Chapter-III INTRODUCTIONshodhganga.inflibnet.ac.in/bitstream/10603/22407/9/09_chapter_3.pdf · Tetrazole derivates are well known as compounds with a high level of biological activity8.

Chapter-III

51

INTRODUCTION

Tetrazole compounds have received wide attention by many chemists as energetic

materials1, pharmaceutical, material sciences2 an increasingly popular functionality with

wide-ranging applications. They have found use in pharmaceuticals as lipophilic spacers3

and carboxylic acid surrogates4 in specialty explosives5 and photography and information

recording systems6, not to mention as precursors to a variety of nitrogen containing

heterocycles7.

Tetrazole derivates are well known as compounds with a high level of biological

activity8. They are also regarded as biologically equivalent to carboxylic acid group9. It

was also noticed that toxic properties of a drug can decrease through the introduction of a

tetrazole ring into the molecule10.

Generally preparation of tetrazoles carried out by the most direct method is via the

formal [2 + 3] cycloaddition of azides and nitriles. However, evidence in the literature

indicates that the mechanism of the reaction is different for different azide species.

When an organic azide is used as the dipole, only certain highly activated nitriles

are competent dipolarophiles11. In these cases the reaction is regioselective, and only the

1-alkylated product is observed12. It is commonly accepted that in these cases the reaction

proceeds via a traditional [2 + 3] mechanism (Scheme-1)3, 13 addition of azide salts and

nitriles to give 1H-tetrazoles.

It has long been known14 that simple heating of certain azide salts with a nitrile in

solution (typically 100-150°C) produces the corresponding 5-substituted tetrazoles. N-

alkylation of 5-substituted tetrazole can result in the formation of two isomers, N1-R or

N2-R with the N2-R isomer generally predominating. This is due to the fact that the

tetrazole itself can exist in two tautomeric forms15 (Scheme-2).

This variant is much more synthetically useful, as the scope of nitriles that are

competent reactants in this reaction is very broad, in contrast with the case of organic

azides. In addition, a wide variety of metal-azide complexes are competent azide

donors16. mechanistically, these cases are considerably more complicated: several

Chapter-III

52

possible reaction pathways can be envisioned. Claims have been made for both an

anionic two-step mechanism17,18 and a concerted [2 + 3] cycloaddition19.

Scheme-1: traditional [2 + 3] mechanism:

GWE

NN

NR

N N

N

N

N

GWE

R

2+3 N

NN

N

GWER

+

Scheme-2: Tetrazoles tautomeric forms:

N N

NN

N N

NN

N N

NN

N N

NN

HH R

R1 2

3

4

5

12

3

4

5

2

34

5

1 2

3

4

5

1

+R-X

1 2

As the literature on tetrazoles is expanding rapidly, in view to synthesis of this

heterocyclic nucleus is of much current importance and diverse activity of coumarins,

tetrazoles made me to plan to synthesize coumarin linked tetrazoles.

PAST WORK:

Synthesis of 5-substituted-1,2,3,4-tetrazoles:

Substituted aromatic and aliphatic nitriles and sodium azide in the presence of a

variety of catalysts gave 5-substituted 1,2,3,4-tetrazoles by 1,3-dipolar (2+3)

cycloaddition.

1. Reaction of 3-cyanopyridine with sodium azide:

John R. Cashman20 and his co-workers reported the synthesis of 3-(1H-Tetrazol-5-

yl) pyridine (4) by treating 3-cyanopyridine with sodium azide and ammonium chloride

in DMF solution. (Scheme-3)

Scheme-3:

N N

CNNH

N

NN

NaN3; NH4Cl

DMF

3 4

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53

2. Reaction of phenacylbromide with sodium azide:

Preparation of 1-Phenyl-2-(1H-tetrazol-5-ylselanyl) (7) is reported by G. V. P.

Chandramouli21 from phenacylbromide with NaN3 and KSeCN. (Scheme-4)

Scheme-4:

O

Br

O

Se

N N

N

HN

KSeCN NaN3R R

++[Bmim]BF4

100oC, 3-5 h

5 6 7

3. Reaction of arylnitriles with sodium azide:

Stenberg et al22 reported the synthesis of 5-aryl-2H-tetrazoles (9) by the reaction

of benzonitrile with NaN3 and NH4Cl in DMF at 120oC. (Scheme-5)

Scheme-5:

CNN

NH

NN

NaN3; NH4Cl, DMF

HCl

8 9

4. Reaction of nitriles with sodium azide in presence of FeCl3-SiO2:

Nasrollahzadeh et al23 reported an efficient method for the synthesis of 5-

substituted 1H-tetrazoles via [2+3] cycloaddition of nitriles and sodium azide in presence

of FeCl3-SiO2. (Scheme-6)

Scheme-6:

CNN

NH

NN

NaN3;

DMF, 120oC

10 11

FeCl3-SiO2

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54

5. Reaction of N-formyl amidrazones with nitrous acid.

Reaction of imidatehydrochloride salt with formyl hydrazine furnished N-formyl

amidrazone, which on nitrosation with sodium nitrite-HCl gives 5-substituted tetrazoles24.

