Biginelli Reaction - American Chemical Society

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Biginelli Reaction: Polymer Supported Catalytic Approaches Rajendra Patil, Jagdish Chavan, Dipak S Dalal, Vaishali Sanjay Shinde, and Anil Beldar ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.8b00120 • Publication Date (Web): 15 Jan 2019 Downloaded from http://pubs.acs.org on January 16, 2019

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ACS Combinatorial Science

“Table of Content Use Only”

Biginelli Reaction: Polymer Supported Catalytic Approaches Rajendra V. Patil†, Jagdish U. Chavan†, Dipak S. Dalal‡, Vaishali S. Shinde§ and Anil G. Beldar*†

ACS Paragon Plus Environment

ACS Combinatorial Science 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Biginelli Reaction: Polymer Supported Catalytic Approaches Rajendra V. Patil†, Jagdish U. Chavan†, Dipak S. Dalal‡, Vaishali S. Shinde§ and Anil G. Beldar*† †Department

of Chemistry, P.S.G.V.P.M’s SIP Arts, GBP Science and STKVS Commerce

College, Shahada, Nandurbar-425409, India ‡School

of Chemical Sciences, North Maharashtra University, Jalgaon-425001, India

§Garware

Research Centre, Department of Chemistry, University of Pune, Pune-411 007, India

KEYWORDS: Biginelli reactions; DHPM; polymer supported catalysts; nanocomposites.

ABSTRACT: The Biginelli product, dihydropyrimidinone (DHPM) core and its derivatives are of immense biological importance. There are several methods reported as modifications to the original Biginelli reaction. Among them, many involve the use of different catalysts. Also, among the advancements that have been made to the Biginelli reaction, improvements in product yields, less hazardous reaction conditions and simplified isolation of products from the reaction predominate. Recently, solid phase synthetic protocols have attracted the research community for improved yields, simplified product purification, recyclability of the solid support which forms a special economic approach for Biginelli reaction. The present review highlights the role of polymer supported catalysts in Biginelli reaction; which may involve organic, inorganic or


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hybrid polymers as support for catalysts. A few of the schemes involve magnetically recoverable catalysts where work up provides green approach relative to traditional methods. Some research groups used polymer–catalyst nanocomposites and polymer supported ionic liquids as catalyst. Solvent free, an ultrasound or microwave assisted Biginelli reactions with polymer supported catalysts are also reported.

CONTENTS INTRODUCTION Biginelli reaction Advancements in classical Biginelli reaction Polymers as support for reagents Scope ORGANIC POLYMERS Organic polymers and copolymers as catalyst Organic polymers and copolymers as catalyst supports Resins as catalyst and supports Amberlyst Resins Dowex-50W Resins Nafion Resins


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Indion Resin Polymeric Carbon Polymeric carbon as catalyst Polymeric carbon as catalyst supports Cyclodextrins as catalyst Calixarenes as catalyst INORGANIC POLYMERS Clays and minerals as inorganic polymers Alumino-silicates based clays or minerals as polymeric catalyst and supports MCM-41 (Mobile Composition Matter No.41) as catalyst and supports Zeolites as polymeric catalyst Montmorillonites as polymeric catalyst Miscellaneous alumino-silicates as polymeric catalyst Zirconia based clay or minerals as polymeric catalyst Apatites based clay or minerals as polymeric catalyst Hydrotalcites based clay or minerals as polymeric catalyst Miscellaneous clay or minerals as polymeric catalyst


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Silica based inorganic polymers as catalyst and supports Heteropolyacid and anions based inorganic polymers as catalyst and supports Phosphotungstic acid based heteropolyacid polymeric catalyst Phosphomolybdic acid based heteropolyacid polymeric catalyst Silicotungstic acid based heteropolyacid polymeric catalyst Multi heteropoly acids as polymeric catalyst Multi-metal heteropoly acids as polymeric catalyst Miscellaneous heteropolyacid based polymeric catalyst Alumina based inorganic polymers as catalyst Alumina based inorganic polymers as catalyst support Polyphosphate esters (PPE) based inorganic polymers as catalyst HYBRID POLYMERS Metal coordination polymers as hybrid catalyst Organosilica based hybrid polymers as catalyst Metallophthalocyanines based hybrid polymers as catalyst Metal-Organic Frameworks based hybrid polymers as catalyst Miscellaneous hybrid polymers as catalyst


