Research Article Synthesis and In Vitro Evaluation of ...downloads.hindawi.com/archive/2013/159164.pdf · e structure of-diacetylamino-H-,, -thiadiazol--one ( ) was deter-mined on

Hindawi Publishing CorporationISRN Organic ChemistryVolume 2013 Article ID 159164 10 pageshttpdxdoiorg1011552013159164

Research ArticleSynthesis and In Vitro Evaluation of Novel Acyclic and CyclicNucleoside Analogs with a Thiadiazole Ring

Yuxiang Zhao1 Peter J McCarthy2 and Cyril Paacuterkaacutenyi3

1 Division of Science and Mathematics Eureka College 300 E College Avenue Eureka IL 61530 USA2Division of Biomedical Marine Research Harbor Branch Oceanographic Institute Florida Atlantic University Fort PierceFL 34946 USA

3Department of Chemistry and Biochemistry Florida Atlantic University 777 Glades Road PO Box 3091 Boca RatonFL 33431-0991 USA

Correspondence should be addressed to Cyril Parkanyi parkanyifauedu

Received 9 July 2012 Accepted 10 October 2012

Academic Editors B Das T Kurtan R Pohl and J Tamariz

Copyright copy 2013 Yuxiang Zhao et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The synthesis of six thiadiazole nucleoside analogs is reported 5-diacetylamino-124-thiadiazol-3-one (1) 5-amino-2-(tetrahydrofuran-2-yl)-124-thiadiazol-3-one (2) 5-amino-3-[(21015840-hydroxyethoxy)methyl]-134-thiadiazol-2-one (3) 5-amino-3-(41015840-hydroxy-21015840-hydroxymethyl-butyl)-134-thiadiazole-2-thione (4) (R)-5-amino-3-(21015840 31015840-dihydroxypropyl)-134-thiadiazole-2-thione (5) and (S)-5-amino-3-(21015840 31015840-dihydroxypropyl)-134-thiadiazole-2-thione (6) The synthesis characterization andproperties of these new synthesized thiadiazole derivatives are discussed A dimerization of 5-amino-3H-134-thiadiazole-2-thione (14) by sodium nitrite resulting in di-(5-amino-134-thiadiazol-2-yl) disulfide (19) is also reportedThe preliminary in vitroevaluation of these newly synthesized compounds is discussed

1 Introduction

Since Heidelberger et al discovered 5-fluorouracil a pyrimi-dine antimetabolite in 1957 pyrimidine antimetabolites havebecome one of the most important groups of anticanceragents Some pyrimidine nucleosides have been proven topossess promising anticancer activity [1ndash8] such as Flox-uridine Cytarabine and Gemcitabine Many analogs ofpyrimidine nucleosides are active against viruses as wellFor example Zidovudine (Azidothymidine AZT or ZDV)Lamivudine Idoxuridine Trifluridine and Cytarabine areall used for treating viral infections [9ndash23] A number ofthese highly successful antiviral compounds are due to thecollaboration between Dracinsky et al [17] and de Clercqand Holy [17ndash21] (Viread Truvada Atripla LamivudineVistide Hepsera) In our laboratory we have focused on thedevelopment of novel antimetabolites for many years includ-ing some compounds with a thiadiazole ring Experimentalevidence indicates similarities in physical and chemical prop-erties between a ndashCH=CHndash bond in aromatic hydrocarbonsand bivalent sulfur ndashSndash in sulfur heterocycles [24 25]

For this reason 5-amino-2H-124-thiadiazol-3-one and 5-amino-3H-134-thiadiazol-2-one can be considered as theanalogs of cytosine Based on this analogy within the frame-work of our systematic studies we have synthesized somenovel acyclic or cyclic nucleoside analogs with a thiadiazolering instead of a pyrimidine ring

2 Results and Discussion

In the present paper we report the preparation of 5-diacetyl-amino-124-thioadiazol-3-one (1) and five thiadiazole-basednucleoside analogs 5-diacetylamino-124-thiadiazol-3-one(1) 5-amino-2 (tetrahydrofuran-2-yl)-124-thiadiazol-3-one(2) 5-amino-3-[(21015840-hydroxyethoxy)-methyl]-134-thiadia-zol-2-one (5-amino-3-(41015840-hydroxy-21015840-hydroxymethyl-butyl)-134-thiadiazole-2-thione (4) (S)-5-amino-3-(2101584031015840-dihy-droxypropyl)-134-thiadiazole-2-thione (5) and (R)-5-amino-3-(2101584031015840 dihydroxypropyl)-134-thiadiazole-2-thione(6) 5 and 6 are stereoisomers (see Figure 1) Their racemicmixture 7 was also prepared and tested

2 ISRN Organic Chemistry

NN

SS

NN

SS

OH

OH

OH

OH

H2NH2N

5 6

Figure 1

21 Preparation of 5-Diacetylamino-124-thiadiazol-3-one (1)and 5-amino-2-(tetrahydrofuran-2-yl)-124-thiadiazol-3-one(2) The synthesis of 5-diacetylamino-124-thiadiazol-3-one(1) and 5-amino-2-(tetrahydrofuran-2-yl)-124-thiadiazol-3-one (2) is shown in Scheme 1 5-Amino-2H- 124-thiadiazol-3-one (10) was prepared first according to a known methodand then based on 10 124-thiadiazole derivatives 1 and2 were produced The preparation of 10 was carried outusing modified procedures based on an approach by Kurzer[26] and Kurzer and Taylor [27] The starting materialswere benzoyl chloride and potassium thiocyanate Potassiumthiocyanate (KSCN) reacted with benzoyl chloride by theacylation reaction Benzoylisothiocyanate reacted via addi-tion reaction with urea to give 8 The yield for the first twosteps of this syntheticmethodwas 36N-Ureidocarbothioylbenzamide (8)was debenzoylated by refluxingwithmethanoland hydrochloric acid Thiobiuret (9) was obtained as lightyellow crystals in a 75 yield In the next step with the addi-tion ofNaOH andH

2O2at 0ndash5∘C a condensation-cyclization

reaction was carried out and resulted in 5-amino-2H-124-thiadiazol-3-one (10) as white crystals in a 65 yield Thestructures of the known compounds were determined on thebasis of their analytical and spectral data such as IR 1HNMR and 13C NMR and melting point These data were inagreement with not only their proposed structures but alsothe information reported in the literature

Compound 10 reacted with acetic anhydride atroom temperature to produce 5-diacetylamino-2H-124-thiadiazol-3-one (1) with a 96 yield The structure of5-diacetylamino-2H-124-thiadiazol-3-one (1) was deter-mined on the basis of its analytical and spectral data

In the presence of acetic acid 10 was refluxed withtwo equivalents of 23-dihydrofuran to afford 5-amino-2-(tetrahydrofuran-2-yl)-124-thiadiazol-3-one (2) as a whitesolid in 15 yield This method was modified based onLukevicsrsquo procedures He studied the reaction between 23-dihydrofuran and 5-fluorouracil under various conditions[28] In our approach we avoid using high pressure orany strong acids since thiadiazole ring may be cleavedby acids 23-Dihydrofuran was protonated by acetic acidElectrophilic attack on annular nitrogen by protonated 23-dihydrofuran gave 2 as the product The annular nitrogen in124-thiadiazole is reactive towards electrophiles

The structure of 5-amino-2-(tetrahydrofuran-2-yl)-124-thiadiazol-3-one (2) was determined by its analytical andspectral data which are in agreement with the proposedstructure [2]

22 Preparation of 5-Amino-3-[(21015840-hydroxyethoxy)methyl]-134-thiadiazol-2-one (3) The synthesis of 5-amino-3-[(21015840-hydroxyethoxy)methyl]-134-thiadiazol-2-one (3) is shownin Scheme 2 5-Amino-3H-134-thiadiazol-2-one (13) wasprepared first and then based on 13 134-thiadiazolederivative 3 was obtained The synthesis of 13 was notinitially successful with the synthetic approach basedon Freund and Schanderrsquos procedure [29] They claimedthat 5-amino-3H-134-thiadiazol-2-one (13) was preparedby heating 2-thiodiurea with concentrated hydrochloricacid

The literature shows two other possible syntheticapproaches Rufenacht [30] used potassium methyl xanthateand hydrazine hydrate to form O-methylester Phosgenewas introduced to O-methyl ester to produce 5-amino-2-methoxy-134-thiadiazole by a cyclization reactionSubsequently the hydrolysis of 5-amino-2-methoxy-134-thiadiazole yielded 13 as the product Clarkson and Landquist[31] reported a similar approach but they used cyanogenchloride for the cyclization reaction Considering that bothphosgene and cyanogen chloride are war gases and not easyto handle solid cyanogen bromide was used in our synthesisto perform this cyclization reaction Following Clarkson andLandquistrsquos procedure 2-amino-5-ethoxy-134-thiadiazole(12) was successfully synthesized in an 80 yield Thehydrolysis of 12 with a trace of hydrochloric acid gave 13 aswhite crystals in 53 yield The structures of compounds11ndash13 were identified by their analytical and spectral dataThese data were also compared with literature values foridentification

