Chapter 3

General introduction

132

General Introduction

The nature presents organic chemists with unique opportunities to pursue new chemical entities. In the construction of six-membered ring, which is widely distributed in the nature,1 the value of DA methodology has greatly been realized.2 After the first heterocycles, accessed from electron rich diene―cyclopentadiene with electron poor dienophile―azodicarboxylate,3 there come into view a variety of dienes and dienophiles. Cyclic frameworks achieved in chemo–, regio–, diastereo– and enantioseletive manner are central cores of many bio-active scaffolds.4 In addition, pyran, thiopyran, chromene and piperidine which these scaffolds incorporate exist in alkaloids, terpenes, pharmaceuticals, agrochemicals, pesticides and steroids.5 With application in bidirectional search (combined retrosyntheic and synthetic search), total synthesis and of course in medicinal chemistry, the area seems interesting to explore further.6 The sequential transformations,7 which couple two or more reactions, ease the effort further simple in the synthesis of complex heterocycles.Simple dienes

Based on the location of double bond, a diene can be classified into three categories; conjugated, non-conjugated- and cumulated ones. The former in comparison with later two however is most stable due to delocalization of the electron. Open chain-, outer ring-, inner-outer ring-, across ring- and inner ring-dienes are other forms this diene exist in the natural and synthetic compounds. This simple diene consists of four carbons with two π bonds, which are joined in a linear fashion. Four π electrons are delocalized onto the four-atom system. The resonance not only makes the charge distribution feasible but provides diene with an extra stability, too. Rotation of C2―C3 bond in the molecule is therefore become tough, requires higher energy.

Chapter 3 133

3.1 HeterodiensHeterodienes is another class of dienes that contains one or more hetero

atoms in place of carbon(s) in simple diene, which include nitrogen, oxygen sulphur and phosphorous. The in situ generation of heterodiene from a specially designed substrate, which allows its indirect use in hetero–Diels―Alder (HDA)strategy, is an interesting area of heterocyclic preparations. In the literature, there are many reports on the synthesis and application of heterodienes.Azabutadienes, oxabutadienes, thiabutadienes and phosphabutadienes are among the vastly exploited heterodienes. Examples include 1-aza-1,3-butadiene 1, 2-aza-1,3-butadiene 2,8 1,2-diaza-1,3 butadienes 3,9 2,3-diaza-1,3-butadienes 4,10 1,3-diaza-1,3-butadienes 5, 11 1,4-diaza-1,3-butadienes 612 and 1,2,4-triaza-1,3-butadienes 7.13 Others which contain more hetero atoms include N-acyl mine 8,14 vinyl nitroso or nitro alkene 9,15 acyl nitroso 10, 1,2-diaza-4-oxa-1,3-butadiene 11,16 and 4-oxa-1-aza-butadiene 12.17

Oxabutadiene, thiabutadiene, phosphabutdiene are examples of oxygen, sulfur and phosphorous containing hetero atoms, respectively. Hetero-thiabutadienes include; 1-thiabutadienes 13, 1,4-dithiabutadienes 14,18 4-oxa-1-thiabutadiene 15,19 1-aza-4-thiabutadiene 16, 1-thio-3-azadienes 17.20

The hetero-phosphabutadienes with other heteroatoms include 1-phosphabutadienes 18, 2-phosphabutadienes 19, 1,3-diphosphabutadienes 20,21

Chapter 3 134

1,4-diphosphabutadienes or 1,4-diphosphinine 21,22 2,3-diphosphabutadienes 22, 1-aza-4-phosphabutadiene 23, 1-phospha-3-azabutadiene or 1,3,5-diazaphosphinines 24,23 1-phospha-2-azabutadiene 25,24 1,3,2-diazaphosphinine 26,25 2-aza-3-phosphabutadiene or 1,2-azaphosphinines 27, 1-oxa-4-phosphabutadiene 28.

