“Synthesis, Characterization And Bioassay Of 1,4 ...shodhganga.inflibnet.ac.in/bitstream/10603/32390/13/13...An intermediate compound 4,4'-(4-chlorobut-1-ene-1,1-diyl)bis(fluorobenzene)

Chapter

4

Chapter-4 P a g e | 127

Ph.D. Thesis, Girish Bansilal Patel, School of Chemical Sciences, NMU, Jalgaon, 2012

CHAPTER-4

SYNTHESIS OF NEWER N-SUBSTITUTED 2-{[4,4-BIS-(4-

FLUOROPHENYL)BUT-3-ENYL}THIO}-1H-BENZIMIDAZOLES

Introduction:

As discussed in Chapter-1, the benzimidazole nucleus plays a vital role in deciding the

bioactivity. Owing to the immense importance and varied bioactivities exhibited by

compounds containing benzimidazole nucleus, efforts have been made from time to time

to generate libraries of benzimidazole derivatives and screen them for potential biological

activities1. Similarly 2-substituted benzimidazole and their derivatives have been found to

be potent biological active compounds. As 2-substituted benzimidazoles are known to

exhibit good biological activity, it would have been appropriate to synthesize

benzimidazole derivatives having substituents at 2-position and which is an integral part

of compound having interesting biological activity.

2-mercaptobenzimidazole derivatives, one of the most important derivatives of

benzimidazole also exhibited a wide variety of interesting biological activities such as

antimicrobial2, antihistamine

3 and neutropic

4 activities. Thus, syntheses of these series of

compounds are highly desirable.

NH

N

SN

O

OF

F

F

Lansoprazole

N-

N

SN

O

OO

Na+

Rabeprazole Na



N

NN

S

O

OF

F

O

O

N

N O

SN

O

O

H

Pantoprazole Omeprazole

With this view in mind, it was decided to introduce functionalities such as

fluorobiphenyls since these groups are present in various compounds which exhibit

biological activity. For example the fluorobiphenyl is an integral part of Pimozide,

Amperozide, Almitrine,Flunarizine, Fluspirilene, Penfluridol, Lomerizine,

Flusilazole and exhibiting varied biological activities. Pimozide is used as antipsychotic,

which is commercially known as Orap5. Similarly Flunarizine is used as calcium

channel blocker having antiallergic and antivasococonstructing activity, which is

commercially known as Redeptin, Imap6. Almitrine is used as a respiratory stimulant,

commercially known as Duxi7. Flusilazole is used as an Fungicide which is used to

control fungal infections on a variety of fruit and vegetable crops8, 9

.

NH

N

O

N

F

F

Pimozide

N

NF

F

O

HN

Amperozide

http://en.wikipedia.org/wiki/Respiratory

http://en.wikipedia.org/wiki/Stimulant



NN

F

F

Flunarizine

N N

N

N

N

HN

NH

F

F

Alimitrine

SiN N

N

F

FFlusilazole

NF

F

NH

N

O

Fluspirilene

Owing to the importance of substituted benzimidazole, synthesis of a newer class of

alkynylbenzimidazole derivatives and their biological activity screening studies have

been included in present chapter.

Result and discussion:

In view of introducing the functionalities such as flurobiphenyls into the taget

benzimidazoles at the 2-position, we have prepared the required starting material 2-

mercapro benzimidazole (5) by the condensation of OPDA with potassium ethyl xanthate

in ethanol and subsequent simple work up10

. An intermediate compound 4,4'-(4-

chlorobut-1-ene-1,1-diyl)bis(fluorobenzene) (4) was synthesized using the literature

procedures11

in laboratory by reacting 4-bromo fluorobenzene (1) with ethyl

cyclopropanecarboxylate (2) under Grignard condition. Further the reaction of compound

3 with thionyl chloride in toluene to obtain 4,4'-(4-chlorobut-1-ene-1,1-

diyl)bis(fluorobenzene) (4) (Scheme-1)



F

F

ClF

F

OH

Mg SOCl2

Br

F

COOEt

+

(1) (2)

(3)(4)

THF

Scheme-1

The condensation of compound 4 with 1H-benzo[d]imidazole-2-thiol (5) in

presence of potassium carbonate in methyl isobutyl ketone to obtain 2-{[4,4-bis-(4-

fluorophenyl)but-3-enyl}thio}-1H-benzimidazoles (6) (Scheme-2).