After the preparation of 5-amino-3H-134-thiadiazol-2-one (13) acyclonucleoside analog 3 was successfully syn-thesized by a convenient one-pot method This syntheticmethod was based on modified reactions reported by Keyseret al [32] and Ubasawa et al [33] Keyser et al reportedthat 13-dioxolane can react with iodotrimethylsilane atminus78∘C under nitrogen to produce iodomethyl [(trimethylsi-lyl)oxy]ethyl ether which could react with purine or pyrim-idine sodium salt to form acyclonucleosides Ubasawaet al reported a similar reaction with silylated pyrimidinebases instead of the sodium salt Our synthetic approachused silylated 134-thiadiazole to perform this reactionBis(trimethylsilyl) acetamide was stirred with 13 to producebis-trimethylsilyl-134- thiadiazole which was allowed toreact with 13-dioxolane chlorotrimethylsilane and potas-sium iodide without further separation to yield 5-amino-3-[(21015840- hydroxyethoxy)methyl]-134-thiadiazol-2-one (3)

ISRN Organic Chemistry 3

O

N

N

O

C

S

O

O

O

S

N

S

O

N

O

O

S

N O

S N

N O

O

O

ClKSCN

H

H

2N

H2N

H2N

H2N

NH

NH

NH

HN

2

S

H2N

O

NH

NH

2

8 36

CH3OH

HCl

1 9610 65 9 75

CH3COOHDMF

2 15

NaOHH2O2

Ac2O

Scheme 1

The structure of 5-amino-3-[(21015840-hydroxyethoxy)methyl]-134-thiadiazol-2-one (3) was determined on the basis of itsanalytical and spectral data which are in agreement with theproposed structure

23 Preparation of 5-Amino-3-(41015840-hydroxy-21015840-hydroxymethyl-butyl)-134-thiadiazole-2-thione (4) In the course of thepreparation of nucleoside analogs purine and pyrimidinebases are generally introduced by substitution Only a fewacyclic nucleosides were synthesized by Michael addition[34ndash37] The Michael-type addition uses amino groups asthe nucleophiles and not enolate anions as in the originalMichael addition It is interesting to prove that this strategycould work with thiadiazoles as well On the basis of previouspublications a synthetic method was modified to make thereactions with 5-amino-3H-134- thiadiazole-2-thione (14)plausible (Scheme 3)

5-Amino-3H-134-thiadiazole-2-thione (14) containsa primary amino group which needs to be protectedin this synthetic approach A very common protectinggroup Boc (tert-butoxycarbonyl) was introduced and itworked with this synthetic method very well 5-Amino-3H-134-thiadiazole-2-thione (14) was treated withdi-tert-butyl dicarbonate (Boc anhydride) to produce5-tert-butylcarbamate-3H-134-thiadiazol-2-thione (15) as alight yellow solid in 65 yield Nucleophile 15 reacted withMichael acceptor dimethyl itaconate at room temperature toafford dimethyl 2-[(5-(tert-butoxycarbonyl)-2-thioxo-134-thiadiazol-3-yl)methyl] succinate (16) in 81 yield A strongbase 18-diazabicyclo[540]undec-7-ene (DBU) was usedin this Michael-type addition reaction In the next step twoester groups in 16 were reduced to two alcohol groups byCa(BH

4)2 Ca(BH

4)2was prepared in situ by treating NaBH

4

with calcium chloride A clear gel-like product obtained


C

S

S

S

Ck

NN

S

NHN

S

NN

S

O

O

O

EtOEtO

NH2NHNH2

NH2

NH2

H2O

OO

OCH2CH3CNBr

2N NaOH

NH2

11

HCI

Dioxane

OH

Me3SiClKl

(1) 2eq BSACH3CN

(2)

12 8

3 5013 53

H2N

Scheme 2

H

HOHO

N

NHN

HN

N

N

N N

N

N N

SSS S

S

SS

S

OH

OH

S

SNHNH

Pyridine DBUDMF

RT 24 hrs

RT 3 hrs

O

O O

O OO

O

O

O

OO

O

O

OO

O

OO

OH2N

H2N

3 eq Ca(BH4)2 THF

60 TFACH2Cl2

14 15 65

17 96

4 78

16 81

Scheme 3

after this reduction reaction was 5-tert- butoxycarbonyl-3-[41015840-hydroxy-21015840-(hydroxymethyl)butyl]-134-thiadiazole-2-thione (17) Although attempts to produce 5-tert-butoxycarbonyl-3-[41015840-hydroxy-21015840-(hydroxymethyl)butyl]-134-thiadiazole-2-thione (17) with other reducing agentssuch as NaBH

4 DIBAL (diisobutylaluminum hydride) or

LiAlH4 were also carried out Ca(BH

4)2was proven to afford

the highest yield 96 It appears that DIBAL and LiAlH4can

cleave the thiadiazole ring A Boc deprotection of compound17 by 60 trifluoroacetic acid (TFA) in methylene chlorideat room temperature reproduced the primary amino groupand afforded the final product 4 in 78 yield

The analytical and spectral data of 5-tert-butylcarbamate-3H-134-thiadiazole-2-thione (15) dimethyl2-[(5-(tert-butoxycarbonyl)-2-thioxo-134-thiadiazole[-3-yl)methyl]succinate (16) 5-tert-butoxycarbonyl-3-[41015840-hydroxy-21015840-(hy-droxymethyl)butyl]-134-thiadiazole-2-thione (17) and5-amino-3-(41015840-hydroxy-21015840-hydroxymethyl-butyl)- 134-thi-adiazole-2-thione (4) are in agreement with the proposedstructure

24 Preparation of 5-Amino-3-(2101584031015840-dihydroxypropyl)-134-thiadiazole-2-thione The racemic mixture of (S)-5-amino-3-(2101584031015840-dihydroxypropyl)-134-thiadiazole-2- thione (5) and


N

SN

O

OCl

N

S

N

SN

O

O

NH

HH

S

OH OH

OH

N

S

N

S

OH

OH

HO

NaH dioxane RT 3 hrs

60 TFACH2Cl2H2N

1815

7 69

lowast

lowastlowast

Scheme 4

N

SS

NN

SS

NN

SSNaNO2CH3CO2H orSnCl4 5H2O

H2NH2N

NH

NH

2

14 19

Scheme 5

(R)-5-amino-3-(2101584031015840-dihydroxypropyl)-134-thiadiazole-2-thione (6) was prepared by using the synthetic methoddescribed in Scheme 4 The protection of the primaryamino group in 5-amino-3H-134-thiadiazole-2-thione(14) using Boc anhydride was the same as the previousreactions in Scheme 3 Then 15 was converted into asodium salt with sodium hydride in anhydrous dioxanefollowed by a nucleophilic substitution reaction with racemic3-chloro-12-propanediol to obtain 5-tert-butoxycarbonyl-3-(2101584031015840-dihydroxypropyl)-134-thiadiazole-2-thione (18) Theexperimental procedure for this nucleophilic substitutionreaction was modified on the basis of a similar reactionreported by Parkanyi et al [38] in 1989 The deprotectionof the crude product 18 with 60 trifluoroacetic acidin methylene chloride restored the primary amine Thisreaction removed the Boc group and obtained acyclicnucleoside analog 7 as a racemic mixture of 5 and 6 in a 69yield To prepare a pure enantiomer with the same approach(R)-3-chloro-12-propanediol was used to yield (S)-5-amino-3-(2101584031015840-dihydroxypropyl)-134-thiadiazole-2-thione (5) andthe (S)-3-chloro-12-propanediol was used to yield (R)-5-amino-3-(2101584031015840-dihydroxypropyl)-134-thiadiazole-2-thione(6)

As enantiomers 5 and 6 have identical melting pointsboiling points infrared spectra NMR spectra and solubilityBecause the most common property in which enantiomersdiffer is their behavior toward plane-polarized light spe-cific rotation was measured to identify the separate enan-tiomers 5 and 6 Specific rotation of the (S)-5-amino-3-(2101584031015840- dihydroxypropyl)-134-thiadiazole-2-thione (5) was[120572]D20 = minus330

∘ (119888 = 10 CH3OH) and specific

rotation of the (R)-5-amino-3-(2101584031015840-dihydroxypropyl)-134-thiadiazole-2-thione (6) was [120572]D20 = +311

∘ (119888 = 09

CH3OH) These results proved that separate enantiomers 5

and 6 have been obtained

25 Preparation of Bis-(5-amino-134-thiadiazol-2-yl) Disul-fide (19) by Dimerization In our attempts to carry out adiazotization reaction we discovered an interesting dimer-ization reaction The reaction was designed to use sodiumnitrite and an acid to prepare nitrous acid in situwhich couldreact with 14 to form a diazonium salt Then this diazoniumgroup could be replaced by a functional group such as OHVarious experimental conditions and acids have been used tostudy this reaction After treating 14 with sodium nitrite andacetic acid in an ice bath a yellow solid was produced in 73yield Surprisingly the NMR and mass spectrometry haveshown that this yellow product was not the compound weproposed from a diazotization reaction but a disulfide bis-(5- amino-134-thiadiazol-2-yl) disulfide (19) (Scheme 5)The primary amino group on the aromatic thiadiazole ringwas not affected by the diazotization reaction at all Besidesacetic acid another reagent-stannic chloride (SnCl

4sdot5H2O)

was also used with sodium nitrite to yield 19 successfully in68 yield

It is of interest to report that sodium nitrite with an acidor stannic chloride can oxidize 14 to produce disulfide 19The preparation of 19 was reported by Mahieu et al in 1986with sulfonyl chloride as the oxidant [39] Another oxidizingagent reported for this reaction was sodium chlorite whichwas described by Ramadas and Srinivasan [40] and Ramadaset al [41] Our new reaction conditions can represent agood addition to the synthesis of disulfide 19 The structureof 19 was determined by IR 1H NMR13C NMR and themelting point These data were in agreement with not only


the proposed disulfide structure but also the literature values[39 40] for identification and confirmation

