Preparation of amidoalkyl naphthols by a three-component reaction catalyzed by 2,4,6-trichloro-1,3,5-triazine under solvent-free conditions

Article abstract of DOI:10.1007/s00706-008-0059-5

An efficient one-pot synthesis of amidoalkyl naphthols is described. This involves the three-component reaction of 2-naphthol, aromatic aldehydes and amide or urea in the presence of a catalytic amount of 2,4,6-trichloro-1,3,5- triazine (TCT, cyanuric chloride) under solvent-free conditions. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-008-0059-5

Monatsh Chem (2009) 140:199–203
DOI 10.1007/s00706-008-0059-5
ORIGINAL PAPER
Preparation of amidoalkyl naphthols by a three-component
reaction catalyzed by 2,4,6-trichloro-1,3,5-triazine
under solvent-free conditions
Peng Zhang Æ Zhan-Hui Zhang
Received: 11 June 2008 / Accepted: 8 August 2008 / Published online: 30 September 2008
Ó Springer-Verlag 2008
Abstract An efficient one-pot synthesis of amidoalkyl
naphthols is described. This involves the three-component
reaction of 2-naphthol, aromatic aldehydes and amide or
urea in the presence of a catalytic amount of 2,4,6-trichloro-
1,3,5-triazine (TCT, cyanuric chloride) under solvent-free
conditions.
acid [8], NaHSO4ꢀH2O [9], Fe(HSO4)3 [10], Sr(OTf)2 [11],
iodine [12], heteropoly acid K5CoW12O40ꢀ3H2O [13] and
heterogeneous catalysts like cation-exchange resins [14],
silica supported perchloric acid [15, 16], FeCl3ꢀSiO2 [17],
montmorillonite K10 clay [18], silica sulfuric acid [19]
and sulfamic acid [20, 21]. However, some of the reported
methods suffer from disadvantages such as long reaction
time [13], the use of expensive reagents [11], low yields of
products [20], high catalyst loading [19], corrosive reagents
[7], strongly acidic conditions [15, 16], and the use of an
additional microwave oven [10] or ultrasonic irradiation
[19]. Therefore, to avoid these limitations, the discovery of
a new, easily available catalyst with high catalytic activity
and short reaction time for the preparation of amidoalkyl
naphthols is still desirable.
Keywords Multicomponent reaction ꢀ 2-Naphthol ꢀ
Aldehydes ꢀ Amide ꢀ 2,4,6-Trichloro-1,3,5-triazine
Introduction
Multicomponent reactions (MCRs) have become an effi-
cient and powerful tool for the construction of complex
molecules because of the fact that the products are formed
in a one-pot reaction without isolation of intermediates or
modification the reaction conditions [1–3]. MCRs are
particularly useful to generate diverse chemical libraries of
‘‘drug-like’’ molecules for biological screening.
In recent years, 2,4,6-trichloro-1,3,5-triazine (TCT,
cyanuric chloride) has been used in organic synthesis
because it is stable, non-volatile, inexpensive, commer-
cially available and an easy-to-handle reagent [22, 23].
TCT has been utilized for many important organic trans-
formations, including the ring opening of epoxides with
thiols [24], direct conversion of carboxylic acids to amides
[25], chemoselective transthioacetalization of aldehyde
acetals and oxathioacetals [26], conversion of nitronate into
nitrile oxide [27], the synthesis of homoallylic alcohols and
amines [28], thiiranes [29], dihydropyridine glycoconju-
gates [30], a-amino nitriles [31], allylic chloride [32], a,a0-
bis(substituted-benzylidene) cycloalkanones [33], 14-aryl
or alkyl-14-H-dibenzo[a,j]xanthenes [34] and 1,8-dioxo-
octahydroxanthene derivatives [35]. It is therefore of
interest to examine the behavior of TCT as catalyst in the
synthesis of amidoalkyl naphthols. To the best of our
knowledge, the generality and applicability of TCT in the
preparation of amidoalkyl naphthols are not known. In
continuation of our work on the development of new
Compounds bearing 1,3-arrangement of amino and oxy-
genated functional groups are frequently found in bio-
logically important natural products [4]. Furthermore,
amidoalkyl naphthols can be converted to useful synthetic
building blocks [5] and 1-aminomethyl-2-naphthols, which
exhibit depressor and bradycardiac activity [6]. The prepa-
ration of amidoalkyl naphthols can be carried out by
multicomponent condensation of aldehydes, 2-naphthol and
amide or urea in the presence of Lewis or Brønsted acid
catalysts such as chlorosulfonic acid [7], p-toluene sulfonic
P. Zhang ꢀ Z.-H. Zhang (&)
The College of Chemistry and Material Science,
Hebei Normal University, 050016 Shijiazhuang, China
e-mail: zhanhui@126.com
123

200
P. Zhang, Z.-H. Zhang
of catalyst was sufficient to achieve a fairly high yield.
