(nh4)2.5h0.5pw12o40-catalyzed rapid and efficient one-pot synthesis of dihydropyridines via the...

(NH4)2.5H0.5PW12O40-catalyzed rapid and efficientone-pot synthesis of dihydropyridines viathe Hantzsch reaction under solvent-free conditions

Seyyed Naeim Ghattali • Kazem Saidi •

Hojatollah Khabazzadeh

Received: 2 October 2012 / Accepted: 29 November 2012

� Springer Science+Business Media Dordrecht 2012

Abstract A heterogeneous reaction with the ammonium salt of 12-tungstophos-

phoric acid as catalyst has been designed for synthesis of 1,4-dihydropyridine and

polyhydroquinoline via the Hantzsch condensation. Molten tetrabutylammonium

bromide ionic liquid was used as reaction medium.

Keywords Hantzsch � 1,4-Dihydropyridine � Polyhydroquinoline �12-Tungstophosphoric � Heterogeneous � Tetrabutylammonium bromide

Introduction

Use of heterogeneous, rather than homogeneous, acid catalysts in organic synthesis

is an attractive area of research in the laboratory and in industry. The main

advantage of heterogeneous catalysts over homogeneous catalysts are their high

stability toward air and moisture, lack of corrosion, and ease of handling, recovery,

and regeneration [1]. Keggin-type heteropoly acids and their salts are a class of

highly acidic solid acid catalysts containing metal heteropolyanions coordinated by

octahedral oxygen as the basic structural unit [2]. Salts of 12-tungstophosphoric acid

are very important catalysts in several organic conversions, for example hydrocar-

bon cracking [3], conversion of methanol to hydrocarbons, cracking of alkenes [4],

esterification [5], benzylation, and benzoylation [6].

Multi-component reactions (MCRs) are efficient and powerful methods in

modern synthetic organic chemistry. They enable facile creation of several new

Dedicated with respect and admiration to Professor Issa Yavari, a leading pioneer in the development of

multicomponent reactions.

S. N. Ghattali � K. Saidi (&) � H. Khabazzadeh

Department of Chemistry, Shahid Bahonar University of Kerman, 76169 Kerman, Iran

e-mail: [email protected]

123

Res Chem Intermed

DOI 10.1007/s11164-012-0962-6

bonds in a one-pot reaction [7, 8]. Clearly, for efficient multi-step synthetic

procedures, the number of reactions and purification steps are among the most

important criteria, and should be as low as possible.

1,4-Dihydropyridyl compounds are well known as calcium-channel modulators

and are among the most important drugs used for treatment of cardiovascular

diseases [9]. Cardiovascular agents, for example nifedipine, nicardipine, amlodip-

ine, and related derivatives are dihydropyridyl compounds effective in the treatment

of hypertension. 1,4-Dihydropyridine (DHP) derivatives have a variety of biological

activity for example vasodilator, bronchodilator, antiatherosclerotic, antitumor,

geroprotective, hepatoprotective, and antidiabetic [10]. Extensive studies have

revealed that 1,4-DHP derivatives also have such medicinal functions as neuropro-

tectant, platelet anti-aggregatory activity, cerebral antischemic activity in the

treatment of Alzheimer’s disease, and chemosensitizers in tumor therapy [11].

These examples clearly indicate the remarkable potential of novel DHP derivatives

as a source of valuable drug candidates. Oxidation of these compounds to pyridines

has also been extensively studied [12]. Thus, there is much current interest in the

synthesis of this heterocyclic nucleus, because six-membered nitrogen heterocycles

are contained in many biologically interesting compounds.

Experimental

All chemicals used in the syntheses were purchased from Merck and were used

without further purification. All products are known and were identified by

comparing their spectral data and physical properties with those of the authentic

samples. NMR spectra were recorded on a Bruker DRX-500 Avance NMR

spectrometer using CDCl3 or DMSO-d6 as solvents.

