130

General IntroductionIncreasing molecular complexity in the synthesis has long been an

ultimate goal of chemists as it resembles the Nature, wherein very complicated molecules such as palytoxin, maitotoxin and others could be synthesized, in creating multiple bonds, rings, and stereocenters in a single transformation. In this context, domino strategy is a powerful way to generate complex molecules in a fewer number of steps; a philosophy is used not only in basic research but also in the applied chemistry.4.1 DKHDA strategies in organic synthesis

When the pericyclic reaction, Diels−Alder1 or cycloaddition2 or sigmatropic3 or electrocyclic4 or retro‒pericyclic5 or ene reaction,6 is coupled with itself or with other pericyclic or non‒pericyclic reaction, leading to a sequence of two or more transformations, it leads to a variety of domino routes. Bioactive paracyclophanes,7 taxane,8 (+)‒preussin,9 spinosyns10 etc. have effectively been synthesized via this route. The reaction can be performed under neutral or mild Lewis acidic condition. A combination of two types of cycloadditions, especially [4+2] and [4+2] is the most successive.11 An anionic reaction coupled with a pericyclic one also signifies as one of the widely used strategies. So the DKHDA approach stands first among three versatile anionic–pericyclic domino reactions like DKHDA reaction (1), domino Knoevenagel−ene reaction (2)12 and domino Knoevenagel−allylsilane cyclization (3),13 allowing highly diversified molecules to generate. Proceeding via in situ formed 1-oxa-1,3-butadiene 314 from an aldehyde 1 and a cyclic or heterocyclic or acyclic 1,3-dicarbonyl compound 2, it forms valuable dihydropyran ring 4 via HDA reaction.Exceptionally it also leads to a domino/Knoevenagel−ene transformation.

Chapter 4 131

A wide spectrum of aldehydes and 1,3-dicarbonyl compounds has been used in the strategy. Asymmetric versions are also in use to access natural products. DKHDA reaction begins with simple substrates, but ends with a highly complex molecule.15Two different approaches of the strategy, which are in use are given below:1. Three–component reaction; which assembles 1,3-dicarbonyl, an aldehyde and a vinyl ether. Intermediate 1-oxabutadiene i.e Knoevenagel alkene undergoes an intermolecular HDA reaction with a suitable dienophile.

RO

O

O

R R

CHO

RO

O

O

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

It proceeds via an inverse electron demand Diels−Alder reaction that is governed by an overlap of diene LUMO with dienophile HOMO. EWG at 3rdposition of diene favors the transformation effectively due to lowering of diene’s LUMO energy. Any aldehyde like aromatic or hetero−aromatic, saturated or unsaturated aliphatic aldehydes can also be used. Similarly, any cyclic and acyclic1,3-dicarbonyl units like Meldrum’s acid, barbituric acids, coumarins, 1,3-cycloalkanedione, β−ketoesters, and 1,3-diones can be treated as active methylene units. Further, phosphorus, nitrogen and sulfur analogues of these diketones have successfully been used. Hetero‒analogues of 1,3-dicarbonyl

Chapter 4 132

compounds such as 5-pyrazolones and isoxazolones can also be used as active methylene unit. Sometimes, domino Knoevenagel−ene process seldom becomesa main process or a side reaction to DKHDA reaction, depending upon the nature of substrates.16

Prof. Tietze has widely investigated into the protocol. While, enol ethers are appropriate dienophiles, enamines more difficult to handle. A simple olefin is suitable, only if the Diels−Alder reaction takes place in an intramolecular mode. An excellent stereo–chemical control is possible. While aromatic or aliphatic α,β‒unsaturated aldehydes usually give cis‒fused cyclized product, simple aliphatic aldehydes the trans‒adduct.17 For the enantiopure products, chiral aldehydes, 1,3-dicarbonyl compounds as well as Lewis acids18 can be effectively used.

A wide range of solvents can be used in the transformation. Acetonitrile, dichloromethane and toluene are among the most appropriate ones. Alcohols and water are also suitable. Xylene in case of less reactive dienophile is more suitable.

Figure 4.1 Four possible TS structures of intramolecular HDA reaction.Knoevenagel intermediate exist in either (E)– and a (Z)–configurations.

An orientation of tethered dienophile leads to four possible transition structures; exo–E–anti (1), endo–E–syn (2), exo–Z–syn (3) and endo–Z–anti (4). Most favored among them decide stereochemical out‒come of the reaction (Fig. 4.1).

Based on several experiments and calculations,19 the first and forth TS lead to a trans‒ and the second and third to a cis‒annulated dihydropyran.

