1,3-Dibromo-5,5-dimethylhydantoin as an efficient catalyst for synthesis of thioamidoalkyl and bis(thio)amidoalkyl-2-naphthols under solvent-free conditions

Article abstract of DOI:10.1007/s11164-014-1738-y

Abstract An efficient and easy method for one-pot three-component synthesis of thioamidoalkyl and bis(thio)amidoalkyl naphthols by condensation of aromatic aldehydes, 2-naphthol, and acetamide or thioacetamide under thermal condition at 130°C in the presence of 1,3-dibromo-5,5-dimethylhydantoin is described. The present approach offers several advantages such as reduced reaction time, higher yield, and economic availability of the catalyst.

Full text of DOI:10.1007/s11164-014-1738-y

Res Chem Intermed
DOI 10.1007/s11164-014-1738-y
1,3-Dibromo-5,5-dimethylhydantoin as an efficient
catalyst for synthesis of thioamidoalkyl and bis(thio)
amidoalkyl-2-naphthols under solvent-free conditions
•
Arash Ghorbani-Choghamarani
Shima Rashidimoghadam
Received: 9 May 2014 / Accepted: 3 June 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract An efficient and easy method for one-pot three-component synthesis of
thioamidoalkyl and bis(thio)amidoalkyl naphthols by condensation of aromatic alde-
hydes, 2-naphthol, and acetamide or thioacetamide under thermal condition at 130 °C in
the presence of 1,3-dibromo-5,5-dimethylhydantoin is described. The present approach
offers several advantages such as reduced reaction time, higher yield, and economic
availability of the catalyst.
Keywords 1,3-Dibromo-5,5-dimethylhydantoin (DBH) Á Multicomponent
reaction Á Thioacetamide Á Thioamidoalkyl naphthol Á Solvent-free
Introduction
Multicomponent reactions (MCRs) have elicited increased interest since they are
performed without the need to isolate any intermediate, thus reducing time and
saving energy and raw materials [1]. One of these MCRs is synthesis of amidoalkyl
naphthols, which are ubiquitous in a variety of biologically important natural
products and potent drugs, including a number of nucleoside antibiotics and human
immunodeficiency virus (HIV) protease inhibitors such as ritonavir and lopinavir
[2, 3]. Furthermore, 1-amidoalkyl-2-naphthol and 1-thioamidoalkyl-2-naphthol can
be converted to useful synthetic building blocks for drugs exhibiting depressor and
bradycardiac activities [3, 4]. Thus, synthesis of 1-amidoalkyl-2-naphthols and
1-thioamidoalkyl-2-naphthols is an important and useful task in organic chemistry.
A straightforward method for synthesis of these compounds involves three-
component condensation of 2-naphthol, aromatic aldehyde, and amide in the
presence of catalyst.
A. Ghorbani-Choghamarani (&) Á S. Rashidimoghadam
Department of Chemistry, Faculty of Science, Ilam University, P.O. Box 69315516, Ilam, Iran
e-mail: arashghch58@yahoo.com; a.ghorbani@mail.ilam.ac.ir
123

A. Ghorbani-Choghamarani, S. Rashidimoghadam
CHO
OH
S
DBH (Catalyst)
OH
+
X
CH3CNH2
+
Solvent-free
NH
130 C
°
X
S
CH3
Scheme 1 Preparation of 1-thioamidoalkyl-2-naphthols in the presence of DBH
Scheme 2 1,3-Dibromo-5,5-
dimethylhydantoin (DBH)
Br
N
O
N
Br
O
Many studies have been devoted to preparation of amidoalkyl naphthols by
multicomponent condensation of aldehydes, b-naphthol, and amide in the presence
of various catalysts. However, to the best of our knowledge, only three works with
limited examples have reported on the replacement of amide with thioamide or
thiourea [5–7].
In this paper, we report our results on an efficient and rapid synthesis of
1-thioamidoalkyl-2-naphthols from 2-naphthol, aryl aldehydes, and thioacetamide
in the presence of catalytic amounts of 1,3-dibromo-5,5-dimethylhydantoin (DBH)
under solvent-free conditions (Scheme 1).
DBH is a five-membered heterocycle (Scheme 2) which has been used
extensively as a brominating agent and oxidant [8–18] in organic synthesis. During
the last decade, DBH has attracted special attention as an efficient homogeneous
catalyst for organic transformations, because it is relatively nontoxic, commercially
available, inexpensive, and insensitive to air and moisture.
Experimental
General
Chemicals were purchased from Fluka, Merck, and Aldrich chemical companies.
All yields refer to isolated products. Reactions were monitored by thin-layer
chromatography (TLC) carried out on silica plates. Products were characterized by
1
comparison of their physical data with those of known samples or by their H and
13C nuclear magnetic resonance (NMR) spectral data.
General procedure for synthesis of 1-thioamidoalkyl-2-naphthols A mixture of
aldehydes (1 mmol), 2-naphthol (1 mmol), thioacetamide (1.5 mmol), and DBH
(0.15 mmol, 43 mg) was stirred at 130 °C in an oil bath for appropriate time. The
123

