Synthesis and biological evaluation of novel resveratrol-oxadiazole hybrid heterocycles as potential antiproliferative agents

MEDICINAL

CHEMISTRY

RESEARCH

Med Chem Res

DOI 10.1007/s00044-016-1514-1

ORIGINAL RESEARCH

Synthesis and biological evaluation of novel resveratrol-oxadiazole

hybrid heterocycles as potential antiproliferative agents

M. S. R. Murty¹Raju Penthala¹Sowjanya Polepalli²N. Jain²

•

Received: 19 March 2015 / Accepted: 21 January 2016

Ó Springer Science+Business Media New York 2016

Abstract A novel class of resveratrol-oxadiazole hybrid

compounds was synthesized to screen for their in vitro

antiproliferative activity against three human cancer cell

lines. All the compounds showed superior antiproliferative

activity than the reference compound resveratrol. The most

promising active compounds in this series were 1g, 2g, 1c,

2c, 2i and 1a (GI₅₀\ 0.1 lM), endowed with excellent

antiproliferative activity. Thus, we believe that resveratrol-

oxadiazole hybrid compounds may possibly be used as a

good leads for the development of new antiproliferative

agents. Structures of newly synthesized compounds were

conﬁrmed by NMR and IR spectral data.

nature and have become of particular interest to chemists

and biologists because of their wide range of biological

activities, usually associated with low toxicity, and form an

elite class of compounds which occupy a special role in

nature. Indeed, a large number of polyphenolic stilbenes

are having various pharmacological activities which have

been isolated from a variety of plant sources. Some rele-

vant polyphenolic stilbenes such as resveratrol (1) [anti

cancer activity] (Mgbonyebi et al., 1998), chiricanine A

(2), arahypin-1(3), arahypin-5 (4), trans-arachidin-2 (5),

trans-arachidin-3 (6) [antifungal activity] (Park et al.,

2011), rhapontigenin (7) [breast cancer activity] (Kim

et al., 2014), pawhuskin A (8), pawhuskin C (9) [opioid

receptor antagonists] (Hartung et al., 2014), gigantol (10)

[lung cancer activity] (Charoenrungruang et al., 2014) and

2,3,5,4⁰-tetrahydroxystilbene-2-O-b-D-glucopyranoside

(11) [tyrosinase inhibitory activity] (Cheung et al., 2014)

are shown in Fig. 1.

Keywords Resveratrol Á 1 Á 3 Á 4-Oxadiazole 2-thione Á

Molecular hybridization Á Antiproliferative activity

Introduction

In particular, resveratrol has received great interest in

drug discovery mainly due to its potent activity for the

treatment of various types of cancer and good safety pro-

ﬁle. It has shown potential anticancer activity at the initi-

ation, promotion, and progression stages (Jang et al.,

1997). This was evidenced by its in vitro and in vivo

inhibitory effects on the growth of a number of tumor cell

lines including lymphoma, myeloma, melanoma, breast,

pancreatic, colorectal, hepatocellular and prostate carci-

noma (Jazirehi and Bonavida, 2004; Udenigwe et al.,

2008).

Natural products represent a signiﬁcant source of inspira-

tion for the designing of new biologically important

molecules with enhanced pharmacological proﬁle.

Polyphenols bearing the stilbene moiety widely occur in

Electronic supplementary material The online version of this

article (doi:10.1007/s00044-016-1514-1) contains supplementary

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& M. S. R. Murty

msrmurty@ymail.com

Resveratrol has also possessed numerous biological

activities that result in antioxidant (Burns et al., 2000),

anti-inﬂammatory (Udenigwe et al., 2008), inhibition of

platelet aggregation (Pace-Asciak et al., 1995), antitumor

(Savouret and Quesne, 2002), induction of apoptosis

1

Medicinal Chemistry and Pharmacology Division, Discovery

Laboratory, Indian Institute of Chemical Technology, Uppal

Road, Hyderabad 500007, India

2

Centre for Chemical Biology, Indian Institute of Chemical

Technology, Uppal Road, Hyderabad 500007, India

¨

(Dorrie et al., 2001; Roberti et al., 2003), antifungal

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Med Chem Res

Fig. 1 Natural occurring biological active molecules that comprising poly phenolic stilbene moiety

´

(Houille et al., 2014) and analgesic activity (Bazzo et al.,

compound and 3,5-dimethoxy-4-aminostilbene [an ana-

logue of pterostilbene (compound-9)] has been reported to

be more potent antiproliferative than resveratrol (Roberti

et al., 2003). This inherent biological relevance has

attracted much interest in the drug discovery ﬁeld, and the

methoxy derivatives of resveratrol (especially compound-9

and compound-15) emerged as valuable molecular tem-

plates for the design and development of a variety of novel

hybrid analogues.

2013). Nevertheless, various studies have documented that

resveratrol, despite an efﬁcient absorption by the organism,

unfortunately has low bioavailability and require a high

dose to induce apoptosis in cancer cells (Walle et al., 2004;

Cecchinato et al., 2007). Therefore, it is an essential

requirement to improve the pharmacokinetic properties of

resveratrol and to extend its anticancer activity. To achieve

this goal, several synthetic analogues such as 3,5,4⁰-tri-

methoxy-trans-stilbene (MR-3), 3,4,5,4⁰-tetramethoxy-

trans-stilbene (MR-4, DMU-212) (Paul et al., 2010),

3,5,3⁰,4⁰,5⁰-pentamethoxy-trans-stilbene (MR-5) (Pan et al.,

2010) and 2,3⁰,4,4⁰,5⁰-pentamethoxy-trans-stilbene (PMS)

(Li et al., 2009) have been synthesized and tested against a

variety of cancer cell lines in vitro and in vivo (Paul et al.,

2010). It has been observed that methoxy derivatives of

resveratrol exhibit better antiproliferative activity (Roberti

et al., 2003). However, minor attention was devoted to the

lipophilic analogues like 3,5-dimethoxy-4-hydroxystil-

bene[pterostilbene(compound-15)] (Rimando et al., 2002)

has demonstrated the cancer chemo preventive active

On the other hand 1,3,4-oxadiazole has become an

important building motif for the development of new drugs.

Compounds containing 1,3,4-oxadiazole cores have a

broad biological activity spectrum, including anticancer,

antibacterial, antifungal, analgesic, anti-inﬂammatory,

antiviral, antihypertensive, anticonvulsant and anti-diabetic

properties (Oliveira et al., 2012).

Over the last few years with the progress of the

medicinal chemistry, the molecular hybridization approach

has received signiﬁcant attention, since it is a drug dis-

covery strategy and involves the rational design of new

chemical entities (NCEs) by the fusion of two drugs or

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Med Chem Res

pharmacophoric units (Murty et al., 2014). It is anticipated

that such an approach may solve the problem of drug

resistance by showing dual drug action. Using this

approach, several research groups have recently designed

and synthesized hybrid molecules by coupling resveratrol

with other biologically active molecules such as coumarins,

chalcones, curcumin, etc. (Belluti et al., 2010; Shen et al.,

2013; Kumar et al., 2014; Ruan et al., 2011).

bromides (10 and 11) and 1,3,4-oxadiazole 2-thiones 19(a–

j)] were synthesized from commercially available starting

materials.

In practice, the synthetic plan was executed for the

synthesis of resveratrol bromides (10 and 11) in the fol-

lowing steps (Schemes 1, 2) (Lee et al., 2012). In these

steps, ﬁrst 3,5-dimethoxybenzaldehyde (3) was chosen as

a starting material and it was reduced to (3,5-dimethox-

yphenyl)methanol (4) with NaBH₄in methanol. This

product was subsequently converted to 1-(bromomethyl)-

3,5-dimethoxybenzene (5) in the presence of PBr₃. The

required organophosphonate ester (6) has been tradition-

ally obtained through a Michaelis-Arbuzov reaction (Ar-

buzov, 1964). The two Wittig products (8 and 14) were

prepared via Wadsworth–Emmons reaction (Wadsworth

and Emmons, 1961) of organophosphonate ester (6) with

corresponding aldehydes (4-nitrobenzaldehyde (7) and

4-(methoxymethoxy)benzaldehyde (13)) in the presence

of t-BuOK and DMF. In these reactions, only the E-iso-

mers (8 and 14) were obtained because of steric hindrance

on both aromatic groups, and we are conﬁrmed that E-

In view of the facts mentioned above, our research’s

ultimate aim is developing novel drug-like molecules from

molecular hybridization. The present work includes

designing, and synthesizes a series of novel hybrid hete-

rocycles, that comprise the resveratrol and oxadiazole

moieties in a single molecule. Such hybridization was

designed to investigate the effect of structural variation on

the antiproliferative activity.

Results and discussion

Chemistry

1

isomers based on H NMR analysis (J = 16.0–17.0 Hz,

The synthetic routes for the novel resveratrol-oxadiazole

analogous were shown in Scheme 1, 2, 3 and 4. Resveratrol-

oxadiazole analogous were prepared from reaction of

resveratrol bromides (10 and 11) with 1,3,4-oxadiazole

2-thiones 19(a–j). These two coupling partners [Resveratrol

Styrylvinyl protons) (Yu et al., 2002). One of the Wittig

products (8) the Nitro group was reduced to amine (9)

with SnCl₂, and this amine (9) was acylated with bro-

moacetyl bromide in the presence of triethylamine to

yielded amide (10).

Scheme 1 Synthesis of resveratrol a-bromoamide. Reagents and

conditions: a NaBH₄, MeOH, 0 °C to rt, 2 h; b PBr₃, Et₂O, 0 °C

e SnCl₂.2H₂O, Conc. HCl, EtOH, 80 °C, 2 h; f Bromoacetyl bromide,

Et₃N, DCM, 0 °C, 20 min to 1 h

30 min;

c

P(OEt)₃, 160 °C, 4 h;

d t-BuOK, DMF, rt, 1 h;

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Med Chem Res

Scheme 2 Synthesis of resveratrol a-bromoester. Reagents and conditions a MOMCl, DIPEA, THF, 65 °C, 20 h; b 6, t-BuOK, DMF, rt, 1 h;

c 6 N HCl, THF, rt, 1 h; d Bromoacetyl bromide, Et₃N, DCM, 0 °C, 20 min to 1 h

Scheme 3 Synthesis of 1,3,4-oxadiazole 2-(3H)-thiones. Reagents and conditions a MeOH, H₂SO₄reﬂux, 6 h; b NH₂NH₂.H₂O, MeOH, reﬂux,

5 h; c CS₂/KOH, EtOH, HCl reﬂux, 10-12 h

Scheme 4 Coupling strategy of resveratrol a-bromoamide/a-bromoester with 1,3,4-oxadiazole 2-thiones. Reagent and condition a 19(a–j),

K₂CO₃, CH₃CN, rt, 30 min to 1 h

In the Wittig product (14), MOM group was depro-

tected to produce phenol (15), which was subsequently

reacted with bromoacetyl bromide in the presence of tri-

ethylamine to provide ester (11).

The synthetic route for the 1,3,4-oxadiazole 2-thiones

19(a–j) is outlined in Scheme 3 (Li et al., 2006). Com-

pounds 19(a–j) were synthesized from a variety of com-

mercially available aromatic and hetero aromatic

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Med Chem Res

carboxylic acids 16(a–j). Esteriﬁcation of carboxylic acids

16(a–j) with methanol in concentrated sulfuric acid affor-

ded the corresponding esters 17(a–j). These esters were

conﬁrmed by the disappearance of broad carboxylic acid

peak and also appearance of ‘‘O–CH₃’’ peak at d 3.82 ppm

Collection) using the sulforhodamine B (SRB) assay

method (Reddy et al., 2011). Resveratrol was used as

standard drug. The GI₅₀values (GI₅₀= molar concentra-

tion of the compound that inhibits 50 % net cell growth)

are listed in Table 1.

1

in the H NMR spectrum. In the next step, esters were

From the screening results in Table 1, it was observed that

all the compounds 1(a–j) and 2(a–j) possessed antiprolifer-

ative activities against these cell lines in a concentration-

dependent manner and were found to be more active than

resveratrol. The 3-(triﬂuoromethyl)phenyl (1g and 2g)

compounds exhibited superior broad-spectrum antiprolifer-

ative activity against the three cell lines with GI₅₀values of

\0.1 lM. The 2-ﬂuorophenyl (1c and 2c), 4-methoxyphenyl

(2i) and 3,4,5-trimethoxyphenyl (1a) compounds are more

potent against SiHa and PANC-1 cell lines, respectively,

with GI₅₀values of \0.1 lM, while the compounds

4-methoxyphenyl (1i), 3,4,5-trimethoxyphenyl (2a) and

4-(triﬂuoromethyl)phenyl (1f and 2f), 4-ﬂuorophenyl

(2e)show antiproliferative activities against SiHa and MDA-

MB-231 cell lines respectively at concentrations of[1 lM.

Based on these results, the presence of 3-(triﬂuo-

romethyl)phenyl (1g and 2g), 2-ﬂuorophenyl (1c and 2c)

(electronegative) substitutions manifested superior antipro-

liferative activity. However, 4-(triﬂuoromethyl)phenyl (1f

and 2f) and 4-ﬂuorophenyl (2e) substitutions displayed

inferior activity. This may be due to the controversial effect

hydrazinolyzed with hydrazine hydrate in methanol under

reﬂux condition results corresponding hydrazides 18(a–j)

in quantitative yields. The ¹H NMR spectrum of these

hydrazides displayed two broad signals at d 9.55 and d

3.98 ppm, which correlated with –NH– and –NH₂protons,

respectively. Further cyclizations were accomplished using

carbon disulﬁde, potassium hydroxide, ethanol followed by

acidiﬁcation of the resulting thiolate salt to furnish the

corresponding 1,3,4-oxadiazole-2-thione derivatives 19(a–

j). These mercapto derivatives 19(a–j) exist in thione–thiol

tautomeric forms as shown in Scheme 3. They mainly exist

in thione form (Koparır et al., 2005), and many reports

state that they exist in thione–thiol tautomeric forms in

solution but the thione structures are dominant in the solid

state. Thus, it has been further evidenced that the crystal

structure of these types of compounds is in the thione form

(Ozturk et al., 2004). These 1,3,4-oxadiazole-2-thione

derivatives 19(a–j) were conﬁrmed by the appearance of

characteristic broad peak at d 14.56 ppm in ¹H NMR

spectrum, which for –NH proton and in ¹³C NMR spectrum

revealed a signal at d 178.0 ppm corresponding to C=S

functionality. Appearance of characteristic oxadiazole –NH

stretching in IR spectra (mNH * 3450 cm^-1) had further

conﬁrmed the formation of 1,3,4-oxadiazole-2-thiones

19(a–j).