In the same way, oxabutadienes, such as 1-oxabutadienes, 1,4-dioxabutadienes and hetero-1-oxabutadienes that contain oxygen atom and/or hetero atom include 1-oxabutadienes 29, 1,4-dioxabutadiene 30,26 acyl sulfines 31,27 acyl sulfenes 32, and acyl thionitroso diene 33, N-sulfinyl amides 34, N-sulfonyl amides or N-sulfonyl urethanes 35.28

These skeletons are present in both simple and complex heterocyclic systems. More on heterodienes in the heterocyclic synthesis can be highlighted below.

Fletcher et al.29 described MW-assisted HDA reaction betweenazabutadienes 36 and electron deficient acetylenes 37. The reactivity of a range of α,β-unsaturated oximes and hydrazones is assessed in the synthesis of tri- and tetra-substituted pyridines 38 bearing an oxygen functionality at C―3.

Moghaddam et al. 30 synthesized polycyclic indole derivatives from O-acrylated salicylaldehyde derivatives 39 and dihydroindole-2-thiones 40 in

Chapter 3 135

water. Reaction proceeds via intermediate 1-thiabutadienes, in situ generated by Knoevenagelcondensation.Productyieldswereinthe65―95%rangewithhigh regio- and stereoselectivities.

Martin et al. generated 1-phosphabutadienes 43 by thermolysis of the corresponding diallylphosphines 42, dimerize on warming in a [4+2] cycloaddition mode to give 44.31

Gohier et al.32 described the HDA reactions between chiral β-substituted N-vinyloxazolidinones 45 and oxabutadienes 46, affording cycloadducts 47 and 48 with high endo and facial selectivities. The choice of the Lewis acid proved critical, affording selectively either the endo α 47 adduct using Eu(fod)3 as the catalyst or endo β 48 if the promotor was SnCl4.

3.2 Oxabutadiene and scope of its reactionOxabutadiene is a heterodiene in which oxygen is one of the four atoms of

simple diene. Generated via many synthetic routes, one of its common forms α,β-unsaturated aldehyde/ketone has been widely used in the construction of heterocycles. Knoevenagel condensation,33 aldol reaction,34 Perkin reaction35and Claisen―Schimdt condensation36 that utilize mono and 1,3-diketones are important routes to generate oxabutadiene. Any ketone that is cyclic or acyclic, heterocyclic or heteroacyclic in nature can be used. Examples of diketones include dimedone, 1,3-cyclohexanedione, 4-hydroxy coumarin, 2,4-dihydroxy quinoline, rhodamine, barbituric acid, Meldrum’s acid and 1,3-cycloalkanedione, β-ketoesters, and 1,3-diones. Pyrazolone and isoxazolone are examples of mono

Chapter 3 136

ketones. Other sources also include Mannich reaction,37Horner―Wadsworth―Emmons reaction,38 Horner―Wittig reaction, and Peterson reaction,39 Meyer―Schuster rearrangement,40 Wittig reaction of acyl bromide,41elimination of groups α or β to carbonyl,42 decarboxylative allylation of α-oxocarboxylates,43 oxidation of allylic alcohols,44 by insertion of carbon monoxide,45 by sequential aldol-type reaction and β-elimination,46 etc. Common structural feature of the oxabutadiene is depicted below.

R4

R2

R3

Oxabutadiene

R1

O

3.2.1 Oxabutadienes in hetero–Diels―Alder strategy Oxabutadienes usually undergoes four types of reaction; electrophilic

addition, nucleophilic addition, Michael addition and Diels―Alder reaction. In the last strategy, which is commonly known as HDA approach, 1-oxa-1,3-butadiene has been widely demonstrated. Few significant examples are as follows.

Tan et al.47 synthesized pyrano[2,3-c]pyrazole 52 derivatives by three component reaction of formaldehyde 49, pyrazolone 50 and alkene 51 under solvent-free conditions.

