Condensation of Aryl Aldehydes, 2-naphthol, and Thioacetamide Catalyzed by N-halo Reagents in Neutral Media

Article abstract of DOI:10.1002/jccs.201500125

A new three-component, highly efficient and solvent-free approach for the synthesis of known and new 1-thioamido-alkyl-2-naphthol derivatives was investigated. This was achieved via a one-pot condensation by reacting aryl aldehydes, 2-naphthol, and thioacetamide in the presence of catalytic amount of 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (TCCA) and 1,3-dichloro-5,5-dimethylhydantoin (DCDMH). Mechanistically, the in situ generation of Cl⁺ ion from TCCA and DCDMH is proposed to catalyse the reactions in neutral media. In the presented work, most of the products have been reported for the first time.

Full text of DOI:10.1002/jccs.201500125

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Article
Condensation of Aryl Aldehydes, 2-naphthol, and Thioacetamide Catalyzed by N-halo
Reagents in Neutral Media
Ardeshir Khazaei,a* Fatemeh Abbasi,a Ahmad Reza Moosavi-Zare,b* Marzieh Khazaeia and
M. Hassan Beyzavic
aFaculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838683, Iran
bDepartment of Chemistry, Sayyed Jamaleddin Asadabadi University, Asadabad, 6541835583, Iran
cDepartment of Chemistry and Chemical Biology, Harvard University, 12 Oxford St., Cambridge MA 02138, USA
(Received: Apr. 1, 2015; Accepted: Jul. 31, 2015; Published Online: Sept. 7, 2015; DOI: 10.1002/jccs.201500125)
A new three-component, highly efficient and solvent-free approach for the synthesis of known and new
1-thioamido-alkyl-2-naphthol derivatives was investigated. This was achieved via a one-pot condensa-
tion by reacting aryl aldehydes, 2-naphthol, and thioacetamide in the presence of catalytic amount of
1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (TCCA) and 1,3-dichloro-5,5-dimethylhydantoin (DCDMH).
Mechanistically, the in situ generation of Cl+ ion from TCCA and DCDMH is proposed to catalyse the re-
actions in neutral media. In the presented work, most of the products have been reported for the first time.
Keywords: Multi-component condensation; 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (TCCA);
1,3-dichloro-5,5-dimethylhydantoin (DCDMH); 1-thioamido-alkyl-2-naphthol;
Solvent-free.
INTRODUCTION
Because of the ability of synthesizing target products
ever, mostly the reported methods suffer from one or more
of disadvantages such as using toxic, corrosive, expensive
and/or large amount of catalysts, long reaction time, toxic
and corrosive solvents, and strong acidic media. Because
of the importance of 1-amido-alkyl-2-naphthols, the
investigatioin for a milder, more eco-friendly and faster
method with higher yields is still needed and challenging.
Trichloro-1,3,5-triazinane-2,4,6-trione (TCCA)
(Scheme 1) is an easily available reagent and inexpensive
compound which has been widely applied in organic synthe-
sis.16 On the other hand, 1,3-dichloro-5,5-dimethylhydantoin
(DCDMH) (Scheme 1) is also a stable, commercially avail-
able and inexpensive heterocycle which has rarely utilized as
a source of chlorine ion or radical in chlorination17,18 or oxida-
tion reactions.19-21 To the best of our knowledge, there is no
report of catalytic application of DCDMH and TCCA in the
preparation of 1-thioacetamido-alkyl-2-naphthols.
with atom economy and higher efficiency by forming struc-
tural complexity in one pot step from three or more reac-
tants, multi-component reactions (MCRs) play a signifi-
cant role in the sustainable and diversity-oriented synthesis
of organic materials. In addition, MCRs bear some advan-
tages of synthetic efficiency and simplicity compared with
conventional reactions.1-3 1-Amidoalkyl-2-naphthols and
1-thiomido-alkyl-2-naphthols are intersting molecules of
choice as they can be easily converted to biologically im-
portant 1-aminoalkyl-2-naphthols via hydrolysis.4 1-Ami-
noalkyl-2-naphthols have been studied as bradycardiac and
hypotensive agents.4,5 1-Amidoalkyl-2-naphthols can be
also converted to 1,3-oxazine derivatives.6 1,3-Oxazines
offer several pharmaceutical properties including antibi-
otic,7 antitumor8 and analgesic activities.9
There are known procedures for the synthesis of
1-amido-alkyl-2-naphthols in the literatures. However,
limited approaches have been reported to replace the amide
with thioamide. The preparation of 1-amidoalkyl and
thioamidoalkyl naphthols can be carried out by multi-
component reactions using different catalysts such as
[Msim]Cl, [Dsim]Cl, [Msim]AlCl4,10 [Dsim]HSO4,11 p-
TSA,12 H2SO4/SiO2,13 Fe(HSO4)3,14 trityl chloride.15 How-
Having above facts, herein, we report DCDMH and
TCCA as homogenous and neutral catalysts for the synthe-
sis of 1-thioacetamido-alkyl-2-naphthols via a one-pot,
multi-component reaction of 2-naphthol, aromatic alde-
hydes, and thioacetamide (Scheme 2).