F

F

Cl

F

F

SN

HN+N

NH

HS

MIBK

K2CO3

(4) (5) (6)

Scheme-2

Further the compound 6 was modified by converting the benzimidazole –NH into

its alkylated and acylated derivatives. Thus the reaction of compound 6 with methyl

iodide, ethyl iodide, propyl bromide, butyl chloride, benzyl bromide in presence of

potassium carbonate as a base yielded the corresponding N-substituted derivatives 7a-e.

In the similar manner reaction of compound 6 with Ethyl chloroformate, phenyl

chloroformate methane sulfonyl chloride and p-toluene sulfonyl chloride in presence of

sodium hydride as a base to yielded the corresponding N-substituted derivatives 7f-i and

characterized with the help of their analytical and spectral data (Scheme-3) (Table-1).



F

F

SN

HN

(6)

F

F

SN

N

(7)

R

Alkylation/acylation

7a, R-Methyl7b, R=Ethyl7c, R=Propyl7d, R=Butyl7e, R=Benzyl

Scheme-3

7f, R=Ethoxy carbonyl7g, R=Phenoxycarbonyl7h, R= Mesyl7i, R= Tosyl

Experimental Section

General Remarks

Melting points of all the synthesized compounds were determined by an open

capillary method and are uncorrected. The synthesized compounds were crystallized

using proper solvent and the purities were ascertained on the basis of thin-layer

chromatography, mass and spectral data. The homogeneity of the compounds was

monitored by ascending thin layer chromatography (TLC) on silica gel (Merck) glass

plates, visualized by iodine-vapor. Developing solvents were chloroform: methanol

(9.5:0.5). IR spectra were recorded on an FTIR spectrophotometer [Shimadzu] using

KBr pallet. 1H NMR spectra were obtained at 300 MHz on a Varian Mercury YH-300

FT NMR spectrometer in CDCl3 using tetramethylsilane as an internal standard.

Alkylating, acylating reagent were obtained from Aldrich. General chemicals and

solvents used were of synthetic grade.

Synthesis of 2-(4,4-bis(4-fluorophenyl)but-3-enylthio)-1H-benzo[d]imidazole (6)

A mixture of 4 (10 mmole), 1H-benzo[d]imidazole-2-thiol (5) (12 mmole) and

fine anhydrous powder of potassium carbonate (15 mmole) in Methyl isobutyketone

(MIBK) (20 ml) was heated to reflux and reaction was monitored by TLC (mobile

phase, Ethyl acetate : n-Hexane, 8:2). The reaction mass was cooled and water (40 ml)

was added. The MIBK layer was washed with water and dried over sodium sulfate.

Evaporation of the solvent gave the corresponding crude product which on further

recrystalliastion from methanol rendered desired product 6 in pure form.



General Procedure for the synthesis of compound (7a-e)

To a mixture of compound 6 (3 mmole) in acetone (10 ml) was added fine

anhydrous powder potassium carbonate (4.5 mmole), aliquat- 336 (0.3 gm) followed by

addition of alkylating agent (4 mmole). The reaction mixture was then refluxed for 2-8

hrs, monitored by TLC (mobile phase, Ethyl acetate: n-Hexane, 6:4). Acetone was

removed under vacuum. Then water was poured to the residue and extracted with

dichloromethane. The dichloromethane layer was washed with water and dried over

sodium sulfate. Evaporation of the solvent yielded the corresponding N-substituted

derivatives 6a-e.The crude products were subject to column chromatography to isolate

the pure products.