(Scheme-7)

Scheme-7:

NH2 BF4

OEt

N

OEt

NHCHO NH

N

NN

NH2-NHCHO NaNO2/ HCl

12 1314

6. Reaction of 3-cyanocoumarin with sodium azide and zinc bromide:

Preparation of 3-(2H-Tetrazol-5-yl)-chromen-2-one is reported from the reaction

between 3-cyanocoumarin, Zinc bromide and sodium azide by Deborah D. Soto-Ortega

et al25. (Scheme-8)

Scheme-8:

O OO O

CN

N N

NHN

NaN3 ZnBr2

150oC 24h

15 16

7. Reaction of Nitrile,alkene in presence of Zn(OTf)2:

S. Hajra et al26 reported a versatile and highly efficient Zn(OTf)2-catalyzed one-

pot reaction of alkenes, NBS, nitriles, and TMSN3 gives various 1,5-disubstituted

tetrazoles containing an additional α-bromo functionality of the N1-alkyl substituent.

(Scheme-9)

Scheme-9:

R''

R

R'

Br

R''

R'

R

N

NN

N

R'''5 mol-% Zn(OTf)2

1.5 eq. TMSN3, 1.1eq. NBS

R'''CN, MS4A

25oC, 20-60 min

17 18

Chapter-III

55

8. Reaction of organoaluminium azides and nitriles:

Sedelmeier et al27 reported the 5-substituted 2H-tetrazoles from click chemistry

approach by the reaction of nitriles with organoaluminium azides. (Scheme-10)

Scheme-10:

Al Cl NaN3Al N N N

Al N N N

N

Cbz

CN

N

Cbz

N N

NNToluene

85oC

+

19 20 21

+

9. Reaction of aryl bromides with (K4[Fe(CN)6]) and palladium acetate:

Cai et al28 reported the one pot synthesis of 5-substituted 1H-tetrazoles through

the three-component reaction between an arylbromide, (K4[Fe(CN)6]) and sodium azide

catalyzed by [Pd(OAc)2] and ZnBr2 in the presence of DABCO. (Scheme-11)

Scheme-11:

BrN N

N

HN

K4[Fe(CN)6] NaN3

[Pd(OAc)2], DABCO

ZnBr2,DMF++

22 23 24

10. Reaction of nitriles with sodium azide in presence of amine salt:

Oga et al29 have prepared the variety of 5-substituted tetrazoles by the reaction of

nitriles with sodium azide in the presence of an amine salt. (Scheme-12)

Scheme-12:

NC CO2CH3

CO2Ben

Et3NHN=C CO2CH3

CO2Ben

CO2CH3

CO2Ben

NN

HN NN3

Et3N.HCl NaN3Et3NHN3

Et3NHN3+

+

100oC

25 26 27 28

Chapter-III

56

11. Reaction of primary amides with triazidochlorosilane.

Elmorsy et al30 reported one step method for the conversion of primary acid

amides to 5-substituted tetrazoles by the reaction of triazidochlorosilane. (Scheme-13)

Scheme-13:

CONH2

NH

N

NN

Si

N3

N3

N3

Cl+CH3CN

29 30 31

12. Reaction of nitriles with tris (2-perfluorohexylethyl) tinazide:

Curran et al31 reported the synthesis of 5-substituted tetrazoles by the reaction of

nitriles with tris (2-perfluorohexylethyl) tinazide. (Scheme-14)

Scheme-14:

CNN N

NN

NH

NNN

Ether / HClBr(C6F13CH2)3SnN3+

Sn(C6F13CH2)32 33 34

13. Reaction of primary alcohols under micro wave:

A series of primary alcohols and aldehydes were treated with iodine in ammonia

water under microwave irradiation to give the intermediate nitriles, which without

isolation underwent [2 + 3] cycloaddition with dicyandiamide and sodium azide to afford

the corresponding triazines and tetrazoles in high yields32.(Scheme-15)

Scheme-15:

R OH R CN RN N

NHN4eq-I2NH3(28%,aq)

MW(100W)

60oC, 15-30min

4eq. NaN3

2eq. ZnBr2

MW(80W)

80oC 10-45min35 36 37

14. Reaction of 3-cyano-3-deoxy-5-O-tritylthymidine with dimethylammonium azide:

Pedersen et al33 reported the synthesis 5-substituted tetrazoles by the reaction of 3-

cyano-3-deoxy-5-O-tritylthymidine with dimethylammonium azide in DMF. (Scheme-

16)

Chapter-III

57

Scheme-16:

