Chapter -1 - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/20756/8/07_chapter-1.pdf · Karnatak Science College, Dharwad 3 The electron impact on coumarins has been studied

An Introduction to Coumarins

Karnatak Science College, Dharwad 0

Chapter -1 Introduction

To

The

Chemistry

Of

Coumarins/1-Azacoumarins

And

Dithiocarbamates



1. Exposure Data

Coumarins are very much present in nature and find their applications as fragrances,

pharmaceuticals and agrochemicals. They are originally discovered in plants from

coumarouna odorata. Coumarin was isolated by Vogel1 from Tonka bean (Dipteryx

odorata wild) in 1820.

1.1 Chemical and physical data

1.1.1 Nomenclature

Chem. Abstr. Serv. Reg. No.: 91-64-5

Chem. Abstr. Name: 2H-1-Benzopyran-2-one

IUPAC Systematic Name: Coumarin

Synonyms: 1,2-Benzopyrone; 5,6-benzo-2-pyrone; benzo-α-pyrone; cis-ortho-

coumarinic acid lactone; coumarinic anhydride; ortho-hydroxycinnamic acid lactone

1.1.2 Structural and molecular formulae and relative molecular mass

O O

C9H6O2 1 Relative molecular mass: 146.15

1.1.3 Chemical and physical properties of the pure substance

(a) Description: Orthorhombic, rectangular plates; pleasant, fragrant odour resembling

that of vanilla beans; burning taste2.

(b) Boiling-point3: 301.7 °C

(c) Melting-point3: 71 °C

(d) Density3: 0.935 g/cm3 at 20 °C



(e) Spectroscopy:

IR-Spectra:

The IR spectrum of coumarin was reported by Murthi and Sheshadri4. 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.

UV-Spectra:

The UV spectra of coumarins and their methyl derivatives were reported by

Ganguly and Bagchi.5 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).

PMR-Spectra:

In the 1H NMR spectrum of coumarin6, 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 coumarins7 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

Mass spectra:



The electron impact on coumarins has been studied by Barnes et al.8 The molecular ion

peak and fragmentation shows transient formation of Benz furan 3.

Crystal structure:

The Crystal structure of coumarin was first reported by S.Ramswamy9 in 1941.

Coumarin crystals are in orthorhombic system, it has space group Pcaz with Z=4.

(f) Solubility2,10,11: Slightly soluble in water (100 mg/L at 25 °C) and ethanol; very

soluble in chloroform, diethyl ether and pyridine

(g) Volatility11: Vapour pressure, 0.13 kPa at 106 °C

(h) Octanol/water partition coefficient (P)11: log P, 1.39.

(i) Conversion factor11: mg/m3 = 5.98 × ppm

1.1.4 Technical products and impurities

Coumarin is commercially available with a minimum purity12 of 99%. Coumarin is

usually sold in the form of colourless shiny leaflets or rhombic crystals13.

1.1.5 Analysis

Coumarin can be determined in vanilla extract by a photometric method, reading the

absorbance or transmittance at 490 nm, and comparing against a standard14.

1.2 Occurrence

1.2.1 Natural occurrence

Coumarin was first isolated by Vogel in 1820 by extraction from tonka beans15 (Dipteryx

odorata)]. It was subsequently identified in a large number of plants belonging to many

O O

+ .

-co

O

+ .

m/z 146 m/z 1182 3



different families. Its better known occurrences are in sweet clover (Melilotus alba and

M. officinalis), sweet woodruff (Asperula odorata), vanilla leaf (Trilisa odoratissima),

vanilla beans (Vanilla planifolia), cassia (Cinnamorum cassia), lavender (Lavendula

officinalis) and balsam of Peru (Myroxylon pereirae)2,13,16,17. Coumarin has been isolated

from legumes, orchids, grasses and citrus fruits16. It is found at particularly high levels in

some essential oils, such as cinnamon leaf and bark oil, cassia leaf oil and lavender oil18.

A broad spectrum of coumarin derivatives (present both in the free state and as

glucosides) have also been found in many plants; to date at least 1300 have been

identified, principally as secondary metabolites in green plants19.

Warfarin 4 is a naturally occurring compound containing the 4-hydroxy coumarin moiety.

It has been isolated from woodruff as well as from lavender and is used to prevent

clotting of blood in the veins, lungs or heart.20,21 Another well-known natural compound

containing the coumarin nucleus is 7-hydroxycoumarin, also known as Umbelliferone

5,22 which is found in a variety of plants, such as carrots, coriander and garden angelica.

It has been used as a sunscreen, a fluorescence indicator and as a dye indicator.22,23,24

Dicoumarol 6 is another natural occurring compound containing the coumarin nucleus,

and is known for causing sweet clover disease in cattle.25,26 It has been isolated from

sweet clover hay and used as an anticoagulant.27

O O

O HO

W a r f a r in

O OU m b e l l i f e r o n e

H O O O

O H

D i c o u m a r o lOO

O H

4 5 6



Compound 7 is isolated from the bark of Kayea assamica (Myanmar) and found to

exhibit cytotoxic-activity against a panel of human cancer lines and Anti-malarial activity

against chloroquine resistant plasmodium falciparium28. Compound 8, a Siderin

containing extracts of Toona ciliate has shown the promising Anti-bacterial and moderate

Anti-fungal activity29. Compounds 9 and 10 are the methanol extracts obtained from the

rhizomes of Japanese plant Glaucidium Palmatum. Amongst these compounds,

compound 10 was identified as a microtubule stabilizing agent with a potent Anti-mitotic

activity inhibiting KB cell proliferation 30.

