CHAPTER IV

PART I

CHEMISTRY OF α-TETRALONES

4.1.1 Introduction

The bicyclic benzofused ring system and related structures such as indanone 109 and

tetralone 110 and 111 incorporate two rings connected by a fused ring having a benzene ring

adjacent to the ring junction. They form the basis of the structural framework of

benzocycloalkanones1-5

.

OO

O

109 110 111

α-Tetralones 110 are used as intermediates in pharmaceutical chemistry6 and are found in

natural products7-8

, the back bone of some of the alkaloids. Stereoselective synthesis of racemic

homochelidonine 113 was achieved from the naturally occurring non-alkaloid artonin 112, which

has an α-tetralone ring system9.

N

O

O

O

O

O

O

O

MeO

MeO

HO

CH3MeO

OMe

112 113

4.1.2 Synthesis of α-tetralones

Different strategies have been employed for the synthesis of α-tetralones. The Haworth

reaction is a classical method of synthesis of 1-tetralone10

. In this method, the benzene ring is

reacted with succinic anhydride by a Friedel-Crafts acylation to produce a keto acid which is

reduced to acid 114. It is then intramolecularly cyclized to form 1-tetralone 110. Shimada et al

achieved the conversion of 4-arylbutyric acid 114 to α-Tetralones 110 using catalytic quantity of

Bi(NTf2)3 in good yields11

.

OO O

O

O

OH

O

OHFC

[H]

O

114

110

Scheme 33

Silica-supported silicotungstic acid H4[SiW12O40]/SiO2 was used an efficient catalyst in

the reaction of xylene and γ-butyrolactone for the formation of 5,8-dimethyl-α-tetralone12

115.

CH3

CH3

+ O

O

20% H4SiW12O40

210oC

O

CH3

CH3

115

(equation 37)

William Vera and Ajoy Banerjee prepared a mixture of 5,6-dimethoxy-2-tetralone 117

from 6-methoxy tetralin 116 by oxidation using KMnO4 in acetonitrile13

.

MeO

MeO

MeO

O

KMnO4

CH3CN

MeO

(equation 38)

116 117

4-substituted α-tetralones 119 were prepared by cyclization of aryl cyclopropyl ketones 118

using stannous chloride as catalyst14

O

R1

R2

R1

O

R2

SnCl2

118 119

(equation 39)

4-phenyl-1-tetralone was also prepared by a series of reactions as shown in the Scheme

3415

. The first step is Friedel-Crafts acylation which gives 3-benzoyl propionic acid 120 in good

yield. The next step done was the reductive ring closure of the 120 to give γ-phenyl- γ-

butyrolactone 121. Friedel-Crafts alkylation was used to covert 121 to 4,4-diphenylbutyric acid

122 which was then cyclized using polyphosphoric acid to get 4-phenyl-1-tetralone 123.

+ O

O

O O

OH

OAlCl3NaBH4

O

O

AlCl3C6H6

O

OH

O

PPA,

120

121

122123

Scheme 34

Synthesis of 1-tetralone derivatives 125 was reported by Olah et al16

through superacid-

catalyzed cycli-acyalkylation of aromatics with alkenyl carboxylic acids 124. Triflic acid was

used as the catalyst/medium for the conversion.

R

+

COOH

n

R1

R2

CF3SO3H

O

n

R

R = H, CH3, Cl

R1= H, CH3, Ph

R2= H, CH3

124 125

(equation 40)

PART II

DISCUSSION ON THE

PREPARATION OF

PODOPHYLLOTOXIN DERIVATIVES

4.2.1 Synthesis of α-tetralones (78)

In our strategy of synthesis outlined in chapter II-part I, we had proposed the preparation

of α-tetralones from γ-hydroxy ketones. Based on this, 1-(3,4-Dimethoxyphenyl)-4-hydroxy-4-

phenyl-butan-1-one 77d, and 1-(3,5-dichloro-4-hydroxy-phenyl)-4-hydroxy-4-phenyl-butan-1-

one butanone 77f were converted to the respective tetralones. The cyclization reaction was

accomplished using p-toluene sulphonic acid in nitromethane.