General procedure for synthesis of 1,4-DHPs

Aldehyde (1 mmol), b-ketoester (2 mmol), NH4OAc (1 mmol) (NH4)2.5H0.5PW12O40

(0.02 mmol), and TBAB (1 mmol) were mixed and stirred at 110 �C. After completion

of the reaction, as indicated by TLC, 10 ml ethanol was added. After isolation of the

catalyst by filtration the mixture was poured into ice cold water. The resulting precipitate

was purified by recrystallization from ethanol to afford 1,4-DHPs. The same procedure

was used for synthesis of polyhydroquinolines with b-ketoester (1 mmol), cyclic

diketone (1 mmol), and TBAB (2 mmol). The catalyst was dried at 120 �C and reused.

Spectroscopic data for selected examples are shown below.

Dimethyl 1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate(Table 1, entry 4)

1H NMR (500 MHz, CDCl3): d (ppm) 2.36 (s, 6H, 2 CH3), 3.68 (s, 6H, 2 CH3), 5.04

(s, 1H, CH), 5.81 (s, 1H, NH), 7.16-7.30 (m, 5H, arom). 13C NMR (125 MHz,

CDCl3): d (ppm) 19.9, 39.7, 51.4, 104.3, 126.6, 128.0, 128.4, 144.7, 147.8, 168.5.

S. N. Ghattali et al.

123

Table 1 (NH4)2.5H0.5PW12O40-catalyzed synthesis of 1,4-DHP derivatives via the Hantzsch reaction

Entry R1 R2 Product Time

(min)

Yield

(%)

mp (�C)

Observed Reported

[Ref.]

1 4-Cl–C6H4 Et

NH

O O

EtO OEt

Cl 10 89 140–143 144–145

[17]

2 4-CH3–

C6H4

Et

NH

O O

EtO OEt

Me 18 81 131–134 135–138

[15]

3 3-NO2–

C6H4

Et

NH

O O

EtO OEt

NO24 96 158–161 162–164

[15]

4 4-Br–C6H4 Et

NH

O O

EtO OEt

Br 8 73 162–165 160–162

[18]

5 4-OCH3–

C6H4

Et

NH

O O

EtO OEt

OMe 14 64 162–164 157–159

[15]

(NH4)2.5H0.5PW12O40-catalyzed rapid and efficient one-pot synthesis

123

Dimethyl 4-(4-bromophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate(Table 1, entry 9)

1H NMR (500 MHz, CDCl3): d (ppm) 2.36 (s, 6H, 2 CH3), 3.67 (s, 6H, 2 OCH3),

4.99 (s, 1H, CH), 5.77 (s, 1H, NH), 7.17 (d, J = 8.4 Hz, 2H, arom), 7.36 (d,

J = 8.4 Hz, 2H, arom). 13C NMR (125 MHz, CDCl3): d (ppm) 20.0, 39.5, 51.5,

104.0, 120.4, 129.9, 131.5, 144.7, 146.9, 168.2.

Ethyl 1,4,5,6,7,8-hexahydro-4-(4-methoxyphenyl)-2-methyl-5-oxoquinoline-3-carboxylate (Table 2, entry 12)

1H NMR (500 MHz, CDCl3): d (ppm) 1.13 (t, J = 7.0 Hz, 3H, CH3), 1.74 (m, 1H),

1.88 (m, 1H), 2.16–2.24 (m, 2H), 2.27 (s, 3H, CH3), 2.46 (m, 2H), 3.67 (s, 3H,

OCH3), 3.97 (q, J = 7.0 Hz, 2H, CH2), 4.83 (s, 1H, CH), 6.73 (d, J = 8.4 Hz, 2H,

arom), 7.04 (d, J = 8.4 Hz, 2H, arom), 9.07 (s, 1H, NH).

Table 1 continued

Entry R1 R2 Product Time

(min)

Yield

(%)

mp (�C)

Observed Reported

[Ref.]

