CHAPTER-I INTRODUCTION TO THE CHEMISTRY OF BENZIMIDAZOLES...
Transcript of CHAPTER-I INTRODUCTION TO THE CHEMISTRY OF BENZIMIDAZOLES...
12
CHAPTER-I
INTRODUCTION TO THE CHEMISTRY OF BENZIMIDAZOLES
General:- In the past decades, the literature seems to brim over with
research work on nitrogen containing heterocycles, as they are
present in nucleic acids, vitamins, proteins and biologically important
molecular systems. Benzimidazole is one such leading nitrogen
heterocycles containing potential pharmacological properties. The
discovery of 5, 6-dimethyl-1-(α-D-ribofuranosyl) benzimidazole1 is
fundamental structure of the vitamin-B12.
When a benzene ring (I) is fused to an imidazole ring (II)
through its 4, 5-bond, a benzimidazole ring (III) is formed.
N
N
N
N
HH
12
34
5
(II) (III)(I)
N
N
H
(III)
1
2
345
6
7
The two nitrogens present in the imidazole ring are different from
one another in their nature, and makes the properties of the ring
system diverse in character. The hydrogen attached to the nitrogen in
tautomerism with the other nitrogen.
13
N
NH
N
N
H(III) (IIIa)
Due to this tautomerism, certain benzimidazole derivatives, which
appear at first as isomers, are in reality tautomers.
N
N
H
H3C
N
NH3CH
1
2
3456
7
12
345
67
(IV) (IVa)
To prevent any confusion between the two tautomers, both the
designating structures are written with the second one in
parentheses, e.g., 5(6)-methylbenzimidazole, and 4(7)-
methylbenzimidzole.
N
N
HN
NH
12
3456
12
3
67
(V) (Va)
CH3
5CH3
4 7
When a group attached to nitrogen in the 1-position is larger than
hydrogen, such tautomerism is prevented and isomeric forms exist.
Thus, 1, 5-dimethylbenzimidazole (VI) and 1, 6-dimethylbenzimidazole
(VII) exist as distinct, isomeric compounds.
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N
NH3C
CH3
12
345
67
N
NCH3
H3C 12
3456
7
(VI) (VII)
IMPORTANCE OF BENZIMIDAZOLE RING SYSTEM:-
A large number of benzimidazole derivatives find use as
pharmaceuticals. Some of the commercially important benzimidazole
derivatives, are shown in Table-1.
S.
N0
Structure Importance
1 N
N
F
NH
N
OCH3
Astemizole
Antihistam
inic
2 N
NO
CH3O
NCN
Bezitramide
Analgesic
15
3 N
N
COOH
O CH3
NNN
N H
Candesartan
Antihypert
ensive
4
N
NH
O
NN
NO
H
Cl
Domperidone
Antiemetic
5
N
NN N CH3
O
CH3
Emedastine
Antiallegric
6
N
NN
N
H
CH3
Irtemazole
Uricosuric
agent
7 N
NH
SO N
CH3
O CF3
Lansoprazole
Antiulcer
16
8
N
N
ClO
H
N F
O
Milenperone
Antipsycho
tic
9 N
NCl
Cl
O
NH
H3CCH3
OH
OH
OH Maribavir
Antiviral
10 N
NH
H3COSO N
CH3
CH3
OCH3
Omeprazole
Antiulcer
11 N
NH
OCH3
NNH
CH3
O
Pimobendan
Cardiotoni
c
12 N
NH
NH CO
OCH3H3C
Parbendazole
Antielmenti
c
13 N
NH
SO N
CH3
O OCH3
Rabeprazole
Antiulcer
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SYNTHESIS OF BENZIMIDAZOLES:-
The reviews17-19 and articles20-22 covering the chemistry of both
imidazoles and benzimidazoles have been published earlier. Therefore,
only a brief account is given here.