3 Bioactivity Results and Discussion

All new synthesized thiadiazole acyclic and cyclic nucleosideanalogs (1ndash7) and disulfide 19 were tested for cytotoxicityagainst P388 murine leukemia cells PANC-1 human pancre-atic cancer cells A549 nonsmall cell lung adenocarcinomacells DLD-1 human colon cancer cells and NCIADR drug-resistant human breast cancer cells These structures of thia-diazole nucleoside analogs did not prove to be significantlycytotoxic to the tumor tissue cultures at concentrations of5 120583gmL This result did not surprise us because most of ourtarget compounds are acyclic nucleosides which are mostlyantiviral agents and not anticancer agents

Compounds 1ndash7 and 19 were also tested for their antimi-crobial activity against Candida albicans Staphylococcusaureus Pseudomonas aeruginosa and methicillin-resistantStaphylococcus aureus (MRSA) Better results were obtainedin screening for antimicrobial activity Two compounds 3and 19 were active against Staphylococcus aureus and MRSAat 50120583g per disc The minimum inhibitory concentration(MIC) for compound 3 toward S aureus was gt50120583gmLand toward MRSA was gt50120583gmL as well MIC of disulfide19 toward S aureus was 50 120583gmL and toward MRSA was25 120583gmL

In summary the thiadiazole acyclic and cyclic nucleosideanalogs 1ndash7 and disulfide 19 are not active against five avail-able kinds of cancer cells Although they are not cytotoxicit was noted that 3 and 19 possess considerable antibacterialactivity against S aureus and MRSA

4 Experimental

The melting points were determined on a Fisher-Johnsmelting point apparatus (WH Curtin amp Co) or Mel-Temp(Electrothermal) 1H and 13C NMR spectra were recordedwith a Varian 400-MHz spectrometer Infrared spectra weremeasured on a 4020 GALAXY series FT-IR spectrometer(Mattson Instruments) (potassium bromide disk) or on anAvatar 320 FT-IR spectrometer (Nicolet Instruments) UVspectra were measured on a Cary 3 UV-visible spectropho-tometer Thin layer chromatography (TLC) used silica gel60 F-254 precoated plates and the spots were located inthe UV light or by iodine vapor Low resolution MS spectrawere recorded on an M-8000 Hitachi mass spectrometerwith an L-7100 pump and ion trap mass analyzer All lowresolution mass spectra were obtained in ESI positive modeHigh resolution mass spectra were determined by MassSpectrometry Services at University of Florida GainesvilleFL USA Elemental analyses were performed by DesertAnalytics Tucson AZ USA Specific rotation measurementswere conducted at Perkin-Elmer model 141 polarimeter byDr David A Lightner at the University of Nevada RenoNV USA All solvents used were reagent grade except fordimethyl sulfoxide chloroform acetone and methanol usedin NMR spectroscopic measurements

N-Ureidocarbothioyl Benzamide (8) [41] Potassium thio-cyanate was predried with anhydrous tetrahydrofuran (THF)by stirring overnight Then the white powder was filteredoff and dried under vacuum on the rotary evaporator toremove THF A solution was prepared by the addition of48 g (049mol) potassium thiocyanate in 600mL toluene Tothis solution 60mL (050mol) benzoyl chloride was addeddropwise with stirringThe solution becamemilkywhite afterthe addition of benzoyl chlorideThemixturewas refluxed for4 hours under argonThe color changed fromwhite to orangeThen the solutionwas cooled to room temperature the whiteprecipitate was filtered off and the amber filtrate was refluxedwith 240 g urea (040mol) for 5 hours Then the reactionmixture was cooled to room temperature and placed in an icebath for 2 hours to form the crystalsThe solution was stirredperiodically and the walls of the flask were scratched whenthe solution was in the ice bath After crystallization brightyellow crystals (3339 g) were filtered off from the cold solu-tion and dried This was the crude product mp 168ndash171∘CRecrystallization from acetonitrile yielded 3206 g of brightyellow solid yield 36mp 174-175∘C (lit mp 175∘C [38]) 1HNMR (DMSO-d

6) 787ndash789 ppm (m 2CH in benzene) 765ndash

768 ppm (m 2CH in benzene) 754ndash758 ppm (m CH in ben-zene) 539 ppm (s 4H) 13CNMR (DMSO-d

6) 18001 16120

13397 12964 12854 ppm IR (KBr) 3354 (m NH2) 3207

(m NndashH) 3001 (m aromatic CndashH) 1716 (s C=O) 1540 (sNH2bending) 1493 (s NndashH bending) cmminus1 MSmz 22390

(M + H)+Thiobiuret (9) N-ureidocarbothioyl benzamide (11 g

49mmol) was added to a solution of 220mL methanol with05mL of concentrated HCl The mixture was refluxed for 55hoursThe reactionmixture was cooled to room temperatureand then all the solvent was evaporated The yellow residuewas washed with 5mL of hexane twice to remove the methylbenzoate and then dried under reduced pressure Recrystal-lization fromwater yielded 434 g of light yellowpowder yield75 mp 176-177∘C The second crystallization from acetoni-trile gave a white powder mp 186ndash188∘C (lit mp 189ndash193∘C[38]) 1HNMR (DMSO-d

6) 969 ppm (s 1H) 947 ppm (s 1H

in NH2) 896 ppm (s 1H in NH

2) 695 ppm (s 1H in NH

2)

629 ppm (s 1H in NH2) 13C NMR (DMSO-d

6) 18169 ppm

15515 ppm IR (KBr) 3439 (m NH2) 3251 (m NndashH) 1717

(s C=O) 1580 (s NH2bending) 1490 (s NndashH bending)

cmminus15-Amino-2H-124-thiadiazol-3-one (10) Thiobiuret 9

(5 g 42mmol) was dissolved in 32mL of a 2M NaOHsolution The cloudy solution was stirred in ice bath forone hour and then 6 mL 30 H

2O2was added dropwise

After stirring in the ice bath for 2 hours this mixture wasneutralized with 3M HCl to pH 6 After neutralization awhite precipitate was formed The mixture was filtered and348 g of crude product was collected The crude productwas recrystallized from boiling water to give 318 g 5-amino-2H-124-thiadiazol-3-one (10) as fine white crystals yield65 mp 218ndash221∘C (lit mp 220ndash222∘C [38]) 1H NMR(DMSO-d

6) 933 ppm (s NH) 806 ppm (s NH

2) 13C

NMR (DMSO-d6) 17623 ppm 16831 ppm IR (KBr) 3407

(m NH2) 3059 (m NndashH) 1651 (s C=O) 1557 (s NH

2


bending) 1540 (s NH bending) 1380 (s aromatic C=N)cmminus1

5-Diacetylamino-124-thiadiazol-3-one (1) 5-Amino-2H-124-thiadiazol-3-one (10) (0117 g 1mmol) was added to2mLof acetic anhydride solution and themixturewas stirredfor 5 hours The white solid was collected by filtration Theproduct was washed with 3mL cold water twice and driedunder reduced pressure 5-Diacetylamino-124-thiadiazol-3-one (1) 019 g was collected yield 96 mp 247-248∘C 1HNMR (DMSO-d

6) 1339 ppm (s NH) 226 ppm (s 2CH

3)

13C NMR (DMSO-d6) 17478 ppm 17073 ppm 16898 ppm

15807 ppm 2413 ppm 2231 ppm IR 3118 (m NndashH) 2882(m CH

3) 1683 (s C=O) 1552 (s C=N) 1368 (s CndashN) cmminus1

MS mz 2019M+ HRMS Anal Calcd for C6H7N3O3S

2020281 Found 20202875-Amino-2-(tetrahydrofuran-2-yl)-124-thiadiazol-3-

one (2) 5-Amino-2H-124-thiadiazole-3-one (10) 1117 g(95mmol) was added to a mixture of 5mL 23-dihydrofuranand 10 drops of glacial acetic acid in 15mL of DMF Thenit was refluxed for 6 hours in an oil bath (after the cloudymixture became clear it was refluxed for an additionalhour) After the reaction was completed the solvent wasevaporated under vacuum and 5-amino-2-(tetrahydrofuran-2-yl)- 124-thiadiazol-3-one (2) was separated by columnchromatography 026 g white crystals were collected yield15 mp 150ndash152∘C 1H NMR (CDCl

3) 171 ppm (m 1H

from CH2) 189 ppm (m CH

2) 216 ppm (m 1H from CH

2)

382 ppm (m 1H from CH2) 393 ppm (m 1H from CH

2)

559 ppm (s CH on furan) 966 ppm (s NH2) 13C NMR

(acetone-d6) 18338 ppm 15393 ppm 8165 ppm 6715 ppm

3202 ppm 2479 ppm IR 3337 (m NH2) 2990 (m CH

2)

