, 26.6, 25.6, 24.9, 24.3 ppm.
6-(1,2:3,4-Di-O-isopropylidene-6-O-oxymethylene-α-D-galactopyranose)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine, 14c. Compound 13c (140 mg, 0.39 mmol), sodium hydride (28 mg, 1.1 mmol) and propargyl bromide (0.045 ml, 0.5 mmol) were reacted in DMF (8 ml) using the procedure described above to give 14c (130 g, 84%) as a yellowish viscous liquid; R_f = 0.30 (60% ethyl acetate–n-hexane); MS: m/z 398 [M + H]⁺; IR (KBr) cm⁻¹ 3457, 3142, 2988, 2936, 1640, 1374, 1217, 1078: ¹H NMR (300 MHz, CDCl₃): δ 7.49 (s, 1H), 5.53 (d, J = 4.5 Hz, 1H), 5.11 (d, J = 15.0 Hz, 1H), 4.83 (d, J = 15.0 Hz, 1H), 4.62–4.55 (m, 2H), 4.33–4.16 (m, 3H), 4.09–4.00 (m, 1H), 3.90–3.70 (m, 4H), 1.54, 1, 1.45, 1.33 (each s, 12H); ¹³C NMR (75 MHz, CDCl₃): δ 130.4, 128.0, 109.3, 108.6, 96.2, 72.7, 71.1, 70.7, 70.6, 70.4, 67.1, 66.9, 61.8, 47.2, 25.9, 25.8, 24.7, 24.2 ppm.
6-(Methyl-2,3-O-isopropylidene-5-O-oxymethylene-β-D-ribofuranose)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine, 14d. Compound 13d (100 mg, 0.33 mmol), sodium hydride (23 mg, 1.0 mmol) and propargyl bromide (0.038 ml, 0.42 mmol) were reacted in DMF (8 ml) using the procedure described above to give 14d (95 mg, 85%) as a yellowish viscous liquid; R_f = 0.30 (60% ethyl acetate–n-hexane); MS: m/z 342 [M + H]⁺; IR (KBr) cm⁻¹ 2925, 2855, 1724, 1635, 1455, 1383, 1216, 1165, 1075, 1020, 857: ¹H NMR (300 MHz, CDCl₃): δ 7.48 (s, 1H), 5.11 (d, J = 15.3 Hz, 1H), 4.96 (s, 1H), 4.84 (d, J = 15.0 Hz, 1H), 4.67–4.53 (m, 3H), 4.36–4.05 (m, 3H), 3.85–3.70 (m, 2H), 3.58–3.56 (m, 2H), 3.32 (s, 3H), 1.48, 1.32 (each s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 130.3, 127.8, 112.2, 109.1, 84.8, 84.6, 81.7, 72.5, 72.4, 70.8, 61.7, 54.6, 46.9, 26.1, 24.6 ppm.
6-(3-O-Benzyl-1,2-O-isopropylidene-5-O-oxymethylene-α-D-galactopyranose)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine, 14e. Compound 13e (100 mg, 0.26 mmol), sodium hydride (19 mg, 0.79 mmol) and propargyl bromide (0.03 ml, 0.33 mmol) were reacted in DMF (8 ml) using the procedure described above to give 14e (95 mg, 88%) as a yellowish liquid; R_f = 0.30 (60% ethyl acetate–n-hexane); MS: m/z 418 [M + H]⁺; IR (KBr) cm⁻¹ 3409, 2987, 2938, 1712, 1454, 1373, 1138, 869: ¹H NMR (300 MHz, CDCl₃): δ 7.48 (s, 1H), 7.31–7.27 (m, 5H), 5.94 (d, J = 3.6 Hz, 1H), 5.08 (dd, J = 1.8 Hz, 15.0 Hz, 1H), 4.82–4.38 (m, 7H), 4.18–3.65 (m, 6H), 1.49, 1.32 (each s, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 137.3, 130.4, 128.5, 128.0, 127.6, 111.7, 105.1, 82.0, 81.7, 79.1, 72.7, 72.6, 71.8, 71.3, 69.4, 61.8, 46.9, 26.6, 26.1 ppm.
6-(Morpholine)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazine, 14f. Compound 13f (80 mg, 0.43 mmol), sodium hydride (30 mg, 1.2 mmol) and propargyl bromide (0.049 ml, 0.55 mmol) were reacted in DMF (8 ml) using the procedure described above to give 14f (77 mg, 80%) as a reddish semi solid; IR (KBr) cm⁻¹ R_f = 0.15 (70% ethyl acetate–n-hexane); MS: m/z 225 [M + H]⁺; 3416, 2980, 2934, 1710, 1630, 1456, 1116, 1058, 868, 471: ¹H NMR (300 MHz, CDCl₃): δ 7.49 (s, 1H), 5.10 (d, J = 15.0 Hz, 1H), 4.81 (d, J = 15.0 Hz, 1H), 4.56 (d, J = 10.2 Hz, 1H), 4.14–4.07 (m, 2H), 3.75–3.72 (m, 4H), 2.84–2.75 (m, 1H), 2.64–2.57 (m, 4H); ¹³C NMR (75 MHz, CDCl₃): δ 130.4, 127.0, 71.8, 66.7, 61.8, 60.4, 54.3, 48.4 ppm.

Acknowledgements

VKT gratefully acknowledges Council of Scientific & Industrial Research (CSIR), New Delhi (Grant No. 02(0173)/13/EMR-II) for the funding and CISC, Department of Chemistry, Banaras Hindu University for providing spectroscopic data of synthesized compounds. KBM gratefully acknowledges UGC, New Delhi, for a fellowship (JRF & SRF).

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR for all the novel compounds has been provided. See DOI: 10.1039/c5ra17181d

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