Benzimidazoles may be synthesized from:
1. o-phenylenediamines
2. o-(N-acylamino and aroylamino)arylamines and nitroamines and
nitroarenes.
3. o-Nitroarylamines and o-dinitroarenes
4. o-substituted-N-benzlideneanilines
5. Amidines and
6. Other heterocyclic compounds.
1) From o-phenylenediamines:
o-phenylenediamines react with (a) carboxylic acids and their
derivatives, (b) imino-ethers (c) carbonyl compounds and (d) nitriles
to yield differently substituted benzimidazoles.
a) By reaction with carboxylic acids and their derivatives:
o-phenylenediamine (VIII) when condensed with carboxylic
acids under a variety of conditions gave 2-
substitutedbenzimidazoles in good yields.
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NH2
NH2+ HOOCH
(VIII) (IX)
N
NH
H
(III)
Scheme-1.1
Benzimidazoles were syntheized from o-phenylenediamines and
aliphatic acids.24-27 Phillips.28-31 developed a satisfactory method for
the preparation of 2-alkylbenzimidazoles (X, R=CH3).
⭪ EMBED ChemDraw.Document.6.0
NH2
NH2+ HOOC-R
(VIII) (XI)
N
NH
R
(X)
4N HCl
(R=CH3) Scheme-1.2
The role of hydrochloric acid37 is to activate carboxyl group by
addition of a proton to oxygen, forming carbonium ion. The
reaction mechanism involves carbonium ion intermediate.
R C OOH H
R COH
OH
H2N
H2N
R COH
OHH2N
H2N
N
NR
H-2H2O
-H
(R=CH3)
(X)
Scheme-1.3
19
This procedure however, fails to give any respectable yields of 2-
arylbenzimidazoles (XIII)37 with aromatic acids. Yields of 2-
arylbenzimidazoles were increased with o-phenylenediamines in a
sealed tube at 180-190oC. Polyphosphoric acid or polyphosphate42
esters were used as condensing agents for o-phenylenediamines and
aromatic acids for good yields.
NH2
NH2
+ HOOC-ArPPA or PPE
N
NAr
H
(VIII) (XII) (XIII)
Scheme-1.4
The procedures described above were utilized in recent years for
the preparation of benzimidazoles possessing thiazolyl, thiadiazolyl
substituents in 2nd - position.43-44 The other derivatives include 1-aryl-
5-amino45, 2-trifluoromethyl46, 2,6-bis(trifluoromethyl)-4-nitro47, 2-β-
mercaptoethyl48, 2-(1-aminoalkyl)49, 2-(p-iodobenzyl) and 2-(p-
iodostryl)50 are benzimidazole derivatives.
The reaction between o-diamine and an ester was first investigated
by Von Niemantowski51 who prepared (XVI) by condensing equimolar
amounts of XIIII and XV at 225oC in sealed tube for 3hrs.
NH2
NH2
(XIIII)
H3C.2HCl + H C
OOC2H5
(XV)
225oCN
N
H3C
H
CH3
(XVI)
Scheme -1.5
20
Landenburg52 first prepared XVI by refluxing XVII in glacial
acetic acid.
NH2
NH2
(XVII)
H3C+ C
HO R
O
(XI)
N
NH
RH3C
(XVI) (R=CH3)
Scheme -1.6
X was obtained by prolonged treatment of VIII with XVIII
whereas treatment for a short time yielded only XIX53 Wagner54
reported improved yields X from VIII and XVIII by using dilute HCl.
NHCOCH3
NHCOCH3
NH2
NH2+ (CH3CO)2O N
NH
CH3
(XIX) (VIII) (XVIII) (X)
Scheme -1.7
XX when reacted with XVII in benzene solution yields XVI if the
reaction is done without cooling and XXI when the reaction is
cooled.55
H3C NHCOCH3
NHCOCH3
CH3COCl +NH2
NH2
H3C
N
NH3CH
CH3
(XXI) (XX) (XVII) (XVI)
Scheme -1.8
21
Niementowski synthesized IV by heating XIV with the
corresponding amides.56 Bisbenzimidazoles (XXV) were synthesized by
heating o-diamines or their salts with aliphatic acid amides XXIV in
solvents like ethylene glycol and glycerol57 having high boiling points.