General Procedure for the synthesis of compound (7, f-i)

To a solution of compound 6 (3 mmole) in pyridine (10 ml) respective alkyl

chloroformate or acyl/aryl sulfonyl chloride (4.5 mmole) were added slowly at 5-

100C.The reaction mixture was allowed at attain room temperature and stirred for 8 hr

(monitor by TLC, Ethyl acetate : n-Hexane 3:7). A solution of 2 N acetic acid (100 ml)

was slowly added to the reaction mixture until neutralization. The product was extracted

in ethyl acetate (80 ml) and the extract was washed with water (100 ml X 2), 2 %

aqueous sodium bicarbonate solution (50 ml) and dried over anhydrous sodium sulfate.

The dried extract was concentrated under reduced pressure and recrystalized in ethanol

to afford the compounds (7, f-i).



Table-1: Spectral & Physical Characterization Data for Synthesized Compounds 6,

7,a-g.

6

F

F

SN

HN

2-(4,4-bis(4-fluorophenyl)but-3-enylthio)-1H-benzo[d]imidazole

IR(KBr):

(Fig. 1)

3074.59, 2963.68, 1600.94, 1508.36, 1405.17, 1224.82, 1094.62,

1015.54, 979.86, 829.41, 753.22

1H-NMR:

(CDCl3)

(Fig. 2)

δ 2.57-2.61 (m, 2H, S-CH2-CH2), 3.39-3.43 (t, 2H, S-CH2-CH2-),

6.03 ( m, 1H, olefnic proton), 6.9-6.99 ( m, 4H, Ar-H), 7.05-7,06

(m, 4H, Ar-H), 7.19-7.26 (m, 2H, Ar-H), 7.47 ( m, 2H, Ar-H), 9.26

(s, 1H, -NH).

Molecular Formula : C23H18F2N2S Yield (%) : 88 M.P.(0C): 154-164

7a F

F

SN

N

H3C

2-(4,4-bis(4-fluorophenyl)but-3-enylthio)-1-methyl-1H-

benzo[d]imidazole

IR(KBr):

(Fig. 3)

2935.71, 1708.00, 1600.94, 1507.40, 1222.89, 1157.31, 1014.57,

839.05, 740.68

1H-NMR:

(CDCl3)

(Fig. 4)

δ2.53-2.66 ( m, 2H, S-CH2-CH2-), 3.48-3.55 (t, 2H, S-CH2-CH2),

3.66 ( s, 3H, -N-CH3) , 6.08-6.13 ( t, 1H, Olefinic), 6.9-7.0 (m, 4H,

Ar-H), 7.07-7.2 (m, 5H, Ar-H), 7.24-7.26 (m, 2H, Ar-H), 7.68 (m,

1H, Ar-H).



Molecular Formula : C24H20F2N2S Yield(%) : 76 M.P.(0C): 55-62

7b F

F

SN

N

CH3

2-(4,4-bis(4-fluorophenyl)but-3-enylthio)-1-ethyl-1H-

benzo[d]imidazole

1H-NMR:

(CDCl3)

(Fig. 5)

δ1.34-1.39 ( t, 3H, N-CH2-CH3), 2.59-2.66 (m, 2H, -S-CH2-CH2-),

3.49-4.16 (t, 2H, -S-CH2-CH2), 4.09-4.16 (m, 2H, -N-CH2-), 6.02-

6.11( t, 1H, Olefinic), 6.88-7.00( m, 4H, Ar-H), 7.06-7.12 (m, 4H,

Ar-H), 7.23-7.26 ( m, 3H, Ar-H), 7.67 ( m, 1H, Ar-H).


7c F

F

SN

N

CH3

2-(4,4-bis(4-fluorophenyl)but-3-enylthio)-1-propyl-1H-

benzo[d]imidazole

1H-NMR:

(CDCl3)

(Fig. 6)

δ0.82-0.87 (t, 3H, -N-CH2-CH2-CH3), 1.69-1.76 ( m, 2H, -N-CH2-

CH2-CH3), 2.52-2.57 ( m, 2H, -S-CH2-CH2-), 3.38-3.43 (m, 2H, -S-

CH2-CH2-), 3.91-3.96 (t, 2H, N-CH2-CH2-CH3), 5.97-6.02 ( t, 1H,

Olefinc), 6.82-6.91 ( m, 4H, Ar-H), 6.98-7.14 ( m, 7H, Ar-H), 7.58

( m, 1H, Ar-H).




