Amino functionalized mesoporous silica decorated with iron oxide nanoparticles as a magnetically recoverable nanoreactor for the synthesis of a new series of 2,4-diphenylpyrido[4,3-d]pyrimidines

DOI: 10.1039/c4ra00038b

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RSC Advances p. 18117 - 18126 (2014)

Update date:2022-07-30

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Authors:

Shadjou, Nasrin

Hasanzadeh, Mohammad

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Article abstract of DOI:10.1039/c4ra00038b

(Fe₂O₃)-MCM-41-nPrNH₂ as a magnetically recoverable nanoreactor, was prepared through the reaction of (Fe ₂O₃)-MCM-41 with 3-aminopropyltriethoxysilane in refluxing dry toluene. The catalyst with 10 wt% of loaded iron oxide nanoparticles was found to be a highly efficient nanocatalyst for the synthesis of a new class of 2,4-diphenylpyrido[4,3-d]pyrimidines under solvent free conditions in high to quantitative yields. By using an external magnet the catalyst was recovered and reused several times without any loss of efficiency. The prepared catalyst was characterized by transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy, X-ray powder diffraction (XRD), and nitrogen physisorption measurements.

Full text of DOI:10.1039/c4ra00038b

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Amino functionalized mesoporous silica decorated

with iron oxide nanoparticles as a magnetically

recoverable nanoreactor for the synthesis of a new

series of 2,4-diphenylpyrido[4,3-d]pyrimidines†

Cite this: RSC Adv., 2014, 4, 18117

Nasrin Shadjou and Mohammad Hasanzadeh

(Fe₂O₃)–MCM-41–nPrNH₂as a magnetically recoverable nanoreactor, was prepared through the reaction

of (Fe₂O₃)–MCM-41 with 3-aminopropyltriethoxysilane in reﬂuxing dry toluene. The catalyst with 10 wt% of

loaded iron oxide nanoparticles was found to be a highly eﬃcient nanocatalyst for the synthesis of a new

class of 2,4-diphenylpyrido[4,3-d]pyrimidines under solvent free conditions in high to quantitative yields.

By using an external magnet the catalyst was recovered and reused several times without any loss of

eﬃciency. The prepared catalyst was characterized by transmission electron microscopy (TEM), Fourier

transform infrared (FT-IR) spectroscopy, X-ray powder diﬀraction (XRD), and nitrogen physisorption

measurements.

Received 3rd January 2014

Accepted 27th March 2014

DOI: 10.1039/c4ra00038b

www.rsc.org/advances

The integration of functionalized mesoporous silica with

magnetic nanoparticles to form porous magnetic nano-

Introduction

composite is undoubtedly of great interest for practical appli-

cations. This type of magnetic nanocomposites, have the

advantages of both mesoporous silica and magnetic nano-

particles. Also magnetic separation by an appropriate magnetic

eld provides a convenient and low cost method for the sepa-

ration of these magnetic catalysts in a multiphase suspension

without using extra organic solvents and additional ltration

steps or tedious work-up.¹²

Pyrido[4,3-d]pyrimidines display various remarkable bio-

logical activities such as antibacterial,¹³antiallergic,¹⁴

fungicidal, antiviral, anti-inammatory, and antimicrobial

properties.^15–20Inhibition of the adenosine kinase enzyme,²¹

or dihydrofolate reductase, and irreversible inhibition of

epidermal growth factor receptor²²stimulated our interest

immensely. Also, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

and related compounds have been used as starting materials

for the multi-step synthesis of tetrahydropteroic acid

derivatives.²³

In view of the useful properties of pyrido[4,3-d]pyrimi-

dines and since there are no reports for the synthesis of

these interesting compounds in the literature, herein,

following our immense desire to adopt rather greener and

economical reaction conditions,²⁴we report an eﬃcient

synthesis of 2,4-diphenylpyrido[4,3-d]pyrimidines (3)

through the two component reactions between (E)-3,5-bis-

(benzylidene)-4-piperidones (1) and benzamidine hydro-

chloride (2) in the presence of a magnetically recoverable

nanoreactor [(Fe₂O₃)–MCM-41–nPrNH₂] under solvent free

conditions (Scheme 1).