Additionally, we report that TCCA and DCDMH can
also catalyze the preparation of bis(1-thioacetamido-al-
kyl-2-naphthol) (Scheme 3).
* Corresponding author. Email: moosavizare@yahoo.com & moosavi-zare@sjau.ac.ir
Supporting information for this article is available on the www under http://dx.doi.org/10.1002/jccs.201500125
850
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Synthesis of Thioamido-alkyl-2-naphthols
The structure of trichloro-1,3,5-triazinane-
Scheme 1
10 mol% of TCCA and 15 mol% of DCDMH at 120 °C un-
2,4,6-trione (TCCA) and 1,3-dichloro-5,5-
dimethylhydantoin (DCDMH).
der solvent-free conditions.
Table 1. Optimization of the amount of TCCA and the reaction
temperature
Catalyst
(mol%)
Temperature
Time
(min)
Yield
(%)a
Entry
(°C)
1
2
3
4
5
6
7
5
120
120
120
80
50
25
25
60
50
45
30
65
85
84
60
67
71
75
10
15
10
10
10
10
90
100
110
a Yield of purified product.
Scheme 2. The synthesis of 1-thioacetamido-alkyl-2-
naphthols.
Table 2. Optimization of the amount of DCDMH and the
reaction temperature
Catalyst
(mol%)
Temperature
Time
(min)
Yield
(%)a
Entry
(°C)
1
2
3
4
5
6
7
8
9
5
120
120
120
120
120
80
60
50
40
35
35
70
55
50
40
60
65
69
80
80
52
60
64
70
10
13
15
20
15
15
15
15
Scheme 3. The synthesis of bis(1-thioacetamido-alkyl-
2-naphthol).
90
100
110
a Yield of purified product.
To assess the efficiency and the scope of the organic
catalyst in the synthesis of 1-thioacetamido-alkyl-2-
naphthols, the reaction of 2-naphthol with a variety of
arylaldehydes and thioacetamide was studied under opti-
mized conditions. The corresponding results are sum-
merized in Table 3. As it can be seen in Table 3, the reac-
tions were carried out efficiently within 20-150 min and the
expected products were obtained in moderate to excellent
yields (40-82%). In addition, the influence of electron-re-
leasing and electron-withdrawing substituents and halo-
gens on the aromatic ring of arylaldehydes was studied (Ta-
ble 3).
RESULTS AND DISCUSSION
Initially, to optimize the reaction conditions (cata-
lysts loading and temperature), the reaction of 2-naphthol
(1 mmol), benzaldehyde (1 mmol) and thioacetamide (1.2
mmol) was chosen as the model reaction, and we in-
vesitigated this model reaction in the presence of different
amounts of catalysts (TCCA and DCDMH) under thermal
solvent-free conditions. The results are summarized in Ta-
ble 1 and 2. As Table 1 and 2 indicates, higher yield of puri-
fied product and shorter reaction time were obtained using
Based on these results, TCCA and DCDMH are con-
sidered as highly efficient and mild organic catalysts with a
good substrate scope for the synthesis of 1-thioacetamido-
alkyl-2-naphthol derivatives.
Moreover, the presented protocol was also examined
on the condensation of 2-naphthol with bis-aldehyde
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Khazaei et al.
Table 3. The Preparation of 1-thioacetamido-alkyl-2-naphthols from 2-naphthol, aromatic aldehydes
and thioacetamide using TCCA and DCDMH at 120 °C
Entry
R
Time (min)/Yield (%)a,b Time (min)/Yield (%)a,c
M P °C (lit.)