HN

N

O

O

O

O(Ph3)C

CN

HN

N

O

O

O

O(Ph3)C

NN

NH

N

Me2NH2N3

DMF

100oC

+

38 39

15. Reaction of 4-cyanochromen-2-one analog with NaN3:

3-Benzothiazol-2-yl-7-diethylamino-4-(1H-tetrazol-5-yl)-chromen-2-one is

prepared from 3-Benzothiazol-2-yl-7-diethylamino-4-cyanochromen-2-one and sodium

azide in presence of zinc bromide in 1,4-Dioxane25. (Scheme-17)

Scheme-17:

OEt2N O

CN S

N

OEt2N O

S

N

N

N N

NH

NaN3, ZnBr2

Dioxane 76%

40 41

PRESENT WORK

SYNTHESIS OF 6[(2-ALKYL-2H-TETRAZOL-5-YL) METHOXY]-4-

METHYL-2H-CHROMEN-2-ONES

The synthesis of 6[(2-alkyl-2H-tetrazol-5-yl) methoxy]-4-methyl-2H-cromen-2-ones

involves 3 steps.

1. Synthesis of 2-(4-methyl-2-oxo-2H-chromen-6-yloxy)acetonitrile (44a-b)

2. Synthesis of 6-((2H-tetrazol-5-yl)methoxy)-4-methyl-2H-chromen-2-one (45a-b)

3. Synthesis of 6[(2-alkyl-2H-tetrazol-5-yl) methoxy]-4-methyl-2H-cromen-2-ones

(47a-l)

Chapter-III

58

1. Synthesis of 2-(4-methyl-2-oxo-2H-chromen-6-yloxy)acetonitrile (44a-b)

6-hydroxy-4-methyl-2H-chromen-2-one (42a-b) and Chloroacetonotrile (43) were

dissolved in dry acetone and refluxed over anhydrous potassium carbonate for 3 hrs on

water bath to get the products (44a-b) which were purified on column chromatography

with pet.ether:ethylacetate (85:15) gave as white solid. (Scheme-18)

Scheme-18: Synthesis of 2-(4-methyl-2-oxo-2H-chromen-6-yloxy)acetonitrile (44a-b)

HO

O O

CH3

NC

O

O O

CH3

NC

Cl+

Acetone/K2CO3

Reflux; 3hr

R1 R1

42a-b 43 44a-b

a) R1 = H b) R1 = CH3

2-(4-methyl-2-oxo-2H-chromen-6-yloxy)acetonitrile (44a) is characterized from

its spectral data. In the IR spectra (Fig-3.1) the -C≡N group showed absorption at 2120

cm-1, C=O group showed absorption at 1707 cm-1 and the C=C of coumarin at 1571 cm-1.

In the 1H-NMR: (CDCl3, 400MHz) (Fig-3.2) -OCH2 appeared as a singlet at δ 4.85 and

the remaining coumarin moiety protons resonated at δ 7.33-7.35 (d, 1H, J=8.8Hz, 8-H),

7.17-7.22 (m, 2H, 7-H, 5-H), 6.34 (d, 1H, J=1.2Hz, 3-H), 2.44 (d, 3H, J=1.2Hz, 4-CH3).

13C-NMR: (CDCl3, 100MHz) (Fig-3.3) nitrile carbon (CN) clearly showed at δ 118.5 and

the other carbon signals appeared at δ 160.4 (C-2), 152.7 (C-6), 151.5 (C-4), 149.3 (C-

8a), 120.8 (C-8), 119.6 (C-4a), 116.0 (C-7), 114.7 (C-3), 110.2 (C-5), 54.6 (OCH2), and

18.6 (4-CH3). In the Mass (ES) spectra (Fig-3.4) the m/z [M+H]+ peak appeared at 216.2

confirm the structure.

2. Synthesis of 6-((2H-tetrazol-5-yl)methoxy)-4-methyl-2H-chromen-2-one (45a-b)

A mixture of 2-(4-methyl-2-oxo-2H-chromen-6-yloxy)acetonitrile (44a-b),

sodium azide and NH4Cl in DMF was heated for 8 hours at 120oC. The reaction mixture

was cooled to room temperature add crushed ice then a light cream colour precipitate was

obtained. It was collected by filtration and washed with water, dried at 50oC to get crude

compound which was purified by recrystallisation in methanol, if necessary compound

was purified on column chromatography with pet. ether: ethylacetate (70:30) gave as

Chapter-III

59

(45a-b) as light cream solid. In the above reaction nitrile of 44 is involved in the

formation of tetrazole to give 45.

Scheme-19: Synthesis of 6-((2H-tetrazol-5-yl)methoxy)-4-methyl-2H-chromen-2-one

(45a-b)

a) R1 = H, b) R1 = CH3

O O

CH3

ON

N

N NH

O

O O

CH3

NCNaN3

NH4Cl

DMF 120oC

+

R1R1

44a-b 45a-b

O O

CH3

ON

N

N N

R1

46a-b

H

not formed

There is a possibility for the formation of 2H-tetrazol (45a), 1H-tetrazol (46a), but

on the basis of literature survey and spectral characterization we confirmed the formation

of only 2H-tetrazol (45a) and the same is also confirmed by spectral studies of its N-alkyl

derivatives (48a-l).

