Synthesis and E/Z configuration determination of novel derivatives of 3-Aryl-2-(benzothiazol-2′-ylthio) acrylonitrile, 3-(benzothiazol-2′- ylthio)-4-(furan-2′ ′-yl)-3-buten-2-one and 2-(1-(Furan-2′ ′-yl)-3′-oxobut-1′ ′-en-2-ylthio)-3-phenylquinazolin- 4(3H)-one

Molecules 2011, 16, 6129-6147; doi:10.3390/molecules16076129

OPEN ACCESS

molecules

ISSN 1420-3049

www.mdpi.com/journal/molecules

Article

Synthesis and E/Z Configuration Determination of Novel

Derivatives of 3-Aryl-2-(benzothiazol-2'-ylthio) Acrylonitrile,

3-(Benzothiazol-2'-ylthio)-4-(furan-2''-yl)-3-buten-2-one and

2-(1-(Furan-2''-yl)-3'-oxobut-1''-en-2-ylthio)-3-

phenylquinazolin-4(3H)-one

Fatima Al-Omran ^1,*, Rafat M. Mohareb ^2,3and Adel Abou El-Khair ¹

1

Department of Chemistry, Faculty of Science, Kuwait University, P.O. box 12613,

safat 13060, Kuwait

2

Department of Chemistry, Faculty of Science, Cairo University, Giza, A.R., Egypt

3

Department of Organic Chemistry, Faculty of Pharmacy, October University for Modern Sciences

and Arts, Elwahaat Road, October City, A.R., Egypt

* Author to whom correspondence should be addressed; E-Mail: fatima.alomran@ ku.edu.kw.

Received: 21 June 2011; in revised form: 11 July 2011 / Accepted: 14 July 2011 /

Published: 20 July 2011

Abstract: Knoevenagel condensation of 2-(benzothiazol-2-ylthio) acetonitrile (2) with

either furan-2-carbaldehyde or thiophene-2-carbaldehydes leads to E-isomers 4a–b

exclusively, while the condensation of the compound 2 with benzaldehyde or para-

substituted benzaldehydes with an electron-donating group afforded E/Z mixtures 4c–e

with preferentially formation of the E-isomer. Condensation of furan-2-carbaldehyde (3a)

with either 1-(benzothiazol-2'-ylthio) propan-2-one (5) or 2-(2'-oxo propylthio)-3-phenyl-

quinazolin-4(3H)-one (9) leads exclusively to the Z-isomers of 6 and 10, respectively. The

structures of the newly synthesized compounds were elucidated by elemental analyses,

¹H-NMR and ¹³C-NMR spectra, COSY, HSQC, HMBC, NOE, MS and X-ray crystallographic

investigations.

Keywords: benzothiazole; 2-mercaptobenazothiazole; 3-phenylquinazolin-4(3H)-one;

methyl vinyl ketone; acrylonitrile

Molecules 2011, 16

6130

1. Introduction

The benzothiazole nucleus is a highly important scaffold for drug development, which has been

reported to show good biological activities ranging from anti-microbial [1], anti-inflammatory [1],

antibacterial [2], antitumor [3] and anticancer [4,5] to antifungal [6]. On other hand, quinazolin-4-

(3H)-ones substituted in the 3-position with a heterocyclic system are attracting the attention of

chemists, because of their biological activities ranging from antibacterial, antimicrobial, antifungal,

anticonvulsive, sedative, anti-inflammatory, to hypnotic and CNS depression [7-12]. Furthermore,

several other publications have pointed out the value of 3-arylacylonitriles with either triazole [13] or

benzimidazole [14] substituents in position 2 of the acrylonitrile also have good cytotoxic activity on

human cancer cells and are antibacterial agents [14]. It was recently reported that 2-acetyl-3-

(6-methoxybenzothiazo)-2-yl-amino-acylonitrile (AMBAN) possesses significant anti-proliferative

activity and is a potent inducer programmed cell death in human leukemia cells [5].

Based on the abovementioned effects of benzothiazoles, 3-arylacrylonitriles and quinazolin-4-(3H)-

ones a series of novel 3-arylacrylonitriles with 2-mercaptobenzothiazoles moiety in the position 2- of

the acrylonitrile were synthesized to obtain new potential biologically active agents. On other hand, a

series of 4-aryl-3-buten-2-ones with either 2-mercaptobenzothiazole or quinazolin-4-(3H)-one rings in

the 3-position of 4-aryl-3-buten-2-one were synthesized. The structures of the newly synthesized

compounds have been established by x-ray diffraction studies and on the basis of their spectral data.

2. Result and Discussion

In continuation to our recent research programme dealing with the synthesis of heterocyclic

systems, particularly those containing the 2-mercaptobenzothiazole moiety [15,16], 1-(benzothiazol-2-

yl-thio)acetonitrile (2) was readily prepared in an excellent yield by treatment of 2-mercapto-

benzothiazole (1) with α-chloroacetonitrile in refluxing acetone containing anhydrous potassium

carbonate (cf. Scheme 1). The structure of 2 was unambiguously confirmed by X-ray crystallography

[17] as well as on the basis of its spectral data (cf. Figure 1 and Tables 1–3).

Scheme 1. Synthesis of 2.

N

S

ClCH₂CN

SH

S

N

K₂CO₃/acetone

N

heat

2

1

Figure 1. Perspective view and atom labeling of the X-ray structure of compound 2.

Molecules 2011, 16

6131

Table 1. Bond lengths (Å) for compound 2.

atom distance atom atom distance

atom

S1

S2

S3

S4

S5

S6

N1

N2

N3

N5

N6

C1

C3

C5

C10

C11

C13

C17

C19

C21

C23

C1

C7

1.730(3)

1.747(3)

1.732(3)

1.745(3)

1.731(3)

1.747(3)

1.400(4)

1.136(5)

1.292(3)

1.402(3)

1.136(6)

1.404(4)

1.388(5)

1.384(4)

1.392(4)

1.366(4)

1.373(5)

1.447(5)

1.400(4)

1.391(4)

1.386(4)

S1

S2

C7

C8

1.741(3)

1.802(3)

1.750(3)

1.806(3)

1.748(3)

1.807(3)

1.293(3)

1.396(4)

1.131(6)

1.296(4)

1.391(5)

1.375(5)

1.370(5)

1.460(5)

1.403(3)

1.389(4)

1.386(4)

1.394(4)

1.373(5)

1.383(4)

1.446(5)

C10

C16

C19

C25

C6

S3

S4

S5

S6

N1

N3

N4

N5

C1

C16

C17

C25

C26

C7

C15

C18

C25

C2

C9

C16

C24

C27

C6

C2

C3

C4

C5

C6

C8

C9

C11

C12

C14

C18

C24

C22

C24

C10

C12

C14

C19

C20

C22

C26

C15

C13

C15

C20

C21

C23

C27

o

Table 2. Bond angles ( ) for compound 2.

