Research Article Stereochemical Investigations of ...downloads.hindawi.com/archive/2015/609250.pdf · Nuclear Magnetic Resonance Spectroscopy (1D and 2D) ÖznurDemir-Ordu, 1 HaleDemir-Dündar,

Research ArticleStereochemical Investigations of Diastereomeric N-[2-(Aryl)-5-methyl-4-oxo-13-thiazolidine-3-yl]-pyridine-3-carboxamides byNuclear Magnetic Resonance Spectroscopy (1D and 2D)

Oumlznur Demir-Ordu1 Hale Demir-Duumlndar2 and Sumru Ozkirimli2

1Department of Chemistry Abant Izzet Baysal University 14030 Bolu Turkey2Department of Pharmaceutical Chemistry Istanbul University 34116 Istanbul Turkey

Correspondence should be addressed to Oznur Demir-Ordu demirorduibuedutr

Received 13 October 2015 Revised 19 November 2015 Accepted 10 December 2015

Academic Editor Craig J Eckhardt

Copyright copy 2015 Oznur Demir-Ordu et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Some newN-[2-(aryl)-5-methyl-4-oxo-13-thiazolidine-3-yl]-pyridine-3-carboxamides were synthesized and their structures wereinvestigated by IRNMR (1H 13C and 2D) andmass spectraThe presence of C-2 andC-5 stereogenic centers on the thiazolidinonering resulted in diastereoisomeric pairs The configurations of two stereogenic centers were assigned based upon 1H NMRanalysis of coupling constants and 2D nuclear overhauser enhancement spectroscopy (NOESY) experiment Resolution of thediastereoisomers was performed by high performance liquid chromatography (HPLC) using a chiral stationary phase

1 Introduction

Pyridine-3-carboxamide (nicotinamide) known as vitaminPP (pellagra protective) is part of the vitamin B group andplays an important role in biological oxidative chemistryPyridine-3-carboxamide derivatives have gained attentionbecause of their diverse pharmacological activities such ascytoprotective [1] antiviral [2] antitumor [3] and anxiolytic[4] activities

Thiazolidin-4-one derivatives possess versatile biologicalactivities [5] including antifungal [6] antibacterial [7 8]anticancer [9 10] anti-inflammatory [11ndash13] analgesic [14]anticonvulsant [15 16] antiviral [17 18] and antidiabeticactivities [19 20]

Currently nearly 50 of the drugs are in use as race-mates But stereochemical factors generally have importantinfluence on biological activity of the drug molecules Thetwo enantiomers present in a racemic mixture can possessdifferent biological activities that is one enantiomer hastherapeutic value the other enantiomer may be less effectiveinactive or highly toxic [21ndash27] Therefore the identificationand separation of stereoisomers are considered to be impor-tant Chiral compounds bearing thiazolidin-4-one ring have

also been studied for their stereochemistry Several studieshave been done on these compounds regarding enantiodiffer-entiation of stereoisomers in the presence of chiral auxiliary[28] separation of enantiomers by chiral HPLC [29 30] anddetermination of absolute conformations [31 32]

It is well known that combinations of two or more het-erocyclic scaffolds in onemolecule can provide a series of com-pounds with a broad spectrum of biological activity Here wecombine thiazolidin-4-one andpyridine-3-carboxamide scaf-folds together as part of an ongoing project directed towardsthe design and synthesis of biologically active nitrogen andsulfur containing heterocyclic compounds [33] Our researchfocused on stereochemical investigations on diastereomeric119873-[2-(aryl)-5-methyl-4-oxo-13-thiazolidine-3-yl]-pyridine-3-carboxamides (2andashf) (Figure 1) by one- and two-dimen-sionalNMR techniques In addition the analytical chromato-graphic separation of some derivatives by chiral HPLC hasbeen examined using a chiral column

2 Experimental21 General 1D 1H and 13C NMR spectra of all compoundswere recorded on a Varian-Unity Inova 500 spectrometer

Hindawi Publishing CorporationInternational Journal of SpectroscopyVolume 2015 Article ID 609250 9 pageshttpdxdoiorg1011552015609250

2 International Journal of Spectroscopy

Table 1 1H NMR (500MHz) data of compounds 2andash2f in DMSO-1198896a

Entry C-6 methyl C-5 methine C-2 methine CO-NH

2a 155 (d 119869 = 70Hz) 413 (qd 119869 = 70Hz 097Hz)423 (qd 119869 = 70 147Hz)b 592 (s) 1094 (s)

2b 154 (d 119869 = 70)155 (d 119869 = 68Hz)

412 (q 119869 = 68Hz)b422 (q 119869 = 68Hz)c 590 (s) 1094 (s)

1095 (s)

2c 155 (d 119869 = 73Hz)157 (d 119869 = 73Hz)

415 (q 119869 = 68Hz)b425 (qd 119869 = 68 147Hz)

601 (d 119869 = 147Hz)602 (s)

1099 (s)1101 (s)

2d 153 (d 119869 = 73Hz)155 (d 119869 = 73Hz)

410 (q 119869 = 73Hz)416 (qd 119869 = 73 147Hz)b

587 (s)588 (d 119869 = 147Hz) 1090 (s)

2e 154 (d 119869 = 73)155 (d 119869 = 68Hz)

411 (q 119869 = 68Hz)b418 (qd 119869 = 68 146Hz)

589 (s)590 (s) 1097 (s)

2f 148 (d 119869 = 73)152 (d 119869 = 68Hz)

410 (q 119869 = 70Hz)b421 (qd 119869 = 70 196Hz)

622 (d 119869 = 196Hz)626 (s)

1104 (s)1105 (s)

aFor 1H NMR data of the other protons see Section 2bThe signals corresponding to major diastereomercCoupling with C-2 methine was observed as a shoulder

NH

N

SO

R

123

45

O

N6

2a R 4-Cl2b R 4-Br

CH3

2c R 4-CF3

2d R 4-OCH2Ph2e R 3-OCH32f R 2-NO2

Figure 1 The synthesized compounds 2andashf

operating at 4997MHz for 1H and 1249MHz for 13C usingtetramethylsilane (TMS) as an internal standard Chemicalshifts (120575) were reported in parts per million (ppm) Spectralwidths of 14 and 230 ppm were used in 1H and 13C NMRrespectivelyThe splitting patterns of 1HNMRwere designedas follows s singlet d doublet q quartet qd quartet ofdoublets dd doublet of doublets and m multiplet NOESYexperiment was performed on a Varian-Mercury VX-400-BB (spectrometer frequency 39998MHz temperature 24∘Crelaxation delay 20 sec acquisition time 015 sec numberof increments the number of points in t1 200 numberof points in each FID (t2) 1920 and spectral width 1Hchannel 14 ppm) HMBC experiment was performed ona Varian-Unity Inova 500 spectrometer (spectrometer fre-quency 4997MHz temperature 30∘C relaxation delay10 sec acquisition time 0128 sec 400 increments and spec-tral width 1H channel 14 ppm 13C channel 230 ppm)IR analyses were performed on a Shimadzu IR Affinity-I FTIR using KBr discs peaks are reported in cmminus1 UVanalyses were performed on ShimadzuUV-1601 wavelengthsare reported in nm Liquid chromatography analyses wereperformed on Shimadzu SCL-10AVP with a diode arraydetector and using ChiralpakAD column (particle size 5120583mcolumn size 250times 46mm) Eluentwas n-hexane 2-propanol(85 15) (v v) with a flow rate of 09mLminminus1 Reactions

were followed by TLC using silica gel 60-F254

Elementalanalyses were performed on Thermo Finnigan Flash EA1112 CHNS-932 analyzer Melting points were recorded usingBuchi B-540 melting point apparatus The mass spectra wereobtained using Finnigan LCQ Advantage Max Waters 2695Alliance Micromass ZQ