6-((2H-tetrazol-5-yl)methoxy)-4-methyl-2H-chromen-2-one (45a) is characterized

from its spectral data. In the IR (KBr) (Fig-3.5) spectrum NH group showed absorption at

3221cm-1, C=O of coumarin at 1716 cm-1 and C=C of coumarin at 1575 cm-1. In the 1H-

NMR spectrum (Fig-3.6) -OCH2 appeared as a singlet at δ 5.60 and the remaining

coumarin protons were observed at δ 7.34-7.42 (m, 3H, 8-H, 5-H, 7-H), 6.43 (s, 1H, 3-

H), 2.44 (s, 3H, 4-CH3).

In the 13C-NMR (Fig-3.7) Tetrazole ‘C’ appeared at δ 161.8 and remaining at δ 163.1 (C-

2), 154.6 (C-6), 153.3 (C-4), 148.7 (C-8a), 120.9 (C-8), 119.9 (C-4a), 118.0 (C-7), 115.7

(C-3), 109.2 (C-5), 61.7 (OCH2), and 19.0 (4-CH3).

In the ES Mass Spectra (Fig-3.8) [M-H]+ peak appeared at m/z 257.0 also confirms the

formation of tetrazole.

3. Synthesis of 6[(2-alkyl-2H-tetrazol-5-yl) methoxy]-4-methyl-2H-cromen-2-ones

(48a-l)

6-((2H-tetrazol-5-yl)methoxy)-4-methyl-2H-chromen-2-one (45a-b) and Alkyl

bromide (47a-f) were dissolved in dry acetone and refluxed over anhydrous potassium

carbonate for 3 hrs on water bath. The completion of the reaction was monitored by TLC.

The acetone was removed under reduced pressure and crushed ice was added to the

Chapter-III

60

residue, compound was filtered and washed with plenty of water. The compounds were

purified on column chromatography with pet. ether: ethylacetate (85:15) gave as white

solid.

Scheme-20: Synthesis of 6[(2-alkyl-2H-tetrazol-5-yl) methoxy]-4-methyl-2H-cromen-2-

ones (48a-l)

O O

CH3

ON

N

N N

R1

not formed

R2

O O

CH3

ON

N

N NH

R1

O O

CH3

ON

N

N NR2

R1

Acetone/K2CO3

Reflux; 3hrR2

Br+

45a-b 47a-f

48a-l

R1 = H, CH3

a)

b)

c)

d)

e)

f)

g)

h)

i)

R1 R2

-H

-H

-H

-H

-H

-H

-CH3

-CH3

-CH3

-CH3

j)

k)

l)

R1 R2

-CH3

-CH3

Methyl

Ethyl

n-Propyl

n-Butyl

n-Pentyl

IsobutylIsobutyl

n-Butyl

n-Pentyl

n-Propyl

Ethyl

Methyl

In the NOESY spectrum (Fig-3.13) N-alkyl group does not show any nOe with

either R1 group or H-5 of coumarin moiety indicates that alkylation occurs at 2nd position

rather than 1st position of the tetrazole.

6[(2-ethyl-2H-tetrazol-5-yl) methoxy]-4-methyl-2H-cromen-2-ones (48b) is

characterized from its IR, NMR and Mass spectral data. In the 1H-NMR: (CDCl3,

400MHz) (Fig-3.9) N-CH2 proton appeared as a quartet at δ 4.54 with J=7.3Hz and 2"-

CH3 as triplet at δ 1.64 with J=7.3Hz, remaining protons at δ 7.22- 7.31 (m, 3H, Ar-H),

6.32 (s, 1H, 3-H), 5.48 (s, 2H, OCH2), 2.43 (s, 3H, 4-CH3). In the 13C-NMR: (CDCl3,

Chapter-III

61

100MHz) (Fig-3.10) 1"CH2 at δ 48.6 and 2"-CH3 at δ 16.5, remaining at δ 162.0 (C-2),

160.8 (C-5’), 154.2 (C-6), 151.9 (C-4), 148.4 (C-8a), 126.2 (C-8), 122.3 (C-4a), 121.0 (C-

7), 116.5 (C-3), 112.4 (C-5), 62.4 (OCH2) and 22.0 (4-CH3). In the ES Mass spectrum

(Fig-3.11) M+1 peak appeared at m/z 287.3.

EXPERIMENTAL

(i) 2-(4-methyl-2-oxo-2H-chromen-6-yloxy)acetonitrile (44a)

6-hydroxy-4-methyl-2H-chromen-2-one (42a) (5gr,

0.028mmol) and Chloroacetonotrile (43) (2.5ml, 0.03mmol)

were dissolved in 80 ml of dry acetone and refluxed over

anhydrous potassium carbonate for 3 hrs on water bath. The

completion of the reaction was monitored by TLC. The acetone was removed under

reduced pressure and crushed ice was added to the residue. The product 44a was filtered

and washed with plenty of water. Compound was characterized by IR, 1H-NMR, 13C-

NMR and Mass spectroscopic methods.