atom

C1

C10

C19

C6

C24

S1

C1

C3

N1

C1

S1

S2

S3

C11

C13

N3

atom

S1

S3

atom

C7

C16

C25

C7

C25

C6

C3

C5

C1

C5

N1

angle

88.34(12)

88.53(12)

88.36(12)

109.3(2)

109.60(18)

109.9(2)

117.7(3)

120.9(3)

114.9(2)

120.0(3)

117.6(2)

112.7(3)

129.56(18)

120.7(3)

121.1(3)

119.0(3)

125.2(2)

118.30(13)

atom

C7

C16

C25

C15

S1

C2

C4

N1

S1

S2

N2

S3

C10

C12

N3

C10

S3

atom

S2

S4

S6

N3

C1

C3

C5

C6

C7

C9

C10

C11

C13

C15

C16

atom

C8

C17

C26

C16

C2

C6

C4

C6

C5

S2

N1

C8

C15

C12

C14

C10

C14

N3

angle

98.36(13)

98.83(13)

99.08(12)

109.99(19)

129.17(19)

121.0(3)

121.5(4)

118.9(3)

125.1(3)

117.68(14)

124.7(2)

179.6(3)

109.71(19)

118.5(3)

121.0(3)

115.0(3)

119.8(3)

116.8(2)

S5

N1

N5

C1

C2

C4

C6

C7

C8

C10

C12

C14

C15

C16

C9

C11

C15

C13

C15

C14

S4

S3

Molecules 2011, 16

6132

Table 2. Cont.

atom

S4

N4

atom

C16

C18

C19

C20

C22

C24

C25

C26

atom

N3

angle

124.92(18)

178.8(4)

110.11(16)

117.9(3)

120.9(3)

114.8(2)

120.3(2)

117.12(16)

112.65(17)

atom

S4

S5

C20

C22

N5

S5

S6

N6

atom

C17

C19

C21

C23

C24

C25

C27

atom

C18

C20

C24

C22

C24

C23

S6

angle

112.2(3)

128.9(2)

121.0(3)

121.5(3)

118.4(3)

124.9(2)

117.87(15)

125.00(16)

178.8(3)

C17

C24

C21

C23

C19

C23

N5

S5

C19

C21

N5

C19

S5

N5

C26

S6

C27

Table 3. Bond lengths involving hydrogen’s (Å) for compound 2.

atom

C2

C4

atom distance atom

atom

H3

H5

H8B

H12

H14

H17B

H21

H23

H26B

distance

0.930

0.970

0.930

0.970

0.930

0.970

H2

H4

0.930

0.970

0.930

0.970

0.930

0.970

C3

C5

C8

H8A

H11

H13

H17A

H20

H22

H26A

C8

C11

C13

C17

C20

C22

C26

C12

C14

C17

C21

C23

C26

Knoevenagel condensation of the ethanolic solution of 1-(benzothiazol-2-yl-thio) acetonitrile (2)

with either hetero-2-carbaldehydes 3a–b or benzaldehyde or para-substituted benzaldehydes 3c–e with

an electron-donating group at the para-position, as depicted in Scheme 2. The reactions were carried

out in the presence of a catalytic amount of piperidine at the reflux temperature leading to novel 3-aryl-

2-(benzothiazol-2'-ylthio)acrylonitriles 4a–e (cf. Scheme 2).

Scheme 2. Syntheses of 4.

N

C

S

EtOH/pip

S

ArCH₂O

+

S

reflux

N

CN

N

3a-e

2

Ar

4a-e

3-4 a : Ar =2-furyl

b: Ar= 2-thienyl

c: Ar = phenyl

d: Ar = p-methoxyphenyl

e: Ar = p-hydroxyphenyl

Molecules 2011, 16

6133

The new 3-aryl-2-(benzothiazol-2'-ylthio)acrylonitrile derivatives 4a–e which were formed are

highly conjugated systems containing heteroaromatic or phenyl rings, or para-substituted phenyl rings

with an electron-donating group in the para- position such as –OCH₃or –OH. One the other hand, all

systems are linked to the benzothiazole nuclei through an S linkage at the α-vinylic carbon. The

formation of a carbon-carbon double bond usually lead to the creation of acrylonitriles with either E or

Z configuration or a mixture of E and Z isomers (cf. Scheme 2). The yields are based on isolated

products and the E/Z ratio was affected by the kind of substitution of the aryl aldehydes 3a–e. The E/Z

1

ratio was determined on the basis of the H-NMR spectra of the products. The structures of isolated

S-alkylated acrylonitrile products 4a–e were confirmed on the basis of elemental analysis and spectral

data. The mass spectrum of 4a revealed a molecular ion peak (M⁺) with m/z 284. The chemical shifts

of protons for 4a were assigned using the COSY (correlation spectroscopy) measurement which

1

provided the proton-proton couplings. The H-NMR revealed in addition to an aromatic multiplet, a

singlet signal for a vinylic proton (H-3), that appears at δ_H8.06 ppm. Moreover, the chemical shifts of

carbons for compound 4a were assigned using HSQC (Heteronuclear Single Quantum Coherence) and

HMBC (Heteronuclear Multiple Bond Coherence) measurements. The ¹³C-NMR spectrum for 4a is

characterized by two signals at δ_C142.2 and δ_C91.9 ppm for the carbon-carbon double bond group.

13

The C signal of the β carbon at the higher frequency coupled with a proton, while the C signal of

the α-carbon appears at lower frequency (cf. Figure 2).

Figure 2. The complete assignment of H¹and ¹³C chemical shift for 4a based on the

COSY, HSQC and HMBC experiments.

H

8.0

(

121

.6)

6

7.3

0

(14

8.2

)

(14

2.2

)

3''

(113

.8)

C

4'

'

6.8

4

2''

3

2

S

C

5''

(1

(9

O

1.9

)

(

1

6

4

.6

48.8

)

15

)

8.

N

C

2

'

(1

16.

9)

(

1

5

3

.1

)

S

N

8.0

9

4

'

(

1

3

5

.3

)

(1

22.

1)

7

'

5

'

(

1

2

9

1

4

.9

)

7.4

3

6

'

7

.

(12

5.2

)

(

1

2

6

.

8

)

7

5

1

Nuclear Overhauser Effect (NOE) experiments were run to establish the stereo-orientation for

acrylonitrile derivatives 4 as either E or Z isomers. NOE experiments for 4a showed an enhanced

triplet signal (H-4'') at δ_H6.84 ppm upon irradiating the doublet signal (H-5'') at δ_H8.15 ppm. On

irradiating the doublet signal (H-3”) at δ_H7.30 ppm both the triplet signal (H-4”) and the singlet signal

(H-3) at δ_H6.84 and 8.06 ppm, respectively, were enhanced, while the benzothiazole protons showed

no effect, confirming that the benzothiazol-2-ylthio moiety and 2'-furyl groups are on opposite sides of

the double bond as required by the E-form. The structure of 4a was unambiguously confirmed by X-ray

crystallography [18] (cf. Figure 3 and Tables 4–6).

