introduction to benzimidazoles and...
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Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 64
Section-1
Introduction
To
Benzimidazoles
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 65
SECTION –1
Imidazole (1) nucleus was first discovered by Debus
1 in the year 1959
by reacting glyoxal and ammonia and to indicate its source he proposed the
name glyoxaline. The term imidazole which is due to Hantzsch2 implies a five
membered heterocyclic ring system containing imino group in addition to a
tertiary nitrogen atom, that are located in the positions 1 and 3, respectively.
The ring is completely planar. This imidazole ring has been found in several
naturally occurring products, which include the -amino acid histidine, a
normal constituent of most proteins, histamine, purine and biotin.
Benzimidazole is a class of heterocyclic aromatic organic compound
which share a fundamental structural characteristic of sixmembered benzene
fused to the 4 and 5-position of five membered imidazole ring system(2). The
hydrogen atom attached to nitrogen in the 1-position of benzimidazole nucleus
readily tautomerizes which is responsible for isomerization in the derived
compounds3, 4
. The various positions on the benzimidazole ring are numbered
in the manner indicated, with the imino function as number 1 as shown below.
The heterocyclic benzimidazole scaffold is a useful structural motif for the
development of molecules of pharmaceutical or biological interest.
In 1872, Hobrecker reported the first benzimidazole synthesis of 2,5-
and 2,6-dimethylbenzimidazole and he never suspected that benzimidazole
scaffold would become such a preeminent structure3. The interest in
benzimidazole chemistry has been spawned by the discovery that N-ribosyl-
dimethylbenzimidazole is the most prominent benzimidazole compound in
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 66
nature which serves as an axial ligand for cobalt in vitamin B125. The NH
group present in benzimidazole is relatively strongly acidic and also weakly
basic in nature4. Benzimidazole is an amphoteric compound with ionization
constant (pKa) value for benzimidazole and its conjugate acid is 12.8 and 5.6,
respectively6.
NH
N
12
34
5
(1)
NH
N
1
2
34
5
6
7
8
9
(2)
Benzimidazole possessing a free imino hydrogen and are tautomeric
systems. The two possible tautomeric forms of the benzimidazole are identical.
Substitution of the imino hydrogen eliminates the possibility for tautomerism
and a definite assignment of the structure becomes possible.
Aromaticity
The imidazole molecule is planar and exhibits aromaticity associated
with six –electrons one from each carbon atom, one from the pyridine
nitrogen and two from the pyrrole nitrogen. Actually, a similar situation exists
in case of benzimidazole, which can be envisaged as two overlapping sextets
having 10–electrons. Benzimidazole is amphoteric compound, which is
pseudo acidic character. Their basic properties result from their ability of the
pyridine nitrogen to accept a proton. Thus, benzimidazole (pKb 5.5) is a base
N
N
HNH
N
H
H
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 67
considerably weaker than imidazole (pKb 6.95).
Spectroscopic Studies
Ultraviolet (UV)
The ultraviolet spectra of benzimidazole and its derivatives have been
studied in alkaline, neutral and acidic media. The bands observed in the case of
benzimidazole7 are given below.
Solvent λ max (logε) m μ
Ethanol 280 (3.89); 272 (3.91); 243 (3.80)
0.01 N HCl 274 (3.91); 268 (3.92), 235 (3.61)
0.01 N NaoH 277 (3.75); 271 (3.74), 240 (3.63)
The marked shifts in the position and intensity of the absorption spectra
are because of the difference in electron distribution between the charged and
uncharged ions.
Infrared (IR)
The infrared spectra of benzimidazole ring system had strong absorption
band around 1400 – 1650 cm-1
for –C=N- stretching. It is very difficult to
distinguish7,8
the C-H stretching vibrations occurring in the range of 3300 –
3100 cm-1
from the broad N-H stretching frequencies around 3300 – 2800 cm-1
.
Proton Nuclear Magnetic Resonance (1H NMR)
The chemical shifts of benzimidazole has been manifested9,10
at lower
field 7.71 (C2-H), 7. 67 (C4-H), 7. 17 (C5-H), 7.24 (C6-H) and 7.32 (C7- H),
respectively. The overlapping signals ascribable to aromatic protons and
protons to N-H have been observed at 7.5 - 8.2, which are disappeared on
D2O addition. The chemical shift of C4-H and its deviation, because of various
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 68
substituents is due to the magnetic anisotropy of the unsaturated nitrogen lone
pair11
, which is removed when protonation occurs at this nitrogen.
