facile synthesis of 3 4 dihydropyrimidin 2 1h ones and thiones and indeno 1 2 d pyrimidines catalyzed by p dodecylbenzenesulfonic acid

e-mail: smansoors2000@yahoo.co.in Abstract: A facile synthesis of 3,4-dihydropyrimidin-21H-ones/-thiones DHPMs through Biginelli reaction by the condensation reaction of aldehydes, β-ke

Title: A facile synthesis of

3,4-dihydropyrimidin-2(1H)-ones/thiones and

indeno[1,2-d]pyrimidines catalyzed by

p-dodecylbenzenesulfonic acid

Author: Krishnamoorthy Aswin Syed Sheik Mansoor Kuppan

Logaiya Prasanna Nithiya Sudhan R Nasir Ahmed

Please cite this article as: K Aswin, S.S Mansoor, K Logaiya, P.N Sudhan,

R.N Ahmed, A facile synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones and indeno[1,2-d]pyrimidines catalyzed by p-dodecylbenzenesulfonic acid, Journal of Taibah University for Science (2014), http://dx.doi.org/10.1016/j.jtusci.2014.03.005

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Accepted Manuscript

A facile synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones and

indeno[1,2-d]pyrimidines catalyzed by p-dodecylbenzenesulfonic acid

Krishnamoorthy Aswin, Syed Sheik Mansoor * , Kuppan Logaiya, Prasanna

Nithiya Sudhan, R Nasir Ahmed

Bioactive Organic Molecule Synthetic Unit, Research Department of Chemistry,

C Abdul Hakeem College, Melvisharam – 632 509, Tamil Nadu.

e-mail: smansoors2000@yahoo.co.in

Abstract: A facile synthesis of 3,4-dihydropyrimidin-2(1H)-ones/-thiones (DHPMs)

through Biginelli reaction by the condensation reaction of aldehydes, β-ketoesters and

urea/thiourea employing p-dodecylbenzenesulfonic acid (DBSA) as a recyclable catalyst

under solvent-free condition at 80 oC is described Furthermore, a series of

indeno[1,2-d]pyrimidines have also been synthesized using the same conditions by the Biginelli-like

reaction of 2H-indene-1,3-dione, with urea/thiourea and aromatic aldehyde All the

products in both reactions obtained in good to excellent yields by proceeding through a

simple and efficient procedure All the synthesized compounds structure has been

established by advanced spectroscopic data

Keywords: Biginelli reaction; p-dodecylbenzenesulfonic acid; dihydropyrimidinones;

indeno[1,2-d]pyrimidines; 2H-indene-1,3-dione; one-pot synthesis

Accepted Manuscript

1 Introduction

Multi-component reactions (MCRs) are of increasing importance in organic and

medicinal chemistry, because the strategies of MCR offer significant advantages over

conventional linear-type syntheses [1] Compared with conventional methods of organic

synthesis, MCRs have the advantages of high-selectivity, good yields, milder reaction

conditions, and simple work-up procedures, among others Thus, a vast number of

diverse compounds can be obtained in a parallel synthesis [2] The development of new

and efficient synthetic methodologies for the rapid construction of potentially bio-active

compounds constitutes a major challenge for chemists in organic synthesis MCRs allow

the construction of several bonds in a single operation and are getting considerable

importance as one of the most powerful emerging synthetic tools for the creation of

molecular complexity and diversity [3]

The Biginelli synthesis is an easy and useful multicomponent reaction that is

gaining increasing importance in organic and medicinal chemistry for its generation of

multifunctionalized products, including 3,4-dihydropyrimidin-2(1H)-ones and their

thione analogs and other related heterocyclic compounds [4] Recently, appropriately

functionalized dihydropyrimidine analog of novel

4-aryl-5-isopropoxycarbonyl-6-methyl-3,4-dihydropyrimidinones has emerged as anti-microbiological agent [5] A novel

