1.1 Catalysis - INFLIBNET

Chapter 1

Multicomponent reactions catalyzed by Hydrotalcites and Hydroxyapatites 1

1.1 Catalysis

The term ‘catalysis’ originally coined by Berzelius in 1835 and since then the

concept of catalysis has evolved greatly. Catalysis can be defined as ‘the change of

the rate of chemical reactions under the action of certain substances’. A catalyst is

the substance that speeds up the rate of a reaction, by lowering the activation energy,

without being consumed in the reaction (Figure 1.1). They preserve their

composition throughout the chemical reaction and are not wasted in the course of the

catalysis. Furthermore, catalysts can speed up the reaction in a more selective

manner which allows chemical processes to work more efficiently and with less

waste. This makes catalysts of great importance in industrial applications.

Fig. 1.1 Progress of the reaction with catalyst and without catalyst

Apart from accelerating reactions, catalysts have another important property: they

can influence the selectivity of chemical reactions. This means that completely

different products can be obtained from a given starting material by using different

catalyst systems. Industrially, this targeted reaction control is often even more

important than the catalytic activity.

Catalysts can be gases, liquids, or solids. Most industrial catalysts are liquids

or solids, whereby the latter react only via their surface. The importance of catalysis

in the chemical industry is shown by the fact that 75 % of all chemicals are produced

with the aid of catalysts; in newly developed processes, the figure is over 90 %.

Chapter 1


Numerous organic intermediate products, required for the production of plastics,

synthetic fibers, pharmaceuticals, dyes, crop-protection agents, resins, and pigments,

can only be produced by catalytic processes. Most of the processes involved in

crude-oil processing and petrochemistry, such as purification stages, refining, and

chemical transformations, require catalysts. Environmental protection measures such

as automobile exhaust control and purification of off-gases from power stations and

industrial plant would be inconceivable without catalysts.

Catalysts have been successfully used in the chemical industry for more than

100 years, examples being the synthesis of sulfuric acid, the conversion of ammonia

to nitric acid, and catalytic hydrogenation. Later developments include new highly

selective multicomponent oxide and metallic catalysts, zeolites and the introduction

of homogeneous transition metal complexes in the chemical industry. This was

supplemented by new high-performance techniques for probing catalysts and

elucidating the mechanisms of heterogeneous and homogenous catalysis. The brief

historical survey given in Table 1.1 shows just how the closely the development of

catalysis is linked to the history of industrial chemistry.

Table 1.1 History of the catalysis of industrial processes

Catalytic reaction Catalyst Discoverer or company/year

Sulfuric acid (lead-chamber process)

NOx Désormes, Clement, 1806

Chlorine production by HCl oxidation

CuSO4 Deacon, 1867

Sulfuric acid (contact process)

Pt, V2O5 Winkler, 1875; Knietsch,

1888

Nitric acid by NH3 oxidation

Pt/Rh Ostwald, 1906

Fat hardening Ni Normann, 1907

Ammonia synthesis from N2, H2

Fe Mittasch, Haber, Bosch,

1908

Hydrogenation of coal to hydrocarbons

Fe, Mo, Sn Bergius, 1913; Pier, 1927

Oxidation of benzene V2O5 Weiss, Downs, 1920

Chapter 1


Methanol synthesis from CO/H2

ZnO/Cr2O3 Mittasch, 1923

Hydrocarbons from CO/H2 Fe, Co, Ni Fischer, Tropsch, 1925

Oxidation of ethylene Ag Lefort, 1930

Cracking of hydrocarbons Al2O3/SiO2 Houdry, 1937

Olefin metathesis Re, W, Mo Banks, Bailey, 1964

Hydrogenation, isomerization,

hydroformylation Rh-, Ru- complexes Wilkinson, 1964

1.1.1 Classification of Catalyst

The numerous catalysts known today can be classified according to various criteria:

structure, composition, area of application, or state of aggregation. Here we shall

classify the catalysts according to the state of aggregation in which they act. There

are two large groups: heterogeneous catalysts (solid-state catalysts) and

homogeneous catalysts (Fig. 1.2)

Fig. 1.2 Classification of catalysts

Catalysts

Homogeneous

Catalysts

Heterogenized

homogeneous Catalysts

Biocatalysts (Enzymes)

Acid/Base Catalyst

Heterogeneous Catalysts

Bulk Catalysts

Transition

metal Catalyst

Supported catalysts

Chapter 1


Catalytic processes that take place in a uniform gas or liquid phase are

classified as homogeneous catalysis. Homogeneous catalysts are generally well-

defined chemical compounds or coordination complexes, which, together with the

reactants, are molecularly dispersed in the reaction medium. Examples of

homogeneous catalysts include mineral acids and transition metal compounds (e. g.,

rhodium carbonyl complexes in oxo synthesis).

Heterogeneous catalysis takes place between several phases. Generally the

catalyst is a solid, and the reactants are gases or liquids. Examples of heterogeneous

catalysts are Pt/Rh nets for the oxidation of ammonia to nitrous gases (Ostwald

process), supported catalysts such as nickel on kieselguhr for fat hardening, and

amorphous or crystalline aluminosilicates for cracking petroleum fractions. Of

increasing importance are the so-called biocatalysts (enzymes).

Enzymes are protein molecules of colloidal size [e. g., poly(amino acids)].

Some of them act in dissolved form in cells, while others are chemically bound to

cell membranes or on surfaces. Enzymes can be classified somewhere between

molecular homogeneous catalysts and macroscopic heterogeneous catalysts.

Enzymes are the driving force for biological reactions. They exhibit

remarkable activities and selectivities. For example, the enzyme catalase decomposes

hydrogen peroxide 109 times faster than inorganic catalysts. The enzymes are

organic molecules that almost always have a metal as the active center. Often the

only difference to the industrial homogeneous catalysts is that the metal center is

ligated by one or more proteins, resulting in a relatively high molecular mass.

Apart from high selectivity, the major advantage of enzymes is that they

function under mild conditions, generally at room temperature in aqueous solution at

pH values near 7. Their disadvantage is that they are sensitive, unstable molecules

which are destroyed by extreme reaction conditions. They generally function well

only at physiological pH values in very dilute solutions of the substrate.

Table 1.2 shows distinguishing features of homogeneous and heterogeneous

catalysis.

Chapter 1


Table 1.2 Distinguishing features of homogeneous and heterogeneous catalysis

Homogeneous Heterogeneous

Form Soluble metal complexes,

usually mononuclear

Metals, usually supported,

or metal oxides

Active site Well-defined, discrete

molecules

Poorly defined

Phase Same as reactants Different from reactants

Temperature Low (<250˚C) High (250-500˚C)

Activity Moderate High

Selectivity High Low

Diffusion Facile Can be very important

Heat transfer Facile Can be problematic

Product separation Generally problematic Facile

Catalyst recycle Expensive Simple

Catalyst

modification Easy Difficult

Reaction

mechanisms Reasonably well understood Poorly understood

1.1.2 The importance of catalysis

The principal theme in catalysis is the desire to control chemical test reactions and

the secondary theme is to understand the mechanisms of the control. Catalysis is of

crucial importance for the environment and for chemical industry, the number of

catalysts applied in industry is very large and catalysts come in many different forms,

from heterogeneous catalysts in the form of porous solids over homogeneous

catalysts dissolved in the liquid reaction mixture to biological catalysts in the form of

enzymes.

� Environmental impact

Progress towards environmentally responsibility is marked by the reduced

dependence on hazardous chemicals and by-product generation. The key to both is

often provided by catalytic processes as alternatives to stoichiometric processes.

Chapter 1


Heterogeneous catalysis, long established in bulk–chemical processing, is

beginning to make inroads into the fine chemicals industry also. In the past, the need

to reduce costs was the driving power for improvements in process efficiency;

science wasteful processes are also uneconomic. However, recent public concern

about the environment, leading to regulatory activity by governments has accelerated

this tendency.

Two useful measures of the environmental impact of chemical process are the

E-factor defined by the mass of waste to desired product, and the atom utilization,

calculated by dividing the molecular weight of the desired product by the sum of

molecular weights all substances produced in the stoichiometric redox reagents,

represent the major sources of waste production in the form of salts and heavy metals

and high E-factors allow high atom utilization.

Reactions of this type, employed in the fine–chemicals industry particularly,

include Friedel-Crafts alkylation’s mediated by Lewis acids such as aluminium

chloride, reductions with metal hydrides or dissolving metals such as zinc or iron,

and stoichiometric oxidations with dichromate or permanganate, all of which

generate prohibitive amounts of metal–containing wastes.

The elimination of such wastes is the first goal of environmentally friendly

processing; the second is the reduction dependence on the use of hazardous

chemicals such as phosgene, dimethyl sulphate and peracids.

A good example of an environmental benefit occurring from the introduction

of heterogeneously catalysed process is provided by the petrochemical ethylene

(EO), in which the direct oxidation of ethene over silver catalyst replaced the old

chlorohydrins process. The direct process has an atom utilization of 100% and a E-

factor of zero (Zhang et al. 1988).

In petroleum refining, it is catalytic processes that allow refiners to produce

the broad mix of fuels and other products that drive today's economy and there is an

entire body of catalysis, outside the scope of this report, in environmental correction;

the most obvious examples are catalytic converters on automobiles that clean up auto

exhausts. Even our bodies are operated by catalysts, the biological catalysts called

Chapter 1


enzymes, another important area of bio-catalysis that is outside our scope as well

(Thomas et al. 1999).

Catalysts have been used commercially for more than a century, dating from

the Deacon and contact processes, first used in the late 1800ies. Fritz Haber's

ammonia synthesis of 1908 can be considered the process that heralded the birth of

modern industrial catalysis. Catalysis thus has a strong impact on the global economy

and the economy of developing countries, since it is widely applied, in sectors

including polymer production, agricultural production, and the petrochemical,

pharmaceutical and fine chemicals industries. Within the industrialization

programmes of many developing countries, the transfer of the latest know-how and

technologies on catalytic systems and processes and their industrial application and

adoption is recognized as urgent.

In order to optimize an industrial process, special attention should be given to

recycling and reuse of specific fluids or semi-products into the mainstream of the

process line, introduction of innovative clean technologies into the process cycle, use

of new catalysts to give better kinetics of critical process reactions, thereby

improving process and product efficiency as well as environmental quality of the

waste byproduct, development and use of new catalysts in small and medium

enterprises.

Both homogeneous and heterogeneous catalysis may offer advanteges in

particular cases. Heterogeneous catalysts generally offer the advantage of simple

separation and recovery, are employed for both gas and liquid-phase operations, and

lend themselves for continuous reactor operations.

The advantages of heterogeneous catalysis were first appreciated in the

petroleum refining and bulk-chemical industries. However, fine chemicals

operations, although of smaller scale, are more numerous and on the average. Their

E-factors are of the order of 5-50 kg waste per kg product, compared with values of

<1-5 for bulk chemicals and about 0.1 for refinery operations.

The small-scale operations of the fine-chemicals industry make the costs of

developing catalysts, and possibly installing specialized equipment, for specific

reaction slow recoup.

Chapter 1


In general, acid and base are paired concepts; a number of chemical

interactions have been understood in terms of acid-base interaction. Among chemical

reactions which involve acid/base reactions are acid catalysed and base catalyzed

reactions which are initiated by acid-base interactions followed by catalytic cycles.

In contrast, relatively few studies solid basic catalysts. One of the reasons why the

studies of heterogeneous basic catalysts are not as extensive as those of

heterogeneous acidic catalysts seems to be the requirement for severe pretreatment

conditions for active basic catalysts.

Solid basic catalysts are becoming extensively studied in the past years and

the scientific literature on the subject is becoming more and more abundant because

of their necessity for the chemical industry. For more insight to the role of base

catalysis in chemical reaction, the next point presents some examples.