Mass spectroscopy (MS)
The mass spectrum of benzimidazoles exhibits molecular ion as a base
peak12
. It also shows an odd electron ion (a) m/z 91 (C6H5N) by the loss of
hydrogen cyanide, which further looses acetylene to lead to another odd
electron ion, m/z 65 (C4H3N) and not the second molecule of hydrogen
cyanide13
.
In the case of 2-methyl benzimidazole, molecular ion m/z 131 is formed
by the loss of hydrogen radical from the methyl group, with a concomitant ring
expansion to form the stable quinoxalinium cation.
NH
N
N
N
H
N
N
H
NCH C6H5
+ .
+
+
+
..
+
- HCN +
-H
-HCN
13
C NMR Spectroscopy
The 13
C NMR chemical shifts have been reported by Pugmire and
Grant14
for benzimidazole anion, benzimidazole and benzimidazole cation are
tabulated as follows.
NH
NNH
(a)
+.+.
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 69
Compound Position δ ppm
Benzimidazole anion
N
N
-
2
4,7
5,6
8,9
150.45
116.41
120.10
143.88
Benzimidazole
NH
N
2
4,7
5,6
8,9
141.46
115.41
122.87
137.92
Benzimidazole cation
NH
N+
H
2
4,7
5,6
8,9
139.58
114.44
127.29
129.79
Recent Literature:
Generally, the derivatives of o-nitroaniline and o-phenylenediamine are
the starting materials for the synthesis of benzimidazoles15,16
. The other
starting materials have also been used to synthesize the most important
benzimidazole molecule. This part emphasis the important synthetic methods
reported in the benzimidazole chemistry.
Nakao. et al.,17
synthesized a series of 1-aryl-3,4-substituted-1H-
pyrazol-5-ol derivatives 3 and evaluated as prostate cancer antigen-1 (PCA-
1/ALKBH3) inhibitors to obtain a novel anti-prostate cancer drug.
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 70
NH
N
N
N
OH
Me R2R1
3
Nanda et al.,18
were designed, synthesized, SAR and evaluated
pharmacokinetic data a new series of CB2-selective agonists containing a
benzimidazole core 4.
N
N
N
OH
O
NH
N
N
O
NHR
(racemic) 4
Pereira et al.,19
were arylated electron poor benzimidazole substrates 5
via an intramolecular cross-dehydrogenative coupling (CDC) reaction. These
CDC reactions were catalyzed by a Pd(II)/Cu(I) catalyst system, capable of
producing moderate yields on a large library of substrates. The substrate scope
consisted of tethered arene-benzimidazoles that upon coupling produced a
fused polycyclic motif.
N
N
H
R1
R2H
N
N
R1
R2
5
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 71
Lal A. K. and Milton M. D.20
were synthesized a series of novel, water-
soluble benzimidazolium salts 6, 7, 8 with common ‘fluorophore–spacer–
receptor’ PET design has been synthesized. Despite the common PET scaffold
these benzimidazolium salts displayed diverse emission intensities in pure
aqueous solutions. The observed emission intensities were found to be
influenced by the functionalized alkyl side arms present on the
benzimidazolium ring. These benzimidazolium salts were also found to act as
selective sensors for Fe3+
ions over other metal ions like Na+, K
+, Ca
2+, Mg
2+,
Ba2+
, Al3+
, Cr3+
, Co2+
, Ni2+
, Mn2+
, Zn2+
, Pb2+
, Ag+, Cu
2+ and Hg
2+ in pure
aqueous media.
N N+
N Br-OH
(i)
N N
N
(ii)
(iii)
N N
N Br-
NH+Br-
N N+
N BrBr
nn
68
7 El-Feky et al.,
21 were synthesized several new fluorinated quinoline
derivatives 9 and tested for their anti-inflammatory and ulcerogenic effect. A
docking study on the COX-2 binding pocket was carried out for the target
compounds to rationalize the possible selectivity of them against COX-2
enzyme.