211 General Procedure for the Preparation of N-[2-(Aryl)-5-methyl-4-oxo-13-thiazolidine-3-yl]-pyridine-3-carboxamidesTo a suspension of 001mol of aryl 1198731015840-(substituted benzyl-idene)pyridine-3-carbohydrazide (1andashf) in 30mL dry benzene was added 25mL (0028mol) of 2-sulfanylpropanoicacid The mixture was refluxed for 6ndash18 hours using a Dean-Stark trap Excess benzene was evaporated in vacuo Theresulting residue was triturated with NaHCO

3solution until

CO2evolution ceased and was allowed to stand refrigerated

until solidification The solid thus obtained was washed withwater dried and recrystallized from ethanol

Some spectral and X-ray crystallographic data of com-pounds 2a 2b and 2f were reported regardless of stereo-chemistry in our previously published articles [34ndash36]

212 N-[2-(4-Chlorophenyl)-5-methyl-4-oxo-13-thiazolidin-3-yl]-pyridine-3-carboxamide (2a) Diastereomer ratio (majorminor) 54 46 1H-NMR (500MHz DMSO-119889

6) 120575 743ndash747

(2H m phenyl-H) 748ndash750 (1H m pyridine-H) 752-753(2H m phenyl-H) 804ndash809 (1H m pyridine-H) 873(1H dd 119869 = 63Hz 14Hz pyridine-H) 884 885 (1H 2d119869 = 29Hz 14Hz pyridine-H) [35] (for 1H NMR data ofother protons see Table 1) 13C-NMR (125MHz) (DMSO-119889

6)

120575 (ppm) 206 (C-6 CH3) 398 399 (C-5 CH) 604 606 (C-

2 CH) 1243 1244 (C13 CH) 1279 1280 (C9 C) 1293 1294(C16 20 CH) 1304 1307 (C17 19 CH) 1342 1344 (C18 C)1359 1360 (C14 CH) 1372 1381 (C15 C) 1491 1492 (C10CH) 1535 1536 (C12 CH) 1645 1646 (C-8 C=O) 17251726 (C-4 C=O) (for designations of carbons see Figure 3)

213 N-[2-(4-Bromophenyl)-5-methyl-4-oxo-13-thiazolidin-3-yl]-pyridine-3-carboxamide (2b) Diastereomer ratio (majorminor) 60 40 1H-NMR (500MHz DMSO-119889

6) 120575 744ndash746

International Journal of Spectroscopy 3

(2H m phenyl-H) 749ndash756 (1H m pyridine-H) 757ndash760(2H m phenyl-H) 805ndash809 (1H m pyridine-H) 872ndash873(1H m pyridine-H) 886 887 (1H 2d 119869 = 1Hz pyridine-H) [36] (for 1H NMR data of other protons see Table 1)13C-NMR (125MHz) (DMSO-119889

6) 120575 (ppm) 202 (CH

3 C-6

60) 206 (CH3 C-6 40) 397 (CH C-5 40) 398 (CH

C-5 60) 604 (CH C-2 40) 607 (CH C-2 60) 1228(C C18 40) 1231 (C C18 60) 1243 (CH C13 40)1244 (CH C13 60) 1278 (C C9 60) 1279 (C C9 40)1307 (CH C16 20 40) 1309 (CH C16 20 60) 1322(CH C17 19 40) 1323 (CH C17 19 60) 1359 (CH C1460) 1360 (CH C14 40) 1377 (C C15 60) 1386 (CC15 40) 1491 (CH C10 60) 1492 (CH C10 40) 1536(CH C12 40) 1537 (CH C12 60) 1645 (C=O C-840) 1646 (C=O C-8 60) 1726 (C=O C-4 40) 1727(C=O C-4 60) (for designations of carbons see Figure 3)

214 N-[2-(4-Trifluoromethylphenyl)-5-methyl-4-oxo-13-thi-azolidin-3-yl]-pyridine-3-carboxamide (2c) Diastereomer ratio (majorminor) 53 47 White powder (278 g 73) mp1700ndash1731∘C 1H-NMR (500MHz DMSO-119889

6) 120575 749ndash751

(1H m pyridine-H) 772ndash778 (4H m 2-phenyl-H) 805ndash810 (1Hm pyridine-H) 872ndash873 (1Hm pyridine-H) 885888 (1H 2d 119869 = 20Hz pyridine-H) (for 1H NMR data ofother protons see Table 1) 13C-NMR (100MHz DMSO-119889

6)

120575 202 203 (C-6 CH3) 386 392 (C-5 CH) 601 604 (C-

2 CH) 1242 1243 (C13 CH) 1246 (CF3 q 119869 = 271Hz)

1261 1262 (C17 19 CH) 1276 1277 (C9 C) 1290 1294 (C1620 CH) 1298 and 1300 (C18 C q 119869 = 32Hz) 1358 1359(C14 CH) 1431 1440 (C15 C) 1489 1490 (C10 CH) 15351536 (C12 CH) 1644 1645 (C-8 C=O) 1725 1727 (C-4C=O) (for designations of carbons see Figure 3) IR (KBr)]max = 3143 3037 1732 1676 1620 1595 1544 UV (EtOH)120582max(log 120576) = 2032 (28135) 2196 (23655) 2628 (6368)ESI MS 119898119911 = 38008 ([M minus H]minus 100) Anal Calcd forC17H14F3N3O2S C 5354H 370 N 1102 Found C 5375

H 392 N 1096

215 N-[2-(4-Benzyloxyphenyl)-5-methyl-4-oxo-13-thiazolidin-3-yl]-pyridine-3-carboxamide (2d) Diastereomer ratio (majorminor) 80 20 White powder yield 368 g (88)mp 1404ndash1435∘C 1H-NMR (500MHz DMSO-119889

6) 120575 508

(2H s O-CH2-C6H5) 699ndash702 (2H m 2-phenyl-H)

731ndash735 (1H m pyridine-H) 737ndash751 (7H m 2-phenyland -O-CH

2-C6H5) 806ndash809 (1H m pyridine-H) 873

(1H dd 119869 = 75Hz 20Hz pyridine-H) 884 886 (1H 2d119869 = 20Hz pyridine-H) (for 1H NMR data of other protonssee Table 1) 13C-NMR (125MHz DMSO-119889

6) 120575 200 (CH

3

C-6 20) 208 (CH3 C-6 80) 398 (CH C-5 20) 399

(CH C-5 80) 608 (CH C-2) 700 (CH2 C21) 1155 (C17

19 CH) 1243 (CH C13 80) 1244 (CH C13 20) 1280(C9 C) 1283 (CH C24 26 80) 1284 (CH C24 26 20)1286 (CH C25) 1291 (CH C23 27) 1300 (CH C16 2080) 1303 (CH C16 20 20) 1306 (C15 C) 1359 (CHC14 20) 1360 (CH C14 80) 1375 (C C22 20) 1376(C C22 80) 1491 (CH C10 20) 1492 (CH C10 80)1536 (C12 CH) 1596 (C18 C) 1645 (C-8 C=O) 1726 (C-4C=O) (for designations of carbons see Figure 5) IR (KBr)

]max = 3473 3163 3066 1710 1672 1606 1591 1244 UV(EtOH) 120582max(log 120576) = 2048 (59593) 2332 (28089) 2668(13560) ESI MS119898119911 = 41810 ([M minusH]minus 100) Anal Calcdfor C

