Green Chemistry Greener Alternatives to Synthetic Organic Transformations

V.K. Ahluwalia

Alpha Science International Ltd. Oxford, U.K. Contents

Preface v Parti

1. Introduction 1.1-1.10 1.1 Principles of Green Chemistry 1.1

1.2 How to Plan a Green Synthesis 1.2 Part II Green Alternatives to Synthesis Organic Transformations

2. Aqueous Phase Transformations 2.1-2.48 2.1 p-Acetylaminophenol (Tylenol) 2.1 2.2 3-Aminopyridine 2.2 2.2a Anthranilic Acid 2.3

2.3 Benzilic Acid 2.3

2.4 Benzoin 2.5

2.5 Benzotriazole 2.6

2.6 2-Benzoyl-3,5-dimethylbenzofuran 2.7 2.7 n-Butyl Bromide 2.8 2.8 Tert.Butylchloride 2.8 2.9 Chalcone (Benzalacetophenone) 2.9 2.10 Cycloheptanone 2.10 2.11 2,3-Dihydroxy Anisole (Pyrigallol Monomethyl-ether) 2.12 2.12 2,4-Dihydroxybenzoic acid (P-resorcylic Acid) 2.13 2.13 3,4-Dimethoxyphenol 2.14 2.14 2,3-Dimethyl-l-phenylpyrazol-5-one 2.15 2.15 3, 5-Dimethylpyrazole 2.16 2.16 5,5-Diphenylhydantoin 2.17 2.17 Endo-cis-1,4-endoxo-A5-cyclohexene-2,3-dicarboxylic Acid 2.18 2.18 p-Ethoxyacetanilide (Phenacetin) 2.19 2.19 6-Ethoxycarbonyl-3,5-diphenyI-2-cyclohexenone 2.20 2.20 HeteroDiels-AlderAdduct 2.22 2.21 Hippuric Acid (Benzoyl Glycine) 2.22 Viii Contents

2.22 Hydantion 2.23 2.25 3-Hydroxy-3-phenyl-2-methylene Proponamide 2.24 2.24 Iodoform 2.25

2.25 Inodole 2.26 2.26 3-(p-Methoxyphenyl)-2H-1,4-Benzoxazine 2.27 2.27 3-Methylcyclopent-2-enone 2.27 2.28 2-(2'-Methlindol-3yl)-1,4-benzoquinone 2.28 2.29 2-methyl-2-(3-oxobutyl)-1,3-cyclopentanedione 2.29 2.30 P-Naphthyl Acetate 2.30 2.31 (5-Naphthyl Methyl Ether (Nerolin) 2.31 2.32 Naphthaldehyde 2.31 2.33 2-Naphthoic Acid 2.33 2.34 Phenyl Acetate 2.34 2.35 2.35 2.36 2-Phenyl p-benzoquinone 2.36 2.37 1 -phenyl-2, 2-dichlorocyclopropane 2.36 2.38 P-Phenylpropionic Acid 2.37 2.39 Pinacolone 2.38

2.40 Salicylic Acid 2.39 2.41 Stilbene (Trans) 2.41 2.42 2,3,4-Trimethoxyphenol 2.43

2.43 o-Toluamide 2.44

2.44 Vanillideneacetone 2.45

2.45 Miscellaneous Transformations in Water 2.46 Autocatalysis 2.46

2.46 Conclusion 2.48

Transformations in Solid Phase 3.1-3.28 3.1 2-Allyl Phenol 3.1 3.2 Anthraquinone 3.3 3.3 Benzanilide 3.4

3.4 Benzamide 3.5

3.5 Benzil 3.5

3.5a Benzonitrile 3.7 3.6 Benzyl 3.8 3.7 Benzylidene Aniline 3.9 3.8 2-Carbethoxycyclopentanone 3.10 3.9 3.11 3.10 l,4-Dihydro-quinoxaline-2,3-dione 3.12 Contents ix

