Zeolite H-Bea catalysed multicomponent reaction: One-Pot synthesis of amidoalkyl naphthols - Biologically active drug-like molecules

Article abstract of DOI:10.1007/s12039-011-0095-2

Zeolite has been used as an efficient and a novel heterogeneous catalyst for one-pot synthesis of biologically active drug-like molecules, amidoalkyl naphthols. This green route involves multicomponent reaction of 2-naphthol, aromatic aldehydes and amide

Full text of DOI:10.1007/s12039-011-0095-2

c
J. Chem. Sci. Vol. 123, No. 4, July 2011, pp. 427–432. ꢀ Indian Academy of Sciences.
Zeolite H-BEA catalysed multicomponent reaction: One-pot synthesis
of amidoalkyl naphthols – Biologically active drug-like molecules
SUNIL R MISTRYa, RIKESH S JOSHIb and KALPANA C MAHERIAa,∗
aApplied Chemistry Department, S V National Institute of Technology, Surat 395 007, India
bSud Chemie India Pvt. Ltd., Nandesari-391 340, Gujarat, India
e-mail: maheria@gmail.com
MS received 10 September 2010; revised 2 December 2010; accepted 16 May 2011
Abstract. Zeolite has been used as an efficient and a novel heterogeneous catalyst for one-pot synthesis
of biologically active drug-like molecules, amidoalkyl naphthols. This green route involves multicomponent
reaction of 2-naphthol, aromatic aldehydes and amide in the presence of a catalytic amount of zeolite H-Beta
(H-BEA) under solvent reflux as well as solvent-free conditions.
Keywords. Zeolite; multicomponent reaction; amidoalkyl naphthol; green chemistry.
1. Introduction
reaction, 1-amidomethyl-2-naphthols can be converted
to important biologically active 1-aminomethyl- 2-
naphthol derivatives. The hypotensive and bradycar-
diac effects of these compounds have been reported.4
The preparation of 1-amidoalkyl-2-naphthols can be
carried out by multi-component condensation of aryl
aldehydes, 2-naphthol and acetonitrile or amide in the
presence of Lewis or Brønsted acid catalysts such
as montmorillonite K10 clay,5 HClO4–SiO2,6 iodine,7
heteropolyacids,8 p-TSA,9 sulfamic acid,10 and cation-
exchange resins.11 However, some of these methods
associated with prolonged reaction time, toxicity and
low yields of desired product. Further, when a solid
aldehyde or high amounts of catalyst is used, an organic
solvent such as dichloroethane is needed.10 In this
context, there is growing interest in development of
clean processes involving green catalysts. Increasing
demand for environmentally benign procedures with
heterogeneous and reusable catalyst12 encourage us to
develop a safe alternate method for the synthesis of
amidoalkyl naphthols using acidic zeolite. To the best
of our knowledge, no reports are available on the syn-
thesis of amidoalkyl naphthol using zeolite as catalyst
(scheme 1).
The use of acidic zeolites in different areas of the
organic chemistry has now reached significant levels,
not only for the possibility to perform environmentally
benign synthesis, but also for the good yields.1 Further,
zeolites are broadly used in the synthesis of specialty
and fine chemicals. They have received an increasing
attention because of their tunable acidity and the vari-
ety of structures and pore dimensions. The other salient
features of zeolite include their low cost and excel-
lent thermal stability which make them economically
and environmentally feasible.2 The use of zeolites as a
catalyst is important in the development of clean tech-
nologies, since it avoids the drawbacks of the con-
ventional technologies, mainly environmental pollution
and corrosion of the equipment (figure 1).
Multicomponent reactions (MCRs) have attracted
considerable attention since an increasing number of
organic chemical compounds are formed by multicom-
ponent reactions (MCRs) that convert more than two
educts directly into their products by one-pot reactions.
Further, they are performed without need to isolate any
intermediate during their processes; this reduces time
and saves both energy and raw material. They have me-
rits over two-component reactions in several aspects in-
cluding the simplicity of a one-pot procedure, possible
structural variations and building up complex molecules.3
One of these MCRs is the preparation of amidoalkyl
naphthols. It is worthy to note that by amide hydrolysis
2. Experimental
2.1 Materials and methods
The composition of anhydrous Na-BEA zeolite was
obtained from Sud-Chemie India Pvt Ltd., India. The
∗For correspondence
427