3,4-dihydropyrimidin-2(1H)-one has been reported as HIV-1 replication inhibitors with

improved metabolic stability [6] In addition, their special structure has been found in

natural marine alkaloid batzelladines, which are the first low molecular weight natural

products reported in the literature that inhibits the binding of HIVgp-120 to CD4 cell

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This could be a new path for the development of AIDS therapy [7-8] In 1893, the Italian

chemist Pietro Biginelli reported the cyclocondensation of ethyl acetoacetate, urea and an

aryl aldehyde in the presence of an acid, furnishing 3,4-dihydropyrimidin-2(1H)-ones as

products [9] However, this reaction often requires harsh conditions and long reaction

times and affords low yields, particularly when substituted aromatic and aliphatic

aldehydes are employed The scope of this reaction was gradually extended by the

variation of all three building blocks, allowing access to a large number of multi

functionalized dihydropyrimidines of medicinal use [10]

The most straightforward procedure for the preparation of dihydropyrimidinones

and thiones is by condensation of β-dicarbonyl compounds with an aromatic aldehyde

and urea or thiourea in the presence of Lewis and Brønsted acid promoters such as silica

immobilized nickel complex [11], cellulose sulfuric acid [12], lanthanum oxide [13],

bioglycerol-based sulfonic acid functionalized carbon [14], p-sulfonic acid calixarenes

[15], copper(II) sulfamate [16], triphenylphosphine [17], melamine trisulfonic acid [18],

montmorillonite KSF [19], natural catalyst [20], heteropoly acid supported on zeolite

[21], In(OTf)3 [22], Ruthenium(III) chloride [23], silica sulfuric acid [24], Nafion-H [25],

sulfonated carbon [26], lactic acid [27] and so on The classical Biginelli reaction is

considerably extended by use of 1-indanone [28] However, some of these procedures

require expensive reagents, strongly acidic conditions, long reaction times, high

temperatures, or stoichiometric amounts of catalysts, or they result in environmental

pollution or give unsatisfactory yields Therefore, there is a need for new catalysts that

are readily available or easy to prepare, inexpensive, and recoverable Moreover, the

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workup procedure should be simple Therefore, to avoid these limitations, the

introduction of a milder and more efficiently methods accompanied with higher yields are

needed In this regard, p-dodecylbenzenesulfonic acid (DBSA) has found many

applications [29–34]

In recent years, p-dodecylbenzenesulfonic acid (DBSA) has gained considerable

popularity as an efficient Bronsted-acid surfactant combined catalyst for carrying out

various organic transformations in water as well as under solvent-free conditions [29–34]

p-dodecylbenzenesulfonic acid has been used extensively as Brønsted

acid−surfactant-combined catalyst in Mannich-type reactions of aldehydes, amines, and ketones [29],

ester, ether, thioether, and dithioacetal formation in water [30], organic synthesis inside

particles in water [31], solvent-free esterification [32], for the synthesis of

6-amino-4-aryl-5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles in aqueous media

[33] and green synthesis of dibenzo[a,j]xanthenes [34] However, there is no report on

the use of p-dodecylbenzenesulfonic acid (DBSA) for the synthesis of 3,4-dihydropyrimidine derivatives and also indeno[1,2-d]pyrimidines.

In recent years, the target of science and technology has been shifting more

towards environmentally friendly and has encouraged the application of solvent-free

conditions A move away from the use of solvents in organic synthesis has led in some

cases to improved results and more benign synthetic procedures Adopting the principles

of Green Chemistry, we have established that using solvent-free conditions for synthesis

of 1,4-dihydropyridines results in a dramatic improvement in yields [35]

As part of our continuing studies of organic processes on the development of

environmentally friendly procedures for the synthesis of biologically active heterocyclic