¨

of ﬂuorine atoms (Bohm et al., 2004). Moreover, the com-

pounds with p-tolyl substitution (1j and 2j) (electron

releasing) are active against for all the cell lines at concen-

trations of[1 lM. Remaining all other compounds exhib-

ited good cytotoxicity with GI₅₀values ranging from 0.1 to

1 lM. The results of antiproliferative activity indicated that

the hybrid molecules, which are having 3-(triﬂuo-

romethyl)phenyl (1g and 2g) (electron withdrawing) sub-

stitution at 5-position to 1,3,4-oxadiazole ring, have shown

signiﬁcant effect, and p-tolyl (1j and 2j) (electron donating)

substitution at 5-position to 1,3,4-oxadiazole ring has shown

a trivial effect against all the cell lines screened. In addition

to this, 4-methoxyphenyl at 5-position of oxadiazole toge-

ther with 3,5-dimethoxy-4-hydroxystilbene (2i) and 3,4,5-

trimethoxyphenyl at 5-position of oxadiazole together with

3,5-dimethoxy-4-aminostilbene (1a) are selectively more

active on SiHa and PANC-1 cell lines, respectively. The

increased activity is attributed to the presence of ﬂuorine and

methoxy substitutions in the molecules which may enhance

the lipophilicity of the molecules and may facilitate

hydrophobic interactions of the molecules with speciﬁc

The two resveratrol bromide fragments (10 and 11) are

individually coupled with 1,3,4-oxadiazole 2-thiones 19(a–

j) in the presence of potassium carbonate to obtain

resveratrol-oxadiazole analogous 1(a–j) and 2(a–j)

(Scheme 4). The formation of S-alkylated products 1(a–j)

and 2(a–j) was conﬁrmed by the absence of C=S charac-

teristic peak at d 178.0 ppm and the appearance of a signal

for the methylene group at d 33.0–33.5 ppm in ¹³C NMR

spectrum, which is typical for S–CH₂connectivity. The

spectroscopic data of all the newly synthesized compounds

are in full accordance with their depicted structures.

Antiproliferative activity

The prepared resveratrol-oxadiazole hybrid compounds

were evaluated to determine their antiproliferative activi-

ties against a panel of three different human tumor cells

from cervix(SiHa), brest(MDA-MB-231) and pancreatic

carcinoma(PANC-1) (SIHA, MDA-MB-231 and PANC-1

cell lines were obtained from American Type Culture

¨

binding sites on either receptor or enzymes (Bohm et al.,

2004, Kamal et al., 2015). The present study revealed that

among all the tested compounds most of the compounds

showed good results on PANC-1 followed by SiHa and

MDA-MB-231 cell lines.

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Med Chem Res

Table 1 Cytotoxic effects of compounds 1 (a–j), 2 (a–j) and resveratrol on SiHa, MDA-MB-231, and PANC-1 human cancer cells

S. No

Compound

R

GI₅₀(lm)^a

SiHa

MDA-MB-

231

PANC-1

1

1a

3,4,5-Trimethoxyphenyl

Pyridin-4-yl

0.361 0.02

0.149 0.01

0.07 0.00

0.287 0.02

0.258 0.01

0.241 0.03

0.094 0.00

0.163 0.03

6.334 0.02

8.364 0.07

8.451 0.04

0.405 0.04

0.089 0.01

0.266 0.02

1.00 0.03

0.112 0.01

0.064 0.02

0.82 0.03

0.072 0.02

11.321 0.08

21 0.00

0.518 0.02

0.47 0.01

0.51 0.03

0.26 0.02

0.221 0.01

3.484 0.09

0.094 0.02

0.59 0.05

0.49 0.03

3.516 0.06

0.299 0.01

0.692 0.04

0.259 0.02

1.0 0.01

0.064 0.00

0.407 0.02

0.897 0.03

0.37 0.01

0.164 0.05

0.396 0.02

0.089 0.01

0.628 0.01

0.724 0.02

2.891 0.05

0.767 0.06

0.314 0.01

0.588 0.06

0.283 0.03

0.673 0.05

0.727 0.03

0.094 0.01

0.254 0.02

0.217 0.01

2.135 0.07

24 0.13

2

1b

1c

3

2-Fluorophenyl

4

1d

1e

2,6-Diﬂuorophenyl

4-Fluorophenyl

5

6

1f

4-(Triﬂuoromethyl)phenyl

3-(Triﬂuoromethyl)phenyl

Pyrazin-2-yl

7

1 g

1 h

1i

8

9

4-Methoxyphenyl

p-tolyl

10

11

12

13

14

15

16

17

18

19

20

21

1j

2a

3,4,5-Trimethoxyphenyl

Pyridin-4-yl

2b

2c

2-Fluorophenyl

2d

2e

2,6-Diﬂuorophenyl

4-Fluorophenyl

2.427 0.02

2.252 0.03

0.072 0.01

0.738 0.03

0.384 0.04

15.427 0.07

18 0.00

2f

4-(Triﬂuoromethyl)phenyl

3-(Triﬂuoromethyl)phenyl

Pyrazin-2-yl

2 g

2 h

2i

4-Methoxyphenyl

p-tolyl

2j

RSV^b

Cell lines were treated with different concentration of compounds for 48 h as mentioned in materials and methods section. Cell viability was

measured employing SRB assay

a

GI₅₀values (in lM) are indicated as mean SD (standard deviation) of three independent experiments

b

Resveratrol (RSV) was used as reference drug

Experimental protocols

were recorded on Buchi R-535 apparatus and are

uncorrected.

General

General procedure for the synthesis of hybrid compounds

1(a–j) and 2(a–j) To a stirred solution of 1,3,4-oxadia-

zole-2-thiones 19(a–j) (1.0 mmol) in 2 mL of acetonitrile,

K₂CO₃(1.5 mmol) was added and the mixture was stirred

for 5 min and then resveratrol a-bromoamide (10)/resver-

atrol a-bromoester (11) (1.0 mmol) was added drop wise to

the mixture, which was stirred 30 min to 1 h until the

completion of reaction (monitored by TLC). Then, the

reaction mixture was diluted with EtOAc (25 mL). The

organic layer was washed with water (25 mL) and brine

(25 mL), dried over anhydrous Na₂SO₄and concentrated.

The residue was puriﬁed using column chromatography to

obtain hybrid compounds 1(a–j) and 2(a–j).

Analytical thin-layer chromatography (TLC) was carried

out using silica gel 60 F254 pre-coated plates. Visualiza-

tion was accomplished with UV lamp and I₂stain. All

products were characterized by their NMR and HRMS

spectra. The ¹HNMR (300 and 500 MHz) spectra were

recorded on Bruker Avance spectrometer, and ¹³C NMR

(75 and 125 MHz) spectra were recorded on Bruker

Avance spectrometers using TMS as an internal standard;

Chemical shifts were reported in parts per million (ppm, d)

downﬁeld from tetra methyl silane. IR spectra (KBr) were

measured with a Thermo Nicolet Nexus 670 Spectrometer

(t in cm^-1). ESI and HRMS were recorded on ‘‘High

Resolution QSTAR XL hybrid MS/MS system, applied bio

systems’’ under electron spray ionization conditions

preparing sample solutions in methanol. Melting points

(E)-N-(4⁰-(3,5-Dimethoxystyryl)phenyl)-2-((5-(3⁰⁰,4⁰⁰,5⁰⁰-tri-

methoxyphenyl)-1,3,4-oxadiazol-2-yl)thio)acetamide 1(a)

White solid; Yield: 88 %; mp 177–179 °C; IR (KBr)

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(mmax/cm^-1): 3442, 2935, 1662, 1591, 1472, 1418, 1160,

1128, 963, 838; H NMR (CDCl₃, 300 MHz): d 9.34 (1H,

F = 260.3 Hz, C–2⁰⁰), 160.8 (C, C–3, C–5), 139.2 (C, C–

4⁰), 137.1 (C, C–1), 134.0 (CH, d, ³JC–F = 8.7 Hz, C–4⁰⁰),

133.5 (C, C–1⁰), 129.4 (CH, d, JC–F = 8.5 Hz, C–6⁰⁰),

1

3

brs, Ar–NH), 7.57 (2H, d, J = 8.3 Hz, H–2⁰, H–6⁰), 7.45

(2H, d, J = 8.3 Hz, H–3⁰, H–5⁰), 7.22 (2H, s, H–2⁰⁰, H–6⁰⁰),

7.03 (1H, d, J(trans) = 16.6 Hz, CH = (2)), 6.95 (1H, d,

J(trans) = 16.6 Hz, CH=(1)), 6.65 (2H, d, J = 2.2 Hz, H–

2, H–6), 6.38 (1H, t, J = 2.2 Hz, H–4), 4.04 (2H, s, S–

CH₂), 3.93 (6H, s, 2 X O–CH₃), 3.92 (3H, s, O–CH₃), 3.82

(6H, s, 2 X O–CH₃); ¹³C NMR (CDCl₃, 75 MHz): d 166.3

(C=O), 165.2 (C, Het–C–2), 164.6 (C, Het–C–5), 160.8 (C,

C–3, C–5), 153.6 (C, C–3⁰⁰, C–5⁰⁰), 141.2 (C, C–4⁰⁰), 139.2

(C, C–4⁰), 137.0 (C, C–1), 133.5 (C, C–1⁰), 128.3 (CH, C–

2⁰, C–6⁰), 127.9 (CH=(2)), 127.1 (CH=(1)), 119.9 (C, C–

1⁰⁰), 117.9 (CH, C–3⁰, C–5⁰), 104.3 (CH, C–2⁰⁰, C–6⁰⁰),

103.8 (CH, C–2, C–6), 99.8 (CH, C–4), 61.0 (O–CH₃), 56.2

(O–CH₃), 55.3 (O–CH₃), 36.2 (S–CH₂); MS (ESI) (m/z)

564 [M ? H]^?; HRMS (ESI m/z) for C₂₉H₂₉N₃O₇S calcd

564.1852, found 564.1873 [M ? H]^?.

128.3 (CH, C–2⁰, C–6⁰), 127.9 (CH=(2)), 127.1 (CH=(1)),

4

124.8 (CH, d, JC–F = 4.3 Hz, C–5⁰⁰), 120.0 (CH, C–3⁰,

2

C–5⁰), 117.1 (CH, d, J = 20.8 Hz, C–3⁰⁰), 104.5 (C, d,

²JC–F = 9.2 Hz, C–1⁰⁰), 104.3 (CH, C–2, C–6), 99.9 (CH,

C–4), 55.3 (O–CH₃), 36.2 (S–CH₂); MS (ESI) (m/z) 492

[M ? H]^?; HRMS (ESI m/z) for C₂₆H₂₂FN₃O₄S calcd

492.1377, found 492.1380 [M ? H]^?.

(E)-2-((5-(2⁰⁰,6⁰⁰-Diﬂuorophenyl)-1,3,4-oxadiazol-2-yl)thio)-

N-(4⁰-(3,5-dimethoxystyryl)phenyl)acetamide 1(d) White

solid; Yield: 86 %; mp 186–188 °C; IR (KBr) (mmax/

cm^-1): 3430, 2925, 1695, 1592, 1520, 1459, 1155, 1057,

1

965, 790; H NMR (CDCl₃, 500 MHz): d 9.32 (1H, brs,

Ar–NH), 7.59–7.53 (3H, m, H–2⁰, H–6⁰, H–4⁰⁰), 7.46 (2H,

d, J = 8.6 Hz, H–3⁰, H–5⁰), 7.15–7.08 (2H, m, H–3⁰⁰, H–

5⁰⁰), 7.04 (1H, d, J(trans) = 16.1 Hz, CH=(2)), 6.96 (1H, d,

J(trans) = 16.1 Hz, CH=(1)), 6.66 (2H, d, J = 2.1 Hz, H–

2, H–6), 6.38 (1H, t, J = 2.1 Hz, H–4), 4.05 (2H, s, S–

CH₂), 3.83 (6H, s, 2 X O–CH₃); ¹³C NMR (CDCl₃,

75 MHz): d 166.2 (C=O), 165.1 (Het–C–2), 162.3 (C, d,

¹JC–F = 263.5 Hz, C–2⁰⁰, C–6⁰⁰), 160.9 (C, C–3, C–5),

159.4 (Het–C–5), 139.3 (C, C–4⁰), 137.0 (C, C–1), 133.9

(C, d, ³JC–F = 8.5 Hz, C–4⁰⁰), 133.6 (C, C–1⁰), 128.4 (CH,

C–2⁰, C–6⁰), 128.0 (CH=(2)), 127.1 (CH=(1)), 120.0 (CH,

C–3⁰, C–5⁰), 112.6 (CH, d, ²JC–F = 24.2 Hz, C–3⁰⁰, C–5⁰⁰),

(E)-N-(4⁰-(3,5-Dimethoxystyryl)phenyl)-2-((5-(pyridin-4-yl)-

1,3,4-oxadiazol-2-yl)thio)acetamide 1(b) White solid;

Yield: 80 %; mp 171–173 °C; IR (KBr) (mmax/cm^-1):

3440, 2932, 1665, 1590, 1473, 1415, 1162, 1125, 963, 835;

¹H NMR (CDCl₃, 500 MHz): d 9.15 (1H, brs, Ar–NH),

8.84 (2H, d, J = 5.0 Hz, H–2⁰⁰, H–6⁰⁰), 7.87 (2H, d,

J = 5.4 Hz, H–3⁰⁰, H–5⁰⁰), 7.56 (2H, d, J = 8.3 Hz, H–2⁰,

H–6⁰), 7.46 (2H, d, J = 8.3 Hz, H–3⁰, H–5⁰), 7.04 (1H, d,

J(trans) = 16.4 Hz, CH=(2)), 6.96 (1H, d, J(-

trans) = 16.0 Hz, CH=(1)), 6.65 (2H, d, J = 1.3 Hz, H–2,

H–6), 6.38 (1H, t, J = 1.3 Hz, H–4), 4.07 (2H, s, S–CH₂),

3.82 (6H, s, 2 X O–CH₃); ¹³C NMR (CDCl₃, 75 MHz): d

166.6 (C=O), 165.3 (C, Het–C–2), 164.2 (C, Het–C–5),

160.9 (C, C–3, C–5), 150.9 (C, C–2⁰⁰, C–6⁰⁰), 141.4 (C, C–

4⁰⁰), 139.2 (C, C–4⁰), 136.9 (C, C–1), 133.6 (C, C–1⁰), 128.2

(CH, C–2⁰, C–6⁰), 128.0 (CH=(2)), 127.1 (CH=(1)), 119.9

(CH, C–3⁰⁰, C–5⁰⁰), 119.8 (CH, C–3⁰, C–5⁰), 104.3 (CH, C–

2, C–6), 100.1 (CH, C–4), 55.3 (O–CH₃), 36.1 (S–CH₂);

MS (ESI) (m/z) 475 [M ? H]^?; HRMS (ESI m/z) for

C₂₅H₂₂N₄O₄S calcd 475.1425, found 475.1426 [M ? H]^?.

