Technical White Paper - .xyzlibvolume6.xyz/.../coumarins/coumarinsnotes2.pdf · 2015-06-22 · 3.3 5-Membered Coumarin Heterocycles with Two Nitrogen Atoms, e.g., Pyrazoles 3.4 6-Membered

Technical White Paper

CHEMISTRY OF COUMARINS

Rao S Bezwada

INDOFINE Chemical Company

127 Stryker Lane

Hillsborough, NJ 08844

Outline

1.0 Introduction

2.0 Reactions of Coumarins (Benzopyran-2-ones)

2.1 3:4-Fused Coumarins

2.2 Cycloaddition Reactions

2.3 Dibenzo-α-pyrones

2.4 Heterocyclic Coumarins

2.4.1 Furocoumarins

2.4.2 Isocoumastan

2.4.3 Pyranocoumarins

2.4.4 Chromenocoumarins (Chromans)

2.4.5 Coumarino-α-pyrones

2.4.6 Coumarino-γ-pyrones

2.4.7 Coumarino Coumarins

2.4.8 Chromones

3.0 Synthesis of Coumarin Heterocycles

3.1 5-Membered Coumarin Heterocycles with One Nitrogen Atom, e.g., Indoles

3.2 6-Membered Coumarin Heterocycles with One Nitrogen Atom, e.g.,

Coumarinopyridines, Coumarinoquinolines

November 2008 Copyright©2008 INDOFINE Chemical Company

1

3.3 5-Membered Coumarin Heterocycles with Two Nitrogen Atoms, e.g., Pyrazoles

3.4 6-Membered Coumarin Heterocycles with Two Nitrogen Atoms, e.g.,

Pyridazines, Pyrazines

3.5 5-Membered Coumarin Heterocycles with One Oxygen, One Nitrogen and One

Sulphur Atom, e.g., Isothiazoles, Thiazoles

3.6 5-Membered Coumarin Heterocycles with One Oxygen and One Nitrogen

Atom, e.g., Oxazoles, Isoxazoles, Oxazines

3.7 5-Membered Coumarin Heterocycles with One Oxygen, One Nitrogen and One


3.8 6-Membered Coumarin Heterocycles with One Sulphur and One Nitrogen

Atom, e.g., Thiazines

4.0 Naturally Occurring Coumarins

5.0 Biologically Active Coumarins

6.0 Photosensitive Coumarins

7.0 Summary

8.0 Acknowledgement

1.0 Introduction

Coumarins (benzopyran-2-ones) 1 constitute an important class of naturally occurring

compounds; they are widely used in the perfume, cosmetic, agrochemical and

pharmaceutical industries. Several coumarin derivatives have been synthetically prepared

and reported to possess cardiovascular, ageing, antibacterial and photosensitive

properties. The chemistry of coumarins has received much attention and is used by

chemists to develop several useful products.

2.0 Reactions of Coumarins (Benzopyran-2-ones)

The chemistry of coumarins has centered on performing reactions at the activated C-3,4-

double bond of the α,β-unsaturated lactone. Based on this chemistry, heterocyclic


2

systems have been built. Coumarins with the desired aromatic substitution were built by

synthesis starting from appropriate starting material and/or by electrophilic or

nucleophilic substitution.

2.1 3:4-Fused Coumarins

Reaction of 3-acetylcoumarin (1, X1 =COCH3) with phenacyl halide1,2 in the presence of

NaOEt, according to the procedure of Widman et al.1 gives 3,4-phenacylidene-3-

acetylcoumarin (2, X1 = COCH3) due to insertion3 of methylene across the C-3,4-double

bond; the product is a 3,4-dihydrocoumarin derivative [Figure I].

2.2 Cycloaddition Reactions

The photodimers of coumarin have been known for nearly 60 years. These have been of

interest as furocoumarins, and are known to react with the skin in the presence of light.

They have been used for the treatment of skin depigmentation. Photochemical

reaction4,5,6,7 across the double bond of coumarins (1, X = H) is reported to give four 4-10

and six membered11,12 3,4-dihydrocoumarin dimers 3 and 4, respectively, due to (2+2)

and (2+4) cyclo-addition reactions as shown in [Figure I].