2878 (m CndashH) 1677 (s C=O) 1589 (s C=N) 1537 (s NH2

bending) 1037 (s CndashOndashC) cmminus1 MS mz 18797 (M+H)+HRMS Anal Calcd for C

6H9N3O2S 1900634 (M +3H)3+

Found 19006412-Amino-5-ethoxy-134-thiadiazole (12) Ethylxanthic

acid potassium salt (80 g 046mol) and 40mL of water weremixed with vigorous stirring to make a paste Then 24 g(06mol) of 99 hydrazine monohydrate was added to thepaste with vigorous stirring The mixture was stirred for 4hours at room temperature and then placed in a separatoryfunnel When the two layers separated in the separatoryfunnel the bottom layer was removed and the top layer waslight yellow-greenish oil which was collected as the crudeproduct ethyl thiocarbazate (11) This oil was used as thesubstrate for the next step without further purification Thecrude ethyl thiocarbazate (11) 96 g was dissolved in 48mLof 2M NaOH solution and put in an ice bath for 45 minutesA solution of 82 g cyanogen bromide in 40mL ethanolwas added to the above reaction mixture dropwise withstirring Upon addition of cyanogen bromide a light yellowprecipitate was formed This mixture was kept in ice bathwith stirring for 45 minutes The light yellow precipitate wascollected by filtration After drying under reduced pressure883 g light yellow solid was collected yield 80 To obtainthe analytical sample the product was recrystallized fromethanol mp 195ndash202∘C (lit mp 190ndash202∘C [31]) 1H NMR(DMSO-d

6) 672 ppm (s NH

2) 429 ppm (q CH

2) 129 ppm

(t CH3) 13C NMR (DMSO-d

6) 16545 ppm 16280 ppm

6808 ppm 1501 ppm IR 3293 (m NH2) 3134 (m NndashH)

2986 (m CH3) 2931 (m CH

2) 1605 (m NH

2bending) 1562

(s C=N) 1497 (s CH2bending) 1014 (s CndashOndashC) cmminus1

5-Amino-3H-134-thiadiazolin-3-one (13) 2-Amino-5-ethoxy-134-thiadiazole (12) (5 g 345mmol) was addedto a solution of 50mL dioxane with 33mL concentratedHCl The mixture was refluxed for 45 hours Then thesolvent was evaporated under reduced pressure The lightbrown solid residue was washed with 3mL ether three timesAfter recrystallization from water 216 g off-white crystalswere collected yield 53 mp 170ndash172∘C (lit mp 170ndash172∘C[31]) 1H NMR (DMSO-d

6) 1126 ppm (s NH) 646 ppm

(s NH2) 13C NMR (DMSO-d

6) 16999 ppm 15364 ppm

IR 3321 (m NH2) 3156 (m NndashH) 1658 (s C=O) 1638 (m

NH2bending) 1562 (s C=N) 1353 (s CndashN) cmminus1 HRMS

Anal Calcd for C2H3N3OS 2569886 (2M + Na)+ Found

25698835-Amino-3-[(21015840-hydroxyethoxy)methyl]-134-thiadiazol-

2-one (3) 5-Amino-3H-134-thiadiazolin-3-one (13) (060 g0005mol) was suspended in 10mL of anhydrous CH

3CN

276mL (001mol) of bis(trimethylsilyl)acetamide was addeddropwise The mixture turned clear after several minutes Tothis solution 07mL (001mol) 13-dioxolane 17 g (001mol)KI and 138mL (001mol) chlorotrimethylsilane were addedThe mixture was stirred for 16 hours at room temperatureunder argon After the reaction 20mL of methanol wasadded to quench the reaction and the reaction mixturechanged from light yellow to dark brown NaHCO

3was

added to neutralize the mixture to pH 8 Then the solventwas evaporated under reduced pressure and the residuewas loaded onto a silica gel column for purification Thefinal product was 052 g yield 50 mp 65ndash67∘C 1H NMR(DMSO-d

6) 721 ppm (s NH

2) 537 ppm (s CH

2) 467 ppm

(t OH) 360 ppm (t CH2) 349 ppm (m CH

2) 13C NMR

(DMSO-d6) 18181 ppm 15775 ppm 7704 ppm 7164 ppm

5985 ppm IR 3410 (m NH2) 3292 (m OH) 2925 (m CH

2)

1600 (s C=O) 1568 (m NH2bending) 1412 (s C=N) 1350

(s CndashN) 1100 (s CndashOndashC) cmminus1 HRMS Anal Calcd forC5H9N3O3S 2140257 (M + Na)+ Found 2140274

5-tert-Butylcarbamate-3H-134-thiadiazol-2-thione(15) 5-Amino-3H-134-thiadiazole-2-thione (14) [42](106 g 8mmol) was dissolved in 20mL pyridine 174 g(8mmol) melted (Boc)

2O was added to the mixture

dropwise and stirred at room temperature overnightPyridine was evaporated under reduced pressure and theresidue was washed with diethyl ether twice followed withrecrystallization from CH

3Cl 121 g off-white solid was

collected yield 65 mp 157ndash159∘C 1H NMR (DMSO-d6)

1392 ppm (s NH) 1187 ppm (s NH) 145 ppm (s 3CH3)


8317 ppm 2846 ppm IR 3145 (m NndashH) 1704 (s C=O)1578 (m NH

2bending) 1545 (s C=N) 1305 (s CndashN) 1071 (s

CndashO) cmminus1 HRMS Anal Calcd for C7H11N3O2S2 2560185

(M+Na)+ Found 25601902-[(5-(tert-Butoxycarbonyl)-2-thioxo-134-thiadiazol-3-

yl)methyl]succinate (16) 5-tert-Butylcarbamate-3H-134-thiadiazole-2-thione (15) (233 g 10mmol) was dissolved


in 30mL DMF followed by the addition of 18 g (12mmol)DBU and 19 g (12mmol) dimethyl itaconate The mixturewas stirred for 40 hours under room temperature Thenthe solvent DMF was evaporated under high vacuum Theresidue was loaded onto a silica gel column for purificationAfter column chromatography 382 g white solid wascollected yield 81 mp 140ndash142∘C 1H NMR (CDCl

3)

789 ppm (s NH) 442ndash462 ppm (m CH2) 371 ppm (s

CH3) 366 ppm (s CH

3) 343ndash350 ppm (m CH) 256ndash

278 ppm (m CH2) 149 ppm (s 3CH

3) 13C NMR (CDCl

3)

18333 ppm 17226 ppm (2 C=O) 17160 ppm 15100 ppm8450 ppm 5257 ppm 5204 ppm 5017 ppm 3997 ppm3282 ppm 2798 ppm IR 3238 (m NndashH) 2980 (m CndashH)1708 (s C=O) 1587 (s C=N) 1480 (s NH bending) 1447 (sCndashH bending) 1317 (s CndashN) 1151 (s CndashOndashC) cmminus1 HRMSAnal Calcd for C

14H21N3O6S2 4140769 (M + Na)+ Found

41407785-tert-Butoxycarbonyl-3-[41015840-hydroxy-21015840-(hydroxymethyl)

butyl]-134-thiadiazole-2-thione (17) NaBH4

(008 g211mmol) was stired with CaCl

2(012 g 108mmol) in

25mL anhydrous THF for one hour After the addition of011 g (036mmol) 2-[(5-(tert-butoxycarbonyl)-2-thioxo-134-thiadiazol-3-yl)methyl]succinate (16) the mixture wasstirred under nitrogen for 24 hours 05mL of methanol wasadded to quench the reaction Then the solid in the mixturewas eliminated by filtration The solvent in the filtrate wasevaporated under reduced pressure The residue was loadedonto a silica gel column for separation 012 g clear gel-likeproduct was collected via column chromatography yield96 1H NMR (CD

3OD) 442ndash462 ppm (d CH

2) 362ndash

365 ppm (t CH2) 349ndash359 ppm (m CH

2) 228ndash238 ppm

(m CH) 155ndash168 ppm (m CH2) 151 ppm (s 3CH

3)

13C NMR (CD3OD) 18342 ppm 15488 ppm 15401 ppm

8387 ppm 6305 ppm 6066 ppm 5270 ppm 3883 ppm3279 ppm 2833 ppm IR 3337 (m NndashH) 2926 (m CndashH)1715 (s C=O) 1578 (s C=N) 1447 (m NH bending) 1370(s CndashN) 1150 (s CndashO) cmminus1 HRMS Anal Calcd forC12H21N3O4S2 3580865 (M + Na)+ Found 3580880

5-Amino-3-(41015840-hydroxy-21015840-hydroxymethyl-butyl)-134-thiadiazole-2-thione (4) 3mL chilled 60 TFA in CH

2Cl2

was added to 018 g (05mmol) 5-tert-butoxycarbonyl-3-[41015840-hydroxy-21015840-(hydroxymethyl)butyl]-134- thiadiazole-2-thione (17) in an ice bath After stirring at room temperaturefor 3 hours the reaction mixture was extracted with 2mLH2O twice The saturated NaHCO

3solution was added to

the aqueous phase to neutralize the acid The solvent in theaqueous phase was evaporated under high vacuum andthen the residue was loaded onto a column for purificationAfter column chromatography 0092 g clear liquid wascollected yield 78 1H NMR (CD

3OD) 415ndash417 ppm

(dd CH2) 363ndash366 ppm (t CH

2) 350ndash359 ppm (m

CH2) 226ndash236 ppm (m CH) 155ndash171 ppm (m CH

2)


6066 ppm 5270 ppm 3883 ppm 3279 ppm IR 3321 (mNH2) 3145 (m NH) 2844 (m CndashH) 1616 (s C=N) 1514 (m