2

104.7 (C, d, JC–F = 9.2 Hz, C–1⁰⁰), 104.4 (CH, C–2, C–

6), 100.0 (CH, C–4), 55.3 (O–CH₃), 36.2 (S–CH₂); MS

(ESI) (m/z) 510 [M ? H]^?; HRMS (ESI m/z) for C₂₆H_21-

F₂N₃O₄S calcd 510.1304, found 510.1303 [M ? H]^?.

(E)-N-(4⁰-(3,5-Dimethoxystyryl)phenyl)-2-((5-(4⁰⁰-ﬂuorophenyl)-

1,3,4-oxadiazol-2-yl)thio)acetamide 1(e) White solid; Yield:

85 %; mp 193–195 °C; IR (KBr) (mmax/cm^-1): 3432,

1

2923, 1692, 1595, 1521, 1456, 1153, 1058, 964, 795; H

NMR (CDCl₃, 300 MHz): d 9.35 (1H, brs, Ar–NH),

8.05–8.02 (2H, m, H–2⁰⁰, H–6⁰⁰), 7.58 (2H, d, J = 8.5 Hz,

H–2⁰, H–6⁰), 7.47 (2H, d, J = 8.5 Hz, H–3⁰, H–5⁰), 7.22

(2H, d, J = 8.5 Hz, H–3⁰⁰, H–5⁰⁰), 7.03 (1H, d, J(-

(E)-N-(4⁰-(3,5-Dimethoxystyryl)phenyl)-2-((5-(2⁰⁰-ﬂuorophenyl)-

1,3,4-oxadiazol-2-yl)thio)acetamide 1(c) White solid; Yield:

85 %; mp 197–199 °C; IR (KBr) (mmax/cm^-1): 3424,

trans) = 16.6 Hz,

CH=(2)),

6.96

(1H,

d,

J(-

trans) = 16.6 Hz, CH=(1)), 6.65 (2H, d, J = 2.2 Hz, H–2,

H–6), 6.39 (1H, t, J = 2.2 Hz, H–4), 4.04 (2H, s, S–CH₂),

3.83 (6H, s, 2 X O–CH₃); ¹³C NMR (CDCl₃, 75 MHz): d

166.6 (C=O), 165.2 (Het–C–2), 163.2 (C, d, ¹JC–

F = 250.5 Hz, C–4⁰⁰), 160.9 (C, C–3, C–5), 159.6 (Het–C–

5), 139.2 (C, C–4⁰), 137.0 (C, C–1), 133.5 (C, C–1⁰), 129.1

1

2926, 1662, 1519, 1469, 1204, 1155, 1061, 962, 818; H

NMR (CDCl₃, 500 MHz): d 9.36 (1H, brs, Ar–NH),

8.06–7.93 (1H, m, H–6⁰⁰), 7.59–7.54 (3H, m, H–2⁰, H–6⁰,

H–4⁰⁰), 7.45 (2H, d, J = 8.6 Hz, H–3⁰, H–5⁰), 7.34–7.24

(2H, m, H–3⁰⁰, H–5⁰⁰), 7.03 (1H, d, J(trans) = 16.1 Hz,

CH=(2)), 6.96 (1H, d, J(trans) = 16.3 Hz, CH=(1)), 6.65

(2H, d, J = 2.2 Hz, H–2, H–6), 6.38 (1H, t, J = 2.2 Hz,

H–4), 4.05 (2H, s, S–CH₂), 3.82 (6H, s, 2 X O–CH₃); ¹³C

NMR (CDCl₃, 75 MHz): d 165.2 (C=O), 161.7 (C, d, ¹JC–

3

4

(CH, d, JC–F = 9.0 Hz, C–2⁰⁰, C–6⁰⁰), 128.9 (C, d, JC–

F = 3.2 Hz, C–1⁰⁰), 128.3 (CH, C–2⁰, C–6⁰), 128.0

(CH=(2)), 127.1 (CH=(1)), 119.9 (CH, C–3⁰, C–5⁰), 116.7

2

(CH, d, JC–F = 22.4 Hz, C–3⁰⁰, C–5⁰⁰), 104.3 (CH, C–2,

123

Med Chem Res

C–6), 99.9 (CH, C–4), 55.3 (O–CH₃), 36.1 (S–CH₂); MS

(ESI) (m/z) 492 [M ? H]^?; HRMS (ESI m/z) for C₂₆H_22-

FN₃O₄S calcd 492.1383, found 492.1384 [M ? H]^?.

id; Yield: 78 %; mp 212–214 °C; IR (KBr) (mmax/cm^-1):

3441, 2930, 1663, 1592, 1472, 1413, 1160, 1127, 962, 833;

¹H NMR (CDCl₃, 300 MHz): d 9.43 (1H, m, H–3⁰⁰), 9.17

(1H, brs, Ar–NH), 8.79–8.75 (2H, m, H–6⁰⁰, H–5⁰⁰), 7.56

(2H, d, J = 9.0 Hz, H–2⁰, H–6⁰), 7.46 (2H, d, J = 9.0 Hz,

H–3⁰, H–5⁰), 7.03 (1H, d, J(trans) = 16.6 Hz, CH=(2)),

6.96 (1H, d, J(trans) = 16.6 Hz, CH=(1)), 6.66 (2H, d,

J = 2.2 Hz, H–2, H–6), 6.39 (1H, t, J = 2.2 Hz, H–4),

4.09 (2H, s, S–CH₂), 3.83 (6H, s, 2 X O–CH₃); ¹³C NMR

(CDCl₃, 125 MHz): d 165.8 (C=O), 165.1 (C, Het–C–2),

163.5 (C, Het–C–5), 160.9 (C, C–3, C–5), 149.8 (C, C–2⁰⁰),

146.5 (CH, C–3⁰⁰), 144.5 (CH, C–6⁰⁰), 143.9 (CH, C–5⁰⁰),

139.1 (C, C–4⁰), 139.0 (C, C–1), 135.5 (C, C–1⁰), 129.2

(CH, C–2⁰, C–6⁰), 127.9 (CH=(2)), 127.5 (CH=(1)), 121.4

(CH, C–3⁰, C–5⁰), 104.5 (CH, C–2, C–6), 100.1 (CH, C–4),

55.3 (O–CH₃), 34.3 (S–CH₂); MS (ESI) (m/z) 476

[M ? H]^?; HRMS (ESI m/z) for C₂₄H₂₁N₅O₄S calcd

476.1387, found 476.1384 [M ? H]^?.

(E)-N-(4⁰-(3,5-Dimethoxystyryl)phenyl)-2-((5-(4⁰⁰-(triﬂuo-

romethyl)phenyl)-1,3,4-oxadiazol-2-yl)thio)acetamide 1(f)

White solid; Yield: 82 %; mp 156–158 °C; IR (KBr)

(mmax/cm^-1): 3431, 2923, 1693, 1590, 1521, 1453, 1154,

1

1055, 961, 793; H NMR (CDCl₃, 500 MHz): d 9.23 (1H,

brs, Ar–NH), 8.15 (2H, d, J = 8.1 Hz, H–2⁰⁰, H–6⁰⁰), 7.80

(2H, d, J = 8.3 Hz, H–3⁰⁰, H–5⁰⁰), 7.57 (2H, d, J = 8.6 Hz,

H–2⁰, H–6⁰), 7.46 (2H, d, J = 8.6 Hz, H–3⁰, H–5⁰), 7.02

(1H, d, J(trans) = 16.2 Hz, CH=(2)), 6.96 (1H, d, J(-

trans) = 16.2 Hz, CH=(1)), 6.65 (2H, d, J = 2.2 Hz, H–2,

H–6), 6.39 (1H, d, J = 2.2 Hz, H–4), 4.06 (2H, s, S–CH₂),

3.83 (6H, s, 2 X O–CH₃); ¹³C NMR (CDCl₃, 125 MHz): d

164.1 (C=O), 163.9 (Het–C–5), 160.2 (C, C–3, C–5), 138.5

(C, C–4⁰), 137.3 (C, C–1), 134.5 (CH, q, ²JC–F = 25.8 Hz,

C–4⁰⁰), 132.4 (C, C–1⁰⁰), 132.1 (C, C–1⁰), 127.7 (CH=(2)),

126.9 (CH=(1)), 126.3 (CH, C–2⁰⁰, C–6⁰⁰), 126.0 (CH, C–2⁰,

(E)-N-(4⁰-(3,5-Dimethoxystyryl)phenyl)-2-((5-(4⁰⁰-meth-

3

C–6⁰), 125.3 (CH, q, JC–F = 3.3 Hz, C–3⁰⁰, C–5⁰⁰), 124.4

oxyphenyl)-1,3,4-oxadiazol-2-yl)thio)acetamide 1(i)

White solid; Yield: 87 %; mp 158–160 °C; IR (KBr)

1

(C, q, JC–F = 258.6 Hz, –CF₃), 119.1 (CH, C–3⁰, C–5⁰),

103.6 (CH, C–2, C–6), 99.1 (CH, C–4), 54.6 (O–CH₃), 36.5

(S–CH₂); MS (ESI) (m/z) 542 [M ? H]^?; HRMS (ESI m/z)

for C₂₇H₂₂F₃N₃O₄S calcd 542.1355, found 542.1359

[M ? H]^?.

(mmax/cm^-1): 3440, 2933, 1660, 1590, 1473, 1415, 1163,

1

1125, 962, 835; H NMR (CDCl₃, 300 MHz): d 9.48 (1H,

brs, Ar–NH), 7.95 (2H, d, J = 9.0 Hz, H–2⁰⁰, H–6⁰⁰), 7.57

(2H, d, J = 9.0 Hz, H–2⁰, H–6⁰), 7.45 (2H, d, J = 9.0 Hz,

H–3⁰, H–5⁰), 7.04 (1H, d, J(trans) = 16.6 Hz, CH=(2)),

7.01 (2H, d, J = 9.0 Hz, H–3⁰⁰, H–5⁰⁰), 6.95 (1H, d, J(-

trans) = 16.6 Hz, CH=(1)), 6.65 (2H, d, J = 2.2 Hz, H–2,

H–6), 6.38 (1H, d, J = 2.2 Hz, H–4), 4.02 (2H, s, S–CH₂),

3.88 (3H, s, O–CH₃), 3.83 (6H, s, 2 X O–CH₃); ¹³C NMR

(CDCl₃, 125 MHz): d 165.1 (C=O), 164.3 (C, Het–C–2),

162.2 (C, Het–C–5), 160.9 (C, C–3, C–5), 142.4 (C, C–4⁰⁰),

139.3 (C, C–4⁰), 137.2 (C, C–1), 133.5 (C, C–1⁰), 128.9

(CH, C–2⁰⁰, C–6⁰⁰), 128.6 (CH, C–2⁰, C–6⁰), 128.0

(CH=(2)), 127.2 (CH=(1)), 120.0 (CH, C–3⁰, C–5⁰), 114.6

(CH, C–3⁰⁰, C–5⁰⁰), 104.4 (CH, C–2, C–6), 100.0 (CH, C–

4), 55.7 (O–CH₃), 55.4 (O–CH₃), 36.1 (S–CH₂); MS (ESI)

(m/z) 504 [M ? H]^?; HRMS (ESI m/z) for C₂₇H₂₅N₃O₅S

calcd 504.1582, found 504.1583 [M ? H]^?.

(E)-N-(4⁰-(3,5-Dimethoxystyryl)phenyl)-2-((5-(3⁰⁰-(triﬂuo-

romethyl)phenyl)-1,3,4-oxadiazol-2-yl)thio)acetamide 1(g)

White solid; Yield: 83 %; mp 169–171 °C; IR (KBr)

(mmax/cm^-1): 3377, 2925, 1694, 1593, 1513, 1463, 1163,

1

1061, 962, 841; H NMR (CDCl₃, 500 MHz): d 9.25 (1H,

brs, Ar–NH), 8.29 (1H, s, H–2⁰⁰), 8.21 (1H, d, J = 7.7 Hz,

H–6⁰⁰), 7.82 (1H, d, J = 7.7 Hz, H–4⁰⁰), 7.68 (1H, t,

J = 7.9 Hz, H–5⁰⁰), 7.57 (2H, d, J = 8.6 Hz, H–2⁰, H–6⁰),

7.46 (2H, d, J = 8.6 Hz, H–3⁰, H–5⁰), 7.03 (1H, d, J(-

trans) = 16.3 Hz,

CH=(2)),

6.96

(1H,

d,

J(-

trans) = 16.3 Hz, CH=(1)), 6.65 (2H, d, J = 2.1 Hz, H–2,

H–6), 6.39 (1H, t, J = 2.1 Hz, H–4), 4.06 (2H, s, S–CH₂),

3.82 (6H, s, 2 X O–CH₃); ¹³C NMR (CDCl₃, 125 MHz): d

165.7 (C=O), 165.0 (Het–C–2), 163.4 (Het–C–5), 160.9 (C,

C–3, C–5), 139.2 (C, C–4⁰), 137.0 (C, C–1), 133.6 (C, C–

(E)-N-(4⁰-(3,5-Dimethoxystyryl)phenyl)-2-((5-(p-tolyl)-1,3,4-

oxadiazol-2-yl)thio)acetamide 1(j) White solid; Yield:

86 %; mp 202–204 °C; IR (KBr) (mmax/cm^-1): 3442,

2

1⁰), 131.7 (C, q, JC–F = 32.6, C–3⁰⁰), 129.9 (CH, C–6⁰⁰),

129.8 (CH, C–2⁰, C–6⁰), 128.7 (CH, C–5⁰⁰), 128.6 (CH, q,

1

³JC–F = 3.8 Hz, C–2⁰⁰), 128.3 (C, C–1⁰⁰), 128.1 (CH=(2)),

2930, 1664, 1592, 1470, 1413, 1160, 1123, 961, 833; H

3

127.1 (CH=(1)), 123.8 (CH, q, JC–F = 3.5 Hz, C–4⁰⁰),

NMR (CDCl₃, 500 MHz): d 9.43 (1H, brs, Ar–NH), 7.90

(2H, d, J = 8.1 Hz, H–2⁰⁰, H–6⁰⁰), 7.57 (2H, d, J = 8.6 Hz,

H–2⁰, H–6⁰), 7.45 (2H, d, J = 8.6 Hz, H–3⁰, H–5⁰), 7.32

(2H, d, J = 8.1 Hz, H–3⁰⁰, H–5⁰⁰), 7.04 (1H, d, J(-

1

123.7 (C, q, JC–F = 217.2 Hz, –CF₃), 119.9 (CH, C–3⁰,

C–5⁰), 104.4 (CH, C–2, C–6), 100.0 (CH, C–4), 55.3 (O–

CH₃), 36.2 (S–CH₂); MS (ESI) (m/z) 542 [M ? H]^?;

HRMS (ESI m/z) for C₂₇H₂₂F₃N₃O₄S calcd 542.1356,

found 542.1354 [M ? H]^?.

trans) = 16.4 Hz,

CH=(2)),

6.96

(1H,

d,

J(-

trans) = 16.4 Hz, CH=(1)), 6.65 (2H, d, J = 2.2 Hz, H–2,

H–6), 6.38 (1H, d, J = 2.2 Hz, H–4), 4.02 (2H, s, S–CH₂),

3.83 (6H, s, 2 X O–CH₃), 2.44 (3H, s, Ar–CH₃); ¹³C NMR

(CDCl₃, 75 MHz): d 165.4 (C=O), 164.7 (C, Het–C–2),

(E)-N-(4⁰-(3,5-Dimethoxystyryl)phenyl)-2-((5-(pyrazin-2-

yl)-1,3,4-oxadiazol-2-yl)thio)acetamide 1(h) White sol

123

Med Chem Res

162.2 (C, Het–C–5), 160.9 (C, C–3, C–5), 142.8 (C, C–4⁰),

137.1 (C, C–1), 133.5 (C, C–1⁰), 132.5 (C, C–4⁰⁰) 129.8

(CH, C–2⁰⁰, C–6⁰⁰), 128.4 (CH, C–2⁰, C–6⁰), 127.9

(CH=(2)), 127.1 (CH=(1)), 126.7 (CH, C–3⁰⁰, C–5⁰⁰), 126.2

(C, C–1⁰⁰), 119.9 (CH, C–3⁰, C–5⁰), 104.3 (CH, C–2, C–6),

99.9 (CH, C–4), 55.3 (O–CH₃), 36.1 (S–CH₂), 21.6 (Ar–

CH₃); MS (ESI) (m/z) 488 [M ? H]^?; HRMS (ESI m/z) for

C₂₇H₂₅N₃O₄S calcd 488.1631, found 488.1632 [M ? H]^?.