180-182 (190-193)15
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
11a
C6H5
2-NO2C6H4
3-NO2C6H4
2-ClC6H4
25/80
105/68
120/65
25/82
80/78
45/65
35/70
80/79
55/70
150/55
30/44
35/73
110/64
135/61
30/78
90/69
60/59
45/62
85/72
70/60
155/51
45/40
202-204
187-190
253-255
240-242 (246-248)14
4-ClC6H4
2,6-diClC6H3
4-Cl-3-NO2C6H3
4-BrC6H4
241-242
246-249
190-193
4-CF3C6H4
4-CH3C6H4
4-OCH3C6H4
230-231
192-195
180-185 (192-194)14
a Yield of purified product, b TCCA, c DCDMH.
(terephthaldehyde) and thioacetamide in the presence of 10
mol% of TCCA and 15 mol% of DCDMH (Scheme 3). For
this reaction, 1 equiv. of 2-naphthol, 1 equiv. of tere-
phthalaldehyde and 1.2 equiv. of thioacetamide were uti-
lized which beared purified 1-thioacetamido-alkyl-2-
naphthol (1b) and bis(thioacetamido-alkyl-2-naphthol)
(2b) in the ratio of 65%:16% yields in 7 min and ratio of
61%:14% yields in 8 min utililizing TCCA and DCDMH,
respectively.
Scheme 4. The plausible mechanism for the synthesis
of 1-thioacetamido-alkyl-2-naphthols cata-
lyzed by TCCA and DCDMH.
Once we changed the reaction conditions by utilizing
2 equiv. of 2-naphthol, 1 equiv. of terphetaldehyde and 2.4
equiv. of thioacetamide, the products were obtained in the
ratio of 1b:2b as 13%:70% yields in 15 min and in ratio of
11%:67% yields in 17 min for TCCAand DCDMH, respec-
tively.
Since TCCA and DCDMH contain chlorine atoms
bonded to nitrogen atoms in heterocyclic ring, based on the
literature,16,22-25 it is speculated that the in situ generation of
Cl+ ion from the catalysts initiate the catalytic processes. in
a way that Cl+ ion from the catalysts (TCCAor DCDMH) is
abstracted by the aldehyde and I and II as activated forms
of aldehyde are generated (Scheme 4). Then, from attack-
ing of 2-naphthol to the activated forms of I and II interme-
diate III is achieved and tautomerized to IV. Finally, fol-
lowed by dehydration, the attacking of thioacetamide to IV
intermediate is led to the corresponded products and the
catalysts are regenerated for the next catalytic cycles.
In a separate experiment, to confirm that HCl could
not be generated from TCCA and DCDMH to catalyze the
reaction, the model reactions were performed in the pres-
ence of hydrochloric acid (10% and 20%). As shown in Ta-
ble 4, TCCA and DCDMH were more effective than HCl to
catalyze the reactions.
To prove the formation of intermediate I and II,
benzaldehyde was reacted with catalysts at 120 °C, and
then IR and UV spectra of the aldehydic functional group
in the reaction mixture were compared with those in ben-
zaldehyde. Indeed, the carbonyl streching frequeccy of
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Synthesis of Thioamido-alkyl-2-naphthols
Table 4. Comparison result of TCCA and DCDMH with HCl in
the synthesis of N-((2-hydroxynaphthalen-1-yl) (phenyl)
methyl) thioacetamide at 120 °C
Catalyst
(mol%)
Time
(min)
Yield
(%)a
TOF
(min-1)b
Entry
Catalyst
1
2
3
4
TCCA
DCDMH
HCl
10
15
10
20
25
35
85
80
32
36
0.34
0.23
300
300
0.015
0.009
HCl
a Yield of purified product, b Turn over frequency.
benzaldehyde (1703 cm-1) was decreased to 1682 cm-1 in
the reaction mixture. It is indicative of decreased nature of
double bond and the formation of activated carbonyls. UV
spectra were another evidence to confirm the formation of I
and II. The maximum absorbance for benzaldehyde ap-
peared at 243 nm and for TCCA at 234 nm and DCDMH at
231 nm. But the lmax of the complexes of aldehyde and Cl+
ion which are formed by the addition TCCA and DCDMH
to benzaldehyde was observed at 238 nm.25
Intermediates I and II act as activated carbonyl com-
pounds to react with 2-naphthol to give III intermediate.
