A three-component novel synthesis of 1-[aryl(thioacetamido)methyl]-2- naphthol derivatives

Article abstract of DOI:10.3184/174751912X13408123396599

A three-component reaction between 2-naphthol, an aryl aldehydes and thioacetamide catalysed by p-toluenesulfonic acid under reflux conditions provided a simple and efficient one-pot route for the synthesis of 1-[aryl(thioaceta mido)methyl]-2-naphthol derivatives in excellent yields.

Full text of DOI:10.3184/174751912X13408123396599

510 RESEARCH PAPER
SEPTEMBER, 510–511
JOURNAL OF CHEMICAL RESEARCH 2012
A three-component novel synthesis of 1-[aryl(thioacetamido)methyl]-2-
naphthol derivatives
Alireza Hassanabadi* and Mohammad R. Hosseini-Tabatabaei
Department of Chemistry, Islamic Azad University, Zahedan Branch, PO Box 98135-978, Zahedan, Iran
A three-component reaction between 2-naphthol, an aryl aldehydes and thioacetamide catalysed by p-toluenesul-
fonic acid under reflux conditions provided a simple and efficient one-pot route for the synthesis of 1-[aryl(thioaceta
mido)methyl]-2-naphthol derivatives in excellent yields.
Keywords: 2-naphthol, aryl aldehydes, thioacetamide, p-toluenesulfonic acid, 1-[aryl(thioacetamido)methyl]-2-naphthols
Multi-component reactions (MCRs) have attracted consider-
able interest from organic chemists because they can be widely
employed for the rapid assembly of arrays with high molecular
diversity.1 These processes are performed without the need to
isolate an intermediate which reduces time and saves both
energy and raw materials.2,3
Acetamido- or amino-ketone derivatives are important for
their biological and pharmaceutical properties,4,5 particularly
in the preparation of antibiotic drugs such as nikkomycine or
neopolyoxine.6,7
Furthermore, amidoalkyl naphthols can be converted to
useful synthetic building blocks8 and 1-(alkylamidomethyl)-2-
naphthol, which exhibit depressor and bradycardiac activity.9
The preparation of 1-(alkylamidomethyl)-2-naphthol can be
carried out by multicomponent condensation of aldehydes,
2-naphthol and amide or urea in the presence of Lewis or
Bronsted acid catalysts.10 Note that 1-(alkylamidomethyl)-2-
naphthols can be converted to important biologically active
1-(alkylaminomethyl)-2-naphthol derivatives by hydrolysis.
The hypotensive and bradycardiac effects of these compounds
have been evaluated.9,11,12 Despite the broad range of applica-
tions, only a few members of this family of compounds
have been reported. The development of new methods for their
synthesis is therefore of considerable synthetic importance.
for the aromatic and methine protons. Two single signals are
observed at 8.53 and 10.02 ppm that disappeared after addition
of a few drops of D2O to d6-DMSO solution of compound 4a.
These signals are related to OH and NH protons. 13C NMR
spectrum of compound 4a showed 17 distinct signals in
agreement with the proposed structure.
To optimise the amount of catalyst and the reaction tem-
perature, the reaction of benzaldehyde (1 equiv.), 2-naphthol
(1 equiv.), and thioacetamide (1.2 equiv.) under reflux condi-
tions was selected as a model. The best result was obtained by
carrying out the reaction using 0.1 equiv. of p-TSA at 100 ºC
under reflux conditions after 1h (Table 1, entry 5).
Using these optimised reaction conditions, the scope and
efficiency of the reaction were explored for the synthesis of a
wide variety of substituted 1-[aryl(thioacetamido)methyl]-2-
naphthol using various aryl aldehydes, 2-naphthol, and thio-
acetamide. The results are summarised in Table 2. The direct
three-component reactions worked well with a variety of aryl
aldehydes including those bearing electron-withdrawing and
Table 1 Optimisation of the amounts of p-TSA and the raction
temperature for the reaction between 2-napthol, bezaldehyde
and thioacetamide
Yield/%a
Results and discussion
Entry
Catalyst/equiv. Temp./°C Time/min
Recently, we reported the reaction of 2-naphthol, aryl alde-
hydes, and acetonitrile to form amidoalkyl naphthol deriva-
tives.13 The reaction proceeds through the in situ formation
of o-quinone methides (o-QMs), and acetonitrile acted as a
nucleophile. We describe here a practical and inexpensive
method for the preparation of new 1-[aryl(thioacetamido)meth
yl]-2-naphthol derivatives via a three-component condensation
reaction between aryl aldehydes 3, 2-naphthol 1, and thioacet-
amide 2 in the presence of 0.1 mmol of p-toluenesulfonic
acid (p-TSA) in refluxing 1,2-dichloroethane after 1h afforded
1-[aryl(thioacetamido)methyl]-2-naphthols (Scheme 1).