Chapter 4 133

Further, in case of an aromatic aldehyde and aliphatic α,β‒unsaturated aldehydes, it favors an endo‒E‒syn orientation giving cis–cycloadducts. The normal aliphatic aldehydes via favored exo–E–anti orientation lead to transproducts along with a minor cis one. The TS seems to be non–symmetric; so we assumed that the dienophile attacks the carbon at position–4 of oxabutadiene along a trajectory of about 109°. It causes planarity of the phenyl group to deviate via endo–E–syn TS. In the latter case, steric interaction of the ortho–substituent at the phenyl group, and the second carbonyl group are clearly diminished. High stereocontrol in all cases is clearly due to two substituents at terminal double bonds of the acceptor moiety which controls the conformation of the chain. We call this effect a sp2 geminal effect,20 which is due to the phenomenon of the 1,3-allylic strain.21

Thus, the Knoevenagel reaction of 5 with the tert-butylpyrazolone 6 gives exclusively (Z)–compound 7 which isomerizes at higher temperature to the (E)–compound 8 leading to the cycloadduct 9 via an endo–E–syn TS. This mechanism was observed under irradiation, allows a Z/E–isomerization of 7/8, the domino reaction already takes place at 40 °C instead of 110 °C.22

CHO

O

NNO

Ph

t-Bu

NN

O

t-Bu

Ph

O

O NN

Ph

t-BuOO

O

NN

Ph

t-Bu H

H

5 6 7

89

4.1.1 Natural products synthesis4.1.1.1 Enantiomerically pure heterosteroids and homosteroids

Tietze, L. F. et al.23 described stereoselective trans–bonded hetero–steroids 12 (de >98 %) from an aldehyde 11 and cyclic 1,3-dioxo compound 10 or its analogs.

Chapter 4 134

Asymmetric DKHDA reaction of a D–secoestrone derivative 13 with Meldrum’s acid 14 afforded corresponding bridged D–homoestrones 15 to other diketones also. 24

4.1.1.2 Tetrahydrocannabinol and hexahydrocannabinol

Marihuana tetrahydrocannabinol ingredient and its hydrogenated products are well known psychoactive agents. Alkylidene-1,3-dicarbonyls 18from citronellal 16 and 5-pentyl-1,3-cyclohexandione 17 in the presence of EDDA undergoes a cycloaddition in a highly stereoselective manner to tricycle 19which aromatize to enantiopure hexahydrocannabinol 20.254.1.1.3 Deoxyloganin and secologanin

Monoterpene glycosides deoxyloganin and secologanin of iridoids and secoiridoids families respectively, are key intermediates in the biosynthesis of

Chapter 4 135

monoterpenoid indole alkaloids; ipecacuanha, cinchona, and pyrroloquinoline. The key step in the synthesis of deoxyloganin 24 is condensation of Meldrum’s acid 14 and the aldehyde 22. Domino product 23 further transforms into deoxyloganin 24 via solvolysis in methanol, reduction with diisobutylaluminium hydride (DIBAH), acid–catalyzed elimination, and glycosidation.26

Secologanin aglycon ethyl ether 29 was obtained via a three–component reaction of monoprotected dialdehyde 25, trichlorooxobutanone 26, and enol ether 27 containing a sulfoxide group to give 28.27

4.1.1.4 Monoterpenoid indole alkaloidsSeveral alkaloids hirsutine 30, dihydro–corynantheine 31,

dihydroantirhin28 32, corynanthe type alkaloid 33, emetine29 34 and tubulosine3035 have been synthesized by this approach.

Chapter 4 136

N

HN

H

H

H

H

OMe

MeO

MeO

MeON

HN

H

H

H

H

MeO

MeO

HN

OH33 34

NN

HTs

N N

O

OO

H

H

35

NNCbz

CHOTs

H

OBn O

O

O

O

NNCbz

TsH

O

EDDA,

20 0C

12 h (((

H2/Pd/C37 14

O

OBn

H

H

36

38

NN

TsH

H

CHO

H

LiAlH4N

N

TsH

H

CH2OH32 39

O

H

40

41 42

NNCbz

CHOTs

H

OBn N

N

O

O O

NNCbz

TsH

O

N N

O

O

H

OBn

NN

TsH

N N

H

HO

O

EDDA,

20 0C

12h (((H2/Pd/C

O

37 33

4.1.1.5 Natural product preethulia coumarinCravotto, G. et al. have accessed enol ether 45, 4-hydroxycoumarin 44, and

α-diketone 43, which gave cycloadduct 46 in 79 % yields using catalyst Yb(OTf)3. Compound 46 could be transformed into the natural product preethulia coumarin 47.31

Chapter 4 137

O O

OH

O

O

O

O

O

O

O

O

Yb(OTf)3

Dioxane, r.t.

O

O

O

43

44

4546 47

4.1.1.6 Meroterpenoid GuajadialGuajadial 51 is a novel meroterpenoid that was isolated from the leaves of

Psidium guajava (guava). Lee, V. et al. described its biomimetic synthesis from caryophyllene 48, benzaldehyde 49 and diformylphloroglucinol 5032 via three–component coupling reaction in an aqueous media.

