1. introduction - shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/20757/15/9.chapter ii.pdf ·...

Chapter II

41

1. INTRODUCTION

Hydroxymethylation of organic compounds leads to the introduction of a

–CH2OH function. The reaction is generally carried out using aqueous

formaldehyde (formalin 37-41%) in alcoholic solvents. This reaction has also

been employed as tool for one carbon homologation in the generation of

nitrogen heterocycles. Hydroxymethylation has been a reaction of biological

interest since it is observed in biosynthetic pathways of many alkaloids. A

survey of hydroxymethylation reported in coumarins, imidazoles,

benzimidazoles and its application is presented as follows.

A. Hydroxymethylation of coumarins:

Hydroxymethylation of 4-hydroxycoumarin 1 leads to the synthesis of well

known anti-coagulant dicoumarol 2 [1].

O

OH

O

2 HCHO

O

OH

O

CH2

OO

OH

1 2

Hydroxymethylation of 7-hydroxy coumarin 3 has lead to the formation of

7-hydroxy-8-formyl coumarin 4 [2].

OHO

CH3

O OHO

CH3

O OHO

CH3

O

HMTA

AcOH

CH2OH CHO

3 4

Formaldehyde along with dry HCl in presence of fused ZnCl2 has been

employed for the preparation of 3-chloromethyl coumarin 5 [3].

Chapter II

42

O

CH3

H3C

O O

CH3

H3C

O O

CH3

H3C

O

CH2OH CH2ClHCHO

ZnCl2

5

B. Hydroxymethylation of structurally related heterocycles:

Hydroxymethylation of nitrogen heterocycles gained medicinal importance

since they were found to be prodrugs of allopurinols 6, 7 glutethimide 8 and

phenobarbital 9 [4].

O

NN

N

N

O

NN

N

NH

HOH2CHOH2C

CH2OHHN

NO

O

O

CH2OH

N

O

O

HOH2C

1-hydroxymethyl allopurinol

1,5-dihydroxymethyl allopurinol

1-hydroxymethyl phenobarbital

1-hydroxymethyl glutethimide

6 7 8 9

Hydroxymethylation of imidazole was found to be sensitive to the substituents

in the imidazole ring. N-alkyl, N-arylalkyl imidazoles 10 underwent

hydroxymethylation at C2 resulting in 2-hydroxymethyl imidazoles 11, whereas

5-substituted imidazoles 12 resulted in 4-hydroxymethyl 5 substituted

imidazoles 13 [5].

N

N

R

CH2O N

N

R OH

10 11

N

N

H

N

N

H

HO

RR

CH2O

12 13

Chapter II

43

Unusual hydroxymethylation of 2-amino-4-thiazolinones 14 was reported by

Ramesh and Ivanenko [6] where in they observed C-hydroxymethylation in

presence of two nucleophilic nitrogens resulting in 2-amino-5,5-bis

(hydroxymethyl) thiazolinone 15.

S

NO

H2N S

NO

H2N

CH2O

CH2OH

CH2OHNEt3

14 15

Nd(OTf)3 catalyzed hydroxymethylation of 3-substituted Indolinones 16

resulted in enantioselective synthesis of 17.

NH

O

R1

R2

NO

R1OH

R2

OH

aq.HCHO (2eq)

Nd(OTf)3

16 17

Hydroxymethylation of imidazole 18 using formaldehyde in a sealed tube at

about 120-130 °C resulted in mixture of imidazoles 19, 20, 21, 22 with

hydroxymethyl groups at different positions [8].

N

NH

N

N

N

NN

NHCH2OH

CH2OH

CH2OHCH2OH

HOH2C

HOH2C

CH2O

H2O/100 0C

N

NH

CH2OH

18 19 20 21

22

-CH2O

Hydroxymethylation of 1-(2-hydroxyethyl), 1-(2-acetoxyethyl), and 1-(2-

chloroethyl) substituted 5-nitroimidazoles 23 with paraformaldehyde in

dimethyl sulfoxide yielded the respective 2-hydroxymethyl analogs 24 [9].

Chapter II

44

N

NR

HOH2CN

NR

NO2Paraformaldehyde

DMSO

R= -OH, -CN, CH3COO-

23 24

NO2

N-hydroxymethylated benzimidazole 26 was obtained by the reaction of

benzimidazole 25 with 37% formalin in presence of methanol [10].

NH

N

N

N

CH2OH

HCHO

Reflux

25 26

Reaction of 2-hydroxybenzimidazole/2-mercaptobenzimidazole 27 with

formaldehyde resulted in the hydroxymethylation at both the nitrogens

resulting in the formation of 1,3-Bis (hydroxymethy) benzimidazolone/thione

28 [11,12]. At higher temperature compounds exhibit thermal extrusion of

formaldehyde leading to the formation of benzimidazolin-2-one 27 [13].

NH

HN

XN

NX

CH2OH

HCHO

H2O, reflux

CH2OH

X= S,O

NH

HN

X + 2 HCHO

27 28

C. Application in the construction of N-heterocycles.

Reaction of imidazoisoquinolones with formaldehyde gave expected

symmetrical heterocycle 29 and more complex polycyclic heterocycle 30

which was formed by hetero Diel’s Alder reaction of two units of azadiene [14]

28.

Chapter II

45

N

NH

O

N

N

O

N

N

O

CH2CH2+

N

N

N

N

O

O

CH2O

28

29

30

A hydroxymethylation-Cyclization route was employed [15] for the synthesis

of quinolone antibacterials Pyrido[3,2,1-ij]-1,3,4-benzoxadiazines 34. Reaction

of 6,7,8-Trifluoro-1-(methylamino) quinoline 31 with aqueous

paraformaldehyde resulted in hydroxymethylated quinoline 32 which was

cyclized using Bu4NF/THF resulting in pyrido benzoxadiazine derivative 33.

Further introduction of (S) or (R) 3-aminopyridine at C7 afforded

pyridobenzoxadiazines.

F

F

F

N

O

CO2Et

NHCH3

Paraformaldehyde

H2O, reflux, 36h, > 90%N

O

NCH3

F

F

F

CO2Et

OH

F

F

O

N

O

CO2Et

NCH3

Bu4NF/THF additionreflux, 20 min, 60%

F

N

O

N

O

CO2Et

NCH3

NH

H3COCHN

1. Pyr,reflux

2. HCl, H2O, rt to 80 0C

H2N*

*

R / S

31 32

3334

Chapter II

46

Total synthesis of (±) Solidaline 35 was achieved [16] by photochemical

hydroxymethylation, wherein introduction of hydroxymethyl group was

achieved by photoaddition of methanol.

N

MeO

MeO

MeOMe

OMe

Cl-

N

OMe

OMe

MeO

MeO

R1

R2

O

1) hv, MeOH/HCl

2) O2/MeOH/H2O/ pH= 6

R1= Me, R2= OHR1= OH, R2= Me

35

Recently, we have also applied hydroxymethylation as a tool for one carbon

homologation to construct coumarin analogues of protoberberine alkaloids [17]

36.

NH

R1

R2

O

OH

N

R1

R2

O

O

HCHO,AcOH Reflux

R R

36

In the light of these observations, it was thought of considerable interest to

study the hydroxymethylation of 2-(4'-coumarinomethyl) benzimidazoles. The

synthetic aspects and the results obtained are presented in the next section.

Chapter II

47

2. PRESENT WORK AND DISCUSSION

2A. Hydroxymethylation of 2-(4'-coumarinomethyl) benzimidazoles:

The required 2-(4'-coumarinomethyl) benzimidazoles were synthesized by the

reaction of coumarin-4-acetic acids [18] 1 and ortho phenylenediamine 2 to

obtain intermediates 3.

The purpose of hydroxymethylation of these intermediates was to obtain cyclic

systems 4 via N-hydroxymethylated intermediate 3A.

O

COOH

OR

Anhydrous H3PO4

170-180 0C

HCHO/Ethanol

H2N

H2N

31 2

O O

NH

N

R

3A

O O

N

N

ROH

O O

N

HN

R

Expected

-H2O

4

O O

N

N

R

Expected

4A

Scheme 1: Expected hydroxymethylation of compound 3.

Reaction of 1 and 2 was accomplished in orthophosphoric acid around

170-180 °C since the reactants were insoluble in dil HCl. The product obtained

3 (R= 6-CH3) was characterized by spectral data. IR spectrum was

characterized by the presence of bands at 1725 cm-1 (lactone carbonyl) and

3311 cm-1 (benzimidazole N-H). The 1H-NMR indicated CH3, CH2 protons as

singlets at 2.33 and 4.46 ppm. The aromatic protons resonated in the region

7.16-7.68 ppm and the exchangeable NH proton appeared at 12.39 ppm. The

singlet observed at 6.43 ppm was assigned to C3-H of coumarin.

Chapter II

48

Compound 3a when reacted with aq. HCHO in ethanol under reflux condition

afforded a product which was purified by crystallization. The spectral features

of this product were not in agreement with structure 4 (Scheme 1). Structure 4

requires the absence of C3-H around 6.50 ppm, absence of exchangeable N-H

protons and a new signal for the N-CH2 protons. However, the spectral features

for the observed compound 6a indicated the presence of C3-H at 6.50 and an

exchangeable proton at 12.68 ppm (Spectrum Nos. 2&3). Further, two singlets

were observed at 5.87 and 6.61 ppm. The 13C-DEPT spectrum (Spectrum No.

