PPA-SiO2-catalyzed multicomponent synthesis of amidoalkyl naphthols

Article abstract of DOI:10.1080/00397910802138231

Silica gel-supported polyphosphoric acid (PPA-SiO2) was found to be an efficient catalyst for the multicomponent condensation reaction of aryl aldehydes, 2-naphthol, and urea or amides to afford the corresponding 1-amidoalkyl-2-naphthols in good to excellent yields. This new approach consistently had short reaction times, high conversions, clean reaction profiles, and simple experimental and workup procedures. Copyright Taylor & Francis Group, LLC.

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PPA-SiO2–Catalyzed
Multicomponent Synthesis of
Amidoalkyl Naphthols
Hamid Reza Shaterian a , Asghar Hosseinian a
Majid Ghashang a
&
a Department of Chemistry, Faculty of Sciences,
University of Sistan and Baluchestan, Zahedan, Iran
Version of record first published: 12 Sep 2008
To cite this article: Hamid Reza Shaterian, Asghar Hosseinian & Majid Ghashang
(2008): PPA-SiO2–Catalyzed Multicomponent Synthesis of Amidoalkyl Naphthols,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:19, 3375-3389
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Synthetic Communications1, 38: 3375–3389, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802138231
PPA-SiO2–Catalyzed Multicomponent Synthesis
of Amidoalkyl Naphthols
Hamid Reza Shaterian, Asghar Hosseinian, and Majid Ghashang
Department of Chemistry, Faculty of Sciences, University of Sistan and
Baluchestan, Zahedan, Iran
Abstract: Silica gel–supported polyphosphoric acid (PPA-SiO2) was found to
be an efficient catalyst for the multicomponent condensation reaction of aryl
aldehydes, 2-naphthol, and urea or amides to afford the corresponding 1-
amidoalkyl-2-naphthols in good to excellent yields. This new approach consist-
ently had short reaction times, high conversions, clean reaction profiles, and
simple experimental and workup procedures.
Keywords: Amide, aryl aldehyde, multicomponent reaction, 2-naphthol,
PPA-SiO2
INTRODUCTION
Multi component reactions (MCRs) make possible the speedy synthesis
of molecular libraries that have a high degree of structural diversity.
Combinations of different starting materials can produce a variety of
products with facility, which is of great value in the search for new drugs
and chemical compounds.[1]
Compounds bearing 1,3-amino-oxygenated functional groups are
ubiquitous to a variety of biologically important natural products and
potent drugs, including a number of nucleoside antibiotics and HIV protease
inhibitors, such as ritonavir and lipinavir.[2,3] Our research is an advance in
multicomponent synthetic methodology of a class of biologically important
molecules; it is noteworthy that 1-amidomethyl-2-naphthols can convert to
Received February 21, 2008.
Address correspondence to Hamid Reza Shaterian, Department of Chemistry,
Faculty of Sciences, University of Sistan and Baluchestan, P. O. Box 98135–674,
Zahedan, Iran. E-mail: hrshaterian@hamoon.usb.ac.ir
3375

3376
H. R. Shaterian, A. Hosseinian, and M. Ghashang
Scheme 1. One-pot preparation of 1-amidoalkyl-2-naphthols using PPA-SiO2 as
catalyst.
important biologically active 1-aminomethyl-2-naphthol derivatives by an
amide hydrolysis reaction. The hypotensive and bradycardiac effects of these
compounds have been evaluated.[2–4]
As reported in a previous article,[5] the reaction of 2-naphthol with
aromatic aldehydes in the presence of an acid catalyst is known to give
ortho-quinone methides (o-QMs). The o-QMs, generated in situ, have
been reacted with 2-naphthol and prepared aryl 14H-dibenzo[a,j]-
xanthene derivatives. In this research, reaction of o-QMs with another
nucleophiles such as amides for synthesis of 1-amidoalkyl-2-naphthol
derivatives in the presence of PPA-SiO2 as solid acid heterogeneous cata-
lyst was investigated (Scheme 1).
The preparation of 1-amidoalkyl-2-naphthols can be carried out
by condensation of aryl aldehydes, 2-naphthol, and acetonitrile or
ethaneamide in the presence of Lewis or Brønsted acid catalysts such as
montmorillonite K10 clay,[6] Ce(SO4)2,[7] iodine,[8] K5CoW12O40ꢀ3H2O,[9]
p-toluene sulfonic acid (p-TSA),[10] sulfamic acid,[11] cation-exchanged
resins,[12] silica-sulfuric acid,[13] SiO2-HClO4,[14] and NaHSO4ꢀH2O.[15]
However, some of the reported methods suffer from drawbacks such as
unsatisfactory yields,[7] long reaction times,[9,10] and environmental pollu-
tants.[8] Therefore, a great need still exists for versatile, simple, and
environmentally friendly processes whereby 1-amidoalkyl-2-naphthols
may be formed under simple practical conditions. PPA-SiO2 has emerged
as a promising solid acid catalyst for acid-catalyzed reactions such as con-
version of carbonyl compounds into oxathioacetals and dithioacetals[16]
and cyclodehydration of dimedone and aldehydes.[17]