Molecules 2011, 16

Figure 3. Perspective view and atom labeling of the X-ray structure of 4a.

6134

Table 4. Bond lengths (Å) for compound 4a.

atom

S1

S2

O1

N1

N2

C1

C3

C5

C8

C10

C12

atom

C1

C7

C10

C6

C14

C6

C4

C6

C14

C11

C13

distance

1.727(3)

1.762(3)

1.381(3)

1.391(4)

1.136(4)

1.403(4)

1.382(6)

1.387(5)

1.438(4)

1.356(4)

1.322(4)

atom

S1

S2

O1

N1

C1

C2

C4

C8

C9

atom distance

C7

C8

1.747(3)

1.770(3)

1.352(4)

1.298(4)

1.406(5)

1.363(5)

1.355(7)

1.349(4)

1.401(4)

1.403(4)

C13

C7

C2

C3

C5

C9

C10

C12

C11

Table 5. Bond lengths involving hydrogen's (Å) for compound 4a.

atom

C2

C4

C9

C12

atom distance atom

atom distance

H2

H4

0.93

C3

C5

H3

H5

0.93

H9

H12

C11

C13

H11

H13

The condensation of 2 with thiophene-2-carbaldehyde (3b) afforded a mixture of (E)- and (Z)-2-

(benzothiazol-2'-ylthio)-3-(2''-thienyl) acrylonitriles in a ratio of 6:0.5 based on the ¹H-NMR spectrum,

which revealed, in addition to the expected aromatic signals, two downfield signals at δ_H8.52 and

8.70 ppm assignable to the E and Z-vinylic protons. Upon recrystallization of the crude product from a

1

mixture of ethanol and diethyl ether in a ratio of 3:2 one isomer 4b was obtained. The H-NMR

spectrum of the crystallized product showed the vinylic proton resonance at δ_H8.52 ppm. In order to

determine the configuration of the obtained isomer, different NMR experiments have been carried out

such as COSY, HSQC and NOE experiments. The NOE experiments showed a strong NOE coupling

between H-3 and (vinylic-H) and the thiophene protons H-3'' and H-4'' and no coupling between the

benzothiazole and the thienyl ring protons, indicating that the benzothiazole and the thienyl rings are

on opposite sides of the double bond, confirming that compound 4b exists in the E-configuration.

Molecules 2011, 16

6135

o

Table 6. Bond angles ( ) for compound 4a.

atom

C1

C10

S1

C2

C4

N1

S1

S2

C8

O1

C10

O1

atom

C7

C13

C2

C6

C4

C6

C5

S2

N1

C14

C10

C11

C12

angle

88.04(14)

106.66(19)

128.6(3)

121.3(3)

119.6(4)

119.9(4)

126.9(3)

121.46(15)

121.0(3)

114.9(2)

129.9(3)

107.9(2)

107.7(3)

111.2(3)

atom

C7

C6

S1

C1

C3

N1

C1

S1

atom

S2

N1

C1

C2

C4

C6

C7

C8

C10

C12

C14

atom

C8

C7

C6

C3

C5

C1

C5

N1

C9

C14

C9

C11

C13

C8

angle

101.83(13)

109.2(3)

110.1(3)

118.6(4)

122.5(4)

115.2(3)

118.0(3)

117.5(3)

120.82(19)

123.9(3)

119.7(3)

132.4(3)

106.6(3)

174.9(3)F

S1

O1

C1

C3

C5

C6

C7

C8

C9

C10

C11

C13

S2

C9

O1

C9

C11

N2

On the other hand, condensation of 2 with either benzaldehyde or para-substituted benzaldehydes

3c–e in refluxing ethanol containing a catalytic amount of piperidine, afforded a mixture of E and Z

1

isomers of 3-aryl-2-(benzothiazol-2'-ylthio) acrylonitriles 3c–e in a ratio of 7:2 based on the H-NMR

1

13

spectra of the crude products. The chemical shifts of the H- and C- spectra were assigned on the

basis of the proton-proton and the carbon-proton coupling patterns observed in the COSY and HSQC

1

spectra. The H-NMR spectra display vinylic proton singlets in the δ_H8.12–8.29 ppm region. The

chemical shifts for the carbon-carbon double bond are observed at δ_C91–97 and at δ_C157–158 ppm

for the α- and β carbon, respectively. Moreover, Nuclear Overhauser Effect (NOE) experiments were

run to establish the stereo-orientation for either the E or Z isomers of 2-(benzothiazol-2'-ylthio)-3-(4''-

methoxyphenyl)acylonitrile 4d. On irradiating the singlet of the vinylic proton at δ_H8.17 ppm the

doublet of H-2'' of phenyl ring at δ_H8.00 ppm was enhanced. On irradiating the doublet signal of the

phenyl ring H-3'' at δ_H7.15 ppm both the doublet of the phenyl ring H-2'' and the para-methoxy group

protons at δ_H8.00 and 3.87 ppm, respectively, were enhanced, while the benzothiazole protons showed

no effect, indicating that the benzothiazole and the 4-methoxyphenyl rings are on opposite sides of the

double bond, as required by an E-form.

In a similar manner, the 1-(benzothiazol-2'-ylthio)propan-2-one (5) used in our experiments has

been recently prepared in an excellent yield by treatment of 2-mercaptobenzothiazole (1) with

α-chloroacetone in refluxing acetone containing anhydrous potassium carbonate [15]. The structure of 5

was unambiguously confirmed by X-ray crystallography [19] (cf. Scheme 3, Figure 4 and Tables 7–9).

Condensation of 5 with the furan-2-carbaldehyde in refluxing ethanol containing a catalytic amount

of piperidine afforded 3-(benzothiazol-2'-ylthio)-4-(furan-2''yl)-3-buten-2-one in excellent yield

(cf. Scheme 3). The structure of the isolated product was confirmed on the basis of its elemental

analysis and spectral data (see Experimental section).

Molecules 2011, 16

6136

Synthesis of compound .

Scheme 3.

6

S

SH

N

1

ClCH₂OCCH₃

K₂CO₃/acetone ,heat

CH₃

3a

O

S

C

N

EtOH/pip

reflux

S

N

COCH₃

O

5

6

Figure 4. Perspective view and atom labeling of the X-ray structure of 5.

