Solvent-free condensation of 2-naphthol with aromatic aldehydes and acetamide/urea to 1-amidoalkyl-2-naphthols

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Solvent-free Condensation of 2-Naphthol
with Aromatic Aldehydes and Acetamide/
Urea to 1-Amidoalkyl-2-naphthols
Abdolkarim Zare a
a Department of Chemistry, Payame Noor University, PO Box
19395-4697 , Tehran , Iran
Published online: 19 Jan 2012.
To cite this article: Abdolkarim Zare (2012) Solvent-free Condensation of 2-Naphthol with
Aromatic Aldehydes and Acetamide/Urea to 1-Amidoalkyl-2-naphthols, Organic Preparations
and Procedures International: The New Journal for Organic Synthesis, 44:1, 82-90, DOI:
10.1080/00304948.2012.643199
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Organic Preparations and Procedures International, 44:82–90, 2012
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2012.643199
Solvent-free Condensation of 2-Naphthol
with Aromatic Aldehydes and Acetamide/Urea
to 1-Amidoalkyl-2-naphthols
Abdolkarim Zare
Department of Chemistry, Payame Noor University, PO Box 19395-4697
Tehran, Iran
In recent years, the use of solid-supported reagents has attained considerable attention both
in industrial and academic research due to their unique properties such as enhanced reactiv-
ity as well as selectivity, efficiency, facile work-up, and eco-friendly reaction conditions.1–18
Silica-supported phosphorus-containing reagents are a class of interesting solid-supported
reagents which are inexpensive, safe and environmentally benign, and have been used in
various organic transformations.4–17 Nevertheless, most of the existing processes in organic
synthesis involve toxic and volatile organic solvents as reaction media, and these are en-
vironmentally unacceptable from a green chemistry view point. One of the most effective
techniques to solve this problem is solvent-free conditions which leads to remarkable de-
creases in reaction times, increased yields, easier workup,3 and prevents waste, hazards,
and toxicity due to solvents.18 Consequently, it is noteworthy that the combination of safe
reagents with the use of solvent-free reaction conditions represents a suitable way toward
the so-called “ideal synthesis”.1–18
1-Amidoalkyl-2-naphthol derivatives are of importance as they can be easily hy-
drolyzed to 1-aminoalkyl-2-naphthols. 1-Aminoalkyl-2-naphthols have been frequently
applied as hypotensive and bradycardiac agents.19–20 1-Amidoalkyl-2-naphthols can also be
converted to 1,3-oxazine derivatives.21 1,3-Oxazines have demonstrated a variety of
biological activities including antibiotic,22 antitumor,23 antipsychotic,24 and antianginal.25
One-pot multi-component condensations of 2-naphthol with aromatic aldehydes and
amide derivatives or acetonitrile has been used as a practical synthetic route toward
1-amidoalkyl-2-naphthols.26–38 Several reagents including Ce(SO4)2,26 K5CoW12O40.
3H2O,27 montmorillonite K-10,28 iodine,29 FeCl3/SiO2,30 Fe(HSO4)3,31 sulfamic acid/
ultrasound,32 p-toluenesulfonic acid,33 N-(4-sulfonic acid)butyl triethylammonium
bisulfate,34 H3PW12O40,35 Sr(OTf)2,36 trityl chloride,37 and 4-(1-imidazolium)butan-
esulfonate38 have been used for this transformation. However, some of these reported
methods suffer from one or more of the following drawbacks: (i) low product yield, (ii)
Received March 4, 2011; in final form September 12, 2011.
Address correspondence to Abdolkarim Zare, Department of Chemistry, Payame Noor Univer-
sity, PO Box 19395-4697 Tehran, Iran. E-mail: abdolkarimzare@yahoo.com
82