O

R1

R2

R1

R2

OH

O

R3

R3

SO3H

CH3NO2

77 78

(equation 41)

R1 = OMe,R2 = OMe, R3 = Hd

R1 = Cl, R2 = OH, R3 = Clf

4.2.1.1 Discussion on the experiments leading to the synthesis of 4-phenyl-3,4-dihydro-

2H-naphthalen-1-ones (78)

γ-Hydroxy ketones having electro donating groups on the phenyl ring at 1-postion was

selected for accomplishing the desired transformation to α-tetralones. A mixture of hydroxyl

ketone in nitromethane and catalytic amount of p-toluene sulphonic acid was heated at 70oC for

3 hours. The completion of the reaction was monitored using TLC. The reaction was performed

under nitrogen atmosphere. Catalytic quantity of p-toluene sulphonic acid is sufficient for the

transformation. The use of Lewis acid catalysts like zinc chloride and boron trifluoride ethereate

did not give complete conversion. The use of sulphuric acid and triflic acid as catalysts gave

some conversion but resulted in the formation of tars in the system. Hence p-toluene sulphonic

acid was chosen as the catalyst which gave optimum yields and where the isolation of the

product is easy. The use of solvents other than nitromethane hampered the progress of the

reaction. After the completion of reaction, the reaction mixture was diluted with water and

extracted with ethyl acetate. The organic layer was stripped to get the crude product. The crude

product was purified using hexane/ethylacetate (95:5) as the eluent.

The products formed are identified by IR, 1H and

13C-NMR and mass spectra. The IR

spectra showed the absence of characteristic O-H stretching at ~ 3400 cm-1

in the product. The

proton on the C-3 showed signals as a doublet of doublet in the region δ 4.2-4.3 ppm while the

protons on the carbon adjacent to carbonyl gave a triplet in the region of δ 2.5-2.7 ppm as

compared to around 2.9-3.1 in γ-hydroxy ketones. The 13

C-NMR showed signals consistent with

that expected for the molecule.

4.2.2 Preparation of α-bromo derivative of 1-tetralone (79)

Bromination of the 78d and 5,7-dichloro-6-hydroxy-4-phenyl-3,4-dihydro-2H-naphthale-

1-one 78f was carried out in acetonitrile using N-bromo succinimide as the brominating agent.

The conditions adopted are a modification of the reported procedure16

. The bromination

happened selectively at the α position to the carbonyl group of the tetralone. The bromo

derivative 2-bromo-6,7-dimethoxy-4-phenyl-3,4-dihydro-2H-naphthalen-1-one 79d and 2-

bromo-5,7-dichloro-6-hydroxy-4-phenyl-3,4-dihydro-2H-naphthalen-1-one 79f were isolated in

good yields.

O

R1

R2

R3

O

R1

R2

R3

Br

CH3CN

SO3H

NBS,

R1 = OMe,R2 = OMe, R3 = Hd

R1 = Cl, R2 = OH, R3 = Clf

(equation 42)

78 79

4.2.2.1 Discussion on the experiments leading to the preparation of 2-bromo-4-

phenyl-3,4-dihydro-2H-naphthalen-1-ones (79)

The selective bromination was performed using N-bromosuccinimide in acidic medium

in acetonitrile solvent. An optimum temperature of 70oC was maintained for the reaction. p-

toluene sulphonic acid was used in stoichiometric amounts for the reaction. NBS is activated by

the p-toluene sulphonic acid at the carbonyl oxygen thus facilitating the formation of bromonium

ions which leads to the formation of α-bromo tetralones. One equivalent of NBS was used for the

reaction. NBS was added slowly in lots. Single time addition of NBS resulted in formation of

more dibromo derivative. An excess of NBS also resulted in the formation of dibromo derivative.

Ring brominated compounds were not observed in the reaction. The reaction was monitored by

TLC. Trace amounts of starting material remained unreacted after the reaction. This was

removed during crystallization. The reaction mixture after the completion of the reaction was

washed with water and extracted with ethyl acetate. The ethyl acetate layer was evaporated to get

the product which was recrystallized from 10% ethanol in hexane to give the product.