Table 7. Bond lengths (Å) for compound 5.

atom

S1

S2

O1

N1

C2

C4

C6

C9

atom

C1

C9

C7

C5

C7

C10

distance

1.758(3)

1.738(3)

1.206(4)

1.392(4)

1.410(4)

1.393(7)

1.389(5)

1.494(5)

atom

S1

S2

N1

C2

C3

C5

C8

atom distance

C2

C8

C1

C3

C4

C6

C9

1.730(4)

1.785(3)

1.289(4)

1.387(5)

1.369(6)

1.371(5)

1.501(4)

Molecules 2011, 16

Table 8. Bond lengths involving hydrogen's (Å) for compound 5.

6137

atom

C3

C5

C8

C10

atom distance

atom

C4

C6

C8

C10

atom distance

H3

H5

0.930

0.970

0.960

H4

H6

0.930

0.970

0.960

H8A

H10A

H10C

H8B

H10B

Table 9. Bond angles (^o) for compound 5.

atom

C1

S1

atom

S1

atom

C2

C7

N1

C3

C7

C5

C7

C6

C9

angle

atom atom atom angle

88.71(14)

110.6(3)

116.3(3)

129.9(3)

120.5(3)

120.8(4)

118.8(4)

125.4(3)

116.2(3)

122.3(3)

C1

S1

S2

S1

C2

C4

N1

C2

O1

C8

S2

C1

C2

C3

C5

C7

C9

C8

S2

101.10(14)

116.94(16)

126.8(2)

109.6(3)

118.8(4)

121.3(4)

114.8(3)

119.8(3)

122.8(3)

114.9(3)

N1

C1

C2

C4

C6

C7

C8

C9

N1

C7

C4

C6

C2

C6

C8

C10

S1

C3

C5

N1

S2

O1

C10

The mass spectrum of 6 revealed a molecular ion peak [M⁺]. with m/z 301 The effect of the

conjugatation of the carbonyl group with the carbon-carbon double bond reduces the frequency of the

absorption at υ_max1662cm⁻¹. It is considered lower than the isolated carbonyl group in compound 5,

which revealed a carbonyl stretching band at υ_max1720 cm⁻¹[15]. The chemical shift of protons for 6

were assigned using COSY (correlation spectroscopy) measurements which provided the proton-

proton coupling. The ¹H-NMR spectrum showed a resonance at δ_H8.25 ppm corresponding to H-4 of

the vinylic proton. Moreover, the ¹³C-NMR chemical shift assignments were straightforward using

13

HSQC (Heteronuclear Quantum Coherence) measurements (cf. Figure 5). The C-NMR spectrum of

the reaction product revealed a low field signal at δ_C194.8 that corresponds to the carbonyl carbon.

Also were revealed two low field signals at ca. δ_C148 and 136 ppm corresponding to a carbon coupled

with a proton. As in the furan ring system, the carbon resonating at ca. δ_C148 ppm corresponds to C-

5'', while the carbon resonating at ca. δ_C136 ppm corresponds to the vinylic carbon C-4. The complete

assignment of H¹and ¹³C chemical shifts for 6 are presented in Figure 6.

Moreover, the configuration of the product 6 was assigned as the Z-isomer based on Nuclear

Overhauser Effect (NOE) experiments; on irradiating the methyl proton at δ_H2.54 ppm only the signal

at δ_H8.25 ppm for the vinylic proton was enhanced and there is no effect on the benzothiazole protons

or furyl protons, which indicate that acetyl group and the vinylic proton are on the same side of the

carbon 3,4 double bond as numbered, therefore it has the Z configuration. On irradiating the vinylic

H-4 at δ_H8.25 ppm both the singlet and doublet signals at δ_H2.54 and 7.47 ppm, respectively, were

enhanced. The signal at δ_H2.54 ppm corresponds to the acetyl group, while the doublet signal at

δ_H7.47 ppm corresponds to the furyl system H-3". On other hand, on irradiating the doublet signal of

the H-4' proton at δ_H7.92 ppm only the triplet signal at δ_H7.32 ppm was enhanced. These two signals

Molecules 2011, 16

6138

correspond to the benzothiazole H-4' and H-5' protons. On irradiating the triplet signal H-4'' at

δ_H6.74 ppm both the H-5'' and H-3'' signals at δ_H8.05 and 7.47 ppm, respectively, were enhanced. The

NOE experiments show that the Z-isomer of compound 6 was preferred over the E-isomer indicating

that the furyl and 2-benzothiazol-2-thio nuclei are on the same sides of the double bond, but away from

each other in space.

¹³C-HSQC spectra for the compound in DMSO-d .

Figure 5.

6

Figure 6. The complete assignment of H¹and ¹³C chemical shifts for 6 based on the COSY

and HSQC experiments.

2.54

(121.3)

7.82

CH₃

(194.8)

2

(26.6)

O

(126.4

7.43

7'

(135.8)

8.25

6'

5'

S

H

(123.9)

3

7.32

(124.5)

C

4

(166.3)

(136.0)

C

2'

4'

(Z)

S

7.92

(121.7)

(153.2)

(149.2)

N

7.47

(121.4)

2''

3''

O

4''

5''

8.05

6.74

(113.7)

(148.4)

Thus it can be concluded that Knoevenagel condensation of 2-(benzothiazol-2-ylthio) acetonitrile

with furan-2-carbaldehyde leads preferentially to (E)-2-(benzothiazol-2'-ylthio)-3-(furan-2''-yl)

acrylonitrile (4a). In this conformation the lone pair electrons of the sulfur atom can conjugated with

the π orbital of the double bond, and thereby stabilize the molecule. That is why this conformation is

the most stable conformer. On the other hand, the Knoevenagel condensation of 3-(benzothiazl-2'-

ylthio) propan-2-one with furan-2-carbaldehyde lead preferentially to (Z)-3-(benzothiazol-2'-ylthio)-4-

(furan-2''-yl)-3-buten-2-one. By changing the size and the geometry of the group attached to the

α-carbon from a cyano group to an acetyl group, the conformation changes from E to Z. One may

Molecules 2011, 16

6139

therefore conclude that under these circumstances the most E-isomer is unlikely to be the most stable

conformer, because of the steric strain between the acetyl group and furan ring. The steric strain makes

this conformation energetically highly unfavorable in the E-isomer so the conformer changes from E to Z.

On the other hand, 2-(2'-oxopropylthio)-3-phenylquinazolin-4(3H)-one (9) was readily prepared in

good yield by the treatment of 2-mercapto-3-phenylquinazolin-4(3H)-one (8) [20] with

α-chloroacetone in refluxing acetone containing potassium carbonate. The structure was established on

the basis of its spectral data. The mass spectrum of the reaction product showed a molecular ion peak

1

at m/z 310. The H-NMR spectrum revealed, in addition to aromatic signals, two upfield singlets at

δ_H2.33 and 4.06 ppm, assignable to methyl and methylene protons, respectively. Moreover, the

¹³C-NMR spectrum showed two downfield signals at δ_C202.5 and 161.1 ppm. The signal at δ_C202.5

ppm corresponds to the ketone carbonyl carbon, while that at δ_C161.1 ppm corresponds to the cyclic

amide carbon .The data are therefore consistent with structure 9 (cf. Scheme 4).