Amidoalkyl Naphthol Synthesis
3377
RESULTS AND DISCUSSION
The one-pot synthesis of amidoalkyl naphthols was achieved by the
three-component condensation of aryl aldehydes, 2-naphthol, and amide
or urea derivatives in the presence of PPA-SiO2 as a heterogeneous cata-
lyst (Scheme 1). To find optimum conditions, the reaction of benzal-
dehyde (1 equiv.), 2-naphthol (1 equiv.), and acetamide (1 equiv.) in
the presence of PPA-SiO2 (0.03 g) as a model was performed under ther-
mal solvent-free conditions at different temperatures in an oil bath. As
can be seen from Table 1, the shortest time and best yield were achieved
at 120 ꢁC.
Next, to determine the optimum quantity of PPA-SiO2, the reaction
of 2-naphthol, benzaldehyde, and acetamide was carried out under the
previously mentioned conditions using different quantities of catalyst at
120 ꢁC. The use of 30 mg of catalyst resulted in the highest yield in 7 min
min (Table 1). A slight excess of the acetamide was advantageous; there-
fore the molar ratio of 2-naphthol, aldehyde, and acetamide was kept at
1:1:1.2, respectively.
Thus, we prepared a range of amidoalkyl naphthols under the opti-
mized reaction conditions. In all cases, aromatic aldehydes reacted suc-
cessfully and gave the products in good to excellent yields. Aromatic
aldehydes with electron-withdrawing groups, reacted faster than those
with electron-releasing groups, as expected (Table 2). Sterically hindered
aromatic aldehydes required longer reaction times (Table 2, entry 20).
Aliphatic aldehydes such as propionaldehyde were also examined, but
the yield of product was low (49%) after 30 minutes at 120 ꢁC (Table 2,
entry 26).
A possible mechanism for this transformation is proposed in
Scheme 2. As reported in the literature,[10] reaction of 2-naphthol with
Table 1. Optimization of the amount of catalyst and temperature in the
preparation of N-[phenyl-(2-hydroxynapthalen-1-yl)-methyl]acetamide
Amount of
SiO2-PPA (g)
Entry
Temperature (ꢁC)
Time (min)
Yield (%)a
1
2
4
5
3
6
0.03
0.03
0.03
0.05
0.08
0.015
100
70
120
120
120
120
17
85
7
6
6
10
84
62
86
85
70
83
aYield refers to the isolates pure products.