84 %; mp 121–123 °C; IR (KBr) (mmax/cm^-1): 2921,

1

1751, 1594, 1473, 1294, 1137, 1051, 971, 821; H NMR

(CDCl₃, 300 MHz): d 8.05–7.99 (1H, m, H–6⁰⁰), 7.58–7.48

(3H, m, H–2⁰, H–6⁰, H–4⁰⁰), 7.33–7.21 (2H, m, H–3⁰⁰, H–

5⁰⁰), 7.15 (2H, d, J = 8.6 Hz, H–3⁰, H–5⁰), 7.07 (1H, d,

J(trans) = 16.2 Hz, CH=(2)), 6.98 (1H, d, J(-

trans) = 16.2 Hz, CH=(1)), 6.66 (2H, d, J = 2.2 Hz, H–2,

H–6), 6.40 (1H, t, J = 2.2 Hz, H–4), 4.35 (2H, s, S–CH₂),

3.83 (6H, s, 2 X O–CH₃); ¹³C NMR (CDCl₃, 75 MHz): d

166.1 (C=O), 163.1 (C, Het–C–2), 162.9 (C, d, ¹JC–

F = 262.3 Hz, C–2⁰⁰), 161.5 (C, Het–C–5), 160.9 (C, C–3,

C–5), 149.8 (C, C–4⁰), 139.0 (C, C–1), 135.4 (C, C–1⁰),

133.6 (CH, d, ³JC–F J = 8.7 Hz, C–4⁰⁰), 129.4 (CH, ³JC–F

J = 8.5 Hz, C–6⁰⁰), 129.1 (CH, C–2⁰, C–6⁰), 127.9

(E)-4⁰-(3,5-Dimethoxystyryl)phenyl

2-((5-(3⁰⁰,4⁰⁰,5⁰⁰-tri-

2(a)

methoxyphenyl)-1,3,4-oxadiazol-2-yl)thio)acetate

White solid; Yield: 84 %; mp 148–150 °C; IR (KBr)

(mmax/cm^-1): 2920, 1750, 1592, 1470, 1290, 1135, 1051,

1

971, 821; H NMR (CDCl₃, 500 MHz): d 7.51 (2H, d,

J = 8.6 Hz, H–2⁰, H–6⁰), 7.24 (2H, s, H–2⁰⁰, H–6⁰⁰), 7.15

(2H, d, J = 8.6 Hz, H–3⁰, H–5⁰), 7.05 (1H, d, J(-

4

(CH=(2)), 127.5 (CH=(1)), 124.7 (CH, JC–F J = 3.7 Hz,

C–5⁰⁰), 121.4 (CH, C–3⁰, C–5⁰), 116.8 (CH, ²JC–F

trans) = 16.1 Hz,

CH=(2)),

6.98

(1H,

d,

J(-

2

J = 20.7 Hz, C–3⁰⁰), 104.6 (C, JC–F J = 9.5 Hz, C–1⁰⁰),

trans) = 16.1 Hz, CH=(1)), 6.66 (2H, d, J = 2.1 Hz, H–2,

H–6), 6.40 (1H, t, J = 2.1 Hz, H–4), 4.34 (2H, s, S–CH₂),

3.93 (6H, s, 2 X O–CH₃), 3.92 (3H, s, O–CH₃), 3.83 (6H, s,

2 X O–CH₃); ¹³C NMR (CDCl₃, 75 MHz): d 166.2 (C=O),

162.4 (C, Het–C–5), 160.9 (C, C–3, C–5), 153.6 (C, C–3⁰⁰,

C–5⁰⁰), 149.8 (C, C–4⁰), 141.0 (C, C–4⁰⁰), 139.0 (C, C–1),

135.4 (C, C–1⁰), 129.2 (CH, C–2⁰, C–6⁰), 127.9 (CH=(2)),

127.5 (CH=(1)), 121.5 (C, C–1⁰⁰), 118.4 (CH, C–3⁰, C–5⁰),

104.5 (CH, C–2⁰⁰, C–6⁰⁰), 103.9 (CH, C–2, C–6), 100.1

(CH, C–4), 61.0 (O–CH₃), 56.3 (O–CH₃), 55.4 (O–CH₃),

34.3 (S–CH₂); MS (ESI) (m/z) 565 [M ? H]^?; HRMS (ESI

m/z) for C₂₉H₂₈N₂O₈S calcd 565.1635, found 565.1632

[M ? H]^?.

104.5 (CH, C–2, C–6), 100.0 (CH, C–4), 55.3 (O–CH₃),

34.3 (S–CH₂); MS (ESI) (m/z) 493 [M ? H]^?; HRMS (ESI

m/z) for C₂₆H₂₁FN₂O₅S calcd 493.1253, found 493.1250

[M ? H]^?.

(E)-4⁰-(3,5-Dimethoxystyryl)phenyl

2-((5-(2⁰⁰,6⁰⁰-diﬂuo-

rophenyl)-1,3,4-oxadiazol-2-yl)thio)acetate 2(d) White

solid; Yield: 85 %; mp 147–149 °C; IR (KBr) (mmax/

cm^-1): 2925, 1749, 1594, 1495, 1294, 1138, 1053, 974,

819; ¹H NMR (CDCl₃, 300 MHz): d 7.56–7.49 (3H, m, H–

2⁰, H–6⁰, H–4⁰⁰), 7.15 (2H, d, J = 8.6 Hz, H–3⁰, H–5⁰), 7.10

(2H, d, J = 8.3 Hz, H–3⁰⁰, H–5⁰⁰), 7.05 (1H, d, J(-

trans) = 16.3 Hz,

CH=(2)),

6.98

(1H,

d,

J(-

trans) = 16.3 Hz, CH=(1)), 6.66 (2H, d, J = 2.1 Hz, H–2,

H–6), 6.40 (1H, t, J = 2.1 Hz, H–4), 4.36 (2H, s, S–CH₂),

3.83 (6H, s, 2 X O–CH₃); ¹³C NMR (CDCl₃, 75 MHz): d

166.0 (C=O), 163.9 (C, Het–C–2), 162.3 (C, d, ¹JC–

F = 262.3 Hz, C–2⁰⁰, C–6⁰⁰), 161.1 (C, Het–C–5), 160.9 (C,

C–3, C–5), 149.9 (C, C–4⁰), 139.0 (C, C–1), 135.4 (C, C–

(E)-4⁰-(3,5-Dimethoxystyryl)phenyl

2-((5-(pyridin-4-yl)-

1,3,4-oxadiazol-2-yl)thio)acetate 2(b) White solid; Yield:

78 %; mp 170–172 °C; IR (KBr) (mmax/cm^-1): 2922,

1

1755, 1590, 1472, 1291, 1133, 1050, 972, 820; H NMR

(CDCl₃, 300 MHz): d 8.82 (2H, d, J = 6.0 Hz, H–2⁰⁰, H–

6⁰⁰), 7.89 (2H, d, J = 6.0 Hz, H–3⁰⁰, H–5⁰⁰), 7.52 (2H, d,

J = 8.3 Hz, H–2⁰, H–6⁰), 7.14 (2H, d, J = 8.3 Hz, H–3⁰,

H–5⁰), 7.06 (1H, d, J(trans) = 16.6 Hz, CH=(2)), 6.99 (1H,

d, J(trans) = 16.6 Hz, CH=(2)), 6.66 (2H, d, J = 2.2 Hz,

H–2, H–6), 6.40 (1H, t, J = 2.2 Hz, H–4), 4.38 (2H, s, S–

CH₂), 3.83 (6H, s, 2 X O–CH₃); ¹³C NMR (CDCl₃,

125 MHz): d 165.9 (C=O), 164.4 (C, Het–C–2), 164.3 (C,

Het–C–5), 160.9 (C, C–3, C–5), 150.9 (C, C–2⁰⁰, C–6⁰⁰),

149.8 (C, C–4⁰), 139.0 (C, C–1), 135.5 (C, C–1⁰), 130.4 (C,

C–4⁰⁰), 129.3 (CH, C–2⁰, C–6⁰), 127.8 (CH=(2)), 127.5

(CH=(1)), 121.4 (CH, C–3⁰⁰, C–5⁰⁰), 120.0 (CH, C–3⁰, C–

5⁰), 104.5 (CH, C–2, C–6), 100.1 (CH, C–4), 55.3 (O–

CH₃), 34.3 (S–CH₂); MS (ESI) (m/z) 476 [M ? H]^?;

HRMS (ESI m/z) for C₂₅H₂₁N₃O₅S calcd 476.1265, found

476.1262 [M ? H]^?.

3

1⁰), 133.6 (CH, d, JC–F = 9.9 Hz, C–4⁰⁰), 129.2 (CH, C–

2⁰, C–6⁰), 127.9 (CH=(2)), 127.5 (CH=(1)), 121.4 (CH, C–

2

3⁰, C–5⁰), 112.3 (CH, d, JC–F = 24.4 Hz, C–3⁰⁰, C–5⁰⁰),

105.4 (C, d, ²JC–F = 10.2 Hz, C–1⁰⁰), 104.6 (CH, C–2, C–

6), 100.1 (CH, C–4), 55.3 (O–CH₃), 34.3 (S–CH₂); MS

(ESI) (m/z) 511 [M ? H]^?; HRMS (ESI m/z) for C₂₆H_20-

F₂N₂O₅S calcd 511.1123, found 511.1125 [M ? H]^?.

(E)-4⁰-(3,5-Dimethoxystyryl)phenyl 2-((5-(4⁰⁰-ﬂuorophenyl)-

1,3,4-oxadiazol-2-yl)thio)acetate 2(e) White solid; Yield:

83 %; mp 111–113 °C; IR (KBr) (mmax/cm^-1): 2923,

1

1745, 1592, 1495, 1292, 1135, 1051, 975, 825; H NMR

(CDCl₃, 300 MHz): d 8.06–7.99 (2H, m, H–2⁰⁰, H–6⁰⁰),

7.52 (2H, d, J = 9.0 Hz, H–2⁰, H–6⁰), 7.24–7.12 (4H, m,

H–3⁰, H–5⁰, H–3⁰⁰, H–5⁰⁰), 7.05 (1H, d, J(trans) = 16.6 Hz,

CH=(2)), 6.98 (1H, d, J(trans) = 16.6 Hz, CH=(1)), 6.66

(2H, d, J = 2.2 Hz, H–2, H–6), 6.40 (1H, t, J = 2.2 Hz,

H–4), 4.34 (2H, s, S–CH₂), 3.83 (6H, s, 2 X O–CH₃); ¹³C

(E)-4⁰-(3,5-Dimethoxystyryl)phenyl 2-((5-(2⁰⁰-ﬂuorophenyl)-

1,3,4-oxadiazol-2-yl)thio)acetate 2(c) White solid; Yield:

123

Med Chem Res

NMR (CDCl₃, 125 MHz): d 166.1 (C=O), 163.5 (C, Het–

123.6 (CH, C–5⁰⁰) 121.4 (CH, C–3⁰, C–5⁰), 104.3 (CH, C–2,

C–6), 100.1 (CH, C–4), 55.3 (O–CH₃), 34.3 (S–CH₂); MS

(ESI) (m/z) 543 [M ? H]^?; HRMS (ESI m/z) for C₂₇H_21-

F₃N₂O₅S calcd 543.1237, found 543.1235 [M ? H]^?.

1

C–2), 162.6 (C, d, JC–F = 262.3 Hz, C–4⁰⁰), 161.1 (C,

Het–C–5), 160.9 (C, C–3, C–5), 149.8 (C, C–4⁰), 139.0 (C,

3

C–1), 135.4 (C, C–1⁰), 133.6 (CH, d, JC–F = 9.3 Hz, C–

4

2⁰⁰, C–6⁰⁰), 129.0 (C, d, JC–F = 3.1 Hz, C–1⁰⁰), 127.9

(E)-4⁰-(3,5-Dimethoxystyryl)phenyl 2-((5-(pyrazin-2-yl)-

(CH=(2)), 127.5 (CH=(1)), 121.4 (CH, C–2⁰, C–6⁰), 118.6

1,3,4-oxadiazol-2-yl)thio)acetate

2(h) White

solid;

2

(CH, C–3⁰, C–5⁰), 116.5 (CH, d, JC–F = 24.4 Hz, C–3⁰⁰,

Yield: 76 %; mp 150–152 °C; IR (KBr) (mmax/cm^-1):

2923, 1745, 1592, 1455, 1233, 1154, 1060, 965, 833; H

C–5⁰⁰), 104.5 (CH, C–2, C–6), 100.1 (CH, C–4), 55.3 (O–

CH₃), 34.3 (S–CH₂); MS (ESI) (m/z) 493 [M ? H]^?;

HRMS (ESI m/z) for C₂₆H₂₁FN₂O₅S calcd 493.1252, found

493.1253 [M ? H]^?.