4.1.2 DKHDA strategy towards diversified heterocyclesBesides natural products, the approach afforded many diversified

heterocycles. Various aspects like substrates, catalysts, reaction conditions, medicinal properties, industrial applications etc. have been covered in the new methodologies. Some recent reports are given below.

Moghaddam, F. M. et al.33 synthesized bi–functional starting aldehyde 52with an unsaturated sultonate group in side chain, which gave novel thiopyrano indole–annulated benzo--sultones 54 and 55 with indoline-2-thiones 53 in water via DKHDA reaction.

Chapter 4 138

Balalaie, S. et al.34 reported CuI–ionic liquids as efficient reaction media for the synthesis of pyrano–annulated benzopyran derivatives.

Antibacterial pyranoquinolinones 61 and 62 were prepared from quinolinone 60 with aldehyde 59 in EDDA.35

Gallos, J. and Koumbis, A.36 used sugar derived δ,ε–unsaturated aldehydes63 for synthesis of polyhydroxylated carbocycle–dihydropyran fused ring systems 64.

Alonso, S. J. et al.37 reported novel pyranonaphthquinones 67 & 68 based on their previous pharmacophore modeling studies, potential drugs that target human topoisomerase II catalytic inhibitors.

Chapter 4 139

Tietze, L. F. et al.38 described a very short approach, using a three–component DKHDA reaction, to 2-alkoxy-6-methyl-5-nitro-3,4-dihydro-2H-pyran 72 obtained in 81―95%.

Using different lengths of a tether between aldehyde and dienophiles (in aromatic/heteroaromatic–based substrates), a broad variety of highly diversified heterocyclic compounds could be prepared. Reaction between 73 and 74 gave 75 containing a new 5,6–ring system, whereas reaction of 76 and 74 gave 77 with a 7,6–ring system.39

76 77

CHO

ONNO

Ph

EDDA

187 0CNN

O

H

H

Ph

O

74

SO

O

O

R1 R2O

N

O

OPh

O O

O

Ti

Cl

ClO

OO O

OO

O OO O

OO

78 79 8081

Chiral 1,3-dicarbonyl compounds 78, 79 and oxathiolanes 80 have also been used to prepare enantiopure products.40 In addition, chiral mediators 81have been employed with great success.41

Yadav, J. S. et al. described O-propargylated sugar aldehyde 83 with 1,3-diketones; dimedone, cyclohexane-1,3-dione 82, to afford a novel class of carbohydrate analogues furochromene 84 via a DKHDA reaction in good yields.42

Chapter 4 140

Nagaiah, K. et al.43 described synthesis and antiproliferative activity of chromeno–annulated cis–fused pyrano[3,4-c]pyrans. 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones 85 and 1,3-dicarbonyl/analogues active methylene unit 86 react to give desired products 87.

Bandyopadhyay, C. et al.44 reported N-alkenyl-N-arylamino-4-oxo-4H-1-benzopyran-3-carbaldehyde 88 with dimedone 89 in pyridine in ethanol to assess polycyclic heterocycles 90 containing pyridine and chromon rings by one–pot method.

A new version of DKHDA strategy was described by Balalaie, S. et al.45 in the preparation of pyrano[3,4-c]chromenes scaffolds. An aldehyde 91 gave new pyrano[3,4-c]chromenes 93 with benzoylacetonitrile 92, in the presence of CuI and diammoniumhydrogen phosphate in good yields and high bond–forming efficiency.

Chapter 4 141

Sarkar, A. et al.46 synthesized julolidine hybrid analogs 96 via DKHDAreaction of O–prenylated aldehyde 94 with 1,3-diketones 95.

Dehaen, W. et al. reported thiopyranopyrazolo–fused–pyrano pyrazoles 99 from pyrazolone–based aldehydes 97 and pyrazolones 98. They also attempted for several other heterocycles from pyrazole, pyrimidine, pyridine, indole and thiazole.47

NN S

CHOR

Ph

NN

Ph

R1

O

NN

R

Ph

S

O

NN

Ph

R1

HH

EDDA

CH3CN

97 98

99R Me, Ph R1 H, Me, Ph, CF3Moghaddam, F. M et al.48 synthesized polycyclic indole derivatives 102from O-acrylated salicylaldehydes 100 and dihydroindole-2-thiones 101 in water. Product yields were in the 65―95 % range with high regio– and stereoselectivity.

Chapter 4 142

Raghunathan, R. et al.49 synthesized indolo[2,1-a]pyrrolo[4’,3’:4,5]pyrano[5,6-c]coumarins 105 and indolo[2,1-a]pyrrolo[4’,3’:4,5]pyrano[6,5-c]chromones 106 from N-alkylated indole-2-carbaldehyde 103 and coumarins 104.