Synthesis of and .

10

Scheme 4.

9

O

C

COOH

N

PhNCS

NH₂

EtOH/Et₃N

reflux

N

SH

7

8

K₂CO₃,

acetone/reflux

ClCH₂COCH₃

O

C

O

N

C

N

3a

N

S

N

S

EtOH, pip.

reflux

COCH₃

9

COCH₃

O

10

Condensation of 2-(2'-oxopropylthio)-3-phenylquinazolin-4(3H)-one (9) with furan-2-carbaldehyde

(3a) afforded a product which could have been either E or Z-isomer of α,β-unsaturated ketone 10

(cf. Scheme 4). The structure of α,β-unsaturated ketone 10 was deduced from its elementanal anaylsis

and spectra data. The mass spectrum revealed a molecular ion peak (M⁺) with m/z 388. The chemical

shifts of the protons for 10 were assigned using COSY (correlation spectroscopy) measurements which

1

provided the proton-proton coupling. The H-NMR revealed in addition to an aromatic multiplet, a

singlet for a vinylic proton (H-1') which appears at low field at ca. δ_H7.88 ppm. Moreover, the

¹³C-NMR chemical shift assignments were straightforward using HSQC (Heteronuclear Single

13

Quantum Coherence) measurements (cf. Figure 7). The C-NMR spectrum for 10 is characterized by

two signals at δ_C132.0 and δ_C119.7 ppm for the α,β-unsaturated ketone group. The vinylic carbons at

Molecules 2011, 16

6140

the higher frequency is the one coupled with a proton, while the other one is a disubstituted sp²carbon.

The complete assignment of H¹and ¹³C chemical shift for 10 are presented in Figure 8.

¹³C-HSQC spectra for the compound

in DMSO-d .

10

Figure 7.

6

Figure 8. The complete assignment of H¹and ¹³C chemical shifts for 10 based on the

COSY and HSQC experiments.

7.46

(126.2)

7.77

(134.6)

7

8.08

(126.6)

6

8

7.42

(126.0)

5

4'

(149.2)

O

(195.5)

2.48

(26.7)

CH₃

(125.1)

C

N

3'

(160.7)

4

(119.7)

(155.9)

2

C

(Z)

O

7.88

H

2'

N

S

C

(132.0)

1'

(136.2)

1'''

7.18

2''

6'''

5'''

(118.2)

2'''

3''

4''

7.59-7.67

(129.2,129.7,130.1)

O

5''

6.68

(113.2)

3'''

4'''

7.92

(147.0)

Moreover, the configuration of the product 10 was assigned as the Z-isomer based on Nuclear

Overhauser Effect (NOE) experiments; on irradiating the methyl proton at δ_H2.48 ppm the vinylic

proton signal at δ_H7.88 ppm was enhanced. There is no effect on the 3-phenylquinazolin-4(3H)-one or

furan protons, which indicates that the acetyl group and the vinylic proton are on the same side of the

C1',2' double bond as numbered, which therefore has Z configuration. On irradiating the vinylic H'-1 at

δ_H7.88 ppm the methyl signal at δ_H2.48 ppm was enhanced.

On the other hand irradiation of the H-8 proton at δ_H8.08 ppm has no effect, confirming that

the 3-phenylquinazolin-4(3H)-one moiety and 2'-furyl groups are on same sides of the double bondas

required by a Z-form. The structure of 10 was also confirmed by X-ray crystallography [21] (cf. Figure 9

and Tables 10–12).

Molecules 2011, 16

Figure 9.

6141

Perspective view and atom labeling of the X-ray structure of

.

10

Table 10. Bond lengths (Å) for compound 10.

atom

S1

O1

O2

N1

N2

C1

C3

atom

C8

C7

C20

C7

C9

C8

C6

C4

C6

C10

C11

C13

C16

C17

C19

C22

distance

1.7609(19)

1.219(3)

1.398(4)

1.402(3)

1.440(3)

1.285(3)

1.397(3)

1.388(4)

1.399(4)

1.378(4)

1.393(5)

1.354(6)

1.354(3)

1.424(3)

1.385(4)

1.499(4)

atom

S1

O2

O3

N1

N2

C1

C2

C4

atom

C15

C17

C21

C8

C1

C2

C3

C5

distance

1.7687(19)

1.350(3)

1.216(3)

1.400(3)

1.389(3)

1.404(3)

1.382(4)

1.365(4)

1.456(3)

1.382(4)

1.374(6)

1.384(5)

1.483(3)

1.345(4)

1.324(5)

C5

C9

C6

C9

C7

C14

C12

C14

C21

C18

C20

C10

C12

C15

C16

C18

C21

C11

C13

C15

C17

C19

Table 11. Bond lengths involving hydrogen's (Å) for compound 10.

atom

C2

C4

C10

C12

C14

C18

C20

C22

atom

H2

H4

H10

H12

H14

H18

H20

H22B

distance atom atom distance

0.930

0.960

C3

C5

H3

H5

0.930

0.960

C11

C13

C16

C19

C22

H11

H13

H16

H19

H22A

H22C

Molecules 2011, 16

6142

o

Table 12. Bond angles ( ) for compound 10.

atom

C8

C7

C8

N2

atom

S1

N1

C1

atom

C15

C8

C9

C2

angle

atom

C17

C7

C1

N2

C1

atom

O2

N1

N2

C1

atom

C20

C9

C8

C6

angle

106.1(2)

118.33(15)

117.26(15)

122.50(16)

119.7(2)

100.89(9)

121.46(16)

120.21(15)

118.64(16)

118.86(17)

120.9(3)

C2

C1

C3

C6

C4

C2

C4

C3

C5

C3

119.9(3)

C4

C1

O1

N1

S1

N1

C10

C12

S1

C16

O2

C16

C18

O3

C5

C6

C7

C8

C9

C11

C13

C15

C17

C19

C21

C6

C7

N1

C6

120.3(3)

119.83(17)

120.0(2)

114.04(16)

122.04(14)

119.6(2)

121.5(3)

119.7(3)

120.5(3)

121.83(16)

122.06(18)

125.4(2)

125.1(2)

107.6(3)

C1

C5

C6

C7

C8

C9

C10

C12

C14

C15

C16

C17

C18

C20

C21

C5

C7

C6

N1

120.22(19)

119.91(18)

125.9(2)

113.15(13)

124.81(17)

118.9(2)

118.6(3)

121.2(4)

118.6(3)

116.04(14)

131.01(19)

109.4(2)

107.8(3)

109.1(3)

O1

S1

N1

C9

C11

C9

S1

C15

O2

C17

O2

O3

N2

C10

C14

C12

C14

C16

C21

C16

C18

C20

C15

C22

C14

C11

C13

C21

C17

C18

C19

C22

120.5(2)