NH2
NH2
.2HCl + (CH2)n(CONH2)2N
NH
(CH2)XN
NH
Xn
(XIV) (XXIV) (XXV)
Scheme -1.9
b) By reaction with imino-ethers (Imidates):
o - phenylenediamine on reaction with imino ether in dil.acidic
medium led to the formation of benzimidazole in high yields. The
drawback in the Phillips procedure is that diamine competes for the
proton of the acid. E.g. XXVIII was synthesized in 95% yield by
reacting o-phenylenediamine hydrochloride (XXVI) with
trichloroacetimidate (XXVII) at room temperature.59-60
NH2
NH3Cl+ CHN
H3COCCl3
RT
N
NH
CCl3
(XXVI) (XXVII) (XXVIII)
Scheme -1.10
The scope of imidate procedure has been assessed by Acheson
and King.68
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c) By reaction with carbonyl compounds:
Rao and Ratnam,69 and by Smith and Ho70 independently
reviewed the reaction between o-diamines and aldehydes as a method
to synthesize benzimidazoles. o-phenylenediamine when condensed
with aldehydes resulting various 2-substitutedbenzimidazoles in the
presence of oxidising agents such as cupric acetate (Weidenhagen
procedure),71 mercuric oxide (for 2-NHCOOMe),72 chloranil (for 2-
furyl),73 lead tetra acetate,74 manganese dioxide,75 Nickel peroxide76
and nitrobenzene.77
NH2
NH2+ OHC-Ar
N
NH
Ar
(VIII) (XII) (XIII)
Scheme -1.11
The reaction between o-arylenediamines with formaldehyde gives
rise to 1-methylbenzimidazoles,79-80 and this type of procedures has
been studied in detail.81
Depending on the nature of the aldehyde and the molar
proportions in the reaction, o-phenylenediamine when condensed with
aromatic aldehydes results in the formation monoanils and dianils in
some cases69. Products containing cyclic structures such as XIII, 1:1
product and XXXI, 1:2 product are formed in varying proportions in
acetic acid at room temparature.
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NH2
NH2
N
NH2
CH Ar
N
N
CH Ar
CH Ar
N
NH
Ar
N
NCH2
Ar
Ar(VIII)
(XXIX)
(XXX)
(XIII)
(XXXI)
Scheme -1.12
The monoanils (XXIX) which are prepared separately are
converted to 2-substitutedbenzimidazoles by treating with
dehydrogenating agents.76-80
NH2
NH2+
NH2
N CH Ar
N
NH
Ar
(VIII) (XXII) (XXIX) (XIII)
OHC-Ar
Scheme -1.13
Both under acidic as well as thermal conditions.82-83, 85-87 dianils
(XXX) can also be cyclised to 1, 2-disubstitutedbenzimidazoles.
N
N CH
Ar
CH
Ar
N
NCH2
Ar
Ar
(XXX) (XXXI)
Scheme -1.14
24
Rao and Co-Workers, 88 studied the isolation, of XXXII (1:3
product) in the condensation of o-phenylenediamine with simple o-
chloro and m-nitrobenzimidazoles in acetic acid at room temparature.
NH2
NH2+
N
NH
Ar +N
NCH2-Ar
ArN
NCH2-Ar
H
ArCH2-Ar
+
(VIII) (XXII) (XIII) (XXXI) (XXXII)
Scheme -1.15
The monoanils have been shown89 to exist in taotomeric form
with the corresponding dihydrobenzimidazole by NMR spectroscopy.
