Synthesis of 1-amidoalkyl-2-naphthols via three-component condensation of 2-naphthol, aldehydes, and amides/urea

Article abstract of DOI:10.1007/s10600-012-0200-x

An efficient three-component one-pot synthesis of 1-amidoalkyl-2-naphthols from 2-naphthol, aldehydes, and amides/urea using tin tetrachloride as catalyst at 80°C without solvent is described. The structures of the new compounds were characterized by IR,

Full text of DOI:10.1007/s10600-012-0200-x

Chemistry of Natural Compounds, Vol. 48, No. 2, May, 2012 [Russian original No. 2, March–April, 2012]
SYNTHESIS OF 1-AMIDOALKYL-2-NAPHTHOLS VIA THREE-COMPONENT
CONDENSATION OF 2-NAPHTHOL, ALDEHYDES, AND AMIDES/UREA
M. Wang*, Y. Liang, T. T. Zhang, and J. J. Gao
UDC 547.655
An efficient three-component one-pot synthesis of 1-amidoalkyl-2-naphthols from 2-naphthol, aldehydes,
and amides/urea using tin tetrachloride as catalyst at 80ꢀC without solvent is described. The structures of
1
13
the new compounds were characterized by IR, H NMR, and C NMR spectra and by elemental analysis.
The advantages of the new method were good yields (45–97%), short reaction times (0.1–4 h), simple work-up,
inexpensive catalyst, and the diversity of the method.
Keywords: amidoalkyl naphthols, multicomponent synthesis, tin tetrachloride, solvent-free conditions.
In recent years, multicomponent reactions (MCRs) have gained much attention in organic synthesis as they furnish
the desired products in a single operation without isolating the intermediates. Thus, reaction times are reduced and energy and
raw materials saved. Therefore, researchers have made great efforts to find and develop new MCRs.
Compounds containing 1,3-amino-oxygenated functional groups are frequently found in biologically active natural
products and potent drugs such as nucleoside antibiotics and HIV protease inhibitors [1–3]. Furthermore, 1-amidoalkyl-2-
naphthols can be converted to useful and important biological building blocks and to 1-aminomethyl-2-naphthols by an amide
hydrolysis reaction, since these compounds exhibit antibacterial, hypotensive, and bradycardiac effects, etc. [4, 5]. 1-Amidoalkyl-
2-naphthols can be prepared by three-component condensation of 2-naphthol, aldehydes, and acetonitrile or different amides
in the presence of Bronsted or Lewis acids such as p-toluene sulfonic acid [6], H NSO H [7], Fe(HSO ) [8], Sr(OTf) [9],
2
3
4 3
2
I [10], Al(H PO ) [11], and other types of catalysts such as heteropoly acid K CoW O ·3H O [12] and HPMo [13],
2
2
4 3
5
12 40
2
Bronsted acidic ionic liquid [14], and cation-exchange resin catalysts like Indion-130 [15], montmorillonite K10 [16],
Al O –HClO [17], and HClO –SiO [18, 19]. However, some of the reported methods suffer from disadvantages such as
2
3
4
4
2
prolonged reaction time, low product yields, toxic and corrosive reagents, and the use of additional microwave or ultrasonic
irradiation. Therefore, it was of interest to develop a more universal method for the synthesis of these products.
NHCOR
OH
2
R
1
OH
a
R CHO
1
R CONH
2
+
+
2
4a - w
1
2
3
a, l, w: R = C H ; b, m: R = 2-NO C H ; c, n: R = 3-NO C H
1
6
5
1
2
6
4
1
2
6
4
d, o: R = 4-NO C H ; e, p: R = 2-ClC H ; f, q: R = 4-ClC H
1
2
6
4
1
6
4
1
6 4
g, r: R = 2,4-Cl C H ; h, s: R = 4-CH C H
1
2
6
3
1
3 6 4
i, t: R = 4-CH OC H ; j, u: R = CH CH ; k, v: R = CH CH CH
1
3
6
4
1
3
2
1
3
2
2
a – k: R = C H , l – v: R = CH , w: R = NH
2
6
5
2
3
2
2
a. SnCl 45H O, 80ꢀC, Neat
4
2
College of Chemistry and Chemical Engineering, Bohai University, Jinzhou 121000, P. R. China, e-mail:
minwangszg@yahoo.com.cn. Published in Khimiya Prirodnykh Soedinenii, No. 2, March–April, 2012, pp. 174–176. Original
article submitted October 31, 2010.
0009-3130/12/4802-0185 02012 Springer Science+Business Media, Inc.
185