Recently, mesoporous molecular sieves have attracted signi-

cant attention in the eld of adsorption, catalysis, and separa-

tion as they exhibit excellent characteristics such as a high

surface area up to 1500 m²g^ꢀ1, a large pore volume, and a

narrow pore size distribution between 1.5 and 10 nm. In addi-

tion, they are highly eﬃcient, sustainable, recyclable, and eco-

friendly materials. MCM-41 (Mobil Composition of Matter no.

41) is a mesoporous material and consists of a hexagonal array

of unidirectional pore structures which has been synthesized

under basic condition using cationic surfactants as a structure-

directing agent. Pure MCM-41 is neutral in charge and exhibits

only weak hydrogen-bonding type sites which limit its applica-

tion in catalysis.^1–5An additional possibility to develop basic

catalysts is modication of supports, as the chemical func-

tionalities of these materials can be uniformly achieved by

covalent anchoring of diﬀerent organic moieties.⁶One of the

modied organic–inorganic hybrid materials that have been

applied as eﬀective solid base catalyst in organic trans-

formations is 3-aminopropylated silica (MCM-41–nPrNH₂).^7–10

The functional aminopropyl group was anchored on MCM-41

silica by the post-modication method and was prepared

according to the procedure reported in the literature from the

reaction of MCM-41 with 3-aminopropyltriethoxysilane in

reuxing dry toluene.¹¹

Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

E-mail: Nasrin.shadjou@gmail.com; mhmmd_hasanzadeh@yahoo.com; Fax: +98

411 3363231; Tel: +98 914 3610877

† Electronic supplementary information (ESI) available. See DOI:

10.1039/c4ra00038b

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Scheme 1 Synthesis of 2,4-diphenylpyrido[4,3-d]pyrimidine derivatives in the presence of (Fe₂O₃)–MCM-41–nPrNH₂.

The IR spectrum of catalyst before and aer functionalization

was shown in Fig. 2. In IR spectra, the band from 400–650 cm^ꢀ1

is assigned to the stretching vibrations of the (Fe–O) bond in

Fe₂O₃, and the band at about 1100 cm^ꢀ1belongs to the

stretching of the (Si–O) bond (Fig. 2a and b). Aer functionali-

zation with amine groups, the absorption bands at 1550 cm^ꢀ1

and at 1650 cm^ꢀ1belong to the bending vibration of N–H groups.

It should be mentioned that the C–N stretching vibration in the

region of 1030–1230 cm^ꢀ1overlap with the broad absorption

band of the silanol group and the Si–O–Si vibrations (Fig. 2b).

The XRD analysis of prepared catalyst was performed from

2.0^ꢁ(2q) to 80.0^ꢁ(2q). XRD pattern in this region conrmed that

the change of sample's color from black to brick-red aer

calcination of the catalyst is due to the oxidation of embedded

Fe₃O₄to Fe₂O₃nanoparticles (Fig. 3).

The specic surface area and pore volume obtained by the N₂

adsorption isotherms and calculated by the Brunauer–Emmett–

Teller (BET) method²⁶were 362 m²g^ꢀ1and 0.35 cm³g^ꢀ1

respectively. The pore diameter of the (Fe₂O₃)–MCM-41–nPrNH₂

was 3.93 nm derived from the adsorption and desorption

branches by the Broekhoﬀ and de Boer model (Fig. 4).²⁷

The results of N₂sorption experiments of (Fe₂O₃)–MCM-41

and (Fe₂O₃)–MCM-41–nPrNH₂are summarized in Table 1, in

which the surface area and pore volume of functionalized

magnetic MCM-41 were lower than those of corresponding

mesoporous silica due to the graing of -nPrNH₂groups.

Initially for optimization of the reaction conditions, the

reaction involving (E)-3,5-bis(4-methylbenzylidene)-4-piper-

idones (1a) and benzamidine hydrochloride (2) was chosen as a

model reaction (Scheme 2).

Results and discussion

At rst the (Fe₂O₃)–MCM-41 with 10 wt% of loaded iron oxide

nanoparticles was prepared according to the method reported

in literature with some modications.²⁵

The prepared magnetic nanocatalyst was characterized by

Fourier transform infrared (FT-IR), X-ray powder diﬀraction

(XRD), and nitrogen physisorption measurements.