1

NMR (CDCl₃, 300 MHz): d 9.44 (1H, d, J = 1.2 Hz, H–

3⁰⁰), 8.76–8.73 (2H, m, H–5⁰⁰, H–6⁰⁰), 7.52 (2H, d,

J = 8.6 Hz, H–2⁰, H–6⁰), 7.16 (2H, d, J = 8.6 Hz, H–3⁰,

H–5⁰), 7.06 (1H, d, J(trans) = 16.3 Hz, CH=(2)), 6.99 (1H,

d, J(trans) = 16.3 Hz, CH=(1)), 6.66 (2H, d, J = 2.1 Hz,

H–2⁰, H–6⁰), 6.40 (1H, t, J = 2.1 Hz, H–4), 4.39 (2H, s, S–

CH₂), 3.83 (6H, s, 2 X O–CH₃); ¹³C NMR (CDCl₃,

125 MHz): d 165.8 (C=O), 165.1 (C, Het–C–2), 163.5 (C,

Het–C–5), 160.9 (C, C–3, C–5), 149.8 (C, C–4⁰), 146.5

(CH, C–3⁰⁰), 144.5 (CH, C–6⁰⁰), 143.9 (CH, C–5⁰⁰), 139.0

(C, C–1), 135.5 (C, C–1⁰), 129.2 (CH, C–2⁰, C–6⁰), 127.9

(CH=(2)), 127.5 (CH=(1)), 121.4 (CH, C–3⁰, C–5⁰), 104.5

(CH, C–2, C–6), 100.1 (CH, C–4), 55.3 (O–CH₃), 34.3 (S–

CH₂); MS (ESI) (m/z) 477 [M ? H]^?; HRMS (ESI m/z) for

C₂₄H₂₀N₄O₅S calcd 477.1286, found 477.1285 [M ? H]^?.

(E)-4⁰-(3,5-Dimethoxystyryl)phenyl

2-((5-(4⁰⁰-(triﬂuo-

2(f)

romethyl)phenyl)-1,3,4-oxadiazol-2-yl)thio)acetate

White solid; Yield: 80 %; mp 141–143 °C; IR (KBr)

(mmax/cm^-1): 2923, 1747, 1595, 1492, 1293, 1135, 1051,

1

975, 819; H NMR (CDCl₃, 500 MHz): d 8.15 (2H, d,

J = 8.3 Hz, H–2⁰⁰, H–6⁰⁰), 7.78 (2H, d, J = 8.3 Hz, H–3⁰⁰,

H–5⁰⁰), 7.51 (2H, d, J = 8.6 Hz, H–2⁰, H–6⁰), 7.15 (2H, d,

J = 8.6 Hz, H–3⁰, H–5⁰), 7.06 (1H, d, J(trans) = 16.3 Hz,

CH=(2)), 6.99 (1H, d, J(trans) = 16.3 Hz, CH=(1)), 6.66

(2H, d, J = 2.2 Hz, H–2, H–6), 6.40 (1H, t, J = 2.2 Hz,

H–4), 4.37 (2H, s, S–CH₂), 3.83 (6H, s, 2 X O–CH₃); ¹³C

NMR (CDCl₃, 125 MHz): d 166.0 (C=O), 165.1 (C, Het–

C–2), 163.6 (C, Het–C–5), 160.9 (C, C–3, C–5), 149.8 (C,

(E)-4⁰-(3,5-Dimethoxystyryl)phenyl

2-((5-(4⁰⁰-methox-

2(i) White

2

C–4⁰), 139.0 (C, C–1), 135.5 (C, C–1⁰), 133.4 (C, q, JC–

F = 33.0 Hz, C–4⁰⁰), 129.2 (CH, C–2⁰⁰, C–6⁰⁰), 127.9 (C,

C–2⁰, C–6⁰), 127.5 (CH=(2)), 127.0 (CH=(1)), 126.5 (C, C–

1⁰⁰), 126.1 (CH, q, ³JC–F = 3.2 Hz, C–3⁰⁰, C–5⁰⁰), 124.5 (C,

yphenyl)-1,3,4-oxadiazol-2-yl)thio)acetate

solid; Yield: 85 %; mp 156–158 °C; IR (KBr) (mmax/

cm^-1): 2925, 1747, 1595, 1459, 1239, 1159, 1063, 969,

835; ¹H NMR (CDCl₃, 300 MHz): d 7.95 (2H, d,

J = 8.9 Hz, H–2⁰⁰, H–6⁰⁰), 7.52 (2H, d, J = 8.6 Hz, H–2⁰,

H–6⁰), 7.14 (2H, d, J = 8.6 Hz, H–3⁰, H–5⁰), 7.07 (1H, d,

J(trans) = 16.6 Hz, CH=(2)), 7.00 (2H, d, J = 8.9 Hz, H–

3⁰⁰, H–5⁰⁰), 6.98 (1H, d, J(trans) = 16.6 Hz, CH=(1)), 6.66

(2H, d, J = 2.2 Hz, H–2, H–6), 6.40 (1H, t, J = 2.2 Hz,

H–4), 4.32 (2H, s, S–CH₂), 3.88 (3H, s, O–CH₃), 3.83 (6H,

s, 2 X O–CH₃); ¹³C NMR (CDCl₃, 75 MHz): d 166.2

(C=O), 162.4 (C, Het–C–2), 161.7 (C, Het–C–5), 160.9 (C,

C–3, C–5), 149.9 (C, C–4⁰), 139.0 (C, C–1), 135.4 (C, C–

1⁰), 129.2 (CH, C–2⁰⁰, C–6⁰⁰), 128.5 (CH, C–2⁰, C–6⁰), 127.9

(CH=(2)), 127.5 (CH=(1)), 121.4 (CH, C–3⁰, C–5⁰), 114.5

(CH, C–3⁰⁰, C–5⁰⁰), 104.6 (CH, C–2, C–6), 100.1 (CH, C–

4), 55.4 (O–CH₃), 55.3 (O–CH₃), 34.4 (S–CH₂); MS (ESI)

(m/z) 505 [M ? H]^?; HRMS (ESI m/z) for C₂₇H₂₄N₂O₆S

calcd 505.1476, found 505.1475 [M ? H]^?.

1

q, JC–F = 279.3 Hz, –CF₃), 121.4 (CH, C–3⁰, C–5⁰),

104.5 (CH, C–2, C–6), 100.1 (CH, C–4), 55.3 (O–CH₃),

34.3 (S–CH₂); MS (ESI) (m/z) 543 [M ? H]^?; HRMS (ESI

m/z) for C₂₇H₂₁F₃N₂O₅S calcd 543.1263, found 543.1265

[M ? H]^?.

(E)-4⁰-(3,5-Dimethoxystyryl)phenyl

2-((5-(3⁰⁰-(triﬂuo-

2(g)

romethyl)phenyl)-1,3,4-oxadiazol-2-yl)thio)acetate

White solid; Yield: 81 %; mp 143–145 °C; IR (KBr)

(mmax/cm^-1): 2931, 1752, 1593, 1477, 1295, 1130, 1062,

1

971, 819; H NMR (CDCl₃, 300 MHz): d 8.28 (1H, s, H–

2⁰⁰), 8.22 (1H, d, J = 8.3 Hz, H–6⁰⁰), 7.80 (1H, d,

J = 8.3 Hz, H–4⁰⁰), 7.66 (1H, t, J = 7.5 Hz, H–5⁰⁰), 7.52

(2H, d, J = 8.3 Hz, H–2⁰, H–6⁰), 7.15 (2H, d, J = 8.3 Hz,

H–3⁰, H–5⁰), 7.06 (1H, d, J(trans) = 15.8 Hz, CH=(2)),

6.99 (1H, d, J(trans) = 15.8 Hz, CH=(1)), 6.66 (2H, d,

J = 2.2 Hz, H–2, H–6), 6.40 (1H, t, J = 2.2 Hz, H–4),

4.37 (2H, s, S–CH₂), 3.83 (6H, s, 2 X O–CH₃); ¹³C NMR

(CDCl₃, 125 MHz): d 166.0 (C=O), 165.0 (C, Het–C–2),

163.4 (C, Het–C–5), 160.9 (C, C–3, C–5), 149.8 (C, C–4⁰),

139.0 (C, C–1), 135.5 (C, C–1⁰) 131.9 (CH, C–6⁰⁰), 131.3

(E)-4⁰-(3,5-Dimethoxystyryl)phenyl 2-((5-(p-tolyl)-1,3,4-

oxadiazol-2-yl)thio)acetate 2(j) White solid; Yield:

83 %; mp 147–149 °C; IR (KBr) (mmax/cm^-1): 2923,

1

1745, 1590, 1455, 1235, 1152, 1065, 966, 830; H NMR

2

(CDCl₃, 300 MHz): d 7.90 (2H, d, J = 8.3 Hz, H–2⁰⁰, H–

6⁰⁰), 7.52 (2H, d, J = 9.0 Hz, H–2⁰, H–6⁰), 7.30 (2H, d,

J = 8.3 Hz, H–3⁰⁰, H–5⁰⁰), 7.15 (2H, d, J = 9.0 Hz, H–3⁰,

H–5⁰), 7.07 (1H, d, J(trans) = 16.6 Hz, CH=(2)), 6.98 (1H,

(C, q, JC–F = 33.8 Hz, C–3⁰⁰), 131.0 (C, C–1⁰⁰), 129.8

3

(CH, C–2⁰,C–6⁰), 129.2 (CH, q, JC–F = 3.5 Hz, C–2⁰⁰),

3

128.3 (CH, q, JC–F = 3.4 Hz, C–4⁰⁰), 127.9 (CH=(2)),

3

127.5 (CH=(1)), 124.3 (C, q, JC–F = 275.3 Hz, –CF₃),

123

Med Chem Res

d, J(trans) = 16.6 Hz, CH=(1)), 6.66 (2H, d, J = 2.2 Hz,

H–2, H–6), 6.40 (1H, d, J = 2.2 Hz, H–4), 4.33 (2H, s, S–

in triethyl phosphite (8.78 mL, 47.544 mmol) was stirred

at 160 °C for 4 h using a pressure vial. The reaction mix-

ture was transferred to a round-bottomed ﬂask using EtOAc

(100 mL) and then concentrated in vacuo. The crude pro-

duct was puriﬁed by ﬂash column chromatography.

CH₂), 3.83 (6H, s, 2 X O–CH₃), 2.43 (3H, s, Ar–CH₃); ¹³

C

NMR (CDCl₃, 75 MHz): d 165.4 (C=O), 164.6 (C, Het–C–

2), 160.9 (C, C–3, C–5), 149.9 (C, C–4⁰), 139.0 (C, C–1),

129.7 (C, C–1⁰), 130.2 (C, C–4⁰⁰), 129.6 (CH, C–2⁰⁰, C–6⁰⁰),

127.9 (CH, C–2⁰, C–6⁰), 127.5 (CH=(2)), 126.7 (CH=(1)),

126.5 (CH, C–3⁰⁰, C–5⁰⁰), 125.9 (C, C–1⁰⁰) 121.4 (CH, C–3⁰,

C–5⁰), 104.6 (CH, C–2, C–6), 100.1 (CH, C–4), 55.3 (O–

CH₃), 34.4 (S–CH₂), 21.6 (Ar–CH₃); MS (ESI) (m/z) 489

[M ? H]^?; HRMS (ESI m/z) for C₂₇H₂₄N₂O₅S calcd

489.1425, found 489.1423 [M ? H]^?.

Diethyl 3,5-dimethoxybenzylphosphonate (6) Light yel-

low oil; Yield: 90 %;¹H NMR (CDCl₃, 300 MHz): d 6.46

(2H, d, J = 2.5 Hz, H–2, H–6), 6.35 (1H, t, J = 2.0 Hz,

H–4), 4.05–4.02 (4H, m, 2 X O–CH₂), 3.78 (6H, s, 2 X O–

CH₃), 3.11 (1H, s, Ar–CH₂), 3.07 (1H, s, Ar–CH₂), 1.26 (t,

J = 7.0 Hz, 6H, 2 X –CH₃); ¹³C NMR (CDCl₃, 75 MHz):

d 160.8 (C, C–3, C–5), 133.7 (C, C–1), 107.9 (CH, C–2, C–

6), 99.2 (CH, C–4), 62.2 (O–CH₂), 55.3 (O–CH₃), 34.0

(Ar–CH₂), 16.4 (–CH₃); for C₁₃H₂₁O₅P MS (ESI) (m/z)

288 [M ? H]^?.

Synthetic method for the preparation of (3,5-dimethox-

yphenyl)methanol (4) To an ice cold solution of 3,5-

dimethoxybenzaldehyde (3) 10 g (60.175 mmol) in

methanol (100 mL) was added in small portions sodium

borohydride (179.751 mmol), and the mixture was stirred

for 2 h at rt. Methanol was distilled off under vacuum, and

the product diluted with cold water, and the solution was

extracted with EtOAc. The EtOAc layer was successively

washed with water, 10 % sodium bicarbonate and brine.

The organic layer was dried over Na₂SO₄, and evaporated

under vacuum obtaining the compound (4) as a white solid.

Synthetic method for the preparation of 4-(Methoxymethoxy)

benzaldehyde (13) DIPEA (28 mL, 173.0 mmol) was

slowly added to a solution of 4-hydroxybenzaldehyde (12)

10 g (81.886 mmol) in THF (300 mL) at 0 °C, with the

subsequent drop wise addition of chloromethylmethyl ether

(12.43 mL, 173.0 mmol) at the same temperature. The

reaction mixture was warmed to room temperature and

stirred for 1 h and then at 65 °C for 20 h. At the end of the

reaction, the mixture was quenched with a saturated NH₄Cl

solution (aq, 700 mL) and extracted with EtOAc (700 mL);

then, the combined organic layer was washed with brine

(700 mL) and dried over Na₂SO₄. The crude product was

puriﬁed by ﬂash column chromatography.

(3,5-Dimethoxyphenyl)methanol (4) White solid; Yield:

94 %; mp 47–49 °C;¹H NMR (CDCl₃, 500 MHz): d

6.55–6.53 (2H, m, H–2, H–6), 6.42–6.40 (1H, m, H–4),

4.52 (2H, s, –CH₂–OH), 3.80 (6H, s, 2 X O–CH₃); ¹³C

NMR (CDCl₃, 75 MHz): d 160.9 (C, C–3, C–5), 143.6 (C,

C–1), 104.6 (CH, C–2, C–6), 99.6 (CH, C–4), 65.1 (H₂C–

OH), 55.3 (O–CH₃); for C₉H₁₂O₃MS (ESI) m/z) 169

[M ? H]^?.

4-(Methoxymethoxy)benzaldehyde

(13) Colorless oil;

Yield: 95 %; ¹H NMR (CDCl₃, 300 MHz): d 9.91 (1H, s, –

CHO), 7.84 (2H, d, J = 9.0 Hz, H–2, H–6), 7.15 (2H, d,

J = 8.5 Hz, H–3, H–5), 5.25 (2H, s, O–CH₂–O), 3.49 (3H,

s, O–CH₃); ¹³C NMR (CDCl₃, 75 MHz): d 191.0 (–CHO),

162.4 (C, C–4), 132.0 (CH, C–2⁰, C–6⁰), 130.9 (C, C–1),

116.5 (CH, C–3, C–5), 94.3 (O–CH₂–O), 56.4 (O–CH₃);

for C₉H₁₀O₃MS (ESI) (m/z) 167 [M ? H]^?.