3

2.3 Dibenzo-α-pyrones

The preparation of 3:4-fused 5-member ring coumarins have been accomplished mostly

y two protocols. The first and popular one is condensation of the appropriate phenol

) have been prepared by Pechmann condensation. Thus, reaction of various phenols 5

b

with cyclopentanone-2-carboxylate under Pechmann condensation reaction conditions as

depicted in [Figure II]. Phenols 513-16 bearing various substituents (Me, HO, COOH) at

C-2 and C-5 were condensed with cyclic β-ketoesters 617,18 (n = 1) by use of POCl3or

H2SO4 to give 1, 2, 3, 4-tetrahydro cyclopenta [c][2] benzopyran 7 (n = 1) derivatives

[Figure II]. Pechmann reaction conditions leading to the synthesis of colchicines have

been reported.19,20 In the second approach, straight chain β-ketoesters 8 were condensed

with phenols 5, initially resulting in propionic acid residue at C-4; cyclization followed

by reduction gives the 5-membered ring containing coumarins 721,22 (n = 1) [Figure II].

In an analogous way, the corresponding six membered ring containing coumarins 7 (n =

2

with ethyl cyclohexanone-2-carboxylate 6 under acidic conditions7,8,9,10-12 gives

tetrahydrodibenzo-α-pyrones 713, 15, 16, 23-30-33 (n = 2) [Figure II] in yields ranging from 5

to 75 %.


4

Condensation of phenols 9 with o-halobenzoic acid (10, Y = Br), catalyzed by copper

a

salts, gives fair yields of dibenzo-α-pyrones 1134 as shown in [Figure III]. Ethanol has

been found to be a suitable solvent for the reaction of 2-chloro-,34 2-bromo-34 and 2-

bromo-4-methyl benzoic acid.35-37 The yield of 11 decreased in the order 2-bromo->2-

chloro-> 2-iodobenzoic acid.38 The condensation reaction of phenols 9 with

diazoanthranilic acids 39-41 (10, Y = N2+), demethylative cyclization of 2-methoxy-2’-

carboxybiphenyl42,43 12 and oxidative cyclization of 2’-carboxy biphenyl 1344 gives

dibenzo-2-pyrones 11 [Figure III]. For oxidative cyclization, chromic acid44, I2/CCl4,

and peracetic acid44 are added to silver salts of biphenyl carboxylic acids. Oxidation was

also effected by use of aroyl peroxides, 44,45,46 cobalt-(II)-catalyst/molecular oxygen and

di-tert-butylperoxide,47 Pb(IV)OAc48 and K2S2O849,50 [Figure III]. The potassium salt of

2’-nitrophenyl-2-carboxylate 13 (X=2’-NO2) gives 11(X=1-NO2), due to facile

intramolecular displacement45 . The presence of fluorine or bromine in place of the nitro

group gives lower yields of 11. Among other methods, dehydrogenation of 3:4-

cyclohexenocoumarins 14 by Pd/C51 and Baeyer-Villiger oxidation52 of fluorenones gives

11.43 The reaction of 2-methoxycarbonyl-1,4-benzoquinone 15 with substituted phenols

16 catalyzed by acid in regiospecific way gives substituted dibenzo-α-pyrones 17.53

Regiospecific cyclization leading to the formation of 3-chloro-dibenzo-α-pyrone 17 (X =

3-Cl; A, B, C = H) has been reported.53


5

Reaction of 3-methoxycoumarin derivative 18 with primary amine and acetone gives

dibenzo-α-pyrone derivative 17.43 Cycloaddition reaction (2+2) of 3-cyano/-

ethoxycarbonyl coumarin derivative 19 with diene 20 (xylene/heat) followed by

dehydrogenation (Pd/C) gives dibenzo- -pyrone 11 [Figure III]. Oxidation of

dibenzopyran derivative 21 with CrO

α

ycloaddition of 4-vinyl coumarin derivative 22 with maleic anhydride (23, Y = O) and

3 or H2O2/AcOH gives 11.40

C

maleimide (23, Y = N) separately (xylene/heat) gives the coumarin adducts 24 and 25,54

respectively as shown in [eq 1].


6

2.4 Heterocyclic Coumarins

2.4.1 Furanocoumarins

oumarins bearing a heterocyclic system fused at C-3, 4 have been prepared.

ondensation of two moles of 4-hydroxy coumarin derivative 26 with one mole of α-

C

Heteroatoms such as oxygen, nitrogen, sulphur or combinations thereof have been

incorporated into the heterocycle. A five-membered ring containing oxygen atoms can

fuse to C-3,4 of coumarin in two possible ways to form furan isomers. Both the isomers

can be prepared, starting from 3- or 4-hydroxycoumarin, or directly by decarboxylation

of carboxy derivatives as shown in [Figure IV].