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BIOCATALYSTS Enzymes as polymeric biocatalyst Cellulose as polymeric biocatalyst Polysaccharides as polymeric biocatalyst Phytic acid as polymeric biocatalyst NANOCATALYSTS Magnetic nanocomposites as catalysts Magnetic heteropolyacid based nanocatalysts Hybrid magnetic nanocatalysts Magnetic Carbon Nanotubes (CNTs) as hybrid magnetic nanocatalysts Magnetic nanoparticles supported ionic liquids as hybrid nanocatalysts Magnetic organo-functionalized catalysts as hybrid nanocatalysts Miscellaneous magnetic nanocomposites Nanocomposites Clay or mineral based nanocomposites as catalyst Silica based nanocomposites as catalyst Polymeric carbon nanocomposites as catalyst


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Nanotubes based polymeric carbon nanocomposites as catalyst Nanosheets based polymeric carbon nanocomposites as catalyst Ionic liquid based nanocomposites as polymeric catalyst Hybrid nanocatalysts as polymeric catalyst Clay-organopolymer based hybrid nanocatalysts as polymeric catalyst Metal or Metal Oxide-Organopolymer based hybrid nanocatalysts as catalyst Silica based nanohybrids as polymeric catalysts Miscellaneous nanohybrids as polymeric catalyst Miscellaneous nanocatalysts as polymeric catalyst CONCLUSIONS AND FUTURE PERSPECTIVES AUTHOR INFORMATION NOTES ACKNOWLEDGMENT REFERENCES


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INTRODUCTION Multifunctionalised

dihydropyrimidinones

(DHPMs)

are

known

for

their

diverse

pharmacological and therapeutic activities such as antiviral, antitumor, antibacterial, and antiinflammatory properties1-4 also as calcium channel blockers,5-7 antihypertensive agents,8-11 , α1a -adrenergic antagonists12-13 and neuropeptide Y (NPY) antagonists,14 and mitotic kinesin inhibitors.15 Several marine alkaloids possessing the dihydropyrimidinone moiety, such as Batzelladine B, are found to have potent HIVgp-120-CD4 inhibitors.16-18 A DHPM derivative Phenobarbital is used as well-known anti-epilectics.19 Biginelli Reaction Pietro Biginelli (1893) first synthesized dihydropyrimidinones (DHPMs) as a simple, one-pot cyclo-condensation of an aldehyde, a β-keto ester, and a urea or thiourea in the presence of catalytic amount of acid.20 Biginelli reaction is one of the most important multicomponent reactions which directly yield potential bioactive scaffolds. The original Biginelli reaction is the three component one pot condensation of benzaldehyde (1), ethyl acetoacetate (2) and urea (3) in presence of strong acid as catalyst to give substituted

3,4-dihydropyrimidin-2(1H)-one(4)

(Scheme 1(A)). The modified Biginelli products, differently substituted DHPMs (8) were synthesized from various aldehydes (5), β-keto esters (6) and urea (7, X=O) or thiourea (7, X=S) in presence of variety of catalysts (Scheme 1 (B)). The Biginelli substrate β-keto ester was replaced in many protocols with active methylene compounds such as β-diketones, cyano-esters etc.


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Ph

CHO

O

O

O Me + H2N

+ EtO

NH2 EtOH, 3

2

1

H+

EtO2C

NH

Me 4

N H

O

(A) The original Biginelli reaction O

O H

R1 5

Me + H2N

+ R2O

O

X

O

6

Catalyst NH2

7

R1

R2O Me

NH N H

X 8

(B) General scheme for synthesis of DHPM derivatives.