428
Sunil R Mistry et al.
H
O
O
O
O
O
+
Si
O
O
O
550 ˚C
Al
Si
Al
Si
Si
2
Δ
O
O
O
O
O
O
O
Lewis acid form of zeolite
H
+
O
O
O
O
O
Si
H2O
Al
+
Si
O
O
O
Bronsted acid form of zeolite
Figure 1. Lewis and Bronsted acidic form of zeolite.
H-form zeolite was prepared by ion exchange of the Na- 2.2 Procedure for the synthesis of amidoalkyl
form sample with aqueous solution of NH4NO3 (1M) or naphthols
alkali metal acetate, followed by drying and calcination
To a mixture of 2-naphthol (1 mmol), aldehydes
(1 mmol) and acetamide (1.2 mmol), effective amount
of zeolite H-BEA was added. The mixture was stirred
under thermal solvent-free condition at 120◦C in oil
bath for 5–7 min and the reaction was followed by
TLC. After completion of reaction, mass was cooled to
25◦C, then the solid residue was dissolved in EtOAc and
the mixture stirred for 5 min. The catalyst was recov-
ered. Then solvent was evaporated, the remaining solid
product was recrystallized in aqueous EtOH (15%).
All products are known and compounds were charac-
terized by melting point (mp), 1H-NMR, 13C-NMR and
FT-IR and MS. Some physical data of these compounds
are represented below:
at 823 K.
The X-ray diffractogram (2θ = 5–65◦) were obtained
on X-ray diffractometer (D8 Advanced Brucker AXS,
Germany) with Cu–Kα radiation and nickel filter. Sur-
face area measurement (BET method) was carried
out on Micromeritics Gemini at 196◦C using nitrogen
adsorption isotherms. Acidity of zeolites were deter-
mined on Micromeritics Chemisorb 2720, by a tem-
perature programmed desorption of ammonia. Ammo-
nia was chemisorbed at 120◦C and then desorption was
carried out up to 700◦C at heating rate of 10◦C/min.
The solvents were distilled before use. All reagents
used were of analytical grade. NMR spectra were
recorded on a Varian 200 MHz. IR spectra were run on
a (FT-IR) (Shimadzu make, model 8400 S) using KBr
powder. Mass spectra were recorded on VG micromass
7070 H. The purity of the substances and the progress
of the reactions were monitored by TLC on silica gel.
2.2a N-[Phenyl-(2-hydroxy-naphthalen-1-yl)-methyl]-
acetamide (table 2, entry 1): White solid; M.p.
O
H
C
Zeolite H-BEA
OH
+
Method A and B
OH
CH
O
NH
+
H3C
O
H3C
NH2
Method A: Under toluene reflux
Method B: Thermal Solvent-Free conditions
Scheme 1.