C

chloro acetaldehyde diethyl acetal gives55 3-(hydroxycoumarin-3-yl)-[3,2-b]

dihydrofuranyl coumarin 27. Two moles of 26 condenses with one mole of oximino

acetone and56 undergoes dehydration (Ac2O/NaOAc) to give furano coumarin derivative

28. A similar reaction of 26 with glycerol gives the hydroxymethyl analog 29.57 A-ring-

fused furan derivative 30 was obtained from 3-propargyl-4-hydroxy coumarin derivative

(26, R = CH2CH=CH) due to addition followed by dehydration58. Alternatively, the furan

derivative 30 was obtained from the 4-O-allyl coumarin derivative 31 by Claisen

migration.59-61 Reaction of 3-phenylcarbonyl coumarin 26 (R=COPh) with acetone,

followed by treatment with alkali (NaOH/EtOH) and Cu/quinoline, gives substituted

furano coumarin 3062 (R1 = COOEt, COOH, H; R2 = C6H5; X = H, Me).


7

Reaction of the 3-β-hydroxymethyl-4-hydroxycoumarin derivative 32 gives the

dihydropyran derivative of coumarin on reaction with HCl/MeOH. Bromination (NBS)

followed by elimination of HBr gives the furano coumarin 3063, 64 (R1 = R2 = X = H)

[Scheme IV]. The same product, α,β-unsaturated pyrone 30, was also obtained by

condensation of 4-hydroxy succinic acid in conc. H2SO4. Treatment of the pyrone with

NBS gives the corresponding 3-bromo derivative 33. The bromo derivative 33, on

treatment with alkali, gives furan-α-carboxylic acid derivative 34 which, on

decarboxylation (Cu/quinioline) at 240oC, gives the furano coumarin derivative 30.65-69

2.4.2 Isocoumestan

Pechmann condensation of ethyl 3-oxo-2,3-dihydrobenzofuran-2-carboxylate derivative

35 with resorcinol 36 (X = 3-HO) using 85% aq. H2SO4 gives 9-hydroxybenzofuro[2,3-

c][1]benzopyran-6-one 3770-72 (isocoumestan) as shown in [eq 2]. 3-Hydroxy coumarin

38, on dehydrogenative coupling with catechol 39 in NaOAc/KIO3 in acetone, gives

isocoumestan 4072 as depicted in [eq. 3].


8

2.4.3 Pyranocoumarins

A number of pyranocoumarins have been readily synthesized from 4-hydroxycoumarin

41 [Figure V]. Michael addition of 4-hydroxycoumarin 41 to α,β-unsaturated ketones or

aldehydes (pyridine/reflux) followed by cyclization in R4-OH/HCl gives various

hemiacetals of pyranocoumarins 42.73-78 Many of these compounds have anti-coagulant

properties. In a similar way, condensation of 4-hydroxyxoumarin 41 with unsaturated

nitriles 43 gives 2-imino-3-ethoxy carbonyl pyranocoumarins 44.79 Reaction of 41 with

cinnamyl bromide 45 gives 3-alkylated coumarin derivative which, on reaction with

bromine in CHCl3, yields 2-phenyl-3-bromo pyranobenzopyran 46.80 Warfarin 47 on

reflux in Ac2O/HClO4 gives the corresponding acetal 48 (20%) and pyran 4981 (50%).


9

2.4.4 Chromenocoumarins (Chromans)

Chromenocoumarins have been prepared by i) Pechmann condensation, ii) Michael

addition of coumarins to α,β-unsaturated ketones, iii) condensation of Mannich bases,

and iv) condensation reactions of aromatic aldehydes as shown in [Figure VI].

Thus, Pechmann reaction of resorcinol with 3-hydroxy-6,7-dimethoxy-A3-chromene-4-

carboxylate in 85% H2SO4 gives chromenocoumarin.82 In the second method, Michael

addition of 4-hydroxycoumarin 41 to α,β-unsaturated ketones 50 in pyridine gives 6-oxo-

7-acetonylbenzopyrano-[4,3-b][1]benzopyran 51b83. In the third method, reaction of 4-

hydroxycoumarin 41 with HCHO/PhCH2NH2 gives Mannich base 52 which, on heating


10

with phenol, gives coumarinochroman 53.84 In the fourth method, reaction of 41 with

aldehydes such as citral, citronellal 54 in pyridine, gives chromenocoumarin 55.84

Reaction of two moles of 41 with glyceraldehydes 56 by refluxing in dioxane gives

chromenocoumarin 5757 [Figure VI], and on reaction with o-chlorobenzaldehyde

derivative 58, by first refluxing in ethanol and then heating to 200oC in xylene, gives

chromenocoumarin 59.85 Under similar reaction conditions, heterocyclic

chromenocoumarins containing nitrogen 60 have also been prepared85-85 by reaction of 41

with 2-pyridine-2-aldehyde derivatives 61. Reaction of 41 with o-halophenol 62 in

pyridine followed by reflux in MeOH/HCl gives chromenocoumarin 63 in good yield.73

The same product has also been prepared by reaction of 41 (HCl and POCl3) with

hydroxyl α-phenyl ethyl alcohol 6488 as shown in [Figure VI].