With 1 mol% of TCT, a lower yield was observed under
the same reaction period. This encouraged us to study
the scope of the reaction under the optimized reaction
parameters in the presence of 5 mol% of catalyst under
solvent-free condition at 100 °C. The results of using TCT
as a catalyst in the multicomponent reaction of 2-naphthol,
aromatic aldehydes and amide or urea are summarized in
Table 2.
OH
O
OH
R
TCT (5 mol%)
ArCHO
+
+
Ar
R
NH2
NH
solvent-free, 100 o
C
1
4
3
2
O
Scheme 1
synthetic methodologies [36–44], we herein describe a
new, convenient synthesis of amidoalkyl naphthols by
multicomponent reaction of 2-naphthol, aromatic alde-
hydes and amide or urea catalyzed by TCT under solvent-
free conditions (Scheme 1).
A variety of aromatic aldehydes, 2-naphthol and dif-
ferent amides, including acetamide, benzamide and pro-
penionamide, were submitted to these reaction conditions,
and the desired products were obtained in good to excellent
yields. This catalyst worked excellently with aromatic
aldehydes bearing electron-donating substituents. It was
shown that the aromatic aldehydes with electron-with-
drawing groups reacted faster than the aromatic aldehydes
with electron-donating groups, as would be expected. A
reasonable explanation for this result has been suggested by
Shaterian et al. [10]. The condensation of 2-naphthol with
aldehydes under acid catalysts gave ortho-quinone meth-
ides (o-QMs). The generated o-QMs reacted with acetamide
via the conjugated addition to afford 1-amidoalkyl-2-
naphthols. Electron-withdrawing groups on the benzalde-
hydes in the o-QMs increase the rate of the 1,4-nucleophilic
addition reaction because the alkene LUMO is at lower
energy in the presence of electron-withdrawing groups
compared with electron-donating groups. For ortho-substi-
tuted aromatic aldehydes such as 2-chlorobenzaldehyde,
2,4-dichlorobenzaldehyde and 2-nitrobenzaldehyde, a pro-
longed reaction time was required. Furthermore, this
reaction was further explored for the synthesis of bis-
amidoalkyl naphthol 6 by the four-compoponent reaction of
Results and discussion
We first investigated the catalytic activities of various
catalysts, which promoted the model reaction of 2-naphthol
(1 mmol), 3-nitrobenzaldehyde (1 mmol) and acetamide
(1.3 mmol) under solvent-free condition. In the course of
this study, we found that TCT was the most effective
catalyst producing amidoalkyl naphthol in higher yields
than other catalysts, which furnished the product in lower
yields (20–65%). In the absence of catalyst, the yield of the
product was found to be very low. We also studied the
model reaction catalyzed by TCT (5 mol%) at different
temperatures. The reaction rate was increased as the reac-
