Solvent-free, one-pot synthesis of amidoalkyl naphthols by a copper p-toluenesulfonate catalyzed multicomponent reaction

Article abstract of DOI:10.1007/s00706-010-0429-7

An efficient synthesis of amidoalkyl naphthols using copper p-toluenesulfonate (CPTS) as catalyst for the three-component condensation reaction of 2-naphthol, aldehydes, and amides under thermal, solvent-free conditions is described. This new approach has

Full text of DOI:10.1007/s00706-010-0429-7

Monatsh Chem (2011) 142:153–157
DOI 10.1007/s00706-010-0429-7
ORIGINAL PAPER
Solvent-free, one-pot synthesis of amidoalkyl naphthols by a
copper p-toluenesulfonate catalyzed multicomponent reaction
•
Min Wang Yan Liang
Received: 12 August 2010 / Accepted: 18 November 2010 / Published online: 15 December 2010
Ó Springer-Verlag 2010
Abstract An efficient synthesis of amidoalkyl naphthols
using copper p-toluenesulfonate (CPTS) as catalyst for the
three-component condensation reaction of 2-naphthol,
aldehydes, and amides under thermal, solvent-free condi-
tions is described. This new approach has advantages such
as short reaction time, high yield, simple work-up, and
reusable catalyst.
1-aminomethyl-2-naphthol derivatives, which exhibit
important cardiovascular activity [1]. The preparation of
1-amidoalkyl-2-naphthols can be carried out by three-
component condensation of 2-naphthol, aldehydes, and
acetonitrile or different amides in the presence of
homogeneous or heterogeneous catalysts such as p-tolu-
enesulfonic acid [2], H2NSO3H [3], oxalic acid [4],
Fe(HSO4)3 [5], Sr(OTf)2 [6], I2 [7], K5CoW12O40Á3H2O
[8], HPMo [9], Yb(OTf)3 in ionic liquid [10], Indion-130
[11], montmorillonite K10 [12], TMSCl/NaI [13], Al2O3–
HClO4 [14], InCl3 [15], 2,4,6-trichloro-1,3,5-triazine [16],
CuPW and CuPMo [17], H3MoO40P [18], H4SiW12O40
[19], and P2O5 [20]. However, some of the reported
methods suffer from disadvantages such as long reaction
time, toxic and corrosive solvent, high reaction tempera-
ture ([100 °C), and the use of additional microwave or
ultrasonic irradiation. Furthermore, the yields of the
corresponding amidoalkyl naphthols are not always satis-
factory. Because of the importance of these compounds,
the introduction of a milder, faster, and more ecofriendly
method accompanied with higher yields is needed.
Keywords Amidoalkyl naphthol
Three-component reaction Á Metal sulfonates Á
One-pot synthesis Á Solvent-free
Introduction
Multicomponent reactions (MCRs) have attracted consid-
erable attention in organic synthesis as they can produce
the target products in a single operation without isolating
the intermediates, thus reducing reaction times and energy
consumption. MCRs have merits over conventional linear-
type syntheses in several aspects including simple proce-
dures, possible structural variations, and rapid access to
complex molecules. Therefore, discovery and development
of new MCRs is highly desirable.
In recent years, metal sulfonates have received consid-
erable attention as inexpensive and recyclable catalysts for
numerous organic transformations, affording the corre-
sponding products in excellent yields with high selectivity
[21–25]. Their low toxicity, easy preparation, moisture
resistance, and air tolerance are other common features that
make the use of metal sulfonates an attractive alternative to
conventional Lewis acids and triflates. As part of our
ongoing work on the application of metal sulfonate catalysts
for developing useful synthetic methodologies, we now
show that amidoalkyl naphthols can be prepared by using
copper p-toluenesulfonate (CPTS) as an efficient catalyst via
one-pot, three-component condensation of 2-naphthol, var-
ious aldehydes, and different amides (Scheme 1).
Amidoalkyl naphthols are important synthetic building
blocks and are used as precursors for the synthesis of
M. Wang (&) Á Y. Liang
College of Chemistry and Chemical Engineering,
Bohai University, Jinzhou 121000, China
e-mail: minwangszg@yahoo.com.cn
123