Seo and Kim48 described asymmetric organocatalytic Michael addition reaction of 2-arylacetates/acetonitriles 53 having an EWG to α,β-unsaturated aldehydes 54 has been established using diphenylprolinol trimethylsilyl ether 55as organocatalyst.R2 R1 Ph H

O

H

OPh

R1

55 and 4-NO2C6H4CO2H(10 mol %)

MeOH, rt

R2 NH

Ph

OTMS

Ph

55

R1 CO2Me/Bn/Et, CN; R2 p/o-CO2Me, p/o-NO2, p/o-CN53 54

56

Fotiadou and Zografos 49 demonstrated a tandem Knoevenagel/6π-electrocyclization sequence using 4-hydroxypyrid-2-one 57 and α,β-unsaturated aldehydes 58 to produce highly substituted pyranopyridones 59 from moderate to high yields in a one-step reaction.

Chapter 3 137

Other transformations are Nazarov cyclization50 for cyclopentenones, Rauhut―Currier reaction51 for dimerization or isomerization of α,β-unsaturated ketone, Baylis―Hillman reaction52 for allylicalcohol, Morita−Baylis−HillmanReaction53 for cyclopentenes, Mukaiyama―Michael addition,54 and many others.553.2.2 Oxabutadines in Domino Knoevenagel–hetero–Diels−Alder (DKHDA) strategy

Promoted via formation of 1-oxa-1,3-butadiene 6256, DKHDA approach is among the versatile anionic–pericyclic domino reactions,57,58 affording dihydropyrans 63 (Fig 3.1). DKHDA reaction begins with the simple substrate, but ends with formation of a highly complex molecule.59

According to Prof. Lutz F. Tietze, a domino reaction is the ‘’process whichinvolves two or more bond-forming transformations which take place under thesame reaction conditions without adding additional reagents and catalysts, andin which the subsequent reactions result as a consequence of the functionalityformed in the previous step”60. The strategy is a powerful tool to construct complex heterocycles rapidly in one-pot, offering environmental and industrial both the advantages. Cascade and tandem are other similar terms.

R3

O

R1

R2

X

O Y

R1 R2 O X

YR3

OR2

R1

X

YR3

60 6162 63Fig 3.1 DKHDA reaction promoted via oxabutadiene intermediate.

Generation of oxabutadiene takes place in both the DKHDA approaches:1. Three-component reaction between 1,3-dicarbonyl, an aldehyde and a vinyl ether.

Fig 3.2 Intermolecular HDA reaction.

Chapter 3 138

2. Two-component reaction: Intermolecularly formed oxabutadiene undergoes intramolecular HDA reaction.

O

O

CHO

O

O

O

O

HO

O

O

Fig 3.3 Intramolecular HDA reaction.As an inverse electron demand Diels―Alder reaction, HDA involves the

overlap of diene LUMO with dienophile HOMO. The reaction has excellent stereochemical control. Aromatic and aliphatic α,β-unsaturated aldehydes usually give cis-fused products, whereas simple aliphatic aldehydes the trans-adduct.61 Chiral aldehydes, diketones and Lewis acids62 also help afford enantiopure products. Acetonitrile, CH2Cl2 and toluene are among the most appropriate solvents used in the strategy. Alcohols and water are also suitable. 3.2.3 Transition states (TS)

Fig 3.4 Four possible TS that different orientations of dienophile towards oxabutadiene results in.

The orientation of a tethered dienophile leads to four possible TS; exo-E-anti (1), endo-E-syn (2), exo-Z-syn (3) and endo-Z-anti (4). From the experiments and theoretical calculations,63 it showed that the most favoredamong them which decides stereochemical out-come of the reaction (Fig 3.4) are first and forth leading to trans- and second and third leading to cis-annulated dihydropyran.