N
NH2
CH
Ar
N
NH
H
ArH
(XXIX) (XXXIII)
Scheme -1.16
These dihydro derivatives could not be isolated in a free state in
the reaction of o-phenylenediamine with aromatic aldehydes. They
were, however, isolated90 in pure form in the reactions of 2,3-
pyridinediamine with aromatic aldehydes. Furthermore, the
structures of the monoanils obtained from the reaction between 2,3-
pyridinediamines and aromatic aldehydes has also been established91
unequivocally by X-ray crystallographic methods.
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ii) By reaction with ketones:
IT has been reported92-94 that O-phenylenediamine when
condensed with ketones gave 2, 2-disubstitutedbenzimidazoles (XVI)
which decompose under the influence of heat to a 2-
substitutedbenzimidazole and a hydrocarbon.
NH2
NH2+ CO
RR
(VIII) (XXXV)N
NH
H
R
R1
(XXXIV)
R1 > R N
NH
R R1-H+
(X) R = CH3
Scheme -1.17
d) By reaction with nitriles:
XIV when heated with Nitriles at 200oC gave X. This reaction has
been studied by Hollies and Wagner95 and they proposed the following
mechanism for the reaction.
NH2
NH2
.2HCl + RCNNH2
NH2
+ R-CH NH.Cl
NH
NH2
CNH
R N
NH
H
NH3Cl
R N
NH
R + NH4Cl
R=CH3
(XIV) (XXXVI) (VIII)
(X)
Scheme -1.18
Using this procedure 2- substituted benzimidazoles have been
synthesized.
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2) From o-(N-acylamino and N-aroylamino)arylamines and
nitroarenes:
The o-phyenylenediamine can be synthesized insitu from the
appropriate o-nitroarylamine by using a variety of reducing agents
such as Sn/AcOH,108 Na2S2O4,109 H2/PD/C,110 Raney Ni,111
SnCl2/HCl,112 Fe/AcOH,113 Zn dust/AcOH,32 Na2S114 (sod.sulphide)
etc.
N
NH2
R1COR2 aq. HCl or
Heat N
NR2
R1Reductant N
NO2
R1COR2
(XXXVIII)(III)(XXXVII) R1, R2 = H
Scheme -1.19
Thus, Bisbenzimidazoles115-116 and releated derivatives were
synthesized by the cyclisation of mono-aryl-o-phenylenediamine.
N
NPh
XN
NPh
N
N N
NPh Ph
PhPh
SN
N
Ph
Ph
O
ON
NPh
Ph
X = p- and m-phenylene,4,41-C6H4-C6H4 etc
(XXXiX)
(XL)
(XIL)
Scheme -1.20
27
3) From o-nitroarylamines and o-dinitroarenes:
Benzimidazoles are synthesized in a single step from an o-
nitroarylamine or an o-dinitroarene by using various reducing agents.
These procedures have got commercial importance since reasonable
yields were obtained. A secondary reaction occurs and converts the 2-
alkylbenzimidazole into 1, 2-dialkylbenzimidazoles,122 when o-
nitroanilines are used in thermolysis.
N(CN)COOR
NO2
H2 / Raney NiN
NCOOR
NH2N
NH
NHCOOR
(XIIL) (XIIIL) (XIVL)
Scheme -1.21
In thermally uncatalysed cyclisation reactions benzimidazoles
were obtained from N-substituted-o-nitroaniline (XVL) derivatives.124
NHCH2Ar
NO2
Heat in sandN
NH
Ar
(XVL) (XIII)
Scheme -1.22
The acid catalysed cyclisation of XVIL to N-aminobenzimidazoles
(XVIIL) has been reported.125
28
N
NO2
HN aq. HCl / Heat
N
NNH
(XVIL) (XVIIL)
Scheme -1.23
4) From o-substituted N-benzimideneanilines:
Aromatic nitro compounds on reduction by triethylphosphite and
related reagents has been widely used as a simple, route to a variety
of nitrogen containing heterocycles.127 XVIIIL derivatives are
converted128 into 2-phenylbenzimidazoles by using triethylphosphite
and similar reducing reagents and the yields are slightly higher than
those obtained by the use of classical weidenhagen aldehyde method.