A number of Brazilian medicinal plants containing coumarin 1 as the major

constituent have been screened for Anti-nociceptive, Anti-inflammatory and

Bronchodilator activities. The results have shown that the hydrochloric extracts of J.

pectoralis and P.polygaliflours were found to be most promising bronchodilators in

isolated guineapig tracea 31. Recently the production of coumarin 1 and Umbelliferon 5

O OO

O

OH

O OO

O

OH11 12

O O

O HO H

H OR

O O

O

O O O

OH O

O O

H O

7 8 9 10



was induced by cupric chloride treated leaves of Conium macaluatam and these

phytoalexins inhibited the growth of pathogenic fungi, viz alternaria spp. Bipolaris spp.

And fusarium32 over a hundred of chinese medicinal plants containing coumarins and

related oxygen heterocycles have been screened for their anti-oxidant activity, in view of

their medicinal value as anti-cancer agents33.

The title compounds 11 and 12 were isolated from the seeds of calophyllum

cerasiferaum and calophyllum ionophyllum and were found to exhibit anti-HIV activity 34

The compounds 13 and 14 isolated from ethyl acetate extracts of fruits and stem

bark of calophyllum dispar have been reported to exhibit significant cytotoxicity against

KB cell lines35 the 5.7-dimethoxy coumarin 15 was extracted from the roots of the

Kenyan plant toddalia asiatica was traditionally used for the treatment of malarial

disorders and as a novel antispasmodic compound36 the furano coumarin 16 isolated from

the ethanol extracts from fruits of cnidium monneri (china) was found to exhibit anti-

oxidative activity in both lipid peroxidation and haemolysis assays37.

List of some of the biologically active and naturally occurring coumarins

O OHO

O

OH

O OHO

O

O H O

O OO

O

OH

O OO

O

O

O

13 14 15 16

O O O O O OH O

O

H OO H

O

O H

1 7 1 8 1 9S c o p o le tin 3 4 D a p h x e t in 3 6 P a n ic u la l3 7



F

Further investigation led to the discovery of compounds containing a 3-

substituted-4- hydroxycoumarin moiety, such as warfarin 442 and phenprocoumon 2443.

However, compound 4 is weakly active against HIV-PR. The phenprocoumon 24,

however, is more active against the protease enzyme with an inhibition potential of 1 μM.

The hydroxyl group on phenprocoumon 24 has the potential to hydrogen-bond with the

catalytic aspartic residues, while the carbonyl group of the coumarin nucleus hydrogen-

bonds with the Ile- 50 residue of protease enzyme.

Coumarins can be divided into four sub-types: i) simple coumarins which are

hydroxylated, alkoxylated or alkylated on the benzene ring (e.g. umbelliferone 5);44,45 ii)

Furanocoumarins, which contain a five-membered furan ring attached to the coumarin

moiety and which are sub-divided into the linear furanocoumarins (e.g. Xanthotoxin 25)

and the angular furanocoumarins (e.g. Angeligin 26);44,46 iii) pyranocoumarins,

containing a six-membered ring attached to the coumarin moiety (e.g. Seselin 27 and

Xanthyletin 28);44,47 and iv) coumarins with substituents in the pyrone ring (e.g. warfarin

O OO O O OOHO O

R

2021 22

Angustifolin387-ethoxy-3,4-dimethyl coumarin39 Piloselloidam40

O O

H O

H O

O H

O O

O H

p h e n p ro c o u m o n 4 3

2 3 2 4S e re tin 4 1

O O O OO O

O

OO

O M e

O OO

xanthotoxin angeligin seselin xanthy letin

25 26 27 28



4).48

1.2.2 METABOLISM OF COUMARINS IN THE BIOLOGICAL SYSTEMS:

Coumarin is rapidly and extensively absorbed after topical or oral administration

to human subjects. It undergoes very extensive metabolism along two major pathways, 7-

hydroxylation and ring-opening to ortho-hydroxyphenylacetaldehyde. There are

numerous minor metabolites, many of which are secondary products from the primary

metabolites. The relative extent of these two major pathways is highly variable between

species. Ring-opening predominates in rodents, while 7-hydroxylation is particularly

evident in humans.

The absorption, distribution, metabolism and excretion of coumarin in humans

have been reviewed18,49,50. Toxicokinetic studies in humans have demonstrated that

coumarin is rapidly absorbed from the gastrointestinal tract after oral administration and

extensively metabolized by the liver in the first pass, with only 2–6% reaching the

systemic circulation intact51,52,53. The elimination of coumarin from the systemic

circulation is rapid, the half-lives following intravenous doses of 0.125, 0.2 and 0.25

mg/kg bw being 1.82, 1.46 and 1.49 h [109, 88 and 89 min], respectively54. Coumarin is

also extensively absorbed after dermal application. In one study with human subjects,

some 60% of a 2.0-mg dose applied for 6 h was absorbed19. The percutaneous absorption

of coumarin has also been demonstrated in vitro with human skin55,56.

