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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
Chapter-III
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
Chapter-III
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.
Mass (ES): m/z 273.1 [M+H]+. Anal. Calcd for C13H12N4O3: C, 57.35; H, 4.44; N, 20.58.
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.
Mass (ES): m/z 273.2 [M+H]+. Anal. Calcd for C13H12N4O3: C, 57.35; H, 4.44; N, 20.58.
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.
Found: C, 58.54; H, 4.62; N, 19.84. M.P: 139oC, Yield: 80%.
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.
Mass (ES): m/z 301.19 [M+H]+. Anal. Calcd for C15H16N4O3: C, 59.99; H, 5.37; N, 18.66.
Found: C, 59.75; H, 5.21; N, 18.90. M.P: 120oC, Yield: 81%.
(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.
Mass (ES): m/z 315.18 [M+H]+. Anal. Calcd for C16H18N4O3: C, 61.13; H, 5.77; N, 17.82.
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
coumarin at 1574 cm-1.
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.
Mass (ES): m/z 329.14 [M+H]+. Anal. Calcd for C17H20N4O3: C, 62.18; H, 6.14; N, 17.06.
Found: C, 62.09; H, 6.02; N, 17.35. M.P: 88-91oC, Yield: 90%.
(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.
Mass (ES): m/z 315.2 [M+H]+. Anal. Calcd for C16H18N4O3: C, 61.13; H, 5.77; N, 17.82.
Found: C, 60.76; H, 5.63; N, 18.22. M.P: 126oC, Yield: 78%.
(xi) 6-((2-methyl-2H-tetrazol-5-yl)methoxy)-4,7-dimethyl-2H-chromen-2-one (48g)
IR (KBr): υ C=O at 1732 cm-1, C=C of coumarin at
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.
Mass (ES): m/z 287.3 [M+H]+. Anal. Calcd for C14H14N4O3: C, 58.73; H, 4.93; N, 19.57.
Found: C, 58.51; H, 4.85; N, 19.75. M.P: 177oC, Yield: 69%.
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)
IR (KBr): υ C=O at 1728 cm-1, C=C of coumarin at
1573 cm-1.
1H-NMR: (CDCl3, 400MHz): δ 7.13 (s, 1H, 8-H),
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.
Mass (ES): m/z 301.22 [M+H]+. Anal. Calcd for C15H16N4O3: C, 59.99; H, 5.37; N, 18.66.
Found: C, 59.82; H, 5.18; N, 18.87. M.P: 120oC, Yield: 81%.
(xiii) 6-((2-propyl-2H-tetrazol-5-yl)methoxy)-4,7-dimethyl-2H-chromen-2-one (48i)
IR (KBr): υ C=O at 1728 cm-1, C=C of coumarin at
1571 cm-1.
1H-NMR: (CDCl3, 400MHz): δ 7.13 (s, 1H, 8-H),
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.
Mass (ES): m/z 315.18 [M+H]+. Anal. Calcd for C16H18N4O3: C, 61.13; H, 5.77; N, 17.82.
Found: C, 60.92; H, 5.51; N, 18.09. M.P: 116oC, Yield: 88%.
(xiv) 6-((2-butyl-2H-tetrazol-5-yl)methoxy)-4,7-dimethyl-2H-chromen-2-one (48j)
IR (KBr): υ C=O at 1729 cm-1, C=C of
coumarin at 1566 cm-1.
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.
Mass (ES): m/z 329.14 [M+H]+. Anal. Calcd for C17H20N4O3: C, 62.18; H, 6.14; N, 17.06.
Found: C, 62.10; H, 6.02; N, 17.37. M.P: 93oC, Yield: 88%.
(xv) 6-((2-pentyl-2H-tetrazol-5-yl)methoxy)-4,7-dimethyl-2H-chromen-2-one (48k)
IR (KBr): υ C=O at 1722 cm-1, C=C of
coumarin at 1572 cm-1.
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.
Mass (ES): m/z 343.16 [M+H]+. Anal. Calcd for C18H22N4O3: C, 63.14; H, 6.48; N, 16.36.
Found: C, 63.07; H, 6.24; N, 16.71. M.P: 82-85oC, Yield: 92%.
(xvi)6-((2-isobutyl-2H-tetrazol-5-yl)methoxy)-4,7-dimethyl-2H-chromen-2-one (48l)
IR (KBr): υ C=O at 1724 cm-1, C=C of coumarin at
1568 cm-1.
1H-NMR: (CDCl3, 400MHz): δ 7.18 (s, 1H, 8-H),
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.
Found: C, 61.95; H, 5.93; N, 17.42. M.P: 131oC, Yield: 80%.
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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Chapter-III
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Chapter-III
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Chapter-III
71
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