Chapter 3 139

Knoevenagel reaction of 64 with 65 gives exclusively (Z)-compound 66which isomerizes at higher temperature to (E)-form 67 and then to 68 via an endo-E-syn TS. The mechanism was observed under irradiation also which allowed the Z/E-isomerization of 67/68.64

3.2.4 DKHDA strategy in natural products synthesisDKHDA approach allows synthesis of heterosteroids,65 cannabinols,

deoxyloganin and secologanin,66 monoterpenoid indole alkaloids67 and preethulia coumarin.68 Tietze et al. described stereoselective trans-bonded hetero-steroids 71 (de >98 %) from 69 and 70 or its analogs.

3.2.5 DKHDA strategy in diversified heterocycles synthesis Besides natural products, the DKHDA route also allowed many diversified

heterocyclic preparation. Ghoshal et al. reported MW-assisted, piperidine-catalysed highly stereoselective synthesis of julolidine hybrid analogs 74 and 75using asymmetrical and unsymmetrical 1,3-diones 73.69

Ramesh et al.70 reported MW assisted, K-10 Montmorillonitrile catalysed intramolecular DKHDA reaction to afford pyrano[2,3,4-kl]xanthenes 78 and 79.

Chapter 3 140

Tietze et al.71 described a very short, three component DKHDA approach to 2-alkoxy-6-methyl-5-nitro-3,4-dihydro-2H-pyran 83 with 81―95% yields.

Gandhi et al.72 employed one-pot DKHDA reaction using bifunctional materials 84 containing an aldehyde and an sulfonate groups with N,N-dimethylbarbituric acid 85 in water. It gave a mixture of novel pyrano[2,3-d] pyrimidine-annulated benzo-δ-sultones 86 and 87 in moderate to high yields.

Majumdar et al.73 reported catalyst-free synthesis of pentacyclic benzopyran-annulated thiopyrano[2,3-b]thiochromenones 90 from 4-hydroxy dithiocoumarin 88 and O-propargylated salicylaldehyde 89 in aqueous medium.

Majumder and Bhuyan74 obtained thiopyrano[2,3-b]indoles 93 from oxindole 91 and 1,3-diketones 92 in the 62―75 % range in the presence ofcatalyst EDDA in MeCN.

Subba Reddy et al.75 reported angularly fused chromenes 96 from alkene-tethered chromene-3-aldehyde 94 and 1,3-cyclic diketones 95.

Chapter 3 141

3.2.6 Oxabutadienes in Domino/Knoevenagel―Michael–cyclization (DKMC) reaction

Like DKHDA reaction, DKMC reaction is also an important domino strategy to afford pyran-annulated heterocycles. Oxabutadiene, a Knoevenagel condensate, obtained from two- or three-component reaction, undergoes a Michael addition step and finally Michael products a cyclization―throughwaterremoval step.

Fig 3.5 Knoevenagel―Michael–cyclization reaction.Jin et al.76 developed a highly efficient, less expensive and toxic method

for 2,2’-alkylmethylene 1,8-dioxo-octahydroxanthenes 99, by grinding aldehyde97 and dimedone 98 in solid state using catalyst TiO2/SO42-.

Chebanov et al.77 reported regio- and chemoselective multicomponent protocols for hexahydro-pyrazolo[3,4-b]quinolin-5-ones 103.

Sakhuja et al.78 synthesized spiro[indole-pyran] 105 from one mole of isatin 104 with two mole of pyrazolone 77 in ethanol at rt, highlighting a Knovenagel-Michael-cyclization.

Chapter 3 142

Wen et al.79 successfully synthesized unusual fused tricyclic thiochromeno[2,3-b]pyridines 108 and 111 by [3+3] annulation and SNAr of β-(2-chloroaroyl)thioacetanilides 106 in tandem with activated 4-arylidene-2-phenyloxazol-5(4H)-ones 107 or aromatic aldehydes 109 and ethyl 2-cyanoacetate 110 under MW irradiation.

Liu et al.80 developed an enzymatic method to construct highly substituted dihydropyridinones 115 via a three-component reaction of aldehyde112, cyanoacetamide 113, and 1,3-dicarnonyl compound 114.