The rapid excretion of coumarin, primarily as 7-hydroxycoumarin conjugates, in

the urine of human subjects given coumarin orally suggests that there is little or no biliary

excretion of coumarin metabolites in humans57,58,59,60,61. Coumarin exhibits marked

species differences in its metabolism18,49. The major primary pathways of coumarin



metabolism are 7-hydroxylation or metabolism of the lactone ring by ring opening and

cleavage at carbon atom 2 to yield carbon dioxide. The first step in the latter pathway is

the formation of the unstable coumarin 3,4-epoxide which degrades spontaneously to

form ortho-hydroxyphenylacetaldehyde and may be subsequently converted to ortho-

hydroxyphenylethanol and ortho-hydroxyphenylacetic acid. Coumarin may also be

metabolized by hydroxylation to yield 3-, 4-, 5-, 6- or 8-hydroxycoumarin and 6,7-

dihydroxycoumarin and, by opening of the lactone ring, to yield ortho-coumaric acid

(ortho- hydroxyphenylcinnamic acid) and ortho-hydroxyphenylpropionic acid62,63,64,65,66.

The pathways of coumarin metabolism are shown in Figure 1.

Metabolic pathways of Coumarin in animals and humans

The major pathway of coumarin metabolism in most human subjects is 7-

hydroxylation to form 7-hydroxycoumarin, which is excreted in the urine as both

glucuronic acid and sulfate conjugates. Coumarin 7-hydroxylation activity exhibits a

Gaussian distribution in Caucasian populations58,60, but some individuals are deficient in

O O O OO O

O O O OO O

OO H

H O

O H

S G

O H

H O

O H

O O

O O

H O

H O

O HC H C O O H

O H

C H 2 C H 2 C O O H

O H

C H 2 C H O

O H

C H 2 C O O H

O H

C H 2 C H 2 O H

O H

C H 2C H O H C O O H

O H

C o u m a r in4 -H yd ro xy c o u m a r in

7 -H yd ro x y c o u m a r in

3 -H y d ro xy co u m a rin

5 ,6 ,8 -H y d ro xy c o u m a r in

6 ,7 -H y d ro xy c o u m a r in

o -h y d ro xy p h e n y la c e ta ld e h y d e o -h yd ro xy p h e n y l

a c e tic a c id

o -h y d ro x y p h e n y lla c tic a c id

o -h yd ro x y p h e n y lp ro p io n ic a c id

o -c o u m a ric a c id

o -h y d ro xy p h e n y le th a n -1 -o l

C O 2

C O 2

G S H

G lic u ro n ic a c id a n d s u lfa te c o n ju g a te s

4 -h id ro xy d ih y d ro -c o u m a rin g lu ta th io n ec o n ju g a te

c o u m a r in -3 ,4 -e p o x id e

c o u m a r in -3 -m e rc a p tu ric a c id

Figure-1



this activity. Hadidi et al.60 gave members of a family 2 mg coumarin orally and collected

their urine for 8 h. One subject excreted < 0.03% of the dose as 7-hydroxycoumarin and

50% as ortho-hydroxyphenylacetic acid, but three others excreted mainly 7-

hydroxycoumarin (> 41% of dose) and 4–10% as ortho-hydroxyphenylacetic acid.

Oscarson et al.68 refer to two individuals (among a population of two hundred) who were

totally deficient in 7-hydroxycoumarin excretion after an oral dose of 5 mg coumarin.

CYP2A6 (cytochrome P450 2A6) has been purified from human liver and CYP2A6

cDNA expression systems are available. Many studies have demonstrated marked

interindividual variation in the levels of hepatic CYP2A6 protein, mRNA and associated

microsomal coumarin 7-hydroxylase activity18,50. The role of CYP2A6 in the metabolism

of coumarin by human liver microsomes has been confirmed by Sai et al.69, who found

that a monoclonal antibody to CYP2A6 inhibited coumarin 7-hydroxylation by more than

94%. The marked interindividual variation in coumarin metabolism to 7-

hydroxycoumarin has led to studies to evaluate whether a genetic polymorphism exists in

human CYP2A6.

The occurrence of variant alleles in the human CYP2A6 gene was shown by

Fernandez-Salguero et al.70; these were designated CYP2A6*1 (wild type), CYP2A6*2

and CYP2A6*3. CYP2A6*2 has a point mutation in codon 160 and the resulting protein

product is unable to 7-hydroxylate coumarin67,70. The functional significance of the rare

CYP2A6*3 allele is uncertain. The population frequency of these mutant alleles is

uncertain at present; initial claims that the incidence of the CYP2A6*2 allele is 4–17% of

European populations70 have been challenged by Oscarson et al.68, who found the

incidence to be 1–3%. These authors highlighted methodological uncertainties in



polymerase chain reaction based genotyping procedures. Establishment of the

significance of the genetic polymorphism in CYP2A6 must await definitive genotyping

and phenotyping procedures. While 7-hydroxylation is the major metabolic pathway of

coumarin in most subjects, humans also convert coumarin to ortho-hydroxyphenylacetic

acid. Shilling et al. (1969) reported that after an oral dose of 200 mg coumarin per

subject, while 7-hydroxycoumarin accounted for 79% of the excreted dose (range, 68–

92%), a further 4% of the dose (range, 1–6%) was present in the first 24-h urine as ortho-

hydroxyphenylacetic acid.



