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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
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Ph.D. Thesis, Girish Bansilal Patel, School of Chemical Sciences, NMU, Jalgaon, 2012
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
Chapter-4 P a g e | 129
Ph.D. Thesis, Girish Bansilal Patel, School of Chemical Sciences, NMU, Jalgaon, 2012
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)
Chapter-4 P a g e | 130
Ph.D. Thesis, Girish Bansilal Patel, School of Chemical Sciences, NMU, Jalgaon, 2012
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).
Chapter-4 P a g e | 131
Ph.D. Thesis, Girish Bansilal Patel, School of Chemical Sciences, NMU, Jalgaon, 2012
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.
Chapter-4 P a g e | 132
Ph.D. Thesis, Girish Bansilal Patel, School of Chemical Sciences, NMU, Jalgaon, 2012
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).
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Ph.D. Thesis, Girish Bansilal Patel, School of Chemical Sciences, NMU, Jalgaon, 2012
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).
Chapter-4 P a g e | 134
Ph.D. Thesis, Girish Bansilal Patel, School of Chemical Sciences, NMU, Jalgaon, 2012
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).
Molecular Formula : C25H22F2N2S Yield (%) : 83 M.P.(0C): 58-61
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).
Molecular Formula : C26H24F2N2S Yield (%) : 81 M.P.(0C): 88-93
Chapter-4 P a g e | 135
Ph.D. Thesis, Girish Bansilal Patel, School of Chemical Sciences, NMU, Jalgaon, 2012
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).
Molecular Formula : C27H26F2N2S Yield (%) : 78 M.P.(0C): 75-83
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).
Molecular Formula : C30H24F2N2S Yield (%) : 70 M.P.(0C): 88-95
Chapter-4 P a g e | 136
Ph.D. Thesis, Girish Bansilal Patel, School of Chemical Sciences, NMU, Jalgaon, 2012
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
Chapter-4 P a g e | 137
Ph.D. Thesis, Girish Bansilal Patel, School of Chemical Sciences, NMU, Jalgaon, 2012
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
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Ph.D. Thesis, Girish Bansilal Patel, School of Chemical Sciences, NMU, Jalgaon, 2012
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