Synthesis and Characterization of 2 ( 2-Tetrahydropyranylthio ) methyl cyclopropylamine

2(2-Tetrahydropyranylthio) methyl cyclopropyl amines were synthesized from allylmercaptan through several steps. The structures of the intermediates and the final products where confirmed through IR, NMR and elemental analysis, these compounds may be of value in the treatment of diseases where free radicals are implicated in their pathogensis, since the thio and the amino groups of the synthesized compounds may act as free radical scavengers. ةصلاـــــــــــــــخلا ــ لـا تانيما نم ةعومجم ريضحت مت دقل 2 ) 2 و ياث ن اريبورديهارتت ( لذو ناتباكريم ليللا نم ليبورب ولكياس ليثم ددع للاخ نم ك تاوطخلا نم . ءارـمحلا تـحت ةعشا ه ينقت ةطساوب ةيئاهنلاو ة يطسولا تابكرملا صيخشت مت (IR) يـسيطانغملا ن ينر لـا ف يـطو (HNMR ) ةيلولاا رصانعلا صيخشتو (eleme ntal analyses ) . ةجلاعم يف ةميق تاذ نوكت نا نكمم ةرضحملا تابكرملا هذه للاخ نم ةببستملا ضارملاا ةقيلط لا روذجلا ررحت (free radicals) . نا نكمم تابكرملا هذه يف ونيملااو وياثلا عيماجم دوجو نلا ضارملأل ةببسملاو ةقيلطلا روذج لا ةذهل ةطبهم نوكت . INTRODUCTION Free radicals have been implicated in many diseases, among these are atherosclerosis, rheumatoid arthritis, cataracts, neoplastic diseass, diabetic retinopathy, Parkinson's, Alzheimer inflammatory diseases of gastro-intestinal tract and aging. Free radicals are defined as atoms or molecules that contain one or more unpaired electrons and are species that cause metabolic disturbances and cell injury by interacting with macromolecules and other cellular constituents such as proteins, lipids, carbohydrates and DNA resulting in a variety of biological consequences, including cellular and tissue damage, mutation carcinogensis and cell death. The observation that 2 mercaptoethylamine , 2 –mercatopropylamine , disulfide , Thioethers and sulfoxides were capable in protecting animals against free radicals generated as a result of ionizing radiation promoted our interest to synthesize2(2-tetrahydropyranylthio) methylcyclopropylamine 1 . the thioether and the amino groups in 1 or the corresponding “sulfhydryl and amino groups in their expected major metabolites may act cooperatively as free radical scavengers”. Therefore these compounds may be utilized selectively to treat one or more of the previously mentioned diseases. SYNTHETIC MATERIAL Allylmercaptan , ptoluenesulfonic acid , dihydropyran ethldiazocetate , were obtained from Aldrich Chemical Co. (Milwaukee , WI ,USA ) . Analytical Equipment Melting points were determinated by using a calibrated Thomas Hoover melting point apparatus .IR spectra were recorded using a Unicam SP300 spectrophotometer . NMR spectra were obtained using a Variant FT80A spectrometer. Chemical shifts are reported as part per million downfield from tetramethylsilane as internal standard for HNMR spectra . Elemental microanalysis were performed by H.Malissa and G.Reuter,FRG. pyran ( 3) . Allylthiotetrahyro 2 Allylmercaptan ( 3,74g ,1 mole) and 200 mg of p-toluene sulfonic acid were placed in a 500ml RBflask fitted with a reflux condenser and magnetic stirrer . Dihydropyran ( 84g , 1 mole ) was added dropwise . The reaction mixture was heated on a steam bath for 10 minutes . After heating for 5-10 minutes , a vigorous exothermic reaction started and continued during the addition of dihydropyran . After 1 1/2 hours , refluxing was stopped and potassium carbonate ( 1.0 g) was added . The mixture was stirred at room temperature for 1 hour , filtered and fractionally distilled yielding 80.2 g . ( 50% ) of 2allylthiotetrahydropyran ( 3) b.p . 42-44 ( 0.1 mm ) * Department of medicinal chemistry ,Collage of Pharmacy,University of Petra, Aman-Jordan; ** Department of Pharmaceutical chemistry, Collage of Pharmacy,University of Baghdad,

Free radicals are defined as atoms or molecules that contain one or more unpaired electrons and are species that cause metabolic disturbances and cell injury by interacting with macromolecules and other cellular constituents such as proteins, lipids, carbohydrates and DNA resulting in a variety of biological consequences, including cellular and tissue damage, mutation carcinogensis and cell death 6 .The observation that 2 mercaptoethylamine , 2 -mercatopropylamine , disulfide , Thioethers and sulfoxides 7 were capable in protecting animals against free radicals generated as a result of ionizing radiation promoted our interest to synthesize-2(2-tetrahydropyranylthio) methylcyclopropylamine 1 .the thioether and the amino groups in 1 or the corresponding "sulfhydryl and amino groups in their expected major metabolites may act cooperatively as free radical scavengers".Therefore these compounds may be utilized selectively to treat one or more of the previously mentioned diseases.

