A common route to the synthesis of 1,3,4-oxadiazole -2-thione and 1,2,4-triazole -3-thiols derivatives of trioses and pentoses as models for acyclic C-nucleosides

The 5-(1,2-dihydroxy-ethyl)-3 H -[1,3,4]oxadiazole-2-thione ( 12) and 1-(5-mercapto-4 H - [1,2,4]triazole-3-yl)-ethane-1,2-diol (13) derived from (±) glyceraldehyde (resembles trioses ) have been synthesized from glycerol ( 1) via a common route. The synthesis of the optical active 5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-3 H -[1,3,4] oxadiazole-2-thione ( 17) and 5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-4 H -[1,2,4]triazole-3-thiol ( 18) may be achieved by the same common route when the D-glyceraldehyde (3) was obtained by cleavage oxidation of 1,2:5,6-Di-O - isopropylidene D-mannitol ( 15). Similar derivatives 23 and 24 of D-xylose ( 19) (resembles pentoses) may also be synthesized by the same common route from (tetrahydro-[1,3]dioxino[5,4-d][1,3]dioxin-4-yl)-methanol (21 ) . This common route provides a simple synthetic pathway to acyclic C-nucleosides and to less extent to cyclic C-nucleosides.


Introduction
Hydrazides and related compounds have been described as useful building blocks for the assembly of various heterocyclic rings.Thus, different carbohydrazides were found to be useful as medicines.The synthesis of compounds incorporating both 1,2,4-triazole, and 1,3,4oxadiazole rings has been attracting widespread attention due to their diverse pharmacological proprieties such as antimicrobial, anti-inflammatory, analgesic and antitumor activities.
Many commonly known cyclic N-nucleosides as well as acyclic analogues have strong biological effects. 1,2,3 Te less common O-, S-and C-nucleosides are also known to have antiproliferating activity and can be used for antiviral, anti-cancer and anti-aids therapies. 4he synthesis of the different kinds of the nucleosides can be performed in any one of the four strategies (A, B, C and D).Strategy (A) involves a substitution of the glycosidic link X with a leaving group (e.g.halogen, acetate, etc...) to replace it with the base acting as the nucleophile to build up the desired heterocycles.
Strategy (B) achieving the nucleosides from hetero-sugars (X = S) as in thio-sugars where S acts as nucleophile to react with heterocyclic ring.
Strategy (C) use a sugar containing a base (X = N) as in amino-sugars where N acts as a nucleophile to build up the heterocycles.
Strategy (D) involves nucleophilic addition reaction to the aldehydic carbonyl followed with the lost of water followed by building up the heterocycles.C-nucleosides are excellent natural products antibiotics and in comparison with the normal nucleosides, they contain no acetal unit and hence they are much more stable compared to normal nucleosides and nucleotides.
The synthetic route to the cyclic C-nucleosides using sugar lactones, while for the acyclic analogue, more often followed strategy (D).
The 1,3,4-oxadiazole derivatives show leprostatic and tuberculostatic properties and exhibit antibacterial, antiproteolytic and anticonvulsant activities.Also they have analgesic, antipyretic, antiphologistic, bactericides, insecticides, fungicidical and several other biological activities. 6he relatively simple 1,2,4-triazoles display biological activities such as inhibition of cholinesterase, interference with mitosis and reversible denaturation of serum proteins.The 1,2,4-triazole thiones afford some protection of mice against irradiation with X-rays, and have anti-inflammatory properties.They have appreciable biochemical effects when replacing histidine derivatives in nucleic acids.Also, compounds with a thiourea function NH-(CS)-NH have a strong potential for manufacturing drugs since the SH group can easily converted to their S-substituted derivatives. 7As a continuation of our investigation of antimicrobial activities of 1,3,4-oxadiazole -thione and 1,2,4-triazole-thiole derivatives , we wish to report a common route to the synthesis of 1,3,4-oxadiazolo-thiones 12, 17, 23, and 1,2,4-triazolo-thiols 13, 18 , 24 as model compounds for acyclic C-nucleosides.

Results and Discussion
Scheme 1 shows the common route for the synthesis of open chain C-nucleosides possessing a 1,3,4-oxadiazolo-2-thione 12 and a 1,2,4-triazolo-3-thiol 13 derived from glycerol.This route initially required a selective protection of the adjacent OH groups of glycerol in order to leave the terminal OH group for further modifications.
Racemic 2,3-O-isopropylidene glycerol (2) has been prepared in a excellent yield (98%) by refluxing glycerol with an excess of acetone and a catalytic amount of acid when a Dean-Stark apparatus was used to remove the water which formed during the reaction.The amount of acetone may be reduced if chloroform was utilized as a reaction medium.Between the two acids used (concentrated H 2 SO 4 or p-toluensulfonic acid), the latter was found to be more effective and to give a higher yield.
The second route was achieved by a complete oxidation of the 2 with CrO 3 / pyridine to give the corresponding aldehyde 3. The crude aldehyde 3 was oxidized with KMnO 4 / KOH then acidified with a mineral acid (HCl) to give a quantitative yield of the corresponding acid 4.
The (±)-methyl-2,3-O-isopropylideneglycerate (5) was obtained either by direct esterification of 4 with methanol in presence of conc.H 2 SO 4 or by treatment of the potassium salt 6 with methyl iodide in presence of N,N,N',N'-tetramethylethylenediamine (TMED) .
In case the methylation was performed on crude 6, 1-methoxy-2,3-O-isopropylidene glycerol as a side product was isolated.The second route gave a better yield since the latter procedure does not involve the risk of a back hydrolysis of the ester group and the protecting isopropylidene ring.
The racemic hydrazide 7 was prepared in a yield of about 90 % by treating the ester 5 with hydrazine monohydrate (55 %).The product was identified by IR which showed a moderately strong band at 3258 cm -1 region for the free and bonded N-H and a band at 1631 cm -1 for CO-N.The structure 7 was confirmed by 1 H-NMR which exhibited a signal at 8 ppm for N-H and mass spectrometry which showed the fragment M+1 = 161.081for C 6 H 12 N 2 O 3 .

ARKAT Experimental Section
General Procedures.Chemicals were purchased from Fluka and Aldrich.Melting points were determined with a Buchi Apparatus and are uncorrected.The progress of reactions were followed by thin layer chromatography (TLC) prepared in our laboratory using Silica Gel (Merck) on glass (layer thickness 0.25 mm) used without pretreatment.Eluents used volume-to-volume (v/v), and the spots were detected by exposure to iodine vapor for a few minutes.All solvents evaporations were performed in a Buchi rotary evaporator under diminished pressure.The IR spectra were measured as potassium bromide pellets using Perkin-Elmer 1600 FTIR spectrometer.The 1 H NMR spectra were obtained using a Bruker AC 250 NMR and were recorded at 250 MHz.Chemicals shifts are reported in part per million δ (ppm) using internal TMS and DMSO-d 6 as solvent .The mass spectra were measured on DX 300-SX102 spectrometer using a FAB (fast atom bombardment) as ionization mode.

1 .
Scheme 1. Common pathway to the synhesis of compounds 12 and 13