4) indicated a CH2 carbon at 122.4 ppm. These features could be accounted by

the hydroxymethylation at the C4-methylene group followed by dehydration

which is shown as follows:

HCHO/Ethanol

R= 6-CH3, 7-CH3, 7-OH, 7,8-CH3, 7,8-Benzo

-H2O

3

6 (a-d)

5

O O

NH

N

R

O O

NH

N

R

OH

H

O O

NH

N

R

H

H

Observed

O O

NH

N

R

OH

Reflux

R= 6-CH3, 7-CH3, 7,8-CH3, 7,8-Benzo

HCHO/DMF

MW

5 (a-d)

Scheme 2: Hydroxymethylation of 2-(4'-coumarinomethyl) benzimidazoles 3.

The methylene protons did not show any geminal coupling though exhibited

different chemical shifts in view of their diastereotopic nature. This was

Chapter II

49

confirmed by the HETCOR spectrum (Spectrum No. 5) wherein the two

singlets at 5.87 and 6.61 ppm correlated with the 13C signal at 122.4 ppm. The

generation of a conjugated double bond is also supported by bathochromic shift

in absorption band (compound 3d) from 278 nm (14,528) to (compound 6d)

296 nm (26,455). Formation of compound 6a was further confirmed by the

molecular ion at m/z 302 (Spectrum No. 1).

O O

NH

NH

H

H3C H

5.87

6.60

6.57

12.69

7.16, t, J = 7.6 Hz

7.21, t, J = 7.6 Hz

7.37, d, J = 8.8 Hz

7.42, d, J = 8.8 Hz

7.08

7.46, d, J = 7.6 Hz

7.56, d, J = 8.0 Hz

2.19

H H

H

H

H

H

Fig. 1: 1H-NMR spectral assignment for compound 6a.

O O

NH

NH

H

H3C H

122.40 5.87

6.60

6.50

116.47

Fig. 2: 13C-1H correlations observed for =CH2, and C3-H fragments (6a).

NOE studies:

Irradiation of signal at 5.82 ppm in compound 6c resulted in the enhancement

of peaks at 6.55 and 6.25 ppm, which indicates that one of vinylic protons at

5.82 ppm is in spatial proximity with C3-H of coumarin. Irradiation of signal at

6.55 ppm enhanced only one signal at 5.82 ppm which indicated that the other

vinylic proton is not in close proximity with any of the ring protons.

Chapter II

50

H

H

O

HN N

O

HO

H

5.82

6.55

6.25

Fig. 3: NOE for the protons in compound 6c.

Irradiation of signal at 12.66 ppm and observing peak at 6.25 ppm and vice

versa did not indicate any NOE enhancement. This is readily explained by the

optimal structure. Due to steric repulsion the coumarin and benzimidazole

moieties are nearly perpendicular to each other. The distance between these

pair of hydrogen atoms is rather long, of the order of 3.69 Å which is too high

for NOE observation, as revealed by the optimized geometry of the compound

6a.

Fig.4: Optimized geometry of compound 6a.

2B. Microwave assisted hydroxymethylation of 2-(4'-coumarinomethyl)

Benzimidazoles.

In view of the longer hours of refluxing time needed for hydroxymethylation in

alcoholic solvents, the present reaction was attempted in domestic microwave

oven. Initial attempts resulted in total evaporation of the solvent without any

Chapter II

51

reaction. Hence high boiling solvent like DMF was employed in the reaction

(Scheme 2).

The products obtained were compared with the two possible products of

N-hydroxymethylation and C-hydroxymethylation followed by dehydration

(Compound 6). But the product obtained did not match either of the products.

In the 1H-NMR, N-H (5a, R= 6-CH3) (Spectrum No. 6) and C3-H were

observed at 12.32 and 6.47 ppm respectively which eliminated the possibility

of N-hydroxymethylation and ring closure (Compound 4). Absence of singlets

at 5.87 and 6.61 ppm ruled out the possibility of formation of product 6.

The 1H-NMR exhibited (Spectrum No. 7) two triplets (Fig. 4) corresponding to

one proton each at 4.85 (J = 6.4 Hz) and 5.21 (J = 5.6 Hz). Triplet at 5.21

ppmis assigned to –OH which is D2O exchangeable and triplet at 4.85 is due to

C4-H. Two doublet of doublet of doublets observed for methylene protons at

4.08 (Jvic(CH) = 6.4 Hz, Jvic(OH)= 5.6 Hz, Jgem = 11.2 Hz) and 4.17 ppm ( Jvic(CH) =

6.0, Jvic(OH)= 5.2 Hz, Jgem = 11.2 Hz) due to the geminal coupling and vicinal

coupling with –OH and C4-H protons. The multiplicity of these peaks changes

(Spectrum No. 8) to two doublet of doublets at 4.08 (dd, 1H, Jvic(CH) = 6.8 Hz,

Jgem= 10.8 Hz) and 4.15 ppm (dd, 1H, Jvic(CH) = 6.8 Hz, Jgem= 10.8 Hz) after

deuterium exchange (Fig. 5) indicating that these protons are coupled to the

triplet at 5.21 ppm. Aromatic protons resonated at expected region between

7.12 7.82 ppm.

In 13C-NMR (5b, R= 7-CH3), carbonyl carbon observed at 159.96 ppm, and 7-

CH3 carbon resonated at 20.87 ppm (Spectrum No. 9). HETCOR

measurements (Spectrum No. 10) confirmed that the doublet of doublet of

doublets at 4.13 and 4.22 ppm are due to CH2 protons. 13C-DEPT spectrum

(Spectrum No. 11) confirmed the presence of –CH2 at 62.37 ppm. C3-H

resonated at 6.48 ppm and peak at 2.39 ppm attributed to 7-CH3 protons.

These observations led us to conclude that the product formed in the

microwave reaction is C-hydroxymethylated product without dehydration.

Chapter II

52

Formation of the product is further supported by –OH stretching at 3324 cm-1,

and the molecular ion peak at m/z 321 (M+H)+.

O O

NH

N

HH

HH

H

H

H

H

H3C

OHH

H

2.32

4.08, ddd,

Jvic (CH) = 6.4 Hz

Jvic (OH) = 5.6 Hz

Jgem = 11.2 Hz

4.17, ddd, Jvic (CH) = 6.0,Hz

Jvic (OH) = 5.2 Hz

Jgem = 11.2 Hz 4.85, t, 1H, J = 6.4 Hz

6.47

5.21, t, 1H, J = 5.6 Hz

12.34, D2O exchangeable

7.11, dd, J = 1. 2, 6.0 Hz

7.28 d, 1H, J = 8.4 Hz

7.40, d, 1H, J = 8.4 Hz

7.55 m, 2H, C4&7-H benzimidazole

Fig. 4: 1H NMR Spectral assignment for compound 6a.

O O

ND

N

HHH3C

ODH

H

4.08, dd, Jvic (CH) = 6.8 HzJgem = 10.8 Hz

4.15, dd, Jvic (CH) = 6.8 Hz

Jgem = 10.8 Hz 4.85, t, 1H, J = 6.8 Hz

Fig. 5: 1H- NMR after D2O exchange for compound 6a.

2C. Hydroxymethylation of 2-(4'-coumarinomethyl) Benzthiazoles and

Benzoxazoles.

In continuation of our work on hydroxymethylation of coumarinomethyl

benzimidazoles, in order to generalize the reaction and to observe the effect of

hydroxymethylation on other similar systems, we have synthesized substituted

2-(4'-coumarinomethyl) benzthiazoles and benzoxazoles, and attempted the

hydroxymethylation under both reflux and domestic MW conditions.

Chapter II

53

2-(4'-coumarinomethyl) benzthiazoles 7a-7c and benzoxazoles 7d-7g have

been synthesized from substituted coumarin-4-acetic acids 1 and

2- aminothiophenol 2b and 2-aminophenol 2c respectively, by heating the

mixture in anhydrous phosphoric acid, resulted syrupy liquid was quenched in

ice cold water and basified carefully with liquor ammonia to get the

intermediate 7.

Compound 7a-7g when reacted with aq. HCHO in ethanol under reflux

condition afforded products which were purified by crystallization and

chromatographic techniques. When the same reaction was attempted in

domestic MW conditions, the product obtained were identical with that

obtained under thermal conditions (Scheme 3).

O

COOH

OR

Anhydrous H3PO4

170-180 0C

H2N

X

71

O O

X

N

R

8

O O

X

N

R

H

X= S,O

OH

Reflux or MW

HCHO

(a-g)

(a-g)

2b,2c

Scheme 3: Synthesis and Hydroxymethylation of compounds 7.

The product 2-(4'-coumarinomethyl) benzothiazoles 7a (R = 6-CH3, X= S) was

characterized by spectral data. IR spectrum indicated the presence of lactone

carbonyl at 1712 cm-1. 1H-NMR indicated CH3, CH2 protons as singlets at 2.39

and 4.78 ppm respectively. Aromatic protons resonated in the region of 7.32-

Chapter II

54

8.05 ppm. The singlet observed at 6.54 ppm was assigned to C3-H of coumarin.

Molecular ion peak was observed at m/z 307.

The product 2-(4'-coumarinomethyl) Benzoxazole 7d (R= 6-CH3, X= O) was

characterized by spectral data. IR spectrum indicated the presence of lactone

carbonyl at 1729 cm-1. In 1H-NMR (Spectrum No. 12), 6-CH3 protons resonated

as singlet at 2.61 ppm, CH2 protons resonated at 4.40 ppm and peak at 6.42

ppm is due to C3-H of coumarin. Aromatic protons resonated between 7.24-

7.70 ppm. Molecular ion peak was observed at m/z 291.