11

2.4.5 Coumarino-α-pyrones

Coumarino-α-pyrones have been synthesized by: i) condensation of o-

hydroxyphenylacetic acid with benzylpyruvic acid, ii) condensation of 4-

hydroxycoumarin with either benzylidene malononitrile or malonic acid under Pechmann

conditions, iii) cyclisation of 4-hydroxycoumarin-3-propionic acid, and iv) by acylation

of 3-acyl-4-hydroxycoumarin as shown in [Figure VII]. Condensation of 4-

hydroxycoumarin (41) with benzylidene malononitrile 65 in pyridine and

AcOH/HCl/Ac2O gives 4-phenylcoumarino-3,4-dihydro-α-pyrone 66.89

Pechmann condensation of 41 with ethylacetoacetate (R = H) gives coumarino-α-pyrone

67,90 in the presence of condensing agents such as AlCl3, 80% H2SO4 and POCl3.90

Reaction of 41 with diaryl malonates 68 and AlCl3, or malic acid 6965,66 and cyanoacetic


12

acid 7091 catalyzed by acid, gives coumarino-α-pyrones 71 and 72, respectively. Reaction

of 4-hydroxy coumarin 41 with α,β-unsaturated esters 73, catalyzed by piperidine and

acetic acid, gives 74.92,93 Reaction of 4-hydroxy coumarin 41 with triethyl orthoformate

in the presence of aniline gives 75.93b Reaction of 41 with 2-acetyl diethyl malonate 76 in

AlCl3/C6H5NO2 at 110oC gives 77.90 Chlorine containing derivatives of coumarino-α-

pyrones (78, R1 = R2 = Cl) were prepared by reaction of 41 with hexachloroethylene 79

in AlCl3/CS2.94 Several 3-cyano-3-carboethoxy and 3-carbamido coumarino-a-pyrones 80

were prepared by reaction of 41 with the corresponding malonic acid derivatives 81 (X1-

CH2-X2) in pyridine at room temperature.95


13

2.4.6 Coumarino-γ-pyrones

The synthesis of coumarino-γ-pyrones 82, 83 have been described by: i) Michael addition

of 4-hydroxy-coumarin 41 to α,β-unsaturated carboxylic acids 84 or acid chlorides

followed by cyclization in PPA to give dihydro-y-pyrones 8296,97 as depicted in [Scheme

VIII], ii) reaction of 2-acetyl coumarins 85 with acetic anhydride in the presence of

NaOAc or KOAc,98-100 and iii) by reaction of 41 with ethylacetoacetate/CF3COOH.35a

Reaction of 41 with isoxazole 86 by refluxing in pyridine/CuCl2 gives coumarino-γ-

pyrone 87, containing the isoxazole ring.101

2.4.7 Coumarino Coumarins:

Reaction of 3-hydroxyflavone with Ac2O/NaOAc, followed by photolysis, gives bis-3,3’-

oxaindanone derivative 88 which, on oxidation with KMnO4, gives coumarino coumarins

89102 [Figure IX]. Alternatively, demethylative ring closure of 3-(2’methoxyphenyl)-4-

ethoxycarbonyl coumarins 90 in pyridine/HCl also gives 88.103 A new synthesis of 88 has

been described from 2, 2’-dimethoxydiphenyl succinonitrile 91 by reaction with pyridine

hydrochloride at 210oC.103 A simple 3,3’-bis-oxaindnone 92, on reduction with 10 %

NaOH, gives 88.103 Condensation reaction of 4-hydroxycoumarin 41 with o-halobenzoic

acid derivatives 93 in alkaline aq.CuSO4 gives 89.104

2.4.8 Chromones

Condensation of resorcinol 5 with coumarin 3-carboxylic acid chloride 94 under Friedel-

Craft’s conditions (AlCl3/C6H5-NO2), followed by oxidation with Pb(IV)OAc/AcOH,

gives chromone 95105 as shown in [eq 6]. Coumarino benzopyrans 96 on oxidation with

(CrO3/AcOH) also gives 95.104,106


14

Oxidation of active methylene containing rotenone 97 by CrO3/AcOH gives the oxidized

product of rotenone 98 [eq 7].106 Acid catalyzed reaction of isoflavone 99 with

HBr/AcOH gives [1] benzopyrano-[3,4-b][1]benzopyran-6,12-dione 100 [eq 8].