NH bending) 1386 (m CndashN) 1097 (s CndashO) cmminus1 HRMSAnal Calcd for C

7H13N3O2S2 2580341 (M + Na)+ Found

2580349

5-Amino-3-(2101584031015840-dihydroxypropyl)-134-thiadiazole-2-thione (7) 5-tert-butylcarbamate-3H-134-thiadiazole-2-thione (15) (0133 g 1mmol) was suspended in 20mLanhydrous dioxane followed by an addition of 0028 gNaH The mixture was stirred for one hour at roomtemperature under argon Then 010 g (1mmol) of 3-chloro-12-propanediol was added dropwise The mixture wasrefluxed for 24 hours under argon After refluxing thesolvent was evaporated under reduced pressure The residuewas dissolved in 10mL methanol and then the solid wasfiltered out The solvent in the filtrate was evaporated toobtain the crude product of 5-tert-butoxycarbonyl-3-(2101584031015840-dihydroxypropyl)-134- thiadiazole-2-thione (18) Next thiscrude product was stirred with 20mL chilled 60 TFA inCH2Cl2at room temperature for 3 hours Then this mixture

was extracted with water three times and all the aqueouslayers were combined The saturated NaHCO

3solution

was added to the aqueous phase to neutralize the acid Thesolvent in the aqueous phase was evaporated under reducedpressure and then the residue was loaded onto a columnfor purification After column chromatography 014 g whitesolid was collected yield 69 mp 139ndash142∘C 1H NMR(CD3OD) 392ndash398 ppm (m CH) 369ndash382 ppm (m CH

2)

349ndash357 ppm (m CH2) 13C NMR (CD

3OD) 16990 ppm

15378 ppm 7107 ppm 6502 ppm 5013 ppm IR 3255 (mNH2) 2900 (m CndashH) 1616 (s C=N) 1514 (m NH bending)

1386 (m CndashN) 1097 (s CndashO) cmminus1 HRMS Anal Calcd forC5H9N3O2S2 2080209 (M + H)+ Found 2080202

(S)-5-Amino-3-(2101584031015840-dihydroxypropyl)-134-thiadiazole-2-thione (5) The preparation of 5 followed the procedurefor the synthesis of racemic mixture 7 except that (R)-3-chloro-12-propanediol was used instead of the racemic3-chloro-12-propanediol in the reaction The melting pointIR NMR and MS results are identical with its enantiomer 6and racemate 7 [120572]D20 = minus330∘ (119888 = 10 CH3OH)

(R)-5-Amino-3-(2101584031015840-dihydroxypropyl)-134-thiadiazole-2-thione (6) The preparation of 6 followed the procedurefor the synthesis of racemic mixture 7 except that (S)-3-chloro-12-propanediol was used instead of racemic3-chloro-12-propanediol in the reaction The melting pointIR NMR and MS results are identical with its enantiomer 5and racemate 7 [120572]D20 = +311∘ (119888 = 09 CH3OH)

Bis-(5-Amino-134-thiadiazol-2-yl) Disulfide (19) [43](a) 5-Amino-3H-134-thiadiazole-2-thione (14) (0133 g1mmol) was added to a solution of 15mL H

2O and 03

mL of glacial acetic acid This mixture was cooled in anice bath for 10 minutes Then a solution of 009 g (1mmol)NaNO

2in 02mL of H

2O was added dropwise After the

mixture was stirred in an ice bath for 10 minutes the darkyellow solid was filtered off and rinsed with two portions of05mL ethanol After drying under reduced pressure 0098 gyellow solid was collected yield 73 (b) 5-Amino-3H-134-thiadiazole-2-thione (14) (0133 g 1mmol) was added into asolution of 3mL 5050 ethanolH

2O mixture and kept in an

ice bath After the addition of 008 g NaNO2to the mixture

064 g melted SnCl4sdot5H2Owas added dropwise Immediately

after the addition of SnCl4 a dark yellow solid formed After

stirring at room temperature for almost 20 minutes the dark


yellow solid was filtered off and rinsed twice with 05mLcold water After drying under reduced pressure 0091 g theyellow solid was collected yield 68 mp 235-236∘C (lit mp235ndash238∘C [40]) 1H NMR (DMSO-d

6) 776 (s NH

2) ppm

13C NMR (DMSO-d6) 14913 ppm 17268 ppm IR 3266 (m

anti-sym NH2) 3069 (m sym NH

2) 1633 (s NH

2bending)

1494 (s C=N) 1381 (m CndashN) 1135 (s C=S) cmminus1 MS mz2649M+ HRMS Anal Calcd for C

4H4N6S4 2649453 (M

+ H)+ Found 2649459Anal Calcd for C

4H4N6S4 C 1817 H 153 N 3179 S

4851 Found C 1831 H 144 N 3186 S 4810

Acknowledgments

The authors wish to thank Patricia Linley and Dedra Har-mody for performing the biological evaluation and Dr DavidA Lightner for optical rotation measurements This is anHBOI (Harbor Branch Oceanographic Institute at FloridaAtlantic University) contribution no 1871

References

[1] J Jato and J J Windheuser ldquo5-fluorouracil and derivatives incancer chemotherapy 3 In vivo enhancement of antitumoractivity of 5-fluorouracil (FU) and 5-fluoro-2rsquo-deoxyuridine(FUDR)rdquo Journal of Pharmaceutical Sciences vol 62 no 12 pp1975ndash1978 1973

[2] B A Kamen J Casper S Lauer B M Camitta and JS Holcenberg ldquoTreatment of refractory acute lymphoblasticleukemia with teniposide and cytarabinerdquo Cancer TreatmentReports vol 70 no 7 pp 935ndash936 1986

[3] M Hidalgo D Castellano L Paz-Ares et al ldquoPhase I-II studyof gemcitabine and fluorouracil as a continuous infusion inpatients with pancreatic cancerrdquo Journal of Clinical Oncologyvol 17 no 2 pp 585ndash592 1999

[4] LH EinhornM J Stender and SDWilliams ldquoPhase II trial ofgemcitabine in refractory germ cell tumorsrdquo Journal of ClinicalOncology vol 17 no 2 pp 509ndash511 1999

[5] H von der Maase S W Hansen J T Roberts et al ldquoGemc-itabine and cisplatin versus methotrexate vinblastine doxoru-bicin and cisplatin in advanced or metastatic bladder cancerResults of a large randomized multinational multicenterphase III studyrdquo Journal of Clinical Oncology vol 18 no 17 pp3068ndash3077 2000

[6] G Frasci V Lorusso N Panza et al ldquoGemcitabine plus vinorel-bine versus vinorelbine alone in elderly patients with advancednon-small-cell lung cancerrdquo Journal of Clinical Oncology vol 18no 13 pp 2529ndash2536 2000

[7] H Y Jiang R J Hickey W Abdel-Aziz and L H MalkasldquoEffects of gemcitabine and araC on in vitro DNA synthesismediated by the human breast cell DNA synthesomerdquo CancerChemotherapy and Pharmacology vol 45 no 4 pp 320ndash3282000

[8] B Lund P E G Kristjansen and H H Hansen ldquoClinicaland preclinical activity of 2rsquo2rsquo- difluorodeoxycytidine (gemc-itabine)rdquo Cancer Treatment Reviews vol 19 no 1 pp 45ndash551993

[9] G I Birnbaum J Giziewicz E J Gabe T S Lin andW H Prusoff ldquoStructure and conformation of 3rsquo-azido-3rsquo-deoxythymidine (AZT) an inhibitor of the HIV (AIDS) virusrdquo

Canadian Journal of Chemistry vol 65 no 9 pp 2135ndash21391987

[10] G Antonelli O Turriziani A Verri et al ldquoLong-term exposureto zidovudine affects in vitro and in vivo the efficiency ofphosphorylation of thymidine kinaserdquo AIDS Research andHuman Retroviruses vol 12 no 3 pp 223ndash228 1996

[11] J D Lundgren A N Phillips C Pedersen et al ldquoComparisonof long-term prognosis of patients with AIDS treated andnot treated with zidovudinerdquo Journal of the American MedicalAssociation vol 271 no 14 pp 1088ndash1092 1994

[12] R E McKinney Jr and C Wilfert ldquoGrowth as a prognosticindicator in children with human immunodeficiency virusinfection treatedwith zidovudinerdquoThe Journal of Pediatrics vol125 no 5 part 1 pp 728ndash733 1994

[13] G Moyle ldquoDrug evaluation anti-infectives activity and role oflamivudine in the treatment of adults with human immunod-eficiency virus type 1 infection a reviewrdquo Expert Opinion onInvestigational Drugs vol 5 no 8 pp 913ndash924 1996

[14] N Leung ldquoLamivudine for chronic hepatitis Brdquo Expert Reviewof Anti-Infective Therapy vol 2 no 2 pp 173ndash180 2004

[15] W H Prusoff ldquoSynthesis and biological activities of iodo-deoxyuridine an analog of thymidinerdquoBiochimica et BiophysicaActa vol 32 pp 295ndash296 1959

[16] W H Prusoff and B Goz ldquoPotential mechanisms of action ofantiviral agentsrdquo Federation Proceedings vol 32 no 6 pp 1679ndash1687 1973

[17] M Dracinsky M Krecmerova and A Holy ldquoStudy of chemicalstability of antivirally active 5-azacytosine acyclic nucleosidephosphonates using NMR spectroscopyrdquo Bioorganic amp Medic-inal Chemistry vol 16 no 14 pp 6778ndash6782 2008