Moghadam et al.81 reported an IL N,N,N,N-tetramethylguanidium triflate mediated, synthesis of 4-substituted pyrano[4,3-b]pyran-2,5-diones 119 by taking an 4-hydroxy-2-pyranone116, Meldrum acid 117 and aldehyde 118.

3.3 Catalysts and ionic liquids (ILs) in domino reaction 3.3.1 Catalysts used in HDA reaction

Catalyst82 has generally less influence on DA reaction rate.83 But Lewis acid greately promotes it. Yates and Eaton reported a remarkable increase in rate of reaction between anthracene and maleic anhydride at rt and between 1,4-

Chapter 3 143

benzoquinone and dimethyl fumarate catalysed by AlCl3.84 SnCl4 also promoted the reaction. Many other examples have been reported in the literature.853.3.2 Lewis acids in Diels―Alder reaction

Examples of Lewis acids used in HDA reaction include ZnCl2, BF3, MeAlCl2, and Et2AlCl.86 Their influence on this reaction has been rationalized by applying FMO theory. Normally DA reaction involves interaction of dienophile LUMO with diene HOMO. The smaller is the HOMO―LUMO energy gap, the batter is the overlap and hence more readily the occurrence of reaction.87 For example, activation occurs when carbonyl oxygen lone pair electrons co-ordinate to the Lewis acid. Such co-ordination decreases the LUMO and HOMO energies of the aldehyde, resulting into decrease in an energy gap HOMO―LUMO (Fig 3.6). Additionally, co-ordination of Lewis acid towards carbonyl oxygen increases magnitude of its LUMO, making it more susceptible to the diene. Polarization, therefore, may change the reaction pathway from a concerted non-synchronous mechanism to a stepwise one. Substituents on the reactants and the reaction conditions also affect the mechanism.88

Fig 3.6 FMO diagram of HDA reaction in the presence and absence of a Lewis acid.

Fig 3.7 The endo-selectivity is seen in the Lewis acid catalyzed HDA reaction as the solvated Lewis acid is exo, due to its size.

Chapter 3 144

The orientation of dienophile towards diene in TS decides the stereochemistry of products. Lewis acid catalyzed HDA reactions are endo-selective due to the preference of the Lewis acid being exo as a result of its size (Fig 3.7).89 In addition, the Lewis acid and the carbonyl R group are proposed to be trans to each other.90 Similarly, the uncatalyzed reaction of aldehydes and a diene demonstrate endo-selectivity for the carbonyl substituent.91

Lewis acids employed are chosen based on experimental trial and error. Kobayashi et al. developed a concept of Lewis acids activity with aldehydes and imines.92 It states that strong acids didn’t necessarily promote the reaction smoothly and that observed selectivities of aldehyde or aldimine depends upon Lewis acid employed. In conjunction with Kobayashi, Cozzi et al. reported a deleterious effect stating that a decrease in diastereo- and enantioselectivity with strong Lewis acids employed in a catalytic enantio-selective addition of allyl organometallic reagents to aldehydes. However, the presence of weak Lewis acids drives the stereochemistry toward a high level of enantio- and diasterocontrol.93

Many metals like Eu, Ti, Yb, Cr, Zn, Co, Cu, Al, Sc, Li, etc., and its chiral auxiliaries have been used as Lewis acids in the DA reaction.94 From earlier reports, it also infers that required catalyst loadingswouldbe in 5―25mol%range. Solvent affect the rate of the reaction. Traditionaly, there were non-polar organic solvents such as aromatic hydrocarbons. However, water and other highly polar solvents, such as ethylene glycol, and formamide accelerate the DA reaction.95 ILs are also employed as a both solvent and catalyst.963.3.3 Catalysts used in DKHDA reaction

A variety of catalysts/conditions have effectively been employed in DKHDA reaction. Examples include Lewis acids,97 EDDA,144 CuI,98 BiCl3,99 InCl3,100LiClO4,101 PPh3.HClO4,102 ZnO,103 D-proline,104 ILs,105 TEA in acetic acid,143pyridine,106 ZrO2-nanopowder (NP) in IL,146 water,141 melt reaction139 etc.3.3.4 TBA―HS as a catalyst in organic synthesis

In the development of new synthetic methodologies that minimize the wastes generation, the PTC often improved the results.107

PTC are used in small quantity, is quaternary ‘onium’ salt such as ammonium, phosphonium, antimonium, and tertiary sulfonium salts.