15

3.0 Synthesis of Coumarino Heterocycles

3.1 5-Membered Coumarin Heterocycles with One Nitrogen Atom, e.g., Indoles

Pechmann reaction of resorcinol 5 and substituted resorcinol with pyrrolidine β-ketoester

101 and indole β-ketoester 102, separately in the presence of conc. H2SO4, gives the

corresponding 7-(1,2-dimethylheptyl)-9-hydroxypyrrolo [3,4-c] benzopyran-4-one

derivative 103107,108 and 3-hydroxy[1]benzopyrano[4,3-b]indol-6-one 10470 as shown in

[eqs 9 & 10], respectively. Reaction of 3-aminocoumarin 105 with NaNO2/HCl

(diazotization), followed by reduction with Sn(II)Cl, gives coumarin-3-yl hydrazine

which, without isolation, reacts with various carbonyl compounds in a Fischer indole

synthesis to yield [1] benzopyran [3,4-b]pyrrol-4(3H,4H)-one 106 [eq 11].70

3.2 6-Membered Coumarin Heterocycles with One Nitrogen Atom, e.g.,

Coumarinopyridines, Coumarinoquinolines


16

Coumarins having 3:4-fused six membered heterocycles having one nitrogen atom have

been reported.109,110 The best method developed reacts 4-(o-methylphenyl)-lutidine-3-

carboxylic acid sulphate 107 with AlCl3 in nitrobenzene to give 2,4-

dimethyl[1]benzopyrano [3,4-c]pyridine-5-(2H)-one 108 as shown in [Scheme X].114,109

The same compound 108 has also been prepared by reaction of 3-acetylcoumarin 109

with cyanoacetamide and acetone in a sealed tube.111 Reaction of o-cyano substituted 4-

phenyl pyridine derivatives 110, on reflux in 48 % aq. HBr, gives the corresponding

coumarinopyridine 108.110,112 Reaction of 3-acetylcoumarin 109 with cyanoethylacetate

and a keto compound at 165oC gives 108.113 Reaction of o-hydroxybenzaldehyde 111

with dicyanomethane and a ketocompound by heating in NH4OAc, followed by reaction

with HCl, gives 108.114Reaction of the flavonone derivative 112 with a secondary amine

in the presence of acid gives coumarinopyridines 113; the same product is formed on

reaction of 112 with cyanoacetamide.114

Reaction of 111 with 2-cyanoethyl acetate in NH4OAc under refluxing conditions gives

coumarinopyridine 114.115 Reaction of 3-coumarino derivative 115 with N-[3-ketobutyl]

pyridinium bromide 116 in NH4OAc/AcOH, followed by oxidation with CrO3, gives 114.

Reaction of 3-aminocoumarin derivative 117 with unsaturated compounds such as β-

ethoxyacrylates 118 [eq 12], propargylic ester 119 [eq 13], and ethyl acetoacetate [eq 14]

separately, under thermal conditions, gives coumarinopyridine-4-one derivatives 120,

121 and 122, respectively.116 2-Aminocoumarins 117 have been important substrates for

preparation of coumarino pyridine derivatives 123 [eq 15] by reaction with glycerol and

H2SO4.


17

O

N

OR6

R2

R1

R4

R5

R3

CNOMe

N

R6R2

R1

R4

R5

R3

CHO

OHR6

COOHOMe

N

R6

Me

O OR6

R3

O

O O

Ph

O Ph

NC CN

O

N

O

Ph

NR7R8

O

N

O

Me

R1

R6

R

O

MeCH2

CN

CN

R3

O

R4

CH2

CN

CO2Et

R1 = H, NO2, NH2R2 = H, HO, MeOR3 = R4 = Me, C6H5R6 = HR5 = H, CN, CO2HR6 = H

110 108 111

109

112

NH

R7

R8

i) NH4OAc

ii) HCl

NCCH2CO2EtNH4OAcreflux

NH4OAc/AcOH;CrO3H+

H+

NCCH2CONH2 113 115

107

114

48% aq. HBror Fe/HCl

AlCl3

N+R2

O

116

Scheme X

++

+ +

+

R7 = R8 = H

165 0C

Thus, reaction of 4-hydroxycoumarin 41 with anilines 124 and formaldehyde at high

temperature (240oC/0.5 torr) gives dihydro coumarinoquinolines 125;121-123 when 3-

amino-6-methoxypyridine 126 was used in place of aniline it gives 9-methoxy [1]