Compounds 7a-7g when reacted with aq. HCHO in ethanol under reflux/MW

conditions afforded products, which were purified by crystallization and

chromatographic techniques. The spectral pattern of compounds 8a-8g

resembled that of hydroxymethylated products of 2-(4'-coumarinomethyl)

benzimidazoles 5a-5d. For compound 8c (R= 7,8-CH3) (Fig. 6), in 1H-NMR

(Spectrum No. 12), OH proton was observed at 5.35 ppm as a triplet (D2O

exchangeable), C4-H resonated as triplet at 5.17 ppm and CH2 protons observed

as two doublet of doublet of doublets at 4.17 (Jvic (CH) = 6.0 Hz, Jvic(OH)=5.6 Hz,

Jgem = 11.2 Hz) and 4.23 (1H, Jvic(CH) = 6.4 Hz, Jvic (OH)=6.0 Hz, Jgem = 11.2 Hz)

ppm, due to geminal coupling and vicinal coupling with C4-H and –OH

protons, the multiplicity of which changes to doublet of doublets after

deuterium exchange (Fig. 7). Peak at 6.55 ppm was due to C3 proton and

aromatic protons resonated between 7.16-8.04 ppm. Molecular ion peak at

(m/z) 352 (M+H) + confirmed the formation of the compound.

Chapter II

55

Fig. 6: 1H NMR Spectral assignment for compound 8c.

Fig. 7: 1H- NMR after D2O exchange for compound 8c.

Spectral data for representative benzoxazole derivative 8d (R= 6-CH3, X= O)

(Fig.8) indicated (Spectrum No. 13) that D2O exchangeable -OH resonated at

5.31 ppm as a triplet, C4-H observed at 5.05 ppm as triplet. Similar to

benzothiophene analog, methylene protons observed as two doublet of doublet

of doublets at 4.14 (Jvic (CH) = 5.6 Hz, Jvic (OH)= 6.0, Hz, Jgem = 11.4 Hz) and 4.22

ppm (Jvic (CH) = 6.4 Hz, Jvic (OH)=5.6 Hz, Jgem = 11.4 Hz), the multiplicity of

which changes to doublet of doublets after deuterium exchange (Spectrum No.

14) (Fig. 9). C3-H resonated as singlet at 6.47 ppm. Aromatic protons were

observed in the expected region between 7.30-7.74 ppm.

O O

S

N

H

CH3

H3C

4.15, dd

Jvic (CH) = 6.0 Hz

Jgem = 11.2 Hz

4.21, ddJvic (CH) = 6.4,Hz

Jgem = 11.2 Hz

5.17, t, J = 6.4 HzHO

HH

O O

S

N

HH

HH

H

H

CH3

H3C

H

4.17, ddd,

Jvic (CH) = 6.0Hz

Jvic (OH)= 5.6 Hz

Jgem = 11.2 Hz4.23, ddd, Jvic (CH) = 6.4,Hz Jvic (OH) = 6.0 Hz

Jge m = 11.2 Hz

5.17, t, J = 6.4 Hz

6.55

5.35, t, J = 5.6 Hz

HO

HH

H

2.27, 2.32

7.16, d, J = 8.0 Hz

7.67, d, J = 8.0 Hz

7.39, dt, J =1.2, 7.6 Hz

7.48, dt, J =1.2, 7.6 Hz

7.97d, J = 7.6 Hz

8.04, d, J = 7.6 Hz

Chapter II

56

In IR spectrum, lactone carbonyl stretching observed at 1692 cm-1 and –OH

stretching band appeared at 3377 cm-1. Molecular ion peak at m/z 321

confirmed the formation of the compound (Spectrum No. 15).

O O

O

N

HH

HH

H

H

H

H

H3C

OHH

H

2.33

4.14, ddd

Jvic (CH) = 5.6Hz

Jgem = 11.4 Hz

Jvic(OH) = 6.0 Hz

4.22, ddd Jvic (CH) = 6.4,Hz

Jvic (OH) = 5.6 Hz

Jgem = 11.4 Hz 5.05, t, J = 6.4 Hz

6.47

5.31, t, J = 5.6 Hz

7.33-7.36, m

7.42, dd, J = 1.2, 8.4 Hz

7.30, d, J = 8.4 Hz

7.65-7.74 m, C4&7 H Benzoxazole7.70 , bs, 1H, C5-H coumarin

Fig. 8: 1H-NMR Spectral assignment for compound 8d.

O O

O

N

HH3C

ODH

H

2.33

4.14, dd

Jvic (CH) = 6.4 Hz

Jgem = 10.8 Hz

4.22, dddJvic (CH) = 6.4 Hz

Jvic (OH) = 5.6 Hz

Jgem = 11.4 Hz 5.05, t, J = 6.4 Hz

Fig. 9: 1H-NMR after D2O exchange for compound 5a.

The spectral features indicated that the products formed are hydroxymethylated

product without dehydration, unlike coumarinomethyl benzimidazoles,

wherein, under thermal condition dehydration is observed. Extended hours of

refluxing did not aid dehydration.

Chapter II

57

2D. Theoretical and Spectroscopic studies [19]:

The preference for C-hydroxymethylation over N-hydroxymethylation in these

compounds has been investigated by molecular modeling and UV visible

studies which have been centered on the stabilities of the intermediates and

products.

Stability of Intermediates:

Out of two possible intermediates A and B, the C-hydroxymethylated

intermediate A is more favoured, since it is stabilized by an intramolecular

O-H…..N hydrogen bonding via a six membered ring. This has been

confirmed by DFT calculations which has been estimated the difference to be

of the order of 2.9 kcal/mol. If the solvent effects are taken into account with

polarizable continuum method (PMC) approximation the difference increases

to about 5 kcal/mole in methanol. The most stable structures of these

intermediates are indicated in Fig. 10.

A B

+0.0 kcal/mol 2.9 kcal/mol

O N

N

OH

HH

O

CH3

H....

H

A

N

N

O

O

HH

O

H3C

H

HH

B

Fig. 10: Possible intermediates of hydroxymethylation.

Chapter II

58

Stability of products:

The expected cyclized product in this sequence is 4 which can exist as a more

stable tautomer 4A by a 1,3-prototropic shift from N to C leading to generation

of a tautomer which possesses a double bond which is conjugated with C3-C4 of

coumarin. The actual product obtained 6 is from the dehydration of the

C4-hydroxymethyl compound. Different theoretical models have been used to

estimate the energies of the three compounds (Table 1).

Table 1: Total (Hartree) energies of isomers at different level of theory.

Method

O O

N

HN

R

4A O O

N

N

R

4 O O

NH

N

R

H

H

6

HF 09.3 0.0 17.3 MP2 14.6 0.0 19.5 MP3 13.6 0.0 19.7 MP4D 15.3 0.0 19.2 MP4DQ 14.8 0.0 19.3 CC(D) 14.7 0.0 19.4 B3LYP 5.54 0.0 15.4

All the methods indicated that the presently formed compound is high in

energy than the other two compounds. It is likely that the greater stability of the

C-hydroxymethylated intermediate is the driving force in this reaction.

UV-spectral Studies:

The precursor showed two bands around 242 and 278 nm in EtOH (Fig. 11).

The product exhibited a broad band around 296 nm (Fig. 12). A structural

comparison indicates that a bathochromic shift observed in the latter compound

is actually due to the extension of conjugation. Calculated wavelength for the

product (Fig. 13) matches with that of the observed bathochromic shift, which

supports the proposed product 6.

Chapter II

59

Fig. 11: UV spectrum of Intermediate 3d.

Fig. 12: Experimental UV spectrum of product 6a.

Fig. 13: Calculated UV spectrum of Compound 6a.

TD spectrum

Wavelength, nm

370 360 350 340 330 320 310 300 290 280 270 260 250 240 230 220 210 200

f

0,5

0,48

0,46

0,44

0,42

0,4

0,38

0,36

0,34

0,32

0,3

0,28

0,26

0,24

0,22

0,2

0,18

0,16

0,14

0,12

0,1

0,08

0,06

0,04

0,02

0

295

Wavelenght (nm)

Wavelenght (nm)

Inte

nsity

Inte

nsity

Chapter II

60

Sp

ectr

um

No

. 1

: Mas

s S

pect

rum

of

Com

poun

d 6a

.

Chapter II

61

Sp

ectr

um

No.

2: 1 H

-NM

R o

f C

ompo

und

6a

.

Solv

ent:

DM

SO-d

6

Chapter II

62

Sp

ectr

um

No

. 3

: 1 H-N

MR

of

Com

poun

d 6a

(E

xpan

sion

).

Solv

ent:

DM

SO-d

6

Chapter II

63

Sp

ectr

um

No.

4: 13

C D

EPT

-NM

R o

f C

ompo

und

6a

.

Solv

ent:

DM

SO-d

6

Chapter II

64

O O

NH

NH

H

H3C H

122.40 5.87

6.60

6.57

116.47

Spectrum No. 5: 1H -13C HETCOR of Compound 6a.

Chapter II

65

Sp

ectr

um

No.

6: 1 H

-NM

R o

f C

ompo

und

5a

.Solv

ent:

DM

SO-d

6

Chapter II

66

Sp

ectr

um

No.

7:

1 H-N

MR

of

Com

poun

d 5a

(E

xpan

sion

).

Chapter II

67

Sp

ectr

um

No

. 8

: 1 H

-NM

R o

f co

mpo

und

5a

(E

xpan

sion

) (A

fter

D2O

Exc

hang

e).

Chapter II

68

Sp

ectr

um

No.

9:

13C

-NM

R o

f co

mpo

und

5b

.