Introduction

To

The

Chemistry

Of

1-azacoumarins



2. Exposure Data

Carbostyrils (1-aza coumarins) represent a group of naturally occurring lactams

whose potential as anti-microbial, analgesic, anti-inflammatory, and anti-cancer and anti

HIV agents have been recently reviewed71. Carbostyrils with various substituents at C-4

position have been reported as being potential anti microbial, analgesic and anti

inflammatory agents from our laboratory72 – 73.

2.1 Chemical and physical data

2.1.1 Nomenclature

Chem. Abstr. Name: 2H-1-Benzopyridin-2-one

IUPAC Systematic Name: Carbostyril

Synonyms: 2(1h)-quinolinone; 2(1H)-Quinolone; 2-Quinoline; 2-Quinolinol50; 2-

quinolinone; alpha-Hydroxyquinoline; alpha-Quinolone; o-Aminocinnamic acid lactams

and Carbostyril.

2.1.2 Structural and molecular formulae and relative molecular mass

The chemical structure of carbostyril (1-aza coumarins) can be looked upon as arising

out of the fusion of benzene ring to pyridin-2 (1H)-one 1, across the 5 and 6 positions.

C9H7NO Relative molecular mass: 291

2.1.3 Chemical and physical properties of the pure substance

(a) Description: Orthorhombic, rectangular plates; pleasant.

(b)Melting-point: 198-199 °C

NH

O NH

ONH

O

1 2 3

123

4567

8



(c) Solubility:

Although derivatives of carbostyril 2, are less frequently found in nature than

their oxygen counterpart coumarins, a large number of plant alkaloids with their skeleton

has been isolated,74 which have provided a great impetus for the synthesis of structurally

diverse carbostyril. Structure 3, represents the numbering system in carbostyril

skeleton75.

d. Spectroscopy:

UV-Spectra:

The UV spectra of carbostyril were first studied by Morton and Rogers76. The λ max and

ε values of the parent carbostyril in water are 324 (63,500) and 270 (65,500).

IR-Spectra:

The IR spectrum of carbostyril (1-aza coumarin) was reported by Simons77 in

KBr. The parent carbostyril shows amide carbonyl stretching at 1660cm-1, νC=C at 1598

cm-1, 1447 cm-1 and the ν-NH stretching vibration at 3410 cm-1. Similarly the IR spectrum

of carbostyril reported by Peterson78 in CCl4 exhibit the ν-NH stretching vibration at 3408

cm-1 and amide carbonyl stretching at 1680 cm-1 (Free) and 1664 cm-1 (bonded) based on

this observation Peterson has suggested the dimeric structure 7 for the carbostyril.

PMR-Spectra:

The PMR spectra of carbostyril (1-aza coumarin) were reported by Simons79. The

C3-H of carbostyril was resonated at δ 6.57 ppm and C4-H at δ 7.91 ppm. All the

aromatic protons resonated at around δ 7.03-7.81 ppm, while the NH proton appeared at δ

11.78 ppm.



Mass-Spectra:

The electron impact of carbostyril (1-aza coumarin) has been studied by J. Moller

and O.Buchardt.80 The molecular ion peak and fragmentation shows transient formation

of Indole 4, by the loss of carbon monoxide.

Crystal structure:

The Crystal structure of Carbostyril (1-aza coumarin) was first reported by

S.Peterson81 in 1948. Carbostyril 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 data of some coumarins are tabulated below.

2.1.4 Technical products and impurities

Carbostyril (1-aza coumarin) is commercially available with a minimum purity of 99%.

Carbostyril is usually sold in the form of white to light purple or purple-brownish

powder.

2.2 STRUCTURE AND REACTIVITY

The UV absorption spectrum82 of carbostyril (1-aza coumarin), show that it is a

mixture of more predominant form of lactam tautomer 2, as compared with its lactim

isomer 5. Further Huisgen83 has proposed a dipolar structure 6, for carbostyril based on

UV absorption spectra, in which case it can be regarded as simple amide.

NH

O

+ .

-co

NH

+ .

m /z 145 m /z 1172 4

NH

O N OH NH

O

2 5 6



Later Mason84 has shown that, the zwitter-ionic form 6, is the best single

representation of carbostyrils 2. This exists almost entirely in the N-protonated form

stabilized by resonance as shown below.

NH

O NH

O

N OH N OH

..

62

4 7

PKT = 3.88

The N-protonated tautomer has the advantage that the dipolar canonical structure

6, carries the negative charge on oxygen, the more electronegative element, where as the

reverse is the case for the O-protonated tautomer 7, in which PKT = 3.88 showing a

preponderance of the N-protonated form by the factor of over 7500:1.

Later Peterson85 has proposed the existence of cyclic dimer 8, for carbostyril

formed by the π-hydrogen bonding based on IR studies in CCl4 solution.