The TEM images showed that the encapsulated nano-

particles were present as uniform particles and the size of

encapsulated nanoparticles was about 100 nm. Fig. 1 shows

TEM images of mesoporous (Fe₂O₃)–MCM-41–nPrNH₂in which

all the materials possess hollow structures. They provide a large

active surface area for the eﬃcient synthesis of 2,4-diphe-

nylpyrido[4,3-d]pyrimidines (3) through the two component

reactions between (E)-3,5-bis(benzylidene)-4-piperidones (1)

and benzamidine hydrochloride (2). Also, TEM micrograph

conrms that (Fe₂O₃)–MCM-41–nPrNH₂have typical MCM-41

type, highly parallel channel-like porous structure packed in a

hexagonal symmetry.

In order to show the unique catalytic behavior of (Fe₂O₃)–

MCM-41–nPrNH₂, the reaction was performed in the presence

of MCM-41–SO₃H under reux conditions in H₂O and H₂O–

DMF in which no product was formed (Table 2, entries 1, 2). It

was observed that only basic catalysts were able to catalyze this

reaction. When the reaction was done in the presence of sodium

hydroxide under reux condition in aqueous ethanol and

methanol for 120 min (Table 2, entries 3, 4), in addition to the

desired product (3a), the non-aromatic product (3h) was also

formed as major component. However, in the presence of

(Fe₂O₃)–MCM-41–nPrNH₂and solvent free conditions only the

product 3a was formed.

Comparative yields were also obtained in the presence of

catalytic amount of other catalysts such as KF/Al₂O₃, nano MgO,

and MCM-41–nPrNH₂(Table 2, entries 6–8). The results of

Fig. 1 TEM image of (Fe₂O₃)–MCM-41–nPrNH₂.

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Fig. 2 The IR spectra of (a) (Fe₂O₃)–MCM-41 and (b) (Fe₂O₃)–MCM-41–nPrNH₂.

Table 2 show that (Fe₂O₃)–MCM-41–nPrNH₂is an eﬀective basic

With these results in hand, a variety of 3,5-dibenzylide-

catalyst for this transformation and 30 mg of the catalyst was nepiperidin-4-one possessing both electron-donating

the optimum amount under solvent free conditions. It is worth and electron-withdrawing groups were employed for the

mentioning that, the yield of product 3 did not increase largely synthesis of 2,4-diphenylpyrido[4,3-d]pyrimidine derivatives

with a larger amount of the catalyst (Table 2, entry 11).

in which those with electron-withdrawing groups reacted

Solvent screening also revealed that the solvent free condition rapidly whereas for those with electron-rich groups longer

is the best condition for this transformation. The higher reaction times were required. Electron-withdrawing groups

concentration of reactants in the absence of solvents usually on the phenyl rings induce greater electronic positive charge

leads to more favorable kinetics than in solution.²⁸Hence the on the corresponding b-atoms than electron donating moie-

solvent free condition has been selected as optimized condition. ties (Table 3).

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Fig. 3 The XRD pattern of prepared catalyst in the region of 2.0^ꢁ(2q) to 80.0^ꢁ(2q).

Fig. 4 (a) Nitrogen adsorption/desorption isotherm, (b) BJH and (c) pore size distribution of (Fe₂O₃)–MCM-41–nPrNH₂.

The proposed mechanism was shown in Scheme 3. that the presence of a base (NH₂groups) is essential to

Because of two-dimensional pores of MCM-41, the reactants convert the benzamidine hydrochloride to free base. At rst,

easily transfer toward the nanocatalyst channels, and they intermediate (A), (B) was generated by Michael addition of

are accompanied by the inherent hydrogen bonding of –OH the free base of benzamidine hydrochloride (2) to 3,5-

and –NH₂groups which both are capable of bonding with the dibenzylidenepiperidin-4-one (1). Subsequently, elimination

carbonyl oxygen of the 3,5-dibenzylidenepiperidin-4-one of water occurred and nally aer aromatization the product

moiety to increase its electrophilicity. It should be mentioned (3) was formed (Scheme 3).