Scheme 1. Biginelli reaction Advancements in classical Biginelli reaction In the classical Biginelli conditions, low yields and difficult isolation of the products are the main drawbacks due to strongly acidic conditions, particularly when substituted aromatic or aliphatic aldehydes and thiourea were employed.21- Several of the variations being practiced consistently to enhance the efficiency of Biginelli reaction are different reaction conditions and catalysts. Recently, many approaches including classical conditions were applied with, microwave irradiation,24 and ultrasound irradiation.25 Recently, Sandhu et al. reported a broad perspective over different catalysts employed for Biginelli reaction. The article is enriched with a variety of catalysts claiming enhancements in modified Biginelli reactions, involving Lewis acids such as halides, triflates and other salts of many metals, ionic liquids, biocatalysts, clays, minerals, alumina, silica, cyclodextrins, heteropolyacids, heteropolyanions, organocatalysts, polymers as catalysts etc.26 The polymer supported strategies seem more attractive because of their greener approaches. However, some of these procedures require expensive reagents,


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strongly acidic conditions, long reaction times, high temperatures, stoichiometric amounts of catalysts, or they result in environmental pollution or give unsatisfactory yields. Polymeric support for reagents A study of the literature reveals that some research groups have reported solid phase synthetic protocols for synthesis of bioactive heterocyclic compounds.27This approach involves one of the components of the reaction attached to polymer support and after completion of reaction, detachment of product moiety from the support. It found different polymers (both soluble and insoluble) form supports for reagents, such as Wang's resin, polyphosphate ester (PPE), hydroxymethylpolystyrene resin (PS-OH), polyethylene glycol (PEG), Merrifield’s resin, polystyrene:1% divinylbenzene sodium sulfinate and

fluorous phase protocols were also

demonstrated for Biginelli reactions.28 These kinds of solid supported strategies involve very simple workup processes and have produced diversely substituted DHPMs of high purity without need of chromatographic techniques. The polymeric supports were recycled for many times without losing their efficiency. Scope In this review, it is attempted for the first time to gather all the literature regarding the polymers and polymeric supports to catalysts for improvements in Biginelli reaction. Some researchers have also employed polymers itself as catalysts. Polymeric supports having different composition, nature, size, properties were successfully employed. Polymers of different origin are considered under separate section such as organic polymers, inorganic polymers, polymers of hybrid in nature, biopolymers as biocatalysts, ionic liquids supported on polymers as catalysts etc. In addition, this review also covers nanocatalysts as nanoparticles, nanocomposites,


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nanosheets and nanotubes which functions as nano polymers. The variety of polymers and polymeric supports collectively forms a unique platform for researchers in the field of solid or polymer supported catalytic synthesis of other heterocyclic scaffolds. ORGANIC POLYMERS In this section, all types of polymers which are organic in origin involved in modification of Biginelli reaction are discussed. These organopolymers are classified on the basis of structural composition and considered under separate headings. Organic polymers and copolymers as catalyst Different polymers and copolymers were found to function as catalysts themselves and also in the form of their salts. However, the major contribution of such polymers in the advancements of the Biginelli reaction involves their role as a support for catalysts, either in the form of complexes or functionalization to the polymers. In 2007, Pourjavadi et al. reported poly (2-acrylamido-2-methyl propane sulphonic acid, AMPS) crosslinked with N, N’-methylene bisacrylamide (MBA) copolymer as efficient catalyst for Biginelli reaction (Table 1).29 The catalyst was prepared from 2-acrylamido-2methylpropane sulphonic acid with N,N’-methylene bisacrylamide as a crosslinker. Optimized reaction conditions were mild, involved product isolation by simple filtration, which separates the solid polymer, and concentration of the filtrate to afford products. The polymeric catalyst was reused for three times with negligible loss in activity. Although the methodology claimed to show a greener approach, reaction times were not appreciably reduced and yields of some substituted dihydropyrimidinones were also poor.


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Organic polymers and copolymers as catalyst supports In 2005, Wang et al. employed polymer supported ionic liquid as a catalyst for Biginelli reaction. Room temperature ionic liquids (RTILs) such as 1-butyl-3-methyl-1H-imidazol-3-ium tetrafluoroborate (BMimBF4) or corresponding hexafluorophosphate (BMimPF6) are very expensive and their removal from the reaction medium was found difficult. To overcome this challenge Wang and coworkers immobilized these RTILs on Merrifield’s resin thereby obtaining polystyrene-methylimidazolium (PsMim)-based ionic liquids (Figure 1 (A)) which catalyzed the Biginelli reaction efficiently.30 The catalyst PsMimPF6 was found more effective in acetic acid solvent, which has also successfully reduced the reaction time (Table 1). This group reported five sequential reuses of the recovered catalyst without significant loss of activity. The use of these expensive, polymer supported ionic liquids as catalysts have shown enhancements in yields and noticeable reduction in reaction time. Palaniappan and coworkers (2005) performed along with the Biginelli reaction some other organic transformations using polyaniline–fluoroboric acid–dodecylhydrogensulfate (PANI–HBF4–DHS, Table 1) salt as a catalyst.31 This polymeric salt was directly synthesized via emulsion polymerization where aniline was oxidized to polyaniline salt by benzoyl peroxide in presence of sodium lauryl sulfate and fluoroboric acid. This group has reported typical Biginelli reaction using polymeric salt as catalyst. The recycling of polymeric salt catalyst was not reported. Palaniappan and coworkers in the same year (2006) patented the synthesis of substituted dihydropyrimidinones using different polyaniline salts as catalyst.32A rich and diverse source of contributions in advancement of the Biginelli reaction were reported by the group. They prepared a variety of polyaniline salts such as polyaniline-sulphate, polyanilinehydrochloride, polyaniline-perchlorate, polyaniline-nitrate, polyaniline-phosphate, polyaniline-