1.1.3 Solid catalysts in chemical reactions

Solid base catalysts exhibit high activities and selectivities for many kinds of

reactions, including some condensation, alkylation, cyclization and isomerization

which are carried out using liquid bases as catalysts in industrial applications. Many

of these applications require stoichiometric amounts of the liquid base for conversion

to the desired product. Replacement of these liquid bases with solid base catalysts

would allow easier separation from the product as well as possible regeneration and

reuse of the catalyst (Prins, 1997).

Examples of commercially applied solid base catalysts are fewer than of solid

acids. However, in this area also, newer solids including basic zeolites and related

aluminosilicate, layered-structure materials such as hydrotalcite and immobilized

organic bases are enabling applications to be extended (Aramendia, 1999).

The next advance in the manufacture of the bulk chemical styrene may come

from processes in development for the side-chain alkylation of toluene with

methanol, employing solid basic catalysts such as Cs-X zeolites. The feed stock costs

are lower than for benzene alkylation, while the fact that methanol is preferentially

Chapter 1


produced from natural gas and from renewable resources, gives this process an

environmental premium (Martin et al. 1994).

Additionally, the use of alkali-exchanged zeolites such as K-Y and Cs-X can

be used as effective base catalysts for the methylation of aniline and

phenylacetonitrile with methanol or dimethyl carbonate. For bulky substrates,

cesium-exchanged mesoporous MCM-41 prove and to be effective mild basic solid

catalyst for Knoevenagel condensation (Martin et al. 1994). Hydrotalcite clays are

built of positively charged brucite layers; upon calcinations they become active as

solid bases useful for reactions such as aldolizstion and Knoevenagel condensation,

exemplified by the reaction of benzaldehyde with ethylcyanoacetate (Figueras,

1998).

1.3.1 Generation of basic sites

At present, several classes of basic catalysts can be distinguished according how they

are synthesized. A first class would contain unmodified oxide solids, i.e. intrinsically

basic oxides, namely alkaline earth oxides like MgO or CaO and Al2O3 or ZrO2 that

have both acid and basic centers. The basic site of these solids is either oxygen or a

basic hydroxyl. A second group of basic solids could be modified oxides (Utiyama et

al. 1978).

γ-Alumina is widely used as catalyst and catalyst supports. Its catalytic

activity is closely related to certain “acid” sites developed when chemisorbed water

is removed from the surface. From the classical Lewis definition, the base strength of

a solid catalyst is determined by its ability to donate an electron pair to an adsorbed

molecule. These sites are believed to be aluminium ions (Lewis acids) exposed at the

surface in small amounts as a result of condensation of surface hydroxyl groups.

Ionic surfaces, unless highly dried, are usually covered with hydroxyl groups

formed by chemisorption of water. Removal of such groups from alumina leaves a

strained surface on which strained oxide linkages have been postulated as active

sites. The surface properties of heterogeneous basic catalysts have been studied by

various methods by which the existence of basic sites has been realized. Different

characterization methods give different information about the surface properties.

Chapter 1


Surfaces of solids are covered either with carbon dioxide, water or oxygen

and therefore show no activity for base catalyzed reactions. Generation of basic sites

requires high temperature pretreatment to remove the adsorbed species (Zechina et

al. 1957).

Figure 1.3 Ions in low coordination on the surface of MgO

Ion pairs of MgO of low coordination numbers exist at corners, edges. Ion pairs with

low coordination numbers are stronger sites than the pairs with high coordination

numbers, see Figure 1.3.

The appearance of basic sites depends on pretreatment temperature, higher

temperature generates stronger basic sites. Among the ion pairs of different

coordination numbers, the ion pair of Mg2+3c O2-

3c is most reactive and adsorbs

carbon dioxide most strongly. To reveal the ion pair Mg2+3c O

2-3c, the highest pre-

treatment temperature is required (Otake, 1995).

It was prepared Mg-Al oxides with Mg/Al molar ratios of 0.5-9.0 were

obtained by thermal decomposition of precipitated hydrotalcite precursors (Otake,

Chapter 1


1995). The effect of composition on structure has been reported by different

characterizations methods like x-ray photo electron spectroscopy, temperature

program desorption of carbon dioxide, BET surface area and x-ray diffraction.

It was found that addition of small amounts of Al to MgO diminished

drastically the density of surface basic sites because of a significant Al surface

enrichment. Formation of surface amorphous alloy structures in samples with low Al

content (5>Mg/Al>1), the basic site density increased because the Al3+ cation within

the MgO lattice created a defect in order to compensate the positive charge generated

and the adjacent oxygen anions became coordinatively unsaturated. In samples

Mg/Al<1, segregation of bulk MgAl2O4 spinels occurred and caused the basic site

density to diminish.

The dehydrogenation of ethanol to acetaldehyde and the aldol condensation

to n-butanol both involved the initial surface ethoxide formation on a lewis acid-

strong base pair. Pure MgO exhibited poor activity because of the predominant

presence of isolated O2- basic centers hindered formation of the ethoxide

intermediate by ethanol dissociative adsorption (Otake, 1995).

1.3.2 Characterization of basic surfaces

There are many methods allowing determination of acidic and basic properties of

solids as described above. Apart from titration and spectroscopic techniques (FTIR,

XPS, NMR) (Choudary et al. 1999) temperature-programmed desorption is often used

(Yashima et al. 1972). The most widely applied molecular probes are ammonia (to

study acidic sites) and carbon dioxide (basic sites). Recently, the application of

catalytic test reactions for characterization of acidic and basic properties of solids has

been intensively developed (Bull et al. 1999).

1.3.2.1 Indicator methods

Typical measurements of basicity have been obtained by using titration of adsorbed

indicators having a wide range of pKa values. Acid–base indicators change their

colours according to the strength of the surface sites of the catalysts. The strengths of

the surface sites are expressed by an acidity function (H_). The H_ function is

defined by the following equation (Clark et al. 1983):

Chapter 1


H_ = pKBH + log [B-]/[BH]

Where [BH] and [B–] are, respectively, the concentration of the indicator BH and its

conjugated base, and pKBH, is the logarithm of the dissociation constant of BH. The

reaction of the indicator BH with the basic site (B_) is:

BH + B_ B- + B_H+

One problem with using adsorbed indicators to evaluate basicity is the

interference of indicator reactions that are not due to acid-base chemistry. In

addition, evidence of reaction is often provided by a color change, which requires the

use of colorless catalyst.

1.3.2.2 Temperature programmed desorption (TPD)

This method is used to measure the number and base strengths of sites found on solid

base catalysts. Since strongly bound probe molecules have high binding energies,

increases temperatures are necessary to desorb these adsorbates. Experiments are

typically performed under identical experimental conditions (heating rates and

sample size) so that a qualitative comparison can be made between samples.

During a TPD experiment, the amount of desorbed molecules is often

monitored by mass spectrometry and the surface interactions are explored with

infrared spectroscopy. Numerous texts describe in detail the TPD method (Hattori,

1995; Prins, 1997).

� Temperature programmed desorption (TPD) of carbon dioxide

The desorption of carbon dioxide is often used in order to determine the strength and

amount of basic centers. The strength of the centers calculated then correlated with

the desorption temperature. At the same time it is found to be difficult because of the

large amount of the received area peaks, quantitative results. Often qualitative

measurements are carried out for different experiments under same conditions. TPD

of adsorbed carbon dioxide has been widely used to probe basic materials.

For example, rubidium–modified supports have been investigated using

stepwise TPD of CO2. The addition of Rb species to supports like MgO, Al2O3 TiO2

and SiO2, via the decomposition of supported rubidium acetate, increases the surface

Chapter 1


density of adsorbed CO2 over that pure support. The high desorption temperatures

required to liberate CO2 from RbO/MgO indicated the formation of very strong basic

sites. Carbon dioxide temperature programmed desorption has also been used to

measure the base strengths of various alkali metals-containing (exchanged and

occluded) zeolites (Tsuji et al. 1992). TPD plots of carbon dioxide desorbed from

alkaline earth oxides are compared in Figure 1.4.

Figure 1.4 TPD plots of carbon dioxide desorbed from the alkaline earth oxide

� Temperature programmed desorption (TPD) of hydrogen

This method gives information about the coordination state of the surface ion pairs

when combined with other methods such as UV absorption and luminescence

spectroscopy. Hydrogen is heterolytically dissociated on the surface of MgO to form

H+ and H- which are adsorbed on the surface O²- and Mg²+ ions (Ito et al. 1983). The

adsorption sites on MgO are pretreated at different temperatures, a heterolytical

dissociation of hydrogen on the MgO surface can be verified by IR spectroscopies

(Ito et al. 1983).

� Temperature programmed desorption of Pyrrole

Pyrrole adsorption has been found to be useful for probing the basicity of zeolites.

An increase in solid base strength has been correlated to a shift in the NH vibration

Chapter 1


frequency to lower wavenumbers in the IR spectrum for numerous alkali-exchanged

zeolites (Lavalley, 1996) and for various metal oxides (Murphy et al. 1996).

When the O2- species is highly basic, the surface OH species are unperturbed

and the H atom of the pyrrole molecule is localized near the basic oxygen,

undergoing dissociative chemisorption. When the O2- species are less basic, the

surface oxygen forms an NH-O bridge with pyrrole.

Complexities in the IR spectrum result from interaction with surface hydroxy

and pyrrole since hydroxy species are as both a basic surface species and as product

formed from pyrrole dissociation (Auroux et al. 1990).

1.3.2.3 Spectroscopic methods

� UV absorption and luminescence spectroscopies

UV absorption and luminescence spectroscopies give information about the

coordination states of the surface atoms. High surface area MgO absorbs UV light

and emits luminescence, which is not observed with MgO single crystal. Nelson and

Hale first observed the absorption at 5.7 eV, which is lower than the band gap (8.7

eV, 163 nm) for bulk MgO at 3 eV (Nelson et al. 1958).

Tench and Pott observed photoluminescence. The UV absorption corresponds

to the following electron transfer process involving surface ion pairs (Zechina et al.

1957).

Mg2++ O2- + hν Mg+O-

Absorption bands were observed at 230 nm and 274 nm, which are considerably

lower in energy than the band at 163 nm for bulk ion pair. The bands at 230 nm and

274 nm are assigned to be due to the surface O²- ion of coordination numbers 4 and 3

respectively.

Luminescence corresponds to the reverse process of UV absorption, and the

shape of the luminescence spectrum varies with the excitation light frequency and

with absorption of molecules. Emission sites and excitation sites are not necessarily

the same. Exactions move on the surface and emit at the ion pair of low coordination

Chapter 1


numbers where emission of efficiency is high. Ion pairs of low coordination numbers

responsible for UV absorption and luminescence exist at corners edges.

The surface model for MgO shown in figure 1.1 was proposed on the basis of

UV absorption and luminescence spectrum excited by the 274 nm light and was it

much more severely influenced by hydrogen adsorption than that excited by the 230

nm light. Hydrogen molecules interact more strongly with the ion pairs of

coordination number 3 than with those of coordination number 4 are heterolytically

dissociated on these sites.

The UV absorption and luminescence spectroscopes give us useful information

about the coordination state, but it is difficult to quantify the sites of a certain

coordination state (Figueras et al. 1998).

� IR spectroscopy

CO2 interact strongly interaction with the basic centers of a surface. Three species of

adsorbed CO2 shown as Figure 1.5, correspond with three different types of surface

basic sites:

Figure 1.5 IR bands of adsorbed CO2 surface species

At the formation of the bidentate carbonates, also a metal ion is involved. Three

species of adsorbed CO2, which are shown in figure 3, were detected on samples of

MgO and Al2O3. Apparently reflecting three different types of surface basic sites.

Unidentate and bidentate carbonate formation requires surface oxygen atoms.