N
NO2
CH
Ph (EtO)3P/ t-BuC6H5
reflux N
NH
Ph
(XVIIIL) (XIII)
Scheme -1.24
Good yields of benzimidzoles were obtained by heating XVIIIL in
1, 2-dichlorobenzene129 or dimethylformamide130 .
N
NO2
CH
Ph
N
NH
Ph
(XVIIIL) (XIII)
Scheme -1.25
29
5) From amidines:
Generally, benzimidazoles are synthesized from o-
phenylenediamine and its derivatives. The reactions were carried out
under mild conditions using benzenesulphonyl chloride in pyridine or
in triethylamine resulting good yields. Consequently, it has been
shown that such products can be obtained from the parent amidines
by oxidation under basic conditions.132
HN R
NH
PhSO2Cl / Et3N or Pyridine
<10oC N
NH
R
(XIXL) (X) R=CH3
Scheme -1.26
6) From heterocyclic compounds:
Benzimidazole derivatives (LI) were extracted133 from reductive
cyclisation of o-benzoquinonedibenzimide (L) by triphenylphosphine.
NCOPh
NCOPh+ Ph3P
N
NCOPh
Ph + Ph3PO
(L) (LI)
Scheme -1.27
Thus, in the absence of a substituent, LII is converted into
benzimidazole in poor yield together with trace quantities of LIII; LIV
are converted in very good yield into LV and LIV by opening of the N-
30
N-bond and migration of the hydrogen from C3 to Ni to give 2-
alkylaminobenzonitriles.134
NNH
N
NH
+CN
NH2(LII) (III) (LIII)(27%)
(Trace)
NN
R
H
N
NR
(LV)(LIV)
hv
hv
(73-96 for R=alkyl, aralkyl, Ar)
N
NR
(LV)
hv CN
NH2
(LIII)
Scheme -1.28
Recent work for the synthesis of benzimidazoles derivatives:-
Singh et. al. reported136 that bisbenzimidazole derivaties were
obtained by coupling of aromatic orthodiamines with aromatic and
heterocyclic aldehydes by oxidation.
31
NH2
NH2H3C+ OHC-Ar Fe III-FeII
IOI
N
N
H3CAr
H
N
N
HOH2CAr
HPCC / CH2Cl2
N
N
OHCAr
HNH2
NH2Hr
(XVII) (XXII) (LIX)
(LX) (LXI)
(LXII) N
NH
N
NH
ArHr
(LXIII)
Lu et al reported137 the synthesis 2-substitutedbenzimidazoles
by using polyphosphoric acid as a catalyst from organic acids under
micro-wave irradiation.
NH2
NH2+ HOOC-Ar
PPA / MW
N
NAr
H
(VII) (XXII) (XXIII)
Scheme -1.29
Substituted benzimidazoles were synthesized by using
ytterbium triflate as a catalyst.139
NH2
NH2ROHC-Ar
Yb (OTf)3N
NAr
H
R
(XXIII) (XXII) (LIX) R=CH3
+
Scheme -1.30
Taylor et al. reported140 the synthesis of 2-substitutedbenzi-
midazoles in good yields directly in the presence of manganesedioxide
and molecular sieves in a one-pot method.
32
NH
NH2
CH3
+ Ar-CH2-OH
MnO2Sieves
18hrN
NCH3
Ar
(LXIV) (LXV) (LXVI)
Scheme -1.31
Perumal et al. reported141 the synthesis of 2-aryl-1-arylmethyl-
1H-1,3-benzimidazoles in the presence of montmorillonite k-10 from
o-phenylenediamine and aromatic aldehydes in the absence of solvent
under microwave conditions.