18

benzopyran[4,3-b][1,5]naphthyridine-6-one 127.124 Reaction of 41 with o-

nitrobenzaldehyde derivatives in the presence of AcOH/NaOAc and Zn/AcOH gives

coumarinoquinolines 128 [Figure XI].125 Refluxing 3-(2’-hydroxyaryl)-4-

carboxyquinoline (129, R = H) in pyridine hydrochloride gives coumarino quinoline

130.126,127

124

126

125

127128

129 130

124

126

125

127128

129 130

Several coumarino piperidone derivatives 131 have been prepared starting from 3-

carboethoxy coumarin 132. Thus, reaction of 132 with several keto compounds

(R1CH2COR2) and primary amines (R-NH2) or NH4OAc at 170oC gives

coumarinopyridinones 131 [eq 16]. 117

Pechmann condensation of resorcinol derivative 133 with 4-carboethoxy-3-keto

piperidine derivative 134 in H2SO4 or POCl3 gives 3:4-fused coumarino piperidines

135118,119. Mannich reaction of 135 gives aminomethyl coumarino piperdine 136120 [eq

17].


19

3.3 5-Membered Coumarin Heterocycles with Two Nitrogen Atoms, e.g., Pyrazoles

Reaction of 4-chloro-3-formyl coumarin 137128,129 with phenylhydrazine [eq 18] and

phenylsulfoxy coumarin 138 with diazomethane [eq 19] separately gives the

corresponding coumarinopyrazoles 139 and 140, respectively.130,131 Coumarins bearing

cyano, carboxamido and formyl substitutents at C-3 and halo at C-4 are suitable

substrates for preparation of coumarinopyrazolines.


20

3.4 6-Membered Coumarin Heterocycles with Two Nitrogen Atoms, e.g.,

Pyridazines, Pyrazines

Coumarino pyridazines have been prepared by several methods. Reaction of 4-

hydroxycoumarino-γ-pyrone 141 with phenyl diazonium salt followed by cleavage with

KOH gives 3-phenylpyridazine intermediate 142 which, on reaction with HBr, yields 1-

phenyl[1]benzopyrano [4,3-c]pyridazin-5(4H)-one 143 [eq 23].132 In another method,

reaction of 3-formyl flavone 144 with cynamide derivatives 145 in the presence of aq.

NaOH gives 146. If one follows this by oxidation with CrO3/pyridine, one obtains

benzopyranopyrimidine 147 [eq 24].133,134

Reaction of 3,4,6-trichlorocoumarin 148 with o-phenylene diamine 149 in the presence of

metallic Na, followed by heating in pyridine, gives 2-chloro[1]benzopyrano[3,4-

b]quinoxalin-6-one 150 [eq 25].135 Reaction of 3-(4-methylphenylsulphonyl)-coumarin

151 with NaN3/DMF at 95 oC gives 1-benzopyrano [3,4-d][1,2,3] triazol-4-(1H)-one 152

[eq 26].130


21

Reaction of 7-amino-3-phenylcoumarin with NaNO2/H+ gives the corresponding 7-diazo

salt 154 which, on coupling with 3-aminocoumarin 153 followed by oxidation with

CuSO4, gives fluorescent whitener coumarinotriazole 155 [eq 27]. 136

3.5 5-Membered Coumarin Heterocycles with One Oxygen, One Nitrogen, and One


3:4-Fused coumarinothiophene derivatives were prepared by Pechmann condensation119-

119b of substituted resorcinol with β-ketoesters and thio keto esters. They have also been

prepared by reaction of o-hydroxybenzaldehyde derivatives with thiolactones137 or via 4-

thiocoumarin derivatives.138

Pechmann reaction of resorcinol 156 with cyclic thio β-ketoesters 157, 158 separately on

heating with acid gives the corresponding coumarinothiophenes 159 and 160,119

respectively [eq 28]. Alternatively, reaction of o-hydroxybenzaldehyde 161 with

thiolactones 162, 163 separately under acid catalyzed cyclization gives the corresponding

coumarinothiophenes 164 and 165, respectively. A similar reaction of 161 with

benzothiolactone 166 gives the coumarinothiophene derivative 167137 [eq 29].