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aluminum chloride, polyaniline-ferric chloride, polyaniline-bismuth chloride, polyaniline-ptoulene sulphonate and polyaniline-sulfosalicylate by treating polyaniline base with H2SO4, HCl, HClO4, HNO3, H3PO4, AlCl3, FeCl3, BiCl3, p-toluene sulfonic acid and sulfosalicylic acid respectively.33 They found the catalyst was efficient when used at 5% and 10% by weight with respect to aldehyde in methanol. The attractive feature of mentioned catalysts was that all catalysts were reused for three to four times without loss in activity. The authors claimed environmentally safe disposal of used catalyst; albeit to make environmentally safe disposal of mineral acid catalyst needs expensive treatment. In 2006, Wang and coworkers reported solvent free Biginelli reaction under microwave irradiation using poly (ethylene glycol)-bound sulfonic acid (PEG-SO3H, Table 1) as catalyst.34This demonstrated the role of PEG-SO3H as a catalyst as well as solvent where the isolation of products from medium seems easier Products were obtained in excellent purity without the need of any chromatographic techniques. The effectiveness of this methodology compares improvement in yields and large reduction in reaction time with classical solutionphase reaction. In 2007, Polshettiwar et al. demonstrated polystyrenesulfonic acid (PSSA, Table 1) as a catalyst for synthesis of substituted 3,4-dihydropyrimidin-2(1H)-ones in water as solvent under microwave irradiation.35 The procedure reported used all the components of reaction dissolved in 20% PSSA solution in water (three times the weight of aldehyde). Microwave assistance was found effective to reduce reaction time and improve yields. The researchers claimed an environmentally safe protocol as water used as solvent, but the reusability of PSSA catalyst was not reported.


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In 2008, Wang and coworkers employed polystyrene supported aluminium chloride (PsAlCl3, Table 1) as a heterogeneous catalyst for synthesis of dihydropyrimidinones.36 The PsAlCl3 catalyst shown maximum efficiency in ethanol. Five times reusability of catalyst was also reported with slight loss in catalytic activity. The methodology claims improved modification in Biginelli reaction although the yields are moderate to high in a shorter time. Lei and coworkers synthesized and successfully employed the novel polymer-supported 4-aminoformoyldiphenylammonium triflate (PS-AFDPAT, Figure 1 (B)) catalyst for synthesis of DHPMs via Biginelli reaction in 2009 (Table 1). Ethanol was the preferred solvent affording higher yields in a shorter reaction time. The reported noticeable feature of used catalyst was the efficiency of conversion with insignificant loss in activity after reusability for 10 more cycles. In 2009, Quan et al. reported sulfonic acid bounded polystyrene–poly(ethylene glycol) (PS–PEG-SO3H, Figure 1 (C)) as catalyst for synthesis of DHPMs (Table 1).38 Polystyrenesupported poly(ethylene glycol) prepared from chloromethyl polystyrene and polyethylene glycol (PEG600) was allowed to swell in DCM with addition of chlorosulfonic acid. Further, the resulting mixture was stirred at room temperature for 24 h. Thereafter, the resulting polymer was separated by filtration and washed with DCM, methanol and acetone and dried. Using the PSPEG-SO3H catalyst, the synthesis of DHPMs was achieved. Although six times recyclability of catalyst was reported, which proves the greener approach but, yields were average to good with longer reaction times.