IR (KBr): υ C≡N at 2120 cm-1, C=O at 1707 cm-1 and C=C of coumarin at 1571 cm-1.

1H-NMR: (CDCl3, 400MHz): δ 7.33-7.35 (d, 1H, J=8.8Hz, 8-H), 7.17-7.22 (m, 2H, 5-H,

7-H), 6.34 (d, 1H, J=1.2Hz, 3-H), 4.85 (s, 2H, OCH2), 2.44 (d, 3H, J=1.2Hz, 4-CH3).

13C-NMR: (CDCl3, 100MHz): δ 160.4, 152.7, 151.5, 149.3, 120.8, 119.6, 118.5, 116.0,

114.7, 110.2, 54.6, and 18.6.

Mass (ES): m/z 216 [M+H]+. Anal. Calcd for C12H9NO3: C, 66.97; H, 4.22; N, 6.51.

Found: C, 66.85; H, 4.14; N, 6.77 %. M.P: 140oC, Yield: 85%.

(ii) 2-(4,7-dimethyl-2-oxo-2H-chromen-6-yloxy)acetonitrile (44b)

IR (KBr): υ C≡N at 2118 cm-1, C=O at 1705 cm-1 and C=C

of coumarin at 1567 cm-1.

1H-NMR: (CDCl3, 400MHz): δ 7.26 (s, 1H, 8-H), 7.23 (s,

1H, 5-H), 6.38 (d, 1H, J=1.2Hz, 3-H), 4.79 (s, 2H, OCH2),

2.36 (d, 3H, J=1.2Hz, 4-CH3), 2.12 (s, 3H, 7-CH3).

13C-NMR: (CDCl3, 100MHz): δ 161.2, 152.6, 150.3, 148.8, 121.1, 119.2, 117.3, 115.5,

112.0, 106.3, 52.6, 25.5, and 21.0.

O

O O

CH3

NC

12

3

44a5

6

7

88a

O

O O

CH3

NC

12

3

44a5

6

7

88aH3C

Chapter-III

62

Mass (ES): m/z 230.11 [M+H]+. Anal. Calcd for C13H11NO3: C, 68.11; H, 4.84; N, 6.11.

Found: C, 67.94; H, 4.66; N, 6.32.M.P: 162oC, Yield: 83%.

(iii) 6-((2H-tetrazol-5-yl)methoxy)-4-methyl-2H-chromen-2-one (45a)

A mixture of 2-(4-methyl-2-oxo-2H-chromen-6-

yloxy)acetonitrile (44a) (3gr, 0.013mmol), sodium

azide (1gr, 0.014mmol) and NH4Cl (0.85gr,

0.015mmol) in 75 ml of DMF was heated for 8 hours

at 120oC. The reaction mixture was cooled to room temperature and crushed ice was

added, a light cream colour precipitate was obtained. It was collected by filtration and

washed with water, dried at 50oC to get crude compound which was purified by

recrystallisation in methanol furnished pure compound (45a) as light cream solid.

IR (KBr): υ NH at 3221cm-1 and C=O at 1716 cm-1, C=C of coumarin at 1575 cm-1.

1H-NMR: (DMSO-D6, 400MHz): δ 7.34-7.42 (m, 3H, 8-H, 5-H, 7-H), 6.43 (s, 1H, 3-H),

5.60 (s, 2H, OCH2), 2.44 (s, 3H, 4-CH3).

13C-NMR: (DMSO-D6, 100MHz): δ 163.1, 161.8, 154.6, 153.3, 148.7, 120.9, 119.9,

118.0, 115.7, 109.2, 61.7, and 19.0.

Mass (ES): m/z 259.10 [M+H]+. Anal. Calcd for C12H10N4O3: C, 55.81; H, 3.90; N, 21.70.

Found: C, 55.55; H, 3.78; N, 22.03. M.P:246oC, Yield: 76%.

(iv) 6-((2H-tetrazol-5-yl)methoxy)-4,7-dimethyl-2H-chromen-2-one (45b)

IR (KBr): υ NH at 3218cm-1 and C=O at 1718 cm-1, C=C

of coumarin at 1566 cm-1.

1H-NMR: (DMSO-D6, 400MHz): δ 7.16 (s, 1H, 8-H),

7.12 (s, 1H, 5-H), 6.46 (s, 1H, 3-H), 5.68 (s, 2H, OCH2),

2.92 (s, 3H, 4-CH3), 2.87 (s, 3H, 7-CH3).

13C-NMR: (DMSO-D6, 100MHz): δ 162.4, 161.7, 157.4, 154.0, 149.5, 126.7, 121.8,

119.8, 111.4, 109.2, 64.6, 25.1 and 21.7.


Found: C, 57.16; H, 4.23; N, 20.64. M.P: 251oC, Yield: 68%.