23H21N3O3S C 6447 H 517 N 981 Found C

6463 H 506 N 976

216N-[2-(3-Methoxyphenyl)-5-methyl-4-oxo-13-thiazolidin-3-yl]-piridine-3-carboxamide (2e) Diastereomer ratio (majorminor) 73 27 White powder yield 224 g (65)mp 1010ndash1050∘C 1H-NMR (500MHz DMSO-119889

6) 120575 374

(3 h s OCH3) 690ndash693 (1H m 2-phenyl-H) 702ndash704

(2H m 2-phenyl-H) 727ndash730 (1H m 2-phenyl-H) 750(1H dd 119869 = 53 48Hz pyridine-H) 805ndash808 (1H mpyridine-H) 872 (1H dd 119869 = 78 20Hz pyridine-H) 885(major diastereomer) 887 (minor diastereomer) (1H 2d119869 = 19Hz 119869 = 19Hz pyridine-H) (for 1H NMR data ofother protons see Table 1) 13C-NMR (125MHz DMSO-119889

6)

120575 202 (CH3 C-6 73) 206 (CH

3 C-6 27) 398 (CH

C-5 27) 399 (CH C-5 73) 558 (OCH3) 609 (CH

C-2 27) 612 (CH C-2 73) 1135 (CH C18 27) 1138(CH C18 73) 1153 (CH C16 27) 1154 (CH C16 73)1204 (CH C20 27) 1208 (CH C20 73) 1243 (CH C1327) 1244 (CH C13 73) 1279 (C C9 73) 1280 (C C927) 1304 (CH C19 27) 1305 (CH C19 73) 1360 (CHC14 73) 1361 (CH C14 27) 1398 (C C15 73) 1405(C C15 27) 1491 (CH C10 73) 1492 (CH C10 27)1536 (CH C12) 1601 (C C17 73) 1602 (C C17 27)1646 (C-8 C=O) 1728 (C=O C-4 27) 1729 (C=O C-473) (for designations of carbons see Figure 3) IR (KBr)]max = 3487 3176 3076 1707 1670 1610 1591 1546 1260 UV(EtOH) 120582max(log 120576) = 2040 (42863) 2250 (17859) 2638(6101) ESI MS 119898119911 = 34223 ([M minus H]minus 100) Anal Calcdfor C17H17N3O3S C 5650 H 530 N 1163 Found C

5647 H 477 N 1150

217 N-[2-(2-Nitrophenyl)-5-methyl-4-oxo-13-thiazolidin-3-yl]-piridine-3-carboxamide (2f) Diastereomer ratio (majorminor) 52 48 1H-NMR (500MHz DMSO-119889

6) 120575 751

(1H dd 119869 = 48Hz 44Hz pyridine-H) 761ndash765 (1H m2-phenyl-H) 785ndash790 (2H m 2-phenyl-H) 804ndash811 (2Hm 2-phenyl-H and pyridine-H) 873 (1H dd 119869 = 83Hz20Hz pyridine-H) 871 879 (1H 2d 119869 = 24Hz 119869 = 24Hzpyridine-H) [34] (for 1H NMR data of other protons seeTable 1) 13C-NMR (125MHz) (DMSO-119889

6) 120575 (ppm) 190

219 (C-6 CH3) 372 392 (C-5 CH) 566 567 (C-2 CH)

1242 1243 (C13 CH) 1256 1257 (C9 C) 1279 1280 (C17CH) 1283 1285 (C20 CH) 1303 1305 (C19 CH) 13531354 (C18 CH) 1355 1358 (C15 C) 1361 1362 (C14 CH)1481 1486 (C16 C) 1492 1493 (C10 CH) 1535 1536 (C12CH) 1647 1648 (C-8 C=O) 1728 1732 (C-4 C=O) (fordesignations of carbons see Figure 3)

3 Results and Discussion

31 Chemistry Novel compounds 2andashf have been synthe-sized by the reaction of compounds 1andashf with racemic (plusmn)-2-sulfanylpropanoic acid in dry benzene (Figure 2)

The structures of the compounds were determined bymicroanalysis IR 1H-NMR 13C-NMR HMBC and ESI


N

NH

O

N CH

Ar + HS HC C

O

OH 2andashf

1andashf

Ar 4-chlorophenyl 4-bromophenyl 4-trifluoromethylphenyl 4-benzyloxyphenyl 3-methoxyphenyl 2-nitrophenyl

CH3C6H6

Figure 2 The preparation of compounds 2andashf

13

12N

10

914

8

HN N

4

5

S

2

15

20 19

18

1716

Br

O

O11

7

3H

1

6

H

H

HH3C

Figure 3 Selected HMBC correlations for 2b

mass spectrometry IR spectra of 2andashf showed common char-acteristic absorption bands at 3142ndash3176 cmminus1 (NH) 1707ndash1732 cmminus1 (thiazolidinone C=O) and 1670ndash1681 cmminus1 (NH-C=O) which provided evidence for the ring closure reactionbetween 1andashf and 2-sulfanylpropanoic acid Disappearanceof the peak at 8 ppm corresponding to N=CH proton of 1andashf [37] and the observation of C-2 proton of 2andashf at 588ndash630 ppm in the 1H-NMR spectra were also taken as the proofof the formation of thiazolidin-4-one ring

The structure of 2b was confirmed by the HMBC spec-trum in which the correlations of C-8 (120575C 1645 1646 ppm)with H-10 (120575H 886 ppm) H-14 (120575H 807 ppm) and N-H(H-7) (120575H 1094 1095 ppm) C-4 (120575C 1726 1727 ppm) withH-5 (120575H 412 422 ppm) and H-6 (120575H 154 155 ppm) andC-6 (120575C 206 202 ppm) with H-2 (120575H 590 ppm) H-5 (120575H412 422 ppm) and H-6 (120575H 154 155 ppm) enabled definiteassignment of CONH (C-8) and thiazolidinone C=O (C-4)carbons (Figure 3)

32 Stereochemical Investigations Due to the formation ofa new stereocenter at C-2 in principle four stereoisomerswere expected to form the following two enantiomeric (2S-5R2R-5S 2S-5S2R-5R) and two diastereomeric pairs (2S-5R2S-5S 2R-5S2R-5R) (Figure 4) In fact compounds 2andashf were obtained as mixtures of unequal composition of twodiastereomers which were differentiated by their 1H NMRspectra (Figure 5) It has been observed that the ratios ofthe major and minor diastereomers calculated from theintegration values of the C-5 methine proton signals were54 46 40 60 47 53 80 20 27 73 and48 52 for compounds 2andashf respectively 13C signals atC-2 C-4 C-5 and C-6 positions for compounds 2b and 2e

also appeared as double peaks in the HMBC spectra due tothe formation diastereoisomers (see Section 2) Chiral HPLCof compounds 2b and 2c on the Chiralpak AD-H columnresulted in four peaks (Figure 6) which further proved thepresence of four stereoisomers

For all diastereomeric compounds (Figure 4) it wasobserved that C-5 methine proton on the thiazolidinonemoiety was coupled with C-6 methyl protons and appearedas two quartets (Table 1 Figure 5) Similarly the signal of C-6methyl protons was coupled with C-5 methine and observedas two doublets for compounds 2bndash2f In all of the 1H NMRspectra of compounds2andash2f (except2b) the higher frequencysignals of C-5 methine appeared as a quartet of doublets dueto the long-range coupling with the C-2 proton The twodiastereotopic C-2 hydrogens could be observed separatelyonly for compounds 2cndash2f Aromatic protons of pyridyl andC-2 aryl rings gave signals between 69 and 90 ppm In thisregion some of the aromatic peaks corresponding to twodiastereomers could also be observed separately for all com-pounds (Figure 5) The N-H proton was observed at around11 ppm as two singlets with unequal integral ratios for com-pounds 2b 2c and 2f and only one singlet for 2a 2d and 2e