22


23

3.6. 5-Membered Coumarin Heterocycles with One Oxygen and One Nitrogen

Atom, e.g., Oxazoles, Isoxazoles, Oxazines

Reaction of 3-amino-4-hydroxycoumarin 170 either with acetic anhydride or aliphatic

aldehydes in nitrobenzene gives 2-methylbenzopyrano [3,4-d]oxazol-4-one 171 [eq

31].139-141

Heating of 3-ethoxycarbonyl-4-hydroxycoumarins 172 with phenylhydroxyl amine at 150 oC gives a coumarinoisoxazole, namely, 2-N-phenylbenzo-pyrano [3,4-d] isoxazole-3,4-

dione 173 [eq 32]. Refluxing substituted 4-chloro-3-formylcoumarins 174 (R = H) with

hydroxylamine in NaOAc gives coumarinoisoxoles 175 [eq 33].129,142 Reaction of 3,6-

dichloro-4-(2-hydroxyethylamino)-coumarin 176, prepared from 3,4,6-trichlorocoumarin

148 and ethanolamine, in NaH/THF results in intramolecular cyclization yields 2-

chlorobenzopyrano[3,4-b][1,4]oxazin-6-one 177 [eq 34].


24

4-Hydroxycoumarin 41,143,144 on heating with hexamethylene tetramine at 180-190 oC or

Schiff base in lactic acid,144 separately gives 3,4-dihydro-1,3-oxazino[5,6-

c][1,2]benzopyran-5-one derivatives 178 and 179, respectively [eq 35].

3.7 5-Membered Coumarin Heterocycles with One Oxygen and One Sulphur Atom,

e.g., Isothiazoles, Thiazoles

Reaction of 2-methylcoumarino-γ-pyrone 181 with B2S3/CHCl3 initially gives 182.

Further reaction with P4S10/toluene gives 8-methyl-5,10-dioxa-9,9a-

dithia[9a,Siv]pentaleno[2,1-a]naphthalene-6-one 183; compound 181 itself is obtained


25

from 3-acetyl-4-hydroxycoumain 180145. Further hydrolysis of 183 with H2SO4 gives 8-

methyl-5,9-dioxa-9a,10-dithia[9a, Siv]pentaleno[2,1-a]naphthalene-6-one 184 as shown

in [Scheme XII].145

Reaction of 4-mercaptocoumarin-3-carboxamide 185 with bromine in EtOAc at reflux

gives benzopyrano[3,4-d][1,2]isothiazole-3,4-dione 186143 [eq 36]. Electrolysis of 3-

thioacetamidocoumarin 187 in CH3CN containing Et4N+ClO4

- gives 2-methyl

benzopyran[3,4-d][1,3]-thiazol-4-one 188 [eq 37].146


26

3.8. 6-Membered Coumarin Heterocycles with One Sulphur and One Nitrogen

Atom, e.g., Thiazines

Coumarinothiazines have been prepared starting from 4-hydroxy- 41 and 3,4-

dichlorocoumarin derivatives.135,147 Thus, reaction of 3,4,6-trichlorocoumarin 148 with 2-

mercaptoethyl alcohol in NaOMe gives 3,6-dichloro-4-(2-mercaptoethylamino)-coumarin

189, which cyclizes in NaH/DMF to give 5-oxo[1]benzopyrano[4,3-b][1,4]thiazine 190

[eq 38].135 Heating of 2-mercaptoaniline 191 and 4-hydroxycoumarin 41 in DMSO at

140-145oC gives the coumarinobenzothiazine derivative 192 [eq 39].123 Ullmann-Fetvad

Jian-type condensation of 4-hydroxycoumarin 41 with 5-aminobenzothiazole 193 and

HCHO gives 12-oxo-chromeno [5,3-b] thiazolo [4,5-f] quinoline 194 [eq 39].147 4-

Hydroxycoumarin-3-sulphonic acid 195 gives 2-methyl-5-oxo benzopyrano [4,3-e][1,2,4]

thiadiazine-4,4(3H)-dioxide 197 on reaction with acetamidine hydrochloride 196 [eq 40].


27

4.0 Naturally Occurring Coumarins

Aflatoxins (B1, B2, G1, G2, M1, M2) 199148-151 form a group of acutely toxic and

extremely carcinogenic, hepatotoxic metabolites produced by some strains of Aspergillus

flavus. Aflatoxin B1 has been synthesized,152 starting from 5-benzyloxy-4-methyl-7-

methoxy coumarin 198, via the corresponding 4-formyl derivative [eq 41].