NH

O

HNO

8

By considering the possible electron movements in carbostyril (1-aza coumarin)

molecule (Figure 1), it can be seen that C6 and C8 are the most reactive centres. 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 nitrogen atom,

similar to the reactivity of para substitution of aniline. Structure A though imparts more

electron density to the C3 position; electrophilic substitution at C3 is less probable due to

its closeness to the electron withdrawing carbonyl group.

NH

ONH

O

NH

O

NH

O

NH

O

A

B

C

D

Figure 1

2.3 BIOLOGICALLY ACTIVE AND NATURALLY OCCURRING

CARBOSTYRIL DERIVATIVES

Carbostyrils (1-aza coumarins) are less frequently found in nature than coumarins;

although its fused ring system has been found in skeleton of many Quinoline alkaloids.86

the source of these alkaloids encompass plants, sponges and even arthropods. The

simplest carbostyrils-like alkaloid is probably the semecarpifoline 9, isolated from the

root bark of the tree Meliocope semecarpifolia in Taiwan.87 The similar structure of the

hemiterpenoid alkaloid Orixiarine 10 has been confirmed by an independent synthesis.88



2.4 METABOLISM OF CARBOSTYRIL IN THE BIOLOGICAL SYSTEMS:

Carbostyril (1-aza coumarin) is itself the metabolic product of quinoline as

observed in the bacterial degradation of Rhodococcus strain B193. Two types of aromatic

hydroxylation pathways are involved (Figure. 2 & 3.). Such degradation of quinoline

derivatives has been reviewed from different aspects94. The 5, 6-dihydroxy intermediate

was observed in Pseudomonas putida K1 and 7, 8-dihydroxy derivative was reported in

the degradation of 4-methyl carbostyril95.

Figure. 2

NH

O

O

O

NH

O

OO

S em e ca rp ifo lin e 87 O rix ia r in e 88

9 1 0

NH

O

O

O

H O

7-B en zy l-3 -m e th o xy c a rb os ty ril8 9

1 1

NH

O

O

NH

O

O O

H alophytin9 0

12Flinde rsine90

13

NH

O

O OO

O4-m ethoxy-3-m ethoxyv iny l-qu ino line-trione91

14

NH

OOO

Presk im m ian ine92

15

NH

O

NH

O

NH

ONH

O OHHO

OHHO

OH OHOH

OH

O

Carbostyril

8-Hydroxy Carbostyril

7,8-Dihydroxy Carbostyril5,6-Diydroxy

Carbostyril

3,5-Dihydroxy phenylpropionic acid



Another pathway involving the initial cleavage of the lactam ring was also found

in Pseudomonas stutzeri.96 in this pathway, 8-hydroxy-carbostyril, 8-hydroxy coumarin

and 3, 4-dihydroxy phenylpropionic acid have been detected as intermediates. The

formation of 8-hydroxy derivative was also observed in Pseudomonas ptida97 and in

human urine.98 The proposed mechanistic pathway94 involves that an initial

dihydroxylation induced a C-N bond cleavage and formed a 2, 3-dihydroxy cinnamamide

which can undergo hydrolysis to generate the cinnamic acid. The subsequent

lactonisation of the acid produces 8-hydroxy coumarin (Figure. 3)

Figure. 3

3.0 Occupational exposure

According to the 1981–83 National Occupational Exposure Survey99,

approximately 240 000 workers in the United States were potentially exposed to

coumarin. National estimates of workers potentially exposed were not available from

other countries. Occupational exposure to coumarin may occur in its production and in its

use in the manufacture and formulation of many products.

NH

O NH

OOH

OH

NH2

O

OHOH

OH

O

HOHO

O OOH

Carbostyril2,3-Dihydroxycinnamamide 2,3-Dihydroxy

cinnamic acid

8-Hydroxy Coumarin



3.1 Environmental occurrence

Reports of the release of coumarin to the environment through various waste

streams are scant. The maximum total daily human exposure to coumarin has been

estimated to be 0.06 mg/kg bw, comprising 0.02 mg/kg bw per day from dietary

exposure, and 0.04 mg/kg bw per day from fragrance use in cosmetic products18.

(a) Foods and fragrances

Coumarin is a natural product found at high levels in some essential oils,

particularly cinnamon leaf oil (40 600 ppm (mg/kg)), cinnamon bark oil (7000 ppm),

other types of cinnamon (900 ppm), cassia leaf oil (17 000–87 300 ppm), peppermint oil

(20 ppm), lavender oil, woodruff and sweet clover as well as in green tea (0.2–1.7 ppm),

fruits such as bilberry and cloudberry and other foods such as chicory root13,18,100. It is

also found in Mexican vanilla extracts17,101.

3.2 Uses

Coumarin is widely distributed in the plant kingdom, but for commercial use has

been mostly produced synthetically for many years. In addition to its use in the

perfumery, cosmetic and related industries, coumarin has several other industrial

applications. Formerly, large quantities of coumarin were used in the food industry,

mostly associated with vanillin, for flavoring chocolates, baked goods, and in cream

soda-flavoured beverages16, but since 1954 its use as a direct food additive has been

suspended in the United States13,18. Because of its unique sweet note and stability,

coumarin has long been recognized as an important raw material in the fragrance

industry. It is widely used in hand soaps, detergents, lotions and perfumes at

concentrations usually extending from 0.01 to 0.8%. It is normally associated in



perfumery with herbaceous odours and enters into the formulation of fern and Chypre-

type fragrances. It is used as an odour-enhancer to achieve a long-lasting effect when

combined with natural essential oils such as lavender, citrus, rosemary and oak moss.