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 72
N N
N
F
F
NH
O
ArN NH
N
F
F
iii
9
Borodina et al.,22
has been investigated the interaction of polyfluorinated
chalcones (pentafluorobenzalacetophenone, benzalpentafluoroacetophe- none
and decafluorochalcone) with 1,2-diaminobenzene in alcohols in the presence
of triethylamine or quaternary ammonium salt (TEBAC). In the presence of
TEBAC in 2-propanol polyfluorinated 2,4-diaryl-2,3-dihydro-1H-1,5-
benzodiazepines are formed. Some of them undergo intramolecular fluorine
substitution and unusual rearrangement into a previously unknown polyfluoro-
containing tetracyclic compounds-(6aR)-1,2,3,4-tetrafluoro-6a-aryl-6a,7-
dihydrobenzimidazo[1,2-a] quinolines 10, under the reaction conditions as well
as in absence of TEBAC.
Ar Ar/
O NH2
NH2
HN
NAr
Ar/
N
HN
1 23
456
6
6aAr
F
F F
F1
2 34
10
Brzozowski et al.,23
has been developed a preparative route to a series
of novel 4-(1H-indol-6-yl)-1H-indazole 11 compounds as potential PDK1
inhibitors is described. The synthetic strategy centres on the late-stage Suzuki
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 73
crosscoupling of N-unprotected indazole and indole fragments. The use of a
monoligated palladium catalyst system was found to be highly beneficial in the
cross-coupling reaction. The indazole and indole fragments were constructed
by diazotisation/cyclisation and SNAr/reductive cyclisation sequences,
respectively.
NH2
O
Br
NH
N
Br
NH
N
O NH
OBr
NH
N
H2N
Br
NH
N
NH2 NH
O
11
Shelkar et al.,24
were synthesized a series of substituted benzimidazoles
12, benzothiazoles, and benzoxazoles by combining 1,2-phenylenediamine, 2-
aminothiophenol, or 2-aminophenol with aryl, heteroaryl, aliphatic, a,b-
unsaturated aldehydes in the presence of nano ceria (CeO2) as an efficient
heterogeneous catalyst.
NH2
NH2
CHO
R
Nano CeO2
H2O,RT N
N R
R
12
Pramanik et al.,25
has been developed a cost-effective and eco-friendly
synthesis of 2-aryl-1-arylmethyl-1H-benzimidazoles 13 through the
condensation of different aldehydes with o-phenylenediamine using alumina-
sulfuric acid as a recyclable heterogeneous solid acid catalyst. Morphological
properties of the catalyst have been investigated. Effect of different solvents
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 74
and comparison of alumina-sulfuric acid with different acid catalysts have also
been studied.
NH2
NH2
Me CHO
N
N
Me
Me
13
Senthilkumar S. and Kumarraja M.26
were prepared highly ordered
nanoporous aluminosilicate (MMZY) and employed as a catalyst for the
synthesis of benzimidazoles from 1,2-diaminobenzene and aromatic aldehydes.
In all the cases, the reactions are highly chemoselective and afford 1, 2-
disubstituted benzimidazoles 14, 15 in excellent yield.
NH2
NH2
OHC
N
N
N
HN
14 15
Chen et al.,27
were synthesized a series of fused benzimidazole–
quinoxalinones 16, 17 utilizing a one-pot UDC (Ugi/de-protection/cyclization)
strategy to form a benzimidazole group with subsequent intermolecular
nucleophilic substitution reaction to form quinoxalinone functionality. Using
combinations of either a tethered ketone acid or aldehyde acid input the Ugi
reaction was shown to afford a ring system through lactamization, a
benzimidazole through de-protection and cyclization, and a quinoxalinone
through the nucleophilic substitution reaction.
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 75
NHBoc
N
N COOH
NH2
F
O
N
ONH
F
NH
N
N
O
N
N
N
16 17
Tardy et al.,28
were synthesized a series of functionalized
benzo[4,5]imidazo[1,2-c]pyrimidines 18 and benzo[4,5]imidazo[1,2-
a]pyrazines 19 by an aza-Graebe–Ullman reaction, followed by palladium-
catalyzed cross-coupling reactions. A sequential regioselective cross-coupling
route is reported for the synthesis of unsymmetrically disubstituted
benzo[4,5]imidazo[1,2-a]pyrazines. The inhibition of anaplastic lymphoma
kinase (ALK) was evaluated for the compounds against both the wild type and
crizotinib-resistant L1196M mutant in vitro and in ALK-transfected BaF3 cells.
NN
NI
BrNH2
NH
NN
N
Br
18
NN
NI
BrB(OH)2
O
NN
N
Br
O 19
Park et al.,29
has been synthesized a library of 376 novel 2,5,6-
trisubstituted benzimidazoles 20, 21, 22 bearing ether or thioether linkage at
the 6-position as a part of SAR studies on benzimidazoles.