Zeolite catalyst in MCRs
429
1
244–245◦C; H NMR (DMSO-d6): δ = 1.98 (s, 3H), 2.2d N-[(2-Chloro-phenyl)-(2-hydroxy-napthalen-1-yl)-
7.18–1.10 (m, 4H), 7.25–7.20 (m, 4H), 7.33 (t, methyl]-acetamide (table 2, entry 11) M.p. 213–215◦C::
J = 7.5 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H,), 7.81 (d, 1H NMR (DMSO-d6): δ = 1.91 (s, 3H), 7.08–7.56 (m,
J = 8.0 Hz, 1H), 7.84 (s, 1H), 8.46 (d, J = 8.5 Hz, 1H), 8H), 7.73 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 6.1 Hz, 1H),
10.02 (s, 1H) ppm; 13C NMR (125 MHz, DMSO-d6): 8.00 (t, J = 7.0 Hz, 1H), 8.50 (s, 1H), 9.75 (s, 1H) ppm;
23.3, 40.1, 119.2, 119.4, 122.4, 123.8, 126.6, 126.9, IR (KBr): 3427, 3061, 1640, 1514, 1438, 1268, 808,
128.4, 128.6, 128.9, 129.1, 129.8, 132.9, 143.1, 153.7, 752, 501 cm−1; MS m/z: 325 ([M+H]+).
168.9 ppm; IR (KBr): 3400, 3250, 3063, 1640, 1581,
1514, 1372, 1337, 1060, 808, 742, 696, 623 cm−1; MS
3. Results and discussion
m/z : 292 ([M+H]+).
In order to carry out synthesis of amidoalkyl naph-
thol in a more efficient way that minimizes time and
the amount of catalyst, the reaction of 2-naphthol, ben-
zaldehyde and acetamide was selected as a model reac-
tion. The best result was obtained by carrying out the
reaction with 1:1:1.2 molar ratios of 2-naphthol, ben-
zaldehyde acetamide and 7 wt% of zeolite H-BEA.
Further, looking towards the % yield (85%) and shorter
2.2b N-[(4-Methylphenyl)-(2-hydroxynapthalen-1-
yl)-methyl]-acetamide (table 2, entry 2): M.p. 222–
224 ◦C; 1H NMR (DMSO-d6): δ = 1.96 (s, 3H), 2.21(s,
3H), 7.08–7.03(m, 5H), 7.19(d, J = 8.8 Hz, 1H), 7.24(t,
J = 7.1 Hz, 1H), 7.34(m, 1H), 7.74(d, J = 8.8 Hz,
1H), 7.78(d, J = 7.9 Hz, 1H), 7.82(brd, 1H), 8.36(d,
J = 8.1 Hz, 1H), 9.91(s, 1H) ppm; 13C NMR (125 MHz,
reaction time (5–7 min), thermal solvent-free condition
DMSO-d6): 20.4, 22.6, 47.6, 118.4, 118.9, 122.2,
is found to be more beneficial compared to the solvent
123.1, 125.9, 126.1, 128.3, 128.4, 128.9, 132.2, 134.9,
139.4, 143.3, 152.9, 168.9 ppm.; IR (KBr): 3419, 3316,
reflux condition (table 1).
Thus, we have made an attempt to prepare a range
3070, 1621, 1595, 1561, 1514, 1466, 1392, 1283, 1202,
1141, 1051, 939, 884, 784, 745, 712 cm−1; MS m/z:
305 ([M+H]+); Anal. Calcd. for C20H19NO2: C:
78.66; H: 6.27; N: 4.59 %. Found: C: 78.75; H: 6.19; N:
4.62 %.
of amidoalkyl naphthols under the optimized reac-
tion conditions i.e., 2-naphthol (1 mmol), aryl aldehy-
des (1 mmol), and acetamide (1.2 mmol) in the pres-
ence of zeolite H-BEA (7 wt%). A series of amidoalkyl
naphthols were prepared in high to excellent yields in
thermal solvent-free conditions (table 2). In all cases,
aromatic aldehydes with substituents carrying either
electron-donating or electron-withdrawing groups gave
the desired products in Method A and B with yield of
70–90%. The XRD patterns of zeolite before and after
the reaction revealed that the zeolite retained its crys-
tallinity throughout. Thus, the catalyst can be reused.
Further, the catalysts were recycled for five runs without
significant loss of activity (figure 2).
2.2c N-[(4-Methoxy-phenyl)-(2-hydroxy-napthalen-1-
yl)- methyl]-acetamide (table 2, entry 9) M.p. 181–
183◦C: 1H NMR (DMSO-d6): δ = 10 (s, 1H), 8.4 (d,
1H), 7.80–7.73 (m, 4H), 7.35–7.05 (m, 6H), 2.51 (s,
3H), 1.94 (s, 3H). IR (KBr): 3399, 3063, 3000, 2964,
2830, 2785, 2704, 1626, 1581, 1514, 1438, 1372, 1337,
1280, 1257, 1180, 1086, 1060, 1045, 928, 879, 847,
820, 746 cm−1; MS m/z: 322 ([M+H]+).
Table 1. Optimization of catalyst concentration.a
Entry H-BEA Reflux condition Thermal solvent-free condition
Time (h) Yield (%) Time (min)
Yieldb (%)
1
2
3
4
5
2 wt %
5 wt %
7 wt %
10 wt %
15 wt %
10-11
7-9
4-6
4-6
4-6
55
69
78
70
72
10-15
9-10
5-7
5-7
5-7
61
75
85
79
73
aReaction condition:
2-naphthol/aldehyde/acetamide (1/1/1.2) under toluene reflux,
2-naphthol/aldehyde/acetamide/catalyst (1/1/1.2) under thermal solvent-free
condition, oil bath, 120◦C
bYields refers to the pure isolated products

