Double Intramolecular 1,3-Dipolar Cycloaddition of Diazo-terminal Dialkyne: Synthesis of a New Bis(1,2,3-triazolo-1,4-oxazine)

Abstract

A new bis(1,2,3-triazolo-1,4-oxazine) fused heterocyclic compound was synthesized from terminal meso-1,2,3,4-diepoxybutane via azide ring opening reaction, followed by propargylation and double 1,3-dipolar intramolecular cycloaddition. No effect on the reaction outcome was observed when Cu(I) was used as catalyst. In both cases catalyzed and uncatalyzed reactions, only the exo-tetracyclic two to two fused isomer was obtained. 1,2,3-Triazoles and oxazines, are heterocycles which constitute a large number of synthetic compounds. Applications of these heterocycles in various areas have been reported. For example, they are used as an anti-HIV, anti-allergic, antibacterial, fungicides, herbicides, paints, corrosion inhibitors, pesticides and agrochemical agents. For oxazines and their derivatives, a particular interest has emerged since the discovery of Efavirenz (trifluoromethyl-1,3-oxazin-2-one) inhibitor non-nucleoside reverse transcriptase used as a selective anti-HIV drug. On the other hand, the 1,3-dipolar azide-alkyne cycloaddition is a well known reaction which has been recently applied in the Click Chemistry. A remarkable development is potentiated by the use of catalytic metals such as (Cu) and (Ru). The majority of azide/alkyne reaction studies deal with intermolecular cycloadducts. However those related to the intramolecular processes remain limited. Furthermore, previous studies have focused on the synthesis of target and specific molecules rather than on a general systematic investigation of its potential application in organic synthesis. In the present work, we describe the synthesis of one compound having four hetrerocycles, two to two fused, in three steps starting from diepoxybutane. The preparation of the meso-diazido-dialkyne ether 2 was carried out through opening of the meso-diepoxybutane rings 1 by azide ion followed by reaction of propargyl bromide (Scheme 1). The meso-diazido-dialkyne ether 3 was obtained in satisfactory yields (81%). The meso-diazido-dialkyne 3 is unstable and decomposes on contact with air. Therefore, the mixture obtained from the propargylation reaction was diluted in situ in dry toluene and used in situ without purification in the next step. The uncatalyzed dipolar [3+2] double intramolecular cycloaddition reaction of product 3 proceeds spontaneously at room temperature, producing exclusively the exo-tetraheterocyclic compound 4. To reduce the reaction time, the mixture was heated at 50 C in toluene (A Condition). In an attempt to direct the reaction towards the formation of another polyheterocyclic compound, the reaction was performed in the presence of a catalytic amount of CuCl (5%) (B Condition). Either carried out according to A (79%) or B (75%) conditions, the double intramolecular cycloaddition reaction of diazido-dialkyne ether 3 leads always to the formation of the same isomer 4 (Scheme 1). Scheme 1. Synthesis of the meso-bis(1,2,3-triazolo-1,4-oxazine) It is worth to note that several conformers are possible for compound 3, due to the free rotation around the CH-CH central bond. Because of the free rotation around the two CH-O bonds, the stable conformation can exist in three geometric forms (a), (b) and (c). From these forms, two exo-cyclic isomers may be formed 4 and 5 (Scheme 2). The (a) form has both azide and alkyne dipoles one in face to the other with a favorable orbital overlap flatness which explain the exclusive formation of the exo-tetracyclic isomer 4. For the (b) form, the  part of favorable flatness cyclizes easily (Scheme 2). So in the  side, the propargylic group must rotate around C-O to cyclize with the second azide group and would lead once again to the isomer 4. The (c) form does not afford a favorable orbital overlap which can explain the absence of the exo-cyclic isomer 5. Therefore, (c) turns into (b) and/or (a) to give also compound 4. Scheme 2. Explication of the formation of the tetracyclic isomer 4 The H and C NMR spectral data confirm the symmetrical structure proposed. In particular the H NMR spectrum shows an AB system corresponding to the allylic protons O-CH2-C=C, appearing into 5.0 ppm (JAB = 15 Hz). Moreover, the -CH2-N protons show another AB system (JAB  12 Hz) which is partially coupled with the proton of the asymmetric carbon. ANTIBACTERIAL TEST The preliminary antibacterial activity study of compound 4 was followed by the disk diffusion method against five bacteria (Gram+ and Gram-) of widely encountered references in many human diseases. The results are given in Table 1. As can be seen from Table 1, it appears that compound 4 has no activity against Escherichia coli (DH5α), Pseudomonas aeruginosa (PAO1), Salmonella typhi (ATCC 25922) and Staphylococcus aureus (ATCC 6538). However, it presents a moderate activity against Enterococcus feacium strain ATCC (19,436) for which inhibition diameter is 11 mm. This value is the average of three experimental tries (10 mm, 11 mm