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 76
N
HNN
HN
O O
N
HNN
HN
O O
N
HNN
HN
O
O
20 21 22
N.C. Desai et al.,
30 were synthesized a series of benzimidazole 23
bearing 2-pyridones and assessed in vitro for their activity as antimicrobial
agents using the conventional broth dilution method. It was observed that the
presence of inductively electron withdrawing groups remarkably enhance the
antibacterial activity of the newly synthesized compounds. Cytotoxicity studies
suggested that none of the tested compounds exhibited any significant
cytotoxic effects.
N
HN
O
N
HN
NNH
CN
OCN
NC NO2
N
HN
N
H2NCN
CNO
NO2CHO
R
N
HN
N
N CN
R
NO2
O CNH H
23
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 77
References:
1. Debus H., Ann., 107, 199, (1958).
2. Hantzsch A., Ibid., 107, 249, (1958).
3. Wright J. B., Chem. Rev., 48 (3), 397, (1951).
4. Ingle R. G., Magar D. D., Heterocyclic chemistry of benzimidazoles and
potential activities of derivatives, Int. J. Drug. Res. Technol., 1 (1), 26,
(2011).
5. Barker H. A., Smyth R. D., Weissbach H., Toohey J. I., Ladd J. N., Volcani
B. E., J. Biol. Chem., 235 (2), 480, (1960).
6. Walba H., Isensee R. W., Acidity constants of some arylimidazoles and their
publications, J. Org. Chem., 26, 2789, (1961).
7. Rabiger D. J., Joullie M. M., J. Org. Chem., 29, 476, (1964).
8. Harrison D., Ralph J. J., J. Chem. Soc. (B), 14, (1967).
9. Black P. J., Heffernan M. L., Aust. J. Chem., 15, 862, (1962).
10. Dembech P., Seconi G., Vivarelli P., Schenettil L., Taddei F., J. Chem. Soc.
(B), 1670, (1971).
11. Gill V. M. S. and Murrell J. N., Trans. Faraday Soc., 60, 248, (1964).
12. Lawesson S. O., Schroll G., Cooks F. F., Bowie J. H., Tetrahedron, 24,
1875, (1968).
13. Nishiwaki A., J. Chem. Soc. (C), 428, (1968).
14. Pugmire R. J., Grant D. M., J. Amer. Chem. Soc., 93(8), 1880, (1971).
15. Hoffmann K., ‘The Chemistry of Heterocyclic compounds’ A. Weissberger,
Ed. Interscience Publishers, Inc. New york. 379, (1953).
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 78
16. Wright J.B., Chem. Rev., 48, 397, (1951).
17. Syuhei Nakao , Miyuki Mabuchi, Tadashi Shimizu, Yoshihiro Itoh, Yuko
Takeuchi, Masahiro Ueda, Hiroaki Mizuno, Naoko Shigi, Ikumi Ohshio,
Kentaro Jinguji, Yuko Ueda, Masatatsu Yamamoto, Tatsuhiko Furukawa,
Shunji Aoki, Kazutake Tsujikawa , Akito Tanaka; Bioorg. Med. Chem.
Lett., 24, 1071, (2014).
18. Kausik K. N., Darrell A. H., Kimberly D. P., Reshma D., Michael L., Wei
L., Rebecca B. W., Suzie Y., Janine N. B., George D. H., Mark T. B.,
Trotter B. W.; Bioorg. Med. Chem. Lett., 24, 1218, (2014).
19. Kyle C. P., Ashley L. P., Brenton D.; Tetrahedron Letters, 55, 1729,
(2014).
20. Amita K. L. And Marilyn D. M.; Tetrahedron Letters, 55, 1810, (2014).
21. El-Feky S. A., Thabet H. K., Ubeid M. T.; Journal of Fluorine Chemistr,y
161, 87, (2014).
22. Borodina E. A., Orlova N. A., Kargapolova I. Y., Gatilov Y. V.; Journal of
Fluorine Chemistry, 162, 66, (2014).
23. Brzozowski M., O’Brien N. J., Wilson D. J. D, Abbott B. M.; Tetrahedron,
70, 318, (2014).
24. Radheshyam S., Sachin S., Jayashree N.; Tetrahedron Letters, 54, 6986,
(2013).
25. Amit P., Rimi R., Sagar K., Avishek G., Sanjay B.; Tetrahedron Letters,
55, 1771, (2014).