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Table 1 Surface area, average pore size, and pore volume of (Fe₂O₃)–MCM-41 and (Fe₂O₃)–MCM-41–nPrNH₂

Adsorbent

Surface area (m²g^ꢀ1

)

Average pore size^a(nm)

Pore volume^b(cm³g^ꢀ1

)

(Fe₂O₃)–MCM-41

(Fe₂O₃)–MCM-41–nPrNH₂

1213

362

5.26

3.93

1.59

0.35

Pore size is calculated by method described by Brunauer–Emmett–Teller. ^bPore volume determined from nitrogen physisorption isotherm.

d]pyrimidine derivatives under solvent free conditions. This

novel synthetic method is especially favoured because it provides

a synergy of the nanosized (Fe₂O₃)–MCM-41–nPrNH₂and

solvent-free conditions which oﬀers the advantages of high

yields, simplicity and easy workup. Most signicantly, this solid

basic catalyst has large surface area (362 m²g^ꢀ1), thermal

stability, and reusable for a number of times with consistent

activity. Also, magnetic nanocomposite facilitates easy catalyst

recovery and recycling, as well as product separation.

Experimental section

General remarks

Melting points were recorded on a Buchi B-540 apparatus. IR

spectra were recorded on an ABB Bomem Model FTLA200-100

instrument. ¹H and ¹³C NMR spectra were measured on a

Bruker DRX-300 spectrometer, at 300 and 75 MHz, using TMS as

an internal standard. Chemical shis (d) were reported relative

to TMS, and coupling constants (J) were reported in hertz (Hz).

Mass spectra were recorded on a Shimadzu QP 1100 EX mass

spectrometer with 70 eV ionization potential.

Scheme 2 A model reaction for the optimization.

It should be noted that the catalyst was unaﬀected under the

condition of the reaction. Therefore, the catalyst was eﬀectively

collected from the reaction mixture and the recovered catalyst

was used in subsequent runs without observation of signicant

decrease in activity even aer 5 runs (Fig. 5). This type of

magnetic nanocatalyst, have the advantages of both meso-

porous silica and magnetic nanoparticles. The immobilization

of homogeneous catalysts on magnetic nanocomposite facili-

tates easy catalyst recovery and recycling, as well as product

separation, is a longstanding pursuit of catalysis.

Preparation of (Fe₂O₃)–MCM-41

solution

with

molar

composition

3.2FeCl₃: 1.6FeCl₂: 1CTABr : 39 NH₄OH : 2300H₂O was used

for preparation of naked Fe₃O₄nanoparticles at room temper-

ature. Typically, 2 g of iron(^III) chloride (FeCl₃$6H₂O) and 0.8 g

of iron(^II) chloride (FeCl₂$4H₂O) were dissolved in 10 mL of

distilled water under N₂atmosphere. The resultant solution

Conclusion

In summary, (Fe₂O₃)–MCM-41–nPrNH₂was found as an eﬃcient dropwise was added to a 100 mL solution of 1.0 M NH₄OH

catalyst for the synthesis of new class of 2,4-diphenylpyrido[4,3- containing 0.4 g of cetyltrimethylammonium bromide (CTABr)

Table 2 Comparing the eﬃciency of diﬀerent catalysts and solvents in the synthesis of 3a

Entry

Catalyst

Solvent

Reaction condition

Time (h)

Yield (%)

MCM-41–SO₃H

NaOH

No catalyst

KF/Al₂O₃

Nano MgO

MCM-41–nPrNH₂

(Fe₂O₃)–MCM-41–nPrNH₂(0.02 g)

(Fe₂O₃)–MCM-41–nPrNH₂(0.03 g)

(Fe₂O₃)–MCM-41–nPrNH₂(0.04 g)

H₂O

Reux

2:00

1:00

3:00

2:00

1:30

2:00

1:30

1:20

—

H₂O–DMF

EtOH

MeOH

—

90^a

Solvent free/130 ^ꢁ

—

In this case the major product was 3h.

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Table 3 The reaction time (h) and the yield (%) of 2,4-diphenylpyrido[4,3-d]pyrimidine products

Entry

Product

Time (h)

Yield (%)

M.P. (^ꢁC) found

M.P. (^ꢁC) reported