Synthesis of thioamidoalkyl and bis(thio)amidoalkyl-2-naphthols
reaction was monitored by TLC. After completion of the reaction, the reaction
mixture was cooled to room temperature and subjected to column chromatography
on silica gel and eluted with acetone/n-hexane (3:7) to give pure product.
General procedure for preparation of bis-1-(thio)amidoalkyl-2-naphthols A
mixture of terephthaldehyde/iso-terephthaldehyde (1 mmol), 2-naphthol (2.5 mmol),
acetamide/thioacetamide (3.75 mmol), and DBH (0.15 mmol, 43 mg) was stirred at
130 °C in an oil bath for appropriate time. After completion of the reaction, as
monitored by TLC, the reaction mixture was cooled to room temperature, and was
subjected to column chromatography on silica gel and eluted with acetone/n-hexane
(5:5) to give product.
Selected spectral data
N-[(2-Hydroxynaphthalen-1-yl)(2-hydroxy-4-methoxyphenyl)methyl)] thioacetamide
(L) 1H NMR (400 MHz, DMSO): d = 11.05 (s, 1H), 10.56 (s, 1H), 7.96 (d,
J = 8 Hz, 1H), 7.27–7.62 (m, 3H), 6.40–6.54 (m, 6H), 3.77 (s, 3H), 1.25 (s, 3H)
ppm; 13C NMR (100 MHz, DMSO): d = 179.1, 164.0, 161.8, 155. 9, 134.3, 128.6,
128.5, 128.4, 128.4, 128.3, 124.3, 124.2, 122.8, 117.3, 110.2, 106.6, 101.0, 58.8, 55.
-1
ꢀ
5, 24.6 ppm; IR (KBr): m = 3,344, 2,251, 2,125, 1,767, 1,641, 1,396, 758 cm
.
N-[{4-[Acetylamino-(2-hydroxynaphthalen-1-yl)-methyl]-phenyl}-(2-hydroxynaphtha-
len-1-yl)-methyl] acetamide (A) 1H NMR (400 MHz, DMSO): d = 9.96 (s, 2H),
8.38 (d, J = 8 Hz, 2H), 7.73–7.81 (m, 4H), 7.04–7.34 (m, 14H), 1.92 (s, 6H) ppm;
13C NMR (100 MHz, DMSO): d = 140.3, 132.2, 129.1, 128.4, 128.3, 126.2, 125.7,
ꢀ
122.3, 118.7, 118.6, 118.3, 118.2, 118.2, 47.6, 22.5 ppm; IR (KBr): m = 3,400,
3,389, 3,059, 1,700, 1,642, 1,512, 744 cm-1
.
N-[{2-[Acetylamino-(2-hydroxynaphthalen-1-yl)-methyl]-phenyl}-(2-hydroxynaphth-
alen-1-yl)-methyl] acetamide (B) 1H NMR (400 MHz, DMSO): d = 9.95 (s, 2H),
8.32 (d, J = 8 Hz, 2H), 7.73–7.79 (m, 4H), 6.87–7.27 (m, 14H), 1.90 (s, 6H) ppm;
13C NMR (100 MHz, DMSO): d = 169.0, 153.0, 142.2, 132.2, 129.1, 128.4, 127.4,
127.4, 126.1, 126.1, 126.0, 124.1, 123.9, 123.8, 47.8, 22.4 ppm; IR (KBr):
-1
ꢀ
m = 3,406, 3,062, 3,030, 1,642, 1,516, 1,439, 622 cm
.
N-[{4-[Acetylamino-(2-hydroxynaphthalen-1-yl)-methyl]-phenyl}-(2-hydroxynaphtha-
len-1-yl)-methyl] thioacetamide (C) 1H NMR (400 MHz, DMSO): d = 9.99 (s,
2H), 8.88 (d, J = 8 Hz, 2H), 8.33–8.44 (m, 4H), 7.72–7.83 (m, 14H), 2.09 (s, 6H)
ppm.
N-[{2-[Acetylamino-(2-hydroxynaphthalen-1-yl)-methyl]-phenyl}-(2-hydroxynaphtha-
len-1-yl)-methyl] thioacetamide (D) 1H NMR (400 MHz, DMSO): d = 9.95 (s,
2H), 8.32 (d, J = 8 Hz, 2H), 7.72–7.79 (m, 4H), 6.86–7.24 (m, 14H), 1.90 (s, 6H)
ppm; 13C NMR (100 MHz, DMSO): d = 169.0, 152.9, 142.2, 132.2, 129.2, 129.1,
128.4, 127.4, 126.0, 124.1, 123.8, 122.2, 118.6, 118.3, 47.8, 22.4 ppm.
123