Chapter 3 145

Dichlorocarbene can be generated by thermal decomposition of sodium trichloroacetate, suspending in anhydrous chloroform in the presence of quaternary salt. Requiring no vigorous conditions, it offers fast reaction, even in anhydrous condition, and involves no tedious workup procedure. TBA―HS has been widely used in the synthetic organic chemistry.

Kotha S. et al. prepared various 2,2-spirobiindane-1,3-diones 122 from 1,3-indenedione 120 and 2,3-bis(iodomethyl)buta-1,3-diene 121, which are useful precursors for unsymmetrical benzo-annulated fenestranes obtained viakey steps [2+2+2] and [4+2] cycloadditions.108

TBA―HS109 was used in the reaction of 2-phenylalkanenitriles 123 with 1,1- or cis-dichloroethylene 124, which gives ethynylated 125 in good yield.

Carbamate 127110(5-methoxy-N-acetyltryptamine-hormone produced and secreted in the pineal gland) is obtained from 126 with ethyl chloroformate in TBA―HS and NaOH in CH2Cl2.

Similarly, TBA―HS is used in alkylation,111 allylation,112 and sulfonylation.113

Also found that TBA―HS has been used to convert alkyl halides into azides. Under milder condition, heterocyclic chloroaldehyde 128 react with NaN3in DMSO to give azides 129 in higher yields.114

Chapter 3 146

3.3.5 ILs in the organic synthesis Rate enhancement, better yields and selectivity of a chemical reaction are key requirements of modern synthetic management.115 ILs, being best alternative to toxic and hazardous organic solvents (particularly chlorinated hydrocarbons)have received considerable attention.116 The green media has improved many synthetic routes;117 hence its demonstration is must in the chemical synthesis.3.3.5.1 ILs, their composition and properties

As low-melting salts (i.e. below 100 ℃), ILs are electrolytes consisting of cationic and anionic species. Since their properties like melting point, viscosity, density and hydrophobicity can be modified with a particular end use, they are also known as designer solvents. Immiscibility with many organic solvents is useful polar alternative for two phase system. With thermal stability allowing a wide working temperature range, they have no vapor pressure, dissolving organic, inorganic and organometallic compounds. Significant impact on the reactivities and selectivities are due to their polar and non-coordinating properties. ILs are of two categories; simple salts and binary ILs. Example of former is [Et3NH3][NO3] and of later is mixture of AlCl3 and 1,3-dialkylimidazolium. Cations in use to build up ILs include ammonium, pyrrolidinium, phosphonium, sulfonium, and imidazolium. Anionic species include mononuclear [Cl⁻, Br⁻, NO3⁻, BF4⁻ etc.], bi- and polynuclear anions [Al2Cl7⁻, Al3Cl⁻,Fe2Cl7⁻ etc], which are sensitive to water. Sulfonamides are those ILs which contains both cationic and anionic centres in a single molecule. Asymmetric cation confers ILs with lower melting.118 ILs may be hydrophilic and hydrophobic. Most tetra alkylammonium, alkylpyridinium, and 1,3-dialkylimidazolium ILs with perflorinated anions are hydrophobic. 3.3.5.2 Synthetic uses of ILs

Nature of ILs has great effect on the reaction. Acidic C(2) of imidazolium cation easily exchanges proton with base even in mild condition.119Baylis―Hillman reaction120 although 100% atom economic in diazabicyclo [2.2.2] octane (DABCO), it takes more time. In [bmin][PF6] however it is 33 timesfaster. Solubility of Knoevenagel adducts in malanonitrile in base KOH is drawback of [bmim][PF6]121 . Imidazolium ILs are thus suitable under basic condition for only few reactions.