The product identified using 1H and

13C-NMR.

1H NMR showed characteristic doublet of

doublet at δ 4.7-4.8 ppm for hydrogen at the carbon bearing the bromo group. The tertiary

hydrogen at γ-carbon to the carbonyl showed a doublet at δ 4.45-4.48 ppm. 13

C-NMR showed

carbonyl carbon at δ 189.934 ppm. The mass spectrum of showed peaks at M-1, M+1 peaks are

observed in the ratio of 50.5 : 49.5 indicating the presence of bromine atom in the compound.

4.2.3 Preparation of Podophyllotoxin derivative (81)

4.2.3.1 Synthesis of 4-phenyl-4H-naphthale-1-ones (126)

The brominated tetralone was dehydrohalogenated to an α,β-unsaturated ketone, 4-

phenyl-4H-naphthale-1-ones. The reaction was done using sodium-tert-butoxide in THF at

reflux. The product was isolated in good yield and quality. Using this reaction, the bromo

derivatives, 2-bromo-6,7-dimethoxy-4-phenyl-3,4-dihydro-2H-naphthalen-1-one 79d and 2-

bromo-5,7-dichloro-6-hydroxy-4-phenyl-3,4-dihydro-2H-naphthalen-1-one 79f were

dehydrobrominated to give the respective products 6,7-dimethoxy-4-phenyl-4H-naphthalen-1-

one 126d and 5,7-dichloro-6-hydroxy-4-phenyl-4H-naphthalen-1-one 126f.

O

R1

R2

R3

Br

O

R1

R2

R3

79 126

Na-t-butoxide

THF

R1 = OMe,R2 = OMe, R3 = Hd

R1 = Cl, R2 = OH, R3 = Clf

(equation 43)

4.2.3.1.1 Discussion on the experiments leading to the preparation of 4-phenyl-4H-

naphthale-1-ones The

bromo compound was taken in THF and treated sodium tert-butoxide and refluxed for 10 hour.

1.1 equivalents of sodium tert-butoxide was used for 79d while 2.1 moles was used for 79f. The

reaction was done under nitrogen atmosphere. The crude compound from the reaction was

purified by column chromatography using ethyl acetate/hexane (90:10) on silica gel. Use of

milder bases like triethyl amine and sodium carbonate led to lesser yield and incomplete

reaction. Slight excess of sodium tert-butoxide caused faster reaction but lesser yield after

purification. The optimum amount of base was critical for the reaction. THF was found to be the

ideal solvent for the reaction.

The product was identified by 1H-NMR and

13C-NMR and mass spectra and IR spectra.

Mass spectra showed absence of peaks associated with bromine atom. The 1H-NMR showed

signal at δ 6.8-7.1 ppm for the protons across the double bond. The absence of multiplet also at δ

2.6 ppm also confirms the formation of the product.

4.2.3.2 Preparation of 1-phenyl-1,2,3,4-tetrahydronaphthalene-2-carbonitriles (127)

The mixture of 4-phenyl-4H-naphthale-1-ones 126 and tetra butyl ammonium bromide

was treated with dibromomethane and potassium cyanide in THF to get the adduct 127.

Potassium cyanide adds by a 1,4-conugate addition to the double bond of the α,β-unsaturated

ketone to generate the anion which then eliminates bromide ion simultaneously from

dibromomethane to give the product. The reaction was done under nitrogen atmosphere. Slight

excess of dibromomethane was used for the reaction. Using this method, 3-bromomethyl-6,7-

dimethoxy-4-oxo-1-phenyl-1,2,3,4-tetrahydro-naphthalene-2-carbonitrile, 127d and 3-

bromomethyl-6,8-dichloro-7-hydroxy-4-oxo-1-phenyl-1,2,3,4-tetrahydropaphthalene-2-

carbonitrile 127f were obtained in good yields.