12

3

45

6

7

8O O

CH3

ON

N

N NH 1'2'

3'

4'

5'

8a

4a

12

3

45

6

7

8O O

CH3

ON

N

N NH

H3C

1'2'

3'

4'

5'

8a

4a

Chapter-III

63

(v) 6-((2-methyl-2H-tetrazol-5-yl)methoxy)-4-methyl-2H-chromen-2-one (48a)

6-((2H-tetrazol-5-yl)methoxy)-4-methyl-2H-

chromen-2-one (45a) (1gr, 0.003mmol) and methyl

bromide (47a) (0.35ml, 0.003mmol) were dissolved

in 50ml of dry acetone, refluxed over anhydrous

potassium carbonate for 3 hrs on water bath. The completion of reaction was monitored

by TLC. The acetone was removed under reduced pressure and crushed ice was added to

the residue. The product (48a) was filtered and washed with plenty of water.

IR (KBr): υ C=O at 1720 cm-1, C=C of coumarin at 1577 cm-1.

1H-NMR: (CDCl3, 400MHz): δ 7.16-7.24 (m, 3H, 8-H, 5-H, 7-H), 6.39 (s, 1H, 3-H), 5.42

(s, 2H, OCH2), 4.38 (s, 3H, N-CH3), 2.82 (s, 3H, 4-CH3).

13C-NMR: (CDCl3, 100MHz): δ 161.9, 160.8, 152.3, 149.8, 147.3, 120.6, 118.0, 116.9,

115.2, 108.0, 60.7, 50.7, and 24.7.


Found: C, 57.04; H, 4.22; N, 20.88. M.P:180oC, Yield: 65%.

(vi) 6-((2-ethyl-2H-tetrazol-5-yl)methoxy)-4-methyl-2H-chromen-2-one (48b)

IR (KBr): υ C=O at 1726 cm-1, C=C of coumarin at

1572 cm-1.

1H-NMR: (CDCl3, 400MHz): δ 7.24-7.31 (m, 1H, 8-

H), 7.20-7.23 (m, 2H, 5-H, 7-H), 6.32 (s, 1H, 3-H),

5.48 (s, 2H, OCH2), 4.54 (q, 2H, J=7.3Hz, N-CH2),

2.43 (s, 3H, 4-CH3), 1.64 (t, 3H, J=7.3Hz, 2"-CH3).

13C-NMR: (CDCl3, 100MHz): δ 162.0, 160.8, 154.2, 151.9, 148.4, 120.5, 119.3, 118.1,

115.6, 109.4, 61.4, 48.6, 18.7, and 14.5.

Mass (ES): m/z 287 [M+H]+. Anal. Calcd for C14H14N4O3: C, 58.73; H, 4.93; N, 19.57.


12

3

45

6

7

8O O

CH3

ON

N

N NH3C 1'2'

3'

4'

5'

8a

4a

12

3

45

6

7

8O O

CH3

ON

N

N N1'2'

3'

4'

5'

1''

2''

8a

4a

Chapter-III

64

(vii) 6-((2-propyl-2H-tetrazol-5-yl)methoxy)-4-methyl-2H-chromen-2-one (48c)

IR (KBr): υ C=O at 1732 cm-1, C=C of coumarin

at 1571 cm-1.

1H-NMR: (CDCl3, 400MHz): δ 7.01-7.12 (m, 3H,

8-H, 5-H, 7-H), 6.22 (d, 1H, J=0.8Hz, 3-H), 5.33

(s, 2H, OCH2), 4.38(t, 2H, J=7.2Hz, 1"-CH2), 2.41

(d, 3H, J=0.8Hz, 4-CH3), 1.92-1.99 (m, 2H, 2"-CH2), 1.28 (t, 3H, J=7.2Hz, 3"- CH3).

13C-NMR: (CDCl3, 100MHz): δ 161.9, 160.2, 150.6, 150.1, 148.7, 132.3, 116.2, 114.7,

112.8, 101.1, 62.8, 50.8, 31.3, 25.7 and 23.8.



(viii) 6-((2-butyl-2H-tetrazol-5-yl)methoxy)-4-methyl-2H-chromen-2-one (48d)

IR (KBr): υ C=O at 1734 cm-1, C=C of

coumarin at 1569 cm-1.

1H-NMR: (CDCl3, 400MHz): δ 7.27-7.29 (m,

1H, 8-H), 7.22-7.25 (m, 2H, 5-H, 7-H), 6.31 (d,

1H, J=1.2Hz, 3-H), 5.39 (s, 2H, OCH2), 4.64 (t,

2H, J=7.2Hz, 1"-CH2), 2.42 (d, 3H, J=1.2Hz, 4-CH3), 1.97-2.04 (m, 2H, 2"-CH2), 1.32-

1.38 (m, 2H, 3"- CH2), 0.95 (t, 3H, J=7.6Hz, 4"-CH3).

13C-NMR: (CDCl3, 100MHz): δ 162.0, 160.8, 154.2, 151.9, 148.4, 120.5, 119.4, 118.0,

115.6, 109.5, 61.4, 53.1, 31.1, 19.5, 18.7and13.3.