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*

n*

N

X

X = BF4 (PsMimBF4 )

+ N Me

O H N C

H N

. CF3SO3H

X = PF6 (PsMimPF6 )

(A). Polymer supported ionic liquids.

(B). PS-AFDPAT catalyst. O O

O

O 14

OSO3H

O

OMe

PEG400 H N

O

O (C). PS-PEG-SO3H catalyst

NH2 O

(D). PEG.TUD catalyst. *

SO3H *

C S

n* +

Cl N SO3H

n

(F). NSPVPC catalyst.

(E). PVSA catalyst. n

N

SO3H

HSO4 N

SO3H

Cl

N

n OSO3H OH

(G). PSBIL catalyst

(H). (PVPP-SO3H)+Cl catalyst

n

(I). Calixarene sulfonic acid

Figure 1. Polymer supported catalysts


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In 2010, Verma et al. explored firstly the host-guest complex between polyethylene glycol and thiourea dioxide (PEG.TUD, Figure 1 (D)) as organocatalyst for synthesis of 3,4dihydropyrimidinones via a Biginelli condensation (Table 1).39 Poly(ethylene glycol)–thiourea complexes, PEG.TU, were prepared by both co-crystallization method and by a chemical reaction. In the co-crystallization method, PEG400 was dissolved in a methanol solution saturated with thiourea dioxide (TUD) and the resulting solution was stirred until a white precipitate appeared, which was separated by filtration to afford white solid, PEG.TUD. The chemical approach involved the reaction of TUD and MeOPEG400 in a fixed molar ratio (1:2) in dry DMF give a white powdered PEG.TUD. A loading of 10 mol% of catalyst was sufficient to effect the reaction under solvent free conditions. The use of thiourea dioxide alone as a catalyst showed poor catalytic efficiency, indicating the importance of the PEG support in making the reactions faster. Excellent yields, low temperature conditions and recyclability of catalyst without loss in activity were the claimed features of said methodology. In 2011, Quan and coworkers performed the Biginelli reaction using the previously reported PS–PEG-SO3H catalyst (2009) in glycerol as a solvent (Table 1). The use of this solvent enhanced the yields to high with reusability of the catalyst without noticeable loss of catalytic efficiency. Both the solvent and the catalyst system seem eco-friendly, but the method required a higher temperature while the reaction time was not appreciably reduced. In 2012, Ali Rahmatpour's synthesis of DHPMs used polyvinyl sulfonic acid (PVSA, Figure 1 (E) as catalyst (Table 1).41Water was found to be an efficient solvent as well as ethanol under reflux conditions for Biginelli condensation using PVSA catalyst with a reduction in reaction time. The recovered catalyst was activated by standard procedure and reused for five more times with either water or ethanol as the solvent retaining its catalytic activity. This


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methodology involved water as solvent and recyclability of catalyst seems to be environmentally benign and economic with excellent yields of substituted DHPMs. Shi and coworkers (2013) prepared sulfonic acid-functionalized polypropylene fiber (PPF-SO3H, Table 1) and demonstrated it as a catalyst for the Biginelli reaction.42 The catalyst was prepared using a newer developed methodology involving the reaction of PPF with sulfonyl chloride under 250W mercury lamp to a gentle reflux and then stirring at room temperature for (without illumination). Lastly, the fiber was dried overnight to give PPF-SO3H. Ethanol was the preferred solvent for the Biginelli reaction. The recoverability of the PPF was essentially quantitative. Although, the yields with this protocol were moderate to good and reaction time was not significantly reduced. The role of the fibers as a catalytic support added another dimension to the advancements in the Biginelli reaction, as well as other organic transformations involving catalysis. In 2014, Shirini et al. demonstrated a solvent free Biginelli reaction using N-sulfonic acid poly (4-vinylpyridinium) chloride (NSPVPC, Figure 1 (F)) as catalyst (Table 1).43The separated catalyst was reused five times with minimal loss. The NSPVPC catalyzed solvent free protocol seems economic with significant reduction in reaction time and good reusability of catalyst, although it employed high temperature conditions. Siddiqui et al. (2014) reported the use of perchloric acid modified PEG-6000 (PEGHClO4, Table 1) as a biodegradable catalyst for substituted DHPMs under solvent free conditions.44 Terephthaldehyde /isophthalaldehyde were also used to synthesize bis-DHPMs. A typical procedure involved the homogenization of mixture of substituted benzaldehydes, 1,3diketones (cyclic and acyclic), urea and PEG-HClO4 using a mortar and pestle for 1-2 min.