Analytical Equipment
Melting points were determinated by using a calibrated Thomas Hoover melting point apparatus .IR spectra were recorded using a Unicam SP-300 spectrophotometer .NMR spectra were obtained using a Variant FT80A spectrometer.Chemical shifts are reported as part per million downfield from tetramethylsilane as internal standard for HNMR spectra .Elemental microanalysis were performed by H.Malissa and G.Reuter,FRG.

Allylthiotetrahyro -2
-Allylmercaptan ( 3,74g ,1 mole) and 200 mg of p-toluene sulfonic acid were placed in a 500ml RB-flask fitted with a reflux condenser and magnetic stirrer .Dihydropyran ( 84g , 1 mole ) was added dropwise .The reaction mixture was heated on a steam bath for 10 minutes .After heating for 5-10 minutes , a vigorous exothermic reaction started and continued during the addition of dihydropyran .After 1 1/2 hours , refluxing was stopped and potassium carbonate ( 1.0 g) w as added .

allythiotetarhyropyran -Reaction of 2 (3) with ethyl diazoacetate
In a 250 ml three -necked flask provided with a reflux condenser, dropping funnel and magnetic stirrer was placed 2allythiotetraahydropyran (4,15.8g , 0.1mole ) and 50 mg of copper pow der .The mixture was stirred rapidly (160 -165 C° , oil bath ) and the ethyl diazoacetate (11.4 g , 0.1) was added at such rate so as to avoid a vigorous reaction .After ethyl diazoacetate addition the evolution of nitrogen ceased .The reaction mixture was refluxed distillate ( 40-60 C° at 0.2 mm ) .The distillate was analyzed by gas liquid partition chromatgraphy which shows the presence of several products .These products were tentatively identified as diethyl maleate , diethyl fumarate and the starting material .

2(2-tetrahydropyranylthio) methylcyclopropylcarboxyhydrazide(6)
A solution of (4.88g,2.0x10 - mole) of 2-(2`tetrahydropyranylthio)methyl-1carboethoxycyclopropane 4 and 20 ml of 85% hydrazine hydrate was refluxed for 24 hours.The mixture was cooled and held at 0°C for 24 hours; no precipitate formed.The excess of hydrazine hydrate was removed under reduced pressure affording a semi-solid that failed to crystallize under various conditions.The unreacted ester 4 was removed by dissolving the crude hydrazide in chloform.The hydrazide 6 was precipitated with anhydrous ether.A white solid was obtained in Et 2 O; this turned to a semi-solid upon removal of ether.The hyrazide 6 had an infrared spectrum (neat,cm-1) that showed bands at 3300 (NH2 , stretch ) ;2920,2830(CH

DISUSSION and S RESULT
The new compound 1 was prepared as depicted in scheme 1 Allymercaptan 2 which serves as starting material was readily converted in 80% yield to 2-allylthiotetrahydropyran 3 through reaction with 2,3-dihydropyran in the presence of p-toluenesulfonic acid.The IR and NMR spectra were consistent with the assigned structure .Treatment of 3 with ethyldiazoacetate afforded a mixture of trans -and cis-2-(2tetrahydropyranylthio) methyl-1carboethoxycyclopropane 4 and a sulfonium ylide rearrangement product namelyethyl-α-allyl-α (2-tetrahydropyranylthio) acetate 5 in 81.4% and 18.6% yield at 150-155C° respectively 8 .Ethyldiazoacetate reacts with allymercaptan to generate trans-and ciscyclopropane derivative 4 through carbene addition to the double bond 9 and with thioether group to form sulfonium ylide 10 .Such sulfonium ylide is known to undergo Steven's rearrangement, which depends on the structure of the ylide, may either involve an antrafacial 1,3-sigmatropic rearrangement or suprafacial 1,5-sigmatropic rearrangement 11 .In our case both 1,3-and 1,5-rearrangements afforded the same compound 5.The mixture of 4 could not be separated by physical methods and was used as a mixture in the next step.Reaction of 4 with 85% hydrazine hydrate afforded the hydrazide 6 as a gummy solid in almost quantitative yield; Attempts to crystallize this gummy hydrazide were unsuccessful.The purity of the compound was determine by gass liquid partition chromatography (glpc); the non-crystalline hydrazide was then subjucted to Curtius rearrangement.The rearrangement proceeded through the azide 7 and the isocyanate 8.The intermediate azide 7 was detected by its IR spectrum (CON 3 , 2150 cm -1 ).The isocyanate 8 could be isolated as a brown solid which showed an IR absorption band at 2280 cm -1 (N=C=O).The isocyanate 8 was refluxed with 25% methanolic KOH to generate the desired trans-and cis-cyclopropylamine 1 as a mixture in a ratio of 85:15 respectively.The IR and NMR spectra were consistent with the assigned structure as discussed in the experimental part.