Solv

ent:

DM

SO-d

6

Chapter II

69

O O

NH

N

H3C

HHO

H H

62.63

43.41

4.85

4.13, 4.22

Spectrum No. 10: 1H -13C HETCOR of Compound 5b.

Chapter II

70

Sp

ectr

um

No

. 11

: 13C

DE

PT-N

MR

of

Com

poun

d 5

b.So

lven

t: D

MSO

-d6

Chapter II

71

Solv

ent:

DM

SO-d

6

Sp

ectr

um

No

. 1

2:

1 H-N

MR

of

Com

poun

d 8

c.

Chapter II

72

Solv

ent:

DM

SO-d

6

Sp

ectr

um

No.

13

: 1 H

-NM

R o

f C

ompo

und

8d

.

Chapter II

73

Sp

ectr

um

No.

14

: 1 H

-NM

R o

f C

ompo

und

8d

(E

xpan

sion

).

Chapter II

74

-+

Sp

ectr

um

No

. 15

: M

ass

spec

trum

of

Com

poun

d 8

d.

Chapter II

75

3. EXPERIMENTAL:

Melting points were determined in open capillaries and are uncorrected. IR

spectra (KBr disc) were recorded on a Nicolet-5700 FT-IR spectrophotometer. 1H NMR spectra were recorded on Bruker 300 and 400 MHz spectrometers

using and DMSO -d6 as solvent and TMS as an internal standard. The chemical

shifts are expressed in δ ppm. Mass spectra were recorded using Shimadzu

GCMS-QP2010S. Elemental analyses were carried out using Hereaus CHN

rapid analyzer. The purity of the compounds was checked by TLC.

Synthesis of coumarin-4-acetic acids:

Coumarin-4-acetic acids have been synthesized by literature method [18] by

the cyclisation of phenols and citric acid monohydrate using sulfuric acid as the

cyclising agent.

General procedure: Synthesis of 4-((1H-benzo[d]imidazol-2-yl) methyl)-

2H-chromen-2-ones 3:

Procedure is given in the experimental section chapter I

4-((1H-benzo[d]imidazol-2-yl) methyl)-6-methyl-2H-chromen-2-one 3a:

Details of the compound is given in the experimental section chapter I

4-((1H-benzo[d]imidazol-2-yl ) methyl)-7-methyl-2H-chromen-2-one 3b:

Details of the compound is given in the experimental section chapter I

4-((1H-benzo[d]imidazol-2-yl) methyl)-7-hydroxy-2H-chromen-2-one 3c:

Light Greenish yellow solid, yield: 58% (Ethanol),

mp: 302-05 °C, FT-IR (KBr) cm-1: 1741 (C=O),

3237 (N-H); 1H-NMR (DMSO, 300 MHz, TMS)

δ ppm: 4.39 (s, 2H, C4-CH2), 6.22 (s, 1H, C3-H of

coumarin), 6.74 (m, 2H, Ar-H), 7.16 (m, 2H, Ar-H),

7.50 (m, 2H, Ar-H), 7.68 (d, 1H, J = 9.0 Hz, Ar-H,), 10.60 (s, 1H, 7-OH, D2O

O O

N

HN

HO

Chapter II

76

exchangeable), 12.35 (s, 1H, N-H D2O exchangeable), MS(m/z)= (M+H)+ 293,

Anal. Calcd for C17H12N2O3 (%): C, 69.86; H, 4.14; N, 9.58, Found: C, 69.82;

H, 4.18; N, 9.60.

4-((1H-benzo[d]imidazol-2-yl) methyl)-7, 8-dimethyl-2H-chromen-2-one

(3d):

Off white solid, yield: 60% (Ethyl acetate),

mp= 238-40 °C; FT-IR (KBr) cm-1: 1711 (C=O),

3319 (N-H); 1H-NMR (DMSO, 300 MHz, TMS) δ

ppm: 2.30, 2.34 (2s, each, 3H, 7,8-CH3 of

coumarin), 4.52 (s, 2H, C4-CH2), 6.47 (s, 1H, C3-H

of coumarin), 7.16 (d, 1H, J = 8.0 Hz, Ar-H,), 7.22

(dd, 2H, J = 2.8, 6.0 Hz, Ar-H), 7.54 (m, 3H, Ar-H), 12.38 (s, 1H, NH, D2O

exchangeable); MS (m/z)= (M+H)+ 305, Anal. Calcd for C19H16N2O2 (%) C,

74.98; H, 5.30; N, 9.20; O, Found; C, 74.94; H, 5.33; N, 9.16.

4-((1H-benzo[d]imidazol-2-yl)methyl)-2H-benzo[h]chromen-2-one (3e):

Off white solid, yield: 55% (Ethanol); mp= 266-68

°C; FT-IR (KBr) cm-1: 1712 (C=O), 3309 (N-H); 1H-

NMR (DMSO, 300 MHz, TMS) δ ppm: 4.58 (s, 2H,

C4-CH2), 6.64 (s, 1H, C3-H of coumarin), 7.14 (m, 2H,

Ar-H), 7.44 (m, 1H, Ar-H), 7.53 (m, 1H, Ar-H), 7.73-

8.00 (m, 5H, Ar-H ), 8.38 (m, 1H, Ar-H), 12.41 (s,

1H, N-H D2O exchangeable), MS (m/z)= (M+H)+ 327; Anal. Calcd for

C21H14N2O2 (%) C, 77.29; H, 4.32; N, 8.58; Found; C, 77.26; H, 4.27; N,8.61.

General procedure: Synthesis 4-(1-(1H-benzo[d]imidazol-2-yl) vinyl)-2H-

chromen-2-ones 6:

Compound 3 (0.01 M) was dissolved in ethanol, and formalin (0.05 M) was

added and refluxed for 16 hours. Then the reaction mixture was concentrated

and cooled. Solid separated was washed with cold ethanol and recrystallised to

O O

N

HN

H3C

CH3

O O

N

HN

Chapter II

77

get the pure compound (6a and 6c). For compounds 6b, 6d and 6e reaction

mixture was concentrated to half and quenched in ice cold water and solid

separated was filtered, dried and crystallized in different solvents.

4-(1-(1H-benzo[d]imidazol-2-yl)vinyl)-6-methyl-2H-chromen-2-one 6a:

Pale yellow solid; Yield : 68%, mp= 270-72 °C

(DMF); FT-IR (KBr) cm-1: 1730 (C=O), 3439 (N-

H); 1H-NMR (DMSO, 400 MHz, TMS) δ ppm:

2.19 (s, 3H, C6- CH3 of coumarin), 5.84 (s, 1H,-

vinylic -CH2), 6.50 (s, 1H, C3-H of coumarin),

6.61 (s, 1H, vinylic CH2), 7.08 (s, 1H, C5-H of coumarin), 7.16 (t, 1H, J = 7.6

Hz, C6-H benzimidazole) 7.21 (t, 1H, J = 7.6 Hz, C5-H benzimidazole), 7.41

(m, 2H, Ar-H) 7.46 (d, 1H, J = 7.6 Hz C4- H benzimidazole), 7.56 (d, 1H, J =

8.0 Hz, C7-H benzimidazole) 12.68 (s, 1H, NH, D2O exchangeable), 13C-NMR

(DMSO, 100 MHz, TMS) δ ppm: 20.78, 111.85, 116.47, 117.01, 119.18,

119.67, 122.30, 122.43, 123.65, 126.34, 133.49, 134.12, 134.69, 134.98,

143.86, 150.04, 151.94, 153.25, 160.41; MS (m/z)= (M+) 302 (2%); Anal.

Calcd for C19H14N2O2 (%) C, 75.48; H, 4.67; N, 9.27, Found: C, 75.44; H,

4.70; N, 9.31.

4-(1-(1H-benzo[d]imidazol-2-yl)vinyl)-7-methyl-2H-chromen-2-one 6b:


(Ethanol); FT-IR (KBr) cm-1: 1720 (C=O), 3418

(N-H); 1H-NMR (DMSO, 400 MHz, TMS) δ ppm:

2.37 (s, 3H, C7-CH3) 5.86 (s, 1H, vinylic -CH2),

6.46 (s, 1H, C3-H of coumarin), 6.57 (s, 1H,

vinylic -CH2) 7.03 (d, 1H, J = 8.0 Hz, C6-H coumarin), 7.11-7.16 (m, 2H, Ar-

H) 7.22 (m, 1H, C6-H benzimidazole), 7.30 (s, 1H, C8-H coumarin), 7.45 (d,

1H, J = 8.0 Hz, C4-H benzimidazole), 7.55 (d, 1H, J = 8.0 Hz, C7-H

benzimidazole), 12.68 (s, 1H, NH, D2O exchangeable); MS (m/z)= (M+) 302

O O

NH

NH

H

H3C

O O

NH

NH

H

H3C

Chapter II

78

(70%); Anal. Calcd for C19H14N2O2 (%): C, 75.48; H, 4 .67; N, 9.27. Found: C,

75.47; H, 4.63; N, 9.31.