Unidenate carbonate exhibits symmetric O-C-O stretching at 1360–1400 cm-1

asymmetric O-C-O stretching at 1510-1560 cm-1. Bidentate carbonate shows

symmetric O–C-O stretching at 1320 – 1340 cm-1 and asymmetric O-C-O stretching

Chapter 1


at 1610-1630 cm-1. Bicarbonate species formation involves surface hydroxyl groups

showing C-OH bending mode at 1220 cm-1 as well as symmetric and asymmetric O-

C-O stretching modes at 1480 cm-1 and 1650 cm-1, respectively (Prins, 1997).

The oxygen exchange between CO2 and MgO surface basic sites suggest an

important aspect of the nature of surface basic sites. The basic sites are not fixed on

the surface but are able to move over the surface when carbon dioxide is adsorbed

and desorbed. The position of the basic site (surface O atom) changes as CO2

migrates over the basic site. In addition, it became clear that not only O2- basic sites

but also adjacent Mg2+ sites participate in CO2 adsorption. Therefore, it is reasonable

to consider that the metal cations adjacent to the basic site participate in the base-

catalyzed reactions (Figueras et al. 1998; Utiyama et al. 1978).

Chapter 1


1.2 Multicomponent reactions

Multicomponent reactions (MCRs) are defined as reactions that occur in one reaction

vessel and involve more than two starting reagents that form a single product which

contains the essential parts of the starting materials (Domling, 2006; Hulme et al.

2003).

Organic-chemical synthesis performed through one-pot, or multicomponent

reactions (Fogg et al. 2004, Poli et al. 2002) have become a significant area of

research in organic chemistry (Malacria, 1996; Tietze, 1996; Climent et al. 2011) since

such processes improve atom economy. The one-pot transformations can be carried

out through multi-step sequential processes where the consecutive steps take place

under the same reaction conditions or, when this is not possible, they can be

performed in two or more stages under different reaction conditions, with the correct

addition sequence of reactants. There are cases however, in where the desired

product can be prepared in a one-pot mode throughout a multicomponent reaction.

An ideal multicomponent reaction involves the simultaneous addition of

reactants, reagents and catalyst at the beginning of the reaction and requires that all

reactants couple in an exclusive ordered mode under the same reaction conditions.

The success of multi-step sequential or multicomponent one-pot transformations

requires a balance of equilibria and a suitable sequence of reversible and irreversible

steps. Thus, in the case of MCRs three types of reactions are known:

(a) Type I MCRs in which there is an equilibrium between reactants, intermediates

and final products

(b) Type II MCRs in where an equilibrium exists between reactants and

intermediates with the final product being irreversibly formed

(c) Type III MCRs which involve a sequence of practically irreversible steps that

proceed from the reactants to the products. Type III MCRs are usual in biochemical

transformations, but rarely occur in preparative chemistry.

MCRs have been known for over 150 years and it is generally considered that

this chemistry began in 1850 when Strecker reported the general formation of a-

aminocyanides from ammonia, carbonyl compounds and hydrogen cyanide. Since

then, many multicomponent reactions have been developed. Some of the first

Chapter 1


examples are the Hantzsch dihydropyridine synthesis and the Biginelli reaction

(Scheme 1.1). The first isocyanide-based 3CRs was introduced by Passerini in 1921,

while in 1959 Ugi introduced the four component reaction of the isocyanides (Ugi et

al. 1959) which involves the one-pot reaction of amines, carbonyl compounds, acid

and isocyanides. The Ugi reaction has been the most extensively studied and applied

MCR in the drug discovery process.

Scheme 1.1 (a) Biginelli reaction, (b) Hantzsch synthesis and (c) Ugi deBoc/cyclize

methodology

One key aspect of multicomponent reactions is that they are an important

source of molecular diversity (Eilbracht, 1999). For instance, a three component

coupling reaction will provide 1000 compounds when 10 variants of each component

are employed. This aspect together with its inherent simple experimental procedures

and its one-pot character, make MCRs highly suitable for automated synthesis. They

are powerful tools in modern drug discovery processes allowing rapid, automated

Chapter 1


and high throughput generation of organic compounds (Weber, 2002). Additionally,

the one pot character delivers fewer by-products compared to classical stepwise

synthetic routes, with lower costs, time and energy.

1.2.1 Importance of heterogeneous catalysts in MCR

The simplest approximation to heterogeneous catalysis starting from

homogeneous mineral and organic acids has been to support them on porous solids.

For instance, perchloric, sulphuric and phosphoric acids are normally supported on

silica either by simple pore filling and/or by interacting with the surface of the solid.

In the case of the sulfonic acids a heterogenization procedure involves the

synthesis of organic polymers bearing sulphonic groups. In this case organic resins

can be excellent catalysts, especially when their pore structure is adapted to the

nature and dimensions of reactants (Guyot, 1998). Inorganic solid acids can be

prepared with acidity that ranges from weak to strong. One type of inorganic solid

acid is the family of silicates. In high surface area silica, the silicon atoms are

tetrahedrally coordinated and the system is charge neutral (Fig. 1.6 a).

However the silica nanoparticles terminate at the surface with silanol groups

(Fig. 1.6 b). In this silanol group the density of positive charge on the hydrogen of

the hydroxyl group is very small and it can be considered as a very weak Brønsted

acid site. Nevertheless they could be used for acid catalyzed reactions that require

weak acidity, provided that the silica has a relatively high surface area. With this

type of catalyst the reactants become activated by surface adsorption, being the heat

of adsorption the additive effect of the small van der Waals and hydrogen bridging

type of interactions.

Larger O–H polarizations are achieved when an isomorphic substitution of Al

by Si occurs. In this case, the tetrahedrally coordinated Al generates a negative

charge that is compensated by the positive charge associated with the hydrogen of

the bridging hydroxyl groups (Fig. 1.6 c).

Chapter 1


Fig. 1.6 Structure of silicates

These Brønsted acid sites are clearly stronger than the silanol groups and they exist

in well prepared amorphous and long range structured silica aluminas and in

crystalline aluminosilicates (Corma, 1995). When the T–O–T’ bond in

aluminosilicates is not constrained, as it occurs in amorphous silica alumina, the

tendency to release the proton and to relax the structure is lower and consequently

the Brønsted acidity is mild.

However, in the case of crystalline aluminosilicates such as zeolites the

bridging T–O–T’ bond is constrained and the Brønsted acidity of these materials is

higher than in amorphous silica alumina. If one takes into account that it is possible

to synthesize zeolites with different Al contents and with pores within a wide range

of diameters (Jiang et al. 2010), it is not surprising that zeolites have found and still

find a large number of applications as solid acid catalysts. Their applications can be

even enlarged through the synthesis of acid zeolites with pores of different

dimensions within the same structure.

If one takes into account that other metal atoms, such as Ti, Sn, Fe and Cr

with catalytic activity for oxidations, can be incorporated in the structure of the

crystalline microporous silicates or aluminosilicates (Boronat et al. 2007) enlarging

the reactivity of the zeolites and allowing the preparation of bifunctional acid-

oxidations catalysts. When metal nanoparticles are formed on the internal and/or

external surface of acid zeolites, bifunctional hydrogenation/ dehydrogenation solid

Chapter 1


acid catalysts are obtained (Chupin et al. 2001; Silva et al. 2000) allowing zeolites to

catalyze multistep reactions (Iosif et al. 2004).

There are reactions that require sites with an acid strength stronger than that

of zeolites. Then, solid catalysts containing sulfonic groups can be used. For

instance, acidic resins with sulfonic acid groups are strong solid acid catalysts that

can be useful for acid catalysis, provided that the reaction temperature does not

surpass their thermal stability limit (Jermy et al. 2005). Along this line, Nafion is a

strong solid acid catalyst but its surface area is too low. To avoid this limitation,

Harmer et al. have shown that it is possible to partially depolymerize Nafion and to

disperse it in silica (Harmer et al. 1996; Harmer et al. 2000). The resultant high

surface solid catalysts can be used in a relatively larger number of acid catalyzed

reactions (Wabnitz et al. 2003; Beltrame et al. 2003).

Nevertheless, the acidity of this hybrid material is somewhat lower than

Nafion, owing to the interaction of sulfonic groups with the silanols of the silica

(Alvaro et al. 2005; Botella et al. 1999). In any case it should be considered that

polymer derived catalysts may be difficult to regenerate if poisoned by deposition of

organic compounds. Indeed, regeneration by calcination with air will be limited

because of thermal stability, and washing out the adsorbed products with solvents

cannot always restore the initial activity.

Looking for strong acid catalysts, heteropolyacids such as H3PW12O40

(H3PW) are able to catalyze at low temperatures a wide range of homogeneous

catalytic processes (Okuhara et al. 1996). Heteropolyacids can be heterogeneized by

either supporting them on a high surface area carrier such as silica or by forming

their cesium or potassium salts (Cs2.5H0.5PW or K2.5H0.5PW) that are solids with

micro and mesoporosity and are insoluble for organic reactions (Izumi et al. 1995).

Other solid acids such as metal organic frameworks bearing sulfonic groups

or metal Lewis acids (Corma et al. 2010), sulfonated zirconia (White et al. 1995) and

metal phosphates have also been used as catalysts (Campelo et al. 1986). With

respect to solid bases, basic resins, amines and alkyl ammonium hydroxides grafted

on silicas, or amines bearing part of MOF structures, KF on Al2O3, alkaline metal

oxides on alumina and zeolites, zeolites exchanged with alkaline cations, alkaline

earth oxides and anionic clays such as hydrotalcites and their corresponding mixed

Chapter 1


oxides are useful catalysts and their basic properties and catalytic activity have been

very well described in a series of reviews (Ono et al. 1997; Gascon et al. 2009;

Weitkamp et al. 2001).

1.2.2 Multicomponent reactions catalyzed by solid catalysts

1) Synthesis of propargylamines

The Mannich reaction is a classic example of a three component condensation (A3

coupling). In general, an aldehyde, an amine and an active hydrogen compound such

as an enolizable ketone or terminal alkyne, react affording the corresponding β-

aminoketone or β-aminoalkyne (propargylamine) (Scheme 1.2).

Propargylamines are important synthetic intermediates for potential

therapeutic agents and polyfunctional amino derivatives (Matyus et al. 2004).

Traditionally these compounds have been synthesized by nucleophilic attack of

lithium acetylides or Grignard reagents to imines or their derivatives. However these

reagents must be used in stoichiometric amounts, are highly moisture sensitive, and

sensitive functionalities such as esters are not tolerated. Therefore, the most

convenient synthetic method for preparing propargylamines has been the Mannich

one-pot three component coupling reaction of an aldehyde, a secondary amine and a

terminal alkyne.

Scheme 1.2 Mannich type reactions

Chapter 1


The reactions are usually performed in polar solvents (mostly dioxane) and in the

presence of a catalytic amount of a copper salt [CuCl, Cu(OAc)2] which increases the

nucleophilicity of the acetylenic substrate towards the Mannich reaction. Mechanistic

studies indicate that the reaction involves the formation of an iminium intermediate

from the starting aldehyde and amine. The C–H bond of the alkyne is activated by

the metal to form a metal acetylide intermediate which subsequently reacts with the

iminium ion leading to the corresponding propargylamine (Scheme 1.3).

Scheme 1.3 Plausible mechanism

A variety of transition metals such as AgI salts (Wei et al. 2003), AuI/AuIII

salts (Wei et al. 2004), AuIII salen complexes (Lo et al. 2006), CuI salts

(Gommermann et al. 2006), Ir complexes (Sakaguchi et al. 2004), InCl3 (Zhang et al.

2009), Hg2Cl2 (Li et al. 2005) and Cu/RuII bimetallic system (Li et al. 2002) have

been employed as catalysts under homogeneous conditions. In addition, alternative

energy sources like microwave (Shi et al. 2004) and ultrasonic (Sreedhar et al. 2005)

radiations have been used in the presence of CuI salts.