We have previously elucidated the stereostructures ofsome oxazolidine derivatives byNOESY experiment [38ndash40]The configurations of the major and minor stereoisomersof thiazolidin-4-one derivatives (2andash2f) were determinedby means of 1H NMR and NOESY spectra of compound2f The 1H NMR spectrum of 2f showed that the majordiastereomer had its C-5 methine signal (quartet) at a lowerfrequency (410 ppm 119869H-5CH3-6 = 70Hz) than the signalof the minor component (421 ppm qd 119869H-5CH3-6 = 70Hz119869H-5H-2 196Hz) The signal of C-2 proton of compound2f was observed as two separate signals (Δ120575 004 ppm)corresponding to two diastereomers a singlet at 626 ppm forthemajor diastereomer and a doublet at 622 ppm (4119869H-2H-5 =

196Hz) for the minor diastereomer The observed long-range coupling constant (4119869) of the doublet which is char-acteristic of trans protons [41] was consistent with that ofthe higher frequency quartet ofminor diastereomer Based onthese results the stereochemistry of the minor diastereomerwas assigned as 2S 5S or 2R 5R in which C-2 and C-5methine protons are trans to each other (Figure 4)

NOESY spectrum for compound 2f was taken in orderto further prove that the stereochemistry of the minor andthe major diastereomers was 2S 5S2R 5R and 2S 5R2R5S respectively (Figure 7) Observation of the cross peaks at


N

HN N

S

HO

OH

N

NH

N

S

HO

OH

N

NH

N

S

HO

OH

N

HN N

S

HO

OH

Enantiomers

Enantiomers

Diastereomers Diastereomers

R R

RR

2R 5S 2S 5R

2S 5S 2R 5R

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

H3C H3C

H3CH3C

R = Cl Br CF3 PhCH2O OCH3 NO2

Figure 4 The stereoisomers of compounds 2andashf

1234567891011

S

8080

20

20

S13

12 N10

9148

HN N

45

S

2

O

O

H

H

15

1

3

6

20 1918

1716O 21

7

11

2227 26

252423

H3C

Figure 5 500MHz 1H NMR spectrum of compound 2d in DMSO-1198896 S solvent


lowast

lowast clubsclubs150

100

50

0

(mAU

)

0 10 20 30 40 50

(min)

lowast

lowast

clubs

clubs

Retention time(min)25643

35772

37548

39537

Area ()

2023

2922

3066

1988

(a)

300

200

100

0

(mAU

)

0 5 10 15 20 25

(min)

lowast

lowast

clubsclubs

lowast

lowast

clubs

clubs


13626

14601

17427

Area ()

2370

2623

2707

2292

(b)Figure 6 (a) HPLC chromatogram of compound 2b (b) HPLC chromatogram of compound 2c Peaks marked with the same sign belong toenantiomers according to their areas Column Chiralpak AD-H eluent n-hexane 2-propanol (85 15) (v v) diode array detector

N

HN N

S

H

O

O

(a) (b)

(c) (d)

H

N

NH

N

S

H

O

OH

R R

2R 5S 2S 5S

lowast

lowast lowast

lowast

H3C H3C

C-5 methineMajor

Major

Minor

Minor

C-2 methine

629

628

627

626

625

624

623

622

F2

(ppm

)

F1 (ppm)395400405410415420425

F2

(ppm

)

F1 (ppm)

Ar-H

C-6 methyl

765770775780785790795

136

140

144

148

152

156

160

Major Minor

Minor

C-2 methine

F2

(ppm

)

F1 (ppm)

C-6 methyl

135140145150155160

623

622

621

620

619

618

617

616

C-5 methineMajor

Minor

F2

(ppm

)

F1 (ppm)

Ar-H

800

790

780

770

760

383940414243444546

Figure 7 Selected 2D NOESY correlations for compound 2f (solvent DMSO-1198896 400MHz)


Table 2 The configurations of C-2 and C-5 centers of major andminor diastereomers

Compounds Diastereomerratio

Configurations of C-2 and C-5Major

stereoisomerMinor

stereoisomer2a 54 46 2S 5S or 2R 5R 2S 5R or 2R 5S2b 60 40 2S 5R or 2R 5S 2S 5S or 2R 5R2c 53 47 2S 5R or 2R 5S 2S 5S or 2R 5R2d 80 20 2S 5S or 2R 5R 2S 5R or 2R 5S2e 73 27 2S 5R or 2R 5S 2S 5S or 2R 5R2f 52 48 2S 5R or 2R 5S 2S 5S or 2R 5R

626 ppm and 410 ppm in 2D NOESY spectrum indicatedthe spatial proximity of C-2 and C-5 methine hydrogens ofthemajor diastereomer (Figure 7(a)) Cross peaks at 152 ppmand 786 ppmalso revealed thatC-6methyl and the hydrogensof the aryl ring [42 43] of the major diastereomer arein close proximity (Figure 7(b)) These observations wereconsistent with the 2R 5S or 2S 5R configurations Similarlyfor the minor diastereomer cross peaks between the signalsof C-6 methyl and C-2 methine hydrogens were observed(Figure 7(c)) A NOESY correlation between C-5 methineand aromatic protons (Figure 7(d)) further confirmed thatthe configurations of C-2 and C-5 positions of the minordiastereomer were 2S 5S or 2R 5R Since the spectra of2andash2f have the feature in common by analogy it could beconcluded that all the deshielded signals of C-5 methinebelong to 2S 5S or 2R 5R stereoisomer (Table 1) Based onthese results the configurations of C-2 and C-5 centers of themajor and minor diastereomers are given in Table 2

The diastereomeric isomer ratios of compounds 2b and2c obtained by the integration of the 1H NMR signals havebeen found identical with those obtained by HPLC analysisTherefore with the knowledge of the configurations of the C-2 and C-5 centers of the major and minor diastereomers of2b and 2c the HPLC peaks (Figures 6(a) and 6(b)) markedby ldquoclubsrdquo could be assigned to 2S 5R or 2R 5S (major) and theothers to 2S 5S or 2R 5R (minor)

In order to determine the reason of the diastereoselectiv-ity of the synthesis samples of 2d and 2e were recrystallizedonce again from ethanol and the composition of crystalsprecipitated first was analyzed by NMR We have found adifferent composition for 2d and 2e Therefore the differentisomer ratios showed that the obvious diastereoselectivityupon recrystallization from ethanol was due to differentsolubilities of the diastereomeric isomers in ethanol whichwas observed previously [29 30 39 40] and not related to anyremarkable favorable attack during ring closure Neverthelessfractional crystallization of the product from ethanol allowedfor an easy access to diastereomerically enriched 2b 2d and2e (Table 2)

4 Conclusions

The reaction of aryl 1198731015840-(substituted benzylidene)pyridine-3-carbohydrazide with 2-mercaptopropanoic acid produced

mixtures of unequal composition of two diastereomeric119873-[2-(aryl)-5-methyl-4-oxo-13-thiazolidine-3-yl]-pyridine-3-carboxamide derivatives which were differentiated by 1HNMR spectra The configurations of C-2 and C-5 stereogeniccenters of thiazolidin-4-one ring for the major and theminor diastereomers have been found via one- and two-dimensional NMR spectroscopy Four stereoisomers ofcompounds 2b and 2c were resolved by chiral HPLC

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgment

This work was supported by the Istanbul University ScientificResearch Projects (Project no T-3691)

References

[1] E M Slominska A Yuen L Osman J Gebicki M H Yacouband R T Smolenski ldquoCytoprotective effects of nicotinamidederivatives in endothelial cellsrdquo Nucleosides Nucleotides andNucleic Acids vol 27 no 6-7 pp 863ndash866 2008