tion temperature was raised. When it was carried out at
100 °C, the maximum yield was obtained in a short reac-
tion period (Table 1, entry 15). To evaluate the effect of
catalyst concentration, the model reaction was carried out
in the presence of different amounts of catalyst (1, 5, 10
and 20 mol%) at 100 °C. The results showed that 5 mol%
Table 1 Catalytic activity of
Entry
Catalyst
Temperature/°C
Time/min
Yield/%a
various catalysts for the reaction
of 2-naphthol, 3-nitro-
benzaldehyde and acetamide
1
H3BO3 (10 mol%)
100
100
100
100
100
100
100
100
100
100
100
80
180
60
50
25
20
60
40
30
35
65
78
30
95
65
92
80
95
93
2
H2C2O4ꢀ3H2O (10 mol%)
L-Proline (10 mol%)
LaF3 (10 mol%)
3
120
90
4
5
NH4Ce(NO3)2 (10 mol%)
60
6
C16H35 NꢀH2SO4 (10 mol%)
60
7
KAl(SO4)2ꢀ12H2O/SiO2 (10 mol%)
(NH4)2PO4ꢀ12WO3ꢀ3H2O (10 mol%)
N-Chlorosuccinimide
HBF4/SiO2 (10 mol%)
TCT (10 mol%)
60
8
120
100
60
9
10
11
12
13
14
15
16
40
TCT (5 mol%)
40
TCT (5 mol%)
120
100
100
100
40
TCT (1 mol%)
40
TCT (5 mol%)
40
TCT (20 mol%)
40
a
Isolated yields
123

Preparation of amidoalkyl naphthols by a three-component reaction
201
Table 2 TCT-promoted
synthesis of amidoalkyl
naphthol derivatives
Entry
Aldehydes
R
Time/min
Yield/%a
Rfb
Mp/°C
Found
Reported
a
b
c
d
e
f
PhCHO
Me
50
50
50
40
60
40
50
40
40
40
60
40
40
23
25
20
20
20
23
25
20
20
55
60
50
45
93
93
90
93
92
95
94
93
95
93
95
95
93
92
93
92
94
95
92
93
94
95
94
93
95
92
0.39
0.30
0.29
0.35
0.33
0.32
0.42
0.43
0.40
0.37
0.38
0.32
0.32
0.80
0.77
0.79
0.78
0.77
0.78
0.54
0.70
0.68
0.13
0.11
0.14
0.13
243–245
220–222
185–186
232–233
210–212
228–229
202–204
241–243
250–252
228–230
210–212
240–242
246–248
240–241
215–216
194–196
187–189
240–242
253–255
220–222
210–212
253–254
175–176
118–120
169–170
180–181
245–246 [9]
222–223 [9]
183–185 [10]
230–232 [10]
213–215 [10]
228–229 [13]
201–203 [15]
4-MeC6H4CHO
4-MeOC6H4CHO
4-FC6H4CHO
2-ClC6H4CHO
4-ClC6H4CHO
2,4-Cl2C6H3CHO
3,4-Cl2C6H3CHO
3-BrC6H4CHO
4-BrC6H4CHO
2-NO2C6H4CHO
3-NO2C6H4CHO
4-NO2C6H4CHO
PhCHO
Me
Me
Me
Me
Me
g
h
i
Me
Me
Me
j
Me
227–229 [9]
212–215 [9]
241–242 [9]
248–250 [15]
242–243 [15]
216–217 [11]
193–194 [20]
187–188 [11]
241–242 [11]
255–256 [11]
222–223 [11]
213–215 [14]
255–256 [11]
174–175 [11]
117–118 [11]
168–169 [14]
179–180 [11]
k
l
Me
Me
m
n
o
p
q
r
Me
Ph
4-MeC6H4CHO
4-FC6H4CHO
4-ClC6H4CHO
3-NO2C6H4CHO
PhCHO
Ph
Ph
Ph
Ph
s
CH2=CH
CH2=CH
CH2=CH
CH2=CH
NH2
NH2
NH2
NH2
t
4-MeOC6H4CHO
4-ClC6H4CHO
3-NO2C6H4CHO
PhCHO
u
v
w
x
y
z
a
Yields refer to isolated
b
products, Rf values were
4-MeC6H4CHO
4-ClC6H4CHO
3-NO2C6H4CHO
examined by TLC with
a mixture of ethylacetate:
n-hexane (1:1) as the solvent
system
CHO
HO
O
O
OH
+
O
that TCT is an equally or more efficient catalyst with
respect to reaction time and yield than previously reported
ones.