Considering that chiral propargylamines are widely present in many

important bioactive compounds, enantioselective synthesis of propargylamines

throughout this protocol have been recently developed using chiral Cu(I) complexes

(Bisai et al. 2006). However, operating under homogenous media two main

drawbacks must be considered: the difficulty to recover and reuse the catalyst and the

possible absorption of some of the metal catalyst on the final product (fine chemical).

In order to achieve the recyclability of transitionmetal catalysts, gold, silver

and copper salts in ionic liquids, [Bmim]PF6 (Li et al. 2004) as well as heterogeneous

catalysts have been used to obtain propargylamines. Thus, different metal exchanged

hydroxyapatites (metal–HAP) are able to catalyze the condensation of benzaldehyde,

Chapter 1


piperidine and phenylacetylene in acetonitrile under reflux temperature (Choudary et

al. 2004). The results showed that the order of efficiency was Cu–HAP, Cu(OAc)2,

Ru–HAP, Fe–HAP achieving yields of the corresponding propargylamine of 85%,

80%, 60%, and 25% respectively.

A variety of structurally different aldehydes, amines and acetylenes in the

presence of Cu–HAP were converted into the corresponding propargylamines with

55–92% yield. Cu–HAP was reused several times showing consistent activity even

after the fourth cycle.

Silica gel anchored copper chloride has been described by Sreedhar and co-

workers as an efficient catalyst for the synthesis of propargylamines via C–H

activation (Sreedhar et al. 2007). Both aromatic and aliphatic aldehydes and amines

and phenylacetylene have been used to generate a diverse range of acetylenic amines

in good to moderate yields (52–98%) using water as a solvent and without any

organic solvent or co-catalyst. A stable and efficient catalyst for the three component

coupling Mannich reaction of aldehydes, amines and alkynes was prepared by Li et

al. by immobilizing Cu(I) on organic–inorganic hybrid materials (Li et al. 2007).

Thus, a silica-CHDA-CuI catalyst was prepared from benzylchloride

functionalized silica gel which was subsequently reacted with 1, 2-

diaminecyclohexane. This organic–inorganic hybrid material was reacted with

couprous iodide to generate a silica-CHDA-CuI catalyst with 1.6 wt% of Cu.

Reactions performed in the absence of solvent afforded the corresponding

propargylamines in excellent yields (82–96%). No catalyst leaching was observed in

the reaction media, and the catalyst remained active through at least 15 consecutive

runs. Others immobilized metals such as Ag(I) and Au(I) exhibited lower activity

than Cu catalysts while silica supported Pd(II) failed in this reaction.

Recently Wang et al. have reported a novel silica-immobilized N-heterocyclic

carbene metal complex (Si–NHC–CuI) as an efficient and reusable catalyst for the

synthesis of propargylamines (Wang et al. 2008). Different metal-supported zeolites

such as Cu-modified zeolites (H–USY, HY, H–Beta, Mordenite and ZSM-5), have

been successfully used for the synthesis of propargylamines (Patil et al. 2008).

Chapter 1


Very recently Namitharan et al. have reported that Ni exchanged Y zeolite

(Ni–Y) exhibits excellent activity for the A3 coupling of cyclohexanecarbaldehyde,

morpholine and phenylacetylene giving the corresponding propargylamine in 97%

yield under solvent free conditions at 80 oC (Namitharan et al. 2010). No leaching of

metal ions provides strong support for the heterogeneous nature of the catalyst.

While homogeneous gold complexes were reasonable active catalysts for the

three component reaction, it has now been shown that gold supported catalysts can

also catalyze the A3 coupling for preparation of propargylamines with excellent

success (Zhang et al. 2008). For instance, Zhang et al. reported the same reaction

using Au nanoparticles supported on nanocrystalline ZrO2 and CeO2 for the Mannich

reaction (Table 1.3).

Table 1.3 MCR of benzaldehyde, piperidine and phenyl acetylene with supported

gold catalyst[a]

Entry Catalyst Gold

conc. (mol %)

% Yield of

Propargylamine TON

1 Au/SiO2 0.013 - -

2 Au/C 0.081 Nd 161

3 Au/TiO2 0.075 Nd 464

4 Au/Fe2O3 0.247 Nd 162

5 Au/ZrO2 0.142 93 668

6 Au/CeO2 0.127 99 788

[a] Reactions were performed with benzaldehyde (1 mmol), piperidine (1.2

mmol) and phenyl acetylene (1.3 mmol) in 1 mL water, 6 h, 100 oC.

Chapter 1


Scheme 1.4 Plausible mechanism of gold supported on CeO2 or ZrO2

Table 1.4 A3 coupling of benzaldehyde, piperidine and phenyl acetylene with

reusable catalysts.

Catalyst Reaction conditions Yield (%) References

CuI–(bmim)PF6

(bmim)PF6, 120 oC, 2 h 85 Chem. Commun., 2005, 1315.

Cu-np CH3CN, 100 oC, 6 h 94 Synlett, 2007, 1581

Cu–HAP CH3CN, Reflux, 6 h 85 Tet. Lett., 2004, 45, 7319

Silica gel

CuCl H2O, 100 oC, 10 h 86 Tet. Lett., 2007, 48, 7882.

Si-NHC–Cu rt, 24 h 79 Eur J. Org. Chem, 2008, 2255

Si-CHDA–Cu

80 oC, 12 h 92 Eur. J. Org. Chem, 2008, 2255

USY–Cu 80 oC, 15 h 95 Eur. J. Org. Chem., 2008, 4440

Ag-TPA CH3CN, 80 oC, 6 h 92 Tet. Lett., 2006, 47, 7563

Au–np CH3CN, 80 oC, 5 h 94 Green Chem., 2007, 9, 742

Zn-dust CH3CN, Reflux, 9 h 90 Chem Rev, 2006, 106, 2875

Au/CeO2 H2O, 100 oC, 6 h 99 Angew Chem. Int. Ed. 2008, 47, 4358

LDH–AuCl4 THF, reflux, 5 h 92 Synlett, 2005, 2329

Fe3O4 np THF, 80 oC, 24 h 45 Journal of Catalysis, 2009, 265, 155

Chapter 1


Table 1.4 summarizes the results obtained in the MCR of benzaldehyde, piperidine,

and phenylacetylene using different reusable catalysts.

2) Synthesis of indole derivatives

Functionalized indoles are biologically active compounds (Rivara et al. 2005)

that can be obtained using a variety of approaches (Humphrey et al. 2006). Recently,

following the Mannich approach functionalized indols have been obtained by three

component coupling and cyclization of N-tosyl protected ethynylaniline,

paraformaldehyde and piperidine in the presence of Au/ZrO2 (Zhang et al. 2008)

(Scheme 1.5). It was found that only a fraction of the total gold species i.e. only the

Au(III) are active for this reaction.

Scheme 1.5 Three component coupling and cyclization of an aldehyde, amine, and

N-protected ethynylaniline.

More recently the same authors (Zhang et al. 2009) have prepared metal

organic frameworks (MOF-Si–Au) containing a Au(III) Schiff base complex lining

the pore walls (Table 1.5). This material was obtained by reacting the NH2 groups of

MOF with salicylaldehyde to form the corresponding imine. The final step consists

of reacting a gold precursor (NaAuCl4) with the imine.

Chapter 1


Table 1.5 Three component coupling and cyclization of an aldehyde, amine and N-

protected ethynylaniline with gold supported catalysts.

Catalyst R1-CHO R2R3NH Yield (%)

Au/ZrO2

H piperidine 95

Heptyl Piperidine 97

Cyclohexyl piperidine 75

H pyrrolidine 87

H morpholine 70

H diethylamine 90

MOF-Si-Au

H piperidine 90

Heptyl piperidine 95

Cyclohexyl piperidine 80

3) Synthesis of Substituted benzo[b]furans

Benzo[b]furan derivatives are compounds of relevance because of their natural

occurrence associated with their biological properties (Chang et al. 2004).

Recently, following the Mannich protocol, Kabalka et al. have reported the

synthesis of a variety of propargylamines in good yields from different alkynes,

primary or secondary amines and paraformaldehyde using cuprous iodide doped

alumina as the catalyst under microwave irradiation (Kabalka et al. 2006). The

reaction was extended to the synthesis of 2-substituted benzo[b]furan derivatives

when ethynylphenol was condensed with secondary amines (such as piperidine,

morpholine, 1-phenylpiperazine etc.) and paraformaldehyde. In this case the

Mannich adduct resulting from the A3 coupling undergoes a subsequent cyclization

into the benzofuran ring (Scheme 1.6). The reaction is highly efficient and moderated

Chapter 1


to good yields of 2-substituted benzo[b]furans (52–70%) were obtained in a short

reaction time, but high amounts of catalyst were required.

Scheme 1.6 Synthesis of substituted benzo[b]furans through a MC Mannich reaction

followed by cyclization

4) Synthesis of β -aminocarbonyl compounds

The MCR between an aldehyde, amine and ketones using Lewis (Prukala, 2004) or

Brønsted acids (Sahoo et al. 2006) and Lewis bases (Takahashi et al. 2004) as

catalysts produces β-aminocarbonyl compounds (Scheme 1.7). β-Aminocarbonyl

compounds are important building blocks for the synthesis of biologically active

nitrogencontaining compounds such as β-amino alcohols, β-amino acids and β-

lactams and pharmaceuticals (Kleinmann, 1991).

Mechanistically the reaction proceeds typically via imine formation through

the condensation of aldehyde and amine followed by the attack of the enol form of

ketone on imine to afford the desired product.

Scheme 1.7 Synthesis of β-aminocarbonyl compounds

Chapter 1


Recently, the synthesis of β-amino ketones by a three component Mannich reaction

in liquid phase under solvent free and at room temperature, have been carried out

using tungstated zirconia (WOx-ZrO2) (Reddy et al. 2008). WOx from ammonium

metatungstate was incorporated into hydrous zirconia and calcined at 923 K to give a

solid, which exhibits strong acidity. Different aromatic aldehydes, anilines and

cyclohexanone give the corresponding β-amino ketones in good yields (66–90%) as a

mixture of syn and anti-stereoisomers (Scheme 1.8).

Also, the sulfated ceria-zirconia (SO42-/CexZr1-xO2) reported by Reddy et al.

was an efficient catalyst for the synthesis of β-amino ketones via a Mannich reaction

(Reddy et al. 2006). The reaction between benzaldehyde, aniline and cyclohexanone

proceeded smoothly to afford 82% of 2-[1-phenyl-1-N-phenylamino]

methylcyclohexanone, with an anti/syn ratio of 18:82. The catalyst could be recycled

and no appreciable change in activity was observed for 2–3 runs.

Scheme 1.8 Synthesis of β-aminocarbonyl compounds

Recyclable Cu nanoparticles for the one-pot reaction to obtain β-amino

ketones have been proposed by Kidwai and coworkers (Kidwai et al. 2009). The

authors found that Cu-np (particle diameter of about 20 nm), was the most active

catalyst.

5) Synthesis of dihydropyrimidinones

The synthesis of functionalized dihydropyrimidinones (DHPM) represents an

excellent example of the utility of one-pot multiple component condensation

reactions.

Aryl substituted 3,4-dihydropyrimidinones are important heterocyclic

compounds in organic synthesis and medicinal chemistry due to their therapeutic and

Chapter 1


pharmacological properties. The DHPM and their derivatives exhibit a broad

spectrum of biological effects such as antitumor, antiviral, antibacterial and anti-

inflammatory activities and antioxidative properties (Ashok et al. 2007).

The simplest method for synthesising 3,4-dihydropyrimidin-2-(1H)-one was

reported first by Biginelli and involves a three component one-pot cyclocondensation

reaction of an aldehyde, an open chain β-ketoester and urea or thiourea in presence of

acid catalysts such as hydrochloric acid in ethanol at reflux temperature (Kappe,

1993) (Scheme 1.9).

Scheme 1.9 Synthesis of dihydropyrimidinones

Many synthetic methods for preparing DHPM based on the Biginelli reaction

have been reported which include classical conditions and microwave and ultrasound

irradiation in the presence of Brønsted and Lewis acids as catalysts (Lu et al. 2000).