119.8(2)

119.7(3)

C15

In particular, we were interested in the reasons for the predominance of the s-cis conformation of

the Z configuration and the E/Z determination of the prepared novel derivatives of 2-(benzothiazol-2'-

ylthio)-3-arylacrylonitrile, 3-(benzothiazol-2'-ylthio)-4-(furan-2''-yl)-3-buten-2-one and 2-(1-(furan-2''-yl)-

3-oxobut-1-en-2-ylthio)3-phenylquinazolin-4(3H)-one in accordance with expectations, it was

ascertained that s-trans conformations were more stable than s-cis conformations for both the E and Z

molecular configurations. Thus the disparity displayed here where s-cis conformations in case of

compound 6 dominated over the s-trans conformation was of interest and one supposition was that

electronic interactions could be responsible, e.g., by delocalization of a sulfur lone electron pair with

the unsaturated segments residing in the newly formed heterocyclic ring and attendant side-chains or

through hyperconjugation. The s-cis conformational preference over s-trans in a structurally similar

system has been reported previously [22] and an electronic cause was also postulated, though that

system differed significantly in the distribution of unsaturation. It is obvious to note that compounds

4c–e are predominantly in the E/Z form and this is due to the large range of mesomeric effects due to

large conjugations in the phenyl group present in such compounds. However, the existence of

compounds 4a and 4b in the E form is due to the existence of the heterocyclic, furan and thiophene

rings, respectively, where less conjugation occurs in such compounds.

Molecules 2011, 16

6143

3. Experimental

General

Melting points are reported uncorrected and were determined on a Gallenkamp apparatus. The

1

Infrared spectra were recorded on a Jasco FT/IR-6300 FT-IR using KBr disks. H-NMR and

¹³C-NMR spectra were measured on a Bruker DPX 400 MHz and Bruker AVANCE ΙΙ 600 MHz

spectrometers, with DMSO-d₆or CDCl₃as solvent using TMS as an internal standard. The methods

used for the purpose of NMR assignment were COSY, HSQC and HMBC. The chemical shifts are

expressed as δ unit in parts per million (ppm) and TMS = 0.00 ppm. The following abbreviation are

used: s = singlet, d = doublet, t = triplet; q = quartet; m = multiple; br. = broad. Mass spectra were

measured on GC/MS DFS, THERMO instrument. Microanalyses were performed on a CHNS-Vario

Micro Cube analyzer, Single crystal X-ray crystallography was perfomed using a Rigaku Rapid ΙΙ

located at the Chemistry Department of Kuwait University. Compound 5 was prepared according to

our recent reference [15] and its X-ray data was reported in reference [19].

2-(Benzothiazol-2-ylthio) acetonitrile (2): A mixture of 1 (1.67 g, 10.0 mmol), chloroacetonitrile (0.63 g,

10.0 mmol), and anhydrous potassium carbonate (1.38 g, 10.0 mmol) in acetone (100 mL), were

heated in water bath for 2 h. The solvent was then evaporated under reduced pressure. The solid

product, so formed, was collected by filtration and crystallized from ethanol as brown crystals. Yield:

1.85 g (90%), mp. 70–72 °C; FT-IR: ν_max/cm⁻¹: 2243 (CN); ¹H-NMR (DMSO-d₆): δ_H4.58 (s, 2H, CH₂),

7.43 (t, 1H, J = 8.0 Hz, H-5'), 7.52 (t, 1H, J = 8.0 Hz , H-6'), 7.95 (d, 1H, J = 8.0 Hz, H-7'), 8.08 (d,

1H, J = 8.0 Hz, H-4'); ¹³C-NMR (DMSO-d₆): δ_C163.8 (C-2'), 152.7 (C-3a'), 135.6 (C-7a'), 127.1 (C-6'),

125.5 (C-5'), 122.6 (C-4'), 122.0 (C-7'), 117.9 (CN), 18.6 (CH₂) ppm; MS m/z (%) 206 [M⁺, 100%].

Anal. Calcd. for C₉H₆N₂S₂(206.28): C, 52.40; H, 2.93; N, 13.57%. Found: C, 52.29; H, 3.19; N,

13.45%.

General Procedure for Synthesis of 3-Aryl-2-(benzothiazol-2'-ylthio) acrylonitriles 4a–e. A mixture of

2 (2.06 g, 10.0 mmol) and aromatic aldehydes 3a–e (10.0 mmol) in ethanol (20 mL) containing a few

drops of piperidine was refluxed for 4 h. The reaction was allowed to cool to room temperature for 24 h.

The solid product so formed was collected by filtration and crystallized from the appropriate solvent.

(E)-2-(Benzothiazol-2'-ylthio)-3-(furan-2''-yl) acrylonitrile (4a): This compound was crystallized from

ethanol as brown crystals. Yield: 2.24g (79%) yield, mp. 134–136 °C; FT-IR: ν_max/cm⁻¹: 2209 (CN);

¹H-NMR (DMSO-d₆): 6.84 (dd, 1H, J = 3.6 & 1.2 Hz, H-4''), 7.30 (d, 1H, J = 3.6 Hz, H-3''), 7.43 (t,

J = 8.2 Hz, H-5'), 7.51 (t, 1H, J = 8.0 Hz, H-6'), 7.94 (d, 1H, J = 8.2 Hz, H-7'), 8.06 (s, 1H, H-3), 8.07 (d,

13

1H, J = 8.0 Hz, H-4'), 8.15 (d, 1H, J = 1.2 Hz, H-5''); C-NMR (DMSO-d₆): δ_C164.6 (C-2'), 153.1

(3a'), 148.8 (C-5"), 148.2 (C-2''), 142.2 (C-3), 135.3 (C-7a'), 126.8 (C-6'), 125.2 (C-5'), 122.1 (C-4'),

121.9 (C-7'), 121.6 (C-3''), 116.9 (CN), 113.8 (C-4''), 91.9 (C-2) ppm. MS m/z (%) 284 [M⁺, 18%].

Anal. Calcd. for C₁₄H₈N₂OS₂(284.36): C, 59.13; H, 2.84; N, 9.85; S, 22.55%. Found: C, 58.95; H,

2.81; N, 10.07; S, 22.56%.