4-(1-(1H-benzo[d]imidazol-2-yl)vinyl)-7-hydroxy-2H-chromen-2-one 6c:

Light brownish solid; Yield : 60%, mp= 299-300

°C (Ethanol); FT-IR (KBr) cm-1: 1713 (C=O), 3415

(N-H); 1H-NMR (DMSO, 400 MHz, TMS) δ ppm:

5.82 (s, 1H, vinylic -CH2), 6.25 (s, 1H, C3-H of

coumarin) 6.55 (s, 1H, vinylic -CH2), 6.65 (d, 1H,

J = 8.0 Hz, C6-H coumarin), 6.77 (s, 1H, C8-H

coumarin), 7.08 (d, 1H, J = 8.4 Hz, C5-H coumarin), 7.19 (m, 2H, Ar-H), 7.46

(bs, 1H, C4-H benzimidazole), 7.56 (bs, 1H, C7-H benzimidazole), 10.58 (s,

1H, 7-OH), 12.66 (s, 1H, NH, D2O exchangeable); 13C-NMR (DMSO, 100

MHz, TMS) δ ppm: 102.85, 111.68, 111.97, 113.60, 122.31, 123.61, 128.18,

135.25, 150.12, 153.69, 155.69, 160.84, 161.78; MS= m/z (M+H)+ 305 Anal.

Calcd for C18H12N2O3 (%): C, 71.05; H, 3.97; N, 9.21, Found: C, 71.01; H,

3.93; N, 9.25.

4-(1-(1H-benzo[d]imidazol-2-yl)vinyl)-7,8-dimethyl-2H-chromen-2-one 6d:

Cream coloured solid; Yield : 55%, mp= 227-28

°C (Chloroform); FT-IR (KBr) cm-1: 1737 (C=O),

3417 (N-H), ;1H-NMR (DMSO, 400 MHz, TMS)

δ ppm: 2.33 (s, 6H, 7,8-CH3), 5.84 (s, 1H, vinylic-

CH2), 6.46 (s, 1H, C3-H of coumarin), 6.57 (s, 1H,

vinylic-CH2), 6.98 (d, 1H, J = 8.0 Hz, C6-H

coumarin), 7.01 (d, 1H, J = 8.0 Hz , C5-H coumarin), 7.14 (t, 1H, J = 8.0 Hz,

C6-H benzimidazole), 7.21 (t, 1H, J = 8.0 Hz, C5-H benzimidazole), 7.44 (d,

1H J = 8.0 Hz, C4-H benzimidazole), 7.55 (d, 1H, J = 8.0 Hz, C7-H

benzimidazole), 12.65 (s, 1H, NH, D2O exchangeable); 13C-NMR (DMSO, 100

MHz, TMS) δ ppm: 16.40, 25.07, 110.00, 119.63, 121.85, 127.09, 127.86,

128.44, 129.02, 130.79, 139.99, 144.57, 146.62, 154.89, 156.57, 158.56,

O O

NH

NH

H

HO

O O

NH

NH

H

H3C

CH3

Chapter II

79

165.30; MS (m/z)= (M+) 316 (53%) Anal. Calcd for C20H16N2O2 (%): C, 75.93;

H, 5.10; N, 8.86, Found: C, 75.89; H, 5.14; N, 8.89.

4-(1-(1H-benzo[d]imidazol-2-yl)vinyl)-2H-benzo[h]chromen-2-one 6e:

Pale Yellow solid; Yield : 50%, mp= 224-25 °C

(column purification 4:6 Ethylacetate : Hexane); FT-

IR (KBr) cm-1: 1714 (C=O), 3418 (N-H); 1H-NMR

(DMSO, 400 MHz, TMS) δ ppm: 5.95 (s, 1H,vinylic-

CH2) 6.64 (s, 1H, C3-H of coumarin), 6.67 (s, 1H,

vinylic, -CH2), 7.14 (t, 1H, J = 8.0 Hz, C6-H

benzimidazole), 7.21 (t, 1H, J = 8.0 Hz, C5-H benzimidazole), 7.24 (d, 1H, J =

8.0 Hz, C6-H coumarin), 7.46 (d, 1H, J = 8.0 Hz, C4-H benzimidazole), 7.54 (d,

1H, J= 8.0 Hz, C7-H benzimidazole), 7.69 (d, 1H, J = 8.0 Hz, C5-H coumarin),

7.71 (m, 2H, Ar-H), 7.98 (d, 1H, J = 8.0 Hz, Ar-H), 8.45 (d ,1H J = 8.0 Hz, Ar-

H), 12.73 (s, 1H, NH, D2O exchangeable); 13C-NMR (DMSO-d6 100 MHz,

TMS) δ ppm: 110.00, 111.86, 114.99, 115.91, 119.65, 122.02, 122.32, 122.63,

122.81, 123.69, 124.46, 128.07, 128.45, 129.38, 134.71, 134.99, 135.29,

143.88, 150.06, 150.57, 154.31, 160.25; MS (m/z)= (M+) 338 (54%); Anal.


4.23; N, 8.25.

General procedure: Synthesis of 4-(1-(1H-benzo[d]imidazol-2-yl)-2-

hydroxyethyl)-2H-chromen-2-ones 5:

Compound 1 (0.01 M) was dissolved in DMF and formalin (0.05 M) was added

irradiated under domestic microwave for one minute, cooled and diluted with

cold water. Solid separated was filtered, washed with water dried. Compounds

5a and 5b were purified by column chromatography and compounds 5c and 5d

were recrystallised.

O O

NH

NH

H

Chapter II

80

4-(1-(1H-benzo[d]imidazol-2-yl)-2-hydroxyethyl)-6-methyl-2H-chromen-2-

one 5a:

Off white solid; Yield : 50%, mp= 183-85 °C

(Column Purification 20:80 Ethylacetate: Hexane);

FT-IR (KBr) cm-1: 1719 (C=O), 3179 (N-H), 3273

(OH); 1H-NMR (DMSO, 400 MHz, TMS) δ ppm:

2.32 (s, 3H, C6- CH3), 4.08 (ddd, 1H, Jvic(CH) = 6.4

Hz, Jgem = 11.2 Hz, Jvic(OH)= 5.6 Hz, -CH2), 4.17 (ddd, 1H, Jvic(CH) = 6.0 Hz,

Jvic(OH)= 5.2 Hz, Jgem = 11.2 Hz, -CH2), 4.85 (t, 1H, J = 6.4 Hz, -C4-H), 5.21 (t,

1H, J = 5.6 Hz, -OH, D2O exchangeable), [After D2O exchange, 4.08 (dd, 1H,

Jvic(CH) = 6.8 Hz, Jgem = 10.8 Hz, –CH2), 4.15 (dd, 1H, Jvic(CH) = 6.8 Hz, Jgem =

10.8 Hz, -CH2)], 6.47 (s, 1H, C3-H of coumarin), 7.11 (dd, 2H, J = 1.2, 6.0 Hz,

C5&6-H benzimidazole), 7.28 (d, 1H, J = 8.4 Hz, C7-H coumarin), 7.40 (d, 1H, J

= 8.4 Hz, C8-H coumarin), 7.55 (m, 2H, Ar-H), 7.75 (s, 1H, C5-H coumarin),

12.34 (s, 1H, NH, D2O exchangeable); MS (m/z)= (M+H) + 321 (100 %); Anal.


5.00; N, 8.79.

4-(1-(1H-benzo[d]imidazol-2-yl)-2-hydroxyethyl)-7-methyl-2H-chromen-2-

one 5b:

White solid; Yield : 48%, mp= 262-64 °C (Column

Purification 20:80 Ethylacetate:Hexane); FT-IR

(KBr) cm-1 1719 (C=O), 3070 (N-H), 3324 (-OH); 1H-NMR (DMSO, 400 MHz, TMS) δ ppm: 2.39 (s,

3H, C7-CH3), 4.13 (ddd, 1H, Jvic(CH)= 5.6 Hz,

Jvic(OH)= 5.6 Hz, Jgem = 11.2 Hz, -CH2), 4.22 (ddd,

1H, Jvic(CH) = 6.0 Hz, Jvic(OH)= 5.6 Hz, Jgem = 11.2 Hz, -CH2), 4.85 (t, 1H, J = 6.4

Hz, -C4-H), 5.25 (t, 1H, J = 5.6 Hz, -OH, D2O exchangeable), [After D2O

exchange, 4.12 (dd, 1H, Jvic(CH) = 6.8 Hz, Jgem = 10.8 Hz, –CH2), 4.17 (dd, 1H,

Jvic(CH) = 6.4 Hz, Jgem = 10.8 Hz, –CH2)], 6.48 (s, 1H, C3-H of coumarin) , 7.12-

7.26 (m, 3H, Ar-H C5 &6-H benzimidazole & C6-H coumarin), 7.26 (s, 1H,

O O

NH

NOH

HH3C

O O

NH

N

H3C

OH

H

Chapter II

81

C8-H coumarin), 7.43 (d, 1H, J = 7.6 Hz, C7-H benzimidazole), 7.59 (d, 1H, J =

8.4 Hz, C4-H benzimidazole), 7.81 (d, 1H, J = 8.0 Hz, C5-H coumarin), 12.37

(s, 1H, NH, D2O exchangeable); 13C-NMR (DMSO, 100 MHz, TMS) δ ppm:

20.87, 43.41, 62.63, 111.17, 113.85, 116.28, 116.84, 118.51, 121.19, 122.01,

124.60, 125.45, 134.12, 142.78, 142.91, 152.34, 152.92, 153.32, 159.96; MS

(m/z)= (M+H) + 321 (100%); Anal. Calcd for C19H16N2O3 (%): C, 71.24; H,

5.03; N, 8.74, Found: C, 71.29; H, 4.96; N, 8.82.