Lee, Y. R. et al.50 developed EDDA–catalyzed, efficient one–pot synthetic approach to benzopyranobenzopyrans 109 and naphthopyranobenzo–pyrans viaa DKHDA reaction of resorcinol 107 or naphthols with O-allyl–ether–tethered salicylaldehydes 108 or naphthaldehyde. It allows a rapid access to polyheterocycles with stereochemically defined quaternary carbon centers.

Majumdar, K. C. et al.51 demonstrated an efficient and simple strategy for indole–annulated thiopyranobenzopyrans 112 and 113, in excellent yields from simple substrates 110 and 111. The reaction is highly stereoselective that lead to cis–annulated polyheterocycles.

Chapter 4 143

Majumder, S. and Bhuyan, P. J.52 reported some novel complex thiopyrano[2,3-b]indoles 116 from simple thioindole 114 and 1,3-diketones 115yielding products in the 62―75 % range in the presence of catalyst EDDA.

Reddy, B. V. et al.53 reported angularly fused chromenes 119 from alkene–tethered chromene-3-aldehyde 117 and 1,3-cyclic diketones 118.

4.2 TBA―HS, glycerol and ionic liquids in organic synthesis4.2.1 TBA–HS in organic synthesis

To develop new methodologies that minimize the wastes generation, the PTC is often an alternative choice.54 As quaternary ‘onium’ salt such as ammonium, phosphonium, antimonium, and tertiary sulfonium salts, they are used in small quantity. Thermal decomposition of sodium trichloroacetatesuspended in anhydrous chloroform in quaternary salt is useful reaction to generate reactive intermediate dichlorocarbene. Requiring no vigorous conditions, it offers fast reaction, even in anhydrous condition, and involves no tedious workup procedure. TBA–HS is an acid catalyst and has been widely used in the organic synthesis. Its use in DKHDA strategy is however very rare.

Acid–catalyzed DKHDA strategy is efficient synthetic route to complex heterocycles. Lewis acid particularly55 influences both the DA and HDA reactionsin terms of reaction rate.56 Out of two reactions; anthracene with maleic anhydride at rt (1) and 1,4-benzoquinone and dimethyl fumarate in AlCl3 (2), the increased rate of later (2) is due to lewis acid.57 Along with SnCl4 which also promotes the reaction there are many other reports in the literature.58 Lewis acids such as ZnCl2, BF3, MeAlCl2, and Et2AlCl59 are common in HDA reaction.

Chapter 4 144

The influence of acid can be rationalized by FMO theory. Normal DA reaction involves a dienophileLUMO–dieneHOMO interaction. Decrease in HOMO–LUMO energy gap favors the reaction due to effective orbitals–overlap.60 In the process, coordination of Lewis acid towards carbonyl oxygen via lone pair electrons helps reduce LUMO–HOMO energy gap of aldehyde (Fig 4.2). Additionally with increased magnitude of carbonyl LUMO, it makes it more susceptible to the diene. Polarization as well changes the reaction pathway from a concerted non–synchronous mechanism to a stepwise mechanism. Substituents on reactants and reaction conditions also affect the mechanism.61

Figure 4.2 FMO diagram of HDA reaction in the presence and absence of a Lewis acid.

Figure 4.3 The endo–selectivity is seen in the Lewis acid catalyzed HDA reaction as the solvated Lewis acid is exo, due to its size.

The orientation of dienophile at TS decides the stereochemistry of products. The endo–selective is generally due to the preference of the Lewis acid being exo as a result of its size (Fig 4.3).62 In addition, the Lewis acid and the carbonyl R group are proposed to be trans to each other.63 Similarly, the uncatalyzed reaction of aldehydes and a diene demonstrate endo–selectivity for the carbonyl substituent.64

Lewis acids are chosen based on experimental trial and error works. Kobayashi, S. et al. reported Lewis acids activity with aldehydes and imines.65 It

Chapter 4 145

states that strong acids don’t necessarily promote the reaction and that observed selectivities of aldehyde or aldimine depends upon nature of Lewis acid. Many metals like Eu, Ti, Yb, Cr, Zn, Co, Cu, Al, Sc, Li, etc., and its chiral auxiliaries are also used as Lewis acids.66 ILs are also employed as a both solvent and catalyst.67

In view above, thus acid catalysts and their role in HDA strategy has been significant investigating area of research. TBA–HS has not been yet explored in DKHDA strategy although studied in many other reactions. The examples are given below.

TBA–HS 68 was used in reaction of 2-phenylalkanenitriles 120 with 1,1- or cis–dichloroethylene 121, which gives ethynylated 122 in good yield.

Carbamate 12469(5-methoxy N-acetyltryptamine‒hormone produced and secreted in the pineal gland) is obtained from 123 with ethyl chloroformate in TBA–HS and NaOH in CH2Cl2.