HN
TCT (5 mol%), 100 o
C
+
H3
C
NH2
30 min, 92%
NH
2
OH
CHO
5
6
In conclusion, we developed a new application for 2,4,6-
trichloro-1,3,5-triazine. By using this catalyst, a series of
amidoalkyl naphthols were obtained in high yields via
three-component reaction of 2-naphthol, aromatic alde-
hydes and amide or urea under solvent-free conditions.
Further applications of TCT in organic transformation are
currently in progress in our laboratories.
Scheme 2
terphthalaldehyde (5), acetamide and two equivalents
of 2-naphthol (2) under similar conditions (Scheme 2).
Unfortunately, with aliphatic aldehydes, a mixture of
products was obtained and the desired product could not be
isolated, consistent with literature precedent [9, 10, 13, 14].
On reaction of heterocyclic aldehydes such as pyridine-
4-carboxaldehyde, indole-3-carboxaldehyde and furfural
with 2-naphthol and acetamide under the same conditions,
only trace amounts of the corresponding products were
isolated.
Experimental
Melting points were determined on a X-4 apparatus. Ana-
lytical thin-layer chromatography was performed on glass
plates of silica gel GF254 of 0.2 mm thickness. IR spectra
were obtained using a Shimadzu FTIR-8900 spectrometer.
1H NMR spectra were recorded with a Varian Mercury
Plus 400 spectrometer using TMS as an internal standard.
Elemental analyses were performed on a Vario EL III
In order to show the merit of TCT in comparison with
other reported catalysts, we summarized some of the results
for the preparation of N-[(2-hydroxy-naphthalen-1-yl)-
phenylmethyl]-acetamide (3a) in Table 3, which shows
123

202
P. Zhang, Z.-H. Zhang
Table 3 Comparison of TCT
with reported catalysts in
synthesis of N-[(2-hydroxy-
naphthalen-1-yl)-
Catalyst/solvent/temperature/°C
Catalyst load
Time/h
Yield/%
Ref.
Fe(HSO4)3/solvent-free/85
K5CoW12O40ꢀ3H2O/solvent-free/125
Montmorillonite K-10/solvent-free/125
HClO4ꢀSiO2/solvent-free/125
Sr(OTf)2/CHCl3/60
5 mol%
1 mol%
0.1 g/mol
100 mg
1.08
2.00
1.50
6.50
10.00
5.50
6.00
0.18
0.83
83
90
89
82
90
85
89
86
93
[10]
[13]
phenylmethyl]-acetamide (3a)
[18]
[16]
10 mol%
5 mol%
10 mol%
25 mg/mol
5 mol%
[11]
I2/solvent-free/125
[12]
p-TSA/solvent-free/125
[8]
FeCl3ꢀSiO2/solvent-free/120
TCT/solvent-free/100
[17]
This work
(m, 4H), 7.76–7.81 (m, 3H), 8.59 (d, J = 8.4 Hz, 1H),
10.00 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 23.2, 48.1, 118.9, 119.1, 122.2, 123.2, 123.7, 125.89,
127.3, 129.1, 129.3, 129.7, 130.2, 130.3, 130.9, 132.8,
146.3, 153.9, 170.2 ppm.
CHNOS Elemental Analyzer, and their results agreed
favorably with the calculated values.
General procedure for the synthesis of amidoalkyl
naphthols
N-[{4-[Acetylamino-(2-hydroxy-naphthalen-1-yl)-
methyl]-phenyl}-(2-hydroxy-naphthalen-1-yl)-methyl]-
acetamide (6, C32H28N2O4)
A mixture of 1 mmol 2-naphthol, 1 mmol aromatic alde-
hyde and 1.3 mmol amide or urea and 0.05 mmol TCT was
heated at 100 °C. After completion of the reaction (moni-
tored by TLC), the mixture was diluted with 20 cm3 ethyl
acetate, washed with 20 cm3 water, and the aqueous layer
was then extracted with 2 9 10 cm3 ethyl acetate. The
combined organic layer was dried over MgSO4 and con-
centrated under vacuum to obtain a product in almost pure
form. Further purification was carried out by short-column
chromatography on silica gel eluting with ethyl acetate/n-
hexane (1/4 v/v).