Chapter 3 147

3.3.5.3 ILs used in chemical reactions Alkylation of isobutane by 2-butene in [bmim]Cl/AlCl3 increases octane

number of alkene produced. The reaction is more advantageous than the one in HF or H2SO4. Other examples are alkylation122 of benzene, indol and 2-napthol and active methylene units in C―C bond formation.

More eco-friendly allylation123 of methylene units is in palladium(0) by diphenylallyl acetate in [bmim][BF4].

Hydroformylation124 of higher olefins competently soluble in ILs with PF6⁻, SbF6⁻ and BF4⁻ anions is industrially useful reaction.

The reaction rates and selectivity are enhanced more in [emim]Cl-AlCl3 than in conventional AlCl3125. Chloroaluminates in Knoevenagel condensation have variable Lewis acidity.

The Heck reaction126 of arylhalides 139 and alkene 140 in ionic liquids with catalyst Pd(OAc)2 can be performed at rt with excellent yields. Consequently, the catalyst and ionic liquid can be recycled and reused.

Michel addition of acetylacetone 142 to methyl vinyl ketone 143 in Ni(acac)2 in IL [bmim][BF4] provides with excellent results in terms of activity, high selectivity and recyclable catalytic system.

Chapter 3 148

Stereo-controlled Wittig reaction in [bmim][BF4]127 involves no by-product (Ph3PO) isolation. High yields of diaryl ethers from phenol, diaryl from aryl halide can be achieved in a base in [bmim][BF4]-immobilized-CuCl than in DMF. ILs also promote enzyme catalyzed reactions with other transformations. It includes Z-aspartame from carbobenzoxy-L-aspartate and L-phenylalanine methyl ester in catalyst thermolysin in [bmim][PF6]. The usefulness of Diels―Alder128 reaction lies in its high yield and high stereospecificity in ILs, and examples include [bmim][BF4], [bmim][ClO4], [emim][CF3SO3],[emim][NO3] and [emim][PF6]. The reduction of aromatic and aliphatic aldehydes with trialkylborane generally requires higher temperature (150 ℃). But in [bmim][BF4] and [emim][PF6] reaction rate enhances at low temperature. Other IL mediated reactions includes oxidation of aldehyde,129 alcohol130 and oximes,131 oxidative carbonylation of amines,132 Wacker type oxidation133 and hydrogenation,134 C―C bond forming Aldol reaction,135 Suzuki,136 Still,137 and Negishi, 138 and Trost―Tsuji139 type coupling reactions, Sakui,140 Henry,141Stetter,142 and Songashira143 type reactions.3.3.5.4 ILs used in hetero–Diels−Alderreaction

Fischer et al.144 reported Diels―Alder reaction between methyl acrylate and cyclobutadiene in a number of air and moisture stable ILs; [bmim][BF4], [bmim][CIO4], [emim][CF3SO3], etc. with endo selectivity.

Yadav et al.145 converted (R)-(+)-citronellal/3-methylcitronellal 149 and aromatic amines 150 into octahydroacridines 151 and 152 via intramolecular HDA reaction in IL.

Chapter 3 149

Balalaie et al.146 performed DKHDA reaction of substrates 153 with unactivated dienophile 154 in catalyst CuI in [bmim][NO3].

Fazila et al.147 employed ILs as a safe recyclable media, using catalyst microencapsulated Sc(SO3CF3)3 in aza–DA for pyridones.3.4 Chromenes

Among the oxygenated heterocycles, chromenes are widely distributed in the nature. Known as benzopyrans, they are obtained from fusing benzene with six-membered pyran unit. Benzopyran exit in two isomeric forms 1-benzopyran (chromene) and 2-benzopyran (isochromene). The numbering is universally accepted, and is also supported by IUPAC system.