NH2
NH2
+ OHC-Ar
(VIII) (XXII)
K-10 Clay
MWI N
NAr
Ar
(XXXI)
Scheme -1.32
Salehi et. al. reported145 selective synthesis of 2-aryl-1-
arylmethyl-1H-1, 3 benzimidazoles in the presence of silica and
sulphuric acid in water or ethanol.
NH2
NH2+ Silica sulfuric acid
N
NAr
(XXII) (XXXI) R=CH3
OHC-Arwater
(VIII)
Ar
Scheme -1.33
SPECTRAL PROPERTIES OF BENZIMIDAZOLES:-
IR spectra of benzimidazole were studied in detail by Rabiger and
Morgan.147 Turchin148 studied in detail, NMR spectrum of the
benzimidazole in the acid solutions, which was found to give the
33
following chemical shift values (ppm) in CD3OH and TMS as internal
standard.
N
NH
H
12
34
56
7
4H, 7H 5H, 6H 2H
7.61 7.24 8.12
13C spectrum of the benzimidazoles149 was found to give the
following chemical shift values in CD3OH.
N
NH
H
12
34
56
7
2 7 5, 6 8, 9
141.46 115.41 122.87 137.92
The mass spectral fragmentation of the benzimidzoles was
observed by Bowie150 from which it appears that the fragmentation
pathways of benzimidazoles are similar to that of imidazole. The
spectrum of benzimidazole indicates a sequential loss of two
molecules of hydrogen cyanide from the molecular ion.
N
NH
HC
NH2
N
-H
-HCN
C6H5N
C6H5N
(m/e 91)
(m/e 92)
34
CHEMICAL PROPERTIES OF THE BENZIMIDAZOLES:-
1) Reactions with electrophillic reagents:-
i) Electrophilic aromatic substitution does not occur easily in the
imidazole ring of benzimidazoles. Benzimidazole on treatment with Cl2
gives 4, 5, 6-trichlorobenzimidazole.152
N
NH
I2 / NaOH
N
NH
I
(III) (LXVII)
N
NH
N
NH
I
(III) (LXVIII)
Cl2Cl
ClCl
Scheme -1.34
ii) Sulphonation of the benzimdazole can be carried out in Conc.
Sulphuric acid or in chlorosulphonic acid to yield benzimidazole-5-
sulfonic acid.153
N
NH
H2SO4 or
ClSO3H N
NH
HO3S(III) (LXIX)
Scheme -1.35
iii) Nitration of the benzimdzole in presence of nitrating mixture gives
a mixture of 5, 6 or 4, 6-dintrobenzimidazole.154
N
NH
H2SO4/ HNO3
N
NH
(III) NO2
O2N+
N
NH
O2N
O2N
(LXX) (LXXI)
Scheme -1.36
35
iv) Alkylation of benzimidazoles:-
a) Alkylation: alkylation of alkyl halides usually occurs by SE2
mechanism.
b) Alkylation by Mannich reaction :- alkylation of benzimidazole
by Mannich reaction156 procedure .
N
NH
(III)
CH2O / morpholine
CH3OH N
NCH2 N O
N
NH
(III)
PhCO(CH2)2NR2
Xylene N
N(CH2)2COPh
(LXXII)
(LXXIII)
Scheme -1.37
c) Alkylation by activated alkenes :- Benzimidazole derivatives
have been alkylated by activated alkenes in thermal conditions and
also in acid and base catalysed processes.
N
NH
CH
CN CH2
N
NCH2-CH2-CN
(III) (LXXIV)
Scheme -1.38
d) Activated alkynes:- 1-Vinylbenzimdiazole is formed by the
reaction of benzimidazole with acetylene in aqueous dioxane at 160
oC.158
36
N
NH
CH CH
aq.Dioxane N
NHC CH2
(III) (LXXV)
Scheme -1.39
Reactions with Nucleophilic reagents:-
a) Tschitsichibabin reaction:- The tschitsichibabin reaction is
extensively used for the preparation of 2-aminobenzimidazole
derivatives.