[18] E de Clercq and A Holy ldquoCase history acyclic nucleosidephosphonates a key class of antiviral drugsrdquo Nature ReviewsDrug Discovery vol 4 no 11 pp 928ndash940 2005

[19] E de Clercq ldquoDiscovery and development of BVDU (brivudin)as a therapeutic for the treatment of herpes zosterrdquo BiochemicalPharmacology vol 68 no 12 pp 2301ndash2315 2004

[20] E de Clerq ldquoTenofovir quo vadis anno 2012 (where is it goingin the year 2012)rdquoMedicinal Research Reviews vol 32 pp 765ndash785 2012

[21] E de Clercq ldquoPre-exposure chemoprophylaxis of HIV infec-tion quo vadisrdquo Biochemical Pharmacology vol 2012 no 5 pp567ndash573 2012

[22] W Hryniuk J Foerster M Shojania and A Chow ldquoCytarabinefor herpesvirus infectionsrdquo Journal of the American MedicalAssociation vol 219 no 6 pp 715ndash718 1972

[23] H E Kaufman E D Ellison and W M Townsend ldquoThechemotherapy of herpes iritis with adenine arabinoside andcytarabinerdquo Archives of Ophthalmology vol 84 no 6 pp 783ndash787 1970

[24] R Zahradnık ldquoElectronic structure of heterocyclic sulfur com-poundsrdquo Advances in Heterocyclic Chemistry vol 5 pp 1ndash671965

[25] C Parkanyi ldquoRecent progress in the quantum chemistry oforganic sulfur compoundsrdquo The Mechanism of Reactions ofSulfur Compounds vol 4 pp 69ndash93 1970

[26] F Kurzer ldquo870 Thiadiazoles Part IV The oxidation of N-(aroylamidino)thioureasrdquo Journal of the Chemical Society pp4524ndash4531 1956

[27] FKurzer and SA Taylor ldquo70Thiadiazoles PartVI 5-amino-3-hydroxy-1 2 4-thiadiazole derivativesrdquo Journal of the ChemicalSociety pp 379ndash386 1958


[28] E Lukevics M Trusule V Udre and E Liepins ldquoAdditionof 5-fluorouracil to 23-dihydrofuranrdquo Izvestiia Akademii NaukLatviiskoi SSR vol 3 pp 317ndash320 1982

[29] T Freund and A Schander ldquoZur Kenntniss des ThiourazolsrdquoBerichte der Deutschen Chemischen Gesellschaft vol 29 no 3pp 2506ndash2511 1896

[30] K Rufenacht ldquoZur Chemie von GS 13005 einem neuen Insek-tiziden PhosphorsaureesterrdquoHelvetica Chimica Acta vol 51 no3 pp 518ndash526 1968

[31] R Clarkson and J K Landquist ldquo2-alkoxy-5-amino-and -5-arenesulphonamido-134-thiadiazoles and relatedcompoundsrdquo Journal of the Chemical Society C Organic vol24 pp 2700ndash2704 1967

[32] G E Keyser J D Bryant and J R Barrio ldquoIodomethylethersfrom 13-dioxolane and 13-oxathiolane preparation of acyclicnucleoside analogsrdquo Tetrahedron Letters vol 20 no 35 pp3263ndash3264 1979

[33] M Ubasawa H Takashima and K Sekiya ldquoA convenient one-pot synthesis of acyclonucleosidesrdquo Chemical and Pharmaceu-tical Bulletin vol 43 no 1 pp 142ndash143 1995

[34] E P Lira and C W Huffman ldquoSome Michael-type reactionswith adeninerdquo Journal of Organic Chemistry vol 31 no 7 pp2188ndash2191 1966

[35] L A Yanovskaya G V Kryshtal and V V Kulrsquoganek ldquoNucle-ophilic addition of CH acids to 120572120573-unsaturated aldehydes andketonesrdquoUspekhi Khimii vol 53 p 1280 1984RussianChemicalReviews vol 53 p 744 1984

[36] G R Geen P M Kincey and B M Choudary ldquoRegiospecificMichael additions with 2-aminopurinesrdquo Tetrahedron Lettersvol 33 no 32 pp 4609ndash4612 1992

[37] S Guillarme S Legoupy N Bourgougnon A M Aubertinand F Huet ldquoSynthesis of new acyclonucleosides comprisingunexpected regioisomers in the case of purinesrdquo Tetrahedronvol 59 no 48 pp 9635ndash9639 2003

[38] C Parkanyi H L Yuan N S Cho J J Jaw T E Wood-house and T L Aung ldquoSynthesis of 2-(2rsquo3rsquo-dihydroxypro-pyl)-5-amino-2H-124-thiadiazol-3-one and 3-(2rsquo3rsquo-dihydrox-ypropyl)-5-amino-3H-134-thiadiazol-2-onerdquo Journal of Hete-rocyclic Chemistry vol 26 no 5 pp 1331ndash1334 1989

[39] J P Mahieu M Gosselet B Sebille and Y Beuzard ldquoSynthesisof new thiosulfonates and disulfides from sulfonyl chlorides andthiolsrdquo Synthetic Communications vol 16 no 13 pp 1709ndash17221986

[40] K Ramadas and N Srinivasan ldquoSodium chloritendashyet anotheroxidant for thiols to disulphidesrdquo Synthetic Communicationsvol 25 no 2 pp 227ndash234 1995

[41] K Ramadas N Srinivasan N Janarthanan and R Pritha ldquoAcomparative study of oxidants on thiolsrdquo Organic Preparationsand Procedures International vol 28 no 3 pp 352ndash354 1996

[42] ACastroA Encinas CGil et al ldquoNon-ATP competitive glyco-gen synthase kinase 3120573 (GSK-3120573) inhibitors study of structuralrequirements for thiadiazolidinone derivativesrdquo Bioorganic ampMedicinal Chemistry vol 16 no 1 pp 495ndash510 2008

[43] N S Cho G N Kim and C Parkanyi ldquoSynthesis of5-aroylamino-3H-134-thiadiazole-2-thiones and their tau-tomerismrdquo Journal of Heterocyclic Chemistry vol 30 no 2 pp397ndash401 1993

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


Journal of

Chemistry


Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


NN

SS

NN

SS

OH

OH

OH

OH

H2NH2N

5 6

Figure 1

21 Preparation of 5-Diacetylamino-124-thiadiazol-3-one (1)and 5-amino-2-(tetrahydrofuran-2-yl)-124-thiadiazol-3-one(2) The synthesis of 5-diacetylamino-124-thiadiazol-3-one(1) and 5-amino-2-(tetrahydrofuran-2-yl)-124-thiadiazol-3-one (2) is shown in Scheme 1 5-Amino-2H- 124-thiadiazol-3-one (10) was prepared first according to a known methodand then based on 10 124-thiadiazole derivatives 1 and2 were produced The preparation of 10 was carried outusing modified procedures based on an approach by Kurzer[26] and Kurzer and Taylor [27] The starting materialswere benzoyl chloride and potassium thiocyanate Potassiumthiocyanate (KSCN) reacted with benzoyl chloride by theacylation reaction Benzoylisothiocyanate reacted via addi-tion reaction with urea to give 8 The yield for the first twosteps of this syntheticmethodwas 36N-Ureidocarbothioylbenzamide (8)was debenzoylated by refluxingwithmethanoland hydrochloric acid Thiobiuret (9) was obtained as lightyellow crystals in a 75 yield In the next step with the addi-tion ofNaOH andH

2O2at 0ndash5∘C a condensation-cyclization

reaction was carried out and resulted in 5-amino-2H-124-thiadiazol-3-one (10) as white crystals in a 65 yield Thestructures of the known compounds were determined on thebasis of their analytical and spectral data such as IR 1HNMR and 13C NMR and melting point These data were inagreement with not only their proposed structures but alsothe information reported in the literature

Compound 10 reacted with acetic anhydride atroom temperature to produce 5-diacetylamino-2H-124-thiadiazol-3-one (1) with a 96 yield The structure of5-diacetylamino-2H-124-thiadiazol-3-one (1) was deter-mined on the basis of its analytical and spectral data

In the presence of acetic acid 10 was refluxed withtwo equivalents of 23-dihydrofuran to afford 5-amino-2-(tetrahydrofuran-2-yl)-124-thiadiazol-3-one (2) as a whitesolid in 15 yield This method was modified based onLukevicsrsquo procedures He studied the reaction between 23-dihydrofuran and 5-fluorouracil under various conditions[28] In our approach we avoid using high pressure orany strong acids since thiadiazole ring may be cleavedby acids 23-Dihydrofuran was protonated by acetic acidElectrophilic attack on annular nitrogen by protonated 23-dihydrofuran gave 2 as the product The annular nitrogen in124-thiadiazole is reactive towards electrophiles

The structure of 5-amino-2-(tetrahydrofuran-2-yl)-124-thiadiazol-3-one (2) was determined by its analytical andspectral data which are in agreement with the proposedstructure [2]

22 Preparation of 5-Amino-3-[(21015840-hydroxyethoxy)methyl]-134-thiadiazol-2-one (3) The synthesis of 5-amino-3-[(21015840-hydroxyethoxy)methyl]-134-thiadiazol-2-one (3) is shownin Scheme 2 5-Amino-3H-134-thiadiazol-2-one (13) wasprepared first and then based on 13 134-thiadiazolederivative 3 was obtained The synthesis of 13 was notinitially successful with the synthetic approach basedon Freund and Schanderrsquos procedure [29] They claimedthat 5-amino-3H-134-thiadiazol-2-one (13) was preparedby heating 2-thiodiurea with concentrated hydrochloricacid