Found: C, 60.77; H, 5.54; N, 18.01. M.P: 95-98oC, Yield: 86%.

(ix) 6-((2-pentyl-2H-tetrazol-5-yl)methoxy)-4-methyl-2H-chromen-2-one (48e)

IR (KBr): υ C=O 1735 cm-1, C=C of


1H-NMR: (CDCl3, 400MHz): δ 7.24-7.29 (m,

3H, 8-H, 5-H, 7-H), 6.31 (d, 1H, J=1.2Hz, 3-

H), 5.39 (s, 2H, OCH2), 4.63 (t, 2H, J=6.8Hz,

12

3

45

6

7

8O O

CH3

ON

N

N N1'2'

3'

4'

5'

1''

2''

3''

8a

4a

12

3

45

6

7

8O O

CH3

ON

N

N N1'2'

3'

4'

5'

1''

2''

3''

4''

8a

4a

12

3

45

6

7

8O O

CH3

ON

N

N N1'2'

3'

4'

5'

1''

2''

3''

4''

5''

8a

4a

Chapter-III

65

1"-CH2), 2.42 (d, 3H, J=1.2Hz, 4-CH3), 1.99-2.06 (m, 2H, 2"-CH2), 1.29-1.39 (m, 4H, 3"-

CH2, 4"-CH2), 0.90(t, 3H, J=6.8Hz, 5"-CH3).

13C-NMR: (CDCl3, 100MHz): δ 161.9, 160.8, 154.2, 151.9, 148.3, 120.5, 119.4, 118.0,

115.5, 109.4, 61.4, 53.4, 28.9, 28.3, 21.9, 18.7 and 13.7.



(x) 6-((2-isobutyl-2H-tetrazol-5-yl)methoxy)-4-methyl-2H-chromen-2-one (48f)

IR (KBr): υ C=O at 1726 cm-1, C=C of coumarin

at 1573 cm-1.

1H-NMR: (CDCl3, 400MHz): δ 7.27-7.30 (m, 1H,

8-H), 7.20-7.24 (m, 2H, 5-H, 7-H), 6.29 (s, 1H, 3-

H), 5.56 (s, 2H, OCH2), 4.58 (d, 2H, J=7.2Hz, 1"-

CH2), 2.56 (s, 3H, 4-CH3), 2.39-2.48 (m, 1H, 2"-CH), 1.01 (d, 6H, J=6.8Hz, 3"- (CH3)2).

13C-NMR; (CDCl3, 100MHz): δ 163.8, 162.7, 153.7, 153.0, 149.1, 134.8, 120.7, 118.8,

115.1, 106.9, 62.2, 60.9, 20.2, 19.3 and 17.8.



(xi) 6-((2-methyl-2H-tetrazol-5-yl)methoxy)-4,7-dimethyl-2H-chromen-2-one (48g)


1568 cm-1.

1H-NMR: (CDCl3, 400MHz): δ 7.18 (s, 1H, 8-H),

7.15 (s, 1H, 5-H), 6.54 (s, 1H, 3-H), 5.59 (s, 2H,

OCH2), 4.61 (s, 3H, N-CH3), 2.97 (s, 3H, 4-CH3),

2.91 (s, 3H, 7-CH3).

13C-NMR (CDCl3, 100MHz): δ 162.6, 161.2, 154.6, 152.3, 148.9, 121.1, 120.8, 118.8,

116.2, 109.8, 61.4, 51.6, 26.4and 22.6.



12

3

45

6

7

8O O

CH3

ON

N

N N1'2'

3'

4'

5'

1''

2''

3''

8a

4a3''

12

3

45

6

7

8O O

CH3

ON

N

N NH3C

H3C

1'2'

3'

4'

5'

8a

4a

Chapter-III

66

(xii) 6-((2-ethyl-2H-tetrazol-5-yl)methoxy)-4,7-dimethyl-2H-chromen-2-one (48h)


1573 cm-1.


7.11 (s, 1H, 5-H), 6.25 (d, 1H, J=1.2Hz, 3-H), 5.40 (s,

2H, OCH2), 4.69 (q, 2H, J=7.6Hz, 1"-CH2), 2.43 (d,

3H, J=1.2Hz, 4-CH3), 2.33 (s, 3H, 7-CH3), 1.67 (t, 3H, J=7.6Hz, 2"-CH3).

13C-NMR: (CDCl3, 100MHz): δ 162.2, 161.2, 152.8, 152.1, 148.3, 133.3, 119.0, 118.0,

114.3, 106.1, 61.4, 48.6, 18.8, 16.7 and 14.4.



(xiii) 6-((2-propyl-2H-tetrazol-5-yl)methoxy)-4,7-dimethyl-2H-chromen-2-one (48i)


1571 cm-1.