N
NR
NaNH2 / xylene
N
NR
NH2
(LV) (LXXVII)
Scheme - 1.40
b) Reaction with reactive intermediates:- Benzimidazole -2-
carboxamide (LXXVII) is prepared by the reaction of benzimidazole
(III) with a carboxylic acid in the presence of ammonium
thiosulphate.161
N
NH 10% H2SO4 / AgNO3 /
(NH4)2S2O8
RCO2H / H2O N
NH
CO
NH2
(III) (LXXVIII)
Scheme -1.41
c) Reaction with benzyne:- Benzimidazole (III) reacts as a
nucleophile with benzyne in conventional fashion to give 1-
phenylbenzimidazole (LXXIX) along with polymeric materials.162
37
N
NH
benzyne
N
NC6H5
+ Polymeric materials
(III) (LXXIX)
Scheme -1.42
Photochemical reactions:- Benzimidazole (III) on irradiation with UV
light transforms into a mixture of dehydroisomers, the two dimmers
are formed by homolyic substitution at the 4 and 5 positions of
benzimidazole by a 2-benzimidazolyl free radical.163
N
NH
(III)
EtOH
253.7 nm N
NHN
N
H
N
NH
NNH
+
(LXXX) (LXXXI)
Scheme -1.43
Oxidation:- Oxidation of benzimidazole (III) with lead dioxide gives
2,2’-biisobenzimidazolylidine (LXXXII). Alternatively, the compound
can also be prepared by a similar oxidation of 2, 2’-
biisobenzimidazole.164
N
NH
PbO2 / C6H6 / reflux
24 hrs N
N
N
NPbO2 / C6H6/reflux
24 hrs N
NH
N
NH
(III) (LXXXII) (LXXXIII)
Scheme -1.44
Reduction:- Benzimidazoles on reduction with H2 in the presence of
charcoal results in the formation of hexadehydrobenzimidazole
(LXXXIV).165
38
N
NH
H2 (100 atm) / Rh-C
aq. MeOH N
NH
(III) (LXXXIV)
Scheme -1.45
Present Work:- It is evident from the literature that benzimidazoles
are known to be biologically and pharmacologically important
molecules. Also, not much work seems to have done on the synthesis
of 1-substituted benzimidazole derivatives.
Chapter 2: The present chapter deals with the studies on preparation
of 2-Acetylbenzimidazole based on o-phenylenediamine. Condensation
of o-phenylenediamine with lactic acid under Phillips conditions to
give 2-(α-hydroxyethyl)benzimidazole, followed by oxidation studies
with various oxidizing agents such as K2Cr2O7, MnO2, H2O2 in AcOH,
CaOCl2, m-CPBA,10% HNO3, 50% HNO3, CAN has been described.
This chapter also discuss the studies on reactions of 2-(α-
hydroxyethyl)benzimidazole with acid chlorides such as benzoyl
chloride, benzenesulphonyl chloride and tosylation under various
conditions and subsequently alkylations reactions on 2-
acetylbenzimidazole and O-benzoylated products . This chapter also
describes the reactions of 2-(α-chloroethyl)benzimidazole with
anilines.
39
Chapter 3: A study of literature showed that derivatives of
thiadiazines, thiazolidinones and thiadiazol containing heterocyclic
compounds have potential biological activity. Keeping this in view, it
was considered worthwhile to study the synthesis of benzimidazole-2-
acetyl thiosemicarbazone derivatives and their further chemical
modifications.
This chapter deals with the synthesis of 1, 3, 4-thiadiazolines. 2-
Acetylbenzimidazole (4) on condensation with thiosemicarbazide gave
thiosemicarbazone (82). The latter on condensation with p-
chlorophenacyl bromide (83) gave 3-[1H-benzimidazol-2-yl)-
ethylideneamino]-4-(4-chlorophenyl)-3H-thiazol-2-one (84). 84 on
reaction with m-CPBA in chloroform at (-)10 oC for 6 hrs yielded [1-
(1H-benzimidazol-2-yl)ethylidene]-[5-(4-chlorophenyl)-1,1-dioxo-
1,2,5,6-tetrahydro-1λ6-{1,3,4}thiadiazin-2-yl]amine (85).