The literature shows two other possible syntheticapproaches Rufenacht [30] used potassium methyl xanthateand hydrazine hydrate to form O-methylester Phosgenewas introduced to O-methyl ester to produce 5-amino-2-methoxy-134-thiadiazole by a cyclization reactionSubsequently the hydrolysis of 5-amino-2-methoxy-134-thiadiazole yielded 13 as the product Clarkson and Landquist[31] reported a similar approach but they used cyanogenchloride for the cyclization reaction Considering that bothphosgene and cyanogen chloride are war gases and not easyto handle solid cyanogen bromide was used in our synthesisto perform this cyclization reaction Following Clarkson andLandquistrsquos procedure 2-amino-5-ethoxy-134-thiadiazole(12) was successfully synthesized in an 80 yield Thehydrolysis of 12 with a trace of hydrochloric acid gave 13 aswhite crystals in 53 yield The structures of compounds11ndash13 were identified by their analytical and spectral dataThese data were also compared with literature values foridentification

After the preparation of 5-amino-3H-134-thiadiazol-2-one (13) acyclonucleoside analog 3 was successfully syn-thesized by a convenient one-pot method This syntheticmethod was based on modified reactions reported by Keyseret al [32] and Ubasawa et al [33] Keyser et al reportedthat 13-dioxolane can react with iodotrimethylsilane atminus78∘C under nitrogen to produce iodomethyl [(trimethylsi-lyl)oxy]ethyl ether which could react with purine or pyrim-idine sodium salt to form acyclonucleosides Ubasawaet al reported a similar reaction with silylated pyrimidinebases instead of the sodium salt Our synthetic approachused silylated 134-thiadiazole to perform this reactionBis(trimethylsilyl) acetamide was stirred with 13 to producebis-trimethylsilyl-134- thiadiazole which was allowed toreact with 13-dioxolane chlorotrimethylsilane and potas-sium iodide without further separation to yield 5-amino-3-[(21015840- hydroxyethoxy)methyl]-134-thiadiazol-2-one (3)


O

N

N

O

C

S

O

O

O

S

N

S

O

N

O

O

S

N O

S N

N O

O

O

ClKSCN

H

H

2N

H2N

H2N

H2N

NH

NH

NH

HN

2

S

H2N

O

NH

NH

2

8 36

CH3OH

HCl

1 9610 65 9 75

CH3COOHDMF

2 15

NaOHH2O2

Ac2O

Scheme 1




4)2 Ca(BH


4



C

S

S

S

Ck

NN

S

NHN

S

NN

S

O

O

O

EtOEtO

NH2NHNH2

NH2

NH2

H2O

OO

OCH2CH3CNBr

2N NaOH

NH2

11

HCI

Dioxane

OH

Me3SiClKl

(1) 2eq BSACH3CN

(2)

12 8

3 5013 53

H2N

Scheme 2

H

HOHO

N

NHN

HN

N

N

N N

N

N N

SSS S

S

SS

S

OH

OH

S

SNHNH

Pyridine DBUDMF

RT 24 hrs

RT 3 hrs

O

O O

O OO

O

O

O

OO

O

O

OO

O

OO

OH2N

H2N

3 eq Ca(BH4)2 THF

60 TFACH2Cl2

14 15 65

17 96

4 78

16 81

Scheme 3










N

SN

O

OCl

N

S

N

SN

O

O

NH

HH

S

OH OH

OH

N

S

N

S

OH

OH

HO


60 TFACH2Cl2H2N

1815

7 69

lowast

lowastlowast

Scheme 4

N

SS

NN

SS

NN


H2NH2N

NH

NH

2

14 19

Scheme 5





∘ (119888 = 09




4sdot5H2O)









4 Experimental





6) 18001 16120

13397 12964 12854 ppm IR (KBr) 3354 (m NH2) 3207




6) 969 ppm (s 1H) 947 ppm (s 1H



2)


6) 18169 ppm







6) 933 ppm (s NH) 806 ppm (s NH

2) 13C



2




6) 1339 ppm (s NH) 226 ppm (s 2CH

3)







3) 171 ppm (m 1H



2)


2)



3202 ppm 2479 ppm IR 3337 (m NH2) 2990 (m CH

2)



6H9N3O2S 1900634 (M +3H)3+



6) 672 ppm (s NH

2) 429 ppm (q CH

2) 129 ppm


6) 16545 ppm 16280 ppm


2986 (m CH3) 2931 (m CH

2) 1605 (m NH

2bending) 1562



6) 1126 ppm (s NH) 646 ppm


6) 16999 ppm 15364 ppm






3CN


3was


6) 721 ppm (s NH

2) 537 ppm (s CH

2) 467 ppm


2) 13C NMR


5985 ppm IR 3410 (m NH2) 3292 (m OH) 2925 (m CH

2)

















3)


CH3) 366 ppm (s CH



3) 13C NMR (CDCl

3)


14H21N3O6S2 4140769 (M + Na)+ Found




2(012 g 108mmol) in



2) 362ndash


2) 228ndash238 ppm


3)




2Cl2








2)




7H13N3O2S2 2580341 (M + Na)+ Found

2580349



3solution


2)


3OD) 16990 ppm






2O and 03


2in 02mL of H










6) 776 (s NH

2) ppm



2) 1633 (s NH

2bending)


4H4N6S4 2649453 (M


4H4N6S4 C 1817 H 153 N 3179 S

4851 Found C 1831 H 144 N 3186 S 4810

Acknowledgments


References























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


O

N

N

O

C

S

O

O

O

S

N

S

O

N

O

O

S

N O

S N

N O

O

O

ClKSCN

H

H

2N

H2N

H2N

H2N

NH

NH

NH

HN

2

S

H2N

O

NH

NH

2

8 36

CH3OH

HCl

1 9610 65 9 75

CH3COOHDMF

2 15

NaOHH2O2

Ac2O

Scheme 1




4)2 Ca(BH


4



C

S

S

S

Ck

NN

S

NHN

S

NN

S

O

O

O

EtOEtO

NH2NHNH2

NH2

NH2

H2O

OO

OCH2CH3CNBr

2N NaOH

NH2

11

HCI

Dioxane

OH

Me3SiClKl

(1) 2eq BSACH3CN

(2)

12 8

3 5013 53

H2N

Scheme 2

H

HOHO

N

NHN

HN

N

N

N N

N

N N

SSS S

S

SS

S

OH

OH

S

SNHNH

Pyridine DBUDMF

RT 24 hrs

RT 3 hrs

O

O O

O OO

O

O

O

OO

O

O

OO

O

OO

OH2N

H2N

3 eq Ca(BH4)2 THF

60 TFACH2Cl2

14 15 65

17 96

4 78

16 81

Scheme 3










N

SN

O

OCl

N

S

N

SN

O

O

NH

HH

S

OH OH

OH

N

S

N

S

OH

OH

HO


60 TFACH2Cl2H2N

1815

7 69

lowast

lowastlowast

Scheme 4

N

SS

NN

SS

NN


H2NH2N

NH

NH

2

14 19

Scheme 5





∘ (119888 = 09




4sdot5H2O)









4 Experimental





6) 18001 16120

13397 12964 12854 ppm IR (KBr) 3354 (m NH2) 3207




6) 969 ppm (s 1H) 947 ppm (s 1H



2)


6) 18169 ppm







6) 933 ppm (s NH) 806 ppm (s NH

2) 13C



2




6) 1339 ppm (s NH) 226 ppm (s 2CH

3)







3) 171 ppm (m 1H



2)


2)



3202 ppm 2479 ppm IR 3337 (m NH2) 2990 (m CH

2)



6H9N3O2S 1900634 (M +3H)3+



6) 672 ppm (s NH

2) 429 ppm (q CH

2) 129 ppm


6) 16545 ppm 16280 ppm


2986 (m CH3) 2931 (m CH

2) 1605 (m NH

2bending) 1562



6) 1126 ppm (s NH) 646 ppm


6) 16999 ppm 15364 ppm






3CN


3was


6) 721 ppm (s NH

2) 537 ppm (s CH

2) 467 ppm


2) 13C NMR


5985 ppm IR 3410 (m NH2) 3292 (m OH) 2925 (m CH

2)

















3)


CH3) 366 ppm (s CH



3) 13C NMR (CDCl

3)


14H21N3O6S2 4140769 (M + Na)+ Found




2(012 g 108mmol) in



2) 362ndash


2) 228ndash238 ppm


3)




2Cl2








2)




7H13N3O2S2 2580341 (M + Na)+ Found

2580349



3solution


2)


3OD) 16990 ppm






2O and 03


2in 02mL of H










6) 776 (s NH

2) ppm



2) 1633 (s NH

2bending)


4H4N6S4 2649453 (M


4H4N6S4 C 1817 H 153 N 3179 S

4851 Found C 1831 H 144 N 3186 S 4810

Acknowledgments


References























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


C

S

S

S

Ck

NN

S

NHN

S

NN

S

O

O

O

EtOEtO

NH2NHNH2

NH2

NH2

H2O

OO

OCH2CH3CNBr

2N NaOH

NH2

11

HCI

Dioxane

OH

Me3SiClKl

(1) 2eq BSACH3CN

(2)

