HETEROCYCLES

Short Paper | Regular issue | Vol. 92, No. 8, 2016, pp. 1490-1496
Received, 8th May, 2016, Accepted, 31st May, 2016, Published online, 9th June, 2016.
DOI: 10.3987/COM-16-13498

■ Intramolecular 1,3-Dipolar Cycloaddition of Diazido-terminal Dialkynes: Synthesis of New Polyoxyethylene Fused exo-Bis(1,2,3-triazolo-1,4-oxazines)

Nejib Hussein Mekni*

Organic Structural Chemistry Laboratory, Synthesis and Physico-Chemical Studies, Department of Chemistry, University of Tunis El-Manar, 2092 Tunis, Tunisia

Abstract

The synthesis of new tetraheterocyclic 1,5-disubstituted exo-heterocyclic polyoxyethylene bis(1,2,3-triazolo-1,4-oxazine) is achieved through nucleophilic azide ion ring opening reaction on polyoxyethylene dioxiranes, followed by an O-propargylation, then thermal uncatalyzed 1,3-dipolar intramolecular cycloaddition.

The polyheterocyclic compounds are widely found within natural substances such as steroids.1 In particular the N-heterocyclic derivatives have found many applications.2 The 1,2,3-triazoles are biologically active compounds, they are used in medicinal,3 pharmaceutical,4 agrochemical5 and industrial fields.6
Oxazines constitute also an important class of heterocycles,7 having a synthetic interest due to their large range of biological activities.8 Several oxazine derivatives have various medicinal and pharmacological properties, such as anti-HIV drug.9-11
On the other hand, polyoxyethylene chains (p.o.e) are well described,12 they are known for their biodegradability.13 Polyoxyethylenes are used in different application fields,14 such as pharmaceutical and medical adjuvants,15 polymers16 and tensioactive agents.17
In addition to their uses to modify physical properties of some molecules,18 especially to increase their lipophilicity,19 one of the interesting applications of the p.o.e. in chemistry is their use as spacers for different proposes20 such as to separate functional group to each other,21 to decrease the hindrance interactions, to obtain some functional groups so far from to each other22 in order to make possible their reaction based on the important property related to their flexibility around the oxygen atoms.23
The (Cu+ or Ru2+) catalyzed azide-alkyne cycloaddition is the best known of the 1,3-dipolar cycloaddition reaction.24,25 It constitute actually the backbones reaction of the ”Click Chemistry”.26 While the intramolecular cycloaddition presents a particular interest due to its potential use in the synthesis of polyheterocyclic systems,27 it is very less described compared to the intermolecular one.28 In the major cases the interest is focused on the target molecule rather than the mechanism, the structure and the development of the reaction.28, 29
Whereas the uncatalyzed intermolecular azide-terminal alkyne cycloaddition conduce generally to a mixture of 1,4- and 1,5-disubstituted 1,2,3-triazolo isomers, the uncatalyzed intramolecular azido-alkyne cycloaddition conduce exclusively to the exo-cyclic 1,5-disubstituted isomer, especially in the case of five, six and seven membered heterocycles.30 The 1,4-disubstituted 1,2,3-triazole (endo-cyclic) isomer cannot be produced due to the geometrical constraints and the low overlapping encountered.
Despite the great development of the intramolecular 1,3-dipolar azide-alkyne cyloaddition, only diazides were reacted with dialkynes or mono azido-alkynes.31 But, to our knowledge basic reagents having both the two azide and two alkyne functional groups were not described. Until now the only diazido-dialkyne reported was described in our previous work and especially for the cycloaddition reactions.32
Herein we describe the synthesis of polyoxyethylene di(1,2,3-triazolo-1,4-oxazines) via simple ring opening of the corresponding dioxiranes, followed by O-propargylation.
The polyoxyethylene diazido-diols (2) are obtained in good yields (Table 1) from the nucleophilic ring opening azide ion action on polyoxyethylene diepoxydes (1) (Scheme 1).

The O-propargylation of the polyoxyethylene diazido-diols (2) is achieved by condensation with propargyl bromide in basic medium using of a phase transfer catalyst,33 giving rise to the corresponding unstable polyoxyethylene di(azido-alkynes) (3) (Scheme 2). Compounds (3) decompose on their contact with air oxygen. So, they are not isolated but diluted in toluene to avoid their contact with air.
The synthesized diazido-dialkynes (3), can undergo different types of chemical reactions, such as the free radical and ionic additions, inter and intramolecular cycloadditions, oxidation, reduction reactions, etc.
As a direct application, compounds (3) were heated in the same solvent, without catalyst. An intramolecular 1,3-dipolar cycloaddition occurs, yielding exclusively the stable 1,5-disubstituted exo-tetraheterocyclic polyoxyethylene di(1,2,3-triazolo-1,4-oxazines) (4) (Scheme 2).