Chapter 4: The present chapter describes the alkylation studies on
benzimidazole chalcones and subsequent functional modifications of
resulting products into pyrazole and isoxazole derivatives. 2-
Acetylbenzimidazole (4) was prepared by oxidation of 2-(α-
hydroxyethyl) benzimidazole (3) in acetic dichromate conditions. 4 on
reaction with benzaldehyde in 5%NaOH solution at room temperature
for 3hrs resulted in the formation of known benzaldehyde chalcone
(97). Benzimidazole-2-chalcone (97) on reaction with ethyl
chloroacetate, in DMF containing K2CO3 and catalytic amount of
phase transfer catalyst TBAB, at room temperature for 1 hr resulted
40
in the formation of [2-(3-pheylacryloyl)benzimidazolyl] acetic acid ethyl
ester (103). Reaction of 103a with NaBH4 in methanol at room
temperature for 1 hr resulted in the formation of 1-[1-(2-
hydroxyethyl)-1H-benzimidazolyl]-3-phenyl propanol 105. 2-
Acetylbenzimidazole (4) on heating with dimethyl formamide diemthyl
acetal [CH(OMe)2NMe2] at 105oC for 1 hr resulted in the formation of
1-(1H-benzimidazolyl)-3-dimethylamino propenone (108). Reaction of
108 with hydrazine hydrate in methanol on refluxing for 1 hr resulted
in the formation of 2-(1H-pyrazolyl)-1H benzimidazole 110. The
isoxazole derivative of the benzimidazole was prepared by the reaction
of 108 with NH2OH.HCl in methanol under refluxing conditions for 3
hrs resulting in the formation of 2-isoxazolyl-1H-benzimidazole (113).
Chapter 5: It has been reported that pyrazolines possess analgesic,
anti-inflammatory and antimicrobial activities. Therefore, it has been
considered worthwhile to study the synthesis of pyrazoles hooked to
benzimidazole ring system. This chapter deals with the synthesis of
pyrazolyl derivatives of benzimidazole chalcone. 97 on reaction with
dimethyl sulphate (DMS) in the presence of K2CO3 and TBAB as PTC
in CH3CN at room temperature for 3 hrs yielded N-methyl-2-
acetylchalcone (129a, i.e., 129, R=CH3) which is also known in
literature. 129a (i.e., 129, R=CH3) on refluxing with hydrazine hydrate
in glacial acetic acid for 3 hrs resulted in the formation of 1-[3-(1-
methyl-benzimidazole-2-yl)-5-phenyl-4, 5-dihydro pyrazol-1-yl]
ethanone (130). 130 was condensed with different aromatic aldehydes
such as benzaldehyde (14), in 10% methanolic NaOH under reflux for
41
4 hrs resulting in 1-[3-(1-methyl-1H-benzimidazol-2-yl)-5-phenyl-4, 5-
dihydro-pyrazol-1-yl]-3-phenyl-propenone (132). 97 on reaction with
malononitrile in the presence of sodium ethoxide in ethanol for 3 hrs
at room temperature yielded a new product. This
product was assigned as 6-(1H-benzimidazol-2-yl)-2-ethoxy-4-phenyl
nicotinonitrile (136). 97 on reaction with melononitrile in the
presence of sodium methoxide in methanol for 3 hrs yielded a new
product 6-(1H-benzimidazol-2-yl)-3-methoxy-2-phneyl-isonicotinonitril
(137). 137 on reaction with hydrazine hydrate in the presence of BF3
in ethanol under reflux for 3 hrs yielded a product (138).