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(Scheme 2). The catalyst remains unaffected after nine cycles. The great reduction in time with excellent yields, solvent free reaction and reusability of catalyst were the advantages of PEGHClO4 catalyst. Comparatively, the methodology was found to be effective and attractive. O

O

O

O

HN

NH

10 HN = Cyclic active methylene compounds

NH O

11

O O

CHO +

3

X 9 X= -CHO

PEG-HClO4

R'

R'

R 12

R

HN

R'

HN

0

70 C

R

NH O

O

O

NH

13

O 14

X

HN NH O

15

Scheme 2. PEG-HClO4 catalyzed modified Biginelli reaction. In 2016, Khiratkar et al. synthesized polymer-supported benzimidazolium based ionic liquid (PSBIL, Figure 1 (G)) as a Bronsted-acidic, heterogenous organocatalyst for the Biginelli reaction (Table 1).45 The catalyst was prepared by reaction of poly(vinylbenzyl chloride) and benzimidazole followed by ring opening of 1,4-butane sultone and acidification with sulphuric acid. Among various polar solvents, ethanol was found effective with the PSBIL catalyst. The authors claim after a simple workup, the catalyst was reusable. The yields of the resulting DHPMs were good to high but the temperature for an efficient conversion was higher compared to other reported methods. With a thermal stability up to 334℃ marks the noticeable significance


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of PSBIL catalyst, which makes it more applicable for organic transformations involving higher temperatures. In 2017, Elhamifar and coworkers prepared and applied polyethylene-supported ionic liquid/iron complex (PEt@Fe/IL, Table 1) as catalyst in synthesis of DHPMs under solvent free conditions.46 Firstly, the ionic liquid methyl-octyl-imidazolium bromide ([MOIM][Br]) was prepared from N-methyl-imidazole and octyl-bromide in toluene. Iron acetate was then added into this ionic liquid with stirring at room temperature to afford the ionic liquid/iron (Fe/IL) complex. The Fe/IL complex then immobilized on polyethylene was achieved via earlier reported coacervation approach. The (Fe/IL) complex was supported on high density polyethylene (HDPE) under reflux (2 h) conditions in xylene. Then the resulting mixture was precipitated into methanol to afford PEt@Fe/IL composite. The homogeneous mixture of Biginelli components with PEt@Fe/IL catalyst was heated, yields were reported high to excellent. The recovered catalyst then reused for seven times more without loss in activity. The complex ([MOIM][Fe(OAc)3Br]) worked as the actual catalyst supported on HDPE. Chegini et al. (2017) demonstrated the use of polyvinylpolypyrrolidone-supported chlorosulfonic acid [(PVPP-SO3H)+Cl− Figure 1 (H)] as a catalyst for the Biginelli condensation (Table 1).47 The catalyst was prepared by dropwise addition of a solution of chlorosulfonic acid in DCM to a suspension of PVPP in DCM, and the mixture stirred at room temperature. The resulting polymer supported catalyst was found stable to 200℃. The catalyst proved its efficiency with reduced reaction times and excellent yields of DHPMs. The general procedure involved stirring the mixture of Biginelli components with (PVPP-SO3H)+Cl− catalyst at 70℃ under solvent free conditions. They also reported, after six cycles the catalyst showed insignificant loss in activity. Easy preparation of catalyst, short reaction time, and excellent