[2] AMoell O Skog E AhlinOKorsgren andG Frisk ldquoAntiviraleffect of nicotinamide on enterovirus-infected human isletsin vitro effect on virus replication and chemokine secretionrdquoJournal of Medical Virology vol 81 no 6 pp 1082ndash1087 2009

[3] A S Girgis H M Hosni and F F Barsoum ldquoNovel synthesisof nicotinamide derivatives of cytotoxic propertiesrdquo Bioorganicand Medicinal Chemistry vol 14 no 13 pp 4466ndash4476 2006

[4] C Spanka R Glatthar S Desrayaud et al ldquoPiperidyl amides asnovel potent and orally active mGlu5 receptor antagonists withanxiolytic-like activityrdquo Bioorganic and Medicinal ChemistryLetters vol 20 no 1 pp 184ndash188 2010

[5] A K Jain A Vaidya V Ravichandran S K Kashaw and RK Agrawal ldquoRecent developments and biological activities ofthiazolidinone derivatives a reviewrdquo Bioorganic and MedicinalChemistry vol 20 no 11 pp 3378ndash3395 2012

[6] A P Liesen T M de Aquino C S Carvalho et al ldquoSynthesisand evaluation of anti-Toxoplasma gondii and antimicrobialactivities of thiosemicarbazides 4-thiazolidinones and 134-thiadiazolesrdquo European Journal of Medicinal Chemistry vol 45no 9 pp 3685ndash3691 2010

[7] K Omar A Geronikaki P Zoumpoulakis et al ldquoNovel 4-thiazolidinone derivatives as potential antifungal and antibac-terial drugsrdquoBioorganic ampMedicinal Chemistry vol 18 no 1 pp426ndash432 2010

[8] A Kocabalkanli O Ates and G Otuk ldquoSynthesis of Mannichbases of some 25-disubstituted 4-thiazolidinones and evalua-tion of their antimicrobial activitiesrdquoArchiv der Pharmazie vol334 no 2 pp 35ndash39 2001

[9] M M Kamel H I Ali M M Anwar N A Mohamed andA M Soliman ldquoSynthesis antitumor activity and moleculardocking study of novel Sulfonamide-Schiff rsquos bases thiazolidi-nones benzothiazinones and their C-nucleoside derivativesrdquoEuropean Journal ofMedicinal Chemistry vol 45 no 2 pp 572ndash580 2010


[10] D Havrylyuk L Mosula B Zimenkovsky O Vasylenko AGzella and R Lesyk ldquoSynthesis and anticancer activity eval-uation of 4-thiazolidinones containing benzothiazole moietyrdquoEuropean Journal of Medicinal Chemistry vol 45 no 11 pp5012ndash5021 2010

[11] A A Bekhit H T Y Fahmy S A F Rostom and A E-D A Bekhit ldquoSynthesis and biological evaluation of somethiazolylpyrazole derivatives as dual anti-inflammatory antimi-crobial agentsrdquo European Journal of Medicinal Chemistry vol45 no 12 pp 6027ndash6038 2010

[12] A Kumar C S Rajput and S K Bhati ldquoSynthesis of 3-[41015840-(p-chlorophenyl)-thiazol-21015840-yl]-2-[(substituted azetidinonethia-zolidinone)-aminomethyl]-6-bromoquinazolin-4-ones as anti-inflammatory agentrdquo Bioorganic and Medicinal Chemistry vol15 no 8 pp 3089ndash3096 2007

[13] S K Bhati and A Kumar ldquoSynthesis of new substitutedazetidinoyl and thiazolidinoyl-134-thiadiazino (65-b) indolesas promising anti-inflammatory agentsrdquo European Journal ofMedicinal Chemistry vol 43 no 11 pp 2323ndash2330 2008

[14] K M Amin M M Kamel M M Anwar M Khedr andY N Syam ldquoSynthesis biological evaluation and moleculardocking of novel series of spiro [(2H3H) quinazoline-211015840-cyclohexan-4(1H)-one derivatives as anti-inflammatory andanalgesic agentsrdquo European Journal of Medicinal Chemistry vol45 no 6 pp 2117ndash2131 2010

[15] H Kaur S Kumar P Vishwakarma M Sharma K K Saxenaand A Kumar ldquoSynthesis and antipsychotic and anticonvulsantactivity of some new substituted oxathiadiazolylazetidinonylthiazolidinonylcarbazolesrdquo European Journal of MedicinalChemistry vol 45 no 7 pp 2777ndash2783 2010

[16] G Akula B Srinivas M Vidyasagar and S KandikondaldquoSynthesis of 3-(1H-benzimidazol-2-yl amino)2-phenyl-13-thiazolidin-4-one as potential CNS depressantrdquo InternationalJournal of PharmTech Research vol 3 pp 360ndash364 2011

[17] V Ravichandran A Jain K S Kumar H Rajak and R KAgrawal ldquoDesign synthesis and evaluation of thiazolidinonederivatives as antimicrobial and anti-viral agentsrdquo ChemicalBiology and Drug Design vol 78 no 3 pp 464ndash470 2011

[18] F Goktas E Vanderlinden L Naesens N Cesur and Z CesurldquoMicrowave assisted synthesis and anti-influenza virus activityof 1-adamantyl substituted N-(1-thia-4-azaspiro[45]decan-4-yl)carboxamide derivativesrdquo Bioorganic and Medicinal Chem-istry vol 20 no 24 pp 7155ndash7159 2012

[19] D Kini andMGhate ldquoSynthesis and oral hypoglycemic activityof3-[51015840-Methyl-21015840-aryl-31015840-(thiazol-210158401015840-yl amino)thiazolidin-4rsquo-one]coumarin derivativesrdquo European Journal of Chemistry vol8 no 1 pp 386ndash390 2011

[20] R MacCari A D Corso M Giglio R Moschini U Muraand R Ottan ldquoIn vitro evaluation of 5-arylidene-2-thioxo-4-thiazolidinones active as aldose reductase inhibitorsrdquo Bioor-ganic and Medicinal Chemistry Letters vol 21 no 1 pp 200ndash203 2011

[21] J M Beale and J H Block Wilson and Gisvoldrsquos Textbook ofOrganic Medicinal and Pharmaceutical Chemistry LippincottWilliams ampWilkins Philadelphia Pa USA 2011

[22] D Tasdemir A Karakucuk-Iyidogan M Ulasli T Taskin-TokE E Oruc-Emre and H Bayram ldquoSynthesis molecular model-ing and biological evaluation of novel chiral thiosemicarbazonederivatives as potent anticancer agentsrdquo Chirality vol 27 no 2pp 177ndash188 2015

[23] P S Shankar S Bigotti P Lazzari et al ldquoSynthesis and cytotoxi-city evaluation of diastereoisomers andN-terminal analogues of

tubulysin-Urdquo Tetrahedron Letters vol 54 no 45 pp 6137ndash61412013

[24] J Bauer M Vine I Coric et al ldquoImpact of stereochemistryon the biological activity of novel oleandomycin derivativesrdquoBioorganic and Medicinal Chemistry vol 20 no 7 pp 2274ndash2281 2012

[25] M Ohashi I Nakagome J-I Kasuga et al ldquoDesign syn-thesis and in vitro evaluation of a series of 120572-substitutedphenylpropanoic acid PPAR120574 agonists to further investigate thestereochemistryndashactivity relationshiprdquo Bioorganic and Medici-nal Chemistry vol 20 no 21 pp 6375ndash6383 2012

[26] M G Vigorita R Ottana F Monforte et al ldquoChiral 331015840-(12-ethanediyl)-bis[2-(34-dimethoxyphenyl)-4-thiazolidinones]with anti-inflammatory activity Part 11 evaluation of COX-2selectivity and modellingrdquo Bioorganic amp Medicinal Chemistryvol 11 no 6 pp 999ndash1006 2003