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 79
26. Samuthirarajan S. and Mayilvasagam K.; Tetrahedron Letters, 55, 1971,
(2014).
27. Zhong-Zhu C., Jin Z., Dian-Yong T., Zhi-Gang X.; Tetrahedron Letters,55,
2742, (2014).
28. Sébastien T., Alexandre O., Luca M., William H. B., Carla D.i, Carlo G. P.,
Leonardo S., David G., Peter G. G.; Bioorg. Med. Chem., 22, 1303, (2014).
29. Bora P., Divya A., Soumya R. C., Eduard H. M., Kunal K., Susan E. K.,
Richard A. S., Iwao O.; Bioorg. Med. Chem., 22, 2602, (2014).
30. Desai N. C., Shihory N. R., Kotadiya G. M.; Chinese Chemical Letters, 25,
305, (2014).
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 80
Section-2
Introduction To
Coumarins
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 81
SECTION –2
Coumarins are an important class of oxygen heterocycles, which are
widespread in plant kingdom and have been extensively reported on. Their
chemical structure can be looked upon as arising out of the fusion of a benzene
ring to pyran-2-one 24, across the 5 and 6 positions in skeleton.
O OO O O O1
32
5 46
78
24 25 26
The parent coumarin 25 was first isolated by Vogel in 19th
century from
Tonka beans1
and even to this date finds itself still in use as perfumery and
flavoring agent. Figure 26 represent the numbering system used in coumarin
skeleton2.
Structure and reactivity
Aromatic nature of heterocyclic ring of coumarin is disputable, because
coumarin shows some reactions of aliphatic compounds and other
characteristics of aromatic compounds. The complete aromaticity in coumarin
can be only realized if O-CO function contributes two electrons to form 10л
electron system. This means that coumarin should be a resonance hybrid, to
which contribution from canonical form 27 is significant. However, no
evidence is found in the spectra of coumarin to suggest that contribution from
betaine form 27 is considerable.
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 82
O O O O
25 27
The infrared absorption spectrum of coumarin shows an absorption band
at 1710 cm-1
which is attributed to lactone carbonyl group but not a betain
from. In the 1H NMR spectrum of coumarin
3, the signal due to protons of C3
and C4 appears in the region of 6.45 δ ppm and 7.80 δ ppm with coupling
constants of 9.8Hz. These values are typical of cis alkene rather than an aryl
ring4. Finally the
13C NMR spectra of coumarins
5 are consistent with an
essentially aliphatic heterocyclic ring. The chemical shifts of C2, C3 and C4 in
coumarin remarkably close to the values for the corresponding carbons in α-
pyrone and are given below.
Compound C2 C3 C4
α-Pyrone 162.0 116.7 144.3
Coumarin 160.4 116.4 143.4
The carbonyl oxygen can be alkylated6 by powerful agents to give stable
pyrillium salts 28.
O O O OEtBF4
Et3OBF4
25 28
Coumarin nucleus is susceptible to electrophilic substitution6.
Sulphonation takes place initially in the carboxylic ring at C6, to give 29, but
under more forcing conditions one more –SO3H group can be introduced at C3,
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Karnatak Science College, Dharwad 83
to obtained coumarin-3, 6-disulphonic acid 30.
O O O O O O
HO3S HO3S SO3H
Sulphonation Sulphonation
25 29 30
As in case of simple pyrones the properties of heterocyclic ring of
coumarin are greatly influenced by the presence of substituents.
Anantatakrishanan7 discussed the “Mills-Nixon effect” in which the
reactivity of coumarin was rationalized based on the comparative studies of
bromination and nitration of coumarin, naphthalene and benzene. By
considering the possible electron movements in coumarin molecule, Thakur
and Shah8 predicted that C6 and C8 as the most reactive centres. The electron
movements are as shown below.
O OO O
O O
O O
O O
A
B
C
D
Greater electron densities can be seen on C6 and C8 from the resonating
structures B and C. Out of these two, C6 seems to be more reactive because of
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 84
its proximity to the oxygen atom, similar to the reactivity of para position of
phenol. Structure A though imparts more electron density to the C3 position,
the electrophilic substitution at C3 is less, probable due to its closeness to the
electron withdrawing carbonyl group. Infact the л electron densities calculated
by Song and Gorden9 are quite close to the resonance picture of the molecule.
The structure 31 represents the л electron densities for the ground state of
coumarin.