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molecules [36-39], we now describe the synthesis of 3,4-dihydropyrimidine derivatives

using DBSA as an efficient novel catalyst under solvent-free condition at 80 oC

By using the same procedure which we applied for the synthesis of

3,4-dihydropyrimidine derivatives, we have also synthesized a series of

4-aryl-3,4-dihydro-

1H-indeno[1,2-d]pyrimidine-2,5-diones/4-aryl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-ones by the Biginelli-like reaction of 2H-indene-1,3-dione, with

urea/thiourea and aromatic aldehydes

2 Experimental

2.1 Chemicals and analysis

Chemicals were purchased from Merck, Fluka and Aldrich Chemical Companies

1H NMR (500 MHz) and 13C NMR (125 MHz) spectra were obtained using Bruker

DRX-500 Avance at ambient temperature, using TMS as internal standard FT-IR spectra were

obtained as KBr discs on Shimadzu spectrometer Mass spectra were determined on a

Varion - Saturn 2000 GC/MS instrument Elemental analysis was measured by means of

Perkin Elmer 2400 CHN elemental analyzer flowchart All yields refer to isolated

products unless otherwise stated

2.2 General procedure for the preparation of 3,4-dihydropyrimidinones / thiones

A mixture of aldehyde (1 mmol), ethyl acetoacetate (1 mmol), urea/thiourea (1.5 mmol)

and DBSA (5 mol%) under solvent-free condition was heated with stirring at 80 oC for

appropriate time The progress of the reaction was monitored by TLC After cooling, the

reaction mixture was poured into crushed ice with stirring The crude product was

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filtered, washed with cold water, dried and recrystallized from 95% ethanol or ethyl

acetate to give pure products After the separation of the product, CH2Cl2 (20 mL) was

added, and the catalyst was removed by filtration The recovered catalyst was washed

two times with an aliquot of fresh CH2Cl2 (2×10 mL), then drying to ready for later run

The IR, 1H NMR, 13C NMR, mass and elemental analysis data of the synthesized

compounds are given below

2.3 Spectral data for the synthesized compounds (4a-v)

2.3.1 5-Ethoxycarbonyl- 6-methyl-4-phenyl- 3,4- dihydropyrimidin-2(1H)-one (4a)

A mixture of aldehyde (1 mmol), 2H-indene-1,3-dione (1 mmol), urea (1.5 mmol), and

DBSA (5 mol%) under solvent-free condition was heated to 80 oC, with stirring, for 2.5

-3.5 h to complete the reaction (monitored by TLC) After cooling to room temperature,

the reaction was quenched with 20 ml of H2O and stirred for 10 min The pure product

was isolated by filtration, followed by washing with EtOAc The IR, 1H NMR, 13C NMR,

mass and elemental analysis data of the synthesized compounds are given below

2.5 Spectral data of the synthesized compounds (6a-l)

2.5.1 4-Phenyl-3,4-dihydro-1H-indeno[1,2-d]pyrimidine-2,5-dione (6a)

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135.7, 136.2, 142.3, 144.3, 183.3, 189.4 ppm; MS(ESI): m/z 307 (M+H)+; Anal Calcd

for C18H14N2OS: C, 70.59; H, 4.58; N, 9.15 % Found: C, 70.55; H, 4.54; N, 9.13 %

3 Results and discussion

Dihydropyrimidines show a diverse range of biological activities We are interested in

studying Biginelli reaction with the aim to develop an operationally simple method for

the synthesis of a large range of DHPMs Different analogues were synthesized by

varying aldehydes with ethylacetoacetate or methylacetoacetate and urea or thiourea We

started our study of the one-pot three-component Biginelli condensation using DBSA as

the catalyst (Scheme 1), by examining the conditions for the reaction using benzaldehyde,

ethylacetoacetate and urea to afford the corresponding DHPM product

One important aspect of green chemistry is the elimination of solvents in chemical

processes or the replacement of hazardous solvents with relatively benign solvents [40]