430
Sunil R Mistry et al.
ArCHO
Table 2. Synthesis of amidoalkyl naphthols using zeolite
H-BEA.a
Zeolite H-BEA
OH
O
Entry
Aldehydes
C6H5CHO
Time (min)/yield (%)c
Ar
H
1
2
3
4
5
6
7
8
5-7/85
5-7/73
5-7/90
5-7/70
5-7/80
5-7/82
5-7/78
5-7/80
5-7/82
5-7/80
5-7/76
5-7/80
5-7/65
10/-
O-QMs
4-Me C6H4CHO
4-NO2-C6H4CHO
4-NMe2 C6H3CHO
4-Cl-C6H4 CHO
4-Br-C6H4CHO
4-F- C6H4CHO
2,4-Cl2- C6H3CHO
4-MeOC6H4CHO
3-MeO C6H4CHO
2-Cl-C6H4CHO
2-NO2-C6H4CHO
C6H5CH=CHCHO
CH3CHO
O
OH
CH
NH2
Zeolite H-BEA
H3C
Ar
NH
H3C
O
9
Scheme 2.
10
11
12
13
14
15
by Shaterian et al.13 The condensation of 2-naphthol
with aldehydes under acid catalysts gave ortho-quinone
methides (o-QMs). The generated o-QMs reacted with
acetamide via the conjugated addition to afford 1-
amidoalkyl-2-naphthols. Electron-withdrawing groups
on the benzaldehydes in the o-QMs increase the rate
of the 1,4-nucleophilic addition reaction because the
alkene LUMO is at lower energy in the presence of
electron-withdrawing groups compared with electron-
donating groups. Ortho substituents decrease the yield
of the reaction probably due to the steric effect (table 2,
CH3(CH2)2CHO
10/-
aReaction conditions:
2-naphthol/aldehyde/acetamide/catalyst (1/1/1.2/7 wt%) un-
der thermal solvent-free condition, oil bath, 120◦C
bYields refer to the pure isolated products
cAll known products have been reported previously in the
literature and were characterized by comparison of IR and
NMR spectra with authentic samples.13–19
The proposed mechanism for the H-BEA catalysed entry 11, 12). The scope of the reaction was also inves-
preparation of amidoalkyl naphthols from the reaction tigated with aliphatic aldehydes and α, β-unsaturated
of 2-naphthol, aromatic aldehydes and acetamide under aldehydes. In our preliminary attempts with aliphatic
reflux and thermal conditions is shown in scheme 2.
aldehydes13 such as acetaldehyde and butyraldehyde
As can be seen from the results (table 2), this reac- (table 2, entry 14 and 15 respectively) the reaction failed
tion is affected by electronic and steric factors. Alde- to yield the corresponding amidoalkyl naphthols. How-
hydes with electron-withdrawing groups, gave higher ever, in case of α, β-unsaturated aldehydes i.e., cin-
yields than those with electron-donating groups. A rea- namaldehyde, we have isolated the product, amidoalkyl
sonable explanation for this result has been suggested naphthol along with impurity (table 2, entry 13). In
Figure 2. (a) Recyclability of zeolite H-BEA, (b) XRD patterns of
H-BEA before used (H-BEA-1) and after four run (H-BEA-2).