A. Ghorbani-Choghamarani, S. Rashidimoghadam
CHO
OH
S
DBH (Catalyst)
OH
+
CH3CNH2
+
Solvent-free
NH
130 C
°
S
CH3
Scheme 3 Effect of different amounts of DBH on the preparation of N-((2-hydroxynaphthalen-1-
yl)(phenyl)methyl)ethanethioamide
Table 1 Effect of different amounts of DBH on the reaction of 2-naphthol, thioacetamide, and
benzaldehyde
Entry
Catalyst amount (mmol)
Time (min)
Yielda (%)
1
2
3
4
5
a
–
1,800
310
290
165
315
10
68
80
95
73
0.05
0.1
0.15
0.2
Isolated yield
Results and discussion
In continuation of the search for simple, nonhazardous methods for transformations
in organic synthesis using halogenating agents [19–22], we disclose a very effective
procedure for synthesis of 1-thioamidoalkyl-2-naphthols in the presence of DBH as
an efficient catalyst.
Initially, we decided to examine the applicability of DBH for synthesis of
1-thioamidoalkyl-2-naphthols. For this purpose, as a model, the reaction of
benzaldehyde (1 mmol), 2-naphthol (1 mmol), and thioacetamide (1.5 mmol) was
examined in the presence of different amounts of DBH at 130 °C (Scheme 3). The
results are summarized in Table 1.
Table 2 Optimization of temperature using DBH (0.15 mmol) as catalyst
Entry
Temperature (°C)
Time (min)
Yielda (%)
1
2
3
4
5
6
7
a
25
50
150
150
150
150
150
150
150
No reaction
15
35
38
60
95
68
80
100
120
130
140
Isolated yield
123

Synthesis of thioamidoalkyl and bis(thio)amidoalkyl-2-naphthols
123

A. Ghorbani-Choghamarani, S. Rashidimoghadam
123

Synthesis of thioamidoalkyl and bis(thio)amidoalkyl-2-naphthols
As can be seen from Table 1, higher yields of the product and shorter reaction
times were obtained when the reaction was performed using 0.15 mmol of the
catalyst (entry 4). It is noteworthy that, in the absence of catalyst, low yield of
product was obtained in long reaction time (entry 1).
Also the effect of temperature was studied, and the results indicated that the best
yield was provided at 130 °C (Table 2). At lower temperatures than that, the
reaction did not proceed properly and most of the initial substances remained
unreacted.
These results prompted us to investigate the scope and generality of this new
protocol for various arylaldehydes under optimized conditions (Table 3).
As shown in Table 3, aromatic aldehydes with substituents carrying either
electron-donating or electron-withdrawing groups reacted successfully and gave the
products in high yields. It could also be concluded that aromatic aldehydes with
electron-withdrawing groups reacted faster than those with electron-donating
groups, as expected. Sterically hindered aromatic aldehydes required longer reaction
times (entries 11, 12).
The presence of an electron-withdrawing group on the benzaldehyde led to an
increase in the rate of the 1,4-nucleophilic addition reaction of the o-quinone
methide (o-QM) intermediates, because the electron-withdrawing group led to a
reduction in the energy of the lowest unoccupied molecular orbital of the alkene.
Due to the lower reactivity of the thio analogs of acetamide and urea, substitution
of acetamide with thioacetamide gives lower yields.
In an effort to further investigate the utility of DBH, we examined the reaction
between 2-naphthol, acetamide or thioacetamide, and bisaldehydes (terephthalde-
hyde or iso-terephthaldehyde).
When 2.5 mmol of 2-naphthol and 1 mmol of the bisaldehyde were reacted with
3.75 mmol of acetamide or thioacetamide in the presence of 0.15 mmol of DBH at
130 °C, bis-1-(thio) amidoalkyl-2-naphthol was obtained in good yield (Scheme 4).
The results are displayed in Table 4.
More interestingly, reaction with thioacetamide in place of acetamide proceeded
smoothly to afford the corresponding bisthioamidoalkyl naphthols in excellent
yields (Table 4, entries 3, 4). For the first time, we could successfully achieve
synthesis of products B, C, and D in very good yields using DBH.
CHO
OH
X
OH
0.15 mmol DBH
Solvent-free
+
+
CH3CNH2
X
NHCCH3
X
X= O, S
H3CCHN
130 C
°
CHO
HO
Scheme 4 Synthesis of bis-1-(thio)amidoalkyl-2-naphthols catalyzed by DBH
123