6 2-OCH3–

C6H4

Et

NH

O O

EtO OEt

OMe

14 65 135–137 139–141[15]

7 4–Br–C6H4 Me

NH

O O

Br

MeO OMe

8 88 195–198 200–201

[16]

8 4-NO2–

C6H4

Me

NH

O O

NO2

OMeMeO

4 93 190–193 195–196

[16]


123

Table 2 (NH4)2.5H0.5PW12O40-catalyzed synthesis of polyhydroquinoline derivatives via the Hantzsch

Reaction

Entry R1 R2 R3 Product Time

(min)

Yield

(%)

mp (�C)

Observed Reported

[Ref.]

1 C6H5 Et Me

NH

O O

OEt

8 70 198–200 203–205

[19]

2 4-CH3–

C6H4

Et Me

NH

O O

OEt

Me 4 73 255–257 261–263

[19]

3 4-Cl–

C6H4

Et Me

NH

O O

OEt

Cl 4 76 235–238 242–244

[19]

4 3-NO2–

C6H4

Et Me

NH

O O

OEt

NO24 68 236–239 242–244

[19]

5 4-NO2–

C6H4

Et Me

NH

O O

OEt

NO24 92 172–175 178–180

[19]


123

Table 2 continued


(min)

Yield

(%)

mp (�C)

Observed Reported

[Ref.]

6 4-OCH3–

C6H4

Et Me

NH

O O

OEt

OMe 4 68 245–249 252–255

[19]

7 4-Br–

C6H4

Et Me

NH

O O

OEt

Br 4 86 248–250 253–255

[19]

8 4-OH–

C6H4

Et Me

NH

O O

OEt

OH 8 90 229–232 231–233

[19]

9 4-CH3–

C6H4

Me Me

NH

O O

Me

OMe

6 85 260–264 270 [18]

10 C6H5 Et H

NH

O O

OEt

6 74 236–239 243–245

[19]


123

Table 2 continued


(min)

Yield

(%)

mp (�C)

Observed Reported

[Ref.]

11 4-CH3–

C6H4

Et H

NH

O O

OEt

Me 10 89 238–240 242–243

[19]

12 4-OCH3–

C6H4

Et H

NH

O O

OEt

OMe 4 70 248–253 252–255

[19]

13 4-Cl–

C6H4

Et H

NH

O O

OEt

Cl 6 92 230–232 234–236

[19]

14 4-OH–

C6H4

Et H

NH

O O

OEt

OH 8 71 222–225 220–222

[20]

15 3-NO2–

C6H4

Et H

NH

O O

OEt

NO24 82 195–196 200–201

[20]


123

Results and discussion

Because of the significant effect of heteropoly acid catalysts in many organic

transformations [13, 14] and our interest in their catalytic activity in the synthesis of

six membered nitrogen heterocycles, for example 1,4-dihydropyridines (DHPs), we

have undertaken the synthesis of 1,4-DHPs and related polyhydroquinolines

promoted by a catalytic amount of (NH4)2.5H0.5PW12O40 in molten tetrabutylam-

monium bromide (TBAB).

To pursue this approach the conditions were optimized by examining the reaction

involving p-chlorobenzaldehyde, ethyl acetoacetate, and ammonium acetate to

afford the appropriate DHP. The best results were obtained at 110 �C with 2 mol%

of (NH4)2.5H0.5PW12O40.

Several types of aldehyde with electron-donating or electron-withdrawing

substituents were reacted under the optimized conditions to establish the scope

and generality of the process (Scheme 1).

In all cases good yields of the expected 1,4-DHP derivatives were obtained. The

results are summarized in Table 1.

After successful synthesis of a series of Hantzsch DHPs, we turned our attention

to the synthesis of polyhydroquinoline derivatives via unsymmetrical Hantzsch

reaction. A procedure analogous to that used to prepare compounds (1–14), the four-

component coupling reaction of cyclic 1,3-diketone, aldehyde, acetoacetic ester, and

ammonium acetate, was conducted under similar reaction conditions (Scheme 2).

All products were obtained in high yields under the same reaction conditions as

shown in Table 2.