154
M. Wang, Y. Liang
R1
NHCOR2
OH
Scheme 1
OH
CPTS
+
R1CHO
+
R2CONH2
Solvent-free
80 °C
1
2
3
4
Results and discussion
catalyst did not increase the yields. To show the merit of
this CPTS-catalyzed method, we compared the results of
CPTS with those of reported catalysts such as Sr(OTf)2,
K5CoW12O40Á3H2O, montmorillonite K10, Yb(OTf)3,
HPMo, p-TSA, and P2O5 in synthesizing N-((2-hydrox-
ynaphth-1-yl)phenylmethyl)benzamide (Table 1, entries
13–19). As shown in Table 1, CPTS is a better catalyst with
respect to reaction time, reaction temperature, and product
yield. Thus, the present protocol with CPTS catalyst is
superior to the recently reported catalytic methods.
First, we compared the catalytic activity of metal p-tolu-
enesulfonates with some other catalysts reported in the
literature for the three-component condensation reaction of
2-naphthol, benzaldehyde, and benzamide (Table 1). In the
absence of catalyst, no product was formed even after 8 h at
80 °C (Table 1, entry 1). After several experiments, CPTS
was found to the most efficient catalyst among all the
examined metal p-toluenesulfonates under these conditions.
CPTS gave the highest yield of product in the shortest
reaction time (Table 1, entry 2). In order to evaluate the most
appropriate reaction temperature, the model reaction was
carried out at different temperatures (Table 1, entries 7–10).
The reaction rate was increased as the reaction temperature
was raised from r.t. to 80 °C, but higher temperature
(100 °C) did not increase the yields significantly. Thus,
80 °C was found to be the optimal reaction temperature
(Table 1, entry 2). We also studied the model reaction cat-
alyzed by CPTS with different catalyst loading (Table 1,
entries 11 and 12). The optimal quantity of catalyst was
found to be 2 mol% (Table 1, entry 2). Excess amount of
As shown in Table 2, amidoalkyl naphthols were syn-
thesized in excellent yields by the reaction of 2-naphthol,
aromatic or aliphatic aldehydes, and amides using CPTS as
catalyst at 80 °C. In all cases, amidoalkyl naphthols were
the sole products and no by-product was observed. Aro-
matic aldehydes carrying electron-withdrawing groups
reacted faster than those carrying electron-donating groups.
To demonstrate the scope and limitations of the procedure,
ortho-substituted aromatic aldehydes such as 2-nitrobenz-
aldehyde and 2-chlorobenzaldehyde were studied. The
results show the position of the substituent on the aromatic
ring does not show effects on the conversion. Aliphatic
Table 1 Comparison of results
Entry
Catalyst (mol%)
Time (h)
Temp (°C)
Yield (%)
Ref.
of metal p-toluenesulfonates
with other catalysts reported in
the literature
1
–
8
80
80
0
95
85
74
71
45
96
62
17
0
2
Cu(p-CH3C6H4SO3)2Á6H2O (2)
Pb(p-CH3C6H4SO3)2Á6H2O (2)
Zn(p-CH3C6H4SO3)2Á5H2O (2)
La(p-CH3C6H4SO3)2Á2H2O (2)
Sm(p-CH3C6H4SO3)2Á2H2O (2)
Cu(p-CH3C6H4SO3)2Á6H2O (2)
Cu(p-CH3C6H4SO3)2Á6H2O (2)
Cu(p-CH3C6H4SO3)2Á6H2O (2)
Cu(p-CH3C6H4SO3)2Á6H2O (2)
Cu(p-CH3C6H4SO3)2Á6H2O (1)
Cu(p-CH3C6H4SO3)2Á6H2O (3)
Sr(OTf)2 (10)
0.3
0.5
0.5
0.5
1
3
80
4
80
5
80
6
80
7
0.3
0.7
1
100
60
8
9
40
10
11
12
13
14
15
16
17
18
19
1
r.t.
80
0.6
0.15
9
78
81
93
80
78
35
92
86
85
80
60
[6]
K5CoW12O40Á3H2O (1)
Montmorillonite K10
2
125
125
80
[8]
1.5
10
3.5
6
[12]
[10]
[9]
Yb(OTf)3 (20)
HPMo (1.6)
65
p-TSA (10)
125
60
[2]
P2O5 (10)
0.17
[20]
123