a
TABLE 1. Effect of Solvent Conditions in the Synthesis of 4 (SnCl ·5H O , 2 h)
4
2
Entry
Solvent
Yield, %
Entry
Solvent
Yield, %
1
2
3
4
5
THF
CH2Cl2
CH3COOC2H5
Toluene
33
38
45
51
56
6
7
8
9
CH3CN
H2O
Cyclohexane
None*
66
71
88
97
EtOH
______
a
SnCl ·5H O was 2 mol%, the amount of solvent used in entries 1–8 was 3 mL.
4
2
*Time reaction was 0.3 h.
TABLE 2. Catalyst Screening in the Reaction for the Synthesis of 4
Entry
Catalyst*
Time, h
Yield, %
Entry
Catalyst*
Time, h
Yield, %
1
2
3
4
ZnCl2
MnSO4·H2O
FeSO4(NH4)2SO4·6H2O
SrCl2·6H2O
Pr(CH3SO3)3·2H2O
2
2
2
1.5
1.5
5
6
7
8
9
La(CH3SO3)3·2H2O
KAl(SO4)2·12H2O
SnCl4·5H2O
1.5
1
0.3
0.3
67
84
97
91
14
42
45
55
SnCl4·5H2O**
5
______
*Amount of catalyst was 2 mol%; ** amount of catalyst, 1 mol%.
Recently, tin tetrachloride has emerged as an efficient Lewis acid in promoting various organic transformations, such
as aromatization [20], heterocycloadditions [21], coupling reactions [22], rearrangement of epoxides [23], oxidation [24], and
ring opening reactions [25]. The versatility of this reagent encourages us to study its utility for the three-component
amidoalkylation reaction. To our knowledge, amidoalkylation of arenes and the extension of Mannich-type reactions catalyzed
by SnCl ·5H O have not been reported. In this communication, we report a facile and efficient synthetic strategy for preparing
4
2
1-amidoalkyl-2-naphthols 4 from 2-naphthol (1), aldehydes 2, and amides/urea 3 at short reaction times and with excellent
yields using SnCl ·5H O as a catalyst.
4
2
At the onset of the research, we investigated the model reaction of 2-naphthol, benzaldehyde, and benzamide in
different reaction media at 80ꢀC. The results are summarized in Table 1. After screening a variety of reaction media, solvent-free
conditions were determined to be the best. Compared with reactions carried out in organic solvent, condensation without
solvent required only 0.3 h to furnish excellent yields (Table 1, entry 9). Indeed in many cases, solid organic reactions occur
efficiently and more selectively than those of their solution counterparts [8, 18, 19]. Moreover, solvent-free conditions for
organic transformations offer several environmental benefits. So for the synthesis of our target compounds, solvent-free
conditions were selected.
Next, the catalytic activity of several Lewis acids was compared with SnCl ·5H O in the same model reaction at
4
2
80ꢀC; the results are shown in Table 2. After several trials, it could be noted that SnCl ·5H O was the most efficient catalyst for
4
2
this transformation, since it results in the highest conversion to the desired product in the shortest reaction time (Table 2, entry 8).
It should be mentioned that 2 mol% of SnCl ·5H O was suitable to catalyze the reaction, and reducing the amount of catalyst
4
2
would decrease the yields to a certain extent (Table 2, entry 9).
In order to evaluate the generality of the process, several examples illustrating the present method for the synthesis of
1-amidoalkyl-2-naphthols 4 were studied (Table 3). The reactions of 2-naphthol with various aromatic or aliphatic aldehydes
and amides or urea were carried out in the presence of SnCl ·5H O at 80ꢀC. In all the reactions, good to excellent yields were
4
2
obtained at short reaction times (0.1–4 h). Clean and complete conversions leading to the corresponding amidoalkyl naphthols
were observed. No side products such as dibenzoxanthenes were formed, which are normally observed under the influence of
strong acids. Aromatic aldehydes carrying either electron-withdrawing (nitro) or electron-donating (halide, alkyl, alkoxyl)
groups were all suitable for the reactions. It is worth mentioning that the yields of products from aliphatic aldehydes were as
high as those of products from aromatic aldehydes, whereas the reactions of aliphatic aldehydes in most of the reported
literature were sluggish and no desired products were isolated [6, 7, 11–13, 15, 17]. On the other hand, the scope of different
amide components was studied. Both amides (benzamide and acetamide) and urea participated well in the reactions. As
compared to the amides, urea afforded the corresponding amidoalkyl naphthol at longer reaction times (Table 3, entry 23).
186