4-(1-(1H-benzo[d]imidazol-2-yl)-2-hydroxyethyl)-7,8-dimethyl-2H-

chromen-2-one 5c:

White solid; Yield : 55%, mp= 194-95 °C

(Chloroform); FT-IR (KBr) cm-1: 1691 (C=O),

3184 (N-H), 3269 (OH); 1H-NMR (DMSO, 400

MHz, TMS) δ ppm: 2.27, 2.32 (2s, 3H each, C7&8 -

CH3), 4.10 (ddd, 1H, Jvic (CH) = 6.4 Hz, Jvic(OH)=5.6

Hz, Jgem = 11.2 Hz, -CH2), 4.20 (ddd, 1H, Jvic(CH) =

6.0 Hz, Jvic (OH)=5.4 Hz, Jgem = 11.2 Hz , -CH2), 4.83 (t, 1H, J = 6.4 Hz, -C4-H),

5.22 (t, 1H, J = 5.6 Hz, -OH, D2O exchangeable), [After D2O exchange, 4.10

(dd, 1H, Jvic(CH) = 6.8 Hz, Jgem = 10.8 Hz, –CH2), 4.17 (dd, 1H, Jvic(CH) = 6.4

Hz, Jgem = 10.8 Hz, –CH2)], 6.48 (s, 1H, C3-H of coumarin), 7.10-7.16 (m, 2H,

Ar-H), 7.16 (d, 1H, J = 7.6 Hz, C6-H coumarin), 7.41 (d, 1H, J = 7.6 Hz, C4-H

benzimidazole), 7.51(d, 1H, J = 8.4 Hz, C7-H benzimidazole), 7.65 (d, 1H, J =

8.4 Hz, C5-H coumarin), 12.33 (s, 1H, NH, D2O exchangeable); 13C-NMR

(DMSO, 100 MHz, TMS) δ ppm: 11.65, 20.19, 43.76, 62.81, 111.74, 113.79,

116.74, 118.88, 121.99, 122.06, 122.88, 124.61, 126.21, 134.26, 142.11,

142.98, 151.74, 152.73, 153.63, 160.86; MS (m/z)= (M+H) + 335 (100 %);

Anal. Calcd for C20H18N2O3 (%): C, 71.84; H, 5.43; N, 8.38, Found: C, 71.90;

H, 5.47; N, 8.34.

O O

NH

NOH

H

H3C

CH3

Chapter II

82

4-(1-(1H-benzo[d]imidazol-2-yl)-2-hydroxyethyl)-2H-benzo[h]chromen-2-

one 5d:


(Chloroform); FT-IR (KBr) cm-1: 1720 (C=O), 3062

(N-H), 3286 (-OH); 1H-NMR (DMSO, 400 MHz,

TMS) δ ppm: 4.27 (ddd, 1H, Jvic (CH) = 5.6 Hz,

Jvic(OH)= 5.6 Hz, Jgem = 11.2 Hz, -CH2), 4.20 (ddd, 1H,

Jvic(CH) = 6.0, Jvic (OH)= 5.6 Hz, Jgem = 11.2 Hz, -CH2),

4.99 (t, 1H, J = 6.4 Hz, -C4-H), 5.28 (t, 1H, J = 5.2 Hz, -OH, D2O

exchangeable), [After D2O exchange, 4.18 (dd, 1H, Jvic(CH) = 6.8 Hz, Jgem =

10.8 Hz, -CH2), 4.17 (dd, 1H, Jvic(CH) = 6.0, Jgem = 10.8 Hz, -CH2)], 6.67 (s,

1H, C3-H of coumarin), 7.13-7.16 (m, 2H, Ar-H), 7.42 (d, 1H, J = 6.8 Hz, C4-

H benzimidazole), 7.59 (d, 1H, J = 6.8 Hz, C7-H benzimidazole, 7.69 -7.73 (m,

2H, Ar-H), 7.83 (d, 1H, J = 9.2 Hz, C6-H coumarin), 7.93 (d, 1H, J = 9.2 Hz,

C5-H coumarin), 7.99 -8.01 (m, 1H, Ar-H), 8.38 -8.40 (m, 1H, Ar-H), 12.39 (s,

1H, NH, D2O exchangeable); MS (m/z)= (M+) 357 (100%); Anal. Calcd for

C22H16N2O3 (%): C, 74.15; H, 4.53; N, 7.86, Found: C, 74.11; H, 4.55; N, 7.83.

General procedure: Synthesis of 2-(4'-coumarinomethyl

benzothiazole/benzoxazole) 7:

Substituted coumarin-4-acetic acid 1 (0.01 M) and o-aminothiophenol 2b/o-

aminophenol 2c (0.01 M) were mixed with 25 mL of anhydrous phosphoric

acid and heated in an oil bath at 170-180 °C for four hours and cooled,

resulting thick syrupy liquid was added carefully to ice cold water and stirred

well. Solid separated was basified carefully using 25% liquor ammonia till

basic. The solid obtained was washed with water and dried and recrystallised

using ethanol.

O O

NH

NOH

H

Chapter II

83

4-(benzo[d]thiazol-2-ylmethyl)-6-methyl-2H-chromen-2-one 7a:

Yellow crystalline solid, yield: 70% (Ethanol),

mp= 202-03 °C; FT-IR (KBr) cm-1: 1712 (C=O); 1H-NMR (DMSO, 300 MHz, TMS) δ ppm: 2.39

(s, 3H, C6-CH3 coumarin), 4.78 (s, 2H, C4-CH2),

6.54 (s, 1H, C3-H of coumarin), 7.32 (d, 1H, J =

8.4 Hz, Ar-H), 7.38-7.50 (m, 3H, Ar-H), 7.67 (s,

1H, C5-H coumarin), 7.94 (d, 1H, J = 7.9 Hz, Ar-H), 8.05 (d, 1H, J = 7.9 Hz,

Ar-H), MS (m/z) = (M+) 307 (53%); Anal. Calcd for C18H13NO2S (%): C,

70.34; H, 4.26; N, 4.56; S, 10.43, Found: C, 70.32; H, 4.29; N, 4.50; S, 10.45.

4-(benzo[d]thiazol-2-ylmethyl)-7-methyl-2H-chromen-2-one 7b:

Light yellow solid, yield: 70% (Ethanol), mp= 170-

72 °C; FT-IR(KBr) cm-1: 1710 (C=O); 1H-NMR

(CDCl3, 300 MHz, TMS) δ ppm: 2.37 (s, 3H, C7-

CH3 coumarin), 4.68 (s, 2H, C4-CH2), 6.51 (s, 1H,

C3-H of coumarin), 7.35 -7.68 (m, 5H, Ar-H), 7.85-

7.99 (m, 2H, Ar-H); MS (m/z) = (M+) 307 (55%);

Anal. Calcd for C18H13NO2S (%): C, 70.34; H, 4.26; N, 4.56; S, 10.43, Found:

C, 70.38; H, 4.22; N, 4.60; S, 10.40.

4-(benzo[d]thiazol-2-ylmethyl)-7, 8-dimethyl-2H-chromen-2-one 7c:

Light brown solid, yield: 65% (Ethanol), mp= 160-

62 °C; FT-IR (KBr) cm-1: 1709 (C=O); 1H-NMR

(CDCl3, 300 MHz, TMS) δ ppm: 2.41 (s, 6H, C7,8-

CH3 coumarin), 4.58 (s, 2H, C4-CH2), 6.33 (s, 1H,

C3-H of coumarin), 7.05 (d, 1H, J = 8.1 Hz,

Ar-H), 7.38 (t, 2H, J = 7.6 Hz, Ar-H), 7.47 (d, 1H,

J = 8.0 Hz, Ar-H), 7.80 (d, 1H, J = 7.8 Hz, Ar-H), 8.01 (d, 1H, J = 8.1 Hz,

Ar-H); MS (m/z)= (M+) 321(52%); Anal. Calcd for C19H15NO2S (%) : C,

71.00; H, 4.70; N, 4.36; S, 9.98, Found: C, 71.04; H, 4.74; N, 4.37; S, 10.00.

O O

S

N

H3C

O O

S

N

H3C

O O

S

N

H3C

CH3

Chapter II

84

4-(benzo[d]oxazol-2-ylmethyl)-6-methyl-2H-chromen-2-one 7d:

Off white solid, yield: 65% (Ethanol), mp= 204-05

°C; FT-IR (KBr) cm-1: 1729 (C=O); 1H-NMR

(CDCl3, 300 MHz, TMS) δ ppm: 2.61 (s, 3H,

C6-CH3 coumarin), 4.40 (s, 2H, C4-CH2), 6.42 (s,

1H, C3-H of coumarin), 7.24 (m, 1H, Ar-H), 7.33

(s, 1H, Ar-H), 7.36 (m, 2H, Ar-H), 7.51 (m, 2H,

Ar-H), 7.70 (m, 1H, Ar-H); MS (m/z)= (M+) 291 (7%); Anal. Calcd for

C18H13NO3 (%): C, 74.22; H, 4.50; N, 4.81, found: C, 74.18; H, 4.52; N, 4.85.

4-(benzo[d]oxazol-2-ylmethyl)-7-methyl-2H-chromen-2-one 7e:



(DMSO, 300 MHz, TMS) δ ppm: 2.39 (s, 3H, C6-

CH3 coumarin) 4.64 (s, 2H, C4-CH2), 6.52 (s, 1H,

C3-H of coumarin), 7.15 (d, 2H, J = 8.3 Hz, Ar-H),

7.32-7.36 (m, 2H, Ar-H), 7.68 (m, 3H, Ar-H); MS

(m/z) = (M+) 291 (38%); Anal. Calcd for C18H13NO3 (%): C, 74.22; H, 4.50; N,

4.81, Found: C, 74.18; H, 4.54; N, 4.84.