O O
1.801 1.955
0.720
1.107
0.9400.982
1.006
0.977
1.028
31
By considering the structure’s B, C and D Bassingnan and Cogrossi10
have proposed structure 32 which is according to them represents the hybrid or
resonating state of molecule.
O O
+ -
32
However the contributing structure of the type (D) does not have strong
spectral evidences, the position of the carbonyl frequency in the IR spectrum
(1710 cm-1
) is more in favor of an enol lactone11
. Hence the contribution from
such type of structures is negligible and the resonating state 32 appears to be
less probable.
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Karnatak Science College, Dharwad 85
Coumarin has been used as a powerful model in elucidating the
electronic structures and photo reactivity of psoralenes. The configurational
analysis of coumarin by Song et al.12
in the ground state indicates some charge
transfer delocalization extending to the ethylenic region. The dipole
movements of coumarin (4.82x10-8
e.s.u) determined earlier by Rao13
also
indicates the similar delocalization.
Spectral studies
UV-Spectra:
The UV spectra of coumarins and their methyl derivatives were reported
by Ganguly and Bagchi.14
The introduction of methyl group in various
positions does not change the nature of the spectrum to a greater extant. The λ
max and ε values of coumarins are 273 nm (40,368) & 309 nm (37,449).
IR-Spectra:
The IR spectrum of coumarin was reported by Murthi and Sheshadri.15
The parent coumarin shows lactone carbonyl at 1705 cm-1
, νC=C at 1608 cm-1
,
1450 cm-1
and νC-O-C at 1254 cm-1
.
PMR-Spectra:
The PMR spectrum of coumarins was reported by Dharmatti et al.16
The
C3- H of coumarin resonates at 6.45 δ ppm and C4-H at 7.80 δ ppm.
Mass spectra:
The electron impact on coumarins has been studied by Baenes et al.17
The
molecular ion peak and fragmentation shows transient formation of Benzofuran
33.
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 86
O O
+ .
-co
O
+ .
m/z 146 m/z 118
25 33
Crystal structure:
The Crystal structure of coumarin was first reported by S.Ramswamy18
in 1941. Coumarin crystals are in orthorhombic system, it has space group Pcaz
with Z=4. The structure consists of nearly planar molecules held together by
Vander Waals forces, x-ray crystallographic data19
of some coumarins are
tabulated below.
Coumarin Space group.
No of molecules Unit cell
Unit cell parameters (Å) (0)
Coumarin20 Orthorhombic
Pcaz1; Z=4
a=15.46, b=5.67, c=7.91
α=β=γ= 90
4-Hydroxy Coumarin21 Orthorhombic
P212121; Z=4
a=10.11, b=12.18, c=6.95
α =β=γ= 90
7-Hydroxy-4-methyl
coumarin22
Orthorhombic
P212121; Z=4
a=10.18, b=12.02, c=6.15
α =β=γ= 90
4-[(4-Fluoro)
arylaminomethyl
coumarin23
Orthorhombic
P212121; Z=4
a= 5.7973, b=13.9415,
c=17.9166
α =β=γ= 90
Biologically active and naturally occurring coumarins
Coumarins are widely distributed in nature and are found in all parts of
plants24
. These compounds are especially common in grasses, orchids, citrus
fruits, and legumes24
. Being so abundant in nature, coumarins make up an
important part of the human diet. Based on chemical structure, they can be
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 87
broadly classified as (a) simple coumarins (e.g., coumarin, 25), (b)
furanocoumarins of the linear (e.g., psoralen, 44) or angular (e.g., angelicin,
70) type, and (c) pyranocoumarins of the linear (e.g., xanthyletin, 72) or
angular (e.g., seselin, 77) type24
. Simple coumarins are very widely distributed
in the plant kingdom24
.
Interestingly, citrus oils, in particular, contain abundant amounts of both
simple as well as furanocoumarins25
. Human are also exposed to
furanocoumarins (e.g., bergapten, 46 and xanthotoxin, 52) in umbelliferous
vegetables such as parsnips, celery, and parsley in substantial amounts26
. For
example, parsnip root reportedly contains as much as 40 mg/kg of certain linear
furanocoumarins such as psoralen (44), bergapten (46), and xanthotoxin (52),
which are destroyed by normal cooking procedures (boiling or microwave) 26
.