1-Thioacetamido-alkyl-2-naphthol is synthesized by react-
ing of this intermediate with thioacetamide. To examine
that the catalyst was completely regained during the reac-
tion the UV spectra of the catalyst and reaction mixture in
dichloromethane were recorded. As Figure 1 indicates, the
maximum of absorption for the catalysts in UV spectrum of
the reaction mixture is similar to UV spectra of TCCA and
DCDMH. Based on, it is clear that TCCA and DCDMH
were recovered unchanged after the completion of the reac-
tion and the proposed mechanisms were acceptable.
Fig. 1. UV spectra of TCCA, DCDMH and mixture of
reaction with TCCA and DCDMH at 120 °C in
dichloromethane respectively.
mido-alkyl-2-naphthol derivatives (Scheme 3): A mixture of
2-naphthols (0.29 g, 2.0 mmol), aldehydes (2.0 mmol), thio-
acetamide (0.18 g, 2.4 mmol) and TCCA (46.4 mg, 0.2 mmol, 10
mol%) or DCDMH (59.1 mg, 0.3 mmol, 15 mol%) in a 10 mL
round-bottomed flask sealed with a stopper was stirred in an
oil-bath (120 °C). After completion of the reaction, as monitored
by TLC, the reaction was cooled to room temperature and washed
with hot water. Subsequently, the crude products (compounds
1a-11a) were purified by plate chromatography on silica gel
eluted with EtOAc/n-hexane.
EXPERIMENTAL
General: Chemicals were purchased from Merck and
Aldrich Chemical Companies and used without further purifica-
tion. The known products were identified by comparison of their
melting points and spectral data with those in the authentic sam-
ples. Infrared (IR) spectra were recorded on a Shimadzu IR 470
spectrophotometer. 13C NMR and 1H NMR spectra were recorded
on a Bruker 400 and JEOL FT-NMR 90 MHz using TMS as an in-
ternal standard in dimthylsulfoxide (DMSO) as the solvent. Mass
spectra were recorded on an Agilent technologies (HP) 5973 net-
work mass selective detector (MSD). Melting points were deter-
mined in open capillaries with a Stuart Scientific melting point
apparatus. TLC was performed on Silica–gel polygram SILG/UV
254 plates.
General procedure for the condensation between 2-
naphthol, terephthaldehyde and thioacetamide (Scheme 3):
To a mixture of 2-naphthols (0.29 g, 2.0 mmol), thioacetamide
(0.18 g, 2.4 mmol) and TCCA (46.4 mg, 0.2 mmol, 10 mol%) or
DCDMH (59.1 mg, 0.3 mmol, 15 mol%), in two 10 mL round-
bottomed flask, was added terephthaldehyde (0.27 g, 2.0 mmol)
and (134.0 mg, 1.0 mmol) respectively. The reaction mixtures
were stirred in an oil-bath (120 °C) for approprate times. After
completion of the reactions, as monitored by TLC, The reactions
were cooled to room temperature, washed with hot water. After-
ward, the crude products were purified by plate chromatography
on silica gel eluted with EtOAc/n-hexane and 1-thioacetamido-
General procedure for the synthesis of 1-thioaceta-
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Article
Khazaei et al.
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(2b) completely separated. Note: It should be mentioned that, in
the above procedure, 2.0 mmol of terephthaldehyde gives 1b
more than 2b and 1.0 mmol of terephthaldehyde gives 2b as the
main product.
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636-641.
In conclusion, it has been reported a new procedure
for the preparation of 1-thioacetamido-alkyl)-2-naphthol
derivatives via a one-pot, three-component condensation
of 2-naphthol with aromatic aldehydes and thioacetamide
using TCCA and DCDMH as homogenous organic cata-
lysts at 120 °C under the solvent-free and neutral condi-
tions. The presented approach also is allowed for the prepa-
ration of bis(1-thioacetamido-alkyl-2-naphthol).
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ACKNOWLEDGEMENT
The authors acknowledge to Bu-Ali Sina University
Research Councils, Center of Excellence in Development
of Chemistry Methods (CEDCM) and National Foundation
of elites (BMN) for support of this work.
15. Khazaei, A.; Zolfigol, M. A.; Moosavi-Zare, A. R.; Abi, F.;
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