Molecules 2011, 16

6144

(E)-2-(Benzothiazol-2'-ylthio)-3-(thiophen-2''-yl) acrylonitrile (4b). This compound was crystallized

from a 3:2 mixture of ethanol/diethyl ether as yellow crystals. Yield: 2.4 g (88%), mp. 98–100 °C;

FT-IR: ν_max/cm⁻¹: 2210 (CN); H-NMR (DMSO-d₆): δ_H7.35 (dd, 1H, J = 4.8 & 3.5 Hz, H-4''),

1

7.43 (t, 1H, J = 7.6 Hz, H-5'), 7.52 (t, 1H, J = 7.6 Hz, H-6'), 7.89 (d, 1H, J = 3.5 Hz, H-3''), 7.95 (d,

1H, J = 8.0 Hz, H-7'), 8.09 (d, 1H, J = 8.0 Hz, H-4'), 8.14 (d, 1H, J = 4.8 Hz, H-5''), 8.52 ppm (s, 1H,

13

H-3); C-NMR (DMSO-d₆): δ_C164.8 (C-2'), 153.2 (C-3a'), 150.4 (C-3), 137.5 (C-3''), 135.9 (C-2''),

135.3 (C-7a'), 135.1 (C-5''), 128.6 (C-4''), 126.8 (C-6'), 125.2 (C-5'), 122.1 (C-4'), 121.9 (C-7'), 117.1

(CN), 92.3 (C-3) ppm; MS m/z (%) 300 [M⁺, 14%]. Anal. Calcd. for C₁₄H₈N₂S₃(300.42): C, 55.97; H,

2.68; N, 9.32; S, 32.01%. Found: C, 56.04; H, 2.52; N, 9.54; S, 32.08%.

(E)-2-(Benzothiazol-2'-ylthio)-3-phenyl acrylonitrile (4c). This compound was crystallized from a 2:1

mixture of ethanol/diethyl ether as yellow crystals. Yield: 2.08 g (71%) , mp. 103–105 °C;

FT-IR: ν_max/cm⁻¹: 2206 (CN); H-NMR (DMSO-d₆): δ_H7.38 (t, 1H, J = 7.8 Hz, H-5'), 7.49 (t, 1H,

1

J = 8.4 Hz, H-6' ), 7.58–7.63 (m, 3H, H-3'', H-4'' & H-5''), 7.96 (d, 1H, J = 8.4 Hz, H-7), 7.97 (d, 2H,

J = 8.4 Hz, H-2''& H-6''), 8.10 (d, 1H, J = 8.0 Hz, H-4'), 8.29 ppm (s, 1H vinylic-H); ¹³C-NMR

(DMSO-d₆): δ_C163.7 (C-2'), 157.0 (C-3), 153.1 (C-3a'),135.4 (C-7a'), 132.6 (C-4''), 130.8 (C-1''),

129.5 (C-2'' & C-6''), 128.9 (C-3'' & C-5''),126.8 (C-6'),125.5 (C-5'), 122.2 (C-4'), 122.0 (C-7'), 116.8

(CN), 97.5 (C-2) ppm. MS m/z (%) 294 [M⁺, 83%]. Anal. Calcd. for C₁₆H₁₀N₂S₂, (294.39) requires: C,

65.28 ; H, 3.42; N, 9.52; S, 21.78%. Found: C, 64.98; H, 3.25; N, 9.73; S, 22.03%.

(E)-2-(Benzothiazol-2'-ylthio)-3-(4''-methoxyphenyl) acrylonitrile (4d). This compound was

crystallized from ethanol as brown crystals. Yield: 2.62 g (81%), mp. 95–97 °C. FT-IR: ν_max/cm⁻¹: 2202

(CN); ¹H-NMR (DMSO-d₆): δ_H3.87 (s, 3H, OCH₃), 7.15 (d, 2H, J = 9.0 Hz, H-3'' & H-5''), 7.42 (t,1H,

J = 7.8 Hz, H-5'), 7.51 (t, 1H, J = 7.8 Hz, H-6'), 7.94 (d, 1H, J = 7.8 Hz, H-7'), 8.00 (d, 2H, J = 8.4 Hz,

H-2’’ & H-6’’), 8.06 (d, 1H, J = 7.8 Hz, H-4'), 8.17 ppm (s, 1H, H-3); ¹³C-NMR (DMSO-d₆): δ_C165.0

(C-2'), 162.9 (C-4''), 157.3 (C-3), 153.3 (C-3a'), 135.3 (C-7a'), 132.1 (C-2'', C-6"), 126.7 (C-6'), 125.1

(C-5'), 124.9 (C-1''), 122.1 (C-4'), 121.9 (C-7'), 117.5 (CN), 114.8 (C-3'' & C-5"), 92.8 (C-2), 55.7

(OCH₃) ppm; MS m/z (%) 324 [M⁺, 20% ]. Anal. Calcd. for C₁₇H₁₂N₂OS₂(324.42): C, 62.94; H, 3.73;

N, 8.63; S, 19.76%. Found: C, 63.06; H, 3.63; N, 8.87; S, 20.06%.

(E)-2-(Benzothiazol-2'-ylthio)-3-(4''-hydroxyphenyl) acrylonitrile (4e). This compound was

crystallized from a 2:1 mixture of ethanol/diethyl ether as yellow crystals. Yield: 2.32 (75%), mp.

1

113–114 °C ; FT-IR: ν_max/cm⁻¹: 3417 (OH), 2200 (CN); H-NMR (DMSO-d₆): δ_H6.97 (d, 2H,

J = 8.4 Hz, H-3'' & H-5''), 7.39 (t, 1H, J = 8.4 Hz, H-5'), 7.50 (t, 1H, J = 8.4 Hz, H-6'), 7.91 (d, 2H_,

J = 8.4 Hz, H-2’’ & H-6’’), 7.93 (d, 1H, J = 8.4, Hz, H-7'), 8.06 (d, 1H, J = 8.4 Hz, H-4'), 8.12 (s,1H, H-

3), 9.05 (bs., 1H ,OH, D₂O exchangeable); ¹³C-NMR (DMSO-d₆): δ_C165.6 (C-2')_,162.2 (C-4''), 158.0 (C-

3), 153.3 (C-3a'), 135.2 (C-7a'), 132.5 (C-2'' & C-6''), 126.7 (C-6'), 125.0 (C-5'), 123.0 (C-1''), 122.1

(C-4'), 121.8 (C-7'), 117.8 (CN), 116.3 (C-3'' & C-5''), 91.2 (C-2) ppm; MS m/z (%) 310 [M⁺, 44%].

Anal. Calcd. for C₁₆H₁₀N₂OS₂(310.39): C, 61.91; H, 3.25 ; N, 9.03; S, 20.66%. Found: C, 61.63; H,

3.40; N, 9.27; S, 20.92%.