In addition, in certain countries (e.g., China, India, and Mexico) and in certain
geographical areas within the United States (e.g., the Southwest) fresh
coriander leaves (also known as cilantro or Chinese parsley) are used
extensively. The cilantro leaves are used in soups, chutneys, and sauces and
flavoring curries and even wine. Recently, we reported the b-secretase
(BACE1) inhibitory activities of several furanocoumarins isoimperatorin (47),
oxypeucedanin (48), imperatorin (52), (+)-byakangelicol (65), and (+)-
byakangelicine (66) from Angelica dahurica27
.
The list of naturally occurring (a) simple coumarins (25, 34–43), (b)
furanocoumarins of the linear (44–46, 49–52, 54–64, 67–70), or angular type
(70 and 71), and (c) pyranocoumarins of the linear (72–76), or angular type (77
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 88
and 78) are listed below.
(a) Simple coumarins:
O OHO O OMeO O OO
umbeliferone (34) methylumbeliferone (35) O-prenylumbeliferone (36)
O OO O OHO
HO
aurapten (37) esculetol (38)
O OMeO
MeO
O OHO O OMeO
esculetin (39) demethylsuberosin (40) suberosin (41)
O OHO O OMeO
osthenol (42) osthol (43)
(b) Furanocoumarins:
O OO O O
O O OO
OH OMe
psoralen (44) bergaptol (45) bergapten (46)
O OO
O
O OO
O
O
O OO
O
OH
OH
isoimperatorin (47) oxypeucedanin (48) oxypeucedanin hydrate (49)
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 89
O OO
O
O OO
O OO
OH OMe
bergamottin (50) xanthotoxol (51) xanthotoxin (52)
O OO
O
O OO
O
O
O OO
O
HOHO
imperatorin (53) heraclenin (54) heraclenol (55)
O OO
OH
O OO
O
O OO
OH
OH
8-geranyloxypsoralen (56)
5,8-dihydroxypsoralen (57)
OMe
8-hydroxy-5-methoxypsoralen (58)
O OO
OH
OMe
8-hydroxy-5-methoxypsoralen (59)
O OO
OH
O
8-hydroxy-5-prenyloxypsoralen (60)
O OO
O
OH
isopimpinellin (61)
O OO
OMe
OMe
kinidilin (62)
O OO
OMe
O
O OO
O
OMe
5-geranyloxy-8-methoxypsoralen (63) phellopterin (64)
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 90
O OO
O
O
O OO
O
HOHO
byakangelicol (65) byakangelicine (66)
O OO
O
8-geranyl-5-methoxypsoralen (67)
OMe OMe
OMe
O OO
O OO
O
O
OH
O OO
cnidicin (68)
marmesin (69) angelicin (70)
O OO
OH
columnbianetin (70)
(c) Pyranocoumarins:
O O O O O O O O O
HO
xanthyletin (72) dihydroxanthyletin (73) decursinol (74)
O O O
O
O
O O O
O
O
decursinol tiglate (75) decursin (76)
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 91
O OO O OO
OH
seselin (77) lomatin (78)
Metabolism of coumarin:
There are two major pathways involved in coumarin metabolism
(Scheme 1). In human body, coumarin is metabolized to 7-hydroxy coumarin
via aromatic hydroxylation by cytochrome P450 2A6 gene, which is then
excreted as the glucouronide and sulphate-conjugates28
. In the case of rodents
like rats and mice, coumarin undergoes C-3 hydroxylation in the pyran ring and
ultimately metabolized to o-hydroxy phenyl acetic acid29
, via the reactive
intermediate of 3, 4-epoxide30
, which is predicted to be responsible for the
hepatotoxicity caused by coumarin. Thus, the hepatotoxicity of coumarin is
dependent upon its species-specific metabolism31
. Biochemical studies in mice
have shown that coumarin at dose of 100 mg kg-1
caused a 2 to 15-fold increase
in plasma aminotransferases and also subcapsular and centrilobular necrosis in
histopathological studies32
. It has also been observed that coumarin at the dose
of 200 mg kg-1
caused selective clara cell injury in mouse lung33
, whereas 3,4-
dihydro coumarin did not cause any injury at higher dosage (800 mg kg-1
).
These results support the hypothesis that the existence of 3, 4-epoxide
intermediate contributes to the observed toxicity.