O

R1

R2

R3

KCN, CH2Br2

THF

O

R1

R2

R3

Br

CN

126 127R1 = OMe,R2 = OMe, R3 = Hd

R1 = Cl, R2 = OH, R3 = Clf

(equation 44)

4.2.3.2.1 Discussion on the experiments leading to the preparation of

3-bromomethyl-1-phenyl-1,2,3,4-tetrahydronaphthalene-2-carbonitrile

(127)

Potassium cyanide was added to a solution of dibromomethane, 126 and tetra-n-

butylammonium bromide in dry THF under nitrogen atmosphere and kept at 60oC. The reaction

was monitored by TLC. The product obtained was purified by column chromatography on silica

gel using hexane/ ethyl acetate (80:20). THF is thoroughly dried before use in the reaction.

The products are identified by NMR and mass spectra. 1H-NMR did not show signals at δ

6.8 ppm indicative of the absence of double bond protons. It showed a doublet at δ 3.5 ppm for

the protons on carbon bearing the bromine atom. 13

C-NMR shows signals at δ 119.3 ppm

indicates the presence of the cyanide group. The carbonyl group is intact at δ 200.4 ppm.

4.2.3.3 Preparation of tetrahydro-naphtho[2,3-c]furan-1,4-diones (81)

The phenyl-1,2,3,4-tetrahydropaphthalene-2-carbonitrile on hydrolysis gave the required

podophyllotoxin derivative 81. The reaction is accomplished in sulphuric acid and water mixture

at 90oC. The nitrile group is hydrolyzed to the acid which combines with the hydroxyl group

formed from the hydrolysis of the bromo group at C-3 to from the lactone. The compounds

prepared by this are 81d and 81f.

O

R1

R2

R3

Br

CN

H2SO4/H2O

O

R1

R2

R3

O

O

127 81

R1 = OMe,R2 = OMe, R3 = Hd

R1 = Cl, R2 = OH, R3 = Clf

(equation 45)

4.2.3.3.1 Discussion on the experiments leading to the preparation of tetrahydro-

naphtho[2,3-c]furan-1,4-diones

The 3-bromomethyl-1-phenyl-1,2,3,4-tetrahydronaphthalene-2-carbonitrile was added to

20% sulphuric acid in and refluxed for 15 hours. The reaction mixture was poured into ice and

extracted with ethyl acetate. The crude compound is purified by column chromatography on

silica gel using ethyacetate/hexane (80: 20).

IR spectra showed two strong carbonyl absorptions, one at 1755 cm-1

attributed to the

lactone ring and the other at 1635 cm-1

attributed to a benzylic carbonyl group. 1H-NMR of the

compound shows signals of doublet at δ 4.5 ppm and at δ 4.7 ppm indicating the protons at C-1

and C-9. Multiplets are seen at δ 3.5 ppm which indicates the protons on the carbon in the

tetrahydro naphthalene ring system. 13

C-NMR shows signals as singlet at δ 176 ppm pertaining

to the carbonyl group of the lactone moiety while the carbonyl on the tetralone ring shows as

singlet at δ 200.7 ppm.

4.2.4 Preparation of thiazole derivative (82)

Literature reveals that thiazole moiety incorporated in the molecule adds to the

theraupetic effect of the molecule17,18

. This prompted us to synthesize podophyllotoxin

derivatives with amino-thiazolyl groups attached to the aryl tetralin ring system.

O

R1

R2

R3

BrR1

R2

R3

S

N

NH2

NH2-C(S)-NH2

DMF, rt

7982

R1 = OMe,R2 = OMe, R3 = Hd

R1 = Cl, R2 = OH, R3 = Clf

(equation 46)

Using this reaction, 7,8-dimethoxy-5-phenyl-4,5-dihydro-naphtha[1,2-d] thiazol-2-yl

amine 82d and 2-amino-6,8-dichloro-5-phenyl-4,5-dihydro-naphtho[1,2-d] thiazol-7-ol 82f are

prepared in good quality and yields. The reaction was performed by a modification of the

procedure reported for simple molecules19

.