3378

3379

3380

3381

3382

3383

3384
H. R. Shaterian, A. Hosseinian, and M. Ghashang
Scheme 2. Suggested mechanism for preparation of 1-amidoalkyl-2-naphthols.
aromatic aldehydes in the presence of an acid catalyst is known to give
ortho-quinone methides (o-QMs). The same o-QMs, generated in situ,
have been reacted with acetamide via conjugate addition to form
1-amidoalkyl-2-naphthol derivatives. Electron-withdrawing groups on
the benzaldehyde in the o-QMs intermediates increase the rate of the
1,4-nucleophilic addition reaction because the alkene lowest unoccupied
molecular orbital (LUMO) is at lower energy in the presence of electron-
withdrawing groups compared with electron-donating groups.[18]
The recyclability of the catalyst in the reaction of benzaldehyde
(10 mmol), 2-naphthol (10 mmol), and acetamide (12 mmol) in the pres-
ence of PPA-SiO2 (0.3 g) was checked (Table 2, entry 1). The separated
catalyst can be reused after washing with acetone and drying at 100 ꢁC.
The catalyst was recovered in excellent yields and used in the reaction five
times; it showed the same activity as fresh catalyst without any loss of its
activity.
The stability of the solid-supported catalyst was examined to evalu-
ate if the PPA from PPA-SiO2 could be leached out by solvent. In a con-
trol experiment, the catalyst was removed by simple filtration after
washing with acetone at half of the reaction time. The filtrate solution
was evaporated, and the reaction was continued using the resulting
mixture. The reaction stopped in the absence of the solid heterogeneous
catalyst (Table 2, entry 1). Thus, the absence of free PPA species in
the reaction medium was confirmed. When the separated catalyst was
transferred to the reaction medium, the conversion of benzaldehyde to
N-[phenyl-(2-hydroxy-napthalen-1-yl)-methyl]-acetamide progressed and
completed. To reconfirm that there were no active catalyst species in sol-
ution, the PPA-SiO2 catalyst was subjected to vigorous stripping in acet-
one for 1 h. The catalyst was filtered, and the filtrate solution was
evaporated. No residue and species of PPA was observed by IR spec-
troscopy. This phenomenon confirmed that PPA bonded on the silica-
gel surface and that this bond is stable in reaction media. This evidence
showed that the process is heterogeneous and that no leaching occurs.
In addition, the weight of the recovered catalyst is the same as the
amount of the fresh catalyst that was used the first time in the reaction.

Amidoalkyl Naphthol Synthesis
3385
To show the merit of the present work in comparison with reported
results in the literature, we compared reactions of PPA-SiO2 with mont-
morillonite K10 clay,[6] Ce(SO4)2,[7] iodine,[8] K5CoW12O40ꢀ3H2O,[9]
p-TSA,[10] sulfamic acid,[11] cation-exchanged resins,[12] silica-sulfuric
acid,[13] and SiO2-HClO4
in the synthesis of 1-amidomethyl-2-
[14]
naphthol derivatives. As shown in Table 3, PPA-SiO2 is a better catalyst
with respect to reaction times and yields of the obtained products. Thus,
the present protocol with PPA-SiO2 catalyst is convincingly superior to
the recently reported catalytic methods.
CONCLUSION
In conclusion, a reliable, rapid, and environmentally benign method for
synthesizing 1-amidoalkyl-2-naphthols has been developed, which
involves the use of PPA-SiO2. In addition to the purity of the products,
the short reaction times and ease of workup make the method
advantageous.
EXPERIMENTAL
All reagents were purchased from Merck and Aldrich and used without
further purification. All yields refer to isolated products after purifi-
cation. Products were characterized by comparison with authentic sam-
ples and by spectroscopy data (IR, 1H NMR spectra). The NMR
spectra were recorded on a Bruker Avance DPX 500-MHz instrument.
The spectra were measured in dimethyl sulfoxide-d6 (DMSO-d6) relative
to tetramethylsilane (TMS, 0.00 ppm). Mass spectra were recorded on an
Agilent Technologies 5973 network mass selective detector (MSD) oper-
ating at an ionization potential of 70 eV. Elemental analyses for C, H,
and N were performed using a Heraeus CHN-O-Rapid analyzer. Melting
points were determined in open capillaries with a Buchi 510 melting-point
apparatus. Thin-layer chromatography (TLC) was performed on silica-
gel polygram SIL G=UV 254 plates.
Preparation of PPA-SiO2
PPA (2.1 g) was charged in a round-bottom flask, and CHCl3 (100 mL)
was added. After the mixture was stirred at 50 ꢁC for 1 h, SiO2 [Merck,
(100–200 mesh), 4.91 g] was added to the solution, and the mixture
was stirred for another 1 h. The CHCl3 was removed with a rotary