Solvent-free, one-pot synthesis of amidoalkyl naphthols
155
Table 2 Synthesis of
amidoalkyl naphthols in the
presence of CPTS
Entry
R1
R2
Time (h)
Product
Yield (%)
M.p. (lit. m.p.) (°C)
1
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
0.3
0.1
0.1
0.3
0.15
0.4
0.3
0.5
3
4a
4b
4c
4d
4e
4f
95–89a
93
236–239 (233–235 [14])
260–263 (266–267 [20])
235–237 (233–235 [26])
237–239 (239–241 [4])
266–268
2
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
2-ClC6H4
3
95
4
94
5
91
6
4-ClC6H4
96
186–188 (187–188 [6])
237–238
7
2,4-Cl2C6H3
4-CH3C6H4
4-CH3OC6H4
4-(CH3)2NC6H4
CH3CH2
4g
4h
4i
92
8
93
210–212 (209–211 [26])
208–210 (206–208 [20])
219–221 (220–221 [20])
246–247 (244–245 [6])
240–242
9
72
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
10
0.1
0.1
9
4j
31
4k
4l
87
CH3CH2CH2
C6H5CH=CH
C6H5
88
4m
4n
4o
4p
4q
4r
4s
Trace
94
–
1.5
0.5
0.7
1.3
1.7
12
5.5
1
242–244 (241–243 [8])
255–257 (255–256 [6])
207–209 (206–207 [20])
234–237 (237–238 [20])
217–220 (222–223 [5])
180–182 (183–185 [5])
178–180 (173–175 [27])
179–181 (172–174 [3])
198–200 (192–193 [26])
–
3-NO2C6H4
2-ClC6H4
CH3
92
CH3
95
4-ClC6H4
CH3
87
4-CH3C6H4
4-CH3OC6H4
CH3CH2
CH3
65
CH3
16
CH3
4t
60
C6H5
NH2
NH2
NH2
NH2
NH2
4u
4v
4w
4x
4y
86
3-NO2C6H4
4-ClC6H4
1
43
6
Trace
Trace
Trace
4-CH3C6H4
CH3CH2
6
–
a
Yield after four recoveries of
the catalyst
9
–
R1
H
R1
NHCOR2
OH
Scheme 2
OH
O
R2CONH2
CPTS
R1CHO
CPTS
-QMs
o
4
aldehydes such as propionaldehyde and butyraldehyde
were also examined, and in the case of benzamide the
yields of products were as high as those of products from
aromatic aldehydes (Table 2, entries 11 and 12). On the
other hand, only traces of corresponding product were
produced in the reaction with a,b-unsaturated aldehydes
such as cinnamaldehyde (Table 2, entry 13). In the case of
amide, besides benzamide and acetamide, urea was also
employed. The condensation yields with urea were lower
than those with benzamide and acetamide.
even in up to four runs (Table 2, entry 1), which demon-
strated that CPTS was water-tolerant and efficient for this
condensation.
A possible mechanism for this transformation is pro-
posed in Scheme 2. As reported in the literature [2],
reaction of 2-naphthol with 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 amides via conjugate addition to form
1-amidoalkyl-2-naphthol derivatives 4.
To investigate the reusability and recycling of CPTS,
2-naphthol, benzaldehyde, and benzamide were used as a
model reaction. When the reaction was completed, the
reaction mixture was washed with water. The catalyst
remaining in the aqueous phase could be recovered by
evaporating the filtrate, furnishing CPTS to be reused in the
next run. No significant decrease in activity was observed
Experimental
Melting points were determined by using an RY-1 micro-
melting point apparatus. Infrared spectra were recorded on a
Varian Scimitar 2000 series Fourier transform instrument.
123

156
M. Wang, Y. Liang
1H and 13C NMR spectra were recorded on a Bruker AV-500
spectrometer in DMSO-d6 using TMS as an internal stan-
dard. Elemental analyses were carried out on an EA 2400II
elemental analyzer (Perkin Elmer) and agreed favorably
with the calculated values.
N-(1-(2-Hydroxynaphth-1-yl)butyl)benzamide
(4l, C21H21NO2)
ꢀ
White solid. IR (KBr): m = 3,415, 3,222, 3,204, 1,633,
1,575, 1,528, 1,342, 1,074, 815, 747, 716 cm-1; H NMR
1
(500 MHz, DMSO-d6): d = 10.09 (s, 1H, OH), 8.60 (d,
1H, J = 6.3 Hz, NH), 8.23 (d, 1H, J = 7.6 Hz, ArH), 7.81
(t, 3H, J = 7.2 Hz, ArH), 7.71 (d, 1H, J = 8.8 Hz, ArH),
7.53–7.44 (m, 4H, ArH), 7.31 (t, 1H, J = 7.3 Hz, ArH),
7.20 (d, 1H, J = 8.8 Hz, ArH), 6.04 (q, 1H, J = 7.1 Hz,
CH), 2.18–2.11 (m, 1H, CH2), 1.92–1.85 (m, 1H, CH2),
1.51–1.42 (m, 1H, CH2), 1.33–1.23 (m, 1H, CH2), 0.93 (t,
3H, J = 7.3 Hz, CH3) ppm; 13C NMR (125 MHz, DMSO-
d6): d = 165.2, 152.8, 134.7, 132.1, 131.1, 128.5, 128.4,
128.3, 128.2, 126.9, 126.3, 122.3, 119.8, 118.6, 118.5,
46.6, 36.0, 19.6, 13.8 ppm.
General procedure for the synthesis of amidoalkyl
naphthols 4
A mixture of 2-naphthol (10 mmol), an aldehyde (10 mmol),
an amide (11 mmol), and CPTS (0.2 mmol) was added to a
25-cm3 conical flask. The reaction mixture was magnetically
stirred on a preheated water bath at 80 °C. After completion
of the reaction (monitored by TLC), the reaction mixture
was cooled to r.t., washed with water, and the residue was
recrystallized from ethanol. The catalyst remaining in the
aqueous phase could be recovered by evaporating the filtrate.
The products were characterized by comparing their m.p., IR,
1H NMR, 13C NMR, and elemental analysis with those
reported for the authentic samples.
Acknowledgments We are grateful to the Committee of Science
and Technology of Liaoning Province of China for financial support
(No. 20091001).
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;
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White solid. IR (KBr):m = 3,423, 3,069, 1,633, 1,574,
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;
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123

Solvent-free, one-pot synthesis of amidoalkyl naphthols
157
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