Synthetic method for the preparation of 1-(bromomethyl)-

3,5-dimethoxybenzene (5) PBr₃(3.10 mL) was added

drop wise to a solution of (4) 9 g (53.545 mmol) in diethyl

ether at 0 °C. The mixture was stirred at 0 °C for 30 min,

and after completion of the reaction (monitored by TLC),

the reaction mixture was quenched by slow addition of

potassium bromide solution, extracted with diethyl ether,

washed with brine, dried over Na₂SO₄and concentrated to

provide the product (5).

General procedure for the synthesis of (E)-1-(4⁰-ni-

trostyryl)-3,5-dimethoxybenzene (8) or (E)-1-(4⁰-(Methox-

ymethoxy)styryl)-3,5-dimethoxybenzene (14) Potassium

t-butoxide (4.28 g, 38.157 mmol) was added to a solution

of (6) 5 g (17.344 mmol) and an appropriate aldehyde (4-

nitrobenzaldehyde (7) or 4-(methoxymethoxy)benzalde-

hyde (13) (17.344 mmol) in DMF (20 mL) at 0 °C. The

reaction mixture was warmed to room temperature and

stirred for 1 h. At the end of the reaction, the mixture was

diluted with water (50 mL) and extracted twice with

EtOAc (100 mL) then, combined organic layer and washed

with brine (300 mL) and dried over Na₂SO₄. The crude

product was puriﬁed by ﬂash column chromatography.

1-(Bromomethyl)-3,5-dimethoxybenzene (5) White solid;

Yield: 97 %; mp 68–70 °C;¹H NMR (CDCl₃, 400 MHz): d

6.55–6.53 (2H, m, H–2, H–6), 6.40–6.38 (1H, m, H–4),

4.42 (2H, s, –CH₂–Br), 3.79 (6H, s, 2 X O–CH₃); ¹³C NMR

(CDCl₃, 75 MHz): d 161.1 (C, C–3, C–5), 139.7 (C, C–1),

106.1 (CH, C–2, C–6), 98.2 (CH, C–4), 55.5 (O–CH₃), 30.5

(H₂C–Br); for C₉H₁₁BrO₂MS (ESI) (m/z) 230 [M ? H]^?.

Synthetic method for the preparation of diethyl 3,5-

dimethoxybenzylphosphonate (6) A solution of 1-(bro-

momethyl)-3,5-dimethoxybenzene (5) 10 g (43.273 mmol)

123

Med Chem Res

(E)-1-(4⁰-Nitrostyryl)-3,5-dimethoxybenzene (8) Yellow

solid; Yield: 70 %; mp 135–137 °C; ¹H NMR (CDCl₃,

300 MHz): d 8.22 (2H, d, J = 9.0 Hz, H–3⁰, H–5⁰), 7.63

(d, J = 8.7 Hz, 2H, H–2⁰, H–6⁰), 7.21 (1H, d, J(-

1 h. At the end of the reaction, the reaction mixture was

treated with water (150 mL) and extracted with EtOAc

(250 mL); then, the combined organic layer was washed

with water (250 mL) and dried over Na₂SO₄. The crude

product was puriﬁed by ﬂash column chromatography.

trans) = 16.2 Hz,

CH=(1)),

7.11

(1H,

d,

J(-

trans) = 16.2 Hz, CH=(2)), 6.72–6.68 (2H, m, H–2, H–6),

6.44–6.40 (1H, m, H–4), 3.85 (6H, s, 2 X O–CH₃); ¹³C

NMR (CDCl₃, 75 MHz): d 161.2 (C, C–3, C–5), 148.3 (C,

C–4⁰), 142.8 (C, C–1⁰), 139.5 (C, C–1), 129.2 (CH, C–2⁰,

C–6⁰), 128.6 (CH=(1)), 127.2 (CH=(2)), 124.0 (CH, C–3⁰,

C–5⁰), 106.2 (CH, C–2, C–6), 100.0 (CH, C–4), 56.0 (O–

CH₃); for C₁₆H₁₅NO₄MS (ESI) (m/z) 286 [M ? H]^?.

(E)-1-(4⁰-Hydroxystyryl)-3,5-dimethoxybenzene (15) White

solid; Yield: 86 %; mp 46–48 °C; ¹H NMR (CDCl₃,

300 MHz): d 7.39 (2H, d, J = 7.0 Hz, H–2⁰, H–6⁰), 7.02

(1H, d, J(trans) = 16.5 Hz, CH=(2)), 6.89 (1H, d, J(-

trans) = 16.5 Hz, CH=(1)), 6.82 (2H, d, J = 7.0 Hz, H–3⁰,

H–5⁰), 6.64 (2H, d, J = 2.0 Hz, H–2, H–6), 6.37 (1H, t,

J = 2.5 Hz, H–4), 3.82 (6H, s, 2 X O–CH₃); ¹³C NMR

(CDCl₃, 75 MHz,): d 161.5 (C, C–3, C–5), 158.9 (C, C–4⁰),

139.9 (C, C–1), 129.9 (CH, C–2⁰, C–6⁰), 128.7 (CH=(2)),

127.6 (C, C–1⁰), 126.8 (CH=(1)), 116.4 (CH, C–3⁰, C–5⁰),

106.3 (CH, C–2, C–6), 100.1 (CH, C–4), 56.0 (O–CH₃); for

C₁₆H₁₆O₃MS (ESI) (m/z) 257 [M ? H]^?.

(E)-1-(4⁰-(Methoxymethoxy)styryl)-3,5-dimethoxybenzene

(14) Colorless oil; Yield: 56 % ¹H NMR (CDCl₃,

300 MHz): d 7.43 (2H, d, J = 9.0 Hz, H–2⁰, H–6⁰), 7.03

(1H, d, J(trans) = 16.5 Hz, CH=(2)), 7.02 (2H, d,

J = 8.5 Hz, H–3⁰, H–5⁰), 6.91 (1H, d, J(trans) = 16.5 Hz,

CH=(1)), 6.65 (2H, d, J = 2.0 Hz, H–2, H–6), 6.38 (1H, t,

J = 2.5 Hz, H–4), 5.19 (2H, s, O–CH₂–O), 3.82 (6H, s, 2

X O–CH₃), 3.49 (3H, s, O–CH₃); ¹³C NMR (CDCl₃,

75 MHz): d 161.5 (C, C–3, C–5), 158.7 (C, C–4⁰), 139.6

(C, C–1), 130.2 (C, C–1⁰), 129.5 (CH, C–2⁰, C–6⁰), 128.3

(CH=(2)), 126.7 (CH=(1)), 116.3 (CH, C–3⁰, C–5⁰), 106.5

(CH, C–2, C–6), 100.1 (CH, C–4), 98.2 (O–CH₂–O), 56.0

(O–CH₃), 55.3 (O–CH₃); for C₁₈H₂₀O₄MS (ESI) (m/z) 301

[M ? H]^?.

Preparation of (E)-2-bromo-N-(4⁰-(3,5-dimethoxystyryl)

phenyl)acetamide (10) and (E)-4⁰-(3,5-dimethoxystyryl)

phenyl 2-bromoacetate (11) Bromoacetyl bromide (3.901

mmol, 1.0 equiv) was added drop wise over 5 min to a

solution of amine (9) or phenol (15) 1 g (3.885 mmol, 1.0

equiv) and triethylamine (4.291 mmol, 1.1 equiv) in

dichloromethane (50 mL), at 0 °C. The reaction mixture

was stirred at 0 °C for 20 min to 1 h, diluted with

dichloromethane (50 mL), washed with saturated NH₄Cl (3

X 30 mL), dried (Na₂SO₄), and concentrated in vacuo to

afford the crude product. The crude product was puriﬁed by

ﬂash column chromatography, to yield pure (E)-2-bromo-

N-(4⁰-(3,5-dimethoxystyryl)phenyl)acetamide or (E)-4⁰-

(3,5-dimethoxystyryl)phenyl 2-bromoacetate.

Synthesis method for (E)-1-(4⁰-Aminostyryl)-3,5-dimethoxy-

benzene (9) SnCl₂Á2H₂O (9.68 g, 42.898 mmol) and

conc. HCl (288 lL) were added to a solution of (8) 3 g

(10.515 mmol) in EtOH (100 mL) and the reaction mixture

was stirred at 80 °C for 2 h. The mixture was neutralized

with a saturated NaHCO₃solution (aq, 200 mL) and

extracted twice with EtOAc (300 mL) and then the com-

bined organic layer was washed with brine (300 mL) and

dried over Na₂SO₄.

(E)-2-Bromo-N-(4⁰-(3,5-dimethoxystyryl)phenyl)acetamide

(10) White solid; Yield: 78 %; mp 174–176 °C; ¹H NMR

(CDCl₃, 300 MHz): d 8.22 (1H, brs, Ar–NH), 7.53 (2H, d,

J = 8.6 Hz, H–2⁰, H–6⁰), 7.48 (2H, d, J = 8.6 Hz, H–3⁰,

H–5⁰), 7.04 (1H, d, J(trans) = 16.3 Hz, CH=(2)), 6.98 (1H,

d, J(trans) = 16.3 Hz, CH=(1)), 6.66 (2H, d, J = 2.1 Hz,

H–2, H–6), 6.39 (1H, t, J = 2.1 Hz, H–4), 4.02 (2H, s,

CH₂–Br), 3.80 (6H, s, 2 X O–CH₃); ¹³C NMR (CDCl₃,

75 MHz): d 166.5 (C=O), 160.9 (C, C–3, C–5), 139.6 (C,

C–4⁰), 139.2 (C, C–1), 133.2 (C, C–1⁰), 129.3 (CH=(2)),

128.2 (CH, C–2⁰, C–6⁰), 126.8 (CH=(1)), 119.8 (CH, C–3⁰,

C–5⁰), 105.6 (CH, C–2, C–6), 100.1 (CH, C–4), 55.3 (O–

CH₃), 30.2 (Br–CH₂); for C₁₈H₁₈BrNO₃MS (ESI) (m/z)

377 [M ? H]^?.

(E)-1-(4⁰-Aminostyryl)-3,5-dimethoxybenzene

9

White

solid; Yield: 70 %; mp 88–90 °C; ¹H NMR (CDCl₃,

300 MHz): d 7.33 (2H,d, J = 8.3 Hz, H–2⁰, H–6⁰), 7.00

(1H, d, J(trans) = 15.8 Hz, CH=(2)), 6.85 (1H, d, J(-

trans) = 15.8 Hz, CH=(1)), 6.67 (2H, d, J = 8.3 Hz, H–3⁰,

H–5⁰), 6.63 (2H, d, J = 2.2 Hz, H–2, H–6), 6.35 (1H, t,

J = 2.2 Hz, H–4), 3.82 (6H, s, 2 X O–CH₃); ¹³C NMR

(CDCl₃, 75 MHz): d 161.2 (C, C–3, C–5), 150.2 (C, C–4⁰),

139.4 (C, C–1), 130.8 (CH, C–2⁰, C–6⁰), 128.6 (CH=(2)),

126.9 (CH=(1)), 125.5 (C, C–1⁰), 114.0 (CH, C–3⁰, C–5⁰),

106.2 (CH, C–2, C–6), 100.1 (CH, C–4), 56.0 (O–CH₃); for

C₁₆H₁₇NO₂MS (ESI) (m/z) 256 [M ? H]^?.

(E)-4⁰-(3,5-Dimethoxystyryl)phenyl 2-bromoacetate (11) White

solid; Yield: 75 %; mp 151–153 °C; ¹H NMR (CDCl₃,

300 MHz): d 7.53 (2H, d, J = 8.5 Hz, H–2⁰, H–6⁰), 7.13

(2H, d, J = 8.5 Hz, H–3⁰, H–5⁰), 7.06 (1H, d, J(-

Synthesis method for (E)-1-(4⁰-Hydroxystyryl)-3,5-

dimethoxybenzene (15) Twenty-two mL of 6 N HCl was

added to a solution of (14) 2.5 g (8.323 mmol) in THF

(25 mL) and was allowed to stir at room temperature for

trans) = 16.3 Hz,

CH=(2)),

6.99

(1H,

d,

J(-

trans) = 16.3 Hz, CH=(1)), 6.67 (2H, d, J = 1.8 Hz, H–2,

123

Med Chem Res

H–6), 6.41 (1H, t, J = 1.8 Hz, H–4), 4.07 (2H, s, CH₂–Br),

3.80 (6H, s, 2 X O–CH₃); ¹³C NMR (CDCl₃, 75 MHz): d

165.8 (C=O), 161.2 (C, C–3, C–5), 154.8 (C, C–4⁰), 139.0

(C, C–1), 132.3 (C, C–1⁰), 129.2 (CH=(2)), 127.9 (CH, C–

2⁰, C–6⁰), 127.5 (CH=(1)), 121.9 (CH, C–3⁰, C–5⁰), 104.6

(CH, C–2, C–6), 100.1 (CH, C–4), 55.2 (O–CH₃), 29.6

(Br–CH₂); for C₁₈H₁₇BrO₄MS (ESI) (m/z) 378 [M ? H]^?.

Methyl 4-ﬂuorobenzoate (17e) Yellow oil; Yield: 80 %;

¹H NMR (CDCl₃, 300 MHz): d 8.09–7.98 (2H, m, H–2, H–

6), 7.13–7.04 (2H, m, H–3, H–5); 3.90 (3H, s, O–CH₃); ¹³

C

NMR (CDCl₃, 100 MHz): d 166.1 (C=O), 165.7 (C, d,

3

¹JC–F = 252.2 Hz, C–4), 132.0 (CH, d, JC–F = 9.2 Hz,

C–2, C–6), 126.4 (C, d, ⁴JC–F = 3.0 Hz, C–1), 115.4 (CH,

d, ²JC–F = 21.9 Hz, C–3, C–5), 52.1 (O–CH₃); for

C₈H₇FO₂MS (ESI) (m/z) 155 [M ? H]^?.

General procedure for the preparation of methyl esters

(17a–j) A catalytic amount of concentrated H₂SO₄was

added to a solution of carboxylic acids 16(a–j) (1.0 mmol)

in 50 mL of methanol, and the mixture was reﬂuxed for

6 h. It was allowed to cool. The saturated solution of

NaHCO₃was added to the reaction mixture, and it was

extracted with EtOAc (2 X 50 mL). The combined organic

layer was dried Na₂SO₄and concentrated to obtain pure

methyl esters 17(a–j).