NH

MeOClCO2Et

TBA-HS, NaOH

N

MeO(CH2)NHCOCH3

EtOOC123 124

(CH2)NHCOCH3

Similarly, TBA–HS is used in alkylation,70 allylation,71 and sulfonylation.72Also found that TBA–HS has been used to convert alkyl halides into

azides. Under milder condition, heterocyclic chloroaldehyde 125 react with NaN3in DMSO to give azides 126 in higher yields.73

Recently, our research group reported a solvent–free, TBA–HS catalyzed DKHDA reaction of 2-alkenyloxy-acetophenones 127 with pyrazolones 128,giving chromeno–fused pyrazoles 129. Access to bioactive aminochromen–annulated heterocycles 130 from nitro analogous is useful application of this synthetic route.74

Chapter 4 146

One more report from our research laboratory that described TBA–HS mediated DKHDA appeared for synthesis of benzopyran–annulated pyrano[2,3-c]pyrazoles 133.75

4.2.2 Glycerol as a green solvent in organic synthesisSolvents are useful in numerous processes such as medium in the organic

synthesis, dissolving medium in the separation procedure, and diluters in the solution preparation. Traditionally, many non–polar organic solvents are in use.But due to environmental awareness, water and other highly polar solvents like ethylene glycol and formamide have emerged as effective medium, particularly,in the DA reaction.76 Thus, from environmental, economic, safety, handling, and products isolation point of view, the chemical, physical, and biological nature of the solvent plays a key role in the chemical process. Considering an impact of chemical processes on the environment, the search for innovative concepts thatsubstitute volatile organic solvents has become a tremendous challenge in academia and industry.77 According to the twelve principles of green chemistry, a green solvent should meet numerous criteria such as low toxicity, non–flammability, non–mutagenicity, non–volatility and widespread availability among others. Moreover these green solvents have to be cheap and easy to handle and recycle.78

Very recently glycerol (also known as 1,2,3-propanetriol or glycerin) has appeared as an alternative feed–stock source79 for green and sustainable organic

Chapter 4 147

chemistry. As a byproduct of transesterification of triglyceride in the soap and biodiesel industries, glycerol has a very high boiling point and negligible vapor pressure, making it compatible with most organic and inorganic compounds, requiring no special handling or storage. Derivatives are also useful intermediates of pharmaceutical and food products. Like other polar organic solvents, glycerol not only dissolves inorganic salts, acids, and bases, as well as enzymes and transition metal complexes (TMCs), but also organic compounds that are poorly miscible in water, and is non–hazardous. Different hydrophobic solvents such as ethers and hydrocarbons which are immiscible in glycerol allow removal of reaction products simply by extraction. Distillation of products is also feasible due to the high boiling point of glycerol. In particular, the low toxicity of glycerol also allows the synthesis of pharmaceutically active ingredients in which the toxicity and residue of solvents are needed to be carefully controlled. Along with peculiar physical and chemical properties‒such as polarity, low toxicity, biodegradability, glycerol with renewable feed stocks has prompted us to extend its use as a green solvent in DKHDA reaction. There are many known organicsynthesis reported in this reaction medium. Useful references can be cited below.

Wolfson, A. and Dlugy, C.80 explored Palladium–catalyzed Heck coupling of halobenzenes 134 with various alkenes 135 and the Suzuki cross coupling of halobenzenes 134 with phenylboronic acid 136 in this medium.

Wolfson, A. et al.81 also reported nucleophilic substitution of benzyl chloride 139 by potassium thiocyanate and the reduction of benzaldehyde 49 by sodium borohydride.

Chapter 4 148

Jerome, F. et al.82 demonstrated catalyst–free aza–Michael addition of amines 142 to α,β–unsaturated carbonyl compounds 143.

The medium is also advantageous for electrophilic activation of aldehydes,83 wherein bis(indolyl)methane derivatives 147 could be accessed through a thermal reaction between 2-methylindole 146 and aldehydes 145, involving no acid catalyst.

2-Bromoketones 148 gave interesting thiazole derivatives 150 with thiourea/thioamide 149 in glycerol84

Kumar, A. et al.85 described a catalyst–free approach for C–H hydroarylation of in situ generated ortho-quinone methide 154 from 4-hydroxycoumarins 151 and aldehydes 152, with electron rich arenes 153(tertiary aryl amines) in glycerol.

Chapter 4 149

Perin, G. et al.86 demonstrated efficient thioacetalization of aldehydes and ketones in glycrol, which combine carbonyl compounds 155 with 1,2-ethanedithiol 156 and thiols 157, affording dithiolanes 158 and thioacetals 159respectively.

Gu, Y. et al.87 used this medium in Diels–Alder reaction. Heating a mixturecontaining phenylhydrazines 160, β–ketoesters 161, paraformaldehyde 162, and styrenes 163 in glycerol at 110 oC gave pyrano[2,3-c]pyrazoles 164 in good yields.

Gu, Y. et al.88 also described a three–component intermolecular HDAreaction taking, together dimedone 89, formaldehyde 162 and styrene 165, in glycerol.

