Monatshefte für Chemie - Chemical Monthly

, 140:199

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

Authors

  • Peng Zhang
    • The College of Chemistry and Material ScienceHebei Normal University
    • The College of Chemistry and Material ScienceHebei Normal University
Original Paper

DOI: 10.1007/s00706-008-0059-5

Cite this article as:
Zhang, P. & Zhang, Z. Monatsh Chem (2009) 140: 199. doi:10.1007/s00706-008-0059-5

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.

Graphical abstract

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Keywords

Multicomponent reaction2-NaphtholAldehydesAmide2,4,6-Trichloro-1,3,5-triazine

Introduction

Multicomponent reactions (MCRs) have become an efficient 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 [13]. MCRs are particularly useful to generate diverse chemical libraries of “drug-like” molecules for biological screening.

Compounds bearing 1,3-arrangement of amino and oxygenated functional groups are frequently found in biologically 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 preparation 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 acid [8], NaHSO4·H2O [9], Fe(HSO4)3 [10], Sr(OTf)2 [11], iodine [12], heteropoly acid K5CoW12O40·3H2O [13] and heterogeneous catalysts like cation-exchange resins [14], silica supported perchloric acid [15, 16], FeCl3·SiO2 [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.

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, commercially available and an easy-to-handle reagent [22, 23]. TCT has been utilized for many important organic transformations, 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 glycoconjugates [30], α-amino nitriles [31], allylic chloride [32], α,α′-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 synthetic methodologies [3644], we herein describe a new, convenient synthesis of amidoalkyl naphthols by multicomponent reaction of 2-naphthol, aromatic aldehydes and amide or urea catalyzed by TCT under solvent-free conditions (Scheme 1).
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Scheme 1

  

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 reaction temperature was raised. When it was carried out at 100 °C, the maximum yield was obtained in a short reaction 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% 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.
Table 1

Catalytic activity of various catalysts for the reaction of 2-naphthol, 3-nitro-benzaldehyde and acetamide

Entry

Catalyst

Temperature/°C

Time/min

Yield/%a

1

H3BO3 (10 mol%)

100

180

50

2

H2C2O4·3H2O (10 mol%)

100

60

25

3

L-Proline (10 mol%)

100

120

20

4

LaF3 (10 mol%)

100

90

60

5

NH4Ce(NO3)2 (10 mol%)

100

60

40

6

C16H35 N·H2SO4 (10 mol%)

100

60

30

7

KAl(SO4)2·12H2O/SiO2 (10 mol%)

100

60

35

8

(NH4)2PO4·12WO3·3H2O (10 mol%)

100

120

65

9

N-Chlorosuccinimide

100

100

78

10

HBF4/SiO2 (10 mol%)

100

60

30

11

TCT (10 mol%)

100

40

95

12

TCT (5 mol%)

80

40

65

13

TCT (5 mol%)

120

40

92

14

TCT (1 mol%)

100

40

80

15

TCT (5 mol%)

100

40

95

16

TCT (20 mol%)

100

40

93

aIsolated yields

Table 2

TCT-promoted synthesis of amidoalkyl naphthol derivatives

Entry

Aldehydes

R

Time/min

Yield/%a

Rfb

Mp/°C

Found

Reported

a

PhCHO

Me

50

93

0.39

243–245

245–246 [9]

b

4-MeC6H4CHO

Me

50

93

0.30

220–222

222–223 [9]

c

4-MeOC6H4CHO

Me

50

90

0.29

185–186

183–185 [10]

d

4-FC6H4CHO

Me

40

93

0.35

232–233

230–232 [10]

e

2-ClC6H4CHO

Me

60

92

0.33

210–212

213–215 [10]

f

4-ClC6H4CHO

Me

40

95

0.32

228–229

228–229 [13]

g

2,4-Cl2C6H3CHO

Me

50

94

0.42

202–204

201–203 [15]

h

3,4-Cl2C6H3CHO

Me

40

93

0.43

241–243

 

i

3-BrC6H4CHO

Me

40

95

0.40

250–252

 

j

4-BrC6H4CHO

Me

40

93

0.37

228–230

227–229 [9]

k

2-NO2C6H4CHO

Me

60

95

0.38

210–212

212–215 [9]

l

3-NO2C6H4CHO

Me

40

95

0.32

240–242

241–242 [9]

m

4-NO2C6H4CHO

Me

40

93

0.32

246–248

248–250 [15]

n

PhCHO

Ph

23

92

0.80

240–241

242–243 [15]

o

4-MeC6H4CHO

Ph

25

93

0.77

215–216

216–217 [11]

p

4-FC6H4CHO

Ph

20

92

0.79

194–196

193–194 [20]