Methyl 4-(triﬂuoromethyl)benzoate

(17f) Colorless

oil; Yield: 78 %; ¹H NMR (CDCl₃, 300 MHz): d 7.99 (2H,

d, J = 7.5 Hz, H–2, H–6), 7.75 (2H, d, J = 7.5 Hz, H–3,

H–5), 3.89 (3H, s, O–CH₃); ¹³C NMR (CDCl₃, 100 MHz):

d 165.8 (C=O), 134.5 (C, q, ²JC–F = 32.7 Hz, C–4), 133.3

(C, C–1), 129.9 (CH, C–2, C–6), 125.3 (CH, q, ³JC–

F = 3.8 Hz, C–3, C–5), 123.6 (C, q, ¹JC–F = 272.7 Hz, –

CF₃), 52.4 (O–CH₃); for C₉H₇F₃O₂MS (ESI) (m/z) 205

[M ? H]^?.

Methyl 3,4,5-trimethoxybenzoate

(17a) White solid;

1

Yield: 83 %; mp 85–87 °C; H NMR (CDCl₃, 400 MHz):

d 7.31 (2H, s, H–2, H–6), 3.92 (6H, s, O–CH₃), 3.84 (3H, s,

O–CH₃) 3.82 (3H, s, O–CH₃); ¹³C NMR (CDCl₃,

100 MHz): d 166.7 (C=O), 152.9 (C, C–3, C–5), 142.2 (C,

C–4), 125.1 (C, C–1), 106.8 (CH, C–2, C–6), 60.9 (O–

CH₃), 58.2 (O–CH₃), 52.2 (O–CH₃); for C₁₁H₁₄O₅MS

(ESI) (m/z) 227 [M ? H]^?.

Methyl 3-(triﬂuoromethyl)benzoate (17g) Colorless oil;

1

Yield: 76 %; H NMR (CDCl₃, 400 MHz): d 8.33 (1H, s,

H–2), 8.25 (1H, d, J = 7.8 Hz, H–6), 7.84 (1H, d,

J = 7.8 Hz, H–4), 7.61 (1H, t, J = 7.8 Hz, H–5), 3.98

(3H, s, O–CH₃); ¹³C NMR (CDCl₃, 100 MHz): d 165.7

2

(C=O), 132.7 (CH, C–6), 131.0 (C, q, JC–F = 33.0 Hz,

3

C–3), 131.0 (C, C–1), 129.4 (CH, q, JC–F = 3.6 Hz, C–

4), 129.0 (CH, C–5), 126.5 (CH, q, ³JC–F = 3.8 Hz, C–2),

Methyl isonicotinate (17b) Colorless oil; Yield: 75 %;

¹H NMR (CDCl₃, 500 MHz): d 8.70 (2H, d, J = 7.5 Hz,

H–2, H–6), 7.77 (2H, d, J = 7.5 Hz, H–3, H–5), 3.88 (3H,

s, O–CH₃); ¹³C NMR (CDCl₃, 125 MHz,): d 165.4 (C=O),

150.4 (CH, C–2, C–6), 137.1 (C, C–4), 122.7 (CH, C–3, C–

5), 52.5 (O–CH₃); for C₇H₇NO₂MS (ESI) (m/z) 138

[M ? H]^?.

1

123.6 (C, q, JC–F = 270.7 Hz, –CF₃), 52.4 (O–CH₃); for

C₉H₇F₃O₂MS (ESI) (m/z) 205 [M ? H]^?.

Methyl pyrazine-2-carboxylate (17h) Pale brown solid;

1

Yield: 72 %; mp 60–62 °C; H NMR (CDCl₃, 400 MHz):

d 9.30 (1H, s, H–3), 8.80 (1H, d, J = 2.5 Hz, H–5), 8.75

(1H, d, J = 2.5 Hz, H–6), 4.08 (3H, s, O–CH₃); ¹³C NMR

(CDCl₃, 100 MHz): d 165.7 (C=O), 147.2 (CH, C–3),

146.3 (CH, C–5), 144.8 (CH, C–6), 143.2 (C, C–2), 51.8

(O–CH₃); for C₆H₆N₂O₂MS (ESI) (m/z) 139 [M ? H]^?.

Methyl 2-ﬂuorobenzoate (17c) Colorless oil; Yield:

1

80 %; H NMR (CDCl₃, 300 MHz): d 7.95–7.82 (1H, m,

H–6), 7.65–7.53 (1H, m, H–4), 7.35–7.21 (2H, m, H–3, H–

5), 3.86 (3H, s, O–CH₃); ¹³C NMR (CDCl₃, 100 MHz): d

164.8 (C=O), 161.8 (C, d, ¹JC–F = 260.2 Hz, C–2), 134.4

(CH, d, ³JC–F = 9.0 Hz, C–6), 132.0 (CH, d, ³JC–

Methyl 4-methoxybenzoate (17i) Colorless oil; Yield:

82 %; ¹H NMR (CDCl₃, 300 MHz): d 7.94 (2H, d,

J = 9.1 Hz, H–3, H–5), 6.86 (2H, d, J = 9.1 Hz, H–2, H–

6), 3.86 (3H, s, O–CH₃), 3.84 (3H, s, O–CH₃); ¹³C NMR

(CDCl₃, 125 MHz): d 166.8 (C=O), 163.3 (C, C–4), 131.5

(CH, C–3, C–5), 122.5 (CH, C–2, C–6), 113.5 (C, C–1),

55.3 (O–CH₃), 51.8 (O–CH₃); for C₉H₁₀O₃MS (ESI) (m/

z) 167 [M ? H]^?.

4

F = 9.2 Hz, C–4), 123.9 (CH, d, JC–F = 3.9 Hz, C–5),

2

118.6 (C, d, JC–F = 9.9 Hz, C–1), 117.0 (CH, d, JC–

F = 22.3 Hz, C–3), 52.2 (O–CH₃); for C₈H₇FO₂MS (ESI)

(m/z) 155 [M ? H]^?.

Methyl 2,6-diﬂuorobenzoate (17d) Yellow oil; Yield:

1

82 %; H NMR (CDCl₃, 400 MHz): d 7.46–7.37 (1H, m,

Methyl 4-methylbenzoate (17j) Colorless oil; Yield: 82 %;

¹H NMR (CDCl₃, 300 MHz): d 7.89 (2H, d, J = 7.6 Hz, H–

2, H–6), 7.18 (2H, d, J = 8.3 Hz, H–3, H–5), 3.87 (3H, s, O–

CH₃), 2.39 (3H, s, Ar–CH₃); ¹³C NMR (CDCl₃, 75 MHz): d

166.6 (C=O), 143.7 (C, C–4), 129.7 (CH, C–2, C–6), 129.1

(CH, C–3, C–5), 127.3 (C, C–1), 51.2 (O–CH₃), 21.5 (Ar–

CH₃); for C₉H₁₀O₂MS (ESI) (m/z) 151 [M ? H]^?.

H–4), 6.98–6.91 (2H, m, H–3, H–5), 3.95 (3H, s, O–CH₃);

¹³C NMR (CDCl₃, 75 MHz): d 164.5 (C=O), 161.2 (C, d,

¹JC–F = 260.0 Hz, C–2, C–6), 133.6 (CH, d, ³JC–

F = 9.0 Hz, C–4), 116.9 (C, d, ²JC–F = 9.9 Hz, C–1),

112.3 (CH, d, ²JC–F = 22.0 Hz, C–3, C–5), 52.3 (O–

CH₃); for C₈H₆F₂O₂MS (ESI) (m/z) 173 [M ? H]^?.

123

Med Chem Res

General procedure for the preparation of acid hydrazi-

des (18a–j) To a solution of an appropriate methyl esters

17(a–j) (1.0 mmol) in 50 mL of methanol was added 99 %

hydrazine hydrate (4.0 mmol) and the mixture was reﬂuxed

for 5 h up to reaction completed (TLC). After completion

of reaction, it was allowed to cool and the obtained solid

was washed with methanol. The crude products were

recrystallized from ethanol.

4-(Triﬂuoromethyl)benzohydrazide (18f) White solid;

Yield: 85 %; mp 162–164 °C; ¹H NMR (DMSO–d₆,

300 MHz): d 9.54 (1H, brs, –NH), 7.97 (2H, d, J = 7.3 Hz,

H–3, H–5), 7.79 (2H, d, J = 7.3 Hz, H–2, H–6), 3.98 (2H,

brs, –NH₂); ¹³C NMR (DMSO–d₆, 75 MHz): d 166.2

(C=O), 135.2 (C, C–1), 134.6 (C, q, ²JC–F = 32.6 Hz, C–

3

4), 129.2 (CH, C–2, C–6), 127.8 (CH, q, JC–F = 3.5 Hz,

C–3, C–5), 124.3 (C, q, ¹JC–F = 271.3 Hz, –CF₃); for

C₈H₇F₃N₂O MS (ESI) (m/z) 205 [M ? H]^?.

3,4,5-Trimethoxybenzohydrazide

(18a) White solid;

Yield: 88 %; mp 162–164 °C; ¹H NMR (DMSO–d₆,

400 MHz): d 9.55 (1H, brs, –NH), 7.18 (2H, s, H–2, H–6),

3.98 (2H, brs, –NH₂), 3.83 (9H, s, 3 X O–CH₃); ¹³C NMR

(DMSO–d₆, 125 MHz): d 165.6 (C=O), 158.7 (C, C–3, C–

5), 130.0 (C, C–4), 128.4 (C, C–1), 127.5 (CH, C–2, C–6),

59.1 (O–CH₃), 56.3 (O–CH₃); for C₁₀H₁₄N₂O₄MS (ESI)

(m/z) 227 [M ? H]^?.

3-(Triﬂuoromethyl)benzohydrazide (18g) White solid;

Yield: 83 %; mp 105–107 °C; ¹H NMR (DMSO–d₆,

500 MHz): d 10.04 (1H, brs, –NH), 8.15 (1H, s, H–2), 8.13

(1H, d, J = 7.8 Hz, H–6), 7.88 (1H, d, J = 7.8 Hz, H–4),

7.70 (1H, t, J = 7.8 Hz, H–5), 4.65 (2H, brs, –NH₂); ¹³C

NMR (DMSO–d₆, 125 MHz): d 164.2 (C=O), 134.1 (C, C–

1), 130.9 (C, q, ²JC–F = 33.5 Hz, C–3), 129.6 (CH, C–6),

3

129.1 (CH, C–5), 127.6 (CH, q, JC–F = 3.2 Hz, C–4),

Isonicotinohydrazide (18b) White crystalline; Yield:

78 %; mp 171–173 °C; ¹H NMR (DMSO–d₆, 400 MHz): d

9.57 (1H, brs, –NH), 8.89–8.82 (2H, m, H–2, H–6),

7.82–7.80 (2H, m, H–3, H–5), 3.99 (2H, brs, –NH₂); ¹³C

NMR (DMSO–d₆, 75 MHz): d 170.3 (C=O), 149.2 (CH,

C–2, C–6), 141.0 (C, C–4), 121.6 (CH, C–3, C–5); for

C₆H₇N₃O MS (ESI) (m/z) 138 [M ? H]^?.

3

1

123.5 (CH, q, JC–F = 3.5 Hz, C–2), 123.9 (C, q, JC–

F = 272.1 Hz); for C₈H₇F₃N₂O MS (ESI) (m/z) 205

[M ? H]^?.

Pyrazine-2-carbohydrazide (18h) Pale brown solid;

Yield: 75 %; mp 73–75 °C; ¹H NMR (DMSO–d₆,

500 MHz): d 10.08 (1H, brs, –NH), 9.12 (1H, s, H–3), 8.83

(1H, d, J = 7.5 Hz, H–5) 8.70 (1H, d, J = 7.5 Hz, H–6),

4.65 (2H, brs, –NH₂); ¹³C NMR (DMSO–d₆,

75 MHz): d 162.0 (C=O), 147.8 (C, C–2), 146.2 (CH, C–

6), 145.4 (CH, C–3), 144.0 (CH, C–5); for C₅H₆N₄O MS

(ESI) (m/z)139 [M ? H]^?.

2-Fluorobenzohydrazide (18c) Pale yellow solid; Yield:

1

82 %; mp 72–74 °C; H NMR (CDCl₃, 300 MHz): d 9.54

(1H, brs, –NH), 8.01–7.95 (1H, m, H–4), 7.67–7.53 (1H,

m, H–6), 7.38–7.25 (2H, m, H–3, H–5), 4.00 (2H, brs, –

NH₂); ¹³C NMR (CDCl₃, 75 MHz): d 165.2 (C=O), 152.3

(C, d, ¹JC–F = 246.9 Hz, C–2), 135.1 (CH, d, ³JC–

4-methoxybenzohydrazide (18i) White solid; Yield:

85 %; mp 128–130 °C; ¹H NMR (DMSO–d₆, 300 MHz): d

9.57 (1H, brs, –NH), 7.69 (2H, d, J = 8.6 Hz, H–2, H–6),

6.89 (2H, d, J = 8.6 Hz, H–3, H–5), 3.96 (2H, brs, –NH₂),

3.84 (3H, s, O–CH₃); ¹³C NMR (DMSO–d₆, 75 MHz): d

165.7 (C=O), 161.5 (C, C–4), 128.8 (CH, C–2, C–6), 125.5

(C, C–1), 113.5 (CH, C–3, C–5), 55.3 (O–CH₃); for

C₈H₁₀N₂O₂MS (ESI) (m/z) 167 [M ? H]^?.

3

F = 8.6 Hz, C–4), 132.6 (CH, d, JC–F = 9.0 Hz, C–6),

4

126.9 (CH, d, JC–F = 3.6 Hz, C–5), 125.0 (C, d, JC–

2

F = 12.2 Hz, C–1), 114.2 (CH, d, JC–F = 25.6 Hz, C–

3); for C₇H₇FN₂O MS (ESI) (m/z) 155 [M ? H]^?.

2,6-Diﬂuorobenzohydrazide

(18d) Light pink solid;

1

Yield: 80 %; mp 82–84 °C; H NMR (CDCl₃, 400 MHz):

d 9.55 (1H, brs, –NH), 7.49–7.38 (1H, m, H–4), 7.01–6.95

(2H, m, H–3, H–5), 4.01 (2H, brs, –NH₂); ¹³C NMR

(CDCl₃, 75 MHz): d 165.3 (C=O), 159.3 (C, d, ¹JC–

4-Methylbenzohydrazide (18j) White solid; Yield: 83 %;

mp 117–119 °C; ¹H NMR (CDCl₃, 300 MHz): d 9.55 (1H,

brs, –NH), 7.62 (2H, d, J = 8.4 Hz, H–2, H–6), 7.21 (2H,

d, J = 8.4 Hz, H–3, H–5); 4.01 (2H, brs, –NH₂), 2.41 (3H,

s, Ar–CH₃); ¹³C NMR (CDCl₃, 75 MHz): d 166.5 (C=O),

136.4 (C, C–4), 129.6 (CH, C–3, C–5), 129.1 (C, C–1)

126.8 (CH, C–2, C–6), 21.7 (Ar–CH₃); for C₈H₁₀N₂O MS

(ESI) (m/z) 151 [M ? H]^?.