3.11 5,5-Dimethyl Hydantoin 3.12

3.12 2,5-Dimethylpyrrole 3.13

3.13 Diphenylcarbinol 3.14

3.14 Flavone 3.15

3.15 Imidazo [1,2-a] Pyridines 3.16

3.16 3-Nitro-2-phenyl-2H-Chromenes 3.16

3.17 (o-Nitrostyrene 3.17

3.18 Sec-Phenethyl Alcohol 3.18

3.19 Phenyl Benzoate 3.20 3.20 2-Phenyl-l,2,3,4-tetrahydro-4-quinolone 3.20 3.21 Phthalic Anhydride 3.21 3.22 3-Pyridyl-4(3 H) Quinazolone 3.22 3.23 cis-1, 2, 3, 6-Tetrahydro-4, 5-dimethyl Phthalic Anhydride 3.23 3.24 Miscellaneous Applications of Solid State Reactions 3.24 Oxidation of to Carbonyl Compounds 3.24

Oxidation of Sulfides to Sulfoxides 3.25

Pinacol-Pinacolene Rearrangement 3.26 Beckmann Rearrangement 3.27

Crossed Cannizzaro Reaction 3.27

Benzimidazoles 3.27 Alkylation of Reactive Methylene Compounds 3.27 Aziridines 3.28

3.25 Conclusion 3.28

4. Photochemical Transformations 4.1-4.12

4.1 Cis-Azobenzene 4.1 4.2 Benzopinacol 4.2 4.3 Maleic Acid 4.3 4.4 Methyl a-naphthyl Acetate 4.4 4.5 1,4-Naphthaquinone Photodimer 4.6 4.6 9-phenylphenanthrene 4.6 4.7 Cis-Stilbene 4.8 4.8 Miscellaneous Applications of Photolysis 4.9 Photochemical Cycloaddition Reactions 4.9 Paterno-Buchi Reaction 4.9

Photochemical Cycloadditions in Water 4.9

Phoinduced Substitution 4.10

Photorearrangement 4.10

Photochemical Reaction in Solid State 4.11

Photochlorination 4.11 X Contents

Photo Sulfochlorination 4.12

Photochemical Sulfoxidation 4.12

Photonitrosation 4.12

4.9 Conclusion 4.12

5. Transformations Using Phase Transfer Catalysts 5.1-5.26 5.1 Benzoic Acid 5.1

5.2 Benzonitrile 5.3 5.2a 5.4 5.3 n-Butyl Benzyl Ether 5.4 5.4 1-Cyanooctane 5.6 5.5 Dichloronorcarane [2,2-Dichlorobicycyo (4.1.0) heptane] 5.7 5.6 4,6-Dimethyl-3-phenylcoumarin 5.9 5.7 2,2 Dimethyl-3-phenyl Propion Aldehyde 5.10 5.8 3,4-Diphenyl-7-hydroxycoumarin 5.11 5.9 Flavone 5.12

5.10 1-fluorooctane 5.14 5.11 l-Oxaspiro-[2,5]-octane-2-carbonitrile 5.15 5.12 2-Phenylbutyronitrile 5.16 5.13 Phenylisocyanide (C6H5 N s C) 5.17 5.14 Salicyaldehyde 5.19 5.15 2,4,6- Trimethylbenzoic Acid 5.20 5.16 Miscellaneous Application of PTC 5.21 Benzoin Condensation 5.21

Darzen's Reaction 5.22

Michael Reaction 5.22 Welliamson Ether Synthesis 5.22 Witting Reaction 5.23 Wittig-Horner Reaction 5.23 3-Aryl-2H-l, 4-benzoxazines 5.23 2-Aroylbenzofurans 5.23 1,4-Benzoxazines 5.24

Oxidation 5.24

6. Transformations Using Sonication 6.1-6.19 6.1 Benzyl Cyanide 6.1 6.2 Biphenyl 6.2 6.3 Butyraldehyde 6.4 6.4 Cannizzaro Reaction 6.5 6.5 2-Carbethoxy Cyclopentanone 6.5 6.6 N-2-Chlorophenyl Anthranilic Acid 6.6 Contents Xi

6.7 Cinnamaldehyde 6.7 6.8 Cyclohexanone 6.7 6.9 7.7-Dibromobicyclo (4.1.0) Heptane 6.8 6.10 Ethyl 2-hydroxy-2-phenyl acetate 6.8 6.11 Ethyl Phenyl Ether (Phenetole) 6.9 6.12 Miscellaneous Applications of Ultrasound 6.10 Hydrosis of Nitriles 6.10 Solvolysis 6.10 Formation of Azides and Sulphocyanides 6.10 Cyclopropanation 6.10 Methylenation 6.11 N-Alkylation of Amines 6.11 Ethers 6.12