[27] T-D Tessema F Gassler Y Shu S Jones and B S SelinskyldquoStructuremdashactivity relationships in aminosterol antibioticsthe effect of stereochemistry at the 7-OH grouprdquo Bioorganic andMedicinal Chemistry Letters vol 23 no 11 pp 3377ndash3381 2013

[28] E D Gomez I Dogan M Yilmaz O Demir-Ordu D Albertand H Duddeck ldquoAtropisomeric 3-aryl-2-oxo-4-oxazolidino-nes and some thione analoguesmdashenantiodifferentiation and lig-and competition in applying the dirhodiummethodrdquo Chiralityvol 20 no 3-4 pp 344ndash350 2008

[29] S Erol and I Dogan ldquoDetermination of barriers to rotation ofaxially chiral 5-methyl-2-(o-aryl)imino-3-(o-aryl)thiazolidine-4-onesrdquo Chirality vol 24 no 6 pp 493ndash498 2012

[30] S Erol and I Dogan ldquoAxially chiral 2-arylimino-3-aryl-thiazolidine-4-one derivatives enantiomeric separation anddetermination of racemization barriers by chiral HPLCrdquo Jour-nal of Organic Chemistry vol 72 no 7 pp 2494ndash2500 2007

[31] S Erol and I Dogan ldquoStereochemical assignments of aldol pro-ducts of 2-arylimino-3-aryl-thiazolidine-4-ones by 1H NMRrdquoMagnetic Resonance in Chemistry vol 50 no 5 pp 402ndash4052012

[32] O Demir-Ordu E M Yilmaz and I Dogan ldquoDeterminationof the absolute stereochemistry and the activation barriers ofthermally interconvertible heterocyclic compounds bearing anaphthyl substituentrdquo Tetrahedron Asymmetry vol 16 no 22pp 3752ndash3761 2005

[33] S Ozkırımlı F Kazan and Y Tunali ldquoSynthesis antibac-terial and antifungal activities of 3-(124-triazol-3- yl)-4-thiazolidinonesrdquo Journal of Enzyme Inhibition and MedicinalChemistry vol 24 no 2 pp 447ndash452 2009

[34] M Akkurt I Celik H Demir S Ozkrml and O Buyukgun-gor ldquoN-[5-Methyl-2-(2-nitrophenyl)-4-oxo-13-thiazolidin-3-yl]pyridine-3-carboxamidemonohydraterdquoActaCrystallograph-ica Section E vol 67 no 2 pp o293ndasho294 2011

[35] M Akkurt I Celik H Demir S Ozkırımlı and O Buyukgun-gor ldquoN-[2-(4-chlorophenyl)-5-methyl-4-oxo-13-thiazolidin-3-yl]pyridine-3-carboxamiderdquo Acta Crystallographica Section Evol 67 pp o745ndasho746 2011

[36] M Akkurt I Celik H Demir S Ozkırımlı and O Buyukgun-gor ldquoN-[2-(4-bromophenyl)-5-methyl-4-oxo-13-thiazolidin-3-yl]pyridine-3-carboxamiderdquo Acta Crystallographica Section Evol 67 pp o914ndasho915 2011

[37] A Solankee P Solankee and H Patel ldquoSynthesis of somenovel hydrazones and their thiazolidine-4-onesrdquo InternationalJournal of Chemical Sciences vol 6 pp 1017ndash1020 2008

[38] O Demir-Ordu and I Dogan ldquoAxially chiral N-(o-aryl)-4-hydroxy-2-oxazolidinone derivatives from diastereoselective


reduction ofN-(o-aryl)-24-oxazolidinediones thermally inter-convertible atropisomers via ring-chain-ring tautomerizationrdquoChirality vol 22 no 7 pp 641ndash654 2010

[39] O Demir-Ordu and I Dogan ldquoStereoselective lithiation andalkylation and aldol reactions of chiral 5-methyl-3-(o-aryl)-oxazolidinonesrdquo Tetrahedron Asymmetry vol 21 no 20 pp2455ndash2464 2010

[40] O Demir and I Dogan ldquoConformational preferences indiastereomeric (5s)-methyl-3-(o-aryl)-24-oxazolidinedionesrdquoChirality vol 15 no 3 pp 242ndash250 2003

[41] V P M Rahman S Mukhtar W H Ansari and G LemiereldquoSynthesis stereochemistry and biological activity of somenovel long alkyl chain substituted thiazolidin-4-ones andthiazan-4-one from 10-undecenoic acid hydraziderdquo EuropeanJournal of Medicinal Chemistry vol 40 no 2 pp 173ndash184 2005

[42] K M Khan M Rasheed Z Ullah et al ldquoSynthesis and in vitroleishmanicidal activity of some hydrazides and their analoguesrdquoBioorganic andMedicinal Chemistry vol 11 no 7 pp 1381ndash13872003

[43] D Williams and I Fleming Spectroscopic Methods in OrganicChemistry McGraw-Hill Book Company London UK 1989

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


Table 1 1H NMR (500MHz) data of compounds 2andash2f in DMSO-1198896a

Entry C-6 methyl C-5 methine C-2 methine CO-NH

2a 155 (d 119869 = 70Hz) 413 (qd 119869 = 70Hz 097Hz)423 (qd 119869 = 70 147Hz)b 592 (s) 1094 (s)

2b 154 (d 119869 = 70)155 (d 119869 = 68Hz)

412 (q 119869 = 68Hz)b422 (q 119869 = 68Hz)c 590 (s) 1094 (s)

1095 (s)

2c 155 (d 119869 = 73Hz)157 (d 119869 = 73Hz)

415 (q 119869 = 68Hz)b425 (qd 119869 = 68 147Hz)

601 (d 119869 = 147Hz)602 (s)

1099 (s)1101 (s)

2d 153 (d 119869 = 73Hz)155 (d 119869 = 73Hz)

410 (q 119869 = 73Hz)416 (qd 119869 = 73 147Hz)b

587 (s)588 (d 119869 = 147Hz) 1090 (s)

2e 154 (d 119869 = 73)155 (d 119869 = 68Hz)

411 (q 119869 = 68Hz)b418 (qd 119869 = 68 146Hz)

589 (s)590 (s) 1097 (s)

2f 148 (d 119869 = 73)152 (d 119869 = 68Hz)

410 (q 119869 = 70Hz)b421 (qd 119869 = 70 196Hz)

622 (d 119869 = 196Hz)626 (s)

1104 (s)1105 (s)

aFor 1H NMR data of the other protons see Section 2bThe signals corresponding to major diastereomercCoupling with C-2 methine was observed as a shoulder