3386

Amidoalkyl Naphthol Synthesis
3387
evaporator, and the resulting solid was dried in vacuum at room
temperature for 3 h (50 mg of PPA-SiO2, 0.025 mmol).[16]
General Procedure
PPA-SiO2 (30 mg) was added to a mixture of 2-naphthol (1 mmol), alde-
hydes (1 mmol), and acetamide or urea (1.2 mmol). The mixture was stir-
red at 120 ꢁC in an oil bath, and the reaction was followed by TLC. After
completion of the reaction, the mass was cooled to 25 ꢁC, the solid residue
was dissolved in acetone, and the mixture was stirred for 5 min. The cata-
lyst was filtered and washed with acetone, then dried in an oven at 100 ꢁC.
The solvent of the filtrate solution was evaporated, and the remaining
solid product was recrystallized in aqueous EtOH (15%).
All of the desired pure product(s) were characterized by comparison
of their physical data with those of known compounds.[6–15]
Spectral Data of Two Representative Amidoalkyl Naphthols
N-[(4-Methylphenyl)-(2-hydroxynapthalen-1-yl)-methyl]-acetamide
(Table 2, Entry 12)
ꢁ
1
Mp: 222–223 C]; H NMR (500 MHz, DMSO-d6): d ¼ 1.96 (s, 3H), 2.21
(s, 3H), 7.08–7.03 (m, 5H), 7.19 (d, J ¼ 8.8 Hz, 1H), 7.24 (t, J ¼ 7.1 Hz,
1H), 7.34 (m, 1H), 7.74 (d, J ¼ 8.8 Hz, 1H), 7.78 (d, J ¼ 7.9 Hz, 1H),
7.82 (brd, 1H), 8.36 (d, J ¼ 8.1 Hz, 1H), 9.91 (s, 1H) ppm; 13C NMR
(125 MHz, DMSO-d6): 20.4, 22.6, 47.6, 118.4, 118.9, 122.2, 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, cmꢂ1): 3419, 3316, 3070, 1621, 1595, 1561, 1514,
1466, 1392, 1283, 1202, 1141, 1051, 939, 884, 784, 745, 712; MS (EI,
70 eV): m=z ¼ 305 (Mþ, 21.00%), 246 (29.16%), 245 (50.55%), 231
(100.00%), 232 (31.20%), 202 (16.12%), 115 (10.04%). Anal. calcd. for
C20H19NO2: C, 78.66; H, 6.27; N, 4.59%. Found: C, 78.72; H, 6.21; N,
4.63%.
N-[(4-Nitrophenyl)-(2-hydroxynapthalen-1-yl)-methyl]-acetamide
(Table 2, Entry 15)
Mp: 247–249 ꢁC); 1H NMR (500 MHz, DMSO-d6): d ¼ 2.02 (s, 3H), 7.19
(d, J ¼ 8.0, 1H), 7.22 (d, J ¼ 8.8, 1H), 7.28 (t, J ¼ 7.47 Hz, 1H), 7.41
(t, J ¼ 7.34, 1H), 7.52–7.58 (m, 2H), 7.81 (t, J ¼ 9.38 Hz, 2H), 7.89
(brd, 1H), 8.05–8.03 (m, 2H), 8.60 (d, J ¼ 8.0 Hz, 1H), 10.11 (s, 1H)

3388
H. R. Shaterian, A. Hosseinian, and M. Ghashang
ppm; 13C NMR (125 MHz, DMSO-d6): 22.5, 47.6, 117.7, 118.4, 120.3,
121.1, 122.5, 126.7, 128.6, 129.4, 129.8, 132.1, 132.7, 145.3, 147.7,
153.2, 169.5 ppm; IR (KBr, cmꢂ1): 3391, 3267, 2593, 1648, 1603, 1522,
1438, 1063, 825, 739, 447; MS (EI, 70 eV): m=z ¼ 336 (Mþ, 26.66%),
319 (75.99%), 276 (52.02%), 260 (54.15%), 231 (63.80%), 202
(45.11%), 230 (100.00%), 115 (18.05%). Anal. calcd. for C19H16N2O4:
C, 67.85; H, 4.79; N, 8.33%. Found: C, 67.91; H, 4.81; N, 8.24%.
ACKNOWLEDGMENTS
We are thankful to the Sistan and Baluchestan University Research
Council for the partial support of this research.
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