28

One of the yellow pigments isolated from the scent glands of beaver has been identified

as urolithin-A 200 and urolithin-B 201.153,154 Alternariol 202 is the first 3:4-

benzocoumarin antibacterial agent of fungal origin isolated from Alternaria tenus.155,156

Benzocoumarins autumnariol 203 and autumnarriniol 204 isolated from bulbs157

constitute the flavored components of Shilajit. A furocoumarin glapalol 205158,159 and a

coumastan, namely coumasterol 206, have been isolated, also. The accumulation of

compounds known as phytoalexins (rotenonones, stemonone 207 and stemonal 208) and

the concomitant shifts in metabolism are believed to be the mechanism for disease

resistance in plants.

5.0 Biologically Active Coumarins

Several pharmacologically active coumarin derivatives have been invented and tested for

various activities. Cyclocoumarol 209 is one of the most active anti-coagulants among

the 106 synthetic compounds tested for the activity.160 Cyclocoumarol has 60% of the

activity of dicoumarol 210. 4-Methyl-2,5-dioxo-3-phenyl-2H-5H-pyrano[3,2-

c][1]benzopyran 211 exhibited considerable anti-coagulant activity.161 Many aromatic

coumarin glycosides 212 bearing C-2 and C-3-alkoxy substituents were reported as anti-

diabetic agents162 and bactericides.163 7-(Bromomethyl)-4-(furan-3-yl) coumarin 213 was

studied as an inhibitor of leukotriene biosynthesis for treatment of angina in preventing

formation of atherosclerotic plagues,164 and as an anti-allergy compound.165


29

4-Methoxy-coumarin derivatives 214 166 were reported as therapeutic agents for fibrosis,

and 3-acyl-7-nitro-6,8-dialkyl coumarins 215 as plant growth regulating agents.167 4-

Methylcoumarins, bearing 7-O-alkyl- and/or aminoalkyl, hydroxyl alkyl, and 7-amino

halo alky l groups, were cited as cardiovascular agents;168 and 3-benzazolyl-7-aminoalkyl

coumarins 216 have been reported as diagnostic probes for amyloid accumulation

disease.169 7-(2-Piperizinyl) coumarin derivatives were studied for treatment of pain,170 as

were furo[3,2-g]4-hydroxy-9-alkenyl coumarin 217 derivatives as antibacterial agents.171

In a study, 6,7-dihydroxy-8-(sulfoxy)-coumarins were examined for treatment of

oxidative stress,172 and bis-4-hydroxy coumarins for anticoagulant activity. 3,3’-(4-

Chlorophenylmethylene)bis-4-hydroxycoumarin 218173 was the most prospective

compound in the study. 6-Hydroxy-3,4-dihydrocoumarin 219 derivatives were studied for

control of anti-ageing and their prospects as skin-lightening compounds.174

6.0 Photosensitive Coumarins

Several coumarins were found to have the property of fluorescence. Notable among them

are 2-chromone for skin composition, and 3-[4-bromoethyl] phenyl-7-(diethylamino)-


30

coumarins 220 as fluorescent derivatization reagents for carboxylic acid in High Pressure

Liquid Chromatography.175 Coumarins fused to naphthopyrans were reported as

fluorescent brighteners;176 novel hetarylazo coumarins made from 4-hydroxycoumarins

provided disperse dyes,177 and the derivatives from the reaction of 3-aryl-7-diethylamino

coumarins 221 with isatin served as fluorescent materials.178 7-Amino-4-hydroxymethyl

coumarins 222 were used for making caged γ-Amino Butyric Acid (GABA) to

investigate neuronal circuits in tissues179 and coumarins having tertiary amino group as

photosensitive resins for PCBs.180 Chiral N-(coumarin-3-yl carbonyl)-α-amino acids have

been prepared as fluorescent markers for amino acids and dipeptides181.

7.0 Summary

A brief outline of chemistry done in the area of coumarins, almost for more than a

century, has been reviewed to benefit the community of chemists and manufacturers of

various commercial products.

8.0 Acknowledgement

INDOFINE Chemical Company, Inc. expresses their thanks to Dr Mereyala Hari Babu,

Ex. Deputy Director, Indian Institute of Chemical Technology, Hyderabad 500007, India

for compiling the manuscript.

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Technical White Paper - .xyzlibvolume6.xyz/.../coumarins/coumarinsnotes2.pdf · 2015-06-22 · 3.3 5-Membered Coumarin Heterocycles with Two Nitrogen Atoms, e.g., Pyrazoles 3.4 6-Membered