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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:
Pale yellow solid; Yield : 62%, mp= 181-82 °C
(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.
Calcd for C22H14N2O2 (%): C, 78.09; H, 4.17; N, 8.28, Found: C, 78.05; H,
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.
Calcd for C19H16N2O3 (%): C, 71.24; H, 5.03; N, 8.74, Found: C, 71.20; H,
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:
Pale yellow solid; Yield : 45%, mp= 159-60 °C
(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:
Off white solid, yield: 63% (Ethanol), mp= 176-78
°C; FT-IR (KBr) cm-1: 1725 (C=O); 1H-NMR
(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:
Off white solid, yield: 65% (Ethanol), mp= 133-35
°C; FT-IR (KBr) cm-1: 1720 (C=O); 1H-NMR
(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
Jvic(CH) = 6.4 Hz, Jgem = 11.2 Hz, –CH2), 4.21 (dd, 1H, Jvic(CH) = 6.4 Hz, Jgem =
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
(Column Purification 25:75 Ethylacetate: Hexane);
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
(Ethyl acetate); FT-IR (KBr) cm-1: 1693 (C=O),
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
(Ethyl acetate); FT-IR (KBr) cm-1: 1690 (C=O),
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,
Jvic(CH) = 6.4 Hz, Jgem = 10.8 Hz, –CH2), 4.23 (dd, 1H, Jvic(CH) = 6.8 Hz, Jgem =
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
(Column Purification 15:85 Ethylacetate: Hexane);
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
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Southern Federal University, Russia.
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