4-(benzo[d]oxazol-2-ylmethyl)-7,8-dimethyl-2H-chromen-2-one 7f:



(DMSO, 300 MHz, TMS) δ ppm: 2.36 (s, 3H,

C7&8 -CH3 coumarin) 4.39 (s, 2H, C4-CH2), 6.38 (s,

1H, C3-H of coumarin), 7.08 (d, 1H, J = 7.9 Hz,

Ar-H), 7.31-7.34 (m, 2H, Ar-H), 7.45-7.48 (m, 2H,

Ar-H), 7.68-7.69 (m, 1H, Ar-H); MS (m/z) = (M+)

305 (100%); Anal. Calcd for C19H15NO3 (%): C, 74.74; H, 4.95; N, 4.59,

found: C, 74.71; H, 4.91; N, 4.64.

O O

O

N

H3C

O O

O

N

H3C

CH3

O O

O

N

H3C

Chapter II

85

4-(benzo[d]oxazol-2-ylmethyl)-2H-benzo[h]chromen-2-one 7g:

Light brown solid; yield: 62% (Ethanol), mp= 174-75

°C; FT-IR (KBr) cm-1: 1722 (C=O); 1H-NMR (CDCl3,

300 MHz, TMS) δ ppm: 4.52 (s, 2H, C4-CH2), 6.55 (s,

1H, C3-H of coumarin), 7.33-7.36 (m, 2H, Ar-H), 7.49-

7.52 (m, 1H, Ar-H), 7.62-7.70 (m, 5H, Ar-H), 7.85 (m,

1H, Ar-H), 8.57 (m, 1H, Ar-H); MS (m/z) = (M+) 327

(100%); Anal. Calcd for (%) C21H13NO3: C, 77.05; H,

4.00; N, 4.28, Found: C, 77.08; H, 4.05; N, 4.24.

General Procedure: Synthesis of 4-(1-(benzo[d]thiazol-2-yl)-2-

hydroxyethyl)-6-methyl-2H-chromen-2-ones / 4-(1-(benzo[d]oxazol-2-yl)-2-

hydroxyethyl)-6-methyl-2H-chromen-2-ones 8:

Compound 7 (0.01 M) was dissolved in ethanol, and formalin (0.05 M) was

added and refluxed for 16 hours. The reaction mixture was concentrated and

then diluted with ice cold water. Resulting solid was filtered and washed with

water and dried to get hydroxymethylated compound 8, which was further

purified using appropriate method.

4-(1-(benzo[d]thiazol-2-yl)-2-hydroxyethyl)-6-methyl-2H-chromen-2-one

8a:

White solid; Yield: 48%, mp= 180-81 °C (Column

Purification 25:75 Ethylacetate: Hexane); FT-IR

(KBr) cm-1: 1703 (C=O), 3491 (-OH); 1H-NMR

(DMSO, 400 MHz, TMS) δ ppm: 2.34 (s, 3H, C6-

CH3), 4.17 (ddd, 1H, Jvic (CH) = 5.6 Hz, Jvic(OH)= 5.2

Hz, Jgem = 11.4 Hz, -CH2), 4.23 (ddd, 1H, Jvic(CH) = 6.4 Hz, Jvic (OH)= 5.6 Hz,

Jgem = 11.4 Hz, -CH2), 5.23 (t, 1H, J = 6.4 Hz, C4-H), 5.37 (t, 1H, J = 5.6 Hz,

-OH, D2O exchangeable), [After D2O exchange, 4.17 (dd, 1H, Jvic(CH) = 6.4

Hz, Jgem = 10.8 Hz, –CH2), 4.21 (dd, 1H, Jvic(CH) = 6.4 Hz, Jgem = 10.8 Hz, –

CH2)], 6.58 (s, 1H, C3-H of coumarin), 7.32 (d, 1H, J = 8.0 Hz, C7-H

O O

O

N

O O

S

NOH

H3C

Chapter II

86

coumarin), 7.41 (m, 1H, Ar-H), 7.42 (t, 1H, J = 7.6 Hz, C6-H benzothiophene),

7.49 (t, 1H, J = 7.6 Hz, C5-H benzothiophene), 7.81 (s, 1H, C5-H coumarin),

7.99 (d, 1H, J = 8.0 Hz, C4-H benzothiophene), 8.06 (d, 1H, J = 8.0 Hz, C7-H

benzothiophene); MS (m/z)= (M+) 337 (2%); Anal. Calcd for C19H15NO3S (%):

C, 67.64; H, 4.48; N, 4.15; S, 9.50, Found: C, 67.61; H, 4.53; N, 4.12; S, 9.55.

4-(1-(benzo[d]thiazol-2-yl)-2-hydroxyethyl)-6-methyl-2H-chromen-2-one

8b:

Off white solid; Yield: 43%, mp= 160-62 °C (Ethyl

acetate); FT-IR (KBr) cm-1: 1704 (C=O), 3448

(-OH); 1H-NMR (DMSO, 400 MHz, TMS) δ ppm:

2.39 (s, 3H, C7- CH3), 4.17 (ddd, 1H, Jvic (CH) = 5.6

Hz, Jvic(OH)= 5.6 Hz, Jgem = 11.2 Hz, -CH2), 4.26

(ddd, 1H, Jvic(CH) = 6.4 Hz, Jvic (OH)= 6.0 Hz, Jgem =

11.2 Hz, -CH2), 5.03 (t, 1H, J = 6.4 Hz, -C4-H), 5.33 (t, 1H, J = 5.6 Hz, -OH,

D2O exchangeable), [After D2O exchange, 4.14 (dd, 1H, Jvic(CH) = 6.4 Hz, Jgem

= 10.8 Hz, –CH2), 4.23 (dd, 1H, Jvic(CH) = 6.4 Hz, Jgem = 10.8 Hz, –CH2)], 6.51

(s, 1H, C3-H of coumarin), 7.19 (d, 1H, J = 8.0 Hz, C6-H coumarin), 7.20 (s,

1H, C8-H of coumarin), 7.26- 7.40 (m, 2H, Ar-H), 7.63- 7.76 (m, 2H, Ar-H),

7.82 (d, 1H, J = 8.0 Hz, C5-H coumarin); MS (m/z)= (M+H) + 338 (93%); Anal.

Calcd for C19H15NO3S (%): C, 67.64; H, 4.48; N, 4.15; S, 9.50, Found: C,

67.69; H, 4.54; N, 4.09; S, 9.48.

4-(1-(benzo[d]thiazol-2-yl)-2-hydroxyethyl)-7,8-dimethyl-2H-chromen-2-

one 8c:

Light brown solid; Yield: 44%, mp= 113-14 °C

(Ethyl acetate); FT-IR (KBr) cm-1: 1699 (C=O),

3442 (-OH); 1H-NMR (DMSO, 400 MHz, TMS) δ

ppm: 2.27, 2.32 (2s, 3H each, C7&8-CH3), 4.17

(ddd, 1H, Jvic (CH) = 6.0 Hz, Jvic(OH)=5.6 Hz, Jgem =

11.2 Hz, -CH2), 4.23 (ddd, 1H, Jvic(CH) = 6.4 Hz,

Jvic (OH)= 6.0 Hz, Jgem = 11.2 Hz, -CH2), 5.17 (t, 1H, J = 6.4 Hz, -C4-H), 5.35 (t,

1H, J = 5.6 Hz, -OH, D2O exchangeable), [After D2O exchange, 4.15 (dd, 1H,

O O

S

N

H3C

OH

O O

S

N

H3C

CH3

OH

Chapter II

87


11.2 Hz, –CH2)], 6.55 (s, 1H, C3-H of coumarin), 7.16 (d, 1H, J = 8.0 Hz, C6-H

coumarin), 7.39 (dt, 1H, J = 1.2, 7.6 Hz, C6-H benzothiophene), 7.48 (dt, 1H, J

=1.2, 7.6 Hz, C5-H benzothiophene), 7.67 (d, 1H, J = 8.0 Hz, C5-H coumarin),

7.97 (d, 1H, J = 7.6 Hz, C4-H benzothiophene), 8.04 (d, 1H, J = 7.6 Hz, C7-H

benzothiophene); MS (m/z)= (M+H)+ 352 (100%); Anal. Calcd for

C20H17NO3S (%): C, 68.36; H, 4.88; N, 3.99; S, 9.12, Found: C, 68.41; H, 4.92;

N, 3.95; S, 9.07.

4-(1-(benzo[d]oxazol-2-yl)-2-hydroxyethyl)-6-methyl-2H-chromen-2-one

8d:

Off white solid; Yield: 40%, mp= 142-43 °C


FT-IR (KBr) cm-1: 1692 (C=O), 3377 (-OH); 1H-

NMR (DMSO, 400 MHz, TMS) δ ppm: 2.33 (s,

3H, C6- CH3), 4.14 (ddd, 1H, Jvic (CH) = 5.6 Hz,

Jvic(OH)=6.0 Hz, Jgem = 11.4 Hz, -CH2), 4.22 (ddd,

1H, Jvic(CH) = 6.4 Hz, Jvic (OH)=5.6 Hz, Jgem = 11.4, Hz, -CH2), 5.05 (t, 1H, J =

6.4 Hz, -C4-H), 5.31 (t, 1H, J = 5.6 Hz, -OH, D2O exchangeable), [After D2O

exchange, 4.14 (dd, 1H, Jvic(CH) = 6.4 Hz, Jgem = 10.8 Hz, –CH2), 4.22 (dd, 1H,

Jvic(CH) = 6.4 Hz, Jgem = 10.8 Hz, –CH2)], 6.58 (s, 1H, C3-H of coumarin) , 7.30

(d, 1H, J = 8.0 Hz, C8-H coumarin), 7.33-7.36 (m, 2H, Ar-H), 7.42 (dd, 1H,

J = 1.2, 8.4 Hz, C7-H coumarin), 7.65-7.74 (m, 2H, Ar-H), 7.70 (bs, 1H, C5-H

coumarin); 13C-NMR (DMSO, 100 MHz, TMS) δ ppm: 18.79, 46.81, 63.35,

115.06, 116.92, 118.31, 122.35, 122.77, 124.88, 125.52, 126.49, 128.81,

133.26, 134.10, 151.55, 152.49, 153.37, 160.09, 169.45; MS (m/z)= (M+) 321

(8%); Anal. Calcd for C19H15NO4 (%): C, 71.02; H, 4.71; N, 4.36, Found: C,

70.97; H, 4.76; N, 4.40.