Oxidation 6.12

Reduction 6.13 Hydroboration 6.14 Coupling of Aryl Halides 6.14 Dichloro Carbene 6 15 Conversion of Aryl Halides into the Corresponding Aldehydes 6.15 Cannizzaro Reaction 6.16

Strecker Synthesis 6.16 Reformatsky Reaction 6.16 Barbier Reaction 6.17 Curtius Rearrangement 6.17 Oxymercuration of Olefins 6.17 Isotopic Labelling 6.18 Grignard Reagents 6.18

Isomerisation of Maleic Acid to Fumaric Acid 6.18 Dieckmann Cyclisation 6.19 6.13 Conclusion 6.19

7. Transformations Using Microwave Irradiations 7.1-7.20 7.1 Anthracene-maleic Anhydride Adduct 7.1 7.2 Aspirin (Acetylsalicylic Acid) 7.2 7.3 Benzaldehyde 7.3 7.4 Benzimidazole 7.5 7.5 Benzophenone 7.6 7.6 Benzylideneaniline 7.7 7.7 2,3-Diphenylquinoxaline 7.8 7.8 Ethyl Benzoate 7.8 Xii Contents

7.9 Indole 7.9 7.10 4-Methylcarbostyril (2-Hydroxy 4-methyl quinoline 7.10 7.11 4-Methyl-7-hydroxycoumarin 7.10 7.12 3- methyl-7-methoxy Coumarin 7.11 7.13 3-Methyl-l-phenyl-5-pyrazolone 7.12 7.14 2-Phenylindole 7.13 7.15 Piperazine-2,5-dione (Diketopiperazine) 7.14 7.16 Phenylacetic Acid 7.15 7.17 Phenyl Propyl Thioether 7.15 7.18 1,2,3,4-Tetrahydrocarbazole 7.16 7.19 Miscellaneous Applications of Microwave Reactions 7.17 Deactylation of Benzaldehyde Diacetates 7.17 Deacetylation of Acetyl Derivatives of Phenols and Alcohols 7.17 Deportation of Benzyl Esters 7.17 Deportation of t-butyldimethylsily Ethers 7.18 Decarboxylation of Aromatic Carboxylic Acids 7.18 Sponification of Esters 7.18 Dethioacetalization of Thioacetals and Thioketals of Aldehydes and Ketones 7.18 Deprotection of Oximes 7.19 Cleavage of Semicarbazones and Phenylhydrazones 7.19 Witug Reaction 7.19 7.20 Conclusion 7.20

8. Enzymatic Transformations 8.1-8.13 8.1 Benzoin 8.1

8.2 8.3 8.3 (S) -(+)-Ethyl 3-hydroxybutanoate 8.4 8.4 l-Phenyl-(lS)ethan-l-ol 8.6 8.5 2-(Quinolin—8-yloxy)-naphtho [2, l-b]pyran-3-one 8.7 8.6 Reduction of Aldehyles and Ketones 8.7 8.7 Miscallanlous Enzymatic Transformations 8.8 Oxidation at Ethyl Alcohol to Acetic Acid 8.8 Baeyer-villiger Reaction 8.9 Oxidation to Trans, Trans Muconic Acid 8.9

Oxidation at Oleic Acid 8.9

Oxidation of Primary Alkyl Halides to Carboxylic Acids 8.10 Hydroxylation of a,|}-unsaturated Ketones 8.10 Oxidation of Aldehydes to Carboxylic Acids 8.10 Oxidation of Aromatic Side Charins to Carboxyl Group 8.11 Contents Xl\\

Oxidation of Primary Amines to Carboxylic Acids 8.11 Oxidation of Primaryamines to Nitro Compounds 8.11

Conversion of Penicillin into 6-APA 8.12

Miscellaneous Applications of Enzymes 8.12

Reductions 8.12

8.8 Conclusion 8.13

9. Transformations in Ionic Liquids 9.1-9.12 9.1 1-Acetylnaphthalene 9.1 9.2 4-Acetyl-l-methylcyclohexene 9.2 9.3 p-methylacetophenone 9.3 9.4 Oxidation of Benzylic Alcohols to Aldehydes 9.4 9.5 Miscelloneous Applications of Ionic Liquids 9.4 Alkylation of Active Methylene Compounds 9.4 Cyclopropanation 9.4 Synthesis of Ethers 9.5