Solvent-free Condensation of 1-Amidoalkyl-2-naphthols
83
prolonged reaction time, (iii) the use of a large amount of reagent, (iv) the use of expensive,
corrosive and toxic reagents, and (v) poor compliance with green chemistry protocols.
Therefore, a search for finding a protocol for the synthesis of 1-aminoalkyl-2-naphthols
which is not associated with the above disadvantages is still relevant. This paper reports a
new, clean and efficient solvent-free method for the synthesis of 1-aminoalkyl-2-naphthols
from 2-naphthol, aromatic aldehydes and acetamide/urea in the presence of a catalytic
amount of silphox [POCl3-n(SiO2)n] or silphos [PCl3-n(SiO2)n] as inexpensive, green and
heterogeneous silica-supported phosphorus-containing reagents (Scheme 1).
Scheme 1
As previously mentioned, silica-supported phosphorus-containing reagents are very
important.4-17 Silphox and silphos are two types of these reagents which have been suc-
cessfully used to perform several organic reactions.4–9 This precedent combined with the
importance of 1-aminoalkyl-2-naphthols encouraged us to examine the preparation of
these organic compounds using silphox and silphos. For this purpose, the condensation of
2-naphthol (2 mmol) with benzaldehyde (2 mmol) and acetamide (2.6 mmol) was chosen
as a model reaction (Scheme 1), and its behavior was studied in the presence of different
amounts of silphox as well as silphos under solvent-free conditions with a temperature
range of 90-130◦C. As indicated in Table 1, higher yields of the product were obtained
when the reaction was carried out using 0.7 g of silphox or 0.6 g of silphos at 120◦C.
Increasing the reaction times or the temperature did not improve the yields.
The solvent-free reaction of 2-naphthol, benzaldehyde and acetamide was also checked
in the presence of POCl3, PCl3 and SiO2. POCl3 and PCl3 afforded the product in low yields,
and SiO2 gave only trace product. Moreover, POCl3 and PCl3 are very toxic and their use
is very difficult especially at high temperatures because of their low boiling points and
evolved HCl gas. It should be mentioned that silphox and silphos also generate HCl gas but
much less than POCl3 and PCl3. In addition, the problem related to the low boiling point of
POCl3 and PCl3 was solved by supporting them on silica gel, thus making use of of silphox
and silphos in the reaction is easy.
After optimization of the reaction conditions, 2-naphthol was condensed with dif-
ferent aromatic aldehydes bearing electron-releasing, electron-withdrawing, and halogens
substituents with and acetamide or urea in the presence of the silica-supported phosphorus-
containing reagents. The results are displayed in the Table 2. All reactions proceeded
efficiently and the 1-amidoalkyl-2-naphthols were obtained in good to excellent yields
(80–94%) within relatively short reaction times (20–55 min), thus making the method is
general and efficient.

84
Zare
Table 1
Effect of Amount of the Reagents and Temperature on the Solvent-free Condensation of
2-Naphthol (2 mmol) with Benzaldehyde (2 mmol) and Acetamide (2.6 mmol)
Entry
Reagent (amount)
Temperature (◦C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Silphox (0.7 g)
Silphox (0.7 g)
Silphox (0.7 g)
Silphox (0.7 g)
Silphox (0.7 g)
Silphox (0.6 g)
Silphox (0.8 g)
Silphos (0.6 g)
Silphos (0.6 g)
Silphos (0.6 g)
Silphos (0.6 g)
Silphos (0.6 g)
Silphos (0.5 g)
Silphos (0.7 g)
90
100
110
120
130
120
120
90
100
110
120
130
120
120
70
55
40
30
30
45
30
50
35
25
20
20
30
20
54
70
85
92
86
87
91
62
74
90
93
89
84
90
The condensation of 2-naphthol with bis-aldehydes (terephthaldehyde) and acetamide
was also performed efficiently using silphox as well as silphos in the absence of solvent.
The corresponding results are illustrated in Scheme 2 (Table 3). When one equivalent
of 2-naphthol and one equivalent of the terephthaldehyde were reacted with 1.3 equiva-
lents of acetamide in the presence of the reagents, 1-amidoalkyl-2-naphthol 17 and bis(1-
amidoalkyl-2-naphthol) 18 were obtained in moderate yields. However, the reaction of
two equivalents of 2-naphthol with one equivalent of the aldehyde and 2.6 equivalents of
acetamide afforded compound 18 as a main product.
Scheme 2
To compare the efficiency and the applicability of silphox and silphos with the reported
reagents for the synthesis of 1-amidoalkyl-2-naphthols, the results of these reagents to effect
the condensation of 2-naphthol with benzaldehyde and acetamide are reported in Table 4;

Solvent-free Condensation of 1-Amidoalkyl-2-naphthols
85
Table 2
The Solvent-free Synthesis of 1-Aminoalkyl-2-naphthols from 2-Naphthol, Aromatic
Aldehydes and Amides using Silphox or Silphos at 120◦C
Product
Silphox
Silphos
mp. ◦C (lit.)
Time (min)/Yield (%) Time (min)/Yield (%)
30/92
20/93
238-240 (241-243)26
40/90
45/83
25/92
30/87
222-224 (220-230)35
197-199 (200-202)32
45/89
50/91
25/91
35/91
183-185 (183-185)30
201-203 (203-205)31
230-232 (235-236)31
245-247 (248-250)35
55/80
45/91
40/89
40/83
40/92
20/90
238-240 (236-237)32
(Continued on next page)

86
Zare
Table 2
The Solvent-free Synthesis of 1-Aminoalkyl-2-naphthols from 2-Naphthol, Aromatic
Aldehydes and Amides using Silphox or Silphos at 120◦C (Continued)
Product
Silphox
Silphos
mp. ◦C (lit.)
Time (min)/Yield (%) Time (min)/Yield (%)
40/82
45/93
40/86
25/89
40/94
40/92
229-231 (232-234)34
220-222 (224-227)26
196-198 (194-196)32
45/88
35/91
50/89
50/81
55/90
25/91
25/93
30/90
35/86
50/91
226-228 (228-230)31
205-207 (203-205)32
174-176 (172-174)32
183-185 184-186)32
171-173(168-169)32