Perin, G. et al. 89 obtained octahydroacridines 169 and 170 in good yields via one–pot HDA reaction of (R)–citronellal 167 with substituted arylamines 168at 90 oC.

Chapter 4 150

CHO

H2N

RN

R

HH

H

N

HH

H

R++

Glycerol

90 oC

167168

169 170

4.2.3 Ionic liquids in the organic synthesisRate enhancement, better yields and selectivity of a chemical reaction are

key requirements of modern synthetic management.90 ILs, being best alternative to toxic and hazardous organic solvents (particularly chlorinated hydrocarbons) has received considerable attention in the synthesis.91 The green media has improved many synthetic routes;92 hence its demonstration is must and worth in the chemical synthesis.4.2.3.1 ILs, their composition and properties

As low–melting salts (i.e. below 100 oC), 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 [EtNH3][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.93 ILs may be hydrophilic and hydrophobic. Most tetra alkylammonium, alkylpyridinium, and 1,3-dialkylimidazolium ILs with perflorinated anions are hydrophobic. 4.2.3.2 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.94 Baylis–

Chapter 4 151

Hillman reaction95 although 100% atom economic in diazabicyclo[2.2.2]octane (DABCO), it takes more time. In [bmin]PF6 however it is 33 times faster. Solubility of Knoevenagel adducts of malanonitrile in base KOH is drawback of [bmim][PF6]96 . Imidazolium ILs are thus suitable under basic condition for only few reactions.4.2.3.3 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 alkylation97 of benzene, indol and 2-napthol and active methylene units in C–C bond formation.

More eco–friendly allylation98 of methylene units is in palladium(0) by diphenylallyl acetate in [bmim]BF4.

Hydroformylation99 of higher olefins 173 competently soluble in ILs with PF6�, SbF6� and BF4� anions is industrially useful reaction.

The reaction rates and selectivity are enhanced more in [bmim]Cl–AlCl3 than in conventional AlCl3100. Chloroaluminates in Knoevenagel condensation have variable Lewis acidity.

The Heck reaction101 of chlorobenzene with styrene in trans–di(μ-acetato) bis[o-tolyphosphino]benzyldipalladium(II) in Bu4NBr is more economic than the one in expensive palladium catalyst.

Chapter 4 152

Michel addition of acetylacetone 183 to methyl vinyl ketone 184 in Ni(acac)2 in IL [bmim][BF4] provides with excellent results in terms of activity, high selectivity and recyclable catalytic system.

Stereo–controlled Wittig reaction in [bmim]BF4102 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 promotes 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―Alder103 reaction lies in its high yield and high stereospecificity in ILs, and examples include [bmim][BF4], [bmim][ClO4], [bmim][CF3SO3], [bmim][NO3] and [bmim][PF6]. The reduction of aromatic and aliphatic aldehydes with trialkylborane generally requires higher temperature (150 °C). But in [bmim][BF4] and [bmim][PF6] reaction rate enhances at low temperature. Other IL mediated reactions includes oxidation of aldehyde,104 alcohol105 and oximes,106 oxidative carbonylation of amines,107 Wacker type oxidation108 and hydrogenation,109 C―C bond forming Aldol reaction,110 Suzuki,111 Still,112 and Negishi,113 and Trost–Tsuji114 type coupling reactions, Sakui,115 Henry,116Stetter,117 and Songashira118 type reactions. 4.2.3.4 ILs used in HDA reaction

Fischer, T. et al.119 reported Diels–Alder reaction between methyl acrylate187 and cyclobutadiene 186 in a number of air and moisture stable ILs; [bmim][BF4], [bmim][CIO4], [bmim][CF3SO3], etc. with endo selectivity.

Chapter 4 153

Yadav, J. S. et al.120 converted (R)-(+)-citronellal/3-methylcitronellal 190and aromatic amines 191 into octahydroacridines 192 & 193 via intramolecular HDA reaction in IL.

Recently, we121 reported some new angular benzopyrano[3,4-c]pyranofused pyrazoles 196 from O-allylated/prenylated 2-hydroxy acetophenones 194 in ionic liquid cum–catalyst TEAA. The method is highly efficient, even in case of unactivated dienophile too.

Another report from our laboratory122 also describes the application of TEAA in efficient synthesis of pyrano– and thiopyrano fused heterocycles 199 viaDKHDA strategy.

Balalaie, S. et al.123 performed DKHDA reaction of substrates 200 & 201with unactivated dienophile in catalyst zirconium oxide (NP)–[bmim][NO3].

Chapter 4 154

4.3 Pyran−annulated heterocyclesPyran is a six–membered oxygen containing heterocycle with two double

bonds. It has four sp2 and one sp3 hybridized carbon making it a non–aromatic system.