Oxidations 9.5

Fridel Crafts Reaction 9.7

Diels-Alder Reaction 9.8 Knoevenagel Condensation 9.8 Aldol Condensation 9.8 Wittig Reaction 9.9 Suzuki Coupling Reaction 9.9 Still Coupling Reaction 9.10 Henry Reaction 9.10 Stetter Reaction 9.10

Esterification, Ether Formation and Pinacol-Pinacolone Rearrangement 9.11

Pechmann Condensation 9.12

10. Transformations in Polyethylene Glycol 10.1-10.17 10.1 AdipicAcid 10.1 10.2 Azobenzene 10.1 10.3 Tertiary Butyl Alcohol 10.2 10.4 Benzyl Acetate 10.3 10.5 Benzylalcohol 10.3 10.6 2-p-chlorophenyl-5-semicarbazidethiazolin-4-one 10.5 10.7 l,2-Diphenyl-l,2-ethanediol 10.6 10.8 Ethyl Cinnamate 10.8 10.9 Ethyl 3-hydroxy-3-phenyl-2-methylene Propanate 10.9 10.10 (4 S)-hydroxy-4-(4'-nitrophenyl)-butan-2-one 10.9 10.11 3(s)-Hydroxy-3-phenyl Propanone-2 10.10 Xiv Contents

10.12 4-methylbyphenyl 10.11 10.13 Stilbene 10.12 10.14 Styrene diol 10.13 10.15 Miscellaneous Application of PEG in Organic Transformation 10.14 Diel-Alder Reaction 10.14 Sandmeyers Reaction 10.14 Heck Coupling 10.15 Baylis-Hillman Reaction 10.15 Suzuki Cross Coupling Reaction 10.15 Asymmetric Aldol Condensation 10.15 Oxidations 10.15 Reductions 10.16 Williamson Ether Synthesis 10.17 10.16 Conclusion 10.17

Transformations Involving Polymer Support Reagents or Substrates 11.1-11.5 11.1 Bromination of Cumene using Poly-N-bromosuccinimede (PNBS) 11.1 11.2 Bromopolystyrene 11.2 11.3 Peptides 11.2 11.4 Polystyrene acetic acid 11.3 11.5 Polystyrene- 11.4 11.6 Polystyrene boronic acid 11.4 11.7 Polystyrene peracid 11.4 11.8 Witting Reaction 11.5 11.9 Conclusion 11.5

Miscellaneous Transformations 12.1-12.27 12.1 2-Acetylcyclohexanone 12.1 12.2 Alkyl Azides 12.3 12.3 3-Aryl-2H-1,4-benzoxazines 12.4 12.4 Barbituric Acid 12.4

12.5 Benzidine 12.5 12.6 Benzopinacolone 12.6 12.7 But-2-en-l-ol () 12.7 12.8 o-chlorobenzaldehyle 12.8 12.9 Cinnamaldehyde 12.8 12.10 Cinnamic Acid 12.9

12.11 Dimedone 12.10 12.12 2,3-Diphenylquinoxaline 12.11 Contents XV

12.13 Esterification 12.12

n-Butylacetate 12.13 Ethylbenzoate 12.15 Methyl Salicylate 12.15 Diethyl Adipate 12.16 Dimethyl Adipa^e 12.16 Ethy lphenyl Acetate 12.16 Ethyl p-aminobenzoate 12.16 Isopenty1 Acetate 12.17 12.14 Ethyl Resorcinol 12.18 12.15 Hydroxyhydroquinonetriacetate 12.19 12.16 Hydroquinone diacetate 12.20 12.17 Methyl Cyclopentane carboxylate 12.21 12.18 a-Naphthyl acetic Acid 12.21 12.19 2-Phenylquinoline-4-Carboxylic Acid (Atophan) 12.23 12.20 Reduction of Aldehydes to Alcohol 12.24 12.21 P-Resacetophenone (2,4-Dihydroxyacetophonone) 12.25 12.22 Tolan (Diphenylethyne) 12.25 12.23 Trimethyl acetic acid (2,2-Dimethyl propionic Acid) 12.26

Index I-1-I-5