1
2
3
4
5
6
7
8
0.01
0.03
0.05
0.07
0.10
0.20
0.10
0.10
100
100
100
100
100
100
135
75
120
120
120
120
60
120
60
120
55
67
77
86
95
97
95
88
a Isolated yield.
Table 2 Three component reaction of aryl aldehydes, 2-napthol
and thioacetamide catalysed by p-TSA
Products 4a–i were all new compounds and their structures
were deduced from their elemental analyses and spectral data.
1
The H NMR spectrum of compound 4a displayed a sharp
single signal at δ = 1.97 ppm for the protons of the methyl
group, along with characteristic signals at δ = 7.02–7.82 ppm
Entry
Ar
Product Yield/%a Time/min M.p./°C
1
2
3
4
5
6
7
8
9
C6H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
95
94
95
92
93
90
94
95
87
60
60
60
60
60
60
60
60
60
196–198
226–228
174–176
188–190
229–231
234–236
225–227
217–219
213–215
4-ClC6H4
2-ClC6H4
4-CH3C6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-BrC6H4
Scheme 1 Reaction between 2-naphthol, aryl aldehydes and
thioacetamide catalysed by p-TSA.
2-OMeC6H4
a Isolated yield.
* Correspondent. E-mail: ar_hasanabadi@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2012 511
(CH), 119.18, 119.52, 123.43, 124.09, 127.14, 129.31, 129.44, 130.25,
132.98 and 153.65 (naphthol moiety), 126.77, 128.92, 140.28 and
143.45 (phenyl moiety), 170.36 (NC=S).
1-[2-Nitrophenyl(thioacetamido)methyl]-2-naphthol (4e): White
powder, m.p. 161–163 °C, IR (KBr) (νmax cm−1): 3400, 3210–2820,
1643. Anal. Calcd for C19H16N2O3S: C, 64.76; H, 4.58; N, 7.95. Found:
C, 64.48; H, 4.80; N, 8.32%. 1H NMR (500 MHz, d6-DMSO): δ 1.92
(3 H, s, CH3), 7.01–8.54 (11 H, m, aromatic and NCH), 8.66 (1 H, d,
3JHH = 8 Hz, NH), 10.01(1 H, s, OH). 13C NMR (125.8 MHz, d6-
DMSO): δ 23.37 (CH3), 48.45 (CH), 118.57, 119.25, 123.44, 126.31,
127.54, 128.97, 129.50, 130.37, 133.65 and 154.17 (naphthol moiety),
121.23, 122.06, 130.65, 133.08, 146.13 and 148.57 (phenyl moiety),
170.52 (NC=S).
1-[3-Nitrophenyl(thioacetamido)methyl]-2-naphthol (4f): White
powder, m.p. 234–236 °C, IR (KBr) (νmax cm−1): 4010, 3360–2915,
1627. Anal. Calcd for C19H16N2O3S: C, 64.76; H, 4.58; N, 7.95. Found:
C, 64.53; H, 4.86; N, 8.27%. 1H NMR (500 MHz, d6-DMSO): δ 1.97
(3 H, s, CH3), 6.97–8.59 (11 H, m, aromatic and NCH), 8.61 (1 H, d,
3JHH = 8 Hz, NH), 10.06(1 H, s, OH). 13C NMR (125.8 MHz, d6-
DMSO): δ 23.42 (CH3), 48.50 (CH), 118.66, 119.33, 123.48, 126.38,
127.64, 129.02, 129.57, 130.44, 133.72 and 154.23 (naphthol moiety),
121.29, 122.10, 130.76, 133.03, 146.27 and 148.60 (phenyl moiety),
170.59 (NC=S).