In the last years, replacement of conventional toxic and polluting Brønsted

and Lewis acid catalysts by eco-friendly reusable solid acid heterogeneous catalysts,

has achieved considerable importance in the synthesis of 3,4-dihydropyrimidinones.

Thus, a wide variety of solid acid catalysts including supported Brønsted and Lewis

acids, heteropolyacids, zeolites and metal complexes have been reported in the

literature for performing the Biginelli reaction with variable success.

Table 1.6 summarizes results corresponding to the Biginelli reaction between

benzaldehyde, ethyl acetoacetate and urea to synthesize 5-(ethoxycarbonyl)-6-

methyl-4-phenyl-3,4-dihydropyridin-2(1H)-one over different heterogeneous

catalysts using both conventional heating or microwaves.

Chapter 1


Table 1.6 Comparison of different catalyst used in the Biginelli reaction for the

synthesis of 5-(ethoxycarbonyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(H)-one

Catalyst Reaction conditions Yield (%) References

I2–Al2O3 MW, 0.02 h 90 Tet. Lett., 2005, 46,1159

SiO2–NaHSO4 CH3CN, Reflux, 1.5 h 93 J. Mol. Catal.A: Chem., 2004,

221, 137

Alum–SiO2 80 oC, 4 h 92 Appl. Catal., A, 2006, 300, 85

Ferrihydrite in a silica

aerogel EtOH, Reflux, 84 h 65 Tetrahedron, 2003, 59, 1553.

SSA EtOH, Reflux, 6 h 91 Tet. Lett., 2003, 44, 2889

FeCl3–SiMCM MW, 0.08 h 89 Catal. Commun., 2003, 4, 449.

FeCl3–Nanopore Silica MW, 0.025 h 55 J. Ind. Eng. Chem., 2008, 14,

401

Montmorillonite 130 oC, 48 h 82 Tet. Lett., 1999, 40, 3465

ZrO2–pillared clay MW, 0.08 h 92 Catal. Commun., 2006, 7, 571

Nafion CH3CN, Reflux, 3 h 96 J. Mol. Catal. A: Chem.,

2006,247, 99

Amberlyst-15 CH3CN, Reflux, 5.5 h 85 J. Mol. Catal.A: Chem.,

2006,247, 99

Ag3PW12O40 H2O, 80 oC, 4 h 92 Eur. J. Org. Chem., 2004, 552

(PVP)-Cu complex MeOH, Reflux, 24 h 70 Catal. Commun., 2004, 5, 511

Scolecite CH3CN, Reflux, 0.5 h 83 Catal. Lett., 2008, 125, 57

ZrO2/SO42- MW, 0.5 h 98 Lett. Org. Chem., 2006, 3, 484

Heulandite AcOH, 100 oC, 5 h 75 J. Mol. Catal. A Chem, 2005,

236, 216

HY Toluene, Reflux, 12 h 21 Green Chem., 2001, 3, 305

HZSM-5 Toluene, Reflux, 12 h 80 Green Chem., 2001, 3, 305

Chapter 1


Ersorb-4 EtOH, Reflux, 8 h 93 Synth. Comm., 2006, 129

Co(II) phthalocyanine CH3CN, Reflux, 1 h 98 J. Mol. Catal., 2007, 268, 134

TS-1 50 oC, 0.16 h 98 Beilstein JOC, 2009, 5.

HBF4–SiO2 EtOH, rt, 2 h 94 Chin. J. Chem., 2010, 28, 388

6) Synthesis of tetrahydroquinoline derivatives

Tetrahydroquinolines are an important class of natural product and exhibit diverse

biological properties such as antiallergic, antiinflammatory, estrogenic and

psychotropic activity (Yamada et al. 1992; Carling et al. 1993). The classical method

for the synthesis of tetrahydroquinolines involves the aza Diels–Alder reaction

between N-aryl-imines and nucleophilic olefins in the presence of Lewis acids, such

as FeCl3 in Et2O/t-BuOH, BF3.Et2O, AlCl3/Et3N (Loh et al. 1999).

Scheme 1.10 Synthesis of quinolone derivatives through a three component reaction

Sartori et al. have reported the synthesis of cyclopentatetrahydroquinoline

derivatives by one pot three component reactions from aromatic aldehydes, aromatic

amines, and cyclopentadiene in the presence of acid clays as catalysts (Scheme 1.10)

(Sartori et al. 2001). Reactions performed in aqueous or polar solvents at 40 oC

afforded the corresponding cyclopentatetrahydroquinoline derivatives in good yields

(85–98%) and selectivities (97–99%) independently of the electronic effect of

substituents.

Chapter 1


Scheme 1.11 MC synthesis of tetrahydroquinoline derivatives

Kobayashi et al. have prepared diverse tetrahydroquinoline derivatives

(Scheme 1.11) (Kobayashi et al. 1996) using a polymer supported scandium

[(polyallyl) scandium trifylamide ditriflate, (PA-Sc-TAD)] as a catalyst. The method

is especially useful for the construction of a quinoline library due to the efficiency

and simplicity of the process.

Scheme 1.12 Synthesis of quinoline derivatives

Quinoline derivatives having a spyrocyclopropyl ring can be synthesised by a

one-pot three component reaction using Montmorillonite KSF clay under mild

reaction conditions (Scheme 1.12) (Shao et al. 1996).

Chapter 1


Scheme 1.13 Multicomponent synthesis of pyran- and furandihydroquinolines

Recently, it has been reported that Brønstedand Lewis solid acids such as

antimony chloride doped on hydroxyapatite (SbCl3-HAP) (Mahajan, et al. 2006),

perchloric acid adsorbed on silica gel (HClO4–SiO2) (Kamble, et al. 2010), Fe3+–K10

Montmorillonite clay and HY zeolite (Srinivas, et al. 2004) are highly efficient and

diastereoselective solid acid catalysts for the one-pot synthesis of pyrano and

furoquinolines by coupling the three components, benzaldehydes, anilines and 3,4-

dihydro-2H-pyran or 3,4-dihydro-2H-furan (Scheme 1.13).

7) Synthesis of α-amino nitrile derivatives

α-Amino nitriles are a very useful intermediate compounds for the synthesis of

versatile α-amino acids, various nitrogencontaining heterocyclic compounds

(imidazoles, thiadiazoles etc.) and biologically useful molecules (such as Saframycin

A, a highly potent antitumor drug from Streptomyces lavendulae).

Scheme 1.14 Strecker reaction

Chapter 1


The most important route for the synthesis of α-amino acids via the formation of a-

amino nitriles is the well-known Strecker reaction (1850). The classical Strecker

reaction involves a direct multi-component reaction of an aldehyde or a ketone, an

ammonium salt and alkaline cyanides in aqueous solution to form α-amino nitriles,

which can be subsequently converted to amino acids (Scheme 1.14).

Several modifications of the Strecker reaction have been reported using a

variety of cyanating agents in the presence of solid or supported acids as

heterogeneous catalysts.

Scheme 1.15 Strecker reaction of aldehyde, amine and TMSCN

Yadav and coworkers prepared 2-anilino-2-phenylacetonitrile in 90% yield

by treatment of benzaldehyde, aniline and trimethylsilyl cyanide (TMSCN) in

dichloromethane at room temperature with Montmorillonite KSF clay as the catalyst

(Scheme 1.15) (Yadav et al. 2004). The mechanism of the process involves the

formation of imines or iminium ions and the subsequent nucleophilic attack of the

cyanide ion of TMSCN to provide the final product.

Following the Strecker route, efficient synthesis of a-amino nitriles using

aldehydes, ketones and fluorinated ketones has been achieved with Nafion-H, Nafion

SAC-13 (10-20% Nafion-H polymer on amorphous silica porous nanocomposite)

silica gel and fumed silica (Prakash et al. 2008).

It is interesting to note that when ketones are involved in the reaction the

nature of the solvent plays an important role. Acetonitrile, THF, and toluene are not

suitable for the direct Strecker reaction of ketones, since they are more basic and

interact with the acidic sites, thus reducing the catalytic activity (Kawahara et al.

Chapter 1


2005). However, dichloromethane minimizes such interactions enhancing the

catalytic activity.

8) Synthesis of imidazole derivatives

Polysubstituted imidazole derivatives are an important class of compounds which

exhibit a wide spectrum of biological activities as for instance antiinflammatory and

antithrombotic activities. The well-known microtubule stabilizing agents such as

Eleutherobin and Sarcodictyn, among other marine and plant derived products

contain imidazole (Lindel et al. 1997). In addition 2,4,5-triarylimidazole have

received great attention for the development of fluorescence labelling agents for

biological imaging applications (Sun et al. 2009) or chromophores for non-linear

optics systems (Stahelin et al. 1992).

Numerous classical methods for the synthesis of polysubstituted imidazoles

have been developed. Among these methods a typical procedure is the

multicomponent reaction approach involving the cyclocondensation of a 1,2-diketone

(or α-hydroxy ketones), an aldehyde and ammonia or ammonium acetate (scheme

1.16) in the presence of a homogeneous strong protic acid catalysts (such as

phosphoric acid, sulphuric acid, acetic acid), (Liu et al. 2003), Lewis acids (Heravi et

al. 2007) or oxidant agents such as ceric ammonium nitrate.

Scheme 1.16 Synthesis of 2,4,5-trisubtituted and 1,2,4,5- tetra substituted imidazole

derivatives.

Chapter 1


Xu et al. have reported the condensation of a-hydroxy ketone (benzoin)

(instead of benzyl) with an aldehyde over silica gel or alumina impregnated with

ammonium acetate (Xu et al. 2004). Reactions performed under solvent free

conditions and microwave irradiation gave the corresponding trisubstituted

imidazoles in good yields.

Scheme 1.17 Synthesis of 2,4,5-triarylimidazoles

HY zeolite and silica gel (Balalaie et al. 2000) have also been used as

heterogeneous acid catalysts for the synthesis of triarylimidazoles by condensation of

benzyl, benzaldehyde derivatives and ammonium acetate under solvent free

conditions and microwave irradiation (Scheme 1.17).

Scheme 1.18 Synthesis of 2,4,5-triarylimidazol from benzil or benzoin or

benzylmonoxime, aldehyde and ammonium acetate in the presence of silica sulphuric

acid (SSA) catalyst.

Shaabani et al. have reported that silica supported sulphuric acid (SSA) is an

excellent and recyclable catalyst for the synthesis of trisubstituted imidazoles under

reflux of water or solvent free conditions (scheme 1.18) (Shaabani et al. 2000).

Chapter 1


Shelke et al. have been prepared cellulose sulphuric acid (CSA) as a bio-

supported and recyclable solid acid catalyst for the one-pot synthesis of 2,4,5-

triarylimidazoles (Shelke et al. 2010).

9) Synthesis of quinazolin-4-(3H)-one derivatives

Quinazolinone derivatives were reported to possess analgesical, antibacterial,

antifungical, antihelmentics, antiparkinson, anticancer, anti-HIV, MAO inhibitory,

central nervous system and antiaggregating activity.

Scheme 1.19 Some biological active quinazolinones

Recently, it has been reported that silica gel-supported ferric chloride

catalyzes efficiently the three component reaction of anthralinic acid, orthoesters and

amines to afford 4-(3H)-quinazolinones in one-pot reaction (Scheme 1.20) (Chari et

al. 2006).

Nafion has also been used as an efficient catalyst in this multicomponent

reaction to obtain 2,3-disubstituted 4-(3H)-quinazolinones under solvent free

microwave irradiation (Lingaiah et al. 2006).

Chapter 1


Scheme 1.20 Synthesis of 2,3-disusbtituted-4-(3H)-quinazolinones from anthranilic

acid or isatoic anhydride, orthoesters and amines.