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yields under solvent free conditions with catalyst reusability are valuable improvements in traditional Biginelli reaction. Recently (2017), Patel and coworkers reported polyaniline supported FeCl3 (PANI-FeCl3, Table 1) as an efficient heterogeneous Lewis acid catalyst for Biginelli reaction.48The catalyst was prepared and characterized by usual analytical and spectral techniques. The general procedure used acetonitrile as solvent and the reaction mixture including PANI-FeCl3 catalyst was refluxed. This methodology used fresh catalyst only. Reusability of the catalyst is not reported. Also, the yields of DHPMs were good to high after longer reaction times. Resins as catalyst and supports Different research groups have reported a variety of resins as catalysts or as support for catalysts as advancements in Biginelli condensation. All reported resins are discussed below. Amberlyst Resins In 2001, Dondoni et al. reported the use of ion exchange resin Amberlyst-15 in the synthesis of dihydropyrimidinones (Table 1). They employed polymer-bound lanthanide (III) reagent to exploit the advantages of both lanthanide (III) catalysts and solid support. They prepared Yb(III)-resin from Yb(III) salts supported on Amberlyst-15 resin. Toluene was found to be an acceptable solvent at reflux with the Yb(III) resin catalyst to afford product in average yield after 48H. However, under solvent free conditions, the reaction yield was good. In addition, strongly basic resin Ambersep 900 OH was used to scavenge excess urea and byproducts derived from side condensation reactions. It seems that, the said synthetic protocol


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contributed newer approach for Biginelli reaction, but the yields were not found satisfactory and the reusability of Yb(III) resin resulted in substantial loss in activity.49 In 2009, Chandak and coworkers demonstrated the use Amberlyst-70 as catalyst for synthesis of DHPMs through Biginelli reaction (Table 1).50The reaction mixture containing Biginelli components including Amberlyst-70 catalyst in water was heated. Methodology claimed easy workup, use of green solvent and reusability of catalyst. It found that, the catalyst efficiency was appreciably diminished in subsequent runs. Although the said protocol seems attractive; it uses high temperature for success of the catalyst which limits yields to good. Dowex-50W Resins In 2006, Singh et al. performed synthesis of dihydropyrimidinones using Dowex-50W (ion exchange resin) as the catalyst under solvent free conditions (Table 1).51A typical procedure involved heating of the solvent free reaction mixture with Dowex-50W catalyst. The reusability of the catalyst was not reported. The method seems novel but, it fails to prove economic conversion (yields varies); although it used comparatively high temperature. In 2007, Mukhopadhyay et al. reported Dowex-50W in aqueous medium for Biginelli condensation (Table 1).52The reaction mixture including Dowex-50W in water was heated. The reusability of the catalyst was also demonstrated for three more cycles without loss in activity. Compared to the reported solvent free use of Dowex-50W, this protocol, which used a green solvent (water), surprisingly improved yields while lowering the temperature. However, it is limited to short reaction times. Nafion Resins


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In 2006, Joseph and coworkers developed a heterogeneous catalyst protocol for Biginelli reaction. The ion exchange resin Nafion-NR-50 (Table 1) as catalyst under nitrogen in acetonitrile solvent was employed for synthesis of DHPMs.53 The reaction was complete under reflux after 3h.The catalyst was separated by filtration for reuse without loss of activity. Excellent yields of DHPMs were obtained from the filtrate. This approach has marked another attractive improved modification in the Biginelli reaction though organic solvent was used under reflux condition. In 2007, Lin et al. employed Nafion-H catalyzed synthetic protocol for the Biginelli reaction. Ethanol was found best as solvent under reflux conditions. Reaction time was not specified but, the yields were high to excellent. A usual, simple reaction procedure for heterogeneous catalysis recovery was followed and was recycled several times, but the efficiency and numbers of cycles were not clarified.54The same research groups also reported the role of Nafion-H catalyst in the synthesis of octahydroquinazolinone derivatives using cyclic βdiketones via Biginelli condensation. Yields were good and the Nafion-H was filtered from hot mixture after the reaction. The separated Nafion-H catalyst then activated and dried for reuse.55 In 2010, Wang and coworkers demonstrated a new approach involving the use of NafionH catalyst under ultraviolet irradiation and solvent free conditions (Table 1).56The reaction mixture containing Nafion-H catalyst was irradiated in the water bath of an ultra-sonicator for some time (not specified). The catalyst was simply separated by filtration. Although, the catalyst was reusable but, recyclability was not reported in this work. This method found effective and advantageous over classical Biginelli reaction with mild reaction conditions, excellent yields, easy workup and short reaction times.


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Prakash et al. reported Nafion-gallium (Nafion-Ga) as a catalyst under solvent free conditions for the Biginelli reaction in 2014 (Table 1).57 Nafion-Ga was prepared using metal exchange between powdered Nafion-K (potassium salt of Nafion-H, particle size

Biginelli Reaction - American Chemical Society

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