NH

N

SO

R

123

45

O

N6

2a R 4-Cl2b R 4-Br

CH3

2c R 4-CF3

2d R 4-OCH2Ph2e R 3-OCH32f R 2-NO2

Figure 1 The synthesized compounds 2andashf

operating at 4997MHz for 1H and 1249MHz for 13C usingtetramethylsilane (TMS) as an internal standard Chemicalshifts (120575) were reported in parts per million (ppm) Spectralwidths of 14 and 230 ppm were used in 1H and 13C NMRrespectivelyThe splitting patterns of 1HNMRwere designedas follows s singlet d doublet q quartet qd quartet ofdoublets dd doublet of doublets and m multiplet NOESYexperiment was performed on a Varian-Mercury VX-400-BB (spectrometer frequency 39998MHz temperature 24∘Crelaxation delay 20 sec acquisition time 015 sec numberof increments the number of points in t1 200 numberof points in each FID (t2) 1920 and spectral width 1Hchannel 14 ppm) HMBC experiment was performed ona Varian-Unity Inova 500 spectrometer (spectrometer fre-quency 4997MHz temperature 30∘C relaxation delay10 sec acquisition time 0128 sec 400 increments and spec-tral width 1H channel 14 ppm 13C channel 230 ppm)IR analyses were performed on a Shimadzu IR Affinity-I FTIR using KBr discs peaks are reported in cmminus1 UVanalyses were performed on ShimadzuUV-1601 wavelengthsare reported in nm Liquid chromatography analyses wereperformed on Shimadzu SCL-10AVP with a diode arraydetector and using ChiralpakAD column (particle size 5120583mcolumn size 250times 46mm) Eluentwas n-hexane 2-propanol(85 15) (v v) with a flow rate of 09mLminminus1 Reactions

were followed by TLC using silica gel 60-F254

Elementalanalyses were performed on Thermo Finnigan Flash EA1112 CHNS-932 analyzer Melting points were recorded usingBuchi B-540 melting point apparatus The mass spectra wereobtained using Finnigan LCQ Advantage Max Waters 2695Alliance Micromass ZQ

211 General Procedure for the Preparation of N-[2-(Aryl)-5-methyl-4-oxo-13-thiazolidine-3-yl]-pyridine-3-carboxamidesTo a suspension of 001mol of aryl 1198731015840-(substituted benzyl-idene)pyridine-3-carbohydrazide (1andashf) in 30mL dry benzene was added 25mL (0028mol) of 2-sulfanylpropanoicacid The mixture was refluxed for 6ndash18 hours using a Dean-Stark trap Excess benzene was evaporated in vacuo Theresulting residue was triturated with NaHCO

3solution until

CO2evolution ceased and was allowed to stand refrigerated

until solidification The solid thus obtained was washed withwater dried and recrystallized from ethanol

Some spectral and X-ray crystallographic data of com-pounds 2a 2b and 2f were reported regardless of stereo-chemistry in our previously published articles [34ndash36]

212 N-[2-(4-Chlorophenyl)-5-methyl-4-oxo-13-thiazolidin-3-yl]-pyridine-3-carboxamide (2a) Diastereomer ratio (majorminor) 54 46 1H-NMR (500MHz DMSO-119889

6) 120575 743ndash747

(2H m phenyl-H) 748ndash750 (1H m pyridine-H) 752-753(2H m phenyl-H) 804ndash809 (1H m pyridine-H) 873(1H dd 119869 = 63Hz 14Hz pyridine-H) 884 885 (1H 2d119869 = 29Hz 14Hz pyridine-H) [35] (for 1H NMR data ofother protons see Table 1) 13C-NMR (125MHz) (DMSO-119889

6)

120575 (ppm) 206 (C-6 CH3) 398 399 (C-5 CH) 604 606 (C-

2 CH) 1243 1244 (C13 CH) 1279 1280 (C9 C) 1293 1294(C16 20 CH) 1304 1307 (C17 19 CH) 1342 1344 (C18 C)1359 1360 (C14 CH) 1372 1381 (C15 C) 1491 1492 (C10CH) 1535 1536 (C12 CH) 1645 1646 (C-8 C=O) 17251726 (C-4 C=O) (for designations of carbons see Figure 3)

213 N-[2-(4-Bromophenyl)-5-methyl-4-oxo-13-thiazolidin-3-yl]-pyridine-3-carboxamide (2b) Diastereomer ratio (majorminor) 60 40 1H-NMR (500MHz DMSO-119889

6) 120575 744ndash746



6) 120575 (ppm) 202 (CH

3 C-6

60) 206 (CH3 C-6 40) 397 (CH C-5 40) 398 (CH



6) 120575 749ndash751


6)

120575 202 203 (C-6 CH3) 386 392 (C-5 CH) 601 604 (C-

2 CH) 1242 1243 (C13 CH) 1246 (CF3 q 119869 = 271Hz)


H 392 N 1096


6) 120575 508





6) 120575 200 (CH

3

C-6 20) 208 (CH3 C-6 80) 398 (CH C-5 20) 399

(CH C-5 80) 608 (CH C-2) 700 (CH2 C21) 1155 (C17



23H21N3O3S C 6447 H 517 N 981 Found C

6463 H 506 N 976


6) 120575 374



6)

120575 202 (CH3 C-6 73) 206 (CH

3 C-6 27) 398 (CH

C-5 27) 399 (CH C-5 73) 558 (OCH3) 609 (CH


5647 H 477 N 1150


6) 120575 751


6) 120575 (ppm) 190

219 (C-6 CH3) 372 392 (C-5 CH) 566 567 (C-2 CH)






N

NH

O

N CH

Ar + HS HC C

O

OH 2andashf

1andashf


CH3C6H6


13

12N

10

914

8

HN N

4

5

S

2

15

20 19

18

1716

Br

O

O11

7

3H

1

6

H

H

HH3C











N

HN N

S

HO

OH

N

NH

N

S

HO

OH

N

NH

N

S

HO

OH

N

HN N

S

HO

OH

Enantiomers

Enantiomers


R R

RR

2R 5S 2S 5R

2S 5S 2R 5R

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

H3C H3C

H3CH3C



1234567891011

S

8080

20

20

S13

12 N10

9148

HN N

45

S

2

O

O

H

H

15

1

3

6

20 1918

1716O 21

7

11

2227 26

252423

H3C



lowast


100

50

0

(mAU

)

0 10 20 30 40 50

(min)

lowast

lowast

clubs

clubs


35772

37548

39537

Area ()

2023

2922

3066

1988

(a)

300

200

100

0

(mAU

)

0 5 10 15 20 25

(min)

lowast

lowast

clubsclubs

lowast

lowast

clubs

clubs


13626

14601

17427

Area ()

2370

2623

2707

2292


N

HN N

S

H

O

O

(a) (b)

(c) (d)

H

N

NH

N

S

H

O

OH

R R

2R 5S 2S 5S

lowast

lowast lowast

lowast

H3C H3C

C-5 methineMajor

Major

Minor

Minor

C-2 methine

629

628

627

626

625

624

623

622

F2

(ppm

)

F1 (ppm)395400405410415420425

F2

(ppm

)

F1 (ppm)

Ar-H

C-6 methyl

765770775780785790795

136

140

144

148

152

156

160

Major Minor

Minor

C-2 methine

F2

(ppm

)

F1 (ppm)

C-6 methyl

135140145150155160

623

622

621

620

619

618

617

616

C-5 methineMajor

Minor

F2

(ppm

)

F1 (ppm)

Ar-H

800

790

780

770

760

383940414243444546






stereoisomerMinor





4 Conclusions





Acknowledgment


References

























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



6) 120575 (ppm) 202 (CH

3 C-6

60) 206 (CH3 C-6 40) 397 (CH C-5 40) 398 (CH



6) 120575 749ndash751


6)

120575 202 203 (C-6 CH3) 386 392 (C-5 CH) 601 604 (C-

2 CH) 1242 1243 (C13 CH) 1246 (CF3 q 119869 = 271Hz)


H 392 N 1096


6) 120575 508





6) 120575 200 (CH

3

C-6 20) 208 (CH3 C-6 80) 398 (CH C-5 20) 399

(CH C-5 80) 608 (CH C-2) 700 (CH2 C21) 1155 (C17



23H21N3O3S C 6447 H 517 N 981 Found C

6463 H 506 N 976


6) 120575 374



6)

120575 202 (CH3 C-6 73) 206 (CH

3 C-6 27) 398 (CH

C-5 27) 399 (CH C-5 73) 558 (OCH3) 609 (CH


5647 H 477 N 1150


6) 120575 751


6) 120575 (ppm) 190

219 (C-6 CH3) 372 392 (C-5 CH) 566 567 (C-2 CH)