4.2.4.1 Discussion on the experiments leading to the preparation of substituted

5-phenyl-4,5-dihydro-naphtha[1,2-d] thiazol-2-yl amines (82)

The bromo compounds 79d and 79f were reacted with thiourea in dimethylformamide at

ambient conditions to afford 5-phenyl-4,5-dihydro-naphtha[1,2-d] thiazol-2-yl amines. The

chloro group, hydroxyl and the methoxy group in the benzene ring were unaffected in the

reaction. The reaction happened with one equivalent of thiourea for 10 hours. The reaction

mixture after the reaction was added to a mixture of ethyl acetate and water and the layer

separated. The ethyl acetate layer was evaporated to get the crude product which was

recrystallized from 10% ethanol in hexane to give crystallized product.

The formation of the product was identified by 1H and

13C-NMR.

1H-NMR shows absence of

signal corresponding to α-carbon in the tetralin ring. It shows a broad signal at δ 5.2-5.3 ppm

corresponding to the amino group in the thiazole ring system. 13

C-NMR shows signals at δ 166

ppm corresponding to the carbon bearing the amino group in the thiazole ring system. Mass

spectrum of 7,8-dimethoxy-5-phenyl-4,5-dihydro-naphtha[1,2-d] thiazol-2-yl amine shows

corresponding to M+1 at 339 while the mass spectrum values for 2-amino-6,8-dichloro-5-

phenyl-4,5-dihydro-naphtho[1,2-d] thiazol-7-ol shows M+, M+2 and M+1 in the ratio of

100:68:19 at 363, 365 and 364 respectively.

4.2.5 Preparation of chalcone derivative (80)

Chalcones are compounds which shows good biological activity20

. This formed the basis

for preparing podophyllotoxin derivatives having chalcone group in the molecule. The 4-phenyl-

1-tetralone 78d, 78f moieties prepared from 1,2-dimethoxybenzene and 2,6-dichlorophenol were

subjected to a chalcone preparation reaction using benzaldehyde and sodium hydroxide in

ethanol. The podophyllotoxin derivatives prepared are 2-benzylidene-6,7-dimethoxy-4-phenyl-

3,4-dihydro-2H-naphthalen-1-one 80d and 2-benzylidene-5,7-dichloro-6-hydroxy-4-phenyl-3,4-

dihydro-2H-naphthalen-1-one 80f.

O

R1

R2

R3

O

R1

R2

R3

+

CHO

NaOH

EtOH

78 80

R1 = OMe,R2 = OMe, R3 = Hd

R1 = Cl, R2 = OH, R3 = Clf

(equation 47)

4.2.5.1 Discussion on the experiments leading to the preparation of 2-benzylidene-6,7-

dimethoxy-4-phenyl-3,4-dihydro-2H-naphthalen-1-one (80)

The α-tetralones reactions were reacted with 1 equivalent of benzaldehyde and 2 or more

equivalent of NaOH in ethanol to give 2-benylidene derivatives. 2 equivalents of NaOH was

used for 6,7-dimethoxy-4-phenyl-3,4-dihydro-2H-naphthalen-1-one 78d while 3 equivalents

were used for 5,7-dichloro-6-hydroxy-4-phenyl-3,4-dihydro-2H-naphthale-1-one 78f. The

reactions were carried out at room temperature. More equivalents of NaOH resulted in the

formation of Cannizaro’s product of benzaldehyde as the side product. The completion of the

reaction was monitored by TLC. After the reaction, in the case of 78f the product was acidified

with 20% HCl to pH=4 and then extracted with ethyl acetate while in case of 78d product was

added to more water and extracted with ethyl acetate. The ethyl acetate layer was washed with

brine till neutral pH and evaporated to give the crude product. The crude products was purified

by column chromatography on silica gel using hexane/ethyl acetate (80:20) as the eluent.

The product was characterized by 1H,

13C-NMR and Mass spectra.

1H-NMR showed a singlet at

δ 7.8 ppm corresponding to the proton on the benzylidene carbon. 1H-NMR also shows doublet

of the doublet corresponding to the proton on C-3 in the range of δ 3.2 to 3.4 ppm for 6e and 6g.

13C-NMR shows signal corresponding to the carbonyl carbon at δ 187 ppm. Mass spectra of the

compound shows molecular ion peak consistent with the mass corresponding to the compounds.

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