Coumarin is used in tobacco to enhance its natural aroma. It is also applied in large

quantities to give pleasant aromas to household materials and industrial products or to

mask unpleasant odours13,102.

(a) In industry:

It is used in rubber and plastic materials and in paints and sprays to neutralize

unpleasant odours18. In other fields, coumarin has a significant use in the electroplating

industry, mostly in the automotive area, to provide high polished quality to chrome-plated

steel, but this use is declining13,102.

(b) Medical uses

As a consequence of its medical use, many individuals have been exposed to

therapeutic doses of coumarin ranging from 100 to 7000 mg per day for periods ranging

from two weeks to over two years103. Coumarin possesses both immunomodulatory and

direct anti-tumour activity. Coumarin has been recommended for treatment of a number

of clinical conditions, including high protein oedema and brucellosis. It is currently

undergoing clinical trials for treatment of lymphoedema following breast cancer

treatment and in treatment of lung and kidney cancer and of melanoma alone or in

combination with cimetidine18,104-110. It has also been used for prevention of dental

caries16. Coumarin and some of its derivatives have been tested for treatment of

schizophrenia, microcirculation disorders and angiopathic ulcers, and also for treatment

of high protein oedemas in animals13.



(c) Personal care products

Coumarin has also found use in toothpastes, antiperspirant deodorants, bath

products, body lotions, face creams, fragrance creams, hair sprays, shampoos, shower

gels and toilet soaps18,111. It has been used in detergents as a brightener or bleaching

agent16. In personal care products, usual (and maximum) concentrations were found to be

for soap, 0.03% (0.2%), detergent, 0.003% (0.02%), creams and lotions, 0.015% (0.1%)

and perfumes111, 0.3% (0.8%). More recently, coumarin was found in 11 of 22 perfumes

at concentrations112 (w/v) of 0.046–6.043% and 40 of 73 deodorants on the European

market at concentrations ranging from 1 to 1411 ppm [0.0001–0.14%]113. Coumarin

penetrates human skin rapidly and efficiently.



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INTRODUCTION

TO

DITHIOCARBAMATES



INTRODUCTION:

Dithiocarbamates (DTCs) are a group of organosulfur compounds that have

extensively been used as pesticides in agriculture for more than 50 years with some

products being already introduced in the 1930s. Today, the yearly consumption is

between 25,000 and 35,000 metric tones1. Most of the DTCs are applied as fungicides

and some are classified by the World Health Organization as being hazardous2. As a

consequence, an array of various methods has been developed for the analysis of DTCs

and their potential degradation products in environmental samples and in food stuff.

Carbon disulfide is a small electrophilic molecule that has found numerous uses in

organic synthesis as a one-carbon building block primarily for the preparation of

organosulfur compounds. Initial experiments have focused on the reaction of nucleophilic

amines with CS2. This is a well-known and widely used reaction for the high yielding

formation of dithiocarbamate compounds3. A range of primary and secondary amines

were selected for reaction with CS2, and included aniline, benzylamine, diethylamine and

methylamine. Organic dithiocarbamates have attracted a great deal of importance due to

their interesting chemistry and wide utility4-10. Dithiocarbamates have a wide range of

uses and applications and are produced in great quantities throughout the world.

Dithiocarbamate acid ester is a common class of organic molecules. They exhibit

valuable biological effects, including anti-bacterial, anti-fungal, anti-oxidant activity11,

inhibition of cardiac hypertrophy12, etc. Dithiocarbamates are also known to be active as

anti-cancer agents13-17. Since, brassinin18 (Fig. 1), a crucial plant defense first isolated

from cabbage, had cancer preventive activity, structural modification on this compound

led to the synthesis of sulforamate19 (Fig. 1) and a series of dithiocarbamates, some of



which were found to have in-vitro and in-vivo antitumor activity15. A steadily increasing

number of studies have been published on dithiocarbamates and their anti-cancer activity.

4-Methanesulfinylbutyl dithiocarbamic acid methyl ester has proved to be a potential

cancer chemo preventive compound as a phase II enzyme inducer20.

Figure-1 Brassinin(1), Sulforamate(2)

Recently, it was found by Hirschelman’s group that 5- oxohexyl dithiocarbamic

acid methyl ester (3) (figure 2) are potent phase II enzyme inducers which could be used

as cancer chemo preventive agents21-23. However, little systematic research has been

reported about anti-cancer activity of this class of compounds, although compound (4)

(figure 2) was unexpectedly found to have attenuating effects on tumor necrosis factor a

(TNFa)-induced apoptosis in murine fibro sarcoma WEHI 164 cells.90 One of the best

compounds is 4-methyl-piperazine-1-carbodithioic acid 3-cyano-3,3-diphenyl-propyl

ester (5) (figure 2) with 79% and 75% inhibition rates against HL-60 and Bel-7402 cell

lines at 33 lM in-vitro, respectively.More recently, a se- vivo antitumor activity24-25.