Figure 4.4 General structures of pyranPyran–annulated heterocycles constitute an important class of

compounds, found as important constituents of natural and synthetic products.They are well known antioxidant, anti–inflammatory, antiviral, antiallergic, hepatoprotective, anticarcinogenic, hypnotic, anthelminthic, insecticidalhepatoprotective, anticarcinogenic, anticoagulant and antifungal agents, in addition to HIV protease inhibitors.124 Naturally occurring compounds that include isoethuliacoumarin A, isoethuliacoumarin B, isoethuliacoumarin C, ethuliacoumarin A, ethuliacoumarin B, pterophyllin, calonone, isocalonone, (+) calanolide A, soulattroide and (+)-isofer–prenin,125 all possess a pyrano coumarin skeleton.

Compounds containing pyranone unit exist in plants, animals, marine organisms, bacteria and insects. They also involve in different biological processes like defense against other organisms, biosynthetic and intermediates, and as metabolites. They are also precursors to pharmacologically active compounds such as HIV protease inhibitors,126 antifungal,127 cardiotonics,128anticonvulsants,129 antimicrobials,130 pheromones,131 natural pigments,132antitumor agents,133 and plant growth regulators.134 Microbially derived 2-pyranones, from fungi of various genera, are found to display a wide range of cytotoxic, neurotoxic and phytotoxic properties.

Chapter 4 155

Figure 4.5 Naturally occurring compounds containing pyranPalasz, A.135 synthesized pyrano[2,3-d]pyrimidiness 206 & 207 via

intermolecular HDA reaction of an aldehydes 203, barbituric acids 204 and ethyl vinyl ether 205.

Braun, A. E. et al.136 synthesized pyrano embelin derivatives 210 viaDKHDA reaction of embelin 208 with paraformaldehyde and electron rich alkenes 209.

Intramolecular HDA reaction of 6-(4-alkenyloxymethylene)-2,4-cyclohexadien-1-ones 213―generated from salicylaldehyde derivatives 211 and unsaturated alcohols 212, afforded pyrano[3,2-c]benzopyrans 214.137

Prajapati, D. and Gohain, M.138 investigated a new, simple and efficient synthesis of novel fused pyrimidines 217 via an inverse electron–demand HDA reaction. Dienophiles such as ethyl vinyl ether or dihydrofuran 216 were reacted

Chapter 4 156

with in situ generated heterodiene α,β–ethylenic ketones 215 in the presence of 1 mol % indium(III) trichloride.

Lee, Y. R. and Hung, T. V.139 described synthesis of pyrano–fused tetrahydroquinoline 220 from N,N-dialkylated aminobenzaldehydes 218 and 1,3-diketones 219 in xylene using EDDA.

Phenylsulfinyl– or phenylsulfonyl-2-propanone as well as phenylsulfonyl-acetophenone yielded corresponding Knoevenagel condensation products 221with methyl-2-butenyloxy- and (E)-phenyl pro-penyloxybenzaldehyde that underwent intramolecular cycloaddition to major cis–fused 2H-pyran derivatives 222. Generally, a cis–diastereomer 222 or its mixture with trans–223was obtained.140

Deb, M. L. and Bhuyan, P. J.141 synthesized pyrano annulated–pyrido[2,3-d]pyrimidines 226 & 227 from 6-N-allyl-1,3-dimethyl-5-formyl uracils 224 and 1,3-diketones 225.

Chapter 4 157

Nair, V. et al. reported in situ generated quinine 228 via Knoevenagel condensation of 4-hydroxycoumarin 44 and formaldehyde that underwent a facile Diels−Alder reaction with pentafulvenes 229 to afford novel pyranocoumarin derivatives 230 in good yield.142

Our research group has also reported a solvent– and catalyst–free DKHDA reaction for pyrano–fused polyheterocycles from 231 and 232. Subsequent reduction of azo group afforded analogues amino frameworks 233.143

Ghandi, M. et al.144 described catalyst–free and diastereoselective synthesis of novel dihydropyrano[3,2-c]chromen–annulated benzosultams 235 &236 from N-(2-formylphenyl)-N-methyl- 2-phenylethenesulfonamides 234 and coumarin 44.

Chapter 4 158

Baruah, B. and Bhuyan, P. J. described some complex pyrano[2,3-b]quinolines 239 from quinoline 237 and 1,3-dimethylbarbituric acid 238 using water.145

Majumdar, K. C. et al.146 described regioselective synthesis of chromeno[4’,3’:4,5]pyrano[3,2-c][1,8]naphthyridin-13-ones 242 via DKHDA reaction of 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one 241 with O-allylated/propargylated salicylaldehydes 240.

Raghunathan, R. et al.147 reported pyranoquinolinones 245, 246 from 4-hydroxy-1,2-dihydro-2-quinolinones 243 and O-prenylated aromatic aldehydes 244 or aliphatic aldehyde citronellal via an intramolecular HDA strategy. A high degree of chemoselectivity was achieved under a MWI condition.