1-[4-Nitrophenyl(thioacetamido)methyl]-2-naphthol (4g): White
powder, m.p. 225–227 °C, IR (KBr) (νmax cm−1): 3385, 3354–2910,
1638. Anal. Calcd for C19H16N2O3S: C, 64.76; H, 4.58; N, 7.95. Found:
C, 64.43; H, 4.73; N, 8.35%. 1H NMR (500 MHz, d6-DMSO): δ 1.93
(3 H, s, CH3), 7.03–8.12 (11 H, m, aromatic and NCH), 8.56 (1 H, d,
3JHH = 8 Hz, NH), 10.11(1 H, s, OH). 13C NMR (125.8 MHz, d6-
DMSO): δ 23.41 (CH3), 48.78 (CH), 118.72, 119.31, 123.44, 124.08,
126.39, 128.01, 129.06, 130.74, 133.06 and 154.24 (naphthol moiety),
127.57, 129.54, 138.82 and 146.78 (phenyl moiety), 170.65 (NC=S):
1-[4-Bromophenyl(thioacetamido)methyl]-2-naphthol (4h): White
powder, m.p. 217–219 °C, IR (KBr) (νmax cm−1): 3378, 3165–2700,
1631. Anal. Calcd for C19H16BrNOS: C, 59.07; H, 4.17; N, 3.63.
Found: C, 59.31; H, 4.27; N, 3.81%. 1H NMR (500 MHz, d6-DMSO):
δ 1.90 (3 H, s, CH3), 6.99–7.77 (11 H, m, aromatic and NCH), 8.47
(1 H, d, 3JHH = 8 Hz, NH), 10.04(1 H, broad s, OH). 13C NMR (125.8
MHz, d6-DMSO): δ 23.46 (CH3), 48.30 (CH), 119.31, 119.90, 123.32,
123.94, 128.99, 129.46, 130.34, 130.35, 138.70 and 154.07 (naphthol
moiety), 126.35, 129.15, 131.67 and 146.29 (phenyl moiety), 170.27
(NC=S).
Scheme 2 Suggested mechanism for formation of
compounds 4a–i.
electron-donating groups such as OMe, Cl, F, and NO2, and the
desired compounds were obtained in high yields.
As reported in the literature,13 the reaction of 2-naphthol
with aryl aldehydes in the presence of an acid catalyst is known
to give o-quinone methides (o-QMs). These o-QMs, generated
in situ, react with thioacetamide to form the 1-[aryl(thioacet-
amido)methyl]-2-naphthol products (Scheme 2).
In conclusion, we have developed a highly efficient synthe-
sis of 1-[aryl(thioacetamido)methyl]-2-naphthol derivatives from
aryl aldehydes, 2-naphthol and thioacetamide under reflux
conditions. The advantages of the reported method are inex-
pensive and easily available starting materials, simple reaction
conditions, high yields, single-product reaction and simple
workup procedure.
Experimental
Melting points were determined with an Electrothermal 9100 appara-
tus. Elemental analyses were performed using a Heraeus CHN-
O-Rapid analyser. IR spectra were recorded on a Shimadzu IR-470
1
spectrometer. H and 13C NMR spectra were recorded on Bruker
DRX-500 Avance spectrometer at solution in d6-DMSO using TMS as
internal standard. The chemicals used in this work were purchased
from Fluka (Buchs, Switzerland) and were used without further
purification.
Synthesis of compounds 4a–i; general procedure
A mixture of thioacetamide (3 mmol) aryl aldehyde (3 mmol) 2-naph-
thol (3 mmol) and p-TSA (0.1 mmol) in 15 mL 1,2-dichloroethane
was refluxed for 1h. The reaction was followed by TLC. After com-
pletion, the reaction mixture was poured into 50 mL ice-water. The
solid product was filtered, washed with ice-water and recrystallised
from ethyl acetate/ hexane to give the pure product.