The cyclization reaction of compounds (3) is spontaneously possible at room temperature, but it is relatively slow. For this reason, the polyoxyethylene di(azido-alkynes) (3) were heated at reflux in toluene yielding exclusively compounds (4) (Table 2). The two reaction side groups are so remote from each other that they react as two independent molecules.

Compounds (2 and 4) were identified by IR, 1H and 13C NMR spectroscopies, as well as by HRMS and elementary analysis. On the 1H NMR spectrum of compounds (4), the two allylic protons O-CH2-C= constitute an AB system resonating at 5 ppm, (2JAB 15 Hz). Two other protons CH2-N are also non equivalent and constitute the AB part of an ABX system (2JAB 12 Hz), with the proton of the asymmetric carbon atom HC*, constitute the X part and resonates at 4.0 ppm, indicating the formation of the 1,4-oxazine ring with two nonequivalent faces. The NMR proton COSY spectrum demonstrates a low interactions of the O-CH2-C= protons with the triazolic proton, which appears as ordinary singlet at 7.41 ppm. This latter information confirms therefore the formation of 1,5-disubstituted, exo-cyclic isomer (4).
The ring opening azide ion reaction on polyoxyethylene dioxiranes (1), gives the corresponding di(azido-diols) (2). The O-propargylation of compounds 2, yields the air unstable di(azido-alkynes) (3). The latter are thermally refluxed without catalyst in toluene to give rise to the unique tetraheterocyclic (1,5-disubstituted) exo-polyoxyethylene di(1,2,3-triazolo-1,4-oxazines) (4). The synthesized exo- heterotetracyclic polyoxyethylene di(1,2,3-triazolo-1,4-oxazines) (4) obtained from simple reagents can probably present some interesting applications in biological field. Compounds (3) are under investigations.