Dithiocarbamic acid ester (5) represents a new kind of compound with a novel structure,

significant anti-cancer activity, and very low toxicity. Compound (5) as a lead compound

to further explore the structure–activity relationships with the aim of optimizing potency

and anticancer activity.

NH

HN

S

S

S

O

NH

S

S

12



Figure 2. Structures of oxomate(3) , RWJ-025856(4) and 990207(5)

Investigations on various types of compounds possessing aminoalkylation ability

showed that substituted aminomethyl N,N-dialkyldithiocarbamates have cytostatic

features16,17 presumably via a similar mechanism proposed for antibacterial action.

Furthermore, dithiocarbonate derivatives have been demonstrated to possess

antifungal26,27 and antibacterial27,28 properties, and inhibitory action against brassinin

detoxification by phytopathogenic fungus Leptosphaeria maculans (Phoma lingam)29.

Typical representatives of dithiocarbamate and thiazino[6,5-b]indole-type

phytoalexins from cruciferous plants are brassinin (1),1- methoxybrassinin (6), 4-

methoxybrassinin (7), cyclobrassinin (8) and sinalbin B (9) (figure 3). Among these

compounds, brassinin (1) and cyclobrassinin (8) proved active in inhibiting the formation

of preneoplastic mammary lesions in culture30. The former also exerts an anti-

proliferative effect in human acute T-lymphoblastic leukemia cells31. Brassinin and its

derivatives are inhibitors of indolamine 2,3- dioxygenase, a new cancer

immunosuppression target32. These compounds can serve as lead compounds for the

generation of more efficient analogues33.

Figure-3:1-Methoxy brassinin (6), 4-Methoxy brassinin (7), Cyclobrassinin (8), sinalbin B (9)

O

NH

S

SR1

3

NN

ClS

NMe2

S

4

NC

S

S

NN

H3C 5

N

HN

S

S

O C H 3

NH

N

S

S

6 8

NH

HN

S

S

O C H 3

N

N

S

S

O C H 37 9



Besides the compounds mentioned above, probably the most interesting group of

dithiocarbamates exhibiting anti-tumour activity are the phytoalexins from cruciferous

plants. The phytoalexins are a group of structurally diverse, low molecular weight,

generally lipophilic anti-microbial substances formed in plants. They response to

pathogen attack or physical or chemical stress; probably as a result of the de novo

synthesis of enzymes34. Some of the cruciferae species that have been examined

accumulate a series of specific indole-sulfur compounds. The basic structures are

characterized by an indole ring variably substituted at positions 2 and/or 3 with nitrogen

and sulfur containing substituents35.

A Dithiocarbamate is a functional group in organic chemistry. It is the analogue of

carbamate in which both oxygen atoms are replaced by sulfur atoms (figure 4).

Figure 4: General formula of the dithiocarbamate.

The dithiocarbamate containing two donor sulfur atoms, which it is prepared from

the reaction of primary amine or secondary amine with base and carbon disulfide. On the

other hand, dithiocarbamates are of growing interest due to their biological potencies36,

such as anti-histaminic37, anti-bacterial38, and anti-cancer activties39. Owing to their

strong metal-binding capacity, they can also act as enzyme inhibitors, such as

indoleamine 2, 3-dioxygenase, which plays an important role in tumor growth40. For

these reasons, the synthesis of dithiocarbamate derivatives with different substitution

XX

X

X

XX

X10



patterns at the thiol chain by a convenient and safe method has become a field of

increasing interest in synthetic organic chemistry during the past few years. Traditional

methods for the synthesis of dithiocarbamates involve the use of costly and toxic

reagents, such as thiophosgene, chlorothioformates, and isothiocyanates.

Dithiocarbamates have received considerable attention due to their numerous

biological activities41 and their pivotal role in agriculture42 and as linkers in solid phase

organic synthesis43. They are also used in the rubber industry as accelerators for rubber

vulcanization, as rubber antioxidants 44 and in controlled radical polymerization

techniques45. Typically, the thiocarbonyl moiety has been utilized ubiquitously as a

protecting group46, and as an intermediate in further synthesis47.

In industry, DTCs are used as slimicides in pulp and paper as well as in sugar

production, in waste water treatment, and as anti-foulant for water cooling systems48-50.

Some DTCs were also found to be pharmacologically active and are being used for the

treatment of alcoholism51 and have been tested in clinical trials for various indications

including HIV52-55 and cancer56-58. As a consequence, analytical methods for quality

control and bioanalysis of DTCs and metabolites in biological matrices were elaborated.

Dithiocarbamate (DTC) derivatives are well known as organic intermediates,

rubber additive, additive of polluted water, vulcanizing agents and fungicides59.