7d F

F

SN

N

CH3

2-(4,4-bis(4-fluorophenyl)but-3-enylthio)-1-butyl-1H-

benzo[d]imidazole

IR(KBr):

(Fig. 7)

3019.61, 2400.45, 1602.87, 1508.36, 1429.28, 1216.14, 1157.31,

1014.57, 840.01, 758.04, 688.35

1H-NMR:

(CDCl3)

(Fig. 8)

δ0.91-0.95 (t, 3H, -N-CH2-CH2-CH2-CH3), 1.32-1.40 (m, 2H, -N-

CH2-CH2-CH2-CH3), 1.73-178 (m, 2H, N-CH2-CH2-CH2-CH3),

2.59-2.60 ( m, 2H, -S-CH2-CH2-), 3.49-3.52 (m, 2H, -N-CH2-CH2-)

4.04-4.08 ( m, 2H, -S-CH2-CH2-), 6.06-6.11( t, 1H, Olefinic), 6.88-

6.97 (m, 4H, Ar-H), 7.06-7.26 (m, 7H, Ar-H), 7.66 (m, 1H, Ar-H).


7e F

F

SN

N

1-benzyl-2-(4,4-bis(4-fluorophenyl)but-3-enylthio)-1H-

benzo[d]imidazole

1H-NMR:

(CDCl3)

(Fig. 9)

δ2.63-2.71 ( m, 2H, -S-CH2-CH2-), 3.40-3.45 (t, 2H, -S-CH2-CH2-),

5.64 (s, 2H, -CH2-Ph), 6.01 ( m, 1H, Olefinic), 6.9-7.2 (m, 9H,Ar-

H), 7.29-7.36 (m, 7H, Ar-H), 7.55 (m,1H, Ar-H).




7f F

F

SN

N

O

O

ethyl 2-(4,4-bis(4-fluorophenyl)but-3-enylthio)-1H-

benzo[d]imidazole-1-carboxylate

1H-NMR:

(CDCl3)

(Fig. 10)

δ1.50-1.55 (t, 3H, -N-COO-CH2-CH3), 2.61-2.68 (m, 2H, -S-CH2-

CH2-), 3.38-3.43 (t, 2H, S-CH2-CH2-), 4.52-4.60 ( m, 2H, -N-

COO-CH2-CH3), 6.10-6.15 ( t, 1H, Olefinic), 6.94-7.11 (m, 4H, Ar-

H), 7.12-7.28 ( m, 6H,Ar-H),7.57-7.59 (d, 1H, Ar-H),7.83-7.85 (d,

1H, Ar-H).

Molecular Formula : C26H22F2N2O2S Yield (%) : 77 M.P.(0C):110-120

7g F

F

SN

N

O

O

phenyl 2-(4,4-bis(4-fluorophenyl)but-3-enylthio)-1H-benzo[d]

imida zole-1-carboxylate

1H-NMR:

(CDCl3)

(Fig. 11)

δ2.62-2.67 (m,2H, -S-CH2-CH2-), 3.41-3.46 ( t, 2H, -S-CH2-CH2-),

6.12 ( t, 1H, Olefinic), 6.90-7.10 ( m, 2H, Ar-H), 7.12-7.18 ( m, 2H

, Ar-H), 7.25-7.41 ( 11 H, Ar-H), 7.61 ( d, 1H, Ar-H), 7.95 ( d, 1H,

Ar-H).