(Z)-3-(Benzothiazol-2'-ylthio)-4-(furan-2''-yl)-3-buten-2-one (6): A mixture of 5 (2.33 g, 10.0 mmol)

and furan-2-carbaldehyde 3a (10.0 mmol) in ethanol (20 mL) containing a few drops of piperidine was

Molecules 2011, 16

6145

refluxed to 4 h. The reaction was allowed to cool to room temperature for 24 h. The solid product so

formed was collected by filtration and crystallized from the ethanol as yellow crystals. Yield: 2.16 g

(72%) yield, mp. 85–87 °C ; FT-IR: ν_max/cm⁻¹: 1662 (CO); H-NMR (DMSO-d₆): 2.54 (s, 3H, CH₃),

1

6.74 (dd, 1H, J = 3.6 & 1.2 Hz, H-4''), 7.32 (t, 1H, J = 8.0 Hz, H-5'), 7.43 (t, 1H, J = 8.0 Hz,

H-6'), 7.47 (d, 1H, J = 3.6 Hz, H-3''), 7.82 (d, 1H, J = 8.0 Hz, H-7'), 7.92 (d, 1H, J = 8.0 Hz, H-4'),

8.05 (d, 1H, J = 1.6 Hz, H-5''), 8.25 (s, 1H, H-4); ¹³C-NMR (DMSO-d₆): δ_C194.8 (C-2), 166.3

(C-2'), 153.2 (C-3a'), 149.2 (C-2''), 148.4 (C-5''), 136.0 (C-4), 135.8 (C-7a'),126.4 (C-6'), 124.5 (C-5'),

123.9 (C-3), 121.7 (C-4'), 121.4 (C-3''), 121.3 (C-7') ,113.7 (C-4''), 26.6 (CH₃) ppm; MS m/z (%) 301

[M⁺, 30%]. Anal. Calcd. for C₁₅H₁₁NO₂S₂(301.38): C, 59.78; H, 3.67; N, 4.64%. Found: C, 59.41; H,

3.68; N, 4.80%.

3-(2'-Oxopropylthio)-3-phenylquinazolin-4(3H)-one (9): A mixture 8 (2.54 g, 10.0 mmol), chloro-

acetone (0.79 g, 10.0 mmol), and anhydrous potassium carbonate (1.38 g, 10.0 mmol) in acetone

(100 mL) were heated in water bath for 2 h. The solvent was then evaporated under reduced pressure.

The solid product, so formed, was collected by filtration and crystallized from ethanol as yellow

crystals. Yield: 2.4 g (79%), mp. 140–142 °C. FT-IR: ν_max/cm⁻¹: 1725 (CO ketone), 1683 (CO amide);

¹H-NMR (DMSO-d₆): δ_H2.33 (s, 3H, CH₃) ,4.06 (s, 2H, CH₂), 7.29 (d, 1Hz, J = 7.6 Hz, H-5), 7.35 (t,

1H, J = 7.6 Hz, H-7), 7.63–7.41 (m, 5H, phenyl–H), 7.81 (t, 1H, J = 8.0 Hz, H-6), 8.08 (d, 1H,

J = 7.6Hz, H-8); ¹³C-NMR (DMSO-d₆): δ_C202.5 (C-2'), 161.1 (C-4), 157.3 (C-2), 147.5 (C-8a), 136.4

(C-6), 135.4 (C-1''), 130.4, 129.8, 129.5 (phenyl carbons), 127.1 (C-8), 126.5 (C-7), 126.4 (C-5), 123.9

(C-4a), 42.6 (C-1'), 28.7 (CH₃) ppm; MS m/z (%) 310 [M⁺, 12%]. Anal. Calcd. for C₁₇H₁₄N₂O₂S

(310.37): C, 65.79, H, 4.55, N, 9.03%. Found: C, 65.65, H, 4.30, N, 9.06%.

(Z)-2-(1'-(Furan-2''-yl)-3'-oxobut-1''-en-2-ylthio)-3-phenylquinazolin-4(3H)-one (10): A mixture of 9

(3.10 g, 10 mmol) and 3a (0.83 g, 10 mmol) in ethanol (20 mL) containing a few drops of piperidine

was refluxed for 4 h. The reaction was allowed to cool to room temperature for 24 h. The solid product

so formed was collected by filtration and crystallized from ethanol as brown crystals. Yield: 2.83 g

(73%) yield, mp. 190–192 °C; FT-IR: ν_max/cm⁻¹: 1675 (CO ketone), 1610 (CO amide); H-NMR

1

(DMSO-d₆): 2.48 (s, 3H, CH₃), 6.68 (dd, 1H, J = 3.6 Hz & 1.8 Hz, H-4''), 7.18 (d, 1H, J = 3.6 Hz, H-3''),

7.42 (d, 1H, J = 8.0 Hz, H-5), 7.46 (t, 1H, J = 8.0 Hz, H-7), 7.67–7.59 (m, 5H, phenyl–H),7.77 (t, 1H,

J = 8.0 Hz, H-6), 7.88 (s, 1H, H-1'), 7.92 (d, 1H, J = 1.8 Hz, H-5''), 8.08 (d, 1H, J = 8.0 Hz, H-8) ppm;

¹³C-NMR (DMSO-d₆): δ_C195.5 (C-3'), 160.7 (C-4), 155.9 (C-2), 149.2 (C-8a), 147.0 (C-5''), 146.8 (C-2''),

136.2 (C-1'''), 134.9 (C-6), 132.0 (C-1', vinylic–H), 130.1, 129.7, 129.2 (phenyl carbons), 126.6 (C-8),

126.2 (C-7), 126.0 (C-5), 125.1 (C-4a), 119.7 (C-2'), 118.2 (C-3''), 113.2 (C-4''), 26.7 (CH₃) ppm;

MS m/z (%) 388 [M⁺, 82]. Anal. Calcd. for C₂₂H₁₆N₂O₃S( 388.44): C, 68.02; H, 4.15; N, 7.21; S,

8.25%. Found: C, 67.78; H, 4.26; N, 7.16, S, 8.32%.

4. Conclusions

Knoevenagel condensation of 2-(benzothiazol-2'-ylthio) acrylonitrile (2) with aromatic

benzaldehydes 3a–e leads preferentially to E-isomers. The 3-aryl-2-(benzothiazol-2'-ylthio)

acrylonitriles 4a–e were characterized by spectroscopic measurements. Condensation of furan-2-

carbaldehyde with either 1-(benzothiazol-2'-ylthio)propan-2-one or with 2-(2'-oxopropylthio)-3-

Molecules 2011, 16

6146

phenylquinazolin-4(3H)-one afforded compounds 6 and 10 respectively. The condensation products 6

and 10 were characterized by spectroscopic measurements and were shown to be the Z-isomers.

Acknowledgements

This work was financed by the University of Kuwait research grant SC02/08 .We are grateful to the

Faculty of Science, Chemistry Department, SAF facility for the spectral and analytical data (Project

GS01/01, GS03/08, GS01/03).

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Synthesis and E/Z configuration determination of novel derivatives of 3-Aryl-2-(benzothiazol-2′-ylthio) acrylonitrile, 3-(benzothiazol-2′- ylthio)-4-(furan-2′ ′-yl)-3-buten-2-one and 2-(1-(Furan-2′ ′-yl)-3′-oxobut-1′ ′-en-2-ylthio)-3-phenylquinazolin- 4(3H)-one

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