1-[2-Methoxyphenyl(thioacetamido)methyl]-2-naphthol(4i):White
powder, m.p. 213–215 °C, IR (KBr) (νmax cm−1): 3500, 3348–2930,
1633. Anal. Calcd for C20H19NO2S: C, 71.19; H, 5.68; N, 4.15. Found:
C, 71.42; H, 5.39; N, 4.40%. 1H NMR (500 MHz, d6-DMSO): δ 1.86
(3 H, s, CH3), 3.53 (3 H, s, OCH3), 6.83–8.13 (11 H, m, aromatic and
1-[Phenyl(thioacetamido)methyl]-2-naphthol (4a): White powder,
m.p. 196–198 °C, IR (KBr) (νmax cm−1): 3405, 3180–2935, 1636. Anal.
Calcd for C19H17NOS: C, 74.24; H, 5.57; N, 4.56. Found: C, 74.56; H,
5.19; N, 4.81%. 1H NMR (500 MHz, d6-DMSO): δ 1.97 (3 H, s, CH3),
3
3
NCH), 8.26 (1 H, d, JHH = 8 Hz, NH), 9.73 (1 H, s, OH). 13C NMR
7.02–7.82 (12 H, m, aromatic and NCH), 8.53 (1 H, d, JHH = 8 Hz,
NH), 10.02 (1 H, broad s, OH). 13C NMR (125.8 MHz, d6-DMSO):
δ 23.62 (CH3), 48.37 (CH), 119.24, 119.48, 123.35, 124.05, 127.98,
129.32, 129.38, 130.19, 133.08 and 154.02 (naphthol moiety), 126.92,
127.86, 128.98 and 143.11 (phenyl moiety), 170.29 (NC=S).
1-[4-Chlorophenyl(thioacetamido)methyl]-2-naphthol (4b): White
powder, m.p. 226–228 °C, IR (KBr) (νmax cm−1): 3385, 3045–2605,
1621. Anal. Calcd for C19H16ClNOS: C, 66.75; H, 4.72; N, 4.10.
Found: C, 66.98; H, 4.49; N, 4.35%. 1H NMR (500 MHz, d6-DMSO):
δ 1.96 (3 H, s, CH3), 7.09–7.78 (11 H, m, aromatic and NCH), 8.45
(1 H, d, 3JHH = 8 Hz, NH), 10.02 (1 H, broad s, OH). 13C NMR (125.8
MHz, d6-DMSO): δ 23.49 (CH3), 48.30 (CH), 119.29, 119.34, 123.34,
123.99, 128.78, 129.34, 129.47, 130.35, 133.11 and 154.09 (naphthol
moiety), 128.93, 129.07, 131.51 and 142.67 (phenyl moiety), 170.14
(NC=S).
1-[2-Chlorophenyl(thioacetamido)methyl]-2-naphthol (4c): White
powder, m.p. 174–176 °C, IR (KBr) (νmax cm−1): 3410, 3265–2915,
1640. Anal. Calcd for C19H16ClNOS: C, 66.75; H, 4.72; N, 4.10.
Found: C, 66.93; H, 4.43; N, 4.41%. 1H NMR (500 MHz, d6-DMSO):
δ 1.85 (3 H, s, CH3), 6.98–7.63 (11 H, m, aromatic and NCH), 8.57
(1 H, d, 3JHH = 8 Hz, NH), 10.09(1 H, broad s, OH). 13C NMR (125.8
MHz, d6-DMSO): δ 23.14 (CH3), 48.42 (CH), 117.65, 119.63, 123.62,
124.74, 127.11, 129.23, 130.07, 130.64, 133.72 and 155.03 (naphthol
moiety), 125.99, 127.93, 131.17, 133.22, 140.14 and 142.19 (phenyl
moiety), 169.94 (NC=S).
(125.8 MHz, d6-DMSO): δ 23.53 (CH3), 45.38 (CH), 56.17 (OCH3),
119.49, 119.80, 122.99, 124.29, 126.37, 129.12, 129.39, 129.53,
133.47, and 154.12 (naphthol moiety), 111.68, 120.47, 128.54,
128.95, 131.01 and 157.45 (phenyl moiety), 169.17 (NC=S).
We gratefully acknowledge financial support from the Research
Council of Islamic Azad University of Zahedan of Iran.
Received 8 May 2012; accepted 14 June 2012
Paper 1201301 doi: 10.3184/174751912X13408123396599
Published online: 28 August 2012
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