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 92
O O
Coumarin
O OHO
7-Hydroxy coumarin
O O
OH
3-Hydroxy coumarin
O O
O
H
H
3,4-Epoxide coumarin
OH
O OH
O-Hydroxy phenyl acetic acid
Scheme-1
Recent Literature:
Arellano et al.,34
derived new ferrocenyl-b-enaminone-coumarins 79 and
ferrocenyl-pyrano[3,2-g]quinolin-2-ones 80 obtained through a
heterocyclization reaction from 7-amino-4-methyl-2H-chromen-2-one and
several ferrocenyl-a-ketoalkynes in a nickel homogeneous aqueous catalytic
system formed by Ni(CN)2/CO/NaOH/KCN.
O OH2N
CH3
O OHN
CH3
Fe
R
O
FeR
OO O
CH3R
Fe
79 80
Bourbon et al.,35
reported the synthesis of three coumarin-caged
cholesterols 81 that contain the 7-diethylaminocoumarin (DEACM), 6-bromo-
7-hydroxycoumarin (BHC) and 6-bromo-7-methoxycoumarin (BMCM)
photocleavable groups.
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 93
O OR1
O
O
O
H
H
H
R
81
Dakanali et al.,36
were synthesized a new, UV-excited fluorescent Zn2+
indicator and the spectral profile of its free and Zn2+
bound forms were studied.
The fluorescent properties of this probe are due to the 7-amino-4-
methylcoumarin fluorophore 82, which is conjugated with the tris(2-
aminoethyl)amine (TREN) that functions as the zinc-chelating moiety.
O ONH
CH3
O ONH
CH3
N
N
N3
N3
H2N
H2N
82
Li et al.,37
developed a novel coumarin-derived fluorescent probe 83,
FCP, for Zn2þ quantification based on the photo-induced electron transfer
(PET) mechanism.
O SNH
CF3
O SNH
CF3
Br
N
N
N
83
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 94
Fournier et al.,38
were studied the small and synthetically easily
accessible 7- diethylamino-4-thiocoumarinylmethyl photolabile 84 protecting
group has been validated for uncaging with blue light.
O SEt2N
OH
O SEt2N
OHN
O
O
OH
84
Jiemin Jiao et al.,39
were synthesized a chiral host L1 incorporating (S)-
BINOL and substituted coumarin moieties 85 via a nucleophilic addition–
elimination reaction, and ligand L2 could be obtained by the reduction reaction
of the imine-based L1 with NaBH4.
O OH2N
CH3
CHO
OH
OH
n-Bu
n-Bu CHO
OH
OH
n-Bu
n-Bu
O ON
CH3
O ON
CH3
85
Veronica San Miguel et al.,40
has been studied the possibility of
wavelength-selective cleavage of seven photolabile caging groups from
different families. Amine-, thiol-, and carboxylic-terminated organosilanes
were caged with o-nitrobenzyl (NVOC, NPPOC), benzoin (BNZ), (coumarin-
4-yl)methyl (DEACM), 7-nitroindoline (DNI, BNI), and p-hydroxyphenacyl
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 95
(pHP) derivatives. Caged surfaces modified with the different chromophores 86
were prepared, and their photosensitivity at selected wavelengths was
quantified. Different pairs, trios, and quartets of chromophore combinations
with wavelength-selective photoresponse were identified.
O OEt2N
OH
O OEt2N
O O
O
NO2
86
Zhigang Yang et al.,41
were synthesized a self-calibrating bipartite
viscosity sensor 1 for cellular mitochondria, composed of coumarin and boron-
dipyrromethene (BODIPY) 87 with a rigid phenyl spacer and a mitochondria-
targeting unit. The sensor showed a direct linear relationship between the
fluorescence intensity ratio of BODIPY to coumarin or the fluorescence
lifetime ratio and the media viscosity, which allowed us to determine the
average mitochondrial viscosity in living HeLa cells as ca. 62 cP (cp). Upon
treatment with an ionophore, monensin, or nystatin, the mitochondrial viscosity
was observed to increase to ca. 110 cP.
O ON
N
N+
NH
O
P+
B
FF
87
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 96
Heltweg et al.,42
were synthesized lysine-derived small molecule
substrates 88, 89 and examined structure-reactivity relationships with various
histone deacetylases.
O ONH
O
HNR
O
HN
OO
88
O ONH
O
HNR
O
HN
OO
89
Pauline Bourbon et al.,43
has been described the synthesis and
photophysical/photochemical properties of two amide-tethered coumarin-
labeled nicotinamides 90.
O OEt2N
Cl
O OEt2N
HN
O
N
90
Introduction to Benzimidazoles and Coumarins
Karnatak Science College, Dharwad 97
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