1,3-Dibromo-5,5-dimethylhydantoin as an efficientcatalyst 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

� 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) � Multicomponent

reaction � Thioacetamide � Thioamidoalkyl naphthol � 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 (&) � 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

Res Chem Intermed

DOI 10.1007/s11164-014-1738-y

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

comparison of their physical data with those of known samples or by their 1H and13C 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

OH

+

CHO

X + CH3CNH2

SDBH (Catalyst)

130 C°Solvent-free

OH

NH

CH3S

X

Scheme 1 Preparation of 1-thioamidoalkyl-2-naphthols in the presence of DBH

N

N

BrO

OBr

Scheme 2 1,3-Dibromo-5,5-dimethylhydantoin (DBH)

A. Ghorbani-Choghamarani, S. Rashidimoghadam

123

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.

5, 24.6 ppm; IR (KBr): �m = 3,344, 2,251, 2,125, 1,767, 1,641, 1,396, 758 cm-1.

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):

�m = 3,406, 3,062, 3,030, 1,642, 1,516, 1,439, 622 cm-1.

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.

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

123

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 1 Effect of different amounts of DBH on the reaction of 2-naphthol, thioacetamide, and

benzaldehyde

Entry Catalyst amount (mmol) Time (min) Yielda (%)

1 – 1,800 10

2 0.05 310 68

3 0.1 290 80

4 0.15 165 95

5 0.2 315 73

a Isolated yield

Table 2 Optimization of temperature using DBH (0.15 mmol) as catalyst

Entry Temperature (�C) Time (min) Yielda (%)

1 25 150 No reaction

2 50 150 15

3 80 150 35

4 100 150 38

5 120 150 60

6 130 150 95

7 140 150 68

a Isolated yield

OH

+

CHO

+ CH3CNH2

S DBH (Catalyst)

130 C°Solvent-free

OH

NH

CH3S

Scheme 3 Effect of different amounts of DBH on the preparation of N-((2-hydroxynaphthalen-1-yl)(phenyl)methyl)ethanethioamide

A. Ghorbani-Choghamarani, S. Rashidimoghadam

123

Ta

ble

3S

ynth

esis

of

1-t

hio

amid

oal

ky

l-2

-nap

hth

ols

cata

lyze

db

yD

BH

En

try

Ald

ehy

de

Am

ide

Pro

du

ctT

ime

(min

)Y

ield

a(%

)M

.p.

(�C

)(l

it.

m.p

.,�C

)[r

ef.]

1

CH

OCH3CNH2

Sa

20

09

32

48

–2

50

(24

0–2

42

)[6

]

2

CH

OC

lCH3CNH2

Sb

25

09

52

40

–2

42

(24

6–2

48

)[6

]

3

CH

OB

rCH3CNH2

Sc

30

09

12

30

–2

32

4

CH

OF

CH3CNH2

Sd

90

93

20

8–2

10

5

CH

O

NO

2

CH3CNH2

Se

30

09

61

85

–1

87

6

CH

O

O2N

CH3CNH2

Sf

15

09

32

34

–2

36

7

CH

O

HO

CH3CNH2

Sg

31

08

02

29

–2

31

8

CH

OH

OCH3CNH2

Sh

30

08

32

40

–2

42

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

123

Ta

ble

3co

nti

nu

ed

En

try

Ald

ehy

de

Am

ide

Pro

du

ctT

ime

(min

)Y

ield

a(%

)M

.p.

(�C

)(l

it.

m.p

.,�C

)[r

ef.]

9

CH

OE

tOCH3CNH2

Si

33

08

52

19

–2

21

10

CH

OH

3CCH3CNH2

Sj

28

08

92

20

–2

22

11

CH

O

OH

Br

CH3CNH2

Sk

32

09

02

21

–2

23

12

CH

O

OH

MeO

CH3CNH2

Sl

31

09

12

18

–2

20

Rea

ctio

nco

nd

itio

n:

2-n

aph

tho

l(1

mm

ol)

,al

deh

yd

e(1

mm

ol)

,th

ioac

etam

ide

(1.5

mm

ol)

,D

BH

(0.1

5m

mo

l),

tem

per

atu

re1

30

�Ca

Iso

late

dy

ield

A. Ghorbani-Choghamarani, S. Rashidimoghadam

123

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.

OH

+

CHO

CHO

+ CH3CNH2

X

X= O, S 130 C°Solvent-free

0.15 mmol DBH OH

NHCCH3

HO

H3CCHN X

X

Scheme 4 Synthesis of bis-1-(thio)amidoalkyl-2-naphthols catalyzed by DBH

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

123

Ta

ble

4S

ynth

esis

of

bis

-1-(

thio

)am

idoal

kyl-

2-n

aphth

ols

cata

lyze

dby

DB

H

En

try

Ald

ehy

de

Am

ide

Pro

du

ctT

ime

(min

)Y

ield

a(%

)M

.p.

(�C

)(l

it.

m.p

.,�C

)[r

ef.]

1

CH

OO

HC

CH

3CN

H2

OA

18

09

52

80

–2

82

(27

7–2

79

)[2

3]

2

CH

O

CH

O

CH

3CN

H2

OB

60

90

27

8–2

80

3

CH

OO

HC

CH3CNH2

SC

24

08

52

86

–2

88

4

CH

O

CH

O

CH3CNH2

SD

18

08

02

83

–2

85

aIs

ola

ted

yie

ld

A. Ghorbani-Choghamarani, S. Rashidimoghadam

123

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.

BrN

NBrO

Me

Me

O

BrN

NO

Me

Me

O + Br

CHOBr H

OBr

R1H

OBr

O H

OBr

OHH

R1 N NBr

O

O

R1

OH

H2N CH3

S

OH

NHCSCH3R1

o-QMs

Scheme 5 Mechanism of the preparation of 1-thioamidoalkyl-2-naphthols in the presence of DBH

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

123

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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2-naphthols

Aldehyde Catalyst Time (min) Isolated yield (%) Ref.

CHODBH 200 93 This work

Fe(HSO4)3 390 88 [5]

Silica sulfuric acid 79 79 [6]

CHOClDBH 250 95 This work

Fe(HSO4)3 360 88 [5]

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

123