Our initial work started with screening of solvent and catalyst loading so as to identify

optimal reaction conditions for the synthesis of DHPM derivatives A range of solvents

like acetonitrile, dioxane, acetic acid, water and ethanol were examined (Table 1, enries

1-5) The reaction without any solvent at 80 oC was more successful (Table -1, entry 6)

We also evaluated the amount of DBSA required for the reaction It was found that when

decreasing the amount of the catalyst from 5 mol% to 3 mol%, the yield decreased from

94 to 73% (entry 7) But, when increasing the amount of the catalyst from 5 mol% to 10

mol%, there is no change in the yield (Table 1, entry 8) The use of 5 mol% of DBSA

maintaining the yield at 94%, so this amount is sufficient to promote the reaction In the

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presence of more than this amount of the catalyst, neither the yield nor the reaction time

were improved (Table 1, entry 8) Thus, the best result was obtained with 5 mol% of

DBSA under solvent-free condition at 80 oC (Table 1, entry 6)

<Table 1>

In order to investigate the scope of these conditions, we have undertaken

the synthesis of different derivatives of 3,4-dihydropyrimidin-2(1H)-one/thione from a

variety of substrates from aldehydes, either ethylacetoacetate or methylacetoacetate and

either urea or thiourea in the presence of DBSA as catalyst The results are presented in

Table 2 All the reactions, consisting of those involving ortho-, meta-, and

para-substituted benzaldehydes, proceeded smoothly and afforded the corresponding

3,4-dihydropyrimidin-2(1H)-one in moderate to high yields Electronic effects can be

observed The electron-donating group substituted benzaldehydes required prolonged

reaction time to give the yields, while electron-withdrawing group substituted ones gave

evidently increasing yields ortho-Substituted benzaldehydes, whether the substituent is

electron-donating group or electron-withdrawing group, afforded the corresponding

3,4-dihydropyrimidin-2(1H)-one in relatively lower yields, indicating an obvious steric

effect Thiourea exhibited behavior similar to that of urea (Scheme 1)

<Scheme 1>

<Table 2>

To explore the advantages of this DBSA-catalyzed synthesized of

3,4-dihydropyrimidin-2(1H)-one, we compared the results we obtained under the optimized

conditions with results reported in the literature by other catalysts (Table 3) Among the

solid acid catalysts copper(II) sulfamate, zeolite-supported HPA, nafion-H, p-sulfonic

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acid calixarenes, triphenyl phosphine, silica sulfuric acid, bioglycerol based carbon,

montmorillonite KSF, cellulose sulfuric acid, quartz or granite and Ruthenium(III)

chloride, DBSA was found to be superior in terms of yield and time of reaction

<Table 3>

The possibility of recycling the catalyst was examined using the model reaction

for the synthesis of 3,4-dihydropyrimidin-2(1H)-one under the optimized conditions

Upon completion of the reaction, the mixture was poured into crushed ice with stirring

The crude product was filtered, washed with cold water and recrystallized from hot

ethanol The catalyst was recovered as described in the experimental section and the

recycling ability of the catalyst was tested for further runs As shown in Figure 1, the

recycled catalyst was used for further runs, the yields ranged from 94% to 88%

<Figure 1>

During the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones, we found that

several compounds are synthesized smoothly in the presence of DBSA as catalyst

Therefore, we applied the same reaction conditions to carry out the synthesis of a new

series of

4-aryl-3,4-dihydro-1H-indeno[1,2-d]pyrimidine-2,5-diones/4-aryl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidine-5-ones A mixture of benzaldehyde (1a),

2H-indene-1,3-dione (5), and urea (3a) at a mol ratio of 1:1:1.5 in the presence of 5 mol%

DBSA under solvent-free condition was heated at 80 oC of for 2.5 h To our delight, the

desired product 6a was obtained in 91% yield (Scheme 2) Encouraged by the result, a

series of aldehydes were selected to undergo the condensation (Table 4)

<Scheme 2>

<Table 4>