12 8

3 5013 53

H2N

Scheme 2

H

HOHO

N

NHN

HN

N

N

N N

N

N N

SSS S

S

SS

S

OH

OH

S

SNHNH

Pyridine DBUDMF

RT 24 hrs

RT 3 hrs

O

O O

O OO

O

O

O

OO

O

O

OO

O

OO

OH2N

H2N

3 eq Ca(BH4)2 THF

60 TFACH2Cl2

14 15 65

17 96

4 78

16 81

Scheme 3










N

SN

O

OCl

N

S

N

SN

O

O

NH

HH

S

OH OH

OH

N

S

N

S

OH

OH

HO


60 TFACH2Cl2H2N

1815

7 69

lowast

lowastlowast

Scheme 4

N

SS

NN

SS

NN


H2NH2N

NH

NH

2

14 19

Scheme 5





∘ (119888 = 09




4sdot5H2O)









4 Experimental





6) 18001 16120

13397 12964 12854 ppm IR (KBr) 3354 (m NH2) 3207




6) 969 ppm (s 1H) 947 ppm (s 1H



2)


6) 18169 ppm







6) 933 ppm (s NH) 806 ppm (s NH

2) 13C



2




6) 1339 ppm (s NH) 226 ppm (s 2CH

3)







3) 171 ppm (m 1H



2)


2)



3202 ppm 2479 ppm IR 3337 (m NH2) 2990 (m CH

2)



6H9N3O2S 1900634 (M +3H)3+



6) 672 ppm (s NH

2) 429 ppm (q CH

2) 129 ppm


6) 16545 ppm 16280 ppm


2986 (m CH3) 2931 (m CH

2) 1605 (m NH

2bending) 1562



6) 1126 ppm (s NH) 646 ppm


6) 16999 ppm 15364 ppm






3CN


3was


6) 721 ppm (s NH

2) 537 ppm (s CH

2) 467 ppm


2) 13C NMR


5985 ppm IR 3410 (m NH2) 3292 (m OH) 2925 (m CH

2)

















3)


CH3) 366 ppm (s CH



3) 13C NMR (CDCl

3)


14H21N3O6S2 4140769 (M + Na)+ Found




2(012 g 108mmol) in



2) 362ndash


2) 228ndash238 ppm


3)




2Cl2








2)




7H13N3O2S2 2580341 (M + Na)+ Found

2580349



3solution


2)


3OD) 16990 ppm






2O and 03


2in 02mL of H










6) 776 (s NH

2) ppm



2) 1633 (s NH

2bending)


4H4N6S4 2649453 (M


4H4N6S4 C 1817 H 153 N 3179 S

4851 Found C 1831 H 144 N 3186 S 4810

Acknowledgments


References























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

SN

O

OCl

N

S

N

SN

O

O

NH

HH

S

OH OH

OH

N

S

N

S

OH

OH

HO


60 TFACH2Cl2H2N

1815

7 69

lowast

lowastlowast

Scheme 4

N

SS

NN

SS

NN


H2NH2N

NH

NH

2

14 19

Scheme 5





∘ (119888 = 09




4sdot5H2O)









4 Experimental





6) 18001 16120

13397 12964 12854 ppm IR (KBr) 3354 (m NH2) 3207




6) 969 ppm (s 1H) 947 ppm (s 1H



2)


6) 18169 ppm







6) 933 ppm (s NH) 806 ppm (s NH

2) 13C



2




6) 1339 ppm (s NH) 226 ppm (s 2CH

3)







3) 171 ppm (m 1H



2)


2)



3202 ppm 2479 ppm IR 3337 (m NH2) 2990 (m CH

2)



6H9N3O2S 1900634 (M +3H)3+



6) 672 ppm (s NH

2) 429 ppm (q CH

2) 129 ppm


6) 16545 ppm 16280 ppm


2986 (m CH3) 2931 (m CH

2) 1605 (m NH

2bending) 1562



6) 1126 ppm (s NH) 646 ppm


6) 16999 ppm 15364 ppm






3CN


3was


6) 721 ppm (s NH

2) 537 ppm (s CH

2) 467 ppm


2) 13C NMR


5985 ppm IR 3410 (m NH2) 3292 (m OH) 2925 (m CH

2)

















3)


CH3) 366 ppm (s CH



3) 13C NMR (CDCl

3)


14H21N3O6S2 4140769 (M + Na)+ Found




2(012 g 108mmol) in



2) 362ndash


2) 228ndash238 ppm


3)




2Cl2








2)




7H13N3O2S2 2580341 (M + Na)+ Found

2580349



3solution


2)


3OD) 16990 ppm






2O and 03


2in 02mL of H










6) 776 (s NH

2) ppm



2) 1633 (s NH

2bending)


4H4N6S4 2649453 (M


4H4N6S4 C 1817 H 153 N 3179 S

4851 Found C 1831 H 144 N 3186 S 4810

Acknowledgments


References























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of







4 Experimental





6) 18001 16120

13397 12964 12854 ppm IR (KBr) 3354 (m NH2) 3207




6) 969 ppm (s 1H) 947 ppm (s 1H



2)


6) 18169 ppm







6) 933 ppm (s NH) 806 ppm (s NH

2) 13C



2




6) 1339 ppm (s NH) 226 ppm (s 2CH

3)







3) 171 ppm (m 1H



2)


2)



3202 ppm 2479 ppm IR 3337 (m NH2) 2990 (m CH

2)



6H9N3O2S 1900634 (M +3H)3+



6) 672 ppm (s NH

2) 429 ppm (q CH

2) 129 ppm


6) 16545 ppm 16280 ppm


2986 (m CH3) 2931 (m CH

2) 1605 (m NH

2bending) 1562



6) 1126 ppm (s NH) 646 ppm


6) 16999 ppm 15364 ppm






3CN


3was


6) 721 ppm (s NH

2) 537 ppm (s CH

2) 467 ppm


2) 13C NMR


5985 ppm IR 3410 (m NH2) 3292 (m OH) 2925 (m CH

2)

















3)


CH3) 366 ppm (s CH



3) 13C NMR (CDCl

3)


14H21N3O6S2 4140769 (M + Na)+ Found




2(012 g 108mmol) in



2) 362ndash


2) 228ndash238 ppm


3)




2Cl2








2)




7H13N3O2S2 2580341 (M + Na)+ Found

2580349



3solution


2)


3OD) 16990 ppm






2O and 03


2in 02mL of H










6) 776 (s NH

2) ppm



2) 1633 (s NH

2bending)


4H4N6S4 2649453 (M


4H4N6S4 C 1817 H 153 N 3179 S

4851 Found C 1831 H 144 N 3186 S 4810

Acknowledgments


References























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




6) 1339 ppm (s NH) 226 ppm (s 2CH

3)







3) 171 ppm (m 1H



2)


2)



3202 ppm 2479 ppm IR 3337 (m NH2) 2990 (m CH

2)



6H9N3O2S 1900634 (M +3H)3+



6) 672 ppm (s NH

2) 429 ppm (q CH

2) 129 ppm


6) 16545 ppm 16280 ppm


2986 (m CH3) 2931 (m CH

2) 1605 (m NH

2bending) 1562



6) 1126 ppm (s NH) 646 ppm


6) 16999 ppm 15364 ppm






3CN


3was


6) 721 ppm (s NH

2) 537 ppm (s CH

2) 467 ppm


2) 13C NMR


5985 ppm IR 3410 (m NH2) 3292 (m OH) 2925 (m CH

2)

















3)


CH3) 366 ppm (s CH



3) 13C NMR (CDCl

3)


14H21N3O6S2 4140769 (M + Na)+ Found




2(012 g 108mmol) in



2) 362ndash


2) 228ndash238 ppm


3)




2Cl2








2)




7H13N3O2S2 2580341 (M + Na)+ Found

2580349



3solution


2)


3OD) 16990 ppm






2O and 03


2in 02mL of H










6) 776 (s NH

2) ppm



2) 1633 (s NH

2bending)


4H4N6S4 2649453 (M


4H4N6S4 C 1817 H 153 N 3179 S

4851 Found C 1831 H 144 N 3186 S 4810

Acknowledgments


References























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



3)


CH3) 366 ppm (s CH



3) 13C NMR (CDCl

3)


14H21N3O6S2 4140769 (M + Na)+ Found




2(012 g 108mmol) in



2) 362ndash


2) 228ndash238 ppm


3)




2Cl2








2)




7H13N3O2S2 2580341 (M + Na)+ Found

2580349



3solution


2)


3OD) 16990 ppm






2O and 03


2in 02mL of H










6) 776 (s NH

2) ppm



2) 1633 (s NH

2bending)


4H4N6S4 2649453 (M


4H4N6S4 C 1817 H 153 N 3179 S

4851 Found C 1831 H 144 N 3186 S 4810

Acknowledgments


References























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



6) 776 (s NH

2) ppm



2) 1633 (s NH

2bending)


4H4N6S4 2649453 (M


4H4N6S4 C 1817 H 153 N 3179 S

4851 Found C 1831 H 144 N 3186 S 4810

Acknowledgments


References























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

Documents

Research Article Synthesis and In Vitro Evaluation of ...downloads.hindawi.com/archive/2013/159164.pdf · e structure of-diacetylamino-H-,, -thiadiazol--one ( ) was deter-mined on