q

4-ClC6H4CHO

Ph

20

94

0.78

187–189

187–188 [11]

r

3-NO2C6H4CHO

Ph

20

95

0.77

240–242

241–242 [11]

s

PhCHO

CH2=CH

23

92

0.78

253–255

255–256 [11]

t

4-MeOC6H4CHO

CH2=CH

25

93

0.54

220–222

222–223 [11]

u

4-ClC6H4CHO

CH2=CH

20

94

0.70

210–212

213–215 [14]

v

3-NO2C6H4CHO

CH2=CH

20

95

0.68

253–254

255–256 [11]

w

PhCHO

NH2

55

94

0.13

175–176

174–175 [11]

x

4-MeC6H4CHO

NH2

60

93

0.11

118–120

117–118 [11]

y

4-ClC6H4CHO

NH2

50

95

0.14

169–170

168–169 [14]

z

3-NO2C6H4CHO

NH2

45

92

0.13

180–181

179–180 [11]

a Yields refer to isolated products, bRf values were examined by TLC with a mixture of ethylacetate:n-hexane (1:1) as the solvent system

A variety of aromatic aldehydes, 2-naphthol and different amides, including acetamide, benzamide and propenionamide, 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-withdrawing 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 methides (o-QMs). The generated o-QMs reacted with acetamide via the conjugated addition to afford 1-amidoalkyl-2-naphthols. Electron-withdrawing groups on the benzaldehydes 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-substituted aromatic aldehydes such as 2-chlorobenzaldehyde, 2,4-dichlorobenzaldehyde and 2-nitrobenzaldehyde, a prolonged reaction time was required. Furthermore, this reaction was further explored for the synthesis of bis-amidoalkyl naphthol 6 by the four-compoponent reaction of 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.
https://static-content.springer.com/image/art%3A10.1007%2Fs00706-008-0059-5/MediaObjects/706_2008_59_Sch2_HTML.gif
Scheme 2

  

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 that TCT is an equally or more efficient catalyst with respect to reaction time and yield than previously reported ones.
Table 3

Comparison of TCT with reported catalysts in synthesis of N-[(2-hydroxy-naphthalen-1-yl)-phenylmethyl]-acetamide (3a)

Catalyst/solvent/temperature/°C

Catalyst load

Time/h

Yield/%

Ref.

Fe(HSO4)3/solvent-free/85

5 mol%

1.08

83

[10]

K5CoW12O40·3H2O/solvent-free/125

1 mol%

2.00

90

[13]

Montmorillonite K-10/solvent-free/125

0.1 g/mol

1.50

89

[18]

HClO4·SiO2/solvent-free/125

100 mg

6.50

82

[16]

Sr(OTf)2/CHCl3/60

10 mol%

10.00

90

[11]

I2/solvent-free/125

5 mol%

5.50

85

[12]

p-TSA/solvent-free/125

10 mol%

6.00

89

[8]

FeCl3·SiO2/solvent-free/120

25 mg/mol

0.18

86

[17]

TCT/solvent-free/100

5 mol%

0.83

93

This work

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 aldehydes and amide or urea under solvent-free conditions. Further applications of TCT in organic transformation are currently in progress in our laboratories.

Experimental

Melting points were determined on a X-4 apparatus. Analytical 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 CHNOS Elemental Analyzer, and their results agreed favorably with the calculated values.

General procedure for the synthesis of amidoalkyl naphthols

A mixture of 1 mmol 2-naphthol, 1 mmol aromatic aldehyde and 1.3 mmol amide or urea and 0.05 mmol TCT was heated at 100 °C. After completion of the reaction (monitored 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 × 10 cm3 ethyl acetate. The combined organic layer was dried over MgSO4 and concentrated 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).

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:hexane = 1:1); IR (KBr): \( \bar{\nu } = 3,386, \) 3,143, 1,627, 1,577, 1,508, 1,473, 1,400, 1,384, 1,330, 1,276, 1,249, 1,091, 1,068, 821, 767, 669 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 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): δ = 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.

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:hexane = 1:1); IR (KBr): \( \bar{\nu } = 3,406, \) 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): δ = 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 (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): δ = 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.

N-[{4-[Acetylamino-(2-hydroxy-naphthalen-1-yl)-methyl]-phenyl}-(2-hydroxy-naphthalen-1-yl)-methyl]-acetamide (6, C32H28N2O4)

White solid, Mp 267–269 °C; Rf = 0.21 (ethylacetate:hexane = 1:1); IR (KBr): \( \bar{\nu } = 3,386, \) 3,143, 1,685, 1,637, 1,577, 1,473, 1,400, 1,276, 1,195, 1,091, 945, 821, 669 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 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): δ = 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.

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© Springer-Verlag 2008