Molecular Formula : C30H22F2N2O2S Yield (%) : 73 M.P.(0C):76-90



7h F

F

SN

N

SO

O

1H-NMR:

(CDCl3)

(Fig. 12)

δ2.43-2.45 (m, 2H, -S-CH2-CH2-), 3.10 ( s, 3H, -SO2-CH3), 3.44-

3.46 ( m, 2H, -S-CH2-CH2-), 5.94-5.98 (m, 1H, olefinic ), 6.87-7.02

(m, 8H, Ar-H), 7.06-7.26 (m, 2H, Ar-H), 7.62-7.64 ( m, 2H, Ar-H)

Molecular Formula : C24H20F2N2O2S2 Yield (%) : 88 M.P.(0C):95-103

7i F

F

SN

N

SO

O

H3C

IR(KBr):

(Fig. 13)

1597.09, 1507.40, 1449.53, 1379.13, 1224.82, 1173.70, 1088.84,

1039.65, 1014.57, 905.59, 839.05, 812.05, 759.00, 680.08

1H-NMR:

(CDCl3)

(Fig. 14)

δ2.36 (s, 3H, CH3-Ar), 2.49 ( m, 2H, -S-CH2-CH2-), 3.40 ( m, 2H,

-S-CH2-CH2-), 5.90 ( m , 1H, Olefinic), 6.84-7.01 (m, 7H, Ar-H),

7.12-7.26 ( m, 5H, Ar-H), 7.39-7.42 ( m, 1H, Ar-H), 7.55-7.56 ( m,

1H, Ar-H), 7.81-7,94 ( m, 2H, Ar-H)

Molecular Formula : C30H24F2N2O2S2 Yield (%) : 72 M.P.(0C):113-121

















References:

1. (a) Levin, J.I., and Venkatesan, A.M., Chem Abstr., 1994, 120,323589q ,

(b) Robert, D.A., Pearce R.J., and Bradbury R.H., Chem. Abstr., 1992, 117,111587a,

(c) Chakravarty, P.K., Strelitz, R.A., Chen, T.B., Chang, R.S.L., Lotti, V.J., Zingaro,

G.J., Schorn, T.W., Kivlighn, D., Siegl, P.K.S., Patchett, A. A., Greenlee, W.J.,

Bioorg. Med.Chem. Lett., 1994, 4, 75,

(d) Thomas, A.P., Allot, C.P., Gibson, K.H., Major, J.S., Masek, B.B., Oldham, A.

A., Ratcliffe, A. H., Roberts, D.A., Russel, S.T., Thomason, D. A., J. Med.

Chem., 1992,35, 877,

(e) Kubo, K., Kohara, Y., Yoshimura, Y., Inada, Y., Furukawa, Y., Kato, T.,

Nishikawa, K., Naka, T., J. Med. Chem., 1993,36, 2343.

2. Mauro V. A., Silvia H. C., Joao V. A. and Marcus V. N. S., J. Sulfur Chem., 2007,

28, 17.

3. Marco M., Claudia B. F. S., Rivara S., Valentina Z., Federica V., Mirko R.,

Elisabetta B., Simona B., Vigilio B.,. Francesca M, Mariannina I. and Pier V. P.,

Bioorg. Med. Chem., 2004, 12, 663.

4. Bakhareva E. V., Voronkov M. G., Sorokin M. S., Lopyrev V. A., Seredenin S. B.

and Gaidarov G. M., Pharmaceutical Chemistry Journal, 1996, 30, 89.

5. Janssen, Fr. pat. M3695 (1965 to Janssen), C.A. 1967, 66, 115709t.

6. Holmes B. et al., Drugs, 1984, 29, 6.

7. Ger. Pat., 1970, 1 947 332, CA, 72, 121586.

8. Moberg, W. K., Basarab, G. S., Cuomo, J., Liang, P. H. , Biologically Active Organosilicon

Compounds, 1987, 355, 288.

9. Tacke R. et al., Appl. Organomet. Chem., 1989, 3, 133.

10. Organic Syntheses, Coll. Vol. 4, 569 (1963) and 30, .56 (1950).

11. Joseph T. Strupczewski, Richard C. Allen, US patent 4352811, 1982.

Documents

“Synthesis, Characterization And Bioassay Of 1,4 ...shodhganga.inflibnet.ac.in/bitstream/10603/32390/13/13...An intermediate compound 4,4'-(4-chlorobut-1-ene-1,1-diyl)bis(fluorobenzene)