A new multi-component synthesis of 4-arylaminoquinazolines has been

reported by Heravi and co-workers (Heravi et al. 2009). The protocol involves the

reaction of 2-aminobenzamide, orthoesters, and substituted anilines in the presence

of acid catalysts such as different Keggin-type heteropolyacids (Scheme 1.21).

Various anilines and orthoesters were reacted with 2-aminobenzamide in the

presence of different heteropolyacids H6[PMo9V3O40], H5[PMo10V2O40],

H4[PMo11VO40], H3[PMo12O40]) in acetonitrile under refluxing conditions.

Scheme 1.21 Multicomponent synthesis of 4-arylaminoquinazolines from reaction of

2-aminobenzamide, aniline derivative and orthoesters

Chapter 1


10) Synthesis amidoalkyl naphthol derivatives

Generally, 1-amidoalkyl-2-naphthol derivatives can be prepared through MCR (via a

Ritter type reaction) of aryl aldehydes, 2-naphthol and acetonitrile or amides in the

presence of Lewis or Brønsted acid catalysts (Scheme 1.22).

Scheme 1.22 Multicomponent synthesis of 1-amidomethyl-2-naphthol derivatives

A variety of heterogeneous catalysts such as Montmorillonite K-10 clay,

Amberlyst-15, K5CoW12O40.3H2O, H3PW12O40, FeCl3–SiO2, Al2O3–SO3H, HClO4–

SiO2 and Al2O3–HClO4 have been reported in the literature to perform this MCR.

Recently Shaterian et al. have introduced the synthesis of 1-carbamate-alkyl-

2-naphthol in the presence of silica-supported sodium hydrogen sulphate (SiO2–

NaHSO4) as a catalyst (scheme 1.23) (Shaterian et al. 2008).

Scheme 1.23 Synthesis of 1-carbamato-alkyl-2-naphthol derivatives

Das et al. have found that perchloric acid supported on silica (HClO4–SiO2) is

an efficient catalyst for the synthesis of N- [(2-hydroxynaphthalen-1-yl)methyl]

amides through the condensation of 2-naphthol, aromatic aldehydes and urea (or an

amide) (Scheme 1.24) (Das et al. 2007).

Chapter 1


Scheme 1.24 Synthesis of N-[(2-hydroxynaphthalen-1- yl)methyl]amides

derivatives.

11) Synthesis of dihydropyridine derivatives

Dihydropyridines (DHPs) are an important class of compounds which cover a variety

of pharmaceutical and agrochemical activities such as insecticidal, herbicidal and

acaricidal (Kawase et al. 2002).

Scheme 1.25 1,4-Dihydropyridines of pharmaceutical interest

Chapter 1


The classical method to obtain DHPs is the MC Hantzsch reaction involving the

condensation of and aldehyde, a β-ketoester and ammonia either in acetic acid or by

refluxing in alcohol for long reaction times (Scheme 1.26).

Scheme 1.26 Synthesis of DHPs through the Hantzsch reaction

Recently, heterogeneous acid–base catalysts have been used for the

preparation of DHPs. Gupta et al. have reported that sulfonic acid covalently

anchored onto the surface of silica gel (SiO2–SO3H) is an efficient and recyclable

catalyst to synthesize 1,4-dihydropyridines (1,4-DHPs) (Gupta et al. 2007). Various

aldehydes (aromatic, heterocyclic and unsaturated) and β-keto esters (ethyl and

methyl acetoacetate) in the presence of ammonium acetate at 60 oC under solvent

free conditions afforded the corresponding 1,4-DHPs in good yield (83–90%).

Scheme 1.27 Plausible mechanism for the synthesis of 1,4-DHP

Chapter 1


Nikpassan et al. have developed the synthesis of fused 1,4-DHPs starting

from dimedone (5,5-dimethyl-1, 3-cyclohexadienone), different aldehydes and

ammonium acetate in the presence of HY zeolite (Nikpassan et al. 2009). The

reactions were carried out at reflux temperature of ethanol giving the corresponding

1,4-DHPs in good yields (70–90%) and in short reaction times (2.5–3.5 h) (Scheme

1.28). The catalyst was recovered and its activity was maintained after three

consecutive runs.

Scheme 1.28 Synthesis of fused 1,4-DHP

Various heterogeneous acid catalysts such as silica supported perchloric acid

(HClO4–SiO2) (Maheswara et al. 2006), Montmorillonite K10 (Song et al. 2005),

heteropolyacid (K7[PW11CoO40]) (Heravi et al. 2007), HY zeolite (Das et al. 2006)

and nickel nanoparticles (Sapkal et al. 2009) have been reported for the synthesis of

DHP.

Besides heterogeneous acid catalysts, solid base catalysts have also been

used to perform the MC synthesis of 1,4-DHP. Antonyraj et al. have reported the

coupling of benzaldehyde, ethyl acetoacetate and ammonium acetate using

hydrotalcites (HT) and hydrotalcite-like materials as solid base catalysts (Antonyraj

et al. 2008).

12) Synthesis of pyridine derivatives

Pyridines are interesting compounds because their saturated and partially saturated

derivatives are present in many biologically active and natural products such as for

instance pyridoxol (vitamin B6), NAD nucleotide (nicotin adenosin) and pyridine

alkaloids (Scheme 1.29).

Chapter 1


Scheme 1.29 Some examples of pyridine derivatives with pharmacological interest

As an alternative strategy to the homogeneous acid catalyzed Hantzsch reaction-

oxidation, De Paolis et al. developed a heterogeneous bifunctional noble metal–solid

acid catalyst system (Pd/C/K10 Montmorillonite) for the one-pot three component

reaction to obtain pyridines under microwave irradiation (Scheme 1.30) (Paolis et al.

2008).

Scheme 1.30 Synthesis of pyridine derivatives

Recently the synthesis of 2,4,6-triarylpyridines through one-pot condensation

of aldehydes, ketones and ammonium acetate have been carried out in the presence

Chapter 1


of perchloric acid supported on silica gel (HClO4–SiO2) as heterogeneous catalyst

(Scheme 1.31) (Nagarapu et al. 2007).

Scheme 1.31 Synthesis of 2,4,6-trialkylpyridine derivatives

Heravi et al. have prepared a series of 3-cyanopyridine derivatives through

the MCR involving aldehydes, 3,4-dimethoxyacetophenone, malononitrile and

ammonium acetate using different heteropolyacids as heterogeneous and recyclable

acid catalysts (Scheme 1.32) (Heravi et al. 2009). The screening of different

heteropolyacids (H14[NaP5W30O110], H6[P2W18O62], H4[PMo11VO40], H3[PMo12O40]),

showed that the highest activity was achieved with H14[NaP5W30O110].

Scheme 1.32 Synthesis 3-cyanopyridine derivatives

13) Synthesis of 3-cyano-6-hydroxy-2(1H)-pyridinone

Balalaie et al. have performed the three component condensation of

alkylacetoacetates, primary amines and alkyl cyanoacetates catalyzed by solid acids

such as silica gel, Montmorillonite K-10, HY zeolite and acidic alumina under

Chapter 1


microwave irradiation obtaining the corresponding 3-cyano-6-hydroxy-2(1H)-

pyridinones in good yields (Scheme 1.33). Using silica gel excellent yields of

different 3-cyano-6-hydroxy-2(1H)-pyridinones (87–94%) were obtained after two

minutes (Balalaie et al. 2003).

Scheme 1.33 One-pot three component synthesis of 3-cyano-6-hydroxy-2(1H)-

pyridinone derivatives

14) Synthesis β-acetamido ketone derivatives

The main route for the synthesis of these compounds is the Dakin–West reaction

which involves the condensation of α-aminoacid with acetic anhydride in the

presence of a base via an intermediate azalactone.

Recently Bathia et al. have proposed another general route for the synthesis

of β-acetamido ketones that involves the condensation of an aryl aldehyde, an

enolizable ketone or ketoester, acetyl chloride and acetonitrile in the presence of

Lewis acid catalysts such as CoCl2 (Scheme 1.34) (Bathia et al. 1994). The same

author performed this MCR using Montmorillonite K10 as the acid catalyst

(Bahulayan et al. 2003; Rao et al. 2003).

Scheme 1.34 One-pot synthesis of β-acetamido Ketones derivatives

Chapter 1


Besides Montmorillonite K10, a variety of solid acid catalysts promoting this

MCR have been reported. HBeta zeolite has been used as an active and reusable

catalyst to perform this reaction at room temperature (Bhat et al. 2005). Also

heteropolyacids (Rafiee et al. 2006; Heravi et al. 2007; Nagarapu et al. 2007), acid

resins (Yakaiah et al. 2007; Das et al. 2006), sulfated zirconia (Krishnaiah et al.

2007), sulfuric acid supported on silica (Khodaei et al. 2005) or phosphomolybdic

acid supported on silica (PMA/SiO2) (Das et al. 2009) have been used to perform this

MCR using a wide variety of aromatic aldehydes and ketones or ketoesters.

14) Synthesis imidazo[1,2-a]pyridine derivatives

A variety of imidazo[1,2-a]pyridines were prepared starting from 2-

aminopyridine, aldehydes and isocyanides using Montmorillonite K10 clay as the

catalyst in a microwave reactor (scheme 1.35) (Rousseau et al. 2007).

Scheme 1.35 MC synthesis of imidazo-pyridine, -pyrazine and –pyrimidine using

Montmorillonite K10 as the catalyst

Sulfuric acid supported on silica has also been used recently as a reusable

acid catalyst to perform the synthesis of 3-aminoimidazo [1,2-a]pyridines and -

pyrazines by condensation of an aldehyde, 2-amino-5-substitutedpyridines or 2-

aminopyrazine and alkyl or aryl isocyanides (Shaabani et al. 2007).

14) 1,2,4,5-tetrazinan-3-one derivatives

The formation of N–N bonds is not easy and 1,2,4,5-tetrazines have generally

been prepared from hydrazine derivatives or from nitrilimines (Lamon et al. 1969).

Chapter 1


Recently Gopalakrishnan and co-workers have reported the synthesis of 6-aryl-

1,2,4,5-tetrazin-3-ones or thiones through a MC reaction involving urea, various

substituted benzaldehydes and ammonium acetate in the presence of NaHSO4

supported on silica gel (NaHSO4–SiO2) as an acid catalyst (Scheme 1.36)

(Kanagarajan at al. 2009). Reactions performed under microwave irradiation

afforded 6-aryl-1,2,4,5-tetrazin-3-ones in 68–75% yield within 2 or 3 min, while

under thermal conditions (heating at 75 oC) lower yield was achieved (30–38%) in

35–43 min.

Scheme 1.36 MC synthesis tetrazine derivatives

15) Synthesis of Tetrahydroisoquinolonic acid derivatives

Azizian et al. have reported the synthesis of cis-isoquinolonic acid derivatives

by coupling homophthalic anhydride, aldehydes and amines in the presence of

KAl(SO4)2.12H2O (Alum) and silica sulphuric acid as heterogeneous catalysts

(Scheme 1.37) (Azizian et al. 2006). When a mixture of equimolar amounts of

homophthalic anhydride, benzaldehyde and aniline in acetonitrile is allowed to react

in the presence of Alum catalyst at room temperature, 1-oxo-2,3-diphenyl-1,2,3,4-

tetrahydro-isoquinoline-4-carboxylic acid was obtained with yield of 88% after 7 h.

The reaction was extended to a range of different aldehydes and amines giving the

corresponding cis-isoquinolonic acid in good yields (81–91%).

Scheme 1.37 Synthesis of tetrahydroisoquinolonic acid derivatives

Chapter 1


Karimi et al. have reported the use of sulfonic acid functionalized silica

(SAFS) as a recyclable heterogeneous catalyst for the synthesis of isoquinolonic

acids by a three component condensation of homophthalic anhydride, aldehydes and

amines (Karimi et al. 2010). The reaction was highly stereoselective and only the cis

isomer was obtained in all cases.