EXPERIMENTAL
IR spectra were realized on Perkin Elmer Paragon 1000 PC spectrometer. 1H and 13C NMR spectra were realized on a Bruker 300 spectrometer at 300 and 75 MHz respectively. TMS is the standard reference. HRMS spectra in C. I. mode, were carried out on a MAT 95 SBE spectrometer. All chemical are purchased from Sigma-Aldrich. Except for propargyl bromide, which is distilled, all other chemicals are used without further purification. The used silica gel is of the Merck 7734 type.
Preparation of di(azido-alcohols) (2):
A solution of 32 mmol of polyoxyethylene di(oxirane) (1), 8 g of sodium azide, 2 g of ammonium chloride in 20 mL of water and 80 mL of MeOH was stirred for 24 h at 80 °C, then filtered. The MeOH was evaporated. The crude product was extracted with Et2O (3 x 80 mL), washed with water and dried on MgSO4 and purified on chromatography column of silica gel. The mixture EtOAc/Et2O (70/30) was used as eluant to obtain compounds (2a-d) as yellowish viscous oils.
Synthesis of polyoxyethylene di(1,2,3-triazolo-1,4-oxazines) (4):
To a mixture of water (0.25 mL), sodium hydroxide (3 g, 75 mmol), tetrabutylammonium hydrogen sulfate (0.1 g) and 75 mmol of propargyl bromide at 40 °C, 25 mmol of di(azido-alcohol) (2) were added. The mixture was stirred for 40 min at 40 °C. Then 50 mL of toluene were added, the mixture was filtered and the salt washed with CH2Cl2 (3 x 20 mL). CH2Cl2 and the propargyl bromide excess were evaporated under vacuum. The obtained crude product (3) was diluted with toluene and heated to reflux for 24 h. Then toluene was distilled, the viscous obtained residue was purified on silica gel chromatography column. Et2O was used as eluent, yielding compounds (4a-d) as yellowish viscous oils (Table 2).
1,2-Bis((6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6-yl)methoxy)ethane (4a):
IR: C=C = 1454, N=N = 1496 cm-1; 1H NMR (CDCl3), δ: 3.68-3.73 (m., 8H, 4CH2, O-CH2), 4.00 (m., 2H, 2CH, 3JHH = 2.9 Hz), 4.13 and 4.47 (m., 4H, 2CH2-N, 2JHH = 12.5 Hz, 3JHH = 2.9 Hz), 4.75 and 5.54 (d.d., 4H, 2CH2-O, 2JHH = 15.4. Hz), 7.40 (s, 2H, 2HC=); 13C NMR (CDCl3), δ: 46.8 (2C, 2CH2-N), 61.8 (2C, 2CH2-C=), 71.0 (4C, 2CH2-O), 72.6 (2C, 2CH), 127.8 (2C, 2HC=), 130.3 (2C, 2C=); HRMS: for C14H20N6O4 Calcd: 336.15460, Found: 336.15490; Anal. Calcd for C16H20N6O4: C, 49.99; H, 5.99; N, 24.99. Found: C, 49.92; H, 5.95; N, 24.95.
6,6'-(((Oxybis(ethane-2,1-diyl))bis(oxy))bis(methylene))bis(6,7-dihydro-4H-[1,2,3]triazolo[5,1-c]-
[1,4] oxazine) (4b):
IR: C=C = 1453, N=N = 1495 cm-1; 1H NMR (CDCl3), δ: 3.65-3.71 (m., 12H, 6CH2-O), 3.99 (m., 2H, 2CH, 3JHH = 3.2 Hz), 4.12 and 4.46 (m., 4H, 2CH2-N, 2JHH = 12.1 Hz, 3JHH = 3.2 Hz), 4.74 and 5.53 (d.d., 4H, 2CH2-O, 2JHH = 15.2 Hz), 7.40 (s, 2H, 2HC=); 13C NMR (CDCl3), δ: 46.7 (2C, 2CH2-N), 61.5 (2C, 2CH2-C=), 70.6 (6C, 6CH2-O), 72.3 (2C, 2CH), 127.4 (2C, 2HC=), 129.9 (2C, 2C=); HRMS: for C16H24N6O5 Calcd: 380.18082, Found: 380.18132 Anal. Calcd for C16H24N6O5: C, 50.52; H, 6.36; N, 22.09. Found: C, 50.39; H, 6.30; N, 22.02.
1,12-Bis(6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6-yl)-2,5,8,11-tetraoxadodecane (4c):
IR: C=C = 1454, N=N = 1496 cm-1; 1H NMR (CDCl3), δ: 3.66-3.72 (m., 16H, 8CH2-O), 4.01 (m., 2H, 2CH, 3JHH = 3.2 Hz), 4.14 and 4.48 (m., 4H, 2CH2-N, 2JHH = 12.2 Hz, 3JHH = 3.2 Hz), 4.74 and 5.52 (d.d., 4H, 2CH2-O, 2JHH = 15.13 Hz), 7.42 (s, 2H, 2HC=); 13C NMR (CDCl3), δ: 46.9 (2C, 2CH2-N), 62.0 (2C, 2CH2-C=), 71.2 (8C, 8CH2-O), 72.9 (2C, 2CH), 128.0 (2C, 2HC=), 130.5 (2C, 2C=); HRMS: for C18H28N6O6 Calcd: 424.20703, Found: 424.20743; Anal. Calcd for C18H28N6O6: C, 50.93; H, 6.65; N, 19.80. Found: C, 50.84; H, 6.59; N, 19.71.
1,15-Bis(6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6-yl)-2,5,8,11,14-pentaoxapentadecane (4d):
IR: C=C = 1452, N=N = 1493 cm-1. 1H NMR (CDCl3), δ: 3.65-3.72 (m., 20H, 10CH2, O-CH2), 4.01 (m., 2H, 2CH, 3JHH = 3.2 Hz), 4.11 and 4.45 (m., 4H, 2CH2-N, 2JHH = 12.1 Hz, 3JHH = 3.2 Hz), 4.74 and 5.53 (d.d., 4H, 2CH2-O, 2JHH = 15.2 Hz), 7.42 (s, 2H, 2HC=); 13C NMR (CDCl3), δ: 47.0 (2C, 2CH2-N), 62.0 (2C, 2CH2-C=), 71.3 (10C, 10CH2-O), 72.9 (2C, 2CH), 128.1 (2C, 2HC=), 130.8 (2C, 2C=); HRMS: for C20H32N6O7 Calcd: 468.23325, Found: 468.23385; Anal. Calcd for C20H32N6O7: C, 51.27; H, 6.88; N, 17.94. Found: C, 51.13; H, 6.82; N, 17.88.

ACKNOWLEDGEMENTS
The author would like to thank the Tunisian Ministry of Higher Education and Scientific Research and Technology for financial support of this work, Pr. A. Baklouti and Dr. M.A.K. Sanhoury, MRSC from the Chemistry Department, Faculty of Sciences of Tunis for technical assistance.

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