N

NH

O

N CH

Ar + HS HC C

O

OH 2andashf

1andashf


CH3C6H6


13

12N

10

914

8

HN N

4

5

S

2

15

20 19

18

1716

Br

O

O11

7

3H

1

6

H

H

HH3C











N

HN N

S

HO

OH

N

NH

N

S

HO

OH

N

NH

N

S

HO

OH

N

HN N

S

HO

OH

Enantiomers

Enantiomers


R R

RR

2R 5S 2S 5R

2S 5S 2R 5R

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

H3C H3C

H3CH3C



1234567891011

S

8080

20

20

S13

12 N10

9148

HN N

45

S

2

O

O

H

H

15

1

3

6

20 1918

1716O 21

7

11

2227 26

252423

H3C



lowast


100

50

0

(mAU

)

0 10 20 30 40 50

(min)

lowast

lowast

clubs

clubs


35772

37548

39537

Area ()

2023

2922

3066

1988

(a)

300

200

100

0

(mAU

)

0 5 10 15 20 25

(min)

lowast

lowast

clubsclubs

lowast

lowast

clubs

clubs


13626

14601

17427

Area ()

2370

2623

2707

2292


N

HN N

S

H

O

O

(a) (b)

(c) (d)

H

N

NH

N

S

H

O

OH

R R

2R 5S 2S 5S

lowast

lowast lowast

lowast

H3C H3C

C-5 methineMajor

Major

Minor

Minor

C-2 methine

629

628

627

626

625

624

623

622

F2

(ppm

)

F1 (ppm)395400405410415420425

F2

(ppm

)

F1 (ppm)

Ar-H

C-6 methyl

765770775780785790795

136

140

144

148

152

156

160

Major Minor

Minor

C-2 methine

F2

(ppm

)

F1 (ppm)

C-6 methyl

135140145150155160

623

622

621

620

619

618

617

616

C-5 methineMajor

Minor

F2

(ppm

)

F1 (ppm)

Ar-H

800

790

780

770

760

383940414243444546






stereoisomerMinor





4 Conclusions





Acknowledgment


References

























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

NH

O

N CH

Ar + HS HC C

O

OH 2andashf

1andashf


CH3C6H6


13

12N

10

914

8

HN N

4

5

S

2

15

20 19

18

1716

Br

O

O11

7

3H

1

6

H

H

HH3C











N

HN N

S

HO

OH

N

NH

N

S

HO

OH

N

NH

N

S

HO

OH

N

HN N

S

HO

OH

Enantiomers

Enantiomers


R R

RR

2R 5S 2S 5R

2S 5S 2R 5R

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

H3C H3C

H3CH3C



1234567891011

S

8080

20

20

S13

12 N10

9148

HN N

45

S

2

O

O

H

H

15

1

3

6

20 1918

1716O 21

7

11

2227 26

252423

H3C



lowast


100

50

0

(mAU

)

0 10 20 30 40 50

(min)

lowast

lowast

clubs

clubs


35772

37548

39537

Area ()

2023

2922

3066

1988

(a)

300

200

100

0

(mAU

)

0 5 10 15 20 25

(min)

lowast

lowast

clubsclubs

lowast

lowast

clubs

clubs


13626

14601

17427

Area ()

2370

2623

2707

2292


N

HN N

S

H

O

O

(a) (b)

(c) (d)

H

N

NH

N

S

H

O

OH

R R

2R 5S 2S 5S

lowast

lowast lowast

lowast

H3C H3C

C-5 methineMajor

Major

Minor

Minor

C-2 methine

629

628

627

626

625

624

623

622

F2

(ppm

)

F1 (ppm)395400405410415420425

F2

(ppm

)

F1 (ppm)

Ar-H

C-6 methyl

765770775780785790795

136

140

144

148

152

156

160

Major Minor

Minor

C-2 methine

F2

(ppm

)

F1 (ppm)

C-6 methyl

135140145150155160

623

622

621

620

619

618

617

616

C-5 methineMajor

Minor

F2

(ppm

)

F1 (ppm)

Ar-H

800

790

780

770

760

383940414243444546






stereoisomerMinor





4 Conclusions





Acknowledgment


References

























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

HN N

S

HO

OH

N

NH

N

S

HO

OH

N

NH

N

S

HO

OH

N

HN N

S

HO

OH

Enantiomers

Enantiomers


R R

RR

2R 5S 2S 5R

2S 5S 2R 5R

lowast

lowast

lowast

lowast

lowast

lowast

lowast

lowast

H3C H3C

H3CH3C



1234567891011

S

8080

20

20

S13

12 N10

9148

HN N

45

S

2

O

O

H

H

15

1

3

6

20 1918

1716O 21

7

11

2227 26

252423

H3C



lowast


100

50

0

(mAU

)

0 10 20 30 40 50

(min)

lowast

lowast

clubs

clubs


35772

37548

39537

Area ()

2023

2922

3066

1988

(a)

300

200

100

0

(mAU

)

0 5 10 15 20 25

(min)

lowast

lowast

clubsclubs

lowast

lowast

clubs

clubs


13626

14601

17427

Area ()

2370

2623

2707

2292


N

HN N

S

H

O

O

(a) (b)

(c) (d)

H

N

NH

N

S

H

O

OH

R R

2R 5S 2S 5S

lowast

lowast lowast

lowast

H3C H3C

C-5 methineMajor

Major

Minor

Minor

C-2 methine

629

628

627

626

625

624

623

622

F2

(ppm

)

F1 (ppm)395400405410415420425

F2

(ppm

)

F1 (ppm)

Ar-H

C-6 methyl

765770775780785790795

136

140

144

148

152

156

160

Major Minor

Minor

C-2 methine

F2

(ppm

)

F1 (ppm)

C-6 methyl

135140145150155160

623

622

621

620

619

618

617

616

C-5 methineMajor

Minor

F2

(ppm

)

F1 (ppm)

Ar-H

800

790

780

770

760

383940414243444546






stereoisomerMinor





4 Conclusions





Acknowledgment


References

























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


lowast


100

50

0

(mAU

)

0 10 20 30 40 50

(min)

lowast

lowast

clubs

clubs


35772

37548

39537

Area ()

2023

2922

3066

1988

(a)

300

200

100

0

(mAU

)

0 5 10 15 20 25

(min)

lowast

lowast

clubsclubs

lowast

lowast

clubs

clubs


13626

14601

17427

Area ()

2370

2623

2707

2292


N

HN N

S

H

O

O

(a) (b)

(c) (d)

H

N

NH

N

S

H

O

OH

R R

2R 5S 2S 5S

lowast

lowast lowast

lowast

H3C H3C

C-5 methineMajor

Major

Minor

Minor

C-2 methine

629

628

627

626

625

624

623

622

F2

(ppm

)

F1 (ppm)395400405410415420425

F2

(ppm

)

F1 (ppm)

Ar-H

C-6 methyl

765770775780785790795

136

140

144

148

152

156

160

Major Minor

Minor

C-2 methine

F2

(ppm

)

F1 (ppm)

C-6 methyl

135140145150155160

623

622

621

620

619

618

617

616

C-5 methineMajor

Minor

F2

(ppm

)

F1 (ppm)

Ar-H

800

790

780

770

760

383940414243444546






stereoisomerMinor





4 Conclusions





Acknowledgment


References

























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





stereoisomerMinor





4 Conclusions





Acknowledgment


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










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

Documents

Research Article Stereochemical Investigations of ...downloads.hindawi.com/archive/2015/609250.pdf · Nuclear Magnetic Resonance Spectroscopy (1D and 2D) ÖznurDemir-Ordu, 1 HaleDemir-Dündar,