TABLE 3. Preparation of 1-Amidoalkyl-2-naphthols Catalyzed by SnCl ·5H O
4
2
Product
Time, h
Yield, %
Product
Time, h
Yield, %
Mp ( C) [ref.]
Mp ( C) [ref.]
ꢀ
ꢀ
0.3
0.2
0.2
0.2
0.2
0.3
0.15
0.4
0.8
0.1
0.1
0.3
97
93
96
82
92
85
95
90
70
90
93
91
236–238 [14]
261–263 [26]
233–235 [14]
237–239 [27]
266–268
187–189 [9]
238–239
207–209 [14]
208–210 [26]
246–248 [9]
240–242
0.2
0.2
0.3
1
1
1.2
1
4
1
0.1
4
81
78
84
68
63
75
87
45
69
92
85
218–220 [26]
253–255 [9]
245–247 [11]
208–210 [26]
236–238 [26]
226–228 [28]
217–219 [8]
185–187 [8]
176–178 [29]
221–223
4a
4b
4c
4d
4e
4f
4g
4h
4i
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4j
4k
4l
178–180 [7]
241–243 [12]
In conclusion, a very simple and efficient method for the synthesis of 1-amidoalkyl-2-naphthol derivatives has been
developed. Several derivatives of the title compounds with different substituents were synthesized, which shows the diversity
of the method. The catalyst showed good efficiency for this transformation under solvent-free conditions at 80ꢀC. Work-up
procedure was simple, which only includes washing the mixture with H O–EtOH and recrystallization from EtOH. Therefore,
2
we believe this method could be an attractive alternative to existing methods for the synthesis of 1-amidoalkyl-2-naphthols.
EXPERIMENTAL
General Methods. Melting points were determined using an RY-1 micromelting point apparatus. Infrared spectra
1
were recorded on a Scimitar 2000 series Fourier transform instrument (Varian). H NMR spectra were recorded on a Bruker
13
AV-500 spectrometer in DMSO-d using TMS as an internal standard. C NMR spectra were performed on a Bruker AV-500
6
spectrometer at 125 MHz in DMSO-d using TMS as an internal standard. Elemental analyses were carried out on EA 2400II
6
elemental analyzer (Perkin–Elmer) and agreed favorably with the calculated values.
General Procedure for the Synthesis of 1-Amidoalkyl-2-naphthols. To a mixture of 2-naphthol (10 mmol), an
aldehyde (10 mmol), and an amide (11 mmol), SnCl ·5H O (0.2 mmol) was added. The reaction mixture was magnetically
4
2
stirred on a preheated water bath at 80ꢀC. After completion of the reaction (monitored by TLC), the reaction mixture was
cooled to r.t., washed with H O–EtOH (v/v 1:1), and recrystallized from EtOH. The products were characterized by comparing
2
1
13
their mp, IR, H NMR, C NMR, and elemental analysis with those reported for authentic samples and with spectral data for
some representative compounds.
–1
N-((2-Chlorophenyl)(2-hydroxynaphthalen-1-yl)methyl)benzamide (4e). White solid. IR spectrum (KBr, ꢁ, cm ):
1
3426, 3067, 1632, 1573, 1538, 1346, 1075, 822, 753, 711. H NMR spectrum (500 MHz, DMSO-d , ꢂ, ppm, J/Hz): 9.90 (1H,
6
s, OH), 8.98 (1H, d, J = 6.2, NH), 8.08 (1H, d, J = 8.6, ArH), 7.89 (2H, d, J = 7.3, ArH), 7.82 (1H, d, J = 7.7, ArH), 7.78 (1H,
d, J = 8.8, ArH), 7.52 (1H, t, J = 7.3, ArH), 7.44–7.40 (5H, m, ArH), 7.36 (1H, d, J = 5.0, CH), 7.30–7.22 (3H, m, ArH), 7.19
13
(1H, d, J = 8.8, ArH). C NMR spectrum (125 MHz, DMSO-d , ꢂ): 165.3, 153.6, 138.7, 134.2, 132.9, 132.7, 131.1, 130.1,
6
129.4, 128.6, 128.5, 128.3, 128.1, 127.4, 126.6, 126.3, 122.8, 122.3, 118.6, 116.8, 48.6. C H NO Cl (387.8).
24 18
2
N-((2,4-Dichlorophenyl)(2-hydroxynaphthalen-1-yl) methyl)benzamide (4g). White solid. IR spectrum (KBr, ꢁ,
–1
1
cm ): 3423, 3069, 1633, 1574, 1537, 1344, 1074, 819, 749, 709. H NMR spectrum (500 MHz, DMSO-d , ꢂ, ppm, J/Hz):
6
9.96 (1H, s, OH), 9.17 (1H, d, J = 6.3, NH), 8.05 (1H, d, J = 8.6, ArH), 7.89 (2H, d, J = 7.2, ArH), 7.82 (1H, d, J = 7.5, ArH),
7.78 (1H, d, J = 8.8, ArH), 7.57 (1H, d, J = 2.1, ArH), 7.52–7.42 (5H, m, ArH), 7.37 (1H, dd, J = 2.1, 6.3, CH), 7.30–7.27 (2H,
13
m, ArH), 7.18 (1H, d, J = 8.8, ArH). C NMR spectrum (125 MHz, DMSO-d , ꢂ): 165.5, 153.7, 138.2, 134.1, 133.6, 132.7,
6
132.1, 131.4, 131.2, 129.6, 128.6, 128.3, 128.1, 127.5, 126.7, 126.5, 122.6, 122.3, 118.6, 116.1, 48.3. C H NO Cl (422.3).
24 17
–1
2
2
N-(1-(2-Hydroxynaphthalen-1-yl)butyl)benzamide (4k). White solid. IR spectrum (KBr, ꢁ, cm ): 3415, 3221,
1
3204, 1633, 1575, 1529, 1342, 1075, 815, 747, 715. H NMR spectrum (500 MHz, DMSO-d , ꢂ, ppm, J/Hz): 10.08 (1H, s, OH),
6
8.60 (1H, d, J = 6.3, NH), 8.23 (1H, d, J = 7.6, ArH), 7.81 (3H, t, J = 7.2, ArH), 7.70 (1H, d, J = 8.8, ArH), 7.53–7.44 (4H, m,
ArH), 7.31 (1H, t, J = 7.3, ArH), 7.20 (1H, d, J = 8.8 ArH), 6.04 (1H, q, J = 7.1, CH), 2.19–2.11 (1H, m, CH ), 1.92–1.85 (1H,
2
187