15) Synthesis of 4-amidotetrahydropyran derivatives

The most general method to obtain tetrahydropyran derivatives is via Prins

cyclization reaction using acid catalysts (Miranda et al. 2005). Recently 4-

amidotetrahydropyrans have been prepared by a three component coupling of

carbonyl compounds, homoallylic alcohols and nitriles using phosphomolybdic acid

(H3PMo12O40, PMA) as catalyst via Prins–Ritter reaction (Scheme 1.38) (Yadav et

al. 2008).

Scheme 1.38 Synthesis N-(2-cyclohexyltetrahydro-2H-4-pyranyl)-acetamide

For comparison purposes other solid acid catalysts such as Montmorillonite

KSF and Amberlyst-15 were tested, however the PMA catalyst was more efficient in

terms of conversion. Spirocyclic-4-amidotetrahydropyrans were also obtained in

good yields (84–88%) from cycloketones, homoallylic alcohols and nitriles (Scheme

1.39).

Scheme 1.39 Synthesis of pirocyclic-4-amidotetrahydropyrans

Chapter 1


15) Synthesis of DL-5-(4-hydroxyphenyl) hydantoin

DL-5-(4-Hydroxyphenyl) hydantoin is an important intermediate for the enzymatic

production of (R)-2-(4-hydroxyphenyl)glycine, a compound widely used in the

preparation of semi-synthetic penicillins and cephalosporines (Long et al. 1971).

Scheme 1.40 Synthesis of DL-5-(4-Hydroxyphenyl)hydantoin

Cativiela et al. have reported the synthesis of DL-5-(4- hydroxyphenyl)

hydantoin following this approach using solid acids catalysts such as clays (KSF and

K10 Montmorillonite), beta zeolite, and sulfonic organic polymers (scheme 1.40).

The condensation reaction of phenol, urea and glyoxylic acid performed in water at

70 oC in the presence of clay or beta zeolite afforded the target product (Cativiela et

al. 2002).

16) Synthesis of 2H-indazolo[2,1-b]phthalazine-trione derivatives

Among the large variety of nitrogen-containing heterocyclic compounds,

heterocycles containing the phthalazine moiety are of interest because they show

important pharmaceutical and biological activities (Jain et al. 2004).

Shaterian et al. have reported the use of silica supported sulfuric acid as an

efficient heterogeneous catalyst for the preparation of 2H-indazolo[2,1-b]

phthalazine-1,6,11(13H)-trione derivatives (Scheme 1.41). The catalyst could be

successfully recovered and recycled at least for five runs without significant loss in

activity (Shaterian et al. 2008).

Chapter 1


Scheme 1.41 Synthesis of 3,4-dihydro-3,3-dimethyl-13-phenyl-2H-indazolo- [2,1-

b]phthalazine-1,6,11(13H)-trione

17) Synthesis of polyfunctionalized pyran, pyranodipirimidine and chromene

derivatives

4H-Pyrans rings can be also obtained through a A3 coupling reaction of an aldehyde,

malononitrile and an active methylenic diketo compound.

Recently, Babu et al. have synthesized this type of compound using a Mg/La

mixed oxide as the heterogeneous basic catalysts (Scheme 1.42) (Babu et al. 2008).

Compared to other solid basic catalysts such as MgO, KF/Alumina, Mg/Al

hydrotalcite, and Mg-Al-CO3, the Mg/La mixed oxide catalyst was the most active

promoting the coupling of benzaldehyde, ethyl acetoacetate and malononitrile in high

yield (92%).

Scheme 1.42 A3 coupling process for the synthesis of 4H-pyran derivatives

18) Synthesis of dihydropyran [3,2-c]chromene derivatives

Dihydropyran[3,2-c]chromene derivatives are important heterocyclic compounds

used in the treatment of neurodegenerative diseases including Alzheimer’s disease,

AIDS associated dementia, for the treatment of schizophrenia, Down’s syndrome and

Chapter 1


Huntington’s disease. In addition, 2-amino-chromene derivatives exhibit

antihypertensive and antischemia activity.

Recently Heravi et al. have reported this 3CR using heterogeneous acid

catalysts such as H6P2W18O62.18H2O as a Wells–Dawson type heteropolyacid

catalyst (scheme 1.43) (Heravi et al 2008).

Scheme 1.43 MCR of 4-hydroxycoumarin, aldehydes and alkylnitriles

Seifi et al. presented a highly efficient method for the synthesis of a pyrano

annulated heterocyclic system via a three component reaction of an aldehyde,

malononitrile and a ahydroxy or an α-amino activated C–H acid in the presence of

MgO as the catalyst (scheme 1.44) (Seifi et al. 2008).

A variety of tetrahydrobenzo[b]pyran-, [2,3-d]pyrano- and pyrido[2,3-

d]pyrimidine derivatives were synthesized with this protocol in excellent yields in

the presence of MgO catalyst from aryl aldehyde, malononitrile and cyclic β-

diketones (A: 1,3-cyclohexanedione or dimedone, B: 4-hydroxy-6-methylpyrone, 4-

hydroxycoumarin,C: 1,3-dimethylbarbituric acid and D: 1,3-dimethyl-6-amino

uracil).

Chapter 1


Scheme 1.44 Synthesis of pyran annulated heterocyclic systems via three component

reaction

19) Synthesis of pyranodipyrimidine derivatives

The MCR involving benzaldehyde, malononitrile and barbituric acid or its thio

analogue was performed using neutral alumina as the catalyst under microwave

irradiation, and yields 7-amino-6-cyano-5-aryl-5H-pyrano[2,3-d]pyrimidine-2,

4(1H,3H)-diones, an intermediate in the synthesis of pyranodipyrimidines (Scheme

1.45) (Kidwai et al. 2007). This intermediate compound was allowed to react with

different aromatic carboxylic acids adsorbed on Montmorillonite under microwave

irradiation to give the desired product.

Chapter 1


Scheme 1.45 One-pot synthesis of pyranodipyrimidine derivatives

19) Synthesis of 2-amino-4H-benzo[h]chromene derivatives

The most straightforward synthesis for 2-aminobenzochromene derivatives involves

a three-component coupling of aromatic aldehyde, malononitrile and an activated

phenol in the presence of organic bases (such as piperidine), which is frequently used

in stoichiometric amounts using ethanol or acetonitrile as solvents (Scheme 1.46) )

(Bloxham et al. 1994).

Scheme 1.46 Synthesis of 2-aminochromene derivatives

Nevertheless, diverse heterogeneous catalysts have been employed for this

multicomponent reaction. Wang et al. synthesized a series of 2-aminochromene

derivatives from aryl aldehydes, malononitrile or ethyl cyanoacetate with 1-naphtol

or 1,5-naphthalenediol, in the presence of alumina coated with potassium fluoride

(KF-Alumina) (Wang et al. 2004).

Chapter 1


When aryl aldehydes, malononitrile or ethyl cyanoacetate and 1-naphthol

react in the presence of KF-Alumina in refluxing ethanol for 5–6 h, the 2-amino-4-

aryl-4H-benzo[h]chromene derivatives were obtained in slightly high yields (72–

90%). When 1,5-naphthalenediol was used instead of 1-naphthol, naphthol[1,2-b;6,5-

b’]dipyrans derivatives were isolated in good yields (83–94%) (Scheme 1.47).

Scheme 1.47 Synthesis of the naphthol[1,2-b;6,5-b’]dipyrans derivatives from aryl

aldehydes, malononitrile or ethyl cyanoacetate and 1, 5- naphthalenediol

Basic alumina was proposed by Maggi et al. as a catalyst in the synthesis of

substituted 2-amino-2-chromenes by coupling benzaldehyde, malononitrile and a-

naphthol using water as a solvent (Maggi et al.2004).

Nanosized magnesium oxide has been reported as an efficient catalyst for the

three component condensation of aldehyde, malononitrile and a-naphthol in

methanol, water or PEG-water as the reaction medium (Kumar et al. 2007).

Chapter 1


1.3 Hydrotalcites as green heterogeneous catalysts

1.3.1 Introduction

Hydrotalcite-like layered double hydroxides (LDHs), also known as anionic clays,

are natural or synthetic materials consisting of positively charged brucite-like sheets.

The structure of hydrotalcite can be visualized as the structure of brucite, Mg(OH)2,

in which some of the Mg2+ cations, coordinated octahedrally by hydroxyl groups, are

substituted by trivalent ions such as Al3+ (Fig. 1.7).

Fig 1.7 Structure of double layered hydrotalcites intercalated with CO32- anions.

The excess of positive charge in the LDHs’ layers is compensated by anions

located together with water in the interlayer space. The general formula of

hydrotalcite is:

[M1-x 2+Mx

3+(OH)2][An-]x/n · yH2O

where M2+ and M3+ represent divalent and trivalent cations in the octahedral sites

within the hydroxyl layers, x is equal to the ratio M3+/(M2+ + M3+) with a value

varying in the range of 0.17-0.50, and A is an exchangeable interlayer anion. It is

very important that M2+ and M3+ cations should have ionic radii not too different

from 0.65 Å (characteristic of Mg2+) to form a stable structure of hydrotalcite

(Yashima et al., 1972; Taylor et al., 1969).

Chapter 1


In naturally occurring hydrotalcite, carbonate is the interlayer anion.

However, the number of counterbalancing ions is essentially unlimited, and LDHs

intercalated by various simple inorganic (Cavani et al., 1991; Miyata, 1975),

polyoxometalate (Constantino et al., 1995; Narita et al., 1993; Evens, 1996), complex

(Dziembaj et al., 2002; Perez et al., 1991; Boclair, 2001) as well as organic anions

(Rives et al., 1999; Miyata et al., 1973; Meyn et al., 1990) have been synthesized.

Therefore, it seems to be possible to prepare tailor-made materials for

specific applications by changing the cationic and anionic compositions of

hydrotalcite. Unique basic properties of LDHs, which behave as solid bases, make

these materials very useful for catalytic purposes. The replacement of homogeneous

basic catalysts by solid bases would make separation and recovery of catalysts easier

and allow to avoid corrosion and environmental problems. Thus, LDHs as well as

mixed metal oxides formed by calcination of hydrotalcites have been studied as basic

catalysts in many chemical processes.

1.3.2 Catalytic applications of Hydrotalcites

In a time of growing need for green catalysts, hydrotalcites have been rediscovered

as a family of catalysts of great diversity and versatility for liquid phase organic

reactions. Recently hydrotalcites have been used as efficient catalysts for a liquid

phase organic reactions.

1.3.2.1 C-C and C-N bond formation reactions

Choudary, et al. have reported that the highly polarised basic fluoride ions in

developed LDHs, shown unprecedented catalytic activity both in Knoevenagel and

Michael reactions among the family of solid bases, in general, and known fluoride

catalysts, in particular, under very mild liquid phase conditions (Choudary et al.,

2001) (Scheme 1.48-1.49).

The other advantages of LDH-F include easy separation of the catalyst by

simple filtration, high atom economy to enable waste minimization, reduced

corrosion and reusability thus making the catalyst an attractive and potential

candidate for commercial realization in C–C coupling reactions.

Chapter 1


Ar-CHO

CN

CN

OH

140 0

CO NH2

CN

Ar

HT/MW

R1

O

H2CX

YR2

R1 CN

Y

LDH-F

MeCN, RT

R2

R1

LDH-FO H2C

CN

YR

2

R1 CN

Y

H2O

Scheme 1.48 Knoevenagel reaction on hydrotalcite

Scheme 1.49 Michael reaction over hydrotalcite

Surpur et al. have developed highly efficient methodology for the synthesis of

heterocyclic compounds via the multicomponent condensation of aromatic aldehyde,

malononitrile and 1-naphthol under microwave in the presence of Mg/Al hydrotalcite

(Surpur et al., 2009) (Scheme 1.50).