Fictionalization of the carbamate moiety offers an attractive method for the generation of

derivatives, which may constitute interesting medicinal and biological properties. As

shown in Fig.5, for example, DSF, an irreversible inhibitor of aldehyde dehydrogenase, is

one of the two drugs approved by FDA for treatment of alcoholism60. Clinical trials have

shown the efficacy of DSF without toxicity. In clinical trials DDTC was used in patients



with HIV-1 infection and found to delay progression to AIDS. PDTC is a stable

pyrrolidine derivative of dithiocarbamates and an antioxidant. Previous studies have

shown that PDTC strongly inhibits replication of human rhino viruses and coxsackie

virus myocarditis. PDTC also showed inhibitory ability against murine colon

adenocarcinoma bearing mice through the inhibition of nuclear factor kB in the tumor

tissue59,60. Recently, Dou et al. reported that the DSF–Cu complex showed inhibition of

proteasome activity and induction of apoptotic cell death60.

Figure-5: DSF(11), DDTC(12) and PDTC(13)

The carbamate moiety is an important structural element in numerous biologically

active compounds61 and has played a crucial role in the area of synthetic organic

chemistry primarily as a novel protecting group62. Therefore; functionalization of organic

carbamates offers great potential in the generation of large combinatorial libraries for

rapid screening63 and drug design64. Furthermore; dithiocarbamates are versatile classes

of ligands with the ability to stabilize transition metals in a wide range of oxidation

states65,66 the ability to chelate heavy metals66-67, to function as NO scavengers68, radical

chain transfer agents in the reversible addition fragmentation chain transfer

polymerizations69, for the protection of amino groups in peptide synthesis70, as radical

precursors71 and recently in the synthesis of ionic liquids72. They have also been widely

used in the synthesis of trifluoromethylamines73, thioureas74, aminobenzimidazoles75,

N S

S

S

11

N

S

S

N S

12

N

S

S

13



isothiocyanates76, alkoxyamines77, 2-imino-1,3-dithiolane78, and total synthesis of (-)-

aphanorphine79.

Furthermore, diarylalkyl thioureas have merged as one of the promising non-

vanilloid TRPV1 antagonists, possessing excellent therapeutic potentials in pain

regulation80 and human CB1 and CB2 cannabinoid receptor affinity81. For these reasons,

the synthesis of dithiocarbamate derivatives with different substitution patterns at the

thiol chain has become a field of increasing interest in synthetic organic chemistry during

the past few years.

A survey of the literature showed that carbamoyl xanthates have been proposed as

intermediates in the reaction between readily prepared carbamoyl chlorides and xanthate

salts, which ultimately affords the corresponding S substituted thiocarbamates upon loss

of carbon oxysulfide82. Dithiocarbamates are intensively used as fungicides83-85. The

mode of action and the metabolism of thiocarbonyl compounds has been studied86-91.

Among other possibilities it has been proposed that the biological active species would be

the corresponding sulfines arising from the cytochrome P-450 monoxygenase mediated

oxidation of the C=S moiety. Moreover, a dithiocarbamate oxide has recently been

evidenced92-94 as the oxidation product of a cruciferous phytoalexin (brassinin) by Phoma

lingam fungi strains. The high radicophilicity of the thiocarbonyl group has resulted in a

long association with synthetic free radical chemistry. Radicals typically add reversibly at

the sulfur of the thiocarbonyl group leading to a new carbon-centered radical, which can

in turn undergo further free-radical processes. This reactivity forms the basis of a number

of important functional group transformations.



Mo

OO

S

S

S

S

N N CH3

CH3H3C

H3C (14)

Figure-6: Molybdenum xanthate [MoO2(Et2NCS2)2]

The literature survey indicates that dialkyl dithiocarbamate complex of molybdenum

(VI as well as IV) appears to posses these features. Molybdenum xanthate (14, MoO2

(Et2NCS2)2 was first synthesized by Moore and Larson in 1967. Reagent 14 is slightly

soluble in CHCl3, CH2Cl2, acetone, and warm benzene and insoluble in CCl4 and aliphatic

hydrocarbons. Reagent 14 contains four sulfur atoms as bidentate ligands, which are

coordinated to dioxo-molybdenum core. Moreover, it is also reported that the four sulfur

donor atoms in MoO2 (Et2NCS2)2 (14) consequently make this complex one of the strongest

oxidizing MoO22+ complexes known95.

Additional several applications in chemistry such as supramolecular chemistry due to

the fact that the dithiocarbamate ligand is an attractive structural motif for metal-directed self

assembly to polymetallic including cages, helicages, ladders, racks and grids have been

constructed. The optical and electrochemical properties of dithiocarbamate complexes can be

used to construct sensors for the guest molecules. Different metal [Pt(II), Pd(II), Au(III),

Cu(II)] complexes of dithiocarbamate derivatives (methyl- and ethylsarcosinedithio

carbamate, N,N-dimethyldithiocarbamate, S-methyl-N,N-dimethyldithiocarbamate and

diethyldithiocarbamate) have been prepared and their cytotoxicities were studied96-98. The



Pt(II) complexes of these sulfur-containing molecules can act as chemoprotectants in

platinum-based chemotherapy, modulating cisplatin nephrotoxicity99. The platinum

complexes have similar activity but less toxicity than the cisplatin100-102. Recently

dithiocarbamate metal complexes have been used to prepare nanoparticles and nanowires of

a variety of semiconducting materials including CdS, CuS, ZnS, PbS and EuS103-109.



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Chapter -1 - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/20756/8/07_chapter-1.pdf · Karnatak Science College, Dharwad 3 The electron impact on coumarins has been studied