N

R

O

OH

CHO

O

N

O O

OR

N

R

O

OO

243244

245 246

4.4 Present workPresent Chapter 4 of Part-II introduced to DKHDA strategies, TBA-HS,

Glycerol and ionic liquids in organic synthesis, along with pyran-based heterocycles. Rest of the Part-II disseminates the synthesis and biological evaluation of pyran‒annulated heterocycles in two Chapters 5 and 6. Both

Chapter 4 159

intramolecular (Chapter 5) and intermolecular (Chapter 6) DKHDA approaches had been optimized and studied in three different conditions; TBA-HS under solvent‒free environment―demonstrating pyrazolo―, benzopyrazolo andbenzopyrano[2,3,4-kl] xanthenes, in glycerol―demonstrating pyrazolopyrano-fused thiochromeno[2,3-b] quinolines and in ionic liquid TEAA―demonstrating quinolyl― and indolylpyrano[2,3-c]pyrazoles. Biological screening tests were employed to determine in vitro antimicrobial, anti‒tuberculosis and antioxidant activities.References 1. (a) Elliott, G. I.; Velcicky, J.; Ishikawa, H.; Li, Y. K.; Boger, D. L. Angew. Chem. Int.Ed. 2006, 45, 620; (b) Zeng, Y.; Aube, J. J. Am. Chem. Soc. 2005, 127, 15712; (c) Inanaga, K.; Takasu, K.; Ihara, M. J. Am. Chem. Soc. 2004, 126, 1352.2. (a) Shintani, R.; Fu, G. C. Angew. Chem. Int. Ed. 2003, 42, 4082; (b) Yu, M.; Pagenkopf, B. L. Org. Lett. 2003, 5, 5099.3. (a) Nicolaou, K. C.; Xu, H.; Wartmann, M. Angew. Chem. Int. Ed. 2005, 44, 756; (b) Majumdar, K. C.; Das, U. J. Org. Chem. 1998, 63, 9997; (c) Wipf, P.; Waller, D. L.; Reeves, J. T. J. Org. Chem. 2005, 70, 8096.4. (a) Anderson, E. A.; Alexanian, E. J.; Sorensen, E. J. Angew. Chem. Int. Ed. 2004, 43, 1998; (b) Ohmori, K.; Mori, K. ; Ishikawa, Y.; Tsuruta, H.; Kuwahara, S.; Harada, N.; Suzuki, K. Angew. Chem. Int. Ed. 2004, 43, 3167.5. (a) Goti, A.; Cicchi, S.; Cacciarini, M.; Cardona, F.; Fedi, V.; Brandi, A. Eur. J. Org.Chem. 2000, 3633. (b) Jung, M. E.; Davidov, P. Org. Lett. 2001, 3, 3025.6. (a) Cheng, D.; Knox, K. R.; Cohen, T. J. Am. Chem. Soc. 2000, 122, 412; (b) Tietze, L. F.; Rischer, M. Angew. Chem. Int. Ed. 1992, 31, 1221.7. (a) Hopf, H.; Böhm, I.; Kleinschroth, J. Org. Synth. 1981, 60, 41; (b) Hopf, H.; Lenich, F. Chem. Ber. 1974, 107, 1891.8. Winkler, J. D.; Kim, H. S.; Kim, S. Tetrahedron Lett. 1995, 36, 687.9. Deng, W.; Overman, L. E. J. Am. Chem. Soc. 1994, 116, 11241.10. Mergott, D. J.; Frank, S. A.; Roush, W. R. Org. Lett. 2002, 4, 3157.11. Alcaide, B.; Almendros, P.; Redondo, M. Chem. Commun. 2002, 1472.12. Tietze, L. F.; Beifuss, U.; Antel, J.; Sheldrick, G. M. Angew. Chem. Int. Ed. 1988, 100, 739; Angew. Chem. Int. Ed. 1988, 27, 703.13. (a) Tietze, L. F.; Schunke, C. Angew. Chem. Int. Ed. 1995, 107, 1901; Angew Chem.Int. Ed. 1995, 34, 1731.14. Tietze, L. F.; Beifuss, U. In Comprehensive Organic Synthesis; Trost, B. M., Ed. Permagon: Oxford, 1991; Vol. 2, p 341.15. (a) Tietze, L. F.; Kettschau, G.; Gewert, J. A; Schuffenhauer, A. Curr. Org. Chem.1998, 2, 19; (b) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967.16. Tietze, L. F.; Brumby, T.; Brand, S.; Bratz, M. Chem. Ber. 1988, 121, 499.17. (a) Tietze, L. F.; Geissler, H.; Fennen, J.; Brumby, T.; Brand, S.; Schulz, G. J. Org.Chem. 1994, 59, 182; (b) Tietze, L. F.; Ott, C.; Geissler, H.; Haunert, F. Eur. J. Org.Chem. 2001, 1625.

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