Scheme 1.50 Multicomponent reaction over Mg/Al hydrotalcite

Kantam et al. have developed a simple and efficient method for the preparation of 5-

substituted 1H-tetrazoles via (2 + 3) cycloaddition using Zn/Al hydrotalcite as a

heterogeneous catalyst (Kantam et al., 2006) (Scheme 1.51).

Scheme 1.51 Cycloaddition reaction of nitrile and azide over Zn-Al hydrotalcite

CN DMF, 120-130

0C

Zn/Al hydrotalcite

R

NaN3

RN

N

N

HN

Chapter 1


Kantam et al. have described a simple and effective protocol for the 1,4-conjugate

addition of amines to α-β--unsaturated compounds using Cu-Al hydrotalcite catalyst

at room temperature in very good yields (Kantam et al., 2005) (Scheme 1.52).

Scheme 1.52 Coupling of alkyne compounds on Cu-Al hydrotalcite

1.3.2.1 Coupling reactions

Bing et al. have demonstrated a novel and efficient protocol for the synthesis

of conjugated diynes through oxidative dimerization of terminal alkynes that is

catalytic in CuAl–LDH at room temperature (Bing et al., 2007) (Scheme 1.53).

Scheme 1.53 Coupling of alkyne compounds on Cu-Al hydrotalcite

Namitharan et al. have reported for the first time, CuII as an active species in

the Huisgen [3+2] cycloaddition of azides with terminal alkynes in a nonaqueous

medium (Namitharan et al., 2009). Furthermore, CuII–HT serves as a novel

environmentally benign, highly reactive, recyclable and efficient heterogeneous

catalyst without any additives under aerobic conditions (Scheme 1.54).

Scheme 1.54 Cycloaddition reaction of alkyne and azide on Cu-Al hydrotalcite

ACN, RTR N

NN

CuII hydrotalciteN N N

R

R1 R1

Chapter 1


HT/DMSOX

R

CHO

R

1.3.2.1 Transesterfication reactions

Choudary et al. have reported that β-ketoesters can be successfully transesterify with

primary, secondary, unsaturated, allylic, cyclic, hindered alcohols and amines by

Mg–Al–O–t-Bu hydrotalcite catalyst (Choudary et al., 2000) (Scheme 1.55).

Scheme 1.55 Transesterification reaction catalyzed be Mg/Al-tBuO hydrotalcite

1.3.2.1 Oxidation reactions

Kshirsagar et al. have reported Mg–Al hydrotalcites as the first heterogeneous basic

catalysts for the Kornblum oxidation of benzyl halides to benzaldehydes using

DMSO (Kshirsagar et al. 2008) (Scheme 1.56).

Scheme 1.56 Oxidation of benzyl halide on Mg-Al hydrotalcite

1.3.2.1 Reduction reactions

Qixun et al. have developed an exceedingly efficient and highly chemoselective

approach to prepare aromatic amines from the corresponding aromatic nitro

compounds using hydrazine hydrate over nickel-iron mixed oxide obtained by

calcinations of nickel-iron hydrotalcite-like precursor (Qixun et al., 2007) (Scheme

1.57).

The catalytic system described by Qixun et al. may be a promising alternative

to the sulphide reduction and Fe/HCl reduction which are widely used for preparing

sulphur-containing aromatic amines at present in industry.

Toluene, 90-100 0C

HT catalyst

R

O O

OR1R2- OH

R

O O

OR2

R1- OH

Chapter 1


NO2

R

hydrazine hydrate, propan-2-ol

NH2

R

nickel-iron mixed oxide, reflux

Scheme 1.57 Reduction of aromatic nitro compounds on Ni-Fe hydrotalcite

Thus, in the present era of catalysis, looking at the growing interest in the

development of new and sustainable catalysts, hydrotalcites have immense scope as

robust heterogeneous catalysts for a wide variety of liquid phase organic reactions.

Chapter 1


1.4 Hydroxyapatites as heterogeneous catalysts

1.4.1 Introduction

Apatites have the general formula, Ca10(PO4)6X2 where X is typically F

(fluoroapatite, FAP), OH (hydroxyapatite, HAP), or Cl (chloroapatite, CAP). The

apatite lattice is very tolerant of substitutions, vacancies and solid solutions, for

example, X can be replaced by CO3, Ca by Sr, Cu, Ba, Pd and PO4 by HPO4, AsO4,

VO4, SiO4 or CO3 [Elliott, 1994].

Apatites are widely distributed as accessory minerals in igneous rocks and in

small quantities in most metamorphic rocks. This wide-spread occurrence is an

important factor in their extensive use in fission-track chronothermometry for the

study of geological thermal history. Rock phosphates (microcrystalline apatites),

mostly of biological origin, are the starting material for phosphate fertilizer

manufacture and a source of phosphorus for the chemical industry. The mineral of

bones and teeth is an impure form of HAP, the major departures in composition

being a variable Ca/P mol ratio (1.6 to 1.7, HAP is 1.66), and a few percent CO3 and

water. The mineral is microcrystalline. HAP is also used as a biomaterial, for

example, for bone replacement and augmentation, and for coating metal prostheses to

improve their biocompatibility.

The basic apatite structure was published nearly simultaneously by Elliott et

al. [Elliott et al. 1994]. The structure is hexagonal with space group P63/m and

approximate lattice parameters a = 9.37Å and c = 6.88Å. There are two

crystallographically different Ca atoms, and three O atoms [Elliott et al. 2002]. The

unit cell comprises Ca(1)4 Ca(2)6 (PO4)6 (OH)2.

Chapter 1


Fig. 1.8 (a) Oxygen coordination of columnar Ca(1) ions in apatite, (b) linking of

columns via PO4 tetrahedra, (c) Arrangement of ions around the c-axis in

hydroxyapatite, the F--- ion is at the centre of the Ca(2) triangle.

C

Chapter 1


1.4.2 Catalytic applications of Hydroxyapatites

1.4.2.1 Fixation of Carbon dioxide with epoxide

Mori et al. have developed ZnHAP as an extremely active and versatile catalyst

system for the coupling of epoxides and CO2 (Mori et al., 2005) (Scheme 1.58). The

present protocol can be considered as environmentally-benign due to the following

attractive features: (i) high activity and selectivity under mild reaction conditions, (ii)

additional organic solvents are unnecessary, and (iii) the simple work-up procedure

and ability to recycle the solid catalyst.

Scheme 1.58 Coupling of epoxides and CO2 catalyzed by the ZnHAP

1.4.2.2 C-C and C-N bond formation reaction

Kantam et al. have developed a simple and efficient method for N-arylation of

heterocycles using CuFAP as a heterogeneous catalyst (Kantam et al. 2006,

Subrahmanyam et al., 2010) (Scheme 1.59). Various bromo- and iodoarenes were

coupled with N-heterocyclic to yield the corresponding N-arylated products with

good to excellent yields (85–98%). The catalyst can be readily recovered and reused.

This methodology may find widespread use for the preparation of N-arylated

products.

Scheme 1.59 N-Arylation of N-heterocycles with bromo- or iodoarenes

Chapter 1


Solhy et al. have demonstrated the use of hydroxyapatite–water system as an

efficient and clean catalyst for the preparation of chalcone derivatives via Claisen–

Schmidt condensation under microwave irradiation (Solhy et al., 2010) (Scheme

1.60). The high reactivity of HAP–water coupled with its ease of use and reduced

environmental problems makes it attractive as an alternative to homogeneous

reagents.

H2O, MW (700 watt)

HAP

O

O

R2

R1R1

O

R2

Scheme 1.60 Synthesis of chalcone using HAP

Sebti et al. have reported fluroapatite as a new solid catalyst of the

Knoevenagel reaction in heterogeneous media without solvent for the first time

(Sebti et al., 2000) (Scheme 1.61).

Scheme 1.61 Knoevenagel reaction catalyzed by FAP

1.4.2.3 Hydroxylation of phenol

The chlorobenzene hydrolysis to phenol over Cu-promoted hydroxyapatites at

different operational conditions was reported by Figoli et al. in flow equipment under

atmospheric pressure (Figoli et al., 1982) (Scheme 1.62).

Cl OH

H2O HCl K = 9.50 x 10-1

Scheme 1.62 Hydroxylation of chlorobenzene catalyzed by CAP

Chapter 1


1.4.2.4 Coupling reactions

The coupling of three-components, namely an aldehyde, an alkyne and an amine to

prepare propargylamines was reported by Choudary et al. using copper exchanged

hydroxyapatite (Cu-HAP) as the catalyst under mild reaction conditions and in the

absence of any co-catalyst (Choudary et al., 2004) (Scheme 1.63).

A variety of aldehydes and amines were converted to the corresponding

propargylamines, demonstrating the versatility of the reaction.

Scheme 1.63 Three-component coupling reaction catalyzed by Cu-HAP

Ranu et al. reported a simple procedure for the synthesis of substituted (E)-2-

alkene-4-ynecarboxylic esters using hydroxyapatite-supported palladium as efficient

catalyst surface (Ranu et al., 2008) (Scheme 1.64).

.

Scheme 1.64 Coupling of diiodoalkenes and alkenes catalyzed by Pd-HAP

1.4.2.5 Allylation of Aldehyde

Sreedhar et al. reported a facile synthesis of homoallylic alcohols by the allylation of

aldehydes with allylic metal reagents or allyl halides using copper fluoroapatite

(CuFAP) as catalyst under mild reaction conditions (Sreedhar et al., 2008) (Scheme

1.65).

Chapter 1


A variety of aldehydes were converted to the corresponding homoallylic

alchohols, demonstrating the versatility of the reaction.

Scheme 1.65 Allylation of aldehydes with allyltributylstannane and

allytrimethylsilane catalyzed by CuFAP

1.4.2.6 Oxidation of alcohol

Mori et al have demonstrated a novel approach to catalyst design using

hydroxyapatites and tested its catalytic performances for the oxidation of alcohols to

aldehydes or ketones (Scheme 1.66).

OH

CO H2OPd/HAP

1/2 O2

Scheme 1.66 Oxidation of alcohol to aldehydes catalyzed by PdHAP

Chapter 1


1.5 Objectives of the research work

In the present era, the main objective in the field of catalysis is on placing

precincts to the use of conventional, corrosive, non recoverable and hazardous

catalytic materials and identifying robust, easy to handle, recoverable and

environmentally viable counter parts.

Multicomponent reactions using solid acid/base catalysts are particularly

important in synthetic chemistry. The heterogeneous catalysts can have more than

one type of active sites such as lewis and bronsted acidic/basic sites, which are

capable of catalyzing more than one type of reactions.

With this objective, several hydrotalcites and hydroxyapatites were prepared

by suitable methods. The catalysts were characterized by various analytical

techniques such as X-ay diffraction (XRD), FT-IR, DSC-TGA, SEM, TEM, BET

surface area, ICP-AES, elemental analysis (EDX), and basicity measurement by

phenol adsorption method.

Thus, the present work aims at

● Developing environmentally benign heterogeneous catalytic protocols with

better activity and selectivity for liquid phase organic reactions of industrial

importance.

● To correlate the activity / selectivity of these catalysts with their physico-

chemical properties, wherever possible.

● To check the reusability of the catalysts.

Depending upon the properties and possible active sites present, the catalytic

activity of these materials has been planned and will be explored for the following

important chemical transformations.

� Synthesis of 1,2,3-triazoles using copper apatite � Synthesis of 2-amino-4H-chromene using Mg/Al hydrotalcite � Synthesis of highly substituted pyridines using Mg/Al hydrotalcites � One pot reaction of aldehydes, amines, nitromethane and 1,3-dicarbonyl

compound to give functionalized pyrrole on γ-Fe2O3/HAP nanoparticles � Cycloaddition reaction of alkynes, halides and azides on γ-Fe2O3/HAP

nanoparticles in aqueous medium. � Synthesis of α-aminophosphonates using Palladium hydroxyapatite as a reusable

and heterogeneous catalyst.

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1.1 Catalysis - INFLIBNET