Each has more isomers depending on position of carbon whether fully saturated giving rise to 2H-1-benzopyran (2H-chromene) and 4H-1-bezopyran (4H-chromene). Former with allyl ether type unit is known as α-chromene or Δ3-chromene. Later with vinyl ether unit is γ-chromene or Δ2-chromene. 3.4.1 Physical properties

Just like most of natural products, chromenes are also derived fromisoprene units and show physical properties like isolated isoprene like products. 2H-chromene is liquid; density 1.099 g/cm3 and bp 132 ℃, refractive index 1.5869 (at 297 K). The dihydro 4H-chromene is oil with peppermint like odor; bp 215 ℃, volatile in steam.3.4.2 Synthesis of chromenes

Isolated in 19th century from natural products, syntheses of chromene were known in early 20th century.3.4.2.1 From phenol

Resorcinol 156 with acetylacetone compound in acetic acid or formic acid gave 157 reported in 1923 first by Buck and Heilborn148.

Chapter 3 150

Phenol 158 with AcOH in the presence of ZnCl2 forms chromenes 159.149

3.4.2.2 From O-hydroxybenzaldehydesO-Hydroxybenzaldehyde gave chromenes with ketone, which is probably

the commonest method.150 Acetone on being condensed in abnormal manner with 160 in alkali forms 2-methyl-4-acetonyl-5,6-benzo-γ-chromene 161.151

Salicylaldehyde 162 gives 2-(O-hydroxyphenyl)-3-nitro-Δ3-chromene 163with nitromethane.152

3.4.2.3 Other methods for chromene derivativesYoun and Eom153 reported chromene ring 165 via palladium catalyzed

oxidative cyclization of 164.

Worlikar et al. gave route to chromenes 167, 168 via electrophilic cyclization of 166 by I2, ICl in excellent yields.154

O

R1

R

I2 / ICl

O O

R1 R1R

R166 167 168

Chapter 3 151

Naturally occurring chromenes mollugin were synthesized via pericyclic reaction of 3-(3-methylbut-2-enyl)-naphthoquinon-2-carboxylate.155 Cacchi etal.156 reported addition type reaction of (2-hydroxy-aryl) mercury chlorides with chalcones in a two-phase system.3.4.3 Biological significance

Since a long back, chromenes have been therapeutic agents. Besides being intermediates in the synthesis of natural and medicinal products, they also resemble potassium channel activating drugs.157 Serving as framework of a range of tannins,158 are becoming increasingly important due to their health-promoting effects in vegetables, fruits, fruit juices and red wines. Chromenes are also usedin treating proliferative skin disorders and microbial infections.159Coutoreagenin possesses antidiabetic activity.160 Reported as antiproliferative,161antichemo-preventive,162 antibacterial,163 antifungal,164 anticancer,165 pasmolitic, diuretic, anticoagulant, and antianaphylactic agents.

6-Substituted benzopyran are good potassium channel activators,166 anti-picornavirus capsid-binders,167 selective estrogen receptor-β agonist,168 and potential antagonists of Mycobacterium bovis BCG.169 6-Substituent contributesto receptor affinity either by a direct interaction or indirect by withdrawing electrons from the phenyl moiety of the benzopyran nucleus, optimizing charge-transfer interactions of the aromate with the receptor. In addition, chromenesare well-known for their photochromic properties.1703.5 Present Work

In view of significance of pyran-annulated heterocycles (introduced in present Chapter 3), included in Part-II are some improved DKHDA and DKMC reactions in ionic liquid TEAA (Chapter 4) and in solvent-free TBA―HS (Chapter 5) respectively, for the synthesis of related heterocycles. All polyheterocycles have been screened in vitro for their antimicrobial, anti-tuberculosis and antioxidant activities.

Chapter 3 152

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