This method not only affords the products in excellent yields but also avoids the

disadvantages associated with catalyst cost, handling, safety, and pollution. Shorter

reaction times and improved selectivity were obtained in the presence of this

heterogeneous catalyst.

The reusability of the catalyst was also examined by treating ethyl acetoacetate

with 3-nitrobenzaldehyde in the presence of 2 mol % catalyst for four consecutive

Table 2 continued


(min)

Yield

(%)

mp (�C)

Observed Reported

[Ref.]

16 4-NO2–

C6H4

Et H

NH

O O

OEt

NO24 76 210–212 204–205

[20]


123

reactions. The reactions proceeded smoothly with little increase in reaction time and

furnished yields between 92 and 96 %, indicating the catalyst can be reused without

significant loss of activity (Table 3).

To show the merit of (NH4)2.5H0.5PW12O40 in comparison with the other

catalysts used for similar reactions, we have listed some results in Table 4. As it is

evident from the results, the required ratio for most of the catalysts used for this

purpose is higher and also the required reaction times are much longer.

Conclusions

We have developed a novel and highly efficient method for synthesis of 1,4-DHP

and polyhydroquinoline derivatives by treatment of aromatic aldehydes with a 1,

Table 3 Reusability of (NH4)2.5H0.5PW12O40 for Hantzsch reaction of 3-nitrobenzaldehyde with ethyl

acetoacetate

NH

O O

EtO OEt

NO2

OO

OEt

CHO

NO2

+ 2molten TBAB, NH4OAc

(NH4)2.5H0.5 PW12O40

2 mol%

Number of recycles Time (min) Yield (%)

Fresh 4 96

2 6 93

3 10 92

4 14 92

NH

O O

ORRO

R

R CHO

OO

OR+ 21 2

1

2 2molten TBAB, NH4OAc

(NH4)2.5H0.5PW12O40

2 mol%

Scheme 1 (NH4)2.5H0.5PW12O40-catalyzed synthesis of DHP derivatives in molten tetrabutylammoniumbromide

R CHO OR

OO

N

CO2R

RO

R

R H

O

OR

R

+1 2

1

2

+molten TBAB, NH4OAc

(NH4)2.5H0.5PW12O40

2 mol%

3

3

3

3

Scheme 2 (NH4)2.5H0.5PW12O40-catalyzed synthesis of polyhydroquinoline derivatives in moltentetrabutylammonium bromide


123

3-dicarbonyl compound in the presence of (NH4)2.5H0.5PW12O40 as heterogeneous

catalyst. The novelty of this method is the use of molten (tetrabutylammonium

bromide) as reaction medium; it has a very low vapor pressure and is very stable. In

this medium (NH4)2.5H0.5PW12O40 acts as a heterogeneous catalyst. Many other

catalysts are soluble in this type of medium and cannot act as heterogeneous

catalysts and cannot be recovered. This method has such attractive features as

reduced reaction times, higher yields, using of a molten salt instead of organic

solvents, and economic reusability of the catalyst compared with conventional

methods and with other catalysts. The simple procedure combined with ease of

recovery and reuse of the catalyst makes this an economic and benign chemical

process for synthesis of 1,4-DHPs. The catalyst can be recovered by filtration

several times without significant loss of activity. In addition no cumbersome

apparatus is needed to perform this reaction.

Acknowledgments We gratefully acknowledge financial support from the Research Council of Shahid

Bahonar University of Kerman.

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Table 4 Comparison of the Hantzsch reaction in the presence of different catalysts

Product Catalyst Catalyst molar

ratio

Solvent Time

(min)

Yield (%)

[Ref.]

NH

O O

EtO OEt

Cl (NH4)2.5H0.5PW12O40 2 Molten TBAB 10 89

PPh3 20 EtOH 120 81 [21]

SiO2 –RSO3H 0.1 g Solvent-free 60 90 [22]

HClO4–SiO2 0.05 g Solvent-free 20 89 [23]


123

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(nh4)2.5h0.5pw12o40-catalyzed rapid and efficient one-pot synthesis of dihydropyridines via the...

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