Zeolite catalyst in MCRs
431
Ph
HN
O
H
NH2
Ph
H
C
Zeolite H-BEA
OH
+
+
OH
Scheme 3.
Table 3. Comparison of catalytic activity of H-BEA with several catalysts for synthesis of amidoalkyl naphthol.
Entry
Catalyst
Time
Solvent (temp)
Yield (%)
Ref
1
2
3
4
5
6
7
8
Montmorillonite K-10 clay
HClO4-SiO2
I2
K5CoW12O40 3H2O
NaHSO4
Fe(HSO4)3
Wet TCT (Cyanuric chloride)
[TEBSA][HSO4] (Bronsted acidic Ionic liquid)
FeCl3-SiO2
H-BEA
1 h
40 min
4.5 h
2 h
20 h
50 min
10 min
10 min
11 min
4–6
—- (125◦C)
—- (110◦C)
—- (125◦C)
—- (125◦C)
ACN (85◦C)
—- (85◦C)
84
89
87
90
80
93
91
87
86
78
90
[4]
[5]
[7]
[8]
[13]
[14]
[15]
[16]
[17]
—- (100◦C)
—- (120◦C )
—- (120◦C)
Tolune (110◦C)
—- (120◦C)
9
10
11
This work
This work
H-BEA
5–7 min
Table 4. Characterization of zeolite.
Catalysts Channel
Pore
SiO2/Al2O3
SBET
(m2/g)
Ammonia uptake (mmol/g)
structure structure (nm)
ratio
Weak
0.89
Strong
0.70
Total
1.60
H-BEA
3D
0.76 × 0.64
0.55 × 0.55
25
710
our laboratory, we have been working in the direction zeolite catalyst as restricted pore architecture of zeo-
to optimize the yield of amidoalkyl naphthols using lite (BEA - 0.76 × 0.64 nm, table 4) sometimes limiting
various conjugated aldehydes. On the other hand, the the diffusion of bulkier reactant molecules as well as
reactions with thiourea were considered, but no corre- geometrical constraints for the formation of intermedi-
sponding products were produced. Also, amine such as ates inside the pores. Moreover, we observed that solid
aniline was utilized and no aminoalkyl naphthol was aldehydes are reacted smoothly where as trace amount
obtained (scheme 3).
of liquid aldehydes were found unreacted during the
Moreover, table 3 shows the merit of the present work reaction.
in comparison with the results reported in the literature.
The results revealed that zeolite H-BEA can act as an
effective catalyst with respect to reaction times, yields
4. Conclusion
and the obtained products. The efficiency of zeolite H-
BEA towards these reactions can be explained by the
various physiochemical parameters (table 4) as it pos-
sess higher surface area and weak to moderate acidity
which are the prime factor for higher catalytic activity
of zeolite catalyst. Further, the loss of 10–20% yields
in these reactions are probably ascribed to geometry of
In conclusion, we demonstrated a new application of
zeolite H-BEA in the synthesis of amidoalkyl naph-
thols. A series of amidoalkyl naphthols were obtained in
high yields via three-component reaction of 2-naphthol,
aromatic aldehydes and amide under two different con-
ditions (Method A and B). The thermal solvent-free

432
Sunil R Mistry et al.
(Method B) green procedures offer advantages such as
shorter reaction times, simple work-up, environmen-
tally benign, excellent yield, cost effective recovery and
reusability of catalyst for a number of times without sig-
nificant loss of activity. Further applications of zeolite
in organic transformations are currently in progress in
our laboratories.
5. Kantevari S, Vuppalapati S V N and Nagarapu L 2007
Catal. Commun. 8 1857
6. Shaterian H R, Yarahmadi H and Ghashang M 2008
Tetrahedron. 64 1236
7. Das B, Laxminarayana K, Ravikanth B and Rao B R
2007 J. Mol. Catal. A: Chem. 261 180
8. (a) Nagarapu L, Baseeruddin M, Apuri S and Kantevari
S 2007 Catal. Commun. 8 1729; (b) Supale A R and
Gokavi G S 2010 J. Chem. Sci. 122 192
9. Khodaei M M, Khosropour A R and Moghanian H 2006
Synlett. 6 916
Acknowledgements
10. Patil S B, Singh P R, Surpur M P and Samant S D 2007
Ultrason. Sonochem. 14 515
11. Patil S B, Singh P R, Surpur M P and Samant S D 2007
Synth. Commun. 37 1659
The authors thank the Applied Chemistry Department,
Sardar Vallabhbhai National Institute of Technology,
Surat for providing research facility.
12. Clark J H 1999 Green Chem. 1 1
13. Shaterian H R and Yarahmadi H 2008 Arkivoc. 2 105
14. Shaterian H R, Yarahmadi H and Ghashang M 2008
Bioorg. Med. Chem. Lett. 18 788
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