13
m, CH ), 1.51–1.41 (1H, m, CH ), 1.33–1.23 (1H, m, CH ), 0.93 (3H, t, J = 7.3, CH ). C NMR spectrum (125 MHz,
2
2
2
3
DMSO-d , ꢂ): 165.2, 152.8, 134.7, 132.0, 131.0, 128.5, 128.4, 128.3, 128.2, 126.9, 126.2, 122.3, 119.8, 118.6, 118.5, 46.6,
6
36.0, 19.6, 13.8. C H NO (319.4).
N-(1-(2-Hydroxynaphthalen-1-yl)butyl)acetamide (4v). White solid. IR spectrum (KBr, ꢁ, cm ): 3409, 3220,
2956, 1642, 1583, 1531, 1515, 1337, 1076, 815, 749, 705. H NMR spectrum (500 MHz, DMSO-d , ꢂ, ppm, J/Hz): 9.86 (1H,
21 21
2
–1
1
6
s, OH), 8.14 (1H, d, J = 8.6, NH), 8.02 (1H, s, ArH), 7.77 (1H, d, J = 7.7, ArH), 7.68 (1H, d, J = 8.8, ArH), 7.46 (1H, t, J = 7.2,
ArH), 7.28 (1H, t, J = 7.4, ArH), 7.18 (1H, d, J = 8.8, ArH), 5.83 (1H, q, J = 7.6, CH), 2.05–1.97 (1H, m, CH ), 1.88–1.80
2
13
(4H, m, CH and CH ), 1.40–1.30 (1H, m, CH ), 1.22–1.13 (1H, m, CH ), 0.88 (3H, t, J = 7.4, CH ). C NMR spectrum
2
3
2
2
3
(125 MHz, DMSO-d , ꢂ): 168.4, 152.9, 132.2, 128.4, 128.2, 128.1, 126.0, 122.1, 119.8, 118.5, 45.5, 35.9, 22.7, 19.5, 13.7;
6
C H NO (257.3).
16 19
2
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