White solid, Mp 267–269 °C; Rf = 0.21 (ethylacetate:hex-
ꢀ
ane = 1:1); IR (KBr): m ¼ 3; 386; 3,143, 1,685, 1,637,
1,577, 1,473, 1,400, 1,276, 1,195, 1,091, 945, 821, 669
1
cm-1; H NMR (400 MHz, DMSO-d6): d = 1.91 (s, 6H),
7.02–7.77 (m, 18H), 8.40 (d, J = 8.0 Hz, 2H), 9.98 (s, 2H)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 23.2, 48.7,
119.2, 119.3, 123.3, 124.8, 127.0, 129.2, 129.4, 130.1,
133.0, 153,8, 128.5, 142.9, 170.3 ppm.
Acknowledgments We thank the Science Foundation from Hebei
Normal University (L20061314), the Nature Science Foundation of
Hebei Province (B2008000149) and the Natural Science Foundation
of Hebei Education Department (2006318) for financial support.
N-[(3,4-Dichloro-phenyl)-(2-hydroxy-naphthalen-1-yl)-
methyl]-acetamide (Table 2, 4h, C19H15Cl2NO2)
White solid, Mp 241–243 °C; Rf = 0.44 (ethylacetate:hex-
ꢀ
ane = 1:1); IR (KBr): m ¼ 3; 386; 3,143, 1,627, 1,577,
1,508, 1,473, 1,400, 1,384, 1,330, 1,276, 1,249, 1,091,
1
1,068, 821, 767, 669 cm-1; H NMR (400 MHz, DMSO-
References
d6): d = 1.97 (s, 3H), 6.99–7.01 (m, 2H), 7.19
(d, J = 8.4 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.35–7.41
(m, 2H), 7.48 (d, J = 8.4 Hz, 1H), 7.76–7.81 (m, 3H), 8.53
(d, J = 7.6 Hz, 1H), 10.10 (s, 1H) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 23.5, 47.7, 110.0, 118.4,
119.0, 123.4, 127.3, 128.5, 129.1, 129.3, 129.4, 130.5,
131.3, 132.8, 144.9, 149.3, 153.7, 153.9, 170.2 ppm.
¨
1. Domling A (2006) Chem Rev 106:17
2. Shestopalov AM, Shestopalov AA, Rodinovskaya LA (2008)
Synthesis:1
3. Mironov MA (2006) QSAR Comb Sci 25:423
4. Knapp S (1995) Chem Rev 95:1859
5. Szatmari I, Fu¨lop F (2004) Curr Org Synth 1:155
6. Shen AY, Tsai CT, Chen CL (1999) Eur J Med Chem 34:877
7. Anary-Abbasinejad M, Hassanabadi A, Kamali-Gharamaleki M,
Saidipoor A, Anaraki-Ardakani H (2007) J Chem Res: 644
8. Khodaei MM, Khosropour AR, Moghanian H (2006) Synlett: 916
9. Shaterian HR, Yarahmadi H (2008) Arkivoc ii:105
10. Shaterian HR, Yarahmadi H, Ghashang M (2008) Bioorg Med
Chem Lett 18:788
11. Su WK, Tang WY, Li JJ (2008) J Chem Res: 123
12. Das B, Laxminarayana K, Ravikanth B, Rao R (2007) J Mol
Catal A Chem 261:180
13. Nagarapu L, Baseeruddin M, Apuri S, Kantevari S (2007) Catal
Commun 8:1729
´
¨
N-[(3-Bromo-phenyl)-(2-hydroxy-naphthalen-1-yl)-
methyl]-acetamide (Table 2, 4i, C19H16BrNO2)
White solid, Mp 250–252 °C; Rf = 0.41 (ethylacetate:hex-