A. Ghorbani-Choghamarani, S. Rashidimoghadam
123

Synthesis of thioamidoalkyl and bis(thio)amidoalkyl-2-naphthols
e
e
M
r
r
M
B
B
N
N
e
M
e
M
+ Br
O
O
N
N
O
O
r
B
r
B
O
H
C O
H
Br
r
B
O
H
O
R1
R1
N
NBr
OBr
H
O
H
O
H
O
S
R1
H2N
H
C
3
H
O
H
O
NH
H
CSC
3
R1
o- s
M
Q
Scheme 5 Mechanism of the preparation of 1-thioamidoalkyl-2-naphthols in the presence of DBH
A reasonable mechanism for this reaction is shown in Scheme 5 based on
pathways reported in the literature [14, 23].
We supposed that the reaction may proceed via the ortho-o-QM intermediate,
which was formed by nucleophilic addition of 2-naphthol to aldehyde catalyzed by
DBH. Subsequent Michael addition of the o-QMs with the thioacetamide afforded
the expected thioamidoalkyl naphthol. In this reaction, DBH could act as a
bifunctional catalyst (a–c), in that it would activate both the carbonyl oxygen in the
aldehyde and the acidic hydrogen in 2-naphthol. Since DBH contains Br atoms that
are attached to N atoms, it is likely that Br? would be released in situ, and that this
species would act as a catalyst in the reaction medium, leading to a considerable
increase in the electrophilicity of the aldehyde.
As is evident from Scheme 3, no side reaction such as overoxidation to sulfone or
oxidation of hydroxyl group was observed.
To show the merit of the present work in comparison with results reported in the
literature, we compared the results for DBH with those for Fe(HSO4)3 and silica
sulfuric acid in synthesis of 1-thioamidoalkyl-2-naphthols.
123

A. Ghorbani-Choghamarani, S. Rashidimoghadam
Table 5 Comparison of DBH with Fe(HSO4)3 and silica sulfuric acid in synthesis of 1-thioamidoalkyl-
2-naphthols
Aldehyde
Catalyst
Time (min)
Isolated yield (%)
Ref.
DBH
200
390
79
93
88
79
95
88
This work
[5]
CHO
Fe(HSO4)3
Silica sulfuric acid
DBH
[6]
250
360
This work
[5]
Cl
CHO
Fe(HSO4)3
As shown in Table 5, DBH can act as an effective catalyst with respect to
reaction time, yield, and the obtained products.
Conclusions
We have developed a new protocol for synthesis of 1-thioamidoalkyl-2-naphthol
and bis-1-(thio)amidoalkyl-2-naphthol via one-pot multicomponent condensation of
2-naphthol, aromatic aldehydes, and amides using DBH under solvent-free
conditions. To the best of our knowledge, DBH is the most active catalyst so far
developed for synthesis of these compounds.
The mild reaction conditions, low catalyst loading, high to quantitative yield,
chemical stability, and simple preparation of the catalyst illustrate the attractive
features of this protocol.
Acknowledgments Financial support for this work by the research affairs of Ilam University, Ilam, Iran
is gratefully acknowledged. Authors thank the research facilities of Ilam University, Ilam, Iran, for
financial support of this research project.
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