4-(1-(benzo[d]oxazol-2-yl)-2-hydroxyethyl)-7-methyl-2H-chromen-2-one

8e:

O O

O

NOH

H3C

Chapter II

88

Light yellow solid; Yield: 40%, mp= 171-73 °C


3368 (OH); 1H-NMR (DMSO, 400 MHz, TMS) δ

ppm: 2.37 (s, 3H, C6- CH3), 4.17 (ddd, 1H, Jvic (CH)

= 6.0 Hz, Jvic(OH)=5.6 Hz, Jgem = 11.5 Hz, -CH2),

4.23 (ddd, 1H, Jvic(CH) = 6.4 Hz, Jvic (OH)= 6.0 Hz,

Jgem = 11.5 Hz, -CH2), 5.18 (t, 1H, J = 6.4 Hz, -C4-H), 5.36 (t, 1H, J = 5.6 Hz, -

OH, D2O exchangeable), [After D2O exchange, 4.12 (dd, 1H, Jvic(CH) = 6.4 Hz,

Jgem = 11.0 Hz, –CH2), 4.17 (dd, 1H, Jvic(CH) = 6.4 Hz, Jgem = 11.0 Hz, –CH2)],

6.55 (s, 1H, C3-H of coumarin) , 7.17 (d, 1H, J = 8.4 Hz, C6-H coumarin), 7.25

(s, 1H, C8-H coumarin), 7.41 (t, 1H, J = 7.6 Hz, C6-H benzoxazole), 7.48 (t,

1H, J = 7.6 Hz, C5-H benzoxazole),7.82 (d, 1H, J = 8.4 Hz C5-H coumarin),

7.98(d, 1H, J = 7.6 Hz, C4-H benzoxazole), 8.05 (d, 1H, J = 8.0 Hz, C7-H

benzoxazole); MS (m/z)= (M+H) + 322 (88%); Anal. Calcd for C19H15NO4 (%):

C, 71.02; H, 4.71; N, 4.36, Found: C, 71.05; H, 4.72; N, 4.33.

4-(1-(benzo[d]oxazol-2-yl)-2-hydroxyethyl)-7,8-dimethyl-2H-chromen-2-

one 8f:

Light brown solid; Yield : 55%; mp= 138-40 °C


3354 (OH); 1H-NMR (DMSO, 400 MHz, TMS) (δ

ppm): 2.27,2.32 (2s, 3H each, C7&8- CH3), 4.16

(ddd, 1H, Jvic (CH) = 6.0 Hz, Jvic(OH)=5.6 Hz, Jgem =

11.2 Hz, -CH2), 4.26 (ddd, 1H, Jvic(CH) = 6.4 Hz, Jvic

(OH)=6.0 Hz, Jgem = 11.2 Hz, -CH2), 5.02 (t, 1H, J = 6.4 Hz, -C4-H), 5.33 (t, 1H,

J = 5.6 Hz, -OH, D2O exchangeable), [After D2O exchange, 4.13 (dd, 1H,


10.8 Hz, –CH2)], 6.51 (s, 1H, C3-H of coumarin), 7.17 (d, 1H, J = 8.4 Hz, C6-H

coumarin), 7.33- 7.39 (m, 2H, Ar-H), 7.65 (d, 1H, J = 8.4 Hz, C5-H coumarin),

7.68- 7.74 (m, 2H, Ar-H); 13C-NMR (DMSO, 100 MHz, TMS) δ ppm:11.61,

20.19, 43.47, 62.44, 111.17, 111.29, 113.92, 116.40, 120.09, 121.83, 122.41,

124.75, 125.20, 125.93, 126.34, 140.77, 142.44, 150.59, 151.70, 152.22,

O O

O

N

H3C

OH

O O

O

N

H3C

CH3

OH

Chapter II

89

160.61, 164.59; MS (m/z)= (M+H) + 336 (98%); Anal. Calcd for C20H17NO4

(%): C, 71.63; H, 5.11; N, 4.18, Found: C, 71.60; H, 5.08; N, 4.24.

4-(1-(benzo[d]oxazol-2-yl)-2-hydroxyethyl)-2H-benzo[h]chromen-2-one 8g:

Brownish white solid; Yield: 45%, mp =155-57 °C


FT-IR (KBr) cm-1: 1695 (C=O), 3325 (-OH); 1H-

NMR (DMSO, 400 MHz, TMS) δ ppm: 4.24 (ddd,

1H, Jvic (CH) = 5.6 Hz, Jvic(OH)=5.6 Hz, Jgem = 11.4 Hz,

-CH2), 4.32 (ddd, 1H, Jvic(CH) = 6.4 Hz, Jvic (OH)=6.0

Hz, Jgem = 11.4, Hz, -CH2), 5.19 (t, 1H, J = 6.4 Hz, -C4-H), 5.38 (t, 1H, J = 5.6

Hz, -OH, D2O exchangeable), [After D2O exchange, 4.22 (dd, 1H, Jvic(CH) = 6.4

Hz, Jgem = 10.8 Hz, –CH2), 4.29 (dd, 1H, Jvic(CH) = 6.4 Hz, Jgem = 10.8 Hz, –

CH2)], 6.70 (s, 1H, C3-H of coumarin), 7.36- 7.41 (m, 2H, Ar-H), 7.69- 7.76

(m, 4H, Ar-H), 7.86 (d, 1H, J = 8.8 Hz, C6-H coumarin), 7.95 (d, 1H, J = 8.8

Hz, C5-H coumarin), 8.01-8.03 (m, 1H, Ar-H), 8.38 (m, 1H, Ar-H); MS (m/z)=

(M+H) + 358 (36%); Anal. Calcd for C22H15NO4 (%): C, 73.94; H, 4.23; N,

3.92, found: C, 73.91; H, 4.25; N, 3.87.

4. CONCLUSIONS

In hydroxymethylation of 2-(4'-coumarinomethyl) benzimidazoles,

C-hydroxymethylation predominates over N-hydroxymethylation which is

probably due to the stability of C-hydroxymethylated intermediate compared

to N-hydroxymethylated intermediate, followed by dehydration. However, in

microwave conditions hydroxymethylation is not followed by dehydration.

2-(4'-coumarinomethyl)benzthiazoles and benzoxazoles undergo

hydroxymethylation in both thermal and microwave conditions, but

dehydration is not achieved in either of the reaction conditions.

5. REFERENCES:

O O

O

NOH

Chapter II

90

[1] Sullivan, W. R.; Huebner, C. F.; Stahmann, M. A.; Link, K. P., J. Am.

Chem. Soc. 1943, 65, 2288.

[2]. Spath, E.; Pailer, M., Chem. Ber. 1935, 68B, 941.

[3]. Jainamma, K. M., Ind. J. Chem. 1975, 13, 985.

[4]. Bansal, P. C.; Pitman, I. H.; Higuchi, T., J Pharm. Sci. 1981, 70, 855.

[5]. Erlemeyer, H.; Waldi, D.; Sorkin E., Helv. Chim. Acta 1948, 31, 32.

[6]. Ramesh, S. M.; Ivanenko, A. G., Chem. Heterocycl. Compd. 2003, 390,

1541.

[7]. Shen, K.; Liu, X.; Wang, W.; Wang, G.; Cao, W.; Li, W.; Hu, X.; Lin, L.;

Feng, X., Chem. Sci. 2010, 1, 590.

[8]. Alley, P. W., J. Org. Chem. 1975, 40, 1837.

[9]. Sehgal, R. K.; Agrawal, K. C., J. Heterocycl. Chem. 1979, 16, 876.

[10]. Bachman, G. B.; Heisey, L., J. Am. Chem. Soc. 1946, 68, 2496.

[11]. Zinner, H.; Spangenberg, B., Chem. Ber. 1958, 91, 1432.

[12]. Monti, L.; Venturi, M., Gazz. Chim. Ital. 1946, 76, 365.

[13]. Anklekar, K. Y.; Kulkarni, M. V., Ind. J. Chem. 1995, 34B, 677.

[14]. Nagarajan, K., J. Chem. Sci. 2006, 118, 291.

[15]. Dax, S. L; Wei, C. -C., J. Org. Chem. 1992, 57, 744.

[16]. Suau, R.; Najera, F.; Rico, R., Tetrahedron Lett. 1996, 37, 3575.

[17]. Jadhav, V. B.; Nayak, S. K.; Guru Row, T. N.; Kulkarni, M.V., Eur. J.

Med. Chem. 2010, 45, 3575.

[18]. Laskowski, S. C.; Clinton, R. O., J Am. Chem. Soc. 1950, 72, 3987.

[19].Theoretical studies were carried out by Dr.Igor Shcherbakov, at the

Southern Federal University, Russia.

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