ꢀ
ane = 1:1); IR (KBr): m ¼ 3; 406; 3,168, 3,066, 1,647,
1,577, 1,515, 1,438, 1,400, 1,384, 1,336, 1,280, 1,207,
1,188, 987, 812, 756 m-1; 1H NMR (400 MHz, DMSO-d6):
d = 1.97 (s, 3H), 7.08 (d, J = 7.2 Hz, 1H), 7.19
(t, J = 7.2 Hz, 2H), 7.26 (t, J = 7.6 Hz, 1H), 7.31–7.40
123

Preparation of amidoalkyl naphthols by a three-component reaction
203
14. Patil SB, Singh PR, Surpur MP, Samant SD (2007) Synth
Commun 37:1659
29. Bandgar BP, Joshi NS, Kamble VT (2006) Tetrahedron Lett
47:4775
15. Shaterian HR, Yarahmadi H, Ghashang M (2008) Tetrahedron
64:1263
30. Sharma GVM, Reddy KL, Lakshmi PS, Krishna PR (2006)
Synthesis: 55
16. Das B, Kumar DN, Laxminarayana K, Ravikanth B (2007) Helv
Chim Acta 90:1330
17. Shaterian HR, Yarahmadi H (2008) Tetrahedron Lett 49:1297
18. Kantevari S, Vuppalapati SVN, Nagarapu L (2007) Catal Com-
mun 8:1857
31. Das B, Kumar RA, Thirupathi P (2007) Helv Chim Acta 90:1206
32. Roy S, Das T, Saha M, Chaudhuri SK, Bhar S (2007) Synth
Commun 37:4367
33. Bigdeli MA, Mahdavinia GH, Jafari S, Hazarkhani H (2007)
Catal Commun 8:2229
19. Srihari G, Nagaraju M, Murthy MM (2007) Helv Chim Acta
90:1497
34. Bigdeli MA, Heravi MM, Mahdavinia GH (2007) Catal Commun
8:1595
20. Patil SB, Singh PR, Surpur MP, Samant SD (2007) Ultrason
Sonochem 14:515
21. Nagawade RR, Shinde DB (2007) Chin J Chem 25:1710
22. Blotny G (2006) Tetrahedron 62:9507
23. Haval KP (2006) Synlett: 2156
24. Bandgar BP, Joshi NS, Kamble VT, Sawant SS (2008) Aust J
Chem 61:231
25. Khalafi-Nezhad A, Zare A, Parhami A, Rad MNS, Nejabat GR
(2007) Phosphorus Sulfur Silicon Relat Elem 182:657
26. Bandgar BP, Joshi NS, Bettigeri SV (2007) Monatsh Chem
138:67
35. Zhang Z-H, Tao X-Y (2008) Aust J Chem 61:77
36. Zhang Z-H (2005) Monatsh Chem 136:1191
37. Zhang Z-H, Li T-S, Li J-J (2007) Monatsh Chem 138:89
38. Mo L-P, Ma Z-C, Zhang Z-H (2005) Synth Commun 35:1997
39. Zhang Z-H, Li J-J, Gao Y-Z, Liu Y-H (2007) J Heterocyclic
Chem 44:1509
40. Zhang Z-H, Yang S-T, Lin J (2006) Synth Commun 36:1645
41. Zhang Z-H, Lin J (2007) Synth Commun 37:209
42. Zhang Z-H, Hu J-Y (2006) J Braz Chem Soc 17:1447
43. Cui Z-S, Zhang Z-H, Liu S-F (2006) J Chem Res: 390
44. Li J-J, Tao X-Y, Zhang Z-H (2008) Phosphorus Sulfur Silicon
Relat Elem 183:1672
27. Gao S, Tu Z, Kuo C-W, Liu J-T, Chu C-M, Yao C-F (2006) Org
Biomol Chem 4:2851
28. Das B, Laxminarayana K, Ravikanth B (2006) Tetrahedron Lett
47:9103
123