Solvent-free Condensation of 1-Amidoalkyl-2-naphthols
87
Table 3
Reaction of 2-Naphthol with Terephthaldehyde and Acetamide using Silphox or Silphos
Conditions
Reagent
(amount)
2-Naphthol/aldehyde/
acetamide (molar ratio)
Time
(min)
Yield (%)
17
18
A
B
C
D
Silphox (0.7 g)
Silphox (1 g)
Silphos (0.6 g)
Silphos (1 g)
2/2/2.6
4/2/5.2
2/2/2.6
4/2/5.2
50
70
40
60
33
16
38
13
14
59
21
65
evidentially, our reagents are superior to those previously reported in terms of yields and/or
reaction times.
In summary, we have developed a new method for the one-pot three-component con-
densation of 2-naphthol with aromatioc aldehydes and acetamide or urea. The promising
aspects of the present methodology are efficiency, generality, high yields, short reaction
times, cleaner reaction profile, simplicity, ease of preparation of the reagents, and com-
pliance with green chemistry protocols which, makes it an attractive procedure for the
preparation of 1-amidoalkyl-2-naphthols as biologically interesting compounds.
Experimental Section
All chemicals were purchased from Merck or Fluka Chemical Companies. Silphox4-6 and
silphos7 were prepared according to the reported methods. All products are known, and
Table 4
Comparison of the Results of the Reaction of 2-Naphthol with Benzaldehyde and
Acetamide using Silphox and Silphos with those Obtained by Reported Reagents
Entry
Reagent, Temperature
Silphox
Silphos
Ce(SO4)2, 85
K5CoW12O40.3H2O
Montmorillonite K10 clay
I2
FeCl3.SiO2
Fe(HSO4)3
(◦C)Temp Time (min) Yield (%) Ref.
a
1
2
3b
4
5
6
7
8
9
120
120
85
30
20
92
93
72
90
89
85
86
83
89
90
92
85
—
—
a
2160
120
90
330
11
65
15
600
105
120
26
27
28
29
30
31
32
36
37
38
125
125
125
120
85
28-30
Reflux
RT
Sulfamic acid (ultrasound)
Sr(OTf)2 CHCl3
Trityl chloride
10
11b
12
4-(1-Imidazolium)butanesulfonate
80
aOur reagents. bIn this work, acetonitrile instead of acetamide has been used.

88
Zare
their structures were identified by comparison of their melting points and spectral data with
1
those reported in the literature. The H NMR (250 or 300 MHz) and 13C NMR (62.5 or
75 MHz) were run on a Bruker Avance DPX-250 FT-NMR spectrometer. Melting points
were recorded on a Bu¨chi B-545 apparatus in open capillary tubes.
General Procedure for the Synthesis of 1-Amidoalkyl-2-naphthol Derivatives (1–16)
A well-ground mixture of 2-naphthol (2 mmol, 0.288 g), aldehyde (2 mmol), amide
(2.6 mmol) and silphox (0.7 g) or silphos (0.6 g) was added to a 10 mL round-bottomed
flask fitted to a reflux condenser, and stirred in an oil-bath (120) ◦C for the times reported in
Table 2. After the appropriate time, the reaction mixture was cooled to room temperature,
and chromatographed on silica gel, and eluted with EtOAc/n-hexane (1/1) to give the pure
products.
Note: When liquid aldehydes were utilized in the reaction, 2-naphthol, the amide
derivative and the reagent were ground first vigorously, and then the aldehyde was subse-
quently added.
General Procedure for the Synthesis of 1-Amidoalkyl-2-naphthol (17)
and bis(1-Amidoalkyl-2-naphthol) (18)
A mixture of compounds consisting of 2-naphthol (4 mmol, 0.576 g), acetamide (5.2 mmol,
0.307 g), terephthalaldehyde (2 mmol, 0.268 g) and silphox (1 g) or silphos (1 g) was ground
vigorously, added to a 10 mL round-bottomed flask connected to a reflux condenser, and
was stirred in an oil-bath (120 ◦C) for the times reported in Table 3. Afterward, the reaction
mixture was cooled to room temperature, and warm aqueous ethanol (15%, 20 mL) was
added to it, and the mixture was stirred for 5 min (1-amidoalkyl-2-naphthol is soluble in
warm aqueous ethanol; however, bis(1-amidoalkyl-2-naphthol) is insoluble in this solvent).
During this time, the crude 1-amidoalkyl-2-naphthol was dissolved in the ethanol, and
pure bis(1-amidoalkyl-2-naphthol) remained undissolved; thus, two products were easily
separated by filtration. Then, the crude 1-amidoalkyl-2-naphthol was purified by column
chromatography on silica gel eluted with EtOAc/n-hexane (1/1), and the bis(1-amidoalkyl-
2-naphthol) was separated from the reagent by short column chromatography on silica gel
eluted with methanol.
Acknowledgements
The author thanks Payame Noor University Research Council for the financial support of
this work.
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