7.10 (s, 1H, 5-H), 6.27 (d, 1H, J=1.2Hz, 3-H), 5.43

(s, 2H, OCH2), 4.67 (t, 2H, J=7.2Hz, 1"-CH2), 2.48

(d, 3H, J=1.2Hz, 4-CH3), 2.37 (s, 3H, 7-CH3) 2.09-2.14 (m, 2H, 2"-CH2), 1.30 (t, 3H,

J=7.2Hz, 3"- CH3).

13C-NMR: (CDCl3, 100MHz): δ 162.1, 161.8, 151.9, 151.2, 149.0, 132.9, 119.3, 118.6,

115.2, 103.2, 63.4, 55.1, 30.2, 29.6, 26.3 and 21.8.



(xiv) 6-((2-butyl-2H-tetrazol-5-yl)methoxy)-4,7-dimethyl-2H-chromen-2-one (48j)



1H-NMR: (CDCl3, 400MHz): δ 7.11 (s, 1H, 8-

H), 7.07 (s, 1H, 5-H), 6.20 (d, 1H, J=1.2Hz, 3-

H), 5.38 (s, 2H, OCH2), 4.66 (t, 2H, J=7.2Hz, 1"-

12

3

45

6

7

8O O

CH3

ON

N

N N

H3C

1'2'

3'

4'

5'

1''

2''

8a

4a

12

3

45

6

7

8O O

CH3

ON

N

N N

H3C

1'2'

3'

4'

5'

1''

2''

3''

8a

4a

12

3

45

6

7

8O O

CH3

ON

N

N N

H3C

1'2'

3'

4'

5'

1''

2''

3''

4''

8a

4a

Chapter-III

67

CH2), 2.41 (d, 3H, J=1.2Hz, 4-CH3), 2.30 (s, 3H, 7-CH3), 1.96-2.02 (m, 2H, 2"-CH2),

1.30-1.37 (m, 2H, 3"- CH2), 0.85 (t, 3H, J=7.2Hz, 4"-CH3).

13C-NMR; (CDCl3, 100MHz): δ 61.9, 159.0, 152.7, 151.9, 147.6, 132.8, 117.6, 117.1,

113.7, 105.1, 61.2, 52.9, 27.5, 20.8, 18.2, 16.2 and 14.3.



(xv) 6-((2-pentyl-2H-tetrazol-5-yl)methoxy)-4,7-dimethyl-2H-chromen-2-one (48k)



1H-NMR: (CDCl3, 400MHz): δ 7.13 (s, 1H, 8-

H), 7.09 (s, 1H, 5-H), 6.23 (d, 1H, J=1.2Hz,

3-H), 5.40 (s, 2H, OCH2), 4.63 (t, 2H,

J=7.2Hz, 1"-CH2), 2.43 (d, 3H, J=1.2Hz, 4-CH3), 2.32 (s, 3H, 7-CH3), 2.01-2.04 (m, 2H,

2"-CH2), 1.27-1.36 (m, 4H, 3"-CH2, 4"-CH2), 0.88 (t, 3H, J=7.2Hz, 5"-CH3).

13C-NMR: (CDCl3, 100MHz): δ 162.1, 161.2, 152.7, 152.2, 148.3, 133.3, 118.9, 118.0,

114.2, 106.2, 61.4, 53.3, 28.9, 28.3, 21.9, 18.7, 16.6 and 13.7.



(xvi)6-((2-isobutyl-2H-tetrazol-5-yl)methoxy)-4,7-dimethyl-2H-chromen-2-one (48l)


1568 cm-1.


7.15 (s, 1H, 5-H), 6.24 (s, 1H, 3-H), 5.41 (s, 2H,

OCH2), 4.46 (d, 2H, J=7.2Hz, 1"-CH2), 2.42 (s, 3H,

4-CH3), 2.31-2.42 (m, 1H, 2"-CH), 2.32 (s, 3H, 7-CH3), 0.96 (d, 6H, J=6.8Hz, 3"-

(CH3)2).

13C-NMR; (CDCl3, 100MHz): δ 162.1, 161.2, 152.8, 152.1, 148.3, 133.3, 119.0, 118.0,

114.3, 106.2, 61.5, 60.2, 29.2, 19.7, 18.7 and 16.7.

Mass (ES): m/z 329.3[M+H]+. Anal. Calcd for C17H20N4O3: C, 62.18; H, 6.14; N, 17.06.


12

3

45

6

7

8O O

CH3

ON

N

N N

H3C

1'2'

3'

4'

5'

1''

2''

3''

4''

5''

8a

4a

12

3

45

6

7

8O O

CH3

ON

N

N N1'2'

3'

4'

5'

1''

2''

3''

8a

4a3''

H3C

Chapter-III

68

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heterotetrazoles.

Chapter-III

69

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Chapter-III

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Chapter-III

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Chapter-III INTRODUCTIONshodhganga.inflibnet.ac.in/bitstream/10603/22407/9/09_chapter_3.pdf · Tetrazole derivates are well known as compounds with a high level of biological activity8.

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