3

F = 258.9 Hz, C–2, C–6), 133.5 (CH, d, JC–F = 8.6 Hz,

2

C–4), 115.3 (C, d, JC–F = 9.5 Hz, C–1), 112.5 (CH, d,

²JC–F = 23.5 Hz, C–3, C–5); for C₇H₆F₂N₂O MS (ESI)

(m/z) 173 [M ? H]^?.

4-Fluorobenzohydrazide (18e) White solid; Yield: 83 %;

mp 161–163 °C; ¹H NMR (CDCl₃, 300 MHz): d 9.54 (1H,

brs, –NH), 8.24–7.95 (2H, m, H–2, H–6), 7.21–7.09 (2H,

m, H–3, H–5), 3.98 (2H, brs, –NH₂); ¹³C NMR (CDCl₃,

75 MHz): d 166.5 (C=O), 165.2 (C, d, ¹JC–F = 250.0 Hz,

C–4), 129.3 (CH, d, ³JC–F = 9.0 Hz, C–2, C–6), 127.3 (C,

d, ⁴JC–F = 2.9 Hz, C–1), 115.5 (CH, d, ²JC–F = 21.5 Hz,

C–3, C–5), for C₇H₇FN₂O MS (ESI) (m/z) 155 [M ? H]^?.

General procedure for the preparation of 1,3,4-oxadiazole-

2-thiones (19a–j) Acid hydrazides 18(a–j) (1.0 mmol)

were dissolved in ethanol (50 mL),and to this potassium

hydroxide was added (1.49 mmol) which is dissolved in

water (2 mL), and then carbondisulﬁde was added

(4.0 mmol). Then, the reaction mixture was heated at reﬂux

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Med Chem Res

for 10-12 h. Solvent was evaporated, and the residue was

acidiﬁed with 10 % HCl. The precipitate was collected by

ﬁltration, washed with water and dried. The products 19(a–

j) were used without further puriﬁcation.

¹JC–F = 250.3 Hz, C–4), 158.3 (C, Het–C–5), 132.2 (CH,

d, ³JC–F = 9.2 Hz, C–2, C–6), 130.7 (C, d, ⁴JC–

2

F = 3.1 Hz, C–1), 128.9 (CH, d, JC–F = 21.5 Hz, C–3,

C–5); for C₈H₅FN₂OS MS (ESI) (m/z) 197 [M ? H]^?.

5-(3,4,5-Trimethoxyphenyl)-1,3,4-oxadiazole-2-thione (19a)

White solid; Yield: 90 %; mp 187–189 °C; IR (KBr)

(mmax/cm^-1): 3450, 1642, 1563, 1255, 1025, 680; ¹H NMR

(CDCl₃, 300 MHz): d 14.30 (1H, brs, –NH), 7.15 (2H, s,

H–2, H–6), 3.93 (9H, s, 3 X O–CH₃); ¹³C NMR (CDCl₃,

75 MHz): d 178.0 (C=S), 160.9 (C, Het–C–5), 153.4 (C,

C–3, C–5), 140.9 (C, C–4), 117.5 (C, C–1), 103.3 (CH, C–

2, C–6), 60.7 (O–CH₃), 56.0 (O–CH₃); for C₁₁H₁₂N₂O₄S

MS (ESI) (m/z) 269 [M ? H]^?.

5-(4-(Triﬂuoromethyl)phenyl)-1,3,4-oxadiazole-2-thione (19f)

Pale brown solid; Yield: 85 %; mp 151–153 °C; IR (KBr)

(mmax/cm^-1): 3452, 1645, 1562, 1250, 1028, 685; ¹H NMR

(DMSO–d₆, 300 MHz): d 14.43 (1H, brs, –NH), 8.08 (2H,

d, J = 8.2 Hz, H–2, H–6), 7.79 (2H, d, J = 8.2 Hz, H–3,

H–5); ¹³C NMR (DMSO–d₆, 100 MHz): d 177.3 (C=S),

2

163.0 (C, Het–C–5), 133.5 (C, q, JC–F = 32.5 Hz, C–4),

3

129.0 (CH, C–2, C–6), 128.8 (CH, q, JC–F = 3.5 Hz, C–

1

3, C–5), 127.4 (C, C–1), 124.5 (C, q, JC–F = 273.0 Hz,

–CF₃); for C₉H₅F₃N₂OS MS (ESI) (m/z) 247 [M ? H]^?.

5-(Pyridin-4-yl)-1,3,4-oxadiazole-2-thione (19b) Yellow

solid; Yield: 80 %; mp 275–277 °C; IR (KBr) (mmax/

cm^-1): 3455, 1645, 1562, 1258, 1020, 682; ¹H NMR

(DMSO–d₆, 400 MHz): d 14.28 (1H, brs, –NH), 8.79–8.67

(2H, m, H–2, H–6), 7.75–7.62 (2H, m, H–3, H–5); ¹³C

NMR (DMSO–d₆, 400 MHz): d 177.8 (C=S), 158.8 (C,

Het–C–5), 150.8 (CH, C–2, C–6), 129.8 (C, C–4), 119.6

(CH, C–3, C–5); for C₇H₅N₃OS MS (ESI) (m/z) 180

[M ? H]^?.

5-(3-(Triﬂuoromethyl)phenyl)-1,3,4-oxadiazole-2-thione

(19g) Pale brown solid; Yield: 85 %; mp 153–155 °C; IR

(KBr) (mmax/cm^-1): 3456, 1648, 1560, 1255, 1032, 688;

¹H NMR (DMSO–d₆, 300 MHz): d 14.53 (1H, brs, –NH),

8.09 (1H, s, H–2), 7.98 (1H, d, J = 7.5 Hz, H–6), 7.68

(1H, d, J = 7.5 Hz, H–4), 7.48 (1H, t, J = 7.5 Hz, H–5);

¹³C NMR (DMSO–d₆, 75 MHz): d 177.5 (C=S), 165.1 (C,

Het–C–5), 132.0 (CH, C–6), 130.6 (C, q, ²JC–

F = 33.9 Hz, C–3), 130.0 (C, C–1), 129.3 (CH, C–5),

5-(2-Fluorophenyl)-1,3,4-oxadiazole-2-thione (19c)

Light yellow solid; Yield: 85 %; mp 171–173 °C; IR (KBr)

(mmax/cm^-1): 3452, 1642, 1560, 1257, 1023, 684; ¹H NMR

(DMSO–d₆, 300 MHz): d 14.35 (1H, brs, –NH), 7.96–7.89

(1H, m, H–6), 7.63–7.54 (1H, m, H–4), 7.36–7.21 (2H, m,

H–3, H–5); ¹³C NMR (DMSO–d₆, 75 MHz): d 177.2

3

124.5 (CH, q, JC–F = 3.7 Hz, C–4), 123.6 (CH, q, JC–

F = 3.8 Hz, C–2), 123.32 (C, q, ¹JC–F = 273.1 Hz, –

C F₃); for C₉H₅F₃N₂OS MS (ESI) (m/z) 247 [M ? H]^?.

5-(Pyrazin-2-yl)-1,3,4-oxadiazol-2-thione (19h) Brown

solid; Yield: 75 %; mp 205–207 °C; IR (KBr) (mmax/

cm^-1): 3452, 1643, 1558, 1256, 1020, 683; ¹H NMR

(DMSO–d₆, 400 MHz): d 14.48 (1H, brs, –NH), 9.12 (1H,

d, J = 1.2 Hz, H–3), 8.81 (2H, dd, J = 6.4, 2.0 Hz, H–5,

H–6); ¹³C NMR (DMSO–d₆, 75 MHz): d 177.6 (C=S),

162.1 (C, Het–C–5), 148.9 (C, C–2), 147.6 (CH, C–3),

145.3 (CH, C–6), 144.8 (CH, C–5); for C₆H₄N₄OS MS

(ESI) (m/z) 181 [M ? H]^?.

1

(C=S), 162.5 (C, d, JC–F = 263.5 Hz, C–2), 158.3 (C,

Het–C–5), 133.2 (CH, d, ³JC–F = 9.5 Hz, C–4), 129.6

(CH, d, ³JC–F = 9.2 Hz, C–6), 124.8 (CH, d, ⁴JC–

2

F = 4.5 Hz, C–5), 116.3 (CH, d, JC–F = 23.5 Hz, C–3),

2

105.2 (C, d, JC–F = 9.5 Hz, C–1); for C₈H₅FN₂OS MS

(ESI) (m/z) 197 [M ? H]^?.

5-(2,6-Diﬂuorophenyl)-1,3,4-oxadiazole-2-thione

(19d)

Light yellow solid; Yield: 86 %; mp 144–146 °C; IR (KBr)

(mmax/cm^-1): 3455, 1645, 1562, 1255, 1028, 686; ¹H NMR

(DMSO–d₆, 300 MHz): d 14.42 (1H, brs, –NH), 7.50–7.45

(1H, m, H–4), 7.18–7.12 (2H, m, H–3, H–5); ¹³C NMR

5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-thione (19i)

Light pink solid; Yield: 88 %; mp 200–202 °C; IR (KBr)

(mmax/cm^-1): 3450, 1645, 1556, 1257, 1025, 685; ¹H NMR

(DMSO–d₆, 300 MHz): d 14.54 (1H, brs, –NH), 8.05–8.03

(2H, m, H–2, H–6), 7.08–7.02 (2H, m, H–3, H–5), 3.86

(3H, s, O–CH₃); ¹³C NMR (DMSO–d₆, 75 MHz): d 177.8

(C=S), 163.2 (C, Het–C–5), 161.8 (C, C–4), 129.2 (CH, C–

2, C–6), 116.9 (C, C–1), 114.5 (CH, C–3, C–5), 55.7 (O–

CH₃); for C₉H₈N₂O₂S MS (ESI) (m/z) 209 [M ? H]^?.

1

(DMSO–d₆, 75 MHz): d 177.0 (C=S), 162.3 (C, d, JC–

F = 262.3 Hz, C–2, C–6), 158.1 (C, Het–C–5), 132.0 (CH,

d, ³JC–F = 8.9 Hz, C–4), 112.4 (CH, d, ²JC–F = 22.3 Hz,

2

C–3, C–5), 104.9 (C, d, JC–F = 9.2 Hz, C–1); for C_8-

H₄F₂N₂OS MS (ESI) (m/z) 215 [M ? H]^?.

5-(4-Fluorophenyl)-1,3,4-oxadiazole-2-thione (19e)

White solid; Yield: 85 %; mp 203–205 °C; IR (KBr)

(mmax/cm^-1): 3453, 1640, 1565, 1252, 1025, 687; ¹H NMR

(DMSO–d₆, 300 MHz): d 14.51 (1H, brs, –NH), 7.85–7.80

(2H, m, H–2, H–6), 7.37–7.32 (2H, m, H–3, H–5); ¹³C

NMR (DMSO–d₆, 75 MHz): d 177.8 (C=S), 162.4 (C, d,

5-(p-tolyl)-1,3,4-oxadiazole-2-thione (19j) White solid;

Yield: 86 %; mp 208–210 °C; IR (KBr) (mmax/cm^-1):

3454, 1640, 1555, 1256, 1027, 683; HNMR (DMSO–d₆,

1

400 MHz): d 14.51 (1H, brs, –NH), 7.77–7.75 (2H, d,

J = 7.5 Hz, H–2, H–6), 7.39–7.37 (2H, d, J = 7.5 Hz, H–

3, H–5), 2.37 (3H, s, –CH₃); ¹³C NMR (DMSO–d₆,

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Med Chem Res

respectively

75 MHz): d 177.3 (C=S), 163.4 (C, Het–C–5), 142.5 (C,

C–4), 129.9 (CH, C–2, C–6), 128.6 (CH, C–3, C–5), 121.3

(C, C–1), 21.5 (Ar–CH₃); for C₉H₈N₂OS MS (ESI) (m/

z) 193 [M ? H]^?.

cervix

and

pancreatic

carcinoma,

(GI₅₀\ 0.1 lM). The structural features of these com-

pounds 1g, 2g [3-(triﬂuoromethyl)phenyl], 1c, 2c (2-ﬂuo-

rophenyl), 2i (4-methoxyphenyl) and 1a (3,4,5-

trimethoxyphenyl) are suggesting that these substitutes at

5-position of 1,3,4-oxadiazole 2-thiol moiety supportive for

potent antiproliferative activity.

In vitro cytotoxic activity studies

The cell lines used in this study (SiHa, MDA-MB-231 and

PANC-1) were purchased from the American Type Culture

Collection (ATCC, United States). These entire cell lines

were grown in Dulbecco’s modiﬁed Eagle’s medium

(containing 10 % fetal bovine serum (FBS) in a humidiﬁed

atmosphere of 5 % CO₂at 37 °C). Cells were trypsinized

when subconﬂuent from T25 ﬂasks/60-mm dishes and

seeded in 96-well plates. The synthesized resveratrol-oxa-

diazoles hybrid compounds were evaluated for their

in vitro cytotoxicity in three different human cancer cell

lines. A protocol of 48 h continuous drug exposure was

used, and a SRB cell proliferation assay (Reddy et al.,

2011) was used to estimate cell viability or growth. The

cell lines were grown in the media containing 10 % fetal

bovine serum and were seeded into 96-well microtiter

plates in 100 lL aliquots at plating densities depending on

the doubling time of individual cell lines. The microtiter

plates were incubated at 37 °C, 5 % CO₂, 95 % air, and

100 % relative humidity for 24 h prior to addition of

experimental drugs and were incubated for 48 h with dif-

ferent doses (1, 10, 100 lM) of prepared derivatives. After

48 h incubation at 37 °C, cell monolayers were ﬁxed by the

addition of 100 lL of 10 % (wt/vol) cold trichloroacetic

acid and incubated at 4 °C for 1 h. The supernatant was

discarded, and the cells were then stained with 0.057 %

SRB dissolved in 1 % acetic acid for 30 min at room

temperature. Unbound SRB was washed away with four

washes of 1 % acetic acid, and the bound SRB stain, rep-

resenting surviving cells, was dissolved in 50 lL of Tris

base (10 mM). The optical density was determined at

510 nm using a microplate reader (Enspire, Perkin Elmer,

USA).

Acknowledgments The authors are thankful to the Director, Indian

Institute of Chemical Technology, Hyderabad, for the encouragement,

RP thankful to CSIR, New Delhi, India for the award of research

fellowships. We thank CSIR for ﬁnancial support under the 12^thFive

Year plan projects ‘‘Affordable Cancer Therapeutics (ACT)’’ (CSC

0301) and ‘‘Small Molecules in Lead Exploration (SMiLE)’’

(CSC0111).

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Article Doi

Synthesis and biological evaluation of novel resveratrol-oxadiazole hybrid heterocycles as potential antiproliferative agents

DOI: 10.1007/s00044-016-1514-1

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Article abstract of DOI:10.1007/s00044-016-1514-1

Full text of DOI:10.1007/s00044-016-1514-1

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