introduction to benzimidazoles and...

Introduction to Benzimidazoles and Coumarins

Karnatak Science College, Dharwad 64

Section-1

Introduction

To

Benzimidazoles



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



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



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



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)

+.+.



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.



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



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.



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



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



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.



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.



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



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).



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).



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).



Section-2

Introduction To

Coumarins



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.



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,



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



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.



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.



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



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



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)



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)



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)



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.



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.



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



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



(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



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



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